5'-modified monomers, oligonucleotides and double-stranded rnas

Abstract

The technology described herein relates to 5'-modified nucleosides, nucleotides, oligonucleotides and double-stranded RNAs, e.g., siRNAs, and kits comprising them and methods of their use for inhibiting target genes.

Description

5’-MODIFIED MONOMERS, OLIGONUCLEOTIDES AND DOUBLE-STRANDED RNAS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit under 35 U.S.C. § 119 of U.S. Provisional Application No.63 / 660,129 filed June 14, 2024, and U.S. Provisional Application No.63 / 705,390 filed October 9, 2024, the contents of all of which are incorporated herein by reference in their entirety. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on June 12, 2025, is named “ALN-525_ST_26.xml” and is 1,538,503 bytes in size. TECHNICAL FIELD

[0003] The technology described herein relates generally to 5’-modified nucleosides, nucleotides, oligonucleotides and double-stranded RNAs, e.g., siRNAs, compositions and kits comprising them and methods of their use for inhibiting target genes. BACKGROUND

[0004] There remains a need in the art for oligonucleotides and siRNAs having improved activity and / or pharmacodynamics. The present disclosure addresses some of these needs. SUMMARY

[0005] In one aspect, provided herein is a compound of formulae I-XXI,or a saltthereof, wherein: M is a monocyclic or bicyclic ring (such as C3-8cycloalkyl (e.g., cyclohexyl, cyclopentyl or cyclobutyl) or heterocyclyl (e.g., piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, or tetrahydrothienyl), a 5-membered sugar, or a 6- membered sugar, optionally, M is in the south conformation (i.e., C2’-endo);n is an integer selected from 1 - 3; n5is an integer selected from 2 - 5 (e.g., 2, 3, or 4, preferably 2); n6is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1); n7is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1); n8is an integer selected from 1 - 3 (e.g., 1 or 2); n9is an integer selected from 1 - 3 (e.g., 1 or 2); n10is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1); y is 0 or 1; A is -C(*)(H)-, -CH2C(*)(H)-, or -C(*)(H)CH2-, wherein * is the bond to E; E is a bond or -CH2-; B is an optionally modified nucleobase (e.g., uracil); Q is propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2- ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2- methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2- ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2- methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q are both replaced with O or S; one methine in Q is optionally replaced with -N=; Q4is ethylene, ethenylene, propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2-ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2- methyl)cyclopropyl, (2-methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3- cyclopropyl)propyl, (2-ethyl)cyclopropylmethyl, cyclopropyl, 2-(2- methyl)cyclopropylethyl, 2-methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q4are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q4are both replaced with O or S;one methine in Q4is optionally replaced with -N=; Q5is methylene, ethylene, ethenylene, propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2-ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2-methyl)cyclopropylmethyl, 2- propylcyclopropyl, (3-cyclopropyl)propyl, (2-ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2-methylcyclobutyl, 3- methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q5are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q5are both replaced with O or S; one methine in Q5is optionally replaced with -N=; X is O or S; XAis O, S, SO2, CH2, NHRS’or N(CO)RS’, wherein RS’is vinyl, ethynyl, allyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; YAis O, S, SO2, CH2, NHRS’or N(CO)RS’, wherein RS’is vinyl, ethynyl, allyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; each RPis independently C1-3alkyl, -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RSis independently hydrogen, C1-3alkyl, or a thiol protecting group; each RNis independently hydrogen, C1-3alkyl, or an amine protecting group; and R2Sis C1-3alkyl; RPSis C1-3alkyl, -ORO, -N(RN)2, -N(RN)S(O)2R2S, -N(RN)P(O)(ORO)(RPC), or - N=P(ORO)2(RPC), wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RNis independently hydrogen, C1-3alkyl, or an amine protecting group; and RPCis C1-6alkyl (e.g., C1-3alkyl or methyl); and R2Sis C1-3alkyl;RAis alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amin, alkenyl (e.g., vinyl or allyl), alkynyl (e.g., ethynyl or propargyl) or alkyl ester; R4’is C1-6alkyl (e.g., methyl),r C1-6alkoxy (e.g., methoxy), hydrogen; R5Xis H or C1-6alkyl (e.g., methyl); one of R2’and R3’is hydrogen, halogen, -OR20, alkyl, branched alkyl, aminoC1-6alkyl(e.g., branched aminoC1-6alkyl), C2-6alkenyl, C2-6alkynyl, C1-6alkyl ester, C1-6alkylthio (e.g., branched C1-6alkylthio), C1-6alkylamino (e.g., branched N- C1-6alkylamino), C2-6alkenylthio (e.g., branched C2-6alkenylthio), N- C2-6alkenylamino (e.g., branched N- C2-6alkenylamino), C2-6alkylthioester, N-C1-6alkylcarbamyl,wherein: R20is hydrogen, hydroxyl protecting group, optionally substituted alkyl, (e.g., optionally substituted C1-6alkyl, (e.g., methyl, 2-methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N-methylamino)-2-oxoethyl, 2-[N,N- dimethyl)aminooxy]ethyl, or 3-oxo-3-(N-methylamino)prop-1-yl)), optionally substituted branched alkyl, optionally substituted alkenyl (e.g., optionally substituted C2-6alkenyl,) or optionally substituted alkynyl, (e.g., optionally substituted C2-6alkynyl (e.g., propargyl); and R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amin, and the other of R2’and R3’is -OR30, wherein R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide.

[0006] In some embodiments, Q is notwherein * is the bond to the phosphorousatom.

[0007] In some embodiments, when X is O or S, and each Rpis ORO, wherein each ROis hydrogen or an oxygen protecting group, then Q is notwherein * is the bond to the phosphorous atom.

[0008] In some embodiments, the compound is not of the formula,.

[0009] Some compounds of Formula (I) can be of Formula (Ia),For example, some compounds of Formula (I) can be of formula,wherein: Q1is -O-, -S-, or -N(RN)-, and RNis hydrogen, methyl, C1-3alkoxy, or C1-3acyl.

[0010] Some compounds of Formula (I) can be of formula,.

[0011] Some other compounds of Formula (I) can be of formula,.

[0012] Yet some other compounds of Formula (I) can be of formula,,

[0013] Still some other compounds of Formula (I) can be of formula,

[0014] Some compounds of Formula (I) can be of formula,.

[0015] Some compounds of Formula (I) can be of formula,wherein RNQis hydrogen).

[0016] Some other compounds of Formula (I) can be of formula (Ib),

[0017] Some other compounds of Formula (I) can be of the structure: . For example, some compounds of Formula (I) can be of the structure:

[0018] Yet some other compounds of Formula (I) can be of the structure: For some compounds of Formula (I) can be of the structure:

[0019] In some embodiments, the compound of Formula (II) is of Formula (IIa), (IIb), (IIc) or (IId):

[0020] Yet some other compounds of Formula (II) can be formula,.

[0021] Still some other compounds of Formula (II) can be of formula,.

[0022] Some compounds of Formula (III) can be of formula (IIIa),, wherein n is 1, 2 or 3.

[0023] In some embodiments Q iswhere * is the bond to thephosphorous atom. For example Q is.

[0024] In some embodiments, a compound of Formula (IV) is a compound is of Formula (V),where B, X, RP, Q4, R2’and R3’ are as defined in Formula (IV). For example, the compound is of Formula (V), wherein R3’is -OR30and R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide. In some further aspects of these embodiments, R2’ is H, OH, alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or allyl), alkenyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, -O-2-methoxyethyl, -O-[2- (methylamino)-2-oxoethyl], -O-(2-[N,N-dimethyl)aminooxy]ethyl) or 3-oxo-3-(N- methylamino)prop-1-yl)), S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O- alkyl ester, S-alkyl ester, N-alkyl ester,1 2wherein R and R independently are alkyl, branched alkyl, alkyl ester or alkyl amine.

[0025] In some other embodiments, the compound is of Formula (V), wherein R2’is -OR30and R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide. In some further aspects of these embodiments, R3’ is H, OH, alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or allyl), alkenyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, -O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N- dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl)),S-alkyl, N-alkyl, branched O- alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester,wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine.

[0026] In some embodiments, the compound of Formula (IV) is a compound is of Formula (VI):or a salt thereof, wherein: XAis O, S, SO2, CH2, NHRS’or N(CO)RS’, wherein RS’is vinyl, ethynyl, allyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; YAis O, S, SO2, CH2, NHRS’or N(CO)RS’, wherein RS’is vinyl, ethynyl, allyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; and R3’is hydrogen, halogen, or -OR30, wherein: R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide, and B, X, RP, and Q4are as defined in Formula (IV).

[0027] In some compounds of Formula (VI), YAis O, and the compound is of Form or a salt thereof, where B, X, XA, RP, a4nd Q are as defined in Formula (VI).

[0028] In some compounds of Formula (VI), XAis O, and the compound is of Formula (VIII), or a sA P 4alt thereof, where B, X, Y , R , and Q are as defined in Formula (VI).

[0029] In some compounds of Formula (VI), XAand YAare O, and the compound is of compound of Formula (IX),or a salt thereof, where B, X, RP, and Q4are as defined in Formula (VI). For example, the compound is of Formula (IX),or a salt thereof, wherein: B is an optionally modified nucleobase (e.g., uracil); Q4is ethylene, ethenylene, propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2-ethylcyclopropyl, (2- cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2- methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2-ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2-methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q4are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q4are both replaced with O or S; one methine in Q4is optionally replaced with -N=; X is O or S; each RPis independently C1-3alkyl, -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RSis independently hydrogen, C1-3alkyl, or a thiol protecting group;each RNis independently hydrogen, C1-3alkyl, or an amine protecting group; and R2Sis C1-3alkyl; R3’is hydrogen, halogen, or -OR30, wherein: R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide.

[0030] In some embodiments, the compound of formula (IV) is a compound of Formula (X),or a salt thereof, wherein: XAis O, S, SO2, CH2, NHRS’or N(CO)RS’, wherein RS’is vinyl, ethynyl, allyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; and B, X, RP, R2’, R3’and Q4are as defined in Formula (IV).

[0031] In some compounds of Formula (X), XAis O. In some other compounds of Formula (X), XAis S.

[0032] In some compounds of Formula (X), R3’is hydrogen, halogen, or -OR30, and R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide. In some further embodiments of these compounds, R2’is alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or allyl), alkenyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, - O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N-dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl)),S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester,, wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine. For example, R2’is alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or allyl), alkenyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, -O-2- methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N-dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl)), S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S- alkyl, O-alkenyl, S-alkenyl, N-alkenyl, branched O-alkenyl, branched N-alkenyl, branched S- alkenyl, O-alkyl ester, S-alkyl ester, or N-alkyl ester.

[0033] In some compounds of Formula (X), R2’is hydrogen, halogen, or -OR30, and R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide. In some further embodiments of these compounds, R3’is alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or allyl), alkenyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, - O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N-dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl)),S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester,, wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine. For example, R3’is alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or allyl), alkenyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, -O-2- methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N-dimethyl)aminooxy]ethyl) or 3-oxo- 3-(N-methylamino)prop-1-yl)), S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S- alkyl, O-alkenyl, S-alkenyl, N-alkenyl, branched O-alkenyl, branched N-alkenyl, branched S- alkenyl, O-alkyl ester, S-alkyl ester, or N-alkyl ester.

[0034] In some embodiments, the compound of formula (IV) is a compound of Formula (XI),or a salt thereof, wherein: XAis O, S SO2CH2, NHRS’or N(CO)RS’, wherein RS’is vinyl, ethynyl, allyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; and B, X, RP, R2’, R3and Q4are as defined in Formula (IV).

[0035] In some compounds of Formula (XI), XAis O. In some other compounds of Formula (XI), XAis S.

[0036] In some compounds of Formula (XI), R3’is hydrogen, halogen, or -OR30, and R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide. In some further embodiments of these compounds, R2’is alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or allyl), alkenyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, - O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N-dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl)),S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester,, wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine.

[0037] In some compounds of Formula (XI), R2’is hydrogen, halogen, or -OR30, and R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide. In some further embodiments of these compounds, R2’is alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or allyl), alkenyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, - O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N-dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl)),S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester,, wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine.

[0038] In some embodiments, the compound of Formula (IV) is of formulae (XII)-(XIV):wherein:XAis O, S SO2CH2, NHRS’or N(CO)RS’, wherein RS’is vinyl, ethynyl, allyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; RAis alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amin, alkenyl (e.g., vinyl or allyl), alkynyl (e.g., ethynyl or propargyl) or alkyl ester; and B, X, RP, R2’, R3and Q4are as defined in Formula (IV).

[0039] In some compounds of formulae (XII)-(XIV), XAis O. In some other compounds of formulae (XII)-(XIV), XAis S.

[0040] In some compounds of Formula (XI), R3’is hydrogen, halogen, or -OR30, and R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide. In some further embodiments of these compounds, R2’is halogen (e.g., F), alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or allyl), alkenyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, -O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N- dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl)), S-alkyl, N-alkyl, branched O- alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, or N-alkyl ester.

[0041] In some compounds of formulae (XII)-(XIV), R2’is F, alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or allyl), alkynyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, -O-2-methoxyethyl, -O-[2-(methylamino)-2- oxoethyl], -O-(2-[N,N-dimethyl)aminooxy]ethyl)), S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, branched O-alkenyl, branched N- alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester,orwherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine.

[0042] In some embodiments, a compound of Formula (XV) has the structure:. In some compounds of Formla (XV), n5is 2 or 3, e.g., n5is 2.

[0043] In some embodiments, a compound of Formula (XVI) has the structure: In some compounds of Formula (XVI), n6i6s 1 or 2, e.g., n is 1.

[0044] In some embodiments, a compound of Formula (XVII) has the structure:

[0045] In some embodiments, a compound of Formula (XVII) has the structure:

[0046] In some compounds of Formula (XVII), R4’is methyl, ethyl or propyl, e.g., R4’is methyl. In some compounds of Formula (XVII), n7is 1 or 2, e.g., n7is 1. In some compounds of Formula (XVII), XAis O. In some other compounds of Formula (XVII), XAis S. In some compounds of Formula (XVII), n7is 1, R4’is methyl, and XAis O.

[0047] In some embodiments, a compound of Formula (XX) has the structure: In some c8ompounds of Formla (XX), n is 1. In some other compounds of Formula (XX), n8is 2.

[0048] In some embodiments, a compound of Formula (XXI) has the structure:

[0049] In some embodiments, a compound of Formula (XXI) has the structure:

[0050] In some compounds of Formula (XXI), R4’is methyl, ethyl or propyl, e.g., R4’is methyl. In some compounds of Formula (XXI), n9is 1. In some compounds of Formula (XXI), n9is 2. In some compounds of Formula (XXI), XAis O. In some other compounds of Formula (XXI), XAis S. In some compounds of Formula (XXI), n9is 1, R4’is methyl, and XAis O. In some other compounds of Formula (XXI) n9is 2, R4’is methyl, and XAis O.

[0051] In some compounds of Formula (XXI), R4’is hydrogen and n9is 2. In some other compounds of Formula (XXI), R4’is hydrogen and n9is 1. In some other compounds of Formula (XXI), R4’is hydrogen, XAis O, and n9is 2. In some other compounds of Formula (XXI), R4’is hydrogen, XAis O and n9is 1. In some other compounds of Formula (XXI), R4’is hydrogen, XAis S, and n9is 2. In some other compounds of Formula (XXI), R4’is hydrogen, XAis S and n9is 1. Some compounds of Formula (XXI), R4’is hydrogen, XAis O, n9is 2, and the compounds have the structure:

[0052] In some embodiments, a compound of Formula (XVIII) has the structure:

[0053] In some compounds of Formula (XVIII), Q5is *-NHCH2-, where * is the bond to the S(O2)RPSgroup. In In some other compounds of Formula (XVIII), Q5is ethylene. In yet some other compounds of Formula (XVIII), Q5is ethenylene. In some compounds of Formula (XVIII), Q5is propylene. In some compounds of Formula (XVIII), XAis O. In some other compounds of Formula (XVIII), XAis S. In some compounds of Formula (XVIII), XAis O and Q5is methylene, ethylene, ethenylene, or propylene.

[0054] In some compounds of Formula (XVIII), XAis O, Q5is methylene and the compounds are of the structure:.

[0055] In some compounds of Formula (XVIII), XAis O, Q5is ethylene and the compounds are of the structure:.

[0056] In some compounds of Formula (XVIII), XAis O, Q5is propylene. and the compounds are of the structure:.

[0057] In some embodiments, a compound of Formula (XIX) has the structure: In some other embodiments, a compound of Formula (XIX) has the structure:. In some compounds of Formula (XIX), R5Xis methyl. In some compounds of Formula (XIX), XAis O. In some other compounds of Formula (XIX), XAis S. In some compounds of Formula (XIX), y is 0. In some compounds of Formula (XIX) y is 1. In some compounds of Formula (XIX), XAis O and R5Xis methyl. In some compounds of Formula (XIX), XAis O, R5Xis methyl, and y 0. In some compounds of Formula (XIX), XAis O, R5Xis methyl, and y is 1.

[0058] In some embodiments, a compound of Formula (XXII) has the structure:. In some embodiments, n10is 0, 12 or 3 (e.g., 1).

[0059] In some embodiments, a compound of Formula (XXIII) has the structure:.

[0060] In some compounds of formulae (XV)-(XXIII), R3’is hydrogen, halogen, or -OR30, and R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide. In some further embodiments of these compounds, R2’is alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or allyl), alkenyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, -O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N-dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl)),S-alkyl, N-alkyl, branched O- alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester,wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine.

[0061] In some compounds of formulae (XV)-(XXIII), R3’is -OR30, and R30is a reactive phosphorous group (e.g., a phosphoramidite).

[0062] In some compounds of formulae (XV)-(XXI), R2’is hydrogen, halogen, or -OR30, and R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide. In some further embodiments of these compounds, R2’is alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or allyl), alkenyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, -O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N- dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl)),S-alkyl, N-alkyl, branched O- alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester,wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine.

[0063] In some compounds of formulae (XV)-(XXI), R2’is hydrogen, halogen (e.g., F), O-alkyl (e.g., -OMe ,-OEt, or -O-2-methoxyethyl), or -OR30, and R30is hydrogen, a hydroxy protecting group.

[0064] In some embodiments, Q4iswhere * is the bond to the phosphorous atom. For example, Q4iswhere * is the bond to the phosphorous atom. In some embodiments, Q4isFor example,Q4is , where * is the bond to the phosphorous atom.

[0065] In some compounds of formulae (IV)-(XIV), Q4iswhere * is the bond to the phosphorous atom. For example, in some compounds of formulae (IV)-(XIV), Q4iswhere * is the bond to the phosphorous atom. In some preferred embodiments of compounds of formulae (IV)-(XIV),.

[0066] In some compounds of Formula (XII), Q4iswhere * is the bond to the phosphorous atom. For example, in some compounds of Formula (XII), Q4is pref4erably Q iswhere * is the bond to the phosphorous atom. In some preferred compounds of Formula (XII), Q4is.

[0067] In some embodiments, Q iswhere * is the bond to the phosphorous atom.

[0068] In some embodiments, Q iswhere * is the bond to the phosphorous atom.

[0069] In some embodiments, Q iswhere * is the bond to the phosphorous atom

[0070] In some compounds of formulae I-XXIII, X is O. In some other embodiments, X is S.

[0071] In some embodiments, A is -C(*)(H)-. In some embodiments, A is -CH2C(*)(H)-. In yet some other embodiments, A is -C(*)(H)CH2-.

[0072] In some embodiments, E is a bond. In some other embodiments, E is -CH2-.

[0073] In compounds of formulae I-XXVII and XIX-XXIII, each RPis independently -ORO, - SRS, -N(RN)2, or -N(RN)S(O)2R2S. In some embodiments, at least one RPis -ORO, e.g., each RPis independently -ORO. Each ROcan be independently hydrogen, C1-6alkyl (e.g., C1-3alkyl), or a hydroxyl protecting group. For example, each ROcan be independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, or a hydroxyl protecting group. In some embodiments, each ROis hydrogen, methyl, or ethyl. In some embodiments, each ROis a hydroxyl protecting group, such as pivaloyloxymethyl ((CH3)3CC(O)OCH2-, POM).

[0074] In some compounds of formulae I-XXVII and XIX-XXIII, at least one RPis -SRS, e.g., each RPis independently -SRS. Each RScan be independently hydrogen, C1-3alkyl, or a thiol protecting group. For example, each RScan be independently hydrogen, methyl, ethyl, propyl, isopropyl, or a thiol protecting group. In some embodiments, each RSis hydrogen, methyl or ethyl. In some embodiments, each RSis a thiol protecting group.

[0075] In some compounds of formulae I-XXVII and XIX-XXIII, at least one RPis -N(RN)2, e.g., each RPis independently -N(RN)2. Each RNcan be independently hydrogen, C1-3alkyl, or an amine protecting group. For example, each RNcan be independently hydrogen, methyl, ethyl, propyl, isopropyl, or an amine protecting group. In some embodiments, each RNis hydrogen, methyl or ethyl. In some embodiments, at least one RNis an amine protecting group.

[0076] In some compounds of formulae I-XXVII and XIX-XXIII, at least one RPis - N(RN)S(O)2R2S, e.g., each RPis independently -N(RN)S(O)2R2S. RNcan be hydrogen, C1-3alkyl, or an amine protecting group. For example, RNcan be hydrogen, methyl, ethyl, propyl, isopropyl, or an amine protecting group. In some embodiments, RNis hydrogen, methyl or ethyl. In some embodiments, RNis an amine protecting group. R2Scan be methyl, ethyl, propyl, or isopropyl. In some embodiments, R2Sis methyl or ethyl, e.g., R2Sis methyl. In some embodiments, R2Sis a C3-6cycloalkyl (e.g., cyclopropyl or cyclobutyl). In some compounds, RNis hydrogen, methyl, ethyl, propyl, or isopropyl, and R2Sis methyl, ethyl, propyl, or isopropyl. In some compounds, RNis an amine protecting group, and R2Sis methyl, ethyl, propyl, or isopropyl.

[0077] In some embodiments, one RPis -ORO, and the other RPis -SRS, -N(RN)2, or - N(RN)S(O)2R2S. For example, one RPis -ORO, and the other RPis -SRS. In another example, one RPis -ORO, and the other RPis -N(RN)2. In yet another example, one RPis -ORO, and the other RPis N(RN)S(O)2R2S.

[0078] In some other embodiments, one RPis -SRS, and the other RPis -N(RN)2, or - N(RN)S(O)2R2S. For example, one RPis -SRS, and the other RPis -N(RN)2. In another example, one RPis -SRS, and the other RPis N(RN)S(O)2R2S.

[0079] In yet some other embodiments, one RPis -N(RN)2, and the other RPis -N(RN)S(O)2R2S.

[0080] In some compounds of Formula (XVIII), RPSis -ORO, -N(RN)2, or -N(RN)S(O)2R2S. In some embodiments, RPSis -ORO. Each ROcan be independently hydrogen, C1-6alkyl (e.g., C1-3alkyl), or a hydroxyl protecting group. For example, each ROcan be independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, or a hydroxyl protecting group. In some embodiments, each ROis hydrogen, methyl, or ethyl. In some embodiments, each ROis a hydroxyl protecting group, such as pivaloyloxymethyl ((CH3)3CC(O)OCH2-, POM). In some compounds of Formula (XVIII), RPSis OH.

[0081] In some compounds of Formula (XVIII), RPSis -N(RN)2. Each RNcan be independently hydrogen, C1-3alkyl, or an amine protecting group. For example, each RNcan be independently hydrogen, methyl, ethyl, propyl, isopropyl, or an amine protecting group. In some embodiments, each RNis hydrogen, methyl or ethyl. In some embodiments, at least one RNis an amine protecting group.

[0082] In some compounds of Formula (XVIII), RPSis -N(RN)S(O)2R2S. RNcan be hydrogen, C1-3alkyl, or an amine protecting group. For example, RNcan be hydrogen, methyl, ethyl, propyl, isopropyl, or an amine protecting group. In some embodiments, RNis hydrogen, methyl or ethyl. In some embodiments, RNis an amine protecting group. R2Scan be methyl, ethyl, propyl, or isopropyl. In some embodiments, R2Sis methyl or ethyl, e.g., R2Sis methyl. In some embodiments, R2Sis a C3-6cycloalkyl (e.g., cyclopropyl or cyclobutyl). In some compounds, RNis hydrogen, methyl, ethyl, propyl, or isopropyl, and R2Sis methyl, ethyl, propyl, or isopropyl. In some compounds, RNis an amine protecting group, and R2Sis methyl, ethyl, propyl, or isopropyl.

[0083] In some compounds of Formula (XVIII), RPSis -N(RN)P(O)(ORO)(RPC) (e.g., - N(H)P(O)(ORO)(RPC). For example, RPis -OROand RPCis C1-3alkyl (e.g., methyl), wherein ROis hydrogen, C1-6alkyl (e.g., C1-3alkyl), or a hydroxyl protecting group. In some embodiments, RPis -OROand RPCis C1-3alkyl (e.g,. methyl), wherein ROis hydrogen or C1-3alkyl. In some embodiments, RPis methoxy or ethoxy and RPCis methyl. In some embodiments, RPis -OH and RPCis methyl. In some compounds of Formula (XVIII), RPSis -N(H)P(O)(OH)(CH3)

[0084] In some compounds of Formula (XVIII), RPSis -N=P(ORO)2(RPC). For example, each RPis -OROand RPCis C1-3alkyl (e.g,. methyl), wherein ROis hydrogen, C1-6alkyl (e.g., C1-3alkyl), or a hydroxyl protecting group. In some embodiments, each RPis -OROand RPCis C1-3alkyl (e.g,. methyl), wherein ROis hydrogen or C1-3alkyl. In some embodiments, each RPis methoxy or ethoxy and RPCis methyl. In some embodiments, each RPis -OH and RPCis methyl.

[0085] In some compounds described herein, R3’is -OR30. For example, R3’is -OR30, and R30is a reactive phosphorous group. Exemplary reactive phosphorous groups are described herein below and include, but are not limited to, phosphoramidite, H-phosphonate, alkyl-phosphonate, phosphate triesters and phosphorus containing chiral auxiliaries. Thus, in some embodiments, R3’is -OR30, and R30is a reactive phosphorous group selected from phosphoramidite, H-phosphonate, alkyl-phosphonate, and phosphate triester, optionally R30is a phosphoramidite. Accordingly, in some compounds, R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, -P(O)(ORP1)N(RP2)2, - P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, -P(S)(ORP1)H, - P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP3is an optionally substituted C1-C30alkyl, optionally substituted C2- C30alkenyl, or optionally substituted C2-C30alkynyl (e.g., optionally substituted C1-C10alkyl, optionally substituted C2-C10alkenyl, or optionally substituted C2- C10alkynyl); each RP1is independently an optionally substituted C1-6alkyl; and each RP2is independently optionally substituted C1-6alkyl (e.g., methyl, ethyl, propyl, or isopropyl, such as isopropyl) or both RP2taken together with the nitrogen atom to which they are attached form an optionally substituted 3-8 membered heterocyclyl; or RP1and one of RP2taken together with the atoms to which they are attached form an optionally substituted 4-8 membered heterocyclyl.

[0086] In some embodiments, R3’is -OR30, and R30is -P(ORP1)N(RP2)2. For example, R3’is - OR30, and R30is -P(ORP1)N(RP2)2, and where RP1is C1-6alkyl substituted with cyano or -SC(O)Ph. In some embodiments, R3’is -OR30, and R30is -P(ORP1)N(RP2)2, and where RP1is –CH2CH2CN.

[0087] In some embodiments, R3’is -OR30, and R30is -P(ORP1)N(RP2)2, and each RP2is independently methyl, ethyl, propyl, or isopropyl. For example, R3’is -OR30, and R30is - P(ORP1)N(RP2)2, and where each RP2is isopropyl.

[0088] In some preferred embodiments, R3’is -OR30, and R30is -P(ORP1)N(RP2)2, and where RP1is C1-6alkyl substituted with cyano or -SC(O)Ph, and each RP2is independently methyl, ethyl, propyl, or isopropyl. For example, R3’is -OR30, and R30is -P(ORP1)N(RP2)2, and where RP1is – CH2CH2CN, and each RP2is isopropyl.

[0089] In some embodiments, R3’is -OR30, and R30is a phosphoramidite group such as 3'-[(2- cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite or 3'-[(ß-thiobenzoylethyl)-(1-pyrrolidinyl)]- thiophosphoramidite).

[0090] In another example, R3’is -OR30, and R30is hydrogen or a hydroxyl protecting group (e.g., a silyl based hydroxyl protecting group). Some exemplary hydroxyl protecting group for R30of R3’include, but are not limited to, t-butyldimethylsilyl (TBDMS), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), or t-butylmethoxyphenylsilyl (TBMPS), optionally, the hydroxyl protecting group is TBDMS.

[0091] In yet another example, R3’is -OR30, and R30is a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide. For example, R30is a bond to an oligonucleotide. When R30is a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide, R3’can be connected to the 5’- hydroxyl of the nucleoside or nucleotide or the 5’-hydroxyl at the 5’-terminal of the oligonucleotide. It is noted that the internucleotide linkage between the compound or nucleoside of formulae I-XXIII and the nucleoside, nucleotide, or oligonucleotide it is linked to can be an unmodified internucleotide linkage (i.e., phosphodiester) or a modified internucleotide linkage (e.g., phosphorothioate, MMI or imidp, preferably the modified internucleotide linkage is phosphorothioate). Exemplary modified internucleotide linkages are described herein below.

[0092] In some embodiments, R3’is hydrogen or halogen (e.g., F, Br, Cl or I). For example, R3’is H or F.

[0093] In some compounds of formulae I-XXIII, R3’is -OR20, where R20is optionally substituted C1-6alkyl. For example, R3’is -OR20, where R20is methyl, ethyl, or propyl. In some embodiments, R3’is -OR20, where R20is methyl.

[0094] In some compounds of formulae I-XXIII, R3’is -OR20, where R20is optionally substituted C2-6alkenyl. For example, R3’is -OR20, where R20is vinyl or allyl. In some compounds of formulae I-IV, R3’is -OR20, where R20is optionally substituted C2-6alkynyl. For example, R3’is -OR20, where R20is acetylenyl, propargyl, or 5-hexyn-1-yl.

[0095] In some compounds of formulae I-XXIII, R3’is -OR20, where R20is C1-6alkoxyC1-6alkyl. For example, R3’is -OR20, where R202-methoxyethyl.

[0096] Preferably, R3’is -OR30and R2’is hydrogen, halogen, or -OR20. For example, R3’is - OR30and R2’is hydrogen, halogen, or -OR20, and where R30is a reactive phosphorous group, hydroxyl protecting group, a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide.

[0097] In some embodiments, R2’is hydrogen or halogen (e.g., F, Br, Cl or I). For example, R2’is H or F.

[0098] In some compounds of formulae I-V and IX-XXI, R2’is -OR20, where R20is optionally substituted C1-6alkyl. In one example, R20is C1-6alkyl substituted with one, two, or three substituents selected independently from the group consisting of halogen, -OR22,-N(R22)2, -SR22, - C(O)OR22, -C(O)N(R22)2, wherein R22is hydrogen or C1-3alkyl (e.g., 2,2,2-trifluoroethyl, 1,3- dimethoxyprop-2-yl). In another example, R20is C1-6alkyl substituted with one or two substituentsselected independently from the group consisting of halogen, -OR22,-N(R22)2, -SR22, -C(O)OR22, - C(O)N(R22)2, wherein R22is hydrogen or C1-3alkyl (e.g., 2,2,2-trifluoroethyl, 1,3-dimethoxyprop- 2-yl).

[0099] In another example, R2’is -OR20, where R20is methyl, ethyl, or propyl. In some embodiments, R2’is -OR20, where R20is methyl.

[0100] In some compounds of formulae I-V and IX-XXI, R2’is -OR20, where R20is C1-6alkoxyC1-6alkyl. For example, R2’is -OR20, where R20is 2-methoxyethyl.

[0101] In some compounds of formulae I-V and IX-XXI, R2’is -OR20, where R20is N-(C1-6alkyl)aminocarbonylC1-6alkyl. For example, R2’is -OR20, where R20is 2-(N-methylamino)-2- oxoethyl or 3-oxo-3-(N-methylamino)prop-1-yl.

[0102] In another example, R2’is -OR30, and R30is hydrogen or a hydroxyl protecting group (e.g., a silyl based hydroxyl protecting group). Some exemplary hydroxyl protecting group for R30of R2’include, but are not limited to, t-butyldimethylsilyl (TBDMS), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), or t-butylmethoxyphenylsilyl (TBMPS), optionally, the hydroxyl protecting group is TBDMS.

[0103] In some compounds of formulae I-V and IX-XXI, R2’is halogen, (e.g., F), alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or allyl), alkenyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, -O-2-methoxyethyl, -O-[2- (methylamino)-2-oxoethyl], -O-(2-[N,N-dimethyl)aminooxy]ethyl) or 3-oxo-3-(N- methylamino)prop-1-yl)),S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O- alkyl ester, S-alkyl ester, N-alkyl ester,1 2wherein R and R independently are alkyl, branched alkyl, alkyl ester or alkyl amine.

[0104] In some compounds described herein, R2’is -OR30. For example, R2’is -OR30, and R30is a reactive phosphorous group. Exemplary reactive phosphorous groups are described herein below and include, but are not limited to, phosphoramidite, H-phosphonate, alkyl-phosphonate, phosphate triesters and phosphorus containing chiral auxiliaries. Thus, in some embodiments, R2’is -OR30, and R30is a reactive phosphorous group selected from phosphoramidite, H-phosphonate, alkyl-phosphonate, and phosphate triester, optionally R30is a phosphoramidite. Accordingly, in some compounds, R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, -P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, -P(S)(ORP1)H, - P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP3is an optionally substituted C1-C30alkyl, optionally substituted C2-C30alkenyl, or optionally substituted C2-C30alkynyl (e.g., optionally substituted C1-C10alkyl, optionally substituted C2-C10alkenyl, or optionally substituted C2-C10alkynyl); each RP1is independently an optionally substituted C1-6alkyl; and each RP2is independently optionally substituted C1-6alkyl (e.g., methyl, ethyl, propyl, or isopropyl, such as isopropyl) or both RP2taken together with the nitrogen atom to which they are attached form an optionally substituted 3-8 membered heterocyclyl; or RP1and one of RP2taken together with the atoms to which they are attached form an optionally substituted 4-8 membered heterocyclyl.

[0105] In some embodiments, R2’is -OR30, and R30is -P(ORP1)N(RP2)2. For example, R2’is - OR30, and R30is -P(ORP1)N(RP2)2, and where RP1is C1-6alkyl substituted with cyano or -SC(O)Ph. In some embodiments, R2’is -OR30, and R30is -P(ORP1)N(RP2)2, and where RP1is –CH2CH2CN.

[0106] In some embodiments, R2’is -OR30, and R30is -P(ORP1)N(RP2)2, and each RP2is independently methyl, ethyl, propyl, or isopropyl. For example, R2’is -OR30, and R30is - P(ORP1)N(RP2)2, and where each RP2is isopropyl.

[0107] In some preferred embodiments, R2’is -OR30, and R30is -P(ORP1)N(RP2)2, and where RP1is C1-6alkyl substituted with cyano or -SC(O)Ph, and each RP2is independently methyl, ethyl, propyl, or isopropyl. For example, R2’is -OR30, and R30is -P(ORP1)N(RP2)2, and where RP1is – CH2CH2CN, and each RP2is isopropyl.

[0108] In some embodiments, R2’is -OR30, and R30is a phosphoramidite group such as 2’-[(2- cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite or 2’-[(ß-thiobenzoylethyl)-(1-pyrrolidinyl)]- thiophosphoramidite).

[0109] In yet another example, R2’is -OR30, and R30is a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide. For example, R30is a bond to an oligonucleotide. When R30is a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide, R2’can be connected to the 5’- hydroxyl of the nucleoside or nucleotide or the 5’-hydroxyl at the 5’-terminal of the oligonucleotide. It is noted that the internucleotide linkage between the compound or nucleoside of formulae I-XXIII and the nucleoside, nucleotide, or oligonucleotide it is linked to can be an unmodified internucleotide linkage (i.e., phosphodiester) or a modified internucleotide linkage (e.g., phosphorothioate, MMI or imidp, preferably the modified internucleotide linkage is phosphorothioate). Exemplary modified internucleotide linkages are described herein below.

[0110] In compounds of formulae I-XXIII, B is an optionally modified natural or non-natural nucleobase. For example, B is an optionally modified natural or non-natural nucleobase. For example, B is uracil, adenine, cytosine, 5-methylcytosine, guanine, or thymine (i.e., 5- methyluracil). In some embodiments, B is a modified or protected nucleobase. For example, B is a protected nucleobase comprising at least one amine or hydroxyl protecting group. In some embodiments, B is adenine, cytosine, 5-methylcytosine, or guanine comprising at least one amine protecting group. Exemplary modified, unmodified natural and non-natural nucleobase are described herein below.

[0111] In some compounds of formulae I-XVII and XIX-XXIII, X is O; each RPis -ORO; R2’is hydrogen, F, or -OR20, where R20is hydrogen, optionally substituted C1-6alkyl (e.g., methyl, ethyl or propyl), such as C1-6alkoxyC1-6alkyl (e.g., methoxy, 2-methoxyethyl) or N-(C1-6alkyl)aminocarbonylC1-6alkyl (e.g. 2-(N-methylamino)-2-oxoethyl or 3-oxo-3-(N- methylamino)prop-1-yl); and R3’is -OR30, where R30is hydrogen, hydroxyl protecting group, or a reactive phosphorous group.

[0112] In some compounds of formulae I-XVII and XIX-XXIII, X is O; each RPis -ORO; R2’is hydrogen, F, or -OR20, where R20is hydrogen, optionally substituted C1-6alkyl (e.g., methyl, ethyl or propyl), such asC1-6alkoxyC1-6alkyl (e.g., methoxy, 2-methoxyethyl) or N-(C1-6alkyl)aminocarbonylC1-6alkyl (e.g., 2-(N-methylamino)-2-oxoethyl or 3-oxo-3-(N- methylamino)prop-1-yl); and R3’is -OR30, where R30is reactive phosphorous group (e.g., a phosphoramidite, H-phosphonate, alkyl-phosphonate, or phosphate triester). In some further embodiments of this, the reactive phosphorous group is: -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3(e.g., - P(ORP1)N(RP2)2), wherein: each RP3is an optionally substituted C1-C30alkyl, optionally substituted C2-C30alkenyl, or optionally substituted C2-C30alkynyl (e.g., optionally substituted C1-C10alkyl, optionally substituted C2-C10alkenyl, or optionally substituted C2-C10alkynyl); each RP1is independently an optionally substituted C1-6alkyl (e.g., C1-6alkyl substituted with cyano or - SC(O)Ph, such as 2-cyanoethyl); and each RP2is independently optionally substituted C1-6alkyl (e.g., methyl, ethyl, propyl, or isopropyl, preferably isopropyl), or both RP2taken together with the nitrogen atom to which they are attached form an optionally substituted 3-8 membered heterocyclyl; or RP1and one of RP2taken together with the atoms to which they are attached form an optionally substituted 4-8 membered heterocyclyl.

[0113] In some compounds of formulae I-XVII and XIX-XXIII, X is O; each RPis -ORO; R2’is hydrogen, F, or -OR20, where R20is hydrogen, optionally substituted C1-6alkyl (e.g., methyl, ethyl or propyl, preferably methyl), such as C1-6alkoxyC1-6alkyl (e.g., methoxy, 2-methoxyethyl) or N-(C1-6alkyl)aminocarbonylC1-6alkyl (e.g., 2-(N-methylamino)-2-oxoethyl or 3-oxo-3-(N- methylamino)prop-1-yl) ; and R3’is -OR30, where R30is -P(ORP1)N(RP2)2, and where RP1is – CH2CH2CN, and each RP2is isopropyl.

[0114] In some preferred embodiments, X is O; each RPis -ORO, where each ROis independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl; R2’is hydrogen, F, or -OR20, where R20is hydrogen, methyl, 2-methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N- methylamino)-2-oxoethyl, or 3-oxo-3-(N-methylamino)prop-1-yl; and R3’is R30, where R30is - P(ORP1)N(RP2)2, where RP1is –CH2CH2CN, and each RP2is isopropyl.

[0115] In some compounds of Formula (XVIII), X is O; RPSis -ORO; R2’is hydrogen, F, or - OR20, where R20is hydrogen, optionally substituted C1-6alkyl (e.g., methyl, ethyl or propyl), such as C1-6alkoxyC1-6alkyl (e.g., methoxy, 2-methoxyethyl) or N-(C1-6alkyl)aminocarbonylC1-6alkyl (e.g. 2-(N-methylamino)-2-oxoethyl or 3-oxo-3-(N-methylamino)prop-1-yl); and R3’is -OR30, where R30is hydrogen, hydroxyl protecting group, or a reactive phosphorous group.

