SOD1-modulating oligonucleotides for treating central nervous system diseases

Abstract

The present disclosure provides oligonucleotides, pharmaceutical compositions, kits, and methods of using the oligonucleotide. The oligonucleotides comprise a central nervous system (CNS) ligand. A strand of the oligonucleotides may be a therapeutic or prophylactic agent. The oligonucleotides may be able to deliver the therapeutic or prophylactic agent to a subject. The oligonucleotides may be useful in modulate (e.g., inhibiting) the expression or activity of superoxide dismutase 1 (SOD1) and in treating or preventing diseases, e.g., central nervous system (CNS) diseases, in the subject.

Description

[0001] SOD1-MODULATING OLIGONUCLEOTIDES FOR TREATING CENTRAL NERVOUS SYSTEM DISEASES

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U. S. C. § 119(e) to U. S.

[0003] Provisional Patent Application No. 63 / 723,269, filed November 21, 2024. The disclosure of the prior application is considered part of and is incorporated by reference in its entirety in the disclosure of this application.

[0004] REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0005] The contents of the electronic sequence listing (A127870039WO00-SEQ-WWZ.xml; Size: 835,000 bytes; and Date of Creation: November 19, 2025) are incorporated herein by reference in their entirety.

[0006] SUMMARY OF THE PRESENT DISCLOSURE

[0007] The present disclosure provides compounds, compositions, and methods for modulating the expression or activity of superoxide dismutase 1 (SOD1). In certain embodiments, the compounds, compositions, and methods can be used to reduce the expression of SOD1 mRNA in a cell or animal. In certain embodiments, the compounds, compositions, and methods can be used to reduce the amount of SOD1 protein in a cell or animal.

[0008] In certain embodiments, the animal has a CNS related disease, disorder or condition. In certain embodiments, the disease, disorder or condition is a neurodegenerative disease, including amyotrophic lateral sclerosis (ALS) or a symptom thereof such as loss of motor function or neuron death. Certain compounds, compositions and methods provided herein are directed to reducing a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including ALS or a symptom thereof such as loss of motor function or neuron death in an animal. In certain embodiments, the compounds and compositions provided herein are potent and tolerable and inhibit SOD1 expression, which can be used to treat, prevent, ameliorate, or slow progression of a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including ALS or a symptom thereof such as loss of motor function or neuron death.

[0009] In certain embodiments, the compounds and compositions comprise one or more features that are effective for increasing potency. In certain embodiments, the compounds and compositions comprise one or more features that are effective for increasing tolerability. In certain embodiments, compounds and compositions comprise one or more features that are A1278.70039WO00 1 effective for targeting the compound or composition to a cell or tissue. In certain embodiments, the compounds and compositions are more potent, have greater duration of action or have greater therapeutic value than compounds publicly disclosed.

[0010] The present disclosure provides oligonucleotides comprising a first modified oligonucleotide strand of Formula:

[0011] 5' 3'

[0012] X5- X6

[0013] (I),

[0014] or a pharmaceutically acceptable salt or prodrug thereof, wherein:

[0015]

[0016] ?* is a divalent radical of a first oligonucleotide strand, wherein the first oligonucleotide strand is 14- to 30-nucleoside in length and has a nucleobase sequence comprising at least 14 contiguous nucleobases of, or having at least 90% identity to, a sequence shown in Table 2;

[0017] each of X5and X6is independently of the formula:

[0018] L1L1— (A1)y1

[0019]

[0020] (A1)y1, –L1–(A2)y2, or E;

[0021] provided that at least one of X5and X6is of the formula:

[0022]

[0023] A1278.70039WO00 2 L1L1— (A1)y1

[0024] (A1)yi

[0025]

[0026] each instance of N1is independently a radical of a nucleobase or bond;

[0027] each instance of tl, when present, is independently 1, 2, or 3;

[0028] each instance of L1when present and L2is a linker;

[0029] each instance of yl when present and y2 is independently 1, 2, 3, 4, 5, or 6;

[0030] each instance of A1when present and A2is independently a radical of a ligand or lipid; or one or more instances o

[0031]

[0032] f are E;

[0033] provided that at least one instance of A1is a radical of a central nervous system (CNS) receptor ligand;

[0034] each instance of E is independently 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;

[0035] each instance of Rbis 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 Rbattached A1278.70039WO00 3 to the same intervening atom are joined together with the intervening atom to form an substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring;

[0036] vl instances of the intemucleosidic linkers of

[0037]

[0038] 2* are LM

[0039] L4

[0040] (A4) A

[0041] independently replaced w

[0042]

[0043] ithv / y4;

[0044] vl is 0, 1, 2, 3, 4, 5, or 6;

[0045] each instance of LA, when present, is independently a linker;

[0046] each instance of L4, when present, is independently a linker or bond;

[0047] each instance of y4, when present, is independently 1, 2, 3, 4, 5, or 6; and

[0048] each instance of A4, when present, is independently a radical of a ligand or lipid.

[0049] The oligonucleotides may be useful for delivering the modified oligonucleotide strands to a subject (e.g., a human). The first modified oligonucleotide strands may be able to interact with the gene SOD1 (superoxide dismutase 1). The first modified oligonucleotide strands may be able to interfere with (e.g., inhibit) the expression of SOD1. SOD1 (e.g., overexpression of SODl) is implicated in diseases, e.g., central nervous system (CNS) diseases. Therefore, the oligonucleotides may be able to treat and / or prevent diseases in subjects in need thereof.

[0050] In some embodiments, at least one instance of the CNS ligands is able to selectively bind to or otherwise selectively recognize one or more CNS receptors. In certain embodiments, at least one instance of the CNS ligands is able to target a location (e.g., a CNS tissue or cell) within a subject. In some embodiments, the oligonucleotides are capable of selectively targeting the first modified oligonucleotide strands to a location (e.g., a CNS tissue or cell) within a subject.

[0051] Therefore, the oligonucleotides may be advantageous for treating and / or preventing CNS diseases in subjects in need thereof over known therapeutic and / or prophylactic agents ((e.g., certain known oligonucleotides that do not comprise one or more radicals of CNS receptor ligands at the positions indicated in Formula I)) for treating and / or preventing CNS diseases. One or more of the advantages may be higher potency, efficacy, bioavailability, safety, and / or subject compliance; wider therapeutic window; fewer and / or less severe side effects; and / or lower toxicity and / or resistance to treatment than the latter. One or more of the advantages may be at least in part because the oligonucleotides comprise one or more radicals of CNS receptor ligands at the positions indicated in Formula I.

[0052] In another aspect, the present disclosure provides pharmaceutical compositions comprising the oligonucleotide and a pharmaceutically acceptable excipient.

[0053] A1278.70039WO00 4 In another aspect, the present disclosure provides kits comprising:

[0054] the oligonucleotide or pharmaceutical composition; and

[0055] instructions for using the provided oligonucleotide or pharmaceutical composition.

[0056] In another aspect, the present disclosure provides methods of delivering the oligonucleotide to a subject in need thereof, cell, tissue, or biological sample comprising administering to the subject or contacting the cell, tissue, or biological sample with the provided oligonucleotide or pharmaceutical composition.

[0057] In another aspect, the present disclosure provides methods of inhibiting the expression of SOD1 in a subject in need thereof, cell, tissue, or biological sample comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of the oligonucleotide or pharmaceutical composition.

[0058] In another aspect, the present disclosure provides methods of treating a disease in a subject in need thereof comprising administering to the subject an effective amount of the oligonucleotide or pharmaceutical composition.

[0059] In another aspect, the present disclosure provides methods of preventing a disease in a subject in need thereof comprising administering to the subject an effective amount of the oligonucleotide or pharmaceutical composition.

[0060] It is understood that the embodiments provided herein with respect to preferred variable selections can be taken alone or in combination with one or more embodiments, or other preferred variable selections provided herein, as if each combination were explicitly listed herein.

[0061] It should be appreciated that the foregoing concepts, and additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in this respect. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments.

[0062] BRIEF DESCRIPTION OF THE DRAWING FIG. 1 provides a bar graph of the percent of SOD1 mRNA remaining in certain tissues following administration of Example 5D (RD5279) relative to the percent of SOD1 mRNA in certain tissues following administration of aCSF to mice, “ug” refers to pg.

[0063] DEFINITIONS

[0064] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of A1278.70039WO00 5 organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March’ s Advanced Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0065] Compounds (e.g., oligonucleotides) described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0066] Unless otherwise provided, the compounds described herein include their tautomers. The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

[0067] Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays. The compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0068] The term “isotopic variant” refers to a therapeutic agent (e.g., an oligonucleotide and / or modified oligonucleotide strand disclosed herein) that contains an unnatural proportion of an A1278.70039WO00 6 isotope at one or more of the atoms that constitute such a therapeutic agent. In certain embodiments, an “isotopic variant” of a therapeutic agent contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (H), deuterium (2H), tritium (3H), carbon-11 (nC), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O), oxygen-15 (15O), oxygen-16 (16O), oxygen-17 (17O), oxygen- 18 (18O), fluorine- 17 (17F), fluorine- 18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (35C1), chlorine-36 (36C1), chlorine-37 (37C1), bromine-79 (79Br), bromine-81 (81Br), iodine 123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I), and iodine-131 (131I). In certain embodiments, an “isotopic variant” of a therapeutic agent contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (H), deuterium (2H), tritium (3H), carbon-11 (nC), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O), oxygen-15 (15O), oxygen-16 (16O), oxygen- 17 (17O), oxygen- 18 (18O), fluorine- 17 (17F), fluorine- 18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (35C1), chlorine-36 (36C1), chlorine-37 (37C1), bromine-79 (79Br), bromine-81 (81Br), iodine 123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I), and iodine-131 (131I).

[0069] It will be understood that, in a therapeutic agent (e.g., a compound and / or modified oligonucleotide strand disclosed herein), any hydrogen can be2H, for example, or any carbon can be13C, for example, or any nitrogen can be15N, for example, or any oxygen can be18O, for example, where feasible according to the judgment of one of skill. In certain embodiments, an “isotopic variant” of a therapeutic agent contains unnatural proportions of deuterium (D).

[0070] 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, Ci-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0071] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 100 carbon atoms (“Ci-100 alkyl”). In some embodiments, an alkyl group has 1 to 20 carbon atoms (“Ci-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“Ci-12 alkyl”). In some embodiments, an alkyl group has 13 to 20 carbon atoms (“C13-20 alkyl”). In some embodiments, an alkyl group has 21 to 30 carbon atoms (“C21-30 alkyl”). In some embodiments, an alkyl group has 31 to 50 carbon atoms (“C31-50 alkyl”). In some embodiments, an alkyl group has 51 to 100 carbon atoms (“C51-100 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“Ci-10 alkyl”). In some embodiments, an A1278.70039WO00 7 alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-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 (“Ci-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 (“C1-4 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 Ci-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., zz-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (Ce) (e.g., n-hexyl). 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.,

[0072] -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).

[0073] 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 100 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-100 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 certain embodiments, a heteroalkyl group refers to a saturated group having from 13 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 13-20 alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 21 to 30 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC2i-3o alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group A1278.70039WO00 8 having from 31 to 50 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCsi-so alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 51 to 100 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCsi-ioo 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-io 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-8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-7 alkyl”). In some embodiments, a 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 (“heteroCi-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 Ci-6 alkyl (e.g., -CH3)). In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-12 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-12 alkyl. In some embodiments, unsubstituted heteroCi alkyl is -OCH3 or -CH2OH. In some embodiments, substituted heteroCi alkyl is -C(=O)NH2. In some embodiments, unsubstituted heteroC2 alkyl is -OCH2CH3, -CH2OCH3, or -CH2CH2OH. The terms “heteroCzi-z2 alkyl” and “Czi-z2 heteroalkyl” are used interchangeably, wherein each of zl and z2 is independently an integer.

[0074] 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 100 carbon atoms (“Ci-100 A1278.70039WO00 9 alkenyl”). In some embodiments, an alkenyl group has at least 2 carbon atoms. In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“C1-20 alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“Ci-12 alkenyl”). In some embodiments, an alkenyl group has 2 to 12 carbon atoms (“C2-12 alkenyl”). In some embodiments, an alkenyl group has 13 to 20 carbon atoms (“C13-20 alkenyl”). In some embodiments, an alkenyl group has 21 to 30 carbon atoms (“C21-30 alkenyl”). In some embodiments, an alkenyl group has 31 to 50 carbon atoms (“C31-50 alkenyl”). In some embodiments, an alkenyl group has 51 to 100 carbon atoms (“C51-100 alkenyl”). In some embodiments, an alkenyl group has 1 to 11 carbon atoms (“Ci-11 alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“Ci-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 (“Ci-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 (“Ci-6 alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“C1-5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“Ci^i alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C1-3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C1-2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“Ci alkenyl”, e.g., =CH2). 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-I6 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 Ci^i alkenyl groups include methylidenyl (Ci), ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of Ci-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C1-20 alkenyl. In certain embodiments, the alkenyl group is a substituted C1-20 alkenyl. In an alkenyl group, a C=C double bond for

[0075] which the stereochemistry is not specified e.g., -CH=CHCH3 or

[0076]

[0077] )may bejnthe (E)-or (Z)-configuration.

[0078] 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 A1278.70039WO00 10 phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 100 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-ioo alkenyl”). In some embodiments, a heteroalkenyl group has at least 2 carbon atoms. In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-20 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-12 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-i2 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 13 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi3-2o alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 21 to 30 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2i-3o alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 31 to 50 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCsi-so alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 51 to 100 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCsi-ioo alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-11 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-10 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-9 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-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 (“heteroCi-7 alkenyl”). In some embodiments, a heteroalkenyl group has Ito 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-6 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi-5 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 1 4 alkenyl”). In A1278.70039WO00 11 some embodiments, a heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroCi-3 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroCi-2 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi-6 alkenyl”). In certain embodiments, a heteroalkenyl group is C2-3 heteroalkenyl, C2-4 heteroalkenyl, C2-5 heteroalkenyl, C2-6 heteroalkenyl, C2-7 heteroalkenyl, C2-8 heteroalkenyl, C2-9 heteroalkenyl, C2-10 heteroalkenyl, C2-12 heteroalkenyl, C2-I6 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 heteroCi-20 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroCi-20 alkenyl. In some embodiments, unsubstituted heteroCi alkenyl is -CH=NH or =N-CH3. The terms “heteroCzi-z2 alkenyl” and “Czi-z2 heteroalkenyl” are used interchangeably, wherein each of zl and z2 is independently an integer.

[0079] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 100 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“Ci-100 alkynyl”). In some embodiments, an alkynyl group has 1 to 20 carbon atoms (“C1-20 alkynyl”). In some embodiments, an alkynyl group has 1 to 12 carbon atoms (“Ci-12 alkynyl”). In some embodiments, an alkynyl group has 2 to 12 carbon atoms (“C2-12 alkynyl”). In some embodiments, an alkynyl group has 13 to 20 carbon atoms (“C13-20 alkynyl”). In some embodiments, an alkynyl group has 21 to 30 carbon atoms (“C21-30 alkynyl”). In some embodiments, an alkynyl group has 31 to 50 carbon atoms (“C31-50 alkynyl”). In some embodiments, an alkynyl group has 51 to 100 carbon atoms (“C51-100 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 A1278.70039WO00 12 group has 1 to 2 carbon atoms (“C1-2 alkynyl”). In some embodiments, an alkynyl group has 1 carbon atom (“Ci alkynyl”). In certain embodiments, an alkynyl group is C2-3 alkynyl, C2-4 alkynyl, C2-5 alkynyl, C2-6 alkynyl, C2-7 alkynyl, C2-8 alkynyl, C2-9 alkynyl, C2-10 alkynyl, C2-12 alkynyl, C2-I6 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 (Ci), ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C1-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C1-20 alkynyl. In certain embodiments, the alkynyl group is a substituted C1-20 alkynyl.

[0080] 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 100 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1-100 alkynyl”). In some embodiments, a heteroalkynyl group has at least 2 carbon atoms. In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-20 alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-i2 alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 13 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 13-20 alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 21 to 30 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2i-3o alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 31 to 50 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC3i-5o alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 51 to 100 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCsi-ioo 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 A1278.70039WO00 13 within the parent chain (“heteroCi-io alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-9 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-s 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 (“heteroCi-7 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-6 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi-5 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“heteroC i 4 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroCi-3 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroCi-2 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi-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-I6 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 heteroCi-20 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroCi-20 alkynyl. In some embodiments, unsubstituted heteroCi alkynyl is -ON. The terms “heteroCzi-z2 alkynyl” and “Czi-z2 heteroalkynyl” are used interchangeably, wherein each of zl and z2 is independently an integer.

[0081] 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 A1278.70039WO00 14 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like.

[0082] 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 (Cn), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0083] 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 A1278.70039WO00 15 carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0084] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered nonaromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0085] A1278.70039WO00 16 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.

[0086] 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, 1 H-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- lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro- 1H- A1278.70039WO00 17 pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0087] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system (e.g., having 6, 10, or 14 u electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“Ci4 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted Ce-i4 aryl. In certain embodiments, the aryl group is a substituted Ce-14 aryl.

[0088] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) aromatic ring system (e.g., having 6, 10, or 14 n electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continues to designate the number of ring members in the heteroaryl ring system. “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 A1278.70039WO00 18 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.

[0089] 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.

[0090] 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 A1278.70039WO00 19 tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0091] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0092] The term “alkoxy” refers to an -O-alkyl substituent.

[0093] Affixing the suffix “-ene” to a group indicates the resulting group is a polyvalent (e.g., divalent, trivalent, or tetravalent) moiety. For example, alkylene is a polyvalent moiety of alkyl, alkenylene is a polyvalent moiety of alkenyl, alkynylene is a polyvalent moiety of alkynyl, heteroalkylene is a polyvalent moiety of heteroalkyl, heteroalkenylene is a polyvalent moiety of heteroalkenyl, heteroalkynylene is a polyvalent moiety of heteroalkynyl, carbocyclylene is a polyvalent moiety of carbocyclyl, heterocyclylene is a polyvalent moiety of heterocyclyl, arylene is a polyvalent moiety of aryl, and heteroarylene is a polyvalent moiety of heteroaryl. In some embodiments, unsubstituted Ci heteroalkylene is -OCH2- or -CH2O-. In some embodiments, substituted Ci heteroalkylene is -NHC(=O)- or -C(=O)NH- In some embodiments, unsubstituted C2 heteroalkylene is -OCH2CH2- or -CH2CH2O-. In some embodiments, unsubstituted C4 heteroalkylene is -(OCFhCFh - or -(CFhCIfcO^-. In some embodiments, unsubstituted G, heteroalkylene is -(OCFhCFh)?- or -(CFhQfcO)?-. In some embodiments, unsubstituted Cs heteroalkylene is -(OCH2CH2)4- or -(CFhCFhO^-. In some embodiments, unsubstituted C10 heteroalkylene is -(OCFhCFys- or -(CFhCIfcC s-. In some embodiments, unsubstituted C12 heteroalkylene is -(OCH2CH2)6- or -(CFhCIfcC e-.

[0094] 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 A1278.70039WO00 20 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.

[0095] 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), Ci 20 alkyl, C1-20 perhaloalkyl, Ci-20 alkenyl, Ci-20 alkynyl, heteroCi-20 alkyl, heteroCi-20 alkenyl, heteroCi-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-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 Rddgroups; wherein X“ is a counterion;

[0096] or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORCC; each instance of Raais, independently, selected from Ci-20 alkyl, Ci-20 perhaloalkyl, Ci-20 alkenyl, Ci-20 alkynyl, heteroCi-20 alkyl, heteroCi-2oalkenyl, heteroCi-2oalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;

[0097] A1278.70039WO00 21 each instance of Rbbis, independently, selected from hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, CI-20 alkyl, Ci-20 perhaloalkyl, C1-20 alkenyl, C1-20 alkynyl, heteroCi-2oalkyl, heteroCi-2oalkenyl, heteroCi-2oalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;

[0098] each instance of Rccis, independently, selected from hydrogen, Ci-20 alkyl, Ci-20 perhaloalkyl, Ci-20 alkenyl, Ci-20 alkynyl, heteroCi-20 alkyl, heteroCi-20 alkenyl, heteroCi-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;

[0099] each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)3+X’, -N(ORee)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, Ci-10 alkyl, Ci-10 perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroCi-ioalkyl, heteroCi-ioalkenyl, heteroCi-ioalkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents are joined to form =0 or =S; wherein X“ is a counterion;

[0100] each instance of Reeis, independently, selected from Ci-10 alkyl, Ci-10 perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroCi-10 alkyl, heteroCi-10 alkenyl, heteroCi-10 alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups;

[0101] A1278.70039WO00 22 each instance of Rffis, independently, selected from hydrogen, Ci-io alkyl, Ci-io perhaloalkyl, Ci-io alkenyl, Ci-io alkynyl, heteroCi-io alkyl, heteroCi-io alkenyl, heteroCi-io alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups;

[0102] each instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OCi-6 alkyl, -ON(Ci6alkyl)2, -N(Ci-6 alkyl)2, -N(Ci-6 alkyl^X’, -NH(Ci^ alkyl^X’, -NH2(C| 6 alkyl)+X“, -NH3+X“, -NfOCi alkyl)(Ci-6 alkyl), -N(OH)(Ci-6 alkyl), -NH(OH), -SH, -SCi-6 alkyl, -SS(Ci-6alkyl), -C(=O)(Ci^ alkyl), -CO2H, -CO2(Ci 6 alkyl), -OC(=O)(Ci-6 alkyl), -OCO2(Ci 6 alkyl), -C(=O)NH2, -C(=O)N(Ci-6 alkyl)2, -OC(=O)NH(Ci 6 alkyl), -NHC(=O)( Ci-6alkyl), -N(Ci^ alkyl)C(=O)( Ci-6alkyl), -NHCO2(CI 6 alkyl), -NHC(=O)N(CI-6alkyl)2, -NHC(=O)NH(Ci6alkyl), -NHC(=O)NH2, -C(=NH)O(Ci6alkyl), -OC(=NH)(CI-6alkyl), -OC(=NH)OCi6alkyl, -C(=NH)N(Ci6alkyl)2, -C(=NH)NH(Ci6alkyl), -C(=NH)NH2, -OC(=NH)N(CI6alkyl)2, -OC(NH)NH(Ci6alkyl), -OC(NH)NH2, -NHC(NH)N(CI-6alkyl)2, -NHC(=NH)NH2, -NHSO2(CI6alkyl), -SO2N(CI6alkyl)2, -SO2NH(CI 6 alkyl), -SO2NH2, -SO2C16alkyl, -SO2OC16alkyl, -OSO2C16alkyl, -SOCi6alkyl, -Si(Ci-6alkyl)3, -OSi(Ci-6alkyl)3-C(=S)N(Ci^ alkyl)2, C(=S)NH(Ci alkyl), C(=S)NH2, -C(=O)S(CI-6 alkyl), -C(=S)SCi-6alkyl, -SC(=S)SCi alkyl, -P(=O)(OCi^ alkyl)2, -P(=O)(Ci-6 alkyl)2, -OP(=O)(Ci-6 alkyl)2, -OP(=O)(OCi6alkyl)2, Ci-io alkyl, CHO perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroCi-io alkyl, heteroCi-io alkenyl, heteroCi-io alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =0 or =S; and

[0103] each X“ is a counterion.

[0104] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-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 Ci- 10 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, -NO2, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=O)N(Rbb)2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, A1278.70039WO00 23 pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted e.g., substituted with one or more halogen) or unsubstituted Ci-io 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 Ci-6 alkyl, -OR32, -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 Ci-10 alkyl, -ORaa, -SR351, -N(Rbb)2, -CN, -SCN, or -NO2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0105] 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 Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-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.

[0106] 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, CI-IO alkyl (e.g., aralkyl, heteroaralkyl), Ci-2o alkenyl, C1-20 alkynyl, hetero Ci-20 alkyl, hetero Ci-20 alkenyl, hetero Ci-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, A1278.70039WO00 24 alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rcc, and Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999.

[0107] 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-phenylbenzarnide, 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.

