Oligonucleotides containing a ligand at an internal position

Abstract

The present disclosure provides oligonucleotides comprising a radical of a ligand at an internal position. The present disclosure also provides pharmaceutical compositions and kits comprising said oligonucleotides, methods of delivering said oligonucleotides, methods of modulating the activity of a protein using such oligonucleotides, and methods of treating, preventing, or diagnosing diseases (e.g., central nervous system diseases, neurodegenerative diseases, and neurocognitive diseases) in a subject in need thereof using said oligonucleotides or pharmaceutical compositions thereof.

Description

[0001] OLIGONUCLEOTIDES CONTAINING A LIGAND AT AN INTERNAL POSITION

[0002] RELATED APPLICATIONS

[0003] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application, U.S.S.N. 63 / 520,337, filed August 17, 2023, the contents of which are incorporated herein by reference.

[0004] BACKGROUND

[0005] In the use of compounds (e g., oligonucleotides) in therapeutic, prophylactic, or diagnostic applications, it is often desirable that the compounds be delivered to a specific location (for example, to desired cell(s). to a desired organ or tissue, or to a particular location in a subject) to enhance the therapeutic or prophylactic effect or to be advantageous for diagnostic purposes. This is frequently the case when attempting to deliver a therapeutic compound in vivo. Further, being able to efficiently deliver a compound to a specific location can limit or potentially eliminate unintended consequences (such as off-target effects) that may be caused byadministration of the compound. One strategy to facilitate delivery of a compound, such as a therapeutic, prophylactic, or diagnostic compound, to a desired location in vivo, is by linking or attaching the compound to a targeting ligand.

[0006] One class of compounds that can be targeted using targeting ligands are oligomeric compounds, such as. for example, proteins, peptides, antibodies, and oligonucleotides. Oligomeric compounds that include nucleotide sequences (e.g., oligonucleotides) at least partially complementary to a target nucleic acid have been show n to alter the function and activity of the target both in vitro and in vivo. When delivered to a cell containing a target nucleic acid (such as mRNA or pre-mRNA), oligonucleotides have been shown to modulate the expression or activity of the target nucleic acid. In certain instances, the oligonucleotide can reduce the expression of the gene by inhibiting translation of the nucleic acid target and / or triggering the degradation of the target nucleic acid.

[0007] If the target nucleic acid is mRNA, one mechanism by which an oligonucleotide can modulate the expression of the mRNA target is through RNA interference. RNA interference is a biological process by which RNA or RNA-like compounds (such as chemically modified RNA compounds) are able to silence gene expression, at least in part, through the RNA-induced silencing complex (RISC) pathway. Additionally, oligonucleotides can modulate the expression of a target nucleic acid, such as a target mRNA. through an RNase recruitment mechanism, microRNA mechanisms, occupancy-based mechanisms, and editing mechanisms. Oligonucleotides may be single-stranded or double-stranded. Oligonucleotides may comprise DNA, RNA, and RNA-like compounds, which can also include modified nucleosides including one or more modified sugars, modified nucleobases, and modified intemucleoside linkages.

[0008] There is a need for new compounds for delivering to subjects pharmaceutical agents (e.g., therapeutic, prophylactic, and diagnostic agents).

[0009] SUMMARY

[0010] In one aspect, the present disclosure provides oligonucleotides comprising an oligonucleotide strand modified with at least one ligand at an internal position. In one aspect, the present disclosure is directed to oligonucleotides comprising a modified oligonucleotide strand of Formula I:

[0011] (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: is a divalent radical of an oligonucleotide strand; si instances of the intemucleosidic linkers of are independently replaced with si is 1, 2, 3, 4, 5, or 6; each instance of LAand L4is independently a linker; each instance of A4is independently a radical of a ligand or lipid, provided that at least one instance of A4is a radical of a ligand; each of y5 and y6 is independently 0 or 1 ; when y5 is 0, L5is hydrogen, substituted or unsubstituted, Ci-6 alkyl, or an oxygen protecting group; or when y5 is 1, L5is a linker; when y6 is 0. L6is hydrogen, substituted or unsubstituted. Ci-6 alkyl, or an oxygen protecting group; or when y6 is 1, L6is a linker; each of A5and A6, if present, is independently a radical of a ligand or lipid; and each of the ligands is different from each of the lipids.

[0012] The oligonucleotides comprise one or more radicals of ligands conjugated at one or more internal positions on the oligonucleotide (e.g, at a position on the oligonucleotide other than the 5' or 3' end). In some embodiments, the ligands are not lipids. In some embodiments, the oligonucleotides further comprise one or more radicals of lipids at one or more internal positions. In some embodiments, the oligonucleotides further comprise one or more radicals of ligands and / or radicals of lipids at the 5'-end and / or at the 3'-end.

[0013] The oligonucleotides may be useful for delivering pharmaceutical agents to a subject (e.g., a human). In some embodiments, at least one instance of the pharmaceutical agents is the oligonucleotide strand. In some embodiments, the ligands are capable of selectively targeting a location within a subject (e.g., the brain of a subject, or a region of the brain of a subject). In some embodiments, the ligands are capable of selectively targeting a particular type of cell (e.g., a cell of the central nervous system, such as a neuron). In some embodiments, the ligands are capable of selectively binding to or otherwise selectively recognizing one or more receptors. In some embodiments, the oligonucleotides are capable of selectively targeting the oligonucleotide strand to a location within a subject (e.g., the brain of a subject, or a region of the brain of a subject). In some embodiments, the oligonucleotides are capable of selectively delivering the oligonucleotide strand to a cell (e.g.. a cell of the central nervous system, such as a neuron). In certain embodiments, the oligonucleotides are capable of selectively binding to or otherwise selectively recognizing one or more receptors. The oligonucleotides may be useful in treating, preventing, or diagnosing a disease. The oligonucleotides may be advantageous over the pharmaceutical agents and certain known oligonucleotides (e.g., certain known oligonucleotides that do not comprise one or more radicals of ligands conjugated at one or more internal positions) because the former may show higher potency, efficacy, bioavailability, safety, and / or subject compliance; wider therapeutic window; fewer and / or less severe side effects; and / or lower toxicity and / or resistance to treatment than the latter. One or more of the advantages may be at least in part because the oligonucleotides comprise one or more radicals of ligands conjugated at one or more internal positions.

[0014] The present disclosure also provides pharmaceutical compositions and kits, each of which comprise the oligonucleotides disclosed herein. The present disclosure also provides methods of using such oligonucleotides, pharmaceutical compositions, and kits.

[0015] In another aspect, the present disclosure provides methods for delivering any of the oligonucleotides or pharmaceutical compositions provided herein to a subject.

[0016] In another aspect, the present disclosure provides any of the oligonucleotides or pharmaceutical compositions provided herein for the manufacture of a medicament for delivering any of the oligonucleotides or pharmaceutical compositions to a subject. In another aspect, the present disclosure provides any of the oligonucleotides or pharmaceutical compositions provided herein for use in delivering any of the oligonucleotides or pharmaceutical compositions to a subject.

[0017] In another aspect, the present disclosure provides methods for treating a disease in a subject in need thereof using any of the oligonucleotides or pharmaceutical compositions provided herein.

[0018] In another aspect, the present disclosure provides uses of any of the oligonucleotides or pharmaceutical compositions provided herein for the manufacture of a medicament for treating a disease in a subject in need thereof.

[0019] In another aspect, the present disclosure provides any of the oligonucleotides or pharmaceutical compositions provided herein for use in treating a disease in a subject in need thereof.

[0020] In another aspect, the present disclosure provides methods of preventing a disease in a subject in need thereof using any of the oligonucleotides or pharmaceutical compositions provided herein.

[0021] In another aspect, the present disclosure provides uses of any of the oligonucleotides or pharmaceutical compositions provided herein for the manufacture of a medicament for preventing a disease in a subject in need thereof.

[0022] In another aspect, the present disclosure provides any of the oligonucleotides or pharmaceutical compositions provided herein for use in preventing a disease in a subject in need thereof.

[0023] In another aspect, the present disclosure provides methods of making any of the oligonucleotides provided herein comprising contacting under suitable conditions a compound of Formula A- 1: or a salt thereof, with a compound of Formula A-2: or a salt thereof, wherein: each of M1and M2is independently a radical of: a fragment of the oligonucleotide strand or a nucleoside; each of L4D1and L4D2is independently a single bond or linker;

[0024] L4E1is a first reactive moiety;

[0025] L4E2is a second reactive moiety;

[0026] L4E1and L4E2are capable of reacting with each other under the suitable conditions to form L4E3; and

[0027] L4D1_L4E3_L4D2ig L4

[0028] It is understood that the embodiments provided herein with respect to preferred variable selections can be taken alone or in combination with one or more embodiments, or other preferred variable selections provided herein, as if each combination were explicitly listed herein.

[0029] It should be appreciated that the foregoing concepts, and additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in this respect. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments.

[0030] DEFINITIONS

[0031] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Michael B. Smith, March 's Advanced Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock. Comprehensive Organic Transformations, John Wiley & Sons. Inc., New York, 2018; and Carruthers, Some Modem Methods of Organic Synthesis, 3rdEdition. Cambridge University Press, Cambridge, 1987.

[0032] Compounds (e.g., oligonucleotides) described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al.. Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981 ); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed.. Univ, of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0033] Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F w ith18F, or the replacement of a carbon by a13C- or14C-enriched carbon are w ithin the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0034] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example, “Ci-6 alkyl” encompasses, Ci, C2, C3, C4, C5, C6, C1-6, C1-5, CH, C1-3, Ci-2, C26. C2-5, C2n. C2-3, C3-6, C3-5, C3-4, C4-6. C4-5, and C5^ alkyl.

[0035] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 100 carbon atoms (“Ci-100 alkyl”). In some embodiments, an alkyl group has 1 to 20 carbon atoms (“C1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyd”). In some embodiments, an alky 1 group has 1 to 10 carbon atoms (“Ci-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyd”). In some embodiments, an alkyd group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“CIH alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyd”). In some embodiments, an alkyd group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyd groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g, n- propyl, isopropyl), butyl (C4) (e.g, n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n- pentyl, 3-pentanyL amyl, neopenty l, 3-methyl-2-butanyl, tert-amyl), and hexyl (Ce) (e.g, n- hexyl). Additional examples of alkyl groups include w-heptyl (C7), n-octy l (Cs), n-dodecyl (C12), and the like. Unless otherw ise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyd”) with one or more substituents (e.g, halogen, such as fluorine). In certain embodiments, the alkyl group is an unsubstituted Ci-12 alkyl (such as unsubstituted C1-6 alkyl, e.g, -CHs (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (z-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted te / 7-butyl (tert-Qu or t- Bu), unsubstituted sec-butyl (sec-Bu or s-Bu). unsubstituted isobutyl (z-Bu)). In certain embodiments, the alkyl group is a substituted C1-12 alkyd (such as substituted C1-6 alkyl, e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).

[0036] The term “heteroalkyd” refers to an alkyl group, which further includes at least one heteroatom (e.g.. 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 100 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-ioo alkyl”). 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 (“heteroCi-2o alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-i2alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-11 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-9 alkyd”). 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 (“heteroCi-8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-7 alkyl”). In some embodiments, a heteroalky l group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroCi-5 alkyd”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms within the parent chain (“heteroCi-4 alkyl”). In some embodiments, a heteroalky l group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-3alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-2alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyd”) or substituted (a “substituted heteroalkyl”) with one or more substituents (e g., oxo, substituted or unsubstituted Ci-6 alkyl (e.g, -CH3)). In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-12 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-12 alkyl. In some embodiments, unsubstituted heteroCi alkyl is -OCH3 or -CH2OH. In some embodiments, substituted heteroCi alkyl is -C(=0)NH2. In some embodiments, unsubstituted heteroC2 alkyl is -OCH2CH3, -CH2OCH3, or -CH2CH2OH. The terms “heteroCzi-Z2 alkyl” and “Czi-Z2 heteroalkyl” are used interchangeably, wherein each of zl and z2 is independently an integer.

[0037] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 100 carbon atoms and one or more carbon-carbon double bonds (e. , 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 1 to 100 carbon atoms (“Ci-100 alkenyl”). In some embodiments, an alkenyl group has at least 2 carbon atoms. In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“C1-20 alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“C1-12 alkenyl”). In some embodiments, an alkenyl group has 1 to 11 carbon atoms (“C1-11 alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“C1-10 alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C1-9 alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C1-8 alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C1-7 alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C1-6 alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“C1-5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“Ci^ alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C1-3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C1-2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“Ci alkenyl”). In certain embodiments, an alkenyl group is C2-3 alkenyl, C2 4 alkenyl, C2-5 alkenyl, C2-6 alkenyl, C2-7 alkenyl, C2-8 alkenyl. C2-9 alkenyl, C2-10 alkenyl, C2-12 alkenyl, C2-16 alkenyl, C2-20 alkenyl, C2-30 alkenyl, C2 40 alkenyl, C2-50 alkenyl, C2-60 alkenyl, C2-70 alkenyl, C2-80 alkenyl, C2-90 alkenyl, or C 2-100 alkenyl. The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C1-4 alkenyl groups include methylidenyl (Ci), ethenyl (C2). 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of Ci 6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C1-20 alkenyl. In certain embodiments, the alkenyl group is a substituted C1-20 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g.. -CH=CHCH3 or inthe (E)- or (^-configuration.

[0038] 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, sulfur, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 100 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1-100 alkenyl”). In some embodiments, a heteroalkenyl group has at least 2 carbon atoms. In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1-20 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-12 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-11 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1-10 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-9 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-s alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1-7 alkeny l”). In some embodiments, a heteroalkenyl group has Ito 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-6 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 1-5 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroCi-3 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroCi-2 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi-6 alkenyl”). In certain embodiments, a heteroalkenyl group is C2-3 heteroalkenyl, C2-4 heteroalkenyl, C2-5 heteroalkenyl, C2-6 heteroalkenyl, C2-7 heteroalkenyl, C2-8 heteroalkenyl, C2-9 heteroalkenyl, C2-10 heteroalkenyl, C2-12 heteroalkenyl, C2-16 heteroalkenyl, C2-20 heteroalkenyl, C2-30 heteroalkenyl, C2-40 heteroalkenyl, C2-50 heteroalkenyl, C2-60 heteroalkenyl, C2-70 heteroalkenyl, C2-80 heteroalkenyl, C2-90 heteroalkenyl, or C 2-100 heteroalkenyl. 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 (e.g, oxo, substituted or unsubstituted Ci-6 alkyl (e.g, -CH3)). In certain embodiments, the heteroalkenyl group is an unsubstituted heteroCi 20 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroCi-20 alkenyl. In some embodiments, unsubstituted heteroCi alkenyl is -CH=NH or =N-CH3 The terms “heteroCzi-Z2 alkenyl” and “Czi-z2 heteroalkenyl” are used interchangeably, wherein each of zl and z2 is independently an integer.

[0039] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 100 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“Ci-100 alkynyl”). In some embodiments, an alkynyl group has 1 to 20 carbon atoms (“Ci -20 alkynyl”). In some embodiments, an alkynyl group has at least 2 carbon atoms. In some embodiments, an alkynyl group has 1 to 10 carbon atoms (“C1-10 alky nyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C1-9 alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“C1-8 alky nyl”). In some embodiments, an alkynyl group has 1 to 7 carbon atoms (“C1-7 alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“C1-6 alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C1-5 alkynyl”). In some embodiments, an alky nyl group has 1 to 4 carbon atoms (“C1-4 alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“C1-3 alkynyl”). In some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C1-2 alkynyl”). In some embodiments, an alkynyl group has 1 carbon atom (“Ci alkynyl”). In certain embodiments, an alkynyl group is C2-3 alkynyl, C2-4 alkynyl, C2-5 alkynyl, C2-6 alkynyl, C2-7 alkynyl, C2-8 alkynyl, C2-9 alkynyl, C2-10 alky nyl, C2-12 alkynyl, C2-16 alkynyl, C2-20 alkynyl, C2-30 alkynyl, C2-40 alkynyl, C2-50 alkynyl, C2-60 alkynyl, C2-70 alkynyl, C2-80 alkynyl, C2-90 alkynyl, or C 2-100 alkynyl. The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C1-4 alkynyl groups include, without limitation, methylidynyl (Ci), ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of Ci-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce). and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C1-20 alkynyl. In certain embodiments, the alkynyl group is a substituted C1-20 alkynyl.

[0040] The term “heteroalkynyk’ refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 100 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1-100 alkynyl’'). In some embodiments, a heteroalkynyl group has at least 2 carbon atoms. In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1-20 alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-10 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-9 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1-8 alkynyl”). In some embodiments, a heteroalky nyl group has 1 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-7 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-6 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi-5 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“heteroCi-4 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroCi-3 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroCi-2 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 1 6 alkynyl”). In certain embodiments, a heteroalkynyl group is C2-3 heteroalkynyl, C2-4 heteroalkynyl, C2-5 heteroalkynyl, C2-6 heteroalkynyl, C2-7 heteroalkynyl, C2-8 heteroalkynyl. C2-9 heteroalkynyl, C2-10 heteroalkynyl, C2-12 heteroalkynyl, C2-16 heteroalkynyl, C2-20 heteroalkynyl. C2-30 heteroalkynyl, C2 40 heteroalkynyl, C2-50 heteroalkynyl, C2-60 heteroalkynyl, C2-70 heteroalkynyl, C2-80 heteroal kynyl, C2-90 heteroalkynyl, or C 2-100 heteroalky nyl. 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 (e.g., oxo, substituted or unsubstituted Ci-6 alkyl (e.g, -CH3)). In certain embodiments, the heteroalky nyl group is an unsubstituted heteroCi-20 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroCi-20 alkynyl. In some embodiments, unsubstituted heteroCi alkynyl is -ON. The terms “heteroCzi-Z2 alkynyl” and “Czi-z2 heteroalkynyl” are used interchangeably, wherein each of zl and z2 is independently an integer.

[0041] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to

[0042] 13 ring carbon atoms (“C3-13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to

[0043] 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to

[0044] 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to

[0045] 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce). and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- H- indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-10 carbocyclyl groups as well as cycloundecyl (Cn), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g, containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and 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 such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl’") or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0046] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalky l groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalky l. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0047] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered nonaromatic 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 continues to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an ’unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0048] 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.

[0049] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl. oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary76-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary' 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl. dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolmyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-l,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-lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-lH- pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2- b]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0050] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 n electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-i4 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted Ce-i4 ary l. In certain embodiments, the ary l group is a substituted Ce-14 aryl.

[0051] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 n electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continues to designate the number of ring members in the heteroaryl ring system. "Heteroar 1” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, e.g., either the ring bearing a heteroatom (e.g. , 2-indolyl) or the ring that does not contain a heteroatom (e.g.. 5-indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted. 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0052] 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 heteroaiyl 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 heteroary l”) with one or more substituents. In certain embodiments, the heteroary l group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroary l group is a substituted 5-14 membered heteroaryl.

[0053] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5- membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary’ 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl. benzoisofuranyl. benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl. benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

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

[0055] The term “alkoxy” refers to an -O-alkyl substituent.

[0056] Affixing the suffix “-ene” to a group indicates the resulting group is a polyvalent (e.g., divalent, trivalent, or tetravalent) moiety. For example, alkylene is a polyvalent moiety of alkyl, alkenylene is a polyvalent moiety of alkenyl, alkynylene is a polyvalent moiety of alkynyl, heteroalkylene is a polyvalent moiety of heteroalkyl, heteroalkenylene is a polyvalent moiety of heteroalkenyl, heteroalkynylene is a polyvalent moiety of heteroalkynyl, carbocyclylene is a polyvalent moiety of carbocyclyl, heterocyclylene is a polyvalent moiety of heterocyclyl, arylene is a polyvalent moiety of aryl, and heteroarylene is a polyvalent moiety of heteroaryl. In some embodiments, unsubstituted Ci heteroalkylene is -OCH2- or -CH2O-. In some embodiments, substituted Ci heteroalkylene is -NHC(=O)- or -C(=O)NH- In some embodiments, unsubstituted C2 heteroalkylene is -OCH2CH2- or -CH2CH2O-. In some embodiments, unsubstituted C4 heteroalkylene is -(OCH2CH2)2- or -(CH2CH2O)2-. In some embodiments, unsubstituted C6 heteroalkylene is -(OCH2CH2)3- or -(CH2CH2O)6-. In some embodiments, unsubstituted C8 heteroalkylene is (OCH2CH2)4 or (CH2CH2O)4. In some embodiments, unsubstituted C10 heteroalkylene is -(OCH2CH2)5- or -(CH2CH2O)5-. In some embodiments, unsubstituted C12 heteroalkylene is -(O CH2CH2)6- or -(CH2CH2O)6-.

[0057] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl. heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. ‘‘Optionally substituted" refers to a group which is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl. “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds and includes any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The disclosure is not limited in any manner by the exemplary substituents described herein.

[0058] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORaa. -ON(Rbb)2, -N(Rbb)2, ~N(Rbb)3X . -N(ORcc)Rbb, -SH, -SRaa, -SSRCG, -C(=O)Raa, -CO2H, -CHO. -C(ORCO)2. -CO2Raa, -OC(=O)Raa, -QCO2Raa. -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, NRbbC(=NRbb)N(Rbb)2, C(=O)NRbbSO2Raa. NRbbSOaa, SO2N(Rbb)2, SO2Raa, SO2ORaa, -OSO2Raa, -S(=O)Raa, -OS(=O)Raa, -Si(Raa)3, -OSi(Raa)3-C(=S)N(Rbb)2, -C(=O)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=O)SRaa, -OC(=O)SRaa, -SC(=O)ORaa, -SC(=O)Raa, -P(=O)(Raa)2, -P(=O)(ORcc)2, -OP(=O)(Raa)2, -OP(=O)(ORCO)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, -NRbbP(=O)(Raa)2, -NRbbP(=O)(ORGG)2, -NRbbP(=O)(N(Rbb)2)2, -P(Rcc)2, -P(ORcc)2, -P(RCC)3+X , -P(ORGO)3+X , -P(RGG)4, -P(ORGG)4, -OP(RGG)2, -OP(RGG)3+X , -OP(ORGG)2, -OP(ORGG)3' X , -OP(RGG)4, -OP(ORGC)4, -B(Raa)2, -B(ORGG)2, -BRaa(ORGG), Ci -20 alkyl. Ci -20 perhaloalkyl, Ci-20 alkenyl, Ci-20 alkynyl, heteroCi-2o alkyl, heteroCi-2o alkenyl, heteroCi-2o alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, wherein each alky l, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=0)Raa. =NNRbbC(=0)0Raa, =NNRbbS(=0)2Raa, =NRbb, or =NORC0; each instance of Raais, independently, selected from C1-20 alkyl, C1-20 perhaloalkyl, C1-20alkenyl, C1-20 alkynyl, heteroCi-2o alkyl, heteroCi-2oalkenyl, heteroCi-2oalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1. 2, 3, 4. or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, -OH, -ORaa, -N(RCC)2, CN, C(=O)Raa, C(=O)N(ROC)2, CO2Raa, SO2Raa, C(=NR°°)0Raa, C(=NROC)N(RCC)2, -SO2N(R°°)2, -SO2R°°, -SO2OR°°, -SORaa. -C(=S)N(R°°)2, -C(=O)SROC, -C(=S)SR°°, -P(=O)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, C1-20 alkyl, C1-20 perhaloalkyl, C1-20 alkenyl, C1-20alkynyl, heteroCi-2oalkyl, heteroCi-2oalkenyl, heteroCi-2oalkynyl, C3-10 carbocyclyl, 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; each instance of Rccis, independently, selected from hydrogen, C1-20 alkyl, C1-20 perhaloalkyl, Ci-20 alkenyl, Ci-20 alkynyl, heteroCi-2o alky l, heteroCi-2o alkenyl, heteroCi-2o alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, 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, ary l, and heteroaryl is independently substituted with 0, 1, 2, 3, 4. or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -0N(Rff)2, -N(Rff)2, -N(Rff)3+X , -N(0Ree)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -QC(=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, -0P(=0)(0Ree)2, Ci-io alkyl, Ci-io perhaloalkyl, Ci-io alkenyl, Ci-io alkynyl, heteroCi-ioalkyl, heteroCi-ioalkenyl, heteroCi-ioalkynyl, C3-10 carbocyclyk 3-10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents are joined to form =0 or =S; wherein X is a counterion; each instance of Reeis, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C1-10 alkenyl. Ci 10 alkynyl, heteroCi 10 alkyl, heteroCi 10 alkenyl, heteroCi 10 alkynyl, C3-10 carbocyclyl, C6-10aryl, 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 Rgsgroups; each instance of Rlfis, independently, selected from hydrogen, C1-10alkyl, Ci-10 perhaloalkyl, C1-10 alkenyl, C1-10 alkynyl, heteroCi-10 alkyd, heteroCi-10 alkenyl, heteroCi-10 alkynyl, C3-10 carbocyclyl, 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, heteroalkyd, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H. -OH, -OC1-6alkyl, -QN(CI-6 alkyl)2. -N(CI-6 alkyl)2, -N(CI-6 alkyl)3+XX -NHfCi 6 alkyl^ X . -NH2(CI-6 alkyl) X , -NH< X . -N(OCi _6alkyl)(Ci^ alky 4), -N(OH)(Ci^ alkyl), -NH(OH), -SH, -SCi^ alkyd, -SS(Ci-6alkyl), -C(=O)(Ci^ alkyl), -CO2H, -CO2(Ci 6 alkyd), -OC(=O)(Ci-6alkyd), -OCO2(Ci 6 alkyl), -C(=O)NH2, -C(=O)N(CI-6 alkyl)2, -OC(=O)NH(Ci 6 alkyl), -NHC(=O)( Ci^ alkyl), -N(CI-6 alky d)C(=O)( Ci^ alkyl). -NHCO2(CI6alkyd), -NHC(=O)N(CI-6alkyl)2, -NHC(=O)NH(Ci6alkyl), -NHC(=O)NH2, -C(=NH)O(Ci^ alkyl), -OC(=NH)(CI-6 alkyl), -OC(=NH)OCI-6alkyl, -C(=NH)N(CI-6alkyl)2, -C(=NH)NH(CI-6 alkyl), -C(=NH)NH2, OC(=NH ) N(CI6alkyd)2, OCfNI I)NH(C ,6alkyl), -OC(NH)NH2, -NHC(NH)N(CI-6alkyl)2. -NHC(=NH)NH2, -NHSO2(CI-6 alkyl). -SO2(HC1_6alkyl)2, -SO2NH(C1-6alkyl), -SO2NH2, -SO2C1 6 alkyl, -SO2OC1-6alkyd, -OSO2C1 6 alkyl, -SOCi6alkyl, -Si(Ci6alkyl)3, -OSi(Ci6alky d)3-C(=S)N(Ci6alkyl)2, C(=S)NH(Ci6alkyl), C(~S)NH2. -C(=O)S(CI-6 alkyl), -C(=S)SCi- _6alkyd, -SC(=S)SCi- _6alkyd, -P(=O)(OCi6alkyl)2, -P(=O)(C1-6alky 1)2, -OP(=O)(Ci-6 alky 1)2, -OP(=O)(OCi6alkyl)2, Ci-io alkyl, Ci-io perhaloalkyl. C1-10alkenyl, C1-10 alkynyl, heteroCi-10 alkyl, heteroCi-10 alkenyl, heteroCi-10 alkynyl, C3-10 carbocycly l, C6-10aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or tyvo geminal Rggsubstituents can be joined to form =0 or =S; and each X is a counterion.

[0059] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g, substituted with one or more halogen) or unsubstituted Ci-6 alky l, -ORaa, -SRaa, -N(Rbh)2, -CN, -SCN, -NO2, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, OC(=O)N(Rbb)2, NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=O)N(Rbb)2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g, substituted with one or more halogen) or unsubstituted C1-10 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, -NO2, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=0)N(Rbb)2, wherein Raais hydrogen, substituted (e.g, substituted with one or more halogen) or unsubstituted Ci-10 alkyl, an oxygen protecting group (e.g, silyl. TBDPS, TBDMS. TIPS. TES. TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g, acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g, substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group (e.g, Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, or -NO2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g. substituted with one or more halogen moieties) or unsubstituted C1-10 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, or -NO2, wherein Raais hydrogen, substituted (e.g, substituted with one or more halogen) or unsubstituted C1-10 alky l, an oxygen protecting group (e.g, silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn. allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g, acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g, substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0060] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g, substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)Raa, -CCER31. -C(=O)N(Rbb)2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g, substituted with one or more halogen) or unsubstituted C1-10 alkyl. -C(=O)Raa, -CC>2Raa, -C(=0)N(Rbb)2, or a nitrogen protecting group, wherein Raais hydrogen, substituted (e.g, substituted with one or more halogen) or unsubstituted Ci-10 alky l, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or a nitrogen protecting group.

[0061] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include -OH, -ORaa -N(Rcch, -C(=O)Raa -C(=O)N(Rcc)2, -COiR", -SOTRaa-C(=NRcc)Raa-C(=NRcc)ORaa-C(=NRccN(Rcc)2, -SO2N(Rcc)2, -SO2Rcc, -SO2ORcc, -SOR", -C(=S)N(Rcc)2, -C(=O)SRcc, -C(=S)SRcc, Ci-10 alkyl (e.g, aralkyl, heteroaralkyl), C1-20alkenyl, C1-20 alkynyl, hetero C1-20 alkyl, hetero C1-20 alkenyl, hetero C1-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^ groups, and wherein R", R1*, Rcc, and R^ are as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999.

[0062] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., -C(=O)R“) is directly attached). In certain such embodiments, each nitrogm protecting group, together with the nitrogm atom to which the nitrogm protecting group is attached, is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phmylpropanamide, picolinamide, 3- pyridylcarboxamide, jV-benzoylphmylalanyl derivatives, benzamide, p-phenylbenzamide, o- nitrophenylacetamide, o-nitrophenoxy acetamide, acetoacetamide, (AT- 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, A^-acetylmethionine derivatives, o-nitrobenzamide, and o- (benzoyloxymethyl)benzamide.

[0063] In certain embodiments, at least one nitrogm protecting group is a carbamate group (e.g., a moiety that include the nitrogm atom to which the nitrogen protecting groups (e.g, -C(=O)OR") is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogm atom to which the nitrogm protecting group is attached, is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9- fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7- dibromo)fluorenylmethy 1 carbamate, 2,7 -di - t-buty 1 - [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), l-(l-adamantyl)-! -methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, l.l-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2,2,2- trichloroethyl carbamate (TCBOC), 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc). l-(3,5-di- t-butylphenyl)-l -methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, / -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-ni trobenzyl carbamate, / ?-bromobenzyl carbamate, p- chlorobenzyl carbamate, 2.4-dichlorobenzyl carbamate, 4-methylsulfinylbenzy 1 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), l,l-dimethyl-2-cy anoethyl carbamate. / n-chloro-p- acyloxy benzyl carbamate. / ?- (dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6- chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3.4-dimetho\y-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, / -amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobuty l carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate. o-(NJ\l- dimethylcarboxamido)benzyl carbamate, l,l-dimethyl-3-(A,A-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobomyl carbamate, isobutyl carbamate, isonicotinyl carbamate. p-(p ’-methoxyphenylazo)benzyl carbamate. 1 -methylcyclobutyl carbamate, 1- methyl cyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, 1 -methyl- 1 -(3,5- dimethoxyphenyl)ethyl carbamate, 1 -methyl- 1 -(p-phenylazophenyl)ethyl carbamate, 1 -methyl- 1- phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p- (phenylazo)benzyl carbamate, 2.4.6- ln- / -butyl phenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0064] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g, a moiety7that include the nitrogen atom to which the nitrogen protecting groups (e.g, -S(=0)2Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of -toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6- trimethoxy benzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),

[0065] 2.3.5.6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs),

[0066] 2.4.6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), - trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS). benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0067] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, A'-p-toluenesulfonylaminoacyl derivatives. A -phen laminothioac l derivatives. A-benzoylphenylalanyl derivatives. A-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, A-phthalimide, A-dithiasuccinimide (Dts), A-2,3- diphenylmal eimide, A-2.5-dimethy I pyrrole. N- 1 , 1 ,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted 1,3- dibenzyl-1.3.5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, A-methylamine, N- allylamine, A-[2-(trimethylsilyl)ethoxy]methylamine (SEM), A-3-acetoxypropylamine, A-(l- isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, A-benzyl amine, N- di(4-methoxyphenyl)methylamine, A-5-dibenzosuberyl amine, A-triphenylmethylamine (Tr), N- [(4-methoxyphenyl)diphenylmethyl]amine (MMTr), A-9-phenylfluorenylamine (PhF). A-2,7- dichloro-9-fluorenylmethyleneamine, A-lerroceny I methyl amino (Fem). A-2-picolylamino N'- oxide, N- 1 , 1 -dimethylthiomethyleneamine, A-benzylideneamine, A-p- methoxybenzylideneamine, A-diphenylmethyleneamine, A-[(2-pyridyl)mesityl]methyleneamine, A-(A’,A -dimethylaminomethylene)amine, A-p-nitrobenzylideneamine, A-salicylideneamine, A- 5-chlorosalicylideneamine, A-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, A- cyclohexylideneamine, A-(5,5-dimethyl-3-oxo-l -cyclohexenyl)amine, A-borane derivatives, A- diphenylborinic acid derivatives, A-[phenyl(pentaacylchromium- or tungsten)acyl] amine, A- copper chelate, A-zinc chelate. A-nitroamine, A-nitrosoamine, amine A-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphorami date, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide. and 3-nitropyridinesulfenamide (Npys). In some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are MA” -isopropyl idenediamine.

[0068] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0069] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Cnio alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa. -CO2Raa, -C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g. substituted with one or more halogen) or unsubstituted Ci-io alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alky l, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or an oxygen protecting group.

[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 -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(RCO)3+X , -P(ORCO)2, -P(ORCO)3+X , -P(=O)(Raa)2, -P(=O)(OROC)2, and -P(=O)(N(Rbb)2)2, wherein X , Raa, Rbb, and Rcoare 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.

[0071] In certain embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is attached, is selected from the group consisting of methyl, methoxymethyl (MOM), methylthiomethyl (MTM), f-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM). benzyloxymethyl (BOM). / ?- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), f-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP). 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl MS'-dioxide. 1 -[(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, l-(2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxy ethyl, 1 -methyl- 1 -benzyloxy ethyl, 1 -methyl- 1 -benzyloxy-2-fluoroethyl. 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, / -butyl. allyl, p-chlorophenyl. p- methoxyphenyl. 2,4-dinitrophenyl, benzyl (Bn), p- methoxybenzyl (PMB), 3,4- dimethoxybenzyl, o-nitrobenzyl. / ?-nitrobenzyl. p-halobenzyl. 2,6-dichlorobenzyl, p- cyanobenzyl. / / -phenylbenzyl. 2-picolyl. 4-picolyl, 3-methyl-2-picolyl / V-oxido. diphenylmethyl. p.p -dinitrobenzhydryl, 5-dibenzosuberyl. triphenylmethyl, 4,4'-dimethoxytrityl (4,4'- dimethoxytriphenylmethyl or DMT), a-naphthyldiphenylmethyl, p- methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri( / ?- methoxyphenyl)methyl, 4-(4’-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5- dichlorophthalimidophenyl)methyl, 4.4',4"-tris(levulinoyloxyphenyl)methyl. 4, 4', 4"- tris(benzoyloxyphenyl)methyl, 4,4’-Dimethoxy-3"‘-[N-(imidazolylmethyl) (trityl Ether (IDTr- OR), 4,4:-Dimethoxy-3"‘-[N-(imidazolylethyl)carbamoyl]trityl Ether (lETr-OR), l,l-bis(4- methoxyphenyl)-l'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl <S’,5-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, / -butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri- / ?-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), / -butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxy acetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4- methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc). ethyl carbonate, 2.2.2-tri chloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, / -butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p- methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p- nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6- dichloro-4-methylphenoxyacetate. 2,6-dichloro-4-(l,l,3,3-tetramethylbutyl)phenoxyacetate. 2,4- bis(l ,l -dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N.N.N'.N'- tetramethylphosphorodiamidate, alkyl A'-phenylcarbamate. borate, dimethylphosphinothioyl, alkyl 2.4-dinitrophenylsulfenate. sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0072] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES. TMS, MOM, THP, t-Bu, Bn, allyl, acety l, pivaloyl, or benzoyl.

