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WO2025080995A1 - Pharmaceutical agent-integrin ligand conjugates for muscle delivery - Google Patents

Pharmaceutical agent-integrin ligand conjugates for muscle delivery Download PDF

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Publication number
WO2025080995A1
WO2025080995A1 PCT/US2024/050986 US2024050986W WO2025080995A1 WO 2025080995 A1 WO2025080995 A1 WO 2025080995A1 US 2024050986 W US2024050986 W US 2024050986W WO 2025080995 A1 WO2025080995 A1 WO 2025080995A1
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unsubstituted
instance
independently
certain embodiments
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French (fr)
Inventor
Zhen Li
Rui ZHU
Alan Robert Macleod
Wen SHEN
Seyed Ali Reza MOUSAVI
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AdaRx Pharmaceuticals Inc
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AdaRx Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • C—CHEMISTRY; METALLURGY
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/321—2'-O-R Modification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/322—2'-R Modification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/351—Conjugate
    • C12N2310/3515—Lipophilic moiety, e.g. cholesterol

Definitions

  • oligonucleotides e.g., oligonucleotides
  • One strategy to facilitate delivery of a pharmaceutical to a desired location in vivo is by linking or attaching the pharmaceutical agent to a targeting ligand.
  • 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 shown to alter the function and activity of the target both in vitro and in vivo.
  • a target nucleic acid such as mRNA or pre-mRNA
  • oligonucleotides 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.
  • 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.
  • 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.
  • RISC RNA-induced silencing complex
  • 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 internucleoside linkages.
  • the present disclosure provides a method of treating a muscle disease in a subject in need thereof comprising administering to the subject an effective amount of a conjugate of Formula I: (A) y –L–(R 1 ) r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an ⁇ 4 ⁇ 1/7 integrin ligand; L is a linker; each instance of R 1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6.
  • ⁇ 4 ⁇ 1/7 integrin receptors may be expressed (e.g., selectively expressed) in muscle cells.
  • the conjugates may be useful for delivering pharmaceutical agents to a muscle (e.g., muscle cell) of a subject (e.g., a human).
  • at least one pharmaceutical agent is an oligonucleotide.
  • the conjugates may be useful in treating, preventing, or diagnosing a muscle disease.
  • the ⁇ 4 ⁇ 1/7 integrin ligand is capable of selectively targeting a muscle (e.g., muscle cell) of a subject.
  • the ⁇ 4 ⁇ 1/7 integrin ligand is capable of selectively targeting a particular type of muscle cell (e.g., a skeletal muscle cell, cardiac muscle cell, smooth muscle cell).
  • the ⁇ 4 ⁇ 1/7 integrin ligand is capable of selectively binding to or otherwise selectively recognizing one or more receptors on a muscle cell.
  • the conjugate may be advantageous over the pharmaceutical agent not conjugated with an ⁇ 4 ⁇ 1/7 integrin ligand 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 pharmaceutical agents are conjugated with at least one instance of a radical of an ⁇ 4 ⁇ 1/7 integrin ligand.
  • the present disclosure provides uses of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for treating a muscle disease in a subject in need thereof.
  • the present disclosure provides the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use in treating a muscle disease in a subject in need thereof.
  • the present disclosure provides methods of preventing a muscle disease in a subject in need thereof comprising administering to the subject an effective amount of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof.
  • the present disclosure provides uses of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for preventing a muscle disease in a subject in need thereof.
  • the present disclosure provides the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use in preventing a muscle disease in a subject in need thereof.
  • the present disclosure provides methods of diagnosing a muscle disease in a subject in need thereof comprising administering to the subject an effective amount of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof.
  • the present disclosure provides uses of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for diagnosing a muscle disease in a subject in need thereof.
  • the present disclosure provides the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use in diagnosing a muscle disease in a subject in need thereof.
  • the present disclosure provides methods for delivering a pharmaceutical agent to a muscle of a subject comprising administering to the subject the conjugate, or a pharmaceutically acceptable salt or prodrug thereof.
  • the present disclosure provides uses of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for delivering a pharmaceutical agent to a muscle of a subject.
  • the present disclosure provides the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use in delivering a pharmaceutical agent to a muscle of a subject.
  • Compounds (e.g., conjugates) described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • 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.
  • HPLC high pressure liquid chromatography
  • formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • range 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.
  • “Ci-6 alkyl” encompasses, Ci, C2, C3, C4, C5, Ce, C1-6, C1-5, CM, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3 A, C4-6, C4-5, and C5-6 alkyl.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 150 carbon atoms (“Ci-150 alkyl”).
  • an alkyl group has 100 to 150 carbon atoms (“C100-150 alkyl”). In some embodiments, an alkyl group has 50 to 100 carbon atoms (“C50-100 alkyl”). In some embodiments, an alkyl group has 20 to 50 carbon atoms (“C20-50 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 (“Ci-12 alkyl”). In some embodiments, an alkyl 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”).
  • an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“CM alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”).
  • an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., zz-propyl, isopropyl), butyl (C4) (e.g., n- butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., zz-pentyl, 3-pentanyl, amyl, neopentyl, 3- methyl-2-butanyl, tert-amyl), and hexyl (Ce) (e.g., n-hcxyl).
  • alkyl groups include zz-heptyl (C7), zz-octyl (Cs), zz-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as fluorine).
  • substituents e.g., halogen, such as fluorine
  • the alkyl group is an unsubstituted Ci-12 alkyl (such as unsubstituted Ci- 6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n- propyl (n-Pr), unsubstituted isopropyl (z-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted zz-butyl (zz-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (z-Bu)).
  • unsubstituted Ci-12 alkyl such as unsubstituted Ci- 6 alkyl, e.g., -CH3 (
  • the alkyl group is a substituted Ci-12 alkyl (such as substituted C i 6 alkyl, e.g., -CH 2 F, -CHF 2 , -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).
  • substituted C i 6 alkyl such as substituted C i 6 alkyl, e.g., -CH 2 F, -CHF 2 , -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)
  • heteroalkyl refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, 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.
  • a heteroalkyl group refers to a saturated group having from 1 to 150 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-150 alkyl”).
  • a heteroalkyl group refers to a saturated group having from 100 to 150 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCioo-iso alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 50 to 100 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCso-ioo alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 20 to 50 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC20-50 alkyl”).
  • 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 20 alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-12 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-n alkyl”).
  • 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 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-s alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-7 alkyl”).
  • a heteroalkyl 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 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms within the parent chain (“hctcroCi 4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-3 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkyl”).
  • each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents (e.g., oxo, substituted or unsubstituted C1-6 alkyl (e.g., -CH3)).
  • the heteroalkyl group is an unsubstituted heteroCi-12 alkyl.
  • the heteroalkyl group is a substituted heteroCi-12 alkyl.
  • unsubstituted heteroCi alkyl is -OCH3 or -CH2OH.
  • unsubstituted heteroC2 alkyl is -OCH2CH3, - CH2OCH3, or –CH2CH2OH.
  • heteroCz1-z2 alkyl and “Cz1-z2 heteroalkyl” are used interchangeably, wherein each of z1 and z2 is independently an integer.
  • 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.g., 1, 2, 3, or 4 double bonds).
  • an alkenyl group has 1 to 150 carbon atoms (“C1-150 alkenyl”). In some embodiments, an alkenyl group has at least 2 carbon atoms. In some embodiments, an alkenyl group has 100 to 150 carbon atoms (“C100-150 alkenyl”). In some embodiments, an alkenyl group has 50 to 100 carbon atoms (“C50-100 alkenyl”). In some embodiments, an alkenyl group has 20 to 50 carbon atoms (“C 20-50 alkenyl”). In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“C 1-20 alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“C1–12 alkenyl”).
  • an alkenyl group has 1 to 11 carbon atoms (“C1–11 alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“C 1–10 alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“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 (“C 1–7 alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C1–6 alkenyl”).
  • an alkenyl group has 1 to 5 carbon atoms (“C1–5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“C1–4 alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C 1–3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C 1–2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“C1 alkenyl”).
  • an alkenyl group is C2–3 alkenyl, C2–4 alkenyl, C2–5 alkenyl, C2–6 alkenyl, C2–7 alkenyl, C2–8 alkenyl, C 2–9 alkenyl, C 2–10 alkenyl, C 2–12 alkenyl, C 2–16 alkenyl, C 2–20 alkenyl, C 2–30 alkenyl, C 2–40 alkenyl, C2–50 alkenyl, C2–60 alkenyl, C2–70 alkenyl, C2–80 alkenyl, C2–90 alkenyl, or C2–100 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 C 1–4 alkenyl groups include methylidenyl (C 1 ), ethenyl (C 2 ), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like.
  • Examples of C1–6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like.
  • alkenyl examples include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
  • each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents.
  • the alkenyl group is an unsubstituted C 1-20 alkenyl.
  • the alkenyl group is a substituted C1-20 alkenyl.
  • 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.
  • heteroatom e.g., 1, 2, 3, or 4 heteroatoms
  • a heteroalkenyl group refers to a group having from 1 to 150 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–150 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 100 to 150 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 100–150 alkenyl”).
  • a heteroalkenyl group refers to a group having from 50 to 100 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC50–100 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 20 to 50 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 20–50 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–20 alkenyl”).
  • a heteroalkenyl group refers to a group having from 1 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–12 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–11 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–10 alkenyl”).
  • a heteroalkenyl group has 1to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–6 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–5 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 1–4 alkenyl”).
  • 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 C 1-6 alkyl (e.g., –CH3)).
  • the heteroalkenyl group is an unsubstituted heteroC1–20 alkenyl.
  • the heteroalkenyl group is a substituted heteroC1–20 alkenyl.
  • heteroCz1-z2 alkenyl and “Cz1-z2 heteroalkenyl” are used interchangeably, wherein each of z1 and z2 is independently an integer.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 150 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C1-150 alkynyl”). In some embodiments, an alkynyl group has 100 to 150 carbon atoms (“C 100-150 alkynyl”). In some embodiments, an alkynyl group has 50 to 100 carbon atoms (“C 50-100 alkynyl”).
  • an alkynyl group has 20 to 50 carbon atoms (“C 20-50 alkynyl”). In some embodiments, an alkynyl group has 1 to 20 carbon atoms (“C1-20 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 (“C 1-10 alkynyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C1-9 alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“C1-8 alkynyl”).
  • an alkynyl group has 1 to 7 carbon atoms (“C 1-7 alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“C 1-6 alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C1-5 alkynyl”). In some embodiments, an alkynyl group has 1 to 4 carbon atoms (“C1-4 alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“C 1-3 alkynyl”). In some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C 1-2 alkynyl”).
  • an alkynyl group has 1 carbon atom (“C1 alkynyl”).
  • 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 alkynyl, C 2–12 alkynyl, C 2–16 alkynyl, C 2–20 alkynyl, C 2–30 alkynyl, C 2–40 alkynyl, C 2–50 alkynyl, C2–60 alkynyl, C2–70 alkynyl, C2–80 alkynyl, C2–90 alkynyl, or C2–100 alkynyl.
  • the one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1- butynyl).
  • C1-4 alkynyl groups include, without limitation, methylidynyl (C1), ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like.
  • Examples of C 1-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C6), and the like.
  • alkynyl examples include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C1-20 alkynyl. In certain embodiments, the alkynyl group is a substituted C1-20 alkynyl.
  • heteroalkynyl refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, 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.
  • a heteroalkynyl group refers to a group having from 1 to 150 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–150 alkynyl”).
  • a heteroalkynyl group has at least 2 carbon atoms.
  • a heteroalkynyl group refers to a group having from 100 to 150 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC100–150 alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 50 to 100 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 50–100 alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 20 to 50 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC20–50 alkynyl”).
  • a heteroalkynyl group refers to a group having from 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–20 alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–10 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–9 alkynyl”).
  • a heteroalkynyl group has 1 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–8 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–7 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–6 alkynyl”).
  • a heteroalkynyl group has 1 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–5 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“heteroC1–4 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 1–3 alkynyl”).
  • a heteroalkynyl group has 1 to 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC1–2 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 1– 6 alkynyl”).
  • 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, C 2–10 heteroalkynyl, C 2–12 heteroalkynyl, C 2–16 heteroalkynyl, C 2–20 heteroalkynyl, C 2–30 heteroalkynyl, C 2–40 heteroalkynyl, C 2–50 heteroalkynyl, C 2–60 heteroalkynyl, C2–70 heteroalkynyl, C2–80 heteroalkynyl, C2–90 heteroalkynyl, or C2–100 heteroalkynyl.
  • 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 C1-6 alkyl (e.g., –CH3)).
  • the heteroalkynyl group is an unsubstituted heteroC1–20 alkynyl.
  • the heteroalkynyl group is a substituted heteroC 1–20 alkynyl.
  • unsubstituted heteroC1 alkynyl is –C ⁇ N.
  • heteroCz1-z2 alkynyl and “C z1-z2 heteroalkynyl” are used interchangeably, wherein each of z1 and z2 is independently an integer.
  • carbocyclyl or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C 3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”).
  • a carbocyclyl group has 3 to 13 ring carbon atoms (“C 3-13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C 3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”).
  • 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 (“C 3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C 4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“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 (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), 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 (C8), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), 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-1H- indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • Exemplary C 3-8 carbocyclyl groups include the aforementioned C3-10 carbocyclyl groups as well as cycloundecyl (C11), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C 14 ), and the like.
  • 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.
  • each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3-14 carbocyclyl.
  • the carbocyclyl group is a substituted C 3-14 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”).
  • a cycloalkyl group has 3 to 10 ring carbon atoms (“C 3-10 cycloalkyl”).
  • a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”).
  • a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”).
  • a cycloalkyl group has 4 to 6 ring carbon atoms (“C 4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“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 (C 5 ).
  • C 3-6 cycloalkyl groups include the aforementioned C 5-6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • Examples of C 3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8).
  • each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl.
  • heterocyclyl or “heterocyclic” refers to a radical of a 3- to 14-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”).
  • 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.
  • each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is an unsubstituted 3–14 membered heterocyclyl.
  • the heterocyclyl group is a substituted 3–14 membered heterocyclyl.
  • 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.
  • 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”).
  • 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”).
  • 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”).
  • the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • 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.
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl.
  • Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl.
  • Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]di
  • 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 ⁇ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
  • aromatic ring system e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms (“C 14 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.
  • each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
  • the aryl group is an unsubstituted C6-14 aryl.
  • the aryl group is a substituted C6-14 aryl.
  • 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 ⁇ 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”).
  • 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. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • 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.
  • 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.
  • 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”).
  • 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”).
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”).
  • the 5-6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.
  • 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.
  • halo or “halogen” refers to fluorine (fluoro, ⁇ F), chlorine (chloro, ⁇ Cl), bromine (bromo, ⁇ Br), or iodine (iodo, ⁇ I).
  • alkoxy refers to an -O-alkyl substituent. Affixing the suffix “-ene” to a group indicates the resulting group is a polyvalent (e.g., divalent, trivalent, or tetravalent) moiety.
  • unsubstituted C 1 heteroalkylene is –OCH 2 – or –CH 2 O–.
  • unsubstituted C2 heteroalkylene is –OCH2CH2– or –CH2CH2O–.
  • unsubstituted C 4 heteroalkylene is –(OCH 2 CH 2 ) 2 – or –(CH 2 CH 2 O) 2 –.
  • unsubstituted C6 heteroalkylene is –(OCH2CH2)3– or –(CH2CH2O)3–.
  • unsubstituted C8 heteroalkylene is –(OCH2CH2)4– or –(CH2CH2O)4–.
  • unsubstituted C 10 heteroalkylene is –(OCH 2 CH 2 ) 5 – or –(CH 2 CH 2 O) 5 –.
  • unsubstituted C 12 heteroalkylene is –(OCH 2 CH 2 ) 6 – or –(CH 2 CH 2 O) 6 –.
  • a group is optionally substituted unless expressly provided otherwise.
  • the term “optionally substituted” refers to being substituted or unsubstituted.
  • 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).
  • 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.
  • 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.
  • each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C 1-6 alkyl, ⁇ OR aa , ⁇ SR aa , ⁇ N(R bb ) 2 , –CN, –SCN, or –NO2.
  • each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C1–10 alkyl, ⁇ OR aa , ⁇ SR aa , ⁇ N(R bb ) 2 , –CN, –SCN, or –NO 2 , wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-
  • each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C 1-6 alkyl or a nitrogen protecting group.
  • the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”).
  • Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999.
  • each nitrogen protecting group is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o- nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’- dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o- nitro
  • each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9- fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7- dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10- tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl, 2,2,2-trichlor
  • each nitrogen protecting group is independently selected from the group consisting of p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6- trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms),
  • Ts p-toluenesulfonamide
  • Mtr
  • each nitrogen protecting group is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N’-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3- diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3- dibenzyl-1,
  • two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are N,N’-isopropylidenediamine.
  • at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.
  • each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or an oxygen protecting group.
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”).
  • Oxygen protecting wherein X ⁇ , R aa , R bb , and R cc are as defined herein.
  • Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999.
  • each oxygen protecting group is selected from the group consisting of methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclohexyl
  • At least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.
  • each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a sulfur protecting group.
  • the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”).
  • 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.
  • 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. Barry Sharpless in 2001 and tailored to generate substances quickly and reliably by joining small units together through coupling reactions.
  • 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).
  • 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)
  • Diels–Alder reactions
  • 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.
  • 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • 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.
  • 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, per
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1–4 alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19.
  • Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • 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.
  • 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,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • prodrug refers to a compound that may be converted under physiological conditions or by solvolysis to a conjugate described herein.
  • the prodrug may be a precursor of the conjugate 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 conjugate, may be active.
  • the prodrug may offer advantages, such as higher solubility, higher permeability, higher absorption, improved distribution, improved metabolism, improved excretion, higher exposure, higher tissue compatibility, slower delivery, more sustained delivery, lower toxicity, and/or wider therapeutic window (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp.7-9, 21-24 (Elsevier, Amsterdam).
  • prodrugs as Novel Delivery Systems
  • A.C.S. Symposium Series Vol.14
  • Bioreversible Carriers in Drug Design ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • PG protecting group
  • 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” Top. Curr. Chem., 2015, 360:115-160.
  • the prodrug is a prodrug of any of the formulae described herein.
  • 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.
  • 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)).
  • primate e.g., cynomolgus monkey or rhesus monkey
  • commercially relevant mammal e.g., cattle, pig, horse, sheep, goat, cat, or dog
  • bird e.g., commercially relevant bird, such as
  • 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.
  • patient refers to a human subject in need of treatment of a disease.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a pharmaceutical composition thereof, in or on a subject.
  • treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein.
  • 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.
  • 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.
  • 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.
  • condition “disease,” and “disorder” are used interchangeably.
  • 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.
  • an effective amount is a therapeutically effective amount.
  • an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • 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.
  • 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.
  • 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.
  • the prophylactically effective amount is an amount that improves overall prophylaxis and/or enhances the prophylactic efficacy of another prophylactic agent.
  • composition means a mixture of substances.
  • pharmaceutical composition means a composition suitable for administering to a subject.
  • T he symbol “ ” denotes the point of attachment of a chemical moiety to the remainder of a compound or chemical formula.
  • 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 (i.e., it contains carbon). The small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.).
  • 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.
  • 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.
  • the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S.
  • the small molecule may also be complexed with one or more metal atoms and/or metal ions.
  • 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.
  • the small molecule is a drug.
  • 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.
  • peptide 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.
  • a peptide comprises between 2 and 10, between 11 and 20, between 21 and 30, between 31 and 40, or between 41 and 50, inclusive, amino acid residues.
  • 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.
  • 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 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 farnesyl group, an isofarnesyl 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.
  • 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.
  • RNA ribonucleic acids
  • DNA deoxyribonucleic acids
  • oligomeric compound or “oligomer” means a compound that consists of a small number of linked (e.g., covalently linked) subunits.
  • subunit refers to an amino acid (e.g., protected or unprotected amino acid) or peptide bond.
  • “subunit” refers to a nucleotide, nucleoside, nucleobase, internucleosidic linker, or sugar, or a modified nucleotide, nucleoside, nucleobase, internucleosidic linker, or sugar, or a combination thereof (e.g., a combination of nucleobase, internucleosidic linker, or sugar, each of which may be modified or unmodified).
  • the small number may be between 6 and 100, inclusive.
  • 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.
  • 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.
  • 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 mDNA), 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 lncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-
  • RNAi compounds include double-stranded compounds (e.g., short- interfering 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).
  • RISC RNA- induced silencing complex
  • 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.
  • RNAi is meant to be equivalent to other terms used to describe sequence-specific RNA interference.
  • an oligonucleotide comprises 6-100 nucleotides and nucleosides.
  • 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. In certain embodiments, the oligonucleotide strand comprises between 14 and 23, inclusive, nucleosides. In certain embodiments, the oligonucleotide strand comprises between 10 and 30, inclusive, nucleosides.
  • the oligonucleotide strand comprises between 14 and 23, inclusive, nucleosides.
  • a double-stranded oligonucleotide may comprise “blunt ends” or “overhangs.”
  • 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.
  • an oligonucleotide has blunt ends at both ends.
  • an oligonucleotide has overhangs at each end.
  • an oligonucleotide has a blunt end at one end and an overhang at the other end.
  • the oligonucleotide comprises between 6 and 8, between 9 and 11, 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.
  • the term “nucleobase” refers to a nitrogen-containing moiety at the 1′ position of a nucleoside. Nucleobases may include purine bases and pyrimidine bases.
  • nucleobases 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.
  • nucleobase sequence means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage.
  • 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).
  • the terms “internucleoside linkage,” “internucleoside linker,” “internucleosidic linkage,” and “internucleosidic linker” are used interchangeably.
  • target nucleic acid all mean a nucleic acid capable of being targeted by oligonucleotides (e.g., a radical of a ligand included in the oligonucleotides) described herein.
  • 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.
  • antisense oligonucleotide 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.
  • the antisense strand does not carry a translatable code in the 5′ to 3′ direction.
  • 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.
  • the antisense strand and the sense strand or target nucleic acid are completely complementary (100% complementary) to one another.
  • miRNA 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.
  • RNAs ribonucleic acids
  • the primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce a stem-loop precursor miRNA (pre-miRNA) approximately 70 nucleotides in length, which is further processed in the RNAi pathway.
  • pre-miRNA stem-loop precursor miRNA
  • 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 (i.e., partial complementarity) with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA.
  • RISC RNA-induced silencing complex
  • miRNA 3′ untranslated region
  • UTR 3′ untranslated region
  • miRNA may be used herein to refer to any form of the subject miRNA (e.g., precursor, primary, and/or mature miRNA).
  • small interfering RNA refers 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 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.
  • a miRNA-loaded RISC complex scans cytoplasmic mRNAs for potential complementarity (e.g., partial complementarity).
  • complementarity e.g., partial complementarity
  • the term “circular RNA” (“circRNA”) refers to an RNA that is covalently closed (i.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.
  • 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.
  • 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.
  • ADAR recruiting compound 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.
  • an ADAR targeting compound comprises an ADAR recruiting compound and a single-stranded guide nucleic acid.
  • an ADAR targeting compound comprises a double-stranded RNA duplex and a single-stranded guide nucleic acid.
  • the target sequence is at, adjacent to, or in proximity to, a location where it is desirable to modulate ADAR concentration.
  • the level of complementarity is sufficient to facilitate binding (e.g., annealing) of the single-stranded guide nucleic acid to the target sequence.
  • “Modified oligonucleotide” means an oligonucleotide, wherein at least one sugar, nucleobase, or internucleoside linkage is modified.
  • the modification may be any of those described in the present disclosure or known in the art.
  • the modification may be by chemical means, enzymatic means, and/or biological means.
  • the modification may be substitution with a chemical moiety.
  • the modification may be replacement with a chemical moiety.
  • Nucleobase sequence means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage.
  • 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 “duplex oligomeric compound.” The oligonucleotides of each oligomeric compound of an oligomeric duplex may include non-complementary overhanging nucleosides.
  • 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.
  • ligand refers to a substance that binds to or otherwise interacts with a protein, nucleic acid, or other biological molecule.
  • a ligand is selected from the group consisting of small molecules; saccharides; 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.
  • a ligand is a small molecule.
  • a ligand binds to a protein (e.g., a receptor).
  • a ligand binds to an ⁇ 4 ⁇ 1/7 integrin receptor.
  • 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.
  • a ligand is capable of targeting an oligonucleotide (e.g., an oligonucleotide strand thereof) to the muscle of a subject.
  • a ligand is capable of targeting an oligonucleotide (e.g., an oligonucleotide strand thereof) to a muscle.
  • a ligand is not a lipid.
  • ⁇ 4 ⁇ 1/7 integrin receptor refers to heterodimeric integrin receptors formed by association of integrin alpha 4 and integrin beta 1 (i.e., the ⁇ 4 ⁇ 1 integrin receptor) and/or integrin alpha 4 and integrin beta 7 (i.e., the ⁇ 4 ⁇ 7 integrin receptor).
  • the ⁇ 4 ⁇ 1/7 integrin receptor ligand has a higher binding affinity for ⁇ 4 ⁇ 1 integrin receptor than ⁇ 4 ⁇ 7 integrin receptor.
  • the ⁇ 4 ⁇ 1/7 integrin receptor ligand has a higher binding affinity for ⁇ 4 ⁇ 7 integrin receptor than ⁇ 4 ⁇ 1 integrin receptor.
  • the term “internal position” of an oligonucleotide strand refers to a position of the oligonucleotide strand other than the 5′ or 3′ nucleoside.
  • the internal position is at an internucleoside linkage (e.g., the internucleoside linkage between the 5′ nucleoside and the second nucleoside counted from the 5′ end; the internucleoside linkage between the 3′ nucleoside and the second nucleoside counted from the 3′ end; the internucleoside linkage between the first n and n+1 nucleosides counted from the 5′ end, wherein n is an integer between 1 and 20, inclusive, as the number of nucleosides of the oligonucleotide strand permits).
  • an internucleoside linkage e.g., the internucleoside linkage between the 5′ nucleoside and the second nucleoside counted from the 5′ end; the internucleoside linkage between the 3′ nucleoside and the second nucleoside counted from the 3′ end; the internucleoside linkage between the first n and n+1 nucleosides counte
  • 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.”
  • 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 fatty acyl may be a fatty acid or conjugate, octadecanoid, eicosanoid, docosanoid, fatty alcohol, fatty aldehyde, fatty ester, fatty amide, fatty nitrile, fatty ether, hydrocarbon, oxygenated hydrocarbon, or fatty acyl glycoside.
  • a glycerolipid may be a monoradylglycerol, diradylglycerol, triradylglycerol, glycosylmonoradylglycerol, glycosyldiradylglycerol, betaine monoradylglycerol, or betaine diradylglycerol.
  • a glycerophospholipid may be a glycerophosphocholine, glycerophosphoethanolamine, glycerophosphoserine, glycerophosphoglycerol, glycerophosphoglycerophosphate, glycerophosphoinositol, glycerophosphoinositol monophosphate, glycerophosphoinositol bisphosphate, glycerophosphoinositol trisphosphate, glycerophosphate, glyceropyrophosphate, glycerophosphoglycerophosphoglycerol, CDP-glycerol, glycosylglycerophospholipid, glycerophosphoinositolglycan, glycerophosphonocholine, glycerophosphonoethanolamine, di- glycerol tetraether phospholipid, glycerol-nonitol tetraether phospholipid, oxidized glycer
  • 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.
  • lipid includes, e.g., cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1- pyrene butyric acid, dihydrotestosterone, 1,3-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.
  • cholesterol e.g., cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1- pyrene butyric acid, dihydrotestosterone, 1,3-bis-O(hex
  • 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 C 7 -C 36 (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.
  • the term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.
  • the phrases “in certain embodiments” and “in some embodiments” are used interchangeably.
  • the present disclosure provides methods of treating a muscle disease in a subject in need thereof comprising administering to the subject an effective amount of a conjugate of Formula I: (A)y–L–(R 1 )r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one instance of A is a radical of an ⁇ 4 ⁇ 1/7 integrin ligand; L is a linker; each instance of R 1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6.
  • y is 1, 2, 3, 4, 5, or 6
  • each instance of A is independently a radical of a ligand or lipid, provided that at least one instance of A is a radical of an ⁇ 4 ⁇ 1/7 integrin ligand
  • L is a linker
  • each instance of R 1 is independently a radical of a pharmaceutical agent
  • r is 1, 2, 3, 4, 5,
  • the present disclosure provides uses of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for treating a muscle disease in a subject in need thereof.
  • the present disclosure provides the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use in treating a muscle disease in a subject in need thereof.
  • the present disclosure provides methods of preventing a muscle disease in a subject in need thereof comprising administering to the subject an effective amount of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof.
  • the present disclosure provides uses of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for preventing a muscle disease in a subject in need thereof.
  • the present disclosure provides the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use in preventing a muscle disease in a subject in need thereof.
  • the present disclosure provides methods of diagnosing a muscle disease in a subject in need thereof comprising administering to the subject an effective amount of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof.
  • the present disclosure provides uses of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for diagnosing a muscle disease in a subject in need thereof.
  • the present disclosure provides the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use in diagnosing a muscle disease in a subject in need thereof.
  • the present disclosure provides methods for delivering a pharmaceutical agent to a muscle of a subject comprising administering to the subject the conjugate, or a pharmaceutically acceptable salt or prodrug thereof.
  • the present disclosure provides uses of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for delivering a pharmaceutical agent to a muscle of a subject.
  • the present disclosure provides the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use in delivering a pharmaceutical agent to a muscle of a subject.
  • conjugate refers to a conjugate, or a pharmaceutically acceptable salt or prodrug thereof.
  • conjugate refers to a conjugate, or a pharmaceutically acceptable salt thereof.
  • r is 1. In certain embodiments, r is 2, 3, 4, 5, or 6.
  • y is 1. In certain embodiments, y is 2, 3, 4, 5, or 6.
  • at least one instance of A is a radical of a lipid. In certain embodiments, at least two instances of A are independently a radical of a lipid. In certain embodiments, at least two instances of A are independently a radical of a ligand.
  • the conjugate is of Formula I-A: , (I-A) or a pharmaceutically acceptable salt or prodrug thereof, wherein: is a radical of an oligonucleotide strand; s1 instances of the nucleobase-sugar moieties at internal positions of are independently replaced with a moiety of Formula A: (A); s1 is 0, 1, 2, 3, 4, 5, or 6; when s1 is 1, 2, 3, 4, 5, or 6: each instance of N 1 is independently a radical of a nucleobase or a bond; each instance of t1 is independently 1, 2, or 3; each instance of y1 and y2 is independently 0, 1, 2, 3, 4, 5, or 6; provided that at least one instance of y1 and y2 is 1, 2, 3, 4, 5, or 6; each instance of A 1 and A 2 , when present, is independently a radical of a ligand or lipid; when y1 of an instance of is 0, L 1 thereof is hydrogen, halogen, substituted or unsubstituted alky
  • each instance of R c is independently 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;
  • L 4 independently replaced with (A 4 )y 4 .
  • vl is 0, 1, 2, 3, 4, 5, or 6; each instance of L A and L 4 , when present, is independently a linker; each instance of y4, when present, is independently 1, 2, 3, 4, 5, or 6; each instance of A 4 , when present, is independently a radical of a ligand or lipid; each instance of y5 and y6 is independently 0, 1, 2, 3, 4, 5, or 6; when y5 is 0, L 5 is hydrogen, substituted or unsubstituted, Ci-6 alkyl, or an oxygen protecting group; or when y5 is 1, 2, 3, 4, 5, or 6, L 5 is a linker; when y6 is 0, L 6 is hydrogen, substituted or unsubstituted, Ci-6 alkyl, or an oxygen protecting group; or when y6 is 1, 2, 3, 4, 5, or 6, L 6 is a linker; and each instance of A 5 and A 6 , when present, is independently a radical of a ligand or lipid; provided that at
  • At least one instance is one instance. In certain embodiments, at least one instance is two instances. In certain embodiments, at least one instance is each instance.
  • At least one instance of yl is 0. In certain embodiments, at least one instance of yl is 1. In certain embodiments, at least one instance of yl is 2, 3, 4, 5, or 6. In certain embodiments, at least one instance of yl is 2. In certain embodiments, each instance of y2, y4, y5, and y6 is 0. In certain embodiments, at least one instance of y2 is 0. In certain embodiments, at least one instance of y2 is 1. In certain embodiments, at least one instance of y2 is 2, 3, 4, 5, or 6. In certain embodiments, at least one instance of y2 is 2. In certain embodiments, each instance of y1, y4, y5 and y6 is 0. In certain embodiments, at least one instance of y4 is 0.
  • At least one instance of y4 is 1. In certain embodiments, at least one instance of y4 is 2, 3, 4, 5, or 6. In certain embodiments, at least one instance of y4 is 2. In certain embodiments, at least one instance of y1, y2, y5, and y6 is 0. In certain embodiments, at least one instance of y5 is 0. In certain embodiments, at least one instance of y5 is 1. In certain embodiments, at least one instance of y5 is 2, 3, 4, 5, or 6. In certain embodiments, at least one instance of y5 is 2. In certain embodiments, each instance of y1, y2, y4, and y6 is 0. In certain embodiments, at least one instance of y6 is 0.
  • At least one instance of y6 is 1. In certain embodiments, at least one instance of y6 is 2, 3, 4, 5, or 6. In certain embodiments, at least one instance of y6 is 2. In certain embodiments, each instance of y1, y2, y4, and y5 is 0. In certain embodiments, at least one instance of y1 is 1, and at least one instance of y2, y4, y5, and y6 is 1. In certain embodiments, at least one instance of y2 is 1, and at least one instance of y1, y4, y5, and y6 is 1. In certain embodiments, at least one instance of y4 is 1, and at least one instance of y1, y2, y5, and y6 is 1.
  • At least one instance of y5 is 1, and at least one instance of y1, y2, y4, and y6 is 1. In certain embodiments, at least one instance of y6 is 1, and at least one instance of y1, y2, y4, and y5 is 1. In certain embodiments, at least one instance of N 1 is a radical of a nucleobase. In certain embodiments, at least one instance of N 1 is a radical of adenine, cytosine, guanine, thymine or uracil. In certain embodiments, at least one instance of N 1 is a radical of a nucleobase with one or more nucleobase modifications described herein.
  • At least one instance of N 1 is a radical of a nucleobase with one nucleobase modification described herein. In certain embodiments, at least one instance of N 1 is a radical of a nucleobase with two or three nucleobase modifications described herein. In certain embodiments, at least one instance of N 1 is a bond. In certain embodiments, at least one instance of t1 is 1. In some embodiments, at least one pharmaceutical agent is a therapeutic agent, prophylactic agent, or diagnostic agent. In some embodiments, at least one pharmaceutical agent is an oligonucleotide, small molecule, peptide, or protein. In some embodiments, at least one pharmaceutical agent is an antibody. In some embodiments, at least one pharmaceutical agent is a monoclonal antibody.
  • At least one pharmaceutical agent inhibits the expression of a superoxide dismutase type 1 (SOD1) gene (e.g., a human SOD1 gene).
  • SOD1 superoxide dismutase type 1
  • at least one 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 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
  • At least one oligonucleotide is an siRNA. In certain embodiments, at least one RNA is an siRNA. In certain embodiments, at least one oligonucleotide is a single-stranded oligonucleotide. In certain embodiments, at least one oligonucleotide is a double-stranded oligonucleotide comprising a sense oligonucleotide strand and an antisense oligonucleotide strand. In certain embodiments, the oligonucleotide strand is the sense oligonucleotide strand.
  • the oligonucleotide strand is the antisense oligonucleotide strand.
  • an oligonucleotide strand has a nucleobase sequence that is at least partially complementary to a target nucleic acid sequence (e.g., an expressed target nucleic acid within a cell).
  • the oligonucleotide upon delivery to a cell expressing a target nucleic acid, is able to modify the expression of the underlying gene.
  • the oligonucleotide, upon delivery to a cell expressing a target nucleic acid is able to inhibit the expression of the underlying gene.
  • 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 internucleoside linkages), or a combination thereof.
  • an oligonucleotide comprises a ribonucleic acid (RNA).
  • an oligonucleotide comprises a deoxyribonucleic acid (DNA).
  • an oligonucleotide comprises a modification (e.g., modified nucleobase, modified sugar, or modified internucleoside linkage).
  • a strand of at least one oligonucleotide has 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 identity to SEQ ID NO.: 2, 4, 5, or 6.
  • a strand of at least one oligonucleotide has at least 80%, at least 85%, at least 90%, or at least 95% identity to SEQ ID NO.: 2, 4, 5, or 6.
  • an oligonucleotide is double-stranded (e.g., comprised of two single-stranded nucleic acids).
  • 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 complementary to the first oligonucleotide strand.
  • the first and second oligonucleotide strands can be independently modified.
  • the first oligonucleotide strand is linked to one or more radicals of ligands (e.g., ⁇ 4 ⁇ 1/7 integrin receptor ligands).
  • the second oligonucleotide strand is linked to one or more radicals of ligands (e.g., ⁇ 4 ⁇ 1/7 integrin receptor ligands).
  • a conjugate comprises one or more radicals of ligands at one or more internal positions.
  • a conjugate comprises one or more radicals of ligands at one or more internal positions.
  • a conjugate comprises one or more radicals of ligands at a nucleobase.
  • a conjugate comprises one or more radicals of ligands at the 1′ position of a nucleoside.
  • a conjugate comprises one or more radicals of ligands at the 2′ position of a nucleoside. In certain embodiments, a conjugate comprises one or more radicals of ligands at the 3′ position of a nucleoside. In certain embodiments, a conjugate comprises one or more radicals of ligands at the 5′ position of a nucleoside.
  • 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, 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, 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, 95, 96, 97, 98, 99, or 100 nucleotides in length.
  • 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.
  • 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).
  • an antisense oligonucleotide strand is complementary to a pre-mRNA.
  • an antisense oligonucleotide strand blocks translation and promotes degradation of the mRNA transcript.
  • an oligonucleotide comprises a sense oligonucleotide strand having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity to a gene described herein. In certain embodiments, an oligonucleotide comprises a sense oligonucleotide strand having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% complementarity to a gene described herein.
  • 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).
  • a linker comprises in the backbone thereof amide, ester, disulfide, or a combination thereof.
  • a linker comprises in the backbone thereof hydrazone, oxime, imine, guanidine, urea, carbamate, alkyl, sulfonamide, heterocyclic, or a combination thereof.
  • 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.
  • a linker is substituted with one, two, three, four, five, six, seven, eight, nine, ten, or more than ten substituents.
  • a linker is a bond (e.g., a single bond).
  • a linker is optionally substituted alkylene.
  • a terminal backbone carbon atom of alkylene is an attachment point.
  • an internal backbone carbon atom of alkylene is an attachment point.
  • a linker is optionally substituted alkenylene.
  • a linker is optionally substituted alkynylene.
  • a linker is substituted or unsubstituted, C1-150 alkylene, substituted or unsubstituted, C 2-150 alkenylene, or substituted or unsubstituted, C 2-150 alkynylene.
  • one or more (e.g., two, three, or four) backbone atoms of the C 1-150 alkylene, C2-150 alkenylene, or C2-150 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.
  • a linker is substituted or unsubstituted, C1-100 alkylene, substituted or unsubstituted, C2-100 alkenylene, or substituted or unsubstituted, C2-100 alkynylene.
  • one or more (e.g., two, three, or four) backbone atoms of the Ci-100 alkylene, C2-100 alkenylene, or C2- 100 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.
  • a linker is substituted or unsubstituted, C7-70 alkylene, substituted or unsubstituted, C7-70 alkenylene, or substituted or unsubstituted, C7-70 alkynylene.
  • 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 arylene, or substituted or unsubstituted heteroarylene, as valency permits.
  • 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.
  • 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 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, C13-18, C19-24, C25-30, C31-36, C37-44, C45-52, C53-60, or Cei-70 alkynylene.
  • 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 alkynylene 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.
  • a linker is optionally substituted heteroalkylene.
  • a terminal backbone atom of heteroalkylene is an attachment point.
  • an internal backbone atom of hetero alkylene is an attachment point).
  • a linker is optionally substituted heteroalkenylene.
  • a linker is optionally substituted heteroalkynylene.
  • a linker is substituted or unsubstituted, Ci-150 heteroalkylene, substituted or unsubstituted, C2-150 heteroalkenylene, or substituted or unsubstituted, C2-isoheteroalkynylene.
  • one or more (e.g., two, three, or four) backbone atoms of the Ci-150 heteroalkylene, C2-150 heteroalkenylene, or C2-150 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.
  • a linker is substituted or unsubstituted, Ci-100 heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, or substituted or unsubstituted, C2-100 heteroalkynylene.
  • 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.
  • a linker is substituted or unsubstituted, C7-70 heteroalkylene, substituted or unsubstituted, C7-70 heteroalkenylene, or substituted or unsubstituted, C7-70 heteroalkynylene.
  • one or more (e.g., two, three, or four) backbone atoms of the 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.
  • one or two backbone atoms of the 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.
  • 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 heteroalkylene, substituted or unsubstituted, C1-6, C7-12, C13-18, C19-24, C25-30, C31-36, C37-44, C45-52, C53-60, or C61-70 heteroalkenylene, or substituted or unsubstituted, C2-6, C7-12, C13-18, C19-24, C25-30, C31-36, C37-44, C45-52, C53-60, or C61-70 heteroalkynylene.
  • the substituted or unsubstituted heteroarylene that replaces one of the backbone atoms is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroarylene.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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-chemistry reactive moieties.
  • the substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms is of the formula: k 21 is 0, 1, 2, 3, or 4; each instance of R d , if present, is independently halogen, substituted or unsubstituted, C 1-6 alkyl, or –O–(substituted or unsubstituted, C 1-6 alkyl); k 22 is 0, 1, 2, 3, or 4; each instance of R e , if present, is independently halogen, substituted or unsubstituted, C1-6 alkyl, or –O–(substituted or unsubstituted, C 1-6 alkyl); k 23 is an integer between 0 and 11, inclusive; each instance of R f , if present, is independently halogen, substituted or unsubstituted, C1-6 alkyl, or –O–(substituted or unsubstituted or unsub
  • the substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms may be attached at either direction.
  • the substituted or unsubstituted heteroarylene that replaces one of the backbone atoms is of the formula:
  • the substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms may be attached at any orientation.
  • the conjugate is of the formula: (I-A-16), (I-A-17), (I-A-18), or (I-A-19).
  • L 6 is attached to the 3′ end of the oligonucleotide strand.
  • L 6 is attached to the oxygen atom substituted at the 3′ position of the 3′ end of the oligonucleotide strand. In certain embodiments, L 6 is attached to the 3′ position of the 3′ end of the oligonucleotide strand. In certain embodiments, L 6 is attached to the nucleobase of the 3′ end of the oligonucleotide strand. In certain embodiments, L 6 is attached to the 1′ position of the 3′ end of the oligonucleotide strand, wherein the 3′ end is an abasic nucleoside. In certain embodiments, L 6 is attached to the 2′ position of the 3′ end of the oligonucleotide strand.
  • L 6 is attached to the oxygen atom substituted at the 2′ position of the 3′ end of the oligonucleotide strand. .
  • L 6 is substituted or unsubstituted, C 10-100 heteroalkylene.
  • L 6 comprises one or more of the following –CH 2 –, , combination of two or more of each one of the foregoing, provided that: the number of backbone atoms of L 6 is between 10 and 100, inclusive; and L 6 does not comprise O–O, O–N, N–O, or N–N.
  • the number of backbone atoms of the at least one instance of L 6 is between 10 and 100, inclusive; and the at least one instance of L 6 does not comprise O–O, O–N, N–O, or N–N.
  • a linker is optionally substituted heteroalkenylene comprising one, two, three, four, five, six, seven, eight, nine, ten, or more than ten double bonds.
  • a linker is optionally substituted heteroalkynylene comprising one, two, three, four, five, six, seven, eight, nine, ten, or more than ten triple bonds.
  • 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.
  • optionally substituted heteroalkylene is optionally substituted polyethylene glycol (optionally substituted PEG).
  • a terminal backbone atom of the PEG is an attachment point.
  • an internal backbone atom of the PEG is an attachment point.
  • a linker comprises one or more PEG repeating units (–OCH 2 CH 2 – or –CH 2 CH 2 O–).
  • 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. 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 ⁇ , ⁇ -unsaturated- carbonyl. In some embodiments, the Michael donor is –SH.
  • the Michael acceptor i is substituted or unsubstituted, C 1-100 alkylene, substituted or unsubstituted, C 2-100 alkenylene, substituted or unsubstituted, C 2-100 alkynylene, substituted or unsubstituted, C1-100 heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, or substituted or unsubstituted, C2-100 heteroalkynylene; optionally wherein one or more backbone atoms of the C 1-100 alkylene, C 2-100 alkenylene, C2-100 alkynylene, C1-100 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 un
  • At least one instance of L is substituted or unsubstituted, C7-70 alkylene, substituted or unsubstituted, C 7-70 alkenylene, substituted or unsubstituted, C 7-70 alkynylene, substituted or unsubstituted, C 7-70 heteroalkylene, substituted or unsubstituted, C 7-70 heteroalkenylene, or substituted or unsubstituted, C7-70 heteroalkynylene; optionally wherein one, two, three, or four backbone atoms of the C7-70 alkylene, C7-70 alkenylene, C 7-70 alkynylene, C 7-70 heteroalkylene, C 7-70 heteroalkenylene, or C 7-70 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted
  • At least one instance of L is substituted or unsubstituted, C7-70 alkylene or substituted or unsubstituted, C7-70 heteroalkylene; and one, two, three, or four backbone atoms of the C 7-70 alkylene or C 7-70 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.
  • at least one instance of L is substituted or unsubstituted, C 7-70 heteroalkylene.
  • At least one instance of L comprises one or more of the following – combination of two or more of each one of the foregoing, provided that: the number of backbone atoms of the at least one instance of L 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 at least one instance of L does not comprise O–O, O–N, N–O, or N–N.
  • At least one instance of L comprises one or more of the following – combination of two or more of each one of the foregoing, provided that: the number of backbone atoms of the at least one instance of L is between 7 and 70, inclusive; and the at least one instance of L does not comprise O–O, O–N, N–O, or N–N.
  • At least one instance of L comprises one or more of the following – the number of backbone atoms of the at least one instance of L is between 7 and 70, inclusive; the at least one instance of L does not comprise O–O, O–N, N–O, or N–N; and the combined number the linker is between 0 and 4, inclusive.
  • at least one instance of L is a combination of –CH 2 –, , at: the number of backbone atoms of the at least one instance of L is between 10 and 100, inclusive; and the at least one instance of L does not comprise O–O, O–N, N–O, or N–N.
  • a linker comprises a cleavable bond or moiety.
  • a linker does not comprise a cleavable bond or moiety.
  • a linker comprises a covalent attachment to a solid support.
  • a linker includes multiple positions for attachment of radicals of ligands.
  • the linker comprises a peptide in the backbone of the linker.
  • the peptide comprises 1-5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, or 36- 40, inclusive, amino acids.
  • a linker comprises a polyradical of: pyrrolidine, 8-amino-3,6- dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC), 6-aminohexanoic acid ( ⁇ or AHA), or a combination thereof.
  • At least one instance of R a is independently hydrogen or substituted or unsubstituted, C 1-6 alkyl. In some embodiments, each instance of R a is independently hydrogen or substituted or unsubstituted, C 1-6 alkyl. In certain embodiments, each instance of R a is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of L B1 , L B2 , and L B6 is independently a single bond, substituted or unsubstituted, C 1-20 alkylene or substituted or unsubstituted, C 1-20 heteroalkylene.
  • each of L B1 , L B2 , and L B6 is independently substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L B1 , L B2 , and L B6 is independently unsubstituted C 1-10 alkylene. In certain embodiments, each of L B1 , L B2 , and L B6 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, each of L C1 and L C2 are independently a single bond.
  • each of L C1 and L C2 are independently substituted or unsubstituted heteroarylene that replaces one of the backbone atoms. In certain embodiments, each of L C1 and L C2 are independently (which may be attached at either direction).
  • y1 of an instance of is 0, and L 1 thereof is hydrogen, halogen, substituted or unsubstituted, C1-6 alkyl, –OR b , or –N(R b )2. In certain embodiments, y1 of an instance of is 0, and L 1 thereof is hydrogen, halogen, or substituted or unsubstituted, C 1-6 alkyl. In certain embodiments, y1 of an instance of is 0, and L 1 thereof is hydrogen. In some embodiments, each instance of R b is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In certain embodiments, each instance of R b is independently hydrogen.
  • each instance of R b is independently unsubstituted alkyl. In certain embodiments, each instance of R b is independently CH 3 , CH 2 CH 3 , or CH 2 CH 2 CH 3 . In some embodiments, y1 of an instance of is 1, 2, 3, 4, 5, or 6, and L 1 thereof is substituted or unsubstituted, C 1-100 alkylene, substituted or unsubstituted, C 2-100 alkenylene, substituted or unsubstituted, C2-100 alkynylene, substituted or unsubstituted, C1-100 heteroalkylene, substituted or unsubstituted, C 2-100 heteroalkenylene, or substituted or unsubstituted, C 2-100 heteroalkynylene; optionally wherein one or more backbone atoms of the C1-100 alkylene, C2-100 alkenylene, C2-100 alkynylene, C1-100 heteroalkylene, C2-100 heteroalkenylene, or C2-100 hetero
  • y1 of an instance of is 1, 2, 3, 4, 5, or 6, and L 1 thereof is substituted or unsubstituted, C7-70 alkylene, substituted or unsubstituted, C7-70 alkenylene, substituted or unsubstituted, C 7-70 heteroalkylene, or substituted or unsubstituted, C 7- 70 heteroalkenylene; optionally wherein one, two, three, or four backbone atoms of the C7-70 alkylene, C7-70 alkenylene, C 7-70 heteroalkylene, or C 7-70 heteroalkenylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.
  • y1 of an instance of is 1, 2, 3, 4, 5, or 6, and L 1 thereof is substituted or unsubstituted, C 7-70 alkylene or substituted or unsubstituted, C 7-70 heteroalkylene; and one, two, three, or four 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.
  • each instance of R a is independently hydrogen or substituted or unsubstituted, C 1-6 alkyl. In certain embodiments, each instance of R a is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of L 1B1 and L 1B2 is independently a single bond, substituted or unsubstituted, C 1-20 alkylene or substituted or unsubstituted, C 1-20 heteroalkylene. In some embodiments, each of L 1B1 and L 1B2 is independently substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene.
  • each of L 1B1 and L 1B2 is independently unsubstituted C 1-10 alkylene. In certain embodiments, each of L 1B1 and L 1B2 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, L 1C1 is a single bond. In certain embodiments, L 1C1 is substituted or unsubstituted heteroarylene that replaces one of the backbone atoms. In certain embodiments, L 1C1 is (which may be attached at either direction). In some embodiments, L 1 thereof is of the formula: .
  • y1 of an instance of is 1, 2, 3, 4, 5, or 6, and L 1 thereof comprises one or more of the following –CH2–, , , –O–, –CH2CH2O–, – combination of two or more of each one of the foregoing, provided that: the number of backbone atoms of L 1 thereof is between 7 and 70, inclusive; and L 1 thereof does not comprise O–O, O–N, N–O, or N–N.
  • y2 of an instance of is 1, 2, 3, 4, 5, or 6, and L 2 thereof is substituted or unsubstituted, C1-100 alkylene, substituted or unsubstituted, C2-100 alkenylene, substituted or unsubstituted, C 2-100 alkynylene, substituted or unsubstituted, C 1-100 heteroalkylene, substituted or unsubstituted, C 2-100 heteroalkenylene, or substituted or unsubstituted, C2-100 heteroalkynylene; optionally wherein one or more backbone atoms of the C1-100 alkylene, C2-100 alkenylene, C 2-100 alkynylene, C 1-100 heteroalkylene, C 2-100 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 un
  • y2 of an instance of is 1, 2, 3, 4, 5, or 6, and L 2 thereof is substituted or unsubstituted, C7-70 alkylene, substituted or unsubstituted, C7-70 alkenylene, substituted or unsubstituted, C7-70 heteroalkylene, or substituted or unsubstituted, C7- 70 heteroalkenylene; optionally wherein one, two, or three backbone atoms of the C 7-70 alkylene, C 7-70 alkenylene, C7-70 heteroalkylene, or C7-70 heteroalkenylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.
  • y2 of an instance of is 1, 2, 3, 4, 5, or 6, and L 2 thereof is substituted or unsubstituted, C 7-70 alkylene or substituted or unsubstituted, C 7-70 heteroalkylene; and one, two, or three 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.
  • at least one instance of is of the formula: . In certain embodiments, at least one instance of is of the .
  • At least one instance of is of the formula:
  • at least one instance of R a is independently hydrogen or substituted or unsubstituted, C1-6 alkyl.
  • each instance of R a is independently hydrogen or substituted or unsubstituted, C 1-6 alkyl. In certain embodiments, each instance of R a is independently hydrogen or unsubstituted C 1-6 alkyl.
  • each of L 2B1 and L 2B2 is independently a single bond, substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L 2B1 and L 2B2 is independently substituted or unsubstituted, C 1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene.
  • each of L 2B1 and L 2B2 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L 2B1 and L 2B2 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, L 2C1 is a single bond. In certain embodiments, L 2C1 is substituted or unsubstituted heteroarylene that replaces one of the backbone atoms. In certain embodiments, L 2C1 is (which may be attached at either direction). In certain embodiments, y2 of an instance of is 0, L 2 thereof is a sugar modification described herein.
  • y2 of an instance of is 0, L 2 thereof is –OCH3, F, or –CH3.
  • s1 is 1, 2, 3, 4, 5, or 6, at least one instance of y20, and the L 2 thereof is –OH, –OCH 3 , or F.
  • at least one instance of is of the formula: .
  • At least one instance of R a is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In some embodiments, each instance of R a is independently hydrogen or substituted or unsubstituted, C 1-6 alkyl. In certain embodiments, each instance of R a is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of L 2B3 , L 2B4 , L 2B5 , L 2B6 , L 2B7 , and L 2B8 is independently a single bond, substituted or unsubstituted, C 1-20 alkylene or substituted or unsubstituted, C 1-20 heteroalkylene.
  • each of L 2B3 , L 2B4 , L 2B5 , L 2B6 , L 2B7 , and L 2B8 is independently substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L 2B3 , L 2B4 , L 2B5 , L 2B6 , L 2B7 , and L 2B8 is independently unsubstituted C 1-10 alkylene.
  • each of L 2B3 , L 2B4 , L 2B5 , L 2B6 , L 2B7 , and L 2B8 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats.
  • each of L 2C2 and L 2C3 is independently a single bond.
  • each of L 2C2 and L 2C3 is independently substituted or unsubstituted heteroarylene that replaces one of the backbone atoms.
  • each of L 2C2 and L 2C3 is independently (which may be attached at either direction). In some embodiments, at least one instance the formula:
  • at least one instance of –L 2A17 –L 2A18 – is –O–.
  • y2 of an instance of is 1, 2, 3, 4, 5, or 6, and L 2 thereof is substituted or unsubstituted, C 7-70 heteroalkylene.
  • y2 of an instance of is 1, 2, 3, 4, 5, or 6, and L 2 thereof comprises one or more of the following –CH 2 –, , , –O–, –CH 2 CH 2 O–, – , or a combination of two or more of each one of the foregoing, provided that: the number of backbone atoms of L 2 thereof is between 7 and 70, inclusive; and L 2 thereof does not comprise O–O, O–N, N–O, or N–N.
  • At least one instance of L 2 is a combination of –CH2–, , at: the number of backbone atoms of the at least one instance of L 2 is between 10 and 100, inclusive; and the at least one instance of L 2 does not comprise O–O, O–N, N–O, or N–N.
  • the conjugate is of the formula: (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-8), or (I-A-9).
  • At least one instance of the internucleosidic linkers is between the first n and n+1 nucleoside of the oligonucleotide strand counted from the 5’ end; and n is an integer between 1 and 20, inclusive, as the number of nucleosides of the oligonucleotide strand permits. In certain embodiments, at least one instance between the first n and n+1 nucleosides of the oligonucleotide strand counted from the 5’ end; and n is an integer between 1 and 20, inclusive, as the number of nucleosides of the oligonucleotide strand permits.
  • At least one instance of Z A1 is substituted or unsubstituted, C1-6 alkylene. In some embodiments, at least one instance of Z A1 is substituted or unsubstituted, C1-3 alkylene. In certain embodiments, at least one instance of Z A1 is unsubstituted C 1-3 alkylene. In some embodiments, at least one instance of Z A2 is substituted or unsubstituted, C1-6 alkylene. In some embodiments, at least one instance of Z A2 is substituted or unsubstituted, C1-3 alkylene. In certain embodiments, at least one instance of Z A2 is unsubstituted C 1-3 alkylene.
  • each instance of R c is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.
  • At least one instance of L A is of the formula . .
  • at least one instance of L 4 is substituted or unsubstituted, C1-100 alkylene, substituted or unsubstituted, C 2-100 alkenylene, substituted or unsubstituted, C 2-100 alkynylene, substituted or unsubstituted, C 1-100 heteroalkylene, substituted or unsubstituted, C 2-100 heteroalkenylene, or substituted or unsubstituted, C2-100 heteroalkynylene; optionally wherein one or more backbone atoms of the C1-100 alkylene, C2-100 alkenylene, C 2-100 alkynylene, C 1-100 heteroalkylene, C 2-100 heteroalkenylene, or C 2-100 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted
  • At least one instance of L 4 is substituted or unsubstituted, C7-70 alkylene, substituted or unsubstituted, C7-70 alkenylene, substituted or unsubstituted, C7-70 alkynylene, substituted or unsubstituted, C 7-70 heteroalkylene, substituted or unsubstituted, C 7-70 heteroalkenylene, or substituted or unsubstituted, C7-70 heteroalkynylene; optionally wherein one, two, three, or four backbone atoms of the C7-70 alkylene, C7-70 alkenylene, C 7-70 alkynylene, C 7-70 heteroalkylene, C 7-70 heteroalkenylene, or C 7-70 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substitute
  • At least one instance of L 4 is substituted or unsubstituted, C 7-70 alkylene or substituted or unsubstituted, C7-70 heteroalkylene; and one, two, three, or four 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.
  • At least one instance of R a is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In some embodiments, each instance of R a is independently hydrogen or substituted or unsubstituted, C 1-6 alkyl. In certain embodiments, each instance of R a is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of L 4B1 , L 4B2 , and L 4B3 is independently a single bond, substituted or unsubstituted, C 1-20 alkylene or substituted or unsubstituted, C 1-20 heteroalkylene.
  • each of L 4B1 , L 4B2 , and L 4B3 is independently substituted or unsubstituted, C 1- 10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L 4B1 , L 4B2 , and L 4B3 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L 4B1 , L 4B2 , and L 4B3 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, each of L 4C1 and L 4C2 is independently a single bond.
  • each of L 4C1 and L 4C2 is independently substituted or unsubstituted heteroarylene that replaces one of the backbone atoms. In certain embodiments, each of L 4C1 and L 4C2 is independently (which may be attached at either direction).