[0108] 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)fhiorenyhnethyl 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), l-(l-adamantyl)-l -methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l -methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N, N-dicyclohexylcarboxamido)ethyl carbamate, / -butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1 -isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p- A1278.70039WO00 25 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-( / ?-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), l,l-dimethyl-2-cyanoethyl carbamate, / n-chloro- -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, / -amyl carbamate,. S'- benzyl thiocarbamate, -cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o- N, N-dimethylcarboxamido)benzyl carbamate, l,l-dimethyl-3-( imethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p ’-methoxyphenylazo)benzyl carbamate, 1 -methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, l-methyl-l-(3,5-dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-( / ?-phenylazophenyl)ethyl carbamate, 1 -methyl- 1-phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri - / - buty I pheny I carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0109] 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 -toliienesiilfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2.3.5.6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2.4.6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMB S), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0110] A1278.70039WO00 26 In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, A'-p-toliienesulfonylaminoacyl derivatives, A’-phenylaminothioacyl derivatives, A-benzoylphenylalanyl derivatives, A-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, A-phthalimide, A-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, A-2,5-dimethylpyrrole, N- 1, 1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-l,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, A-methylamine, N-allylamine, N- [2- (trimethylsilyl)ethoxy] methylamine (SEM), A-3-acetoxypropylamine, A-(l-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, A-benzylamine, N-di(4-methoxyphenyl)methylamine, A-5-dibenzosuberylamine, A-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), A-9-phenylfluorenylamine (PhF), A-2,7-dichloro-9-fluorenylmethyleneamine, A-ferrocenylmethylamino (Fem), A-2-picolylamino N’-oxide, A- 1,1 -dimethylthiomethyleneamine, A- benzylideneamine, A-p-methoxybenzylideneamine, A-diphenylmethyleneamine, A- [(2-pyridyl)mesityl]methyleneamine, A-(A’, A’-dimethylaminomethylene)amine, A-p-nitrobenzylideneamine, A-salicylideneamine, A-5-chlorosalicylideneamine, A-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, A-cyclohexylideneamine, A-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, A-borane derivatives, A-diphenylborinic acid derivatives, A-[phenyl(pentaacylchromium- or tungsten)acyl] amine, A-copper chelate, A- zinc chelate, A-nitroamine, A-nitrosoamine, amine A-oxide, diphenylphosphinamide (Dpp), dimethylthiopho sphinamide (Mpt), diphenylthiopho sphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are A, A’-isopropylidenediamine.

[0111] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0112] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted A1278.70039WO00 27 Ci-io alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io 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 Ci-6 alkyl or an oxygen protecting group.

[0113] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3+X“, -P(ORCC)2, -P(ORCC)3+X“, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb)2)2, wherein X“, Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999.

[0114] 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), -methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), / -biitoxymethyl, 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, -dioxide, 1 - [(2-chloro-4-methyl)phenyl] -4-methoxypiperidin-4-yl (CTMP), l,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2, 3, 3a, 4, 5, 6, 7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1 -ethoxy ethyl, l-(2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxy ethyl, 1 -methyl- 1 -benzyloxyethyl, 1 -methyl- 1 -benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, / -butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl A-oxido, diphenylmethyl, p,p ’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, 4,4'-dimethoxytrityl (4,4'-dimethoxytriphenylmethyl or DMT), a-naphthyldiphenylmethyl, j>-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''- A1278.70039WQ00 28 tris(benzoyloxyphenyl)methyl, 4,4’-Dimethoxy-3"‘-[N-(imidazolylmethyl) ]trityl Ether (IDTr-OR), 4,4’-Dimethoxy-3"‘-[N-(imidazolylethyl)carbamoyl]trityl Ether (lETr-OR), 1, l-bis(4-methoxyphenyl)- l'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl, -dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, z-butyldi methyl si lyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri- / ?- xy ly 1 si ly 1, triphenylsilyl, diphenylmethylsilyl (DPMS), / -biitylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, -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, / -butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate,. S'- benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-( 1, 1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(l,l-dimethylpropyl)phenoxy acetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (£’)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N, N, N’, N’-tetramethylphosphorodiamidate, alkyl iV-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0115] 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.

[0116] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, =0, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -C(=O)Raa, -C02Raa, -C(=0)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted A1278.70039WQ00 29 Ci-io alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io 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 Ci-6 alkyl or a sulfur protecting group.

[0117] 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 Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999.

[0118] 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.

[0119] “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); nucleophilic ring opening reactions of epoxides and aziridines; formation of hydrazones; carbonyl-chemistry-like formation of ureas; [3+2] cycloadditions (e.g., Huisgen 1,3-dipolar cycloadditions, e.g., azidealkyne cycloadditions); thiol-ene additions; thiol-yne additions; imine formations; Michael additions (e.g., maleimide addition); oxidative formations of epoxides; Diels-Alder reactions (e.g., tetrazine [4 + 2] cycloaddition); inverse electron demand Diels-Alder reactions; [4+1] A1278.70039WQ00 30 cycloadditions between isonitriles (isocyanides) and tetrazines; alkene dihydroxylations; and sulfur (VI) fluoride exchange.

[0120] As used herein, the term “salt” refers to any and all salts and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of this the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4 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.

[0121] 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, A1278.70039WO00 31 oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(CI-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0122] The term “prodrug” refers to a compound that may be converted under physiological conditions or by solvolysis to an oligonucleotide described herein. The prodrug may be a precursor of the oligonucleotide and may be pharmaceutically acceptable. The prodrug may be inactive when administered to a subject, but at least one of the converted products, e.g., the oligonucleotide, may be active. Compared to the oligonucleotide, the prodrug may offer advantages, such as higher solubility, higher permeability, higher absorption, improved distribution, improved metabolism, improved excretion, higher exposure, higher tissue 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 oligonucleotide is replaced with a protecting group (“PG,” e.g., a carbon-bound moiety, such as substituted or unsubstituted alkyl or substituted or unsubstituted phenyl). The prodrug that comprises -OPG, -NPG2, -SPG, -C(=O)OPG, -OP(=O)(OPG)O-, -SP(=O)(OPG)O-, -OP(=O)(OPG)S-, or -OP(=O)(SPG)O- may be converted under physiological conditions or by solvolysis to form -OH, -NH2, -SH, -C(=O)OH, -OP(=O)(OH)O-, -SP(=O)(OH)O-, -OP(=O)(OH)S-, or -OP(=O)(SH)O- Examples of prodrugs include, but are not limited to A1278.70039WQ00 32 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.

[0123] 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., a chimpanzee, 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.

[0124] 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. Routes of administration that can be used include, but are not limited to, intrathecal (IT) administration, intracerebroventricular (ICV) administration, parenteral administration, such as subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, or intracranial administration, e.g. intrathecal or intracerebroventricular administration.

[0125] “Parenteral administration” means administration through injection or infusion. Parenteral administration includes subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, or intracranial administration, e.g. intrathecal or intracerebroventricular administration.

[0126] 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

[0127] A1278.70039WO00 33 resolved, for example, to delay or prevent recurrence. In embodiments, treating does not include preventing.

[0128] 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.

[0129] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0130] 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).

[0131] 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. For example, for the given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy can also be expressed as “-fold” increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control.

[0132] 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 A1278.70039WO00 34 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.

[0133] The term “composition” means a mixture of substances. The term “pharmaceutical composition” means a composition suitable for administering to a subject.

[0134] The symbol “ ” denotes the point of attachment of a chemical moiety to the remainder of a compound or chemical formula.

[0135] 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 3,000 g / mol. 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.

[0136] A1278.70039WQ00 35 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, -NHs+, -C(=O)OH, or -C(=O)O ). One or more of the amino acid residues in a peptide, polypeptide, or protein may be modified or unmodified. A modification to an amino acid residue in a peptide, polypeptide, or protein may be an addition of a carbohydrate group, a hydroxyl group, a phosphate group, a famesyl group, an 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.

[0137] “Superoxide dismutase 1,” used interchangeably with the term “SOD1,” refers to any nucleic acid or protein of SOD1. Exemplary nucleotide and amino acid sequences of SOD1 can be found, for example, at GenBank Accession No. NM_000454.5 (incorporated herein as SEQ ID NO:1), and nucleotides 5001 to 14310 of NG_008689.1 (incorporated herein as SEQ ID NO: 2. 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 ncbi.nlm.nih.gov / gene / ?term=SODl. SOD1, as used herein, also refers to variations A1278.70039WQ00 36 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., ncbi.nlm.nih.gov / snp / ?term=SODl). “SOD1 mRNA” means an mRNA encoding a SOD1 protein. SOD1 may be referred to in either upper or lower case.

[0138] “SOD1 specific inhibitor” refers to any agent capable of specifically inhibiting SOD1 RNA and / or SOD1 protein expression or activity at the molecular level. For example, SOD1 specific inhibitors include nucleic acids (including oligonucleotide compounds), peptides, antibodies, small molecules, and other agents capable of inhibiting the expression of SOD1 RNA and / or SOD1 protein.

[0139] “Modulating” refers to changing or adjusting a feature in a cell, tissue, organ or organism. For example, modulating SOD1 RNA can mean to increase or decrease the level of SOD1 RNA and / or SOD1 protein in a cell, tissue, organ or organism. A “modulator” effects the change in the cell, tissue, organ or organism. For example, a SOD1 compound can be a modulator that decreases the amount of SOD1 RNA and / or SOD1 protein in a cell, tissue, organ or organism.

[0140] “Tropomyosin Receptor Kinase B” or “TrkB,” as may be used interchangeably herein, means the receptor for brain-derived neurotrophic factor (BDNF) protein encoded by the NTRK2 gene. TrkB is also known as tyrosine receptor kinase B, BDNF / NT-3 growth factors receptor and neurotrophic tyrosine kinase, receptor, type 2.

[0141] “2’-0-methoxyethyl” or “2’-M0E” means a 2’-O(CH2)2-OCHs modification. A 2’-O-methoxyethyl modified sugar is a modified sugar with 2’-O(CH2)2-OCHs in the place of the 2’-OH group of a ribosyl ring.

[0142] “5’ start site” means the nucleotide of the target nucleic acid or region which is aligned to the 3 ’-most nucleoside of an antisense oligonucleotide.

[0143] “3’ stop site” means the nucleotide of the target nucleic acid or region which is aligned to the 5 ’-most nucleoside of an antisense oligonucleotide.

[0144] “About” means within ±10% of a value. For example, if it is stated, “a compound achieved about 70% inhibition of SOD1”, it is implied that SOD1 levels are inhibited within a range of 60% and 80%. When about is present before a series of numbers or a range, it is understood that “about” can modify each of the numbers in the series or range.

[0145] 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.

[0146] 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 A1278.70039WO00 37 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.

[0147] 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.

[0148] 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), micro satellite 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 IncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, antisense oligonucleotides (e.g., antisense DNA and antisense RNA), interfering RNA compounds (RNAi compounds), circular RNA (circRNA) compounds, microRNA (miRNA) targeting oligonucleotides, miRNA mimics, occupancy-based compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds) and editing compounds (e.g., ADAR recruiting compounds, ADAR targeting compounds, single- stranded guide nucleic acids, or a combination thereof). RNAi compounds include double- stranded compounds (e.g., shortinterfering RNA (siRNA) and double- stranded RNA (dsRNA)) and single- stranded compounds (e.g., single-stranded siRNA (ssRNA), single- stranded RNAi (ssRNAi), short hairpin RNA A1278.70039WQ00 38 (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 strand, 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.

[0149] 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.

[0150] The term “nucleobase” refers to a nitrogen-containing moiety at the T position of a nucleoside. Nucleobases may include purine bases and pyrimidine bases. Five nucleobases — adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U) — are referred to as primary or canonical nucleobases. Nucleobases may include unmodified and modified nucleobases. When a nucleobase is listed in a formula definition, it refers to that moiety covalently bonded to the recited formula.

[0151] The term “nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or intemucleoside linkage.

[0152] 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 A1278.70039WO00 39 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).

[0153] The terms “internucleoside linkage,” “internucleoside linker,” “intemucleosidic linkage,” and “intemucleosidic linker” are used interchangeably. As used herein, the term “intemucleoside linkage” is the covalent linkage between adjacent nucleosides in an oligonucleotide. As used herein, “modified intemucleoside linkage” means any intemucleoside linkage other than a phosphodiester intemucleoside linkage. “Phosphorothioate intemucleoside linkage” is a modified intemucleoside linkage in which one of the non-bridging oxygen atoms of a phosphodiester intemucleoside linkage is replaced with a sulfur atom. Representative intemucleoside linkages having a chiral center include but are not limited to alkylphosphonates and phosphorothioates. Modified oligonucleotide strands comprising intemucleoside linkages having a chiral center can be prepared as populations of modified oligonucleotide strands comprising stereorandom intemucleoside linkages, or as populations of modified oligonucleotide strands comprising phosphorothioate linkages in particular stereochemical configurations as further described below. Unless otherwise indicated, chiral intemucleoside linkages of modified oligonucleotide strands described herein can be stereorandom or in a particular stereochemical configuration. 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.

[0154] “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.

[0155] “Terminal group” means a chemical group or group of atoms that is covalently linked to a terminus of an oligonucleotide.

[0156] “Subunit” with reference to an oligonucleotide means a nucleotide, nucleoside, nucleobase or sugar or a modified nucleotide, nucleoside, nucleobase or sugar as provided herein.

[0157] 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.

[0158] 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 A1278.70039WO00 40 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.

[0159] The terms “small interfering RNA,” “short interfering RNA,” and “siRNA,” as may be used interchangeably herein, refer to RNA compounds that present as non-coding single- stranded RNA or double-stranded RNA (dsRNA) compounds having a strand or strands of about 20 to about 24 nucleotides in length and are useful in RNA interference (RNAi). siRNAs are often found with phosphorylated 5' ends and hydroxylated 3' ends, which 3' ends typically have a 2-nucleotide overhang beyond the 5' end of the anti-parallel strand (e.g., complementary strand of the dsRNA compound). siRNAs can interfere with the expression of specific genes through binding of target sequences (e.g., target nucleic acid sequences) to which they are complementary and promoting (e.g., facilitating, triggering, initiating) degradation of the mRNA, thereby preventing (e.g., inhibiting, silencing, interfering with) translation. RNAi act, at least in part, through an RNA-induced silencing complex (RISC) pathway or Ago2, but not through RNaseH, to modulate a target nucleic acid and / or protein encoded by a target nucleic acid. After integration and separation into the RISC complex, siRNAs base-pair (e.g., full complementarity) to their target mRNA and cleave it, thereby preventing it from being used as a translation template. As discussed herein above, also part of the RNAi pathway, a miRNA-loaded RISC complex scans cytoplasmic mRNAs for potential complementarity (e.g., partial complementarity).

[0160] 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.

[0161] “Targeting moiety” means a conjugate group that provides an enhanced affinity for a selected target, e.g., molecule, cell or cell type, compartment, e.g., a cellular or organ compartment, tissue, organ or region of the body, as, e.g., compared to a compound absent such a moiety.

[0162] 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.

[0163] A1278.70039WQ00 41 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.

[0164] “Modified oligonucleotide strand” means an oligonucleotide, wherein at least one sugar, nucleobase, or intemucleoside linkage is modified.

[0165] “Motif’ means the pattern of unmodified and modified sugar moieties, nucleobases, and / or internucleoside linkages, in an oligonucleotide.

[0166] “Nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or intemucleoside linkage.

[0167] The term “oligomeric duplex” means a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of an oligomeric duplex may be referred to as a “duplexed oligomeric compound.” The oligonucleotides of each oligomeric compound of an oligomeric duplex may include non-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.

[0168] “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.

[0169] 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.

[0170] The term “ligand” refers to a substance that binds to or otherwise interacts with a protein, nucleic acid, or other biological molecule. In some embodiments, a ligand is selected from the group consisting of small molecules; saccharines; oligosaccharides; polysaccharides; biological macromolecules, e.g., peptides, proteins, and peptide analogs and derivatives; peptidomimetics; antibodies and antigen binding fragments thereof; nucleic acids; nucleic acid analogs and derivatives; an extract made from biological materials such as bacteria, plants, fungi, or animal cells; animal tissues; and naturally occurring or synthetic compositions. In some embodiments, a ligand is a small molecule. In some embodiments, a ligand binds to a protein (e.g., a receptor). In certain embodiments, a ligand binds to tropomyosin receptor kinase B (TrkB), cannabinoid receptor type 1 (CB1), a.4 1 / 7 integrin receptor, or N-methyl-D-aspartate (NMD A) 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 A1278.70039WQ00 42 brain of a subject (e.g., to the striatum, cerebellum, brain stem, hippocampus, frontal cortex, or spinal cord of the subject). In some embodiments, a ligand is capable of targeting an oligonucleotide e.g., an oligonucleotide strand thereof) to a central nervous system (CNS) cell (e.g., a neuron). In some embodiments, a ligand is not a lipid.

[0171] 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 intemucleoside linkage between the 5' nucleoside and the second nucleoside counted from the 5' end; the intemucleoside linkage between the 3' nucleoside and the second nucleoside counted from the 3' end; the intemucleoside linkage between the first n and n+1 nucleosides counted from the 5' end, wherein n is an integer between 2 and 20, inclusive, as the number of nucleosides of the oligonucleotide strand permits). In some embodiments, the internal position is at a position on an “internal nucleoside” (a nucleoside that is not the 5' or 3' nucleoside). An oligonucleotide comprising a modification (e.g., conjugation of a radical of a ligand) at an internal position may be referred to as an “internally-modified oligonucleotide strand.”

[0172] 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, faty 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, diglycerol tetraether phospholipid, glycerol-nonitol tetraether phospholipid, oxidized glycerophospholipid, glycerophosphoethanolamine glycan, dihydroxyacetonephosphate, glycerophosphoethanol, glycerophosphothreonine, or cyclic glycerophosphatidic acid. A sphingolipid may be a sphingoid base, ceramide, phosphosphingolipid, phosphonosphingolipid, neutral glycosphingolipid, acidic glycosphingolipid, basic glycosphingolipid, amphoteric A1278.70039WQ00 43 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, l,3-bis-0(hexadecyl)glycerol, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3- propanediol, heptadecyl group, palmitic acid, myristic acid, 03-(oleoyl)lithocholic acid, 03-(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).

[0173] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0174] The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

[0175] “Complementarity” in reference to an oligonucleotide means the nucleobase sequence of such oligonucleotide or one or more regions thereof that is complementary to the nucleobase sequence of another oligonucleotide or nucleic acid or one or more regions thereof when the two nucleobase sequences are aligned in opposing directions. Complementary nucleobases, as described herein, are limited to the following pairs: adenine (A) and thymine (T), adenine (A) and uracil (U), and cytosine (C) and guanine (G) unless otherwise specified. Complementary oligonucleotides and / or nucleic acids need not have nucleobase complementarity at each nucleoside and may include one or more nucleobase mismatches.

[0176] “Mismatch” or “non-complementary” means a nucleobase of a first oligonucleotide or nucleic acid that is not complementary to the corresponding nucleobase of a second oligonucleotide or nucleic acid when the first oligonucleotide / nucleic acid and second A1278.70039WO00 44 oligonucleotide / nucleic acid are aligned in an antiparallel orientation. For example, nucleobases including, but not limited to, a universal nucleobase, inosine, and hypoxanthine, are capable of hybridizing with at least one nucleobase but are still mismatched or non-complementary with respect to the nucleobase to which they are hybridized. As another example, a nucleobase of a first oligonucleotide / nucleic acid that is not capable of hybridizing to the corresponding nucleobase of a second oligonucleotide / nucleic acid when the first and second oligonucleotides are aligned in an antiparallel orientation is a mismatch or non-complementary nucleobase.

[0177] “Conjugate group” means a group of atoms that is attached to an oligonucleotide. A conjugate group is optionally attached to an oligonucleotide through a conjugate linker. A conjugate group may, for example, alter the distribution, targeting, or half-life of a compound into which it is incorporated. Conjugate groups include lipids (or lipophilic moieties), ligands, and other targeting moieties.

[0178] “Conjugate linker” means a group of atoms comprising at least one bond that connects a linked moiety to an oligonucleotide.

[0179] “Identity” in reference to an oligonucleotide means the nucleobase sequence of such oligonucleotide or one or more regions thereof that matches the nucleobase sequence of another oligonucleotide or nucleic acid or one or more regions thereof. Identity of an oligonucleotide to another oligonucleotide or nucleic acid need not require each nucleobase to match and may include one or more different nucleobases. By contrast, “fully identical” or “100% identity” in reference to oligonucleotides means that such oligonucleotides have the same nucleobase at each relative position over its length as the other oligonucleotide or nucleic acid.

[0180] DETAILED DESCRIPTION

[0181] It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only and are not restrictive of the embodiments, as claimed. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0182] All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, treatises, and GenBank, NCBI and other sequence reference records are hereby expressly incorporated by reference for the portions of the document discussed herein, as well as in their entirety as of the date of filing this application.

[0183] In certain embodiments, the sequence set forth in each SEQ ID NO contained herein is independent of any modification to a sugar moiety, an internucleoside linkage, or a nucleobase even if shown in context with a modified compound. In certain embodiments, compounds (e.g., oligonucleotides, first oligonucleotide strands, first modified oligonucleotide strands, second A1278.70039WQ00 45 oligonucleotide strands, second modified oligonucleotide strands, sense strands, modified sense strands, antisense strands, modified antisense strands) defined by a SEQ ID NO may comprise, independently, one or more modifications to a sugar moiety, an intemucleoside linkage, and / or a nucleobase. Oligomeric compounds referenced by Oligonucleotide No. or Ref ID NO indicate a combination of nucleobase sequence, chemical modification, and motif.

[0184] In one aspect, the present disclosure provides oligonucleotides comprising a first modified oligonucleotide strand of Formula:

[0185] 5' 3'

[0186] X5- X6

[0187] (I),

[0188] or a pharmaceutically acceptable salt or prodrug thereof, wherein:

[0189]

[0190] 5* is a divalent radical of a first oligonucleotide strand, wherein the first oligonucleotide strand is 14- to 30-nucleoside in length and has a nucleobase sequence comprising at least 14 contiguous nucleobases of, or having at least 90% identity to, a sequence shown in Table 2;

[0191] each of X5and X6is independently of the formula:

[0192] L1L1— (A1)y1

[0193]

[0194] (A1)y1, –L1–(A2)y2, or E;

[0195] provided that at least one of X5and X6is of the formula:

[0196]

[0197] A1278.70039WO00 46 L1L1— (A1)y1

[0198] (A1)yi

[0199]

[0200] each instance of N1is independently a radical of a nucleobase or bond;

[0201] each instance of tl, when present, is independently 1, 2, or 3;

[0202] each instance of L1when present and L2is a linker;

[0203] each instance of yl when present and y2 is independently 1, 2, 3, 4, 5, or 6;

[0204] each instance of A1when present and A2is independently a radical of a ligand or lipid; or one or more instances o

[0205]

[0206] f are E;

[0207] provided that at least one instance of A1is a radical of a central nervous system (CNS) receptor ligand;

[0208] each instance of E is independently 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;

[0209] each instance of Rbis 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 Rbattached A1278.70039WO00 47 to the same intervening atom are joined together with the intervening atom to form an substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring;

[0210] vl instances of the intemucleosidic linkers of

[0211]

[0212] 2* are LAH

[0213] L4

[0214] (A4) A

[0215] independently replaced w

[0216]

[0217] ithv / y4;

[0218] vl is 0, 1, 2, 3, 4, 5, or 6;

[0219] each instance of LA, when present, is independently a linker;

[0220] each instance of L4, when present, is independently a linker or bond;

[0221] each instance of y4, when present, is independently 1, 2, 3, 4, 5, or 6; and

[0222] each instance of A4, when present, is independently a radical of a ligand or lipid. In certain embodiments, the first modified oligonucleotide strand is of the formula:

[0223] L^ L1— (A1)y1

[0224]

[0225] A1278.70039WO00 48 (1-6), L2^ L1— (A1)y1

[0226] (1-7),

[0227]

[0228] (1-8), A1278.70039WO00 49 5'

[0229] (1-9),

[0230] (1-10), (Ml),

[0231] (1-12),

[0232]

[0233] (A1)yl - L1L1— (A1)yi(1-13), A1278.70039WO00 50 (A1)yl - L1L1— (A1)y1(1-15),

[0234] (A1)y— L1L1-(A1)y1 (I. 17),or

[0235]

[0236] A1278.70039WO00 51 or a pharmaceutically acceptable salt or prodrug thereof; and

[0237] each instance of yl is present.

[0238] In certain embodiments, the first modified oligonucleotide strand is of the formula:

[0239] 3’. A®' (A

[0240]

[0241] 4)y4(1-22),

[0242] A1278.70039WO00 52 (1-25),

[0243] L4

[0244] (1-26),

[0245] 5’

[0246]

[0247] (1-27),

[0248] A1278.70039WO00 53 (1-29),

[0249] L4(A4)y4(1-30),

[0250] (A1)y1- L1L1— (A1)y1

[0251] L4(A4)

[0252]

[0253] y4(A1)y1- L1L1— (A1)y1

[0254] (1-32), A1278.70039WO00 54 5’

[0255] (A1)yi - L1L1— (A1)yi(J_33^

[0256] (A1)y1L1L1— (A1)y1 (I-35),Qr

[0257]

[0258] or a pharmaceutically acceptable salt or prodrug thereof; and

[0259] each instance of yl is present.

[0260] In certain embodiments, the first modified oligonucleotide strand is of the formula:

[0261] A1278.70039WO00 55 (1-39),

[0262] L1L1— (A1)y1(A1)y1 (1-41),

[0263] L1L1— (A1)y1(A1)y1

[0264]

[0265] A1278.70039WO00 56 (Aq)yi- L1E (1-43), (A1)y1- L1E (1-44), (Aq)yi- L1E

[0266] (A1)y1(1-45), (A1)yi(1-46), L1L1— (A1)y1(A1)yi(1-47),

[0267]

[0268] (1-48), A1278.70039WO00 57 (A1)yi- L1L1— (A1)yi(1-49),

[0269] (A1)y— L1L1— (A1)yi(1-50),

[0270] (1-51),

[0271] (A1)yi- L1L1— (A1)yi

[0272] (1-52),

[0273] (A1)yi- L1L1— (A1)yiL1L1— (A1)yi(A1)yi(1-53), or

[0274] (A1)yi- L1L1— (A1)yiL1L1— (A1)yi

[0275]

[0276] (A1)y1 (1-54), or a pharmaceutically acceptable salt or prodrug thereof; and

[0277] each instance of yl is present.

