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

Docket No.: 051058-000105WOP25’-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 / 660,020 filed June 14, 2024, and U.S. Provisional Application No.63 / 761,405 filed February 21, 2025, the contents of al of which are incorporated herein by reference in their entirety. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submited electronicaly in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on June 11, 2025, is named “ALN-524_ST_26.xml” and is 603,482 bytes in size. TECHNICAL FIELD

[0003] The technology described herein relates generaly 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 Formula (A) or (B):a salt thereof, wherein: h is 1, 2 or 3; B is an optionaly modified nucleobase (e.g., uracil or thymine); Ring G 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; X is O or S; 1Docket No.: 051058-000105WOP2R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R75 and R76 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alkyl, -ORO, -SRS, -N(RN), o N 2S 1-3 2 r -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl P 1-3 , provided no more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0006] In some embodiments, h is 1 or 2. In some embodiments, h is 1. For example, the compound is of Formula A-I:, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); 2Docket No.: 051058-000105WOP2X is O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R75 and R76 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C O S N N 2S 1-3alkyl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, p P 1-3 rovided no more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0007] Some compounds of Formula (A), e.g., of Formula (A-I) can be of Formula (I):a salt thereof, 3Docket No.: 051058-000105WOP2 wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alkyl, -ORO, -SRS, -N N N 2S 1-3 (R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, provided no more than on P 1-3 e R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0008] Some compounds of Formula (A-I) can be of Formula (A-IB):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); 4Docket No.: 051058-000105WOP2 each RP is independently C alkyl, -ORO, -SRS, -N(RN), or -N(RN)S(O 2S 1-3 2 )2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C1-3alkyl, provided no more than one RP is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0009] Some compounds of Formula (A-I) can be of Formula (A-IC):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R75 and R76 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alkyl, O S N N 2S 1-3 -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; 5Docket No.: 051058-000105WOP2 each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, provided no more t P 1-3 han one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0010] Some compounds of Formula (I) can be of Formular a salt thereof. In one embodiment, at least one of R71 and R72 is halogen (e.g., fluoro). In one embodiment, at least one of R71 and R72 is methyl (e.g. both are methyl). In one embodiment, R71 and R72, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0011] Some other compounds of Formula (I) can be of Formula (Ic),or a salt thereof. In one embodiment, at least one of R71 and R72 is halogen (e.g., fluoro). In one embodiment, at least one of R71 and R72 is methyl (e.g. both are methyl). In one embodiment, R71 and R72, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0012] Yet some other compounds of Formula (I) can be of Formula (Id),a salt thereof. 6Docket No.: 051058-000105WOP2

[0013] Yet stil some other compounds of Formula (I) can be of Formula (Ie), f

[0014] In some embodiments, at least one of R71 and R72 is a halogen (e.g., fluoro). For example, R71 is halogen (e.g., fluoro). In another example, R72 is halogen (e.g., fluoro). In some embodiments, both of R71 and R72 are independently a halogen. For example, both of R71 and R72 are fluoro.

[0015] In some embodiments, at least one of R71 and R72 is methyl. In some embodiments, both of R71 and R72 are methyl.

[0016] In some embodiments, X is O. In some other embodiments, X is S.

[0017] In some embodiments, R71 and R72, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl). For example, compounds of Formula (I) can be of Formula (Id)a salt thereof.

[0018] Some compounds of Formula (A-IB) can be of Formula (A-IB-b),a salt thereof. In one embodiment, at least one of R73 and R74 is halogen (e.g., fluoro). In one embodiment, at least one of R73 and R73 is methyl (e.g. both are methyl). In one embodiment, R73 and R74, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl).

[0019] Some other compounds of Formula (A-IB) can be of Formula (A-IB-c),a salt thereof. In one embodiment, at least one of R73 and R74 is halogen (e.g., fluoro). In one embodiment, at least one of R73 and R74 is methyl (e.g. both are methyl). In one embodiment, R73 and R74, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl). 7Docket No.: 051058-000105WOP2

[0020] Some other compounds of Formula (I) can be of Formula (A-IB-d), f

[0021] Some compounds of Formula (A-IC) can be of Formula (A-IC-b),a salt thereof. In one embodiment, at least one of R75 and R76 is halogen (e.g., fluoro). In one embodiment, at least one of R75 and R76 is methyl (e.g. both are methyl). In one embodiment, R75 and R76, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0022] Some other compounds of Formula (A-IC) can be of Formula (A-IC-c),a salt thereof. In one embodiment, at least one of R75 and R76 is halogen (e.g., fluoro). In one embodiment, at least one of R75 and R76 is methyl (e.g. both are methyl). In one embodiment, R75 and R76, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0023] Some other compounds of Formula (A-IC) can be of Formula (A-IC-d),or a salt thereof. Yet some other compounds of Formula (A-IC) can be of Formulaa salt thereof.

[0024] In some compounds of Formula (I), at least one of R71 and R72 is a halogen (e.g., fluoro). For example, R71 is halogen (e.g., fluoro). In another example, R72 is halogen (e.g., fluoro). In some compounds of Formula (I), both of R71 and R72 are independently a halogen. For example, both of R71 and R72 are fluoro. 8Docket No.: 051058-000105WOP2

[0025] In some compounds of Formula (I), at least one of R71 and R72 is methyl. In some embodiments, both of R71 and R72 are methyl.

[0026] In some compounds of Formula (I), R71 and R72, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0027] In some compounds of Formula (A-IB), at least one of R73 and R74 is a halogen (e.g., fluoro). For example, R73 is halogen (e.g., fluoro). In another example, R74 is halogen (e.g., fluoro). In some compounds of Formula (A-IB), both of R73 and R74 are independently a halogen. For example, both of R73 and R74 are fluoro.

[0028] In some compounds of Formula (A-IB), at least one of R73 and R74 is methyl. In some embodiments, both of R73 and R75 are methyl.

[0029] In some compounds of Formula (A-IB), R73 and R74, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0030] In some compounds of Formula (A-IC), at least one of R75 and R76 is a halogen (e.g., fluoro). For example, R75 is halogen (e.g., fluoro). In another example, R76 is halogen (e.g., fluoro). In some compounds of Formula (A-IC), both of R75 and R76 are independently a halogen. For example, both of R75 and R76 are fluoro.

[0031] In some compounds of Formula (A-IC), at least one of R75 and R76 is methyl. In some embodiments, both of R75 and R76 are methyl.

[0032] In some compounds of Formula (A-IC), R73 and R74, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0033] In some embodiments, h is 2. For example, the compound is of Formula A-I:a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73A and R74A are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73A and R74A together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); 9Docket No.: 051058-000105WOP2R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R75 and R76 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alkyl, -ORO, -SRS, -N(RN), or -N(N 2S 1-3 2 R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, provided no mo P 1-3 re than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0034] Some compounds of Formula (A-I) can be for Formula (A-I-a), r

[0035] Some compounds of Formula (A-I) can be of Formula (A-IA): 10Docket No.: 051058-000105WOP2a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C al O S N N 2S 1-3 kyl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, provided no m P 1-3 ore than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0036] Some compounds of Formula (A-I) can be of Formula (A-IB): ,B is an optionaly modified nucleobase (e.g., uracil or thymine); 11Docket No.: 051058-000105WOP2X is O or S; R73A and R74A are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73A and R74A together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C O S N N 2S 1-3alkyl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alk P 1-3 yl, provided no more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0037] Some compounds of Formula (A-I) can be of Formula (A-IC):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alk O S N N 2S 1-3 yl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: 12Docket No.: 051058-000105WOP2 each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C1-3alkyl, provided no more than one RP is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0038] Some compounds of Formula (A-I) can be of Formula (A-ID):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R75 and R76 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alkyl, -ORO, -SRS, -N(RN), or -N(RN)S(O) 2S 1-3 2 2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C P 1-3alkyl, provided no more than one R is C1-3alkyl; 13Docket No.: 051058-000105WOP2 one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0039] Some compound of Formula (A-I) can be of Formula (A-I-a), a,a salt thereof. In one embodiment, at least one of R71 and R72 is halogen (e.g., fluoro). In one embodiment, at least one of R71 and R72 is methyl (e.g. both are methyl). In one embodiment, R71 and R72, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl).

[0041] Some compounds of Formula (A-IA) can be of Formula (A-IA-c),a salt thereof. In one embodiment, at least one of R71 and R72 is halogen (e.g., fluoro). In one embodiment, at least one of R71 and R72 is methyl (e.g. both are methyl). In one embodiment, R71 and R72, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl). 14Docket No.: 051058-000105WOP2

[0042] Some compounds of Formula (A-IB) can be of Formula (A-IB-b),a salt thereof. In one embodiment, at least one of R73A and R74A is halogen (e.g., fluoro). In one embodiment, at least one of R73A and R74A is methyl (e.g. both are methyl). In one embodiment, R73A and R74A, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0043] Some compounds of Formula (A-IB) can be of Formula (A-IB-c),a salt thereof. In one embodiment, at least one of R73A and R74A is halogen (e.g., fluoro). In one embodiment, at least one of R73A and R74A is methyl (e.g. both are methyl). In one embodiment, R73A and R74A, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0044] Some compounds of Formula (A-IC) can be of Formula (A-IB-b),a salt thereof. In one embodiment, at least one of R73 and R74 is halogen (e.g., fluoro). In one embodiment, at least one of R73 and R74 is methyl (e.g. both are methyl). In one embodiment, R73 and R74, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl).

[0045] Some compounds of Formula (A-IC) can be of Formula (A-IC-c),a salt thereof. In one embodiment, at least one of R73 and R74 is halogen (e.g., fluoro). In one embodiment, at least one of R73 and R74 is methyl (e.g. both are methyl). In one embodiment, R73 and R74, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0046] Some compounds of Formula (A-ID) can be of Formula (A-ID-b),a salt thereof. In one embodiment, at least one of R75 and R76 is 15Docket No.: 051058-000105WOP2 halogen (e.g., fluoro). In one embodiment, at least one of R75 and R76 is methyl (e.g. both are methyl). In one embodiment, R75 and R76, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl).

[0047] Some compounds of Formula (A-ID) can be of Formula (A-ID-c), a salt thereof. In one embodim 76 76ent, at least one of R and R is halogen (e.g., fluoro). In one embodiment, at least one of R75 and R75 is methyl (e.g. both are methyl). In one embodiment, R75 and R76, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl).

[0048] Yet some other compounds of Formula (A-I) can be of Formula (A-IE),a salt thereof. Yet stil some other compounds of Formula (A-I) can be of Formulaa salt thereof. Some other compounds of Formula (A-I) can be of Formulaa salt thereof.

[0049] In some compounds of Formula (A-IA), at least one of R71 and R72 is a halogen (e.g., fluoro). For example, R71 is halogen (e.g., fluoro). In another example, R72 is halogen (e.g., fluoro). In some compounds of Formula (A-IA), both of R71 and R72 are independently a halogen. For example, both of R71 and R72 are fluoro.

[0050] In some compounds of Formula (A-IA), at least one of R71 and R72 is methyl. In some embodiments, both of R71 and R72 are methyl.

[0051] In some compounds of Formula (A-IA), R71 and R72, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0052] In some compounds of Formula (A-IB), at least one of R73A and R74A is a halogen (e.g., fluoro). For example, R73A is halogen (e.g., fluoro). In another example, R74A is halogen (e.g., fluoro). In some compounds of Formula (A-IB), both of R73A and R74A are independently a halogen. For example, both of R73A and R74A are fluoro.