  • At least one instance thereof is each of –L 4A21 –L 4A22 –, –L 4A23 –L 4A24 –, –L 4A25 –L 4A26 –, –L 4A27 –L 4A28 –, –L 4A29 –L 4A30 –, – L 4A31 –L 4A32 –, –L 4A33 –L 4A34 –, –L 4A35 –L 4A36 –, –L 4A37 –L 4A38 –, –L 4A39 –L 4A40 –, –L 4A41 –L 4A42 –, – L 4A43 –L 4A44 –, –L 4A45 –L 4A46 –, –L 4A47 –L 4A48 –, and –L 4A49 –L 4A50 – is independently a single bond, — O–, –S–,
  • each of –L 4A21 –L 4A22 –, –L 4A23 –L 4A24 –, –L 4A25 –L 4A26 –, –L 4A27 – L 4A28 –, –L 4A29 –L 4A30 –, –L 4A31 –L 4A32 –, –L 4A33 –L 4A34 –, –L 4A35 –L 4A36 –, –L 4A37 –L 4A38 –, –L 4A39 – L 4A40 –, –L 4A41 –L 4A42 –, –L 4A43 –L 4A44 –, –L 4A45 –L 4A46 –, –L 4A47 –L 4A48 –, and –L 4A49 –L 4A50 — is independently a single bond, —O–, –NR a –, –C
  • At least one instance of R a is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In some embodiments, each instance of R a is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, each instance of R a is independently hydrogen or unsubstituted C 1-6 alkyl.
  • each of L 4B4 , L 4B5 , L 4B6 , L 4B7 , L 4B8 , L 4B9 , L 4B10 , L 4B11 , and L 4B12 is independently a single bond, substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene.
  • each of L 4B4 , L 4B5 , L 4B6 , L 4B7 , L 4B8 , L 4B9 , L 4B10 , L 4B11 , and L 4B12 is independently substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C 1-10 heteroalkylene.
  • each of L 4B4 , L 4B5 , L 4B6 , L 4B7 , L 4B8 , L 4B9 , L 4B10 , L 4B11 , and L 4B12 is independently unsubstituted C1-10 alkylene.
  • each of L 4B4 , L 4B5 , L 4B6 , L 4B7 , L 4B8 , L 4B9 , L 4B10 , L 4B11 , and L 4B12 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats.
  • each of L 4C3 , L 4C4 , L 4C5 , L 4C6 , L 4C7 , and L 4C8 is independently a single bond.
  • each of L 4C3 , L 4C4 , L 4C5 , L 4C6 , L 4C7 , and L 4C8 is independently substituted or unsubstituted heteroarylene that replaces one of the backbone atoms.
  • each of L 4C3 , L 4C4 , L 4C5 , L 4C6 , L 4C7 , and L 4C8 is independently (which may be attached at either direction).
  • at least one instance of L 4 is substituted or unsubstituted, C7-70 heteroalkylene.
  • At least one instance of L 4 comprises one or more of the bination of two or more of each one of the foregoing, provided that: the number of backbone atoms of the at least one instance of L 4 is between 10 and 100, inclusive; and the at least one instance of L 4 does not comprise O–O, O–N, N–O, or N–N.
  • at least one instance of L 4 is a combination of –CH 2 –, , at: the number of backbone atoms of the at least one instance of L 4 is between 10 and 100, inclusive; and the at least one instance of L 4 does not comprise O–O, O–N, N–O, or N–N.
  • the conjugate is of the formula: (I-A-10), (I-A-11), (I-A-12), (I-A-13), (I-A-14), or (I-A-15).
  • L 5 is attached to the 5′ end of the oligonucleotide strand.
  • L 5 is attached to the oxygen atom substituted at the 5′ position of the 5′ end of the oligonucleotide strand.
  • L 5 is attached to the 5′ position of the 5′ end of the oligonucleotide strand.
  • L 5 is attached to the nucleobase of the 5′ end of the oligonucleotide strand.
  • L 5 is attached to the 1′ position of the 5′ end of the oligonucleotide strand, wherein the 5′ end is an abasic nucleoside. In certain embodiments, L 5 is attached to the 2′ position of the 5′ end of the oligonucleotide strand. In certain embodiments, L 5 is attached to the oxygen atom substituted at the 2′ position of the 5′ end of the oligonucleotide strand.
  • L 5 is substituted or unsubstituted, C1-150 alkylene, substituted or unsubstituted, C2-150 alkenylene, substituted or unsubstituted, C2-150 alkynylene, substituted or unsubstituted, C 1-150 heteroalkylene, substituted or unsubstituted, C 2-150 heteroalkenylene, or substituted or unsubstituted, C2-150 heteroalkynylene; optionally wherein one or more backbone atoms of the C1-150 alkylene, C2-150 alkenylene, C2-150 alkynylene, C1-150 heteroalkylene, C2-150 heteroalkenylene, or C2-150 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.
  • L 5 is substituted or unsubstituted, C 10-100 alkylene, substituted or unsubstituted, C10-100 alkenylene, substituted or unsubstituted, C10-100 alkynylene, substituted or unsubstituted, C10-100 heteroalkylene, substituted or unsubstituted, C10-100 heteroalkenylene, or substituted or unsubstituted, C 10-100 heteroalkynylene; optionally wherein one, two, or three backbone atoms of the C 10-100 alkylene, C 10-100 alkenylene, C10-100 alkynylene, C10-100 heteroalkylene, C10-100 heteroalkenylene, or C10-100 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene
  • L 5 is substituted or unsubstituted, C10-100 alkylene or substituted or unsubstituted, C 10-100 heteroalkylene; and one, two, or three backbone atoms of the C10-100 alkylene or C10-100 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.
  • At least one instance of y5 is 1;
  • At least one instance of R a is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In some embodiments, each instance of R a is independently hydrogen or substituted or unsubstituted, C 1-6 alkyl. In certain embodiments, each instance of R a is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of L 5B1 , L 5B2 , and L 5B6 is independently a single bond, substituted or unsubstituted, C 1-20 alkylene or substituted or unsubstituted, C 1-20 heteroalkylene.
  • each of L 5B1 , L 5B2 , and L 5B6 is independently substituted or unsubstituted, C 1- 10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L 5B1 , L 5B2 , and L 5B6 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L 5B1 , L 5B2 , and L 5B6 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, each of L 5C1 and L 5C2 is independently a single bond.
  • At least one instance of R a is independently hydrogen or substituted or unsubstituted, C 1-6 alkyl. In some embodiments, each instance of R a is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, each instance of R a is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of L 5B1 , L 5B4 , and L 5B6 is independently substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene.
  • each of L 5B1 , L 5B4 , and L 5B6 is independently substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L 5B1 , L 5B4 , and L 5B6 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L 5B1 , L 5B4 , and L 5B6 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats.
  • each of L 5B2 , L 5B3 , L 5B5 , and L 5B7 is independently a single bond, substituted or unsubstituted, C 1-20 alkylene or substituted or unsubstituted, C 1-20 heteroalkylene. In some embodiments, each of L 5B2 , L 5B3 , L 5B5 , and L 5B7 is independently a single bond, substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L 5B2 , L 5B3 , L 5B5 , and L 5B7 is independently a single bond.
  • each of L 5B2 , L 5B3 , L 5B5 , and L 5B7 is independently unsubstituted C 1-10 alkylene. In certain embodiments, each of L 5B2 , L 5B3 , L 5B5 , and L 5B7 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, each of L 5C1 , L 5C2 , L 5C3 , and L 5C4 is independently a single bond.
  • each of L 5C1 , L 5C2 , L 5C3 , and L 5C4 is independently substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms.
  • each of L 5C1 , L 5C2 , L 5C3 , and L 5C4 is independently (which may be attached at either direction).
  • at least one instance of y5 is 2; and
  • At least one instance of y5 is 2; and is
  • At least one instance of – L 5A21 –L 5A22 – is a single bond.
  • At least one instance of R a is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In some embodiments, each instance of R a is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, each instance of R a is independently hydrogen or unsubstituted C 1-6 alkyl. In some embodiments, each of L 5B16 , L 5B19 , and L 5B21 is independently substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene.
  • each of L 5B16 , L 5B19 , and L 5B21 is independently substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C 1-10 heteroalkylene. In certain embodiments, each of L 5B16 , L 5B19 , and L 5B21 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L 5B16 , L 5B19 , and L 5B21 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats.
  • each of L 5B17 , L 5B18 , L 5B20 , and L 5B22 is independently a single bond, substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L 5B17 , L 5B18 , L 5B20 , and L 5B22 is independently a single bond, substituted or unsubstituted, C 1-10 alkylene or substituted or unsubstituted, C 1-10 heteroalkylene. In certain embodiments, each of L 5B17 , L 5B18 , L 5B20 , and L 5B22 is independently a single bond.
  • each of L 5B17 , L 5B18 , L 5B20 , and L 5B22 is independently unsubstituted C 1-10 alkylene. In certain embodiments, each of L 5B17 , L 5B18 , L 5B20 , and L 5B22 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, each of L 5C9 , L 5C10 , L 5C11 , and L 5C12 is independently a single bond.
  • each of L 5C9 , L 5C10 , L 5C11 , and L 5C12 is independently substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms.
  • each of L 5C9 , L 5C10 , L 5C11 , and L 5C12 is independently (which may be attached at either direction).
  • at least one instance of y5 is 2;
  • At least one instance of – L 5A67 –L 5A68 – is a single bond.
  • at least one instance of y5 is 3; and each of –L 5A23 –L 5A24 –, –L 5A25 –L 5A25 –, –L 5A27 –L 5A28 –, –L 5A29 –L 5A30 –, –L 5A31 –L 5A32 –, – L 5A33 –L 5A34 –, –L 5A35 –L 5A36 –, –L 5A37 –L 5A38 –, –L 5A39 –L 5A40 –, –L 5A41 –L 5A42 –, –L 5A43 –L 5A44 –, and – L 5A45 –L 5A46 — is independently a single bond, —O–, –S–, –S–S–, –
  • At least one instance of R a is independently hydrogen or substituted or unsubstituted, C 1-6 alkyl. In some embodiments, each instance of R a is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, each instance of R a is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of L 5B8 , L 5B9 , L 5B10 , L 5B11 , L 5B12 , L 5B13 , L 5B14 , and L 5B15 is independently substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene.
  • each of L 5B8 , L 5B9 , L 5B10 , L 5B11 , L 5B12 , L 5B13 , L 5B14 , and L 5B15 is independently substituted or unsubstituted, C 1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene.
  • each of L 5B8 , L 5B9 , L 5B10 , L 5B11 , L 5B12 , L 5B13 , L 5B14 , and L 5B15 is independently unsubstituted C1-10 alkylene.
  • each of L 5B8 , L 5B9 , L 5B10 , L 5B11 , L 5B12 , L 5B13 , L 5B14 , and L 5B15 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats.
  • each of L 5C5 , L 5C6 , L 5C7 , and L 5C8 is independently a single bond.
  • each of L 5C5 , L 5C6 , L 5C7 , and L 5C8 is independently substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms.
  • each of L 5C5 , L 5C6 , L 5C7 , and L 5C8 is independently (which may be attached at either direction). In certain embodiments, at least one instance of y5 is 3; and each of L 5C6 , L 5C7 , and L 5C8 is independently a single bond, bond C 5F is attached t
  • L 5 is substituted or unsubstituted, C10-100 heteroalkylene.
  • L 5 comprises one or more of the following -CH2-, combination of two or more of each one of the foregoing, provided that: the number of backbone atoms of L 5 is between 10 and 100, inclusive; and
  • L 5 does not comprise O-O, O-N, N-O, or N-N.
  • At least one instance of L 5 is a combination of -CH2-, ? at: the number of backbone atoms of the at least one instance of L 5 is between 10 and 100, inclusive; and the at least one instance of L 5 does not comprise O-O, 0-N, N-0, or N-N.
  • L 6 is substituted or unsubstituted, Ci-150 alkylene, substituted or unsubstituted, C2-150 alkenylene, substituted or unsubstituted, C2-150 alkynylene, substituted or unsubstituted, Ci-150 heteroalkylene, substituted or unsubstituted, C2-150 heteroalkenylene, or substituted or unsubstituted, C2-i5oheteroalkynylene; optionally wherein one or more backbone atoms of the Ci-150 alkylene, C2-150 alkenylene, C2-150 alkynylene, Ci-150 heteroalkylene, C2-150 heteroalkenylene, or C2-150 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.
  • L 6 is substituted or unsubstituted, C10-100 alkylene, substituted or unsubstituted, C10-100 alkenylene, substituted or unsubstituted, C10-100 alkynylene, substituted or unsubstituted, C10-100 heteroalkylene, substituted or unsubstituted, C10-100 heteroalkenylene, or substituted or unsubstituted, Cio-iooheteroalkynylene; optionally wherein one, two, or three backbone atoms of the C10-100 alkylene, C10-100 alkenylene, C10-100 alkynylene, C10-100 heteroalkylene, C10-100 heteroalkenylene, or C10-100 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or un
  • L 6 is substituted or unsubstituted, C10-100 alkylene or substituted or unsubstituted, C10-100 heteroalkylene; and one, two, or three backbone atoms of the C10-100 alkylene or C10-100 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.
  • R a is 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
  • At least one instance of R a is independently hydrogen or substituted or unsubstituted, Ci-6 alkyl. In some embodiments, each instance of R a is independently hydrogen or substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, each instance of R a is independently hydrogen or unsubstituted Ci-6 alkyl.
  • each of L 6B1 , L 6B2 , and L 6B6 is a single bond, independently substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L 6B1 , L 6B2 , and L 6B6 is independently substituted or unsubstituted, Ci- 10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L 6B1 , L 6B2 , and L 6B6 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L 6B1 , L 6B2 , and L 6B6 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats.
  • each of L 6C1 and L 6C2 is independently a single bond. In certain embodiments, each of L 6C1 and L 6C2 is independently substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms. In certain embodiments, each of L 6C1 and L 6C2 is
  • At least one instance of y6 is 1;
  • At least one instance of y6 is 2;
  • At least one instance of R a is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In some embodiments, each instance of R a is independently hydrogen or substituted or unsubstituted, C 1-6 alkyl. In certain embodiments, each instance of R a is independently hydrogen or unsubstituted C 1-6 alkyl. In some embodiments, each of L 6B1 , L 6B4 , and L 6B6 is independently a single bond, substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene.
  • each of L 6B1 , L 6B4 , and L 6B6 is independently substituted or unsubstituted, C 1- 10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L 6B1 , L 6B4 , and L 6B6 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L 6B1 , L 6B4 , and L 6B6 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats.
  • each of L 6B2 , L 6B3 , L 6B5 , and L 6B7 is independently a single bond, substituted or unsubstituted, C 1-20 alkylene or substituted or unsubstituted, C 1-20 heteroalkylene. In some embodiments, each of L 6B2 , L 6B3 , L 6B5 , and L 6B7 is independently a single bond, substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L 6B2 , L 6B3 , L 6B5 , and L 6B7 is independently a single bond.
  • each of L 6B2 , L 6B3 , L 6B5 , and L 6B7 is independently unsubstituted C 1-10 alkylene. In certain embodiments, each of L 6B2 , L 6B3 , L 6B5 , and L 6B7 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, each of L 6C1 L 6C2 , L 6C3 , and L 6C4 is independently a single bond.
  • each of L 6C1 L 6C2 , L 6C3 , and L 6C4 is independently substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms.
  • each of L 6C1 L 6C2 , L 6C3 , and L 6C4 is independently (which may be attached at either direction).
  • at least one instance of y6 is 2; and ,
  • At least one instance of R a is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In some embodiments, each instance of R a is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, each instance of R a is independently hydrogen or unsubstituted C 1-6 alkyl. In some embodiments, each of L 6B16 , L 6B19 , and L 6B21 is independently substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene.
  • each of L 6B16 , L 6B19 , and L 6B21 is independently substituted or unsubstituted, C 1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L 6B16 , L 6B19 , and L 6B21 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L 6B16 , L 6B19 , and L 6B21 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats.
  • each of L 6B17 , L 6B18 , L 6B20 , and L 6B22 is independently a single bond, substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L 6B17 , L 6B18 , L 6B20 , and L 6B22 is independently a single bond, substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L 6B17 , L 6B18 , L 6B20 , and L 6B22 is independently a single bond.
  • each of L 6B17 , L 6B18 , L 6B20 , and L 6B22 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L 6B17 , L 6B18 , L 6B20 , and L 6B22 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, each of L 6C9 , L 6C10 , L 6C11 , and L 6C12 is independently a single bond.
  • each of L 6C9 , L 6C10 , L 6C11 , and L 6C12 is independently substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms.
  • each of L 6C9 , L 6C10 , L 6C11 , and L 6C12 is independently (which may be attached at either direction).
  • at least one instance of y6 is 2;
  • At least one instance of R a is independently hydrogen or substituted or unsubstituted, C 1-6 alkyl. In some embodiments, each instance of R a is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, each instance of R a is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of L 6B8 , L 6B9 , L 6B10 , L 6B11 , L 6B12 , L 6B13 , L 6B14 , and L 6B15 is independently substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene.
  • each of L 6B8 , L 6B9 , L 6B10 , L 6B11 , L 6B12 , L 6B13 , L 6B14 , and L 6B15 is independently substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene.
  • each of L 6B8 , L 6B9 , L 6B10 , L 6B11 , L 6B12 , L 6B13 , L 6B14 , and L 6B15 is independently unsubstituted C 1-10 alkylene.
  • each of L 6B8 , L 6B9 , L 6B10 , L 6B11 , L 6B12 , L 6B13 , L 6B14 , and L 6B15 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats.
  • each of L 6C5 , L 6C6 , L 6C7 , and L 6C8 is independently a single bond.
  • each of L 6C5 , L 6C6 , L 6C7 , and L 6C8 is independently substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms.
  • each of L 6C5 , L 6C6 , L 6C7 , and L 6C8 is independently (which may be attached at either direction). In certain embodiments, at least one instance
  • each of L 6C6 , L 6C7 , and L 6C8 is independently a single bond, .
  • 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.
  • a linker comprises a structure selected from: , ,
  • 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.
  • a linker comprises a structure selected from:
  • a linker comprises a structure selected from: ,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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: , 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. 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, 19, or 20. In certain embodiments, a linker comprises the structure: , 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.
  • each instance of each of A 1 , A 2 , A 4 , A 5 , and A 6 may independently be a radical of a ligand.
  • at least one instance of A 1 is a radical of a ligand.
  • at least two instances of A 1 are radicals of ligands.
  • at least one instance of A 2 is a radical of a ligand.
  • at least two instances of A 2 are radicals of ligands.
  • at least one instance of A 4 is a radical of a ligand.
  • at least two instances of A 4 are radicals of ligands.
  • At least one instance of A 5 is a radical of a ligand. In certain embodiments, at least two instances of A 5 are radicals of ligands. In some embodiments, at least one instance of A 6 is a radical of a ligand. In certain embodiments, two or three instances of A 1 , A 2 , A 4 , A 5 , and/or A 6 are independently a radical of a ligand. In certain embodiments, four or five instances of A 1 , A 2 , A 4 , A 5 , and/or A 6 are independently a radical of a ligand. In certain embodiments, at least two instances of A 6 are radicals of ligands.
  • At least one ligand is a muscle receptor ligand. In certain embodiments, at least one ligand is an ⁇ 4 ⁇ 1/7 integrin receptor ligand. In certain embodiments, at least one instance of A 1 is a radical of an ⁇ 4 ⁇ 1/7 integrin ligand. In certain embodiments, at least one instance of A 2 is a radical of an ⁇ 4 ⁇ 1/7 integrin ligand. In certain embodiments, at least one instance of A 4 is a radical of an ⁇ 4 ⁇ 1/7 integrin ligand. In certain embodiments, at least one instance of A 5 is a radical of an ⁇ 4 ⁇ 1/7 integrin ligand.
  • At least one instance of A 6 is a radical of an ⁇ 4 ⁇ 1/7 integrin ligand.
  • a ligand directs the pharmaceutical agent to a muscle in a subject.
  • a ligand directs the pharmaceutical agent to a muscle cell in a subject.
  • a ligand targets a cell receptor.
  • a cell receptor is an ⁇ 4 ⁇ 1/7 integrin receptor.
  • a receptor is in the muscle.
  • a ligand is used to target a pharmaceutical agent to a cell type.
  • the cell is a muscle cell.
  • a ligand is an agonist of a receptor (e.g., an ⁇ 4 ⁇ 1/7 integrin receptor agonist). In some embodiments, a ligand is an antagonist of a receptor (e.g., an ⁇ 4 ⁇ 1/7 integrin receptor antagonist). In some embodiments, at least one ligand is an antibody. In some embodiments, at least one ligand is a monoclonal antibody. In some embodiments, at least one ligand is a polyclonal antibody. In certain embodiments, at least one ⁇ 4 ⁇ 1/7 integrin ligand is an ⁇ 4 ⁇ 1 integrin ligand.
  • At least one ⁇ 4 ⁇ 1/7 integrin ligand is an ⁇ 4 ⁇ 7 integrin ligand.
  • at least one ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: ; wherein: each instance of R 1Z is independently optionally substituted heteroaryl or optionally substituted phenyl; each instance of R 33Z is independently –O(optionally substituted alkyl), –OH, –NH 2 , – NHOH, –NH(optionally substituted alkyl), –NH(optionally substituted polyethylene glycol), – N(optionally substituted alkyl)2, or –N(optionally substituted alkyl)(optionally substituted polyethylene glycol); each instance of R 34Z is of the formula: each instance of R 2Z is independently hydrogen, optionally substituted polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, or optionally substituted heteroaryl; and each instance of X 4Z is N or C
  • At least one ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: each instance of R 2Z is independently hydrogen, polyethylene glycol, optionally substituted heteroalkyl, or optionally substituted heteroaryl; and each instance of R 3Z and R 4Z is independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted alkoxy. In certain embodiments, at least one instance of R 1Z is optionally substituted 6-membered heteroaryl. In certain embodiments, at least one instance of R 1Z is optionally substituted pyridinyl (e.g., optionally substituted 3-pyridinyl or optionally substituted 4-pyridinyl).
  • At least one instance of R 1Z is optionally substituted 5-membered heteroaryl. In certain embodiments, at least one instance of R 1Z is optionally substituted pyrrolyl (e.g., optionally substituted 2-pyrrolyl). In certain embodiments, at least one instance of R 1Z is unsubstituted phenyl. In certain embodiments, at least one instance of R 1Z is 2-monosubstituted phenyl, 3-monosubstituted phenyl, or 4-monosubstituted phenyl.
  • At least one instance of R 1Z is 2,3-disubstituted phenyl, 2,4-disubstituted phenyl, 2,5-disubstituted phenyl, 2,6-disubstituted phenyl, 3,4-disubstituted phenyl, or 3,5-disubstituted phenyl.
  • at least one instance of R 33Z is –O(optionally substituted alkyl), – OH, –NH2, –NHOH, –NH(optionally substituted alkyl), or –N(optionally substituted alkyl)2.
  • At least one instance of R 33Z is –O(unsubstituted C 1-6 alkyl); –OH; –NH 2 ; – NHOH; –NH(unsubstituted C 1-6 alkyl); –NH(C 1-6 alkyl substituted with one or more substituents independently selected from the group consisting of –O(unsubstituted C1-6 alkyl), –OH, –NH2, – NHOH, –NH(unsubstituted C 1-6 alkyl), and –N(unsubstituted C 1-6 alkyl) 2 ); –N(unsubstituted C 1-6 alkyl)2; or –N(unsubstituted C1-6 alkyl)(C1-6 alkyl substituted with one or more substituents independently selected from the group consisting of –O(unsubstituted C1-6 alkyl), –OH, –NH2, – NHOH, –NH(unsubstituted C
  • At least one instance of R 2Z is hydrogen or substituted or unsubstituted heteroalkyl. In certain embodiments, at least one instance of R 2Z is hydrogen. In certain embodiments, at least one instance of R 2Z is optionally substituted alkyl. In certain embodiments, at least one instance of R 2Z is unsubstituted C1-6 alkyl (e.g., Me). In some embodiments, each of R 3Z and R 4Z is independently hydrogen or halogen. In certain embodiments, each of R 3Z and R 4Z is independently halogen. In some embodiments, at least one instance of R 36Z is hydrogen or halogen (e.g., –F).
  • At least one radical of the ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: . In certain embodiments, at least one radical of the ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: . In certain embodiments, at least one radical of the ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: . In certain embodiments, at least one ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: . In certain embodiments, at least one ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: . In certain embodiments, at least one ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: .
  • At least one ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: . .
  • at least one radical of the ⁇ 4 ⁇ 1/7 integrin ligand is of the formula:
  • at least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula:
  • R 4Z is hydrogen, halogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted –O–alkyl, or optionally substituted cycloalkyl
  • R 5Z is optionally substituted heteroalkyl or optionally substituted heterocyclyl
  • n1Z is 1, 2, or 3.
  • R 4Z is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R 4Z is hydrogen. In some embodiments, R 5Z is optionally substituted heteroalkyl. In some embodiments, n1Z is 1 or 2. In certain embodiments, n1Z is 1.
  • At least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: , R 6Z is hydrogen, –OH, –NH 2 , –NHR 7Z , –OR 7Z , or absent; and R 7Z is hydrogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.
  • R 6Z is hydrogen, –OH, –NH 2 , or absent.
  • R 6Z is hydrogen.
  • R 6Z is absent.
  • R 7Z is hydrogen or optionally substituted alkyl.
  • R 7Z is hydrogen or unsubstituted alkyl.
  • at least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: ,
  • n2Z is 0, 1, 2, or 3. In some embodiments, n2Z is 0 or 1. In certain embodiments, n2Z is 0. In certain embodiments, at least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: ,
  • n3Z is 0, 1, 2, or 3. In some embodiments, n3Z is 0 or 1. In certain embodiments, n3Z is 0. In certain embodiments, at least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: , each of R 8Z , R 9Z , R 10Z , and R 11Z is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted –O–alkyl, or substituted or unsubstituted cycloalkyl; each of R 12Z and R 13Z is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, , , , R 14Z is optionally substituted C 1 -C 5 alkyl, optionally substituted C 1 -C 5 alkylene-(C 3 -C 6 )- cycloalkyl, or optionally substituted (C1-C4)-alkylene-(C1-C4)-alkoxy.
  • each of R 8Z , R 9Z , R 10Z , and R 11Z is independently hydrogen, halogen, or optionally substituted alkyl. In certain embodiments, each of R 8Z , R 9Z , R 10Z , and R 11Z is independently optionally substituted alkyl. In certain embodiments, each of R 8Z , R 9Z , R 10Z , and R 11Z is independently unsubstituted alkyl. In some embodiments, each of R 12Z and R 13Z is independently hydrogen, , or . In certain embodiments, each of R 12Z and R 13Z is independently H or . In some embodiments, R 14Z is optionally substituted C 1 - C 5 alkyl.
  • R 14Z is optionally substituted C 4 alkyl.
  • at least one ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: .
  • at least one ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: .
  • at least one radical of the ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: .
  • at least one ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: .
  • at least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: .
  • at least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: .
  • At least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula:
  • R 15Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; each of R 16Z and R 17Z is independently H, halogen, optionally substituted alkyl, or optionally substituted –O–alkyl; and Y Z is –CH 2 – or –(CH 2 ) 2 –.
  • R 15Z is H, optionally substituted alkyl, or optionally substituted heteroalkyl.
  • R 15Z is H.
  • each of R 16Z and R 17Z is independently H or optionally substituted alkyl. In certain embodiments, each of R 16Z and R 17Z is independently H. In certain embodiments, Y Z is –CH2–. In certain embodiments, Y Z is –(CH2)2–.
  • At least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula:
  • R 18Z is H, –OH, –NH 2 , –NHR 19Z , –OR 19Z , or –CONHR 19Z ; each instance of R 19Z is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and n4Z is 1 or 2.
  • at least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: .
  • R 18Z is H, –OH, or –NH2.
  • R 18Z is H.
  • each instance of R 19Z is independently H or optionally substituted alkyl. In certain embodiments, each instance of R 19Z is independently H or unsubstituted alkyl. In certain embodiments, n4Z is 1. In certain embodiments, n4Z is 2. In certain embodiments, at least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: R 19Z is H, –CH2OR 20Z , –(CH2)2OR 20Z , –CH2NHCOR 20Z , or –OR 20Z ; and R 20Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.
  • R 19Z is H or –CH2NHCOR 20Z . In certain embodiments, R 19Z is – CH 2 NHCOR 20Z . In some embodiments, R 20Z is H or optionally substituted alkyl. In certain embodiments, R 20Z is H or unsubstituted alkyl.
  • At least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula:
  • R 21Z is H, –CONHR 22Z , –CH 2 OR 22Z , –(CH 2 ) 2 OR 22Z , –CH 2 NHCOR 22Z , or –OR 22Z ;
  • R 22Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and
  • X 1Z is H or halogen.
  • At least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: wherein: R 21Z is H, –CONHR 22Z , –CH2OR 22Z , –(CH2)2OR 22Z , –CH2NHCOR 22Z , or –OR 22Z ; R 22Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and X 1Z is H or halogen. In certain embodiments, at least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: .
  • R 21Z is H or –CH2NHCOR 22Z . In certain embodiments, R 21Z is – CH 2 NHCOR 22Z . In some embodiments, R 22Z is H or optionally substituted alkyl. In certain embodiments, R 22Z is H or unsubstituted alkyl. In certain embodiments, X 1Z is H. In certain embodiments, X 1Z is halogen.
  • At least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula:
  • R 23Z is H, -CONHR 24Z , -CH2OR 24Z , -(CH2)2OR 24Z , -CH2NHCOR 24Z , or -OR 24Z ;
  • R 24Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and n5Z is 0, 1, 2, or 3.
  • at least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: .
  • R 23Z is H or -CONHR 24Z .
  • R 23Z is -CONHR 24Z .
  • R 24Z is H or optionally substituted alkyl.
  • R 24Z is H or unsubstituted alkyl.
  • n5z is 0, 1, or 2. In certain, embodiments, n5z is 1.
  • At least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: , R 25Z is H, –CONHR 27Z , –CH 2 OR 27Z , –(CH 2 ) 2 OR 27Z , –CH 2 NHCOR 27Z , or –OR 27Z ; R 26Z is H, optionally substituted alkyl, or optionally substituted cycloalkyl; R 27Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and X 2Z is optionally substituted CH 2 or optionally substituted NH.
  • At least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: wherein: R 25Z is H, –CONHR 27Z , –CH2OR 27Z , –(CH2)2OR 27Z , –CH2NHCOR 27Z , or –OR 27Z ; R 26Z is H, optionally substituted alkyl, or optionally substituted cycloalkyl; and R 27Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl. In certain embodiments, at least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: .
  • R 25Z is H or –CH2NHCOR 27Z . In certain embodiments, R 25Z is –CH2NHCOR 27Z . In some embodiments, R 26Z is H or optionally substituted alkyl. In some embodiments, R 26Z is H or unsubstituted alkyl. In certain embodiments, R 26Z is H or -CH 3 . In some embodiments, R 27Z is H, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R 27Z is H, unsubstituted alkyl, or unsubstituted heteroalkyl. In some embodiments, X 2Z is optionally substituted NH. In certain embodiments, X 2Z is NH.
  • At least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula:
  • R 28Z is H, –CH2OR 30Z , –(CH2)2OR 30Z , –CH2NHCOR 30Z , or –OR 30Z ;
  • R 29Z is H, –OH, –NH 2 , –NHR 31Z , or –OR 31Z ;
  • R 30Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;
  • R 31Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;
  • n3Z is 1, 2, or 3.
  • R 28Z is H, –CH 2 NHCOR 30Z , or –OR 30Z . In certain embodiments, R 28Z is –CH 2 NHCOR 30Z . In some embodiments, R 29Z is H, –OH, or –NH 2 . In some embodiments, R 30Z is H, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R 30Z is H, unsubstituted alkyl, or unsubstituted heteroalkyl. In some embodiments, R 31Z is H, optionally substituted alkyl, or optionally substituted heteroalkyl.
  • R 31Z is H, unsubstituted alkyl, or unsubstituted heteroalkyl.
  • n3Z is 1.
  • n3Z is 2.
  • at least one ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: ; or at least one radical of an ⁇ 4 ⁇ 1/7 integrin ligand is of the formula: .
  • a ligand is an antibody (e.g., an anti- ⁇ 4 ⁇ 1/7 integrin receptor antibody).
  • a ligand is an antibody fragment or an antibody variant.
  • an “anti- ⁇ 4 ⁇ 1/7 integrin receptor antibody” refers to an immune system protein that recognizes, binds to, or otherwise interacts with a ⁇ 4 ⁇ 1/7 integrin.
  • a conjugate comprises at least two ligands (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 ligands).
  • a conjugate comprises two ligands.
  • a conjugate comprises three ligands.
  • a conjugate comprises at least one ligand conjugated at the 5′-end.
  • a conjugate comprises at least one ligand conjugated at the 3′-end.
  • a conjugate comprises at least one ligand conjugated at the 5′-end and at least one ligand conjugated at the 3′-end. In some embodiments, a conjugate comprises at least two ligands conjugated at the 5′-end. In some embodiments, a conjugate comprises at least two ligands conjugated at the 3′-end. In certain embodiments, a conjugate comprises at least two ligands conjugated at the 5′-end and at least two ligands conjugated at the 3′-end. In some embodiments, a conjugate comprises at least one ligand conjugated at a nucleobase. In some embodiments, a conjugate comprises at least two ligands conjugated at a nucleobase.
  • a conjugate comprises at least one ligand conjugated at the 2′ position of a nucleoside. In some embodiments, a conjugate comprises at least two ligands conjugated at the 2′ position of a nucleoside. In some embodiments, at least two ligands are of the same ligand type. In some embodiments, each ligand is of the same ligand type. 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 type.
  • ligands when they are of the same ligand type, they bind the same target.
  • at least one ligand is a small molecule, peptide, or protein.
  • y is 2, 3, 4, 5, or 6; and at least two instances of A are radicals of ligands.
  • y is 2, 3, 4, 5, or 6; and at least two instances of A are radicals of ligands of the same ligand type (e.g., ⁇ 4 ⁇ 1/7 integrin ligands).
  • y is 2, 3, 4, 5, or 6; and at least two instances of A are radicals of different ligands of the same ligand type.
  • y is 2, 3, 4, 5, or 6; and at least two instances of A are radicals of the same ligand. In certain embodiments, y is 2, 3, 4, 5, or 6; and at least two instances of A are radicals of ligands of different ligand types (e.g., at least one instance of A is a radical of an ⁇ 4 ⁇ 1/7 integrin ligand, and at least one instance of A is a radical of a ligand that is not an ⁇ 4 ⁇ 1/7 integrin ligand). In certain embodiments, y is 2, 3, 4, 5, or 6; and at least one ligand is a tropomyosin receptor B (TrkB) ligand.
  • TrkB tropomyosin receptor B
  • y is 2, 3, 4, 5, or 6; and at least one ligand is a cannabinoid receptor type 1 (CB 1 ) ligand. In certain embodiments, y is 2, 3, 4, 5, or 6; and at least one ligand is a N-methyl-D-aspartate (NMDA) ligand.
  • CB 1 cannabinoid receptor type 1
  • y is 2, 3, 4, 5, or 6; and at least one ligand is a N-methyl-D-aspartate (NMDA) ligand.
  • NMDA N-methyl-D-aspartate
  • an ⁇ 4 ⁇ 1/7 integrin receptor ligand is any of those disclosed in Baiula, M. et al. Novel Ligands Targeting ⁇ 4 ⁇ 1 Integrin: Therapeutic Applications and Perspectives. Front. Chem.2019, 7, 489, which is incorporated herein by reference.
  • Exemplary ⁇ 4 ⁇ 1/7 integrin receptor ligands for use in the present disclosure include, but are not limited to, any of the following ⁇ 4 ⁇ 1/7 integrin receptor ligands, and derivatives thereof: ,
  • an ⁇ 4 ⁇ 1/7 integrin receptor ligand is , or a derivative thereof.
  • an ⁇ 4 ⁇ 1/7 integrin receptor ligand is an anti- ⁇ 4 ⁇ 1/7 integrin receptor antibody.
  • an ⁇ 4 ⁇ 1/7 integrin receptor ligand is an anti- ⁇ 4 ⁇ 1/7 integrin receptor antibody fragment, or an anti- ⁇ 4 ⁇ 1/7 integrin receptor antibody variant.
  • An “anti- ⁇ 4 ⁇ 1/7 integrin receptor antibody” refers to an immune system protein that recognizes, binds to, or otherwise interacts with an ⁇ 4 ⁇ 1/7 integrin receptor.
  • an ⁇ 4 ⁇ 1/7 integrin receptor ligand is conjugated (e.g., linked, connected, attached, associated with) to one or more pharmaceutical agent moieties (i.e., radicals of pharmaceutical agents).
  • at least one pharmaceutical agent is a therapeutic, prophylactic, or diagnostic (e.g., imaging) agent.
  • at least one pharmaceutical agent is a therapeutic agent that treats a muscle disease.
  • at least one pharmaceutical agent is a contrast agent.
  • at least one pharmaceutical agent is a small molecule.
  • at least one pharmaceutical agent is a protein or peptide.
  • at least one pharmaceutical agent is an antibody.
  • At least one pharmaceutical agent is a monoclonal antibody. In certain embodiments, at least one pharmaceutical agent is an oligonucleotide. In certain embodiments, at least one pharmaceutical agent is an oligonucleotide. In some embodiments, more than one ⁇ 4 ⁇ 1/7 integrin receptor ligand is conjugated to an agent moiety. In some embodiments, at least two ⁇ 4 ⁇ 1/7 integrin receptor ligands (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more ⁇ 4 ⁇ 1/7 integrin receptor ligands) are conjugated to an agent moiety. In some embodiments, two ⁇ 4 ⁇ 1/7 integrin receptor ligands are conjugated to an agent moiety.
  • three ⁇ 4 ⁇ 1/7 integrin receptor ligands are conjugated to an agent moiety.
  • four ⁇ 4 ⁇ 1/7 integrin receptor ligands are conjugated to an agent moiety.
  • five ⁇ 4 ⁇ 1/7 integrin receptor ligands are conjugated to an agent moiety.
  • more than five ⁇ 4 ⁇ 1/7 integrin receptor ligands are conjugated to an agent moiety.
  • at least 1 to about 5 ⁇ 4 ⁇ 1/7 integrin receptor ligands are conjugated to an agent moiety.
  • at least 1 to about 4 ⁇ 4 ⁇ 1/7 integrin receptor ligands are conjugated to an agent moiety.
  • At least 1 to about 3 ⁇ 4 ⁇ 1/7 integrin receptor ligands are conjugated to an agent moiety. In some embodiments, at least 1 to about 2 ⁇ 4 ⁇ 1/7 integrin receptor ligands are conjugated to an agent moiety. When an agent moiety is conjugated to multiple ⁇ 4 ⁇ 1/7 integrin receptor ligands, all of the ⁇ 4 ⁇ 1/7 integrin receptor ligands may be conjugated at or near the same position on the agent moiety, or the ⁇ 4 ⁇ 1/7 integrin receptor ligands may be conjugated to multiple different positions on the agent moiety.
  • an oligonucleotide strand is conjugated (e.g., connected, attached, associated with) to an ⁇ 4 ⁇ 1/7 integrin receptor ligand through either a 5′ end and/or a 3′ end of the oligonucleotide strand, or at an internal position in an oligonucleotide strand (i.e., at a nucleotide on the oligonucleotide strand other than the 5′ or 3′ nucleotide).
  • an oligonucleotide strand is conjugated to an ⁇ 4 ⁇ 1/7 integrin receptor ligand through the 5′ end of the oligonucleotide strand.
  • an oligonucleotide strand is conjugated to an ⁇ 4 ⁇ 1/7 integrin receptor ligand through the 3′ end of the oligonucleotide strand. In some embodiments, an oligonucleotide strand is conjugated to ⁇ 4 ⁇ 1/7 integrin receptor ligands through both the 5′ end and the 3′ end of the oligonucleotide strand. In some embodiments, an oligonucleotide strand is conjugated to an ⁇ 4 ⁇ 1/7 integrin receptor ligand at an internal position within the oligonucleotide strand (e.g., in an “internally-modified oligonucleotide”).
  • an oligonucleotide strand is conjugated to more than one ⁇ 4 ⁇ 1/7 integrin receptor ligand. In some embodiments, an oligonucleotide strand is conjugated to at least two ⁇ 4 ⁇ 1/7 integrin receptor ligands (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more ⁇ 4 ⁇ 1/7 integrin receptor ligands). In some embodiments, an oligonucleotide strand is conjugated to two ⁇ 4 ⁇ 1/7 integrin receptor ligands. In some embodiments, an oligonucleotide strand is conjugated to three ⁇ 4 ⁇ 1/7 integrin receptor ligands.
  • an oligonucleotide strand is conjugated to four ⁇ 4 ⁇ 1/7 integrin receptor ligands. In some embodiments, an oligonucleotide strand is conjugated to five ⁇ 4 ⁇ 1/7 integrin receptor ligands. In some embodiments, an oligonucleotide strand is conjugated to more than five ⁇ 4 ⁇ 1/7 integrin receptor ligands. In some embodiments, an oligonucleotide strand is conjugated to at least 1 to about 5 ⁇ 4 ⁇ 1/7 integrin receptor ligands.
  • an oligonucleotide strand is conjugated to at least 1 to about 4 ⁇ 4 ⁇ 1/7 integrin receptor ligands. In some embodiments, an oligonucleotide strand is conjugated to at least 1 to about 3 ⁇ 4 ⁇ 1/7 integrin receptor ligands. In some embodiments, an oligonucleotide strand is conjugated to at least 1 to about 2 ⁇ 4 ⁇ 1/7 integrin receptor ligands.
  • ⁇ 4 ⁇ 1/7 integrin receptor ligands When an oligonucleotide strand is conjugated to multiple ⁇ 4 ⁇ 1/7 integrin receptor ligands, all of the ⁇ 4 ⁇ 1/7 integrin receptor ligands may be conjugated at or near the same position on the oligonucleotide strand, or the ⁇ 4 ⁇ 1/7 integrin receptor ligands may be conjugated to multiple different positions on the oligonucleotide strand. In some embodiments, multiple ⁇ 4 ⁇ 1/7 integrin receptor ligands (i.e., two, three, four, five, or more ⁇ 4 ⁇ 1/7 integrin receptor ligands) are conjugated at the 5′ end of the oligonucleotide strand.
  • multiple ⁇ 4 ⁇ 1/7 integrin receptor ligands are conjugated at the 3′ end of the oligonucleotide strand.
  • multiple ⁇ 4 ⁇ 1/7 integrin receptor ligands are conjugated at one or more internal positions of the oligonucleotide strand.
  • an oligonucleotide strand is conjugated to one or more ⁇ 4 ⁇ 1/7 integrin receptor ligands at the 5′ end of the oligonucleotide strand and/or one or more ⁇ 4 ⁇ 1/7 integrin receptor ligands at the 3′ end of the oligonucleotide strand and/or one or more ⁇ 4 ⁇ 1/7 integrin receptor ligands at an internal position, or multiple internal positions, of the oligonucleotide strand.
  • Two or more ligands may be attached to the same or different positions of the corresponding linker, as valency permits.
  • each instance of each of A 1 , A 2 , A 4 , A 5 , and A 6 is independently a radical of a ligand or lipid.
  • at least one instance of A 1 , A 2 , A 4 , A 5 , and A 6 is a radical of a lipid.
  • two or three instances of A 1 , A 2 , A 4 , A 5 , and/or A 6 are independently a radical of a lipid.
  • a 1 , A 2 , A 4 , A 5 , and/or A 6 are independently a radical of a lipid.
  • at least one instance of A 1 is a radical of a lipid.
  • at least one instance of A 2 is a radical of a lipid.
  • at least one instance of A 4 is a radical of a lipid.
  • at least one instance of A 5 is a radical of a lipid.
  • at least one instance of A 6 is a radical of a lipid.
  • at least one instance of A 1 , A 2 , A 4 , A 5 , and A 6 is independently a radical of a lipid.
  • no instance of A 1 , A 2 , A 4 , A 5 , and A 6 is a radical of a lipid.
  • at least one lipid is a fatty acyl, glycerolipid, glycerophospholipid, sphingolipid, saccharolipid, polyketide, sterol lipid, or prenol lipid.
  • At least one lipid is a fatty acid or conjugate, octadecanoid, eicosanoid, docosanoid, fatty alcohol, fatty aldehyde, fatty ester, fatty amide, fatty nitrile, fatty ether, hydrocarbon, oxygenated hydrocarbon, or fatty acyl glycoside.
  • at least one lipid is a hydrocarbon.
  • the hydrocarbon chain is saturated or unsaturated.
  • 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).
  • At least one radical of a lipid is unsubstituted C 7-36 alkyl, C 7-36 alkyl substituted with one or more fluoro as valency permits, unsubstituted C7-36 alkenyl, or C7-36 alkenyl substituted with one or more fluoro as valency permits.
  • at least one radical of a lipid is unsubstituted C 7-36 alkyl or unsubstituted C 7-36 alkenyl.
  • at least one radical of a lipid is unsubstituted C7-36 alkyl.
  • At least one radical of a lipid is unsubstituted C7- 20 alkyl, C7-20 alkyl substituted with one or more fluoro as valency permits, unsubstituted C7-20 alkenyl, or C 7-20 alkenyl substituted with one or more fluoro as valency permits.
  • at least one radical of a lipid is unsubstituted C 7-20 alkyl or unsubstituted C 7-20 alkenyl.
  • at least one radical of a lipid is unsubstituted C7-20 alkyl.
  • At least one radical of a lipid is unsubstituted C21-28 alkyl, C21-28 alkyl substituted with one or more fluoro as valency permits, unsubstituted C 21-28 alkenyl, or C 21-28 alkenyl substituted with one or more fluoro as valency permits.
  • at least one radical of a lipid is unsubstituted C21-28 alkyl or unsubstituted C21-28 alkenyl.
  • at least one radical of a lipid is unsubstituted C 21-28 alkyl.
  • At least one radical of a lipid is unsubstituted C29-36 alkyl, C29-36 alkyl substituted with one or more fluoro as valency permits, unsubstituted C29-36 alkenyl, or C29-36 alkenyl substituted with one or more fluoro as valency permits.
  • at least one radical of a lipid is unsubstituted C 29-36 alkyl or unsubstituted C 29-36 alkenyl.
  • at least one radical of a lipid is unsubstituted C29-36 alkyl.
  • 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.
  • at least one radical of a lipid is unbranched unsubstituted C 14-18 alkyl.
  • At least one radical of a lipid is –(CH2)13CH3, –(CH2)14CH3, –(CH2)15CH3, –(CH2)16CH3, or –(CH2)17CH3. In certain embodiments, at least one radical of a lipid is –(CH2)15CH3. In certain embodiments, at least one radical of a lipid is unbranched unsubstituted C 18-26 alkyl.
  • At least one radical of a lipid is –(CH 2 ) 17 CH 3 , –(CH 2 ) 18 CH 3 , –(CH 2 ) 19 CH 3 , – (CH2)20CH3, –(CH2)21CH3, –(CH2)22CH3, –(CH2)23CH3, –(CH2)24CH3, or –(CH2)25CH3.
  • at least one radical of a lipid is –(CH2)16CH3 or –(CH2)17CH3.
  • at least one radical of a lipid is –(CH 2 ) 21 CH 3 .
  • At least one lipid is a monoradylglycerol, diradylglycerol, triradylglycerol, glycosylmonoradylglycerol, glycosyldiradylglycerol, betaine monoradylglycerol, or betaine diradylglycerol.
  • 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, glycerophosphonocholine, glycerophosphonoethanolamine, di-glycerol tetraether phospholipid, glycerol-nonitol tetraether phospholipid, oxidized glycer
  • At least one lipid is a sphingoid base, ceramide, phosphosphingolipid, phosphonosphingolipid, neutral glycosphingolipid, acidic glycosphingolipid, basic glycosphingolipid, amphoteric glycosphingolipid, or arsenosphingolipid.
  • at least one lipid is a sterol, steroid, secosteroid, bile acid, or a derivative thereof, or steroid conjugate.
  • at least one lipid is cholesterol.
  • at least one radical of the lipid is of the formula: .
  • at least one lipid is lithocholic acid.
  • At least one lipid is an isoprenoid, quinone, hydroquinone, polyprenol, or hopanoid. In certain embodiments, at least one lipid is an acylaminosugar, acylaminosugar glycan, acyltrehalose, or acyltrehalose glycan.
  • 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.
  • the oligonucleotide strands may further comprise additional modifications.
  • the oligonucleotide strand further comprises at least one modified sugar, at least one modified nucleobase, at least one modified internucleoside linkage, or a combination thereof.
  • an 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.
  • an 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.
  • an 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 internucleoside linkages.
  • 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.
  • a modified sugar is used in the oligonucleotides disclosed herein.
  • a modified sugar is a substituted furanosyl sugar or non-bicyclic modified sugar.
  • a modified sugar is a bicyclic or tricyclic modified sugar.
  • a modified sugar is a sugar surrogate.
  • a sugar surrogate may comprise one or more substitutions described herein.
  • a modified sugar is a substituted furanosyl or non-bicyclic modified sugar.
  • the furanosyl sugar is a ribosyl sugar.
  • the furanosyl sugar comprises one or more substituent groups, including, but not limited to, substituent groups at the 1′, 2′, 3′, 4′, and 5′ positions.
  • substituents at the 2′ position include, but are not limited to, F and OCH 3 (“OMe”, “O-methyl”, or “methoxy”).
  • 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, – ⁇ 2 , – ⁇ 2 , – ⁇ 3 , and – ⁇ 2 .
  • substituent groups at the 2′ position include, but are not limited to, alkaryl, aralkyl, –O-alkaryl, and –O-aralkyl.
  • these 2′ substituent groups can be further substituted with one or more substituent groups independently selected from hydroxyl, alkoxy, carboxy, benzyl, phenyl, nitro (– ⁇ 2 ), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl, and alkynyl.
  • 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.
  • 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.
  • 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.
  • 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-O- 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
  • 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.
  • the 5′ modification is at the terminus of an antisense oligonucleotide.
  • substituents described herein for the 2′, 4′, and 5′ position can be added to other specific positions on the sugar.
  • 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.
  • a non-bicyclic modified sugar may comprise more than one non-bridging sugar substituent.
  • non-bicyclic modified sugar substituents include, but are not limited to, 5′-Me-2′-F, 5′-Me-2′-OMe (including both R and S isomers).
  • modified sugar substituents include those described in Migawa et al., WO 2008/101157.
  • 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.
  • a bicyclic sugar comprises a bridging substituent that bridges two atoms of the furanosyl ring to form a second ring.
  • a bicyclic sugar does not comprise a furanosyl moiety.
  • a “bicyclic nucleoside” (“BNA”) is a nucleoside having a bicyclic sugar.
  • the bicyclic sugar comprises a bridge between the 4′ and 2′ furanose ring atoms.
  • the bicyclic sugar comprises a bridge between the 5′ and 3′ furanose ring atoms.
  • the furanose ring is a ribose ring.
  • 4′ to 2′ bridging substituents include, but are not limited to, 4'-CH2-2', 4'-(CH2)2-2', 4'-(CH2)3-2', 4'- CH 2 -O-2' (“LNA”), 4'-CH 2 -S-2', 4'-(CH 2 ) 2 -O-2' (“ENA”), 4'-CH(CH 3 )-O-2' (“constrained ethyl” or “cEt” when in the S configuration), 4'-CH 2 -O-CH 2 -2', 4'-CH 2 -N(R)-2', 4'- CH(CH 2 OCH 3 )-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'-CH 2 -O-N(CH 3 )-2' (e.g., U.S. Patent Publication No.2004/0171570), 4'-CH2-N(R)-O-2', wherein R is ⁇ , C1-C12 alkyl, or a protecting group (e.g., U.S.
  • 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.
  • sugar surrogates comprise rings having other than 5 atoms.
  • the sugar surrogate comprises a cyclobutyl moiety in place of the pentofuranosyl sugar.
  • the sugar surrogate comprises a six membered ring in place of the pentofuranosyl sugar.
  • the sugar surrogate comprises a tetrahydropyran (“THP”) in place of the pentofuranosyl sugar.
  • the sugar surrogate comprises a morpholino in place of the pentofuranosyl sugar.
  • sugar surrogates comprise acyclic moieties.
  • the sugar surrogate is an unlocked nucleic acid (“UNA”).
  • UNA is unlocked acyclic nucleic acid, wherein any of the bonds of the sugar has been removed, forming an unlocked “sugar” residue.
  • UNA also encompasses a monomer where the bonds between C1′-C4′ have been removed (i.e., the covalent carbon-oxygen-carbon bond between the C1′ and C4′ carbons).
  • the C2′-C3′ bond i.e., the covalent carbon-carbon bond between the C2′ and C3′ carbons
  • Representative U.S. publications that teach the preparation of UNA include, but are not limited to, U.S. Patent No.
  • 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.
  • PNA peptide nucleic acid
  • acyclic butyl nucleic acid see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865)
  • 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.
  • modified sugars and/or unmodified sugars are arranged along the oligonucleotide strand or regions thereof in a defined pattern or “sugar motif”.
  • sugar motifs include, but are not limited to, any of the patterns of sugar modifications described herein.
  • 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.
  • the wing regions comprise a majority of modified sugars, and the gap comprises a majority of unmodified sugars.
  • the nucleosides of the gap are deoxynucleosides. Oligonucleotides with a gapmer sugar motif are described in, for example, U.S. Patent No.8,790,919. 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.
  • 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).
  • a strand of a double-stranded oligonucleotide may contain more than one triplet sugar motif.
  • 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.
  • 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.
  • the quadruplet is at or near the cleavage site.
  • a strand of a double-stranded oligonucleotide may contain more than one quadruplet sugar motif.
  • the identical sugar modification of the quadruplet sugar motif is a 2′-F modification.
  • the cleavage site of the antisense oligonucleotide strand is typically around the 10, 11, and 12 positions from the 5′-end.
  • 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.
  • the quadruplet sugar motif is at the 8, 9, 10, and 11 positions; the 9, 10, 11, and12 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.
  • an oligonucleotide strand comprises an alternating sugar motif.
  • 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.
  • the alternating motif can be “ABABABABABAB...,” “AABBAABBAABB...,” “AABAABAABAAB...,” “AAABAAABAAAB...,” “AAABBBAAABBB...,” or “ABCABCABCABC...,” etc.
  • 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.
  • the alternating sugar motif is comprised of two different sugar modifications.
  • the alternating sugar motif comprises 2′-OMe and 2′-F sugar modifications.
  • each nucleoside of an oligonucleotide strand is independently modified with one or more sugar modifications provided herein.
  • each strand of a double-stranded oligonucleotide independently has one or more sugar modifications provided herein.
  • an oligonucleotide strand containing a sugar motif is fully modified in that each nucleoside comprises a sugar modification.
  • 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-nitrobenzyl)-2′-deoxyribose, 3′-O-methylribose, 5′- aminoribose, 5′-thioribose, 5-nitro-1-indolyl-2′-deoxyribose, 5′-biotin-ribose, 2′-O,
  • a modified sugar is present at the 3′-end of the oligonucleotide strand. In certain embodiments, a modified sugar is present within 3 nucleosides of 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.
  • 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.
  • 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. In certain embodiments, a modified sugar is 2′-O-methyl ribose, 2′-F ribose, or inverted abasic deoxyribose.
  • 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.
  • Any modified nucleobases known in the art may be used in the oligonucleotides provided herein.
  • modified oligonucleotides comprise one or more nucleosides comprising a modified nucleobase.
  • modified oligonucleotides comprise one or more nucleosides that do not comprise a nucleobase, referred to as an abasic nucleoside.
  • modified nucleobases are selected from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and ⁇ -2, N-6 and O-6 substituted purines.
  • 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
  • modified nucleobases include tricyclic pyrimidines, such as 1,3- diazaphenoxazine-2-one, 1,3-diazaphenothiazine-2-one, and 9-(2-aminoethoxy)-1,3- 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.
  • a modified nucleobase is xanthine, allyaminouracil, 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-carboxycytosine, 5- carboxymethylesteruracil, 5-carboxyuracil, 5-fluor
  • nucleobases include those disclosed in U.S. Patent No.3,687,808; Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, ⁇ . 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.T.
  • 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.
  • each nucleobase is modified.
  • none of the nucleobases are modified.
  • each purine or each pyrimidine is modified.
  • each adenine is modified.
  • each guanine is modified.
  • each thymine is modified.
  • each uracil is modified.
  • each cytosine is modified.
  • cytosine nucleobases in an oligonucleotide strand are 5-methylcytosines.
  • 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.
  • 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.
  • 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.
  • any modified internucleoside linkages can be used in the oligonucleotides provided herein.
  • a 3′ to 5′ phosphodiester linkage is the naturally occurring internucleoside linkage of RNA and DNA.
  • an oligonucleotide strand has one or more modified, i.e., non-naturally occurring, internucleoside linkages.
  • Certain non-naturally occurring internucleoside 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.
  • Methods of preparation of phosphorous- containing and non-phosphorous-containing internucleoside linkages are well known to those skilled in the art.
  • Further neutral internucleoside 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 internucleoside linkages include nonionic linkages comprising mixed ⁇ , O, S and CH 2 component parts.
  • an oligonucleotide strand comprises at least one modified internucleoside linkage.
  • a modified internucleoside linkage may be placed at any position of an oligonucleotide strand.
  • a modified internucleoside linkage may be placed within the sense oligonucleotide strand, antisense oligonucleotide strand, or both oligonucleotide strands of the double-stranded oligonucleotide.
  • the internucleoside linkage modification may occur on every nucleoside of an oligonucleotide strand.
  • internucleoside linkage modifications may occur in an alternating pattern along an oligonucleotide strand.
  • each internucleoside linking group of an oligonucleotide strand is independently selected from phosphorothioate and phosphate internucleoside linkages.
  • the pattern of the internucleoside linkage modification on each strand of a double-stranded oligonucleotide is the same.
  • the pattern of the internucleoside linkage modification on each strand of a double- stranded oligonucleotide is different.
  • a double-stranded oligonucleotide comprises 6-8 modified internucleoside linkages.
  • the 6-8 modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages.
  • the sense oligonucleotide strand comprises at least two modified internucleoside linkages at either or both the 5′-end and the 3′-end.
  • the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages.
  • the antisense oligonucleotide strand comprises at least two modified internucleoside linkages at either or both the 5′-end and the 3′-end.
  • the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages.
  • a double-stranded oligonucleotide comprises an overhang region.
  • a double-stranded oligonucleotide comprises a phosphorothioate or alkylphosphonate internucleoside linkage modification in the overhang region. In certain embodiments, a double-stranded oligonucleotide comprises a phosphorothioate or alkylphosphonate internucleotide linkage linking the overhang nucleotide with a paired nucleotide that is next to the overhang nucleotide.
  • terminal three nucleosides there may be at least two phosphorothioate internucleoside 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.
  • oligonucleotide strands comprise one or more internucleoside linkages having chiral centers.
