Oligonucleotides having a synthetic backbone and their synthesis

Abstract

Provided herein are oligonucleotide-containing compounds, methods of delivering the compounds, and methods of using the compounds to treat diseases, disorders, and conditions (e.g., diseases, disorders, and conditions of the central nervous system) in a subject. The present disclosure relates to compounds (e.g., any of those defined herein), modified oligonucleotides, and methods of modulating the function and / or expression of proteins and methods of treating diseases, disorders, and conditions of a subject.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 342,018, filed on May 13, 2022. The disclosure of the prior application is considered a part of the disclosure of this application and is hereby incorporated by reference in its entirety into the disclosure of this application.

Background Art

[0002] In the use of compounds for therapeutic, prophylactic, or diagnostic purposes, it is often desirable for the compound to be delivered to a specific location (e.g., the desired cell(s)) in order to enhance the therapeutic or prophylactic effect or to be advantageous for diagnostic purposes. This frequently occurs when attempting to deliver a therapeutic compound in vivo. Furthermore, if a compound can be efficiently delivered to a specific location, unintended consequences (such as off - target effects) that may result from the administration of the compound can be limited or potentially eliminated. One strategy to facilitate the in vivo delivery of a compound, such as a therapeutic, prophylactic, or diagnostic compound, to a desired location is to link or conjugate the compound to a targeting ligand.

[0003] One type of compound that can be targeted using a targeting ligand is an oligomeric compound such as a protein, peptide, antibody, and oligonucleotide. Oligomeric compounds containing a nucleotide sequence that is at least partially complementary to a target nucleic acid (e.g., an oligonucleotide) have been shown to alter the function and activity of the target both in vitro and in vivo. Oligonucleotides have been shown to regulate the expression or activity of a target nucleic acid when delivered to a cell containing the target nucleic acid (such as mRNA or pre - mRNA). In certain cases, an oligonucleotide can reduce gene expression by inhibiting the translation of the nucleic acid target and / or inducing the degradation of the target nucleic acid.

[0004] When the target nucleic acid is mRNA, one mechanism by which an oligonucleotide can regulate the expression of the mRNA target is through RNA interference. RNA interference is a biological process by which an RNA or RNA-like molecule (such as a chemically modified RNA molecule) can silence gene expression, at least in part, through the RNA-induced silencing complex (RISC) pathway. Additionally, oligonucleotides can regulate the expression of target nucleic acids such as target mRNA through RNase recruitment mechanisms, microRNA mechanisms, occupancy-based mechanisms, and editing mechanisms. The oligonucleotide can be single-stranded or double-stranded. The oligonucleotide can include DNA, RNA, and RNA-like molecules, and can also include modified nucleosides containing one or more non-phosphodiester linkages.

[0005] Another class of compounds that can be targeted using a targeting ligand are small molecule compounds. Small molecule compounds (e.g., organic compounds having a molecular weight of less than about 1000 daltons) have typically been shown to alter the function and / or activity of a target, and thus to modulate or ameliorate a disease and / or disease symptom, or to be useful as diagnostic markers when localized to a target. By more efficiently delivering a compound to a particular location, unintended consequences (such as off-target effects) that can result from administration of the compound can be limited or potentially eliminated, and the localization of diagnostic compounds can be improved. SUMMARY OF THE INVENTION

[0006] The present disclosure relates to compounds (e.g., any of those defined herein), modified oligonucleotides, and methods of modulating the function and / or expression of proteins and methods of treating diseases, disorders, and symptoms of a subject. The methods can include the compounds and modified oligonucleotides disclosed herein.

[0007] It should be understood that the embodiments of the present invention described below regarding the selection of preferred variables can be employed alone or in combination with one or more embodiments of the present invention or the selection of preferred variables, and each combination can be employed in the same manner as if it were explicitly listed in this specification.

[0008] In some embodiments, the present disclosure provides an oligonucleotide of formula (I’): [Chemical formula] (wherein, A, B, W 1 , W 2 , W 3 , W 4 , R 8 , and R 9 are as defined herein).

[0009] In some embodiments, the present disclosure provides an oligonucleotide of formula (VIII): [Chemical formula] (wherein, A, B, W 1 , W 2 , W 3 , W 4 , R 8 , and R 9 are as defined herein).

[0010] In some embodiments, the present disclosure provides an oligonucleotide of formula (I): [Chemical formula] (wherein, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7 , Y, R 2 , R 3 , R 8 , R 9, Z 1 , and Z 2 are as defined herein).

[0011] In some embodiments, the disclosure provides an oligonucleotide of formula (VII):

Chemical formula

[0012] In some embodiments, the disclosure provides an oligonucleotide of formula (II):

Chemical formula

[0013] In some embodiments, the disclosure provides an oligonucleotide of formula (VI):

Chemical formula

[0014] In some embodiments, the disclosure provides an oligonucleotide of formula (X): [Chemical formula] (wherein, X, R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , and R C are as defined herein).

[0015] In some embodiments, the disclosure provides an oligonucleotide of formula (XI): [Chemical formula] (wherein, X, R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , and R c are as defined herein). In some embodiments, the disclosure provides an oligonucleotide of formula (XII): [Chemical formula] (wherein, X, R2 , R 3 , R 4 , R 5 , R 8 , R 9 , and R c are as defined herein).

[0016] In some embodiments, the disclosure provides an oligonucleotide of formula (XIII): [Chemical formula] (wherein X, R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , and R c are as defined herein).

[0017] In some embodiments, the disclosure provides an oligonucleotide of formula (XIV): [Chemical formula] (wherein X, R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , and R c are as defined herein).

[0018] In some embodiments, the disclosure provides an oligonucleotide of formula (IX-a): [Chemical formula] (wherein X, R 2 , R 3 , R 4 , R 5 , R 8 , and R 9 are as defined herein).

[0019] In some embodiments, the present disclosure provides an oligonucleotide of formula (IX-b):

Chemical formula

[0020] In some embodiments, the present disclosure provides an oligonucleotide of formula (X-a):

Chemical formula

Chemical formula

[0021] In some embodiments, the present disclosure provides an oligonucleotide of formula (XVI):

Chemical formula

[0022] In some embodiments, the disclosure provides an oligonucleotide of formula (XVIII): [Chemical formula] (wherein, X, R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , and R c are as defined herein).

[0023] In some embodiments, the disclosure provides an oligonucleotide of formula (IX-c): [Chemical formula] (wherein, X, R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , and R c are as defined herein).

[0024] In some embodiments, the disclosure provides an oligonucleotide of formula (IX-d): [Chemical formula] (wherein, X, R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , and R c are as defined herein). In some embodiments, the present disclosure provides an oligonucleotide of formula (IX-e): [Chemical formula] (wherein, X, R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , and R c are as defined herein).

[0025] In some embodiments, the present disclosure provides a compound of the formula: [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula]

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0026] In another aspect, the disclosure provides a composition comprising any of the compounds provided herein and a pharmaceutically acceptable excipient.

[0027] In some embodiments, R 4 and R 5Each contains an oligonucleotide. In some embodiments, one or both of the oligonucleotides are attached at their 5' ends. In some embodiments, one or both of the oligonucleotides are attached at their 3' ends. In some embodiments, one or both of the oligonucleotides are attached at an internal position of the oligonucleotide. In certain embodiments, the internal position is an internucleoside linkage. In some embodiments, R 4 and R 5 are joined together to form a single oligonucleotide. In some embodiments, R 4 contains an oligonucleotide and R 5 contains a protecting group. In some embodiments, R 4 contains a protecting group and R 5 contains an oligonucleotide. In some embodiments, R 4 and R 5 each contain a protecting group.

[0028] In certain embodiments, R 4 is attached at the 3' end of the oligonucleotide. In certain embodiments, R 4 is attached at the 5' end of the oligonucleotide.

[0029] In certain embodiments, R 5 is attached at the 3' end of the oligonucleotide. In certain embodiments, R 5 is attached at the 5' end of the oligonucleotide.

[0030] In another aspect, the present disclosure provides a method for delivering a therapeutic oligonucleotide to a subject, the method comprising administering to the subject any of the compounds or compositions provided herein. In another aspect, the present disclosure provides a method for delivering a therapeutic oligonucleotide to the brain of a subject, the method comprising administering to the subject any of the compounds or compositions provided herein. In another aspect, the present disclosure provides a method for treating or ameliorating a disease, disorder, or symptom thereof in a subject, the method comprising administering to the subject any of the compounds or compositions provided herein. In some embodiments, the disease, disorder, or symptom thereof is a disease, disorder, or symptom of the central nervous system (CNS). In certain embodiments, the disease, disorder, or symptom thereof is Alzheimer's disease, or a symptom thereof. In some embodiments, the compound is administered intrathecally to the subject.

[0031] In another aspect, the present disclosure provides a method for making any of the compounds provided herein, the method comprising one or more compounds and the chemical transformations described herein.

[0032] Definitions It should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claimed embodiments. As used herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of "or" means "and / or" unless otherwise indicated. Further, the use of the terms "including" and other forms, such as "includes" and "included," is not limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0033] Unless otherwise indicated, the following terms have the following meanings.

[0034] As used herein, the term "treating" a disorder encompasses ameliorating, alleviating, and / or managing the disorder and / or a condition that may cause the disorder. The terms "treating" and "treatment" refer to methods of alleviating or reducing a disease and / or its attendant symptoms. According to the present disclosure, "treating" includes, for example, blocking, inhibiting, attenuating, protecting from, modulating, reversing, or reducing the occurrence of the detrimental effects of a disorder. As used herein, "inhibiting" encompasses preventing, attenuating, and stopping progression.

[0035] The terms "isolated," "purified," or "biologically pure" refer to a substance that is substantially or essentially free of components that are normally associated with it 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). In particular, in certain embodiments, a compound is at least 85% pure, more preferably at least 90% pure, more preferably at least 95% pure, and most preferably at least 99% pure.

[0036] The term "administering" or "administration" includes a route by which a compound(s) is introduced into a subject to perform its intended function. Examples of administration routes that can be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal.

[0037] "Parenteral administration" means administration by injection or infusion. Parenteral administration includes subcutaneous, intravenous, intramuscular, intraarterial, intraperitoneal, or intracranial administration, for example, intrathecal or intraventricular administration.

[0038] "Pharmaceutically acceptable carrier or diluent" means any substance suitable for use in administration to an individual. In certain embodiments, a pharmaceutically acceptable carrier or diluent can assist in the administration of the compound to the individual and its absorption by the individual, and can be included in the compositions of the present disclosure without causing a significantly harmful toxicological effect to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, etc. For example, a pharmaceutically acceptable carrier can be a sterile aqueous solution such as PBS or water for injection. Those skilled in the art will recognize that other pharmaceutical excipients are also useful in the present disclosure.

[0039] The term "effective amount" includes an amount effective at the dosage and for the period required to achieve the desired result. The effective amount of a compound can vary depending on factors such as the subject's disease state, age, and weight, as well as the ability of the compound to elicit the desired response in the subject. The dosing regimen can be adjusted to provide the optimal therapeutic response. An effective amount is also an amount in which any intolerable or harmful effects (e.g., side effects) of the compound are outweighed by the therapeutically beneficial effects.

[0040] As used herein, the terms "systemic administration", "systemically administered", "peripheral administration" and "peripherally administered" refer to the administration of a compound(s), oligonucleotide(s), drug, or other substance such that it enters the patient's circulatory system and undergoes metabolism and other similar processes.

[0041] The term "therapeutically effective amount" refers to an amount of the compound administered that is sufficient to prevent, or to some extent alleviate, the occurrence of one or more of the symptoms of the condition or disorder being treated.

[0042] A therapeutically effective amount of the compound (i.e., an effective dosage) can range from about 0.005 μg / kg body weight to about 200 mg / kg body weight, preferably from about 0.01 mg / kg body weight to about 200 mg / kg body weight, more preferably from about 0.015 mg / kg body weight to about 30 mg / kg body weight. In other embodiments, the therapeutically effective amount can range from about 1.0 pM to about 10 μM.

[0043] One of ordinary skill in the art will recognize that certain factors, such as, but not limited to, the severity of the disease or disorder, previous treatment, the overall health and / or age of the subject, and other diseases present, can affect the dosage required to effectively treat the subject. Further, treatment of a subject with a therapeutically effective amount of the compound can include a single treatment or, preferably, a series of treatments. In one example, a subject is treated daily, weekly, monthly, quarterly, or annually with a compound in the range of about 0.005 μg / kg body weight to about 200 mg / kg body weight. In another example, a subject can be treated daily, weekly, monthly, quarterly, or annually for several years in the case of a chronic condition or disease. It will also be understood that the effective dosage of the compound used in the treatment can increase or decrease over a particular course of treatment.

[0044] The term "chiral" refers to a molecule having the property that it cannot be superimposed on its mirror image partner, and the term "achiral" refers to a molecule that can be superimposed on its mirror image partner.

[0045] The term "diastereomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other.

[0046] The term "enantiomer" refers to two stereoisomers of a compound that are mirror images of each other and cannot be superimposed on each other. An equimolar mixture of two enantiomers is called a "racemic mixture" or "racemate".

[0047] Certain compounds of the present disclosure have an asymmetric carbon atom (optical center or chiral center) or a double bond, and their enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomers that can be defined as (R)- or (S)- from the perspective of absolute stereochemistry or (D)- or (L)- in the case of amino acids, and individual isomers are included within the scope of the present disclosure. Compounds that are known in the art to be too unstable to be synthesized and / or isolated are not included in the present disclosure. The present disclosure means that it includes compounds in racemic and optically pure forms. Optically active (R)- and (S)-isomers, or (D)- and (L)-isomers can also be prepared using chiral synthons or chiral reagents, or resolved using prior art. When the compounds described herein contain olefinic bonds or other geometrically asymmetric centers, unless otherwise specified, the compounds are intended to include both E geometric isomers and Z geometric isomers.

[0048] The term "tautomer" as used herein refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another.

[0049] Certain compounds of the present disclosure may exist in tautomeric forms, and it will be apparent to those skilled in the art that any form of such tautomers of the compounds is within the scope of the present disclosure.

[0050] The term "isomer" or "stereoisomer" refers to a compound that has the same chemical constitution but a different arrangement of atoms or groups in space.

[0051] The term "prodrug" means a compound that can be converted, under physiological conditions or by solvolysis, into a biologically active nucleic acid or an analog thereof as described herein. Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active nucleic acid or an analog thereof. A prodrug may be inactive at the time of administration to a subject, but is converted in vivo, for example, by hydrolysis, into an active compound. Prodrug compounds often provide advantages of solubility, tissue compatibility, or delayed release in mammals (see, e.g., Bundgard, H., DESIGN OF PRODRUGS (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Considerations regarding prodrugs are described in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and BIOREVERSIBLE CARRIERS IN DRUG DESIGN, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety. The term "prodrug" also means any covalently attached carrier that releases an active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the active compounds described herein can be prepared by modifying the functional groups present in the active compounds in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to form the parent active compounds. Prodrugs include compounds in which a hydroxy group, an amino group, or a mercapto group is attached to any group that cleaves when the prodrug of the active compound is administered to a mammalian subject to form a free hydroxy group, a free amino group, or a 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 phosphorus atom-modified nucleic acids. The terms “prodigo nucleotide,” “prodrug nucleotide,” or “nucleic acid prodrug” refer to oligonucleotides modified to be prodrugs of oligonucleotides. Phosphonic acid 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, which is hereby incorporated by reference in its entirety.

[0052] In certain embodiments, the compounds of the disclosure are prodrugs of any of the formulas herein.

[0053] The term “subject” refers to an animal, e.g., a mammal, e.g., but not limited to, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

[0054] The terms “a,” “an,” and “the,” as used in this application, including in the claims, refer to “one or more.” Thus, for example, a reference to “a sample” includes a plurality of samples, unless the context clearly dictates otherwise (e.g., multiple samples), and the same applies to other cases.

[0055] 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.

[0056] As used herein, the term "about", when referring to a value, means in some embodiments a variation of ±20% from the specified amount, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1%, such variations being appropriate to the practice of the disclosed method or the use of the disclosed composition.

[0057] The term "aliphatic" includes both saturated and unsaturated, straight-chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic hydrocarbons, which may optionally be substituted with one or more functional groups. As will be understood by those skilled in the art, "aliphatic" is intended to include, but not be limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, the term "alkyl" includes linear, branched, and cyclic alkyl groups. Similar conventions apply to other general terms such as "alkenyl", "alkynyl", etc. Further, terms such as "alkyl", "alkenyl", "alkynyl", etc. encompass both substituted and unsubstituted groups. In certain embodiments, "lower alkyl" is used to denote an alkyl group having from 1 to 6 carbon atoms (cyclic, acyclic, substituted, unsubstituted, branched or unbranched).

[0058] In certain embodiments, the alkyl, alkenyl, and alkynyl groups employed in the present disclosure contain 1 to 30 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the present disclosure contain 1 to 20 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the present disclosure contain 10 to 30 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the present disclosure contain 10 to 20 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the present disclosure contain 1 to 10 carbon atoms. Thus, exemplary aliphatic groups include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH 2 -cyclopropyl, vinyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH 2 -cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, -CH 2 -cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, -CH 2 -cyclohexyl moieties, etc., but are not limited thereto, and these may also have one or more substituents. Alkenyl groups include, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc., but are not limited thereto. Representative alkynyl groups include ethynyl, 2-propynyl (propargyl), 1-propynyl, etc., but are not limited thereto.

[0059] As used herein, the term "alkyl" means, by itself or as part of another substituent, a straight-chain (i.e., unbranched) or branched carbon chain (or carbon) having the specified number of carbon atoms, or a combination thereof, and may be fully saturated, monounsaturated (e.g., alkene or alkenyl) or polyunsaturated (e.g., alkyne or alkynyl), and may include monovalent, divalent, and polyvalent radicals. For example, C1 -C 30 means from 1 to 30 carbon atoms. Specific numbers of carbon atoms within this range include, for example, C 1 -C 30 alkyl (having 1 to 20 carbon atoms), C 1 -C 20 alkyl (having 1 to 20 carbon atoms), C 1 -C 12 alkyl (having 1 to 12 carbon atoms) and C 1 -C 4 alkyl (having 1 to 4 carbon atoms), and C 18 (having 18 carbon atoms) may be mentioned.

[0060] The term "alkenyl" refers to an unsaturated hydrocarbon chain which may be straight or branched and which contains at least 2 carbon atoms and at least one carbon-carbon double bond (for example, which contains 2 to 30 carbon atoms and at least one carbon-carbon double bond). The alkenyl group may be substituted with one or more substituents or may be unsubstituted.

[0061] The term "alkynyl" refers to an unsaturated hydrocarbon chain which may be straight or branched and which contains at least 2 carbon atoms and at least one carbon-carbon triple bond (for example, which contains 2 to 30 carbon atoms and at least one carbon-carbon triple bond). The alkynyl group may be substituted with one or more substituents or may be unsubstituted.

[0062] The term "lower alkyl" refers to a C 1 -C 6 alkyl chain. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-pentyl. The alkyl group may be substituted with one or more substituents or may be unsubstituted.

[0063] The term "haloalkyl" refers to an alkyl group substituted by one or more halo substituents. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, chloromethyl, and 2,2,2-trifluoroethyl.

[0064] The term "arylalkenyl" refers to an unsaturated hydrocarbon chain that may be straight or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon double bond, and having one or more of the sp 2 hybridized carbons of the alkenyl unit bonded to an aryl moiety. The alkenyl group may be substituted with one or more substituents or may be unsubstituted.

[0065] The term "arylalkynyl" refers to an unsaturated hydrocarbon chain that may be straight or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond, and having one or more of the sp2 hybridized carbons of the alkynyl unit bonded to an aryl moiety. The alkynyl group may be substituted with one or more substituents or may be unsubstituted.

[0066] The sp 2 hybridized carbon or sp hybridized carbon of the alkenyl group or alkynyl group may each optionally be the point of attachment of the alkenyl group or alkynyl group.

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

[0068] As used herein, the terms "halogen", "hal", or "halo" mean -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 -O-alkyl substituted by one or more halo substituents. Examples of haloalkoxy groups include trifluoromethoxy and 2,2,2-trifluoroethoxy.

[0072] The term "haloalkoxyalkyl" refers to alkyl-O-alkyl', where alkyl' is substituted by one or more halo substituents.

[0073] The term "haloalkylaminocarbonyl" refers to -C(O)-amino-alkyl, where alkyl is substituted by one or more halo substituents.

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

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

[0076] The term "cycloalkyl" refers to a 3- to 8-membered monocyclic or 7- to 14-membered bicyclic hydrocarbon ring system having at least one saturated ring or at least one non-aromatic ring, and the non-aromatic ring may have a certain degree of unsaturation. The cycloalkyl group may be substituted with one or more substituents or may be unsubstituted. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of the cycloalkyl group may be substituted by a substituent. Representative examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.

[0077] The term "cycloalkoxy" refers to an -O-cycloalkyl substituent.

[0078] The term "cycloalkoxyalkyl" refers to an -alkyl-O-cycloalkyl substituent.

[0079] The term "cycloalkylalkoxy" refers to an -O-alkyl-cycloalkyl substituent.

[0080] The term "cycloalkylaminocarbonyl" refers to a -C(O)-NH-cycloalkyl substituent.

[0081] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic ring system of hydrocarbons. The aryl group may be substituted with one or more substituents or may be unsubstituted. In one embodiment, 0, 1, 2, 3, 4, 5, or 6 atoms of each ring of the aryl group may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.

[0082] The term "aryloxy" refers to an -O-aryl substituent.

[0083] The term "arylalkoxy" refers to an -O-alkyl-aryl substituent.

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

[0085] The term "aryloxyalkyl" refers to an alkyl-O-aryl substituent.

[0086] The term "alkylaryl" refers to an -aryl-alkyl substituent.

[0087] The term "arylalkyl" refers to an -alkyl-aryl substituent.

[0088] The term "heteroalkyl", by itself or in combination with another term, unless otherwise indicated, means a stable straight-chain or branched-chain, or combinations thereof, containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and / or S), with the nitrogen and sulfur atoms optionally oxidized and the nitrogen heteroatom optionally quaternized. The heteroatom(s) (e.g., O, N, P, Si, and / or S) can be located at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an acyclic chain. Examples include, but are not limited to, -CH 2 -CH 2 -O-CH 3 、-CH 2 -CH 2 -NH-CH 3 、-CH 2 -CH 2 -N(CH 3 )-CH 3 、-CH 2 -S-CH 2 -CH 3 、-CH 2 -CH 2 、-S(O)-CH 3 、-CH 2 -CH 2 -S(O) 2 -CH 3 、-CH=CH-O-CH 3 、-Si(CH 3 ) 3 、-CH 2 -CH=N-OCH 3 、-CH=CH-N(CH 3 )-CH 3 、-O-CH 3 、-O-CH 2 -CH 3 、and -CN, among others. Up to two or three heteroatoms can be present, for example, in -CH 2 -NH-OCH 3 and -CH 2 -O-Si(CH 3 ) 3It may be continuous as shown. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). The heteroalkyl moiety may optionally contain two different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may optionally contain three different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may optionally contain four different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may optionally contain five different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may optionally contain up to eight different heteroatoms (e.g., O, N, S, Si, or P).

[0089] Similarly, the term "heteroalkylene" means, by itself or as part of another substituent, a divalent radical derived from heteroalkyl, unless otherwise indicated, and includes, but is not limited to, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 - are exemplified. In the case of a heteroalkylene group, the heteroatom can also occupy one or both ends of the chain (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, in the case of alkylene and heteroalkylene linking groups, the orientation of the linking group is not indicated by the direction described in the formula of the linking group. For example, the formula -C(O) 2 R'- represents both -C(O) 2 R'- and -R'C(O) 2 -. As described above, heteroalkyl groups used herein include -C(O)R', -C(O)NR', -NR'R", -OR', -SR', and / or -SO 2Groups are included that are attached to the remainder of the molecule via a heteroatom such as R'. When "heteroalkyl" is indicated and then specific heteroalkyl groups such as -NR'R" are enumerated, it will be understood that the terms heteroalkyl and -NR'R" are neither redundant nor mutually exclusive. Rather, the specific heteroalkyl groups are enumerated for clarity. Thus, the term "heteroalkyl" should not be construed herein as excluding specific heteroalkyl groups such as -NR'R".

