WO2022043531A1

WO2022043531A1 - 7'-substituted 2'-o-4'-c-ethylene-bridged nucleic acid (ena) monomers and uses thereof

Info

Publication number: WO2022043531A1
Application number: PCT/EP2021/073803
Authority: WO
Inventors: Leonid Beigelman; Jérôme Émile Georges GUILLEMONT; Serge Piettre; Julien Brioche; Prabhakar SUNCHU
Original assignee: Janssen Sciences Ireland Unlimited Company; Universite De Rouen Normandie; Centre National De La Recherche Scientifique; Institut National Des Sciences Appliquees De Rouen Normandie
Priority date: 2020-08-28
Filing date: 2021-08-27
Publication date: 2022-03-03

Abstract

The present disclosure relates to ethylene-bridged nucleic acid (ENA) compounds, which may find use in therapy and/or prophylaxis. These ENA compounds may also find use as building blocks for preparing oligonucleotides, said oligonucleotides also finding use in therapy and/or prophylaxis. These compounds may be mono- or oligonucleotide derivatives comprising at least one of the following fragment: Formula (IV), wherein R¹ is an optionally substituted C₁-C₆ alkyl moiety.

Description

7’-SUBSTITUTED 2’-O-4’-C-ETHYLENE-BRIDGED NUCLEIC ACID (ENA) MONOMERS AND USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the priority benefit of U.S. Provisional Application Serial No. 63/071,926, filed August 28, 2020, the content of which is incorporated herein by reference in its entirety.

FIELD OF THE DISCLOSURE

[0002] The present disclosure relates to ethylene-bridged nucleic acid (ENA) compounds useful for therapy and/or prophylaxis in a mammal. These ENA compounds may also find use as building blocks for preparing oligonucleotides, said oligonucleotides also finding use in therapy and/or prophylaxis in a mammal.

BRIEF DESCRIPTION

[0003] Nucleosides represent a class of molecules of paramount importance in living cells. They are essentially known as monomers which, joined together through phosphodiester links, constitute DNA and RNA strands holding genetic information. Furthermore, several nucleosides phosphates are the cornerstones of many fundamental biological processes such as energy transfer and cell signaling pathways

[0004] Consequently, there is interest in modifying the nucleoside framework with the aim of developing drugs (e.g., antiviral and anticancer chemotherapies) and tools for chemical biology. Among the numerous modifications of the nucleoside core reported to date, the introduction of a covalent tether between the C2’ and C4’ positions of the ribose unit has received considerable attention. This class of nucleosides, commonly known as 2’,4’-bridged nucleic acid (BNA) monomers, possesses a carbohydrate ring adopting preferentially a preorganized C3’ -endo RNA- like conformation. This particular puckered conformation of furanose ring is also observed in RNA/RNA duplexes and, as a result, chemically modified oligonucleotides (ONs) incorporating at least one 2’,4’-BNA modification usually demonstrate an increase in binding affinity with their cognate m-RNA compared to their unmodified ONs, partly thanks to the loss of entropy during the hybridization process. 2’, 4’ -BNA monomers are thus exploited in medicinal chemistry, especially in the development of antisense oligonucleotides (ASOs), a class of promising therapeutic drugs. Indeed, the strength of the binding affinity between an ASO and its complementary m-RNA strand is a crucial starting point in the design of a potential ASO drug, in addition to its metabolic stability and pharmacokinetic properties.

[0005] Conformationally restricted 2’-(9-4’-C-methylene bridged nucleosides are also known as locked nucleic acid (LNA) monomers. While ONs containing LNA units exhibit a strong binding efficiency to complementary RNA strands and a moderate nuclease resistance, they also induce a certain level of hepatotoxicity in animals, thus limiting their development in antisense technology. Thus, there is a need in the art to provide modified 2’-(9-4’-C-Ethylene bridged nucleic acid (ENA) monomers, and oligonucleotides comprising the same, that do not exhibit such hepatotoxic effects.

SUMMARY OF THE DISCLOSURE

[0006] In some aspects, provided herein is a compound of the following formula (A):

or a pharmaceutically acceptable salt thereof, wherein R¹ is optionally substituted Ci-ealkyl; R² is H, an optionally substituted phosphonate moiety, an optionally substituted phosphorothioate moiety, or an optionally substituted thiophosphoroamidate moiety; and Y is an optionally substituted heterocyclic base.

[0007] In some aspects, provided herein is a compound of the following formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ is optionally substituted Ci-ealkyl; R² is H, an optionally substituted phosphonate moiety, an optionally substituted phosphorothioate moiety, or an optionally substituted thiophosphoroamidate moiety; and R³ is H or methyl.

[0008] In some aspects, provided herein is a compound of the following formula (IA):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R³ are as defiend above for a compound of formula (I).

[0009] In some aspects, provided herein is a compound of the following formula (IB):

[0010] In some aspects, provided herein is a compound of the following formula (IC):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², and R³ are as defiend above for a compound of formula (I).

[0011] In some aspects, provided herein is a compound of the following formula (ID):

[0012] In some aspects, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties selected from the group consisting of

wherein R¹, R², and Y are as defined above for a compound of formula (A).

[0013] In some aspects, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties selected from the group consisting of

wherein R¹, R², and R³ are as defined above for a compound of formula (I). [0014] In some aspects, provided herein is a pharmaceutical composition comprising a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0015] In some aspects, provided herein is a pharmaceutical composition comprising an oligonucleotide comprising one or more moieties of formulae (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0016] In some aspects, provided herein is a pharmaceutical composition comprising an oligonucleotide comprising one or more moieties of formulae (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0017] In some aspects, provided herein is a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in medical therapy.

[0018] In some aspects, provided herein is an oligonucleotide comprising one or more moieties of formulae (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said oligonucleotide, or a pharmaceutically acceptable salt thereof, for use in medical therapy.

[0019] some aspects, provided herein is an oligonucleotide comprising one or more moieties of formulae (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said oligonucleotide, or a pharmaceutically acceptable salt thereof, for use in medical therapy.

[0020] In some aspects, provided herein is a method for treating a condition, disease, or disorder in a mammal, the method comprising administering a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, to the mammal.

[0021] In some aspects, provided herein is a method for treating a condition, disease, or disorder in a mammal, the method comprising administering an oligonucleotide comprising one or more moieties of formulae (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said oligonucleotide, or a pharmaceutically acceptable salt thereof, to the mammal. [0022] In some aspects, provided herein is a method for treating a condition, disease, or disorder in a mammal, the method comprising administering an oligonucleotide comprising one or more moieties of formulae (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said oligonucleotide, or a pharmaceutically acceptable salt thereof, to the mammal.

[0023] In some aspects, provided herein is a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, for use for the preparation of a medicament for the treatment or prophylaxis of a condition, disease, or disorder in a mammal.

[0024] In some aspects, provided herein is an oligonucleotide comprising one or more moieties of formulae (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, for use for the preparation of a medicament for the treatment or prophylaxis of a condition, disease, or disorder in a mammal.

[0025] In some aspects, provided herein is an oligonucleotide comprising one or more moieties of formulae (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof, for use for the preparation of a medicament for the treatment or prophylaxis of a condition, disease, or disorder in a mammal.

[0026] In some aspects, provided herein is a method for preparing a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof.

[0027] In some aspects, provided herein is a method for preparing an oligonucleotide comprising one or more moieties of formulae (II), (III), or (IV), or a pharmaceutically acceptable salt thereof.

[0028] In some aspects, provided herein is a method for preparing an oligonucleotide comprising one or more moieties of formulae (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

DEFINITIONS

[0029] Unless otherwise indicated, the following specific terms and phrases used in the description and claims are defined as follows. [0030] The term “moiety” refers to an atom or group of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds, thereby forming part of a molecule.

[0031] The term “oligonucleotide” refers to a molecule formed by the covalent linkage of two or more nucleotides. Oligonucleotides may include naturally or non-naturally occurring nucleobases, sugars, and/or covalent internucleoside (backbone) linkages. Oligonucleotides generally are less than about two hundred fifty, or two hundred, or one hundred, or fifty, nucleotides in length. Thus, oligonucleotides are at least 2 but may be fewer than about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, or 250 nucleotides in length. Compounds of formula (A) or formula (I), as described herein, may be used to prepare an oligonucleotide provided herein, and such oligonucleotides may comprise one or more moieties of formula (II), (III), (IV), (V), (VI), or (VII), or any embodiment, variation, or combination thereof, as described herein.

[0032] The term “substituted” refers to the fact that at least one of the atoms of that moiety is replaced by another substituent or moiety. The term “optionally substituted” indicates that such substitution may or may not occur. For illustratation, but not limitation: a “substituted alkyl” is an alkyl moiety in which at least one of the hydrogen atoms in the alkyl moiety is replaced by another substituent or moiety, e.g., a F atom may replace a H atom in a methyl moiety to produce a -CH2F moieity. In another illustration, a “substituted phosphonate” is a phosphonate moiety, as defined herein, in which at least one of the -OH moieties and/or at least one of the H atoms in the phosphonate moiety is replaced by another substitutent or moiety, e.g., an amino group may replace an -OH moiety in a monophosphonate moiety to produce a -P(=O)(OH)(NH2) moiety, which is also referred to as a phosphoroamidate moiety. In a further illustration, a “substituted phosphorothioate” is a phosphorothioate moiety, as defined herein, in which at least one of the - OH moieties and/or at least one of the H atoms in the phosphorothioate moiety is replaced by another substitutent or moiety, e.g., an amino group may replace an -OH moiety in a monophosphorothioate moiety to produce a -P(=S)(OH)(NH2) moiety, which may also be referred to as a thiophosphoroamidate moiety.

[0033] The term “alkyl” refers to an aliphatic straight-chain or branched-chain saturated hydrocarbon moiety having 1 to 20 carbon atoms, such as 1 to 12 carbon atoms, or 1 to 6 carbon atoms. Alkyl groups may be optionally substituted. [0034] As used herein, “alkoxy” refers to the formula -OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl is defined herein. A non-limiting list of alkoxys is methoxy, ethoxy, n-propoxy, 1 -methyl ethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted or unsubstituted.

[0035] The term “halo” refers to a halogen (for example, fluoro, bromo, chloro, or iodo).

[0036] As used herein, “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl and tri -haloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, l-chloro-2-fluorom ethyl and 2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.

[0037] As used herein, “haloalkoxy” refers to an -O-alkyl group in which one or more of the hydrogen atoms are replaced by a halogen e.g., mono-haloalkoxy, di- haloalkoxy and trihaloalkoxy). Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1 -chi oro-2-fluorom ethoxy and 2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.

[0038] As used herein, the term “phosphate” is used in its ordinary sense as understood by those skilled in the art, and includes its protonated forms (for example,

s used herein, the terms “monophosphate,” “diphosphate,” and triphosphate are used in their ordinary sense as understood by those skilled in the art, and include protonated forms. Phosphate moieties may be optionally substituted.

[0039] Likewise, the term “phosphonate” is also used in its ordinary sense as understood by those skilled in the art, and includes its protonated forms (for example,

). As used herein, the terms “monophosphonate,” “diphosphonate,” and “triphosphonate” are used in their ordinary sense as understood by those skilled in the art, and include protonated forms. Phosphonate moieties may be optionally substituted.

[0040] The term “phosphoroamidate”, as used herein, refers to a phosphonate moiety wherein one or more of the OH or O' of the phosphonate moiety has been replaced by -NH2 (for example,

Phosphoramidate moieties may be optionally substituted.

[0041] The term “phosphorothioate”, as used herein, refers to a phosphonate moiety wherein the =0 of the phosphonate moiety is replaced with =S, and includes its protonated forms

(for example,

As used herein, the terms “monophosphorothioate,” “diphosphothiorate” and “triphosphothiorate” are used in their ordinary sense as understood by those skilled in the art, and include protonated forms. Phosphorothioate moieties may be optionally substituted.

[0042] The term “thiophosphoroamidate,” as used herein, refers to a phosphorothioate moiety wherein one or more of the OH or O' of the phosphorothioate moiety has been replaced by

-NH2 (for example,

Thiophosphoroamidate moieties may be optionally substituted.