  • Representative chiral internucleoside linkages include, but are not limited to, alkylphosphonates and phosphorothioates.
  • the oligonucleotide strands comprising internucleoside linkages having chiral centers can be prepared as populations of oligonucleotide strands comprising stereorandom internucleoside linkages, or as populations of oligonucleotide strands comprising phosphorothioate linkages in particular stereochemical configurations.
  • populations of oligonucleotide strands comprise phosphorothioate internucleoside linkages, wherein all of the phosphorothioate internucleoside linkages are stereorandom.
  • Such 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.
  • populations of oligonucleotide strands are enriched for oligonucleotide strands comprising one or more particular phosphorothioate internucleoside linkages in a particular, independently selected stereochemical configuration.
  • 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.
  • 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 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.
  • a population of oligonucleotide strands is enriched for oligonucleotide strands having at least one indicated phosphorothioate in the (Sp) configuration. In certain embodiments, a population of oligonucleotide strands is enriched for oligonucleotide strands having at least one phosphorothioate in the (Rp) configuration.
  • a modified internucleoside linkage is present at the 3′-end of the oligonucleotide strand. In certain embodiments, a modified internucleoside linkage is present within 3 nucleosides of the 3′-end of the oligonucleotide strand.
  • a modified internucleoside linkage is present at the 5′-end of the oligonucleotide strand. In certain embodiments, a modified internucleoside linkage is present within 3 nucleosides of the 5′-end of the oligonucleotide strand. In certain embodiments, a modified internucleoside linkage is present at an internal position on an oligonucleotide strand. In certain embodiments, a modified internucleoside linkage is present more than 3 nucleosides from the 3′-end of the oligonucleotide strand.
  • a modified internucleoside linkage is present more than 3 nucleosides from the 5′-end of the oligonucleotide strand.
  • modified oligonucleotides comprise a block of modified internucleoside linkages.
  • the block is at the 3′-end of the oligonucleotide strand.
  • the block is within 3 nucleosides of the 3′-end of the oligonucleotide strand.
  • the block is at the 5′-end of the oligonucleotide strand.
  • 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. In certain embodiments, a modified internucleosidic linkage comprises 5′- ethylenephosphonate, phosphorothioate, or an amide.
  • the present disclosure provides a conjugate of any one of the formulae described herein, or a pharmaceutically acceptable salt or prodrug thereof.
  • the conjugates described herein include pharmaceutically acceptable salts and prodrugs thereof.
  • the conjugates described herein include pharmaceutically acceptable salts thereof.
  • the conjugate, or a pharmaceutically acceptable salt or prodrug thereof is in the form of a pharmaceutical composition.
  • the pharmaceutical composition comprises the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, and optionally a pharmaceutically acceptable excipient.
  • a conjugate or pharmaceutical composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents.
  • a pharmaceutical agent is a therapeutic agent.
  • a pharmaceutical agent is a prophylactic agent. In some embodiments, a pharmaceutical agent is a diagnostic agent.
  • the conjugates 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 muscle disease in a subject in need thereof, in preventing a muscle disease in a subject in need thereof, and/or in reducing the risk of developing a muscle 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.
  • the combination exhibits a synergistic effect that is absent in a pharmaceutical composition including one of the conjugates described herein or the additional pharmaceutical agent, but not both.
  • the conjugate 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.
  • 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).
  • the additional pharmaceutical agent is a therapeutic agent useful for treating a muscle disease.
  • the additional pharmaceutical agent is a prophylactic agent useful for preventing a muscle 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 conjugate 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 conjugate 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.
  • the levels utilized in combination will be lower than those utilized individually.
  • the pharmaceutical compositions comprise an effective amount of a conjugate described herein and a pharmaceutically acceptable excipient.
  • a conjugate described herein is administered to a subject using a pharmaceutically acceptable formulation.
  • a pharmaceutically acceptable formulation may provide sustained delivery of the conjugate to a subject for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after the pharmaceutically acceptable formulation is administered to the subject.
  • a conjugate of the disclosure is administered acutely.
  • the conjugate of the disclosure may therefore be administered for a short course of treatment, such as for about 1 day to about 1 week.
  • the conjugate 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.
  • the conjugate 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.
  • the active ingredients e.g., a conjugate of the disclosure
  • the conjugate can be coated by, or administered with, a material to prevent inactivation.
  • the conjugate may be administered parenterally or intraperitoneally.
  • Dispersions can also be prepared, for example, in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils.
  • substances that can serve as pharmaceutical excipients are sugars, such as lactose, glucose, and sucrose; starches, such as corn 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, corn 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
  • 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.
  • 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 conjugates 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) a conjugate delineated herein with one or more suitable excipients, including those described herein (e.g., for pharmaceutical, agricultural, or veterinary use).
  • 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.
  • 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 pulmonary administration.
  • Useful injectable preparations include sterile suspensions, solutions, or emulsions of the conjugate(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.
  • 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.
  • the conjugate(s) can be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.
  • the conjugate can be formulated as a depot preparation for administration by implantation or intramuscular injection.
  • the conjugates 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.
  • suitable polymeric or hydrophobic materials e.g., as an emulsion in an acceptable oil
  • ion exchange resins e.g., as an emulsion in an acceptable oil
  • sparingly soluble derivatives e.g., as a sparingly soluble salt
  • other pharmaceutical delivery systems can be employed. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver the conjugate. Certain organic solvents such as dimethyl sulfoxide (DMSO) also can be employed.
  • DMSO dimethyl sulfoxide
  • 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 conjugates.
  • the pack can
  • the pack or dispenser device can be accompanied by instructions for administration.
  • the conjugates 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 conjugates can be administered therapeutically to achieve therapeutic benefit or prophylactically to achieve prophylactic benefit.
  • 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.
  • the conjugates can be administered to a subject at risk of developing one of the previously described diseases.
  • a subject at risk of developing a muscle 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.
  • 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.
  • prophylactic administration can be applied to avoid the onset of symptoms in a subject diagnosed with the underlying disease.
  • the amount of the conjugates 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 bioavailability of the conjugates, and the like. Determination of an effective dosage is well within the capabilities of those skilled in the art. 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 conjugate that is at or above an IC 50 of the particular conjugate as measured in an in vitro assay, such as an in vitro fungal MIC or MFC, and other in vitro assays.
  • 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 conjugate, 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 conjugates 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 conjugates cannot be related to plasma concentration. Skilled artisans will be able to optimize effective local dosages without undue experimentation.
  • the conjugates will provide an intended (e.g., therapeutic or prophylactic) benefit and will have acceptable tolerability.
  • kits comprising a conjugate or pharmaceutical composition provided herein.
  • the kits comprise an effective amount of a conjugate provided herein.
  • the kits comprise the conjugate or pharmaceutical composition in unit dosage form.
  • the kits further comprise instructions for using the conjugate or pharmaceutical composition.
  • the kits may further comprise a first container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
  • the first container contains the conjugate or pharmaceutical composition.
  • kits may optionally further include a second container.
  • the second container contains a pharmaceutical excipient.
  • the pharmaceutical excipient is suitable for dilution or suspension of a pharmaceutical composition or conjugate described herein.
  • the pharmaceutical composition or conjugate described herein are combined to form one unit dosage form.
  • the kits are useful for treating a muscle disease in a subject in need thereof.
  • the kits are useful for preventing a muscle disease in a subject in need thereof.
  • the kits are useful for reducing the risk of developing a muscle disease in a subject in need thereof.
  • the kits are useful for diagnosing a muscle disease in a subject in need thereof.
  • 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.
  • a kit described herein further includes instructions for using the conjugate or pharmaceutical composition thereof in a method or use described herein.
  • a kit described herein may also include information as required by a regulatory agency such as the FDA or EMA.
  • the information included in the kits is prescribing information.
  • the kits and instructions provide for treating a muscle disease in a subject in need thereof.
  • the kits and instructions provide for preventing a muscle disease in a subject in need thereof.
  • kits and instructions provide for reducing the risk of developing a muscle disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for diagnosing a muscle 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. In certain embodiments, the delivery is selective for the muscle over another organ or tissue. In certain embodiments, another organ or tissue is liver. In certain embodiments, another organ or tissue is kidney.
  • another organ or tissue is heart.
  • the delivery of the conjugate to the muscle is higher (e.g., 10-30%, 30-100%, 1-3 fold, 3-10 fold, 10-30 fold, 30-100 fold, 100-300 fold, 300-1000 fold, or greater than 1000 fold higher) than the delivery of the conjugate to organ or tissue that is not a muscle.
  • the delivery is determined by the definite integral of the concentration of the conjugate in the muscle or the organ or tissue that is not a muscle as a function of time.
  • the muscle is a skeletal muscle.
  • the muscle is a cardiac muscle.
  • the muscle is a smooth muscle.
  • the muscle disease is a congenital myopathy.
  • the congenital myopathy is central core disease, minimulticore disease, centronuclear myopathy, myotubular myopathy, congenital fiber-Type disproportion myopathy, King-Denborough syndrome, or nemaline myopathy.
  • the muscle disease is a metabolic myopathy.
  • the metabolic myopathy is acid maltase deficiency (AMD).
  • the acid maltase deficiency is Pompe disease, glycogenosis Type 2, or lysosomal storage disease.
  • the metabolic myopathy is carnitine deficiency, debrancher enzyme deficiency (Cori or Forbes disease, glycogenosis Type 3), lactate dehydrogenase deficiency (glycogenosis Type 11), phosphofructokinase deficiency (Tarui disease, glycogenosis Type 7), phosphogylcerate kinase deficiency (glycogenosis Type 9), phosphogylcerate mutase deficiency (glycogenosis Type 10), phosphorylase deficiency (McArdle disease, myophosphorylase deficiency, glycogenosis Type 5), or myoadenylate deaminase deficiency.
  • debrancher enzyme deficiency Cori or Forbes disease, glycogenosis Type 3
  • lactate dehydrogenase deficiency glycogenosis Type 11
  • the metabolic myopathy is carnitine palmitoyl transferase deficiency. In certain embodiments, the carnitine palmitoyl transferase deficiency is carnitine palmitoyl transferase II (CPTII) deficiency. In certain embodiments, the metabolic myopathy is glycogen storage disease (GSD). In certain embodiments, the glycogen storage disease is glycogen storage disease Type 0b, II (Pompe disease), III, IV (Andersen disease), V (McArdle disease), VII (Tarui disease), IX, X, XI XII, XIII, or XV. In certain embodiments, the muscle disease is muscle atrophy.
  • the muscle atrophy is pathologic atrophy, neurogenic atrophy, or physiologic atrophy.
  • the muscle disease is muscular dystrophy.
  • the muscular dystrophy is Becker muscular dystrophy (BMD), collagen Type VI- related disorder, congenital muscular dystrophy (CMD), Duchenne muscular dystrophy (DMD), Emery-Dreifuss muscular dystrophy (EDMD), Facioscapulohumeral muscular dystrophy (FSHD), myotonic muscular dystrophy, or oculopharyngeal muscular dystrophy (OMD).
  • the muscular dystrophy is a distal muscular dystrophy (Distal MD).
  • the distal muscular dystrophy is Laing distal myopathy, Miyoshi distal myopathy, Nonaka distal myopathy, or VCP myopathy.
  • the muscular dystrophy is limb-girdle muscular dystrophy.
  • the limb-girdle muscular dystrophy is limb-girdle muscular dystrophy Type 1A, 1B, 1C, 1D, 1E, 1F, 1G, 1H, 2, 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T, 2U, 2V, or 2W.
  • the muscle disease is myotonia congenita. In certain embodiments, the myotonia congenita is autosomal dominant myotonia congenita (Thomsen disease). In certain embodiments, the muscle disease is myotonic dystrophy. In certain embodiments, the myotonic dystrophy is myotonic dystrophy Type 1 (DM1) or 2 (DM2). In certain embodiments, the muscle disease is a neuromuscular disease. In certain embodiments, the neuromuscular disease is amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, multiple sclerosis, myasthenia gravis, myopathy, peripheral neuropathy, or spinal muscular atrophy. In certain embodiments, the neuromuscular disease is myositis.
  • the myositis is polymyositis or dermatomyositis.
  • the neuromuscular disease is neuromuscular junction disease.
  • the neuromuscular junction disease is congenital myasthenic syndromes (CMS).
  • the muscle disease is Barth syndrome, Brody myopathy, cap myopathy, centronuclear myopathy (CNM), fibrodysplasia ossificans progressiva (FOP), fingerprint body myopathy, Friedreich's ataxia (FRDA), hereditary myopathy with early respiratory failure, inclusion body myopathy (IBM), multisystemic smooth muscle dysfunction syndrome, muscle wasting, myofibrillar myopathy (MFM), myopathy with extrapyramidal signs (MPXPS), myosin storage myopathy, ophthalmoplegia, paramyotonia congenita (PMC), reducing body myopathy, rippling muscle disease (RMD), Satoyoshi syndrome, torsion dystonia, tubular aggregate myopathy, or X-linked myotubular myopathy (XLMTM).
  • CCM centronuclear myopathy
  • FOP fibrodysplasia ossificans progressiva
  • FRDA Friedreich's ataxia
  • IBM inclusion body myopathy
  • MFM my
  • the muscle disease is anismus, muscle cramp, muscle degeneration, muscle hypertrophy, muscle hypotonia, muscle injury, muscle ischemia, muscle lesion, muscle necrosis, muscle neoplasm, muscle rigidity, muscle weakness, muscular dysgenesis, muscular fibrosis, myalgia, myoclonus, myokymia, paratonia, or rhabdomyolysis.
  • the muscle disease may be associated with one or more genes.
  • at least one gene is a mammal gene.
  • at least one gene is a human gene.
  • at least one gene is a non-human mammal gene.
  • the muscle disease may be associated with the up-regulation of at least one gene.
  • the muscle disease may be associated with the down-regulation of at least one gene.
  • at least one gene is a gene described in this paragraph.
  • the cap myopathy is associated with ACTA1, TPM2, or TPM3.
  • the multisystemic smooth muscle dysfunction syndrome is associated with ACTA2.
  • the fibrodysplasia ossificans progressiva (FOP) is associated with ACVR1.
  • the myoadenylate deaminase deficiency is associated with AMPD1.
  • the limb-girdle muscular dystrophy Type 2L (LGMD2L) is associated with ANO5.
  • the Brody myopathy is associated with ATP2A1.
  • the limb-girdle muscular dystrophy Type 2 (LGMD2X) is associated with BVES. In some embodiments, the limb-girdle muscular dystrophy Type 2A (LGMD2A) is associated with CAPN3. In some embodiments, the limb-girdle muscular dystrophy Type 1C (LGMD1C) is associated with CAV3. In some embodiments, the rippling muscle disease (RMD) is associated with CAV3 or CAVIN1.
  • the congenital myasthenic syndromes is associated with CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, DOK7, MUSK, MYO9A, AGRN, LRP4, PREP1, SCN4A, RAPSN, PLEC, or SLC25A1.
  • the autosomal dominant myotonia congenita is associated with CLCN1.
  • the myotonic dystrophy Type 2 is associated with CNBP.
  • the carnitine palmitoyl transferase II (CPTII) deficiency is associated with CPT2.
  • the limb-girdle muscular dystrophy Type 2P is associated with DAG1.
  • the limb-girdle muscular dystrophy Type 1E is associated with DES.
  • the limb-girdle muscular dystrophy Type 2R is associated with DES.
  • the myofibrillar myopathy is associated with DES, MYOT, or LDB3.
  • the Becker muscular dystrophy is associated with DMD.
  • the Duchenne muscular dystrophy (DMD) is associated with DMD.
  • the myotonic dystrophy Type 1 is associated with DMPK.
  • the limb-girdle muscular dystrophy Type 1D (LGMD1D) is associated with DNAJB6.
  • the centronuclear myopathy (CNM) is associated with DNM2, BIN1, or TTN.
  • the Facioscapulohumeral muscular dystrophy (FSHD) is associated with DUX4.
  • the Miyoshi distal myopathy is associated with DYSF.
  • the limb-girdle muscular dystrophy Type 2B (LGMD2B) is associated with DYSF.
  • the reducing body myopathy is associated with FHL1.
  • the limb-girdle muscular dystrophy Type 2I is associated with FKRP. In some embodiments, the limb-girdle muscular dystrophy Type 2M (LGMD2M) is associated with FKTN. In some embodiments, the Friedreich's ataxia (FRDA) is associated with FXN. In some embodiments, the limb-girdle muscular dystrophy Type 2V (LGMD2V) is associated with GAA. In some embodiments, the muscle wasting is associated with GDF15, FBXO32, TRIM63, or MSTN. In some embodiments, the limb-girdle muscular dystrophy Type 2T (LGMD2T) is associated with GMPPB.
  • the inclusion body myopathy is associated with GNE.
  • the Nonaka distal myopathy is associated with GNE.
  • the glycogen storage disease (GSD) is associated with GYS1, GAA, AGL, GBE1, PYGM, PFKM, PHKA, PHKA2, PHKAB, PHKAG1, PHKG2, PHKD, PGAM2, ALDOA, ENO3, GYG1, or LDHA.
  • the limb-girdle muscular dystrophy Type 1G (LGMD1G) is associated with HNRNPDL.
  • the limb-girdle muscular dystrophy Type 2U (LGMD2U) is associated with ISPD.
  • the limb-girdle muscular dystrophy Type 2W (LGMD2W) is associated with LIMS2.
  • the limb-girdle muscular dystrophy Type 1B (LGMD1B) is associated with LMNA.
  • the Emery-Dreifuss muscular dystrophy (EDMD) is associated with LMNA, EMD, or FHL1.
  • the fingerprint body myopathy is associated with LMOD3.
  • the myopathy with extrapyramidal signs (MPXPS) is associated with MICU1.
  • the X-linked myotubular myopathy (XLMTM) is associated with MTM1.
  • the Laing distal myopathy is associated with MYH7.
  • the myosin storage myopathy is associated with MYH7.
  • the limb-girdle muscular dystrophy Type 1A (LGMD1A) is associated with MYOT.
  • the nemaline myopathy is associated with NEB or ACTA1.
  • the oculopharyngeal muscular dystrophy (OMD) is associated with PABPN1.
  • the limb-girdle muscular dystrophy Type 2Q (LGMD2Q) is associated with PLEC1.
  • the ophthalmoplegia is associated with POLG, TWNK, RRM2B, or SLC25A4.
  • the limb-girdle muscular dystrophy Type 2O is associated with POMGnT1. In some embodiments, the limb-girdle muscular dystrophy Type 2K (LGMD2K) is associated with POMT1. In some embodiments, the limb- girdle muscular dystrophy Type 2N (LGMD2N) is associated with POMT2. In some embodiments, the congenital myopathy is associated with RYR1, NEM2, ACTA1, TPM2, DNM2, BIN1, MTM1, or TPM3. In some embodiments, the paramyotonia congenita (PMC) is associated with SCN4A.
  • the congenital muscular dystrophy is associated with SEPN1, TTN, ITGA7, IGTA9, PLEC, FKRP, LARGE, DOK7, LMNA, SBP2, FKTN, LAMA2, POMGnT1, COLGA1, COL6A2, COL6A3, B3GNT1, POMT1, POMT2, ISPD, GTDC2, TMEM5, B3GALNT2, or SGK196.
  • the limb-girdle muscular dystrophy Type 2D (LGMD2D) is associated with SGCA.
  • the limb-girdle muscular dystrophy Type 2E (LGMD2E) is associated with SGCB.
  • the limb-girdle muscular dystrophy Type 2F is associated with SGCD. In some embodiments, the limb-girdle muscular dystrophy Type 2C (LGMD2C) is associated with SGCG. In some embodiments, the carnitine deficiency is associated with SLC22A5. In some embodiments, the amyotrophic lateral sclerosis is associated with SOD1, TDP43, FUS, or C9orf72. In some embodiments, the tubular aggregate myopathy is associated with STIM1. In some embodiments, the Barth syndrome is associated with TAFAZZIN. In some embodiments, the limb-girdle muscular dystrophy Type 2G (LGMD2G) is associated with TCAP.
  • the limb-girdle muscular dystrophy Type 1F is associated with TNPO3.
  • the torsion dystonia is associated with TOR1A, TUBB4, THAP1, PRKRA, CIZ1, ANO3, GNAL, AF1, GCH1, TH, ATP1A3, SGCE, MR-1, PRRT2, or SLC2A1.
  • the limb-girdle muscular dystrophy Type 2 (LGMD2Y) is associated with TOR1A1P1.
  • the limb-girdle muscular dystrophy Type 2S is associated with TRAPPC11.
  • the limb-girdle muscular dystrophy Type 2H (LGMD2H) is associated with TRIM32.
  • the hereditary myopathy with early respiratory failure is associated with TTN.
  • the limb-girdle muscular dystrophy Type 2J (LGMD2J) is associated with TTN.
  • the VCP myopathy is associated with VCP.
  • the subject treated using the methods provided herein may be a mammal, for example, a primate, such as a human or non-human primate.
  • the subject is a human.
  • the subject is a human younger than 2 years.
  • the subject is a human aged 2-6 years, inclusive.
  • a conjugate of Formula I (A)y–L–(R 1 )r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an ⁇ 4 ⁇ 1/7 integrin ligand; L is a linker; each instance of R 1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6; for use in treating a muscle disease in a subject in need thereof. 2.
  • a conjugate of Formula I (A)y–L–(R 1 )r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an ⁇ 4 ⁇ 1/7 integrin ligand; L is a linker; each instance of R 1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6; for use in preventing a muscle disease in a subject in need thereof. 3.
  • a conjugate of Formula I (A) y –L–(R 1 ) r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an ⁇ 4 ⁇ 1/7 integrin ligand; L is a linker; each instance of R 1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6; for use in diagnosing a muscle disease in a subject in need thereof. 4.
  • the metabolic myopathy is carnitine deficiency, debrancher enzyme deficiency (Cori or Forbes disease, glycogenosis Type 3), lactate dehydrogenase deficiency (glycogenosis Type 11), phosphofructokinase deficiency (Tarui disease, glycogenosis Type 7), phosphogylcerate kinase deficiency (glycogenosis Type 9), phosphogylcerate mutase deficiency (glycogenosis Type 10), phosphorylase deficiency (McArdle disease, myophosphorylase deficiency, glycogenosis
  • glycogen storage disease is glycogen storage disease Type 0b, II (Pompe disease), III, IV (Andersen disease), V (McArdle disease), VII (Tarui disease), IX, X, XI XII, XIII, or XV.
  • glycogen storage disease is glycogen storage disease Type 0b, II (Pompe disease), III, IV (Andersen disease), V (McArdle disease), VII (Tarui disease), IX, X, XI XII, XIII, or XV.
  • the muscle disease is muscular dystrophy.
  • the muscular dystrophy is Becker muscular dystrophy (BMD), collagen Type VI-related disorder, congenital muscular dystrophy (CMD), Duchenne muscular dystrophy (DMD), Emery-Dreifuss muscular dystrophy (EDMD), Facioscapulohumeral muscular dystrophy (FSHD), myotonic muscular dystrophy, or oculopharyngeal muscular dystrophy (OMD).
  • BMD Becker muscular dystrophy
  • CMD congenital muscular dystrophy
  • DMD Duchenne muscular dystrophy
  • EDMD Emery-Dreifuss muscular dystrophy
  • FSHD Facioscapulohumeral muscular dystrophy
  • myotonic muscular dystrophy or oculopharyngeal muscular dystrophy (OMD).
  • DM1 myotonic dystrophy Type 1
  • DM2 myotonic dystrophy Type 1
  • the neuromuscular junction disease is congenital myasthenic syndromes (CMS). 32.
  • the muscle disease is Barth syndrome, Brody myopathy, cap myopathy, centronuclear myopathy (CNM), fibrodysplasia ossificans progressiva (FOP), fingerprint body myopathy, Friedreich's ataxia (FRDA), hereditary myopathy with early respiratory failure, inclusion body myopathy (IBM), multisystemic smooth muscle dysfunction syndrome, muscle wasting, myofibrillar myopathy (MFM), myopathy with extrapyramidal signs (MPXPS), myosin storage myopathy, ophthalmoplegia, paramyotonia congenita (PMC), reducing body myopathy , rippling muscle disease (RMD) , Satoyoshi syndrome, torsion dystonia , tubular aggregate myopathy, or X-linked myotubular myopathy (XLMTM).
  • CCM centronuclear myopathy
  • FOP fibrodysplasia ossificans progressiva
  • FRDA Friedreich's ataxia
  • IBM inclusion body myopathy
  • a conjugate of Formula I (A)y–L–(R 1 )r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an ⁇ 4 ⁇ 1/7 integrin ligand; L is a linker; each instance of R 1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6 for use in delivering the pharmaceutical agent to a muscle of a subject.
  • y is 1, 2, 3, 4, 5, or 6
  • each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an ⁇ 4 ⁇ 1/7 integrin ligand
  • L is a linker
  • each instance of R 1 is independently a radical of a pharmaceutical agent
  • r is 1, 2, 3, 4, 5, or 6 for use in delivering the pharmaceutical agent to a muscle of a subject.
  • 38. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-37, wherein the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, is administered to the subject parenterally. 39.
  • SOD1 superoxide dismutase type 1
  • oligonucleotide is a double- stranded oligonucleotide comprising a sense oligonucleotide strand and an antisense oligonucleotide strand.
  • a strand of at least one oligonucleotide has at least 80%, at least 85%, at least 90%, or at least 95% identity to SEQ ID NO.: 2, 4, 5, or 6. 67.
  • conjugate for use of any one of embodiments 1-41, wherein the conjugate is of Formula I-A: , (I-A) or a pharmaceutically acceptable salt or prodrug thereof, wherein: is a radical of an oligonucleotide strand; s1 instances of the nucleobase-sugar moieties at internal positions of are independently replaced with a moiety of Formula A: (A); s1 is 0, 1, 2, 3, 4, 5, or 6; when s1 is 1, 2, 3, 4, 5, or 6: each instance of N 1 is independently a radical of a nucleobase or a bond; each instance of t1 is independently 1, 2, or 3; each instance of y1 and y2 is independently 0, 1, 2, 3, 4, 5, or 6; provided that at least one instance of y1 and y2 is 1, 2, 3, 4, 5, or 6; each instance of A 1 and A 2 , when present, is independently a radical of a ligand or lipid; when y1 of an
  • N 1 is a radical of adenine, cytosine, guanine, thymine or uracil.
  • Ci-100 alkylene substituted or unsubstituted, C 2 -ioo alkenylene, substituted or unsubstituted, C 2 -ioo alkynylene, substituted or unsubstituted, Ci-100 heteroalkylene, substituted or unsubstituted, C 2 -ioo heteroalkenylene, or substituted or unsubstituted, C 2 -ioo heteroalkynylene; optionally wherein one or more backbone atoms of the Ci-100 alkylene, C 2 -ioo alkenylene, C 2 -ioo alkynylene, Ci-100 heteroalkylene, C 2 -ioo heteroalkenylene, or C 2 -ioo heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or un
  • L 1 thereof is substituted or unsubstituted, C7-70 alkylene, substituted or unsubstituted, C7-70 alkenylene, substituted or unsubstituted, C7-70 heteroalkylene, or substituted or unsubstituted, C7-70 heteroalkenylene; optionally wherein one, two, three, or four backbone atoms of the C7-70 alkylene, C7-70 alkenylene, C7-70 heteroalkylene, or C7-70 heteroalkenylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.
  • L 1 thereof is substituted or unsubstituted, C7-70 alkylene or substituted or unsubstituted, C7-70 heteroalkylene; and one, two, three, or four 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.
  • L 1 thereof is substituted or unsubstituted, C7-70 heteroalkylene.
  • L 1 thereof comprises one or more of the following -CH2-, A, , tion of two or more of each one of the foregoing, provided that: the number of backbone atoms of L 1 thereof is between 7 and 70, inclusive; and
  • L 1 thereof does not comprise O-O, O-N, N-O, or N-N.
  • conjugate or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-89, wherein at least one instance of A 2 is a radical of a lipid.
  • L 2 — (A 2 ) 2 one of embodiments 67-95, wherein y2 of an instance of ' ' y2 is 1, 2, 3, 4,
  • 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,
  • C2-100 alkynylene, 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.
  • L e of embodiments 67-96 wherein y2 of an instance of 2 -(A 2 ) on y2 is 1, 2, 3, 4, 5, or 6, and L 2 thereof is substituted or unsubstituted, C7-70 alkylene, substituted or unsubstituted, C7-70 alkenylene, substituted or unsubstituted, C7-70 heteroalkylene, or substituted or unsubstituted, C7-70 heteroalkenylene; optionally wherein one, two, or three backbone atoms of the C7-70 alkylene, C7-70 alkenylene, C7-70 heteroalkylene, or C7-70 heteroalkenylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.
  • L 2 — (A 2 ) 2 one of embodiments 67-97, wherein y2 of an instance of ' ' y2 is 1, 2, 3, 4, 5, or 6, and L 2 thereof is substituted or unsubstituted, C7-70 alkylene or substituted or unsubstituted, C7-70 heteroalkylene; and one, two, or three 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.
  • L 2 — (A 2 ) 9 one of embodiments 67-98, at least one instance of ' /y2 is of the formula:
  • each instance of R a is 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 R a attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L 2B1 and L 2B2 is independently a single bond, substituted or unsubstituted, Ci-100 alkylene, or substituted or unsubstituted, Ci-100 heteroalkylene;
  • L 2C1 is 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 C 2A is attached to A 2 .
  • L 2 — (A 2 ) 2 one of embodiments 67-105, wherein y2 of an instance of ' /y2 is 1, 2, 3, 4,
  • L 2 thereof is substituted or unsubstituted, C7-70 heteroalkylene.
  • L 2 thereof comprises one or more of the following -CH2-, tion of two or more of each one of the foregoing, provided that: the number of backbone atoms of L 2 thereof is between 7 and 70, inclusive; and
  • L 2 thereof does not comprise O-O, O-N, N-O, or N-N.
  • AgA A' A more of the following -CH2-, , -O-, -CH2CH2O-, -OCH2CH2-, - combination of two or more of each one of the foregoing, provided that: the number of backbone atoms of the at least one instance of L 4 is between 10 and 100, inclusive; and the at least one instance of L 4 does not comprise O-O, O-N, N-O, or N-N.
  • L 5 does not comprise O-O, O-N, N-O, or N-N.
  • the substituted or unsubstituted heteroarylene that replaces one of the backbone atoms is of the formula: k21 is 0, 1, 2, 3, or 4; each instance of R d , 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 R e , 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 R f , if present, is independently halogen, substituted or unsubstituted, Ci-6 alkyl, or -O
  • L 6 comprises one or more of the following- combination of two or more of each one of the foregoing, provided that: the number of backbone atoms of L 6 is between 10 and 100, inclusive; and
  • L 6 does not comprise O-O, 0-N, N-0, or N-N.
  • conjugate or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-181, wherein at least one ligand is a monoclonal antibody.
  • each instance of R 1Z is independently optionally substituted heteroaryl or optionally substituted phenyl; each instance of R 33z is independently -O(optionally substituted alkyl), -OH, -NH2, - NHOH, -NH(optionally substituted alkyl), -NH(optionally substituted polyethylene glycol), - N(optionally substituted alkyl)2, or -N(optionally substituted alkyl)(optionally substituted polyethylene glycol); each instance of R 34z is of the formula: each instance of R 2Z is independently hydrogen, optionally substituted polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, or optionally substituted heteroaryl; and each instance of X 4Z is N or C(R 35Z ); and each instance of R 35z is
  • each instance of R 2Z is independently hydrogen, polyethylene glycol, optionally substituted heteroalkyl, or optionally substituted heteroaryl; and each instance of R 3Z and R 4Z is independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted alkoxy.
  • each of R 8Z , R 9Z , R 10z , and R 11Z is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted -O-alkyl, or substituted or unsubstituted cycloalkyl; each of R 12z and R 13z is independently H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl,
  • R 14Z is optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkylene-(C3-C6)- cycloalkyl, or optionally substituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy.
  • each of R 9Z , R 10z , and R 11Z is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted -O-alkyl, or substituted or unsubstituted cycloalkyl; each of R 12z and R 13z is independently H, halogen, optionally substituted alkyl, optionally R 14Z is optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkylene-(C3-C6)- cycloalkyl, or optionally substituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy.
  • R 4Z is hydrogen, halogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted -O-alkyl, or optionally substituted cycloalkyl;
  • R 5Z is optionally substituted heteroalkyl or optionally substituted heterocyclyl; and
  • nlZ is 1, 2, or 3. 205.
  • R 6Z is hydrogen, -OH, -NH2, -NHR 7Z , -OR 7Z , or absent; and R 7Z is hydrogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.
  • R 7Z is hydrogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.
  • n3Z is 0, 1, 2, or 3.
  • R 15Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; each of R 16z and R 17Z is independently H, halogen, optionally substituted alkyl, or optionally substituted -O-alkyl; and
  • Y z is -CH 2 - or -(CH 2 ) 2 -.
  • R 18Z is H, -OH, -NH 2 , -NHR 19Z , -OR 19Z , or -CONHR 19Z ; each instance of R 19z is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and n4Z is 1 or 2.
  • R 19Z is H, -CH 2 OR 20Z , -(CH 2 ) 2 OR 20Z , -CH 2 NHCOR 20Z , or -OR 20Z ;
  • R 20z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.
  • R 21Z is H, -CONHR 22Z , -CH 2 OR 22Z , -(CH 2 ) 2 OR 22Z , -CH 2 NHCOR 22Z , or -OR 22Z ;
  • R 22Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;
  • X 1Z is H or halogen.
  • R 21Z is H, -CONHR 22Z , -CH 2 OR 22Z , -(CH 2 ) 2 OR 22Z , -CH 2 NHCOR 22Z , or -OR 22Z ;
  • R 22Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;
  • X 1Z is H or halogen. 213.
  • R 23Z is H, -CONHR 24Z , -CH 2 OR 24Z , -(CH 2 ) 2 OR 24Z , -CH 2 NHCOR 24Z , or -OR 24Z ;
  • R 24Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and
  • n5Z is 0, 1, 2, or 3. 215.
  • R 25Z is H, –CONHR 27Z , –CH2OR 27Z , –(CH2)2OR 27Z , –CH2NHCOR 27Z , or –OR 27Z ;
  • R 26Z is H, optionally substituted alkyl, or optionally substituted cycloalkyl;
  • R 27Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and
  • X 2Z is optionally substituted CH2 or optionally substituted NH. 217.
  • R 25Z is H, –CONHR 27Z , –CH2OR 27Z , –(CH2)2OR 27Z , –CH2NHCOR 27Z , or –OR 27Z ;
  • R 26Z is H, optionally substituted alkyl, or optionally substituted cycloalkyl; and
  • R 27Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl. 218.
  • R 28Z is H, –CH 2 OR 30Z , –(CH 2 ) 2 OR 30Z , –CH 2 NHCOR 30Z , or –OR 30Z ;
  • R 29Z is H, –OH, –NH 2 , –NHR 31Z , or –OR 31Z ;
  • R 30Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;
  • R 31Z
  • R 28Z is H, –CH 2 OR 30Z , –(CH 2 ) 2 OR 30Z , –CH 2 NHCOR 30Z , or –OR 30Z ;
  • R 29Z is H, –OH, –NH 2 , –NHR 31Z , or –OR 31Z ;
  • R 30Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;
  • R 31Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;
  • n3Z is 1, 2, or 3.
  • CB 1 cannabinoid receptor type 1
  • 224 The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-223, wherein y is 2, 3, 4, 5, or 6; and at least one ligand is a N- methyl-D-aspartate (NMDA) ligand.
  • lipid is a glycerophosphocholine, glycerophosphoethanolamine, glycerophosphoserine, glycerophosphoglycerol, glycerophosphoglycerophosphate, glycerophosphoinositol, glycerophosphoinositol monophosphate, glycerophosphoinositol bisphosphate, glycerophosphoinositol trisphosphate, glycerophosphate, glyceropyrophosphate, glycerophosphoglycerophosphoglycerol, CDP-glycerol, glycosylglycerophospholipid, glycerophosphoinositolglycan, glycerophosphonocholine, glycerophosphonoethanolamine, di-glycerol tetraether phospholipid, glycerophosphocholine, glycerophosphonoethanolamine, di-glycerol tetraether phospholipid,
  • conjugate for use of any one of embodiments 1-239, wherein 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. 241.
  • conjugate for use of any one of embodiments 241-242, wherein between 20% and 100%, inclusive, of the combined number of the sugars, nucleobases, and internucleosidic linkers of the oligonucleotide strand, sense oligonucleotide strand, or antisense oligonucleotide strand is modified. 244.
  • conjugate for use of any one of embodiments 241-243, wherein between 50% and 100%, inclusive, of the sugars of the oligonucleotide strand, sense oligonucleotide strand, or antisense oligonucleotide strand are modified sugars. 245.

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Abstract

The present disclosure provides methods of treating, preventing, or diagnosing muscle diseases in a subject in need thereof using a conjugate of Formula I: (I), wherein each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an α4β1/7 integrin ligand; L is a linker; and each instance of R1 is independently a radical of a pharmaceutical agent (e.g., an oligonucleotide). The conjugate may be able to selectively deliver the pharmaceutical agent to a muscle of the subject.

Description

PHARMACEUTICAL AGENT-INTEGRIN LIGAND CONJUGATES FOR MUSCLE DELIVERY
RELATED APPLICATIONS
This application claims priority to U.S. Provisional Patent Application No. 63/589975, filed October 12, 2023, which is incorporated herein by reference.
BACKGROUND
In the use of pharmaceutical agents (e.g., oligonucleotides) in therapeutic, prophylactic, or diagnostic applications, it is often desirable that the pharmaceutical agents 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 pharmaceutical agent in vivo. Further, being able to efficiently deliver a pharmaceutical agent to a specific location can limit or potentially eliminate unintended consequences (such as off-target effects) that may be caused by administration of the pharmaceutical agent. One strategy to facilitate delivery of a pharmaceutical to a desired location in vivo, is by linking or attaching the pharmaceutical agent to a targeting ligand.
One class of pharmaceutical agents 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 shown 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.
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 internucleoside linkages. There is a need for new methods for delivering pharmaceutical agents to a muscle of a subject. SUMMARY OF THE DISCLOSURE In one aspect, the present disclosure provides a method of treating a muscle disease in a subject in need thereof comprising administering to the subject an effective amount of a conjugate of Formula I: (A)y–L–(R1)r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an α4β1/7 integrin ligand; L is a linker; each instance of R1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6. α4β1/7 integrin receptors may be expressed (e.g., selectively expressed) in muscle cells. The conjugates may be useful for delivering pharmaceutical agents to a muscle (e.g., muscle cell) of a subject (e.g., a human). In some embodiments, at least one pharmaceutical agent is an oligonucleotide. The conjugates may be useful in treating, preventing, or diagnosing a muscle disease. In some embodiments, the α4β1/7 integrin ligand is capable of selectively targeting a muscle (e.g., muscle cell) of a subject. In some embodiments, the α4β1/7 integrin ligand is capable of selectively targeting a particular type of muscle cell (e.g., a skeletal muscle cell, cardiac muscle cell, smooth muscle cell). In some embodiments, the α4β1/7 integrin ligand is capable of selectively binding to or otherwise selectively recognizing one or more receptors on a muscle cell. The conjugate may be advantageous over the pharmaceutical agent not conjugated with an α4β1/7 integrin ligand 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 pharmaceutical agents are conjugated with at least one instance of a radical of an α4β1/7 integrin ligand. In another aspect, the present disclosure provides uses of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for treating a muscle disease in a subject in need thereof.
In another aspect, the present disclosure provides the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use in treating a muscle disease in a subject in need thereof.
In another aspect, the present disclosure provides methods of preventing a muscle disease in a subject in need thereof comprising administering to the subject an effective amount of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof.
In another aspect, the present disclosure provides uses of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for preventing a muscle disease in a subject in need thereof.
In another aspect, the present disclosure provides the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use in preventing a muscle disease in a subject in need thereof.
In another aspect, the present disclosure provides methods of diagnosing a muscle disease in a subject in need thereof comprising administering to the subject an effective amount of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof.
In another aspect, the present disclosure provides uses of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for diagnosing a muscle disease in a subject in need thereof.
In another aspect, the present disclosure provides the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use in diagnosing a muscle disease in a subject in need thereof.
In another aspect, the present disclosure provides methods for delivering a pharmaceutical agent to a muscle of a subject comprising administering to the subject the conjugate, or a pharmaceutically acceptable salt or prodrug thereof.
In another aspect, the present disclosure provides uses of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for delivering a pharmaceutical agent to a muscle of a subject.
In another aspect, the present disclosure provides the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use in delivering a pharmaceutical agent to a muscle of a subject. DEFINITIONS
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, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Michael B. Smith, March’ s Advanced Organic Chemistry, 7th Edition, 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, 3rd Edition, Cambridge University Press, Cambridge, 1987.
Compounds (e.g., conjugates) 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.
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 of 19F with 18F, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.
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, Ce, C1-6, C1-5, CM, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3 A, C4-6, C4-5, and C5-6 alkyl. The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 150 carbon atoms (“Ci-150 alkyl”). In some embodiments, an alkyl group has 100 to 150 carbon atoms (“C100-150 alkyl”). In some embodiments, an alkyl group has 50 to 100 carbon atoms (“C50-100 alkyl”). In some embodiments, an alkyl group has 20 to 50 carbon atoms (“C20-50 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 (“Ci-12 alkyl”). In some embodiments, an alkyl 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 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“CM alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., zz-propyl, isopropyl), butyl (C4) (e.g., n- butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., zz-pentyl, 3-pentanyl, amyl, neopentyl, 3- methyl-2-butanyl, tert-amyl), and hexyl (Ce) (e.g., n-hcxyl). Additional examples of alkyl groups include zz-heptyl (C7), zz-octyl (Cs), zz-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as fluorine). In certain embodiments, the alkyl group is an unsubstituted Ci-12 alkyl (such as unsubstituted Ci- 6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n- propyl (n-Pr), unsubstituted isopropyl (z-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted zz-butyl (zz-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (z-Bu)). In certain embodiments, the alkyl group is a substituted Ci-12 alkyl (such as substituted Ci 6 alkyl, e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).
The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, 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 150 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-150 alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 100 to 150 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCioo-iso alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 50 to 100 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCso-ioo alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 20 to 50 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC20-50 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 20 alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-12 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-n alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“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 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-s alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-7 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“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 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms within the parent chain (“hctcroCi 4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents (e.g., oxo, substituted or unsubstituted C1-6 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(=O)NH2. In some embodiments, unsubstituted heteroC2 alkyl is -OCH2CH3, - CH2OCH3, or –CH2CH2OH. The terms “heteroCz1-z2 alkyl” and “Cz1-z2 heteroalkyl” are used interchangeably, wherein each of z1 and z2 is independently an integer. 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.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 1 to 150 carbon atoms (“C1-150 alkenyl”). In some embodiments, an alkenyl group has at least 2 carbon atoms. In some embodiments, an alkenyl group has 100 to 150 carbon atoms (“C100-150 alkenyl”). In some embodiments, an alkenyl group has 50 to 100 carbon atoms (“C50-100 alkenyl”). In some embodiments, an alkenyl group has 20 to 50 carbon atoms (“C20-50 alkenyl”). 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 (“C1–4 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 (“C1 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 C2–100 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 (C1), ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C1–6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted 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 ) may be in the (E)- or (Z)-configuration. 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 150 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–150 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 100 to 150 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC100–150 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 50 to 100 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC50–100 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 20 to 50 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC20–50 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–20 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–12 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–11 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 (“heteroC1–10 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–9 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–8 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–7 alkenyl”). In some embodiments, a heteroalkenyl group has 1to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–6 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 (“heteroC1–5 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–4 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC1–3 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC1–2 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–6 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 C2–100 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 C1-6 alkyl (e.g., –CH3)). In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC1–20 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC1–20 alkenyl. In some embodiments, unsubstituted heteroC1 alkenyl is –CH=NH or =N–CH3. The terms “heteroCz1-z2 alkenyl” and “Cz1-z2 heteroalkenyl” are used interchangeably, wherein each of z1 and z2 is independently an integer. The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 150 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C1-150 alkynyl”). In some embodiments, an alkynyl group has 100 to 150 carbon atoms (“C100-150 alkynyl”). In some embodiments, an alkynyl group has 50 to 100 carbon atoms (“C50-100 alkynyl”). In some embodiments, an alkynyl group has 20 to 50 carbon atoms (“C20-50 alkynyl”). In some embodiments, an alkynyl group has 1 to 20 carbon atoms (“C1-20 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 alkynyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C1-9 alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“C1-8 alkynyl”). In some embodiments, an alkynyl group has 1 to 7 carbon atoms (“C1-7 alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“C1-6 alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C1-5 alkynyl”). In some embodiments, an alkynyl group has 1 to 4 carbon atoms (“C1-4 alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“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 (“C1 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 alkynyl, 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 C2–100 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 (C1), ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C1-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C1-20 alkynyl. In certain embodiments, the alkynyl group is a substituted C1-20 alkynyl. The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, 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 150 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–150 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 100 to 150 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC100–150 alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 50 to 100 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC50–100 alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 20 to 50 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC20–50 alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–20 alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–10 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 (“heteroC1–9 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–8 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–7 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–6 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 (“heteroC1–5 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“heteroC1–4 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC1–3 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC1–2 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1– 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 heteroalkynyl, C2–90 heteroalkynyl, or C2–100 heteroalkynyl. 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 C1-6 alkyl (e.g., –CH3)). In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC1–20 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC1–20 alkynyl. In some embodiments, unsubstituted heteroC1 alkynyl is –C≡N. The terms “heteroCz1-z2 alkynyl” and “Cz1-z2 heteroalkynyl” are used interchangeably, wherein each of z1 and z2 is independently an integer. The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), 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 (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), 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-1H- 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 (C11), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and 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. In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits. The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members 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. 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. 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. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2- b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3- dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H- pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2- b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like. The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 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 C6-14 aryl. In certain embodiments, the aryl group is a substituted C6-14 aryl. The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In 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. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl. 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. The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I). The term “alkoxy” refers to an -O-alkyl substituent. 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 C1 heteroalkylene is –OCH2– or –CH2O–. In some embodiments, substituted C1 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)3–. 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 –(OCH2CH2)6– or –(CH2CH2O)6–. 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. Exemplary carbon atom substituents include halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORaa, −ON(Rbb)2, −N(Rbb)2, −N(Rbb)3+X−, −N(ORcc)Rbb, −SH, −SRaa, −SSRcc, −C(=O)Raa, −CO2H, −CHO, −C(ORcc)2, −CO2Raa, −OC(=O)Raa, −OCO2Raa, −C(=O)N(Rbb)2, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −OC(=NRbb)Raa, −OC(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −OC(=NRbb)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −C(=O)NRbbSO2Raa, −NRbbSO2Raa, −SO2N(Rbb)2, −SO2Raa, −SO2ORaa, −OSO2Raa, −S(=O)Raa, −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)(ORcc)2, −P(=O)(N(Rbb)2)2, −OP(=O)(N(Rbb)2)2, −NRbbP(=O)(Raa)2, −NRbbP(=O)(ORcc)2, −NRbbP(=O)(N(Rbb)2)2, −P(Rcc)2, −P(ORcc)2, −P(Rcc)3 +X−, −P(ORcc)3 +X−, −P(Rcc)4, −P(ORcc)4, −OP(Rcc)2, −OP(Rcc)3 +X−, −OP(ORcc)2, −OP(ORcc)3 +X−, −OP(Rcc)4, −OP(ORcc)4, −B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20 alkyl, heteroC1–20 alkenyl, heteroC1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; wherein X− is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; each instance of Raa is, independently, selected from C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20 alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rbb is, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rbb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rcc is, independently, selected from hydrogen, C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20 alkyl, heteroC1–20 alkenyl, heteroC1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rcc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rdd is, independently, selected from halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORee, −ON(Rff)2, −N(Rff)2, −N(Rff)3+X−, −N(ORee)Rff, −SH, −SRee, −SSRee, −C(=O)Ree, −CO2H, −CO2Ree, −OC(=O)Ree, −OCO2Ree, −C(=O)N(Rff)2, −OC(=O)N(Rff)2, −NRffC(=O)Ree, −NRffCO2Ree, −NRffC(=O)N(Rff)2, −C(=NRff)ORee, −OC(=NRff)Ree, −OC(=NRff)ORee, −C(=NRff)N(Rff)2, −OC(=NRff)N(Rff)2, −NRffC(=NRff)N(Rff)2, −NRffSO2Ree, −SO2N(Rff)2, −SO2Ree, −SO2ORee, −OSO2Ree, −S(=O)Ree, −Si(Ree)3, −OSi(Ree)3, −C(=S)N(Rff)2, −C(=O)SRee, −C(=S)SRee, −SC(=S)SRee, −P(=O)(ORee)2, −P(=O)(Ree)2, −OP(=O)(Ree)2, −OP(=O)(ORee)2, C1–10 alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups, or two geminal Rdd substituents are joined to form =O or =S; wherein X− is a counterion; each instance of Ree is, independently, selected from C1–10 alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10 alkyl, heteroC1–10 alkenyl, heteroC1–10 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; each instance of Rff is, independently, selected from hydrogen, C1–10 alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10 alkyl, heteroC1–10 alkenyl, heteroC1–10 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, or two Rff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; each instance of Rgg is, independently, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OC1–6 alkyl, −ON(C1–6 alkyl)2, −N(C1–6 alkyl)2, −N(C1–6 alkyl)3+X−, −NH(C1–6 alkyl)2+X−, −NH2(C1–6 alkyl) +X−, −NH3 +X−, −N(OC1–6 alkyl)(C1–6 alkyl), −N(OH)(C1–6 alkyl), −NH(OH), −SH, −SC1–6 alkyl, −SS(C1–6 alkyl), −C(=O)(C1–6 alkyl), −CO2H, −CO2(C1–6 alkyl), −OC(=O)(C1–6 alkyl), −OCO2(C1–6 alkyl), −C(=O)NH2, −C(=O)N(C1–6 alkyl)2, −OC(=O)NH(C1– 6 alkyl), −NHC(=O)( C1–6 alkyl), −N(C1–6 alkyl)C(=O)( C1–6 alkyl), −NHCO2(C1–6 alkyl), −NHC(=O)N(C1–6 alkyl)2, −NHC(=O)NH(C1–6 alkyl), −NHC(=O)NH2, −C(=NH)O(C1–6 alkyl), −OC(=NH)(C1–6 alkyl), −OC(=NH)OC1–6 alkyl, −C(=NH)N(C1–6 alkyl)2, −C(=NH)NH(C1–6 alkyl), −C(=NH)NH2, −OC(=NH)N(C1–6 alkyl)2, −OC(NH)NH(C1–6 alkyl), −OC(NH)NH2, −NHC(NH)N(C1–6 alkyl)2, −NHC(=NH)NH2, −NHSO2(C1–6 alkyl), −SO2N(C1–6 alkyl)2, −SO2NH(C1–6 alkyl), −SO2NH2, −SO2C1–6 alkyl, −SO2OC1–6 alkyl, −OSO2C1–6 alkyl, −SOC1–6 alkyl, −Si(C1–6 alkyl)3, −OSi(C1–6 alkyl)3 −C(=S)N(C1–6 alkyl)2, C(=S)NH(C1–6 alkyl), C(=S)NH2, −C(=O)S(C1–6 alkyl), −C(=S)SC1–6 alkyl, −SC(=S)SC1–6 alkyl, −P(=O)(OC1–6 alkyl)2, −P(=O)(C1–6 alkyl)2, −OP(=O)(C1–6 alkyl)2, −OP(=O)(OC1–6 alkyl)2, C1–10 alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10 alkyl, heteroC1–10 alkenyl, heteroC1–10 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rgg substituents can be joined to form =O or =S; and each X− is a counterion. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, –NO2, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −OC(=O)Raa, −OCO2Raa, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, –NO2, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −OC(=O)Raa, −OCO2Raa, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2, wherein Raa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbb is 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 Raa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbb is 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 nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a nitrogen protecting group, wherein Raa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a nitrogen protecting group. In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include −OH, −ORaa, −N(Rcc)2, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, C1–10 alkyl (e.g., aralkyl, heteroaralkyl), C1–20 alkenyl, C1–20 alkynyl, hetero C1–20 alkyl, hetero C1–20 alkenyl, hetero C1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein Raa, Rbb, Rcc, and Rdd 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, 3rd edition, John Wiley & Sons, 1999. For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −C(=O)Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o- nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’- dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o- nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o- (benzoyloxymethyl)benzamide. In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −C(=O)ORaa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9- fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7- dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10- tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1–(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2- trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di- t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and 4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1- adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p- methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p- chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2- methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6- chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N- dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1- methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5- dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1- phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p- (phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate. In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −S(=O)2Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6- trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β- trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4′,8′- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide. In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N’-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3- diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3- dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N- allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1- isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N- di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N- [(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7- dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N’- oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N’,N’-dimethylaminomethylene)amine, N-p-nitrobenzylideneamine, N-salicylideneamine, N- 5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N- cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N- diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N- copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are N,N’-isopropylidenediamine. In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or an oxygen protecting group. 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
Figure imgf000025_0001
wherein X−, Raa, Rbb, and Rcc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999. In certain embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is attached, is selected from the group consisting of methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin- 4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a- octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p- cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, 4,4′-dimethoxytrityl (4,4′- dimethoxytriphenylmethyl or DMT), α-naphthyldiphenylmethyl, p- methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p- methoxyphenyl)methyl, 4-(4’-bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″- tris(benzoyloxyphenyl)methyl, 4,4’-Dimethoxy-3"‘-[N-(imidazolylmethyl) ]trityl Ether (IDTr- OR), 4,4’-Dimethoxy-3"‘-[N-(imidazolylethyl)carbamoyl]trityl Ether (IETr-OR), 1,1-bis(4- methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4- methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p- methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p- nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6- dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4- bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a sulfur protecting group. 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(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, −P(=O)(ORcc)2, and −P(=O)(N(Rbb) 2)2, wherein Raa, Rbb, and Rcc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999. 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. Barry 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). 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+(C1–4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. The term “prodrug” refers to a compound that may be converted under physiological conditions or by solvolysis to a conjugate described herein. The prodrug may be a precursor of the conjugate 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 conjugate, may be active. Compared to the conjugate, the prodrug may offer advantages, such as higher solubility, higher permeability, higher absorption, improved distribution, improved metabolism, improved excretion, higher exposure, higher tissue compatibility, slower delivery, more sustained delivery, lower toxicity, and/or wider therapeutic window (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 conjugate 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” Top. Curr. Chem., 2015, 360:115-160. In certain embodiments, the prodrug is a prodrug of any of the formulae described herein. 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. 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. 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. 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. The terms “condition,” “disease,” and “disorder” are used interchangeably. An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). 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. 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. The term “composition” means a mixture of substances. The term “pharmaceutical composition” means a composition suitable for administering to a subject. The symbol “ ” denotes the point of attachment of a chemical moiety to the remainder of a compound or chemical formula. 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 (i.e., it contains carbon). The small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.). In certain embodiments, the molecular weight of a small molecule is not more than 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. 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, between 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 farnesyl group, an isofarnesyl 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. 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. 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, internucleosidic linker, or sugar, or a modified nucleotide, nucleoside, nucleobase, internucleosidic linker, or sugar, or a combination thereof (e.g., a combination of nucleobase, internucleosidic 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. 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 mDNA), 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 lncRNA), 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., short- interfering 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. In certain embodiments, the oligonucleotide strand comprises between 14 and 23, inclusive, nucleosides. In certain embodiments, the oligonucleotide strand comprises between 10 and 30, inclusive, nucleosides. In certain embodiments, the oligonucleotide strand comprises between 14 and 23, inclusive, nucleosides. 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 11, 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. The term “nucleobase” refers to a nitrogen-containing moiety at the 1′ 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. The term “nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage. 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). The terms “internucleoside linkage,” “internucleoside linker,” “internucleosidic linkage,” and “internucleosidic linker” are used interchangeably. 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. “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. 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. 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. 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 by the Drosha ribonuclease III enzyme 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 (i.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 (i.e., miRNA) may be used herein to refer to any form of the subject miRNA (e.g., precursor, primary, and/or mature miRNA). 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 RNaseΗ, 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). The term “circular RNA” (“circRNA”) refers to an RNA that is covalently closed (i.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. 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. 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. 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. 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, internucleoside 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. 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. “Modified oligonucleotide” means an oligonucleotide, wherein at least one sugar, nucleobase, or internucleoside linkage is modified. The modification may be any of those described in the present disclosure or known in the art. The modification may be by chemical means, enzymatic means, and/or biological means. The modification may be substitution with a chemical moiety. The modification may be replacement with a chemical moiety. “Nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage. 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 “duplex oligomeric compound.” The oligonucleotides of each oligomeric compound of an oligomeric duplex may include non-complementary overhanging nucleosides. “Phosphorothioate,” “phosphorothioate linkage,” or “phosphorothioate linker” means a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced with a sulfur atom. “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. 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. 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; saccharides; 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 an α4β1/7 integrin 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 muscle of a subject. In some embodiments, a ligand is capable of targeting an oligonucleotide (e.g., an oligonucleotide strand thereof) to a muscle. In some embodiments, a ligand is not a lipid. The term “α4β1/7 integrin receptor” refers to heterodimeric integrin receptors formed by association of integrin alpha 4 and integrin beta 1 (i.e., the α4β1 integrin receptor) and/or integrin alpha 4 and integrin beta 7 (i.e., the α4β7 integrin receptor). In certain embodiments, the α4β1/7 integrin receptor ligand has a higher binding affinity for α4β1 integrin receptor than α4β7 integrin receptor. In certain embodiments, the α4β1/7 integrin receptor ligand has a higher binding affinity for α4β7 integrin receptor than α4β1 integrin receptor. 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 internucleoside linkage (e.g., the internucleoside linkage between the 5′ nucleoside and the second nucleoside counted from the 5′ end; the internucleoside linkage between the 3′ nucleoside and the second nucleoside counted from the 3′ end; the internucleoside linkage between the first n and n+1 nucleosides counted from the 5′ end, wherein n is an integer between 1 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.” 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 fatty acyl may be a fatty acid or conjugate, octadecanoid, eicosanoid, docosanoid, fatty alcohol, fatty aldehyde, fatty ester, fatty amide, fatty nitrile, fatty ether, hydrocarbon, oxygenated hydrocarbon, or fatty acyl glycoside. A glycerolipid may be a monoradylglycerol, diradylglycerol, triradylglycerol, glycosylmonoradylglycerol, glycosyldiradylglycerol, betaine monoradylglycerol, or betaine diradylglycerol. A glycerophospholipid may be a glycerophosphocholine, glycerophosphoethanolamine, glycerophosphoserine, glycerophosphoglycerol, glycerophosphoglycerophosphate, glycerophosphoinositol, glycerophosphoinositol monophosphate, glycerophosphoinositol bisphosphate, glycerophosphoinositol trisphosphate, glycerophosphate, glyceropyrophosphate, glycerophosphoglycerophosphoglycerol, CDP-glycerol, glycosylglycerophospholipid, glycerophosphoinositolglycan, glycerophosphonocholine, glycerophosphonoethanolamine, di- glycerol 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, angucycline, polyether 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, 1,3-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. The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds. The phrases “in certain embodiments” and “in some embodiments” are used interchangeably. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE DISCLOSURE In one aspect, the present disclosure provides methods of treating a muscle disease in a subject in need thereof comprising administering to the subject an effective amount of a conjugate of Formula I: (A)y–L–(R1)r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one instance of A is a radical of an α4β1/7 integrin ligand; L is a linker; each instance of R1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6. In another aspect, the present disclosure provides uses of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for treating a muscle disease in a subject in need thereof. In another aspect, the present disclosure provides the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use in treating a muscle disease in a subject in need thereof. In another aspect, the present disclosure provides methods of preventing a muscle disease in a subject in need thereof comprising administering to the subject an effective amount of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof. In another aspect, the present disclosure provides uses of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for preventing a muscle disease in a subject in need thereof. In another aspect, the present disclosure provides the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use in preventing a muscle disease in a subject in need thereof. In another aspect, the present disclosure provides methods of diagnosing a muscle disease in a subject in need thereof comprising administering to the subject an effective amount of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof. In another aspect, the present disclosure provides uses of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for diagnosing a muscle disease in a subject in need thereof. In another aspect, the present disclosure provides the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use in diagnosing a muscle disease in a subject in need thereof. In another aspect, the present disclosure provides methods for delivering a pharmaceutical agent to a muscle of a subject comprising administering to the subject the conjugate, or a pharmaceutically acceptable salt or prodrug thereof. In another aspect, the present disclosure provides uses of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for delivering a pharmaceutical agent to a muscle of a subject. In another aspect, the present disclosure provides the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use in delivering a pharmaceutical agent to a muscle of a subject. In certain embodiments, “conjugate” refers to a conjugate, or a pharmaceutically acceptable salt or prodrug thereof. In certain embodiments, “conjugate” refers to a conjugate, or a pharmaceutically acceptable salt thereof. In certain embodiments, r is 1. In certain embodiments, r is 2, 3, 4, 5, or 6. In certain embodiments, y is 1. In certain embodiments, y is 2, 3, 4, 5, or 6. In certain embodiments, at least one instance of A is a radical of a lipid. In certain embodiments, at least two instances of A are independently a radical of a lipid. In certain embodiments, at least two instances of A are independently a radical of a ligand. In some embodiments, the conjugate is of Formula I-A: , (I-A) or a pharmaceutically acceptable salt or prodrug thereof, wherein: is a radical of an oligonucleotide strand; s1 instances of the nucleobase-sugar moieties at internal positions of
Figure imgf000043_0001
are independently replaced with a moiety of Formula A:
Figure imgf000043_0002
(A); s1 is 0, 1, 2, 3, 4, 5, or 6; when s1 is 1, 2, 3, 4, 5, or 6: each instance of N1 is independently a radical of a nucleobase or a bond; each instance of t1 is independently 1, 2, or 3; each instance of y1 and y2 is independently 0, 1, 2, 3, 4, 5, or 6; provided that at least one instance of y1 and y2 is 1, 2, 3, 4, 5, or 6; each instance of A1 and A2, when present, is independently a radical of a ligand or lipid; when y1 of an instance of
Figure imgf000044_0001
is 0, L1 thereof is hydrogen, halogen, 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, –CN, –ORb, –SCN, –SRb,
Figure imgf000044_0002
–OS(=O)Rb, –OS(=O)ORb, –OS(=O)SRb, –OS(=O)N(Rb)2, –OS(=O)2Rb, –OS(=O)2ORb, –OS(=O)2SRb, –OS(=O)2N(Rb)2, –ON(Rb)2, –SC(=O)Rb, –SC(=O)ORb, –SC(=O)SRb, –SC(=O)N(Rb)2, –NRbC(=O)Rb, –NRbC(=O)ORb, –NRbC(=O)SRb, –NRbC(=O)N(Rb)2, –NRbS(=O)Rb, –NRbS(=O)ORb, –NRbS(=O)SRb, –NRbS(=O)N(Rb)2, –NRbS(=O)2Rb, –NRbS(=O)2ORb, –NRbS(=O)2SRb, –NRbS(=O)2N(Rb)2, –Si(Rb)3, –Si(Rb)2ORb, –Si(Rb)(ORb)2, –Si(ORb)3, –OSi(Rb)3, –OSi(Rb)2ORb, –OSi(Rb)(ORb)2, or –OSi(ORb)3; or when y1 of an instance of
Figure imgf000044_0003
is 1, 2, 3, 4, 5, or 6, L1 thereof is a linker; each instance of Rb is independently hydrogen, 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, 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 Rb attached to the same intervening atom are joined together with the intervening atom to form an substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring; when y2 of an instance
Figure imgf000045_0001
2 thereof is -OH, -ORC, -SH,
-SRC, -NH2, -NHRC, -N(RC)2, halogen, -CN, or -N3; or when y2 of an instance of
Figure imgf000045_0002
2 thereof is a linker; and each instance of Rc is independently 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;
5' 3' vl instances of the internucleosidic linkers of are
L4 independently replaced with (A4)y4 . vl is 0, 1, 2, 3, 4, 5, or 6; each instance of LA and L4, when present, is independently a linker; each instance of y4, when present, is independently 1, 2, 3, 4, 5, or 6; each instance of A4, when present, is independently a radical of a ligand or lipid; each instance of y5 and y6 is independently 0, 1, 2, 3, 4, 5, or 6; when y5 is 0, L5 is hydrogen, substituted or unsubstituted, Ci-6 alkyl, or an oxygen protecting group; or when y5 is 1, 2, 3, 4, 5, or 6, L5 is a linker; when y6 is 0, L6 is hydrogen, substituted or unsubstituted, Ci-6 alkyl, or an oxygen protecting group; or when y6 is 1, 2, 3, 4, 5, or 6, L6 is a linker; and each instance of A5 and A6, when present, is independently a radical of a ligand or lipid; provided that at least one instance of yl, y2, y4, y5, and y6 is 1, 2, 3, 4, 5, or 6; that the sum of yl, y2, y4, y5, and y6 is not greater than 6; and that at least one instance of A1, A2, A4, A5, and A6 is a radical of an 0401/? integrin ligand.