[0053] In some compounds of Formula (A-IB), at least one of R73A and R74A is methyl. In some embodiments, both of R73A and R74A are methyl. 16Docket No.: 051058-000105WOP2

[0054] In some compounds of Formula (A-IB), R73A and R74A, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0055] In some compounds of Formula (A-IC), at least one of R73 and R74 is a halogen (e.g., fluoro). For example, R73 is halogen (e.g., fluoro). In another example, R74 is halogen (e.g., fluoro). In some compounds of Formula (A-IC), both of R73 and R74 are independently a halogen. For example, both of R73 and R74 are fluoro.

[0056] In some compounds of Formula (A-IC), at least one of R73 and R74 is methyl. In some embodiments, both of R73 and R74 are methyl.

[0057] In some compounds of Formula (A-IC), R73 and R74, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0058] In some compounds of Formula (A-ID), at least one of R75 and R76 is a halogen (e.g., fluoro). For example, R75 is halogen (e.g., fluoro). In another example, R76 is halogen (e.g., fluoro). In some compounds of Formula (A-ID), both of R75 and R76 are independently a halogen. For example, both of R75 and R76 are fluoro.

[0059] In some compounds of Formula (A-ID), at least one of R75 and R76 is methyl. In some embodiments, both of R75 and R76 are methyl.

[0060] In some compounds of Formula (A-ID), R75 and R76, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0061] In some embodiments, h is 3. For example, the compound is of Formula A-II:a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73A and R74A are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73A and R74A together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73B and R74B are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73B and R74B together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); 17Docket No.: 051058-000105WOP2R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R75 and R76 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alkyl, -ORO, -SRS, -N(RN), or -N(RN 2S 1-3 2 )S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, provided no mor P 1-3 e than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0062] Some compounds of Formula (A-II) can be of Formula (A-II-a),

[0063] Some compounds of Formula (A-II) can be of Formula (A-IIA): 18Docket No.: 051058-000105WOP2, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alkyl, -ORO, -SRS, -N(RN) N 2S 1-3 2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C P 1-3alkyl, provided no more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0064] Some compounds of Formula (A-II) can be of Formula (A-IIB):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; 19Docket No.: 051058-000105WOP2R73B and R74B are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73B and R74B together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alkyl, -ORO S N N 2S 1-3 , -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C1-3alkyl, provided no more than one RP is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0065] Some compounds of Formula (A-II) can be of Formula (A-IIC):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; R73A and R74A are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73A and R74A together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alkyl, -ORO, -SRS, -N(RN), or N 2S 1-3 2 -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; 20Docket No.: 051058-000105WOP2 each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, provided no more than on P 1-3 e R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0066] Some compounds of Formula (A-II) can be of Formula (A-IID):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alk O S N N 2S 1-3 yl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C3alkyl, provided n P 1- o more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is hydrogen, hydroxyl protecting group, optionaly substituted C1-6alkyl, (e.g., methyl, 2-methoxyethyl, 1,3-dimethoxyprop-2-yl, 2-(N- 21Docket No.: 051058-000105WOP2 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 the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0067] Some compounds of Formula (A-II) can be of Formula (A-IIE):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alkyl, -ORO, -SRS, - N N 2S 1-3 N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C P 1-3alkyl, provided no more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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. 22Docket No.: 051058-000105WOP2

[0068] Some compounds of Formula (A-IIA) can be of Formula (A-IIA-b),a salt thereof. In one embodiment, at least one of R71 and R72 is halogen (e.g., fluoro). In one embodiment, at least one of R71 and R72 is methyl (e.g. both are methyl). In one embodiment, R71 and R72, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl).

[0069] Some compounds of Formula (A-IIA) can be of Formula (A-IIA-c),a salt thereof. In one embodiment, at least one of R71 and R72 is halogen (e.g., fluoro). In one embodiment, at least one of R71 and R72 is methyl (e.g. both are methyl). In one embodiment, R71 and R72, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl).

[0070] Some compounds of Formula (A-IIB) can be of Formula (A-IIB-b),a salt thereof. In one embodiment, at least one of R73B and R74B is halogen (e.g., fluoro). In one embodiment, at least one of R73B and R74B is methyl (e.g. both are methyl). In one embodiment, R73B and R74B, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl).

[0071] Some compounds of Formula (A-IIB) can be of Formula (A-IIB-c),a salt thereof. In one embodiment, at least one of R73B and R74B is halogen (e.g., fluoro). In one embodiment, at least one of R73B and R74B is methyl (e.g. both are methyl). In one embodiment, R73B and R74B, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0072] Some compounds of Formula (A-IIC) can be of Formula (A-IIC-b),a salt thereof. In one embodiment, at least one of R73A and R74A is 23Docket No.: 051058-000105WOP2 halogen (e.g., fluoro). In one embodiment, at least one of R73A and R74A is methyl (e.g. both are methyl). In one embodiment, R73A and R74A, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0073] Some compounds of Formula (A-IIC) can be of Formula (A-IIC-c),a salt thereof. In one embodiment, at least one of R73A and R74A is halogen (e.g., fluoro). In one embodiment, at least one of R73A and R74A is methyl (e.g. both are methyl). In one embodiment, R73A and R74A, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0074] Some compounds of Formula (A-IID) can be of Formula (A-IID-b),or a salt thereof. In one embodiment, at least one of R73 and R74 is halogen (e.g., fluoro). In one embodiment, at least one of R73 and R74 is methyl (e.g. both are methyl). In one embodiment, R73 and R74, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl).

[0075] Some compounds of Formula (A-IID) can be of Formula (A-IID-c),or a salt thereof. In one embodiment, at least one of R73 and R74 is halogen (e.g., fluoro). In one embodiment, at least one of R73 and R74 is methyl (e.g. both are methyl). In one embodiment, R73 and R74, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl).

[0076] Some compounds of Formula (A-IIE) can be of Formula (A-IIE-b), a salt thereof. 75 76In one embodiment, at least one of R and R is halogen (e.g., fluoro). In one embodiment, at least one of R75 and R76 is methyl (e.g. both are methyl). In one embodiment, R75 and R76, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl).

[0077] Some compounds of Formula (A-IIE) can be of Formula (A-IIE-c),a salt thereof. In one embodiment, at least one of R75 and R76 is 24Docket No.: 051058-000105WOP2 halogen (e.g., fluoro). In one embodiment, at least one of R75 and R76 is methyl (e.g. both are methyl). In one embodiment, R75 and R76, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl).

[0078] Yet some other compounds of Formula (A-II) can be of Formula (A-IIF),r a salt thereof. Yet stil some other compounds of Formula (A-II) canbe of Formula (A-IIF-a), or a salt thereof. Some other compounds of Formula (A-II) can be of Formula (A-IIF-b),or a salt thereof.

[0079] In some compounds of Formula (A-IIA), at least one of R71 and R72 is a halogen (e.g., fluoro). For example, R71 is halogen (e.g., fluoro). In another example, R72 is halogen (e.g., fluoro). In some compounds of Formula (A-IIA), both of R71 and R72 are independently a halogen. For example, both of R71 and R72 are fluoro.

[0080] In some compounds of Formula (A-IIA), at least one of R71 and R72 is methyl. In some embodiments, both of R71 and R72 are methyl.

[0081] In some compounds of Formula (A-IIA), R71 and R72, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0082] In some compounds of Formula (A-IIB), at least one of R73B and R74B is a halogen (e.g., fluoro). For example, R73B is halogen (e.g., fluoro). In another example, R74B is halogen (e.g., fluoro). In some compounds of Formula (A-IIB), both of R73B and R74B are independently a halogen. For example, both of R73B and R74B are fluoro.

[0083] In some compounds of Formula (A-IIB), at least one of R73B and R74B is methyl. In some embodiments, both of R73B and R74B are methyl.

[0084] In some compounds of Formula (A-IIB), R73B and R74B, together with the carbon they are atached to, form a C3-C6cycloalkyl, e.g., cyclopropyl.

[0085] In some compounds of Formula (A-IIC), at least one of R73A and R74A is a halogen (e.g., fluoro). For example, R73A is halogen (e.g., fluoro). In another example, R74A is halogen (e.g., fluoro). In some compounds of Formula (A-IIC), both of R73A and R74A are independently a halogen. For example, both of R73A and R74A are fluoro.

[0086] In some compounds of Formula (A-IIC), at least one of R73A and R74A is methyl. In some embodiments, both of R73A and R74A are methyl. 25Docket No.: 051058-000105WOP2

[0087] In some compounds of Formula (A-IIC), R73A and R74A, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0088] In some compounds of Formula (A-IID), at least one of R73 and R74 is a halogen (e.g., fluoro). For example, R73 is halogen (e.g., fluoro). In another example, R74 is halogen (e.g., fluoro). In some compounds of Formula (A-IID), both of R73 and R74 are independently a halogen. For example, both of R73 and R74 are fluoro.

[0089] In some compounds of Formula (A-IID), at least one of R73 and R74 is methyl. In some embodiments, both of R73 and R74 are methyl.

[0090] In some compounds of Formula (A-IID), R73 and R74, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0091] In some compounds of Formula (A-IIE), at least one of R75 and R76 is a halogen (e.g., fluoro). For example, R75 is halogen (e.g., fluoro). In another example, R76 is halogen (e.g., fluoro). In some compounds of Formula (A-IIE), both of R75 and R76 are independently a halogen. For example, both of R75 and R76 are fluoro.

[0092] In some compounds of Formula (A-IIE), at least one of R75 and R76 is methyl. In some embodiments, both of R75 and R76 are methyl.

[0093] In some compounds of Formula (A-IIE), R75 and R76, together with the carbon they are atached to, form a C3-C6cycloalkyl, (e.g., cyclopropyl).

[0094] Some compounds of Formula (B), can be of Formula (B-I):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; Ring G 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; X is O or S; 26Docket No.: 051058-000105WOP2R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73A and R74A are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73A and R74A together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R75 and R76 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl) each RP is independently C alkyl, -ORO, -SRS, N N 2S 1-3 -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, provided no mo P 1-3 re than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0095] Some compounds of Formula (B-I), can be of Formula (B-IA):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; 27Docket No.: 051058-000105WOP2Ring G 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; X is O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C O S N N 2S 1-3alkyl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C P 1-3alkyl, provided no more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0096] Some compounds of Formula (B-I) can be of Formula (B-IB):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; 28Docket No.: 051058-000105WOP2Ring G 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; X is O or S; R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C O S N N 2S 1-3alkyl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C P 1-3alkyl, provided no more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0097] Some compounds of Formula (B-I) can be of Formula (B-IC):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; 29Docket No.: 051058-000105WOP2Ring G 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; X is O or S; R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R75 and R76 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C1-3alkyl, -ORO, -SRS, -N(RN)2, or -N(RN)S(O)2R2S, wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, provided no more t P 1-3 han one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0098] Some compounds of Formula (B-I) can be of Formula (B-ID):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; Ring G is a monocyclic or bicyclic ring (such as C3-8cycloalkyl (e.g., cyclohexyl, cyclopentyl or cyclobutyl) or heterocyclyl (e.g., piperidinyl, piperazinyl, 30Docket No.: 051058-000105WOP2 morpholinyl, pyrolidinyl or tetrahydrothienyl), a 5-membered sugar, or a 6- membered sugar; X is O or S; each RP is independently C alkyl, -ORO, -SRS, -N(RN), or -N(RN)S 2S 1-3 2 (O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, P 1-3 provided no more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0099] In some compounds of Formula (B-IA), at least one of R71 and R72 is a halogen (e.g., fluoro). For example, R71 is halogen (e.g., fluoro). In another example, R72 is halogen (e.g., fluoro). In some compounds of Formula (B-IA), both of R71 and R72 are independently a halogen. For example, both of R71 and R72 are fluoro.