[0090] The term "alkylene", by itself or as part of another substituent, unless otherwise indicated, means a divalent radical derived from an alkyl, and includes, but is not limited to, -CH 2 CH 2 CH 2 CH 2 - as an example. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, and in this specification, groups having 10 or fewer carbon atoms are preferred. "Lower alkyl" or "lower alkylene" refers to a shorter-chain alkyl or alkylene group, generally having 8 or fewer carbon atoms. The term "alkenylene", by itself or as part of another substituent, unless otherwise indicated, means a divalent radical derived from an alkene.

[0091] The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with another term, unless otherwise indicated, mean the cyclic forms of "alkyl" and "heteroalkyl", respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Further, in the case of heterocycloalkyl, the heteroatom can occupy the position where 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, etc. 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, etc. "Cycloalkylene" and "heterocycloalkylene" mean divalent radicals derived from cycloalkyl and heterocycloalkyl, respectively, alone or as part of another substituent. "Cycloalkyl" also means, for example, bicyclic and polycyclic hydrocarbon rings such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.

[0092] The term "heteroaryl" refers to a 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic aromatic ring system having 1 to 4 ring heteroatoms in the monocyclic case, 1 to 6 heteroatoms in the bicyclic case, or 1 to 9 heteroatoms in the tricyclic case, said heteroatoms being selected from O, N, or S, and the remaining ring atoms being carbon (with appropriate hydrogen atoms where not otherwise specified). The heteroaryl group may be substituted with one or more substituents or may be unsubstituted. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of the heteroaryl group may be substituted by a substituent. The heteroaryl group may be fully unsaturated, partially unsaturated, or partially saturated. Examples of heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolylthiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and the like.

[0093] The term "heteroarylalkyl" refers to an -alkyl-heteroaryl substituent.

[0094] The term "heteroaryloxy" refers to an -O-heteroaryl substituent.

[0095] The term "heteroarylalkoxy" refers to an -O-alkyl-heteroaryl substituent.

[0096] The term "heteroaryloxyalkyl" refers to an -alkyl-O-heteroaryl substituent.

[0097] The term "nitrogen-containing heteroaryl" refers to a heteroaryl group having 1 to 4 ring nitrogen heteroatoms in the monocyclic case, 1 to 6 ring nitrogen heteroatoms in the bicyclic case, or 1 to 9 ring nitrogen heteroatoms in the tricyclic case.

[0098] The term "heterocycloalkyl" refers to a 3- to 8-membered monocyclic, 7- to 12-membered bicyclic, or 10- to 14-membered tricyclic non-aromatic ring system containing 1 to 3 heteroatoms in the monocyclic case, 1 to 6 heteroatoms in the bicyclic case, or 1 to 9 heteroatoms in the tricyclic case, said heteroatoms being selected from O, N, S, B, P or Si, and the non-aromatic ring system being completely saturated. The heterocycloalkyl group may be substituted with one or more substituents or may be unsubstituted. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of the heterocycloalkyl group may be substituted by a substituent. Representative heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl, thienylenyl, and the like.

[0099] The term "heterocycloalkylalkyl" refers to an -alkyl-heterocycloalkyl substituent.

[0100] The term "alkylamino" refers to an amino substituent further substituted with one or two alkyl groups. The term "aminoalkyl" refers to an alkyl further substituted with one or more amino groups. The term "hydroxyalkyl" or "hydroxylalkyl" refers to an alkyl substituent further substituted with one or more hydroxyl groups. The alkyl portion or aryl portion of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be substituted with one or more substituents or may be unsubstituted.

[0101] The term "nucleobase" refers to a nitrogen-containing biological compound that forms a nucleoside. Nucleobases include purine bases and pyrimidine bases. Five nucleobases, adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U), are referred to as primary nucleobases or canonical nucleobases. When a nucleobase is listed in the definition of a formula, it refers to the moiety covalently attached to the listed formula.

[0102] The term "modified nucleobase" refers to a derivative 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 the definition of a formula, it refers to the moiety covalently attached to the listed formula.

[0103] The terms "substituent" and "substituent group" mean an atom or group that replaces an atom or group of a specified parent compound. For example, a substituent of a modified nucleoside is an atom or group that is different from the atoms or groups found in a naturally occurring nucleoside (e.g., a modified 2'-substituent is any atom or group other than H or OH at the 2'-position of the nucleoside). A substituent may or may not be protected. A substituent may also be further substituted with other substituents and is bonded to the parent compound directly or via a linking group such as an alkyl group or a hydrocarbyl group. Similarly, as used herein, "substituent" with respect to a chemical functional group means an atom or group of atoms that is different from the atoms or groups normally present in the specified functional group. In certain embodiments, a substituent on any group (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) can be on any atom of the group, where any group that can be substituted (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl, etc.) may be substituted with one or more substituents (which may be the same or different) each replacing a hydrogen atom or may be unsubstituted.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, hydroxyalkyl, 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, amide, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, carboxamide, carbamide, carbamyl, thioureido, thiocyanato, sulfonamide, 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, hydroxyalkyl, 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 amide. In certain embodiments, substituents on any group include alkyl, halogen, haloalkyl, cyano, nitro, alkoxy, hydroxyl, hydroxyalkyl, carboxyl, formyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, thio, mercapto, mercaptoalkyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, or alkylamino.

[0104] The term "protecting group" or "protecting moiety" refers to a substituent commonly used to block or protect a particular functionality while allowing reaction of other functional groups on a compound, its derivatives, or conjugates, and includes nitrogen protecting groups when attached to a nitrogen atom and oxygen protecting groups 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).

[0105] In certain embodiments, the substituent present on the 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, -OR aa , -N(R cc ) 2 , -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR cc )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , C 1-10 alkyl (e.g., aralkyl, heteroaralkyl), C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclic, 3- to 14-membered heterocyclic, C 6-14 aryl, and 5- to 14-membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and each R aa , R bb , and R cc is independently alkyl, cycloalkyl, aryl, or heteroaryl, each of which may be substituted with 1 to 3 independent R dd groups or may be unsubstituted, and each R ddis, independently, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxyl, hydroxyalkyl, 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, amide, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, carbamide, carbamyl, thioureido, thiocyanato, sulfamide, 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, 3 rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0106] Amide nitrogen protecting groups (e.g., -C(=O)R aa) includes, but is not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyl-oxyacylamino)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.

[0107] A carbamate nitrogen protecting group (e.g., -C(=O)OR aa) includes 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, alkyldithiocarbamate, 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)]methylcarbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acetyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonylmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzylcarbamate, o-nitrobenzylcarbamate, 3,4-dimethoxy-6-nitrobenzylcarbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amylcarbamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, cyclobutylcarbamate, cyclohexylcarbamate, cyclopentylcarbamate, cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 2,2-dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamide)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamide)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p’-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1-methylcyclohexylcarbamate, 1-methyl-1-cyclopropylmethylcarbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethylcarbamate, 1-methyl-1-(p-phenylazophenyl)ethylcarbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethylcarbamate, phenylcarbamate, p-(phenylazo)benzylcarbamate, 2,4,6-tri-t-butylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate, and 2,4,It includes, but is not limited to, 6-trimethylbenzyl carbamate.,

[0108] Sulfonamide nitrogen protecting groups (e.g., -S(=O) 2 R aa ) 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.,

[0109] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilazacyclopentane 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-dibenzosuberlylamine, 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'-isopropylidenediamine, 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-diphenylboric acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphine amide (Dpp), dimethylthiophosphine amide (Mpt), diphenylthiophosphine amide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate benzene sulfenamide, o-nitrobenzene sulfenamide (Nps), 2,4-dinitrobenzene sulfenamide, pentachlorobenzene sulfenamide, 2-nitro-4-methoxybenzene sulfenamide, triphenylmethyl sulfenamide, and 3-nitropyridine sulfenamide (Npys), but are not limited thereto.,

[0110] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups include -R aa , -N(R bb ), 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ), 2 , -C(=NR bb )R aa , -C(=NR bb )OR aa , -C(=NR bb )N(R bb ), 2 , -S(=O)R aa , -SO 2 R aa , -Si(R aa ), 3 , -P(R cc ), 2 , -P(R cc ), 3 , -P(=O) 2 R aa , -P(=O)(R aa ), 2, -P(=O)(OR cc ) 2 , -P(=O) 2 N(R bb ) 2 , and -P(=O)(NR bb ) 2 (wherein R aa , R bb , and R cc are as defined herein), but are not limited thereto. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3 rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0111] Exemplary oxygen protecting groups include methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyl oxymethyl (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-picolyl, 3-methyl-2-picolyl N-oxide, 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-benzodithiol-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethyltexylsilyl, 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), alkylmethyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkylethyl 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-naphthyl 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) are included, but not limited to these. In certain embodiments, the protecting group or oxygen protecting group is a dimethoxytrityl group. In certain embodiments, the protecting group or oxygen protecting group is a 2-cyanoethyl 5’-O-(4,4’-dimethoxytrityl)thymidine-3’-O-(N,N-diisopropylamino)-phosphoramidite group.,

[0112] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2 , -C(=NR bb )R aa , -C(=NR bb )OR aa , -C(=NR bb )N(R bb ) 2 , -S(=O)R aa , -SO 2 R aa , -Si(R aa ) 3 , -P(R cc ) 2 , -P(R cc ) 3 , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , -P(=O) 2 N(R bb ) 2 , and -P(=O)(NR bb ) 2 (wherein R aa , R bb , and R cc are as defined herein), but are not limited thereto. 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, 3 rd rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0113] The term "antisense oligonucleotide" or "antisense strand" means an oligonucleotide that includes a region complementary to a target nucleic acid.

[0114] The term "composition" or "pharmaceutical composition" means a mixture of substances suitable for administration to a subject. For example, a composition can include one or more compounds or salts thereof and a sterile aqueous solution.

[0115] The term "nucleic acid" refers to a molecule consisting of linked monomeric nucleotides or nucleosides. Nucleic acids include, but are not limited to, ribonucleic acid (RNA), deoxyribonucleic acid (DNA), single-stranded nucleic acids, and double-stranded nucleic acids.

[0116] The term "nucleic acid base sequence" means the order of consecutive nucleic acid bases in a nucleic acid or oligonucleotide, regardless of any sugar or internucleoside linkage.

[0117] The term "nucleoside" means a compound that includes a nucleic acid base and a sugar moiety. The nucleic acid base and the sugar moiety are each independently unmodified or modified. A "modified nucleoside" means a nucleoside that includes a modified nucleic acid base and / or a modified sugar moiety. Modified nucleosides include abasic nucleosides that lack a nucleic acid base.

[0118] The term "oligomeric compound" means a polymer of linked subunits. With respect to a protein, peptide, polypeptide, or antibody, a "subunit" refers to an amino acid or a peptide bond. With respect to an oligonucleotide, a "subunit" refers to a nucleotide, nucleoside, nucleic acid base, or sugar, or a modified nucleotide, modified nucleoside, modified nucleic acid base, or modified sugar as provided herein.

[0119] The term "oligonucleotide" means a polymer of linked nucleosides (e.g., polynucleotide, nucleic acid, polymer of nucleotides), each of which may or may not be modified, independently of one another. Without limitation, oligonucleotides can consist of ribonucleic acid (e.g., consisting of ribonucleosides), deoxyribonucleic acid (e.g., consisting of deoxyribonucleosides), modified nucleic acids (e.g., consisting of modified nucleobases, sugars, and / or phosphate groups), or combinations thereof. Examples of oligonucleotide compounds include single-stranded and double-stranded compounds, such as oligonucleotides, antisense oligonucleotides, interfering RNA compounds (RNAi compounds), oligonucleotides targeting microRNA (miRNA) and miRNA mimics, occupancy-based compounds (e.g., compounds that block mRNA processing or translation and splicing compounds). RNAi compounds include double-stranded compounds (e.g., small 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 miRNA mimics), which act at least in part via the RNA-induced silencing complex (RISC) pathway, thereby resulting in sequence-specific degradation and / or sequestration of the target nucleic acid via a process known as RNA interference (RNAi). The term "RNAi compound" means a nucleic acid compound capable of mediating sequence-specific RNA interference, such as interfering RNA (iRNA), iRNA agent, RNAi agent, small interfering RNA, small interfering RNA, small interfering oligonucleotide, small interfering nucleic acid, small interfering modified oligonucleotide, chemically modified siRNA, etc., and is equivalent to other terms used to describe such. Further, the term "RNAi" means equivalent to other terms used to describe sequence-specific RNA interference.

[0120] The terms "target nucleic acid", "target RNA", and "nucleic acid target" all mean a nucleic acid that can be targeted by the compounds described herein.

[0121] The term "therapeutic compound" includes any pharmaceutical agent or compound that provides a therapeutic benefit. Therapeutic compounds include nucleic acids, oligomeric compounds, oligonucleotides, proteins, peptides, antibodies, small molecules, and other such agents.

[0122] "Target region" means a part of a target nucleic acid to which one or more compounds are targeted.

[0123] "Targeting moiety" means a conjugate group that improves the affinity for a selected target, such as a molecule, cell or cell type, compartment, such as a cellular or organ compartment, tissue, organ, or region of the body, as compared to a compound in which the moiety is absent.

[0124] "Terminal group" means a chemical group or atomic group covalently bonded to the end of an oligonucleotide.

[0125] The term "conjugate group" means an atomic group bonded to an oligonucleotide. The conjugate group is optionally bonded to the oligonucleotide via a linker. The conjugate group can, for example, change the distribution, targeting, or half-life of the compound in which the group is incorporated. Conjugate groups include lipids (or lipophilic moieties), ligands, and other targeting moieties such as GalNAc moieties.

[0126] "Conjugate linker" means an atomic group containing at least one bond that connects a linking portion to an oligonucleotide and / or another therapeutic agent.

[0127] The term "lipid" or "lipophilic moiety" refers to aliphatic, cyclic (such as alicyclic), or polycyclic (such as polyalicyclic) compounds, for example, steroids (such as sterols) or linear or branched aliphatic hydrocarbons. The term lipid includes cholesterol, retinoic acid, cholic acid, adamantaneacetic acid, 1-pyrenebutyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl) lithocholic acid, O3-(oleoyl) chenodeoxycholic acid, ibuprofen, naproxen, dimethoxytrityl, or phenoxazine. The term lipid includes saturated or unsaturated C 4 -C 30 hydrocarbon chains (e.g., C 4 -C 30 alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated C 6 -C 18 hydrocarbon chain (e.g., linear C 6 -C 18 alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated C 16 hydrocarbon chain (e.g., linear C 16 alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated C 18 hydrocarbon chain (e.g., linear C 18 alkyl or alkenyl).

[0128] The term "ligand" refers to a substance that binds to or otherwise interacts with a protein, nucleic acid, or other biological molecule. In some embodiments, the ligand is a small molecule. In some embodiments, the ligand binds to a protein (e.g., a receptor). In certain embodiments, the ligand binds to an α 4 β 1 / 7 integrin receptor. In certain embodiments, the ligand binds to a receptor (e.g., α 4 β1 / 7 Integrin, TrkB, CB 1 or binds to the NMDA receptor). In certain embodiments, the ligand binds to the CB 1 receptor. In certain embodiments, the ligand binds to the tropomyosin receptor B (TrkB) receptor. In certain embodiments, the ligand binds to the α 4 β 1 / 7 integrin receptor. In certain embodiments, the ligand binds to the N-methyl-D-aspartic acid (NMDA) receptor.

[0129] In certain embodiments, a compound comprising a receptor (e.g., α 4 β 1 / 7 integrin, TrkB, or CB 1 receptor) ligand selectively or preferentially targets cells expressing the receptor (e.g., α 4 β 1 / 7 integrin, TrkB, CB 1 , or the NMDA receptor) compared to cells that do not express the receptor. In certain embodiments, a compound comprising a receptor ligand (e.g., α 4 β 1 / 7 integrin, TrkB, CB 1 , or the NMDA receptor) selectively or preferentially targets cells expressing the receptor ligand (e.g., α 4 β 1 / 7 integrin, TrkB, CB 1 , or the NMDA receptor) compared to a compound that does not comprise the receptor ligand (e.g., α 4 β 1 / 7 integrin, TrkB, CB 1 , or the NMDA receptor).

[0130] The term "α 4 β 1 / 7 integrin receptor" refers to integrin alpha 4 and integrin beta 1 (i.e., α 4 β 1 integrin receptor) and integrin alpha 4 and integrin beta 7 (i.e., α4 β 7 refers to a heterodimeric integrin receptor formed by the association of (integrin receptor).

[0131] The term "cannabinoid type 1 receptor" or "CB 1 " means a G-protein coupled receptor for cannabinoids. In humans, CB 1 is encoded by the CNR1 gene. CB 1 is also known as cannabinoid receptor 1.

[0132] In some embodiments, the nucleic acid is conjugated to a GalNAc moiety. GalNAc (N-acetylgalactosamine) is an amino sugar derivative of galactose. In some embodiments, the GalNAc moiety has the structure [Chemical formula] and includes. In some embodiments, the GalNAc moiety has the structure [Chemical formula] and includes. The GalNAc moiety is a targeting moiety that has an affinity for various tissues and cell receptors. Thus, the GalNAc moiety can facilitate the targeting of a cargo (e.g., nucleic acid) to such tissues and receptors. In some embodiments, the GalNAc moiety is useful for delivering a nucleic acid. In some embodiments, the GalNAc moiety delivers the nucleic acid locally. In some embodiments, the GalNAc moiety targets a tissue. In some embodiments, the tissue is the liver. In some embodiments, the GalNAc moiety targets a cell receptor. In some embodiments, the cell receptor is the asialoglycoprotein receptor. In some embodiments, the asialoglycoprotein receptor on hepatocytes.

[0133] The term "sense oligonucleotide" or "sense strand" means a strand of a double-stranded compound that includes a region that is substantially complementary to a region of the antisense strand of the double-stranded compound.

[0134] The terms "microRNA" and "miRNA", which 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 the post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNA. miRNAs are transcribed by RNA polymerase II as capped and polyadenylated primary transcripts (pri-miRNAs), which may or may not encode proteins. The primary transcripts are cleaved by the Drosha ribonuclease III enzyme to generate stem-loop precursor miRNAs (pre-miRNAs) that are approximately 70 nucleotides in length, which are further processed in the RNAi pathway. As part of this pathway, pre-miRNAs are cleaved by the cytoplasmic Dicer ribonuclease to generate mature miRNA products and antisense miRNA star (miRNA*) products. Mature miRNAs are incorporated into the 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 inhibition of translation or destabilization of the target mRNA. This mechanism most often occurs by binding of the miRNA to the 3' untranslated region (UTR) of the target mRNA, and gene expression can be decreased either by inhibiting translation (e.g., by blocking access of ribosomes required for translation) or by directly causing degradation of the transcript. This term (i.e., miRNA) may be used herein to refer to any form of the miRNA of interest (e.g., precursor miRNA, primary miRNA, and / or mature miRNA).

[0135] The terms "small interfering RNA", "short interfering RNA", and "siRNA", which may be used interchangeably herein, refer to non-coding double-stranded RNA (dsRNA) molecules that are approximately 20 to approximately 24 nucleotides in length and are useful for RNA interference (RNAi). siRNAs have been found to often have a phosphorylated 5' end and a hydroxylated 3' end, and the 3' end typically has an overhang that extends 2 nucleotides beyond the 5' end of the antiparallel strand (e.g., the complementary strand of the dsRNA molecule). siRNAs can bind to a complementary target sequence (e.g., a target nucleic acid sequence), induce (e.g., promote, trigger, initiate) the degradation of mRNA, thereby inhibiting (e.g., suppressing, silencing, interfering with) translation, and thus interfering with the expression of a specific gene. After incorporation into and dissociation from the RISC complex, the siRNA base pairs with (e.g., has perfect complementarity to) its target mRNA and cleaves it, thereby preventing the target mRNA from being used as a translation template. As described herein, this is also part of the RNAi pathway, but the RISC complex loaded with miRNA scans cytoplasmic mRNA for potential complementarity (e.g., partial complementarity).

[0136] The term "ADAR mobilizing molecule", which may be used herein, refers to a nucleic acid configured to increase the concentration of the adenosine deaminase (ADAR) enzyme that acts on ribonucleic acid in the local vicinity of the nucleic acid. In some embodiments, the increase in concentration is relative to the concentration in a given locale in the absence of the ADAR mobilizing molecule. In some embodiments, the ADAR mobilizing molecule includes a double-stranded RNA duplex.

[0137] As used herein, the term "ADAR targeting molecule" refers to a nucleic acid configured to direct an ADAR molecule to a desired location (e.g., local). As used herein, the term "direct" refers to increasing the concentration of ADAR at a desired location as compared to the concentration in the absence of the ADAR targeting molecule. In some embodiments, the ADAR targeting molecule can be configured to control a desired location by changing the sequence and / or properties of the nucleic acid (e.g., by modification to a nucleobase, sugar, phosphate, or other component). In some embodiments, the ADAR targeting molecule includes an ADAR mobilizing molecule and a single-stranded guide nucleic acid. In some embodiments, the ADAR targeting molecule includes a double-stranded RNA duplex and a single-stranded guide nucleic acid.

[0138] As used herein, the term "single-stranded guide nucleic acid" refers to a single-stranded nucleic acid that includes a specific sequence that is at least partially complementary to a target sequence. In some embodiments, the target sequence is at a local, adjacent, or proximal location where it is desirable to modulate the ADAR concentration. In some embodiments, the degree of complementarity is sufficient to facilitate binding (e.g., annealing) of the single-stranded guide nucleic acid to the target sequence.

[0139] "Modified oligonucleotide" means an oligonucleotide in which at least one sugar, nucleobase, or internucleoside linkage is modified.

[0140] "Nucleobase sequence" means the order of consecutive nucleobases in a nucleic acid or oligonucleotide, regardless of any sugar or internucleoside linkage.

[0141] The term "oligomer duplex" means a duplex formed by two oligomer compounds having complementary nucleic acid base sequences. Each oligomer compound of the oligomer duplex may also be referred to as a "duplex oligomer compound". The oligonucleotides of each oligomer compound of the oligomer duplex may contain non-complementary overhang nucleosides. In some embodiments, the terms "duplex oligomer compound" and "modified oligonucleotide" are used interchangeably. In other embodiments, the terms "oligomer duplex" and "compound" are used interchangeably.

[0142] "Phosphorothioate linkage" means a modified phosphate linkage in which one of the unbridged oxygen atoms is replaced by a sulfur atom.

[0143] The terms "RNA interference compound", "RNAi compound", and / or "iRNA agent" mean a compound that acts, at least in part, via the RNA-induced silencing complex (RISC) pathway or Ago2, rather than RNase Η, to regulate a target nucleic acid and / or a protein encoded by the target nucleic acid. RNAi compounds include, but are not limited to, double-stranded siRNAs, single-stranded siRNAs, and microRNAs including microRNA mimics.

[0144] The compounds of the present disclosure may also contain an atom isotope in a ratio not found in nature in one or more of the atoms constituting such compounds. For example, the compound may be radioactively labeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). Any isotope variants of the compounds of the present disclosure are included within the scope of the present disclosure, regardless of the presence or absence of radioactivity.

[0145] The term "isotope variant" refers to a therapeutic agent (e.g., a compound and / or modified oligonucleotide disclosed herein) that contains isotopes in a ratio not found in nature in one or more of the atoms that make up the therapeutic agent. In certain embodiments, an "isotope variant" of a therapeutic agent contains one or more isotopes in a ratio not found in nature, including hydrogen (H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl), chlorine-37 ( 37 Cl), bromine-79 ( 79 Br), bromine-81 ( 81 Br), iodine-123 ( 123 I), iodine-125 ( 125 I), iodine-127 ( 127 I), iodine-129 ( 129 I), and iodine-131 ( 131I), but not limited to these. In certain embodiments, an "isotope variant" of a therapeutic agent contains one or more isotopes in ratios not found in nature, including, but not limited to, hydrogen (H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl), chlorine-37 ( 37 Cl), bromine-79 ( 79 Br), bromine-81 ( 81 Br), iodine 123 ( 123 I), iodine-125 ( 125 I), iodine-127 ( 127 I), iodine-129 ( 129 I), and iodine-131 ( 131 I), but not limited to these.