[0073] In certain embodiments, each sulfur atom substituent is independently substituted (e.g.. substituted with one or more halogen) or unsubstituted Ci-io alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl. -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g. substituted with one or more halogen) or unsubstituted Ci-io alky l, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alky l, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or a sulfur protecting group.

[0074] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). In some embodiments, each sulfur protecting group is selected from the group consisting of -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2. -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(R“)2, -P(RCO)3+X , -P(OR00)2, -P(OROC)3+X , -P(=O)(Raa)2, -P(=O)(ORC0)2, and -P(=O)(N(Rbb) 2)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition. John Wiley & Sons, 1999.

[0075] In certain embodiments, the molecular weight of a substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms. In certain embodiments, a substituent comprises 0, 1. 2, or 3 hydrogen bond donors. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors. “Click chemistry” is a chemical approach first introduced by K. Barn Sharpless in 2001 and tailored to generate substances quickly and reliably by joining small units together through coupling reactions. See, e.g., Kolb, Finn and Sharpless Angewandte Chemie International Edition (2001) 40: 2004-2021; Evans, Australian Journal of Chemistry (2007) 60: 384-395). Exemplary coupling reactions include, but are not limited to, formation of esters, thioesters, amides (e.g., peptide coupling) from activated acids or acyl halides; nucleophilic displacement reactions (e.g, 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); and Diels-Alder reactions (e.g, tetrazine [4 + 2] cycloaddition).

[0076] As used herein, the term “salt” refers to any and all salts and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of this the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate. 2-naphthalenesulfonate. nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(CI-4 alky 1)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and ary l sulfonate.

[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 lower animals without undue toxicity7, 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. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods know n 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 alkyd sulfonate, and aryl sulfonate.

[0078] The term “prodrug'’ refers to a compound that may be converted under physiological conditions or by solvolysis to an oligonucleotide described herein. The prodrug may be a precursor of the oligonucleotide and may be pharmaceutically acceptable. The prodrug may be inactive when administered to a subject, but at least one of the converted products, e.g., the oligonucleotide, may be active. Compared to the oligonucleotide, the prodrug may offer advantages, such as higher solubility, higher permeability, higher absorption, improved distribution, improved metabolism, improved excretion, higher exposure, higher tissue compatibility7, slower delivery, more sustained delivery, lower toxicity, and / or wider therapeutic window7(see, e.g., Bundgard, H., DESIGN OF PRODRUGS (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A. C.S. Symposium Series. Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. The prodrug may be a compound wherein a hydrogen atom of -OH, -NH2, -SH, -C(=O)OH, -OP(=O)(OH)O- -SP(=O)(OH)O- -OP(=O)(OH)S- or -OP(=O)(SH)O- of the oligonucleotide is replaced with a protecting group ( "PG. " e.g.. a carbon-bound moiety, such as substituted or unsubstituted alkyl or substituted or unsubstituted phenyl). The prodrug that comprises -OPG, -NPG2, -SPG, -C(=O)OPG, -OP(=O)(OPG)O-, -SP(=O)(OPG)O- -OP(=O)(OPG)S-, or -OP(=O)(SPG)O- may be converted under physiological conditions or by solvolysis to form -OH, -NH2, -SH, -C(=O)OH, -OP(=O)(OH)O-, -SP(=O)(OH)O-. -OP(=O)(OH)S-, or -OP(=O)(SH)O- Examples of prodrugs include, but are not limited to glutathione, acyloxy, thioacyloxy, 2-carboalkoxyethyl, disulfide, thiaminal, and enol ester derivatives of a phosphorus atom-modified nucleic acid. Phosphonate and phosphate prodrugs can be found, for example, in Wiener et al., “Prodrugs or phosphonates and phosphates: crossing the membrane’7Top. Curr. Chem.. 2015, 360: 115-160. In certain embodiments, the prodrug is a prodrug of any of the formulae described herein.

[0079] A “subject” to which administration is contemplated refers to a human (e.g., 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.

[0080] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a pharmaceutical composition thereof, in or on a subject.

[0081] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g. , in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0082] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population of subjects.

[0083] The terms "condition." “disease,” and “disorder” are used interchangeably.

[0084] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound , the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, the desired dosage is delivered three times a day. two times a day, once a day, every other day, even' third day, every week, even' two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0085] A “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more signs and / or symptoms associated with the condition. In certain embodiments, the therapeutically effective amount is 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.

[0086] A “prophylactically effective amount” of a compound is an amount sufficient to prevent a condition, or one or more signs and / or symptoms associated with the condition or prevent its recurrence. In certain embodiments, the prophylactically effective amount is an amount that improves overall prophylaxis and / or enhances the prophylactic efficacy of another prophylactic agent.

[0087] The term “composition” means a mixture of substances. The term “pharmaceutical composition” means a composition suitable for administering to a subject.

[0088] The symbol “ - ” denotes the point of attachment of a chemical moiety to the remainder of a compound or chemical formula.

[0089] The term “small molecule” 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 (z.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 2,000 g / mol. In certain embodiments, the molecular weight of a small molecule is not more than 1,500 g / mol. In certain embodiments, the molecular weight of a small molecule is not more than 1,000 g / mol, not more than 900 g / mol, not more than 800 g / mol, not more than 700 g / mol, not more than 600 g / mol, not more than 500 g / mol, not more than 400 g / mol, not more than 300 g / mol, not more than 200 g / mol, or not more than 100 g / mol. In certain embodiments, the molecular weight of a small molecule is at least 100 g / mol, at least 200 g / mol, at least 300 g / mol, at least 400 g / mol, at least 500 g / mol, at least 600 g / mol, at least 700 g / mol. at least 800 g / mol, or at least 900 g / mol. or at least 1,000 g / mol. Combinations of the above ranges (e.g, at least 200 g / mol and not more than 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 in animals, preferably mammals, more preferably humans. Small molecules include 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; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589. All listed drugs are considered acceptable for use in accordance with the present disclosure.

[0090] The term “peptide,” “polypeptide,” or “protein” refers to an oligomer or polymer of amino acid residues covalently connected together by peptide bonds. A peptide, polypeptide, or protein may be of any size, structure, and function, and may be an individual peptide, polypeptide, or protein, or a collection (e.g, a complex) of peptides, polypeptides, and proteins, and optionally small molecules and / or metal ions. In certain embodiments, a peptide comprises between 2 and 10, betw een 11 and 20, between 21 and 30, between 31 and 40, or between 41 and 50, inclusive, amino acid residues. In certain embodiments, a polypeptide or protein comprises between 51 and 100. between 101 and 200, between 201 and 300, between 301 and 500. between 501 and 1 ,000, between 1,001 and 3,000, between 3,001 and 10,000, or between 10,001 and 30,000, inclusive, amino acid residues. A peptide, polypeptide, or protein may contain only natural amino acids but no non-natural amino acids; only non-natural amino acids but no natural amino acids; or both natural and non-natural amino acids. A peptide, polypeptide, or protein may contain amino acid analogs only or in addition to natural and / or non-natural amino acids. In certain embodiments, the amino acid residues of a peptide, polypeptide, or protein are residues of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and / or valine, in D and / or L form (e.g, in L form). One or more of the amino acid residues in a peptide, polypeptide, or protein may be alpha amino acid residues or homologs thereof (e.g, beta amino acid residues). One or more of the amino acid residues in a peptide, polypeptide, or protein may be protected or unprotected. One or more (e.g., two) of the termini of a peptide, polypeptide, or protein may be protected (e.g., to form an ester or amide) or unprotected (e.g., as -NH2, -NH3 , -C(=O)OH, or -C(=O)O ). One or more of the amino acid residues in a peptide, polypeptide, or protein may be modified or unmodified. A modification to an amino acid residue in a peptide, polypeptide, or protein may be an addition of a carbohydrate group, a hydroxyl group, a phosphate group, a famesyl group, an isofamesyl group, a fatty acid group, or a linker for conjugation or functionalization. A peptide, polypeptide, or protein may be naturally occurring, recombinant, synthetic, or a combination thereof. A peptide, polypeptide, or protein may be a fragment of a naturally occurring peptide, polypeptide, or protein.

[0091] The term “nucleic acid” refers to compounds composed of linked monomeric nucleotides or nucleosides. A nucleic acid includes, but is not limited to, ribonucleic acids (RNA). deoxyribonucleic acids (DNA), single-stranded nucleic acids, and double-stranded nucleic acids.

[0092] The term “oligomeric compound” or “oligomer” means a compound that consists of a small number of linked (e.g., covalently linked) subunits. With reference to a protein, peptide, polypeptide, or antibody, “subunit” refers to an amino acid (e.g, protected or unprotected amino acid) or peptide bond. With reference to an oligonucleotide, “subunit” refers to a nucleotide, nucleoside, nucleobase, intemucleosidic linker, or sugar, or a modified nucleotide, nucleoside, nucleobase, intemucleosidic linker, or sugar, or a combination thereof (e.g., a combination of nucleobase, intemucleosidic linker, or sugar, each of which may be modified or unmodified). The small number may be between 6 and 100, inclusive. In some embodiments, the small number is between 6 and 9, between 10 and 13, between 14 and 18, between 19 and 23, between 24 and 30, between 31 and 40, between 41 and 50, between 51 and 60, between 61 and 80, or between 81 and 100, inclusive.

[0093] The term “oligonucleotide” means an oligomer of linked (e.g., covalently linked) nucleotides and / or nucleosides (e.g., nucleic acid, oligomer of nucleotides), each of which can be modified or unmodified, independent from one another. Without limitation, an oligonucleotide may be comprised of ribonucleic acids (e.g., comprised of ribonucleosides), deoxyribonucleic acids (e.g., comprised of deoxyribonucleosides), modified nucleic acids (e.g., comprised of modified nucleobases, sugars, and / or phosphate groups), or a combination thereof. Oligonucleotides may comprise one or more loops in their structure (e.g., a stem loop, hairpin loop, or internal loop in the structure of an RNA). Oligonucleotides may be single-stranded or double-stranded and may be RNA, DNA, or a hybrid thereof. Oligonucleotides may include single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), plasmid DNA (pDNA), genomic DNA (gDNA), complementary DNA (cDNA), chloroplast DNA (ctDNA or cpDNA), microsatellite DNA, mitochondrial DNA (mtDNA or rnDNA), kinetoplast DNA (kDNA), provirus, lysogen, repetitive DNA, satellite DNA, viral DNA. single-stranded RNA (ssRNA), double-stranded RNA (dsRNA). messenger RNA (mRNA). precursor messenger RNA (pre- mRNA), transfer RNA (tRNA), heterogeneous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or IncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA). Piwi-interacting RNA (piRNA). polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, antisense oligonucleotides (e.g., antisense DNA and antisense RNA), interfering RNA compounds (RNAi compounds), circular RNA (circRNA) compounds, microRNA (miRNA) targeting oligonucleotides. miRNA mimics, occupancy -based compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds) and editing compounds (e.g., ADAR recruiting compounds, ADAR targeting compounds, single-stranded guide nucleic acids, or a combination thereof). RNAi compounds include double-stranded compounds (e.g., shortinterfering RNA (siRNA) and double-stranded RNA (dsRNA)) and single-stranded compounds (e.g, single-stranded siRNA (ssRNA), single-stranded RNAi (ssRNAi), short hairpin RNA (shRNA), and microRNA mimics). RNAi compounds work at least in part through the RNA- induced silencing complex (RISC) pathway resulting in sequence specific degradation and / or sequestration of a target nucleic acid through a process known as RNA interference (RNAi). The term “RNAi compound" is meant to be equivalent to other terms used to describe nucleic acid compounds that are capable of mediating sequence-specific RNA interference, for example, interfering RNA (iRNA), iRNA agent, RNAi agent, small interfering RNA, short interfering RNA, short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically modified siRNA, and others. Additionally, the term “RNAi’' is meant to be equivalent to other terms used to describe sequence-specific RNA interference. In some embodiments, an oligonucleotide comprises 6-100 nucleotides and nucleosides. In some embodiments, an oligonucleotide comprises 10-50 nucleotides and nucleosides. In some embodiments, an oligonucleotide comprises 14-30 nucleotides and nucleosides. In some embodiments, an oligonucleotide comprises 20-23 nucleotides and nucleosides. In certain embodiments, an oligonucleotide comprises 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides and nucleosides.

[0094] A double-stranded oligonucleotide may comprise “blunt ends” or “overhangs.” In a blunt- ended oligonucleotide, both strands of the oligonucleotide are of equal length and end at the same base position, leaving no unpaired bases on either end. An oligonucleotide with overhangs (or “sticky ends”), in contrast, comprises unpaired nucleotides at each end. In some embodiments, an oligonucleotide has blunt ends at both ends. In some embodiments, an oligonucleotide has overhangs at each end. In some embodiments, an oligonucleotide has a blunt end at one end and an overhang at the other end. In certain embodiments, the oligonucleotide comprises between 6 and 8, between 9 and 1 1 , between 12 and 14, between 15 and 17, between 18 and 20, between 21 and 24, between 25 and 28, between 29 and 32, between 33 and 36, or between 37 and 40, inclusive, paired base pairs.

[0095] The term “nucleobase” refers to a nitrogen-containing moiety at the T position of a nucleoside. Nucleobases may include purine bases and pyrimidine bases. Five nucleobases — adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U) — are referred to as primary or canonical nucleobases. Nucleobases may include unmodified and modified nucleobases. When a nucleobase is listed in a formula definition, it refers to that moiety covalently bonded to the recited formula.

[0096] The term “nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or intemucleoside linkage.

[0097] The term “nucleoside” means a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each, independently, unmodified or modified. The nucleoside may an unmodified or modified nucleoside. “Modified nucleoside” means a nucleoside comprising a modified nucleobase and / or a modified sugar moiety. Modified nucleosides include abasic nucleosides, which lack a nucleobase and optionally include a non- nucleobase moiety at the corresponding position (e.g, 1' position).

[0098] The terms “intemucleoside linkage,” “intemucleoside linker,” “intemucleosidic linkage,” and “intemucleosidic linker” are used interchangeably.

[0099] The term “target nucleic acid,” “target RNA,” and “nucleic acid target” all mean a nucleic acid capable of being targeted by oligonucleotides (e.g.. a radical of a ligand included in the oligonucleotides) described herein.

[0100] “Target region” means a portion of a target nucleic acid to which one or more oligonucleotides (e.g., a radical of a ligand included in the oligonucleotides) is targeted. “Terminal group'’ means a chemical group or group of atoms that is covalently linked to a terminus of an oligonucleotide.

[0101] The term “sense oligonucleotide,” “sense oligonucleotide strand,” or “sense strand” means the strand of a double-stranded oligonucleotide that includes a region that is substantially complementary' to a region of the antisense strand of the double-stranded oligonucleotide. The sense strand may carry a translatable code in the 5' to 3' direction.

[0102] The term “antisense oligonucleotide,” "antisense oligonucleotide strand,” or “antisense strand” means an oligonucleotide which includes a region that is complementary, or at least partially complementary', to a target nucleic acid or sense strand of a nucleic acid. In some embodiments, the antisense strand does not carry a translatable code in the 5' to 3' direction. In some embodiments, the antisense strand and the sense strand or target nucleic acid are at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% complementary' to one another. In certain embodiments, the antisense strand and the sense strand or target nucleic acid are completely complementary (100% complementary ) to one another.

[0103] The terms “microRNA” and “miRNA,” as may be used interchangeably herein, refer to short (e.g., about 20 to about 24 nucleotides in length) non-coding ribonucleic acids (RNAs) that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by7the Drosha ribonuclease III enzy me to produce a stem-loop precursor miRNA (pre-miRNA) approximately 70 nucleotides in length, which is further processed in the RNAi pathway. As part of this pathway, the pre-miRNA is cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into an RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing (z.e.. partial complementarity) with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. This mechanism is most often seen through the binding of the miRNA on the 3' untranslated region (UTR) of the target mRNA, which can decrease gene expression by either inhibiting translation (for example, by blocking the access of ribosomes for translation) or directly causing degradation of the transcript. The term (z.e., miRNA) may be used herein to refer to any form of the subject miRNA (e.g., precursor, primary, and / or mature miRNA).

[0104] The terms “small interfering RNA,” “short interfering RNA,” and “siRNA,” as may be used interchangeably herein, refer to RNA compounds that present as non-coding single-stranded RNA or double-stranded RNA (dsRNA) compounds having a strand or strands of about 20 to about 24 nucleotides in length and are useful in RNA interference (RNAi). siRNAs are often found with phosphorylated 5' ends and hydroxylated 3' ends, which 3' ends typically have a 2- nucleotide overhang beyond the 5' end of the anti -parallel strand (e.g., complementary strand of the dsRNA compound). siRNAs can interfere with the expression of specific genes through binding of target sequences (e.g., target nucleic acid sequences) to which they are complementary and promoting (e.g., facilitating, triggering, initiating) degradation of the mRNA, thereby preventing (e.g., inhibiting, silencing, interfering with) translation. RNAi act, at least in part, through an RNA-induced silencing complex (RISC) pathway or Ago2, but not through RNaseH, to modulate a target nucleic acid and / or protein encoded by a target nucleic acid. After integration and separation into the RISC complex, siRNAs base-pair (e.g, full complementarity) to their target mRNA and cleave it, thereby preventing it from being used as a translation template. As discussed herein above, also part of the RNAi pathway, a miRNA-loaded RISC complex scans cytoplasmic mRNAs for potential complementarity (e g., partial complementarity).

[0105] The term ‘‘circular RNA’’ (‘‘circRNA”) refers to an RNA that is covalently closed (z.e., the 5' and 3' ends have been joined together) to form a continuous loop. CircRNAs are resistant to exonuclease degradation and are often much more stable than a corresponding linear RNA of the same sequence. CircRNAs therefore typically have longer half-lives than linear RNAs. They have many different biological functions and are known to act, for example, as transcriptional regulators, microRNA sponges, and protein templates. CircRNAs are also known to interact with proteins, e.g., by mediating or altering protein-protein interactions, sequestering proteins, recruiting proteins to chromatin, and facilitating protein translocation.

[0106] A “short hairpin RNA” (“shRNA”) refers to an RNA compound with a tight hairpin turn that can be used, for example, to silence target gene expression via RNAi. shRNA often have lower rates of degradation and turnover relative to other RNAi agents due to the presence of the hairpin structure.

[0107] The term “mRNA” or “mRNA molecule” refers to messenger RNA, or the RNA that serves as a template for protein synthesis in a cell. The sequence of a strand of mRNA is based on the sequence of a complementary strand of DNA comprising a sequence coding for the protein to be synthesized.

[0108] The term “ADAR recruiting compound,” as may be used herein, refers to a nucleic acid that is configured to increase the concentration of Adenosine Deaminase Acting on Ribonucleic Acid (ADAR) enzyme in a location around the nucleic acid. In some embodiments, an increased concentration is relative to the concentration in a given location absent the ADAR recruiting compound. In some embodiments, an ADAR recruiting compound comprises a double-stranded RNA duplex.

[0109] The term '‘ADAR targeting compound,” as may be used herein, refers to a nucleic acid that is configured to direct an ADAR compound to a desirable location (e.g., location). As used herein, the term “direct” refers to increasing the concentration of ADAR in the desirable location as compared to the concentration absent the ADAR targeting compound. In some embodiments, the ADAR targeting compound can be configured to control the desirable location by altering the sequence and / or properties of the nucleic acid (e.g., by modifications to the nucleobase, sugar, intemucleoside linkage, or other component). In some embodiments, an ADAR targeting compound comprises an ADAR recruiting compound and a single-stranded guide nucleic acid. In some embodiments, an ADAR targeting compound comprises a double-stranded RNA duplex and a single-stranded guide nucleic acid.

[0110] The term “single-stranded guide nucleic acid” or “guide RNA,” as may be used herein, refers to a nucleic acid of a single strand, which comprises a specific sequence that is at least partially complementary to a target sequence. In some embodiments, the target sequence is at, adjacent to, or in proximity to, a location where it is desirable to modulate ADAR concentration. In some embodiments, the level of complementarity is sufficient to facilitate binding (e.g., annealing) of the single-stranded guide nucleic acid to the target sequence.

[0111] “Modified oligonucleotide” means an oligonucleotide, wherein at least one sugar, nucleobase, or intemucleoside linkage is modified.

[0112] “Nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or intemucleoside linkage.

[0113] The term “oligomeric duplex” means a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of an oligomeric duplex may be referred to as a “duplexed oligomeric compound.” The oligonucleotides of each oligomeric compound of an oligomeric duplex may include non-compl ementaiy overhanging nucleosides. “Phosphorothioate,” “phosphorothioate linkage,” or “phosphorothioate linker” means a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced wi th a sulfur atom.

[0114] “Phosphorothiolate,” “phosphorothiolate linkage,” or “phosphorothiolate linker” means a modified phosphate linkage in which one or each of the bridging oxygen atoms is replaced with a sulfur atom.

[0115] A “linker” refers to a polyvalent (e.g, divalent, trivalent, or tetravalent) chemical moiety (e.g., a combination of atoms having appropriate valency according to known chemistry principles) that covalently connects two or more (e.g. three or four) components of a compound (e.g, oligonucleotide) provided herein.

[0116] The term '‘ligand’’ refers to a substance that binds to or otherwise interacts with a protein, nucleic acid, or other biological molecule. In some embodiments, a ligand is selected from the group consisting of small molecules; saccharines; oligosaccharides: polysaccharides; biological macromolecules, e g., peptides, proteins, and peptide analogs and derivatives; peptidomimetics; antibodies and antigen binding fragments thereof; nucleic acids; nucleic acid analogs and derivatives; an extract made from biological materials such as bacteria, plants, fungi, or animal cells; animal tissues; and naturally occurring or synthetic compositions. In some embodiments, a ligand is a small molecule. In some embodiments, a ligand binds to a protein (e.g., a receptor). In certain embodiments, a ligand binds to tropomyosin receptor kinase B (TrkB), cannabinoid receptor type 1 (CB1 ), α4β1 / 7 integrin receptor, or A-methyl-D-aspartate (NMDA) receptor. In some embodiments, a ligand is capable of selectively targeting an oligonucleotide (e.g., an oligonucleotide strand thereof) to a region of the body, or to a cell. In some embodiments, a ligand is capable of targeting an oligonucleotide (e.g. an oligonucleotide strand thereof) to the brain of a subject (e.g., to the striatum, cerebellum, brain stem, hippocampus, frontal cortex, or spinal cord of the subject). In some embodiments, a ligand is capable of targeting an oligonucleotide (e.g, an oligonucleotide strand thereof) to a central nervous system (CNS) cell (e.g, a neuron). In some embodiments, a ligand is not a lipid.

[0117] The term “internal position” of an oligonucleotide strand refers to a position of the oligonucleotide strand other than the 5' or 3' nucleoside. In some embodiments, the internal position is at an intemucleoside linkage (e.g., the intemucleoside linkage between the 5' nucleoside and the second nucleoside counted from the 5' end; the intemucleoside linkage between the 3' nucleoside and the second nucleoside counted from the 3' end; the intemucleoside linkage between the first n and n+1 nucleosides counted from the 5' end, wherein n is an integer between 2 and 20, inclusive, as the number of nucleosides of the oligonucleotide strand permits). In some embodiments, the internal position is at a position on an “internal nucleoside” (a nucleoside that is not the 5' or 3' nucleoside). An oligonucleotide comprising a modification (e.g., conjugation of a radical of a ligand) at an internal position may be referred to as an “internally - modified oligonucleotide.”

[0118] The term “lipid” or “lipophilic moiety ” refers to organic compounds that are substantially insoluble in water at ambient temperature and pressure. A lipid may be a lipid recited in the LIPID MAPS® Structure Database (LMSD). A lipid may be a fatty acyl, glycerolipid, glycerophospholipid, sphingolipid, saccharolipid, polyketide, sterol lipid, or prenol lipid. A fatty7acyl may be a fatty acid or conjugate, octadecanoid, eicosanoid, docosanoid, fatty alcohol, fatty aldehyde, fatly ester, fatly amide, folly nitrile, fatly ether, hydrocarbon, oxygenated hydrocarbon, or fatly acyl glycoside A glycerolipid may be a monoradylglycerol, diradylglycerol, triradylglycerol, glycosylmonoradylglycerol, glycosyldiradylglycerol, betaine monoradylglycerol, or betaine diradylglycerol. A glycerophospholipid may be a glycero phosphocholine, glycerophosphoethanolamine, glycerophosphoserine, glycerophosphoglycerol. glycerophosphoglycerophosphate. glycerophosphoinositol, glycerophosphoinositol monophosphate, glycerophosphoinositol bisphosphate, glycerophosphoinositol trisphosphate, glycerophosphate, glyceropyrophosphate, glycerophosphoglycerophosphoglycerol, CDP-glycerol, glycosylglycerophospholipid, glycerophosphoinositolglycan. glycerophosphonocholine. glycerophosphonoethanolamine, diglycerol tetraether phospholipid, glycerol-nonitol tetraether phospholipid, oxidized glycerophospholipid, glycerophosphoethanolamine glycan, dihydroxyacetonephosphate, glycerophosphoethanol, glycerophosphothreonine, or cyclic glycerophosphatidic acid. A sphingolipid may be a sphingoid base, ceramide, phosphosphingolipid, phosphonosphingolipid, neutral glycosphingolipid, acidic glycosphingolipid, basic glycosphingolipid, amphoteric glycosphingolipid, or arsenosphingolipid. A saccharolipid may be an acylaminosugar, acylaminosugar glycan, acyltrehalose, or acyltrehalose glycan. A polyketide may be a linear polyketide, halogenated acetogenin, annonaceae acetogenin, macrolide, lactone polyketide, ansamycin. polyene, linear tetracycline, angucy cline, poly ether antibiotic, aflatoxin, cytochalasin, flavonoid, aromatic polyketide, non-ribosomal peptide / polyketide hybrid, or phenolic lipid. A sterol lipid may be a sterol, steroid, secosteroid, bile acid or a derivative thereof, or steroid conjugate. A prenol lipid may be an isoprenoid, quinone, hydroquinone, polyprenol, or hopanoid. The term lipid includes, e.g., cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1- pyrene butyric acid, dihydrotestosterone, l,3-bis-O(hexadecyl)glycerol, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3- propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, ibuprofen, naproxen, dimethoxytrityl, or phenoxazine. A lipid may be a hydrocarbon (e.g, substituted or unsubstituted, saturated or unsaturated, branched or unbranched hydrocarbon). A hydrocarbon may be an alkane, alkene, or alkyne. The size of an unsubstituted hydrocarbon may be C7-C36 (that is, the unsubstituted hydrocarbon contains totally 7-36 carbon atoms in the backbone and, if present, the branches). A substituted hydrocarbon may be a hydrocarbon substituted at least with one or more halogen (e.g., F) atoms, as valency permits. In certain embodiments, each substituent of a substituted hydrocarbon is not another hydrocarbon. The size of a substituted hydrocarbon may be C7-C36 (that is, the substituted hydrocarbon contains totally 7-36 carbon atoms in the backbone and, if present, the branches, excluding the atoms in the substituents). The term “unsaturated"’ or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0119] The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

[0120] DETAILED DESCRIPTION

[0121] In one aspect, the present disclosure provides oligonucleotides comprising a radical of a ligand at an internal position. The present disclosure also provides pharmaceutical compositions and kits comprising any of the oligonucleotides disclosed herein. The present disclosure also provides methods of delivering any of the oligonucleotides disclosed herein to a subject, methods of treating a disease in a subject in need thereof using any of the oligonucleotides disclosed herein, methods of preventing a disease in a subject in need thereof using any of the oligonucleotides disclosed herein, and methods of modulating the activity of a protein in a subject, cell, tissue, or biological sample. In certain embodiments, the disease is a CNS disease, neurodegenerative disease, or neurocognitive disorder.

[0122] Oligonucleotides

[0123] In one aspect, the present disclosure provides oligonucleotides comprising a modified oligonucleotide strand of Formula I:

[0124] (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: is a divalent radical of an oligonucleotide strand; si instances of the intemucleosidic linkers of are independently replaced with si is 1, 2. 3, 4, 5, or 6; each instance of LAand L4is independently a linker; each instance of A4is independently a radical of a ligand or lipid, provided that at least one instance of A4is a radical of a ligand; each of y5 and y6 is independently 0 or 1; when y5 is 0. L5is hydrogen, substituted or unsubstituted. Ci-6 alkyl, or an oxygen protecting group; or when y5 is 1, L5is a linker; when y6 is 0, L6is hydrogen, substituted or unsubstituted, Ci-6 alkyl, or an oxygen protecting group; or when y6 is 1, L6is a linker; each of A5and A6, if present, is independently a radical of a ligand or lipid; and each of the ligands is different from each of the lipids.

[0125] In certain embodiments, si is 1. In certain embodiments, si is 2, 3, 4, 5, or 6.

[0126] In certain embodiments, y5 is 0. In certain embodiments, y5 is 1. In certain embodiments, y6 is 0. In certain embodiments, y6 is 1.

[0127] In certain embodiments, an oligonucleotide strand has anucleobase sequence that is at least partially complementary to a target nucleic acid sequence (e.g., an expressed target nucleic acid within a cell). In some embodiments, the oligonucleotide, upon delivery7to a cell expressing a target nucleic acid, is able to modify the expression of the underlying gene. In some embodiments, the oligonucleotide, upon delivery to a cell expressing a target nucleic acid, is able to inhibit the expression of the underlying gene. The gene expression can be modified or inhibited in vitro or in vivo. In certain embodiments, an oligonucleotide comprises one or more ribonucleic acids (e.g., one or more ribonucleosides), deoxyribonucleic acids (e.g, one or more deoxyribonucleosides), modified nucleic acids (e.g, one or more modified nucleobases, sugars, and / or intemucleoside linkages), or a combination thereof. In some embodiments, an oligonucleotide comprises a ribonucleic acid (RNA). In some embodiments, an oligonucleotide comprises a deoxyribonucleic acid (DNA). In some embodiments, an oligonucleotide comprises a modification (e.g., modified nucleobase, modified sugar, or modified intemucleoside linkage).

[0128] In some embodiments, an oligonucleotide is double-stranded (e.g., comprised of two single-stranded nucleic acids). In some embodiments, a double-stranded oligonucleotide comprises a first oligonucleotide strand having a region complementary' to a target nucleic acid and a second oligonucleotide strand having a region complementary7to the first oligonucleotide strand. The first and second oligonucleotide strands can be independently modified. In certain embodiments, the first oligonucleotide strand is linked to one or more radicals of ligands (e.g, a TrkB, CB1, a,4p>i 7 integrin, or NMDA receptor ligand). In certain embodiments, the second oligonucleotide strand is linked to one or more radicals of ligands (e.g., a TrkB, CB1, 0401 / 7 integrin, or NMDA receptor ligand). In certain embodiments, an oligonucleotide comprises one or more radicals of ligands at one or more internal positions. In certain embodiments, an oligonucleotide comprises one or more radicals of ligands at one or more internal positions and optionally further comprises a radical of a ligand at the 5' end and / or a radical of a ligand at the 3' end.

[0129] In some embodiments, an oligonucleotide strand is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,

[0130] 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68,

[0131] 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81. 82. 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,

[0132] 95, 96, 97, 98, 99, or 100 nucleotides in length.

[0133] In some embodiments, an oligonucleotide strand is 6-10, 11-15, 16-20, 21-25, 26-30, 31- 35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, or 96- 100, inclusive, nucleotides in length. In some embodiments, an oligonucleotide strand is about 6 nucleotides in length to about 100 nucleotides in length, inclusive. In some embodiments, an oligonucleotide strand is about 20 nucleotides in length to about 90 nucleotides in length, inclusive. In some embodiments, an oligonucleotide strand is about 30 nucleotides in length to about 80 nucleotides in length, inclusive. In some embodiments, an oligonucleotide strand is about 40 nucleotides in length to about 70 nucleotides in length, inclusive. In some embodiments, an oligonucleotide strand is about 50 nucleotides in length to about 60 nucleotides in length, inclusive.

[0134] In certain embodiments, an oligonucleotide strand is about 14 nucleotides in length to about 23 nucleotides in length.

[0135] In some embodiments, an oligonucleotide is a therapeutic oligonucleotide. A therapeutic oligonucleotide may comprise, for example, without limitation, an RNA (e.g, a small interfering RNA (siRNA), a microRNA (miRNA) antagonist, a miRNA mimic, an ADAR recruiting compound, an ADAR targeting compound, a guide RNA, an antisense oligonucleotide, a short hairpin RNA (shRNA), a circular RNA (circRNA)) or combinations thereof.

[0136] In certain embodiments, a miRNA is a precursor, primary, and / or mature miRNA.

[0137] In certain embodiments, an oligonucleotide comprises an antisense oligonucleotide strand. In certain embodiments, an antisense oligonucleotide strand is complementary to a sense oligonucleotide strand (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% complementary). In certain embodiments, an antisense oligonucleotide strand is complementary to a pre-mRNA. In certain embodiments, an antisense oligonucleotide strand blocks translation and promotes degradation of the mRNA transcript. In certain embodiments, the antisense oligonucleotide (alone or together with a complementary sense oligonucleotide) is able to silence gene expression through the RNA-induced silencing complex (RISC) pathway. In certain embodiments, an antisense oligonucleotide strand recruits RNase H and promotes degradation of the mRNA transcript. In certain embodiments, an antisense oligonucleotide strand targets miRNA, inhibiting the miRNA from modulating mRNA expression and promoting degradation of the miRNA. In certain embodiments, an oligonucleotide comprises or recruits an editing complex to edit RNA.

[0138] Certain oligonucleotides of the present disclosure can exist in an unsolvated forms as well as solvated forms, including hydrated forms. Certain oligonucleotides of the present disclosure may exist in crystalline or amorphous forms.

[0139] In certain embodiments, an oligonucleotide comprises an oligonucleotide strand having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity or complementarity7to a gene (e.g., human gene) with which a disease (e.g., CNS disease) is associated, or a portion thereof (e.g.. 10 nucleotides thereof, 11 nucleotides thereof, 12 nucleotides thereof, 13 nucleotides thereof, 14 nucleotides thereof, 15 nucleotides thereof, 16 nucleotides thereof, 17 nucleotides thereof, 18 nucleotides thereof, 19 nucleotides thereof, 20 nucleotides thereof, 21 nucleotides thereof, 22 nucleotides thereof, 23 nucleotides thereof, 24 nucleotides thereof, 25 nucleotides thereof, 26 nucleotides thereof, 27 nucleotides thereof, 28 nucleotides thereof, 29 nucleotides thereof, or 30 nucleotides thereof). In certain embodiment, the oligonucleotide comprises an antisense oligonucleotide. In certain embodiments, the oligonucleotide comprises a sense oligonucleotide. In certain embodiments, the oligonucleotide is a single-stranded oligonucleotide. In certain embodiments, the oligonucleotide is a doublestranded oligonucleotide. In certain embodiments, the disease is associated with the overexpression of the gene. In certain embodiments, “associated with7’ refers to “caused at least in part by.”