[0278] A1278.70039WO00 58 In certain embodiments, the first modified oligonucleotide strand is of the formula:

[0279] (E or -L1-(A2)y2)

[0280] (1-55),

[0281] (E or -L1-(A2)y2)

[0282] (1-56),

[0283] (1-57),

[0284] 3'. A®' (E or -L1-(A2)y2) 5’

[0285] L4

[0286] (1-58),

[0287] L2^ L1— (A1)y1

[0288] (E or-L1-(A2)y2)

[0289]

[0290] 5’ (1-59), or

[0291] A1278.70039WO00 59L\ L1(A1)yi

[0292] (A4)

[0293]

[0294] y4(1-60),

[0295] or a pharmaceutically acceptable salt or prodrug thereof; and

[0296] each instance of yl is present.

[0297] In certain embodiments, the first modified oligonucleotide strand is of the formula:

[0298] | - 2. - (E or — L1— (A2)y2)5' (1-61),

[0299] .(E or-L1-(A2)y2)

[0300] L4

[0301] (A4)y4(1-62),

[0302] E or-L1-(A2)y2)

[0303] (1-63),

[0304] (E or-L1-(A2)y2)

[0305]

[0306] (1-64),

[0307] A1278.70039WO00 60 E or -I ■1-(A2)y2)

[0308] (1-65), or

[0309] 3', A 5' < E or-L1-(A2)y2)

[0310]

[0311] (1-66), or a pharmaceutically acceptable salt or prodrug thereof; and

[0312] each instance of yl is present.

[0313] In certain embodiments, the first modified oligonucleotide strand is of the formula:

[0314] 5’ 3' 4 o

[0315] | - - (E or — L1— (A2)y2) L2N1— E

[0316] E L1- <Al)yi (1-67),

[0317] p - M - £_(e or_Li_(A2)y2) L2N1— E L

[0318] n \ ( (A L4)y4

[0319] E L1-<A% (1-68),

[0320] r - - - (E or -L1(A2)y2)

[0321]

[0322] (A1)yi (1-69),

[0323] A1278.70039WO00 61 I

[0324] (A1)*1(1-70),

[0325] L1L1— (A1)yi

[0326] (Al)yi (1-71), or

[0327] L1L1— (A1)yi

[0328]

[0329] (A1)y1 (1-72),

[0330] or a pharmaceutically acceptable salt or prodrug thereof; and

[0331] each instance of yl is present.

[0332] In certain embodiments, the first modified oligonucleotide strand is of the formula:

[0333] (E or (A2)y2-L1) - - 5’

[0334] (1-73),

[0335] 3'

[0336] (E or (A2)y2-L1}3'LA£.

[0337] y

[0338] (A4)y4

[0339] (1-74),

[0340]

[0341] E L1— (A1)yi(!-75),

[0342] A1278.70039WO00 62 (A1)yi- L1L1— (A1)yi(1-77), or

[0343] (E or (A2)y2-L1)5‘ 2'LA—

[0344] L

[0345] (A

[0346]

[0347] 4)y4(1-78), or a pharmaceutically acceptable salt or prodrug thereof; and

[0348] each instance of yl is present.

[0349] In certain embodiments, the first modified oligonucleotide strand is of the formula:

[0350] (A1)yi- L1

[0351] (E or (A2)y2-L1) - - - L2

[0352] 5' (1-79),

[0353] (A1)yi- L1

[0354] (E or (A2)y2-L1) - -3.'LA- - ^L2

[0355] E

[0356] (E or (A2)y2-L1) - - - — L2

[0357]

[0358] 5' (1-81),

[0359] A1278.70039WO00 63 E

[0360] (E or (A2)y2-L1) - - - - - L2

[0361] (A1)y1- L1

[0362] (E or (A2)y2-L1) - - 1— L2

[0363] 5' (1-83), or

[0364] (A1)y1 -L

[0365] (A1)y1- L1

[0366] (E or (A2)y2-L1) - -LA- - - L2

[0367] I

[0368] L4

[0369]

[0370] (A4)y4 (1-84),

[0371] or a pharmaceutically acceptable salt or prodrug thereof; and

[0372] each instance of yl is present.

[0373] In certain embodiments, the first modified oligonucleotide strand is of the formula:

[0374] (E or (A2)y2-L1). 3’

[0375] (A1)y1

[0376] (1-85),

[0377] (E or (A2)y2-L1

[0378] 5'

[0379] L4

[0380]

[0381] (AV (1-86),

[0382] A1278.70039WO00 64 (1-87),

[0383] (E or(A2)y2-L1) - £

[0384] (E or (A2)y2-L1}

[0385] (E or (A2)y2-L1)5'

[0386]

[0387] (1-90), or a pharmaceutically acceptable salt or prodrug thereof; and

[0388] each instance of yl is present.

[0389] In certain embodiments, each of X5and X6is independently of the formula:

[0390]

[0391] A1278.70039WO00 65 In certain embodiments, X5is of the formula:

[0392]

[0393] X6is E.

[0394] In certain embodiments, X5is of the formula:

[0395]

[0396] X6is -dJ- A

[0397] In certain embodiments, X5is E; and

[0398] X6is of the formula:

[0399] A1278.70039WO00 66 L1L1— (A1)y1

[0400]

[0401] (A1)yiIn certain embodiments, X5is -L1-(A2)y2; and

[0402] X6is of the formula:

[0403] L1L1— (A1)y1

[0404]

[0405] (A1)yiIn certain embodiments, at least one instance is each instance. In certain embodiments, at least one instance are two instances. In certain embodiments, at least one instance are three instances.

[0406] In certain embodiments, at least one instance of N1is a radical of a nucleobase. In certain embodiments, at least one instance of N1is a radical of adenine, cytosine, guanine, or uracil. In certain embodiments, at least one instance of N1is adenin-9-yl, cytosin-l-yl, guanin-9-yl, or uracil-l-yl. In certain embodiments, at least one instance of N1is uracil-l-yl. In certain embodiments, at least one instance of N1is a radical of xanthine, allyaminouracil, allyaminothymidine, hypoxanthine, digoxigeninated adenine, digoxigeninated cytosine, digoxigeninated guanine, digoxigeninated uracil, 6-chloropurineriboside, N6-methyladenine, A1278.70039WO00 67 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, Nl-ethylpseudouracil, N1 -methoxymethylpseudouracil, N1 -methyladenine, N1 -methylpseudouracil, N1 -propylpseudouracil, N2-methylguanine, N4-biotin-OBEA-cytosine, N4-methylcytosine, N6-methyladenine, O6-methylguanine, pseudoisocytosine, pseudouracil, thienocytosine, thienoguanine, thienouracil, xanthosine, 3-deazaadenine, 2,6-diaminoadenine, 2,6-daminoguanine, 5-carboxamide-uracil, 5-ethynyluracil, N6-isopentenyladenine (i6A), 2-methyl-thio-N6-isopentenyladenine (ms2i6A), 2-methylthio-N6-methyladenine (ms2m6A), N6-(cis-hydroxyisopentenyl)adenine (io6A), 2-methylthio-N6-(cis-hydroxyisopentenyl)adenine (ms2io6A), N6-glycinylcarbamoyladenine (g6A), N6-threonylcarbamoyladenine (t6A), 2-methylthio-N6-threonyl carbamoyladenine (ms2t6A), N6-methyl-N6-threonylcarbamoyladenine (m6t6A), N6-hydroxynorvalylcarbamoyladenine (hn6A), 2-methylthio-N6-hydroxynorvalyl carbamoyladenine (ms2hn6A), N6, N6-dimethyladenine (m62A), or N6-acetyladenine (ac6A). In some embodiments, at least one instance of N1is a bond.

[0407] In certain embodiments, at least one instance of tl, when present, is 1. In certain embodiments, at least one instance of tl, when present, is 2 or 3.

[0408] In certain embodiments, at least one instance of -[L1-(A1)yi]tiis E. In certain embodiments, at least one instance of -[L1-(A1)yi]tiis -H. In certain embodiments, at least one instance of -^^(A^yijti is halogen (e.g., -F). In certain embodiments, at least one instance of -Ild- A^yilti is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted Ci-6 alkyl). In certain embodiments, at least one instance of -^-(A^yijti is -CH3.

[0409] A1278.70039WO00 68 In certain embodiments, at least one instance of yl is 1 or 2. In certain embodiments, at least one instance of yl is 3, 4, 5, or 6.

[0410] In certain embodiments, y2 is 1 or 2. In certain embodiments, y2 is 3, 4, 5, or 6.

[0411] In certain embodiments, the first modified oligonucleotide strand comprises one radical of a ligand. In certain embodiments, the first modified oligonucleotide strand comprises two or three radicals of ligands. In certain embodiments, the first modified oligonucleotide strand comprises four, five, or six radicals of ligands.

[0412] In certain embodiments, the first modified oligonucleotide strand comprises one radical of a CNS ligand. In certain embodiments, the first modified oligonucleotide strand comprises two or three radicals of CNS ligands. In certain embodiments, the first modified oligonucleotide strand comprises four, five, or six radicals of CNS ligands.

[0413] In certain embodiments, at least one instance

[0414]

[0415] of is

[0416]

[0417] In certain embodiments, vl is 0. In certain embodiments, vl is 1. In certain embodiments, vl is 2, 3, 4, 5, or 6.

[0418] L4

[0419] In some embodiments, at least once instance

[0420]

[0421] of, when present, is between the first and second nucleosides of the modified oligonucleotide strand counted from the 5’ end. In

[0422] A1278.70039WO00 69 i— LA-4

[0423] i4

[0424] (A4) A

[0425] certain embodiments, at least one instance

[0426]

[0427] ofv'y4, when present, is between the first n and n+1 nucleosides of the modified oligonucleotide strand counted from the 5’ end; and n is an integer between 2 and 20, inclusive, as the number of nucleosides of the modified oligonucleotide strand permits.

[0428] In certain embodiments, at least one instance of E is hydrogen, halogen, substituted or unsubstituted methyl, -OP(=O)(ORb)2, -SP(=O)(ORb)2, -OP(=O)(ORb)(SRb), -ORb, -SRb, -SSRb, -N(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.

[0429] In certain embodiments, at least one instance of E is -CH2OP(=O)(ORb)2, -CH2SP(=O)(ORb)2, -CH2OP(=O)(ORb)(SRb), -CH2ORb, -CH2SRb, -CH2SSRb, -CH2N(Rb)2, -CH2OC(=O)Rb, -CH2OC(=O)ORb, -CH2OC(=O)SRb, -CH2OC(=O)N(Rb)2, -CH2OS(=O)Rb, -CH2OS(=O)ORb, -CH2OS(=O)SRb, -CH2OS(=O)N(Rb)2, -CH2OS(=O)2Rb, -CH2OS(=O)2ORb, -CH2OS(=O)2SRb, -CH2OS(=O)2N(Rb)2, -CH2ON(Rb)2, -CH2SC(=O)Rb, -CH2SC(=O)ORb, -CH2SC(=O)SRb, -CH2SC(=O)N(Rb)2, -CH2NRbC(=O)Rb, -CH2NRbC(=O)ORb, -CH2NRbC(=O)SRb, -CH2NRbC(=O)N(Rb)2, -CH2NRbS(=O)Rb, -CH2NRbS(=O)ORb, -CH2NRbS(=O)SRb, -CH2NRbS(=O)N(Rb)2, -CH2NRbS(=O)2Rb, -CH2NRbS(=O)2ORb, -CH2NRbS(=O)2SRb, or -CH2NRbS(=O)2N(Rb)2.

[0430] In certain embodiments, at least one instance of E is -ORbor -CH2ORb.

[0431] In certain embodiments, at least one instance of Rbis hydrogen or substituted or unsubstituted Ci-6 alkyl. In some embodiments, each instance of Rbis independently hydrogen or substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, each instance of Rbis independently hydrogen or unsubstituted Ci-6 alkyl. In certain embodiments, at least one instance of Rbis substituted or unsubstituted phenyl.

[0432] Linkers

[0433] In some embodiments, the oligonucleotides provided herein comprise one or more linkers (e.g^ L^ L2, LA, and L4).

[0434] A1278.70039WO00 70 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.

[0435] In certain embodiments, a linker contains in the backbone thereof carbon atoms (e.g., 1-5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, or 96-100, inclusive, carbon atoms). In certain embodiments, a linker contains in the backbone thereof heteroatoms (e.g., nitrogen, oxygen, sulfur, phosphorous) (e.g., 1-3, 4-6, 7-9, 10-12, 13-15, 16-18, 19-21, 22-24, 25-27, 28-30, 31-33, 34-36, or 37-40, inclusive, heteroatoms). In certain embodiments, a linker comprises in the backbone thereof amide, ester, disulfide, or a combination thereof. In certain embodiments, a linker comprises in the backbone thereof hydrazone, oxime, imine, guanidine, urea, carbamate, alkyl, sulfonamide, heterocyclic, or a combination thereof. In certain embodiments, a linker comprises in the backbone thereof one or more groups independently selected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino. In certain embodiments, a linker comprises in the backbone thereof at least one phosphorus atom. In certain embodiments, a linker includes at least one non-polar linking group. In certain embodiments, a linker includes at least one polar linking group. In certain embodiments, a linker includes at least one linking group formed by a clickchemistry reaction of a first and second click-chemistry reactive moieties. In certain embodiments, a linker is substituted. In certain embodiments, a linker is substituted with alkyl, alkenyl, alkynyl, amino, alkylamino, dialkylamino, trialkylamino, hydroxyl, alkoxy, carbonyl, halogen, aryl, heterocyclic, aromatic heterocyclic, cyano, amide, carbamoyl, carboxylic acid, ester, thioether, alkylthioether, thiol, ureido, or a combination thereof. As would be appreciated by one of skill in this art, each of these groups may in turn be substituted. In some embodiments, a linker is substituted with one, two, three, four, five, six, seven, eight, nine, ten, or more than ten substituents.

[0436] 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 A1278.70039WO00 71 embodiments, a linker is substituted or unsubstituted, Ci-100 alkylene, substituted or unsubstituted, C2-100 alkenylene, or substituted or unsubstituted, C2-100 alkynylene. In certain embodiments, one or more (e.g., two, three, or four) backbone atoms of the Ci-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.

[0437] 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.

[0438] 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 A1278.70039WO00 72 embodiments, a linker is optionally substituted heteroalkenylene. In some embodiments, a linker is optionally substituted heteroalkynylene. In some embodiments, a linker is substituted or unsubstituted, Ci-100 heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, or substituted or unsubstituted, C2-100 heteroalkynylene. In certain embodiments, one or more (e.g., two, three, or four) backbone atoms of the Ci-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 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 Cei-70 heteroalkenylene, or substituted or unsubstituted, C2-6, C7-12, C13-18, C19-24, C25-30, C31-36, C 37-44, C45-52, C53-60, or Cei-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 Cei-70 heteroalkylene, C1-6, C7-12, C13-18, C19-24, C25-30, C31-36, C37-44, C45-52, C53-60, or Cei-70 heteroalkenylene, or C2-6, C7-12, C13-18, C19-24, C25-30, C31-36, C37-44, C45-52, C53-60, or Cei-7oheteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.

[0439] 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 A1278.70039WO00 73 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.

[0440] In some embodiments, the substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms is of the formula:

[0441]

[0442] k21 is 0, 1, 2, 3, or 4;

[0443] each instance of Rd, if present, is independently halogen, substituted or unsubstituted, Ci-6 alkyl, or -O-(substituted or unsubstituted, Ci-6 alkyl);

[0444] k22 is 0, 1, 2, 3, or 4;

[0445] each instance of Re, if present, is independently halogen, substituted or unsubstituted, Ci-6 alkyl, or -O-(substituted or unsubstituted, Ci-6 alkyl);

[0446] k23 is an integer between 0 and 11, inclusive;

[0447] A1278.70039WO00 74 each instance of Rf, if present, is independently halogen, substituted or unsubstituted, Ci-6 alkyl, or -O-(substituted or unsubstituted, Ci-6 alkyl); and

[0448] Rgis hydrogen, halogen, substituted or unsubstituted, Ci-6 alkyl, or -O-(substituted or unsubstituted, Ci-6 alkyl).

[0449] The substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms may be attached at either direction.

[0450] In certain embodiments, the substituted or unsubstituted heteroarylene that replaces one of the backbone atoms is of the formula:

[0451]

[0452] 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.

[0453] 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.

[0454] A1278.70039WO00 75 In some embodiments, a linker comprises a moiety formed by a Michael addition reaction of a Michael donor and a Michael acceptor. In some embodiments, the Michael donor is an enolate. In some embodiments, the Michael acceptor is a moiety comprising a,p-unsaturated-carbonyl. In some embodiments, the Michael donor is -SH. In some embodiments, the Michael

[0455] acceptor is

[0456]

[0457] O.

[0458] In certain embodiments, a linker comprises one or more of the following -CH2-,

[0459] v / VW AgA A' A X,, -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -C(=O)N(CH3)-, - X A A

[0460] N

[0461]

[0462] HC(=O)-, -N(CH3)C(=O)-,, or, or a combination of two or more of each one of the foregoing, provided that:

[0463] the number of backbone atoms of the linker is between 10 and 100, inclusive; and the linker does not comprise 0-0, O-N, N-O, or N-N.

[0464] AgA Al A In some embodiments, a linker is a combination of-CH2-,, -O-, - CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -C(=O)N(CH3)-,

[0465] 050 A A K A

[0466] -

[0467]

[0468] NHC(=O)-, -N(CH3)C(=O)-,, and, provided that:

[0469] the number of backbone atoms of the at least one instance of the linker is between 10 and 100, inclusive; and

[0470] the at least one instance of the linker does not comprise 0-0, O-N, N-O, or N-N.

[0471] 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 0-0, O-N, N-O, or N-N.

[0472] 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 A1278.70039WO00 76 linker comprises a covalent attachment to a solid support. In certain embodiments, a linker includes multiple positions for attachment of radicals of ligands.

[0473] 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.

[0474] In certain embodiments, a linker includes pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl) cyclohexane- 1 -carboxylate (SMCC), 6-aminohexanoic acid (AHEX or AHA), or a combination thereof.

[0475] 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.

[0476] 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 etal., J. Med. Chem. 1995, 38, 1846-1852; Lee etal., 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.

[0477] 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.

[0478] 1987, 4, 317-328; Toyokuni et al., Tetrahedron Lett. 1990, 31, 2673-2676; Biessen et al., J. Med. Chem. 1995, 38, 1538-1546; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Kim et al., Tetrahedron Lett. 1997, 38, 3487-3490; Lee et al., Bioconjug. Chem. 1997, 8, 762-765; Kato et al., Glycobiol. 2001, 11, 821-829; Rensen etal., J. Biol. Chem. 2001, 276, 37577-37584; Lee et al., Methods Enzymol. 2003, 362, 38-43; Westerlind et al., Glycoconj. J. 2004, 21, 227-241; Lee et al., Bioorg. Med. Chem. Lett. 2006, 16(19), 5132-5135; Maierhofer et al., Bioorg. Med. Chem.

[0479] 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 etal., J. Org. Chem. 2012, 77, 7564-7571; Biessen etal., FASEB J. 2000, 14, 1784-1792; Rajur et al., Bioconjug. Chem. 1997, 8, 935-940; Duff et al., Methods Enzymol.

[0480] 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; A1278.70039WO00 77 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;

[0481] 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.

[0482] 2012 / 0230938; U. S. 2005 / 0164235; U. S. 2006 / 0183886; U. S. 2012 / 0136042; U. S.

[0483] 2012 / 0095075; U. S. 2013 / 0109817; U. S. 2006 / 0148740; U. S. 2008 / 0206869; U. S.

[0484] 2012 / 0165393; U. S. 2012 / 0101148; U. S. 2013 / 0121954; U. S. 2011 / 0123520; U. S.

[0485] 2003 / 0077829; U. S. 2008 / 0108801; and U. S. 2009 / 0203132.

[0486] In certain embodiments, a linker comprises a structure selected from:

[0487]

[0488] A1278.70039WO00 78

[0489]

[0490] 2, 3, 4, 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.

[0491] In certain embodiments, a linker comprises a structure selected from:

[0492]

[0493] A1278.70039WO00 79

[0494]

[0495] 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0496] In certain embodiments, a linker comprises a structure selected from:

[0497] ° H ° ° H ° H °

[0498]

[0499] 0 0 o o A1278.70039WO00 80

[0500]

[0501] 6 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0502] In certain embodiments, a linker comprises a structure selected from:

[0503]

[0504] A1278.70039WO00 81

[0505]

[0506] O O, 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.

[0507] In certain embodiments, a linker comprises a structure selected from:

[0508]

[0509] o

[0510]

[0511] O, wherein each L is, independently, a phosphotriester, alkylphosphonate, phosphoramidate, phosphorothioate, phosphorodithioate, or phosphoro thiolate; 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.

[0512] In certain embodiments, a linker comprises a structure selected from:

[0513] A1278.70039WO00 82

[0514]

[0515]

[0516] 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.

[0517] In certain embodiments, a linker comprises a structure selected from:

[0518]

[0519] o o oM

[0520] A1278.70039WO00 84 OH

[0521] A

[0522]

[0523] 1278.70039WO00 85

[0524]

[0525]

[0526] , 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.

[0527] In certain embodiments, a linker comprises a structure selected from:

[0528]

[0529] , wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0530] In certain embodiments, a linker comprises a structure selected from:

[0531]

[0532] , 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.

[0533] In certain embodiments, a linker comprises a structure selected from:

[0534]

[0535] 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.

[0536] A1278.70039WO00 86 In certain embodiments, a linker comprises a structure selected from:

[0537] O °0

[0538] O H OH II H "..

[0539]

[0540] o and o, 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.

[0541] In certain embodiments, a linker comprises the structure:

[0542]

[0543] , wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0544] In certain embodiments, a linker comprises the structure:

[0545] 0 0

[0546]

[0547] H, 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.

[0548] In certain embodiments, at least one instance of L1is substituted or unsubstituted, Ci-ioo alkylene, substituted or unsubstituted, C2-100 alkenylene, substituted or unsubstituted, C2-100 alkynylene, substituted or unsubstituted, Ci-100 heteroalkylene, substituted or unsubstituted, C 2-100 heteroalkenylene, or substituted or unsubstituted, C 2-100 heteroalkynylene;

[0549] optionally wherein one or more backbone atoms of the Ci-100 alkylene, C 2-100 alkenylene, C2-100 alkynylene, Ci-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 unsubstituted heteroarylene, as valency permits.

[0550] In certain embodiments, at least one instance of L1is substituted or unsubstituted, C1-12 alkylene, substituted or unsubstituted, C2-12 alkenylene, substituted or unsubstituted, C2-12 alkynylene, substituted or unsubstituted, C1-12 heteroalkylene, substituted or unsubstituted, C2-12 heteroalkenylene, or substituted or unsubstituted, C2-12 heteroalkynylene;

[0551] optionally wherein one or two backbone atoms of the C1-12 alkylene, C2-12 alkenylene, C2-12 alkynylene, C1-12 heteroalkylene, C2-12 heteroalkenylene, or C2-12 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.

[0552] A1278.70039WO00 87 In certain embodiments, at least one instance of L1is substituted or unsubstituted, C13-24 alkylene, substituted or unsubstituted, C13-24 alkenylene, substituted or unsubstituted, C13-24 alkynylene, substituted or unsubstituted, C13-24 heteroalkylene, substituted or unsubstituted, C13-24 heteroalkenylene, or substituted or unsubstituted, C13-24 heteroalkynylene;

[0553] optionally wherein one, two, or three backbone atoms of the C13-24 alkylene, C13-24 alkenylene, C13-24 alkynylene, C13-24 heteroalkylene, C13-24 heteroalkenylene, or C13-24 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.

[0554] In certain embodiments, at least one instance of L1is substituted or unsubstituted, C25-50 alkylene, substituted or unsubstituted, C25-50 alkenylene, substituted or unsubstituted, C25-50 alkynylene, substituted or unsubstituted, C25-50 heteroalkylene, substituted or unsubstituted, C 25-50 heteroalkenylene, or substituted or unsubstituted, C 25-50 heteroalkynylene;

[0555] optionally wherein one, two, three, or four backbone atoms of the C 25-50 alkylene, C 25-50 alkenylene, C25-50 alkynylene, C25-50 heteroalkylene, C25-50 heteroalkenylene, or C25-50 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.

