Oligonucleotides with synthetic backbone and synthesis thereof

Abstract

Provided herein are oligonucleotide-containing compounds, methods of delivering the compounds, and methods of using the compounds to treat diseases, disorders, and symptoms (e.g., central nervous system diseases, disorders, and symptoms) in a subject.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 342,018, filed May 13, 2022. The disclosure of the prior application is considered part of the disclosure of the present application and is incorporated by reference in its entirety into the disclosure of the present application. Background Art

[0003] In the use of compounds in therapeutic, preventive or diagnostic applications, it is generally desirable to deliver the compound to a specific location (e.g., to a desired cell) to enhance the therapeutic or preventive effect or to facilitate diagnostic purposes. This is often the case when attempting to deliver a therapeutic compound in vivo. In addition, being able to effectively deliver the compound to a specific location can limit or potentially eliminate the unintended consequences (such as off-target effects) that may be caused by the administration of the compound. One strategy to facilitate the delivery of a compound (such as a therapeutic, preventive or diagnostic compound) to a desired location in vivo is by connecting or attaching the compound to a targeting ligand.

[0004] The class compound that can use targeting ligand targeting is oligomeric compound, such as protein, peptide, antibody and oligonucleotide.The oligomeric compound comprising the nucleotide sequence (for example, oligonucleotide) that is at least partially complementary to target nucleic acid has been shown to change the function and activity of target in vitro and in vivo.When being delivered to the cell containing target nucleic acid (such as mRNA or pre-mRNA), oligonucleotide has been shown to regulate the expression or activity of target nucleic acid.In some cases, oligonucleotide can reduce the expression of gene by suppressing the translation of nucleic acid target and / or triggering the degradation of target nucleic acid.

[0005] If the target nucleic acid is mRNA, one mechanism by which the expression of the oligonucleotide-regulated mRNA target is through RNA interference. RNA interference is a biological process in which RNA or RNA-like molecules (such as chemically modified RNA molecules) can silence gene expression at least in part through an RNA-induced silencing complex (RISC) pathway. In addition, oligonucleotides can regulate the expression of target nucleic acids (such as target mRNA) through RNA enzyme recruitment mechanisms, microRNA mechanisms, placeholder mechanisms, and editing mechanisms. Oligonucleotides can be single-stranded or double-stranded. Oligonucleotides may comprise DNA, RNA, and RNA-like molecules, which may further comprise modified nucleosides comprising one or more non-phosphodiester bonds.

[0006] Another class of compounds that can be targeted using targeting ligands is small molecule compounds. Small molecule compounds (e.g., organic compounds with a molecular weight of about 1000 Daltons or less) are generally shown to be able to change the function and / or activity of the target, so that the disease and / or disease symptoms are regulated or improved or are generally used as diagnostic markers when positioned to the target. More effectively delivering the compound to a specific location can limit or potentially eliminate the unexpected consequences (such as off-target effects) that may be caused by the administration of the compound and provide improved positioning of the diagnostic compound. Summary of the Invention

[0007] The present disclosure relates to compounds (e.g., any of those described herein), modified oligonucleotides, and methods for modulating protein function and / or expression in a subject and treating a disease, disorder, and symptom in the subject. The method may include compounds disclosed herein and modified oligonucleotides.

[0008] It should be understood that the embodiments of the invention discussed below with respect to preferred variants may be employed alone or in combination with one or more embodiments or preferred variants of the invention, as if each combination were expressly listed herein.

[0009] In some aspects, the present disclosure provides oligonucleotides of formula (I'):

[0010]

[0011] in:

[0012] A, B, W 1 、W 2 、W 3 、W 4 、R 8 and R 9 As defined herein.

[0013] In some aspects, the present disclosure provides an oligonucleotide of formula (VIII):

[0014]

[0015] in:

[0016] A, B, W 1 、W 2 、W 3 、W 4 、R 8 and R 9 As defined herein.

[0017] In some aspects, the present disclosure provides oligonucleotides of formula (I):

[0018]

[0019] in:

[0020] 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 As defined herein.

[0021] In some aspects, the present disclosure provides oligonucleotides of formula (VII):

[0022]

[0023] in:

[0024] Q 1 , Q 2 , Y, R 2 、R 3 、R 8 、R 9 , Z 1 and Z 2 As defined herein.

[0025] In some aspects, the present disclosure provides oligonucleotides of formula (II):

[0026]

[0027] in:

[0028] X, Y, R 2 、R 3 、R 4 、R 5 、R 8 、R 9 , Z 1 , Z 2 , Z 3 , Z 4 , n and p are as defined herein.

[0029] In some aspects, the present disclosure provides an oligonucleotide of formula (VI):

[0030]

[0031] in:

[0032] X, Y, R 2 、R3 、R 4 、R 5 、R 8 、R 9 , Z 1 , Z 2 , Z 3 , Z 4 and n are as defined herein. In some aspects, the present disclosure provides an oligonucleotide of formula (IX):

[0033]

[0034] in:

[0035] X, R 2 、R 3 、R 4 、R 5 、R 8 、R 9 and R c As defined herein.

[0036] In some aspects, the present disclosure provides oligonucleotides of formula (X):

[0037]

[0038] in:

[0039] X, R 2 、R 3 、R 4 、R 5 、R 8 、R 9 and R C As defined herein.

[0040] In some aspects, the present disclosure provides an oligonucleotide of formula (XI):

[0041]

[0042] in:

[0043] X, R 2 、R 3 、R 4 、R 5 、R 8 、R 9 and R c As defined herein. In some aspects, the present disclosure provides an oligonucleotide of formula (XII):

[0044]

[0045] in:

[0046] X, R 2 、R 3 、R 4 、R 5 、R 8 、R 9 and R c As defined herein.

[0047] In some aspects, the present disclosure provides an oligonucleotide of formula (XIII):

[0048]

[0049] in:

[0050] X, R 2 、R 3 、R 4 、R 5 、R 8 、R 9 and R c As defined herein.

[0051] In some aspects, the present disclosure provides an oligonucleotide of formula (XIV):

[0052]

[0053] in:

[0054] X, R 2 、R 3 、R 4 、R 5 、R 8 、R 9 and R c As defined herein.

[0055] In some aspects, the present disclosure provides an oligonucleotide of formula (IX-a):

[0056]

[0057] in:

[0058] X, R 2 、R 3 、R 4 、R 5 、R 8 and R 9 As defined herein.

[0059] In some aspects, the present disclosure provides an oligonucleotide of Formula (IX-b):

[0060]

[0061] in:

[0062] X, R 2 、R 3 、R 4 、R 5 、R 8 and R 9 As defined herein.

[0063] In some aspects, the present disclosure provides oligonucleotides of formula (Xa):

[0064]

[0065] in:

[0066] X, R 2 、R 3 、R 4 、R 5 、R 8 and R 9 As defined herein. In some aspects, the present disclosure provides an oligonucleotide of formula (XV):

[0067]

[0068] in:

[0069] X, R 2 、R 3 、R 4 、R 5 、R 8 、R 9 and R c As defined herein.

[0070] In some aspects, the present disclosure provides an oligonucleotide of Formula (XVI):

[0071]

[0072] in:

[0073] X, R 2 、R 3 、R 4 、R 5 、R 8 and R 9 As defined herein. In some aspects, the present disclosure provides an oligonucleotide of formula (XVII):

[0074]

[0075] in:

[0076] X, R 2 、R 3 、R 4 、R5 、R 8 、R 9 and R c As defined herein.

[0077] In some aspects, the present disclosure provides an oligonucleotide of formula (XVIII):

[0078]

[0079] in:

[0080] X, R 2 、R 3 、R 4 、R 5 、R 8 、R 9 and R c As defined herein.

[0081] In some aspects, the present disclosure provides an oligonucleotide of formula (IX-c):

[0082]

[0083] in:

[0084] X, R 2 、R 3 、R 4 、R 5 、R 8 、R 9 and R c As defined herein.

[0085] In some aspects, the present disclosure provides an oligonucleotide of Formula (IX-d):

[0086]

[0087] in:

[0088] X, R 2 、R 3 、R 4 、R 5 、R 8 、R 9 and R c As defined herein. In some aspects, the present disclosure provides an oligonucleotide of formula (IX-e):

[0089]

[0090] in:

[0091] X, R 2 、R 3 、R 4、R 5 、R 8 、R 9 and R c As defined herein.

[0092] In some aspects, the present disclosure provides compounds of the formula:

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111] or a salt thereof.

[0112] In another aspect, the present disclosure provides compositions comprising any of the compounds provided herein and a pharmaceutically acceptable excipient.

[0113] In some embodiments, R 4 and R 5Each comprises an oligonucleotide. In some embodiments, one or two oligonucleotides are attached at their 5' end. In some embodiments, one or two oligonucleotides are attached at their 3' end. In some embodiments, one or two 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 linked together to form a single oligonucleotide. In some embodiments, R 4 Contains oligonucleotides, and R 5 In some embodiments, R 4 Contains a protecting group, and R 5 In some embodiments, R 4 and R 5 Each includes protecting groups.

[0114] In certain embodiments, R 4 Attached at the 3' end of the oligonucleotide. In certain embodiments, R 4 Attached at the 5' end of the oligonucleotide.

[0115] In certain embodiments, R 5 Attached at the 3' end of the oligonucleotide. In certain embodiments, R 5 Attached at the 5' end of the oligonucleotide.

[0116] On the other hand, the present disclosure provides a method for delivering therapeutic oligonucleotides to a subject, the method comprising administering any compound or composition provided herein to the subject. On the other hand, the present disclosure provides a method for delivering therapeutic oligonucleotides to the brain of a subject, the method comprising administering any compound or composition provided herein to the subject. On the other hand, the present disclosure provides a method for treating or improving a disease, illness or its symptom of a subject, the method comprising administering any compound or composition provided herein to the subject. In some embodiments, disease, illness or its symptom is a central nervous system (CNS) disease, illness or its symptom. In certain embodiments, disease, illness or its symptom is Alzheimer's disease or its symptom. In some embodiments, compound is administered intrathecally to a subject.

[0117] In another aspect, the present disclosure provides methods for preparing any of the compounds provided herein, comprising one or more compounds and chemical transformations described herein.

[0118] definition

[0119] It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not limitations of the claimed embodiments. In this document, unless otherwise specifically stated, the use of the singular includes the plural. As used herein, the use of "or" means "and / or" unless otherwise stated. In addition, the use of the term "including" and other forms such as "include" and "included" is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0120] Unless otherwise indicated, the following terms have the following meanings:

[0121] As used herein, the term "treating" a condition encompasses improving, alleviating, and / or managing a condition and / or symptoms that may cause a condition. The terms "treating" and "treatment" refer to a method of alleviating or alleviating a disease and / or its attendant symptoms. According to the present disclosure, "treating" includes blocking, inhibiting, attenuating, preventing, modulating, reversing the effects of a condition, and reducing the occurrence of, for example, harmful effects of a condition. As used herein, "inhibiting" encompasses preventing, reducing, and stopping progression.

[0122] The terms "isolated," "purified," or "biologically pure" refer to material that is substantially or essentially free from components that normally accompany it as found in its native state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography (HPLC). Specifically, in certain embodiments, the 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.

[0123] The term "administration" or "administering" includes a route by which a compound is introduced into a subject to perform its intended function. Examples of routes of administration that can be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal.

[0124] "Parenteral administration" means administration by injection or infusion. Parenteral administration includes subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, or intracranial administration, such as intrathecal or intracerebroventricular administration.

[0125] "Pharmaceutically acceptable carrier or diluent" means any substance suitable for administration to an individual. In certain embodiments, a pharmaceutically acceptable carrier or diluent facilitates administration to an individual and absorption by an individual and can be included in the compositions of the present disclosure without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solution, and the like. 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 can also be used in the present disclosure.

[0126] The term "effective amount" includes an amount effective to achieve the desired result within the necessary dosage and time period. The effective amount of a compound may vary depending on factors such as the disease state, age, and weight of the subject, as well as the ability of the compound to elicit the desired response in the subject. The dosing regimen may be adjusted to provide the optimal therapeutic response. An effective amount is also an amount in which any intolerable or deleterious effects (e.g., side effects) of the compound are outweighed by the therapeutically beneficial effects.

[0127] As used herein, the phrases "systemic administration," "systemic administration," "peripheral administration," and "peripheral administration" refer to the administration of a compound, oligonucleotide, drug, or other substance so that it enters the patient's circulatory system and thereby undergoes metabolism and other similar processes.

[0128] The term "therapeutically effective amount" refers to that amount of the compound being administered which is sufficient to prevent the development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated.

[0129] The therapeutically effective amount (i.e., effective dose) of the compound may be in the range of about 0.005 μg / kg to about 200 mg / kg, preferably about 0.01 mg / kg to about 200 mg / kg, and more preferably about 0.015 mg / kg to about 30 mg / kg body weight. In other embodiments, the therapeutically effective amount may be in the range of about 1.0 pM to about 10 μM.

[0130] Those skilled in the art will appreciate that certain factors may affect the dosage required to effectively treat a subject, including but not limited to the severity of the disease or condition, previous treatment, the general health and / or age of the subject, and other diseases present. In addition, treating a subject with a therapeutically effective amount of a compound may include a single treatment, or preferably may include a series of treatments. In one example, a subject is treated with a compound in the range of about 0.005 μg / kg to about 200 mg / kg body weight daily, weekly, monthly, quarterly, or annually. In another example, in the case of a chronic condition or disease, a subject may be treated daily, weekly, monthly, quarterly, or annually for several years. It will also be understood that the effective dose of the compound used for treatment may increase or decrease over the course of a particular treatment.

[0131] The term "chiral" refers to molecules that have the property of non-superimposability on their mirror image partner, whereas the term "achiral" refers to molecules that are superimposable on their mirror image partner.

[0132] The term "diastereomer" refers to stereoisomers that have two or more asymmetric centers and whose molecules are not mirror images of one another.

[0133] The term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. An equimolar mixture of two enantiomers is called a "racemic mixture" or a "racemate."

[0134] Certain compounds of the present disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms (which can be defined as (R)- or (S)- or (D)- or (L)- of an amino acid based on absolute stereochemistry) and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those known in the art to be too unstable to synthesize and / or separate. The present disclosure is intended to include racemic and optically pure forms of the compounds. Optically active (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are expected to include both E and Z geometric isomers.

[0135] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and that is readily converted from one isomeric form to another.

[0136] It will be apparent to those skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present disclosure.

[0137] The term "isomers" or "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0138] The term "prodrug" means a compound that can be converted into a biologically active nucleic acid or its analog as described herein under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a precursor of a pharmaceutically acceptable biologically active nucleic acid or its analog. A prodrug may be inactive when administered to a subject, but is converted into an active compound in vivo, for example, by hydrolysis. Prodrug compounds generally provide advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, for example, Bundgard, H., DESIGN OF PRODRUGS (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T. et al., "Pro-drugs as Novel Delivery Systems," ACS 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 incorporated herein by reference in their entirety. The term "prodrug" is also intended to include any covalently bonded carriers that release the active compound in vivo when such prodrugs are administered to mammalian subjects. Prodrugs of active compounds as described herein can be prepared by modifying the functional groups present in the active compound in a manner such that the modifications are cleaved into the parent active compound in conventional operations or in vivo. Prodrugs include compounds in which hydroxyl, amino or sulfhydryl groups are bonded to any group, and when the prodrug of the active compound is administered to a mammalian subject, the group cleaves to form free hydroxyl, free amino or free sulfhydryl groups, respectively. Examples of suitable prodrugs include, but are not limited to, glutathione, acyloxy, thioacyloxy, 2-carbon alkoxyethyl, disulfide, thiamine hydrochloride (thiaminal) and enol ester derivatives of nucleic acids modified with phosphorus atoms. The term "pre-oligonucleotide" or "prenucleotide" or "nucleic acid prodrug" refers to an oligonucleotide modified to become a prodrug of an oligonucleotide. Phosphonate and phosphate prodrugs can be found, for example, in Wiener et al., “Prodrugs or phosphonates and phosphates: crossing the membrane” TOP. CURR. CHEM. 2015, 360: 115–160, which is incorporated herein by reference in its entirety.

[0139] In certain aspects, the compounds of the present disclosure are prodrugs of any of the formulae herein.

[0140] The term "subject" refers to an animal, such as a mammal, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

[0141] When used in this application, including the claims, the terms "a," "an," and "the" mean "one or more." Thus, for example, reference to "a sample" includes a plurality of samples unless the context clearly dictates otherwise (e.g., a plurality of samples), etc.

[0142] Throughout the specification and claims, the word "comprise" is used in its non-exclusive sense, unless the context requires otherwise.

[0143] As used herein, the term "about" when referring to a value is intended to encompass variations of the specified amount, in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1%, as such variations are suitable for performing the disclosed methods or employing the disclosed compositions.

[0144] The term "aliphatic" includes saturated and unsaturated straight-chain (i.e., unbranched), branched, acyclic, cyclic or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be understood by those skilled in the art, "aliphatic" is intended to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl moieties herein. Therefore, the term "alkyl" includes straight-chain, branched and cyclic alkyl groups. Similar conventions apply to other general terms, such as "alkenyl", "alkynyl" etc. In addition, the terms "alkyl", "alkenyl", "alkynyl" etc. encompass substituted and unsubstituted groups. In certain embodiments, "low alkyl" is used to indicate those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms.

[0145] In certain embodiments, the alkyl, alkenyl and alkynyl groups employed in the present disclosure contain 1-30 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl and alkynyl groups employed in the present disclosure contain 1-20 aliphatic carbon atoms. In other embodiments, the alkyl, alkenyl and alkynyl groups employed in the present disclosure contain 10-30 aliphatic carbon atoms. In other embodiments, the alkyl, alkenyl and alkynyl groups employed in the present disclosure contain 10-20 aliphatic carbon atoms. In other embodiments, the alkyl, alkenyl and alkynyl groups employed in the present disclosure contain 1-10 carbon atoms. Thus, exemplary aliphatic groups include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH2-cyclopropyl, vinyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH2-cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, -CH2-cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, -CH2-cyclohexyl moiety, etc., which may also carry one or more substituents. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-butene-1-yl, etc. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, etc.

[0146] As used herein, unless otherwise indicated, the term "alkyl" by itself or as part of another substituent means a straight chain (i.e., unbranched) or branched carbon chain (or carbon), or combinations thereof, which may be fully saturated, monounsaturated (e.g., alkene or alkenyl), or polyunsaturated (e.g., alkyne or alkynyl), and may include monovalent, divalent, and polyvalent groups having the specified number of carbon atoms. For example, C1-C 30 It means 1 to 30 carbon atoms. The specified number of carbon atoms in this range includes, for example, C1-C 30 Alkyl (having 1-20 carbon atoms), C1-C 20 Alkyl (having 1-20 carbon atoms), C1-C 12 Alkyl (having 1-12 carbon atoms) and C1-C4 alkyl (having 1-4 carbon atoms) and C 18 (having 18 carbon atoms).

[0147] The term "alkenyl" refers to an unsaturated hydrocarbon chain that may be linear or branched, containing at least 2 carbon atoms and at least one carbon-carbon double bond (e.g., containing 2 to 30 carbon atoms and at least one carbon-carbon double bond). An alkenyl group may be substituted with one or more substituents or may be unsubstituted.

[0148] The term "alkynyl" refers to an unsaturated hydrocarbon chain that may be linear or branched, containing at least 2 carbon atoms and at least one carbon-carbon triple bond (e.g., containing 2 to 30 carbon atoms and at least one carbon-carbon triple bond). An alkynyl group may be substituted with one or more substituents or may be unsubstituted.

[0149] The term "lower alkyl" refers to a C1-C6 alkyl chain. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-pentyl. Alkyl groups may be substituted or unsubstituted with one or more substituents.

[0150] The term "haloalkyl" refers to an alkyl group substituted with one or more halogen substituents. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, chloromethyl and 2,2,2-trifluoroethyl.

[0151] The term "arylalkenyl" refers to an unsaturated hydrocarbon chain which may be linear or branched, containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond, wherein one or more sp 2 The hybridized carbon is attached to the aryl portion. The alkenyl group may be substituted with one or more substituents or unsubstituted.

[0152] The term "arylalkynyl" refers to an unsaturated hydrocarbon chain, which may be linear or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond, wherein one or more sp-hybridized carbons of the alkynyl unit are attached to the aryl portion. The alkynyl group may be substituted with one or more substituents or may be unsubstituted.

[0153] sp of an alkenyl group or an alkynyl group 2 An sp or sp hybridized carbon can optionally be the point of attachment for an alkenyl or alkynyl group, respectively.

[0154] The term "alkoxy" refers to an -O-alkyl substituent.

[0155] As used herein, the term "halogen," "halo," or "halo" means -F, -Cl, -Br, or -I.

[0156] The term "alkylthio" refers to an -S-alkyl substituent.

[0157] The term "alkoxyalkyl" refers to an -alkyl-O-alkyl substituent.

[0158] The term "haloalkoxy" refers to an -O-alkyl group substituted with one or more halo substituents. Examples of haloalkoxy groups include trifluoromethoxy and 2,2,2-trifluoroethoxy.

[0159] The term "haloalkoxyalkyl" refers to an -alkyl-O-alkyl' group wherein the alkyl' group is substituted with one or more halo substituents.

[0160] The term "haloalkylaminocarbonyl" refers to a -C(O)-amino-alkyl group wherein the alkyl group is substituted with one or more halo substituents.

[0161] The term "haloalkylthio" refers to an -S-alkyl group substituted with one or more halogen substituents. Examples of haloalkylthio groups include trifluoromethylthio and 2,2,2-trifluoroethylthio.

[0162] The term "haloalkylcarbonyl" refers to a -C(O)-alkyl group substituted with one or more halogen substituents. Examples of haloalkylcarbonyl groups include trifluoroacetyl.

[0163] The term "cycloalkyl" refers to a hydrocarbon 3-8 membered monocyclic or 7-14 membered bicyclic ring system having at least one saturated ring or having at least one non-aromatic ring, wherein the non-aromatic ring may have a certain degree of unsaturation. The cycloalkyl group may be substituted or unsubstituted by one or more substituents. 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 etc.

[0164] The term "cycloalkoxy" refers to an -O-cycloalkyl substituent.

[0165] The term "cycloalkoxyalkyl" refers to an -alkyl-O-cycloalkyl substituent.

[0166] The term "cycloalkylalkoxy" refers to an -O-alkyl-cycloalkyl substituent.

[0167] The term "cycloalkylaminocarbonyl" refers to a -C(O)-NH-cycloalkyl substituent.

[0168] The term "aryl" refers to a hydrocarbon monocyclic, bicyclic or tricyclic aromatic ring system. The aryl group may be substituted or unsubstituted by one or more substituents. 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, etc.

[0169] The term "aryloxy" refers to an -O-aryl substituent.

[0170] The term "arylalkoxy" refers to an -O-alkyl-aryl substituent.

[0171] The term "aralkylaminocarbonyl" refers to a -C(O)-amino-alkyl-aryl substituent.

[0172] The term "aryloxyalkyl" refers to an -alkyl-O-aryl substituent.

[0173] The term "alkaryl" refers to an -aryl-alkyl substituent.

[0174] The term "aralkyl" refers to an -alkyl-aryl substituent.

[0175] Unless otherwise indicated, the term "heteroalkyl" by itself or in combination with another term means a stable straight or branched chain or combination thereof comprising at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si and / or S), and wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom (e.g., O, N, P, Si and / or S) may be located at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the rest of the molecule. A heteroalkyl group is an uncyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH═CH-O-CH3, -Si(CH3)3, -CH2-CH═N-OCH3, -CH═CH—N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain two optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P).

[0176] Similarly, unless otherwise indicated, the term "heteroalkylene," by itself or as part of another substituent, means a divalent radical derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms may also occupy one or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Additionally, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups as used herein include those groups that are attached to the remainder of the molecule through a heteroatom, such as —C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and / or —S02R′. When “heteroalkyl” is recited, followed by a specific heteroalkyl group such as —NR′R″, etc., it should be understood that the terms heteroalkyl and —NR′R″ are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is recited to increase clarity. Thus, the term “heteroalkyl” should not be construed herein to exclude specific heteroalkyl groups, such as —NR′R″, etc.

[0177] Unless otherwise stated, the term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkyl group, such as, but not limited to, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those having 10 or fewer carbon atoms being preferred herein. "Lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, typically having eight or fewer carbon atoms. The term "alkenylene" by itself or as part of another substituent means, unless otherwise stated, a divalent radical derived from an alkene group.

[0178] Unless otherwise indicated, the terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, mean cyclic versions of "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl groups are not aromatic. Additionally, for heterocycloalkyl groups, a heteroatom may occupy the position at which the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, and cycloheptyl. Examples of heterocycloalkyl groups include, but are not limited to, 1-(1,2,5,6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, and 2-piperazinyl. "Cycloalkylene" and "heterocycloalkylene" by themselves or as part of another substituent mean divalent radicals derived from cycloalkyl and heterocycloalkyl, respectively. "Cycloalkyl" also means bicyclic and polycyclic hydrocarbon rings, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like.

[0179] The term "heteroaryl" refers to an aromatic 5-8 yuan monocyclic, 8-12 yuan bicyclic or 11-14 yuan tricyclic ring system with 1-4 ring heteroatoms (if monocyclic), 1-6 heteroatoms (if bicyclic) or 1-9 heteroatoms (if tricyclic), wherein the heteroatoms are selected from O, N or S, and the remaining ring atoms are carbon (with suitable hydrogen atoms, unless otherwise specified). The heteroaryl group may be substituted or unsubstituted by one or more substituents. 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 can be completely unsaturated, or they can be partially unsaturated and partially saturated. Examples of heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and the like.

[0180] The term "heteroarylalkyl" refers to an -alkyl-heteroaryl substituent.

[0181] The term "heteroaryloxy" refers to an -O-heteroaryl substituent.

[0182] The term "heteroarylalkoxy" refers to an -O-alkyl-heteroaryl substituent.

[0183] The term "heteroaryloxyalkyl" refers to an -alkyl-O-heteroaryl substituent.

[0184] The term "nitrogen-containing heteroaryl" refers to heteroaryl groups having 1-4 ring nitrogen heteroatoms (if monocyclic), 1-6 ring nitrogen heteroatoms (if bicyclic), or 1-9 ring nitrogen heteroatoms (if tricyclic).

