Targeted delivery of therapeutic agents to hepatocytes

Abstract

The present disclosure provides compounds comprising at least one GalNAc moiety. The compounds may further comprise or be a therapeutic moiety and / or compound. The compounds thus provide a means of controlled delivery of therapeutic moieties to biological targets by incorporation of the GalNAc moiety. The present disclosure also provides synthetic precursors to the compounds. The present disclosure further provides pharmaceutical compositions and kits comprising the compounds, methods of inhibiting expression of a target nucleic acid, and methods of treating or preventing a disease or disorder by administering to a subject in need thereof the compounds or pharmaceutical compositions.

Description

TARGETED DELIVERY OF THERAPEUTIC AGENTS TO HEPATOCYTESRELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application 63 / 568,493, filed March 22, 2024, the entirety of which is incorporated herein by reference.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (T083370045WO00-SEQ-MOD.xml;Size: 157,427 bytes; and Date of Creation: March 20, 2025) is herein incorporated by reference in its entirety.BACKGROUND

[0003] A- Acetylgalactosamine (GalNAc) ligands bind to the asialoglycoprotein receptor (ASGPR), which is abundantly and specifically expressed on the cell surface of hepatocytes in the liver. Conjugating GalNAc ligands to therapeutic agents (e.g., oligonucleotides, such as antisense oligonucleotides (ASO) and small interfering ribonucleic acid (siRNA)), provides targeted and efficient delivery of the therapeutic agent exclusively to hepatocytes.SUMMARY

[0004] The present disclosure stems from the recognition that GalNAc ligands in the form of GalNAc-comprising monomers may be incorporated into therapeutic compounds (e.g., oligonucleotides), leading to efficient delivery of the therapeutic compound to hepatocytes. For example, siRNA featuring monomers of the disclosure exhibit excellent knockdown of target genes in vivo. Thus, the disclosed compounds provide a new platform upon which targeted therapeutics may be constructed for their controlled delivery to biological targets for the treatment of diseases and disorders associated with the biological targets.

[0005] In one aspect, provided are compounds comprising at least one group of Formula (I) or (F):and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched compounds, and prodrugs thereof, wherein the moieties and variables included in Formula (I) and (I’) are as described herein.

[0006] In another aspect, provided are compounds comprising at least one group of Formula(II) or (II’):and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched compounds, and prodrugs thereof, wherein the moieties and variables included in Formula (II) and (II’) are as described herein.

[0007] In another aspect, provided are compounds comprising at least one group of Formula (III) or (III’):and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched compounds, and prodrugs thereof, wherein the moieties and variables included in Formula (III) and (III’) are as described herein.

[0008] In another aspect, provided are compounds comprising at least one group of Formula (IV) or (IV’):and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched compounds, and prodrugs thereof, wherein the moieties and variables included in Formula (IV) and (IV’) are as described herein.

[0009] In another aspect, provided are compounds of Formula (V) or (V’):and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched compounds, and prodrugs thereof, wherein the moieties and variables included in Formula (V) and (V’) are as described herein.

[0010] In another aspect, provided are compounds of Formula (VI) or (VI’):and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched compounds, and prodrugs thereof, wherein the moieties and variables included in Formula (VI) and (VI’) are as described herein.

[0011] In another aspect, provided are compounds of Formula (VII) or (VII’):and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched compounds, and prodrugs thereof, wherein the moieties and variables included in Formula (VII) and (VII’) are as described herein.

[0012] In another aspect, provided are compounds of Formula (VIII) or (VIII’):and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched compounds, and prodrugs thereof, wherein the moieties and variables included in Formula (VIII) and (VIII’) are as described herein.

[0013] In another aspect, provided are compounds of Formula (IX): (IX),and salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, and isotopically enriched compounds thereof, wherein the moieties and variables included in Formula (IX) are as described herein.

[0014] In another aspect, provided are compounds of Formula (X):and salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, and isotopically enriched compounds thereof, wherein the moieties and variables included in Formula (X) are as described herein.

[0015] In another aspect, provided are compounds of Formula (XI):and salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, and isotopically enriched compounds thereof, wherein the moieties and variables included in Formula (XI) are as described herein.

[0016] In another aspect, provided are compounds of Formula (XII):and salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, and isotopically enriched compounds thereof, wherein the moieties and variables included in Formula (XI) are as described herein.

[0017] In another aspect, provided are pharmaceutical compositions comprising a provided compound and optionally a pharmaceutically acceptable excipient.

[0018] In another aspect, provided are methods of inhibiting expression of a target nucleic acid in a cell, a tissue, or an organism, the method comprising contacting the cell, tissue, or organism with a provided compound or pharmaceutical composition in an amount effective to inhibit expression of the target nucleic acid.

[0019] In another aspect, provided are methods of treating a disease or disorder that would benefit from administration of a therapeutic compound, the method comprising administering a provided compound or pharmaceutical composition to a subject in need thereof.

[0020] In another aspect, provided are kits comprising a provided compound or pharmaceutical composition and instructions for using the provided compound or pharmaceutical composition.

[0021] The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Drawings, Examples, and Claims.DEFINITIONS

[0022] 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 Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March’ s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0023] 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 invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0024] In a formula, • / vvvis a single bond where the stereochemistry of the moieties immediately attached thereto is not specified, - is absent or a single bond, and = or =-= is a single or double bond.

[0025] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more 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 of12C with13C or14C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0026] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “ C1-6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5.6alkyl.

[0027] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0028] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C1-10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6alkyl”). Examples of C1-6alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n- butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3- methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), 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 C1-10alkyl (such as unsubstituted C1-6alkyl,e.g., -CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec -butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1-10alkyl (such as substituted C1-6alkyl, e.g., -CF3, Bn).

[0029] 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. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1-8haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2haloalkyl”). Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCI3, -CFCl2, -CF2Cl, and the like.

[0030] The term “alkoxy” refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. In some embodiments, the alkoxy moiety has 1 to 8 carbon atoms (“C1-8alkoxy”). In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms (“C1-6alkoxy”). In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms (“C1-4alkoxy”). In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms (“C1-3alkoxy”). In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms (“C1-2alkoxy”). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.

[0031] The term “alkoxyalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by an alkoxy group, as defined herein. In some embodiments, the alkoxyalkyl moiety has 1 to 8 carbon atoms (“C1-8alkoxy alkyl”). In some embodiments, the alkoxyalkyl moiety has 1 to 6 carbon atoms (“C1-6alkoxy alkyl”). In some embodiments, the alkoxyalkyl moiety has 1 to 4 carbon atoms (“C1-4alkoxy alkyl”). In some embodiments, the alkoxyalkyl moiety has 1 to 3 carbon atoms (“C1-3alkoxy alkyl”). In some embodiments, the alkoxyalkyl moiety has 1 to 2 carbon atoms (“C1-2alkoxy alkyl”).

[0032] 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 (i.e., 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 (“heteroC1-20alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 18 carbonatoms and 1 or more heteroatoms within the parent chain (“heteroC1-18alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-16alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-14alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-12alkyl”). 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 (“hetero C1-10alkyl”). 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 (“heteroC1-8alkyl”). 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 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1-4alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-3alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-2alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1alkyl”). In some embodiments, the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group may comprise an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups. 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 heteroC1-20alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-20alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10alkyl.

[0033] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 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 2 to 9 carbon atoms (“C2-9alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5alkenyl”). In some embodiments, an alkenyl group has 2 to4 carbon atoms (“C2-4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). 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 C2-4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified -double bond.

[0034] 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 (i.e., 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 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-10alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2-3alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6alkenyl”). 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. Incertain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-10alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-10alkenyl.

[0035] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-10alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). 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 C2-4alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C2-10alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10alkynyl.

[0036] 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 (i.e., 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 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-10alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain(“heteroC2-5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“heteroC2-4alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2-3alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6alkynyl”). 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 heteroC2-10alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10alkynyl.

[0037] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). Exemplary C3-6carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8carbocyclyl groups include, without limitation, the aforementioned C3-6carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10carbocyclyl groups include, without limitation, the aforementioned C3-8carbocyclyl 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. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in suchinstances, 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 C3-14carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14carbocyclyl.

[0038] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10cycloalkyl”). Examples of C5-6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6cycloalkyl groups include the aforementioned C5-6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the aforementioned C3-6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14cycloalkyl.

[0039] 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, eachinstance 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.

[0040] 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.

[0041] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl.Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5- membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinyl. Exemplary 7- membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, 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, l,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H- thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4, 5, 6, 7- tetrahydrothieno[3,2-b]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0042] 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, orelectrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; 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 (“C14aryl”; 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 C6-14aryl. In certain embodiments, the aryl group is a substitutedC6-14aryl.

[0043] “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.

[0044] 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, orelectrons 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 heteroarylring, 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, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5- indolyl).

[0045] 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.

[0046] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6- membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, 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, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, pheno thiazinyl, phenoxazinyl, and phenazinyl.

[0047] “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.

[0048] The term “unsaturated bond” refers to a double or triple bond.

[0049] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0050] The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

[0051] 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.

[0052] 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 may be 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 spontaneouslyundergo 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 intended to be limited in any manner by the exemplary substituents described herein.

[0053] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR33, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X“, -N(ORcc)Rbb, -SH, -SR33, -SSRCC, -C(=O)Raa, -CO2H, -CHO, -C(ORCC)3, -CO2R33, -OC(=O)R33, -OCO2R33, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)R33, -NRbbCO2R33, -NRbbC(=O)N(Rbb)2, -C(=NRbb)R33, -C(=NRbb)0R33, -OC(=NRbb)R33, -OC(=NRbb)0R33, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2R33, -NRbbSO2R33, -SO2N(Rbb)2, -SO2R33, -SO2OR33, -OSO2R33, -S(=O)R33, -OS(=O)R33, -Si(Raa)3, -OSi(Raa)3-C(=S)N(Rbb)2, -C(=O)SR33, -C(=S)SR33, -SC(=S)SR33, -SC(=O)SR33, -OC(=O)SR33, -SC(=O)0R33, -SC(=O)R33, -P(=O)(R33)2, -P(=O)(ORCC)2, -OP(=O)(R33)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, -NRbbP(=O)(R33)2, -NRbbP(=O)(ORcc)2, -NRbbP(=O)(N(Rbb)2)2, -P(RCC)2, -P(ORCC)2, -P(RCC)3+X“, -P(ORCC)3+X“, -P(RCC)4, -P(ORCC)4, -OP(RCC)2, -OP(RCC)3+X“, -OP(ORCC)2, -OP(ORCC)3+X“, -OP(RCC)4, -OP(ORCC)4, -B(R33)2, -B(ORCC)2, -BR33(ORCC), C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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 =O, =S, =NN(Rbb)2, =NNRbbC(=O)R33, =NNRbbC(=O)OR33, =NNRbbS(=O)2R33, =NRbb, or =NORCC; each instance of R33is, independently, selected from C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two R33groups 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 Rbbis, independently, selected from hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -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, -P(=O)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2- 10 alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-1 0alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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; wherein X- is a counterion; each instance of Rccis, independently, selected from hydrogen, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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, -ON(Rff)2, -N(Rff)2, -N(Rff)3+X“, -N(ORee)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, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, 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 can be joined to form =O or =S; wherein X- is a counterion; each instance of Reeis, independently, selected from C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 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, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl 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; and 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“, -N(OC1-6alkyl)(C1-6alkyl), -N(OH)(C1-6alkyl), -NH(OH), -SH, -SC1-6alkyl, -SS(C1-6alkyl), -C(=O)(C1-6alkyl), -CO2H, -CO2(C1-6alkyl), -OC(=O)(C1-6 alkyl), -OCO2(C1-6alkyl), -C(=O)NH2, -C(=O)N(C1-6alkyl)2, -OC(=O)NH(C1-6alkyl), -NHC(=O)(C1-6alkyl), -N(C1-6alkyl)C(=O)( C1-6alkyl), -NHCO2(C1-6alkyl), -NHC(=O)N(C1-6 alkyl)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(C1-6alkyl)2, -NHC(=NH)NH2, -NHSO2(C1-6alkyl), -SO2N(C1-6alkyl)2, -SO2NH(C1-6alkyl), -SO2NH2, -SO2(C1-6alkyl), -SO2O(C1-6alkyl), -OSO2(C1-6alkyl), -SO(C1-6alkyl), -Si(C1-6alkyl)3, -OSi(C1-6alkyl)3-C(=S)N(C1-6alkyl)2, C(=S)NH(C1-6alkyl), C(=S)NH2, -C(=O)S(C1-6alkyl), -C(=S)SC1-6alkyl, -SC(=S)SC1-6alkyl, -P(=O)(OC1-6alkyl)2, -P(=O)(C1-6alkyl)2, -OP(=O)(C1-6alkyl)2, -OP(=O)(OC1-6alkyl)2, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; wherein X- is a counterion. In certain embodiments, an exemplary carbon atom substituent is halogen (.e.g, -F, -Cl, -Br, -I), -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -O(C1-6alkyl) (e.g., -OMe), -NH2, -SH, -S(C1-6alkyl) (e.g., -SMe), -C(=O)(C1-6alkyl) (e.g., -C(=O)Me), -CO2H, or -CHO.

[0054] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0055] The term “hydroxyl” or “hydroxy” refers to the group -OH. The term “substituted hydroxyl” or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from -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, -OSi(Raa)3, -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)2, wherein X-, Raa, Rbb, and Rccare as defined herein.

[0056] 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.

[0057] 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, -NHCO2Raa, -NHC(=O)N(Rbb)2, -NHC(=NRbb)N(Rbb)2, -NHSChR^, -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.

[0058] 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 R^, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0059] 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.

[0060] The term “sulfonyl” refers to a group selected from -SO2N(Rbb)2, -SO2Raa, and - SO2ORaa, wherein Raaand Rbbare as defined herein.

[0061] The term “sulfinyl” refers to the group -S(=O)Raa, wherein Raais as defined herein.

[0062] 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, -C(=S)O(RX1), -C(=S)S(RX1), -C(=NRX1)RX1, -C(=NRX1)ORX1, -C(=NRX1)SRX1, or -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 orunsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, hetero aliphaticoxy, alkyloxy, hetero alkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, 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).

[0063] The term “oxo” refers to the group =O, and the term “thiooxo” refers to the group =S.

[0064] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR33, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2R33, -SO2R33, -C(=NRbb)R33, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SOR33, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(ORCC)2, -P(=O)(R33)2, -P(=O)(N(RCC)2)2, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2- 10 alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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 R33, Rbb, Rccand Rddare as defined herein.

[0065] In certain embodiments, the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include, but are not limited to, -OH, -OR33, -N(RCC)2, -C(=O)R33, -C(=O)N(RCC)2, -CO2R33, -SO2R33, -C(=NRCC)R33, -C(=NRcc)0R33, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SOR33, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, C1-10alkyl (e.g., aralkyl, heteroaralkyl), C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 memberedheteroaryl 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.

[0066] For example, nitrogen protecting groups such as amide groups (e.g., -C(=O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o- nitophenylacetamide, o-nitrophenoxy acetamide, acetoacetamide, (N’- dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o- nitrocinnamide, N- acetylmethionine derivative, o-nitrobenzamide and o- (benzoyloxymethyl)benzamide.

[0067] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)ORaa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9- (2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl- [9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4- methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1- methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2- dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1- methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-l -methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl 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-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9- anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2- methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(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-dimethyl-2-cy anoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6- chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N- dimethylcarboxamido)benzyl carbamate, 1 , 1 -dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’ -methoxyphenylazo )benzyl carbamate, 1 -methylcyclobutyl carbamate, 1- methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, l-methyl-1-(3,5- dimethoxyphenyl)ethyl carbamate, 1 -methyl- 1-(p-phenylazophenyl)ethyl carbamate, 1 -methyl- 1- phenylethyl carbamate, 1 -methyl- 1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p- (phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0068] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)2Raa) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4- methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6- dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9- anthracenesulfonamide, 4-(4',' / -dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0069] Other nitrogen protecting groups include, but are not limited to, phenothiaziny1-(lO)- acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'-phcnylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2- one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1 ,3-dimethyl- 1 ,3 ,5-triazacyclohexan-2-one, 5 - sub stituted 1 ,3-dibenzyl- 1 ,3 ,5-triazacyclohexan-2- one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2- (trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(l-isopropyl-4-nitro-2- oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4- methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7- dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fem), N-2-picolylamino N’- oxide, N- 1,1 -dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N- [(2-pyridyl)mesityl]methyleneamine, N-(N’ ,N’ -dimethylaminomethylene)amine, N,N’ -isopropylidenediamine, N-p- nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2- hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-l- cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N- [phenyl(pentaacylchromium- or tungsten)acyl] amine, N-copper chelate, N-zinc chelate, N- nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiopho sphinamide (Mpt), diphenylthiopho sphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o- nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In certain embodiments, a nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9- flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2- trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[0070] 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, but are not limited to, -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", R^, 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.

[0071] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (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-methoxy tetrahydropyranyl (MTHP), 4-methoxy tetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, l-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin- 4-yl (CTMP), l,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, 1-(2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxy ethyl, 1 -methyl- 1 -benzyloxyethyl, 1 -methyl- 1 -benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o- nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5- dibenzosuberyl, triphenylmethyl, 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, 3-(imidazol- 1- yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-l'-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, triphenylmethoxy acetate, phenoxy acetate, 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, 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1 ,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis( 1 , 1 -dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o- (methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N,N,N’,N’-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). In certain embodiments, an oxygen protecting group is silyl. In certain embodiments, an oxygen protecting group is t- butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2- trimethylsilylethyl carbonate, methoxymethyl (MOM), 1 -ethoxy ethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2- trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMTr), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0072] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). Sulfur protecting groups include, but are not limited to, -R^, -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 R^, 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. In certain embodiments, a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.

[0073] 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 (i.e., including one formal negative charge). An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F , Cl", Br , I"), NO3, CIO4-, OH", H2PO4, HCO3-. HSO4-, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p- toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-1 -sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4-, PF4, PF6, AsF6", SbF6, B[3,5-(CF3)2C6H3]4]", B(C6F5)4-, BPh4,A1(OC(CF3)3)4’, and carborane anions (e.g., CBnHi2" or (HCBnMesBre) ). Exemplary counterions which may be multivalent include CO32-, HPCU2-, PO43-, B4O?2-, SCU2-, 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.

[0074] ‘ ‘Click chemistry” refers to a chemical approach to conjugation introduced by Sharpless in 2001 and describes chemistry tailored to generate substances quickly and reliably by joining units together. See, e.g., Kolb, Finn and Sharpless Angewandte Chemie International Edition 2001 40, 2004-2021; Evans, Australian Journal of Chemistry 2007 60, 384-395). A functional group that participates in or is capable of participating in a click chemistry reaction is a click chemistry functional group or click functional group (e.g., alkyne, azide). Exemplary coupling reactions (some of which may be classified as “click chemistry”) include, but are not limited to, formation of esters, thioesters, amides (e.g., such as peptide coupling) from activated acids or acyl halides; nucleophilic displacement reactions (e.g., such as nucleophilic displacement of a halide or ring opening of strained ring systems); azide-alkyne Huisgen cycloaddition; thiol-yne addition; imine formation; Michael additions (e.g., maleimide addition reactions); and Diels- Alder reactions (e.g., tetrazine [4 + 2] cycloaddition). Examples of click chemistry reactions and click-chemistry handles can be found in, e.g., Kolb, H. C.; Finn, M. G. and Sharpless, K. B.Angew. Chem. Int. Ed. 2001, 40, 2004-2021. Kolb, H. C. and Sharpless, K. B. Drug Disc. Today, 2003, 8, 112-1137; Rostovtsev, V. V.; Green L. G.; Fokin, V. V. and Shrapless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596-2599; Tomoe, C. W.; Christensen, C. and Meldal, M. J. Org. Chem. 2002, 67, 3057-3064. Wang, Q. et al. J. Am. Chem. Soc. 2003, 725, 3192-3193; Lee, L. V. et al. J. Am. Chem. Soc. 2003 725, 9588-9589; Lewis, W. G. et al. Angew. Chem. Int. Ed. 2002, 41, 1053- 41057; Manetsch, R. et al., J. Am. Chem. Soc. 2004, 126, 12809- 12818; Mocharla, V. P. et al. Angew. Chem., Int. Ed. 2005, 44, 116-120. Any methods known in the art of bioconjugation can be used (e.g., click chemistry reactions).

[0075] The term “repeat unit” refers to a part of a compound whose repetition would produce the complete compound (except for the end-groups, e.g., A and R4in the disclosed compounds) by linking the repeat units together successively along the chain.

[0076] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts.

[0077] 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 / or animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(CI-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.

[0078] 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.

[0079] The term “hydrate” refers to a compound that is associated with water molecules. 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 acompound 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)).

[0080] 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.

[0081] 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”.

[0082] 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”.

