Mannose receptor ligand-tropomyosin receptor b ligand conjugates for drug delivery

Abstract

Provided herein are mannose receptor ligand-containing compounds, methods of delivering said compounds to subjects, and methods of treating diseases (e.g., central nervous system diseases) and symptoms thereof in a subject using said compounds.

Description

MANNOSE RECEPTOR LIGAND-TROPOMYOSIN RECEPTOR B LIGAND CONJUGATES FOR DRUG DELIVERY RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No 63 / 568,242, filed March 21, 2024, which is incorporated herein by reference. BACKGROUND

[0002] In the use of compounds in therapeutic, prophylactic, or diagnostic applications, it is often desirable that the compounds be delivered to a specific location (for example, to desired cell(s)) to enhance the therapeutic or prophylactic effect or to be advantageous for diagnostic purposes. This is frequently the case when attempting to deliver a therapeutic compound in vivo. Further, being able to efficiently deliver a compound to a specific location can limit or potentially eliminate unintended consequences (such as off-target effects) that may be caused by administration of the compound. One strategy to facilitate delivery of a compound, such as a therapeutic, prophylactic, or diagnostic compound, to a desired location in vivo, is by linking or attaching the compound to a targeting ligand.

[0003] One class of compounds that can be targeted using targeting ligands are oligomeric compounds such as, for example, proteins, peptides, antibodies, and oligonucleotides. Oligomeric compounds that include nucleotide sequences (e.g., oligonucleotides) that are at least partially complementary to a target nucleic acid, have been shown to alter the function and activity of the target both in vitro and in vivo. When delivered to a cell containing a target nucleic acid (such as mRNA or pre-mRNA), oligonucleotides have been shown to modulate the expression or activity of the target nucleic acid. In certain instances, the oligonucleotide can reduce the expression of the gene by inhibiting translation of the nucleic acid target and / or triggering the degradation of the target nucleic acid.

[0004] If the target nucleic acid is mRNA, one mechanism by which an oligonucleotide can modulate the expression of the mRNA target is through RNA interference. RNA interference is a biological process by which RNA or RNA-like molecules (such as chemically modified RNA molecules) are able to silence gene expression, at least in part, through the RNA-induced silencing Complex (RISC) pathway. Additionally, oligonucleotides can modulate the expression of a target nucleic acid, such as a target mRNA, through an RNase recruitment mechanism, microRNA mechanisms, occupancy-based mechanisms, and editing mechanisms. Oligonucleotides may be single-stranded or double-stranded. Oligonucleotides may comprise DNA, RNA, and RNA-like molecules, which can also include modified nucleosides including one or more non-phosphodiester linkages.A1278.70032WO00 1 12280650.2

[0005] Another class of compounds that can be targeted using targeting ligands are small molecule compounds. The small molecule compounds (e.g., an organic compound having a molecular weight of ca.1000 daltons or less) are typically shown to alter the function and / or activity of the target such that disease and / or disease symptoms are modulated or ameliorated or are typically useful as a diagnostic marker when localized to the target. More efficient delivery of a compound to a specific location can limit or potentially eliminate unintended consequences (such as off-target effects) that may be caused by administration of the compound and provide improved localization of a diagnostic compound. SUMMARY

[0006] Embodiments provided herein are directed to compounds (e.g., any of those delineated herein) and methods for targeting cells expressing Mannose Receptor (MR). Certain embodiments provided herein are directed to compounds and methods for delivering an agent (e.g., pharmaceutical agent) to cells expressing mannose receptor. In certain embodiments, the cell is a microglial cell. In certain embodiments, the cell is a microglial cell in the brain. In certain embodiments, the cell is in the frontal cortex. In certain embodiments, the cell is in the striatum. In certain embodiments, the cell is in the cerebellum. In certain embodiments, the cell is in the brain stem. In certain embodiments, the cell is in the hippocampus. In certain embodiments, the cell is in the spinal cord. In certain embodiments, the agent is a therapeutic agent. In certain embodiments, delivery of the agent is for the treatment of diseases, disorders, and symptoms in a subject. In certain embodiments, the agent is a diagnostic compound. In certain embodiments, a compound comprises a mannose ligand and one or more linker moieties for attachment to a therapeutic, prophylactic, or diagnostic agent. In certain embodiments, a compound comprises a mannose ligand, one or more linker moieties, and a therapeutic agent. In certain embodiments, a compound comprises a mannose ligand, a TrkB ligand, linker moieties, and a therapeutic agent. In certain embodiments, the therapeutic agent is selected from a small molecule or oligomeric compound. In certain embodiments, the oligomeric compound is a protein, peptide, antibody, oligonucleotide, or combination thereof. In certain embodiments, the mannose ligand is a mannose receptor agonist. In certain embodiments, the mannose ligand is a small molecule, aptamer, peptide, or antibody. In certain embodiments, the mannose ligand is mannose, or a derivative thereof. In certain embodiments, the mannose ligand is mannose. In certain embodiments, the mannose ligand is D-mannopyranose. In certain embodiments, the mannose ligand is α-D-mannopyranose. In certain embodiments, the mannose ligand is β-D- mannopyranose. In certain embodiments, the mannose ligand is L-mannopyranose. In certain embodiments, the mannose ligand is α-L-mannopyranose. In certain embodiments, the mannoseA1278.70032WO00 2 12280650.2ligand is β-L-mannopyranose. In certain embodiments, the mannose ligand is mannofuranose. In certain embodiments, the mannose ligand is chemically modified mannose. In certain embodiments, the mannose ligand is any of those delineated herein or a prodrug thereof.

[0007] In certain embodiments, contacting a cell expressing mannose receptor, such as a brain cell, with a compound provided herein, delivers the agent to the cell. In certain embodiments, the cell is a microglial cell. In certain embodiments, the microglial cell is in the brain or the spinal cord. In certain embodiments, contacting a cell expressing mannose receptor, such as a brain cell, with a compound provided herein, treats a disease or symptom thereof in a subject in need thereof. In certain embodiments, a compound comprising a mannose ligand selectively or preferentially targets a cell expressing mannose receptor compared to a cell not expressing mannose receptor. In certain embodiments, a compound comprising a mannose ligand selectively or preferentially targets a cell expressing mannose receptor compared to a compound not comprising a mannose receptor ligand.

[0008] Certain embodiments provided herein are directed to compounds and methods for modulating expression of a nucleic acid target in cells expressing mannose receptor. In certain embodiments, the cell is a microglial cell. In certain embodiments, the microglial cell is in the brain. In certain embodiments, the microglial cell is in the frontal cortex. In certain embodiments, the microglial cell is in the striatum. In certain embodiments, the microglial cell is in the cerebellum. In certain embodiments, the microglial cell is in the brain stem. In certain embodiments, the microglial cell is in the hippocampus. In certain embodiments, the microglial cell is in the spinal cord. In certain embodiments, contacting a cell expressing mannose receptor, such as a brain cell, with a compound provided herein, modulates the expression or activity of a nucleic acid target in the cell. In certain embodiments, a compound comprises one or more mannose ligands, one or more linker moieties, and an oligonucleotide.

[0009] 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.

[0010] In one aspect, the present disclosure provides compounds of Formula (I):Formula (I) and stereoisomers, tautomers, prodrugs, and salts thereof, wherein: A is a mannose receptor ligand; B is a Tropomyosin receptor B (TrkB) ligand; each of L1, L2, L3, L4, L5, L6, L7and L8is independently a linker, a bond, or absent;A1278.70032WO00 3 12280650.2R is an oligonucleotide, a small molecule, a protein, an antibody or a peptide; m is 1, 2, or 3; and n is 0, 1, 2 or 3. For further clarity, in certain embodiments, of L1, L2, L3, L4, for example: if only L1is absent, then A is covalently bonded to L2; if only L2is absent, then L1is covalently bonded to L3; if only L3is absent, then L2is covalently bonded to L4; if only L4is absent, then L3is covalently bonded to R; and if L1, L2, L3, and L4are all absent, then A is covalently bonded to R.

[0011] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (I):Formula (I) or a stereoisomer, tautomer, prodrug or salt thereof, wherein: A is a mannose receptor ligand; B is a Tropomyosin receptor B (TrkB) ligand; each of L1, L2, L3, L4, L5, L6, L7and L8is independently a linker, a bond, or absent, wherein at least one of L1, L2, L3, and L4is a linker or a bond; R is an oligonucleotide, a protecting group, a small molecule, a protein, an antibody or a peptide; m is 1, 2, or 3; and n is 0, 1, 2 or 3.

[0012] In certain embodiments, a compound of the present disclosure, a compound provided herein, a compound disclosed herein, or a compound described herein is a compound of Formula (I), or a stereoisomer, tautomer, prodrug, or salt thereof. In certain embodiments, a compound provided herein, a compound disclosed herein, or a compound described herein is a compound of Formula (I), or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof. In certain embodiments, a compound provided herein, a compound disclosed herein, or a compound described herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the salt is a potassium salt or a sodium salt.

[0013] In another aspect, there is provided a pharmaceutical composition, comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0014] In another aspect, there is provided a kit comprising: a compound or pharmaceutical composition provided herein; and instructions for using the compound or pharmaceutical composition provided herein.A1278.70032WO00 4 12280650.2

[0015] In an aspect, there is provided a method for delivering an oligonucleotide, small molecule, protein, antibody, or peptide to a biological sample, cell, or tissue, comprising contacting the biological sample, cell, or tissue with or administering to a subject a compound or pharmaceutical composition provided herein, wherein R is an oligonucleotide, a small molecule, a protein, an antibody or a peptide.

[0016] In an aspect, there is provided a method for delivering an oligonucleotide, small molecule, protein, antibody, or peptide to a biological sample, cell, or tissue, comprising contacting the biological sample, cell, or tissue with a compound or pharmaceutical composition provided herein, wherein R is an oligonucleotide, a small molecule, a protein, an antibody or a peptide; and the biological sample, cell, or tissue is in vitro.

[0017] In an aspect, there is provided use of a compound or pharmaceutical composition provided herein for the manufacture of a medicament for delivering an oligonucleotide, small molecule, protein, antibody, or peptide to a cell or tissue of a subject, wherein R is an oligonucleotide, a small molecule, a protein, an antibody or a peptide.

[0018] In an aspect, there is provided a compound or pharmaceutical composition provided herein for use in delivering an oligonucleotide, small molecule, protein, antibody, or peptide to a cell or tissue of a subject, wherein R is an oligonucleotide, a small molecule, a protein, an antibody or a peptide.

[0019] In an aspect, there is provided a method for treating a disease or symptom thereof in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein, wherein R is an oligonucleotide, a small molecule, a protein, an antibody or a peptide.

[0020] In an aspect, there is provided use of a compound or pharmaceutical composition provided herein for the manufacture of a medicament for treating a disease or symptom thereof in a subject in need thereof, wherein R is an oligonucleotide, a small molecule, a protein, an antibody or a peptide.

[0021] In an aspect, there is provided a compound or pharmaceutical composition provided herein for use in treating a disease or symptom thereof in a subject in need thereof, wherein R is an oligonucleotide, a small molecule, a protein, an antibody or a peptide. DETAILED DESCRIPTION Definitions

[0022] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the embodiments, as claimed. Herein, the use of the singular includes the plural unless specificallyA1278.70032WO00 5 12280650.2stated otherwise. As used herein, the use of “or” means “and / or” unless stated otherwise. Furthermore, the use of the term “including” as well as other forms, such as “includes” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0023] Unless otherwise indicated, the following terms have the following meanings:

[0024] As used herein, the term “treating” a disorder encompasses ameliorating, mitigating and / or managing the disorder and / or conditions that may cause the disorder. The terms “treating” and “treatment” refer to a method of alleviating or abating a disease and / or its attendant symptoms. In accordance with the present disclosure, “treating” includes blocking, inhibiting, attenuating, protecting against, modulating, reversing the effects of, and reducing the occurrence of, e.g., the harmful effects of a disorder. As used herein, “inhibiting” encompasses preventing, reducing, and halting progression.

[0025] The terms “isolated,” “purified,” or “biologically pure” refer to material that is substantially or essentially free from components that normally accompany it as found in its native state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high-performance liquid chromatography (HPLC). Particularly, in certain embodiments, the compound is at least 85% pure, at least 90% pure, at least 95% pure, or at least 99% pure.

[0026] The term “administration” or “administering” includes routes of introducing the compound(s) to a subject to perform their intended function. Examples of routes of administration which can be used include injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), topical, oral, inhalation, rectal, and transdermal.

[0027] The term “effective amount” includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result. An effective amount of compound may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. An effective amount is also one in which any non- tolerable or detrimental effects (e.g., side effects) of the compound are outweighed by the therapeutically beneficial effects.

[0028] The phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound(s), oligonucleotide(s), drug, or other material, such that it enters the subject’s circulatory system and, thus, is subject to metabolism and other like processes.A1278.70032WO00 6 12280650.2

[0029] The term “therapeutically effective amount” refers to the amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.

[0030] A therapeutically effective amount of compound (i.e., an effective dosage) may range from about 0.005 µg / kg to about 200 mg / kg, from about 0.01 mg / kg to about 200 mg / kg, or from about 0.015 mg / kg to about 30 mg / kg of body weight. In other embodiments, the therapeutically effect amount may range from about 1.0 pM to about 10 µM. The skilled artisan will appreciate that certain factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a compound can include a single treatment or can include a series of treatments. In one example, a subject is treated with a compound in the range of between about 0.005 µg / kg to about 200 mg / kg of body weight, daily, weekly, monthly, quarterly, or yearly. In another example, a subject may be treated daily, weekly, monthly, quarterly, or yearly for several years in the setting of a chronic condition or illness. It will also be appreciated that the effective dosage of a compound used for treatment may increase or decrease over the course of a particular treatment.

[0031] The term “chiral” refers to molecules that have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules that are superimposable on their mirror image partner.

[0032] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)-for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and / or isolate. The present disclosure is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0033] 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.A1278.70032WO00 7 12280650.2

[0034] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.

[0035] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure (i.e., the R and S configurations for each asymmetric center). Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0036] As used herein, “chirally enriched population” means a plurality of molecules of identical molecular formula, wherein the number or percentage of molecules within the population that contain a particular stereochemical configuration at a particular chiral center is greater than the number or percentage of molecules expected to contain the same particular stereochemical configuration at the same particular chiral center within the population if the particular chiral center were stereorandom. Chirally enriched populations of molecules having multiple chiral centers within each molecule may contain one or more stereorandom chiral centers. In certain embodiments, the molecules are modified oligonucleotides. In certain embodiments, the molecules are compounds comprising modified oligonucleotides.

[0037] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0038] As used herein, “stereorandom chiral center” in the context of a population of molecules of identical molecular formula means a chiral center having a random stereochemical configuration. For example, in a population of molecules comprising a stereorandom chiral center, the number of molecules having the (S) configuration of the stereorandom chiral center may be but is not necessarily the same as the number of molecules having the (R) configuration of the stereorandom chiral center. The stereochemical configuration of a chiral center is considered random when it is the results of a synthetic method that is not designed to control the stereochemical configuration. In certain embodiments, a stereorandom chiral center is a stereorandom phosphorothioate internucleoside linkage.

[0039] The term “diastereomers” refers to stereoisomers with two or more centers of dissymmetry and whose molecules are not mirror images of one another.

[0040] The term “enantiomers” refers to two stereoisomers of a compound that are non- superimposable mirror images of one another. An equimolar mixture of two enantiomers is called a “racemic mixture” or a “racemate.”A1278.70032WO00 8 12280650.2

[0041] The term “isomers” or “stereoisomers” refers to compounds that have identical chemical constitution but differ with regard to the arrangement of the atoms or groups in space.

[0042] The term “prodrug” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active form of the compound (e.g., biologically active form of a nucleic acid) or analogue thereof as described herein. Thus, the term “prodrug” refers to a precursor of a biologically active compound (e.g., nucleic acid) or analogue thereof that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (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, both of which are incorporated in full by reference herein. The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of suitable prodrugs include, but are not limited to glutathione, acyloxy, thioacyloxy, 2-carboalkoxyethyl, disulfide, thiaminal, and enol ester derivatives of a phosphorus atom-modified nucleic acid. The term “pro-oligonucleotide” or “pronucleotide” or “nucleic acid prodrug” refers to an oligonucleotide which has been modified to be a prodrug of the oligonucleotide. Phosphonate and phosphate prodrugs can be found, for example, in Wiener et al., “Prodrugs or phosphonates and phosphates: crossing the membrane” Top. Curr. Chem.2015, 360:115–160, the entirety of which is herein incorporated by reference. Prodrugs that are converted to active forms through other mechanisms in vivo are also included. In aspects, the compounds of the present disclosure are prodrugs of any of the formulae herein.

[0043] The term “subject” refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like. In certain embodiments, the subject is a human. In certain embodiments, the subject is a human younger than 2 years. In some embodiments, the subject is a human not younger than 2 years but younger than 18 years. In certain embodiments, the subject is a human aged 18 years and older.A1278.70032WO00 9 12280650.2

[0044] The terms “a,” “an,” and “the” refer to “one or more” when used in this application, including the claims. Thus, for example, reference to “a sample” includes a plurality of samples, unless the context clearly is to the contrary (e.g., a plurality of samples), and so forth.

[0045] Throughout this specification and the claims, the words “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense, except where the context requires otherwise.

[0046] As used herein, the term “about,” when referring to a value, is meant to encompass variations of, in some embodiments ± 20%, in some embodiments ± 10%, in some embodiments ± 5%, in some embodiments ± 1%, in some embodiments ± 0.5%, and in some embodiments ± 0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions.

[0047] As used herein, the term “aliphatic,” by itself or as part of another substituent, means, unless otherwise stated, a straight-chained (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated (e.g., alkane or alkyl), mono-, (e.g., alkene or alkenyl) or polyunsaturated (e.g., alkyne or alkynyl) and can include mono-, di- and multivalent radicals. In certain embodiments, aliphatic has the number of carbon atoms designated. For example, C1-C24 means 1 to 24 carbon atoms. A specified number of carbon atoms within this range includes, for example, C1-C20alkyl (having 1-20 carbon atoms), C1-C12alkyl (having 1-12 carbon atoms), C1-C6 alkyl (having 1-6 carbon atoms), and C1-C4 alkyl (having 1-4 carbon atoms). A range expressed in the format of C1-C6 is the same as a range expressed in the format of C1-6.

[0048] The term “alkyl” refers to a fully saturated hydrocarbon chain that may be a straight chain or branched chain, containing 1 to 100 carbon atoms unless the number of carbon atoms is otherwise designated. Alkyl groups may be optionally substituted with one or more substituents.

[0049] The term “alkenyl” refers to an unsaturated hydrocarbon chain that may be a straight chain or branched chain, containing 2 to 100 carbon atoms unless the number of carbon atoms is otherwise designated and at least one carbon-carbon double bond. Alkenyl groups may be optionally substituted with one or more substituents.

[0050] The term “alkynyl” refers to an unsaturated hydrocarbon chain that may be a straight chain or branched chain, containing 2 to 100 carbon atoms unless the number of carbon atoms is otherwise designated and at least one carbon-carbon triple bond. Alkynyl groups may be optionally substituted with one or more substituents.

[0051] The term “lower alkyl” refers to a C1-C6 alkyl chain. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-pentyl.

[0052] The term “heteroalkyl” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at leastA1278.70032WO00 10 12280650.2one carbon atom and at least one heteroatom (e.g., O, N, P, Si, B, and / or S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., O, N, P, Si, B, and / or S) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: —CH2—CH2—O—CH3, —CH2—CH2—NH—CH3, —CH2—CH2—N(CH3)—CH3, —CH2—S—CH2—CH3, —CH2—CH2, —S(O)—CH3, —CH2—CH2—S(O)2—CH3, — CH═CH—O—CH3, —Si(CH3)3, —CH2—CH═N—OCH3, —CH═CH—N(CH3)—CH3, —O— CH3, —O—CH2—CH3, and —CN. Up to two or three heteroatoms may be consecutive, such as, for example, —CH2—NH—OCH3and —CH2—O—Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, B, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, B, and / or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, B, and / or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, B, and / or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, B, and / or P). A heteroalkyl moiety may include up to 8 or more optionally different heteroatoms (e.g., O, N, S, Si, B, and / or P). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 100 carbon atoms and 1 or more heteroatoms (“heteroC1-100alkyl” or “C1-100 heteroalkyl”). As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as —C(O)R′, — C(O)NR′, —NR′R″, —OR′, —SR′, and / or —SO2R′. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as —NR′R″ or the like, it will be understood that the terms heteroalkyl and —NR′R″ are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as —NR′R″ or the like.

[0053] The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a polyvalent (e.g., divalent) radical derived from an alkyl, as exemplified, but not limited by, —CH2CH2CH2CH2—.

[0054] The term “alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a polyvalent (e.g., divalent) radical derived from an alkene.

[0055] The term “alkynylene,” by itself or as part of another substituent, means, unless otherwise stated, a polyvalent (e.g., divalent) radical derived from an alkyne.

[0056] Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a polyvalent (e.g., divalent) radical derived from heteroalkyl, asA1278.70032WO00 11 12280650.2exemplified, but not limited by, —CH2—CH2—S—CH2—CH2— and —CH2—S—CH2—CH2— NH—CH2—.

[0057] The term “heteroalkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a polyvalent (e.g., divalent) radical derived from heteroalkenyl.

[0058] The term “heteroalkynylene,” by itself or as part of another substituent, means, unless otherwise stated, a polyvalent (e.g., divalent) radical derived from heteroalkynyl. For heteroalkylene, heteroalkenylene, and heteroalkynylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for a formula comprising alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene, no orientation is implied by the direction in which the formula is written unless otherwise specified. For example, the formula —C(=O)OR′— represents both —C(=O)OR′— and —R′OC(=O)—.

[0059] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 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 (“C4-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H- indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3-8carbocyclyl groups include the aforementioned C3-10 carbocyclyl groups as well as cycloundecylA1278.70032WO00 12 12280650.2(C11), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0060] 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 (“C3-8cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10cycloalkyl”). Examples of C5-6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 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 C3-6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0061] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can eitherA1278.70032WO00 13 12280650.2be 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.

[0062] 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.

[0063] 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-A1278.70032WO00 14 12280650.2membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2- b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3- dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H- pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2- b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0064] The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. “Cycloalkyl” is also meant to refer to bicyclic and polycyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.

[0065] The term “haloalkyl” refers to an alkyl group that is substituted by one or more halo substituents. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, chloromethyl, and 2,2,2-trifluoroethyl.A1278.70032WO00 15 12280650.2

[0066] The sp2- or sp-hybridized carbons of an alkenyl group and an alkynyl group, respectively, may optionally be the point of attachment of the alkenyl or alkynyl groups.

[0067] The term “alkoxy” refers to an -O-alkyl substituent.

[0068] As used herein, the terms “halogen,” “hal,” or “halo” means -F, -Cl, -Br or -I.

[0069] The term “alkylthio” refers to an -S-alkyl substituent.

[0070] The term “alkoxyalkyl” refers to an -alkyl-O-alkyl substituent.

[0071] The term “haloalkoxy” refers to an -O-alkyl that is substituted by one or more halo substituents. Examples of haloalkoxy groups include trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0072] The term “haloalkoxyalkyl” refers to an –alkyl-O-alkyl′ where the alkyl′ is substituted by one or more halo substituents.

[0073] The term “haloalkylaminocarbonyl” refers to a –C(O)-amino-alkyl where the alkyl is substituted by one or more halo substituents.

[0074] The term “haloalkylthio” refers to an -S-alkyl that is substituted by one or more halo substituents. Examples of haloalkylthio groups include trifluoromethylthio, and 2,2,2- trifluoroethylthio.

[0075] The term “haloalkylcarbonyl” refers to an –C(O)-alkyl that is substituted by one or more halo substituents. An example of a haloalkylcarbonyl group includes trifluoroacetyl.

[0076] The term “cycloalkoxyalkyl” refers to an -alkyl-O-cycloalkyl substituent.

[0077] The term “cycloalkylalkoxy” refers to an -O-alkyl-cycloalkyl substituent.

[0078] The term “cycloalkylaminocarbonyl” refers to an –C(O)-NH-cycloalkyl substituent.

[0079] The term “aryl” refers to a hydrocarbon monocyclic, bicyclic, or tricyclic aromatic ring system. Aryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5 or 6 atoms of each ring of an aryl group may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. “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.

[0080] The term “aryloxy” refers to an -O-aryl substituent.

[0081] The term “arylalkoxy” refers to an -O-alkyl-aryl substituent.

[0082] The term “arylalkylthio” refers to an -S-alkyl-aryl substituent.

[0083] The term “arylthioalkyl” refers to an –alkyl-S -aryl substituent.

[0084] The term “arylalkylaminocarbonyl” refers to a –C(O)-amino-alkyl-aryl substituent.

[0085] The term “arylalkylsulfonyl” refers to an –S(O)2-alkyl-aryl substituent.

[0086] The term “arylalkylsulfinyl” refers to an –S(O)-alkyl-aryl substituent.A1278.70032WO00 16 12280650.2

[0087] The term “aryloxyalkyl” refers to an –alkyl-O-aryl substituent.

[0088] The term “alkylaryl” refers to an –aryl-alkyl substituent.

[0089] The term “arylalkyl” refers to an –alkyl-aryl substituent.

[0090] The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-4 ring heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, and the remainder ring atoms being carbon (with appropriate hydrogen atoms unless otherwise indicated). 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). Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted by a substituent. Heteroaryl groups may be fully unsaturated, or they may be partially unsaturated and partially saturated. 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,A1278.70032WO00 17 12280650.2benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0091] The term “heteroarylalkyl” refers to an –alkyl-heteroaryl substituent.

[0092] The term “heteroaryloxy” refers to an -O-heteroaryl substituent.

[0093] The term “heteroarylalkoxy” refers to an -O-alkyl-heteroaryl substituent.

[0094] The term “heteroaryloxyalkyl” refers to an –alkyl-O-heteroaryl substituent.

[0095] The term “nitrogen-containing heteroaryl” refers to a heteroaryl group having 1-4 ring nitrogen heteroatoms if monocyclic, 1-6 ring nitrogen heteroatoms if bicyclic, or 1-9 ring nitrogen heteroatoms if tricyclic.

[0096] The term “heterocycloalkylalkyl” refers to an –alkyl-heterocycloalkyl substituent.

[0097] The term “alkylamino” refers to an amino substituent which is further substituted with one or two alkyl groups. The term “aminoalkyl” refers to an alkyl substituent which is further substituted with one or more amino groups. The term “hydroxyalkyl” or “hydroxylalkyl” refers to an alkyl substituent which is further substituted with one or more hydroxyl groups. The alkyl or aryl portion of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionally substituted with one or more substituents.

[0098] The symbol” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

[0099] The term “nucleobase” refers to nitrogen-containing biological compounds that form nucleosides. They 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. When a nucleobase is listed in a formula definition, it refers to that moiety covalently bonded to the recited formula.

[0100] The term “modified nucleobase” refers to derivatives of a nucleobase. Examples of modified nucleobases include, but are not limited to, xanthine, hypoxanthine,7-methylguanine, 5,6-dihydrouracil, 5-methylcytosine, 5-hydroxymethylcytosine, purine, 2,6-diaminopurine, and 6,8-diaminopurine. When a modified nucleobase is listed in a formula definition, it refers to that moiety covalently bonded to the recited formula.

[0101] The term “substituent” and “substituent group” means an atom or group that replaces the atom or group of a named parent compound. For example, a substituent of a modified nucleoside is an atom or group that differs from the atom or group found in a naturally occurring nucleosideA1278.70032WO00 18 12280650.2(e.g., a modified 2′-substituent is any atom or group at the 2′-position of a nucleoside other than H or OH). Substituent groups can be protected or unprotected. Substituents may also be further substituted with other substituent groups and may be attached directly or via a linking group such as an alkyl or hydrocarbyl group to the parent compound. Similarly, as used herein, “substituent” in reference to a chemical functional group means an atom or group of atoms that differs from the atom or group of atoms normally present in the named functional group. In certain embodiments, substituents on any group (such as, for example, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroalkyl, cycloalkyl, heterocycloalkyl) can be at any atom of that group, wherein any group that can be substituted (such as, for example, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroalkyl, cycloalkyl, heterocycloalkyl) can be optionally substituted with one or more substituents (which may be the same or different), each replacing a hydrogen atom. Examples of suitable substituents include, but are not limited to alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl, or arylamino- substituted aryl; arylalkylamino, aralkylaminocarbonyl, amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, carboxamido, carbamido, carbamyl, thioureido, thiocyanato, sulfoamido, sulfonylalkyl, sulfonylaryl, mercaptoalkoxy, N-hydroxyamidinyl, or N′-aryl, N′′-hydroxyamidinyl. In certain embodiments, substituents on any group include alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, thiocarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl, or arylamino-substituted aryl; arylalkylamino, aralkylaminocarbonyl, or amido. In certain embodiments, substituents on any group include alkyl, halogen, haloalkyl, cyano, nitro, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, formyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, thio, mercapto, mercaptoalkyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, or alkylamino.