In certain embodiments, at least one instance is one instance. In certain embodiments, at least one instance is two instances. In certain embodiments, at least one instance is each instance.
In certain embodiments, at least one instance of yl is 0. In certain embodiments, at least one instance of yl is 1. In certain embodiments, at least one instance of yl is 2, 3, 4, 5, or 6. In certain embodiments, at least one instance of yl is 2. In certain embodiments, each instance of y2, y4, y5, and y6 is 0. In certain embodiments, at least one instance of y2 is 0. In certain embodiments, at least one instance of y2 is 1. In certain embodiments, at least one instance of y2 is 2, 3, 4, 5, or 6. In certain embodiments, at least one instance of y2 is 2. In certain embodiments, each instance of y1, y4, y5 and y6 is 0. In certain embodiments, at least one instance of y4 is 0. In certain embodiments, at least one instance of y4 is 1. In certain embodiments, at least one instance of y4 is 2, 3, 4, 5, or 6. In certain embodiments, at least one instance of y4 is 2. In certain embodiments, at least one instance of y1, y2, y5, and y6 is 0. In certain embodiments, at least one instance of y5 is 0. In certain embodiments, at least one instance of y5 is 1. In certain embodiments, at least one instance of y5 is 2, 3, 4, 5, or 6. In certain embodiments, at least one instance of y5 is 2. In certain embodiments, each instance of y1, y2, y4, and y6 is 0. In certain embodiments, at least one instance of y6 is 0. In certain embodiments, at least one instance of y6 is 1. In certain embodiments, at least one instance of y6 is 2, 3, 4, 5, or 6. In certain embodiments, at least one instance of y6 is 2. In certain embodiments, each instance of y1, y2, y4, and y5 is 0. In certain embodiments, at least one instance of y1 is 1, and at least one instance of y2, y4, y5, and y6 is 1. In certain embodiments, at least one instance of y2 is 1, and at least one instance of y1, y4, y5, and y6 is 1. In certain embodiments, at least one instance of y4 is 1, and at least one instance of y1, y2, y5, and y6 is 1. In certain embodiments, at least one instance of y5 is 1, and at least one instance of y1, y2, y4, and y6 is 1. In certain embodiments, at least one instance of y6 is 1, and at least one instance of y1, y2, y4, and y5 is 1. In certain embodiments, at least one instance of N1 is a radical of a nucleobase. In certain embodiments, at least one instance of N1 is a radical of adenine, cytosine, guanine, thymine or uracil. In certain embodiments, at least one instance of N1 is a radical of a nucleobase with one or more nucleobase modifications described herein. In certain embodiments, at least one instance of N1 is a radical of a nucleobase with one nucleobase modification described herein. In certain embodiments, at least one instance of N1 is a radical of a nucleobase with two or three nucleobase modifications described herein. In certain embodiments, at least one instance of N1 is a bond. In certain embodiments, at least one instance of t1 is 1. In some embodiments, at least one pharmaceutical agent is a therapeutic agent, prophylactic agent, or diagnostic agent. In some embodiments, at least one pharmaceutical agent is an oligonucleotide, small molecule, peptide, or protein. In some embodiments, at least one pharmaceutical agent is an antibody. In some embodiments, at least one pharmaceutical agent is a monoclonal antibody. In certain embodiments, at least one pharmaceutical agent inhibits the expression of a superoxide dismutase type 1 (SOD1) gene (e.g., a human SOD1 gene). In certain embodiments, at least one 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 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). 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: 7), and GenBank Accession No NM_016835.5 (incorporated herein as SEQ ID NO: 8). 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=SOD1. SOD1 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=SOD1). 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)). In some embodiments, at least one pharmaceutical agent is an oligonucleotide. In certain embodiments, at least one oligonucleotide comprises an RNA. In certain embodiments, at least one oligonucleotide is an RNA. In certain embodiments, at least one oligonucleotide is an siRNA. In certain embodiments, at least one RNA is an siRNA. In certain embodiments, at least one oligonucleotide is a single-stranded oligonucleotide. In certain embodiments, at least one oligonucleotide is a double-stranded oligonucleotide comprising a sense oligonucleotide strand and an antisense oligonucleotide strand. In certain embodiments, the oligonucleotide strand is the sense oligonucleotide strand. In certain embodiments, the oligonucleotide strand is the antisense oligonucleotide strand. In certain embodiments, an oligonucleotide strand has a nucleobase 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 delivery to 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 internucleoside 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 internucleoside linkage). In certain embodiments, a strand of at least one oligonucleotide has 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 identity to SEQ ID NO.: 2, 4, 5, or 6. In certain embodiments, a strand of at least one oligonucleotide has at least 80%, at least 85%, at least 90%, or at least 95% identity to SEQ ID NO.: 2, 4, 5, or 6. 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 complementary to 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., α4β1/7 integrin receptor ligands). In certain embodiments, the second oligonucleotide strand is linked to one or more radicals of ligands (e.g., α4β1/7 integrin receptor ligands). In certain embodiments, a conjugate comprises one or more radicals of ligands at one or more internal positions. In certain embodiments, a conjugate comprises one or more radicals of ligands at one or more internal positions. In certain embodiments, a conjugate comprises one or more radicals of ligands at a nucleobase. In certain embodiments, a conjugate comprises one or more radicals of ligands at the 1′ position of a nucleoside. In certain embodiments, a conjugate comprises one or more radicals of ligands at the 2′ position of a nucleoside. In certain embodiments, a conjugate comprises one or more radicals of ligands at the 3′ position of a nucleoside. In certain embodiments, a conjugate comprises one or more radicals of ligands at the 5′ position of a nucleoside. 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, 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, 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, 95, 96, 97, 98, 99, or 100 nucleotides in length. 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. In certain embodiments, an oligonucleotide strand is about 14 nucleotides in length to about 23 nucleotides in length. 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. In certain embodiments, a miRNA is a precursor, primary, and/or mature miRNA. 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. Certain conjugates of the present disclosure can exist in an unsolvated forms as well as solvated forms, including hydrated forms. Certain conjugates of the present disclosure may exist in crystalline or amorphous forms. 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 gene (e.g., human gene) with which a muscle 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 embodiments, the disease is associated with the overexpression of the gene. In certain embodiments, “associated with” refers to “caused at least in part by.” In certain embodiments, an oligonucleotide comprises a sense oligonucleotide strand having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity to a gene described herein. In certain embodiments, an oligonucleotide comprises a sense oligonucleotide strand having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% complementarity to a gene described herein. In certain embodiments, an oligonucleotide comprises an antisense oligonucleotide strand having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% complementarity to the sense oligonucleotide strand. In some embodiments, the conjugates provided herein comprise one or more linkers (e.g., L). 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. 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, οxο, 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 click- chemistry 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. In some embodiments, a linker is a bond (e.g., a single bond). In some embodiments, a linker is optionally substituted alkylene. 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, C1-150 alkylene, substituted or unsubstituted, C2-150 alkenylene, or substituted or unsubstituted, C2-150 alkynylene. In certain embodiments, one or more (e.g., two, three, or four) backbone atoms of the C1-150 alkylene, C2-150 alkenylene, or C2-150 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, C1-100 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-100 alkylene, C2-100 alkenylene, or C2- 100 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, 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 arylene, 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 Cei-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, C13-18, 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, C25-30, 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.
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 alkynylene 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.
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 hetero alkylene 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-150 heteroalkylene, substituted or unsubstituted, C2-150 heteroalkenylene, or substituted or unsubstituted, C2-isoheteroalkynylene. In certain embodiments, one or more (e.g., two, three, or four) backbone atoms of the Ci-150 heteroalkylene, C2-150 heteroalkenylene, or C2-150 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, Ci-100 heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, or substituted or unsubstituted, C2-100 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 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. In certain embodiments, one or two backbone atoms of the 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. 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 heteroalkylene, substituted or unsubstituted, C1-6, C7-12, C13-18, C19-24, C25-30, C31-36, C37-44, C45-52, C53-60, or C61-70 heteroalkenylene, or substituted or unsubstituted, C2-6, C7-12, C13-18, C19-24, C25-30, C31-36, C37-44, C45-52, C53-60, or C61-70 heteroalkynylene. 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 C61-70 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-chemistry reactive moieties.
In some embodiments, the substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms is of the formula:
Figure imgf000054_0001
Figure imgf000055_0001
k21 is 0, 1, 2, 3, or 4; each instance of Rd, if present, is independently halogen, substituted or unsubstituted, C1-6 alkyl, or –O–(substituted or unsubstituted, C1-6 alkyl); k22 is 0, 1, 2, 3, or 4; each instance of Re, if present, is independently halogen, substituted or unsubstituted, C1-6 alkyl, or –O–(substituted or unsubstituted, C1-6 alkyl); k23 is an integer between 0 and 11, inclusive; each instance of Rf, if present, is independently halogen, substituted or unsubstituted, C1-6 alkyl, or –O–(substituted or unsubstituted, C1-6 alkyl); and Rg is hydrogen, halogen, substituted or unsubstituted, C1-6 alkyl, or –O–(substituted or unsubstituted, C1-6 alkyl). The substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms may be attached at either direction. In certain embodiments, the substituted or unsubstituted heteroarylene that replaces one of the backbone atoms is of the formula:
Figure imgf000055_0002
The substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms may be attached at any orientation. In certain embodiments, the conjugate is of the formula: (I-A-16),
Figure imgf000056_0001
(I-A-17),
Figure imgf000056_0002
Figure imgf000056_0003
Figure imgf000056_0008
(I-A-18), or
Figure imgf000056_0004
(I-A-19). In certain embodiments, L6 is attached to the 3′ end of the oligonucleotide strand. In certain embodiments, L6 is attached to the oxygen atom substituted at the 3′ position of the 3′ end of the oligonucleotide strand. In certain embodiments, L6 is attached to the 3′ position of the 3′ end of the oligonucleotide strand. In certain embodiments, L6 is attached to the nucleobase of the 3′ end of the oligonucleotide strand. In certain embodiments, L6 is attached to the 1′ position of the 3′ end of the oligonucleotide strand, wherein the 3′ end is an abasic nucleoside. In certain embodiments, L6 is attached to the 2′ position of the 3′ end of the oligonucleotide strand. In certain embodiments, L6 is attached to the oxygen atom substituted at the 2′ position of the 3′ end of the oligonucleotide strand.
Figure imgf000056_0007
. In certain embodiments, L6 is substituted or unsubstituted, C10-100 heteroalkylene.
Figure imgf000056_0005
In certain embodiments, L6 comprises one or more of the following –CH2–, ,
Figure imgf000056_0006
Figure imgf000057_0001
combination of two or more of each one of the foregoing, provided that: the number of backbone atoms of L6 is between 10 and 100, inclusive; and L6 does not comprise O–O, O–N, N–O, or N–N. ,
Figure imgf000057_0002
the number of backbone atoms of the at least one instance of L6 is between 10 and 100, inclusive; and the at least one instance of L6 does not comprise O–O, O–N, N–O, or N–N. 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. 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. 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 α,β-unsaturated- carbonyl. In some embodiments, the Michael donor is –SH. In some embodiments, the Michael acceptor i
Figure imgf000058_0001
. In certain embodiments, at least one instance of L is substituted or unsubstituted, C1-100 alkylene, substituted or unsubstituted, C2-100 alkenylene, substituted or unsubstituted, C2-100 alkynylene, substituted or unsubstituted, C1-100 heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, or substituted or unsubstituted, C2-100 heteroalkynylene; optionally wherein one or more backbone atoms of the C1-100 alkylene, C2-100 alkenylene, C2-100 alkynylene, C1-100 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 certain embodiments, at least one instance of L is substituted or unsubstituted, C7-70 alkylene, 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, two, three, or four 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. In certain embodiments, at least one instance of L is substituted or unsubstituted, C7-70 alkylene or substituted or unsubstituted, C7-70 heteroalkylene; and one, two, three, or four 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. In certain embodiments, at least one instance of L is substituted or unsubstituted, C7-70 heteroalkylene. In some embodiments, at least one instance of L comprises one or more of the following –
Figure imgf000058_0002
Figure imgf000059_0001
combination of two or more of each one of the foregoing, provided that: the number of backbone atoms of the at least one instance of L 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 at least one instance of L does not comprise O–O, O–N, N–O, or N–N. In some embodiments, at least one instance of L comprises one or more of the following –
Figure imgf000059_0002
Figure imgf000059_0003
combination of two or more of each one of the foregoing, provided that: the number of backbone atoms of the at least one instance of L is between 7 and 70, inclusive; and the at least one instance of L does not comprise O–O, O–N, N–O, or N–N. In some embodiments, at least one instance of L comprises one or more of the following –
Figure imgf000059_0004
Figure imgf000059_0005
combination of two or more of each one of the foregoing, provided that: the number of backbone atoms of the at least one instance of L 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 at least one instance of L does not comprise O–O, O–N, N–O, or N–N; and the combined number of –C(=O)NH–, –NHC(=O)–, , and of the at least one instance of L is between 0 and 4, inclusive. In some embodiments, at least one instance of L comprises one or more of the following –
Figure imgf000060_0001
Figure imgf000060_0006
the number of backbone atoms of the at least one instance of L is between 7 and 70, inclusive; the at least one instance of L does not comprise O–O, O–N, N–O, or N–N; and the combined number
Figure imgf000060_0002
the linker is between 0 and 4, inclusive. In some embodiments, at least one instance of L is a combination of –CH2–,
Figure imgf000060_0003
,
Figure imgf000060_0004
at: the number of backbone atoms of the at least one instance of L is between 10 and 100, inclusive; and the at least one instance of L does not comprise O–O, O–N, N–O, or N–N. 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 two 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(=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, O–N, N–O, or N–N. In certain embodiments, when a linker comprises one or more of the following –CH2–,
Figure imgf000060_0005
Figure imgf000061_0001
combination of two or more of each one of the foregoing, the linker comprises all possible permutations, e.g., –CH2–CH2–, – CH2–C(=O)NH–, and –CH2–CH2–C(=O)NH–. 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. 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. In certain embodiments, a linker comprises a polyradical of: pyrrolidine, 8-amino-3,6- dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC), 6-aminohexanoic acid (ΑΗΕΧ or AHA), or a combination thereof. In some embodiments, at least one instance of L is
Figure imgf000061_0002
each of –LA1–LA2–, –LA3–LA4–, –LA5–LA6–, –LA7–LA8–, –LA17–LA18–, and –LA19–LA20– 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 Ra is 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of LB1, LB2, and LB6 is independently a single bond, substituted or unsubstituted, C1- 100 alkylene, or substituted or unsubstituted, C1-100 heteroalkylene; each of LC1 and LC2 is 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 CA is attached to A. In some embodiments, each of –LA1–LA2–, –LA3–LA4–, –LA5–LA6–, –LA7–LA8–, –LA17– LA18–, and –LA19–LA20– is independently a single bond, –O–, –NRa–, –C(=O)NRa–, or –NRaC(=O)–. In some embodiments, each of –LA1–LA2–, –LA3–LA4–, –LA5–LA6–, –LA7–LA8–, –LA17–LA18–, and –LA19–LA20– is independently a single bond, –O–, –NH–, –C(=O)NH–, or –NHC(=O)–. In certain embodiments, each of –LA1–LA2–, –LA3–LA4–, –LA5–LA6–, –LA7–LA8–, –LA17–LA18–, and –LA19–LA20– is independently a single bond, –C(=O)NRa–, or –NRaC(=O)–. In certain embodiments, each of –LA1–LA2–, –LA3–LA4–, –LA5–LA6–, –LA7–LA8–, –LA17–LA18–, and –LA19–LA20– is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some embodiments, at least one of –LA1–LA2–, –LA3–LA4–, –LA5–LA6–, –LA7–LA8–, –LA17–LA18–, and –LA19–LA20– 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 –LA1–LA2–, –LA3– LA4–, –LA5–LA6–, –LA7–LA8–, –LA17–LA18–, and –LA19–LA20– is independently –C(=O)O–, –OC(=O)–, –OP(=O)(OH)O–, –SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O–. In some embodiments, at least one instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In some embodiments, each instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, each instance of Ra is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of LB1, LB2, and LB6 is independently a single bond, substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of LB1, LB2, and LB6 is independently substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of LB1, LB2, and LB6 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of LB1, LB2, and LB6 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, each of LC1 and LC2 are independently a single bond. In certain embodiments, each of LC1 and LC2 are independently substituted or unsubstituted heteroarylene that replaces one of the backbone atoms. In certain embodiments, each of LC1 and LC2 are independently
Figure imgf000062_0001
(which may be attached at either direction). In some embodiments, y1 of an instance of is 0, and L1 thereof is hydrogen, halogen, substituted or unsubstituted, C1-6 alkyl, substituted or unsubstituted, C2-6 alkenyl, substituted or unsubstituted, C2-6 heteroalkyl, substituted or unsubstituted, monocyclic carbocyclyl, substituted or unsubstituted, monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted, monocyclic heteroaryl, –CN, –ORb, –SCN, –SRb, –SSRb, –N3, –NO, –N(Rb)2, –NO2, –C(=O)Rb, –C(=O)ORb, –C(=O)SRb, –C(=O)N(Rb)2, –S(=O)Rb, –S(=O)ORb, –S(=O)SRb, –S(=O)N(Rb)2, –S(=O)2Rb, –S(=O)2ORb, –S(=O)2SRb, –S(=O)2N(Rb)2, –OC(=O)Rb, –OC(=O)ORb, –OC(=O)SRb, –OC(=O)N(Rb)2, –OS(=O)Rb, –OS(=O)ORb, –OS(=O)SRb, –OS(=O)N(Rb)2, –OS(=O)2Rb, –OS(=O)2ORb, –OS(=O)2SRb, –OS(=O)2N(Rb)2, –ON(Rb)2, –SC(=O)Rb, –SC(=O)ORb, –SC(=O)SRb, –SC(=O)N(Rb)2, –NRbC(=O)Rb, –NRbC(=O)ORb, –NRbC(=O)SRb, –NRbC(=O)N(Rb)2, –NRbS(=O)Rb, –NRbS(=O)ORb, –NRbS(=O)SRb, –NRbS(=O)N(Rb)2, –NRbS(=O)2Rb, –NRbS(=O)2ORb, –NRbS(=O)2SRb, or –NRbS(=O)2N(Rb)2. In some embodiments, y1 of an instance of is 0, and L1 thereof is hydrogen, halogen, substituted or unsubstituted, C1-6 alkyl, substituted or unsubstituted, C2-6 alkenyl, substituted or unsubstituted, C2-6 heteroalkyl, –CN, –ORb, –SCN, –SRb, –SSRb, –N3, –NO, –N(Rb)2, –NO2, –C(=O)Rb, –C(=O)ORb, –C(=O)SRb, –C(=O)N(Rb)2, –S(=O)Rb, –S(=O)ORb, –S(=O)SRb, –S(=O)N(Rb)2, –S(=O)2Rb, –S(=O)2ORb, –S(=O)2SRb, –S(=O)2N(Rb)2, –OC(=O)Rb, –OC(=O)ORb, –OC(=O)SRb, –OC(=O)N(Rb)2, –OS(=O)Rb, –OS(=O)ORb, –OS(=O)SRb, –OS(=O)N(Rb)2, –OS(=O)2Rb, –OS(=O)2ORb, –OS(=O)2SRb, –OS(=O)2N(Rb)2, –ON(Rb)2, –SC(=O)Rb, –SC(=O)ORb, –SC(=O)SRb, –SC(=O)N(Rb)2, –NRbC(=O)Rb, –NRbC(=O)ORb, –NRbC(=O)SRb, –NRbC(=O)N(Rb)2, –NRbS(=O)Rb, –NRbS(=O)ORb, –NRbS(=O)SRb, –NRbS(=O)N(Rb)2, –NRbS(=O)2Rb, –NRbS(=O)2ORb, –NRbS(=O)2SRb, or –NRbS(=O)2N(Rb)2. In certain embodiments, y1 of an instance of is 0, and L1 thereof is hydrogen, halogen, substituted or unsubstituted, C1-6 alkyl, –ORb, or –N(Rb)2. In certain embodiments, y1 of an instance of
Figure imgf000063_0001
is 0, and L1 thereof is hydrogen, halogen, or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, y1 of an instance of is 0, and L1 thereof is hydrogen. In some embodiments, each instance of Rb is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In certain embodiments, each instance of Rb is independently hydrogen. In certain embodiments, each instance of Rb is independently unsubstituted alkyl. In certain embodiments, each instance of Rb is independently CH3, CH2CH3, or CH2CH2CH3. In some embodiments, y1 of an instance of
Figure imgf000064_0001
is 1, 2, 3, 4, 5, or 6, and L1 thereof is substituted or unsubstituted, C1-100 alkylene, substituted or unsubstituted, C2-100 alkenylene, substituted or unsubstituted, C2-100 alkynylene, substituted or unsubstituted, C1-100 heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, or substituted or unsubstituted, C2-100 heteroalkynylene; optionally wherein one or more backbone atoms of the C1-100 alkylene, C2-100 alkenylene, C2-100 alkynylene, C1-100 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 certain embodiments, y1 of an instance of
Figure imgf000064_0002
is 1, 2, 3, 4, 5, or 6, and L1 thereof is substituted or unsubstituted, C7-70 alkylene, substituted or unsubstituted, C7-70 alkenylene, substituted or unsubstituted, C7-70 heteroalkylene, or substituted or unsubstituted, C7- 70 heteroalkenylene; optionally wherein one, two, three, or four backbone atoms of the C7-70 alkylene, C7-70 alkenylene, C7-70 heteroalkylene, or C7-70 heteroalkenylene 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, y1 of an instance of
Figure imgf000064_0003
is 1, 2, 3, 4, 5, or 6, and L1 thereof is substituted or unsubstituted, C7-70 alkylene or substituted or unsubstituted, C7-70 heteroalkylene; and one, two, three, or four 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. In some embodiments, at least one instance of
Figure imgf000064_0004
is of the formula:
Figure imgf000065_0001
each of –L1A1–L1A2–, –L1A3–L1A4–, –L1A5–L1A6–, and –L1A7–L1A8– 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 Ra is 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L1B1 and L1B2 is independently a single bond, substituted or unsubstituted, C1-100 alkylene, or substituted or unsubstituted, C1-100 heteroalkylene; L1C1 is 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 C1A is attached to A1. In some embodiments, each of –L1A1–L1A2–, –L1A3–L1A4–, –L1A5–L1A6–, and –L1A7–L1A8– is independently a single bond, –O–, –NRa–, –C(=O)NRa–, or –NRaC(=O)–. In some embodiments, each of –L1A1–L1A2–, –L1A3–L1A4–, –L1A5–L1A6–, and –L1A7–L1A8– is independently a single bond, –O–, –NH–, –C(=O)NH–, or –NHC(=O)–. In certain embodiments, each of –L1A1–L1A2–, –L1A3–L1A4–, –L1A5–L1A6–, and –L1A7–L1A8– is independently a single bond, –C(=O)NRa–, or –NRaC(=O)–. In certain embodiments, each of –L1A1–L1A2–, –L1A3–L1A4–, – L1A5–L1A6–, and –L1A7–L1A8– is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some embodiments, at least one of –L1A1–L1A2–, –L1A3–L1A4–, –L1A5–L1A6–, and –L1A7–L1A8– 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 –L1A1–L1A2–, –L1A3–L1A4–, –L1A5– L1A6–, and –L1A7–L1A8– is independently –C(=O)O–, –OC(=O)–, –OP(=O)(OH)O–, – SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O–. In some embodiments, at least one instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In some embodiments, each instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, each instance of Ra is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of L1B1 and L1B2 is independently a single bond, substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L1B1 and L1B2 is independently substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L1B1 and L1B2 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L1B1 and L1B2 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, L1C1 is a single bond. In certain embodiments, L1C1 is substituted or unsubstituted heteroarylene that replaces one of the backbone atoms. In certain embodiments, L1C1 is
Figure imgf000066_0001
(which may be attached at either direction). In some embodiments, L1 thereof is of the formula:
Figure imgf000066_0002
. In certain embodiments, at least one instance of –L1A7–L1A8– is –NRa–C(=O)– or –C(=O)–NRa–. In certain embodiments, at least one instance of –L1A7–L1A8– is –NH–C(=O)– or –C(=O)–NH–. In certain embodiments, at least one instance of –L1A7–L1A8– is –O–C(=O)– or –C(=O)–O–. In certain embodiments, at least one instance of –L1A7–L1A8– is –O–. In certain embodiments, at least one instance of –L1A7–L1A8– is –NH–. In certain embodiments, at least one instance of –L1A7–L1A8– is –C(=O)–. In certain embodiments, at least one instance of –L1A7– L1A8– is a single bond. In certain embodiments, y1 of an instance of
Figure imgf000066_0003
is 1, 2, 3, 4, 5, or 6, and L1 thereof is substituted or unsubstituted, C7-70 heteroalkylene. In certain embodiments, y1 of an instance of
Figure imgf000066_0004
is 1, 2, 3, 4, 5, or 6, and L1
Figure imgf000066_0005
thereof comprises one or more of the following –CH2–, , , –O–, –CH2CH2O–, –
Figure imgf000067_0001
Figure imgf000067_0002
combination of two or more of each one of the foregoing, provided that: the number of backbone atoms of L1 thereof is between 7 and 70, inclusive; and L1 thereof does not comprise O–O, O–N, N–O, or N–N. In some embodiments, at least one instance of L1 is a combination of –CH2–,
Figure imgf000067_0003
, , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, , and , provided that: the number of backbone atoms of the at least one instance of L1 is between 10 and 100, inclusive; and the at least one instance of L1 does not comprise O–O, O–N, N–O, or N–N. In some embodiments, y2 of an instance of
Figure imgf000067_0004
is 1, 2, 3, 4, 5, or 6, and L2 thereof is substituted or unsubstituted, C1-100 alkylene, substituted or unsubstituted, C2-100 alkenylene, substituted or unsubstituted, C2-100 alkynylene, substituted or unsubstituted, C1-100 heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, or substituted or unsubstituted, C2-100 heteroalkynylene; optionally wherein one or more backbone atoms of the C1-100 alkylene, C2-100 alkenylene, C2-100 alkynylene, C1-100 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.
Figure imgf000067_0005
In some embodiments, y2 of an instance of is 1, 2, 3, 4, 5, or 6, and L2 thereof is substituted or unsubstituted, C7-70 alkylene, substituted or unsubstituted, C7-70 alkenylene, substituted or unsubstituted, C7-70 heteroalkylene, or substituted or unsubstituted, C7- 70 heteroalkenylene; optionally wherein one, two, or three backbone atoms of the C7-70 alkylene, C7-70 alkenylene, C7-70 heteroalkylene, or C7-70 heteroalkenylene 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, y2 of an instance of
Figure imgf000068_0001
is 1, 2, 3, 4, 5, or 6, and L2 thereof is substituted or unsubstituted, C7-70 alkylene or substituted or unsubstituted, C7-70 heteroalkylene; and one, two, or three 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.
Figure imgf000068_0002
In certain embodiments, at least one instance of is of the formula:
Figure imgf000068_0003
. In certain embodiments, at least one instance of is of the
Figure imgf000068_0004
. In some embodiments, at least one instance of
Figure imgf000068_0005
is of the formula:
Figure imgf000068_0006
Each of –L2A1–L2A2–, –L2A3–L2A4–, –L2A5–L2A6–, and –L2A7–L2A8– 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 Ra is 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L2B1 and L2B2 is independently a single bond, substituted or unsubstituted, C1-100 alkylene, or substituted or unsubstituted, C1-100 heteroalkylene; L2C1 is 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 C2A is attached to A2. In some embodiments, each of –L2A1–L2A2–, –L2A3–L2A4–, –L2A5–L2A6–, and –L2A7–L2A8– is independently a single bond, –O–, –NRa–, –C(=O)NRa–, or –NRaC(=O)–. In some embodiments, each of –L2A1–L2A2–, –L2A3–L2A4–, –L2A5–L2A6–, and –L2A7–L2A8– is independently a single bond, –O–, –NH–, –C(=O)NH–, or –NHC(=O)–. In certain embodiments, each of –L2A1–L2A2–, –L2A3–L2A4–, –L2A5–L2A6–, and –L2A7–L2A8– is independently a single bond, –C(=O)NRa–, or –NRaC(=O)–. In certain embodiments, each of –L2A1–L2A2–, –L2A3–L2A4–, – L2A5–L2A6–, and –L2A7–L2A8– is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some embodiments, at least one of –L2A1–L2A2–, –L2A3–L2A4–, –L2A5–L2A6–, and –L2A7–L2A8– 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 –L2A1–L2A2–, –L2A3–L2A4–, –L2A5– L2A6–, and –L2A7–L2A8– is independently –C(=O)O–, –OC(=O)–, –OP(=O)(OH)O–, – SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O–. In some embodiments, at least one instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In some embodiments, each instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, each instance of Ra is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of L2B1 and L2B2 is independently a single bond, substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L2B1 and L2B2 is independently substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L2B1 and L2B2 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L2B1 and L2B2 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, L2C1 is a single bond. In certain embodiments, L2C1 is substituted or unsubstituted heteroarylene that replaces one of the backbone atoms. In certain embodiments, L2C1 is
Figure imgf000070_0001
(which may be attached at either direction).
Figure imgf000070_0002
In certain embodiments, y2 of an instance of is 0, L2 thereof is a sugar
Figure imgf000070_0003
modification described herein. In certain embodiments, y2 of an instance of is 0, L2 thereof is –OCH3, F, or –CH3. In some embodiments, s1 is 1, 2, 3, 4, 5, or 6, at least one instance of y20, and the L2 thereof is –OH, –OCH3, or F. In some embodiments, at least one instance of
Figure imgf000070_0004
is of the formula:
Figure imgf000070_0005
. In certain embodiments, at least one instance of –L2A7–L2A8– is –NRa–C(=O)– or –C(=O)–NRa–. In certain embodiments, at least one instance of –L2A7–L2A8– is –NH–C(=O)– or –C(=O)–NH–. In certain embodiments, at least one instance of –L2A7–L2A8– is –O–C(=O)– or –C(=O)–O–. In certain embodiments, at least one instance of –L2A7–L2A8– is –O–. In certain embodiments, at least one instance of –L2A7–L2A8– is –NH–. In certain embodiments, at least one instance of –L2A7–L2A8– is –C(=O)–. In certain embodiments, at least one instance of –L2A7– L2A8– is a single bond. In some embodiments, at least one instance
Figure imgf000070_0006
the formula:
Figure imgf000071_0001
each of –L2A9–L2A10–, –L2A11–L2A12–, –L2A13–L2A14–, –L2A15–L2A16–, –L2A17–L2A18–, – L2A19–L2A20–, –L2A21–L2A22–, and –L2A23–L2A24– 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 Ra is 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L2B3, L2B4, L2B5, L2B6, L2B7, and L2B8 is independently a single bond, substituted or unsubstituted, C1-100 alkylene, or substituted or unsubstituted, C1-100 heteroalkylene; each of L2C2 and L2C3 is independently is 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; bond C2B is attached to a first instance of A2; and bond C2C is attached to a second instance of A2. In some embodiments, each of –L2A9–L2A10–, –L2A11–L2A12–, –L2A13–L2A14–, –L2A15– L2A16–, –L2A17–L2A18–, –L2A19–L2A20–, –L2A21–L2A22–, and –L2A23–L2A24– is independently a single bond, –O–, –NRa–, –C(=O)NRa–, or –NRaC(=O)–. In some embodiments, each of –L2A9– L2A10–, –L2A11–L2A12–, –L2A13–L2A14–, –L2A15–L2A16–, –L2A17–L2A18–, –L2A19–L2A20–, –L2A21– L2A22–, and –L2A23–L2A24– is independently a single bond, –O–, –NH–, –C(=O)NH–, or – NHC(=O)–. In certain embodiments, each of –L2A9–L2A10–, –L2A11–L2A12–, –L2A13–L2A14–, – L2A15–L2A16–, –L2A17–L2A18–, –L2A19–L2A20–, –L2A21–L2A22–, and –L2A23–L2A24– is independently a single bond, –C(=O)NRa–, or –NRaC(=O)–. In certain embodiments, each of –L2A9–L2A10–, – L2A11–L2A12–, –L2A13–L2A14–, –L2A15–L2A16–, –L2A17–L2A18–, –L2A19–L2A20–, –L2A21–L2A22–, and – L2A23–L2A24– is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some embodiments, at least one of –L2A9–L2A10–, –L2A11–L2A12–, –L2A13–L2A14–, –L2A15–L2A16–, – L2A17–L2A18–, –L2A19–L2A20–, –L2A21–L2A22–, and –L2A23–L2A24– 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 –L2A9–L2A10–, –L2A11–L2A12–, –L2A13–L2A14–, –L2A15–L2A16–, – L2A17–L2A18–, –L2A19–L2A20–, –L2A21–L2A22–, and –L2A23–L2A24– is independently –C(=O)O–, – OC(=O)–, –OP(=O)(OH)O–, –SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O–. In some embodiments, at least one instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In some embodiments, each instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, each instance of Ra is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of L2B3, L2B4, L2B5, L2B6, L2B7, and L2B8 is independently a single bond, substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L2B3, L2B4, L2B5, L2B6, L2B7, and L2B8 is independently substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L2B3, L2B4, L2B5, L2B6, L2B7, and L2B8 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L2B3, L2B4, L2B5, L2B6, L2B7, and L2B8 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, each of L2C2 and L2C3 is independently a single bond. In certain embodiments, each of L2C2 and L2C3 is independently substituted or unsubstituted heteroarylene that replaces one of the backbone atoms. In certain embodiments, each of L2C2 and L2C3 is independently
Figure imgf000072_0001
(which may be attached at either direction). In some embodiments, at least one instance
Figure imgf000072_0002
the formula:
Figure imgf000073_0001
. In certain embodiments, at least one instance of –L2A17–L2A18– is –NRa–C(=O)– or –C(=O)–NRa–. In certain embodiments, at least one instance of –L2A17–L2A18– is –NH–C(=O)– or –C(=O)–NH–. In certain embodiments, at least one instance of –L2A17–L2A18– is –O–C(=O)– or –C(=O)–O–. In certain embodiments, at least one instance of –L2A17–L2A18– is –O–. In certain embodiments, at least one instance of –L2A17–L2A18– is –NH–. In certain embodiments, at least one instance of –L2A17–L2A18– is –C(=O)–. In certain embodiments, at least one instance of – L2A17–L2A18– is a single bond. In certain embodiments, at least one instance of –L2A23–L2A24– is –NRa–C(=O)– or –C(=O)–NRa–. In certain embodiments, at least one instance of –L2A23–L2A24– is –NH–C(=O)– or –C(=O)–NH–. In certain embodiments, at least one instance of –L2A23–L2A24– is –O–C(=O)– or –C(=O)–O–. In certain embodiments, at least one instance of –L2A23–L2A24– is –O–. In certain embodiments, at least one instance of –L2A23–L2A24– is –NH–. In certain embodiments, at least one instance of –L2A23–L2A24– is –C(=O)–. In certain embodiments, at least one instance of –
Figure imgf000073_0002
bond. In certain embodiments, y2 of an instance of is 1, 2, 3, 4, 5, or 6, and L2 thereof is substituted or unsubstituted, C7-70 heteroalkylene.
Figure imgf000073_0003
In certain embodiments, y2 of an instance of is 1, 2, 3, 4, 5, or 6, and L2 thereof comprises one or more of the following –CH2–, , , –O–, –CH2CH2O–, –
Figure imgf000074_0001
Figure imgf000074_0002
, or a combination of two or more of each one of the foregoing, provided that: the number of backbone atoms of L2 thereof is between 7 and 70, inclusive; and L2 thereof does not comprise O–O, O–N, N–O, or N–N.
Figure imgf000074_0003
In some embodiments, at least one instance of L2 is a combination of –CH2–, ,
Figure imgf000074_0004
at: the number of backbone atoms of the at least one instance of L2 is between 10 and 100, inclusive; and the at least one instance of L2 does not comprise O–O, O–N, N–O, or N–N. In certain embodiments, the conjugate is of the formula: (I-A-1),
Figure imgf000074_0005
(I-A-2), (I-A-3), (I-A-4), (I-A-5),
Figure imgf000075_0001
(I-A-6),
Figure imgf000075_0002
(I-A-7), (I-A-8), or
Figure imgf000075_0003
(I-A-9). In certain embodiments, at least one instance of the internucleosidic linkers is between the first n and n+1 nucleoside of the oligonucleotide strand counted from the 5’ end; and n is an integer between 1 and 20, inclusive, as the number of nucleosides of the oligonucleotide strand permits. In certain embodiments, at least one instance
Figure imgf000075_0004
between the first n and n+1 nucleosides of the oligonucleotide strand counted from the 5’ end; and n is an integer between 1 and 20, inclusive, as the number of nucleosides of the oligonucleotide strand permits. In certain embodiments, at least one instance
Figure imgf000076_0001
between the first and second nucleosides of the oligonucleotide strand counted from the 5’ end. In certain embodiments, at least one instance
Figure imgf000076_0002
internal position of the oligonucleotide strand. In certain embodiments, at least one instance
Figure imgf000076_0003
between the first and second nucleosides of the oligonucleotide strand counted from the 3’ end. In some embodiments, at least one instance of LA is of the formula:
Figure imgf000076_0004
each instance of ZA1 and ZA2 is independently a single bond, substituted or unsubstituted, C1-6 alkylene, or substituted or unsubstituted, C2-6 alkenylene; each instance of WA is independently a radical, as valency permits, of substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -O-, -OP(=O)(ORc)O-, -N(Rc)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NRc-, -NRcC(=O)-, -C(=O)Rc-, -NRcC(=O)O-, -NRcC(=O)NRc-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(Rc)-, -S(=O)2NRc-, -NRcS(=O)2-, or a combination thereof; each instance of Rc 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 RC are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and bond C4A is attached to L4. In some embodiments, at least one instance of ZA1 is substituted or unsubstituted, C1-6 alkylene. In some embodiments, at least one instance of ZA1 is substituted or unsubstituted, C1-3 alkylene. In certain embodiments, at least one instance of ZA1 is unsubstituted C1-3 alkylene. In some embodiments, at least one instance of ZA2 is substituted or unsubstituted, C1-6 alkylene. In some embodiments, at least one instance of ZA2 is substituted or unsubstituted, C1-3 alkylene. In certain embodiments, at least one instance of ZA2 is unsubstituted C1-3 alkylene. In some embodiments, WA is -N(Rc)-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRc-, or -NRcC(=O)-. In certain embodiments, WA is -N(Rc)-, -C(=O)NRc-, or -NRcC(=O)-. In some embodiments, each instance of Rc is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In some embodiments, at least one instance of LA is of the formula
Figure imgf000077_0001
Figure imgf000077_0003
.
Figure imgf000077_0002
. In certain embodiments, at least one instance of L4 is substituted or unsubstituted, C1-100 alkylene, substituted or unsubstituted, C2-100 alkenylene, substituted or unsubstituted, C2-100 alkynylene, substituted or unsubstituted, C1-100 heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, or substituted or unsubstituted, C2-100 heteroalkynylene; optionally wherein one or more backbone atoms of the C1-100 alkylene, C2-100 alkenylene, C2-100 alkynylene, C1-100 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 certain embodiments, at least one instance of L4 is substituted or unsubstituted, C7-70 alkylene, 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, two, three, or four 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. In certain embodiments, at least one instance of L4 is substituted or unsubstituted, C7-70 alkylene or substituted or unsubstituted, C7-70 heteroalkylene; and one, two, three, or four 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. In some embodiments, at least one instance
Figure imgf000078_0001
thereof is
Figure imgf000078_0002
each of –L4A1–L4A2–, –L4A3–L4A4–, –L4A5–L4A6–, –L4A7–L4A8–, –L4A17–L4A18–, and –L4A19–L4A20– 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 Ra is 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 Ra attached 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 L4B3 is independently a single bond, substituted or unsubstituted, C1-100 alkylene, or substituted or unsubstituted, C1-100 heteroalkylene; each of L4C1 and L4C2 is 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 C4A is attached to A4. In some embodiments, each of –L4A1–L4A2–, –L4A3–L4A4–, –L4A5–L4A6–, –L4A7–L4A8–, – L4A17–L4A18–, and –L4A19–L4A20– 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 independently a single 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–L4A20– 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–L4A20– 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–L4A20– 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–L4A20– is independently –C(=O)O–, –OC(=O)–, –OP(=O)(OH)O–, – SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O–. In some embodiments, at least one instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In some embodiments, each instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, each instance of Ra is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of L4B1, L4B2, and L4B3 is 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 L4B3 is independently substituted or unsubstituted, C1- 10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L4B1, L4B2, and L4B3 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L4B1, L4B2, and L4B3 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, each of L4C1 and L4C2 is independently a single bond. In certain embodiments, each of L4C1 and L4C2 is independently substituted or unsubstituted heteroarylene that replaces one of the backbone atoms. In certain embodiments, each of L4C1 and L4C2 is independently
Figure imgf000080_0001
(which may be attached at either direction). In some embodiments, at least one instance
Figure imgf000080_0002
thereof is
Figure imgf000080_0003
each of –L4A21–L4A22–, –L4A23–L4A24–, –L4A25–L4A26–, –L4A27–L4A28–, –L4A29–L4A30–, – L4A31–L4A32–, –L4A33–L4A34–, –L4A35–L4A36–, –L4A37–L4A38–, –L4A39–L4A40–, –L4A41–L4A42–, – L4A43–L4A44–, –L4A45–L4A46–, –L4A47–L4A48–, and –L4A49–L4A50– 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 Ra is 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L4B4, L4B5, L4B6, L4B7, L4B8, L4B9, L4B10, L4B11, and L4B12 is independently a single bond, substituted or unsubstituted, C1-100 alkylene, or substituted or unsubstituted, C1-100 heteroalkylene; each of L4C3, L4C4, L4C5, L4C6, L4C7, and L4C8 is 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; bond C4B is attached to a first instance of A4; and bond C4C is attached to a second instance of A4. In some embodiments, each of –L4A21–L4A22–, –L4A23–L4A24–, –L4A25–L4A26–, –L4A27– L4A28–, –L4A29–L4A30–, –L4A31–L4A32–, –L4A33–L4A34–, –L4A35–L4A36–, –L4A37–L4A38–, –L4A39– L4A40–, –L4A41–L4A42–, –L4A43–L4A44–, –L4A45–L4A46–, –L4A47–L4A48–, and –L4A49–L4A50– is independently a single bond, –O–, –NRa–, –C(=O)NRa–, or –NRaC(=O)–. In some embodiments, each of –L4A21–L4A22–, –L4A23–L4A24–, –L4A25–L4A26–, –L4A27–L4A28–, –L4A29–L4A30–, –L4A31– L4A32–, –L4A33–L4A34–, –L4A35–L4A36–, –L4A37–L4A38–, –L4A39–L4A40–, –L4A41–L4A42–, –L4A43– L4A44–, –L4A45–L4A46–, –L4A47–L4A48–, and –L4A49–L4A50– is independently a single bond, –O–, – NH–, –C(=O)NH–, or –NHC(=O)–. In certain embodiments, each of –L4A21–L4A22–, –L4A23– L4A24–, –L4A25–L4A26–, –L4A27–L4A28–, –L4A29–L4A30–, –L4A31–L4A32–, –L4A33–L4A34–, –L4A35– L4A36–, –L4A37–L4A38–, –L4A39–L4A40–, –L4A41–L4A42–, –L4A43–L4A44–, –L4A45–L4A46–, –L4A47– L4A48–, and –L4A49–L4A50– is independently a single bond, –C(=O)NRa–, or –NRaC(=O)–. In certain embodiments, each of –L4A21–L4A22–, –L4A23–L4A24–, –L4A25–L4A26–, –L4A27–L4A28–, – L4A29–L4A30–, –L4A31–L4A32–, –L4A33–L4A34–, –L4A35–L4A36–, –L4A37–L4A38–, –L4A39–L4A40–, – L4A41–L4A42–, –L4A43–L4A44–, –L4A45–L4A46–, –L4A47–L4A48–, and –L4A49–L4A50– is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some embodiments, at least one of –L4A21– L4A22–, –L4A23–L4A24–, –L4A25–L4A26–, –L4A27–L4A28–, –L4A29–L4A30–, –L4A31–L4A32–, –L4A33– L4A34–, –L4A35–L4A36–, –L4A37–L4A38–, –L4A39–L4A40–, –L4A41–L4A42–, –L4A43–L4A44–, –L4A45– L4A46–, –L4A47–L4A48–, and –L4A49–L4A50– 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 –L4A21–L4A22–, –L4A23–L4A24–, –L4A25–L4A26–, –L4A27–L4A28–, – L4A29–L4A30–, –L4A31–L4A32–, –L4A33–L4A34–, –L4A35–L4A36–, –L4A37–L4A38–, –L4A39–L4A40–, – L4A41–L4A42–, –L4A43–L4A44–, –L4A45–L4A46–, –L4A47–L4A48–, and –L4A49–L4A50– is independently –C(=O)O–, –OC(=O)–, –OP(=O)(OH)O–, –SP(=O)(OH)O–, –OP(=O)(OH)S–, or – OP(=O)(SH)O–. In some embodiments, at least one instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In some embodiments, each instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, each instance of Ra is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of L4B4, L4B5, L4B6, L4B7, L4B8, L4B9, L4B10, L4B11, and L4B12 is independently a single bond, substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L4B4, L4B5, L4B6, L4B7, L4B8, L4B9, L4B10, L4B11, and L4B12 is independently substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L4B4, L4B5, L4B6, L4B7, L4B8, L4B9, L4B10, L4B11, and L4B12 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L4B4, L4B5, L4B6, L4B7, L4B8, L4B9, L4B10, L4B11, and L4B12 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, each of L4C3, L4C4, L4C5, L4C6, L4C7, and L4C8 is independently a single bond. In certain embodiments, each of L4C3, L4C4, L4C5, L4C6, L4C7, and L4C8 is independently substituted or unsubstituted heteroarylene that replaces one of the backbone atoms. In certain embodiments, each of L4C3, L4C4, L4C5, L4C6, L4C7, and L4C8 is independently
Figure imgf000082_0001
(which may be attached at either direction). In certain embodiments, at least one instance of L4 is substituted or unsubstituted, C7-70 heteroalkylene. In certain embodiments, at least one instance of L4 comprises one or more of the
Figure imgf000082_0005
bination of two or more of each one of the foregoing, provided that: the number of backbone atoms of the at least one instance of L4 is between 10 and 100, inclusive; and the at least one instance of L4 does not comprise O–O, O–N, N–O, or N–N.
Figure imgf000082_0002
In some embodiments, at least one instance of L4 is a combination of –CH2–,
Figure imgf000082_0003
,
Figure imgf000082_0004
at: the number of backbone atoms of the at least one instance of L4 is between 10 and 100, inclusive; and the at least one instance of L4 does not comprise O–O, O–N, N–O, or N–N. In certain embodiments, the conjugate is of the formula:
Figure imgf000083_0001
(I-A-10),
Figure imgf000083_0002
(I-A-11), (I-A-12), (I-A-13),
Figure imgf000083_0003
(I-A-14), or (I-A-15). In certain embodiments, L5 is attached to the 5′ end of the oligonucleotide strand. In certain embodiments, L5 is attached to the oxygen atom substituted at the 5′ position of the 5′ end of the oligonucleotide strand. In certain embodiments, L5 is attached to the 5′ position of the 5′ end of the oligonucleotide strand. In certain embodiments, L5 is attached to the nucleobase of the 5′ end of the oligonucleotide strand. In certain embodiments, L5 is attached to the 1′ position of the 5′ end of the oligonucleotide strand, wherein the 5′ end is an abasic nucleoside. In certain embodiments, L5 is attached to the 2′ position of the 5′ end of the oligonucleotide strand. In certain embodiments, L5 is attached to the oxygen atom substituted at the 2′ position of the 5′ end of the oligonucleotide strand. In certain embodiments, L5 is substituted or unsubstituted, C1-150 alkylene, substituted or unsubstituted, C2-150 alkenylene, substituted or unsubstituted, C2-150 alkynylene, substituted or unsubstituted, C1-150 heteroalkylene, substituted or unsubstituted, C2-150 heteroalkenylene, or substituted or unsubstituted, C2-150 heteroalkynylene; optionally wherein one or more backbone atoms of the C1-150 alkylene, C2-150 alkenylene, C2-150 alkynylene, C1-150 heteroalkylene, C2-150 heteroalkenylene, or C2-150 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, L5 is substituted or unsubstituted, C10-100 alkylene, substituted or unsubstituted, C10-100 alkenylene, substituted or unsubstituted, C10-100 alkynylene, substituted or unsubstituted, C10-100 heteroalkylene, substituted or unsubstituted, C10-100 heteroalkenylene, or substituted or unsubstituted, C10-100 heteroalkynylene; optionally wherein one, two, or three backbone atoms of the C10-100 alkylene, C10-100 alkenylene, C10-100 alkynylene, C10-100 heteroalkylene, C10-100 heteroalkenylene, or C10-100 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 certain embodiments, L5 is substituted or unsubstituted, C10-100 alkylene or substituted or unsubstituted, C10-100 heteroalkylene; and one, two, or three backbone atoms of the C10-100 alkylene or C10-100 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. In some embodiments, at least one instance of y5 is 1; L5 is
Figure imgf000084_0001
each of –L5A1–L5A2–, –L5A3–L5A4–, –L5A5–L5A6–, –L5A7–L5A8–, –L5A17–L5A18–, and –L5A19–L5A20– 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 Ra is 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 Ra attached 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 L5B6 is independently a single bond, substituted or unsubstituted, C1-100 alkylene or substituted or unsubstituted, C1-100 heteroalkylene; each of L5C1 and L5C2 is 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 C5B is attached to A5. In some embodiments, each of –L5A1–L5A2–, –L5A3–L5A4–, –L5A5–L5A6–, –L5A7–L5A8–, –L5A17–L5A18–, and –L5A19–L5A20– is independently a single bond, –O–, –NRa–, –C(=O)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–L5A20– 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–L5A20– 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–, –L5A17–L5A18–, and –L5A19–L5A20– 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 –L5A1–L5A2–, –L5A3–L5A4–, –L5A5–L5A6–, –L5A7–L5A8–, –L5A17–L5A18–, and –L5A19–L5A20– is independently –C(=O)O–, –OC(=O)–, –OP(=O)(OH)O–, –SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O–. In some embodiments, at least one instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In some embodiments, each instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, each instance of Ra is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of L5B1, L5B2, and L5B6 is independently a single bond, substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L5B1, L5B2, and L5B6 is independently substituted or unsubstituted, C1- 10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L5B1, L5B2, and L5B6 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L5B1, L5B2, and L5B6 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, each of L5C1 and L5C2 is independently a single bond. In certain embodiments, each of L5C1 and L5C2 is independently substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms. In certain embodiments, each of L5C1 and L5C2 is
Figure imgf000086_0001
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 Ra is 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of –L5B1–, –L5B4–, and –L5B6– is independently a single bond, substituted or unsubstituted, C1-150 alkylene or substituted or unsubstituted, C1-150 heteroalkylene; each of –L5B2–, –L5B3–, –L5B5–, and –L5B7– is independently a single bond, substituted or unsubstituted, C1-150 alkylene, or substituted or unsubstituted, C1-150 heteroalkylene; each of L5C1, L5C2, L5C3, and L5C4 is 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; bond C5A is attached to a first instance of A5; and bond C5B is attached to a second instance of A5. In some embodiments, each of –L5A1–L5A2–, –L5A3–L5A4–, –L5A5–L5A6–, –L5A7–L5A8–, – L5A9–L5A10–, –L5A11–L5A12–, –L5A13–L5A14–, –L5A15–L5A16–, –L5A17–L5A18–, –L5A19–L5A20–, and – L5A21–L5A22– is independently a single bond, –O–, –NRa–, –C(=O)NRa–, or –NRaC(=O)–. In some embodiments, each of –L5A1–L5A2–, –L5A3–L5A4–, –L5A5–L5A6–, –L5A7–L5A8–, –L5A9–L5A10–, –L5A11–L5A12–, –L5A13–L5A14–, –L5A15–L5A16–, –L5A17–L5A18–, –L5A19–L5A20–, and –L5A21–L5A22– 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–, –L5A9–L5A10–, – L5A11–L5A12–, –L5A13–L5A14–, –L5A15–L5A16–, –L5A17–L5A18–, –L5A19–L5A20–, and –L5A21–L5A22– is independently a single bond, –C(=O)NRa–, or –NRaC(=O)–. In certain embodiments, each of – L5A1–L5A2–, –L5A3–L5A4–, –L5A5–L5A6–, –L5A7–L5A8–, –L5A9–L5A10–, –L5A11–L5A12–, –L5A13– L5A14–, –L5A15–L5A16–, –L5A17–L5A18–, –L5A19–L5A20–, and –L5A21–L5A22– 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–, –L5A9–L5A10–, –L5A11–L5A12–, –L5A13–L5A14–, –L5A15– L5A16–, –L5A17–L5A18–, –L5A19–L5A20–, and –L5A21–L5A22– 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 –L5A1–L5A2–, –L5A3–L5A4–, –L5A5–L5A6–, –L5A7–L5A8–, –L5A9– L5A10–, –L5A11–L5A12–, –L5A13–L5A14–, –L5A15–L5A16–, –L5A17–L5A18–, –L5A19–L5A20–, and –L5A21– L5A22– is independently –C(=O)O–, –OC(=O)–, –OP(=O)(OH)O–, –SP(=O)(OH)O–, – OP(=O)(OH)S–, or –OP(=O)(SH)O–. In some embodiments, at least one instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In some embodiments, each instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, each instance of Ra is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of L5B1, L5B4, and L5B6 is independently substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L5B1, L5B4, and L5B6 is independently substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L5B1, L5B4, and L5B6 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L5B1, L5B4, and L5B6 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In some embodiments, each of L5B2, L5B3, L5B5, and L5B7 is independently a single bond, substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L5B2, L5B3, L5B5, and L5B7 is independently a single bond, substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L5B2, L5B3, L5B5, and L5B7 is independently a single bond. In certain embodiments, each of L5B2, L5B3, L5B5, and L5B7 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L5B2, L5B3, L5B5, and L5B7 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, each of L5C1, L5C2, L5C3, and L5C4 is independently a single bond. In certain embodiments, each of L5C1, L5C2, L5C3, and L5C4 is independently substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms. In certain embodiments, each of L5C1, L5C2, L5C3, and L5C4 is independently
Figure imgf000088_0001
(which may be attached at either direction). In some embodiments, at least one instance of y5 is 2; and
Figure imgf000088_0002
,
Figure imgf000089_0001
,
,
Figure imgf000090_0001
,
,
Figure imgf000091_0001
,
Figure imgf000092_0001
. In certain embodiments, at least one instance of y5 is 2; and
Figure imgf000092_0002
is
Figure imgf000092_0003
Figure imgf000093_0001
each of p2, p5, p6, and p9 is independently an integer from 1 to 10, inclusive; each of p3, p7, p8, p10, p11, p12, and p13 is independently an integer from 0 to 10, inclusive; p4 is 0 or 1; each of –L5A15–L5A16– and –L5A21–L5A22– 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 Ra is 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; bond C5A is attached to a first instance of A5; and bond C5B is attached to a second instance of A5.