[0100] In some compounds of Formula (B-IA), at least one of R71 and R72 is methyl. In some embodiments, both of R71 and R72 are methyl.

[0101] In some compounds of Formula (B-IA), R71 and R72, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0102] In some compounds of Formula (B-IB), at least one of R73 and R74 is a halogen (e.g., fluoro). For example, R73 is halogen (e.g., fluoro). In another example, R74 is halogen (e.g., fluoro). In some compounds of Formula (B-IB), both of R73 and R74 are independently a halogen. For example, both of R73 and R74 are fluoro.

[0103] In some compounds of Formula (B-IB), at least one of R73 and R74 is methyl. In some embodiments, both of R73 and R74 are methyl. 31Docket No.: 051058-000105WOP2

[0104] In some compounds of Formula (B-IB), R73 and R74, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0105] In some compounds of Formula (B-IC), at least one of R75 and R76 is a halogen (e.g., fluoro). For example, R75 is halogen (e.g., fluoro). In another example, R76 is halogen (e.g., fluoro). In some compounds of Formula (B-IC), both of R75 and R76 are independently a halogen. For example, both of R75 and R76 are fluoro.

[0106] In some compounds of Formula (B-IC), at least one of R75 and R76 is methyl. In some embodiments, both of R75 and R76 are methyl.

[0107] In some compounds of Formula (B-IC), R75 and R76, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0108] Some compounds of Formula (B) can be of Formula (B-I):, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; Ring G 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; X is O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73A and R74A are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73A and R74A together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); 32Docket No.: 051058-000105WOP2R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R75 and R76 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C O S N N 2S 1-3alkyl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, p P 1-3 rovided no more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0109] Some compounds of Formula (B) can be of Formula (B-IA):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; Ring G 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; X is O or S; 33Docket No.: 051058-000105WOP2R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C O S N N 2S 1-3alkyl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alky P 1-3 l, provided no more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0110] Some compounds of Formula (B-I) can be of Formula (B-IB):, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; Ring G 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; X is O or S; 34Docket No.: 051058-000105WOP2R73A and R74A are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73A and R74A together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C O S N N 2S 1-3alkyl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl P 1-3 , provided no more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0111] Some compounds of Formula (B-I) can be of Formula (B-IC):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; Ring G 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; X is O or S; 35Docket No.: 051058-000105WOP2R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C O S N N 2S 1-3alkyl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, pr P 1-3 ovided no more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0112] Some compounds of Formula (B-I) can be of Formula (B-ID):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; Ring G 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; X is O or S; 36Docket No.: 051058-000105WOP2R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R75 and R76 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C O S N N 2S 1-3alkyl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, p P 1-3 rovided no more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0113] Some compounds of Formula (B) can be of Formula (B-IE):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; Ring G 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; X is O or S; 37Docket No.: 051058-000105WOP2 each RP is independently C alky O S N N 2S 1-3 l, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, provided no m P 1-3 ore than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0114] In some compounds of Formula (B-IA), at least one of R71 and R72 is a halogen (e.g., fluoro). For example, R71 is halogen (e.g., fluoro). In another example, R72 is halogen (e.g., fluoro). In some compounds of Formula (B-IA), both of R71 and R72 are independently a halogen. For example, both of R71 and R72 are fluoro.

[0115] In some compounds of Formula (B-IA), at least one of R71 and R72 is methyl. In some embodiments, both of R71 and R72 are methyl.

[0116] In some compounds of Formula (B-IA), R71 and R72, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0117] In some compounds of Formula (B-IB), at least one of R73A and R74A is a halogen (e.g., fluoro). For example, R73A is halogen (e.g., fluoro). In another example, R74A is halogen (e.g., fluoro). In some compounds of Formula (B-IB), both of R73A and R74A are independently a halogen. For example, both of R73A and R74A are fluoro.

[0118] In some compounds of Formula (B-IB), at least one of R73A and R74A is methyl. In some embodiments, both of R73A and R74A are methyl.

[0119] In some compounds of Formula (B-IB), R73A and R74A, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl). 38Docket No.: 051058-000105WOP2

[0120] In some compounds of Formula (B-IC), at least one of R73 and R74 is a halogen (e.g., fluoro). For example, R73 is halogen (e.g., fluoro). In another example, R74 is halogen (e.g., fluoro). In some compounds of Formula (B-IC), both of R73 and R74 are independently a halogen. For example, both of R73 and R74 are fluoro.

[0121] In some compounds of Formula (B-IC), at least one of R73 and R74 is methyl. In some embodiments, both of R73 and R74 are methyl.

[0122] In some compounds of Formula (B-IC), R73 and R74, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0123] In some compounds of Formula (B-ID), at least one of R75 and R76 is a halogen (e.g., fluoro). For example, R75 is halogen (e.g., fluoro). In another example, R76 is halogen (e.g., fluoro). In some compounds of Formula (B-ID), both of R75 and R76 are independently a halogen. For example, both of R75 and R76 are fluoro.

[0124] In some compounds of Formula (B-ID), at least one of R75 and R76 is methyl. In some embodiments, both of R75 and R76 are methyl.

[0125] In some compounds of Formula (B-ID), R75 and R76, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0126] In some embodiments, the compound of Formula (B) is of Formula B-II:a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; Ring G 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; X is O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73A and R74A are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73A and R74A together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); 39Docket No.: 051058-000105WOP2R73B and R74B are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73B and R74B together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R75 and R76 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alkyl, -ORO, -SRS N N 2S 1-3 , -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, provided no mo P 1-3 re than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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] Some compounds of Formula (B-II) can be of Formula (B-IIA):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; 40Docket No.: 051058-000105WOP2Ring G 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; X is O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alkyl, -ORO, -SRS, -N(RN), or -N(RN)S(O)R2S 1-3 2 2 , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, provided no mo P 1-3 re than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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] Some compounds of Formula (B-II) can be of Formula (B-IIB):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); Ring G is a monocyclic or bicyclic ring (such as C3-8cycloalkyl (e.g., cyclohexyl, cyclopentyl or cyclobutyl) or heterocyclyl (e.g., piperidinyl, piperazinyl, 41Docket No.: 051058-000105WOP2 morpholinyl, pyrolidinyl or tetrahydrothienyl), a 5-membered sugar, or a 6- membered sugar; X is O or S; R73B and R74B are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73B and R74B together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C O S N N 2S 1-3alkyl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl P 1-3 , provided no more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0129] Some compounds of Formula (B-II) can be of Formula (B-IIC):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; Ring G is a monocyclic or bicyclic ring (such as C3-8cycloalkyl (e.g., cyclohexyl, cyclopentyl or cyclobutyl) or heterocyclyl (e.g., piperidinyl, piperazinyl, 42Docket No.: 051058-000105WOP2 morpholinyl, pyrolidinyl or tetrahydrothienyl), a 5-membered sugar, or a 6- membered sugar; X is O or S; R73A and R74A are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73A and R74A together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alkyl, -ORO, -SS N N 2S 1-3 R, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C-3alkyl, provided n P 1 o more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0130] Some compounds of Formula (B-II) can be of Formula (B-IID):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; Ring G 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; 43Docket No.: 051058-000105WOP2X is O or S; R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C O S N N 2S 1-3alkyl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alk P 1-3 yl, provided no more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0131] Some compounds of Formula (B-II) can be of Formula (B-IIE):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; Ring G 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; X is O or S; 44Docket No.: 051058-000105WOP2R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C O S N N 2S 1-3alkyl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, pr P 1-3 ovided no more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0132] Some compounds of Formula (B-II) can be of Formula (B-IIF):a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; Ring G 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; X is O or S; 45Docket No.: 051058-000105WOP2R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alkyl, -ORO, -SRS, -N(RN), or - N 2S 1-3 2 N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, provide P 1-3 d no more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0133] In some compounds of Formula (B-IIA), at least one of R71 and R72 is a halogen (e.g., fluoro). For example, R71 is halogen (e.g., fluoro). In another example, R72 is halogen (e.g., fluoro). In some compounds of Formula (B-IIA), both of R71 and R72 are independently a halogen. For example, both of R71 and R72 are fluoro.

[0134] In some compounds of Formula (B-IIA), at least one of R71 and R72 is methyl. In some embodiments, both of R71 and R72 are methyl.

[0135] In some compounds of Formula (B-IIA), R71 and R72, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0136] In some compounds of Formula (B-IIB), at least one of R73B and R74B is a halogen (e.g., fluoro). For example, R73B is halogen (e.g., fluoro). In another example, R74B is halogen (e.g., fluoro). In some compounds of Formula (B-IIB), both of R73B and R74B are independently a halogen. For example, both of R73B and R74B are fluoro.

[0137] In some compounds of Formula (B-IIB), at least one of R73B and R74B is methyl. In some embodiments, both of R73B and R74B are methyl. 46Docket No.: 051058-000105WOP2

[0138] In some compounds of Formula (B-IIB), R73B and R74B, together with the carbon they are atached to, form a C3-C6cycloalkyl, e.g., cyclopropyl.

[0139] In some compounds of Formula (B-IIC), at least one of R73A and R74A is a halogen (e.g., fluoro). For example, R73A is halogen (e.g., fluoro). In another example, R74A is halogen (e.g., fluoro). In some compounds of Formula (B-IIC), both of R73A and R74A are independently a halogen. For example, both of R73A and R74A are fluoro.

[0140] In some compounds of Formula (B-IIC), at least one of R73A and R74A is methyl. In some embodiments, both of R73A and R74A are methyl.

[0141] In some compounds of Formula (B-IIC), R73A and R74A, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0142] In some compounds of Formula (B-IID), at least one of R73 and R74 is a halogen (e.g., fluoro). For example, R73 is halogen (e.g., fluoro). In another example, R74 is halogen (e.g., fluoro). In some compounds of Formula (B-IID), both of R73 and R74 are independently a halogen. For example, both of R73 and R74 are fluoro.

[0143] In some compounds of Formula (B-IID), at least one of R73 and R74 is methyl. In some embodiments, both of R73 and R74 are methyl.

[0144] In some compounds of Formula (B-IID), R73 and R74, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0145] In some compounds of Formula (B-IIE), at least one of R75 and R76 is a halogen (e.g., fluoro). For example, R75 is halogen (e.g., fluoro). In another example, R76 is halogen (e.g., fluoro). In some compounds of Formula (B-IIE), both of R75 and R76 are independently a halogen. For example, both of R75 and R76 are fluoro.

[0146] In some compounds of Formula (B-IIE), at least one of R75 and R76 is methyl. In some embodiments, both of R75 and R76 are methyl.

[0147] In some compounds of Formula (B-IIE), R75 and R76, together with the carbon they are atached to, form a C3-C6cycloalkyl, (e.g., cyclopropyl).

[0148] In some compounds of Formula (B), e.g., of formulae B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF, ring G is cycloalkyl. For example, ring G is cyclohexyl, cyclopentyl or cyclobutyl.

[0149] In some other compounds of Formula (B), e.g., of formulae B-I, B-IA – B-ID, B-I, B- IA – B-IE, B-II and B-IIA – B-IIF, ring G is heterocyclyl. For example, ring G is piperidinyl, piperazinyl, morpholinyl, pyrolidinyl or tetrahydrothienyl.

[0150] In compounds of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A-IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF, each RP is independently -ORO, -SRS, -N(RN) N 2S 2, or -N(R)S(O)2R . In some embodiments, at least one 47Docket No.: 051058-000105WOP2RP is -ORO, e.g., each RP is independently -ORO. Each RO can be independently hydrogen, C1-6alkyl (e.g., C alkyl), or a hydroxyl protecting group. For example O 1-3 , each R can be independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, or a hydroxyl protecting group. In some embodiments, each RO is hydrogen, methyl, or ethyl. In some embodiments, each RO is a hydroxyl protecting group, such as pivaloyloxymethyl (CH3)3CC(O)OCH2-, POM).