[0102] 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,A1278.70032WO00 19 12280650.2−OP(=O)(N(Rbb)2)2, −NRbbP(=O)(Raa)2, −NRbbP(=O)(ORcc)2, −NRbbP(=O)(N(Rbb)2)2, −P(Rcc)2, −P(ORcc)2, −P(Rcc)3+X−, −P(ORcc)3+X−, −P(Rcc)4, −P(ORcc)4, −OP(Rcc)2, −OP(Rcc)3+X−, −OP(ORcc)2, −OP(ORcc)3+X−, −OP(Rcc)4, −OP(ORcc)4, −B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1–20alkyl, C1–20perhaloalkyl, C1–20alkenyl, C1–20alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X−is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; each instance of Raais, independently, selected from C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20 alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from hydrogen, C1–20alkyl, C1–20perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20 alkyl, heteroC1–20 alkenyl, heteroC1–20A1278.70032WO00 20 12280650.2alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORee, −ON(Rff)2, −N(Rff)2, −N(Rff)3+X−, −N(ORee)Rff, −SH, −SRee, −SSRee,−NRffC(=O)Ree, −NRffCO2Ree, −NRffC(=O)N(Rff)2, −C(=NRff)ORee, −OC(=NRff)Ree, −OC(=NRff)ORee, −C(=NRff)N(Rff)2, −OC(=NRff)N(Rff)2, −NRffC(=NRff)N(Rff)2, −NRffSO2Ree, −SO2N(Rff)2, −SO2Ree, −SO2ORee, −OSO2Ree, −S(=O)Ree, −Si(Ree)3, −OSi(Ree)3, −C(=S)N(Rff)2, −C(=O)SRee, −C(=S)SRee, −SC(=S)SRee, −P(=O)(ORee)2, −P(=O)(Ree)2, −OP(=O)(Ree)2, −OP(=O)(ORee)2, C1–10 alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents are joined to form =O or =S; wherein X−is a counterion; each instance of Reeis, independently, selected from C1–10 alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1–10alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1–10alkyl, C1–10perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10 alkyl, heteroC1–10 alkenyl, heteroC1–10 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rggis, independently, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OC1–6 alkyl, −ON(C1–6 alkyl)2, −N(C1–6 alkyl)2, −N(C1–6 alkyl)3+X−, −NH(C1–6 alkyl)2+X−, −NH2(C1–6 alkyl)+X−, −NH3+X−, −N(OC1–6 alkyl)(C1–6 alkyl), −N(OH)(C1–6 alkyl), −NH(OH), −SH, −SC1–6alkyl, −SS(C1–6alkyl), −C(=O)(C1–6alkyl), −CO2H, −CO2(C1–6alkyl), −OC(=O)(C1–6 alkyl), −OCO2(C1–6 alkyl), −C(=O)NH2, −C(=O)N(C1–6 alkyl)2, −OC(=O)NH(C1–A1278.70032WO00 21 12280650.26alkyl), −NHC(=O)( C1–6alkyl), −N(C1–6alkyl)C(=O)( C1–6alkyl), −NHCO2(C1–6alkyl), −NHC(=O)N(C1–6 alkyl)2, −NHC(=O)NH(C1–6 alkyl), −NHC(=O)NH2, −C(=NH)O(C1–6 alkyl), −OC(=NH)(C1–6 alkyl), −OC(=NH)OC1–6 alkyl, −C(=NH)N(C1–6 alkyl)2, −C(=NH)NH(C1–6 alkyl), −C(=NH)NH2, −OC(=NH)N(C1–6alkyl)2, −OC(NH)NH(C1–6alkyl), −OC(NH)NH2, −NHC(NH)N(C1–6 alkyl)2, −NHC(=NH)NH2, −NHSO2(C1–6 alkyl), −SO2N(C1–6 alkyl)2, −SO2NH(C1–6 alkyl), −SO2NH2, −SO2C1–6 alkyl, −SO2OC1–6 alkyl, −OSO2C1–6 alkyl, −SOC1–6 alkyl, −Si(C1–6alkyl)3, −OSi(C1–6alkyl)3−C(=S)N(C1–6alkyl)2, C(=S)NH(C1–6alkyl), C(=S)NH2, −C(=O)S(C1–6 alkyl), −C(=S)SC1–6 alkyl, −SC(=S)SC1–6 alkyl, −P(=O)(OC1–6 alkyl)2, −P(=O)(C1–6 alkyl)2, −OP(=O)(C1–6 alkyl)2, −OP(=O)(OC1–6 alkyl)2, C1–10 alkyl, C1–10 perhaloalkyl, C1–10alkenyl, C1–10alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; and each X−is a counterion. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −ORaa, −SRaa,−OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN,−NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, or –NO2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C1–10 alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, or –NO2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, orA1278.70032WO00 22 12280650.2benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0103] The term “protecting group” or “protecting moiety” refers to a substituent that is commonly employed to block or protect a particular functionality while reacting other functional groups on the compound, a derivative thereof, or a conjugate thereof, and includes a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom. Nitrogen and oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0104] In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups include, but are not limited to, –OH, –ORaa, –N(Rcc)2, –C(=O)Raa, –C(=O)N(Rcc)2, –CO2Raa, – SO2Raa, –C(=NRcc)Raa, –C(=NRcc)ORaa, –C(=NRcc)N(Rcc)2, –SO2N(Rcc)2, –SO2Rcc, –SO2ORcc, – SORaa, –C(=S)N(Rcc)2, –C(=O)SRcc, –C(=S)SRcc, C1–10alkyl (e.g., aralkyl, heteroaralkyl), C2–10alkenyl, C2–10 alkynyl, C3–10 carbocyclyl, 3–14 membered heterocyclyl, C6–14 aryl, and 5–14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein each Raa, Rbb, and Rccis independently alkyl, cycloalkyl, aryl, or heteroaryl, each of which may be optionally substituted with 1-3 independent Rdd, and each Rddis independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl, or arylamino- substituted aryl; arylalkylamino, aralkylaminocarbonyl, amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, carbamido, carbamyl, thioureido, thiocyanato, sulfoamido, sulfonylalkyl, sulfonylaryl, or mercaptoalkoxy. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.A1278.70032WO00 23 12280650.2

[0105] Amide nitrogen protecting groups (e.g., –C(=O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3–phenylpropanamide, picolinamide, 3–pyridylcarboxamide, N– benzoylphenylalanyl derivative, benzamide, p–phenylbenzamide, o–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, o– nitrobenzamide, and o–(benzoyloxymethyl)benzamide.

[0106] Carbamate nitrogen protecting groups (e.g., –C(=O)ORaa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9–fluorenylmethyl carbamate (Fmoc), 9–(2– sulfo)fluorenylmethyl carbamate, 9–(2,7–dibromo)fluorenylmethyl carbamate, 2,7–di–t–butyl– [9–(10,10–dioxo–10,10,10,10–tetrahydrothioxanthyl)]methyl carbamate (DBD–Tmoc), 4– methoxyphenacyl carbamate (Phenoc), 2,2,2–trichloroethyl carbamate (Troc), 2– trimethylsilylethyl carbamate (Teoc), 2–phenylethyl carbamate (hZ), 1–(1–adamantyl)–1– methylethyl carbamate (Adpoc), 1,1–dimethyl–2–haloethyl carbamate, 1,1–dimethyl–2,2– dibromoethyl carbamate (DB–t–BOC), 1,1–dimethyl–2,2,2–trichloroethyl carbamate (TCBOC), 1–methyl–1–(4–biphenylyl)ethyl carbamate (Bpoc), 1–(3,5–di–t–butylphenyl)–1–methylethyl carbamate (t–Bumeoc), 2–(2′– and 4′–pyridyl)ethyl carbamate (Pyoc), 2–(N,N– dicyclohexylcarboxamido)ethyl carbamate, t–butyl carbamate (BOC), 1–adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1–isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4–nitrocinnamyl carbamate (Noc), 8–quinolyl carbamate, N– hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p–methoxybenzyl carbamate (Moz), p–nitrobenzyl carbamate, p–bromobenzyl carbamate, p–chlorobenzyl carbamate, 2,4–dichlorobenzyl carbamate, 4–methylsulfinylbenzyl carbamate (Msz), 9– anthrylmethyl carbamate, diphenylmethyl carbamate, 2–methylthioethyl carbamate, 2– methylsulfonylethyl carbamate, 2–(p–toluenesulfonyl)ethyl carbamate, [2–(1,3–dithianyl)]methyl carbamate (Dmoc), 4–methylthiophenyl carbamate (Mtpc), 2,4–dimethylthiophenyl carbamate (Bmpc), 2–phosphonioethyl carbamate (Peoc), 2–triphenylphosphonioisopropyl carbamate (Ppoc), 1,1–dimethyl–2–cyanoethyl carbamate, m–chloro–p–acyloxybenzyl carbamate, p– (dihydroxyboryl)benzyl carbamate, 5–benzisoxazolylmethyl carbamate, 2–(trifluoromethyl)–6– chromonylmethyl carbamate (Tcroc), m–nitrophenyl carbamate, 3,5–dimethoxybenzyl carbamate, o–nitrobenzyl carbamate, 3,4–dimethoxy–6–nitrobenzyl carbamate, phenyl(o– nitrophenyl)methyl carbamate, t–amyl carbamate, S–benzyl thiocarbamate, p–cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate,A1278.70032WO00 24 12280650.2cyclopropylmethyl carbamate, p–decyloxybenzyl carbamate, 2,2–dimethoxyacylvinyl carbamate, o–(N,N–dimethylcarboxamido)benzyl carbamate, 1,1–dimethyl–3–(N,N– dimethylcarboxamido)propyl carbamate, 1,1–dimethylpropynyl carbamate, di(2–pyridyl)methyl carbamate, 2–furanylmethyl carbamate, 2–iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p–(p′–methoxyphenylazo)benzyl carbamate, 1– methylcyclobutyl carbamate, 1–methylcyclohexyl carbamate, 1–methyl–1–cyclopropylmethyl carbamate, 1–methyl–1–(3,5–dimethoxyphenyl)ethyl carbamate, 1–methyl–1–(p– phenylazophenyl)ethyl carbamate, 1–methyl–1–phenylethyl carbamate, 1–methyl–1–(4– pyridyl)ethyl carbamate, phenyl carbamate, p–(phenylazo)benzyl carbamate, 2,4,6–tri–t– butylphenyl carbamate, 4–(trimethylammonium)benzyl carbamate, and 2,4,6–trimethylbenzyl carbamate.

[0107] Sulfonamide nitrogen protecting groups (e.g., –S(=O)2Raa) include, but are not limited to, p–toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,–trimethyl–4– methoxybenzenesulfonamide (Mtr), 2,4,6–trimethoxybenzenesulfonamide (Mtb), 2,6–dimethyl– 4–methoxybenzenesulfonamide (Pme), 2,3,5,6–tetramethyl–4–methoxybenzenesulfonamide (Mte), 4–methoxybenzenesulfonamide (Mbs), 2,4,6–trimethylbenzenesulfonamide (Mts), 2,6– dimethoxy–4–methylbenzenesulfonamide (iMds), 2,2,5,7,8–pentamethylchroman–6– sulfonamide (Pmc), methanesulfonamide (Ms), β–trimethylsilylethanesulfonamide (SES), 9– anthracenesulfonamide, 4–(4′,8′–dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0108] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl–(10)–acyl derivative, N′–p–toluenesulfonylaminoacyl derivative, N′–phenylaminothioacyl derivative, N– benzoylphenylalanyl derivative, N–acetylmethionine derivative, 4,5–diphenyl–3–oxazolin–2– one, N–phthalimide, N–dithiasuccinimide (Dts), N–2,3–diphenylmaleimide, N–2,5– dimethylpyrrole, N–1,1,4,4–tetramethyldisilylazacyclopentane adduct (STABASE), 5– substituted 1,3–dimethyl–1,3,5–triazacyclohexan–2–one, 5–substituted 1,3–dibenzyl–1,3,5– triazacyclohexan–2–one, 1–substituted 3,5–dinitro–4–pyridone, N–methylamine, N–allylamine, N–[2–(trimethylsilyl)ethoxy]methylamine (SEM), N–3–acetoxypropylamine, N–(1–isopropyl–4– nitro–2–oxo–3–pyrrolin–3–yl)amine, quaternary ammonium salts, N–benzylamine, N–di(4– methoxyphenyl)methylamine, N–5–dibenzosuberylamine, N–triphenylmethylamine (Tr), N–[(4– methoxyphenyl)diphenylmethyl]amine (MMTr), N–9–phenylfluorenylamine (PhF), N–2,7– dichloro–9–fluorenylmethyleneamine, N–ferrocenylmethylamino (Fcm), N–2–picolylamino N′– oxide, N–1,1–dimethylthiomethyleneamine, N–benzylideneamine, N–p– methoxybenzylideneamine, N–diphenylmethyleneamine, N–[(2– pyridyl)mesityl]methyleneamine, N–(N′,N′–dimethylaminomethylene)amine, N,N′–A1278.70032WO00 25 12280650.2isopropylidenediamine, N–p–nitrobenzylideneamine, N–salicylideneamine, N–5– chlorosalicylideneamine, N–(5–chloro–2–hydroxyphenyl)phenylmethyleneamine, N– cyclohexylideneamine, N–(5,5–dimethyl–3–oxo–1–cyclohexenyl)amine, N–borane derivative, N–diphenylborinic acid derivative, N–[phenyl(pentaacylchromium– or tungsten)acyl]amine, N– copper chelate, N–zinc chelate, N–nitroamine, N–nitrosoamine, amine N–oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o–nitrobenzenesulfenamide (Nps), 2,4–dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2–nitro–4–methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3–nitropyridinesulfenamide (Npys).

[0109] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups include, but are not limited to, –Raa, –N(Rbb)2, –C(=O)SRaa, –C(=O)Raa, –CO2Raa,–P(=O)(NRbb)2, wherein Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0110] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t–butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p– methoxybenzyloxymethyl (PMBM), (4–methoxyphenoxy)methyl (p–AOM), guaiacolmethyl (GUM), t–butoxymethyl, 4–pentenyloxymethyl (POM), siloxymethyl, 2–methoxyethoxymethyl (MEM), 2,2,2–trichloroethoxymethyl, bis(2–chloroethoxy)methyl, 2– (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3–bromotetrahydropyranyl, tetrahydrothiopyranyl, 1–methoxycyclohexyl, 4–methoxytetrahydropyranyl (MTHP), 4– methoxytetrahydrothiopyranyl, 4–methoxytetrahydrothiopyranyl S,S–dioxide, 1–[(2–chloro–4– methyl)phenyl]–4–methoxypiperidin–4–yl (CTMP), 1,4–dioxan–2–yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a–octahydro–7,8,8–trimethyl–4,7–methanobenzofuran–2– yl, 1–ethoxyethyl, 1–(2–chloroethoxy)ethyl, 1–methyl–1–methoxyethyl, 1–methyl–1– benzyloxyethyl, 1–methyl–1–benzyloxy–2–fluoroethyl, 2,2,2–trichloroethyl, 2– trimethylsilylethyl, 2–(phenylselenyl)ethyl, t–butyl, allyl, p–chlorophenyl, p–methoxyphenyl, 2,4–dinitrophenyl, benzyl (Bn), p–methoxybenzyl, 3,4–dimethoxybenzyl, o–nitrobenzyl, p– nitrobenzyl, p–halobenzyl, 2,6–dichlorobenzyl, p–cyanobenzyl, p–phenylbenzyl, 2–picolyl, 4–A1278.70032WO00 26 12280650.2picolyl, 3–methyl–2–picolyl N–oxido, diphenylmethyl, p,p′–dinitrobenzhydryl, 5– dibenzosuberyl, triphenylmethyl, α–naphthyldiphenylmethyl, p–methoxyphenyldiphenylmethyl, di(p–methoxyphenyl)phenylmethyl, tri(p–methoxyphenyl)methyl, 4–(4′– bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″–tris(4,5–dichlorophthalimidophenyl)methyl, 4,4′,4″–tris(levulinoyloxyphenyl)methyl, 4,4′,4″–tris(benzoyloxyphenyl)methyl, 3–(imidazol–1– yl)bis(4′,4″–dimethoxyphenyl)methyl, 1,1–bis(4–methoxyphenyl)–1′–pyrenylmethyl, 9–anthryl, 9–(9–phenyl)xanthenyl, 9–(9–phenyl–10–oxo)anthryl, 1,3–benzodisulfuran–2–yl, benzisothiazolyl S,S–dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t– butyldimethylsilyl (TBDMS), t–butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri–p–xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t–butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p–chlorophenoxyacetate, 3– phenylpropionate, 4–oxopentanoate (levulinate), 4,4–(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4–methoxycrotonate, benzoate, p– phenylbenzoate, 2,4,6–trimethylbenzoate (mesitoate), t–butyl carbonate (BOC), alkyl methyl carbonate, 9–fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2–trichloroethyl carbonate (Troc), 2–(trimethylsilyl)ethyl carbonate (TMSEC), 2–(phenylsulfonyl) ethyl carbonate (Psec), 2–(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl p–nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p–methoxybenzyl carbonate, alkyl 3,4–dimethoxybenzyl carbonate, alkyl o–nitrobenzyl carbonate, alkyl p–nitrobenzyl carbonate, alkyl S–benzyl thiocarbonate, 4–ethoxy–1–napththyl carbonate, methyl dithiocarbonate, 2–iodobenzoate, 4–azidobutyrate, 4–nitro–4– methylpentanoate, o–(dibromomethyl)benzoate, 2–formylbenzenesulfonate, 2– (methylthiomethoxy)ethyl, 4–(methylthiomethoxy)butyrate, 2– (methylthiomethoxymethyl)benzoate, 2,6–dichloro–4–methylphenoxyacetate, 2,6–dichloro–4– (1,1,3,3–tetramethylbutyl)phenoxyacetate, 2,4–bis(1,1–dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)–2–methyl–2–butenoate, o– (methoxyacyl)benzoate, α–naphthoate, nitrate, alkyl N,N,N′,N′–tetramethylphosphorodiamidate, alkyl N–phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4–dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0111] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include, but are notA1278.70032WO00 27 12280650.2wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0112] The term “sense oligonucleotide” 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.

[0113] Unless otherwise stated, –X- is –O- or –S-.

[0114] Unless otherwise stated, –X is –OH or –SH.

[0115] Unless otherwise stated, =X is =O or =S.

[0116] The term “antisense oligonucleotide” or “antisense strand” means an oligonucleotide which includes a region that is complementary, or at least partially complementary, to a target nucleic acid or a sense strand of a nucleic acid. In some embodiments, the antisense strand does not carry a translatable code in the 5′ to 3′ direction. In some embodiments, the antisense strand and the sense strand or target nucleic acid are at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% complementary to one another. In certain embodiments, the antisense strand and the sense strand or target nucleic acid are completely complementary (100% complementary) to one another.

[0117] The term “composition” or “pharmaceutical composition” means a mixture of substances suitable for administering to a subject. For example, a composition may comprise one or more compounds provided herein or a pharmaceutically acceptable salt thereof and a sterile aqueous solution.

[0118] The term “nucleic acid” refers to molecules 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.

[0119] The term “nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage.

[0120] The term “nucleoside” means a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each, independently, unmodified or modified. “Modified nucleoside” means a nucleoside comprising a modified nucleobase and / or a modified sugar moiety. Modified nucleosides include abasic nucleosides, which lack a nucleobase.

[0121] The term “oligomeric compound” or “oligomer” means 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 or peptide bond. With reference to an oligonucleotide,A1278.70032WO00 28 12280650.2“subunit” refers to a nucleotide, nucleoside, nucleobase, or sugar, or a modified nucleotide, nucleoside, nucleobase, or sugar as provided herein. 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.

[0122] The term “oligonucleotide” means a polymer of linked nucleosides (e.g., polynucleotide, nucleic acid, polymer 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. Examples of oligonucleotide compounds include single-stranded and double-stranded compounds, such as, oligonucleotides, antisense oligonucleotides, interfering RNA compounds (RNAi compounds), microRNA (miRNA) targeting oligonucleotides and miRNA mimics, occupancy-based compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds). RNAi compounds include double-stranded compounds (e.g., short-interfering RNA (siRNA) and double-stranded RNA (dsRNA)) and single-stranded compounds (e.g., single-stranded siRNA (ssRNA), single- stranded RNAi (ssRNAi), short hairpin RNA (shRNA), and microRNA mimics) which 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). Oligonucleotides may include single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), plasmid DNA (pDNA), genomic DNA (gDNA), complementary DNA (cDNA), chloroplast DNA (ctDNA or cpDNA), microsatellite DNA, mitochondrial DNA (mtDNA or mDNA), kinetoplast DNA (kDNA), provirus, lysogen, repetitive DNA, satellite DNA, viral DNA, single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), messenger RNA (mRNA), precursor messenger RNA (pre-mRNA), transfer RNA (tRNA), heterogeneous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or lncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, antisense oligonucleotides (e.g., antisense DNA and antisense RNA), interfering RNA compounds (RNAi compounds), circular RNA (circRNA) compounds, microRNA (miRNA) targeting oligonucleotides, miRNA mimics, occupancy-based compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds) and editing compounds (e.g., ADAR recruiting compounds, ADARA1278.70032WO00 29 12280650.2targeting compounds, single-stranded guide nucleic acids, or a combination thereof). RNAi compounds include double-stranded compounds (e.g., short-interfering RNA (siRNA) and double-stranded RNA (dsRNA)) and single-stranded compounds (e.g., single-stranded siRNA (ssRNA), single-stranded RNAi (ssRNAi), short hairpin RNA (shRNA), and microRNA mimics). The term “RNAi compound” is meant to be equivalent to other terms used to describe nucleic acid compounds that are capable of mediating sequence-specific RNA interference, for example, interfering RNA (iRNA), iRNA agent, RNAi agent, small interfering RNA, short interfering RNA, short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically modified siRNA, and others. Additionally, the term “RNAi” is meant to be equivalent to other terms used to describe sequence-specific RNA interference. In some embodiments, an oligonucleotide comprises 6-100 nucleotides and nucleosides. In some embodiments, an oligonucleotide comprises 10-50 nucleotides and nucleosides. In some embodiments, an oligonucleotide comprises 14-30 nucleotides and nucleosides. In some embodiments, an oligonucleotide comprises 20-23 nucleotides and nucleosides. In certain embodiments, an oligonucleotide comprises 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides and nucleosides. In certain embodiments, the oligonucleotide strand comprises between 14 and 23, inclusive, nucleosides. In certain embodiments, the oligonucleotide strand comprises between 10 and 30, inclusive, nucleosides. In certain embodiments, the oligonucleotide strand comprises between 14 and 23, inclusive, nucleosides.

[0123] The term “internal position” of an oligonucleotide strand refers to a position of the oligonucleotide strand other than the 5′ or 3′ nucleoside. In some embodiments, the internal position is at an internucleoside linkage (e.g., the internucleoside linkage between the 5′ nucleoside and the second nucleoside counted from the 5′ end; the internucleoside linkage between the 3′ nucleoside and the second nucleoside counted from the 3′ end; the internucleoside linkage between the first n and n+1 nucleosides counted from the 5′ end, wherein n is an integer between 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.”

[0124] The terms “target nucleic acid,” “target RNA,” and “nucleic acid target” all mean a nucleic acid capable of being targeted by compounds described herein.

[0125] The term “therapeutic agent” includes any pharmaceutical agent or compound that provides a therapeutic benefit to a subject. Therapeutic agents include nucleic acids, oligomericA1278.70032WO00 30 12280650.2compounds, oligonucleotides, proteins, peptides, antibodies, small molecules, and other such agents.

[0126] “Target region” means a portion of a target nucleic acid to which one or more compounds is targeted.

[0127] “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.

[0128] “Terminal group” means a chemical group or group of atoms that is covalently linked to a terminus of an oligonucleotide.

[0129] The terms “mannose receptor” or “MR” or “MRC1”, or “Cluster of Differentiation 206”, or “CD206” refer to a 175 kDa type I transmembrane receptor protein that is a member of the C- type lectin (CLEC) family, which can recognize, bind and internalize a variety of endogenous and pathogen-associated ligands.

[0130] The terms “mannose receptor ligand” and “mannose ligand” are used interchangeably.

[0131] The terms “receptor tyrosine kinase” or “RTK” refer to a class of enzyme-linked transmembrane glycoproteins. One subfamily of RTKs is the tropomyosin-related kinase (Trk) receptor family, which is composed of three members: Tropomyosin Receptor Kinase A (TrkA), Tropomyosin Receptor Kinase B (TrkB), and Tropomyosin Receptor Kinase (TrkC).

[0132] The terms “Tropomyosin Receptor Kinase A” or “TrkA,” as may be used interchangeably herein, mean the receptor for Nerve Growth Factor (NGF) protein encoded by the NTRK1 gene.

[0133] The terms “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.

[0134] The terms “Tropomyosin Receptor Kinase C” or “TrkC,” as may be used interchangeably herein, mean the receptor for neurotropin-3 (NT-3) protein encoded by the NTF3 gene.

[0135] The terms “microRNA” and “miRNA,” as may be used interchangeably herein, refer to short (e.g., about 20 to about 24 nucleotides in length) non-coding ribonucleic acids (RNAs) that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce a stem-loop precursor miRNA (pre-miRNA) approximately 70 nucleotides in length, which is further processed in the RNAi pathway. As part of thisA1278.70032WO00 31 12280650.2pathway, the pre-miRNA is cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into an RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing (i.e., partial complementarity) with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. This mechanism is most often seen through the binding of the miRNA on the 3′ untranslated region (UTR) of the target mRNA, which can decrease gene expression by either inhibiting translation (for example, by blocking the access of ribosomes for translation) or directly causing degradation of the transcript. The term (i.e., miRNA) may be used herein to refer to any form of the subject miRNA (e.g., precursor, primary, and / or mature miRNA).

[0136] The terms “small interfering RNA,” “short interfering RNA,” and “siRNA,” as may be used interchangeably herein, refer to RNA molecules that present as non-coding double-stranded RNA (dsRNA) molecules of about 20 to about 24 nucleotides in length and are useful in RNA interference (RNAi). siRNA 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 molecule). siRNA 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. 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).

[0137] The term “ADAR recruiting molecule,” as may be used herein, refers to a nucleic acid that is configured to increase the concentration of Adenosine Deaminase Acting on Ribonucleic Acid (ADAR) enzyme in a locality around the nucleic acid. In some embodiments, an increased concentration is relative to the concentration in a given locality absent the ADAR recruiting molecule. In some embodiments, an ADAR recruiting molecule comprises a double-stranded RNA duplex.

[0138] The term “ADAR targeting molecule,” as may be used herein, refers to a nucleic acid that is configured to direct an ADAR molecule to a desirable location (e.g., locality). As used herein, the term “direct” refers to increasing the concentration of ADAR in the desirable location as compared to the concentration absent the ADAR targeting molecule. In some embodiments, the ADAR targeting molecule can be configured to control the desirable location by altering theA1278.70032WO00 32 12280650.2sequence and / or properties of the nucleic acid (e.g., by modifications to the nucleobase, sugar, phosphate, or other component). In some embodiments, an ADAR targeting molecule comprises an ADAR recruiting molecule and a single-stranded guide nucleic acid. In some embodiments, an ADAR targeting molecule comprises a double-stranded RNA duplex and a single-stranded guide nucleic acid.

[0139] The term “single-stranded guide nucleic acid,” 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 locality where it is desirable to modulate ADAR concentration. In some embodiments, the level of complementarity is sufficient to facilitate binding (e.g., annealing) of the single-stranded guide nucleic acid to the target sequence.

[0140] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, 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.

[0141] The term “isotopic variant” refers to a therapeutic agent (e.g., a compound and / or modified oligonucleotide disclosed herein) that contains an unnatural proportion of an 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 (11C), 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 (35Cl), chlorine-36 (36Cl), chlorine-37 (37Cl), 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 (11C), 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 (35Cl), chlorine-36 (36Cl), chlorine-37 (37Cl), bromine-79 (79Br), bromine-81A1278.70032WO00 33 12280650.2(81Br), iodine 123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I), and iodine-131 (131I).

[0142] It will be understood that, in a therapeutic agent (e.g., a compound and / or modified oligonucleotide 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).

[0143] “Modified oligonucleotide” means an oligonucleotide, wherein at least one sugar, at least one nucleobase, and / or at least one internucleoside linkage is modified.

[0144] “Nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage.

[0145] “Phosphorothioate linkage” means a modified phosphate linkage in which one of the non- bridging oxygen atoms is replaced with a sulfur atom. Modified phosphate linkages where at least one of the oxygen linked to the phosphate has been replaced or the phosphate group has been replaced by a non-phosphorous group, are also referred to as “non-phosphodiester internucleoside linkage” or “non-phosphodiester linker. Certain Embodiments

[0146] In certain embodiments are compounds comprising a mannose ligand and one or more linker moieties. In certain embodiments, the compound is selected from any of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX or XXI or a stereoisomer, tautomer, prodrug, or salt thereof, as described herein.

[0147] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (I):Formula (I).

[0148] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (II):Formula (II).

[0149] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (III):A1278.70032WO00 34 12280650.2Formula (III).

[0150] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (IV): Formula (IV).

[0151] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (V):Formula (V) or a stereoisomer, tautomer, prodrug, or salt thereof, wherein ▬▬▬▬▬▬ is an oligonucleotide.

[0152] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (VI): Formula (VI).

[0153] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (VII): Formula (VII).

[0154] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (VIII): Formula (VIII).

[0155] In certain embodiments, comprises:. BA-123 (Na)A1278.70032WO00 35 12280650.2

[0156] In certain embodiments, comprises:. BA-198 (N71)

[0157] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of the formula:wherein q is 0-20; r is 4-10; and X is -OH or -SH.

[0158] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (IX):Formula (IX)A1278.70032WO00 36 12280650.2wherein q is 0-20; r is 4-10; and X is -OH or -SH.

[0159] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (X):Formula (X) wherein q is 0-20; r is 4-10; and X is -OH or -SH.

[0160] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XI):Formula (XI) wherein q is 0-20; r is 4-10; and X is -OH or -SH.A1278.70032WO00 37 12280650.2

[0161] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XII):Formula (XII) wherein T is NH, O or S; T1is O, NH, or CH2; –T5--- is –O–, –NH–, –CH= or –CH2–; zero, one, or two of T2R2, T3R3, and T4R4is H; each remaining T2, T3, and T4is O; each of R1, R5, and remaining R2, R3, and R4is independently H, Me, -C(=O)Me, - C(=O)NH2, a second mannose group, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; and wherein ^L1^L2^L3^L4^R-[-L5^L6^L7^L8^B]nreplaces one of R1, R2, R3, R4or R5.

[0162] In certain embodiments, ^L1^L2^L3^L4^R-[-L5^L6^L7^L8^B]nreplaces R1A1278.70032WO00 38 12280650.2

[0164] In certain embodiments, Formula (XII) is Formula (XII-2a):Formula (XII-2a),

[0165] wherein, R is an oligonucleotide represented by “ ,”and wherein the –L1–A1278.70032WO00 39 12280650.2).

[0168] In certain embodiments, Formula (XII) is Formula (XII-4a):A1278.70032WO00 40 12280650.2Formula (XII-4a),

[0169] wherein, R is an oligonucleotide represented by “ ,” and wherein the –

[0171] In certain embodiments, Formula (XII) is Formula (XII-A):A1278.70032WO00 41 12280650.2Formula (XII-A).

[0172] In certain embodiments, ^L1^L2^L3^L4^R-[-L5^L6^L7^L8^B]nreplaces R5, e.g.,Formula (XII-A5).

[0173] In certain embodiments, Formula (XII-A5) is Formula (XII-A5a):

[0175] In certain embodiments, Formula (XII) is Formula (XII-B):A1278.70032WO00 42 12280650.2Formula (XII-B).