[0116] In some compounds of Formula (XVIII), X is O; RPSis -ORO; R2’is hydrogen, F, or - OR20, where R20is hydrogen, optionally substituted C1-6alkyl (e.g., methyl, ethyl or propyl), such asC1-6alkoxyC1-6alkyl (e.g., methoxy, 2-methoxyethyl) or N-(C1-6alkyl)aminocarbonylC1-6alkyl (e.g., 2-(N-methylamino)-2-oxoethyl or 3-oxo-3-(N-methylamino)prop-1-yl); and R3’is -OR30, where R30is reactive phosphorous group (e.g., a phosphoramidite, H-phosphonate, alkyl- phosphonate, or phosphate triester). In some further embodiments of this, the reactive phosphorous group is: -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, -P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, - P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, -P(S)(ORP1)H, -P(O)(SRP1)H, - P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3(e.g., -P(ORP1)N(RP2)2), wherein: each RP3is an optionally substituted C1-C30alkyl, optionally substituted C2-C30alkenyl, or optionally substituted C2-C30alkynyl (e.g., optionally substituted C1-C10alkyl, optionally substituted C2- C10alkenyl, or optionally substituted C2-C10alkynyl); each RP1is independently an optionally substituted C1-6alkyl (e.g., C1-6alkyl substituted with cyano or -SC(O)Ph, such as 2-cyanoethyl); and each RP2is independently optionally substituted C1-6alkyl (e.g., methyl, ethyl, propyl, or isopropyl, preferably isopropyl), or both RP2taken together with the nitrogen atom to which they are attached form an optionally substituted 3-8 membered heterocyclyl; or RP1and one of RP2taken together with the atoms to which they are attached form an optionally substituted 4-8 membered heterocyclyl.

[0117] In some compounds of Formula (XVIII), X is O; RPSis -ORO; R2’is hydrogen, F, or - OR20, where R20is hydrogen, optionally substituted C1-6alkyl (e.g., methyl, ethyl or propyl, preferably methyl), such as C1-6alkoxyC1-6alkyl (e.g., methoxy, 2-methoxyethyl) or N-(C1-6alkyl)aminocarbonylC1-6alkyl (e.g., 2-(N-methylamino)-2-oxoethyl or 3-oxo-3-(N-methylamino)prop-1-yl) ; and R3’is -OR30, where R30is -P(ORP1)N(RP2)2, and where RP1is – CH2CH2CN, and each RP2is isopropyl.

[0118] In some preferred compounds of Formula (XVIII), X is O; RPSis -ORO, where each ROis independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl; R2’is hydrogen, F, or -OR20, where R20is hydrogen, methyl, 2-methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N- methylamino)-2-oxoethyl, or 3-oxo-3-(N-methylamino)prop-1-yl; and R3’is R30, where R30is - P(ORP1)N(RP2)2, where RP1is –CH2CH2CN, and each RP2is isopropyl.

[0119] In some embodiments, the compound is of the formula,or a salt thereof, wherein: Q iswherein: * is the bond to the phosphorous atom; Q1is -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl; B is an optionally modified nucleobase (e.g., uracil); X is O or S; each RPis independently -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RSis independently hydrogen, C1-3alkyl, or a thiol protecting group;each RNis independently hydrogen, C1-3alkyl, or an amine protecting group; and R2Sis C1-3alkyl; one of R2’and R3’is hydrogen, halogen, or -OR20, wherein: R20is hydrogen, hydroxyl protecting group, optionally substituted C1-6alkyl, (e.g., methyl, 2-methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N- methylamino)-2-oxoethyl, or 3-oxo-3-(N-methylamino)prop-1-yl), optionally substituted C2-6alkenyl, or optionally substituted C2-6alkynyl (e.g., propargyl); and the other of R2’and R3’is -OR30, wherein: R30is hydrogen, a hydroxyl protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide.

[0120] In some embodiments, the compound is of the formula,or a salt thereof, wherein: Q iswherein: * is the bond to the phosphorous atom; B is an optionally modified nucleobase (e.g., uracil);X is O; each RPis independently -ORO, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; one of R2’and R3’is hydrogen, halogen, or -OR20, wherein: R20is hydrogen, hydroxyl protecting group, optionally substituted C1-6alkyl, (e.g., methyl, 2-methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N- methylamino)-2-oxoethyl, or 3-oxo-3-(N-methylamino)prop-1-yl), optionally substituted C2-6alkenyl, or optionally substituted C2-6alkynyl (e.g., propargyl); and the other of R2’and R3’is -OR30, wherein: R30is hydrogen, a hydroxyl protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide.

[0121] In some embodiments, R3’is -OR30. For example, the compound is of formula,.or a salt thereof, wherein: R3’is -OR30, wherein: R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide; n is an integer selected from 1 - 3; B is an optionally modified nucleobase (e.g., uracil); Q is propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2- ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2- methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2- ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2- methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein: RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q are both replaced with O or S; one methine in Q is optionally replaced with -N=; X is O or S; each RPis independently C1-3alkyl, -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RSis independently hydrogen, C1-3alkyl, or a thiol protecting group; each RNis independently hydrogen, C1-3alkyl, or an amine protecting group; and R2Sis C1-3alkyl; R2’is hydrogen, halogen, or -OR20, wherein: R20is hydrogen, hydroxyl protecting group, optionally substituted C1-6alkyl, (e.g., methyl, 2-methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N- methylamino)-2-oxoethyl, or 3-oxo-3-(N-methylamino)prop-1-yl), optionally substituted C2-6alkenyl, or optionally substituted C2-6alkynyl (e.g., propargyl);and Q1is -O-, -S-, or -N(RNQ)-, wherein: RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl.

[0122] In some embodiments, R3’is -OR30, X is O, and each RPis -ORO. For example, the compound is of formula,or a salt thereof,wherein: R3’is -OR30, wherein: R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide; each RPis -ORO, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; X is O; n is an integer selected from 1 - 3; B is an optionally modified nucleobase (e.g., uracil); Q is propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2- ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2- methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2- ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2- methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein: RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q are both replaced with O or S; one methine in Q is optionally replaced with -N=; R2’is hydrogen, halogen, or -OR20, wherein: R20is hydrogen, hydroxyl protecting group, optionally substituted C1-6alkyl, (e.g., methyl, 2-methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N- methylamino)-2-oxoethyl, or 3-oxo-3-(N-methylamino)prop-1-yl), optionally substituted C2-6alkenyl, or optionally substituted C2-6alkynyl (e.g., propargyl); and Q1is -O-, -S-, or -N(RNQ)-, wherein: RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl.

[0123] In certain embodiments of the above compounds, ROis C1-6alkyl (e.g., methyl or ethyl). In certain embodiments, ROis a hydroxyl protecting group (e.g. pivaloyloxymethyl). In certain embodiments, R20is hydrogen. In certain embodiments, R20is a hydroxyl protecting group (e.g., TBS, TMS).

[0124] In some embodiments, R3’is -OR30, R30is -P(ORP1)N(RP2)2, X is O, and each RPis - ORO. For example, the compound is of formula,or a salt thereof,wherein: R3’is -OR30, wherein: R30is -P(ORP1)N(RP2)2, wherein: each RP1is optionally substituted C1-6alkyl, (e.g., -CH2CH2CN); each RP2is independently optionally substituted C1-6alkyl (e.g., isopropyl); each RPis -ORO, wherein: each ROis independently C1-6alkyl, or a hydroxyl protecting group; X is O; n is an integer selected from 1 - 3; B is an optionally modified nucleobase (e.g., uracil); Q is propylene, propenylene, propynylene, methylcyclopropyl, or cyclopropylmethyl, 2-ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2- methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2- ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2- methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein: RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q are both replaced with O or S; one methine in Q is optionally replaced with -N=; R2’is hydrogen, halogen, or -OR20, wherein: R20is hydrogen, hydroxyl protecting group, optionally substituted C1-6alkyl, (e.g., methyl, 2-methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N- methylamino)-2-oxoethyl, or 3-oxo-3-(N-methylamino)prop-1-yl), optionally substituted C2-6alkenyl, or optionally substituted C2-6alkynyl (e.g., propargyl); and Q1is -O-, -S-, or -N(RNQ)-, wherein: RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl.

[0125] In certain embodiments of the above compounds, B is uracil or thymine. In certain embodiments, ROis C1-6alkyl (e.g., methyl or ethyl). In certain embodiments, ROis a hydroxylprotecting group (e.g. pivaloyloxymethyl). In certain embodiments, R20is hydrogen. In certain embodiments, R20is a hydroxyl protecting group (e.g., TBS, TMS).

[0126] In some embodiments, the compound is of the formula,or a salt thereof, wherein: Q4iswhere * is the bond to the phosphorous atom, and Q1is -O-, -S-, or -N(RNQ)-, wherein: RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl;M is a monocyclic or bicyclic ring (such as C3-8cycloalkyl (e.g., cyclohexyl, cyclopentyl or cyclobutyl) or heterocyclyl (e.g., piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, or tetrahydrothienyl), a 5-membered sugar, or a 6- membered sugar; B is an optionally modified nucleobase (e.g., uracil); X is O or S; XAis O or S; YAis O or S; each RPis independently -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RSis independently hydrogen, C1-3alkyl, or a thiol protecting group; each RNis independently hydrogen, C1-3alkyl, or an amine protecting group; and R2Sis C1-3alkyl; R3’is -OR30, wherein: R30is hydrogen, a hydroxyl protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide.

[0127] In some embodiments, the compound is of the formula,or a salt thereof, wherein:, , ,, where * is the bond to the phosphorous atom; B is an optionally modified nucleobase (e.g., uracil); X is O; XAis O; YAis O; each RPis independently -ORO, , wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; R3’is -OR30, wherein: R30is hydrogen, a hydroxyl protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide.

[0128] In some embodiments, R3’is -OR30. For example, the compound is of formula,,, or a salt thereof, wherein:M is a monocyclic or bicyclic ring (such as C3-8cycloalkyl (e.g., cyclohexyl, cyclopentyl or cyclobutyl) or heterocyclyl (e.g., piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, or tetrahydrothienyl), a 5-membered sugar, or a 6- membered sugar; R3’is -OR30, wherein: R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide; B is an optionally modified nucleobase (e.g., uracil); Q4is propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2-ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2- methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2- ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2- methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q4are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein: RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q4are both replaced with O or S; one methine in Q4is optionally replaced with -N=; Q5is methylene, ethylene, ethenylene, propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2-ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2-methyl)cyclopropylmethyl, 2- propylcyclopropyl, (3-cyclopropyl)propyl, (2-ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2-methylcyclobutyl, 3- methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q5are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q5are both replaced with O or S; one methine in Q5is optionally replaced with -N=; y is 0 or 1; n5is an integer selected from 2 - 5 (e.g., 2, 3, or 4, preferably 2);n6is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1); n7is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1); n8is an integer selected from 1 - 3 (e.g., 1 or 2); n9is an integer selected from 1 - 3 (e.g., 1 or 2); n10is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1); R4’is C1-6alkyl (e.g., methyl), C1-6alkoxy (e.g., methoxy), or hydrogen; R5Xis H or C1-6alkyl (e.g., methyl); X is O or S; XAis O or S; YAis O or S; each RPis independently C1-3alkyl, -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RSis independently hydrogen, C1-3alkyl, or a thiol protecting group; each RNis independently hydrogen, C1-3alkyl, or an amine protecting group; and R2Sis C1-3alkyl; RPSisC1-3alkyl, -ORO, -N(RN)2, -N(RN)S(O)2R2S, -N(RN)P(O)(ORO)(RPC), or - N=P(ORO)2(RPC), wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RNis independently hydrogen, C1-3alkyl, or an amine protecting group; RPCis C1-6alkyl (e.g., C1-3alkyl or methyl); and R2Sis C1-3alkyl; and R2’is hydrogen, halogen, or -OR20, wherein: R20is hydrogen, hydroxyl protecting group, optionally substituted C1-6alkyl, (e.g., methyl, 2-methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N- methylamino)-2-oxoethyl, 2-[N,N-dimethyl)aminooxy]ethyl, or 3-oxo-3- (N-methylamino)prop-1-yl), optionally substituted C2-6alkenyl, or optionally substituted C2-6alkynyl (e.g., propargyl).

[0129] In some embodiments, R3’is -OR30, X is O, and each RPis -ORO. For example, the compound is of formula,,, or a salt thereof, wherein: M is a monocyclic or bicyclic ring (such as C3-8cycloalkyl (e.g., cyclohexyl, cyclopentyl or cyclobutyl) or heterocyclyl (e.g., piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, or tetrahydrothienyl), a 5-membered sugar, or a 6- membered sugar; R3’is -OR30, wherein: R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide; each RPand RPSis -ORO, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; y is 0 or 1; n5is an integer selected from 2 - 5 (e.g., 2, 3, or 4, preferably 2); n6is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1); n7is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1); n8is an integer selected from 1 - 3 (e.g., 1, or 2); n9is an integer selected from 1 - 3 (e.g., 1, or 2); n10is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1); R4’is C1-6alkyl (e.g., methyl), C1-6alkoxy (e.g., methoxy), or hydrogen; R5Xis H or C1-6alkyl (e.g., methyl); X is O; XAis O; YAis O; RAis alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amin, alkenyl (e.g., vinyl or allyl), alkynyl (e.g., ethynyl or propargyl) or alkyl ester;B is an optionally modified nucleobase (e.g., uracil); Q is propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2- ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2- methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2- ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2- methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein: RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q are both replaced with O or S; one methine in Q is optionally replaced with -N=; Q4is ethylene, ethenylene, propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2-ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2- methyl)cyclopropyl, (2-methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3- cyclopropyl)propyl, (2-ethyl)cyclopropylmethyl, cyclopropyl, 2-(2- methyl)cyclopropylethyl, 2-methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q4are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q4are both replaced with O or S; one methine in Q4is optionally replaced with -N=; and Q5is methylene, ethylene, ethenylene, propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2-ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2-methyl)cyclopropylmethyl, 2- propylcyclopropyl, (3-cyclopropyl)propyl, (2-ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2-methylcyclobutyl, 3- methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q5are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that:no two consecutive methylene groups in Q5are both replaced with O or S; one methine in Q5is optionally replaced with -N=; R2’is hydrogen, halogen, or -OR20, wherein: R20is hydrogen, hydroxyl protecting group, optionally substituted C1-6alkyl, (e.g., methyl, 2-methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N- methylamino)-2-oxoethyl, 2-[N,N-dimethyl)aminooxy]ethyl, or 3-oxo-3- (N-methylamino)prop-1-yl), optionally substituted C2-6alkenyl, or optionally substituted C2-6alkynyl (e.g., propargyl).

[0130] In certain embodiments of the above compounds, ROis C1-6alkyl (e.g., methyl or ethyl). In certain embodiments, ROis a hydroxyl protecting group (e.g. pivaloyloxymethyl). In certain embodiments, R20is hydrogen. In certain embodiments, R20is a hydroxyl protecting group (e.g., TBS, TMS).

[0131] In some embodiments, R3’is -OR30, R30is -P(ORP1)N(RP2)2, X is O, and each RPis - ORO. For example, the compound is of formula,,,, or a salt thereof, wherein: M is a monocyclic or bicyclic ring (such as C3-8cycloalkyl (e.g., cyclohexyl, cyclopentyl or cyclobutyl) or heterocyclyl (e.g., piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, or tetrahydrothienyl), a 5-membered sugar, or a 6- membered sugar; R3’is -OR30, wherein: R30is -P(ORP1)N(RP2)2, wherein: each RP1is optionally substituted C1-6alkyl, (e.g., -CH2CH2CN); each RP2is independently optionally substituted C1-6alkyl (e.g., isopropyl); each RPand RPSis -ORO,wherein: each ROis independently C1-6alkyl, or a hydroxyl protecting group; y is 0 or 1; n5is an integer selected from 2 - 5 (e.g., 2, 3, or 4, preferably 2);n6is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1); n7is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1); n8is an integer selected from 1 - 3 (e.g., 1, or 2); n9is an integer selected from 1 - 3 (e.g., 1, or 2); n10is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1); R4’is C1-6alkyl (e.g., methyl), C1-6alkoxy (e.g., methoxy), or hydrogen; R5Xis H or C1-6alkyl (e.g., methyl); X is O; XAis O; YAis O; RAis alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amin, alkenyl (e.g., vinyl or allyl), alkynyl (e.g., ethynyl or propargyl) or alkyl ester; B is an optionally modified nucleobase (e.g., uracil); Q4is ethylene, ethenylene, propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2-ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2- methyl)cyclopropyl, (2-methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3- cyclopropyl)propyl, (2-ethyl)cyclopropylmethyl, cyclopropyl, 2-(2- methyl)cyclopropylethyl, 2-methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q4are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q4are both replaced with O or S; one methine in Q4is optionally replaced with -N=; Q5is methylene, ethylene, ethenylene, propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2-ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2-methyl)cyclopropylmethyl, 2- propylcyclopropyl, (3-cyclopropyl)propyl, (2-ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2-methylcyclobutyl, 3- methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q5are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that:no two consecutive methylene groups in Q5are both replaced with O or S; one methine in Q5is optionally replaced with -N=; and R2’is hydrogen, halogen, or -OR20, wherein: R20is hydrogen, hydroxyl protecting group, optionally substituted C1-6alkyl, (e.g., methyl, 2-methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N- methylamino)-2-oxoethyl, 2-[N,N-dimethyl)aminooxy]ethyl, or 3-oxo-3- (N-methylamino)prop-1-yl), optionally substituted C2-6alkenyl, or optionally substituted C2-6alkynyl (e.g., propargyl).

[0132] In certain embodiments of the above compounds, B is uracil or thymine. In certain embodiments, ROis C1-6alkyl (e.g., methyl or ethyl). In certain embodiments, ROis a hydroxyl protecting group (e.g. pivaloyloxymethyl). In certain embodiments, R20is hydrogen. In certain embodiments, R20is a hydroxyl protecting group (e.g., TBS, TMS).

[0133] In some embodiments, the compound is of formulae IV-XIV, wherein: Q4iswhere * is the bond to the phosphorous atom; X is O; each RPis independently -OROor is -N(RN)2, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; and each RNis independently hydrogen, C1-3alkyl, or an amine protecting group R3’is -OR30, wherein: R30is hydrogen, hydroxyl protecting group, or a reactive phosphorous group.

[0134] In some embodiments, the compound is of formulae IV-XIV wherein:where * is the bond to the phosphorous atom; X is O; each RPis independently -OROor is -N(RN)2, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; and each RNis independently hydrogen, C1-3alkyl, or an amine protecting group R3’is -OR30, wherein: R30is hydrogen, hydroxyl protecting group, or a reactive phosphorous group.

[0135] In some embodiments, the compound is of formulae IV-XIV wherein: Q4is, where * is the bond to the phosphorous atom; X is O; each RPis independently -OROor is -N(RN)2, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; and each RNis independently hydrogen, C1-3alkyl, or an amine protecting group R3’is -OR30, wherein: R30is hydrogen, hydroxyl protecting group, or a reactive phosphorous group.

[0136] In some embodiments, the compound is of formulae IV-XIV, wherein: Q4is, where * is the bond to the phosphorous atom; X is O; each RPis independently -OROor is -N(RN)2, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; and each RNis independently hydrogen, C1-3alkyl, or an amine protecting group R3’is -OR30, wherein: R30is hydrogen, hydroxyl protecting group, or a reactive phosphorous group.

[0137] In some embodiments, the compound is of formulae IV-XIV, wherein: Q4is, where* is the bond to the phosphorous atom; X is O; each RPis independently -OROor is -N(RN)2, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; and each RNis independently hydrogen, C1-3alkyl, or an amine protecting group R3’is -OR30, wherein: R30is hydrogen, hydroxyl protecting group, or a reactive phosphorous group.

[0138] In some embodiments, the compound is of formulae IV-XIV, wherein: Q4iswhere* is the bond to the phosphorous atom. X is O; each RPis independently -OROor is -N(RN)2, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; and each RNis independently hydrogen, C1-3alkyl, or an amine protecting group R3’is -OR30, wherein: R30is hydrogen, hydroxyl protecting group, or a reactive phosphorous group

[0139] In some embodiments, the compound is of formulae IV-XIV, wherein: Q4iswhere * is the bond to the phosphorous atom; X is O; each RPis independently -OROor is -N(RN)2, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; and each RNis independently hydrogen, C1-3alkyl, or an amine protecting group R3’is -OR30, wherein: R30is hydrogen, hydroxyl protecting group, or a reactive phosphorous group.

[0140] In some embodiments, the compound is of formulae IV-XIV, wherein: Q4is, , ,,, where * is the bond to the phosphorous atom; X is O; each RPis independently -OROor is -N(RN)2, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; and each RNis independently hydrogen, C1-3alkyl, or an amine protecting group R3’is -OR30, wherein: R30is hydrogen, hydroxyl protecting group, or a reactive phosphorous group.

[0141] In some compounds of formulae IV-XVII and XIX-XIII, R3’is -OR30, X is O, and each RPis -ORO. In some compounds of Formula (IV), R3’is -OR30, X is O, each RPis -ORO, and each ROindependently is C1-6alkyl (e.g., methyl or ethyl). In some compounds of Formula (IV), R3’is -OR30, X is O, each RPis -ORO, and each ROindependently is a hydroxyl protecting group (e.g. pivaloyloxymethyl).

[0142] In some compounds of formulae IV-VII and XIX-XXIII, R3’is -OR30, R30is - P(ORP1)N(RP2)2, X is O, and one RPis -OROand the other RPis C1-3alkyl. In some compounds of formulae IV-XXIII, R3’is -OR30, R30is -P(ORP1)N(RP2)2, X is O, one RPis -ORO, and each ROindependently is C1-6alkyl (e.g., methyl or ethyl), and the other RPis C1-3alkyl. In some compounds of formulae IV-XXIII, R3’is -OR30, R30is -P(ORP1)N(RP2)2, X is O, one RPis -ORO, and each ROindependently is a hydroxyl protecting group (e.g. pivaloyloxymethyl), and the other RPis C1-3alkyl (e.g., methyl).

[0143] In some compounds of formulae IV-XVII and XIX-XXIII, B is uracil or thymidine, R3’is -OR30, X is O, and each RPis -ORO. In some compounds of formulae IV-XXIII, B is uracil or thymidine, R3’is -OR30, X is O, each RPis -ORO, and each ROindependently is C1-6alkyl (e.g., methyl or ethyl). In some compounds of formulae IV-XXIII, B is uracil or thymidine, R3’is -OR30, X is O, each RPis -ORO, and each ROindependently is a hydroxyl protecting group (e.g. pivaloyloxymethyl).

[0144] In certain compounds of formulae IV-XVII and XIX-XXIIII, R3’is -OR30, R30is - P(ORP1)N(RP2)2, X is O, and each RPis -ORO. In some compounds of formulae IV-XXIII, R3’is - OR30, R30is -P(ORP1)N(RP2)2, X is O, each RPis -ORO, and each ROindependently is C1-6alkyl (e.g., methyl or ethyl). In some compounds of formulae IV-XXIII, R3’is -OR30, R30is - P(ORP1)N(RP2)2, X is O, each RPis -ORO, and each ROindependently is a hydroxyl protecting group (e.g. pivaloyloxymethyl).

[0145] In some compounds of formulae IV-XVII and XIX-XXIII, B is uracil or thymidine, R3’is -OR30, R30is -P(ORP1)N(RP2)2, X is O, and each RPis -ORO. In some compounds of formulae IV-XXIII, B is uracil or thymidine, R3’is -OR30, R30is -P(ORP1)N(RP2)2, X is O, each RPis -ORO, and each ROindependently is C1-6alkyl (e.g., methyl or ethyl). In some compounds of formulae IV-XXIII, B is uracil or thymidine, R3’is -OR30, R30is -P(ORP1)N(RP2)2, X is O, each RPis -ORO, and each ROindependently is a hydroxyl protecting group (e.g. pivaloyloxymethyl).

[0146] In some compounds of formulae IV-XVII and XIX-XXIII, B is uracil or thymidine, R3’is -OR30, R30is -P(ORP1)N(RP2)2, X is O, and one RPis -OROand the other RPis C1-3alkyl. In some compounds of formulae IV-XXIII, B is uracil or thymidine, R3’is -OR30, R30is -P(ORP1)N(RP2)2, X is O, one RPis -ORO, and each ROindependently is C1-6alkyl (e.g., methyl or ethyl), and the other RPis C1-3alkyl. In some compounds of formulae IV-XXIII, B is uracil or thymidine, R3’is - OR30, R30is -P(ORP1)N(RP2)2, X is O, one RPis -ORO, and each ROindependently is a hydroxyl protecting group (e.g. pivaloyloxymethyl), and the other RPis C1-3alkyl (e.g., methyl).

[0147] In some compounds of Formula (XVIII), R3’is -OR30, R30is -P(ORP1)N(RP2)2, X is O, and RPSis -ORO. In some compounds of Formula (XVIII), R3’is -OR30, R30is -P(ORP1)N(RP2)2, X is O, RPSis -ORO, and ROis C1-6alkyl (e.g., methyl or ethyl). In some compounds of Formula (XVIII), R3’is -OR30, R30is -P(ORP1)N(RP2)2, X is O, RPSis -ORO, and RPis C1-3alkyl (e.g., methyl).

[0148] In some compounds of Formula (XVIII), B is uracil or thymidine, R3’is -OR30, X is O, and RPSis -ORO. In some compounds of Formula (XVIII), B is uracil or thymidine, R3’is -OR30, X is O, RPSis -ORO, and ROis C1-6alkyl (e.g., methyl or ethyl). In some compounds of Formula (XVIII), B is uracil or thymidine, R3’is -OR30, X is O, RPSis -ORO, and ROis a hydroxyl protecting group (e.g. pivaloyloxymethyl).

[0149] In certain compounds of Formula (XVIII), R3’is -OR30, R30is -P(ORP1)N(RP2)2, X is O, and RPSis -ORO. In some compounds of Formula (XVIII), R3’is -OR30, R30is -P(ORP1)N(RP2)2, X is O, RPSis -ORO, and ROis C1-6alkyl (e.g., methyl or ethyl). In some compounds of Formula (XVIII), R3’is -OR30, R30is -P(ORP1)N(RP2)2, X is O, RPSis -ORO, and ROis a hydroxyl protecting group (e.g. pivaloyloxymethyl).

[0150] In some compounds of formulae IV-XXI, B is uracil or thymidine, R3’is -OR30, R30is -P(ORP1)N(RP2)2, X is O, and each RPis -ORO. In some compounds of Formula (IV), B is uracil or thymidine, R3’is -OR30, R30is -P(ORP1)N(RP2)2, X is O, each RPis -ORO, and ROis C1-6alkyl (e.g., methyl or ethyl). In some compounds of Formula (IV), B is uracil or thymidine, R3’is -OR30, R30is -P(ORP1)N(RP2)2, X is O, each RPis -ORO, and each ROis a hydroxyl protecting group (e.g. pivaloyloxymethyl).

[0151] In some embodiments, R3’is -OR30and R30is a bond to an oligonucleotide, e.g., R3’iswherein: Y is O or S (e.g., S) andrepresents the remainder of an oligonucleotide (e.g., the antisense strand of a double-stranded RNA). In the preceding, the oxygen atom that is illustrated linking the 5’-end of the oligonucleotide to the phosphorous atom is the 5’-oxygen of the 5’-terminal nucleoside of the oligonucleotide. For example, the compound is of formula,,, , or a salt thereof, wherein: R3’ iswherein:Y is O or S;represents the remainder of an oligonucleotide (e.g., the antisense strand of a double-stranded RNA); n is an integer selected from 1 - 3; M is a monocyclic or bicyclic ring (such as C3-8cycloalkyl (e.g., cyclohexyl, cyclopentyl or cyclobutyl) or heterocyclyl (e.g., piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, or tetrahydrothienyl), a 5-membered sugar, or a 6- membered sugar; B is an optionally modified nucleobase (e.g., uracil); Q is propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2- ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2- methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2- ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2- methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein: RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q are both replaced with O or S;one methine in Q is optionally replaced with -N=; Q4is ethylene, ethenylene (e.g.,preferably ), where * is the bond to the phosphorous atom), propylene, propenylene (e.g., orpropynylene, methylcyclopropyl, cyclopropylmethyl, 2- ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2- methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2- ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2- methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q4are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein: RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q4are both replaced with O or S; one methine in Q4is optionally replaced with -N=; y is 0 or 1; n5is an integer selected from 2 - 5 (e.g., 2, 3, or 4, preferably 2); n6is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1); n7is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1); n8is an integer selected from 1 - 3 (e.g., 1, or 2); n9is an integer selected from 1 - 3 (e.g., 1, or 2); n10is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1); R4’is C1-6alkyl (e.g., methyl), C1-6alkoxy (e.g., methoxy), or hydrogen; R5Xis H or C1-6alkyl (e.g., methyl); Q5is methylene, ethylene, ethenylene, propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2- ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2- methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2- ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2- methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q5are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that:no two consecutive methylene groups in Q5are both replaced with O or S; one methine in Q5is optionally replaced with -N=; RPSis C1-3alkyl, -ORO, -N(RN)2, -N(RN)S(O)2R2S, -N(RN)P(O)(ORO)(RPC), or - N=P(ORO)2(RPC); wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RNis independently hydrogen, C1-3alkyl, or an amine protecting group; RPCis C1-6alkyl (e.g., C1-3alkyl or methyl); and R2Sis C1-3alkyl; X is O or S; XAis O or S; YAis O or S; each RPis independently C1-3alkyl, -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RSis independently hydrogen, C1-3alkyl, or a thiol protecting group; each RNis independently hydrogen, C1-3alkyl, or an amine protecting group; and R2Sis C1-3alkyl; R2’is hydrogen, halogen, or -OR20, wherein: R20is hydrogen, hydroxyl protecting group, optionally substituted C1-6alkyl, (e.g., methyl, 2-methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N- methylamino)-2-oxoethyl, 2-[N,N-dimethyl)aminooxy]ethyl, or 3-oxo-3- (N-methylamino)prop-1-yl), optionally substituted C2-6alkenyl, or optionally substituted C2-6alkynyl (e.g., propargyl); RAis alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amin, alkenyl (e.g., vinyl or allyl), alkynyl (e.g., ethynyl or propargyl) or alkyl ester; and Q1is -O-, -S-, or -N(RNQ)-, wherein: RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl.

[0152] In some embodiments, Y is S. In other embodiments, Y is O.

[0153] Herein,is used to represent an oligonucleotide; such oligonucleotides may be an RNA, a DNA, a single-stranded RNA, such as an antisense oligonucleotide (ASO), the antisense strand of a double-stranded RNA (such as an siRNA), and oligonucleotide derivatives such as phosphorodiamidate morpholino oligomers (PMOs).

[0154] In some embodiments, X is O, each RPis -ORPO, and R3’is -OR30, where R30is a bond to an oligonucleotide, e.g., R3’is, wherein: Y is O or S (e.g., S) andrepresents the remainder of an oligonucleotide (e.g., the antisense strand of a double- stranded RNA). For example, the compound is of formula,,or a salt thereof, wherein: R3’iswherein: Y is O or S;represents the remainder of an oligonucleotide (e.g., the antisense strand of a double-stranded RNA); each RPis -ORO, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; X is O; XAis O; YAis O; n is an integer selected from 1 - 3; M is a monocyclic or bicyclic ring (such as C3-8cycloalkyl (e.g., cyclohexyl, cyclopentyl or cyclobutyl) or heterocyclyl (e.g., piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, or tetrahydrothienyl), a 5-membered sugar, or a 6- membered sugar; B is an optionally modified nucleobase (e.g., uracil); Q is propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2- ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2- methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2- ethyl)cyclopropylmethyl, 2-(2-methyl)cyclopropylethyl, 2-methylcyclobutyl, 3- methylcyclobutyl or cyclobutylmethyl, wherein:one or two methylene groups in Q are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein: RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q are both replaced with O or S; one methine in Q is optionally replaced with -N=; Q4is ethylene, ethenylene (e.g.,or,, preferably, where * is the bond to the phosphorous atom), propylene, propenylene, or propynylene, methylcyclopropyl, cyclopropylmethyl, 2-ethylcyclopropyl, (2- cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2-methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2-ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2-methylcyclobutyl, 3- methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q4are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein: RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q4are both replaced with O or S; one methine in Q4is optionally replaced with -N=; y is 0 or 1; n5is an integer selected from 2 - 5 (e.g., 2, 3, or 4, preferably 2); n6is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1); n7is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1); n8is an integer selected from 1 - 3 (e.g., 1, or 2); n9is an integer selected from 1 - 3 (e.g., 1, or 2); n10is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1); R4’is C1-6alkyl (e.g., methyl), C1-6alkoxy (e.g., methoxy), or hydrogen; R5Xis H or C1-6alkyl (e.g., methyl); Q5is methylene, ethylene, ethenylene, propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2-ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2-methyl)cyclopropylmethyl, 2- propylcyclopropyl, (3-cyclopropyl)propyl, (2-ethyl)cyclopropylmethyl,cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2-methylcyclobutyl, 3- methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q5are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q5are both replaced with O or S; one methine in Q5is optionally replaced with -N=; RPSis C1-3alkyl, -ORO, -N(RN)2, -N(RN)S(O)2R2S, -N(RN)P(O)(ORO)(RPC), or - N=P(ORO)2(RPC); wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RNis independently hydrogen, C1-3alkyl, or an amine protecting group; RPCis C1-6alkyl (e.g., C1-3alkyl or methyl); and R2Sis C1-3alkyl; R2’is hydrogen, halogen, or -OR20, wherein: R20is hydrogen, hydroxyl protecting group, optionally substituted C1-6alkyl, (e.g., methyl, 2-methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N- methylamino)-2-oxoethyl, or 3-oxo-3-(N-methylamino)prop-1-yl), optionally substituted C2-6alkenyl, or optionally substituted C2-6alkynyl (e.g., propargyl); RAis alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amin, alkenyl (e.g., vinyl or allyl), alkynyl (e.g., ethynyl or propargyl) or alkyl ester; and Q1is -O-, -S-, or -N(RNQ)-, wherein: RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl.

[0155] In certain embodiments, B is uracil or thymine. In certain embodiments, ROis C1-6alkyl (e.g., methyl or ethyl). In certain embodiments, ROis a hydroxyl protecting group (e.g. pivaloyloxymethyl). In some embodiments, Y is S. In other embodiments, Y is O.

[0156] In some embodiments, the compound is selected from the group of compound shown in Table A: Table A: Some exemplary compounds

[0166] In another aspect, provided herein is an oligonucleotide with a 5’-terminal phosphate mimic comprising the structure:wherein: * is a carbon atom in a sugar moiety of the 5’-terminal nucleotide (e.g., C4’ of a ribose); A is -C(*)(H)-, -CH2C(*)(H)-, or -C(*)(H)CH2-, wherein * is the bond to E; E is a bond or -CH2-; Q is propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2- ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2- methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2- ethyl)cyclopropylmethyl, 2-(2-methyl)cyclopropylethyl, 2-methylcyclobutyl, 3- methylcyclobutyl or cyclobutylmethyl;X is O or S; each RPis independently -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RSis independently hydrogen, C1-3alkyl, or a thiol protecting group; each RNis independently hydrogen, C1-3alkyl, or an amine protecting group; and R2Sis C1-3alkyl.

[0167] In another aspect, provided herein is an oligonucleotide with a 5’-terminal phosphate mimic comprising the structure:wherein: X is O or S; Q4is ethylene, ethenylene, propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2-ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2- methyl)cyclopropyl, (2-methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3- cyclopropyl)propyl, (2-ethyl)cyclopropylmethyl, 2-(2-methyl)cyclopropylethyl, 2- methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl; each RPis independently -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RNis independently hydrogen, C1-3alkyl, or an amine protecting group; and R2Sis C1-3alkyl; Q5is methylene, ethylene, ethenylene, propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2-ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2-methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2-ethyl)cyclopropylmethyl, cyclopropyl, 2-(2- methyl)cyclopropylethyl, 2-methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q5are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q5are both replaced with O or S; one methine in Q5is optionally replaced with -N=; andRPSis C1-3alkyl, -ORO, -N(RN)2, -N(RN)S(O)2R2S,-N(RN)P(O)(ORO)(RPC), or - N=P(ORO)2(RPC); wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RNis independently hydrogen, C1-3alkyl, or an amine protecting group; RPCis C1-6alkyl (e.g., C1-3alkyl or methyl); and R2Sis C1-3alkyl.

[0157] It is noted that the sugar moiety of the nucleotide comprising the 5’-terminalphosphate mimic (e.g.i.e., the nucleotide at 5’-end of theoligonucleotide (5’-terminal nucleotide) can comprise a 5- or 6- membered ring. For example, the sugar moiety of the nucleotide comprising the above modification can be a furanose (e.g., ribofuranose, arabinofuranose, lyxofuranose, xylofuranose, ribulofuranose or xylulofuranose, including alpha and beta, D and L, deoxy, and modified derivates thereof), or a pyranose (e.g., glucopyranose, galactopyranose, mannopyranose, allopyranose, altropyranose, gulopyranose, idopyranose, and talopyranose, including alpha and beta, D and L, deoxy, and modified derivates thereof). It is noted that the 5’-terminal phosphate mimic can be attached to any atom, e.g., anycarbon atom of the sugar moiety. The 5’-terminal phosphate mimic (e.g.,can replace a -CH2OH group or a -OH group (e.g., a -CH2OH group) on the sugar moiety of a 5’-terminal nucleotide of the oligonucleotide. For example, the 5’-terminal phosphatemimic (e.g.,replaces the 4’-CH2OH group on the furanose ring(e.g. ribofuranose, arabinofuranose, lyxofuranose, xylofuranose, ribulofuranose or xylulofuranose, preferably ribofuranose) or the 5’-CH2OH group on the pyranose (e.g., glucopyranose, galactopyranose, mannopyranose, allopyranose, altropyranose, gulopyranose, idopyranose, or talopyranose, preferably glucopyranose, galactopyranose, or mannopyranose) of the 5’-terminal nucleotide of the oligonucleotide.

[0158] Similarly, the sugar moiety of the nucleotide comprising the, modification, i.e., the nucleotide at 5’-end of the oligonucleotide (5’-terminal nucleotide) can comprise a 5- or 6- membered ring. For example, the sugar moiety of the nucleotide comprising the above modification can be a furanose (e.g., ribofuranose, arabinofuranose, lyxofuranose, xylofuranose, ribulofuranose or xylulofuranose, including alpha and beta, D and L, deoxy, and modified derivates thereof), or a pyranose (e.g., glucopyranose, galactopyranose, mannopyranose, allopyranose, altropyranose, gulopyranose, idopyranose, and talopyranose, including alpha and beta, D and L, deoxy, and modified derivates thereof). Generally, the, modification replaces carbon atom in the ring portion of the sugar moiety of a 5’-terrminal nucleotide of the oligonucleotide. For example, the, modification replaces the 4’-C atom in the furanose (e.g. ribofuranose, arabinofuranose, lyxofuranose, xylofuranose, ribulofuranose or xylulofuranose, preferably ribofuranose) or the 5’-C atom in the pyranose (e.g., glucopyranose, galactopyranose, mannopyranose, allopyranose, altropyranose, gulopyranose, idopyranose, or talopyranose, preferably glucopyranose, galactopyranose, or mannopyranose) ring of the 5’- terminal nucleotide of the oligonucleotide.

[0159] In some embodiments, the oligonucleotide comprises at its 5’-end a compound of formulae I-IV described herein. In certain embodiments, X is O. In certain embodiments, X is O, and each RPis ORO. In certain embodiments, X is O, and each RPis OH. In certain embodiments, X is O, and each RPis ethoxy. In certain embodiments, X is O, and each RPis OH. In certain embodiments, X is O, and each RPis OROwherein ROis pivaloyloxymethyl.