[0185] The term "heterocycloalkyl" refers to a non-aromatic 3-8 membered monocyclic, 7-12 membered bicyclic, or 10-14 membered tricyclic ring system containing 1-3 heteroatoms (if monocyclic), 1-6 heteroatoms (if bicyclic), or 1-9 heteroatoms (if tricyclic), wherein the heteroatoms are selected from O, N, S, B, P, or Si, and wherein the non-aromatic ring system is fully saturated. The heterocycloalkyl group may be substituted or unsubstituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of the heterocycloalkyl group may be substituted with substituents. Representative heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl, thienyl, etc.

[0186] The term "heterocycloalkylalkyl" refers to an -alkyl-heterocycloalkyl substituent.

[0187] The term "alkylamino" refers to an amino substituent further substituted with one or two alkyl groups. The term "aminoalkyl" refers to an alkyl substituent further substituted with one or more amino groups. The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl substituent further substituted with one or more hydroxy groups. The alkyl or aryl portion of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl groups may be substituted with one or more substituents or may be unsubstituted.

[0188] The term "nucleobase" refers to nitrogenous biological compounds that form nucleosides. These include purine bases and pyrimidine bases. Five nucleobases—adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U)—are referred to as the principal or canonical nucleobases. When a nucleobase is listed in a formula definition, it refers to the moiety that is covalently bonded to the formula.

[0189] 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 a formula definition, it refers to the moiety that is covalently bonded to the formula.

[0190] The terms "substituent" and "substituent group" mean an atom or group that replaces the atom or group of the named parent compound. For example, the substituent of a modified nucleoside is an atom or group different from the atom or group found in a naturally occurring nucleoside (for example, a modified 2'-substituent is any atom or group other than H or OH at the 2'-position of a nucleoside). A substituent may be protected or unprotected. A substituent may also be further substituted with other substituent groups and may be attached to the parent compound directly or via a linking group such as an alkyl or hydrocarbyl group. Similarly, as used herein, a "substituent" with respect to a chemical functional group means an atom or group of atoms that is different from the atom or group of atoms that is typically present in a specified functional group. In certain embodiments, substituents on any group (such as alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) may be at any atom of the group, wherein any group (such as alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) that can be substituted may be substituted or unsubstituted by one or more substituents (which may be the same or different), each substituent replacing a hydrogen atom. Examples of suitable substituents include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxy, 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, amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, carboxamido, urea In some embodiments, substituents on any group include alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxy, hydroxyalkyl, oxo (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, thiocarbonyl, thio, thio, thioalkyl, 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, halo, haloalkyl, cyano, nitro, alkoxy, hydroxy, hydroxyalkyl, carboxyl, formyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, thio, mercapto, mercaptoalkyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, or alkylamino.

[0191] The term "protecting group" or "protecting moiety" refers to a substituent typically used to block or protect a particular functional group while reacting other functional groups on a compound, its derivative, or its conjugate, and includes a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom. Nitrogen and oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0192] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also known 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, -CO2R aa 、-SO2R aa 、-C(=NR cc )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR 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 group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R ddgroup substituted, and each R aa 、R bb and R cc R is independently alkyl, cycloalkyl, aryl or heteroaryl, each of which may be replaced by 1-3 independent R dd substituted or unsubstituted, and each R dd are independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxy, 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, acylamino, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, urea, carbamoyl, thiourea, thiocyanato, sulfonamido, 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, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0193] Amide nitrogen protecting groups (e.g., -C(=O)R aa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, picolinamide, 3-pyridylformamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyamido)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamamide, N-acetylmethionine, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0194] Carbamate nitrogen protecting groups (e.g., -C(=O)OR aa) include but are not limited to methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthenyl)]methyl carbamate (DBD-Tmoc), 4-methoxybenzoylmethyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adp oc), 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-tert-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, tert-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), ammonia allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolinyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, 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-methyl)carbamate phenylsulfonyl) ethyl ester, [2-(1,3-dithianyl)] methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphoethyl carbamate (Peoc), 2-triphenylphosphinopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolemethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-Dimethoxy-6-nitrobenzyl ester, phenyl (o-nitrophenyl) methyl carbamate, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylformamide)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylformamide)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, amino isobutyl carbamate, isonicotinoyl carbamate, p-(p-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-tert-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0195] Sulfonamide nitrogen protecting groups (e.g., -S(=O)2R 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), benzenemethylsulfonamide, trifluoromethylsulfonamide, and phenylacylsulfonamide.

[0196] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N'-toluenesulfonylaminoacyl derivatives, N'-phenylaminosulfonyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiosuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilazide adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2 -ketone, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenamine (PhF), N-2 ,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-pyridylamino 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-cyclohexyleneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl) Amines, N-borane derivatives, N-diphenylboronic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitramines, N-nitrosamines, amine N-oxides, diphenylphosphoramide (Dpp), dimethylphosphoramide (Mpt), diphenylphosphoramide (Ppt), dialkylphosphoramidates, dibenzylphosphoramidate, diphenylphosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

[0197] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also known as a hydroxy protecting group). Oxygen protecting groups include but are not limited to -R aa 、-N(R bb )2, -C(=O)SRaa 、-C(=O)R aa 、-CO2R 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 、-SO2R aa 、-Si(R aa ) 3、 -P(R cc )2、-P(R cc )3, -P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)(OR cc )2、-P(=O)2N(R bb )2 and -P(=O)(NR bb )2, where R aa 、R bb and R cc As described herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd ed., John Wiley & Sons, 1999, incorporated herein by reference.

[0198] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), tert-butoxymethyl, 4-pentenyloxymethyl (POM), silyloxymethyl, 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-(phenylhydrogen selenyl)ethyl, tert-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'-dinitrodibenzyl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl , bis(p-methoxyphenyl)phenylmethyl, tris(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinyloxyphenyl)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-benzodisulfan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylhexylsilyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), tert-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetic acid Ester, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinic acid ester), 4,4-(ethylenedithio)pentanoate (levulinic acid dithioacetal), pivalate, adamantanoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (trimethylbenzoate), tert-butyl carbonate (BOC), methyl alkyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl alkyl carbonate, 2,2,2-trichloroethyl alkyl carbonate (Troc), 2-(trimethylsilyl) )ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonium)ethyl carbonate (Peoc), isobutyl alkyl carbonate, vinyl alkyl carbonate, allyl alkyl carbonate, p-nitrophenyl alkyl carbonate, benzyl alkyl carbonate, p-methoxybenzyl alkyl carbonate, 3,4-dimethoxybenzyl alkyl carbonate, o-nitrobenzyl alkyl carbonate, p-nitrobenzyl alkyl carbonate, S-benzyl alkyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formyl Benzenesulfonate, 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, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphoramide, N-phenylcarbamic acid alkyl ester, borate, dimethylphosphinothioate, 2,4-dinitrophenylsulfenic acid alkyl ester, sulfate, methanesulfonate (mesylate), benzylsulfonate and toluenesulfonate (Ts). In certain embodiments, the protecting group or oxygen protecting group is dimethoxytrityl. In certain embodiments, the protecting group or oxygen protecting group is 2-cyanoethyl 5′-O-(4,4′-dimethoxytrityl)thymidine-3′-O-(N,N-diisopropylamino)-phosphoramidite group.

[0199] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also known as a thiol protecting group). Sulfur protecting groups include but are not limited to -R aa 、-N(R bb )2, -C(=O)SR aa 、-C(=O)R aa 、-CO2R 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 、-SO2R aa 、-Si(R aa ) 3、 -P(R cc )2、-P(R cc )3、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)(OR cc )2、-P(=O)2N(R bb )2 and -P(=O)(NR bb )2, where R aa 、R bb and R cc As defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd ed., John Wiley & Sons, 1999, incorporated herein by reference.

[0200] The term "antisense oligonucleotide" or "antisense strand" means an oligonucleotide that contains a region that is complementary to a target nucleic acid.

[0201] The term "composition" or "pharmaceutical composition" means a mixture of substances suitable for administration to a subject. For example, a composition may include one or more compounds or their salts and a sterile aqueous solution.

[0202] The term "nucleic acid" refers to a molecule composed of linked monomeric nucleotides or nucleosides. Nucleic acids include, but are not limited to, ribonucleic acid (RNA), deoxyribonucleic acid (DNA), single-stranded nucleic acid, and double-stranded nucleic acid.

[0203] The term "nucleobase sequence" means the order of consecutive nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkages.

[0204] The term "nucleoside" means a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each independently unmodified or modified. "Modified nucleoside" means a nucleoside comprising a modified nucleobase and / or a modified sugar moiety. Modified nucleosides include abasic nucleosides that lack a nucleobase.

[0205] The term "oligomeric compound" means a polymer of linked subunits. With respect to proteins, peptides, polypeptides, or antibodies, "subunit" refers to an amino acid or peptide bond. With respect to oligonucleotides, "subunit" refers to a nucleotide, nucleoside, nucleobase, or sugar, or a modified nucleotide, nucleoside, nucleobase, or sugar as provided herein.

[0206] The term "oligonucleotide" means a polymer of linked nucleosides (e.g., polynucleotides, nucleic acids, nucleotide polymers), each of which may be modified or unmodified independently of one another. Without limitation, an oligonucleotide may comprise a ribonucleic acid (e.g., comprising a ribonucleoside), a deoxyribonucleic acid (e.g., comprising a deoxyribonucleoside), a modified nucleic acid (e.g., comprising a modified core base, sugar and / or phosphate group), or a combination thereof. Examples of oligonucleotide compounds include single-stranded and double-stranded compounds such as oligonucleotides, antisense oligonucleotides, interfering RNA compounds (RNAi compounds), microRNA (miRNA) targeting oligonucleotides and miRNA mimics, placeholder compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds). RNAi compounds include double-stranded compounds (e.g., short interfering RNA (siRNA) and double-stranded RNA (dsRNA)) and single-stranded compounds (e.g., single-stranded siRNA (ssRNA), single-stranded RNAi (ssRNAi), short hairpin RNA (shRNA), and microRNA mimics) that act at least in part through the RNA-induced silencing complex (RISC) pathway, resulting in sequence-specific degradation and / or sequestration of target nucleic acids through a process known as RNA interference (RNAi). The term "RNAi compound" is intended to refer to other terms equivalent to those used to describe nucleic acid compounds capable of mediating sequence-specific RNA interference, such as interfering RNA (iRNA), iRNA agents, RNAi agents, small interfering RNA, short interfering RNA, short interfering oligonucleotides, short interfering nucleic acids, short interfering modified oligonucleotides, chemically modified siRNA, and the like. Additionally, the term "RNAi" is intended to refer to other terms equivalent to those used to describe sequence-specific RNA interference.

[0207] The terms "target nucleic acid," "target RNA," and "nucleic acid target" all refer to a nucleic acid that can be targeted by the compounds described herein.

[0208] The term "therapeutic compound" includes any agent or compound that provides a therapeutic benefit to a subject. Therapeutic compounds include nucleic acids, oligomeric compounds, oligonucleotides, proteins, peptides, antibodies, small molecules, and other such agents.

[0209] "Target region" means a portion of a target nucleic acid that is targeted by one or more compounds.

[0210] By "targeting moiety" is meant a conjugated group that provides enhanced affinity for a selected target (e.g., a molecule, cell or cell type), compartment (e.g., a cellular or organ compartment), tissue, organ or body region, e.g., compared to a compound in the absence of such moiety.

[0211] "Terminus group" means a chemical group or group of atoms covalently attached to the terminus of an oligonucleotide.

[0212] The term "conjugate group" means an atomic group attached to an oligonucleotide. The conjugate group is optionally attached to the oligonucleotide via a linker. The conjugate group can, for example, change the distribution, targeting, or half-life of the compound into which it is incorporated. The conjugate group comprises a lipid (or lipophilic moiety), a ligand, and other targeting moieties, such as a GalNAc moiety.

[0213] "Conjugation linker" means a group of atoms comprising at least one bond that connects a linking moiety to an oligonucleotide and / or other therapeutic agent.

[0214] The term "lipid" or "lipophilic moiety" refers to an aliphatic, cyclic (such as alicyclic) or polycyclic (such as polyalicyclic) compound, such as a steroid (e.g., sterol) or a straight or branched aliphatic hydrocarbon. 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-propylene glycol, a heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, ibuprofen, naproxen, dimethoxytrityl or phenoxazine. The term lipid includes saturated or unsaturated C4-C 30 Hydrocarbon chains (e.g., C4-C 30 In certain embodiments, the lipophilic moiety contains a saturated or unsaturated C6-C 18 Hydrocarbon chain (e.g., straight chain C6-C 18 In certain embodiments, the lipophilic moiety contains a saturated or unsaturated C 16 Hydrocarbon chains (e.g., straight chain C 16 In certain embodiments, the lipophilic moiety contains a saturated or unsaturated C 18 Hydrocarbon chains (e.g., straight chain C 18 alkyl or alkenyl).

[0215] The term "ligand" refers to a substance that binds to or 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 α4β 1 / 7 In certain embodiments, the ligand binds to the receptor (e.g., α4β 1 / 7 In some embodiments, the ligand binds to the CB1 receptor. In some embodiments, the ligand binds to the tropomyosin receptor B (TrkB) receptor. In some embodiments, the ligand binds to the α4β 1 / 7 Integrin Receptor Binding. In certain embodiments, the ligand binds to the N-methyl-D-aspartate (NMDA) receptor.

[0216] In certain embodiments, the α4β 1 / 7 Compared to cells that contain integrins, TrkB, CB1, or NMDA receptors, cells that contain receptors (e.g., α4β 1 / 7 In some embodiments, the compound that is a ligand for a receptor (e.g., α4β4 receptor) selectively or preferentially targets cells expressing the receptor. 1 / 7 Compared to compounds that target integrins, TrkB, CB1, or NMDA receptors, compounds that target receptor ligands (e.g., α4β 1 / 7 Compounds that selectively or preferentially target the expression of integrins, TrkB, CB1, or NMDA receptors (e.g., α4β 1 / 7 integrin, TrkB, CB1 or NMDA receptor).

[0217] The term "α4β 1 / 7 The term "integrin receptor" refers to heterodimeric integrin receptors formed by the association of integrin α4 and integrin β1 (i.e., α4β1 integrin receptor) and integrin α4 and integrin β7 (i.e., α4β7 integrin receptor).

[0218] The term "cannabinoid receptor type 1" or "CB1" refers to the G protein-coupled receptor for cannabinoids. In humans, CB1 is encoded by the CNR1 gene. CB1 is also known as cannabinoid receptor 1.

[0219] 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 comprises the structure In some embodiments, the GalNAc moiety comprises the structure The GalNAc moiety is a targeting moiety that has affinity for various tissues and cell receptors. Thus, the GalNAc moiety can promote the targeting of cargo (e.g., nucleic acids) to such tissues and receptors. In some embodiments, the GalNAc moiety can be used to guide nucleic acids. In some embodiments, the GalNAc moiety guides nucleic acids to a certain location. In some embodiments, the GalNAc moiety targets tissues. In some embodiments, the tissue is the liver. In some embodiments, the GalNAc moiety targets cell receptors. In some embodiments, the cell receptor is an asialoglycoprotein receptor. In some embodiments, the asialoglycoprotein receptor is located on hepatocytes.

[0220] The term "sense oligonucleotide" or "sense strand" means the strand of a double-stranded compound that comprises a region that is substantially complementary to a region of the antisense strand of the double-stranded compound.

[0221] The terms "microRNA" and "miRNA", used interchangeably herein, refer to short (e.g., about 20 to about 24 nucleotides in length) non-coding ribonucleic acids (RNAs) that participate in post-transcriptional regulation of gene expression in multicellular organisms by affecting the stability and translation of mRNA. miRNAs are transcribed by RNA polymerase II as part of a capped and polyadenylated primary transcript (pri-miRNA), which can be protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce a stem-loop precursor miRNA (pre-miRNA) of about 70 nucleotides in length, which is further processed in the RNAi pathway. As part of this pathway, pre-miRNAs are cleaved by the cytoplasmic Dicer ribonuclease to produce mature miRNAs and antisense miRNA star (miRNA*) products. Mature miRNA is incorporated into the silencing complex (RISC) induced by RNA, which recognizes target mRNA by incomplete base pairing (i.e., partial complementation) with miRNA, and most commonly results in translational inhibition or destabilization of target mRNA. The most common mechanism of this is the combination of miRNA on the 3' untranslated region (UTR) of target mRNA, which can reduce gene expression by inhibiting translation (e.g., by blocking ribosome entry translation) or directly causing the degradation of transcripts. The term (i.e., miRNA) can be used herein to refer to any form (e.g., precursor, primary and / or mature miRNA) of subject miRNA.

[0222] The terms "small interfering RNA," "short interfering RNA," and "siRNA," used interchangeably herein, refer to RNA molecules that exist as non-coding double-stranded RNA (dsRNA) molecules of about 20 to about 24 nucleotides in length and can be used for RNA interference (RNAi). siRNAs are typically found with a phosphorylated 5' end and a hydroxylated 3' end, the 3' end typically having a 2-nucleotide overhang beyond the 5' end of the antiparallel strand (e.g., the complementary strand of the dsRNA molecule). siRNAs can interfere with the expression of specific genes by binding to their complementary target sequence (e.g., target nucleic acid sequence) and promoting (e.g., favoring, triggering, initiating) the degradation of mRNA, thereby preventing (e.g., inhibiting, silencing, interfering with) translation. After integration and sequestration into the RISC complex, siRNA forms base pairs (e.g., fully complementary) with its target mRNA and cleaves it, thereby preventing it from serving as a translation template. As described above, and also as part of the RNAi pathway, the miRNA-loaded RISC complex scans cytoplasmic mRNA for potential complementarity (e.g., partial complementarity).

[0223] As used herein, the term "ADAR recruiting molecule" refers to a nucleic acid that is configured to increase the concentration of adenosine deaminases (ADARs) acting on ribonucleic acids in a location surrounding the nucleic acid. In some embodiments, the increased concentration is relative to the concentration in a given location where the ADAR recruiting molecule is not present. In some embodiments, the ADAR recruiting molecule comprises a double-stranded RNA duplex.

[0224] As used herein, the term "ADAR targeting molecule" refers to a nucleic acid that is configured to guide the ADAR molecule to a desired position (e.g., a site). As used herein, the term "directly" refers to increasing the concentration of ADAR at a desired position compared to the concentration in the absence of the ADAR targeting molecule. In some embodiments, the ADAR targeting molecule can be configured to control the desired position by changing the sequence and / or properties of the nucleic acid (e.g., by modification of nucleobases, sugars, phosphates or other components). In some embodiments, the ADAR targeting molecule comprises an ADAR recruitment molecule and a single-stranded guide nucleic acid. In some embodiments, the ADAR targeting molecule comprises a double-stranded RNA duplex and a single-stranded guide nucleic acid.

[0225] As used herein, the term "single-stranded guide nucleic acid" refers to a single-stranded nucleic acid comprising a specific sequence that is at least partially complementary to a target sequence. In some embodiments, the target sequence is located at, adjacent to, or near a location where modulation of ADAR concentration is desired. In some embodiments, the level of complementarity is sufficient to promote binding (e.g., annealing) of the single-stranded guide nucleic acid to the target sequence.

[0226] "Modified oligonucleotide" means an oligonucleotide in which at least one sugar, nucleobase or internucleoside linkage is modified.

[0227] "Nucleobase sequence" means the order of consecutive nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkages.

[0228] The term "oligoduplex" means a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of an oligoduplex may be referred to as a "double-stranded oligomeric compound." The oligonucleotides of each oligomeric compound of an oligoduplex may contain non-complementary overhanging nucleosides. In some embodiments, the terms "double-stranded oligomeric compound" and "modified oligonucleotide" are used interchangeably. In other embodiments, the terms "oligoduplex" and "compound" are used interchangeably.

[0229] "Phosphorothioate linkage" means a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced by a sulfur atom.

[0230] The terms "RNA interference compound," "RNAi compound," and / or "iRNA agent" mean a compound that acts at least in part through the RNA-induced silencing complex (RISC) pathway or Ago2, but not through RNase H, to modulate a target nucleic acid and / or a protein encoded by the target nucleic acid. RNAi compounds include, but are not limited to, double-stranded siRNA, single-stranded siRNA, and microRNA, including microRNA mimics.

[0231] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be treated with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) Radiolabeled. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0232] The term "isotopic variant" refers to a therapeutic agent that contains unnatural ratios of isotopes at one or more atoms comprising the therapeutic agent (e.g., a compound and / or modified oligonucleotide disclosed herein). In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural ratios of one or more isotopes, 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 O), 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). In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural proportions of one or more isotopes including, but not limited to, hydrogen (H), deuterium ( 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 O), 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).

[0233] It is understood that, where feasible according to the judgment of the skilled artisan, in a therapeutic agent (e.g., a compound and / or modified oligonucleotide disclosed herein), any hydrogen may be, for example, 2 H, or any carbon can be e.g. 13 C, or any nitrogen may be e.g. 15 N, or any oxygen may be e.g. 18 O. In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural proportions of deuterium (D). DETAILED DESCRIPTION

[0234] In certain embodiments, described herein are compounds of formula (I'), or salts or prodrugs thereof:

[0235]

[0236] in:

[0237] A is a substituted tetrahydrofuranyl group, a substituted tetrahydropyranyl ring, or a modified sugar;

[0238] B is a substituted tetrahydrofuranyl group, a substituted tetrahydropyranyl ring, or a modified sugar;

[0239] W 1 and W 4 are independently modified or unmodified nucleosides, oligonucleotides, ligands, lipophilic moieties, or protecting groups;

[0240] R 8 and R 9 are independently substituted or unsubstituted heteroaryl;

[0241] L is a linker, ligand, lipophilic part, -Z 1 -YZ 2 - or a combination thereof;

[0242] W 2 and W 3 are independently 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(R A )-, -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-、-NRA C(=O)N(R A )-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(R A )-、-S(O)2NR A -、-NR A SO2- or a combination thereof;

[0243] Each R A R is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A The groups are linked to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring with the atoms to which they are attached;

[0244] Z 1 and Z 2 are independently a bond, 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(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 SO2- or a combination thereof;

[0245] Each R BR is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R B The groups are linked to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring;

[0246] Y is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -O-, -OP(O)O2-, -N(R C )-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR C -、-NR C C(=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)2NR C -、-NR C SO2- or a combination thereof; and

[0247] Each R C R is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group, or two R C The groups are linked to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0248] In certain embodiments, the compound of formula (I') is a compound of formula (VIII) or a salt or prodrug thereof:

[0249]

[0250] The present disclosure also provides compounds of formula (I):

[0251]

[0252] in:

[0253] Q 1 -H, -OR 4 , ligands or lipids;

[0254] Each Q 2 Independently key, ligand, linker, or lipid;

[0255] Each Q 3 Independently key, ligand, linker, or lipid;

[0256] Each Q 4 independently a bond, -R 10 O-, ligand, linker, or lipid;

[0257] Each Q 5 Independently key, ligand, linker, or lipid;

[0258] Each Q 6 Independently key, ligand, linker, or lipid;

[0259] Q 7 -H, -R 5 , ligands or lipids;

[0260] Each Y is independently substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -O-, -OP(O)O2-, -N(R C )-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR C -、-NR C C(=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)2NR C -、-NR C SO2- or a combination thereof;

[0261] Each R CR is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R C The groups are linked to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring;

[0262] Each R 2 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 、-N(R 6 ) or -SR 6 ;

[0263] Each R 3 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 、-N(R 7 ) or -SR 7 ;

[0264] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide;

[0265] Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0266] Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0267] Each R 8 are independently substituted or unsubstituted heteroaryl rings;

[0268] Each R 9 are independently substituted or unsubstituted heteroaryl rings;

[0269] Each R 10 independently an oligonucleotide;

[0270] Each X is independently O or S;

[0271] Z 1 , Z 2 , Z 3 or Z4 Each instance of is independently a bond, C1-C6 alkylene, or C2-C6 alkenylene;

[0272] n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0273] each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[0274] p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0275] or a salt or prodrug thereof.

[0276] Also provided herein are compounds of formula (II):

[0277]

[0278] in:

[0279] Each Y is independently substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -O-, -OP(O)O2-, -N(R C )-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR C -、-NR C C(=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)2NR C -、-NR C SO2- or a combination thereof;

[0280] Each R C R is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R C The groups are linked to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring;

[0281] Each R 2 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 、-N(R 6 ) or -SR 6 ;

[0282] Each R 3 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 、-N(R 7 ) or -SR 7 ;

[0283] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide;

[0284] Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0285] Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0286] Each R 8 are independently substituted or unsubstituted heteroaryl;

[0287] Each R 9 are independently substituted or unsubstituted heteroaryl;

[0288] Each R 10 independently an oligonucleotide;

[0289] Each X is independently O or S;

[0290] Z 1 , Z 2 , Z 3 or Z 4 Each instance of is independently a bond, C1-C6 alkylene, or C2-C6 alkenylene;

[0291] n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0292] each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[0293] p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0294] or a salt or prodrug thereof.

[0295] In certain embodiments, the compound of formula (II) is a salt according to the following chemical structure:

[0296]

[0297] in:

[0298] Each Y is independently substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -O-, -OP(O)O2-, -N(R C )-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR C -、-NR C C(=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)2NR C -、-NR C SO2- or a combination thereof;

[0299] Each R C R is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R C The groups are linked to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring;

[0300] Each R 2 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 、-N(R 6 ) or -SR 6 ;

[0301] Each R 3are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 、-N(R 7 ) or -SR 7 ;

[0302] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide;

[0303] Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0304] Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0305] Each R 8 are independently substituted or unsubstituted heteroaryl;

[0306] Each R 9 are independently substituted or unsubstituted heteroaryl;

[0307] Each R 10 independently an oligonucleotide;

[0308] Each X is independently O or S;

[0309] Z 1 , Z 2 , Z 3 or Z 4 Each instance of is independently a bond, C1-C6 alkylene, or C2-C6 alkenylene;

[0310] n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0311] each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[0312] p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0313] or a salt or prodrug thereof.

[0314] 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.

[0315] In certain embodiments, the compound of formula (II) or a salt or prodrug thereof has formula (II-a):

[0316]

[0317] In certain embodiments, Z 1 In certain embodiments, Z 1 In certain embodiments, Z 1 In certain embodiments, Z 1 In certain embodiments, Z 1 In certain embodiments, Z 1 It is -CH2CH2-.

[0318] In certain embodiments, Z 2 In certain embodiments, Z 2 In certain embodiments, Z 2 In certain embodiments, Z 2 In certain embodiments, Z 2 In certain embodiments, Z 2 It is -CH2CH2-.