[0176] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XIII):Formula (XIII).

[0177] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XIV):Formula (XIV).

[0178] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XV):Formula (XV).

[0179] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XVI):Formula (XVI) wherein:A1278.70032WO00 43 12280650.2▬▬▬▬▬▬ is an oligonucleotide.

[0180] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XVII):Formula (XVII).

[0181] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XVIII):Formula (XVIII).

[0182] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XIX):Formula (XIX), wherein X is OH or SH.

[0183] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XX):A1278.70032WO00 44 12280650.2

[0184] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XX-A):Formula (XX-A).

[0185] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XX-A-b1):A1278.70032WO00 45 12280650.2

[0187] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XX-A-b2):A1278.70032WO00 46 12280650.2[ ,A1278.70032WO00 47 12280650.2

[0189] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XXI):

[0190] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XXII):wherein: ▬▬▬▬▬▬ is an oligonucleotide; X- is O- or S-; each of L1, L2, and L3is independently a linker, a bond or absent, wherein at least one of L1, L2, and L3is a linker or a bond; and each of R2, R3, R4, and R5is independently H, Me, -C(=O)Me, -C(=O)NH2, a second mannose group, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; or a stereoisomer, tautomer, prodrug, acid or salt thereof.

[0191] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XXII-A):A1278.70032WO00 48 12280650.2Formula (XXII-A).

[0192] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XXII-A5a):Formula (XXII-A5a).

[0193] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XXII-A3):A1278.70032WO00 49 12280650.2Formula (XXII-A3).

[0194] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XXII-A5b):Formula (XXII-A5b).

[0195] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XXII-B):A1278.70032WO00 50 12280650.2Formula (XXII-B).

[0196] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XXIII):▬▬▬▬▬▬ is an oligonucleotide; B is a Tropomyosin receptor B (TrkB) ligand; X- is O- or S-; each of L1, L2, L3, L5, L6, L7and L8is independently a linker, a bond or absent, wherein at least one of L1, L2, and L3is a linker or a bond; and each of R2, R3, R4, and R5is independently H, Me, -C(=O)Me, -C(=O)NH2, a second mannose group, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; or a stereoisomer, tautomer, prodrug or salt thereof.

[0197] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XXIII-A):A1278.70032WO00 51 12280650.2Formula (XXIII-A).

[0198] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XXIII-A5):Formula (XXIII-A5).

[0199] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XXIII-A3):A1278.70032WO00 52 12280650.2Formula (XXIII-A3).

[0200] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XXIII-B):Formula (XXIII-B).

[0201] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XXIV):A1278.70032WO00 53 12280650.2Formula (XXIV), wherein: R is an oligonucleotide, a protecting group, a small molecule, a protein, an antibody, or a peptide; r is 4-10; n is 0, 1, 2, or 3; X- is -O- or -S-; andwherein: q is 0-20; T is NH, O or S; zero, one, or two of T2R2, T3R3, and T4R4is H; each remaining T2, T3, and T4is O; and each remaining R2, R3, and R4is independently H, Me, -C(=O)Me, -C(=O)NH2, a second mannose group, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom.

[0202] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XXIV-A):A1278.70032WO00 54 12280650.2

[0203] wherein, R is an oligonucleotide represented by “ ,” and wherein the –L1–Ligand

[0204] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XXV):Formula (XXV), wherein: R is an oligonucleotide, a protecting group, a small molecule, a protein, an antibody, or a peptide; r is 4-10; n is 0, 1, 2, or 3; X- is -O- or -S-; andwherein: q is 0-20; zero, one, or two of T2R2, T3R3, and T4R4is H; each remaining T2, T3, and T4is O; –T5--- is –O–, –NH–, –CH= or –CH2–; and each of R5and remaining R2, R3, and R4is independently H, Me, -C(=O)Me, - C(=O)NH2, a second mannose group, an oxygen protecting group when attachedA1278.70032WO00 55 12280650.2to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom.

[0205] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (XXV-A):Formula (XXV-A),

[0206] wherein, R is an oligonucleotide represented by “ ,” and wherein the –L1–Ligand

[0207] In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, comprising the structure of Formula (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), or (XV) as described herein. In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, comprising the structure of Formula (XII-2a), (XII-4a), (XII-A), (XII- A5), (XII-A5a), or (XII-B) as described herein. In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, comprising the structure of Formula (XX-A), (XX-A-b1), or (XX-A-b2) as described herein. In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, comprising the structure of Formula (XXII-A), (XXII- A5a), (XXII-A3), (XXII-A5b), or (XXII-B) as described herein. In certain embodiments there isA1278.70032WO00 56 12280650.2provided a compound, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, comprising the structure of Formula (XXIII-A), (XXIII-A5), (XXIII-A3), or (XXIII-B) as described herein. In certain embodiments there is provided a compound, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, comprising the structure of Formula (XXIV-A) or (XXV-A) as described herein.

[0208] In certain embodiments, at least one instance is each instance.

[0209] In certain embodiments m is 1. In certain embodiments m is 2. In certain embodiments m is 3. In certain embodiments n is 0. In certain embodiments n is 1. In certain embodiments n is 2. In certain embodiments n is 3. In certain embodiments m is 1 and n is 0. In certain embodiments m is 1 and n is 1. In certain embodiments m is 1 and n is 2. In certain embodiments m is 1 and n is 3. In certain embodiments m is 2 and n is 0. In certain embodiments m is 2 and n is 1. In certain embodiments m is 2 and n is 2. In certain embodiments m is 2 and n is 3. In certain embodiments m is 3 and n is 0. In certain embodiments m is 3 and n is 1. In certain embodiments m is 3 and n is 2. In certain embodiments m is 3 and n is 3. Linkers

[0210] In certain embodiments, the compounds provided herein comprise a mannose ligand covalently coupled to an agent moiety. In certain embodiments, the compounds provided herein comprise one or more linker moieties. In certain embodiments, the one or more linker moieties link a mannose ligand to an agent moiety. In certain embodiments, the agent moiety is a protein, peptide, antibody, nucleic acid, small molecule, large molecule, therapeutic, prophylactic, diagnostic, or imaging agent. In some embodiments, a compound provided herein comprises an oligonucleotide. In certain embodiments, a mannose ligand is conjugated to an oligonucleotide. In certain embodiments, a compound provided herein comprises one or more mannose ligands, one or more linker moieties, and one or more agent moieties, wherein the mannose ligands are conjugated (e.g., linked, connected, attached, associated with) to the one of more agent moieties through one or more linker moieties.

[0211] Compounds disclosed herein can be manufactured using any available method. When associating compounds provided herein with agent moieties (e.g., a mannose ligand with an oligonucleotide), the moieties may be linked directly or indirectly (e.g., through a linker moiety; that is, the linker is covalently bonded to each of the oligonucleotide and the mannose ligand; in some formulae herein “-Ln-” wherein n is a number (e.g., L1, L2, L3, L4, L5, L6, L7, L8). For example, the oligonucleotide and mannose ligand may be directly associated with one another, e.g., by one or more covalent bonds, or may be associated by means of one or more linkers.A1278.70032WO00 57 12280650.2

[0212] A “linker” refers to any chemical moiety (e.g., a combination of atoms having appropriate valency according to known chemistry principles) used to conjugate two components of the compounds provided herein (e.g., a mannose ligand and an oligonucleotide) to one another. Each of the two components may be connected to any portion of any of the linkers provided herein. In some embodiments, one component of the compounds provided herein (e.g., a mannose ligand or an oligonucleotide) is connected by a bond to one end of a linker, and the other component is connected by a bond to the other end of the linker. In some embodiments, one or both components of the compounds provided herein may be connected by a bond to an internal position within any of the linkers described herein. For example, in the context of an “alkyl linker,” a mannose ligand may be joined by a bond to a carbon at one end of the alkyl linker, and an oligonucleotide may be joined by a bond to a carbon at the other end of the alkyl linker. In some embodiments, a linker is optionally substituted, and a mannose ligand or another linker may be joined by a bond to the optional substituent.

[0213] In certain embodiments, the compounds provided herein comprise one or more linking groups. In certain embodiments, each of L1, L2, L3, and L4comprises a linking group. In certain embodiments, each of L5, L6, L7, and L8comprises a linking group. In certain embodiments, a linking group is covalently bound to a mannose ligand. In certain embodiments, a linking group is covalently bound to an oligonucleotide. In certain embodiments, a linking group is covalently bound to a cleavable moiety. In certain embodiments, a linking group comprises a cleavable bond. In certain embodiments, a linking group does not comprise a cleavable moiety. In certain embodiments, a linking group comprises a covalent attachment to a solid support. In certain embodiments, a linking group includes multiple positions for attachment of mannose ligands.

[0214] In certain embodiments, the terms “linker” and “linking group” are used interchangeably.

[0215] In certain embodiments, a linking group 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 linking group comprises 1 to 50 repeating units, 1 to 40 repeating units, 1 to 25 repeating units, 1 to 20 repeating units, 1 to 15 repeating units, 1 to 10 repeating units, or 1 to 5 repeating units. In certain embodiments, a linking group is 1 to 50 atoms long, 1 to 40 atoms long, 1 to 25 atoms long, 1 to 20 atoms long, 1 to 15 atoms long, 1 to 10 atoms long, or 1 to 5 atoms long.

[0216] In certain embodiments, a linking group contains carbon atoms. In certain embodiments, a linking group contains heteroatoms (e.g., nitrogen, oxygen, sulfur, etc.). In certain embodiments, a linking group forms amide linkages, ester linkages, or disulfide linkages. In certain embodiments, a linking group forms hydrazone linkages, oxime linkages, imine linkages, guanidine linkages, urea linkages, carbamate linkages, unsaturated alkyl linkages, sulfonamideA1278.70032WO00 58 12280650.2linkages or 4-8 membered hetero cyclic linkages. In certain embodiments, a linking group comprises one or more groups selected from alkyl, amino, οxο, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino. In certain embodiments, a linking group comprises at least one phosphorus group. In certain embodiments, a linking group comprises at least one phosphate group. In certain embodiments, a linking group includes at least one neutral linking group. In certain embodiments, a linking group is substituted with various substituents including, but not limited to, hydrogen atoms, alkyl, alkenyl, alkynyl, amino, alkylamino, dialkylamino, trialkylamino, hydroxyl, alkoxy, halogen, aryl, heterocyclic, aromatic heterocyclic, cyano, amide, carbamoyl, carboxylic acid, ester, thioether, alkylthioether, thiol, and ureido groups. As would be appreciated by one of skill in this art, each of these groups may in turn be substituted.

[0217] In certain embodiments, a linking group includes, but is not limited to, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, or substituted or unsubstituted C2-C10 alkynyl, wherein a nonlimiting list of preferred substituent groups includes hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, a linking group is an aliphatic or heteroaliphatic. For example, the linking group can a polyalkyl linking group. The linking group can be a polyether linking group. The linking group can be a polyethylene linking group, such as PEG.

[0218] In certain embodiments, the linking group is a short peptide chain. In certain embodiments, a linking group comprises 1 to 40 amino acids, 1 to 25 amino acids, 1 to 20 amino acids, 1 to 15 amino acids, 1 to 10 amino acids, or 1 to 5 amino acids.

[0219] In certain embodiments, a linking group comprises linker-nucleosides. In certain embodiments, a linking group comprises 1 to 40 linker-nucleosides, 1 to 25 linker-nucleosides, 1 to 20 linker-nucleosides, 1 to 15 linker-nucleosides, 1 to 10 linker-nucleosides, or 1 to 5 linker- nucleosides. In certain embodiments, such linker-nucleosides may be modified or unmodified nucleosides. It is typically desirable for linker-nucleosides to be cleaved from the compound after it reaches a target tissue. Accordingly, linker-nucleosides herein can be linked to one another and to the remainder of the compound through cleavable bonds. Herein, linker-nucleosides are not considered to be part of an oligonucleotide payload. Accordingly, in embodiments in which a compound comprises an oligonucleotide consisting of a specified number or range of linked nucleosides and / or a specified percent complementarity to a reference nucleic acid and the compound also comprises a mannose ligand comprising a linking group comprising linker- nucleosides, those linker-nucleosides are not counted toward the length of the oligonucleotide and are not used in determining the percent complementarity of the oligonucleotide for the reference nucleic acid.A1278.70032WO00 59 12280650.2

[0220] In certain embodiments, the linking group includes a protein binding group. In certain embodiments, the protein binding group is a lipid such as for example including but not limited to cholesterol, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-Bis- O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3- (oleoyl)cholenic acid, dimethoxytrityl, or phenoxazine), a vitamin (e.g., folate, vitamin A, vitamin E, biotin, pyridoxal), a peptide, a carbohydrate (e.g., monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide, polysaccharide), an endosomolytic component, a steroid (e.g., uvaol, hecigenin, diosgenin), a terpene (e.g., triterpene, e.g., sarsasapogenin, friedelin, epifriedelanol derivatized lithocholic acid), or a cationic lipid. In certain embodiments, the protein binding group is a C16to C22long chain saturated or unsaturated fatty acid, cholesterol, cholic acid, vitamin E, adamantane or 1-pentafluoropropyl.

[0221] In certain embodiments, a linking group includes, but is not limited to, pyrrolidine, 8- amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1- carboxylate (SMCC) and 6-aminohexanoic acid (ΑΗΕΧ or AHA).

[0222] In certain embodiments, a linking group includes, without limitation, those linking groups described in the following references: US 5,994,517; US 6,300,319; US 6,660,720; US 6,906,182; US 7,262,177; US 7,491,805; US 8,106,022; US 7,723,509; US 9,127,276; US 2006 / 0148740; US 2011 / 0123520; WO2013 / 033230; WO2012 / 037254, Biessen et al., J. Med. Chem.1995, 38, 1846-1852; Lee et al., Bioorganic & Medicinal Chemistry 2011,19, 2494-2500; Rensen et al., J. Biol. Chem.2001, 276, 37577-37584; Rensen et al., J. Med. Chem.2004, 47, 5798-5808; Sliedregt et al., J. Med. Chem.1999, 42, 609-618; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Lee, Carhohydr Res, 1978, 67, 509-514; Connolly et al., J Biol Chem, 1982, 257, 939-945; Pavia et al., Int J Pep Protein Res, 1983, 22, 539-548; Lee et al., Biochem, 1984, 23, 4255-4261; Lee et al., Glycoconjugate J, 1987, 4, 317-328; Toyokuni et al., Tetrahedron Lett, 1990, 31, 2673-2676; Biessen et al., J Med Chem, 1995, 38, 1538-1546; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Kim et al., Tetrahedron Lett, 1997, 38, 3487-3490; Lee et al., Bioconjug Chem, 1997, 8, 762-765; Kato et al., Glycobiol, 2001, 11, 821-829; Rensen et al., J Biol Chem, 2001, 276, 37577-37584; Lee et al., Methods Enzymol, 2003, 362, 38-43; Westerlind et al., Glycoconj J, 2004, 21, 227-241; Lee et al., Bioorg Med Chem Lett, 2006, 16(19), 5132- 5135; Maierhofer et al., Bioorg Med Chem, 2007, 15, 7661-7676; Khorev et al., Bioorg Med Chem, 2008, 16, 5216-5231; Lee et al., Bioorg Med Chem, 2011, 19, 2494-2500; Kornilova et al., Analyt Biochem, 2012, 425, 43-46; Pujol et al., Angew Chemie Int Ed Engl, 2012, 51, 7445- 7448; Biessen et al., J Med Chem, 1995, 38, 1846-1852; Sliedregt et al., J Med Chem, 1999, 42, 609-618; Rensen et al., J Med Chem, 2004, 47, 5798-5808; Rensen et al., Arterioscler ThromhA1278.70032WO00 60 12280650.2Vase Biol, 2006, 26, 169-175; van Rossenberg et al., Gene Ther, 2004, 11, 457-464; Sato et al., JAm Chem Soc, 2004, 126, 14013-14022; Lee et al., J Org Chem, 2012, 77, 7564-7571; Biessen et al., FASEB J, 2000, 14, 1784-1792; Rajur et al., Bioconjug Chem, 1997, 8, 935-940; Duff et al., Methods Enzymol, 2000, 313, 297-321; Maier et al., Bioconjug Chem, 2003, 14, 18-29; Jayaprakash et al., Org Lett, 2010, 12, 5410-5413; Manoharan, Antisense Nucleic Acid Drug Dev, 2002, 12, 103-128; Merwin et al., Bioconjug Chem, 1994, 5, 612-620; Tomiya et al., Bioorg Med Chem, 2013, 21, 5275-5281; International applications WO1998 / 013381; WO2011 / 038356; WO1997 / 046098; W02008 / 098788; W02004 / 101619; WO2012 / 037254; WO2011 / 120053; WO2011 / 100131; WO2011 / 163121; WO2012 / 177947; W02013 / 033230; W02013 / 075035; WO2012 / 083185; WO2012 / 083046; W02009 / 082607; WO2009 / 134487; W02010 / 144740; W02010 / 148013; WO1997 / 020563; W02010 / 088537; W02002 / 043771; W02010 / 129709; WO2012 / 068187; WO2009 / 126933; W02004 / 024757; WO2010 / 054406; WO2012 / 089352; WO2012 / 089602; WO2013 / 166121; WO2013 / 165816; U.S. Patents 4,751,219; 7,582,744; 8,552,163; 8,137,695; 6,908,903; 6,383,812; 7,262,177; 6,525,031; 5,994,517; 6,660,720; 6,300,319; 7,723,509; 8,106,022; 7,491,805; 7,491,805; 8,541,548; 8,344,125; 8,313,772; 8,349,308; 8,450,467; 8,501,930; 8,158,601; 7,262,177; 6,906,182; 6,620,916; 8,435,491; 8,404,862; 7,851,615; Published U.S. Patent Application Publications US2011 / 0097264; US2011 / 0097265; US2013 / 0004427; US2003 / 0119724; US2011 / 0207799; US2012 / 0035115; US2012 / 0230938; US2005 / 0164235; US2006 / 0183886; US2012 / 0136042; US2012 / 0095075; US2013 / 0109817; US2006 / 0148740; US2008 / 0206869; US2012 / 0165393; US2012 / 0101148; US2013 / 0121954; US2011 / 0123520; US2003 / 0077829; US2008 / 0108801; and US2009 / 0203132; each of which is incorporated herein by reference in its entirety.

[0223] In certain embodiments, each of L1, L2, L3, and L4is independently a linker. In certain embodiments, each of L5, L6, L7and L8is independently a linker. Each linker may be attached to the rest of the compounds at either direction.

[0224] In certain embodiments, at least one linker is L1. In certain embodiments, at least one linker is L2. In certain embodiments, at least one linker is L3. In certain embodiments, at least one linker is L4. In certain embodiments, at least one linker is L5. In certain embodiments, at least one linker is L6. In certain embodiments, at least one linker is L7. In certain embodiments, at least one linker is L8.

[0225] In certain embodiments, at least one linker is –L1–L2–. In certain embodiments, at least one linker is –L2–L3–. In certain embodiments, at least one linker is –L3–L4–. In certain embodiments, at least one linker is –L5–L6–. In certain embodiments, at least one linker is –L6– L7–. In certain embodiments, at least one linker is –L7–L8–.A1278.70032WO00 61 12280650.2

[0226] In certain embodiments, at least one linker is –L1–L2–L3–. In certain embodiments, at least one linker is –L2–L3–L4–. In certain embodiments, at least one linker is –L5–L6–L7–. In certain embodiments, at least one linker is –L6–L7–L8–.

[0227] In certain embodiments, at least one linker is –L1–L2–L3–L4–. In certain embodiments, at least one linker is –L5–L6–L7–L8–.

[0228] In certain embodiments, at least one linker is a bond (e.g., a single bond).

[0229] In certain embodiments, at least one linker is substituted or unsubstituted, C1-100alkylene. In certain embodiments, at least one linker is substituted or unsubstituted, C1-3 alkylene. In certain embodiments, at least one linker is substituted or unsubstituted, C4-10 alkylene. In certain embodiments, at least one linker is substituted or unsubstituted, C11-20alkylene. In certain embodiments, at least one linker is substituted or unsubstituted, C21-30alkylene. In certain embodiments, at least one linker is substituted or unsubstituted, C31-40 alkylene. In certain embodiments, at least one linker is substituted or unsubstituted, C41-60 alkylene. In certain embodiments, at least one linker is substituted or unsubstituted, C61-80alkylene. In certain embodiments, at least one linker is substituted or unsubstituted, C81-100 alkylene. In certain embodiments, at least one linker is substituted or unsubstituted, C1-30 alkylene.

[0230] In certain embodiments, at least one linker is substituted or unsubstituted, C1-100heteroalkylene. In certain embodiments, at least one linker is substituted or unsubstituted, C1-3 heteroalkylene. In certain embodiments, at least one linker is substituted or unsubstituted, C4-10 heteroalkylene. In certain embodiments, at least one linker is substituted or unsubstituted, C11-20heteroalkylene. In certain embodiments, at least one linker is substituted or unsubstituted, C21-30heteroalkylene. In certain embodiments, at least one linker is substituted or unsubstituted, C31-40 heteroalkylene. In certain embodiments, at least one linker is substituted or unsubstituted, C41-60 heteroalkylene. In certain embodiments, at least one linker is substituted or unsubstituted, C61-80heteroalkylene. In certain embodiments, at least one linker is substituted or unsubstituted, C81-100 heteroalkylene. In certain embodiments, at least one linker is substituted or unsubstituted, C1-30 heteroalkylene.

[0231] In certain embodiments, at least one linker is a combination of –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, – OP(=O)(OH)O–, and –OP(=S)(OH)O–, provided that: the number of backbone atoms of the linker is 1-100; and the linker does not comprise O–O, O–N, N–O, or N–N.

[0232] In certain embodiments, at least one linker is a combination of –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, – OP(=O)(OH)O–, and –OP(=S)(OH)O–, provided that:A1278.70032WO00 62 12280650.2the number of backbone atoms of the linker is 2-60 (e.g., 4-40); and the linker does not comprise O–O, O–N, N–O, or N–N.

[0233] In certain embodiments, at least one linker is a combination of –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, and –N(CH3)C(=O)–, provided that: the number of backbone atoms of the linker is 1-100; and the linker does not comprise O–O, O–N, N–O, or N–N.

[0234] In certain embodiments, at least one linker is a combination of –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, and –N(CH3)C(=O)–, provided that: the number of backbone atoms of the linker is 2-60 (e.g., 4-40); and the linker does not comprise O–O, O–N, N–O, or N–N.

[0235] In certain embodiments, at least one linker is a combination of –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, – OP(=O)(OH)O–, and –OP(=S)(OH)O–, provided that: the number of backbone atoms of the linker is 1-30; and the linker does not comprise O–O, O–N, N–O, or N–N.

[0236] In certain embodiments, at least one linker is a combination of –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, and –N(CH3)C(=O)–, provided that: the number of backbone atoms of the linker is 1-30; and the linker does not comprise O–O, O–N, N–O, or N–N.

[0237] In certain embodiments, at least one linker is a combination of –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, – OP(=O)(OH)O–, and –OP(=S)(OH)O–, provided that: the number of backbone atoms of the linker is 1-10; and the linker does not comprise O–O, O–N, N–O, or N–N.

[0238] In certain embodiments, at least one linker is a combination of –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, and –N(CH3)C(=O)–, provided that: the number of backbone atoms of the linker is 1-10; and the linker does not comprise O–O, O–N, N–O, or N–N.

[0239] In certain embodiments, at least one linker comprises–C(=O)NH– or –NHC(=O)–.A1278.70032WO00 63 12280650.2

[0240] In certain embodiments, at least one linker comprises substituted or unsubstitutedalkylene. In certain embodiments, at least one linker comprises ^–^(CH2^)r ^ ^ , wherein r is 4-10.In certain embodiments, at least one linker is unsubstituted hexylene.

[0241] In certain embodiments, at least one linker comprises ^–^(CH2^CH2^O^^)q^ ^,wherein q is 0-20 (e.g., 1-10 or 11-20). In certain embodiments, at least one linker comprises ^–^(CH2^CH2^O^^)4^ ^. In certain embodiments, at least one linker comprises ^–

[0242] In certain embodiments, at least one linker is substituted or unsubstituted, C1-100 alkylene, substituted or unsubstituted, C2-100 alkenylene, substituted or unsubstituted, C2-100 alkynylene, substituted or unsubstituted, C1-100heteroalkylene, substituted or unsubstituted, C2-100heteroalkenylene, or substituted or unsubstituted, C2-100heteroalkynylene; optionally wherein one or more (e.g., 2) backbone atoms of the C1-100 alkylene, C2-100 alkenylene, C2-100 alkynylene, C1-100 heteroalkylene, C2-100 heteroalkenylene, or C2-100 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.

[0243] In certain embodiments, at least one linker is substituted or unsubstituted, C2-70alkylene or substituted or unsubstituted, C2-70 heteroalkylene; and one backbone atom of the C2-70 alkylene or C2-70 heteroalkylene is replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0244] In certain embodiments, at least one linker is substituted or unsubstituted, C4-40 heteroalkylene; and one backbone atom of the C4-40heteroalkylene is replaced with substituted or unsubstituted heterocyclylene or substituted or unsubstituted heteroarylene.

[0245] In certain embodiments, at least one linker is substituted or unsubstituted, C1-30 alkylene, substituted or unsubstituted, C2-30alkenylene, substituted or unsubstituted, C2-30alkynylene, substituted or unsubstituted, C1-30 heteroalkylene, substituted or unsubstituted, C2-30 heteroalkenylene, or substituted or unsubstituted, C2-30 heteroalkynylene; optionally wherein one or more backbone atoms of the C1-30alkylene, C2-30alkenylene, C2-30alkynylene, C1-30heteroalkylene, C2-30heteroalkenylene, or C2-30heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.A1278.70032WO00 64 12280650.2

[0246] In certain embodiments, at least one linker is substituted or unsubstituted, C2-20alkylene or substituted or unsubstituted, C2-20 heteroalkylene; and one backbone atom of the C2-20 alkylene or C2-20 heteroalkylene is replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0247] In certain embodiments, the substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms is of the formula:k21 is 0, 1, 2, 3, or 4; each instance of Rd, if present, is independently halogen, substituted or unsubstituted, C1-6 alkyl, or –O–(substituted or unsubstituted, C1-6 alkyl); k22 is 0, 1, 2, 3, or 4; each instance of Re, if present, is independently halogen, substituted or unsubstituted, C1-6 alkyl, or –O–(substituted or unsubstituted, C1-6 alkyl); k23 is an integer between 0 and 11, inclusive;A1278.70032WO00 65 12280650.2each instance of Rf, if present, is independently halogen, substituted or unsubstituted, C1-6alkyl, or –O–(substituted or unsubstituted, C1-6 alkyl); and Rgis hydrogen, halogen, substituted or unsubstituted, C1-6 alkyl, or –O–(substituted or unsubstituted, C1-6alkyl).

[0248] In certain embodiments, the substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms is of the formula: , ,

[0249] In certain embodiments, at least one linker comprises, wherein qis 0-20 (e.g., 1-10 or 11-20).

[0250] In certain embodiments, at least one linker comprises:A1278.70032WO00 66 12280650.2

[0251] In certain embodiments, at least one linker comprises a phosphate or a phosphorothioate group. In certain embodiments at least one linker comprises , wherein X is OH or SH.

[0252] In certain embodiments, at least one linker is an optionally substituted PEG linker. In certain embodiments, the PEG linker is two to twenty PEG units in length. In certain embodiments, the PEG linker is two to ten PEG units in length. In certain embodiments, the PEG linker is six PEG units in length. In certain embodiments, the PEG linker is five PEG units in length. In certain embodiments, the PEG linker is four PEG units in length. In certain embodiments, the PEG linker is three PEG units in length.

[0253] In certain embodiments, at least one linker is an optionally substituted alkyl linker. In certain embodiments, at least one linker comprises –C(=O)NH– or –NHC(=O)–. In certain embodiments, at least one linker is an optionally substituted C1-20 alkyl linker. In certain embodiments, the linker is an optionally substituted C10 alkyl linker. In certain embodiments, the linker is an optionally substituted C8alkyl linker. In certain embodiments, the linker is an optionally substituted C6alkyl linker. In certain embodiments, the linker is an unsubstituted C8or C6 alkyl linker. In certain embodiments at least one linker is unsubstituted hexylene.

[0254] In certain embodiments, at least one linker is an optionally substituted heteroaryl linker. In certain embodiments, at least one linker is an optionally substituted partially unsaturated heteroaryl linker. In certain embodiments, at least one linker is an optionally substituted heteroalkyl linker. In certain embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In some embodiments, the heteroalkyl linker comprises two substituents joined together to form an optionally substituted carbocyclyl ring.

[0255] In certain embodiments, at least one linker comprises ^–^(CH2^CH2^O^^)q^ ^,wherein q is 0-20 (e.g., 1-10 or 11-20). In certain embodiments, at least one linker comprises ^–^(CH2^CH2^O^^)4^ ^. In certain embodiments, at least one linker comprises ^–.

[0257] In certain embodiments, at least one linker comprises the structure.

[0258] In certain embodiments, at least one linker comprises ^–^C(=O)NH–(CH2^CH2^O^^)q^ ^, wherein q is 0-20 (e.g., 1-10 or 11-20).A1278.70032WO00 67 12280650.2

[0259] In certain embodiments, at least one linker comprises the structure.

[0260] In certain embodiments, at least one linker comprises the structure

[0261] In certain embodiments, at least one linker comprises^ ^^ (CH2^CH2^O^)q^P(=X)(OH)O–^, wherein q is 0-20 (e.g., 1-10 or 11-20), and X is O or

[0262] In certain embodiments, at least one linker comprises the structure, wherein X is O or S.

[0263] In certain embodiments, at least one linker comprises the structure, wherein X is O or S.

[0264] In certain embodiments, at least one linker comprises the structurecertain embodiments, at least one linker comprises the structureembodiments, at least one linker comprises the structureembodiments, at least one linker comprises the structure.A1278.70032WO00 68 12280650.2

[0265] In certain embodiments, at least one linker comprises the structure . In certain embodiments, at least one linker comprises the structure.

[0266] In certain embodiments, at least one linker comprises the structure . at least one linker comprises the structure.

[0268] In certain embodiments, at least one linker comprises the structure.A1278.70032WO00 69 12280650.2

[0269] In certain embodiments, at least one linker comprises the structure or.