[0151] In some compounds of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A- IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF, at least one RP is -SRS, e.g., each RP is independently -SRS. Each RS can be independently hydrogen, C1-3alkyl, or a thiol protecting group. For example, each RS can be independently hydrogen, methyl, ethyl, propyl, isopropyl, or a thiol protecting group. In some embodiments, each RS is hydrogen, methyl or ethyl. In some embodiments, each RS is a thiol protecting group.

[0152] In some compounds of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A- IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF, at least one RP is -N(RN) P N N 2, e.g., each R is independently -N(R)2. Each R can be independently hydrogen, C alkyl, or a N 1-3 n amine protecting group. For example, each R can be independently hydrogen, methyl, ethyl, propyl, isopropyl, or an amine protecting group. In some embodiments, each RN is hydrogen, methyl or ethyl. In some embodiments, at least one RN is an amine protecting group.

[0153] In some compounds of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A- IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF, at least one RP is -N(RN)S(O) 2S P N 2S N 2R , e.g., each R is independently -N(R)S(O)2R . R can be hydrogen, C alkyl, or an amine prote N 1-3 cting group. For example, R can be hydrogen, methyl, ethyl, propyl, isopropyl, or an amine protecting group. In some embodiments, RN is hydrogen, methyl or ethyl. In some embodiments, RN is an amine protecting group. R2S can be methyl, ethyl, propyl, or isopropyl. In some embodiments, R2S is methyl or ethyl, e.g., R2S is methyl. In some compounds, RN is hydrogen, methyl, ethyl, propyl, or isopropyl, and R2S is methyl, ethyl, propyl, or isopropyl. In some compounds, RN is an amine protecting group, and R2S is methyl, ethyl, propyl, or isopropyl.

[0154] In some embodiments, one RP is -ORO, and the other RP is -SRS, -N(RN)2, or - N(RN)S(O)R2S. For example, one P O P S P 2 R is -OR, and the other R is -SR. In another example, one R is -ORO, and the other RP is -N(RN). In P O P 2 yet another example, one R is -OR, and the other R is N(RN)S(O) 2S 2R .

[0155] In some other embodiments, one RP is -SRS, and the other RP is -N(RN)2, or - N(RN)S(O)R2S. For example, one RP is -SS P N 2 R, and the other R is -N(R)2. In another example, one RP is -SRS, and the other RP is N(RN)S(O)2R2S.

[0156] In yet some other embodiments, one RP is -N(RN) P N 2S 2, and the other R is -N(R)S(O)2R . 48Docket No.: 051058-000105WOP2

[0157] In yet some other embodiments of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A- IC, A-I, A-IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B- IIA – B-IIF, one RP is -ORO (e.g., methoxy or ethoxy), and the other RP is C1-3alkyl (e.g. methyl).

[0158] In some compounds described herein, R3’ is -OR30. For example, R3’ is -OR30, and R30 is 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 R30 is a reactive phosphorous group selected from phosphoramidite, H-phosphonate, alkyl-phosphonate, and phosphate triester, optionaly R30 is a phosphoramidite. Accordingly, in some compounds, R30 is -P(ORP1)N(RP2), -P(SRP1)N(P2 P1 P2 P1 P2 2 R )2, -P(O)(OR )N(R )2, -P(S)(OR )N(R )2, - P(RP3)N(RP2), -P(O)(SRP1)N(RP2), -P(O)(ORP1)H, -P(S)(ORP1)H, -P(O)(SRP1)H, -P(O) P1 P3 2 2 (OR )R , -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP3 is an optionaly substituted C1-30alkyl, optionaly substituted C2-30alkenyl, or optionaly substituted C2-30alkynyl (e.g., optionaly substituted C1-10alkyl, optionaly substituted C2-10alkenyl, or optionaly substituted C2-10alkynyl); each RP1 is independently an optionaly substituted C1-6alkyl; and each RP2 is independently optionaly substituted C1-6alkyl (e.g., methyl, ethyl, propyl, or isopropyl, such as isopropyl) or both RP2 taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; or RP1 and one of RP2 taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl.

[0159] In some embodiments, R3’ is -OR30, and R30 is -P(ORP1)N(RP2) 3’ 2. For example, R is - OR30, and R30 is -P(ORP1)N(RP2)2, and where RP1 is C1-6alkyl substituted with cyano or -SC(O)Ph. In some embodiments, R3’ is -OR30, and R30 is -P(ORP1)N(RP2) P1 2, and where R is –CH2CH2CN.

[0160] In some embodiments, R3’ is -OR30, and R30 is -P(ORP1)N(RP2) P2 2, and each R is independently methyl, ethyl, propyl, or isopropyl. For example, R3’ is -OR30, and R30 is - P(ORP1)N(RP2)2, and where each RP2 is isopropyl.

[0161] In some prefered embodiments, R3’ is -OR30, and R30 is -P(ORP1)N(RP2), and whe P1 2 re R is C1-6alkyl substituted with cyano or -SC(O)Ph, and each RP2 is independently methyl, ethyl, propyl, or isopropyl. For example, R3’ is -OR30, and R30 is -P(ORP1)N(RP2), and P1 2 where R is –CH2CH2CN, and each RP2 is isopropyl.

[0162] In some embodiments, R3’ is -OR30, and R30 is a phosphoramidite group such as 3'-[(2- cyanoethyl)-(N,N-disopropyl)]-phosphoramidite or 3'-[(ß-thiobenzoylethyl)-(1-pyrolidinyl)]- thiophosphoramidite). 49Docket No.: 051058-000105WOP2

[0163] In another example, R3’ is -OR30, and R30 is hydrogen or a hydroxyl protecting group (e.g., a silyl based hydroxyl protecting group). Some exemplary hydroxyl protecting group for R30 of R3’ include, but are not limited to, 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.

[0164] In yet another example, R3’ is -OR30, and R30 is a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide. For example, R3’ is a bond to an oligonucleotide. When R30 is 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 internucleoside linkage between the compound or nucleoside of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A-IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF and the nucleoside, nucleotide, or oligonucleotide it is linked to can be an unmodified internucleoside linkage (i.e., phosphodiester) or a modified internucleoside linkage (e.g., phosphorothioate, N-mesylphosphoramidate, MMI or imidp, preferably the modified internucleoside linkage is phosphorothioate). Exemplary modified internucleoside linkages are described herein below.

[0165] In some embodiments, R3’ is hydrogen or halogen (e.g., F, Br, Cl or I). For example, R3’ is H or F.

[0166] In some compounds of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A- IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF, R3’ is -OR20, where R20 is optionaly substituted C 3’ 20 20 1-6alkyl. For example, R is -OR , where R is methyl, ethyl, or propyl. In some embodiments, R3’ is -OR20, where R20 is methyl.

[0167] In some compounds of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A- IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF, R3’ is -OR20, where R20 is optionaly substituted C 3’ 20 20 2-6alkenyl. For example, R is -OR , where R is vinyl or alyl. In some compounds of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A- I, A-IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF, R3’ is -OR20, where R20 is optionaly substituted C 3’ 20 2-6alkynyl. For example, R is -OR, where R20 is acetylenyl, propargyl, or 5-hexyn-1-yl.

[0168] In some compounds of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A- IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF, R3’ is -OR20, where R20 is C alkoxyC alkyl. For exam 3’ 20 20 1-6 1-6 ple, R is -OR , where R 2-methoxyethyl. 50Docket No.: 051058-000105WOP2

[0169] Preferably, R3’ is -OR30 and R2’ is hydrogen, halogen, or -OR20. For example, R3’ is - OR30 and R2’ is hydrogen, halogen, or -OR20, and where R30 is a reactive phosphorous group, hydroxyl protecting group, a bond to a nucleoside or nucleotide, or a bond to an oligonucleotide.

[0170] In some embodiments, R2’ is hydrogen or halogen (e.g., F, Br, Cl or I). For example, R2’ is H or F.

[0171] In some compounds of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A- IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF, R2’ is -OR20, where R20 is optionaly substituted C alkyl. In one example 20 1-6 , R is C1-6alkyl substituted with one, two, or three substituents selected independently from the group consisting of halogen, -OR22 -N(R22), -SR22, -C(O)OR22, -C(O)N(R22), wherein 22 , 2 2 R is hydrogen or C1-3alkyl (e.g., 2,2,2-trifluoroethyl, 1,3-dimethoxyprop-2-yl). In another example, R20 is C1-6alkyl substituted with one or two substituents selected independently from the group consisting of halogen, -OR22, - N(R22), -SR22, -C(O)OR22, -C(O)N(R22), w 22 2 2 herein R is hydrogen or C1-3alkyl (e.g., 2,2,2- trifluoroethyl, 1,3-dimethoxyprop-2-yl).

[0172] In another example, R2’ is -OR20, where R20 is methyl, ethyl, or propyl. In some embodiments, R2’ is -OR20, where R20 is methyl.

[0173] In some compounds of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A- IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF, R2’ is -OR20, where R20 is C alkoxyC alkyl. For example, R2’ is -OR20 20 1-6 1-6 , where R is 2- methoxyethyl.

[0174] In some compounds of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A- IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF, R2’ is -OR20, where R20 is N-(C alkyl)aminocarbonylC alkyl. For exa 2’ 20 1-6 1-6 mple, R is -OR , where R20 is 2-(N-methylamino)-2-oxoethyl or 3-oxo-3-(N-methylamino)prop-1-yl.

[0175] In another example, R2’ is -OR30, and R30 is hydrogen or a hydroxyl protecting group (e.g., a silyl based hydroxyl protecting group). Some exemplary hydroxyl protecting group for R30 of R2’ include, but are not limited to, 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.

[0176] In some compounds described herein, R2’ is -OR30. For example, R2’ is -OR30, and R30 is 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 51Docket No.: 051058-000105WOP2-OR30, and R30 is a reactive phosphorous group selected from phosphoramidite, H-phosphonate, alkyl-phosphonate, and phosphate triester, optionaly R30 is a phosphoramidite. Accordingly, in some compounds, R30 is -P(ORP1)N(RP2) P1 P2 P1 P2 P1 P2 2, -P(SR )N(R )2, -P(O)(OR )N(R )2, -P(S)(OR )N(R )2, - P(RP3)N(RP2) P1 P2 P1 P1 P1 P1 P3 2, -P(O)(SR )N(R )2, -P(O)(OR )H, -P(S)(OR )H, -P(O)(SR )H, -P(O)(OR )R , -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP3 is an optionaly substituted C1-30alkyl, optionaly substituted C2-30alkenyl, or optionaly substituted C2-30alkynyl (e.g., optionaly substituted C1-10alkyl, optionaly substituted C2-10alkenyl, or optionaly substituted C2-10alkynyl); each RP1 is independently an optionaly substituted C1-6alkyl; and each RP2 is independently optionaly substituted C1-6alkyl (e.g., methyl, ethyl, propyl, or isopropyl, such as isopropyl) or both RP2 taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; or RP1 and one of RP2 taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl.

[0177] In some embodiments, R2’ is -OR30, and R30 is -P(ORP1)N(RP2). For e 2’ 2 xample, R is - OR30, and R30 is -P(ORP1)N(RP2)2, and where RP1 is C1-6alkyl substituted with cyano or -SC(O)Ph. In some embodiments, R2’ is -OR30, and R30 is -P(ORP1)N(RP2), and whe P1 2 re R is –CH2CH2CN.