[0556] In certain embodiments, at least one instance of L1is substituted or unsubstituted, C51-100 alkylene, substituted or unsubstituted, C51-100 alkenylene, substituted or unsubstituted, C51-100 alkynylene, substituted or unsubstituted, C51-100 heteroalkylene, substituted or unsubstituted, C51-100 heteroalkenylene, or substituted or unsubstituted, C51-100 heteroalkynylene;

[0557] optionally wherein one, two, three, four, or five backbone atoms of the C51-100 alkylene, C51-100 alkenylene, C51-100 alkynylene, C51-100 heteroalkylene, C51-100 heteroalkenylene, or C51-100 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.

[0558] In certain embodiments, at least one instance of L1is substituted or unsubstituted, C7-70 alkylene or substituted or unsubstituted, C7-70 heteroalkylene;

[0559] optionally wherein 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.

[0560] In certain embodiments, at least one instance of L1is substituted or unsubstituted, C7-70 heteroalkylene;

[0561] A1278.70039WO00 88 optionally wherein one, two, or three backbone atoms of the C7-70 heteroalkylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted phenylene, or substituted or unsubstituted heteroarylene, as valency permits.

[0562] In certain embodiments, at least one instance of L1is of the formula:

[0563] ^|_1A2 |_1A3 j_1Ar ^1B1X^|_1A4XL1C1, L1*6, L137_LLC21 1A10 1 1A11

[0564] |_1A6 |_1A6X'L1A9''

[0565]

[0566] each of -L1A1-L1A2-, -L1A3-L1A4-, -L1A5-L1A6-, -L1A7-L1A8-, -L1A9-L1A10-, and -L1A11-L1A12- 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-, -OP(=O)(SRa)O-, or -OP(=S)(ORa)O-;

[0567] each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl;

[0568] each of L1B1, L1B2, and L1B3is independently a single bond, substituted or unsubstituted, Ci-100 alkylene, or substituted or unsubstituted, Ci-100 heteroalkylene;

[0569] each of L1C1and L1C2is independently a single bond, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene; and

[0570] bond C1Ais attached to A1.

[0571] In certain embodiments, at least one instance of L1is of the formula:

[0572] Z, |_1A2 [_1A3 [_1C1. 1A6 I 1A7

[0573] |_1A1' YB< \1A4^ \1A5' ^L1 B2^ \lA8

[0574]

[0575] In some embodiments, each of-L1A1-L1A2-, -L1A3-L1A4-, -L1A5-L1A6-, -L1A7-L1A8-, -L1A9-L1A10-, and -L1A11-L1A12- is independently Option Al; or, in some embodiments, Option A2; or, in certain embodiments, Option A3; or, in certain embodiments, Option A4. In some embodiments, at least one of -L1A1-L1A2-, -L1A3-L1A4-, -L1A5-L1A6-, -L1A7-L1A8-, -L1A9-L1A10_,and -L1 Al’-L1 Al2_ is independently Option A5; or, in some embodiments, Option A6.

[0576] A1278.70039WO00 89 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.

[0577] In some embodiments, each of L1B1, L1B2, and L1B3independently is Option Bl; or, in some embodiments, Option B2; or, in some embodiments, Option B3; or, in certain embodiments, Option B4; or, in certain embodiments, Option B5; or, in certain embodiments, Option B6.

[0578] Table 1A. Options for certain linker components

[0579] Option

[0580] Option

[0581] Number

[0582] Al a single bond, -O-, -NRa-, -C(=O)NRa-, or -NRaC(=O)- A2 a single bond, -O-, -NH-, -C(=O)NH-, or -NHC(=O)- A3 a single bond, -C(=O)NRa-, or -NRaC(=O)- A4 a single bond, -C(=O)NH-, or -NHC(=O)- A5 -C(=O)O-, -OC(=O)-, -OP(=O)(ORa)O-, -SP(=O)(ORa)O-, -OP(=O)(ORa)S-, - OP(=O)(SRa)O-, or -OP(=S)(ORa)O- A6 -C(=O)O-, -OC(=O)-, -OP(=O)(OH)O-, -SP(=O)(OH)O-, -OP(=O)(OH)S-, - OP(=O)(SH)O-, or -OP(=S)(OH)O- Bl a single bond, substituted or unsubstituted, C1-20 alkylene, or substituted or unsubstituted, C1-20 heteroalkylene

[0583] B2 substituted or unsubstituted, C1-10 alkylene or substituted or unsubstituted, C1-10 heteroalkylene

[0584] B3 substituted or unsubstituted, C11-20 alkylene or substituted or unsubstituted, C11-20 heteroalkylene

[0585] B4 unsubstituted C1-10 alkylene

[0586] B5 unsubstituted C11-20 alkylene

[0587] B6 consisting of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats

[0588]

[0589] In certain embodiments, at least one instance of L1C1and L1C2is a single bond. In certain embodiments, at least one instance of L1C1and L1C2is substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms.

[0590] In certain embodiments, L1thereof is of the formula:

[0591] O

[0592]

[0593] A1278.70039WO00 90 H

[0594] O

[0595] In certain embodiments, at least one instance of L1is of the formula:

[0596] [_1A13

[0597] each of -L1A1-L1A2-, -L1A3-L1A4-, -L1A5-L1A6-, -L1A7-L1A8-, -L1A9-L1A10-, -L1A13pl A 14 pl Al 5_pl Al 6 pl Al 7_pl Al 8 pl Al 9_pl A20 pl A21_pl A22 pl A23_pl A24 pl A25

[0598]

[0599] L1A26-, pi A2?_pi A28_ _pi A29_J^I A3o_an(j _pi A3 i_pi A32_ 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-;

[0600] each instance of Rais independently hydrogen, substituted or unsubstituted, Ci-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl;

[0601] each of L1B1, L1B2, L1B3, L1B4, L1B5, L1B6, L1B7, L1B8, and L1B9is independently a single bond, substituted or unsubstituted, Ci-100 alkylene, or substituted or unsubstituted, Ci-100 heteroalkylene;

[0602] each of L1C1, L1C2, L1C3, L1C4, L1C5, and L1C6is a single bond, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene;

[0603] bond C1Bis attached to a first instance of A1; and

[0604] A1278.70039WO00 91 bond Clcis attached to a second instance of A1.

[0605] In some embodiments, each of -L1A1-L1A2-, -L1A3-L1A4-, -L1A5-L1A6-, -L1A7-L1A8-, -L1A9_L1A1° _ Ll A13_J^1 Al 4 _ pl A 1 _pl A 16 _ plA17_plA18 _ pl A 19_pl A20 _ plA2l_plA22 _ L

[0606]

[0607] 1A23-L1A24-, -L1 A25_L'A26_, -L1 A27_L'A28-, _pl A29_pl A30_,anJ _pl A31_j^l A32_ |nJepenJen[ 1 y Option Al; or, in some embodiments, Option A2; or, in certain embodiments, Option A3; or, in certain embodiments, Option A4. In some embodiments, at least one of -L1A1-L1A2-, -L1A3-pl A4 pl A5_ pl A6 pl A7_ pl A8 pl A9_pl A10 pl Al 3_pl A14 pl A 15_pl A 16 pl A17_pl Al 8 pl Al 9_pl A20 pl A21_pl A22 pl A23_pl A24 pl A25_pl A26 pl A27_pl A28 pl A29_pl A30_an(j >

[0608]

[0609] L1A31_L1A32_ is independently Option A5; or, in some embodiments, Option A6.

[0610] In some embodiments, each of L1B1, L1B2, L1B3, L1B4, L1B5, L1B6, L1B7, L1B8, and L1B9independently is Option Bl; or, in some embodiments, Option B2; or, in some embodiments, Option B3; or, in certain embodiments, Option B4; or, in certain embodiments, Option B5; or, in certain embodiments, Option B6.

[0611] In certain embodiments, at least one instance of L1C1, L1C2, L1C3, L1C4, L1C5, and L1C6is a single bond. In certain embodiments, at least one instance of L1C1, L1C2, L1C3, L1C4, L1C5, and L1C6is substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms.

[0612] In certain embodiments, at least one instance of L1is of the formula:

[0613] |_1B9 I 1A29 L1A28, L1 B8

[0614] ^1A30"L\|_1C6^ L1A27

[0615]

[0616] In certain embodiments, at least one instance of L1is of the formula:

[0617] A1278.70039WO00 92 ■^C]C^L1A32

[0618]

[0619] In certain embodiments, at least one instance of L2is -O-, -S-, -S-S-, -NRd-, -C(=O)O-, -C(=NRd)O-, -S(=O)O-, -S(=O)2O-, -C(=O)NRd- -C(=NRd)NRd-, -S(=O)NRd- -S(=O)2NRd-, -OC(=O)-, -OC(=NRd)-, -OS(=O)-, -OS(=O)2- -NRdC(=O)-, -NRdC(=NRd)-, -NRdS(=O)-, -NRdS(=O)2-, -OC(=O)O-, -OC(=NRd)O- -OS(=O)O-, -OS(=O)2O-, -NRdC(=O)O-, -NRdC(=NRd)O-, -NRdS(=O)O- -NRdS(=O)2O- -OC(=O)NRd- -OC(=NRd)NRd-, -OS(=O)NRd-, -OS(=O)2NRd- -NRdC(=O)NRd-, -NRdC(=NRd)NRd-, -NRdS(=O)NRd-, -NRdS(=O)2NRd-, -C(=O)-, -C(=NRd)-, -S(=O)-, -S(=O)2- -OP(=O)(ORd)O-, -SP(=O)(ORd)O-, -OP(=O)(ORd)S-, -OP(=O)(SRd)O- -OP(=S)(ORd)O-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;

[0620] 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; and

[0621] each instance of Rdis 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 Rdattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.

[0622] A1278.70039WO00 93 In certain embodiments, at least one instance of Rdis hydrogen or substituted or unsubstituted Ci-6 alkyl. In some embodiments, each instance of Rdis independently hydrogen or substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, each instance of Rdis independently hydrogen or unsubstituted Ci-6 alkyl.

[0623] In certain embodiments, at least one instance of L2is substituted or unsubstituted, Ci-6 heteroalkylene. In certain embodiments, at least one instance of L2is of the formula: -O-, -O-P(=O)(ORd)-O-, -O-P(=O)(ORd)-S-, -S-P(=O)(ORd)-O-, -O-P(=S)(ORd)-O-, -CH2-O-, -CH2-O-P(=O)(ORd)-O-, -CH2-O-P(=O)(ORd)-S-, -CH2-S-P(=O)(ORd)-O-, -CH2-O-P(=S)(ORd)-O-, -O-CH2-, -O-P(=O)(ORd)-O-CH2-, -O-P(=O)(ORd)-S-CH2-, -S-P(=O)(ORd)-O-CH2-, or -O-P(=S)(ORd)-O-CH2- In certain embodiments, at least one instance of L2is of the formula: -O-, -O-P(=O)(OH)-O-, -O-P(=O)(OH)-S-, -S-P(=O)(OH)-O-, -O-P(=S)(OH)-O-, -CH2-O-, -CH2-O-P(=O)(OH)-O-, -CH2-O-P(=O)(OH)-S-, -CH2-S-P(=O)(OH)-O-, -CH2-O-P(=S)(OH)-O-, -O-CH2-, -O-P(=O)(OH)-O-CH2-, -O-P(=O)(OH)-S-CH2-, -S-P(=O)(OH)-O-CH2-, or -O-P(=S)(OH)-O-CH2-.

[0624] In certain embodiments, at least one instance of LA, when present, is of the formula:

[0625]

[0626] each instance of ZA1and ZA2is independently a single bond, substituted or unsubstituted, C1-6 alkylene, or substituted or unsubstituted, C2-6 alkenylene;

[0627] each instance of WAis 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;

[0628] each instance of Rcis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two instances of Rcare joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and

[0629] A1278.70039WO00 94 bond C4Ais attached to L4.

[0630] In some embodiments, at least one instance of ZA1is substituted or unsubstituted, Ci-6 alkylene. In some embodiments, at least one instance of ZA1is substituted or unsubstituted, C1-3 alkylene. In certain embodiments, at least one instance of ZA1is unsubstituted C1-3 alkylene. In some embodiments, at least one instance of ZA2is substituted or unsubstituted, C1-6 alkylene. In some embodiments, at least one instance of ZA2is substituted or unsubstituted, C1-3 alkylene. In certain embodiments, at least one instance of ZA2is unsubstituted C1-3 alkylene.

[0631] In some embodiments, WAis -N(RC)-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRC-, or -NRCC(=O)-. In certain embodiments, WAis -N(RC)-, -C(=O)NRC-, or -NRCC(=O)-.

[0632] In certain embodiments, at least one instance of Rcis hydrogen or substituted or unsubstituted C1-6 alkyl. In some embodiments, each instance of Rcis independently hydrogen or substituted or unsubstituted, C1-6 alkyl. In certain embodiments, each instance of Rcis independently hydrogen or unsubstituted C1-6 alkyl.

[0633] In certain embodiments, at least one instance of LA, when present, is of the formula:

[0634] O O X ZA1^bA /

[0635] |c4A|c

[0636]

[0637] 4A

[0638] In certain embodiments,

[0639] at least one instance of LA, when present, is of the formula:

[0640]

[0641] bond C4Bis attached to the 3’ position of a first nucleoside; and

[0642] bond C4cis attached to the 5’ position of a second nucleoside.

[0643] In certain embodiments, at least one instance of y4, when present, is 1.

[0644] In certain embodiments, at least one instance of L4, when present, 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, C 2-100 heteroalkynylene;

[0645] optionally wherein one or more backbone atoms of the Ci-100 alkylene, C 2-100 alkenylene, C2-100 alkynylene, Ci-100 heteroalkylene, C 2-100 heteroalkenylene, or C 2-100 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or A1278.70039WO00 95 unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.

[0646] In certain embodiments, at least one instance of L4, when present, is a bond.

[0647] In some embodiments, at least one instance of L4, when present, is

[0648] A J4A2, L4A3^L4A6^|_4A7 / L4“ 4A18 I 4A19 QA [_4A1 [_4B1 [_4A4 [_4A5 [_4B2 [_4A8 Q4A17^ ^|_4B3^ ^4A20

[0649]

[0650] each of -L4A1-L4A2-, -L4A3-L4A4-, -L4A5-L4A6-, -L4A7-L4A8-, _L4A17-L4A18-, and -L4Ai9_L4A2o_isindependently a single bond, -O-, -S-, -S-S-, -NRa-, -C(=O)O-, -C(=NRa)O--S(=O)O-, -S(=O)2O-, -C(=O)NRa-, -C(=NRa)NRa-, -S(=O)NRa-, -S(=O)2NRa-, -OC(=O)-, -OC(=NRa)-, -OS(=O)-, -OS(=O)2-, -NRaC(=O)-, -NRaC(=NRa)-, -NRaS(=O)-, -NRaS(=O)2-, -OC(=O)O-, -OC(=NRa)O-, -OS(=O)O-, -OS(=O)2O-, -NRaC(=O)O-, - NRaC(=NRa)O-, -NRaS(=O)O-, -NRaS(=O)2O-, -OC(=O)NRa-, -OC(=NRa)NRa-, -OS(=O)NRa-, -OS(=O)2NRa-, -NRaC(=O)NRa-, -NRaC(=NRa)NRa-, -NRaS(=O)NRa-, -NRaS(=O)2NRa-, -C(=O)-, -C(=NRa)-, -S(=O)-, -S(=O)2-, -OP(=O)(ORa)O-, -SP(=O)(ORa)O-, -OP(=O)(ORa)S-, or -OP(=O)(SRa)O-;

[0651] each instance of Rais independently hydrogen, substituted or unsubstituted, Ci-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl;

[0652] each of L4B1, L4B2, and L4B3is independently a single bond, substituted or unsubstituted, Ci-ioo alkylene, or substituted or unsubstituted, Ci-ioo heteroalkylene;

[0653] each of L4C1and L4C2is a single bond, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted hetero arylene; and

[0654] bond C4Ais attached to A4.

[0655] In some embodiments, each of -L4A1-L4A2-, -L4A3-L4A4-, -L4A5-L4A6-, -L4A7-L4A8-, -L4A17-L4A18-, and _L4A19-L4A20- is independently Option Al; or, in some embodiments, Option A2; or, in certain embodiments, Option A3; or, in certain embodiments, Option A4. In some embodiments, at least one of -L4A1-L4A2-, -L4A3-L4A4-, -L4A5-L4A6-, -L4A7-L4A8-, -L4A17-L4A18_,anc| _J^4AI9_J^4A2O_ -sindependeniy Option A5; or, in some embodiments, Option A6.

[0656] In some embodiments, each of L4B1, L4B2, and L4B3is independently Option Bl; or, in some embodiments, Option B2; or, in some embodiments, Option B3; or, in certain embodiments, Option B4; or, in certain embodiments Option B5; or, in certain embodiments, Option B6.

[0657] A1278.70039WO00 96 In certain embodiments, each of L4C1and L4C2is a single bond. In certain embodiments, each of L4C1and L4C2is independently substituted or unsubstituted heteroarylene. In certain embodiments, at least one instance of L4C1and L4C2is substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms.

[0658] In some embodiments, at least one instance of L4, when present, is

[0659] [_4C6 [_4A35 [_4A34 |_4C5 p4B I 4A39 J \38 / "'L4A36 / X'[_4B8 / ^4A33^ Q4A32 \L4A40^L4B9L4A37

[0660] O L4A31[_4A22 [_4A23 L4CJ? |_4A26 [_4A27 [_4C44A3Q[_4B7 L4A21^ \4B4^ > A24" ^^25^ \4B5^ > A28^ \4A2<L^4B6

[0661] ^50. 4B124A47>4A4<LX4A48 / L\ J4A46XL4B11A<43 / L4A42 / L4B1°

[0662] L |^4C8 |_4A45 |_4A44 ^\|_4C7 ^'"'|_4A41

[0663]

[0664] each of -L4A21-L4A22p4A23_p4A24 p4A25_p4A26 p4A27_p4A28 p4A29_p4A30 L4A31_L4A32_ p4A33_p4A34 _ p4A35_p4A36 _ J^4A37_J^4A38 _ p4A39_p4A40 _ p4 A41 _p4 A42 _ p4A43_p4A44_, _p4A45_p4A46_, _p4A47_p4A48_,an(j _p4A49_p4A50_ •sjnc|epen(Jen11 yasingle 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-;

[0665] each instance of Rais independently hydrogen, substituted or unsubstituted, Ci-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl;

[0666] each of L4B4, L4B5, L4B6, L4B7, L4B8, L4B9, L4B1°, L4B11, and L4B12is independently a single bond, substituted or unsubstituted, Ci-100 alkylene, or substituted or unsubstituted, Ci-100 heteroalkylene;

[0667] each of L4C3, L4C4, L4C5, L4C6, L4C7, and L4C8is a single bond, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene;

[0668] bond C4Bis attached to a first instance of A4; and

[0669] bond C4cis attached to a second instance of A4.

[0670] A1278.70039WO00 97 In some embodiments, each of -L4A21-L4A22-, _L4A23-L4A24-, -L4A25-L4A26-, _L4A27_ J^4A28 _ J^4A29_J^4A30 _ J^4A31_J^4A32 _ J^4A33_J^4A34 _ J^4A35_J^4A36 _ J^4A37_J^4A38 _ j^4A39_ j^4A40 _ j^4A4 l_j^4A42 _ J^4A43_J^4A44 _ J^4A45_J^4A46 _ J^4A47_J^4A48_aRj _J^4A49_J^4A50_ independently Option Al; or, in some embodiments, Option A2; or, in certain embodiments, Option A3; or, in certain embodiments, Option A4. In some embodiments, at least one of -L4A21- j^4A22 _ ]^4A23_]^4A24 _ J^4A25_J^4A26 _ J^4A27_J^4A28 _ J^4A29_J^4A30 _ J^4A31_J^4A32 _ j^4A33_ j^4A34 _ ]^4A35_]^4A36 _ J^4A37_J^4A38 _ J^4A39_J^4A40 _ j^4 A41 _^4 A42 _ J^4A43_J^4A44 _ j^4A45_

[0671]

[0672] ^4A46_, _J^4A47_J^4A48_,an(j _J^4A49_J^4A5O_ jnc|epen(jen11 y Option A5; or, in some embodiments, Option A6.

[0673] In some embodiments, each of L4B4, L4B5, L4B6, L4B7, L4B8, L4B9, L4B10, L4B11, and L4B12is independently Option Bl; or, in some embodiments, Option B2; or, in some embodiments, Option B3; or, in certain embodiments, Option B4; or, in certain embodiments, Option B5; or, in certain embodiments, Option B6.

[0674] In certain embodiments, each of L4C3, L4C4, L4C5, L4C6, L4C7, and L4C8is a single bond. In certain embodiments, each of L4C3, L4C4, L4C5, L4C6, L4C7, and L4C8is independently substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms.

[0675] Ligands

[0676] In an oligonucleotide of the present disclosure, each instance of each of A1, A2, and A4, if present, may independently be a radical of a ligand.

[0677] Two or more ligands may be attached to the same or different positions of the corresponding linker, as valency permits. For example, when yl is 2, the two instances of A1may be attached to the same position of L1or two different positions of L1, as valency permits.

[0678] In some embodiments, at least one instance of A1, if present, is a radical of a ligand. In certain embodiments, at least two instances of A1, if present, are radicals of ligands. In some embodiments, at least one instance of A2, if present, is a radical of a ligand. In certain embodiments, at least two instances of A2, if present, are radicals of ligands. In some embodiments, at least one instance of A4, if present, is a radical of a ligand. In certain embodiments, at least two instances of A4, if present, are radicals of ligands. In some embodiments, at least one ligand is a central nervous system receptor ligand. In certain embodiments, at least one ligand is a TrkB receptor ligand. In certain embodiments, at least one ligand is a selective TrkB modulator. In certain embodiments, at least one ligand is a non- selective TrkB modulator (z.e., a pan TrkABC modulator). In certain embodiments, at least one ligand is a CBi receptor ligand. In certain embodiments, at least one ligand is an a.4 1 / 7 integrin A1278.70039WO00 98 receptor ligands. In certain embodiments, at least one ligand is an NMDA receptor ligand. In some embodiments, a ligand directs an oligonucleotide to a location in a subject. In some embodiments, a ligand targets a tissue. In some embodiments, the tissue is brain tissue. In some embodiments, the ligand targets an organ. In some embodiments, the organ is a brain. In some embodiments, a ligand targets a cell.

[0679] In some embodiments, a ligand targets a cell receptor. In certain embodiments, a cell receptor is a TrkB receptor, a CBi receptor, an a.4 1 / 7 integrin receptor, or an NMDA receptor. In some embodiments, a receptor is in the brain. In some embodiments, a receptor is in the frontal cortex. In some embodiments, a receptor is in the striatum. In some embodiments, a receptor is in the cerebellum. In some embodiments, a receptor is in the brain stem. In some embodiments, a receptor is in the hippocampus. In some embodiments, a receptor is in the spinal cord. In some embodiments, a ligand is used to target an oligonucleotide to a cell type. In some embodiments, the cell is a central nervous system cell. In certain embodiments, the cell is a neuron. In certain embodiments, the cell is a glial cell. In certain embodiments, the cell is an astrocyte. In certain embodiments, the cell is an oligodendrocyte. In certain embodiments, the cell is an ependymal cell. In certain embodiments, the cell is a microglia.

[0680] In some embodiments, a ligand is an agonist of a receptor (e.g., a TrkB, CBi, a.401 / 7 integrin, or NMDA receptor agonist). In some embodiments, a ligand is an antagonist of a receptor (e.g., a TrkB, CBi, ai 1 / ? integrin, or NMDA receptor antagonist).