[0160] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide is of the structure:, , ,or a salt thereof, wherein: n is an integer selected from 1 - 3; B is an optionally modified nucleobase (e.g., uracil); Q is propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2- ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2- methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2- ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2- methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q are both replaced with O or S; one methine in Q is optionally replaced with -N=; Q4is ethylene, ethenylene (e.g.,or,, preferablywhere * is the bond to the phosphorous atom), propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2-ethylcyclopropyl, (2- cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2-methyl)cyclopropylmethyl,2-propylcyclopropyl, (3-cyclopropyl)propyl, (2-ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2-methylcyclobutyl, 3- methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q4are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q4are both replaced with O or S; one methine in Q4is optionally replaced with -N=; X is O or S; XAis O or S; YAis O or S; each RPis independently C1-3alkyl, -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RSis independently hydrogen, C1-3alkyl, or a thiol protecting group; each RNis independently hydrogen, C1-3alkyl, or an amine protecting group; and R2Sis C1-3alkyl; one of R2’and R3’is hydrogen, halogen, or -OR20, wherein: R20is hydrogen, hydroxyl protecting group, optionally substituted C1-6alkyl, (e.g., methyl, 2-methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N- methylamino)-2-oxoethyl, 2-[N,N-dimethyl)aminooxy]ethyl, or 3-oxo-3- (N-methylamino)prop-1-yl), optionally substituted C2-6alkenyl, or optionally substituted C2-6alkynyl (e.g., propargyl); the other of R2’and R3’is -OR30, wherein: R30is a bond to the rest of the oligonucleotide; and RAis alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amin, alkenyl (e.g., vinyl or allyl), alkynyl (e.g., ethynyl or propargyl) or alkyl ester.

[0161] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:. For example, the 5’-terminal nucleotide of the oligonucleotide can beof formula,,, wherein: Q1is -O-, -S-, or -N(RN)-, and RNis hydrogen, methyl, C1-3alkoxy, or C1-3acyl.

[0162] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide is of formula,

[0163] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide is of formula,

[0164] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide is of formula,.

[0165] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide is of formula,In some embodiments, the 5’-terminal nucleotide of the oligonucleotide is of formula,.

[0166] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide is of formula,

[0167] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide is of formula,

[0168] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide is of formula, e.g., offormula .

[0169] In some embodiments, the ‘5-terminal nucleotide of the oligonucleotide is of formula, e.g., of formula

[0170] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide is of formula,

[0171] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide is of formula,.

[0172] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide is of formula,.

[0173] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide is of formula,, wherein n is 1, 2 or 3.

[0174] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure: . For example, the 5’-terminal nucleotide of the oligonucleotide is of formula: In some embodiments, the 5’-terminal nucleotde is of formula: . In some other embodiments, the the 5’-terminal nucleotde is of formula:. In some aspects of these embodiments, Q4is ethylene or ethenylene, where * is the bond to the phosphorous atom).

[0175] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:For example, the 5’-terminal nucleotide of the oligonucleotide is of formula: . In some embodiments, the 5’-terminal nucleotde is of formula: In some other embodiments, the the 5’-terminal nucleotde is of formula:. In some aspects of these embodiments, Q4is ethylene or ethenylene (e.g.,preferablywhere * is the bond to the phosphorous atom).

[0176] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:For example, the 5’-terminal nucleotide of the oligonucleotide is of formula: In some embodiments, the 5’-terminal nucleotde is of formula: . In some other embodiments, the the 5’-terminal nucleotde is of formula: In so4me aspects of these embodiments, Q is ethylene or ethenylene (e.g., preferably , where * is the bond to the phosphorous atom).

[0177] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure: For example, the 5’-terminal nucleotide of the oligonucleotide is of formula:In some embodiments, the 5’-terminal nucleotde is of formula:In some other embodiments, the the 5’-terminal nucleotde is of formula: In s4ome aspects of these embodiments, Q is ethylene or ethenylene (e.g.,preferablywhere * is the bond to the phosphorous atom).

[0178] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:, , , ,

[0179] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide is of the structure:each as defined in Table 14 (below), where s at the end of the abbreviation indicates the internucleoside linkage between the 5’-terminal nucleoside and the subsequent nucleoside is a phosphorothioate internucleoside linkage, and the absence of “s” indicates that the internucleoside linkage between the 5’-terminal nucleoside and the subsequent nucleoside is a phosophodiester (e.g., a phosphate internucleotide linkage).

[0180] Generally, the oligonucleotide comprises at least three nucleotides. For example, the oligonucleotide comprises from 5 to 100, e.g., from 10 to 50 nucleotides. In some embodiments, the oligonucleotide comprises from 15 to 40 nucleotides. For example, the oligonucleotide is 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides in length. In some embodiments, the oligonucleotide is 17, 18, 19, 21, 22, 23, 24 or 25 nucleotides in length. For example, the oligonucleotide is 19, 20, 21, 22, or 23 nucleotides in length. It is noted that the compound of formulae I-XXIII counts as one nucleotide.

[0181] The oligonucleotide described herein can comprise at least one nucleic acid modification (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more independently selected modifications). Exemplary nucleic acid modifications are described herein below, and include, but are not limited to nucleobase modifications, sugar modifications, internucleotide linkage modifications, conjugates (e.g., ligands), and combinations thereof.

[0182] In some embodiments, the oligonucleotide comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2’-OMe nucleotides.

[0183] In some embodiments, the oligonucleotide comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) thermally destabilizing modification of the duplex. For example, the oligonucleotide comprises a thermally destabilizing modification at at least one of position 4, 5, 6, 7, or 8, counting from the 5’-end of the oligonucleotide, where the compound of formulae I-XXIII is at position 1 from the 5’-end of the oligonucleotide; optionally, the thermally destabilizing modification is located at position 6, 7, or 8, counting from the 5’-end of the oligonucleotide, preferably the thermally destabilizing modification is located at position 7, counting from the 5’- end of the oligonucleotide.

[0184] In some embodiments, the oligonucleotide comprises least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2’-F nucleotides. For example, the oligonucleotide comprises 2, 3, 4, 5, or 62’-F nucleotides, optionally, the oligonucleotide comprises 3, 4, 5 or 6 2’-F nucleotides. In some embodiments, the oligonucleotide comprises a 2’-F nucleotide at least at positions 2, 14 and 16, counting from the 5’-end of the oligonucleotide, where the compound of formulae I-XXIII is at position 1 from the 5’-end of the oligonucleotide. For example, the oligonucleotide comprises a2’-F nucleotide at least at positions 2, 6, 14 and 16, counting from the 5’-end of the oligonucleotide, optionally, the oligonucleotide comprises a 2’-F nucleotide at least at positions 2, 6, 9, 14 and 16, preferably, the oligonucleotide comprises a 2’-F nucleotide at least at positions 2, 6, 8, 9, 14 and 16, counting from the 5’-end of the oligonucleotide. It is noted that when more than one 2’-F nucleotide is present in the oligonucleotide, each 2’-F nucleotide is an independently selected nucleotide.

[0185] The oligonucleotide can also comprise one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2’-deoxy (2’-H) nucleotides. For example, the oligonucleotide comprises 2, 3, 4, 5, 6, or 7 2’-deoxy nucleotides, optionally, the oligonucleotide comprises 3, 4, 5 or 62’-deoxy nucleotides. The oligonucleotide can comprise a 2’-deoxy nucleotide at any one of positions 2, 5, 7, 12, 14 and 16, counting from the 5’-end of the oligonucleotide, where the compound of formulae I-XXIII is at position 1 from the 5’-end of the oligonucleotide. For example, the oligonucleotide comprises a 2’-deoxy nucleotide at least at position 5, counting from the 5’-end of oligonucleotide. In some embodiments, the oligonucleotide comprises a 2’-deoxy nucleotide at least at positions 2, 5 and 9, counting from the 5’-end of oligonucleotide. For example, the oligonucleotide comprises a 2’- deoxy nucleotide at least at positions 2, 5, 7, and 12, counting from the 5’-end of oligonucleotide. For example, thew oligonucleotide comprises a 2’-deoxy nucleotide at least at positions 2, 5, 7, 12, 14, and 16, counting from the 5’-end of the oligonucleotide. It is noted that when more than one 2’-dexy nucleotide is present in the oligonucleotide, each 2’-deoxy nucleotide is an independently selected nucleotide.

[0186] One or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) nucleobases in the oligonucleotide can be non-natural or modified nucleobases. For example, the oligonucleotide can comprise one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) modified or protected nucleobases.

[0187] The internucleotide linkages in the oligonucleotide can be independently unmodified (e.g., phosphodiester) or modified (e.g., phosphorothioate). Thus, in some embodiments, the oligonucleotide comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) modified internucleoside linkages. Generally, the oligonucleotide comprises at least one (e.g., 1, 2, 4, or 5) modified internucleoside linkages (e.g., phosphorothioate) at the first 1-5 positions at one or both ends of the oligonucleotide. For example, the oligonucleotide comprises a modified oligonucleotide linkage (e.g., (e.g., phosphorothioate) between nucleotides at positions 1 and 2, and between nucleotides at positions 2 and 3, counting from the 5’-end of the oligonucleotide; and the oligonucleotide comprises a modified oligonucleotide linkage (e.g., (e.g., phosphorothioate) between nucleotides at positions 1 and 2, and between nucleotides at positions 2 and 3, counting from the 3’-end of the oligonucleotide.

[0188] In some embodiments, the oligonucleotide is covalently linked to a support, e.g., a solid support.

[0189] In yet another aspect, provided herein is a double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, wherein the sense strand is substantially complementary to the antisense strand, and wherein one of the sense or the antisense strand is an oligonucleotide described herein, i.e., an oligonucleotide with a 5’-terminal modification comprising the structure:wherein: * is a carbon atom in a sugar moiety of the 5’-terminal nucleotide (e.g., C4’ of a ribose); A is -C(*)(H)-, -CH2C(*)(H)-, or -C(*)(H)CH2, wherein * is the bond to E; E is a bond or -CH2-; Q is propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2- ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2- methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2- ethyl)cyclopropylmethyl, 2-(2-methyl)cyclopropylethyl, 2-methylcyclobutyl, 3- methylcyclobutyl or cyclobutylmethyl, X is O or S; each RPis independently -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RSis independently hydrogen, C1-3alkyl, or a thiol protecting group; each RNis independently hydrogen, C1-3alkyl, or an amine protecting group; and R2Sis C1-3alkyl.

[0190] Generally, themodification replaces a CH2OH group on the sugar moiety of the 5’-terrminal nucleotide of the sense or antisense strand. For example, themodification replaces the 4’-CH2OH group on the furanose ring (e.g. ribofuranose, arabinofuranose, lyxofuranose, xylofuranose, ribulofuranose or xylulofuranose, preferably ribsofuranose) or the 5’- CH2OH group on the pyranose (e.g., glucopyranose, galactopyranose, mannopyranose, allopyranose, altropyranose, gulopyranose, idopyranose, or talopyranose, preferablyglucopyranose, galactopyranose, or mannopyranose) of the 5’-terminal nucleotide of the sense or antisense strand.

[0191] Similarly, themodification replaces carbon atom in the sugar moiety of the 5’-terminal nucleotide of the sense or antisense strand. For example, themodification replaces the 4’-C atom in the furanose (e.g. ribofuranose, arabinofuranose, lyxofuranose, xylofuranose, ribulofuranose or xylulofuranose, preferably ribsofuranose) ring or the 5’-C atom in the pyranose (e.g., glucopyranose, galactopyranose, mannopyranose, allopyranose, altropyranose, gulopyranose, idopyranose, or talopyranose, preferably glucopyranose, galactopyranose, or mannopyranose) ring of the 5’-terminal nucleotide of the sense or antisense strand.

[0192] In other words, the sense or antisense strand comprises at its 5’-end a compound of formulae I-XXIII described herein. In certain embodiments, X is O. In certain embodiments, X is O, and each RPis ORO. In certain embodiments, X is O, and each RPis OH. In certain embodiments, X is O, and each RPis ethoxy. In certain embodiments, X is O, and each RPis OH. In certain embodiments, X is O, and each RPis OROwherein ROis pivaloyloxymethyl.

[0193] For example, the 5’-terminal nucleotide of one of the sense or antisense strand is of the structure: ,, , , ,,where one of R2’and R3’is -OR30, and R30is a bond to the rest of the sense or antisense strand, provided that R3’is -OR30in formulae, ,.

[0194] Preferably, the antisense strand comprises the above 5’-terminal modification.

[0195] In still another aspect, provided herein is a method for reducing the expression of a target gene in a subject. The method comprises administering to the subject either: (i) a double- stranded RNA described herein, where the antisense strand is substantially complementary to a target gene; or (ii) an oligonucleotide described herein, where the oligonucleotide is substantially complementary to a target gene.

[0196] In another aspect, provided herein is a pharmaceutical composition comprising an oligonucleotide or dsRNA molecule described herein alone or in combination with a pharmaceutically acceptable carrier or excipient.

[0197] In yet another aspect, provided herein is a cell comprising an oligonucleotide or dsRNA molecule described herein.

[0198] In still another aspect, provided herein is a gene silencing kit comprising an oligonucleotide or dsRNA molecule described herein.

[0199] Also, provided herein is a method for silencing a target gene, in a cell. The method comprises a step of introducing: (i) a dsRNA molecule described herein into the cell, where one of the strands, e.g., the antisense of the dsRNA comprises a nucleotide sequence substantiallycomplementary to a nucleotide sequence of the target gene; and / or (ii) an oligonucleotide described herein, wherein the oligonucleotide comprises a nucleotide sequence substantially complementary to a nucleotide sequence of the target gene.

[0200] In another aspect, provided herein is a method for inhibiting or reducing the expression of a target gene in a subject. The method comprises administering to the subject: (i) a dsRNA molecule described herein, where one of the strands, e.g., the antisense of the dsRNA comprises a nucleotide sequence substantially complementary to a nucleotide sequence of the target gene; and / or (ii) an oligonucleotide described herein, wherein the oligonucleotide comprises a nucleotide sequence substantially complementary to a nucleotide sequence of the target gene. BRIEF DESCRIPTION OF THE DRAWINGS

[0201] FIG. 1 shows mTTR protein levels at different timepoints after administration of a single dose (0.3 mg / kg) of exemplary duplexes AD-286913, AD-2140883, AD-2140885, AD- 2140887, AD-2140888, and AD-64958 (parent) in mice.

[0202] FIG. 2 shows mTTR protein levels at different timepoints after administration of a single dose (0.3 mg / kg) of exemplary duplexes AD-286913, AD-2140884, AD-2140882, AD- 2140886, AD-2261036, and AD-64958 (parent) in mice.

[0203] FIG. 3 shows mTTR protein levels at different timepoints after administration of a single dose (0.5 mg / kg) of exemplary duplexes AD-286913, AD-2633769, AD-2633771, AD- 2633772, AD-2633774, AD-2633775, AD-2633777, and AD-64958 (parent) in mice.

[0204] FIG. 4 shows mTTR protein levels at different timepoints after administration of a single dose (0.3 mg / kg) of exemplary duplexes AD-286913, AD-2140883, AD-2140885, AD- 2140887, AD-2140888, and AD-64958 (parent) in mice.

[0205] FIG. 5 shows mTTR protein levels at different timepoints after administration of a single dose (0.3 mg / kg) of exemplary duplexes AD-286913, AD-2680450, AD-2680452, AD- 2680454, AD-2680455, AD-2680456, and AD-64958 (parent) in mice.

[0206] FIG. 6 shows mSOD1 mRNA remaining in brain (right hemisphere) after intracerebroventricular administration of exemplary duplexes AD-401824, AD-2919280, AD- 2919281, AD-2919282, AD-2919283, AD-2919284, AD-2919285, AD-2919286, AD-2919288, and AD-2919289 targeting SOD1 mRNA in mice.

[0207] FIG. 7 shows mSOD1 mRNA remaining in brain (right hemisphere) after intracerebroventricular administration of exemplary duplexes AD-401824, AD-401825, AD- 2919282, AD-2919289, AD-3116172 and AD-3116181 targeting SOD1 mRNA in mice.

[0208] FIG. 8 shows mSOD1 mRNA remaining in brain (right hemisphere) after intracerebroventricular administration of exemplary duplexes AD-1271086, AD-3367267, and AD- 3367269 targeting SOD1 mRNA in mice.

[0209] FIG. 9 shows sAPPα protein levels at different timepoints after intrathecal administration of exemplary duplexes AD-960499, AD-454844, and AD-2905746 in non-human primate.

[0210] FIG. 10 shows APP mRNA remaining in various organs at day 91 after intrathecal administration of exemplary duplexes AD-960499, AD-454844, and AD-2905746 in non-human primate.

[0211] FIG. 11 shows MAP2 mRNA remaining in various organs at day 91 after intrathecal administration of exemplary duplexes AD-476454, AD-2912412, and AD-2912413 in non-human primate.

[0212] FIG. 12 shows APP protein levels after intrathecal administration of exemplary duplexes AD-454844, AD-3175047, and AD-3216841 in non-human primate.

[0213] FIG 13 shows 5ʹ-(E)-VP modified nucleotides previously tested in the context of siRNAs (I-VI) and conformational equilibrium between C2′-endo (South) and C3′-endo (North) sugars. R = 2’-modification.

[0214] FIG.14shows Configurational and conformational features of LNA, α-L-LNA, and 5ʹ-VP-functionalized LNA and α-L-LNA studied.

[0215] FIG.15A shows siRNAs with LNA or α-L-LNA at the 5' terminus of the antisense strands result in diminished silencing of gene expression in cultured cells or mice. Ttr mRNA remaining in primary mouse hepatocytes cultured with the indicated siRNAs at the indicated concentrations under free uptake conditions. mRNAs were quantified by RT-qPCR, and averages ± standard deviations are plotted (n=3). normalized to pre-dose levels in individual animals (n=3).

[0216] FIG.15B shows siRNAs with LNA or α-L-LNA at the 5' terminus of the antisense strands result in diminished silencing of gene expression in cultured cells or mice. Ttr protein amounts in serum at indicated days after mice were dosed subcutaneously with 1 mg / kg indicated siRNA. Plotted are averages ± standard deviations

[0217] FIG.16A shows the 5'-VP-α-L-LNA modification results in a more active siRNA than the 5'-VP-LNA modification. Ttr mRNA remaining in primary mouse hepatocytes cultured with the indicated siRNAs at the indicated concentrations under free uptake conditions. mRNAs were quantified by RT-qPCR, and averages ± standard deviations are plotted (n=3).

[0218] FIG.16B shows the 5'-VP-α-L-LNA modification results in a more active siRNA than the 5'-VP-LNA modification. Ttr protein amounts in serum at indicated days after mice weredosed subcutaneously with 0.4 mg / kg indicated siRNA. Plotted are averages ± standard deviations normalized to pre-dose levels in individual animals (n=3).

[0219] FIG.17A shows 5'-VP-α-L-LNA makes interactions with the Ago2 MID domain that are similar to those of the antisense strand modified with 5'-VP-Ome, models of antisense strands modified with 5'-VP-2’-Ome.

[0220] FIG.17B shows 5'-VP-α-L-LNA makes interactions with the Ago2 MID domain that are similar to those of the antisense strand modified with 5'-VP-Ome, models of antisense strands modified with 5'-VP-α-L-LNA.

[0221] FIG.17C shows 5'-VP-α-L-LNA makes interactions with the Ago2 MID domain that are similar to those of the antisense strand modified with 5'-VP-Ome, models of antisense strands modified with 5'-VP-LNA lodged at the Ago2 MID domain binding site.

[0222] FIG.17D shows 5'-VP-α-L-LNA makes interactions with the Ago2 MID domain that are similar to those of the antisense strand modified with 5'-VP-OMe. Overlay of 5'-VP-α-L-LNA (golden) and 5'-VP-LNA (violet) bound to the Ago2 MID domain.

[0223] FIG.18 shows TTR protein amounts in serum at indicated days after mice were dosed subcutaneously with 1 mg / kg indicated siRNA. Plotted are averages ± standard deviations normalized to pre-dose levels in individual animals (n=3).

[0224] FIG.19 shows RNAi-mediated gene silencing is more efficient when the antisense strand of the siRNA is modified at 5' end with a 5'-vinyl-phosphonate carrying nucleotide that adopts a C3’-exo (South) conformation than a C3′-endo (North) pucker.

[0225] FIG.20A shows models of 5ʹ-terminal guide strand nucleotides lodged at the MID domain of RISC Ago2: LNA with a 5ʹ-phosphate.

[0226] FIG. 20B shows models of 5ʹ-terminal guide strand nucleotides lodged at the MID domain of RISC Ago2: Overlay of the LNA model shown in FIG.20A, LNA with an E-VP moiety, and E-VP-RNA. Carbon atoms of AS1 residues are colored in magenta, purple and green for P- LNA (5ʹ-phosphate LNA), E-VP-LNA and E-VP-RNA, respectively, and the AS1 and AS2 phosphorus atoms of RNA are highlighted in black. The phosphorus position of P-LNA virtually matches the position of the E-VP-RNA phosphorus (FIG. 20B), but the b torsion angle of the former nucleotide is in a gauche conformation to do so (FIG. 20A). Combining LNA with an E- VP moiety at AS1 results in a shift by the phosphorus of almost 1 Å relative to E-VP-RNA in addition to a shift by the entire LNA nucleoside (FIG.20B).

[0227] FIG.21 depicts some exemplary compounds of Formula (V).

[0228] FIG. 22 depicts a synthetic scheme for synthesis of compounds of Formula (V). Reference (ref) for compound 1 is Ref: Marquez et. al. J. Chem. Soc. Perkins Trans.1: Org. Bioorg. Chem.1997, 1073-1078.

[0229] FIG.23 depicts some exemplary compounds of Formula (VI).

[0230] FIG.24 depicts some exemplary compounds of Formula (VII).

[0231] FIG.25 depicts some exemplary compounds of Formula (VIII).

[0232] FIG.26 depicts some exemplary compounds of Formula (X).

[0233] FIG.27 depicts some exemplary compounds of Formula (XI).

[0234] FIG. 28 depicts some exemplary compounds of Formulae (XII)-(XIV). Reference, Damha et. al. J. Am. Chem. Soc.2017, 139, 14542-14555.

[0235] FIG. 29 depicts % mouse SOD1 (mSOD1) mRNA remaining relative to aCSF in the brain (right hemisphere).

[0236] FIG. 30 depicts % mSOD1 mRNA remaining relative to aCSF / GADPH.in the brain (right hemisphere), liver and heart. DETAILED DESCRIPTION

[0237] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. Herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of “or” means “and / or” unless stated otherwise. Furthermore, the use of the term “including” as well as other forms, such as “includes” and “included”, is not limiting. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit, unless specifically stated otherwise.

[0238] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference in their entirety for any purpose. M ring

[0239] Compounds of Formula (IV) have the structure:. In compounds of Formula (IV) the ring M can be a monocyclic or bicyclic ring (such as C3-8cycloalkyl (e.g., cyclohexyl, cyclopentyl or cyclobutyl) or heterocyclyl (e.g., piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, or tetrahydrothienyl), or a 5- or 6- membered sugar.

[0240] In some embodiments, ring M is a cycloalkyl (e.g., cyclohexyl, cyclopentyl or cyclobutyl). IN some embodiments, ring M is a heterocyclyl (e.g., piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, or tetrahydrothienyl)..

[0241] In some embodiments, ring M is a sugar. The sugar moiety can be a furanose (e.g., ribofuranose, arabinofuranose, lyxofuranose, xylofuranose, ribulofuranose or xylulofuranose, including alpha and beta, D and L, deoxy, and modified derivates thereof), or a pyranose (e.g., glucopyranose, galactopyranose, mannopyranose, allopyranose, altropyranose, gulopyranose, idopyranose, and talopyranose, including alpha and beta, D and L, deoxy, and modified derivates thereof). It is noted that phosphate moiety, B, R2’and R3’can be attached to any atom, e.g., any carbon atom of the ring M, e.g., of the sugar moiety.

[0242] In some embodiments, ring M is a furanose (e.g., ribofuranose, arabinofuranose, lyxofuranose, xylofuranose, ribulofuranose or xylulofuranose, including alpha and beta, D and L, deoxy, and modified derivates thereof), and B is attached to C1, R2is attached to C2 or is absent, R3’is attached to C3, and the phosphate moiety is attached to C4 of the furanose. In some embodiments, ring M is a furanose (e.g., ribofuranose, arabinofuranose, lyxofuranose, xylofuranose, ribulofuranose or xylulofuranose, including alpha and beta, D and L, deoxy, and modified derivates thereof), and B is attached to C1, R2is absent, R3’is attached to C2, and the phosphate moiety is attached to C3 of the furanose. In some embodiments, ring M is a furanose (e.g., ribofuranose, arabinofuranose, lyxofuranose, xylofuranose, ribulofuranose or xylulofuranose, including alpha and beta, D and L, deoxy, and modified derivates thereof), and B is attached to C1, R2is absent, R3’is attached to C4, and the phosphate moiety is attached to C3 of the furanose. In some embodiments, ring M is a furanose (e.g., ribofuranose, arabinofuranose, lyxofuranose, xylofuranose, ribulofuranose or xylulofuranose, including alpha and beta, D and L, deoxy, and modified derivates thereof), and B is attached to C1, R2is absent, and both of R3’and the phosphate moiety are attached to C3 of the furanose. It is noted that R2’, R3’and the phosphate moiety can replace the hydroxyl group present on the carbon of the furanose the R2’, R3’and the phosphate moiety are attached to. When the phosphate moiety is attached to C4 of the furanose, it can replace the -CH2OH group at the C4 of the ribose. The attachment of the B can be in the alpha or beta configuration. The attachment of the R2’, R3’and the phosphate moiety independently can be in the R or S configuration.

[0243] In some embodiments, ring M is cyclopentane. In some embodiments, ring M is cyclopentane, and B is attached to C1, R2is attached to C2 or is absent, R3’is attached to C3, and the phosphate moiety is attached to C4 of the cyclopentane. In some embodiments, ring M is cyclopentane and B is attached to C1, R2is absent, R3’is attached to C2, and the phosphate moiety is attached to C3 of the cyclopentane. In some embodiments, ring M is cyclopentane, and B isattached to C1, R2is absent, R3’is attached to C4, and the phosphate moiety is attached to C3 of the cyclopentane. In some embodiments, ring M is cyclopentane, and B is attached to C1, R2is absent, and both of R3’and the phosphate moiety are attached to C3 of the cyclopentyl. It is noted that carbon of the cyclopentane to which the B is attached is denotated as C1 and numbering proceeds in a clockwise fashion. It is noted that attachment of the B, R2’, R3’and the phosphate moiety independently can be in the R or S configuration.

[0244] In some embodiments, ring M is a pyranose (e.g., glucopyranose, galactopyranose, mannopyranose, allopyranose, altropyranose, gulopyranose, idopyranose, and talopyranose, including alpha and beta, D and L, deoxy, and modified derivates thereof), and B is attached to C1 of the pyranose, R2’is absent, R3’ is attached to C4 and the phosphate moiety is attached to C5 of the pyranose. It is noted that R2’, R3’and the phosphate moiety can replace the hydroxyl group present on the carbon of the pyranose the R2’, R3’and the phosphate moiety are attached to. The attachment of the B can be in the alpha or beta configuration. The attachment of the R2’, R3’and the phosphate moiety independently can be in the R or S configuration.

[0245] DNA typically favors the C2'-endo sugar pucker (also known as the South conformer). This conformation is associated with the B-form of DNA, which is the canonical double helix structure. In C2'-endo, the C2' carbon atom is positioned above the plane of the sugar ring. Accordingly, in some embodiments, ring M is in the south conformation (i.e., C2’- endo). On the other hand, RNA typically favors the C3'-endo sugar pucker (also known as the North conformer). This conformation is associated with the A-form of RNA, which is a more compact helix. In C3'-endo, the C3' carbon atom is positioned above the plane of the sugar ring. Accordingly, in some other embodiments, ring M is in the north conformation (i.e., C3’-endo). R3’

[0246] In the various aspects described herein, R3’can be hydrogen, halogen, -OR20, or -OR30.

[0247] In some embodiments, R3’is -OR30, where R30is hydrogen, a hydroxyl protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide. For example, R3’is -OR30and R30is hydrogen or hydroxyl protecting group.

[0248] In some embodiments, R3’is -OR30and R30is a reactive phosphorus group. For example, R30is a phosphoramidite, H-phosphonate, alkyl-phosphonate, or phosphate triester. In some embodiments, R3’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where:each RP1is C1-6alkyl, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from OH, CN, SC(O)Ph, oxo (=O), SH, SO2NH2, SO2(C1-C4)alkyl, SO2NH(C1-C4)alkyl, halogen, carbonyl, thiol, cyano, NH2, NH(C1-C4)alkyl, N[(C1- C4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-C8)alkyl, O(C1-C8)alkyl (i.e., C1-C8alkoxy), O(C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, aryl, heteroaryl, substituted aryl, NH2— C(O)-alkylene, NH(Me)-C(O)-alkylene, CH2—C(O)- alkyl, C(O)- alkyl, alkylcarbonylaminyl, CH2—[CH(OH)]m—(CH2)p—OH, CH2—[CH(OH)]m— (CH2)p—NH2or CH2-aryl-alkoxy, where “m” and “p” are independently 1, 2, 3, 4, 5 or 6; each RP2is independently C1-6alkyl, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from OH, CN, SC(O)Ph, oxo (=O), SH, SO2NH2, SO2(C1- C4)alkyl, SO2NH(C1-C4)alkyl, halogen, carbonyl, thiol, cyano, NH2, NH(C1- C4)alkyl, N[(C1-C4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-C8)alkyl, O(C1- C8)alkyl (i.e., C1-C8alkoxy), O(C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, aryl, heteroaryl, substituted aryl, NH2—C(O)-alkylene, NH(Me)-C(O)-alkylene, CH2—C(O)- alkyl, C(O)- alkyl, alkylcarbonylaminyl, CH2—[CH(OH)]m—(CH2)p—OH, CH2— [CH(OH)]m—(CH2)p—NH2or CH2-aryl-alkoxy, where “m” and “p” are independently 1, 2, 3, 4, 5 or 6, optionally each RP2is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, preferably each RP2is isopropyl; or both RP2taken together with the nitrogen atom to which they are attached form an optionally substituted 3-8 membered heterocyclyl; or RP1 and one of RP2taken together with the atoms to which they are attached form an optionally substituted 4-8 membered heterocyclyl; and each RP3is independently C1-30alkyl, C2-C30alkenyl, or C2-C30alkynyl, each optionally independently substituted with 1, 2, 3, 4 or 5 substituents independently selected from OH, CN, SC(O)Ph, oxo (=O), SH, SO2NH2, SO2(C1-C4)alkyl, SO2NH(C1- C4)alkyl, halogen, carbonyl, thiol, cyano, NH2, NH(C1-C4)alkyl, N[(C1-C4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-C8)alkyl, O(C1-C8)alkyl (i.e., C1- C8alkoxy), O(C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, aryl, heteroaryl, substituted aryl, NH2— C(O)-alkylene, NH(Me)-C(O)-alkylene, CH2—C(O)- alkyl, C(O)- alkyl, alkylcarbonylaminyl, CH2—[CH(OH)]m—(CH2)p—OH, CH2—[CH(OH)]m—(CH2)p—NH2or CH2-aryl-alkoxy, where “m” and “p” are independently 1, 2, 3, 4, 5 or 6, optionally each RP3is independently methyl, ethyl, propyl, isopropyl, n- butyl, iso-butyl, pentyl or hexyl, each of which can be optionally substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-C6alkoxy.

[0249] In some embodiments, R3’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1is C1-6alkyl, optionally substituted with a CN or –SC(O)Ph; each RP2is independently optionally substituted C1-6alkyl; and each RP3is independently optionally substituted C1-6alkyl.

[0250] In some embodiments, R3’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1 is C1-6alkyl, optionally substituted with a CN or –SC(O)Ph; each RP2is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl; and each RP3is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionally substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-C6alkoxy.

[0251] In some embodiments, R3’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1 is 2-cyanoethyl (-CH2CH2CN); each RP2is independently optionally substituted C1-6alkyl; and each RP3is independently optionally substituted C1-6alkyl.

[0252] In some embodiments, R3’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1 is 2-cyanoethyl (-CH2CH2CN); each RP2is independently methyl, ethyl, propyl, isopropyl, n- butyl, iso-butyl, pentyl or hexyl; and each RP3is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionally substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-C6alkoxy.

[0253] In some embodiments, R3’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1 is 2-cyanoethyl (-CH2CH2CN); each RP2is independently isopropyl; and each RP3is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionally substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-C6alkoxy.

[0254] In some embodiments, R3’is -OR30and R30is -P(ORP1)N(RP2)2, where: RP1 is 2- cyanoethyl (-CH2CH2CN); each RP2is independently isopropyl.

[0255] In some embodiments, R3’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1 is C1-6alkyl, optionally substituted with a CN or –SC(O)Ph; both RP2taken together with the nitrogen atom to which they are attached form an optionally substituted 3-8 membered heterocyclyl; and each RP3is independently optionally substituted C1-6alkyl.

[0256] In some embodiments, R3’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1 is C1-6alkyl, optionally substituted with a CN or –SC(O)Ph; both RP2taken together with the nitrogen atom to which they are attached form an optionally substituted 3-8 membered heterocyclyl; and each RP3is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionally substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-C6alkoxy.

[0257] In some embodiments, R3’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1 is 2-cyanoethyl (-CH2CH2CN); both RP2taken together with the nitrogen atom to which they are attached form an optionally substituted 3-8 membered heterocyclyl; and each RP3is independently optionally substituted C1-6alkyl.

[0258] In some embodiments, R3’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1 is 2-cyanoethyl (-CH2CH2CN); both RP2taken together with the nitrogen atom to which they are attached form an optionally substituted 3-8 membered heterocyclyl; and each RP3is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionally substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-C6alkoxy.

[0259] In some embodiments, R3’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: RP1 and one of RP2taken together with the atoms to which they are attached form an optionally substituted 4-8 membered heterocyclyl; other RP2is independently optionally substituted C1-6alkyl; and each RP3is independently optionally substituted C1-6alkyl.

[0260] In some embodiments, R3’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: RP1 and one of RP2taken together with the atoms to which they are attached form an optionally substituted 4-8 membered heterocyclyl; other RP2is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl; and each RP3is independently optionally substituted C1-6alkyl.

[0261] In some embodiments, R3’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: RP1 and one of RP2taken together with the atoms to which they are attached form an optionally substituted 4-8 membered heterocyclyl; other RP2is independently optionally substituted C1-6alkyl; and each RP3is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionally substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1- C6alkoxy.

[0262] In some embodiments, R3’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: RP1 and one of RP2taken together with the atoms to which they are attached form an optionally substituted 4-8 membered heterocyclyl; other RP2is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl; and each RP3is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionally substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-C6alkoxy.

[0263] In some embodiments, R3’is -OR30and R30is a bond to a nucleoside or a nucleotide, or an oligonucleotide. When R30is a bond to a nucleoside, a nucleotide, or an oligonucleotide, the internucleotide linkage between compound of formulae I-IV and the nucleoside, nucleotide, or oligonucleotide can be an unmodified (e.g., phosphodiester) internucleotide linkage or a modified (e.g., phosphorothioate) internucleotide linkage.

[0264] In some embodiments, R3’is -OR30and R30is linked to 5’-position of a nucleoside, nucleotide, or oligonucleotide by an unmodified (e.g., phosphodiester) internucleotide linkage (e.g., or a modified (e.g., phosphorothioate) internucleotide linkage. For example, R30is linked to the 5’-terminal (e.g., 5’-OH) of the oligonucleotide. In some embodiments, R30is linked to the 5’- terminal (e.g., 5’-OH) of the oligonucleotide by an unmodified (e.g., phosphodiester) internucleotide linkage. In some other embodiments, R30is linked to the 5’-terminal (e.g., 5’-OH) of the oligonucleotide by a modified (e.g., phosphorothioate) internucleotide linkage.

[0265] In some embodiments, R3’is -OR30and R30is a hydroxyl protecting group. For example, R3’is -OR30and R30is a hydroxyl protecting group selected from the group consisting of BOC or Boc, MOM, MTM, t-butylthiomethyl, SMOM, BOM, PMBM, p-AOM, GUM, t- butoxymethyl, POM, siloxymethyl, MEM, 2,2,2-trichloroethoxymethyl, bis(2- chloroethoxy)methyl, SEMOR, THP, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclohexyl, MTHP, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl- S,S-dioxide, CTMP, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a- octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1- methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p- methoxyphenyl, 2,4-dinitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p- halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4- picolyl, 3- methyl-2-picolyl N-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4′- bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″- tris(benzoyloxyphenyl)methyl, 3-(imidazol-1- yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1- bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9- (9-phenyl)xanthenyl, 9-(9-phenyl- 10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl- S,S-dioxido, TMS, TES, TIPS, IPDMS, DEIPS, dimethylthexylsilyl, TBDMS, TBDPS, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, DPMS, TBMPS, formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio)pentanoate (levulinoyldithioacetal), adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, Fmoc, alkyl ethyl carbonate, Troc, TMSEC, Psec, Peoc, alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2- formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α- naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate,dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate.

[0266] In some embodiments, R3’is -OR30and R30is TBDMS, TBDPS, TMS, TES, TIPS, IPDMS, DEIPS, TBMPS, DPMS, dimethylthexylsilyl, tribenzylsilyl, tri-p-xylylsilyl, or triphenylsilyl, optionally, R30is TBDMS.

[0267] In some embodiments, R3’is hydrogen or halogen. For example, R3is H or F.

[0268] In some embodiments, R3’is -OR20, where R20is hydrogen, hydroxyl protecting group, optionally substituted C1-6alkyl, such as C1-6alkoxyC1-6alkyl (e.g., 2-methoxyethyl) or N-(C1-6alkyl)aminocarbonylC1-6alkyl (e.g., 2-(N-methylamino)-2-oxoethyl or 3-oxo-3-(N- methylamino)prop-1-yl). For example, R3’is -OR20, and R20is hydrogen or hydroxyl protecting group.

[0269] In some embodiments, R3’is -OR20, and R20is C1-6alkyl, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from OH, CN, SC(O)Ph, oxo (=O), SH, SO2NH2, SO2(C1-4)alkyl, SO2NH(C1-4)alkyl, halogen, carbonyl, thiol, cyano, NH2, NH(C1-C4)alkyl, N[(C1-4)alkyl]2, C(O)NH2, C(O)NH(C1-6alkyl), C(O)N(C1-6alkyl)2, COOH, COO(C1-6alkyl) (e.g., COOMe), C2-6acyl (e.g., acetyl), (C1-8)alkyl, O(C1-8)alkyl (i.e., C1-8alkoxy), O(C1-8)haloalkyl, (C2-8)alkenyl, (C2-8)alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, aryl, heteroaryl, substituted aryl, NH2—C(O)-alkylene, NH(Me)-C(O)-alkylene, CH2—C(O)- alkyl, C(O)- alkyl, alkylcarbonylaminyl, CH2—[CH(OH)]m—(CH2)p—OH, CH2—[CH(OH)]m—(CH2)p—NH2or CH2-aryl-alkoxy, where “m” and “p” are independently 1, 2, 3, 4, 5 or 6. For example, R3’is - OR20, and R20is methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, optionally, R20is methyl.

[0270] In some embodiments, R3’is -OR20, and R20is C1-6alkoxyC1-6alkyl. For example, R3’is -OR20, and R20is 2-methoxyethyl.

[0271] In some embodiments, R3’is -OR20and R20is a hydroxyl protecting group. For example, R3’is -OR20and R20is a hydroxyl protecting group selected from the group consisting of BOC or Boc, MOM, MTM, t-butylthiomethyl, SMOM, BOM, PMBM, p-AOM, GUM, t- butoxymethyl, POM, siloxymethyl, MEM, 2,2,2-trichloroethoxymethyl, bis(2- chloroethoxy)methyl, SEMOR, THP, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclohexyl, MTHP, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl- S,S-dioxide, CTMP, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a- octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1- methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p- methoxyphenyl, 2,4-dinitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p- halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4- picolyl, 3- methyl-2-picolyl N-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4′- bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″- tris(benzoyloxyphenyl)methyl, 3-(imidazol-1- yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1- bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9- (9-phenyl)xanthenyl, 9-(9-phenyl- 10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl- S,S-dioxido, TMS, TES, TIPS, IPDMS, DEIPS, dimethylthexylsilyl, TBDMS, TBDPS, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, DPMS, TBMPS, formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio)pentanoate (levulinoyldithioacetal), adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, Fmoc, alkyl ethyl carbonate, Troc, TMSEC, Psec, Peoc, alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2- formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α- naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate,dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate.

[0272] In some embodiments, R3’is -OR20and R20is TBDMS (or TBS), TBDPS, TMS, TES, TIPS, IPDMS, DEIPS, TBMPS, DPMS, dimethylthexylsilyl, tribenzylsilyl, tri-p-xylylsilyl, or triphenylsilyl, optionally, R20is TBDMS (or TBS).

[0273] In some embodiments, R3’ is alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or allyl), alkenyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, -O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N- dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl)), S-alkyl, N-alkyl, branched O- alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, branched O-alkenyl,branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester,,wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine. R2’

[0274] In the various aspects described herein, R2’can be hydrogen, halogen, -OR20, or -OR30.

[0275] In some embodiments, R2’is hydrogen or halogen. For example, R2’is H or F.