[0178] In some embodiments, R2’ is -OR30, and R30 is -P(ORP1)N(RP2) P2 2, and each R is independently methyl, ethyl, propyl, or isopropyl. For example, R2’ is -OR30, and R30 is - P(ORP1)N(RP2), and where eac P2 2 h R is isopropyl.

[0179] In some prefered embodiments, R2’ is -OR30, and R30 is -P(ORP1)N(RP2) P1 2, and where R is C alkyl substituted P2 1-6 with cyano or -SC(O)Ph, and each R is independently methyl, ethyl, propyl, or isopropyl. For example, R2’ is -OR30, and R30 is -P(ORP1)N(RP2) P1 2, and where R is –CH2CH2CN, and each RP2 is isopropyl.

[0180] In some embodiments, R2’ is -OR30, and R30 is a phosphoramidite group such as 2’-[(2- cyanoethyl)-(N,N-disopropyl)]-phosphoramidite or 2’-[(ß-thiobenzoylethyl)-(1-pyrolidinyl)]- thiophosphoramidite).

[0181] In yet another example, R2’ is -OR30, and R30 is an internucleoside bond to a nucleoside or nucleotide, or a bond to an oligonucleotide. For example, R2’ is an internucleoside bond to an oligonucleotide. When R30 is an internucleoside bond to a nucleoside or nucleotide, or an internucleoside 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 internucleoside linkage between the compound or nucleoside of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A-IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B- 52Docket No.: 051058-000105WOP2IE, B-II and B-IIA – B-IIF and the nucleoside, nucleotide, or oligonucleotide it is linked to can be an unmodified internucleoside linkage (i.e., phosphodiester) or a modified internucleoside linkage (e.g., phosphorothioate, N-mesylphosphoramidate, MMI or imidp, preferably the modified internucleoside linkage is phosphorothioate). Exemplary modified internucleoside linkages are described herein below.

[0182] In compounds of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A-IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF, B is an optionaly 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.

[0183] In some compounds of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A- IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF, X is O; each RP is -ORO; R2’ is hydrogen, F, or -OR20, where R20 is hydrogen, optionaly 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 R30 is hydrogen, hydroxyl protecting group, or a reactive phosphorous group.

[0184] In some compounds of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A- IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF, X is O; each RP is -ORO; R2’ is hydrogen, F, or -OR20, where R20 is hydrogen, optionaly 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 R30 is 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), -P(SRP1)N P2 2 (R )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 RP3 is an optionaly substituted C1-30alkyl, optionaly substituted C2- 30alkenyl, or optionaly substituted C2-30alkynyl (e.g., optionaly substituted C1-10alkyl, optionaly substituted C-alkenyl, or optionaly subs P1 210 tituted C2-10alkynyl); each R is independently an optionaly substituted C1-6alkyl (e.g., C1-6alkyl substituted with cyano or -SC(O)Ph, such as 2- cyanoethyl); and each RP2 is independently optionaly substituted C1-6alkyl (e.g., methyl, ethyl, 53Docket No.: 051058-000105WOP2 propyl, or isopropyl, preferably isopropyl), or both RP2 taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; or RP1 and one of RP2 taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl.

[0185] In some compounds of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A- IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF, X is O; each RP is -ORO; R2’ is hydrogen, F, or -OR20, where R20 is hydrogen, optionaly 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 R30 is -P(ORP1)N(RP2)2, and where RP1 is –CH P2 2CH2CN, and each R is isopropyl.

[0186] In some prefered embodiments, X is O; each RP is -ORO, where each RO is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl; R2’ is hydrogen, F, or -OR20, where R20 is 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 R30 is -P(ORP1)N(RP2) P1 2, where R is – CHCHCN, and ea P2 2 2 ch R is isopropyl.

[0187] In some embodiments, the compound is of the formula,or a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl; each RP is independently C O S N N 2S 1-3alkyl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and 54Docket No.: 051058-000105WOP2R2S is C alky P 1-3 l, provided no more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen, or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0188] In some embodiments, the compound is of the formula,; or a salt thereof, wherein RO is C1-6alkyl or a hydroxyl protecting group. In certain embodiments, B is uracil or thymine. In certain embodiments, RO is C1-6alkyl (e.g., methyl or ethyl). In certain embodiments, RO is a hydroxyl protecting group (e.g. pivaloyloxymethyl). In certain embodiments, R30 is hydrogen. In certain embodiments, R30 is a hydroxyl protecting group (e.g., TBS, TMS).

[0189] In some embodiments, the compound is of the formula,; or a salt thereof, wherein RO is C1-6alkyl or a hydroxyl protecting group. In certain embodiments, B is uracil or thymine. In certain embodiments, RO is C1-6alkyl (e.g., methyl or ethyl). In certain embodiments, RO is a hydroxyl protecting group (e.g. pivaloyloxymethyl). 55Docket No.: 051058-000105WOP2

[0190] In some embodiments, the compound is of formula:t thereof, wherein: R20 is C alky 30 1-3 l or C1-3alkoxyC1-3alkyl; and R is hydrogen, a hydroxyl protecting group or a reactive phosphorous group. In some embodiments, R20 is methyl and R30 is a reactive phosphorous group (e.g., -P(ORP1)N(RP2)2, where RP1 –CH2CH2CN, and each RP2 is isopropyl). In some embodiments R20 is 2-methoxyethyl and R30 is a reactive phosphorous group (e.g., -P(ORP1)N(RP2)2, where RP1 –CHCHCN, and each RP2 is isopropyl). In some embodiment 20 30 2 2 s, R is methyl and R is a hydroxyl protecting group (e.g., t-butyldimethylsilyl) or hydrogen. In some embodiments, R20 is 2-methoxyethyl and R30 is a hydroxyl protecting group (e.g., t-butyldimethylsilyl) or hydrogen. In some embodiments, X is O and each RP is -ORO, where each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl (e.g., ethyl). In some embodiments, B is uracil or thymine (e.g., uracil).

[0191] In some embodiments, the compound is of formula:t thereof, wherein: R20 is methyl; R30 is a reactive phosphorous group; X is O; and each RP is -ORO. In certain embodiments, the reactive phosphorous group is -P(ORP1)N(RP2)2, where RP1 –CH2CH2CN, and each RP2 is isopropyl. In certain embodiments, each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0192] In some embodiments, the compound is of formula:t thereof, wherein: R20 is 2-methoxyethyl; R30 is a reactive phosphorous group; X is O; and each RP is -ORO. In certain embodiments, the reactive phosphorous group is -P(ORP1)N(RP2) P1 2, where R – CHC P2 O 2 H2CN, and each R is isopropyl. In certain embodiments, each R is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil). 56Docket No.: 051058-000105WOP2

[0193] In some embodiments, the compound is of formula:t thereof, wherein: R20 is methyl; R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl protecting group. In some prefered embodiments, R30 is t-butyldimethylsilyl. In certain embodiments, each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0194] In some embodiments, the compound is of formula:a salt thereof, wherein: R20 is 2-methoxyethyl; R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl group. In some prefered embodiments, R30 is t-butyldimethylsilyl. In certain embodiments, each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0195] In some embodiments, the compound is of formula:a salt thereof, wherein: R20 is C alkyl or C a 30 1-3 1-3lkoxyC1-3alkyl; and R is hydrogen, a hydroxyl protecting group or a reactive phosphorous group. In some embodiments, R20 is methyl and R30 is a reactive phosphorous group (e.g., -P(ORP1)N(RP2)2, where RP1 –CH2CH2CN, and each RP2 is isopropyl). In some embodiments R20 is 2-methoxyethyl and R30 is a reactive phosphorous group (e.g., -P(ORP1)N(RP2)2, where RP1 –CH P2 20 30 2CH2CN, and each R is isopropyl). In some embodiments, R is methyl and R is a hydroxyl protecting group (e.g., t-butyldimethylsilyl) or hydrogen. In some embodiments, R20 is 2-methoxyethyl and R30 is a hydroxyl protecting group (e.g., t-butyldimethylsilyl) or hydrogen. In some embodiments, X is O and each RP is -ORO, where each RO is independently methyl, ethyl, 57Docket No.: 051058-000105WOP2 propyl, isopropyl, butyl, or tert-butyl (e.g., ethyl). In some embodiments, B is uracil or thymine (e.g., uracil).

[0196] In some embodiments, the compound is of formula:t thereof, wherein: R20 is methyl; R30 is a reactive phosphorous group; X is O; and each RP is -ORO. In certain embodiments, the reactive phosphorous group is -P(ORP1)N(RP2) P1 2, where R –CH2CH2CN, and each RP2 is isopropyl. In certain embodiments, each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0197] In some embodiments, the compound is of formula:t thereof, wherein: R20 is 2-methoxyethyl; R30 is a reactive phosphorous group; X is O; and each RP is -ORO. In certain embodiments, the reactive phosphorous group is -P(ORP1)N(RP2) P1 2, where R – CHCHCN, and each RP2 is isopropyl. I O 2 2 n certain embodiments, each R is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0198] In some embodiments, the compound is of formula:a salt thereof, wherein: R20 is methyl; R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl protecting group. In some prefered embodiments, R30 is t-butyldimethylsilyl. In certain embodiments, each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil). 58Docket No.: 051058-000105WOP2

[0199] In some embodiments, the compound is of formula:t thereof, wherein: R20 is 2-methoxyethyl; R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl group. In some prefered embodiments, R30 is t-butyldimethylsilyl. In certain embodiments, each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0200] In some embodiments, the compound is of the formula,, or a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alkyl, -ORO, -SRS, N N 2S 1-3 -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C3alkyl, provided no P 1- more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen, or -OR20, wherein: R20 is 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); and 59Docket No.: 051058-000105WOP2 the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0201] In some embodiments, the compound is of the formula,, or a salt thereof, wherein RO is C1-6alkyl or a hydroxyl protecting group. In certain embodiments, B is uracil or thymine. In certain embodiments, RO is C1-6alkyl (e.g., methyl or ethyl). In certain embodiments, RO is a hydroxyl protecting group (e.g. pivaloyloxymethyl). In certain embodiments, R30 is hydrogen. In certain embodiments, R30 is a hydroxyl protecting group (e.g., TBS, TMS).

[0202] In some embodiments, the compound is of the formula,, or a salt thereof, wherein RO is C1-6alkyl or a hydroxyl protecting group. In certain embodiments, B is uracil or thymine. In certain embodiments, RO is C1-6alkyl (e.g., methyl or ethyl). In certain embodiments, RO is a hydroxyl protecting group (e.g. pivaloyloxymethyl).

[0203] In some embodiments, the compound is of the formula,, or a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, methyl, or R75 and R76 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alkyl, -ORO, -SRS, -N(RN), or -N(RN)S(O)R2S 1-3 2 2 , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; 60Docket No.: 051058-000105WOP2 each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, provid P 1-3 ed no more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen, or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0204] In some embodiments, the compound is of the formula,, or a salt thereof, wherein RO is C1-6alkyl or a hydroxyl protecting group. In certain embodiments, B is uracil or thymine. In certain embodiments, RO is C1-6alkyl (e.g., methyl or ethyl). In certain embodiments, RO is a hydroxyl protecting group (e.g. pivaloyloxymethyl). In certain embodiments, R30 is hydrogen. In certain embodiments, R30 is a hydroxyl protecting group (e.g., TBS, TMS).

[0205] In some embodiments, the compound is of the formula,, or a salt thereof, wherein RO is C1-6alkyl or a hydroxyl protecting group. In certain embodiments, B is uracil or thymine. In certain embodiments, RO is C1-6alkyl (e.g., methyl or ethyl). In certain embodiments, RO is a hydroxyl protecting group (e.g. pivaloyloxymethyl).