[0681] In certain embodiments, at least one TrkB ligand is a compound of the formula:

[0682]

[0683] A1278.70039WO00 99 OH

[0684]

[0685] R2is hydrogen, -OR7, -SR8, or -NR9R10;

[0686] R3is hydrogen, -OR31, -SR32, or -NR33R34;

[0687] R4is hydrogen, -OR35, -SR36, or -NR37R38;

[0688] R5is hydrogen, -OR39, -SR40, or -NR41R42;

[0689] R6is hydrogen, -OH, optionally substituted -O-alkyl, optionally substituted -OAc, -NH2, optionally substituted -NHAc, -SH, or =0;

[0690] R7, R8, R9, R10, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, and R42are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0691] Y is CH2, NH, S, or O;

[0692] Z is optionally substituted aryl or optionally substituted heteroaryl;

[0693] R11and R13are each independently absent, hydrogen, or optionally substituted alkyl; R12, R14, and R15are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0694] R16is hydrogen, halogen, -CN, -N3, -SOni6R1A, -SOv16NR16BR16C, -NHNR16BR16C, -ONR16BR16C, -NHC(O)NHNR16BR16C, -NHC(O)NR16BR16C, -N(0)mi6, -NR16BR16C, -C(O)R16D, -C(O)OR16D, -C(O)NR16BR16C, -0R16A, -NR16BSO2R16A, -NR16BC(O)R16D, -NR16BC(O)OR16D, -NR16BOR16D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0695] and =^= are each independently a single bond or a double bond, wherein if ~ is a single bond, then =^= is a double bond, and R13is absent; and further wherein if

[0696]

[0697] is a single bond, then is a double bond, and R11is absent;

[0698] R16A, R16B, R16C, R16Dare each independently hydrogen, halogen, -CF3, -CCh,-CBr3, -CI3, -C00H, -C0NH2, substituted or unsubstituted alkyl, substituted or unsubstituted

[0699] A1278.70039WO00 100 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R16Band R16Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

[0700] R17, R18, and R19are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0701] R20is hydrogen, halogen, -CN, -N3, -SOn20R1A, -SOv20NR20BR20C, -NHNR20BR20C, -ONR20BR20C, -NHC(O)NHNR20BR20C, -NHC(O)NR20BR20C, -N(O)m20, -NR20BR20C, -C(O)R20D, -C(O)OR20D, -C(O)NR20BR20C, -OR20A, -NR20BSO2R20A, -NR20BC(O)R20D, -NR20BC(O)OR20D, -NR20BOR20D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0702] R21is hydrogen, halogen, -CN, -N3, -SOn2iR1A, -SOV2INR21BR21C, -NHNR21BR21C, -ONR21BR21C, -NHC(O)NHNR21BR21c, -NHC(O)NR21BR21c, -N(O)m2i, -NR21BR21C, -C(O)R21D, -C(O)OR21D, -C(O)NR21BR21c, -OR21A, -NR21BSO2R21A, -NR21BC(O)R21D, -NR21BC(O)OR21D, -NR21BOR21D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0703] R22and R23are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0704] R24is hydrogen, halogen, -CN, -N3, -SOn24R1A, -SOv24NR24BR24C, -NHNR24BR24C, -ONR24BR24C, -NHC(O)NHNR24BR24C, -NHC(O)NR24BR24C, -N(O)m24, -NR24BR24C, -C(O)R24D, -C(O)OR24D, -C(O)NR24BR24C, -OR24A, -NR24BSO2R24A, -NR24BC(O)R24D, -NR24BC(O)OR24D, -NR24BOR24D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0705] R20A,R20B,R20(R20DR21AR2WR21CR21 DR24AR24B,R24CAND R24DAFE EACHindependently hydrogen, halogen, -CF3, -CC13, -CBr3, -CI3,-COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R20B, R20C, R21B, R21C, R24B, R24C, R24B, and R24Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

[0706] A1278.70039WO00 101 nl6, n20, n21, n23, n24, z6, and z8 are each independently 0, 1, 2, 3, or 4;

[0707] vl6, v20, v21, ml6, m20, m21, and m24 are each independently 1 or 2;

[0708] z3 is 0, 1, 2, 3, 4, or 5;

[0709] z4 and z7 are each independently 0, 1, or 2;

[0710] z5 is 0, 1, 2, or 3; and

[0711] z6 and z8 are each independently 0, 1, 2, 3, or 4.

[0712] In some embodiments, R2is hydrogen or -OR7. In certain embodiments, R2is hydrogen. In certain embodiments, R2is -OR7. In certain embodiments, R2is -OH. In certain embodiments, R2is -OCH3. In some embodiments, R3is hydrogen or -OR31. In certain embodiments, R3is hydrogen. In certain embodiments, R3is -OR31. In certain embodiments, R3is -OH. In certain embodiments, R3is -OCH3. In some embodiments, R4is hydrogen or -OR35. In certain embodiments, R4is hydrogen. In certain embodiments, R4is -OR35. In certain embodiments, R4is -OH. In certain embodiments, R4is -OCH3. In some embodiments, R5is hydrogen or -OR39. In certain embodiments, R5is hydrogen. In certain embodiments, R5is -OR39. In certain embodiments, R5is -OH. In certain embodiments, R5is -OCH3. In some embodiments, R6is hydrogen, -OH, or optionally substituted -O-alkyl. In certain embodiments, R6is hydrogen.

[0713] In some embodiments, R7, R8, R9, R10, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, and R42are each independently hydrogen or optionally substituted alkyl. In certain embodiments, R7, R8, R9, R10, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, and R42are each independently hydrogen. In certain embodiments, R7, R8, R9, R10, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, and R42are each independently optionally substituted alkyl. In certain embodiments, R7, R8, R9, R10, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, and R42are each independently unsubstituted alkyl. In certain embodiments, R7, R8, R9, R10, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, and R42are each independently -CH3.

[0714] In some embodiments, Y is NH or O. In certain embodiments, Y is O.

[0715] In some embodiments, Z is optionally substituted aryl. In certain embodiments, Z is optionally substituted phenyl. In certain embodiments, Z is unsubstituted phenyl.

[0716] In certain embodiments, at least one radical of a TrkB ligand is of the formula

[0717]

[0718] O, O, or O. In certain

[0719] A1278.70039WO00 102 embodiments, at least one radical of a TrkB ligand is of the formula

[0720]

[0721] O

[0722]

[0723] O

[0724] In some embodiments, R11and R13are each independently absent or hydrogen. In certain embodiments, R11and R13are each independently absent. In some embodiments, R12, R14, and R15are each independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R12, R14, and R15are each independently hydrogen. In certain embodiments, R12, R14, and R15are each independently optionally substituted alkyl. In certain embodiments, R12, R14, and R15are each independently unsubstituted alkyl. In certain embodiments, R12is -CH3. In some embodiments, R16is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R16is hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, R16is -NHCH3.

[0725] In some embodiments, R17, R18, and R19are each independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R17, R18, and R19are each independently hydrogen, unsubstituted alkyl, or unsubstituted heteroalkyl.

[0726] In some embodiments, R20is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R20is hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, R20is hydrogen. In some embodiments, R21is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R21is hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, R21is hydrogen. In some embodiments, R22and R23are each independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R22and R23are each independently hydrogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, R22and R23are each independently A1278.70039WO00 103 hydrogen. In some embodiments, R24is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R24is hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, R24is hydrogen.

[0727] In some embodiments, nl6, n20, n21, n23, n24, z6, and z8 are each independently 0, 1, 2. In certain embodiments, nl6, n20, n21, n23, n24, z6, and z8 are each independently 0. In certain embodiments, vl6, v20, v21, ml6, m20, m21, and m24 are each independently 1. In certain embodiments, vl6, v20, v21, ml6, m20, m21, and m24 are each independently 2. In some embodiments, z3 is 0, 1, 2, or 3. In certain embodiments, z3 is 0. In some embodiments, z4 and z7 are each independently 0 or 1. In certain embodiments, z4 and z7 are each independently 0. In some embodiments, z5 is 0, 1, or 2. In certain embodiments, z5 is 0. In some embodiments, z6 and z8 are each independently 0, 1, or 2. In certain embodiments, z6 and z8 are each independently 0.

[0728] In some embodiments, at least one radical of a TrkB ligand is of the formula

[0729]

[0730] A1278.70039WO00 104 In some embodiments, at least one radical of a TrkB ligand is of the formula:

[0731]

[0732] In certain embodiments, at least one TrkB ligand is flavone, tropoflavin, or a derivative thereof. In certain embodiments, at least one TrkB ligand is 3,7-dihydroxyflavone, 3,7, 8,2'-tetrahydroxyflavone, 7,3 '-dihydroxyflavone, 7, 8,2 '-trihydroxyflavone, 7,8,3 '-trihydroxyflavone, 7,8,4'-trihydroxyflavone, diosmetin (5,7,3'-trihydroxy-4'-methoxyflavone), 7-hydroxy-4'-methoxyflavone, 8-hydroxy-7-methoxyflavone, eutropoflavin (4'-dimethylamino-7,8-dihydroxyflavone), norwogonin (5,7,8-trihydroxyflavone), R7, R13, tropoflavin (7,8-dihydroxyflavone), 7,8-dimethoxyflavone, quercetin (3,3',4',5,7-pentahydroxyflavone), apigenin (4',5,7-trihydroxyflavone), isocoumarin, gossypetin (3,5,7,8,3',4'-hexahydroxyflavone), 2-methyl-8-phenylchromeno[7,8-d]imidazol-6(3H)-one, 8-phenylchromeno[7,8-d]imidazol-6(3H)-one, 4-oxo-2-phenyl-4H-chromene-7,8-diyl diacetate, or ANA- 12.

[0733] In certain embodiments, at least one a.4 1 / 7 integrin ligand is of the formula:

[0734]

[0735] wherein:

[0736] each instance of R1Zis independently optionally substituted heteroaryl or optionally substituted phenyl;

[0737] A1278.70039WO00 105 each instance of R33Zis 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);

[0738] each instance of R34Zis of the formula:

[0739]

[0740] each instance of R2Zis independently hydrogen, optionally substituted polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, or optionally substituted heteroaryl; and

[0741] each instance of X4Zis N or C(R35Z); and

[0742] each instance of R35zis independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted alkoxy.

[0743] In certain embodiments, at least one a.4 1 / 7 integrin ligand is of the formula:

[0744]

[0745] each instance of X3Zand X5Zis independently N or C(R32Z);

[0746] each instance of R32Zis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted polyethylene glycol, or -S(=0)2(optionally substituted alkyl);

[0747] each instance of R3Z, R4Z, and R36Zis independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted alkoxy.

[0748] A1278.70039WO00 In certain embodiments, at least one a.4 1 / 7 integrin ligand is of the formula:

[0749]

[0750] each instance of R2Zis independently hydrogen, polyethylene glycol, optionally substituted heteroalkyl, or optionally substituted heteroaryl; and

[0751] each instance of R3Zand R4Zis independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted alkoxy.

[0752] In certain embodiments, at least one instance of R1Zis optionally substituted 6-membered heteroaryl. In certain embodiments, at least one instance of R1Zis optionally substituted pyridinyl (e.g., optionally substituted 3-pyridinyl or optionally substituted 4-pyridinyl). In certain embodiments, at least one instance of R1Zis optionally substituted 5-membered heteroaryl. In certain embodiments, at least one instance of R1Zis optionally substituted pyrrolyl (e.g., optionally substituted 2-pyrrolyl). In certain embodiments, at least one instance of R1Zis unsubstituted phenyl. In certain embodiments, at least one instance of R1Zis 2-monosubstituted phenyl, 3-monosubstituted phenyl, or 4-monosubstituted phenyl. In certain embodiments, at least one instance of R1Zis 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(=0)2(optionally substituted alkyl). In certain embodiments, the substituents described in this paragraph are independently halogen, unsubstituted Ci-6 alkyl, or -S(=O)2(unsubstituted Ci-6 alkyl).

[0753] In certain embodiments, at least one instance of R33Zis -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 R33Zis -O(unsubstituted C1-6 alkyl); -OH; -NH2; -NHOH; -NH(unsubstituted C1-6 alkyl); -NH(CI-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^); -N (unsubstituted C1-6 alkyl)2; or -N (unsubstituted C1-6 alkyl)(Ci-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).

[0754] In some embodiments, at least one instance of R2Zis hydrogen or substituted or unsubstituted heteroalkyl. In certain embodiments, at least one instance of R2Zis hydrogen. In A1278.70039WO00 107 certain embodiments, at least one instance of R2Zis optionally substituted alkyl. In certain embodiments, at least one instance of R2Zis unsubstituted Ci-6 alkyl (e.g., Me). In some embodiments, each of R3Zand R4Zis independently hydrogen or halogen. In certain embodiments, each of R3Zand R4Zis independently halogen. In some embodiments, at least one instance of R36Zis hydrogen or halogen (e.g., -F).

[0755] In certain embodiments, at least one radical of the a40i / 7 integrin ligand is of the formula:

[0756]

[0757] In certain embodiments, at least one radical of the a.4 1 / 7 integrin ligand is of the formula:

[0758]

[0759] In certain embodiments, at least one radical of the a.401 / 7 integrin ligand is of the formula:

[0760]

[0761] In certain embodiments, at least one a40i / 7 integrin ligand is of the formula:

[0762]

[0763] A1278.70039WO00 108 In certain embodiments, at least one a.4 1 / 7 integrin ligand is of the formula:

[0764]

[0765] In certain embodiments, at least one a.401 / 7 integrin ligand is of the formula:

[0766]

[0767] In certain embodiments, at least one a40i / 7 integrin ligand is of the formula:

[0768]

[0769] In certain embodiments, at least one radical of the a40i / 7 integrin ligand is of the formula:

[0770]

[0771] In certain embodiments, at least one radical of an a40i / 7 integrin ligand is of the formula: A1278.70039WO00 109

[0772]

[0773] R4Zis hydrogen, halogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted -O-alkyl, or optionally substituted cycloalkyl;

[0774] R5Zis optionally substituted heteroalkyl or optionally substituted heterocyclyl; and nlZ is 1, 2, or 3.

[0775] In some embodiments, R4Zis hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R4Zis hydrogen. In some embodiments, R5Zis optionally substituted heteroalkyl. In some embodiments, nlZ is 1 or 2. In certain embodiments, nlZ is 1.

[0776] In certain embodiments, at least one radical of an a.4 1 / 7 integrin ligand is of the formula:

[0777]

[0778] R6Zis hydrogen, -OH, -NH2, -NHR7Z, -OR7Z, or absent; and

[0779] A1278.70039WO00 110 R7Zis hydrogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.

[0780] In some embodiments, R6Zis hydrogen, -OH, -NH2, or absent. In certain embodiments, R6Zis hydrogen. In certain embodiments, R6Zis absent. In some embodiments, R7Zis hydrogen or optionally substituted alkyl. In certain embodiments, R7Zis hydrogen or unsubstituted alkyl.

[0781] In certain embodiments, at least one radical of an a.4 1 / 7 integrin ligand is of the formula:

[0782]

[0783] A1278.70039WO00 111 HCk / O

[0784]

[0785] n2Z is 0, 1, 2, or 3.

[0786] In some embodiments, n2Z is 0 or 1. In certain embodiments, n2Z is 0.

[0787] In certain embodiments, at least one radical of an a.4 1 / 7 integrin ligand is of the formula:

[0788]

[0789] A1278.70039WO00 112

[0790]

[0791] n3Z is 0, 1, 2, or 3.

[0792] In some embodiments, n3Z is 0 or 1. In certain embodiments, n3Z is 0.

[0793] In certain embodiments, at least one radical of an a.4 1 / 7 integrin ligand is of the formula:

[0794]

[0795] each of R8Z, R9Z, R1OZ, and R11Zis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted -O-alkyl, or substituted or unsubstituted cycloalkyl; A1278.70039WO00 113 each of R12Zand R13Zis independently hydrogen, halogen, optionally substituted alkyl,

[0796]

[0797] R14Zis optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkylene- (Cs-Ce)-cycloalkyl, or optionally substituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy.

[0798] In some embodiments, each of R8Z, R9Z, R10Z, and R11Zis independently hydrogen, halogen, or optionally substituted alkyl. In certain embodiments, each of R8Z, R9Z, R10Z, and R11Zis independently optionally substituted alkyl. In certain embodiments, each of R8Z, R9Z, R10Z, and R11Zis independently unsubstituted alkyl. In some embodiments, each of R12Zand R13Zis

[0799]

[0800] independently hydrogen, \, or \. In certain embodiments, each of R12Zand

[0801]

[0802] — N

[0803] R13Zis independently H or \. In some embodiments, R14Zis optionally substituted Ci-C5 alkyl. In certain embodiments, R14Zis optionally substituted C4 alkyl.

[0804] In certain embodiments, at least one a.4 1 / 7 integrin ligand is of the formula:

[0805]

[0806] R13Z

[0807] In certain embodiments, at least one a.401 / 7 integrin ligand is of the formula:

[0808] A1278.70039WO00 114

[0809]

[0810] In certain embodiments, at least one radical of the a.4 1 / 7 integrin ligand is of the formula:

[0811]

[0812] In certain embodiments, at least one a.401 / 7 integrin ligand is of the formula:

[0813]

[0814] In certain embodiments, at least one radical of an a40i / 7 integrin ligand is of the formula:

[0815]

[0816] A1278.70039WO00 115 In certain embodiments, at least one radical of an a.4 1 / 7 integrin ligand is of the formula:

[0817]

[0818] In certain embodiments, at least one radical of an a.401 / 7 integrin ligand is of the formula:

[0819]

[0820] R15Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;

[0821] each of R16Zand R17Zis independently H, halogen, optionally substituted alkyl, or optionally substituted -O-alkyl; and

[0822] Yzis -CH2- or -(CH2)2-.

[0823] A1278.70039WO00 116 In some embodiments, R15zis H, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R15zis H. In some embodiments, each of R16Zand R17Zis independently H or optionally substituted alkyl. In certain embodiments, each of R16Zand R17Zis independently H. In certain embodiments, Yzis -CH2-. In certain embodiments, Yzis -(CH2)2- In certain embodiments, at least one radical of an a.4 1 / 7 integrin ligand is of the formula:

[0824] 0

[0825] O

[0826]

[0827] R18Zis H, -OH, -NH2, -NHR19Z, -OR19Z, or -CONHR19Z;

[0828] each instance of R19Zis independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and

[0829] n4Z is 1 or 2.

[0830] In certain embodiments, at least one radical of an a.401 / 7 integrin ligand is of the formula:

[0831] O

[0832]

[0833] In some embodiments, R18Zis H, -OH, or -NH2. In certain embodiments, R18Zis H. In some embodiments, each instance of R19Zis independently H or optionally substituted alkyl. In certain embodiments, each instance of R19Zis independently H or unsubstituted alkyl. In certain embodiments, n4Z is 1. In certain embodiments, n4Z is 2.

[0834] In certain embodiments, at least one radical of an a40i / 7 integrin ligand is of the formula:

[0835]

[0836] R19Zis H, -CH2OR20Z, -(CH2)2OR20Z, -CH2NHCOR20Z, or -OR20Z; and

[0837] A1278.70039WO00 117 R20Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.

[0838] In some embodiments, R19Zis H or -CH2NHCOR20Z. In certain embodiments, R19Zis -CH2NHCOR20Z. In some embodiments, R20Zis H or optionally substituted alkyl. In certain embodiments, R20Zis H or unsubstituted alkyl.

[0839] In certain embodiments, at least one radical of an a.4 1 / 7 integrin ligand is of the formula:

[0840] O

[0841] or

[0842]

[0843] R21Zis H, -CONHR22Z, -CH2OR22Z, -(CH2)2OR22Z, -CH2NHCOR22Z, or -OR22Z;

[0844] R22Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and

[0845] X1Zis H or halogen.

[0846] In certain embodiments, at least one radical of an a.401 / 7 integrin ligand is of the formula:

[0847]

[0848] wherein:

[0849] R21Zis H, -CONHR22Z, -CH2OR22Z, -(CH2)2OR22Z, -CH2NHCOR22Z, or -OR22Z;

[0850] R22Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and

[0851] X1Zis H or halogen.

[0852] A1278.70039WO00 118 In certain embodiments, at least one radical of an a.4 1 / 7 integrin ligand is of the formula:

[0853]

[0854] In some embodiments, R21Zis H or -CH2NHCOR22Z. In certain embodiments, R21Zis -CH2NHCOR22Z. In some embodiments, R22Zis H or optionally substituted alkyl. In certain embodiments, R22Zis H or unsubstituted alkyl. In certain embodiments, X1Zis H. In certain embodiments, X1Zis halogen.

[0855] In certain embodiments, at least one radical of an a40i / 7 integrin ligand is of the formula:

[0856]

[0857] R23Zis H, -CONHR24Z, -CH2OR24Z, -(CH2)2OR24Z, -CH2NHCOR24Z, or -OR24Z;

[0858] R24Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and

[0859] n5Z is 0, 1, 2, or 3.

[0860] In certain embodiments, at least one radical of an a.401 / 7 integrin ligand is of the formula:

[0861]

[0862] In some embodiments, R23Zis H or -CONHR24Z. In certain embodiments, R23Zis -CONHR24Z. In some embodiments, R24Zis H or optionally substituted alkyl. In certain embodiments, R24Zis H or unsubstituted alkyl. In some embodiments, n5z is 0, 1, or 2. In certain, embodiments, n5z is 1.

[0863] In certain embodiments, at least one radical of an a40i / 7 integrin ligand is of the formula:

[0864] A1278.70039WO00 119

[0865]

[0866] R25Zis H, -CONHR27Z, -CH2OR27Z, -(CH2)2OR27Z, -CH2NHCOR27Z, or -OR27Z;

[0867] R26Zis H, optionally substituted alkyl, or optionally substituted cycloalkyl;

[0868] R27Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and X2Zis optionally substituted CH2 or optionally substituted NH.

[0869] In certain embodiments, at least one radical of an a.4 1 / 7 integrin ligand is of the formula:

[0870]

[0871] wherein:

[0872] R25Zis H, -CONHR27Z, -CH2OR27Z, -(CH2)2OR27Z, -CH2NHCOR27Z, or -OR27Z;

[0873] R26Zis H, optionally substituted alkyl, or optionally substituted cycloalkyl; and R27Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.

[0874] A1278.70039WO00 120 In certain embodiments, at least one radical of an a.4 1 / 7 integrin ligand is of the formula:

[0875]

[0876] In certain embodiments, at least one radical of an a.401 / 7 integrin ligand is of the formula:

[0877]

[0878] or; wherein:

[0879] R28Zis H, -CH2OR30Z, -(CH2)2OR30Z, -CH2NHCOR30Z, or -OR30Z;

[0880] R29Zis H, -OH, -NH2, -NHR31Z, or -OR31Z;

[0881] R30Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;

[0882] R31Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;

[0883] n3Z is 1, 2, or 3;

[0884] each instance of R37Zis halogen or optionally substituted alkyl; and

[0885] n6Z is 0, 1, 2, 3, or 4.

[0886] In some embodiments, R25zis H or -CH2NHCOR27Z. In certain embodiments, R25zis -CH2NHCOR27Z. In some embodiments, R26Zis H or optionally substituted alkyl. In some embodiments, R26Zis H or unsubstituted alkyl. In certain embodiments, R26Zis H or -CH3. In some embodiments, R27Zis H, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R27Zis H, unsubstituted alkyl, or unsubstituted heteroalkyl. In some embodiments, X2Zis optionally substituted NH. In certain embodiments, X2Zis NH.

[0887] In certain embodiments, at least one radical of an a40i / 7 integrin ligand is of the formula:

[0888] A1278.70039WO00 121

[0889]

[0890] R28Zis H, -CH2OR30Z, -(CH2)2OR30Z, -CH2NHCOR30Z, or -OR30Z;

[0891] R29Zis H, -OH, -NH2, -NHR31Z, or -OR31Z;

[0892] R30Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;

[0893] R31Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and

[0894] n3Z is 1, 2, or 3.

[0895] In some embodiments, R28Zis H, -CH2NHCOR30Z, or -OR30Z. In certain embodiments, R28Zis -CH2NHCOR30Z. In some embodiments, R29Zis H, -OH, or -NH2. In some embodiments, R30Zis H, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R30Zis H, unsubstituted alkyl, or unsubstituted heteroalkyl. In some embodiments, R31Zis H, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R31Zis H, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, n3Z is 1. In certain embodiments, n3Z is 2.

[0896] In certain embodiments, at least one a.401 / 7 integrin ligand is of the formula:

[0897]

[0898] ; or

[0899] at least one radical of an a.4 1 / 7 integrin ligand is of the formula:

[0900]

[0901] A1278.70039WO00 122 In some embodiments, a ligand is an antibody (e.g., an anti-cuPm integrin receptor antibody). In certain embodiments, a ligand is an antibody fragment or an antibody variant. An “anti-a4Pi / 7 integrin receptor antibody” refers to an immune system protein that recognizes, binds to, or otherwise interacts with a 014P1 / 7 integrin.

[0902] In some embodiments, an 014P1 / 7 integrin receptor ligand is an 014P1 / 7 integrin receptor agonist. In some embodiments, an 014P1 / 7 integrin receptor ligand is an 014P1 / 7 integrin receptor antagonist. In some embodiments, an 014P1 / 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 014P1 / 7 integrin receptor ligand is any of those disclosed in Baiula, M. et al. Novel Ligands Targeting cuP 1 Integrin: Therapeutic Applications and Perspectives. Front. Chem. 2019, 7, 489, which is incorporated herein by reference. Exemplary 014P1 / 7 integrin receptor ligands for use in the present disclosure include, but are not limited to, any of the following 014P1 / 7 integrin receptor ligands, and derivatives thereof:

[0903]

[0904] A1278.70039WO00 123

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911] In certain embodiments, an a.4 1 / 7 integrin receptor ligand is

[0912]

[0913] In some embodiments, an a.401 / 7 integrin receptor ligand is an anti-cuPm integrin receptor antibody. In certain embodiments, an a40i / 7 integrin receptor ligand is an anti-ouPi / ? integrin receptor antibody fragment, or an anti-cuPm integrin receptor antibody variant. An “anti-ouPi / ? integrin receptor antibody” refers to an immune system protein that recognizes, binds to, or otherwise interacts with an 014P1 / 7 integrin receptor.