[0319] In certain embodiments, Z 3 In certain embodiments, Z 3 In certain embodiments, Z 3 In certain embodiments, Z 3 In certain embodiments, Z 3 In certain embodiments, Z 3 It is -CH2CH2-.

[0320] In certain embodiments, Z 4 In certain embodiments, Z 4 In certain embodiments, Z 4 In certain embodiments, Z 4 In certain embodiments, Z 4 In certain embodiments, Z 4 It is -CH2CH2-.

[0321] In certain embodiments, the compound of formula (II) or a salt or prodrug thereof has formula (II-b):

[0322]

[0323] In some embodiments, R 4 and R 5 Each comprises an oligonucleotide. In some embodiments, R 4 and R 5 are linked together to form a single oligonucleotide. In some embodiments, R 4 Contains oligonucleotides, and R 5 In some embodiments, R 4 Contains a protecting group, and R 5 In some embodiments, R 4 and R 5 Each comprises a protecting group. In some embodiments, one or two oligonucleotides are attached at their 5' end. In some embodiments, one or two oligonucleotides are attached at their 3' end. In some embodiments, one or two oligonucleotides are attached at an internal position of the oligonucleotide. In certain embodiments, the internal position is an internucleoside linkage.

[0324] In certain embodiments, an oligonucleotide as disclosed herein is an oligonucleotide of formula (IX):

[0325]

[0326] in:

[0327] 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;

[0328] Each R 2 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 、-N(R 6 ) or -SR 6 ;

[0329] Each R 3 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 、-N(R 7 ) or -SR 7 ;

[0330] R 4 and R 5 is independently an oligonucleotide or a protecting group, or R 4 and R 5 ligated together to form a single oligonucleotide;

[0331] Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0332] Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0333] Each R 8 are independently substituted or unsubstituted heteroaryl rings;

[0334] Each R 9 is independently a substituted or unsubstituted heteroaryl ring; and

[0335] Each X is independently O or S;

[0336] or a salt or prodrug thereof.

[0337] In certain embodiments, an oligonucleotide as disclosed herein is an oligonucleotide of formula (X):

[0338]

[0339] in:

[0340] 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;

[0341] Each R 2 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 、-N(R 6 ) or -SR 6 ;

[0342] Each R 3 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 、-N(R 7 ) or -SR 7 ;

[0343] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide;

[0344] Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0345] Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0346] Each R 8 are independently substituted or unsubstituted heteroaryl rings;

[0347] Each R 9 is independently a substituted or unsubstituted heteroaryl ring; and

[0348] Each X is independently O or S;

[0349] or a salt or prodrug thereof.

[0350] In certain embodiments, an oligonucleotide as disclosed herein is an oligonucleotide of formula (XI):

[0351]

[0352] in:

[0353] 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;

[0354] Each R 2 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 、-N(R 6 ) or -SR 6 ;

[0355] Each R 3 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 、-N(R 7 ) or -SR 7 ;

[0356] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide;

[0357] Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0358] Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0359] Each R 8 are independently substituted or unsubstituted heteroaryl rings;

[0360] Each R 9 is independently a substituted or unsubstituted heteroaryl ring; and

[0361] Each X is independently O or S;

[0362] or a salt or prodrug thereof.

[0363] In certain embodiments, an oligonucleotide as disclosed herein is an oligonucleotide of formula (XI-a):

[0364]

[0365] in:

[0366] 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;

[0367] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide;

[0368] Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0369] Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0370] Each R 8 are independently substituted or unsubstituted heteroaryl rings;

[0371] Each R 9 is independently a substituted or unsubstituted heteroaryl ring; and

[0372] Each X is independently O or S;

[0373] or a salt or prodrug thereof.

[0374] In certain embodiments, an oligonucleotide as disclosed herein is an oligonucleotide of formula (XI-b):

[0375]

[0376] in:

[0377] 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;

[0378] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide;

[0379] Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0380] Each R 8 are independently substituted or unsubstituted heteroaryl rings;

[0381] Each R 9 is independently a substituted or unsubstituted heteroaryl ring; and

[0382] Each X is independently O or S;

[0383] or a salt or prodrug thereof.

[0384] In certain embodiments, an oligonucleotide as disclosed herein is an oligonucleotide of formula (XI-c):

[0385]

[0386] in:

[0387] 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;

[0388] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide;

[0389] Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0390] Each R 8 are independently substituted or unsubstituted heteroaryl rings;

[0391] Each R 9is independently a substituted or unsubstituted heteroaryl ring; and

[0392] Each X is independently O or S;

[0393] or a salt or prodrug thereof.

[0394] In certain embodiments, the oligonucleotide as disclosed herein is an oligonucleotide of formula (XII):

[0395]

[0396] in:

[0397] R C each instance of is independently -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;

[0398] Each R 2 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 、-N(R 6 ) or -SR 6 ;

[0399] Each R 3 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 、-N(R 7 ) or -SR 7 ;

[0400] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide;

[0401] Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0402] Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0403] Each R 8 are independently substituted or unsubstituted heteroaryl rings;

[0404] Each R 9 is independently a substituted or unsubstituted heteroaryl ring; and

[0405] Each X is independently O or S;

[0406] or a salt or prodrug thereof.

[0407] In certain embodiments, the oligonucleotide as disclosed herein is an oligonucleotide of formula (XIII):

[0408]

[0409] in:

[0410] 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;

[0411] Each R 2 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 、-N(R 6 ) or -SR 6 ;

[0412] Each R 3 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 、-N(R 7 ) or -SR 7 ;

[0413] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide;

[0414] Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0415] Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0416] Each R 8 are independently substituted or unsubstituted heteroaryl rings;

[0417] Each R 9 is independently a substituted or unsubstituted heteroaryl ring; and

[0418] Each X is independently O or S;

[0419] or a salt or prodrug thereof.

[0420] In certain embodiments, an oligonucleotide as disclosed herein is an oligonucleotide of formula (XIV):

[0421]

[0422] in:

[0423] 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;

[0424] Each R 2 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 、-N(R 6 ) or -SR 6 ;

[0425] Each R 3 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 、-N(R 7 ) or -SR 7 ;

[0426] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide;

[0427] Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0428] Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0429] Each R 8 are independently substituted or unsubstituted heteroaryl rings;

[0430] Each R 9 is independently a substituted or unsubstituted heteroaryl ring; and

[0431] Each X is independently O or S;

[0432] or a salt or prodrug thereof.

[0433] In certain embodiments, an oligonucleotide as disclosed herein is an oligonucleotide of formula (IX-a):

[0434]

[0435] in:

[0436] Each R 2 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 、-N(R 6 ) or -SR 6 ;

[0437] Each R 3 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 、-N(R 7 ) or -SR 7 ;

[0438] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide;

[0439] Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0440] Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0441] Each R 8 are independently substituted or unsubstituted heteroaryl rings;

[0442] Each R 9 is independently a substituted or unsubstituted heteroaryl ring; and

[0443] Each X is independently O or S;

[0444] or a salt or prodrug thereof.

[0445] In certain embodiments, an oligonucleotide as disclosed herein is an oligonucleotide of formula (IX-b):

[0446]

[0447] in:

[0448] Each R 2are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 、-N(R 6 ) or -SR 6 ;

[0449] Each R 3 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 、-N(R 7 ) or -SR 7 ;

[0450] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide;

[0451] Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0452] Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0453] Each R 8 are independently substituted or unsubstituted heteroaryl rings;

[0454] Each R 9 is independently a substituted or unsubstituted heteroaryl ring; and

[0455] Each X is independently O or S;

[0456] or a salt or prodrug thereof.

[0457] In certain embodiments, an oligonucleotide as disclosed herein is an oligonucleotide of formula (IX-c):

[0458]

[0459] in:

[0460] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide; and

[0461] Each X is independently O or S;

[0462] or a salt or prodrug thereof.

[0463] In certain embodiments, an oligonucleotide as disclosed herein is an oligonucleotide of formula (IX-d):

[0464]

[0465] in:

[0466] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide; and

[0467] Each X is independently O or S;

[0468] or a salt or prodrug thereof.

[0469] In certain embodiments, an oligonucleotide as disclosed herein is an oligonucleotide of formula (IX-e):

[0470]

[0471] in:

[0472] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide; and

[0473] Each X is independently O or S;

[0474] or a salt or prodrug thereof.

[0475] In certain embodiments, an oligonucleotide as disclosed herein is an oligonucleotide of formula (Xa):

[0476]

[0477] in:

[0478] Each R 2 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 、-N(R 6 ) or -SR 6 ;

[0479] Each R 3 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 、-N(R 7 ) or -SR7 ;

[0480] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide;

[0481] Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0482] Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0483] Each R 8 are independently substituted or unsubstituted heteroaryl rings;

[0484] Each R 9 is independently a substituted or unsubstituted heteroaryl ring; and

[0485] Each X is independently O or S;

[0486] or a salt or prodrug thereof.

[0487] In certain embodiments, an oligonucleotide as disclosed herein is an oligonucleotide of formula (XV):

[0488]

[0489] in:

[0490] Each R 2 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 、-N(R 6 ) or -SR 6 ;

[0491] Each R 3 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 、-N(R 7 ) or -SR 7 ;

[0492] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide;

[0493] Each R6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0494] Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0495] Each R 8 are independently substituted or unsubstituted heteroaryl rings;

[0496] Each R 9 is independently a substituted or unsubstituted heteroaryl ring; and

[0497] Each X is independently O or S;

[0498] or a salt or prodrug thereof.

[0499] In certain embodiments, an oligonucleotide as disclosed herein is an oligonucleotide of formula (XVI):

[0500]

[0501] in:

[0502] Each R 2 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 、-N(R 6 ) or -SR 6 ;

[0503] Each R 3 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 、-N(R 7 ) or -SR 7 ;

[0504] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide;

[0505] Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0506] Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0507] Each R 8are independently substituted or unsubstituted heteroaryl rings;

[0508] Each R 9 is independently a substituted or unsubstituted heteroaryl ring; and

[0509] Each X is independently O or S;

[0510] or a salt or prodrug thereof.

[0511] In certain embodiments, an oligonucleotide as disclosed herein is an oligonucleotide of formula (XVII):

[0512]

[0513] in:

[0514] Each R 2 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 、-N(R 6 ) or -SR 6 ;

[0515] Each R 3 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 、-N(R 7 ) or -SR 7 ;

[0516] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide;

[0517] Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0518] Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0519] Each R 8 are independently substituted or unsubstituted heteroaryl rings;

[0520] Each R 9 is independently a substituted or unsubstituted heteroaryl ring; and

[0521] Each X is independently O or S;

[0522] or a salt or prodrug thereof.

[0523] In certain embodiments, an oligonucleotide as disclosed herein is an oligonucleotide of formula (XVIII):

[0524]

[0525] in:

[0526] Each R 2 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 、-N(R 6 ) or -SR 6 ;

[0527] Each R 3 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 、-N(R 7 ) or -SR 7 ;

[0528] R 4 and R 5 are independently oligonucleotides, protecting groups, or R 4 and R 5 ligated together to form a single oligonucleotide;

[0529] Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0530] Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0531] Each R 8 are independently substituted or unsubstituted heteroaryl rings;

[0532] Each R 9 is independently a substituted or unsubstituted heteroaryl ring; and

[0533] Each X is independently O or S;

[0534] or a salt or prodrug thereof.

[0535] In certain embodiments, the compound of formula (II) has the following formula:

[0536]

[0537]

[0538]

[0539] Its salt.

[0540] Also provided herein are oligonucleotides of formula (VI), or salts or prodrugs thereof, having formula (VI):

[0541]

[0542] in:

[0543] Each Y is independently substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -O-, -OP(O)O2-, -N(R C )-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR C -、-NR C C(=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)2NR C -、-NR C SO2- or a combination thereof;

[0544] Each R C R is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R C The groups are linked to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring;

[0545] Each R 2 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 、-N(R 6 ) or -SR 6 ;

[0546] Each R 3are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 、-N(R 7 ) or -SR 7 ;

[0547] R 4 and R 5 Each independently is an oligonucleotide, a protecting group, or R 4 and R 5 ligated together to form a single oligonucleotide;

[0548] Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0549] Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0550] Each R 8 are independently substituted or unsubstituted heteroaryl;

[0551] Each R 9 are independently substituted or unsubstituted heteroaryl;

[0552] Each X is independently O or S;

[0553] Z 1 , Z 2 , Z 3 or Z 4 Each instance of is independently a bond, C1-C6 alkylene, or C2-C6 alkenylene;

[0554] n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0555] or a salt or prodrug thereof.

[0556] In certain embodiments, R 4 and R 5 Each is independently an oligonucleotide or a protecting group.

[0557] Also provided herein are compounds of formula (VII):

[0558]

[0559] in:

[0560] Y is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -O-, -OP(O)O2-, -N(R C )-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR C -、-NR C C(=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)2NR C -、-NR C SO2- or a combination thereof;

[0561] Q 1 -H, -OR 4 , ligands, linkers, or lipids;

[0562] Q 2 Independently key, ligand, linker, or lipid;

[0563] Each R C R is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R C The groups are linked to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring;

[0564] Each R 2 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 、-N(R 6 ) or -SR 6 ;

[0565] Each R 3 are independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7、-N(R 7 ) or -SR 7 ;

[0566] Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0567] Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

[0568] Each R 8 are independently substituted or unsubstituted heteroaryl;

[0569] Each R 9 are independently substituted or unsubstituted heteroaryl;

[0570] Z 1 , Z 2 , Z 3 or Z 4 Each instance of , when present, is independently a bond, C1-C6 alkylene, or C2-C6 alkenylene;

[0571] n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0572] or a salt or prodrug thereof.

[0573] In certain embodiments, the compound of formula (I') has the formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: where R C1 are independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an oxygen protecting group. 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: where R C1 are independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an oxygen protecting group, and wherein W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein. In certain embodiments, the compound of formula (I') has the following formula: Where W 1 、W 2 、W 3 、W 4 、R 2 、R 3 、R 8 and R 9 As defined herein.

[0574] In certain embodiments, the compound of formula (I), or a salt or prodrug thereof, has the formula:

[0575]

[0576] in:

[0577] R 4 and R 5 are independently an oligonucleotide or a protecting group; and

[0578] Each X is independently O or S.

[0579] In certain embodiments, the compound of formula (I) has the formula:

[0580]

[0581] in:

[0582] R 4 and R 5 are independently an oligonucleotide or a protecting group; and

[0583] Each X is independently O or S;

[0584] or a salt or prodrug thereof.

[0585] In certain embodiments, the compound of formula (I) has the formula:

[0586]

[0587] in:

[0588] R 4 and R 5 are independently an oligonucleotide or a protecting group; and

[0589] Each X is independently O or S;

[0590] or a salt or prodrug thereof.

[0591] 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 In certain embodiments, W 1 In certain embodiments, W 1 In certain embodiments, W 1 For the protecting group.

[0592] In certain embodiments, the compounds described herein contain the substituent W 2 In certain embodiments, W 2 In certain embodiments, W 2 In certain embodiments, W 2 In certain embodiments, W 2 In certain embodiments, W 2 Is a substituted or unsubstituted carbocyclylene. In certain embodiments, W 2 Is a substituted or unsubstituted heterocyclyl. In certain embodiments, W 2 is a substituted or unsubstituted arylene group. In certain embodiments, W 2 In certain embodiments, W 2 In certain embodiments, W 2In certain embodiments, W 2 -N(R A )-. In certain embodiments, W 2 In certain embodiments, W 2 In certain embodiments, W 2 is -C(=O)O-. In certain embodiments, W 2 -C(=O)NR A -. In certain embodiments, W 2 -NR A C(=O)-. In certain embodiments, W 2 -NR A C(=O)R A -. In certain embodiments, W 2 -C(=O)R A -. In certain embodiments, W 2 -NR A C(=O)O-. In certain embodiments, W 2 -NR A C(=O)N(R A )-. In certain embodiments, W 2 In certain embodiments, W 2 is -OC(=O)O-. In certain embodiments, W 2 -OC(=O)N(R A )-. In certain embodiments, W 2 -S(O)2NR A -. In certain embodiments, W 2 -NR A SO2-.

[0593] In certain embodiments, the compounds described herein contain the substituent W 3 In certain embodiments, W 3 In certain embodiments, W 3 In certain embodiments, W 3 In certain embodiments, W 3 In certain embodiments, W 3 Is a substituted or unsubstituted carbocyclylene. In certain embodiments, W 3 Is a substituted or unsubstituted heterocyclyl. In certain embodiments, W 3 is a substituted or unsubstituted arylene group. In certain embodiments, W 3In certain embodiments, W 3 In certain embodiments, W 3 In certain embodiments, W 3 -N(R A )-. In certain embodiments, W 3 In certain embodiments, W 3 is -C(=O)-. In certain embodiments, W 3 is -C(=O)O-. In certain embodiments, W 3 -C(=O)NR A -. In certain embodiments, W 3 -NR A C(=O)-. In certain embodiments, W 3 -NR A C(=O)R A -. In certain embodiments, W 3 -C(=O)R A -. In certain embodiments, W 3 -NR A C(=O)O-. In certain embodiments, W 3 -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 -OC(=O)N(R A )-. In certain embodiments, W 3 -S(O)2NR A -. In certain embodiments, W 3 -NR A SO2-.

[0594] 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 In certain embodiments, W 4 In certain embodiments, W 4 In certain embodiments, W 4 For the protecting group.

[0595] In certain embodiments, W 1is 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 For oligonucleotides.

[0596] In certain embodiments, W 1 is a modified or unmodified nucleoside, W 2 is the key, and W 4 Is a modified or unmodified nucleoside. In certain embodiments, W 1 is a modified or unmodified nucleoside, W 2 is the key, and W 4 For oligonucleotides.

[0597] In certain embodiments, W 1 is a modified or unmodified nucleoside, W 2 is a joint, and W 4 Is a modified or unmodified nucleoside. In certain embodiments, W 1 is a modified or unmodified nucleoside, W 2 is a joint, and W 4 For oligonucleotides.

[0598] In certain embodiments, W 1 is a modified or unmodified nucleoside, W 3 is the key, and W 4 Is a modified or unmodified nucleoside. In certain embodiments, W 1 is a modified or unmodified nucleoside, W 3 is the key, and W 4 For oligonucleotides.

[0599] In certain embodiments, W 1 is a modified or unmodified nucleoside, W 3 is a joint, and W 4 Is a modified or unmodified nucleoside. In certain embodiments, W 1 is a modified or unmodified nucleoside, W 3 is a joint, and W 4 For oligonucleotides.

[0600] In certain embodiments, W 1 is a modified or unmodified nucleoside, W 3 is a substituted or unsubstituted heteroalkylene group, and W 4 Is a modified or unmodified nucleoside. In certain embodiments, W 1 is a modified or unmodified nucleoside, W 3is a substituted or unsubstituted heteroalkylene group, and W 4 For oligonucleotides.

[0601] In certain embodiments, the compounds described herein contain the substituent Q 1 In certain embodiments, Q 1 In certain embodiments, Q 1 For-OR 4 In certain embodiments, Q 1 In certain embodiments, Q 1 In certain embodiments, Q 1 For lipids.

[0602] In certain embodiments, the compounds described herein contain the substituent Q 2 In certain embodiments, Q 2 In certain embodiments, Q 2 Independently In certain embodiments, Q 2 In certain embodiments, Q 2 In certain embodiments, Q 2 are independently lipids.

[0603] In certain embodiments, the compounds described herein contain the substituent Q 3 In certain embodiments, Q 3 In certain embodiments, Q 3 Independently In certain embodiments, Q 3 In certain embodiments, Q 3 In certain embodiments, Q 3 are independently lipids.

[0604] In certain embodiments, the compounds described herein contain the substituent Q 4 In certain embodiments, Q 4 In certain embodiments, Q 4 Independently -R 10 In certain embodiments, Q 4 In certain embodiments, Q 4 In certain embodiments, Q 4 are independently lipids.

[0605] In certain embodiments, the compounds described herein contain the substituent Q 5 In certain embodiments, Q5 In certain embodiments, Q 5 Independently In certain embodiments, Q 5 In certain embodiments, Q 5 In certain embodiments, Q 5 are independently lipids.

[0606] In certain embodiments, the compounds described herein contain the substituent Q 6 In certain embodiments, Q 6 In certain embodiments, Q 6 Independently In certain embodiments, Q 6 In certain embodiments, Q 6 In certain embodiments, Q 6 are independently lipids.

[0607] 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 Independently -R 5 In certain embodiments, Q 7 In certain embodiments, Q 7 In certain embodiments, Q 7 are independently lipids.

[0608] In certain embodiments, the compounds described herein contain a substituent Y. In certain embodiments, Y is independently substituted or unsubstituted alkylene. In certain embodiments, Y is independently substituted or unsubstituted heteroalkylene. In certain embodiments, Y is independently substituted or unsubstituted carbocyclylene. In certain embodiments, Y is independently substituted or unsubstituted heterocyclylene. In certain embodiments, Y is independently substituted or unsubstituted arylene. In certain embodiments, Y is independently substituted or unsubstituted heteroarylene. In certain embodiments, Y is independently -O-. In certain embodiments, Y is independently -OP(O)O2-. 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)2NR C In certain embodiments, Y is independently -NR C SO2-.

[0609] 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. C is independently substituted or unsubstituted aryl. In certain embodiments, R C is independently substituted or unsubstituted heteroaryl. In certain embodiments, R C are independently substituted or unsubstituted lipophilic moieties. In certain embodiments, R C Each instance of is independently alkyl. In certain embodiments, R C Each instance of -C8-C 100 -alkyl. In certain embodiments, R C Each instance of -C8-C 40 -alkyl. In certain embodiments, R C Each instance of -C8-C 20 -alkyl. In certain embodiments, R C Each instance of -C 12 -C 20 -alkyl. In certain embodiments, R C Each instance of -C 16 -C 20-alkyl. In certain embodiments, R C Each instance of is independently -H.

[0610] In certain embodiments, R C is tocopherol (e.g., α (alpha), β (beta), γ (gamma), or δ (delta) tocopherol). In certain embodiments, R C For vitamin E.

[0611] In certain embodiments, R c is saturated or unsaturated C1-C 30 Hydrocarbon chain (e.g., C1-C 30 alkyl or alkenyl), which is optionally substituted with a functional group selected from the group consisting of hydroxyl, amine, carboxylic acid, azide and alkyne.

[0612] In some embodiments, R c The group contains saturated or unsaturated C1-C 17 Hydrocarbon chain (e.g., straight chain C1-C 17 In one embodiment, the lipophilic moiety contains a saturated or unsaturated C 17 Hydrocarbon chain.

[0613] In some embodiments, R c The group is C1-C 30 Acids (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, anandamide.

[0614] 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 Independently -OR 6 In certain embodiments, R 2 In certain embodiments, R 2 is independently -F. In certain embodiments, R 2 is independently substituted or unsubstituted alkyl. In certain embodiments, R 2 is independently substituted or unsubstituted alkenyl. In certain embodiments, R 2 is independently substituted or unsubstituted alkynyl. In certain embodiments, R 2 is independently -OMe. In certain embodiments, R 2 are independently -N(R 6). In certain embodiments, R 2 Independently -SR 6 .

[0615] 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 Independently -OR 7 In certain embodiments, R 3 In certain embodiments, R 3 is independently -F. In certain embodiments, R 3 is independently substituted or unsubstituted alkyl. In certain embodiments, R 3 is independently substituted or unsubstituted alkenyl. In certain embodiments, R 3 is independently substituted or unsubstituted alkynyl. In certain embodiments, R 3 is independently -OMe. In certain embodiments, R 3 are independently -N(R 7 ). In certain embodiments, R 3 Independently -SR 7 .

[0616] In certain embodiments, the compounds described herein contain the substituent R 4 In certain embodiments, R 4 In certain embodiments, R 4 For the protecting group.

[0617] In certain embodiments, the compounds described herein contain the substituent R 5 In certain embodiments, R 5 In certain embodiments, R 5 For the protecting group.

[0618] In certain embodiments, R 4 and R 5 Each is independently an oligonucleotide.

[0619] In certain embodiments, R 4 is an oligonucleotide; and R 5 For the protecting group.

[0620] In certain embodiments, R 4 is a protecting group; and R 5 For oligonucleotides.

[0621] In certain embodiments, R 4 and R5 Each is independently a protecting group.

[0622] In some embodiments, R 4 and R 5 ligated together to form a single oligonucleotide.

[0623] In certain embodiments, the compounds described herein contain the substituent R 6 In certain embodiments, R 6 is independently substituted or unsubstituted alkyl. In certain embodiments, R 6 and independently substituted or unsubstituted heteroalkyl.

[0624] In certain embodiments, the compounds described herein contain the substituent R 7 In certain embodiments, R 7 is independently substituted or unsubstituted alkyl. In certain embodiments, R 7 and independently substituted or unsubstituted heteroalkyl.

[0625] In certain embodiments, the compounds described herein contain the substituent R 8 In certain embodiments, R 8 In certain embodiments, R 8 In certain embodiments, R 8 In certain embodiments, R 8 In certain embodiments, R 8 In certain embodiments, R 8 In certain embodiments, R 8 is independently substituted or unsubstituted heteroaryl. In certain embodiments, R 8 are independently nucleobases. In certain embodiments, R 8 are independently modified nucleobases.

[0626] In certain embodiments, the compounds described herein contain the substituent R 9 In certain embodiments, R 9 In certain embodiments, R 9 In certain embodiments, R 9 In certain embodiments, R 9 In certain embodiments, R 9 In certain embodiments, R 9 In certain embodiments, R 9is independently substituted or unsubstituted heteroaryl. In certain embodiments, R 9 are independently nucleobases. In certain embodiments, R 9 are independently modified nucleobases.

[0627] In certain embodiments, the compounds described herein contain the substituent R 10 In certain embodiments, R 10 are independently oligonucleotides.

[0628] In certain embodiments, the compounds described herein contain a substituent X. In certain embodiments, X is independently O. In certain embodiments, X is independently S.

[0629] 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 In certain embodiments, Z 1 、Z 2 、Z 3 or Z 4 is independently C1-C6 alkylene (e.g., methylene, ethylene, propylene). 1 、Z 2 、Z 3 or Z 4 is independently C2-C6 alkenylene. In certain embodiments, Z 1 、Z 2 、Z 3 or Z 4 Independently In certain embodiments, Z 1 、Z 2 、Z 3 or Z 4 Independently

[0630] In certain embodiments, the compounds as 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.

[0631] In certain embodiments, the compounds as 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.