[0043] The term “N-acetyl galactosamine” refers to a moiety of the following structures:

An oligonucleotide, as provided herein, may be conjugated to one or more ligands comprising one or more N-acetyl galactosamine moieties. N- acetyl galactosamine moieties may be optionally substituted. In some instances, the one or more ligands are in the form of a galactose cluster. As used herein, a galactose cluster includes a ligand having two to four terminal galactose derivatives. [0044] The term “N-linked amino acid ester” refers to an amino acid in which a main- chain carboxylic acid group has been converted to an ester group. In some embodiments, the ester group has a formula selected from alkyl-O-C(=O)-, cycloalkyl-O-C(=O)-, aryl-O-C(=O)- and aryl(alkyl)-O-C(=O)-. A non-limiting list of ester groups include substituted and unsubstituted versions of the following: methyl-O-C(=O)-, ethyl-O-C(=O)-, n-propyl-O-C(=O)-, isopropyl-O- C(=O)-, n-butyl-O-C(=O)-, isobutyl -O-C(=O)-, tert-butyl-O-C(=O)-, neopentyl-O-C(=O)-, cyclopropyl-O-C(=O)-, cyclobutyl-O-C(=O)-, cyclopentyl-O-C(=O)-, cyclohexyl-O-C(=O)-, phenyl-O-C(=O)-, benzyl-O-C(=O)- and naphthyl-O-C(=O)-. N-linked amino acid esters may be optionally substituted.

[0045] As herein, the term “heterocyclic base” refers to an optionally substituted nitrogencontaining heterocyclyl that can be attached to an optionally substituted pentose moiety or modified pentose moiety. In some embodiments, the heterocyclic base can be selected from an optionally substituted purine-base, an optionally substituted pyrimidine-base and an optionally substituted triazole-base (for example, a 1,2,4-triazole). The term “purine-base” is used herein in its ordinary sense as understood by those skilled in the art, and includes its tautomers. Similarly, the term “pyrimidine-base” is used herein in its ordinary sense as understood by those skilled in the art, and includes its tautomers. A non-limiting list of optionally substituted purine-bases includes purine, adenine, guanine, hypoxanthine, xanthine, alloxanthine, 7-alkyl guanine (e.g., 7- methylguanine), theobromine, caffeine, uric acid and isoguanine. Examples of pyrimidine-bases include, but are not limited to, cytosine, thymine, uracil, 5,6-dihydrouracil and 5-alkylcytosine (e.g., 5-methyl cytosine). An example of an optionally substituted triazole-base is 1,2,4-triazole- 3 -carboxamide. Other non-limiting examples of heterocyclic bases include diaminopurine, 8-oxo- N⁶-alkyladenine (e.g., 8-oxo-N⁶-methyladenine), 7-deazaxanthine, 7-deazaguanine, 7- deazaadenine, N⁴,N⁴-ethanocytosin, N⁶,N⁶-ethano-2,6-diaminopurine, 5-halouracil (e.g, 5- fluorouracil and 5 -bromouracil), pseudoisocytosine, isocytosine, and isoguanine, some embodiments, the heterocyclic base can have the structure

, wherein X¹, X², X³,

X⁴, X⁵, X⁶ and X⁷ are independently selected from N and CR²⁵, and each R²⁵ can be independently selected from hydrogen, halogen, -NH2, -OH, an optionally substituted Ci-6-alkyl and an optionally substituted (Ci.e)alkoxy. In other embodiments, the heterocyclic base can have the structure

, wherein X⁸, X⁹, X¹⁰, X¹¹, X¹², X¹³ and X¹⁴ are independently selected from N and CR²⁵, and each R²⁵ can be independently selected from hydrogen, halogen, -NH2, -OH, an optionally substituted Ci-6-alkyl and an optionally substituted (Ci.e)alkoxy. In some embodiments, the heterocyclic base can have the structure

, wherein X¹⁵ and X¹⁶ can be independently selected from N and CR²⁵, and each R²⁵ can be independently selected from hydrogen, halogen, -NH2, -OH, an optionally substituted Ci-6-alkyl and an optionally substituted (Ci-6)alkoxy. Non -limiting examples of suitable heterocyclic base moi eties include the following:

. In some embodiments, the heterocyclic base can be substituted with -NH2. In some embodiments, the heterocyclic base can be optionally substituted with halo (for example, F).

[0046] The term “aryl” refers to a cyclic aromatic hydrocarbon moiety having a mono-, bi-, or tricyclic aromatic ring of 6 to 20 carbon ring atoms. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, benzyl, and the like. In some aspects, monocyclic aryl rings may have 5 or 6 carbon ring atoms. Aryl groups may be optionally substituted.

[0047] As used herein, an “amino acid” is an organic compound containing an amino group and a carboxylic acid group. A polypeptide contains two or more amino acids.

[0048] As used herein, the terms “treat,” “treating,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease, disorder, or condition, to any extent, can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.

[0049] As used herein, the terms “prevent” and “preventing,” mean lowering the efficiency of viral replication and/or inhibiting viral replication to a greater degree in a subject who receives the compound compared to a subject who does not receive the compound.

[0050] As used herein, a “subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject can be an adult human (18 years or older). In other embodiments, the subject can be child (>1-17 years). In still other embodiments, the subject can be an infant (1 year and younger). In yet still other embodiments, the subject can be a pediatric subject, wherein the term “pediatric” is used as understood by those skilled in the art. For example, pediatrics subjects include infants, children and adolescents.

[0051] Unless otherwise indicated, the term “a compound of the formula” or “a compound of formula” or “compounds of the formula” or “compounds of formula” refers to any compound selected from the genus of compounds as defined by the formula. In some embodiments or aspects, the term also includes a pharmaceutically acceptable salt or ester of any such compound, a stereoisomer of any such compound, or a tautomer of any such compound.

[0052] The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.

[0053] The terms “therapeutically effective amount” and “effective amount” are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, an effective amount of compound can be the amount needed to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated This response may occur in a tissue, system, animal, or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.

[0054] The term “pharmaceutically acceptable excipient” is intended to include any and all material compatible with pharmaceutical administration including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials and compounds compatible with pharmaceutical administration. Except insofar as any conventional media or agent is incompatible with a compound of the disclosure, use thereof in the compositions of the disclosure is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0055] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0056] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense. It is also understood that aspects and embodiments of the disclosure described herein may include “consisting” and/or “consisting essentially of’ aspects and embodiments.

[0057] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R configuration or S configuration or any mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. [0058] Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included. Additionally, all tautomers of heterocyclic bases known in the art are intended to be included, including tautomers of natural and non-natural purine-bases and pyrimidine-bases.

[0059] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0060] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.

COMPOUNDS

[0061] In some embodiments, a compound of the following formula (A) is provided:

[0062] In some embodiments, provided herein is a compound of formula (A), or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heterocyclic base of Y is an optionally substituted purine base or an optionally substituted pyrimidine base. In some embodiments, the optionally substituted heterocyclic base of Y is an optionally substituted purine base. In other embodiments, the optionally substituted heterocyclic base of Y is an optionally substituted pyrimidine base. In certain embodiments,

, wherein R³ is H or methyl.

In some embodiments,

other embodiments,

[0063] In some embodiments, provided herein is a compound of formula (A), or a pharmaceutically acceptable salt thereof, wherein

, wherein R³ is H or methyl, such that the compound of formula (A) is a compound of formula (I):

or pharmaceutically acceptable salt thereof, wherein R¹ is optionally substituted Ci-ealkyl; R² is H, an optionally substituted phosphonate moiety, an optionally substituted phosphorothioate moiety, or an optionally substituted thiophosphoroamidate moiety; and R³ is H or methyl.

[0064] In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R³ is H. In other embodiments, R³ is methyl.

[0065] In certain embodiments, provided herein is a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, wherein R² is H. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R² is H, such that the compound of formula (I) is a compound of formula (IA):

or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, provided herein is a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, wherein R² is an optionally substituted phosphonate moiety, an optionally substituted phosphorothioate moiety, or an optionally substituted thiophosphoroamidate moiety.

[0067] In other embodiments, provided herein is a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, wherein R² is an optionally substituted phosphonate moiety. In some embodiments, the phosphonate moiety of R² is an optionally substituted monophosphonate moiety. In other embodiments, the phosphonate moiety of R² is an optionally substituted diphosphonate moiety. In still other embodiments, the phosphonate moiety of R² is an optionally substituted triphosphonate moiety. In certain embodiments, the phosphonate moiety of R² is unsubstituted. In some embodiments, the phosphonate moiety of R² is an O II

\ I OH unsubstituted monophosphonate moiety of formula OH in other embodiments, the o °

II II

\ I O I OH phosphonate moiety of R² is an unsubstituted diphosphonate moiety of formula OH OH

In still other embodiments, the phosphonate moiety of R² is an unsubstituted triphosphonate moiety of formula

[0068] In certain embodiments, provided herein is a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, wherein R² is a phosphonate moiety (such as a monophosphonate moiety, a diphosphonate moiety, or a triphosphonate moiety), wherein the phosphonate moiety of R² is substituted with one or more optionally substituted N-linked amino acid esters. In some embodiments, R² is a monophosphonate moiety, wherein the monophosphonate of R² is substituted with one or more optionally substituted N-linked amino acid esters. In certain embodiments of the foregoing, the one or more optionally substituted N-linked amino acid esters comprise one or more optionally substituted N-linked alanine esters.

[0069] In some embodiments, provided herein is a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, wherein R² is a phosphonate moiety (such as a monophosphonate moiety, a diphosphonate moiety, or a triphosphonate moiety), wherein the phosphonate moiety of R² is substituted with one or more optionally substituted Ce-2oaryl. In certain embodiments, the phosphonate moiety of R² is substituted with one or more optionally substituted Ce-ioaryl. In some embodiments, the phosphonate moiety of R² is substituted with one or more phenyl. In some embodiments, the phosphonate moiety of R² is a monophosphonate moiety, wherein the monophosphonate moiety is substituted with one or more phenyl.

[0070] In some embodiments, provided herein is a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, wherein R² is a phosphonate moiety (such as a monophosphonate moiety, a diphosphonate moiety, or a triphosphonate moiety), wherein the phosphonate moiety of R² is substituted with one or more optionally substituted Ce-2oaryl and one or more optionally substituted N-linked amino acid esters. In some embodiments, R² is a monophosphonate moiety, wherein the monophosphonate moiety of R² is substituted with one or more optionally substituted Ce-2oaryl and one or more optionally substituted N-linked amino acid esters. In certain embodiments, R² is a monophosphonate moiety, wherein the monophosphonate moiety of R² is substituted with one or more phenyl and one or more optionally substituted N- linked alanine esters. [0071] In some embodiments, provided herein is a compound of formula (A) or formula

(I), or a pharmaceutically acceptable salt thereof, wherein

In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt

or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments, provided herein is a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, wherein R² is an optionally substituted phosphorothioate moiety. In some embodiments, R² is an optionally substituted monophosphorothioate moiety. In other embodiments, R² is an optionally substituted diphosphorothioate moiety. In still other embodiments, R² is an optionally substituted triphosphorothioate moiety. In some embodiments, R² is an unsubstituted phosphorothioate moiety. In some embodiments, R² is

[0073] In some embodiments, provided herein is a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, wherein R² is an optionally substituted thiophosphoroamidate moiety. In some embodiments, R² is an optionally substituted monothiophosphoroamidate moiety. In other embodiments, R² is an optionally substituted dithiophosphoroamidate moiety. In still other embodiments, R² is an optionally substituted trithiophosphoroamidate moiety. In some embodiments, R² is an unsubstituted thiophosphoroamidate moiety. In some embodiments, R² is

[0074] In some embodiments, provided herein is a compound of formula (A) or formula

(I), wherein

[0075] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt thereof, wherein R¹ is optionally substituted Ci-ealkyl. In other embodiments, R¹ is optionally substituted Ci-salkyl. In other embodiments, R¹ is optionally substituted Ci.2alkyl. In certain embodiments, R¹ is optionally substituted ethyl. In other embodiments, R¹ is optionally substituted methyl. In some embodiments, R¹ is Ci-ealkyl, wherein the Ci-ealkyl of R¹ is optionally substituted with one or more halo, -OH, -SH, -CN, Ci-ealkoxy, Ci-ehaloalkoxy, -C(O)OH, -C(O)-Ci-6alkyl, - C(O)-Ci-6alkoxy, -C(O)-Ci-6haloalkoxy, or -NH2. In other embodiments, R¹ is Ci-salkyl, wherein the Ci-3alkyl of R¹ is optionally substituted with one or more halo, -OH, -SH, -CN, Ci-ealkoxy, Ci- ehaloalkoxy, -C(O)OH, -C(O)-Ci-ealkyl, -C(O)-Ci-ealkoxy, -C(O)-Ci-ehaloalkoxy, or -NH2.