[0083] The term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). Many compounds can adopt a variety of different crystal forms (i.e., different polymorphs). Typically, such different crystalline forms have different X-ray diffraction patterns, infrared spectra, and / or can vary in some or all properties such as melting points, density, hardness, crystal shape, optical and electrical properties, stability, solubility, and bioavailability. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate a given preparation. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0084] The term “co-crystal” refers to a crystalline structure composed of at least two components. In certain embodiments, a co-crystal contains a compound of the present disclosureand one or more other component(s), including, but not limited to, atoms, ions, molecules, or solvent molecules. In certain embodiments, a co-crystal contains a compound of the present disclosure and one or more solvent molecules. In certain embodiments, a co-crystal contains a compound of the present disclosure and one or more acid or base. In certain embodiments, a co- crystal contains a compound of the present disclosure and one or more components related to said compound, including, but not limited to, an isomer, tautomer, salt, solvate, hydrate, synthetic precursor, synthetic derivative, fragment, or impurity of said compound.

[0085] The term “prodrugs” refers to compounds that have cleavable groups that are removed, by solvolysis or under physiological conditions, to provide the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. C1-8alkyl, C2-8alkenyl, C2-8alkynyl, aryl, C7-12substituted aryl, and C7-12arylalkyl esters of the compounds described herein may be preferred.

[0086] The terms “composition” and “formulation” are used interchangeably.

[0087] 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 or disorder.

[0088] 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.

[0089] 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.

[0090] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease or disorder 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). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0091] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease or disorder but is at risk of developing the disease or disorder or who was with a disease or disorder, is not with the disease or disorder, but is at risk of regression of the disease or disorder. In certain embodiments, the subject is at a higher risk of developing the disease or disorder or at a higher risk of regression of the disease or disorder than an average healthy member of a population of subjects.

[0092] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0093] 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, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health 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 certainembodiments, an effective amount is the combined amounts of a compound described herein in multiple doses.

[0094] 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, e.g. for inhibiting expression of a target nucleic acid (e.g., at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% inhibition of the expression). In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease or disorder. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting expression of a target nucleic acid and treating a disease or disorder.

[0095] A “prophylactic ally effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more signs or symptoms associated with the condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting expression of a target nucleic acid. In certain embodiments, a prophylactically effective amount is an amount sufficient for treating a disease or disorder. In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting expression of a target nucleic acid and treating a disease or disorder.

[0096] The term “molecular payload” refers to a molecule or species that functions to modulate a biological outcome. In certain embodiments, the molecular payload is a therapeutic moiety or therapeutic compound. In certain embodiments, the molecular payload is a polynucleotide, a polypeptide or a small molecule. In certain embodiments, the molecular payload is a double stranded nucleic acid. In certain embodiments, the molecular payload is an oligomer. In certain embodiments, the molecular payload is an expression-inhibiting oligomer. In certain embodiments, the molecular pay load is a ribonucleic acid (RNA). In certain embodiments, themolecular payload is an RNAi agent. In certain embodiments, the molecular payload is a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide.

[0097] In certain embodiments, the molecular payload is double stranded and bound to the phosphorous or oxygen labeled y of a disclosed compound (e.g., compounds of Formula (V)- (VIII) or (V’)-(VIII’)) at the 5’ end of its sense strand. In certain embodiments, the molecular payload is double stranded and bound to the phosphorous or oxygen labeled y of a disclosed compound (e.g., compounds of Formula (V)-(VIII) or (V’)-(VIII’)) at the 5’ end of its antisense strand. In certain embodiments, the molecular payload is double stranded and bound to the phosphorous or oxygen labeled y of a disclosed compound (e.g., compounds of Formula (V)- (VIII) or (V’)-(VIII’)) at the 3’ end of its sense strand. In certain embodiments, the molecular payload is double stranded and bound to the phosphorous or oxygen labeled y of a disclosed compound (e.g., compounds of Formula (V)-(VIII) or (V’)-(VIII’)) at the 3’ end of its antisense strand.

[0098] In certain embodiments, the molecular payload is double stranded and bound to the phosphorous or oxygen labeled z of a disclosed compound (e.g., compounds of Formula (V)- (VIII) or (V’)-(VIII’)) at the 5’ end of its sense strand. In certain embodiments, the molecular payload is double stranded and bound to the phosphorous or oxygen labeled z of a disclosed compound (e.g., compounds of Formula (V)-(VIII) or (V’)-(VIII’)) at the 5’ end of its antisense strand. In certain embodiments, the molecular payload is double stranded and bound to the phosphorous or oxygen labeled z of a disclosed compound (e.g., compounds of Formula (V)- (VIII) or (V’)-(VIII’)) at the 3’ end of its sense strand. In certain embodiments, the molecular payload is double stranded and bound to the phosphorous or oxygen labeled z of a disclosed compound (e.g., compounds of Formula (V)-(VIII) or (V’)-(VIII’)) at the 3’ end of its antisense strand.

[0099] In certain embodiments, the molecular payload is double stranded and bound to the phosphorous or oxygen labeled y of a disclosed compound (e.g., compounds of Formula (V)- (VIII) or (V’)-(VIII’)) at the 3’ or 5’ end of its sense strand and also bound to the phosphorous or oxygen labeled z of the disclosed at the 3’ or 5’ end of its antisense strand. In certain embodiments, the molecular payload is double stranded and bound to the phosphorous or oxygen labeled y of a disclosed compound (e.g., compounds of Formula (V)-(VIII) or (V’)-(VIII’)) at the 3’ or 5’ end of its antisense strand and also bound to the phosphorous or oxygen labeled z of the disclosed at the 3’ or 5’ end of its sense strand. In certain embodiments, a disclosed compound (e.g., compounds of Formula (V)-(VIII) or (V’)-(VIII’)) comprises a molecular payload. In certain embodiments, a disclosed compound (e.g., compounds of Formula (V)-(VIII) or (V’)-(VIII’)) has only one molecular payload. In certain embodiments, a disclosed compound(e.g., compounds of Formula (V)-(VIII) or (V’)-(VIII’)) has no molecular payload (i.e., when neither of “A” and “R4” in a compound of Formula (V)-(VIII) or (V’)-(VIII’) are a molecular pay load).

[0100] The term “nucleic acid” refers to biopolymers, macromolecules, essential to all known forms of life. Nucleic acids comprise nucleotides, which are its monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main classes of nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).

[0101] The terms “nucleoside” and “nucleotide” refer to moieties which contain not only the known purine and pyrimidine bases, but also other heterocyclic bases which have been modified. In certain embodiments, the nucleobase is replaced with a moiety that is not a nucleobase. Modified nucleosides or nucleotides can also include modifications on the sugar moiety, e.g., wherein one or more of the hydroxyl groups are replaced with hydrogen, halogen (e.g., fluoro), aliphatic groups, or are functionalized as ethers or amines. The term “nucleotidic unit” is intended to encompass nucleosides and nucleotides as well as modified forms of both.

[0102] The term “polynucleotide” as used herein includes polymers of deoxyribose nucleic acids (DNA) or ribose nucleic acids (RNA) having the standard nucleotide bases A, G, T, and C for DNA or in the case of RNA A, G, C, and U, a subset of the standard nucleotide bases that uses less than four of the standard nucleotide bases, and unnatural bases such as 7-(2- thienyl)imidazo[4,5-b]pyridine (Ds), pyrrole-2-carbaldehyde (Pa), 2-amino-8-(2-thienyl)purine (s), f 2-amino-6-(N,N-dimethylamino)purine (x), pyridine-2-one (y), 3-nitropyrrole, 5- nitroindole, and 4-[3-(6-aminohexanamido)-l-propynyl]-2-nitropyrrole (Px) or other unnatural bases currently known or subsequently discovered. Examples provided in this disclosure may reference DNA or RNA, or any of the nucleotide bases A, G, T, C, and U. However, this is to be understood as merely illustrative and does not exclude implementations using RNA, DNA-RNA hybrids, and / or unnatural bases. In certain embodiments, a polynucleotide may include a chemically modified nucleotide.

[0103] The term “oligomeric compound” or “oligomer” refers to a nucleotide sequence containing about 10-200 nucleotides or nucleotide base pairs. In some embodiments, an oligomer has a nucleobase sequence that is at least partially complementary to a coding sequence in an expressed target nucleic acid or target gene within a cell. In some embodiments, the oligomers, upon delivery to a cell expressing a gene, are able to inhibit the expression of the underlying gene, and are referred to herein as “expression-inhibiting oligomeric compounds” or “expression- inhibiting oligomers.” The gene expression can be inhibited in vitro or in vivo. “Oligomers” include, but are not limited to: oligonucleotides, single-stranded oligonucleotides, single- stranded antisense oligonucleotides, short interfering RNAs (siRNAs), double-strand RNAs (dsRNA),micro RNAs (miRNAs), short hairpin RNAs (shRNA), ribozymes, interfering RNA molecules, and dicer substrates.

[0104] The term “oligonucleotide” refers to an oligomeric nucleic acid compound of up to 200 nucleotides in length. Examples of oligonucleotides include, but are not limited to, RNAi oligonucleotides (e.g., siRNAs, shRNAs), small activating RNA (saRNA), microRNAs, gapmers, mixmers, phosphorodiamidite morpholinos, peptide nucleic acids, aptamers, guide nucleic acids (e.g., Cas9 guide RNAs), etc. Oligonucleotides may be single-stranded or double-stranded. In some embodiments, an oligonucleotide may comprise one or more modified nucleotides (e.g. 2'- O-methyl sugar modifications, purine or pyrimidine modifications). In some embodiments, an oligonucleotide may comprise one or more modified internucleotide linkage. In some embodiments, an oligonucleotide may comprise one or more phosphorothioate linkages, which may be in the Rp or Sp stereochemical conformation.

[0105] The term “single-stranded oligonucleotide” means a single-stranded oligomeric compound having a sequence at least partially complementary to a target mRNA, that is capable of hybridizing to a target mRNA through hydrogen bonding under mammalian physiological conditions (or comparable conditions in vitro). In some embodiments, a single-stranded oligonucleotide is a single stranded antisense oligonucleotide.

[0106] The term “RNAi agent” means an agent that contains an RNA or RNA-like (e.g., chemically modified RNA) oligonucleotide molecule that is capable of degrading or inhibiting translation of messenger RNA (mRNA) transcripts of a target mRNA in a sequence specific manner. As used herein, RNAi agents may operate through the RNA interference mechanism (i.e., inducing RNA interference through interaction with the RNA interference pathway machinery (RNA-induced silencing complex or RISC) of mammalian cells), or by any alternative mechanism(s) or pathway(s). While it is believed that RNAi agents, as that term is used herein, operate primarily through the RNA interference mechanism, the disclosed RNAi agents are not bound by or limited to any particular pathway or mechanism of action. RNAi agents include, but are not limited to: single-stranded oligonucleotides, single- stranded antisense oligonucleotides (ASO), short interfering RNAs (siRNAs), double-strand RNAs (dsRNA), micro RNAs (miRNAs), short hairpin RNAs (shRNA), and dicer substrates. The RNAi agents described herein are comprised of an oligonucleotide having a strand that is at least partially complementary to the mRNA being targeted. In some embodiments, the RNAi agents described herein are double- stranded, and are comprised of an antisense strand and a sense strand that is at least partially complementary to the antisense strand. RNAi agents may be comprised of modified nucleotides and / or one or more non-phosphodiester linkages. In some embodiments, the RNAi agents described herein are single- stranded.

[0107] The terms “silence,” “reduce,” “inhibit,” “down-regulate,” or “knockdown” when referring to expression of a given gene, mean that the expression of the gene, as measured by the level of RNA transcribed from the gene or the level of polypeptide, protein or protein subunit translated from the mRNA in a cell, group of cells, tissue, organ, or subject in which the gene is transcribed, is reduced when the cell, group of cells, tissue, organ, or subject is treated with a compound described herein as compared to a second cell, group of cells, tissue, organ, or subject that has not or have not been so treated.

[0108] In some embodiments, the reduction, inhibition, down-regulation or knockdown is to a level that is less than 95%, less than 90%, less than 80%, less than 75%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of expression of the gene. In some embodiments, the term refers to a reduction, inhibition, down-regulation or knockdown of the level of expression of the gene to a level that is less than 95%, less than 90%, less than 80%, less than 75%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of expression of the gene.

[0109] In certain embodiments, the molecular payload may be an agent that enhances or increases expression of a gene (e.g., the molecular payload is an saRNA). The terms “enhance” or “increase” when referring to expression of a given gene, mean that the expression of the gene, as measured by the level of RNA transcribed from the gene or the level of polypeptide, protein or protein subunit translated from the mRNA in a cell, group of cells, tissue, organ, or subject in which the gene is transcribed, is increased when the cell, group of cells, tissue, organ, or subject is treated with a compound described herein as compared to a second cell, group of cells, tissue, organ, or subject that has not or have not been so treated.

[0110] In some embodiments, the enhancement or increase is to a level that is greater than 95%, greater than 90%, greater than 80%, greater than 75%, greater than 70%, greater than 60%, greater than 50%, greater than 40%, greater than 30%, greater than 25%, greater than 20%, greater than 10%, greater than 9%, greater than 8%, greater than 7%, greater than 6%, greater than 5%, greater than 4%, greater than 3%, greater than 2%, greater than 1%, greater than 0.5%, greater than 0.1%, greater than 0.01%, greater than 0.001%, or greater than 0.0001% of an initial level, which may, for example, be a baseline level of expression of the gene. In someembodiments, the term refers to an enhancement or increase of the level of expression of the gene to a level that is greater than 95%, greater than 90%, greater than 80%, greater than 75%, greater than 70%, greater than 60%, greater than 50%, greater than 40%, greater than 30%, greater than 25%, greater than 20%, greater than 10%, greater than 9%, greater than 8%, greater than 7%, greater than 6%, greater than 5%, greater than 4%, greater than 3%, greater than 2%, greater than 1%, greater than 0.5%, greater than 0.1%, greater than 0.01%, greater than 0.001%, or greater than 0.0001% of an initial level, which may, for example, be a baseline level of expression of the gene.

[0111] The term “sequence” or “nucleotide sequence” mean a succession or order of nucleobases or nucleotides, described with a succession of letters using the standard nucleotide nomenclature.

[0112] As used herein, and unless otherwise indicated, the term “complementary,” when used to describe a first nucleotide sequence (e.g., RNAi agent sense strand or targeted mRNA) in relation to a second nucleotide sequence (e.g., single- stranded antisense oligonucleotide or a double-stranded RNAi agent antisense strand), means the ability of an oligonucleotide or polynucleotide including the first nucleotide sequence to hybridize (form base pair hydrogen bonds under mammalian physiological conditions (or comparable conditions in vitro)) and form a duplex or double helical structure under certain conditions with an oligonucleotide or polynucleotide including the second nucleotide sequence. Complementary sequences include Watson-Crick base pairs or non-Watson-Crick base pairs and include natural or modified nucleotides or nucleotide mimics, at least to the extent that the above requirements with respect to the ability to hybridize are fulfilled.

[0113] As used herein, “perfectly complementary” or “fully complementary” means that all (100%) of the bases in a contiguous sequence of a first polynucleotide will hybridize with the same number of bases in a contiguous sequence of a second polynucleotide. The contiguous sequence may comprise all or a part of a first or second nucleotide sequence.

[0114] As used herein, “partially complementary” means that in a hybridized pair of nucleobase sequences, at least 70%, but not all, of the bases in a contiguous sequence of a first polynucleotide will hybridize with the same number of bases in a contiguous sequence of a second polynucleotide.

[0115] As used herein, “substantially complementary” means that in a hybridized pair of nucleobase sequences, at least 85%, but not all, of the bases in a contiguous sequence of a first polynucleotide will hybridize with the same number of bases in a contiguous sequence of a second polynucleotide.

[0116] The terms “complementary,” “fully complementary,” and “substantially complementary” herein may be used with respect to the base matching between the sense strand and the antisense strand of a double- stranded RNAi agent, between the antisense strand of a double-stranded RNAi agent and a sequence of a target mRNA, or between a single- stranded antisense oligonucleotide and a sequence of a target mRNA.

[0117] As used herein, the phrase “introducing into a cell,” e.g., when referring to an oligomeric compound, means functionally delivering the oligomeric compound into a cell.

[0118] The phrase “functional delivery,” means that delivering the oligomeric compound to the cell in a manner that enables the oligomeric compound to have the expected biological activity, e.g., sequence-specific inhibition of gene expression.

[0119] The terms “biologic,” “biologic drug,” and “biological product” refer to a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, nucleic acids, and proteins. Biologies may include sugars, proteins, or nucleic acids, or complex combinations of these substances, or may be living entities, such as cells and tissues. Biologies may be isolated from a variety of natural sources (e.g., human, animal, microorganism) and may be produced by biotechnological methods and other technologies.

[0120] The term “small molecule” or “small molecule therapeutic” refers to molecules, whether naturally occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight. Typically, a small molecule is an organic compound (i.e., it contains carbon). The small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.). In certain embodiments, the molecular weight of a small molecule is not more than about 1,000 g / mol, not more than about 900 g / mol, not more than about 800 g / mol, not more than about 700 g / mol, not more than about 600 g / mol, not more than about 500 g / mol, not more than about 400 g / mol, not more than about 300 g / mol, not more than about 200 g / mol, or not more than about 100 g / mol. In certain embodiments, the molecular weight of a small molecule is at least about 100 g / mol, at least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at least about 500 g / mol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges (e.g., at least about 200 g / mol and not more than about 500 g / mol) are also possible. In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (C.F.R.)). The small molecule may also be complexed with one or more metal atoms and / or metal ions. In this instance, the small molecule is also referred to as a “small organometallic molecule.” Preferred small molecules are biologically active in that they produce a biological effect inanimals, preferably mammals, more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. Preferably, though not necessarily, the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate governmental agency or regulatory body. For example, drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460, incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589, incorporated herein by reference. All listed drugs are considered acceptable for use in accordance with the present invention.

[0121] The terms “therapeutic compound,” “therapeutic agent,” or “therapeutic moiety” refer to any substance having therapeutic properties that produce a desired, usually beneficial, effect. For example, therapeutic compounds, agents, and moieties may treat and / or ameliorate a disease or disorder. Therapeutic compounds, agents, and moieties, as disclosed herein, may be biologies or small molecule therapeutics, or combinations thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0122] FIG. 1 shows the structures of a series of exemplary ALDH2 siRNA incorporating monomers A, B, or C at the 3 ’-end of the sense strand. Sequences shown correspond (top- bottom) to SEQ ID NOs: 1 (NA1 - sense), 2 (NA1 - antisense), 3 (NA2 - sense), 4 (NA2 - antisense), 5 (NA3 - sense), and 6 (NA3 - antisense).

[0123] FIG. 2 is a graph showing ALDH2 knockdown of the siRNA in FIG. 1.

[0124] FIG. 3 shows the structures of a series of exemplary ALDH2 siRNA incorporating monomer A at the 3 ’-end of the antisense strand or 5 ’-end of the sense strand. Sequences shown correspond (top-bottom) to SEQ ID NOs: 7 (NA4 - antisense), 8 (NA5 - sense), 9 (NA5 - antisense), 10 (NA6 - sense), and 11 (NA6 - antisense).

[0125] FIG. 4 shows the structures of a series of exemplary ALDH2 siRNA of varying lengths incorporating monomer A at the 3 ’-end of the sense strand or 5 ’-end of the sense strand. Sequences shown correspond (top-bottom) to SEQ ID NOs: 12 (NA7 - sense), 13 (NA7 - antisense), 14 (NA8 - sense), 15 (NA8 - antisense), 16 (NA9 - sense), 17 (NA9 - antisense), 18 (NA 10 - sense), 19 (NA 10 - antisense), 20 (NA 11 - sense), 21 (NA 11 - antisense), 22 (NA 12 - sense), 23 (NA12 - antisense), 24 (NA13 - sense), 25 (NA13 - antisense), 26 (NA14 - sense), 27 (NA 14 - antisense), 28 (NA 15 - sense), and 29 (NA 15 - antisense).

[0126] FIG. 5 shows the structures of a series of exemplary ALDH2 siRNA incorporating monomers B, C, D, or E at the 3 ’-end of the sense strand. Sequences shown correspond (top-bottom) to SEQ ID NOs: 3 (NA2 - sense), 4 (NA2 - antisense), 5 (NA3 - sense), 6 (NA3 - antisense), 30 (NA16 - sense), 31 (NA16 - antisense), 32 (NA17 - sense), 33 (NA17 - antisense).

[0127] FIG. 6 shows the structures of a series of exemplary ALDH2 siRNA incorporating monomers A, D, or E at the 3 ’-end of the sense strand and having an additional phosphorothioate linkage at the 3 ’-end of the sense strand. Sequences shown correspond (top-bottom) to SEQ ID NOs: 34 (NA18 - sense), 35 (NA18 - antisense), 36 (NA19 - sense), 37 (NA19 - antisense), 38 (NA20 - sense), 39 (NA20 - antisense)

[0128] FIG. 7 shows the structures of a series of exemplary ALDH2 siRNA incorporating monomers B, C, D, or E at the 5 ’-end of the sense strand. Sequences shown correspond (top- bottom) to SEQ ID NOs: 40 (NA21 - sense), 41 (NA21 - antisense), 42 (NA22 - sense), 43 (NA22 - antisense), 44 (NA23 - sense), 45 (NA23 - antisense), 46 (NA24 - sense), 47 (NA24 - antisense).