[0270] In certain embodiments, at least one linker comprises the structure, wherein X is O or S.

[0271] In certain embodiments, at least one linker comprises the structure, wherein X is O or S.

[0272] In certain embodiments, at least one linker comprises the structureA1278.70032WO00 70 12280650.2

[0274] In certain embodiments, at least one linker comprises the structure

[0275] In certain embodiments, at least one linker comprises the structure, wherein X is O or S.

[0276] In certain embodiments, at least one linker comprises the structure, wherein X is O or S and n is 1-20.

[0277] In certain embodiments, at least one linker comprises the structureA1278.70032WO00 71 12280650.2wherein X is O or S and n is 1-20.

[0278] In certain embodiments, at least one linker comprises the structurewherein X is O or S and n is 1-20.

[0279] In certain embodiments, at least one linker comprises the structureA1278.70032WO00 72 12280650.2, wherein X is O or S and n is 1-20.

[0280] In certain embodiments, at least one linker comprises the structureX is O or S.A1278.70032WO00 73 12280650.2

[0281] In certain embodiments, at least one linker comprises the structure

[0282] In certain embodiments, at least one linker comprises the structureA1278.70032WO00 74 12280650.2, wherein X is S or O.

[0283] In certain embodiments, at least one linker comprises the structure

[0284] In certain embodiments, at least one linker comprises the structureA1278.70032WO00 75 12280650.2

[0285] In certain embodiments, at least one linker comprises the structure

[0286] In certain embodiments, at least one linker comprises the structure, wherein n is 1-20.

[0287] In certain embodiments, at least one linker comprises the structure.A1278.70032WO00 76 12280650.2

[0288] In certain embodiments, at least one linker comprises the structure

[0290] In certain embodiments, at least one linker comprises the structure, wherein X is O or S.

[0291] In certain embodiments, at least one linker comprises the structure, wherein X is O or S.

[0292] In certain embodiments, at least one linker comprises the structure, wherein X is O or S.A1278.70032WO00 77 12280650.2

[0293] In certain embodiments, at least one linker comprises the structure, wherein X is O or S.

[0294] In certain embodiments, at least one linker comprises the structure

[0295] In certain embodiments, at least one linker comprises the structure, wherein X is O or S.A1278.70032WO00 78 12280650.2

[0296] In certain embodiments, at least one linker comprises the structureO or S.

[0297] In certain embodiments, at least one linker comprises the structurewherein X is O or S.A1278.70032WO00 79 12280650.2

[0298] In certain embodiments, at least one linker comprises the structure, wherein X is O or S.

[0299] In certain embodiments, at least one linker comprises the structureA1278.70032WO00 80 12280650.2, wherein X is O or S.

[0300] In certain embodiments, at least one linker comprises the structureX is O or S and n is 1-20.A1278.70032WO00 81 12280650.2

[0301] In certain embodiments, at least one linker comprises the structure, wherein n is 1-20.

[0302] In certain embodiments, at least one linker comprises the structurewherein n is 1-20.

[0303] In certain embodiments, at least one linker comprises the structureA1278.70032WO00 82 12280650.2.

[0304] In certain embodiments, at least one linker comprises the structurewherein n is 1-20.

[0305] In certain embodiments, at least one linker comprises the structure, wherein n is 1-20.A1278.70032WO00 83 12280650.2

[0306] In certain embodiments, at least one linker comprises the structure.

[0307] In certain embodiments, at least one linker comprises the structure

[0308] In certain embodiments, at least one linker comprises the structure.

[0309] In certain embodiments, at least one linker comprises the structureA1278.70032WO00 84 12280650.2.

[0310] In certain embodiments, at least one linker comprises the structurewherein each Rais -OH, -CH2-OH, -CH2-OMe, or NH2.

[0311] In certain embodiments, at least one instance of L1is substituted or unsubstituted, C1-100 heteroalkylene.

[0312] In certain embodiments, at least one instance of L1is a combination of –CH2–, –O–, – CH2CH2O–, –OCH2CH2–, –C(=O)–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, – N(CH3)C(=O)–, –OP(=O)(OH)O–, and –OP(=S)(OH)O–, provided that: the number of backbone atoms of L1is 1-100; and L1does not comprise O–O, O–N, N–O, or N–N.

[0313] In certain embodiments, at least one instance of L1comprises ^–^(CH2^CH2^O^^)q^ ^, wherein q is 0-20.

[0314] In certain embodiments, at least one instance of L1is substituted or unsubstituted, C1-100 alkylene, substituted or unsubstituted, C2-100 alkenylene, substituted or unsubstituted, C2-100 alkynylene, substituted or unsubstituted, C1-100heteroalkylene, substituted or unsubstituted, C2-100heteroalkenylene, or substituted or unsubstituted, C2-100 heteroalkynylene; optionally wherein one or more backbone atoms of the C1-100 alkylene, C2-100 alkenylene, C2-100alkynylene, C1-100heteroalkylene, C2-100heteroalkenylene, or C2-100heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.

[0315] In certain embodiments, at least one instance of L1is substituted or unsubstituted, C2-70 alkylene or substituted or unsubstituted, C2-70 heteroalkylene; and one backbone atom of the C2-70alkylene or C2-70heteroalkylene is replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstitutedA1278.70032WO00 85 12280650.2heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0316] In certain embodiments, at least one instance of L1comprise:, wherein q is 0-20.

[0317] In certain embodiments, at least one instance of L8is substituted or unsubstituted, C1-100heteroalkylene.

[0318] In certain embodiments, at least one instance of L8is a combination of –CH2–, –O–, – CH2CH2O–, –OCH2CH2–, –C(=O)–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, – N(CH3)C(=O)–, –OP(=O)(OH)O–, and –OP(=S)(OH)O–, provided that: the number of backbone atoms of L8is 1-100; and L8does not comprise O–O, O–N, N–O, or N–N.

[0319] In certain embodiments, at least one instance of L8comprises ^–^(CH2^CH2^O^^)q^ ^, wherein q is 0-20.

[0320] In certain embodiments, at least one instance of L8is substituted or unsubstituted, C1-100alkylene, substituted or unsubstituted, C2-100alkenylene, substituted or unsubstituted, C2-100alkynylene, substituted or unsubstituted, C1-100 heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, or substituted or unsubstituted, C2-100 heteroalkynylene; optionally wherein one or more backbone atoms of the C1-100alkylene, C2-100alkenylene, C2-100alkynylene, C1-100heteroalkylene, C2-100heteroalkenylene, or C2-100heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.

[0321] In certain embodiments, at least one instance of L8is substituted or unsubstituted, C2-70alkylene or substituted or unsubstituted, C2-70heteroalkylene; and one backbone atom of the C2-70 alkylene or C2-70 heteroalkylene is replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0322] In certain embodiments, at least one instance of L8comprise:A1278.70032WO00 86 12280650.2, wherein q is 0-20.

[0323] In certain embodiments, at least one instance of L2is substituted or unsubstituted, C1-30heteroalkylene.

[0324] In certain embodiments, at least one instance of L2is a combination of –CH2–, –O–, – CH2CH2O–, –OCH2CH2–, –C(=O)–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, – N(CH3)C(=O)–, –OP(=O)(OH)O–, and –OP(=S)(OH)O–, provided that: the number of backbone atoms of L2is 1-30; and L2does not comprise O–O, O–N, N–O, or N–N.

[0325] In certain embodiments, at least one instance of L2comprises –C(=O)NH– or – NHC(=O)–.

[0326] In certain embodiments, at least one instance of L2comprises:

[0327] In certain embodiments, at least one instance of L2is substituted or unsubstituted, C1-30 alkylene, substituted or unsubstituted, C2-30alkenylene, substituted or unsubstituted, C2-30alkynylene, substituted or unsubstituted, C1-30 heteroalkylene, substituted or unsubstituted, C2-30 heteroalkenylene, or substituted or unsubstituted, C2-30 heteroalkynylene; optionally wherein one or more backbone atoms of the C1-30alkylene, C2-30alkenylene, C2-30alkynylene, C1-30heteroalkylene, C2-30heteroalkenylene, or C2-30heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.

[0328] In certain embodiments, at least one instance of L2is substituted or unsubstituted, C2-20 alkylene or substituted or unsubstituted, C2-20heteroalkylene; and one backbone atom of the C2-20 alkylene or C2-20 heteroalkylene is replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.A1278.70032WO00 87 12280650.2

[0329] In certain embodiments, at least one instance .

[0330] In certain embodiments, at least one instance of L2is substituted or unsubstituted, C1-30 heteroalkylene.

[0331] In certain embodiments, at least one instance of L7is a combination of –CH2–, –O–, – CH2CH2O–, –OCH2CH2–, –C(=O)–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, – N(CH3)C(=O)–, –OP(=O)(OH)O–, and –OP(=S)(OH)O–, provided that: the number of backbone atoms of L7is 1-30; and L7does not comprise O–O, O–N, N–O, or N–N.

[0332] In certain embodiments, at least one instance of L7comprises –C(=O)NH– or – NHC(=O)–.

[0333] In certain embodiments, at least one instance of L7comprises:

[0334] In certain embodiments, at least one instance of L7is.

[0335] In certain embodiments, at least one instance of L7is substituted or unsubstituted, C1-30 alkylene, substituted or unsubstituted, C2-30alkenylene, substituted or unsubstituted, C2-30alkynylene, substituted or unsubstituted, C1-30 heteroalkylene, substituted or unsubstituted, C2-30 heteroalkenylene, or substituted or unsubstituted, C2-30 heteroalkynylene; optionally wherein one or more backbone atoms of the C1-30alkylene, C2-30alkenylene, C2-30alkynylene, C1-30heteroalkylene, C2-30heteroalkenylene, or C2-30heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.

[0336] In certain embodiments, at least one instance of L7is substituted or unsubstituted, C2-20 alkylene or substituted or unsubstituted, C2-20heteroalkylene; and one backbone atom of the C2-20 alkylene or C2-20 heteroalkylene is replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.A1278.70032WO00 88 12280650.2

[0337] In certain embodiments, at least one instance of L3is substituted or unsubstituted, C1-30alkylene or substituted or unsubstituted, C1-30 heteroalkylene.

[0338] In certain embodiments, at least one instance of L3is substituted or unsubstituted, C1-30 alkylene.

[0339] In certain embodiments, at least one instance of L3is ^–^(CH2^)r ^ ^ , wherein r is 4-10.

[0340] In certain embodiments, at least one instance of L3is unsubstituted hexylene.

[0341] In certain embodiments, at least one instance of L6is substituted or unsubstituted, C1-30 alkylene or substituted or unsubstituted, C1-30 heteroalkylene.

[0342] In certain embodiments, at least one instance of L6is substituted or unsubstituted, C1-30alkylene.

[0343] In certain embodiments, at least one instance of L6 is ^–^(CH2^)r ^ ^ , wherein r is 4-10.

[0344] In certain embodiments, at least one instance of L6is unsubstituted hexylene.

[0345] In certain embodiments, at least one instance of L4is a combination of –CH2–, –O–, – CH2CH2O–, –OCH2CH2–, –C(=O)–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, – N(CH3)C(=O)–, –OP(=O)(OH)O–, and –OP(=S)(OH)O–, provided that: the number of backbone atoms of L4is 1-10; and L4does not comprise O–O, O–N, N–O, or N–N.

[0346] In certain embodiments, at least one instance of L4is a substituted or unsubstituted phosphate or a substituted or unsubstituted phosphorothioate group.

[0347] In certain embodiments, at least one instance of L4is, wherein X is OH or SH.

[0348] In certain embodiments, wherein at least one instance of L5is a combination of –CH2–, – O–, –CH2CH2O–, –OCH2CH2–, –C(=O)–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, – N(CH3)C(=O)–, –OP(=O)(OH)O–, and –OP(=S)(OH)O–, provided that: the number of backbone atoms of L5is 1-10; and L5does not comprise O–O, O–N, N–O, or N–N.

[0349] In certain embodiments, wherein at least one instance of L5is a substituted or unsubstituted phosphate or a substituted or unsubstituted phosphorothioate group.

[0350] In certain embodiments, wherein at least one instance of L5is , wherein X is OH or SH.A1278.70032WO00 89 12280650.2

[0351] In certain embodiments, at least one L1, at least one L2, at least one L3, and at least one L4independently comprise or together comprise, or at least one L5, at least one L6, at least one L7, and at least one L8independently comprise or together comprise, a structure selected from among:wherein each n is, independently, from 1 to 20 (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and p is from 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6).A1278.70032WO00 90 12280650.2

[0352] In certain embodiments, at least one L1, at least one L2, at least one L3, and at least one L4independently comprise or together comprise, or at least one L5, at least one L6, at least one L7, and at least one L8independently comprise or together comprise, the structure selected from among:, wherein each n is, independently, from 1 to 20.

[0353] In certain embodiments, at least one L1, at least one L2, at least one L3, and at least one L4independently comprise or together comprise, or at least one L5, at least one L6, at least one L7,A1278.70032WO00 91 12280650.2and at least one L8independently comprise or together comprise, the structure selected from among:A1278.70032WO00 92 12280650.2, , dependently, from 1 to 20.

[0354] In certain embodiments, at least one L1, at least one L2, at least one L3, and at least one L4independently comprise or together comprise, or at least one L5, at least one L6, at least one L7, and at least one L8independently comprise or together comprise, the structure selected from among:, wherein each L is, independently, a phosphorous linking group; and each n is, independently, from 1 to 20.A1278.70032WO00 93 12280650.2

[0355] In certain embodiments, at least one L1, at least one L2, at least one L3, and at least one L4independently comprise or together comprise, or at least one L5, at least one L6, at least one L7, and at least one L8independently comprise or together comprise, the structure selected from among:A1278.70032WO00 94 12280650.2.

[0356] In certain embodiments, at least one L1, at least one L2, at least one L3, and at least one L4independently comprise or together comprise, or at least one L5, at least one L6, at least one L7, and at least one L8independently comprise or together comprise, the structure selected from among:A1278.70032WO00 95 12280650.2

[0357] In certain embodiments, at least one L1, at least one L2, at least one L3, and at least one L4independently comprise or together comprise, or at least one L5, at least one L6, at least one L7, and at least one L8independently comprise or together comprise, the structure selected from among:A1278.70032WO00 96 12280650.2

[0358] In certain embodiments, at least one L1, at least one L2, at least one L3, and at least one L4independently comprise or together comprise, or at least one L5, at least one L6, at least one L7, and at least one L8independently comprise or together comprise, the structure selected from among:5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).

[0359] In certain embodiments, at least one L1, at least one L2, at least one L3, and at least one L4independently comprise or together comprise, or at least one L5, at least one L6, at least one L7, and at least one L8independently comprise or together comprise, the structure selected from among:

[0361] In certain embodiments, at least one L1, at least one L2, at least one L3, and at least one L4independently comprise or together comprise, or at least one L5, at least one L6, at least one L7, and at least one L8independently comprise or together comprise, the structure selected from among:

[0362] In certain embodiments, at least one L1, at least one L2, at least one L3, and at least one L4independently comprise or together comprise, or at least one L5, at least one L6, at least one L7,A1278.70032WO00 97 12280650.2and at least one L8independently comprise or together comprise, the structure selected from among:

[0363] In certain embodiments, at least one L1, at least one L2, at least one L3, and at least one L4independently comprise or together comprise, or at least one L5, at least one L6, at least one L7, and at least one L8independently comprise or together comprise, the structure selected from among:.

[0364] In certain embodiments, at least one L1, at least one L2, at least one L3, and at least one L4, or at least one L5, at least one L6, at least one L7, and at least one L8independently comprise or together comprise, independently comprise or together have the structure:.

[0365] In certain embodiments, at least one L1, at least one L2, at least one L3, and at least one L4, or at least one L5, at least one L6, at least one L7, and at least one L8independently comprise or together comprise, independently comprise or together have the structure:

[0366] In certain embodiments, at least one L1, at least one L2, at least one L3, and at least one L4independently comprise or together comprise, or at least one L5, at least one L6, at least one L7, and at least one L8independently comprise or together comprise, the structure selected from among:

[0367] In certain embodiments, at least one L1, at least one L2, at least one L3, and at least one L4independently comprise or together comprise, or at least one L5, at least one L6, at least one L7,A1278.70032WO00 98 12280650.2and at least one L8independently comprise or together comprise, the structure selected from among:, wherein each n is independently 0, 1, 2, 3, 4, 5, 6, or 7.

[0368] In some embodiments, each of L1, L2, L3, L4, L5, L6, L7, and L8is independently absent, a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker (e.g., a C1-20 alkyl linker in which any one or more carbon atoms is replaced with a heteroatom, such as N, O, P, or S), or an optionally substituted heteroaryl linker. In some embodiments, at least one instance of L1or L8is an optionally substituted heteroaryl linker. In some embodiments, at least one instance of L1is an optionally substituted unsaturated heteroaryl linker.

[0369] In certain embodiments, at least one instance of L1comprises the structuresome embodiments, at least one instance of L1is an optionally substituted heteroalkyl linker. Incertain embodiments, at least one instance of L1 comprises the structure. Incertain embodiments, at least one instance of L1comprises the structureor –N(CH3) –.

[0370] In some embodiments, at least one instance of L2is an optionally substituted PEG linker. In some embodiments, at least one PEG linker is five PEG units in length. In some embodiments, at least one PEG linker is four PEG units in length. In some embodiments, at least one PEG linker is three PEG units in length. In some embodiments, at least one instance of L2is an optionally substituted alkyl linker. In some embodiments, at least one instance of L2is an optionally substituted C1-20 alkyl linker. In certain embodiments, at least one instance of L2is an optionally substituted C8alkyl linker.

[0371] In some embodiments, at least one instance of L3is an optionally substituted heteroaryl linker. In some embodiments, at least one instance of L3is an optionally substituted partiallyA1278.70032WO00 99 12280650.2unsaturated heteroaryl linker. In certain embodiments, L3comprises the structure

[0372] In some embodiments, at least one instance of L4is an optionally substituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In some embodiments, at least one heteroalkyl linker comprises two substituents joined together to form an optionally substituted carbocyclyl ring. In certain embodiments, atleast one instance of L4 comprises the structure, whereinX is O or S. In certain embodiments, at least one instance of L4comprises the structure

[0373] In some embodiments, at least one L1, at least one L2, at least one L3, and at least one L4together comprise, or at least one L5, at least one L6, at least one L7, and at least one L8independently comprise or together comprise, the structure, wherein X is O or S.

[0374] In some embodiments, at least one L1, at least one L2, at least one L3, and at least one L4together comprise, or at least one L5, at least one L6, at least one L7, and at least one L8independently comprise or together comprise, the structureA1278.70032WO00 100 12280650.2, wherein X is O or S.

[0375] In some embodiments, at least one L1, at least one L2, at least one L3, and at least one L4together comprise, or at least one L5, at least one L6, at least one L7, and at least one L8independently comprise or together comprise, the structure

[0376] In some embodiments, at least one L1, at least one L2, at least one L3, and at least one L4together comprise, or at least one L5, at least one L6, at least one L7, and at least one L8independently comprise or together comprise, the structurewherein X is O or S.A1278.70032WO00 101 12280650.2

[0377] In some embodiments, at least one L1, at least one L2, at least one L3, and at least one L4together comprise, or at least one L5, at least one L6, at least one L7, and at least one L8independently comprise or together comprise, the structurewherein X is O or S.

[0378] In some embodiments, at least one L1, at least one L2, at least one L3, and at least one L4together comprise, or at least one L5, at least one L6, at least one L7, and at least one L8independently comprise or together comprise, the structureO or S.

[0379] In certain embodiments, R is a pharmaceutical agent (e.g., therapeutic, prophylactic, or diagnostic agent). In certain embodiments, the therapeutic, prophylactic, or diagnostic agent is a small molecule, or an oligomeric compound. In certain embodiments, the therapeutic, prophylactic, or diagnostic agent is an oligomeric compound. In certain embodiments, the oligomeric compound comprising a protein, peptide, antibody, oligonucleotide, or combination thereof.

[0380] In certain embodiments, an oligomeric compound is any of those described herein. In certain embodiments, the oligomeric compound is about 10-50 subunits in length. In certain embodiments the oligomeric compound is an oligonucleotide. In certain embodiments, an oligonucleotide is any of those described herein. In certain embodiments, the oligonucleotide is 8A1278.70032WO00 102 12280650.2to 80 linked nucleosides in length, 12-30 linked nucleosides in length, 12-30 linked nucleosides in length, or 15-30 linked nucleosides in length. In certain embodiments, the oligonucleotide is 8 to 11 linked nucleosides in length, 12-20 linked nucleosides in length, 21-30 linked nucleosides in length, 31-50 linked nucleosides in length, 51-70 linked nucleosides in length, or 71-100 linked nucleosides in length. In certain embodiments, the oligonucleotide is a modified oligonucleotide comprising at least one modified internucleoside linkage, at least one modified sugar, and / or at least one modified nucleobase. In certain embodiments, the oligonucleotide is single-stranded. In certain embodiments, the oligonucleotide is double-stranded. In certain embodiments, the oligonucleotide comprises ribonucleic acids (e.g., comprised of ribonucleosides), deoxyribonucleic acids (e.g., comprised of deoxyribonucleosides), or a combination thereof. In certain embodiments, the oligonucleotide is a small interfering RNA (siRNA), a microRNA (miRNA) antagonist, an miRNA mimic, an ADAR recruiting molecule, an ADAR targeting molecule, a guide RNA, an antisense oligonucleotide, a short hairpin RNA (shRNA), or combinations thereof.

[0381] In certain embodiments, a compound comprises or consists of one of the structures:A1278.70032WO00 103 12280650.2or a stereoisomer, tautomer, prodrug, or salt thereof, wherein X is O or S.

[0382] In certain embodiments, a compound comprises or consists of one of the structures:,A1278.70032WO00 104 12280650.2, , or a stereoisomer, tautomer, prodrug, or salt thereof, wherein X is O or S.

[0383] In certain embodiments, there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising or consisting of the structure:A1278.70032WO00 105 12280650.2

[0384] In certain embodiments, there is provided a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising or consisting of the structure:wherein is an oligonucleotide.

[0385] In certain embodiments, a compound comprises one of the structures:,A1278.70032WO00 106 12280650.2or a stereoisomer, tautomer, prodrug, or salt thereof, wherein is an oligonucleotide, and X is O or S.

[0386] In certain embodiments, a compound comprises or consists of one of the structures:Formula (XX-A)A1278.70032WO00 107 12280650.2, Formula (XXI-A), or an acid or salt thereof, wherein is an oligonucleotide, and X- is O- or S-.

[0387] In some embodiments, X is O. In some embodiments, X is S.

[0388] In some embodiments, R is an oligonucleotide. In some embodiments, the oligonucleotide is attached at its 5′ end to at least one instance of L4. In some embodiments, the oligonucleotide is attached at its 3′ end to at least one instance of L4. In some embodiments, the oligonucleotide is attached at its 5′ end to at least one instance of L5. In some embodiments, the oligonucleotide is attached at its 3′ end to at least one instance of L5. In some embodiments, the oligonucleotide is attached at an internal position on the oligonucleotide to at least one instance of L4. In some embodiments the internal position is at an internucleoside linkage. In certain embodiments, the internal position is at a nucleobase or a sugar.A1278.70032WO00 108 12280650.2

[0389] In certain embodiments, the oligonucleotide is a modified oligonucleotide. Oligonucleotides

[0390] In certain embodiments, R is an oligonucleotide. In certain embodiments, is or .

[0391] In certain embodiments, is a sense oligonucleotide strand, and the oligonucleotide further comprises an antisense oligonucleotide strand.

[0392] In certain embodiments, is an antisense oligonucleotide strand, and the oligonucleotide further comprises a sense oligonucleotide strand. In certain embodiments, an oligonucleotide has a nucleobase sequence that is at least partially complementary to a target nucleic acid sequence (e.g., an expressed target nucleic acid within a cell). In some embodiments, the oligonucleotide, upon delivery to a cell expressing a target nucleic acid, is able to inhibit the expression of the underlying gene. The gene expression can be inhibited in vitro or in vivo. In certain embodiments, an oligonucleotide comprises one or more ribonucleic acids (e.g., one or more ribonucleosides), deoxyribonucleic acids (e.g., one or more deoxyribonucleosides), modified nucleic acids (e.g., one or more modified nucleobases, sugars, and / or phosphate groups), or a combination thereof. In some embodiments, an oligonucleotide comprises a ribonucleic acid (RNA). In some embodiments, an oligonucleotide comprises a deoxyribonucleic acid (DNA). In some embodiments, an oligonucleotide comprises a modification (e.g., modified nucleobase, modified sugar, or modified phosphate).

[0393] In certain embodiments, an oligonucleotide is single-stranded. In some embodiments, a single-stranded oligonucleotide is single-stranded RNA (ssRNA), ssDNA, or a ssRNA / DNA hybrid (e.g., a single-stranded oligonucleotide comprised of both ribonucleosides (modified or unmodified) and deoxyribonucleosides (modified or unmodified)). In some embodiments, an oligonucleotide is double-stranded (e.g., comprised of two single-stranded nucleic acids). Such double-stranded oligonucleotides comprise a first oligonucleotide having a region complementary to a target nucleic acid and a second oligonucleotide having a region complementary to the first oligonucleotide. The first and second oligonucleotides can be independently modified. In certain embodiments the first oligonucleotide is linked to one or more mannose ligands. In certain embodiments, the second oligonucleotide is linked to one or more mannose ligands.

[0394] In some embodiments, an oligonucleotide is at least 2 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,A1278.70032WO00 109 12280650.264, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, or more) nucleotides in length. In some embodiments, an oligonucleotide is at least 5 nucleotides in length. In some embodiments, an oligonucleotide is at least 10 nucleotides in length. In some embodiments, an oligonucleotide is at least 15 nucleotides in length. In some embodiments, an oligonucleotide is at least 16 nucleotides in length. In some embodiments, an oligonucleotide is at least 17 nucleotides in length. In some embodiments, an oligonucleotide is at least 18 nucleotides in length. In some embodiments, an oligonucleotide is at least 19 nucleotides in length. In some embodiments, an oligonucleotide is at least 20 nucleotides in length. In some embodiments, an oligonucleotide is at least 21 nucleotides in length. In some embodiments, an oligonucleotide is at least 22 nucleotides in length. In some embodiments, an oligonucleotide is at least 23 nucleotides in length. In some embodiments, an oligonucleotide is at least 24 nucleotides in length. In some embodiments, an oligonucleotide is at least 25 nucleotides in length. In some embodiments, an oligonucleotide is at least 26 nucleotides in length. In some embodiments, an oligonucleotide is at least 27 nucleotides in length. In some embodiments, an oligonucleotide is at least 28 nucleotides in length. In some embodiments, an oligonucleotide is at least 29 nucleotides in length. In some embodiments, an oligonucleotide is at least 30 nucleotides in length. In some embodiments, an oligonucleotide is at least 40 nucleotides in length. In some embodiments, an oligonucleotide is at least 50 nucleotides in length. In some embodiments, an oligonucleotide is at least 60 nucleotides in length. In some embodiments, an oligonucleotide is at least 70 nucleotides in length. In some embodiments, an oligonucleotide is at least 80 nucleotides in length. In some embodiments, an oligonucleotide is at least 90 nucleotides in length. In some embodiments, an oligonucleotide is at least 100 nucleotides in length. In some embodiments, an oligonucleotide is at least 150 nucleotides in length.

[0395] In some embodiments, an oligonucleotide is less than or equal to 150 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150) nucleotides in length. In some embodiments, an oligonucleotide is less thanA1278.70032WO00 110 12280650.2or equal to 150 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 100 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 90 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 80 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 70 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 60 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 50 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 40 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 30 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 29 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 28 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 27 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 26 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 25 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 24 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 23 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 22 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 21 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 20 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 19 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 18 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 17 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 16 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 15 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 10 nucleotides in length. In some embodiments, an oligonucleotide is less than or equal to 5 nucleotides in length.

[0396] In some embodiments, an oligonucleotide is about 5 nucleotides in length to about 150 nucleotides in length. In some embodiments, an oligonucleotide is about 10 nucleotides in length to about 100 nucleotides in length. In some embodiments, an oligonucleotide is about 20 nucleotides in length to about 90 nucleotides in length. In some embodiments, an oligonucleotide is about 30 nucleotides in length to about 80 nucleotides in length. In some embodiments, an oligonucleotide is about 40 nucleotides in length to about 70 nucleotides in length. In some embodiments, an oligonucleotide is about 50 nucleotides in length to about 60 nucleotides in length.A1278.70032WO00 111 12280650.2

[0397] In some embodiments, an oligonucleotide is a therapeutic oligonucleotide. A therapeutic oligonucleotide may comprise, for example, without limitation, a small interfering RNA (siRNA), a microRNA (miRNA) antagonist, a miRNA mimic, an ADAR recruiting molecule, an ADAR targeting molecule, a guide RNA, an antisense oligonucleotide, a short hairpin RNA (shRNA), or combinations thereof.

[0398] In certain embodiments, a miRNA is a precursor, primary, and / or mature miRNA.

[0399] In certain embodiments, an oligonucleotide comprises or consists of an antisense oligonucleotide. In certain embodiments, an antisense oligonucleotide is complementary to an mRNA. In certain embodiments, an antisense oligonucleotide is complementary to a pre-mRNA. In certain embodiments, an antisense oligonucleotide blocks translation and promotes degradation of the mRNA transcript. In certain embodiments, an antisense oligonucleotide recruits RNase H and promotes degradation of the mRNA transcript. In certain embodiments, an antisense oligonucleotide targets miRNA, inhibiting the miRNA from modulating mRNA expression and promoting degradation of the miRNA. Certain Oligonucleotide Modifications

[0400] In certain aspects, the disclosure relates to compounds that comprise oligonucleotides. In certain embodiments, oligonucleotides may be unmodified RNA, unmodified DNA modified RNA, or modified DNA. In certain embodiments, the oligonucleotides are modified oligonucleotides. In certain embodiments, the modified oligonucleotides comprise at least one modified sugar, modified nucleobase, and / or modified internucleoside linkage relative to an unmodified RNA or DNA. In certain embodiments, an oligonucleotide has a modified nucleoside. A modified nucleoside may comprise a modified sugar, a modified nucleobase, or both a modified sugar and a modified nucleobase. Modified oligonucleotides may also include end modifications, e.g., 5′-end modifications and 3′-end modifications. Sugar Modifications and Motifs

[0401] 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.