[0146] In a therapeutic agent (e.g., a compound and / or modified oligonucleotide disclosed herein), where practicable by the judgment of one of ordinary skill in the art, for example, any hydrogen is 2It may be H, or for example, any carbon may be 13 C, or for example, any nitrogen may be 15 N, or for example, any oxygen may be 18 O. It will be understood that in certain embodiments, an “isotope variant” of a therapeutic agent contains deuterium (D) in a ratio not found in nature. DETAILED DESCRIPTION OF THE INVENTION

[0147] In certain embodiments, described herein is a compound of formula (I’), or a salt or prodrug thereof:

Chemical formula

[0148] In certain embodiments, the compound of formula (I’) is a compound of formula (VIII), or a salt or prodrug thereof:

Chemical formula

[0149] The present disclosure also provides a compound of formula (I):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

[0150] Furthermore, provided herein is a compound of formula (II):

Chemical formula

[0151] In certain embodiments, the compound of formula (II) is a salt having the following chemical structure:

Chemical formula

[0152] In certain embodiments, the salt is a potassium salt or a sodium salt. In certain embodiments, the salt is a potassium salt. In certain embodiments, the salt is a sodium salt.

[0153] In certain embodiments, the compound of formula (II) or a salt or prodrug thereof is represented by formula (II-a):

Chemical formula

[0154] In certain embodiments, Z 1 is a bond. In certain embodiments, Z 1 is C 1 -C 6 alkylene. In certain embodiments, Z 1 is C 2 -C 6is an alkenylene. In certain embodiments, Z 1 is -CH=CH-. In certain embodiments, Z 1 is -CH 2 -. In certain embodiments, Z 1 is -CH 2 CH 2 -.

[0155] In certain embodiments, Z 2 is a bond. In certain embodiments, Z 2 is C 1 -C 6 alkylene. In certain embodiments, Z 2 is C 2 -C 6 alkenylene. In certain embodiments, Z 2 is -CH=CH-. In certain embodiments, Z 2 is -CH 2 -. In certain embodiments, Z 2 is -CH 2 CH 2 -.

[0156] In certain embodiments, Z 3 is a bond. In certain embodiments, Z 3 is C 1 -C 6 alkylene. In certain embodiments, Z 3 is C 2 -C 6 alkenylene. In certain embodiments, Z 3 is -CH=CH-. In certain embodiments, Z 3 is -CH 2 -. In certain embodiments, Z 3 is -CH 2 CH 2 -.

[0157] In certain embodiments, Z 4 is a bond. In certain embodiments, Z4 is C 1 -C 6 is alkylene. In certain embodiments, Z 4 is C 2 -C 6 is alkenylene. In certain embodiments, Z 4 is -CH=CH-. In certain embodiments, Z 4 is -CH 2 -. In certain embodiments, Z 4 is -CH 2 CH 2 -.

[0158] In certain embodiments, the compound of formula (II) or a salt or prodrug thereof is represented by formula (II-b):

Chemical formula

[0159] In some embodiments, R 4 and R 5 each contain an oligonucleotide. In some embodiments, R 4 and R 5 are joined together to form a single oligonucleotide. In some embodiments, R 4 contains an oligonucleotide and R 5 contains a protecting group. In some embodiments, R 4 contains a protecting group and R 5 contains an oligonucleotide. In some embodiments, R 4 and R 5 each contain a protecting group. In some embodiments, one or both of the oligonucleotides are attached at their 5'-ends. In some embodiments, one or both of the oligonucleotides are attached at their 3'-ends. In some embodiments, one or both of the oligonucleotides are attached at an internal position of the oligonucleotide. In certain embodiments, the internal position is an internucleoside linkage.

[0160] In certain embodiments, the oligonucleotides disclosed herein are oligonucleotides of formula (IX):

Chemical formula

[0161] In certain embodiments, the oligonucleotides disclosed herein are oligonucleotides of formula (X): [Chemical Formula] (wherein R C is -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, each R 2 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 , -N(R 6 ), or -SR 6 , each R 3 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 , -N(R 7 ), or -SR 7 , R 4 and R 5 are independently an oligonucleotide, a protecting group, or R 4 and R 5 are joined together to form a single oligonucleotide, each R 6 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl, each R 7 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl, each R 8 is independently a substituted or unsubstituted heteroaryl ring, each R9 is, independently, a substituted or unsubstituted heteroaryl ring, each X is, independently, O or S) or a salt or prodrug thereof.

[0162] In certain embodiments, the oligonucleotides disclosed herein are oligonucleotides of formula (XI):

Chemical formula

[0163] In certain embodiments, the oligonucleotides disclosed herein are oligonucleotides of formula (XI-a):

Chemical formula

[0164] In certain embodiments, the oligonucleotides disclosed herein are oligonucleotides of formula (XI-b): [Chemical formula] (wherein R C is -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 4 and R 5 are independently an oligonucleotide, a protecting group, or R 4 and R 5 are joined together to form a single oligonucleotide, each R 7 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl, each R 8 is independently a substituted or unsubstituted heteroaryl ring, each R 9 is independently a substituted or unsubstituted heteroaryl ring, each X is independently O or S) or a salt or prodrug thereof.

[0165] In certain embodiments, the oligonucleotides disclosed herein are oligonucleotides of formula (XI-c): [Chemical formula] (wherein R C is -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 4 and R 5is, independently, an oligonucleotide, a protecting group, or R 4 and R 5 are joined together to form a single oligonucleotide, each R 6 is, independently, hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl, each R 8 is, independently, a substituted or unsubstituted heteroaryl ring, each R 9 is, independently, a substituted or unsubstituted heteroaryl ring, each X is, independently, O or S) or a salt or prodrug thereof.

[0166] In certain embodiments, the oligonucleotides disclosed herein are oligonucleotides of formula (XII):

Chemical formula

[0167] In certain embodiments, the oligonucleotides disclosed herein are oligonucleotides of formula (XIII):

Chemical formula

[0168] In certain embodiments, the oligonucleotides disclosed herein are oligonucleotides of formula (XIV):

Chemical formula

[0169] In certain embodiments, the oligonucleotides disclosed herein are oligonucleotides of formula (IX-a):

Chemical formula

[0170] In certain embodiments, the oligonucleotides disclosed herein are oligonucleotides of formula (IX-b): [Chemical formula] (wherein, each R 2 is, independently, -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 , -N(R 6 ), or -SR 6 ), and each R 3 is, independently, -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 , -N(R 7 ), or -SR 7 ), and R 4 and R5 is, independently, an oligonucleotide, a protecting group, or R 4 and R 5 are joined together to form a single oligonucleotide, each R 6 is, independently, hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl, each R 7 is, independently, hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl, each R 8 is, independently, a substituted or unsubstituted heteroaryl ring, each R 9 is, independently, a substituted or unsubstituted heteroaryl ring, each X is, independently, O or S) or a salt or prodrug thereof.

[0171] In certain embodiments, the oligonucleotides disclosed herein are oligonucleotides of formula (IX-c):

Chemical formula

[0172] In certain embodiments, the oligonucleotides disclosed herein are oligonucleotides of formula (IX-d):

Chemical formula

[0173] In certain embodiments, the oligonucleotides disclosed herein are oligonucleotides of formula (IX-e):

Chemical formula

[0174] In certain embodiments, the oligonucleotides disclosed herein are oligonucleotides of formula (X-a):

Chemical formula

[0175] In certain embodiments, the oligonucleotides disclosed herein are oligonucleotides of formula (XV):

Chemical formula

[0176] In certain embodiments, the oligonucleotides disclosed herein are oligonucleotides of formula (XVI):

Chemical formula

[0177] In certain embodiments, the oligonucleotides disclosed herein are oligonucleotides of formula (XVII):

Chemical formula

[0178] In certain embodiments, the oligonucleotides disclosed herein are oligonucleotides of formula (XVIII): [Chemical formula] (wherein each R 2 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 , -N(R 6 ), or -SR 6 ; each R 3 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 , -N(R 7 ), or -SR 7 ; R 4 and R 5 are independently an oligonucleotide, a protecting group, or R 4 and R 5 are joined together to form a single oligonucleotide, each R 6 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl, each R 7 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl, each R 8is, independently, a substituted or unsubstituted heteroaryl ring, each R 9 is, independently, a substituted or unsubstituted heteroaryl ring, each X is, independently, O or S) or a salt or prodrug thereof.

[0179] In certain embodiments, the compound of formula (II) is of the formula:

Chemical formula

Chemical formula

[0180] Also provided herein is an oligonucleotide of formula (VI) or a salt or prodrug thereof, of formula (VI):

Chemical formula

[0181] In certain embodiments, R 4 and R 5 are each, independently, an oligonucleotide or a protecting group.

[0182] Also provided herein are compounds of formula (VII):

Chemical formula

Chemical formula

[0183] In certain embodiments, the compound of formula (I’) is of the formula:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0184] In certain embodiments, the compound of formula (I), or a salt or prodrug thereof, is represented by the following formula: [Chemical formula] (wherein R 4 and R 5 are independently an oligonucleotide or a protecting group, Each X is independently O or S).

[0185] In certain embodiments, the compounds of formula (I) are of the following formula:

Chemical formula

[0186] In certain embodiments, the compounds of formula (I) are of the following formula:

Chemical formula

[0187] In certain embodiments, the compounds described herein contain the substituent W 1 . In certain embodiments, W 1 is a modified or unmodified nucleoside. In certain embodiments, W 1 is an oligonucleotide. In certain embodiments, W 1 is a ligand. In certain embodiments, W 1 is a lipid. In certain embodiments, W 1 is a protecting group.

[0188] In certain embodiments, the compounds described herein contain the substituent W 2 . In certain embodiments, W 2is a linkage. In certain embodiments, W 2 is a linker. In certain embodiments, W 2 is a substituted or unsubstituted alkylene. In certain embodiments, W 2 is a substituted or unsubstituted heteroalkylene. In certain embodiments, W 2 is a substituted or unsubstituted carbocyclylene. In certain embodiments, W 2 is a substituted or unsubstituted heterocyclylene. In certain embodiments, W 2 is a substituted or unsubstituted arylene. In certain embodiments, W 2 is a substituted or unsubstituted heteroarylene. In certain embodiments, W 2 is -O-. In certain embodiments, W 2 is -OP(O)O 2 -. In certain embodiments, W 2 is -N(R A )-. In certain embodiments, W 2 is -S-. In certain embodiments, W 2 is -C(=O)-. In certain embodiments, W 2 is -C(=O)O-. In certain embodiments, W 2 is -C(=O)NR A -. In certain embodiments, W 2 is -NR A C(=O)-. In certain embodiments, W 2 is -NR A C(=O)R A -. In certain embodiments, W 2 is -C(=O)R A -. In certain embodiments, W 2 is -NR A C(=O)O-. In certain embodiments, W 2 is -NR A C(=O)N(R A )-. In certain embodiments, W2 is -OC(=O)-. In certain embodiments, W 2 is -OC(=O)O-. In certain embodiments, W 2 is -OC(=O)N(R A )-. In certain embodiments, W 2 is -S(O) 2 NR A -. In certain embodiments, W 2 is -NR A SO 2 -.

[0189] In certain embodiments, the compounds described herein contain the substituent W 3 . In certain embodiments, W 3 is a bond. In certain embodiments, W 3 is a linker. In certain embodiments, W 3 is substituted or unsubstituted alkylene. In certain embodiments, W 3 is substituted or unsubstituted heteroalkylene. In certain embodiments, W 3 is substituted or unsubstituted carbocyclylene. In certain embodiments, W 3 is substituted or unsubstituted heterocyclylene. In certain embodiments, W 3 is substituted or unsubstituted arylene. In certain embodiments, W 3 is substituted or unsubstituted heteroarylene. In certain embodiments, W 3 is -O-. In certain embodiments, W 3 is -OP(O)O 2 -. In certain embodiments, W 3 is -N(R A )-. In certain embodiments, W 3 is -S-. In certain embodiments, W 3 is -C(=O)-. In certain embodiments, W 3is -C(=O)O-. In certain embodiments, W 3 is -C(=O)NR A -. In certain embodiments, W 3 is -NR A C(=O)-. In certain embodiments, W 3 is -NR A C(=O)R A -. In certain embodiments, W 3 is -C(=O)R A -. In certain embodiments, W 3 is -NR A C(=O)O-. In certain embodiments, W 3 is -NR A C(=O)N(R A )-. In certain embodiments, W 3 is -OC(=O)-. In certain embodiments, W 3 is -OC(=O)O-. In certain embodiments, W 3 is -OC(=O)N(R A )-. In certain embodiments, W 3 is -S(O) 2 NR A -. In certain embodiments, W 3 is -NR A SO 2 -.

[0190] In certain embodiments, the compounds described herein contain the substituent W 4 . In certain embodiments, W 4 is a modified or unmodified nucleoside. In certain embodiments, W 4 is an oligonucleotide. In certain embodiments, W 4 is a ligand. In certain embodiments, W 4 is a lipid. In certain embodiments, W 4 is a protecting group.

[0191] In certain embodiments, W 1 is a modified or unmodified nucleoside, and W 4 is a modified or unmodified nucleoside. In certain embodiments, W 1 is a modified or unmodified nucleoside, and W 4 is an oligonucleotide.

[0192] In certain embodiments, W 1 is a modified or unmodified nucleoside, and W 2 is a bond, and W 4 is a modified or unmodified nucleoside. In certain embodiments, W 1 is a modified or unmodified nucleoside, and W 2 is a bond, and W 4 is an oligonucleotide.

[0193] In certain embodiments, W 1 is a modified or unmodified nucleoside, and W 2 is a linker, and W 4 is a modified or unmodified nucleoside. In certain embodiments, W 1 is a modified or unmodified nucleoside, and W 2 is a linker, and W 4 is an oligonucleotide.

[0194] In certain embodiments, W 1 is a modified or unmodified nucleoside, and W 3 is a bond, and W 4 is a modified or unmodified nucleoside. In certain embodiments, W 1 is a modified or unmodified nucleoside, and W 3 is a bond, and W 4 is an oligonucleotide.

[0195] In certain embodiments, W 1 is a modified or unmodified nucleoside, and W 3is a linker, W 4 is a modified or unmodified nucleoside. In certain embodiments, W 1 is a modified or unmodified nucleoside, W 3 is a linker, W 4 is an oligonucleotide.

[0196] In certain embodiments, W 1 is a modified or unmodified nucleoside, W 3 is a substituted or unsubstituted heteroalkylene, W 4 is a modified or unmodified nucleoside. In certain embodiments, W 1 is a modified or unmodified nucleoside, W 3 is a substituted or unsubstituted heteroalkylene, W 4 is an oligonucleotide.

[0197] In certain embodiments, the compounds described herein contain the substituent Q 1 . In certain embodiments, Q 1 is -H. In certain embodiments, Q 1 is -OR 4 . In certain embodiments, Q 1 is a ligand. In certain embodiments, Q 1 is a linker. In certain embodiments, Q 1 is a lipid.

[0198] In certain embodiments, the compounds described herein contain the substituent Q 2 . In certain embodiments, Q 2 is independently a bond. In certain embodiments, Q 2 is independently

Chemical formula

[0199] In certain embodiments, the compounds described herein contain the substituent Q 3 In certain embodiments, Q 3 is, independently, a bond. In certain embodiments, Q 3 is, independently,

Chemical formula

[0200] In certain embodiments, the compounds described herein contain the substituent Q 4 In certain embodiments, Q 4 is, independently, a bond, and in certain embodiments, Q 4 is, independently, -R 10 O-. In certain embodiments, Q 4 is, independently, a ligand. In certain embodiments, Q 4 is, independently, a linker. In certain embodiments, Q 4 is, independently, a lipid.

[0201] In certain embodiments, the compounds described herein contain the substituent Q 5 In certain embodiments, Q 5 is, independently, a bond. In certain embodiments, Q 5 is, independently,

Chemical formula

[0202] In certain embodiments, the compounds described herein contain the substituent Q 6 . In certain embodiments, Q 6 is, independently, a bond. In certain embodiments, Q 6 is, independently,

Chemical formula

[0203] In certain embodiments, the compounds described herein contain the substituent Q 7 . In certain embodiments, Q 7 is, independently, -H. In certain embodiments, Q 7 is, independently, -R 5 . In certain embodiments, Q 7 is, independently, a ligand. In certain embodiments, Q 7 is, independently, a linker. In certain embodiments, Q 7 is, independently, a lipid.

[0204] In certain embodiments, the compounds described herein contain substituent Y. In certain embodiments, Y is independently a substituted or unsubstituted alkylene. In certain embodiments, Y is independently a substituted or unsubstituted heteroalkylene. In certain embodiments, Y is independently a substituted or unsubstituted carbocyclylene. In certain embodiments, Y is independently a substituted or unsubstituted heterocyclylene. In certain embodiments, Y is independently a substituted or unsubstituted arylene. In certain embodiments, Y is independently a substituted or unsubstituted heteroarylene. In certain embodiments, Y is independently -O-. In certain embodiments, Y is independently -OP(O)O 2 -. In certain embodiments, Y is independently -N(R C ). In certain embodiments, Y is independently -S-. In certain embodiments, Y is independently -C(=O)-. In certain embodiments, Y is independently -C(=O)O-. In certain embodiments, Y is independently C(=O)N(RC). In certain embodiments, Y is independently N(R C )C(=O). In certain embodiments, Y is independently -NR C C(=O)R C . In certain embodiments, Y is independently -C(=O)R C . In certain embodiments, Y is independently -NR C C(=O)O-. In certain embodiments, Y is independently -NR C C(=O)N(R C ). In certain embodiments, Y is independently -OC(=O)-. In certain embodiments, Y is independently -OC(=O)O-. In certain embodiments, Y is independently -OC(=O)N(R C ). In certain embodiments, Y is independently -S(O) 2 NR C- is. In certain embodiments, Y is independently -NR C SO 2 - is.

[0205] In certain embodiments, R C is independently -H. In certain embodiments, R C is independently substituted or unsubstituted alkyl. In certain embodiments, R C is independently substituted or unsubstituted alkenyl. In certain embodiments, R C is independently substituted or unsubstituted alkynyl. In certain embodiments, R C is independently substituted or unsubstituted heteroalkyl. In certain embodiments, R C is independently substituted or unsubstituted aryl. In certain embodiments, R C is independently substituted or unsubstituted heteroaryl. In certain embodiments, R C is independently substituted or unsubstituted lipophilic moiety. In certain embodiments, each R C is independently alkyl. In certain embodiments, each R C is independently -C 8 -C 100 -alkyl. In certain embodiments, each R C is independently -C 8 -C 40 -alkyl. In certain embodiments, each R C is independently -C 8 -C 20 -alkyl. In certain embodiments, each R C is independently -C 12 -C 20 -alkyl. In certain embodiments, each R C is independently -C 16 -C 20 -alkyl. In certain embodiments, each R C is independently -H.

[0206] In certain embodiments, R C is tocopherol (e.g., α (alpha), β (beta), γ (gamma), or δ (delta) tocopherol). In certain embodiments, R C is vitamin E.

[0207] In certain embodiments, R c is a saturated or unsaturated C 1 -C 30 hydrocarbon chain (e.g., C 1 -C 30 alkyl or alkenyl) optionally substituted with a functional group selected from the group consisting of hydroxyl, amine, carboxylic acid, azide, and alkyne.

[0208] In some embodiments, the R c group contains a saturated or unsaturated C 1 -C 17 hydrocarbon chain (e.g., linear C 1 -C 17 alkyl or alkenyl). In one embodiment, the lipophilic moiety contains a saturated or unsaturated C 17 hydrocarbon chain.

[0209] In some embodiments, the R c group is a C 1 -C 30 acid (e.g., hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, tetradecanoic acid, pentadecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid, oleic acid, linoleic acid, arachidonic acid, and anandamide).

[0210] In certain embodiments, the compounds described herein contain the substituent R 2 . In certain embodiments, R 2 is independently -H. In certain embodiments, R 2 is independently -OR6 It is. In certain embodiments, R 2 is independently a halogen. In certain embodiments, R 2 is independently -F. In certain embodiments, R 2 is independently a substituted or unsubstituted alkyl. In certain embodiments, R 2 is independently a substituted or unsubstituted alkenyl. In certain embodiments, R 2 is independently a substituted or unsubstituted alkynyl. In certain embodiments, R 2 is independently -OMe. In certain embodiments, R 2 is independently -N(R 6 ). In certain embodiments, R 2 is independently -SR 6 .

[0211] In certain embodiments, the compounds described herein contain the substituent R 3 . In certain embodiments, R 3 is independently -H. In certain embodiments, R 3 is independently -OR 7 . In certain embodiments, R 3 is independently a halogen. In certain embodiments, R 3 is independently -F. In certain embodiments, R 3 is independently a substituted or unsubstituted alkyl. In certain embodiments, R 3 is independently a substituted or unsubstituted alkenyl. In certain embodiments, R 3 is independently a substituted or unsubstituted alkynyl. In certain embodiments, R 3 is independently -OMe. In certain embodiments, R 3 is independently -N(R 7 ). In certain embodiments, R 3 is independently -SR 7 .

[0212] In certain embodiments, the compounds described herein contain substituent R 4 . In certain embodiments, R 4 is an oligonucleotide. In certain embodiments, R 4 is a protecting group.

[0213] In certain embodiments, the compounds described herein contain substituent R 5 . In certain embodiments, R 5 is an oligonucleotide. In certain embodiments, R 5 is a protecting group.

[0214] In certain embodiments, R 4 and R 5 are each independently an oligonucleotide.

[0215] In certain embodiments, R 4 is an oligonucleotide and R 5 is a protecting group.

[0216] In certain embodiments, R 4 is a protecting group and R 5 is an oligonucleotide.

[0217] In certain embodiments, R 4 and R 5 are each independently a protecting group.

[0218] In some embodiments, R 4 and R 5 are joined together to form a single oligonucleotide.

[0219] In certain embodiments, the compounds described herein contain substituent R 6 . In certain embodiments, R 6is, independently, a substituted or unsubstituted alkyl. In certain embodiments, R 6 is, independently, a substituted or unsubstituted heteroalkyl.

[0220] In certain embodiments, the compounds described herein contain the substituent R 7 In certain embodiments, R 7 is, independently, a substituted or unsubstituted alkyl. In certain embodiments, R 7 is, independently, a substituted or unsubstituted heteroalkyl.

[0221] In certain embodiments, the compounds described herein contain the substituent R 8 In certain embodiments, R 8 is, independently, uracil. In certain embodiments, R 8 is, independently, cytosine. In certain embodiments, R 8 is, independently, adenine. In certain embodiments, R 8 is, independently, guanine. In certain embodiments, R 8 is, independently, inosine. In certain embodiments, R 8 is, independently, thymine. In certain embodiments, R 8 is, independently, a substituted or unsubstituted heteroaryl. In certain embodiments, R 8 is, independently, a nucleobase. In certain embodiments, R 8 is, independently, a modified nucleobase.

[0222] In certain embodiments, the compounds described herein contain the substituent R 9 In certain embodiments, R 9 is, independently, uracil. In certain embodiments, R 9 is, independently, cytosine. In certain embodiments, R 9is, independently, adenine. In certain embodiments, R 9 is, independently, guanine. In certain embodiments, R 9 is, independently, inosine. In certain embodiments, R 9 is, independently, thymine. In certain embodiments, R 9 is, independently, a substituted or unsubstituted heteroaryl. In certain embodiments, R 9 is, independently, a nucleobase. In certain embodiments, R 9 is, independently, a modified nucleobase.

[0223] In certain embodiments, the compounds described herein contain the substituent R 10 In certain embodiments, R 10 is, independently, an oligonucleotide.

[0224] In certain embodiments, the compounds described herein contain the substituent X. In certain embodiments, X is, independently, O. In certain embodiments, X is, independently, S.