Figure imgf000094_0001
each of p2, p5, p6, p8, p9, and p11 is independently an integer from 1 to 10, inclusive; each of p3, p7, p10, p12, and p13 is independently an integer from 0 to 10, inclusive; p4 is 0 or 1; each of –L5A15–L5A16– and –L5A21–L5A22– 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 Ra is 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; bond C5A is attached to a first instance of A5; and bond C5B is attached to a second instance of A5. In certain embodiments, at least one instance of –L5A15–L5A16– is –NRa–C(=O)– or –C(=O)–NRa–. In certain embodiments, at least one instance of –L5A15–L5A16– is –NH–C(=O)– or –C(=O)–NH–. In certain embodiments, at least one instance of –L5A15–L5A16– is –O–C(=O)– or –C(=O)–O–. In certain embodiments, at least one instance of –L5A15–L5A16– is –O–. In certain embodiments, at least one instance of –L5A15–L5A16– is –NH–. In certain embodiments, at least one instance of –L5A15–L5A16– is –C(=O)–. In certain embodiments, at least one instance of – L5A15–L5A16– is a single bond. In certain embodiments, at least one instance of –L5A21–L5A22– is –NRa–C(=O)– or –C(=O)–NRa–. In certain embodiments, at least one instance of –L5A21–L5A22– is –NH–C(=O)– or –C(=O)–NH–. In certain embodiments, at least one instance of –L5A21–L5A22– is –O–C(=O)– or –C(=O)–O–. In certain embodiments, at least one instance of –L5A21–L5A22– is –O–. In certain embodiments, at least one instance of –L5A21–L5A22– is –NH–. In certain embodiments, at least one instance of –L5A21–L5A22– is –C(=O)–. In certain embodiments, at least one instance of – L5A21–L5A22– is a single bond. In some embodiments, at least one instance of y5 is 2, and
Figure imgf000095_0001
is
Figure imgf000095_0002
; each of –L5A47–L5A48–, –L5A49–L5A50–, –L5A51–L5A52–, –L5A53–L5A54–, –L5A55–L5A56–, – L5A57–L5A58–, –L5A59–L5A60–, –L5A61–L5A62–, –L5A63–L5A64–, –L5A65–L5A66–, and –L5A67–L5A68– 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 Ra is 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of –L5B16–, –L5B19–, and –L5B21– is independently a single bond, substituted or unsubstituted, C1-150 alkylene or substituted or unsubstituted, C1-150 heteroalkylene; each of –L5B17–, –L5B18–, –L5B20–, and –L5B22– is independently a single bond, substituted or unsubstituted, C1-150 alkylene, or substituted or unsubstituted, C1-150 heteroalkylene; each of L5C9, L5C10, L5C11, and L5C12 is 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; bond C5A is attached to a first instance of A5; and bond C5B is attached to a second instance of A5. In some embodiments, each of –L5A47–L5A48–, –L5A49–L5A50–, –L5A51–L5A52–, –L5A53– L5A54–, –L5A55–L5A56–, –L5A57–L5A58–, –L5A59–L5A60–, –L5A61–L5A62–, –L5A63–L5A64–, –L5A65– L5A66–, and –L5A67–L5A68– is independently a single bond, –O–, –NRa–, –C(=O)NRa–, or – NRaC(=O)–. In some embodiments, each of –L5A47–L5A48–, –L5A49–L5A50–, –L5A51–L5A52–, – L5A53–L5A54–, –L5A55–L5A56–, –L5A57–L5A58–, –L5A59–L5A60–, –L5A61–L5A62–, –L5A63–L5A64–, – L5A65–L5A66–, and –L5A67–L5A68– is independently a single bond, –O–, –NH–, –C(=O)NH–, or – NHC(=O)–. In certain embodiments, each of –L5A47–L5A48–, –L5A49–L5A50–, –L5A51–L5A52–, – L5A53–L5A54–, –L5A55–L5A56–, –L5A57–L5A58–, –L5A59–L5A60–, –L5A61–L5A62–, –L5A63–L5A64–, – L5A65–L5A66–, and –L5A67–L5A68– is independently a single bond, –C(=O)NRa–, or –NRaC(=O)–. In certain embodiments, each of –L5A47–L5A48–, –L5A49–L5A50–, –L5A51–L5A52–, –L5A53–L5A54–, – L5A55–L5A56–, –L5A57–L5A58–, –L5A59–L5A60–, –L5A61–L5A62–, –L5A63–L5A64–, –L5A65–L5A66–, and – L5A67–L5A68– is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some embodiments, at least one of –L5A47–L5A48–, –L5A49–L5A50–, –L5A51–L5A52–, –L5A53–L5A54–, – L5A55–L5A56–, –L5A57–L5A58–, –L5A59–L5A60–, –L5A61–L5A62–, –L5A63–L5A64–, –L5A65–L5A66–, and – L5A67–L5A68– 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 –L5A47–L5A48–, – L5A49–L5A50–, –L5A51–L5A52–, –L5A53–L5A54–, –L5A55–L5A56–, –L5A57–L5A58–, –L5A59–L5A60–, – L5A61–L5A62–, –L5A63–L5A64–, –L5A65–L5A66–, and –L5A67–L5A68– is independently –C(=O)O–, – OC(=O)–, –OP(=O)(OH)O–, –SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O–. In some embodiments, at least one instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In some embodiments, each instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, each instance of Ra is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of L5B16, L5B19, and L5B21 is independently substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L5B16, L5B19, and L5B21 is independently substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L5B16, L5B19, and L5B21 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L5B16, L5B19, and L5B21 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In some embodiments, each of L5B17, L5B18, L5B20, and L5B22 is independently a single bond, substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L5B17, L5B18, L5B20, and L5B22 is independently a single bond, substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L5B17, L5B18, L5B20, and L5B22 is independently a single bond. In certain embodiments, each of L5B17, L5B18, L5B20, and L5B22 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L5B17, L5B18, L5B20, and L5B22 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, each of L5C9, L5C10, L5C11, and L5C12 is independently a single bond. In certain embodiments, each of L5C9, L5C10, L5C11, and L5C12 is independently substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms. In certain embodiments, each of L5C9, L5C10, L5C11, and L5C12 is independently
Figure imgf000097_0001
(which may be attached at either direction). In certain embodiments, at least one instance of y5 is 2;
Figure imgf000098_0001
each of p2, p5, and p6 is independently an integer from 1 to 10, inclusive; each of p3, p7, p8, p9, p10, and p11 is independently an integer from 0 to 10, inclusive;
Figure imgf000098_0002
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 Ra is 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; bond C5A is attached to a first instance of A5; and bond C5B is attached to a second instance of A5. In certain embodiments, at least one instance of –L5A61–L5A62– is –NRa–C(=O)– or –C(=O)–NRa–. In certain embodiments, at least one instance of –L5A61–L5A62– is –NH–C(=O)– or –C(=O)–NH–. In certain embodiments, at least one instance of –L5A61–L5A62– is –O–C(=O)– or –C(=O)–O–. In certain embodiments, at least one instance of –L5A61–L5A62– is –O–. In certain embodiments, at least one instance of –L5A61–L5A62– is –NH–. In certain embodiments, at least one instance of –L5A61–L5A62– is –C(=O)–. In certain embodiments, at least one instance of – L5A61–L5A62– is a single bond. In certain embodiments, at least one instance of –L5A67–L5A68– is –NRa–C(=O)– or –C(=O)–NRa–. In certain embodiments, at least one instance of –L5A67–L5A68– is –NH–C(=O)– or –C(=O)–NH–. In certain embodiments, at least one instance of –L5A67–L5A68– is –O–C(=O)– or –C(=O)–O–. In certain embodiments, at least one instance of –L5A67–L5A68– is –O–. In certain embodiments, at least one instance of –L5A67–L5A68– is –NH–. In certain embodiments, at least one instance of –L5A67–L5A68– is –C(=O)–. In certain embodiments, at least one instance of – L5A67–L5A68– is a single bond. In certain embodiments, at least one instance of y5 is 3; and
Figure imgf000099_0001
each of –L5A23–L5A24–, –L5A25–L5A25–, –L5A27–L5A28–, –L5A29–L5A30–, –L5A31–L5A32–, – L5A33–L5A34–, –L5A35–L5A36–, –L5A37–L5A38–, –L5A39–L5A40–, –L5A41–L5A42–, –L5A43–L5A44–, and – L5A45–L5A46– 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 Ra is 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of –L5B8–, –L5B9–, –L5B10–, –L5B11–, –L5B12–, –L5B13–, –L5B14–, and –L5B15– is independently a single bond, substituted or unsubstituted, C1-150 alkylene or substituted or unsubstituted, C1-150 heteroalkylene; each of L5C5, L5C6, L5C7, and L5C8 is 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 bonds C5C, C5D, and C5E are attached to a first, second, and third instances of A5, respectively. In some embodiments, each of –L5A23–L5A24–, –L5A25–L5A25–, –L5A27–L5A28–, –L5A29– L5A30–, –L5A31–L5A32–, –L5A33–L5A34–, –L5A35–L5A36–, –L5A37–L5A38–, –L5A39–L5A40–, –L5A41– L5A42–, –L5A43–L5A44–, and –L5A45–L5A46– is independently a single bond, –O–, –NRa–, – C(=O)NRa–, or –NRaC(=O)–. In some embodiments, each of –L5A23–L5A24–, –L5A25–L5A25–, – L5A27–L5A28–, –L5A29–L5A30–, –L5A31–L5A32–, –L5A33–L5A34–, –L5A35–L5A36–, –L5A37–L5A38–, – L5A39–L5A40–, –L5A41–L5A42–, –L5A43–L5A44–, and –L5A45–L5A46– is independently a single bond, – O–, –NH–, –C(=O)NH–, or –NHC(=O)–. In certain embodiments, each of –L5A23–L5A24–, – L5A25–L5A25–, –L5A27–L5A28–, –L5A29–L5A30–, –L5A31–L5A32–, –L5A33–L5A34–, –L5A35–L5A36–, – L5A37–L5A38–, –L5A39–L5A40–, –L5A41–L5A42–, –L5A43–L5A44–, and –L5A45–L5A46– is independently a single bond, –C(=O)NRa–, or –NRaC(=O)–. In certain embodiments, each of –L5A23–L5A24–, – L5A25–L5A25–, –L5A27–L5A28–, –L5A29–L5A30–, –L5A31–L5A32–, –L5A33–L5A34–, –L5A35–L5A36–, – L5A37–L5A38–, –L5A39–L5A40–, –L5A41–L5A42–, –L5A43–L5A44–, and –L5A45–L5A46– is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some embodiments, at least one of –L5A23– L5A24–, –L5A25–L5A25–, –L5A27–L5A28–, –L5A29–L5A30–, –L5A31–L5A32–, –L5A33–L5A34–, –L5A35– L5A36–, –L5A37–L5A38–, –L5A39–L5A40–, –L5A41–L5A42–, –L5A43–L5A44–, and –L5A45–L5A46– 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 –L5A23–L5A24–, –L5A25–L5A25–, – L5A27–L5A28–, –L5A29–L5A30–, –L5A31–L5A32–, –L5A33–L5A34–, –L5A35–L5A36–, –L5A37–L5A38–, – L5A39–L5A40–, –L5A41–L5A42–, –L5A43–L5A44–, and –L5A45–L5A46– is independently –C(=O)O–, – OC(=O)–, –OP(=O)(OH)O–, –SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O–. In some embodiments, at least one instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In some embodiments, each instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, each instance of Ra is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of L5B8, L5B9, L5B10, L5B11, L5B12, L5B13, L5B14, and L5B15 is independently substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L5B8, L5B9, L5B10, L5B11, L5B12, L5B13, L5B14, and L5B15 is independently substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L5B8, L5B9, L5B10, L5B11, L5B12, L5B13, L5B14, and L5B15 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L5B8, L5B9, L5B10, L5B11, L5B12, L5B13, L5B14, and L5B15 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, each of L5C5, L5C6, L5C7, and L5C8 is independently a single bond. In certain embodiments, each of L5C5, L5C6, L5C7, and L5C8 is independently substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms. In certain embodiments, each of L5C5, L5C6, L5C7, and L5C8 is independently
Figure imgf000101_0001
(which may be attached at either direction). In certain embodiments, at least one instance of y5 is 3; and
Figure imgf000102_0001
each of L5C6, L5C7, and L5C8 is independently a single bond,
Figure imgf000102_0002
Figure imgf000102_0003
bond C5F is attached t
Figure imgf000103_0001
In certain embodiments, L5 is substituted or unsubstituted, C10-100 heteroalkylene.
AHA
In certain embodiments, L5 comprises one or more of the following -CH2-,
Figure imgf000103_0002
Figure imgf000103_0003
combination of two or more of each one of the foregoing, provided that: the number of backbone atoms of L5 is between 10 and 100, inclusive; and
L5 does not comprise O-O, O-N, N-O, or N-N.
In some embodiments, at least one instance of L5 is a combination of -CH2-,
Figure imgf000103_0004
?
Figure imgf000103_0005
at: the number of backbone atoms of the at least one instance of L5 is between 10 and 100, inclusive; and the at least one instance of L5 does not comprise O-O, 0-N, N-0, or N-N.
In certain embodiments, L6 is substituted or unsubstituted, Ci-150 alkylene, substituted or unsubstituted, C2-150 alkenylene, substituted or unsubstituted, C2-150 alkynylene, substituted or unsubstituted, Ci-150 heteroalkylene, substituted or unsubstituted, C2-150 heteroalkenylene, or substituted or unsubstituted, C2-i5oheteroalkynylene; optionally wherein one or more backbone atoms of the Ci-150 alkylene, C2-150 alkenylene, C2-150 alkynylene, Ci-150 heteroalkylene, C2-150 heteroalkenylene, or C2-150 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, L6 is substituted or unsubstituted, C10-100 alkylene, substituted or unsubstituted, C10-100 alkenylene, substituted or unsubstituted, C10-100 alkynylene, substituted or unsubstituted, C10-100 heteroalkylene, substituted or unsubstituted, C10-100 heteroalkenylene, or substituted or unsubstituted, Cio-iooheteroalkynylene; optionally wherein one, two, or three backbone atoms of the C10-100 alkylene, C10-100 alkenylene, C10-100 alkynylene, C10-100 heteroalkylene, C10-100 heteroalkenylene, or C10-100 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 certain embodiments, L6 is substituted or unsubstituted, C10-100 alkylene or substituted or unsubstituted, C10-100 heteroalkylene; and one, two, or three backbone atoms of the C10-100 alkylene or C10-100 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.
In some embodiments, at least one instance of y6 is 1;
L6 is
Figure imgf000104_0001
each of -L6A1-L6A2-, -L6A3-L6A4-, -L6A5-L6A6-, -L6A7-L6A8-, _L6A17-L6A18-, and - L6AI9_J^6A20_ js injepenjentiy 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, 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 Ra attached 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 L6B6 is independently a single bond, substituted or unsubstituted, Ci-ioo alkylene or substituted or unsubstituted, Ci-ioo heteroalkylene; each of L6C1 and L6C2 is 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 C6B is attached to A6.
In some embodiments, at least one of -L6A1-L6A2-, -L6A3-L6A4-, -L6A5-L6A6-, -L6A7-
Figure imgf000105_0001
single bond, -O-, -NRa-,
-C(=O)NRa-, or -NRaC(=O)-. In some embodiments, each of -L6A1-L6A2-, -L6A3-L6A4-, -L6A5- L6A6_ -L6A7-L6A8- — L6A 17-L6A 18~, and -L6A 19-L6A20- is independently a single bond, -O-, - NH-, -C(=O)NH-, or -NHC(=O)-. In certain embodiments, each of -L6A1-L6A2-, -L6A3-L6A4-, -L6A5-L6A6-, -L6A7-L6A8-, — L6A 17-L6A 18~, and _L6A19_L6A20_ is independently a single bond, - C(=O)NRa-, or -NRaC(=O)-. In certain embodiments, each of -L6A1-L6A2-, -L6A3-L6A4-, -L6A5- L6A6_ -L6A7-L6A8- — L6A 17-L6A 18~, and -L6A 19-L6A20- is independently a single bond, -C(=O)NH-, or -NHC(=O)-. In some embodiments, at least one of -L6A1-L6A2-, -L6A3-L6A4-, _L6A5_L6A6_ _L6A7_L6A8_, _L6A i 7_L6A 18_ and _L6Ai9_L6A20_ 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-L6A20- is independently -C(=O)O-, -OC(=O)-, -OP(=O)(OH)O- -SP(=O)(OH)O-, -OP(=O)(OH)S-, or -OP(=O)(SH)O-
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.
In some embodiments, each of L6B1, L6B2, and L6B6 is 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 L6B6 is independently substituted or unsubstituted, Ci- 10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L6B1, L6B2, and L6B6 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L6B1, L6B2, and L6B6 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats.
In certain embodiments, each of L6C1 and L6C2 is independently a single bond. In certain embodiments, each of L6C1 and L6C2 is independently substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms. In certain embodiments, each of L6C1 and L6C2 is
Figure imgf000106_0001
In certain embodiments, at least one instance of y6 is 1; and
Figure imgf000106_0002
Figure imgf000107_0001
In certain embodiments, at least one instance of y6 is 2;
4
Figure imgf000107_0002
Figure imgf000108_0001
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, C2-6 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of -L6B1-, -L6B4-, and -L6B6- is independently a single bond, substituted or unsubstituted, C2-iso alkylene or substituted or unsubstituted, C2-iso heteroalkylene; each of -L6B2-, -L6B3-, -L6B5-, and -L6B7- is independently a single bond, substituted or unsubstituted, C2-iso alkylene, or substituted or unsubstituted, C2-iso heteroalkylene; each of L6C1, L6C2, L6C3, and L6C4 is 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; bond C6A is attached to a first instance of A6; and bond C6B is attached to a second instance of A6.
In some embodiments, at least one of -L6A1-L6A2-, -L6A3-L6A4-, -L6A5-L6A6-, -L6A7- j^6A8_ _£j5A9_£j5A10_ _j^6Al l_j^6A12_ _J^6A13_J^6A14_ _J^6A15_J^6A16_ _J^6A17_J^6A18_ _£j5A19_ L6A20-, and _L6A21_L6A22_ is independently a single bond, -O-, -NRa-, -C(=O)NRa-, or - NRaC(=O)–. In some embodiments, each of –L6A1–L6A2–, –L6A3–L6A4–, –L6A5–L6A6–, –L6A7– L6A8–, –L6A9–L6A10–, –L6A11–L6A12–, –L6A13–L6A14–, –L6A15–L6A16–, –L6A17–L6A18–, –L6A19– L6A20–, and –L6A21–L6A22– is independently a single bond, –O–, –NH–, –C(=O)NH–, or – NHC(=O)–. In certain embodiments, each of –L6A1–L6A2–, –L6A3–L6A4–, –L6A5–L6A6–, –L6A7– L6A8–, –L6A9–L6A10–, –L6A11–L6A12–, –L6A13–L6A14–, –L6A15–L6A16–, –L6A17–L6A18–, –L6A19– L6A20–, and –L6A21–L6A22– is independently a single bond, –C(=O)NRa–, or –NRaC(=O)–. In certain embodiments, each of –L6A1–L6A2–, –L6A3–L6A4–, –L6A5–L6A6–, –L6A7–L6A8–, –L6A9– L6A10–, –L6A11–L6A12–, –L6A13–L6A14–, –L6A15–L6A16–, –L6A17–L6A18–, –L6A19–L6A20–, and –L6A21– L6A22– is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some embodiments, at least one of –L6A1–L6A2–, –L6A3–L6A4–, –L6A5–L6A6–, –L6A7–L6A8–, –L6A9–L6A10–, –L6A11–L6A12–, –L6A13–L6A14–, –L6A15–L6A16–, –L6A17–L6A18–, –L6A19–L6A20–, and –L6A21–L6A22– 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–, –L6A9–L6A10–, –L6A11–L6A12–, –L6A13–L6A14–, –L6A15–L6A16–, –L6A17–L6A18–, – L6A19–L6A20–, and –L6A21–L6A22– is independently –C(=O)O–, –OC(=O)–, –OP(=O)(OH)O–, –SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O–. In some embodiments, at least one instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In some embodiments, each instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, each instance of Ra is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of L6B1, L6B4, and L6B6 is independently a single bond, substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L6B1, L6B4, and L6B6 is independently substituted or unsubstituted, C1- 10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L6B1, L6B4, and L6B6 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L6B1, L6B4, and L6B6 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In some embodiments, each of L6B2, L6B3, L6B5, and L6B7 is independently a single bond, substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L6B2, L6B3, L6B5, and L6B7 is independently a single bond, substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L6B2, L6B3, L6B5, and L6B7 is independently a single bond. In certain embodiments, each of L6B2, L6B3, L6B5, and L6B7 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L6B2, L6B3, L6B5, and L6B7 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, each of L6C1 L6C2, L6C3, and L6C4 is independently a single bond. In certain embodiments, each of L6C1 L6C2, L6C3, and L6C4 is independently substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms. In certain embodiments, each of L6C1 L6C2, L6C3, and L6C4 is independently
Figure imgf000110_0001
(which may be attached at either direction). In some embodiments, at least one instance of y6 is 2; and
Figure imgf000110_0002
,
,
Figure imgf000111_0001
,
,
Figure imgf000112_0001
,
Figure imgf000113_0001
. In certain embodiments, at least one instance of y6 is 2; and
Figure imgf000114_0001
each of p2, p5, p6, and p9 is independently an integer from 1 to 10, inclusive; each of p3, p7, p8, p10, p11, p12, and p13 is independently an integer from 0 to 10, inclusive; p4 is 0 or 1; each of –L6A15–L6A16– and –L6A21–L6A22– 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 Ra is 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; bond C6A is attached to a first instance of A6; and bond C6B is attached to a second instance of A6. In certain embodiments, at least one instance of y6 is 2;
Figure imgf000115_0001
each of p2, p5, p6, p8, p9, and p11 is independently an integer from 1 to 10, inclusive; each of p3, p7, p10, p12, and p13 is independently an integer from 0 to 10, inclusive; p4 is 0 or 1; each of –L6A15–L6A16– and –L6A21–L6A22– 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 Ra is 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; bond C6A is attached to a first instance of A6; and bond C6B is attached to a second instance of A6. In certain embodiments, at least one instance of –L6A15–L6A16– is –NRa–C(=O)– or –C(=O)–NRa–. In certain embodiments, at least one instance of –L6A15–L6A16– is –NH–C(=O)– or –C(=O)–NH–. In certain embodiments, at least one instance of –L6A15–L6A16– is –O–C(=O)– or –C(=O)–O–. In certain embodiments, at least one instance of –L6A15–L6A16– is –O–. In certain embodiments, at least one instance of –L6A15–L6A16– is –NH–. In certain embodiments, at least one instance of –L6A15–L6A16– is –C(=O)–. In certain embodiments, at least one instance of – L6A15–L6A16– is a single bond. In certain embodiments, at least one instance of –L6A21–L6A22– is –NRa–C(=O)– or –C(=O)–NRa–. In certain embodiments, at least one instance of –L6A21–L6A22– is –NH–C(=O)– or –C(=O)–NH–. In certain embodiments, at least one instance of –L6A21–L6A22– is –O–C(=O)– or –C(=O)–O–. In certain embodiments, at least one instance of –L6A21–L6A22– is –O–. In certain embodiments, at least one instance of –L6A21–L6A22– is –NH–. In certain embodiments, at least one instance of –L6A21–L6A22– is –C(=O)–. In certain embodiments, at least one instance of – L6A21–L6A22– is a single bond. In some embodiments, at least one instance
Figure imgf000116_0001
Figure imgf000117_0001
each of –L6A47–L6A48–, –L6A49–L6A50–, –L6A51–L6A52–, –L6A53–L6A54–, –L6A55–L6A56–, – L6A57–L6A58–, –L6A59–L6A60–, –L6A61–L6A62–, –L6A63–L6A64–, –L6A65–L6A66–, and –L6A67–L6A68– 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 Ra is 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of –L6B16–, –L6B19–, and –L6B21– is independently a single bond, substituted or unsubstituted, C1-150 alkylene or substituted or unsubstituted, C1-150 heteroalkylene; each of –L6B17–, –L6B18–, –L6B20–, and –L6B22– is independently a single bond, substituted or unsubstituted, C1-150 alkylene, or substituted or unsubstituted, C1-150 heteroalkylene; each of L6C9, L6C10, L6C11, and L6C12 is 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; bond C6A is attached to a first instance of A6; and bond C6B is attached to a second instance of A6. In some embodiments, each of –L6A47–L6A48–, –L6A49–L6A50–, –L6A51–L6A52–, –L6A53– L6A54–, –L6A55–L6A56–, –L6A57–L6A58–, –L6A59–L6A60–, –L6A61–L6A62–, –L6A63–L6A64–, –L6A65– L6A66–, and –L6A67–L6A68– is independently a single bond, –O–, –NRa–, –C(=O)NRa–, or – NRaC(=O)–. In some embodiments, each of –L6A47–L6A48–, –L6A49–L6A50–, –L6A51–L6A52–, – L6A53–L6A54–, –L6A55–L6A56–, –L6A57–L6A58–, –L6A59–L6A60–, –L6A61–L6A62–, –L6A63–L6A64–, – L6A65–L6A66–, and –L6A67–L6A68– is independently a single bond, –O–, –NH–, –C(=O)NH–, or – NHC(=O)–. In certain embodiments, each of –L6A47–L6A48–, –L6A49–L6A50–, –L6A51–L6A52–, – L6A53–L6A54–, –L6A55–L6A56–, –L6A57–L6A58–, –L6A59–L6A60–, –L6A61–L6A62–, –L6A63–L6A64–, – L6A65–L6A66–, and –L6A67–L6A68– is independently a single bond, –C(=O)NRa–, or –NRaC(=O)–. In certain embodiments, each of –L6A47–L6A48–, –L6A49–L6A50–, –L6A51–L6A52–, –L6A53–L6A54–, – L6A55–L6A56–, –L6A57–L6A58–, –L6A59–L6A60–, –L6A61–L6A62–, –L6A63–L6A64–, –L6A65–L6A66–, and – L6A67–L6A68– is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some embodiments, at least one of –L6A47–L6A48–, –L6A49–L6A50–, –L6A51–L6A52–, –L6A53–L6A54–, – L6A55–L6A56–, –L6A57–L6A58–, –L6A59–L6A60–, –L6A61–L6A62–, –L6A63–L6A64–, –L6A65–L6A66–, and – L6A67–L6A68– 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 –L6A47–L6A48–, – L6A49–L6A50–, –L6A51–L6A52–, –L6A53–L6A54–, –L6A55–L6A56–, –L6A57–L6A58–, –L6A59–L6A60–, – L6A61–L6A62–, –L6A63–L6A64–, –L6A65–L6A66–, and –L6A67–L6A68– is independently –C(=O)O–, – OC(=O)–, –OP(=O)(OH)O–, –SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O–. In some embodiments, at least one instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In some embodiments, each instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, each instance of Ra is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of L6B16, L6B19, and L6B21 is independently substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L6B16, L6B19, and L6B21 is independently substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L6B16, L6B19, and L6B21 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L6B16, L6B19, and L6B21 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In some embodiments, each of L6B17, L6B18, L6B20, and L6B22 is independently a single bond, substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L6B17, L6B18, L6B20, and L6B22 is independently a single bond, substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L6B17, L6B18, L6B20, and L6B22 is independently a single bond. In certain embodiments, each of L6B17, L6B18, L6B20, and L6B22 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L6B17, L6B18, L6B20, and L6B22 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, each of L6C9, L6C10, L6C11, and L6C12 is independently a single bond. In certain embodiments, each of L6C9, L6C10, L6C11, and L6C12 is independently substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms. In certain embodiments, each of L6C9, L6C10, L6C11, and L6C12 is independently
Figure imgf000119_0001
(which may be attached at either direction). In certain embodiments, at least one instance of y6 is 2;
Figure imgf000119_0002
Figure imgf000120_0001
each of p2, p5, and p6 is independently an integer from 1 to 10, inclusive; each of p3, p7, p8, p9, p10, and p11 is independently an integer from 0 to 10, inclusive; p4 is 0 or 1; –L6A61–L6A62– and –L6A67–L6A68– are each 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 Ra is 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; bond C6A is attached to a first instance of A6; and bond C6B is attached to a second instance of A6. In certain embodiments, at least one instance of –L6A61–L6A62– is –NRa–C(=O)– or –C(=O)–NRa–. In certain embodiments, at least one instance of –L6A61–L6A62– is –NH–C(=O)– or –C(=O)–NH–. In certain embodiments, at least one instance of –L6A61–L6A62– is –O–C(=O)– or –C(=O)–O–. In certain embodiments, at least one instance of –L6A61–L6A62– is –O–. In certain embodiments, at least one instance of –L6A61–L6A62– is –NH–. In certain embodiments, at least one instance of –L6A61–L6A62– is –C(=O)–. In certain embodiments, at least one instance of –
Figure imgf000121_0001
bond. In certain embodiments, at least one instance of –L6A67–L6A68– is –NRa–C(=O)– or –C(=O)–NRa–. In certain embodiments, at least one instance of –L6A67–L6A68– is –NH–C(=O)– or –C(=O)–NH–. In certain embodiments, at least one instance of –L6A67–L6A68– is –O–C(=O)– or – C(=O)–O–. In certain embodiments, at least one instance of –L6A67–L6A68– is –O–. In certain embodiments, at least one instance of –L6A67–L6A68– is –NH–. In certain embodiments, at least one instance of –L6A67–L6A68– is –C(=O)–. In certain embodiments, at least one instance of –
Figure imgf000121_0002
, –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 Ra is 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of –L6B8–, –L6B9–, –L6B10–, –L6B11–, –L6B12–, –L6B13–, –L6B14–, and –L6B15– is independently a single bond, substituted or unsubstituted, C1-150 alkylene or substituted or unsubstituted, C1-150 heteroalkylene; each of L6C5, L6C6, L6C7, and L6C8 is 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 bonds C6C, C6D, and C6E are attached to a first, second, and third instances of A6, respectively. In some embodiments, each of –L6A23–L6A24–, –L6A25–L6A26–, –L6A27–L6A28–, –L6A29– L6A30–, –L6A31–L6A32–, –L6A33–L6A34–, –L6A35–L6A36–, –L6A37–L6A38–, –L6A39–L6A40–, –L6A41– L6A42–, –L6A43–L6A44–, and –L6A45–L6A46– is independently a single bond, –O–, –NRa–, – C(=O)NRa–, or –NRaC(=O)–. In some embodiments, each of –L6A23–L6A24–, –L6A25–L6A26–, – L6A27–L6A28–, –L6A29–L6A30–, –L6A31–L6A32–, –L6A33–L6A34–, –L6A35–L6A36–, –L6A37–L6A38–, – L6A39–L6A40–, –L6A41–L6A42–, –L6A43–L6A44–, and –L6A45–L6A46– is independently a single bond, – O–, –NH–, –C(=O)NH–, or –NHC(=O)–. In certain embodiments, each of –L6A23–L6A24–, – L6A25–L6A26–, –L6A27–L6A28–, –L6A29–L6A30–, –L6A31–L6A32–, –L6A33–L6A34–, –L6A35–L6A36–, – L6A37–L6A38–, –L6A39–L6A40–, –L6A41–L6A42–, –L6A43–L6A44–, and –L6A45–L6A46– is independently a single bond, –C(=O)NRa–, or –NRaC(=O)–. In certain embodiments, each of –L6A23–L6A24–, – L6A25–L6A26–, –L6A27–L6A28–, –L6A29–L6A30–, –L6A31–L6A32–, –L6A33–L6A34–, –L6A35–L6A36–, – L6A37–L6A38–, –L6A39–L6A40–, –L6A41–L6A42–, –L6A43–L6A44–, and –L6A45–L6A46– is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some embodiments, at least one of –L6A23– L6A24–, –L6A25–L6A26–, –L6A27–L6A28–, –L6A29–L6A30–, –L6A31–L6A32–, –L6A33–L6A34–, –L6A35– L6A36–, –L6A37–L6A38–, –L6A39–L6A40–, –L6A41–L6A42–, –L6A43–L6A44–, and –L6A45–L6A46– 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 –L6A23–L6A24–, –L6A25–L6A26–, – L6A27–L6A28–, –L6A29–L6A30–, –L6A31–L6A32–, –L6A33–L6A34–, –L6A35–L6A36–, –L6A37–L6A38–, – L6A39–L6A40–, –L6A41–L6A42–, –L6A43–L6A44–, and –L6A45–L6A46– is independently –C(=O)O–, – OC(=O)–, –OP(=O)(OH)O–, –SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O–. In some embodiments, at least one instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In some embodiments, each instance of Ra is independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, each instance of Ra is independently hydrogen or unsubstituted C1-6 alkyl. In some embodiments, each of L6B8, L6B9, L6B10, L6B11, L6B12, L6B13, L6B14, and L6B15 is independently substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In some embodiments, each of L6B8, L6B9, L6B10, L6B11, L6B12, L6B13, L6B14, and L6B15 is independently substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene. In certain embodiments, each of L6B8, L6B9, L6B10, L6B11, L6B12, L6B13, L6B14, and L6B15 is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L6B8, L6B9, L6B10, L6B11, L6B12, L6B13, L6B14, and L6B15 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, each of L6C5, L6C6, L6C7, and L6C8 is independently a single bond. In certain embodiments, each of L6C5, L6C6, L6C7, and L6C8 is independently substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms. In certain embodiments, each of L6C5, L6C6, L6C7, and L6C8 is independently
Figure imgf000123_0001
(which may be attached at either direction). In certain embodiments, at least one instance
Figure imgf000123_0002
Figure imgf000124_0001
each of L6C6, L6C7, and L6C8 is independently a single bond,
Figure imgf000124_0002
Figure imgf000124_0003
. In certain embodiments, at least one instance of –L6A33–L6A34– is –NRa–C(=O)– or –C(=O)–NRa–. In certain embodiments, at least one instance of –L6A33–L6A34– is –NH–C(=O)– or –C(=O)–NH–. In certain embodiments, at least one instance of –L6A33–L6A34– is –O–C(=O)– or –C(=O)–O–. In certain embodiments, at least one instance of –L6A33–L6A34– is –O–. In certain embodiments, at least one instance of –L6A33–L6A34– is –NH–. In certain embodiments, at least one instance of –L6A33–L6A34– is –C(=O)–. In certain embodiments, at least one instance of – L6A33–L6A34– is a single bond. In certain embodiments, at least one instance of –L6A39–L6A40– is –NRa–C(=O)– or –C(=O)–NRa–. In certain embodiments, at least one instance of –L6A39–L6A40– is –NH–C(=O)– or –C(=O)–NH–. In certain embodiments, at least one instance of –L6A39–L6A40– is –O–C(=O)– or – C(=O)–O–. In certain embodiments, at least one instance of –L6A39–L6A40– is –O–. In certain embodiments, at least one instance of –L6A39–L6A40– is –NH–. In certain embodiments, at least one instance of –L6A39–L6A40– is –C(=O)–. In certain embodiments, at least one instance of – L6A39–L6A40– is a single bond. 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. 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 et al., 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.2011, 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 et al., 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. 2000, 313, 297-321; Maier et al., Bioconjug. Chem.2003, 14, 18-29; Jayaprakash et al., Org. 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; WO 2011/163121; WO 2012/177947; WO 2013/033230; WO 2013/075035; WO 2012/083185; WO 2012/083046; WO 2009/082607; WO 2009/134487; WO 2010/144740; WO 2010/148013; WO 1997/020563; WO 2010/088537; WO 2002/043771; WO 2010/129709; WO 2012/068187; WO 2009/126933; WO 2004/024757; WO 2010/054406; WO 2012/089352; WO 2012/089602; WO 2013/166121; WO 2013/165816; U.S. Patent Nos.4,751,219; 7,582,744; 8,552,163; 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. 2003/0077829; U.S.2008/0108801; and U.S.2009/0203132. In certain embodiments, a linker comprises a structure selected from:
Figure imgf000126_0001
, ,
Figure imgf000127_0001
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. In certain embodiments, a linker comprises a structure selected from:
Figure imgf000127_0002
,
Figure imgf000128_0001
Figure imgf000129_0001
, 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. In certain embodiments, a linker comprises a structure selected from:
Figure imgf000129_0002
In certain embodiments, a linker comprises a structure selected from:
Figure imgf000129_0003
,
Figure imgf000130_0001
Figure imgf000130_0002
, 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. In certain embodiments, a linker comprises a structure selected from:
Figure imgf000130_0003
,
Figure imgf000131_0001
Figure imgf000131_0002
, 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:
Figure imgf000131_0003
, ,
Figure imgf000132_0001
Figure imgf000133_0001
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.
Figure imgf000133_0002
Figure imgf000134_0001
, 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. In certain embodiments, a linker comprises a structure selected from:
Figure imgf000134_0002
Figure imgf000135_0001
, 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. In certain embodiments, a linker comprises a structure selected from:
Figure imgf000135_0002
, wherein n is 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:
Figure imgf000135_0003
, 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. In certain embodiments, a linker comprises a structure selected from:
Figure imgf000135_0004
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:
Figure imgf000135_0005
, 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. In certain embodiments, a linker comprises the structure:
Figure imgf000135_0006
, wherein n is 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 the structure:
Figure imgf000136_0001
, 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. In a conjugate of the present disclosure, each instance of each of A1, A2, A4, A5, and A6 may independently be a radical of a ligand. In some embodiments, at least one instance of A1 is a radical of a ligand. In certain embodiments, at least two instances of A1 are radicals of ligands. In some embodiments, at least one instance of A2 is a radical of a ligand. In certain embodiments, at least two instances of A2 are radicals of ligands. In some embodiments, at least one instance of A4 is a radical of a ligand. In certain embodiments, at least two instances of A4 are radicals of ligands. In some embodiments, at least one instance of A5 is a radical of a ligand. In certain embodiments, at least two instances of A5 are radicals of ligands. In some embodiments, at least one instance of A6 is a radical of a ligand. In certain embodiments, two or three instances of A1, A2, A4, A5, and/or A6 are independently a radical of a ligand. In certain embodiments, four or five instances of A1, A2, A4, A5, and/or A6 are independently a radical of a ligand. In certain embodiments, at least two instances of A6 are radicals of ligands. In some embodiments, at least one ligand is a muscle receptor ligand. In certain embodiments, at least one ligand is an α4β1/7 integrin receptor ligand. In certain embodiments, at least one instance of A1 is a radical of an α4β1/7 integrin ligand. In certain embodiments, at least one instance of A2 is a radical of an α4β1/7 integrin ligand. In certain embodiments, at least one instance of A4 is a radical of an α4β1/7 integrin ligand. In certain embodiments, at least one instance of A5 is a radical of an α4β1/7 integrin ligand. In certain embodiments, at least one instance of A6 is a radical of an α4β1/7 integrin ligand. In some embodiments, a ligand directs the pharmaceutical agent to a muscle in a subject. In some embodiments, a ligand directs the pharmaceutical agent to a muscle cell in a subject. In some embodiments, a ligand targets a cell receptor. In certain embodiments, a cell receptor is an α4β1/7 integrin receptor. In some embodiments, a receptor is in the muscle. In some embodiments, a ligand is used to target a pharmaceutical agent to a cell type. In some embodiments, the cell is a muscle cell. In some embodiments, a ligand is an agonist of a receptor (e.g., an α4β1/7 integrin receptor agonist). In some embodiments, a ligand is an antagonist of a receptor (e.g., an α4β1/7 integrin receptor antagonist). In some embodiments, at least one ligand is an antibody. In some embodiments, at least one ligand is a monoclonal antibody. In some embodiments, at least one ligand is a polyclonal antibody. In certain embodiments, at least one α4β1/7 integrin ligand is an α4β1 integrin ligand. In certain embodiments, at least one α4β1/7 integrin ligand is an α4β7 integrin ligand. In certain embodiments, at least one α4β1/7 integrin ligand is of the formula:
Figure imgf000137_0001
; wherein: each instance of R1Z is independently optionally substituted heteroaryl or optionally substituted phenyl; each instance of R33Z is independently –O(optionally substituted alkyl), –OH, –NH2, – NHOH, –NH(optionally substituted alkyl), –NH(optionally substituted polyethylene glycol), – N(optionally substituted alkyl)2, or –N(optionally substituted alkyl)(optionally substituted polyethylene glycol); each instance of R34Z is of the formula:
Figure imgf000137_0002
each instance of R2Z is independently hydrogen, optionally substituted polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, or optionally substituted heteroaryl; and each instance of X4Z is N or C(R35Z); and each instance of R35Z is independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted alkoxy. In certain embodiments, at least one α4β1/7 integrin ligand is of the formula:
Figure imgf000137_0003
; each instance of X3Z and X5Z is independently N or C(R32Z); each instance of R32Z is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted polyethylene glycol, or –S(=O)2(optionally substituted alkyl); each instance of R3Z, R4Z, and R36Z is independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted alkoxy. In certain embodiments, at least one α4β1/7 integrin ligand is of the formula:
Figure imgf000138_0001
each instance of R2Z is independently hydrogen, polyethylene glycol, optionally substituted heteroalkyl, or optionally substituted heteroaryl; and each instance of R3Z and R4Z is independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted alkoxy. In certain embodiments, at least one instance of R1Z is optionally substituted 6-membered heteroaryl. In certain embodiments, at least one instance of R1Z is optionally substituted pyridinyl (e.g., optionally substituted 3-pyridinyl or optionally substituted 4-pyridinyl). In certain embodiments, at least one instance of R1Z is optionally substituted 5-membered heteroaryl. In certain embodiments, at least one instance of R1Z is optionally substituted pyrrolyl (e.g., optionally substituted 2-pyrrolyl). In certain embodiments, at least one instance of R1Z is unsubstituted phenyl. In certain embodiments, at least one instance of R1Z is 2-monosubstituted phenyl, 3-monosubstituted phenyl, or 4-monosubstituted phenyl. In certain embodiments, at least one instance of R1Z is 2,3-disubstituted phenyl, 2,4-disubstituted phenyl, 2,5-disubstituted phenyl, 2,6-disubstituted phenyl, 3,4-disubstituted phenyl, or 3,5-disubstituted phenyl. In certain embodiments, the substituents described in this paragraph are independently halogen, optionally substituted alkyl, or –S(=O)2(optionally substituted alkyl). In certain embodiments, the substituents described in this paragraph are independently halogen, unsubstituted C1-6 alkyl, or – S(=O)2(unsubstituted C1-6 alkyl). In certain embodiments, at least one instance of R33Z is –O(optionally substituted alkyl), – OH, –NH2, –NHOH, –NH(optionally substituted alkyl), or –N(optionally substituted alkyl)2. In certain embodiments, at least one instance of R33Z is –O(unsubstituted C1-6 alkyl); –OH; –NH2; – NHOH; –NH(unsubstituted C1-6 alkyl); –NH(C1-6 alkyl substituted with one or more substituents independently selected from the group consisting of –O(unsubstituted C1-6 alkyl), –OH, –NH2, – NHOH, –NH(unsubstituted C1-6 alkyl), and –N(unsubstituted C1-6 alkyl)2); –N(unsubstituted C1-6 alkyl)2; or –N(unsubstituted C1-6 alkyl)(C1-6 alkyl substituted with one or more substituents independently selected from the group consisting of –O(unsubstituted C1-6 alkyl), –OH, –NH2, – NHOH, –NH(unsubstituted C1-6 alkyl), and –N(unsubstituted C1-6 alkyl)2). In some embodiments, at least one instance of R2Z is hydrogen or substituted or unsubstituted heteroalkyl. In certain embodiments, at least one instance of R2Z is hydrogen. In certain embodiments, at least one instance of R2Z is optionally substituted alkyl. In certain embodiments, at least one instance of R2Z is unsubstituted C1-6 alkyl (e.g., Me). In some embodiments, each of R3Z and R4Z is independently hydrogen or halogen. In certain embodiments, each of R3Z and R4Z is independently halogen. In some embodiments, at least one instance of R36Z is hydrogen or halogen (e.g., –F). In certain embodiments, at least one radical of the α4β1/7 integrin ligand is of the formula:
Figure imgf000139_0001
. In certain embodiments, at least one radical of the α4β1/7 integrin ligand is of the formula:
Figure imgf000139_0002
. In certain embodiments, at least one radical of the α4β1/7 integrin ligand is of the formula:
Figure imgf000139_0003
. In certain embodiments, at least one α4β1/7 integrin ligand is of the formula:
Figure imgf000140_0001
. In certain embodiments, at least one α4β1/7 integrin ligand is of the formula:
Figure imgf000140_0002
. In certain embodiments, at least one α4β1/7 integrin ligand is of the formula:
Figure imgf000140_0003
. In certain embodiments, at least one α4β1/7 integrin ligand is of the formula: .