[0206] In some embodiments, the compound is of the formula, 61Docket No.: 051058-000105WOP2 , , rB is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73A and R74A are independently hydrogen, halogen (e.g., fluoro), or methyl, methyl, or R73A and R74A together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, methyl, or R75 and R76 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C O S N N 2S 1-3alkyl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; 62Docket No.: 051058-000105WOP2 each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C1-3alkyl, provided no more than one RP is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen, or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0207] In some embodiments, the compound is of the formula, , ,a salt thereof, wherein RO is C1-6alkyl or a hydroxyl protecting group. In certain embodiments, B is uracil or thymine. In certain embodiments, RO is C1-6alkyl (e.g., methyl or ethyl). In certain embodiments, RO is a hydroxyl protecting group (e.g. pivaloyloxymethyl). In certain embodiments, R30 is hydrogen. In certain embodiments, R30 is a hydroxyl protecting group (e.g., TBS, TMS).

[0208] In some embodiments, the compound is of the formula, 63Docket No.: 051058-000105WOP2 , , r, or a salt thereof, wherein RO is C1-6alkyl or a hydroxyl protecting group. In certain embodiments, B is uracil or thymine. In certain embodiments, RO is C1-6alkyl (e.g., methyl or ethyl). In certain embodiments, RO is a hydroxyl protecting group (e.g. pivaloyloxymethyl).

[0209] In some embodiments, the compound is of the formula, ,, 64Docket No.: 051058-000105WOP2 ,B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, methyl, or R71and R2 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73B and R74B are independently hydrogen, halogen (e.g., fluoro), or methyl, methyl, or R73B and R74B together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73A and R74A are independently hydrogen, halogen (e.g., fluoro), or methyl, methyl, or R73A and R74A together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, methyl, or R75 and R76 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alkyl, -ORO, -SRS, - N N 2S 1-3 N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, provi P 1-3 ded no more than one R is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen, or -OR20, wherein: 65Docket No.: 051058-000105WOP2 R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

[0210] In some embodiments, the compound is of the formula, , ,s C1-6alkyl or a hydroxyl protecting group. In certain embodiments, B is uracil or thymine. In certain embodiments, RO is C alkyl (e.g., methyl or ethyl). In cer O 1-6 tain embodiments, R is a hydroxyl protecting group (e.g. pivaloyloxymethyl). In certain embodiments, R30 is hydrogen. In certain embodiments, R30 is a hydroxyl protecting group (e.g., TBS, TMS).

[0211] In some embodiments, the compound is of the formula, 66Docket No.: 051058-000105WOP2 , , ,is C1-6alkyl or a hydroxyl protecting group. In certain embodiments, B is uracil or thymine. In certain embodiments, RO is C alkyl (e.g., methyl or ethyl). In certain em O 1-6 bodiments, R is a hydroxyl protecting group (e.g. pivaloyloxymethyl).

[0212] In some embodiments, the compound is of formula:a salt thereof, wherein: R20 is C1-3alkyl or C1-3alkoxyC1-3alkyl; and R30 is hydrogen, a hydroxyl protecting group or a reactive phosphorous group. In some embodiments, R20 is methyl and R30 is a reactive phosphorous group (e.g., -P(ORP1)N(RP2), where RP1 –CHCHCN, and each P2 2 2 2 R is isopropyl). In some embodiments R20 is 2-methoxyethyl and R30 is a reactive phosphorous group (e.g., - P(ORP1)N(RP2), where RP1 –CHCHCN, and P2 20 2 2 2 each R is isopropyl). In some embodiments, R is 67Docket No.: 051058-000105WOP2 methyl and R30 is a hydroxyl protecting group (e.g., t-butyldimethylsilyl) or hydrogen. In some embodiments, R20 is 2-methoxyethyl and R30 is a hydroxyl protecting group (e.g., t- butyldimethylsilyl) or hydrogen. In some embodiments, X is O and each RP is -ORO, where each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl (e.g., ethyl). In some embodiments, B is uracil or thymine (e.g., uracil).

[0213] In some embodiments, the compound is of formula:or a salt thereof, wherein: R20 is methyl; R30 is a reactive phosphorous group; X is O; and each RP is -ORO. In certain embodiments, the reactive phosphorous group is -P(ORP1)N(RP2) P1 2, where R – CHCH2CN, and each RP2 is isopropyl. I O 2 n certain embodiments, each R is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0214] In some embodiments, the compound is of formula:or a salt thereof, wherein: R20 is 2-methoxyethyl; R30 is a reactive phosphorous group; X is O; and each RP is -ORO. In certain embodiments, the reactive phosphorous group is -P(ORP1)N(RP2) P1 2, where R – CHCHCN, and each RP2 is isopropyl. I O 2 2 n certain embodiments, each R is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0215] In some embodiments, the compound is of formula:or a salt thereof, wherein: R20 is methyl; R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl protecting group. In some prefered embodiments, R30 is t-butyldimethylsilyl. In certain embodiments, each RO is independently methyl, 68Docket No.: 051058-000105WOP2 ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0216] In some embodiments, the compound is of formula:or a salt thereof, wherein: R20 is 2-methoxyethyl; R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl group. In some prefered embodiments, R30 is t-butyldimethylsilyl. In certain embodiments, each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0217] In some embodiments, the compound is of formula:or a salt thereof, wherein: R20 is C alkyl or C 30 1-3 1-3alkoxyC1-3alkyl; and R is hydrogen, a hydroxyl protecting group or a reactive phosphorous group. In some embodiments, R20 is methyl and R30 is a reactive phosphorous group (e.g., -P(ORP1)N(RP2) P1 P2 2, where R –CH2CH2CN, and each R is isopropyl). In some embodiments R20 is 2-methoxyethyl and R30 is a reactive phosphorous group (e.g., - P(ORP1)N(RP2), where RP1 –CHCHCN, and each RP2 is isopropyl). In some embod 20 2 2 2 iments, R is methyl and R30 is a hydroxyl protecting group (e.g., t-butyldimethylsilyl) or hydrogen. In some embodiments, R20 is 2-methoxyethyl and R30 is a hydroxyl protecting group (e.g., t- butyldimethylsilyl) or hydrogen. In some embodiments, X is O and each RP is -ORO, where each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl (e.g., ethyl). In some embodiments, B is uracil or thymine (e.g., uracil).

[0218] In some embodiments, the compound is of formula:or a salt thereof, wherein: R20 is methyl; R30 is a reactive phosphorous group; X is O; and each RP is -ORO. 69Docket No.: 051058-000105WOP2In certain embodiments, the reactive phosphorous group is -P(ORP1)N(RP2), whe P1 2 re R – CHCHCN, and each RP2 is isopropyl. In certain embod O 2 2 iments, each R is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0219] In some embodiments, the compound is of formula:or a salt thereof, wherein: R20 is 2-methoxyethyl; R30 is a reactive phosphorous group; X is O; and each RP is -ORO. In certain embodiments, the reactive phosphorous group is -P(ORP1)N(RP2) P1 2, where R – CHCHCN, and each RP2 is isopropyl. In certain embodiment O 2 2 s, each R is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0220] In some embodiments, the compound is of formula:or a salt thereof, wherein: R20 is methyl; R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl protecting group. In some prefered embodiments, R30 is t-butyldimethylsilyl. In certain embodiments, each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0221] In some embodiments, the compound is of formula:or a salt thereof, wherein: R20 is 2-methoxyethyl; R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl group. In some prefered embodiments, R30 is t-butyldimethylsilyl. In certain embodiments, each RO is independently methyl, 70Docket No.: 051058-000105WOP2 ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0222] In some embodiments, the compound is of formula:a salt thereof, wherein: R20 is C alkyl or C alkoxyC alkyl; a 30 1-3 1-3 1-3 nd R is hydrogen, a hydroxyl protecting group or a reactive phosphorous group. In some embodiments, R20 is methyl and R30 is a reactive phosphorous group (e.g., -P(ORP1)N(RP2), where RP1 –CHCHCN P2 2 2 2 , and each R is isopropyl). In some embodiments R20 is 2-methoxyethyl and R30 is a reactive phosphorous group (e.g., - P(ORP1)N(RP2), where RP1 –CHCHCN, and each RP2 is isopropyl). In some embodiments, R20 2 2 2 is methyl and R30 is a hydroxyl protecting group (e.g., t-butyldimethylsilyl) or hydrogen. In some embodiments, R20 is 2-methoxyethyl and R30 is a hydroxyl protecting group (e.g., t- butyldimethylsilyl) or hydrogen. In some embodiments, X is O and each RP is -ORO, where each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl (e.g., ethyl). In some embodiments, B is uracil or thymine (e.g., uracil).

[0223] In some embodiments, the compound is of formula:a salt thereof, wherein: R20 is methyl; R30 is a reactive phosphorous group; X is O; and each RP is -ORO. In certain embodiments, the reactive phosphorous group is -P(ORP1)N(RP2) P1 2, where R – CHCHCN, and each RP2 is isopropyl. In certain em O 2 2 bodiments, each R is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil). 71Docket No.: 051058-000105WOP2

[0224] In some embodiments, the compound is of formula:t thereof, wherein: R20 is 2-methoxyethyl; R30 is a reactive phosphorous group; X is O; and each RP is -ORO. In certain embodiments, the reactive phosphorous group is -P(ORP1)N(RP2) P1 2, where R – CHCHCN, and each RP2 is i O 2 2 sopropyl. In certain embodiments, each R is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0225] In some embodiments, the compound is of formula:or a salt thereof, wherein: R20 is methyl; R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl protecting group. In some prefered embodiments, R30 is t-butyldimethylsilyl. In certain embodiments, each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0226] In some embodiments, the compound is of formula:a salt thereof, wherein: R20 is 2-methoxyethyl; R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl group. In some prefered embodiments, R30 is t-butyldimethylsilyl. In certain embodiments, each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil). 72Docket No.: 051058-000105WOP2

[0227] In some embodiments, the compound is of formula:or a salt thereof, wherein: R20 is C 30 1-3alkyl or C1-3alkoxyC1-3alkyl; and R is hydrogen, a hydroxyl protecting group or a reactive phosphorous group. In some embodiments, R20 is methyl and R30 is a reactive phosphorous group (e.g., -P(ORP1)N(RP2) P1 P2 2, where R –CH2CH2CN, and each R is isopropyl). In some embodiments R20 is 2-methoxyethyl and R30 is a reactive phosphorous group (e.g., - P(ORP1)N(RP2), where RP1 –CHCHCN, and each RP2 is isopropyl). In som 20 2 2 2 e embodiments, R is methyl and R30 is a hydroxyl protecting group (e.g., t-butyldimethylsilyl) or hydrogen. In some embodiments, R20 is 2-methoxyethyl and R30 is a hydroxyl protecting group (e.g., t- butyldimethylsilyl) or hydrogen. In some embodiments, X is O and each RP is -ORO, where each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl (e.g., ethyl). In some embodiments, B is uracil or thymine (e.g., uracil).