[0402] 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.A1278.70032WO00 112 12280650.2

[0403] In certain embodiments, substituents at the 2′ position include, but are not limited to, F and OCH3 (“OMe”, “O-methyl” or “methoxy”). In certain embodiments, substituent groups at the 2′ position suitable for non-bicyclic modified sugars include, but are not limited to, halo, allyl, amino, azido, SH, CN, OCN, CF3, OCF3, F, Cl, Br, SCH3, SOCH3, SO2CH3, ΟΝΟ2, ΝΟ2, Ν3, and ΝΗ2. In certain embodiments, substituent groups at the 2′ position include, but are not limited to, O-(C1-C10) alkoxy, alkoxyalkyl, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N- alkenyl, O-alkynyl, S-alkynyl, N-alkynyl, O-alkyl-O-alkyl, alkynyl, wherein the alkyl, alkenyl and alkynyl can be substituted or unsubstituted C1 to C10 alkyl or C2 to C10 alkenyl and alkynyl. In certain embodiments, substituent groups at the 2′ position include, but are not limited to, alkaryl, aralkyl, O-alkaryl, and O-aralkyl. In certain embodiments, these 2′ substituent groups can be further substituted with one or more substituent groups independently selected from hydroxyl, alkoxy, carboxy, benzyl, phenyl, nitro (ΝΟ2), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, substituent groups at the 2′ position include, but are not limited to, O[(CH2)nO]mCH3, O(CH2)nOCH3, O(CH2)nCH3, O(CH2)nONH2, O(CH2)nNH2, O(CH2)nSCH3, and O(CH2)nON[(CH2)nCH3)]2, where n and m are independently from 1 to about 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”).

[0404] 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 (e.g., the 4'-modified nucleosides) described in Manoharan et al., WO 2015 / 106128.

[0405] In certain embodiments, substituent groups at the 5′ position suitable for non-bicyclic modified sugars include, but are not limited to, methyl (“Me” or “CH3”) (R or S), vinyl, and methoxy. In certain embodiments, the 5′ modification is a 5′-monophosphate ((HO)2(O)P-O-5′); 5′-diphosphate ((HO)2(O)P-O-P(HO)(O)-O-5′); 5′-triphosphate ((HO)2(O)P-O-(HO)(O)P-O- P(HO)(O)-O-5′); 5′-guanosine cap (7-methylated or non-methylated) (7m-G-O-5′-(HO)(O)P-O- (HO)(O)P-O-P(HO)(O)-O-5′); 5′adenosine cap (Appp), and any modified or unmodified nucleotide cap structure (N-O-5′(HO)(O)P-O-(HO)(O)P-O-P(HO)(O)-O-5′); 5′- monothiophosphate (phosphorothioate; (HO)2(S)P-O-5′); 5′-monodithiophosphate (phosphorodithioate; (HO)(HS)(S)P-O-5′), 5′phosphorothiolate ((HO)2(O)P-S-5′); any additional combination of oxygen / sulfur replaced monophosphate, diphosphate and triphosphates (e.g., 5′- alpha-thiotriphosphate, 5′-gammathiotriphosphate, etc.), 5′-phosphoramidates ((HO)2(O)P-NH- 5′, (HO)(NH2)(O)P-O-5′), 5′alkylphosphonates (R=alkyl=methyl, ethyl, isopropyl, propyl, etc., e.g. RP(OH)(O)-O-5′-, 5′alkenylphosphonates (i.e., vinyl, substituted vinyl), (OH)2(O)P-5′-CH2- ), 5′alkyletherphosphonates (R=alkylether=methoxymethyl (MeOCH2-), ethoxymethyl, etc., e.g.,A1278.70032WO00 113 12280650.2RP(OH)(O)-O-5′-). In certain embodiments, one or more sugars comprise a 5′-vinylphosphonate modification. In certain embodiments the 5′ modification is at the terminus of an oligonucleotide. In certain embodiments the 5′ modification is at the terminus of an antisense oligonucleotide.

[0406] In certain embodiments, substituents described herein for the 2′, 4′, and 5′ position can be added to other specific positions on the sugar. In certain embodiments, such substituents may be added to the 3′ position of the sugar on the 3′ terminal nucleoside or the 5′ position of the 5′ terminal nucleoside. In certain embodiments, a non-bicyclic modified sugar may comprise more than one non-bridging sugar substituent. In certain such embodiments, non-bicyclic modified sugars 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 and Rajeev et al., US2013 / 0203836.

[0407] In certain embodiments, a modified sugar is a bicyclic sugar. A bicyclic sugar is a modified sugar comprising two rings, wherein the second ring is formed via a bridge connecting two of the atoms in the first ring, thereby forming a bicyclic structure. In certain embodiments, a bicyclic sugar comprises a bridging substituent that bridges two atoms of the furanosyl ring to form a second ring. In certain embodiments, a bicyclic sugar does not comprise a furanosyl moiety. A “bicyclic nucleoside” (“BNA”) is a nucleoside having a bicyclic sugar. In certain embodiments, the bicyclic sugar comprises a bridge between the 4′ and 2′ furanose ring atoms. In certain embodiments, the bicyclic sugar comprises a bridge between the 5′ and 3′ furanose ring atoms. In certain such embodiments, the furanose ring is a ribose ring. In certain embodiments, 4′ to 2′ bridging substituents include, but are not limited to, 4′-CH2-2′, 4′-(CH2)2-2′, 4′- (CH2)3-2′, 4′-CH2-O-2′ (“LNA”), 4′-CH2-S-2′, 4′-(CH2)2-O-2′ (“ENA”), 4′-CH(CH3)-O-2′ (“constrained ethyl” or “cEt” when in the S configuration), 4′-CH2-O-CH2-2′, 4′-CH2-N(R)-2′, 4′- CH(CH2OCH3)-O-2′ (“constrained MOE” or “cMOE”) and analogs thereof (e.g., U.S. Patent No. 7,399,845), 4′-C(CH3)(CH3)-O-2′ and analogs thereof (e.g., U.S. Patent No.8,278,283), 4′-CH2- N(OCH3)-2′ and analogs thereof (e.g., U.S. Patent No.8,278,425), 4′-CH2-O-N(CH3)-2′ (e.g., U.S. Patent Publication No.2004 / 0171570), 4′-CH2-N(R)-O-2′, wherein R is Η, C1-C12alkyl, 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). The entire contents of each of the foregoing are hereby incorporated herein by reference. Additional representative U.S. Patents and U.S. Patent Publications that teach the preparation of bicyclic nucleic acid nucleotides include, but are not limited to, the following: U.S. Patent Nos.6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 6,998,484; 7,053,207; 7,034,133;7,084,125; 7,399,845; 7,427,672; 7,569,686; 7,741,457; 8,022,193; 8,030,467; 8,278,425; 8,278,426; 8,278,283; US 2008 / 0039618; and US 2009 / 0012281, USA1278.70032WO00 114 12280650.22013 / 0190383; and WO 2013 / 036868, the entire contents of each of which are hereby incorporated herein by reference. Any of the foregoing bicyclic nucleosides can be prepared having one or more stereochemical sugar configurations including, for example, α-L- ribofuranose and β-D-ribofuranose (see, e.g., WO 99 / 14226). Specified bicyclic nucleosides herein are in the β-D configuration, unless otherwise specified.

[0408] In certain embodiments, a modified sugar is a sugar surrogate. In certain embodiments, a sugar surrogate has the oxygen atom replaced, e.g., with a sulfur, carbon or nitrogen atom. In certain such embodiments, the sugar surrogate may also comprise bridging and / or non-bridging substituents as described herein. In certain embodiments, sugar surrogates comprise rings having other than 5 atoms. In certain such embodiments, the sugar surrogate comprises a cyclobutyl moiety in place of the pentofuranosyl sugar. In certain embodiments, the sugar surrogate comprises a six membered ring in place of the pentofuranosyl sugar. In certain embodiments, the sugar surrogate comprises a tetrahydropyran (“THP”) in place of the pentofuranosyl sugar. In certain embodiments, the sugar surrogate comprises a morpholino in place of the pentofuranosyl sugar. Representative U.S. Patent Nos that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Patent Nos.4,981,957; 5,118,800; 5,166,315; 5,185,444; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; 5,700,920; 7,875,733; 7,939,677, 8,088,904; 8,440,803; and 9,005,906, the entire contents of each of the foregoing are hereby incorporated herein by reference.

[0409] In some embodiments, sugar surrogates comprise acyclic moieties. In certain embodiments, the sugar surrogate is an unlocked nucleic acid (“UNA”). A UNA is unlocked acyclic nucleic acid, wherein any of the bonds of the sugar has been removed, forming an unlocked "sugar" residue. In one example, UNA also encompasses a monomer where the bonds between C1′-C4′ have been removed (i.e., the covalent carbon-oxygen-carbon bond between the C1′ and C4′ carbons). In another example, the C2′-C3′ bond (i.e., the covalent carbon-carbon bond between the C2′ and C3′ carbons) of the sugar has been removed. Representative U.S. publications that teach the preparation of UNA include, but are not limited to, U.S. Patent No. 8,314,227; and U.S. Patent Publication Nos.2013 / 0096289; 2013 / 0011922; and 2011 / 0313020, the entire contents of each of which are hereby incorporated herein by reference. 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., US2013 / 130378, the entire contents of which is hereby incorporated herein by reference. Many other bicyclic and tricyclic sugar and sugar surrogate ring systems are known in the art that can be used in modified nucleosides.A1278.70032WO00 115 12280650.2

[0410] In certain aspects, the disclosure relates to compounds comprising at least one oligonucleotide wherein the nucleosides of such oligonucleotide comprise one or more types of modified sugars and / or unmodified sugars arranged along the oligonucleotide or region 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.

[0411] In certain embodiments, an oligonucleotide comprises a gapmer sugar motif. A gapmer oligonucleotide comprises or consists of a region having two external “wing” regions and a central or internal “gap” region. The gap and wing regions form a contiguous sequence of nucleosides, wherein the majority of nucleoside sugars of each of the wings differ from the majority of nucleoside sugars of the gap. In certain embodiments, the wing regions comprise a majority of modified sugars and the gap comprises a majority of unmodified sugars. In certain embodiments, the nucleosides of the gap are deoxynucleosides. Compounds with a gapmer sugar motif are described in, for example, U.S. Patent No.8,790,919, the entire contents of which is hereby incorporated herein by reference.

[0412] In certain embodiments, one or both oligonucleotides of a double-stranded compound comprise a triplet sugar motif. An oligonucleotide 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. In certain embodiments, an oligonucleotide of a double-stranded compound 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. Compounds with a triplet sugar motif are disclosed, for example, in U.S. Patent No.10,668,170, the entire contents of which is incorporated herein by reference.

[0413] In certain embodiments, one or both oligonucleotides of a double-stranded compound comprise a quadruplet sugar motif. An oligonucleotide 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, an oligonucleotide of a double- stranded compound 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 compound having a duplex region of 19-23 nucleotides in length, the cleavage site of the antisense oligonucleotide 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, 11 positions; the 9, 10, 11, 12 positions; the 10, 11, 12, 13 positions; the 11, 12, 13, 14 positions; or the 12, 13, 14, 15 positions of the sense oligonucleotide, counting from the first nucleoside of the 5′-end of the sense oligonucleotide, or, the count starting from the first paired nucleotide within the duplex region from the 5′-end of the sense oligonucleotide. In certain embodiments, the quadruplet sugarA1278.70032WO00 116 12280650.2motif is at the 8, 9, 10, 11 positions; the 9, 10, 11, 12 positions; the 10, 11, 12, 13 positions; the 11, 12, 13, 14 positions; or the 12, 13, 14, 15 positions of the antisense oligonucleotide, counting from the first nucleoside of the 5′-end of the antisense oligonucleotide, or, the count starting from the first paired nucleotide within the duplex region from the 5′- end of the antisense oligonucleotide. The cleavage site may change according to the length of the duplex region of the double-stranded compound and may change the position of the quadruplet accordingly.

[0414] In certain embodiments, an oligonucleotide comprises an alternating sugar motif. In certain embodiments, one or both oligonucleotides of a double-stranded compound comprise an alternating sugar motif. An oligonucleotide with an alternating sugar motif comprises at least two different sugar modifications, wherein one or more consecutive nucleosides comprising a first sugar modification alternates with one or more consecutive nucleosides comprising a second sugar modification, and one or more consecutive nucleosides comprising a third sugar modification, etc. For example, if A, Β, and C each represent one type of modification to the nucleoside, the alternating motif can be “ABABABABABAB...,” “AABBAABBAABB...,” “AABAABAABAAB “AAABAAABAAAB...,” “AAABBBAAABBB...,” or “ABCABCABCABC...” etc. In certain embodiments, the alternating sugar motif is repeated for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 contiguous nucleobases along an oligonucleotide. 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.

[0415] In certain embodiments, each nucleoside of an oligonucleotide is independently modified with one or more sugar modifications provided herein. In certain embodiments, each oligonucleotide of a double-stranded compound independently has one or more sugar motifs provided herein. In certain embodiments, an oligonucleotide containing a sugar motif is fully modified in that each nucleoside other than the nucleosides comprising the sugar motif comprises a sugar modification.

[0416] In certain embodiments, a modified sugar is 2′-fluoro-2′-deoxyribose, 2′-O-methylribose, 2′-thioribose, 2′,3′-dideoxyribose, 2′-amino-2′-deoxyribose, 2′ deoxyribose, 2′-azido-2′- deoxyribose, 2′-O-methyldeoxyribose, 3′-amino-2′,3′-dideoxyribose, 3′-azido-2′,3′- dideoxyribose, 3′-deoxyribose, 3′-O-(2-nitrobenzyl)-2′-deoxyribose, 3′-O-methylribose, 5′- aminoribose, 5′-thioribose, 5-nitro-1-indolyl-2′-deoxyribose, 5′-biotin-ribose, 2′-O,4′-C-amino- linked ribose, 2′-O,4′-C-thio-linked ribose, 2′-O-methoxyethyl ribose, 2′-O,4′-C-methylene- linked ribose, 2′-O,4′-C-ethylene-linked ribose, 2′,4′-constrained ethyl ribose, locked sugar, or a bicyclic sugar.A1278.70032WO00 117 12280650.2

[0417] In certain embodiments, a modified sugar is present at the 3′-end of the oligonucleotide. In certain embodiments, a modified sugar is present within 3 nucleosides the 3′-end of the oligonucleotide. In certain embodiments, a modified sugar is present at the 5′-end of the oligonucleotide. In certain embodiments, a modified sugar is present within 3 nucleosides of the 5′-end of the oligonucleotide. In certain embodiments, a modified sugar is present at an internal position on an oligonucleotide. In certain embodiments, a modified sugar is present more than 3 nucleosides from the 3′-end of the oligonucleotide. In certain embodiments, a modified sugar is present more than 3 nucleosides from the 5′-end of the oligonucleotide. 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. In certain embodiments, the block is within 3 nucleosides of the 3′-end of the oligonucleotide. In certain embodiments, the block is at the 5′- end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides of the 5′- end of the oligonucleotide. In certain embodiments, the block is at an internal position in the oligonucleotide. In certain embodiments, the block is more than 3 nucleosides from the 3′-end of the oligonucleotide. In certain embodiments, the block is more than 3 nucleosides from the 5′-end of the oligonucleotide. In certain embodiments, the oligonucleotide described in this paragraph refers to a strand of the oligonucleotide.

[0418] 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. Nucleobase Modifications and Motifs

[0419] In certain embodiments, modified oligonucleotides comprise one or more nucleosides comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleosides that do not comprise a nucleobase, referred to as an abasic nucleoside.

[0420] In certain embodiments, modified nucleobases are selected from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and Ν-2, N-6 and O-6 substituted purines. In certain embodiments, modified nucleobases are selected from: 2-aminopropyladenine, 5- hydroxymethyl cytosine, 5- methylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N- methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (C≡C-CH3) uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl, 8-aza and other 8- substituted purines, 5-halo, particularly, 5-bromo, 5-trifluoromethyl, 5-halouracil, and 5-A1278.70032WO00 118 12280650.2halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-Ν-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-Ν-benzoylcytosine, 5-methyl 4-N- benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size expanded bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as 1,3- diazaphenoxazine-2-one, 1,3-diazaphenothiazine-2-one, and 9-(2-aminoethoxy)-1,3- diazaphenoxazine-2-one (G-clamp). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example, 7-deaza-adenine, 7- deazaguanosine, 2-aminopyridine and 2-pyridone.

[0421] Further nucleobases include those disclosed in U.S. Patent No.3,687,808; Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, Ρ. ed. Wiley-VCH, 2008; The Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859; Kroschwitz, J.L., Ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, Y.S., Chapter 15, dsRNA Research and Applications, pages 289-302; Antisense Research and Applications, Crooke, S.T. and Lebleu, Β., Eds., CRC Press, 1993, 273-288; Antisense Drug Technology, Crooke S.T., Ed., CRC Press, 2008, 163-166 and 442-443 (Chapters 6 and 15), each of which are hereby incorporated herein by reference.

[0422] 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 Publication Nos.2003 / 0158403 and 2003 / 0175906; U.S. Patents Nos.4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,434,257; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121; 5,596,091; 5,614,617; 5,645,985; 5,681,941; 5,811,534; 5,750,692; 5,948,903; 5,587,470; 5,457,191; 5,763,588; 5,830,653; 5,808,027; 6,005,096.6,015,886; 6,147,200; 6,166,197; 6,166,199; 6,222,025; 6,235,887; 6,380,368; 6,528,640; 6,639,062; 6,617,438; 7,045,610; 7,427,672; and 7,495,088, the entire contents of each of which are hereby incorporated herein by reference.

[0423] In certain embodiments, oligonucleotides comprise modified and / or unmodified nucleobases arranged along 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 are 5-methylcytosines.A1278.70032WO00 119 12280650.2

[0424] In certain embodiments, modified oligonucleotides comprise a block of modified nucleobases. In certain such embodiments, the block is at the 3′-end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides of the 3′-end of the oligonucleotide. In certain embodiments, the block is at the 5′-end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides of the 5′-end of the oligonucleotide.

[0425] In certain embodiments, a modified nucleobase is present at the 3′-end of the oligonucleotide. In certain embodiments, a modified nucleobase is present within 3 nucleosides of the 3′-end of the oligonucleotide. In certain embodiments, a modified nucleobase is present at the 5′-end of the oligonucleotide. In certain embodiments, a modified nucleobase is present within 3 nucleosides of the 5′-end of the oligonucleotide. In certain embodiments, a modified nucleobase is present at an internal position on an oligonucleotide. In certain embodiments, a modified nucleobase is present more than 3 nucleosides from the 3′-end of the oligonucleotide. In certain embodiments, a modified nucleobase is present more than 3 nucleosides from the 5′-end of the oligonucleotide. In certain embodiments, modified oligonucleotides comprise a block of modified nucleobases. In certain such embodiments, the block is at the 3′-end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides of the 3′-end of the oligonucleotide. In certain embodiments, the block is at the 5′-end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides of the 5′-end of the oligonucleotide. In certain embodiments, the block is at an internal position in the oligonucleotide. In certain embodiments, the block is more than 3 nucleosides from the 3′-end of the oligonucleotide. In certain embodiments, the block is more than 3 nucleosides from the 5′-end of the oligonucleotide. In certain embodiments, the oligonucleotide described in this paragraph refers to a strand of the oligonucleotide. Internucleoside Linkage Modifications and Motifs

[0426] A 3′ to 5′ phosphodiester linkage is the naturally occurring internucleoside linkage of RNA and DNA. In certain embodiments, an oligonucleotide has one or more modified, i.e., non- naturally occurring, internucleoside linkages. Certain non-naturally occurring internucleoside linkages may impart desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases. Representative phosphorus-containing modified internucleoside linkages include, but are not limited to, phosphotriesters, alkylphosphonates (e.g., methylphosphonates), phosphoramidates, and phosphorothioates (“P=S”), and phosphorodithioates (“HS-P=S”). Representative non- phosphorus containing internucleoside linking groups include, but are not limited to, methylenemethylimino (-CH2-N(CH3)-O-CH2), thiodiester, thionocarbamate (-O-C(=O)(NH)-S-A1278.70032WO00 120 12280650.2); siloxane (-O-SiH2-O-); and N,N′-dimethylhydrazine (-CH2-Ν((CΗ3)-Ν((CΗ3)-). Methods of preparation of phosphorous-containing and non-phosphorous-containing internucleoside linkages are well known to those skilled in the art. Neutral internucleoside linkages include, without limitation, phosphotriesters, methylphosphonates, MMI (3′-CH2-N(CH3)-O-5′), amide-3 (3′-CH2- C(=O)-N(H)-5′), amide-4 (3′-CH2-N(H)-C(=O)-5′), formacetal (3′-O-CH2-O-5′), methoxypropyl, and thioformacetal (3′-S-CH2-O-5′). Further neutral internucleoside linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester and amides (See, for example: Carbohydrate Modifications in Antisense Research; Y.S. Sanghvi and P.D. Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Further neutral internucleoside linkages include nonionic linkages comprising mixed Ν, O, S and CH2component parts.

[0427] In certain embodiments, an oligonucleotide comprises at least one modified internucleoside linkage. A modified internucleoside linkage may be placed at any position of an oligonucleotide. For double-stranded compounds, a modified internucleoside linkage may be placed within the sense oligonucleotide, antisense oligonucleotide, or both oligonucleotides of the double-stranded compound.

[0428] In certain embodiments, the internucleoside linkage modification may occur on every nucleoside of an oligonucleotide. In certain embodiments, internucleoside linkage modifications may occur in an alternating pattern along an oligonucleotide. In certain embodiments, essentially each internucleoside linking group is a phosphate internucleoside linkage (Ρ=O). In certain embodiments, each internucleoside linking group of a modified oligonucleotide is a phosphorothioate (P=S). In certain embodiments, each internucleoside linking group of a modified oligonucleotide is independently selected from a phosphorothioate and phosphate internucleoside linkage. In certain embodiments, the pattern of the internucleoside linkage modification on each oligonucleotide of a double-stranded compound is the same. In certain embodiments, the pattern of the internucleoside linkage modification on each oligonucleotide of a double-stranded compound is different. In certain embodiments, a double-stranded compound comprises 6-8 modified internucleoside linkages. In certain embodiments, the 6-8 modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. In certain embodiments, the sense oligonucleotide comprises at least two modified internucleoside linkages at either or both the 5′-end and the 3′-end. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. In certain embodiments, the antisense oligonucleotide comprises at least two modified internucleoside linkages at either or both the 5′-A1278.70032WO00 121 12280650.2end and the 3′-end. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages.

[0429] In certain embodiments, a double-stranded compound comprises an overhang region. In certain embodiments, a double-stranded compound comprises a phosphorothioate or alkylphosphonate internucleoside linkage modification in the overhang region. In certain embodiments, a double-stranded compound comprises a phosphorothioate or alkylphosphonate internucleotide linkage linking the overhang nucleotide with a paired nucleotide that is next to the overhang nucleotide. For instance, there may be at least two phosphorothioate internucleoside linkages between the terminal three nucleosides, in which two of the three nucleosides are overhang nucleosides, and the third is a paired nucleoside next to the overhang nucleoside. These terminal three nucleosides may be at the 3′-end of the antisense oligonucleotide, the 3′-end of the sense oligonucleotide, the 5′-end of the antisense oligonucleotide, or the 5′-end of the antisense oligonucleotide.

[0430] In certain embodiments, modified oligonucleotides comprise one or more internucleoside linkages having chiral centers. Representative chiral internucleoside linkages include, but are not limited to, alkylphosphonates and phosphorothioates. Modified oligonucleotides comprising internucleoside linkages having chiral centers can be prepared as populations of modified oligonucleotides comprising stereorandom internucleoside linkages, or as populations of modified oligonucleotides comprising phosphorothioate linkages in particular stereochemical configurations. In certain embodiments, populations of modified oligonucleotides comprise phosphorothioate internucleoside linkages wherein all of the phosphorothioate internucleoside linkages are stereorandom. Such modified oligonucleotides 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 molecule has a defined stereoconfiguration. In certain embodiments, populations of modified oligonucleotides are enriched for modified oligonucleotides comprising one or more particular phosphorothioate internucleoside linkages in a particular, independently selected stereochemical configuration. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 65% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 70% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 80% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 90% of the molecules in the population. In certain embodiments, the particular configuration of the particularA1278.70032WO00 122 12280650.2phosphorothioate linkage is present in at least 99% of the molecules in the population. Such enriched populations of modified oligonucleotides 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 oligonucleotides is enriched for modified oligonucleotides having at least one indicated phosphorothioate in the (Sp) configuration. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration.

[0431] In certain embodiments, a modified internucleoside linkage is present at the 3′-end of the oligonucleotide. In certain embodiments, a modified internucleoside linkage is present within 3 nucleosides of the 3′-end of the oligonucleotide. In certain embodiments, a modified internucleoside linkage is present at the 5′-end of the oligonucleotide. In certain embodiments, a modified internucleoside linkage is present within 3 nucleosides of the 5′-end of the oligonucleotide. In certain embodiments, a modified internucleoside linkage is present at an internal position on an oligonucleotide. In certain embodiments, a modified internucleoside linkage is present more than 3 nucleosides from the 3′-end of the oligonucleotide. In certain embodiments, a modified internucleoside linkage is present more than 3 nucleosides from the 5′- end of the oligonucleotide. In certain embodiments, modified oligonucleotides comprise a block of modified internucleoside linkages. In certain such embodiments, the block is at the 3′-end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides of the 3′-end of the oligonucleotide. In certain embodiments, the block is at the 5′-end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides of the 5′-end of the oligonucleotide. In certain embodiments, the block is at an internal position in the oligonucleotide. In certain embodiments, the block is more than 3 nucleosides from the 3′-end of the oligonucleotide. In certain embodiments, the block is more than 3 nucleosides from the 5′-end of the oligonucleotide. In certain embodiments, a modified internucleosidic linkage comprises 5′-ethylenephosphonate, phosphorothioate, or an amide. Mannose Receptor

[0432] The mannose receptor (MR) is a type I transmembrane protein of the C-type lectin (CLEC) family. It is known that the mannose receptor is expressed in microglial cells, located in the brain (see for example "Mannose receptor is present in a functional state in rat microglial cells", Marzolo, M et.al., J. Neurosci. Res.1999, 58, 387–395). Microglia constantly survey their microenvironment and rapidly react thereto by changing their morphology, migrating toward stimuli and adopting gene expression profiles characteristic of their activated state. Activation ofA1278.70032WO00 123 12280650.2microglia contributes to neuroinflammation, and thus they are implicated in many pathological conditions, in particular neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, etc.

[0433] The mannose receptor encompasses various extracellular regions, which play an important function in ligand recognition, binding and internalization, including: - C-type lectin domains (CTLDs), responsible for recognition of glycoconjugates, e.g., CTLD4 binds to glycostructures with terminal mannose, fucose or N-Acetylglucosamine (GlcNAc); - an N-terminal cysteine-rich domain, which mediates binding to sulphated sugars including glycosylated hormones, chondroitin sulphate and sulphated LewisXand LewisA, as well as specific proteins attached to sulphated glycostructures, such as CD169 and CD45; and - a fibronectin type II domain, which recognizes collagen and mediates collagen internalization. Since each mannose receptor region has its own binding specificity, ligands can vary substantially in their molecular structure. Mannose Ligands

[0434] The compounds provided herein comprise a mannose ligand (or mannose receptor ligand). In some embodiments, a mannose ligand is useful for directing a pharmaceutical agent (e.g., a therapeutic, prophylactic, or diagnostic agent). In certain embodiments, a therapeutic agent is an oligonucleotide (e.g., a therapeutic oligonucleotide). In some embodiments, a mannose ligand directs an oligonucleotide to a locality. In some embodiments, a mannose ligand targets tissues. In some embodiments, a mannose ligand targets brain tissue. In some embodiments, a mannose ligand targets a cell receptor. In some embodiments, a cell receptor is a mannose receptor. In some embodiments, the cell is a microglial cell. In some embodiments, the cell is a microglial cell is in the brain. In some embodiments, a mannose receptor is in the brain. In some embodiments, a mannose receptor is in the frontal cortex. In some embodiments, a mannose receptor is in the striatum. In some embodiments, a mannose receptor is in the cerebellum. In some embodiments, a mannose receptor is in the brain stem. In some embodiments, a mannose receptor is in the hippocampus. In some embodiments, a mannose receptor is in the spinal cord.

[0435] The use of any mannose ligand in the compounds provided herein is contemplated by the present disclosure. Mannose ligands are known in the art, and a person of ordinary skill in the art would be capable of identifying additional mannose ligands for use in the compounds described herein beyond those explicitly provided by the present disclosure. The present disclosure alsoA1278.70032WO00 124 12280650.2contemplates the use of derivatives of any mannose ligand provided herein or known in the art in the presently described compounds, and a person of ordinary skill in the art would know how to make such derivatives.

[0436] Mannose ligands for use in the present disclosure include, but are not limited to, the following:.

[0437] T is NH, O or S; T1is O, NH, or CH2; –T5--- is –O–, –NH–, –CH= or –CH2–; zero, one, or two of T2R2, T3R3, and T4R4is H; each remaining T2, T3, and T4is O; each of R1, R5, and remaining R2, R3, and R4is independently H, Me, -C(=O)Me, - C(=O)NH2, a second mannose group, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; and the point of attachment replaces one of R1, R2, R3, R4and R5.

[0438] In certain embodiments, zero of T2R2, T3R3, and T4R4is H. In certain embodiments, T2R2is H. In certain embodiments, T3R3is H. In certain embodiments, T4R4is H. In certain embodiments, each of T2R2and T3R3is H. In certain embodiments, each of T2R2and T4R4is H. In certain embodiments, each of T3R3and T4R4is H.

[0439] In certain embodiments, each of R2, R3, R4and R5is independently H, Me, -C(=O)Me, or -C(=O)NH2. In certain embodiments, each of R1, R3, R4and R5is independently H, Me, - C(=O)Me, or -C(=O)NH2. In certain embodiments, each of R1, R2, R4and R5is independently H, Me, -C(=O)Me, or -C(=O)NH2. In certain embodiments, each of R1, R2, R3and R5is independently H, Me, -C(=O)Me, or -C(=O)NH2. In certain embodiments, each of R1, R2, R3and R4is independently H, Me, -C(=O)Me, or -C(=O)NH2.