[0129] FIG. 8 shows the structures of a series of exemplary ALDH2 siRNA incorporating monomers B, C, D, or E at the 3 ’-end of the antisense strand. Sequences shown correspond (top- bottom) to SEQ ID NOs: 48 (NA25 - sense), 49 (NA25 - antisense), 50 (NA26 - sense), 51 (NA26 - antisense), 52 (NA27 - sense), 53 (NA27 - antisense), 54 (NA28 - sense), 55 (NA28 - antisense)DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0130] Provided herein are compounds that comprise one or more monomeric units having a GalNAc moiety. The compounds possess advantageous properties, such as selectively inhibiting expression of a target nucleic acid, that allow the compounds to be useful as therapeutic agents. In certain embodiments, siRNA incorporating monomers of the disclosure exhibit excellent knockdown of target genes in vivo. Thus, the disclosed compounds provide a new platform upon which targeted therapeutics may be constructed for their controlled delivery to biological targets for the treatment of diseases and disorders associated with the biological targets.

[0131] In certain embodiments herein, the GalNAc moiety is the “D” sugar isomer:wherein P1is as defined herein. In any embodiment where a GalNAc moiety is the “D” sugar isomer, the GalNAc moiety may be replaced with the “L” sugar isomer: wherein P1is as defined herein. For example, in certain embodiments, theGalNAc moiety is: AcHN OH , which may be replaced with: AcHN OH . In another example, in certain embodiments, the GalNAc moiety is:?which may be replaced with

[0132] Likewise, in any embodiment where a GalNAc moiety is the “D” sugar isomer:?wherein P1is as defined herein, the GalNAc moiety may also be replaced with the GalNAc moiety having an absence of stereochemical assignments:wherein P1is as defined herein. For example, in certain embodiments, the GalNAc moiety is:, which may be replaced with: In another example, in certainembodiments, the GalNAc moiety is:, which may be replaced with:

[0133] The compounds may be provided for use in any composition, kit, or method described herein as a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof.Compounds comprising Formula (1) or (F)

[0134] In one aspect, provided are compounds comprising at least one group of Formula (I) or (I’), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof:wherein: each X is independently -N(RA)2, -SRA, or -ORA; each R1is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, -ORA, or a group of formula:each R2is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, -ORA, or a group of formula:each R3is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, -ORA, or a group of formula:each P1is independently hydrogen or an oxygen protecting group; each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, - O-, -N(RA)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, - NRAC(=O)O-, -NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, - NRAS(O)2-, or a combination thereof; and each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; provided that Formula (I) or (I’) has only one instance of formula:

[0135] In certain embodiments, the compound comprising a group of Formula (I) or (I’) has at least one instance of formula:

[0136] In certain embodiments, the compound comprises at least one group of Formula (I-a) oror a pharmaceutically acceptable salt thereof; wherein R2, R3, and X are as defined herein.

[0137] In certain embodiments, the compound comprises at least one group of Formula (I-b) or(I-b'):or a pharmaceutically acceptable salt thereof; wherein R2, L, P1, and X are as defined herein.

[0138] In certain embodiments, the compound comprises at least one group of Formula (I-c) or(I-c'):or a pharmaceutically acceptable salt thereof; wherein R2, R10, R20, RA, P1, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -0-).

[0139] In certain embodiments, the compound comprises at least one group of Formula (I-d) or(I-d’):or a pharmaceutically acceptable salt thereof; wherein R2, R10, RA, P1, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0140] In certain embodiments, the compound comprises at least one group of Formula (I-e) or (I-e’):or a pharmaceutically acceptable salt thereof; wherein R10, RA, P1, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0141] In certain embodiments, the compound comprises at least one group of Formula (I-f) or (I-F):or a pharmaceutically acceptable salt thereof; wherein R10, RA, P1, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0142] In certain embodiments, the compound comprises at least one group of Formula (I-g) or (I-g’):or a pharmaceutically acceptable salt thereof; wherein P1and X are as defined herein.

[0143] In certain embodiments, the compound comprises at least one group of Formula (I-h) or(I-h’):or a pharmaceutically acceptable salt thereof; wherein P1and X are as defined herein.

[0144] In certain embodiments, the compound comprises at least one group of Formula (I-i) or(I-i’):or a pharmaceutically acceptable salt thereof; wherein P1and X are as defined herein.

[0145] In certain embodiments, the compound comprises at least one group of Formula (I-j) or (I-j’):or a pharmaceutically acceptable salt thereof; wherein P1and X are as defined herein.

[0146] In certain embodiments, the compound comprises at least one group of formula:or a pharmaceutically acceptable salt thereof.

[0147] In certain embodiments, the compound comprises at least one group of formula:or a pharmaceutically acceptable salt thereof.

[0148] In certain embodiments, the compound comprises 1-20 (e.g., 1-5, 5-10, 10-15, 15-20) groups of Formula (I) or (I’). In certain embodiments, the compound comprises 1-6 groups of Formula (I) or (I’). In certain embodiments, the compound comprises at least two groups of Formula (I) or (I’). In certain embodiments, the compound comprises at least three groups of Formula (I) or (I’). In certain embodiments, the compound comprises three groups of Formula (I) or (I’). In certain embodiments, the compound comprises three groups of Formula (I) or (I’), wherein the three groups (i.e., “repeat units”) are bound to each other in succession at the denoted attachment points. In certain embodiments, the compound comprises 1-20 (e.g., 1-5, 5- 10, 10-15, 15-20) groups of Formula (I) or (I’), wherein all groups are of the same type (all of Formula (I) or all of Formula (I’))- In certain embodiments, the compound comprises three groups of Formula (I) or (I’), wherein all groups are of the same type (all of Formula (I) or all of Formula (I’)), and wherein the three groups (i.e., “repeat units”) are bound to each other in succession at the denoted attachment points.

[0149] In certain embodiments, the compound comprises at least one group of Formula (I) and at least one group of Formula (I’). In certain embodiments, the compound comprises 1-6 groups of Formula (I) and 1-6 groups of Formula (I’). In certain embodiments, the compound comprises at least two groups of Formula (I) and at least two groups of Formula (I’). In certain embodiments, the compound comprises at least three groups of Formula (I) at least three groups of Formula (I’). In certain embodiments, the compound comprises three groups of Formula (I) and three groups of Formula (I’). In certain embodiments, the compound comprises three groups of Formula (I) and three groups of Formula (I’), wherein the three groups (i.e., “repeat units”) of Formula (I) are bound to each other in succession at the denoted attachment points, and the three groups (i.e., “repeat units”) of Formula (I’) are bound to each other in succession at the denotedattachment points. In certain embodiments, a group of Formula (I) is bound to a group of Formula (I’).

[0150] In certain embodiments, the compound is or comprises a therapeutic compound. In certain embodiments, the compound comprises a polynucleotide, a polypeptide, or a small molecule. In certain embodiments, the compound comprises a double stranded nucleic acid. In certain embodiments, the compound comprises an oligomer. In certain embodiments, the compound comprises an expression-inhibiting oligomer. In certain embodiments, the compound comprises a ribonucleic acid (RNA). In certain embodiments, the compound comprises an RNAi agent. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA). In certain embodiments, the compound comprises an antisense oligonucleotide.

[0151] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H).

[0152] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); and each P1is independently hydrogen or an oxygen protecting group.

[0153] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof; wherein each P1is independently hydrogen or an oxygen protecting group.

[0154] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof.

[0155] In certain embodiments of Formula (I) or (I’), when R1and R2are hydrogen, and R3is a group of formulathen L is not

[0156] In certain embodiments of Formula (I) or (I’), when R1and R2are hydrogen, R3is a group of formulaand L isthen R10is a C1-5alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-.

[0157] In certain embodiments of Formula (I) or (I’), when R1and R2are hydrogen, and R3is a group of formulathen L attaches to the 1’ position of the ribose by a non- oxygen atom (e.g., carbon, nitrogen).

[0158] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-9) or (P-9’), wherein X is -ORAor -SRA(e.g., where RAis H); and R2is hydrogen, fluoro, -OCH3, -OTBS, - OCH2CH2OCH3.

[0159] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-10) or (P-10’), wherein X is -ORAor -SRA(e.g., where RAis H); R2is hydrogen, fluoro, -OCH3, -OTBS, -OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0160] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-11), wherein R2is hydrogen, fluoro, -OCH3, -OTBS, - OCH2CH2OCH3.

[0161] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-12), wherein R2is hydrogen, fluoro, -OCH3, -OTBS, -OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0162] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); Y is -O-, -S-, -CH2-, - NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-13) or (P-13’), wherein X is -ORAor -SRA(e.g„ where RAis H); Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or - NH(C=O)O-; and R2is hydrogen, fluoro, -OCH3, -OTBS, -OCH2CH2OCH3.

[0163] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); Y is -O-, -S-, -CH2-, - NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-14) or (P-14’), wherein X is -ORAor -SRA(e.g., where RAis H);Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, fluoro, -OCH3, - OTBS, -OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0164] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-15), wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, fluoro, -OCH3, -OTBS, -OCH2CH2OCH3.

[0165] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-16), wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, fluoro, -OCH3, - OTBS, -OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0166] In certain embodiments of Formula (I) or (I’), when R3is a group of formula ? then L is not

[0167] In certain embodiments of Formula (I) or (I’), when R3is a group of formula, then L is not, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0168] In certain embodiments of Formula (I) or (I’), when R3is a group of formula then L attaches to the 1’ position of the ribose by a non-nitrogen atom (e.g.,carbon, oxygen).

[0169] In certain embodiments of Formula (I) or (I’), when R1is hydrogen, R2is not a hydrogen, and R3is a group of formulathen L attaches to the 1’ position of the ribose by a non-nitrogen atom (e.g., carbon, oxygen).Compounds comprising Formula (1)

[0170] In one aspect, provided are compounds comprising at least one group of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof:wherein: each X is independently -N(RA)2, -SRA, or -ORA; each R1is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, -ORA, or a group of formula:each R2is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, -ORA, or a group of formula:each R3is independently hydrogen, halogen, substituted or unsubstituted aliphatic,substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, -ORA, or a group of formula:each P1is independently hydrogen or an oxygen protecting group; each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, - O-, -N(RA)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, - NRAC(=O)O-, -NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, - NRAS(O)2-, or a combination thereof; and each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; provided that Formula (I) has only one instance of formula:

[0171] In certain embodiments, Formula (I) is of Formula (I-a):or a pharmaceutically acceptable salt thereof; wherein R2, R3, and X are as defined herein.

[0172] In certain embodiments, Formula (I) is of Formula (I-b):or a pharmaceutically acceptable salt thereof; wherein R2, L, P1, and X are as defined herein.

[0173] In certain embodiments, Formula (I) is of Formula (I-c):or a pharmaceutically acceptable salt thereof; wherein R2, R10, R20, RA, P1, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0174] In certain embodiments, Formula (I) is of Formula (I-d):or a pharmaceutically acceptable salt thereof; wherein R2, R10, RA, P1, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0175] In certain embodiments, Formula (I) is of Formula (I-e):or a pharmaceutically acceptable salt thereof; wherein R10, RA, P1, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0176] In certain embodiments, Formula (I) is of Formula (I-f):or a pharmaceutically acceptable salt thereof; wherein R10, RA, P1, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0177] In certain embodiments, Formula (I) is of Formula (I-g):or a pharmaceutically acceptable salt thereof; wherein P1and X are as defined herein.

[0178] In certain embodiments, Formula (I) is of Formula (I-h):or a pharmaceutically acceptable salt thereof; wherein P1and X are as defined herein.

[0179] In certain embodiments, Formula (I) is of Formula (I-i):or a pharmaceutically acceptable salt thereof; wherein P1and X are as defined herein.

[0180] In certain embodiments, Formula (I) is of Formula (I-j):or a pharmaceutically acceptable salt thereof; wherein P1and X are as defined herein.

[0181] In certain embodiments, Formula (I) is of formula:or a pharmaceutically acceptable salt thereof.

[0182] In certain embodiments, Formula (I) is of formula:or a pharmaceutically acceptable salt thereof.

[0183] In certain embodiments, the compound comprises 1-20 (e.g., 1-5, 5-10, 10-15, 15-20) groups of Formula (I). In certain embodiments, the compound comprises 1-6 groups of Formula (I). In certain embodiments, the compound comprises at least two groups of Formula (I). In certain embodiments, the compound comprises at least three groups of Formula (I). In certain embodiments, the compound comprises three groups of Formula (I). In certain embodiments, the compound comprises three groups of Formula (I), wherein the three groups (i.e., “repeat units”) are bound to each other in succession at the denoted attachment points.

[0184] In certain embodiments, the compound is or comprises a therapeutic compound. In certain embodiments, the compound comprises a polynucleotide, a polypeptide, or a small molecule. In certain embodiments, the compound comprises a double stranded nucleic acid. In certain embodiments, the compound comprises an oligomer. In certain embodiments, the compound comprises an expression-inhibiting oligomer. In certain embodiments, the compound comprises a ribonucleic acid (RNA). In certain embodiments, the compound comprises an RNAi agent. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA). In certain embodiments, the compound comprises an antisense oligonucleotide.

[0185] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H).

[0186] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); and each P1is independently hydrogen or an oxygen protecting group.

[0187] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof; wherein each P1is independently hydrogen or an oxygen protecting group.

[0188] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof.

[0189] In certain embodiments of Formula (I), when R1and R2are hydrogen, and R3is a group

[0190] In certain embodiments of Formula (I), when R1and R2are hydrogen, R3is a group of formula?and L is, then R10is a C1-5alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-.

[0191] In certain embodiments of Formula (I), when R1and R2are hydrogen, and R3is a group of formula?then L attaches to the 1’ position of the ribose by a non-oxygen atom (e.g., carbon, nitrogen).

[0192] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-9), wherein X is -0RAor -SRA(e.g., where RAis H); and R2is hydrogen, fluoro, -OCH3, -OTBS, - OCH2CH2OCH3.

[0193] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-10), wherein X is -ORAor -SRA(e.g., where RAis H); R2is hydrogen, fluoro, -OCH3, -OTBS, -OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0194] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-11), wherein R2is hydrogen, fluoro, -OCH3, -OTBS, - OCH2CH2OCH3.

[0195] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-12), wherein R2is hydrogen, fluoro, -OCH3, -OTBS, -OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0196] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); Y is -O-, -S-, -CH2-, - NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-13), wherein X is -ORAor -SRA(e.g„ where RAis H); Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, fluoro, -OCH3, -OTBS, -OCH2CH2OCH3.

[0197] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); Y is -O-, -S-, -CH2-, - NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-14), wherein X is -ORAor -SRA(e.g., where RAis H); Y is -O-, - S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, fluoro, -OCH3, -OTBS, - OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0198] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-15), wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, fluoro, -OCH3, -OTBS, -OCH2CH2OCH3.

[0199] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-16), wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, fluoro, -OCH3, - OTB S, -OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0200] In certain embodiments of Formula (I), when R3is a group of formula, then L is not

[0201] In certain embodiments of Formula (I), when R3is a group of formula, then L is not , wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0202] In certain embodiments of Formula (I), when R3is a group of formulathen L attaches to the 1’ position of the ribose by a non-nitrogen atom (e.g., carbon, oxygen).

[0203] In certain embodiments of Formula (I), when R1is hydrogen, R2is not a hydrogen, andR3is a group of formula then L attaches to the 1 ’ position of the ribose by anon-nitrogen atom (e.g., carbon, oxygen).Compounds comprising Formula (I')

[0204] In one aspect, provided are compounds comprising at least one group of Formula (I’), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof:wherein: each X is independently -N(RA)2, -SRA, or -ORA; each R1is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, -ORA, or a group of formula:each R2is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, -ORA, or a group of formula:each R3is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, -ORA, or a group of formula:each P1is independently hydrogen or an oxygen protecting group; each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, - O-, -N(RA)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, - NRAC(=O)O-, -NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, - NRAS(O)2-, or a combination thereof; and each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; provided that Formula (I’) has only one instance of formula:

[0205] In certain embodiments, Formula (I’) is of Formula (I-a’):or a pharmaceutically acceptable salt thereof; wherein R2, R3, and X are as defined herein.

[0206] In certain embodiments, Formula (I’) is of Formula (I-b’):or a pharmaceutically acceptable salt thereof; wherein R2, L, P1, and X are as defined herein.

[0207] In certain embodiments, Formula (I’) is of Formula (I-c’):or a pharmaceutically acceptable salt thereof; wherein R2, R10, R20, RA, P1, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0208] In certain embodiments, Formula (I’) is of Formula (I-d’):or a pharmaceutically acceptable salt thereof; wherein R2, R10, RA, P1, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0209] In certain embodiments, Formula (I’) is of Formula (I-e’):or a pharmaceutically acceptable salt thereof; wherein R10, RA, P1, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0210] In certain embodiments, Formula (I’) is of Formula (I-f’):or a pharmaceutically acceptable salt thereof; wherein R10, RA, P1, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0211] In certain embodiments, Formula (I’) is of Formula (I-g’):or a pharmaceutically acceptable salt thereof; wherein P1and X are as defined herein.

[0212] In certain embodiments, Formula (I’) is of Formula (I-h’):or a pharmaceutically acceptable salt thereof; wherein P1and X are as defined herein.

[0213] In certain embodiments, Formula (I’) is of Formula (I-i’):or a pharmaceutically acceptable salt thereof; wherein P1and X are as defined herein.

[0214] In certain embodiments, Formula (I’) is of Formula (I-j’):or a pharmaceutically acceptable salt thereof; wherein P1and X are as defined herein.

[0215] In certain embodiments, Formula (I’) is of formula:or a pharmaceutically acceptable salt thereof.

[0216] In certain embodiments, Formula (I’) is of formula:or a pharmaceutically acceptable salt thereof.

[0217] In certain embodiments, the compound comprises 1-20 (e.g., 1-5, 5-10, 10-15, 15-20) groups of Formula (I’). In certain embodiments, the compound comprises 1-6 groups of Formula (I’). In certain embodiments, the compound comprises at least two groups of Formula (I’). In certain embodiments, the compound comprises at least three groups of Formula (I’). In certain embodiments, the compound comprises three groups of Formula (I’). In certain embodiments, the compound comprises three groups of Formula (I’), wherein the three groups (i.e., “repeat units”) are bound to each other in succession at the denoted attachment points.

[0218] In certain embodiments, the compound is or comprises a therapeutic compound. In certain embodiments, the compound comprises a polynucleotide, a polypeptide, or a small molecule. In certain embodiments, the compound comprises a double stranded nucleic acid. In certain embodiments, the compound comprises an oligomer. In certain embodiments, the compound comprises an expression-inhibiting oligomer. In certain embodiments, the compound comprises a ribonucleic acid (RNA). In certain embodiments, the compound comprises an RNAi agent. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA). In certain embodiments, the compound comprises an antisense oligonucleotide.

[0219] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H).

[0220] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); and each P1is independently hydrogen or an oxygen protecting group.

[0221] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof; wherein each P1is independently hydrogen or an oxygen protecting group.

[0222] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof.

[0223] In certain embodiments of Formula (I’), when R1and R2are hydrogen, and R3is a

[0224] In certain embodiments of Formula (I’), when R1and R2are hydrogen, R3is a group of formula?and L is , then R10is a C1-5alkylene having 0-3carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-.

[0225] In certain embodiments of Formula (I’), when R1and R2are hydrogen, and R3is a group of formula?then L attaches to the 1’ position of the ribose by a non- oxygen atom (e.g., carbon, nitrogen).

[0226] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-9’), wherein X is - ORAor -SRA(e.g., where RAis H); and R2is hydrogen, fluoro, -OCH3, -OTBS, - OCH2CH2OCH3.

[0227] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, thecompound does not comprise a group of formula (P-10’), wherein X is -ORAor -SRA(e.g., where RAis H); R2is hydrogen, fluoro, -OCH3, -OTBS, -OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0228] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-11), wherein R2is hydrogen, fluoro, -OCH3, -OTBS, - OCH2CH2OCH3.

[0229] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-12), wherein R2is hydrogen, fluoro, -OCH3, -OTBS, -OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0230] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); Y is -O-, -S-, -CH2-, - NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-13’), wherein X is -ORAor -SRA(e.g„ where RAis H); Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, fluoro, -OCH3, -OTBS, -OCH2CH2OCH3.

[0231] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); Y is -O-, -S-, -CH2-, - NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-14’), wherein X is -ORAor -SRA(e.g., where RAis H); Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, fluoro, -OCH3, -OTBS, - OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0232] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-15), wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, fluoro, -OCH3, -OTBS, -OCH2CH2OCH3.

[0233] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-16), wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, fluoro, -OCH3, - OTBS, -OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0234] In certain embodiments of Formula (I’), when R3is a group of formulathen L is not

[0235] In certain embodiments of Formula (I’), when R3is a group of formula , then L is not, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0236] In certain embodiments of Formula (I’), when R3is a group of formulathen L attaches to the 1’ position of the ribose by a non-nitrogen atom (e.g., carbon, oxygen).

[0237] In certain embodiments of Formula (I’), when R1is hydrogen, R2is not a hydrogen, andR3is a group of formula?then L attaches to the 1 ’ position of the ribose by anon-nitrogen atom (e.g., carbon, oxygen).Compounds comprising Formula (11) or (11’)

[0238] In another aspect, provided are compounds comprising at least one group of Formula(II) or (II’), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof:wherein: each X is independently -N(RA)2, -SRA, or -ORA; each P1is independently hydrogen or an oxygen protecting group; each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, -O-, -N(RA)-, -S-, -C(=O)-, - C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, -NRAC(=O)O-, - NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, -NRAS(O)2-, or a combination thereof; and each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0239] In certain embodiments, the compound comprises at least one group of Formula (Il-a) or (II-a’):or a pharmaceutically acceptable salt thereof; wherein R10, R20, RA, P1, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0240] In certain embodiments, the compound comprises at least one group of Formula (Il-b) or (II-b’):or a pharmaceutically acceptable salt thereof; wherein R10, RA, P1, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -0-).