[0140] In certain embodiments, an oligonucleotide comprises an oligonucleotide strand having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity or complementarity to a microtubule-associated protein tau (MAPT) gene (e.g, human MAPT gene), or a portion thereof (e.g, 10 nucleotides thereof, 11 nucleotides thereof, 12 nucleotides thereof, 13 nucleotides thereof, 14 nucleotides thereof, 15 nucleotides thereof, 16 nucleotides thereof, 17 nucleotides thereof, 18 nucleotides thereof, 19 nucleotides thereof, 20 nucleotides thereof, 21 nucleotides thereof, 22 nucleotides thereof, 23 nucleotides thereof, 24 nucleotides thereof, 25 nucleotides thereof, 26 nucleotides thereof, 27 nucleotides thereof, 28 nucleotides thereof, 29 nucleotides thereof, or 30 nucleotides thereol). In certain embodiment, the oligonucleotide comprises an antisense oligonucleotide. In certain embodiments, the oligonucleotide comprises a sense oligonucleotide. In certain embodiments, the oligonucleotide is a single-stranded oligonucleotide. In certain embodiments, the oligonucleotide is a doublestranded oligonucleotide. Exemplary' nucleotide sequences of the human MAPT gene can be found, for example, at GenBank Accession No. NM_001377265.1 (incorporated herein as SEQ ID NO: 1), and nucleotides 2624000 to 2761000 ofNT_010783.14 (incorporated herein as SEQ ID NO: 2). Additional examples of MAPT sequences are readily available through publicly available databases, e.g., GenBank, UniProt, and OMIM. Further information on MAPT can be found, for example, at www.ncbi.nlm.nih.gov / gene / ?term=MAPT. MAPT, as used herein, also refers to variations of the MAPT gene including variants provided in the SNP database. Numerous sequence variations within the MAPT gene have been identified and may be found at, for example, NCBI dbSNP and UniProt (see, e.g., www.ncbi.nlm.nih.gov / snp / ?term=MAPT). In certain embodiments, the oligonucleotide inhibits the expression, translation, or activity of MAPT in a subject, cell, tissue, or biological sample. In certain embodiments, the oligonucleotide inhibits the expression, translation, or activity of MAPT in a subject, cell, tissue, or biological sample by 3-10%, 10-20%, 20-40%. 40-60%, 60-90%, or 90-99% relative to the expression, translation, or activity in a negative control (e.g., as measured by an immunoassay, a hybridization-based assay, or a sequencing-based assay (e.g., RNA-Seq)).

[0141] In certain embodiments, an oligonucleotide comprises an oligonucleotide strand having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity or complementarity to a superoxide dismutase type 1 (SOD1) gene (e.g., a human SOD1 gene), or a portion thereof (e.g., 10 nucleotides thereof, 11 nucleotides thereof, 12 nucleotides thereof, 13 nucleotides thereof, 14 nucleotides thereof, 15 nucleotides thereof, 16 nucleotides thereof, 17 nucleotides thereof, 18 nucleotides thereof, 19 nucleotides thereof, 20 nucleotides thereof, 21 nucleotides thereof, 22 nucleotides thereof, 23 nucleotides thereof, 24 nucleotides thereof, 25 nucleotides thereof, 26 nucleotides thereof, 27 nucleotides thereof, 28 nucleotides thereof, 29 nucleotides thereof, or 30 nucleotides thereof). In certain embodiment, the oligonucleotide comprises an antisense oligonucleotide. In certain embodiments, the oligonucleotide comprises a sense oligonucleotide. In certain embodiments, the oligonucleotide is a single-stranded oligonucleotide. In certain embodiments, the oligonucleotide is a double-stranded oligonucleotide. Exemplary nucleotide sequences of the human SOD1 gene can be found, for example, at nucleotides 5092 to 138872 of NG_007398.2 (incorporated herein as SEQ ID NO: 3), and GenBank Accession No NM_016835.5 (incorporated herein as SEQ ID NO: 4). Additional examples of SOD1 sequences are readily available through publicly available databases, e.g., GenBank, UniProt, and OMIM. Further information on SOD1 can be found, for example, at www.ncbi.nlm.nih.gov / gene / ?term=SODl. SOD1, as used herein, also refers to variations of the SOD1 gene including variants provided in the SNP database. Numerous sequence variations within the SOD1 gene have been identified and may be found at, for example, NCBI dbSNP and UniProt (see, e.g., www.ncbi.nlm.nih. gov / snp / ?term=SODl). In certain embodiments, the oligonucleotide inhibits the expression, translation, or activity of SOD1 in a subject, cell, tissue, or biological sample. In certain embodiments, the oligonucleotide inhibits the expression, translation, or activity of SOD1 in a subject, cell, tissue, or biological sample by 3-10%, 10-20%, 20-40%, 40-60%, 60-90%, or 90-99% relative to the expression, translation, or activity in a negative control (e.g., as measured by an immunoassay, a hybridization-based assay, or a sequencing-based assay (e.g., RNA-Seq)).

[0142] In certain embodiments, an oligonucleotide comprises an oligonucleotide strand having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity or complementarity to an leucine-rich repeat kinase 2 (LRRK2) gene (e.g., a human LRRK2 gene), or a portion thereof (e.g, 10 nucleotides thereof, 11 nucleotides thereof, 12 nucleotides thereof, 13 nucleotides thereof, 14 nucleotides thereof, 15 nucleotides thereof, 16 nucleotides thereof, 17 nucleotides thereof, 18 nucleotides thereof, 19 nucleotides thereof, 20 nucleotides thereof, 21 nucleotides thereof, 22 nucleotides thereof, 23 nucleotides thereof, 24 nucleotides thereof, 25 nucleotides thereof, 26 nucleotides thereof, 27 nucleotides thereof, 28 nucleotides thereof, 29 nucleotides thereof, or 30 nucleotides thereof). In certain embodiment, the oligonucleotide comprises an antisense oligonucleotide. In certain embodiments, the oligonucleotide comprises a sense oligonucleotide. In certain embodiments, the oligonucleotide is a single-stranded oligonucleotide. In certain embodiments, the oligonucleotide is a double-stranded oligonucleotide. Exemplar}7nucleotide sequences of the human LRRK2 gene can be found, for example, at GenBank Accession No. NM_198578.4 (incorporated herein as SEQ ID NO: 5). and nucleotides 5002 to 149290 of NG_01 1709.2 (incorporated herein as SEQ ID NO: 6). Additional examples of LRRK2 sequences are readily available through publicly available databases, e.g., GenBank, UniProt, and OMIM. Further information on LRRK2 can be found, for example, at w vw.ncbi.nlm.nih.gov / gene / ?term=LRRK2. LRRK2. as used herein, also refers to variations of the LRRK2 gene including variants provided in the SNP database. Numerous sequence variations within the LRRK2 gene have been identified and may be found at, for example, NCBI dbSNP and UniProt (see, e.g., www.ncbi.nlm.nih.gov / snp / ?term=LRRK2). In certain embodiments, the oligonucleotide inhibits the expression, translation, or activity of LRRK2 in a subject, cell, tissue, or biological sample. In certain embodiments, the oligonucleotide inhibits the expression, translation, or activity of LRRK2 in a subject, cell, tissue, or biological sample by 3-10%, 10- 20%, 20-40%, 40-60%, 60-90%, or 90-99% relative to the expression, translation, or activity’ in a negative control (e.g., as measured by an immunoassay, a hybridization-based assay, or a sequencing-based assay (e.g., RNA-Seq)).

[0143] 5' 3'

[0144] In certain embodiments,L~ is a sense oligonucleotide strand, and the oligonucleotide further comprises an antisense oligonucleotide strand. In certain embodiments, is an antisense oligonucleotide strand, and the oligonucleotide further comprises a sense oligonucleotide strand.

[0145] Linkers

[0146] In some embodiments, the oligonucleotides provided herein comprise one or more linkers (e.g, LA, L4, L5, and L6).

[0147] In certain embodiments, a linker comprises a chain structure, such as a hydrocarbyl chain, or an oligomer of repeating units or combination of such repeating units. In certain embodiments, a linker comprises 1-5. 6-10. 11-15, 16-20, 21-25. 26-30, 31-35, 36-40. 41-45, or 46-50, inclusive, repeating units. In certain embodiments, the repeating unit is -CH2-. In certain embodiments, the repeating unit is -CH2CH2O- or -OCH2CH2-. In certain embodiments, a linker is 1-5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, or 96-100, inclusive, atoms long, between any two of the attachment points.

[0148] In certain embodiments, a linker contains in the backbone thereof carbon atoms (e.g. , 1 -5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, or 96-100, inclusive, carbon atoms). In certain embodiments, a linker contains in the backbone thereof heteroatoms (e.g., nitrogen, oxygen, sulfur, phosphorous) (e.g, 1-3, 4-6, 7-9, 10-12, 13-15, 16-18, 19-21, 22-24, 25-27, 28-30, 31-33, 34-36, or 37-40, inclusive, heteroatoms). In certain embodiments, a linker comprises in the backbone thereof amide, ester, disulfide, or a combination thereof. In certain embodiments, a linker comprises in the backbone thereof hydrazone, oxime, imine, guanidine, urea, carbamate, alkyl, sulfonamide, heterocyclic, or a combination thereof. In certain embodiments, a linker comprises in the backbone thereof one or more groups independently selected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino. In certain embodiments, a linker comprises in the backbone thereof at least one phosphorus atom. In certain embodiments, a linker includes at least one non-polar linking group. In certain embodiments, a linker includes at least one polar linking group. In certain embodiments, a linker includes at least one linking group formed by a clickchemistry reaction of a first and second click-chemistry reactive moieties. In certain embodiments, a linker is substituted. In certain embodiments, a linker is substituted with alkyl, alkenyl, alkynyl, amino, alkylamino, dialkylamino, trialkylamino, hydroxyl, alkoxy, carbonyl, halogen, aryl, heterocyclic, aromatic heterocyclic, cyano, amide, carbamoyl, carboxylic acid, ester, thioether, alkylthioether, thiol, ureido, or a combination thereof. As would be appreciated by one of skill in this art, each of these groups may in turn be substituted. In some embodiments, a linker is substituted with one, two, three, four, five, six, seven, eight, nine, ten, or more than ten substituents.

[0149] In some embodiments, a linker is a bond (e.g. , a single bond).

[0150] In some embodiments, a linker is optionally substituted alky lene. In some embodiments, a terminal backbone carbon atom of alkylene is an attachment point. In some embodiments, an internal backbone carbon atom of alkylene is an attachment point. In some embodiments, a linker is optionally substituted alkenylene. In some embodiments, a linker is optionally substituted alkynylene. In some embodiments, a linker is substituted or unsubstituted, Ci-100 alkylene, substituted or unsubstituted, C2-100 alkenylene, or substituted or unsubstituted, C2-100 alkynylene. In certain embodiments, one or more (e.g., two, three, or four) backbone atoms of the Ci-ioo alkylene. C2-100 alkenylene, or C2-100 alkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted ary lene, or substituted or unsubstituted heteroarylene, as valency permits. In some embodiments, a linker is substituted or unsubstituted, C7-70 alkylene, substituted or unsubstituted, C7-70 alkenylene, or substituted or unsubstituted, C7-70 alkynylene. In certain embodiments, one or more (e.g , two, three, or four) backbone atoms of the C7-70 alkylene, C7-70 alkenylene, or C7-70 alkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted ary lene, or substituted or unsubstituted heteroarylene, as valency permits. In certain embodiments, one or two backbone atoms of the C7-70 alkylene, C7-70 alkenylene, or C7-70 alkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits. In some embodiments, a linker is substituted or unsubstituted, C1-6, C7-12, C13-18, C19-24, C25-30, C31-36. C37-44, C45-52. C53-60, or C61-70 alkylene, substituted or unsubstituted. C2-6, C7-12, C13- 18, C19-24, C25-30, C31-36, C37-44, C45-52, C53-60, or Cei-70 alkenylene, or substituted or unsubstituted, C2-6, C7-12, C 13-18, C19-24, C25-30, C31-36, C37-44, C45-52, C53-60, or Cei-70 alkynylene. In certain embodiments, one or more (e.g., two, three, or four) backbone atoms of the C1-6, C7-12, C13-18, C19- 24, C25-30, C31-36, C37-44, C45-52, C53-60. or Cei-70 alkylene, C2-6, C7-12, C13-18, C19-24, C 25-30, C31-36, C37-44, C45-52, C53-60, or Cei-70 alkenylene, or C2-6, C7-12, C13-18, C19-24, C25-30, C31-36, C37-44, C45-52, C53-60, or Cei-70 alkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.

[0151] In some embodiments, a linker is optionally substituted alkenylene comprising one, two. three, four, five, six, seven, eight, nine, ten, or more than ten double bonds. In some embodiments, a linker is optionally substituted alky nylene comprising one, two, three, four, five, six, seven, eight, nine, ten, or more than ten triple bonds. In some embodiments, a linker is optionally substituted, alkylene, alkenylene. or alkynylene and comprises one or more (e.g , two, three, four, five) branch points. In certain embodiments, the linker comprises two, three, four, or five branch points.

[0152] In some embodiments, a linker is optionally substituted heteroalkylene. In some embodiments, a terminal backbone atom of heteroalkylene is an attachment point. In some embodiments, an internal backbone atom of heteroalkylene is an attachment point). In some embodiments, a linker is optionally substituted heteroalkenylene. In some embodiments, a linker is optionally substituted heteroalkynylene. In some embodiments, a linker is substituted or unsubstituted, Ci-100 heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, or substituted or unsubstituted, C 2-100 heteroalkynylene. In certain embodiments, one or more (e.g , two, three, or four) backbone atoms of the Ci-100 heteroalkylene, C2-100 heteroalkenylene, or C2-100 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits. In some embodiments, a linker is substituted or unsubstituted, C7-70 heteroalkylene, substituted or unsubstituted, C7-70 heteroalkenylene, or substituted or unsubstituted, C7-70 heteroalkynylene. In certain embodiments, one or more (e.g., two, three, or four) backbone atoms of the C7-70 heteroalkydene, C7-70 heteroalkenyl ene, or C7-70 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits. In certain embodiments, one or two backbone atoms of the C7-70 heteroalky dene, C7-70 heteroalkenylene, or C7-70 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene. substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits. In some embodiments, a linker is substituted or unsubstituted, C1-6, C7-12, C13-18, C19-24, C25-30, C31-36, C37-44, C45-52, C53-60, or Cei-70 heteroalkydene, substituted or unsubstituted, C1-6, C7-12, C13-18, C19-24, C 25-30, C31-36, C37-44, C45-52, C53-60, or Cei-70 heteroalkenylene, or substituted or unsubstituted, C2-6, C7-12, C13-18, C19-24, C 25-30, C31-36, C37-44, C45-52, C53-60, or Cei-70 heteroalkynylene. In certain embodiments, one or more (e.g, two, three, or four) backbone atoms ofthe C1-6, C7-12, C13-18, C19-24, C 25-30, C31-36, C37-44, C45-52, C53-60, or Cei-70 heteroalkylene, C1-6, C7-12, C13-18, C19-24, C25-30, C31-36, C37-44, C45-52, C53-60, or Cei-70 heteroalkenylene, or C2-6, C7-12, C13-18, C19-24, C25-30. C31-36, C37-44. C45-52, C53-60. or Cei- 7oheteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits. In some embodiments, the substituted or unsubstituted heteroarylene that replaces one of the backbone atoms is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroarylene. In some embodiments, the substituted or unsubstituted heteroarylene that replaces one of the backbone atoms is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl fused with substituted or unsubstituted, 7- to 9-membered, monocyclic carbocyclyl. In some embodiments, the substituted or unsubstituted heteroarylene that replaces one of the backbone atoms is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl fused with substituted or unsubstituted, 7- to 9-membered, monocyclic heterocyclyl. In some embodiments, the substituted or unsubstituted heteroarylene that replaces one of the backbone atoms is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl fused with substituted or unsubstituted, 7- to 9-membered, monocyclic heterocyclyl fused with one or two substituted or unsubstituted phenyl. In some embodiments, the substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms is substituted or unsubstituted, 5- or 6-membered, monocyclic heterocyclylene. In some embodiments, the substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms is a moiety formed by a click-chemistry reaction of a first and second click-chemistrv reactive moieties.

[0153] In some embodiments, the substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms is of the formula:

[0154] k21 is 0, 1, 2, 3, or 4; each instance of Rd, if present, is independently halogen, substituted or unsubstituted, Ci-6 alkyl, or -©-(substituted or unsubstituted, Ci-6 alkyl); k22 is 0, 1, 2, 3, or 4; each instance of Re, if present, is independently halogen, substituted or unsubstituted, Ci-6 alkyl, or -©-(substituted or unsubstituted, Ci-6 alkyl); k23 is an integer between 0 and 11, inclusive; each instance of Rf, if present, is independently halogen, substituted or unsubstituted. Ci-6 alkyl, or -©-(substituted or unsubstituted. Ci-6 alkyl); and Rgis hydrogen, halogen, substituted or un substituted, Ci-6 alkyl, or -©-(substituted or unsubstituted, Ci-6 alkyl). In certain embodiments, the substituted or unsubstituted heteroarylene that replaces one of the backbone atoms is of the formula:

[0155]

[0156] The substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms may be attached at any orientation.

[0157] In some embodiments, a linker is optionally substituted heteroalkenylene comprising one, two, three, four, five, six, seven, eight, nine, ten, or more than ten double bonds. In some embodiments, a linker is optionally substituted heteroalkynylene comprising one, two, three, four, five, six, seven, eight, nine, ten, or more than ten triple bonds. In some embodiments, a linker is optionally substituted heteroalkylene, heteroalkenylene, or heteroalkynylene and comprises one or more (e.g., two, three, four, or five) branch point. In certain embodiments, the linker comprises two, three, four, or five branch points.

[0158] In some embodiments, optionally substituted heteroalkylene is optionally substituted polyethylene glycol (optionally substituted PEG). In some embodiments, a terminal backbone atom of the PEG is an attachment point. In some embodiments, an internal backbone atom of the PEG is an attachment point. In some embodiments, a linker comprises one or more PEG repeating units (-OCH2CH2- or -CH2CH2O-). In certain embodiments, a linker comprises 2-3, 4-5, 6-7, 8-9, 10-11, 12-13, or 14-15 PEG repeating units. In certain embodiments, a linker comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 PEG repeating units. In some embodiments, a linker comprises one or more (e.g., two, three, or four) PEG.

[0159] In some embodiments, a linker comprises a moiety formed by a Michael addition reaction of a Michael donor and a Michael acceptor. In some embodiments, the Michael donor is an enolate. In some embodiments, the Michael acceptor is a moiety comprising a,P-unsaturated- carbonyl. In some embodiments, the Michael donor is -SH. In some embodiments, the Michael acceptor is

[0160] In some embodiments, a linker is a combination of -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -C(=O)N(CH3)-, -NHC(=O)-, -N(CH3)C(=O)- provided that: the number of backbone atoms of the linker is between 2 and 6, between 7 and 12, between 13 and 20, between 21 and 30, between 31 and 40, between 41 and 50, between 51 and 60, between 61 and 80, between 81 and 100, inclusive; and the linker does not comprise O-O, O-N. N-O, or N-N.

[0161] In some embodiments, a linker is a combination of-CH2- CH2CH2O , OCH2CH2, C(=O)NH , C(=O)N(CH3) , NHC(=O) , N(CH3)C(=O) , provided that: the number of backbone atoms of the linker is between 7 and 70, inclusive; and the linker does not comprise O-O, O-N, N-O, or N-N.

[0162] In some embodiments, a linker is a combination of -CH2-,

[0163] -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -NHC(=O)-, provided that: the number of backbone atoms of the linker is between 2 and 6, between 7 and 12, between 13 and 20, between 21 and 30, between 31 and 40, between 41 and 50, between 51 and 60, between 61 and 80, or between 81 and 100, inclusive; the linker does not comprise O-O, O-N, N-O, or N-N; and the combined number of -C(=O)NH-, -NHC(=O)- , of the linker is between 0 and 4, inclusive.

[0164] In some embodiments, a linker is a combination of-CH2- o-, provided that: the number of backbone atoms of the linker is between 7 and 70, inclusive; the linker does not comprise O-O, O-N. N-O, or N-N; and the combined number of -C(=0)NH-, -NHC(=0)-, , of the linker is between 0 and 4, inclusive.

[0165] In some embodiments, a linker is -CH2- -O-,

[0166] -CH2CH2O-, -OCH2CH2-, -C(=0)NH- -C(=O)N(CH3)-, -NHC(=0)-, -N(CH3)C(=O)-, or a combination of two or more instances of each one of the foregoing, or a combination of two or more of the foregoing, provided that: the number of backbone atoms of the linker is between 2 and 6, between 7 and 12, between 13 and 20, between 21 and 30, between 31 and 40, between 41 and 50, between 51 and 60, between 61 and 80, between 81 and 100, inclusive; and the linker does not comprise O-O. O-N. N-O, or N-N.

[0167] In some embodiments, a linker is -CH2-, CH2CH2O , OCH2CH2, -C(=O)NH-, -C(=O)N(CH3) -, NHC(=O) , N(CH3)C(=O) , or a combination of tw o or more instances of each one of the foregoing, or a combination of two or more of the foregoing, provided that: the number of backbone atoms of the linker is between 7 and 70, inclusive; and the linker does not comprise 0-0, O-N. N-O, or N-N.

[0168] In some embodiments, a linker is -CH2-,

[0169] -CH2CH2O-, -OCH2CH2-, -C(=0)NH-, -NHC(=0)-, combination of two or more instances of each one of the foregoing, or a combination of two or more of the foregoing, provided that: the number of backbone atoms of the linker is between 2 and 6, betw een 7 and 12, between 13 and 20, between 21 and 30, between 31 and 40, between 41 and 50, between 51 and

[0170] 60. between 61 and 80, or between 81 and 100, inclusive; the linker does not comprise O-O, O-N, N-O, or N-N; and the combined number of -C(=O)NH-, -NHC(=O)- of the linker is between 0 and 4, inclusive.

[0171] In some embodiments, a linker is -CH2-,

[0172] -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -NHC(=O)-.Or a combination of two or more instances of each one of the foregoing, or a combination of tw o or more of the foregoing, provided that: the number of backbone atoms of the linker is between 7 and 70, inclusive; the linker does not comprise O-O, O-N. N-O, or N-N; and the combined number of -C(=O)NH-, -NHC(=O)-, of the linker is betw een 0 and 4, inclusive.

[0173] In some embodiments, a linker includes -CH2-, -O-, -CH2CH2O-. -OCH2CH2-, -C(=O)NH-, -C(=O)N(CH3)-, -NHC(=O)-, or -N(CH3)C(=O)-. In some embodiments, a linker is a combination of any tw o or more (e.g., three, four, five, six, seven, eight, nine, or ten) of -CH2-, -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -C(=O)N(CH3)-, -NHC(=O)-, and -N(CH3)C(=0)-, provided that the number of backbone atoms of the instance of the linker is between 7 and 70, inclusive; and the instance of the linker does not comprise O-O. 0-N, N-0, or N-N.

[0174] In certain embodiments, a linker comprises a cleavable bond or moiety. In certain embodiments, a linker does not comprise a cleavable bond or moiety. In certain embodiments, a linker comprises a covalent attachment to a solid support. In certain embodiments, a linker includes multiple positions for attachment of radicals of ligands.

[0175] In certain embodiments, the linker comprises a peptide in the backbone of the linker. In certain embodiments, the peptide comprises 1-5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, or 36- 40, inclusive, amino acids.

[0176] In certain embodiments, a linker includes pyrrolidine. 8-amino-3.6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1 -carboxylate (SMCC), 6- aminohexanoic acid (AHEX or AHA), or a combination thereof.

[0177] In some embodiments, at least once instance of LAis the intemucleosidic linker between the first and second nucleosides of counted from the 5' end. In certain embodiments, LAis the intemucleosidic linker between the first n and n+1 nucleosides of counted from the 5' end; and n is an integer between 2 and 20. inclusive, as the number of nucleosides of permits. In some embodiments, at least once instance of LAis the intemucleosidic linker between the first and second nucleosides of counted from the 3' end. In certain embodiments, LAis the intemucleosidic linker between the first n and n+1 nucleosides of counted from the 3' end; and n is an integer between 2 and 20. inclusive, as the number of nucleosides of permits.

[0178] In some embodiments, LAis of the formula: each instance of ZA1and ZA2is independently a single bond, substituted or unsubstituted, Ci-6 alkylene, or substituted or unsubstituted, C2-6 alkenylene; each instance of WAis independently a radical, as valency permits, of substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkvlene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene. -O-, -OP(=O)(ORC)O-, -N(R°)-, -S-. -C(=O)-, -C(=O)O-, -C(=O)NRC-, -NR°C(=O)-, -C(=O)RC-, -NRCC(=O)O-, -NR°C(=O)NR°-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RC)-, -S(=O)2NRC-, -NRCS(=O)2-, or a combination thereof; each instance of R° is independently hydrogen, substituted or unsubstituted acyl, 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, 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 instances of Rcare joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and bond C4Ais attached to L4.

[0179] In some embodiments, at least one instance of ZA1is substituted or unsubstituted. Ci-6 alkylene. In some embodiments, at least one instance of ZA1is substituted or unsubstituted, C1.3 alkylene. In certain embodiments, at least one instance of ZA1is unsubstituted C1-3 alkylene. In some embodiments, at least one instance of ZA2is substituted or unsubstituted, C1-6 alkylene. In some embodiments, at least one instance of ZA2is substituted or unsubstituted, C1-3 alkylene. In certain embodiments, at least one instance of ZA2is unsubstituted C1-3 alkylene.

[0180] In some embodiments, WAis -N(RC)-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRC-, or -NRCC(=O)-. In certain embodiments, WAis -N(RC)-, -C(=O)NRC-, or -NRCC(=O)-.

[0181] In some embodiments, each instance of Rcis independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0182] In some embodiments, LAis of the formula

[0183] In some embodiments, LAis of the formula In certain embodiments, LAis of the formula

[0184] In some embodiments, L4 is _L4 A19_L4A20 _ is independentlyasingle bond, -O-, -S-, -S-S-, -NRa-, -C(=O)O- -C(=NRa)O-, -S(=O)O-, -S(=O)2O-. -C(=O)NRa-, -C(=NRa)NRa- -S(=O)NRa-

[0185] -S(=O)2NRa- -0C(=0)-, -OC(=NRa)-, -0S(=0)- -0S(=0)2- -NRaC(=O)- -NRaC(=NRa)-,

[0186] NRaS(=O) , NRaS(=O)2, OC(=O)O , OC(=NRa)O , OS(=O)O , OS(=O)2O , -NRaC(=O)O-, -NRaC(=NRa)O-, -NRaS(=O)O-, -NRaS(=O)2O-, -OC(=O)NRa- -OC(=NRa)NRa-, -OS(=O)NRa- -OS(=O)2NRa-, -NRaC(=O)NRa- -NRaC(=NRa)NRa- -NRaS(=O)NRa-, -NRaS(=O)2NRa-, -C(=O)-, -C(=NRa)-, -S(=O)-, -S(=O)2- -OP(=O)(ORa)O-, -SP(=O)(ORa)O-, -OP(=O)(ORa)S-, or -OP(=O)(SRa)O-; each instance of Rais independently hydrogen, substituted or unsubstituted, Ci-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L4B1, L4B2, and L4B6is independently a single bond, substituted or unsubstituted, Ci-ioo alkylene or substituted or unsubstituted. Ci-ioo heteroalkylene; each of L4C1and L4C2is a single bond, substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms, or substituted or unsubstituted heteroarylene that replaces one of the backbone atoms; and bond C4Bis attached to A4.

[0187] In some embodiments, each of -L4A1-L4A2-, -L4A3-L4A4-, -L4A5-L4A6-, -L4A7-L4A8-, -L4A17-L4A18-, and _L4A19-L4A2°- is independently a single bond, -O-, -NRa-, -C(=O)NRa-, or -NRaC(=O)-. In some embodiments, each of -L4A1-L4A2-, -L4A3-L4A4-, -L4A5-L4A6-, -L4A7- L4A8-, _L4A17-L4A18-, and _L4A19-L4A20- is independentlyasingle bond, -O-, -NH-, - C(=O)NH-, or -NHC(=O)-. In certain embodiments, each of -L4A1-L4A2-_ -L4A3-L4A4- -L4A5-L4A6-, -L4A7-L4A8-, -L4A17-L4A18-, and -L4A19-L4A2°- is independently a single bond, -C(=O)NRa-, or -NRaC(=O)-. In certain embodiments, each of -L4A1-L4A2-, -L4A3-L4A4-, -L4A5-L4A6-, -L4A7-L4A8-, -L4A17-L4A18-, and _L4A19-L4A2°- is independently a single bond, -C(=O)NH-, or -NHC(=O)-. In some embodiments, at least one of -L4A1-L4A2-, -L4A3-L4A4-, - L4A5-L4A6-, -L4A7-L4A8-, -L4A17-L4A18-, and -L4A19-L4A2°- is independently -C(=O)O-, -OC(=O)-. -OP(=O)(ORa)O-, -SP(=O)(ORa)O-. -OP(=O)(ORa)S-. or -OP(=O)(SRa)O- In some embodiments, at least one of -L4A1-L4A2-, -L4A3-L4A4-, -L4A5-L4A6-, -L4A7-L4A8-, -L4A17-L4A18-, and -L4A19-L4A2°- IS independently -C(=O)O-, -OC(=O)-, -OP(=O)(OH)O-

[0188] SP(=O)(OH)O , OP(~O)(OH)S , or OP(~O)(SH)O .

[0189] In some embodiments, at least one instance of Rais independently hydrogen or substituted or unsubstituted, Ci-6 alkyl. In some embodiments, each instance of Rais independently hydrogen or substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, each instance of Rais independently hydrogen or unsubstituted Ci-6 alkyl.

[0190] In some embodiments, each of L4B1, L4B2, and L4B6is independently a single bond, substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L4B1, L4B2, and L4B6is independently substituted or unsubstituted, Ci- 10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L4B1, L4B2, and L4B6is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L4B1, L4B2. and L4B6independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats.

[0191] In certain embodiments, each of L4C1and L4C2is independently a single bond. In certain embodiments, each of L4C1and L4C2is independently substituted or unsubstituted heteroarylene that replaces one of the backbone atoms. In certain embodiments, each of L4C1and L4C2is independently (which may be attached at either direction).

[0192] In certain embodiments, L4 is each of pl and p2 is independently an integer from 1 to 10, inclusive; each of p3 and p5 is independently an integer from 0 to 10, inclusive; each instance of-L4A21-L4A22- is independently a single bond, -O-, -S-. -S-S-. -NR0-.

[0193] -C(=O)O- -C(=NRa)O-, -S(=O)O-, -S(=O)2O- -C(=O)NRa-, -C(=NRa)NRa- -S(=O)NRa- -S(=O)2NRa-, -0C(=0)-, -OC(=NRa)-, -0S(=0)-, -0S(=0)2-. -NRaC(=O)-, -NRaC(=NRa)- -NRaS(=O)-, -NRaS(=O)2-. -0C(=0)0- -OC(=NRa)O-, -0S(=0)0- -0S(=0)20-.

[0194] -NRaC(=O)O- -NRaC(=NRa)O- -NRaS(=O)O- -NRaS(=O)2O- -OC(=O)NRa- -OC(=NRa)NRa- -OS(=O)NRa- -OS(=O)2NRa- -NRaC(=O)NRa- -NRaC(=NRa)NRa- -NRaS(=O)NRa- -NRaS(=O)2NRa- -C(=0)-, -C(=NRa)-, -S(=0)-, -S(=0)2- -OP(=O)(ORa)O-. -SP(=O)(ORa)O- -OP(=O)(ORa)S- or -OP(=O)(SRa)O-; each instance of Rais independently hydrogen, substituted or unsubstituted, Ci-6 alkyl, substituted or unsubstituted phenyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; and bond C4Bis attached to A4.

[0195] In certain embodiments, at least one instance of-L4A21-L4A22- is -NRa-C(=O)- or -C(=O)-NRa- In certain embodiments, at least one instance of-L4A21-L4A22- is -NH-C(=O)- or -C(=O)-NH- In certain embodiments, at least one instance of -L4A21-L4A22- is -O-C(=O)- or -C(=O)-O- In certain embodiments, at least one instance of -L4A21-L4A22- is -O-. In certain embodiments, at least one instance of-L4A21-L4A22- is -NH-. In certain embodiments, at least one instance of-L4A21-L4A22- is -C(=O)-.

[0196] In some embodiments. L4is a combination of-CH2-, -O-, -CH2CH2O-. -OCH2CH2- -C(=O)NH- -C(=O)N(CH3)-, -NHC(=O)-, and -N(CH2)C(=O)-, provided that the number of backbone atoms of the instance of the linker is between 7 and 70, inclusive; and the instance of the linker does not comprise O-O, 0-N, N-0, or N-N. In certain embodiments, L4is a combination of-CH2-, -0-. -CH2CH2O-, -OCH2CH2-, -C(=0)NH-, and -NHC(=0)-. provided that the number of backbone atoms of the instance of L4is between 7 and 70, inclusive; the instance of the linker does not comprise 0-0, 0-N, N-0, or N-N; and the combined number of-C(=O)NH- and -NHC(=0)- of the instance of the linker is between 0 and 4, inclusive. In some embodiments, L4is -CH2-, -0-, -CH2CH2O-, -OCH2CH2-, -C(=0)NH- - C(=0)N(CH3)-, -NHC(=0)-, or -N(CH3)C(=0)-, or a combination of two or more instances of each one of the foregoing, or a combination of two or more of the foregoing, provided that the number of backbone atoms of the instance of the linker is betw een 7 and 70, inclusive; and the instance of the linker does not comprise 0-0, 0-N. N-0, or N-N. In certain embodiments, L4is — CH2— , -0-. -CH2CH2O-, -OCH2CH2-, -C(=0)NH-, or -NHC(=0)-, or a combination of two or more instances of each one of the foregoing, or a combination of two or more of the foregoing, provided that the number of backbone atoms of the instance of L4is betw een 7 and 70, inclusive; the instance of the linker does not comprise O-O, 0-N, N-0, or N-N; and the combined number of-C(=O)NH- and -NHC(=0)- of the instance of the linker is between 0 and 4. inclusive. each of- and -L5A19-L5A2°- is independently a single bond, -0-, -S-, -S-S-, -NRa-, -C(=0)0- C(=NRa)0 , -S(=0)0-, S(~0)20 , C(~O)NRa, C(=NRa)NRa, S(~O)NRa, -S(=O)2NRa-, -0C(=0)-, -0C(=NRa)-, -0S(=0)-, -0S(=0)2-. -NRaC(=O)-, -NRaC(=NRa)-, -NRaS(=O)-, -NRaS(=O)2-. -0C(=0)0-, -0C(=NRa)0-, -0S(=0)0-, -0S(=0)20-.

[0197] -NRaC(=O)O-, -NRaC(=NRa)O-, -NRaS(=O)O- -NRaS(=O)2O-, -OC(=O)NRa- -0C(=NRa)NRa-, -OS(=O)NRa-, -OS(=O)2NRa-, -NRaC(=0)NRa-, -NRaC(=NRa)NRa- -NRaS(=0)NRa-, -NRaS(=O)2NRa-, -C(=0)-, -C(=NRa)-, -S(=0)-, -S(=0)2- -OP(=O)(ORa)O-. -SP(=O)(ORa)O-, -OP(=O)(ORa)S-, or -OP(=O)(SRa)O-; each instance of Rais independently hydrogen, substituted or unsubstituted, Ci-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L5B1, L5B2, and L5B6is independently a single bond, substituted or unsubstituted, C1-100 alkylene or substituted or unsubstituted, Ci-ioo heteroalkylene; each of L5C1and L5C2is a single bond, substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms, or substituted or unsubstituted heteroarylene that replaces one of the backbone atoms; and bond C5Bis attached to A5.

[0198] In some embodiments, each of L L , L L , L L , L L , -L5A17-L5A18-, and -L5A19-L5A2°- is independently a single bond. -0-, -NRa-. -C(=0)NRa-, or -NRaC(=O)-. In some embodiments, each of -L5A1-L5A2-, -L5A3-L5A4-, -L5A5-L5A6-, -L5A7- L5A8-, -L5A17-L5A18-, and -L5A19-L5A20- is independently a single bond, -O-, -NH-, -C(=O)NH-, or -NHC(=O)-. In certain embodiments, each of -L5A1-L5A2-, -L5A3-L5A4-, -L5A5-L5A6-, -L5A7-L5A8-, -L5A17-L5A18-, and -L5A19-L5A2°- is independently a single bond, -C(=O)NRa-, or -NRaC(=O)-. In certain embodiments, each of-L5A1-L5A2-, -L5A3-L5A4-, - L5A5-L5A6-, -L5A7-L5A8-, -L5A17-L5A18-, and -L5A19-L5A2°- is independently a single bond, - C(=O)NH-, or -NHC(=O)-. In some embodiments, at least one of -L5A1-L5A2-, -L5A3-L5A4-, -L5A5_L5A6_, _L5A7_L5A8_, _L5 AI 7_L5AI 8_and_L5Ai9_L5A2o_is mdependently -C(=O)O-, - OC(-O) , OP(-O)(ORa)O , -SP(=O)(ORa)O-, -OP(=O)(ORa)S-, or OP( O)(SRa)O . In some embodiments, at least one of-L5A1-L5A2-, -L5A3-L5A4-, -L5A5-L5A6-, -L5A7-L5A8-, -L5A17-L5A18-. and -L5A19-L5A2°- is independently -C(=O)O-. -OC(=O)-. -OP(=O)(OH)O- -SP(=O)(OH)O- -OP(=O)(OH)S-, or -OP(=O)(SH)O-.