[0225] In certain embodiments, the compounds described herein contain the substituent Z 1 , Z 2 , Z 3 , or Z 4 In certain embodiments, Z 1 , Z 2 , Z 3 , or Z 4 is, independently, a bond. In certain embodiments, Z 1 , Z 2 , Z 3 , or Z 4 is, independently, C 1 -C 6 alkylene (e.g., methylene, ethylene, propylene). In certain embodiments, Z 1 , Z 2 , Z 3 , or Z 4is, independently, C 2 -C 6 is an alkenylene. In certain embodiments, Z 1 , Z 2 , Z 3 , or Z 4 is, independently,

Chemical formula

Chemical formula

[0226] In certain embodiments, the compounds described herein contain the variable p. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 0 or 1. In certain embodiments, p is 1, 2, or 3. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain embodiments, p is 6. In certain embodiments, p is 7. In certain embodiments, p is 8. In certain embodiments, p is 9. In certain embodiments, p is 10.

[0227] In certain embodiments, the compounds described herein contain the variable n. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 0 or 1. In certain embodiments, n is 1, 2, or 3. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6. In certain embodiments, n is 7. In certain embodiments, n is 8. In certain embodiments, n is 9. In certain embodiments, n is 10.

[0228] In certain embodiments, the compounds described herein contain the variable m. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 0 or 1. In certain embodiments, m is 1, 2, or 3. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6. In certain embodiments, m is 7. In certain embodiments, m is 8. In certain embodiments, m is 9. In certain embodiments, m is 10.

[0229] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

Chemical formula

[0230] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

Chemical formula

[0231] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

Chemical formula

[0232] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

Chemical formula

[0233] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

Chemical formula

[0234] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

Chemical formula

[0235] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

Chemical formula

[0236] In certain embodiments, provided herein is a compound of the formula attached to the 16th and 17th nucleosides from the 5' end of the sense strand:

Chem.

[0237] In certain embodiments, provided herein is a compound of the formula:

Chem.

[0238] In certain embodiments, provided herein is a compound of the formula attached to the 6th and 7th nucleosides from the 5' end of the sense strand:

Chem.

[0239] In certain embodiments, provided herein is a compound of the formula:

Chem.

[0240] In certain embodiments, provided herein is a compound of the formula attached to the 3rd and 4th nucleosides from the 5' end of the sense strand:

Chem.

[0241] In certain embodiments, provided herein is an oligonucleotide of the formula:

Chemical formula

[0242] In certain embodiments, provided herein is an oligonucleotide of the formula attached to the 3rd and 4th nucleosides from the 5' end of the sense strand:

Chemical formula

[0243] In certain embodiments, provided herein is an oligonucleotide of the formula:

Chemical formula

[0244] In certain embodiments, provided herein is an oligonucleotide of the formula attached to the 3rd and 4th nucleosides from the 5' end of the sense strand:

Chemical formula

[0245] In certain embodiments, provided herein is an oligonucleotide of the formula:

Chemical formula

[0246] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula: [Chemical Formula] bonded to the 4th and 5th nucleosides from the 5' end of the sense strand.

[0247] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula: [Chemical Formula] bonded to the 4th and 5th nucleosides from the 5' end of the sense strand.

[0248] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula: [Chemical Formula] bonded to the 7th and 8th nucleosides from the 5' end of the sense strand.

[0249] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula: [Chemical Formula] bonded to the 7th and 8th nucleosides from the 5' end of the sense strand.

[0250] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula: [Chemical Formula] bonded to the 17th and 18th nucleosides from the 5' end of the sense strand.

[0251] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula: [Chemical Formula] comprising at least one dinucleotide of: Formula:

Chem.

[0252] In certain embodiments, provided herein is an oligonucleotide having attached to the 6th and 7th nucleosides from the 5' end of the sense strand, a dinucleotide of:

Chem.

Chem.

[0253] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of:

Chem.

[0254] In certain embodiments, provided herein is an oligonucleotide having attached to the 5th and 6th nucleosides from the 5' end of the sense strand, a dinucleotide of:

Chem.

[0255] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of:

Chem.

[0256] In certain embodiments, provided herein is an oligonucleotide having attached to the 12th and 13th nucleosides from the 5' end of the sense strand, of the formula:

Chem.

[0257] In certain embodiments, the disclosure provides a compound of the following formula:

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0258] In certain embodiments, the oligomeric compound is any of those described herein. In certain embodiments, the oligomeric compound is about 10 to 50 subunits in length. In certain embodiments, the oligomeric compound is an oligonucleotide. In certain embodiments, the oligonucleotide is any of those described herein. In certain embodiments, the oligonucleotide is 8 to 80 linked nucleoside lengths, 12 to 30 linked nucleoside lengths, 12 to 30 linked nucleoside lengths, or 15 to 30 linked nucleoside lengths.

[0259] In certain embodiments, the compounds described herein are modified oligonucleotides. In certain embodiments, the compounds disclosed herein comprise modified oligonucleotides. 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.

[0260] In certain embodiments, the oligonucleotide is single-stranded. In certain embodiments, the oligonucleotide is double-stranded. In certain embodiments, the oligonucleotide comprises ribonucleic acid (e.g., composed of ribonucleosides), deoxyribonucleic acid (e.g., composed of deoxyribonucleosides), or combinations thereof. In certain embodiments, the oligonucleotide is a small interfering RNA (siRNA), microRNA (miRNA) antagonist, miRNA mimic, ADAR mobilizing molecule, ADAR targeting molecule, guide RNA, antisense oligonucleotide, short hairpin RNA (shRNA), or combinations thereof.

[0261] Certain embodiments provide a composition comprising a compound of any of the embodiments herein and a pharmaceutically acceptable carrier or excipient.

[0262] Certain embodiments provide a composition comprising a compound of any of the embodiments herein for use in a method of treatment.

[0263] In certain embodiments, a method for delivering an agent to a cell comprises contacting the cell with a compound of any of the embodiments herein, thereby delivering the agent to the cell. In certain embodiments, the cell is a brain cell. In certain embodiments, the cell is a cell of the frontal lobe. In certain embodiments, the agent is a therapeutic or diagnostic agent. In certain embodiments, the cell is within an animal.

[0264] In certain embodiments, a method of modulating the expression of a nucleic acid target in a cell comprises contacting the cell with a compound of any of the embodiments herein, thereby modulating the expression of the nucleic acid target in the cell. In certain embodiments, the cell is a brain cell. In certain embodiments, the cell is a cell of the frontal lobe. In certain embodiments, the agent is a therapeutic or diagnostic agent. In certain embodiments, contacting the cell with a compound of any of the embodiments herein inhibits the 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 within an animal.

[0265] In certain embodiments, a method of modulating the expression of a nucleic acid target in a subject comprises administering to the subject any of the compounds or compositions provided herein, thereby modulating the expression of the nucleic acid target in the subject. In certain embodiments, the expression of the nucleic acid is modulated in brain cells. In certain embodiments, the brain cells are cells of the frontal lobe. In certain embodiments, the nucleic acid target is pre-mRNA, mRNA, non-coding RNA, or miRNA. In certain embodiments, the compound is administered intrathecally to the subject.

[0266] In certain embodiments, a method of treating or ameliorating a disease, disorder, or symptom thereof in a subject comprises administering to the subject any of the compounds or compositions provided herein, thereby treating, preventing, or ameliorating the disease, disorder, or symptom thereof in the subject. In certain embodiments, the disease, disorder, or symptom thereof is a disease, disorder, or symptom of the central nervous system (CNS). In certain embodiments, the disease, disorder, or symptom thereof is Alzheimer's disease, or a symptom thereof. In certain embodiments, the compound is administered intrathecally to the subject. In certain embodiments, the compound or composition is administered to the subject in a therapeutically effective amount.

[0267] Also provided is the use of the compounds described herein for the manufacture of a medicament in the treatment of a disease or disorder.

[0268] In another aspect, the disclosure provides a method for making any of the compounds provided herein, comprising one or more compounds and the chemical transformations described herein.

[0269] Certain compounds comprising oligonucleotides In certain embodiments, the compounds described herein comprise oligonucleotides. In certain embodiments, the oligonucleotide has a nucleobase sequence that is at least partially complementary to a target nucleic acid sequence (e.g., a target nucleic acid expressed intracellularly). In some embodiments, the oligonucleotide can inhibit the expression of the underlying gene when delivered to a cell that expresses the target nucleic acid. Gene expression can be inhibited in vitro or in vivo. In certain embodiments, the 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 combinations thereof. In some embodiments, the oligonucleotide comprises ribonucleic acid (RNA). In some embodiments, the oligonucleotide comprises deoxyribonucleic acid (DNA). In some embodiments, the oligonucleotide comprises modifications (e.g., modified nucleobases, modified sugars, or modified phosphates).

[0270] In certain embodiments, the oligonucleotide is single-stranded. In some embodiments, the single-stranded oligonucleotide is single-stranded RNA (ssRNA), ssDNA, or an ssRNA / DNA hybrid (e.g., a single-stranded oligonucleotide composed of both ribonucleosides (modified or unmodified) and deoxyribonucleosides (modified or unmodified)). In some embodiments, the oligonucleotide is double-stranded (e.g., composed of two single-stranded nucleic acids). Such a double-stranded oligonucleotide comprises a first oligonucleotide having a region complementary to the target nucleic acid and a second oligonucleotide having a region complementary to the first oligonucleotide. The first and second oligonucleotides can be independently modified.

[0271] In some embodiments, the oligonucleotide is at least 2 nucleotides (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, or more) in length. In some embodiments, the oligonucleotide is at least 5 nucleotides in length. In some embodiments, the oligonucleotide is at least 10 nucleotides in length. In some embodiments, the oligonucleotide is at least 15 nucleotides in length. In some embodiments, the oligonucleotide is at least 16 nucleotides in length. In some embodiments, the oligonucleotide is at least 17 nucleotides in length. In some embodiments, the oligonucleotide is at least 18 nucleotides in length. In some embodiments, the oligonucleotide is at least 19 nucleotides in length. In some embodiments, the oligonucleotide is at least 20 nucleotides in length. In some embodiments, the oligonucleotide is at least 21 nucleotides in length. In some embodiments, the oligonucleotide is at least 22 nucleotides in length.In some embodiments, the oligonucleotide is at least 23 nucleotides in length. In some embodiments, the oligonucleotide is at least 24 nucleotides in length. In some embodiments, the oligonucleotide is at least 25 nucleotides in length. In some embodiments, the oligonucleotide is at least 26 nucleotides in length. In some embodiments, the oligonucleotide is at least 27 nucleotides in length. In some embodiments, the oligonucleotide is at least 28 nucleotides in length. In some embodiments, the oligonucleotide is at least 29 nucleotides in length. In some embodiments, the oligonucleotide is at least 30 nucleotides in length. In some embodiments, the oligonucleotide is at least 40 nucleotides in length. In some embodiments, the oligonucleotide is at least 50 nucleotides in length. In some embodiments, the oligonucleotide is at least 60 nucleotides in length. In some embodiments, the oligonucleotide is at least 70 nucleotides in length. In some embodiments, the oligonucleotide is at least 80 nucleotides in length. In some embodiments, the oligonucleotide is at least 90 nucleotides in length. In some embodiments, the oligonucleotide is at least 100 nucleotides in length. In some embodiments, the oligonucleotide is at least 150 nucleotides in length.

[0272] In some embodiments, the oligonucleotide has a length of 150 nucleotides or less (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). In some embodiments, the oligonucleotide has a length of 150 nucleotides or less. In some embodiments, the oligonucleotide has a length of 100 nucleotides or less. In some embodiments, the oligonucleotide has a length of 90 nucleotides or less. In some embodiments, the oligonucleotide has a length of 80 nucleotides or less. In some embodiments, the oligonucleotide has a length of 70 nucleotides or less. In some embodiments, the oligonucleotide has a length of 60 nucleotides or less. In some embodiments, the oligonucleotide has a length of 50 nucleotides or less. In some embodiments, the oligonucleotide has a length of 40 nucleotides or less. In some embodiments, the oligonucleotide has a length of 30 nucleotides or less. In some embodiments, the oligonucleotide has a length of 29 nucleotides or less.In some embodiments, the oligonucleotide has a length of 28 nucleotides or less. In some embodiments, the oligonucleotide has a length of 27 nucleotides or less. In some embodiments, the oligonucleotide has a length of 26 nucleotides or less. In some embodiments, the oligonucleotide has a length of 25 nucleotides or less. In some embodiments, the oligonucleotide has a length of 24 nucleotides or less. In some embodiments, the oligonucleotide has a length of 23 nucleotides or less. In some embodiments, the oligonucleotide has a length of 22 nucleotides or less. In some embodiments, the oligonucleotide has a length of 21 nucleotides or less. In some embodiments, the oligonucleotide has a length of 20 nucleotides or less. In some embodiments, the oligonucleotide has a length of 19 nucleotides or less. In some embodiments, the oligonucleotide has a length of 18 nucleotides or less. In some embodiments, the oligonucleotide has a length of 17 nucleotides or less. In some embodiments, the oligonucleotide has a length of 16 nucleotides or less. In some embodiments, the oligonucleotide has a length of 15 nucleotides or less. In some embodiments, the oligonucleotide has a length of 10 nucleotides or less. In some embodiments, the oligonucleotide has a length of 5 nucleotides or less.

[0273] In some embodiments, the oligonucleotide is from about 5 nucleotides in length to about 150 nucleotides in length. In some embodiments, the oligonucleotide is from about 10 nucleotides in length to about 100 nucleotides in length. In some embodiments, the oligonucleotide is from about 20 nucleotides in length to about 90 nucleotides in length. In some embodiments, the oligonucleotide is from about 30 nucleotides in length to about 80 nucleotides in length. In some embodiments, the oligonucleotide is from about 40 nucleotides in length to about 70 nucleotides in length. In some embodiments, the oligonucleotide is from about 50 nucleotides in length to about 60 nucleotides in length. In some embodiments, the oligonucleotide is from about 15 nucleotides in length to about 30 nucleotides in length. In some embodiments, the oligonucleotide is from about 18 nucleotides in length to about 25 nucleotides in length. In some embodiments, the oligonucleotide is from about 19 nucleotides in length to about 23 nucleotides in length. In certain embodiments, the oligonucleotide is a modified oligonucleotide.

[0274] In some embodiments, the oligonucleotide is from about 18 nucleotides in length to about 25 nucleotides in length.

[0275] In some embodiments, the double-stranded region of the double-stranded oligonucleotide is equal to or at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 23, 24, 25, 26, 27, 28, 29, 30 or more nucleotide pairs in length.

[0276] In some embodiments, the antisense strand of the double-stranded oligonucleotide is equal to or at least 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length.

[0277] In some embodiments, the sense strand of the double-stranded oligonucleotide is equal to or at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length.

[0278] In some embodiments, the oligonucleotide is a therapeutic oligonucleotide. Therapeutic oligonucleotides can include, for example, but are not limited to, small interfering RNA (siRNA), microRNA (miRNA) antagonists, miRNA mimics, ADAR mobilizing molecules, ADAR targeting molecules, guide RNAs, antisense oligonucleotides, short hairpin RNA (shRNA), or combinations thereof.

[0279] In certain embodiments, the miRNA is a precursor miRNA, primary miRNA, and / or mature miRNA.

[0280] In certain embodiments, the oligonucleotide comprises or consists of an antisense oligonucleotide. In certain embodiments, the antisense oligonucleotide is complementary to the mRNA. In certain embodiments, the antisense oligonucleotide is complementary to the pre-mRNA. In certain embodiments, the antisense oligonucleotide blocks translation and promotes degradation of the mRNA transcript. In certain embodiments, the antisense oligonucleotide recruits Rnase H and promotes degradation of the mRNA transcript. In certain embodiments, the antisense oligonucleotide targets miRNA, inhibits miRNA-mediated mRNA expression regulation, and promotes degradation of miRNA.

[0281] Certain modifications In certain aspects, the present disclosure relates to compounds comprising an oligonucleotide. In certain embodiments, the oligonucleotide may be unmodified RNA or DNA, or may be modified. In certain embodiments, the oligonucleotide is a modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises at least one modified sugar, modified nucleobase, or modified internucleoside linkage compared to unmodified RNA or DNA. In certain embodiments, the oligonucleotide has modified nucleosides. The modified nucleosides can include a modified sugar, a modified nucleobase, or both a modified sugar and a modified nucleobase. The modified oligonucleotide may also include terminal modifications, e.g., 5'-terminal and 3'-terminal modifications.

[0282] Sugar modifications, motifs of sugar modifications In certain embodiments, the modified sugar is a substituted furanosyl sugar or an acyclic modified sugar. In certain embodiments, the modified sugar is a bicyclic or tricyclic modified sugar. In certain embodiments, the modified sugar is an alternative sugar. The alternative sugar can include one or more of the substitutions described herein.

[0283] In certain embodiments, the 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 contains one or more substituents, for example, but not limited to, substituents at the 2', 3', 4', and 5' positions.

[0284] In certain embodiments, the substituent at the 2' position includes F and OCH 3 (“OMe”, “O-methyl” or “methoxy”), but is not limited thereto. In certain embodiments, suitable substituents at the 2' position for non-bicyclic modified sugars include halo, allyl, amino, azido, SH, CN, OCN, CF 3 , OCF 3 , F, Cl, Br, SCH 3 , SOCH 3 , SO 2 CH 3 , ΟΝΟ 2 , ΝΟ 2 , Ν 3 , and ΝΗ 2 , but is not limited thereto. In certain embodiments, the substituent at the 2' position includes O-(C 1 -C 10 ) 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, including but not limited to, where alkyl, alkenyl and alkynyl are substituted or unsubstituted C 1 ~C 10 alkyl or C 2 ~C 10 alkenyl and alkynyl. In certain embodiments, the substituent at the 2' position includes alkaryl, aralkyl, O-alkaryl, and O-aralkyl, but is not limited thereto. In certain embodiments, these 2'-substituents are hydroxyl, alkoxy, carboxy, benzyl, phenyl, nitro (ΝΟ 2), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, the substituent at the 2' position includes O[(CH 2 ) n O] m CH 3 , O(CH 2 ) n OCH 3 , O(CH 2 ) n CH 3 , O(CH2) n ONH 2 , O(CH 2 ) n NH 2 , O(CH 2 ) n SCH 3 , and O(CH 2 ) n ON[(CH 2 ) n CH 3 )] 2 In certain embodiments, the substituent at the 2' position includes, but is not limited to, OCH 2 CH 2 OCH 3 ("MOE"), O(CH 2 ) 2 ON(CH 3 ) 2 ("DMAOE"), O(CH 2 ) 2 O(CH 2 ) 2 N(CH 3 ) 2 ("DMAEOE"), and OCH 2 C(=O)-N(H)CH 3 ("NMA"), but are not limited to these.

[0285] In certain embodiments, suitable substituents at the 4'-position for the acyclic modified sugars include, but are not limited to, alkoxy (e.g., methoxy), alkyl, those described in Manoharan et al., WO 2015 / 106128. In certain embodiments, suitable substituents at the 5'-position for the acyclic modified sugars include, but are not limited to, methyl ("Me") (R or S), vinyl, and methoxy. In certain embodiments, the 5'-modification is 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), as well as 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 further combination of oxygen / sulfur substituted monophosphate, diphosphate and triphosphate (e.g., 5'-alpha-thiotriphosphate, 5'-gamma-thiotriphosphate, etc.), 5'-phosphoroamidate ((HO) 2 (O)P-NH-5', (HO)(NH 2 )(O)P-O-5'), 5'-alkylphosphonate (R = alkyl = methyl, ethyl, isopropyl, propyl, etc., e.g., RP(OH)(O)-O-5'-), 5'-alkenylphosphonate (i.e., vinyl, substituted vinyl), (OH) 2 (O)P-5'-CH 2 -), 5'-alkyl ether phosphonate (R = alkyl ether methoxymethyl (MeOCH 2-), such as ethoxymethyl, for example, RP(OH)(O)-O-5’-). In certain embodiments, one or more sugars include a 5’-vinylphosphonate modification. In certain embodiments, one or more sugars include a 5’-ethylenephosphonate modification. In certain embodiments, the 5’ modification is at the end of the oligonucleotide. In certain embodiments, the 5’ modification is at the end of an antisense oligonucleotide. In certain embodiments, the substituents at the 2’, 4’, and 5’ positions described herein may be added to other specific positions of the sugar. In certain embodiments, such substituents may be added to the 3’ position of the sugar of the 3’-terminal nucleoside or the 5’ position of the 5’-terminal nucleoside. In certain embodiments, the acyclic modified sugar may include two or more uncrosslinked sugar substituents. In certain such embodiments, the substituents of the acyclic modified sugar include, but are not limited to, 5’-Me-2’-F, 5’-Me-2’-OMe (including both R and S isomers). In certain embodiments, the substituents of the modified sugar include those described in Migawa et al., WO 2008 / 101157 and Rajeev et al., US2013 / 0203836.

[0286] In certain embodiments, the modified sugar is a bicyclic sugar. A bicyclic sugar is a modified sugar that includes two rings, and the second ring is formed via a bridge connecting two atoms of the first ring, thereby forming a bicyclic structure. In certain embodiments, the bicyclic sugar includes a bridging substituent that bridges two atoms of the furanosyl ring to form a second ring. In certain embodiments, the bicyclic sugar does not include a furanosyl moiety. A “bicyclic nucleoside” (“BNA”) is a nucleoside having a bicyclic sugar. In certain embodiments, the bicyclic sugar includes a bridge between the 4’ furanose ring atom and the 2’ furanose ring atom. In certain embodiments, the bicyclic sugar includes a bridge between the 5’ furanose ring atom and the 3’ furanose ring atom. In certain such embodiments, the furanose ring is a ribose ring. In certain embodiments, the 4’-2’ bridging substituent includes 4’-CH2 -2’,4’-(CH 2 ) 2 -2’,4’-(CH 2 ) 3 -2’,4’-CH 2 -O-2’(「LNA」),4’-CH 2 -S-2’,4’-(CH 2 ) 2 -O-2’(「ENA」),4’-CH(CH 3 )-O-2’(when in the S configuration, is 「constrained ethyl」 or 「cEt」),4’-CH2-O-CH 2 -2’,4’-CH 2 -NI-2’’4’-CH(CH 2 OCH 3 )-’-2’(「constrained MOE」 or 「cMOE」) and its analogs (e.g., U.S. Patent No. 7,399,845),4’-C(CH 3 )(CH 3 )-’-2’ and its analogs (e.g., U.S. Patent No. 8,278,283),4’-CH 2 -N(OCH 3 ’-2’ and its analogs (e.g., U.S. Patent No. 8,278,425),4’-CH 2 -O-N(CH 3 ’-2’ (e.g., U.S. Patent Application Publication No. 2004 / 0171570),4’-CH I (’)-O-2’(wherein R is Η, C 1 -C 12 alkyl, or a protecting group)(e.g., U.S. Patent No. 7,427,6’2),4’-CH 2 -C(H)(CH 3 )-2’(e.g., Chattopadhyaya et al., J. Org. Chem., 2009, 74, 118 - 134), as well as 4’-CH 2 -C(=CH 2) - 2’ and its analogs (e.g., U.S. Patent No. 8,278,426) are included, but not limited thereto. The entire content of each of the foregoing is hereby incorporated by reference into this specification. Additional representative U.S. patents and U.S. patent publications that teach the preparation of bicyclic nucleic acid nucleotides include 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, US2008 / 0039618, US2009 / 0012281, US2013 / 0190383, and WO2013 / 036868, but not limited thereto, and the entire content of each is hereby incorporated by reference into this specification. Any of the foregoing bicyclic nucleosides can be prepared to have one or more stereochemical sugar configurations, including, for example, α-L-ribofuranose and β-D-ribofuranose (see, e.g., WO99 / 14226). The specific bicyclic nucleosides herein are in the β-D configuration unless otherwise specified.

[0287] In certain embodiments, the modified sugar is an alternative sugar. In certain embodiments, the alternative sugar has, for example, an oxygen atom replaced by a sulfur atom, a carbon atom, or a nitrogen atom. In certain such embodiments, the alternative sugar may also include crosslinking substituents and / or non-crosslinking substituents described herein. In certain embodiments, the alternative sugar includes a ring having atoms other than five atoms. In certain such embodiments, the alternative sugar includes a cyclobutyl moiety instead of a pentofuranosyl sugar. In certain embodiments, the alternative sugar includes a six-membered ring instead of a pentofuranosyl sugar. In certain embodiments, the alternative sugar includes tetrahydropyran (“THP”) instead of a pentofuranosyl sugar. In certain embodiments, the alternative sugar includes morpholino instead of a pentofuranosyl sugar. Representative U.S. patents teaching 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 which are incorporated herein by reference.