[0632] In certain embodiments, the compounds as 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.

[0633] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

[0634]

[0635] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula: It is attached at the 3rd and 4th nucleoside from the 5' end of the sense strand.

[0636] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

[0637]

[0638] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

[0639] They are attached to the sense strand at the 4th and 5th nucleoside from the 5' end.

[0640] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

[0641]

[0642] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula: They are attached at the 15th and 16th nucleoside from the 5' end on the sense strand.

[0643] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

[0644]

[0645] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

[0646] They are attached at the 16th and 17th nucleoside from the 5' end on the sense strand.

[0647] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

[0648]

[0649] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula: They are attached at the 6th and 7th nucleosides from the 5' end on the sense strand.

[0650] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

[0651]

[0652] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula: They are attached at the third and fourth nucleoside from the 5' end of the sense strand.

[0653] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

[0654]

[0655] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula: They are attached at the third and fourth nucleoside from the 5' end of the sense strand.

[0656] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

[0657]

[0658] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula: They are attached at the third and fourth nucleoside from the 5' end of the sense strand.

[0659] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

[0660] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula: They are attached to the sense strand at the 4th and 5th nucleoside from the 5' end.

[0661] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

[0662]

[0663] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula: They are attached at the 7th and 8th nucleosides from the 5' end on the sense strand.

[0664] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

[0665]

[0666] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula: They are attached at the 17th and 18th nucleosides from the 5' end on the sense strand.

[0667] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

[0668]

[0669] and further comprising at least one dinucleotide of the formula:

[0670]

[0671] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

[0672] It is attached to the sense strand at the 6th and 7th nucleosides from the 5' end, with the following structure: They are attached at the 15th and 16th nucleoside from the 5' end on the sense strand.

[0673] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

[0674]

[0675] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula: They are attached at the 5th and 6th nucleoside from the 5' end on the sense strand.

[0676] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula:

[0677]

[0678] In certain embodiments, provided herein is an oligonucleotide comprising at least one dinucleotide of the formula: They are attached at the 12th and 13th nucleoside from the 5' end on the sense strand.

[0679] In certain embodiments, the present disclosure provides compounds of the formula:

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695] or a salt thereof.

[0696] In certain embodiments, the oligomeric compound is any of those described herein. In certain embodiments, the length of the oligomeric compound is about 10-50 subunits. In certain embodiments, the oligomeric compound is an oligonucleotide. In certain embodiments, the oligonucleotide is any of those described herein. In certain embodiments, the length of the oligonucleotide is the nucleosides of 8 to 80 connections, the nucleosides of 12-30 connections, the nucleosides of 12-30 connections, or the nucleosides of 15-30 connections.

[0697] 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.

[0698] 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., comprising ribonucleosides), deoxyribonucleic acid (e.g., comprising deoxyribonucleosides) or a combination thereof. In certain embodiments, the oligonucleotide is a small interfering RNA (siRNA), a microRNA (miRNA) antagonist, a miRNA mimic, an ADAR recruiting molecule, an ADAR targeting molecule, a guide RNA, an antisense oligonucleotide, a short hairpin RNA (shRNA) or a combination thereof.

[0699] Certain embodiments provide a composition comprising a compound according to any of the embodiments herein and a pharmaceutically acceptable carrier or excipient.

[0700] Certain embodiments provide a composition comprising a compound according to any of the embodiments herein for use in therapy.

[0701] In certain embodiments, a method for delivering an agent to a cell comprises contacting the cell with a compound of any embodiment 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 cortex. In certain embodiments, the agent is a therapeutic agent or a diagnostic agent. In certain embodiments, the cell is in an animal.

[0702] In certain embodiments, a method of regulating the expression of a nucleic acid target in a cell comprises contacting the cell with a compound of any embodiment herein, thereby regulating 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 cortex. In certain embodiments, the pharmaceutical agent is a therapeutic agent or a diagnostic agent. In certain embodiments, contacting the cell with a compound of any embodiment 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 in an animal.

[0703] In certain embodiments, a method for regulating the expression of a nucleic acid target in a subject comprises administering to the subject any of the compounds or compositions provided herein, thereby regulating the expression of the nucleic acid target in the subject. In certain embodiments, the expression of the nucleic acid is regulated in brain cells. In certain embodiments, the brain cells are cells of the frontal cortex. 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.

[0704] In certain embodiments, a method for treating or improving a disease, illness or its symptom of a subject includes administering any compound or composition provided herein to the subject, so as to treat, prevent or improve the disease, illness or symptom of the subject. In certain embodiments, disease, illness or its symptom is a central nervous system (CNS) disease, illness or its symptom. In certain embodiments, disease, illness or its symptom is Alzheimer's disease or its symptom. In certain embodiments, compound is administered to the subject intrathecally. In certain embodiments, compound or composition is administered to the subject in a therapeutically effective amount.

[0705] Also provided herein are uses of the compounds described herein for the preparation of a medicament for treating a disease or condition.

[0706] In another aspect, the present disclosure provides methods for preparing any of the compounds provided herein, comprising one or more compounds and chemical transformations described herein.

[0707] Certain compounds containing oligonucleotides

[0708] In certain embodiments, the compounds described herein include oligonucleotides. In certain embodiments, the oligonucleotides have a core base sequence that is at least partially complementary to a target nucleic acid sequence (e.g., a target nucleic acid expressed in a cell). In some embodiments, the oligonucleotides can inhibit the expression of potential genes after being delivered to cells expressing the target nucleic acid. Gene expression can be inhibited in vitro or in vivo. In certain embodiments, the oligonucleotides include 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 core bases, sugars and / or phosphate groups), or combinations thereof. In some embodiments, the oligonucleotides include ribonucleic acids (RNA). In some embodiments, the oligonucleotides include deoxyribonucleic acids (DNA). In some embodiments, the oligonucleotides include modifications (e.g., modified core bases, modified sugars, or modified phosphates).

[0709] In certain embodiments, oligonucleotide is single-stranded.In some embodiments, single-stranded oligonucleotide is single-stranded RNA (ssRNA), ssDNA or ssRNA / DNA hybrid (for example, single-stranded oligonucleotide comprising ribonucleoside (modified or unmodified) and deoxyribonucleoside (modified or unmodified)). In some embodiments, oligonucleotide is double-stranded (for example, comprising two single-stranded nucleic acids). Such double-stranded oligonucleotides include the first oligonucleotide with a region complementary to the target nucleic acid and the second oligonucleotide with a region complementary to the first oligonucleotide. The first oligonucleotide and the second oligonucleotide can be modified independently.

[0710] In some embodiments, the length of the oligonucleotide is at least 2 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83 ,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,1 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.

[0711] In some embodiments, the length of the oligonucleotide is less than or equal to 150 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 ,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,8 2, 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 In some embodiments, the oligonucleotide has a length of less than or equal to 90 nucleotides. In some embodiments, the oligonucleotide has a length of less than or equal to 80 nucleotides. In some embodiments, the oligonucleotide has a length of less than or equal to 70 nucleotides. In some embodiments, the oligonucleotide has a length of less than or equal to 60 nucleotides. In some embodiments, the oligonucleotide has a length of less than or equal to 50 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 40 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 30 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 29 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 28 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 27 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 26 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 25 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 24 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 23 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 22 nucleotides.In some embodiments, the length of the oligonucleotide is less than or equal to 21 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 20 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 19 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 18 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 17 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 16 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 15 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 10 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 5 nucleotides.

[0712] In some embodiments, the length of the oligonucleotide is about 5 nucleotides to about 150 nucleotides. In some embodiments, the length of the oligonucleotide is about 10 nucleotides to about 100 nucleotides. In some embodiments, the length of the oligonucleotide is about 20 nucleotides to about 90 nucleotides. In some embodiments, the length of the oligonucleotide is about 30 nucleotides to about 80 nucleotides. In some embodiments, the length of the oligonucleotide is about 40 nucleotides to about 70 nucleotides. In some embodiments, the length of the oligonucleotide is about 50 nucleotides to about 60 nucleotides. In some embodiments, the length of the oligonucleotide is about 15 nucleotides to about 30 nucleotides. In some embodiments, the length of the oligonucleotide is about 18 nucleotides to about 25 nucleotides. In some embodiments, the length of the oligonucleotide is about 19 nucleotides to about 23 nucleotides. In certain embodiments, the oligonucleotide is a modified oligonucleotide.

[0713] In some embodiments, the oligonucleotide is about 18 nucleotides to about 25 nucleotides in length.

[0714] In some embodiments, the double-stranded region of the double-stranded oligonucleotide is equal to or is 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.

[0715] 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.

[0716] 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.

[0717] In some embodiments, the oligonucleotide is a therapeutic oligonucleotide. Therapeutic oligonucleotides may include, for example, but are not limited to, small interfering RNA (siRNA), microRNA (miRNA) antagonists, miRNA mimics, ADAR recruiting molecules, ADAR targeting molecules, guide RNA, antisense oligonucleotides, short hairpin RNA (shRNA), or a combination thereof.

[0718] In certain embodiments, the miRNA is a precursor, primary and / or mature miRNA.

[0719] In certain embodiments, the oligonucleotide comprises an antisense oligonucleotide or consists of an antisense oligonucleotide. In certain embodiments, the antisense oligonucleotide is complementary to mRNA. In certain embodiments, the antisense oligonucleotide is complementary to pre-mRNA. In certain embodiments, the antisense oligonucleotide blocks translation and promotes the degradation of mRNA transcripts. In certain embodiments, the antisense oligonucleotide recruits RNase H and promotes the degradation of mRNA transcripts. In certain embodiments, the antisense oligonucleotide targets miRNA, inhibits miRNA from regulating mRNA expression and promotes the degradation of miRNA.

[0720] Certain modifications

[0721] In certain aspects, the present disclosure relates to compounds comprising oligonucleotides. In certain embodiments, the oligonucleotide can be unmodified RNA or DNA, or can be modified. In certain embodiments, the oligonucleotide is a modified oligonucleotide. In certain embodiments, relative to unmodified RNA or DNA, the modified oligonucleotide comprises at least one modified sugar, modified nucleobase, or modified internucleoside linkage. In certain embodiments, the oligonucleotide has a modified nucleoside. The modified nucleoside may comprise a modified sugar, a modified nucleobase, or both a modified sugar and a modified nucleobase. The modified oligonucleotide may also comprise terminal modifications, such as 5' end modifications and 3' end modifications.

[0722] Sugar modifications and motifs

[0723] In certain embodiments, the modified sugar is a substituted furanosyl sugar or a non-bicyclic modified sugar. In certain embodiments, the modified sugar is a bicyclic or tricyclic modified sugar. In certain embodiments, the modified sugar is a sugar surrogate. The sugar surrogate may comprise one or more substitutions as described herein.

[0724] 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 comprises one or more substituent groups, including but not limited to substituent groups at the 2′, 3′, 4′, and 5′ positions.

[0725] In certain embodiments, the substituents at the 2′ position include, but are not limited to, F and OCH3 (“OMe”, “O-methyl” or “methoxy”). In certain embodiments, the substituent groups at the 2′ position of sugars suitable for non-bicyclic modifications include, but are not limited to, halogen, allyl, amino, azido, SH, CN, OCN, CF3, OCF3, F, Cl, Br, SCH3, SOCH3, SO2CH3, ONO2, NO2, N3 and NH2. In certain embodiments, the substituent groups at the 2′ position include, but are not limited to, O—(C1-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, wherein alkyl, alkenyl and alkynyl can be substituted or unsubstituted C1 to C 10 Alkyl or C2 to C 10 In some embodiments, the 2′ substituent groups include, but are not limited to, alkaryl, aralkyl, O-alkaryl, and O-aralkyl. In some embodiments, these 2′ substituent groups may be further substituted with one or more substituent groups independently selected from the group consisting of hydroxyl, alkoxy, carboxyl, benzyl, phenyl, nitro (NO2), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl, and alkynyl. In some embodiments, the 2′ substituent groups include, but are not limited to, O[(CH2) n O] m CH3, O(CH2) n OCH3, O(CH2) n CH3, O(CH2) n ONH2、O(CH2) n NH2, O(CH2) n SCH3 and O(CH2) n ON[(CH2) nCH3)]2, wherein n and m are independently 1 to about 10. In certain embodiments, the substituent groups at the 2' position include, but are not limited to, OCH2CH2OCH3 ("MOE"), O(CH2)2ON(CH3)2 ("DMAOE"), O(CH2)2O(CH2)2N(CH3)2 ("DMAEOE"), and OCH2C(=O)-N(H)CH3 ("NMA").

[0726] In certain embodiments, suitable substituent groups at the 4' position of non-bicyclic modified sugars include, but are not limited to, alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015 / 106128. In certain embodiments, suitable substituent groups at the 5' position of non-bicyclic modified sugars include, but are not limited to, methyl ("Me") (R or S), vinyl, and methoxy. In certain embodiments, the 5' modification is a 5'-monophosphate ((HO)2(O)PO-5'); a 5'-diphosphate ((HO)2(O)POP(HO)(O)-O-5'); a 5'-triphosphate ((HO)2(O)PO-(HO)(O)POP(HO)(O)-O-5'); a 5'-guanosine cap (7-methylated or unmethylated) (7m-GO-5'-(HO)(O)PO-(HO)(O)POP(HO)(O)-O-5'); a 5' adenosine cap (Appp), and any modified or unmodified nucleotide cap structure (NO-5'(HO)(O)PO-(HO)(O)POP(HO)(O)-O-5'); a 5'-monothioate (phosphorothioate; (HO)2(S)PO-5'); a 5'-monodithioate (phosphorodithioate). esters; (HO)(HS)(S)PO-5'), 5'phosphorothioate ((HO)2(O)PS-5'); any additional combination of oxygen / sulfur substituted monophosphates, diphosphates, and triphosphates (e.g., 5'-α-thiotriphosphate, 5'-γ-thiotriphosphate, etc.), 5'-phosphoramidate ((HO)2(O)P-NH-5', (HO)(NH2)(O)PO-5'), 5'alkylphosphonates (R = alkyl = methyl, ethyl, isopropyl, propyl, etc., e.g., RP(OH)(O)-O-5'-, 5'alkenylphosphonates (i.e., vinyl, substituted vinyl), (OH)2(O)P-5'-CH2-), 5'alkyletherphosphonates (R = alkylether = methoxymethyl (MeOCH2-), ethoxymethyl, etc., e.g., RP(OH)(O)-O-5'-). In certain embodiments, one or more sugars comprise a 5'-vinylphosphonate modification. In certain embodiments, one or more sugars 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 the antisense oligonucleotide. In certain embodiments, the substituents described herein for the 2', 4', and 5' positions may be added to other specific positions on the sugar. In certain embodiments, such substituents may be added to the 3' position of the sugar on the 3' terminal nucleoside or the 5' position of the 5' terminal nucleoside. In certain embodiments, non-bicyclic modified sugars may include more than one non-bridging sugar substituent.In certain such embodiments, non-bicyclic modified sugar substituents include, but are not limited to, 5'-Me-2'-F, 5'-Me-2'-OMe (including both R and S isomers). In certain embodiments, modified sugar substituents include those described in Migawa et al., WO 2008 / 101157 and Rajeev et al., US 2013 / 0203836.

[0727] In certain embodiments, modified sugar is a bicyclic sugar. Bicyclic sugar is a modified sugar comprising two rings, wherein the second ring is formed via a bridge connecting two atoms in the first ring, thereby forming a bicyclic structure. In certain embodiments, bicyclic sugar comprises two atoms of a bridging furanosyl ring to form a bridging substituent of the second ring. In certain embodiments, bicyclic sugar does not comprise a furanosyl moiety. " Bicyclic nucleoside " (" BNA ") is a nucleoside with a bicyclic sugar. In certain embodiments, bicyclic sugar comprises a bridge between 4 ' and 2 ' furanose ring atoms. In certain embodiments, bicyclic sugar comprises a bridge between 5 ' and 3 ' furanose ring atoms. In some such embodiments, the furanose ring is a ribose ring. In certain embodiments, 4' to 2' bridged substituents include, but are not limited to, 4'-CH2-2', 4'-(CH2)2-2', 4'-(CH2)3-2', 4'-CH2-O-2' ("LNA"), 4'-CH2-S-2', 4'-(CH2)2-O-2' ("ENA"), 4'-CH(CH3)-O-2' ("constrained ethyl" or "cEt" when in the S configuration), 4'-CH2-O-CH2-2', 4'-CH2-NI-2', 4'-CH (CH2OCH3)-'-2' ("constrained MOE" or "cMOE") and its analogs (e.g., U.S. Patent No. 7,399,845), 4'-C(CH3)(CH3)-'-2' and its analogs (e.g., U.S. Patent No. 8,278,283), 4'-CH2-N(OCH3'-2' and its analogs (e.g., U.S. Patent No. 8,278,425), 4'-CH2-ON(CH3'-2' (e.g., U.S. Patent Publication No. 2004 / 0171570), 4'-CH I (')-O-2' (wherein R is H, C1-C 12alkyl or protecting group) (e.g., U.S. Patent No. 7,427,6'2), 4'-CH2-C(H)(CH3)-2' (e.g., Chattopadhyaya et al., J. Org. Chem., 2009, 74, 118-134) and 4'-CH2-C(=CH2)-2' and the like (e.g., U.S. Patent No. 8,278,426). The entire contents of each of the above are hereby incorporated herein by reference. Other representative U.S. patents and U.S. patent publications that teach the preparation of bicyclic nucleic acid nucleotides include, but are not limited to, the following: U.S. Patent Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 6,998,484; 7,053,207; 7,034,133; 7,084,125; 7,399 ,845; 7,427,672; 7,569,686; 7,741,457; 8,022,193; 8,030,467; 8,278,425; 8,278,426; 8,278,283; US2008 / 0039618; and US2009 / 0012281, US2013 / 0190383; and WO 2013 / 036868, the entire contents of each of which are hereby incorporated by reference herein. Any of the foregoing bicyclic nucleosides can be prepared with one or more stereochemical sugar configurations, including, for example, α-L-ribofuranose and β-D-ribofuranose (see, for example, WO 99 / 14226). Unless otherwise indicated, bicyclic nucleosides designated herein are in the β-D configuration.

[0728] In certain embodiments, modified sugar is a sugar substitute. In certain embodiments, the sugar substitute has an oxygen atom, for example, substituted by a sulfur, carbon, or nitrogen atom. In certain embodiments of this type, the sugar substitute may also include a bridging and / or non-bridging substituent as described herein. In certain embodiments, the sugar substitute includes a ring with non-5 atoms. In certain embodiments of this type, the sugar substitute includes a cyclobutyl moiety replacing the pentofuranosyl sugar. In certain embodiments, the sugar substitute includes a six-membered ring replacing the pentofuranosyl sugar. In certain embodiments, the sugar substitute includes tetrahydropyran ("THP") replacing the pentofuranosyl sugar. In certain embodiments, the sugar substitute includes morpholine replacing the pentofuranosyl sugar. Representative U.S. patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Patent Nos. 4,981,957; 5,118,800; 5,166,315; 5,185,444; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,584,878; No. 591,722; No. 5,597,909; No. 5,610,300; No. 5,627,053; No. 5,639,873; No. 5,646,265; No. 5,658,873; No. 5,670,633; No. 5,700,920; No. 7,875,733; No. 7,939,677; No. 8,088,904; No. 8,440,803; and No. 9,005,906, the entire contents of each of which are hereby incorporated by reference into this document.

[0729] In some embodiments, the sugar surrogate comprises an acyclic portion. In certain embodiments, the sugar surrogate is a non-locked nucleic acid ("UNA"). UNA is a non-locked acyclic nucleic acid in which any bond of the sugar has been removed to form a non-locked "sugar" residue. In one example, UNA also encompasses monomers in which the bond between C1'-C4' has been removed (i.e., a covalent carbon-oxygen-carbon bond between C1' and C4' carbons). In another example, the C2'-C3' bond of the sugar (i.e., a covalent carbon-carbon bond between C2' and C3' carbons) has been removed. Representative U.S. publications teaching the preparation of UNA include, but are not limited to, U.S. Patent No. 8,314,227; and U.S. Patent Publication No. 2013 / 0096289; No. 2013 / 0011922; and No. 2011 / 0313020, the entire contents of each of which are hereby incorporated herein by reference. In certain embodiments, the sugar surrogate comprises a peptide nucleic acid ("PNA"), an acyclic butyl nucleic acid (BuNA) (see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), a glycol nucleic acid (GNA) (see, e.g., Zhang et al., J. Am. Chem. Soc., 2005, 127(12)4174-4175), a threonol nucleic acid (TNA) (see, e.g., Asanuma et al., J. Am. Chem. Soc., 2010, 132(42)14702-14703), or an analog thereof, as well as nucleosides and oligonucleotides described in Manoharan et al., US2013 / 130378, the entire contents of which are hereby incorporated by reference herein. Many other bicyclic and tricyclic sugars and sugar surrogate ring systems are known in the art and can be used in modified nucleosides.

[0730] In certain aspects, the present disclosure relates to compounds comprising at least one oligonucleotide, wherein the nucleosides of such oligonucleotide comprise one or more types of modified sugars and / or unmodified sugars arranged in a defined pattern or "sugar motif" along the oligonucleotide or a region thereof. In some cases, such sugar motifs include, but are not limited to, any of the sugar modification patterns described herein.

[0731] In certain embodiments, oligonucleotide comprises gap polymer (gapmer) sugar motif. Gap polymer oligonucleotide comprises or is composed of the region with two external " wing " district and center or inner " gap " district. Gap district and wing district form continuous nucleoside sequence, and wherein most of the nucleoside sugar of each wing is different from most of the nucleoside sugar of gap. In certain embodiments, wing district comprises most of modified sugar, and gap comprises most of unmodified sugar. In certain embodiments, the nucleoside of gap is deoxynucleoside. Compound with gap polymer sugar motif is described in, for example, U.S. Patent No. 8,790,919, the entire content of which is hereby incorporated by reference into this paper.

[0732] In certain embodiments, one or two oligonucleotides of the double-stranded compound include a triplet sugar motif. An oligonucleotide with a triplet sugar motif includes three identical sugar modifications on three consecutive nucleosides. In certain embodiments, the triplet is located at or near the cleavage site of the oligonucleotide. In certain embodiments, the oligonucleotide of the double-stranded compound may contain more than one triplet sugar motif. In certain embodiments, the identical sugar modification of the triplet sugar motif is a 2'-F modification. Compounds with triplet sugar motifs are disclosed in, for example, U.S. Patent No. 10,668,170, the entire contents of which are incorporated herein by reference.

[0733] In certain embodiments, one or two oligonucleotides of the double-stranded compound include a quadruplex sugar motif. Oligonucleotides with a quadruplex sugar motif include four identical sugar modifications on four consecutive nucleosides. In certain embodiments, the quadruplex is located at or near the cleavage site. In certain embodiments, the oligonucleotides of the double-stranded compound may contain more than one quadruplex sugar motif. In certain embodiments, the identical sugar modification of the quadruplex sugar motif is a 2'-F modification. For double-stranded compounds with a duplex region of 19-23 nucleotides in length, the cleavage sites of the antisense oligonucleotide are typically around positions 10, 11, and 12 of the 5' end. In certain embodiments, counting begins with the first nucleoside at the 5' end of the sense oligonucleotide, and the quadruplex sugar motif is located at position 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, or the counting begins with the first paired nucleotide in the duplex region of the 5' end of the sense oligonucleotide. In certain embodiments, counting begins with the first nucleoside at the 5' end of the antisense oligonucleotide, and the quadruplex sugar motif is located at position 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, or the counting begins with the first paired nucleotide in the duplex region of the 5' end of the antisense oligonucleotide. The cleavage site can be varied depending on the length of the duplex region of the double-stranded compound, and the position of the quadruplex can be altered accordingly.

[0734] In certain embodiments, the oligonucleotide comprises an alternating sugar motif. In certain embodiments, one or two oligonucleotides of the double-stranded compound comprise an alternating sugar motif. The oligonucleotide with 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. For example, if A, B, and C each represent a type of modification to a nucleoside, the alternating motif can be "ABAB ABABABAB...", "AABBAABBAABB...", "AABAABAABAAB," "AAA BAAABAAAB...", "AAABBBAAABBB..." or "ABCABCABCABC" etc. In certain embodiments, the alternating sugar motif is repeated for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobases along the oligonucleotide. In certain embodiments, the alternating sugar motif comprises two different sugar modifications. In certain embodiments, the alternan motif comprises 2'-OMe and 2'-F sugar modifications.

[0735] In certain embodiments, each nucleoside of oligonucleotide is modified independently with one or more sugar modifications provided by this paper. In certain embodiments, each oligonucleotide of double-stranded compound has one or more sugar motifs provided by this paper independently. In certain embodiments, the oligonucleotide comprising sugar motif is modified fully because each nucleoside except the nucleoside comprising sugar motif comprises sugar modification.

[0736] Nucleobase modifications and motifs

[0737] In certain embodiments, a modified oligonucleotide comprises one or more nucleosides comprising a modified nucleobase. In certain embodiments, a modified oligonucleotide comprises one or more nucleosides that do not comprise a nucleobase, termed abasic nucleosides.

[0738] In certain embodiments, the modified nucleobase is selected from the group consisting of a 5-substituted pyrimidine, a 6-azapyrimidine, an alkyl or alkynyl substituted pyrimidine, an alkyl substituted purine, and N-2, N-6, and O-6 substituted purines. In certain embodiments, the modified nucleobase is selected from the group consisting of: 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-CH3) uracil, 5-propynylcytosine, 6-azauracil, 6-azacytosine, 6-azathymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halogen, 8-amino, 8-thiol, 8-sulfanyl, 8-hydroxy, 8-aza and Other 8-substituted purines, 5-halogens, specifically 5-bromo, 5-trifluoromethyl, 5-halouracil and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, hybrid bases, size-extended bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines such as 1,3-diazaphenoxazine-2-one, 1,3-diazaphenthiazine-2-one, and 9-(2-aminoethoxy)-1,3-diazaphenoxazine-2-one (G-clamp). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced by other heterocycles, such as 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine, and 2-pyridone.

[0739] Other nucleobases include U.S. Pat. No. 3,687,808; Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P. ed., Wiley-VCH, 2008; The Concise Encyclopedia Of Polymer Science And Engineering, pp. 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, pp. 289-302; Antisense Research and Applications, Crooke, ST and Lebleu, B. eds., CRC Press, 1993, 273-288; Antisense Drug Technology, Crooke ST ed., CRC Those disclosed in Pharmacopoeia Press, 2008, 163-166 and 442-443 (Chapters 6 and 15), each of which is hereby incorporated by reference.