[0076] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt thereof, wherein R¹ is unsubstituted Ci-ealkyl. In other embodiments, R¹ is unsubstituted Ci-salkyl. In other embodiments, R¹ is unsubstituted Ci-2alkyl. In certain embodiments, R¹ is unsubstituted ethyl. In other embodiments, R¹ is unsubstituted methyl. [0077] In some embodiments, provided herein is a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, wherein R¹ is optionally substituted Ci-ealkyl and R² is H. In some embodiments, provided herein is a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl and R² is H. In some embodiments, provided herein is a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl, such that the compound of formula (IA) is a compound of formula (IA-1):

or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, provided herein is a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, wherein R¹ is ethyl and R² is H. In some embodiments, provided herein is a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein R¹ is ethyl, such that the compound of formula (IA) is a compound of formula (IA-2):

or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, provided herein is a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein R¹ is optionally substituted Ci-ealkyl and R² is an optionally substituted phosphonate moiety. In some embodiments, provided herein is a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl and R² is an optionally substituted phosphonate moiety. In some embodiments, provided herein is a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl

In some embodiments, provided herein is a compound of formula

(IB), or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl, such that the compound of formula (IB) is a compound of formula (IB-1):

or a pharmaceutically acceptable salt thereof.

[0080] In provided herein is a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein R¹ is ethyl and R² is an optionally substituted phosphonate moiety. In some embodiments, provided herein is a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein R¹ is ethyl

In some embodiments, provided herein is a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein R¹ is ethyl, such that the compound of formula (IB) is a compound of formula (IB-2):

or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (IA), (IA-1), (IA-2), (IB), (IB-1), or (IB-2), or a pharmaceutically acceptable salt thereof, wherein R¹ is in the R stereochemical configuration. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R¹ is in the R stereochemical configuration, such that the compound of formula (I) is a compound of formula (IC):

or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (IA), (IA-1), (IA-2), (IB), (IB-1), or (IB-2), or a pharmaceutically acceptable salt thereof, wherein R¹ is in the S stereochemical configuration. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R¹ is in the S stereochemical configuration, such that the compound of formula (I) is a compound of formula (ID):

or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (IA), (IA-1), (IA-2), (IB), (IB-1), (IB-2), (IC), or (ID), or a pharmaceutically acceptable salt thereof, wherein R³ is H or methyl. In certain embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (IA), (IA-1), (IA-2), (IB), (IB-1), (IB-2), (IC), or (ID), or a pharmaceutically acceptable salt thereof, wherein R³ is H. In other embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (IA), (IA-1), (IA-2), (IB), (IB-1), (IB-2), (IC), or (ID), or a pharmaceutically acceptable salt thereof, wherein R³ is methyl.

[0084] In some embodiments, provided herein is a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, wherein R¹ is Ci-ealkyl and R³ is H. In other embodiments, R¹ is optionally substituted Ci-ealkyl and R³ is methyl. In some embodiments, R¹ is methyl and R³ is H. In other embodiments, R¹ is ethyl and R³ is H. In some embodiments, R¹ is methyl and R³ is methyl. In other embodiments, R¹ is ethyl and R³ is methyl.

[0085] In some embodiments, provided herein is a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, wherein R² is H and R³ is H. In other embodiments, provided herein is a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, wherein R² is an optionally substituted phosphonate moiety and R³ is H. In some embodiments, R² is H and R³ is methyl. In other embodiments, R² is an optionally substituted phosphonate moiety and R³ is methyl. In certain embodiments,

and R³ is H. In other embodiments,

[0086] In some embodiments, provided herein is a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl, R² is H, and R³ is H. In other embodiments, R¹ is ethyl, R² is H, and R³ is H. In some embodiments, R¹ is methyl, R² is an optionally substituted phosphonate moiety, and R³ is H. In other embodiments, R¹ is ethyl, R² is an optionally substituted phosphonate moiety, and R³ is H. In some embodiments, R¹ is methyl, R² is H, and R³ is methyl. In some embodiments, R¹ is ethyl, R² is H, and R³ is methyl. In other embodiments, R¹ is methyl, R² is an optionally substituted phosphonate moiety, and R³ is methyl. In some embodiments, R¹ is ethyl, R² is an optionally substituted phosphonate moiety, and R³ is methyl.

[0087] In some embodiments, provided herein is a compound of formula (A) or formula

(I), such as a compound of formula (IA), (IA-1), (IA-2), (IB), (IB-1), (IB-2), (IC), or (ID), as applicable, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from

pharmaceutically acceptable salt thereof.

[0088] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (IA), (IA-1), (IA-2), (IB), (IB-1), (IB-2), (IC), or (ID), as applicable, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: isopropyl ((R)-(((lR,3R,5R,7R,8S)-7-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-5- (hydroxymethyl)-3-methyl-2,6-dioxabicyclo[3.2.1]octan-8-yl)oxy)(phenoxy)phosphoryl)-L- alaninate; isopropyl ((S)-(((lR,3R,5R,7R,8S)-7-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-5- (hydroxymethyl)-3-methyl-2,6-dioxabicyclo[3.2.1]octan-8-yl)oxy)(phenoxy)phosphoryl)-L- alaninate; isopropyl ((R)-(((lR,3S,5R,7R,8S)-7-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-5- (hydroxymethyl)-3-methyl-2,6-dioxabicyclo[3.2.1]octan-8-yl)oxy)(phenoxy)phosphoryl)-L- alaninate; isopropyl ((S)-(((lR,3S,5R,7R,8S)-7-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-5- (hydroxymethyl)-3-methyl-2,6-dioxabicyclo[3.2.1]octan-8-yl)oxy)(phenoxy)phosphoryl)-L- alaninate; isopropyl ((R)-(((lR,3R,5R,7R,8S)-7-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-8-hydroxy-3- methyl-2,6-dioxabicyclo[3.2.1]octan-5-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((R)-(((lR,3S,5R,7R,8S)-7-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-8-hydroxy-3- methyl-2,6-dioxabicyclo[3.2.1]octan-5-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((S)-(((lR,3R,5R,7R,8S)-7-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-8-hydroxy-3- methyl-2,6-dioxabicyclo[3.2.1]octan-5-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((S)-(((lR,3S,5R,7R,8S)-7-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-8-hydroxy-3- methyl-2,6-dioxabicyclo[3.2.1]octan-5-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; l-((lR,3R,5R,7R,8S)-8-hydroxy-5-(hydroxymethyl)-3-methyl-2,6-dioxabicyclo[3.2.1]octan-7- yl)-5-methylpyrimidine-2,4(lH,3H)-dione;

((lR,3R,5R,7R,8S)-8-hydroxy-3-methyl-7-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)- 2,6-dioxabicyclo[3.2.1]octan-5-yl)methyl tetrahydrogen triphosphate; and l-((lR,3S,5R,7R,8S)-3-ethyl-8-hydroxy-5-(hydroxymethyl)-2,6-dioxabicyclo[3.2.1]octan-7-yl)- 5-methylpyrimidine-2,4(lH,3H)-dione, or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, provided herein is a compound of formula (A) or formula (I), such as a compound of formula (IA), (IA-1), (IA-2), (IB), (IB-1), (IB-2), (IC), or (ID), as applicable, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: isopropyl (((7-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-5-(hydroxymethyl)-3-methyl-2,6- dioxabicyclo[3.2.1]octan-8-yl)oxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl (((7-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-8-hydroxy-3-methyl-2,6- dioxabicyclo[3.2.1]octan-5-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; l-(8-hydroxy-5-(hydroxymethyl)-3-methyl-2,6-dioxabicyclo[3.2.1]octan-7-yl)-5- methylpyrimidine-2,4(lH,3H)-dione;

(8-hydroxy-3-methyl-7-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2,6- dioxabicyclo[3.2.1]octan-5-yl)methyl tetrahydrogen triphosphate; and l-(3-ethyl-8-hydroxy-5-(hydroxymethyl)-2,6-dioxabicyclo[3.2.1]octan-7-yl)-5- methylpyrimidine-2,4(lH,3H)-dione, or a pharmaceutically acceptable salt thereof.

[0090] Also provided herein is a pharmaceutically acceptable salt (such as an ester) of any compound provided herein, as well as a stereoisomer, a geometric isomer, a tautomer, a solvate, or an isotope of such compound, or a pharmaceutically acceptable salt of any of the foregoing.

OLIGONUCLEOTIDES

[0091] In some aspects, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties selected from the group consisting of

wherein, independently at each occurrence, R¹ is optionally substituted Ci-ealkyl; R² is H, an optionally substituted phosphonate moiety, an optionally substituted phosphorothioate moiety, or an optionally substituted thiophosphoroamidate moiety; and Y is an optionally substituted heterocyclic base. [0092] In some aspects, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties selected from the group consisting of

wherein, independently at each occurrence, R¹ is optionally substituted Ci-ealkyl; R² is H, an optionally substituted phosphonate moiety, an optionally substituted phosphorothioate moiety, or an optionally substituted thiophosphoroamidate moiety; and R³ is H or methyl.

[0093] In certain embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formula (III) or formula (VI), wherein R² is H. In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formula (VI), wherein R² is H, such that the moiety of formula (VI) is a moiety of formula (VIA):

[0094] In other embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formula (III) or formula (VI), wherein R² is an optionally substituted phosphonate moiety. In some embodiments, the phosphonate moiety of R² is an optionally substituted monophosphonate moiety. In other embodiments, the phosphonate moiety of R² is an optionally substituted diphosphonate moiety. In still other embodiments, the phosphonate moiety of R² is an optionally substituted triphosphonate moiety. In certain embodiments, the phosphonate moiety of R² is unsubstituted. In some embodiments, O II

\ I OH the phosphonate moiety of R² is an unsubstituted monophosphonate moiety of formula OH

. In other embodiments, the phosphonate moiety of R² is an unsubstituted diphosphonate moiety

O £

II II I O I OH of formula OH OH in still other embodiments, the phosphonate moiety of R² is an

O O O

H II II x /^P\ /^p\ /^p\ I O I O I OH unsubstituted triphosphonate moiety of formula OH OH OH

[0095] In certain embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formula (III) or formula (VI), wherein R² is a phosphonate moiety (such as a monophosphonate moiety, a diphosphonate moiety, or a triphosphonate moiety), wherein the phosphonate moiety of R² is substituted with one or more optionally substituted N-linked amino acid esters. In some embodiments, R² is a monophosphonate moiety, wherein the monophosphonate of R² is substituted with one or more optionally substituted N-linked amino acid esters. In certain embodiments of the foregoing, the one or more optionally substituted N-linked amino acid esters comprise one or more optionally substituted N-linked alanine esters.

[0096] In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formula (III) or formula (VI), wherein R² is a phosphonate moiety (such as a monophosphonate moiety, a diphosphonate moiety, or a triphosphonate moiety), wherein the phosphonate moiety of R² is substituted with one or more optionally substituted Ce-2oaryl. In certain embodiments, the phosphonate moiety of R² is substituted with one or more optionally substituted Ce-ioaryl. In some embodiments, the phosphonate moiety of R² is substituted with one or more phenyl. In some embodiments, the phosphonate moiety of R² is a monophosphonate moiety, wherein the monophosphonate moiety is substituted with one or more phenyl.