[0288] In some embodiments, the alternative sugar comprises an acyclic moiety. In certain embodiments, the alternative sugar is an unlocked nucleic acid (“UNA”). UNA is an acyclic unlocked nucleic acid in which one of the sugar linkages is removed to form an unlocked “sugar” residue. In one example, UNA also includes monomers in which the C1’-C4’ linkage (i.e., the carbon-oxygen-carbon covalent bond between the C1’ and C4’ carbons) is removed. In another example, the C2’-C3’ bond of the sugar (i.e., the carbon-carbon covalent bond between the C2’ and C3’ carbons) is 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 Application Publication Nos. 2013 / 0096289, 2013 / 0011922, and 2011 / 0313020, the entire contents of each of which are incorporated herein by reference. In certain embodiments, the alternative sugar includes peptide nucleic acid (“PNA”), acyclic butyl nucleic acid (BuNA) (see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), glycol nucleic acid (GNA) (see, e.g., Zhang et al, J. Am. Chem. Soc., 2005, 127(12)4174-4175), threoninol nucleic acid (TNA) (see, e.g., Asanuma et al., J. Am. Chem. Soc., 2010, 132(42)14702-14703) or analogs thereof, and nucleosides and oligonucleotides described in Manoharan et al., US2013 / 130378, the entire contents of which are incorporated herein by reference. Many other bicyclic and tricyclic sugars and alternative sugar ring systems that can be used in modified nucleosides are known in the art.

[0289] In certain embodiments, the disclosure provides a compound comprising at least one oligonucleotide, wherein the nucleosides of such oligonucleotide comprise one or more modified and / or unmodified sugars arranged in a defined pattern or “sugar motif” along the oligonucleotide or a region thereof. In certain cases, such sugar motifs include, but are not limited to, any of the patterns of sugar modifications described herein.

[0290] In certain embodiments, the oligonucleotide comprises a sugar motif of a gapmer. The oligonucleotide of a gapmer comprises or consists of a region having two outer “wing” regions and a central or internal “gap” region. The gap region and the wing regions form a contiguous sequence of nucleosides, and most of the nucleoside sugars of each wing are different from most of the nucleoside sugars of the gap. In certain embodiments, the wing region comprises 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 comprising a sugar motif of a gapmer are described, for example, in U.S. Patent 8,790,919, the entire content of which is incorporated herein by reference.

[0291] In certain embodiments, one or both of the oligonucleotides of a double-stranded compound comprise a triple sugar motif. An oligonucleotide having a triple sugar motif comprises three identical sugar modifications on three consecutive nucleosides. In certain embodiments, the triple is at or near a cleavage site of the oligonucleotide. In certain embodiments, the oligonucleotides of a double-stranded compound may contain two or more triple sugar motifs. In certain embodiments, the identical sugar modification of the triple sugar motif is a 2′-F modification. Compounds having a triple sugar motif are disclosed, for example, in U.S. Patent 10,668,170, the entire content of which is incorporated herein by reference.

[0292] In certain embodiments, one or both of the oligonucleotides of the double-stranded compound contain a quadruple sugar motif. An oligonucleotide having a quadruple sugar motif contains four identical sugar modifications on four consecutive nucleosides. In certain embodiments, the quadruple is at or near the cleavage site. In certain embodiments, the oligonucleotides of the double-stranded compound may contain two or more quadruple sugar motifs. In certain embodiments, the identical sugar modification of the quadruple sugar motif is a 2'-F modification. For a double-stranded compound having a double-stranded region 19 to 23 nucleotides in length, the cleavage site of the antisense oligonucleotide is typically at positions around 10, 11, and 12 from the 5' end. In certain embodiments, the quadruple sugar motif is at positions 8, 9, 10, 11; 9, 10, 11, 12; 10, 11, 12, 13; 11, 12, 13, 14; or 12, 13, 14, 15 of the sense oligonucleotide, counting from the first nucleoside at the 5' end of the sense oligonucleotide or starting to count from the first paired nucleotide within the double-stranded region from the 5' end of the sense oligonucleotide. In certain embodiments, the quadruple sugar motif is at positions 8, 9, 10, 11; 9, 10, 11, 12; 10, 11, 12, 13; 11, 12, 13, 14; or 12, 13, 14, 15 of the antisense oligonucleotide, counting from the first nucleoside at the 5' end of the antisense oligonucleotide or starting to count from the first paired nucleotide within the double-stranded region from the 5' end of the antisense oligonucleotide. The cleavage site can vary depending on the length of the double-stranded region of the double-stranded compound, and accordingly, the position of the quadruple can also change.

[0293] In certain embodiments, the oligonucleotide comprises an alternating sugar motif. In certain embodiments, one or both of the oligonucleotides of the double-stranded compound comprise an alternating sugar motif. An oligonucleotide having an alternating sugar motif comprises at least two different sugar modifications, wherein one or more consecutive nucleosides comprising a first sugar modification alternate 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 a nucleoside, the alternating motif can be "ABABABABABAB...", "AABBAABBAABB...", "AABAABAABAAB", "AAABAAABAAAB...", "AAABBBAAABBB...", or "ABCABCABCABC...". In certain embodiments, the alternating sugar motif is repeated along the oligonucleotide by 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 consecutive nucleobases. In certain embodiments, the alternating sugar motif is composed of two different sugar modifications. In certain embodiments, the alternating sugar motif comprises 2'-OMe and 2'-F sugar modifications.

[0294] In certain embodiments, each nucleoside of the oligonucleotide is independently modified with one or more of the sugar modifications provided herein. In certain embodiments, each oligonucleotide of the double-stranded compound independently has one or more of the sugar motifs provided herein. In certain embodiments, an oligonucleotide containing a sugar motif is fully modified in that each nucleoside other than the nucleosides containing the sugar motif contains a sugar modification.

[0295] Modifications and Motifs of Nucleobases In certain embodiments, the modified oligonucleotide comprises one or more nucleosides comprising a modified nucleobase. In certain embodiments, the modified oligonucleotide comprises one or more nucleosides that are referred to as abasic nucleosides and that do not contain a nucleobase.

[0296] In certain embodiments, the modified nucleobase is 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, the modified nucleobase is 2-aminopropyladenine, 5-hydroxymethylcytosine, 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-CH 3)Selected from 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-azapurine and other 8-substituted purines, 5-halo, especially 5-bromo, 5-trifluoromethyl, 5-halouracil, and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoyl cytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoyl cytosine, 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-diazaphenoxazin-2-one, 1,3-diazaphenothiazin-2-one, and 9-(2-aminoethoxy)-1,3-diazaphenoxazin-2-one (G-clamp). Modified nucleobases also include those in which the purine or pyrimidine base is replaced by another heterocycle, such as 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine, and 2-pyridone.

[0297] Additional nucleobases include those disclosed in U.S. Patent 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 is hereby incorporated by reference into this specification.

[0298] Publications teaching the preparation of some of the above-described modified nucleobases and other modified nucleobases include, but are not limited to, US Publication Nos. 2003 / 0158403 and 2003 / 0175906, US Patent Nos. 4,845,205, 5,130,302, 5,134,066, 5,175,273, 5,367,066, 5,432,272, 5,434,257, 5,457,187, 5,459,255, 5,484,908, 5,502,177, 5,525,711, 5,552,540, 5,587,469, 5,594,121, 5,596,091, 5,614,617, 5,645,985, 5,681,941, 5,811,534, 5,750,692, 5,948,903, 5,587,470, 5,457,191, 5,763,588, 5,830,653, 5,808,027, 6,005,096, 6,015,886, 6,147,200, 6,166,197, 6,166,199, 6,222,025, 6,235,887, 6,380,368, 6,528,640, 6,639,062, 6,617,438, 7,045,610, 7,427,672, and 7,495,088, the entire contents of each of which are incorporated herein by reference.

[0299] In certain embodiments, an oligonucleotide comprises modified and / or unmodified nucleobases arranged in a defined pattern or motif along the oligonucleotide or a region thereof. 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 the modified oligonucleotide are 5-methylcytosine.

[0300] In certain embodiments, the modified oligonucleotide comprises a modified nucleobase block. In certain such embodiments, the block is at the 3' end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides from 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 from the 5' end of the oligonucleotide.

[0301] Modifications of internucleoside linkages and motifs The 3'-5' phosphodiester linkage is the natural internucleoside linkage of RNA and DNA. In certain embodiments, the oligonucleotide has one or more modified, i.e., non-natural, internucleoside linkages. Certain non-natural internucleoside linkages can provide desired properties such as enhanced cellular uptake, increased affinity for target nucleic acids, and improved stability in the presence of nucleases. Representative phosphorus-containing modified internucleoside linkages include, but are not limited to, phosphotriesters, alkylphosphonates (e.g., methylphosphonate), phosphoramidates, and phosphorothioates ("P=S"), and phosphorodithioates ("HS-P=S"). Representative phosphorus-free internucleoside linking groups include, but are not limited to, methylene methylimino (-CH 2 -N(CH 3 )-O-CH 2 )), thiol esters, thiocarbamates (-O-C(=O)(NH)-S-); siloxanes (-O-SiH 2 -O-); and N,N'-dimethylhydrazine (-CH 2 -Ν((CΗ 3 )-Ν((CΗ 3 ))). Methods for preparing phosphorus-containing and phosphorus-free internucleoside linkages are well known to those of skill in the art. Neutral internucleoside linkages include, but are not limited to, phosphotriesters, methylphosphonate, MMI (3'-CH 2 -N(CH 3)-O-5’), amide-3 (3’-CH 2 -C(=O)-N(H)-5’), amide-4 (3’-CH 2 -N(H)-C(=O)-5’), formacetal (3’-O-CH 2 -O-5’), methoxypropyl, and thioformacetal (3’-S-CH 2 -O-5’) are included. Further neutral internucleoside linkages include nonionic linkages including siloxane (dialkylsiloxane), carboxylic acid ester, carboxamide, sulfide, sulfonic acid ester, and amide (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 including mixtures of Ν, O, S, and CH 2 constituent moieties.

[0302] In certain embodiments, the oligonucleotide comprises at least one modified internucleoside linkage. The modified internucleoside linkage can be located at any portion of the oligonucleotide. In the case of a double-stranded compound, the modified internucleoside linkage can be located within the sense oligonucleotide, the antisense oligonucleotide, or both oligonucleotides of the double-stranded compound.

[0303] In certain embodiments, the internucleoside linkage modification may be present in all nucleosides of the oligonucleotide. In certain embodiments, the internucleoside linkage modification may be present in an alternating pattern along the oligonucleotide. In certain embodiments, essentially all internucleoside linkages are phosphodiester internucleoside linkages (P=O). In certain embodiments, each internucleoside linkage group of the modified oligonucleotide is phosphorothioate (P=S). In certain embodiments, each internucleoside linkage group of the modified oligonucleotide is independently selected from phosphorothioate nucleotide linkages and phosphodiester internucleoside linkages. In certain embodiments, the pattern of internucleoside linkage modification of each oligonucleotide of the double-stranded compound is the same. In certain embodiments, the pattern of internucleoside linkage modification of each oligonucleotide of the double-stranded compound is different. In certain embodiments, the double-stranded compound comprises 6 to 8 modified internucleoside linkages. In certain embodiments, the 6 to 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 of the 5' and 3' termini. 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 of the 5' and 3' termini. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages.

[0304] In certain embodiments, the double-stranded compound includes an overhang region. In certain embodiments, the double-stranded compound includes phosphorothioate or alkylphosphonate internucleotide linkage modifications in the overhang region. In certain embodiments, the double-stranded compound includes phosphorothioate or alkylphosphonate internucleotide linkages that link an overhang nucleotide to a paired nucleotide adjacent to the overhang nucleotide. For example, there can be at least two phosphorothioate internucleotide linkages between the terminal three nucleosides, where two of the three nucleosides are overhang nucleosides and the third nucleoside is a paired nucleoside adjacent to the overhang nucleoside. These terminal three nucleosides can 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.

[0305] In certain embodiments, the modified oligonucleotide comprises one or more internucleoside linkages having a chiral center. Representative chiral internucleoside linkages include, but are not limited to, alkyl phosphonates and phosphorothioates. Modified oligonucleotides comprising internucleoside linkages having a chiral center can be prepared as a population of modified oligonucleotides comprising stereorandom internucleoside linkages or as a population of modified oligonucleotides comprising phosphorothioate linkages of a specific stereochemical configuration. In certain embodiments, the population of modified oligonucleotides comprises phosphorothioate internucleoside linkages, all of which are stereorandom. Such modified oligonucleotides can be generated using synthetic methods in which the stereochemical configuration of each phosphorothioate linkage is randomly selected. As will be well understood by those skilled in the art, the stereochemistry of each individual phosphorothioate of each individual oligonucleotide molecule is defined. In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides comprising one or more specific phosphorothioate internucleoside linkages having a specific stereochemical configuration that is independently selected. In certain embodiments, the specific configuration of a particular phosphorothioate linkage is present in at least 65% of the molecules in the population. In certain embodiments, the specific configuration of a particular phosphorothioate linkage is present in at least 70% of the molecules in the population. In certain embodiments, the specific configuration of a particular phosphorothioate linkage is present in at least 80% of the molecules in the population. In certain embodiments, the specific configuration of a particular phosphorothioate linkage is present in at least 90% of the molecules in the population. In certain embodiments, the specific configuration of a particular phosphorothioate linkage is present in at least 99% of the molecules in the population.A concentrated population of such modified oligonucleotides can be generated using synthetic methods known in the art, such as those described in Oka et al., JACS 125, 8307 (2003), Wan et al. Nuc. Acid. Res. 42, 13456 (2014), and WO2017 / 015555. In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides having at least one specified phosphorothioate in the (Sp) configuration. In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration.

[0306] Linker "Linker" refers to any chemical moiety (e.g., a combination of atoms with appropriate valences according to known chemical principles) used to conjugate two components (e.g., oligonucleotides) of the compounds provided herein to each other. Each of the two components can be connected to any portion of any of the linkers provided herein. In some embodiments, one component (e.g., an oligonucleotide) of the compounds provided herein is connected by a bond to one end of the 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 can be connected by a bond to an internal position of any of the linkers described herein. In some embodiments, the linker is a bond (e.g., including phosphodiester and phosphorothioate bonds). In some embodiments, the linker is a substituted or unsubstituted alkyl linker (i.e., an alkyl chain is used to connect two moieties, and the two moieties may each be conjugated to both ends of the alkyl linker, or one or both moieties may be conjugated to internal carbons on the alkyl linker). In some embodiments, the linker is a substituted or unsubstituted polyethylene glycol (PEG) linker (i.e., a PEG chain is used to connect two moieties, and the two moieties may each be conjugated to both ends of the PEG linker, or one or both moieties may be conjugated to an internal position of the PEG linker). In some embodiments, the linker is a substituted or unsubstituted heteroalkyl linker (i.e., a heteroalkyl chain is used to connect two moieties, and the two moieties may each be conjugated to both ends of the heteroalkyl linker, or one or both moieties may be conjugated to an internal position of the heteroalkyl linker). In some embodiments, the linker is a substituted or unsubstituted heteroaryl linker (i.e., a heteroaryl group is used to connect two moieties, and the two moieties can each be conjugated at any position on the heteroaryl group).

[0307] In some embodiments, the linker has the formula [Chemical formula] represented thereby. In certain embodiments, the linker has the formula: [Chemical formula] represented thereby.

[0308] In some embodiments, the linker is a bond. In some embodiments, the linker is a substituted or unsubstituted PEG linker. In some embodiments, the linker is 3 or 4 PEG units in length. In certain embodiments, the linker has the structure [Chemical formula] and includes. In some embodiments, the linker is 2 or 3 PEG units in length.

[0309] In some embodiments, the linker is a substituted or unsubstituted heteroaryl linker. In some embodiments, the linker is a substituted or unsubstituted partially unsaturated heteroaryl linker. In some embodiments, the linker has the structure [Chemical formula] and includes.

[0310] In some embodiments, the linker is a substituted or unsubstituted heteroalkyl linker. In some embodiments, the linker is substituted with one or more =O substituents. In certain embodiments, the linker has the structure [Chemical formula] and includes, wherein X is O or S.

[0311] In some embodiments, the linker has the structure [Chemical formula] comprising, wherein X is O or S.

[0312] In some embodiments, the linker is a phosphodiester bond or a phosphorothioate bond. In certain embodiments, the linker has the structure [Chemical formula] comprising, wherein X is O or S.

[0313] In certain embodiments, the linker has the structure [Chemical formula] comprising, wherein X is O or S.

[0314] In some embodiments, the linker is a substituted or unsubstituted PEG linker. In some embodiments, the linker is a substituted or unsubstituted PEG linker of 3 PEG units in length. In some embodiments, the linker is a substituted or unsubstituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In certain embodiments, the linker has the structure [Chemical formula] comprising. In some embodiments, the linker is a substituted or unsubstituted heteroaryl linker. In some embodiments, the linker is a substituted or unsubstituted partially unsaturated heteroaryl linker. In certain embodiments, the linker has the structure [Chemical formula] It includes. In some embodiments, the linker is a substituted or unsubstituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In certain embodiments, the linker has the structure [Chemical formula] and in the formula, X is O or S. In some embodiments, the linker has the structure [Chemical formula] and in the formula, X is O or S.

[0315] In some embodiments, the linker is a substituted or unsubstituted PEG linker. In certain embodiments, the linker is a substituted or unsubstituted PEG linker with a length of 2 or 3 PEG units. In some embodiments, the linker is a substituted or unsubstituted PEG linker. In some embodiments, the linker is a substituted or unsubstituted PEG linker with a length of 3 or 4 PEG units. In certain embodiments, the linker has the structure [Chemical formula] and includes. In some embodiments, the linker is a substituted or unsubstituted heteroaryl linker. In some embodiments, the linker is a substituted or unsubstituted partially unsaturated heteroaryl linker. In certain embodiments, the linker has the structure [Chemical formula] and includes. In some embodiments, the linker is a substituted or unsubstituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In certain embodiments, the linker has the structure [Chemical formula] comprising, wherein X is O or S. In some embodiments, the linker has the structure [Chemical Formula] comprising, wherein X is O or S.

[0316] In some embodiments, X is O. In some embodiments, X is S.

[0317] In some embodiments, R 4 and R 5 comprise an oligonucleotide. In some embodiments, the oligonucleotide is attached at its 5'-end. In some embodiments, the oligonucleotide is attached at its 3'-end. In some embodiments, the oligonucleotide is attached at an internal position of the oligonucleotide. In some embodiments, the internal position is at the internucleoside linkage. In certain embodiments, the oligonucleotide is a modified oligonucleotide.

[0318] In certain embodiments, the compounds disclosed herein are in salt form. In certain embodiments, the salt is a sodium salt. In certain embodiments, the salt is a potassium salt.

[0319] In certain embodiments, the compounds provided herein comprise one or more linking groups. In certain embodiments, each of L 1 L 2 L 3 and / or L 4 comprises a linking group. In certain embodiments, each of L 1 L 2 L 3 L 4 and / or L 5 comprises a linking group. In certain embodiments, each of L 1 L 2 L 3 L 4 L 5 L6 and / or L 7 Each of them includes a linking group. In certain embodiments, the linking group is covalently attached to the oligonucleotide. In certain embodiments, the linking group is covalently attached to a cleavable moiety. In certain embodiments, the linking group includes a cleavable bond. In certain embodiments, the linking group does not include a cleavable moiety. In certain embodiments, the linking group includes a covalent bond to a solid support.

[0320] In certain embodiments, the linking group includes a chain structure such as a hydrocarbyl chain, or an oligomer of repeating units or a combination of such repeating units. In certain embodiments, the linking group includes 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, the linking group is 1 to 50 atoms in length, 1 to 40 atoms in length, 1 to 25 atoms in length, 1 to 20 atoms in length, 1 to 15 atoms in length, 1 to 10 atoms in length, or 1 to 5 atoms in length.

[0321] In certain embodiments, the linking group contains a carbon atom. In certain embodiments, the linking group contains a heteroatom (e.g., nitrogen, oxygen, sulfur, etc.). In certain embodiments, the linking group forms an amide linkage, an ester linkage, or a disulfide linkage. In certain embodiments, the linking group forms a hydrazone linkage, an oxime linkage, an imine linkage, a guanidine linkage, a urea linkage, a carbamate linkage, an unsaturated alkyl linkage, a sulfonamide linkage or a 4- to 8-membered heterocyclic linkage. In certain embodiments, the linking group contains one or more groups selected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino. In certain embodiments, the linking group contains at least one phosphorus group. In certain embodiments, the linking group contains at least one phosphoric acid group. In certain embodiments, the linking group contains at least one neutral linking group. In certain embodiments, the linking group is substituted with various substituents including, but not limited to, a hydrogen atom, alkyl, alkenyl, alkynyl, amino, alkylamino, dialkylamino, trialkylamino, hydroxyl, alkoxy, halogen, aryl, heterocycle, aromatic heterocycle, cyano, amide, carbamoyl, carboxylic acid, ester, thioether, alkylthioether, thiol, and ureido groups. As will be appreciated by those skilled in the art, each of these groups may be sequentially substituted.

[0322] In certain embodiments, the linking group includes, but is not limited to, substituted or unsubstituted C 1 -C 10 alkylene, substituted or unsubstituted C 2 -C 10 alkenylene, or substituted or unsubstituted C 2 -C 10It contains alkynylene, and a non-limiting list of preferred substituents includes hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, the linking group is aliphatic or heteroaliphatic. For example, the linking group can be 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.

[0323] In certain embodiments, the linking group is a short peptide chain. In certain embodiments, the linking group contains 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.

[0324] In certain embodiments, the linking group contains a linker nucleoside. In certain embodiments, the linking group contains 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 can be modified or unmodified nucleosides. Typically, it is desirable for the linker nucleoside to be cleaved from the compound after reaching the target tissue. Thus, the linker nucleosides herein can be linked to each other or to the remainder of the compound via a cleavable bond. As used herein, linker-nucleosides are not considered part of the oligonucleotide payload. Thus, in embodiments where the compound comprises an oligonucleotide consisting of a specific number or range of linked nucleosides and / or a specific percent complementarity to a reference nucleic acid, those linker-nucleosides are not counted in the length of the oligonucleotide and are not used in determining the percent complementarity of the oligonucleotide to the reference nucleic acid.

[0325] In certain embodiments, the linking group comprises a protein binding group. In certain embodiments, the protein binding group is a lipid such as, but not limited to, cholesterol, cholanic acid, adamantaneacetic acid, 1-pyrenebutyric 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 endosome-lytic component, a steroid (e.g., uvaol, hecigenin, diosgenin), a terpene (e.g., triterpene such as sarsasapogenin, friedelin, epifriedelanols derivatized lithocholic acid), or a cationic lipid, etc. In certain embodiments, the protein binding group is C 16 ~C 22 a long-chain saturated or unsaturated fatty acid, cholesterol, cholanic acid, vitamin E, adamantane or 1-pentafluoropropyl.

[0326] In certain embodiments, the linking group includes, but is not limited to, pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), N-(4-maleimidomethyl)cyclohexane-1-carboxylic acid succinimidyl ester (SMCC), and 6-aminohexanoic acid (AHEX or AHA).