[0740] Publications teaching the preparation of some of the above-mentioned modified nucleobases, as well as other modified nucleobases, include, but are not limited to, U.S. Application Nos. 2003 / 0158403 and 2003 / 0175906; U.S. Patent Nos. 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,434,257; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121; 5,596,091; 5,614,617; 5,645,985; ,681,941; 5,811,534; 5,750,692; 5,948,903; 5,587,470; 5,457,191; 5,763,588; 5,830,653; 5,808,027; 6,005,096.6,015,886; 6,147,200; 6,166,197; 6,166,199; 6,222,025; 6,235,887; 6,380,368; 6,528,640; 6,639,062; 6,617,438; 7,045,610; 7,427,672; and 7,495,088, the entire contents of each of which are hereby incorporated by reference into this document.

[0741] In certain embodiments, the oligonucleotide comprises modified and / or unmodified nucleobases arranged in a defined pattern or motif along the oligonucleotide or its region. In certain embodiments, each nucleobase is modified. In certain embodiments, no nucleobase is 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.

[0742] In certain embodiments, the modified oligonucleotide comprises a block of modified nucleobases. In certain such embodiments, the block is located at the 3' end of the oligonucleotide. In certain embodiments, the block is located within 3 nucleosides of the 3' end of the oligonucleotide. In certain embodiments, the block is located at the 5' end of the oligonucleotide. In certain embodiments, the block is located within 3 nucleosides of the 5'5' end of the oligonucleotide.

[0743] Internucleoside linkage modifications and motifs

[0744] 3' to 5' phosphodiester linkages are naturally occurring internucleoside linkages of RNA and DNA. In certain embodiments, oligonucleotides have one or more modified (i.e., non-naturally occurring) internucleoside linkages. Certain non-naturally occurring internucleoside linkages can impart desired properties, such as enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases. Representative modified phosphorus-containing internucleoside linkages include, but are not limited to, phosphotriesters, alkylphosphonates (e.g., methylphosphonates), phosphoramidates, and phosphorothioates ("P=S") and phosphorodithioates ("HS-P=S"). Representative non-phosphorus-containing internucleoside linking groups include, but are not limited to, methylenecarbaminyl (-CH2-N(CH3)-O-CH2), thiodiesters, thiocarbamates (-OC(=O)(NH)-S-); siloxanes (-O-SiH2-O-); and N,N'-dimethylhydrazine (-CH2-N((CH3)-N((CH3)-). Methods for preparing phosphorus-containing and non-phosphorus-containing internucleoside linkages are well known to those skilled in the art. Neutral internucleoside linkages include, but are not limited to, phosphotriesters, methylphosphonates, MMI(3 '-CH2-N(CH3)-O-5'), amide-3 (3'-CH2-C(=O)-N(H)-5'), amide-4 (3'-CH2-N(H)-C(=O)-5'), methylal (3'-O-CH2-O-5'), methoxypropyl and thiomethylal (3'-S-CH2-O-5'). Other neutral internucleoside linkages include nonionic linkages, including siloxanes (dialkylsiloxanes), carboxylates, carboxamides, sulfides, sulfonates and amides (see, for example: Carbohydrate Modifications in Antisense Research; YS Sanghvi and P.D. Cook, eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Additional neutral internucleoside linkages include nonionic linkages containing mixed N, O, S and CH2 components.

[0745] In certain embodiments, the oligonucleotide comprises at least one modified internucleoside bond. The modified internucleoside bond may be located at any position of the oligonucleotide. For double-stranded compounds, the modified internucleoside bond may be located within a sense oligonucleotide, an antisense oligonucleotide, or both oligonucleotides of the double-stranded compound.

[0746] In certain embodiments, the internucleoside linkage modification may occur on each nucleoside of the oligonucleotide. In certain embodiments, the internucleoside linkage modification may occur in an alternating pattern along the oligonucleotide. In certain embodiments, substantially each internucleoside linking group is a phosphate internucleoside linkage (P=O). In certain embodiments, each internucleoside linking group of the modified oligonucleotide is a phosphorothioate (P=S). In certain embodiments, each internucleoside linking group of the modified oligonucleotide is independently selected from phosphorothioate and phosphate internucleoside linkages. In certain embodiments, the pattern of internucleoside linkage modification on each oligonucleotide of the double-stranded compound is the same. In certain embodiments, the pattern of internucleoside linkage modification on each oligonucleotide of the double-stranded compound is different. In certain embodiments, the double-stranded compound comprises 6-8 modified internucleoside linkages. In certain embodiments, 6-8 modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. In certain embodiments, the sense oligonucleotide comprises at least two modified internucleoside linkages at either or both of the 5' and 3' ends. 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' ends. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages.

[0747] In certain embodiments, the double-stranded compound includes an overhang region. In certain embodiments, the double-stranded compound includes a phosphorothioate or alkylphosphonate internucleoside bond modification in the overhang region. In certain embodiments, the double-stranded compound includes a phosphorothioate or alkylphosphonate internucleoside bond connecting the overhang nucleotide to the paired nucleotide next to the overhang nucleotide. For example, at least two phosphorothioate internucleoside bonds may be present between the three terminal nucleosides, wherein two of the three nucleosides are overhang nucleosides, and the third nucleoside is a paired nucleoside next to the overhang nucleoside. These three terminal nucleosides may be located 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.

[0748] In certain embodiments, the modified oligonucleotide comprises one or more internucleoside bonds with a chiral center. Representative chiral internucleoside bonds include but are not limited to alkyl phosphonates and thiophosphates. The modified oligonucleotide comprising internucleoside bonds with a chiral center can be prepared as a modified oligonucleotide population comprising a stereo-random internucleoside bond, or as a modified oligonucleotide population comprising a thiophosphate bond comprising a stereochemical configuration. In certain embodiments, the modified oligonucleotide population comprises a thiophosphate internucleoside bond, wherein all thiophosphate internucleoside bonds are stereo-random. Such modified oligonucleotides can be generated using a synthetic method that results in the random selection of the stereochemical configuration of each thiophosphate bond. As is well known to those skilled in the art, each individual thiophosphate of each individual oligonucleotide molecule has a limited stereochemical configuration. In certain embodiments, the modified oligonucleotide population is rich in modified oligonucleotides comprising one or more specific thiophosphate internucleoside bonds, wherein the thiophosphate internucleoside bonds are specific, independently selected stereochemical configurations. In certain embodiments, the specific configuration of a specific phosphorothioate bond is present in at least 65% of the molecules in the population. In certain embodiments, the specific configuration of a specific phosphorothioate bond is present in at least 70% of the molecules in the population. In certain embodiments, the specific configuration of a specific phosphorothioate bond is present in at least 80% of the molecules in the population. In certain embodiments, the specific configuration of a specific phosphorothioate bond is present in at least 90% of the molecules in the population. In certain embodiments, the specific configuration of a specific phosphorothioate bond is present in at least 99% of the molecules in the population. Such enriched modified oligonucleotide populations can be generated using synthetic methods known in the art, such as Oka et al., JACS 125, 8307 (2003); Wan et al., Nuc. Acid. Res. 42, 13456 (2014) and the methods described in WO 2017 / 015555. In certain embodiments, the modified oligonucleotide population is rich in modified oligonucleotides having at least one phosphorothioate represented by the (Sp) configuration. In certain embodiments, the population of modified oligonucleotides is enriched in modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration.

[0749] connector

[0750] "Linker" refers to any chemical moiety (e.g., a combination of atoms with appropriate valence according to known chemical principles) used to conjugate two components (e.g., oligonucleotides) of a compound provided herein. Each of the two components can be connected to any part of any linker provided herein. In some embodiments, one component (e.g., oligonucleotide) of a compound provided herein is connected to one end of a linker by a bond, and another component is connected to the other end of a linker by a bond. In some embodiments, one or both components of a compound provided herein can be connected to an internal position in any linker described herein by a bond. In some embodiments, the linker is a bond (including, for example, a phosphodiester bond and a phosphorothioate bond). In some embodiments, the linker is a substituted or unsubstituted alkyl linker (i.e., an alkyl chain is used to connect two parts, each of which can be conjugated to the opposite end of an alkyl linker, or one or two parts can be conjugated to an internal carbon on an 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 parts, each of which can be conjugated to the opposite end of a PEG linker, or one or two parts can be conjugated to an internal position on a 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, each of which can be conjugated to opposite ends of the heteroalkyl linker, or one or both moieties can be conjugated to internal positions on 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, each of which can be conjugated to any position on the heteroaryl group).

[0751] In some embodiments, the linker has the formula In certain embodiments, the linker has the formula:

[0752] 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 three or four PEG units in length. In certain embodiments, the linker comprises the structure In some embodiments, the linker is two or three PEG units in length.

[0753] 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 comprises the structure

[0754] 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 comprises the structure Wherein X is O or S.

[0755] In some embodiments, the linker comprises the structure

[0756] Wherein X is O or S.

[0757] In some embodiments, the linker is a phosphodiester bond or a phosphorothioate bond. In certain embodiments, the linker comprises the structure Wherein X is O or S.

[0758] In certain embodiments, the linker comprises the structure Wherein X is O or S.

[0759] 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 three 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 comprises the structure 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 comprises the structure In some embodiments, the linker is a substituted or unsubstituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =0 substituents. In certain embodiments, the linker comprises the structure wherein X is O or S. In some embodiments, the linker comprises the structure

[0760] Wherein X is O or S.

[0761] In some embodiments, the linker is a substituted or unsubstituted PEG linker. In certain embodiments, the linker is a substituted or unsubstituted PEG linker of two or three PEG units in length. 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 three or four PEG units in length. In certain embodiments, the linker comprises the structure 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 comprises the structure In some embodiments, the linker is a substituted or unsubstituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =0 substituents. In certain embodiments, the linker comprises the structure wherein X is O or S. In some embodiments, the linker comprises the structure

[0762] Wherein X is O or S.

[0763] In some embodiments, X is O. In some embodiments, X is S.

[0764] In some embodiments, R 4 and R 5 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 an internucleoside linkage. In certain embodiments, the oligonucleotide is a modified oligonucleotide.

[0765] In certain embodiments, the compounds disclosed herein are in the form of salts. In certain embodiments, the salts are sodium salts. In certain embodiments, the salts are potassium salts.

[0766] In certain embodiments, the compounds provided herein include one or more linking groups. In certain embodiments, each of L1, L2, L3 and / or L4 includes a linking group. In certain embodiments, each of L1, L2, L3, L4 and / or L5 includes a linking group. In certain embodiments, each of L1, L2, L3, L4, L5, L6 and / or L7 includes a linking group. In certain embodiments, the linking group is covalently bound to an oligonucleotide. In certain embodiments, the linking group is covalently bound 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 attachment to a solid support.

[0767] In certain embodiments, the linking group comprises a chain structure, such as a hydrocarbon chain, or an oligomer of a repeating unit or a combination of such repeating units. In certain embodiments, the linking group comprises 1 to 50 repeating units, 1 to 40 repeating units, 1 to 25 repeating units, 1 to 20 repeating units, 1 to 15 repeating units, 1 to 10 repeating units, or 1 to 5 repeating units. In certain embodiments, the linking group is 1 to 50 atoms long, 1 to 40 atoms long, 1 to 25 atoms long, 1 to 20 atoms long, 1 to 15 atoms long, 1 to 10 atoms long, or 1 to 5 atoms long.

[0768] In certain embodiments, the linking group contains carbon atoms. In certain embodiments, the linking group contains heteroatoms (e.g., nitrogen, oxygen, sulfur, etc.). In certain embodiments, the linking group forms amide bonds, ester bonds or disulfide bonds. In certain embodiments, the linking group forms hydrazone bonds, oxime bonds, imine bonds, guanidine bonds, urea bonds, carbamate bonds, unsaturated alkyl bonds, sulfonamide bonds or 4-8 membered heterocycle bonds. In certain embodiments, the linking group comprises one or more groups selected from alkyl, amino, oxo, amides, disulfide, polyethylene glycol, ether, thioether and hydroxyamino groups. In certain embodiments, the linking group comprises at least one phosphorus group. In certain embodiments, the linking group comprises at least one phosphate group. In certain embodiments, the linking group includes at least one neutral linking group. In certain embodiments, the linking group is substituted with various substituents including, but not limited to, hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, amino groups, alkylamino groups, dialkylamino groups, trialkylamino groups, hydroxyl groups, alkoxy groups, halogen groups, aryl groups, heterocycles, aromatic heterocycles, cyano groups, amides, carbamoyl groups, carboxylic acids, esters, thioethers, alkylthioethers, thiols, and ureido groups. As will be appreciated by those skilled in the art, each of these groups may in turn be substituted.

[0769] In certain embodiments, the linking group includes but is not limited to substituted or unsubstituted C1-C 10 Alkylene, substituted or unsubstituted C2-C 10 Alkenylene, or substituted or unsubstituted C2-C 10 Alkynylidene, wherein a non-limiting list of preferred substituent groups includes hydroxy, amino, alkoxy, carboxyl, 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.

[0770] In certain embodiments, the linking group is a short peptide chain.In certain embodiments, the linking group comprises 1 to 40 amino acids, 1 to 25 amino acids, 1 to 20 amino acids, 1 to 15 amino acids, 1 to 10 amino acids, or 1 to 5 amino acids.

[0771] In certain embodiments, the linking group comprises a joint-nucleoside. In certain embodiments, the linking group comprises 1 to 40 joints-nucleosides, 1 to 25 joints-nucleosides, 1 to 20 joints-nucleosides, 1 to 15 joints-nucleosides, 1 to 10 joints-nucleosides or 1 to 5 joints-nucleosides. In certain embodiments, such joints-nucleosides can be modified or unmodified nucleosides. It is generally expected that the joint-nucleosides will crack out from the compound after arriving at the target tissue. Therefore, the joints-nucleosides herein can be connected to each other and connected to the remainder of the compound by a cleavable bond. In this article, joints-nucleosides are not considered to be a part for oligonucleotide payload. Therefore, in the embodiment in which the compound comprises an oligonucleotide consisting of a specified number or scope of connection nucleosides and / or has a specified complementary percentage with a reference nucleic acid, those joints-nucleosides do not insert the length count of the oligonucleotide and are not used to determine the complementary percentage of the oligonucleotide and the reference nucleic acid.

[0772] In certain embodiments, the linking group includes a protein binding group. In certain embodiments, the protein binding group is a lipid, such as including but not limited to cholesterol, cholic acid, adamantaneacetic acid, 1-pyrenebutyric acid, dihydrotestosterone, 1,3-bis-O (hexadecyl) glycerol, geranyloxyhexyl group, hexadecyl glycerol, borneol, menthol, 1,3-propylene glycol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl) lithocholic acid, O3-(oleoyl) cholenic acid, dimethoxytribenzyl or phenoxazine), vitamins (e.g., folic acid, vitamin A, vitamin E, biotin, pyridoxal), peptides, carbohydrates (e.g., monosaccharides, disaccharides, trisaccharides, tetrasaccharides, oligosaccharides, polysaccharides), endosomal dissolution components, steroids (e.g., agave sapogenin, diosgenin), terpenes (e.g., triterpenes, such as smilagenin, terpenoids, epi-suberin-derived lithocholic acid) or cationic lipids. In certain embodiments, the protein binding group is C 16 to C 22 Long-chain saturated or unsaturated fatty acids, cholesterol, bile acid, vitamin E, adamantane or 1-pentafluoropropyl.

[0773] In certain embodiments, the linking group includes, but is not limited to, pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and 6-aminohexanoic acid (AHEX or AHA).

[0774] In certain embodiments, the linking groups include, but are not limited to, those described in the following references: US 5,994,517; US 6,300,319; US 6,660,720; US 6,906,182; US 7,262,177; US 7,491,805; US 8,106,022; US 7,723,509; US 9,127,276; US 2006 / 0148740; US 2011 / 0123520; WO 2013 / 033230; WO 2012 / 037254; Biessen et al., J. Med. Chem. 1995, 38, 1846-1852; Lee et al., Bioorganic & Medicinal Chemistry 2011, 19, 2494-2500; Rensen et al., J. Biol. Chem. 2001, 276, 37577-37584; Rensen et al., J. Med. Chem. 2004, 47, 5798-5808; Sliedregt et al., J. Med. Chem. 1999, 42, 609-618; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Lee, 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., Analy t Biochem, 2012, 425, 43-46; Pujol et al., Angew Chemie Int Ed Engl, 2012, 51, 7445-7448; Biessen et al., J Med Chem, 1995, 38, 1846-1852; Sliedregt et al., J Med Chem, 1999, 42, 609-618; Rensen et al., J Med Chem, 2004, 47, 5798-5808; Rensen et al., Arterioscler Thromh Vase Biol, 2006, 26, 169-175; van Rossenberg et al., Gene Ther, 2004, 11, 457-464; Sato et al., J Am Chem Soc, 2004, 126, 14013-14022; Lee et al., J Org Chem, 2012, 77, 7564-7571; Biessen et al., FASEB J, 2000, 14, 1784-1792; Rajur et al., Bioconjug Chem, 1997, 8, 935-940; Duff et al., Methods Enzymol, 2000, 313, 297-321; Maier et al., Bioconjug Chem, 2003, 14, 18-29; Jayaprakash et al., Org Lett, 2010, 12, 5410-5413; Manoharan, Antisense Nucleic Acid Drug Dev, 2002, 12, 103-128; Merwin et al., Bioconjug Chem, 1994, 5, 612-620; Tomiya et al., Bioorg Med Chem, 2013, 21, 5275-5281; International applications WO1998 / 013381; WO2011 / 038356; WO1997 / 046098; WO2008 / 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; W0201 0 / 148013;WO1997 / 020563;W02010 / 088537;W02002 / 043771;W02010 / 12970 9; WO2012 / 068187; WO2009 / 126933; WO2004 / 024757; WO2010 / 054406; WO2012 / 089352; WO2012 / 089602; WO2013 / 166121; WO2013 / 165816; U.S. Patents 4,751,219; 7,582,744; 8,552,163; 8,137,695; 6,908,903; 6,383,812; 7,262,177; 6,525,031; 5,994,517; 6,660,720; 6,300,319; 7,723,509; 8,106,022; 7, 491,805; 7,491,805; 8,541,548; 8,344,125; 8,313,772; 8,349,308; 8,450,467; 8,501,930; 8,158,601; 7,262,177; 6,906,182; 6,620,916; 8,435,491; 8,404,862; 7,851,615; Published U.S. Patent Applications Nos. US2011 / 0097264; US2011 / 0097265; US2013 / 0004427; US2003 / 0119724; US2011 / 0207799; US2012 / 0035115; U US2012 / 0230938; US2005 / 0164235; US2006 / 0183886; US2012 / 0136042; US2012 / 0095075; US2013 / 0109817; US2006 / 0148740; US2008 / 0206869; US2012 / 0165393; US2012 / 0101148; US2013 / 0121954; US2011 / 0123520; US2003 / 0077829; US2008 / 0108801; and US2009 / 0203132; each of which is incorporated herein by reference in its entirety.

[0775] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0776] wherein each n is independently 1 to 20; and p is 1 to 6.

[0777] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0778] wherein each n is independently 1 to 20.

[0779] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0780] wherein each n is independently 1 to 20.

[0781] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0782] wherein each n is independently 1 to 20.

[0783] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0784] wherein each L is independently a phosphorus linking group; and each n is independently 1 to 20.

[0785] In certain embodiments, each of L1, L2, L3, L4 L5, L6 and / or L7 independently comprises or taken together comprises a structure selected from the group consisting of:

[0786]

[0787]

[0788] In certain embodiments, each of L1, L2, L3, L4, L5, L6, and / or L7 independently comprises or taken together comprises a structure selected from the group consisting of:

[0789]

[0790]

[0791] In certain embodiments, L1, L2, L3, L4, L5, L6 and / or L7 independently comprise or taken together comprise a structure selected from the group consisting of:

[0792]

[0793] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0794] wherein n is an integer in the range of 1 to 20, inclusive.

[0795] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0796]

[0797] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0798]

[0799] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0800]

[0801] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together have the following structure:

[0802]

[0803] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together have the following structure:

[0804]

[0805] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0806]

[0807] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0808] wherein each n is independently 0, 1, 2, 3, 4, 5, 6 or 7.

[0809] In some embodiments, each of L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) 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.

[0810] In some embodiments, L1 is a bond.

[0811] In some embodiments, L2 is a substituted or unsubstituted PEG linker. In some embodiments, the PEG linker is three or four PEG units in length. In certain embodiments, L2 comprises the structure In some embodiments, the PEG linker is two or three PEG units in length.

[0812] In some embodiments, L3 is a substituted or unsubstituted heteroaryl linker. In some embodiments, L3 is a substituted or unsubstituted partially unsaturated heteroaryl linker. In certain embodiments, L3 comprises the structure

[0813] In some embodiments, L4 is a substituted or unsubstituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In certain embodiments, L4 comprises the structure Wherein X is O or S.

[0814] In some embodiments, L1, L2, L3, and L4 together comprise the structure Wherein X is O or S.

[0815] In some embodiments, one of L3 and L4 is a phosphodiester bond or a phosphorothioate bond, and the other of L3 and L4 is a bond. In certain embodiments, L1, L2, L3, and L4 together comprise the structure Wherein X is O or S.

[0816] In certain embodiments, L1, L2, L3, and L4 together comprise the structure Wherein X is O or S.

[0817] In some embodiments, each of L1, L2, L3, L4, and L5 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.

[0818] In some embodiments, L1 and L5 are each a substituted or unsubstituted PEG linker. In some embodiments, L1 and L5 are each a substituted or unsubstituted PEG linker that is three PEG units in length.

[0819] In some embodiments, L2 is a substituted or unsubstituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In certain embodiments, L2 comprises the structure

[0820] In some embodiments, L3 is a substituted or unsubstituted heteroaryl linker. In some embodiments, L3 is a substituted or unsubstituted partially unsaturated heteroaryl linker. In certain embodiments, L3 comprises the structure

[0821] In some embodiments, L4 is a substituted or unsubstituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In certain embodiments, L4 comprises the structure Wherein X is O or S.

[0822] In some embodiments, L1, L2, L3, L4, and L5 together comprise the structure Wherein X is O or S.

[0823] In some embodiments, each of L1, L2, L3, L4, L5, L6, and L7 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.

[0824] In some embodiments, L1 is a substituted or unsubstituted PEG linker. In certain embodiments, L1 is a substituted or unsubstituted PEG linker that is two or three PEG units in length.

[0825] In some embodiments, L2 and L5 are each independently a substituted or unsubstituted PEG linker. In some embodiments, L2 and L5 are each independently a substituted or unsubstituted PEG linker of three or four PEG units in length. In certain embodiments, L1, L2, and L5 together comprise the structure

[0826] In some embodiments, L3 and L6 are each independently a substituted or unsubstituted heteroaryl linker. In some embodiments, L3 and L6 are each independently a substituted or unsubstituted partially unsaturated heteroaryl linker. In certain embodiments, L3 and L6 each comprise the structure

[0827] In some embodiments, L4 and L7 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, L4 and L7 each comprise the structure Wherein X is O or S.

[0828] In some embodiments, L1, L2, L3, L4, L5, L6, and L7 together comprise the structure Wherein X is O or S.

[0829] Methods for preparing compounds

[0830] The compounds of the present disclosure can be prepared by methods known in the art of organic synthesis. If necessary, methods for optimizing reaction conditions and minimizing competing by-products are known in the art. Reaction optimization and scale-up can advantageously utilize high-speed parallel synthesis equipment and computer-controlled microreactors (e.g., Design And Optimization in Organic Synthesis, 2nd edition, Carlson R ed., 2005; Elsevier Science Ltd.; K et al., Angew. Chem. Int. Ed. Engl. 2004 43:406; and references therein). Additional reaction schemes and protocols can be obtained by one skilled in the art using commercially available structure-searchable database software, for example, (CAS division of the American Chemical Society) and CrossFire (Elsevier MDL), or by using an Internet search engine such as or keyword databases such as the U.S. Patent and Trademark Office text database.

[0831] As will be appreciated by those skilled in the art, methods for synthesizing compounds of the formula herein will be readily apparent to those of ordinary skill in the art and are included in the schemes and examples herein. Additionally, the various synthesis steps may be performed in alternate sequences or orders to yield the desired compounds. Furthermore, the solvents, temperatures, reaction durations, etc. described herein are for illustrative purposes only, and those of ordinary skill in the art will recognize that variations in reaction conditions may yield desired compounds of the present disclosure.

[0832] The compounds herein may also contain bonds (e.g., carbon-carbon bonds) where bond rotation is restricted around that particular bond, such as restrictions caused by the presence of a ring or double bond. Thus, all cis / trans and E / Z isomers are expressly included in the present disclosure. The compounds herein may also be represented in multiple tautomeric forms; in such cases, the present disclosure expressly includes all tautomeric forms of the compounds described herein, even if only a single tautomeric form can be represented. All such isomeric forms of such compounds herein are expressly included in the present disclosure. All crystalline forms and polymorphs of the compounds described herein are expressly included in the present disclosure. Also included are extracts and fractions containing the compounds of the present disclosure. The term "isomer" is intended to include diastereomers, enantiomers, regioisomers, structural isomers, rotational isomers, tautomers, and the like. For compounds containing one or more stereocenters, such as chiral compounds, the methods of the present disclosure can be performed with enantiomerically enriched compounds, racemates, or diastereomeric mixtures. All isomers of the compounds described herein are expressly included in the present disclosure.

[0833] 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 preferred embodiments, only one enantiomer or diastereomer of a chiral compound of the present disclosure is administered to a cell or subject.

[0834] Treatment

[0835] In one aspect, provided are methods of treating a subject suffering from or susceptible to a condition or disease, the methods comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein.

[0836] In other aspects, methods are provided for treating a subject suffering from or susceptible to a condition or disease, wherein the subject has been identified as requiring 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, thereby treating the condition in the subject.

[0837] In one aspect, a method of delivering a therapeutic oligonucleotide to the brain of a subject is provided, 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.

[0838] In one aspect, a method of modulating protein function in a subject is provided, comprising contacting the subject with a compound of any of the formulae herein (e.g., Formulas I, I', I-VIII, II-a, and II-b) in an amount and under conditions sufficient to modulate protein function.

[0839] In one embodiment, modulation is inhibition.