[0241] In certain embodiments, the compound comprises at least one group of Formula (II-c) or (II-c’):or a pharmaceutically acceptable salt thereof; wherein P1and X are as defined herein.

[0242] In certain embodiments, the compound comprises at least one group of Formula (Il-d) or (II-d’):or a pharmaceutically acceptable salt thereof; wherein X is as defined herein.

[0243] In certain embodiments, the compound comprises at least one group of formulaor a pharmaceutically acceptable salt thereof.

[0244] In certain embodiments, the compound comprises 1-20 (e.g., 1-5, 5-10, 10-15, 15-20) groups of Formula (II) or (II’)- In certain embodiments, the compound comprises 1-6 groups of Formula (II) or (II’). In certain embodiments, the compound comprises at least two groups of Formula (II) or (II’). In certain embodiments, the compound comprises at least three groups of Formula (II) or (II’). In certain embodiments, the compound comprises three groups of Formula (II) or (II’). In certain embodiments, the compound comprises three groups of Formula (II) or (II’), wherein the three groups (i.e., “repeat units”) are bound to each other in succession at the denoted attachment points.

[0245] In certain embodiments, the compound comprises at least one group of Formula (II) and at least one group of Formula (II’). In certain embodiments, the compound comprises 1-6 groups of Formula (II) and 1-6 groups of Formula (II’). In certain embodiments, the compound comprises at least two groups of Formula (II) and at least two groups of Formula (II’). In certain embodiments, the compound comprises at least three groups of Formula (II) at least three groups of Formula (II’). In certain embodiments, the compound comprises three groups of Formula (II) and three groups of Formula (II’). In certain embodiments, the compound comprises three groupsof Formula (II) and three groups of Formula (II’), wherein the three groups (i.e., “repeat units”) of Formula (II) are bound to each other in succession at the denoted attachment points, and the three groups (i.e., “repeat units”) of Formula (II’) are bound to each other in succession at the denoted attachment points. In certain embodiments, a group of Formula (II) is bound to a group of Formula (II’).

[0246] In certain embodiments, the compound is or comprises a therapeutic compound. In certain embodiments, the compound comprises a polynucleotide, a polypeptide, or a small molecule. In certain embodiments, the compound comprises a double stranded nucleic acid. In certain embodiments, the compound comprises an oligomer. In certain embodiments, the compound comprises an expression-inhibiting oligomer. In certain embodiments, the compound comprises a ribonucleic acid (RNA). In certain embodiments, the compound comprises an RNAi agent. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA). In certain embodiments, the compound comprises an antisense oligonucleotide.

[0247] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein X is -SRAor -ORA(e.g., -SH or -OH); and Y is -O-, -S-, -CH2-, - NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0248] In certain embodiments, the compound does not comprise a group of formulaor a salt thereof, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0249] In certain embodiments, the compound does not comprise a group of formulaor a salt thereof, wherein X is -SRAor -ORA(e.g., -SH or -OH); each P1is independently hydrogen or an oxygen protecting group (e.g., benzoyl); and Y is -O-, -S-, -CH2-, -NH(C=O)-, - (C=O)NH-, or -NH(C=O)O-.

[0250] In certain embodiments, the compound does not comprise a group of formulaor a salt thereof, wherein; each P1is independently hydrogen or an oxygen protecting group (e.g., benzoyl); and Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0251] In certain embodiments of Formula (II) or (II’), L is not, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0252] In certain embodiments of Formula (II) or (II’), when L is, then R10is a C1-5alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-. In certain embodiments, R10is a C1-3alkylene. In certain embodiments, R10is ethylene.Compounds comprising Formula ( II)

[0253] In another aspect, provided are compounds comprising at least one group of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof: wherein:each X is independently -N(RA)2, -SRA, or -ORA; each P1is independently hydrogen or an oxygen protecting group; each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, -O-, -N(RA)-, -S-, -C(=O)-, - C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, -NRAC(=O)O-, - NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, -NRAS(O)2-, or a combination thereof; and each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0254] In certain embodiments, Formula (II) is of Formula (Il-a):or a pharmaceutically acceptable salt thereof; wherein R10, R20, RA, P1, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0255] In certain embodiments, Formula (II) is of Formula (Il-b):or a pharmaceutically acceptable salt thereof; wherein R10, RA, P1, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0256] In certain embodiments, Formula (II) is of Formula (II-c):or a pharmaceutically acceptable salt thereof; wherein P1and X are as defined herein.

[0257] In certain embodiments, Formula (II) is of Formula (Il-d):or a pharmaceutically acceptable salt thereof; wherein X is as defined herein.

[0258] In certain embodiments, Formula (II) is of formulaor a pharmaceutically acceptable salt thereof.

[0259] In certain embodiments, the compound comprises 1-20 (e.g., 1-5, 5-10, 10-15, 15-20) groups of Formula (II). In certain embodiments, the compound comprises 1-6 groups of Formula (II). In certain embodiments, the compound comprises at least two groups of Formula (II). In certain embodiments, the compound comprises at least three groups of Formula (II). In certain embodiments, the compound comprises three groups of Formula (II). In certain embodiments, the compound comprises three groups of Formula (II), wherein the three groups (i.e., “repeat units”) are bound to each other in succession at the denoted attachment points.

[0260] In certain embodiments, the compound is or comprises a therapeutic compound. In certain embodiments, the compound comprises a polynucleotide, a polypeptide, or a small molecule. In certain embodiments, the compound comprises a double stranded nucleic acid. In certain embodiments, the compound comprises an oligomer. In certain embodiments, the compound comprises an expression-inhibiting oligomer. In certain embodiments, the compound comprises a ribonucleic acid (RNA). In certain embodiments, the compound comprises an RNAi agent. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA). In certain embodiments, the compound comprises an antisense oligonucleotide.

[0261] In certain embodiments, the compound does not comprise a group of formulaor a salt thereof, wherein X is -SRAor -ORA(e.g., -SH or -OH); and Y is -O-, -S-, -CH2-, - NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0262] In certain embodiments, the compound does not comprise a group of formulaor a salt thereof, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0263] In certain embodiments, the compound does not comprise a group of formulaor a salt thereof, wherein X is -SRAor -ORA(e.g., -SH or -OH); each P1is independently hydrogen or an oxygen protecting group (e.g., benzoyl); and Y is -O-, -S-, -CH2-, -NH(C=O)-, - (C=O)NH-, or -NH(C=O)O-.

[0264] In certain embodiments, the compound does not comprise a group of formulaor a salt thereof, wherein; each P1is independently hydrogen or an oxygen protecting group (e.g., benzoyl); and Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0265] In certain embodiments, L is not, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0266] In certain embodiments, when, then R10is a C1-5alkylene having0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-. In certain embodiments, R10is a C1-3alkylene. In certain embodiments, R10is ethylene.Compounds comprising Formula (11’)

[0267] In another aspect, provided are compounds comprising at least one group of Formula (II’), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof:wherein: each X is independently -N(RA)2, -SRA, or -ORA; each P1is independently hydrogen or an oxygen protecting group; each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, -O-, -N(RA)-, -S-, -C(=O)-, - C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, -NRAC(=O)O-, - NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, -NRAS(O)2-, or a combination thereof; and each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 sulfuratom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0268] In certain embodiments, the compound comprises at least one group of Formula (II-a’):or a pharmaceutically acceptable salt thereof; wherein R10, R20, RA, P1, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0269] In certain embodiments, the compound comprises at least one group of Formula (Il-b ’ ) :or a pharmaceutically acceptable salt thereof; wherein R10, RA, P1, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0270] In certain embodiments, the compound comprises at least one group of Formula (II-c’):or a pharmaceutically acceptable salt thereof; wherein P1and X are as defined herein.

[0271] In certain embodiments, the compound comprises at least one group of Formula (II-d’):or a pharmaceutically acceptable salt thereof; wherein X is as defined herein.

[0272] In certain embodiments, the compound comprises at least one group of formulaor a pharmaceutically acceptable salt thereof.

[0273] In certain embodiments, the compound comprises 1-20 (e.g., 1-5, 5-10, 10-15, 15-20) groups of Formula (II’)- In certain embodiments, the compound comprises 1-6 groups of Formula (II’). In certain embodiments, the compound comprises at least two groups of Formula (II’). In certain embodiments, the compound comprises at least three groups of Formula (II) or (II’). In certain embodiments, the compound comprises three groups of Formula (II’). In certain embodiments, the compound comprises three groups of Formula (II’), wherein the three groups (i.e., “repeat units”) are bound to each other in succession at the denoted attachment points.

[0274] In certain embodiments, the compound is or comprises a therapeutic compound. In certain embodiments, the compound comprises a polynucleotide, a polypeptide, or a small molecule. In certain embodiments, the compound comprises a double stranded nucleic acid. In certain embodiments, the compound comprises an oligomer. In certain embodiments, the compound comprises an expression-inhibiting oligomer. In certain embodiments, the compound comprises a ribonucleic acid (RNA). In certain embodiments, the compound comprises an RNAiagent. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA). In certain embodiments, the compound comprises an antisense oligonucleotide.

[0275] In certain embodiments, the compound does not comprise a group of formula:or a salt thereof, wherein X is -SRAor -ORA(e.g., -SH or -OH); and Y is -O-, -S-, -CH2-, - NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0276] In certain embodiments, the compound does not comprise a group of formulaor a salt thereof, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0277] In certain embodiments, the compound does not comprise a group of formulaor a salt thereof, wherein X is -SRAor -ORA(e.g., -SH or -OH); each P1is independently hydrogen or an oxygen protecting group (e.g., benzoyl); and Y is -O-, -S-, -CH2-, -NH(C=O)-, - (C=O)NH-, or -NH(C=O)O-.

[0278] In certain embodiments, the compound does not comprise a group of formulaor a salt thereof, wherein; each P1is independently hydrogen or an oxygen protecting group (e.g., benzoyl); and Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0279] In certain embodiments of Formula (II’), L is not, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0280] In certain embodiments of Formula (II’), when L is, then R10is a C1-5alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-. In certain embodiments, R10is a C1-3alkylene. In certain embodiments, R10is ethylene.Compounds comprising Formula (111) or (111’)

[0281] In another aspect, provided are compounds comprising at least one group of Formula (DI) or (III'), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof:wherein: each X is independently -N(RA)2, -SRA, or -ORA; each P1is independently hydrogen or an oxygen protecting group; and each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom.

[0282] In certain embodiments, the compound comprises at least one group of formula:or a pharmaceutically acceptable salt thereof.

[0283] In certain embodiments, the compound comprises 1-20 (e.g., 1-5, 5-10, 10-15, 15-20) groups of Formula (III) or (III') In certain embodiments, the compound comprises 1-6 groups of Formula (III) or (III'). In certain embodiments, the compound comprises at least two groups ofFormula (III) or (III') In certain embodiments, the compound comprises at least three groups ofFormula (III) or (III') In certain embodiments, the compound comprises three groups ofFormula (III). In certain embodiments, the compound comprises three groups of Formula (III) or (III'), wherein the three groups (i.e., “repeat units”) are bound to each other in succession at the denoted attachment points.

[0284] In certain embodiments, the compound comprises at least one group of Formula (III) and at least one group of Formula (III’). In certain embodiments, the compound comprises 1-6 groups of Formula (III) and 1-6 groups of Formula (III’). In certain embodiments, the compound comprises at least two groups of Formula (III) and at least two groups of Formula (III’). In certain embodiments, the compound comprises at least three groups of Formula (III) at least three groups of Formula (III’). In certain embodiments, the compound comprises three groups of Formula (III) and three groups of Formula (III’). In certain embodiments, the compound comprises three groups of Formula (III) and three groups of Formula (III’), wherein the three groups (i.e., “repeat units”) of Formula (III) are bound to each other in succession at the denoted attachment points, and the three groups (i.e., “repeat units”) of Formula (III’) are bound to each other in succession at the denoted attachment points. In certain embodiments, a group of Formula (III) is bound to a group of Formula (III’).

[0285] In certain embodiments, the compound is or comprises a therapeutic compound. In certain embodiments, the compound comprises a polynucleotide, a polypeptide, or a small molecule. In certain embodiments, the compound comprises a double stranded nucleic acid. In certain embodiments, the compound comprises an oligomer. In certain embodiments, the compound comprises an expression-inhibiting oligomer. In certain embodiments, the compound comprises a ribonucleic acid (RNA). In certain embodiments, the compound comprises an RNAi agent. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments, the compound comprises asmall interfering ribonucleic acid (siRNA). In certain embodiments, the compound comprises an antisense oligonucleotide.Compounds comprising Formula ( III)

[0286] In another aspect, provided are compounds comprising at least one group of Formula (III), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof:wherein: each X is independently -N(RA)2, -SRA, or -ORA; each P1is independently hydrogen or an oxygen protecting group; and each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom.

[0287] In certain embodiments, the compound comprises at least one group of formula:or a pharmaceutically acceptable salt thereof.

[0288] In certain embodiments, the compound comprises 1-20 (e.g., 1-5, 5-10, 10-15, 15-20) groups of Formula (III). In certain embodiments, the compound comprises 1-6 groups of Formula (III). In certain embodiments, the compound comprises at least two groups of Formula (III). In certain embodiments, the compound comprises at least three groups of Formula (III). In certain embodiments, the compound comprises three groups of Formula (III). In certain embodiments, the compound comprises three groups of Formula (III), wherein the three groups (i.e., “repeat units”) are bound to each other in succession at the denoted attachment points.

[0289] In certain embodiments, the compound is or comprises a therapeutic compound. In certain embodiments, the compound comprises a polynucleotide, a polypeptide, or a small molecule. In certain embodiments, the compound comprises a double stranded nucleic acid. In certain embodiments, the compound comprises an oligomer. In certain embodiments, the compound comprises an expression-inhibiting oligomer. In certain embodiments, the compound comprises a ribonucleic acid (RNA). In certain embodiments, the compound comprises an RNAi agent. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA). In certain embodiments, the compound comprises an antisense oligonucleotide.Compounds comprising Formula (III’)

[0290] In another aspect, provided are compounds comprising at least one group of Formula (III'), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof:wherein: each X is independently -N(RA)2, -SRA, or -ORA; each P1is independently hydrogen or an oxygen protecting group; and each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom.

[0291] In certain embodiments, the compound comprises at least one group of formula:or a pharmaceutically acceptable salt thereof.

[0292] In certain embodiments, the compound comprises 1-20 (e.g., 1-5, 5-10, 10-15, 15-20) groups of Formula (III’)- In certain embodiments, the compound comprises 1-6 groups of Formula (III'). In certain embodiments, the compound comprises at least two groups of Formula (III') In certain embodiments, the compound comprises at least three groups of Formula (III’). In certain embodiments, the compound comprises three groups of Formula (III’). In certainembodiments, the compound comprises three groups of Formula (III’), wherein the three groups (i.e., “repeat units”) are bound to each other in succession at the denoted attachment points.

[0293] In certain embodiments, the compound is or comprises a therapeutic compound. In certain embodiments, the compound comprises a polynucleotide, a polypeptide, or a small molecule. In certain embodiments, the compound comprises a double stranded nucleic acid. In certain embodiments, the compound comprises an oligomer. In certain embodiments, the compound comprises an expression-inhibiting oligomer. In certain embodiments, the compound comprises a ribonucleic acid (RNA). In certain embodiments, the compound comprises an RNAi agent. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA). In certain embodiments, the compound comprises an antisense oligonucleotide.Compounds comprising Formula (IV) or (IV’)

[0294] In one aspect, provided are compounds comprising at least one group of Formula (IV) or (IV’), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof:wherein: each X is independently -N(RA)2, -SRA, or -ORA; each R1is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; each R2is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; each R3is independently of formula:each P1is independently hydrogen or an oxygen protecting group; each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, -O-, -N(RA)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, - NRAC(=O)O-, -NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, - NRAS(O)2-, or a combination thereof; and each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0295] In certain embodiments, the compound comprises at least one group of Formula (IV-a) or (IV-a’):or a pharmaceutically acceptable salt thereof; wherein R2, L, P1, and X are as defined herein.

[0296] In certain embodiments, the compound comprises at least one group of Formula (IV-b) or (IV-b'):or a pharmaceutically acceptable salt thereof; wherein L, P1, and X are as defined herein.

[0297] In certain embodiments, the compound comprises at least one group of Formula (IV-c) or (IV-c'):or a pharmaceutically acceptable salt thereof; wherein R2, L, P1, and X are as defined herein.

[0298] In certain embodiments, the compound comprises at least one group of Formula (IV-d) or (IV-d’):or a pharmaceutically acceptable salt thereof; wherein L, P1, and X are as defined herein.

[0299] In certain embodiments, the compound comprises at least one group of formula:or a pharmaceutically acceptable salt thereof.

[0300] In certain embodiments, the compound comprises 1-20 (e.g., 1-5, 5-10, 10-15, 15-20) groups of Formula (IV) or (IV’). In certain embodiments, the compound comprises 1-6 groups of Formula (IV) or (IV’). In certain embodiments, the compound comprises one group of Formula (IV) or (IV’). In certain embodiments, the compound comprises one group of Formula (IV) or (IV’). In certain embodiments, the compound comprises two groups of Formula (IV) or (IV’). In certain embodiments, the compound comprises at least three groups of Formula (IV) or (IV’). In certain embodiments, the compound comprises three groups of Formula (IV) or (IV’). In certain embodiments, the compound comprises three groups of Formula (IV) or (IV’), wherein the three groups (i.e., “repeat units”) are bound to each other in succession at the denoted attachment points. In certain embodiments, the compound comprises 1-20 (e.g., 1-5, 5-10, 10-15, 15-20) groups of Formula (IV) or (IV’), wherein all groups are of the same type (all of Formula (IV) or all of Formula (IV’)). In certain embodiments, the compound comprises three groups of Formula (IV) or (IV’), wherein all groups are of the same type (all of Formula (IV) or all of Formula (IV’)), and wherein the three groups (i.e., “repeat units”) are bound to each other in succession atthe denoted attachment points. In certain embodiments, the compound comprises two groups of Formula (IV) or (IV’), wherein all groups are of the same type (all of Formula (IV) or all of Formula (IV’)), and wherein the two groups (i.e., “repeat units”) are bound to each other in succession at the denoted attachment points.

[0301] In certain embodiments, the compound comprises at least one group of Formula (IV) and at least one group of Formula (IV’). In certain embodiments, the compound comprises 1-6 groups of Formula (I) and 1-6 groups of Formula (IV’). In certain embodiments, the compound comprises one group of Formula (IV) and one group of Formula (IV’). In certain embodiments, the compound comprises two groups of Formula (IV) and two groups of Formula (IV’). In certain embodiments, the compound comprises at least two groups of Formula (IV) and at least two groups of Formula (IV’). In certain embodiments, the compound comprises at least three groups of Formula (IV) and at least three groups of Formula (IV’). In certain embodiments, the compound comprises three groups of Formula (I) and three groups of Formula (IV’). In certain embodiments, the compound comprises two groups of Formula (IV) and two groups of Formula (IV’), wherein the two groups (i.e., “repeat units”) of Formula (IV) are bound to each other in succession at the denoted attachment points, and the three groups (i.e., “repeat units”) of Formula (IV’) are bound to each other in succession at the denoted attachment points. In certain embodiments, the compound comprises three groups of Formula (IV) and three groups of Formula (IV’), wherein the three groups (i.e., “repeat units”) of Formula (I) are bound to each other in succession at the denoted attachment points, and the three groups (i.e., “repeat units”) of Formula (IV’) are bound to each other in succession at the denoted attachment points. In certain embodiments, a group of Formula (IV) is bound to a group of Formula (IV’).

[0302] In certain embodiments, the compound is or comprises a therapeutic compound. In certain embodiments, the compound comprises a polynucleotide, a polypeptide, or a small molecule. In certain embodiments, the compound comprises a double stranded nucleic acid. In certain embodiments, the compound comprises an oligomer. In certain embodiments, the compound comprises an expression-inhibiting oligomer. In certain embodiments, the compound comprises a ribonucleic acid (RNA). In certain embodiments, the compound comprises an RNAi agent. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA). In certain embodiments, the compound comprises an antisense oligonucleotide.Compounds comprising Formula (IV)

[0303] In one aspect, provided are compounds comprising at least one group of Formula (IV), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof:(IV), wherein: each X is independently -N(RA)2, -SRA, or -ORA; each R1is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; each R2is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; each R3is independently of formula:each P1is independently hydrogen or an oxygen protecting group; each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene,-0-, -N(RA)-, -S-, -C(=O)-, -C(=O)0-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, - NRAC(=O)O-, -NRAC(=O)N(RA)-, -0C(=O)-, -0C(=O)0-, -OC(=O)N(RA)-, -S(O)2NRA-, - NRAS(O)2-, or a combination thereof; and each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0304] In certain embodiments, the compound comprises at least one group of Formula (IV-a):or a pharmaceutically acceptable salt thereof; wherein R2, L, P1, and X are as defined herein.