[0199] In some embodiments, at least one instance of Rais independently hydrogen or substituted or unsubstituted, Ci-6 alkyl. In some embodiments, each instance of Rais independently hydrogen or substituted or unsubstituted. Ci-6 alkyl. In certain embodiments, each instance of Rais independently hydrogen or unsubstituted Ci-6 alkyl.

[0200] In some embodiments, each of L5B1, L5B2, and L5B6is independently a single bond, substituted or unsubstituted, C1-20 alky lene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L5B1, L5B2, and L5B6is independently substituted or unsubstituted, Ci- 10 alkylene or substituted or unsubstituted. C1-10 heteroalkylene. In certain embodiments, each of L5B1, L5B2, and L5B6is independently unsubstituted CMO alkylene. In certain embodiments, each of L5B1, L5B2, and L5B6independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats.

[0201] In certain embodiments, each of L5C1and L5C2is independently a single bond. In certain embodiments, each of L5C1and L5C2is independently substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms. In certain embodiments, each of L5C1and L5C2is independently (which may be attached at either direction). In some embodiments, L5is k21 is 0, 1, 2. 3, or 4: each instance of Rd, if present, is independently halogen, substituted or unsubstituted, Ci-6 alkyl, or -O-(substituted or unsubstituted, Ci-6 alkyd); k22 is 0, 1, 2. 3, or 4: each instance of Re, if present, is independently halogen, substituted or unsubstituted, Ci-6 alkyl, or -O-(substituted or unsubstituted. Ci -6 alkyl); each of ql, q2, q4, q5, q8, and q9 is independently an integer from 0 to 10, inclusive; each of q3, q6, and q7 is independently an integer from 1 to 10, inclusive; each of-L5A21-L5A22-, -L5A23-L5A24-, and -L5A25-L5A26- is independently a single bond. -O-, -S-, -S-S-, -NRa-, -C(=O)O-. -C(=NRa)O-, -S(=O)O-, -S(=O)2O-. -C(=O)NRa- -C(=NRa)NRa-, -S(=O)NRa-, -S(=O)2NRa- -OC(=O)-, -OC(=NRa)-, -OS(=O)-, -OS(=O)2- -NRaC(=O)-, -NRaC(=NRa)-, -NRaS(=O)-, -NRaS(=O)2-, -OC(=O)O-, -OC(=NRa)O- -OS(=O)O-, -OS(=O)2O-, -NRaC(=O)O-, -NRaC(=NRa)O-, -NRaS(=O)O-, -NRaS(=O)2O- -OC(=O)NRa-, -OC(=NRa)NRa-. -OS(=O)NRa-, -OS(=O)2NRa-. -NRaC(=O)NRa- -NRaC(=NRa)NRa-, -NRaS(=O)NRa-, -NRaS(=O)2NRa- -C(=O)-, -C(=NRa)-, -S(=O)- -S(=O)2-, -OP(=O)(ORa)O-, -SP(=O)(ORa)O-, -OP(=O)(ORa)S-, or -OP(=O)(SRa)O-; each instance of Rais independently hydrogen, substituted or unsubstituted, Ci-6 alkyl, substituted or unsubstituted phenyl, 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 atached to a sulfur atom, or two instances of Raatached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; and bond C5Ais atached to A5.

[0202] In certain embodiments, k21 is 0. In certain embodiments, k21 is 1. In certain embodiments, k21 is 2. In certain embodiments. k22 is 0. In certain embodiments, k22 is 1. In certain embodiments, k22 is 2.

[0203] In some embodiments, each instance of Rd, if present, is independently substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, each instance of Rd, if present, is independently unsubstituted Ci-6 alkyl. In some embodiments, each instance of Re, if present, is independently substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, each instance of Re, if present, is independently unsubstituted Ci-6 alkyl.

[0204] In certain embodiments, each of ql, q2, q4, q5, q8, and q9 is independently 0. In certain embodiments, each of ql, q2, q4, q5, q8, and q9 is independently 1. In certain embodiments, each of ql, q2, q4, q5. q8. and q9 is independently 2. In certain embodiments, each of ql, q2, q4, q5, q8, and q9 is independently 3. In certain embodiments, each of q3, q6, and q7 is independently 0. In certain embodiments, each of q3, q6, and q7 is independently 1. In certain embodiments, each of q3, q6, and q7 is independently 2. In certain embodiments, each of q3, q6, and q7 is independently 3.

[0205] In some embodiments, each of -L5A23-L5A24- and -L5A25-L5A26- is independently a single bond, -O-, -NRa- -NRa-C(=O)-, or -C(=O)-NRa- In certain embodiments, each of -L5A2J- L5A24- and L5 25L5A26is independently -NRa-C(=O)- or -C(=O)-NRa-.

[0206] In some embodiments, -L5A21-L5A22- is -OP(=O)(ORa)O-, -SP(=O)(ORa)O-, - OP(=O)(ORa)S-, or -OP(=O)(SRa)O-. In certain embodiments, -L5A21-L5A22- is - OP(=O)(SRa)O- In certain embodiments, -L5A21-L5A22- is -OP(=O)(SH)O-

[0207] In certain embodiments, L5is a combination of-CH2-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -C(=O)N(CH3)- -NHC(=O)-, -N(CH3)C(=O)-, , provided that the number of backbone atoms of the linker is between 7 and 70, inclusive; and the linker does not comprise O-O, O-N, N-O, or N-N. In certain embodiments, L5is a combination of-CH2- O-, -CH2CH2O-, - OCH2CH2-, -C(=O)NH- -NHC(=O)-, provided that the number of backbone atoms of the linker is between 7 and 70, inclusive; the linker does not comprise O-

[0208] O, O-N, N-O, or N-N; and the combined number of-C(=O)NH-, -NHC(=O)-, and of the linker is between 0 and 4, inclusive.

[0209] In certain embodiments, L5is -CH2-, . -O-, -CH2CH2O-, -OCH2CH2-

[0210] -C(=O)NH- -C(=O)N(CH3)-, -NHC(=O)-, -N(CH3)C(=O)-, or a combination of two or more instances of each one of the foregoing, or a combination of two or more of the foregoing, provided that the number of backbone atoms of the linker is between 7 and 70. inclusive; and the linker does not comprise O-O, O-N. N-O. or N-N. In certain embodiments, L5is -CH2-, , -O-, -CH2CH2O-,

[0211] -OCH2CH2-, -C(=O)NH-, -NHC(=O)- or a combination of two or more instances of each one of the foregoing, or a combination of two or more of the foregoing, provided that the number of backbone atoms of the linker is between 7 and 70, inclusive; the linker does not comprise O-O, O-N, N-O, or N-N; and the combined number of-C(=O)NH-, -

[0212] NHC(=O)-, of the linker is between 0 and 4, inclusive.

[0213]

[0214] In some embodiments, L6is

[0215] L6Ai9_ L6A2o_ is independently a single bond, -O-. -S-. -S-S-. -NRa-. -C(=O)O- -C(=NRa)O-

[0216] -S(=O)O-, -S(=O)2O-, -C(=O)NRa-, -C(=NRa)NRa-, -S(=O)NRa-, -S(=O)2NRa-, -OC(=O)-,

[0217] OC(=NRa) , OS(=O) , OS(=O)2, NRaC(=O) , NRaC(=NRa) , NRaS(=O) ,

[0218] -NRaS(=O)2-, -OC(=O)O-, -OC(=NRa)O-, -OS(=O)O-, -OS(=O)2O-, -NRaC(=O)O-,

[0219] -NRaC(=NRa)O-, -NRaS(=O)O-. -NRaS(=O)2O- -OC(=O)NRa-. -OC(=NRa)NRa- -OS(=O)NRa- -OS(=O)2NRa- -NRaC(=O)NRa- -NRaC(=NRa)NRa- -NRaS(=O)NRa- - NRaS(=O)2NRa- -C(=0)-, -C(=NRa)-, -S(=0)-, -S(=0)2- -OP(=O)(ORa)O- - SP(=O)(ORa)O- -OP(=O)(ORa)S- or -OP(=O)(SRa)O-; each instance of Rais independently hydrogen, substituted or unsubstituted. Ci-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are j oined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L6B1, L6B2, and L6B6is independently a single bond, substituted or unsubstituted, Ci-ioo alkylene or substituted or unsubstituted, Ci-100 heteroalkylene; each of L6C1and L6C2is a single bond, substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms, or substituted or unsubstituted heteroarylene that replaces one of the backbone atoms; and bond C6Bis attached to A6.

[0220] In some embodiments, at least one of-L6A1-L6A2-, -L6A3-L6A4-. -L6A5-L6A6-, -L6A7- L6A8-, _L6A17_L6A18_,and -L 6AI9_L 6A2O_ is endependently a single bond, -O-, -NRa-, -C(=O)NRa-, or -NRaC(=O)-. In some embodiments, each of -L6A1-L6A2-, -L6A3-L6A4-, -L6A5- L6A6-, -L6A7-L6A8-, -L6A17-L6A18-, and _L6A19-L6A20- is independently a single bond, -O-, - NH-, -C(=O)NH-, or -NHC(=O)-. In certain embodiments, each of-L6A1-L6A2-, L6A3L6A4. _L6A5_L6A6__ _L6A7_L6A8_ _L6A17_L6A18_an d_L6Ai9_L6A20_isindependently a single bond, - C(=O)NRa-, or -NRaC(=O)-. In certain embodiments, each of -L6A1-L6A2-, -L6A3-L6A4-. -L6A5- L6A6_, -L6A77-L6A8-. and -L6A19-L6A20- independently a single bond,

[0221] -C(=O)NH-, or -NHC(=O)-. In some embodiments, at least one of -L6A1-L6A2-, -L6A3-L6A4-, _L6A5-L6A6-, -L6A7-L6A8-, -L6A17-L6A18-, and -L6A19-L6A2°- is independently -C(=O)O- -OC(=O)-. -OP(=O)(ORa)O-, -SP(=O)(ORa)O-. -OP(=O)(ORa)S-. or -OP(=O)(SRa)O-. In some embodiments, at least one of -L6A1-L6A2-, -L6A3-L6A4-, -L6A5-L6A6-, -L6A7-L6A8-, -L6A17-L6A18-, and -L6A19-L6A2°- is independently -C(=O)O-, -OC(=O)-, -OP(=O)(OH)O- -SP(=O)(OH)O-, -OP(=O)(OH)S-, or -OP(=O)(SH)O-.

[0222] In some embodiments, at least one instance of Rais independently hydrogen or substituted or unsubstituted. Ci-6 alkyl. In some embodiments, each instance of Rais independently hydrogen or substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, each instance of Rais independently hydrogen or unsubstituted Ci-6 alkyl.

[0223] In some embodiments, each of L6B1, L6B2, and L6B6is a single bond, independently substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1.20 heteroalkylene. In some embodiments, each of L6B1, L6B2, and L6B6is independently substituted or unsubstituted, Ci- 10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L6B1, L6B2, and L6B6is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L6B1, L6B2. and L6B6independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats.

[0224] In certain embodiments, each of L6C1and L6C2is independently a single bond. In certain embodiments, each of L6C1and L6C2is independently substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms. In certain embodiments, each of L6C1and L6C2is each of rl, r2, r4, r5, r8, and r9 is independently an integer from 0 to 10, inclusive; each of r3, r6, and r7 is independently an integer from 1 to 10, inclusive; each of _L6A21-L6A22-, _L6A23-L6A24-, and _L6A25-L6A26- is independently a single bond,

[0225] -O-, -S-, -S-S-, -NRa-, -C(=O)O-, -C(=NRa)O-, -S(=O)O-, -S(=O)2O-, -C(=O)NRa-, - C(=NRa)NRa-_ -S(=O)NRa-, -S(=O)2NRa-, -OC(=O)-, -OC(=NRa)-_ -OS(=O)-_ -OS(=O)2-, - NRaC(=O)-, -NRaC(=NRa)-, -NRaS(=O)-, -NRaS(=O)2- -OC(=O)O- -OC(=NRa)O- - OS(=O)O-, -OS(=O)2O-, -NRaC(=O)O-, -NRaC(=NRa)O-, -NRaS(=O)O-, -NRaS(=O)2O-, -

[0226] OC(=O)NRa-, -OC(=NRa)NRa-, -OS(=O)NRa-, -OS(=O)2NRa-, -NRaC(=O)NRa-, - NRaC(=NRa)NRa-, -NRaS(=O)NRa-, -NRaS(=O)2NRa-, -C(=O)-_ -C(=NRa)-, -S(=O)-, - S(=O)2- -OP(=O)(ORa)O-, -SP(=O)(ORa)O-, -OP(=O)(ORa)S-, or -OP(=O)(SRa)O-; each instance of Rais independently hydrogen, substituted or unsubstituted, Ci-6 alkyl, substituted or unsubstituted phenyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; and bond C6Ais attached to A6.

[0227] In certain embodiments, k21 is 0. In certain embodiments, k21 is 1. In certain embodiments, k21 is 2. In certain embodiments, k22 is 0. In certain embodiments, k22 is 1. In certain embodiments, k22 is 2.

[0228] In some embodiments, each instance of Rd, if present, is independently substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, each instance of Rd, if present, is independently unsubstituted Ci-6 alkyl. In some embodiments, each instance of Re, if present, is independently substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, each instance of Re, if present, is independently unsubstituted Ci-6 alkyd.

[0229] In certain embodiments, each of rl, r2, r4, r5, r8, and r9 is independently 0. In certain embodiments, each of rl, r2. r4, r5, r8, and r9 is independently 1. In certain embodiments, each of rl, r2, r4, r5, r8, and r9 is independently 2. In certain embodiments, each of rl, r2, r4, r5, r8, and r9 is independently 3. In certain embodiments, each of r3, r6, and r7 is independently 0. In certain embodiments, each of r3, r6, and r7 is independently 1. In certain embodiments, each of r3, r6, and r7 is independently 2. In certain embodiments, each of r3, r6, and r7 is independently 3.

[0230] In some embodiments, each of _L6A23-L6A24- and _L6A25-L6A26- is independently a single bond, O , -NRa-, -NRa-C(=O)-, or -C(=O)-NRa-. In certain embodiments, each of-L6A23- L6A24_and _L6A25 _L6A26 _ is independently -NRa-C(=O)- or -C(=O)-NRa-

[0231] In some embodiments, -L6A21-L6A22- is -O-, -OP(=O)(ORa)O-, -SP(=O)(ORa)O-, -OP(=O)(ORa)S-, or -OP(=O)(SRa)O- In certain embodiments, -L6A21-L6A22- is -O-.

[0232] In certain embodiments, L6is a combination of-CH2-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -C(=O)N(CH3)- -NHC(=O)-, -N(CH3)C(=O)-, provided that the number of backbone atoms of the linker is between 7 and 70, inclusive; and the linker does not comprise O-O, O-N, N-O, or N-N. In certain embodiments, the linker is a combination of-CH2-, provided that the number of backbone atoms of the linker is between 7 and 70, inclusive; the linker does not comprise O-O, O-N, N-O, or N-N; and the combined number of C(=O)NH , -NHC(=O)-, foregoing, or a combination of two or more of the foregoing, provided that the number of backbone atoms of the linker is betw een 7 and 70. inclusive; and the linker does not comprise O-

[0233] AgA

[0234] O, O-N, N-O, or N-N. In certain embodiments, the linker is a combination of CH2, , , provided that the number of backbone atoms of the linker is between 7 and 70, inclusive; the linker does not comprise O-O, O-N, N-O, or N-N; and the combined number of- f the linker is between 0 and 4, inclusive.

[0235] In certain embodiments, a linker is a linker described in the following references: U.S. 5,994,517; U.S. 6,300,319; U.S. 6,660,720; U.S. 6,906,182; U.S. 7,262,177; U.S. 7,491,805; U.S. 8,106,022; U.S. 7,723,509; U.S. 9,127,276; U.S. 2006 / 0148740; U.S. 2011 / 0123520; WO 2013 / 033230; WO 2012 / 037254, Biessen et al., J. Med. Chem. 1995, 38, 1846-1852; Lee et al., Bioorganic & Medicinal Chemistry 2011,19, 2494-2500; Rensen et al.. J. Biol. Chem. 2001, 276, 37577-37584; Rensen et al., J. Med. Chem. 2004, 47, 5798-5808; Sliedregt et al., J. Med. Chem.

[0236] 1999, 42. 609-618; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Lee, Carbohydr. Res. 1978, 67, 509-514; Connolly et al., J. Biol. Chem. 1982, 257, 939-945; Pavia et al. , Int. J. Pep. Protein Res. 1983, 22, 539-548; Lee et al. , Biochem. 1984, 23, 4255-4261; Lee et al., Glycoconjugate J. 1987, 4, 317-328; Toyokuni et al., Tetrahedron Lett. 1990, 31, 2673-2676; Biessen et al., J. Med. Chem. 1995, 38, 1538-1546; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Kim et al., Tetrahedron Lett. 1997, 38, 3487-3490; Lee et al., Bioconjug. Chem. 1997, 8, 762-765; Kato et al., Glycobiol. 2001, 11, 821-829; Rensen etal., J. Biol. Chem. 2001, 276, 37577-37584; Lee et al., Methods Enzymol. 2003, 362, 38-43; Westerlind et al., Glycoconj. J. 2004, 21, 227-241; Lee et al., Bioorg. Med. Chem. Lett. 2006, 16(19), 5132-5135; Maierhofer et al., Bioorg. Med. Chem. 2007, 15. 7661-7676; Khorev et al., Bioorg. Med. Chem. 2008. 16, 5216-5231; Lee et al., Bioorg. Med. Chem. 201 1, 19, 2494-2500; Kornilova et al., Analyt. Biochem. 2012, 425, 43-46; Pujol et al., Angew. Chemie Int. Ed. Engl. 2012, 51, 7445-7448; Biessen etal., J. Med. Chem. 1995, 38, 1846-1852; Sliedregt et al., J. Med. Chem. 1999, 42, 609-618; Rensen et al., J. Med. Chem. 2004, 47, 5798-5808; Rensen et al., Arterioscler. Thromh. Vase. Biol. 2006, 26. 169-175; van Rossenberg et al.. Gene Ther. 2004, 11, 457-464; Sato et al., J. Am. Chem. Soc. 2004, 126, 14013-14022; Lee et al., J. Org. Chem. 2012, 77, 7564-7571; Biessen et al., FASEB J. 2000, 14, 1784-1792; Rajur et al., Bioconjug. Chem. 1997, 8, 935-940; Duff et al. , Methods Enzymol.

[0237] 2000, 313, 297-321; Maier et al., Bioconjug. Chem. 2003, 14. 18-29; Jayaprakash et al., Org.

[0238] Lett. 2010. 12, 5410-5413; Manoharan, Antisense Nucleic Acid Drug Dev. 2002. 12. 103-128; Merwin et al., Bioconjug. Chem. 1994, 5, 612-620; Tomiya et al., Bioorg. Med. Chem., 2013, 21, 5275-5281; International Applications WO 1998 / 013381; WO 2011 / 038356; WO 1997 / 046098; WO 2008 / 098788; WO 2004 / 101619; WO 2012 / 037254; WO 2011 / 120053; WO 2011 / 100131;

[0239] WO 2011 / 163121; WO 2012 / 177947; WO 2013 / 033230; WO 2013 / 075035; WO 2012 / 083185;

[0240] WO 2012 / 083046; WO 2009 / 082607; WO 2009 / 134487; WO 2010 / 144740; WO 2010 / 148013;

[0241] WO 1997 / 020563; WO 2010 / 088537; WO 2002 / 043771; WO 2010 / 129709; WO 2012 / 068187;

[0242] WO 2009 / 126933; WO 2004 / 024757; WO 2010 / 054406; WO 2012 / 089352; WO 2012 / 089602;

[0243] WO 2013 / 166121; WO 2013 / 165816; U.S. Patent Nos. 4.751,219; 7,582,744; 8,552,163;

[0244] 8,137,695; 6,908,903; 6,383,812; 7,262,177; 6,525,031; 5,994,517; 6,660,720; 6,300,319; 7,723,509; 8,106,022; 7,491,805; 7,491,805; 8,541,548; 8,344,125; 8,313,772; 8,349,308; 8,450,467; 8,501,930; 8,158,601; 7,262,177; 6,906,182; 6,620,916; 8,435,491; 8,404,862; 7,851,615; U.S. Patent Application Publications Nos. U.S. 2011 / 0097264; U.S. 2011 / 0097265; U.S. 2013 / 0004427; U.S. 2003 / 0119724; U.S. 2011 / 0207799; U.S. 2012 / 0035115; U.S. 2012 / 0230938; U.S. 2005 / 0164235; U.S. 2006 / 0183886; U.S. 2012 / 0136042; U.S. 2012 / 0095075; U.S. 2013 / 0109817; U.S. 2006 / 0148740; U.S. 2008 / 0206869; U.S. 2012 / 0165393; U.S. 2012 / 0101148; U.S. 2013 / 0121954; U.S. 2011 / 0123520; U.S.

[0245] 2 2003 / 0077829; U.S. 2008 / 0108801; and U.S. 2009 / 0203132.

[0246] In certain embodiments, a linker comprises a structure selected from:

[0247] 2 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and p is 1, 2, 3, 4, 5, or 6.

[0248] In certain embodiments, a linker comprises a structure selected from:

[0249]

[0250] 4 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0251] In certain embodiments, a linker comprises a structure selected from: , , ependently, 1, 2, 3, 4, 5, 6, 7, 8,, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In certain embodiments, a linker comprises a structure selected from: , 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In certain embodiments, a linker comprises a structure selected from:

[0252] wherein each L is. independently, a phosphotriester, alkylphosphonate. phosphoramidate, phosphorothioate, phosphorodithioate, or phosphorothiolate; and each n is, independently, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In certain embodiments, a linker comprises a structure selected from:

[0253]

[0254] 4 each n is. independently. 1, 2, 3. 4, 5, 6. 7. 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18. 19. or 20.

[0255] In certain embodiments, a linker comprises a structure selected from:

[0256] wherein each n is, independently, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0257] In certain embodiments, a linker comprises a structure selected from: wherein each n is, independently, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,

[0258] 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In certain embodiments, a linker comprises a structure selected from: , wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0259] In certain embodiments, a linker comprises a structure selected from: wherein each n is, independently, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0260] In certain embodiments, a linker comprises a structure selected from: each n is, independently, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In certain embodiments, a linker comprises a structure selected from: independently, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0261] In certain embodiments, a linker comprises the structure: wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

[0262] 19, or 20.

[0263] In certain embodiments, a linker comprises the structure: wherein each n is, independently, 1, 2. 3, 4, 5, 6. 7, 8, 9. 10.

[0264] 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0265] Ligands

[0266] In an oligonucleotide of the present disclosure, at least one instance of A4is a radical of a ligand; and each of A5and A6, if present, is independently a radical of a ligand or lipid. In some embodiments, at least one ligand is a central nervous system receptor ligand. In certain embodiments, at least one ligand is a TrkB receptor ligand. In certain embodiments, at least one ligand is a selective TrkB modulator. In certain embodiments, at least one ligand is a non- selective TrkB modulator (i.e.. a pan TrkABC modulator). In certain embodiments, at least one ligand is a CBi receptor ligand. In certain embodiments, at least one ligand is an α4β1 / 7 integrin receptor ligands. In certain embodiments, at least one ligand is an NMDA receptor ligand. In some embodiments, a ligand directs an oligonucleotide to a location in a subject. In some embodiments, a ligand targets a tissue. In some embodiments, the tissue is brain tissue. In some embodiments, the ligand targets an organ. In some embodiments, the organ is a brain. In some embodiments, a ligand targets a cell.

[0267] In some embodiments, a ligand targets a cell receptor. In certain embodiments, a cell receptor is a TrkB receptor, a CBi receptor, an cuPi n integrin receptor, or an NMDA receptor. In some embodiments, a receptor is in the brain. In some embodiments, a receptor is in the frontal cortex. In some embodiments, a receptor is in the striatum. In some embodiments, a receptor is in the cerebellum. In some embodiments, a receptor is in the brain stem. In some embodiments, a receptor is in the hippocampus. In some embodiments, a receptor is in the spinal cord. In some embodiments, a ligand is used to target an oligonucleotide to a cell type. In some embodiments, the cell is a central nervous system cell. In certain embodiments, the cell is a neuron. In certain embodiments, the cell is a glial cell. In certain embodiments, the cell is an astrocyte. In certain embodiments, the cell is an oligodendrocyte. In certain embodiments, the cell is an ependymal cell. In certain embodiments, the cell is a microglia.

[0268] In some embodiments, a ligand is an agonist of a receptor (e.g., a TrkB, CBi, α4β1 / 7 integrin, or NMDA receptor agonist). In some embodiments, a ligand is an antagonist of a receptor (e.g., a TrkB, CBi, 014P1 7 integrin, or NMDA receptor antagonist). In some embodiments, the oligonucleotides provided herein include at least one TrkB ligand that is a radical of a compound of the formula:

[0269] R2is hydrogen, -OR7, -SR8, or -NR9R10;

[0270] R3is hydrogen. -OR31, -SR32, or -NR33R34:

[0271] R4is hydrogen, -OR35, -SR36, or -NR37R38;

[0272] R5is hydrogen, -OR39, -SR40, or -NR41R42; R6is hydrogen, -OH, optionally substituted -O-alkyl, optionally substituted -OAc, -NH2, optionally substituted -NHAc, -SH, or =0;

[0273] R7, R8, R9, R10, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, and R42are each independently hydrogen, optionally substituted alkyd, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0274] Y is CH2, NH, S, or O;

[0275] Z is optionally substituted aryl or optionally substituted heteroaryl;

[0276] R11and R13are each independently absent, hydrogen, or optionally substituted alkyl;

[0277] R12, R14, and R15are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0278] R16is hydrogen, halogen, -CN, -N3, -SOni6R1A, -SOv16NR16BR16C, -NHNR16BR16C, -ONR16BR16C, -NHC(O)NHNR16BR16C. -NHC(O)NR16BR16C, — N(0)mi6, -NR16BR16C, -C(O)R16D, -C(O)OR16D, -C(O)NR16BR16C, -0R16A, -NR16BSO2R16A, -NR16BC(O)R16D, - NR16BC(O)OR16D, -NR16BOR16D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0279] Q . Q and = are each independently a single bond or a double bond, wherein if is a single bond, then =^= is a double bond, and R13is absent; and further wherein if =-b= is a single

[0280] 3 bond, then is a double bond, and R11is absent;

[0281] R16A, R16B, R16C, R16Dare each independently hydrogen, halogen, -CF3, -CCI3, -CBr3, -CI3, COOH, -C0NH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryk R16Band R16Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

[0282] R17, R18, and R19are each independently hydrogen, optionally substituted alky l, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0283] R20is hydrogen, halogen, -CN, -N3, -SOn20R1A, -SOv2oNR20BR20C, -NHNR20BR20C, -ONR20BR20C, -NHC(O)NHNR20BR2°C. -NHC(O)NR20BR2°C, -N(O)m20, -NR20BR20C, -C(O)R20D, -C(O)OR20D, -C(O)NR20BR2°C, -OR20A, -NR20BSO2R20A, -NR20BC(O)R20D, -NR20BC(O)OR20D, -NR20BOR20D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0284] R21is hydrogen, halogen, -CN, -Ns, -SOn2iR1A, -SOV2iNR21BR21c, -NHNR21BR21C, -ONR21BR21C, -NHC(O)NHNR21BR21c. -NHC(O)NR21BR21c, — N(O)m2i. -NR21BR21C, -C(O)R21D, -C(O)OR21D, -C(O)NR21BR21c, -OR21A, -NR21BSO2R21A, -NR21BC(O)R21D, -NR21BC(O)OR21D, -NR21BOR21D, optionally substituted alkyd, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalky 1, optionally substituted aryl, or optionally substituted heteroaryl;

[0285] R22and R23are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyd, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl:

[0286] R24is hydrogen, halogen, -CN, -N3. -SOn24R1A. -SOv24NR24BR24C, -NHNR24BR24C, -ONR24BR24C, -NHC(O)NHNR24BR24C, -NHC(O)NR24BR24C, -N(O)m24, -NR24BR24C, -C(O)R24D, -C(O)OR24D, -C(O)NR24BR24C, -OR24A, -NR24BSO2R24A, -NR24BC(O)R24D, -NR24BC(O)OR24D, -NR24BOR24D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0287] R20A,R20B,R20CR20DR21AR21 B.R21CR21DR24A.R24B.R24CAN(|R24DARE EACHindependently hydrogen, halogen, -CF3, -CC -CBrs, -CI3 -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalky 1. substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted and, or substituted or unsubstituted heteroaryl; R20B, R20C, R21B, R21C, R24B, R24C, R24B, and R24Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; nl6, n20. n21, n23. n24, z6, and z8 are each independently 0, 1. 2, 3, or 4; vl6, v20, v21, ml 6, m20, m21, and m24 are each independently 1 or 2; z3 is 0, 1, 2, 3, 4, or 5; z4 and z7 are each independently 0, 1 , or 2; z5 is 0, 1. 2, or 3; and z6 and z8 are each independently 0, 1, 2, 3, or 4.

[0288] In some embodiments, R2is hydrogen or -OR7. In certain embodiments, R2is hydrogen. In certain embodiments, R2is -OR7. In certain embodiments, R2is -OH. In certain embodiments, R2is -OCH3. In some embodiments, R3is hydrogen or -OR31. In certain embodiments, R3is hydrogen. In certain embodiments, R3is -OR31. In certain embodiments, R3is -OH. In certain embodiments, R3is -OCH3. In some embodiments, R4is hydrogen or -OR35. In certain embodiments, R4is hydrogen. In certain embodiments, R4is -OR35. In certain embodiments, R4is -OH. In certain embodiments, R4is -OCH3. In some embodiments, R5is hydrogen or -OR39. In certain embodiments, R5is hydrogen. In certain embodiments, R5is -OR39. In certain embodiments, R5is -OH. In certain embodiments. R5is -OCH3. In some embodiments, R6is hydrogen, -OH, or optionally substituted -O-alkyl. In certain embodiments, R6is hydrogen.

[0289] In some embodiments, R7, R8, R9, R10, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, and R42are each independently hydrogen or optionally substituted alkyl. In certain embodiments, R7, R8, R9, R10. R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, and R42are each independently hydrogen. In certain embodiments, R7, R8, R9. R10, R31, R32, R33, R34. R35, R36, R37. R38, R39, R40, R41, and R42are each independently optionally substituted alkyl. In certain embodiments, R7, R8, R9, R10, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, and R42are each independently unsubstituted alkyl. In certain embodiments, R7. R8, R9, R10, R31, R32. R3' , R34, R35, R36, R'7. R38, R39, R40, R41. and R42are each independently -CH3.

[0290] In some embodiments, Y is NH or O. In certain embodiments, Y is O.

[0291] In some embodiments, Z is optionally substituted aryl. In certain embodiments, Z is optionally substituted phenyl. In certain embodiments, Z is unsubstituted phenyl.

[0292] In certain embodiments, at least one radical of a TrkB ligand is of the formula certain embodiments, at least one radical of a TrkB ligand is of the formula

[0293]

[0294] In some embodiments, R11and R13are each independently absent or hydrogen. In certain embodiments, R11and R13are each independently absent. In some embodiments, R12, R14, and R15are each independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R12, R14. and R13are each independently hydrogen. In certain embodiments, R12, R14, and R13are each independently optionally substituted alkyl. In certain embodiments, R12, R14, and R13are each independently unsubstituted alkyl. In some embodiments, R16is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R16is hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl.

[0295] In some embodiments, R17, R18, and R19are each independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R17, R18, and R19are each independently hydrogen, unsubstituted alkyl, or unsubstituted heteroalkyl.

[0296] In some embodiments, R20is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R20is hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, R20is hydrogen. In some embodiments, R21is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments. R21is hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, R21is hydrogen. In some embodiments, R22and R23are each independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R22and R23are each independently hydrogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments. R22and R23are each independently hydrogen. In some embodiments, R24is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalky l. In certain embodiments, R24is hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, R24is hydrogen.

[0297] In some embodiments, n!6, n20. n21, n23, n24, z6, and z8 are each independently 0, 1. 2. In certain embodiments. n!6, n20. n21, n23. n24, z6, and z8 are each independently 0. In certain embodiments, v!6. v20, v21, ml 6, m20, m21. and m24 are each independently 1. In certain embodiments, vl6. v20, v21, ml 6, m20, m21. and m24 are each independently 2. In some embodiments, z3 is 0, 1, 2, or 3. In certain embodiments, z3 is 0. In some embodiments, z4 and z7 are each independently 0 or 1. In certain embodiments, z4 and z7 are each independently 0. In some embodiments, z5 is 0, 1, or 2. In certain embodiments, z5 is 0. In some embodiments, z6 and z8 are each independently 0, 1, or 2. In certain embodiments. z6 and z8 are each independently 0. In some embodiments, at least one radical of a TrkB ligand is of the formula

[0298] In certain embodiments, at least one TrkB ligand is flavone, tropoflavin, or a derivative thereof. In certain embodiments, at least one TrkB ligand is 3,7-dihydroxyflavone, 3, 7,8,2'- tetrahydroxyflavone, 7,3'-dihydroxyflavone, 7,8,2'-trihydroxyflavone, 7,8,3'-trihydroxyflavone, 7,8,4 -trihydroxyflavone, diosmetin (5,7,3'-trihydroxy-4'-methoxyflavone), 7-hydroxy-4'- methoxyflavone, 8-hydroxy-7-methoxyflavone, eutropoflavin (4'-dimethylamino-7,8- dihydroxyflavone), norwogonin (5,7,8-trihydroxyflavone), R7, R13, tropoflavin (7,8- dihydroxyflavone). 7,8-dimethoxyflavone, quercetin (3,3',4',5,7-pentahydroxyflavone), apigenin (4',5,7-trihydroxyflavone), isocoumarin, gossypetin (3,5,7,8,3',4'-hexahydroxyflavone), 2- methyl-8-phenylchromeno[7,8-d]imidazol-6(3H)-one, 8-phenylchromeno[7,8-d]imidazol-6(3H)- one, 4-oxo-2-phenyl-4H-chromene-7,8-diyl diacetate, or ANA- 12.

[0299] In some embodiments, at least one α4β1 / 7 integrin ligand is a compound of the formula:

[0300] In certain embodiments, at least one radical of an α4β1 / 7 integrin ligand is of the formula: R2Zis hydrogen, polyethylene glycol, substituted or unsubstituted heteroalkyl, or substituted or unsubstituted heteroaryl; and each of R3Zand R4Zis independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted -O-alkyl. In some embodiments, R2Zis hydrogen or substituted or unsubstituted heteroalkyl. In certain embodiments, R2Zis hydrogen. In some embodiments, each of R3Zand R4Zis independently hydrogen or halogen. In certain embodiments, each of R3Zand R4Zis independently halogen.