[0840] In some embodiments, a method for targeting hepatocytes in a subject is provided, the method comprising administering to the subject in need thereof an effective amount of a compound, oligonucleotide, or pharmaceutical composition of any of the formulae herein (e.g., Formula I, I', I-VIII, II-a, and II-b), in an amount and under conditions sufficient to target the hepatocytes.

[0841] In certain embodiments, methods of treating a disease, disorder, or symptom thereof are provided, wherein the disorder is cancer, a proliferative disorder, a neurodegenerative disease, an autoimmune or inflammatory disorder, an infection, a metabolic disorder, a blood disorder, or a cardiovascular disease.

[0842] In certain embodiments, the disease or disease is cancer or proliferative disease. In certain embodiments, cancer or proliferative disease include cancer, leukemia, blastoma, lymphoma, myeloma or melanoma, or a combination thereof. In certain embodiments, the disease or disease is multiple myeloma, melanoma, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, hepatocellular carcinoma, kidney 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's lymphoma, esophageal cancer, Hodgkin's lymphoma, bladder cancer or gastric cancer, or a combination thereof.

[0843] 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 hyperresponsiveness, ulcerative colitis, or a combination thereof.

[0844] 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 disease (MCT), peripheral neuropathy, or cerebral ischemia, or a combination thereof.

[0845] In certain embodiments, the disorder or disease is an infection caused by a virus, fungus, or bacteria, or a combination thereof.

[0846] In certain embodiments, the condition or disease is metabolic syndrome, diabetes, obesity, hypertension, heart failure, cystic growth in autosomal dominant polycystic kidney disease (ADPKD), or a combination thereof.

[0847] In certain embodiments, the condition or disease is cardiovascular stress, pressure overload, chronic ischemia, infarction-reperfusion injury, hypertension, atherosclerosis, peripheral arterial disease, heart failure, cardiac hypertrophy, angina, arrhythmia, hypercholesterolemia, atherosclerosis or stroke, or a combination thereof.

[0848] In certain embodiments, the disorder or disease is liver disease.

[0849] In certain embodiments, the subject is a mammal, preferably a primate or a human.

[0850] In another embodiment, a method as described above is provided, wherein the effective amount of the compound of any of the formulae herein (eg, Formula I, I', I-VIII, II-a, and II-b) or oligonucleotide is as described above.

[0851] In another embodiment, a method as described above is provided, wherein the compound or oligonucleotide of any of the formulae herein (eg, Formula I, I', I-VIII, II-a, and II-b) is administered intravenously, intramuscularly, subcutaneously, intracerebroventricularly, orally, or topically.

[0852] In other embodiments, methods as described above are provided, wherein a compound or oligonucleotide of any of the formulae herein (e.g., Formula I, I', I-VIII, II-a, and II-b) is administered alone or in combination with one or more other therapeutic agents. In another embodiment, the additional therapeutic agent is an anticancer agent, an antifungal agent, a cardiovascular agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an antiproliferative agent, a metabolic disease agent, an ophthalmic disease agent, a central nervous system (CNS) disease agent, a urinary disease agent, or a gastrointestinal disease agent.

[0853] Another object of the present disclosure is the use of a compound or oligonucleotide as described herein (e.g., a compound or oligonucleotide of Formula I, I', I-VIII, II-a, and II-b) in the preparation of a medicament for treating a disorder or disease. Another object of the present disclosure is the use of a compound or oligonucleotide as described herein (e.g., a compound or oligonucleotide of Formula I, I', I-VIII, II-a, and II-b) in the preparation of a medicament for treating a disorder or disease. Another object of the present disclosure is the use of a compound or oligonucleotide as described herein (e.g., a compound or oligonucleotide of Formula I, I', I-VIII, II-a, and II-b) in the preparation of an agricultural composition for treating or preventing a disorder or disease in an agricultural or land environment.

[0854] In certain embodiments, methods of treating a disease, disorder, or symptom thereof are provided, wherein the disease is a central nervous system (CNS) disease, disorder, or symptom thereof. In some embodiments, the disease is a neurodegenerative disease, disorder, or symptom thereof. In some embodiments, the disease is Alzheimer's disease or a symptom thereof.

[0855] Exemplary CNS disorders include, but are not limited to, neurotoxicity and / or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, psychiatric disorders, sleep disorders, movement disorders, nausea and / or vomiting, amyotrophic lateral sclerosis, Alzheimer's disease, and substance abuse.

[0856] In certain embodiments, the CNS disorder is neurotoxic and / or neurotrauma, e.g., as a result of 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 neuroprotection, e.g., against acute neuronal injury or chronic neurodegenerative disorders.

[0857] In certain embodiments, the CNS disorder is a psychiatric disorder, such as depression, anxiety or an anxiety-related disorder, a learning disorder, or schizophrenia.

[0858] In certain embodiments, CNS disorders are depression. "Depression" includes but is not limited to depressive disorders or conditions, 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 or subclinical depression. Depression can be associated with premenstrual syndrome and / or premenstrual dysphoric disorder.

[0859] In certain embodiments, CNS disorders are anxiety." anxiety " includes but is not limited to anxiety and the illness related to anxiety, such as clinical anxiety, panic disorder, agoraphobia, generalized anxiety disorder, specific phobia, social phobia, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder, the adaptive disorder with anxiety features, the anxiety disorder related to depression, the anxiety disorder caused by general medical conditions and the anxiety disorder induced by substances, the anxiety related to substance abuse (for example, withdrawal, dependence, recovery) and the anxiety related to nausea and / or vomiting. The treatment can also induce or promote the sleep of a subject (for example, a subject suffering from anxiety).

[0860] In certain embodiments, the CNS disorder is a learning disorder (eg, attention deficit disorder (ADD)).

[0861] In certain embodiments, the CNS disorder is schizophrenia.

[0862] In certain embodiments, the CNS disorder is a sleep disorder. "Sleep disorders" include, but are not limited to, insomnia, narcolepsy, sleep apnea, restless legs syndrome (RLS), delayed sleep phase syndrome (DSPS), periodic limb movement disorder (PLMD), obstructive sleep apnea, rapid eye movement sleep behavior disorder (RBD), shift work sleep disorder (SWSD), and sleep problems (e.g., parasomnias) such as nightmares, night terrors, sleep talking, head banging, snoring, and trismus and / or teeth grinding (bruxism).

[0863] In certain embodiments, the CNS disorder is a movement disorder, e.g., a basal ganglia disorder, such as Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, Tourette syndrome, tardive dyskinesia, and dystonia.

[0864] In certain embodiments, the CNS disorder is Alzheimer's disease.

[0865] In certain embodiments, the CNS disorder is amyotrophic lateral sclerosis (ALS).

[0866] In certain embodiments, the CNS disorder is nausea and / or vomiting.

[0867] In certain embodiments, the CNS disorder is a substance abuse disorder (SUD) (eg, addiction to opioids, nicotine, cocaine, psychostimulants, and / or alcohol).

[0868] The term "neurological disease" (including, for example, "neurodegenerative disease") refers to any disease of the nervous system, including diseases involving the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves) and the autonomic nervous system (parts of which are located in both the central nervous system and the peripheral nervous system). Neurodegenerative disease refers to a class of neurological diseases marked by nerve cell loss, including but not limited to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, tauopathy (including frontotemporal dementia) and Huntington's disease. Examples of neurological diseases include but are not limited to headaches, stupor and coma, dementia, epileptic seizures, sleep disorders, trauma, infection, vegetation, neuro-ophthalmological diseases, movement disorders, demyelinating diseases, spinal cord disorders and disorders of peripheral nerves, muscles and neuromuscular junctions. Substance abuse and mental illness (including but not limited to substance use disorder, bipolar disorder, eating disorders and schizophrenia) are also included in the definition of neurological disease. Other examples of neurological disorders include acquired epileptic aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers disease; alternating hemiparesis; Alzheimer disease; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; hypoxia; aphasia; apraxia; arachnoid cyst; arachnoiditis; Arnold-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telangiectasia; attention deficit hyperactivity disorder; autism; dysautonomia; back pain; Batten disease; Behçet disease; Bell's palsy; benign essential blepharospasm; benign lesions; amyotrophic lateral sclerosis; benign intracranial hypertension; Binswanger disease; blepharospasm; Bloch-Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumor (including glioblastoma multiforme); spinal tumors; Brown-Ségal syndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia; central pain syndrome; central pontine myelinolysis; head disorders; cerebral aneurysms; cerebral arteriosclerosis; brain atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic pain; chronic regional pain syndrome; Coffin-Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorder; Cushing's syndrome; cytomegalovirus infection; dancing eyes-dancing feet syndrome. eyes-dancing feet syndrome); Dandy-Walker syndrome; Dawson disease; De Morsier's syndrome;Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; familial dysautonomia; dysgraphia; dyslexia; dystonia; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephalocele; cerebral trigeminal angiomatosis; epilepsy; Erb palsy; essential tremor; Fabry disease; Fahr syndrome; syncope; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich's ataxia; frontotemporal dementia and other "tauopathies"; Gaucher disease; Gerstmann syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1-associated myelopathy; Harold's syndrome Leverden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; hereditary movement disorders of the polyneuritic type; 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; hydrocephalus; hydrocortisonephritis; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; children; phytanic acid storage disease; Refsum's disease in children; infantile spasms; inflammatory myopathy; intracranial cysts; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome syndrome; Klippel-Feil syndrome; Krabbe disease; Kugelberg-Weiland disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Klevner syndrome; dorsolateral medullary (Wallenberg) syndrome; learning disabilities; Leigh disease; Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; dementia with Lewy bodies; lissencephaly; locked-in syndrome; Lou Gehrig's disease (also known as motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; Lyme disease - neurologic sequelae; Machado-Joseph disease; megalencephaly; megalencephaly; Meikson-Rosenthal syndrome; Meniere's disease; meningitis; Menkes disease; metachromatic leukodystrophy microcephaly; migraine; Miller-Fisher syndrome; mini-stroke; mitochondrial myopathy; Möbius syndrome; monomelic muscular dystrophy; 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 myelinolytic sclerosis; infantile myoclonic encephalopathy; myoclonus; myopathy; myotonia congenita; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurologic manifestations of AIDS; neurologic sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migratory disorder; Niemann-Pick disease;O'Sullivan-McLeod syndrome; occipital neuralgia; cryptic neural tube dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus-myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesias; Parkinson's disease; paramyotonia congenita; paraneoplastic disorders; paroxysmal seizures; Parkinson-Rötten syndrome; Pelvic-Merzheimer disease; periodic paralysis; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorder; photosensitivity sneeze reflex; phytanic acid storage disease; Pick's disease; nerve compression; pituitary tumor; polymyositis; cerebral puncture malformation; post-polio syndrome; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; orthostatic hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion disease; progressive; hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing gray matter dystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (types I and II); Rasmussen encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive movement disorder; repetitive stress injury; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome syndrome; Reye's syndrome; St. Vitus' chorea; Sandhoff's disease; Scheldt's disease; schizencephaly; septooptic dysplasia; shaken baby syndrome; herpes zoster (shingles); Shy-Drager syndrome; Sjögren's syndrome; sleep apnea; Sotos syndrome; spasticity; spina bifida; 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's chorea; syncope; syringomyelia; tardive dyskinesia; Tay- Saunders disease; temporal arteritis; tethered cord syndrome; Thomson disease; thoracic outlet syndrome; cramps; Todd's palsy; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathy; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis complex; vascular dementia (multi-infarct dementia); vasculitis, including temporal arteritis; Von Hippel-Lindau disease (VHL); Wallenberg syndrome; Werdnig-Hoffmann disease; West syndrome; whiplash; Williams syndrome; Wilson disease; and Zellweger syndrome.

[0869] In certain embodiments, the subject is a mammal, preferably a primate or a human.

[0870] In another embodiment, provided is a method as described above, wherein the effective amount of a compound provided herein is as described above.

[0871] In another embodiment, a method as described above is provided, wherein the compound provided herein is administered intrathecally, intravenously, intramuscularly, subcutaneously, intracerebroventricularly, orally, or topically. In certain embodiments, the compound is administered intrathecally.

[0872] In other embodiments, methods as described above are provided, wherein a compound of any formula provided herein is administered alone or in combination with one or more additional therapeutic agents. In another embodiment, the additional therapeutic agent is a central nervous system (CNS) disease agent.

[0873] Another object of the present disclosure is the use of a compound as described herein in the preparation of a medicament for the treatment of a disorder or disease.Another object of the present disclosure is the use of a compound as described herein for the treatment of a disorder or disease.

[0874] Pharmaceutical composition

[0875] In one aspect, provided is a pharmaceutical composition comprising any compound described herein and a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient.

[0876] Compound or composition as described herein can be applied in combination with one or more other therapeutic agents (for example, treatment and / or prevention active agent).The compound or composition can be applied in combination with other therapeutic agents, and the other therapeutic agents improve their activity (for example, in the treatment of the disease of the subject in need thereof, in the prevention of the disease of the subject in need thereof and / or in the reduction of the risk of the subject in need thereof developing a disease (for example, effect and / or efficacy)), improve bioavailability, improve safety, reduce drug resistance, reduce and / or change metabolism, suppress excretion and / or change the distribution in the subject or cell. It should also be understood that the therapy adopted can achieve the desired effect for the same disease, and / or it can achieve different effects. In certain embodiments, the pharmaceutical composition described herein comprising compound as described herein and other therapeutic agent shows a synergistic effect, which is not present in the pharmaceutical composition comprising one of compound as described herein or other therapeutic agent but not both.

[0877] The compound or composition can be used simultaneously with one or more other therapeutic agents, before or after it, and these therapeutic agents can be used as, for example, combination therapy.Therapeutic agent includes therapeutically active agents.Therapeutic agent also includes preventive active agents.Therapeutic agent comprises organic small molecules, such as pharmaceutical compounds (for example, compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Federal Regulations (CFR), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules connected to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells. In certain embodiments, other therapeutic agents are therapeutic agents that can be used for treating and / or preventing diseases (for example, CNS disorders). Each other therapeutic agent can be used under the dosage and / or timetable determined for the therapeutic agent. Other therapeutic agents can also be used together with each other and / or with compound or composition as herein described with single dose or separately with different doses. The specific combination employed in a regimen will take into account the compatibility of the compounds described herein with the additional therapeutic agent and / or the desired therapeutic and / or prophylactic effect to be achieved. Generally, it is contemplated that the additional therapeutic agents of the combination will be used at levels no greater than those used individually. In some embodiments, the levels used in combination will be lower than those used individually.

[0878] In one aspect, kits are provided comprising an effective amount of a compound provided herein in unit dosage form and instructions for administering the compound to a subject suffering from or susceptible to a disease or condition.

[0879] "Pharmaceutically acceptable salt" means or refers to a physiologically and pharmaceutically acceptable salt of a compound, such as an oligomeric compound or oligonucleotide, i.e., a salt that retains the desired biological activity of the parent compound and does not impart undesirable toxicological effects thereto. As used herein, a pharmaceutically acceptable salt is any salt of a compound as provided herein that retains its biological properties and is non-toxic or otherwise undesirable for pharmaceutical use. Pharmaceutically acceptable salts of the therapeutic agents disclosed herein include salts prepared with relatively nontoxic acids or bases, depending on the specific substituents present on the compounds or modified oligonucleotides described herein.

[0880] When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.

[0881] When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.

[0882] Thus, the compounds of the present disclosure may exist as salts, such as salts prepared with pharmaceutically acceptable acids. Such salts may be derived from a variety of organic and inorganic counterions well known in the art. Such salts include, but are not limited to: (1) acid 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)benzoyl 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, hydroxynaphthyl acid, salicylic acid, stearic acid, cyclohexylaminosulfonic acid, quinic acid, muconic acid and similar acids; or (2) salts formed when an acidic proton present in the parent compound is: (a) replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, or an alkali metal or alkaline earth metal hydroxide, such as sodium, potassium, calcium, magnesium, aluminum, lithium, zinc and barium hydroxides, ammonia, or (b) coordinated with an organic base, such as an 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-methylglucaminepiperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like (see, e.g., Berge et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0883] Pharmaceutically acceptable salts also include, for example, but not limited to, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and, when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrohalides, for example, hydrochlorides and hydrobromides, sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoate, picric acid, In some embodiments, the pharmaceutically acceptable salts of the compounds and modified oligonucleotides disclosed herein are sodium or potassium salts. 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.

[0884] The neutral form of the compound is preferably regenerated by contacting the salt with an alkali or acid and separating the parent compound in a conventional manner. The parent form of the compound may differ from various salt forms in certain physical properties, such as solubility in polar solvents. In an embodiment, the compound of the present disclosure contains both basic and acidic functional groups, which allow the compound to be converted into a base or acid addition salt. The neutral form of the compound may be regenerated by contacting the salt with an alkali or acid and separating the parent compound in a conventional manner. The parent form of the compound may differ from various salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this disclosure, unless otherwise noted, the salts disclosed herein are equivalent to the parent form of the compound.

[0885] When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.

[0886] Thus, the compounds of the present disclosure may exist as salts, for example, salts prepared with pharmaceutically acceptable acids or bases. Such salts may be derived from a variety of organic and inorganic counterions well known in the art. Such salts include, but are not limited to: (1) acid 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-hydroxyphenyl)-1-ol (formyl)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, cyclohexylaminosulfonic acid, quinic acid, muconic acid and similar acids; or (2) salts formed when an acidic proton present in the parent compound is: (a) replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, or an alkali metal or alkaline earth metal hydroxide, such as sodium, potassium, calcium, magnesium, aluminum, lithium, zinc and barium hydroxides, ammonia, or (b) is coordinated with an organic base, such as an aliphatic, alicyclic or aromatic organic amine, 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 the like.

[0887] Pharmaceutically acceptable salts also include, for example, but not limited to, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and, when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrohalides, for example, hydrochlorides and hydrobromides, sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoate, picric acid, In some embodiments, the pharmaceutically acceptable salts of the compounds and modified oligonucleotides disclosed herein are sodium or potassium salts. 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.

[0888] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. 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, which allow the compounds to be converted into base or acid addition salts.

[0889] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this disclosure, the salts are otherwise equivalent to the parent form of the compound.

[0890] In addition to salt forms, the present disclosure provides compounds in the form of prodrugs. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide compounds of the present disclosure. Additionally, prodrugs can be converted to compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, the prodrug can be slowly converted to a compound of the present disclosure.

[0891] Certain compounds of the present disclosure can exist in unsolvated forms as well as 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 can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the purposes contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0892] The present disclosure also provides a pharmaceutical composition comprising an effective amount of a compound as described herein and a pharmaceutically acceptable excipient. In one embodiment, a compound of any formula provided herein is administered to a subject using a pharmaceutically acceptable formulation, for example, 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, one week, two weeks, three weeks, or four weeks after administration of the pharmaceutically acceptable formulation to the subject.

[0893] Actual dosage levels and time courses of administration of the active ingredients in the pharmaceutical compositions 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 acceptably tolerated by the subject.

[0894] In use, at least one compound according to the present disclosure is administered to a subject in need thereof in a pharmaceutical carrier in a pharmaceutically effective amount by intravenous, intrathecal, intramuscular, subcutaneous or intracerebroventricular injection or by oral administration or topical administration. According to the present disclosure, the compounds of the present disclosure can be administered alone or in combination with a second different therapeutic agent. The so-called "combination" means together, substantially simultaneously or sequentially. In one embodiment, the compounds of the present disclosure are administered acutely. Therefore, the compounds of the present disclosure can be administered within a short course of treatment, such as from about 1 day to about 1 week. In another embodiment, the compounds of the present disclosure can be administered over a longer period of time to improve chronic conditions, such as from about one week to several months, depending on the condition to be treated.

[0895] As used herein, the so-called "pharmaceutically effective amount" means that within the scope of reasonable medical judgment, the amount of the compound of the present disclosure is high enough to significantly and actively change the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit / risk ratio). The pharmaceutically effective amount of the compound of the present disclosure will vary with the specific goals to be achieved, the age and physical condition of the patient to be treated, the severity of the underlying disease, the duration of treatment, the nature of the concurrent therapy, and the specific compound used. For example, the therapeutically effective amount of the compound of the present disclosure administered to a child or a newborn will be proportionally reduced according to reasonable medical judgment. Therefore, the effective amount of the compound of the present disclosure will be the minimum amount that will provide the desired effect.

[0896] A definite practical advantage of the present disclosure is that the compounds can be administered in a convenient manner, such as by intrathecal, intravenous, intramuscular, subcutaneous, oral or intraventricular injection routes or by topical application, such as in a cream or gel. Depending on the route of administration, it may be necessary to coat the active ingredient comprising the compounds of the present disclosure in a material to protect the compounds from enzymes, acids, and other natural conditions that may inactivate the compounds. In order to administer the compounds of the present disclosure by non-parenteral administration, the compounds may be coated with or administered with a material that prevents inactivation.

[0897] 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.

[0898] Some examples of substances that can be used as pharmaceutical excipients or pharmaceutical carriers (the 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 carboxymethylcellulose, ethylcellulose, 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, glycerol, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; and phosphate buffered saline; skim milk powder; and other nontoxic, compatible substances used in pharmaceutical formulations, such as vitamin C, estrogen, and echinacea. Wetting agents and lubricants such as sodium lauryl sulfate may also be present, as well as colorants, flavorings, lubricants, excipients, tableting agents, stabilizers, antioxidants, and preservatives. Solubilizing agents including, for example, cremaphore and beta-cyclodextrin may also be used in the pharmaceutical compositions herein.

[0899] The pharmaceutical composition comprising the active compound of the present disclosure (or its prodrug) can be prepared by conventional mixing, dissolving, granulating, making dragees, grinding, emulsifying, encapsulating, embedding or lyophilizing methods. Compositions can be prepared in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients or adjuvants, which contribute to the processing of active compounds into pharmaceutically usable preparations. Compositions herein can be prepared (for example, for pharmaceutical, agricultural or veterinary use) by combining a compound as described herein with one or more suitable carriers, diluents, excipients or adjuvants (including those described herein) (for example, contacting, mixing, dissolving, granulating, making dragees, grinding, emulsifying, encapsulating, embedding or lyophilizing).

[0900] The pharmaceutical compositions of the present disclosure can take a form suitable for virtually any mode of administration, including, for example, intrathecal, topical, ocular, oral, buccal, systemic, nasal, parenteral, transdermal, rectal, vaginal, etc., or a form suitable for administration by inhalation or insufflation.

[0901] Systemic formulations include those designed for administration by injection (eg, subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection), as well as those designed for transdermal, transmucosal, oral, or pulmonary administration.

[0902] Useful injectable formulations include sterile suspensions, solutions or emulsions of the active compound in aqueous or oily vehicles. The composition also contains a preparaton, such as a suspending agent, a stabilizer and / or a dispersant. The formulation for injection can be in unit dosage form (e.g., in an ampoule or in a multidose container) and may contain an added preservative.

[0903] Alternatively, the injectable formulation may be provided in powder form for reconstitution before use with a suitable vehicle including, but not limited to, sterile pyrogen-free water, buffer, dextrose solution, etc. To this end, the active compound may be dried by any technique known in the art, such as lyophilization, and reconstituted before use.

[0904] In order to prolong delivery, the active compound or prodrug can be formulated as a depot preparation for administration by implantation or intramuscular injection. The active ingredient can be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or ion exchange resin, or as a sparingly soluble derivative, such as a sparingly soluble salt.

[0905] Alternatively, other drug delivery systems can be used. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver active compounds, oligonucleotides or prodrugs. Certain organic solvents, such as dimethyl sulfoxide (DMSO), can also be used.

[0906] If desired, the pharmaceutical composition may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active compound. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.

[0907] The active compounds or prodrugs of the present invention or their compositions will generally be used in an amount that is effective to achieve the desired result, for example, in an amount that is effective to treat or prevent the specific disease being treated. The compounds and oligonucleotides can be administered therapeutically to achieve a therapeutic benefit or prophylactically to achieve a preventive benefit. The so-called therapeutic benefit means eradication or improvement of the underlying condition being treated and / or eradication or improvement of one or more symptoms associated with the underlying condition, such that the patient reports an improvement in feeling or condition, although the patient may still be suffering from the underlying condition. Therapeutic benefit also includes stopping or slowing the progression of the disease, regardless of whether improvement is achieved.

[0908] For prophylactic administration, the compound can be administered to a patient at risk of developing one of the aforementioned diseases. A patient at risk of developing a disease can be a patient with characteristics that place the patient in a designated group of risk patients, as defined by appropriate medical professionals or groups. A patient at risk can also be a patient who is typically or routinely exposed to conditions that may lead to the development of the underlying disease. In other words, an at-risk patient is a patient who is typically or routinely exposed to conditions that cause the disease or condition, or who may be acutely exposed for a limited period of time. Alternatively, prophylactic administration can be used to prevent the onset of symptoms in a patient diagnosed with an underlying condition.

[0909] The amount of compound administered will depend on a variety of factors including, for example, the particular indication being treated, the mode of administration, whether the desired benefit is prophylactic or therapeutic, the severity of the indication being treated, the age and weight of the patient, the bioavailability of the particular active compound, etc. The determination of an effective dosage is well within the capability of those skilled in the art.

[0910] Effective doses can be estimated initially from in vitro assays. For example, an initial dose for use in animals can be formulated to achieve circulating blood or serum concentrations of the active compound that are equal to or higher than the IC of the specific compound measured in in vitro assays such as in vitro fungal MIC or MFC and other in vitro assays. 50 Calculating dosages to achieve such circulating blood or serum concentrations, taking into account the bioavailability of a particular compound, is within the capabilities of those skilled in the art. For guidance, see "General Principles" in Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pages 1-112, 13th ed., McGraw-Hill, and references cited therein, which are incorporated herein by reference.

[0911] Initial dosages can also be estimated from in vivo data such as animal models.Animal models useful for testing the efficacy of compounds in treating or preventing the various diseases mentioned above are well known in the art.

[0912] Dosages will generally be in the range of about 0.0001 or 0.001 or 0.01 mg / kg / day to about 100 mg / kg / day, but may be higher or lower, depending on the activity of the compound, its bioavailability, mode of administration, and the various factors mentioned above. Dosage and interval can be adjusted individually to provide plasma levels of the compound sufficient to maintain a therapeutic or prophylactic effect. In the case of local administration or selective uptake such as topical administration, the effective local concentration of the active compound cannot be related to the plasma concentration. A skilled person will be able to optimize the effective local dose without undue experimentation.