[0305] In certain embodiments, the compound comprises at least one group of Formula (IV-b):or a pharmaceutically acceptable salt thereof; wherein L, P1, and X are as defined herein.

[0306] In certain embodiments, the compound comprises at least one group of Formula (IV-c):or a pharmaceutically acceptable salt thereof; wherein R2, L, P1, and X are as defined herein.

[0307] In certain embodiments, the compound comprises at least one group of Formula (IV-d):or a pharmaceutically acceptable salt thereof; wherein L, P1, and X are as defined herein.

[0308] In certain embodiments, the compound comprises at least one group of formula:or a pharmaceutically acceptable salt thereof.

[0309] In certain embodiments, the compound comprises 1-20 (e.g., 1-5, 5-10, 10-15, 15-20) groups of Formula (IV). In certain embodiments, the compound comprises 1-6 groups of Formula (IV). In certain embodiments, the compound comprises one group of Formula (IV). In certain embodiments, the compound comprises two groups of Formula (IV). In certain embodiments, the compound comprises at least two groups of Formula (IV). In certain embodiments, the compound comprises at least three groups of Formula (IV). In certain embodiments, the compound comprises three groups of Formula (IV). In certain embodiments,the compound comprises two groups of Formula (IV), wherein the two groups (i.e., “repeat units”) are bound to each other in succession at the denoted attachment points. In certain embodiments, the compound comprises three groups of Formula (IV), wherein the three groups (i.e., “repeat units”) are bound to each other in succession at the denoted attachment points.

[0310] In certain embodiments, the compound is or comprises a therapeutic compound. In certain embodiments, the compound comprises a polynucleotide, a polypeptide, or a small molecule. In certain embodiments, the compound comprises a double stranded nucleic acid. In certain embodiments, the compound comprises an oligomer. In certain embodiments, the compound comprises an expression-inhibiting oligomer. In certain embodiments, the compound comprises a ribonucleic acid (RNA). In certain embodiments, the compound comprises an RNAi agent. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA). In certain embodiments, the compound comprises an antisense oligonucleotide.Compounds comprising Formula (IV)

[0311] In one aspect, provided are compounds comprising at least one group of Formula (IV’), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof:wherein: each X is independently -N(RA)2, -SRA, or -ORA; each R1is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; each R2is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; each R3is independently of formula:each P1is independently hydrogen or an oxygen protecting group; each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, -O-, -N(RA)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, - NRAC(=O)O-, -NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, - NRAS(O)2-, or a combination thereof; and each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0312] In certain embodiments, the compound comprises at least one group of Formula (IV- a’):or a pharmaceutically acceptable salt thereof; wherein R2, L, P1, and X are as defined herein.

[0313] In certain embodiments, the compound comprises at least one group of Formula (IV- b'):or a pharmaceutically acceptable salt thereof; wherein L, P1, and X are as defined herein.

[0314] In certain embodiments, the compound comprises at least one group of Formula (IV-c'):or a pharmaceutically acceptable salt thereof; wherein R2, L, P1, and X are as defined herein.

[0315] In certain embodiments, the compound comprises at least one group of Formula (IV- d’):or a pharmaceutically acceptable salt thereof; wherein L, P1, and X are as defined herein.

[0316] In certain embodiments, the compound comprises at least one group of formula:or a pharmaceutically acceptable salt thereof.

[0317] In certain embodiments, the compound comprises 1-20 (e.g., 1-5, 5-10, 10-15, 15-20) groups of Formula (IV’). In certain embodiments, the compound comprises 1-6 groups ofFormula (IV’). In certain embodiments, the compound comprises one group of Formula (IV’). In certain embodiments, the compound comprises two groups of Formula (IV’). In certain embodiments, the compound comprises at least two groups of Formula (IV’). In certain embodiments, the compound comprises at least three groups of Formula (IV’). In certain embodiments, the compound comprises three groups of Formula (IV’). In certain embodiments, the compound comprises two groups of Formula (IV’), wherein the two groups (i.e., “repeat units”) are bound to each other in succession at the denoted attachment points. In certain embodiments, the compound comprises three groups of Formula (IV’), wherein the three groups (i.e., “repeat units”) are bound to each other in succession at the denoted attachment points.

[0318] In certain embodiments, the compound is or comprises a therapeutic compound. In certain embodiments, the compound comprises a polynucleotide, a polypeptide, or a small molecule. In certain embodiments, the compound comprises a double stranded nucleic acid. In certain embodiments, the compound comprises an oligomer. In certain embodiments, the compound comprises an expression-inhibiting oligomer. In certain embodiments, the compound comprises a ribonucleic acid (RNA). In certain embodiments, the compound comprises an RNAi agent. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments, the compound comprises a small interfering ribonucleic acid (siRNA). In certain embodiments, the compound comprises an antisense oligonucleotide.Compounds of Formula (V) or (V’)

[0319] In another aspect, provided are compounds of Formula (V) or (V’), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof:wherein:A is a molecular payload, -OH, substituted or unsubstituted alkoxy, hydrogen, substituted or unsubstituted alkyl, oreach X is independently -N(RA)2, -SRA, or -ORA; each R1is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, -ORA, or a group of formula:each R2is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, -ORA, or a group of formula:each R3is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, -ORA, or a group of formula:R4is hydrogen, substituted or unsubstituted alkyl, -OH, substituted orunsubstituted alkoxy, or a molecular payload; each P1is independently hydrogen or an oxygen protecting group; each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, - O-, -N(RA)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, -NRAC(=O)O-, -NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, - NRAS(O)2-, or a combination thereof; each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and n is 1-20; wherein: the compound has only one molecular payload; for Formula (V), when n is greater than 1, with the exception of the phosphorous directly attached to the A, each instance of phosphorous labeled y is bound to the oxygen labeled z of the adjacent unit; for Formula (V), when n is greater than 1, with the exception of the oxygen directly attached to R4, each instance of oxygen labeled z is bound to the phosphorous labeled y of the adjacent unit; for Formula (V’), when n is greater than 1, with the exception of the oxygen directly attached to the A, each instance of oxygen labeled y is bound to the phosphorous labeled z of the adjacent unit; for Formula (V’), when n is greater than 1, with the exception of the phosphorous directly attached to R4, each instance of phosphorous labeled z is bound to the oxygen labeled y of the adjacent unit; and each repeat unit in the compound of Formula (V) or (V’) has only one instance of formula:

[0320] In certain embodiments, the compound is of Formula (V-a) or (V-a’):or a pharmaceutically acceptable salt thereof, wherein A, R2, R3, R4, n, and X are as defined herein.

[0321] In certain embodiments, the compound is of Formula (V-a-1) or (V-a-1’):or a pharmaceutically acceptable salt thereof, wherein A, R2, R3, R4, n, and X are as defined herein.

[0322] In certain embodiments, the compound is of Formula (V-b) or (V-b’):or a pharmaceutically acceptable salt thereof, wherein A, R2, R4, L, P1, n, and X are as defined herein.

[0323] In certain embodiments, the compound is of Formula (V-b-1) or (V-b-1’):or a pharmaceutically acceptable salt thereof, wherein A, R2, R4, L, P1, n, and X are as defined herein.

[0324] In certain embodiments, the compound is of Formula (V-c) or (V-c’):or a pharmaceutically, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0325] In certain embodiments, the compound is of Formula (V-c-1) or (V-c-1’):or a pharmaceutically acceptable salt thereof, wherein A, R2, R4, R10, R20, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0326] In certain embodiments, the compound is of Formula (V-d) or (V-d’):or a pharmaceutically acceptable salt thereof, wherein A, R2, R4, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0327] In certain embodiments, the compound is of Formula (V-d-1) or (V-d-1’):or a pharmaceutically acceptable salt thereof, wherein A, R4, R2, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0328] In certain embodiments, the compound is of Formula (V-e) or (V-e’):or a pharmaceutically acceptable salt thereof, wherein A, R4, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0329] In certain embodiments, the compound is of Formula (V-e-1) or (V-e-1’):or a pharmaceutically acceptable salt thereof, wherein A, R4, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -0-).

[0330] In certain embodiments, the compound is of Formula (V-f) or (V-F):or a pharmaceutically acceptable salt thereof, wherein A, R4, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -0-).

[0331] In certain embodiments, the compound is of Formula (V-f-1) or (V-f-1’):or a pharmaceutically acceptable salt thereof, wherein A, R4, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0332] In certain embodiments, the compound is of formulaor a pharmaceutically acceptable salt thereof, wherein A, R4, and X are as defined herein.

[0333] In certain embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof, wherein A and X are as defined herein.

[0334] In certain embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof; wherein A and R4are as defined herein.

[0335] In certain embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof; wherein A and R4are as defined herein.

[0336] In certain embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof.

[0337] In certain embodiments of the compound of Formula (V) or (V’), n is 1-6. In certain embodiments of the compound of Formula (V) or (V’), n is 1-3. In certain embodiments of the compound of Formula (V) or (V’), n is 2-3. In certain embodiments of the compound of Formula (V) or (V’), n is 1-4. In certain embodiments of the compound of Formula (V) or (V’), n is 2-4. In certain embodiments of the compound of Formula (V) or (V’), n is 3.

[0338] In certain embodiments of the compound of Formula (V), A is -OH. In certain embodiments of the compound of Formula (V’), A is(e.g., RAis H, and X is OH; or RAis H, and X is SH). In certain embodiments of the compound of Formula (V’), A is hydrogen. In certain embodiments of the compound of Formula (V’), A is substituted or unsubstituted alkyl. In certain embodiments of the compound of Formula (V), A is substituted alkoxy. In certain embodiments of the compound of Formula (V), A is alkoxy (e.g., C1-6alkoxy) substituted with - NH2or -N3. In certain embodiments of the compound of Formula (V) or (V’), A is a molecular payload. In certain embodiments of the compound of Formula (V) or (V’), A is a therapeutic moiety or therapeutic compound. In certain embodiments of the compound of Formula (V) or (V’), A is a polynucleotide, a polypeptide, or a small molecule. In certain embodiments of the compound of Formula (V) or (V’), A is a double stranded nucleic acid. In certain embodiments of the compound of Formula (V) or (V’), A is an oligomer. In certain embodiments of the compound of Formula (V) or (V’), A is an expression-inhibiting oligomer. In certain embodiments of the compound of Formula (V) or (V’), A is a ribonucleic acid (RNA). In certain embodiments of the compound of Formula (V) or (V’), A is an RNAi agent. In certain embodiments of the compound of Formula (V) or (V’), A is a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments of the compound of Formula (V) or (V’), A is a small interfering ribonucleic acid (siRNA). In certain embodiments of the compound of Formula (V) or (V’), A is an antisense oligonucleotide. In certain embodiments of the compound of Formula (V) or (V’), A is double stranded and bound to the phosphorous oroxygen labeled y at the 5’ end of its sense strand. In certain embodiments of the compound of Formula (V) or (V’), A is double stranded and bound to the phosphorous or oxygen labeled y at the 5’ end of its antisense strand. In certain embodiments of the compound of Formula (V) or (V’), A is double stranded and bound to the phosphorous or oxygen labeled y at the 3’ end of its sense strand. In certain embodiments of the compound of Formula (V) or (V’), A is double stranded and bound to the phosphorous or oxygen labeled y at the 3’ end of its antisense strand.

[0339] In certain embodiments of the compound of Formula (V’), R4is -OH. In certain embodiments of the compound of Formula (V), R4is(e.g., RAis substituted alkyl and X is OH; or RAis substituted alkyl and X is SH). In certain embodiments of the compound of Formula (V), R4is hydrogen. In certain embodiments of the compound of Formula (V), R4is substituted or unsubstituted alkyl. In certain embodiments of the compound of Formula (V’), R4is substituted alkoxy. In certain embodiments of the compound of Formula (V’), R4is alkoxy (e.g., C1-6alkoxy) substituted with -NH2or -N3. In certain embodiments of the compound of Formula (V) or (V’), R4is a molecular payload. In certain embodiments of the compound of Formula (V) or (V’), R4is a therapeutic moiety or therapeutic compound. In certain embodiments of the compound of Formula (V) or (V’), R4is a polynucleotide, a polypeptide, or a small molecule. In certain embodiments of the compound of Formula (V) or (V’), R4is a double stranded nucleic acid. In certain embodiments of the compound of Formula (V) or (V’), R4is an oligomer. In certain embodiments of the compound of Formula (V) or (V’), R4is an expression- inhibiting oligomer. In certain embodiments of the compound of Formula (V) or (V’), R4is a ribonucleic acid (RNA). In certain embodiments of the compound of Formula (V) or (V’), R4is an RNAi agent. In certain embodiments of the compound of Formula (V) or (V’), R4is a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments of the compound of Formula (V) or (V’), R4is a small interfering ribonucleic acid (siRNA). In certain embodiments of the compound of Formula (V) or (V’), R4is an antisense oligonucleotide. In certain embodiments of the compound of Formula (V) or (V’), R4is double stranded and bound to the phosphorous or oxygen labeled z at the 5’ end of its sense strand. In certain embodiments of the compound of Formula (V) or (V’), R4is double stranded and bound to the phosphorous or oxygen labeled z at the 5’ end of its antisense strand. In certain embodiments of the compound of Formula (V) or (V’), R4is double stranded and bound to the phosphorous or oxygen labeled z at the 3’ end of its sense strand. In certain embodiments of the compound of Formula (V) or (V’), R4is double stranded and bound to the phosphorous or oxygen labeled z at the 3’ end of its antisense strand.

[0340] In certain embodiments, the compound of Formula (V) or (V’) does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H).

[0341] In certain embodiments, the compound of Formula (V) or (V’) does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); and each P1is independently hydrogen or an oxygen protecting group.

[0342] In certain embodiments, the compound of Formula (V) or (V’) does not comprise a group of formula:or a salt thereof; wherein each P1is independently hydrogen or an oxygen protecting group.

[0343] In certain embodiments, the compound of Formula (V) or (V’) does not comprise a group of formula: or a salt thereof.

[0344] In certain embodiments of the compound of Formula (V) or (V’), when R1and R2are hydrogen, and R3is a group of formula then L is not

[0345] In certain embodiments of the compound of Formula (V) or (V’), when R1and R2are hydrogen, R3is a group of formulathen R10is a C1-5alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-.

[0346] In certain embodiments of the compound of Formula (V) or (V’), when R1and R2are hydrogen, and R3is a group of formula?then L attaches to the 1’ position of the ribose by a non-oxygen atom (e.g., carbon, nitrogen).

[0347] In certain embodiments, the compound of Formula (V) or (V’) does not comprise aor a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-9) or (P-9’), wherein X is -ORAor -SRA(e.g., where RAis H); and R2is hydrogen, fluoro, -OCH3, -OTBS, or -OCH2CH2OCH3.

[0348] In certain embodiments, the compound of Formula (V) or (V’) does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-10) or (P-10’), wherein X is -ORAor -SRA(e.g., where RAis H); R2is hydrogen, fluoro, -OCH3, -OTBS, -OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0349] In certain embodiments, the compound of Formula (V) or (V’) does not comprise a group of formula:or a salt thereof, wherein R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-11), wherein R2is hydrogen, fluoro, -OCH3, -OTBS, or -OCH2CH2OCH3.

[0350] In certain embodiments, the compound of Formula (V) or (V’) does not comprise a group of formula:or a salt thereof, wherein R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group offormula (P-12), wherein R2is hydrogen, fluoro, -OCH3, -OTBS, -OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0351] In certain embodiments, the compound of Formula (V) or (V’) does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); Y is -O-, -S-, -CH2-, - NH(C=O)-, -(C=O)NH-, or -NH(C=O)0-; and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-13) or (P-13’), wherein X is -ORAor -SRA(e.g„ where RAis H); Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or - NH(C=O)0-; and R2is hydrogen, fluoro, -OCH3, -OTBS, or -OCH2CH2OCH3.

[0352] In certain embodiments, the compound of Formula (V) or (V’) does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); Y is -O-, -S-, -CH2-, - NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-14) or (P-14’), wherein X is -ORAor -SRA(e.g., where RAis H); Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, fluoro, -OCH3, - OTB S, -OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0353] In certain embodiments, the compound of Formula (V) or (V’) does not comprise a group of formula:or a salt thereof, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-15), wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, fluoro, -OCH3, -OTBS, or -OCH2CH2OCH3.

[0354] In certain embodiments, the compound of Formula (V) or (V’) does not comprise a group of formula:or a salt thereof, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-16), wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, fluoro, -OCH3, - OTBS, -OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0355] In certain embodiments of the compound of Formula (V) or (V’), when R3is a group of O1formula, then L is not

[0356] In certain embodiments of the compound of Formula (V) or (V’), when R3is a group of formula, then L is not , wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0357] In certain embodiments of the compound of Formula (V) or (V’), when R3is a group of formula then L attaches to the 1’ position of the ribose by a non-nitrogenatom (e.g., carbon, oxygen).

[0358] In certain embodiments of the compound of Formula (V) or (V’), when R1is hydrogen,R2is not a hydrogen, and R3is a group of formula then L attaches to the 1’position of the ribose by a non-nitrogen atom (e.g., carbon, oxygen).Compounds of Formula (V)

[0359] In another aspect, provided are compounds of Formula (V), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof:wherein:A is a molecular payload, -OH, or substituted or unsubstituted alkoxy; each X is independently -N(RA)2, -SRA, or -ORA; each R1is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, -ORA, or a group of formula:each R2is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, -ORA, or a group of formula:each R3is independently hydrogen, halogen, substituted or unsubstituted aliphatic,substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, -ORA, or a group of formula:R4is hydrogen, substituted or unsubstituted alkyl,, or a molecular payload; each P1is independently hydrogen or an oxygen protecting group; each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, - O-, -N(RA)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, - NRAC(=O)O-, -NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, - NRAS(O)2-, or a combination thereof; each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and n is 1-20; wherein: the compound has only one molecular payload; when n is greater than 1, with the exception of the phosphorous directly attached to the A, each instance of phosphorous labeled y is bound to the oxygen labeled z of the adjacent unit; when n is greater than 1, with the exception of the oxygen directly attached to R4, each instance of oxygen labeled z is bound to the phosphorous labeled y of the adjacent unit; and each repeat unit in the compound of Formula (V) has only one instance of formula:

[0360] In certain embodiments, the compound of Formula (V) is of Formula (V-a):or a pharmaceutically acceptable salt thereof, wherein A, R2, R3, R4, n, and X are as defined herein.

[0361] In certain embodiments, the compound of Formula (V) is of Formula (V-a-1):or a pharmaceutically acceptable salt thereof, wherein A, R2, R3, n, and X are as defined herein.

[0362] In certain embodiments, the compound of Formula (V) is of Formula (V-b):or a pharmaceutically acceptable salt thereof, wherein A, R2, R4, L, P1, n, and X are as defined herein.

[0363] In certain embodiments, the compound of Formula (V) is of Formula (V-b-1):or a pharmaceutically acceptable salt thereof, wherein A, R2, L, P1, n, and X are as defined herein.

[0364] In certain embodiments, the compound of Formula (V) is of Formula (V-c):or a pharmaceutically acceptable salt thereof, wherein A, R2, R4, R10, R20, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0365] In certain embodiments, the compound of Formula (V) is of Formula (V-c-1):or a pharmaceutically acceptable salt thereof, wherein A, R2, R10, R20, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0366] In certain embodiments, the compound of Formula (V) is of Formula (V-d):or a pharmaceutically acceptable salt thereof, wherein A, R2, R4, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0367] In certain embodiments, the compound of Formula (V) is of Formula (V-d-1):or a pharmaceutically acceptable salt thereof, wherein A, R2, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0368] In certain embodiments, the compound of Formula (V) is of Formula (V-e):or a pharmaceutically acceptable salt thereof, wherein A, R4, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0369] In certain embodiments, the compound of Formula (V) is of Formula (V-e-1):or a pharmaceutically acceptable salt thereof, wherein A, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0370] In certain embodiments, the compound of Formula (V) is of Formula (V-f):or a pharmaceutically acceptable salt thereof, wherein A, R4, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0371] In certain embodiments, the compound of Formula (V) is of Formula (V-f-1):or a pharmaceutically acceptable salt thereof, wherein A, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0372] In certain embodiments, the compound of Formula (V) is of formulaor a pharmaceutically acceptable salt thereof, wherein A and X are as defined herein.

[0373] In certain embodiments, the compound of Formula (V) is of formula:or a pharmaceutically acceptable salt thereof, wherein A and X are as defined herein.

[0374] In certain embodiments, the compound of Formula (V) is of formula:or a pharmaceutically acceptable salt thereof; wherein A is as defined herein.

[0375] In certain embodiments, the compound of Formula (V) is of formula:or a pharmaceutically acceptable salt thereof; wherein A is as defined herein.

[0376] In certain embodiments, the compound of Formula (V) is of formula:or a pharmaceutically acceptable salt thereof, wherein R4and X are as defined herein.

[0377] In certain embodiments of the compound of Formula (V), n is 1-6. In certain embodiments of the compound of Formula (V), n is 1-3. In certain embodiments of the compound of Formula (V), n is 2-3. In certain embodiments of the compound of Formula (V), n is 1-4. In certain embodiments of the compound of Formula (V), n is 2-4. In certain embodiments of the compound of Formula (V), n is 3.