[0097] In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formula (III) or formula (VI), wherein R² is a phosphonate moiety (such as a monophosphonate moiety, a diphosphonate moiety, or a triphosphonate moiety), wherein the phosphonate moiety of R² is substituted with one or more optionally substituted Ce-2oaryl and one or more optionally substituted N-linked amino acid esters. In some embodiments, R² is a monophosphonate moiety, wherein the monophosphonate moiety of R² is substituted with one or more optionally substituted Ce-2oaryl and one or more optionally substituted N-linked amino acid esters. In certain embodiments, R² is a monophosphonate moiety, wherein the monophosphonate moiety of R² is substituted with one or more phenyl and one or more optionally substituted N-linked alanine esters.

[0098] In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formula (III) or formula (VI), wherein

In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formula (VI),

such that the moiety of formula (VI) is a moiety of formula

(VIB):

[0099] In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formulae (II), (III), (IV), (V), (VI), or (VII), wherein R¹ is, independently at each occurrence, optionally substituted Ci-ealkyl. In other embodiments, R¹ is, independently at each occurrence, optionally substituted Ci-salkyl. In still other embodiments, R¹ is, independently at each occurrence, optionally substituted Ci-ialkyl.

[0100] In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formulae (II), (III), (IV), (V), (VI), or (VII), wherein R¹ is, independently at each occurrence, Ci-ealkyl, wherein the Ci-ealkyl of R¹ is optionally substituted with one or more halo, -OH, -SH, -CN, Ci-ealkoxy, Ci-ehaloalkoxy, - C(O)OH, -C(O)-Ci-₆alkyl, -C(O)-Ci-₆alkoxy, -C(O)-Ci-₆haloalkoxy, or -NH₂.

[0101] In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formulae (II), (III), (IV), (V), (VI), or (VII), wherein R¹ is, independently at each occurrence, Ci-salkyl, wherein the Ci-salkyl of R¹ is optionally substituted with one or more halo, -OH, -SH, -CN, Ci-ealkoxy, Ci-ehaloalkoxy, - C(O)OH, -C(O)-Ci-₆alkyl, -C(O)-Ci-₆alkoxy, -C(O)-Ci-₆haloalkoxy, or -NH₂.

[0102] In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formulae (II), (III), (IV), (V), (VI), or (VII), wherein R¹ is, independently at each occurrence, unsubstituted Ci-ealkyl. In other embodiments, R¹ is, independently at each occurrence, unsubstituted Ci-salkyl. In still other embodiments, R¹ is, independently at each occurrence, unsubstituted Ci-₂alkyl. In certain embodiments, R¹ is, independently at each occurrence, ethyl. In other embodiments, R¹ is, independently at each occurrence, methyl.

[0103] In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formula (V), (VI), or (VII), wherein R¹ is, independently at each occurrence, methyl, such that the oligonucleotide, or a pharmaceutically acceptable salt thereof, comprises one or more moieties selected from the group consisting of:

[0104] In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formula (V), (VI), or (VII), wherein R¹ is, independently at each occurrence, ethyl, such that the oligonucleotide, or a pharmaceutically acceptable salt thereof, comprises one or more moieties selected from the group consisting of:

[0105] In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formula (III) or formula (VI), wherein R¹ is methyl and R² is an optionally substituted phosphonate moiety. In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formula (VIB), wherein R¹ is methyl, such that the oligonucleotide, or a pharmaceutically acceptable salt thereof, comprises one or more moieties of formula (VIB-1):

[0106] In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formula (III) or formula (VI), wherein R¹ is ethyl and R² is an optionally substituted phosphonate moiety. In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formula (VIB), wherein R¹ is ethyl, such that the oligonucleotide, or a pharmaceutically acceptable salt thereof, comprises one or more moieties of formula (VIB-2):

[0107] In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formulae (II), (III), (IV), (V), (VI), or (VI), such as a moiety of formulae (VA-1), (VA-2), (VI- A), (VIA-1), (VIA-2), (VIB), (VI-B1), (VIB-2), or (VIIA-1), wherein R¹ is, independently at each occurrence, in the R stereochemical configuration.

[0108] In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formulae (II), (III), (IV), (V), (VI), or (VII), such as a moiety of formulae (VA-1), (VA-2), (VI-A), (VIA-1), (VIA- 2), (VIB), (VI-B1), (VIB-2), or (VIA-1), wherein R¹ is, independently at each occurrence, in the R stereochemical configuration, such that the oligonucleotide, or a pharmaceutically acceptable salt thereof, comprises one or more moieties selected from the group consisting of

[0109] In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formulae (II), (III), (IV), (V), (VI), or (VI), such as a moiety of formulae (VA-1), (VA-2), (VI-A), (VIA-1), (VIA-2), (VIB), (VI-B1), (VIB-2), or (VIA-1), wherein R¹ is, independently at each occurrence, in the S stereochemical configuration, such that the oligonucleotide, or a pharmaceutically acceptable salt thereof, comprises one or more moieties selected from the group consisting of

[0110] In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formulae (V), (VI), or (VII), such as a moiety of formulae (VA-1), (VA-2), (VC), (VI-A), (VIA-1), (VIA-2), (VIB), (VI-B1), (VIB-2),

(VIC), (VID), (IVA-1), (IVC), or (IVD), wherein R³ is H or methyl. In certain embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formulae (V), (VI), or (VII), such as a moiety of formulae (VA-1), (VA- 2), (VC), (VI-A), (VIA-1), (VIA-2), (VIB), (VI-B1), (VIB-2), (VIC), (VID), (VIA-1), (VIC), or

(VID), wherein R³ is H. In other embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formulae (V), (VI), or (VII), such as a moiety of formulae (VA-1), (VA-2), (VC), (VI-A), (VIA-1), (VIA-2), (VIB), (VI-B1), (VIB-2), (VIC), (VID), (VIIA-1), (VIIC), or (VIID), wherein R³ is methyl.

[oni] In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formulae (V), (VI), or (VII), wherein R¹ is methyl and R³ is H. In other embodiments, R¹ is ethyl and R³ is H. In still other embodiments, R¹ is methyl and R³ is methyl. In other embodiments, R¹ is methyl and R³ is ethyl.

[0112] In other embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formula (VI), wherein R² is an optionally substituted phosphonate moiety and R³ is H. In some embodiments, R² is H and R³ is methyl. In other embodiments, R² is an optionally substituted phosphonate moiety and R³ is methyl. In certain embodiments,

other embodiments, R²

[0113] In some embodiments, provided herein is an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formula (VI), wherein R¹ is methyl, R² is H, and R³ is H. In other embodiments, R¹ is ethyl, R² is H, and R³ is H. In some embodiments, R¹ is methyl, R² is an optionally substituted phosphonate moiety, and R³ is H. In other embodiments, R¹ is ethyl, R² is an optionally substituted phosphonate moiety, and R³ is H. In some embodiments, R¹ is methyl, R² is H, and R³ is methyl. In some embodiments, R¹ is ethyl, R² is H, and R³ is methyl. In other embodiments, R¹ is methyl, R² is an optionally substituted phosphonate moiety, and R³ is methyl. In some embodiments, R¹ is ethyl, R² is an optionally substituted phosphonate moiety, and R³ is methyl.

[0114] It is to be understood that an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties of formulae (II), (III), (IV), (V), (VI), or (VII), such as a moiety of formulae (VA-1), (VA-2), (VC), (VI-A), (VIA-1), (VIA-2), (VIB), (VI-B1), (VIB-2), (VIC), (VID), (VIIA-1), (VIIC), or (VIID), as described herein, may further comprise one or more other nucleotides in addition to said moieties of formulae (II), (III), (IV), (V), (VI), or (VII). In some embodiments, the oligonucleotide described herein can be a single-stranded oligonucleotide. In some embodiments, the oligonucleotide described here can be a double-stranded oligonucleotide. In some embodiments, the oligonucleotide described herein can be an antisense oligonucleotide (ASO). In some embodiments, the oligonucleotide described herein can be a short interfering RNA (siRNA).

[0115] In some embodiments, the moieties of formulae (II), (III), (IV), (V), (VI), or (VII), such as a moiety of formulae (VA-1), (VA-2), (VC), (VI-A), (VIA-1), (VIA-2), (VIB), (VI-B1), (VIB-2), (VIC), (VID), (VIIA-1), (VIIC), or (VIID), as described herein, may be incoroproated into an oligonucleotide of the present disclosure at the 3’ terminal of the oligonucleotide. In some embodiments, the moieties of formulae (II), (III), (IV), (V), (VI), or (VII), such as a moiety of formulae (VA-1), (VA-2), (VC), (VI-A), (VIA-1), (VIA-2), (VIB), (VI-B1), (VIB-2), (VIC), (VID), (VIIA-1), (VIIC), or (VIID), as described herein, can be incoroproated into an oligonucleotide of the present disclosure at the 5’ terminal of the oligonucleotide. In some embodiments, the moieties of formulae (II), (III), (IV), (V), (VI), or (VII), such as a moiety of formulae (VA-1), (VA-2), (VC), (VI-A), (VIA-1), (VIA-2), (VIB), (VI-B1), (VIB-2), (VIC), (VID), (VIA-1), (VIIC), or (VIID), as described herein, may be independently incoroproated at one or more positions of an oligonucleotide. In some embodiments, the moieties of formulae (II), (III), (IV), (V), (VI), or (VII), such as a moiety of formulae (VA-1), (VA-2), (VC), (VI-A), (VIA- 1), (VIA-2), (VIB), (VI-B1), (VIB-2), (VIC), (VID), (VIIA-1), (VIIC), or (VIID), as described herein, may be present at one or more positions at one or both wing regions of a gapmer antisense oligonucleotide. In some embodiments, the wing region of the gapmer flanks the central block of the gapmer.

[0116] In some embodiments, an oligonucleotide of the present disclosure may include one or more ligands attached at the 3’ terminal of the oligonucleotide and/or the 5’ terminal of the oligonucleotide. In some embodiments, an oligonucleotide of the present disclosure, or a pharmaceutically acceptable salt thereof, is conjugated to one or more ligands at the 3’ terminal of the oligonucleotide, or pharmaceutically acceptable salt thereof. In some embodiments, an oligonucleotide of the present disclosure, or a pharmaceutically acceptable salt thereof, is conjugated to one or more ligands at the 5’ terminal of the oligonucleotide, or pharmaceutically acceptable salt thereof. In other embodiments, an oligonucleotide of the present disclosure, or a pharmaceutically acceptable salt thereof, is conjugated to one or more ligands at both the 3’ terminal of the oligonucleitde and the 5’ terminal of the oligonucleotide, or pharmaceutically acceptable salt thereof. In some embodiments, the one or more ligands may comprise one or more N-acetylgalactosamine moieties. In some embodiments, the one or more ligands may compirse one or more cholesterol or lipid moieties. In some embodiments, the one or more ligands may comprise one or more tocopherol moieties. In some embodiments, the one or more ligands comprise cholesterol, one or more tocopherols, or one or more N-acetylgalactosamine moieties, or any combination thereof. [0117] In some embodiments, the one or more ligands are comprised of three terminal galactosamines or galactosamine derivatives (such as N-acetyl-galactosamine). In some embodiments, the one or more ligands comprise three terminal N-acetyl-galactosamines (GalNAc or NAG). In some embodiments, the ligand is comprised of four terminal galactosamines or galactosamine derivatives (such as N-acetyl-galactosamine). In some embodiments, the targeting ligand includes four terminal N-acetyl-galactosamines (GalNAc or NAG). Other saccharides that may be used in ligands may be selected from the list including: galactose, galactosamine, N- formyl-galactosamine, N-acetyl-galactosamine, N-propionyl-galactosamine, N-n- butanoylgalactosamine, and N-iso-butanoylgalactosamine. The affinities of numerous galactose derivatives for the asialoglycoprotein receptor have been studied (see, for example: lobst, S.T. and Drickamer, K. J.B.C. 1996, 271, 6686) or are readily determined using methods well known and commonly used in the art. Terms commonly used in the art when referring to three terminal N- acetyl-galactosamines include tri-antennary, tri-valent, and trimer. Terms commonly used in the art when referring to four terminal N-acetyl-galactosamines include tetra-antennary, tetra-valent, and tetramer.

PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION

[0118] In addition to the compounds of formula (A) and formula (I) provided, or any embodiment or aspect thereof, the disclosure also provides for compositions and medicaments comprising a compound of the present disclosure, or any embodiment or aspect thereof, and at least one pharmaceutically acceptable excipient.

[0119] In addition to oligonucleotides comprising one or more moieties of formulae (II), (III), or (IV), or any embodiment or aspect thereof, as provided herein, the disclosure also provides for compositions and medicaments comprising an oligonucleotide of the present disclosure, or any embodiment or aspect thereof, and at least one pharmaceutically acceptable excipient.

[0120] In addition to oligonucleotides comprising one or more moieties of formulae (V), (VI), or (VII), or any embodiment or aspect thereof, as provided herein, the disclosure also provides for compositions and medicaments comprising an oligonucleotide of the present disclosure, or any embodiment or aspect thereof, and at least one pharmaceutically acceptable excipient.

[0121] In one aspect, the disclosure provides for pharmaceutical compositions or medicaments comprising a compound or an oligonucleotide of the disclosure (or embodiments and aspects thereof, including stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts, and prodrugs) and a pharmaceutically acceptable carrier, diluent, or excipient. In another aspect, the disclosure provides for preparing compositions (or medicaments) comprising compounds or oligonucleotides of the disclosure. In another aspect, the disclosure provides for administering compounds or oligonucleotides of the disclosure and pharmaceutical compositions comprising compounds or oligonucleotides of the disclosure to a patient (e.g., a human patient) in need thereof.

INDICATIONS AND METHODS OF TREATMENT

[0122] In another aspect, the disclosure provides for a method for treating a condition, disease, or disorder, comprising the step of administering a therapeutically effective amount of a compound of formula (A) or formula (I), or an embodiment or aspect thereof, as described elsewhere herein, to a subject in need thereof.

[0123] In another aspect, the disclosure provides for a method for treating a condition, disease, or disorder, comprising the step of administering a therapeutically effective amount of an oligonucleotide comprising one or more moieties of formulae (II), (III), or (IV), as described elsewhere herein, or an embodiment or aspect thereof, as described elsewhere herein, to a subject in need thereof.

[0124] In another aspect, the disclosure provides for a method for treating a condition, disease, or disorder, comprising the step of administering a therapeutically effective amount of an oligonucleotide comprising one or more moieties of formulae (V), (VI), or (VII), as described elsewhere herein, or an embodiment or aspect thereof, as described elsewhere herein, to a subject in need thereof.

[0125] In another aspect, the disclosure provides for a method for preventing a condition, disease, or disorder, comprising the step of administering a therapeutically effective amount of a compound of formula (A) or formula (I), or an embodiment or aspect thereof, as described elsewhere herein, to a subject in need thereof.

[0126] In another aspect, the disclosure provides for a method for preventing a condition, disease, or disorder, comprising the step of administering a therapeutically effective amount of an oligonucleotide comprising one or more moieties of formulae (II), (III), or (IV), as described elsewhere herein, or an embodiment or aspect thereof, to a subject in need thereof. [0127] In another aspect, the disclosure provides for a method for preventing a condition, disease, or disorder, comprising the step of administering a therapeutically effective amount of an oligonucleotide comprising one or more moieties of formulae (V), (VI), or (VII), as described elsewhere herein, or an embodiment or aspect thereof, to a subject in need thereof.

[0128] In another aspect, the disclosure provides for a compound of formula (A) or formula (I), as described elsewhere herein, or any embodiment or aspect thereof, for use in medical therapy in a subject in need thereof.

[0129] In another aspect, the disclosure provides for an oligonucleotide comprising one or more moieties of formulae (II), (III), or (IV), as described elsewhere herein, or an embodiment or aspect thereof, for use in medical therapy in a subject in need thereof.

[0130] In another aspect, the disclosure provides for an oligonucleotide comprising one or more moieties of formulae (V), (VI), or (VII), as described elsewhere herein, or an embodiment or aspect thereof, for use in medical therapy in a subject in need thereof.

[0131] In another aspect, the disclosure provides for a compound of formula (A) or formula (I), as described elsewhere herein, or any embodiment or aspect thereof, for the treatment or prevention of a condition, disease, or disorder in a subject in need thereof.

[0132] In another aspect, the disclosure provides for an oligonucleotide comprising one or more moieties of formulae (II), (III), or (IV), as described elsewhere herein, or an embodiment or aspect thereof, for the treatment or prevention of a condition, disease, or disorder in a subject in need thereof.

[0133] In another aspect, the disclosure provides for an oligonucleotide comprising one or more moieties of formulae (V), (VI), or (VII), as described elsewhere herein, or an embodiment or aspect thereof, for the treatment or prevention of a condition, disease, or disorder in a subject in need thereof.

[0134] In another aspect, the disclosure provides for the use of a compound of formula (A) or formula (I), as described elsewhere herein, or any embodiment or aspect thereof, for the preparation of a medicament for the treatment or prophylaxis of a condition, disease, or disorder in a subject in need thereof.

[0135] In another aspect, the disclosure provides for the use of an oligonucleotide comprising one or more moieties of formulae (II), (III), or (IV), as described elsewhere herein, or an embodiment or aspect thereof, for the preparation of a medicament for the treatment or prophylaxis of a condition, disease, or disorder in a subject in need thereof.

[0136] In another aspect, the disclosure provides for the use of an oligonucleotide comprising one or more moieties of formulae (V), (VI), or (VII), as described elsewhere herein, or an embodiment or aspect thereof, for the preparation of a medicament for the treatment or prophylaxis of a condition, disease, or disorder in a subject in need thereof.

[0137] In some aspects, the disclosure provides a compound of formula (A) or formula (I), as described elsewhere herein, or any embodiment or aspect thereof, for the treatment or prophylaxis of a viral disease or disorder. In some embodiments, the viral disease or disorder is selected from the group consisting of influenza, hepatitis B, hepatitis C, hepatitis D, diseases caused by the Respiratory Syncytial Virus (RSV), diseases caused by the Human Immunodeficiency Virus (HIV), Acquired Immunodefiency Syndrome (AIDS), diseases caused by Rhinovirus, diseases caused by the Coxsackievirus, diseases caused by the Chikungunya virus, diseases caused by the Zika virus, and diseases caused by the Dengue virus, or any combination thereof. In some embodiments, the viral disease can be a chronic hepatitis B (HBV) infection.

[0138] In some aspects, the disclosure provides an oligonucleotide comprising one or more moieties of formulae (II), (III), or (IV), as described elsewhere herein, or an embodiment or aspect thereof, for the treatment or prophylaxis of a viral disease or disorder. In some embodiments, the viral disease or disorder is selected from the group consisting of influenza, hepatitis B, hepatitis C, hepatitis D, diseases caused by the Respiratory Syncytial Virus (RSV), diseases caused by the Human Immunodeficiency Virus (HIV), Acquired Immunodefiency Syndrome (AIDS), diseases caused by Rhinovirus, diseases caused by the Coxsackievirus, diseases caused by the Chikungunya virus, diseases caused by the Zika virus, and diseases caused by the Dengue virus, or any combination thereof. In some embodiments, the viral disease can be a chronic hepatitis B (HBV) infection.

[0139] In some aspects, the disclosure provides an oligonucleotide comprising one or more moieties of formulae (V), (VI), or (VII), as described elsewhere herein, or an embodiment or aspect thereof, for the treatment or prophylaxis of a viral disease or disorder. In some embodiments, the viral disease or disorder is selected from the group consisting of influenza, hepatitis B, hepatitis C, hepatitis D, diseases caused by the Respiratory Syncytial Virus (RSV), diseases caused by the Human Immunodeficiency Virus (HIV), Acquired Immunodefiency Syndrome (AIDS), diseases caused by Rhinovirus, diseases caused by the Coxsackievirus, diseases caused by the Chikungunya virus, diseases caused by the Zika virus, and diseases caused by the Dengue virus, or any combination thereof. In some embodiments, the viral disease can be a chronic hepatitis B (HBV) infection.

PREPARATION OF COMPOUNDS

[0140] In one aspect, the disclosure provides for a method of preparing a compound of formula (A) or formula (I), as described elsewhere herein, or any embodiment or aspect thereof.

[0141] The following synthetic reaction schemes are merely illustrative of some of the methods by which the compounds of the present disclosure (or an embodiment or aspect thereof) can be synthesized. Various modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application.

[0142] All reactions were carried out using dried glassware and magnetic stirring under an atmosphere of argon. All reagents were obtained from commercially available sources and used without further purification. Anhydrous reaction solvents were obtained by distillation over either calcium hydride (toluene, pyridine) or sodium/benzophenone (tetrahydrofuran). Unless otherwise indicated, all drying of organic extracts were carried out over magnesium sulfate and all chromatographic separations were performed on silica (40-63 or 60-200 pm) from SdS. Thin- layer chromatography was carried out on Merck DC Kieselgel 60 F-254 aluminum sheets. Compounds were visualized by one or both of the following methods: (1) illumination with a shortwavelength UV lamp ( = 254 nm) and/or (2) staining with phosphomolybdic acid or KMnO4 staining solution followed by heating. ^TH and ¹³C nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance 300 or 500 MHz spectrometers. Chemical shifts are expressed in parts per million (ppm) and coupling constants in hertz (Hz). 'H and ¹³C spectra were calibrated using residual solvent as an internal reference (CDCh, 6 7.24 ppm and 6 77.23 ppm, respectively; MeOH-t/v, 6 3.31 ppm and 6 49.15 ppm, respectively; D SO-if =, 6 2.50 ppm and 6 39.51 ppm, respectively). Heteronuclear single quantum coherence and correlation spectroscopy experiments were run on the same apparatus to confirm the reported assignments. Spin multiplicities are indicated by the following symbols: singlet (s), doublet (d), triplet (t), multiplet (m), and broad signal (br). Infrared (IR) spectra were recorded on a PerkinElmer Fourier transform infrared (FTIR) Spectrum 100 spectrometer; the wave numbers (v) are quoted in cm^-1. Melting points were recorded on a Kofler bench device and are uncorrected. Optical rotations were measured on a PerkinElmer polarimeter. High resolution mass spectra (HRMS) were recorded on Waters LCT Premier mass spectrometer.

[0143] The following generalized schemes are used to prepare the disclosed compounds, intermediates, and pharmaceutically acceptable salts thereof. It will be appreciated that synthetic procedures employed in the preparation of disclosed compounds and intermediates will depend on the particular substituents present in the compound or intermediate and that various protection, deprotection, and conversion steps that are standard in organic synthesis may be required, but may not be illustrated in the following general schemes. It is also to be understood that any of the steps shown in any of the following general schemes may be used in any combination and in any order that is chemically feasible to achieve a desired intermediate or disclosed compound. Although certain exemplary embodiments are depicted and described herein, the compounds of the present disclosure (or an embodiment or aspect thereof) can be prepared using appropriate starting materials according to the methods described generally herein and/or by methods available to one of ordinary skill in the art.

[0144] The following abbreviations are used throughout the synthetic schemes:

[0145] Bn = benzyl

[0146] DCC = N,N'-dicyclohexylcarbodiimide

[0147] DMAP = 4-dimethylaminopyridine

[0148] equiv = equivalent

[0149] Et = ethyl

[0150] h = hour

[0151] Me = methyl

[0152] MW = micro wave

[0153] RCM = ring closing metathesis

[0154] RT = room temperature

[0155] T = thymine

[0156] TFA = trifluoroacetic acid [0157] THF = tetrahydrofuran

[0158] EXAMPLE 1

[0159] Scheme A shows a retrosynthetic analysis of a 7’ -alkyl substituted ENA monomer (compound 1), wherein R¹ is as defined herein for a compound of formula (A) or formula (I).