[0913] Preferably, the compound will provide therapeutic or preventive benefit and will have acceptable tolerability. The tolerability of compounds and oligonucleotides can be determined using standard pharmaceutical methods. The dose ratio between intolerable and therapeutic (or preventive) effects is the therapeutic index. Compounds that exhibit a high therapeutic index are preferred.

[0914] The recitation of a list of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment of a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0915] Example

[0916] In order to make the embodiments described herein more fully understood, the following examples are listed. The examples described in this application are provided to illustrate the compounds, compositions and methods provided herein and should not be interpreted in any way as limiting their scope. The following examples and the associated sequence listings accompanying this application can identify sequences as "RNA" or "DNA"; however, as disclosed herein, these sequences can be modified with any combination of chemical modifications. Those skilled in the art will readily understand that, in some cases, naming a sequence as "RNA" or "DNA" is arbitrary. For example, an oligonucleotide comprising a nucleoside containing a 2'-OH sugar moiety and a thymine base can be described as a DNA with a modified sugar (2'-OH is used for the natural 2'-H of DNA) or as an RNA with a modified base (methylated uracil is used for the natural uracil of RNA). Therefore, the nucleic acid sequences provided herein (including but not limited to those in the sequence listing) are intended to encompass nucleic acids containing any combination of natural or modified RNA and / or DNA, including but not limited to such nucleic acids with modified nucleobases.

[0917] General experimental steps

[0918] The definitions of the variables in the structures in the schemes herein are comparable to those at corresponding positions in the formulae described herein.

[0919] Common abbreviations:

[0920] A Adenine

[0921] ACN acetonitrile

[0922] br broad peak

[0923] C cytosine

[0924] CDI Carbonyldiimidazole

[0925] d Twin Peaks

[0926] DCM dichloromethane

[0927] dd doublet

[0928] dba dibenzylideneacetone

[0929] DBCO Azadibenzocyclooctyne

[0930] DFAA difluoroacetic anhydride

[0931] DIPEA or DIEA diisopropylethylamine

[0932] DMF dimethylformamide

[0933] DMSO dimethyl sulfoxide

[0934] DMT or DMTr dimethoxytrityl

[0935] dppf 1,1'-ferrocenediyl-bis(diphenylphosphine)

[0936] EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0937] EtOAc

[0938] G Guanine

[0939] h hour

[0940] I2O iodine pentoxide

[0941] HRMS High Resolution Mass Spectrometry

[0942] HPLC high-performance liquid chromatography

[0943] LCMS liquid chromatography-mass spectrometry

[0944] MPLC Medium Pressure Liquid Chromatography

[0945] MSCl methanesulfonyl chloride

[0946] MS

[0947] MW microwave

[0948] m multiplet

[0949] MeOH methanol

[0950] min

[0951] mL milliliters

[0952] MWCO molecular weight cut-off

[0953] m / z mass-to-charge ratio

[0954] NB New Main Chain

[0955] NMP N-Methyl-2-pyrrolidone

[0956] NMR Nuclear Magnetic Resonance

[0957] ppm parts per million

[0958] Py pyridine

[0959] Rf retention factor

[0960] rt or room temperature

[0961] R t Retention time

[0962] s single peak

[0963] t Triplet

[0964] U uracil

[0965] TBD Triazabicyclodecene

[0966] TBS or TBDMS tert-butyldimethylsilyl

[0967] TEA triethylamine

[0968] TFAA trifluoroacetic anhydride

[0969] TLC thin layer chromatography

[0970] Example 1: General synthetic procedure

[0971] NB chains were synthesized on a solid phase using an oligonucleotide synthesizer, Oligopilot 100 (Cytiva Life Sciences). Solid supports (CPG, 80-90 μmol / g, 500 Å) were purchased from LGC-Biosearch Technologies, Petaluma, CA, and loaded to a 150-300 μmol scale. All RNA and 2'-modified RNA phosphoramidites were purchased from Hongene Biotech (Union City, CA). Specifically, 2'-O-methylphosphoramidites contained 5'-O-(4,4'-dimethoxytrityl)-N 6 -benzoyl-2'-O-methyl-adenosine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'-O-(4,4'-dimethoxytrityl)-N 4 -acetyl-2'-O-methyl-cytidine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'-O-(4,4'-dimethoxytrityl)-N 2 -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. In addition, 2'-fluoro contains 5'-O-(4,4'-dimethoxytrityl)-N 6 -benzoyl-2'-fluoroadenosine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'-O-(4,4'-dimethoxytrityl)-N 4 -acetyl-2'-fluorocytidine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'-O-(4,4'-dimethoxytrityl)-N 2-isobutyryl-2'-fluoroguanosine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite and 5'-O-(4,4'-dimethoxytrityl)-2'-fluorouridine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite. To generate phosphorothioate linkages, a 0.1 M solution of 3-((dimethylamino-methylene)amino)-3H-1,2,4-dithiazole-3-thione (DDTT, obtained from Chemgenes, Wilmington, MA) was used for 4-6 minutes, and to generate phosphodiester linkages, a 0.05 M 12O solution in pyridine / water (Sigma Aldrich, St Louis, MO) was used. After oxidation / sulfurization, any unreacted chains attached to the CPG were acetylated using a mixture of 20% n-methylimidazole in acetonitrile and 40% acetic anhydride in 60% lutidine in acetonitrile (Sigma Aldrich, St Louis, MO).

[0972] The phosphoramidite was dissolved in anhydrous acetonitrile (0.2 M), molecular sieves (4A) were added and allowed to stand overnight (Sigma Aldrich, St. Louis, MO). For the oligonucleotide chain, 5-(ethylthio)-1H-tetrazole (ETT, 0.6 in acetonitrile, obtained from Sigma Aldrich) was used as an activator solution. The NB modification of the chain (0.15 M, provided internally) was dissolved in dichloromethane:acetonitrile (3: 1) and the reaction was carried out to completion using 5-(ethylthio)-1H-tetrazole solution (ETT, 0.6 M in acetonitrile, obtained from Sigma Aldrich). The coupling time was 60 minutes (NB) and 6 minutes (2'-O-Me / 2'-Fluoro), with each step being carried out with 3.0 equivalents. Prior to coupling, the carrier-bound oligonucleotide was treated with a dichloroacetic acid solution in dichloromethane (3% Deblock, Sigma Aldrich) and washed with anhydrous acetonitrile.

[0973] Cleavage and deprotection of support-bound oligomers.

[0974] After the solid phase synthesis was completed, the support was treated with an AMA solution, a 1:1 volume solution of NH4OH:CH3NH2 (Fisher Scientific, Spectrum Chemicals) at 65° C. for 20 minutes and then the solution was evaporated.

[0975] Prior to purification, in-process analysis was performed on analytical HPLC and LCMS to document the approximate purity of the crude material and to identify the target mass of the oligonucleotide and to monitor the completion of deprotection by LCMS.

[0976] LCMS method

[0977] LCMS conditions: The column used was a Waters XBridge Oligonucleotide BEH C18 column, 2.5 μm, 2.1 mm x 50 mm (P / N 186003952). The buffer solution was 400 mM HFIP + 15 mM TEA (buffer A) and 100% methanol (buffer B). The gradient was set at 5% to 50% buffer B in 2 minutes at 70°C, with a flow rate of 0.5 mL / min.

[0978] TFF concentration

[0979] The crude oligomers were then concentrated using a Pall Minimate EVO system (Product ID: OAPMPUNV).The cassette used was a Pall Minimate TFF capsule with 3k Omega membrane.

[0980] purification

[0981] Purification was performed using reverse phase HPLC. The column used was a Phenomenex Clarity 5 μm Oligo-RP AXIOS, 250 x 30 mm (P / N: 00G-4442-U0-AX). The buffer mixture was 100 mM TEAA, 5% ACN at pH 7.0 (buffer A), and 1:1 acetonitrile:methanol (buffer B). The gradient was set at 60° C. from 5% to 30% buffer B over 60 minutes at a flow rate of 20 mL / min.

[0982] After purification, fractions were analyzed using reverse-phase UPLC. The column used was a Waters ACQUITY UPLC oligonucleotide BEH C18 1.7 μm, 2.1 x 50 mm (P / N: 186003949). The buffer solution mixture was 100 mM TEA, 5% ACN, pH 7.0 (buffer A), and 1:1 acetonitrile:methanol (buffer B). The gradient was set at 80°C from 5% to 30% buffer B over 5 minutes, with a flow rate of 1.0 mL / min. The minimum specification of the purification pool was 85%.

[0983] Desalination

[0984] Once the pool is established, the oligomers are desalted using a Pall Minimate EVO system (Product ID: OAPMP UNV). The cartridge used is a Pall Minimate TFF capsule with a 3k Omega membrane (Product ID: OA003C12). The retentate is collected for lyophilization or direct annealing. After lyophilization, an off-white powder is obtained.

[0985] Example 2: Synthesis of dinucleotide 18.

[0986]

[0987] Synthesis of 2

[0988] A solution of 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione 1 (5 g, 20.309 mmol, 1 eq) in pyridine (50 mL) was treated with DMTr-Cl (6.54 g, 21.324 mmol, 1.05 eq) at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography using CHCN / H0 to give DMT ether 2 (9.5 g, 85.27%) as a light yellow powder.

[0989] Synthesis of 3

[0990] Under nitrogen atmosphere at 0 ℃, a solution of 2 (20 g, 36.459 mmol, 1 eq) in DCM (680 mL) was treated with pyridine (10.09 g, 127.607 mmol, 3.5 eq) for 5 minutes, followed by the dropwise addition of Tf2O (17.00 g, 60.256 mmol, 1.65 eq) at 0 ℃. The resulting mixture was extracted three times with CHCl. ​​The combined organic layers were washed with saturated aqueous CuSO4 and dried over anhydrous Na2SO4. 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.

[0991] Synthesis of 4

[0992] To a solution of trifluoromethanesulfonate 3 (20.8 g, 30.560 mmol, 1 equivalent) in dioxane (450 mL) was added NaOH (17.11 mL, 171.136 mmol, 10 N, 5.60 equivalents) and water (83.86 mL, 4654.899 mmol, 152.32 equivalents). 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM / MeOH / EA to give product 4 (10.0 g, purity: 90%, two steps: 45%) as a light yellow foam.

[0993] Synthesis of 5

[0994] 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) under a nitrogen atmosphere at 0 ° C. The reaction was stirred overnight. The resulting mixture was poured into a saturated NaHCO solution and extracted with CHCl. ​​The combined organic layers were washed with CuSO and brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (50: 1) to give compound 5 (1.95 g, 85%) as a light yellow foam.

[0995] Synthesis of 6

[0996] To a solution of 5 (2 g, 3.192 mmol, 1 eq) in DMF (68 ml, 869.373 mmol, 272.36 eq) was added NaN3 (1.45 g, 22.344 mmol, 7 eq). The mixture was stirred at 90 ° C for 2 days under a nitrogen atmosphere. The resulting mixture was then poured into a NaHCO3 solution and extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (200: 1) to give azide 6 (1.2 g, purity: 67%) as a light yellow oil.

[0997] Synthesis of 7

[0998] Under nitrogen atmosphere, to a solution of azide 6 (5.65 g, 67% purity, 1 equivalent) in 56 ml MeOH was added Pd / C (10%, 0.57 g) in a 250 mL round-bottom flask. Under hydrogen atmosphere, the mixture was stirred for 5 hours at room temperature 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 CHCN / HO to give amine 7 (2.74 g, 51%) as a white solid.

[0999] Synthesis of 8

[1000] A mixture of aldehyde (0.464 g, 1.828 mmol, 1 equivalent), amine (1 g, 1.828 mmol, 1 equivalent) and Et3N (0.76 mL, 5.48 mmol, 3 equivalents) in DCE / MeOH (20 / 5 mL) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (581 mg, 2.74 mmol, 1.5 equivalents) was added and the mixture was stirred at room temperature for 48 hours. LCMS showed 50%-60% conversion. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution 100 mL, extracted with DCM 200 mL, concentrated, and the residue was purified by column chromatography using 0-10% MeOH / DCM to obtain an inseparable mixture of product and starting material 1.16 g 80% as a white solid, which was used in the next step as it was. NMR and LCMS m / z 787 (M+1) corresponded to the product.

[1001]

[1002] Synthesis of 10

[1003] At 0 ° C, imidazole (6.06 g, 89 mmol, 2.5 eq) and TBSCl (8.07 g, 54 mmol, 1.5 eq) were added as solids to a solution of alcohol 9 (20.0 g, 35.7 mmol, 1 eq) in anhydrous pyridine (200 mL). After 21 hours, 14% SM was retained and additional TBSCl (1.77 g, 11.8 mmol, 0.33 eq) was added at 0 ° C, followed by stirring at room temperature. After 4 hours, the reaction mixture was concentrated under reduced pressure at 40 ° C. The resulting slurry was poured into stirred water (200 mL) and then extracted with ethyl acetate (150 mL). The aqueous layer was extracted with ethyl acetate (2x100 mL). The combined organic extracts were washed with saturated NaCl (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude TBS ether 10 (24 g), which was used without further purification.

[1004] Synthesis of 11

[1005] At 0 ° C, TFA (10 mL, 124 mmol, 7 equivalents) was added dropwise to a solution of crude DMT ether 10 (12 g, 17.9 mmol, 1 equivalent) in DCM (100 mL). The reaction mixture was then stirred at room temperature. After 1 hour, the reaction mixture was poured into stirred saturated NaHCO (300 mL). The aqueous layer was extracted with DCM (2x100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel FCC (0 → 60% ethyl acetate in hexane) to obtain alcohol 11 (5.33 g) as a white solid. The procedure was repeated for the remaining 12 g of crude DMT ether 10, and alcohol 11 (10.4 g, 78% yield for two steps) was obtained after merging.

[1006] Synthesis of 12

[1007] Alcohol 11 (1.5g, 4.03mmol, 1 equivalent) was dissolved in anhydrous DCM (40mL) by ultrasonic treatment. Then, solid Dess-Martin periodinane (2.14g, 5.03mmol, 1.25 equivalents) was added once to give a pink / salmon suspension. After 3.5 hours, the reaction mixture was poured into the stirred saturated sodium thiosulfate (150mL) and extracted with DCM (60mL). The organic layer was washed with saturated sodium bicarbonate (150mL) and saturated NaCl (150mL). The aqueous layer was extracted separately with DCM (2x100mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude aldehyde 12 (1.57g) as a white solid, which was used without further purification.

[1008] Synthesis of 13

[1009] At room temperature, triphenylethoxyformylmethylenephosphine (1.76g, 5.06mmol, 1.25 equivalents) was added as a solid to a suspension of crude aldehyde 12 (1.5g, 4.05mmol, 1 equivalent) in anhydrous THF (40mL). After 16 hours, the reaction mixture was concentrated under reduced pressure at 30°C to remove THF. The resulting residue was extracted with ethyl acetate (100mL) and washed with water (50mL) and saturated NaCl (50mL). The aqueous layer was extracted with EtOAc (50mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel FCC (0→50% ethyl acetate / hexane) to obtain ester 13 (1.24g, 70% yield in 2 steps, 20:1E / Z ratio obtained by UV).

[1010] Synthesis of 14

[1011] A solution of alkene 13 (1.24 g, 2.81 mmol, 1 equivalent) in methanol (20 mL) was evacuated and backfilled with nitrogen, and palladium on carbon (300 mg, 0.28 mmol, 0.1 equivalent) was added. The reaction mixture was then evacuated and backfilled with hydrogen from a balloon. After stirring for 75 minutes, the reaction mixture was filtered through diatomaceous earth and rinsed with methanol. The filtrate was concentrated under reduced pressure to give ester 14 (1.17 g, 94% yield) as a white foam, which was used without further purification.

[1012] Synthesis of 15

[1013] At room temperature, a solution of sodium hydroxide (528 mg, 13.2 mmol, 5 equivalents) in water (1 mL) was added dropwise to a solution of crude ester 14 (1.17 g, 2.64 mmol, 1 equivalent) in methanol (10 mL). After 1.5 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water (about 20 mL) to give a white precipitate. The reaction mixture was cooled to 0 ° C under stirring and then acidified by the addition of 1N HCl (14 mL) to obtain pH = 3-4. The reaction mixture was then extracted with DCM (3x50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give carboxylic acid 15 (1.03 g, 94% yield) as a white foam.

[1014] Example 3. Synthesis of dinucleotides NB-101, NB-105, NB-106 and NB-107.

[1015]

[1016] Alcohol 1 (3.0 g, 4.274 mmol, 1 eq), 1,1′ carbonyldiimidazole (1.386 g, 8.548 mmol, 2 eq) and DMAP (1.044 g, 8.548 mmol, 2 eq) were dissolved in dichloromethane (50 mL). After stirring at room temperature for 14 h, the reaction mixture was washed with saturated NH4Cl and extracted with DCM (2×). The combined organic layers were dried over Na2SO4 and concentrated to give 3.5 g of crude product 2 as a white solid, which was used in the next step without purification.

[1017] Compound 2 (1.2g, 1.508mmol, 1 equivalent) and amine 3 (0.663g, 1.809mmol, 1.2 equivalents) are dissolved in anhydrous pyridine (20mL) and evaporated to dryness. The residue is redissolved in anhydrous pyridine (15mL). DMAP (184mg, 1.508mmol, 1 equivalent) is added to the reaction. After stirring at room temperature for 60 hours, the reaction mixture is concentrated under reduced pressure. The residue is washed with saturated NaHCO3. The aqueous phase is extracted with DCM (1X). The combined organic layer is dried with Na2SO4, filtered and concentrated. The residue is purified by silica gel chromatography (50g, 20 μm) using 0-10% MeOH / DCM. The pure fractions are combined, concentrated and dried under high vacuum to obtain 0.7g carbamate 4 (42%) as a white solid.

[1018] To a stirred solution of carbamate 4 (0.7g, 0.64mmol, 1 equivalent) and diisopropylethylamine (0.724mL, 4.158mmol, 6.5 equivalents) in anhydrous DCM (10mL) was added dropwise N,N-diisopropylchlorophosphoramidite (0.428mL, 0.432mmol, 3 equivalents). The reactant was stirred at room temperature for 2 hours, and LCMS showed that the reaction was complete. The reaction was quenched with saturated NaHCO solution and distributed between DCM and saturated NaHCO. The DCM phase was collected. The aqueous phase was extracted with DCM (1x). The organic phase merged was dried over Na2SO4, filtered and concentrated. The residue was loaded onto a pre-equilibrated (2% Et3N-DCM) biotage silica gel column (25g, 20 μm) and purified by flash chromatography using 0-10% MeOH / DCM containing 2% Et3N as an additive. The pure fractions were combined, concentrated and dried under high vacuum to give 610 mg (74%) of phosphoramidite NB-101. MS: m / z = 1316.1 [M+Na] + P31-NMR and H1-NMR were consistent with the product.

[1019]

[1020] Alcohol 5 (1.0 g, 1.784 mmol, 1 equivalent), 1,1′ carbonyldiimidazole (0.578 mg, 3.568 mmol, 2 equivalents) and DMAP (0.436 mg, 3.568 mmol, 2 equivalents) were dissolved in dichloromethane (20 mL). After stirring overnight at room temperature, the reaction mixture was washed with saturated NH4Cl and extracted with DCM (2×). The combined organic layers were dried over Na2SO4 and concentrated to give 1.2 g of crude product 6 as a white solid, which was used directly in the next step without purification.

[1021] Compound 6 (0.75g, 1.146mmol, 1 equivalent) and amine 7 (0.578g, 1.203mmol, 1.05 equivalent) are dissolved in anhydrous pyridine (20mL) and evaporated to dryness. The residue is redissolved in anhydrous pyridine (15mL). DMAP (140mg, 1.146mmol, 1 equivalent) is added to the reaction. After stirring at room temperature for 18 hours, the reaction mixture is concentrated under reduced pressure. The residue is distributed between saturated NaHCO and DCM. The aqueous phase is extracted with DCM (1X). The combined organic layer is dried with NaSO, filtered and concentrated. The residue is purified by silica gel chromatography (50g, 20 μm) using 0-10% MeOH / DCM. The pure fractions are combined, concentrated and dried under high vacuum to obtain 0.91g carbamate 8 (74%) as a white solid.

[1022] Carbamate 8 (530mg, 0.497mmol, 1 equivalent) is dissolved in THF (5mL). TBAF (0.754mL, 0.754mmol, 1.5 equivalents) is added to the reaction. The reactant is stirred at room temperature for 2 hours. LCMS shows that some SM is still left. Additional TBAF (0.251mL, 0.251mmol, 0.5 equivalents) is added to the reaction. The reactant is stirred for 1 hour. LCMS shows that the reaction is complete. The reactant is concentrated under reduced pressure. The residue is purified by silica gel chromatography (25g, 20 μm) using a DCM solution of 0-5-10% MeOH to give 309mg product compound 9 (60%) as a white solid.

[1023] To a stirred solution of carbamate 9 (0.493g, 0.517mmol, 1 equivalent) and diisopropylethylamine (0.586mL, 3.363mmol, 6.5 equivalents) in anhydrous DCM (10mL), 2-cyanoethyl N, N-diisopropyl chlorophosphoramidite (0.346mL, 1.551mmol, 3 equivalents) was added dropwise. The reactant was stirred at room temperature for 1 hour, and LCMS showed that some carbamate 9 was still remaining. Other 2-cyanoethyl N, N-diisopropyl chlorophosphoramidite (0.115mL, 0.517mmol, 1 equivalent) was added dropwise. The reactant was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. The reaction was quenched with saturated NaHCO solution, and distributed between DCM and saturated NaHCO. The DCM phase was collected. The aqueous phase was extracted with DCM (2x). The organic phase merged was dried over NaSO, filtered and concentrated. The residue was loaded onto a pre-equilibrated (1% Et3N-DCM) biotage silica gel column (25 g, 20 μm) and purified by flash chromatography using 0-10% MeOH / DCM containing 1% Et3N as an additive. Pure fractions were combined, concentrated, and dried under high vacuum to yield 520 mg (84%) of phosphoramidite NB-105 (95% HPLC purity). MS: m / z = 1152.9 [M] + P31-NMR and H1-NMR were consistent with the product.

[1024]

[1025] To a suspension of amine 10 (1.044 g, 2.172 mmol, 1 equivalent) and heptadecanal (0.608 g, 2.389 mmol, 1.1 equivalents) in DCE (50 mL), NaBH (OAc) was added (0.691 g, 3.258 mmol, 1.5 equivalents), followed by the addition of 5 drops of AcOH. The reactant was stirred at room temperature for 16 hours. LCMS showed a small amount of SM remaining. 5 mL of MeOH was added to the reaction (to help dissolve). The reactant was stirred at room temperature for 3 hours. LCMS showed no change. The reactant was diluted with DCM and washed with NH4Cl (1x) and NaHCO3 (1x) successively. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to remove the solvent. Residue was purified by silica gel chromatography (50 g, 60 μm) using 0-15% MeOH / DCM (15CV). Pure fractions were combined, concentrated and dried under high vacuum to afford 0.912 g of 11 as a white solid.

[1026] Compound 6 (455 mg, 0.695 mmol, 1 eq) and amine 11 (400 mg, 0.556 mmol, 0.8 eq) were dissolved in anhydrous pyridine (3 mL). DMAP (85 mg, 0.695 mmol, 1 eq) was added to the reaction. The reactants were stirred at 95 ° C for 40 hours. LCMS showed about 60% conversion of SM 6. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between DCM and 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 (25 g, 20 μm) using a DCM solution of 0-10% MeOH (containing 1% Et 3 N) to give 480 mg of carbamate 12 (66%) as a slightly yellow solid. MS: m / z = 1327.4 [M + Na] + .

[1027] Carbamate 12 (480 mg, 0.368 mmol, 1 eq) was dissolved in THF (5 mL). TBAF (0.735 mL, 0.735 mmol, 2 eq) was added to the reaction. The reactants were stirred at room temperature for 2 hours. LCMS showed that some SM was still left. Additional TBAF (0.187 mL, 0.187 mmol, 0.5) was added to the reaction. The reactants were stirred for 1 hour. LCMS showed that the reaction was complete. The reactants were concentrated under reduced pressure. The crude product was purified by silica gel chromatography (25 g, 20 μm) (2X) using a 0-10% MeOH solution in DCM to give 168 mg of product 13 as a white solid. MS: m / z=1212.7 [M+Na] +

[1028] 2-cyanoethyl N, N-diisopropyl chlorophosphoramidite (0.088mL, 0.395mmol, 3 equivalents) is added dropwise to a stirred solution of carbamate 13 (157mg, 0.132mmol, 1 equivalent) and diisopropylethylamine (0.149mL, 0.857mmol, 6.5 equivalents) in anhydrous DCM (5mL). Reactant is stirred at room temperature for 6 hours, and LCMS shows that approximately 6% carbamate 13 is still remaining. Reactant is stirred at room temperature overnight. LCMS shows that the reaction is complete (approximately 0.5% SM 13). The reaction is quenched with saturated NaHCO solution, and distributed between DCM and saturated NaHCO. Collect the DCM phase. Extract the aqueous phase with DCM (1x). The organic phase merged is through Na2SO4 dried, filtered and concentrated. The residue was loaded onto a pre-equilibrated (1% Et3N-DCM) biotage silica gel column (25 g, 20 μm) and purified by flash chromatography using 0-10% MeOH / DCM containing 1% Et3N as an additive. Pure fractions were combined, concentrated, and dried under high vacuum to yield 120 mg (65%) of phosphoramidite NB-106. (92% HPLC purity. MS: m / z = 1413.2 [M+Na]) + P31-NMR and H1-NMR were consistent with the product.

[1029]

[1030] Alcohol 14 (1.0 g, 1.507 mmol, 1 eq), 1,1′ carbonyldiimidazole (0.489 g, 3.013 mmol, 2 eq) and DMAP (0.368 g, 3.013 mmol, 2 eq) were dissolved in dichloromethane (15 mL). After stirring at room temperature for 14 h, the reaction mixture was washed with saturated NH₄Cl and extracted with DCM (2×). The combined organic layers were dried over Na₂SO₄ and concentrated to give 1.2 g of crude product 15 as a white solid, which was used in the next step without purification.