[0440] In certain embodiments, R2, R3, R4and R5are H. In certain embodiments, R1, R3, R4and R5are H. In certain embodiments, R1, R2, R4and R5are H. In certain embodiments, R1, R2, R3and R5are H. In certain embodiments, R1, R2, R3and R4are H.

[0441] In certain embodiments, R2, R3, R4and R5are Me. In certain embodiments, R1, R3, R4and R5are Me. In certain embodiments, R1, R2, R4and R5are Me. In certain embodiments, R1, R2, R3and R5are Me. In certain embodiments, R1, R2, R3and R4are Me.A1278.70032WO00 125 12280650.2

[0442] In certain embodiments, R2, R3, R4and R5are -C(=O)Me. In certain embodiments, R1, R3, R4and R5are -C(=O)Me. In certain embodiments, R1, R2, R4and R5are -C(=O)Me. In certain embodiments, R1, R2, R3and R5are -C(=O)Me. In certain embodiments, R1, R2, R3and R4are - C(=O)Me.

[0443] In certain embodiments, R2, R3, R4and R5are -C(=O)NH2. In certain embodiments, R1, R3, R4and R5are -C(=O)NH2. In certain embodiments, R1, R2, R4and R5are -C(=O)NH2. In certain embodiments, R1, R2, R3and R5are -C(=O)NH2. In certain embodiments, R1, R2, R3and R4are -C(=O)NH2.

[0444] In certain embodiments, the second mannose group is of the formula:, wherein: TAis NH, O or S; T1Ais O, NH, or CH2; –T5A--- is –O–, –NH–, –CH= or –CH2–; zero, one, or two of T2AR2A, T3AR3A, and T4AR4Ais H; each remaining T2A, T3A, and T4Ais O; each of R1A, R5A, and remaining R2A, R3A, and R4Ais independently H, Me, -C(=O)Me, - C(=O)NH2, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; and the point of attachment replaces one of R1A, R2A, R3A, R4Aand R5A.

[0445] In certain embodiments, the second mannose group is of the formula.

[0446] In certain embodiments, the second mannose group is of the formula.A1278.70032WO00 126 12280650.2

[0447] In certain embodiments, the second mannose group is of the formula .

[0448] In certain embodiments, the second mannose group is of the formula.

[0449] In certain embodiments, the second mannose group is of the formula.

[0450] In certain embodiments, the second mannose group is of the.

[0451] In certain embodiments, the point of attachment replaces R1(e.g.,

[0452] In certain embodiments, the point of attachment replaces R2(e.g.,A1278.70032WO00 127 12280650.2

[0453] In certain embodiments, the point of attachment replaces R3(e.g.,

[0454] In certain embodiments, the point of attachment replaces R4(e.g.,

[0455] In certain embodiments, the point of attachment replaces R5(e.g.,

[0456] In certain embodiments, the mannose ligand is:.

[0457] In certain embodiments, the mannose ligand is:.A1278.70032WO00 128 12280650.2

[0458] In certain embodiments, the mannose ligand is:.

[0459] In certain embodiments, the mannose ligand is:.

[0460] In certain embodiments, the mannose ligand is:.

[0461] Exemplary mannose ligands for use in the present disclosure include, but are not limited to, any of the following, and derivatives thereof:A1278.70032WO00 129 12280650.2, , , .

[0462] In certain embodiments, the mannose ligand is:

[0463] In certain embodiments, the mannose ligand is:.

[0464] In certain embodiments, the mannose ligand is:

[0466] In certain embodiments, the mannose ligand is:, , ,A1278.70032WO00 130 12280650.2

[0467] In certain embodiments, the mannose ligand is:

[0468] In certain embodiments at least one instance of A comprises mannose.

[0469] In some embodiments, more than one mannose ligand is conjugated to an agent moiety. In some embodiments, at least two mannose ligands are conjugated to an agent moiety. In some embodiments, two mannose ligands are conjugated to an agent moiety. In some embodiments, three mannose ligands are conjugated to an agent moiety. In some embodiments, one or two mannose ligands are conjugated to an agent moiety.

[0470] When m is 2 or 3, all instances of L4may be conjugated at the same position or different positions on R.

[0471] In some embodiments, when R is an oligonucleotide, at least one instance of L4is conjugated (e.g., covalently connected) to a 5′ end or a 3′ end of the oligonucleotide, or at an internal position in the oligonucleotide. In some embodiments, when R is an oligonucleotide, at least one instance of L4is conjugated to a 5′ end of the oligonucleotide. In some embodiments, when R is an oligonucleotide, at least one instance of L4is conjugated to a 3′ end of the oligonucleotide. In some embodiments, when R is an oligonucleotide, at least two instance of L4are conjugated to a 5′ end and a 3′ end of the oligonucleotide, respectively. In some embodiments, when R is an oligonucleotide, at least one instance of L4is conjugated to an internal position within the oligonucleotide.

[0472] In certain embodiments, when m is 2 or 3, each two mannose receptor ligands are the same or different from each other.A1278.70032WO00 131 12280650.2TrkB Ligands

[0473] In some embodiments, the compounds provided herein comprise at least one mannose ligand and at least one tropomyosin receptor kinase B (TrkB, also known as tyrosine receptor kinase B) ligand. In some embodiments, at least one TrkB ligand is useful for directing a therapeutic, prophylactic, or diagnostic agent. In certain embodiments, at least one therapeutic agent is an oligonucleotide (e.g., a therapeutic oligonucleotide). In some embodiments, at least one TrkB ligand directs an oligonucleotide to a locality. In some embodiments, at least one TrkB ligand targets tissues. In some embodiments, the tissue is brain tissue. In some embodiments, at least one TrkB ligand targets a cell receptor. In some embodiments, at least one cell receptor is TrkB. In some embodiments, at least one TrkB receptor is in the brain. In some embodiments, at least one TrkB receptor is in the frontal cortex. In some embodiments, at least one TrkB receptor is in the striatum. In some embodiments, at least one TrkB receptor is in the cerebellum. In some embodiments, at least one TrkB receptor is in the brain stem. In some embodiments, at least one TrkB receptor is in the hippocampus. In some embodiments, at least one TrkB receptor is in the spinal cord. In certain embodiments, at least one TrkB ligand is a selective TrkB ligand. In certain embodiments, at least one TrkB ligand is a non-selective TrkB modulator (e.g., a pan TrkABC ligand).

[0474] The use of any TrkB ligand in the compounds provided herein is contemplated by the present disclosure. TrkB ligands are known in the art, and a person of ordinary skill in the art would be capable of identifying additional TrkB ligands for use in the compounds described herein beyond those explicitly provided by the present disclosure. The present disclosure also contemplates the use of derivatives of any TrkB ligand provided herein or known in the art in the presently described compounds, and a person of ordinary skill in the art would know how to make such derivatives.

[0475] In some embodiments, at least one TrkB ligand is a TrkB agonist. In some embodiments, at least one TrkB ligand is a TrkB antagonist.

[0476] In certain embodiments, at least one TrkB ligand comprises a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted carbocyclyl. In certain embodiments, at least one TrkB ligand comprises a substituted or unsubstituted polycyclic aryl, substituted or unsubstituted, polycyclic heteroaryl, substituted or unsubstituted, polycyclic heterocycloalkyl or substituted or unsubstituted, mono- or polycyclic cycloalkyl. In certain embodiments, the polycyclic aryl, polycyclic heteroaryl, polycyclic heterocycloalkyl, or polycyclic cycloalkyl comprises two to four fused rings.

[0477] In certain embodiments, at least one TrkB ligand is of the formula:A1278.70032WO00 132 12280650.2Rq2is hydrogen, -OR7, -SR8, or -NR9R10; Rq3is hydrogen, -OR31, -SR32, or -NR33R34; Rq4is hydrogen, -OR35, -SR36, or -NR37R38; Rq5is hydrogen, -OR39, -SR40, or -NR41R42; Rq6is hydrogen, -OH, optionally substituted -O-alkyl, optionally substituted -OAc, -NH2, optionally substituted -NHAc, -SH, or =O; R7, R8, R9, R10, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, and R42are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; Y is CH2, NH, S, or O;A1278.70032WO00 133 12280650.2Z is optionally substituted aryl or optionally substituted heteroaryl; R11and R13are each independently absent, hydrogen, or optionally substituted alkyl; R12, R14, and R15are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R16is hydrogen, halogen, –CN, –N3, –SOn16R16A, –SOv16NR16BR16C, −NHNR16BR16C, −ONR16BR16C, −NHC(O)NHNR16BR16C, −NHC(O)NR16BR16C, –N(O)m16, –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; and are each 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 is a single bond, then is a double bond and R11is absent; R16A, R16B, R16C, R16Dare each independently hydrogen, halogen, –CF3, –CCl3, –CBr3, – CI3, –COOH, –CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R16Band R16Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R17, R18, and R19are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R20is hydrogen, halogen, –CN, –N3, –SOn20R20A, –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; R21is hydrogen, halogen, –CN, –N3, –SOn21R21A, –SOv21NR21BR21C, −NHNR21BR21C, −ONR21BR21C, −NHC(O)NHNR21BR21C, −NHC(O)NR21BR21C, –N(O)m21, –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,A1278.70032WO00 134 12280650.2optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R22and R23are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R24is hydrogen, halogen, –CN, –N3, –SOn24R24A, –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; R20A, R20B, R20C, R20D, R21A, R21B, R21C, R21D, R24A, R24B, R24C, and R24Dare each independently hydrogen, halogen, –CF3, –CCl3, –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, and R24Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; n16, n20, n21, n24, z6, and z8 are each independently 0, 1, 2, 3, or 4; v16, v20, v21, v24, m16, m20, m21, and m24 are each independently 1 or 2; z3 is 0, 1, 2, 3, 4, or 5; z4 and z7 are each independently 0, 1, or 2; and z5 is 0, 1, 2, or 3.

[0478] In some embodiments, Rq2is hydrogen or -OR7. In certain embodiments, Rq2is hydrogen. In certain embodiments, Rq2is -OR7. In certain embodiments, Rq2is -OH. In certain embodiments, Rq2is -OCH3. In some embodiments, Rq3is hydrogen or -ORq31. In certain embodiments, Rq3is hydrogen. In certain embodiments, Rq3is -ORq31. In certain embodiments, Rq3is -OH. In certain embodiments, Rq3is -OCH3. In some embodiments, Rq4is hydrogen or - ORq35. In certain embodiments, Rq4is hydrogen. In certain embodiments, Rq4is -ORq35. In certain embodiments, Rq4is -OH. In certain embodiments, Rq4is -OCH3. In some embodiments, Rq5is hydrogen or -ORq39. In certain embodiments, Rq5is hydrogen. In certain embodiments, Rq5is - ORq39. In certain embodiments, Rq5is -OH. In certain embodiments, Rq5is -OCH3. In some embodiments, Rq6is hydrogen, -OH, or optionally substituted -O-alkyl. In certain embodiments, Rq6is hydrogen.A1278.70032WO00 135 12280650.2

[0479] 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.

[0480] In some embodiments, Y is NH or O. In certain embodiments, Y is O.

[0481] In some embodiments, Z is optionally substituted aryl. In certain embodiments, Z is optionally substituted phenyl. In certain embodiments, Z is unsubstituted phenyl.

[0482] Exemplary TrkB ligands for use in the present disclosure include, but are not limited to, any of the following TrkB ligands, and derivatives thereof:diosmetin (5,7,3′-trihydroxy-4′- 7-hydroxy-4′- 8-hydroxy-7-eutropoflavin (4′-dimethylamino- norwogonin (5,7,8- 7,8-dihydroxyflavone) trihydroxyflavone) R7A1278.70032WO00 136 12280650.2R13 tropoflavin (7,8- quercetin (3,3′,4′,5,7- dihydroxyflavone) pentahydroxyflavone)apigenin (4′,5,7- isocoumarin gossypetin (3,5,7,8,3′,4′-2-methyl-8-phenylchromeno[7,8- d]imidazol-6( chromene-7,8-diyl d]imidazol-6(3H)-one 3H)-one diacetateN- serotoninLM22A-4 GNF-5837.

[0483] 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-A1278.70032WO00 137 12280650.2dihydroxyflavone), norwogonin (5,7,8-trihydroxyflavone), R7, R13, tropoflavin (7,8- dihydroxyflavone), quercetin (3,3′,4′,5,7-pentahydroxyflavone), apigenin (4′,5,7- trihydroxyflavone), isocoumarin, gossypetin (3,5,7,8,3′,4′-hexahydroxyflavone), 2-methyl-8- phenylchromeno[7,8-d]imidazol-6(3H)-one, 8-phenylchromeno[7,8-d]imidazol-6(3H)-one, 4- oxo-2-phenyl-4H-chromene-7,8-diyl diacetate, ANA-12, an anti-TrkB antibody, or a derivative thereof. In certain embodiments, at least one TrkB ligand is flavone, tropoflavin, or a derivative thereof.

[0484] In some embodiments, at least one TrkB ligand is an aptamer. For example, aptamers that are TrkB agonists are described in Huang, Y. Z. et al. RNA Aptamer-Based Functional Ligands of the Neurotrophin Receptor, TrkB. Mol. Pharmacol.2012, 82(4), 623-635.

[0485] In certain embodiments, at least one TrkB ligand is a flavone, a tropoflavin, or a prodrug or derivative thereof.

[0486] In some embodiments, at least one TrkB ligand comprises the structure:, wherein Rq2is hydrogen, -OH, -O-alkyl, -O-alkenyl, -NH2, or -SH; Rq3is hydrogen, -OH, -O-alkyl, -O-alkenyl, -NH2, or -SH; Rq4is hydrogen, -OH, -O-alkyl, -NH2, or -SH; Rq5is hydrogen, -OH, -O-alkyl, -NH2, or -SH; Rq6is hydrogen, -OH, -O-alkyl, -NH2, -SH, or =O; Y is CH2, NH, S, or O; and Z is optionally substituted aryl or optionally substituted heteroaryl.

[0487] In certain embodiments, at least one instance of –B is:.

[0488] In certain embodiments, at least one instance of –B is:A1278.70032WO0012280650.2or a stereoisomer, tautomer, prodrug or salt thereof, wherein Rq2and Rq3are independently -OH or -OMe.

[0489] In certain embodiments, at least one instance of –B is:

[0490] In certain embodiments, at least one TrkB ligand is ANA-12. In some embodiments, at least one TrkB ligand is an anti-TrkB antibody. In certain embodiments, at least one TrkB ligand is an anti-TrkB antibody fragment, or an anti-TrkB antibody variant. An “anti-TrkB antibody” refers to an immune system protein that recognizes, binds to, or otherwise interacts with a TrkB receptor.

[0491] In certain embodiments, when n is 2 or 3, all instances of L5may be conjugated at the same position or different positions on R.

[0492] In some embodiments, when R is an oligonucleotide, at least one instance of L5is conjugated to a 5′ end or a 3′ end of the oligonucleotide, or at an internal position in the oligonucleotide. In some embodiments, when R is an oligonucleotide, at least one instance of L5A1278.70032WO00 139 12280650.2is conjugated to a 5′ end of the oligonucleotide. In some embodiments, when R is an oligonucleotide, at least one instance of L5is conjugated to a 3′ end of the oligonucleotide. In some embodiments, when R is an oligonucleotide, at least two instances of L5are conjugated to a 5′ end and a 3′ end of the oligonucleotide, respectively. In some embodiments, when R is an oligonucleotide, at least one instance of L5is conjugated to an internal position within the oligonucleotide.

[0493] The term “pharmaceutically acceptable salts” is meant to include salts of the compounds described herein which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present disclosure.

[0494] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0495] In addition to salt forms, the present disclosure provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readilyA1278.70032WO00 140 12280650.2undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0496] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0497] In certain embodiments, an oligonucleotide comprises an oligonucleotide strand having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity or complementarity to a gene (e.g., human gene) with which a disease (e.g., CNS disease) is associated, or a portion thereof (e.g., 10 nucleotides thereof, 11 nucleotides thereof, 12 nucleotides thereof, 13 nucleotides thereof, 14 nucleotides thereof, 15 nucleotides thereof, 16 nucleotides thereof, 17 nucleotides thereof, 18 nucleotides thereof, 19 nucleotides thereof, 20 nucleotides thereof, 21 nucleotides thereof, 22 nucleotides thereof, 23 nucleotides thereof, 24 nucleotides thereof, 25 nucleotides thereof, 26 nucleotides thereof, 27 nucleotides thereof, 28 nucleotides thereof, 29 nucleotides thereof, or 30 nucleotides thereof). In certain embodiment, the oligonucleotide comprises an antisense oligonucleotide. In certain embodiments, the oligonucleotide comprises a sense oligonucleotide. In certain embodiments, the oligonucleotide is a single-stranded oligonucleotide. In certain embodiments, the oligonucleotide is a double- stranded oligonucleotide. In certain embodiments, the disease is associated with the overexpression of the gene. In certain embodiments, “associated with” refers to “caused at least in part by.” Methods of Making Compounds

[0498] In some aspects, the disclosure relates to methods of making the compounds and pharmaceutical compositions disclosed herein.

[0499] Compounds of the present disclosure can be made by means known in the art of organic synthesis. Methods for optimizing reaction conditions, and minimizing competing by-products, if necessary, are known in the art. Reaction optimization and scale-up may advantageously utilize high-speed parallel synthesis equipment and computer-controlled microreactors (e.g., Design and Optimization in Organic Synthesis, 2ndEdition, Carlson R, Ed, 2005; Elsevier Science Ltd.;A1278.70032WO00 141 12280650.2Jähnisch, K et al., Angew. Chem. Int. Ed. Engl.200443: 406; and references therein). Additional reaction schemes and protocols may be determined by the skilled artisan by use of commercially available structure-searchable database software, for instance, SciFinder® (CAS division of the American Chemical Society) and CrossFire Beilstein® (Elsevier MDL), or by appropriate keyword searching using an internet search engine such as Google® or keyword databases such as the U.S. Patent and Trademark Office text database.

[0500] As can be appreciated by the skilled artisan, methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art, including in the schemes and examples herein. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. In addition, the solvents, temperatures, reaction durations, etc. delineated herein are for purposes of illustration only and one of ordinary skill in the art will recognize that variation of the reaction conditions can produce the desired compounds of the present disclosure.

[0501] The compounds herein may also contain linkages (e.g., carbon-carbon bonds) wherein bond rotation is restricted about that particular linkage, e.g., restriction resulting from the presence of a ring or double bond. Accordingly, all cis / trans and E / Z isomers are expressly included in the present disclosure. The compounds herein may also be represented in multiple tautomeric forms; in such instances, the present disclosure expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented. All such isomeric forms of such compounds herein are expressly included in the present disclosure. All crystal forms and polymorphs of the compounds described herein are expressly included in the present disclosure. Also embodied are extracts and fractions comprising compounds of the present disclosure. The term “isomers” is intended to include diastereoisomers, enantiomers, regioisomers, structural isomers, rotational isomers, tautomers, and the like. For compounds which contain one or more stereogenic centers, e.g., chiral compounds, the methods of the present disclosure may be carried out with an enantiomerically enriched compound, a racemate, or a mixture of diastereomers. All isomers of compounds delineated herein are expressly included in the present disclosure.

[0502] Preferred enantiomerically enriched compounds have an enantiomeric excess of 50% or more. In certain embodiments, the compound has an enantiomeric excess of 60%, 70%, 80%, 90%, 95%, 98%, 99%, or more. In preferred embodiments, only one enantiomer or diastereomer of a chiral compound of the present disclosure is administered to cells or a subject.A1278.70032WO00 142 12280650.2Methods of Treatment and Uses

[0503] In one aspect, provided are methods of treating a disease or symptom thereof in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein, wherein R is an oligonucleotide, a small molecule, a protein, an antibody or a peptide.

[0504] In certain embodiments, the subject has been identified as in need of modulation of the function of a protein.

[0505] In one aspect, provided are methods of delivering an oligonucleotide, small molecule, protein, antibody, or peptide to a biological sample, cell, tissue, or subject, comprising contacting the biological sample, cell, tissue with or administering to the subject a compound or pharmaceutical composition described herein, wherein R is an oligonucleotide, a small molecule, a protein, an antibody or a peptide. In certain embodiments, the oligonucleotide, small molecule, protein, antibody, or peptide is delivered to the brain of the subject. In certain embodiments, the oligonucleotide, small molecule, protein, antibody, or peptide is delivered to a cell. In certain embodiments, the cell is a microglia cell. In certain embodiments, the oligonucleotide, small molecule, protein, antibody, or peptide is delivered to a microglial cell. In certain embodiments, the oligonucleotide, small molecule, protein, antibody, or peptide is delivered to microglia cells in the brain. In some embodiments, the oligonucleotide, small molecule, protein, antibody, or peptide is delivered to microglial cells. In some embodiments, the microglial cells are located in the brain. In some embodiments, the oligonucleotide, small molecule, protein, antibody, or peptide is delivered to one or more brain regions selected from the group consisting of the striatum, the cerebellum, the brain stem, the hippocampus, the frontal cortex, and the spinal cord.

[0506] In some embodiments, the disease is associated with MAPT, SOD1, or LRRK2. In some embodiments, the disease is associated with SNCA or APP. In some embodiments, the disease is associated with the overexpression of MAPT, SOD1, or LRRK2. In some embodiments, the disease is associated with the overexpression of SNCA or APP. In some embodiments, the disease is associated with mutations of MAPT, SOD1, or LRRK2. In some embodiments, the disease is associated with mutations of SNCA or APP.

[0507] In certain embodiments, an oligonucleotide comprises an oligonucleotide strand having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity or complementarity to a microtubule-associated protein tau (MAPT) gene (e.g., human MAPT gene), or a portion thereof (e.g., 10 nucleotides thereof, 11 nucleotides thereof, 12 nucleotides thereof, 13 nucleotides thereof, 14 nucleotides thereof, 15 nucleotides thereof, 16 nucleotides thereof, 17 nucleotides thereof, 18 nucleotides thereof, 19 nucleotides thereof, 20 nucleotides thereof, 21 nucleotides thereof, 22 nucleotides thereof, 23 nucleotides thereof, 24 nucleotidesA1278.70032WO00 143 12280650.2thereof, 25 nucleotides thereof, 26 nucleotides thereof, 27 nucleotides thereof, 28 nucleotides thereof, 29 nucleotides thereof, or 30 nucleotides thereof). In certain embodiment, the oligonucleotide comprises an antisense oligonucleotide. In certain embodiments, the oligonucleotide comprises a sense oligonucleotide. In certain embodiments, the oligonucleotide is a single-stranded oligonucleotide. In certain embodiments, the oligonucleotide is a double- stranded oligonucleotide. Exemplary nucleotide sequences of the human MAPT gene can be found, for example, at GenBank Accession No. NM_001377265.1 (incorporated herein as SEQ ID NO: 1), and nucleotides 2624000 to 2761000 of NT_010783.14 (incorporated herein as SEQ ID NO: 2). Additional examples of MAPT sequences are readily available through publicly available databases, e.g., GenBank, UniProt, and OMIM. Further information on MAPT can be found, for example, at www.ncbi.nlm.nih.gov / gene / ?term=MAPT. MAPT, as used herein, also refers to variations of the MAPT gene including variants provided in the SNP database. Numerous sequence variations within the MAPT gene have been identified and may be found at, for example, NCBI dbSNP and UniProt (see, e.g., www.ncbi.nlm.nih.gov / snp / ?term=MAPT). In certain embodiments, the oligonucleotide inhibits the expression, translation, or activity of MAPT in a subject, cell, tissue, or biological sample. In certain embodiments, the oligonucleotide inhibits the expression, translation, or activity of MAPT in a subject, cell, tissue, or biological sample by 3-10%, 10-20%, 20-40%, 40-60%, 60-90%, or 90-99% relative to the expression, translation, or activity in a negative control (e.g., as measured by an immunoassay, a hybridization-based assay, or a sequencing-based assay (e.g., RNA-Seq)).

[0508] In certain embodiments, an oligonucleotide comprises an oligonucleotide strand having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity or complementarity to a superoxide dismutase type 1 (SOD1) gene (e.g., a human SOD1 gene), or a portion thereof (e.g., 10 nucleotides thereof, 11 nucleotides thereof, 12 nucleotides thereof, 13 nucleotides thereof, 14 nucleotides thereof, 15 nucleotides thereof, 16 nucleotides thereof, 17 nucleotides thereof, 18 nucleotides thereof, 19 nucleotides thereof, 20 nucleotides thereof, 21 nucleotides thereof, 22 nucleotides thereof, 23 nucleotides thereof, 24 nucleotides thereof, 25 nucleotides thereof, 26 nucleotides thereof, 27 nucleotides thereof, 28 nucleotides thereof, 29 nucleotides thereof, or 30 nucleotides thereof). In certain embodiment, the oligonucleotide comprises an antisense oligonucleotide. In certain embodiments, the oligonucleotide comprises a sense oligonucleotide. In certain embodiments, the oligonucleotide is a single-stranded oligonucleotide. In certain embodiments, the oligonucleotide is a double-stranded oligonucleotide. Exemplary nucleotide sequences of the human SOD1 gene can be found, for example, at nucleotides 5092 to 138872 of NG_007398.2 (incorporated herein as SEQ ID NO: 3), and GenBank Accession No NM_016835.5 (incorporated herein as SEQ ID NO: 4).A1278.70032WO00 144 12280650.2Additional examples of SOD1 sequences are readily available through publicly available databases, e.g., GenBank, UniProt, and OMIM. Further information on SOD1 can be found, for example, at www.ncbi.nlm.nih.gov / gene / ?term=SOD1. SOD1, as used herein, also refers to variations of the SOD1 gene including variants provided in the SNP database. Numerous sequence variations within the SOD1 gene have been identified and may be found at, for example, NCBI dbSNP and UniProt (see, e.g., www.ncbi.nlm.nih.gov / snp / ?term=SOD1). In certain embodiments, the oligonucleotide inhibits the expression, translation, or activity of SOD1 in a subject, cell, tissue, or biological sample. In certain embodiments, the oligonucleotide inhibits the expression, translation, or activity of SOD1 in a subject, cell, tissue, or biological sample by 3-10%, 10-20%, 20-40%, 40-60%, 60-90%, or 90-99% relative to the expression, translation, or activity in a negative control (e.g., as measured by an immunoassay, a hybridization-based assay, or a sequencing-based assay (e.g., RNA-Seq)).

[0509] In certain embodiments, an oligonucleotide comprises an oligonucleotide strand having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity or complementarity to an leucine-rich repeat kinase 2 (LRRK2) gene (e.g., a human LRRK2 gene), or a portion thereof (e.g., 10 nucleotides thereof, 11 nucleotides thereof, 12 nucleotides thereof, 13 nucleotides thereof, 14 nucleotides thereof, 15 nucleotides thereof, 16 nucleotides thereof, 17 nucleotides thereof, 18 nucleotides thereof, 19 nucleotides thereof, 20 nucleotides thereof, 21 nucleotides thereof, 22 nucleotides thereof, 23 nucleotides thereof, 24 nucleotides thereof, 25 nucleotides thereof, 26 nucleotides thereof, 27 nucleotides thereof, 28 nucleotides thereof, 29 nucleotides thereof, or 30 nucleotides thereof). In certain embodiment, the oligonucleotide comprises an antisense oligonucleotide. In certain embodiments, the oligonucleotide comprises a sense oligonucleotide. In certain embodiments, the oligonucleotide is a single-stranded oligonucleotide. In certain embodiments, the oligonucleotide is a double-stranded oligonucleotide. Exemplary nucleotide sequences of the human LRRK2 gene can be found, for example, at GenBank Accession No. NM_198578.4 (incorporated herein as SEQ ID NO: 5), and nucleotides 5002 to 149290 of NG_011709.2 (incorporated herein as SEQ ID NO: 6). Additional examples of LRRK2 sequences are readily available through publicly available databases, e.g., GenBank, UniProt, and OMIM. Further information on LRRK2 can be found, for example, at www.ncbi.nlm.nih.gov / gene / ?term=LRRK2. LRRK2, as used herein, also refers to variations of the LRRK2 gene including variants provided in the SNP database. Numerous sequence variations within the LRRK2 gene have been identified and may be found at, for example, NCBI dbSNP and UniProt (see, e.g., www.ncbi.nlm.nih.gov / snp / ?term=LRRK2). In certain embodiments, the oligonucleotide inhibits the expression, translation, or activity of LRRK2 in a subject, cell, tissue, or biological sample. In certain embodiments, the oligonucleotide inhibits the expression,A1278.70032WO00 145 12280650.2translation, or activity of LRRK2 in a subject, cell, tissue, or biological sample by 3-10%, 10- 20%, 20-40%, 40-60%, 60-90%, or 90-99% relative to the expression, translation, or activity in a negative control (e.g., as measured by an immunoassay, a hybridization-based assay, or a sequencing-based assay (e.g., RNA-Seq)).