Scheme A

(R = alkyl) deprotection

[0160] EXAMPLE 2

[0161] Scheme B shows a Tebbe olefination reaction on ester 4a to prepare enol ether 3a. Enol ether 3a was found to be prone to hydrolysis into a corresponding alcohol 8 during purification or during later storage. However, rapid elution of enol ether 3a on neutralized silica allowed for the isolation of 3a in good and reproducible yields.

Scheme B

[0162] Preparation of Tebbe reagent (7): To solid Cp2TiCh (1.0 g, 4.0 mmol) was added at room temperature (r.t.) and without stirring a solution of AlMes (8.0 mmol, 4.0 mL, 2 M in toluene). After methane evolution ceased (30-60 min), the reaction mixture had turned dark red and was stirred for 60 h under inert atmosphere. After this time, additional MesAl (4 mmol, 2 mL, 2M in toluene) was added to the reaction mixture which was stirred for a further 12 h. The resultant solution of Tebbe reagent was then directly used and its concentration was considered to be 0.66 M in toluene.

[0163] General procedure for Scheme B: To a -40 °C solution of ester 4 (1.0 equiv; see Scheme A) in a mixture of tetrahydrofurampyridine (5: 1, 0.082M) was added dropwise a solution of freshly prepared Tebbe reagent (2.0 equiv). The temperature was internally monitored and maintained at -40 °C during the addition of the Tebbe reagent. After 5 h at -40 °C, additional Tebbe reagent (1.0 equiv) was added to the reaction mixture which was slowly warmed to r.t and stirred for a further 10 h. After this time, the reaction mixture was cooled to -40 °C and carefully quenched with a NaOH aqueous solution (0.5 equiv, IN) added over a 30 min time period. (Warning! Wait between each drop of NaOH for the gas evolution to cease). The reaction mixture was diluted with Et2O, dried over Na2SO4, filtered through Celite (Et2O) and concentrated under reduced pressure. To minimize the hydrolysis of enol ethers 3 (see Scheme A) into alcohol 8, flash chromatography was standardized as following: a) silica gel was prepared using a mixture of petroleum ether/triethylamine (95/5) and allowed to stand for at least 3 h before being loaded and packed into the column; b) petroleum ether/triethylamine mixture (95/5, 200 mL) followed by pure petroleum ether (200 mL) were then eluted through the column. Solid loading of the crude material on Celite and rapid elution with petroleum ether/EtOAc delivered the desired enol ethers 3. (Note: enol ethers 3 should be kept in the cold and under inert atmosphere for storage). [0164] Preparation of l-((2R,3R,4S,5R)-4-(benzyloxy)-5-(benzyloxymethyl)-3-(prop-l- en-2-yloxy)-5-vinyltetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(lH, 3H)-dione (3a). Following the general procedure in Scheme B, the Tebbe olefination reaction was carried out with methyl ester 4a (200 mg, 0.395 mmol) in a mixture of tetrahydrofurampyridine (4.0 : 0.8 mL) and freshly prepared Tebbe reagent (1.2 mL, 0.8 mmol, then 0.6 mL, 0.4 mmol / 0.66 M in toluene). The crude residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc, 75/25) to deliver compound 3a as a viscous oil (135 mg, 68%); [a]²⁰D -32.2 (c 1.0; MeOH); ³H NMR (300 MHz, DMSO-tfe): 8 11.40 (s, 1H), 7.52 (d, J= 1.5 Hz, 1H), 7.39-7.26 (m, 10H), 6.06 (d, J= 6.0 Hz, 1H), 6.00 (dd, J= 17.4, 10.8 Hz, 1H), 5.36 (dd, J= 17.4, 1.5 Hz, 1H), 5.22 (dd, J= 10.8, 1.5 Hz, 1H), 4.80 (dd, apparent t, J= 5.7 Hz, 1H), 4.60-4.53 (m, 5H), 4.01 (d, J= 0.9 Hz, 1H), 3.91 (d, J= 2.1 Hz, 1H), 3.68 (AB syst., d, J= 10.5 Hz, 1H), 3.51 (AB syst., d, J= 10.5 Hz, 1H), 1.72 (s, 3H), 1.57 (d, J = 0.5 Hz, 3H); ¹³C H} NMR (75 MHz, DMSO-t/₆): 6 163.4, 158.0, 150.4, 138.1, 137.8, 135.5, 135.3, 128.4 (2C), 128.2 (2C), 127.7, 126.6 (3C), 127.5 (2C), 114.9, 110.2, 87.2, 85.3, 84.1, 77.5, 76.7, 73.2, 72.9, 72.7, 20.6, 11.8; IR (neat, Vmax / cm'¹): 3385, 3064, 2092, 2305, 1684, 1496, 1467, 1453, 1373, 1269, 1116, 1049, 1024, 994, 925, 821, 739, 698, 558, 463, 412. HRMS (TOF ESI+) m/z calculated for C29H36N3O6 [M+NH₄]⁺: 522.2604. Found: 522.2583.

[0165] Preparation of l-((2R,3R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-3-(but-l- en-2-yloxy)-5-vinyltetrahydrofuran-2-yl)-5-methylpyrimidine-2, 4(1H, 3H)-dione (3b). Following the general procedure in Scheme B, the Tebbe olefination reaction was carried out with methyl ester 4b (500 mg, 0.965 mmol) in a mixture of tetrahydrofurampyridine (10.0 : 2.0 mL) and freshly prepared Tebbe reagent (3.0 mL, 1.92 mmol, then 1.5 mL, 0.96 mmol / 0.66 M in toluene). The crude residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc, 78/22) to deliver compound 3b (299 mg, 60%); M. p. = 166-168 °C; [a]²⁰D -18.1 (c 1.0; MeOH); 'H NMR (300 MHz, DMSO ): 6 11.38 (s, 1H), 7.51 (d, J= 0.9 Hz, 1H), 7.41-7.24 (m, 10H), 6.04 (d, J=

5.7 Hz, 1H), 6.01 (dd, J= 17.4, 10.8 Hz, 1H), 5.36 (dd, J= 17.4, 1.8 Hz, 1H), 5.22 (dd, J= 10.8,

1.8 Hz, 1H), 4.79 (dd, apparent t, J= 5.5 Hz, 1H), 4.62-4.51 (br m, 5H), 3.99 (d, J= 2.4 Hz, 1H), 3.88 (d, J= 2.4 Hz, 1H), 3.67 (AB syst., d, J= 10.5 Hz, 1H), 3.50 (AB syst., d, J= 10.5 Hz, 1H), 2.00 (br q, J= 7.5 Hz, 2H), 1.52 (d, J= 0.9 Hz, 3H), 0.92 (t, J= 7.5 Hz, 3H); ¹³C {³H} NMR (75 MHz, DMSO-tL): 6 163.4, 162.9, 150.4, 138.1, 137.8, 135.6, 135.3, 128.4 (2C), 128.2 (2C), 127.7, 127.6 (3C), 127.4 (2C), 114.9, 110.2, 87.7, 85.6, 82.4, 77.5, 76.8, 73.0, 72.8, 72.7, 27.3, 11.9, 11.5; IR (neat, Vmax / cm'¹): 3187, 3032, 2927, 1684, 1496, 1454, 1361, 1271, 1232, 1208, 1176, 1124, 1070, 1027, 912, 806, 783, 737, 697, 598, 569, 487, 418. HRMS (TOF ESI+) m/z, calcd for C30H38N3O6 [M+NH₄]⁺: 536.2761. Found: 536.2758.

[0166] EXAMPLE 3

[0167] Scheme C shows an exemplary reaction scheme for the formation of bicyclic enol ether 2a via a ring closing metathesis. The combined mass of compounds 2a and 10 represented a 65% yield. 'H NMR analysis of an isolated product mixture revealed a ratio of compound 2a to compound 10 of 1.9:1.

Scheme C

3a 2a 10

[0168] General procedure for Scheme C: In a microwave reactor, HG-II catalyst 9 (20 mol%) was added under nitrogen to a solution of freshly prepared enol ether 3 (1.0 equiv; see Scheme A) in toluene (0.26 M). The reactor was sealed and heated under microwave irradiations at 100 °C for 60 min. After this time, the reaction mixture was allowed to cool down to r.t. and solvent was removed under reduced pressure. The crude residue was purified by flash chromatography on silica (petroleum ether/EtOAc) to give a mixture of cyclic enol ether 2 (see Scheme A) and bicyclic acetal side product which was used in the following step.

[0169] Preparation of l-((lR,5R, 7R,8S)-8-(benzyloxy)-5-((benzyloxy)methyl)-3-methyl- 2,6-dioxabicyclo[3.2.1]oct-3-en-7-yl)-5-methylpyrimidine-2,4(lH,3H)-dione (2a) and 1- ((1S, 2R, 5S, 7R)-2-(benzyloxy)-3-( f>enzyloxy)methyl)-5-methyl-6, 8-dioxabicyclo[ 3.2.1 ]oct-3-en- 7- yl)-5-methylpyrimidine-2,4(lH,3H)-dione (10). Following the general procedure for Scheme 3, the RCM reaction was carried out with freshly prepared enol ether 3a (200 mg, 0.39 mmol) and HG- II catalyst 9 (50 mg, 0.08 mmol) in toluene (1.5 mL). The crude residue was purified by flash chromatography on silica (petroleum ether/EtOAc : 70/30) to give cyclic enol ether 2a and bicyclic acetal 10 (123 mg, 65%) as a white solid and as a 1.9: 1 mixture. For analytical purposes, pure fractions of 2a and 10 were isolated by additional chromatography and characterized separately; 2a: M. p. = 85-88 °C; [a]²⁰ _D +60.5 (c 1.0; CHCh); 'H NMR (300 MHz, DMSO): 8 11.37 (br s, 1H), 7.50 (br d, = 0.5 Hz, 1H), 7.37-7.25 (m, 1 OH), 5.76 (s, 1H), 4.74 (br d, J= 3.0 Hz, 1H), 4.70 (br s, 1H), 4.68 (AB syst., d, J= 12.0 Hz, 1H), 4.60 (AB syst., d, J= 12.0 Hz, 1H), 4.56 (AB syst., d, J = 11.7 Hz, 1H), 4.52 (AB syst., d, J= 11.7 Hz, 1H), 4.08 (br d, J = 2.0 Hz, 1H), 3.69 (AB syst., d, J= 11.4 Hz, 1H), 3.61 (AB syst., d, J= 11.4 Hz, 1H), 1.76 (s, 3H), 1.48 (s, 3H). ¹³C H} NMR (75 MHz, DMSO-t/₆): 6 163.8, 153.0, 150.0, 138.0 (2C), 135.0, 128.3 (2C), 128.2 (2C), 127.6 (4C), 127.4 (2C), 108.7, 97.3, 87.9, 78.4, 76.0, 72.6, 71.1, 68.3, 68.2, 18.4, 12.0; IR (neat, Vmax / cm'¹): 3102, 2924, 2850, 1685, 1453, 1273, 1102, 1085, 1054, 905, 865, 826, 734, 692, 588, 486, 401. HRMS (TOF ESI+) m/z: calcd for C27H29N2O6 [M+H]⁺: 477.2026. Found: 477.2028. 10: M. p. = 91-94 °C; [a]²⁰ _D +30.5 (c 1.0; CHCh); 'H NMR (300 MHz, DMSO-t/₆): 6 11.50 (s, 1H), 7.35-7.22 (m, 9H), 7.18-7.10 (m, 2H), 6.21 (s, 1H), 5.74 (d, J = 5.1 Hz, 1H), 5.23 (d, J = 5.1 Hz, 1H), 4.57 (AB syst., d, J= 11.7 Hz, 1H), 4.37 (AB syst., d, J= 11.7 Hz, 1H), 4.27 (br s, 2H), 3.82 (br s, 2H), 3.41 (s, 1H), 1.62 (s, 6H); ¹³C {³H} NMR (75 MHz, DMSO-d₆): 6 163.8, 150.6,

138.1, 137.6, 135.6, 134.9, 129.7, 128.2 (4C), 128.1 (2C), 127.6, 127.3, 126.9 (2C), 108.1, 103.9,

83.1, 77.4, 71.6, 70.8, 68.3, 67.6, 21.7, 12.1; IR (neat, Vmax / cm'¹): 3100, 3082, 2921, 2853, 1681, 1454, 1389, 1207, 1058, 1053, 905, 865, 826, 734, 696, 584, 485, 402. HRMS (TOF ESI+) m/z: calcd for C27H29N2O6 [M+H]⁺: 477.2026. Found: 477.2012.