[0378] In certain embodiments of the compound of Formula (V), A is -OH. In certain embodiments of the compound of Formula (V), A is substituted alkoxy. In certain embodiments of the compound of Formula (V), A is alkoxy (e.g., C1-6alkoxy) substituted with -NH2or -N3. In certain embodiments of the compound of Formula (V), A is a molecular payload. In certain embodiments of the compound of Formula (V), A is a therapeutic moiety or therapeutic compound. In certain embodiments of the compound of Formula (V), A is a polynucleotide, a polypeptide, or a small molecule. In certain embodiments of the compound of Formula (V), A is a double stranded nucleic acid. In certain embodiments of the compound of Formula (V), A is an oligomer. In certain embodiments of the compound of Formula (V), A is an expression-inhibiting oligomer. In certain embodiments of the compound of Formula (V), A is a ribonucleic acid (RNA). In certain embodiments of the compound of Formula (V), A is an RNAi agent. In certain embodiments of the compound of Formula (V), A is a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments of the compound of Formula (V), A is a small interfering ribonucleic acid (siRNA). In certain embodiments of the compound of Formula(V), A is an antisense oligonucleotide. In certain embodiments of the compound of Formula (V), A is double stranded and bound to the phosphorous labeled y at the 5’ end of its sense strand. In certain embodiments of the compound of Formula (V), A is double stranded and bound to the phosphorous labeled y at the 5’ end of its antisense strand. In certain embodiments of the compound of Formula (V), A is double stranded and bound to the phosphorous labeled y at the 3’ end of its sense strand. In certain embodiments of the compound of Formula (V), A is double stranded and bound to the phosphorous labeled y at the 3’ end of its antisense strand.

[0379] In certain embodiments of the compound of Formula (V), R4is(e.g., RAis substituted alkyl and X is OH; or RAis substituted alkyl and X is SH). In certain embodiments of the compound of Formula (V), R4is hydrogen. In certain embodiments of the compound of Formula (V), R4is substituted or unsubstituted alkyl. In certain embodiments of the compound of Formula (V), R4is a molecular payload. In certain embodiments of the compound of Formula (V), R4is a therapeutic moiety or therapeutic compound. In certain embodiments of the compound of Formula (V), R4is a polynucleotide, a polypeptide, or a small molecule. In certain embodiments of the compound of Formula (V), R4is a double stranded nucleic acid. In certain embodiments of the compound of Formula (V), R4is an oligomer. In certain embodiments of the compound of Formula (V), R4is an expression-inhibiting oligomer. In certain embodiments of the compound of Formula (V), R4is a ribonucleic acid (RNA). In certain embodiments of the compound of Formula (V), R4is an RNAi agent. In certain embodiments of the compound of Formula (V), R4is a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments of the compound of Formula (V), R4is a small interfering ribonucleic acid (siRNA). In certain embodiments of the compound of Formula (V), R4is an antisense oligonucleotide. In certain embodiments of the compound of Formula (V), R4is double stranded and bound to the oxygen labeled z at the 5’ end of its sense strand. In certain embodiments of the compound of Formula (V), R4is double stranded and bound to the oxygen labeled z at the 5’ end of its antisense strand. In certain embodiments of the compound of Formula (V), R4is double stranded and bound to the oxygen labeled z at the 3’ end of its sense strand. In certain embodiments of the compound of Formula (V), R4is double stranded and bound to the oxygen labeled z at the 3’ end of its antisense strand.

[0380] In certain embodiments, the compound of Formula (V) does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H).

[0381] In certain embodiments, the compound of Formula (V) does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); and each P1is independently hydrogen or an oxygen protecting group.

[0382] In certain embodiments, the compound of Formula (V) does not comprise a group of formula:or a salt thereof; wherein each P1is independently hydrogen or an oxygen protecting group.

[0383] In certain embodiments, the compound of Formula (V) does not comprise a group of formula:or a salt thereof.

[0384] In certain embodiments of the compound of Formula (V), when R1and R2are hydrogen, and R3is a group of formulathen L is not

[0385] In certain embodiments of the compound of Formula (V), when R1and R2are hydrogen,R3is a group of formulaand L is then R10is a C1-5alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-.

[0386] In certain embodiments of the compound of Formula (V), when R1and R2are hydrogen, and R3is a group of formulathen L attaches to the 1’ position of the ribose by a non-oxygen atom (e.g., carbon, nitrogen).

[0387] In certain embodiments, the compound of Formula (V) does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-9), wherein X is - ORAor -SRA(e.g., where RAis H); and R2is hydrogen, fluoro, -OCH3, -OTBS, or - OCH2CH2OCH3.

[0388] In certain embodiments, the compound of Formula (V) does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-10), wherein X is -ORAor -SRA(e.g., where RAis H); R2is hydrogen, fluoro, -OCH3, -OTBS, -OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0389] In certain embodiments, the compound of Formula (V) does not comprise a group of formula:or a salt thereof, wherein R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-11), wherein R2is hydrogen, fluoro, -OCH3, -OTBS, or-OCH2CH2OCH3.

[0390] In certain embodiments, the compound of Formula (V) does not comprise a group of formula:or a salt thereof, wherein R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-12), wherein R2is hydrogen, fluoro, -OCH3, -OTBS, -OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0391] In certain embodiments, the compound of Formula (V) does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); Y is -O-, -S-, -CH2-, - NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-13), wherein X is -ORAor -SRA(e.g„ where RAis H); Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, fluoro, -OCH3, -OTBS, or -OCH2CH2OCH3.

[0392] In certain embodiments, the compound of Formula (V) does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); Y is -O-, -S-, -CH2-, - NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-14), wherein X is -ORAor -SRA(e.g., where RAis H); Y is -O-, - S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, fluoro, -OCH3, -OTBS, - OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0393] In certain embodiments, the compound of Formula (V) does not comprise a group of formula:or a salt thereof, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-15), wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, fluoro, -OCH3, -OTBS, or -OCH2CH2OCH3.

[0394] In certain embodiments, the compound of Formula (V) does not comprise a group of formula:or a salt thereof, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-16), wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, fluoro, -OCH3, - OTB S, -OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0395] In certain embodiments of the compound of Formula (V), when R3is a group of formula , then L is not

[0396] In certain embodiments of the compound of Formula (V), when R3is a group of formulaOP1AcHN OP1, then L is not , wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0397] In certain embodiments of the compound of Formula (V), when R3is a group of formula then L attaches to the 1 ’ position of the ribose by a non-nitrogen atom (e.g.,carbon, oxygen).

[0398] In certain embodiments of the compound of Formula (V), when R1is hydrogen, R2is not a hydrogen, and R3is a group of formula then L attaches to the 1’position of the ribose by a non-nitrogen atom (e.g., carbon, oxygen).Compounds of Formula (V’)

[0399] In another aspect, provided are compounds of Formula (V’), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof: wherein:A is a molecular payload, hydrogen, substituted or unsubstituted alkyl, oreach X is independently -N(RA)2, -SRA, or -ORA; each R1is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, -ORA, or a group of formula:each R2is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, -ORA, or a group of formula:each R3is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, -ORA, or a group of formula:R4is -OH, substituted or unsubstituted alkoxy, or a molecular payload; each P1is independently hydrogen or an oxygen protecting group; each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, - O-, -N(RA)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, - NRAC(=O)O-, -NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, - NRAS(O)2-, or a combination thereof; each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and n is 1-20; wherein: the compound has only one molecular payload; when n is greater than 1, with the exception of the oxygen directly attached to the A, each instance of oxygen labeled y is bound to the phosphorous labeled z of the adjacent unit; when n is greater than 1, with the exception of the phosphorous directly attached to R4, each instance of phosphorous labeled z is bound to the oxygen labeled y of the adjacent unit; and each repeat unit in the compound of Formula (V’) has only one instance of formula:

[0400] In certain embodiments, the compound is of Formula (V-a’):or a pharmaceutically acceptable salt thereof, wherein A, R2, R3, R4, n, and X are as defined herein.

[0401] In certain embodiments, the compound is of Formula (V-a-1’):or a pharmaceutically acceptable salt thereof, wherein R2, R3, R4, n, and X are as defined herein.

[0402] In certain embodiments, the compound is of Formula (V-b’):or a pharmaceutically acceptable salt thereof, wherein A, R2, R4, L, P1, n, and X are as defined herein.

[0403] In certain embodiments, the compound is of Formula (V-b-1’):or a pharmaceutically acceptable salt thereof, wherein R2, R4, L, P1, n, and X are as defined herein.

[0404] In certain embodiments, the compound is of Formula (V-c’):or a pharmaceutically acceptable salt thereof, wherein A, R2, R4, R10, R20, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0405] In certain embodiments, the compound is of Formula (V-c-1’):or a pharmaceutically acceptable salt thereof, wherein R2, R4, R10, R20, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0406] In certain embodiments, the compound is of Formula (V-d’):or a pharmaceutically acceptable salt thereof, wherein A, R2, R4, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0407] In certain embodiments, the compound is of Formula (V-d-1’):or a pharmaceutically acceptable salt thereof, wherein R4, R2, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0408] In certain embodiments, the compound is of Formula (V-e’):or a pharmaceutically acceptable salt thereof, wherein A, R4, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0409] In certain embodiments, the compound is of Formula (V-e-1’):or a pharmaceutically acceptable salt thereof, wherein R4, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0410] In certain embodiments, the compound is of Formula (V-f’):or a pharmaceutically acceptable salt thereof, wherein A, R4, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0411] In certain embodiments, the compound is of Formula (V-f-1’):or a pharmaceutically acceptable salt thereof, wherein R4, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0412] In certain embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof, wherein R4and X are as defined herein.

[0413] In certain embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof, wherein R4and X are as defined herein.

[0414] In certain embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof; wherein R4is as defined herein.

[0415] In certain embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof; wherein R4is as defined herein.

[0416] In certain embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof, wherein A and X are as defined herein.

[0417] In certain embodiments of the compound of Formula (V’), n is 1-6. In certain embodiments of the compound of Formula (V’), n is 1-3. In certain embodiments of the compound of Formula (V’), n is 2-3. In certain embodiments of the compound of Formula (V’), n is 1-4. In certain embodiments of the compound of Formula (V’), n is 2-4. In certain embodiments of the compound of Formula (V’), n is 3.

[0418] In certain embodiments of the compound of Formula (V’), A is(e.g., RAis H, and X is OH; or RAis H, and X is SH). In certain embodiments of the compound of Formula (V’), A is hydrogen. In certain embodiments of the compound of Formula (V’), A is substituted or unsubstituted alkyl. In certain embodiments of the compound of Formula (V’), A is a molecular payload. In certain embodiments of the compound of Formula (V’), A is a therapeutic moiety or therapeutic compound. In certain embodiments of the compound of Formula (V’), A is a polynucleotide, a polypeptide, or a small molecule. In certain embodiments of the compound of Formula (V’), A is a double stranded nucleic acid. In certain embodiments of the compound of Formula (V’), A is an oligomer. In certain embodiments of the compound of Formula (V’), A is an expression-inhibiting oligomer. In certain embodiments of the compound of Formula (V’), A is a ribonucleic acid (RNA). In certain embodiments of the compound of Formula (V’), A is an RNAi agent. In certain embodiments of the compound of Formula (V’), A is a small interferingribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments of the compound of Formula (V’), A is a small interfering ribonucleic acid (siRNA). In certain embodiments of the compound of Formula (V’), A is an antisense oligonucleotide. In certain embodiments of the compound of Formula (V’), A is double stranded and bound to the oxygen labeled y at the 5’ end of its sense strand. In certain embodiments of the compound of Formula (V’), A is double stranded and bound to the oxygen labeled y at the 5’ end of its antisense strand. In certain embodiments of the compound of Formula (V’), A is double stranded and bound to the oxygen labeled y at the 3’ end of its sense strand. In certain embodiments of the compound of Formula (V’), A is double stranded and bound to the oxygen labeled y at the 3’ end of its antisense strand.

[0419] In certain embodiments of the compound of Formula (V’), R4is -OH. In certain embodiments of the compound of Formula (V’), R4is substituted alkoxy. In certain embodiments of the compound of Formula (V’), R4is alkoxy (e.g., C1-6alkoxy) substituted with -NH2or -N3. In certain embodiments of the compound of Formula (V’), R4is a molecular payload. In certain embodiments of the compound of Formula (V’), R4is a therapeutic moiety or therapeutic compound. In certain embodiments of the compound of Formula (V’), R4is a polynucleotide, a polypeptide, or a small molecule. In certain embodiments of the compound of Formula (V’), R4is a double stranded nucleic acid. In certain embodiments of the compound of Formula (V’), R4is an oligomer. In certain embodiments of the compound of Formula (V’), R4is an expression - inhibiting oligomer. In certain embodiments of the compound of Formula (V’), R4is a ribonucleic acid (RNA). In certain embodiments of the compound of Formula (V’), R4is an RNAi agent. In certain embodiments of the compound of Formula (V’), R4is a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments of the compound of Formula (V’), R4is a small interfering ribonucleic acid (siRNA). In certain embodiments of the compound of Formula (V’), R4is an antisense oligonucleotide. In certain embodiments of the compound of Formula (V’), R4is double stranded and bound to the phosphorous labeled z at the 5’ end of its sense strand. In certain embodiments of the compound of Formula (V’), R4is double stranded and bound to the phosphorous labeled z at the 5’ end of its antisense strand. In certain embodiments of the compound of Formula (V’), R4is double stranded and bound to the phosphorous labeled z at the 3’ end of its sense strand. In certain embodiments of the compound of Formula (V’), R4is double stranded and bound to the phosphorous labeled z at the 3’ end of its antisense strand.

[0420] In certain embodiments, the compound of Formula (V’) does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H).

[0421] In certain embodiments, the compound of Formula (V’) does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); and each P1is independently hydrogen or an oxygen protecting group.

[0422] In certain embodiments, the compound of Formula (V’) does not comprise a group of formula:or a salt thereof; wherein each P1is independently hydrogen or an oxygen protecting group.

[0423] In certain embodiments, the compound of Formula (V’) does not comprise a group of formula:or a salt thereof.

[0424] In certain embodiments of the compound of Formula (V’), when R1and R2are hydrogen, and R3is a group of formula then L is not

[0425] In certain embodiments of the compound of Formula (V’), when R1and R2are hydrogen, R3is a group of formula and L is then R10is aC1-5alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-.

[0426] In certain embodiments of the compound of Formula (V’), when R1and R2are hydrogen, and R3is a group of formula then L attaches to the 1’ position ofthe ribose by a non-oxygen atom (e.g., carbon, nitrogen).

[0427] In certain embodiments, the compound of Formula (V’) does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-9’), wherein X is - ORAor -SRA(e.g., where RAis H); and R2is hydrogen, fluoro, -OCH3, -OTBS, or - OCH2CH2OCH3.

[0428] In certain embodiments, the compound of Formula (V’) does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-10’), wherein X is -ORAor -SRA(e.g., where RAis H); R2is hydrogen, fluoro, -OCH3, -OTBS, -OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0429] In certain embodiments, the compound of Formula (V’) does not comprise a group of formula:or a salt thereof, wherein R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-11), wherein R2is hydrogen, fluoro, -OCH3, -OTBS, or-OCH2CH2OCH3.

[0430] In certain embodiments, the compound of Formula (V’) does not comprise a group of formula:or a salt thereof, wherein R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-12), wherein R2is hydrogen, fluoro, -OCH3, -OTBS, -OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0431] In certain embodiments, the compound of Formula (V’) does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); Y is -O-, -S-, -CH2-, - NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-13’), wherein X is -ORAor -SRA(e.g. where RAis H); Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, fluoro, -OCH3, -OTBS, or -OCH2CH2OCH3.

[0432] In certain embodiments, the compound of Formula (V’) does not comprise a group of formula:or a salt thereof, wherein X is -ORAor -SRA(e.g., where RAis H); Y is -O-, -S-, -CH2-, - NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-14’), wherein X is -ORAor -SRA(e.g., where RAis H); Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, fluoro, -OCH3, -OTBS, - OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0433] In certain embodiments, the compound of Formula (V’) does not comprise a group of formula:or a salt thereof, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA. In certain embodiments, the compound does not comprise a group of formula (P-15), wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; and R2is hydrogen, fluoro, -OCH3, -OTBS, or -OCH2CH2OCH3.

[0434] In certain embodiments, the compound of Formula (V’) does not comprise a group of formula:or a salt thereof, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; and each P1is independently hydrogen or an oxygen protecting group. In certain embodiments, the compound does not comprise a group of formula (P-16), wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-; R2is hydrogen, fluoro, -OCH3, - OTBS, -OCH2CH2OCH3; and each P1is independently hydrogen or an oxygen protecting group.

[0435] In certain embodiments of the compound of Formula (V’), when R3is a group of formula then L is not

[0436] In certain embodiments of the compound of Formula (V’), when R3is a group of formula then L is notwherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0437] In certain embodiments of the compound of Formula (V’), when R3is a group of formula then L attaches to the 1’ position of the ribose by a non-nitrogenatom (e.g., carbon, oxygen).

[0438] In certain embodiments of the compound of Formula (V’), when R1is hydrogen, R2is not a hydrogen, and R3is a group of formula then L attaches to the 1 ’position of the ribose by a non-nitrogen atom (e.g., carbon, oxygen).Compounds of Formula (VI) or (VI’)

[0439] In another aspect, provided are compounds of Formula (VI) or (VI’), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof:wherein:A is molecular payload, -OH, hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, orR4is hydrogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy,or a molecular payload; each X is independently -N(RA)2, -SRA, or -ORA; each P1is independently hydrogen or an oxygen protecting group;each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, -O-, -N(RA)-, -S-, -C(=O)-, - C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, -NRAC(=O)O-, - NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, -NRAS(O)2-, or a combination thereof; each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and n is 1-20; wherein: the compound has only one molecular payload; for Formula (VI), when n is greater than 1, with the exception of the phosphorous directly attached to the A, each instance of phosphorous labeled y is bound to the oxygen labeled z of the adjacent unit; for Formula (VI), when n is greater than 1, with the exception of the oxygen directly attached to R4, each instance of oxygen labeled z is bound to the phosphorous labeled y of the adjacent unit; for Formula (VI’), when n is greater than 1, with the exception of the oxygen directly attached to the A, each instance of oxygen labeled y is bound to the phosphorous labeled z of the adjacent unit; and for Formula (VI’), when n is greater than 1, with the exception of the phosphorous directly attached to R4, each instance of phosphorous labeled z is bound to the oxygen labeled y of the adjacent unit.

[0440] In certain embodiments, the compound is of Formula (VI-a) or (VI-a’):or a pharmaceutically acceptable salt thereof, wherein A, R4, R10, R20, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0441] In certain embodiments, the compound is of Formula (VI-a-1) or (VI-a-1’):or a pharmaceutically acceptable salt thereof, wherein A, R10, R20, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0442] In certain embodiments, the compound is of Formula (Vl-b) or (VI-b’):or a pharmaceutically acceptable salt thereof, wherein A, R4, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0443] In certain embodiments, the compound is of Formula (VI-b-1) or (VI-b-1’):or a pharmaceutically acceptable salt thereof, wherein A, R4, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0444] In certain embodiments, the compound is of Formula (VI-c) or (VI-c’):or a pharmaceutically acceptable salt thereof, wherein A, R4, P1and X are as defined herein.

[0445] In certain embodiments, the compound is of Formula (Vl-d) or (VI-d’):or a pharmaceutically acceptable salt thereof, wherein A, R4, and X are as defined herein.

[0446] In certain embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof, wherein A and R4are as defined herein.

[0447] In certain embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof.

[0448] In certain embodiments of the compound of Formula (VI) or (VI’), n is 1-6. In certain embodiments of the compound of Formula (VI) or (VI’), n is 1-3. In certain embodiments of the compound of Formula (VI) or (VI’), n is 2-3. In certain embodiments of the compound of Formula (VI) or (VI’) , n is 1-4. In certain embodiments of the compound of Formula (VI) or (VI’) , n is 2-4. In certain embodiments of the compound of Formula (VI) or (VI’), n is 3.

[0449] In certain embodiments of the compound of Formula (VI), A is -OH. In certain embodiments of the compound of Formula (VI’), A is(e.g., RAis H, and X is OH; or RAis H, and X is SH). In certain embodiments of the compound of Formula (VI’), A is hydrogen. In certain embodiments of the compound of Formula (VI’), A is substituted orunsubstituted alkyl. In certain embodiments of the compound of Formula (VI), A is substituted alkoxy. In certain embodiments of the compound of Formula (VI), A is alkoxy (e.g., C1-6alkoxy) substituted with -NH2or -N3. In certain embodiments of the compound of Formula (VI) or (VI’), A is a molecular payload. In certain embodiments of the compound of Formula (VI) or (VI’), A is a therapeutic moiety or therapeutic compound. In certain embodiments of the compound of Formula (VI) or (VI’), A is a polynucleotide, a polypeptide, or a small molecule. In certain embodiments of the compound of Formula (VI) or (VI’), A is a double stranded nucleic acid. In certain embodiments of the compound of Formula (VI) or (VI’), A is an oligomer. In certain embodiments of the compound of Formula (VI) or (VI’), A is an expression-inhibiting oligomer. In certain embodiments of the compound of Formula (VI) or (VI’), A is a ribonucleic acid (RNA). In certain embodiments of the compound of Formula (VI) or (VI’), A is an RNAi agent. In certain embodiments of the compound of Formula (VI) or (VI’), A is a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments of the compound of Formula (VI) or (VI’), A is a small interfering ribonucleic acid (siRNA). In certain embodiments of the compound of Formula (VI) or (VI’), A is an antisense oligonucleotide. In certain embodiments of the compound of Formula (VI) or (VI’), A is double stranded and bound to the phosphorous or oxygen labeled y at the 5’ end of its sense strand. In certain embodiments of the compound of Formula (VI) or (VI’), A is double stranded and bound to the phosphorous or oxygen labeled y at the 5’ end of its antisense strand. In certain embodiments of the compound of Formula (VI) or (VI’), A is double stranded and bound to the phosphorous or oxygen labeled y at the 3’ end of its sense strand. In certain embodiments of the compound of Formula (VI) or (VI’), A is double stranded and bound to the phosphorous or oxygen labeled y at the 3’ end of its antisense strand.