[0228] In some embodiments, the compound is of formula:or a salt thereof, wherein: R20 is methyl; R30 is a reactive phosphorous group; X is O; and each RP is -ORO. In certain embodiments, the reactive phosphorous group is -P(ORP1)N(RP2) P1 2, where R – CH2CH2CN, and each RP2 is isopropyl. In certain embodiments, each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0229] In some embodiments, the compound is of formula:or a salt thereof, wherein: R20 is 2-methoxyethyl; R30 is a reactive phosphorous group; X is O; and each RP is -ORO. In certain embodiments, the reactive phosphorous group is -P(ORP1)N(RP2) P1 2, where R – 73Docket No.: 051058-000105WOP2CHCHCN, and each RP2 is isopropyl. In certain embodiments, O 2 2 each R is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0230] In some embodiments, the compound is of formula:t thereof, wherein: R20 is methyl; R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl protecting group. In some prefered embodiments, R30 is t-butyldimethylsilyl. In certain embodiments, each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0231] In some embodiments, the compound is of formula:t thereof, wherein: R20 is 2-methoxyethyl; R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl group. In some prefered embodiments, R30 is t-butyldimethylsilyl. In certain embodiments, each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil). ,is -OR20; R3’ is -OR30; R20 is C alkyl or C alkoxyC a 30 1-3 1-3 1-3lkyl; and R is hydrogen, a hydroxyl 74Docket No.: 051058-000105WOP2 protecting group or a reactive phosphorous group. In some embodiments, R20 is methyl and R30 is a reactive phosphorous group (e.g., -P(ORP1)N(RP2) P1 P2 2, where R –CH2CH2CN, and each R is isopropyl). In some embodiments R20 is 2-methoxyethyl and R30 is a reactive phosphorous group (e.g., -P(ORP1)N(RP2) P1 P2 2, where R –CH2CH2CN, and each R is isopropyl). In some embodiments, R20 is methyl and R30 is a hydroxyl protecting group (e.g., t-butyldimethylsilyl) or hydrogen. In some embodiments, R20 is 2-methoxyethyl and R30 is a hydroxyl protecting group (e.g., t- butyldimethylsilyl) or hydrogen. In some embodiments, X is O and each RP is -ORO, where each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl (e.g., ethyl). In some embodiments, B is uracil or thymine (e.g., uracil)., s .CH P2 O 2CH2CN, and each R is isopropyl. In certain embodiments, each R is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil)., sCH2CH2CN, and each RP2 is isopropyl. In certain embodiments, each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil). 75Docket No.: 051058-000105WOP2 ,s -OR20; R3’ is -OR30; R20 is methyl; R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl protecting group. In some prefered embodiments, R30 is t-butyldimethylsilyl. In certain embodiments, each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil). ,s -OR20; R3’ is -OR30; R20 is 2-methoxyethyl; R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl protecting group or hydrogen; X is O; and each RP is -ORO. In certain embodiments, R30 is a hydroxyl group. In some prefered embodiments, R30 is t-butyldimethylsilyl. In certain embodiments, each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some prefered embodiments, each RO is ethyl. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0237] In some embodiments, the compound is of the formula, 76Docket No.: 051058-000105WOP2or a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X and Y are independently O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl; each RP is independently C O S N N 2S 1-3alkyl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C P 1-3alkyl, provided no more than one R is C1-3alkyl; R2’is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and 77Docket No.: 051058-000105WOP2represents the remainder of an oligonucleotide (e.g., the antisense strand of a double-stranded RNA). In the preceding, the oxygen atom that isilustrated linking the 5’- end of the oligonucleotide to the phosphorous atom is the 5’-oxygen of the 5’-terminal nucleoside of the oligonucleotide.

[0238] In some embodiments, Y is S. In other embodiments, Y is O.

[0239] 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).

[0240] In some embodiments, the compound is of the formula,or a salt thereof, wherein: RO is C1-6alkyl or a hydroxyl protecting group. In certain embodiments, B is uracil or thymine. In certain embodiments, RO is C alkyl (e.g., meth O 1-6 yl or ethyl). In certain embodiments, R is a hydroxyl protecting group (e.g. pivaloyloxymethyl). In some embodiments, Y is S. In other embodiments, Y is O.

[0241] In some embodiments, the compound is of the formula, 78Docket No.: 051058-000105WOP2, 79Docket No.: 051058-000105WOP2 ,80Docket No.: 051058-000105WOP2 :der of an oligonucleotide (e.g., the antisense strand of a double-stranded RNA); B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; Ring G 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; X is O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro) or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73B and R74B are independently hydrogen, halogen (e.g., fluoro) or methyl, or R73B and R74B together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73A and R74A are independently hydrogen, halogen (e.g., fluoro) or methyl, or R73A and R74A together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73 and R74 are independently hydrogen, halogen (e.g., fluoro) or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R75 and R76 are independently hydrogen, halogen (e.g., fluoro) or methyl, or R75 and R76 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alkyl, -ORO, -SRS, -N(RN), or -N(RN)S(O 2S 1-3 2 )2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; 81Docket No.: 051058-000105WOP2 each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C1-3alkyl, provided no more than one RP is C1-3alkyl; R2’is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and

[0242] In the preceding, the oxygen atom that is ilustrated linking the 5’-end of the oligonucleotide to the phosphorous atom is the 5’-oxygen of the 5’-terminal nucleoside of the oligonucleotide.

[0243] In some embodiments, Y is S. In other embodiments, Y is O.

[0244] Herein,s 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).

[0245] In some embodiments, X is O, each RP is -ORPO, and R3’ is -OR30, where R30 is 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,, 82Docket No.: 051058-000105WOP2 ,83Docket No.: 051058-000105WOP2 ,or a salt thereof, wherein:, wherein: Y is O or S; and 84Docket No.: 051058-000105WOP2represents the remainder of an oligonucleotide (e.g., the antisense strand of a double-stranded RNA); each RP is -ORO, wherein: each RO is independently C1-6alkyl, or a hydroxyl protecting group; X is O; and Ring G 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; X is O or S; B is an optionaly modified nucleobase (e.g., uracil or thymine); R2’ is hydrogen, halogen, or -OR20, wherein: R20 is 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). In certain embodiments, B is uracil or thymine. In certain embodiments, RO is C1-6alkyl (e.g., methyl or ethyl). In certain embodiments, RO is a hydroxyl protecting group (e.g. pivaloyloxymethyl). In some embodiments, Y is S. In other embodiments, Y is O.

[0246] In some embodiments, the compound is selected from the group of compounds shown in Table A1 and A2: Table A1: Some exemplary compounds85Docket No.: 051058-000105WOP286Docket No.: 051058-000105WOP287Docket No.: 051058-000105WOP288Docket No.: 051058-000105WOP289Docket No.: 051058-000105WOP290Docket No.: 051058-000105WOP291Docket No.: 051058-000105WOP2Table A2: Some exemplary compounds92Docket No.: 051058-000105WOP293Docket No.: 051058-000105WOP294Docket No.: 051058-000105WOP2

[0247] In another aspect, provided herein is an oligonucleotide with a 5’-terminal phosphate mimic modification comprising the structure: ,, 95Docket No.: 051058-000105WOP2 rwherein: X is O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the same carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R75 and R76together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently -ORO, -SRS, -N(RN) N 2S 2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C1-3alkyl.

[0248] In some embodiments, the 5’-terminal terminal phosphate mimic modification comprises the structure:, wherein: X is O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); 96Docket No.: 051058-000105WOP2 each RP is independently C alkyl, -ORO, S N N 2S 1-3 -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, provided no more P 1-3 than one R is C1-3alkyl.

[0249] It is noted that the sugar moiety of the nucleotide comprising the 5’-terminal phosphate mimic modification 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, alopyranose, altropyranose, gulopyranose, idopyranose, and talopyranose, including alpha and beta, D and L, deoxy, and modified derivates thereof).

[0250] For example, the 5’-terminal phosphate mimic modification can replace a -OH or - CH2OH group on the sugar moiety of a 5’-terminal nucleotide of the oligonucleotide. For example, the 5’-terminal phosphate mimic modification can replace 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, alopyranose, altropyranose, gulopyranose, idopyranose, or talopyranose, preferably glucopyranose, galactopyranose, or mannopyranose) of the 5’-terminal nucleotide of the oligonucleotide. In other words, the oligonucleotide comprises at its 5’-end a compound of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A-IA – A-IE, A-II, A- IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF described herein. In certain embodiments, X is O. In certain embodiments, X is O and each RP is ORO. In certain embodiments, X is O and each RP is OH. In certain embodiments, X is O and each RP is ethoxy. In certain embodiments, X is O and each RP is OH. In certain embodiments, X is O and each RP is ORO wherein RO is pivaloyloxymethyl.

[0251] For example, the 5’-terminal nucleotide of the oligonucleotide comprising a 5’-terminal phosphate modification is of the structure:97Docket No.: 051058-000105WOP2 ,98Docket No.: 051058-000105WOP2 , ,wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); Ring G 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; X is O or S; R71 and R72 are independently hydrogen,halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73A and R74A are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73A and R74A together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73B and R74B are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73B and R74B together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); 99Docket No.: 051058-000105WOP2R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R75 and R76together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); one of R2’and R3’ is hydrogen, halogen, or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is a bond to an oligonucleotide (e.g., to an internucleoside linkage that connects to the subsequent nucleotide of the oligonucleotide).

[0252] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:.

[0253] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:.

[0254] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:a salt thereof. In one embodiment at least one of R71 and R72 is halogen (e.g., fluoro). In one embodiment at least one of R71 and R72 is methyl (e.g., both are methyl).

[0255] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:a salt thereof. In one embodiment, at least one of R71 and R72 is halogen (e.g., fluoro). In one embodiment at least one of R71 and R72 is methyl (e.g., both are methyl). 100Docket No.: 051058-000105WOP2

[0256] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide comprises the. In some embodiments, the 5’-terminal nucleotide of the oligonucleotide comprises the structure:.

[0257] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:, wherein Z is O or S and R20 is C1-3alkyl or C1-3alkoxyC1-3alkyl. In some embodiments, Z is S and R20 is methyl. In some other embodiments, Z is S and R20 is 2- methoxyethyl. In yet some embodiments, Z is O and R20 is methyl. In stil some other embodiments, Z is O and R20 is 2-methoxyethyl. In some embodiments, X is O and each RP is -OH. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0258] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:, wherein Z is S and R20 is methyl or 2-methoxyethyl, X is O and each RP is -OH, and optionaly, B is uracil or thymine (e.g., uracil).

[0259] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:, wherein Z is O or S and R20 is C1-3alkyl or C1-3alkoxyC1-3alkyl. In some embodiments, Z is S and R20 is methyl. In some other embodiments, Z is S and R20 is 2- methoxyethyl. In yet some embodiments, Z is O and R20 is methyl. In stil some other embodiments, 101Docket No.: 051058-000105WOP2Z is O and R20 is 2-methoxyethyl. In some embodiments, X is O and each RP is -OH. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0260] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:, wherein Z is S and R20 is methyl or 2-methoxyethyl, X is O and each RP is -OH, and optionaly, B is uracil or thymine (e.g., uracil).

[0261] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:.

[0262] In some embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:. In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:.

[0263] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:. In one embodiment at least one of R73 and R74 is halogen (e.g., fluoro). In one embodiment at least one of R73 and R74 is methyl (e.g., both are methyl). In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:one embodiment at least one of R73 and R74 is halogen (e.g., fluoro). In one embodiment at least one of R73 and R74 is methyl (e.g., both are methyl). 102Docket No.: 051058-000105WOP2

[0264] In some embodiments, the 5’-terminal modification comprises the structure: :

[0265] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has thestructure: . In one embodiment at least one of R75 and R76 is halogen (e.g., fluoro). In one embodiment at least one of R75 and R76 is methyl (e.g., both are methyl).

[0266] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:. In one embodiment at least one of R75 and R76 is halogen (e.g., fluoro). In one embodiment at least one of R75 and R76 is methyl (e.g., both are methyl).