[0170] EXAMPLE 4

[0171] Scheme D shows the synthesis of 7’-Me-ENA-T (compound la). Note that starting material compound 2a contained 34% of compound 10, as defined in Scheme A.

Scheme D

[0172] General procedure for upper panel of Scheme D: To a -40 °C solution of an isomer mixture obtained from the RCM reaction of Scheme C (410 mg, 0.86 mmol) in dry THF (0.082M) was added under argon NaBH CN (5.0 equiv.) and trifluoroacetic acid (10.0 equiv). After 2 h at -40 °C, the temperature was allowed to slowly raise to r.t. and the reaction was stirred for further 24 h. After this time, the reaction mixture was diluted with Et2O. The organic layer was washed with a NaHCCh saturated aqueous solution, then brine and dried over MgSCU. Filtration and concentration under reduced pressure left a crude residue which was purified by flash chromatography on silica gel.

[0173] Preparation of l-((lR,3S,5R, 7R,8S)-8-(benzyloxy)-5-((benzyloxy)methyl)-3- methyl-2, 6-dioxabicyclo[ 3.2.1 ]octan- 7-yl)-5-methylpyrimidine-2, 4(1H, 3H)-dione (13a)

Following the general procedure of Scheme D, the enol ether reduction reaction was carried out with a 1.9: 1 mixture of 2a and 10 (410 mg, 0.86 mmol) in dry THF (10.5 mL), NaBHsCN (271 mg, 4.31 mmol) and trifluoroacetic acid (660 pL, 8.60 mmol). The crude residue was purified by flash chromatography on silica gel (C^Ch/E^O : 85/15) to give 13a (245 mg, 60%) as a pale yellow oil and as a single isomer; [a]²⁰D +50.0 (c 1.0; CHCh); ^XHNMR (300 MHz, CDCh): 8 8.62 (s, 1H), 7.84 (d, = 0.9 Hz, 1H), 7.34-7.11 (m, 10H), 5.98 (s, 1H), 4.68 (AB syst., d, J= 11.7 Hz, 1H), 4.50 (AB syst., d, J= 11.7 Hz, 1H), 4.45 (AB syst., d, J= 11.7 Hz, 1H), 4.42 (AB syst., d, J = 11.5 Hz, 1H), 4.30 (d, J = 2.7 Hz, 1H), 4.14-4.03 (m, 1H), 3.84 (d, J= 2.7 Hz, 1H), 3.65 (AB syst., d, J= 11.1 Hz, 1H), 3.50 (AB syst., d, J= 11.1 Hz, 1H), 1.80 (AB syst., dd, J= 12.9, 10.8 Hz, 1H), 1.39 (AB syst., dd, J= 12.9, 3.9 Hz, 1H), 1.34 (s, 3H), 1.22 (d, = 6.0 Hz, 3H); ¹³C H} NMR (75 MHz, CDCh): 6 163.9, 150.0, 137.7, 137.4, 135.7, 128.7 (2C), 128.5 (2C), 128.3, 128.0 (3C), 127.8 (2C), 110.0, 86.3, 84.3, 76.1, 73.7, 71.7, 71.3, 70.0, 67.1, 35.6, 21.2, 12.0. HRMS (TOF ESI-) m/z: calcd for C27H29N2O6 [M-H]’: 477.2026. Found: 477.2014.

[0174] General procedure for lower panel of Scheme D : To a solution of dibenzyl ether 13 (1.0 equiv) in methanol (0.07M) was added under argon Pd/C (20-40 mol%) and triethylsilane (20.0-40.0 equiv). (Note: addition of triethylsilane caused an immediate hydrogen evolution. The overpressure was compensated by attaching a latex balloon to the reaction flask). The reaction mixture was allowed to stir at r.t. for 12 h. After this time, the reaction mixture was filtered through Celite (MeOH), and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica.

[0175] 1-((1R,3S,5R, 7R,8S)-8-hydroxy-5-(hydroxymethyl)-3-methyl-2,6- dioxabicyclo [3.2.1] octan-7-yl)-5-methylpyrimidine-2,4(lH, 3H)-dione (la). Following the general procedure of the lower panel of Scheme D, the benzyl ethers removal reaction was carried out with dibenzyl ether 13a (100 mg, 0.21 mmol), Pd/C (10% w/w, 45 mg, 0.042 mmol), triethylsilane (670 pL, 4.18 mmol) in methanol (3 mL). The crude residue was purified by flash chromatography on silica (CftCh/MeOH : 93/7) to give la (42 mg, 68%) as a colorless oil; [a]²⁰D +20.0 (c 0.8; MeOH); ^XH NMR (300 MHz, MeOH-^): 8 8.25 (s, 1H), 5.98 (s, 1H), 4.22-4.09 (m, 1H), 4.12 (d, J= 3.0 Hz, 1H), 4.02 (d, J= 3.0 Hz, 1H), 3.72 (AB syst., d, J= 12.6 Hz, 1H), 3.66 (AB syst., d, J = 12.6 Hz, 1H), 1.86 (s, 3H), 1.74 (AB syst., dd, J = 13.2, 10.8 Hz, 1H), 1.45 (AB syst., dd, J = 13.2, 3.9 Hz, 1H), 1.26 (d, J= 6.3 Hz, 3H); ¹³C {³H} NMR (75 MHz, MeOH-tZ/): 6 167.8, 152.8, 137.9, 110.5, 87.1, 86.4, 80.6, 68.6, 65.6, 62.9, 35.8, 21.3, 12.9; IR (neat, v_max / cm'¹): 3502, 2931, 2631, 2536, 2328, 1652, 1627, 1468, 1449, 1415, 1368, 1298, 1255, 1173, 1130, 1102, 1062, 989, 933, 898, 818, 794, 772, 708, 596, 573, 489. HRMS (TOF ESI+) m/z: calcd for C13H19N2O6 [M+H]⁺: 299.1243. Found: 299.1246.

[0176] Preparation of l-((lR,3S,5R, 7R,8S)-3-ethyl-8-hydroxy-5-(hydroxymethyl)-2,6- dioxabicyclo [3.2.1] octan-7-yl)-5-methylpyrimidine-2,4(lH, 3H)-dione (lb). Following the general procedure of the lower panel of Scheme D, the benzyl ethers removal reaction was carried out with dibenzyl ether 13b (70 mg, 0.14 mmol), Pd/C (20% w/w, 30 mg, 0.056 mmol), triethylsilane (900 pL, 5.60 mmol) in methanol (2 mL). The crude residue was purified by flash chromatography on silica (CH^Ch/MeOH : 93/7) to give to give lb (30 mg, 69%) as a white solid; M. p. = 186-188 °C; [a]²⁰ _D +12.3 (c 1.0; MeOH); ^XH NMR (500 MHz, DMSO-t/₆): 6 11.30 (s, 1H), 8.16 (d, = 1.1 Hz, 1H), 5.82 (s, 1H), 5.39 (t, J= 5.0 Hz, 1H), 5.23 (d, J= 4.7 Hz, 1H), 3.97 (d, J= 3.2 Hz, 1H), 3.85 (t, J= 3.7 Hz, 1H), 3.83-3.76 (m, 1H), 3.58 (AB syst., dd, J= 15.0, 5.0 Hz, 1H), 3.49 (AB syst., dd, J= 15.0, 5.0 Hz, 1H), 1.74 (d, J= 0.9 Hz, 3H), 1.61 (dd, J = 12.8, 10.8 Hz, 1H), 1.55 (dd, J= 13.9, 7.0 Hz, 1H), 1.41-1.51 (m, 1H), 1.34 (dd, J= 12.9, 4.0 Hz, 1H), 0.89 (t, J= 1A Hz, 3H); ¹³C H} NMR (125 MHz, DMSO-t/₆): 6 163.9, 150.0, 135.7, 107.8, 84.9, 84.6, 78.2, 71.1, 63.5, 61.0, 32.1, 28.1, 12.4, 9.7; IR (neat, Vmax / crn'¹): 3502, 3442, 3070, 2945, 2929, 2302, 1672, 1668, 1464, 1267, 1103, 1050, 989, 933, 898, 818, 794, 772, 708, 596, 573, 489, 401. HRMS (TOF ESI+) m/z, calcd for C14H21N2O6 [M+H]⁺: 313.1400. Found: 313.1397.

[0177] EXAMPLE S

[0178] Scheme E shows the synthesis of 7’-Et-ENA-T (compound lb), wherein the reagents and conditions for each step are as follows: (a) K2CO3, MeOH, RT, 3 h, 85%; (b) DCC, DMAP, propionic acid, 90%; (c) Tebbe reagent, THF, pyridine, -40 °C to RT, 15 h, 60%; (d) HG- II 9 (20 mol%), toluene, M.W. 100 °C, 1 h; (e) NaBH₃CN, TFA, THF, -40 °C to RT, 24 h, (40% from compound 3b); (f) Pd/C (40 mol%), Et₃SiH, MeOH, RT, 12 h, 69%. Propionyl ester 4b was prepared in high yields from acetate 4a by a simple saponification/esterification sequence of reactions. Ester 4b was then submitted to the previously optimized Tebbe olefination conditions to deliver the desired enol ether 3b in fair yields. Subsequent RCM reaction using HG-II catalyst 9 under microwave activation conditions provided cyclic enol ether 2b which could only be partially purified. Treatment of 2b with TFA/NaBH₃CN as above provided 13b in 40% overall yield (two steps from 3b) and as a single diastereoimer. Expectedly and similarly to the methyl derivative 13a, the absolute configuration of the newly created stereocenter in 13b was proven to be (5) (NOESY NMR experiment). Final deprotection of the two remaining benzyl ether protecting groups under the previously developed conditions allowed the formation of 7’-(S)-Et-ENA-T monomer lb in good yield.

Scheme E

[0179] Preparation of l-((lR,3S,5R, 7R,8S)-8-(benzyloxy)-5-((benzyloxy)methyl)-3-ethyl- 2,6-dioxabicyclo[3.2.1]octan-7-yl)-5-methylpyrimidine-2,4(lH,3H)-dione (13b). Step 1: Following the general procedure of Scheme C, the RCM reaction was carried out freshly prepared enol ether 3b (500 mg, 0.964 mmol) and HG-II catalyst 9 (120 mg, 0.19 mmol) in toluene (12.5 mL). The crude residue was filtered through a silica gel plug (petroleum ether/EtOAc : 70/30) to give partially purified cyclic enol ether 2b (307 mg) as a white solid and as a mixture with bicyclic acetal side product. The mixture was used in the next step without further purification. Step 2: Following the general procedure of the upper panel of Scheme D, the the enol ether reduction reaction was carried out with partially purified enol ether 2b (220 mg, 0.45 mmol), NaBFFCN (141 mg, 2.25 mmol), trifluoroactetic acid (400 pL, 5.22 mmol) in THF (4.5 mL). The crude residue which was purified by flash chromatography on silica gel (CThCh/EfoO : 85/15) to furnish 13b (159 mg, 72%) as a pale yellow solid and as a single isomer; M. p. = 94-96 °C; [a]²⁰D +70.0 (c 1.0; CHCh); 'H NMR (300 MHz, CDCh): 8 9.44 (s, 1H), 7.83 (d, J = 0.6 Hz, 1H), 7.34-7.07 (m, 10H), 5.97 (s, 1H), 4.66 (AB syst., d, J= 11.4 Hz, 1H), 4.49 (AB syst., d, J= 11.7 Hz, 1H), 4.44 (AB syst., d, J= 11.7 Hz, 1H), 4.38 (AB syst., d, J= 11.4 Hz, 1H), 4.32 (br d, J= 2.4 Hz, 1H), 3.91-3.78 (m, 1H), 3.83 (br d, J= 2.4 Hz, 1H), 3.64 (AB syst., d, J= 11.1 Hz, 1H), 3.49 (AB syst., d, J= 11.1 Hz, 1H), 1.78 (dd, J= 12.9, 11.4 Hz, 1H), 1.66-1.42 (m, 2H), 1.41-1.29 (m, 1H), 1.34 (s, 3H), 0.86 (t, J = 7.5 Hz, 3H); ¹³C H} NMR (75 MHz, CDCh): 6 164.4, 150.2, 137.7, 137.4, 135.8, 128.7 (2C), 128.5 (2C), 128.2, 128.0 (3C), 127.8 (2C), 110.0, 86.3, 84.2, 75.9, 73.7,

71.8, 71.6, 71.5, 70.1, 33.3, 28.5, 11.9, 9.5. HRMS (TOF ESI+) m/z, calcd for C28H33N2O6 [M+H]⁺: 493.2339. Found: 493.2328.