[0276] In some embodiments, R2’is -OR20, where R20is hydrogen, hydroxyl protecting group, optionally substituted C1-6alkyl, such as C1-6alkoxyC1-6alkyl (e.g., 2-methoxyethyl) or N-(C1-6alkyl)aminocarbonylC1-6alkyl (e.g., 2-(N-methylamino)-2-oxoethyl or 3-oxo-3-(N- methylamino)prop-1-yl). For example, R2’is -OR20, and R20is hydrogen or hydroxyl protecting group. In other examples, R2’is -OR20, where R20is an optionally substituted C1-6alkyl.

[0277] In some embodiments, R2’is -OR20, and R20is C1-6alkyl, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from OH, CN, SC(O)Ph, oxo (=O), SH, SO2NH2, SO2(C1-C4)alkyl, SO2NH(C1-C4)alkyl, halogen, carbonyl, thiol, cyano, NH2, NH(C1-C4)alkyl, N[(C1-C4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-C8)alkyl, O(C1-C8)alkyl (i.e., C1- C8alkoxy), O(C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, aryl, heteroaryl, substituted aryl, NH2—C(O)-alkylene, NH(Me)- C(O)-alkylene, CH2—C(O)- alkyl, C(O)- alkyl, alkylcarbonylaminyl, CH2—[CH(OH)]m— (CH2)p—OH, CH2—[CH(OH)]m—(CH2)p—NH2or CH2-aryl-alkoxy, where “m” and “p” are independently 1, 2, 3, 4, 5 or 6. For example, R2’is -OR20, and R20is methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, optionally, R20is methyl.

[0278] In some embodiments, R2’is -OR20, and R20is C1-6alkoxyC1-6alkyl, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from OH, CN, SC(O)Ph, oxo (=O), SH, SO2NH2, SO2(C1-C4)alkyl, SO2NH(C1-C4)alkyl, halogen, carbonyl, thiol, cyano, NH2, NH(C1-C4)alkyl, N[(C1-C4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-C8)alkyl, O(C1- C8)alkyl (i.e., C1-C8alkoxy), O(C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, aryl, heteroaryl, substituted aryl, NH2—C(O)-alkylene, NH(Me)-C(O)-alkylene, CH2—C(O)- alkyl, C(O)- alkyl, alkylcarbonylaminyl, CH2— [CH(OH)]m—(CH2)p—OH, CH2—[CH(OH)]m—(CH2)p—NH2or CH2-aryl-alkoxy, where “m” and “p” are independently 1, 2, 3, 4, 5 or 6. For example, R2’is -OR20, and R20is 2-methoxyethyl.

[0279] In some embodiments, R2’is -OR20and R20is a hydroxyl protecting group. For example, R2’is -OR20and R20is a hydroxyl protecting group selected from the group consisting of BOC or Boc, MOM, MTM, t-butylthiomethyl, SMOM, BOM, PMBM, p-AOM, GUM, t- butoxymethyl, POM, siloxymethyl, MEM, 2,2,2-trichloroethoxymethyl, bis(2- chloroethoxy)methyl, SEMOR, THP, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclohexyl, MTHP, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl- S,S-dioxide, CTMP, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a- octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1- methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p- methoxyphenyl, 2,4-dinitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p- halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4- picolyl, 3- methyl-2-picolyl N-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4′- bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″- tris(benzoyloxyphenyl)methyl, 3-(imidazol-1- yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1- bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9- (9-phenyl)xanthenyl, 9-(9-phenyl- 10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl- S,S-dioxido, TMS, TES, TIPS, IPDMS, DEIPS, dimethylthexylsilyl, TBDMS, TBDPS, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, DPMS, TBMPS, formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio)pentanoate (levulinoyldithioacetal), adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, Fmoc, alkyl ethyl carbonate, Troc, TMSEC, Psec, Peoc, alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2- formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α- naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate,dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate.

[0280] In some embodiments, R2’is -OR20and R20is TBDMS, TBDPS, TMS, TES, TIPS, IPDMS, DEIPS, TBMPS, DPMS, dimethylthexylsilyl, tribenzylsilyl, tri-p-xylylsilyl, or triphenylsilyl, optionally, R20is TBDMS.

[0281] In some embodiments, R2’is -OR30, where R30is hydrogen, a hydroxyl protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide. For example, R2’is -OR30and R30is hydrogen or hydroxyl protecting group.

[0282] In some embodiments, R2’is -OR30and R30is a reactive phosphorus group. For example, R30is a phosphoramidite, H-phosphonate, alkyl-phosphonate, or phosphate triester. In some embodiments, R2’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1is C1-6alkyl, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from OH, CN, SC(O)Ph, oxo (=O), SH, SO2NH2, SO2(C1-C4)alkyl, SO2NH(C1-C4)alkyl, halogen, carbonyl, thiol, cyano, NH2, NH(C1-C4)alkyl, N[(C1- C4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-C8)alkyl, O(C1-C8)alkyl (i.e., C1-C8alkoxy), O(C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, aryl, heteroaryl, substituted aryl, NH2— C(O)-alkylene, NH(Me)-C(O)-alkylene, CH2—C(O)- alkyl, C(O)- alkyl, alkylcarbonylaminyl, CH2—[CH(OH)]m—(CH2)p—OH, CH2—[CH(OH)]m— (CH2)p—NH2or CH2-aryl-alkoxy, where “m” and “p” are independently 1, 2, 3, 4, 5 or 6; each RP2is independently C1-6alkyl, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from OH, CN, SC(O)Ph, oxo (=O), SH, SO2NH2, SO2(C1- C4)alkyl, SO2NH(C1-C4)alkyl, halogen, carbonyl, thiol, cyano, NH2, NH(C1- C4)alkyl, N[(C1-C4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-C8)alkyl, O(C1- C8)alkyl (i.e., C1-C8alkoxy), O(C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, aryl, heteroaryl, substituted aryl, NH2—C(O)-alkylene, NH(Me)-C(O)-alkylene, CH2—C(O)- alkyl, C(O)- alkyl, alkylcarbonylaminyl, CH2—[CH(OH)]m—(CH2)p—OH, CH2— [CH(OH)]m—(CH2)p—NH2or CH2-aryl-alkoxy, where “m” and “p” are independently 1, 2, 3, 4, 5 or 6, optionally each RP2is independently methyl, ethyl,propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, preferably each RP2is isopropyl; or both RP2taken together with the nitrogen atom to which they are attached form an optionally substituted 3-8 membered heterocyclyl; or RP1and one of RP2taken together with the atoms to which they are attached form an optionally substituted 4-8 membered heterocyclyl; and each RP3is independently C1-30alkyl, C2-C30alkenyl, or C2-C30alkynyl (e.g.,C1-10alkyl, C2- C10alkenyl, or C2-C10alkynyl , each optionally independently substituted with 1, 2, 3, 4 or 5 substituents independently selected from OH, CN, SC(O)Ph, oxo (=O), SH, SO2NH2, SO2(C1-C4)alkyl, SO2NH(C1-C4)alkyl, halogen, carbonyl, thiol, cyano, NH2, NH(C1-C4)alkyl, N[(C1-C4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-C8)alkyl, O(C1-C8)alkyl (i.e., C1-C8alkoxy), O(C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, aryl, heteroaryl, substituted aryl, NH2—C(O)-alkylene, NH(Me)-C(O)-alkylene, CH2—C(O)- alkyl, C(O)- alkyl, alkylcarbonylaminyl, CH2—[CH(OH)]m— (CH2)p—OH, CH2—[CH(OH)]m—(CH2)p—NH2or CH2-aryl-alkoxy, where “m” and “p” are independently 1, 2, 3, 4, 5 or 6, optionally each RP3is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionally substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-C6alkoxy.

[0283] In some embodiments, R2’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1 is C1-6alkyl, optionally substituted with a CN or –SC(O)Ph; each RP2is independently optionally substituted C1-6alkyl; and each RP3is independently optionally substituted C1-6alkyl.

[0284] In some embodiments, R2’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1is C1-6alkyl, optionally substituted with a CN or –SC(O)Ph; each RP2is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl; and each RP3is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionally substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-C6alkoxy.

[0285] In some embodiments, R2’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1is 2-cyanoethyl (-CH2CH2CN); each RP2is independently optionally substituted C1-6alkyl; and each RP3is independently optionally substituted C1-6alkyl.

[0286] In some embodiments, R2’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1is 2-cyanoethyl (-CH2CH2CN); each RP2is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl; and each RP3is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionally substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-C6alkoxy.

[0287] In some embodiments, R2’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1is 2-cyanoethyl (-CH2CH2CN); each RP2is independently isopropyl; and each RP3is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionally substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-C6alkoxy.

[0288] In some embodiments, R2’is -OR30and R30is -P(ORP1)N(RP2)2, where: RP1 is 2- cyanoethyl (-CH2CH2CN); each RP2is independently isopropyl.

[0289] In some embodiments, R2’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1is C1-6alkyl, optionally substituted with a CN or –SC(O)Ph; both RP2taken together with the nitrogen atom to which they are attached form an optionally substituted 3-8 membered heterocyclyl; and each RP3is independently optionally substituted C1-6alkyl.

[0290] In some embodiments, R2’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1is C1-6alkyl, optionally substituted with a CN or –SC(O)Ph; both RP2taken together with the nitrogen atom to which they are attached form an optionally substituted 3-8 membered heterocyclyl; and each RP3is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionally substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-C6alkoxy.

[0291] In some embodiments, R2’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1is 2-cyanoethyl (-CH2CH2CN); both RP2taken together with the nitrogen atom to which they areattached form an optionally substituted 3-8 membered heterocyclyl; and each RP3is independently optionally substituted C1-6alkyl.

[0292] In some embodiments, R2’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1is 2-cyanoethyl (-CH2CH2CN); both RP2taken together with the nitrogen atom to which they are attached form an optionally substituted 3-8 membered heterocyclyl; and each RP3is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionally substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-C6alkoxy.

[0293] In some embodiments, R2’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: RP1and one of RP2taken together with the atoms to which they are attached form an optionally substituted 4-8 membered heterocyclyl; other RP2is independently optionally substituted C1-6alkyl; and each RP3is independently optionally substituted C1-6alkyl.

[0294] In some embodiments, R2’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: RP1and one of RP2taken together with the atoms to which they are attached form an optionally substituted 4-8 membered heterocyclyl; other RP2is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl; and each RP3is independently optionally substituted C1-6alkyl.

[0295] In some embodiments, R2’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: RP1and one of RP2taken together with the atoms to which they are attached form an optionally substituted 4-8 membered heterocyclyl; other RP2is independently optionally substituted C1-6alkyl; and each RP3is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionally substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1- C6alkoxy.

[0296] In some embodiments, R2’is -OR30and R30is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: RP1and one of RP2taken together with the atoms to which they are attached form an optionally substituted 4-8 membered heterocyclyl; other RP2is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl; and each RP3is independently methyl, ethyl, propyl, isopropyl, n-butyl,iso-butyl, pentyl or hexyl, each of which can be optionally substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-C6alkoxy.

[0297] In some embodiments, R2’is -OR30and R30is a bond to a nucleoside or a nucleotide, or an oligonucleotide. When R30is a bond to a nucleoside, a nucleotide, or an oligonucleotide, the internucleotide linkage between compound of formulae I-II and the nucleoside, nucleotide, or oligonucleotide can be an unmodified (e.g., phosphodiester) internucleotide linkage or a modified (e.g., phosphorothioate) internucleotide linkage.

[0298] In some embodiments, R2’is -OR30and R30is linked to 5’-position of a nucleoside, nucleotide, or oligonucleotide by an unmodified (e.g., phosphodiester) internucleotide linkage (e.g., or a modified (e.g., phosphorothioate) internucleotide linkage. For example, R30is linked to the 5’-terminal (e.g., 5’-OH) of the oligonucleotide. In some embodiments, R30is linked to the 5’- terminal (e.g., 5’-OH) of the oligonucleotide by an unmodified (e.g., phosphodiester) internucleotide linkage. In some other embodiments, R30is linked to the 5’-terminal (e.g., 5’-OH) of the oligonucleotide by a modified (e.g., phosphorothioate) internucleotide linkage.

[0299] In some embodiments, R2’is -OR30and R30is a hydroxyl protecting group. For example, R2’is -OR30and R30is a hydroxyl protecting group selected from the group consisting of BOC or Boc, MOM, MTM, t-butylthiomethyl, SMOM, BOM, PMBM, p-AOM, GUM, t- butoxymethyl, POM, siloxymethyl, MEM, 2,2,2-trichloroethoxymethyl, bis(2- chloroethoxy)methyl, SEMOR, THP, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclohexyl, MTHP, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl- S,S-dioxide, CTMP, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a- octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1- methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p- methoxyphenyl, 2,4-dinitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p- halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4- picolyl, 3- methyl-2-picolyl N-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4′- bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″- tris(benzoyloxyphenyl)methyl, 3-(imidazol-1- yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1- bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9- (9-phenyl)xanthenyl, 9-(9-phenyl- 10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl- S,S-dioxido, TMS, TES, TIPS, IPDMS, DEIPS, dimethylthexylsilyl, TBDMS, TBDPS, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, DPMS, TBMPS, formate, acetate, chloroacetate,dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio)pentanoate (levulinoyldithioacetal), adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, Fmoc, alkyl ethyl carbonate, Troc, TMSEC, Psec, Peoc, alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2- formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α- naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate,dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate.

[0300] In some embodiments, R2’is -OR30and R30is TBDMS, TBDPS, TMS, TES, TIPS, IPDMS, DEIPS, TBMPS, DPMS, dimethylthexylsilyl, tribenzylsilyl, tri-p-xylylsilyl, or triphenylsilyl, optionally, R30is TBDMS.

[0301] R2’ is alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or allyl), alkenyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, -O-2- methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N-dimethyl)aminooxy]ethyl) or 3-oxo- 3-(N-methylamino)prop-1-yl)), S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S- alkyl, O-alkenyl, S-alkenyl, N-alkenyl, branched O-alkenyl, branched N-alkenyl, branched S- alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester,, , , wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine. RP

[0302] In various aspects described herein, each RPis independently -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S. In some embodiments, at least one RPis -ORO, e.g., both RPare independently - ORO. When RPis -ORO, each ROcan be independently hydrogen, C1-3alkyl, or a hydroxyl protecting group. In some embodiments, at least one RPis -ORO, e.g., both RPare independently - OROand each ROis independently hydrogen or C1-6alkyl (e.g., C1-3alkyl). For example, at least one RPis -ORO, e.g., both RPare independently -OROand each ROis hydrogen, methyl, ethyl,propyl, isopropyl, butyl, or tert-butyl. For example, at least one RPis -ORO, e.g., both RPare independently -OROand each ROis hydrogen. In another example, at least one RPis -ORO, e.g., both RPare independently -OROand each ROis methyl. In yet another example, at least one RPis -ORO, e.g., both RPare independently -OROand each ROis ethyl. In yet another example, at least one RPis -ORO, e.g., both RPare independently -OROand each ROis tert-butyl.

[0303] In some embodiments, at least one RPis -ORO, e.g., both RPare independently -OROand each ROis independently a hydroxyl protecting group. For example, at least one RPis -ORO, e.g., both RPare independently -OROand each ROis independently a hydroxyl protecting group selected from the group consisting of pivaloyloxymethyl (POM), BOC or Boc, MOM, MTM, t- butylthiomethyl, SMOM, BOM, PMBM, p-AOM, GUM, t-butoxymethyl, siloxymethyl, MEM, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, SEMOR, THP, 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, MTHP, 4- methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl-S,S-dioxide, CTMP, 1,4-dioxan- 2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7- methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1- methyl-1-benzyloxyethyl, 1- methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2- trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4- dinitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p- halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3- methyl-2- picolyl N-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α- naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″- tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1- bis(4- methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl- 10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl-S,S-dioxido, TMS, TES, TIPS, IPDMS, DEIPS, dimethylthexylsilyl, TBDMS, TBDPS, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, DPMS, TBMPS, formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3- phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), adamantoate, crotonate, 4-methoxycrotonate, benzoate, p- phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, Fmoc, alkyl ethyl carbonate, Troc, TMSEC, Psec, Peoc, alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzylcarbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2- formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α- naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate,dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate, preferably the protecting group is POM. Thus, in some embodiments, at least one RPis -ORO, e.g., both RPare independently -OROand each ROis independently pivaloyloxymethyl (POM).

[0304] In some embodiments, at least one RPis -SRS, e.g., both RPare independently -SRS. When RPis - SRS, each RScan be independently hydrogen, C1-3alkyl, or a thiol protecting group. In some embodiments, at least one RPis -SRS, e.g., both RPare independently -SRSand each RSis independently hydrogen or C1-3alkyl. For example, at least one RPis -SRS, e.g., both RPare independently -SRSand each RSis hydrogen, methyl, ethyl, or propyl. For example, at least one RPis -SRS, e.g., both RPare independently -SRSand each RSis hydrogen. In another example, at least one RPis -SRS, e.g., both RPare independently -SRSand each RSis methyl. In yet another example, at least one RPis -SRS, e.g., both RPare independently -SRSand each RSis ethyl. In some embodiments, at least one RPis -SRS, e.g., both RPare independently -SRSand each RSis independently a thiol protecting group. In some embodiments, at least one RPis -SRS, e.g., both RPare independently -SRSand each RSis independently pivaloyloxymethyl.

[0305] In some embodiments, at least one RPis -N(RN)2, e.g., both RNare independently - N(RN)2S. When RPis -N(RN)2, each RNcan be independently hydrogen, C1-3alkyl, or a thiol protecting group. In some embodiments, at least one RPis -N(RN)2, e.g., both RPare independently -N(RN)2and each RNis independently hydrogen or C1-3alkyl. For example, at least one RPis - N(RN)2, e.g., both RPare independently -N(RN)2and each RNis hydrogen, methyl, ethyl, or propyl. For example, at least one RPis -N(RN)2, e.g., both RPare independently -N(RN)2and each RNis hydrogen. In another example, at least one RPis -N(RN)2, e.g., both RPare independently -N(RN)2and each RNis methyl. In yet another example, at least one RPis -N(RN)2, e.g., both RPare independently -N(RN)2and each RNis ethyl. In some embodiments, at least one RPis -N(RN)2, e.g., both RPare independently -N(RN)2and each RNis independently an amine protecting group.

[0306] In some embodiments, at least one RPis -N(RN)S(O)2R2S, e.g., each RPis independently -N(RN)S(O)2R2S. For example, at least one RPis -N(RN)S(O)2R2S, e.g., both RPare independently - N(RN)S(O)2R2S, and each RNis independently hydrogen, methyl, ethyl, propyl, or isopropyl, andeach R2Sis independently methyl, ethyl, propyl, or isopropyl. In some embodiments, at least one RPis -N(RN)S(O)2R2S, e.g., both RPare independently -N(RN)S(O)2R2S, and each RNis independently an amine protecting group, and each R2Sis independently methyl, ethyl, propyl, or isopropyl. B (nucleobase)

[0307] In some embodiments of the various aspects described herein, B is an optionally modified nucleobase. It is noted that the nucleobase can be a natural or non-natural nucleobase. By a “non-natural nucleobase” means a nucleobase other than adenine, guanine, cytosine, uracil, or thymine. Exemplary non-natural nucleobases include, but are not limited to, inosine, xanthine, hypoxanthine, nubularine, isoguanisine, tubercidine, and substituted or modified analogs of adenine, guanine, cytosine and uracil, such as 2-aminoadenine and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 5-halouracil, 5-(2-aminopropyl)uracil, 5-amino allyl uracil, 8-halo, amino, thiol, thioalkyl, hydroxyl and other 8-substituted adenines and guanines, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine, 5-substituted pyrimidines, 6- azapyrimidines and N-2, N-6 and O-6 substituted purines, including 2-aminopropyladenine, 5- propynyluracil and 5-propynylcytosine, dihydrouracil, 3-deaza-5-azacytosine, 2-aminopurine, 5- alkyluracil, 7-alkylguanine, 5-alkyl cytosine,7-deazaadenine, N6, N6-dimethyladenine, 2,6- diaminopurine, 5-amino-allyl-uracil, N3-methyluracil, substituted 1,2,4-triazoles, 2-pyridinone, 5- nitroindole, 3-nitropyrrole, 5-methoxyuracil, uracil-5-oxyacetic acid, 5- methoxycarbonylmethyluracil, 5-methyl-2-thiouracil, 5-methoxycarbonylmethyl-2-thiouracil, 5- methylaminomethyl-2-thiouracil, 3-(3-amino-3carboxypropyl)uracil, 3-methylcytosine, 5- methylcytosine, N4-acetyl cytosine, 2-thiocytosine, N6-methyladenine, N6-isopentyladenine, 2- methylthio-N6-isopentenyladenine, N-methylguanines, or O-alkylated bases. Further purines and pyrimidines include those disclosed in U.S. Pat. No. 3,687,808, those disclosed in the Concise Encyclopedia of Polymer Science and Engineering, pages 858-859, Kroschwitz, J. I., ed. John Wiley & Sons, 1990, and those disclosed by Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613, content of all which is incorporated herein by reference.

[0308] In some embodiments, the non-natural nucleobase can be selected from the group consisting of inosine, xanthine, hypoxanthine, nubularine, isoguanisine, tubercidine, 2- (halo)adenine, 2-(alkyl)adenine, 2-(propyl)adenine, 2-(amino)adenine, 2-(aminoalkyll)adenine, 2-(aminopropyl)adenine, 2-(methylthio)-N6-(isopentenyl)adenine, 7-(deaza)adenine, 8-(alkenyl)adenine, 8-(alkyl)adenine, 8-(alkynyl)adenine, 8-(amino)adenine, 8-(halo)adenine, 8-(hydroxyl)adenine, 8-(thioalkyl)adenine, 8-(thiol)adenine, N6-(isopentyl)adenine, N6-(methyl)adenine, N6, N6-(dimethyl)adenine, 2-(alkyl)guanine,2-(propyl)guanine, 6- (alkyl)guanine, 6-(methyl)guanine, 7-(alkyl)guanine, 7-(methyl)guanine, 7-(deaza)guanine, 8-(alkyl)guanine, 8-(alkenyl)guanine, 8-(alkynyl)guanine, 8-(amino)guanine, 8-(halo)guanine, 8- (hydroxyl)guanine, 8-(thioalkyl)guanine, 8-(thiol)guanine, N-(methyl)guanine, 2-(thio)cytosine, 3-(deaza)-5-(aza)cytosine, 3-(alkyl)cytosine, 3-(methyl)cytosine, 5-(alkyl)cytosine, 5- (alkynyl)cytosine, 5-(halo)cytosine, 5-(methyl)cytosine, 5-(propynyl)cytosine, 5-(propynyl)cytosine, 5-(trifluoromethyl)cytosine, 6-(azo)cytosine, N4-(acetyl)cytosine, 3-(3-amino-3-carboxypropyl)uracil, 2-(thio)uracil,5-(methyl)-2-(thio)uracil, 5-(methylaminomethyl)-2-(thio)uracil, 4-(thio)uracil, 5-(methyl)-4-(thio)uracil, 5-(methylaminomethyl)-4-(thio)uracil, 5-(methyl)-2,4-(dithio)uracil, 5-(methylaminomethyl)- 2,4-(dithio)uracil, 5-(2-aminopropyl)uracil, 5-(alkyl)uracil, 5-(alkynyl)uracil, 5- (allylamino)uracil, 5-(aminoallyl)uracil, 5-(aminoalkyl)uracil, 5-(guanidiniumalkyl)uracil, 5-(1,3- diazole-1-alkyl)uracil, 5-(cyanoalkyl)uracil, 5-(dialkylaminoalkyl)uracil, 5-(dimethylaminoalkyl)uracil, 5-(halo)uracil, 5-(methoxy)uracil, uracil-5-oxyacetic acid, 5-(methoxycarbonylmethyl)-2-(thio)uracil, 5-(methoxycarbonyl-methyl)uracil, 5-(propynyl)uracil, 5-(propynyl)uracil, 5-(trifluoromethyl)uracil, 6-(azo)uracil, dihydrouracil, N3-(methyl)uracil, 5-uracil (i.e., pseudouracil), 2-(thio)pseudouracil,4-(thio)pseudouracil,2,4- (dithio)psuedouracil,5-(alkyl)pseudouracil, 5-(methyl)pseudouracil, 5-(alkyl)-2- (thio)pseudouracil, 5-(methyl)-2-(thio)pseudouracil, 5-(alkyl)-4-(thio)pseudouracil, 5-(methyl)- 4-(thio)pseudouracil, 5-(alkyl)-2,4-(dithio)pseudouracil, 5-(methyl)-2,4-(dithio)pseudouracil, 1-substituted pseudouracil, 1-substituted 2(thio)-pseudouracil, 1-substituted 4-(thio)pseudouracil, 1-substituted 2,4-(dithio)pseudouracil, 1-(aminocarbonylethylenyl)-pseudouracil, 1-(aminocarbonylethylenyl)-2(thio)-pseudouracil, 1-(aminocarbonylethylenyl)- 4-(thio)pseudouracil, 1-(aminocarbonylethylenyl)-2,4-(dithio)pseudouracil, 1-(aminoalkylaminocarbonylethylenyl)-pseudouracil, 1-(aminoalkylamino-carbonylethylenyl)- 2(thio)-pseudouracil, 1-(aminoalkylaminocarbonylethylenyl)-4-(thio)pseudouracil, 1-(aminoalkylaminocarbonylethylenyl)-2,4-(dithio)pseudouracil, 1,3-(diaza)-2-(oxo)-phenoxazin- 1-yl, 1-(aza)-2-(thio)-3-(aza)-phenoxazin-1-yl, 1,3-(diaza)-2-(oxo)-phenthiazin-1-yl, 1-(aza)-2- (thio)-3-(aza)-phenthiazin-1-yl, 7-substituted 1,3-(diaza)-2-(oxo)-phenoxazin-1-yl, 7-substituted 1-(aza)-2-(thio)-3-(aza)-phenoxazin-1-yl, 7-substituted 1,3-(diaza)-2-(oxo)-phenthiazin-1-yl, 7- substituted 1-(aza)-2-(thio)-3-(aza)-phenthiazin-1-yl, 7-(aminoalkylhydroxyl)-1,3-(diaza)-2- (oxo)-phenoxazin-1-yl, 7-(aminoalkylhydroxyl)-1-(aza)-2-(thio)-3-(aza)-phenoxazin-1-yl, 7- (aminoalkylhydroxyl)-1,3-(diaza)-2-(oxo)-phenthiazin-1-yl, 7-(aminoalkylhydroxyl)-1-(aza)-2- (thio)-3-(aza)-phenthiazin-1-yl, 7-(guanidiniumalkylhydroxyl)-1,3-(diaza)-2-(oxo)-phenoxazin-1-yl, 7-(guanidiniumalkylhydroxyl)-1-(aza)-2-(thio)-3-(aza)-phenoxazin-1-yl, 7-(guanidiniumalkyl- hydroxyl)-1,3-(diaza)-2-(oxo)-phenthiazin-1-yl, 7-(guanidiniumalkylhydroxyl)-1-(aza)-2-(thio)- 3-(aza)-phenthiazin-1-yl, 1,3,5-(triaza)-2,6-(dioxa)-naphthalene, inosine, xanthine, hypoxanthine, nubularine, tubercidine, isoguanisine, inosinyl, 2-aza-inosinyl, 7-deaza-inosinyl, nitroimidazolyl, nitropyrazolyl, nitrobenzimidazolyl, nitroindazolyl, aminoindolyl, pyrrolopyrimidinyl, 3- (methyl)isocarbostyrilyl, 5-(methyl)isocarbostyrilyl, 3-(methyl)-7-(propynyl)isocarbostyrilyl, 7- (aza)indolyl, 6-(methyl)-7-(aza)indolyl, imidizopyridinyl, 9-(methyl)-imidizopyridinyl, pyrrolopyrizinyl, isocarbostyrilyl, 7-(propynyl)isocarbostyrilyl, propynyl-7-(aza)indolyl, 2,4,5- (trimethyl)phenyl, 4-(methyl)indolyl, 4,6-(dimethyl)indolyl, phenyl, napthalenyl, anthracenyl, phenanthracenyl, pyrenyl, stilbenyl, tetracenyl, pentacenyl, difluorotolyl, 4-(fluoro)-6- (methyl)benzimidazole, 4-(methyl)benzimidazole, 6-(azo)thymine, 2-pyridinone, 5-nitroindole, 3-nitropyrrole, 6-(aza)pyrimidine, 2-(amino)purine, 2,6-(diamino)purine, 5-substituted pyrimidines, N2-substituted purines, N6-substituted purines, O6-substituted purines, substituted 1,2,4-triazoles, and any O-alkylated or N-alkylated derivatives thereof.

[0309] In some embodiments, a non-natural nucleobase is a modified nucleobase, i.e., the nucleobase comprises a nucleobase modification described herein, e.g., the nucleobase is a substituted or modified analog of any of the natural nucleobases. Examples of the nucleobase modifications include, but not limited to: C-5 pyrimidine with an alkyl group or aminoalkyls and other cationic groups such as guanidinium and amidine functionalities, N2- and N6- with an alkyl group or aminoalkyls and other cationic groups such as guanidinium and amidine functionalities of purines, G-clamps, guanidinium G-clamps, and pseudouridine known in the art.

[0310] In some embodiments of any one of the aspects, the non-natural nucleobase is a universal nucleobase. As used herein, a universal nucleobase is any modified or unmodified natural or non-natural nucleobase that can base pair with all of adenine, cytosine, guanine and uracil without substantially affecting the melting behavior, recognition by intracellular enzymes or activity of the oligonucleotide comprising the universal nucleobase. Some exemplary universal nucleobases include, but are not limited to, 2,4-difluorotoluene, nitropyrrolyl, nitroindolyl, 8-aza- 7-deazaadenine, 4-fluoro-6-methylbenzimidazle, 4-methylbenzimidazle, 3-methyl isocarbostyrilyl, 5- methyl isocarbostyrilyl, 3-methyl-7-propynyl isocarbostyrilyl, 7-azaindolyl, 6- methyl-7-azaindolyl, imidizopyridinyl, 9-methyl-imidizopyridinyl, pyrrolopyrizinyl, isocarbostyrilyl, 7-propynyl isocarbostyrilyl, propynyl-7-azaindolyl, 2,4,5-trimethylphenyl, 4- methylinolyl, 4,6-dimethylindolyl, phenyl, napthalenyl, anthracenyl, phenanthracenyl, pyrenyl, stilbenyl, tetracenyl, pentacenyl, and structural derivatives thereof.

[0311] In some embodiments, the natural or non-natural nucleobase is a protected nucleobase. As used herein, a “protected nucleobase” refers to a nucleobase comprising a nitrogen protecting group, and / or an oxygen protecting group, and / or a sulfur protecting group.

[0312] For example, the nucleobase is a pyrimidine modified at the C4 position. In another non-limiting example, the nucleobase is a pyrimidine modified at the C5 position.

[0313] In some embodiments, the nucleobase is a purine modified at the N2 position. In some embodiments, the nucleobase is a purine modified at the N6 position. For example, the nucleobase is a purine modified at the C6 position. In some non-limiting examples, the nucleobase is a N-7 deaza purine, optionally modified at the N7 position.

[0314] In some embodiments, the nucleobase is a modified, protected or substituted analogs of a nucleobase selected from adenine, cytosine, guanine, thymine, and uracil. For example, the nucleobase is uracil, adenine, guanine, or cytosine, optionally each independently comprising a hydroxyl, or amine protecting group.

[0315] In some embodiments, the nucleobase is selected from the group consisting of:. Double-stranded RNA

[0316] The skilled person is well aware that double-stranded RNAs comprising a duplex structure of between 19 and 24, but specifically 21, base pairs have been hailed as particularly effective in inducing RNA interference (RNAi). However, others have found that shorter or longer double-stranded oligonucleotides can be effective as well. Accordingly, in some embodiments, a longer double-stranded oligonucleotide described herein is capable of inducing RNA interference. Stated another way, the longer double-stranded oligonucleotides described herein can mediate RNA interference. As used herein, the phrase “mediates RNAi” refers to the ability to inhibit or reduce the expression of a target nucleic acid, e.g., a target RNA such as a mRNA in a sequence specific manner.

[0317] Accordingly, in another aspect provided herein is a double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand substantially or 100% (e.g., exactly) complementary to the sense strand, and wherein one of the sense and antisense strand has a 5’- terminal modification comprising the structure:wherein: * is a carbon atom in a sugar moiety of the 5’-terminal nucleotide (e.g., C4’ of a ribose); A is -C(*)(H)-, -CH2C(*)(H)-, or -C(*)(H)CH2-, wherein * is the bond to E; E is a bond or -CH2-; Q is propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2- ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2- methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2- ethyl)cyclopropylmethyl, 2-(2-methyl)cyclopropylethyl, 2-methylcyclobutyl, 3- methylcyclobutyl or cyclobutylmethyl; X is O or S; each RPis independently -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RSis independently hydrogen, C1-3alkyl, or a thiol protecting group; each RNis independently hydrogen, C1-3alkyl, or an amine protecting group; and R2Sis C1-3alkyl.

[0318] Generally, themodification replaces a CH2OH group on the sugar moiety of the 5’-terminal nucleotide of the sense or antisense strand. For example, themodification replaces the 4’-CH2OH group on the furanose ring (e.g. ribofuranose, arabinofuranose, lyxofuranose, xylofuranose, ribulofuranose or xylulofuranose, preferably ribsofuranose) or the 5’- CH2OH group on the pyranose (e.g., glucopyranose, galactopyranose, mannopyranose, allopyranose, altropyranose, gulopyranose, idopyranose, or talopyranose, preferably glucopyranose, galactopyranose, or mannopyranose) of the 5’-terminal nucleotide of the sense or antisense strand.

[0319] Similarly, themodification replaces carbon atom in the sugar moiety of the 5’-terrminal nucleotide of the sense or antisense strand. For example, themodification replaces the 4’-C atom in the furanose (e.g. ribofuranose, arabinofuranose, lyxofuranose, xylofuranose, ribulofuranose or xylulofuranose, preferably ribsofuranose) ring or the 5’-C atom in the pyranose (e.g., glucopyranose, galactopyranose, mannopyranose, allopyranose, altropyranose, gulopyranose, idopyranose, or talopyranose, preferably glucopyranose, galactopyranose, or mannopyranose) ring of the 5’-terminal nucleotide of the sense or antisense strand.

[0320] Thus, in some embodiments, the sense or antisense strand comprises at its 5’-end a compound of formulae I-XXI described herein. In certain embodiments, X is O. In certain embodiments, X is O, and each RPis ORO. In certain embodiments, X is O, and each RPis OH. In certain embodiments, X is O, and each RPis ethoxy. In certain embodiments, X is O, and each RPis OH. In certain embodiments, X is O, and each RPis OROwherein ROis pivaloyloxymethyl.

[0321] In some embodiments, the 5’-terminal nucleotide of one of the sense and antisense strand is of the structure: , ,, , , ,or a salt thereof,wherein: n is an integer selected from 1 - 3; A is -C(*)(H)-, -CH2C(*)(H)-, or -C(*)(H)CH2-, wherein * is the bond to E; E is a bond or -CH2-; B is an optionally modified nucleobase (e.g., uracil); Q is propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2- ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2- methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2- ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2- methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q are both replaced with O or S; one methine in Q is optionally replaced with -N=; Q4is ethylene, ethenylene (e.g.,or,preferably , where * is the bond to the phosphorous atom), propylene, propenylene, or propynylene, methylcyclopropyl, cyclopropylmethyl, 2-ethylcyclopropyl, (2- cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2-methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2-ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2-methylcyclobutyl, 3- methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q4are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein: RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q4are both replaced with O or S; one methine in Q4is optionally replaced with -N=; y is 0 or 1; n5is an integer selected from 2 - 5 (e.g., 2, 3, or 4, preferably 2); n6is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1);n7is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1); n8is an integer selected from 1 - 3 (e.g., 1, or 2); n9is an integer selected from 1 - 3 (e.g., 1, or 2); n10is an integer selected from 1 - 3 (e.g., 1 or 2; preferably 1); Q5is methylene, ethylene, ethenylene, propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2-ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2-methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2-ethyl)cyclopropylmethyl, cyclopropyl, 2-(2- methyl)cyclopropylethyl, 2-methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q5are optionally and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q5are both replaced with O or S; one methine in Q5is optionally replaced with -N=; and RPSis C1-3alkyl, -ORO, -N(RN)2, -N(RN)S(O)2R2S, -N(RN)P(O)(ORO)(RPC), or - N=P(ORO)2(RPC); wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RNis independently hydrogen, C1-3alkyl, or an amine protecting group; and RPCis C1-6alkyl (e.g., C1-3alkyl or methyl); and R2Sis C1-3alkyl; X is O or S; XAis O or S; YAis O or S; each RPis independently C1-3alkyl, -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RSis independently hydrogen, C1-3alkyl, or a thiol protecting group; each RNis independently hydrogen, C1-3alkyl, or an amine protecting group; and R2Sis C1-3alkyl; one of R2’and R3’is hydrogen, halogen, or -OR20, wherein:R20is hydrogen, hydroxyl protecting group, optionally substituted C1-6alkyl, (e.g., methyl, 2-methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N- methylamino)-2-oxoethyl, 2-[N,N-dimethyl)aminooxy]ethyl, or 3-oxo-3- (N-methylamino)prop-1-yl), optionally substituted C2-6alkenyl, or optionally substituted C2-6alkynyl (e.g., propargyl); and RAis alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amin, alkenyl (e.g., vinyl or allyl), alkynyl (e.g., ethynyl or propargyl) or alkyl ester; the other of R2’and R3’is -OR30, wherein: R30is a bond to the rest of the sense or antisense strand, provided that R3’is -OR30in formulae.

[0322] Preferably, the antisense strand of the dsRNA is an oligonucleotide described herein.

[0323] As used herein, the term “antisense strand” refers to an oligonucleotide that is substantially or 100% (e.g., exactly) complementary to a target nucleic acid of interest. For example, an antisense strand can be complementary, in whole or in part, to target nucleic acid of interest, such as a messenger RNA, an RNA sequence that is not mRNA (e.g., microRNA, piwiRNA, tRNA, rRNA and hnRNA) or a sequence of DNA that is either coding or non-coding.

[0324] It is noted that each strand of the dsRNA can range from 12-40 nucleotides in length. For example, each strand independently can be between 14-40 nucleotides in length, 17-37 nucleotides in length, 25-37 nucleotides in length, 27-35 nucleotides in length, 17-23 nucleotides in length, 17-21 nucleotides in length, 17-19 nucleotides in length, 19-25 nucleotides in length, 19- 23 nucleotides in length, 19-21 nucleotides in length, 21-25 nucleotides in length, 21-23 nucleotides in length, 25-35 nucleotides in length, 26-35 nucleotides in length, 27-34 nucleotides in length, 28- 32 nucleotides in length or 29-31 nucleotides in length. Without limitations, the sense and antisense strands can be equal length or unequal length. In some embodiments, the antisense strand is longer, e.g., by 1, 2, 3, 4, or 5 nucleotides than the sense strand.

[0325] In some embodiments, each of the sense and antisense strand is independently 15, 16, 17, 28, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides in length. For, example, each ofthe sense and antisense strand is independently 18, 19, 21, 22, 23, 24, or 25 nucleotides in length. In some embodiments, each strand is independently 19, 20, 21, 22 or 23 nucleotides in length. In some embodiments, one strand (e.g., the sense strand) is 18, 19, 20, 21 or 22 nucleotides in length and the other strand (e.g., the antisense strand) is 21, 22, 23, 24 or 25 nucleotides in length.

[0326] The sense and antisense strands of the dsRNA molecule are complementary to each other and can hybridize to each other to form a double-stranded or duplex region. Accordingly, the dsRNA molecule has a double-stranded or duplex region. The duplex region (double-stranded region) can be 17-25 nucleotide base pairs in length. For example, the dsRNA can have a duplex region of 17-24 nucleotide pairs in length. In some embodiments, the dsRNA has a duplex region of 18, 19, 20, 21, 22, 22, 23, 24, or 25 nucleotide base pairs in length. In some embodiments, the dsRNA has a duplex region of 19, 20, 21 or 22 nucleotide base pairs in length.

[0327] The dsRNA molecule can have one or more overhang regions (i.e., single-stranded region) and / or capping groups of dsRNA molecule at the 3’-end, or 5’-end or both ends of a strand. Without limitations, the overhang can be 1-3 nucleotides, e.g., 1, 2 or 3 nucleotides in length. The overhangs can be the result of one strand being longer than the other, or the result of two strands of the same length being staggered. The overhang can form a mismatch with the sequence being targeted or it can be complementary to the sequence being targeted or can be other sequence. The sense and antisense strands can also be joined, e.g., by additional bases to form a hairpin, or by other non-base linkers. Without limitations the overhang can be present at the 3’-end of only one of the strands or both strands.