[0914] In some embodiments, at least one CBi ligand is a compound of the formula:

[0915] N^N

[0916] NH

[0917]

[0918] X1Yis NR10Yor CR11YR12Y;

[0919] each of R10Y, R11Y, and R12Yis independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0920] A1278.70039WO00 129 R19Yis hydrogen, -SOni9YR19YA, -SOVI9YNR19YBR19YC, -NHNR19YBR19YC, -ONR19YBR19YC, -NHC(O)NHNR19YBR19YC, -NHC(O)NR19YBR19YC, -NR19YBR19YC, -C(O)R19YD, -C(O)OR19YD, -C(O)NR19YBR19YC, -OR19YA, -NR19YBSO2R19YA, -NR19YBC(O)R19YD, -NR19YBC(O)OR19YD, -NR19YBOR19YD, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0921] each of R19YA, R19YB, R19YC, and R19YDis independently hydrogen, halogen, -CF3, -CCI3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R19YBand R19YCbonded to the same nitrogen atom are joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

[0922] nl9Y is 0, 1, 2, 3, or 4; and

[0923] vl9Y is 1 or 2.

[0924] In some embodiments, X1Yis NR10Y. In certain embodiments, X1Yis NH. In some embodiments, R10Yis hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R10Yis hydrogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, R10Yis hydrogen. In some embodiments, R19Yis hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R19Yis hydrogen, unsubstituted alkyl, or unsubstituted heteroalkyl.

[0925] In certain embodiments, at least one radical of a CBi ligand is of the formula:

[0926] NH

[0927]

[0928] . In certain embodiments, at least one radical of a CBi ligand is of the formula:

[0929] A1278.70039WO00 130

[0930]

[0931] In certain embodiments, at least one CB1 ligand is a compound of the formula:

[0932]

[0933] wherein:

[0934] R17Yis hydrogen, -SOni7yR17YA, -SOv17YNR17YBR17YC, -NHNR17YBR17YC, -ONR17YBR17YC, -NHC(O)NHNR17YBR17YC, -NHC(O)NR17YBR17YC, -NR17YBR17YC, -C(O)R17YD, -C(O)OR17YD, -C(O)NR17YBR17YC, -OR17YA, -NR17YBSO2R17YA, -NR17YBC(O)R17YD, -NR17YBC(O)OR17YD, -NR17YBOR17YD, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0935] each of R17YA, R17YB, R17YC, and R17YDis independently hydrogen, halogen, -CF3, -CCI3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R17YBand R17YCsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

[0936] nl7Y is 0, 1, 2, 3, or 4; and

[0937] vl7Y is 1 or 2.

[0938] In some embodiments, R17Yis hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, or -NR17YBR17YC. In certain embodiments, R17Yis -NR17YBR17YC. In certain embodiments, R17Yis -NH2. In some embodiments, each of R17YBand R17YCis

[0939] A1278.70039WO00 131 independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, each of R17YBand R17YCis independently hydrogen.

[0940] In certain embodiments, at least one radical of a CBi ligand is of the formula:

[0941]

[0942] In certain embodiments, at least one CBI ligand is a compound of the formula:

[0943] O

[0944]

[0945] Yjn certain embodiments, at least one radical of a CBi ligand is of the formula:

[0946]

[0947] In certain embodiments, at least one CBI ligand is a compound of the formula:

[0948]

[0949] R3Y, R4Y, R5Y, R6Y, and R8Yare each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0950] R9Yis hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl; or R6Yand R9Ysubstituents may be joined together form an optionally substituted heterocycloalkyl or optionally substituted heteroaryl;

[0951] A1278.70039WO00 132 R7Yis hydrogen, -SO„7YR7YA, -SOV7YNR7YBR7YC, -NHNR7YBR7YC, -ONR7YBR7YC, -NHC(O)NHNR7YBR7YC, -NHC(O)NR7YBR7YC, -NR7YBR7YC, -C(O)R7YD, -C(O)OR7YD, -C(O)NR7YBR7YC, -OR7YA, -NR7YBSO2R7YA, -NR7YBC(O)R7YD, -NR7YBC(O)OR7YD, -NR7YBOR7YD, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0952] R7YA, R7YB, R7YC, R7YDare each independently hydrogen, halogen, -CF3, -CCI3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R7YBand R7YCsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

[0953] n7Y is 0, 1, 2, 3, or 4; and

[0954] v7Y is 1 or 2.

[0955] In some embodiments, R3Yis hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R3Yis hydrogen. In certain embodiments, R3Yis halogen. In some embodiments, R4Yis hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R4Yis hydrogen. In certain embodiments, R4Yis halogen. In some embodiments, R5Yis hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R5Yis hydrogen. In certain embodiments, R5Yis halogen. In some embodiments, R6Yis hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R6Yis hydrogen. In certain embodiments, R6Yis halogen. In some embodiments, R7Yis hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, or -C(O)R7YD. In certain embodiments, R7Yis -C(O)R7YD. In some embodiments, R7YDis optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments, R7YDis optionally substituted aryl. In some embodiments, R8Yis hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R8Yis optionally substituted heteroalkyl. In certain embodiments, R8Yis substituted heteroalkyl. In some embodiments, R9Yis hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R9Yis hydrogen.

[0956] In certain embodiments, at least one radical of a CBi ligand is of the formula:

[0957] A1278.70039WO00 133

[0958]

[0959] In certain embodiments, at least one CBi ligand is a compound of the formula:

[0960]

[0961] R16Yis hydrogen, halogen, -CN, -N3, -NO2, -NR16YBR16YC, -C(O)R16YD, -C(O)OR16YD, -C(O)NR16YBR16YC, -OR16YA, -NR16YBC(O)R16YD, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and

[0962] R16YA, R16YB, R16YC, and R16YDare each independently hydrogen, halogen, -CF3, -CCI3, -CB13, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R16YBand R16YCbonded to the same nitrogen atom are joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0963] In some embodiments, R16Yis hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R16Yis hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl.

[0964] A1278.70039WO00 134 In certain embodiments, at least one radical of a CBi ligand is of the formula:

[0965]

[0966] In certain embodiments, at least one CBi ligand is a compound of the formula:

[0967]

[0968] In some embodiments, at least one NMDA receptor ligand is a compound of the formula:

[0969]

[0970] A1278.70039WO00 135

[0971]

[0972] In certain embodiments, at least one radical of an NMDA receptor ligand is of the

[0973] formula:

[0974]

[0975] . In certain embodiments, at least one radical of an NMDA receptor

[0976] ligand is of the formula:

[0977]

[0978] . In certain embodiments, at

[0979] least one radical of an NMDA receptor ligand is of the formula:

[0980]

[0981] embodiments, at least one radical of an NMDA receptor ligand is of the formula:

[0982]

[0983] . In certain embodiments, at least one radical of an NMDA receptor ligand is of

[0984]

[0985] . In certain embodiments, at least one radical of an

[0986] NMDA receptor ligand is of the formula:

[0987]

[0988]

[0989] . In certain embodiments, at least one radical of an NMDA receptor

[0990] A1278.70039WO00 136 ligand is of the formula:

[0991]

[0992] ZOH. In certain embodiments, at least one radical of an

[0993]

[0994] at least one radical of an NMDA receptor ligand is of the formula:

[0995]

[0996]

[0997] In certain embodiments, at least one radical of an NMDA

[0998]

[0999] In some embodiments, a ligand is an antibody (e.g., an anti-TrkB, anti-CBi, anti-cuPm integrin, or anti-NMDA receptor antibody). In certain embodiments, a ligand is an antibody fragment or an antibody variant. An “an anti-TrkB receptor antibody,” “anti-CBi receptor antibody,” “anti-cuPm integrin receptor antibody,” or “anti-NMDA receptor antibody” refers to an immune system protein that recognizes, binds to, or otherwise interacts with a TrkB, CBi, cuPi / v integrin, or NMDA receptor, respectively.

[1000] In some embodiments, an oligonucleotide comprises at least two ligands (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 ligands). In some embodiments, an oligonucleotide comprises two ligands. In some embodiments, an oligonucleotide comprises three ligands. In some embodiments, an oligonucleotide comprises at least one ligand conjugated at the 5 '-end. In some embodiments, an

[1001] A1278.70039WO00 137 oligonucleotide comprises at least one ligand conjugated at the 3 '-end. In certain embodiments, an oligonucleotide comprises at least one ligand conjugated at the 5 '-end and at least one ligand conjugated at the 3 '-end. In some embodiments, an oligonucleotide comprises at least two ligands conjugated at the 5'-end. In some embodiments, an oligonucleotide comprises at least two ligands conjugated at the 3'-end. In certain embodiments, an oligonucleotide comprises at least two ligands conjugated at the 5 '-end and at least two ligands conjugated at the 3 '-end. In some embodiments, an oligonucleotide comprises at least one ligand conjugated at a nucleobase. In some embodiments, an oligonucleotide comprises at least two ligands conjugated at a nucleobase. In some embodiments, an oligonucleotide comprises at least one ligand conjugated at the 2' position of a nucleoside. In some embodiments, an oligonucleotide comprises at least two ligands conjugated at the 2' position of a nucleoside. In certain embodiments, the modified antisense strand comprises no radicals of ligands. In certain embodiments, the modified sense strand comprises no radicals of ligands.

[1002] 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.

[1003] In some embodiments, each instance of A1is a radical of the same ligand type. In some embodiments, each instance of A1is the same radical of a ligand. In some embodiments, at least two instances of A1are radicals of different ligand types. In some embodiments, at least two instances of A1are radicals of different ligands of the same ligand type. In some embodiments, at least two instances of A1are radicals of different ligands of different ligand types.

[1004] In certain embodiments, one instance of A1is a radical of a CNS ligand. In certain embodiments, two or three instances of A1are radicals of CNS ligands. In certain embodiments, four, five, or six instances of A1are radicals of CNS ligands. In certain embodiments, each instance of A1is a radical of a CNS ligand.

[1005] In certain embodiments, at least one instance of A1is a radical of a cannabinoid receptor type 1 (CB1), 014P1 / 7 integrin, or N-methyl-D-aspartate (NMDA) receptor ligand.

[1006] In certain embodiments, at least one instance of A1is a radical of a ligand, and at least one instance of A1is a radical of a lipid. In certain embodiments, two or three instances of A1are radicals of ligands, and one instance of A1is a radical of a lipid. In certain embodiments, four or five instances of A1are radicals of ligands, and one instance of A1is a radical of a lipid. In A1278.70039WO00 138 certain embodiments, two or three instances of A1are radicals of ligands, and one or two instances of A1are radicals of lipids.

[1007] In certain embodiments, at least one instance of A1is a radical of a CNS ligand, and at least one instance of A1is a radical of a lipid. In certain embodiments, two or three instances of A1are radicals of CNS ligands, and one instance of A1is a radical of a lipid. In certain embodiments, four or five instances of A1are radicals of CNS ligands, and one instance of A1is a radical of a lipid. In certain embodiments, two or three instances of A1are radicals of CNS ligands, and one or two instances of A1are radicals of lipids.

[1008] In some embodiments, each instance of A2is a radical of the same ligand type. In some embodiments, each instance of A2is the same radical of a ligand. In some embodiments, at least two instances of A2are radicals of different ligand types. In some embodiments, at least two instances of A2are radicals of different ligands of the same ligand type. In some embodiments, at least two instances of A2are radicals of different ligands of different ligand types.

[1009] In certain embodiments, at least one instance of A2, when present, is a radical of a ligand. In certain embodiments, at least one instance of A2, when present, is a radical of a CNS ligand. In certain embodiments, at least one instance of A2, when present, is a radical of a CB1, a.4 1 / 7 integrin, or NMDA receptor ligand.

[1010] In some embodiments, each instance of A4is a radical of the same ligand type. In some embodiments, each instance of A4is the same radical of a ligand. In some embodiments, at least two instances of A4are radicals of different ligand types. In some embodiments, at least two instances of A4are radicals of different ligands of the same ligand type. In some embodiments, at least two instances of A4are radicals of different ligands of different ligand types.

[1011] In some embodiments, at least one instance of A1and at least one instance of A2are radicals of the same ligand type. In some embodiments, at least one instance of A1and at least one instance of A2are the same radical of a ligand. In some embodiments, at least one instance of A1and at least one instance of A2are radicals of different ligand types. In some embodiments, at least one instance of A1and at least one instance of A2are radicals of different ligands of the same ligand type. In some embodiments, at least one instance of A1and at least one instance of A2are radicals of different ligands of different ligand types.

[1012] In some embodiments, at least one instance of A1and at least one instance of A4are radicals of the same ligand type. In some embodiments, at least one instance of A1and at least one instance of A4are the same radical of a ligand. In some embodiments, at least one instance of A1and at least one instance of A4are radicals of different ligand types. In some embodiments, at least one instance of A1and at least one instance of A4are radicals of different ligands of the

[1013] A1278.70039WO00 139 same ligand type. In some embodiments, at least one instance of A1and at least one instance of A4are radicals of different ligands of different ligand types.

[1014] In some embodiments, at least one instance of A2and at least one instance of A4are radicals of the same ligand type. In some embodiments, at least one instance of A2and at least one instance of A4are the same radical of a ligand. In some embodiments, at least one instance of A2and at least one instance of A4are radicals of different ligand types. In some embodiments, at least one instance of A2and at least one instance of A4are radicals of different ligands of the same ligand type. In some embodiments, at least one instance of A2and at least one instance of A4are radicals of different ligands of different ligand types.

[1015] In some embodiments, each instance of A1, A2, and A4is the same radical of a ligand. In some embodiments, each instance of A1, A2, and A4is a different radical of a ligand compared to any other radical of a ligand in the oligonucleotide. In some embodiments, each instance of A1, A2, and A4is the same radical of a TrkB ligand. In some embodiments, each instance of A1, A2, and A4is the same radical of a CBi receptor ligand. In some embodiments, each instance of A1, A2, and A4is the same radical of an a.4 1 / 7 integrin receptor ligand. In some embodiments, each instance of A1, A2, and A4is the same radical of an NMDA receptor ligand. In some embodiments, each instance of A1, A2, and A4is a different radical of a TrkB ligand, CBi receptor ligand, a.401 / 7 integrin receptor ligand, and / or NMDA receptor ligand.

[1016] Lipids

[1017] In an oligonucleotide of the present disclosure, each instance of each of A1, A2, and A4, if present, is independently a radical of a ligand or lipid. In some embodiments, at least one instance of A1, if present, is a radical of a lipid. In some embodiments, at least one instance of A2, if present, is a radical of a lipid. In some embodiments, at least one instance of if present, is a radical of a lipid. In some embodiments, at least one instance of A4, if present, is a radical of a lipid. In certain embodiments, at least one instance of A1, A2, and A4, if present, is independently a radical of a lipid. In certain embodiments, the modified antisense strand comprises no radicals of lipids. In certain embodiments, the modified sense strand comprises no radicals of lipids.

[1018] In some embodiments, each instance of A2is the same radical of a lipid. In some embodiments, each instance of A4is the same radical of a lipid.

[1019] In some embodiments, at least one instance of A1and at least one instance of A2are the same radical of a lipid. In some embodiments, at least one instance of A1and at least one instance of A4are the same radical of a lipid. In some embodiments, at least one instance of A2and at least one instance of A4are the same radical of a lipid.

[1020] A1278.70039WO00 140 In some embodiments, each instance of A1that is a lipid, A2, and A4is the same radical of a lipid. In some embodiments, each instance of A1that is a lipid, A2, and A4is a different radical of a lipid compared to any other radical of a lipid in the oligonucleotide.

[1021] 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.

[1022] 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 embodi ments, 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, A1278.70039WO00 141 at least one radical of a lipid is unbranched unsubstituted Cis-26 alkyl. In certain embodiments, at least one radical of a lipid is -(CH2)i7CH3, -(CH₂)₁₈CH₃, -(CH2)i9CH3, -(CH₂)₂₀CH₃, -(CH2)2ICH3, -(CH2)22CH3, -(CH2)23CH3, -(CH2)24CH3, or-(CH2)25CH3. In certain embodiments, at least one radical of a lipid is -(CH₂)₂₁CH₃. In certain embodiments, at least one radical of a lipid is unbranched unsubstituted Cis-26 alkenyl. In certain embodiments, at least one radical of a lipid is unbranched unsubstituted CIS-26 alkenyl comprising one C=C bond. In certain embodiments, at least one lipid is unbranched unsubstituted C12-24 alkyl or unbranched unsubstituted C12-24 alkenyl comprising 1, 2, or 3 CC double bonds and no CC triple bonds. In certain embodiments, at least one lipid is unbranched unsubstituted C14-20 alkyl.

[1023] In certain embodiments, at least one lipid is a monoradylglycerol, diradylglycerol, triradylglycerol, glycosylmonoradylglycerol, glycosyldiradylglycerol, betaine monoradylglycerol, or betaine diradylglycerol.

[1024] 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.

[1025] In certain embodiments, at least one lipid is a sphingoid base, ceramide, phosphosphingolipid, phosphonosphingolipid, neutral glycosphingolipid, acidic glycosphingolipid, basic glycosphingolipid, amphoteric glycosphingolipid, or arsenosphingolipid.

[1026] 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:

[1027]

[1028] A1278.70039WO00 142 In certain embodiments, at least one lipid is lithocholic acid. In certain embodiments, at least one radical of the lipid is of the formula:

[1029]

[1030] (unsubstituted C7-30alkyl or unsubstituted C7-30alkenyl)

[1031]

[1032] 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:

[1033]

[1034] In certain embodiments, at least one lipid is an isoprenoid, quinone, hydroquinone, polyprenol, or hopanoid.

[1035] In certain embodiments, at least one lipid is an acylaminosugar, acylamino sugar glycan, acyltrehalose, or acyltrehalose glycan.

[1036] 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.

[1037] A1278.70039WO00 143 Further Oligonucleotide Strand Modifications

[1038] The modified oligonucleotide strands may further comprise additional modifications (“further modifications”). In certain embodiments, the modified oligonucleotide strand further comprises at least one modified sugar, at least one modified nucleobase, at least one modified intemucleoside linkage, or a combination thereof. In certain embodiments, a modified oligonucleotide strand further comprises 1, 2, 3, 4, 5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, or 96-100, inclusive, modified nucleosides. In certain embodiments, a modified oligonucleotide strand further comprises 1, 2, 3, 4, 5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, or 96-100, inclusive, modified sugars. In certain embodiments, a modified oligonucleotide strand further comprises 1, 2, 3, 4, 5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, or 96-100, inclusive, modified intemucleoside linkages.

[1039] 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.

[1040] Sugar Modifications

[1041] 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.

[1042] In certain embodiments, a modified sugar is a substituted furanosyl or non-bicyclic modified sugar. In certain embodiments, the furanosyl sugar is a ribosyl sugar. In certain embodiments, the furanosyl sugar comprises one or more substituent groups, including, but not limited to, substituent groups at the 2', 3', 4', and 5' positions.

[1043] 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, -ONO2, -NO2, -N3, and -NH2. In certain embodiments, substituent groups at the 2' position include, but are not limited to, -O-(Ci-Cio) alkoxy, alkoxyalkyl, -O-alkyl, -S-alkyl, -N-alkyl, -O-alkenyl, -S-alkenyl, -N-alkenyl, -O-alkynyl, -S-alkynyl, -N-alkynyl, -O-alkyl-O-alkyl, A1278.70039WO00 144 alkynyl, wherein the alkyl, alkenyl and alkynyl can be substituted or unsubstituted Ci to Cio alkyl or C2 to Cio alkenyl and alkynyl. In certain embodiments, substituent groups at the 2' position include, but are not limited to, alkaryl, aralkyl, -O-alkaryl, and -O-aralkyl. In certain embodiments, these 2' substituent groups can be further substituted with one or more substituent groups independently selected from hydroxyl, alkoxy, carboxy, benzyl, phenyl, nitro (-NO2), thiol, thioalkoxy, thioalkyl, halogen, 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”).

[1044] In certain embodiments, substituent groups at the 4' position suitable for non-bicyclic modified sugars include, but are not limited to, alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015 / 106128. In certain embodiments, substituent groups at the 5' position suitable for non-bicyclic modified sugars include, but are not limited to, methyl (“Me”) (R or S), vinyl, and methoxy. In certain embodiments, the 5' modification is a 5'-monophosphate ((HO)2(O)P-O-5'); 5'-diphosphate ((HO)2(O)P-O-P(HO)(O)-O-5'); 5'-triphosphate ((HO)2(O)P-O-(HO)(O)P-O-P(HO)(O)-O-5'); 5'-guanosine cap (7-methylated or non-methylated) (7m-G-0-5'-(HO)(O)P-O-(HO)(O)P-O-P(HO)(O)-O-5'); 5'adenosine cap (Appp), and any modified or unmodified nucleotide cap structure (N-O-5'(HO)(O)P-O-(HO)(O)P-O-P(HO)(O)-O-5'); 5'-monothiophosphate (phosphorothioate; (HO)2(S)P-O-5'); 5'-monodithiophosphate (phosphorodithioate; (HO)(HS)(S)P-O-5'), 5 'phosphoro thiolate ((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 (MeOCIh-), 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 strand. In certain embodiments the 5' modification is at the terminus of an antisense oligonucleotide strand. 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' A1278.70039WO00 145 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.

[1045] 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 H, C1-C12 alkyl, or a protecting group (e.g., U. S. Patent No. 7,427,672), 4'-CH2-C(H)(CH3)-2' (e.g., Chattopadhyaya et 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;

[1046] 8,278,425; 8,278,426; 8,278,283; US 2008 / 0039618; US 2009 / 0012281; US 2013 / 0190383; and WO 2013 / 036868. Any of the foregoing bicyclic nucleosides can be prepared having one or more stereochemical sugar configurations including, for example, a-L-ribofuranose and P-D-ribofuranose (see, e.g., WO 99 / 14226). Specified bicyclic nucleosides herein are in the P-D configuration, unless otherwise specified.

[1047] 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 A1278.70039WO00 146 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;

[1048] 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873;

[1049] 5,670,633; 5,700,920; 7,875,733; 7,939,677, 8,088,904; 8,440,803; and 9,005,906.

[1050] 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 CT-C4' have been removed (z.e., the covalent carbon-oxygen-carbon bond between the Cl' and C4' carbons). In another example, the C2'-C3' bond (z.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.

[1051] 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.

[1052] In some embodiments, modified sugars and / or unmodified sugars are arranged along the modified oligonucleotide strand or regions thereof in a defined pattern or “sugar motif’. In certain instances, such sugar motifs include, but are not limited to, any of the patterns of sugar modifications described herein.

[1053] 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. A1278.70039WO00 147 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.

[1054] 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.

[1055] 10,668,170.

[1056] In certain embodiments, one or both strands of a double- stranded oligonucleotide comprise a quadruplet sugar motif. An oligonucleotide strand with a quadruplet sugar motif comprises four identical sugar modifications on four consecutive nucleosides. In certain embodiments, the quadruplet is at or near the cleavage site. In certain embodiments, a strand of a double-stranded oligonucleotide may contain more than one quadruplet sugar motif. In certain embodiments, the identical sugar modification of the quadruplet sugar motif is a 2'-F modification. For a double-stranded oligonucleotide having a duplex region of 19-23 nucleotides in length, the cleavage site of the antisense oligonucleotide strand is typically around the 10, 11, and 12 positions from the 5'-end. In certain embodiments, the quadruplet sugar motif is at the 8, 9, 10, and 11 positions; the 9, 10, 11, and 12 positions; the 10, 11, 12, and 13 positions; the 11, 12, 13, and 14 positions; or the 12, 13, 14, and 15 positions of the sense oligonucleotide strand, counting from the first nucleoside of the 5 '-end of the sense oligonucleotide strand, or, the count starting from the first paired nucleotide within the duplex region from the 5 '-end of the sense oligonucleotide strand. In certain embodiments, the quadruplet sugar motif is at the 8, 9, 10, and 11 positions; the 9, 10, 11, andl2 positions; the 10, 11, 12, and 13 positions; the 11, 12, 13, and 14 positions; or the 12, 13, 14, and 15 positions of the antisense oligonucleotide strand, counting from the first nucleoside of the 5 '-end of the antisense oligonucleotide strand, or, the count starting from the first paired nucleotide within the duplex region from the 5 '-end of the antisense oligonucleotide strand. The cleavage site may change according to the length of the duplex region of the double- stranded oligonucleotide and may change the position of the quadruplet accordingly.

[1057] 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 A1278.70039WO00 148 different sugar modifications, wherein one or more consecutive nucleosides comprising a first sugar modification alternates with one or more consecutive nucleosides comprising a second sugar modification, and one or more consecutive nucleosides comprising a third sugar modification, etc. For example, if A, B, and C each represent one type of modification to the nucleoside, the alternating motif can be “ABABABABABAB.. “AABBAABBAABB.. “AABAABAABAAB...,” “AAABAAABAAAB...,” “AAABBBAAABBB...,” or “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.

[1058] 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.

[1059] In certain embodiments, a modified sugar is 2'-fluoro-2'-deoxyribose, 2'-0-methylribose, 2'-thioribose, 2',3'-dideoxyribose, 2'-amino-2'-deoxyribose, 2' deoxyribose, 2'-azido-2'-deoxyribose, 2'-0-methyldeoxyribose, 3 '-amino-2 ',3 '-dideoxyribose, 3'-azido-2',3'-dideoxyribose, 3 '-deoxyribose, 3'-0-(2-nitrobenzyl)-2'-deoxyribose, 3'-0-methylribose, 5'-aminoribose, 5 '-thioribose, 5-nitro-l-indolyl-2'-deoxyribose, 5'-biotin-ribose, 2'-0,4'-C-amino-linked ribose, 2'-0,4'-C-thio-linked ribose, 2'-0-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.