[0301] In certain embodiments, at least one cuPi / 7 integrin ligand is of the formula:

[0302] In certain embodiments, at least one radical of an CX4P1 / 7 integrin ligand is of the formula:

[0303] R4Zis hydrogen, halogen, polyethylene glycol, optionally substituted alky l, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted -O-alkyl, or optionally substituted cycloalkyl; R5Zis optionally substituted heteroalkyl or optionally substituted heterocyclyl; and nlZ is 1, 2, or 3. In some embodiments, R4Zis hydrogen, halogen, optionally substituted alkyd, or optionally substituted heteroalkyl. In certain embodiments, R4Zis hydrogen. In some embodiments, R5Zis optionally substituted heteroalkyl. In some embodiments, nlZ is 1 or 2. In certain embodiments, nlZ is 1. In certain embodiments, at least one radical of an α4β1 / 7 integrin ligand is of the formula:

[0304]

[0305] R6Zis hydrogen, -OH, -NH2, -NHR7Z, -OR7Z, or absent; and R77is hydrogen, polyethylene glycol, optionally substituted alky l, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl. In some embodiments, R6Zis hydrogen, -OH, -NH2, or absent. In certain embodiments,

[0306] R6Zis hydrogen. In certain embodiments, R6Zis absent. In some embodiments, R7Zis hydrogen or optionally substituted alkyl. In certain embodiments, R7Zis hydrogen or unsubstituted alkyl.

[0307] In certain embodiments, at least one radical of an α4β1 / 7 integrin ligand is of the formula:

[0308] n2Z is 0, 1, 2, or 3.

[0309] In some embodiments, n2Z is 0 or 1. In certain embodiments, n2Z is 0.

[0310] In certain embodiments, at least one radical of an α4β1 / 7 integrin ligand is of the formula:

[0311]

[0312] 4 n3Z is 0, 1, 2, or 3.

[0313] In some embodiments, n3Z is 0 or 1. In certain embodiments, n3Z is 0.

[0314] 6 In certain embodiments, at least one radical of an α4β1 / 7 integrin ligand is of the formula:

[0315] each of R8Z, R9Z, R10Z, and R11Zis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted -O-alkyl, or substituted or unsubstituted cycloalkyl; each of R12Zand R13Zis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl

[0316] R14Zis optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkylene-(C3-C6)- cycloalkyl, or optionally substituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy.

[0317] In some embodiments, each of R8Z, R9Z, R10Z, and R11Zis independently hydrogen, halogen, or optionally substituted alkyl. In certain embodiments, each of R8Z. R9Z, R10Z, and R11Zis independently optionally substituted alkyl. In certain embodiments, each of R8Z, R9Z, R10Z, and R11Zis independently unsubstituted alkyl. In some embodiments, each of R12Zand R13Zis independently hydrogen . In certain embodiments, each of R12Zand R13Zis independently H or In some embodiments, R14Zis optionally substituted Ci- C5 alky l. In certain embodiments, R14Zis optionally substituted C4 alkyd. In certain embodiments, at least one radical of an α4β1 / 7 integrin ligand is of the formula:

[0318] In certain embodiments, at least one radical of an α4β1 / 7 integrin ligand is of the formula: R15Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryk each of R16Zand R17Zis independently H, halogen, optionally substituted alkyl, or optionally substituted -O-alkyl; and Yzis -CH2- or -(CH2)2-. In some embodiments, R15Zis H, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R15Zis H. In some embodiments, each of R16Zand R17Zis independently H or optionally substituted alkyl. In certain embodiments, each of R16Zand R17Zis independently H. In certain embodiments, Yzis -CH2-. In certain embodiments, Yzis -(CH2)2-

[0319] In certain embodiments, at least one radical of an α4β1 / 7 integrin ligand is of the formula:

[0320] R18Zis H, -OH, -NH2, -NHR19Z, -OR19Z, or -CONHR19Z; each instance of R19Zis independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and n4Z is 1 or 2.

[0321] In some embodiments, R18Zis H, -OH, or -NH2. In certain embodiments, R18Zis H. In some embodiments, each instance of R19Zis independently H or optionally substituted alkyd. In certain embodiments, each instance of R19Zis independently H or unsubstituted alkyl. In certain embodiments, n4Z is 1. In certain embodiments, n4Z is 2.

[0322] In certain embodiments, at least one radical of an α4β1 / 7 integrin ligand is of the formula:

[0323] R19Zis H, -CH2OR20Z, -(CH2)2OR20Z, -CH2NHCOR20Z, or -OR20Z; and

[0324] R20Zis H. polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.

[0325] In some embodiments, R19Zis H or -CH2NHCOR20Z. In certain embodiments, R19Zis - CH2NHCOR20Z. In some embodiments, R20Zis H or optionally substituted alkyl. In certain embodiments, R20Zis H or unsubstituted alkyl. In certain embodiments, at least one radical of an α4β1 / 7 integrin ligand is of the formula:

[0326] R21Zis H. CONHR22Z, CH2OR22Z, (CH2)2OR22Z, CH2NHCOR22Z, or OR22Z;

[0327] R22Zis H. polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and

[0328] X1Zis H or halogen.

[0329] In some embodiments, R21Zis H or -CH2NHCOR22Z. In certain embodiments, R21Zis - CH2NHCOR22Z. In some embodiments, R22Zis H or optionally substituted alkyl. In certain embodiments, R22Zis H or unsubstituted alkyl. In certain embodiments, X1Zis H. In certain embodiments, X1Zis halogen.

[0330] In certain embodiments, at least one radical of an α4β1 / 7 integrin ligand is of the formula:

[0331] R23Zis H, -CONHR24Z, -CH2OR24Z, -(CH2)2OR24Z, -CH2NHCOR24Z, or -OR24Z;

[0332] R24Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and n5Z is 0, 1 , 2. or 3. In some embodiments, R23Zis H or -CONHR24Z. In certain embodiments, R2'7is -CONHR24Z. In some embodiments. R24Zis H or optionally substituted alkyl. In certain embodiments, R24Zis H or unsubstituted alkyl. In some embodiments, n5z is 0, 1, or 2. In certain, embodiments, n5z is 1.

[0333] In certain embodiments, at least one radical of an α4β1 / 7 integrin ligand is of the formula:

[0334] R25Zis H. -CONHR27Z, -CH2OR27Z. -(CH2)2OR27Z. -CH2NHCOR27Z, or -OR27Z;

[0335] R26Zis H, optionally substituted alkyl, or optionally substituted cycloalkyl;

[0336] R27Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and X2Zis optionally substituted CH2or optionally substituted NH.

[0337] In some embodiments, R25Zis H or -CH2NHCOR27Z. In certain embodiments, R25Zis - CH2NHCOR27Z. In some embodiments, R26Zis H or optionally substituted alkyl. In some embodiments, R26Zis H or unsubstituted alkyl. In certain embodiments, R26Zis H or -CH3. In some embodiments, R27Zis H, optionally substituted alkyl, or optionally substituted heteroalkyl.

[0338] In certain embodiments, R27Zis H. unsubstituted alkyl, or unsubstituted heteroalkyl. In some embodiments, X2Zis optionally substituted NH. In certain embodiments, X2Zis NH.

[0339] In certain embodiments, at least one radical of an α4β1 / 7 integrin ligand is of the formula:

[0340] R28Zis H, -CH2OR30Z, -(CH2)2OR30Z, -CH2NHCOR30Zor -OR30Z;

[0341] R29Zis H, -OH, -NH2, -NHR31Z, or -OR31Z;

[0342] R30Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;

[0343] R31Zis H. polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and n3Z is 1, 2, or 3.

[0344] In some embodiments, R28Zis H, -CH2NHCOR30Z, or -OR'02. In certain embodiments, R28Zis -CH2NHCOR30Z. In some embodiments, R29Zis H, -OH, -NH2. In some embodiments, R30Zis H, optionally substituted alkyd, or optionally substituted heteroalkyl. In certain embodiments, R30Zis H, unsubstituted alkyl, or unsubstituted heteroalkyd. In some embodiments, R31Zis H, optionally substituted alky 1, or optionally substituted heteroalkyl. In certain embodiments, R31Zis H, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, n3Z is 1. In certain embodiments, n3Z is 2.

[0345] In some embodiments, at least one CBi ligand is a compound of the formula:

[0346] X1Yis NR10Yor CR11YR12Y; each of R10Y, R11Y, and R12Yis independently hydrogen, optionally substituted alkyd, optionally substituted heteroalky l, optionally substituted cycloalkyd, optionally substituted heterocycloalkyd, optionally substituted aryl, or optionally substituted heteroaryl;

[0347] R19Yis hydrogen, -SOni9YR19YA, -SOVI9YNR19YBR19YC, -NHNR19YBR19YC, -ONR19YBR19YC, -NHC(O)NHNR19YBR19YC, -NHC(O)NR19YBR19YC, -NR19YBR19YC, - C(O)R19YD, -C(O)OR19YD, -C(O)NR19YBR19YC, -OR19YA, -NR19YBSO2R19YA, -NR19YBC(O)R19YD, -NR19 BC(O)OR19YD, -NR19YBOR19YD, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each of R19YA, R19YB, R19YC, and R19YDis independently hydrogen, halogen, -CFs, -CCI3, -CBra, -CI3, -COOH, -CONH2. substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroar l; or R19YBand R19YCbonded to the same nitrogen atom are joined to form a substituted or unsubstituted heterocycloalkyd or substituted or unsubstituted heteroaryl; nl9Y is 0, 1, 2. 3, or 4; and vl9Y is 1 or 2.

[0348] In some embodiments, X1Yis NR10Y. In certain embodiments, X is NH. In some embodiments, R1<nis hydrogen, optionally substituted alkyl, or optionally substituted heteroalky l. In certain embodiments, R10Yis hydrogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, R10Yis hydrogen. In some embodiments, R19Yis hydrogen, optionally substituted alkyl, or optionally substituted heteroalky 1. In certain embodiments, R19'1is hydrogen, unsubstituted alky I, or unsubstituted heteroalkyl.

[0349] In certain embodiments, at least one radical of a CBi ligand is of the formula: certain embodiments, at least one radical of a CBi ligand is of the formula: In certain embodiments, at least one radical of a CBi ligand is a radical of a compound of the formula: wherein:

[0350] R17Yis hydrogen, -SOni7YR17YA. -SOVI7YNR17YBR17YC, -NHNR17YBR17YC, -ONR17YBR17YC, -NHC(O)NHNR17YBR17YC, -NHC(O)NR17YBR17YC, -NR17YBR17YC, - C(O)R17YD, -C(O)OR17YD, -C(O)NR17YBR17YC, -OR17YA, -NR17YBSO2R17YA, - NR17YBC(O)R17YD. -NR17YBC(O)OR17YD, -NR17YBOR17YD, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each of R17YA, R17YB, R17YC, and R17YDis independently hydrogen, halogen, -CF3, -CCI3, -CBr ,. -CI3, -COOH, -CONH2. substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R17YBand R17YCsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; nl7Y is 0, 1, 2. 3, or 4; and vl7Y is 1 or 2.

[0351] In some embodiments, R17Yis hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, or -NR17YBR17YC. In certain embodiments, R17Ais -NR17YBR17YC. In certain embodiments, R17Yis -NH2. In some embodiments, each of R17YBand R17YCis independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, each of R17YBand Rmcis independently hydrogen.

[0352] In certain embodiments, at least one radical of a CBi ligand is of the formula:

[0353]

[0354] In certain embodiments, at least one radical of a CBi ligand is a radical of a compound of the formula: |n certainembodiments, at least one radical of a CBi ligand is of the formula:

[0355] In certain embodiments, at least one radical of a CBi ligand is a radical of a compound of the formula:

[0356] R3Y, R4Y, R5Y, R6Y, and R8Yare each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0357] R9Yis hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl; or R63and R9Ysubstituents may be joined together form an optionally substituted heterocycloalkyd or optionally substituted heteroary l; R7Yis hydrogen, -SO„7YR7YA, -SOV7YNR7YBR7YC. -NHNR7YBR7YC, -ONR7YBR7YC, -NHC(O)NHNR7YBR7YC, -NHC(O)NR7YBR7YC, -NR7YBR7YC, -C(O)R7YD, -C(O)OR7W, -C(O)NR7YBR7YC, -OR7YA, -NR7YBSO2R7YA, -NR7YBC(O)R7YD, -NR7YBC(O)OR7YD, -NR7Y,!OR7YI’. optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryk

[0358] R7YA, R7YB, R73C, R73 13are each independently hydrogen, halogen, -CF3, -CCI3, -CBrs, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R7YBand R7YCsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; n7Y is 0, 1. 2, 3, or 4; and v7Y is 1 or 2.

[0359] In some embodiments, R3Yis hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R3Yis hydrogen. In certain embodiments, R'Yis halogen. In some embodiments, R4Yis hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R4Yis hydrogen. In certain embodiments, R43is halogen. In some embodiments, R53is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R5Yis hydrogen. In certain embodiments, R5Yis halogen. In some embodiments, R6Yis hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R6Yis hydrogen. In certain embodiments, R6Yis halogen. In some embodiments, R7Yis hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, or -C(O)R7YD. In certain embodiments, R7Yis -C(O)R7YD. In some embodiments, R7YDis optionally substituted aryl or optionally substituted heteroaiyl. In certain embodiments, R7YDis optionally substituted aryl. In some embodiments, R8Yis hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R83is optionally substituted heteroalkyl. In certain embodiments, R8Yis substituted heteroalkyl. In some embodiments, R9Yis hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R9Yis hydrogen.

[0360] In certain embodiments, at least one radical of a CBi ligand is of the formula:

[0361]

[0362] R16Yis hydrogen, halogen, -CN. -N3, -NO2, -NR16YBR16YC, -C(O)R16YD, -C(O)OR16YD. -C(O)NR16YBR16YC, -OR16YA. -NR16YBC(O)R16YD, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl: and

[0363] R16YA, R16YB, R16YC, and R16YDare each independently hydrogen, halogen, -CF3, -CCI3, -CBr3, -CI3, -COOH, -CONH2. substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R16YBand R16YCbonded to the same nitrogen atom are joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. In some embodiments, R16Yis hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R16Yis hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, at least one radical of a CBi ligand is of the formula:

[0364] In certain embodiments, at least one CBi ligand is a compound of the formula:

[0365] In some embodiments, at least one NMDA receptor ligand is a compound of the formula:

[0366]

[0367] In certain embodiments, at least one radical of an NMDA receptor ligand is of the In certain embodiments, at least one radical of an NMDA receptor ligand is of the formula: least one radical of an NMDA receptor ligand is of the formula: embodiments, at least one radical of an NMDA receptor ligand is of the formula: certain embodiments, at least one radical of an NMDA receptor ligand is of certain embodiments, at least one radical of an

[0368] NMDA receptor ligand is of the formula: certain embodiments, at least one radical of an NMDA receptor ligand is of the formula: certain embodiments, at least one radical of an at least one radical of an NMDA receptor ligand is of the formula: certain embodiments, at least one radical of an NMDA receptor ligand is of the formula: In some embodiments, a ligand is an antibody (e.g., an anti-TrkB, anti-CBi, anti-α4β1 / 7 integrin, or anti-NMDA receptor antibody). In certain embodiments, a ligand is an antibody fragment or an antibody variant. An “an anti-TrkB receptor antibody.” “anti-CBi receptor antibody.” “anti-α4β1 / 7 integrin receptor antibody,” or “anti-NMDA receptor antibody” refers to an immune system protein that recognizes, binds to, or otherwise interacts with a TrkB, CBi, α4β1 / 7 integrin, or NMDA receptor, respectively. In some embodiments, an oligonucleotide comprises at least two ligands (e.g., 2, 3, 4, 5, 6, 7, 8, 9. or 10 ligands). In some embodiments, an oligonucleotide comprises two ligands. In some embodiments, an oligonucleotide comprises three ligands. In some embodiments, an oligonucleotide further comprises an additional ligand conjugated at the 5'-end. In some embodiments, an oligonucleotide further comprises an additional ligand conjugated at the 3'-end. In certain embodiments, an oligonucleotide further comprises an additional ligand conjugated at the 5'-end and an additional ligand conjugated at the 3'-end. In some embodiments, at least two ligands are of the same ligand type. In some embodiments, each ligand is of the same ligand ty pe. In some embodiments, at least two ligands are the same. In some embodiments, at least two ligands are different ligands of the same ligand type. In some embodiments, at least two ligands are of different ligand types. In some embodiments, none of the ligands are of the same ligand ty pe. In certain embodiments, when ligands are of the same ligand type, they bind the same target. In some embodiments, at least one ligand is a small molecule, peptide, or protein.

[0369] In some embodiments, each instance of A4is a radical of the same ligand type. In some embodiments, each instance of A4is the same radical of a ligand. In some embodiments, at least two instances of A4are radicals of different ligand types. In some embodiments, at least two instances of A4are radicals of different ligands of the same ligand type. In some embodiments, at least two instances of A4are radicals of different ligands of different ligand types.

[0370] In some embodiments, each instance of A5is a radical of the same ligand type. In some embodiments, each instance of A5is the same radical of a ligand. In some embodiments, at least two instances of A5are radicals of different ligand types. In some embodiments, at least two instances of A5are radicals of different ligands of the same ligand type. In some embodiments, at least two instances of A5are radicals of different ligands of different ligand ty pe.

[0371] In some embodiments, each instance of A6is a radical of the same ligand type. In some embodiments, each instance of A6is the same radical of a ligand. In some embodiments, at least two instances of A6are radicals of different ligand types. In some embodiments, at least two instances of A6are radicals of different ligands of the same ligand type. In some embodiments, at least two instances of A6are radicals of different ligands of different ligand type.

[0372] In some embodiments, at least one instance of A4and at least one instance of A5are radicals of the same ligand type. In some embodiments, at least one instance of A4and at least one instance of A5are the same radical of a ligand. In some embodiments, at least one instance of A4and at least one instance of A5are radicals of different ligand types. In some embodiments, at least one instance of A4and at least one instance of A5are radicals of different ligands of the same ligand type. In some embodiments, at least one instance of A4and at least one instance of A5are radicals of different ligands of different ligand types. In some embodiments, at least one instance of A4and at least one instance of A6are radicals of the same ligand type. In some embodiments, at least one instance of A4and at least one instance of A6are the same radical of a ligand. In some embodiments, at least one instance of A4and at least one instance of A6are radicals of different ligand types. In some embodiments, at least one instance of A4and at least one instance of A6are radicals of different ligands of the same ligand type. In some embodiments, at least one instance of A4and at least one instance of A6are radicals of different ligands of different ligand types. In some embodiments, at least one instance of A5and at least one instance of A6are radicals of the same ligand ty pe. In some embodiments, at least one instance of A5and at least one instance of A6are the same radical of a ligand. In some embodiments, at least one instance of A5and at least one instance of A6are radicals of different ligand types. In some embodiments, at least one instance of A5and at least one instance of A6are radicals of different ligands of the same ligand type. In some embodiments, at least one instance of A5and at least one instance of A6are radicals of different ligands of different ligand types.

[0373] In some embodiments, each instance of A4, A5, and A6is the same radical of a ligand. In some embodiments, each instance of A4, A5, and A6is a different radical of a ligand compared to any other radical of a ligand in the oligonucleotide. In some embodiments, each instance of A4, A5, and A6is the same radical of a TrkB ligand. In some embodiments, each instance of A4, A5, and A6is the same radical of a CBi receptor ligand. In some embodiments, each instance of A4, A5, and A6is the same radical of an α4β1 / 7 integrin receptor ligand. In some embodiments, each instance of A4. A5, and A6is the same radical of an NMDA receptor ligand. In some embodiments, each instance of A4, A5, and A6is a different radical of a TrkB ligand, CBi receptor ligand, α4β1 / 7 integrin receptor ligand, and / or NMDA receptor ligand.

[0374] Lipids

[0375] In an oligonucleotide of the present disclosure, each of A5and A6, if present, is independently a radical of a ligand or lipid. In some embodiments, A5is a radical of a lipid. In some embodiments, A6is a radical of a lipid. In certain embodiments, A5and A6are each independently a radical of a lipid.

[0376] In some embodiments, each instance of A4is the same radical of a lipid. In some embodiments, each instance of A5is the same radical of a lipid. In some embodiments, each instance of A6is the same radical of a lipid.

[0377] In some embodiments, at least one instance of A4and at least one instance of A5are the same radical of a lipid. In some embodiments, at least one instance of A4and at least one instance of A6are the same radical of a lipid. In some embodiments, at least one instance of A5and at least one instance of A6are the same radical of a lipid. In some embodiments, each instance of A5and A6is the same radical of a lipid. In some embodiments, each instance of A5and A6is a different radical of a lipid compared to any other radical of a lipid in the oligonucleotide.

[0378] In some embodiments, at least one lipid is a fatty acyl, glycerolipid, glycerophospholipid, sphingolipid, saccharolipid, polyketide, sterol lipid, or prenol lipid. In some embodiments, at least one lipid is a fatty acid or conjugate, octadecanoid, eicosanoid, docosanoid, fatty alcohol, fatly aldehyde, fatly ester, fatty amide, fatty nitrile, fatly ether, hydrocarbon, oxygenated hydrocarbon, or fatty acyl glycoside.

[0379] In some embodiments, at least one lipid is a hydrocarbon. In some embodiments, the hydrocarbon chain is saturated or unsaturated. In certain embodiments, an unsaturated hydrocarbon chain comprises one, two, three, four, five, or six carbon-carbon double bonds (e.g.. cis double bonds and / or trans double bonds) In some embodiments, at least one radical of a lipid is unsubstituted C7-36alkyl. C7-36alkyl substituted with one or more fluoro as valency permits, unsubstituted C7-36alkenyl, or C7-36alkenyl substituted with one or more fluoro as valency permits. In certain embodiments, at least one radical of a lipid is unsubstituted C7-36alkyl or unsubstituted C7-36alkenyl In certain embodiments, at least one radical of a lipid is unsubstituted C7-36alkyl. In some embodiments, at least one radical of a lipid is unsubstituted C7-20 alkyl, C7 -20alkyl substituted with one or more fluoro as valency permits, unsubstituted C7 -20alkenyl, or C7 -20alkenyl substituted with one or more fluoro as valency permits. In certain embodiments, at least one radical of a lipid is unsubstituted C7 -20alkyl or unsubstituted C7 -20alkenyl In certain embodiments, at least one radical of a lipid is unsubstituted C7 -20alkyl. In some embodiments, at least one radical of a lipid is unsubstituted C21-28alkyd, C21-28alkyl substituted with one or more fluoro as valency permits, unsubstituted C21-28alkenyl, or C21-28alkenyl substituted with one or more fluoro as valency permits. In certain embodiments, at least one radical of a lipid is unsubstituted C21-28alkyl or unsubstituted C21-28alkenyl. In certain embodiments, at least one radical of a lipid is unsubstituted C21-28alkyl. In some embodiments, at least one radical of a lipid is unsubstituted C29-36alky l, C29-36alkyl substituted with one or more fluoro as valency permits, unsubstituted C29-36alkenyl, or C29-36alkenyl substituted with one or more fluoro as valency permits In certain embodiments, at least one radical of a lipid is unsubstituted C29-36alkyl or unsubstituted C29-36alkenyl. In certain embodiments, at least one radical of a lipid is unsubstituted C29-36alkyd. In some embodiments, at least one radical of a lipid is unsubstituted C16-28alkyl or unsubstituted C16-28 alkenyl, each of which is independently unbranched, bi-branched, or tri-branched. In certain embodiments, the alkenyl described in this paragraph comprises one C=C bond. In certain embodiments, the alkenyl described in this paragraph comprises two, three, or four C=C bond, as valency permits. In certain embodiments, at least one radical of a lipid is unbranched unsubstituted C18-26 alkyd. In certain embodiments, at least one radical of a lipid is — (CH2)I?CH3, — (CH2)ISCH3, — (CH2)i9CH3, — (CH2)2oCH3, — (CH2)2ICH3, -(CH2)22CH3, -(CH2)23CH3, -(CH2)24CH3, or -(CH2)25CH3. In certain embodiments, at least one radical of a lipid is -(CH2)2iCH3. In certain embodiments, at least one radical of a lipid is unbranched unsubstituted Ci8-26 alkenyl. In certain embodiments, at least one radical of a lipid is unbranched unsubstituted C18-26 alkenyl comprising one C=C bond.

[0380] In certain embodiments, at least one lipid is a monoradylglycerol, diradylglycerol, triradylglycerol, glycosylmonoradylglycerol, glycosyldiradylglycerol, betaine monoradylglycerol, or betaine diradylglycerol.

[0381] In certain embodiments, at least one lipid is a glycerophosphocholine, glycerophosphoethanolamine, glycerophosphoserine, glycerophosphoglyceroL glycerophosphoglycerophosphate, glycerophosphoinositol, glycerophosphoinositol monophosphate, glycerophosphoinositol bisphosphate, glycerophosphoinositol trisphosphate, glycerophosphate, glyceropyrophosphate, glycerophosphoglycerophosphoglycerol. CDP- glycerol, glycosylglycerophospholipid, glycerophosphoinositolglycan, glycerophos phonocholine, glycerophosphonoethanolamine, di-glycerol tetraether phospholipid, glycerol-nonitol tetraether phospholipid, oxidized glycerophospholipid, glycerophosphoethanolamine glycan, dihydroxyacetonephosphate, glycerophosphoethanol, glycerophosphothreonine, or cyclic glycerophosphatidic acid.

[0382] In certain embodiments, at least one lipid is a sphingoid base, ceramide, phosphosphingolipid, phosphonosphingolipid, neutral glycosphingolipid, acidic glycosphingolipid, basic glycosphingolipid, amphoteric glycosphingolipid, or arsenosphingolipid.

[0383] In certain embodiments, at least one lipid is a sterol, steroid, secosteroid, bile acid, or a derivative thereof, or steroid conjugate. In certain embodiments, at least one lipid is cholesterol. In certain embodiments, at least one radical of the lipid is of the formula:

[0384] In certain embodiments, at least one lipid is lithocholic acid. In certain embodiments, at least one radical of the lipid is of the formula: In certain embodiments, at least one radical of the lipid is of the formula: optionally wherein the unsubstituted C7-30 alkyl is unbranched unsubstituted Cn-23 alkyl, and the unsubstituted C7-30 alkenyl is unbranched unsubstituted Cn-23 alkenyl (optionally comprising one C=C bond, or optionally comprising two, three, or four C=C bonds). In certain embodiments, at least one radical of the lipid is of the formula:

[0385] In certain embodiments, at least one lipid is an isoprenoid, quinone, hydroquinone, polyprenol, or hopanoid.

[0386] In certain embodiments, at least one lipid is an acylaminosugar, acylaminosugar glycan, acyltrehalose, or acyltrehalose glycan.

[0387] In certain embodiments, at least one lipid is a linear polyketide, halogenated acetogenin, annonaceae acetogenin, macrolide, lactone polyketide, ansamycin, polyene, linear tetracycline, angucycline, polyether antibiotic, aflatoxin, cytochalasin, flavonoid, aromatic polyketide, non- ribosomal peptide / polyketide hybrid, or phenolic lipid. Additional Oligonucleotide Strand Modifications

[0388] The modified oligonucleotide strands may further comprise additional modifications. In certain embodiments, the modified oligonucleotide strand further comprises at least one modified sugar, at least one modified nucleobase, at least one modified intemucleoside linkage, or a combination thereof. In certain embodiments, a modified oligonucleotide strand further comprises 1, 2. 3, 4, 5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56- 60, 61-65, 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, or 96-100, inclusive, modified nucleosides. In certain embodiments, a modified oligonucleotide strand further comprises 1, 2, 3, 4, 5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 76- 80, 81-85, 86-90, 91-95, or 96-100, inclusive, modified sugars. In certain embodiments, a modified oligonucleotide strand further comprises 1, 2, 3. 4, 5, 6-10, 11-15, 16-20. 21-25, 26-30, 31 -35, 36-40, 41 -45, 46-50, 51-55, 56-60, 61-65, 66-70, 71 -75, 76-80, 81-85, 86-90, 91-95, or 96-100, inclusive, modified intemucleoside linkages.

[0389] When the oligonucleotides comprise additional oligonucleotide strands, e.g., antisense oligonucleotide strands, the additional oligonucleotide strands may independently comprise one or more of the additional modifications described herein.

[0390] Sugar Modifications

[0391] Any modifications known in the art may be used in the oligonucleotides disclosed herein. In some embodiments, a modified sugar is used in the oligonucleotides disclosed herein. In certain embodiments, a modified sugar is a substituted furanosyl sugar or non-bicyclic modified sugar. In certain embodiments, a modified sugar is a bicyclic or tricyclic modified sugar. In certain embodiments, a modified sugar is a sugar surrogate. A sugar surrogate may comprise one or more substitutions described herein.

[0392] In certain embodiments, a modified sugar is a substituted furanosyl or non-bicyclic modified sugar. In certain embodiments, the furanosyl sugar is a ribosyl sugar. In certain embodiments, the furanosyl sugar comprises one or more substituent groups, including, but not limited to, substituent groups at the 2', 3', 4', and 5' positions.

[0393] In certain embodiments, substituents at the 2' position include, but are not limited to, F and OCH3 (“OMe”, “O-methyl” or “methoxy’7). In certain embodiments, substituent groups at the 2' position suitable for non-bicyclic modified sugars include, but are not limited to, halo, allyl, amino, azido, SH, CN, OCN, -CF3, OCF3, F, Cl, Br, SCH3, SOCH3, SO2CH3, -ONO2, -NO2, -N3, and -NH2. In certain embodiments, substituent groups at the 2' position include, but are not limited to. -O-(Ci-Cio) alkoxy, alkoxy alkyl, -O-alkyl, -S-alkyl, -N-alkyL -O-alkenyl, -S-alkenyl, -N-alkenyl, -O-alkynyl, -S-alkynyl, -N-alkynyl, -O-alkyl-O-alkyl, alkynyl, wherein the alkyl, alkenyl and alkynyl can be substituted or unsubstituted Ci to C10 alkyl or C2 to C10 alkenyl and alkynyl. In certain embodiments, substituent groups at the 2' position include, but are not limited to, alkaryl. aralkyl, -O-alkaryl, and -O-aralkyl. In certain embodiments, these 2' substituent groups can be further substituted with one or more substituent groups independently selected from hydroxyl, alkoxy, carboxy, benzyl, phenyl, nitro (-NO2), thiol, thioalkoxy, thioalkyl, halogen, alky l, aryl, alkenyl, and alkynyl. In certain embodiments, substituent groups at the 2' position include, but are not limited to, -O[(CH2)hO]jCH3, -O(CH2)hOCH3, -O(CH2)hCH3, -O(CH2)hONH2, -O(CH2)hNH2, -O(CH2)hSCH3, and -O(CH2)hON[(CH2)hCH3)]2, where h and j are independently from 1 to 10. In certain embodiments, substituent groups at the 2' position include, but are not limited to, -OCH2CH2OCH3(“MOE ”), -O(CH2)2ON(CH3)2("DM AOE"). -O(CH2)2O(CH2)2N(CH3)2 (“DMAEOE”), and -OCH2C(=O)-N(H)CH3(“NMA”).

[0394] In certain embodiments, substituent groups at the 4' position suitable for non-bicyclic modified sugars include, but are not limited to, alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015 / 106128. In certain embodiments, substituent groups at the 5' position suitable for non-bicyclic modified sugars include, but are not limited to, methyl ("Me") (R or S), vinyl, and methoxy. In certain embodiments, the 5’ modification is a 5’ -monophosphate ((HO)2(O)P-O-5’); 5'-diphosphate ((HO)2(O)P-O-P(HO)(O)-O-5'); 5 '-triphosphate ((HO)2(O)P- O-(HO)(O)P-O-P(HO)(O)-O-5'); 5'-guanosine cap (7-methylated or non-methylated) (7m-G-0- 5'-(HO)(O)P-O-(HO)(O)P-O-P(HO)(O)-O-5'); 5'adenosine cap (Appp). and any modified or unmodified nucleotide cap structure (N-O-5'(HO)(O)P-O-(HO)(O)P-O-P(HO)(O)-O-5'); 5'- monothiophosphate (phosphorothioate; (HO)2(S)P-O-5'); 5'-monodithiophosphate (phosphorodithioate; (HO)(HS)(S)P-O-5'), 5'phosphorothiolate ((HO)2(O)P-S-5'); any additional combination of oxygen / sulfur replaced monophosphate, diphosphate and triphosphates (e.g. 5'- alpha-thiotriphosphate, 5'-gammathiotriphosphate, etc.), 5 '-phosphorami dates ((HO)2(O)P-NH-5', (HO)(NH2)(O)P-O-5'), 5'alkylphosphonates (R=alkyl=methyl, ethyl, isopropyl, propyl, etc., e.g. RP(OH)(O)-O-5'-, 5'alkenylphosphonates (i.e. vinyl, substituted vinyl), (OH)2(O)P-5'-CH2-), 5’alkyletherphosphonates (R=alkylether=methoxymethyl (MeOCf I2-). ethoxymethyl, etc., e.g. RP(OH)(O)-O-5'-). In certain embodiments, one or more sugars comprise a 5'-vinylphosphonate modification. In certain embodiments, one or more sugars comprise a 5'-ethylenephosphonate modification. In certain embodiments the 5' modification is at the terminus of an oligonucleotide. In certain embodiments the 5' modification is at the terminus of an antisense oligonucleotide. In certain embodiments, substituents described herein for the 2', 4', and 5' position can be added to other specific positions on the sugar. In certain embodiments, such substituents may be added to the 3' position of the sugar on the 3' terminal nucleoside or the 5' position of the 5' terminal nucleoside. In certain embodiments, a non-bicyclic modified sugar may comprise more than one non-bridging sugar substituent. In certain such embodiments, non-bi cyclic modified sugar substituents include, but are not limited to, 5'-Me-2'-F, 5'-Me-2’-OMe (including both R and S isomers). In certain embodiments, modified sugar substituents include those described in Migawa etal., WO 2008 / 101157.

[0395] In certain embodiments, a modified sugar is a bicyclic sugar. A bicyclic sugar is a modified sugar comprising two rings, wherein the second ring is formed via a bridge connecting two of the atoms in the first ring, thereby forming a bicyclic structure. In certain embodiments, a bicyclic sugar comprises a bridging substituent that bridges two atoms of the furanosyl ring to form a second ring. In certain embodiments, a bicyclic sugar does not comprise a furanosyl moiety. A “bicyclic nucleoside’" (“BNA”) is a nucleoside having a bicyclic sugar. In certain embodiments, the bicyclic sugar comprises a bridge between the 4' and 2’ furanose ring atoms. In certain embodiments, the bicyclic sugar comprises a bridge between the 5' and 3' furanose ring atoms. In certain such embodiments, the furanose ring is a ribose ring. In certain embodiments, 4' to 2' bridging substituents include, but are not limited to, 4'-CH2-2', 4'-(CH2)2-2', 4'- (CH2)3-2', 4'- CH2-O-2' (“LNA”), 4'-CH2-S-2', 4'-(CH2)2-O-2' (“ENA”), 4'-CH(CH3)-O-2' (“constrained ethyl” or “cEf ’ when in the S configuration), 4'-CH2-O-CH2-2', 4'-CH2-N(R)-2', 4'- CH(CH2OCH3)-O- 2' (“constrained MOE” or “cMOE”) and analogs thereof (e.g., U.S. Patent No. 7,399,845), 4'- C(CH3)(CH3)-O-2' and analogs thereof (e.g, U.S. Patent No. 8,278,283), 4'-CH2-N(OCH3)-2' and analogs thereof (e.g.. U.S. Patent No. 8,278.425), 4'-CH2-O-N(CH3)-2’ (e.g., U.S. Patent Publication No. 2004 / 0171570). 4'-CH2-N(R)-O-2'. wherein R is H, C1-C12 alkyl, or a protecting group (e.g., U.S. Patent No. 7,427,672), 4'-CH2-C(H)(CH3)-2' (e.g., Chattopadhyaya et o / ., J. Org. Chem., 2009, 74, 118- 134), and 4'-CH2-C(=CH2)-2' and analogs thereof (e.g., U.S. Patent No. 8,278,426). Additional representative U.S. Patents and U.S. Patent Publications that teach the preparation of bicyclic nucleic acid nucleotides include, but are not limited to, the following: U.S. Patent Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 6,998,484; 7,053,207; 7,034,133;7,084,125; 7,399,845; 7,427,672; 7,569,686; 7,741,457; 8,022,193; 8,030,467; 8,278,425; 8,278,426; 8,278.283; US 2008 / 0039618; US 2009 / 0012281; US 2013 / 0190383; and WO 2013 / 036868. Any of the foregoing bicyclic nucleosides can be prepared having one or more stereochemical sugar configurations including, for example, a-L-nbofuranose and [1-D- ribofuranose (see, e.g., WO 99 / 14226). Specified bicyclic nucleosides herein are in the P-D configuration, unless otherwise specified.