[0328] In some embodiments, the dsRNA molecule comprises a single overhang. For example, the dsRNA molecule has a single overhang and the overhang is no more than one, two or three nucleotides in length. Preferably, the overhang is 2 nucleotides in length. In some embodiments, the overhang is present at the 3’-end of a strand (e.g., the antisense strand). In some embodiments, the dsRNA comprises a two-nucleotide overhang at the 3’-end of a strand (e.g., the antisense strand). For example, the overhang is present at the 3’-end of the antisense strand. For example, the antisense comprises a 1 or 2 nucleotide overhang at its 3’-end.

[0329] The dsRNA can also have a blunt end. For example, one end of the dsRNA is a blunt end and the other end has an overhang. Without limitations, the blunt end can be located at the 5’- end of the antisense strand (or the 3’-end of the sense strand) or vice versa. Generally, the antisense strand of the dsRNA has a nucleotide overhang at the 3’-end, and the 5’-end is blunt. While not bound by theory, the asymmetric blunt end at the 5’-end of the antisense strand and 3’-end overhang of the antisense strand favor the guide strand loading into RISC process. In some embodiments, the dsRNA has a 2-nucleotide overhang on the 3’-end of the antisense strand and a blunt end at the 5’-end of the antisense strand.

[0330] In some other embodiments, the dsRNA molecule has two blunt ends, i.e., at both ends of the dsRNA. For example, the two strands of the dsRNA are of the same length. In some embodiments, the antisense strand is of length 18 to 25 nucleotides. In some embodiments, the antisense strand is 21-25, 19-25, 19-21 or 21-23 nucleotides in length. In some particular embodiments, the antisense strand is 23 nucleotides in length.

[0331] Similar to the antisense strand, the sense strand can be, in some embodiments, 18-25 nucleotides in length. In some embodiments, the sense strand is 21-25, 19-25, 19-21 or 21-23 nucleotides in length. In some embodiments, the sense strand is 21 nucleotides in length.

[0332] In some embodiments, sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length. Nucleic acid modifications

[0333] The longer double-stranded and single-stranded oligonucleotides described herein can comprise one or more nucleic acid modifications. Exemplary nucleic acid modifications include, but are not limited to, nucleobase modifications, sugar modifications, inter-sugar linkage modifications, conjugates (e.g., ligands), and any combinations thereof. It is noted that a nucleic acid modification(s) can be present in any position of longer double-stranded and single-stranded oligonucleotides. A nucleic acid modification(s) can be present in only one strand or both strands of a dsRNA. In some embodiments, only the antisense strand comprises at least one, e.g., two, three, four, five or more nucleic acid modifications. In some embodiments, only the sense strand comprises at least one, e.g., two, three, four, five or more nucleic acid modifications. In some embodiments, both strands independently comprise at least one, e.g., two, three, four, five or more nucleic acid modifications.

[0334] Embodiments of the various aspects described herein recite specific position(s) on a strand, counting from an end of a strand. When the strand is single stranded, e.g., a longer-stranded oligonucleotide, the counting of the position is from the first nucleotide at the specified end. When the strand is part of a double-stranded molecule, e.g., a longer double-stranded oligonucleotide, the counting of the position can be from the first nucleotide at the specified end of the strand, or the first base-paired nucleotide in the strand at the specified end. Preferably, counting of the position is from the first nucleotide at the specified end of the strand. Thermally destabilizing modifications

[0335] In some embodiments of any one of the aspects described herein, the dsRNA comprises a thermally destabilizing modification. By a “thermally destabilizing modification” is meant modification that result in a dsRNA having a lower overall melting temperature (Tm), preferably aTm with one, two, three or four degrees lower, than the Tm of the dsRNA without having such a modification. Exemplary thermally destabilizing modifications are described herein below, and can include, but are not limited to, abasic modifications; mismatch with the opposing nucleotide in the opposing strand; and sugar modification such as 2’-deoxy (i.e., 2’-H) modification, acyclic nucleotide (e.g., unlocked nucleic acids (UNA) or glycol nucleic acid (GNA)), threose nucleic acid (TNA), a nucleotide linked by through its 2’-position (i.e., by its 2’-OH group to 5’-position of the subsequent nucleotide (a 2’-5’ RNA modification)); a Hyp-spacer modification; modified internucleotide linkages that decrease the thermal stability of dsRNA duplexes; or nucleobases with impaired W-C H-bonding to complementary base on the opposite strand.

[0336] In some embodiments, the dsRNA comprises at least one, e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or more independently selected thermally destabilizing modifications. The thermally destabilizing modification can be present at any position of the dsRNA. Further, the thermally destabilizing modifications all can be present in one strand or both strands of the dsRNA. In some embodiments, only the antisense strand comprises at least one, e.g., two, three, four or more thermally destabilizing modifications. In some embodiments, only the sense strand comprises at least one, e.g., two, three, four or more thermally destabilizing modifications. In some embodiments, both the sense and the antisense strands comprise at least one, e.g., two, three, four or more thermally destabilizing modifications.

[0337] The thermally destabilizing modification can occur on any nucleotide of the sense strand or antisense strand. For instance, the thermally destabilizing modification can occur on every nucleotide on the sense strand and / or antisense strand; each thermally destabilizing modification can occur in an alternating pattern on the sense strand or antisense strand; or the sense strand and antisense strand both comprise thermally destabilizing modifications in an alternating pattern. The alternating pattern of the thermally destabilizing modifications on the sense strand can be the same or different from the antisense strand, and the alternating pattern of the thermally destabilizing modifications on the sense strand can have a shift relative to the alternating pattern of the thermally destabilizing modifications on the antisense strand.

[0338] In some embodiments, thermally destabilizing modification is located at position 2, 3, 4, 5, 6, 7, 8 or 9, or preferably at position 4, 5, 6, 7, or 8, counting from the 5’-end of the antisense strand. In some embodiments, the thermally destabilizing modification is located at position 2, 3, 4, 5 or 9 from the 5’-end of the antisense strand. In some other embodiments, the thermally destabilizing modification is located at position 6, 7 or 8 from the 5’-end of the antisense strand. In some particular embodiments, the thermally destabilizing modification is located at position 7 from the 5’-end of the antisense strand.

[0339] In some embodiments, only the antisense strand comprises a thermally destabilizing modification. For example, only the antisense strand comprises a thermally destabilizing modification and said thermally destabilizing modification is located at position 4, 5, 6, 7, or 8, counting from the 5’-end of the antisense strand, preferably the thermally destabilizing modification is located at position 5, 6, 7, or 8; more preferably the thermally destabilizing modification is located at position 6, 7, or 8. In some embodiments, only the antisense strand comprises a thermally destabilizing modification and the thermally destabilizing modification is located at position 7 of the antisense strand, counting from the 5’-end of the antisense strand.

[0340] Similar to the antisense strand, a thermally destabilizing modification can be located at one of position 2, 3, 4, 5, 6, 7, 8 or 9, or preferably at position 4, 5, 6, 7, or 8, counting from the 5’- end of the longer-ssNA. In some embodiments, the thermally destabilizing modification is located at position 2, 3, 4, 5 or 9 from the 5’-end of the longer-ssNA. In some other embodiments, the thermally destabilizing modification is located at position 6, 7 or 8 from the 5’-end of the longer- ssNA. In some particular embodiments, the thermally destabilizing modification is located at position 7 from the 5’-end of the longer-ssNA. Thermally stabilizing modifications

[0341] In some embodiments, dsRNA comprises a thermally destabilizing modification. By a “thermally stabilizing modification” is meant modification that result in a dsRNA having a higher overall melting temperature (Tm), preferably a Tm with one, two, three or four degrees higher, than the Tm of the dsRNA without having such a modification. Exemplary thermally destabilizing modifications are described herein below, and can include, but are not limited to, 2’-fluoro nucleotides (2’-F modifications), bridged nucleic acid (BNA), e.g., locked nucleic acid (LNA), and cyclohexene nucleic acid (CeNA). In some preferred embodiments, the thermally stabilizing modification is a 2’-fluoro nucleotide. Exemplary, thermally stabilizing modification are described herein below. Additional exemplary abasic nucleotides, acyclic nucleotide modifications (including UNA and GNA), and mismatch modifications are described in detail in WO 2011 / 133876 and WO2019222479, contents of both of which are incorporated herein by reference in their entireties.

[0342] In some embodiments, dsRNA can comprise at least two, e.g., three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or more the thermally stabilizing (e.g., 2’-F) modifications. Without limitations, the thermally stabilizing (e.g., 2’-F) modifications all can be present in one strand or both strands of a dsRNA. In some embodiments, the sense strand comprises at least one, e.g., two, three, four or more thermally stabilizing (e.g., 2’-F) modifications. In some embodiments, the antisense strand comprises at least one, e.g., two, three, four or morethermally stabilizing (e.g., 2’-F) modifications. In some embodiments, both the sense and the antisense strands comprise at least one, e.g., two, three, four or more thermally stabilizing (e.g., 2’- F) modifications. The thermally stabilizing (e.g., 2’-F) modification can occur on any nucleotide of the sense strand or antisense strand. For instance, the thermally stabilizing (e.g., 2’-F) modification can occur on every nucleotide on the sense strand and / or antisense strand; each thermally stabilizing (e.g., 2’-F) modification can occur in an alternating pattern on the sense strand or antisense strand; or the sense strand and antisense strand both comprise thermally stabilizing (e.g., 2’-F) modifications in an alternating pattern. The alternating pattern of the thermally stabilizing (e.g., 2’-F) modifications on the sense strand can be the same or different from the antisense strand, and the alternating pattern of the thermally stabilizing (e.g., 2’-F) modifications on the sense strand can have a shift relative to the alternating pattern of the thermally stabilizing (e.g., 2’-F) modifications on the antisense strand.

[0343] In some embodiments, the sense strand of the dsRNA comprises at least one, e.g., two, three, four, five, six, seven, eight, nine, ten or more thermally stabilizing (e.g., 2’-F) modifications. In some embodiments, the sense strand comprises two, three, four, or five thermally stabilizing (e.g., 2’-F) modifications. For example, the sense strand comprises three or four thermally stabilizing (e.g., 2’-F) modifications. Without limitations, a thermally stabilizing (e.g., 2’-F) modification in the sense strand can be present at any positions. In some embodiments, the sense strand comprises at least three thermally stabilizing (e.g., 2’-F) modifications. For example, the sense comprises thermally stabilizing (e.g., 2’-F) modification at least at positions 7, 10 and 11, counting from the 5’-end of the sense strand. In some other embodiments, the sense strand comprises at least four thermally stabilizing (e.g., 2’-F) modifications. For example, the sense comprises thermally stabilizing (e.g., 2’-F) modification at least at positions 7, 9, 10 and 11, counting from the 5’-end of the sense strand.

[0344] In some embodiments, the sense strand comprises thermally stabilizing (e.g., 2’-F) modifications at positions opposite or complimentary to positions 11, 12 and 15 of the antisense strand, counting from the 5’-end of the antisense strand. In some other embodiments, the sense strand comprises thermally stabilizing (e.g., 2’-F) modifications at positions opposite or complimentary to positions 11, 12, 13 and 15 of the antisense strand, counting from the 5’-end of the antisense strand. In some embodiments, the sense strand comprises a block of two, three or four thermally stabilizing (e.g., 2’-F) modification.

[0345] In some embodiments, the sense strand comprises thermally stabilizing (e.g., 2’-F) modifications at least at positions 7, 9, and 11, counting from the 5’-end of the sense strand, and the antisense strand comprises thermally stabilizing (e.g., 2’-F) modifications at least at positions 2, 14 and 16, counting from the 5’-end of the antisense strand. In some other embodiments, thesense strand comprises thermally stabilizing (e.g., 2’-F) modifications at least at positions 7, 9, and 11 from the 5’-end, counting from the 5’-end of the sense strand, and the antisense strand comprises thermally stabilizing (e.g., 2’-F) modifications at least at positions 2, 6, 9, 14 and 16, counting from the 5’-end of the antisense strand. In yet some other embodiments, the sense strand comprises thermally stabilizing (e.g., 2’-F) modifications at least at positions 7, 9, and 11, counting from the 5’-end of the sense strand, and the antisense strand comprises thermally stabilizing (e.g., 2’-F) modifications at least at positions 2, 6, 8, 9, 14 and 16, counting from the 5’-end of the antisense strand.

[0346] In some embodiments, the sense strand comprises thermally stabilizing (e.g., 2’-F) modifications at least at positions 7, 9, 10, and 11, counting from the 5’-end of the sense strand, and the antisense strand comprises thermally stabilizing (e.g., 2’-F) modifications at least at positions 2, 14 and 16, counting from the 5’-end of the antisense strand. In some other embodiments, the sense strand comprises thermally stabilizing (e.g., 2’-F) modifications at least at positions 7, 9, 10, and 11, counting from the 5’-end of the sense strand, and the antisense strand comprises thermally stabilizing (e.g., 2’-F) modifications at least at positions 2, 6, 9, 14 and 16, counting from the 5’-end of the antisense strand. In yet some other embodiments, the sense strand comprises thermally stabilizing (e.g., 2’-F) modifications at least at positions 7, 9, 10, and 11, counting from the 5’-end of the sense strand, and the antisense strand comprises thermally stabilizing (e.g., 2’-F) modifications at least at positions 2, 6, 8, 9, 14 and 16, counting from the 5’- end of the antisense strand.

[0347] In some embodiments, the sense strand does not comprise a thermally stabilizing (e.g., 2’-F) modification in position opposite or complimentary to the thermally destabilizing modification of the duplex in the antisense strand.

[0348] The antisense strand of the dsRNA molecule can comprise at least one, e.g., two, three, four, five, six, seven, eight, nine, ten or more thermally stabilizing (e.g., 2’-F) modifications. In some embodiments, the antisense strand comprises two, three, four, five or six thermally stabilizing (e.g., 2’-F) modifications. Without limitations, a thermally stabilizing (e.g., 2’-F) modification in the antisense strand can be present at any position. In some embodiments, the antisense strand comprises at least three thermally stabilizing (e.g., 2’-F) modifications. For example, the antisense strand comprises thermally stabilizing (e.g., 2’-F) modifications at least at positions 2, 14 and 16, counting from the 5’-end of the antisense strand. In some other embodiments, the antisense comprises at least four thermally stabilizing (e.g., 2’-F) modifications. For example, the antisense comprises thermally stabilizing (e.g., 2’-F) modifications at least at positions 2, 6, 14 and 16, counting from the 5’-end of the antisense strand. In some further embodiments, the antisense strand comprises at least five thermally stabilizing (e.g., 2’-F) modifications. For example, the antisensestrand comprises thermally stabilizing (e.g., 2’-F) modifications at least at positions 2, 6, 9, 14 and 16, counting from the 5’-end of the antisense strand. In still some further embodiments, the antisense strand comprises at least six thermally stabilizing (e.g., 2’-F) modifications. For example, the antisense strand comprises thermally stabilizing (e.g., 2’-F) modifications at least at positions 2, 6, 8, 9, 14 and 16, counting from the 5’-end of the antisense strand.

[0349] In some embodiments, the antisense strand comprises at least one thermally stabilizing (e.g., 2’-F) modification adjacent to a stabilizing destabilizing modification. For example, the thermally stabilizing (e.g., 2’-F) modification can be the nucleotide at the 5’-end or the 3’-end of the thermally destabilizing modification, i.e., at position -1 or +1 from the position of the thermally destabilizing modification. In some embodiments, the antisense strand comprises a thermally stabilizing (e.g., 2’-F) modification at each of the 5’-end and the 3’-end of the thermally destabilizing modification, i.e., positions -1 and +1 from the position of the destabilizing modification.

[0350] In some embodiments, the antisense strand comprises at least two stabilizing modifications at the 3’-end of the destabilizing modification, i.e., at positions +1 and +2 from the position of the destabilizing modification.

[0351] In some embodiments, the sense strand does not comprise a thermally stabilizing (e.g., 2’-F) modification in position opposite or complimentary to the thermally destabilizing modification of the duplex in the antisense strand. 2’-OMe nucleotides

[0166] In some embodiments, the dsRNA described herein can comprise at least one, e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or more 2’-OMe nucleotides. Without limitations, the 2’- OMe nucleotides all can be present in one strand or both strands of a dsRNA. In some embodiments, both the sense and the antisense strands comprise at least one 2’-OMe nucleotide. The 2’-OMe modification can occur on any nucleotide of the sense strand or antisense strand. For instance, the 2’-OMe modification can occur on every nucleotide on the sense strand and / or antisense strand; each 2’-OMe modification can occur in an alternating pattern on the sense strand or antisense strand; or the sense strand and antisense strand both comprise 2’-OMe modifications in an alternating pattern. The alternating pattern of the 2’-OMe modifications on the sense strand can be the same or different from the antisense strand, and the alternating pattern of the 2’-OMe modifications on the sense strand can have a shift relative to the alternating pattern of the 2’-OMe modifications on the antisense strand.

[0167] The antisense strand of the dsRNA molecule can comprise at least one, e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen or more 2’-OMe modifications. Without limitations, a 2’-OMe modification in the antisense strand can be present at any position. In some embodiments, each nucleotide, except for any other specified modification (e.g., thermally destabilizing modification(s), thermally stabilizing modification(s), and / or 2’-deoxy (2’-H) modification(s)) of the antisense strand is independently a 2’-O-methyl nucleotide.

[0168] Like the antisense strand, the sense strand of the dsRNA molecule can comprise at least one, e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen or more 2’-OMe modifications. Without limitations, a 2’-OMe modification in the sense strand can be present at any positions. In some embodiments, each nucleotide, except for any other specified modification (e.g., thermally stabilizing modification(s), lipophilic modification(s), inverted nucleotide(s), thermally destabilizing modification(s), and / or 2’-deoxy (2’-H) modification(s)) of the sense strand is independently a 2’-O-methyl nucleotide. 2’-deoxy (2’-H) nucleotides

[0169] In some embodiments, the dsRNA described herein can comprise a 2’-deoxy, i.e., 2’-H nucleotides. For example, the longer double-stranded and single-stranded oligonucleotides described herein can comprise at least one (e.g., 1, 2, 3, 4, 5 or more) 2’-deoxy nucleotides.

[0170] A 2’-deoxy nucleotide can be present in any position of the sense or antisense strand. Further, 2’-deoxy nucleotides all can be present in one strand or both strands of the dsRNA.

[0171] In some embodiments, sense strand comprises 1, 2, 3, 4, 5 or more 2’-deoxy nucleotides. For example, the sense strand comprises a 2’-deoxy nucleotide at any one of positions 7, 9 and 11, counting from the 5’-end of the sense strand. In some embodiments, the sense strand comprises a 2’-deoxy nucleotide at least at position 9, counting from the 5’-end of the strand. For example, the sense strand comprises a 2’-deoxy nucleotide at least at positions 7 and 9, counting from the 5’-end of the strand. In another non-limiting example, the sense strand comprises a 2’- deoxy nucleotide at least at positions 9 and 11, counting from the 5’-end of the strand.

[0172] In some embodiments, antisense strand comprises 1, 2, 3, 4, 5, 6, 7, 8 or more 2’-deoxy nucleotides. For example, the antisense strand comprises a 2’-deoxy nucleotide at any one of positions 2, 5, 7, 12, 14 and 16, counting from the 5’-end of the antisense strand. In some embodiments, the antisense strand comprises a 2’-deoxy nucleotide at least at position 5, counting from the 5’-end of the strand. For example, the antisense strand comprises a 2’-deoxy nucleotide at least at positions 2, 5 and 9, counting from the 5’-end of the strand. In another non-limiting example, the antisense strand comprises a 2’-deoxy nucleotide at least at positions 2, 5, 7, and 12,counting from the 5’-end of the strand. In another non-limiting example, the antisense strand comprises a 2’-deoxy nucleotide at least at positions 2, 5, 7, 12, 14, and 16, counting from the 5’- end of the strand. Lipophilic modifications

[0173] In some embodiments, the dsRNA described herein can comprise a lipophilic modification. For example, the longer double-stranded and single-stranded oligonucleotides described herein can comprise at least one (e.g., 1, 2, 3, 4, 5 or more) lipophilic modifications. Exemplary lipophilic modifications include nucleotides modified with a lipophilic group, e.g., nucleotides comprising a lipophilic group (e.g., an C10-C30alkyl, or a C10-C30alkenyl group, such as a C16alkyl, a C16alkenyl, a C18alkyl, a C18alkenyl, a C20alkyl, a C20alkenyl, a C22alkyl, a C22alkenyl, a C24alkyl, a C24alkenyl; C15alkyl, a C15alkenyl, a C17alkyl, a C17alkenyl, a C19alkyl, a C19alkenyl, a C21alkyl, a C21alkenyl, a C23alkyl, or a C23alkenyl) at their 2’-position. Some exemplary lipophilic nucleotides include, but are not limited to, 2’-O-hexadecyl-modified nucleotide (Nhd), 2’-O-docosanyl-modified nucleotide (Nda), 2’-O-(omega-hydroxy-hexadecyl)- modified nucleotide (NhdOH), and 2’-O-(omega-hydroxy-docosanyl)-modified nucleotide (NdaOH).

[0174] A lipophilic modification can be present in any position of the sense or antisense strand. Further, lipophilic modifications all can be present in one strand or both strands of a dsRNA. In some embodiments, only the sense strand comprises a lipophilic modification. For example, the sense strand comprises a lipophilic modification at any one of positions 1, 2, 3, 4, 5, 6, 7, 8, 13, 14, 15, 16, 17 or 18, counting from the 5’-end of the sense strand. In some embodiments, the sense strand comprises a lipophilic modification at any one of positions 4, 5, 6, 7, 8, 13, 14, 15, 16, 17 or 18, counting from the 5’-end of the sense strand.

[0175] In some embodiments, each residue of the sense strand and antisense strand is independently modified with 2’-O-methyl, 2’-fluoro, 2’-deoxy, LNA, HNA, CeNA, 2’- methoxyethyl, 2’-O-allyl, or 2’-C-allyl, 2’-deoxy, or. The strands can contain more than one modification. In some embodiments, each residue of the sense strand and antisense strand is independently modified with 2’-O-methyl or 2’-fluoro. It is to be understood that these modifications are in addition to any other specified modification (e.g., at least one thermally destabilizing modification of the duplex present in the antisense strand) of dsRNA molecule.

[0176] In some embodiments, at least two different modifications are typically present on the sense strand and antisense strand. Those two modifications may be the 2’-deoxy, 2’-O-methyl or 2’-fluoro modifications, thermally destabilizing modifications. In some embodiments, the sense strand and antisense strand each comprises two differently modified nucleotides selected from 2’-O-methyl or 2’-deoxy. In some embodiments, each residue of the sense strand and antisense strand is independently modified with 2’-O-methyl nucleotide, 2’-deoxy nucleotide, 2´-deoxy-2’-fluoro nucleotide, 2’-O-N-methylacetamido (2’-O-NMA) nucleotide, a 2’-O-dimethylaminoethoxyethyl (2’-O-DMAEOE) nucleotide, 2’-O-aminopropyl (2’-O-AP) nucleotide, or 2’-ara-F nucleotide. For example, each residue of the sense strand and antisense strand is independently modified with 2’- O-methyl nucleotide, 2’-deoxy nucleotide or 2´-deoxy-2’-fluoro nucleotide. Again, it is to be understood that these modifications are in addition to any thermally destabilizing modification of the duplex present in the antisense strand.

[0177] In some embodiments, the antisense strand comprises at least one thermally destabilizing modification, and the remaining nucleotides are independently a 2’-O-methyl nucleotide, 2’-deoxy nucleotide, 2´-deoxy-2’-fluoro nucleotide, 2’-O-N-methylacetamido (2’-O- NMA) nucleotide, a 2’-O-dimethylaminoethoxyethyl (2’-O-DMAEOE) nucleotide, 2’-O- aminopropyl (2’-O-AP) nucleotide, or 2’-ara-F nucleotide. For example, the antisense strand comprises a thermally destabilizing modification and the remaining nucleotides are independently a 2’-O-methyl nucleotide, 2’-deoxy nucleotide, 2´-deoxy-2’-fluoro nucleotide. In some embodiments, the antisense strand comprises: (i) a thermally destabilizing modification at position 5, 6, 7, or 8, counting from the 5’-end of the antisense strand; (ii) at least two, e.g., 3, 4, 5 or 62’- fluoro nucleotides; and (iii) the remaining nucleotides are independently a 2’-O-methyl nucleotide or 2’-deoxy nucleotide.

[0178] In some embodiments, each nucleotide of the sense strand is independently 2’-O- methyl nucleotide, 2’-deoxy nucleotide, 2´-deoxy-2’-fluoro (2’-F) nucleotide, 2’-O-N- methylacetamido (2’-O-NMA) nucleotide, a 2’-O-dimethylaminoethoxyethyl (2’-O-DMAEOE) nucleotide, 2’-O-aminopropyl (2’-O-AP) nucleotide, or 2’-ara-F nucleotide. For example, each nucleotide of the sense strand is independently 2’-O-methyl nucleotide, 2’-deoxy nucleotide, 2´- deoxy-2’-fluoro nucleotide. In some embodiments, the sense strand comprises at least two, e.g., 3, 4, 5 or 6 2’-fluoro nucleotides, and the remaining nucleotides are independently a 2’-O-methyl nucleotide or 2’-deoxy nucleotide.

[0179] In some embodiments, at least one of the first 1, 2, 3, 4, or 5 base pairs within the duplex regions from the 5’- end of the antisense strand of a dsRNA can be chosen independently from the group of: A:U, G:U, I:C, and mismatched pairs, e.g., non-canonical or other than canonical pairings or pairings which include a universal base, to promote the dissociation of the antisense strand at the 5’-end of the duplex. In some embodiments, the nucleotide at the 1 position within the duplex region from the 5’-end in the antisense strand is selected from the group consisting of A, dA, dU, U, and dT. Alternatively, at least one of the first 1, 2 or 3 base pair within the duplex region from the 5’- end of the antisense strand is an AU base pair. For example, the first base pair within theduplex region from the 5’- end of the antisense strand is an A:U base pair. It is noted that either the sense strand or the antisense strand can comprise the adenosine (A) nucleotide. Modified internucleotide linkages

[0180] The dsRNA described herein can comprise at least one, e.g., two, three, four, five, six, seven, eight, nine, ten or more modified internucleoside linkages. As used herein, “internucleoside linkage” refers to a covalent linkage between adjacent nucleosides. Exemplary modified internucleoside linkage include, but are not limited to, phosphodietetrs, phosphorothioates (R, S, or racemic), phosphorodithioates, methylenemethylimino (MMI, 3'-CH2-N(CH3)-O-5'), phosphotriesters, alkylphosphonates (e.g., methylphosphonates), phosphoramidate, methylenemethylimino (—CH2-N(CH3)-O—CH2-), thiodiester (—O—C(O)—S—), thionocarbamate (—O—C(O)(NH)—S—), siloxane (—O—Si(H)2-O— and dialkylsiloxane), N,N′-dimethylhydrazine (—CH2-N(CH3)-N(CH3)-), amide-3 (3'-CH2-C(=O)-N(H)-5'), amide-4 (3'-CH2-N(H)-C(=O)-5')), hydroxylamino, siloxane (dialkylsiloxane), carboxamide, carbonate, carboxymethyl, carbamate, carboxylate ester, thioether, ethylene oxide linker, sulfide, sulfonate, sulfonamide, sulfonate ester, thioformacetal (3'-S-CH2-O-5'), formacetal (3 '-O-CH2-O-5'), oxime, methyleneimino, methykenecarbonylamino, methylenehydrazo, methylenedimethylhydrazo, methyleneoxymethylimino, ethers (C3’-O-C5’), thioethers (C3’-S-C5’), thioacetamido (C3’-N(H)- C(=O)-CH2-S-C5’, C3’-O-P(O)-O-SS-C5’), C3’-CH2-NH-NH-C5’, 3'-NHP(O)(OCH3)-O-5', 3'- NHP(O)(OCH3)-O-5’), imidophosphoramidate (“imidp”), 2’->5’ internucleoside linkages, 2’->3’ internucleoside linkages, 3’->3’ internucleoside linkages, and 5’->5’ internucleoside linkages, optionally the modified internucleoside linkage is phosphorothioate, methylphosphonate, imidp or MMI, more preferably the modified internucleoside linkage is phosphorothioate (PS).

[0181] A modified internucleotide linkage can occur on any nucleotide of the sense strand or antisense strand or both in any position of the strand. For instance, the internucleotide linkage modification can occur on every nucleotide on the sense strand and / or antisense strand; each internucleotide linkage modification can occur in an alternating pattern on the sense strand or antisense strand; or the sense strand or antisense strand comprises both internucleotide linkage modifications in an alternating pattern. The alternating pattern of the internucleotide linkage modification on the sense strand can be the same or different from the antisense strand, and the alternating pattern of the internucleotide linkage modification on the sense strand can have a shift relative to the alternating pattern of the internucleotide linkage modification on the antisense strand.

[0182] In some embodiments, the dsRNA comprises the modified internucleoside (e.g., phosphorothioate or methylphosphonate internucleotide) linkage(s) in the overhang region. For example, the overhang region comprises two nucleotides having modified internucleoside (e.g.,phosphorothioate or methylphosphonate internucleotide) linkage between the two nucleotides. Internucleotide linkage modifications can also be made to link the overhang nucleotides with the terminal paired nucleotides within duplex region. For example, at least 2, 3, 4, or all the overhang nucleotides can be linked through modified internucleoside (e.g., phosphorothioate or methylphosphonate internucleotide) linkage, and optionally, there can be additional modified internucleoside (e.g., phosphorothioate or methylphosphonate internucleotide) linkage linkages linking the overhang nucleotide with a paired nucleotide that is next to the overhang nucleotide. For instance, there may be at least modified internucleoside (e.g., phosphorothioate or methylphosphonate internucleotide) linkage linkages between the terminal three nucleotides, in which two of the three nucleotides are overhang nucleotides, and the third is a paired nucleotide next to the overhang nucleotide. Preferably, these terminal three nucleotides can be at the 3’-end of the antisense strand.

[0183] With respect to position of an internucleotide linkage, the indicated position refers to the internucleotide linkage that links the nucleotide at said position with the nucleotide one position down stream from said position. In other word, an internucleotide linkage at position N means it is between nucleotides N and N+1. Thus, an internucleotide linkage at position 1, counting from the 5’-end, means the linker is between the nucleotides at positions 1 and 2, counting from the 5’- end.

[0184] In some embodiments, the sense strand comprises one to five (e.g., 1, 2, 3, 4 or 5) modified internucleoside (e.g., phosphorothioate or methylphosphonate internucleotide) linkages within position 1-5, counting from the 5’-end of the sense strand, and one to five (e.g., 1, 2, 3, 4 or 5) modified internucleoside (e.g., phosphorothioate or methylphosphonate internucleotide) linkages within position 1-5, counting from the 5’-end of the sense strand. For example, the sense strand comprises a modified internucleoside (e.g., phosphorothioate or methylphosphonate internucleotide) linkage between nucleotide positions 1 and 2, and between nucleotide positions 2 and 3, counting from the 5’-end of the sense strand, and sense strand further comprises a modified internucleoside (e.g., phosphorothioate or methylphosphonate internucleotide) linkage between nucleotide positions 1 and 2, and between nucleotide positions 2 and 3, counting from the 3’-end of the sense strand.

[0185] In some embodiments, the antisense strand comprises one to five (e.g., 1, 2, 3, 4 or 5) modified internucleoside (e.g., phosphorothioate or methylphosphonate internucleotide) linkages within position 1-5, counting from the 5’-end of the antisense strand, and one to five (e.g., 1, 2, 3, 4 or 5) modified internucleoside (e.g., phosphorothioate or methylphosphonate internucleotide) linkages within position 1-5, counting from the 5’-end of the antisense strand. For example, the antisense strand comprises a modified internucleoside (e.g., phosphorothioate ormethylphosphonate internucleotide) linkage between nucleotide positions 1 and 2, and between nucleotide positions 2 and 3, counting from the 5’-end of the antisense strand, and the antisense strand further comprises a modified internucleoside (e.g., phosphorothioate or methylphosphonate internucleotide) linkage between nucleotide positions 1 and 2, and between nucleotide positions 2 and 3, counting from the 3’-end of the antisense strand.

[0186] In some embodiments, the sense strand comprises a modified internucleoside (e.g., phosphorothioate or methylphosphonate internucleotide) linkage at positions 1 and 2 counting from the 5’-end of the sense strand, a modified internucleoside (e.g., phosphorothioate or methylphosphonate internucleotide) linkage at positions 1 and 2, counting from the 3’-end of the sense strand; and the antisense strand comprises a modified internucleoside (e.g., phosphorothioate or methylphosphonate internucleotide) linkage at positions 1 and 2 counting from the 5’-end of the antisense strand, a modified internucleoside (e.g., phosphorothioate or methylphosphonate internucleotide) linkage at positions 1 and 2, counting from the 3’-end of the antisense strand. Overhang modifications

[0187] The nucleotides in the overhang region of the dsRNA molecule can each independently be a modified or unmodified nucleotide including, but not limited to 2’-sugar modified, such as, 2’-Fluoro, 2’-O-methyl, thymidine (T), 2’-O-methoxyethyl-5-methyluridine, 2’-O- methoxyethyladenosine, 2’-O-methoxyethyl-5-methylcytidine, GNA (glycol nucleic acid), SNA (serinol nucleic acid), TNA (threose nucleic acid), and any combinations thereof. For example, TT (or UU) can be an overhang sequence for either end on either strand. The 5’- or 3’- overhangs at the sense strand, antisense strand or both strands of the dsRNA molecule can be phosphorylated. In some embodiments, the overhang region contains two nucleotides having a phosphorothioate internucleotide linkage between the two nucleotides, where the two nucleotides in the overhang region can be the same or different. 5’-modifications

[0188] The 5’-end of a strand of the dsRNA lacking the 5’-terminal phosphate mimic, can also be modified. Exemplary modifications for the 5’-end include, but are not limited a 5’-morpholino nucleotide (e.g., a nucleotide where the 5’-OH group is replaced with a morpholino group), a 5’- dimethylamino nucleotide (e.g., a nucleotide where the 5’-OH group is replaced with a dimthylamino group, a 5’-deoxy nucleotide, an inverted nucleotide (i.e., a nucleotide linked via a 5’->5’ linkage to the rest of the strand), an inverted abasic nucleotide (e.g., an abasic nucleotide linked by a 5’->5’ linkage), or an inverted abasic locked nucleic acid modification (i.e., an LNA lacking a nucleobase and linked by a 5’->5’ linkage) at the 5’-end.

[0189] In some embodiments, the sense strand of the dsRNA comprises a 5’-morpholino nucleotide, a 5’-dimethylamino nucleotide, a 5’-deoxy nucleotide, an inverted nucleotide, an inverted abasic nucleotide, or an inverted abasic locked nucleic acid modification at the 5’-end. For example, the sense strand comprises an inverted nucleotide, an inverted abasic nucleotide, or an inverted abasic locked nucleic acid modification at the 5’-end. For example, the sense strand of the dsRNA comprises an inverted nucleotide, an inverted abasic nucleotide, or an inverted abasic locked nucleic acid modification at the 3’-end.

[0190] In some embodiments, the sense strand comprises a ligand at its 3’-end. Ligands

[0191] In some embodiments, the oligonucleotide can comprise a ligand. Without wishing to be bound by a theory, a ligand can modify one or more properties of the attached molecule (e.g., the dsRNA described herein) including but not limited to pharmacodynamic, pharmacokinetic, binding, absorption, cellular distribution, cellular uptake (cell targeting), charge and clearance.

[0192] In some embodiments, the ligand is a targeting ligand. As used herein the term “targeting ligand” refers to any molecule that provides an enhanced affinity for a selected target, e.g., a cell, cell type, tissue, organ, region of the body, or a compartment, e.g., a cellular, tissue or organ compartment. Some exemplary targeting ligands include, but are not limited to, antibodies, antigen binding fragments of antibodies, antigens, folates, receptor ligands, carbohydrates, aptamers, integrin receptor ligands, chemokine receptor ligands, transferring receptor ligands (e.g., transferrin), biotin, serotonin receptor ligands, PSMA, endothelin, GCPII, somatostatin, lipoprotein receptor ligands (e.g., LDL and HDL).

[0193] Carbohydrate based targeting ligands include, but are not limited to, D-galactose, multivalent galactose, N-acetyl-D-galactosamine (GalNAc), multivalent GalNAc, e.g. GalNAc2 and GalNAc3; D-mannose, multivalent mannose, multivalent lactose, N-acetyl-gulucosamine, multivalent fucose, glycosylated polyaminoacids and lectins. The term multivalent indicates that more than one monosaccharide unit is present. Such monosaccharide subunits can be linked to each other through glycosidic linkages or linked to a scaffold molecule.

[0194] In some embodiments, the ligand is a CNS tissue targeting ligand. For example, CNS tissue targeting ligand can be a lipophilic group that conjugated to an internal or terminal position within an oligonucleotide. Exemplary lipophilic ligands are described below. Certain receptors are known to be present on the surface of CNS cells that may be utilized in order to achieve delivery of an oligonucleotide, such as to a neuronal cell, a glial cell, a microglial cell, an oligodendrocytic cell, an ependymal cell, astrocytic cell, a unipolar cell, a bipolar cell, a multipolar cell, a psuedounipolar cell, a pyramidal cell, a basket cell, a stellate cell, a purkinje cell, a betz cell, anamacrine cell, a granule cell, an ovoid cell, a medium aspiny neuronal cell, and / or a large aspiny neuronal cell. Such can be present within CNS tissues, such as a forebrain tissue, a midbrain tissue, a hindbrain tissue, a diencephalon tissue, a telencephalon tissue, a myelencepphalon tissue, a metencephalon tissue, a mesencephalon tissue, a prosencephalon tissue, a rhombencephalon tissue, a cortices tissue, a frontal lobe tissue, a parietal lobe tissue, a temporal lobe tissue, an occipital lobe tissue, cerebral tissue, a tissue from the thalamus, a tissue from the hypothalamus, a tissue from the tectum, a tissue from the tegmentum, a tissue from the cerebellum, a tissue from the pons, a tissue from the medulla, a tissue from the amygdala, a tissue from the hippocampus, a basal ganglia tissue, a tissue from the corpus callosum, a tissue from the pituitary gland, a tissue from the ventral horn, a tissue from the dorsal horn and a white matter tissue.

[0195] In some embodiments, the ligand is an ocular tissue targeting ligand. For example, ocular tissue targeting ligand can be a lipophilic group that conjugated to an internal or terminal position within an oligonucleotide. Exemplary lipophilic ligands are described below. Certain receptors are known to be present on the surface of ocular cells that may be utilized in order to achieve delivery of an oligonucleotide, such as to an optic nerve cell, a trabecular meshwork cell, a Schlemm’s canal cell, a juxtacanalicular tissue cell, a ciliary muscle cell, a retinal cell, an astrocyte, a pericyte, a Müller cell, a ganglion cell, an endothelial cell, a photoreceptor cell. Such can be present within ocular tissues, such as a retinal blood vessel , episcleral veins or choroid tissue, including a choroid vessel, cornea, pupil, sclera, conjunctiva, optic nerve, iris, lens, aqueous humor, macula, optic disk, retina, ciliary muscle, vitreous humor, vitreous body, choroid, fovea, ciliary body, blood vessels, muscles (lateral rectus muscle, medial rectus muscle, ciliary muscle), ligaments (suspensory ligaments), anterior chamber, posterior chamber, limbal rings, and fovia.

[0196] In some embodiments, the ligand is an asialoglycoprotein receptor (ASGPR) ligand. By an ASGPR ligand is meant a ligand that binds the ASGPR. In some embodiments, the ASGPR ligand comprises one or more (e.g., 1, 2, 3 or more) GalNAc or GalNAc derivatives attached through a bivalent or trivalent branched linker. An exemplary ASGPR ligand is:where n = 0 -10 (e.g., 1 or 4); or, or a loop forming oligonucleotide where 3 or 4 consecutive nucleosides are modified with GalNAc containing ligands; such as, for example, the loop containing oligonucleotide,(5’-gcagcc(G*A*A*A*)ggcugc3’ ; SEQ ID NO: 113), where each lower case base is 2’-O-Methyl substituted and each G* and A* is substituted at the 2’-O position with.

[0197] It is noted that a ligand can be linked at any position of either strands of the dsRNA. For example, the ligand can be at the 5’-end, 3’-end or at an internal position of a strand, e.g., sense or antisense strand of the dsRNA.

[0198] In some embodiments, the sense strand comprises the ligand, i.e., the ligand is conjugated to the sense strand. For example, the ligand is conjugated to the 3′ end of the sense strand. In some embodiments, the sense strand or antisense strand comprises a lipophilic moiety (e.g., a in vivo delivery enhancing moiety) and a the targeting moiety.