[1060] 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 A1278.70039WO00 149 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.

[1061] 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.

[1062] Nucleobase Modifications

[1063] Any modified nucleobases known in the art may be used in the oligonucleotides provided herein. In certain embodiments, modified oligonucleotide strands comprise one or more nucleosides comprising a modified nucleobase. In certain embodiments, modified oligonucleotide strands comprise one or more nucleosides that do not comprise a nucleobase, referred to as an abasic nucleoside.

[1064] In certain embodiments, modified nucleobases are selected from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, andN-2, N-6 and 0-6 substituted purines. In certain embodiments, modified nucleobases are selected from: 2-aminopropyladenine, 5- hydroxymethyl cytosine, 5-methylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (OC-CH3) uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo, particularly, 5-bromo, 5-trifluoromethyl, 5-halouracil, and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size expanded bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as 1,3-diazaphenoxazine-2-one, l,3-diazaphenothiazine-2-one, and 9-(2-aminoethoxy)-l,3-diazaphenoxazine-2-one (G-clamp). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example, 7-deaza-adenine, 7-deazaguanosine, and 2-aminopyridine and 2-pyridone.

[1065] A1278.70039WO00 150 In certain embodiments, a modified nucleobase is xanthine, ally aminouracil, allyaminothymidine, hypoxanthine, digoxigeninated adenine, digoxigeninated cytosine, digoxigeninated guanine, digoxigeninated uracil, 6-chloropurineriboside, N6-methyladenine, methylpseudouracil, 2-thiocytosine, 2-thiouracil, 5-methyluracil, 4-thiothymidine, 4-thiouracil, 5,6-dihydro-5-methyluracil, 5,6-dihydrouracil, 5-[(3-Indolyl)propionamide-N-allyl]uracil, 5-aminoallylcytosine, 5-aminoallyluracil, 5-bromouracil, 5-bromocytosine, 5-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, Nl-ethylpseudouracil, N1 -methoxymethylpseudouracil, N1 -methyladenine, N1 -methylpseudouracil, N1 -propylpseudouracil, N2-methylguanine, N4-biotin-OBEA-cytosine, N4-methylcytosine, N6-methyladenine, O6-methylguanine, pseudoisocytosine, pseudouracil, thienocytosine, thienoguanine, thienouracil, xanthosine, 3-deazaadenine, 2,6-diaminoadenine, 2,6-daminoguanine, 5-carboxamide-uracil, 5-ethynyluracil, N6-isopentenyladenine (i6A), 2-methyl-thio-N6-isopentenyladenine (ms2i6A), 2-methylthio-N6-methyladenine (ms2m6A), N6-(cis-hydroxyisopentenyl)adenine (io6A), 2-methylthio-N6-(cis-hydroxyisopentenyl)adenine (ms2io6A), N6-glycinylcarbamoyladenine (g6A), N6-threonylcarbamoyladenine (t6A), 2-methylthio-N6-threonyl carbamoyladenine (ms2t6A), N6-methyl-N6-threonylcarbamoyladenine (m6t6A), N6-hydroxynorvalylcarbamoyladenine (hn6A), 2-methylthio-N6-hydroxynorvalyl carbamoyladenine (ms2hn6A), N6, N6-dimethyladenine (m62A), and N6-acetyladenine (ac6A).

[1066] Further nucleobases include those disclosed in U. S. Patent No. 3,687,808; Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P. ed. Wiley-VCH, 2008; The Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859; Kroschwitz, J. L., Ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, Y. S., Chapter 15, dsRNA Research and Applications, pages 289- A1278.70039WO00 151 302; Antisense Research and Applications, Crooke, S. T. and Lebleu, B., Eds., CRC Press, 1993, 273-288; Antisense Drug Technology, Crooke S. T., Ed., CRC Press, 2008, 163-166 and 442-443 (Chapters 6 and 15).

[1067] 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;

[1068] 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121; 5,596,091; 5,614,617;

[1069] 5,645,985; 5,681,941; 5,811,534; 5,750,692; 5,948,903; 5,587,470; 5,457,191; 5,763,588;

[1070] 5,830,653; 5,808,027; 6,005,096. 6,015,886; 6,147,200; 6,166,197; 6,166,199; 6,222,025;

[1071] 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.

[1072] In certain embodiments, oligonucleotides comprise modified and / or unmodified nucleobases arranged along one or both strands of the oligonucleotide or region thereof in a defined pattern or motif. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases are modified. In certain embodiments, each purine or each pyrimidine is modified. In certain embodiments, each adenine is modified. In certain embodiments, each guanine is modified. In certain embodiments, each thymine is modified. In certain embodiments, each uracil is modified. In certain embodiments, each cytosine is modified. In certain embodiments, some or all of the cytosine nucleobases in a modified oligonucleotide strand are 5-methylcytosines.

[1073] 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 oligonucleotide strands 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 A1278.70039WO00 152 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.

[1074] Internucleoside Linkage Modifications

[1075] 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 intemucleoside linkages include, but are not limited to, phosphotriesters, alkylphosphonates (e.g., methylphosphonates), phosphoramidates, phosphorothioates (“P=S”), phosphorodithioates (“HS-P=S”), and phosphorothiolates (“HS-P=O”). Representative non-phosphorus containing internucleoside linking groups include, but are not limited to, methylenemethylimino (-CH2-N(CHs)-O-CH2), thiodiester, thionocarbamate (-O-C(=O)(NH)-S-); siloxane (-O-Sifh-O-); and N, N'-dimethylhydrazine (-CH2-N((CH3)-N((CH3)-). Methods of preparation of phosphorous-containing and non-phosphorous-containing internucleoside linkages are well known to those skilled in the art. Neutral intemucleoside linkages include, without limitation, phosphotriesters, methylphosphonates, MMI (3'-CH2-N(CH3)-O-5'), amide-3 (3'-CH2-C(=O)-N(H)-5'), amide-4 (3'-CH2-N(H)-C(=O)-5'), formacetal (3'-O-CH2-O-5'), methoxypropyl, and thioformacetal (3'-S-CH2-O-5'). Further neutral intemucleoside linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester, and amides (See, for example: Carbohydrate Modifications in Antisense Research', Y. S. Sanghvi and P. D. Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Further neutral intemucleoside linkages include nonionic linkages comprising mixed N, O, S and CH2 component parts.

[1076] In certain embodiments, an oligonucleotide strand comprises at least one modified intemucleoside linkage. A modified intemucleoside linkage may be placed at any position of an oligonucleotide strand. For double- stranded oligonucleotides, a modified intemucleoside linkage may be placed within the sense oligonucleotide strand, antisense oligonucleotide strand, or both oligonucleotide strands of the double-stranded oligonucleotide.

[1077] In certain embodiments, the intemucleoside linkage modification may occur on every nucleoside of an oligonucleotide strand. In certain embodiments, intemucleoside linkage A1278.70039WO00 153 modifications may occur in an alternating pattern along an oligonucleotide strand. In certain embodiments, essentially each intemucleoside linking group is a phosphate intemucleoside linkage (P=O). In certain embodiments, each intemucleoside linking group of a modified oligonucleotide strand is a phosphorothioate (P=S). In certain embodiments, each intemucleoside linking group of a modified oligonucleotide strand is independently selected from phosphorothioate and phosphate intemucleoside linkages. In certain embodiments, the pattern of the intemucleoside linkage modification on each strand of a double- stranded oligonucleotide is the same. In certain embodiments, the pattern of the intemucleoside linkage modification on each strand of a double- stranded oligonucleotide is different. In certain embodiments, a doublestranded oligonucleotide comprises 6-8 modified intemucleoside linkages. In certain embodiments, the 6-8 modified intemucleoside linkages are phosphorothioate intemucleoside linkages or alkylphosphonate intemucleoside linkages. In certain embodiments, the sense oligonucleotide strand comprises at least two modified intemucleoside linkages at either or both the 5'-end and the 3'-end. In certain such embodiments, the modified intemucleoside linkages are phosphorothioate intemucleoside linkages or alkylphosphonate intemucleoside linkages. In certain embodiments, the antisense oligonucleotide strand comprises at least two modified intemucleoside linkages at either or both the 5'-end and the 3'-end. In certain such embodiments, the modified intemucleoside linkages are phosphorothioate intemucleoside linkages or alkylphosphonate intemucleoside linkages.

[1078] In certain embodiments, a double- stranded oligonucleotide comprises an overhang region. In certain embodiments, a double- stranded oligonucleotide comprises a phosphorothioate or alkylphosphonate intemucleoside linkage modification in the overhang region. In certain embodiments, a double- stranded oligonucleotide comprises a phosphorothioate or alkylphosphonate intemucleotide linkage linking the overhang nucleotide with a paired nucleotide that is next to the overhang nucleotide. For instance, there may be at least two phosphorothioate intemucleoside linkages between the terminal three nucleosides, in which two of the three nucleosides are overhang nucleosides, and the third is a paired nucleoside next to the overhang nucleoside. These terminal three nucleosides may be at the 3'-end of the antisense oligonucleotide strand, the 3 '-end of the sense oligonucleotide strand, the 5 '-end of the antisense oligonucleotide strand, or the 5 '-end of the sense oligonucleotide strand.

[1079] In certain embodiments, modified oligonucleotide strands comprise one or more intemucleoside linkages having chiral centers. Representative chiral intemucleoside linkages include, but are not limited to, alkylphosphonates and phosphorothioates. Modified oligonucleotide strands comprising intemucleoside linkages having chiral centers can be prepared as populations of modified oligonucleotide strands comprising stereorandom A1278.70039WO00 154 intemucleoside linkages, or as populations of modified oligonucleotide strands comprising phosphorothioate linkages in particular stereochemical configurations. In certain embodiments, populations of modified oligonucleotide strands comprise phosphorothioate intemucleoside linkages, wherein all of the phosphorothioate intemucleoside linkages are stereorandom. Such modified oligonucleotide strands can be generated using synthetic methods that result in random selection of the stereochemical configuration of each phosphorothioate linkage. As is well understood by those of skill in the art, each individual phosphorothioate of each individual oligonucleotide has a defined stereoconfiguration. In certain embodiments, populations of modified oligonucleotide strands are enriched for modified oligonucleotide strands comprising one or more particular phosphorothioate intemucleoside linkages in a particular, independently selected stereochemical configuration. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 65% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 70% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 80% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 90% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 99% of the molecules in the population. Such enriched populations of modified oligonucleotide strands can be generated using synthetic methods known in the art, e.g., methods described in Oka et al., JACS 125, 8307 (2003), Wan et al., Nuc. Acid. Res. 42, 13456 (2014), and WO 2017 / 015555. In certain embodiments, a population of modified oligonucleotide strands is enriched for modified oligonucleotide strands having at least one indicated phosphorothioate in the (Sp) configuration. In certain embodiments, a population of modified oligonucleotide strands is enriched for modified oligonucleotide strands having at least one phosphorothioate in the (Rp) configuration.

[1080] In certain embodiments, a modified intemucleoside linkage is present at the 3'-end of the oligonucleotide strand. In certain embodiments, a modified intemucleoside linkage is present within 3 nucleosides of the 3 '-end of the oligonucleotide strand. In certain embodiments, a modified intemucleoside linkage is present at the 5 '-end of the oligonucleotide strand. In certain embodiments, a modified intemucleoside linkage is present within 3 nucleosides of the 5'-end of the oligonucleotide strand. In certain embodiments, a modified intemucleoside linkage is present at an internal position on an oligonucleotide strand. In certain embodiments, a modified intemucleoside linkage is present more than 3 nucleosides from the 3 '-end of the oligonucleotide strand. In certain embodiments, a modified intemucleoside linkage is present more than 3 A1278.70039WO00 155 nucleosides from the 5'-end of the oligonucleotide strand. In certain embodiments, modified oligonucleotide strands 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.

[1081] In certain embodiments, a modified internucleosidic linkage comprises 5'-ethylenephosphonate, phosphorothioate, or an amide.

[1082] In certain embodiments, the present disclosure provides an oligonucleotide of any one of the formulae described herein, or a pharmaceutically acceptable salt or prodrug thereof. In certain embodiments, the oligonucleotides described herein include pharmaceutically acceptable salts and prodrugs thereof. In certain embodiments, the oligonucleotides described herein include pharmaceutically acceptable salts thereof.

[1083] In certain embodiments, the first modified oligonucleotide strand is of the formula,

[1084]

[1085] A1278.70039WO00 156 Formula

[1086] OMe

[1087] o

[1088]

[1089] A1278.70039WO00 157

[1090]

[1091]

[1092] 2 In certain embodiments, the first modified oligonucleotide strand is of the formula:

[1093]

[1094] A1278.70039WO00 159 Formula

[1095]

[1096] A1278.70039WO00 160

[1097]

[1098]

[1099]

[1100]

[1101] Oligonucleotide strands and modified oligonucleotide strands

[1102] In certain embodiments, SOD1 is specifically inhibited. In certain embodiments, SOD1 is specifically degraded. In certain embodiments, SOD1 expression is inhibited. In certain embodiments, SOD1 translation...

Claims

1. CLAIMS2.What is claimed is:

1. An oligonucleotide comprising a first modified oligonucleotide strand of Formula:4.5' 3'5.X5- X66.(I),7.or a pharmaceutically acceptable salt or prodrug thereof, wherein:

9. 10.?* is a divalent radical of a first oligonucleotide strand, wherein the first oligonucleotide strand is 14- to 30-nucleoside in length and has a nucleobase sequence comprising at least 14 contiguous nucleobases of, or having at least 90% identity to, a sequence shown in Table 2;11.each of X5and X6is independently of the formula:12.L1L1— (A1)y114. 15.(Al)y1, -L1-(A2)y2, or E; provided that at least one of X5and X6is of the formula:

17. 19.A1278.70039WO00 295 L1L1— (A1)y120.(A1)yi22. 24.each instance of N1is independently a radical of a nucleobase or bond;25.each instance of tl, when present, is independently 1, 2, or 3;26.each instance of L1when present and L2is a linker;27.each instance of yl when present and y2 is independently 1, 2, 3, 4, 5, or 6;28.each instance of A1when present and A2is independently a radical of a ligand or lipid; or one or more instances o29.

30. f are E;31.provided that at least one instance of A1is a radical of a central nervous system (CNS) receptor ligand;32.each instance of E is independently 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;33.each instance of Rbis 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 Rbattached A1278.70039WO00 296 to the same intervening atom are joined together with the intervening atom to form an substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring;34.vl instances of the intemucleosidic linkers of35. 36.2* are LAH37.L438.(A4) A39.independently replaced w40.

41. ithv / y4;42.vl is 0, 1, 2, 3, 4, 5, or 6;43.each instance of LA, when present, is independently a linker;44.each instance of L4, when present, is independently a linker or bond;45.each instance of y4, when present, is independently 1, 2, 3, 4, 5, or 6; and46.each instance of A4, when present, is independently a radical of a ligand or lipid.

2. The oligonucleotide of claim 1, wherein the first modified oligonucleotide strand is of the formula:

49. 51.A1278.70039WO00 297 (1-6),53.

54. (1-7),55.A1278.70039WO00 298 (1-8),56.(1-9), (1-10), (Ml),57.

58. (1-12), A1278.70039WO00 299 (1-14),59.(A1)y1- L1L1— (A1)y160.(1-16),61.

62. A1278.70039WO00 300 L--(A-),,(I- l g)64. 66.or a pharmaceutically acceptable salt or prodrug thereof; and67.each instance of yl is present.

3. The oligonucleotide of claim 1, wherein the first modified oligonucleotide strand is of the formula:

70. 72.A1278.70039WO00 301 2'LA- 5'73.(A4)y474.2’LA- (A4)y4(1-24),75.(1-25),76.L4(A77. 78.4)y4(1-26), A1278.70039WO00 302 (1-27),79.(1-29),80.LA> L4(A4)y4(1-30),81.(A1)y1- L1L1— (A1)y182.

83. A1278.70039WO00 303 L4(A4)y484.5'85.L4(A4)y4(A1)y1- L1L1— (A1)y186.

87. (1-36), A1278.70039WO00 304 or a pharmaceutically acceptable salt or prodrug thereof; and88.each instance of yl is present.

4. The oligonucleotide of claim 1, wherein the first modified oligonucleotide strand is of the formula:90.E L1— (A1)y191.(1-37),92.E L1— (A1)y193.(1-38),94.E L1— (A1)yi95.(1-39),96.L1L1— (A1)yi98.

99. (A1)y1100.A1278.70039WO00 305 L1L1— (A1)y1(A1)yl (1-42),101.5’102.(A1)yi(1-45),103.(A1)yi(1-46),104.L1L1— (A1)y1(A105. 106.1)yi(1-47), A1278.70039WO00 306 L1L1— (A1)y1(A1)yi(1-48),107.(1-49),108.(1-50),109.I110.(A1)*1(1-51),111.I112.(A1)*1(1-52),113.L1L1— (A1)y1114. 115.(A% (1-53), or116.A1278.70039WO00 307 (A1)y1- L1L1— (A1)yi117.L1L1— (A1)yi118.(A120. 121.1)y1 (1-54), or a pharmaceutically acceptable salt or prodrug thereof; and122.each instance of yl is present.

5. The oligonucleotide of claim 1, wherein the first modified oligonucleotide strand is of the formula:124.L2^ L1— (A1)yi125.(E or -L1-(A2)y2)126.(1-55),127.(E or -L1-(A2)y2)128.(1-56),129.■(E or -L1-(A2)y2)130.5' (1-57),131..(E or -L1-(A2)y2)133.

134. (1-58),135.A1278.70039WO00 308 L2^ L1— (A1)y1136.(E or-L1-(A2)y2)137.(1-59), or138.E or -I ■1(A2)y2)140.

141. (1-60), or a pharmaceutically acceptable salt or prodrug thereof; and142.each instance of yl is present.

6. The oligonucleotide of claim 1, wherein the first modified oligonucleotide strand is of the formula:144.E or -L1-(A2)y2)145.(1-61),146..(E or -L1-(A2)y2)147.(1-62),148.E or -L1-(A2)y2)150.

151. (1-63),152.A1278.70039WO00 309 (E or -L1-(A2)y2)153.5'154.4155.(A4)y4(1-64),156.E or -I ■1(A2)y2)157.(1-65), or158.3', A 5'159.< E or-L1(A2)y2)161.

162. (1-66), or a pharmaceutically acceptable salt or prodrug thereof; and163.each instance of yl is present.

7. The oligonucleotide of claim 1, wherein the first modified oligonucleotide strand is of the formula:165.(E or -L1(A2)y2)166.(1-67),167.E or -L1-(A2)y2)169.

170. (1-68),171.A1278.70039WO00 310 5’ 3’172.■(E or -L1-(A2)y2)173.(A1)yi (1-69),174.I175.(A1)*1(1-70), p - - - (E or -L1-(A2)y2)176.L1L1— (A1)yi177.(Al)yi (1-71), or178.L1L1— (A1)yi180.

181. (A1)y1 (1-72), or a pharmaceutically acceptable salt or prodrug thereof; and182.each instance of yl is present.

8. The oligonucleotide of claim 1, wherein the first modified oligonucleotide strand is of the formula:184.(E or (A2)y2-L1) - - 5’186. 187.(Al)y1(1-73),188.A1278.70039WO00 311 L4189.(A4)y4190.I191.(A1)yi (1-74),192.(1-76),193.(A1)yi - L1L1— (A1)yi(1-77), or194.5'195.(E or (A2)y2-L1) 2'LA—196.L197.(A4)198. 199.y4(1-78), or a pharmaceutically acceptable salt or prodrug thereof; and200.each instance of yl is present.

9. The oligonucleotide of claim 1, wherein the first modified oligonucleotide strand is of the formula:202.(A1)yi- L1203.(E or (A2)y2-L1) - - - L2205. 206.5' (1-79),207.A1278.70039WO00 312 F rxN208.Y? (A1)y1- L1(E or (A2)y2-L1) - -LA£ - - L2209.I210.L4(A4)y4(1-80),211.‘-E212.E213.(E or (A2)y2-L1)- (1-81),1-E214.E215.(E or (A2)y2-L1) - - Z |_A 5' |_9216.5'217.(A4)y4(1-82),218.E219.(A1)yi- L1(E or (A2)y2-L1)- (1-83), or -E220.(A1)y1- L1(E or (A2)y2-L1)- 3,' [_A 5' 3'L?221.(A4)222. 223.y4(1-84), or a pharmaceutically acceptable salt or prodrug thereof; and224.each instance of yl is present.225.A1278.70039WO00 313 10. The oligonucleotide of claim 10, wherein the first modified oligonucleotide strand is of the formula:226.(E or (A2)y2-L1) - - 5’ (1-85),227.(E or (A2)y2-L1>228.(E or (A2)y2-L1>229.(E or (A2)y2-L1) - £230.(E or (A2)y2-L1}231.(E or (A2)y2-L1)5'233.

234. (1-90),235.or a pharmaceutically acceptable salt or prodrug thereof; and236.A1278.70039WO00 314 each instance of yl is present.

11. The oligonucleotide of any one of the preceding claims, wherein each of X5and X6is independently of the formula:238.L1L1— (A1)y1239.

240. (A1)yi12. The oligonucleotide of any one of the preceding claims, wherein:242.X5is of the formula:243.L1L1— (A1)y1245. 246.(Al)y1; and X6is E.

13. The oligonucleotide of any one of the preceding claims, wherein:248.X5is of the formula:249.A1278.70039WO00 315250. 251.(Al)y1; and x6is -IJ- A14. The oligonucleotide of any one of the preceding claims, wherein:253.X5is E; and254.X6is of the formula:

256.

15. The oligonucleotide of any one of the preceding claims, wherein:259.X5is -L1-(A2)y2; and260.X6is of the formula:261.A1278.70039WO00 316 L1L1— (A1)y1262.

263. (A1)yi16. The oligonucleotide of any one of the preceding claims, wherein at least one instance of N1is a radical of a nucleobase.

17. The oligonucleotide of any one of the preceding claims, wherein at least one instance of N1is a radical of adenine, cytosine, guanine, or uracil.

18. The oligonucleotide of any one of the preceding claims, wherein at least one instance of tl, when present, is 1.

19. The oligonucleotide of any one of the preceding claims, wherein at least one instance of --[id- A^ydti is E.

20. The oligonucleotide of any one of the preceding claims, wherein at least one instance of yl is 1 or 2.

21. The oligonucleotide of any one of the preceding claims, wherein y2 is 1 or 2.

22. The oligonucleotide of any one of the preceding claims, wherein the first modified oligonucleotide strand comprises one radical of a ligand.

23. The oligonucleotide of any one of the preceding claims, wherein the first modified oligonucleotide strand comprises two or three radicals of ligands.272.A1278.70039WO00 317 24. The oligonucleotide of any one of the preceding claims, wherein each instance of A1is a radical of a CNS ligand.

25. The oligonucleotide of any one of the preceding claims, wherein at least one instance of A1is a radical of a CNS ligand, and at least one instance of A1is a radical of a lipid.

26. The oligonucleotide of any one of the preceding claims, wherein at least one instance of A2, when present, is a radical of a CNS ligand.

27. The oligonucleotide of any one of the preceding claims, wherein at least one instance of277.

28. The oligonucleotide of any one of the preceding claims, wherein at least one instance of L1is substituted or unsubstituted, Ci-ioo 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, C 2-100 heteroalkynylene;280.optionally wherein one or more backbone atoms of the Ci-100 alkylene, C 2-100 alkenylene, C2-100 alkynylene, Ci-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 unsubstituted heteroarylene, as valency permits.

29. The oligonucleotide of any one of the preceding claims, wherein at least one instance of L1is substituted or unsubstituted, C7-70 alkylene or substituted or unsubstituted, C7-70 heteroalkylene;282.optionally wherein 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.283.A1278.70039WO00 318 30. The oligonucleotide of any one of the preceding claims, wherein:284.at least one instance of L1is of the formula:

286.

287. each of -L1A1-L1A2-, -L1A3-L1A4-, -L1A5-L1A6-, -L1A7-L1A8-, -L1A9-L1A10-, and -L1A11-L1A12- 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-, -OP(=O)(SRa)O-, or -OP(=S)(ORa)O-;288.each instance of Rais independently hydrogen, substituted or unsubstituted, Ci-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl;289.each of L1B1, L1B2, and L1B3is independently a single bond, substituted or unsubstituted, Ci-ioo alkylene, or substituted or unsubstituted, Ci-100 heteroalkylene;290.each of L1C1and L1C2is independently a single bond, substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms, or substituted or unsubstituted heteroarylene; and291.bond C1Ais attached to A1.

31. The oligonucleotide of the preceding claim, wherein at least one instance of L1is of the formula:293.Zx|_1A2L1A3 [_1C1 | 1A6L1A7 ClA294.|_1A1' ^L1B<>j_1A4''' \lA5' ^lAS^295.

32. The oligonucleotide of any one of the preceding claims, wherein L1thereof is of the formula:298.A1278.70039WO00 319299.