[0396] In certain embodiments, a modified sugar is a sugar surrogate. In certain embodiments, a sugar surrogate has the oxygen atom replaced, e.g., with a sulfur, carbon or nitrogen atom. In certain such embodiments, the sugar surrogate may also comprise bridging and / or non-bridging substituents as described herein. In certain embodiments, sugar surrogates comprise rings having other than 5 atoms. In certain such embodiments, the sugar surrogate comprises a cyclobutyl moiety in place of the pentofuranosyl sugar. In certain embodiments, the sugar surrogate comprises a six membered ring in place of the pentofuranosyl sugar. In certain embodiments, the sugar surrogate comprises a tetrahydropyran (“THP”) in place of the pentofuranosyl sugar. In certain embodiments, the sugar surrogate comprises a morpholino in place of the pentofuranosyl sugar. Representative U.S. patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Patent Nos. 4,981,957; 5,118,800; 5,166,315; 5,185,444; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; 5.700,920; 7,875,733; 7,939,677, 8,088,904; 8,440,803; and 9,005,906.

[0397] In some embodiments, sugar surrogates comprise acyclic moieties. In certain embodiments, the sugar surrogate is an unlocked nucleic acid (‘'UNA”). A UNA is unlocked acyclic nucleic acid, wherein any of the bonds of the sugar has been removed, forming an unlocked “sugar’ residue. In one example, UNA also encompasses a monomer where the bonds between CI'-C4' have been removed (z.e., the covalent carbon-oxygen-carbon bond between the Cl' and C4' carbons). In another example, the C2'-C3' bond ( / .e., the covalent carbon-carbon bond between the C2' and C3' carbons) of the sugar has been removed. Representative U.S. publications that teach the preparation of UNA include, but are not limited to, U.S. Patent No. 8,314,227; and U.S. Patent Publication Nos. 2013 / 0096289; 2013 / 0011922; and 2011 / 0313020. In certain embodiments, sugar surrogates comprise peptide nucleic acid (“PNA”), acyclic butyl nucleic acid (see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and nucleosides and oligonucleotides described in Manoharan et al., US 2013 / 130378. Many other bicyclic and tricyclic sugar and sugar surrogate ring systems are known in the art that can be used in modified nucleosides.

[0398] In some embodiments, modified sugars and / or unmodified sugars are arranged along the modified oligonucleotide strand or regions thereof in a defined pattern or “sugar motif’. In certain instances, such sugar motifs include, but are not limited to, any of the patterns of sugar modifications described herein.

[0399] In certain embodiments, an oligonucleotide strand comprises a gapmer sugar motif. A gapmer oligonucleotide strand comprises or consists of a region having two external “wing” regions and a central or internal “gap” region. The gap and wing regions form a contiguous sequence of nucleosides, wherein the majority of nucleoside sugars of each of the wings differ from the majority of nucleoside sugars of the gap. In certain embodiments, the wing regions comprise a majority of modified sugars, and the gap comprises a majority of unmodified sugars. In certain embodiments, the nucleosides of the gap are deoxy nucleosides. Oligonucleotides with a gapmer sugar motif are described in. for example. U.S. Patent No. 8,790,919.

[0400] In certain embodiments, one or both strands of a double-stranded oligonucleotide comprise a triplet sugar motif. An oligonucleotide strand with a triplet sugar motif comprises three identical sugar modifications on three consecutive nucleosides. In certain embodiments, the triplet is at or near the cleavage site of the oligonucleotide (e.g.. the site at which a ribonuclease, such as Dicer or Drosha, cleaves the oligonucleotide). In certain embodiments, a strand of a double-stranded oligonucleotide may contain more than one triplet sugar motif. In certain embodiments, the identical sugar modification of the triplet sugar motif is a 2'-F modification. Oligonucleotides with a triplet sugar motif are disclosed, for example, in U.S. Patent No. 10.668.170.

[0401] In certain embodiments, one or both strands of a double-stranded oligonucleotide comprise a quadruplet sugar motif. An oligonucleotide strand with a quadruplet sugar motif comprises four identical sugar modifications on four consecutive nucleosides. In certain embodiments, the quadruplet is at or near the cleavage site. In certain embodiments, a strand of a double-stranded oligonucleotide may contain more than one quadruplet sugar motif. In certain embodiments, the identical sugar modification of the quadruplet sugar motif is a 2'-F modification. For a double-stranded oligonucleotide having a duplex region of 19-23 nucleotides in length, the cleavage site of the antisense oligonucleotide strand is typically around the 10, 11, and 12 positions from the 5'-end. In certain embodiments, the quadruplet sugar motif is at the 8. 9, 10, and 11 positions; the 9, 10, 11, and 12 positions; the 10, 11, 12, and 13 positions; the 11, 12, 13, and 14 positions; or the 12, 13, 14, and 15 positions of the sense oligonucleotide strand, counting from the first nucleoside of the 5'-end of the sense oligonucleotide strand, or, the count starting from the first paired nucleotide within the duplex region from the 5 '-end of the sense oligonucleotide strand. In certain embodiments, the quadruplet sugar motif is at the 8, 9, 10, and 11 positions; the 9, 10, 11, andl2 positions; the 10, 11, 12, and 13 positions; the 11, 12, 13, and 14 positions; or the 12, 13, 14, and 15 positions of the antisense oligonucleotide strand, counting from the first nucleoside of the 5 '-end of the antisense oligonucleotide strand, or, the count starting from the first paired nucleotide within the duplex region from the 5 '-end of the antisense oligonucleotide strand. The cleavage site may change according to the length of the duplex region of the double-stranded oligonucleotide and may change the position of the quadruplet accordingly.

[0402] In certain embodiments, an oligonucleotide strand comprises an alternating sugar motif. In certain embodiments, one or both strands of a double-stranded oligonucleotide comprise an alternating sugar motif. An oligonucleotide with an alternating sugar motif comprises at least two different sugar modifications, wherein one or more consecutive nucleosides comprising a first sugar modification alternates with one or more consecutive nucleosides comprising a second sugar modification, and one or more consecutive nucleosides comprising a third sugar modification, etc. For example, if A, B, and C each represent one type of modification to the nucleoside, the alternating motif can be “ABABABABABAB . . “AABBAABBAABB . . “AABAABAABAAB . . .” ‘‘AAABAAABAAAB . . .,” “AAABBBAAABBB . . .,” or “ABC ABC ABC ABC . . .,” etc. In certain embodiments, the alternating sugar motif is repeated for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 contiguous nucleobases along an oligonucleotide strand. In certain embodiments, the alternating sugar motif is comprised of two different sugar modifications. In certain embodiments, the alternating sugar motif comprises 2'-OMe and 2'-F sugar modifications.

[0403] In certain embodiments, each nucleoside of an oligonucleotide strand is independently modified with one or more sugar modifications provided herein. In certain embodiments, each strand of a double-stranded oligonucleotide independently has one or more sugar modifications provided herein. In certain embodiments, an oligonucleotide strand containing a sugar motif is fully modified in that each nucleoside comprises a sugar modification.

[0404] In certain embodiments, a modified sugar is 2'-fluoro-2'-deoxyribose, 2'-O-methylribose, 2'-thioribose, 2', 3 '-dideoxyribose, 2'-amino-2'-deoxyribose, 2’ deoxyribose, 2'-azido-2'- deoxyribose, 2'-O-methyldeoxyribose. 3'-amino-2', 3 '-dideoxyribose, 3'-azido-2',3'- dideoxyribose. 3 '-deoxyribose, 3'-O-(2-mtrobenzyl)-2'-deoxynbose, 3'-0-methylribose, 5'- aminoribose, 5'-thioribose, 5-nitro-l-indolyl-2'-deoxyribose, 5'-biotin-ribose, 2'-O,4'-C-amino- linked ribose, 2'-O,4'-C-thio-linked ribose, 2'-O-methoxyethyl ribose, 2'-O,4'-C-methylene- linked ribose, 2'-O,4'-C-ethylene-linked ribose, 2',4'-constrained ethyl ribose, locked sugar, or a bicyclic sugar.

[0405] In certain embodiments, a modified sugar is present at the 3'-end of the oligonucleotide strand. In certain embodiments, a modified sugar is present within 3 nucleosides the 3 '-end of the oligonucleotide strand. In certain embodiments, a modified sugar is present at the 5 '-end of the oligonucleotide strand. In certain embodiments, a modified sugar is present within 3 nucleosides of the 5'-end of the oligonucleotide strand. In certain embodiments, a modified sugar is present at an internal position on an oligonucleotide strand. In certain embodiments, a modified sugar is present more than 3 nucleosides from the 3'-end of the oligonucleotide strand. In certain embodiments, a modified sugar is present more than 3 nucleosides from the 5 '-end of the oligonucleotide strand. In certain embodiments, modified sugars are present on a block of modified nucleobases. In certain such embodiments, the block is at the 3'-end of the oligonucleotide strand. In certain embodiments, the block is within 3 nucleosides of the 3 '-end of the oligonucleotide strand. In certain embodiments, the block is at the 5'-end of the oligonucleotide strand. In certain embodiments, the block is within 3 nucleosides of the 5'-end of the oligonucleotide strand. In certain embodiments, the block is at an internal position in the oligonucleotide strand. In certain embodiments, the block is more than 3 nucleosides from the 3'- end of the oligonucleotide strand. In certain embodiments, the block is more than 3 nucleosides from the 5 '-end of the oligonucleotide strand.

[0406] In certain embodiments, a modified sugar is 2'-O-methyl ribose, 2'-F nbose, or inverted abasic deoxyribose. In certain embodiments, a modified nucleoside is 2'-O-methyl adenosine, 2'- O-methyl guanosine, 2'-O-methyl cytosine, 2'-O-methyl uracil, 2'-F adenosine, 2'-F guanosine, 2'-F cytosine, or 2'-F uracil.

[0407] Nucleobase Modifications

[0408] Any modified nucleobases known in the art may be used in the oligonucleotides provided herein. In certain embodiments, modified oligonucleotides comprise one or more nucleosides comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleosides that do not comprise a nucleobase, referred to as an abasic nucleoside.

[0409] In certain embodiments, modified nucleobases are selected from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alky l substituted purines, and N-2, N-6 and 0-6 substituted purines. In certain embodiments, modified nucleobases are selected from: 2-aminopropyladenine, 5- hydroxymethyl cytosine. 5- methylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N- methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (C=C-CH3) uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5 -ribosyluracil (pseudouracil). 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl. 8-hydroxyl, 8-aza and other 8- substituted purines, 5-halo, particularly, 5-bromo, 5 -trifluoromethyl, 5-halouraciL and 5- halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3 -deazaguanine, 3 -deazaadenine, 6-N-benzoyladenine. 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N- benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size expanded bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as 1,3- diazaphenoxazine-2-one, l,3-diazaphenothiazine-2-one, and 9-(2-aminoethoxy)-l,3- diazaphenoxazine-2-one (G-clamp). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example. 7-deaza-adenine. 7- deazaguanosine, and 2-aminopyridine and 2-pyridone. In certain embodiments, a modified nucleobase is xanthine, ally aminouracil, allyaminothymidine. hypoxanthine, digoxigeninated adenine, digoxigeninated cytosine, digoxigeninated guanine, digoxigeninated uracil, 6-chloropurineriboside, N6-methyl adenine, methylpseudouracil, 2-thiocytosine, 2-thiouracil, 5-methyluracil, 4-thiothymidine, 4-thiouracil, 5,6-dihydro-5-methyluracil, 5,6-dihydrouracil, 5-[(3-Indolyl)propionamide-N-allyl]uracil, 5- aminoallylcytosine, 5-aminoallyluracil, 5 -bromouracil, 5 -bromocytosine. 5-carboxy cytosine, 5- carboxymethylesteruracil, 5-carboxyuracil, 5-fluorouracil, 5-formylcytosine, 5-formyluracil, 5- hydroxy cytosine, 5-hydroxymethylcytosine, 5-hydroxymethyluracil, 5-hydroxyuracil, 5- iodocytosine, 5-iodouracil, 5-methoxy cytosine, 5-methoxyuracil, 5 -methylcytosine, 5- methyluracil. 5-propargylaminocytosine, 5-propargylaminouracil, 5-propynylcytosine, 5- propynyluracil, 6-azacytosine. 6-azauracil, 6-chloropurine, 6-thioguanine, 7-deazaadenine. 7- deazaguanine, 7-deaza-7-propargylaminoadenine, 7-deaza-7-propargylaminoguanine, 8- azaadenine, 8-azidoadenine, 8-chloroadenine, 8-oxoadenine, 8-oxoguanine, araadenine, aracytosine, araguanine, arauracil, biotin-16-7-deaza-7-propargylaminoguanine, biotin-16- aminoallylcytosine, biotin- 16-aminoallyluracil, cyanine 3-5-propargylaminocytosine, cyanine 3- 6-propargylaminouraciL cyanine 3-aminoallylcytosine, cyanine 3-aminoallyluracil, cyanine 5-6- propargylaminocytosine, cyanine 5-6-propargylaminouracil, cyanine 5-aminoallylcytosine, cyanine 5-aminoallyluracil, cyanine 7-aminoallyluracil, dabcyl-5-3-aminoallyluracil, desthiobiotin- 16-aminoallyl-uracil, desthiobi otin-6-aminoallylcytosine. isoguanine, Nl- ethylpseudouracil, N1 -methoxymethylpseudouracil. N1 -methyladenine, N 1 -methylpseudouracil. N1 -propylpseudouracil, N2-methylguanine, N4-biotin-OBEA-cytosine, N4-methylcytosine, N6- methyladenine, O6-methylguanine, pseudoisocytosine, pseudouracil, thienocytosine, thienoguanine, thienouracil, xanthosine, 3-deazaadenine, 2,6-diaminoadenine, 2,6- daminoguanine, 5-carboxamide-uracil, 5-ethynyluracil, N6-isopentenyladenine (i6A), 2-methyl- thio-N6-isopentenyladenine (ms2i6A), 2-methylthio-N6-methyladenine (ms2m6A), N6-(cis- hydroxyisopentenyl)adenine (io6A), 2-methylthio-N6-(cis-hydroxyisopentenyl)adenine (ms2io6A). N6-glycinylcarbamoyladenine (g6A), N6-threonylcarbamoyladenine (t6A), 2- methylthio-N6-threonyl carbamoyladenine (ms2t6A), N6-methyl-N6-threonylcarbamoyladenine (m6t6A), N6-hydroxynorvalylcarbamoyladenine (hn6A), 2-methylthio-N6-hydroxynorvalyl carbamoyladenine (ms2hn6A), N6,N6-dimethyladenine (m62A), and N6-acetyladenme (ac6A).

[0410] Further nucleobases include those disclosed in U.S. Patent No. 3,687,808; Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P. ed. Wiley-VCH, 2008; The Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859; Kroschwitz, J.L., Ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, Y.S., Chapter 15, dsRNA Research and Applications, pages 289- 302; Antisense Research and Applications, Crooke, S . and Lebleu, B ., Eds., CRC Press, 1993, 273-288; Antisense Drug Technology. Crooke S.T., Ed., CRC Press, 2008, 163-166 and 442-443 (Chapters 6 and 15).

[0411] Publications that teach the preparation of certain of the above noted modified nucleobases, as well as other modified nucleobases, include without limitation, U.S. Patent Application Publication Nos. 2003 / 0158403 and 2003 / 0175906; U.S. Patent Nos. 4,845,205: 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,434,257; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121; 5,596,091; 5,614,617; 5,645,985; 5,681,941; 5,811,534; 5,750,692; 5,948,903; 5,587,470; 5,457,191; 5,763,588; 5,830,653; 5.808,027; 6,005,096. 6,015,886; 6,147,200: 6,166,197; 6,166,199; 6,222,025; 6,235,887; 6.380,368; 6.528,640; 6,639.062; 6,617.438; 7,045,610; 7,427,672; and 7,495,088.

[0412] In certain embodiments, oligonucleotides comprise modified and / or unmodified nucleobases arranged along one or both strands of the oligonucleotide or region thereof in a defined pattern or motif. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases are modified. In certain embodiments, each purine or each pyrimidine is modified. In certain embodiments, each adenine is modified. In certain embodiments, each guanine is modified. In certain embodiments, each thymine is modified. In certain embodiments, each uracil is modified. In certain embodiments, each cytosine is modified. In certain embodiments, some or all of the cytosine nucleobases in a modified oligonucleotide strand are 5 -methylcytosines.

[0413] In certain embodiments, a modified nucleobase is present at the 3 '-end of the oligonucleotide strand. In certain embodiments, a modified nucleobase is present within 3 nucleosides of the 3'-end of the oligonucleotide strand. In certain embodiments, a modified nucleobase is present at the 5'-end of the oligonucleotide strand. In certain embodiments, a modified nucleobase is present within 3 nucleosides of the 5'-end of the oligonucleotide strand. In certain embodiments, a modified nucleobase is present at an internal position on an oligonucleotide strand. In certain embodiments, a modified nucleobase is present more than 3 nucleosides from the 3'-end of the oligonucleotide strand. In certain embodiments, a modified nucleobase is present more than 3 nucleosides from the 5 '-end of the oligonucleotide strand. In certain embodiments, modified oligonucleotides comprise a block of modified nucleobases. In certain such embodiments, the block is at the 3'-end of the oligonucleotide strand. In certain embodiments, the block is within 3 nucleosides of the 3 '-end of the oligonucleotide strand. In certain embodiments, the block is at the 5 '-end of the oligonucleotide strand. In certain embodiments, the block is w ithin 3 nucleosides of the 5'-end of the oligonucleotide strand. In certain embodiments, the block is at an internal position in the oligonucleotide strand. In certain embodiments, the block is more than 3 nucleosides from the 3 '-end of the oligonucleotide strand. In certain embodiments, the block is more than 3 nucleosides from the 5'-end of the oligonucleotide strand.

[0414] Internucleoside Linkage Modifications

[0415] Any modified intemucleoside linkages can be used in the oligonucleotides provided herein. A 3' to 5' phosphodiester linkage is the naturally occurring intemucleoside linkage of RNA and DNA. In certain embodiments, an oligonucleotide strand has one or more modified, i.e., non-naturally occurring, intemucleoside linkages. Certain non-naturally occurring intemucleoside linkages may impart desirable properties, such as, for example, enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases. Representative phosphorus-containing modified intemucleoside linkages include, but are not limited to, phosphotriesters, alkylphosphonates (e.g., methylphosphonates), phosphoramidates, phosphorothioates (“P=S”), phosphorodithioates (“HS-P=S”), and phosphorothiolates (“HS-P=O”). Representative non-phosphoms containing intemucleoside linking groups include, but are not limited to, methylenemethylimino (-CH2-N(CH3)-O-CH2), thiodiester, thionocarbamate (-O-C(=O)(NH)-S-); siloxane (-O-S1H2-O-); and N,N - dimethylhydrazine (-CH2-N((CH3)-N((CH3)-). Methods of preparation of phosphorous- containing and non-phosphorous-containing intemucleoside linkages are well known to those skilled in the art. Neutral intemucleoside linkages include, without limitation, phosphotriesters, methylphosphonates, MMI (3'-CH2-N(CH3)-O-5'), amide-3 (3'-CH2-C(=O)-N(H)-5'), amide-4 (3'-CH2-N(H)-C(=O)-5'), formacetal (3'-O-CH2-O-5'), methoxypropyl, and thioformacetal (3'-S- CH2-O-5'). Further neutral intemucleoside linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester, and amides (See, for example: Carbohydrate Modifications in Antisense Research,' Y.S. Sanghvi and P.D. Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Further neutral intemucleoside linkages include nonionic linkages comprising mixed N, O, S and CH2component parts.

[0416] In certain embodiments, an oligonucleotide strand comprises at least one modified intemucleoside linkage. A modified intemucleoside linkage may be placed at any position of an oligonucleotide strand. For double-stranded oligonucleotides, a modified intemucleoside linkage may be placed within the sense oligonucleotide strand, antisense oligonucleotide strand, or both oligonucleotide strands of the double-stranded oligonucleotide.

[0417] In certain embodiments, the intemucleoside linkage modification may occur on every nucleoside of an oligonucleotide strand. In certain embodiments, intemucleoside linkage modifications may occur in an alternating pattern along an oligonucleotide strand. In certain embodiments, essentially each intemucleoside linking group is a phosphate intemucleoside linkage (P=O). In certain embodiments, each intemucleoside linking group of a modified oligonucleotide strand is a phosphorothioate (P=S). In certain embodiments, each intemucleoside linking group of a modified oligonucleotide strand is independently selected from phosphorothioate and phosphate intemucleoside linkages. In certain embodiments, the pattern of the intemucleoside linkage modification on each strand of a double-stranded oligonucleotide is the same. In certain embodiments, the pattern of the intemucleoside linkage modification on each strand of a double-stranded oligonucleotide is different. In certain embodiments, a doublestranded oligonucleotide comprises 6-8 modified intemucleoside linkages. In certain embodiments, the 6-8 modified intemucleoside linkages are phosphorothioate intemucleoside linkages or alkylphosphonate intemucleoside linkages. In certain embodiments, the sense oligonucleotide strand comprises at least two modified intemucleoside linkages at either or both the 5'-end and the 3'-end. In certain such embodiments, the modified intemucleoside linkages are phosphorothioate intemucleoside linkages or alkylphosphonate intemucleoside linkages. In certain embodiments, the antisense oligonucleotide strand comprises at least two modified intemucleoside linkages at either or both the 5'-end and the 3'-end. In certain such embodiments, the modified intemucleoside linkages are phosphorothioate intemucleoside linkages or alkylphosphonate intemucleoside linkages.

[0418] In certain embodiments, a double-stranded oligonucleotide comprises an overhang region. In certain embodiments, a double-stranded oligonucleotide comprises a phosphorothioate or alkylphosphonate intemucleoside linkage modification in the overhang region. In certain embodiments, a double-stranded oligonucleotide comprises a phosphorothioate or alkylphosphonate intemucleotide linkage linking the overhang nucleotide with a paired nucleotide that is next to the overhang nucleotide. For instance, there may be at least two phosphorothioate intemucleoside linkages between the terminal three nucleosides, in which two of the three nucleosides are overhang nucleosides, and the third is a paired nucleoside next to the overhang nucleoside. These terminal three nucleosides may be at the 3'-end of the antisense oligonucleotide strand, the 3’-end of the sense oligonucleotide strand, the 5'-end of the antisense oligonucleotide strand, or the 5 '-end of the sense oligonucleotide strand.

[0419] In certain embodiments, modified oligonucleotide strands comprise one or more intemucleoside linkages having chiral centers. Representative chiral intemucleoside linkages include, but are not limited to. alkylphosphonates and phosphorothioates. Modified oligonucleotide strands comprising intemucleoside linkages having chiral centers can be prepared as populations of modified oligonucleotide strands comprising stereorandom intemucleoside linkages, or as populations of modified oligonucleotide strands comprising phosphorothioate linkages in particular stereochemical configurations. In certain embodiments, populations of modified oligonucleotide strands comprise phosphorothioate intemucleoside linkages, wherein all of the phosphorothioate intemucleoside linkages are stereorandom. Such modified oligonucleotide strands can be generated using synthetic methods that result in random selection of the stereochemical configuration of each phosphorothioate linkage. As is well understood by those of skill in the art, each individual phosphorothioate of each individual oligonucleotide compound has a defined stereoconfiguration. In certain embodiments, populations of modified oligonucleotide strands are enriched for modified oligonucleotide strands comprising one or more particular phosphorothioate intemucleoside linkages in a particular, independently selected stereochemical configuration. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 65% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 70% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 80% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 90% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 99% of the molecules in the population. Such enriched populations of modified oligonucleotide strands can be generated using synthetic methods known in the art, e.g., methods described in Oka et al., JACS 125, 8307 (2003), Wan et al., Nuc. Acid. Res. 42, 13456 (2014), and WO 2017 / 015555. In certain embodiments, a population of modified oligonucleotide strands is enriched for modified oligonucleotide strands having at least one indicated phosphorothioate in the (Sp) configuration. In certain embodiments, a population of modified oligonucleotide strands is enriched for modified oligonucleotide strands having at least one phosphorothioate in the (Rp) configuration.

[0420] In certain embodiments, a modified intemucleoside linkage is present at the 3'-end of the oligonucleotide strand. In certain embodiments, a modified intemucleoside linkage is present within 3 nucleosides of the 3'-end of the oligonucleotide strand. In certain embodiments, a modified intemucleoside linkage is present at the 5 '-end of the oligonucleotide strand. In certain embodiments, a modified intemucleoside linkage is present w ithin 3 nucleosides of the 5 '-end of the oligonucleotide strand. In certain embodiments, a modified intemucleoside linkage is present at an internal position on an oligonucleotide strand. In certain embodiments, a modified intemucleoside linkage is present more than 3 nucleosides from the 3'-end of the oligonucleotide strand. In certain embodiments, a modified intemucleoside linkage is present more than 3 nucleosides from the 5'-end of the oligonucleotide strand. In certain embodiments, modified oligonucleotides comprise a block of modified intemucleoside linkages. In certain such embodiments, the block is at the 3'-end of the oligonucleotide strand. In certain embodiments, the block is within 3 nucleosides of the 3 '-end of the oligonucleotide strand. In certain embodiments, the block is at the 5 '-end of the oligonucleotide strand. In certain embodiments, the block is within 3 nucleosides of the 5'-end of the oligonucleotide strand. In certain embodiments, the block is at an internal position in the oligonucleotide strand. In certain embodiments, the block is more than 3 nucleosides from the 3 '-end of the oligonucleotide strand. In certain embodiments, the block is more than 3 nucleosides from the 5 '-end of the oligonucleotide strand.

[0421] In certain embodiments, a modified intemucleosidic linkage comprises 5'- ethylenephosphonate, phosphorothioate. or an amide.

[0422] In certain embodiments, the present disclosure provides an oligonucleotide of any one of the formulae described herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the oligonucleotides described herein include pharmaceutically acceptable salts and prodrugs thereof. In certain embodiments, the oligonucleotides described herein include pharmaceutically acceptable salts thereof.

[0423] Pharmaceutical Compositions, Administration, and Kits

[0424] In another aspect, provided are pharmaceutical compositions comprising any of the oligonucleotides described herein and optionally a pharmaceutically acceptable excipient.

[0425] An oligonucleotide or pharmaceutical composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents. In some embodiments, a pharmaceutical agent is a therapeutic agent. In some embodiments, a pharmaceutical agent is a prophylactic agent. In some embodiments, a pharmaceutical agent is a diagnostic agent. The oligonucleotides or pharmaceutical compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g, activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, and / or in reducing the risk of developing a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject, cell, tissue, or biological sample. The combination may achieve an improvement for the same desired effect, and / or it may achieve different desired effects. In certain embodiments, the combination exhibits a synergistic effect that is absent in a pharmaceutical composition including one of the oligonucleotides described herein or the additional pharmaceutical agent, but not both. The oligonucleotide or pharmaceutical composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combinations. Therapeutic agents include small molecules, peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agents are drugs approved for human or veterinary use by the U.S. Food and Drug Administration (FDA) or European Medicines Agency (EMA). In certain embodiments, the additional pharmaceutical agent is a therapeutic agent useful for treating a disease. In certain embodiments, the additional pharmaceutical agent is a prophylactic agent useful for preventing a disease. Each additional pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the oligonucleotide or pharmaceutical composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the oligonucleotide described herein with the additional pharmaceutical agent(s) and / or the desired effect (e.g., therapeutic and / or prophylactic effect) to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0426] In some embodiments, the pharmaceutical compositions comprise an effective amount of an oligonucleotide described herein and a pharmaceutically acceptable excipient. In some embodiments, an oligonucleotide described herein is administered to a subject using a pharmaceutically acceptable formulation. For example, a pharmaceutically acceptable formulation may provide sustained delivery of the oligonucleotide to a subject for at least 12 hours, 24 hours, 36 hours, 48 hours, one w eek, two weeks, three weeks, or four w eeks after the pharmaceutically acceptable formulation is administered to the subject.

[0427] Actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the disclosure may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular subject, pharmaceutical composition, and mode of administration, while being acceptably tolerant to the subject.

[0428] In one embodiment, an oligonucleotide of the disclosure is administered acutely. The oligonucleotide of the disclosure may therefore be administered for a short course of treatment, such as for about 1 day to about 1 week. In another embodiment, the oligonucleotide of the disclosure may be administered over a longer period of time to ameliorate chronic disorders, such as, for example, for about one week to several months depending upon the condition to be treated.

[0429] The oligonucleotide may be administered in any convenient manner, such as by intrathecal, intravenous, intramuscular, subcutaneous, oral, or intra-cerebroventricular injection routes, or by topical application, such as in creams or gels. Depending on the route of administration, the active ingredients (e.g., an oligonucleotide of the disclosure) may be required to be coated in a material to protect the oligonucleotide from the action of enzy mes, acids, and other natural conditions that may inactivate or otherwise degrade the oligonucleotide. In order to administer an oligonucleotide of the disclosure by a mode other than parenteral administration, the oligonucleotide can be coated by, or administered with, a material to prevent inactivation.

[0430] The oligonucleotide may be administered parenterally or intraperitoneally. Dispersions can also be prepared, for example, in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils.

[0431] Some examples of substances that can serve as pharmaceutical excipients are sugars, such as lactose, glucose, and sucrose; starches, such as com starch and potato starch; cellulose and its derivatives, such as sodium carboxymethycellulose, ethylcellulose, and cellulose acetates; powdered tragancanth; malt; gelatin; talc; stearic acids; magnesium stearate; calcium sulfate; vegetable oils, such as peanut oils, cotton seed oil, sesame oil, olive oil, com oil. and oil of theobroma; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; agar; alginic acids; pyrogen-free water; isotonic saline; and phosphate buffer solution; skim milk powder; as well as other non-toxic compatible substances used in pharmaceutical formulations, such as Vitamin C, estrogen, and echinacea, for example. Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, lubricants, excipients, tableting agents, stabilizers, anti-oxidants, and preservatives, can also be present. Solubilizing agents, including, for example, cremaphore, and beta-cyclodextrins, can also be used in the pharmaceutical compositions described herein.

[0432] The pharmaceutical compositions can be manufactured by means of conventional mixing, dissolving, granulating, dragee-making levigating, emulsifying, encapsulating, entrapping, or lyophilization processes. The pharmaceutical compositions can be formulated in conventional manner using one or more physiologically acceptable excipients, which facilitate processing of the oligonucleotides into preparations that can be used pharmaceutically. The pharmaceutical compositions herein can be made by' combining (e.g., contacting, mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing) an oligonucleotide delineated herein with one or more suitable excipients, including those described herein (e.g, for pharmaceutical, agricultural, or veterinary use).

[0433] Pharmaceutical compositions of the present disclosure can take a form suitable for virtually any mode of administration, including, for example, intrathecal, topical, ocular, oral, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, and the like, or a form suitable for administration by inhalation or insufflation.

[0434] Systemic formulations include those designed for administration by injection, e.g, subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral, or pulmonary7administration.

[0435] Useful injectable preparations include sterile suspensions, solutions, or emulsions of the oligonucleotide(s) in aqueous or oily vehicles. The pharmaceutical compositions may also contain formulating agents, such as suspending, stabilizing, and / or dispersing agents. The formulations for injection can be presented in unit dosage form (e.g, in ampules or in multidose containers) and can contain added preservatives.

[0436] Alternatively, the injectable formulation can be provided in powder form for reconstitution with a suitable vehicle, including, but not limited to, sterile pyrogen free water, buffer, dextrose solution, and the like, before use. To this end, the oligonucleotide(s) can be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.

[0437] For prolonged delivery, the oligonucleotide can be formulated as a depot preparation for administration by implantation or intramuscular injection. The oligonucleotides can be formulated with suitable polymeric or hydrophobic materials (e.g, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g, as a sparingly soluble salt.

[0438] Alternatively, other pharmaceutical delivery systems can be employed. Liposomes and emulsions are w ell-known examples of delivery vehicles that can be used to deliver the oligonucleotide. Certain organic solvents such as dimethyl sulfoxide (DMSO) also can be employed.

[0439] The pharmaceutical compositions can, if desired, be presented in a pack or dispenser device that can contain one or more unit dosage forms containing the oligonucleotides. The pack can, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device can be accompanied by instructions for administration.

[0440] The oligonucleotides or pharmaceutical compositions will generally be used in an amount effective to achieve the intended result, for example in an amount effective to treat or prevent the particular disease being treated. The oligonucleotides can be administered therapeutically to achieve therapeutic benefit or prophylactically to achieve prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disease being treated and / or eradication or amelioration of one or more of the symptoms associated with the underlying disease such that the patient reports an improvement in feeling or condition, notwithstanding that the patient can still be afflicted with the underlying disease. Therapeutic benefit also includes halting or slowing the progression of the disease, regardless of whether improvement is realized.

[0441] For prophylactic administration, the oligonucleotides can be administered to a subject at risk of developing one of the previously described diseases. A subject at risk of developing a disease can be a subject having characteristics placing the subject in a designated group of at-risk subjects, as defined by an appropriate medical professional or group. A subject at risk may also be a subject that is commonly or routinely in a setting where development of the underlying disease could occur. In other words, an at-risk subject is one who is commonly or routinely exposed to the disease or illness causing conditions or may be acutely exposed for a limited time. Alternatively, prophylactic administration can be applied to avoid the onset of symptoms in a subject diagnosed with the underlying disease.

[0442] The amount of the oligonucleotides administered will depend upon a variety of factors, including, for example, the particular indication being treated, the mode of administration, whether the desired benefit is prophylactic or therapeutic, the severity of the indication being treated, the age and weight of the subject, the bioavail ability of the oligonucleotides, and the like. Determination of an effective dosage is well within the capabilities of those skilled in the art.

[0443] Effective dosages can be estimated initially from in vitro assays. For example, an initial dosage for use in animals can be formulated to achieve a circulating blood or serum concentration of oligonucleotide that is at or above an IC50 of the particular oligonucleotide as measured in an in vitro assay, such as an in vitro fungal MIC or MFC, and other in vitro assays. Calculating dosages to achieve such circulating blood or serum concentrations taking into account the bioavailability of the particular oligonucleotide is well within the capabilities of skilled artisans. For guidance, see “General Principles,” In: Goodman and Gilman 's The Pharmaceutical Basis of ThercPeutics , Chapter 1, pp. 1-112, 13th ed., McGraw-Hill, and the references cited therein.

[0444] Initial dosages also can be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of oligonucleotides to treat or prevent the various diseases described above are well-known in the art.

[0445] Dosage amounts will typically be in the range of from about 0.0001 or 0.001 or 0.01 mg / kg / day to about 100 mg / kg / day, but can be higher or lower, depending upon, among other factors, the activity' of the oligonucleotide, its bioavailability, the mode of administration, and various factors discussed above. Dosage amount and interval can be adjusted individually to provide plasma levels of the oligonucleotides that are sufficient to maintain therapeutic or prophylactic effect. In cases of local administration or selective uptake, such as local topical administration, the effective local concentration of active oligonucleotides cannot be related to plasma concentration. Skilled artisans will be able to optimize effective local dosages without undue experimentation.

[0446] Preferably, the oligonucleotides will provide an intended (e.g, therapeutic or prophylactic) benefit and will have acceptable tolerability. Tolerability of the oligonucleotides can be determined using standard pharmaceutical procedures. The dose ratio between non- tolerable and therapeutic (or prophylactic) effect is the therapeutic index. Oligonucleotide(s) that exhibit high therapeutic indices are preferred.

[0447] In another aspect, provided are kits comprising an oligonucleotide or pharmaceutical composition provided herein. In some embodiments, the kits comprise an effective amount of an oligonucleotide provided herein. In some embodiments, the kits comprise the oligonucleotide or pharmaceutical composition in unit dosage form. In some embodiments, the kits further comprise instructions for using the oligonucleotide or pharmaceutical composition.