[0199] In some embodiments, the lipophilic moiety and the targeting moiety are independently present within: (a) an internally-modified nucleosides such as,(i) (ii)(b) a modified internucleotide linkage such as, -OP(Y)(X)O-, wherein Y is O or S (e.g.,O), and X is -N(H)(RL1); or(c) a 5’-terminal modification such as (i) -P(Y)(OH)-R5, wherein Y is O or S and R5iswherein Q2 is abond, C(O), S(O)2, or -P(Y’)(OH)-O-; or (ii) -P(Y)(OH)O-RL3or -C(O)N(H)RL3, wherein Y is O or S; or (iii) -RL3, -C(O)RL3, -C(O)N(H)RL3, -S(O)2RL3, -S(O)2N(H)RL3; or (d) a 3’-terminal modification such as (i) -P(Y)(OH)-R3, wherein Y is O or S; and R3isor (ii) -RL3, -C(O)RL3, -C(O)N(H)RL3, -S(O)2RL3, -S(O)2N(H)RL3;wherein: B is an optionally modified nucleobase; B1is a nucleobase modified with a lipophilic moiety or a targeting moiety (e.g., a pyrimidine nucleobase modified at the 5-position); RL3, RL1, and RL2are each a group containing a lipophilic moiety or a targeting moiety; R2’ or R3’ may be any functional group that is an acceptable 2’-modification for a ribose sugar. Examples of suitable R2’ or R3’groups include, but are not limited to, hydrogen, halogen (e.g., 2’-fluoro), hydroxy, 2’-O-alkyl (e.g., 2’-OMethyl), 2’-O-methoxyalkyl (e.g., 2’-O- methoxymethyl, 2’-O-methoxyethyl, or 2’-O-2-methoxypropanyl) modification, 2’-O-allyl modification, 2’-C-allyl modification, 2'-O-N-methylacetamido (2'-O-NMA, i.e. -OCH2C(O)N(H)Me) modification, 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) modification, 2'-O-aminopropyl (2'-O-AP) modification, or 2'-ara-F modification. For instance, R2’ or R3’ may be H, OH, F, OMe, O-methoxyalkyl, O-allyl, O-N-methylacetamido, O- dimethylaminoethoxyethyl, or O-aminopropyl.

[0200] In one embodiment, RL1, RL2and RL3are each a group containing a lipophilic moiety, such as a C10-26saturated or unsaturated hydrocarbon chain. In one embodiment, RL1, RL2and RL3are each a group containing a C12-26saturated or unsaturated hydrocarbon chain. In one embodiment, RL1, RL2and RL3are each a group containing a C12-24saturated or unsaturated hydrocarbon chain. In one embodiment, RL1, RL2and RL3are each a group containing a C14-24saturated or unsaturated hydrocarbon chain. In one embodiment, RL1, RL2and RL3are each a group containing a C14-18saturated or unsaturated hydrocarbon chain. In one embodiment, RL1, RL2and RL3are each a group containing a C16saturated or unsaturated hydrocarbon chain. In one embodiment, RL1, RL2and RL3are each a group containing a saturated or unsaturated C22-hydrocarbon chain.

[0201] In other embodiments RL1, RL2and RL3are each a group containing a lipophilic moiety, such as a lipophilic vitamin or steroid, including, but not limited to, Vitamin E, Vitamin A (retinol, retinoic acid), and cholesterol.

[0202] In one embodiment, when RL3comprises a lipophilic moiety, then RL3can be selected from the group consisting of:wherein integer m is 0-10 (e.g., 0; or 1-10 or 1-8; or 0-6; or 1; or 2; or 3; or 4; or 5; or 6; or 7; or 8); integer n is 1-21 (e.g., 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2; or 2 or 3 or 4 or 5 or 6); W is C1-C4alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl); R and R’ are each independently H or C1-C4alkyl (e.g., methyl, ethyl, propyl, isopropyl, or t-butyl); G is G1or a saturated or unsaturated C10-26saturated or unsaturated hydrocarbon chain (e.g.,a C21hydrocarbon chain e., G together with the carbonyl to which it is attached may form a group with 22 carbons) (for instance, G may be a linear or branched C21alkyl group), wherein G is optionally substituted with one or two groups selected from the group consisting of halogen, -ORG, -SRG, - N(RG)2, -C(O)ORG, -OC(O)RG, -C(O)N(RG)2, -N(RG)C(O)RG, -N(RG)C(O)ORG, -N(RG)SO2(RG), or -SO2N(RG)2, wherein each RGis independently hydrogen or C1-C6alkyl (for instance, G is optionally substituted with a -ORG, -C(O)ORG, or -N(RG)C(O)RG); and G1is a saturated or unsaturated C10-26saturated or unsaturated hydrocarbon chain (e.g., a C22hydrocarbon chain,for instance, G1may be a linear or branched C22alkyl group), wherein G1is optionally substituted with one or two groups selected from the group consisting of halogen, - ORG1, -SRG1, -N(RG1)2, -C(O)ORG1, -OC(O)RG1, -C(O)N(RG1)2, -N(RG1)C(O)RG1, - N(RG1)C(O)ORG1, -N(RG1)SO2(RG1), or -SO2N(RG1)2, wherein each RG1is independently hydrogen or C1-C6alkyl (for instance, G1is optionally substituted with a -ORG1, -C(O)ORG1, or - N(RG1)C(O)RG1).

[0203] Examples of RL3include, but are not limited to,Other examples of RL3include, but are not limited to the following structures:Further examples of RL3include, but are not limited to,In another embodiment, RL1can be selected from the group consisting of -G1and -S(O)2G1. Examples of RL1include, but are not limited to, the following structures:Further examples of RL1include, but are not limited to, the following structures:

[0204] In another embodiment, RL2is -C(O)RL3, wherein RL3is according to any of the preceding embodiments thereof. In another embodiment, RL2can be selected from the group consisting ofwherein integer m is 0-8 (for instance, m is 0; or m is 1-8; or m is 0-6; or m is 1; or 2; or 3; or 4; or 5; or 6; or 7; or 8); integer n is 1-21 (for instance, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2; or 2 or 3 or 4 or 5 or 6); R and R’ are each independently H or an alkyl group such as a C1-C4alkyl (e.g., methyl, ethyl, propyl, isopropyl, t-butyl); G is G1or a saturated or unsaturated C10-26saturated or unsaturated hydrocarbon chain (e.g., a C21hydrocarbon chain, i.e., G together with the carbonyl to which it is attached may form a group with 22 carbons); for instance, G may be a linear or branched C21alkyl group), wherein G is optionally substituted with one or two groups selected from the group consisting of halogen, - ORG, -SRG, -N(RG)2, -C(O)ORG, -OC(O)RG, -C(O)N(RG)2, -N(RG)C(O)RG, -N(RG)C(O)ORG, - N(RG)SO2(RG), or -SO2N(RG)2, wherein each RGis independently hydrogen or C1-C6alkyl (for instance, G is optionally substituted with a -ORG, -C(O)ORG, or -N(RG)C(O)RG); and G1is a saturated or unsaturated C10-26saturated or unsaturated hydrocarbon chain (e.g.,a C22hydrocarbon chain,(for instance, G1may be a linear or branched C22alkyl group), wherein G1is optionally substituted with one or two groups selected from the group consisting of halogen, - ORG1, -SRG1, -N(RG1)2, -C(O)ORG1, -OC(O)RG1, -C(O)N(RG1)2, -N(RG1)C(O)RG1, - N(RG1)C(O)ORG1, -N(RG1)SO2(RG1), or -SO2N(RG1)2, wherein each RG1is independentlyhydrogen or C1-C6alkyl (for instance, G1is optionally substituted with a -ORG1, -C(O)ORG1, or - N(RG1)C(O)RG1). Additional examples of RL2include, but are not limited to the following structures:Further examples of RL2include, but are not limited to the following structures:

[0205] In some embodiments, B1is a nucleobase modified with a G or G1group, wherein G and G1are as defined above (e.g., a pyrimidine nucleobase modified at the 5’-position with a group comprising G or G1). Examples of B1include, but are not limited to,, wherein t is selected from 0 – 20 (e.g., 1-12, or 1-10, or 3-12, or 3-10).

[0206] In some embodiments, in vivo delivery enhancing moiety is present within a modified nucleoside of the formula:wherein: B is an optionally modified nucleobase; G3is a saturated or unsaturated C1-20hydrocarbon group (e.g., C1-6alkylene; C2-6alkylene; or hexylene);; LKis a linking group such as -O-, -N(H)-, -S-, -S-S-, -C(O)O-, OC(O)-, -C(O)N(H)-, - N(H)C(O), -OC(O)N(H)-, -N(H)C(O)O-, -S(O)2-, -S(O)2O-, -S(O)2N(H)-, -P(O)(OH)O-, - OP(O)(OH)-, -P(S)(OH)O-, -OP(S)(OH)-, -OP(O)(OH)O-, -OP(S)(OH)O-, G2is a saturated or unsaturated C10-26hydrocarbon group (e.g., a C14-C24hydrocarbon group, a C16-C22hydrocarbon group, or a C21-C22hydrocarbon group; and RGis hydrogen, hydroxy, amino, -COOH, or -C(O)NH2.

[0207] For example, when LKcontains a carbonyl attached to G2(e.g., (-N(H)C(O)- or -OC(O)- ), then G2is a C21hydrocarbon group; and when LKdoes not contain a carbonyl attached to G2, then G2is a C22hydrocarbon group. In one embodiment, RGis hydrogen. In another embodiment, RGis OH, In one embodiment, RGis COOH. In another embodiment, RGis CONH2. In one embodiment, RGis amino.

[0208] In the above structures for the lipophilic monomers, the monomers may also contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of the monomers are expressly included. Further, in the preceding and throughout the present application, where a modified internucleotide linkage is shown with substituent atoms fullydescribed at the phosphorous atom, e.g.,where C’ is the 2’-carbon or 3’-carbon atom of a ribose ring, it is understood that the oxygen having the broken bond is the 5'-oxygen of the subsequent nucleotide.

[0209] In one embodiment, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula:,wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21), such as.

[0210] In one embodiment, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula: ,, wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21), such as.

[0211] In one embodiment, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula:wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21), and RGis hydrogen, hydroxy, amino, -COOH, or - C(O)NH2,such as

[0212] In one embodiment, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula:, wherein n is selected from 7-23 (e.g.,11 – 21,or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21), and RGis hydrogen, hydroxy, amino, -COOH, or -C(O)NH2, such as

[0213] In some embodiments, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula:, wherein n is an integer of 1-21, for instance, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2, or 2 or 3 or 4 or 5 or 6); G is a C10-C22hydrocarbon chain (e.g., a C16-C22alkyl chain, or a C16alkyl chain, or a C22alkyl chain)., optionally substituted with one or two groups selected from the group consisting of halogen, -ORG, -SRG, -N(RG)2, -C(O)ORG, - OC(O)RG, -C(O)N(RG)2, -N(RG)C(O)RG, -N(RG)C(O)ORG, -N(RG)SO2(RG), or -SO2N(RG)2, wherein each RGis independently hydrogen or C1-C6alkyl; and nucleobase B is a modified or unmodified nucleobase. In one embodiment, n is 1. In one embodiment, n is 2-6. In one embodiment, n is 6. In one embodiment, G is a C22alkyl chain. In one embodiment, G is a C16alkyl chain

[0214] In some embodiments, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula:, wherein n is an integer of 1-21, for instance, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2, or 2 or 3 or 4 or 5 or 6); G is a C22hydrocarbon chain, optionally substituted with one or two groups selected from the group consisting of halogen, -ORG, -SRG, - N(RG)2, -C(O)ORG, -OC(O)RG, -C(O)N(RG)2, -N(RG)C(O)RG, -N(RG)C(O)ORG, -N(RG)SO2(RG), or - SO2N(RG)2, wherein each RGis independently hydrogen or C1-C6alkyl; and nucleobase B is a modified or unmodified nucleobase. In one embodiment, n is 1. In one embodiment, n is 2-6. In one embodiment, n is 6. In one embodiment, G is C10-C22alkyl chain (e.g., a C14-C24alkyl chain, C16-C22alkyl chain, or a C16alkyl chain, or a C22alkyl chain).

[0215] In one embodiment, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula:In one embodiment, thein vivo delivery enhancing moiety is present within a modified nucleoside of the formula:.

[0216] In one embodiment, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formulawherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21), such asIn one embodiment, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula, wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21), such as

[0217] In one embodiment, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula

[0218] In some embodiments, the in vivo delivery enhancing moiety is present within a modified internucleotide linkage of the form, -OP(Y)(X)O-, wherein Y is O or S (e.g., O), and X is-N(H)(RL1), wherein RL1is -G1or S(O)2-G1, each as defined above, wherein the phosphorous atom in the internucleotide linkage is optionally enriched in the Sp or Rp isomer, or is racemic.

[0219] In some embodiments, the in vivo delivery enhancing moiety is present within a modified internucleotide linkage of the form, -OP(O)(X)O-, wherein X is -N(H)(RL1), wherein RL1is (such as wherein n is selectedfrom 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21) and the phosphorous atom in the internucleotide linkage is optionally enriched in the Sp or Rp isomer, or is racemic.

[0220] In some embodiments, the in vivo delivery enhancing moiety is present within a

[0221] a modified internucleotide linkage of the form,(such aswherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21) and the 3’-O is from the preceding nucleoside and the 5’-O is from the subsequent nucleoside, and wherein the phosphorous atom in the internucleotide linkage is optionally enriched in the Sp or Rp isomer, or is racemic. In certain embodiments, the preceding nucleotide contains a 2’- fluoro modification. In certain embodiments, the preceding nucleotide contains a 2’-O-methyl modification. In certain embodiments, the preceding nucleotide contains a 2’-H modification.

[0222] In some embodiments, the in vivo delivery enhancing moiety is present within a

[0223] a modified internucleotide linkage of the form(such aswherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21) and the 3’-O is from the preceding nucleoside and the 5’-O is from the subsequent nucleoside, and wherein the phosphorous atom in the internucleotide linkage is optionally enriched in the Sp or Rp isomer, or is racemic. In certain embodiments, the preceding nucleotide contains a 2’- fluoro modification. In certain embodiments, the preceding nucleotide contains a 2’-O-methyl modification. In certain embodiments, the preceding nucleotide contains a 2’-H modification.

[0224] In some embodiments, the in vivo delivery enhancing moiety is present within a

[0225] a modified internucleotide linkage of the form, -OP(Y)(X)O-, whereinY is O or S and X iswherein G1is defined above, such aswherein n is selected from 7- 23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21) or

[0226] In some embodiments, in vivo delivery enhancing moiety is conjugated to the 3’-end or 5’-end of one of the sense and antisense strands via a direct bond or through a carrier or linker. In some embodiments, in vivo delivery enhancing moiety is conjugated to the 3’-end of the sense or antisense strand via a direct bond or through a carrier or linker. In some embodiments, in vivo delivery enhancing moiety is conjugated to the 5’-end of the sense or antisense strand via a direct bond or through a carrier or linker.

[0227] In some embodiments, in vivo delivery enhancing moiety is conjugated to the 5’-end of one of the sense and antisense strands (e.g., sense strand) and is of the formulawherein X is O or S (e.g., S); and RL3is according to any of the preceding embodiments there. For example, RL3can bewherein n is selected from 7-23 (e.g., 11-23, or 11 – 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23). In another example, RL3can bewherein m is selected from 1-6, and n is selected from 7-23 (e.g., 11-23, or 11 – 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23). For example, m can be 2-5, or 1, or 2, or 3, or 4 or 5.

[0228] In some embodiments, in vivo delivery enhancing moiety is conjugated to the 5’-end of one of the sense and antisense strands (e.g., sense strand) and is of the formula -RL3, wherein RL3is according to any of the preceding embodiments there. For example, RL3can bewherein n is selected from 7-23 (e.g., 11-23, or 11 – 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23). In another example, RL3can besuch aswherein m is selected from 1-6, and n is selected from 7-23 (e.g., 11-23, or 11 – 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23), and RGis hydrogen, hydroxy, amino, - COOH, or -C(O)NH2.. For example, m can be 2-5, or 1, or 2, or 3, or 4 or 5.

[0229]

[0230] In another example, RL3can be, wherein m is selected from 1-6, and n is selected from 7-23 (e.g., 11-23, or 11 – 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23). For example, m can be 2-5, or 1, or 2, or 3, or 4 or 5.

[0231] In some embodiments, in vivo delivery enhancing moiety is conjugated to the 5’-end of one of the sense and antisense strands (e.g., sense strand) and is of the formula:, or a salt thereof, wherein X is O or S (e.g., S); L is a divalent linking group (e.g., C1-20 alkyl or C1-10alkyl-S-S-C1-10alkyl). In one embodiment, in vivo delivery enhancing moiety is conjugated to the 5’- end of one of the sense and antisense strands and is of the formula(such asor a salt thereof, wherein q is selected from 0 – 18 (e.g., 1-11 or 1-8, or 3-11, or 3-8) and X is O or S (e.g., S). In these embodiments, Rligandis selected from,wherein n is 7-23 (e.g.,11 – 21, or 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21); and a, b, and c are independently selected from 1- 22, provided that the sum of a + b + c is selected from 2 to 22.

[0232] In one embodiment, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formula

[0233]

[0234] wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21). In one embodiment, n is 13. In another embodiment, n is 19.

[0235] In one embodiment, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formula:wherein m is selected from 1-10; n is selected from 7-23 (e.g., 11-23, or 11 – 21, or 13-21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21); E is -C(O)N(H)-(CH2)p-*, -N(H)C(O)-(CH2)p-*, -C(O)O-(CH2)p-*, -OC(O)-(CH2)p-*, - OP(Y)(OH)O-(CH2)p-*, -O-(CH2)p-, -N(H)-(CH2)p, -S-(CH2)p-, -N(H)-O-(CH2)p-, -O-N(H)-(CH2)p-, N(H)N(H)-(CH2)p-, or -S-S-(CH2)p-*, -Ph-(CH2)p-, -OPh-(CH2)p-, or -ZZ1-(CH2)p-; wherein * is the bond to the alpha-amino acid carbon, Ph is phenyl, Y is =O or =S, p is selected from 1 – 6; RGis hydrogen, hydroxy, amino, -COOH, or -C(O)NH2; and ZZ1is a group formed by reaction of a reactive pair (e.g., a reaction between an azide and an alkyne or a cycloalkyne).

[0236] In one embodiment, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formulawherein m is selected from 1-10 (e.g., 3-6, or 3); RGis hydrogen, hydroxy, amino, -COOH, or -C(O)NH2, and n is selected from 7- 23 (e.g., 11-23, or 11 – 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23). For example, m can be 3-6 and RGis hydrogen; or m can be 3-6 and RGis COOH.

[0237] In one embodiment, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and the 5’-terminal nucleotide is of the formula: whereLipoin R is one of:

[0238] In one embodiment, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formula -P(Y)(OH)-R5, wherein Y is O or S and R5is:In one embodiment, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formula -P(Y)(OH)-R5, wherein Y is O or S and R5isL2wherein R selected from:Lipo2wherein R is

[0239] In one embodiment, in vivo delivery enhancing moiety is bonded to the 3’-oxygen of the 3’-terminal nucleotide, and is of the formula -P(Y)(OH)-R3, wherein Y is O or S and R3is:

[0240] In one embodiment, in vivo delivery enhancing moiety is bonded to the 3’-oxygen of the 3’-terminal nucleotide, and is of the formula -P(Y)(OH)-R3, wherein Y is O or S and R3is, wherein RL2selected from:

[0241] In some embodiments, in vivo delivery enhancing moiety is conjugated to the 3’-end or 5’-end of one of the sense and antisense strands via a carrier or linker, and the carrier or linker is an inverted abasic nucleotide, such as an inverted abasic deoxyribonucleotide or an inverted abasic ribonucleotide, each connected to the remainder of the oligonucleotide via a phosphodiester (PO) or phosphorothioate (PS) linkage. Examples include, but are not limited to,, wherein Q2is a bond, C(O), S(O)2, or -P(Y’)(OH)-O-, Y and Y’ are independently O or S; and RL3is as defined above.

[0242] In some embodiments, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide and is of the formulaor a salt thereof, wherein each X is independently O or S (e.g., each is S); Rligandis selected from the groups listed in Table R-1; and L is a divalent linking group (e.g., C1-20alkyl or C1-10alkyl-S-S-C1-10alkyl).

[0243] For example, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’- terminal nucleotide, and is of the formulaor a salt thereof, wherein each X is independently O or S (e.g., each is S) and Rligandis selected fromwherein n is 7-23 (e.g.,11 – 21, or 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21).

[0244] In some embodiments, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formulaor a salt thereof, wherein each X is independently O or S (e.g.,each is S) and Rligand is selected fromwherein n is 7-23 (e.g.,11 –21, or 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21).and L is a divalent linking group (e.g., C1-20alkyl or C1-10alkyl-S-S-C1-10alkyl.

[0245] In one embodiment, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formulaor a salt thereof, wherein each X is O or S (e.g., each is S) and Rligand is selected from,,wherein n is 7-23 (e.g.,11 – 21, or 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21).

[0246] In another embodiment, RL1, RL2, and RL3are each a group containing at least one targeting moiety, such as an integrin receptor ligand (e.g., avB3, avB5, or avB6-targeting ligand), a chemokine receptor ligand, a transferring receptor ligand (e.g., transferrin), a serotonin receptor ligand, an Asialoglycoprotein receptor-targeting ligand, a lipoprotein receptor ligand (e.g., LRP1- targeting ligand), etc. In one embodiment, the targeting moiety can be selected from:

[0247] In one embodiment, the broken bond is connected to a group of the formula, **-L-ZZ- L’- , wherein ** represents the bond to the targeting ligand, ZZ is a bridging group that may be formed, for example, by reaction of two functional groups, and can be selected from the group consisting of, -C(H)=N-, -C(H)=N-N(H)-, -C(H)=N- N(H)C(O)-, -C(H)=N-N(R)-, -C(H)=N-N(R)C(O)-, -C(H)=N-O-, -C(O)N(H)-, -C(O)N(H)-N(H)- , -C(O)N(H)-N(R)-, -C(O)N(R)-, -C(O)O-, -C(O)S-, -C(O)N(H)-, -C(O)N(H)-N(H)-, -C(O)N(H)- N(R)-, -C(O)N(R)-, -C(S)N(H)-, -C(S)N(R)-, -C(S)O-, -C(S)S-, -C(S)N(H)-, -C(S)N(R)-, - N(H)C(O)N(H)-, -N(H)C(O)N(R)-, -N(H)C(O)O-, -N(H)C(O)S-, -N(H)C(S)N(H)-, - N(H)C(S)N(R)-, -N(H)C(S)O-, -N(H)C(S)S-, -S-S-, -CH2-S-, -CH2-O-, -CH2-N(H)-, -CH=CH-, and a click adduct, for example, comprising a group selected from the following structures:wherein each R is independently C1-10alkyl (e.g., methyl, ethyl, propyl, isopropyl, t-butyl, isobutyl, butyl, or hexyl); and RLais hydrogen, C1-10alkyl (e.g., methyl, ethyl, propyl, isopropyl, t- butyl, isobutyl, butyl, or hexyl), C3-8cycloalkyl, 3-8 membered heterocyclyl, aryl (e.g., phenyl), or heteroaryl (e.g., 2-pyridyl).

[0248] “Click adduct” herein included those adducts formed by a copper(I)-catalyzed azide- alkyne cycloaddition reaction, a strain-promoted azide-alkyne cycloaddition, a strain-promoted azide-trans-cycloalkene cycloaddition, and a thiol-maleimide Michael-addition reaction including, for example, (i) an azide with a terminal alkyne or cycloalkyne (e.g. cyclooctyne, BCN, or DBCO); (ii) a tetrazine with a terminal alkyne or cycloalkyne (e.g. cyclooctyne); (iii) a thiol and maleimide (with or without hydrolysis of the product).

[0249] In some embodiments, L and L’ are independently one of: (a) -L1-[G-L2]q-G-L3-* wherein q is 0 or an integer selected from 1-10; (b) -L1-G-L2-G-L3-*; (c) -L1-G-L3-*; (d) -G-L3-*; (e) -L1-G-*; or (f) -G-*. wherein in each of (a) -(f), * represent the bond to ZZ;L1is selected from one of the groups: (a) a bond, C(O), C(S), C(NRN), S(O)2, P(O)(OH), or P(S)(OH), wherein and RNis hydrogen or C1-6alkyl; (b) a bond, C(O), P(O)(OH), or P(S)(OH); (c) a bond; (d) C(O); (e) P(O)(OH); or (f) P(S)(OH); each L2and L3is independently selected from one of the groups: (a) -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, - N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -OP(O)(OH)O- ,-OP(S)(OH)O-, -O-, and - N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (b) -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,- N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (c) -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (d) -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; or (e) -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RNis independently hydrogen or C1-6alkyl; and each G is independently selected from one of the groups: (a) C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; or (b) C1-10alkyl, optionally substituted with 1, 2, or 3 R groups (e.g., 1 or 2 R groups; or 1 R group); or wherein each R group is independently selected from the group consisting of R’, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, C3-8cycloalkylC1-6alkyl, heterocyclylC1-6alkyl, aryl C1-6alkyl, heteroarylC1-6alkyl, each of which, other than R’, is optionally substituted with 1, 2, or 3 R’ groups, wherein each R’ is independently halogen, cyano, azido, nitro, -N(Rb)2, -O(Ra), -S(R0), -C(O)OR0, C(O)R0, -C(O)N(R0)2, -C(NR0)OR0, -C(NR0)R0, -C(NR0)N(R0)2, -C(S)OR0, -C(S)R0, -C( S)N(R0)2, -S(O)2R0, -S(O)2OR0, -S(O)2N(R0)2, -N(R0)C(O)OR0, -N(R0)C(O)R0, -N(R0)C(O)N(R0)2, -N(R0)S(O)2R0, -N(R0)S(O)2OR0, -N(R0)S(O)2N(R0)2, -OC(O)OR0, -OC(O)R0, -OC(O)N(R0)2, -OS(O)2R0, -OS(O)2OR0, -OS(O)2N(R0)2, or -SC(O)R0, wherein each R0is independently hydrogen or C1-6alkyl; each Rais independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; and each Rbis independently hydrogen, C1-6alkyl, or a nitrogen protecting group.

[0250] In one embodiment of L or L’, q is 0, 1, 2, 3, 4, or 5. In another embodiment of L or L’, q is 0, 1, 2, 3, or 4. In another embodiment of L or L’, q is 0, 1, 2, or 3. In another embodiment of L or L’, q is 0, 1, or 2. In another embodiment of L or L’, q is 1, 2, 3, 4, or 5, In another embodiment of L or L’, q is 1, 2, 3, or 4. In another embodiment of L or L’, q is 1, 2, or 3. In another embodiment of L or L’, q is 1 or 2. In another embodiment of L or L’, q is 4. In another embodiment of L or L’, q is 3. In another embodiment of L or L’, q is 2.

[0251] In some embodiments, L is one of: (a) wherein k i1 Ns an integer from 1 to 10; L is bond, C(O), C(S), C(NR ), S(O)2, P(O)(OH), or P(S)(OH) (e.g., L1is a bond, C(O), P(O)(OH), or P(S)(OH)); and RNis hydrogen or C1-6alkyl; (b)wherein k is an integer from 1 to 10; or an integer from 2 to 10; or an integer from 3 to 10; or an integer from 4 to 10; or an integer from 5 to 10; or an integer from 5 to 9; or an integer from 5 to 8; or an integer from 5 to 7; (c) wherein t is an integer from 0 to 10 (e.g., an integer from 1to 5; or 1; or 2; or 3); (d)wherein t is an integer from 0 to 10 (e.g., an integer from 1 to 5 or 1; or 2; or 3); a is an integer from 1 to 3; and s and s’ are each independently an integer from 1 to 24 (e.g., an integer from 1 to 16; an integer from 1 to 10; an integer from 3 to 10; an integer from 3 to 7; or an integer from 4 to 6); (e)wherein and s, s’, and s’’ are independently is an integer from 1 to 24 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7, or an integer from 4 to 6);(f)wherein s and k are independently is an integer from 1 to 20 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7 or an integer from 4 to 6); and w is an integer from 1 to 20 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7 or an integer from 4 to 6); or and wherein in each of the preceding embodiments of L, * represents the bond to ZZ.

[0252] In some embodiments, L’ is : (a)*-G-L1-, wherein L1is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with 1, 2, 3, or 4 R groups; or L1is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and G is C1-10alkyl; (b)*-G-[L2-G]q-L1-, wherein L1is a bond, CH2, C(O), S(O)2, P(O)(OH), or P(S)(OH); each L2is independently -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-, wherein RNis hydrogen or C1-6alkyl each B is independently a bond, CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); each G is independently C1-10alkyl; (c) -[G-L2]q-G-L3-*, wherein each L2is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), OP(O)(OH)O, or OP(S)(OH)O, wherein each RNis independently hydrogen or C1-6alkyl; each G is independently C1-10alkyl or C2-10alkenyl, each of which is optionally substituted with 1 or 2 R groups; or each L2is independently C(O)(NRN), N(RN)C(O), OP(O)(OH)O, or OP(S)(OH)O wherein each RNis independently hydrogen or C1-6alkyl; each G is independently C1-10alkyl, each of which is optionally substituted with 1 or 2 R groups; (d) *-L3-G-L1-, wherein L3is -C(O)O- or C(O)N(RN)-, wherein RNis hydrogen or C1-6alkyl; L1is -OP(O)(OH)O- or -OP(S)(OH)O-; and G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, or 3 R groups (e.g., 1 or no R groups); (e) -L1-[G-L2]q-G-*, wherein L1is a bond or -B-A-; each L2is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), OP(O)(OH)O, or OP(S)(OH)O, wherein each RNis independently hydrogen or C1-6alkyl; and each G is independently C1-10alkyl or C2-10alkenyl, each of which is optionally substituted with 1 or 2 R groups; (f) -[G-L2]q-G-*, wherein each L2is independently C(O)(NRN) , N(RN)C(O), OP(O)(OH)O, or OP(S)(OH)O wherein each RNis independently hydrogen or C1-6alkyl; and each G is independently C1-10alkyl, each of which is optionally substituted with 1 or 2 R groups;(g) -C2-30alkyl-*, such as -C5-20alkyl-* or -C10-20alkyl-*; (h) -C1-10alkyl-*, optionally substituted with 1 or 2 R groups; (i) -C(O)-C2-30alkyl-*, such as -C(O)-C5-20alkyl-* or -C(O)-C10-20alkyl-*; wherein in each of (a) - (i), * is the bond to ZZ, and q, when present, is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., an integer from 1 to 8, an integer from 1 to 5, or an integer from 1 to 3; or 0, 1, 2, or 3; or 0, 1, or 2; or 0 or 1; or 0; or 1; or 2).

[0253] Examples of RLand RL1that comprise a targeting ligand include, but are not limited to,

[0254] Additional examples of RL1and RL3that comprise a targeting ligand include, but are not limited to,

[0255] Examples of RL2that comprise a targeting ligand include, but are not limited to,

[0256] Additional examples of RL2that comprise a targeting ligand include, but are not limited to,

[0257] In one embodiment of any of the preceding structures comprising a targeting moiety, each RXis an integrin-receptor targeting ligand such as,

[0258] In one embodiment, RL1or RL3is.

[0259] In one embodiment, RL2is

[0260] In some embodiments, targeting moiety is bonded to the 3’-oxygen of the 3’-terminal nucleotide, and is of the formula -P(Y)(OH)-R3, wherein Y is O or S and R3is:In some embodiments, targeting moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formula -P(Y)(OH)-R5, wherein Y is O or S and R5is:

[0261] In another embodiment, multiple targeting ligands may be connected to a branched multivalent linker.

[0262] In certain embodiments, RL1, RL2and RL3can comprise a branched linking group (Δ) capable of supporting multiple targeting ligands (e.g., at least 2; or 2-8; or 2-6; or 2-4; or 2; or 3). For example, in one embodiment, the mutiple targeting moieties can be connected through an RL, RL1, and RL2of the form, (RX-L-ZZ-)z-Δ-T- , wherein each RXis a targeting moiety; z is at least 2; or 2-8; or 2-6; or 2-4; or 2; or 3, T is -L’-T’-**, wherein ** is the bond to Δ, and T’ is O, S, N(H), C(O), S(O)2, C(O)N(H), N(H)C(O), OC(O), OC(O), -P(O)(OH)-, -P(S)(OH)-, -OP(O)(OH)-, -OP(S)(OH)-, -P(O)(OH)O-, -P(S)(OH)O-, -OP(O)(OH)O-, or -OP(S)(OH)O-; and L , L’, and ZZ are each as described above, and each * represents the bond to the targeting ligand.

[0263] In some embodiments, T is selected from the following, wherein ** is the bond to Δ: (a) -C(O)-X1-L5-X2-C(O)-**, wherein X1and X2are each independently C1-10alkyl; or C2-10alkyl; or C4-10alkyl; or C6-10alkyl; or C2-8alkyl; or C2-6alkyl; or C2-4alkyl; (b) -C(O)-C2-20alkyl-C(O)-**, such as -C(O)-C2-12alkyl-C(O)-**, (c) -C(O)-C6-20alkyl-C(O)-**, such as -C(O)-C6-12alkyl-C(O)-**, (d) -C(O)-C10alkyl-C(O)-** and(e) -C(O)-CH2CH2-C(O)-**, wherein each L5is a bond, ZZ, or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond; or ZZ), wherein each A1is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1is independently hydrogen or C1-6alkyl; each B1is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and ZZ is as described above (such as -C(O)N(H)-, N(H)C(O)-, - OP(O)(OH)O-, -OP(S)(OH)O-, or a click adduct).

[0264] In some embodiments, T is selected from the following, ** is the bond to Δ: (f) -N(H)C(O)-C2-20alkyl-C(O)-**, (g) - N(H)C(O)-C6-20alkyl-C(O)-**, such as - N(H)C(O)-C6-12alkyl-C(O)-**, (h) - N(H)C(O)-C10alkyl-C(O)-**, (i) -C(O)-C2-20alkyl-C(O)N(H)-**, (j) -C(O)-C6-20alkyl-C(O)N(H)-**, (k) -C(O)-C6-12alkyl-C(O)N(H)-**, (l) -C(O)-C10alkyl-C(O)N(H)-**, (m) -N(H)C(O)-C2-20alkyl-C(O)N(H)-**, (n) - N(H)C(O)-C6-20alkyl-C(O)N(H)-**, (o) - N(H)C(O)-C6-12alkyl-C(O)N(H)-**, and (p) - N(H)C(O)-C10alkyl-C(O)N(H)-**. (q) In some embodiments, T is selected from the following, ** is the bond to Δ: (a) -N(H)C(O)-X3-ZZ-X4-C(O)-**, (b) -C(O)-X3-ZZ-X4-C(O)N(H)-**, (c) N(H)C(O)-X3-ZZ- X4-C(O)N(H)-**, wherein X3and X4 are independently C2-12alkyl; or C4-10alkyl; or C6-10alkyl; or C4-8alkyl; and ZZ is as described above (such as -C(O)N(H)-, N(H)C(O)-, -OP(O)(OH)O-, -OP(S)(OH)O-, or a click adduct).

[0265] In some embodiments, , T is selected from the following (w) -L6-[G5-O]q5-G5-L4-**, wherein L4and L6are independently -A1-B1-A1-, wherein each A1is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1is hydrogen or C1-6alkyl; each B1is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); each G5is independently C1-10alkyl; (x) -C(O)-[CH2CH2-O]q5-G5-L4-**, L4is -A1-B1-A1-, wherein each A1is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1is hydrogen or C1-6alkyl; each B1is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); G5is C1-10alkyl.(y) -C(O)-[CH2CH2-O]q5-G5-L4-**, L4is -A1-B1or -B1-A1-, wherein each A1is independently -O- or -N(H)-, and each B1is independently C(O), G5is C1-10alkyl (e.g., C2-10alkyl or C2-6alkyl); and (z) -C(O)-[CH2CH2-O]q5- C2-10alkyl-C(O)N(H)-**; wherein in each of the preceding ** is the bond to Δ, and q5, when present, is an integer selected from 1 to 20 (e.g., 1 to 10, or 2 to 10; or 2 – 8; or 1; or 2; or 3; or 4.) Examples of branched linking group (Δ) include, but are not limited to,wherein the broken bond is the bond to L’.

[0266] Examples of -T*-Δ- include, but are not limited to,

[0267] Examples of RLand RL1that comprise a branched linker to a targeting ligand include, but are not limited to,

[0268] Examples of branched RL1and RL3include,

[0269] Examples of branched R12include,202

[0270] In some embodiments, targeting moiety is bonded to the 3’-oxygen of the 3’- terminal nucleotide, and is of the formula -P(Y)(OH)-R3, wherein Y is O or S and R3is:selected from 1 - 10 (e.g., r is 7); and each R is:

[0271] In some embodiments, targeting moiety is bonded to the 3’-oxygen of the 3’-terminal nucleotide, and is of the formula -P(Y)(OH)-R3, wherein Y is O or S and R3is:

[0272] In some embodiments, targeting moiety is bonded to the 3’-oxygen of the 3’-terminal nucleotide, and is of the formula -P(Y)(OH)-R3, wherein Y is O or S and R3is:

[0273] In some embodiments, targeting moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formula -P(Y)(OH)-R5, wherein Y is O or S and R5is:selected from 1 - 10 (e.g., r is 7); and each R is:wherein Rxis a targeting ligand.

[0274] In some embodiments, targeting moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formula -P(Y)(OH)-R5, wherein Y is O or S and R5is:ligand.

[0275] In one embodiment of any of the preceding structures comprising a targeting moiety, each Rxis an integrin-receptor targeting ligand such as,

[0276] In another embodiment of any of the preceding structures comprising a targeting moiety, each Rxis an ASGPR ligand, such as

[0277] In certain embodiments, L and / or L’ may be a bond when ZZ is formed by reaction of a functional group within the ligand or oligonucleotide. For example, when the ligand is an antibody or an antigen binding fragment thereof, then ZZ be formed by reaction of: a thiol (SH) group within one or more cysteine (C) residues; oran amino (NH2) group within one or more lysine (K) residues; or a primary amide group (CONH2) within one or more asparagine (N) or glutamine (Q) residues; or an azide group (N3) within one or more modified amino acid residues (e.g., an azide within an 6-azidolysine residue; or a carboxylic acid group within one or more aspartic acid or glutamic acid residues.

[0278] In some embodiments, the dsRNA agent comprises a double-stranded region formed between the sense and antisense strands and optionally one or two single-stranded non-loop overhang, and wherein the one or more lipophilic moieties are conjugated to either the doublestranded region or the non-loop overhang. In some embodiments, the dsRNA agent does not contain a loop (e.g., stem loop) region. In some embodiments, the dsRNA agent contains a loop (e.g., stem loop) region, and the one or more lipophilic moieties are not conjugated to the loop (e.g., stem loop) region.

[0279] In some embodiments, the dsRNA agent comprises a sense strand of 10 to 53 nucleotides in length, in which the sense strand forms a duplex region with the antisense strand. For instance, the sense strand may be 10 to 49, 12 to 49, 12 to 45, 12 to 42, 12 to 40, 15 to 49, 15 to 45, 15 to 42, 15 to 40, 15 to 38, or 15 to 36 nucleotides in length. In some embodiments, the duplex region is at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 nucleotides in length. In some embodiments, the region of complementarity to the target sequence is at least 19 contiguous nucleotides in length.

[0280] In some embodiments, the sense strand comprises at its 3'-end a stem-loop set forth as: S1-L-S2, in which S1is complementary to S2, and in which L forms a loop between S1and S2.

[0281] In some embodiments, the first 17 to 25 nucleotides counting from 5’ end of the sense strand forms a duplex region with the antisense strand, and the last 11 to 28 counting from 5’ end of the sense strand forms a 3'-end a stem-loop set forth as: S1-L-S2.

[0282] In some embodiments, the length of the stem loop S1-L-S2is 11 to 28, 13 to 26, or 15 to 24 nucleotides in length. In one embodiment, the stem loop S1-L-S2is 16 nucleotides in length. In some embodiments, the stem loop S1-L-S2comprises a sequence of GCAGCCGAAAGGCUGC (SEQ ID NO: 105).

[0283] In some embodiments, L is at least 3, 4, or 5 nucleotides in length. In some embodiments, L comprises a sequence of GAAA.

[0284] In some embodiments, the sense strand is 36 nucleotides in length, the first 20 nucleotide counting from 5’ end of the sense strand forms a duplex region with the antisense strand, and the last 16 nucleotides forms a stem loop S1-L-S2. In one embodiment, the 16-nucleotide stemloop S1-L-S2has the sequence of GCAGCCGAAAGGCUGC (SEQ ID NO: 105), wherein L is GAAA.

[0285] In some embodiments, the one or more lipophilic moieties are conjugated to a nonterminal position of the sense strand.