[1031] Compound 15 (1.15g, 1.518mmol, 1 equivalent) and amine 16 (0.41g, 1.593mmol, 1.05 equivalent) are dissolved in anhydrous pyridine (12mL). DMAP (185mg, 1.518mmol, 1 equivalent) is added to the reaction. After stirring for 20 hours, another amine 16 (41mg, 0.159mmol, 0.1 equivalent) is added to the reaction, and the reactant is stirred for 3 hours. The reaction mixture is concentrated under reduced pressure. The residue is distributed between saturated NaHCO and DCM. The aqueous phase is extracted with DCM (1X). The combined organic layer is dried with NaSO, filtered and concentrated. The residue is purified by silica gel chromatography (50g, 20 μm) using 0-10% MeOH / DCM. The pure fractions are combined, concentrated and dried under high vacuum to obtain 0.97g carbamate 17 (68%) as a white solid.

[1032] 2-cyanoethyl N, N-diisopropylchlorophosphoramidite (0.636mL, 2.851mmol, 3 equivalents) was added dropwise to a stirred solution of carbamate 17 (0.9g, 0.95mmol, 1 equivalent) and diisopropylethylamine (0.993mL, 3.7mmol, 6 equivalents) in anhydrous DCM (10mL). The reactant was stirred at room temperature for 45 minutes, and LCMS showed that the reaction was complete. The reaction was quenched with saturated NaHCO solution and distributed between DCM and saturated NaHCO. The DCM phase was collected. The aqueous phase was extracted with DCM (2x). The organic phase merged was dried over NaSO, filtered and concentrated. The residue was loaded onto a pre-equilibrated (1% EtN-DCM) biotage silica gel column (50g, 20 μm) and purified by flash chromatography using 0-10% MeOH / DCM containing 1% EtN as an additive. The pure fractions were combined, concentrated and dried under high vacuum to give 920 mg (84%) of phosphoramidite NB-107 (98% HPLC purity). MS: m / z = 1152.9 [M] + P31-NMR and H1-NMR were consistent with the product.

[1033] Example 4: Synthesis of triazole dinucleotide 9.

[1034]

[1035] Synthesis of 2

[1036] To a stirred solution of alcohol 1 (7.2g, 10.86mmol) in pyridine (25ml), imidazoles (1.9g, 28.23mmol, 2.6 equivalents) were added, followed by TBDMS-Cl (2.12g, 14.11mmol, 1.3 equivalents), and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with DCM 100ml, washed with water 50mL, saline solution 50mL. The organic layer was concentrated, and the residue was co-evaporated with toluene, dried under high vacuum to obtain TBS ether 2 (8.44g, quantitative) as an orange solid, which was used in the next step as it was. The product was confirmed by LCMS. m / z 778 (M+1).

[1037] Synthesis of 3

[1038] To a solution of compound 2 (8.44 g, 10.84 mmol, 1.00 equivalent) in DCM (50 mL) was added TFA (1.82 mL, 23.86 mmol, 2.20 equivalents). The color of the solution turned red. Et3SiH (1.9 mL, 11.93 mmol, 1.1 equivalents) was added at 25 ° C. The reaction mixture was stirred at 25 ° C for 5 hours, and the red solution became colorless. The solvent was removed under reduced pressure, and the residue was dissolved in EtOAc (100 mL). The organic phase was washed with NaHCO3 (40 mL), brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography using 0-100 EtOAc / hexane as eluent, and the pure fractions were combined and concentrated to give alcohol 3 (3.04 g 59%) as a white solid. The product was confirmed by NMR and LCMS. M / z 476 (M+1).

[1039] Synthesis of 4

[1040] Cytosine 5'-ol 3 (0.7 g, 1.474 mmol, 1 eq), triphenylphosphine (0.773 g, 2.947 mmol, 2 eq) and sodium azide (0.383 g, 5.895 mmol, 4 eq) were suspended in anhydrous DMF (20 mL), and carbon tetrabromide (0.977 g, 2.947 mmol, 2 eq) was added to the suspension. After stirring at room temperature for 3 hours, the solvent was evaporated to concentrate. The residue was purified by silica gel column chromatography using ethyl acetate / hexane 0-100% to give azide 4 (556 mg, 75%) as a white foam. NMR and LCMS m / z=501 (M+1) corresponded to the product.

[1041] Synthesis of 6

[1042] To a stirred and cooled (0 ° C) solution of alcohol 5 (3 g, 5.357 mmol, 1 equ...

Claims

1. A compound of formula (I') or a salt thereof: in: A is a substituted tetrahydrofuranyl group, a substituted tetrahydropyranyl ring, or a modified sugar; B is a substituted tetrahydrofuranyl group, a substituted tetrahydropyranyl ring, or a modified sugar; W 1 and W 4 are independently modified or unmodified nucleosides, oligonucleotides, ligands, lipophilic moieties or protecting groups; R 8 and R 9 are independently substituted or unsubstituted heteroaryl; L is a linker, a ligand, a lipophilic part, -Z 1 -YZ 2 - or a combination thereof; W 2 and W 3 are independently 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(R A )-, -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(R A )-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(R A )-、-S(O)2NR A -、-NR A SO2- or their combination; Each R A R is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A The groups are linked to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring with the atoms to which they are attached; Z 1 and Z 2 are independently a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -O-, -OP(O)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 SO2- or their combination; Each R B R is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R B The groups are connected to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; Y is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -O-, -OP(O)O2-, -N(R C )-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR C -、-NR C C(=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)2NR C -、-NR C SO2- or a combination thereof; and Each R C R is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group, or two R C The groups are linked to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

2. The compound or salt thereof according to claim 1, which has formula (VIII):

3. The compound of claim 1 or 2, wherein W 1 It is a modified or unmodified nucleoside.

4. The compound of claim 1 or 2, wherein W 1 For oligonucleotides.

5. The compound of claim 1 or 2, wherein W 1 For the protecting group.

6. The compound of any one of claims 1 to 5, wherein W 4 It is a modified or unmodified nucleoside.

7. A compound as described in any one of claims 1 to 5, wherein W 4 For oligonucleotides.

8. A compound as described in any one of claims 1 to 5, wherein W 4 For the protecting group.

9. The compound of any one of claims 1 to 8, wherein W 2 is the key.

10. The compound of any one of claims 1 to 8, wherein W 2 For the connector.

11. The compound of any one of claims 1 to 8, wherein W 2 is a substituted or unsubstituted heteroalkylene group.

12. A compound as described in any one of claims 1 to 11, wherein W 3 is the key.

13. A compound as described in any one of claims 1 to 11, wherein W 3 For the connector.

14. A compound as described in any one of claims 1 to 11, wherein W 3 is a substituted or unsubstituted heteroalkylene group.

15. The compound of any one of claims 1 to 14, wherein A is substituted tetrahydrofuranyl.

16. A compound as claimed in any one of claims 1 to 15, wherein A has the formula: in: R 2 is -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 、-N(R 6 ) or -SR 6 ; R 8 is a substituted or unsubstituted heteroaryl ring; and Each R 6 and R and R are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

17. The compound of any one of claims 1 to 14, wherein A is a substituted tetrahydropyranyl ring.

18. The compound of any one of claims 1 to 14, wherein A is a modified sugar.

19. The compound of any one of claims 1 to 15, wherein A is a bicyclic sugar.

20. The compound of claim 19, wherein the bicyclic sugar comprises a bridge between the 4' and 2' furanose ring atoms.

21. The compound of claim 19 or 20, wherein the 4' to 2' bridging substituent comprises 4'-(CH2)2-2', 4'-(CH2)3-2', 4'-CH2-O-2', or 4'-CH(CH3)-O-2'.

22. The compound of any one of claims 1 to 15, wherein A is a sugar substitute.

23. The compound of claim 22, wherein the sugar substitute comprises tetrahydropyranose (THP) or morpholine in place of the pentofuranosyl sugar.

24. The compound of claim 22, wherein the sugar surrogate is a non-locked nucleic acid.

25. The compound of any one of claims 1 to 24, wherein B is substituted tetrahydrofuranyl.

26. A compound as described in any one of claims 1 to 25, wherein B has the formula: in: R 3 is -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 7 、-N(R 7 ) or -SR 7 ; R 9 is a substituted or unsubstituted heteroaryl ring; and Each R 7 and R and R are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

27. The compound of any one of claims 1 to 24, wherein B is a substituted tetrahydropyranyl ring.

28. The compound of any one of claims 1 to 24, wherein B is a modified sugar.

29. A compound as described in any one of claims 1 to 24, wherein B is a bicyclic sugar.

30. The compound of claim 29, wherein the bicyclic sugar comprises a bridge between the 4' and 2' furanose ring atoms.

31. The compound of claim 29 or 30, wherein the 4' to 2' bridging substituent comprises 4'-(CH2)2-2', 4'-(CH2)3-2', 4'-CH2-O-2', or 4'-CH(CH3)-O-2'.

32. The compound of any one of claims 1 to 24, wherein B is a sugar substitute.

33. The compound of claim 32, wherein the sugar surrogate comprises tetrahydropyranose (THP) or morpholine in place of the pentofuranosyl sugar.

34. The compound of claim 32, wherein the sugar surrogate is a non-locked nucleic acid.

35. A compound of formula (I): in: Q 1 -H, -OR 4 , ligands or lipids; Each Q 2 Independently key, ligand, linker or lipid; Each Q 3 Independently key, ligand, linker or lipid; Each Q 4 Independently bond, -R 10 O-, ligand, linker, or lipid; Each Q 5 Independently key, ligand, linker or lipid; Each Q 6 Independently key, ligand, linker or lipid; Q 7 -H, -R 5 , ligands or lipids; Each Y is independently substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -O-, -OP(O)O2-, -N(R C )-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR C -、-NR C C(=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)2NR C -、-NR C SO2- or their combination; Each R C R is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group, or two R C The groups are connected to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; Each R 2 are 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 are 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 ligated together to form a single oligonucleotide; Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 7 are 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 R 10 independently an oligonucleotide; Each X is independently O or S; Z 1 , Z 2 , Z 3 or Z 4 Each instance of is independently a bond, C1-C6 alkylene, or C2-C6 alkenylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; or a salt or a prodrug thereof.

36. The compound of claim 35, wherein Q 3 for 37. The compound of claim 35 or 36, wherein Q 4 For-R 10 O-.

38. A compound as described in any one of claims 35 to 37, wherein Q 5 for 39. A compound as described in any one of claims 35 to 38, wherein Q 6 for 40. A compound as described in any one of claims 35 to 39, wherein Q 7 For-R 5 .

41. A compound of formula (VII): in: Y is -C(=O)N(R C )-or-N(R C )C(=O)-; Q 1 -H, -OR 4 , ligands, linkers or lipids; Q 2 Independently key, ligand, linker or lipid; R C is independently -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 are 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 are 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 ligated together to form a single oligonucleotide; Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 8 are independently substituted or unsubstituted heteroaryl; Each R 9 are independently substituted or unsubstituted heteroaryl; Z 1 or Z 2 Each instance of is independently a bond, C1-C6 alkylene, or C2-C6 alkenylene; and Each X is independently O or S; or a salt thereof.

42. A compound as described in any one of claims 35 to 41, wherein Q 1 For-OR 4 .

43. A compound as described in any one of claims 35 to 42, wherein Q 2 for 44. A compound of formula (II): in: Each Y is independently substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -O-, -OP(O)O2-, -N(R C )-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR C -、-NR C C(=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)2NR C -、-NR C SO2- or their combination; Each R C R is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group, or two R C The groups are connected to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; Each R 2 are 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 are 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 ligated together to form a single oligonucleotide; Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 8 are independently substituted or unsubstituted heteroaryl; Each R 9 are independently substituted or unsubstituted heteroaryl; Each R 10 independently an oligonucleotide; Each X is independently O or S; Z 1 , Z 2 , Z 3 or Z 4 Each instance of is independently a bond, C1-C6 alkylene, or C2-C6 alkenylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; or a salt or a prodrug thereof.

45. A compound as described in any one of claims 35 to 40 or 42 to 44, wherein p is 0.

46. ​​A compound as described in any one of claims 35 to 40 or 42 to 44, wherein p is 1, 2 or 3.

47. The compound of claim 44 or 45, wherein the compound has formula (II-a): in: Each Y is independently substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -O-, -OP(O)O2-, -N(R C )-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR C -、-NR C C(=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)2NR C -、-NR C SO2- or their combination; Each R C R is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group, or two R C The groups are connected to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; Each R 2 are 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 are 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 ligated together to form a single oligonucleotide; Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 8 are independently substituted or unsubstituted heteroaryl; Each R 9 are independently substituted or unsubstituted heteroaryl; Each X is independently O or S; Z 1 and Z 2 Each instance of is independently a bond, C1-C6 alkylene, or C2-C6 alkenylene; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; or a salt thereof.

48. A compound of formula (VI): in: Each Y is independently substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -O-, -OP(O)O2-, -N(R C )-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR C -、-NR C C(=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)2NR C -、-NR C SO2- or their combination; Each R C R is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group, or two R C The groups are connected to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; Each R 2 are 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 are 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 Each independently is an oligonucleotide, a protecting group, or R 4 and R 5 ligated together to form a single oligonucleotide; Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 8 are independently substituted or unsubstituted heteroaryl; Each R 9 are independently substituted or unsubstituted heteroaryl; Each X is independently O or S; Z 1 , Z 2 , Z 3 or Z 4 Each instance of is independently a bond, C1-C6 alkylene, or C2-C6 alkenylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; or a salt or a prodrug thereof.

49. A compound as described in any one of claims 35 to 40, 42 to 46 or 48, wherein Z 3 At least one example of is C1-C6 alkylene.

50. The compound of claims 35 to 40, 42 to 46 or 48 to 49, wherein Z 3 It is -CH2- or -CH2CH2-.

51. A compound as described in any one of claims 35 to 40, 42 to 46 or 48, wherein Z 3 At least one example of is C2-C6 alkenylene.

52. The compound of claims 35 to 40, 42 to 46 or 48, wherein Z 3 It is -CH=CH-.

53. A compound as described in any one of claims 35 to 40, 42 to 46 or 48, wherein Z 3 At least one instance of is a key.

54. A compound as described in any one of claims 35 to 40, 42 to 46 or 48 to 53, wherein Z 4 At least one example of is C1-C6 alkylene.

55. A compound as described in any one of claims 35 to 40, 42 to 46 or 48 to 54, wherein Z 4 It is -CH2- or -CH2CH2-.

56. A compound as described in any one of claims 35 to 40, 42 to 46 or 48 to 53, wherein Z 4 At least one example of is C2-C6 alkenylene.

57. A compound as described in any one of claims 35 to 40, 42 to 46, 48 to 53 or 56, wherein Z 4 It is -CH=CH-.

58. A compound as described in any one of claims 35 to 40, 42 to 46 or 48 to 53, wherein Z 4 At least one instance of is a key.

59. A compound as described in any one of claims 35 to 40 or 42 to 58, wherein n is 1.

60. A compound as described in any one of claims 35 to 40 or 42 to 58, wherein n is 2.

61. A compound as described in any one of claims 35 to 40 or 42 to 58, wherein n is 3.

62. The compound of any one of claims 1 to 61, wherein Z 1 At least one example of is C1-C6 alkylene.

63. The compound of any one of claims 1 to 62, wherein Z 1 It is -CH2- or -CH2CH2-.

64. The compound of any one of claims 1 to 61, wherein Z 1 At least one example of is C2-C6 alkenylene.

65. A compound as described in any one of claims 1 to 61 or 64, wherein Z 1 It is -C(H)=C(H)-.

66. A compound as described in any one of claims 1 to 61, wherein Z 1 At least one instance of is a key.

67. A compound as described in any one of claims 1 to 66, wherein Z 2 At least one example of is C1-C6 alkylene.

68. A compound as described in any one of claims 1 to 67, wherein Z 2 It is -CH2- or -CH2CH2-.

69. The compound of any one of claims 1 to 66, wherein Z 2 At least one example of is C2-C6 alkenylene.

70. A compound as described in any one of claims 1 to 66 or 69, wherein Z 2 It is -C(H)=C(H)-.

71. The compound of any one of claims 1 to 66, wherein Z 2 At least one instance of is a key.

72. A compound as described in any one of claims 1 to 71, wherein each Y is independently -C(=O)N(R C )-or N(R C )C(=O)-.

73. A compound as described in any one of claims 1 to 71, wherein each Y independently comprises at least one lipophilic moiety.

74. An oligonucleotide of formula (IX): in: 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 are 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 are 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 ligated together to form a single oligonucleotide; Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 7 are 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; and Each X is independently O or S; or a salt or a prodrug thereof.

75. An oligonucleotide of formula (X): in: 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 are 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 are 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 ligated together to form a single oligonucleotide; Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 7 are 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; and Each X is independently O or S; or a salt or a prodrug thereof.

76. An oligonucleotide of formula (XI): in: 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 are 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 are 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 ligated together to form a single oligonucleotide; Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 7 are 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; and Each X is independently O or S; or a salt or a prodrug thereof.

77. An oligonucleotide of formula (XII): in: R C each instance of is independently -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 are 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 are 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 ligated together to form a single oligonucleotide; Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 7 are 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; and Each X is independently O or S; or a salt or a prodrug thereof.

78. An oligonucleotide of formula (XIII): in: 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 are 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 are 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 ligated together to form a single oligonucleotide; Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 7 are 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; and Each X is independently O or S; or a salt or a prodrug thereof.

79. An oligonucleotide of formula (XIV): in: 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 are 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 are 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 ligated together to form a single oligonucleotide; Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 7 are 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; and Each X is independently O or S; or a salt or a prodrug thereof.

80. A compound as described in any one of claims 1 to 79, wherein R C Each instance of is independently substituted or unsubstituted alkyl.

81. The compound of any one of claims 1 to 80, wherein R C Each instance of is independently substituted or unsubstituted -C8-C 100 -alkyl.

82. The compound of any one of claims 1 to 81, wherein R C Each instance of is independently substituted or unsubstituted -C8-C 40 -alkyl.

83. The compound of any one of claims 1 to 82, wherein R C Each instance of is independently substituted or unsubstituted -C8-C 20 -alkyl.

84. The compound of any one of claims 1 to 83, wherein R C Each instance of is independently substituted or unsubstituted -C 12 -C 20 -alkyl.

85. The compound of any one of claims 1 to 83, wherein R C Each instance of is independently substituted or unsubstituted -C 16 -C 20 -alkyl.

86. A compound as described in any one of claims 1 to 80, wherein R C Each instance of is independently substituted or unsubstituted -C1-C 30 -alkyl.

87. The compound of any one of claims 1 to 80, wherein R C Each instance of is independently substituted or unsubstituted -C1-C 20 -alkyl.

88. A compound as described in any one of claims 1 to 80, wherein R C Each instance of is independently substituted or unsubstituted -C 10 -C 20 -alkyl.

89. The compound of any one of claims 1 to 88, wherein R c Substituted with one or more of hydroxy, amine, carboxylic acid, azide or alkyne.

90. The compound of any one of claims 1 to 88, wherein Rc is substituted with a carboxylic acid.

91. compounds as described in any one in claims 1 to 88, wherein Rc comprises at least one substituent selected from the group consisting of caproic 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.

92. The compound of any one of claims 1 to 79, wherein R C Each instance of is independently -H.

93. An oligonucleotide of formula (IX-a): in: Each R 2 are 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 are 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 ligated together to form a single oligonucleotide; Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 7 are 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; and Each X is independently O or S; or a salt or a prodrug thereof.

94. An oligonucleotide of formula (IX-b): in: Each R 2 are 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 are 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 ligated together to form a single oligonucleotide; Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 7 are 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; and Each X is independently O or S; or a salt or a prodrug thereof.

95. An oligonucleotide of formula (Xa): in: Each R 2 are 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 are 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 ligated together to form a single oligonucleotide; Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 7 are 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; and Each X is independently O or S; or a salt or a prodrug thereof.

96. An oligonucleotide of formula (XV): in: Each R 2 are 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 are 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 ligated together to form a single oligonucleotide; Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 7 are 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; and Each X is independently O or S; or a salt or a prodrug thereof.

97. An oligonucleotide of formula (XVI): in: Each R 2 are 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 are 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 ligated together to form a single oligonucleotide; Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 7 are 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; and Each X is independently O or S; or a salt or a prodrug thereof.

98. An oligonucleotide of formula (XVII): in: Each R 2 are 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 are 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 ligated together to form a single oligonucleotide; Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 7 are 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; and Each X is independently O or S; or a salt or a prodrug thereof.

99. An oligonucleotide of formula (XVIII): in: Each R 2 are 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 are 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 ligated together to form a single oligonucleotide; Each R 6 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 7 are 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; and Each X is independently O or S; or a salt or a prodrug thereof.

100. A compound as described in any one of claims 16 to 99, wherein R 2 At least one instance of -OR 6 .

101. The compound of any one of claims 16 to 100, wherein R 6 At least one example of is -C1-C6-alkyl.

102. The compound of any one of claims 16 to 101, wherein R 6 At least one example of is methyl.

103. The compound of any one of claims 16 to 99, wherein R 2 At least one instance of is -F.

104. The compound of any one of claims 26 to 103, wherein R 3 At least one instance of -OR 7 .

105. The compound of any one of claims 26 to 104, wherein R 7 At least one example of is -C1-C6-alkyl.

106. The compound of any one of claims 26 to 105, wherein R 7 At least one example of is methyl.

107. The compound of any one of claims 26 to 103, wherein R 3 At least one instance of is -F.

108. The compound of any one of claims 1 to 107, wherein R 8 At least one example of is a nucleobase.

109. The compound of any one of claims 1 to 108, wherein R 8 At least one example of is uracil, cytosine, adenine, guanine, inosine or thymine.

110. A compound as described in any one of claims 1 to 108, wherein R 8 At least one example of is a modified nucleobase.

111. A compound as described in any one of claims 1 to 109, wherein R 8 At least one example of is uracil.

112. The compound of any one of claims 1 to 109, wherein R 8 At least one example of is cytosine.

113. The compound of any one of claims 1 to 112, wherein R 9 At least one example of is a nucleobase.

114. The compound of any one of claims 1 to 113, wherein R 9 At least one example of is uracil, cytosine, adenine, guanine, inosine or thymine.

115. A compound as described in any one of claims 1 to 113, wherein R 9 At least one example of is a modified nucleobase.

116. A compound as described in any one of claims 1 to 113, wherein R 9 At least one example of is uracil.

117. A compound as described in any one of claims 1 to 113, wherein R 9 At least one example of is cytosine.

118. An oligonucleotide of formula (IX-c): in: R 4 and R 5 are independently an oligonucleotide, a protecting group, or R 4 and R 5 ligated together to form a single oligonucleotide; and Each X is independently O or S; or a salt or a prodrug thereof.

119. An oligonucleotide of formula (IX-d): in: R 4 and R 5 are independently an oligonucleotide, a protecting group, or R 4 and R 5 ligated together to form a single oligonucleotide; and Each X is independently O or S; or a salt or a prodrug thereof.

120. An oligonucleotide of formula (IX-e): in: R 4 and R 5 are independently an oligonucleotide, a protecting group, or R 4 and R 5 ligated together to form a single oligonucleotide; and Each X is independently O or S; or a salt or a prodrug thereof.

121. A compound as described in any one of claims 1 to 120, wherein R 4 and R 5 Each is independently an oligonucleotide.

122. The compound of any one of claims 1 to 120, wherein R 4 is an oligonucleotide; and R 5 For the protecting group.

123. A compound as described in any one of claims 1 to 120, wherein R 4 is a protecting group; and R 5 For oligonucleotides.

124. The compound of any one of claims 1 to 120, wherein R 4 and R 5 Each is independently a protecting group.

125. A compound as described in any one of claims 1 to 122, wherein R 4 Contains an oligonucleotide attached to its 5' end.

126. A compound as described in any one of claims 1 to 122, wherein R 4 Contains an oligonucleotide attached to its 3' end.

127. The compound of any one of claims 1 to 122, wherein R 4 An oligonucleotide is included, the oligonucleotide being attached at an internal position on the oligonucleotide.

128. A compound as described in any one of claims 1 to 121, 123, 125 to 127, wherein R 5 Contains an oligonucleotide attached to its 5' end.

129. A compound as described in any one of claims 1 to 121, 123, 125 to 127, wherein R 5 Contains an oligonucleotide attached to its 3' end.

130. A compound as described in any one of claims 1 to 121, 123, 125 to 127, wherein R 5 An oligonucleotide is included, the oligonucleotide being attached at an internal position on the oligonucleotide.

131. The compound of any one of claims 1 to 130, wherein the protecting group, when present, is an oxygen protecting group.

132. The compound of any one of claims 1 to 131, wherein the protecting group is an acid-labile oxygen protecting group.

133. The compound of any one of claims 1 to 132, wherein the protecting group is 4,4'-dimethoxytrityl or 2-cyanoethyl 5'-O-(4,4'-dimethoxytrityl)thymidine-3'-O-(N,N-diisopropylamino)phosphoramidite.

134. The compound of any one of claims 35 to 133, wherein at least one X is O.

135. The compound of any one of claims 35 to 134, wherein at least two instances of X are O.

136. The compound of any one of claims 35 to 134, wherein at least one X is S.

137. A compound as described in any one of claims 35 to 133 or 136, wherein at least two instances of X are S.

138. A compound as described in any one of claims 35 to 134, wherein at least one instance of X is O, and at least one instance of X is S.

139. A compound as described in any one of claims 1 to 138, wherein the oligonucleotide comprises at least one siRNA, miRNA, ADAR recruiting molecule, ADAR targeting molecule, guide RNA and / or antisense nucleic acid.

140. The compound of any one of claims 1 to 139, wherein the compound comprises at least one oligonucleotide.

141. A compound of the formula: or a salt thereof.

142. A compound of the formula or a salt thereof.

143. A composition comprising a compound as described in any one of claims 1 to 142 and a pharmaceutically acceptable excipient.

144. A method for delivering a therapeutic oligonucleotide to a subject in need thereof, comprising: The subject is administered a compound as described in any one of claims 1 to 142 or a composition as described in claim 136.

145. A method for delivering a therapeutic oligonucleotide to the brain of a subject in need thereof, comprising: The subject is administered a compound as described in any one of claims 1 to 142 or a composition as described in claim 136.

146. A method for treating or ameliorating a disease, disorder or symptom thereof in a subject in need thereof, comprising: The subject is administered a compound as described in any one of claims 1 to 142 or a composition as described in claim 136.

147. The method of claim 146, wherein the disease, disorder, or symptom thereof is a central nervous system (CNS) disease, disorder, or symptom thereof.

148. The method of claim 146 or 147, wherein the disease, disorder, or symptom thereof is Alzheimer's disease or a symptom thereof.

149. The method of any one of claims 146 to 148, wherein the compound is administered to the subject intrathecally.

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