Figure imgf000140_0004
. In certain embodiments, at least one radical of the α4β1/7 integrin ligand is of the formula:
Figure imgf000140_0005
,
Figure imgf000141_0001
In certain embodiments, at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000141_0002
R4Z is hydrogen, halogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted –O–alkyl, or optionally substituted cycloalkyl; R5Z is optionally substituted heteroalkyl or optionally substituted heterocyclyl; and n1Z is 1, 2, or 3. In some embodiments, R4Z is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R4Z is hydrogen. In some embodiments, R5Z is optionally substituted heteroalkyl. In some embodiments, n1Z is 1 or 2. In certain embodiments, n1Z is 1. In certain embodiments, at least one radical of an α4β1/7 integrin ligand is of the formula: ,
Figure imgf000141_0003
Figure imgf000142_0001
R6Z is hydrogen, –OH, –NH2, –NHR7Z, –OR7Z, or absent; and R7Z is hydrogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl. In some embodiments, R6Z is hydrogen, –OH, –NH2, or absent. In certain embodiments, R6Z is hydrogen. In certain embodiments, R6Z is absent. In some embodiments, R7Z is hydrogen or optionally substituted alkyl. In certain embodiments, R7Z is hydrogen or unsubstituted alkyl. In certain embodiments, at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000142_0002
,
Figure imgf000143_0001
n2Z is 0, 1, 2, or 3. In some embodiments, n2Z is 0 or 1. In certain embodiments, n2Z is 0. In certain embodiments, at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000143_0002
,
Figure imgf000144_0001
n3Z is 0, 1, 2, or 3. In some embodiments, n3Z is 0 or 1. In certain embodiments, n3Z is 0. In certain embodiments, at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000144_0002
,
Figure imgf000145_0001
each of R8Z, R9Z, R10Z, and R11Z is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted –O–alkyl, or substituted or unsubstituted cycloalkyl; each of R12Z and R13Z is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl,
Figure imgf000145_0002
, , ,
Figure imgf000145_0003
R14Z is optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkylene-(C3-C6)- cycloalkyl, or optionally substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, each of R8Z, R9Z, R10Z, and R11Z is independently hydrogen, halogen, or optionally substituted alkyl. In certain embodiments, each of R8Z, R9Z, R10Z, and R11Z is independently optionally substituted alkyl. In certain embodiments, each of R8Z, R9Z, R10Z, and R11Z is independently unsubstituted alkyl. In some embodiments, each of R12Z and R13Z is
Figure imgf000145_0004
independently hydrogen, , or . In certain embodiments, each of R12Z and
Figure imgf000145_0005
R13Z is independently H or . In some embodiments, R14Z is optionally substituted C1- C5 alkyl. In certain embodiments, R14Z is optionally substituted C4 alkyl. In certain embodiments, at least one α4β1/7 integrin ligand is of the formula:
Figure imgf000146_0001
. In certain embodiments, at least one α4β1/7 integrin ligand is of the formula:
Figure imgf000146_0002
. In certain embodiments, at least one radical of the α4β1/7 integrin ligand is of the formula:
Figure imgf000146_0003
. In certain embodiments, at least one α4β1/7 integrin ligand is of the formula:
Figure imgf000146_0004
. In certain embodiments, at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000147_0001
. In certain embodiments, at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000147_0002
. In certain embodiments, at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000147_0003
Figure imgf000148_0001
R15Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; each of R16Z and R17Z is independently H, halogen, optionally substituted alkyl, or optionally substituted –O–alkyl; and YZ is –CH2– or –(CH2)2–. In some embodiments, R15Z is H, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R15Z is H. In some embodiments, each of R16Z and R17Z is independently H or optionally substituted alkyl. In certain embodiments, each of R16Z and R17Z is independently H. In certain embodiments, YZ is –CH2–. In certain embodiments, YZ is –(CH2)2–. In certain embodiments, at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000148_0002
R18Z is H, –OH, –NH2, –NHR19Z, –OR19Z, or –CONHR19Z; each instance of R19Z is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and n4Z is 1 or 2. In certain embodiments, at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000148_0003
. In some embodiments, R18Z is H, –OH, or –NH2. In certain embodiments, R18Z is H. In some embodiments, each instance of R19Z is independently H or optionally substituted alkyl. In certain embodiments, each instance of R19Z is independently H or unsubstituted alkyl. In certain embodiments, n4Z is 1. In certain embodiments, n4Z is 2. In certain embodiments, at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000149_0001
R19Z is H, –CH2OR20Z, –(CH2)2OR20Z, –CH2NHCOR20Z, or –OR20Z; and R20Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl. In some embodiments, R19Z is H or –CH2NHCOR20Z. In certain embodiments, R19Z is – CH2NHCOR20Z. In some embodiments, R20Z is H or optionally substituted alkyl. In certain embodiments, R20Z is H or unsubstituted alkyl. In certain embodiments, at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000149_0002
R21Z is H, –CONHR22Z, –CH2OR22Z, –(CH2)2OR22Z, –CH2NHCOR22Z, or –OR22Z; R22Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and X1Z is H or halogen. In certain embodiments, at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000150_0001
wherein: R21Z is H, –CONHR22Z, –CH2OR22Z, –(CH2)2OR22Z, –CH2NHCOR22Z, or –OR22Z; R22Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and X1Z is H or halogen. In certain embodiments, at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000150_0002
. In some embodiments, R21Z is H or –CH2NHCOR22Z. In certain embodiments, R21Z is – CH2NHCOR22Z. In some embodiments, R22Z is H or optionally substituted alkyl. In certain embodiments, R22Z is H or unsubstituted alkyl. In certain embodiments, X1Z is H. In certain embodiments, X1Z is halogen. In certain embodiments, at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000150_0003
R23Z is H, -CONHR24Z, -CH2OR24Z, -(CH2)2OR24Z, -CH2NHCOR24Z, or -OR24Z; R24Z is 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 certain embodiments, at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000151_0001
. In some embodiments, R23Z is H or -CONHR24Z. In certain embodiments, R23Z is -CONHR24Z. In some embodiments, R24Z is H or optionally substituted alkyl. In certain embodiments, R24Z is H or unsubstituted alkyl. In some embodiments, n5z is 0, 1, or 2. In certain, embodiments, n5z is 1. In certain embodiments, at least one radical of an α4β1/7 integrin ligand is of the formula: ,
Figure imgf000151_0002
R25Z is H, –CONHR27Z, –CH2OR27Z, –(CH2)2OR27Z, –CH2NHCOR27Z, or –OR27Z; R26Z is H, optionally substituted alkyl, or optionally substituted cycloalkyl; R27Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and X2Z is optionally substituted CH2 or optionally substituted NH. In certain embodiments, at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000152_0001
wherein: R25Z is H, –CONHR27Z, –CH2OR27Z, –(CH2)2OR27Z, –CH2NHCOR27Z, or –OR27Z; R26Z is H, optionally substituted alkyl, or optionally substituted cycloalkyl; and R27Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl. In certain embodiments, at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000152_0002
. In certain embodiments, at least one radi f the formula:
Figure imgf000152_0003
Figure imgf000152_0004
; wherein: R28Z is H, –CH2OR30Z, –(CH2)2OR30Z, –CH2NHCOR30Z, or –OR30Z; R29Z is H, –OH, –NH2, –NHR31Z, or –OR31Z; R30Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; R31Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; n3Z is 1, 2, or 3; each instance of R37Z is halogen or optionally substituted alkyl; and n6Z is 0, 1, 2, 3, or 4. In some embodiments, R25Z is H or –CH2NHCOR27Z. In certain embodiments, R25Z is –CH2NHCOR27Z. In some embodiments, R26Z is H or optionally substituted alkyl. In some embodiments, R26Z is H or unsubstituted alkyl. In certain embodiments, R26Z is H or -CH3. In some embodiments, R27Z is H, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R27Z is H, unsubstituted alkyl, or unsubstituted heteroalkyl. In some embodiments, X2Z is optionally substituted NH. In certain embodiments, X2Z is NH. In certain embodiments, at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000153_0001
R28Z is H, –CH2OR30Z, –(CH2)2OR30Z, –CH2NHCOR30Z, or –OR30Z; R29Z is H, –OH, –NH2, –NHR31Z, or –OR31Z; R30Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; R31Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and n3Z is 1, 2, or 3. In some embodiments, R28Z is H, –CH2NHCOR30Z, or –OR30Z. In certain embodiments, R28Z is –CH2NHCOR30Z. In some embodiments, R29Z is H, –OH, or –NH2. In some embodiments, R30Z is H, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R30Z is H, unsubstituted alkyl, or unsubstituted heteroalkyl. In some embodiments, R31Z is H, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R31Z is H, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, n3Z is 1. In certain embodiments, n3Z is 2. In certain embodiments, at least one α4β1/7 integrin ligand is of the formula:
Figure imgf000154_0001
; or at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000154_0002
. In some embodiments, a ligand is an antibody (e.g., an anti-α4β1/7 integrin receptor antibody). In certain embodiments, a ligand is an antibody fragment or an antibody variant. An “anti-α4β1/7 integrin receptor antibody” refers to an immune system protein that recognizes, binds to, or otherwise interacts with a α4β1/7 integrin. In some embodiments, a conjugate comprises at least two ligands (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 ligands). In some embodiments, a conjugate comprises two ligands. In some embodiments, a conjugate comprises three ligands. In some embodiments, a conjugate comprises at least one ligand conjugated at the 5′-end. In some embodiments, a conjugate comprises at least one ligand conjugated at the 3′-end. In certain embodiments, a conjugate comprises at least one ligand conjugated at the 5′-end and at least one ligand conjugated at the 3′-end. In some embodiments, a conjugate comprises at least two ligands conjugated at the 5′-end. In some embodiments, a conjugate comprises at least two ligands conjugated at the 3′-end. In certain embodiments, a conjugate comprises at least two ligands conjugated at the 5′-end and at least two ligands conjugated at the 3′-end. In some embodiments, a conjugate comprises at least one ligand conjugated at a nucleobase. In some embodiments, a conjugate comprises at least two ligands conjugated at a nucleobase. In some embodiments, a conjugate comprises at least one ligand conjugated at the 2′ position of a nucleoside. In some embodiments, a conjugate comprises at least two ligands conjugated at the 2′ position of a nucleoside. In some embodiments, at least two ligands are of the same ligand type. In some embodiments, each ligand is of the same ligand type. 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 type. 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. In certain embodiments, y is 2, 3, 4, 5, or 6; and at least two instances of A are radicals of ligands. In certain embodiments, y is 2, 3, 4, 5, or 6; and at least two instances of A are radicals of ligands of the same ligand type (e.g., α4β1/7 integrin ligands). In certain embodiments, y is 2, 3, 4, 5, or 6; and at least two instances of A are radicals of different ligands of the same ligand type. In certain embodiments, y is 2, 3, 4, 5, or 6; and at least two instances of A are radicals of the same ligand. In certain embodiments, y is 2, 3, 4, 5, or 6; and at least two instances of A are radicals of ligands of different ligand types (e.g., at least one instance of A is a radical of an α4β1/7 integrin ligand, and at least one instance of A is a radical of a ligand that is not an α4β1/7 integrin ligand). In certain embodiments, y is 2, 3, 4, 5, or 6; and at least one ligand is a tropomyosin receptor B (TrkB) ligand. In certain embodiments, y is 2, 3, 4, 5, or 6; and at least one ligand is a cannabinoid receptor type 1 (CB1) ligand. In certain embodiments, y is 2, 3, 4, 5, or 6; and at least one ligand is a N-methyl-D-aspartate (NMDA) ligand. The use of any α4β1/7 integrin receptor ligand in the conjugates provided herein is contemplated by the present disclosure. α4β1/7 integrin receptor ligands are known in the art, and a person of ordinary skill in the art would be capable of identifying additional α4β1/7 integrin receptor ligands for use in the conjugates described herein beyond those explicitly provided by the present disclosure. The present disclosure also contemplates the use of derivatives and prodrugs of any α4β1/7 integrin receptor ligand provided herein or known in the art in the presently described conjugates, and a person of ordinary skill in the art would know how to make such derivatives and prodrugs. In some embodiments, an α4β1/7 integrin receptor ligand is an α4β1/7 integrin receptor agonist. In some embodiments, an α4β1/7 integrin receptor ligand is an α4β1/7 integrin receptor antagonist. In some embodiments, an α4β1/7 integrin receptor ligand is any of those disclosed in International Patent Application Publication No. WO 2019/246455, which is incorporated herein by reference. In some embodiments, an α4β1/7 integrin receptor ligand is any of those disclosed in Baiula, M. et al. Novel Ligands Targeting α4β1 Integrin: Therapeutic Applications and Perspectives. Front. Chem.2019, 7, 489, which is incorporated herein by reference. Exemplary α4β1/7 integrin receptor ligands for use in the present disclosure include, but are not limited to, any of the following α4β1/7 integrin receptor ligands, and derivatives thereof:
Figure imgf000156_0001
,
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
In certain embodiments, an α4β1/7 integrin receptor ligand is
Figure imgf000161_0002
, or a derivative thereof. In some embodiments, an α4β1/7 integrin receptor ligand is an anti-α4β1/7 integrin receptor antibody. In certain embodiments, an α4β1/7 integrin receptor ligand is an anti-α4β1/7 integrin receptor antibody fragment, or an anti-α4β1/7 integrin receptor antibody variant. An “anti-α4β1/7 integrin receptor antibody” refers to an immune system protein that recognizes, binds to, or otherwise interacts with an α4β1/7 integrin receptor. In certain embodiments, an α4β1/7 integrin receptor ligand is conjugated (e.g., linked, connected, attached, associated with) to one or more pharmaceutical agent moieties (i.e., radicals of pharmaceutical agents). In certain embodiments, at least one pharmaceutical agent is a therapeutic, prophylactic, or diagnostic (e.g., imaging) agent. In certain embodiments, at least one pharmaceutical agent is a therapeutic agent that treats a muscle disease. In certain embodiments, at least one pharmaceutical agent is a contrast agent. In certain embodiments, at least one pharmaceutical agent is a small molecule. In certain embodiments, at least one pharmaceutical agent is a protein or peptide. In certain embodiments, at least one pharmaceutical agent is an antibody. In certain embodiments, at least one pharmaceutical agent is a monoclonal antibody. In certain embodiments, at least one pharmaceutical agent is an oligonucleotide. In certain embodiments, at least one pharmaceutical agent is an oligonucleotide. In some embodiments, more than one α4β1/7 integrin receptor ligand is conjugated to an agent moiety. In some embodiments, at least two α4β1/7 integrin receptor ligands (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more α4β1/7 integrin receptor ligands) are conjugated to an agent moiety. In some embodiments, two α4β1/7 integrin receptor ligands are conjugated to an agent moiety. In some embodiments, three α4β1/7 integrin receptor ligands are conjugated to an agent moiety. In some embodiments, four α4β1/7 integrin receptor ligands are conjugated to an agent moiety. In some embodiments, five α4β1/7 integrin receptor ligands are conjugated to an agent moiety. In some embodiments, more than five α4β1/7 integrin receptor ligands are conjugated to an agent moiety. In some embodiments, at least 1 to about 5 α4β1/7 integrin receptor ligands are conjugated to an agent moiety. In some embodiments, at least 1 to about 4 α4β1/7 integrin receptor ligands are conjugated to an agent moiety. In some embodiments, at least 1 to about 3 α4β1/7 integrin receptor ligands are conjugated to an agent moiety. In some embodiments, at least 1 to about 2 α4β1/7 integrin receptor ligands are conjugated to an agent moiety. When an agent moiety is conjugated to multiple α4β1/7 integrin receptor ligands, all of the α4β1/7 integrin receptor ligands may be conjugated at or near the same position on the agent moiety, or the α4β1/7 integrin receptor ligands may be conjugated to multiple different positions on the agent moiety. In some embodiments, an oligonucleotide strand is conjugated (e.g., connected, attached, associated with) to an α4β1/7 integrin receptor ligand through either a 5′ end and/or a 3′ end of the oligonucleotide strand, or at an internal position in an oligonucleotide strand (i.e., at a nucleotide on the oligonucleotide strand other than the 5′ or 3′ nucleotide). In some embodiments, an oligonucleotide strand is conjugated to an α4β1/7 integrin receptor ligand through the 5′ end of the oligonucleotide strand. In some embodiments, an oligonucleotide strand is conjugated to an α4β1/7 integrin receptor ligand through the 3′ end of the oligonucleotide strand. In some embodiments, an oligonucleotide strand is conjugated to α4β1/7 integrin receptor ligands through both the 5′ end and the 3′ end of the oligonucleotide strand. In some embodiments, an oligonucleotide strand is conjugated to an α4β1/7 integrin receptor ligand at an internal position within the oligonucleotide strand (e.g., in an “internally-modified oligonucleotide”). In some embodiments, an oligonucleotide strand is conjugated to more than one α4β1/7 integrin receptor ligand. In some embodiments, an oligonucleotide strand is conjugated to at least two α4β1/7 integrin receptor ligands (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more α4β1/7 integrin receptor ligands). In some embodiments, an oligonucleotide strand is conjugated to two α4β1/7 integrin receptor ligands. In some embodiments, an oligonucleotide strand is conjugated to three α4β1/7 integrin receptor ligands. In some embodiments, an oligonucleotide strand is conjugated to four α4β1/7 integrin receptor ligands. In some embodiments, an oligonucleotide strand is conjugated to five α4β1/7 integrin receptor ligands. In some embodiments, an oligonucleotide strand is conjugated to more than five α4β1/7 integrin receptor ligands. In some embodiments, an oligonucleotide strand is conjugated to at least 1 to about 5 α4β1/7 integrin receptor ligands. In some embodiments, an oligonucleotide strand is conjugated to at least 1 to about 4 α4β1/7 integrin receptor ligands. In some embodiments, an oligonucleotide strand is conjugated to at least 1 to about 3 α4β1/7 integrin receptor ligands. In some embodiments, an oligonucleotide strand is conjugated to at least 1 to about 2 α4β1/7 integrin receptor ligands. When an oligonucleotide strand is conjugated to multiple α4β1/7 integrin receptor ligands, all of the α4β1/7 integrin receptor ligands may be conjugated at or near the same position on the oligonucleotide strand, or the α4β1/7 integrin receptor ligands may be conjugated to multiple different positions on the oligonucleotide strand. In some embodiments, multiple α4β1/7 integrin receptor ligands (i.e., two, three, four, five, or more α4β1/7 integrin receptor ligands) are conjugated at the 5′ end of the oligonucleotide strand. In some embodiments, multiple α4β1/7 integrin receptor ligands (i.e., two, three, four, five, or more α4β1/7 integrin receptor ligands) are conjugated at the 3′ end of the oligonucleotide strand. In some embodiments, multiple α4β1/7 integrin receptor ligands (i.e., two, three, four, five, or more α4β1/7 integrin receptor ligands) are conjugated at one or more internal positions of the oligonucleotide strand. In some embodiments, an oligonucleotide strand is conjugated to one or more α4β1/7 integrin receptor ligands at the 5′ end of the oligonucleotide strand and/or one or more α4β1/7 integrin receptor ligands at the 3′ end of the oligonucleotide strand and/or one or more α4β1/7 integrin receptor ligands at an internal position, or multiple internal positions, of the oligonucleotide strand. Two or more ligands may be attached to the same or different positions of the corresponding linker, as valency permits. For example, when y1 of is 2, the two instances of A1 may be attached to the same position of L1 or two different positions of L1, as valency permits. In a conjugate of the present disclosure, each instance of each of A1, A2, A4, A5, and A6 is independently a radical of a ligand or lipid. In certain embodiments, at least one instance of A1, A2, A4, A5, and A6 is a radical of a lipid. In certain embodiments, two or three instances of A1, A2, A4, A5, and/or A6 are independently a radical of a lipid. In certain embodiments, four or five instances of A1, A2, A4, A5, and/or A6 are independently a radical of a lipid. In some embodiments, at least one instance of A1 is a radical of a lipid. In some embodiments, at least one instance of A2 is a radical of a lipid. In some embodiments, at least one instance of A4 is a radical of a lipid. In some embodiments, at least one instance of A5 is a radical of a lipid. In some embodiments, at least one instance of A6 is a radical of a lipid. In certain embodiments, at least one instance of A1, A2, A4, A5, and A6 is independently a radical of a lipid. In certain embodiments, no instance of A1, A2, A4, A5, and A6 is a radical of a lipid. 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, fatty aldehyde, fatty ester, fatty amide, fatty nitrile, fatty ether, hydrocarbon, oxygenated hydrocarbon, or fatty acyl glycoside. 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 C7-36 alkyl, C7-36 alkyl substituted with one or more fluoro as valency permits, unsubstituted C7-36 alkenyl, or C7-36 alkenyl substituted with one or more fluoro as valency permits. In certain embodiments, at least one radical of a lipid is unsubstituted C7-36 alkyl or unsubstituted C7-36 alkenyl. In certain embodiments, at least one radical of a lipid is unsubstituted C7-36 alkyl. In some embodiments, at least one radical of a lipid is unsubstituted C7- 20 alkyl, C7-20 alkyl substituted with one or more fluoro as valency permits, unsubstituted C7-20 alkenyl, or C7-20 alkenyl substituted with one or more fluoro as valency permits. In certain embodiments, at least one radical of a lipid is unsubstituted C7-20 alkyl or unsubstituted C7-20 alkenyl. In certain embodiments, at least one radical of a lipid is unsubstituted C7-20 alkyl. In some embodiments, at least one radical of a lipid is unsubstituted C21-28 alkyl, C21-28 alkyl substituted with one or more fluoro as valency permits, unsubstituted C21-28 alkenyl, or C21-28 alkenyl substituted with one or more fluoro as valency permits. In certain embodiments, at least one radical of a lipid is unsubstituted C21-28 alkyl or unsubstituted C21-28 alkenyl. In certain embodiments, at least one radical of a lipid is unsubstituted C21-28 alkyl. In some embodiments, at least one radical of a lipid is unsubstituted C29-36 alkyl, C29-36 alkyl substituted with one or more fluoro as valency permits, unsubstituted C29-36 alkenyl, or C29-36 alkenyl substituted with one or more fluoro as valency permits. In certain embodiments, at least one radical of a lipid is unsubstituted C29-36 alkyl or unsubstituted C29-36 alkenyl. In certain embodiments, at least one radical of a lipid is unsubstituted C29-36 alkyl. In some embodiments, 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. 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 C14-18 alkyl. In certain embodiments, at least one radical of a lipid is –(CH2)13CH3, –(CH2)14CH3, –(CH2)15CH3, –(CH2)16CH3, or –(CH2)17CH3. In certain embodiments, at least one radical of a lipid is –(CH2)15CH3. In certain embodiments, at least one radical of a lipid is unbranched unsubstituted C18-26 alkyl. In certain embodiments, at least one radical of a lipid is –(CH2)17CH3, –(CH2)18CH3, –(CH2)19CH3, – (CH2)20CH3, –(CH2)21CH3, –(CH2)22CH3, –(CH2)23CH3, –(CH2)24CH3, or –(CH2)25CH3. In certain embodiments, at least one radical of a lipid is –(CH2)16CH3 or –(CH2)17CH3. In certain embodiments, at least one radical of a lipid is –(CH2)21CH3. In some embodiments, at least one radical of a lipid is C7-20 alkyl substituted with one or more –C(=O)OH as valency permits, C21-28 alkyl substituted with one or more –C(=O)OH as valency permits, or C29-36 alkyl substituted with one or more –C(=O)OH as valency permits. In certain embodiments, at least one radical of a lipid is –(CH2)14-23C(=O)OH. In certain embodiments, at least one radical of a lipid is – (CH2)18C(=O)OH or –(CH2)19C(=O)OH. In certain embodiments, at least one radical of a lipid is unbranched unsubstituted C14-18 alkenyl. In certain embodiments, at least one radical of a lipid is unbranched unsubstituted C18-26 alkenyl. In certain embodiments, at least one radical of a lipid is unbranched unsubstituted C14-18 alkenyl comprising one C=C bond. In certain embodiments, at least one radical of a lipid is unbranched unsubstituted C14-20 alkenyl comprising one C=C bond. In certain embodiments, at least one radical of a lipid is unbranched unsubstituted C14-18 alkenyl comprising two or three C=C bonds. In certain embodiments, at least one radical of a lipid is unbranched unsubstituted C18-26 alkenyl comprising one C=C bond. In certain embodiments, at least one radical of a lipid is unbranched unsubstituted C18-26 alkenyl comprising two, three, or four C=C bonds. In certain embodiments, at least one radical of a lipid is
Figure imgf000166_0001
or
Figure imgf000166_0002
. In certain embodiments, at least one lipid is a monoradylglycerol, diradylglycerol, triradylglycerol, glycosylmonoradylglycerol, glycosyldiradylglycerol, betaine monoradylglycerol, or betaine diradylglycerol. 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, glycerophosphonocholine, glycerophosphonoethanolamine, di-glycerol tetraether phospholipid, glycerol-nonitol tetraether phospholipid, oxidized glycerophospholipid, glycerophosphoethanolamine glycan, dihydroxyacetonephosphate, glycerophosphoethanol, glycerophosphothreonine, or cyclic glycerophosphatidic acid. In certain embodiments, at least one lipid is a sphingoid base, ceramide, phosphosphingolipid, phosphonosphingolipid, neutral glycosphingolipid, acidic glycosphingolipid, basic glycosphingolipid, amphoteric glycosphingolipid, or arsenosphingolipid. 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:
Figure imgf000166_0003
. In certain embodiments, at least one lipid is lithocholic acid. In certain embodiments, at least one radical of the lipid is of the formula:
Figure imgf000167_0001
, In certain embodiments, at least one radical of the lipid is of the formula:
Figure imgf000167_0003
, optionally wherein the unsubstituted C7-30 alkyl is unbranched unsubstituted C11-23 alkyl, and the unsubstituted C7-30 alkenyl is unbranched unsubstituted C11-23 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:
Figure imgf000167_0002
. In certain embodiments, at least one lipid is an isoprenoid, quinone, hydroquinone, polyprenol, or hopanoid. In certain embodiments, at least one lipid is an acylaminosugar, acylaminosugar glycan, acyltrehalose, or acyltrehalose glycan. 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. The oligonucleotide strands may further comprise additional modifications. In certain embodiments, the oligonucleotide strand further comprises at least one modified sugar, at least one modified nucleobase, at least one modified internucleoside linkage, or a combination thereof. In certain embodiments, an 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, an 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, an 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 internucleoside linkages. 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. 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. 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 1′, 2′, 3′, 4′, and 5′ positions. In certain embodiments, substituents at the 2′ position include, but are not limited to, F and OCH3 (“OMe”, “O-methyl”, or “methoxy”). 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, –ΟΝΟ2, –ΝΟ2, –Ν3, and –ΝΗ2. In certain embodiments, substituent groups at the 2′ position include, but are not limited to, –O-(C1-C10) alkoxy, alkoxyalkyl, –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 C1 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 (–ΝΟ2), thiol, thioalkoxy, thioalkyl, halogen, alkyl, 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 (“DMAOE”), –O(CH2)2O(CH2)2N(CH3)2 (“DMAEOE”), and –OCH2C(=O)-N(H)CH3 (“NMA”). 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-O- 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'-phosphoramidates ((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 (MeOCH2-), 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-bicyclic 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 et al., WO 2008/101157. 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 “cEt” 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 Η, 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 al., 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, α-L-ribofuranose and β-D- ribofuranose (see, e.g., WO 99/14226). Specified bicyclic nucleosides herein are in the β-D configuration, unless otherwise specified. 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. 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 C1′-C4′ have been removed (i.e., the covalent carbon-oxygen-carbon bond between the C1′ and C4′ carbons). In another example, the C2′-C3′ bond (i.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. In some embodiments, modified sugars and/or unmodified sugars are arranged along the 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. 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 deoxynucleosides. Oligonucleotides with a gapmer sugar motif are described in, for example, U.S. Patent No.8,790,919. 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. 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, and12 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. 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, Β, and C each represent one type of modification to the nucleoside, the alternating motif can be “ABABABABABAB...,” “AABBAABBAABB...,” “AABAABAABAAB...,” “AAABAAABAAAB...,” “AAABBBAAABBB...,” or “ABCABCABCABC...,” 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. 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. 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-nitrobenzyl)-2′-deoxyribose, 3′-O-methylribose, 5′- aminoribose, 5′-thioribose, 5-nitro-1-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. 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 of 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. In certain embodiments, a modified sugar is 2′-O-methyl ribose, 2′-F ribose, 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. 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. In certain embodiments, modified nucleobases are selected from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and Ν-2, N-6 and O-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-Ν-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-Ν-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, 1,3-diazaphenothiazine-2-one, and 9-(2-aminoethoxy)-1,3- 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, allyaminouracil, 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-carboxycytosine, 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, 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, desthiobiotin-6-aminoallylcytosine, isoguanine, N1- 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). Further nucleobases include those disclosed in U.S. Patent No.3,687,808; Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, Ρ. 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.T. and Lebleu, Β., 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). 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. 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 an oligonucleotide strand are 5-methylcytosines. 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 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. Any modified internucleoside linkages can be used in the oligonucleotides provided herein. A 3′ to 5′ phosphodiester linkage is the naturally occurring internucleoside linkage of RNA and DNA. In certain embodiments, an oligonucleotide strand has one or more modified, i.e., non-naturally occurring, internucleoside linkages. Certain non-naturally occurring internucleoside 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 internucleoside 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-phosphorus containing internucleoside linking groups include, but are not limited to, methylenemethylimino (-CH2-N(CH3)-O-CH2), thiodiester, thionocarbamate (-O-C(=O)(NH)-S-); siloxane (-O-SiH2-O-); and N,N'- dimethylhydrazine (-CH2-Ν((CΗ3)-Ν((CΗ3)-). Methods of preparation of phosphorous- containing and non-phosphorous-containing internucleoside linkages are well known to those skilled in the art. Neutral internucleoside 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 internucleoside 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 internucleoside linkages include nonionic linkages comprising mixed Ν, O, S and CH2 component parts. In certain embodiments, an oligonucleotide strand comprises at least one modified internucleoside linkage. A modified internucleoside linkage may be placed at any position of an oligonucleotide strand. For double-stranded oligonucleotides, a modified internucleoside linkage may be placed within the sense oligonucleotide strand, antisense oligonucleotide strand, or both oligonucleotide strands of the double-stranded oligonucleotide. In certain embodiments, the internucleoside linkage modification may occur on every nucleoside of an oligonucleotide strand. In certain embodiments, internucleoside linkage modifications may occur in an alternating pattern along an oligonucleotide strand. In certain embodiments, essentially each internucleoside linking group is a phosphate internucleoside linkage (Ρ=O). In certain embodiments, each internucleoside linking group of an oligonucleotide strand is a phosphorothioate (P=S). In certain embodiments, each internucleoside linking group of an oligonucleotide strand is independently selected from phosphorothioate and phosphate internucleoside linkages. In certain embodiments, the pattern of the internucleoside linkage modification on each strand of a double-stranded oligonucleotide is the same. In certain embodiments, the pattern of the internucleoside linkage modification on each strand of a double- stranded oligonucleotide is different. In certain embodiments, a double-stranded oligonucleotide comprises 6-8 modified internucleoside linkages. In certain embodiments, the 6-8 modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. In certain embodiments, the sense oligonucleotide strand comprises at least two modified internucleoside linkages at either or both the 5′-end and the 3′-end. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. In certain embodiments, the antisense oligonucleotide strand comprises at least two modified internucleoside linkages at either or both the 5′-end and the 3′-end. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. In certain embodiments, a double-stranded oligonucleotide comprises an overhang region. In certain embodiments, a double-stranded oligonucleotide comprises a phosphorothioate or alkylphosphonate internucleoside linkage modification in the overhang region. In certain embodiments, a double-stranded oligonucleotide comprises a phosphorothioate or alkylphosphonate internucleotide 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 internucleoside 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. In certain embodiments, oligonucleotide strands comprise one or more internucleoside linkages having chiral centers. Representative chiral internucleoside linkages include, but are not limited to, alkylphosphonates and phosphorothioates. The oligonucleotide strands comprising internucleoside linkages having chiral centers can be prepared as populations of oligonucleotide strands comprising stereorandom internucleoside linkages, or as populations of oligonucleotide strands comprising phosphorothioate linkages in particular stereochemical configurations. In certain embodiments, populations of oligonucleotide strands comprise phosphorothioate internucleoside linkages, wherein all of the phosphorothioate internucleoside linkages are stereorandom. Such 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 oligonucleotide strands are enriched for oligonucleotide strands comprising one or more particular phosphorothioate internucleoside 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 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 oligonucleotide strands is enriched for oligonucleotide strands having at least one indicated phosphorothioate in the (Sp) configuration. In certain embodiments, a population of oligonucleotide strands is enriched for oligonucleotide strands having at least one phosphorothioate in the (Rp) configuration. In certain embodiments, a modified internucleoside linkage is present at the 3′-end of the oligonucleotide strand. In certain embodiments, a modified internucleoside linkage is present within 3 nucleosides of the 3′-end of the oligonucleotide strand. In certain embodiments, a modified internucleoside linkage is present at the 5′-end of the oligonucleotide strand. In certain embodiments, a modified internucleoside linkage is present within 3 nucleosides of the 5′-end of the oligonucleotide strand. In certain embodiments, a modified internucleoside linkage is present at an internal position on an oligonucleotide strand. In certain embodiments, a modified internucleoside linkage is present more than 3 nucleosides from the 3′-end of the oligonucleotide strand. In certain embodiments, a modified internucleoside 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 internucleoside 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. In certain embodiments, a modified internucleosidic linkage comprises 5′- ethylenephosphonate, phosphorothioate, or an amide. In certain embodiments, the present disclosure provides a conjugate of any one of the formulae described herein, or a pharmaceutically acceptable salt or prodrug thereof. In certain embodiments, the conjugates described herein include pharmaceutically acceptable salts and prodrugs thereof. In certain embodiments, the conjugates described herein include pharmaceutically acceptable salts thereof. In certain embodiments, the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, is in the form of a pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, and optionally a pharmaceutically acceptable excipient. A conjugate 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 conjugates 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 muscle disease in a subject in need thereof, in preventing a muscle disease in a subject in need thereof, and/or in reducing the risk of developing a muscle 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 conjugates described herein or the additional pharmaceutical agent, but not both. The conjugate 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 muscle disease. In certain embodiments, the additional pharmaceutical agent is a prophylactic agent useful for preventing a muscle 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 conjugate 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 conjugate 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. In some embodiments, the pharmaceutical compositions comprise an effective amount of a conjugate described herein and a pharmaceutically acceptable excipient. In some embodiments, a conjugate described herein is administered to a subject using a pharmaceutically acceptable formulation. For example, a pharmaceutically acceptable formulation may provide sustained delivery of the conjugate to a subject for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after the pharmaceutically acceptable formulation is administered to the subject. 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. In one embodiment, a conjugate of the disclosure is administered acutely. The conjugate 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 conjugate 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. The conjugate 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., a conjugate of the disclosure) may be required to be coated in a material to protect the conjugate from the action of enzymes, acids, and other natural conditions that may inactivate or otherwise degrade the conjugate. In order to administer a conjugate of the disclosure by a mode other than parenteral administration, the conjugate can be coated by, or administered with, a material to prevent inactivation. The conjugate may be administered parenterally or intraperitoneally. Dispersions can also be prepared, for example, in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils. Some examples of substances that can serve as pharmaceutical excipients are sugars, such as lactose, glucose, and sucrose; starches, such as corn 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, corn 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. 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 conjugates 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) a conjugate delineated herein with one or more suitable excipients, including those described herein (e.g., for pharmaceutical, agricultural, or veterinary use). 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. 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 pulmonary administration. Useful injectable preparations include sterile suspensions, solutions, or emulsions of the conjugate(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. 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 conjugate(s) can be dried by any art-known technique, such as lyophilization, and reconstituted prior to use. For prolonged delivery, the conjugate can be formulated as a depot preparation for administration by implantation or intramuscular injection. The conjugates 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. Alternatively, other pharmaceutical delivery systems can be employed. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver the conjugate. Certain organic solvents such as dimethyl sulfoxide (DMSO) also can be employed. 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 conjugates. 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. The conjugates 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 conjugates 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. For prophylactic administration, the conjugates can be administered to a subject at risk of developing one of the previously described diseases. A subject at risk of developing a muscle 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. The amount of the conjugates 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 bioavailability of the conjugates, and the like. Determination of an effective dosage is well within the capabilities of those skilled in the art. 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 conjugate that is at or above an IC50 of the particular conjugate 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 conjugate is well within the capabilities of skilled artisans. For guidance, see “General Principles,” In: Goodman and Gilman’s The Pharmaceutical Basis of Therapeutics, Chapter 1, pp.1-112, 13th ed., McGraw-Hill, and the references cited therein. Initial dosages also can be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of conjugates to treat or prevent the various diseases described above are well-known in the art. 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 conjugate, 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 conjugates 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 conjugates cannot be related to plasma concentration. Skilled artisans will be able to optimize effective local dosages without undue experimentation. Preferably, the conjugates will provide an intended (e.g., therapeutic or prophylactic) benefit and will have acceptable tolerability. Tolerability of the conjugates can be determined using standard pharmaceutical procedures. The dose ratio between non-tolerable and therapeutic (or prophylactic) effect is the therapeutic index. Conjugate(s) that exhibit high therapeutic indices are preferred. In another aspect, provided are kits comprising a conjugate or pharmaceutical composition provided herein. In some embodiments, the kits comprise an effective amount of a conjugate provided herein. In some embodiments, the kits comprise the conjugate or pharmaceutical composition in unit dosage form. In some embodiments, the kits further comprise instructions for using the conjugate or pharmaceutical composition. 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 conjugate 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 conjugate described herein. In some embodiments, the pharmaceutical composition or conjugate described herein are combined to form one unit dosage form. In certain embodiments, the kits are useful for treating a muscle disease in a subject in need thereof. In certain embodiments, the kits are useful for preventing a muscle disease in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a muscle disease in a subject in need thereof. In certain embodiments, the kits are useful for diagnosing a muscle 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. In certain embodiments, a kit described herein further includes instructions for using the conjugate or pharmaceutical composition thereof in a method or use described herein. 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 muscle disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a muscle disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a muscle disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for diagnosing a muscle 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. In certain embodiments, the delivery is selective for the muscle over another organ or tissue. In certain embodiments, another organ or tissue is liver. In certain embodiments, another organ or tissue is kidney. In certain embodiments, another organ or tissue is heart. In some embodiments, the delivery of the conjugate to the muscle is higher (e.g., 10-30%, 30-100%, 1-3 fold, 3-10 fold, 10-30 fold, 30-100 fold, 100-300 fold, 300-1000 fold, or greater than 1000 fold higher) than the delivery of the conjugate to organ or tissue that is not a muscle. In some embodiments, the delivery is determined by the definite integral of the concentration of the conjugate in the muscle or the organ or tissue that is not a muscle as a function of time. In certain embodiments, the muscle is a skeletal muscle. In certain embodiments, the muscle is a cardiac muscle. In certain embodiments, the muscle is a smooth muscle. In certain embodiments, the muscle disease is a congenital myopathy. In certain embodiments, the congenital myopathy is central core disease, minimulticore disease, centronuclear myopathy, myotubular myopathy, congenital fiber-Type disproportion myopathy, King-Denborough syndrome, or nemaline myopathy. In certain embodiments, the muscle disease is a metabolic myopathy. In certain embodiments, the metabolic myopathy is acid maltase deficiency (AMD). In certain embodiments, the acid maltase deficiency is Pompe disease, glycogenosis Type 2, or lysosomal storage disease. In certain embodiments, the metabolic myopathy is carnitine deficiency, debrancher enzyme deficiency (Cori or Forbes disease, glycogenosis Type 3), lactate dehydrogenase deficiency (glycogenosis Type 11), phosphofructokinase deficiency (Tarui disease, glycogenosis Type 7), phosphogylcerate kinase deficiency (glycogenosis Type 9), phosphogylcerate mutase deficiency (glycogenosis Type 10), phosphorylase deficiency (McArdle disease, myophosphorylase deficiency, glycogenosis Type 5), or myoadenylate deaminase deficiency. In certain embodiments, the metabolic myopathy is carnitine palmitoyl transferase deficiency. In certain embodiments, the carnitine palmitoyl transferase deficiency is carnitine palmitoyl transferase II (CPTII) deficiency. In certain embodiments, the metabolic myopathy is glycogen storage disease (GSD). In certain embodiments, the glycogen storage disease is glycogen storage disease Type 0b, II (Pompe disease), III, IV (Andersen disease), V (McArdle disease), VII (Tarui disease), IX, X, XI XII, XIII, or XV. In certain embodiments, the muscle disease is muscle atrophy. In certain embodiments, the muscle atrophy is pathologic atrophy, neurogenic atrophy, or physiologic atrophy. In certain embodiments, the muscle disease is muscular dystrophy. In certain embodiments, the muscular dystrophy is Becker muscular dystrophy (BMD), collagen Type VI- related disorder, congenital muscular dystrophy (CMD), Duchenne muscular dystrophy (DMD), Emery-Dreifuss muscular dystrophy (EDMD), Facioscapulohumeral muscular dystrophy (FSHD), myotonic muscular dystrophy, or oculopharyngeal muscular dystrophy (OMD). In certain embodiments, the muscular dystrophy is a distal muscular dystrophy (Distal MD). In certain embodiments, the distal muscular dystrophy is Laing distal myopathy, Miyoshi distal myopathy, Nonaka distal myopathy, or VCP myopathy. In certain embodiments, the muscular dystrophy is limb-girdle muscular dystrophy. In certain embodiments, the limb-girdle muscular dystrophy is limb-girdle muscular dystrophy Type 1A, 1B, 1C, 1D, 1E, 1F, 1G, 1H, 2, 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T, 2U, 2V, or 2W. In certain embodiments, the muscle disease is myotonia congenita. In certain embodiments, the myotonia congenita is autosomal dominant myotonia congenita (Thomsen disease). In certain embodiments, the muscle disease is myotonic dystrophy. In certain embodiments, the myotonic dystrophy is myotonic dystrophy Type 1 (DM1) or 2 (DM2). In certain embodiments, the muscle disease is a neuromuscular disease. In certain embodiments, the neuromuscular disease is amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, multiple sclerosis, myasthenia gravis, myopathy, peripheral neuropathy, or spinal muscular atrophy. In certain embodiments, the neuromuscular disease is myositis. In certain embodiments, the myositis is polymyositis or dermatomyositis. In certain embodiments, the neuromuscular disease is neuromuscular junction disease. In certain embodiments, the neuromuscular junction disease is congenital myasthenic syndromes (CMS). In certain embodiments, the muscle disease is Barth syndrome, Brody myopathy, cap myopathy, centronuclear myopathy (CNM), fibrodysplasia ossificans progressiva (FOP), fingerprint body myopathy, Friedreich's ataxia (FRDA), hereditary myopathy with early respiratory failure, inclusion body myopathy (IBM), multisystemic smooth muscle dysfunction syndrome, muscle wasting, myofibrillar myopathy (MFM), myopathy with extrapyramidal signs (MPXPS), myosin storage myopathy, ophthalmoplegia, paramyotonia congenita (PMC), reducing body myopathy, rippling muscle disease (RMD), Satoyoshi syndrome, torsion dystonia, tubular aggregate myopathy, or X-linked myotubular myopathy (XLMTM). In certain embodiments, the muscle disease is anismus, muscle cramp, muscle degeneration, muscle hypertrophy, muscle hypotonia, muscle injury, muscle ischemia, muscle lesion, muscle necrosis, muscle neoplasm, muscle rigidity, muscle weakness, muscular dysgenesis, muscular fibrosis, myalgia, myoclonus, myokymia, paratonia, or rhabdomyolysis. The muscle disease may be associated with one or more genes. In certain embodiments, at least one gene is a mammal gene. In certain embodiments, at least one gene is a human gene. In certain embodiments, at least one gene is a non-human mammal gene. The muscle disease may be associated with the up-regulation of at least one gene. The muscle disease may be associated with the down-regulation of at least one gene. In certain embodiments, at least one gene is a gene described in this paragraph. In some embodiments, the cap myopathy is associated with ACTA1, TPM2, or TPM3. In some embodiments, the multisystemic smooth muscle dysfunction syndrome is associated with ACTA2. In some embodiments, the fibrodysplasia ossificans progressiva (FOP) is associated with ACVR1. In some embodiments, the myoadenylate deaminase deficiency is associated with AMPD1. In some embodiments, the limb-girdle muscular dystrophy Type 2L (LGMD2L) is associated with ANO5. In some embodiments, the Brody myopathy is associated with ATP2A1. In some embodiments, the limb-girdle muscular dystrophy Type 2 (LGMD2X) is associated with BVES. In some embodiments, the limb-girdle muscular dystrophy Type 2A (LGMD2A) is associated with CAPN3. In some embodiments, the limb-girdle muscular dystrophy Type 1C (LGMD1C) is associated with CAV3. In some embodiments, the rippling muscle disease (RMD) is associated with CAV3 or CAVIN1. In some embodiments, the congenital myasthenic syndromes (CMS) is associated with CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, DOK7, MUSK, MYO9A, AGRN, LRP4, PREP1, SCN4A, RAPSN, PLEC, or SLC25A1. In some embodiments, the autosomal dominant myotonia congenita (Thomsen disease) is associated with CLCN1. In some embodiments, the myotonic dystrophy Type 2 (DM2) is associated with CNBP. In some embodiments, the carnitine palmitoyl transferase II (CPTII) deficiency is associated with CPT2. In some embodiments, the limb-girdle muscular dystrophy Type 2P (LGMD2P) is associated with DAG1. In some embodiments, the limb-girdle muscular dystrophy Type 1E (LGMD1E) is associated with DES. In some embodiments, the limb-girdle muscular dystrophy Type 2R (LGMD2R) is associated with DES. In some embodiments, the myofibrillar myopathy (MFM) is associated with DES, MYOT, or LDB3. In some embodiments, the Becker muscular dystrophy (BMD) is associated with DMD. In some embodiments, the Duchenne muscular dystrophy (DMD) is associated with DMD. In some embodiments, the myotonic dystrophy Type 1 (DM1) is associated with DMPK. In some embodiments, the limb-girdle muscular dystrophy Type 1D (LGMD1D) is associated with DNAJB6. In some embodiments, the centronuclear myopathy (CNM) is associated with DNM2, BIN1, or TTN. In some embodiments, the Facioscapulohumeral muscular dystrophy (FSHD) is associated with DUX4. In some embodiments, the Miyoshi distal myopathy is associated with DYSF. In some embodiments, the limb-girdle muscular dystrophy Type 2B (LGMD2B) is associated with DYSF. In some embodiments, the reducing body myopathy is associated with FHL1. In some embodiments, the limb-girdle muscular dystrophy Type 2I (LGMD2I) is associated with FKRP. In some embodiments, the limb-girdle muscular dystrophy Type 2M (LGMD2M) is associated with FKTN. In some embodiments, the Friedreich's ataxia (FRDA) is associated with FXN. In some embodiments, the limb-girdle muscular dystrophy Type 2V (LGMD2V) is associated with GAA. In some embodiments, the muscle wasting is associated with GDF15, FBXO32, TRIM63, or MSTN. In some embodiments, the limb-girdle muscular dystrophy Type 2T (LGMD2T) is associated with GMPPB. In some embodiments, the inclusion body myopathy (IBM) is associated with GNE. In some embodiments, the Nonaka distal myopathy is associated with GNE. In some embodiments, the glycogen storage disease (GSD) is associated with GYS1, GAA, AGL, GBE1, PYGM, PFKM, PHKA, PHKA2, PHKAB, PHKAG1, PHKG2, PHKD, PGAM2, ALDOA, ENO3, GYG1, or LDHA. In some embodiments, the limb-girdle muscular dystrophy Type 1G (LGMD1G) is associated with HNRNPDL. In some embodiments, the limb-girdle muscular dystrophy Type 2U (LGMD2U) is associated with ISPD. In some embodiments, the limb-girdle muscular dystrophy Type 2W (LGMD2W) is associated with LIMS2. In some embodiments, the limb-girdle muscular dystrophy Type 1B (LGMD1B) is associated with LMNA. In some embodiments, the Emery-Dreifuss muscular dystrophy (EDMD) is associated with LMNA, EMD, or FHL1. In some embodiments, the fingerprint body myopathy is associated with LMOD3. In some embodiments, the myopathy with extrapyramidal signs (MPXPS) is associated with MICU1. In some embodiments, the X-linked myotubular myopathy (XLMTM) is associated with MTM1. In some embodiments, the Laing distal myopathy is associated with MYH7. In some embodiments, the myosin storage myopathy is associated with MYH7. In some embodiments, the limb-girdle muscular dystrophy Type 1A (LGMD1A) is associated with MYOT. In some embodiments, the nemaline myopathy is associated with NEB or ACTA1. In some embodiments, the oculopharyngeal muscular dystrophy (OMD) is associated with PABPN1. In some embodiments, the limb-girdle muscular dystrophy Type 2Q (LGMD2Q) is associated with PLEC1. In some embodiments, the ophthalmoplegia is associated with POLG, TWNK, RRM2B, or SLC25A4. In some embodiments, the limb-girdle muscular dystrophy Type 2O (LGMD2O) is associated with POMGnT1. In some embodiments, the limb-girdle muscular dystrophy Type 2K (LGMD2K) is associated with POMT1. In some embodiments, the limb- girdle muscular dystrophy Type 2N (LGMD2N) is associated with POMT2. In some embodiments, the congenital myopathy is associated with RYR1, NEM2, ACTA1, TPM2, DNM2, BIN1, MTM1, or TPM3. In some embodiments, the paramyotonia congenita (PMC) is associated with SCN4A. In some embodiments, the congenital muscular dystrophy (CMD) is associated with SEPN1, TTN, ITGA7, IGTA9, PLEC, FKRP, LARGE, DOK7, LMNA, SBP2, FKTN, LAMA2, POMGnT1, COLGA1, COL6A2, COL6A3, B3GNT1, POMT1, POMT2, ISPD, GTDC2, TMEM5, B3GALNT2, or SGK196. In some embodiments, the limb-girdle muscular dystrophy Type 2D (LGMD2D) is associated with SGCA. In some embodiments, the limb-girdle muscular dystrophy Type 2E (LGMD2E) is associated with SGCB. In some embodiments, the limb-girdle muscular dystrophy Type 2F (LGMD2F) is associated with SGCD. In some embodiments, the limb-girdle muscular dystrophy Type 2C (LGMD2C) is associated with SGCG. In some embodiments, the carnitine deficiency is associated with SLC22A5. In some embodiments, the amyotrophic lateral sclerosis is associated with SOD1, TDP43, FUS, or C9orf72. In some embodiments, the tubular aggregate myopathy is associated with STIM1. In some embodiments, the Barth syndrome is associated with TAFAZZIN. In some embodiments, the limb-girdle muscular dystrophy Type 2G (LGMD2G) is associated with TCAP. In some embodiments, the limb-girdle muscular dystrophy Type 1F (LGMD1F) is associated with TNPO3. In some embodiments, the torsion dystonia is associated with TOR1A, TUBB4, THAP1, PRKRA, CIZ1, ANO3, GNAL, AF1, GCH1, TH, ATP1A3, SGCE, MR-1, PRRT2, or SLC2A1. In some embodiments, the limb-girdle muscular dystrophy Type 2 (LGMD2Y) is associated with TOR1A1P1. In some embodiments, the limb-girdle muscular dystrophy Type 2S (LGMD2S) is associated with TRAPPC11. In some embodiments, the limb-girdle muscular dystrophy Type 2H (LGMD2H) is associated with TRIM32. In some embodiments, the hereditary myopathy with early respiratory failure is associated with TTN. In some embodiments, the limb-girdle muscular dystrophy Type 2J (LGMD2J) is associated with TTN. In some embodiments, the VCP myopathy is associated with VCP. The subject treated using the methods provided herein may be a mammal, for example, a primate, such as a human or non-human primate. In certain embodiments, the subject is a human. In some embodiments, the subject is a human younger than 2 years. In some embodiments, the subject is a human aged 2-6 years, inclusive. In some embodiments, the subject is a human aged 6-18 years, inclusive. In certain embodiments, the subject is a human aged 18 years and older. In some embodiments, the subject is a male. In some embodiments, the subject is a female. In certain embodiments, the subject is a non-human animal (e.g., non-human mammal). In certain embodiments, the conjugate or pharmaceutical composition is administered parenterally. In some embodiments, the conjugate or pharmaceutical composition provided herein is administered intravenously, intramuscularly, or subcutaneously. In certain embodiments, the conjugate or pharmaceutical composition is administered intramuscularly. In certain embodiments, the conjugate or pharmaceutical composition is administered subcutaneously. In certain embodiments, the conjugate or pharmaceutical composition is administered orally. In certain embodiments, the conjugate or pharmaceutical composition is administered topically. In some embodiments, any of the conjugates or pharmaceutical compositions provided herein are administered alone or in combination with one or more additional pharmaceutical agents. In certain embodiments, the additional pharmaceutical agent is an agent for treating a muscle disease. In another aspect, the present disclosure provides for veterinary uses of the conjugate, or a pharmaceutically acceptable salt or prodrug thereof (e.g., in a non-human subject as described herein). Numbered Embodiments of The Disclosure 1. A conjugate of Formula I: (A)y–L–(R1)r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an α4β1/7 integrin ligand; L is a linker; each instance of R1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6; for use in treating a muscle disease in a subject in need thereof. 2. A conjugate of Formula I: (A)y–L–(R1)r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an α4β1/7 integrin ligand; L is a linker; each instance of R1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6; for use in preventing a muscle disease in a subject in need thereof. 3. A conjugate of Formula I: (A)y–L–(R1)r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an α4β1/7 integrin ligand; L is a linker; each instance of R1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6; for use in diagnosing a muscle disease in a subject in need thereof. 4. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-3, wherein the muscle disease is a congenital myopathy. 5. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 4, wherein the congenital myopathy is central core disease, minimulticore disease, centronuclear myopathy, myotubular myopathy, congenital fiber-Type disproportion myopathy, King-Denborough syndrome, or nemaline myopathy. 6. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-3, wherein the muscle disease is a metabolic myopathy. 7. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 6, wherein the metabolic myopathy is acid maltase deficiency (AMD). 8. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 7, wherein the acid maltase deficiency is Pompe disease, glycogenosis Type 2, or lysosomal storage disease. 9. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 6, wherein the metabolic myopathy is carnitine deficiency, debrancher enzyme deficiency (Cori or Forbes disease, glycogenosis Type 3), lactate dehydrogenase deficiency (glycogenosis Type 11), phosphofructokinase deficiency (Tarui disease, glycogenosis Type 7), phosphogylcerate kinase deficiency (glycogenosis Type 9), phosphogylcerate mutase deficiency (glycogenosis Type 10), phosphorylase deficiency (McArdle disease, myophosphorylase deficiency, glycogenosis Type 5), or myoadenylate deaminase deficiency. 10. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 6, wherein the metabolic myopathy is carnitine palmitoyl transferase deficiency. 11. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 10, wherein the carnitine palmitoyl transferase deficiency is carnitine palmitoyl transferase II (CPTII) deficiency. 12. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 6, wherein the metabolic myopathy is glycogen storage disease (GSD). 13. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 12, wherein the glycogen storage disease is glycogen storage disease Type 0b, II (Pompe disease), III, IV (Andersen disease), V (McArdle disease), VII (Tarui disease), IX, X, XI XII, XIII, or XV. 14. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-3, wherein the muscle disease is muscle atrophy. 15. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 14, wherein the muscle atrophy is pathologic atrophy, neurogenic atrophy, or physiologic atrophy. 16. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-3, wherein the muscle disease is muscular dystrophy. 17. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 16, wherein the muscular dystrophy is Becker muscular dystrophy (BMD), collagen Type VI-related disorder, congenital muscular dystrophy (CMD), Duchenne muscular dystrophy (DMD), Emery-Dreifuss muscular dystrophy (EDMD), Facioscapulohumeral muscular dystrophy (FSHD), myotonic muscular dystrophy, or oculopharyngeal muscular dystrophy (OMD). 18. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 16, wherein the muscular dystrophy is a distal muscular dystrophy (Distal MD). 19. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 18, wherein the distal muscular dystrophy is Laing distal myopathy, Miyoshi distal myopathy, Nonaka distal myopathy, or VCP myopathy. 20. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 16, wherein the muscular dystrophy is limb-girdle muscular dystrophy. 21. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 20, wherein the limb-girdle muscular dystrophy is limb-girdle muscular dystrophy Type 1A, 1B, 1C, 1D, 1E, 1F, 1G, 1H, 2, 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T, 2U, 2V, or 2W. 22. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-3, wherein the muscle disease is myotonia congenita. 23. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 22, wherein the myotonia congenita is autosomal dominant myotonia congenita (Thomsen disease). 24. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-3, wherein the muscle disease is myotonic dystrophy. 25. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 24, wherein the myotonic dystrophy is myotonic dystrophy Type 1 (DM1) or 2 (DM2). 26. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-3, wherein the muscle disease is a neuromuscular disease. 27. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 26, wherein the neuromuscular disease is amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, multiple sclerosis, myasthenia gravis, myopathy, peripheral neuropathy, or spinal muscular atrophy. 28. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 26, wherein the neuromuscular disease is myositis. 29. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 28, wherein the myositis is polymyositis or dermatomyositis. 30. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 26, wherein the neuromuscular disease is neuromuscular junction disease. 31. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 30, wherein the neuromuscular junction disease is congenital myasthenic syndromes (CMS). 32. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-3, wherein the muscle disease is Barth syndrome, Brody myopathy, cap myopathy, centronuclear myopathy (CNM), fibrodysplasia ossificans progressiva (FOP), fingerprint body myopathy, Friedreich's ataxia (FRDA), hereditary myopathy with early respiratory failure, inclusion body myopathy (IBM), multisystemic smooth muscle dysfunction syndrome, muscle wasting, myofibrillar myopathy (MFM), myopathy with extrapyramidal signs (MPXPS), myosin storage myopathy, ophthalmoplegia, paramyotonia congenita (PMC), reducing body myopathy , rippling muscle disease (RMD) , Satoyoshi syndrome, torsion dystonia , tubular aggregate myopathy, or X-linked myotubular myopathy (XLMTM). 33. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-3, wherein the muscle disease is anismus, muscle cramp, muscle degeneration, muscle hypertrophy, muscle hypotonia, muscle injury, muscle ischemia, muscle lesion, muscle necrosis, muscle neoplasm, muscle rigidity, muscle weakness, muscular dysgenesis, muscular fibrosis, myalgia, myoclonus, myokymia, paratonia, or rhabdomyolysis. 34. A conjugate of Formula I: (A)y–L–(R1)r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an α4β1/7 integrin ligand; L is a linker; each instance of R1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6 for use in delivering the pharmaceutical agent to a muscle of a subject. 35. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 34, wherein the delivery is selective for the muscle over another organ or tissue. 36. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-35, wherein the muscle is a skeletal muscle, smooth muscle, or cardiac muscle. 37. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-36 further comprising administering to the subject an effective amount of one or more additional pharmaceutical agents. 38. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-37, wherein the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, is administered to the subject parenterally. 39. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-37, wherein the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, is administered to the subject subcutaneously, intramuscularly, or intravenously. 40. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-37, wherein the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, is administered to the subject subcutaneously. 41. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-40, wherein the subject is a human. 42. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-41, wherein y is 1. 43. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-41, wherein y is 2, 3, 4, 5, or 6. 44. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-43, wherein at least one instance of A is a radical of a lipid. 45. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-43, wherein at least two instances of A are independently a radical of a ligand. 46. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-45, wherein at least one instance of L is substituted or unsubstituted, C1-100 alkylene, substituted or unsubstituted, C2-100 alkenylene, substituted or unsubstituted, C2-100 alkynylene, substituted or unsubstituted, C1-100 heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, or substituted or unsubstituted, C2-100 heteroalkynylene; optionally wherein one or more backbone atoms of the C1-100 alkylene, C2-100 alkenylene, C2-100 alkynylene, C1-100 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. 47. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-46, wherein at least one instance of L is substituted or unsubstituted, C7-70 alkylene, 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, two, three, or four 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. 48. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-47, wherein at least one instance of L is substituted or unsubstituted, C7-70 alkylene or substituted or unsubstituted, C7-70 heteroalkylene; and one, two, three, or four 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. 49. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-48, wherein: at least one instance of L is
Figure imgf000196_0001
each of –LA1–LA2–, –LA3–LA4–, –LA5–LA6–, –LA7–LA8–, –LA17–LA18–, and –LA19–LA20– 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 Ra is 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of LB1, LB2, and LB6 is independently a single bond, substituted or unsubstituted, C1- 100 alkylene, or substituted or unsubstituted, C1-100 heteroalkylene; each of LC1 and LC2 is 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 CA is attached to A. 50. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-49, wherein at least one instance of L is substituted or unsubstituted, C7-70 heteroalkylene. 51. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-50, wherein at least one instance of L comprises one or more of the following
Figure imgf000197_0001
C(=O)NH–, –C(=O)N(CH3)–,
Figure imgf000197_0002
combination of two or more of each one of the foregoing, provided that: the number of backbone atoms of the at least one instance of L is between 10 and 100, inclusive; and the at least one instance of L does not comprise O–O, O–N, N–O, or N–N. 52. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-51, wherein at least one instance of L is a combination of –
Figure imgf000198_0001
t: the number of backbone atoms of the at least one instance of L is between 10 and 100, inclusive; and the at least one instance of L does not comprise O–O, O–N, N–O, or N–N. 53. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-52, wherein r is 1. 54. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-52, wherein r is 2, 3, 4, 5, or 6. 55. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-54, wherein at least one pharmaceutical agent is a therapeutic agent, prophylactic agent, or diagnostic agent. 56. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-55, wherein at least one pharmaceutical agent inhibits the expression of a superoxide dismutase type 1 (SOD1) gene. 57. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-56, wherein at least one pharmaceutical agent is an oligonucleotide, small molecule, peptide, or protein. 58. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-57, wherein at least one pharmaceutical agent is an antibody. 59. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-58, wherein at least one pharmaceutical agent is a monoclonal antibody. 60. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-59, wherein at least one pharmaceutical agent is an oligonucleotide. 61. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-60, wherein at least one oligonucleotide comprises an RNA. 62. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-61, wherein at least one oligonucleotide is an RNA. 63. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 61-62, wherein at least one RNA is an siRNA. 64. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 57 and 60-63, wherein at least one oligonucleotide is a single- stranded oligonucleotide. 65. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 57 and 60-64, wherein at least one oligonucleotide is a double- stranded oligonucleotide comprising a sense oligonucleotide strand and an antisense oligonucleotide strand. 66. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 57 and 60-65, wherein a strand of at least one oligonucleotide has at least 80%, at least 85%, at least 90%, or at least 95% identity to SEQ ID NO.: 2, 4, 5, or 6. 67. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-41, wherein the conjugate is of Formula I-A: , (I-A) or a pharmaceutically acceptable salt or prodrug thereof, wherein: is a radical of an oligonucleotide strand; s1 instances of the nucleobase-sugar moieties at internal positions of
Figure imgf000199_0001
are independently replaced with a moiety of Formula A:
Figure imgf000199_0002
(A); s1 is 0, 1, 2, 3, 4, 5, or 6; when s1 is 1, 2, 3, 4, 5, or 6: each instance of N1 is independently a radical of a nucleobase or a bond; each instance of t1 is independently 1, 2, or 3; each instance of y1 and y2 is independently 0, 1, 2, 3, 4, 5, or 6; provided that at least one instance of y1 and y2 is 1, 2, 3, 4, 5, or 6; each instance of A1 and A2, when present, is independently a radical of a ligand or lipid; when y1 of an instance of is 0, L1 thereof is hydrogen, halogen, 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, –CN, –ORb, –SCN, –SRb, –SSRb, –N3, –NO, –N(Rb)2, –NO2, –C(=O)Rb, –C(=O)ORb, –C(=O)SRb, –C(=O)N(Rb)2, –S(=O)Rb, –S(=O)ORb, –S(=O)SRb, –S(=O)N(Rb)2, –S(=O)2Rb, –S(=O)2ORb, –S(=O)2SRb, –S(=O)2N(Rb)2, –OC(=O)Rb, –OC(=O)ORb, –OC(=O)SRb, –OC(=O)N(Rb)2, –OS(=O)Rb, –OS(=O)ORb, –OS(=O)SRb, –OS(=O)N(Rb)2, –OS(=O)2Rb, –OS(=O)2ORb, –OS(=O)2SRb, –OS(=O)2N(Rb)2, –ON(Rb)2, –SC(=O)Rb, –SC(=O)ORb, –SC(=O)SRb, –SC(=O)N(Rb)2, –NRbC(=O)Rb, –NRbC(=O)ORb, –NRbC(=O)SRb, –NRbC(=O)N(Rb)2, –NRbS(=O)Rb, –NRbS(=O)ORb, –NRbS(=O)SRb, –NRbS(=O)N(Rb)2, –NRbS(=O)2Rb, –NRbS(=O)2ORb, –NRbS(=O)2SRb, –NRbS(=O)2N(Rb)2, –Si(Rb)3, –Si(Rb)2ORb, –Si(Rb)(ORb)2, –Si(ORb)3, –OSi(Rb)3, –OSi(Rb)2ORb, –OSi(Rb)(ORb)2, or –OSi(ORb)3; or when y1 of an instance of
Figure imgf000200_0001
is 1, 2, 3, 4, 5, or 6, L1 thereof is a linker; each instance of Rb is independently hydrogen, 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, 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 Rb attached to the same intervening atom are joined together with the intervening atom to form an substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring; when y2 of an instance
Figure imgf000201_0001
2 thereof is –OH, –ORc, –SH, – SRc, –NH2, –NHRc, –N(Rc)2, halogen, –CN, or –N3; or when y2 of an instance of
Figure imgf000201_0002
2 thereof is a linker; and each instance of Rc is independently 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; v1 instances of the internucleosidic linkers of are independently replaced
Figure imgf000201_0003
v1 is 0, 1, 2, 3, 4, 5, or 6; each instance of LA and L4, when present, is independently a linker; each instance of y4, when present, is independently 1, 2, 3, 4, 5, or 6; each instance of A4, when present, is independently a radical of a ligand or lipid; each instance of y5 and y6 is independently 0, 1, 2, 3, 4, 5, or 6; when y5 is 0, L5 is hydrogen, substituted or unsubstituted, C1-6 alkyl, or an oxygen protecting group; or when y5 is 1, 2, 3, 4, 5, or 6, L5 is a linker; when y6 is 0, L6 is hydrogen, substituted or unsubstituted, C1-6 alkyl, or an oxygen protecting group; or when y6 is 1, 2, 3, 4, 5, or 6, L6 is a linker; and each instance of A5 and A6, when present, is independently a radical of a ligand or lipid; provided that at least one instance of y1, y2, y4, y5, and y6 is 1, 2, 3, 4, 5, or 6; that the sum of y1, y2, y4, y5, and y6 is not greater than 6; and that at least one instance of A1, A2, A4, A5, and A6 is a radical of an α4β1/7 integrin ligand. 68. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 65-67, wherein the oligonucleotide strand is the sense oligonucleotide strand. 69. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 65-68, wherein the oligonucleotide strand is the antisense oligonucleotide strand. 70. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 65-69, wherein the oligonucleotide strand comprises between 6 and 100, inclusive, nucleosides.
71. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 65-69, wherein the oligonucleotide strand comprises between 10 and 30, inclusive, nucleosides.
72. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 65-69, wherein the oligonucleotide strand comprises between 14 and 23, inclusive, nucleosides.
73. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-72, wherein at least one instance of A1 is a radical of a lipid.
74. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-73, wherein at least one instance of A1 is a radical of a ligand.
75. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-74, wherein at least one instance of A1 is a radical of an ouP 1/7 integrin ligand.
76. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-75, wherein at least one instance of yl is 1.
77. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-76, wherein at least one instance of yl is 2, 3, 4, 5, or 6.
78. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-77, wherein each instance of y2, y4, y5, and y6 is 0.
79. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-78, wherein at least one instance of N1 is a radical of adenine, cytosine, guanine, thymine or uracil.
80. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-79, wherein at least one instance of tl is 1.
81. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-80, wherein yl of an instance of
Figure imgf000202_0001
is 0, and
L1 thereof is hydrogen, halogen, substituted or unsubstituted, C1-6 alkyl, substituted or unsubstituted, C2-6 alkenyl, substituted or unsubstituted, C2-6 heteroalkyl, substituted or unsubstituted, monocyclic carbocyclyl, substituted or unsubstituted, monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted, monocyclic heteroaryl, -CN, -ORb, -SCN, -SRb, -SSRb, -N3, -NO, -N(Rb)2, -NO2, -C(=O)Rb, -C(=O)ORb, -C(=O)SRb, -C(=O)N(Rb)2, - S(=O)Rb,
-S(=O)ORb, -S(=O)SRb, -S(=O)N(Rb)2, -S(=O)2Rb, -S(=O)2ORb, -S(=O)2SRb, - S(=O)2N(Rb)2, -OC(=O)Rb, -OC(=O)ORb, -OC(=O)SRb, -OC(=O)N(Rb)2, - OS(=O)Rb, -OS(=O)ORb,
-OS(=O)SRb, -OS(=O)N(Rb)2, -OS(=O)2Rb, -OS(=O)2ORb, -OS(=O)2SRb, - OS(=O)2N(Rb)2,
-ON(Rb)2, -SC(=O)Rb, -SC(=O)ORb, -SC(=O)SRb, -SC(=O)N(Rb)2, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)SRb, -NRbC(=O)N(Rb)2, -NRbS(=O)Rb, - NRbS(=O)ORb,
-NRbS(=O)SRb, -NRbS(=O)N(Rb)2, -NRbS(=O)2Rb, -NRbS(=O)2ORb, - NRbS(=O)2SRb, or
-NRbS(=O)2N(Rb)2.
82. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-81, wherein yl of an instance of
Figure imgf000203_0001
is 1, 2, 3,
4, 5, or 6, and L1 thereof is substituted or unsubstituted, Ci-100 alkylene, substituted or unsubstituted, C2-ioo alkenylene, substituted or unsubstituted, C2-ioo alkynylene, substituted or unsubstituted, Ci-100 heteroalkylene, substituted or unsubstituted, C2-ioo heteroalkenylene, or substituted or unsubstituted, C2-ioo heteroalkynylene; optionally wherein one or more backbone atoms of the Ci-100 alkylene, C2-ioo alkenylene, C2-ioo alkynylene, Ci-100 heteroalkylene, C2-ioo heteroalkenylene, or C2-ioo 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.
83. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-82, wherein yl of an instance of
Figure imgf000203_0002
is 1, 2, 3,
4, 5, or 6, and L1 thereof is substituted or unsubstituted, C7-70 alkylene, substituted or unsubstituted, C7-70 alkenylene, substituted or unsubstituted, C7-70 heteroalkylene, or substituted or unsubstituted, C7-70 heteroalkenylene; optionally wherein one, two, three, or four backbone atoms of the C7-70 alkylene, C7-70 alkenylene, C7-70 heteroalkylene, or C7-70 heteroalkenylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.
84. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-83, wherein yl of an instance of
Figure imgf000204_0001
is 1, 2, 3,
4, 5, or 6, and L1 thereof is substituted or unsubstituted, C7-70 alkylene or substituted or unsubstituted, C7-70 heteroalkylene; and one, two, three, or four 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.
85. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-84, wherein at least one instance of
Figure imgf000204_0002
is of the formula:
Figure imgf000204_0003
each of -L1A1-L1A2-, -L1A3-L1A4-, -L1A5-L1A6-, and -L1A7-L1A8- 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L1B1 and L1B2 is independently a single bond, substituted or unsubstituted, Ci-100 alkylene, or substituted or unsubstituted, Ci-100 heteroalkylene; L1C1 is 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 C1A is attached to A1.
86. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-85, wherein L1 thereof is of the formula:
Figure imgf000205_0001
87. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-86, wherein yl of an instance of
Figure imgf000205_0002
is 1, 2, 3,
4, 5, or 6, and L1 thereof is substituted or unsubstituted, C7-70 heteroalkylene.
88. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-87, wherein yl of an instance of
Figure imgf000205_0003
is 1, 2, 3,
Figure imgf000205_0004
4, 5, or 6, and L1 thereof comprises one or more of the following -CH2-, A, ,
Figure imgf000205_0005
tion of two or more of each one of the foregoing, provided that: the number of backbone atoms of L1 thereof is between 7 and 70, inclusive; and
L1 thereof does not comprise O-O, O-N, N-O, or N-N.
89. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-88, wherein at least one instance of L1 is a combination of-
Figure imgf000205_0006
t: the number of backbone atoms of the at least one instance of L1 is between 10 and 100, inclusive; and the at least one instance of L1 does not comprise O-O, O-N, N-O, or N-N.
90. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-89, wherein at least one instance of A2 is a radical of a lipid.
91. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-90, wherein at least one instance of A2 is a radical of a ligand.
92. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-91, wherein at least one instance of A2 is a radical of an ouPi/7 integrin ligand.
93. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-92, wherein at least one instance of y2 is 1.
94. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-93, wherein at least one instance of y2 is 2, 3, 4, 5, or 6.
95. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-94, wherein each instance of yl, y4, y5, and y6 is 0.
96. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any
Figure imgf000206_0001
L2 — (A2) 2 one of embodiments 67-95, wherein y2 of an instance of ' 'y2 is 1, 2, 3, 4,
5, or 6, and L2 thereof is 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,
C2-100 alkynylene, 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.
97. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any
Figure imgf000206_0002
L e of embodiments 67-96, wherein y2 of an instance of 2-(A2) on y2 is 1, 2, 3, 4, 5, or 6, and L2 thereof is substituted or unsubstituted, C7-70 alkylene, substituted or unsubstituted, C7-70 alkenylene, substituted or unsubstituted, C7-70 heteroalkylene, or substituted or unsubstituted, C7-70 heteroalkenylene; optionally wherein one, two, or three backbone atoms of the C7-70 alkylene, C7-70 alkenylene, C7-70 heteroalkylene, or C7-70 heteroalkenylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.
98. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any
Figure imgf000207_0001
L2 — (A2) 2 one of embodiments 67-97, wherein y2 of an instance of ' 'y2 is 1, 2, 3, 4, 5, or 6, and L2 thereof is substituted or unsubstituted, C7-70 alkylene or substituted or unsubstituted, C7-70 heteroalkylene; and one, two, or three 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.
99. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any
Figure imgf000207_0002
L2 — (A2) 9 one of embodiments 67-98, at least one instance of ' /y2 is of the formula:
Figure imgf000207_0003
100. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-99, wherein: at least one instance of
Figure imgf000207_0004
is of the formula:
Figure imgf000207_0005
each of -L2A1-L2A2-, -L2A3-L2A4-, -L2A5-L2A6-, and -L2A7-L2A8- 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(=0)-, -C(=NRa)-, -S(=0)-, -S(=0)2- -OP(=O)(ORa)O-, -SP(=O)(ORa)O-
-OP(=O)(OR )S-, or -OP(=O)(SR )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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L2B1 and L2B2 is independently a single bond, substituted or unsubstituted, Ci-100 alkylene, or substituted or unsubstituted, Ci-100 heteroalkylene;
L2C1 is 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 C2A is attached to A2.
101. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-100, wherein at least one instance of y2 is 0.
102. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any
Figure imgf000208_0001
L2 — (A2) 2 one of embodiments 67-101, wherein y2 of an instance of ' 'y2 is 0, L2 thereof is
-OCH3, F, or -CH3.
103. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-102, wherein at least one instance of
Figure imgf000208_0002
is of the formula:
Figure imgf000208_0003
104. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-103, wherein: at least one instance
Figure imgf000208_0004
the formula:
Figure imgf000209_0001
each of -L2A9-L2A10-, _L 2A11-L2A12-, -L2A13-L2A14-, _L 2A15-L2A16-, _L 2A17-L2A18- _L2A19-L2A20-, -L2A21-L2A22-, and -L2A23-L2A24- 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, 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L2B3, L2B4, L2B5, L2B6, L2B7, and L2B8 is independently a single bond, substituted or unsubstituted, Ci-ioo alkylene, or substituted or unsubstituted, Ci-ioo heteroalkylene; each of L2C2 and L2C3 is independently 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; bond C2B is attached to a first instance of A2; and bond C2c is attached to a second instance of A2. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-104, wherein at least one instance
Figure imgf000210_0001
the formula:
Figure imgf000210_0002
The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any
Figure imgf000210_0003
L2 — (A2) 2 one of embodiments 67-105, wherein y2 of an instance of ' /y2 is 1, 2, 3, 4,
5, or 6, and L2 thereof is substituted or unsubstituted, C7-70 heteroalkylene.
The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any
Figure imgf000210_0004
|_2 _ (A2) one of embodiments 67-106, wherein y2 of an instance of ' 'y2 is 1, 2, 3, 4,
5, or 6, and L2 thereof comprises one or more of the following -CH2-,
Figure imgf000210_0005
Figure imgf000210_0006
tion of two or more of each one of the foregoing, provided that: the number of backbone atoms of L2 thereof is between 7 and 70, inclusive; and
L2 thereof does not comprise O-O, O-N, N-O, or N-N.
108. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-107, wherein at least one instance of L2 is a combination of -
Figure imgf000211_0001
t: the number of backbone atoms of the at least one instance of L2 is between 10 and 100, inclusive; and the at least one instance of L2 does not comprise O-O, O-N, N-O, or N-N.
109. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-108, wherein at least one instance of A4 is a radical of a lipid.
110. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-109, wherein at least one instance of A4 is a radical of a ligand.
111. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-110, wherein at least one instance of A4 is a radical of an (X4P1/7 integrin ligand.
112. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-111, wherein at least one instance of y4 is 1.
113. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-112, wherein at least one instance of y4 is 2, 3, 4, 5, or 6.
114. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-113, wherein each instance of yl, y2, y5, and y6 is 0.
115. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-114, wherein at least one instance of the intemucleosidic linkers is between the first n and n+1 nucleoside of the oligonucleotide strand counted from the 5’ end; and n is an integer between 1 and 20, inclusive, as the number of nucleosides of the oligonucleotide strand permits.
116. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-115, wherein the conjugate is of the formula: 5'
(hydrogen, substituted or unsubstituted, ■ LA > (hydrogen, substituted or unsubstituted, C-|_6 alkyl, or an oxygen protecting group) I C-|.6 alkyl, or an oxygen protecting group)
L4
(a4p-i/7 integrin ligand)
(I-A-l),
5' lipid — L5 ■L A > — — — (hydrogen, substituted or unsubstituted,
I C-i-6 alkyl, or an oxygen protecting group)
L4
(a4Pi/7 integrin ligand)
(I-A-2),
Figure imgf000212_0005
(I-A-3),
3’ - L6— lipid
Figure imgf000212_0001
integrin ligand)
(I-A-4),
(a
Figure imgf000212_0006
(I-A-5), 3'
(a4pi/7 integrin ligand) - L6 — lipid
Figure imgf000212_0002
integrin ligand) (I-A-6), 3'
(hydrogen, substituted or unsubstituted, — — L6— (a4p1/7 integrin ligand)
C-|.6 alkyl, or an oxygen protecting group)
Figure imgf000212_0003
integrin ligand) (I-A-7), lipid — L
Figure imgf000212_0004
— (a4p1/7 integrin ligand)
L4
(a4Pi n integrin ligand) (I-A-8), or (a4pi/7 integrin ligand) ———— [_6 — (a4p1/7 integrin ligand)
Figure imgf000213_0001
integrin ligand)
(I-A-9).
117. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-116, wherein: at least one instance of LA is of the formula:
Figure imgf000213_0002
each instance of ZA1 and Z^ is independently a single bond, substituted or unsubstituted, Ci-6 alkylene, or substituted or unsubstituted, C2-6 alkenylene; each instance of WA is independently a radical, as valency permits, of substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -O-, -OP(=O)(ORC)O-, -N(RC)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NRC-, -NRCC(=O)-, -C(=O)RC-, -NRCC(=O)O-, -NRCC(=O)NRC-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RC)-, -S(=O)2NRC-, -NRCS(=O)2-, or a combination thereof; each instance of Rc 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 Rc are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and bond C4A is attached to L4.
118. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 117, wherein at least one instance of LA is of the formula:
Figure imgf000213_0003
119. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 117 or 118, wherein at least one instance of LA is of the formula:
Figure imgf000214_0001
120. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 117-119, wherein ZA1 is unsubstituted C1-3 alkylene.
121. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 117-120, wherein Z^ is unsubstituted C1-3 alkylene.
122. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-121, wherein at least one instance of LA is of the formula:
Figure imgf000214_0002
123. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-122, wherein at least one instance of L4 is 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, C2-100 alkynylene, 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.
124. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-123, wherein at least one instance of L4 is substituted or unsubstituted, C7-70 alkylene, 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, two, three, or four 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.
125. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-124, wherein at least one instance of L4 is substituted or unsubstituted, C7-70 alkylene or substituted or unsubstituted, C7-70 heteroalkylene; and one, two, three, or four 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.
126. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-125, wherein: at least one instance of y4 is 1 ;
Figure imgf000215_0001
each of -L4A1-L4A2-, -L4A3-L4A4-, -L4A5-L4A6-, -L4A7-L4A8-, -L4A17-L4A18-, and -L4A 19_[^4A2o_ is injepenjentiy 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 Ra attached 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 L4B3 is independently a single bond, substituted or unsubstituted, Ci-ioo alkylene, or substituted or unsubstituted, Ci-100 heteroalkylene; each of L4C1 and L4C2 is 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 C4A is attached to A4.
127. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-126, wherein: at least one instance of y4 is 2;
Figure imgf000216_0001
each of -L4A21-L4A22 _ p4A23_p4A24 _ p4A25_p4A26 _ p4A27_p4A28 _ p4A29_p4A30 _
L4A31_L4A32 _ L4A33_L4A34 _ p4A35_p4A36 _ p4A37_p4A38 _ p4A39_p4A40 _ p4A41_p4A42 _
L4A43_L4A44_ _p4A45_p4A46_, _p4A47_p4A48_, an j _p4A49_p4A50_ • s j nc[epenc[en ( J y 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, 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L4B4, L4B5, L4B6, L4B7, L4B8, L4B9, L4B10, L4B11, and L4B12 is independently a single bond, substituted or unsubstituted, Ci-100 alkylene, or substituted or unsubstituted, Ci-100 heteroalkylene; each of L4C3, L4C4, L4C5, L4C6, L4C7, and L4C8 is 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; bond C4B is attached to a first instance of A4; and bond C4c is attached to a second instance of A4.
128. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-127, wherein at least one instance of L4 is substituted or unsubstituted, C7-70 heteroalkylene.
129. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-128, wherein at least one instance of L4 comprises one or
JWV
AgA A' A more of the following -CH2-, , -O-, -CH2CH2O-, -OCH2CH2-, -
Figure imgf000217_0001
Figure imgf000217_0002
combination of two or more of each one of the foregoing, provided that: the number of backbone atoms of the at least one instance of L4 is between 10 and 100, inclusive; and the at least one instance of L4 does not comprise O-O, O-N, N-O, or N-N.
130. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-129, wherein at least one instance of L4 is a combination
Figure imgf000217_0003
he number of backbone atoms of the at least one instance of L4 is between 10 and 100, inclusive; and the at least one instance of L4 does not comprise O-O, O-N, N-O, or N-N.
131. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-130, wherein at least one instance of A5 is a radical of a lipid.
132. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-131, wherein at least one instance of A5 is a radical of a ligand.
133. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-132, wherein at least one instance of A5 is a radical of an 014P1/7 integrin ligand.
134. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-133, wherein at least one instance of y5 is 1.
135. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-134, wherein at least one instance of y5 is 2, 3, 4, 5, or 6.
136. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-135, wherein each instance of yl, y2, y4, and y6 is 0.
137. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-136, wherein the conjugate is of the formula:
5' 3'
(a4p1/7 integrin ligand) — Ls (hydrogen, substituted or unsubstituted,
C-|_6 alkyl, or an oxygen protecting group)
(I- A- 10),
5' 3'
(□43-1/7 integrin ligand) — L5 ~ ~ L6 — lipid
(I-A-l l),
S' 3' R
(U43I/7 integrin ligand) L L (O43I/7 integi in ligand)
(I- A- 12),
. R 5' _ A 3'
(□4Pi/7 integrin ligand) L ■■■■■■ 'L
Figure imgf000218_0001
(hydrogen, substituted oi unsubstiluted,
I C-|.6 alkyl, or an oxygen protecting group)
L4 lipid
(I-A-13),
Figure imgf000218_0002
lipid (I- A- 14), or
(a4p1/7 integrin ligand) — L
Figure imgf000219_0001
LA ------------ L6 — (a4p1/7 integrin ligand)
L4
I lipid
(I-A-15).
138. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-137, wherein L5 is substituted or unsubstituted, Ci-150 alkylene, substituted or unsubstituted, C2-150 alkenylene, substituted or unsubstituted, C2-150 alkynylene, substituted or unsubstituted, Ci-150 heteroalkylene, substituted or unsubstituted, C2-150 heteroalkenylene, or substituted or unsubstituted, C2-150 heteroalkynylene; optionally wherein one or more backbone atoms of the Ci-150 alkylene, C2-150 alkenylene, C2-150 alkynylene, Ci-150 heteroalkylene, C2-150 heteroalkenylene, or C2-150 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.
139. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-138, wherein L5 is substituted or unsubstituted, Cio-100 alkylene, substituted or unsubstituted, Cio-100 alkenylene, substituted or unsubstituted, Cio-100 alkynylene, substituted or unsubstituted, Cio-100 heteroalkylene, substituted or unsubstituted, Cio-100 heteroalkenylene, or substituted or unsubstituted, Cio-100 heteroalkynylene; optionally wherein one, two, or three backbone atoms of the Cio-100 alkylene, Cio-100 alkenylene, Cio-100 alkynylene, Cio-100 heteroalkylene, Cio-100 heteroalkenylene, or Cio-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.
140. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-139, wherein L5 is substituted or unsubstituted, Cio-100 alkylene or substituted or unsubstituted, Cio-100 heteroalkylene; and one, two, or three backbone atoms of the Cio-100 alkylene or Cio-100 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. 141. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-140, wherein: at least one instance of y5 is 1; and
L5 is
Figure imgf000220_0001
each of -L5A1-L5A2-, -L5A3-L5A4-, -L5A5-L5A6-, -L5A7-L5A8-, -L5A17-L5A18-, and -L5A19-L5A2°- 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, 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 Ra attached 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 L5B6 is independently a single bond, substituted or unsubstituted, Ci-ioo alkylene or substituted or unsubstituted, Ci-ioo heteroalkylene; each of L5C1 and L5C2 is 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 C5B is attached to A5.
142. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-141, wherein: at least one instance of y5 is 2;
Figure imgf000221_0001
each of -L5A1-L5A2 _ L5A3-L5 A4 _ L3 A5-L5A6 _ L3A7-L3AS _ L5A9-L5A 10 _ L5A1 1 - j^5A12 _ |^5A I 3_[^5AI4 _ J^5A15_J^5A16 _ J^5A17_J^5A18 _ J^5A19_J^5A20_ anj _J^5A21_J^5A22_ | 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, 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of -L5B1-, -L5B4-, and -L5B6- is independently a single bond, substituted or unsubstituted, Ci-iso alkylene or substituted or unsubstituted, Ci-iso heteroalkylene; each of -L5B2-, -L5B3-, -L5B5-, and -L5B7- is independently a single bond, substituted or unsubstituted, Ci-iso alkylene, or substituted or unsubstituted, Ci-iso heteroalkylene; each of L5C1, L5C2, L5C3, and L5C4 is 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; bond C5A is attached to a first instance of A5; and bond C5B is attached to a second instance of A5. . The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-142, wherein: at least one instance of y5 is 2; and
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
144. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-143, wherein: at least one instance of y5 is 2;
Figure imgf000225_0002
Figure imgf000226_0001
each of p2, p5, p6, and p9 is independently an integer from 1 to 10, inclusive; each of p3, p7, p8, plO, pl 1, pl2, and pl3 is independently an integer from 0 to 10, inclusive; p4 is 0 or 1 ; each of _L5A15-L5A16- and -L5A21-L5A22- 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, 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; bond C5A is attached to a first instance of A5; and bond C5B is attached to a second instance of A5.
145. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-144, wherein: at least one instance of y5 is 2;
Figure imgf000227_0001
each of p2, p5, p6, p8, p9, and pl 1 is independently an integer from 1 to 10, inclusive; each of p3, p7, plO, pl2, and pl3 is independently an integer from 0 to 10, inclusive; p4 is 0 or 1 ; each of _L5A15-L5A16- and -L5A21-L5A22- 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, 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; bond C5A is attached to a first instance of A5; and bond C5B is attached to a second instance of A5.
146. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-145, wherein: at least one instance of y5 is 2;
Figure imgf000228_0001
j^5A57_j^5A58_ _J^5A59_J^5A60_ _J^5A61_J^5A62_ _J^5A63_J^5A64_ _J^5A65_J^5A66_ <^ncl _ |_5A67_|^5A68 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, 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of -L5B16-, -L5B19-, and -L5B21- is independently a single bond, substituted or unsubstituted, Ci-150 alkylene or substituted or unsubstituted, Ci-150 heteroalkylene; each of -L5B17-, -L5B18-, -L5B20-, and -L5B22- is independently a single bond, substituted or unsubstituted, Ci-iso alkylene, or substituted or unsubstituted, Ci-iso heteroalkylene; each of L5C9, L5C10, L5C11, and L5C12 is 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; bond C5A is attached to a first instance of A5; and bond C5B is attached to a second instance of A5. 147. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-146, wherein: at least one instance of y5 is 2;
Figure imgf000229_0001
Figure imgf000230_0001
each of p2, p5, and p6 is independently an integer from 1 to 10, inclusive; each of p3, p7, p8, p9, plO, and pl 1 is independently an integer from 0 to 10, inclusive;
Figure imgf000230_0002
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, 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; bond C5A is attached to a first instance of A5; and bond C5B is attached to a second instance of A5.
148. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-147, wherein: at least one instance of y5 is 3;
Figure imgf000231_0001
,
-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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of -L5B8-, -L5B9-, -L5B10-, -L5B11-, -L5B12-, -L5B13-, -L5B14-, and -L5B15- is independently a single bond, substituted or unsubstituted, Ci-150 alkylene or substituted or unsubstituted, Ci-150 heteroalkylene; each of L5C5, L5C6, L5C7, and L5C8 is 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 bonds C5c, C5D, and C5E are attached to a first, second, and third instances of A5, respectively. . The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-148, wherein: at least one instance of y5 is 3; and
Figure imgf000232_0001
each of L5C6, L5C7, and L5C8 is independently a single bond,
Figure imgf000233_0001
Figure imgf000233_0002
150. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-149, wherein L5 is substituted or unsubstituted, C10-100 heteroalkylene.
151. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-150, wherein L5 comprises one or more of the following-
Figure imgf000233_0003
combination of two or more of each one of the foregoing, provided that: the number of backbone atoms of L5 is between 10 and 100, inclusive; and
L5 does not comprise O-O, O-N, N-O, or N-N.
152. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-151, wherein at least one instance of L5 is a combination of-
Figure imgf000233_0004
C(=O)N(CH3)-,
Figure imgf000234_0001
, provided that: the number of backbone atoms of the at least one instance of L5 is between 10 and 100, inclusive; and the at least one instance of L5 does not comprise O-O, O-N, N-O, or N-N.
153. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-152, wherein at least one instance of A6 is a radical of a lipid.
154. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-153, wherein at least one instance of A6 is a radical of a ligand.
155. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-154, wherein at least one instance of A6 is a radical of an 014P1/7 integrin ligand.
156. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-155, wherein at least one instance of y6 is 1.
157. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-156, wherein at least one instance of y6 is 2, 3, 4, 5, or 6.
158. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-157, wherein each instance of yl, y2, y4, and y5 is 0.
159. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-158, wherein the conjugate is of the formula:
5' 3’
(hydrogen, substituted or unsubstituted, - L6— (a 4R1/7 integrin ligand)
C-i-6 alkyl, or an oxygen protecting group)
(I-A-16),
5' 3' lipid — L5 — L6— (043-1/7 integrin ligand)
(I-A-17),
(hydrogen, substituted or unsubstituted,
Figure imgf000234_0002
5' A 3' 6
C-|.6 alkyl, or an oxygen protecting group) | L <a43i/7 integrin ligand)
L4
I lipid
(I-A-18), or 5' lipid — L5 — - LA— — L6— (CJ4P-1/7 integrin ligand)
L4
I lipid
(I-A-19).
160. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-159, wherein L6 is substituted or unsubstituted, Ci-150 alkylene, substituted or unsubstituted, C2-150 alkenylene, substituted or unsubstituted, C2-150 alkynylene, substituted or unsubstituted, Ci-150 heteroalkylene, substituted or unsubstituted, C2-150 heteroalkenylene, or substituted or unsubstituted, C2-150 heteroalkynylene; optionally wherein one or more backbone atoms of the Ci-150 alkylene, C2-150 alkenylene, C2-150 alkynylene, Ci-150 heteroalkylene, C2-150 heteroalkenylene, or C2-150 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.
161. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-160, wherein L6 is substituted or unsubstituted, Cio-100 alkylene, substituted or unsubstituted, Cio-100 alkenylene, substituted or unsubstituted, Cio-100 alkynylene, substituted or unsubstituted, Cio-100 heteroalkylene, substituted or unsubstituted, Cio-100 heteroalkenylene, or substituted or unsubstituted, Cio-100 heteroalkynylene; optionally wherein one, two, or three backbone atoms of the Cio-100 alkylene, Cio-100 alkenylene, Cio-100 alkynylene, Cio-100 heteroalkylene, Cio-100 heteroalkenylene, or Cio-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.
162. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-161, wherein L6 is substituted or unsubstituted, Cio-100 alkylene or substituted or unsubstituted, Cio-100 heteroalkylene; and one, two, or three backbone atoms of the Cio-100 alkylene or Cio-100 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.
163. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-162, wherein: at least one instance of y6 is 1;
L6 is
Figure imgf000236_0001
each of -L6A1-L6A2-, -L6A3-L6A4-, -L6A5-L6A6-, -L6A7-L6A8-, _L6A17-L6A18-, and - L6AI9_J^6A20_ js injepenjentiy 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, 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 Ra attached 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 L6B6 is independently a single bond, substituted or unsubstituted, Ci-ioo alkylene or substituted or unsubstituted, Ci-ioo heteroalkylene; each of L6C1 and L6C2 is 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 C6B is attached to A6.
164. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-163, wherein: at least one instance of y6 is 1; and
Figure imgf000237_0001
Figure imgf000238_0001
165. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-164, wherein: at least one instance of y6 is 2; and
Figure imgf000238_0002
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(=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, C2-6 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of -L6B1-, -L6B4-, and -L6B6- is independently a single bond, substituted or unsubstituted, C2-150 alkylene or substituted or unsubstituted, C2-150 heteroalkylene; each of -L6B2-, -L6B3-, -L6B5-, and -L6B7- is independently a single bond, substituted or unsubstituted, C2-150 alkylene, or substituted or unsubstituted, C2-150 heteroalkylene; each of L6C1, L6C2, L6C3, and L6C4 is 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; bond C6A is attached to a first instance of A6; and bond C6B is attached to a second instance of A6.
166. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-165, wherein: at least one instance of y6 is 2; and
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
167. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-166, wherein: at least one instance of y6 is 2;
Figure imgf000243_0001
each of p2, p5, p6, and p9 is independently an integer from 1 to 10, inclusive; each of p3, p7, p8, plO, pl 1, pl2, and pl3 is independently an integer from 0 to 10, inclusive; p4 is 0 or 1 ; each of _L6A15-L6A16- and _L6A21_L6A22_ 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-, -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- -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, 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; bond C6A is attached to a first instance of A6; and bond C6B is attached to a second instance of A6.
168. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-167, wherein: at least one instance of y6 is 2; and
Figure imgf000244_0001
Figure imgf000245_0001
each of p2, p5, p6, p8, p9, and pl 1 is independently an integer from 1 to 10, inclusive; each of p3, p7, plO, pl2, and pl3 is independently an integer from 0 to 10, inclusive; p4 is 0 or 1 ; each of _L6A15-L6A16- and _L6A21_L6A22_ 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, 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; bond C6A is attached to a first instance of A6; and bond C6B is attached to a second instance of A6.
169. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-168, wherein: at least one instance of y6 is 2; c6B ig
Figure imgf000246_0001
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, 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of -L6B16-, -L6B19-, and -L6B21- is independently a single bond, substituted or unsubstituted, Ci-iso alkylene or substituted or unsubstituted, Ci-iso heteroalkylene; each of -L6B17-, -L6B18-, -L6B20-, and -L6B22- is independently a single bond, substituted or unsubstituted, Ci-iso alkylene, or substituted or unsubstituted, Ci-iso heteroalkylene; each of L6C9, L6C10, L6C11, and L6C12 is 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; bond C6A is attached to a first instance of A6; and bond C6B is attached to a second instance of A6. . The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-169, wherein: at least one instance of y6 is 2,
Figure imgf000247_0001
each of p2, p5, and p6 is independently an integer from 1 to 10, inclusive; each of p3, p7, p8, p9, plO, and pl 1 is independently an integer from 0 to 10, inclusive; p4 is 0 or 1 ; _^6A6i_[^6A62_ anj _J^6A67_J^6A68_ arc eacj1 injepen jentiy 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, 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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; bond C6A is attached to a first instance of A6; and bond C6B is attached to a second instance of A6.
171. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-170, wherein: at least one instance of y6 is 3; and
Figure imgf000248_0001
each of -L6A23-L6A24_ _J^6A25_J^6A26_ _|^6A27_|^6A28_ _J^6A29_J^6A30_ _J^6A31_J^6A32_ _ |^6A33_|^6A34_ _J^6A35_J^6A36_ _J^6A37_J^6A38_ _J^6A39_J^6A40_ _J^6A41_J^6A42_ _J^6A43_J^6A44_ <^ncl — p6A45_p6A46_ j nc[epenclen ( ] y 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)-,
-0C(=NRa)-, -OS(=O)-, -OS(=O)2-, -NRaC(=0)-, -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(=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 Ra attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of -L6B8-, -L6B9-, -L6B10-, -L6B11-, -L6B12-, -L6B13-, -L6B14-, and -L6B15- is independently a single bond, substituted or unsubstituted, Ci-150 alkylene or substituted or unsubstituted, Ci-150 heteroalkylene; each of L6C5, L6C6, L6C7, and L6C8 is 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 bonds C6c, C6D, and C6E are attached to a first, second, and third instances of A6, respectively.
172. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-171, wherein: at least one instance of y6 is 3; and
Figure imgf000249_0001
Figure imgf000250_0001
173. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-172, wherein: the substituted or unsubstituted heteroarylene that replaces one of the backbone atoms is of the formula:
Figure imgf000251_0001
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 alkyl); and Rg is hydrogen, halogen, substituted or unsubstituted, Ci-6 alkyl, or -O-(substituted or unsubstituted, Ci-6 alkyl). 174. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-173, wherein L6 is substituted or unsubstituted, C10-100 heteroalkylene.
175. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-174, wherein L6 comprises one or more of the following-
Figure imgf000252_0001
combination of two or more of each one of the foregoing, provided that: the number of backbone atoms of L6 is between 10 and 100, inclusive; and
L6 does not comprise O-O, 0-N, N-0, or N-N.
176. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-175, wherein at least one instance of L6 is a combination of -
Figure imgf000252_0002
t: the number of backbone atoms of the at least one instance of L6 is between 10 and 100, inclusive; and the at least one instance of L6 does not comprise 0-0, 0-N, N-0, or N-N.
177. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-176, wherein at least two instances of A1, A2, A4, A5, and A6 are independently a radical of a ligand.
178. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 177, wherein at least two ligands are of the same ligand type.
179. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 177 or 178, wherein at least two ligands are of different ligand types.
180. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-179, wherein at least one ligand is a small molecule, peptide, or protein. 181. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-180, wherein at least one ligand is an antibody.
182. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-181, wherein at least one ligand is a monoclonal antibody.
183. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-182, wherein at least one ouPi/7 integrin ligand is an ouP i integrin ligand.
184. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-183, wherein at least one ouPi/v integrin ligand is an ouP? integrin ligand.
185. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-184, wherein: at least one ouPi/v integrin ligand is of the formula:
Figure imgf000253_0001
each instance of R1Z is independently optionally substituted heteroaryl or optionally substituted phenyl; each instance of R33z is independently -O(optionally substituted alkyl), -OH, -NH2, - NHOH, -NH(optionally substituted alkyl), -NH(optionally substituted polyethylene glycol), - N(optionally substituted alkyl)2, or -N(optionally substituted alkyl)(optionally substituted polyethylene glycol); each instance of R34z is of the formula:
Figure imgf000253_0002
each instance of R2Z is independently hydrogen, optionally substituted polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, or optionally substituted heteroaryl; and each instance of X4Z is N or C(R35Z); and each instance of R35z is independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted alkoxy.
186. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 185, wherein: at least one ouPi/7 integrin ligand is of the formula:
Figure imgf000254_0001
each instance of X3Z and X5Z is independently N or C(R32Z); each instance of R32z is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted polyethylene glycol, or -S(=O)2(optionally substituted alkyl); each instance of R3Z, R4Z, and R36z is independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted alkoxy.
187. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 185-186, wherein: at least one ouPi/v integrin ligand is of the formula:
Figure imgf000254_0002
each instance of R2Z is independently hydrogen, polyethylene glycol, optionally substituted heteroalkyl, or optionally substituted heteroaryl; and each instance of R3Z and R4Z is independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted alkoxy.
188. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 185-187, wherein at least one radical of the ouPi/v integrin ligand is of the formula:
Figure imgf000255_0001
189. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 185-188, wherein at least one radical of the ouPi/7 integrin ligand is of the formula:
Figure imgf000255_0002
190. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 185-189, wherein at least one radical of the ouPi/7 integrin ligand is of the formula:
Figure imgf000255_0003
191. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 185-190, wherein at least one ouPi/7 integrin ligand is of the formula:
Figure imgf000255_0004
192. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 185-191, wherein at least one radical of the ouPi/7 integrin ligand is of the formula:
Figure imgf000256_0001
. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 185-192, wherein at least one radical of the ouPi/7 integrin ligand is of the formula:
Figure imgf000256_0002
. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 185-193, wherein at least one radical of the ouPi/v integrin ligand is of the formula:
Figure imgf000256_0003
. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-194, wherein: at least one ouPi/7 integrin ligand is of the formula:
Figure imgf000257_0001
each of R8Z, R9Z, R10z, and R11Z is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted -O-alkyl, or substituted or unsubstituted cycloalkyl; each of R12z and R13z is independently H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl,
Figure imgf000257_0002
Figure imgf000257_0003
R14Z is optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkylene-(C3-C6)- cycloalkyl, or optionally substituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy.
196. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-195, wherein: at least one 014P1/7 integrin ligand is of the formula:
Figure imgf000257_0004
each of R9Z, R10z, and R11Z is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted -O-alkyl, or substituted or unsubstituted cycloalkyl; each of R12z and R13z is independently H, halogen, optionally substituted alkyl, optionally
Figure imgf000258_0001
R14Z is optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkylene-(C3-C6)- cycloalkyl, or optionally substituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy. 197. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 195-196, wherein at least one radical of the ouPi/v integrin ligand is of the formula:
Figure imgf000258_0002
198. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 195-197, wherein at least one ouPi/v integrin ligand is of the formula:
Figure imgf000258_0003
199. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 195-198, wherein at least one radical of the ouPi/v integrin ligand is of the formula:
Figure imgf000259_0001
200. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 195-199, wherein at least one radical of the ouPi/7 integrin ligand is of the formula:
Figure imgf000259_0002
201. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 195-200, wherein: at least one radical of an ouPi/7 integrin ligand is of the formula:
Figure imgf000260_0001
The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-201, wherein at least one ouPi/7 integrin ligand is a compound of the formula:
Figure imgf000260_0002
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0002
, or is a radical of an anti-ouPi/7 integrin antibody. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-202 wherein at least one ouPi/7 integrin ligand is a compound of the formula:
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
204. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-203, wherein: at least one radical of an ouPi/7 integrin ligand is of the formula:
Figure imgf000268_0002
R4Z is hydrogen, halogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted -O-alkyl, or optionally substituted cycloalkyl; R5Z is optionally substituted heteroalkyl or optionally substituted heterocyclyl; and nlZ is 1, 2, or 3. 205. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-204, wherein: at least one radical of an ouPi/v integrin ligand is of the formula:
Figure imgf000268_0003
Figure imgf000269_0001
R6Z is hydrogen, -OH, -NH2, -NHR7Z, -OR7Z, or absent; and R7Z is hydrogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl. 206. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-205, wherein: at least one radical of an ouPi/7 integrin ligand is of the formula:
Figure imgf000269_0002
Figure imgf000270_0001
n2Z is 0, 1, 2, or 3. . The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-206, wherein: at least one radical of an ouPi/7 integrin ligand is of the formula:
Figure imgf000270_0002
Figure imgf000271_0001
n3Z is 0, 1, 2, or 3. . The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-207, wherein: at least one radical of an ouPi/7 integrin ligand is of the formula:
Figure imgf000271_0002
Figure imgf000272_0001
R15Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; each of R16z and R17Z is independently H, halogen, optionally substituted alkyl, or optionally substituted -O-alkyl; and
Yz is -CH2- or -(CH2)2-.
209. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-208, wherein: at least one radical of an ouPi/v integrin ligand is of the formula:
Figure imgf000272_0002
R18Z is H, -OH, -NH2, -NHR19Z, -OR19Z, or -CONHR19Z; each instance of R19z is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and n4Z is 1 or 2.
210. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-209, wherein: at least one radical of an ouPi/v integrin ligand is of the formula:
Figure imgf000273_0001
R19Z is H, -CH2OR20Z, -(CH2)2OR20Z, -CH2NHCOR20Z, or -OR20Z; and
R20z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.
211. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-210, wherein: at least one radical of an ouPi/v integrin ligand is of the formula:
Figure imgf000273_0002
R21Z is H, -CONHR22Z, -CH2OR22Z, -(CH2)2OR22Z, -CH2NHCOR22Z, or -OR22Z;
R22Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and
X1Z is H or halogen.
212. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-211, wherein: at least one radical of an ouPi/v integrin ligand is of the formula:
Figure imgf000273_0003
R21Z is H, -CONHR22Z, -CH2OR22Z, -(CH2)2OR22Z, -CH2NHCOR22Z, or -OR22Z;
R22Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and
X1Z is H or halogen. 213. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-212, wherein at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000274_0001
. 214. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-213, wherein: at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000274_0002
R23Z is H, -CONHR24Z, -CH2OR24Z, -(CH2)2OR24Z, -CH2NHCOR24Z, or -OR24Z; R24Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and n5Z is 0, 1, 2, or 3. 215. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-214, wherein at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000274_0003
. 216. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-215, wherein: at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000275_0001
R25Z is H, –CONHR27Z, –CH2OR27Z, –(CH2)2OR27Z, –CH2NHCOR27Z, or –OR27Z; R26Z is H, optionally substituted alkyl, or optionally substituted cycloalkyl; R27Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and X2Z is optionally substituted CH2 or optionally substituted NH. 217. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-216, wherein: at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000275_0002
R25Z is H, –CONHR27Z, –CH2OR27Z, –(CH2)2OR27Z, –CH2NHCOR27Z, or –OR27Z; R26Z is H, optionally substituted alkyl, or optionally substituted cycloalkyl; and R27Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl. 218. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-217, wherein at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000276_0001
. 219. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-218, wherein: at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000276_0002
or ; R28Z is H, –CH2OR30Z, –(CH2)2OR30Z, –CH2NHCOR30Z, or –OR30Z; R29Z is H, –OH, –NH2, –NHR31Z, or –OR31Z; R30Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; R31Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; n3Z is 1, 2, or 3; each instance of R37Z is halogen or optionally substituted alkyl; and n6Z is 0, 1, 2, 3, or 4. 220. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-219, wherein: at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000277_0001
R28Z is H, –CH2OR30Z, –(CH2)2OR30Z, –CH2NHCOR30Z, or –OR30Z; R29Z is H, –OH, –NH2, –NHR31Z, or –OR31Z; R30Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; R31Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and n3Z is 1, 2, or 3. 221. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-220, wherein at least one α4β1/7 integrin ligand is of the formula:
Figure imgf000277_0002
at least one radical of an α4β1/7 integrin ligand is of the formula:
Figure imgf000277_0003
. 222. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-221, wherein y is 2, 3, 4, 5, or 6; and at least one ligand is a tropomyosin receptor B (TrkB) ligand. 223. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-222, wherein y is 2, 3, 4, 5, or 6; and at least one ligand is a cannabinoid receptor type 1 (CB1) ligand. 224. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-223, wherein y is 2, 3, 4, 5, or 6; and at least one ligand is a N- methyl-D-aspartate (NMDA) ligand. 225. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 67-224, wherein at least one instance of A1, A2, A4, A5, and A6 is a radical of a lipid. 226. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-225, wherein at least one lipid is a fatty acyl, glycerolipid, glycerophospholipid, sphingolipid, saccharolipid, polyketide, sterol lipid, or prenol lipid. 227. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-226, wherein at least one lipid is a fatty acid or conjugate, octadecanoid, eicosanoid, docosanoid, fatty alcohol, fatty aldehyde, fatty ester, fatty amide, fatty nitrile, fatty ether, hydrocarbon, oxygenated hydrocarbon, or fatty acyl glycoside. 228. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-227, wherein at least one lipid is a hydrocarbon. 229. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-228, wherein at least one radical of a lipid is unsubstituted C6- 30 alkyl, C6-30 alkyl substituted with one or more fluoro as valency permits, unsubstituted C6-30 alkenyl, or C6-30 alkenyl substituted with one or more fluoro as valency permits. 230. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-229, 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. 231. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-230, wherein at least one radical of a lipid is unbranched unsubstituted C18-26 alkyl. 232. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-231, wherein at least one radical of a lipid is unbranched unsubstituted C14-18 alkyl. 233. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-232, wherein at least one lipid is a monoradylglycerol, diradylglycerol, triradylglycerol, glycosylmonoradylglycerol, glycosyldiradylglycerol, betaine monoradylglycerol, or betaine diradylglycerol. 234. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-233, wherein 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, glycerophosphonocholine, glycerophosphonoethanolamine, di-glycerol tetraether phospholipid, glycerol-nonitol tetraether phospholipid, oxidized glycerophospholipid, glycerophosphoethanolamine glycan, dihydroxyacetonephosphate, glycerophosphoethanol, glycerophosphothreonine, or cyclic glycerophosphatidic acid. 235. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-234, wherein at least one lipid is a sphingoid base, ceramide, phosphosphingolipid, phosphonosphingolipid, neutral glycosphingolipid, acidic glycosphingolipid, basic glycosphingolipid, amphoteric glycosphingolipid, or arsenosphingolipid. 236. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-235, wherein at least one lipid is a sterol, steroid, secosteroid, bile acid or a derivative thereof, or steroid conjugate. 237. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-236, wherein at least one lipid is cholesterol. 238. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-237, wherein at least one lipid is an isoprenoid, quinone, hydroquinone, polyprenol, or hopanoid. 239. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-238, wherein at least one lipid is an acylaminosugar, acylaminosugar glycan, acyltrehalose, or acyltrehalose glycan. 240. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-239, wherein 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. 241. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 1-240, wherein the oligonucleotide strand, sense oligonucleotide strand, or antisense oligonucleotide strand further comprises one or more modifications independently selected from modified sugars, modified nucleobases, and modified internucleosidic linkers. 242. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of embodiment 241, wherein none of the modifications is a conjugation with a radical of a ligand or lipid. 243. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 241-242, wherein between 20% and 100%, inclusive, of the combined number of the sugars, nucleobases, and internucleosidic linkers of the oligonucleotide strand, sense oligonucleotide strand, or antisense oligonucleotide strand is modified. 244. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 241-243, wherein between 50% and 100%, inclusive, of the sugars of the oligonucleotide strand, sense oligonucleotide strand, or antisense oligonucleotide strand are modified sugars. 245. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 241-244, 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-1-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. 246. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 241-245, wherein at least one instance of the modified sugars is a 2′-fluoro-2′-deoxyribose or 2′-O-methylribose. 247. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 241-246, wherein at least one instance of the modified nucleobases is xanthine, allyaminouracil, 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-carboxycytosine, 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, 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, desthiobiotin-6- aminoallylcytosine, isoguanine, N1-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 (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). 248. The conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of embodiments 241-247, wherein at least one instance of the modified internucleosidic linkers is a phosphorothioate internucleosidic linker, phosphorothiolate internucleosidic linker, or a methylphosphonate internucleosidic linker. 249. A kit comprising: a conjugate of Formula I: (A)y–L–(R1)r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an α4β1/7 integrin ligand; L is a linker; each instance of R1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6; and instructions for using the conjugate in the use of any one of embodiments 1-248. EXAMPLES In order that the embodiments described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the conjugates, pharmaceutical compositions, uses, and methods provided herein and are not to be construed in any way as limiting their scope. In particular, the structures provided herein are sequence agnostic. For efficacy purposes, specific sequences are demonstrated, but the structures may be applied to any oligonucleotide sequence as described above. General Protocol: The following protocol was used for the examples below. The conjugates used in the examples are double-stranded oligonucleotides. The structures RD4342:
Figure imgf000283_0001
RD5338:
Figure imgf000284_0001
strand in Tables 1 and 2. The antisense strand is as described in Tables 1 and 2. Conjugates were administered to BALB/c mice as follows. Female BALB/c mice were obtained from Charles River Laboratories and randomly assigned to each group. All animals were treated in accordance with IACUC protocols. Mice were dosed intravenously (IV) or subcutaneously (SC) at the indicated concentration with siRNA or phosphate buffered saline (PBS) control on Day 1 (n=3/group). All dosing solutions were stored at 4°C until 1 h before time of injection, when they were removed from storage and allowed to reach room temperature. Animals were sacrificed on the study day specified, and tissues were harvested and snap frozen for gene expression analysis. Mouse tissues were homogenized using a Precellys Evolution Homogenizer in Buffer RLT (Qiagen, catalog number: 79216) or QIAzol Lysis Reagent (Qiagen, catalog number: 79306). RNA isolation was performed using the RNeasy 96 Kit (Qiagen, catalog number: 74181) or RNeasy Lipid Tissue Kit (Qiagen, catalog number: 74804). mRNA levels of mouse Sod1 or a skeletal muscle gene (“SkM”), and a control housekeeping gene (Gapdh) were measured using TaqMan RNA-to-CT 1-Step Kit (ThermoFisher Scientific, catalog number: 4392938). Primer- probe sets of Mouse Sod1 and Gapdh were purchased from ThermoFisher Scientific (Mouse Gapdh: Mm99999915_g1, VIC; Mouse Sod1: Mm01344233_g1, FAM). Similarly, primer/probe sets for the SkM Gene were also commercially purchased. qPCR was performed using a QuantStudio 5 Real-Time PCR system. Mouse Sod1 or SkM Gene expression was normalized to the expression of Gapdh, a housekeeping gene. To measure the serum protein levels of the target gene, an Enzyme-Linked Immunosorbent Assay (ELISA) assay was used. Table 1. Chemical Nomenclature
Figure imgf000285_0001
Figure imgf000286_0001
Table 2. Sequence and Chemistry of Unconjugated Parent Compound (Tool siRNA)
Figure imgf000286_0002
Example 1: Effect of cholesterol conjugated siRNA targeting SOD1 delivered by IV administration in BALB/c mice The double-stranded modified compound comprising SEQ ID NOs: 1 and 2 was conjugated with cholesterol on the 3′ end of the sense strand. The resulting conjugate, RD4342, was administered intravenously to BALB/c mice according to the protocol above. Animals were sacrificed on Day 15 or Day 29. Results are presented in Table 3 as percent inhibition of SOD1, relative to vehicle control. Table 3. Average % SOD1 Inhibition
Figure imgf000287_0002
Quad = Quadriceps; Gast = Gastrocnemius; Diap = Diaphragm; HA = Heart Atrium; HV = Heart Ventricle. Example 2: Effect of dual integrin (BA-128) and C16 lipid conjugated siRNA targeting SOD1 delivered by IV administration in BALB/c mice The double stranded modified compound comprising SEQ ID NOs:1 and 2 was conjugated with the C16 lipid radical n-hexadecanyl on the 3’ end of the sense strand and integrin α4β1/7 ligand BA-128
Figure imgf000287_0001
the 5′ end of the sense strand. The resulting conjugate, RD4942, was administered intravenously to BALB/c mice according to the protocol above. Animals were sacrificed on Day 15. Results are presented in Table 4 as percent inhibition of SOD1, relative to vehicle control. Integrin ligand conjugation together with C16 conjugation showed selective delivery to skeletal muscle over liver compared to cholesterol conjugation (e.g., RD4342). Table 4. Average % SOD1 Inhibition Day 15
Figure imgf000287_0003
Quad = Quadriceps; Gast = Gastrocnemius; Diap = Diaphragm; HA = Heart Atrium; HV = Heart Ventricle. Example 3: Effect of integrin (BA-128) conjugated siRNA targeting SOD1 delivered by IV administration in BALB/c mice The double stranded modified compound comprising SEQ ID NOs: 3 and 4 was conjugated with integrin α4β1/7 ligand BA-128 on the 5’ end of the sense strand. The resulting conjugate, RD4941, was administered intravenously to BALB/c mice according to the protocol above. Animals were sacrificed on Day 15. Results are presented in Table 5 as percent inhibition of SOD1, relative to vehicle control. Integrin ligand conjugation showed selective delivery to skeletal muscle over liver compared to cholesterol conjugation (e.g., RD4342). Table 5. Average % SOD1 Inhibition Day 15
Figure imgf000288_0001
Quad = Quadriceps; Gast = Gastrocnemius; Diap = Diaphragm; HA = Heart Atrium; HV = Heart Ventricle. Example 4: Effect of integrin (BA-128) conjugated siRNA targeting SOD1 compared to the effect of dual integrin (BA-128) and C16 lipid conjugated siRNA targeting SOD1 delivered by IV administration in BALB/c mice The conjugates RD4941 and RD4942 described above were administered intravenously to BALB/c mice according to the protocol above. Results are presented in Table 6 as percent inhibition of SOD1, relative to vehicle control. Integrin ligand conjugation alone (e.g., RD4941) demonstrated increased selectivity to skeletal muscle over liver compared to integrin ligand conjugation plus C16 lipid conjugation (e.g., RD4942). Table 6. Average % SOD1 Inhibition Day 29
Figure imgf000288_0002
Quad = Quadriceps; Gast = Gastrocnemius; Diap = Diaphragm; TA = Tibialis Anterior; HA = Heart Atrium; HV = Heart Ventricle. Example 5: Effect of integrin (BA-171) conjugated siRNA targeting SOD1 delivered by IV The double stranded modified compound comprising SEQ ID NOs: 1 and 6 was conjugated with integrin α4β7 ligand BA-171
Figure imgf000289_0001
sense strand. The resulting conjugate, RD5338, was administered intravenously to BALB/c mice according to the protocol above. Animals were sacrificed on Day 15. Results are presented in Table 7 as percent inhibition of SOD1, relative to vehicle control. Table 7. Average % SOD1 Inhibition Day 15
Figure imgf000289_0003
Quad = Quadriceps; Gast = Gastrocnemius; Diap = Diaphragm; TA = Tibialis Anterior; HA = Heart Atrium; HV = Heart Ventricle. Example 6: Effect of an integrin (BA-215) conjugated siRNA targeting SOD1 and an integrin (BA-128) dual conjugated siRNA targeting SOD1 delivered by IV administration in BALB/c mice RD5339 was prepared by conjugating the double stranded modified compound comprising SEQ ID NOs: 1 and 6 with integrin α4β1 ligand BA-215 (
Figure imgf000289_0002
the 5’ end of the sense strand. RD5342 was prepared by conjugating the double stranded modified compound comprising SEQ ID NOs:1 and 5 with integrin α4β1/7 ligand BA-128 on both the 5’ end and the 3’ end of the sense strand. The conjugates RD5339 and RD5342 were administered intravenously to BALB/c mice according to the protocol above. Animals were sacrificed on Day 15. Results are presented in Table 8 as percent inhibition of SOD1, relative to vehicle control. Table 8. Average % SOD1 Inhibition Day 15
Figure imgf000290_0001
Quad = Quadriceps; Gast = Gastrocnemius; Diap = Diaphragm; TA = Tibialis Anterior; HA = Heart Atrium; HV = Heart Ventricle. Example 7: Effect of a dual integrin (BA-128) and C16 lipid conjugated siRNA targeting SOD1 delivered by subcutaneous administration in BALB/c mice RD4942 (parent compound conjugated with C16 lipid conjugated on the 3’ end of the sense strand and integrin α4β1/7 ligand BA-128 on the 5’ end of the sense strand) was administered subcutaneous to BALB/c mice according to the protocol above. Animals were sacrificed on Day 15. Results are presented in Table 9 as percent inhibition of SOD1, relative to vehicle control. Table 9. Average % SOD1 Inhibition Day 15
Figure imgf000290_0002
Quad = Quadriceps; Gast = Gastrocnemius; Diap = Diaphragm; TA = Tibialis Anterior Example 8: Effect of an integrin (BA-128) conjugated siRNA targeting SOD1 delivered by subcutaneous administration in BALB/c mice RD4941 (double stranded modified compound conjugated with integrin α4β1/7 ligand BA-128 conjugated on the 5’ end of the sense strand) was administered subcutaneous to BALB/c mice according to the protocol above. Animals were sacrificed on Day 15. Results are presented in Table 10 as percent inhibition of SOD1, relative to vehicle control. Consistent with data from IV administration of RD4941, SC administration of RD4941 decreased SOD1 across different skeletal muscle regions. Both activity and selectivity of RD4941 are very comparable between Table 10. Average % SOD1 Inhibition Day 15
Figure imgf000291_0001
Quad = Quadriceps; Gast = Gastrocnemius; Diap = Diaphragm; TA = Tibialis Anterior Example 9: Effect of integrin (BA-128) conjugated siRNA targeting SOD1 compared to the effect of dual integrin (BA-128) and C16 lipid conjugated siRNA targeting SOD1 delivered by IV administration in BALB/c mice The conjugated compounds RD4941 and RD4942 described above, were administered intravenously to BALB/c mice according to the protocol above. Animals were sacrificed on Day 15. Results are presented in Table 11 as percent inhibition of SOD1, relative to vehicle control. Integrin ligand conjugation alone (e.g., RD4941) demonstrated increased selectivity to skeletal muscle over liver compared to integrin ligand conjugation plus C16 lipid conjugation (e.g., RD4942). Table 11. Average % SOD1 Inhibition Day 15
Figure imgf000291_0002
Quad = Quadriceps; Gast = Gastrocnemius; Diap = Diaphragm; TA = Tibialis Anterior; HA = Heart Atrium; HV = Heart Ventricle. Example 10: Effect of different integrin ligands (BA-319, BA-325, BA-326, BA-331, BA-333, BA- 340, and BA-357) conjugated siRNAs targeting an mRNA expressed in skeletal muscle (SkM Gene) delivered by IV administration in BALB/c mice In vivo (mouse) study protocol: Conjugates of the present disclosure included double-stranded siRNAs targeting mRNA of a gene preferentially expressed in skeletal muscle (SkM Gene). The conjugates included both a modified sense strand and a modified antisense strand, where the sense strand was conjugated with an integrin α4β1 ligand on the 5’ end and a DCA on the 3’ end. RD6150 was prepared by conjugating the double stranded modified siRNAs targeting mRNA of SkM Gene with an integrin α4β1 ligand BA-319
Figure imgf000292_0001
on the 5’ end of the sense strand and a DCA on the 3’ end of the sense strand. RD6153 was prepared by conjugating the double stranded siRNA targeting mRNA of
Figure imgf000292_0002
SkM Gene with an integrin α4β1 ligand BA-325 [
Figure imgf000292_0003
] on the 5’ end of the sense strand and a DCA on the 3’ end of the sense strand. RD6154 was prepared by conjugating the double stranded siRNA targeting mRNA of
Figure imgf000292_0004
SkM Gene with an integrin α4β1 ligand BA-326 [
Figure imgf000292_0005
] on the 5’ end of the sense strand and a DCA on the 3’ end of the sense strand. RD6156 was prepared by conjugating the double stranded siRNA targeting mRNA of SkM Gene with an integrin α4β1 ligand BA-331
Figure imgf000293_0001
the 5’ end of the sense strand and a DCA on the 3’ end of the sense strand. RD6158 was prepared by conjugating the double stranded siRNA targeting mRNA of
Figure imgf000293_0002
SkM Gene with an integrin α4β1 ligand BA-333 [
Figure imgf000293_0003
] on the 5’ end of the sense strand and a DCA on the 3’ end of the sense strand. RD6503 was prepared by conjugating the double stranded siRNA targeting mRNA of SkM Gene with an integrin α4β1/PanTrk ligand BA-340 [
Figure imgf000293_0004
. RD6521 was prepared by conjugating the parent compound with an integrin α4β1/cannabinoid receptor ligand BA-357 [
Figure imgf000294_0001
. The conjugates RD6150, RD6153, RD6154, RD6156, RD6158, RD6503, and RD6521 were administered intravenously to BALB/c mice according to the protocol above. Animals were sacrificed on Day 15. Results are presented in Tables 12 and 13 as percent inhibition of SkM Gene mRNA, relative to vehicle control, and as percent inhibition of the protein product of the SkM Gene in the serum, relative to pre-dose levels, respectively. Table 12. Average % SkMGene mRNA Inhibition Day 15
Figure imgf000294_0002
Quad = Quadriceps; Gast = Gastrocnemius; Diap = Diaphragm; Mas = Masseter. Table 13. Average % SkM Gene Serum Protein Inhibition Day 8 and 15
Figure imgf000294_0003
Figure imgf000295_0001
Example 11: Effect of different integrin ligands (BA-325 and BA-333) conjugated siRNAs targeting SkM mRNA delivered by IV administration in BALB/c mice Conjugates of the present disclosure included double-stranded siRNAs targeting mRNA of a gene expressed in skeletal muscle (SkM Gene). The conjugates included both a modified sense strand and a modified antisense strand, where the sense strand was conjugated with an integrin α4β1 ligand on the 5’ end and a DCA on the 3’ end. RD6153 was prepared by conjugating the parent compound with an integrin α4β1 ligand BA-325 on the 5’ end of the sense strand and a DCA on the 3’ end of the sense strand. RD6158 was prepared by conjugating the parent compound with an integrin α4β1 ligand BA-333 on the 5’ end of the sense strand and a DCA on the 3’ end of the sense strand. The conjugates RD6153 and RD6158 were administered intravenously to BALB/c mice according to the protocol above. Animals were sacrificed on Day 57. Results are presented in Tables 14 and 15 as percent inhibition of SkM Gene mRNA, relative to vehicle control, and as percent inhibition of the protein product of SkM Gene in serum, relative to pre-dose levels, respectively. Table 14. Average % SkM Gene mRNA Inhibition Day 57
Figure imgf000295_0002
Quad = Quadriceps; Gast = Gastrocnemius; Diap = Diaphragm; Mas = Masseter Table 15. Average % SkM Gene Serum Protein Inhibition Day 8, 15, 22, 29, 36, 43, 50 and 57
Figure imgf000295_0003
Figure imgf000296_0001
inhibition. Example 12: Effect of an integrin ligand (BA-128) conjugated siRNA targeting SkM mRNA delivered by IV administration in BALB/c mice The conjugate of the present disclosure included a double-stranded siRNA targeting mRNA of a gene expressed in skeletal muscle. The conjugate included both a modified sense strand and a modified antisense strand, where the sense strand was conjugated with an integrin α4β1 ligand on the 5’ end and a PEG24 + DCA on the 3’ end. RD6646 was prepared by conjugating the double stranded siRNA targeting mRNA of SkM Gene with an integrin α4β1 ligand BA-128 on the 5’ end of the sense strand and PEG24 and DCA on the 3’ end of the sense strand. The conjugate RD6646 was administered intravenously to BALB/c mice according to the protocol above. Animals were sacrificed on Day 15. Results are presented in Tables 16 and 17 as percent inhibition of SkM Gene mRNA, relative to vehicle control, and as percent inhibition of the protein product of the SkM Gene in serum, relative to pre-dose levels, respectively. Table 16. Average % SkM Gene mRNA Inhibition Day 15
Figure imgf000296_0002
Quad = Quadriceps; Gast = Gastrocnemius; Diap = Diaphragm; Mas = Masseter Table 17. Average % SkM Gene Serum Protein Inhibition Day 8 and 15
Figure imgf000296_0003
Example 13: Effect of different integrin ligand (BA-412, BA-413, and BA-427) conjugated siRNAs targeting SkM Gene delivered by IV administration in BALB/c mice over time Conjugates of the present disclosure included double-stranded siRNAs targeting mRNA of a gene expressed in skeletal muscle. The conjugates included both a modified sense strand and a modified antisense strand, where the sense strand was conjugated with an integrin α4β1 ligand on the 5’ end and a DCA on the 3’ end. RD6685 was prepared by conjugating the double stranded siRNA targeting mRNA of
Figure imgf000297_0001
end of the sense strand and a DCA on the 3’ end of the sense strand. RD6686 was prepared by conjugating the double stranded siRNA targeting mRNA of SkM Gene with an integrin α4β1 ligand BA-413
Figure imgf000297_0002
end of the sense strand and a DCA on the 3’ end of the sense strand. RD6753 was prepared by conjugating the double stranded siRNA targeting mRNA of SkM Gene with an integrin α4β1 ligand BA-427
Figure imgf000297_0003
the 5’ end of the sense strand and a DCA on the 3’ end of the sense strand. The conjugates RD6685, RD6686, and RD6753 were administered intravenously to BALB/c mice according to the protocol above. Animals were sacrificed on Day 29. Results are presented in Tables 18 and 19 as percent inhibition of SkM Gene mRNA, relative to vehicle control, and as percent inhibition of the protein product of the SkM Gene in serum, relative to pre-dose levels, respectively. on Day 29
Figure imgf000298_0002
Quad = Quadriceps; Gast = Gastrocnemius; Diap = Diaphragm; Mas = Masseter Table 19. Average % SkM Serum Protein Inhibition Day 8, 15, 22, and 29
Figure imgf000298_0003
Example 14: Effect of integrin ligand (BA-128, BA-328, BA-330, or BA-331) conjugated siRNAs targeting SOD1 delivered by IV administration in BALB/c mice over time at multiple doses Conjugates of the present invention are double-stranded siRNAs targeting mRNA of the SOD1 gene. The conjugates included both a modified sense strand and a modified antisense strand, where the sense strand was conjugated with an integrin α4β1 ligand on the 5’ end and optionally a PEG5K on the 3’ end. RD5368 was prepared by conjugating the double stranded modified compound comprising SEQ ID NO: 4 and SEQ ID NO: 3 with an integrin α4β1 ligand BA-128 on the 5’ end of the sense strand and a PEG5K on the 3’ end of the sense strand. RD5453 was prepared by conjugating the double stranded modified compound comprising SEQ ID NO: 4 and SEQ ID NO: 3 with an integrin α4β1 ligand BA-128 on the 5’ end of the sense strand. RD5812 was prepared by conjugating the double stranded modified compound comprising SEQ ID NO: 4 and SEQ ID NO: 3 with an integrin α4β1 ligand BA-328 [
Figure imgf000298_0001
] on the 5’ end of the sense strand. RD5813 was prepared by conjugating the double stranded modified compound comprising SEQ ID NO: 4 and SEQ ID NO: 3 with an integrin α4β1 ligand BA-330 [
Figure imgf000299_0001
RD5814 was prepared by conjugating the double stranded modified compound comprising SEQ ID NO: 4 and SEQ ID NO: 3 with an integrin α4β1 ligand BA-331 on the 5’ end of the sense strand. The conjugates were administered intravenously to BALB/c mice according to the protocol above. Animals were sacrificed on Day 15 or 29. Results are presented in Tables 20 and 21 as percent inhibition of SOD1 mRNA, relative to vehicle control. Table 20. Average % SOD1 mRNA Inhibition Day 15
Figure imgf000299_0002
Quad = Quadriceps; Gast = Gastrocnemius; Diap = Diaphragm; TA = Tibialis Anterior; NT= not tested Table 21. Average % SOD1 mRNA Inhibition Day 29
Figure imgf000300_0001
Quad = Quadriceps; Gast = Gastrocnemius; Diap = Diaphragm; TA = Tibialis Anterior Example 15: Effect of an integrin ligand (BA-128) conjugated siRNA targeting SOD1 delivered by IV administration in BALB/c mice over time at multiple doses The conjugate of the present disclosure included a double-stranded siRNA targeting mRNA of the SOD1 gene. The siRNA sequence, however, differed from the previous examples of SOD1 siRNAs. The conjugate included both a modified sense strand and a modified antisense strand, where the sense strand was conjugated with an integrin α4β1 ligand on the 5’ end and a DCA targeting moiety on the 3’ end. RD6112 was prepared by conjugating the double stranded modified siRNA comprising SEQ ID NOs: 1 and 5 with an integrin α4β1 ligand BA-128 on the 5’ and a DCA on the 3’ end of the sense strand. The conjugate RD6112 were administered intravenously to BALB/c mice according to the protocol above. Animals were sacrificed on Day 15 and 29. Results are presented in Tables 22 and 23 as percent inhibition of SOD1 mRNA, relative to vehicle control. Table 22. Average % SOD1 mRNA Inhibition Day 15
Figure imgf000300_0002
Quad = Quadriceps; Gast = Gastrocnemius; Diap = Diaphragm; Mas = Masseter Table 23. Average % SOD1 mRNA Inhibition Day 29
Figure imgf000301_0002
Quad = Quadriceps; Gast = Gastrocnemius; Diap = Diaphragm; Mas = Masseter Example 16. Synthesis Characteristic examples of ligand synthesis for the conjugates tested are shown below. Synthesis of BA-352 (α4β1 and α4β7):
Figure imgf000301_0001
To a stirred solution of (S)-3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3- oxo-2,3-dihydropyridazin-4-yl)phenyl)-2-(3,5-dichloroisonicotinamido)propanoic acid BA-128 (2 g, 3.012 mmol, 1 eq) in MeOH (20 mL) was added Thionyl chloride (0.65 mL, 9 mmol, 3 eq) at 0oC, the mixture was stirred at 600C for 2h, LCMS showed complete conversion of acid to methyl ester, reaction mixture was concentrated, residue was dissolved in DCM, treated with 2 mL Et3N, and concentrated, purified by column chromatography using 0-20% MeOH/DCM, to obtain methyl (S)-3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3- dihydropyridazin-4-yl)phenyl)-2-(3,5-dichloroisonicotinamido)propanoate BA-352 as a white solid (1.98 g, 96%) LCMS m/z = 678 (M+), and NMR are correspond with product.1H NMR (499 MHz, DMSO-d6) δ 9.44 (d, J = 8.1 Hz, 1H), 8.65 (s, 2H), 8.20 (s, 1H), 7.46 – 7.40 (m, 2H), 7.31 – 7.25 (m, 2H), 5.75 (s, 2H), 4.82 (ddd, J = 10.2, 8.1, 4.9 Hz, 1H), 4.37 – 4.31 (m, 2H), 3.71 – 3.61 (m, 8H), 3.59 – 3.54 (m, 2H), 3.54 – 3.47 (m, 8H), 3.36 (d, J = 5.2 Hz, 3H), 3.21 (dd, J = 14.1, 4.8 Hz, 1H), 2.96 (dd, J = 14.1, 10.2 Hz, 1H), 2.08 (s, 1H). Synthesis of BA-328 (α4β1 and α4β7):
Figure imgf000302_0001
(S)-N-(3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3- dihydropyridazin-4-yl)phenyl)-1-((2-(dimethylamino)ethyl)(methyl)amino)-1-oxopropan-2- yl)-3,5-dichloroisonicotinamide To a solution of BA-128 (100 mg, 0.150 mmol, 1eq) in 3mL DMF, was added HATU (86 mg, 0.226 mmol, 1.5 eq) followed by the Amine (34 µL, 0.301 mmol, 2eq) and DIPEA (100 µL, 0.45 mol, 3eq) at the room temperature. After 30 minutes, the reaction went to completion, and LCMS showed M+H. Mixture was extracted with ethyl acetate and water, dried over Na2SO4 filtered and concentrated. Purified by Biotage 5g, 0 to 5% DCM:MeOH 10CV yielded BA-32875 mg (65%) as sticky oil. MS (ESI) m/z = 749.4 [M+H]+.1H NMR (500 MHz, DMSO- d6) δ 9.45 (d, J=10.0 Hz, 1H), 9.40 (d, J=10.0 Hz, 1H), 8.64 (s, 2H), 8.20 (s,1H), 7.40 (m, 4H), 7.28 (m, 4H), 7.28 (d, J = 10Hz, 2H), 5.20 (m, 1H) 4.34 (m, 4H), 3.66-3.64 (m, 6H), 3.57 (m, 2H), 3.52-3.49 (m, 9H), 3.22 (m, 2H), 2.39-2.25 (m, 3H), 2.17 (s, 3H), 2.14 (s, 3H). Synthesis of BA-330 (α4β1 and α4β7):
Figure imgf000303_0001
A mixture of boronic acid 12 (1 g, 5.74 mmol, 1eq), pyridazine chloride (1.2g, 5.74 mmol, 1 eq) and Na2CO3 (1.58g, 11.49 mmol, 2 eq) was dissolved in 3:1 DME/Water (20 mL), the mixture was degassed by applying vacuum followed by backfilling the reaction mixture with argon for 5 min then Pd(PPh3)4 (332 mg, 0.287 mmol, 0.05 eq) was added and repeated the degassing process another 5 min, then the mixture was sealed under argon and stirred for 18 hrs. at 110 oC. Reaction mixture was diluted with ethyl acetate 50 mL, extracted with water 10 mL, aqueous layer was dried on rotavapor resulting compound as sodium salt was purified using C18 column chromatography eluting with 0-100% MeCN/Water containing 0.1% formic acid to afford the product 13 (464 mg, 26%). As a white solid. LCMS m/z = 304 (M++1) and NMR corresponded with product.