[0327] In certain embodiments, the linking group includes, but is not limited to, the following references: US5,994,517; US6,300,319; US6,660,720; US6,906,182; US7,262,177; US7,491,805; US8,106,022; US7,723,509; US9,127,276; US2006 / 0148740; US2011 / 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., Glycohiol, 2001, 11, 821-829;Rensen et al., J Biol Chem, 2001, 276, 37577 - 37584; Lee et al., Methods Enzymol, 2003, 362, 38 - 43; Westerlind et al., Glycoconj J, 2004, 21, 227 - 241; Lee et al., Bioorg Med Chem Lett, 2006, 16(19), 5132 - 5135; Maierhofer et al., Bioorg Med Chem, 2007, 15, 7661 - 7676; Khorev et al., Bioorg Med Chem, 2008, 16, 5216 - 5231; Lee et al., Bioorg Med Chem, 2011, 19, 2494 - 2500; Kornilova et al., Analyt Biochem, 2012, 425, 43 - 46; Pujol et al., Angew Chemie Int Ed Engl, 2012, 51, 7445 - 7448; Biessen et al., J Med Chem, 1995, 38, 1846 - 1852; Sliedregt et al., J Med Chem, 1999, 42, 609 - 618; Rensen et al., J Med Chem, 2004, 47, 5798 - 5808; Rensen et al., Arterioscler Thromh Vase Biol, 2006, 26, 169 - 175; van Rossenberg et al., Gene Ther, 2004, 11, 457 - 464; Sato et al., J Am Chem Soc, 2004, 126, 14013 - 14022; Lee et al., J Org Chem, 2012, 77, 7564 - 7571; Biessen et al., FASEB J, 2000, 14, 1784 - 1792; Rajur et al., Bioconjug Chem, 1997, 8, 935 - 940; Duff et al., Methods Enzymol, 2000, 313, 297 - 321; Maier et al., Bioconjug Chem, 2003, 14, 18 - 29; Jayaprakash et al., Org Lett, 2010, 12, 5410 - 5413;Manoharan, Antisense Nucleic Acid Drug Dev, 2002, 12, 103 - 128; Merwin et al., Bioconjug Chem, 1994, 5, 612 - 620; Tomiya et al., Bioorg Med Chem, 2013, 21, 5275 - 5281; International Application 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; US Patent 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; US Patent Application Publication US2011 / 0097264; US2011 / 0097265; US2013 / 0004427; US2003 / 0119724; US2011 / 0207799; US2012 / 0035115; US2012 / 0230938; US2005 / 0164235; US2006 / 0183886;Included are linking groups as described in 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 hereby incorporated by reference in its entirety.

[0328] In certain embodiments, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) independently includes or together includes a structure selected from the following:

Chemical formula

[0329] In certain embodiments, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7includes independently or together a structure selected from the following: [Chemical formula] (wherein each n is independently from 1 to 20).

[0330] In a particular embodiment, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) includes independently or together a structure selected from the following: [Chemical formula] (wherein each n is independently from 1 to 20).

[0331] In a particular embodiment, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) includes independently or together a structure selected from the following: [Chemical formula] (wherein each n is independently from 1 to 20).

[0332] In a particular embodiment, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) independently includes or together includes a structure selected from the following: [Chemical formula] (wherein each L is independently a phosphorus linking group, and each n is independently 1 to 20).

[0333] In a particular embodiment, each of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and / or L 7 independently includes or together includes a structure selected from the following: [Chemical formula] [Chemical formula]

[0334] In a particular embodiment, each of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and / or L 7 independently includes or together includes a structure selected from the following: [Chemical formula]

[0335] In a particular embodiment, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and / or L 7 independently includes or includes it together with a structure selected from the following: [Chemical formula]

[0336] In a particular embodiment, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) independently includes or includes it together with a structure selected from the following: [Chemical formula] (wherein n is an integer in the range of 1 to 20 (including both ends)).

[0337] In a particular embodiment, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L3 , L 4 , L 5 , L 6 , and L 7 ), independently includes or collectively includes a structure selected from the following: [Chemical formula]

[0338] In a particular embodiment, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) independently includes or collectively includes a structure selected from the following: [Chemical formula]

[0339] In a particular embodiment, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) independently includes or collectively includes a structure selected from the following: [Chemical formula]

[0340] In a particular embodiment, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) either independently includes or together has the following structure:

Chemical formula

[0341] In a particular embodiment, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) either independently includes or together has the following structure:

Chemical formula

[0342] In a particular embodiment, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4, and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) independently includes or collectively includes a structure selected from the following:

Chemical formula

[0343] In certain embodiments, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) independently includes or collectively includes a structure selected from the following:

Chemical formula

[0344] In some embodiments, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7Each of () )

[0345] ) In some embodiments, L) 1 is a bond. ) )

[0346] ) In some embodiments, L) 2 is a substituted or unsubstituted PEG linker. In some embodiments, the PEG linker is 3 or 4 PEG units in length. In certain embodiments, L) 2 is the structure ) )

Chemical formula

[0347] ) In some embodiments, L) 3 is a substituted or unsubstituted heteroaryl linker. In some embodiments, L) 3 is a substituted or unsubstituted partially unsaturated heteroaryl linker. In certain embodiments, L) 3 is the structure ) )

Chemical formula

[0348] ) In some embodiments, L) 4 is a substituted or unsubstituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In certain embodiments, L) 4 is the structure ) )

Chemical formula

[0349] In some embodiments, L 1 L 2 L 3 and L 4 together form the structure

Chemical Structure

[0350] In some embodiments, L 3 and L 4 one of which is a phosphodiester bond or a phosphorothioate bond, and the other of L 3 and L 4 is a bond. In certain embodiments, L 1 L 2 L 3 and L 4 together form the structure

Chemical Structure

[0351] In certain embodiments, L 1 L 2 L 3 and L 4 together form the structure

Chemical Structure

[0352] In some embodiments, L 1 L 2 L 3 L 4 and L 5Each of them is independently an absent, linked, substituted or unsubstituted alkyl linker, a substituted or unsubstituted polyethylene glycol (PEG) linker, a substituted or unsubstituted heteroalkyl linker, a substituted or unsubstituted heteroaryl linker, a phosphodiester bond, or a phosphorothioate bond.

[0353] In some embodiments, L 1 and L 5 are each a substituted or unsubstituted PEG linker. In some embodiments, L 1 and L 5 are each a substituted or unsubstituted PEG linker having a length of 3 PEG units.

[0354] In some embodiments, L 2 is a substituted or unsubstituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In certain embodiments, L 2 has the structure

Chemical formula

[0355] In some embodiments, L 3 is a substituted or unsubstituted heteroaryl linker. In some embodiments, L 3 is a substituted or unsubstituted partially unsaturated heteroaryl linker. In certain embodiments, L 3 has the structure

Chemical formula

[0356] In some embodiments, L 4 is a substituted or unsubstituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In certain embodiments, L 4 has the structure [Chemical formula] comprising, wherein X is O or S.

[0357] In some embodiments, L 1 , L 2 , L 3 , L 4 , and L 5 together form a structure [Chemical formula] comprising, wherein X is O or S.

[0358] In some embodiments, each of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 is independently absent, a bond, a substituted or unsubstituted alkyl linker, a substituted or unsubstituted polyethylene glycol (PEG) linker, a substituted or unsubstituted heteroalkyl linker, a substituted or unsubstituted heteroaryl linker, a phosphodiester bond, or a phosphorothioate bond.

[0359] In some embodiments, L 1 is a substituted or unsubstituted PEG linker. In certain embodiments, L 1 is a substituted or unsubstituted PEG linker having a length of 2 or 3 PEG units.

[0360] In some embodiments, L 2 and L 5 are each independently a substituted or unsubstituted PEG linker. In some embodiments, L 2 and L 5 are each independently a substituted or unsubstituted PEG linker having a length of 3 or 4 PEG units. In certain embodiments, L 1 , L2 and L 5 together form a structure [Chemical formula] including.

[0361] In some embodiments, L 3 and L 6 are each independently a substituted or unsubstituted heteroaryl linker. In some embodiments, L 3 and L 6 are each independently a substituted or unsubstituted partially unsaturated heteroaryl linker. In certain embodiments, L 3 and L 6 each have the structure [Chemical formula] including.

[0362] In some embodiments, L 4 and L 7 are each independently a substituted or unsubstituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In certain embodiments, L 4 and L 7 each have the structure [Chemical formula] including, wherein X is O or S.

[0363] In some embodiments, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 together form a structure [Chemical formula] including, wherein X is O or S.

[0364] Method for producing a compound The compounds of the present disclosure can be prepared by means known in the art of organic synthesis. Methods for optimizing reaction conditions and minimizing competing by-products as needed are known in the art. High-throughput parallel synthesis equipment and computer-controlled microreactors can be advantageously utilized for reaction optimization and scale-up (e.g., Design And Optimization in Organic Synthesis, 2 nd Edition, Carlson R, Ed, 2005; Elsevier Science Ltd.; Jaehnisch, K et al., Angew.Chem.Int.Ed.Engl.2004 43:406; and references thereof). Additional reaction schemes and protocols can be determined by those skilled in the art by use of generally available structure search database software, such as SciFinder® (CAS division of the American Chemical Society) and CrossFire Beilstein® (Elsevier MDL), or by appropriate keyword searches using Internet search engines such as Google® or keyword databases such as the United States Patent and Trademark Office text database.

[0365] As will be appreciated by those skilled in the art, the methods for synthesizing the compounds of the formulas herein will be apparent to those skilled in the art, including the schemes and examples herein. Further, various synthetic steps may be carried out in a different order or sequence to obtain the desired compounds. In addition, the solvents, temperatures, reaction times, etc. defined herein are for illustrative purposes only, and those skilled in the art will recognize that the reaction conditions can be varied to obtain the desired compounds of the present disclosure.

[0366] The compounds of this specification may also contain linkages (e.g., carbon-carbon bonds), and the rotation of the bonds is restricted to that particular linkage, e.g., a restriction due to the presence of a ring or a double bond. Accordingly, all cis / trans isomers and E / Z isomers are explicitly included in this disclosure. The compounds of this specification may also be represented in multiple tautomeric forms, and in such cases, this disclosure includes all tautomeric forms of the compounds described herein, even if only a single tautomeric form is represented. All such isomeric forms of such compounds in this specification are explicitly included in this disclosure. All crystalline forms and polymorphs of the compounds described herein are also explicitly included in this disclosure. Extracts and fractions containing the compounds of this disclosure are also included in the embodiments. The term "isomer" is intended to include diastereoisomers, enantiomers, positional isomers, structural isomers, rotational isomers, tautomers, etc. In the case of compounds containing one or more stereocenters, e.g., chiral compounds, the methods of this disclosure may be carried out using enantiomerically enriched compounds, racemates, or mixtures of diastereomers. All isomers of the compounds defined herein are explicitly included in this disclosure.

[0367] Preferred enantiomerically enriched compounds have an enantiomeric excess of 50% or more. More preferably, the compounds have an enantiomeric excess of 60%, 70%, 80%, 90%, 95%, 98%, 99%, or more. In a preferred embodiment, only one enantiomer or diastereomer of the chiral compounds of this disclosure is administered to a cell or subject.

[0368] Therapeutic methods In one aspect, there is provided a method of treating a subject suffering from or susceptible to a disorder or disease, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein.

[0369] In another aspect, there is provided a method of treating a subject suffering from a disorder or disease or a subject susceptible to a disorder or disease, where the subject has been identified as in need of modulation of protein function, the method comprising administering to the subject in need thereof an effective amount of a compound or pharmaceutical composition described herein such that the disorder of the subject is treated.

[0370] In one aspect, there is provided a method of delivering a therapeutic oligonucleotide to the brain of a subject, the method comprising contacting the subject with a compound or pharmaceutical composition described herein in an amount and under conditions sufficient to target the brain.

[0371] In one aspect, there is provided a method of modulating protein function in a subject, the method comprising contacting the subject with a compound of any of the formulas herein (e.g., Formulas I, I’, I-VIII, II-a, and II-b) in an amount and under conditions sufficient to modulate protein function.

[0372] In one embodiment, the modulation is inhibition.

[0373] In some embodiments, there is provided a method for targeting hepatocytes of a subject, the method comprising administering to the subject in need thereof an effective amount of a compound, oligonucleotide, or pharmaceutical composition of any of the formulas herein (e.g., Formulas I, I’, I-VIII, II-a, and II-b) in an amount and under conditions sufficient to target hepatocytes.

[0374] In certain embodiments, there is provided a method of treating a disease, disorder, or symptom thereof, where the disorder is cancer, a proliferative disease, a neurodegenerative disease, an autoimmune or inflammatory disorder, an infectious disease, a metabolic disorder, a blood disorder, or a cardiovascular disease.

[0375] In certain embodiments, the disorder or disease is cancer or a proliferative disorder. In certain embodiments, the cancer or proliferative disorder includes carcinoma, leukemia, blastoma, lymphoma, myeloma, or melanoma, or combinations thereof. In certain embodiments, the disorder or disease is multiple myeloma, melanoma, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, hepatocellular carcinoma, renal cancer, leukemia, T-cell lymphoma, bone cancer, glioblastoma, neuroblastoma, oral squamous cell carcinoma, urothelial carcinoma, lung cancer, cervical cancer, colon cancer, head and neck squamous cell carcinoma, Burkitt lymphoma, esophageal cancer, Hodgkin lymphoma, bladder cancer, or gastric cancer, or combinations thereof.

[0376] In certain embodiments, the disorder or disease is rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, graft-versus-host disease, transplant rejection, fibrotic disease, Crohn's disease, type 1 diabetes, eczema, psoriasis, sepsis, airway hypersensitivity, ulcerative colitis, or combinations thereof.

[0377] In certain embodiments, the disorder or disease is epilepsy, attention deficit disorder, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, essential tremor, central nervous system trauma, multiple sclerosis, Charcot-Marie-Tooth (CMT), peripheral neuropathy, or cerebral ischemia, or combinations thereof.

[0378] In certain embodiments, the disorder or disease is an infectious disease caused by a virus, fungus, or bacterium, or combinations thereof.

[0379] In certain embodiments, the disorder or disease is metabolic syndrome, diabetes, obesity, hypertension, heart failure, cyst growth in autosomal dominant polycystic kidney disease (ADPKD), or combinations thereof.

[0380] In certain embodiments, the disorder or disease is cardiovascular stress, pressure overload, chronic ischemia, infarction-reperfusion injury, hypertension, atherosclerosis, peripheral arterial disease, heart failure, hypertrophy, angina, arrhythmia, hypercholesterolemia, atherosclerosis, or stroke, or a combination thereof.

[0381] In certain embodiments, the disorder or disease is a liver disease.

[0382] In certain embodiments, the subject is a mammal, preferably a primate or a human.

[0383] In another embodiment, provided is the above method, wherein an effective amount of a compound or oligonucleotide of any of the formulas herein (e.g., Formulas I, I', I-VIII, II-a, and II-b) is as described above.

[0384] In another embodiment, provided is the above method, wherein a compound or oligonucleotide of any of the formulas herein (e.g., Formulas I, I', I-VIII, II-a, and II-b) is administered intravenously, intramuscularly, subcutaneously, intraventricularly, orally, or topically.

[0385] In other embodiments, provided is the above method, wherein a compound or oligonucleotide of any of the formulas herein (e.g., Formulas I, I', I-VIII, II-a, and II-b) is administered alone or in combination with one or more other therapeutic agents. In a further embodiment, the additional therapeutic agent is an anti-cancer agent, an anti-fungal agent, a cardiovascular agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an anti-proliferative agent, a metabolic disorder agent, an ophthalmic disorder agent, a central nervous system (CNS) disorder agent, a urinary disorder agent, or a gastrointestinal disorder agent.

[0386] Another object of the present disclosure is the use of the compounds or oligonucleotides described herein (e.g., compounds or oligonucleotides of Formula I, I', I-VIII, II-a, and II-b) in the manufacture of a medicament for use in the treatment of a disorder or disease. Another object of the present disclosure is the use of the compounds or oligonucleotides described herein (e.g., compounds or oligonucleotides of Formula I, I', I-VIII, II-a, and II-b) for use in the treatment of a disorder or disease. Another object of the present disclosure is the use of the compounds or oligonucleotides described herein (e.g., compounds or oligonucleotides of Formula I, I', I-VIII, II-a, and II-b) in the manufacture of an agricultural composition for use in the treatment or prevention of a disorder or disease in an agricultural or farming environment.

[0387] In certain embodiments, a method of treating a disease, disorder, or a symptom thereof is provided, wherein the disease is a disease, disorder, or a symptom thereof of the central nervous system (CNS). In some embodiments, the disease is a neurodegenerative disease, disorder, or a symptom thereof. In some embodiments, the disease is Alzheimer's disease, or a symptom thereof.

[0388] Exemplary CNS disorders include, but are not limited to, neurotoxicity and / or nerve trauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, mental disorders, sleep conditions, movement disorders, nausea and / or vomiting, amyotrophic lateral sclerosis, Alzheimer's disease, and substance abuse.

[0389] In certain embodiments, the CNS disorder is, for example, the result of neurotoxicity and / or nerve trauma, such as acute neuronal injury (e.g., traumatic brain injury (TBI), stroke, epilepsy) or chronic neurodegenerative disorders (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 against, for example, acute neuronal injury or chronic neurodegenerative disorders.

[0390] In certain embodiments, the CNS disorder is a mental disorder such as, for example, depression, anxiety or anxiety-related states, learning disorders, or schizophrenia.

[0391] In certain embodiments, the CNS disorder is depression. "Depression" includes, but is not limited to, depressive disorders or states such as major depressive disorder (e.g., unipolar depression), dysthymic disorder (e.g., chronic mild depression), bipolar disorder (e.g., manic depression), seasonal affective disorder, and / or depression associated with substance abuse (e.g., withdrawal). Depression can be clinical depression or subclinical depression. Depression can be associated with premenstrual syndrome and / or premenstrual dysphoric disorder.

[0392] In certain embodiments, the CNS disorder is anxiety. "Anxiety" includes, but is not limited to, anxiety and anxiety-related states such as clinical anxiety, panic disorder, agoraphobia, generalized anxiety disorder, specific phobia, social phobia, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder, adjustment disorder with anxious features, anxiety disorder associated with depression, anxiety disorder due to a general medical condition, and substance-induced anxiety disorder, anxiety associated with substance abuse (e.g., withdrawal, dependence, relapse), and anxiety associated with nausea and / or vomiting. The treatment may be to induce or facilitate sleep in a subject (e.g., a subject with anxiety).

[0393] In certain embodiments, the CNS disorder is a learning disorder (e.g., attention deficit disorder (ADD)).

[0394] In certain embodiments, the CNS disorder is schizophrenia.

[0395] In certain embodiments, the CNS disorder is a sleep disorder. "Sleep disorder" includes, but is 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 disorder (SWSD), and sleep problems such as nightmares, night terrors, sleep talking, head banging, snoring, and jaw clenching and / or teeth grinding (bruxism) (e.g., parasomnias).

[0396] In certain embodiments, the CNS disorder is a movement disorder, such as a basal ganglia disorder, such as Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, Gilles de la Tourette syndrome, late-onset dyskinesia, and dystonia, among others.

[0397] In certain embodiments, the CNS disorder is Alzheimer's disease.

[0398] In certain embodiments, the CNS disorder is amyotrophic lateral sclerosis (ALS).

[0399] In certain embodiments, the CNS disorder is nausea and / or vomiting.

[0400] In certain embodiments, the CNS disorder is a substance use disorder (SUD) (e.g., dependence on, for example, opioids, nicotine, cocaine, stimulants, and / or alcohol).

[0401] The term "nervous system disease" (including, for example, "neurodegenerative disease") refers to any disease of the nervous system, including diseases related to the central nervous system (brain, brainstem, and cerebellum), peripheral nervous system (including cranial nerves), and autonomic nervous system (parts located in both the central and peripheral nervous systems). Neurodegenerative diseases refer to a type of nervous system disease characterized by the loss of nerve cells, including but not limited to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, tauopathy (including frontotemporal dementia), and Huntington's disease. Examples of nervous system diseases include, but are not limited to, headache, disturbance of consciousness and coma, dementia, convulsion, sleep disorder, trauma, infection, neoplasm, neuro-ophthalmology, movement disorder, demyelinating disease, spinal cord disorder, and disorders of the peripheral nerves, muscles, and neuromuscular junctions. Substance abuse and mental illness (including but not limited to substance use disorder, bipolar disorder, eating disorder, and schizophrenia) are also included in the definition of nervous system diseases. Further examples of nervous system diseases include acquired aphemia; 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 cyst; arachnoiditis; Arnold-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia-telangiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behçet's disease; Bell's palsy; benign essential blepharospasm; benign focal; muscular atrophy; benign intracranial hypertension; Binswanger's disease; blepharospasm; Bloch-Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumor (including glioblastoma multiforme); spinal cord tumor; Brown-Séquard syndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia; central pain syndrome; central pontine myelinolysis; head injury; 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 bilateral facial nerve palsy; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorder; Cushing's syndrome;Cytomegalic Inclusion Body Disease (CIBD); Cytomegalovirus Infection; Dancing Eyes - Dancing Feet Syndrome; Dandy - Walker Syndrome; Dawson Disease; De Morsier Syndrome; Dejerine - Klumpke Paralysis; Dementia; Dermatomyositis; Diabetic Neuropathy; Diffuse Sclerosis; Autonomic Neuropathy; Dysgraphia; Dyslexia; Dystonia; Early Infantile Epileptic Encephalopathy; Empty Sella Turcica Syndrome; Encephalitis; Brain Tumor; Cerebrotri geminal Angiomatosis; Epilepsy; Erb Paralysis; Essential Tremor; Fabry Disease; Fahr Syndrome; Absence; Familial Spastic Paralysis; Febrile Convulsions; Fisher Syndrome; Friedreich Ataxia; Frontotemporal Dementia and Other "Tauopathies"; Gaucher Disease; Gerstmann Syndrome; Giant Cell Arteritis; Cytomegalic Inclusion Body Disease; Globoid Cell Leukodystrophy; Guillain - Barré Syndrome; HTLV - 1 Associated Myelopathy; Hallervorden - Spatz Disease; Head Trauma; Headache; Hemifacial Spasm; Hereditary Spastic Paraplegia; Hereditary Polyneuropathic Motor Ataxia; Herpes Zoster Oticus; Herpes Zoster; Hirayama Syndrome; HIV - Associated Dementia and Neuropathy (see also Neurological Manifestations of AIDS); Holoprosencephaly; Huntington Disease and Other Polyglutamine Repeat Disorders; Hydranencephaly; Hydrocephalus; Hypercortisolism; Hypoxia; Immune - Mediated Encephalomyelitis; Inclusion Body Myositis; Incontinentia Pigmenti; Infant; Phytanic Acid Storage Disease; Infantile Refsum Disease; Infantile Spasms; Inflammatory Myopathy; Intracranial Cyst; Increased Intracranial Pressure; 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 Disability; Leigh 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; Megalencephaly; Macrocephaly; Melkersson - Rosenthal Syndrome; Meniere Disease; Meningitis; Menkes Disease; Metachromatic Leukodystrophy; Microcephaly; Migraine; Miller - Fisher Syndrome; Minor Stroke; Mitochondrial Myopathy; Möbius Syndrome; Monomelic Amyotrophy; Motor Neuron Disease; Moyamoya Disease; Mucopolysaccharidosis; Multi - Infarct Dementia; Multifocal Motor Neuropathy;Multiple sclerosis and other demyelinating disorders; Multiple system atrophy with orthostatic hypotension; Muscular dystrophy; Myasthenia gravis; Diffuse myelinoclastic sclerosis; Infantile myoclonic encephalopathy; Myoclonus; Myopathy; Congenital myotonia; Narcolepsy; Neurofibromatosis; Neuroleptic malignant syndrome; Neurological symptoms of AIDS; Neurological sequelae of lupus; Neuromyotonia; Neuronal ceroid lipofuscinosis; Neuronal migration disorders; Niemann-Pick disease; O'Sullivan-McLeod syndrome; Occipital neuralgia; Sequela of latent spinal dysraphism; Ohtahara syndrome; Olivopontocerebellar atrophy; Opsoclonus-myoclonus; Optic neuritis; Orthostatic hypotension; Overuse syndrome; Paresthesia; Parkinson's disease; Congenital paramyotonia; Paraneoplastic disorders; Paroxysmal spells; Parry-Romberg syndrome; Pelizaeus-Merzbacher disease; Periodic paralysis; Peripheral neuropathy; Painful neuropathy and neuropathic pain; Persistent vegetative state; Pervasive developmental disorder; Photic sneeze reflex; Phytanic acid storage disease; Pick's disease; Radiculopathy; Pituitary tumor; Polymyositis; Porencephaly; Post-polio syndrome; Postherpetic neuralgia (PHN); Postinfectious encephalomyelitis; Orthostatic hypotension; Prader-Willi syndrome; Primary lateral sclerosis; Prion disease; Progressive; Progressive multifocal leukoencephalopathy; Progressive sclerosing poliodystrophy; Progressive supranuclear palsy; Pseudotumor cerebri; Ramsay Hunt syndrome (type I and type II); Rasmussen encephalitis; Reflex sympathetic dystrophy syndrome; Refsum disease; Repetitive movement disorder; Repetitive stress injury; Restless legs syndrome; Retrovirus-associated myelopathy; Rett syndrome; Reye syndrome; St. Vitus' dance; Sandhoff disease; Schilder's disease; Split-brain syndrome; Septo-optic dysplasia; Shaken baby syndrome; Shingles; Shy-Drager syndrome; Sjogren's syndrome; Sleep apnea; Sotos syndrome; Spasticity; Diastematomyelia; Spinal cord injury; Spinal cord tumor; Spinal muscular atrophy; Stiff-person syndrome; Stroke; Sturge-Weber syndrome; Subacute sclerosing panencephalitis; Subarachnoid hemorrhage; Subcortical arteriosclerotic encephalopathy; Sydenham chorea; Syncope; Syringomyelia; Tardive dyskinesia; Tay-Sachs disease; Temporal arteritis; Tethered cord syndrome; Tommasen disease; Thoracic outlet syndrome; Tic douloureux; Todd paralysis; Tourette syndrome; Transient ischemic attack; Transmissible spongiform encephalopathy; Transverse myelitis; Traumatic brain injury; Tremor; Trigeminal neuralgia; Tropical spastic paraparesis; Tuberous sclerosisVascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; von Hippel-Lindau disease (VHL); Wallenberg syndrome; Werdnig-Hoffmann disease; West syndrome; infantile spasms; Williams syndrome; Wilson disease; and Zellweger syndrome are included.