33. The oligonucleotide of any one of the preceding claims, wherein:302.at least one instance of L1is of the formula:303.each of -L1A1-L1A2-, -L1A3-L1A4-, -L1A5-L1A6-, -L1A7-L1A8-, -L1A9-L1A10-, -L1A13pl A 14 pl Al 5_pl Al 6 pl Al 7_pl Al 8 pl Al 9_pl A20 pl A21_pl A22 pl A23_pl A24 pl A25304.

305. L1A26-, pi A2?_pi A28_ _pi A29_J^I A3o_an(j _pi A3 i_pi A32_ 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-;306.each instance of Rais independently hydrogen, substituted or unsubstituted, Ci-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl;307.A1278.70039WO00 320 each of L1B1, L1B2, L1B3, L1B4, L1B5, L1B6, L1B7, L1B8, and L1B9is independently a single bond, substituted or unsubstituted, Ci-ioo alkylene, or substituted or unsubstituted, Ci-ioo heteroalkylene;308.each of L1C1, L1C2, L1C3, L1C4, L1C5, and L1C6is a single bond, substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms, or substituted or unsubstituted heteroarylene;309.bond C1Bis attached to a first instance of A1; and310.bond Clcis attached to a second instance of A1.

34. The oligonucleotide of any one of the preceding claims, wherein at least one instance of Rais hydrogen or substituted or unsubstituted Ci-6 alkyl.

35. The oligonucleotide of any one of the preceding claims, wherein at least one instance of L1is of the formula:313.i 1B9 i 1A29 ^|_1A28 1B8314.1A3l" '^1A30'" ~^'|_1 C6^ |_1A27315.

36. The oligonucleotide of the preceding claim, wherein at least one instance of L1is of the formula:318.A1278.70039WO00 321L1A21 / / \ 0- 1 \ L 1 A22 ' '0-6320.

37. The oligonucleotide of any one of the preceding claims, wherein at least one instance of L2is -O-, -S-, -S-S-, -NRd-, -C(=O)O-, -C(=NRd)O- -S(=O)O-, -S(=O)2O-, -C(=O)NRd--C(=NRd)NRd-, -S(=O)NRd-, -S(=O)2NRd-, -OC(=O)-, -OC(=NRd)-, -OS(=O)-, -OS(=O)2--NRdC(=O)-, -NRdC(=NRd)-, -NRdS(=O)-, -NRdS(=O)2- -OC(=O)O-, -OC(=NRd)O- -OS(=O)O-, -OS(=O)2O- -NRdC(=O)O-, -NRdC(=NRd)O-, -NRdS(=O)O- -NRdS(=O)2O- -OC(=O)NRd-, -OC(=NRd)NRd-, -OS(=O)NRd- -OS(=O)2NRd- -NRdC(=O)NRd-, -NRdC(=NRd)NRd-, -NRdS(=O)NRd-, -NRdS(=O)2NRd- -C(=O)-, -C(=NRd)-, -S(=O)-, -S(=O)2- -OP(=O)(ORd)O-, -SP(=O)(ORd)O-, -OP(=O)(ORd)S- -OP(=O)(SRd)O- -OP(=S)(ORd)O-, substituted or unsubstituted, Ci-ioo alkylene, substituted or unsubstituted, C2-ioo alkenylene, substituted or unsubstituted, C2-ioo alkynylene, substituted or unsubstituted, Ci-ioo heteroalkylene, substituted or unsubstituted, C2-ioo heteroalkenylene, or substituted or unsubstituted, C2-ioo heteroalkynylene;323.optionally wherein one or more backbone atoms of the Ci-ioo alkylene, C2-ioo alkenylene, C2-ioo alkynylene, Ci-ioo 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; and324.each instance of Rdis 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 Rdattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.325.A1278.70039WO00 322 38. The oligonucleotide of any one of the preceding claims, wherein at least one instance of Rdis hydrogen or substituted or unsubstituted Ci-6 alkyl.

39. The oligonucleotide of any one of the preceding claims, wherein at least one instance of L2is substituted or unsubstituted, Ci-6 heteroalkylene.

40. The oligonucleotide of any one of the preceding claims, wherein at least one instance of L2is of the formula: -O-, -O-P(=O)(OH)-O-, -O-P(=O)(OH)-S-, -S-P(=O)(OH)-O-, -O-P(=S)(OH)-O-, -CH2-O-, -CH2-O-P(=O)(OH)-O-, -CH2-O-P(=O)(OH)-S-, -CH2-S-P(=O)(OH)-O-, -CH2-O-P(=S)(OH)-O-, -O-CH2-, -O-P(=O)(OH)-O-CH2-, -O-P(=O)(OH)-S-CH2-, -S-P(=O)(OH)-O-CH2-, or -O-P(=S)(OH)-O-CH2-.

41. The oligonucleotide of any one of the preceding claims, wherein vl is 0.

42. The oligonucleotide of any one of the preceding claims, wherein vl is 1.

43. The oligonucleotide of any one of the preceding claims, wherein:331.at least one instance of LA, when present, is of the formula:

333. 335.each instance of ZA1and ZA2is independently a single bond, substituted or unsubstituted, C1-6 alkylene, or substituted or unsubstituted, C2-6 alkenylene;336.each instance of WAis 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;337.each instance of Rcis 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, A1278.70039WO00 323 substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two instances of Rcare joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and338.bond C4Ais attached to L4.

44. The oligonucleotide of any one of the preceding claims, wherein at least one instance of Rcis hydrogen or substituted or unsubstituted Ci-6 alkyl.

45. The oligonucleotide of any one of the preceding claims, wherein at least one instance of341.|C4A|c342.L, when present, is of the formula: JVW * / VW4A344.

46. The oligonucleotide of any one of the preceding claims, wherein:347.at least one instance of LA, when present, is of the formula:

349. 351.bond C4Bis attached to the 3’ position of a first nucleoside; and352.bond C4cis attached to the 5’ position of a second nucleoside.

47. The oligonucleotide of any one of the preceding claims, wherein at least one instance of y4, when present, is 1.

48. The oligonucleotide of any one of the preceding claims, wherein at least one instance of L4, when present, is substituted or unsubstituted, Ci-ioo 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;355.optionally wherein one or more backbone atoms of the Ci-100 alkylene, C 2-100 alkenylene, C2-100 alkynylene, Ci-100 heteroalkylene, C 2-100 heteroalkenylene, or C 2-100 heteroalkynylene are A1278.70039WO00 324 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 oligonucleotide of any one of the preceding claims, wherein at least one instance of L4, when present, is a bond.

50. The oligonucleotide of any one of the preceding claims, wherein at least one instance of A4is a radical of a lipid.

51. The oligonucleotide of any one of the preceding claims, wherein at least one instance of E is hydrogen, halogen, substituted or unsubstituted methyl, -OP(=O)(ORb)2, -SP(=O)(ORb)2, -OP(=O)(ORb)(SRb), -ORb, -SRb, -SSRb, -N(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.

52. The oligonucleotide of any one of the preceding claims, wherein at least one instance of E is -CH2OP(=O)(ORb)2, -CH2SP(=O)(ORb)2, -CH2OP(=O)(ORb)(SRb), -CH2ORb, -CH2SRb, -CH2SSRb, -CH2N(Rb)2, -CH2OC(=O)Rb, -CH2OC(=O)ORb, -CH2OC(=O)SRb, -CH2OC(=O)N(Rb)2, -CH2OS(=O)Rb, -CH2OS(=O)ORb, -CH2OS(=O)SRb, -CH2OS(=O)N(Rb)2, -CH2OS(=O)2Rb, -CH2OS(=O)2ORb, -CH2OS(=O)2SRb, -CH2OS(=O)2N(Rb)2, -CH2ON(Rb)2, -CH2SC(=O)Rb, -CH2SC(=O)ORb, -CH2SC(=O)SRb, -CH2SC(=O)N(Rb)2, -CH2NRbC(=O)Rb, -CH2NRbC(=O)ORb, -CH2NRbC(=O)SRb, -CH2NRbC(=O)N(Rb)2, -CH2NRbS(=O)Rb, -CH2NRbS(=O)ORb, -CH2NRbS(=O)SRb, -CH2NRbS(=O)N(Rb)2, -CH2NRbS(=O)2Rb, -CH2NRbS(=O)2ORb, -CH2NRbS(=O)2SRb, or -CH2NRbS(=O)2N(Rb)2.

53. The oligonucleotide of any one of the preceding claims, wherein at least one instance of E is -ORbor -CH2ORb.

54. The oligonucleotide of any one of the preceding claims, wherein at least one instance of Rbis hydrogen or substituted or unsubstituted Ci-6 alkyl.362.A1278.70039WO00 325 55. The oligonucleotide of any one of the preceding claims, wherein at least one CNS receptor ligand is a tropomyosin receptor B (TrkB) ligand.

56. The oligonucleotide of the preceding claim, wherein:364.at least one TrkB ligand is a compound of the formula:

366.

367. R2is hydrogen, -OR7, -SR8, or -NR9R10;368.R3is hydrogen, -OR31, -SR32, or -NR33R34;369.R4is hydrogen, -OR35, -SR36, or -NR37R38;370.R5is hydrogen, -OR39, -SR40, or -NR41R42;371.R6is hydrogen, -OH, optionally substituted -O-alkyl, optionally substituted -OAc, -NH2, optionally substituted -NHAc, -SH, or =0;372.R7, R8, R9, R10, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, and R42are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;373.Y is CH2, NH, S, or O;374.Z is optionally substituted aryl or optionally substituted heteroaryl;375.R11and R13are each independently absent, hydrogen, or optionally substituted alkyl; A1278.70039WO00 326 R12, R14, and R15are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;376.R16is hydrogen, halogen, -CN, -N3, -SOni6R1A, -SOv16NR16BR16C, -NHNR16BR16C, -ONR16BR16C, -NHC(O)NHNR16BR16C, -NHC(O)NR16BR16C, -N(0)mi6, -NR16BR16C, -C(O)R16D, -C(O)OR16D, -C(O)NR16BR16C, -OR16A, -NR16BSO2R16A, -NR16BC(O)R16D, -NR16BC(O)OR16D, -NR16BOR16D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;377.aha and =-s-= are each independently a single bond or a double bond, wherein if = is a single bond, then378.

379. is a double bond and R13is absent; and further wherein if380.

381. is a single382.bond, then = is a double bond and R11is absent;383.R16A, R16B, R16C, R16Dare each independently hydrogen, halogen, -CF3, -CCh,-CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R16Band R16Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;384.R17, R18, and R19are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;385.R20is hydrogen, halogen, -CN, -N3, -SOn20R1A, -SOv2oNR20BR20C, -NHNR20BR20C, -ONR20BR20C, -NHC(O)NHNR20BR20C, -NHC(O)NR20BR20C, -N(O)m20, -NR20BR20C, -C(O)R20D, -C(O)OR20D, -C(O)NR20BR20C, -OR20A, -NR20BSO2R20A, -NR20BC(O)R20D, -NR20BC(O)OR20D, -NR20BOR20D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;386.R21is hydrogen, halogen, -CN, -N3, -SOn2iR1A, -SOV2INR21BR21C, -NHNR21BR21C, -ONR21BR21C, -NHC(O)NHNR21BR21c, -NHC(O)NR21BR21c, -N(0)m2i, -NR21BR21C, -C(O)R21D, -C(O)OR21D, -C(O)NR21BR21c, -OR21A, -NR21BSO2R21A, -NR21BC(O)R21D, -NR21BC(O)OR21D, -NR21BOR21D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;387.A1278.70039WO00 327 R22and R23are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;388.R24is hydrogen, halogen, -CN, -N3, -SOn24R1A, -SOv24NR24BR24C, -NHNR24BR24C, -ONR24BR24C, -NHC(O)NHNR24BR24C, -NHC(O)NR24BR24C, -N(O)m24, -NR24BR24C, -C(O)R24D, -C(O)OR24D, -C(O)NR24BR24C, -OR24A, -NR24BSO2R24A, -NR24BC(O)R24D, -NR24BC(O)OR24D, -NR24BOR24D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;389.R20A,R20B,R20CR20DR21AR21B,R21CR21 DR24AR24B,R24Cand R24Dafe eachindependently hydrogen, halogen, -CF3, -CCI3, -CB13, -CI3 -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R20B, R20C, R21B, R21C, R24B, R24C, R24B, and R24Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;390.nl6, n20, n21, n23, n24, z6, and z8 are each independently 0, 1, 2, 3, or 4;391.vl6, v20, v21, ml6, m20, m21, and m24 are each independently 1 or 2;392.z3 is 0, 1, 2, 3, 4, or 5;393.z4 and z7 are each independently 0, 1, or 2;394.z5 is 0, 1, 2, or 3; and395.z6 and z8 are each independently 0, 1, 2, 3, or 4.

57. The oligonucleotide of the preceding claim, wherein at least one radical of a TrkB ligand is of the formula:

398.

399. O, or O400.A1278.70039WO00 328 58. The oligonucleotide of any one of the preceding claims, wherein at least one lipid is unbranched unsubstituted C12-24 alkyl or unbranched unsubstituted C12-24 alkenyl comprising 1, 2, or 3 CC double bonds and no CC triple bonds.

59. The oligonucleotide of any one of the preceding claims, wherein at least one lipid is unbranched unsubstituted C14-20 alkyl.

60. The oligonucleotide of any one of the preceding claims, wherein the first modified oligonucleotide strand is of the formula, and optionally comprising a second oligonucleotide404. 406.A1278.70039WO00 329407.

409.

61. The oligonucleotide of any one of the preceding claims, wherein the oligonucleotide is single-stranded.412.A1278.70039WO00 331 62. The oligonucleotide of any one of the preceding claims, wherein the first modified oligonucleotide strand is a modified antisense strand.

63. The oligonucleotide of any one of the preceding claims, wherein the first modified oligonucleotide strand is a modified sense strand.

64. The oligonucleotide of any one of the preceding claims further comprising a second modified oligonucleotide strand, wherein the second modified oligonucleotide strand is 14- to 30-nucleoside in length and has a region of complementarity to the first modified oligonucleotide strand.

65. The oligonucleotide of the preceding claim, wherein the first modified oligonucleotide strand is a modified sense strand, and the second modified oligonucleotide strand is a modified antisense strand.

66. The oligonucleotide of any one of the preceding claims, wherein the region of complementarity between the first modified oligonucleotide and the second modified oligonucleotide is 19 to 23 linked nucleosides in length.

67. The oligonucleotide of any one of the preceding claims, wherein the first modified oligonucleotide strand is fully complementary to the second modified oligonucleotide strand.

68. The oligonucleotide of any one of the preceding claims, wherein the antisense strand has a nucleobase sequence comprising at least 14 contiguous nucleobases of, or having at least 90% identity to, an antisense sequence shown in Table 2.

69. The oligonucleotide of any one of the preceding claims, wherein the antisense strand has a nucleobase sequence comprising at least 14 contiguous nucleobases of, or having at least 90% identity to, a sequence of SEQ ID NO: 198.

70. The oligonucleotide of any one of the preceding claims, wherein the sense strand has a nucleobase sequence comprising at least 14 contiguous nucleobases of, or having at least 90% identity to, a sense strand shown in Table 2.421.A1278.70039WQ00 332 71. The oligonucleotide of any one of the preceding claims, wherein the sense strand has a nucleobase sequence comprising at least 14 contiguous nucleobases of, or having at least 90% identity to, a sequence of SEQ ID NO: 193, 225, or 226.

72. The oligonucleotide of any one of the preceding claims, wherein:423.each of the antisense and sense strands independently has a nucleobase sequence comprising at least 14 contiguous nucleobases of, or having at least 90% identity to, a sequence shown in the table below:424.antisense strand SEQ ID NO: 198, and sense strand SEQ ID NO: 193;425.antisense strand SEQ ID NO: 198, and sense strand SEQ ID NO: 225; or426.antisense strand SEQ ID NO: 198, and sense strand SEQ ID NO: 226.

428.

73. The oligonucleotide of any one of the preceding claims, wherein the first oligonucleotide strand and / or the second modified oligonucleotide strand independently further comprise one or more further modifications independently selected from modified sugars, modified nucleobases, and modified internucleosidic linkers.

74. The oligonucleotide of any one of the preceding claims, wherein at least one instance of the modified sugars is a 2'-fluoro-2'-deoxyribose, 2'-0-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'-0-(2-nitrobenzyl)-2'-deoxyribose, 3'-0-methylribose, 5 '-aminoribose, 5 '-thioribose, 5-nitro-l-indolyl-2'-deoxyribose, 5'-biotin-ribose, 2'-0,4'-C-amino-linked ribose, 2'-0,4'-C-thio-linked ribose, 2’-0-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.

75. The oligonucleotide of any one of the preceding claims, wherein at least one instance of the modified sugars is 2'-O-methyl ribose, 2'-F ribose, or inverted abasic deoxyribose.

76. The oligonucleotide of any one of the preceding claims, wherein at least 90% of the sugars of the first oligonucleotide strand and / or at least 90% of the sugars of the second oligonucleotide strand are modified sugars.434.A1278.70039WQ00 333 77. one instance of the modified sugars is 2'-O-methyl ribose, 2'-F ribose, or inverted abasic deoxyribose.

78. The oligonucleotide of any one of the preceding claims, 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, Nl-ethylpseudouracil, N1 -methoxymethylpseudouracil, N1 -methyladenine, N1 -methylpseudouracil, N1 -propylpseudouracil, N2-methylguanine, N4-biotin-OBEA-cytosine, N4-methylcytosine, N6-methyladenine, O6-methylguanine, pseudoisocytosine, pseudouracil, thienocytosine, thienoguanine, thienouracil, xanthosine, 3-deazaadenine, 2,6-diaminoadenine, 2,6-daminoguanine, 5-carboxamide-uracil, 5-ethynyluracil, N6-isopentenyladenine (i6A), 2-methyl-thio-N6-isopentenyladenine (ms2i6A), 2-methylthio-N6-methyladenine (ms2m6A), N6-(cis-hydroxyisopentenyl)adenine (io6A), 2-methylthio-N6-(cis-hydroxyisopentenyl)adenine (ms2io6A), N6-glycinylcarbamoyladenine (g6A), N6-threonylcarbamoyladenine (t6A), 2-methylthio-N6-threonyl carbamoyladenine (ms2t6A), N6-methyl-N6-threonylcarbamoyladenine (m6t6A), N6-hydroxynorvalylcarbamoyladenine (hn6A), 2-methylthio-N6-hydroxynorvalyl carbamoyladenine (ms2hn6A), N6, N6-dimethyladenine (m62A), and N6-acetyladenine (ac6A).436.A1278.70039WO00 334 79. The oligonucleotide of any one of the preceding claims, wherein at least one instance of the modified internucleosidic linkers is a phosphorothioate intemucleosidic linker, phosphorothiolate internucleosidic linker, or a methylphosphonate intemucleosidic linker.

80. The oligonucleotide of any one of the preceding claims, wherein the modified antisense strand is at least 80% complementary to SEQ ID NO: 1 or 2.

81. The oligonucleotide of any one of the preceding claims, wherein the modified antisense strand has a sequence comprising at least 14 contiguous nucleotides of, or having at least 90% identity to, an antisense sequence shown in Table 3.

82. The oligonucleotide of any one of the preceding claims, wherein the modified antisense strand has a sequence comprising at least 14 contiguous nucleotides of, or having at least 90% identity to, a sequence of SEQ ID NO: 198.

83. The oligonucleotide of any one of the preceding claims, wherein the modified sense strand has a sequence comprising at least 14 contiguous nucleotides of, or having at least 90% identity to, a sense sequence shown in Table 3.

84. The oligonucleotide of any one of the preceding claims, wherein the modified sense strand has a sequence comprising at least 14 contiguous nucleotides of, or having at least 90% identity to, a sequence of any one of SEQ ID NOs: 193, 225, and 226.

85. The oligonucleotide of any one of the preceding claims, wherein:443.each of the modified antisense and modified sense strands independently has a nucleobase sequence comprising at least 14 contiguous nucleobases of, or having at least 90% identity to, a sequence shown in the table below:444.modified antisense strand SEQ ID NO: 198, and modified sense strand SEQ ID NO: 193; modified antisense strand SEQ ID NO: 198, and modified sense strand SEQ ID NO: 225; or modified antisense strand SEQ ID NO: 198, and modified sense strand SEQ ID NO: 226.

446.

86. The oligonucleotide of any one of the preceding claims further comprising a second modified oligonucleotide strand, wherein:449.the first and second modified oligonucleotide strands are as shown in the table:450.A1278.70039WQ00 335 Ref ID NO. of the first modified Ref ID NO. of the second modified oligonucleotide strand oligonucleotide strand451.IS2009 IA1233452.IS2010 IA1233453.IS2042 IA1233454.IS2127 IA1233455.IS2128 IA1233456.IS2146 IA1233457.IS2400 IA1302458.IS2412 IA1302459.IS2414 IA1302461.

87. A pharmaceutical composition comprising the oligonucleotide of any one of the preceding claims and a pharmaceutically acceptable excipient.

88. A kit comprising:465.the oligonucleotide of any one of the preceding claims or the pharmaceutical composition of claim 87; and466.instructions for using the oligonucleotide or pharmaceutical composition.

89. A method of delivering an oligonucleotide to a subject in need thereof, cell, tissue, or biological sample comprising administering to the subject or contacting the cell, tissue, or biological sample with the oligonucleotide of any one of the preceding claims or the pharmaceutical composition of claim 87.

90. The method of the claim 89, wherein the oligonucleotide is delivered to the brain of the subject.

91. A method of inhibiting the expression of the superoxide dismutase 1 (SODl) gene in a subject in need thereof, cell, tissue, or biological sample comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of the oligonucleotide of any one of the preceding claims or the pharmaceutical composition of claim 87.

92. The method of the claims 91, wherein the cell, tissue, or biological sample is in vitro.471.A1278.70039WO00 336 93. The method of any one of claim 91 or 92, wherein the cell, tissue, or biological sample is a central nervous system (CNS) cell, tissue, or biological sample.

94. A method of treating a disease in a subject in need thereof comprising administering to the subject an effective amount of the oligonucleotide of any one of the preceding claims or the pharmaceutical composition of claim 87.

95. A method of preventing a disease in a subject in need thereof comprising administering to the subject an effective amount of the oligonucleotide of any one of the preceding claims or the pharmaceutical composition of claim 87.

96. The method of claim 94 or 95, wherein the disease is a central nervous system (CNS) disease.

97. The method of claim 96, wherein the disease is a brain disease, Edwards syndrome, gliosis, hyperekplexia, Meckel syndrome, myoclonic epilepsy myopathy sensory ataxia, narcolepsy, prion diseases, serotonin syndrome, or spinal cord disease.

98. The method of claim 94 or 95, wherein the disease is a neurodegenerative disease.

99. The method of claim 98, wherein the disease is ABri amyloidosis, aceruloplasminemia, acute neurodegenerative disease, amyotrophic lateral sclerosis, ataxia with vitamin E deficiency, atypical Rett syndrome, beta-propeller protein-associated neurodegeneration, COASY protein-associated neurodegeneration, central nervous system degenerative disease, demyelination, fatty acid hydroxylase-associated neurodegeneration, fragile X tremor ataxia syndrome, Gemignani syndrome, Gers tmann- Straus sler syndrome, Huntington disease, Huntington-like syndrome, hypomyelination with atrophy of basal ganglia and cerebellum, infantile cerebellar-retinal degeneration, infantile neuroaxonal dystrophy, Kosaki overgrowth syndrome, mitochondrial membrane protein-associated neurodegeneration, multiple sclerosis, multiple system atrophy, muscular dystrophy, Nasu-Hakola disease, neuroacanthocytosis, neurogenic ataxia and retinitis pigmentosa syndrome, neuronal ceroid lipofuscinosis, neuronal intranuclear inclusion disease, neuropil thread, pantothenate kinase-associated neurodegeneration, Parkinson disease, posterior column ataxia, pure autonomic failure, retrograde degeneration, Rett syndrome, SPOAN syndrome, Salla disease, spinocerebellar ataxia, subacute combined degeneration, Tabes dorsalis, tauopathy, or Wolfram syndrome.478.A1278.70039WO00 337 100. The method of claim 94 or 95, wherein the disease is a neurocognitive disorder.

101. The method of claim 94 or 95, wherein the disease is amyotrophic lateral sclerosis.

102. The method of claim 94 or 95, wherein the disease is a dementia, HIV- associated neurocognitive disorder, or memory disorder.

103. The method of claim 94 or 95, wherein the disease is Parkinson’s disease.

104. The method of claim 94 or 95, wherein the disease is Alzheimer’s disease.

105. The method of claim 94 or 95, wherein the disease is a tauopathy, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglionic degeneration (CBD), epilepsy, or Dravet’s Syndrome.

106. The method of any one of the claims 89-105, wherein the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition, is administered to the subject parenterally.

107. The method of any one of claims 89-106, wherein the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition, is administered to the subject intrathecally, intracerebroventricularly, or intravenously.

108. The method of any one of claims 89-107, wherein the subject is a human.487.A1278.70039WO00 338

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