[0510] In certain embodiments, an oligonucleotide comprises an oligonucleotide strand having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity or complementarity to an alpha-synuclein (SNCA) gene (e.g., human SNCA gene), or a portion thereof (e.g., 10 nucleotides thereof, 11 nucleotides thereof, 12 nucleotides thereof, 13 nucleotides thereof, 14 nucleotides thereof, 15 nucleotides thereof, 16 nucleotides thereof, 17 nucleotides thereof, 18 nucleotides thereof, 19 nucleotides thereof, 20 nucleotides thereof, 21 nucleotides thereof, 22 nucleotides thereof, 23 nucleotides thereof, 24 nucleotides thereof, 25 nucleotides thereof, 26 nucleotides thereof, 27 nucleotides thereof, 28 nucleotides thereof, 29 nucleotides thereof, or 30 nucleotides thereof). In certain embodiment, the oligonucleotide comprises an antisense oligonucleotide. In certain embodiments, the oligonucleotide comprises a sense oligonucleotide. In certain embodiments, the oligonucleotide is a single-stranded oligonucleotide. In certain embodiments, the oligonucleotide is a double-stranded oligonucleotide. Exemplary nucleotide sequences of the human SNCA gene can be found, for example, at GenBank Accession No. NM_001375287.1 (incorporated herein as SEQ ID NO: 7). Additional examples of SNCA sequences are readily available through publicly available databases, e.g., GenBank, UniProt, and OMIM, and may include, for instance: NCBI Accession Nos. NM_000345.4, NM_001146054.2, NM_001146055.2, 001375285.1, NM_001375286.1, NM_001375288.1, NM_001375290.1, and NM_007308.3; UniProt Accession Nos. P37840 (e.g., P37840-1, P37840-2, P37840-3), E7EPV7, D6RA31, H6UYS7, A0A669KBH5, and A0A669KB41; and OMIM Accession No.163890. Further information on SNCA can be found, for example, on the world wide web at ncbi.nlm.nih.gov / gene / ?term=SNCA. “SNCA,” as used herein, also refers to variations of the SNCA gene including variants provided in the SNP database. Numerous sequence variations within the SNCA gene have been identified and may be found at, for example, NCBI dbSNP and UniProt (see, e.g., ncbi.nlm.nih.gov / snp / ?term=SNCA). In certain embodiments, the oligonucleotide inhibits the expression, translation, or activity of SNCA in a subject, cell, tissue, or biological sample. In certain embodiments, the oligonucleotide inhibits the expression, translation, or activity of SNCA in a subject, cell, tissue, or biological sample by 3-10%, 10-20%, 20-40%, 40-60%, 60-90%, or 90-99% relative to the expression, translation, or activity in a negative control (e.g., as measured by an immunoassay, a hybridization-based assay, or a sequencing-based assay (e.g., RNA-Seq)).A1278.70032WO00 146 12280650.2

[0511] In certain embodiments, an oligonucleotide comprises an oligonucleotide strand having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity or complementarity to a amyloid precursor protein (APP) gene (e.g., human APP gene), or a portion thereof (e.g., 10 nucleotides thereof, 11 nucleotides thereof, 12 nucleotides thereof, 13 nucleotides thereof, 14 nucleotides thereof, 15 nucleotides thereof, 16 nucleotides thereof, 17 nucleotides thereof, 18 nucleotides thereof, 19 nucleotides thereof, 20 nucleotides thereof, 21 nucleotides thereof, 22 nucleotides thereof, 23 nucleotides thereof, 24 nucleotides thereof, 25 nucleotides thereof, 26 nucleotides thereof, 27 nucleotides thereof, 28 nucleotides thereof, 29 nucleotides thereof, or 30 nucleotides thereof). In certain embodiment, the oligonucleotide comprises an antisense oligonucleotide. In certain embodiments, the oligonucleotide comprises a sense oligonucleotide. In certain embodiments, the oligonucleotide is a single-stranded oligonucleotide. In certain embodiments, the oligonucleotide is a double-stranded oligonucleotide. Exemplary nucleotide sequences of the human APP gene can be found, for example, at GenBank Accession No. NM_000484.4 (incorporated herein as SEQ ID NO: 8). Additional examples of APP sequences are readily available through publicly available databases, e.g., GenBank, UniProt, and OMIM, and may include, for instance: NCBI Accession Nos. NM_201414, NM_001136016.3, NM_001136129.3, NM_001136130.3, and NM_001136131.3; UniProt Accession Nos. P05067; and OMIM Accession No.104760. Further information on APP can be found, for example, on the world wide web at ncbi.nlm.nih.gov / gene / ?term=APP. “APP,” as used herein, also refers to variations of the APP gene including variants provided in the SNP database. Numerous sequence variations within the APP gene have been identified and may be found at, for example, NCBI dbSNP and UniProt (see, e.g., ncbi.nlm.nih.gov / snp / ?term=APP). In certain embodiments, the oligonucleotide inhibits the expression, translation, or activity of APP in a subject, cell, tissue, or biological sample. In certain embodiments, the oligonucleotide inhibits the expression, translation, or activity of APP in a subject, cell, tissue, or biological sample by 3-10%, 10-20%, 20-40%, 40- 60%, 60-90%, or 90-99% relative to the expression, translation, or activity in a negative control (e.g., as measured by an immunoassay, a hybridization-based assay, or a sequencing-based assay (e.g., RNA-Seq)).

[0512] In some embodiments, the disease is a nervous system disease. In some embodiments, the disease is an adult polyglucosan body disease, agnosia, akathisia, Angelman syndrome, autonomic nervous system disease, axial apraxia, Blau syndrome, central nervous system disease, Chediak-Higashi syndrome, chronic nervous system disease, complex regional pain syndrome, complex regional pain syndrome type I, congenital central hypoventilation syndrome, congenital disorder of glycosylation, decerebrate state, demyelination, dizziness, dopa-responsive dystonia,A1278.70032WO00 147 12280650.2dopamine receptor supersensitivity, dysmyelination, dysreflexia, extrapyramidal system disease, Feigenbaum-Bergeron-Richardson syndrome, Flynn-Aird syndrome, GABA withdrawal syndrome, Galloway-Mowat syndrome, ganglion disease, glutathionuria, Griscelli syndrome, hereditary nervous system disease, high-pressure neurological syndrome, Horner syndrome, hypomyelination, incontinentia pigmenti, Johnson neuroectodermal syndrome, Kelley-Seegmiller syndrome, language disorder, Lesch-Nyhan syndrome, Machado-Joseph disease, manganism, Manx syndrome, meningeal disease, Moebius syndrome, motion sickness, motor nervous system disease, motor skill disorder, nerve disease, nervous system infection, nervous system inflammation, nervous system injury, nervous system jolting, nervous system lesion, nervous system neoplasm, nervous system sclerosis, neural tube defect, neurobehavioral disorder, neurocognitive disorder, neurocutaneous syndrome, neurocysticercosis, neurodegenerative disease, neurodevelopmental disorder, neurofaciodigitorenal syndrome, neuroglia disease, neuroleptic malignant syndrome, neuromuscular disease, neurosarcoidosis, neurovascular disease, Norrie disease, optic atrophy, Pallidopyramidal syndrome, paraneoplastic neurological syndrome, paresthesia, Parsonage-Turner syndrome, Patau syndrome, Pelizaeus-Merzbacher disease, peripheral nervous system disease, Proud syndrome, Satoyoshi syndrome, seizure, sensation disorder, tonic pupil, unconsciousness, vestibular disorder, or Wobbly possum disease.

[0513] In certain embodiments, the disease is a central nervous system (CNS) disease. In certain embodiments, 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. In some embodiments, the disease is a brain disease, brainstem disease, or cerebellum disease. In some embodiments, the disease is a brain disease. In some embodiments, the disease is a disease of the peripheral nervous system (including cranial nerves) or the autonomic nervous system (parts of which are located in both central and peripheral nervous system).

[0514] In some embodiments, the disease is a neurodegenerative disease. In certain embodiments, the disease is ABri amyloidosis, aceruloplasminemia, acute neurodegenerative disease, amyotrophic lateral sclerosis, ataxia with vitamin E deficiency, atypical Rett syndrome, beta-propeller protein-associated neurodegeneration, COASY protein-associated neurodegeneration, central nervous system degenerative disease, demyelination, fatty acid hydroxylase-associated neurodegeneration, fragile X tremor ataxia syndrome, Gemignani syndrome, Gerstmann-Straussler syndrome, Huntington’s 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,A1278.70032WO00 148 12280650.2muscular 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’s 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. In some embodiments, the disease is Alzheimer’s disease.

[0515] Exemplary CNS diseases include, but are not limited to, neurotoxicity and / or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, a mental disorder, a sleep condition, a movement disorder, nausea and / or emesis, amyotrophic lateral sclerosis, Alzheimer’s disease, and drug addiction.

[0516] In certain embodiments, the CNS disease is neurotoxicity and / or neurotrauma, e.g., for example, as a result of acute neuronal injury (e.g., traumatic brain injury (TBI), stroke, epilepsy) or a chronic neurodegenerative disorder (e.g., multiple sclerosis, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, Alzheimer’s disease). In certain embodiments, the compounds of the present disclosure provide a neuroprotective effect, e.g., against an acute neuronal injury or a chronic neurodegenerative disorder.

[0517] In certain embodiments, the CNS disease is stroke (e.g., ischemic stroke).

[0518] In certain embodiments, the CNS disease is multiple sclerosis.

[0519] In certain embodiments, the CNS disease is spinal cord injury.

[0520] In certain embodiments, the CNS disease is epilepsy.

[0521] In certain embodiments, the CNS disease is a mental disorder, e.g., depression, anxiety or anxiety-related condition, a learning disability, somatic symptom disorder, schizophrenia or schizoaffective disorder.

[0522] In certain embodiments, the CNS disease is depression. “Depression” includes, but is not limited to, depressive disorders or conditions, such as, for example, major depressive disorders (e.g., unipolar depression), treatment-resistant depression, dysthymic disorders (e.g., chronic, mild depression), bipolar disorders (e.g., manic depression), seasonal affective disorder, and / or depression associated with substance abuse or substance abuse disorder (e.g., withdrawal). The depression can be clinical or subclinical depression. The depression can be associated with or premenstrual syndrome and / or premenstrual dysphoric disorder.

[0523] In certain embodiments, the CNS disease is anxiety. “Anxiety” includes, but is not limited to, anxiety and anxiety-related conditions, such as, for example, clinical anxiety, panic disorder, agoraphobia, generalized anxiety disorder (GAD), specific phobia, social phobia, obsessive- compulsive disorder, acute stress disorder, post-traumatic stress disorder, adjustment disorders with anxious features, anxiety disorder associated with depression, anxiety disorder due toA1278.70032WO00 149 12280650.2general medical conditions, and substance-induced anxiety disorders, anxiety associated with substance abuse or substance use disorder (e.g., withdrawal, dependence, reinstatement) and anxiety associated with nausea and / or emesis. This treatment may also be to induce or promote sleep in a subject (e.g., for example, a subject with anxiety).

[0524] In certain embodiments, the CNS disease is a learning disorder (e.g., attention deficit disorder (ADD)).

[0525] In certain embodiments, the CNS disease is schizophrenia or schizoaffective disorder.

[0526] In certain embodiments, the CNS disease is a sleep condition. “Sleep conditions” include, but are not limited to, insomnia, narcolepsy, sleep apnea, restless legs syndrome (RLS), delayed sleep phase syndrome (DSPS), periodic limb movement disorder (PLMD), hypopnea syndrome, rapid eye movement behavior disorder (RBD), shift work sleep condition (SWSD), and sleep problems (e.g., parasomnias) such as nightmares, night terrors, sleep talking, head banging, snoring, and clenched jaw and / or grinding of teeth (bruxism).

[0527] In certain embodiments, the CNS disease is a movement disorder, e.g., basal ganglia disorders, such as, for example, Parkinson’s disease, levodopa-induced dyskinesia, Huntington’s disease, Gilles de Ia Tourette’s syndrome, tardive dyskinesia, and dystonia.

[0528] In certain embodiments, the CNS disease is Alzheimer’s disease.

[0529] In certain embodiments, the CNS disease is amyotrophic lateral sclerosis (ALS).

[0530] In certain embodiments, the CNS disease is nausea and / or emesis.

[0531] In certain embodiments, the CNS disease is drug addiction (e.g., for instance, addiction to opiates, nicotine, cocaine, psychostimulants, or alcohol).

[0532] In some embodiments, the disease is a neurocognitive disorder. In certain embodiments, the disease is dementia, HIV-associated neurocognitive disorder, or a memory disorder.

[0533] The term “neurological disease” (including, e.g., “neurodegenerative diseases”) refers to any disease of the nervous system, including diseases that involve the central nervous system (brain, brainstem, and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Neurodegenerative diseases refer to a type of neurological disease marked by the loss of nerve cells, including, but not limited to, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), and Huntington’s disease. Examples of neurological diseases include, but are not limited to, headache, stupor and coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuro-ophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of peripheral nerves, muscle, and neuromuscular junctions. Substance abuse or substance use disorder (SUD) and mental illness, including, but not limited to, bipolar disorder, schizophrenia, andA1278.70032WO00 150 12280650.2schizoaffective disorder, are also included in the definition of neurological diseases. Further examples of neurological diseases include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers’ disease; alternating hemiplegia; Alzheimer’s disease; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Arnold-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telangiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet’s disease; Bell’s palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger’s disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown- Sequard syndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorders; Cushing’s syndrome; cytomegalic inclusion body disease (CIBD); cytomegalovirus infection; dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier’s syndrome; Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb’s palsy; essential tremor; Fabry’s disease; Fahr’s syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich’s ataxia; frontotemporal dementia and other “tauopathies”; Gaucher’s disease; Gerstmann’s syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1 associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV- associated dementia and neuropathy (see also neurological manifestations of AIDS); holoprosencephaly; Huntington’s disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile; phytanic acid storage disease; Infantile Refsum disease; infantile spasms; inflammatory myopathy; intracranialA1278.70032WO00 151 12280650.2cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh’s disease; Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; lissencephaly; locked-in syndrome; Lou Gehrig’s disease (also known as motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; lyme disease-neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neurone disease; moyamoya disease; mucopolysaccharidoses; multi-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O’Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson’s disease; paramyotonia congenita; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick’s disease; pinched nerve; pituitary tumors; polymyositis; porencephaly; Post-Polio syndrome; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive; hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type I and Type II); Rasmussen’s Encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye’s syndrome; Saint Vitus Dance; Sandhoff disease; Schilder’s disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjogren’s syndrome; sleep apnea; Soto’s syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; stiff-person syndrome; stroke; Sturge- Weber syndrome; subacute sclerosing panencephalitis; subarachnoid hemorrhage; subcorticalA1278.70032WO00 152 12280650.2arteriosclerotic encephalopathy; sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; tic douloureux; Todd’s paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi- infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg’s syndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williams syndrome; Wilson’s disease; and Zellweger syndrome.

[0534] In certain embodiments, the subject is a mammal, e.g., a primate or a human.

[0535] In another embodiment, the compound or pharmaceutical composition provided herein is administered intrathecally, intravenously, intramuscularly, subcutaneously, intracerebroventricularly, orally, or topically. In certain embodiments, the compound or pharmaceutical composition provide herein is administered intrathecally.

[0536] In other embodiments, the compound or pharmaceutical composition provided herein is administered alone or in combination with one or more additional pharmaceutical agents (e.g., additional therapeutic agents). In a further embodiment, at least one additional therapeutic agent is an anti central nervous system (CNS) disease agent.

[0537] In another aspect, the present disclosure provides a method of modulating the expression of a nucleic acid target in a cell comprises contacting the cell with an effective amount of a compound or pharmaceutical described herein. In certain embodiments, the expression of the nucleic acid is modulated in a cell of the subject that expresses TrkB on the surface of the cell. In certain embodiments, the expression of the nucleic acid is modulated in a brain cell. In certain embodiments, the cell expressing TrkB on its surface is a brain cell. In certain embodiments the brain cell is a cell of the frontal cortex. In certain embodiments, the brain cell is a cell of the striatum. In certain embodiments, the brain cell is a cell of the cerebellum. In certain embodiments, the brain cell is a cell of the brain stem. In certain embodiments, the brain cell is a cell of the hippocampus. In certain embodiments, the brain cell is a cell of the spinal cord. In certain embodiments, the nucleic acid target is pre-mRNA, mRNA, non-coding RNA, or miRNA. In certain embodiments, the compound is administered to the subject intrathecally.

[0538] In certain embodiments, the disease or symptom thereof is a central nervous system (CNS) disease or symptom thereof. In certain embodiments, the disease or symptom thereof is Alzheimer’s disease, or a symptom thereof.

[0539] In certain embodiments, the administration is intrathecal administration or intracerebroventricular (ICV) administration.A1278.70032WO00 153 12280650.2

[0540] In certain embodiments, the compound or pharmaceutical composition is administered to the subject in a therapeutically effective amount.

[0541] In certain embodiment, a compound described herein selectively or preferentially targets a cell expressing mannose receptor compared to a cell not expressing mannose receptor. In certain embodiments, a compound described herein selectively or preferentially targets a cell expressing mannose receptor compared to a compound not comprising a mannose ligand. In certain embodiments, the selectivity or preferential targeting is at least in part because the compound described herein comprises a mannose ligand.

[0542] In certain embodiments, the cell expresses mannose on the surface of the cell. In certain embodiments, the cell is a brain cell. In certain embodiments, the cell is a microglial cell. In certain embodiments, the cell is a microglial cell of the brain. In certain embodiments, the cell is a microglial cell of the spinal cord. In certain embodiments the cell is a cell of the frontal cortex. In certain embodiments, the cell is a cell of the striatum. In certain embodiments, the cell is a cell of the cerebellum. In certain embodiments, the cell is a cell of the brain stem. In certain embodiments, the cell is a cell of the hippocampus. In certain embodiments, the cell is a cell of the spinal cord. In certain embodiments, the agent is a therapeutic agent or diagnostic agent. In certain embodiments, contacting the cell with the compound of any embodiments herein inhibits expression of the nucleic acid target. In certain embodiments, the nucleic acid target is pre- mRNA, mRNA, non-coding RNA, or miRNA. In certain embodiments the cell is in an animal. In certain embodiments the cell is in a human.

[0543] In another aspect, the present disclosure provides use of a compound or pharmaceutical composition provided herein for the manufacture of a medicament for delivering an oligonucleotide, small molecule, protein, antibody, or peptide to a cell or tissue of a subject, wherein R is an oligonucleotide, a small molecule, a protein, an antibody or a peptide.

[0544] In another aspect, the present disclosure provides a compound or pharmaceutical composition provided herein for use in delivering an oligonucleotide, small molecule, protein, antibody, or peptide to a cell or tissue of a subject, wherein R is an oligonucleotide, a small molecule, a protein, an antibody or a peptide.

[0545] In another aspect, the present disclosure provides use of a compound or pharmaceutical composition described herein in the manufacture of a medicament for treating a disease or symptom thereof in a subject in need thereof, wherein R is an oligonucleotide, a small molecule, a protein, an antibody or a peptide.

[0546] In another aspect, the present disclosure provides use of a compound or pharmaceutical composition described herein for use in the treatment of a disease or symptom thereof in aA1278.70032WO00 154 12280650.2subject in need thereof, wherein R is an oligonucleotide, a small molecule, a protein, an antibody or a peptide. Pharmaceutical Compositions and Kits

[0547] In one aspect, provided are pharmaceutical compositions comprising any of the compounds described herein and a pharmaceutically acceptable excipient.

[0548] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutic agents or prophylactic agents). The compounds or pharmaceutical compositions described herein can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, and / or in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent exhibits a synergistic effect that is absent in a pharmaceutical composition including one of the compounds described herein or the additional pharmaceutical agent, but not both.

[0549] The compound or pharmaceutical composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. In certain embodiments, the additional pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and / or preventing a disease (e.g., CNS disease). Each additional pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein withA1278.70032WO00 155 12280650.2the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0550] In one aspect, provided are kits comprising a compound or pharmaceutical composition provided herein, and instructions for using the compound or pharmaceutical composition provided herein. In certain embodiments, the kit comprises instructions for administering the compound or pharmaceutical composition provided herein to a subject in need of treatment or prevention of a disease or symptom thereof.

[0551] In certain embodiments, the pharmaceutical composition comprises an effective amount of the compound described herein and a pharmaceutically acceptable excipient. In an embodiment, the pharmaceutical composition is suitable for being administered to a subject. In certain embodiments, the pharmaceutical composition is a pharmaceutically acceptable formulation. In certain embodiments, the pharmaceutical composition is a pharmaceutically acceptable formulation that provides sustained delivery of the compound to a subject for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after the pharmaceutically-acceptable formulation is administered to the subject.

[0552] Actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the disclosure may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular subject, pharmaceutical composition, and mode of administration, while being acceptably tolerant to the subject.

[0553] In use, at least one compound according to the present disclosure is administered in a pharmaceutically effective amount to a subject in need thereof in a pharmaceutical carrier by intravenous, intrathecal, intramuscular, subcutaneous, or intracerebroventricular injection (ICV) or by oral administration or topical application. In accordance with the present disclosure, a compound of the disclosure may be administered alone or in conjunction with a second, different therapeutic. By “in conjunction with” is meant together, substantially simultaneously, or sequentially. In one embodiment, a compound of the disclosure is administered acutely. The compound of the disclosure may therefore be administered for a short course of treatment, such as for about 1 day to about 1 week. In another embodiment, the compound of the disclosure may be administered over a longer period of time to ameliorate chronic disorders, such as, for example, for about one week to several months depending upon the condition to be treated.

[0554] By “pharmaceutically effective amount,” as used herein, is meant an amount of a compound of the disclosure, high enough to significantly positively modify the condition to beA1278.70032WO00 156 12280650.2treated but low enough to avoid serious side effects (at a reasonable benefit / risk ratio), within the scope of sound medical judgment. A pharmaceutically effective amount of a compound of the disclosure will vary with the particular goal to be achieved, the age and physical condition of the subject being treated, the severity of the underlying disease, the duration of treatment, the nature of concurrent therapy and the specific compound employed. For example, a therapeutically effective amount of a compound of the disclosure administered to a child or a neonate will be reduced proportionately in accordance with sound medical judgment. The effective amount of a compound of the disclosure will thus be the minimum amount which will provide the desired effect.

[0555] A compound of the disclosure may be administered in a convenient manner such as by intrathecal, intravenous, intramuscular, subcutaneous, oral, or intra-cerebroventricular injection routes or by topical application, such as in creams or gels. Depending on the route of administration, the active ingredients which comprise a compound of the disclosure may be required to be coated in a material to protect the compound of the disclosure from the action of enzymes, acids and other natural conditions which may inactivate the compound of the disclosure. In order to administer a compound of the disclosure by a mode other than parenteral administration, the compound can be coated by, or administered with, a material to prevent inactivation.

[0556] The compound of the disclosure may be administered parenterally or intraperitoneally. Dispersions can also be prepared, for example, in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils.

[0557] Some examples of substances which can serve as pharmaceutical excipients, or pharmaceutical carriers (which terms are used interchangeably herein), are sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethycellulose, ethylcellulose and cellulose acetates; powdered tragancanth; malt; gelatin; talc; stearic acids; magnesium stearate; calcium sulfate; vegetable oils, such as peanut oils, cotton seed oil, sesame oil, olive oil, corn oil, and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; agar; alginic acids; pyrogen-free water; isotonic saline; and phosphate buffer solution; skim milk powder; as well as other non-toxic compatible substances used in pharmaceutical formulations such as Vitamin C, estrogen and echinacea, for example. Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, lubricants, excipients, tableting agents, stabilizers, antioxidants, and preservatives, can also be present. Solubilizing agents, including for example, cremaphore, and beta-cyclodextrins, can also be used in the pharmaceutical compositions herein.A1278.70032WO00 157 12280650.2

[0558] Pharmaceutical compositions comprising the compounds of the present disclosure can be manufactured by means of conventional mixing, dissolving, granulating, dragee-making levigating, emulsifying, encapsulating, entrapping, or lyophilization processes. The pharmaceutical compositions can be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients, or auxiliaries, which facilitate processing of the compounds of the disclosure into preparations that can be used pharmaceutically. The pharmaceutical compositions herein can be made by combining (e.g., contacting, mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing) a compound provided herein with one or more suitable carriers, diluents, excipients, or auxiliaries, including those described herein (e.g., for pharmaceutical, agricultural, or veterinary use).

[0559] Pharmaceutical compositions of the present disclosure can take a form suitable for virtually any mode of administration, including, for example, intrathecal, topical, ocular, oral, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, and the like, or a form suitable for administration by inhalation or insufflation.

[0560] Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral, or pulmonary administration.

[0561] Useful injectable preparations include sterile suspensions, solutions, or emulsions of the compounds of the present disclosure in aqueous or oily vehicles. The pharmaceutical compositions also can contain formulating agents, such as suspending, stabilizing and / or dispersing agent. The formulations for injection can be presented in unit dosage form (e.g., in ampules or in multidose containers) and can contain added preservatives.

[0562] Alternatively, the injectable formulation can be provided in powder form for reconstitution with a suitable vehicle, including but not limited to, sterile pyrogen free water, buffer, dextrose solution, and the like, before use. To this end, the compounds of the present disclosure can be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.

[0563] For prolonged delivery, the compounds of the present disclosure can be formulated as a depot preparation for administration by implantation or intramuscular injection. The active ingredient can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

[0564] Alternatively, other pharmaceutical delivery systems can be employed. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver compoundsA1278.70032WO00 158 12280650.2of the present disclosure. Certain organic solvents such as dimethylsulfoxide (DMSO) also can be employed.

[0565] The pharmaceutical compositions can, if desired, be presented in a pack or dispenser device that can contain one or more unit dosage forms containing the compounds of the present disclosure. The pack can, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device can be accompanied by instructions for administration.

[0566] The compounds of the present disclosure, or pharmaceutical compositions thereof, will generally be used in an amount effective to achieve the intended result, for example in an amount effective to treat or prevent the particular disease being treated. The compounds of the present disclosure can be administered therapeutically to achieve therapeutic benefit or prophylactically to achieve prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the disease being treated and / or eradication or amelioration of one or more of the symptoms associated with the disease such that the subject reports an improvement in feeling or condition, notwithstanding that the subject can still be afflicted with the disease. Therapeutic benefit also includes halting or slowing the progression of the disease or a symptom thereof, regardless of whether improvement is realized.

[0567] For prophylactic administration, the compound of the present disclosure can be administered to a subject at risk of developing one of the previously described diseases. A subject at risk of developing a disease can be a subject having characteristics placing the subject in a designated group of at-risk subjects, as defined by an appropriate medical professional or group. A subject at risk may also be a subject that is commonly or routinely in a setting where development of the underlying disease could occur. In other words, an at-risk subject is one who is commonly or routinely exposed to the disease or illness causing conditions or may be acutely exposed for a limited time. Alternatively, prophylactic administration can be applied to avoid the onset of symptoms in a subject diagnosed with the underlying disorder.

[0568] The amount of compound of the present disclosure administered will depend upon a variety of factors, including, for example, the particular indication being treated, the mode of administration, whether the desired benefit is prophylactic or therapeutic, the severity of the indication being treated, the age and weight of the subject, the bioavailability of the compound, and the like. Determination of an effective dosage is well within the capabilities of those skilled in the art.

[0569] Effective dosages can be estimated initially from in vitro assays. For example, an initial dosage for use in animals can be formulated to achieve a circulating blood or serum concentration of active compound that is at or above an IC50of the particular compound as measured in an in vitro assay, such as an in vitro fungal MIC or MFC, and other in vitro assays.A1278.70032WO00 159 12280650.2Calculating dosages to achieve such circulating blood or serum concentrations taking into account the bioavailability of the particular compound is well within the capabilities of skilled artisans. For guidance, see “General Principles,” In: Goodman and Gilman’s The Pharmaceutical Basis of Therapeutics, Chapter 1, pp.1-112, 13th ed., McGraw-Hill, and the references cited therein, which are incorporated herein by reference.

[0570] Initial dosages also can be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of compounds to treat or prevent the various diseases described above are well-known in the art.

[0571] Dosage amounts will typically be in the range of from about 0.0001 or 0.001 or 0.01 mg / kg / day to about 100 mg / kg / day, but can be higher or lower, depending upon, among other factors, the activity of the compound, its bioavailability, the mode of administration, and various factors discussed above. Dosage amount and interval can be adjusted individually to provide plasma levels of the compound(s) that are sufficient to maintain therapeutic or prophylactic effect. In cases of local administration or selective uptake, such as local topical administration, the effective local concentration of active compound(s) cannot be related to plasma concentration. Skilled artisans will be able to optimize effective local dosages without undue experimentation.

[0572] In certain embodiments, the compounds of the present disclosure will provide therapeutic or prophylactic benefit and will have acceptable tolerability. Tolerability of the compound(s) and oligonucleotide(s) can be determined using standard pharmaceutical procedures. The dose ratio between non-tolerable and therapeutic (or prophylactic) effect is the therapeutic index. Compounds that exhibit high therapeutic indices are preferred. EXAMPLES

[0573] In order that the embodiments described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, compositions, and methods provided herein and are not to be construed in any way as limiting their scope. Table 1. Chemical NomenclatureA1278.70032WO00 160 12280650.2A1278.70032WO00 161 12280650.2A1278.70032WO00 162 12280650.2A1278.70032WO00 163 12280650.2A1278.70032WO00 164 12280650.2Table 2. Compound ChemistryA1278.70032WO00 165 12280650.2A1278.70032WO00 166 12280650.2“IS” refers to sense strand. “IA” refers to antisense strand.

[0574] N-(17-azido-3,6,9,12,15-pentaoxaheptadecyl)-4-(7,8-dimethoxy-4-oxochroman-2- yl)benzamide (BA-198 (N71)) was prepared according to the procedures specified in WO2025 / 038971 at page 181.

[0575] (2R,3R,4R,5R)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-((1-(1-(4-(7,8- dimethoxy-4-oxo-4H-chromen-2-yl)phenyl)-1-oxo-5,8,11,14,17-pentaoxa-2-azanonadecan-19- yl)-1H-1,2,3-triazol-4-yl)methoxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran- 3-yl (2-cyanoethyl) diisopropylphosphoramidite (BA-337 (B18)) was prepared according to the procedures specified in WO2025 / 038971 at pages 247-248. EXAMPLE 1: Preparation of RD4193

[0576] RD4193 is a double stranded siRNA...

Claims

CLAIMS What is claimed is:

1. A compound comprising the structure of Formula (I):Formula (I) or a stereoisomer, tautomer, prodrug or salt thereof, wherein: A is a mannose receptor ligand; B is a Tropomyosin receptor B (TrkB) ligand; each of L1, L2, L3, L4, L5, L6, L7and L8is independently a linker, a bond, or absent, wherein at least one of L1, L2, L3, and L4is a linker or a bond; R is an oligonucleotide, a small molecule, a protein, an antibody or a peptide; m is 1, 2, or 3; and n is 0, 1, 2 or 3.

2. The compound of claim 1, comprising the structure of Formula (II):Formula (II) or a stereoisomer, tautomer, prodrug, or salt thereof.

3. The compound of claim 1, comprising the structure of Formula (III): Formula (III) or a stereoisomer, tautomer, prodrug, or salt thereof.

4. The compound of claim 1, comprising the structure of Formula (IV): Formula (IV) or a stereoisomer, tautomer, prodrug, or salt thereof.A1278.70032WO00 216 12280650.

25. The compound of claim 1, comprising the structure of Formula (V):Formula (V) or a stereoisomer, tautomer, prodrug, or salt thereof, wherein: ▬▬▬▬▬▬ is an oligonucleotide.

6. The compound of claim 5, comprising the structure of Formula (VI): Formula (VI) or a stereoisomer, tautomer, prodrug, or salt thereof.

7. The compound of claim 5, comprising the structure of Formula (VII):Formula (VII) or a stereoisomer, tautomer, prodrug, or salt thereof.