[0286] In some embodiments, the one or more lipophilic moieties are conjugated to one or more nucleotides of the stem loop S1-L-S2. In some embodiments, the one or more lipophilic moieties are conjugated to one or more nucleotides of the loop L.

[0287] In some embodiments, S1and S2are complementary and contain 4-10 nucelotides, e.g., S1and S2each contain 6 complementary nucelotides.

[0288] In some embodiments, S1and S2are complementary and contain 4-10 nucelotides and L is GAAA, e.g., Si and S2 each contain 6 complementary nucelotides and L is GAAA.

[0289] In some embodiments, the one or more lipophilic moieties containing one or more saturated or unsaturated C22hydrocarbon chains are conjugated to one or more internal positions on at least one strand of the dsRNA agent.Dual Conjugation

[0290] In another embodiment, in vivo delivery enhancing moiety is connected in series with another targeting moiety, as described herein. For example, a sense or antisense strand can contain a series modification at the 3 ’-end or 5 ’-end of the oligonucleotide,such that one of L1 and L2 comprises the in vivo delivery enhancing moiety and the other comprises the targeting moiety.

[0291] In one embodiment, the series modification is of the form,wherein Q is selected fromwherein RL2is according to any preceding embodiment, wherein one of the broken bonds connects to a 5 ’-oxygen of a nucleoside or a 3’- oxygen of a nucleoside and the other connects to a 5 ’-terminal or 3 ’-terminal modification as described herein.

[0292] In another example, a sense or antisense strand can contain a series modification of the form,wherein Q is selected fromwhereinRL2is according to any preceding embodiment, each Y is independently O or S; one of the broken bonds connects to a 5 ’ -oxygen of a nucleoside or a 3 ’ -oxygen of a nucleoside and the other connects any of the 5’-terminal modifications described above or 3’-terminal modifications described above.

[0293] In one embodiment, a sense or antisense strand can contain a series modification of thethe broken bond connects to the 5’-oxygen of a 5’-terminal nucleoside; each Y is independently O or S; one of R51and R52comprises a lipophilic group (e.g., an in vivo delivery enhancing moiety) and the other comprises a second ligand moiety (e.g., a targeting moiety).

[0294]

[0295] In another embodiment, a sense or antisense strand can contain a series modification ofthe broken bond connects to the 5’-oxygen of a 5’-terminal nucleoside; each Y is independently O or S; one of R51and R52comprises a lipophilic group (e.g., an in vivo delivery enhancing moiety, such as any of RLor RL2above) and the other comprises a second ligand moiety (e.g., a targeting moiety).For example an oligonucleotide may have a series modification at the 5 ’-end of the formula:wherein n is selected from 7-23 (e.g.,11 - 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21); and eachY is independently O or S and R510and R520arewherein each Y is independently O or S.In another embodiment, a sense or antisense strand can contain a series modification of the form,wherein the broken bond connects to the 3’-oxygen of a 3’-terminal nucleoside; each Y is independently O or S; one of R31and R32comprises a lipophilic group (e.g., an in vivo delivery enhancing moiety, such as any of RL2above) and the other comprises a second ligand moiety (e.g., a targeting ligand).For example an oligonucleotide may have a series modification at the 3 ’-end of the formula:wherein n is selected from7-23 (e.g.,11 - 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21); and each Y is independently O or S and R310and R320areindepedently O or S.

[0296] In another embodiment, can contain a single modification at the 5’-end, the 3’-end or at an internal position that contains both the in vivo delivery enhancing moiety and the targeting moiety.

[0297] In one embodiment, single modification is bonded to the 3 ’-oxygen of the 3 ’-terminal nucleotide, and is of the formula -P(Y)(OH)-R3, wherein Y is O or S and R3iswherein RL2and RL3comprises the in vivo delivery enhancing moiety (e.g., according to any in vivo delivery enhancing moiety embodiment of RL2or RL3above); RTGcomprises the targeting moiety (e.g., RTGis according to Formula (X) (below), wherein R5is -L-ZZ-L’-, where L, ZZ, and L’ are defined for Formula (X) or an embodiment thereof;

[0298] E is -C(O)N(H)-(CH2)p-*, -N(H)C(O)-(CH2)p-*, -C(O)O-(CH2)p-*, -OC(O)-(CH2)p-*, - OP(Y)(OH)O-(CH2)p-*, -O-(CH2)p-, -N(H)-(CH2)p, -S-(CH2)p-, -N(H)-O-(CH2)p-, -O-N(H)-(CH2)p-, N(H)N(H)-(CH2)p-, or -S-S-(CH2)p-*, -Ph-(CH2)p-, -OPh-(CH2)p-, or -ZZ’-(CH2)p-; wherein * is thebond to the alpha-amino acid carbon, Ph is phenyl, Y is =0 or =S, p is selected from 1 - 6; RGis hydrogen, hydroxy, amino, -COOH, or -C(O)NH2; and ZZ1is a group formed by reaction of a reactive pair (e.g., a reaction between an azide and an alkyne or a cycloalkyne);

[0299] E1is -O-, -S-, or -N(H)-;

[0300] T is a bond or -L6-G1-[L5-G1]q1-L4-**, wherein ** is the bond to E; ql is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each L4, L5, and L6are independently a bond, -A’-B’-A1- or ZZ1; ZZ1is a group formed by reaction of a reactive pair (e.g., a reaction between an azide and an alkyne or a cycloalkyne);

[0301] each G1is independently -D’-E’-F1-, wherein D1, E1, and F1are independently a bond, Ci- loalkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, or 3 R groups;

[0302] each A1is independently a bond, -O-, -S-, or -N(RN1)-;

[0303] each B1is independently a bond, C(O), C(S), C(NRN1), S(O), S(O)2, P(O)(OH),P(S)(OH), or P(S)(SH);

[0304] each RN1is independently hydrogen or C1-6alkyl, or two RN1within an -A’-B’-A1- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl.

[0305] In one embodiment, the single modification is bonded to the 5’-oxygen of the 5’- terminal nucleotide, and is of the formula -P(Y)(OH)-R5, wherein Y is O or S and R5iswherein RDis as defined above.

[0306] In one embodiment of the 3’- or 5 ’-modification, RDisIn one embodiment of the 3’- or 5 ’-modification, RDis for example, G1can be C1-10alkyl. In one embodiment of the 3’-or 5 ’-modification, RDiswherein n is selected from 7-23 (e.g., 11-23, or 11 - 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23); and RGis hydrogen, hydroxy, amino, -COOH, or - C(O)NH2; and G1is C1-10alkyl. In one embodiment of the 3’- or 5 ’-modification, RDiswherein n is selected from 7-23 (e.g., 11-23, or 11 -21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23); RGis hydrogen, hydroxy, amino, -COOH, or -C(O)NH2; G1is C1-10alkyl; and RTGis -(N)H)-(CH2)q-N(H)-RLig, wherein q is selected from 1 - 20 (e.g., 2-20 or 2-18 or 2-16 or 2-14, or 2-12, or 2-10; or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) and RLigis

[0307] In one embodiment of the 3’- or 5 ’-modification, RDis RL3. In one embodiment of the 3 or 5 ’-modification, RDisIn one embodiment of the 3 ’- or5 ’-modification, RDisfor example, G1can be C2-20alkyl. In one embodiment of the 3 ’- or 5 ’-modification,wherein n is selected from 7-23(e.g., 11-23, or 11 - 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23); RGis hydrogen, hydroxy, amino, -COOH, or -C(O)NH2;G1is C2-20alkyl.

[0308] In one embodiment of the 3’- or 5 ’-modification, RDiswherein n is selected from 7-23 (e.g., 11-23, or 11 - 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23); RGis hydrogen, hydroxy, amino, -COOH, or -C(O)NH2; G1is C2-2oalkyl, and -C(O)-RTGis, , and the broken bond is the bond between RTGand the nitrogen.

[0310] In another embodiment, a sense or antisense strand can contain two different ligand modifications, one at the 3'-end of the strand and the other at the 5'-end of the strand:such that one of L1 and L2 comprises the in vivo delivery enhancing moiety and the other comprises the targeting moiety.

[0311] In another embodiment, a sense or antisense strand can contain two different ligand modifications, one is an internal modified nuceloside or modified internucleotide linkage of the strand and the other at the 3 ’-end or 5'-end of the strand:such that one of L1 and L2 comprises the in vivo delivery enhancing moiety and the other comprises the targeting moiety. The modified nuceloside represented by L1 can be located at a position in the strand selected from positions 2 to n-1, where the strand contains n nucleotides (e.g., n-1 is 20 when n is 21). For example, when L1 is at position 6, then segment (1) of the strand contains 5 nucleotides and segment (2) contains the remainder of the nucleotides within the strand. “Position” herein, when referring to a modified nucleotide, nucleoside, or internucleotide linkage is counted from the 5 ’-end of the strand, for example, position 6 includes the 6th nucleotide from the 5 ’-end of the strand and the 6th internucleotide linkage counting from the 5 ’-end of the strand.

[0312] In one embodiment, L1 comprises the in vivo delivery enhancing moiety and a sense or antisense strand can be represented by one of:wherein B is an optionally modified nucleobase (e.g., A, C, G, U, or T); R13or RL1comprises the in vivo delivery enhancing moiety, L2 comprises the targeting moiety.

[0313] In one embodiment, RLis selected from the group consisting of:wherein n is selected from 7-23 (e.g., 11 - 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21); for example, in one embodiment, n is 13; and in another embodiment, n is 19.

[0314] In one embodiment, RL1is selected from the group consisting of:and, wherein n is selected from 7-23 (e.g., 11 - 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21); for example, in one embodiment, n is 7; and in another embodiment, n is 10.

[0315] In another embodiment, RLis selected from the group consisting of:embodiment, RL1is selected from the group consisting of:Exemplary sense strands

[0316] In some embodiments, the sense strand of the dsNA has one of the following modification patterns:Table B: Exemplary sense strand motifswherein n is a 2’-O-methyl-modified nucleotide;(dN) is a 2’-deoxy-nucleotide;Nf is a 2’-fluoro-modified nucleotide (e.g., 2 ’-deoxy-2’ -fluoro modified nucleotide); and the sense strand optionally comprises either:(a) a 3 ’-terminal or 5 ’-terminal modification selected from:(i) 5’-(L1)- attached to the 5’-terminal nucleotide (e.g., through the 5’-O of the terminal nucleoside), optionally via a divalent linking group, such as a phosphodiester or phosphorothioate linkage;(ii) -(L2)-3', attached to the 3’-terminal nucleotide (e.g., through the 3’-O of the terminal nucleoside), optionally via a divalent linking group, such as a phosphodiester or phosphorothioate linkage;(iii) 5’-(L1)(I)- attached to the 5 ’-terminal nucleotide (5 ’-5’), optionally via a divalent linking group, such as a phosphodiester or phosphorothioate linkage; or(iv) -(I)(L2)-3', attached to the 3’-terminal nucleotide (3’-3’), optionally via a divalent linking group, such as a phosphodiester or phosphorothioate linkage; wherein each (I) is an inverted nucleotide (e.g., an inverted abasic nucleotide, such as an inverted abasic ribonucleotide, such as an inverted abasic deoxyribonucleotide);(L1) and (L2) are independently hydrogen or a group comprising a ligand , wherein the ligand is selected from:(i) a lipophilic group; examples include a group comprising an C10-C30alkyl, or a C10-C30alkenyl group, e.g., a C10alkyl, C10alkenyl, C12alkyl, C12alkenyl, C14alkyl, C14alkenyl, C15alkyl, C15alkenyl, C16alkyl, a C16alkenyl, a C18alkyl, a C18alkenyl, a C20alkyl, a C20alkenyl, a C22alkyl, a C22alkenyl, a C24alkyl, a C24alkenyl; C15alkyl, a C15alkenyl, a C17alkyl, a C17alkenyl, a C19alkyl, a C19alkenyl, a C21alkyl, a C21alkenyl, a C23alkyl, or a C23alkenyl group; examples include, but are not limited to, a hexadecyl group, a docosanyl group, an omega-hydroxy-hexadecyl group, and an omega-hydroxy-docosanyl group; or(ii) a cell-receptor targeting ligand, such as a group comprising an Asialoglycoprotein receptor-targeting (ASGPR) ligand, an integrin-receptor targeting ligand (e.g., avB3, avB5, or avB6-targeting ligand), a lipoprotein receptor-targeting ligand (e.g., LRP1 -targeting ligand); or(iii) a precursor functional group, where the precursor functional group is suitable for post-synthetic functionalization with a ligand (e.g. as descirbed in (i) or (ii)) containing or conjugated to a complementary reactive functional group; examples of precursor functional groups include, but are not limited to, amino, carboxy, primary amido (-C(O)NH2), N- succinamido, azido (-N3), mercapto (-SH), active esters (e.g., an N- hydroxysuccinimde ester (NHS ester) or a pentafluorophenyl ester),1.2.4.5-tetrazinyl (e.g., 3-methyl-l,2,4,5-tetrazinyl, 3-(pyridin-2-yl)-1.2.4.5-tetrazinyl, or 3-(pyrimidin-2-yl)-l,2,4,5-tetrazinyl-); cyclooctynyl (e.g., bicyclo[6.1.0]nonynyl (BCN) or dibenzocyclooctynyl (DBCO)), trans-cyclooctenyl, 2-methylsulfonylpyrimidinyl, 4-vinylpyridinyl, and protected forms thereof; or(b) a nucleotide comprising a ligand modification, as described above, that replaces the nucleotide decribed above; examples of lipophile modified nucleotides include, (Nhd) - 2’-O-hexadecyl-modified nucleotide; (Nda) - a 2’-O-docosanyl-modified nucleotide; (NhdOH) - 2’-O-(omega-hydroxy-hexadecyl)-modified nucleotide); or (NdaOH) - a 2’-O-(omega-hydroxy-docosanyl)-modified nucleotide.

[0317] In each of the preceding sense strands, each of the nucleotides are connected in series (i.e., in a 3 ’->5’ manner) via optionally modified internucleotide linkages. For example, each of the nucleotides are connected by phosphodiester or phosphorothioate internucleotide linkages.

[0318]

[0319] In certain embodiments of the preceding sense strand examples, the nucleotide at one of the ...

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I), (I), or (II):or a salt thereof, wherein: n is an integer selected from 1 - 3; A is -C(*)(H)-, -CH2C(*)(H)-, or -C(*)(H)CH2, wherein * is the bond to E; E is a bond or -CH2-; B is an optionaly modified nucleobase (e.g., uracil); Q is propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2- ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2- methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2- ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2- methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q are optionaly and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q are both replaced with O or S; one methine in Q is optionaly replaced with -N=; X is O or S; each RPis independently C1-3alkyl, -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RSis independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2Sis C1-3alkyl;one of R2’and R3’is hydrogen, halogen, or -OR20, alkyl, branched alkyl, aminoC1-6alkyl(e.g., branched aminoC1-6alkyl), C2-6alkenyl, C2-6alkynyl, C1-6alkyl ester, C1-6alkylthio (e.g., branched C1-6alkylthio), C1-6alkylamino (e.g., branched N-C1-6alkylamino), C2-6alkenylthio (e.g., branched C2-6alkenylthio), N- C2-6alkenylamino (e.g., branched N- C2-6alkenylamino), C2-6alkylthioester, N-C1-6alkylcarbamyl, wherein: R20is hydrogen, hydroxyl protecting group, optionaly substituted C1-6alkyl, (e.g., methyl, 2-methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N- methylamino)-2-oxoethyl, or 3-oxo-3-(N-methylamino)prop-1-yl), optionaly substituted C2-6alkenyl, or optionaly substituted C2-6alkynyl (e.g., propargyl); the other of R2’and R3’is -OR30, wherein R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide; provided that: (a) Q is not, wherein * is the bond to the phosphorous atom; (b) when X is O or S, and each Rp is ORO, wherein each ROis hydrogen or an oxygen protecting group, then Q is not, wherein * is the bond to the phosphorous atom; and (c) the compound is not of the formula,.

2. The compound of claim 1, wherein Q is,,, where * is the bond to the phosphorous atom.

3. The compound of claim 1 or 2, wherein Q is, , , , , , , , ,, , , ,.

4. The compound of claim 1, wherein the compound is of Formula (Ia):.

5. The compound of claim 4, wherein the compound is of formula, , ,rQ1is -O-, -S-, or -N(RNQ)-, wherein: RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl.

6. The compound of claim 5, wherein the compound is of formula,.

7. The compound of claim 5, wherein the compound is of formula,.

8. The compound of claim 7, wherein the compound is of formula,,.

9. The compound of claim 5, wherein the compound is of formula,.

10. The compound of claim 5, wherein the compound is of formula,.

11. The compound of claim 5, wherein the compound is of formula,12. The compound of claim 1, wherein the compound is of Formula (Ib), .

13. The compound of claim 1, wherein the compound is of Formula (Ia), (Ib), (Ic) or (Id): a14. The compound of claim 1, wherein the compound is of the formula,r .

15. The compound of claim 1, wherein the compound is of the formula,16. The compound of claim 1, wherein the compound is of Formula (IIa),, wherein n is 1, 2 or 3.

17. The compound of any one of claims 1-16, wherein X is O.

18. The compound of any one of claims 1-16, wherein X is S.

19. The compound of any one of claims 1-18, wherein at least one RPis -ORO, optionaly, each RPis independently -ORO.

20. The compound of claim 19, wherein each ROis independently H, methyl, ethyl, propyl, 1- methylethyl, butyl, or tert-butyl, optionaly each ROis independently H, methyl, or ethyl.

21. The compound of claim 20, wherein each ROis independently a hydroxyl protecting group.

22. The compound of claim 21, wherein each ROis independently pivaloyloxymethyl (POM), ethyl, methyl, isopropyl, tert-butyl, trihaloalkyl, benzyl, nitrobenzyl, chlorobenzyl, fluorenyl-9-methyl, 2-cyanoethyl, 2-chlorophenyl, 2,2,2-25-trihalogen-1,1-dimethylethyl, 5-chloroquin-8-yl, 2-methylthioethyl, or 2-methylthioethyl, optionaly each ROis independently POM or ethyl.

23. The compound of any one of claims 1-22, wherein at least one RPis -SRS.

24. The compound of claim 23, wherein each RSis independently H, methyl, ethyl, propyl, or 1-methylethyl, optionaly each RSis independently H, methyl or ethyl.

25. The compound of claim 24, wherein each RSis independently a thiol protecting group.

26. The compound of any one of claims 1-25, wherein at least one RPis -N(RN)2or - N(RN)S(O)2R2S(e.g, -NHSO2CH3.

27. The compound of any one of claims 1-18, whereinis selected from the group consisting of *-P(O)(OH)2, *-P(O)(OMe)2, *-P(O)(OEt)2, *-P(O)(OPOM)2, *- P(O)(OH)OMe, *-P(O)(CH3)OH, or *-P(O)(OH)N(H)SO2CH3, wherein * represents the bond to the remainder of the compound.

28. The compound of any one of claims 1-27, wherein B is a modified or protected nucleobase.

29. The compound of claim 28, wherein B is a protected nucleobase comprising at least one amine or hydroxyl protecting group.

30. The compound of any one of claims 1-29, wherein R2’is hydrogen or halogen (e.g., fluoro).

31. The compound of any one of claims 1-29, wherein R2’is -OR20.

32. The compound of claim 31, wherein R20is optionaly substituted C1-6alkyl.

33. The compound of claim 32, wherein R20is methyl, ethyl, propyl, 2-methoxyethyl, 1,3- dimethoxyprop-2-yl, 2-(N-methylamino)-2-oxoethyl, or 3-oxo-3-(N-methylamino)prop-1- yl, optionaly, R20is methyl or 2-(N-methylamino)-2-oxoethyl.

34. The compound of claim 31, wherein R20is optionaly substituted C2-6alkenyl.

35. The compound of claim 31, wherein R20is optionaly substituted C2-6alkynyl (e.g., propargyl).

36. The compound of any one of claims 30-35, wherein R3’is -OR30, wherein R30is hydrogen, a hydroxyl protecting group, or a reactive phosphorous group.

37. The compound of claim 36 wherein R30is hydrogen or a hydroxyl protecting group.

38. The compound of claim 37, wherein R30is hydrogen.

39. The compound of claim 37, R30is a hydroxyl protecting group.

40. The compound of claim 39, wherein the hydroxyl protecting group is t-butyldimethylsilyl (TBDMS), trimethylsilyl (TMS), triethylsilyl (TES), trisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), or t-butylmethoxyphenylsilyl (TBMPS), optionaly, the hydroxyl protecting group is TBDMS.

41. The compound of claim 36, wherein R30is a reactive phosphorous group.

42. The compound of claim 41, wherein the reactive phosphorous group is a phosphoramidite, H-phosphonate, alkyl-phosphonate, or phosphate triester.

43. The compound of claim 42, wherein the reactive phosphorous group is -P(ORP)N(RP2)2, -P(SRP)N(RP2)2, -P(O)(ORP)N(RP2)2, -P(S)(ORP)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP)N(RP2)2, -P(O)(ORP)H, -P(S)(ORP)H, -P(O)(SRP)H, -P(O)(ORP)RP3, -P(S)(ORP)RP3, or -P(O)(SRP)RP3, wherein: each RP3is an optionaly substituted C1-C30alkyl, optionaly substituted C2- C30alkenyl, or optionaly substituted C2-C30alkynyl(e.g., optionaly substituted C1-C10alkyl, optionaly substituted C2-C10alkenyl, or optionaly substituted C2- C10alkynyl); each RPis independently an optionaly substituted C1-6alkyl; and each RP2is independently optionaly substituted C1-6alkyl, or both RP2taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; or RPand one of RP2taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl.

44. The compound of claim 43, wherein the reactive phosphorous group is -P(ORP)N(RP2)2.

45. The compound of claim 43 or 44, wherein RPis C1-6alkyl substituted with cyano or - SC(O)Ph.

46. The compound of any one of claims 43-45, wherein RPis –CH2CH2CN.

47. The compound of any one of claims 43-46, wherein each RP2is independently methyl, ethyl, propyl, or isopropyl.

48. The compound of any one of claims 43-47, wherein each RP2is isopropyl.

49. The compound of any one of claims 43-48, wherein RP3is an optionaly substituted C1- C6alkyl, (e.g., methyl).

50. The compound of any one of claims 30-35, wherein R3’is -OR30, wherein R30is a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide.

51. The compound of claim 50, wherein the R30’is a bond to an oligonucleotide.

52. The compound of claim 51, wherein R3’is connected to the oligonucleotide via a phosphodiester or modified internucleotide linkage (e.g., phosphorothioate).

53. The compound of claim 51 or 52, wherein R3’is connected to the 5’-terminal of the oligonucleotide (e.g., 5’-hydroxyl at the 5’-terminal of the oligonucleotide).

54. The compound of any one of claims 1-29, wherein R3’is hydrogen or halogen (e.g., F).

55. The compound of any one of claims 1-29, wherein R3’is -OR20.

56. The compound of claim 55, wherein R20is optionaly substituted C1-6alkyl.

57. The compound of claim 56, wherein R20is methyl, ethyl, propyl, 2-methoxyethyl, 1,3- dimethoxyprop-2-yl, 2-(N-methylamino)-2-oxoethyl, or 3-oxo-3-(N-methylamino)prop-1- yl, optionaly, R20is methyl or 2-(N-methylamino)-2-oxoethyl.

58. The compound of claim 55, wherein R20is optionaly substituted C2-6alkenyl.

59. The compound of claim 55, wherein R20is optionaly substituted C2-6alkenyl (e.g., propargyl).

60. The compound of any one of claims 54-59, wherein R2’is -OR30, wherein R30is hydrogen, a hydroxyl protecting group, or a reactive phosphorous group.

61. The compound of claim 60, wherein R30is hydrogen or a hydroxyl protecting group.

62. The compound of claim 61, wherein R30is hydrogen.

63. The compound of claim 62, wherein R30is a hydroxyl protecting group.

64. The compound of claim 63, wherein the hydroxyl protecting group is t-butyldimethylsilyl (TBDMS), trimethylsilyl (TMS), triethylsilyl (TES), trisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), or t-butylmethoxyphenylsilyl (TBMPS), optionaly, the hydroxyl protecting group is TBDMS.

65. The compound of claim 60, wherein R30is a reactive phosphorous group.

66. The compound of claim 65, wherein the reactive phosphorous group is a phosphoramidite, H-phosphonate, alkyl-phosphonate, or phosphate triester.

67. The compound of claim 66, wherein the reactive phosphorous group is -P(ORP)N(RP2)2, -P(SRP)N(RP2)2, -P(O)(ORP)N(RP2)2, -P(S)(ORP)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP)N(RP2)2, -P(O)(ORP)H, -P(S)(ORP)H, -P(O)(SRP)H, -P(O)(ORP)RP3, -P(S)(ORP)RP3, or -P(O)(SRP)RP3, wherein: each RP3is an optionaly substituted C1-C30alkyl, optionaly substituted C2- C30alkenyl, or optionaly substituted C2-C30alkynyl (e.g., optionaly substituted C1-C10alkyl, optionaly substituted C2-C10alkenyl, or optionaly substituted C2- C10alkynyl); each RPis independently an optionaly substituted C1-6alkyl; and each RP2is independently optionaly substituted C1-6alkyl, or both RP2taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; or RPand one of RP2taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl.

68. The compound of claim 67, wherein the reactive phosphorous group is -P(ORP)N(RP2)2.

69. The compound of claim 66 or 68, wherein RPis C1-6alkyl substituted with cyano or - SC(O)Ph.

70. The compound of any one of claims 67-69, wherein RPis –CH2CH2CN.

71. The compound of any one of claims 67-70, wherein each RP2is independently methyl, ethyl, propyl, or isopropyl.

72. The compound of any one of claims 67-71, wherein each RP2is isopropyl.

73. The compound of any one of claims 67-72, wherein RP3is an optionaly substituted C1- C6alkyl, (e.g., methyl).

74. The compound of any one of claims 54-59, wherein R2’is -OR30, wherein R30is a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide.

75. The compound of claim 74, wherein R30is a bond to an oligonucleotide.

76. The compound of claim 75, wherein R2’is connected to the oligonucleotide via a phosphodiester or modified internucleotide linkage (e.g., phosphorothioate).

77. The compound of claim 75 or 76, wherein R2’is connected to the 5’-terminal of the oligonucleotide (e.g., 5’-hydroxyl at the 5’-terminal of the oligonucleotide).

78. The compound of any one of claims 1-16, wherein: X is O; each RPis independently -OROor is -N(RN)2; R3’is -OR30, wherein R30is hydrogen, hydroxyl protecting group, or a reactive phosphorous group.

79. The compound of claim 78, wherein R30is hydrogen or hydroxyl protecting group.

80. The compound of claim 78, wherein R30is a reactive phosphorous group.

81. The compound of claim 80, wherein the reactive phosphorous group is a phosphoramidite, H-phosphonate, alkyl-phosphonate, or phosphate triester.

82. The compound of claim 81, wherein the reactive phosphorous group is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, -P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, - P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, -P(S)(ORP1)H, -P(O)(SRP1)H,-P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, wherein: each RP3is an optionaly substituted C1-C30alkyl, optionaly substituted C2- C30alkenyl, or optionaly substituted C2-C30alkynyl (e.g., optionaly substituted C1-C10alkyl, optionaly substituted C2-C10alkenyl, or optionaly substituted C2- C10alkynyl); each RP1is independently an optionaly substituted C1-6alkyl; and each RP2is independently optionaly substituted C1-6alkyl, or both RP2taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; or RP1and one of RP2taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl.

83. The compound of claim 82, wherein the reactive phosphorous group is -P(ORP1)N(RP2)2.

84. The compound of claim 82 or 83, wherein RP1is C1-6alkyl substituted with cyano or - SC(O)Ph.

85. The compound of any one of claims 82-84, wherein RP1is –CH2CH2CN.

86. The compound of any one of claims 82-85, wherein each RP2is independently methyl, ethyl, propyl, or isopropyl.

87. The compound of any one of claims 82-86, wherein each RP2is isopropyl.

88. The compound of any one of claims 82-87, wherein the reactive phosphorous group is - P(ORP1)N(RP2)2, where RP1is –CH2CH2CN, and each RP2is isopropyl.

89. The compound of any one of claims 1-16, wherein: X is O; each RPis -ORO, where each ROis independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, POM, or NHSO2CH3; and R3’is R30, where R30is -P(ORP)N(RP2)2, where RPis –CH2CH2CN, and each RP2is isopropyl.

90. The compound of any one of claims 75-86, whereinis selected from the group consisting of *-P(O)(OH)2, *-P(O)(OMe)2, *-P(O)(OEt)2, *-P(O)(OPOM)2, *-P(O)(OH)OMe, *-P(O)(CH3)OH, or *-P(O)(OH)N(H)SO2CH3, wherein * represents the bond to the remainder of the compound.

91. The compound of any one of claims 1-16, wherein: X is O; each RPis independently -OROor is -N(RN)2; R2’is hydrogen, F, or -OR20, wherein R20is hydrogen, optionaly substituted C1-6alkyl, (e.g., methyl, 2- methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N-methylamino)-2-oxoethyl, or 3-oxo- 3-(N-methylamino)prop-1-yl), optionaly substituted C2-6alkenyl, or optionaly substituted C2-6alkynyl (e.g., propargyl); and R3’is -OR30, wherein R30is hydrogen, hydroxyl protecting group, or a reactive phosphorous group.

92. The compound of claim 91, wherein R30is hydrogen or hydroxyl protecting group.

93. The compound of claim 91, wherein R30is a reactive phosphorous group.

94. The compound of claim 93, wherein the reactive phosphorous group is a phosphoramidite, H-phosphonate, alkyl-phosphonate, or phosphate triester.

95. The compound of claim 94, wherein the reactive phosphorous group is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, -P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, - P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, -P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, wherein: each RP3is an optionaly substituted C1-C30alkyl, optionaly substituted C2- C30alkenyl, or optionaly substituted C2-C30alkynyl (e.g., optionaly substituted C1-C10alkyl, optionaly substituted C2-C10alkenyl, or optionaly substituted C2- C10alkynyl); each RP1is independently an optionaly substituted C1-6alkyl; and each RP2is independently optionaly substituted C1-6alkyl, or both RP2taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; or RP1and one of RP2taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl.

96. The compound of claim 95, wherein the reactive phosphorous group is -P(ORP1)N(RP2)2.

97. The compound of claim 95 or 96, wherein RP1is C1-6alkyl substituted with cyano or - SC(O)Ph.

98. The compound of any one of claims 95-97, wherein RP1is –CH2CH2CN.

99. The compound of any one of claims 95-98, wherein each RP2is independently methyl, ethyl, propyl, or isopropyl.

100. The compound of any one of claims 95-99, wherein each RP2is isopropyl.

101. The compound of any one of claims 95-100, wherein the reactive phosphorous group is - P(ORP1)N(RP2)2, where RP1is –CH2CH2CN, and each RP2is isopropyl.

102. The compound of any one of claims 95-101, wherein R2’is hydrogen, F, or -OR20, wherein R20is methyl or 2-methoxyethyl.9 103. The compound of any one of claims 95-102, wherein each ROis independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl.

104. The compound of any one of claims 1-16, wherein: X is O; each RPis -ORO, where each ROis independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, POM or NHSO2CH3; R2’is hydrogen, F, or -OR20, where R20is hydrogen, methyl, 2-methoxyethyl, 1,3- dmethoxyprop-2-yl, or 2-(N-methylamino); and R3’is R30, where R30is -P(ORP)N(RP2)2, where RPis –CH2CH2CN, and each RP2is isopropyl.

105. The compound of any one of claims 91-104, whereinis selected from the group consisting of *-P(O)(OH)2, *-P(O)(OMe)2, *-P(O)(OEt)2, *-P(O)(OPOM)2, *- P(O)(OH)OMe, *-P(O)(CH3)OH, or *-P(O)(OH)N(H)SO2CH3, wherein * represents the bond to the remainder of the compound.

106. The compound of any one of claims 1-16, wherein: Q is, ,,, where * is the bond to the phosphorous atom; X is O; each RPis -ORO; R2’is hydrogen, F, or -OR20, wherein R20is hydrogen, optionaly substituted C1-6alkyl, (e.g., methyl, 2- methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N-methylamino)-2-oxoethyl, or 3-oxo- 3-(N-methylamino)prop-1-yl), optionaly substituted C2-6alkenyl, or optionaly substituted C2-6alkynyl (e.g., propargyl); and R3’is -OR30, wherein R30is hydrogen, hydroxyl protecting group, or a reactive phosphorous group.

107. The compound of claim 106, wherein R30is hydrogen or hydroxyl protecting group.

108. The compound of claim 106, wherein R30is a reactive phosphorous group.

109. The compound of claim 108, wherein the reactive phosphorous group is a phosphoramidite, H-phosphonate, alkyl-phosphonate, or phosphate triester.

110. The compound of claim 109, wherein the reactive phosphorous group is-P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, -P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, - P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, -P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, wherein: each RP3is an optionaly substituted C1-C30alkyl, optionaly substituted C2- C30alkenyl, or optionaly substituted C2-C30alkynyl (e.g., optionaly substituted C1-C10alkyl, optionaly substituted C2-C10alkenyl, or optionaly substituted C2- C10alkynyl); each RP1is independently an optionaly substituted C1-6alkyl; and each RP2is independently optionaly substituted C1-6alkyl, or both RP2taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; or RP1and one of RP2taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl.

111. The compound of claim 110, wherein the reactive phosphorous group is -P(ORP1)N(RP2)2.

112. The compound of claim 110 or 111, wherein RP1is C1-6alkyl substituted with cyano or - SC(O)Ph.

113. The compound of any one of claims 110-112, wherein RP1is –CH2CH2CN.

114. The compound of any one of claims 110-113, wherein each RP2is independently methyl, ethyl, propyl, or isopropyl.

115. The compound of any one of claims 110-114, wherein each RP2is isopropyl.

116. The compound of any one of claims 110-115, wherein the reactive phosphorous group is - P(ORP1)N(RP2)2, where RP1is –CH2CH2CN, and each RP2is isopropyl.

117. The compound of any one of claims 110-116, wherein R2’is hydrogen, F, or -OR20, wherein R20is methyl or 2-methoxyethyl.9 118. The compound of any one of claims 110-117, wherein each ROis independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl.

119. The compound of any one of claims 110-118, wherein:Q is , , , , , , , , , , , , ,, , ,,; X is O; each RPis -ORO, where each ROis independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, POM or NHSO2CH3; R2’is hydrogen, F, or -OR20, where R20is hydrogen, methyl, 2-methoxyethyl, 1,3- dmethoxyprop-2-yl, or 2-(N-methylamino); and R3’is R30, where R30is -P(ORP)N(RP2)2, where RPis –CH2CH2CN, and each RP2is isopropyl.

120. The compound of any one of claims 106-119, whereinis selected from the group consisting of *-P(O)(OH)2, *-P(O)(OMe)2, *-P(O)(OEt)2, *-P(O)(OPOM)2, *- P(O)(OH)OMe, *-P(O)(CH3)OH, or *-P(O)(OH)N(H)SO2CH3, wherein * represents the bond to the remainder of the compound.

121. The compound of claim 1, wherein the compound is selected from the group consisting of:,, ,,,,122. An oligonucleotide, having a 5’-terminal phosphate mimic comprising the structure:, wherein: * is a carbon atom in a sugar moiety of the 5’-terminal nucleotide (e.g., C4’ of a ribose); A is -C(*)(H)-, -CH2C(*)(H)-, or -C(*)(H)CH2, wherein * is the bond to E; E is a bond or -CH2-; X is O or S; Q is propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2- ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2- methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2- ethyl)cyclopropylmethyl, cyclopropyl 2-(2-methyl)cyclopropylethyl, 2- methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, each RPis independently -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S, wherein: eachROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RSis independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2Sis C1-3alkyl.

123. The oligonucleotide of claim 122, wherein the 5’-terminal modification comprises the structure: ,.

124. The oligonucleotide of claim 123, wherein the 5’-terminal modification comprises the structure: , , ,125. An oligonucleotide, having a 5’-terminal phosphate mimic comprising the structure:or ,wherein: X is O or S; Q4is ethylene, ethenylene, propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2-ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2- methyl)cyclopropyl, (2-methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3- cyclopropyl)propyl, (2-ethyl)cyclopropylmethyl, or 2-(2-methyl)cyclopropyl)ethyl; each RPis independently -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RSis independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2Sis C1-3alkyl; Q5is methylene, ethylene, ethenylene, propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2-ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2-methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2-ethyl)cyclopropylmethyl, cyclopropyl, or 2-(2- methyl)cyclopropyl)ethyl, wherein: one or two methylene groups in Q5are optionaly and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q5are both replaced with O or S; one methine in Q5is optionaly replaced with -N=; and RPS is C1-3alkyl, -ORO, -N(RN)2, -N(RN)S(O)2R2S, -N(RN)P(O)(ORO)(RPC), or - N=P(ORO)2(RPC), wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RSis independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; RPC is C1-6alkyl (e.g., C1-3alkyl or methyl); and R2Sis C1-3alkyl.

126. The oligonucleotide of any one of claims 122-125, wherein the 5’-terminal modification is comprised in a nucleotide comprising a furanose (e.g., ribofuranose, arabinofuranose, lyxofuranose, xylofuranose, ribulofuranose or xylulofuranose, optionaly ribofuranose) ora pyranose (e.g., glucopyranose, galactopyranose, mannopyranose, alopyranose, altropyranose, gulopyranose, idopyranose, or talopyranose) sugar, and alpha and beta, D and L, deoxy, and modified derivates thereof.

127. An oligonucleotide, wherein the 5’-terminal nucleotide has the structure: ,wherein: n is an integer selected from 1 - 3; A is -C(*)(H)-, -CH2C(*)(H)-, or -C(*)(H)CH2, wherein * is the bond to E; E is a bond or -CH2-; B is an optionaly modified nucleobase (e.g., uracil); Q is propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2- ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2- methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3-cyclopropyl)propyl, (2- ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2- methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q are optionaly and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RN)-, wherein RN is hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q are both replaced with O or S; one methine in Q is optionaly replaced with -N=; X is O or S; each RPis independently C1-3alkyl, -ORP1, -SRP1, -N(RP1)2, or -N(RP1)S(O)2RS, wherein: each RP1is independently hydrogen, C1-3alkyl, or a hydroxy protecting group; and RSis C1-3alkyl; one of R2’and R3’is hydrogen, halogen, or -OR20, wherein: R20is hydrogen, hydroxyl protecting group, optionaly substituted C1-6alkyl, (e.g., methyl, 2-methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N-methylamino)-2-oxoethyl, or 3-oxo-3-(N-methylamino)prop-1-yl), optionaly substituted C2-6alkenyl, or optionaly substituted C2-6alkynyl (e.g., propargyl); the other of R2’and R3’is -OR30, wherein: R30is a bond to an oligonucleotide (e.g., to an internucleotide linkage that connects to the subsequent nucleotide of the oligonucleotide); provided that: (a) Q is not, wherein * is the bond to the phosphorous atom; (b) when X is O or S, and each Rp is ORO, wherein each ROis hydrogen or an oxygen protecting group, then Q is not, wherein * is the bond to the phosphorous atom; and (c) the 5’-terminal nucleotide is not of the formula,.

128. The oligonucleotide of claim 127, wherein the 5’-terminal nucleotide has the structure:.

129. The oligonucleotide of claim 128, wherein the 5’-terminal nucleotide has the structure: , ,r, wherein: Q1is -O-, -S-, or -N(RN)-, wherein: RN is hydrogen, methyl, C1-3alkoxy, or C1-3acyl.

130. The oligonucleotide of claim 128, wherein the 5’-terminal nucleotide has the structure:.

131. The oligonucleotide of claim 128, wherein the 5’-terminal nucleotide has the structure:.

132. The oligonucleotide of claim 130, wherein the 5’-terminal nucleotide has the structure: r.

133. The oligonucleotide of claim 128, wherein the 5’-terminal nucleotide has the structure:.

134. The oligonucleotide of claim 128, wherein the 5’-terminal nucleotide has the structure:.

135. The compound of claim 128, wherein the compound is of formula,136. The oligonucleotide of claim 127, wherein the 5’-terminal nucleotide has the structure:.

137. The oligonucleotide of claim 127, wherein the 5’-terminal nucleotide has the structure:.

138. The compound oligonucleotide of claim 127, wherein the 5’-nucleotide has the structure:.

139. The compound oligonucleotide of claim 127, wherein the 5’-nucleotide has the structure:r.

140. The oligonucleotide of claim 127, wherein the 5’-terminal nucleotide has the structure:, wherein n is 1, 2 or 3.

141. The oligonucleotide of any one of claims 127-140, wherein R3’is -OR30.

142. An oligonucleotide, wherein the oligonucleotide is a compound of any one of claims 50-53 or 74-77.

143. The oligonucleotide of any one of claims 122-142, wherein the oligonucleotide is from 10 to 50 nucleotides (e.g., from 15 to 40 nucleotides) in length, wherein the compound of Formula (I) is one nucleotide.