[0450] In certain embodiments of the compound of Formula (VI’), R4is -OH. In certain embodiments of the compound of Formula (VI), R4is (e.g., RAis substituted alkyland X is OH; or RAis substituted alkyl and X is SH). In certain embodiments of the compound of Formula (VI), R4is hydrogen. In certain embodiments of the compound of Formula (VI), R4is substituted or unsubstituted alkyl. In certain embodiments of the compound of Formula (VI’), R4is substituted alkoxy. In certain embodiments of the compound of Formula (VI’), R4is alkoxy (e.g., C1-6alkoxy) substituted with -NH2or -N3. In certain embodiments of the compound of Formula (VI) or (VI’), R4is a molecular payload. In certain embodiments of the compound of Formula (VI) or (VI’), R4is a therapeutic moiety or therapeutic compound. In certain embodiments of the compound of Formula (VI) or (VI’), R4is a polynucleotide, a polypeptide, or a small molecule. In certain embodiments of the compound of Formula (VI) or (VI’), R4is adouble stranded nucleic acid. In certain embodiments of the compound of Formula (VI) or (VI’), R4is an oligomer. In certain embodiments of the compound of Formula (VI) or (VI’), R4is an expression-inhibiting oligomer. In certain embodiments of the compound of Formula (VI) or (VI’), R4is a ribonucleic acid (RNA). In certain embodiments of the compound of Formula (VI) or (VI’), R4is an RNAi agent. In certain embodiments of the compound of Formula (VI) or (VI’), R4is a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments of the compound of Formula (VI) or (VI’), R4is a small interfering ribonucleic acid (siRNA). In certain embodiments of the compound of Formula (VI) or (VI’), R4is an antisense oligonucleotide. In certain embodiments of the compound of Formula (VI) or (VI’), R4is double stranded and bound to the phosphorous or oxygen labeled z at the 5’ end of its sense strand. In certain embodiments of the compound of Formula (VI) or (VI’), R4is double stranded and bound to the phosphorous or oxygen labeled z at the 5’ end of its antisense strand. In certain embodiments of the compound of Formula (VI) or (VI’), R4is double stranded and bound to the phosphorous or oxygen labeled z at the 3’ end of its sense strand. In certain embodiments of the compound of Formula (VI) or (VI’), R4is double stranded and bound to the phosphorous or oxygen labeled z at the 3’ end of its antisense strand.

[0451] In certain embodiments, the compound of Formula (VI) or (VI’) does not comprise a group of formula:or a salt thereof, wherein X is -SRAor -ORA(e.g., -SH or -OH); and Y is -O-, -S-, -CH2-, - NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0452] In certain embodiments, the compound of Formula (VI) or (VI’) does not comprise a group of formula:or a salt thereof, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0453] In certain embodiments, the compound of Formula (VI) or (VI’) does not comprise a group of formula:or a salt thereof, wherein X is -SRAor -ORA(e.g., -SH or -OH); each P1is independently hydrogen or an oxygen protecting group (e.g., benzoyl); and Y is -O-, -S-, -CH2-, -NH(C=O)-, - (C=O)NH-, or -NH(C=O)O-.

[0454] In certain embodiments, the compound of Formula (VI) or (VI’) does not comprise a group of formula:or a salt thereof, wherein; each P1is independently hydrogen or an oxygen protecting group (e.g., benzoyl); and Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0455] In certain embodiments of the compound of Formula (VI) or (VI’), L is not, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0456] In certain embodiments of the compound of Formula (VI) or (VI’), when L isthen R10is a C1-5alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-. In certain embodiments, R10is a C1-3alkylene. In certain embodiments, R10is ethylene.Compounds of Formula (VI)

[0457] In another aspect, provided are compounds of Formula (VI), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof:wherein:A is molecular payload, -OH, or substituted or unsubstituted alkoxy;R4is hydrogen, substituted or unsubstituted alkyl, or a molecular payload;each X is independently -N(RA)2, -SRA, or -ORA; each P1is independently hydrogen or an oxygen protecting group; each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, -O-, -N(RA)-, -S-, -C(=O)-, - C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, -NRAC(=O)O-, - NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, -NRAS(O)2-, or a combination thereof; each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and n is 1-20; wherein: the compound has only one molecular payload; when n is greater than 1, with the exception of the phosphorous directly attached to the A, each instance of phosphorous labeled y is bound to the oxygen labeled z of the adjacent unit; and when n is greater than 1, with the exception of the oxygen directly attached to R4, each instance of oxygen labeled z is bound to the phosphorous labeled y of the adjacent unit.

[0458] In certain embodiments, the compound of Formula (VI) is of Formula (Vl-a):or a pharmaceutically acceptable salt thereof, wherein A, R4, R10, R20, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0459] In certain embodiments, the compound of Formula (VI) is of Formula (VI-a-1):or a pharmaceutically acceptable salt thereof, wherein A, R10, R20, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0460] In certain embodiments, the compound of Formula (VI) is of Formula (Vl-b):or a pharmaceutically acceptable salt thereof, wherein A, R4, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0461] In certain embodiments, the compound of Formula (VI) is of Formula (VI-b-1):or a pharmaceutically acceptable salt thereof, wherein A, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0462] In certain embodiments, the compound of Formula (VI) is of Formula (VI-c):or a pharmaceutically acceptable salt thereof, wherein A, P1and X are as defined herein.

[0463] In certain embodiments, the compound of Formula (VI) is of Formula (Vl-d):or a pharmaceutically acceptable salt thereof, wherein A and X are as defined herein.

[0464] In certain embodiments, the compound of Formula (VI) is of formula:or a pharmaceutically acceptable salt thereof, wherein A is as defined herein.

[0465] In certain embodiments, the compound of Formula (VI) is of formula:or a pharmaceutically acceptable salt thereof, wherein R4and X are as defined herein.

[0466] In certain embodiments of the compound of Formula (VI), n is 1-6. In certain embodiments of the compound of Formula (VI), n is 1-3. In certain embodiments of the compound of Formula (VI), n is 2-3. In certain embodiments of the compound of Formula (VI), n is 1-4. In certain embodiments of the compound of Formula (VI), n is 2-4. In certain embodiments of the compound of Formula (VI), n is 3.

[0467] In certain embodiments of the compound of Formula (VI), A is -OH. In certain embodiments of the compound of Formula (VI), A is substituted alkoxy. In certain embodiments of the compound of Formula (VI), A is alkoxy (e.g., C1-6alkoxy) substituted with -NH2or -N3. In certain embodiments of the compound of Formula (VI), A is a molecular payload. In certain embodiments of the compound of Formula (VI), A is a therapeutic moiety or therapeutic compound. In certain embodiments of the compound of Formula (VI), A is a polynucleotide, a polypeptide, or a small molecule. In certain embodiments of the compound of Formula (VI), A is a double stranded nucleic acid. In certain embodiments of the compound of Formula (VI), A is an oligomer. In certain embodiments of the compound of Formula (VI), A is an expression- inhibiting oligomer. In certain embodiments of the compound of Formula (VI), A is a ribonucleic acid (RNA). In certain embodiments of the compound of Formula (VI), A is an RNAi agent. In certain embodiments of the compound of Formula (VI), A is a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments of the compound of Formula(VI), A is a small interfering ribonucleic acid (siRNA). In certain embodiments of the compound of Formula (VI), A is an antisense oligonucleotide. In certain embodiments of the compound of Formula (VI), A is double stranded and bound to the phosphorous labeled y at the 5’ end of its sense strand. In certain embodiments of the compound of Formula (VI), A is double stranded and bound to the oxygen labeled y at the 5’ end of its antisense strand. In certain embodiments of the compound of Formula (VI), A is double stranded and bound to the phosphorous labeled y at the 3’ end of its sense strand. In certain embodiments of the compound of Formula (VI), A is double stranded and bound to the phosphorous labeled y at the 3’ end of its antisense strand.

[0468] In certain embodiments of the compound of Formula (VI), R4is (e.g., RAissubstituted alkyl and X is OH; or RAis substituted alkyl and X is SH). In certain embodiments of the compound of Formula (VI), R4is hydrogen. In certain embodiments of the compound of Formula (VI), R4is substituted or unsubstituted alkyl. In certain embodiments of the compound of Formula (VI), R4is a molecular pay load. In certain embodiments of the compound of Formula (VI), R4is a therapeutic moiety or therapeutic compound. In certain embodiments of the compound of Formula (VI), R4is a polynucleotide, a polypeptide, or a small molecule. In certain embodiments of the compound of Formula (VI), R4is a double stranded nucleic acid. In certain embodiments of the compound of Formula (VI), R4is an oligomer. In certain embodiments of the compound of Formula (VI), R4is an expression-inhibiting oligomer. In certain embodiments of the compound of Formula (VI), R4is a ribonucleic acid (RNA). In certain embodiments of the compound of Formula (VI), R4is an RNAi agent. In certain embodiments of the compound of Formula (VI), R4is a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments of the compound of Formula (VI), R4is a small interfering ribonucleic acid (siRNA). In certain embodiments of the compound of Formula (VI), R4is an antisense oligonucleotide. In certain embodiments of the compound of Formula (VI), R4is double stranded and bound to the oxygen labeled z at the 5’ end of its sense strand. In certain embodiments of the compound of Formula (VI), R4is double stranded and bound to the oxygen labeled z at the 5’ end of its antisense strand. In certain embodiments of the compound of Formula (VI), R4is double stranded and bound to the oxygen labeled z at the 3’ end of its sense strand. In certain embodiments of the compound of Formula (VI), R4is double stranded and bound to the oxygen labeled z at the 3’ end of its antisense strand.

[0469] In certain embodiments, the compound of Formula (VI) does not comprise a group of formula:or a salt thereof, wherein X is -SRAor -ORA(e.g., -SH or -OH); and Y is -O-, -S-, -CH2-, - NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0470] In certain embodiments, the compound of Formula (VI) does not comprise a group of formula:or a salt thereof, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0471] In certain embodiments, the compound of Formula (VI) does not comprise a group of formula:or a salt thereof, wherein X is -SRAor -ORA(e.g., -SH or -OH); each P1is independently hydrogen or an oxygen protecting group (e.g., benzoyl); and Y is -O-, -S-, -CH2-, -NH(C=O)-, - (C=O)NH-, or -NH(C=O)O-.

[0472] In certain embodiments, the compound of Formula (VI) does not comprise a group of formula:or a salt thereof, wherein; each P1is independently hydrogen or an oxygen protecting group (e.g., benzoyl); and Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0473] In certain embodiments of the compound of Formula (VI), L is not wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0474] In certain embodiments of the compound of Formula (VI), when L isthen R10is a C1-5alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-. In certain embodiments, R10is a C1-3alkylene. In certain embodiments, R10is ethylene.Compounds of Formula (VI’)

[0475] In another aspect, provided are compounds of Formula (VI’), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof: wherein:A is molecular payload, hydrogen, substituted or unsubstituted alkyl, orR4is -OH, substituted or unsubstituted alkoxy, or a molecular payload; each X is independently -N(RA)2, -SRA, or -ORA; each P1is independently hydrogen or an oxygen protecting group; each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, -O-, -N(RA)-, -S-, -C(=O)-, - C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, -NRAC(=O)O-, - NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, -NRAS(O)2-, or a combination thereof; each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and n is 1-20; wherein: the compound has only one molecular payload; when n is greater than 1, with the exception of the oxygen directly attached to the A, each instance of oxygen labeled y is bound to the phosphorous labeled z of the adjacent unit; and when n is greater than 1, with the exception of the phosphorous directly attached to R4, each instance of phosphorous labeled z is bound to the oxygen labeled y of the adjacent unit.

[0476] In certain embodiments, the compound is of Formula (VI-a’):or a pharmaceutically acceptable salt thereof, wherein A, R4, R10, R20, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0477] In certain embodiments, the compound is of Formula (VI-a-1’):or a pharmaceutically acceptable salt thereof, wherein R4, R10, R20, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0478] In certain embodiments, the compound is of Formula (VI-b’):or a pharmaceutically acceptable salt thereof, wherein A, R4, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0479] In certain embodiments, the compound is of Formula (VI-b-1’):or a pharmaceutically acceptable salt thereof, wherein R4, R10, RA, P1, n, and X are as defined herein (e.g., wherein R10is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-).

[0480] In certain embodiments, the compound is of Formula (VI-c’):or a pharmaceutically acceptable salt thereof, wherein R4, P1and X are as defined herein.

[0481] In certain embodiments, the compound is of Formula (VI-d’):or a pharmaceutically acceptable salt thereof, wherein R4and X are as defined herein.

[0482] In certain embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof, wherein R4is as defined herein.

[0483] In certain embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof, wherein A and X are as defined herein.

[0484] In certain embodiments of the compound of Formula (VI’), n is 1-6. In certain embodiments of the compound of Formula (VI’), n is 1-3. In certain embodiments of the compound of Formula (VI’), n is 2-3. In certain embodiments of the compound of Formula (VI’), n is 1-4. In certain embodiments of the compound of Formula (VI’), n is 2-4. In certain embodiments of the compound of Formula (VI’), n is 3.

[0485] In certain embodiments of the compound of Formula (VI’), A is(e.g., RAis H, and X is OH; or RAis H, and X is SH). In certain embodiments of the compound of Formula (VI’), A is hydrogen. In certain embodiments of the compound of Formula (VI’), A is substituted or unsubstituted alkyl. In certain embodiments of the compound of Formula (VI’), A is a molecular payload. In certain embodiments of the compound of Formula (VI’), A is a therapeutic moiety or therapeutic compound. In certain embodiments of the compound of Formula (VI’), A is a polynucleotide, a polypeptide, or a small molecule. In certain embodiments of the compound of Formula (VI’), A is a double stranded nucleic acid. In certain embodiments of the compound of Formula (VI’), A is an oligomer. In certain embodiments of the compound of Formula (VI’), A is an expression-inhibiting oligomer. In certain embodiments of the compound of Formula (VI’), A is a ribonucleic acid (RNA). In certain embodiments of the compound of Formula (VI’), A is an RNAi agent. In certain embodiments of the compound of Formula (VI’), A is a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments of the compound of Formula (VI’), A is a small interfering ribonucleic acid (siRNA). In certain embodiments of the compound of Formula (VI’), A is an antisense oligonucleotide. In certain embodiments of the compound of Formula (VI’), A is double stranded and bound to the oxygen labeled y at the 5’ end of its sense strand. In certain embodiments of the compound of Formula (VI’), A is double stranded and bound to the oxygen labeled y at the 5’ end of its antisense strand. In certain embodiments of the compound of Formula (VI’), A is double stranded and bound to the oxygen labeled y at the 3’ end of its sense strand. In certain embodiments of the compound of Formula (VI’), A is double stranded and bound to the oxygen labeled y at the 3’ end of its antisense strand.

[0486] In certain embodiments of the compound of Formula (VI’), R4is -OH. In certain embodiments of the compound of Formula (VI’), R4is substituted alkoxy. In certain embodiments of the compound of Formula (VI’), R4is alkoxy (e.g., C1-6alkoxy) substituted with -NH2or -N3. In certain embodiments of the compound of Formula (VI’), R4is a molecular payload. In certain embodiments of the compound of Formula (VI’), R4is a therapeutic moiety or therapeutic compound. In certain embodiments of the compound of Formula (VI’), R4is a polynucleotide, a polypeptide, or a small molecule. In certain embodiments of the compound ofFormula (VI’), R4is a double stranded nucleic acid. In certain embodiments of the compound of Formula (VI’), R4is an oligomer. In certain embodiments of the compound of Formula (VI’), R4is an expression-inhibiting oligomer. In certain embodiments of the compound of Formula (VI’), R4is a ribonucleic acid (RNA). In certain embodiments of the compound of Formula (VI’), R4is an RNAi agent. In certain embodiments of the compound of Formula (VI’), R4is a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments of the compound of Formula (VI’), R4is a small interfering ribonucleic acid (siRNA). In certain embodiments of the compound of Formula (VI’), R4is an antisense oligonucleotide. In certain embodiments of the compound of Formula (VI’), R4is double stranded and bound to the phosphorous labeled z at the 5’ end of its sense strand. In certain embodiments of the compound of Formula (VI’), R4is double stranded and bound to the phosphorous labeled z at the 5’ end of its antisense strand. In certain embodiments of the compound of Formula (VI’), R4is double stranded and bound to the phosphorous labeled z at the 3’ end of its sense strand. In certain embodiments of the compound of Formula (VI’), R4is double stranded and bound to the phosphorous labeled z at the 3’ end of its antisense strand.

[0487] In certain embodiments, the compound of Formula (VI’) does not comprise a group of formula:or a salt thereof, wherein X is -SRAor -ORA(e.g., -SH or -OH); and Y is -O-, -S-, -CH2-, - NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0488] In certain embodiments, the compound of Formula (VI’) does not comprise a group of formula:or a salt thereof, wherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0489] In certain embodiments, the compound of Formula (VI’) does not comprise a group of formula:or a salt thereof, wherein X is -SRAor -ORA(e.g., -SH or -OH); each P1is independently hydrogen or an oxygen protecting group (e.g., benzoyl); and Y is -O-, -S-, -CH2-, -NH(C=O)-, - (C=O)NH-, or -NH(C=O)O-.

[0490] In certain embodiments, the compound of Formula (VI’) does not comprise a group of formula:or a salt thereof, wherein; each P1is independently hydrogen or an oxygen protecting group (e.g., benzoyl); and Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0491] In certain embodiments of the compound of Formula (VI’), L is notwherein Y is -O-, -S-, -CH2-, -NH(C=O)-, -(C=O)NH-, or -NH(C=O)O-.

[0492] In certain embodiments of the compound of Formula (VI’), when L is, then R10is a C1-5alkylene having 0-3 carbon atoms replaced with -O-; and R20is substituted or unsubstituted C1-8alkylene having 0-3 carbon atoms replaced with -O-. In certain embodiments, R10is a C1-3alkylene. In certain embodiments, R10is ethylene.Compounds of Formula (VII) or (VII’)

[0493] In another aspect, provided are compounds of Formula (VII) or (VII’), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositionswherein:A is a molecular payload, -OH, hydrogen, substituted or unsubstituted alkoxy, substitutedor unsubstituted alkyl,R4is hydrogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, or a molecular payload;each X is independently -N(RA)2, -SRA, or -ORA; each P1is independently hydrogen or an oxygen protecting group; each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; and n is 1-20; wherein: the compound has only one molecular payload; for Formula (VII), when n is greater than 1, with the exception of the phosphorous directly attached to the A, each instance of phosphorous labeled y is bound to the oxygen labeled z of the adjacent unit; for Formula (VII), when n is greater than 1, with the exception of the oxygen directly attached to R4, each instance of oxygen labeled z is bound to the phosphorous labeled y of the adjacent unit for Formula (VII’), when n is greater than 1, with the exception of the oxygen directly attached to the A, each instance of oxygen labeled y is bound to the phosphorous labeled z of the adjacent unit; and for Formula (VII’), when n is greater than 1, with the exception of the phosphorous directly attached to R4, each instance of phosphorous labeled z is bound to the oxygen labeled y of the adjacent unit.

[0494] In certain embodiments, the compound is of formula (VH-a) or (VII-a’):or a pharmaceutically acceptable salt thereof, wherein A, R4, and X are as defined herein.

[0495] In certain embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof, wherein A and R4are as defined herein.

[0496] In certain embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof, wherein A, X, and R4are as defined herein.

[0497] In certain embodiments of the compound of Formula (VII) or (VII’), n is 1-6. In certain embodiments of the compound of Formula (VII) or (VII’), n is 1-3. In certain embodiments of the compound of Formula (VII) or (VII’), n is 2-3. In certain embodiments of the compound of Formula (VII) or (VII’), n is 1-4. In certain embodiments of the compound of Formula (VII) or (VII’), n is 2-4. In certain embodiments of the compound of Formula (VII) or (VII’), n is 3.