8. The compound of claim 5, comprising the structure of Formula (VIII):Formula (VIII) or a stereoisomer, tautomer, prodrug, or salt thereof.

9. The compound of claim 1, comprising the structure of Formula (IX):A1278.70032WO00 217 12280650.2Formula (IX) or a stereoisomer, tautomer, prodrug, or salt thereof, wherein q is 0-20; r is 4-10; and X is -OH or -SH.

10. The compound of claim 9, or a stereoisomer, tautomer, prodrug or salt thereof, wherein q is 4, r is 6, n is 1 and X is SH.

11. The compound of claim 9, comprising the structure of Formula (X):Formula (X) or a stereoisomer, tautomer, prodrug, or salt thereof, wherein q is 0-20; r is 4-10; and X is -OH or -SH.

12. The compound of claim 1, comprising the structure of Formula (XI):Formula (XI) or a stereoisomer, tautomer, prodrug, or salt thereof, whereinA1278.70032WO00 218 12280650.2q is 0-20; r is 4-10; and X is -OH or -SH.

13. The compound of claim 12, or a stereoisomer, tautomer, prodrug or salt thereof, wherein q is 4, r is 6, m is 1, and X is SH.

14. The compound of any one of claims 1-13, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of A comprises mannose.

15. The compound of any one of claims 1-14, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of A is of the formula:, wherein T is NH, O or S; T1is O, NH, or CH2; –T5--- is –O–, –NH–, –CH= or –CH2–; zero, one, or two of T2R2, T3R3, and T4R4is H; each remaining T2, T3, and T4is O; each of R1, R5, and remaining R2, R3, and R4is independently H, Me, -C(=O)Me, - C(=O)NH2, a second mannose group, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; and the point of attachment replaces one of R1, R2, R3, R4and R5.

16. The compound of any one of claims 1-15, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of A is of the formula:.A1278.70032WO00 219 12280650.

217. The compound of any one of claims 1-16, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of A is of the formula:.

18. The compound of any one of claims 1-17, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of A is of the formula:.

19. The compound of any one of claims 1-18, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of A is of the formula:.

20. The compound of claim 1, or a stereoisomer, tautomer, prodrug or salt thereof, comprising the structure of Formula (XII):Formula (XII) or a stereoisomer, tautomer, prodrug or salt thereof, wherein: T is NH, O or S; T1is O, NH, or CH2; –T5--- is –O–, –NH–, –CH= or –CH2–; zero, one, or two of T2R2, T3R3, and T4R4is H; each remaining T2, T3, and T4is O; each of R1, R5, and remaining R2, R3, and R4is independently H, Me, -C(=O)Me, - C(=O)NH2, a second mannose group, an oxygen protecting group when attachedA1278.70032WO00 220 12280650.2to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; and the point of attachment replaces one of R1, R2, R3, R4and R5.

21. The compound of claim 20, or a stereoisomer, tautomer, prodrug or salt thereof, wherein Formula (XII) is Formula (XII-A):Formula (XII-A).

22. The compound of claim 20, or a stereoisomer, tautomer, prodrug or salt thereof, wherein Formula (XII) is Formula (XII-B):Formula (XII-B).

23. The compound of claim 20, or a stereoisomer, tautomer, prodrug or salt thereof, comprising the structure of Formula (XIII):Formula (XIII).

24. The compound of claim 20, or a stereoisomer, tautomer, prodrug or salt thereof, comprising the structure of Formula (XIV):Formula (XIV).A1278.70032WO00 221 12280650.

225. The compound of claim 20, or a stereoisomer, tautomer, prodrug or salt thereof, comprising the structure of Formula (XV):Formula (XV) 26. The compound of claim 20, comprising the structure of Formula (XVI):Formula (XVI) or a stereoisomer, tautomer, prodrug, or salt thereof, or a stereoisomer, tautomer, prodrug or salt thereof, wherein: ▬▬▬▬▬▬ is an oligonucleotide.

27. The compound of claim 20, comprising the structure of Formula (XVII):Formula (XVII) or a stereoisomer, tautomer, prodrug, or salt thereof.

28. The compound of claim 20, comprising the structure of Formula (XVIII):A1278.70032WO00 222 12280650.2Formula (XVIII) or a stereoisomer, tautomer, prodrug, or salt thereof.

29. The compound of claim 20, comprising the structure of Formula (XIX):Formula (XIX) or a stereoisomer, tautomer, prodrug or salt thereof, wherein X is OH or SH.

30. The compound of claim 20, comprising the structure of Formula (XX):or a stereoisomer, tautomer, prodrug or salt thereof.

31. The compound of claim 20, comprising the structure of Formula (XXI):A1278.70032WO00 223 12280650.2or a stereoisomer, tautomer, prodrug or salt thereof.

32. The compound of any one of claims 20-31, or a stereoisomer, tautomer, prodrug or salt thereof, wherein each of R2, R3, R4and R5is independently H, Me, or -C(=O)Me.

33. The compound of claim 32, or a stereoisomer, tautomer, prodrug or salt thereof, wherein R2, R3, R4and R5are H.

34. The compound of claim 32, or a stereoisomer, tautomer, prodrug or salt thereof, wherein R2, R3, R4and R5are Me.

35. The compound of claim 32, or a stereoisomer, tautomer, prodrug or salt thereof, wherein R2, R3, R4and R5are -C(=O)Me.

36. A compound comprising the structure of Formula (XXII):wherein: ▬▬▬▬▬▬ is an oligonucleotide; X- is O- or S-; each of L1, L2, and L3is independently a linker, a bond or absent, wherein at least one of L1, L2, and L3is a linker or a bond; andA1278.70032WO00 224 12280650.2each of R2, R3, R4, and R5is independently H, Me, -C(=O)Me, -C(=O)NH2, a second mannose group, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; or a stereoisomer, tautomer, prodrug, acid or salt thereof.

37. A compound comprising the structure of Formula (XXIII):Formula (XXIII) wherein: ▬▬▬▬▬▬ is an oligonucleotide; B is a Tropomyosin receptor B (TrkB) ligand; X- is O- or S-; each of L1, L2, L3, L5, L6, L7and L8is independently a linker, a bond or absent, wherein at least one of L1, L2, and L3is a linker or a bond; and each of R2, R3, R4, and R5is independently H, Me, -C(=O)Me, -C(=O)NH2, a second mannose group, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; or a stereoisomer, tautomer, prodrug or salt thereof.

38. The compound of claim 1, comprising the structure of Formula (XXIV):A1278.70032WO00 225 12280650.2Formula (XXIV), wherein: R is an oligonucleotide, a small molecule, a protein, an antibody, or a peptide; r is 4-10; B is a Tropomyosin receptor B (TrkB) ligand; each of L5, L6, L7and L8is independently a linker, a bond or absent, wherein at least one of L5, L6, L7and L8is a linker or a bond; n is 0, 1, 2, or 3; X- is -O- or -S-; andwherein: q is 0-20; T is NH, O or S; zero, one, or two of T2R2, T3R3, and T4R4is H; each remaining T2, T3, and T4is O; and each remaining R2, R3, and R4is independently H, Me, -C(=O)Me, -C(=O)NH2, a second mannose group, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; or a stereoisomer, tautomer, prodrug or salt thereof.

39. A compound of claim 1, comprising the structure of Formula (XXV):A1278.70032WO00 226 12280650.2Formula (XXV) wherein: R is an oligonucleotide, a small molecule, a protein, an antibody, or a peptide; r is 4-10; B is a Tropomyosin receptor B (TrkB) ligand; each of L5, L6, L7and L8is independently a linker, a bond or absent, wherein at least one of L5, L6, L7and L8is a linker or a bond; n is 0, 1, 2, or 3; X- is -O- or -S-; andwherein: q is 0-20; zero, one, or two of T2R2, T3R3, and T4R4is H; each remaining T2, T3, and T4is O; –T5--- is –O–, –NH–, –CH= or –CH2–; and each of R5and remaining R2, R3, and R4is independently H, Me, -C(=O)Me, - C(=O)NH2, a second mannose group, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; or a stereoisomer, tautomer, prodrug or salt thereof.

40. The compound of any one of claims 1-2, 5-6, 12, and 14-19, or a stereoisomer, tautomer, prodrug or salt thereof, wherein m is 1.A1278.70032WO00 227 12280650.

241. The compound of any one of claims 1, 5, 9, 14-23, 26, 29, 38, and 29, or a stereoisomer, tautomer, prodrug or salt thereof, wherein n is 0 or 1.

42. The compound of any one of claims 1-8 and 12-35, or a stereoisomer, tautomer, prodrug or salt thereof, wherein each of L1, L2, L3, and L4is independently a linker.

43. The compound of any one of claims 1, 3, 5, 7, 9-10, 20-24, 26, 27, 29, 30-35, 37-39, and 42, or a stereoisomer, tautomer, prodrug or salt thereof, wherein each of L5, L6, L7and L8is independently a linker.

44. The compound of any one of claims 1-8, 12-37, 42, and 43, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L1is substituted or unsubstituted, C1-100 heteroalkylene.

45. The compound of any one of claims 1-8, 12-37, and 42-44, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L1is a combination of –CH2–, –O–, – CH2CH2O–, –OCH2CH2–, –C(=O)–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, – N(CH3)C(=O)–, –OP(=O)(OH)O–, and –OP(=S)(OH)O–, provided that: the number of backbone atoms of L1is 1-100; and L1does not comprise O–O, O–N, N–O, or N–N.

46. The compound of any one of claims 1-8, 12-35, and 42-45, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L1comprises ^–^(CH2^CH2^O^^)q^ ^, wherein q is 0-20.

47. The compound of any one of claims 1-8, 12-37, and 42-46, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L1is substituted or unsubstituted, C1-100 alkylene, substituted or unsubstituted, C2-100 alkenylene, substituted or unsubstituted, C2-100 alkynylene, substituted or unsubstituted, C1-100heteroalkylene, substituted or unsubstituted, C2-100heteroalkenylene, or substituted or unsubstituted, C2-100heteroalkynylene; optionally wherein one or more backbone atoms of the C1-100 alkylene, C2-100 alkenylene, C2-100 alkynylene, C1-100 heteroalkylene, C2-100 heteroalkenylene, or C2-100 heteroalkynylene are independently replaced with substituted or unsubstitutedA1278.70032WO00 228 12280650.2carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.

48. The compound of any one of claims 1-8, 12-37, and 42-47, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L1is substituted or unsubstituted, C2-70 alkylene or substituted or unsubstituted, C2-70 heteroalkylene; and one backbone atom of the C2-70alkylene or C2-70heteroalkylene is replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

49. The compound of any one of claims 1-8, 12-37, and 42-48, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L1comprises:, wherein q is 0-20.

50. The compound of any one of claims 1, 3, 5, 7, 9-10, 20-24, 26, 27, 29, 30-35, 37-39, and 42-49, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L8is substituted or unsubstituted, C1-100heteroalkylene.

51. The compound of any one of claims 1, 3, 5, 7, 9-10, 20-24, 26, 27, 29, 30-35, 37-39, and 42-50, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L8is a combination of –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)–, –C(=O)NH–, – C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, –OP(=O)(OH)O–, and –OP(=S)(OH)O–, provided that: the number of backbone atoms of L8is 1-100; and L8does not comprise O–O, O–N, N–O, or N–N.

52. The compound of any one of claims 1, 3, 5, 7, 9-10, 20-24, 26, 27, 29, 30-35, 37-39, and 42-51, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L8compriseswherein q is 0-20.

53. The compound of any one of claims 1, 3, 5, 7, 9-10, 20-24, 26, 27, 29, 30-35, 37-39, and 42-52, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L8isA1278.70032WO00 229 12280650.2substituted or unsubstituted, C1-100alkylene, substituted or unsubstituted, C2-100alkenylene, substituted or unsubstituted, C2-100 alkynylene, substituted or unsubstituted, C1-100 heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, or substituted or unsubstituted, C2-100 heteroalkynylene; optionally wherein one or more backbone atoms of the C1-100 alkylene, C2-100 alkenylene, C2-100 alkynylene, C1-100 heteroalkylene, C2-100 heteroalkenylene, or C2-100 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.

54. The compound of any one of claims 1, 3, 5, 7, 9-10, 20-24, 26, 27, 29, 30-35, 37-39, and 42-53, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L8is substituted or unsubstituted, C2-70 alkylene or substituted or unsubstituted, C2-70 heteroalkylene; and one backbone atom of the C2-70 alkylene or C2-70 heteroalkylene is replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

55. The compound of any one of claims 1, 3, 5, 7, 9-10, 20-24, 26, 27, 29, 30-35, 37-39, and 42-54, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L8comprise:wherein q is 0-20.

56. The compound of any one of claims 1-8, 12-37, and 42-55, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L2is substituted or unsubstituted, C1-30 heteroalkylene.

57. The compound of any one of claims 1-8, 12-37, and 42-56, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L2is a combination of –CH2–, –O–, – CH2CH2O–, –OCH2CH2–, –C(=O)–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, – N(CH3)C(=O)–, –OP(=O)(OH)O–, and –OP(=S)(OH)O–, provided that: the number of backbone atoms of L2is 1-30; andA1278.70032WO00 230 12280650.2L2does not comprise O–O, O–N, N–O, or N–N.

58. The compound of any one of claims 1-8, 12-37, and 42-57, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L2comprises –C(=O)NH– or – NHC(=O)–.

59. The compound of any one of claims 1-8, 12-37, and 42-58, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L2comprises:

60. The compound of any one of claims 1-8, 12-37, and 42-59, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L2is substituted or unsubstituted, C1-30 alkylene, substituted or unsubstituted, C2-30alkenylene, substituted or unsubstituted, C2-30alkynylene, substituted or unsubstituted, C1-30heteroalkylene, substituted or unsubstituted, C2-30heteroalkenylene, or substituted or unsubstituted, C2-30 heteroalkynylene; optionally wherein one or more backbone atoms of the C1-30alkylene, C2-30alkenylene, C2-30alkynylene, C1-30heteroalkylene, C2-30heteroalkenylene, or C2-30heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits.

61. The compound of any one of claims 1-8, 12-37, and 42-60, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L2is substituted or unsubstituted, C2-20alkylene or substituted or unsubstituted, C2-20heteroalkylene; and one backbone atom of the C2-20 alkylene or C2-20 heteroalkylene is replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

62. The compound of any one of claims 1-8, 12-37, and 42-61, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instanceA1278.70032WO00 231 12280650.

263. The compound of any one of claims 1-8, 12-37, and 42-62, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L2is substituted or unsubstituted, C1-30 heteroalkylene.

64. The compound of any one of claims 1, 3, 5, 7, 9-10, 20-24, 26, 27, 29, 30-35, 37-39, and 42-63, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L7is a combination of –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)–, –C(=O)NH–, – C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, –OP(=O)(OH)O–, and –OP(=S)(OH)O–, provided that: the number of backbone atoms of L7is 1-30; and L7does not comprise O–O, O–N, N–O, or N–N.

65. The compound of any one of claims 1, 3, 5, 7, 9-10, 20-24, 26, 27, 29, 30-35, 37-39, and 42-64, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L7comprises –C(=O)NH– or –NHC(=O)–.

66. The compound of any one of claims 1, 3, 5, 7, 9-10, 20-24, 26, 27, 29, 30-35, 37-39, and 42-65, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L7comprises:

67. The compound of any one of claims 1, 3, 5, 7, 9-10, 20-24, 26, 27, 29, 30-35, 37-39, and 42-66, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L7is.

68. The compound of any one of claims 1, 3, 5, 7, 9-10, 20-24, 26, 27, 29, 30-35, 37-39, and 42-67, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L7is substituted or unsubstituted, C1-30 alkylene, substituted or unsubstituted, C2-30 alkenylene, substituted or unsubstituted, C2-30alkynylene, substituted or unsubstituted, C1-30heteroalkylene, substituted or unsubstituted, C2-30 heteroalkenylene, or substituted or unsubstituted, C2-30 heteroalkynylene;A1278.70032WO00 232 12280650.2optionally wherein one or more backbone atoms of the C1-30alkylene, C2-30alkenylene, C2-30 alkynylene, C1-30 heteroalkylene, C2-30 heteroalkenylene, or C2-30 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.

69. The compound of any one of claims 1, 3, 5, 7, 9-10, 20-24, 26, 27, 29, 30-35, 37-39, and 42-68, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L7is substituted or unsubstituted, C2-20 alkylene or substituted or unsubstituted, C2-20 heteroalkylene; and one backbone atom of the C2-20alkylene or C2-20heteroalkylene is replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

70. The compound of any one of claims 47-69, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms is of the formula:, , ,A1278.70032WO00 233 12280650.2k21 is 0, 1, 2, 3, or 4; each instance of Rd, if present, is independently halogen, substituted or unsubstituted, C1-6 alkyl, or –O–(substituted or unsubstituted, C1-6alkyl); k22 is 0, 1, 2, 3, or 4; each instance of Re, if present, is independently halogen, substituted or unsubstituted, C1-6 alkyl, or –O–(substituted or unsubstituted, C1-6alkyl); k23 is an integer between 0 and 11, inclusive; each instance of Rf, if present, is independently halogen, substituted or unsubstituted, C1-6 alkyl, or –O–(substituted or unsubstituted, C1-6 alkyl); and Rgis hydrogen, halogen, substituted or unsubstituted, C1-6alkyl, or –O–(substituted or unsubstituted, C1-6 alkyl).

71. The compound of claim 70, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms is of the formula:, , , ,A1278.70032WO00 234 12280650.

272. The compound of any one of claims 1-8, 12-37, and 42-71, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L3is substituted or unsubstituted, C1-30alkylene or substituted or unsubstituted, C1-30 heteroalkylene.

73. The compound of any one of claims 1-8, 12-37, and 42-72, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L3is substituted or unsubstituted, C1-30 alkylene.

74. The compound of any one of claims 1-8, 12-37, and 42-73, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L3is^–^(CH2^)r ^ ^ , wherein r is 4-10.

75. The compound of any one of claims 1-8, 12-37, and 42-74, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L3is unsubstituted hexylene.

76. The compound of any one of claims 1, 3, 5, 7, 9-10, 20-24, 26, 27, 29, 30-35, 37-39, and 42-75, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L6is substituted or unsubstituted, C1-30 alkylene or substituted or unsubstituted, C1-30 heteroalkylene.

77. The compound of any one of claims 1, 3, 5, 7, 9-10, 20-24, 26, 27, 29, 30-35, 37-39, and 42-76, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L6is substituted or unsubstituted, C1-30alkylene.

78. The compound of any one of claims 1, 3, 5, 7, 9-10, 20-24, 26, 27, 29, 30-35, 37-39, and 42-77, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L6is^–^(CH2^)r ^ ^ , wherein r is 4-10.A1278.70032WO00 235 12280650.

279. The compound of any one of claims 1, 3, 5, 7, 9-10, 20-24, 26, 27, 29, 30-35, 37-39, and 42-78, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L6is unsubstituted hexylene.

80. The compound of any one of claims 1-8, 12-35, and 42-79, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L4is a combination of –CH2–, –O–, – CH2CH2O–, –OCH2CH2–, –C(=O)–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, – N(CH3)C(=O)–, –OP(=O)(OH)O–, and –OP(=S)(OH)O–, provided that: the number of backbone atoms of L4is 1-10; and L4does not comprise O–O, O–N, N–O, or N–N.

81. The compound of any one of claims 1-8, 12-35, and 42-80, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L4is a substituted or unsubstituted phosphate or a substituted or unsubstituted phosphorothioate group.

82. The compound of any one of claims 1-8, 12-35, and 42-81, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L4is, wherein X is OH or SH.

83. The compound of any one of claims 1, 3, 5, 7, 9-10, 20-24, 26, 27, 29, 30-35, 37-39, and 42-82, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L5is a combination of –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)–, –C(=O)NH–, – C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, –OP(=O)(OH)O–, and –OP(=S)(OH)O–, provided that: the number of backbone atoms of L5is 1-10; and L5does not comprise O–O, O–N, N–O, or N–N.

84. The compound of any one of claims 1, 3, 5, 7, 9-10, 20-24, 26, 27, 29, 30-35, 37-39, and 42-83, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L5is a substituted or unsubstituted phosphate or a substituted or unsubstituted phosphorothioate group.

85. The compound of any one of claims 1, 3, 5, 7, 9-10, 20-24, 26, 27, 29, 30-35, 37-39, and 42-84, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of L5isA1278.70032WO00 236 12280650.2, wherein X is OH or SH.

86. The compound of any one of claims 1, 3, 5, 7, 9, 10, 12-24, 26, 27, 29, 30, 32-35, and 37- 85, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one TrkB ligand comprises a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted carbocyclyl.

87. The compound of any one of claims 1, 3, 5, 7, 9, 10, 12-24, 26, 27, 29, 30, 32-35, and 37- 86, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one TrkB ligand comprises a substituted or unsubstituted polycyclic aryl, substituted or unsubstituted, polycyclic heteroaryl, substituted or unsubstituted, polycyclic heterocycloalkyl or substituted or unsubstituted, mono- or polycyclic cycloalkyl.

88. The compound of claim 87, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the polycyclic aryl, polycyclic heteroaryl, polycyclic heterocycloalkyl, or polycyclic cycloalkyl comprises two to four fused rings.

89. The compound of any one of claims 1, 3, 5, 7, 9, 10, 12-24, 26, 27, 29, 30, 32-35, and 37- 85, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one TrkB ligand is 3,7- dihydroxyflavone, 3,7,8,2′-tetrahydroxyflavone, 7,3′-dihydroxyflavone, 7,8,2′-trihydroxyflavone, 7,8,3′-trihydroxyflavone, 7,8,4′-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), quercetin (3,3′,4′,5,7-pentahydroxyflavone), apigenin (4′,5,7- trihydroxyflavone), isocoumarin, gossypetin (3,5,7,8,3′,4′-hexahydroxyflavone), 2-methyl-8- phenylchromeno[7,8-d]imidazol-6(3H)-one, 8-phenylchromeno[7,8-d]imidazol-6(3H)-one, 4- oxo-2-phenyl-4H-chromene-7,8-diyl diacetate, ANA-12, an anti-TrkB antibody, or a derivative thereof.

90. The compound of any one of claims 1, 3, 5, 7, 9, 10, 12-24, 26, 27, 29, 30, 32-35, and 37- 89, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one TrkB ligand is flavone, tropoflavin, or a derivative thereof.A1278.70032WO00 237 12280650.

291. The compound of any one of claims 1, 3, 5, 7, 9, 10, 12-24, 26, 27, 29, 30, 32-35, and 37- 85, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one TrkB ligand is of the formula:Rq2is hydrogen, -OR7, -SR8, or -NR9R10; Rq3is hydrogen, -OR31, -SR32, or -NR33R34; Rq4is hydrogen, -OR35, -SR36, or -NR37R38; Rq5is hydrogen, -OR39, -SR40, or -NR41R42; Rq6is hydrogen, -OH, optionally substituted -O-alkyl, optionally substituted -OAc, -NH2, optionally substituted -NHAc, -SH, or =O; R7, R8, R9, R10, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, and R42are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; Y is CH2, NH, S, or O; Z is optionally substituted aryl or optionally substituted heteroaryl; R11and R13are each independently absent, hydrogen, or optionally substituted alkyl;A1278.70032WO00 238 12280650.2R12, 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; R16is hydrogen, halogen, –CN, –N3, –SOn16R16A, –SOv16NR16BR16C, −NHNR16BR16C, −ONR16BR16C, −NHC(O)NHNR16BR16C, −NHC(O)NR16BR16C, –N(O)m16, –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; and are each 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 is a single bond, then is a double bond and R11is absent; R16A, R16B, R16C, R16Dare each independently hydrogen, halogen, –CF3, –CCl3, –CBr3, – CI3, –COOH, –CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R16Band R16Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R17, R18, and R19are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R20is hydrogen, halogen, –CN, –N3, –SOn20R20A, –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; R21is hydrogen, halogen, –CN, –N3, –SOn21R21A, –SOv21NR21BR21C, −NHNR21BR21C, −ONR21BR21C, −NHC(O)NHNR21BR21C, −NHC(O)NR21BR21C, –N(O)m21,A1278.70032WO00 239 12280650.2–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; R22and R23are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R24is hydrogen, halogen, –CN, –N3, –SOn24R24A, –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; R20A, R20B, R20C, R20D, R21A, R21B, R21C, R21D, R24A, R24B, R24C, and R24Dare each independently hydrogen, halogen, –CF3, –CCl3, –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, and R24Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; n16, n20, n21, n24, z6, and z8 are each independently 0, 1, 2, 3, or 4; v16, v20, v21, v24, m16, m20, m21, and m24 are each independently 1 or 2; z3 is 0, 1, 2, 3, 4, or 5; z4 and z7 are each independently 0, 1, or 2; and z5 is 0, 1, 2, or 3.

92. The compound of any one of claims 1, 3, 5, 7, 9, 10, 12-24, 26, 27, 29, 30, 32-35, and 37- 91, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one TrkB ligand is:.A1278.70032WO00 240 12280650.

293. The compound of any one of claims 1, 3, 5, 7, 9, 10, 12-24, 26, 27, 29, 30, 32-35, and 37- 92, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of –B is:.

94. The compound of any one of claims 1, 3, 5, 7, 9, 10, 12-24, 26, 27, 29, 30, 32-35, and 37- 93, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of –B is:or a stereoisomer, tautomer, prodrug or salt thereof, wherein Rq2and Rq3are independently -OH or -OMe.

95. The compound of any one of claims 1, 3, 5, 7, 9, 10, 12-24, 26, 27, 29, 30, 32-35, and 37- 85, or a stereoisomer, tautomer, prodrug or salt thereof, wherein at least one instance of –B is:, , ,A1278.70032WO00 241 12280650.

296. The compound of claim 1 of the formula:A1278.70032WO00 242 12280650.2, or a stereoisomer, tautomer, prodrug or salt thereof, wherein ▬▬▬▬▬▬ is an oligonucleotide.

97. The compound of any one of claims 1-96, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof.

98. The compound of any one of claims 1-97, or a pharmaceutically acceptable salt thereof.

99. The compound of any one of claims 1-98, or a potassium salt or a sodium salt thereof.A1278.70032WO00 243 12280650.2100. A pharmaceutical composition comprising a compound of any one of claims 1-99, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

101. The pharmaceutical composition of claim 100 further comprising an additional pharmaceutical agent.

102. A kit comprising: the compound of any one of claims 1-96, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 100-101; and instructions for using the compound, stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt, or pharmaceutical composition.

103. A method for delivering an oligonucleotide, small molecule, protein, antibody, or peptide to a biological sample, cell, tissue, or subject, comprising contacting the biological sample, cell, or tissue with or administering to the subject the compound of any one of claims 1-96, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 100-101.

104. The method of claim 103, wherein the biological sample, cell, or tissue is in vitro.

105. Use of the compound of any one of claims 1-92, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 96-97, for the manufacture of a medicament for delivering an oligonucleotide, small molecule, protein, antibody, or peptide to a cell or tissue of a subject.

106. A compound of any one of claims 1-96, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 100-101 for use in delivering an oligonucleotide, small molecule, protein, antibody, or peptide to a cell or tissue of a subject.

107. The method of claim 103 or 104, the use of claim 105, the compound of any one of claims 1-96, or a stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt thereof, orA1278.70032WO00 244 12280650.2the pharmaceutical composition of claim 100 or 101, wherein the oligonucleotide, small molecule, protein, antibody, or peptide is delivered to the brain of the subject.

108. The method of any one of claims 103, 104 and 107, the use of any one of claims 105-107, the compound of any one of claims 1-96, or a stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 100-101, wherein the oligonucleotide, small molecule, protein, antibody, or peptide is delivered to one or more brain regions selected from the striatum, the cerebellum, the brain stem, the hippocampus, the frontal cortex and the spinal cord.

109. The method of any one of claims 103, 104, 107 and 108, the use of any one of claims 105-108, the compound of any one of claims 1-96 or a stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 100-101, wherein the oligonucleotide, small molecule, protein, antibody, or peptide is delivered to microglia cells in the brain.

110. The method of any one of claims 103, 104, and 107-109, the use of any one of claims 105-108, the compound of any one of claims 1-96, or a stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 100-101, wherein the cell or tissue is a CNS cell or tissue.

111. The method of claim 110, the use of claim 110, the compound of claim 110, or a stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 110, wherein the cell or tissue is a brain cell or tissue.

112. The method of any one of claims 103, 104, and 107-111, the use of any one of claims 105-111, the compound of any one of claims 1-96, or a stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 100-101, wherein the oligonucleotide, small molecule, protein, antibody, or peptide is delivered to a cell.

113. The method of claim 112, the use of claim 112, the compound of claim 112, or a stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 112, wherein the cell is a microglia cell.A1278.70032WO00 245 12280650.2114. A method for treating a disease or symptom thereof in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of claims 1-96, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 100-101.

115. Use of the compound of any one of claims 1-92, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 100-101, for the manufacture of a medicament for treating a disease or symptom thereof in a subject in need thereof.

116. A compound of any one of claims 1-96, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 100-101, for use in treating a disease or symptom thereof in a subject in need thereof.

117. The method of claim 114, the use of claim 115, the compound of claim 116, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 116, wherein the disease a central nervous system (CNS) disease.

118. The method of claim 114, the use of claim 115, the compound of claim 116, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 116, wherein the disease is a neurodegenerative disease.

119. The method of claim 114, the use of claim 115, the compound of claim 116, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 116, wherein the disease is Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), stroke (e.g., ischemic stroke), multiple sclerosis, or spinal cord injury.

120. The method of any one of claims 114 and 117-119, the use of any one of claims 115 and 117-119, the compound of any one of claims 116-119, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 116-119, wherein the administration is intrathecal administration or intracerebroventricular (ICV) administration.A1278.70032WO00 246 12280650.2121. The method of any one of claims 114 and 117-119, the use of any one of claims 115 and 117-119, the compound of any one of claims 116-119, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 116-119, comprising administering to the subject one or more additional therapeutic agents.

122. The method of claim 121, the use of claim 121, the compound of claim 121, or a stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 121, wherein at least one additional therapeutic agent is an anti central nervous system (CNS) disease agent.

123. The method of any one of claims 103, 104, 107-114 and 117-122, the use of any one of claims 105, 107-113, 115, and 117-122, the compound of any one of claims 106-113 and 116- 122, or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 106-113 and 116-122, wherein the subject is a human.A1278.70032WO00 247 12280650.2

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