144. The oligonucleotide of claim 143, wherein the oligonucleotide is 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides in length, optionaly, the oligonucleotide is 17, 18, 19, 21, 22, 23, 24 or 25 nucleotides in length.

145. The oligonucleotide of any one of claims 122-144, wherein the oligonucleotide comprises at least one) nucleic acid modification (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more independently selected modifications).

146. The oligonucleotide of claim 145, wherein the oligonucleotide comprises at least one nucleic acid modification selected from the group consisting of nucleobase modifications, sugar modifications, internucleotide linkage modifications, conjugates (e.g., ligands), and any combinations thereof.

147. The oligonucleotide of any one of claims 122-146, wherein the oligonucleotide comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2’-OMe nucleotides.

148. The oligonucleotide of any one of claims 122-147, wherein the oligonucleotide comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) thermaly destabilizing modification of the duplex.

149. The oligonucleotide of claim 148, wherein said thermaly destabilizing modification of the duplex is located at position 4, 5, 6, 7, or 8, counting from the 5’-end of the oligonucleotide, where the compound of Formula (I) is at position 1 from the 5’-end of the oligonucleotide, optionaly, the thermaly destabilizing modification of the duplex is located at position 6, 7, or 8, counting from the 5’-end of the oligonucleotide, preferably the thermaly destabilizing modification of the duplex is located at position 7, counting from the 5’-end of the oligonucleotide.

150. The oligonucleotide of any one of claims 122-149, wherein the oligonucleotide comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2’-F nucleotides.

151. The oligonucleotide of claim 150, wherein the oligonucleotide comprises a 2’-F nucleotide at least at positions 2, 14 and 16, counting from the 5’-end of the oligonucleotide, where the compound of Formula (I) is at position 1 from the 5’-end of the oligonucleotide, optionaly, the oligonucleotide comprises a 2’-F nucleotide at least at positions 2, 6, 14 and 16, counting from the 5’-end of the oligonucleotide, preferably the oligonucleotide comprises a 2’-F nucleotide at least at positions 2, 6, 9, 14 and 16, or at least at positions 2, 6, 8, 9, 14 and 16, counting from the 5’-end of the oligonucleotide.

152. The compound of any one of claims 122-151, wherein the oligonucleotide comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2’-deoxy (2’-H) nucleotides.

153. The oligonucleotide of claim 152, wherein the oligonucleotide comprises a 2’-deoxy nucleotide at any one of positions 2, 5, 7, 12, 14 and 16, counting from the 5’-end of the oligonucleotide, where the compound of Formula (I) is at position 1 from the 5’-end of the oligonucleotide, optionaly, the oligonucleotide comprises a 2’-deoxy nucleotide at least at position 5, counting from the 5’-end of oligonucleotide, preferably, the oligonucleotide comprises a 2’-deoxy nucleotide at least at positions 2, 5 and 9, or at least at positions 2, 5, 7, and 12, or at least at positions 2, 5, 7, 12, 14, and 16, counting from the 5’-end of the oligonucleotide.

154. The oligonucleotide of any one of claims 122-153, wherein the oligonucleotide comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) non-natural or modified nucleobases.

155. The oligonucleotide of any one of claims 122-154, wherein the oligonucleotide comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) modified internucleoside linkages.

156. The oligonucleotide of claim 122-155, wherein the oligonucleotide comprises a phosphorothioate linkage between nucleotides at positions 1 and 2, and between nucleotides at positions 2 and 3, counting from the 5’-end of the oligonucleotide, where the compound of Formula (I) is at nucleotide position 1 from the 5’-end of the oligonucleotide; and the oligonucleotide comprises a phosphorothioate linkage between nucleotides at positions 1 and 2, and between nucleotides at positions 2 and 3, counting from the 3’-end of the oligonucleotide.

157. The oligonucleotide of any one of claims 122-156, wherein the oligonucleotide is covalently linked to a support, e.g., a solid support.

158. A double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, wherein the sense strand is substantialy complementary to the antisense strand, and wherein one of the sense or the antisense strand is an oligonucleotide of any one of claims 122-157.

159. The dsRNA of claim 158, wherein the antisense strand is the oligonucleotide of any one of claims 119-146.

160. The dsRNA of any one of claims 158-159, wherein the dsRNA is capable of inducing RNA interference.

161. A method of reducing the expression of a target gene in a subject, comprising administering to the subject either: (i) a double-stranded RNA according to any one of claims 158-160, wherein the antisense strand is substantialy complementary to a target gene; or (i) an oligonucleotide according to any one of claims 122-157, wherein the oligonucleotide is substantialy complementary to a target gene.

162. A composition comprising a compound of any one of claims 1-121, an oligonucleotide of any one of claims 122-157, or a dsRNA of any one of claims 158-160.

163. A kit comprising a compound of any one of claims 1-121, an oligonucleotide of any one of claims 122-157, or a dsRNA of any one of claims 158-160.

164. A cel comprising a compound of any one of claims 1-121, an oligonucleotide of any one of claims 122-157, or a dsRNA of any one of claims 158-160.

165. The cel of claim 164, wherein the cel is in in vivo.

166. A compound of the Formula (IV):or a salt thereof, wherein: M is a monocyclic or bicyclic ring (such as C3-8cycloalkyl (e.g., cyclohexyl, cyclopentyl or cyclobutyl) or heterocyclyl (e.g., piperidinyl, piperazinyl, morpholinyl, pyrolidinyl, or tetrahydrothienyl), a 5-membered sugar, or a 6- membered sugar; B is an optionaly modified nucleobase (e.g., uracil); Q4is ethylene, ethenylene, propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2-ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2- methyl)cyclopropyl, (2-methyl)cyclopropylmethyl, 2-propylcyclopropyl, (3- cyclopropyl)propyl, (2-ethyl)cyclopropylmethyl, cyclopropyl, 2-(2- methyl)cyclopropylethyl, 2-methylcyclobutyl, 3-methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q4are optionaly and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q4are both replaced with O or S; one methine in Q4is optionaly replaced with -N=; X is O or S; each RPis independently C1-3alkyl, -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S, wherein:each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RSis independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2Sis C1-3alkyl; one of R2’and R3’is hydrogen, halogen, -OR20, alkyl, branched alkyl, alkyl amine, branched alkyl amine, alkenyl, alkynyl, alkyl ester, S-alkyl, N-alkyl, branched N- alkyl, branched S-alkyl, S-alkenyl, N-alkenyl, branched N-alkenyl, branched S- alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester,, or ,wherein: R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amin, and R20is hydrogen, hydroxyl protecting group, optionaly substituted alkyl (e.g., optionaly substituted C1-6alkyl, (e.g., methyl, 2- methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N-methylamino)-2- oxoethyl, 2-[N,N-dimethyl)aminooxy]ethyl, or 3-oxo-3-(N- methylamino)prop-1-yl), optionaly substituted branched alkyl, optionaly substituted alkenyl (e.g., optionaly substituted C2- 6alkenyl), optionaly substituted branched alkenyl, or optionaly substituted alkynyl (e.g., optionaly substituted C2-6alkynyl (e.g., propargyl)); the other of R2’and R3’is -OR30, wherein R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide.

167. The compound of claim 166, wherein the compound is of Formula (V):or a salt thereof.

168. The compound of claim 167, wherein:R2’is H, OH, alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or alyl), alkynyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, -O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N- dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl), S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N- alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester, wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine; and R3’is -OR30, wherein: R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide.

169. The compound of claim 167, wherein: R3’is alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or alyl), alkynyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., - OMe, -O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N- dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl),S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N- alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester,, wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine; and R2’is -OR30, wherein: R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide.

170. A compound of claim 166, wherein the compound is of Formula (VI):or a salt thereof, wherein: XA is O, S, SO2, CH2, NHRS’or N(CO)RS’, wherein RS’is vinyl, ethynyl, alyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; YA is O, S, SO2, CH2, NHRS’or N(CO)RS’, wherein RS’is vinyl, ethynyl, alyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; and R3’is hydrogen, halogen, or -OR30, wherein: R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide.

171. The compound of claim 170, wherein YA is O, and the compound is of Formula (VI):or a salt thereof.

172. The compound of claim 169, wherein XA is O, and the compound is of Formula (VII) or a salt thereof.

173. The compound of any one of claims 170-172, wherein the compound is of compound of Formula (IX):or a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil); Q4is ethylene, ethenylene, propylene, propenylene, propynylene, methylcyclopropyl, or cyclopropylmethyl, wherein: one or two methylene groups in Q4are optionaly and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q4are both replaced with O or S; one methine in Q4is optionaly replaced with -N=; X is O or S; each RPis independently C1-3alkyl, -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RSis independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2Sis C1-3alkyl; R3’is hydrogen, halogen, or -OR30, wherein: R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide. . The compound of claim 166, wherein the compound is of Formula (X):or a salt thereof, wherein: XA is O, S, SO2, CH2, NHRS’or N(CO)RS’, wherein RS’is vinyl, ethynyl, alyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; R2’is vinyl, ethynyl, alyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amine, alkenyl, alkyl ester, O-alkyl (e.g., -OMe, -O-2-methoxyethyl, -O-[2- (methylamino)-2-oxoethyl], -O-(2-[N,N-dimethyl)aminooxy]ethyl), S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N- alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, or N-alkyl ester; and R3’is hydrogen, halogen, or -OR30, wherein: R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide 175. The compound of claim 174, wherein XA is O.

176. The compound of claim 174 or 175, wherein R2’is H, OH, alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or alyl), alkynyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, -O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N- dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl),S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N- alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, or N-alkyl ester.

177. The compound of claim 166, wherein the compound is of Formula (XI):wherein:XA is O, S SO2CH2, NHRS’or N(CO)RS’, wherein RS’is vinyl, ethynyl, alyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; R2’is H, OH, alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or alyl), alkynyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, -O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N- dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl),S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N- alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester, wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine; and R3’is hydrogen, halogen, or -OR30, wherein: R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide.

178. The compound of claim 177, wherein XA is O.

179. The compound of claim 177 or 178, wherein: R2’alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or alyl), alkynyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, - O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N- dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl), S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N- alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester,, wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine.

180. The compound of claim 166, wherein the compound is of formulae (XI)-(XIV):,or a salet thereof, wherein: XAis O, S SO2CH2, NHRS’or N(CO)RS’, wherein RS’is vinyl, ethynyl, alyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; R2’is H, halogen, alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or alyl), alkynyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, -O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N- dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl), S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N- alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester, wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine; and RAis methyl, vinyl, ethynyl, alyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; R3’is hydrogen, halogen, or -OR30, wherein: R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide.

181. The compound of claim 180, wherein XA is O.

182. The compound of claim 180 or 181, wherein: R2’is F, alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or alyl), alkynyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., - OMe, -O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N- dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl), S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N- alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester,,wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine.

183. The compound of any one of claims 166-182, wherein Q4is, , ,, , w1here * is the bond to the phosphorous atom, and Q is - O-, -S-, or -N(RNQ)-, wherein: RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, optionaly, Q4is, where * is the bond to the phosphorous atom.

184. The compound of any one of claims 166-183, wherein Q4is, , , , , ,, , , , , , , ,, optionaly, optionaly. Q4is, where * is the bond to the phosphorous atom.

185. The compound of any one of claims 166-184, wherein X is O.

186. The compound of any one of claims 166-184, wherein X is S.

187. The compound of any one of claims 166-186, wherein at least one RPis -ORO, optionaly, each RPis independently -ORO.

188. The compound of claim 187, wherein each ROis independently H, methyl, ethyl, propyl, 1-methylethyl, butyl, or tert-butyl, optionaly each ROis independently H, methyl, or ethyl.

189. The compound of claim 188, wherein each ROis independently a hydroxyl protecting group.

190. The compound of claim 189, wherein each ROis independently pivaloyloxymethyl (POM), ethyl, methyl, isopropyl, tert-butyl, trihaloalkyl, benzyl, nitrobenzyl, chlorobenzyl, fluorenyl-9-methyl, 2-cyanoethyl, 2-chlorophenyl, 2,2,2-25-trihalogen-1,1-dimethylethyl, 5-chloroquin-8-yl, 2-methylthioethyl, or 2-methylthioethyl, optionaly each ROis independently POM or ethyl.

191. The compound of any one of claims 166-190, wherein at least one RPis -SRS.

192. The compound of claim 191, wherein each RSis independently H, methyl, ethyl, propyl, or 1-methylethyl, optionaly each RSis independently H, methyl or ethyl.

193. The compound of claim 192, wherein each RSis independently a thiol protecting group.

194. The compound of any one of claims 166-193, wherein at least one RPis -N(RN)2or - N(RN)S(O)2R2S(e.g, -NHSO2CH3.

195. The compound of any one of claims 166-194, whereinis selected from the group consisting of *-P(O)(OH)2, *-P(O)(OMe)2, *-P(O)(OEt)2, *-P(O)(OPOM)2, *- P(O)(OH)OMe, *-P(O)(CH3)OH, or *-P(O)(OH)N(H)SO2CH3, wherein * represents the bond to the remainder of the compound, optionaly,is *-P(O)(OPOM)2, wherein * represents the bond to the remainder of the compound.

196. The compound of any one of claims 166-195, wherein B is a modified or protected nucleobase.

197. The compound of claim 196, wherein B is a protected nucleobase comprising at least one amine or hydroxyl protecting group.

198. The compound of any one of claims 166-197, wherein R3’is -OR30, wherein R30is hydrogen, a hydroxyl protecting group, or a reactive phosphorous group.

199. The compound of claim 198, wherein R30is hydrogen or a hydroxyl protecting group.

200. The compound of claim 199, wherein R30is hydrogen.

201. The compound of claim 200, R30is a hydroxyl protecting group.

202. The compound of claim 201, wherein the hydroxyl protecting group is t-butyldimethylsilyl (TBDMS), trimethylsilyl (TMS), triethylsilyl (TES), trisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), or t-butylmethoxyphenylsilyl (TBMPS), optionaly, the hydroxyl protecting group is TBDMS.

203. The compound of claim 198, wherein R30is a reactive phosphorous group.

204. The compound of claim 203, wherein the reactive phosphorous group is a phosphoramidite, H-phosphonate, alkyl-phosphonate, or phosphate triester.

205. The compound of claim 204, wherein the reactive phosphorous group is -P(ORP)N(RP2)2, -P(SRP)N(RP2)2, -P(O)(ORP)N(RP2)2, -P(S)(ORP)N(RP2)2, -P(RP3)N(RP2)2, -P(O)(SRP)N(RP2)2, -P(O)(ORP)H, -P(S)(ORP)H, -P(O)(SRP)H, -P(O)(ORP)RP3, -P(S)(ORP)RP3, or -P(O)(SRP)RP3, wherein: each RP3is an optionaly substituted C1-C30alkyl, optionaly substituted C2-C30alkenyl, or optionaly substituted C2-C30alkynyl(e.g., optionaly substituted C1-C10alkyl, optionaly substituted C2-C10alkenyl, or optionaly substituted C2-C10alkynyl); each RPis independently an optionaly substituted C1-6alkyl; and each RP2is independently optionaly substituted C1-6alkyl, or both RP2taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; or RPand one of RP2taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl.

206. The compound of claim 205, wherein the reactive phosphorous group is -P(ORP)N(RP2)2.

207. The compound of claim 205 or 206, wherein RPis C1-6alkyl substituted with cyano or - SC(O)Ph.

208. The compound of any one of claims 205-207, wherein RPis –CH2CH2CN.

209. The compound of any one of claims 205-208, wherein each RP2is independently methyl, ethyl, propyl, or isopropyl.

210. The compound of any one of claims 205-209, wherein each RP2is isopropyl.

211. The compound of any one of claims 205-210, wherein RP3is an optionaly substituted C1- C6alkyl, (e.g., methyl).

212. The compound of any one of claims 166-197, wherein R3’is -OR30, wherein R30is a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide.

213. The compound of claim 212, wherein the R30’is a bond to an oligonucleotide.

214. The compound of claim 213, wherein R3’is connected to the oligonucleotide via a phosphodiester or modified internucleotide linkage (e.g., phosphorothioate).

215. The compound of claim 213 or 214, wherein R3’is connected to the 5’-terminal of the oligonucleotide (e.g., 5’-hydroxyl at the 5’-terminal of the oligonucleotide).

216. The compound of claim any one of claims 172 or 182-184, wherein the compound is of Formula (IX): ,or a salt thereof, where: X is O; each RPis independently -OROor is -N(RN)2; and R3’is -OR30, wherein: R30is hydrogen, hydroxyl protecting group, or a reactive phosphorous group.

217. The compound of claim 216, wherein R30is hydrogen or hydroxyl protecting group.

218. The compound of claim 217, wherein R30is a reactive phosphorous group.

219. The compound of claim 218, wherein the reactive phosphorous group is a phosphoramidite, H-phosphonate, alkyl-phosphonate, or phosphate triester.

220. The compound of claim 219, wherein the reactive phosphorous group is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, -P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, - P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, -P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, wherein: each RP3is an optionaly substituted C1-C30alkyl, optionaly substituted C2- C30alkenyl, or optionaly substituted C2-C30alkynyl (e.g., optionaly substituted C1-C10alkyl, optionaly substituted C2-C10alkenyl, or optionaly substituted C2- C10alkynyl); each RP1is independently an optionaly substituted C1-6alkyl; and each RP2is independently optionaly substituted C1-6alkyl, or both RP2taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; or RP1and one of RP2taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl.

221. The compound of claim 220, wherein the reactive phosphorous group is -P(ORP1)N(RP2)2.

222. The compound of claim 220 or 221, wherein RP1is C1-6alkyl substituted with cyano or - SC(O)Ph.

223. The compound of any one of claims 221-222, wherein RP1is –CH2CH2CN.

224. The compound of any one of claims 222-223, wherein each RP2is independently methyl, ethyl, propyl, or isopropyl.

225. The compound of any one of claims 220-224, wherein each RP2is isopropyl.

226. The compound of any one of claims 220-225, wherein the reactive phosphorous group is - P(ORP1)N(RP2)2, where RP1is –CH2CH2CN, and each RP2is isopropyl.

227. The compound of any one of claims 216-226, wherein each ROis independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl 228. The compound of any one of claims 172 or 182-184, wherein the compound is of Formula (IX):or a salt thereof, where: X is O; each RPis -ORO, where each ROis independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, POM, or NHSO2CH3; and R3’is -OR30, wherein: where R30is -P(ORP)N(RP2)2, where RPis –CH2CH2CN, and each RP2is isopropyl.

229. The compound of any one of claims 216-228, whereinis selected from the group consisting of *-P(O)(OH)2, *-P(O)(OMe)2, *-P(O)(OEt)2, *-P(O)(OPOM)2, *- P(O)(OH)OMe, *-P(O)(CH3)OH, or *-P(O)(OH)N(H)SO2CH3, wherein * represents the bond to the remainder of the compound, optionaly,is *-P(O)(OPOM)2, wherein * represents the bond to the remainder of the compound.

230. The compound of any one of claims 172 or 182-184, wherein the compound is of Formula (IX):), or a salt thereof, where: Q is ethenylene; X is O; each RPis independently -OROor is -N(RN)2; and R3’is -OR30, wherein: R30is hydrogen, hydroxyl protecting group, or a reactive phosphorous group.

231. The compound of claim 230, wherein R30is hydrogen or hydroxyl protecting group.

232. The compound of claim 231, wherein R30is a reactive phosphorous group.

233. The compound of claim 232, wherein the reactive phosphorous group is a phosphoramidite, H-phosphonate, alkyl-phosphonate, or phosphate triester.

234. The compound of claim 233, wherein the reactive phosphorous group is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, -P(O)(ORP1)N(RP2)2, -P(S)(ORP1)N(RP2)2, - P(RP3)N(RP2)2, -P(O)(SRP1)N(RP2)2, -P(O)(ORP1)H, -P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, wherein: each RP3is an optionaly substituted C1-C30alkyl, optionaly substituted C2- C30alkenyl, or optionaly substituted C2-C30alkynyl (e.g., optionaly substituted C1-C10alkyl, optionaly substituted C2-C10alkenyl, or optionaly substituted C2- C10alkynyl); each RP1is independently an optionaly substituted C1-6alkyl; and each RP2is independently optionaly substituted C1-6alkyl, or both RP2taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; or RP1and one of RP2taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl.

235. The compound of claim 234, wherein the reactive phosphorous group is -P(ORP1)N(RP2)2.

236. The compound of claim 234 or 235, wherein RP1is C1-6alkyl substituted with cyano or - SC(O)Ph.

237. The compound of any one of claims 234-236, wherein RP1is –CH2CH2CN.

238. The compound of any one of claims 234-237, wherein each RP2is independently methyl, ethyl, propyl, or isopropyl.

239. The compound of any one of claims 234-238, wherein each RP2is isopropyl.

240. The compound of any one of claims 234-239, wherein the reactive phosphorous group is - P(ORP1)N(RP2)2, where RP1is –CH2CH2CN, and each RP2is isopropyl.

241. The compound of any one of claims 234-240, wherein each ROis independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl.

242. The compound of any one of claims 172 or 182-184, wherein:or a salt thereof, where: Q is ethenylene; X is O; each RPis -ORO, where each ROis independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, POM or NHSO2CH3; R3’is R30, where R30is -P(ORP)N(RP2)2, where RPis –CH2CH2CN, and each RP2is isopropyl.

243. The compound of any one of claims 230-242, whereinis selected from the group consisting of *-P(O)(OH)2, *-P(O)(OMe)2, *-P(O)(OEt)2, *-P(O)(OPOM)2, *-P(O)(OH)OMe, *-P(O)(CH3)OH, or *-P(O)(OH)N(H)SO2CH3, wherein * represents the bond to the remainder of the compound.

244. The compound of claim 166, wherein the compound is selected from the group consisting of:

245. An oligonucleotide, wherein the 5’-terminal nucleotide has the structure:or a salt thereof, wherein: M is a monocyclic or bicyclic ring (such as C3-8cycloalkyl (e.g., cyclohexyl, cyclopentyl or cyclobutyl) or heterocyclyl (e.g., piperidinyl, piperazinyl, morpholinyl, pyrolidinyl, or tetrahydrothienyl), a 5-membered sugar, or a 6-membered sugar; B is an optionaly modified nucleobase (e.g., uracil); Q4is ethylene, ethenylene, propylene, propenylene, propynylene, methylcyclopropyl, or cyclopropylmethyl, wherein: one or two methylene groups in Q4are optionaly and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, provided that: no two consecutive methylene groups in Q4are both replaced with O or S; one methine in Q4is optionaly replaced with -N=; X is O or S; each RPis independently C1-3alkyl, -ORO, -SRS, -N(RN) N 2, or -N(R)S(O)2R2S, wherein:each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RSis independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2Sis C1-3alkyl; one of R2’and R3’is hydrogen, halogen, -OR20, absent, alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or alyl), alkynyl (e.g., ethynyl or propargyl), alkyl ester, S-alkyl, N-alkyl, branched N-alkyl, branched S-alkyl, S-alkenyl, N-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester,, wherein: R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amin, and R20is hydrogen, hydroxyl protecting group, optionaly substituted alkyl (e.g., optionaly substituted C1-6alkyl, (e.g., methyl, 2- methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N-methylamino)-2- oxoethyl, 2-[N,N-dimethyl)aminooxy]ethyl, or 3-oxo-3-(N- methylamino)prop-1-yl), optionaly substituted branched alkyl, optionaly substituted alkenyl (e.g., optionaly substituted C2- 6alkenyl), optionaly substituted branched alkenyl, or optionaly substituted alkynyl (e.g., optionaly substituted C2-6alkynyl (e.g., propargyl)); the other of R2’and R3’is -OR30, wherein: R30is a bond to an oligonucleotide (e.g., to an internucleotide linkage that connects to the subsequent nucleotide of the oligonucleotide).

246. The oligonucleotide of claim 245, wherein the 5’-terminal nucleotide has the structure:(Formula V).

247. The oligonucleotide of claim 246, wherein: R2’is alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or alyl), alkynyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., - OMe, -O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N-dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl), S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N- alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester, wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine; and R3’is -OR30, wherein: R30is a bond to an oligonucleotide (e.g., to an internucleotide linkage that connects to the subsequent nucleotide of the oligonucleotide).

248. The compound of claim 246, wherein: R3’is alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or alyl), alkynyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., - OMe, -O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N- dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl), S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N- alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester,, wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine; and R3’is -OR30, wherein: R30is a bond to an oligonucleotide (e.g., to an internucleotide linkage that connects to the subsequent nucleotide of the oligonucleotide).

249. The oligonucleotide of claim 245, wherein the 5’-terminal nucleotide has the structure:wherein: XA is O, S, SO2, CH2, NHRS’or N(CO)RS’, wherein RS’is vinyl, ethynyl, alyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; YA is O, S, SO2, CH2, NHRS’or N(CO)RS’,wherein RS’is vinyl, ethynyl, alyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; and R3’is -OR30, wherein: R30is a bond to an oligonucleotide (e.g., to an internucleotide linkage that connects to the subsequent nucleotide of the oligonucleotide).

250. The oligonucleotide of claim 249, wherein the 5’-terminal nucleotide has the structure:wherein: XA is O, S, SO2, CH2, NHRS’or N(CO)RS’, wherein RS’is vinyl, ethynyl, alyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; and R3’is -OR30, wherein: R30is a bond to an oligonucleotide (e.g., to an internucleotide linkage that connects to the subsequent nucleotide of the oligonucleotide).

251. The oligonucleotide of claim 249, wherein the 5’-terminal nucleotide has the structure:wherein: YA is O, S, SO2, CH2, NHRS’or N(CO)RS’, wherein RS’is vinyl, ethynyl, alyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; and R3’is hydrogen, halogen, or -OR30, wherein: R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide.

252. The oligonucleotide of any one of claims 249-251, wherein the 5’-terminal nucleotide has the structure:wherein: R3’is -OR30, wherein: R30is a bond to an oligonucleotide (e.g., to an internucleotide linkage that connects to the subsequent nucleotide of the oligonucleotide).

253. The oligonucleotide of claim 245, wherein the 5’-terminal nucleotide has the structure:or a salt thereof, wherein: XA is O, S, SO2, CH2, NHRS’or N(CO)RS’, wherein RS’is vinyl, ethynyl, alyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; R2’is H, OH, alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or alyl), alkynyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, -O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N- dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl), S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N- alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester,R3’is hydrogen, halogen, or -OR30, wherein: R30is a bond to an oligonucleotide (e.g., to an internucleotide linkage that connects to the subsequent nucleotide of the oligonucleotide).

254. The oligonucleotide of claim 252, wherein XA is O.

255. The oligonucleotide of claim 252 or 253, wherein:R2’is alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or allyl), alkynyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, - O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -0-(2-[N,N- dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-l-yl)), S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N- alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, or N-alkyl ester.

256. The oligonucleotide of claim 245, wherein the 5 ’-terminal nucleotide has the structure:wherein:XAis O, S SO2CH2, NHRSor N(CO)RS, wherein Rsis vinyl, ethynyl, allyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl arnin, alkenyl, or alkyl ester;Y is H, OH, alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or allyl), alkynyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, -O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -0-(2-[N,N- dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-l-yl)), S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N- alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester,wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine; andR3’is -OR30, wherein:R30is a bond to an oligonucleotide (e.g., to an intemucleotide linkage that connects to the subsequent nucleotide of the oligonucleotide).

257. The oligonucleotide of claim 255, wherein XAis O.

258. The oligonucleotide of claim 244 or 256, wherein:R2’is alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or allyl), alkynyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, -O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N- dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl), S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N- alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester, wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine.

259. The oligonucleotide of claim 245, wherein the 5’-terminal nucleotide is of formulae (XI)- (XIV): rwherein: XA is O, S SO2CH2, NHRS’or N(CO)RS’, wherein RS’is vinyl, ethynyl, alyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; YA is H, halogen, alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or alyl), alkynyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., -OMe, -O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N- dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl), S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N- alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester,, wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine; andRA is methyl, vinyl, ethynyl, alyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; R3’is hydrogen, halogen, or -OR30, wherein R3’is -OR30, wherein: R30is a bond to an oligonucleotide (e.g., to an internucleotide linkage that connects to the subsequent nucleotide of the oligonucleotide).

260. The compound of claim 259, wherein XA is O.

261. The compound of claim 259 or 260, wherein: R2’is F, alkyl (e.g., methyl), branched alkyl, alkyl amine, branched alkyl amine, alkenyl (e.g., vinyl or alyl), alkynyl (e.g., ethynyl or propargyl), alkyl ester, O-alkyl (e.g., - OMe, -O-2-methoxyethyl, -O-[2-(methylamino)-2-oxoethyl], -O-(2-[N,N- dimethyl)aminooxy]ethyl) or 3-oxo-3-(N-methylamino)prop-1-yl), S-alkyl, N-alkyl, branched O-alkyl, branched N-alkyl, branched S-alkyl, O-alkenyl, S-alkenyl, N- alkenyl, branched O-alkenyl, branched N-alkenyl, branched S-alkenyl, O-alkyl ester, S-alkyl ester, N-alkyl ester,, wherein R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amine.

262. The oligonucleotide of any one of claims 245-261, wherein Q4is, , ,,, where * is the bond to the phosphorous atom, and Q1is -O-, -S-, or -N(RNQ)-, wherein:RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl, optionaly, Q4is, where * is the bond to the phosphorous atom.

263. The oligonucleotide of any one of claims 245-261, wherein Q4is ,, , , , , , , , ,, , , ,, optionaly, optionaly. Q4is, where * is the bond to the phosphorous atom.

264. The oligonucleotide of any one of claims 245-263, wherein X is O.

265. The oligonucleotide of any one of claims 245-263, wherein X is S.

266. The oligonucleotide of any one of claims 245-265, wherein at least one RPis -ORO, optionaly, each RPis independently -ORO.

267. The oligonucleotide of claim 266, wherein each ROis independently H, methyl, ethyl, propyl, 1-methylethyl, butyl, or tert-butyl, optionaly each ROis independently H, methyl, or ethyl.

268. The oligonucleotide of claim 267, wherein each ROis independently a hydroxyl protecting group.

269. The oligonucleotide of claim 268, wherein each ROis independently pivaloyloxymethyl (POM), ethyl, methyl, isopropyl, tert-butyl, trihaloalkyl, benzyl, nitrobenzyl, chlorobenzyl, fluorenyl-9-methyl, 2-cyanoethyl, 2-chlorophenyl, 2,2,2-25-trihalogen-1,1-dimethylethyl, 5-chloroquin-8-yl, 2-methylthioethyl, or 2-methylthioethyl, optionaly each ROis independently POM or ethyl.

270. The oligonucleotide of any one of claims 245-269, wherein at least one RPis -SRS.

271. The oligonucleotide of claim 270, wherein each RSis independently H, methyl, ethyl, propyl, or 1-methylethyl, optionaly each RSis independently H, methyl or ethyl.

272. The oligonucleotide of claim 270, wherein each RSis independently a thiol protecting group.

273. The oligonucleotide of any one of claims 245-272, wherein at least one RPis -N(RN)2or - N(RN)S(O)2R2S(e.g, -NHSO2CH3).

274. The oligonucleotide of any one of claims 245-273, whereinis selected from the group consisting of *-P(O)(OH)2, *-P(O)(OMe)2, *-P(O)(OEt)2, *-P(O)(OPOM)2, *- P(O)(OH)OMe, *-P(O)(CH3)OH, or *-P(O)(OH)N(H)SO2CH3, wherein * represents the bond to the remainder of the compound, optionaly,is *-P(O)(OPOM)2, wherein * represents the bond to the remainder of the compound.

275. The oligonucleotide of any one of claims 245-274, wherein B is a modified or protected nucleobase.

276. The oligonucleotide of claim 275, wherein B is a protected nucleobase comprising at least one amine or hydroxyl protecting group.

277. An oligonucleotide, wherein the oligonucleotide is a compound of any one of claims 212- 215 or 245-278.

278. The oligonucleotide of any one of claims 245-277, wherein the oligonucleotide is from 10 to 50 nucleotides (e.g., from 15 to 40 nucleotides) in length, wherein the nucleotide of Formula (IV) (e.g., one of formulae (V)-(XIV) is one nucleotide.

279. The oligonucleotide of claim 278, wherein the oligonucleotide is 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides in length, optionaly, the oligonucleotide is 17, 18, 19, 21, 22, 23, 24 or 25 nucleotides in length.

280. The oligonucleotide of any one of claims 245-279, wherein the oligonucleotide comprises at least one) nucleic acid modification (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more independently selected modifications).

281. The oligonucleotide of claim 280, wherein the oligonucleotide comprises at least one nucleic acid modification selected from the group consisting of nucleobase modifications, sugar modifications, internucleotide linkage modifications, conjugates (e.g., ligands), and any combinations thereof.

282. The oligonucleotide of any one of claims 245-281, wherein the oligonucleotide comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2’-OMe nucleotides.

283. The oligonucleotide of any one of claims 245-282, wherein the oligonucleotide comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) thermaly destabilizing modification of the duplex.

284. The oligonucleotide of claim 283, wherein said thermaly destabilizing modification of the duplex is located at position 4, 5, 6, 7, or 8, counting from the 5’-end of the oligonucleotide, where the nucleotide of Formula (IV) (e.g., one of formulae (V)-(XIV) is at position 1 from the 5’-end of the oligonucleotide, optionaly, the thermaly destabilizing modification of the duplex is located at position 6, 7, or 8, counting from the 5’-end of the oligonucleotide, preferably the thermaly destabilizing modification of the duplex is located at position 7, counting from the 5’-end of the oligonucleotide.

285. The oligonucleotide of any one of claims 245-284, wherein the oligonucleotide comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2’-F nucleotides.

286. The oligonucleotide of claim 284, wherein the oligonucleotide comprises a 2’-F nucleotide at least at positions 2, 14 and 16, counting from the 5’-end of the oligonucleotide, the nucleotide of Formula (IV) (e.g., one of formulae (V)-(XIV) is at position 1 from the 5’- end of the oligonucleotide, optionaly, the oligonucleotide comprises a 2’-F nucleotide at least at positions 2, 6, 14 and 16, counting from the 5’-end of the oligonucleotide, preferably the oligonucleotide comprises a 2’-F nucleotide at least at positions 2, 6, 9, 14 and 16, or at least at positions 2, 6, 8, 9, 14 and 16, counting from the 5’-end of the oligonucleotide.

287. The compound of any one of claims 245-286, wherein the oligonucleotide comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2’-deoxy (2’-H) nucleotides.

288. The oligonucleotide of claim 287, wherein the oligonucleotide comprises a 2’-deoxy nucleotide at any one of positions 2, 5, 7, 12, 14 and 16, counting from the 5’-end of the oligonucleotide, where the nucleotide of Formula (IV) (e.g., one of formulae (V)-(XIV) is at position 1 from the 5’-end of the oligonucleotide, optionaly, the oligonucleotide comprises a 2’-deoxy nucleotide at least at position 5, counting from the 5’-end of oligonucleotide, preferably, the oligonucleotide comprises a 2’-deoxy nucleotide at least at positions 2, 5 and 9, or at least at positions 2, 5, 7, and 12, or at least at positions 2, 5, 7, 12, 14, and 16, counting from the 5’-end of the oligonucleotide.

289. The oligonucleotide of any one of claims 245-288, wherein the oligonucleotide comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) non-natural or modified nucleobases.

290. The oligonucleotide of any one of claims 245-289, wherein the oligonucleotide comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) modified internucleoside linkages.

291. The oligonucleotide of claim 245-289, wherein the oligonucleotide comprises a phosphorothioate linkage between nucleotides at positions 1 and 2, and between nucleotides at positions 2 and 3, counting from the 5’-end of the oligonucleotide, where the nucleotide of Formula (IV) (e.g., one of formulae (V)-(XIV) is at nucleotide position 1 from the 5’-end of the oligonucleotide; and the oligonucleotide comprises a phosphorothioate linkage between nucleotides at positions 1 and 2, and between nucleotides at positions 2 and 3, counting from the 3’-end of the oligonucleotide.

292. The oligonucleotide of any one of claims 245-291, wherein the oligonucleotide is covalently linked to a support, e.g., a solid support.

293. A double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, wherein the sense strand is substantialy complementary to the antisense strand, and wherein one of the sense or the antisense strand is an oligonucleotide of any one of claims 245-292.

294. The dsRNA of claim 293, wherein the antisense strand is the oligonucleotide of any one of claims 245-292.

295. The dsRNA of claim 293 or 294, wherein the dsRNA is capable of inducing RNA interference.

296. A method of reducing the expression of a target gene in a subject, comprising administering to the subject either: (i) a double-stranded RNA according to any one of claims 293-295, wherein the antisense strand is substantialy complementary to a target gene; or (i) an oligonucleotide according to any one of claims 245-292, wherein the oligonucleotide is substantialy complementary to a target gene.

297. A composition comprising a compound of any one of claims 166-244, an oligonucleotide of any one of claims 245-292, or a dsRNA of any one of claims 293-295.

298. A kit comprising a compound of any one of claims 166-244, an oligonucleotide of any one of claims 245-292, or a dsRNA of any one of claims 293-295.

299. A cel comprising a compound of any one of claims 166-244, an oligonucleotide of any one of claims 245-292, or a dsRNA of any one of claims 293-295.

300. The cel of claim 299, wherein the cel is in in vivo.

301. A compound of the Formula (XVII) or Formula (XX): ), or a salt thereof,wherein: n8is an integer selected from 1 - 3 (e.g., 1 or 2); B is an optionaly modified nucleobase (e.g., uracil); Q5is methylene, ethylene, ethenylene, propylene, propenylene, propynylene, methylcyclopropyl, cyclopropylmethyl, 2-ethylcyclopropyl, (2-cyclopropyl)ethyl, methyl-(2-methyl)cyclopropyl, (2-methyl)cyclopropylmethyl, 2- propylcyclopropyl, (3-cyclopropyl)propyl, (2-ethyl)cyclopropylmethyl, cyclopropyl, 2-(2-methyl)cyclopropylethyl, 2-methylcyclobutyl, 3- methylcyclobutyl or cyclobutylmethyl, wherein: one or two methylene groups in Q5are optionaly and independently replaced with -C(O)-, -S(O)2-, -O-, -S-, or -N(RNQ)-, wherein RNQis hydrogen, methyl, C1-3alkoxy, or C1-3acyl,provided that: no two consecutive methylene groups in Q5are both replaced with O or S; one methine in Q5is optionaly replaced with -N=; X is O or S; XA is O, S, SO2, CH2, NHRS’or N(CO)RS’, wherein RS’is vinyl, ethynyl, alyl, propargyl, alkyl, branched alkyl, alkyl amine, branched alkyl amin, alkenyl, or alkyl ester; each RPis independently C1-3alkyl, -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S, wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RSis independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2Sis C1-3alkyl; RPS is C1-3alkyl, -ORO, -N(RN)2, -N(RN)S(O)2R2S, -N(RN)P(O)(ORO)(RPC), or - N=P(ORO)2(RPC), wherein: each ROis independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and RPC is C1-6alkyl (e.g., C1-3alkyl or methyl); and R2Sis C1-3alkyl; R4’is C1-6alkyl (e.g., methyl),r C1-6alkoxy (e.g., methoxy), hydrogen; one of R2’and R3’is hydrogen, halogen, -OR20, alkyl, branched alkyl, aminoC1-6alkyl(e.g., branched aminoC1-6alkyl), C2-6alkenyl, C2-6alkynyl, C1-6alkyl ester, C1-6alkylthio (e.g., branched C1-6alkylthio), C1-6alkylamino (e.g., branched N- C1-6alkylamino), C2-6alkenylthio (e.g., branched C2-6alkenylthio), N- C2- 6alkenylamino (e.g., branched N- C2-6alkenylamino), C2-6alkylthioester, N-C1-6alkylcarbamyl,,wherein: R20is hydrogen, hydroxyl protecting group, optionaly substituted alkyl, (e.g., optionaly substituted C1-6alkyl, (e.g., methyl, 2-methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N-methylamino)-2-oxoethyl, 2-[N,N- dimethyl)aminooxy]ethyl, or 3-oxo-3-(N-methylamino)prop-1-yl), optionaly substituted branched alkyl, optionaly substituted alkenyl(e.g., optionaly substituted C2-6alkenyl,) or optionaly substituted alkynyl, (e.g., optionaly substituted C2-6alkynyl (e.g., propargyl); and R1and R2independently are alkyl, branched alkyl, alkyl ester or alkyl amin, and the other of R2’and R3’is -OR30, wherein R30is hydrogen, a hydroxy protecting group, a reactive phosphorous group (e.g., a phosphoramidite), a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide.

302. The compound of claim 301, where the compound is selected from the group consisting of:

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