[0498] In certain embodiments of the compound of Formula (VII), A is -OH. In certain embodiments of the compound of Formula (VII ’), A is(e.g., RAis H, and X is OH; orRAis H, and X is SH). In certain embodiments of the compound of Formula (VII’), A is hydrogen. In certain embodiments of the compound of Formula (VII’), A is substituted or unsubstituted alkyl. In certain embodiments of the compound of Formula (VII), A is substituted alkoxy. In certain embodiments of the compound of Formula (VII), A is alkoxy (e.g., C1-6alkoxy) substituted with -NH2or -N3. In certain embodiments of the compound of Formula (VII) or (VII’), A is a molecular pay load. In certain embodiments of the compound of Formula (VII) or (VII’), A is a therapeutic moiety or therapeutic compound. In certain embodiments of the compound of Formula (VII) or (VII’), A is a polynucleotide, a polypeptide, or a small molecule. In certain embodiments of the compound of Formula (VII) or (VII’), A is a double stranded nucleic acid. In certain embodiments of the compound of Formula (VII) or (VII’), A is an oligomer. In certain embodiments of the compound of Formula (VII) or (VII’), A is an expression-inhibiting oligomer. In certain embodiments of the compound of Formula (VII) or(VII’), A is a ribonucleic acid (RNA). In certain embodiments of the compound of Formula (VII) or (VII’), A is an RNAi agent. In certain embodiments of the compound of Formula (VII) or (VII’), A is a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments of the compound of Formula (VII) or (VII’), A is a small interfering ribonucleic acid (siRNA). In certain embodiments of the compound of Formula (VII) or (VII’), A is an antisense oligonucleotide. In certain embodiments of the compound of Formula (VII) or (VII’), A is double stranded and bound to the phosphorous or oxygen labeled y at the 5’ end of its sense strand. In certain embodiments of the compound of Formula (VII) or (VII’), A is double stranded and bound to the phosphorous or oxygen labeled y at the 5’ end of its antisense strand. In certain embodiments of the compound of Formula (VII) or (VII’), A is double stranded and bound to the phosphorous or oxygen labeled y at the 3’ end of its sense strand. In certain embodiments of the compound of Formula (VII) or (VII’), A is double stranded and bound to the phosphorous or oxygen labeled y at the 3’ end of its antisense strand.

[0499] In certain embodiments of the compound of Formula (VII’), R4is -OH. In certain embodiments of the compound of Formula (VII), R4is(e.g., RAis substituted alkyl and X is OH; or RAis substituted alkyl and X is SH). In certain embodiments of the compound of Formula (VII), R4is hydrogen. In certain embodiments of the compound of Formula (VII), R4is substituted or unsubstituted alkyl. In certain embodiments of the compound of Formula (VII’), R4is substituted alkoxy. In certain embodiments of the compound of Formula (VII’), R4is alkoxy (e.g., C1-6alkoxy) substituted with -NH2or -N3. In certain embodiments of the compound of Formula (VII) or (VII’), R4is a molecular payload. In certain embodiments of the compound of Formula (VII) or (VII’), R4is a therapeutic moiety or therapeutic compound. In certain embodiments of the compound of Formula (VII) or (VII’), R4is a polynucleotide, a polypeptide, or a small molecule. In certain embodiments of the compound of Formula (VII) or (VII’), R4is a double stranded nucleic acid. In certain embodiments of the compound of Formula (VII) or (VII’), R4is an oligomer. In certain embodiments of the compound of Formula (VII) or (VII’), R4is an expression-inhibiting oligomer. In certain embodiments of the compound of Formula (VII) or (VII’), R4is a ribonucleic acid (RNA). In certain embodiments of the compound of Formula (VII) or (VII’), R4is an RNAi agent. In certain embodiments of the compound of Formula (VII) or (VII’), R4is a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments of the compound of Formula (VII) or (VII’), R4is a small interfering ribonucleic acid (siRNA). In certain embodiments of the compound of Formula (VII) or (VII’), R4is an antisense oligonucleotide. In certain embodiments of the compound of Formula (VII) or (VII’), R4is double stranded and bound to the phosphorous or oxygen labeled zat the 5’ end of its sense strand. In certain embodiments of the compound of Formula (VII) or (VII’), R4is double stranded and bound to the phosphorous or oxygen labeled z at the 5’ end of its antisense strand. In certain embodiments of the compound of Formula (VII) or (VII’), R4is double stranded and bound to the phosphorous or oxygen labeled z at the 3’ end of its sense strand. In certain embodiments of the compound of Formula (VII) or (VII’), R4is double stranded and bound to the phosphorous or oxygen labeled z at the 3’ end of its antisense strand.Compounds of Formula (VII)

[0500] In another aspect, provided are compounds of Formula (VII), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof:wherein:A is a molecular payload, -OH, or substituted or unsubstituted alkoxy;R4is hydrogen, substituted or unsubstituted alkyl,, or a molecular payload; each X is independently -N(RA)2, -SRA, or -ORA; each P1is independently hydrogen or an oxygen protecting group; each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; and n is 1-20; wherein: the compound has only one molecular payload; when n is greater than 1, with the exception of the phosphorous directly attached to the A, each instance of phosphorous labeled y is bound to the oxygen labeled z of the adjacent unit; andwhen n is greater than 1, with the exception of the oxygen directly attached to R4, each instance of oxygen labeled z is bound to the phosphorous labeled y of the adjacent unit.

[0501] In certain embodiments, the compound of Formula (VII) is of formula (VII-a):or a pharmaceutically acceptable salt thereof, wherein A and X are as defined herein.

[0502] In certain embodiments, Formula (VII) is of formula:or a pharmaceutically acceptable salt thereof, wherein A is as defined herein.

[0503] In certain embodiments, Formula (VII) is of formula:or a pharmaceutically acceptable salt thereof, wherein R4and X are as defined herein.

[0504] In certain embodiments of the compound of Formula (VII), n is 1-6. In certain embodiments of the compound of Formula (VII), n is 1-3. In certain embodiments of the compound of Formula (VII), n is 2-3. In certain embodiments of the compound of Formula (VII), n is 1-4. In certain embodiments of the compound of Formula (VII), n is 2-4. In certain embodiments of the compound of Formula (VII), n is 3.

[0505] In certain embodiments of the compound of Formula (VII), A is -OH. In certain embodiments of the compound of Formula (VII), A is substituted alkoxy. In certain embodiments of the compound of Formula (VII), A is alkoxy (e.g., C1-6alkoxy) substituted with -NH2or -N3. In certain embodiments of the compound of Formula (VII), A is a molecular payload. In certain embodiments of the compound of Formula (VII), A is a therapeutic moiety or therapeutic compound. In certain embodiments of the compound of Formula (VII), A is a polynucleotide, a polypeptide, or a small molecule. In certain embodiments of the compound of Formula (VII), A is a double stranded nucleic acid. In certain embodiments of the compound of Formula (VII), A is an oligomer. In certain embodiments of the compound of Formula (VII), A is an expression-inhibiting oligomer. In certain embodiments of the compound of Formula (VII), A is a ribonucleic acid (RNA). In certain embodiments of the compound of Formula (VII), A is an RNAi agent. In certain embodiments of the compound of Formula (VII), A is a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments ofthe compound of Formula (VII), A is a small interfering ribonucleic acid (siRNA). In certain embodiments of the compound of Formula (VII), A is an antisense oligonucleotide. In certain embodiments of the compound of Formula (VII), A is double stranded and bound to the phosphorous labeled y at the 5’ end of its sense strand. In certain embodiments of the compound of Formula (VII), A is double stranded and bound to the phosphorous labeled y at the 5’ end of its antisense strand. In certain embodiments of the compound of Formula (VII), A is double stranded and bound to the phosphorous labeled y at the 3’ end of its sense strand. In certain embodiments of the compound of Formula (VII), A is double stranded and bound to the phosphorous labeled y at the 3’ end of its antisense strand.

[0506] In certain embodiments of the compound of Formula (VII), R4is(e.g., RAis substituted alkyl and X is OH; or RAis substituted alkyl and X is SH). In certain embodiments of the compound of Formula (VII), R4is hydrogen. In certain embodiments of the compound of Formula (VII), R4is substituted or unsubstituted alkyl. In certain embodiments of the compound of Formula (VII), R4is a molecular payload. In certain embodiments of the compound of Formula (VII), R4is a therapeutic moiety or therapeutic compound. In certain embodiments of the compound of Formula (VII), R4is a polynucleotide, a polypeptide, or a small molecule. In certain embodiments of the compound of Formula (VII), R4is a double stranded nucleic acid. In certain embodiments of the compound of Formula (VII), R4is an oligomer. In certain embodiments of the compound of Formula (VII), R4is an expression-inhibiting oligomer. In certain embodiments of the compound of Formula (VII), R4is a ribonucleic acid (RNA). In certain embodiments of the compound of Formula (VII), R4is an RNAi agent. In certain embodiments of the compound of Formula (VII), R4is a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments of the compound of Formula (VII), R4is a small interfering ribonucleic acid (siRNA). In certain embodiments of the compound of Formula (VII), R4is an antisense oligonucleotide. In certain embodiments of the compound of Formula (VII), R4is double stranded and bound to the oxygen labeled z at the 5’ end of its sense strand. In certain embodiments of the compound of Formula (VII), R4is double stranded and bound to the oxygen labeled z at the 5’ end of its antisense strand. In certain embodiments of the compound of Formula (VII), R4is double stranded and bound to the oxygen labeled z at the 3’ end of its sense strand. In certain embodiments of the compound of Formula (VII), R4is double stranded and bound to the oxygen labeled z at the 3’ end of its antisense strand.Compounds of Formula (VII’)

[0507] In another aspect, provided are compounds of Formula (VII’), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof:wherein:A is a molecular payload, hydrogen, substituted or unsubstituted alkyl, orR4is -OH, substituted or unsubstituted alkoxy, or a molecular payload; each X is independently -N(RA)2, -SRA, or -ORA; each P1is independently hydrogen or an oxygen protecting group; each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; and n is 1-20; wherein: the compound has only one molecular payload; when n is greater than 1, with the exception of the oxygen directly attached to the A, each instance of oxygen labeled y is bound to the phosphorous labeled z of the adjacent unit; and when n is greater than 1, with the exception of the phosphorous directly attached to R4, each instance of phosphorous labeled z is bound to the oxygen labeled y of the adjacent unit.

[0508] In certain embodiments, the compound is of formula (VII-a’):or a pharmaceutically acceptable salt thereof, wherein R4, and X are as defined herein.

[0509] In certain embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof, wherein R4is as defined herein.

[0510] In certain embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof, wherein A and X are as defined herein.

[0511] In certain embodiments of the compound of Formula (VII’), n is 1-6. In certain embodiments of the compound of Formula (VII’), n is 1-3. In certain embodiments of the compound of Formula (VII’), n is 2-3. In certain embodiments of the compound of Formula (VII’), n is 1-4. In certain embodiments of the compound of Formula (VII’), n is 2-4. In certain embodiments of the compound of Formula (VII’), n is 3.

[0512] In certain embodiments of the compound of Formula (VII’), A is(e.g., RAis H, and X is OH; or RAis H, and X is SH). In certain embodiments of the compound of Formula (VII’), A is hydrogen. In certain embodiments of the compound of Formula (VII’), A is substituted or unsubstituted alkyl. In certain embodiments of the compound of Formula (VII’), A is a molecular payload. In certain embodiments of the compound of Formula (VII’), A is a therapeutic moiety or therapeutic compound. In certain embodiments of the compound of Formula (VII’), A is a polynucleotide, a polypeptide, or a small molecule. In certain embodiments of the compound of Formula (VII’), A is a double stranded nucleic acid. In certain embodiments of the compound of Formula (VII’), A is an oligomer. In certain embodiments of the compound of Formula (VII’), A is an expression-inhibiting oligomer. In certain embodiments of the compound of Formula (VII’), A is a ribonucleic acid (RNA). In certain embodiments of the compound of Formula (VII’), A is an RNAi agent. In certain embodiments of the compound of Formula (VII’), A is a small interfering ribonucleic acid (siRNA) or an antisense oligonucleotide. In certain embodiments of the compound of Formula (VII’), A is a small interfering ribonucleic acid (siRNA). In certain embodiments of the compound of Formula (VII’), A is an antisense oligonucleotide. In certain embodiments of the compound of Formula (VII’), A is double stranded and bound to the oxygen labeled y at the 5’ end of its sense strand. In certain embodiments of the compound of Formula (VII’), A is double stranded and bound to the oxygen labeled y at the 5...

Claims

CLAIMSWhat is claimed is:

1. A compound, or a pharmaceutically acceptable salt thereof, comprising at least one group of Formula (I) or (I’):wherein: each X is independently -N(RA)2, -SRA, or -ORA; each R1is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, -ORA, or a group of formula:each R2is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, -ORA, or a group of formula:each R3is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, -ORA, or a group of formula:each P1is independently hydrogen or an oxygen protecting group; each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, -O-, -N(RA)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, - NRAC(=O)O-, -NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, - NRAS(O)2-, or a combination thereof; andeach RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; provided that Formula (I) or (I’) has only one instance of formula:and provided that the compound does not comprise a group of formula:

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, comprising at least one group of formula:

3. A compound, or a pharmaceutically acceptable salt thereof, comprising at least one group of formula (II) or (II’):wherein: each X is independently -N(RA)2, -SRA, or -ORA; each P1is independently hydrogen or an oxygen protecting group; each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, -O-, -N(RA)-, -S-, -C(=O)-, - C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, -NRAC(=O)O-, - NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, -NRAS(O)2-, or a combination thereof; and each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 sulfuratom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, comprising at least one group of formula:

5. A compound, or a pharmaceutically acceptable salt thereof, comprising at least one group of Formula (III) or (III’):wherein: each X is independently -N(RA)2, -SRA, or -ORA; each P1is independently hydrogen or an oxygen protecting group; and each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, comprising at least one group of formula:

7. A compound, or a pharmaceutically acceptable salt thereof, comprising at least one group of Formula (IV) or (IV’):wherein: each X is independently -N(RA)2, -SRA, or -ORA; each R1is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; each R2is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; each R3is independently of formula:each P1is independently hydrogen or an oxygen protecting group; each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, -O-, -N(RA)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, - NRAC(=O)O-, -NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, - NRAS(O)2-, or a combination thereof; and each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, comprising at least one group of formula:

9. A compound of Formula (V) or (V’):or a pharmaceutically acceptable salt thereof; wherein:A is a molecular payload, -OH, substituted or unsubstituted alkoxy, hydrogen, substituted or unsubstituted alkyeach X is independently -N(RA)2, -SRA, or -ORA;each R1is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, -ORA, or a group of formula:each R2is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, -ORA, or a group of formula:each R3is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, -ORA, or a group of formula:R4is hydrogen, substituted or unsubstituted alkyl,-OH, substituted or unsubstituted alkoxy, or a molecular payload; each P1is independently hydrogen or an oxygen protecting group; each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl,, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, - O-, -N(RA)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, - NRAC(=O)O-, -NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, - NRAS(O)2-, or a combination thereof; each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and n is 1-20; wherein: the compound has only one molecular payload;for Formula (V), when n is greater than 1, with the exception of the phosphorous directly attached to the A, each instance of phosphorous labeled y is bound to the oxygen labeled z of the adjacent unit; for Formula (V), when n is greater than 1, with the exception of the oxygen directly attached to R4, each instance of oxygen labeled z is bound to the phosphorous labeled y of the adjacent unit; for Formula (V’), when n is greater than 1, with the exception of the oxygen directly attached to the A, each instance of oxygen labeled y is bound to the phosphorous labeled z of the adjacent unit; for Formula (V’), when n is greater than 1, with the exception of the phosphorous directly attached to R4, each instance of phosphorous labeled z is bound to the oxygen labeled y of the adjacent unit; and each repeat unit in the compound of Formula (V) or (V’) has only one instance of10. The compound of claim 9, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

11. A compound of Formula (VI) or (VI’):or a pharmaceutically acceptable salt thereof; wherein:A is a molecular payload, -OH, hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, orR4is hydrogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy,or a molecular payload;each X is independently -N(RA)2, -SRA, or -ORA; each P1is independently hydrogen or an oxygen protecting group; each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, -O-, -N(RA)-, -S-, -C(=O)-, - C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, -NRAC(=O)O-, - NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, -NRAS(O)2-, or a combination thereof; each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and n is 1-20; wherein: the compound has only one molecular payload; for Formula (VI), when n is greater than 1, with the exception of the phosphorous directly attached to the A, each instance of phosphorous labeled y is bound to the oxygen labeled z of the adjacent unit; for Formula (VI), when n is greater than 1, with the exception of the oxygen directly attached to R4, each instance of oxygen labeled z is bound to the phosphorous labeled y of the adjacent unit; for Formula (VI’), when n is greater than 1, with the exception of the oxygen directly attached to the A, each instance of oxygen labeled y is bound to the phosphorous labeled z of the adjacent unit; and for Formula (VI’), when n is greater than 1, with the exception of the phosphorous directly attached to R4, each instance of phosphorous labeled z is bound to the oxygen labeled y of the adjacent unit.

12. The compound of claim 11, wherein the compound of Formula (VI) is of Formula (VI-d) or (VI-d’):or a pharmaceutically acceptable salt thereof.

13. A compound of Formula (VII) or (VII’):or a pharmaceutically acceptable salt thereof, wherein:A is a molecular payload, -OH, hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, orR4is hydrogen, substituted or unsubstituted alkyl, -OH, substituted or unsubstituted alkoxy, or a molecular payload;each X is independently -N(RA)2, -SRA, or -ORA; each P1is independently hydrogen or an oxygen protecting group; each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; and n is 1-20; wherein: the compound has only one molecular payload; for Formula (VII), when n is greater than 1, with the exception of the phosphorous directly attached to the A, each instance of phosphorous labeled y is bound to the oxygen labeled z of the adjacent unit; for Formula (VII), when n is greater than 1, with the exception of the oxygen directly attached to R4, each instance of oxygen labeled z is bound to the phosphorous labeled y of the adjacent unit for Formula (VII’), when n is greater than 1, with the exception of the oxygen directly attached to the A, each instance of oxygen labeled y is bound to the phosphorous labeled z of the adjacent unit; and for Formula (VII’), when n is greater than 1, with the exception of the phosphorous directly attached to R4, each instance of phosphorous labeled z is bound to the oxygen labeled y of the adjacent unit.

14. The compound of claim 13, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

15. A compound of Formula (VIII) or (VIII’):or a pharmaceutically acceptable salt thereof; wherein:A is a molecular payload, -OH, substituted or unsubstituted alkoxy, hydrogen, substituted or unsubstituted alkyl, oreach X is independently -N(RA)2, -SRA, or -ORA; each R1is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA; each R2is independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA;each R3is independently of formula:R4is hydrogen, substituted or unsubstituted alkyl,-OH, substituted or unsubstituted alkoxy, or a molecular payload; each P1is independently hydrogen or an oxygen protecting group; each L is independently a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl,, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, - O-, -N(RA)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, - NRAC(=O)O-, -NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, - NRAS(O)2-, or a combination thereof; each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and n is 1-20; wherein:the compound has only one molecular payload; for Formula (VIII), when n is greater than 1, with the exception of the phosphorous directly attached to the A, each instance of phosphorous labeled y is bound to the oxygen labeled z of the adjacent unit; for Formula (VIII), when n is greater than 1, with the exception of the oxygen directly attached to R4, each instance of oxygen labeled z is bound to the phosphorous labeled y of the adjacent unit; for Formula (VIII’), when n is greater than 1, with the exception of the oxygen directly attached to the A, each instance of oxygen labeled y is bound to the phosphorous labeled z of the adjacent unit; and for Formula (VIII’), when n is greater than 1, with the exception of the phosphorous directly attached to R4, each instance of phosphorous labeled z is bound to the oxygen labeled y of the adjacent unit.

16. The compound of claim 15, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound of any of claims 1-16, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

18. A method of inhibiting expression of a target nucleic acid in a cell, a tissue, or an organism, the method comprising contacting the cell, tissue, or organism with the compound of any of claims 1-16, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 17 in an amount effective to inhibit expression of the target nucleic acid.

19. A compound, wherein the compound is:(i) a compound of Formula (IX): or a salt thereof;wherein:R1is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted orunsubstituted heteroaliphatic, -ORA, or a group of formula:R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, -ORA, or a group of formula:R3is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl -ORA, or a group of formula:each P1is independently hydrogen or an oxygen protecting group;L is a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, - O-, -N(RA)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, - NRAC(=O)O-, -NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, - NRAS(O)2-, or a combination thereof; and each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; provided that the compound has only one instance of formulaprovided that the compound is not:(ii) a compound of Formula (X):or a salt thereof; wherein: each P1is independently hydrogen or an oxygen protecting group;L is a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, -O-, -N(RA)-, -S-, -C(=O)-, -C(=O)O-, - C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, -NRAC(=O)O-, -NRAC(=O)N(RA)-, - OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, -NRAS(O)2-, or a combination thereof; and each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring;or a salt thereof, wherein: each P1is independently hydrogen or an oxygen protecting group; and each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; or(iv) a compound of Formula (XII):or a salt thereof; wherein:R1is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA;R2is hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or -ORA;R3is of formula:P2is hydrogen, an oxygen protecting group, oreach P1is independently hydrogen or an oxygen protecting group;L is a bond, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, - O-, -N(RA)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, - NRAC(=O)O-, -NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, - NRAS(O)2-, or a combination thereof; and each RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

20. The compound of claim 19, wherein the compound is(i) a compound of formula:or a salt thereof;(ii) a compound of formula:or a salt thereof;(iii) a compound of formula:or a salt thereof; or(iv) a compound of formula:or a salt thereof.

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