[0448] The kits may further comprise a first container (e.g, a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, the first container contains the oligonucleotide or pharmaceutical composition. In some embodiments, provided kits may optionally further include a second container. In some embodiments, the second container contains a pharmaceutical excipient. In some embodiments, the pharmaceutical excipient is suitable for dilution or suspension of a pharmaceutical composition or oligonucleotide described herein. In some embodiments, the pharmaceutical composition or oligonucleotide described herein are combined to form one unit dosage form.

[0449] In certain embodiments, the kits are useful for treating a disease in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease (e.g, a brain disease, central nervous system disease, neurodegenerative disease, or neurocognitive disease) in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease (e.g, a brain disease, central nervous system disease, neurodegenerative disease, or neurocognitive disease) in a subject in need thereof. In certain embodiments, the kits are useful for diagnosing a disease (e.g., a brain disease, central nervous system disease, neurodegenerative disease, or neurocognitive disease) in a subject in need thereof. In certain embodiments, the kits are useful for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a protein in a subject, cell, tissue, or biological sample.

[0450] In certain embodiments, a kit described herein further includes instructions for using the oligonucleotide or pharmaceutical composition thereof. A kit described herein may also include information as required by a regulatory' agency such as the FDA or EMA. In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease (e.g, a brain disease, central nervous system disease, neurodegenerative disease, or neurocognitive disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease (e.g, a brain disease, central nervous system disease, neurodegenerative disease, or neurocognitive disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease (e.g, a brain disease, central nervous system disease, neurodegenerative disease, or neurocognitive disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for diagnosing a disease (e.g. a brain disease, central nervous system disease, neurodegenerative disease, or neurocognitive disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for modulating the activity (e.g, inhibiting increased activity or enhancing decreased activity) of a protein in a subject, cell, tissue, or biological sample. The kits may include one or more additional pharmaceutical agents. In some embodiments, the kits further include additional containers. In some embodiments, the additional containers contain the one or more additional pharmaceutical agents.

[0451] Methods of Making the Oligonucleotides

[0452] In another aspect, the present disclosure provides methods of making any of the oligonucleotides provided herein comprising contacting under suitable conditions a compound of Formula A-l: or a salt thereof, with a compound of Formula A-2: or a salt thereof, wherein: each of M1and M2is independently a radical of: a fragment of the oligonucleotide strand or a nucleoside; each of L4U1and L4U2is independently a single bond or linker;

[0453] L4E1is a first reactive moiety; L4E2is a second reactive moiety';

[0454] L4E1and L4E2are capable of reacting with each other under the suitable conditions to form

[0455] L4E3; and

[0456] L4D1_L4E3_L4D21S L4

[0457] In some embodiments, each of M1and M2is independently a radical of a nucleoside. In some embodiments,

[0458] In some embodiments, L4E1is a first click-chemistry reactive moiety, L4E2is a second click-chemistry' reactive moiety, and L4E1and L4E2are capable of reacting with each other through a click-chemistry reaction under the suitable conditions to form L4E3.

[0459] In some embodiments, the first click-chemistry' reactive moiety' is -N3. In some embodiments, the first click-chemistry reactive moiety is substituted or unsubstituted 1, 2,4,5- tetrazinyl. In some embodiments, the first click-chemistry reactive moiety is substituted or unsubstituted tetrazolyl. In some embodiments, the second click-chemistry reactive moiety comprises C=C. In some embodiments, the second click-chemistry reactive moiety' is -C=CH. In some embodiments, the second click-chemistry reactive moiety comprises non-aromatic C=C. In some embodiments, the second click-chemistry reactive moiety is substituted or unsubstituted, monocyclic, bicyclic, or tricyclic, cycloalkenyl or cycloalkynyl. In some embodiments, the second click-chemistry' reactive moiety7is substituted or unsubstituted, monocyclic, bicyclic, or tricyclic, / ra s-cycloalken l or cycloalkynyl. In some embodiments, the second click-chemistry reactive moiety is substituted or unsubstituted, monocyclic, bicyclic, or tricyclic, strained, cycloalkenyl or cycloalkynyl. In some embodiments, the second click-chemistry reactive moiety is substituted or unsubstituted, / rans-cyclooctenyl. substituted or unsubstituted norbomenyl, substituted or unsubstituted 7-oxanorbomenyl, substituted or unsubstituted 7-azanorbomenyl, substituted or unsubstituted cyclooctynyl, substituted or unsubstituted bicyclo[6.1.0]nonynyl, or substituted or unsubstituted dibenzocyclooctynyl. In some embodiments, the second clickchemistry reactive moiety is optionally substituted optionally substituted stituted r optionally substituted some embodiments, the first and second click-chemistry reactive moieties described in this paragraph are capable of reacting with each other through a clickchemistry reaction under the suitable conditions to form L4E3.

[0460] In some embodiments, the first click-chemistry reactive moiety is a Michael donor. In some embodiments, the first click-chemistry reactive moiety is an enolate. In some embodiments, the first click-chemistry reactive moiety is -SH. In some embodiments, the second clickchemistry reactive moiety is a Michael acceptor. In some embodiments, the second clickchemistry reactive moiety is a moiety comprising a.p-unsaturated-carbonyl. In some embodiments, the second click-chemistry reactive moiety i some embodiments, the first and second click-chemistry reactive moieties described in this paragraph are capable of reacting with each other through a click-chemistry reaction under the suitable conditions to form L4E3.

[0461] In some embodiments, L4E3is of the formula:

[0462] k21 is 0, 1, 2. 3, or 4; each instance of Rd, if present, is independently halogen, substituted or unsubstituted, Ci-6 alkyl, or -O-(substituted or unsubstituted, Ci-6 alkyl); k22 is 0, 1, 2, 3, or 4; each instance of Re, if present, is independently halogen, substituted or unsubstituted, Ci-6 alkyl, or -O-(substituted or unsubstituted. Ci-6 alkyl); k23 is an integer between 0 and 11, inclusive; each instance of Rf, if present, is independently halogen, substituted or unsubstituted, Ci-6 alkyl, or -O-(substituted or unsubstituted, Ci-6 alky l); and Rgis hydrogen, halogen, substituted or unsubstituted, Ci-6 alkyl, or -©-(substituted or unsubstituted, Ci-6 alkyl). In certain embodiments, k21 is 0. In certain embodiments, k21 is 1. In certain embodiments, k21 is 2. In certain embodiments, k22 is 0. In certain embodiments, k22 is 1. In certain embodiments, k22 is 2. In certain embodiments, k23 is 0. In certain embodiments, k23 is

[0463] 1. In certain embodiments. k23 is 2. In some embodiments, each instance of Rd, if present, is independently substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, each instance of Rd, if present, is independently unsubstituted Ci-6 alkyl. In some embodiments, each instance of Re, if present, is independently substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, each instance of Re, if present, is independently unsubstituted Ci-6 alkyl.

[0464] In certain embodiments, L4E3is of the formula:

[0465] In some embodiments, L4E3is -O-, -S-. -S-S-. -NRa-, -C(=O)O-, -C(=NRa)O-, - S(=O)O-, -S(=O)2O-. -C(=O)NRa-, -C(=NRa)NRa- -S(=O)NRa-, -S(=O)2NRa- -OC(=O)-, - OC(=NRa)-, -OS(=O)-, -OS(=O)2-, -NRaC(=O)-, -NRaC(=NRa)-, -NRaS(=O)-, - NRaS(=O)2-, -OC(=O)O-, -OC(~NR;|)O-. -OS(~O)O-. -OS(~O)2O-. -NRaC(=O)O-, - NRaC(=NRa)O-, -NRaS(=O)O-, -NRaS(=O)2O-, -OC(=O)NRa-, -OC(=NRa)NRa-. - OS(=O)NRa-, -OS(=O)2NRa-, -NRaC(=O)NRa-_ -NRaC(=NRa)NRa-_ -NRaS(=O)NRa-, - NRaS(=O)2NRa- -C(=O)-, -C(=NRa)-, -S(=O)-, -S(=O)2-, -OP(=O)(ORa)O-, - SP(=O)(ORa)O-, -OP(=O)(ORa)S-, or -OP(=O)(SRa)O-; and each instance of Rais independently hydrogen, substituted or unsubstituted, Ci-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl. In some embodiments, L4E3is -O-. In some embodiments, L4E3is -C(=O)NRa- or -NRa- C(=O)-. In some embodiments, L4E3is -C(=O)NH- or -NHC(=O)-. In some embodiments, L4E3is -C(=O)O- or -OC(=O)-. In some embodiments, L4E3is -OP(=O)(ORa)O-, -SP(=O)(ORa)O- -OP(=O)(ORa)S-, or -OP(=O)(SRa)O- In some embodiments, L4E3is -OP(=O)(OH)O-, - SP(=O)(OH)O-, -OP(=O)(OH)S-, or -OP(=O)(SH)O-.

[0466] In some embodiments, at least one instance of Rais hydrogen. In some embodiments, each instance of Rais hydrogen. In some embodiments, at least one instance of Rais substituted or unsubstituted, Ci-6 alkyl (e.g., -CH;,). In some embodiments, at least one instance of Rais substituted or unsubstituted phenyl.

[0467] The step of contacting under suitable conditions may be performed in the presence of one or more additional reagents. In some embodiments, at least one of the additional reagents is a metal (e g., transition metal) complex. In some embodiments, at least one of the additional reagents is a metal (e.g., transition metal) salt. In some embodiments, at least one of the additional reagents is a copper(I) salt. In some embodiments, at least one of the additional reagents is a copper(II) salt. In certain embodiments, at least one of the additional reagents is Cu(II)SO4, Cu(II)Cl2, Cu(II)CO;„ CU(II)NO3, CU(II)(OH)2, or (Cu(II))3(PO4)2.

[0468] In some embodiments, at least one of the additional reagents is a metal (e.g., transition metal) ligand. The metal ligand may form a metal-metal ligand coordination complex with a metal (e.g.. transition metal). In some embodiments, the metal ligand is an amine, e.g., a tertiary amine. In some embodiments, the metal ligand comprises at least one 1,2,3-triazole moiety. In certain embodiments, the metal ligand is tris(benzyltriazolylmethyl)amine (THPTA).

[0469] In some embodiments, the equivalent ratio of metal to metal ligand is between 1 : 1 and 1:2, between 1:2 and 1:3, between 1:3 and 1:4, between 1:4 and 1:5, between 1:5 and 1 :6, between 1 :6 and 1:7. between 1:7 and 1 :8. between 1 :8 and 1 :9, or between 1 :9 and 1: 10. In certain embodiments, the equivalent ratio of metal to metal ligand is between 1 :4 and 1:6. In certain embodiments, the equivalent ratio of metal to metal ligand is approximately 1:5.

[0470] In some embodiments, the suitable conditions comprise a first solvent. In some embodiments, the first solvent is substantially one single solvent. In some embodiments, the first solvent is a mixture of two or more (e.g., three) solvents. In certain embodiments, the first solvent is a non-organic solvent. In certain embodiments, the first solvent is an aqueous solvent. In certain embodiments, the first solvent is water. In certain embodiments, the first solvent (e.g, water) is free of or substantially free of RNase (e.g.. between 90% and 95%, between 95% and 97%. between 97% and 99%, between 99% and 99.5%. or between 99.5% and 99.9%, free of RNase). In some embodiments, the first s...

Claims

CLAIMSWhat is claimed is:

1. An oligonucleotide comprising a modified oligonucleotide strand of Formula I:or a pharmaceutically acceptable salt or prodrug thereof, wherein:is a divalent radical of an oligonucleotide strand; si instances of the intemucleosidic linkers ofare independently replaced withsi is 1, 2. 3, 4, 5. or 6; each instance of LAand L4is independently a linker; each instance of A4is independently a radical of a ligand or lipid, provided that at least one instance of A4is a radical of a ligand; each of y5 and y6 is independently 0 or 1 ; when y5 is 0, L5is hydrogen, substituted or unsubstituted, C1-6 alkyl, or an oxygen protecting group; or when y5 is 1, L5is a linker; when y6 is 0, L6is hydrogen, substituted or unsubstituted, Ci-6 alkyl, or an oxygen protecting group; or when y6 is 1, L6is a linker; each of A5and A6, if present, is independently a radical of a ligand or lipid; and each of the ligands is different from each of the lipids.

2. The oligonucleotide of claim 1, wherein comprisesbetween 6 and 100, inclusive, nucleosides.

3. The oligonucleotide of claim 1, whereincomprises between 10 and 30, inclusive, nucleosides.

4. The oligonucleotide of claim 1, whereincomprises between 14 and 23, inclusive, nucleosides.

5. The oligonucleotide of any one of claims 1-4, wherein si is 1.

6. The oligonucleotide of any one of claims 1-5, wherein si is 2. 3, 4, 5, or 6.

7. The oligonucleotide of any one of claims 1-6, wherein at least one instance of LAis the intemucleosidic linker between the first and second nucleosides ofcounted from the 5 ' end.

8. The oligonucleotide of any one of claims 1-7, wherein:LAis the intemucleosidic linker between the first n and n+1 nucleosides ofcounted from the 5 ' end; and n is an integer between 2 and 20, inclusive, as the number of nucleosides ofpermits.

9. The oligonucleotide of any one of claims 1-8, wherein the oligonucleotide comprises anRNA.

10. The oligonucleotide of any one of claims 1-9, wherein the oligonucleotide is an RNA.

11. The oligonucleotide of any one of claims 1-10, wherein12. The oligonucleotide of any one of claims 1-11, wherein:at least one instance of LAis of the formula:each instance of ZA1and ZA2is independently a single bond, substituted or unsubstituted, Ci-6 alkylene, or substituted or unsubstituted, C2-6 alkenylene: each instance of WAis independently a radical, as valency permits, of substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkydene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted ary lene, substituted or unsubstituted heteroarylene. -O-, -OP(=O)(ORC)O-, -N(RC)-, -S-. -C(=O)-, -C(=O)O-, -C(=O)NRC-, -NR°C(=O)-, -C(=O)RC-, -NR°C(=O)O-, -NR°C(=O)NR°-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RC)-, -S(=O)2NRC-, -NRCS(=O)2-, or a combination thereof; each instance of R° is independently hydrogen, substituted or unsubstituted acyl, 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, 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 instances of Rcare joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and bond C4Ais attached to L4.

13. The oligonucleotide of any one of claims 1-12, wherein: at least one instance of L is of the formula:

14. The oligonucleotide of any one of claims 1-13, wherein at least one instance of LAis of the formula:

15. The oligonucleotide of any one of claims 1-14, wherein at least one instance of LAis of the formula:

16. The oligonucleotide of any one of claims 1-15, wherein at least one instance of ZA1is unsubstituted C1-3 alkylene.

17. The oligonucleotide of any one of claims 1-16, wherein at least one instance of ZA2is unsubstituted C1-3 alkylene.

18. The oligonucleotide of any one of claims 1-17, wherein at least one instance of L4is substituted or unsubstituted, Ci-100 alkylene, substituted or unsubstituted, C2-100 alkenylene. substituted or unsubstituted, C2-100 alkynylene, substituted or unsubstituted. Ci-100 heteroalkylene, substituted or unsubstituted, C 2-100 heteroalkenylene, or substituted or unsubstituted, C2-100 heteroalkynylene; optionally wherein one or more backbone atoms of the Ci-ioo alkylene, C2-100 alkenylene, C2-100 alkynylene, Ci-ioo heteroalkylene, C2-100 heteroalkenylene, or C2-100 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.

19. The oligonucleotide of any one of claims 1-18, wherein at least one instance of L4is substituted or unsubstituted, C7-70 alkylene, substituted or unsubstituted, C7-70 alkenylene, substituted or unsubstituted, C7-70 alky nylene, substituted or unsubstituted, C7-70 heteroalkylene, substituted or unsubstituted, C7-70 heteroalkenylene, or substituted or unsubstituted, C7-70 heteroalkynylene; optionally wherein one or two backbone atoms of the C7-70 alkylene, C7-70 alkenylene, C7- 70 alkynylene, C7-70 heteroalkylene, C7-70 heteroalkenylene, or C7-70 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.

20. The oligonucleotide of any one of claims 1-19, wherein at least one instance of L4is substituted or unsubstituted, C7-70 alkylene or substituted or unsubstituted, C7-70 heteroalkylene; and one or two backbone atoms of the C7-70 alkylene or C7-70 heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.

21. The oligonucleotide of any one of claims 1-20, wherein: at least one instance of L4isis independentlyasingle bond, -O-, -S-, -S-S-, -NRa-, -C(=O)O--C(=NRa)O-, -S(=O)O-, -S(=O)2O-, -C(=O)NRa-, -C(=NRa)NRa-, -S(=O)NRa- -S(=O)2NRa-, -OC(=O)-, -OC(=NRa)-, -OS(=O)-, -OS(=O)2-. -NRaC(=O)-, -NRaC(=NRa)-, -NRaS(=O)-, -NRaS(=O)2-. -OC(=O)O-, -OC(=NRa)O-, -OS(=O)O- -OS(=O)2O-.-NRaC(=O)O-, -NRaC(=NRa)O- -NRaS(=O)O- -NRaS(=O)2O- -OC(=O)NRa-OC(=NRa)NRa, OS(=O)NRa, OS(=O)2NRa, NRaC(=O)NRa, NRaC(=NRa)NRa, -NRaS(=O)NRa-, -NRaS(=O)2NRa-, -C(=O)-, -C(=NRa)-, -S(=O)-, -S(=O)2- -OP(=O)(ORa)O-. -SP(=O)(ORa)O-, -OP(=O)(ORa)S-, or -OP(=O)(SRa)O-; each instance of Rais independently hydrogen, substituted or unsubstituted, Ci-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are j oined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L4B1, L4B2, and L4B6is independently a single bond, substituted or unsubstituted, Ci-ioo alkylene or substituted or unsubstituted, Ci-100 heteroalkylene; each of L4C1and L4C2is a single bond, substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms, or substituted or unsubstituted heteroarylene that replaces one of the backbone atoms; and bond C4Bis attached to A4.

22. The oligonucleotide of any one of claims 1-21, wherein: at least one instance of L iseach of pl and p2 is independently an integer from 1 to 10, inclusive; each of p3 and p5 is independently an integer from 0 to 10, inclusive; each instance of-L4A21-L4A22- is independently a single bond, -O-, -S-. -S-S-. -NRa-. -C(=O)O- -C(=NRa)O-, -S(=O)O-, -S(=O)2O- -C(=O)NRa-, -C(=NRa)NRa-, -S(=O)NRa- -S(=O)2NRa-, -OC(=O)-, -OC(=NRa)-, -OS(=O)-, -OS(=O)2-, -NRaC(=O)-, -NRaC(=NRa)- -NRaS(=O)-, -NRaS(=O)2-, -OC(=O)O-, -OC(=NRa)O-, -OS(=O)O-, -OS(=O)2O- -NRaC(=O)O-, -NRaC(=NRa)O-. -NRaS(=O)O-, -NRaS(=O)2O- -OC(=O)NRa- -OC(=NRa)NRa-, -OS(=O)NRa-. -OS(=O)2NRa-, -NRaC(=O)NRa-, -NRaC(=NRa)NRa- -NRaS(=O)NRa-, -NRaS(=O)2NRa-, -C(=O)-, -C(=NRa)-, -S(=O)-, -S(=O)2-OP(=O)(ORa)O , SP(=O)(ORa)O , OP(=O)(ORa)S , or OP(=O)(SRa)O ; each instance of Rais independently hydrogen, substituted or unsubstituted. Ci-6 alkyl, substituted or unsubstituted phenyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; and bond C4Bis attached to A4.

23. The oligonucleotide of any one of claims 1-22, wherein at least one instance of-L4A21- L4A22- is -NRa-C(=O)- or -C(=O)-NRa-.

24. The oligonucleotide of any one of claims 1 -23, wherein at least one instance of L4is substituted or unsubstituted, C 7-70 heteroalky lene.

25. The oligonucleotide of any one of claims 1-24, wherein at least one instance of L4is - CH2- -O-, -CH2CH2O-, -OCH2CH2- -C(=O)NH- -C(=O)N(CH?)-, -NHC(=O)-, or - N(CH3)C(=O)-, or a combination of two or more instances of each one of the foregoing, or a combination of two or more of the foregoing, provided that: the number of backbone atoms of the instance of L4is between 7 and 70, inclusive; and the instance of L4does not comprise O-O. O-N, N-O, or N-N.

26. The oligonucleotide of any one of claims 1-25, wherein at least one instance of L4is - CH2-, -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, or -NHC(=O)-, or a combination of two or more instances of each one of the foregoing, or a combination of two or more of the foregoing, provided that: the number of backbone atoms of the instance of L4is between 7 and 70, inclusive; the instance of L4does not comprise O-O. 0-N, N-0, or N-N; and the combined number of-C(=O)NH- and -NHC(=0)- of the instance of L4is between 0 and 4, inclusive.

27. The oligonucleotide of any one of claims 1-26, wherein y5 is 0.

28. The oligonucleotide of any one of claims 1-27, wherein y5 is 1, and A5is a radical of a ligand.

29. The oligonucleotide of any one of claims 1-28, wherein y5 is 1. and A5is a radical of a lipid.

30. The oligonucleotide of any one of claims 1-29, wherein L5is substituted or unsubstituted, Ci-100 alkylene, substituted or unsubstituted, C2-100 alkenylene, substituted or unsubstituted. C2-100 alkynylene, substituted or unsubstituted. Ci -100 heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, or substituted or unsubstituted, C2-100 heteroalkynylene; optionally wherein one or more backbone atoms of the Ci-100 alkylene, C2-100 alkenylene, C 2-100 alkynylene, Ci-ioo heteroalkylene, C2-100 heteroalkenylene, or C 2-100 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene. substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.

31. The oligonucleotide of any one of claims 1-30, wherein L5is substituted or unsubstituted, C7-70 alkydene, substituted or unsubstituted, C7-70 alkenylene, substituted or unsubstituted, C7-70 alkynylene, substituted or unsubstituted, C7-70 heteroalkylene, substituted or unsubstituted, C7-70 heteroalkeny lene, or substituted or unsubstituted, C7-70 heteroalkynylene; optionally wherein one or two backbone atoms of the C7-70 alkylene, C7-70 alkenylene, C7- 70 alkynylene, C7-70 heteroalkylene, C7-70 heteroalkenylene, or C7-70 heteroalkynylene areindependently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene. substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.

32. The oligonucleotide of any one of claims 1-31, wherein L5is substituted or unsubstituted, C7-70 alkylene or substituted or unsubstituted, C7-70 heteroalkylene; and one or two backbone atoms of the C7-70 alkylene or C7-70 heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.

33. The oligonucleotide of any one of claims 1 -32, wherein: L5iseach of-L5A1-L5A2-, -L5A3-L5A4-. -L5A5-L5A6-, -L5A7-L5A8-, -L5A17-L5A18-, and -L5A19-L5 A20- is independently a single bond, -O-, -S-, -S-S-, -NRa-, -C(=O)O-, - C(=NRa)O-. -S(=O)O-. -S(=O)2O-, -C(=O)NRa-. -C(=NRa)NRa-, -S(=O)NRa-. - S(=O)2NRa-, -OC(=O)-, -OC(=NRa)-, -OS(=O)-, -OS(=O)2-, -NRaC(=O)-, -NRaC(=NRa)-, - NRaS(=O) , NRaS(=O)2, OC(=O)O , OC(=NRa)O , OS(=O)O , OS(=O)2O , NRaC(=O)O-, -NRaC(=NRa)O-, -NRaS(=O)O-, -NRaS(=O)2O-, -OC(=O)NRa-, - OC(=NRa)NRa-. -OS(=O)NRa- -OS(=O)2NRa-. -NRaC(=O)NRa-, -NRaC(=NRa)NRa- - NRaS(=O)NRa-, -NRaS(=O)2NRa-, -C(=O)-, -C(=NRa)-, -S(=O)-, -S(=O)2- - OP(=O)(ORa)O-, -SP(=O)(ORa)O- -OP(=O)(ORa)S-, or -OP(=O)(SRa)O-; each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L5B1, L5B2, and L5B6is independently a single bond, substituted or unsubstituted, Ci-100 alkylene or substituted or unsubstituted. Ci-100 heteroalkylene; each of L5C1and L5C2is a single bond, substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms, or substituted or unsubstituted heteroarylene that replaces one of the backbone atoms; andbond C5Bis atached to A5.

34. The oligonucleotide of any one of claims 1-33, wherein: L5isk21 is 0, 1, 2. 3, or 4: each instance of Rd, if present, is independently halogen, substituted or unsubstituted, Ci-6 alkyl, or -O-(substituted or unsubstituted. Ci -6 alkyl); k22 is 0, 1, 2, 3, or 4; each instance of Re, if present, is independently halogen, substituted or unsubstituted, Ci-6 alkyl, or -O-(substituted or unsubstituted. Ci-6 alkyl); each of ql. q2, q4, q5, q8, and q9 is independently an integer from 0 to 10, inclusive; each of q3, q6, and q7 is independently an integer from 1 to 10, inclusive; each of-L5A21-L5A22-, -L5A23-L5A24-, and -L5A25-L5A26- is independently a single bond, -O-, -S-, -S-S-, -NRa-, -C(=O)O-, -C(=NRa)O-, -S(=O)O-, -S(=O)2O-, -C(=O)NRa- -C(=NRa)NRa-, -S(=O)NRa-. -S(=O)2NRa-, -OC(=O)-. -OC(=NRa)-, -OS(=O)-, -OS(=O)2- -NRaC(=O)-, -NRaC(=NRa)-, -NRaS(=O)-, -NRaS(=O)2- -OC(=O)O- -OC(=NRa)O- -OS(=O)O-, -OS(=O)2O-, -NRaC(=O)O-, -NRaC(=NRa)O-, -NRaS(=O)O-, -NRaS(=O)2O- -OC(=O)NRa-, -OC(=NRa)NRa-, -OS(=O)NRa-, -OS(=O)2NRa-, -NRaC(=O)NRa- -NRaC(=NRa)NRa-, -NRaS(=O)NRa-, -NRaS(=O)2NRa- -C(=O)-, -C(=NRa)-, -S(=O)- -S(=O)2-, -OP(=O)(ORa)O-, -SP(=O)(ORa)O-, -OP(=O)(ORa)S-, or -OP(=O)(SRa)O-;each instance of Rais independently hydrogen, substituted or unsubstituted. C1-6alkyl, substituted or unsubstituted phenyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; and bond C5Ais attached to A5.

35. The oligonucleotide of any one of claims 1-34, wherein each of-L5A23-L5A24- and - L5A25-L5A26- is independently -NRa-C(=O)- or -C(=O)-NRa-36. The oligonucleotide of any one of claims 1 -35, wherein is -L5A21-L5A22- is -OP(=O)(ORa)O-, -SP(=O)(ORa)O-, -OP(=O)(ORa)S-, or -OP(=O)(SRa)O-.

37. The oligonucleotide of any one of claims 1-36, wherein L5is substituted or unsubstituted, C7-70 heteroalkylene.

38. The oligonucleotide of any one of claims 1-37, wherein L5is -CH2--O-, -CH2CH2O-. -OCH2CH2-, -C(=O)NH- -C(=O)N(CH3)-. -NHC(=O)- -N(CH3)C(=O)-, or a combination of two or more instances of each one of theforegoing, or a combination of two or more of the foregoing, provided that: the number of backbone atoms of L5is between 7 and 70, inclusive; andL5does not comprise O-O, 0-N, N-0, or N-N.

39. The oligonucleotide of any one of claims 1-38, wherein L5is -CH2-,-0-, -CH2CH2O-. -OCH2CH2-, -C(=0)NH-, -NHC(=0)-, or acombination of two or more instances of each one of the foregoing, or a combination of two or more of the foregoing, provided that: the number of backbone atoms of L5is between 7 and 70, inclusive;L5does not comprise O-O, 0-N, N-0, or N-N; and the combined number ois between 0 and 4, inclusive.

40. The oligonucleotide of any one of claims 1-39, wherein y6 is 0.

41. The oligonucleotide of any one of claims 1-40, wherein y 6 is 1 , and A6is a radical of a ligand.

42. The oligonucleotide of any one of claims 1-41, wherein y6 is 1 , and A6is a radical of a lipid.

43. The oligonucleotide of any one of claims 1-42, wherein L6is substituted or unsubstituted, Ci-ioo alkylene, substituted or unsubstituted, C2-100 alkenylene, substituted or unsubstituted, C2-100 alkynylene, substituted or unsubstituted, C'1-100 heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, or substituted or unsubstituted, C2-iooheteroalkynylene; optionally wherein one or more backbone atoms of the Ci-ioo alkylene, C2-100 alkenylene, C2-100 alkynylene, Ci-ioo heteroalkylene, C2-100 heteroalkenylene, or C2-ioo heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted ary lene, or substituted or unsubstituted heteroarylene, as valency permits.

44. The oligonucleotide of any one of claims 1-43, wherein L6is substituted or unsubstituted, C7-70 alky lene, substituted or unsubstituted, C7-70 alkenylene, substituted or unsubstituted, C7-70 alkynylene, substituted or unsubstituted. C7-70 heteroalkylene, substituted or unsubstituted, C7-70 heteroalkenylene, or substituted or unsubstituted, C7-70 heteroalkynylene; optionally wherein one or two backbone atoms of the C7-70 alkylene, C7-70 alkenylene, C7- 70 alkynylene, C7-70 heteroalkylene, C7-70 heteroalkenylene, or C7-70 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted orunsubstituted heterocyclylene, substituted or unsubstituted ary lene, or substituted or unsubstituted heteroarylene, as valency permits.

45. The oligonucleotide of any one of claims 1-44, yvherein L6is substituted or unsubstituted, C7-70 alkylene or substituted or unsubstituted, C7-70 heteroalkylene; and one or two backbone atoms of the C7-70 alkylene or C7-70 heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.

46. The oligonucleotide of any one of claims 1-45, wherein: L6isL6Ai9_L6A2o_isindependently a single bond, -O-, -S-, -S-S-, -NRa-, -C(=O)O-, -C(=NRa)O- -S(=O)O-. -S(=O)2O-, -C(=O)NRa-. -C(=NRa)NRa-, -S(=O)NRa-. -S(=O)2NRa-, -OC(=O)-,-OC(=NRa)-, -OS(=O)-, -OS(=O)2-. -NRaC(=O)-, -NRaC(=NRa)-, -NRaS(=O)-, - NRaS(=O)2-, -OC(=O)O- -OC(=NRa)O-, -OS(=O)O-, -OS(=O)2O- -NRaC(=O)O-, - NRaC(=NRa)O , NRaS(=O)O , NRaS(=O)2O , OC(=O)NRa, OC(=NRa)NRa, OS(=O)NRa-, -OS(=O)2NRa-, -NRaC(=O)NRa-, -NRaC(=NRa)NRa-, -NRaS(=O)NRa-, - NRaS(=O)2NRa-, -C(=O)-, -C(=NRa)-. -S(=O)-, -S(=O)2- -OP(=O)(ORa)O-. - SP(=O)(ORa)O- -OP(=O)(ORa)S-, or -OP(=O)(SRa)O-; each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L6B1, L6B2, and L6B6is independently a single bond, substituted or unsubstituted, Ci-100 alkylene or substituted or unsubstituted, Ci-100 heteroalkylene; each of L6C1and L6C2is a single bond, substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms, or substituted or unsubstituted heteroarylene that replaces one of the backbone atoms; and bond C6Bis attached to A6.

47. The oligonucleotide of any one of claims 1-46, wherein: the substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms is of the formula:k21 is 0, 1, 2. 3, or 4; each instance of Rd, if present, is independently halogen, substituted or unsubstituted, Ci-6 alkyl, or -O-(substituted or unsubstituted, Ci-6 alkyl); k22 is 0, 1, 2, 3, or 4; each instance of Re, if present, is independently halogen, substituted or unsubstituted, Ci-6 alkyl, or -O-(substituted or unsubstituted. Ci-6 alkyl); k23 is an integer between 0 and 11, inclusive; each instance of R1. if present, is independently halogen, substituted or unsubstituted, Ci-6 alkyl, or -O-(substituted or unsubstituted, Ci-6 alkyl); andRgis hydrogen, halogen, substituted or unsubstituted, Ci-6 alkyl, or -©-(substituted or unsubstituted, Ci-6 alkyl).

48. The oligonucleotide of any one of claims 1-47, wherein the substituted or unsubstituted heteroarylene that replaces one of the backbone atoms is of the formula:

49. The oligonucleotide of any one of claims 1-48, wherein:L6iseach of rl, r2, r4, r5, r8, and r9 is independently an integer from 0 to 10, inclusive; each of r3, r6, and r7 is independently an integer from 1 to 10, inclusive; each of _L6A21-L6A22-, _L6A23-L6A24-, and _L6A25-L6A26- is independently a single bond, -O-, -S-, -S-S-, -NRa-, -C(=O)O-, -C(=NRa)O-, -S(=O)O-, -S(=O)2O- -C(=O)NRa-, - C(=NRa)NRa- -S(=O)NRa-, -S(=O)2NRa- -OC(=O)-, -OC(=NRa)-, -OS(=O)-, -OS(=O)2-, - NRaC(=O)-, -NRaC(=NRa)-, -NRaS(=O)-, -NRaS(=O)2-, -OC(=O)O- -OC(=NRa)O-, - OS(-O)O-. -OS( O)2O-. -NRaC(=O)O-, -NRaC(=NRa)O-, -NRaS(=O)O-, -NRaS( O)2O-. - OC(=O)NRa-, -OC(=NRa)NRa-, -OS(=O)NRa-, -OS(=O)2NRa-, -NRaC(=O)NRa- - NRaC(=NRa)NRa- -NRaS(=O)NRa-, -NRaS(=O)2NRa-, -C(=O)-_ -C(=NRa)-, -S(=O)-, - S(=O)2- -OP(=O)(ORa)O-, -SP(=O)(ORa)O-, -OP(=O)(ORa)S-, or -OP(=O)(SRa)O-; each instance of Rais independently hydrogen, substituted or unsubstituted, Ci-6 alkyl, substituted or unsubstituted phenyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; and bond C6Ais attached to A6.

50. The oligonucleotide of any one of claims 1-49, wherein each of _L6A23-L6A24- and - L6A25L6 26is independently -NRa-C(=O)- or C(=O) NRa.

51. The oligonucleotide of any one of claims 1-50, wherein -L6A21-L6A22- is -O-.

52. The oligonucleotide of any one of claims 1-51, wherein L6is substituted or unsubstituted, C7-70 heteroalkylene.

53. The oligonucleotide of any one of claims 1-52, wherein L6is -CH2-,,-O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH- -C(=O)N(CH3)-, -NHC(=O)-, -N(CH3)C(=O)-,combination of two or more instances of each one of the foregoing, or a combination of two or more of the foregoing, provided that: the number of backbone atoms of L6is between 7 and 70, inclusive; and L6does not comprise O-O, O-N, N-O, or N-N.

54. The oligonucleotide of any one of claims 1-53, wherein L6is -CH2-,combination of two or more instances of each one of the foregoing, or a combination of two or more of the foregoing, provided that: the number of backbone atoms of L6is between 7 and 70, inclusive;L6does not comprise O-O, O-N, N-O, or N-N: and the combined number of-Cis between 0 and 4. inclusive.

55. The oligonucleotide of any one of claims 1-54 further comprising one or more modifications independently selected from modified sugars, modified nucleobases, and modified intemucleosidic linkers.

56. The oligonucleotide of any one of claims 1-55, wherein at least two ligands are of the same ligand type.

57. The oligonucleotide of any one of claims 1-56, wherein at least two ligands are the same.

58. The oligonucleotide of any one of claims 1-57, wherein at least two ligands are different ligands of the same ligand type.