Figure imgf000304_0001
To a stirred solution of acid 13 (1.6 g, 5.28 mmol, 1 eq) in MeOH (10 mL) was added Thionyl chloride (1.91 mL, 26.4 mmol, 5 eq) the mixture was stirred at 600C for 2h, LCMS showed complete conversion of acid to methyl ester, reaction mixture was concentrated to obtain HCl salt 14 as a white solid (1.86 g 99%) used as it is for next step. LCMS m/z = 318 (M++1).
Figure imgf000304_0002
To a stirred solution of 3,5-dichloroisonicotinic acid (1.51 g, 7.9 mmol, 1.5 eq), amine 14 (1.86 g, 5.26 mmol, 1 eq) and HATU (2.6 g, 6.85 mmol, 1.3 eq) in DCM (20 mL) was added DIPEA (3.66 mL, 21 mmol, 4 eq) and the mixture was stirred for 12h at RT, reaction mixture was concentrated, the residue was purified by column chromatography using MeOH/Ethyl acetate, 0- 10% as an eluent, pure fractions were combined and concentrated to obtain amide (2.3 g, 88%) as an orange gum. NMR and LCMS m/z 492 (M++1) corresponded with product.
Figure imgf000304_0003
To a solution of ester 15 (2 g, 4 mmol, 1eq) in THF (20 mL) was added sodium hydroxide (326 mg, 8.14 mmol, 2 eq) dissolved in water (2 mL) and the reaction was left to stir at 500C for 3 h. The THF was removed under vacuum resulting residue was diluted with water 2 mL, acidified with 1M HCl, to 5-6 PH, resulting slurry was filtered to get 600 mg product as white HCl salt, filtrate was evaporated, resulting salt was purified by column chromatography using 0-20% MeOH/DCM as an eluent to obtain acid 16, 900 mg as a white solid (total 1.5g 65% ). NMR and LCMS m/z = 477 (M+) corresponded with product
Figure imgf000305_0001
To a stirred solution of acid 16 (0.2 g, 0.419 mmol, 1 eq), and HATU (0.191 g, 0.503 mmol, 1.2 eq) in DCM (5 mL) was added DIPEA (0.22 mL, 1.26 mmol, 3 eq) after stirring the mixture for 10 min at RT, N3-PEG3-amine (0.091 g, 0.419 mmol, 1 eq) in DCM (1 ML) was added and the mixture was stirred for 12h at RT. Reaction mixture was concentrated and the residue was purified by column chromatography using 0-20% MeOH/Ethyl acetate to obtain BA-330 (150 mg, 53%) as a white solid. LCMS m/z 677 (M+) and NMR corresponded with product. LCMS purity >95%. 1H NMR (499 MHz, DMSO-d6) δ 9.23 (d, J = 8.6 Hz, 1H), 8.62 (s, 2H), 8.22 (s, 1H), 8.13 (t, J = 5.6 Hz, 1H), 7.35 – 7.26 (m, 4H), 4.82 (td, J = 9.5, 4.9 Hz, 1H), 3.91 (s, 3H), 3.67 (s, 3H), 3.61 – 3.49 (m, 10H), 3.42 (t, J = 5.8 Hz, 2H), 3.38 (dd, J = 5.6, 4.3 Hz, 2H), 3.26 (td, J = 14.5, 13.6, 5.6 Hz, 2H), 3.07 (dd, J = 14.0, 4.8 Hz, 1H), 2.85 (dd, J = 13.9, 10.1 Hz, 1H), 2.69 (s, 1H). Synthesis of BA-331 (α4β1 and α4β7):
Figure imgf000305_0002
To a stirred solution of acid 16 (0.2 g, 0.419 mmol, 1 eq), and HATU (0.191 g, 0.503 mmol, 1.2 eq) in DCM (5 mL) was added DIPEA (0.22 mL, 1.26 mmol, 3 eq) after stirring the mixture for 10 min at RT, N3-PEG3-methylamine (0.097 g, 0.419 mmol, 1 eq) in DCM (1 ML) was added and the mixture was stirred for 12h at RT. Reaction mixture was concentrated and the residue was purified by column chromatography using 0-20% MeOH/Ethyl acetate to obtain amide BA- 331 (160 mg, 55%) as a white solid. LCMS m/z 691 (M+) and NMR corresponded with product. LCMS purity >95%.1H NMR (499 MHz, DMSO-d6) δ 9.43 – 9.35 (m, 1H), 8.63 (d, J = 9.8 Hz, 2H), 8.22 (d, J = 1.5 Hz, 1H), 7.36 – 7.26 (m, 4H), 5.30 – 5.16 (m, 1H), 4.13 – 3.99 (m, 1H), 3.91 (s 3H) 367 (s 3H) 365 – 343 (m 14H) 336 (m 2H) 306 (dd J = 148 56 Hz 1H), 3.00 – 2 Synthesis of BA-325 (α4β1 and α4β7):
Figure imgf000306_0001
Figure imgf000307_0001
(S)-2-amino-3-(4-(2-methyl-3-oxo-5-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)-2,3- dihydropyridazin-4-yl)phenyl)propanoic acid 17 To a solution of Chloride 1 (4.5 g, 10.6 mmol, 1 eq) in 20.6 mL DME, boronic acid 12 (3.32 g, 15.9 mmol, 1.5 eq) added followed by the 1M Na2CO3 (aq) (20.6 mL, 20.6 mmol, 2 eq) and the reaction mixture was purged with argon for 15 minutes. After 15 minutes, Pd(PPh3)2Cl2 (1.48 g, 2.12 mmol, 0.2 eq) added and purged for an additional 10 minutes. Then the reaction flask was carefully sealed and heated at 150oC overnight. After overnight, LCMS showed 100% conversion with desired product formation M+H. Reaction mixture was diluted with water, ethyl acetate and the aqueous layer was collected and concentrated. Crude amino acid 17 was used without further purification.
Figure imgf000307_0002
methyl (S)-2-amino-3-(4-(2-methyl-3-oxo-5-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)- 2,3-dihydropyridazin-4-yl)phenyl)propanoate 18 To a crude amino acid 17 in 50 mL MeOH, SOCl2 (6.0 mL, 101 mmol, 10 eq) was added and reaction mixture was heated to reflux. After 2 hrs, reaction went to completion, and LCMS showed M+H Reaction mixture was concentrated and diluted back with DCM organic layer ified by Biotage 100 g, 20 micron, DCM:MeOH 0 to 20% 15CV yielded desired product 18, 3.5g (2 step, 2 61%) as sticky oil.
Figure imgf000308_0001
Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(2-methyl-3-oxo-5-((1-phenyl-2,5,8,11- tetraoxatridecan-13-yl)oxy)-2,3-dihydropyridazin-4-yl)phenyl)propanoate 19 To a solution of amine 18 (2.78 g, 4.88 mol, 1eq) in 40 mL DCM, was added Et3N (2 mL, 14.6 mmol, 3 eq) followed by the Boc2O (1.38 g, 6.34 mmol, 1.3 eq) at RT. After 90 minutes, reaction went to completion and LCMS showed M+H. Mixture was quenched with sat NaHCO3, extracted with DCM, combined organic layer was washed with sat NaCl solution, dried over Na2SO4, filtered and concentrated. Purified by Biotage 50g, 20micron, 0 to 5% DCM:MeOH 15CV yielded desired product 19, 2.8g (86%) as clear oil. Preparation of amine 23
Figure imgf000309_0001
Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(5-(2-(2-(2-(2- hydroxyethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4- yl)phenyl)propanoate (20) To a solution of 19 (2.29 g, 3.42 mmol, 1 eq) in 25mL MeOH, was added Pd/C (364 mg, 3.42 mmol, 1 eq) the mixture was stirred under H2 balloon pressure for 2 h. After 2hr, reaction went to completion and LCMS showed M+H. Reaction mixture was filtered through celite, and concentrated to obtain rude alcohol 20 was used without further purification. methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(2-methyl-5-(2-(2-(2-(2-((methyls ulfonyl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-3-oxo-2,3-dihydropyridazin-4- yl)phenyl)propanoate (21) To a crude alcohol 20 in 25 mL DCM, was added Et3N (1.4 mL, 10.2 mmol, 3 eq) followed by the MsCl (0.32 mL, 3.8 mmol, 1.1 eq) at 0 oC , and the reaction mixture was warmed to RT. After 5 minutes, the reaction went to completion. LCMS showed M+H. Reaction was quenched with sat. NaHCO3, extracted with DCM, dried over Na2SO4, filtered and concentrated. Crude mesylate 21 was used without further purification. methyl (S)-3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3- To a crude mesylate (21) in 10 mL DMF, was added NaN3 (1.1 g, 17.2 mmol, 5 eq) and reaction mixture was heated to 90 oC. After 3hrs, reaction went to completion and the LCMS showed M+H. Reaction mixture was diluted with water, extracted with ethyl acetate, combined organic layer was washed with 10% LiCl solution, and dried over Na2SO4 filtered and concentrated. Crude azide (22) was used without further purification. methyl (S)-2-amino-3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo- 2,3-dihydropyridazin-4-yl)phenyl)propanoate (23) To a crude azide (22) in 10 mL DCM, was added 10 mL TFA at the room temperature. After 2hrs, reaction went to completion and the LCMS showed M+H, and the reaction mixture was carefully concentrated. Crude mixture was diluted back with DCM, washed with sat NaHCO3, brine, dried over Na2SO4 filtered and concentrated. Purified by Biotage 50g, 20micron, 0 to 10% DCM:MeOH 8 CV yielded 1.38 g of desired product 23 (4 steps 80%) as a clear oil.
Figure imgf000310_0001
methyl (S)-3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3- dihydropyridazin-4-yl)phenyl)-2-(2-chloronicotinamido)propanoate To a solution of SM (204 mg, 0.404 mmol, 1 eq) in 3mL DCM, was added Et3N (.169mL, 1.2mmol, 3eq) followed by the Acid chloride (85 mg, 0.485 mmol, 1.2 eq) at the room temperature. After 5minutes, reaction went to completion and LCMS showed M+H. Reaction mixture was quenched with sat NaHCO3 solution, extracted with DCM, combined organic layer was dried over Na2SO4 filtered and concentrated. Purified by Biotage 5g, 0 to 8% DCM:MeOH 20CV yielded BA-352175mg (65.2%) as sticky oil. MS (ESI) m/z = 646.2 [M+Na]+.1H NMR (500 MHz, DMSO- d6) δ 9.11 (d, J=5.0 Hz, 1H), 8.46 (m, 1H), 8.20 (s,1H), 7.66 (m, 1H), 7.49- 7.44 (m, 3H), 7.28 (d, J=10.0Hz, 1H), 4.70 (m, 1H) 4.34 (m, 2H), 3.68-3.62 (m, 8H), 3.58 (m, 2H), 3.55-3.51 (m, 8H), 3.36 (m, 3H), 3.17 (m, 1H), 2.95 (m, 1H). Synthesis of BA-326 (α4β1 and α4β7):
Figure imgf000311_0001
(S)-3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3- dihydropyridazin-4-yl)phenyl)-2-(2-chloronicotinamido)propanoic acid To a solution of BA-325 (130 mg, 0.201mmol, 1eq) in 4 mL MeOH, was added 1M NaOH (aq) (0.7m L, 0.704 mmol, 3.5 eq) at the room temperature. After 30 minutes the reaction went to completion, and LCMS showed M+Na. Mixture was acidified with 1M HCl, extracted with DCM, dried over Na2SO4 filtered and concentrated. Purified by Biotage 5g, 20 micron, DCM:MeOH 0 to 20% 10CV yielded BA-32698mg (77%) as sticky solid. MS (ESI) m/z = 652.3 [M+Na]+.1H NMR (500 MHz, DMSO- d6) δ 12.8 (br, 1H), 9.00 (d, J=10.0 Hz, 1H), 8.46 (m, 1H), 8.20 (s,1H), 7.66 (m, 1H), 7.49-7.44 (m, 3H), 7.30 (d, J=10.0Hz, 1H), 4.65 (m, 1H) 4.33 (m, 2H), 3.69-3.61 (m, 5H), 3.58 (m, 2H), 3.55-3.48 (m, 9H), 3.21 (m, 1H), 2.95 (m, 1H). Synthesis of BA-412 (α4β1 and α4β7):
Figure imgf000311_0002
(S)-N-(3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3-2 dihydropyridazin-4-yl)phenyl)-1-((2-methoxyethyl)amino)-1-oxopropan-2-yl)-2- chloronicotinamide 4 To a solution of BA-326 (260 mg, 0.413 mmol, 1eq) in 3mL DMF, was added HATU (235 mg, 0.620 mmol, 1.5 eq) followed by the Amine (80 µL, 0.826 mmol, 2 eq) and DIPEA (215 µL, 1.24 mol, 3 eq) at the room temperature. After 30 minutes, the reaction went to completion, and LCMS showed M+H. Mixture was extracted with ethyl acetate and water, dried over Na2SO4 filtered and concentrated. Purified by Biotage 5g, 0 to 5% DCM:MeOH 10CV yielded BA-412 75mg (69%) as a sticky oil. MS (ESI) m/z = 684.8[M+Na]+.1H NMR (500 MHz, DMSO- d6) δ 8.86 (d, J=10.0 Hz, 1H), 8.44 (m, 1H), 8.20 (s,1H), 8.11 (t, J= 5.0Hz, 1H), 7.64 (m, 1H), 7.47- 7.43 (m, 3H), 7.40 (d, J = 10.0 Hz, 2H), 4.75 (m, 1H) 4.33 (m, 2H), 3.70-3.63 (m, 6H), 3.54 (m, 2H), 3.52-3.49 (m, 9H), 3.38-3.37 (m, 4H), 3.28-3.26 (m, 6H), 3.1 (m, 1H), 2.88(m, 1H).
Figure imgf000312_0001
(S)-N-(1-amino-3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3- dihydropyridazin-4-yl)phenyl)-1-oxopropan-2-yl)-2-chloronicotinamide To a solution of BA-326 (268 mg, 0.426 mmol, 1 eq) in 3mL MeCN, was added Pyridine (21 µL, 0.264 mmol, 0.62 eq) followed by the Boc2O (125 mg, 0.575 mmol, 1.35 eq) and Ammonium bicarbonate (45mg, 0.575mmol, 1.35eq) at the room temperature. After 4hours, the reaction went to completion and LCMS showed M+Na. Mixture was filtered and concentrated. Purified by Biotage 25g, 20micron, 0 to 5% DCM:MeOH 10CV, yielded BA-41398mg (97%) as white solid. MS (ESI) m/z = 651.3[M+Na]+.1H NMR (500 MHz, DMSO- d6) δ 8.81 (d, J=10.0 Hz, 1H), 8.44 ( 1H) 820 ( 1H) 767 ( 1H) 752 ( 1H) 747743 ( 3H) 731 (d J 100 H , 2H), 7.18 (s, 1H), 4.70 (m, 1H) 3.69 (s, 3H), 3.63 (m, 2H), 3.56 (m, 2H), 3.52-3.47 (m, 8H), 3.36 (m, 2H), 3.14 (m, 1H), 2.88(m, 1H). Synthesis of BA-431 (α4β1 and α4β7):
Figure imgf000313_0001
6-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-chloronicotinic acid 26: To a solution of 2-chloro-6-fluoronicotinic acid (2.0 g, 11.4 mmol, 1 eq) and PEG4 azidoalcohol (2.75 g, 12.53 mmol, 1.1 eq) in 50mL THF was added NaH (60%) (1.14 g, 28.5 mmol, 2.5 eq) at 0oC, and the reaction mixture was stirred at 0 oC and slowly warmed to the room temperature. After 3hours at room temperature, the reaction went to completion and LCMS showed M+H. Reaction mixture was acidified with with 1M HCl extracted with ethyl acetate, dried over Na2SO4 filtered and concentrated. Purified by Biotage,50g, 20micron, 0 to 100% Hexane:Ethylacetate 10CV, yielded azide 26, 3.6g (85%) as a white solid.
Figure imgf000314_0001
methyl (S)-2-(6-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-chloronicotinamido)-3-(4- (5-methoxy-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)propanoate BA-431: Acid 26 (296 mg, 0.79 mmol, 1 eq), Amine (336 mg, 0.95 mmol, 1.2 eq), HATU (361 mg, 0.95 mmol, 1.2 eq) in 4mL of DMF was added DIPEA (0.412 mL, 2.37 mmol, 3 eq) added at room temperature. After 3miutes, reaction went to completion, and mixture was diluted with water, extracted with Ethyl acetate, and the combined organic layer was washed with 10% LiCl solution, dried over Na2SO4 filtered and concentrated. Purified by Biotage 25g, 20micron, 0 to 100% Hexane:Ethylaceate 8CV yielded BA-431, 444 mg (83%) as clear oil. MS (ESI) m/z = 696.2 [M+Na]+.1H NMR (500 MHz, DMSO- d6) δ 8.96(d, J = 10.0Hz, 1H), 8.22(s, 1H), 7.59 (d, J=5.0Hz, 1H), 7.36 (d, J=5.0Hz, 2H), 7.29 (d, J=10.0Hz, 2H), 6.89 (d, J=10.0Hz, 1H), 4.69 (m, 1H), 4.38 (m, 2H) 3.9 (s, 3H), 3.74 (m, 2H), 3.69 (s, 3H), 3.68 (s, 3H), 3.58-3.53 (m, 10H), 3.38 (t, J=5.0Hz, 2H), 3.18 (m, 1H).
Figure imgf000314_0002
(S)-2-(6-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-chloronicotinamido)-3-(4-(5- methoxy-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)propanoic acid BA-432: To a solution of BA-431 (328 mg, 0.487 mmol, 1.0 eq) in THF:H2O (2.5mL:0.5mL), was added LiOH 1.0M solution (0.974 mL, 0.974 mmol, 2 eq) at the room temperature. After 30 minutes, reaction went to completion, and mixture was acidified with 1M HCl, extracted with DCM, dried over Na2SO4 filtered and concentrated. Purified by Biotage 10g, 20micron, 0 to 20% M+Na]+. 1H NMR (500 MHz, DMSO- d6) δ 12.86 (br, 1H), 8.78 (s, 1H), 8.21(s, 1H), 7.59 (d, J=5.0Hz, 1H), 7.36 (d, J=5.0Hz, 2H), 7.29 (d, J=10.0Hz, 2H), 6.88 (d, J=10.0Hz, 1H), 4.61 (m, 1H), 4.37 (m, 2H) 3.98 (s, 3H), 3.73 (m, 2H), 3.67 (s, 3H), 3.68 (s, 3H), 3.59-3.54 (m, 10H), 3.20 (m, 1H), 2.89 (m, 1H).
Figure imgf000315_0001
(S)-6-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-chloro-N-(3-(4-(5-methoxy-2-methyl- 3-oxo-2,3-dihydropyridazin-4-yl)phenyl)-1-((2-methoxyethyl)amino)-1-oxopropan-2- yl)nicotinamide BA-433: BA-432 (212 mg, 0.79 mmol, 1.0 eq), Amine (31 µL, 0.48 mmol, 1.5 eq), HATU (144 mg, 0.385 mmol, 1.2 eq) in 4 mL of DMF, was added DIPEA (167 µL, 0.960 mmol, 3eq) added at the room temperature. After 3 minutes the reaction went to completion, and mixture was diluted with water, extracted with ethyl acetate, and the organic layer was washed with 10% LiCl solution, dried over Na2SO4 filtered and concentrated. Purified by Biotage 25 g, 20 micron, 0 to 100% Hexane:Ethylaceate 8CV yielded BA-433182 mg (69%) as a tan oil. MS (ESI) m/z = 739.2 [M+Na]+.1H NMR (500 MHz, DMSO- d6) δ 8.66 (d, J=5.0Hz, 1H), 8.21(s, 1H), 8.10 (t, J=5.0Hz, 1H), 7.60 (d, J=5.0Hz, 1H), 7.35 (d, J=5.0Hz, 2H), 7.29 (d, J=10.0Hz, 2H), 6.89 (d, J=10.0Hz, 1H), 4.71 (m, 1H), 4.37 (m, 2H) 3.74 (s, 3H), 3.65 (m, 2H), 3.60 (s, 3H), 3.68 (s, 3H), 3.39-3.31 (m, 4H), 3.20 (m, 1H), 2.89 (m, 2H). Synthesis of BA-316 (α4β1 and α4β7):
Figure imgf000316_0001
To the vial containing compound 17, was added DIPEA (0.52 mL, 6 eq). The vial was capped, and Ar balloon added followed by addition of ACN (2 mL). Then, the solution of fresh Acid chloride (0.098 g, 1eq) in 1mL of ACN was added via syringe and the reaction stirred for 3h at room temperature. LCMS was taken and the product mass was confirmed (712 m/z). The crude material was purified by column chromatography using 0-5% MeOH/EtOAC. Pure fractions were combined and concentrated to obtain 350 mg of amide 27 as yellow gum LCMS m/z = 712 (M+).
Figure imgf000316_0002
To a stirred solution of acid 27 (350 mg, 0.492 mmol, 1 eq) in MeOH (2mL) was added Thionyl wed complete conversion of acid to methyl ester, reaction mixture was concentrated and purified by column chromatography using 0-100% EtOAc/Hexane as an eluent pure fractions were combined and concentrated to obtain 220 mg of ester 28 as a beige gum. LCMS m/z = 726 (M+)
Figure imgf000317_0001
Benzyl ether 28 (210 mg, 0.665 mmol) was dissolved in MeOH (5 mL) and the reaction mixture was degassed by purging with nitrogen, then 10% Pd/C (30 mg, 10% w/w) was added the reaction mixture was purged with hydrogen gas from a balloon and stirred under slight positive pressure of hydrogen (balloon) at room temperature for 16h. LCMS showed complete deprotection. Reaction mixture was filtered through celite, washed with MeOH and concentrated to obtain alcohol 29 (180 mg 99%) as a beige solid used as it is for next step. LCMS (m/z = 836 M+) corresponded with product.
Figure imgf000317_0002
To a mixture of alcohol 29 (180 mg, 0.283 mmol, 1 eq) and Triethylamine (0.1 ml, 0.73 mmol, 2.6 eq) in dry DCM (2 mL) was added Methanesulfonyl chloride (0.026 mL, 0.34 mmol, 1.2 eq). The solution was stirred for 10 min at RT. LCMS showed formation desired product. Reaction mixture quenched with MeOH, concentrated, to obtain Mesyl product 30 as a brown gum (250 mg, 123%). LCMS (m/z = 714 M+) used as it is for next step.
Figure imgf000317_0003
Mixture of Mesyl derivative 30 (200 mg, 0.280 mmol, 1 eq), and Sodium azide (91 mg, 1.4 mmol, 5 eq) in dry DMF (1 mL) was stirred for 3 h at 60 oC. The reaction was cooled to room x50 mL), dried over Na2SO4, and evaporated. The residue was purified by silica gel chromatography, eluting with 0-100% Ethyl acetate/Hexane to afford azide BA-316 (140 mg, 75%) as a clear gum, NMR and LCMS m/z 661 (M+) are consistent with product.95% HPLC purity.1H NMR (499 MHz, DMSO-d6) δ 9.07 (d, J = 7.9 Hz, 1H), 8.20 (s, 1H), 7.53 (dd, J = 8.9, 4.9 Hz, 1H), 7.48 – 7.42 (m, 2H), 7.38 – 7.32 (m, 1H), 7.32 – 7.26 (m, 2H), 7.08 (dd, J = 8.3, 3.1 Hz, 1H), 5.76 (s, 1H), 4.68 (ddd, J = 10.0, 7.9, 5.3 Hz, 1H), 4.35 – 4.30 (m, 2H), 3.68 (s, 3H), 3.66 (s, 3H), 3.65 – 3.58 (m, 2H), 3.58 – 3.54 (m, 2H), 3.53 – 3.45 (m, 8H), 3.36 (dd, J = 5.6, 4.4 Hz, 3H), 3.18 (dd, J = 14.0, 5.3 Hz, 1H), 3.02 (dd, J = 14.0, 9.9 Hz, 1H). Synthesis of BA-319:
Figure imgf000318_0001
methyl (S)-3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3- dihydropyridazin-4-yl)phenyl)-2-(1-methyl-1H-pyrrole-2-carboxamido)propanoate To a solution of SM (152 mg, 0.301mmol, 1eq) in 5mL DMF, was added HATU (149 mg, 0.391 mmol, 1.3 eq) followed by the acid (37.6 mg, 0.301 mmol, 1 eq) and DIPEA (156 µL, 0.905 mol, 3 eq) at the room temperature. After 5 minutes, the reaction went to completion, and LCMS showed M+H. Mixture was extracted with Ethyl acetate and water, dried over Na2SO4, filtered and concentrated. Purified by Biotage 5g, 0 to 5% DCM:MeOH 10CV yielded BA-319143 mg (77%) as sticky oil. MS (ESI) m/z = 612.2 [M+H]+.1H NMR (500 MHz, DMSO- d6) δ 8.31 (d, J=5.0Hz, 1H), 8.18(s, 1H), 7.42 (d, J=10.0Hz, 2H), 7.28 (d, J=10.0Hz, 2H), 6.88 (m, 1H), 6.01 (m, 1H), 4.59 (m, 1H) 4.3 (m, 2H), 3.75 (s, 3H), 3.68 (m, 6H), 3.60 (m, 2H), 3.57 (m, 2H), 3.50 (m, 3H), 3.45 (m, 3H), 2.89 (s, 3H). Synthesis of BA-322 (α4β1 and α4β7):
Figure imgf000319_0001
(S)-3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3- dihydropyridazin-4-yl)phenyl)-2-(2,6-dichlorobenzamido)propanoic acid To a solution of BA-321 (252 mg, 0.372 mmol, 1 eq) in 5mL MeOH, was added 1M NaOH (1.45 mL, 1.45 mmol, 4 eq) at room temperature. After 30 minutes, reaction went to completion and mixture was acidified with 1M HCl, extracted with DCM, dried over Na2SO4 filtered and concentrated. Purified by Biotage 25g, 20 micron, 0 to 8% DCM:MeOH, 10CV yielded desired BA-322186 mg (75%) as sticky waxy solid. MS (ESI) m/z = 685.3 [M+Na]+.1H NMR (500 MHz, DMSO- d6) δ 12.79 (br, 1H), 9.10 (d, J=5.0 Hz, 1H), 8.20 (s, 1H), 7.44-7.39 (m, 5H), 7.30 (d, J=10.0Hz, 1H), 4.72 (m, 1H) 4.34 (m, 2H), 3.66-3.64 (m, 5H), 3.58 (m, 2H), 3.57-3.51 (m, 8H), 3.36 (m, 3H), 3.17 (m, 1H), 2.95 (m, 1H). Synthesis of BA-456 (Ligand at internal position):
Figure imgf000320_0001
In a 2L pressure tank reactor, to a stirred solution of 1-[(2R,3R,4S,5R)-5-[({[bis(4- methoxyphenyl)]phenylmethyl}oxy)methyl]-3,4-dihydroxytetrahydro-2-furyl]-1,2,3,4- tetrahydropyrimidine-2,4-dione (170 g, 311.025 mmol), dibutyl(oxo)-λ4-stannane (85.17 g, 342.127 mmol), tetrabutylammonium iodide (57.44 g, 155.512 mmol) in ACN (700 rt. The resulting mixture was stirred for 2 hr at 100℃ at N2 atmosphere. LCMS: ~68% P1+P2, 23% SM, ~6% over-reacted BPs. The reaction was quenched by the addition of saturated NaHCO3 solution. The reaction mixture was filtered through diatomite. The filtrate was extracted with EA. The combined organic layers were washed with saturated NaHCO3 solution, water and brine, dried by Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel(660g) column chromatography, eluted with 0.5% TEA in DCM:EA (B%: 0~100%) to afford 1-[(2R,3R,4R,5R)-5-[({[bis(4- methoxyphenyl)]phenylmethyl}oxy)methyl]-4-hydroxy-3-(prop-2-ynyloxy)tetrahydro-2-furyl]- 1,2,3,4-tetrahydropyrimidine-2,4-dione 31 (43 g, 73.257 mmol, 23.55%) as an off- white solid. MS ESI m/z = 585.2 [M++H].1H NMR (300 MHz, DMSO- d6) δ 11.41 (d, J = 1.9 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.45 – 7.19 (m, 9H), 6.96 – 6.85 (m, 4H), 5.86 (d, J = 4.3 Hz, 1H), 5.75 (s, 1H), 5.38 – 5.25 (m, 2H), 4.44 – 4.28 (m, 2H), 4.32 – 4.23 (m, 1H), 4.19 (t, J = 4.8 Hz, 1H), 4.10 – 3.94 (m, 2H), 3.74 (s, 6H), 3.50 (t, J = 2.4 Hz, 1H), 3.36 – 3.17 (m, 2H), 1.99 (s, 1H), 1.17 (t, J = 7.1 Hz, 1H) and 1-[(2R,3R,4S,5R)-5-[({[bis(4- methoxyphenyl)]phenylmethyl}oxy)methyl]-3-hydroxy-4-(prop-2-ynyloxy)tetrahydro-2-furyl]- 1,2,3,4-tetrahydropyrimidine-2,4-dione 31-2 (35 g, 59.867 mmol, 19.25%) as a Light yellow solid. MS ESI m/z = 585.2 [M++H].1H NMR (300 MHz, DMSO- d6) δ 11.38 (s, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.45 – 7.19 (m, 9H), 6.92 (d, J = 8.5 Hz, 4H), 5.74 (d, 1H), 5.65 (d, J = 5.6 Hz, 1H), 5.29 (d, J = 8.0 Hz, 1H), 4.43 – 4.20 (m, 4H), 4.12 – 3.95 (m, 1H),3.75 (s, 6H), 3.53 – 3.46 (m, 1H), 3.37 – 3.20 (m, 2H).
Figure imgf000321_0001
N-((S)-3-(2-(2-(2-(2-(2-(4-((((2R,3R,4R,5R)-5-((bis(4- -yl)-4- hydroxytetrahydrofuran-3-yl)oxy)methyl)-1H-1,2,3-triazol-1- yl)ethoxy)ethoxy)ethoxy)ethoxy)-4-(2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)-1- ((2-methoxyethyl)amino)-1-oxopropan-2-yl)-3,5-dichloroisonicotinamide 32: To a solution of Alkyne 31 (2 g, 3.421 mmol, 1 eq) and Azide BA-333 (2.468 g, 3.421 mmol, 1eq) in 25 mL THF, was added CuSO4.5H2O (427 mg, 1.71 mmol, 0.5 eq in 2 mL Water) followed by the Sodium Ascorbate (541 mg, 2.74 mmol, 0.8 eq in 2 mL of Water) at RT. After 35 minutes, the reaction went to completion and LCMS showed M++H. Reaction mixture was filtered through celite and concentrated. Purified by Biotage 200 g, 20 micron, 0 to 20% 10 CV yielded desired product 32, 3.6 g (80.5%) as a white solid.
Figure imgf000322_0001
(2R,3R,4R,5R)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-((1-(2-(2-(2-(2-(2-((S)- 2-(3,5-dichloroisonicotinamido)-3-((2-methoxyethyl)amino)-3-oxopropyl)-5-(2-methyl-3- oxo-2,3-dihydropyridazin-4-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4- yl)methoxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl (2- cyanoethyl) diisopropylphosphoramidite BA 456: To a solution of alcohol 32 (3.39 g, 2.59 mmol, 1eq) in 30 mL DCM was added DIPEA (2.7 mL, 6.49 mmol, 6eq) followed by the CE-DIP-Cl (1.5 mL, 6.59 mmol, 2.5 eq) at RT. After 30 minutes, the reaction went to completion, and quenched with sat NaHCO3, extracted with DCM, combined organic layers were washed with brine dried over Na2SO4 filtered and concentrated. Purified by Biotage 100g, 20micron, 0 to 20% Ethyl acetate:Methanol both containing 1% Et3N as an additive 10 CV, yielded desired product BA-456, 2.98 g (76.3%) as light yellow solid. MS ESI m/z = 1527.8 [M++Na].1H NMR (500 MHz, DMSO- d6) δ 11.5 (s, 1H), 9.2 (d, J =10Hz, 1H), 8.6 (s, 2H), 8.18 (s, 1H), 8.1 (m, 1H), 7.4-7.2 (m, 13H), 6.9 (m, 4H), 5.85 (t, 5Hz, 1H), 4.85 (m, 1H), 4.7 (m, 2H), 4.4 (m, 3H), 4.3 (m, 3H), 4.2 (m, 2H), 3.78-3.76 (m, 9H), 3.5 (m, 10H), 2.9 (dd, 10Hz, 5Hz, 1H), 2.72 (m, 1H), 2.6 (m, 1H), 1.1 (m, 9H).31P (DMSO-d6, 202 MHz). δ 149.70, 149.24. Synthesis of BA-458:
Figure imgf000324_0001
Figure imgf000325_0001
(S)-N-(3-(4-(5-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3- dihydropyridazin-4-yl)phenyl)-1-((2-methoxyethyl)amino)-1-oxopropan-2-yl)-3,5- dichloroisonicotinamide 33: To a solution of Azide BA-333 (3.07 g, 4.3 mmol, 1eq) in 20 mL MeOH, was added Pd/C (307 mg, 10% by weight). The reaction mixture was stirred under H2 gas balloon for 1h. The reaction went to completion, mixture was filtered through celite and concentrated. Purified by reverse phase C-18, 0 to 100% Water/Acetonitrile both containing 0.1% formic acid as an additive for 15 minutes yielded amine 33, 2.3 g (79.5%) as tan oil (LCMS m/z = 718 [M++Na]. Synthesis of Acid 34:
Figure imgf000326_0001
To a stirred suspension of DMP (11.36 g, 26.786 mmol, 1.5 eq.) in EtOAc (200 mL) was added compound 37 (10 g, 17.857 mmol, 1 eq.). The mixture was stirred at room temperature for 12 h. Reaction mixture was filtered, washed with EtOAc (100 mL). Filtrate was washed with aq. saturated NaHCO3 solution (2x200 mL), dried over Na2SO4, concentrated to dryness. The crude product was purified by column chromatography using 0-100% EtOAc/Hexane as an eluent to obtain ketone 38 (5.2 g, 52%) as a white foam. NMR and LCMS corresponded with product.
Figure imgf000326_0002
A mixture of ketone 38 (511 g 9161 mmol 1 eq) and (ethoxycarbonylmethylene) d to reflux for 2 h. After cooling down to room temperature, the resulting mixture was concentrated and purified by silica gel column (EtOAc/hexane 0-100%) to afford the olefin 39 (5.24 g, 91%) as a white solid. NMR and LCMS corresponded with product.
Figure imgf000327_0001
To a stirred solution of DMT ether 39 (4.55 g, 7.245 mmol, 1.00 eq.) in DCM (50 mL) was added TFA (2.77 mL, 36.22 mmol, 5 eq.). The reaction mixture was stirred at RT for 5 h. LCMS showed complete deprotection. Reaction mixture was quenched with NaHCO3 (50 mL), Extracted with DCM (2X200 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using 0-100 EtOAc/Hexane as an eluent, pure fractions were combined and concentrated to obtain alcohol 40 (1.84 g 77%) as a white solid. Product confirmed by NMR and LCMS m/z 327 [M++H].
Figure imgf000327_0002
Olefin 40 (1.84 g, 5.644 mmol) was dissolved in MeOH/EtOAc (1:1) (20 mL) and the reaction mixture was degassed by purging with nitrogen, then 10% Pd/C (368 mg, 20% w/w) was added the reaction mixture was purged with hydrogen gas from a balloon and stirred under slight positive pressure of hydrogen (balloon) at room temperature for 2h. LCMS showed complete reduction. Reaction mixture was filtered through celite and concentrated to obtain desired product 41 (1.8 mg 97%) as a white solid. Used as it is for the next step. NMR and LCMS m/z = 350 [M++Na] corresponded with product.
Figure imgf000327_0003
To a stirred solution of alcohol 41 (1.8 g, 5.488 mmol, 1 eq) in pyridine (10 ml.) was added DMT-Cl (2.22 g, 6.585 mmol 1.2 eq), the reaction mixture was stirred at room temperature for 12h. Reaction mixture was diluted with Ethyl acetate 100 ml washed with water 2x100 mL, brine solution 100 mL. Organic layer was concentrated, the crude product was purified by flash chromatography using 0-100% EtOAc/Hexane, pure fractions were combined and concentrated to obtain DMT ether 42 (3.24 g 93%) as a yellow solid. NMR and LCMS m/z = 631 [M++1] corresponded with the product.
Figure imgf000328_0001
NaOH (606 mg, 15.159 mmol, 5-eq) was added to a solution of ester 42 (1.91 g, 3.032 mmol, 1 eq) in 90% ethanol (20 mL) and the resulting mixture was stirred for 5h at RT. LCMS showed complete hydrolysis, ethanol was evaporated the residue was diluted with water 10 mL, acidified by the careful addition of a 2N aqueous HCl solution until the pH is 5-6. resulting precipitate was filtered and dried under high vacuum to obtain acid 34 (1.79 g, 98%) as a white solid. NMR and LCMS m/z = 602 [M+] corresponded with product.
Figure imgf000329_0001
3,5-dichloro-N-((S)-3-(4-(5-((1-((2S,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)- 2-(hydroxymethyl)-4-methoxytetrahydrofuran-3-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan- 14-yl)oxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)-1-((2-methoxyethyl)amino)-1- oxopropan-2-yl)isonicotinamide 36: To a solution of 3’-mU-Acid 34 (1.92 g, 3.18 mmol, 1eq) and Amine 33 (2.24 g, 3.22 mmol, 1.05 eq) in 20mL DMF, was added HATU (1.81 g, 4.77 mol, 1.5 eq) followed by the DIPEA (1.8ml, 9.54 mmol, 3eq) at RT. After 30 minutes, the reaction mixture was quenched with NaHCO3 solution, extracted with DCM, dried over Na2SO4 filtered and concentrated to obtain compound 35. To a stirred crude mixture of 35 in 15mL DCM, was added TFA (15 mL) at room ted. The crude mixture was diluted with DCM, washed with sat NaHCO3, brine, organic layer was dried over Na2SO4 filtered and concentrated. Purified by Biotage, 100g, 20 micron 0 to 10% DCM:MeOH 10CV yielded 935 mg of compound 36 (2 step 36%) as a white solid. LCMS m/z = 978 [M++H].
Figure imgf000330_0001
2-cyanoethyl (((2S,3R,4R,5R)-3-(14-((5-(4-((S)-2-(3,5-dichloroisonicotinamido)-3-((2- methoxyethyl)amino)-3-oxopropyl)phenyl)-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)oxy)- 2-oxo-6,9,12-trioxa-3-azatetradecyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4- methoxytetrahydrofuran-2-yl)methyl) diisopropylphosphoramidite BA-458: To a solution of alcohol 36 (800 mg, 0.82 mmol, 1 eq) in 10 mL DCM, was added DIPEA (0.43 mL, 2.46 mmol, 3 eq) followed by the CE-DIP-Cl (0.38 mL, 1.64 mmol, 2 eq) at RT. The mixture was stirred for 1hr at RT, after completion of the reaction the mixture was quenched with sat NaHCO3, extracted with DCM, combined organic layer was washed with brine, dried over Na2SO4 filtered and concentrated. Purified by Biotage 25g, 20 micron column, 0 to 10% Ethyl Acetate:Methanol (both containing 1% Et3N as an additive) to obtain product BA-458, 754 mg, 80% as a white solid. MS ESI m/z = 1201.7 [M++Na].
Figure imgf000330_0002
NMR (500 MHz, DMSO-d6) δ 11.5 (s,1H), 9.2 (d, J = 10Hz, 1H), 8.6 (s, 2H), 8.2 (s, 1H), 8.1 (t, J = 10Hz, 1H), 7.9 (m, 2H), 7.8 (d, J = 10Hz, 1H), 7.4 (d, J = 5Hz, 2H), 7.2 (d, J = 10Hz, 1H), 5.8(d, J = 10Hz, 1H), 5.6 (m, 2H) 4.85 (m,1H), 4.8 (m, 1H), 4.3 (t, J = 5Hz, 1H), 4.2 (m, 2H), 3.78-3.76 (m, 9H), 3.5 (m, 10H), 2.9 (dd, 10Hz, 5Hz, 1H), 2.72 (m, 1H), 2.6 (m, 1H), 1.1 (m,9H).31P (DMSO-d6, 202 MHz). δ 148.51, 148.35. INCORPORATION BY REFERENCE The present application refers to various issued patent, published patent applications, scientific journal articles, and other publications, all of which are incorporated herein by reference. The details of one or more embodiments of the present disclosure are set forth herein. Other features, objects, and advantages of the present disclosure will be apparent from the Detailed Description, the Examples, and the Claims. EQUIVALENTS AND SCOPE In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the present disclosure, or aspects of the present disclosure, is/are referred to as comprising particular elements and/or features, certain embodiments of the present disclosure or aspects of the present disclosure consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore unless otherwise indicated or otherwise evident from the context and understanding cific value or sub-range within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the present disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

Claims

CLAIMS What is claimed is: 1. A method of treating a muscle disease in a subject in need thereof comprising administering to the subject an effective amount of a conjugate of Formula I: (A)y–L–(R1)r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an α4β1/7 integrin ligand; L is a linker; each instance of R1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6. 2. Use of a conjugate of Formula I: (A)y–L–(R1)r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an α4β1/7 integrin ligand; L is a linker; each instance of R1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6; for the manufacture of a medicament for treating a muscle disease in a subject in need thereof. 3. A conjugate of Formula I: (A)y–L–(R1)r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid provided that at least L is a linker; each instance of R1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6; for use in treating a muscle disease in a subject in need thereof. 4. A method of preventing a muscle disease in a subject in need thereof comprising administering to the subject an effective amount of a conjugate of Formula I: (A)y–L–(R1)r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an α4β1/7 integrin ligand; L is a linker; each instance of R1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6. 5. Use of a conjugate of Formula I: (A)y–L–(R1)r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an α4β1/7 integrin ligand; L is a linker; each instance of R1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6; for the manufacture of a medicament for preventing a muscle disease in a subject in need thereof. 6. A conjugate of Formula I: (A)y–L–(R1)r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1 2 3 4 5 or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an α4β1/7 integrin ligand; L is a linker; each instance of R1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6; for use in preventing a muscle disease in a subject in need thereof. 7. A method of diagnosing a muscle disease in a subject in need thereof comprising administering to the subject an effective amount of a conjugate of Formula I: (A)y–L–(R1)r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an α4β1/7 integrin ligand; L is a linker; each instance of R1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6. 8. Use of a conjugate of Formula I: (A)y–L–(R1)r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an α4β1/7 integrin ligand; L is a linker; each instance of R1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6; for the manufacture of a medicament for diagnosing a muscle disease in a subject in need thereof. 9. A conjugate of Formula I: (A)y–L–(R1)r (I) y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an α4β1/7 integrin ligand; L is a linker; each instance of R1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6; for use in diagnosing a muscle disease in a subject in need thereof. 10. A method of delivering a pharmaceutical agent to a muscle of a subject comprising administering to the subject a conjugate of Formula I: (A)y–L–(R1)r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an α4β1/7 integrin ligand; L is a linker; each instance of R1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6. 11. Use of a conjugate of Formula I: (A)y–L–(R1)r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an α4β1/7 integrin ligand; L is a linker; each instance of R1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6; for the manufacture of a medicament for delivering the pharmaceutical agent to a muscle of a subject. 12. A conjugate of Formula I: (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an α4β1/7 integrin ligand; L is a linker; each instance of R1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6; for use in delivering the pharmaceutical agent to a muscle of a subject. 13. The method of any one of claims 1, 4, 7, and 10, the use of any one of claims 2, 5, 8, and 11, and the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of claims 3, 6, 9, and 12, wherein at least one instance of L is substituted or unsubstituted, C1-100 alkylene, substituted or unsubstituted, C2-100 alkenylene, substituted or unsubstituted, C2-100 alkynylene, substituted or unsubstituted, C1-100 heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, or substituted or unsubstituted, C2-100 heteroalkynylene; optionally wherein one or more backbone atoms of the C1-100 alkylene, C2-100 alkenylene, C2-100 alkynylene, C1-100 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. 14. The method of any one of claims 1, 4, 7, 10, and 13, the use of any one of claims 2, 5, 8, 11, and 13, and the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of claims 3, 6, 9, and 12-13, wherein at least one pharmaceutical agent is an oligonucleotide. 15. The method of any one of claims 1, 4, 7, and 10, the use of any one of claims 2, 5, 8, and 11, and the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of claims 3, 6, 9, and 12, wherein the conjugate is of Formula I-A: , (I-A) or a pharmaceutically acceptable salt or prodrug thereof, wherein: is a radical of an oligonucleotide strand; s1 instances of the nucleobase-sugar moieties at internal positions of
Figure imgf000338_0001
are independently replaced with a moiety of Formula A:
Figure imgf000338_0002
(A); s1 is 0, 1, 2, 3, 4, 5, or 6; when s1 is 1, 2, 3, 4, 5, or 6: each instance of N1 is independently a radical of a nucleobase or a bond; each instance of t1 is independently 1, 2, or 3; each instance of y1 and y2 is independently 0, 1, 2, 3, 4, 5, or 6; provided that at least one instance of y1 and y2 is 1, 2, 3, 4, 5, or 6; each instance of A1 and A2, when present, is independently a radical of a ligand or lipid; when y1 of an instance of
Figure imgf000338_0003
is 0, L1 thereof is hydrogen, halogen, 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, –CN, –ORb, –SCN, –SRb,
Figure imgf000338_0004
–OS(=O)Rb, –OS(=O)ORb, –OS(=O)SRb, –OS(=O)N(Rb)2, –OS(=O)2Rb, –OS(=O)2ORb, –OS(=O)2SRb, –OS(=O)2N(Rb)2, –ON(Rb)2, –SC(=O)Rb, –SC(=O)ORb, –SC(=O)SRb, –SC(=O)N(Rb)2, –NRbC(=O)Rb, –NRbC(=O)ORb, –NRbC(=O)SRb, –NRbC(=O)N(Rb)2, NRbS( O)Rb NRbS( O)ORb NRbS( O)SRb NRbS( O)N(Rb) NRbS( O)2Rb, –Si(Rb)(ORb)2, –Si(ORb)3, –OSi(Rb)3, –OSi(Rb)2ORb, –OSi(Rb)(ORb)2, or –OSi(ORb)3; or when y1 of an instance of
Figure imgf000339_0001
is 1, 2, 3, 4, 5, or 6, L1 thereof is a linker; each instance of Rb is independently hydrogen, 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, 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 Rb attached to the same intervening atom are joined together with the intervening atom to form an substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring; when y2 of an instance
Figure imgf000339_0002
2 thereof is –OH, –ORc, –SH, – SRc, –NH2, –NHRc, –N(Rc)2, halogen, –CN, or –N3; or when y2 of an instance of
Figure imgf000339_0003
2 thereof is a linker; and each instance of Rc is independently 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; v1 instances of the internucleosidic linkers of are independently replaced
Figure imgf000339_0004
v1 is 0, 1, 2, 3, 4, 5, or 6; each instance of LA and L4, when present, is independently a linker; each instance of y4, when present, is independently 1, 2, 3, 4, 5, or 6; each instance of A4, when present, is independently a radical of a ligand or lipid; each instance of y5 and y6 is independently 0, 1, 2, 3, 4, 5, or 6; h 5 i 0 L5 i h d b tit t d b tit t d C lk l n when y6 is 0, L6 is hydrogen, substituted or unsubstituted, C1-6 alkyl, or an oxygen protecting group; or when y6 is 1, 2, 3, 4, 5, or 6, L6 is a linker; and each instance of A5 and A6, when present, is independently a radical of a ligand or lipid; provided that at least one instance of y1, y2, y4, y5, and y6 is 1, 2, 3, 4, 5, or 6; that the sum of y1, y2, y4, y5, and y6 is not greater than 6; and that at least one instance of A1, A2, A4, A5, and A6 is a radical of an α4β1/7 integrin ligand. 16. The method, the use, or the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of claim 15, wherein the conjugate is of the formula:
Figure imgf000340_0001
(I-A-1), (I-A-2),
Figure imgf000340_0005
(I-A-3),
Figure imgf000340_0002
(I-A-5),
Figure imgf000340_0003
Figure imgf000340_0004
Figure imgf000341_0001
(I-A-7),
Figure imgf000341_0002
(I-A-8), or
Figure imgf000341_0003
(I-A-9). 17. The method, the use, or the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of claim 15, wherein the conjugate is of the formula: (I-A-10), (I-A-11),
Figure imgf000341_0004
(I-A-12),
Figure imgf000341_0005
(I-A-13),
Figure imgf000341_0006
Figure imgf000341_0007
(I-A-14), or
Figure imgf000342_0001
(I-A-15). 18. The method, the use, or the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of claim 15, wherein the conjugate is of the formula: (I-A-16), (I-A-17), (I-A-18), or (I-A-19). 19. The method of any one of claims 1, 4, 7, 10, and 13-18, the use of any one of claims 2, 5, 8, 11, and 13-18, and the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of claims 3, 6, 9, and 12-18, wherein: at least one α4β1/7 integrin ligand is of the formula:
Figure imgf000342_0002
; each instance of R1Z is independently optionally substituted heteroaryl or optionally substituted phenyl; each instance of R33Z is independently –O(optionally substituted alkyl), –OH, –NH2, – col), – N(optionally substituted alkyl)2, or –N(optionally substituted alkyl)(optionally substituted polyethylene glycol); each instance of R34Z is of the formula:
Figure imgf000343_0001
each instance of R2Z is independently hydrogen, optionally substituted polyethylene glycol, optionally substituted heteroalkyl, or optionally substituted heteroaryl; and each instance of X4Z is N or C(R35Z); and each instance of R35Z is independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted alkoxy. 20. The method of any one of claims 1, 4, 7, 10, and 13-19, the use of any one of claims 2, 5, 8, 11, and 13-19, and the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of claims 3, 6, 9, and 12-19, wherein at least one lipid is a hydrocarbon. 21. A kit comprising: a conjugate of Formula I: (A)y–L–(R1)r (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein: y is 1, 2, 3, 4, 5, or 6; each instance of A is independently a radical of a ligand or lipid, provided that at least one ligand is an α4β1/7 integrin ligand; L is a linker; each instance of R1 is independently a radical of a pharmaceutical agent; and r is 1, 2, 3, 4, 5, or 6; and instructions for using the conjugate in the method of any one of claims 1, 4, 7, 10, and 13- 20, the use of any one of claims 2, 5, 8, 11, and 13-20, and the conjugate, or a pharmaceutically acceptable salt or prodrug thereof, for use of any one of claims 3, 6, 9, and 12-20.
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WO2023196342A1 (en) * 2022-04-04 2023-10-12 Adarx Pharmaceuticals, Inc. α4β1/7 INTEGRIN LIGAND CONJUGATED COMPOUNDS AND USES THEREOF

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