[0402] In certain embodiments, the subject is a mammal, preferably a primate or a human.

[0403] In another embodiment, there is provided the above-described method, wherein an effective amount of the compound provided herein is as described above.

[0404] In another embodiment, there is provided the above-described method, wherein the compound provided herein is administered intrathecally, intravenously, intramuscularly, subcutaneously, intraventricularly, orally, or topically. In certain embodiments, the compound is administered intrathecally.

[0405] In other embodiments, there is provided the above-described method, wherein any of the compounds of the formula provided herein is administered alone or in combination with one or more other therapeutic agents. In further embodiments, the additional therapeutic agent is a central nervous system (CNS) disorder agent.

[0406] Another object of the present disclosure is the use of the compounds described herein in the manufacture of a medicament for use in the treatment of a disorder or disease. Another object of the present disclosure is the use of the compounds described herein for use in the treatment of a disorder or disease.

[0407] Pharmaceutical composition In one aspect, there is provided a pharmaceutical composition comprising any of the compounds described herein and a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient.

[0408] The compounds or compositions described herein can be administered in combination with one or more additional therapeutic agents (e.g., agents that are therapeutically and / or prophylactically active). The compounds or compositions can be combined with additional therapeutic agents that result in an improvement in their activity (e.g., activity in the treatment of a disease in a subject in need thereof, prevention of a disease in a subject in need thereof, and / or reduction of the risk of onset of a disease in a subject in need thereof (e.g., efficacy and / or effectiveness)), improvement in bioavailability, improvement in safety, reduction of drug resistance, reduction and / or modification of metabolism, inhibition of excretion, and / or modification of distribution in a subject or cell. It will also be understood that the treatment methods employed may achieve the desired effect for the same disorder and / or may achieve different effects. In certain embodiments, the pharmaceutical compositions described herein that contain the compounds described herein and additional therapeutic agents exhibit a synergistic effect not present in pharmaceutical compositions that contain only one of the compounds or additional therapeutic agents described herein and not both.

[0409] The compound or composition can be administered simultaneously with, before, or after one or more additional therapeutic agents, which can be useful, for example, as combination therapy. Therapeutic agents include therapeutically active agents. Therapeutic agents also include prophylactically active agents. Therapeutic agents include drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration for human or veterinary use in accordance with the provisions of 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, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and small organic molecules such as cells. In certain embodiments, the additional therapeutic agents are therapeutic agents useful for the treatment and / or prevention of a disease (e.g., a CNS disorder). Each of the additional therapeutic agents can be administered at a determined dosage and / or time schedule for that therapeutic agent. The additional therapeutic agents can also be administered as a single dose, either together with each other and / or with the compound or composition described herein, or separately at different dosages. The particular combination employed in the regimen takes into account the compatibility of the compounds described herein with the additional therapeutic agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. Generally, the additional therapeutic agent(s) in the combination are expected to be utilized at levels that do not exceed those utilized individually. In some embodiments, the levels utilized in the combination are lower than those utilized individually.

[0410] In one aspect, a kit is provided that includes an effective amount of the compound in a unit dosage form provided herein, together with instructions for administering the compound to a subject having or at risk of having a disease or disorder.

[0411] "Pharmaceutically acceptable salts" refers to, or means, physiologically and pharmaceutically acceptable salts of compounds such as oligomeric compounds or oligonucleotides, i.e., salts that retain the desired biological activity of the parent compound and do not impart undesirable toxicological effects. As used herein, a pharmaceutically acceptable salt is any salt of a compound provided herein that retains its biological properties, is non-toxic, and has no other properties that are otherwise undesirable for pharmaceutical use. Pharmaceutically acceptable salts of the therapeutic agents disclosed herein include salts prepared using relatively non-toxic acids or bases, depending on the specific substituents present on the compounds or modified oligonucleotides described herein.

[0412] When the compounds of the present disclosure contain relatively acidic functional groups, the base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either in the neat form or in a suitable inert solvent.

[0413] When the compounds of the present disclosure contain relatively basic functional groups, the acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either in the neat form or in a suitable inert solvent.

[0414] Accordingly, the compounds of the present disclosure may exist as salts, for example, salts with pharmaceutically acceptable acids. Such salts can be derived from various organic and inorganic counterions well known in the art. Such salts include (1) organic or inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.Acid addition salts formed with 2-octen-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid, and similar acids; or (2) acidic protons present in the parent compound are replaced by (a) metal ions, such as alkali metal ions, alkaline earth metal ions, or aluminum ions, or alkali metal hydroxides or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide, and barium hydroxide, ammonia, or (b) organic bases, such as aliphatic, alicyclic, or aromatic organic amines, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and salts formed when coordinated, including but not limited to these (see, for example, Berge et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0415] Pharmaceutically acceptable salts further include, but are not limited to, for example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc. When the compound contains a basic functional group, salts of non-toxic organic or inorganic acids are included, such as hydrohalic acid salts, for example, hydrochloride and hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartrate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, etc. are included. In some embodiments, the pharmaceutically acceptable salts of the compounds and modified oligonucleotides disclosed herein are sodium salts or potassium salts. In some embodiments, the pharmaceutically acceptable salts of the compounds and modified oligonucleotides disclosed herein are sodium salts.

[0416] The neutral form of the compound is preferably regenerated by contacting the salt with a base or an acid and isolating the parent compound by conventional methods. The parent form of the compound may differ from the various salt forms in terms of certain physical properties such as solubility in polar solvents. In embodiments, the compounds of the present disclosure contain both basic and acidic functional groups, whereby the compound can be converted into either a base addition salt or an acid addition salt. The neutral form of the compound can be regenerated by contacting the salt with a base or an acid and isolating the parent compound by conventional methods. The parent form of the compound differs from the various salt forms in certain physical properties such as solubility in polar solvents, but unless otherwise specified, the salts disclosed herein are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0417] When the compounds of the present disclosure contain relatively basic functional groups, the 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.

[0418] Accordingly, the compounds of the present disclosure may exist as salts, for example, salts with pharmaceutically acceptable acids or bases. Such salts can be derived from a variety of organic and inorganic counterions well known in the art.Such salts include (1) addition salts formed with organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid and similar acids; or (2) salts formed when the acidic proton present in the parent compound is replaced by (a) metal ions such as alkali metal ions, alkaline earth metal ions or aluminum ions, or alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide, and barium hydroxide, ammonia, or (b) organic bases such as aliphatic, cycloaliphatic, or aromatic organic amines such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, etc., but are not limited thereto.

[0419] Pharmaceutically acceptable salts further include, but are not limited to, for example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc. When the compound contains a basic functional group, salts of non-toxic organic or inorganic acids are included, such as hydrohalic acid salts, for example, hydrochloride and hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartrate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, etc. are included. In some embodiments, the pharmaceutically acceptable salts of the compounds and modified oligonucleotides disclosed herein are sodium salts or potassium salts. In some embodiments, the pharmaceutically acceptable salts of the compounds and modified oligonucleotides disclosed herein are sodium salts.

[0420] The neutral form of the compound is preferably regenerated by contacting the salt with a base or an acid and isolating the parent compound by conventional methods. The parent form of the compound may differ from the various salt forms in certain physical properties such as solubility in polar solvents. In embodiments, the compounds of the present disclosure contain both basic and acidic functional groups, whereby the compound can be converted into either a base addition salt or an acid addition salt.

[0421] The neutral form of the compound can be regenerated by conventional methods by contacting the salt with a base or an acid and isolating the parent compound. 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 salt is equivalent to the parent form of the compound for the purposes of the present disclosure.

[0422] In addition to the salt forms, the present disclosure provides compounds in prodrug form. The prodrugs of the compounds described herein are compounds that readily undergo chemical change under physiological conditions to provide the compounds of the present disclosure. Further, the prodrug can be converted to the compounds of the present disclosure by chemical or biochemical means in an ex vivo environment. For example, a prodrug 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.

[0423] Certain compounds of the present disclosure can exist not only in unsolvated forms but also in solvated forms including hydrated forms. In general, 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 intended uses of the present disclosure and are intended to be within the scope of the present disclosure.

[0424] The present disclosure also provides a pharmaceutical composition comprising an effective amount of a compound described herein and a pharmaceutically acceptable excipient. In one embodiment, any of the compounds of the formulas provided herein is administered to a subject using a pharmaceutically acceptable formulation that provides sustained delivery of the compound to the subject for at least 12 hours, 24 hours, 36 hours, 48 hours, 1 week, 2 weeks, 3 weeks, or 4 weeks after the pharmaceutically acceptable formulation is administered to the subject.

[0425] The actual dosage level and administration time of the active ingredient in the pharmaceutical composition of the present disclosure may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, while being tolerable to the subject.

[0426] 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 intraventricular injection, or by oral administration or topical application. According to the present disclosure, the compounds of the present disclosure may be administered alone or in combination with a second, different therapeutic agent. "In combination" means together, substantially simultaneously, or sequentially. In one embodiment, the compounds of the present disclosure are administered acutely. Thus, the compounds of the present disclosure may be administered for a short treatment period, such as about 1 day to about 1 week. In another embodiment, the compounds of the present disclosure may be administered over a long period of time, such as about 1 week to several months, depending on the condition being treated, to improve a chronic disorder.

[0427] As used herein, "pharmaceutically effective amount" means an amount of a compound of the present disclosure that is high enough to significantly and positively modify the condition being treated within the scope of sound medical judgment, but low enough to avoid serious side effects (at a reasonable benefit / risk ratio). The pharmaceutically effective amount of a compound of the present disclosure can vary depending on the specific goal to be achieved, the age and physical condition of the patient being treated, the severity of the underlying disease, the duration of treatment, the nature of concurrent treatment, and the specific compound employed. For example, the therapeutically effective amount of a compound of the present disclosure administered to a child or neonate will be proportionally reduced in accordance with sound medical judgment. Accordingly, the effective amount of a compound of the present disclosure is the minimum amount that provides the desired effect.

[0428] A crucial practical advantage of the present disclosure is that the compounds can be administered in a simple manner, for example, by intrathecal, intravenous, intramuscular, subcutaneous, oral, or intraventricular injection routes, or by topical application such as creams or gels. Depending on the administration route, the active ingredient contained in the compounds of the present disclosure may need to be coated with materials that protect the compound from the action of other natural conditions that can inactivate enzymes, acids, and compounds. To administer the compounds of the present disclosure in other modes than parenteral administration, the compounds may be coated with materials to prevent inactivation or may be administered using such materials.

[0429] The compounds can be administered parenterally or intraperitoneally. Dispersions can also be prepared, for example, in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils.

[0430] Some examples of substances that can function as pharmaceutical excipients or carriers (these 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 carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; and phosphate buffer; skim milk powder; as well as other suitable non-toxic substances used in pharmaceutical formulations, such as vitamin C, estrogen and echinacea. Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, lubricants, excipients, tabletting agents, stabilizers, antioxidants, and preservatives may also be present. For example, solubilizing agents including Cremophor and beta-cyclodextrin can also be used in the pharmaceutical compositions herein.

[0431] Pharmaceutical compositions containing the active compounds (or their prodrugs) of the present disclosure can be manufactured by conventional mixing, dissolving, granulating, tabletting, levigating, emulsifying, encapsulating, entrapping, or lyophilization processes. The compositions can be formulated in a convenient manner using one or more physiologically acceptable carriers, diluents, excipients, or auxiliaries which facilitate processing the active compounds into preparations which can be used pharmaceutically. The compositions herein can be made (e.g., for pharmaceutical use, agricultural use, or veterinary use) by mixing (e.g., contacting, mixing, dissolving, granulating, tabletting, levigating, emulsifying, encapsulating, entrapping, or lyophilizing) the compounds defined herein with one or more suitable carriers, diluents, excipients, or auxiliaries including those described herein.

[0432] The pharmaceutical compositions of the present disclosure can be in a form suitable for substantially any mode of administration, including, for example, intrathecal, topical, ocular, oral, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, etc., or in a form suitable for administration by inhalation or insufflation.

[0433] Systemic formulations include those designed for administration by injection, for example, subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, and those designed for transdermal, transmucosal, oral, or pulmonary administration.

[0434] Useful injectable preparations include sterile suspensions, solutions, or emulsions of the active compound(s) in an aqueous or oily vehicle. The composition may also contain formulating agents such as suspending, stabilizing, and / or dispersing agents. Injectable formulations can be provided in unit dosage forms (for example, ampoules or multi-dose containers) and may contain added preservatives.

[0435] Alternatively, the injectable formulation can be provided in powder form and reconstituted before use with a suitable vehicle including, but not limited to, sterile pyrogen-free water, buffer solutions, dextrose solutions, etc. For this purpose, the active compound(s) can be dried by any known technique such as lyophilization and reconstituted before use.

[0436] For long-term delivery, the active compound(s) or prodrug(s) can be formulated as depot preparations for administration by implantation or intramuscular injection. The active ingredient can be formulated using suitable polymeric substances or hydrophobic substances (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as a slightly insoluble derivative, for example, as a slightly insoluble salt.

[0437] Alternatively, other pharmaceutical delivery systems may be employed. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver the active compound(s), oligonucleotide(s), or prodrug(s). Certain organic solvents such as dimethyl sulfoxide (DMSO) can also be utilized.

[0438] The pharmaceutical composition can be provided in a pack or dispenser device which can contain one or more unit dosage forms containing the active compound(s) if desired. The pack can include a metal or plastic foil such as, for example, a blister pack. Instructions regarding administration can be attached to the pack or dispenser device.

[0439] The active compound(s), prodrug(s), or composition thereof of the present disclosure are generally used in an amount effective to achieve the intended result, for example, an amount effective for the treatment or prevention of the particular disease being treated. The compound(s) and oligonucleotide(s) can be administered therapeutically to achieve a therapeutic benefit or prophylactically to achieve a prophylactic benefit. A therapeutic benefit is the eradication or amelioration of the underlying disorder being treated and / or the eradication or amelioration of one or more of the symptoms associated with the underlying disorder, meaning that even if the patient is still suffering from the underlying disorder, the patient reports an improvement in mood or condition. A therapeutic benefit also includes halting or slowing the progression of the disease, whether or not an improvement is realized.

[0440] In the case of prophylactic administration, the compound can be administered to a patient at risk of developing any of the aforementioned diseases. A patient at risk of developing a disease can be a patient having characteristics that place the patient within a designated risk group of patients defined by an appropriate medical professional or group. Also, a risk patient can be a patient who is normally or routinely in an environment where the onset of an underlying disease can occur. In other words, a risk patient is a person who is normally or routinely exposed to the conditions that cause a disease or illness or who has been acutely exposed for a limited time. Alternatively, prophylactic administration can be carried out to avoid the occurrence of symptoms in a patient who has received a diagnosis of an underlying disorder.

[0441] The amount of the compound to be administered depends on various factors, including, for example, the specific 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 patient, the bioavailability of the specific active compound, and the like. Determination of effective dosage amounts is well within the ability of those skilled in the art.

[0442] An effective dosage can first be estimated from in vitro assays. For example, the initial dosage for use in animals can be formulated to achieve a circulating blood concentration or serum concentration of the active compound that is, when measured in in vitro assays such as in vitro fungal MIC or MFC, and other in vitro assays, IC 50 of the active compound that is greater than or equal to the above. Calculation of the dosage to achieve such a circulating blood concentration or serum concentration, taking into account the bioavailability of the specific compound, is well within the ability of those skilled in the art. For guidance, reference is made to “General Principles,” In: Goodman and Gilman’s The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-112, 13th ed., McGraw-Hill and its cited references, which are hereby incorporated by reference into this specification.

[0443] The initial dosage can also be estimated from in vivo data such as animal models. Animal models useful for testing the effectiveness of compounds for treating or preventing the various diseases described above are well known in the art.

[0444] The dosage can typically range from about 0.0001 mg or 0.001 mg or 0.01 mg / kg / day to about 100 mg / kg / day, but can increase or decrease depending on, among other factors, the activity of the compound, its bioavailability, the mode of administration, and the various factors described above. The dosage and dosing interval can be adjusted individually to provide a plasma level of the compound(s) sufficient to maintain a therapeutic or prophylactic effect. In the case of topical administration or selective uptake, for example, in the case of topical local administration, the effective local concentration of the active compound(s) may not be related to the concentration in the plasma. One of ordinary skill in the art will be able to optimize the effective topical dosage without undue experimentation.

[0445] Preferably, the compound(s) provides a therapeutic or prophylactic benefit and has an acceptable tolerance. The tolerance of the compound(s) and oligonucleotide(s) can be determined using standard pharmaceutical procedures. The dose ratio between an intolerable effect and a therapeutic (or prophylactic) effect is the therapeutic index. Compounds(s) showing a high therapeutic index are preferred.

[0446] The recitation of a list of chemical groups in any definition of a variable herein includes the definition of the variable for any single group or combination of the recited groups. The recitation of embodiments regarding a variable herein includes the embodiment as any single embodiment, or the embodiment in combination with any other embodiment or part thereof. The recitation of embodiments herein includes the embodiment as any single embodiment, or the embodiment in combination with any other embodiment or part thereof.

Examples

[0447] The following examples are provided to more fully understand the embodiments described herein. The examples described in this application are provided to illustrate the compounds, compositions, and methods provided herein and should not be construed as limiting the scope in any way. The following examples and the related sequence listings attached to this application may identify sequences as either "RNA" or "DNA", but as disclosed herein, these sequences may be modified with any combination of chemical modifications. One of ordinary skill in the art will readily appreciate that the designation of a sequence as "RNA" or "DNA" is, in some cases, arbitrary. For example, an oligonucleotide containing a nucleoside with a 2'-OH sugar moiety and a thymine base can be described as DNA with a modified sugar (2'-OH relative to the natural 2'-H of DNA) or as RNA with a modified base (methylated uracil relative to the natural uracil of RNA). Thus, the nucleic acid sequences provided herein are intended to include, but are not limited to, nucleic acids containing any combination of natural or modified RNA and / or DNA, including, for example, but not limited to, nucleic acids with modified nucleobases, including those in the sequence listings.

[0448] Basic experimental procedures The definitions of the variables in the structures in the schemes herein are the same as the definitions at the corresponding positions in the formulas defined herein. Common abbreviations: A Adenine ACN Acetonitrile br Broad C Cytosine CDI Carbonyldiimidazole d Doublet DCM Dichloromethane dd Double doublet dba Dibenzylideneacetone DBCO Azadibenzocyclooctyne DFAA Difluoroacetic anhydride DIPEA or DIEA Diisopropylethylamine DMF Dimethylformamide DMSO Dimethyl sulfoxide DMT or DMTr Dimethoxytrityl dppf 1,1’-Ferrocenediyl-bis(diphenylphosphine) EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc Ethyl acetate G Guanine h hour I2O Iodine monoxide HRMS High resolution mass spectrometry HPLC High performance liquid chromatography LCMS Liquid chromatography and mass spectrometry MPLC Medium pressure liquid chromatography MSCl Methanesulfonyl chloride MS Mass spectrometry MW Microwave m Multiplet MeOH Methanol min minute mL Milliliter MWCO Molecular weight cut-off m / z Mass-to-charge ratio NB New backbone NMP N-Methyl-2-pyrrolidone NMR Nuclear magnetic resonance ppm Parts per million Py Pyridine Rf Retention factor rt or RT Room temperature R t Retention time s Singlet t Triplet U Uracil TBD Triazabicyclodecene TBS or TBDMS Tert-butyldimethylsilyl TEA Triethylamine TFAA Trifluoroacetic anhydride TLC Thin layer chromatography

[0449] Example 1: General synthesis procedure The NB lock was synthesized on a solid phase using an oligonucleotide synthesizer, Oligopilot 100 (Cytiva Life Sciences). The solid support (CPG, 80 - 90 μmol / g, 500 Å) was purchased from LGC - Biosearch Technologies, Petaluma, CA and loaded at a scale of 150 - 300 μmol. All RNA and 2'-modified RNA phosphoramidites were purchased from Hongene Biotech (Union City, CA). Specifically, the 2'-O-methyl phosphoramidites included 5'-O-(4,4'-dimethoxytrityl)-N6-benzoyl-2'-O-methyl-adenosine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'-O-(4,4'-dimethoxytrityl)-N4-acetyl-2'-O-methyl-cytidine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'-O-(4,4'-dimethoxytrityl)-N2-isobutyryl-2'-O-methyl-guanosine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, and 5'-O-(4,4'-dimethoxytrityl)-2'-O-methyl-uridine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite. Also, the 2'-fluoro phosphoramidites included 5'-O-(4,4'-dimethoxytrityl)-N6-benzoyl-2'-fluoro-adenosine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'-O-(4,4'-dimethoxytrityl)-N4-acetyl-2'-fluoro-cytidine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'-O-(4,4'-dimethoxytrityl)-N2-isobutyryl-2'-fluoro-guanosine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, and 5'-O-(4,4'-dimethoxytrityl)-2'-fluoro-uridine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite.For the formation of phosphorothioate linkages, a 0.1 M solution of 3-((dimethylamino-methylidene)amino)-3H-1,2,4-dithiazole-3-thione (DDTT obtained from Chemgenes, Wilmington, MA) was used for 4 - 6 minutes, and for the formation of phosphodiester linkages, a 0.05 M I. 2 O solution (Sigma Aldrich, St Louis, MO) was used. After oxidation / sulfurization, a mixture of 20% n-methylimidazole / acetonitrile and 40% acetic anhydride / 60% lutidine / acetonitrile (Sigma Aldrich, St Louis, MO) was used to acetylate the unreacted chains bound to the CPG.

[0450] The phosphoramidite was dissolved in anhydrous acetonitrile (0.2 M), molecular sieves (4A) were added, and it was left standing overnight (Sigma Aldrich, St. Louis, MO). For the oligonucleotide chain, 5-(ethylthio)-1H-tetrazole (ETT, 0.6 in acetonitrile, manufactured by Sigma Aldrich) was used as the activation solution. The NB modification of the chain (0.15 M, in-house) was dissolved in dichloromethane:acetonitrile (3:1), and the reaction was allowed to proceed to completion using a 5-(ethylthio)-1H-tetrazole solution (ETT, 0.6 M in acetonitrile, manufactured by Sigma Aldrich). The coupling times were 60 minutes (NB) and 6 minutes (2'-O-Me / 2'-fluoro), and each step was carried out at 3.0 equivalents. Before coupling, the oligonucleotide bound to the support was treated with a dichloromethane solution of dichloroacetic acid (3% Deblock, Sigma Aldrich) and washed with anhydrous acetonitrile.