59. The oligonucleotide of any one of claims 1-58, wherein at least two ligands are of different ligand ty pes.

60. The oligonucleotide of any one of claims 1-59, wherein at least one ligand is a small molecule, peptide, or protein.

61. The oligonucleotide of any one of claims 1 -60, wherein at least one instance of the modified sugars is a 2'-fluoro-2'-deoxyribose. 2'-O-methylribose. 2’-thioribose, 2', 3'- dideoxyribose, 2'-amino-2'-deoxyribose, 2' deoxyribose, 2'-azido-2’-deoxyribose, 2'-O- methyldeoxyribose, 3 '-amino-2', 3 '-dideoxyribose, 3'-azido-2',3'-dideoxyribose, 3 '-deoxyribose, 3'-O-(2-nitrobenzyl)-2'-deoxyribose, 3'-O-methylribose, 5 '-aminoribose, 5'-thioribose, 5-nitro-l- indolyl-2'-deoxy ribose, 5'-biotin-ribose. 2'-O,4'-C-amino-linked ribose, 2'-O.4'-C-thio-linked ribose, 2 ’-0 -methoxy ethyl ribose, 2’-O,4’-C-methylene-linked ribose, 2’-O,4’-C-ethylene-linked ribose, 2’,4’-constrained ethyl ribose, locked sugar, or a bicyclic sugar.

62. The oligonucleotide of any one of claims 1-61, wherein at least one instance of the modified nucleobases is xanthine, ally aminouracil, allyaminothymidine, hypoxanthine, digoxigeninated adenine, digoxigeninated cytosine, digoxigeninated guanine, digoxigeninated uracil, 6-chloropurineriboside, N6-methyladenine, methylpseudouracil, 2-thiocytosine, 2- thiouracil, 5 -methyluracil, 4-thiothymidine, 4-thiouracil, 5,6-dihydro-5-methyluracil. 5,6- dihydrouracil, 5-[(3-Indolyl)propionamide-N-allyl]uracil. 5-aminoallylcytosine, 5- aminoallyluracil, 5 -bromouracil, 5-bromocytosine, 5 -carboxy cytosine, 5- carboxymethylesteruracil, 5-carboxyuracil, 5-fluorouracil, 5-formylcytosine, 5-formyluracil, 5- hydroxycytosine, 5-hydroxymethylcytosine, 5-hydroxymethyluracil, 5-hydroxyuracil, 5- iodocytosine, 5-iodouracil. 5-methoxycytosine, 5-methoxyuracil, 5 -methylcytosine, 5- methyluracil, 5-propargylaminocytosine, 5-propargylaminouracil, 5-propynylcytosine, 5- propynyluracil, 6-azacytosine, 6-azauracil, 6-chloropurine, 6-thioguanine, 7-deazaadenine, 7- deazaguanine, 7-deaza-7-propargylaminoadenine, 7-deaza-7-propargylaminoguanine. 8- azaadenine, 8-azidoadenine, 8-chloroadenine, 8-oxoadenine, 8-oxoguanine, araadenine, aracytosine, araguanine, arauracil. bi otin-16-7-deaza-7-propargyl aminoguanine, biotin-16- aminoallylcytosine, biotin-16-aminoallyluracil, cyanine 3-5-propargylaminocytosine, cyanine 3- 6-propargylaminouracil, cyanine 3-aminoallylcytosine, cyanine 3-aminoallyluracil, cyanine 5-6-propargylaminocytosine, cyanine 5-6-propargylaminouracil, cyanine 5-aminoallylcytosine, cyanine 5 -aminoallyluracil, cyanine 7-aminoallyluracil. dabcyl-5-3-aminoallyluracil. desthiobiotin-16-aminoallyl-uracil, desthiobiotin-6-aminoallylcytosine, isoguanine, Nl- ethylpseudouracil, N1 -methoxymethylpseudouracil, N1 -methyladenine, N1 -methylpseudouracil, N1 -propylpseudouracil, N2-methylguanine, N4-biotin-OBEA-cytosine, N4-methylcytosine, N6- methyladenine, O6-methylguanine, pseudoisocytosine, pseudouracil, thienocytosine. thienoguanine, thienouracil, xanthosine, 3-deazaadenine, 2,6-diaminoadenine, 2,6- daminoguanine, 5-carboxamide-uracil, 5-ethynyluracil, N6-isopentenyladenine (i6A), 2-methyl- thio-N6-isopentenyladenine (ms2i6A), 2-methylthio-N6-methyladenine (ms2m6A), N6-(cis- hydroxyisopentenyl)adenine (io6A), 2-methylthio-N6-(cis-hydroxyisopentenyl)adenine (ms2io6A), N6-glycinylcarbamoyladenine (g6A). N6-threonylcarbamoyladenine (t6A), 2- methylthio-N6-threonyl carbamoyladenine (ms2t6A), N6-methyl-N6-threonylcarbamoyladenine (m6t6A), N6-hydroxynorvalylcarbamoyladenine (hn6A), 2-methylthio-N6-hydroxynorvalyl carbamoyladenine (ms2hn6A), N6,N6-dimethyladenine (m62A), and N6-acetyladenine (ac6A).

63. The oligonucleotide of any one of claims 1-62, wherein at least one instance of the modified intemucleosidic linkers is a phosphotriester, alkylphosphonate, phosphoramidate, phosphorothioate, phosphorodithioate, or phosphorothiolate.

64. The oligonucleotide of any one of claims 1-63, wherein at least one ligand is a central nervous system receptor ligand.

65. The oligonucleotide of any one of claims 1-64, wherein at least one ligand is a tropomyosin receptor B (TrkB) ligand.

66. The oligonucleotide of any one of claims 1-65, wherein: at least one TrkB ligand is a compound of the formula:R2is hydrogen, -OR7, -SR8, or -NR9R10;R3is hydrogen, -OR31, -SR32, or -NR33R34; R4is hydrogen, -OR35, -SR36, or -NR37R38;R5is hydrogen, -OR39, -SR40, or -NR41R42; R6is hydrogen, -OH. optionally substituted -O-alkyl, optionally substituted -OAc, -NH2. optionally substituted -NHAc, -SH, or =0; R7, R8, R9, R10, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, and R42are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; Y is CH2, NH, S, or O;Z is optionally substituted aryl or optionally substituted heteroaryl; R11and R13are each independently absent, hydrogen, or optionally substituted alkyl;R12, R14, and R15are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyd, optionally substituted aryl, or optionally substituted heteroaryl;R16is hydrogen, halogen, -CN, -N3. -SOnieR1A. -SOvi6NR16BR16C, -NHNR16BR16C, -ONR16BR16C, -NHC(O)NHNR16BR16C, -NHC(O)NR16BR16C, -N(0)mi6, -NR16BR16C, -C(O)R16D, -C(O)OR16D, -C(O)NR16BR16C, -OR16A, -NR16BSO2R16A, -NR16BC(O)R16D, -NR16BC(O)OR'6D, -NRI6BOR16D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; g . a and = are each independently a single bond or a double bond, wherein if = is a single bond, then = b= is a double bond and R13is absent; and further wherein if =-&= is a single a bond, then = is a double bond and R is absent;R16A, R16B, R16C, R16Dare each independently hydrogen, halogen, -CF3, -CCI3, -CBr3, - CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R16Band R16Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R17, R18, and R19are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R20is hydrogen, halogen, -CN, -N3, -SOn2oR1A. -SOv2oNR20BR20C, -NHNR20BR20C, -ONR20BR20C, -NHC(O)NHNR20BR2°C. -NHC(O)NR20BR2°C, — N(0)m2o, -NR20BR20C, -C(0)R20D-C(O)OR20D, -C(O)NR20BR20C, -OR20A, -NR20BSO2R20A-NR20BC(O)R20U, -NR20BC(O)OR20D, -NR20BOR20D, optionally substituted alkyd, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R21is hydrogen, halogen, -CN, -N3, -SOn2iR1A-SOV2iNR21BR21c, -NHNR21BR21C, -ONR21BR21C, -NHC(O)NHNR21BR21c, -NHC(O)NR21BR21c, -N(0)m2i, -NR21BR21C, -C(O)R21D, -C(O)OR21D, -C(O)NR21BR21c, -OR21A, -NR21BSO2R21A, -NR21BC(O)R21D, -NR21BC(O)OR21D, -NR21BOR21D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted ary l, or optionally substituted heteroaryl;R22and R23are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R24is hydrogen, halogen, -CN, -N3. -SOn24R1A. -SOv24NR24BR24C, -NHNR24BR24C, -ONR24BR24C, -NHC(O)NHNR24BR24C, -NHC(O)NR24BR24C, -N(O)m24, -NR24BR24C, -C(O)R24D, -C(O)OR24D, -C(O)NR24BR24C, -OR24A, -NR24BSO2R24A, -NR24BC(O)R24D, -NR24BC(O)OR24D, -NR24BOR24D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R20AR20B,R20C R20D,R21AR21 B.R21CR21 DR24.yR24B.R24CAN(|R24DARE EACHindependently hydrogen, halogen, -CF3, -CCK-CBrs, -CI3 -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted and, or substituted or unsubstituted heteroaryl; R20B, R20C, R21B, R21C, R24B, R24C, R24B, and R24Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; nl6, n20. n21, n23. n24, z6, and z8 are each independently 0, 1. 2, 3, or 4; vl6, v20, v21, ml 6, m20, m21, and m24 are each independently 1 or 2; z3 is 0, 1, 2, 3, 4, or 5; z4 and z7 are each independently 0, 1 , or 2; z5 is 0, 1. 2, or 3; and z6 and z8 are each independently 0, 1, 2, 3, or 4.

67. The oligonucleotide of any one of claims 1-66, wherein at least one radical of a TrkB ligand is of the formula:

68. The oligonucleotide of any one of claims 1-67, wherein at least one radical of a TrkB ligand is of the formula:

69. The oligonucleotide of any one of claims 1-68, wherein at least one radical of a TrkB70. The oligonucleotide of any one of claims 1-69, wherein at least one TrkB ligand is 3.7- dihydroxyflavone, 3.7.8.2'-tetrahydroxyflavone, 7,3'-dihydroxyflavone, 7,8,2'-trihydroxyflavone, 7,8,3 '-trihydroxyflavone, 7, 8,4 '-trihydroxy flavone, diosmetin (5,7,3'-trihydroxy-4'- methoxyflavone), 7-hydroxy-4'-methoxyflavone, 8-hydroxy-7-methoxyflavone, eutropoflavin (4'-dimethylamino-7,8-dihydroxyflavone), norwogonin (5,7,8-trihydroxyflavone), R7, R13, tropoflavin (7,8-dihydroxyflavone), 7.8-dimethoxyflavone, quercetin (3,3'.4',5,7- pentahydroxyflavone), apigenin (4',5,7-trihydroxyflavone), isocoumarin, gossypetin (3, 5, 7, 8, 3', 4' -hexahydroxyflavone), 2-methyl-8-phenylchromeno[7,8-d]imidazol-6(3H)-one, 8- phenylchromeno[7,8-d]imidazol-6(3H)-one, 4-oxo-2-phenyl-4H-chromene-7,8-diyl diacetate, ANA-12, or an anti-TrkB antibody.

71. The oligonucleotide of any one of claims 1-70, wherein at least one ligand is an α4β1 / 7 integrin ligand.

72. The oligonucleotide of any one of claims 1-71, wherein at least one α4β1 / 7 integrin ligandor is a radical of an anti- α4β1 / 7 integrin antibody.

73. The oligonucleotide of any one of claims 1-72, wherein: at least one radical of an α4β1 / 7 integrin ligand is of the formula:R2Zis hydrogen, polyethylene glycol, substituted or unsubstituted heteroalkyl, or substituted or unsubstituted heteroaryl; and each of R3Zand R4Zis independently hydrogen, halogen, optionally substituted alky l, or optionally substituted -O-alkyl.

74. The oligonucleotide of any one of claims 1-73, wherein: at least one radical of an α4β1 / 7 integrin ligand is of the formula:R4Zis hydrogen, halogen, polyethylene glycol, optionally substituted alkyd, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted -O-alkyl, or optionally substituted cycloalkyl;R5Zis optionally substituted heteroalkyl or optionally substituted heterocyclyl; and nlZ is 1, 2. or 3.

75. The oligonucleotide of any7one of claims 1-74, wherein: at least one radical of an α4β1 / 7 integrin ligand is of the formula:R6Zis hydrogen, -OH, -NH2, -NHR7Z, -OR7Z, or absent; andR7Zis hydrogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.

76. The oligonucleotide of any one of claims 1-75, wherein: at least one radical of an α4β1 / 7 integrin ligand is of the formula:n2Z is 0, 1 , 2, or 3.

77. The oligonucleotide of any one of claims 1-76, wherein: at least one radical of an α4β1 / 7 integrin ligand is of the formula:n3Z is 0, 1 , 2, or 3.

78. The oligonucleotide of any one of claims 1-77, wherein: at least one radical of an α4β1 / 7 integrin ligand is of the formula:each of R8Z, R9Z, R10Z, and R11Zis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted -O-alkyl. or substituted or unsubstituted cycloalkyl;each of R12Zand R13Zis independently H, halogen, optionally substituted alkyl, optionallyR14Zis optionally substituted C1-C5 alky l, optionally substituted C1-C5 alkylene-(C3-C6)- cycloalkyl, or optionally substituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy.The oligonucleotide of any one of claims 1-78, wherein: at least one radical of an α4β1 / 7 integrin ligand is of the formula:The oligonucleotide of any one of claims 1-79, wherein: at least one radical of an α4β1 / 7 integrin ligand is of the formula:R15Zis H. polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; each of R16Zand R17Zis independently H, halogen, optionally substituted alkyl, or optionally substituted -O-alkyl; andYzis -CH2- or -(CH2)2-.

81. The oligonucleotide of any one of claims 1-80, wherein: at least one radical of an α4β1 / 7 integrin ligand is of the formula:R18Zis H, OH, NH2, NHR19Z, OR19Z, or CONHR19Z; each instance of R19Zis independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and n4Z is 1 or 2.

82. The oligonucleotide of any one of claims 1-81, wherein: at least one radical of an (X4P1 / 7 integrin ligand is of the formula:R19Zis H, -CH2OR20Z, -(CH2)2OR20Z, -CH2NHCOR20Z, or -OR20Z; andR20Zis H. polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.

83. The oligonucleotide of any one of claims 1-82, wherein: at least one radical of an α4β1 / 7 integrin ligand is of the formula:R21Zis H. -CONHR22Z, -CH2OR22Z. -(CH2)2OR22Z. -CH2NHCOR22Z, or -OR22Z;R22Zis H, polyethylene glycol, optionally substituted alkyd, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaiy 1; andX1Zis H or halogen.

84. The oligonucleotide of any one of claims 1-83, wherein: at least one radical of an α4β1 / 7 integrin ligand is of the formula:R23Zis H, -CONHR24Z, -CH2OR24Z, -(CH2)2OR24Z, -CH2NHCOR24Z, or -OR24Z;R24Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and n5Z is 0, 1 , 2, or 3.

85. The oligonucleotide of any one of claims 1-84, wherein: at least one radical of an C14P1 / 7 integrin ligand is of the formula:R25Zis H. -CONHR27Z, -CH2OR27Z, -(CH2)2OR27Z, -CH2NHCOR27Z, or -OR27Z; R26Zis H. optionally substituted alkyl, or optionally substituted cycloalkyl;R27Zis H. polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl: and X2Zis optionally substituted CH2or optionally substituted NH.

86. The oligonucleotide of any one of claims 1-85, wherein: at least one radical of an oufh 7 integrin ligand is of the formula:R28Zis H, -CH2OR30Z, -(CH2)2OR30Z, -CH2NHCOR30Z, or -OR30Z;R29Zis H, -OH, -NH2, -NHR31Z, or -OR?1Z; R30Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; R31Zis H, polyethylene glycol, optionally substituted alkyd, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroary l; and n3Z is 1, 2, or 3.

87. The oligonucleotide of any one of claims 1-86, wherein at least one ligand is a cannabinoid receptor type 1 (CBi) ligand.

88. The oligonucleotide of any one of claims 1-87, wherein: at least one CBi ligand is a compound of the formula:X1Yis NR10Yor CR11YR12Y; each of R10Y, R11Y, and R12Yis independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R19YIS hydrogen, -SOni9YR19YA, -SOVI9YNR19YBR19YC, -NHNR19YBR19YC, -ONR19YBR19YC. -NHC(O)NHNR19YBR19YC, -NHC(O)NR19YBR19YC. -NR19YBR19YC, - C(O)R19YD, -C(O)OR19YD, -C(O)NR19YBR19YC, -OR19YA, -NR19YBSO2R19YA, -NR19YBC(O)R19YD, -NR19YBC(O)O R19YD, -NR19YBOR19YD, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each of R19I A, R19YB, R19'0, and R19YDis independently hydrogen, halogen, -CF3, -CCl3 -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alky 1, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R19YBand R19YCbonded to the same nitrogen atom are joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; nl9Y is 0, 1, 2, 3, or 4; and v l9Y is 1 or 2.

89. The oligonucleotide of any one of claims 1-88, wherein: at least one radical of a CBi ligand is of the formula:

90. The oligonucleotide of any one of claims 1-89, wherein: at least one radical of a CBi ligand is of the formula:

91. The oligonucleotide of any one of claims 1-90, wherein: at least one radical of a CBi ligand is a radical of a compound of the formula:wherein:R17YIS hydrogen, -SOni7YR17YA, -SOV17YNR17YBR17YC, -NHNR17YBR17YC, -ONR17YBR17YC. -NHC(O)NHNR17YBR17YC, -NHC(O)NR17YBR17YC. -NR17YBR17YC, -C(O)R17YD, -C(O)OR17YD, -C(O)NR17YBR17YC, -OR17YA, -NR17YBSO2R17YA, -NR17YBC(O)R17YD, -NR17YBC(O)OR17YD, -NR17YBOR17YD, optionally substituted alkyd, optionally substituted heteroalkyl, optionally substituted cycloalky l, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each of R17I A, RI7'1 K. Rmc, and RmDis independently hydrogen, halogen, -CF3, -CCI3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alky 1, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted ary l, or substituted or unsubstituted heteroary l; wherein R17YBandR17YCsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; nl7Y is 0, 1, 2, 3, or 4; and vl7Y is 1 or 2.

92. The oligonucleotide of any one of claims 1-91, wherein: at least one radical of a CBi ligand is of the formula:

93. The oligonucleotide of any one of claims 1-92, wherein: at least one radical of a CBi ligand is a radical of a compound of the formula:

94. The oligonucleotide of any one of claims 1-93, wherein: at least one radical of a CBi ligand is of the formula:

95. The oligonucleotide of any one of claims 1-94, wherein: at least one radical of a CBi ligand is a radical of a compound of the formula:R3yR4yR5yR6yand R8Yare independently hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyd, optionally substituted heterocycloalky 1. optionally substituted ary 1, or optionally substituted heteroaiyl;R9Yis hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl; or R6Yand R<Asubstituents may be joined together form an optionally substituted heterocycloalkyl or optionally substituted heteroaryl;R7Yis hydrogen, -SO„7YR7YA, -SOV7YNR7YBR7YC, -NHNR7YBR7YC, -ONR7YBR7YC, -NHC(O)NHNR7YBR7YC, -NHC(O)NR7YBR7YC, -NR7YBR7Y('. -C(O)R7YD, -C(O)OR7YD, - C(O)NR7YBR7YC, -OR7YA, -NR7YBSO2R7YA, -NR7YBC(O)R7YD, -NR7YBC(O)OR7YD, - NR7YBOR7YD, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R7YA, R7YB, R7YC, R7YDare each independently hydrogen, halogen, -CF3, -CCI3, -CBrs, - CI3, COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R7YBand R7YCsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; n7Y is 0, 1, 2, 3, or 4; and v7Y is 1 or 2.

96. The oligonucleotide of any7one of claims 1-95, wherein: at least one radical of a CBi ligand is of the formula:

97. The oligonucleotide of any one of claims 1-96, wherein: at least one CBi ligand is a compound of the formula:R16Yis hydrogen, halogen, -CN. -N3, -NO2, -NR16YBR16YC, -C(O)R16YD, -C(O)OR16YD. -C(O)NR16™R16YC, -OR16YA, -NR16YBC(O)R16YD, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; andR16YA, R16YB, R16YC, and R16YDare each independently hydrogen, halogen, -CF3, -CC13, -CBr3. -CI3. -COOH, -CONH2. substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted and, or substituted or unsubstituted heteroaryl; or R16YBand R16YCbonded to the same nitrogen atom are joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

98. The oligonucleotide of any one of claims 1-97, wherein: at least one radical of a CBi ligand is of the formula:

99. The oligonucleotide of any one of claims 1-98, wherein: at least one CBi ligand is a compound of the formula:

100. The oligonucleotide of any one of claims 1-99, wherein at least one ligand is a 'V-methyl- D-aspartate (NMDA) receptor ligand.

101. The oligonucleotide of any one of claims 1-100, wherein at least one NMDA receptor ligand is a compound of the formula:or is a radical of an anti -NMD A receptor antibody.

102. The oligonucleotide of any one of claims 1-101, wherein at least one radical of an NMDA receptor ligand is of the formula:

103. The oligonucleotide of any one of claims 1-102, wherein at least one radical of an NMDA receptor ligand is of the formula:

104. The oligonucleotide of any one of claims 1-103, wherein at least one radical of an NMDA receptor hgand is of the formula:

105. The oligonucleotide of any one of claims 1-104, wherein at least one radical of an NMDA receptor ligand is of the formula:

106. The oligonucleotide of any one of claims 1-105, wherein at least one radical of an NMDA receptor ligand is of the formula:

107. The oligonucleotide of any one of claims 1-106, wherein at least one radical of an NMDA receptor ligand is of the formula:

108. The oligonucleotide of any one of claims 1-107, wherein at least one radical of an NMDA receptor ligand is of the formula:

109. The oligonucleotide of any one of claims 1-108, wherein at least one radical of an NMDA receptor ligand is of the formula:1 10. The oligonucleotide of any one of claims 1 -109, wherein at least one radical of an NMDA receptor ligand is of the formula:

111. The oligonucleotide of any one of claims 1-110. wherein at least one radical of an NMDA receptor ligand is of the formula:

112. The oligonucleotide of any one of claims 1-111. wherein at least one radical of an NMDA receptor ligand is of the formula:

113. The oligonucleotide of any one of claims 1-112. wherein at least one lipid is a fatty acyl, glycerolipid, glycerophospholipid, sphingolipid, saccharolipid, polyketide, sterol lipid, or prenol lipid.

114. The oligonucleotide of any one of claims 1-113. wherein at least one lipid is a fatty acid or conjugate, octadecanoid, eicosanoid, docosanoid, fatty alcohol, fatty aldehs de. fatty ester, fatty amide, fatty nitrile, fatty ether, hydrocarbon, oxygenated hydrocarbon, or fatty acyl glycoside.

115. The oligonucleotide of any one of claims 1-114. wherein at least one lipid is a hydrocarbon.

116. The oligonucleotide of any one of claims 1-115, wherein at least one radical of a lipid is unsubstituted C7-36alkyl. C7-36alkyl substituted with one or more fluoro as valency permits, unsubstituted C7-36alkenyl, or C7-36alkenyl substituted with one or more fluoro as valency permits.

117. The oligonucleotide of any one of claims 1-116, wherein at least one radical of a lipid comprises one. two, three, four, five, or six carbon-carbon double bonds.

118. The oligonucleotide of any one of claims 1-117, wherein at least one radical of a lipid is unsubstituted C16-28 alkyl or unsubstituted C16-28 alkenyl, each of which is independently unbranched, bi-branched, or tri-branched.

119. The oligonucleotide of any one of claims 1-118, wherein at least one radical of a lipid is unbranched unsubstituted C18-26 alky l.

120. The oligonucleotide of any one of claims 1-119, wherein at least one radical of a lipid is - (CH2)21CH3.

121. The oligonucleotide of any one of claims 1-120, wherein at least one lipid is a monoradylglycerol, diradylglycerol. triradylglycerol, glycosylmonoradylglycerol, glycosyldiradylglycerol, betaine monoradylglycerol, or betaine diradylglycerol.

122. The oligonucleotide of any one of claims 1-121, wherein at least one lipid is a glycero phosphocholine, glycerophosphoethanolamine, glycerophosphoserine, glycerophosphoglycerol, glycerophosphoglycerophosphate, glycerophosphoinositol, glycerophosphoinositol monophosphate, glycerophosphoinositol bisphosphate, glycerophosphoinositol trisphosphate, glycerophosphate, glyceropyrophosphate, glycerophosphoglycerophosphoglycerol, CDP-glycerol. glycosylglycerophospholipid, glycerophosphoinositolglycan, glycerophosphonocholine, glycerophosphonoethanolamine, diglycerol tetraether phospholipid, glycerol-nonitol tetraether phospholipid, oxidized glycerophospholipid, glycerophosphoethanolamine glycan, dihydroxyacetonephosphate, glycero phosphoethanol, glycerophosphothreonine, or cyclic glycerophosphatidic acid.

123. The oligonucleotide of any one of claims 1 -122, wherein at least one lipid is a sphingoid base, ceramide, phosphosphingolipid, phosphonosphingolipid, neutral glycosphingolipid, acidic glycosphingolipid, basic glycosphingolipid, amphoteric glycosphingolipid, or arsenosphingolipid.

124. The oligonucleotide of any one of claims 1-123, wherein at least one lipid is a sterol, steroid, secosteroid, bile acid or a derivative thereof, or steroid conjugate.

125. The oligonucleotide of any one of claims 1-124. wherein at least one lipid is cholesterol.

126. The oligonucleotide of any one of claims 1-125, wherein at least one lipid is an isoprenoid, quinone, hydroquinone, polyprenol, or hopanoid.

127. The oligonucleotide of any one of claims 1-126, wherein at least one lipid is an acylaminosugar, acyl aminosugar glycan, acyltrehalose, or acyltrehalose glycan.

128. The oligonucleotide of any one of claims 1-127. wherein at least one lipid is a linear polyketide, halogenated acetogenin, annonaceae acetogenin, macrolide, lactone polyketide, ansamycin, polyene, linear tetracycline, angucy cline, poly ether antibiotic, aflatoxin, cytochalasin, flavonoid, aromatic polyketide, non-ribosomal peptide / polyketide hybrid, or phenolic lipid.

129. The oligonucleotide of any one of claims 1-128, whereinis:

130. The oligonucleotide of any one of claims 1-129, whereinis131. The oligonucleotide of any one of claims 1-130, or a pharmaceutically acceptable salt or prodrug thereof, wherein Formula I is:5' sense strand 3’132. The oligonucleotide of any one of claims 1-131. whereinis a sense oligonucleotide strand, and the oligonucleotide further comprises an antisense oligonucleotide strand.

133. The oligonucleotide of any one of claims 1-132, wherein is anantisense oligonucleotide strand, and the oligonucleotide further comprises a sense oligonucleotide strand.

134. The oligonucleotide of any one of claims 1-133, wherein the nucleobases of the antisense oligonucleotide strand are complementary to the nucleobases of the sense oligonucleotide strand.

135. The oligonucleotide of any one of claims 1-134, wherein the sense oligonucleotide strand has at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity to SEQ ID NO.: 1 or 2.

136. The oligonucleotide of any one of claims 1-135, wherein the sense oligonucleotide strand has at least 80%. at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity to SEQ ID NO.: 3 or 4.

137. The oligonucleotide of any one of claims 1-136, wherein the sense oligonucleotide strand has at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity to SEQ ID NO.: 5 or 6.

138. A pharmaceutical composition comprising the oligonucleotide of any one of claims 1-137, or pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient.

139. The pharmaceutical composition of claim 138 further comprising an additional pharmaceutical agent.

140. A kit comprising: the oligonucleotide of any one of claims 1-137, or pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 138 or 139; and instructions for using the oligonucleotide, pharmaceutically acceptable salt, prodrug, or pharmaceutical composition.

141. A method of making an oligonucleotide of any one of claims 1-137 comprising contacting under suitable conditions a compound of Formula A-l:or a salt thereof, with a compound of Formula A-2:or a salt thereof, wherein: each of M1and M2is independently a radical of: a fragment of the oligonucleotide strand or a nucleoside;each of L4D1and L4D2is independently a single bond or linker;L4E1is a first reactive moiety;L4E2is a second reactive moiety;L4E1and L4E2are capable of reacting with each other under the suitable conditions to form L4E3; andL4D1_L4E3_L4D2is L4142. The method of claim 141, wherein each of M1and M2is independently a radical of a nucleoside.

143. The method of claim 141 or 142, whereinis:

144. The method of any one of claims 141-143, wherein each of L4E1and L4E2is a click chemistry handle.

145. The method of any of claims 141-144, wherein one of L4E1and L4E2is -N3, and the other of L4E1and L4E2is C =CH146. The method of any of claims 141-145, wherein one of L4E1and L4E2is -Ns, and the other147. The method of any one of claims 141-146, wherein L4E3is of the formula:k21 is 0, 1, 2, 3, or 4: each instance of Rd, if present, is independently halogen, substituted or unsubstituted, Ci-6 alkyl, or -O-(substituted or unsubstituted, Ci-6 alkyl); k22 is 0, 1, 2, 3, or 4;each instance of Re, if present, is independently halogen, substituted or unsubstituted, Ci-6 alkyl, or -O-(substituted or unsubstituted. Ci-6 alkyl); k23 is an integer between 0 and 11, inclusive; each instance of Rf, if present, is independently halogen, substituted or unsubstituted, Ci-6 alkyl, or -©-(substituted or unsubstituted, Ci-6 alkyl); andRsis hydrogen, halogen, substituted or unsubstituted, Ci-6 alkyl, or -©-(substituted or unsubstituted, Ci-6 alkyl).

148. The method of any one of claims 141-147. wherein L4Eis of the formula:

149. The method of any one of claims 141-148. wherein one of L4E1and L4E2is -SH, and the other150. The method of any one of claims 141-149, wherein one of L4E1or L4E2is a Michael donor, and the other of L4E1or L4E2is a Michael acceptor.

151. A method for delivering an oligonucleotide to a subject comprising administering to the subject the oligonucleotide of any one of claims 1-137, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 138 or 139.

152. Use of the oligonucleotide of any one of claims 1-137, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 138 or 139, for the manufacture of a medicament for dehvenng the oligonucleotide to a subject.

153. The oligonucleotide of any one of claims 1-137, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 138 or 139. for use in delivering the oligonucleotide to a subject.

154. The method of claim 151, the use of claim 152, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 153, wherein the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition is delivered to the brain of the subject.

155. The method of claim 151, the use of claim 152, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 153, wherein the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition is delivered to the striatum, cerebellum, brain stem, hippocampus, frontal cortex, or spinal cord of the subject.

156. A method for treating a disease in a subject in need thereof comprising administering to the subject an effective amount of the oligonucleotide of any one of claims 1-137, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 138 or 139.

157. Use of the oligonucleotide of any one of claims 1-137, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 138 or 139, for the manufacture of a medicament for treating a disease in a subject in need thereof.

158. The oligonucleotide of any one of claims 1-137, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 138 or 139, for use in treating a disease in a subject in need thereof.

159. A method for preventing a disease in a subject in need thereof comprising administering to the subject an effective amount of the oligonucleotide of any one of claims 1-137, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 138 or 139.

160. Use of the oligonucleotide of any one of claims 1-137, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 138 or 139, for the manufacture of a medicament for preventing a disease in a subject in need thereof.

161. The oligonucleotide of any one of claims 1-137, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 138 or 139, for use in preventing a disease in a subject in need thereof.

162. The method of claim 156 or 159, the use of claim 157 or 160, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 158 or 161, wherein the disease is associated with microtubule associated protein Tau (MAPT), superoxide dismutase ty pe 1 (SOD1), or leucine-rich repeat kinase 2 (LRRK2).

163. The method of claim 156 or 159. the use of claim 157 or 160. and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 158 or 161, wherein the disease is a central nervous system disease.

164. The method of claim 156 or 159, the use of claim 157 or 160. and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 158 or 161, wherein the disease is a brain disease, Edwards syndrome, gliosis, hyperekplexia, Meckel syndrome, myoclonic epilepsy myopathy sensory ataxia, narcolepsy, prion diseases, serotonin syndrome, or spinal cord disease.

165. The method of claim 156 or 159, the use of claim 157 or 160, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 158 or 161, wherein the disease is a neurodegenerative disease.

166. The method of claim 156 or 159, the use of claim 157 or 160, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for useof claim 158 or 161, wherein the disease is ABri amyloidosis, aceruloplasminemia, acute neurodegenerative disease, amyotrophic lateral sclerosis, ataxia with vitamin E deficiency, atypical Rett syndrome, beta-propeller protein-associated neurodegeneration, COASY protein- associated neurodegeneration, central nervous system degenerative disease, demyelination, fatty acid hydroxylase-associated neurodegeneration, fragile X tremor ataxia syndrome, Gemignani syndrome, Gerstmann-Straussler syndrome, Huntington disease, Huntington-like syndrome, hypomyehnation with atrophy of basal gangha and cerebellum, infantile cerebellar-retinal degeneration, infantile neuroaxonal dystrophy, Kosaki overgrowth syndrome, mitochondrial membrane protein-associated neurodegeneration, multiple sclerosis, multiple system atrophy, muscular dystrophy, Nasu-Hakola disease, neuroacanthocytosis, neurogenic ataxia and retinitis pigmentosa syndrome, neuronal ceroid lipofuscinosis, neuronal intranuclear inclusion disease, neuropil thread, pantothenate kinase-associated neurodegeneration, Parkinson disease, posterior column ataxia, pure autonomic failure, retrograde degeneration, Rett syndrome, SPOAN syndrome, Salla disease, spinocerebellar ataxia, subacute combined degeneration, Tabes dorsalis, tauopathy, or Wolfram syndrome.

167. The method of claim 156 or 159, the use of claim 157 or 160, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 158 or 161, wherein the disease is a neurocognitive disorder.

168. The method of claim 156 or 159, the use of claim 157 or 160, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 158 or 161, wherein the disease is a dementia, HIV-associated neurocognitive disorder, or memory disorder.

169. The method of claim 156 or 159, the use of claim 157 or 160, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 158 or 161, wherein the disease is Parkinson’s disease.

170. The method of claim 156 or 159, the use of claim 157 or 160, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 158 or 161, wherein the disease is amyotrophic lateral sclerosis.

171. The method of claim 156 or 159. the use of claim 157 or 160, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 158 or 161, wherein the disease is Alzheimer’s disease.

172. The method of claim 156 or 159. the use of claim 157 or 160, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 158 or 161, wherein the disease is a tauopathy, frontotemporal dementia (FTD), FTDP- 17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglionic degeneration (CBD), epilepsy, or Dravet’s Syndrome.

173. A method of inhibiting the expression of microtubule associated protein Tau (MAPT), superoxide dismutase type 1 (SOD1 ), or leucine-rich repeat kinase 2 (LRRK2) in a subject, biological sample, tissue, or cell, the method comprising administering to the subject or contacting the biological sample, tissue, or cell with an effective amount of the oligonucleotide of any one of claims 1-137. or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 138 or 139.

174. Use of the oligonucleotide of any one of claims 1-137, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 139 or 139, for the manufacture of a medicament for inhibiting the expression of microtubule associated protein Tau (MAPT), superoxide dismutase type 1 (SOD1), or leucine-rich repeat kinase 2 (LRRK2) in a subject, biological sample, tissue, or cell.

175. The oligonucleotide of any one of claims 1-137, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 138 or 139, for use in inhibiting the expression of microtubule associated protein Tau (MAPT), superoxide dismutase type 1 (SOD1), or leucine-rich repeat kinase 2 (LRRK2) in a subject, biological sample, tissue, or cell.

176. The method of claim 173, the use of claim 174, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 175, wherein the biological sample, tissue, or cell is in vitro.

177. The method of claim 173, the use of claim 174, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use ofclaim 175 further comprising administering to the subject or contacting the biological sample, tissue, or cell with an effective amount of an additional pharmaceutical agent.

178. The method of claim 173, the use of claim 174, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 175, wherein the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition, is administered to the subject parenterally.

179. The method of claim 173, the use of claim 174, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 175, wherein the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition, is administered to the subject intrathecally, intracerebroventricularly, or intravenously.

180. The method of claim 173, the use of claim 174, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 175, wherein the subject is a human.

Images