[0180] Preparation of l-((2R,3R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-3-hydroxy- 5-vinyltetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(lH,3H)-dione (8). To a solution of methyl ester 4a (3.00 g, 5.93 mmol) in MeOH (30 mL) was added at r.t. K2CO3 (2.46 g, 17.8 mmol) and the reaction was stirred for 3 h. After this time, MeOH was removed under reduced pressure. The resulting residue was dissolved in EtOAc (200 mL) and was sequentially washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc: 45/55) to give alcohol 8 (2.34 g, 85%) as a white solid. The compound showed satisfactory NMR data;^12a 'H NMR (300 MHz, CDCh): 8 9.05 (br.s, 1H), 7.47 (d, J= 1.5 Hz, 1H), 7.33-7.15 (m, 10H), 5.99-5.95 (m, 1H), 5.89 (dd, J = 17.3, 10.9 Hz, 1H), 5.45 (dd, J= 17.3, 1.4 Hz, 1H), 5.23 (dd, J = 10.9, 1.4 Hz, 1H), 4.63 (AB syst., J= 11.7 Hz , 1H), 4.54 (AB syst., J= 11.7 Hz , 1H),

4.47 (AB syst., J = 11.8 Hz , 1H), 4.42 (AB syst., J= 11.7 Hz , 1H), 4.30-4.14 (m, 2H), 3.47 (s, 2H), 1.45 (s, 3H). ¹³C {³H} NMR (75 MHz, CDCh): 6 163.9, 150.8, 137.3, 137.1, 136.0, 134.3, 128.8 (2C), 128.7 (2C), 128.4, 128.2, 128.1 (2C), 127.8 (2C), 116.8, 111.1, 89.5, 87.5, 78.6, 74.7,

73.8, 73.7, 73.1, 12.1. HRMS (TOF ESI+) m/z: calcd for C26H29N2O6 [M+H]⁺: 465.2026. Found: 465.2043.

[0181] Preparation of (2R,3R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-(5-methyl- 2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-5-vinyltetrahydrofuran-3-yl propionate (4b). To a 0 °C solution of propionic acid (0.21 mL, 2.80 mmol) in CH2CI2 (10 mL) were added DCC (1.33 g,

6.47 mmol) and DMAP (0.26 g, 2.16 mmol). After 10 min, alcohol 8 (1.00 g, 2.16 mmol) was added to the reaction mixture which was allowed to warm up to r.t. and stirred for 10 h. After this time, the reaction was hydrolyzed with H2O (30 mL). The aqueous layer was extracted with CH2Q2 (50 mL x 3 times) and the combined organic extracts were washed with brine (50 mL), dried over MgSCU, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc: 65/35) to give ethyl ester 4b as a white solid (955 mg, 85%); M. p. = 82-84 °C; [a]²⁰ _D -60.0 (c 1.0; CHCh); 'H NMR (300 MHz, CDCh): 6 9.34 (br.s, 1H), 7.82-7.51 (d, J = 1.2 Hz, 1H), 7.45-7.25 (m, 10H), 6.25 (d, J = 3.3 Hz, 1H), 6.00 (dd, J= 17.4, 10.8, 1H), 5.54 (dd, 17.4, 1.2, 1H), 5.40 (dd, 6.0, 3.6 Hz, 1H), 5.33 (dd, J= 10.8, 1.2 Hz, 1H), 4.68 (AB syst., d, J=11.7, 1H), 4.57-4.42 (m, 4H), 3.57 (AB syst., d, J = 10.5, 1H), 3.52 (AB syst., d, J= 10.5, 1H), 2.40 (2 x qd, J= 7.5, 3.0 Hz, 2 x 1H), 1.56 (d, J = 1.2 Hz, 3H), 1.14 (t, J = 7.5 Hz, 3H); ¹³C H} NMR (75 MHz, CDCh): 6 173.4, 163.9, 150.4, 137.6, 137.3, 135.7, 134.1, 128.7 (2C), 128.5 (2C), 128.15, 128.09, 128.0 (2C), 127.8 (2C), 116.4, 111.3, 87.5, 87.0, 77.1, 74.6, 73.9, 73.5, 72.1, 27.4, 12.1, 9.0; IR (neat, v_max / cm'¹): 3188, 3032, 2927, 1683, 1496, 1453, 1361, 1271, 1233, 1207, 1175, 1070, 1027, 989, 912, 870, 806, 782, 736, 697, 597, 568, 487, 467, 415. HRMS (TOF ESI+) m/z, calcd for C29H33N2O7 [M+H]⁺: 521.2288. Found: 521.2290.

[0182] In summary, provided herein is a modular synthesis towards unprecedented 7’- alkyl-substituted-ENA thymidine monomers. The efficiency of the reported synthetic strategy was demonstrated by the preparation of 7’-(5)-Me-ENA-T and 7’-(5)-Et-ENA-T monomers la and lb from readily available methyl ester 4a. The construction of such bicyclic modified nucleosides relies on a key Tebbe olefination/ring closing metathesis sequence of reactions followed by a stereoselective reduction of the resultant enol ether unit.

[0183] EXAMPLE 6

[0184] An oligonucleotide (for example, an antisense oligonucleotide or an siRNA oligonucleotide) is prepared using one or more of the compounds described in Examples 1-5 above, as appropriate, using methods well known to those in the art. The one or more compounds from Examples 1-5 are independently incorporated at the 3’ terminal of the oligonucleotide or at the 5’ terminal of the oligonucleotide, as desired. Successive additions of any number and any combination of compounds from Examples 1-5 and/or other nucleotides can be used to produce an oligonucleotide of the desired composition and length. In some instances, a compound from Examples 1-5 ends up at the 3’ terminal of the oligonucleotide or at the 5’ terminal of the oligonucleotide. In other instances, a compound from Examples 1-5 is added to the middle of an oligonucleotide.

PREPARATION OF OLIGONUCLEOTIDES

[0185] It is to be understood that a compound of formula (A) or formula (I), or any variation or embodiment thereof, as described elsewhere herein, may find use as a building block for the preparation of an oligonucleotide comprising one or more moieties of formulae (II), (III), or (IV), or any variation or embodiment thereof, or an oligonucleotide comprising one or more moieties of formulae (V), (VI), or (VII), or any variation or embodiment thereof, as described elsewhere herein. Preparation of an oligonucleotide comprising one or more moieties of formulae (II), (III), or (IV), or any variation or embodiment thereof, or an oligonucleotide comprising one or more moieties of formulae (V), (VI), or (VII), or any variation or embodiment thereof, as described elsewhere herein, from one or more compounds of formula (A) or formula (I), or any variation or embodiment thereof, as described elsewhere herein, is well within the capability of those skilled in the art in view of this disclosure.

[0186] This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal language of the claims.

[0187] It is to be understood that the invention is not limited to the particular embodiments and aspects of the disclosure described above, as variations of the particular embodiments and aspects may be made and still fall within the scope of the appended claims. All documents cited to or relied upon herein are hereby expressly incorporated herein by reference in their entirety.

Claims

1. A compound of formula (A):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is optionally substituted Ci-ealkyl;

R² is H, an optionally substituted phosphonate moiety, an optionally substituted phosphorothioate moiety, or an optionally substituted thiophosphoroamidate moiety; and

Y is an optionally substituted heterocyclic base.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heterocyclic base of Y is an optionally substituted purine base or an optionally substituted pyrimidine base.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heterocyclic base of Y is an optionally substituted pyrimidine base.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein

57

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R² is H, such that the compound of formula (I) is a compound of formula (IA):

or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R² is an optionally substituted phosphonate moiety, an optionally substituted phosphorothioate moiety, or an optionally substituted thiophosphoroamidate moiety.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein the phosphonate moiety of R² is substituted with one or more optionally substituted N-linked amino acid esters.

8. The compound of claim 6 or claim 7, or a pharmaceutically acceptable salt thereof, wherein the phosphonate moiety of R² is substituted with one or more optionally substituted Ce- 2oaryl.

9. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R² is

such that the compound of formula (I) is a compound of formula (IB):

or a pharmaceutically acceptable salt thereof.

10. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R² is an unsubstituted phosphonate moiety, an unsubstituted phosphorothioate moiety, or an unsubstituted thiophosphoroamidate moiety.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R² is

12. The compound of claim 10 or claim 11, or a pharmaceutically acceptable salt thereof, wherein

13. The compound of any one of claims 4-12, or a pharmaceutically acceptable salt thereof, wherein R³ is H.

14. The compound of any one of claims 4-12, or a pharmaceutically acceptable salt thereof, wherein R³ is methyl.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R¹ is Ci-ealkyl, wherein the Ci-ealkyl of R¹ is optionally substituted with one or more halo, -OH, -SH, -CN, Ci-ealkoxy, Ci-ehaloalkoxy, -C(O)OH, -C(O)-Ci-6alkyl, -C(O)-Ci-6alkoxy, -C(O)-Ci-6haloalkoxy, or -NH2.

16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R¹ is Ci-salkyl, wherein the Ci-salkyl of R¹ is optionally substituted with one or more halo, -OH, -SH, -CN, Ci-ealkoxy, Ci-ehaloalkoxy, -C(O)OH, -C(O)-Ci-6alkyl, -C(O)-Ci-6alkoxy, -C(O)-Ci-6haloalkoxy, or -NH2.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R¹ is ethyl.

18. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R¹ is in the R stereochemical configuration.

20. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R¹ is in the S stereochemical configuration.

60

21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting

pharmaceutically acceptable salt thereof.

22. An oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties independently selected from the group consisting of:

wherein

R¹ is optionally substituted Ci-ealkyl;

Y is an optionally substituted heterocyclic base.

23. An oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising one or more moieties independently selected from the group consisting of:

wherein:

R¹ is optionally substituted Ci-ealkyl;

R³ is H or methyl.

24. The oligonucleotide of claim 22 or claim 23, or a pharmaceutically acceptable salt thereof, wherein the oligonucleotide is a single-stranded oligonucleotide, or a pharmaceutically acceptable salt thereof.

25. The oligonucleotide of any one of claims 22-24, or a pharmaceutically acceptable salt thereof, wherein the oligonucleotide is an antisense oligonucleotide, or a pharmaceutically acceptable salt thereof.

26. The oligonucleotide of claim 22 or claim 23, or a pharmaceutically acceptable salt thereof, wherein the oligonucleotide is a double-stranded oligonucleotide, or a pharmaceutically acceptable salt thereof.

27. The oligonucleotide of any one of claims 22-26, or a pharmaceutically acceptable salt thereof, wherein the oligonucleotide is an siRNA oligonucleotide, or a pharmaceutically acceptable salt thereof.

28. The oligonucleotide of any one of claims 22-27, or a pharmaceutically acceptable salt thereof, wherein the oligonucleotide is conjugated to one or more ligands

(i) at the 3’ terminal of the oligonucleotide, or

(ii) at the 5’ terminal of the oligonucleotide, or

(iii) at both the 3’ terminal and the 5’ terminal of the oligonucleotide.

29. The oligonucleotide of claim 28, or a pharmaceutically acceptable salt thereof, wherein the one or more ligands comprise cholesterol, one or more tocopherols, or one or more N- acetylgalactosamine moieties, or any combination thereof.

30. A pharmaceutical composition comprising an oligonucleotide of any one of claims 22-29, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

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