[0451] Cleavage and deprotection of the oligomer bound to the support. After the completion of solid-phase synthesis, the support was treated with an AMA solution, a 1:1 volume of NH 4 OH:CH 3 NH 2 solution (Fisher Scientific, Spectrum Chemicals) at 65 °C for 20 minutes. Then the solution was evaporated.

[0452] Prior to proceeding with purification, in-process analysis is performed by analytical HPLC and LCMS to record the approximate crude purity, identify the target mass of the oligonucleotide, and monitor the completion of deprotection by LCMS.

[0453] LCMS method LCMS conditions: The column used is a Waters XBridge Oligonucleotide BEH C18 Column, 130 Å, 2.5 μm, 2.1 mm × 50 mm (P / N 186003952). The buffers are 400 mM HFIP + 15 mM TEA (buffer A) and 100% methanol (buffer B). The gradient is set at 5 - 50% buffer B at 70 °C for 2 minutes at a flow rate of 0.5 mL / min.

[0454] Concentration by TFF The crude oligo is then concentrated using a Pall Minimate EVO System (product ID: OAPMPUNV). The cassette used is a Pall Minimate TFF capsule equipped with a 3k Omega membrane.

[0455] Purification Purification was performed using reverse-phase HPLC. The column used is a Phenomenex Clarity 5 μm Oligo-RP AXIOS, 250 × 30 mm (P / N: 00G - 4442 - U0 - AX). The buffer mixture is 100 mM TEAA, 5% ACN (pH 7.0) (buffer A) and 1:1 acetonitrile:methanol (buffer B). The gradient is set at 5 - 30% buffer B at 60 °C for 60 minutes at a flow rate of 20 mL / min.

[0456] After purification, the fraction is analyzed by reverse-phase UPLC. The column used is Waters ACQUITY UPLC Oligonucleotide BEH C18 1.7 μm, 2.1×50 mm (P / N: 186003949). The buffer mixture is 100 mM TEAA, 5% ACN (pH 7.0) (buffer A) and 1:1 acetonitrile:methanol (buffer B). The gradient is set at 5 - 30% buffer B at 80 °C for 5 minutes at a flow rate of 1.0 mL / min. The minimum specification of the purified pool is 85%.

[0457] Desalting Once the pool is established, the oligo is desalted using a Pall Minimate EVO System (Product ID: OAPMPUNV). The cassette used is a Pall Minimate TFF capsule (Product ID: OA003C12) with a 3k Omega membrane. The hold solution is recovered for lyophilization or direct annealing. After lyophilization, an off-white powder was obtained.

[0458] Example 2: Synthesis of dinucleotide 18.

Chemical Structure

[0459] Synthesis of 3 Solution 2 (20 g, 36.459 mmol, 1 equiv) in DCM (680 mL) was treated with pyridine (10.09 g, 127.607 mmol, 3.5 equiv) at 0 °C for 5 min under a nitrogen atmosphere, and then Tf 2 O (17.00 g, 60.256 mmol, 1.65 equiv) was added dropwise at 0 °C. The resulting mixture was extracted three times with CH 2 Cl 2 The combined organic layers were washed with saturated CuSO 4 aqueous solution and dried over anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The crude product 3 was used directly in the next step without further purification.

[0460] Synthesis of 4 To a solution of triflate 3 (20.8 g, 30.560 mmol, 1 equiv) in dioxane (450 mL) were added NaOH (17.11 mL, 171.136 mmol, 10 N, 5.60 equiv) and water (83.86 mL, 4654.899 mmol, 152.32 equiv). The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. The resulting mixture was extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH / EA, to give the product 4 (10.0 g, purity: 90%, 2 steps: 45%) as a pale yellow foam.

[0461] Synthesis of 5 To a solution of 4 (2.0 g, 3.646 mmol, 1 equiv) in pyridine (33 mL) was added MsCl (1.67 g, 14.584 mmol, 4 equiv) at 0 °C under a nitrogen atmosphere. The reaction was stirred overnight. The resulting mixture was poured into saturated NaHCO 3 solution and extracted with CHCl 3 The combined organic layers were washed with CuSO 4 and brine and dried over anhydrous Na 2 SO 4It was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (50:1), and compound 5 (1.95 g, 85%) was obtained as a pale yellow foam.

[0462] Synthesis of 6 To a solution of 5 (2 g, 3.192 mmol, 1 eq) in DMF (68 ml, 869.373 mmol, 272.36 eq) was added NaN 3 (1.45 g, 22.344 mmol, 7 eq). The mixture was stirred at 90 °C for 2 days under a nitrogen atmosphere. Then, the resulting mixture was poured into a NaHCO 3 solution, and extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (200:1), and azide 6 (1.2 g, purity: 67%) was obtained as a pale yellow oil.

[0463] Synthesis of 7 To a solution of azide 6 (5.65 g, purity 67%, 1 eq) in 56 ml of MeOH in a 250 mL round-bottom flask was added Pd / C (10%, 0.57 g) under a nitrogen atmosphere. The mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere using a hydrogen balloon, filtered through a celite pad, and concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography using CH 3 CN / H 2 O to obtain amine 7 (2.74 g, 51%) as a white solid.

[0464] Synthesis of 8 Aldehyde (0.464 g, 1.828 mmol, 1 eq), amine (1 g, 1.828 mmol, 1 eq) and Et 3A mixture of N (0.76 mL, 5.48 mmol, 3 equiv) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (581 mg, 2.74 mmol, 1.5 equiv) was added and the mixture was stirred at room temperature for 48 hours. LCMS showed a conversion of 50 - 60%. The reaction mixture was quenched with 100 mL of saturated aqueous sodium bicarbonate, extracted with DCM, concentrated to 200 mL, and the residue was purified by column chromatography using 0 - 10% MeOH / DCM to give 1.16 g (80%) of a mixture of product and starting material inseparable as a white solid, which was used directly in the next step. NMR and LCMS m / z 787 (M+1) corresponded to the product.

[0465]

Chemical formula

[0466] Synthesis of 11 TFA (10 mL, 124 mmol, 7 equiv) was added dropwise to a solution of crude DMT ether 10 (12 g, 17.9 mmol, 1 equiv) in DCM (100 mL) at 0 °C. Then the reaction mixture was stirred at room temperature. After 1 hour, the reaction mixture was stirred into saturated NaHCO 3(300 mL) was poured into. The aqueous layer was extracted with DCM (2 × 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica gel (0→60% ethyl acetate / hexane) to obtain alcohol 11 as a white solid (5.33 g). This procedure was repeated with the remaining 12 g of crude DMT ether 10, and these were combined to obtain alcohol 11 (10.4 g, 78% yield in 2 steps).

[0467] Synthesis of 12 Under sonication, alcohol 11 (1.5 g, 4.03 mmol, 1 equiv) was dissolved in anhydrous DCM (40 mL). Then Dess-Martin periodinane (2.14 g, 5.03 mmol, 1.25 equiv) was added all at once as a solid to obtain a pink / salmon-colored suspension. After 3.5 h, the reaction mixture was poured into saturated sodium thiosulfate (150 mL) with stirring and extracted with DCM (60 mL). The organic layer was washed with saturated sodium bicarbonate (150 mL) and saturated NaCl (150 mL). The aqueous layer was extracted separately with DCM (2 × 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude aldehyde 12 (1.57 g) as a white solid, which was used without further purification.

[0468] Synthesis of 13 Triphenylcarbethoxymethylene phosphorane (1.76 g, 5.06 mmol, 1.25 equiv) was added all at once as a solid to a suspension of crude aldehyde 12 (1.5 g, 4.05 mmol, 1 equiv) in anhydrous THF (40 mL) at room temperature. After 16 h, the reaction mixture was concentrated at 30 °C under reduced pressure to remove THF. The resulting residue was extracted with ethyl acetate (100 mL) and washed with water (50 mL) and saturated NaCl (50 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica gel (0→50% ethyl acetate / hexane) to obtain ester 13 (1.24 g, 70% yield in 2 steps, E / Z ratio 20:1 by UV).

[0469] Synthesis of 14 A solution of alkene 13 (1.24 g, 2.81 mmol, 1 equiv) in methanol (20 mL) was degassed, filled with nitrogen, and palladium / carbon (300 mg, 0.28 mmol, 0.1 equiv) was added. Then, the reaction mixture was degassed and filled with hydrogen gas from a balloon. After stirring for 75 minutes, the reaction mixture was filtered through celite and rinsed with methanol. The filtrate was concentrated under reduced pressure to obtain ester 14 (1.17 g, 94% yield) as a white foam, which was used without further purification.

[0470] Synthesis of 15 A solution of sodium hydroxide (528 mg, 13.2 mmol, 5 equiv) in water (1 mL) was added dropwise to a solution of crude ester 14 (1.17 g, 2.64 mmol, 1 equiv) in methanol (10 mL) at room temperature. After 1.5 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water (about 20 mL) to obtain a white precipitate. The reaction mixture was cooled to 0 °C with stirring and then acidified to pH = 3 - 4 by the dropwise addition of 1N HCl (14 mL). Then, the reaction mixture was extracted with DCM (3 × 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain carboxylic acid 15 (1.03 g, 94% yield) as a white foam.

[0471] Example 3. Synthesis of dinucleotides NB - 101, NB - 105, NB - 106, and NB - 107.

Chemical formula

Chemical formula

[0472] Alcohol 1 (3.0 g, 4.274 mmol, 1 equiv), 1,1'-carbonyldiimidazole (1.386 g, 8.548 mmol, 2 equiv) and DMAP (1.044 g, 8.548 mmol, 2 equiv) were dissolved in dichloromethane (50 mL). After stirring at room temperature for 14 h, the reaction mixture was washed with saturated NH 4 Cl and extracted with DCM (2X). The combined organic layers were dried over Na 2 SO 4 and concentrated to give 3.5 g of crude product 2 as a white solid, which was used in the next step without purification.

[0473] Compound 2 (1.2 g, 1.508 mmol, 1 equiv) and amine 3 (0.663 g, 1.809 mmol, 1.2 equiv) were dissolved in anhydrous pyridine (20 mL) and evaporated to dryness. The residue was redissolved in anhydrous pyridine (15 mL). DMAP (184 mg, 1.508 mmol, 1 equiv) was added to the reaction. After stirring at room temperature for 60 h, the reaction mixture was concentrated under reduced pressure. The residue was washed with saturated NaHCO 3 The aqueous phase was extracted with DCM (1X). The combined organic layers were dried over Na 2 SO 4 filtered and concentrated. The residue was purified by silica gel chromatography (50 g, 20 μm) using 0 - 10% MeOH / DCM. The pure fractions were combined, concentrated and dried under high vacuum to give 0.7 g of carbamate 4 (42%) as a white solid.

[0474] To a stirred solution of carbamate 4 (0.7 g, 0.64 mmol, 1 equiv) and diisopropylethylamine (0.724 mL, 4.158 mmol, 6.5 equiv) in anhydrous DCM (10 mL), N,N - diisopropylchlorophosphoramidite (0.428 mL, 0.432 mmol, 3 equiv) was added dropwise. The reaction was stirred at room temperature for 2 h. LCMS indicated completion of the reaction. The reaction was quenched with saturated NaHCO 3 solution and partitioned between DCM and saturated NaHCO 3 The DCM layer was collected. The aqueous phase was extracted with DCM (1x). The combined organic phases were dried over Na 2 SO4 It was dried, filtered, and concentrated. The residue was pre-equilibrated with (2% Et 3 N-DCM) and loaded onto a biotage silica gel column (25 g, 20 μm), and purified by flash chromatography using 0 - 10% MeOH / DCM (containing 2% Et 3 N). The pure fractions were combined, concentrated, and dried under high vacuum to obtain 610 mg (74%) of phosphoramidite NB-101. MS: m / z = 1316.1 [M+Na] + . P31-NMR and H1-NMR corresponded to the product.

[0475]

Chemical formula

[0476] Compound 6 (0.75 g, 1.146 mmol, 1 equivalent) and amine 7 (0.578 g, 1.203 mmol, 1.05 equivalents) were dissolved in anhydrous pyridine (20 mL) and evaporated to dryness. The residue was redissolved in anhydrous pyridine (15 mL). DMAP (140 mg, 1.146 mmol, 1 equivalent) was added to the reaction. After stirring at room temperature for 18 hours, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between saturated NaHCO 3 and DCM. The aqueous phase was extracted with DCM (1X). The combined organic layers were dried over Na 2 SO 4It was dried, filtered, and concentrated. The residue was purified by silica gel chromatography (50 g, 20 μm) using 0 - 10% MeOH / DCM. The pure fractions were combined, concentrated, and dried under high vacuum to obtain 0.91 g of carbamate 8 (74%) as a white solid.

[0477] Carbamate 8 (530 mg, 0.497 mmol, 1 equiv) was dissolved in THF (5 mL). TBAF (0.754 mL, 0.754 mmol, 1.5 equiv) was added to the reaction. The reaction was stirred at room temperature for 2 h. LCMS indicated that some starting material still remained. Additional TBAF (0.251 mL, 0.251 mmol, 0.5 equiv) was added to the reaction. The reaction was stirred for 1 h. LCMS indicated that the reaction was complete. The reaction was concentrated under reduced pressure. The residue was purified by silica gel chromatography (25 g, 20 μm) using 0 - 5 - 10% MeOH / DCM to obtain 309 mg of product compound 9 (60%) as a white solid.

[0478] To a stirred solution of carbamate 9 (0.493 g, 0.517 mmol, 1 equiv) and diisopropylethylamine (0.586 mL, 3.363 mmol, 6.5 equiv) in anhydrous DCM (10 mL), 2 - cyanoethyl N,N - diisopropyl chlorophosphoramidite (0.346 mL, 1.551 mmol, 3 equiv) was added dropwise. The reaction was stirred at room temperature for 1 h. LCMS indicated that some carbamate 9 still remained. Additional 2 - cyanoethyl N,N - diisopropyl chlorophosphoramidite (0.115 mL, 0.517 mmol, 1 equiv) was added dropwise. The reaction was stirred at room temperature for 1 h. LCMS indicated that the reaction was complete. The reaction was quenched with saturated NaHCO 3 solution and partitioned between DCM and saturated NaHCO 3 The DCM layer was collected. The aqueous phase was extracted with DCM (2x). The combined organic phases were dried over Na 2 SO 4 filtered...

Claims

1. A compound of formula (II-a), or a salt thereof: 【Chemical 569】 (In the formula, Each Y is independently a substituted or unsubstituted alkylene, a substituted or unsubstituted heteroalkylene, a substituted or unsubstituted carbocyclylene, a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, a substituted or unsubstituted heteroarylene, -O-, -OP(O)O ２ -, -N(R Ｃ ), -, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR Ｃ -, -NR Ｃ C(=O)-, -NRC(=O)-, -NR Ｃ C(=O)R Ｃ -, -C(=O)R Ｃ -, -NR Ｃ C(=O)O-, -NR Ｃ C(=O)N(R Ｃ ), -, -OC(=O)-, -OC(=O)O-, -OC(=O)N(R Ｃ ), -, -S(O)NR ２ -, -NR Ｃ SO Ｃ -, or a combination thereof,​​ Each R Ｃ These are independently hydrogen, a substituted or unsubstituted acyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heteroaliphatic, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a nitrogen protecting group, or two R Ｃ The groups bond to form substituted or unsubstituted heterocyclyl rings, or substituted or unsubstituted heteroaryl rings. Each R ２ These are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR ６ , -N(R ６ ), or -SR ６ And, Each R ３ These are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR ７ , -N(R ７ ), or -SR ７ And, R ４ and R ５ These are independently oligonucleotides, protecting groups, or R ４ and R ５ They combine together to form a single oligonucleotide. Each R ６ These are independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group. Each R ７ These are independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group. Each R ８ These are independently substituted or unsubstituted heteroaryl compounds. Each R ９ These are independently substituted or unsubstituted heteroaryl compounds. Each X is independently either O or S. Z １ , and Z ２ Each of these is independent, combined, C １ -C ６ Alkylene, or C ２ -C ６ It is alkenylene, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

2. The compound is Oligonucleotides of formula (IX): 【Chemistry 571】 Oligonucleotide of formula (X): 【Chemistry 572】 Oligonucleotide of formula (XI): 【Chemistry 573】 Oligonucleotide of formula (XII): 【Chemistry 574】 Oligonucleotide of formula (XIII): 【Chemical 575】 Oligonucleotide of formula (XIV): 【Chemical 576】 Oligonucleotide of formula (XV): 【Chemical 580】 Oligonucleotide of formula (XVI): 【Chemistry 581】 Oligonucleotide of formula (XVII): 【Chemical Formula 582】 or Oligonucleotide of formula (XVIII): 【Chemical 583】 (In the formula, R Ｃ is -H, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. Each R ２ These are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR ６ , -N(R ６ ), or -SR ６ And, Each R ３ These are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR ７ , -N(R ７ ), or -SR ７ And, R ４ and R ５ These are independently oligonucleotides, protecting groups, or R ４ and R ５ They combine together to form a single oligonucleotide. Each R ６ These are independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group. Each R ７ These are independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group. Each R ８ These are independently substituted or unsubstituted heteroaryl rings, Each R ９ These are independently substituted or unsubstituted heteroaryl rings, Each X is independently either O or S. A compound or salt or prodrug according to claim 1, comprising the compound or salt thereof.

3. R Ｃ Each of these independently performs a substitution or non-substitution of -C. ８ -C ４０ - Alkyl; and / or At least one R c is substituted with one or more of the following: hydroxyl, amine, carboxylic acid, azide, or alkyne; and / or The compound according to claim 1, wherein at least one R c comprises at least one substituent selected from the group consisting of hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, tetradecanoic acid, pentadecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid, oleic acid, linoleic acid, and arachidonic acid.

4. The oligonucleotide is of formula (IX-a): 【Chemical 577】 (In the formula, Each R ２ These are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR ６ , -N(R ６ ), or -SR ６ And, Each R ３ These are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR ７ , -N(R ７ ), or -SR ７ And, R ４ and R ５ These are independently oligonucleotides, protecting groups, or R ４ and R ５ They combine together to form a single oligonucleotide. Each R ６ These are independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group. Each R ７ These are independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group. Each R ８ These are independently substituted or unsubstituted heteroaryl rings, Each R ９ These are independently substituted or unsubstituted heteroaryl rings, Each X is independently either O or S. The compound or a salt thereof or prodrug according to claim 2.

5. at least one R ２ However, -F or -OR ６ And R 6 is methyl; and / or The compound according to claim 1, wherein at least one R3 is -F or -OR7, and R7 is methyl.

6. The compound is Oligonucleotide of formula (IX-c): 【Chemical 584】 Oligonucleotide of formula (IX-d): 【Chemical 585】 or Oligonucleotide of formula (IX-e): 【Chemical 586】 (In the formula, R ４ and R ５ These are independently oligonucleotides, protecting groups, or R ４ and R ５ They combine together to form a single oligonucleotide. Each X is independently either O or S. A compound or salt or prodrug according to claim 4, comprising the compound or salt thereof.

7. A compound of formula (I'), or a salt thereof: 【Chemical 553】 (In the formula, A is a substituted tetrahydrofuranyl, a substituted tetrahydropyranyl ring, or a modified sugar; B is a substituted tetrahydrofuranyl, a substituted tetrahydropyranyl ring, or a modified sugar; and W1 and W4 are independently a modified or unmodified nucleoside, oligonucleotide, ligand, lipophilic moiety, or protecting group. R8 and R9 are independently substituted or unsubstituted heteroaryl compounds. L is a linker, ligand, lipophilic moiety, -Z1-Y-Z2-, or a combination thereof. W2 and W3 independently consist of a bond, a linker, a substituted or unsubstituted alkylene, a substituted or unsubstituted heteroalkylene, a substituted or unsubstituted carbocyclylene, a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, a substituted or unsubstituted heteroarylene, -O-, -OP(O)O2-, -N(RA)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR A-, -NR A C(=O)-, -NR A C(=O)R A-, -C(=O)R A-, -NR A C(=O)O-, -NR A C(=O)N(RA A)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA A )-, -S(O) 2NR A-, -NR A SO 2-, or a combination thereof, Each R A is independently a hydrogen atom, a substituted or unsubstituted acyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heteroaliphatic, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a nitrogen protecting group if bonded to a nitrogen atom, an oxygen protecting group if bonded to an oxygen atom, or a sulfur protecting group if bonded to a sulfur atom, or two R A groups bond to the atoms to which they are bonded to form a substituted or unsubstituted heterocyclyl ring or a substituted or unsubstituted heteroaryl ring. Z1 and Z2 are independently bonded, substituted or unsubstituted alkylenes, substituted or unsubstituted heteroalkylenes, substituted or unsubstituted carbocyclylenes, substituted or unsubstituted heterocyclylenes, substituted or unsubstituted arylenes, substituted or unsubstituted heteroarylenes, -O-, -OP(O)O2-, -N(R B)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR B-, -NR B C(=O)-, -NR B C(=O)R B-, -C(=O)R B-, -NR B C(=O)O-, -NR B C(=O)N(R B)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(R B )-, -S(O) 2NR B-, -NR B SO 2-, or a combination thereof, Each R B independently consists of hydrogen, a substituted or unsubstituted acyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heteroaliphatic, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a nitrogen protecting group if bonded to a nitrogen atom, an oxygen protecting group if bonded to an oxygen atom, or a sulfur protecting group if bonded to a sulfur atom, or two R B groups bond to form a substituted or unsubstituted heterocyclyl ring or a substituted or unsubstituted heteroaryl ring. Y is a substituted or unsubstituted alkylene, a substituted or unsubstituted heteroalkylene, a substituted or unsubstituted carbocyclylene, a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, a substituted or unsubstituted heteroarylene, -O-, -OP(O)O 2-, -N(RC C)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR C-, -NR C C(=O)-, -NR C C(=O)RC C-, -C(=O)RC C-, -NR C C(=O)O-, -NR C C(=O)N(RC C)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RC C)-, -S(O) 2 NR C -, -NR C SO 2-, or a combination thereof, Each R C group is independently a hydrogen atom, a substituted or unsubstituted acyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heteroaliphatic group, a substituted or unsubstituted carbocyclyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a nitrogen protecting group, or two R C groups bonded together to form a substituted or unsubstituted heterocyclyl ring or a substituted or unsubstituted heteroaryl ring.

8. The compound is of formula (VIII): 【Chemical 554】 A compound according to claim 7, or a salt thereof, having the properties of the compound according to claim 7.

9. At least one R8 is uracil, cytosine, adenine, guanine, inosine, or thymine; and / or The compound according to claim 1, wherein at least one R9 is uracil, cytosine, adenine, guanine, inosine, or thymine.

10. At least one X is S; and / or R4 and R5 are each independently oligonucleotides; R4 is an oligonucleotide, and R5 is a protecting group; R4 is a protecting group, and R5 is an oligonucleotide; or The compound according to claim 1, wherein R4 and R5 are each independently protecting groups.

11. The compound according to claim 1, wherein the oligonucleotide comprises at least one siRNA, miRNA, ADAR mobilization molecule, ADAR targeting molecule, guide RNA, and / or antisense nucleic acid.

12. The compound is of the following formula: 【Chemical 587】 【Chemical 588】 The compound or salt thereof according to claim 1.

13. The compound is of the following formula: 【Chemical 589】 【Chemical 590】 【Chemistry 591】 【Chem.592】 【Chem.593】 【Chem.594】 【Chemical Formula 595】 【Chemical 596】 【Chem.597】 【Chemical Formula 598】 【Chemical 599】 【Chemical 600】 【Chemical 601】 【Chemical 602】 【Chemical 603】 【Chemical 604】 【Chemical 605】 【Chemical 606】 【Chemical 607】 【Chemical 608】 The compound or salt thereof according to claim 1.

14. A composition comprising a compound or a salt or prodrug according to any one of claims 1 to 11, or a compound or a salt thereof according to claim 12 or 13, and a pharmaceutically acceptable excipient.

15. A composition for use in the treatment or improvement of a disease, disorder, or symptom of the central nervous system (CNS), comprising a compound or salt or prodrug according to any one of claims 1 to 11, or a compound or salt thereof according to claim 12 or 13.

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