[0267] In some embodiments, the 5’-terminal modification comprises the structure: :

[0268] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:one embodiment at least one of R71 and R72 is halogen (e.g., fluoro). In one embodiment at least one of R71 and R72 is methyl (e.g., both are methyl). In one embodiment, of R71 and R72, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl). 103Docket No.: 051058-000105WOP2

[0269] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:one embodiment at least one of R71 and R72 is halogen (e.g., fluoro). In one embodiment at least one of R71 and R72 is methyl (e.g., both are methyl). In one embodiment, of R71 and R72, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl).

[0270] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:. In one embodiment at least one of R73A and R74A is halogen (e.g., fluoro). In one embodiment at least one of R73A and R74A is methyl (e.g., both are methyl). In one embodiment, R73A and R74A, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl).

[0271] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:one embodiment at least one of R73A and R74A is halogen (e.g., fluoro). In one embodiment at least one of R73A and R74A is methyl (e.g., both are methyl). In one embodiment, R73A and R74A, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl).

[0272] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:. In one embodiment at least one of R73 and R74 is halogen (e.g., fluoro). In one embodiment at least one of R73 and R74 is methyl (e.g., both are methyl). In one embodiment, R73 and R74, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl). 104Docket No.: 051058-000105WOP2

[0273] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:a salt thereof. In one embodiment at least one of R73 and R74 is halogen (e.g., fluoro). In one embodiment at least one of R73 and R74 is methyl (e.g., both are methyl). In one embodiment, R73 and R74, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl).

[0274] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure: 75one embodiment at least one of R and R76 is halogen (e.g., fluoro). In one embodiment at least one of R73 and R74 is methyl (e.g., both are methyl). In one embodiment, R75 and R76, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0275] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:one embodiment at least one of R75 and R76 is halogen (e.g., fluoro). In one embodiment at least one of R75 and R76 is methyl (e.g., both are methyl). In one embodiment, R75 and R76, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0276] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:,wherein Z is O or S and R20 is C1-3alkyl or C1-3alkoxyC1-3alkyl. In some embodiments, Z is S and R20 is methyl. In some other embodiments, Z is S and R20 is 2- methoxyethyl. In yet some embodiments, Z is O and R20 is methyl. In stil some other embodiments, Z is O and R20 is 2-methoxyethyl. In some embodiments, X is O and each RP is -OH. In certain embodiments, B is uracil or thymine (e.g., uracil). 105Docket No.: 051058-000105WOP2

[0277] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:, wherein Z is S and R20 is methyl or 2-methoxyethyl, X is O and each RP is -OH, and optionaly, B is uracil or thymine (e.g., uracil).

[0278] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:, wherein Z is O or S and R20 is C1-3alkyl or C1-3alkoxyC1-3alkyl. In some embodiments, Z is S and R20 is methyl. In some other embodiments, Z is S and R20 is 2- methoxyethyl. In yet some embodiments, Z is O and R20 is methyl. In stil some other embodiments, Z is O and R20 is 2-methoxyethyl. In some embodiments, X is O and each RP is -OH. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0279] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:, wherein Z is S and R20 is methyl or 2-methoxyethyl, X is O and each RP is -OH, and optionaly, B is uracil or thymine (e.g., uracil).

[0280] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:a salt thereof. In one embodiment at least one of R71 and R72 is halogen (e.g., fluoro). In one embodiment at least one of R71 and R72 is methyl (e.g., both are methyl). In one embodiment, of R71 and R72, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl). 106Docket No.: 051058-000105WOP2

[0281] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:a salt thereof. In one embodiment at least one of R71 and R72 is halogen (e.g., fluoro). In one embodiment at least one of R71 and R72 is methyl (e.g., both are methyl). In one embodiment, of R71 and R72, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0282] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:a salt thereof. In one embodiment at least one of R73B and R74B is halogen (e.g., fluoro). In one embodiment at least one of R73B and R74B is methyl (e.g., both are methyl). In one embodiment, R73B and R74B, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0283] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:a salt thereof. In one embodiment at least one of R73B and R74B is halogen (e.g., fluoro). In one embodiment at least one of R73B and R74B is methyl (e.g., both are methyl). In one embodiment, R73B and R74B, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0284] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:a salt thereof. In one embodiment at least one of R73A and R74A is halogen (e.g., fluoro). In one embodiment at least one of R73A and R74A is methyl (e.g., both are methyl). In one embodiment, R73A and R74A, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl). 107Docket No.: 051058-000105WOP2

[0285] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:a salt thereof. In one embodiment at least one of R73A and R74A is halogen (e.g., fluoro). In one embodiment at least one of R73A and R74A is methyl (e.g., both are methyl). In one embodiment, R73A and R74A, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0286] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:or a salt thereof. In one embodiment at least one of R73 and R74 is halogen (e.g., fluoro). In one embodiment at least one of R73 and R74 is methyl (e.g., both are methyl). In one embodiment, R73 and R74, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl).

[0287] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:or a salt thereof. In one embodiment at least one of R75 and R76 is halogen (e.g., fluoro). In one embodiment at least one of R73 and R74 is methyl (e.g., both are methyl). In one embodiment, R75 and R76, together with the carbon they are atached to, form a C3-C6cycloalkyl (e.g., cyclopropyl).

[0288] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:a salt thereof. In one embodiment at least one of R75 and R76 is halogen (e.g., fluoro). In one embodiment at least one of R75 and R76 is methyl (e.g., both are methyl). In one embodiment, R75 and R76, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl).

[0289] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:a salt thereof. In one embodiment at least one of R75 and R76 is halogen (e.g., fluoro). In one embodiment at least one of R75 and R76 is methyl (e.g., both are 108Docket No.: 051058-000105WOP2 methyl). In one embodiment, R75 and R76, together with the carbon they are atached to, form a C3- C6cycloalkyl (e.g., cyclopropyl).

[0290] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structuresome embodiments, Z is S and R20 is methyl. In some other embodiments, Z is S and R20 is 2- methoxyethyl. In yet some embodiments, Z is O and R20 is methyl. In stil some other embodiments, Z is O and R20 is 2-methoxyethyl. In some embodiments, X is O and each RP is -OH. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0291] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:, wherein Z is S and R20 is methyl or 2-methoxyethyl, X is O and each RP is -OH, and optionaly, B is uracil or thymine (e.g., uracil).

[0292] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:, wherein Z is O or S and R20 is C1-3alkyl or C1-3alkoxyC1-3alkyl. In some embodiments, Z is S and R20 is methyl. In some other embodiments, Z is S and R20 is 2- methoxyethyl. In yet some embodiments, Z is O and R20 is methyl. In stil some other embodiments, Z is O and R20 is 2-methoxyethyl. In some embodiments, X is O and each RP is -OH. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0293] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:, wherein Z is S and R20 is methyl or 2-methoxyethyl, X is O and each RP is -OH, and optionaly, B is uracil or thymine (e.g., uracil). 109Docket No.: 051058-000105WOP2

[0294] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:,wherein Z is O or S and R20 is C1-3alkyl or C1-3alkoxyC1-3alkyl. In some embodiments, Z is S and R20 is methyl. In some other embodiments, Z is S and R20 is 2- methoxyethyl. In yet some embodiments, Z is O and R20 is methyl. In stil some other embodiments, Z is O and R20 is 2-methoxyethyl. In some embodiments, X is O and each RP is -OH. In certain embodiments, B is uracil or thymine (e.g., uracil).

[0295] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:, wherein Z is S and R20 is methyl or 2-methoxyethyl, X is O and each RP is -OH, and optionaly, B is uracil or thymine (e.g., uracil).

[0296] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:, wherein Z is O or S and R20 is C1-3alkyl or C1-3alkoxyC1-3alkyl. In some embodiments, Z is S and R20 is methyl. In some other embodiments, Z is S and R20 is 2- methoxyethyl. In yet some embodiments, Z is O and R20 is methyl. In stil some other embodiments, Z is O and R20 is 2-methoxyethyl. In some embodiments, X is O and each RP is -OH. In certain embodiments, B is uracil or thymine (e.g., uracil). 110Docket No.: 051058-000105WOP2

[0297] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the structure:, wherein Z is S and R20 is methyl or 2-methoxyethyl, X is O and each RP is -OH, and optionaly, B is uracil or thymine (e.g., uracil).

[0298] In some other embodiments, the 5’-terminal nucleotide of the oligonucleotide has the , , ,, , 111Docket No.: 051058-000105WOP2 , ,; Z is O or S; R3’ and R20 is C a 20 1-3lkyl or C1-3alkoxyC1-3alkyl. In some embodiments, Z is S and R is methyl. In some other embodiments, Z is S and R20 is 2-methoxyethyl. In yet some embodiments, Z is O and R20 is methyl. In stil some other embodiments, Z is O and R20 is 2-methoxyethyl. In some embodiments, X is O and each RP is -OH. In certain embodiments, B is uracil or thymine (e.g., uracil). In some embodiments, Z is S and R20 is methyl or 2-methoxyethyl, X is O and each RP is - OH, and optionaly, B is uracil or thymine (e.g., uracil).

[0299] Generaly, 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 Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A-IA – A-IE, A-II, A-IIA – A-IIF, B-I, B- IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF counts as one nucleotide.

[0300] 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, internucleoside linkage modifications, conjugates (e.g., ligands), and combinations thereof.

[0301] 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.

[0302] In some embodiments, 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. For example, the 112Docket No.: 051058-000105WOP2 oligonucleotide comprises a thermaly 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 Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A-IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF is at position 1 from the 5’-end of the oligonucleotide; optionaly, the thermaly destabilizing modification is located at position 6, 7, or 8, counting from the 5’-end of the oligonucleotide, preferably the thermaly destabilizing modification is located at position 7, counting from the 5’-end of the oligonucleotide.

[0303] 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, optionaly, the oligonucleotide comprises 3, 4, 5 or 62’-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 Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A-IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B- IA – B-IE, B-II and B-IIA – B-IIF is at position 1 from the 5’-end of the oligonucleotide. For example, the oligonucleotide comprises a 2’-F nucleotide at least at positions 2, 6, 14 and 16, counting from the 5’-end of the oligonucleotide, optionaly, 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.

[0304] 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, optionaly, 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 Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A-IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF 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. 113Docket No.: 051058-000105WOP2

[0305] 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.

[0306] The internucleoside linkages in the oligonucleotide can be independently unmodified (e.g., phosphodiester) or modified (e.g., phosphorothioate or N-mesylphosphoramidate). 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. Generaly, the oligonucleotide comprises at least one (e.g., 1, 2, 4, or 5) modified internucleoside linkages (e.g., phosphorothioate or N-mesylphosphoramidate) 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.

[0307] In some embodiments, the oligonucleotide is covalently linked to a support, e.g., a solid support.

[0308] 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 substantialy 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 phosphate mimic modification comprising the structure:.

[0309] Preferably, the antisense strand comprises the above 5’-terminal modification. 114Docket No.: 051058-000105WOP2

[0310] In stil 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 substantialy complementary to a target gene; or (i) an oligonucleotide described herein, where the oligonucleotide is substantialy complementary to a target gene.

[0311] In another aspect, provided herein is a pharmaceutical composition comprising an oligonucleotide or dsRNA molecule described herein alone or in combination with a pharmaceuticaly acceptable carier or excipient.

[0312] In yet another aspect, provided herein is a cel comprising an oligonucleotide or dsRNA molecule described herein.

[0313] In stil another aspect, provided herein is a gene silencing kit comprising an oligonucleotide or dsRNA molecule described herein.

[0314] Also, provided herein is a method for silencing a target gene, in a cel. The method comprises a step of introducing: (i) a dsRNA molecule described herein into the cel, where one of the strands, e.g., the antisense of the dsRNA comprises a nucleotide sequence substantialy complementary to a nucleotide sequence of the target gene; and / or (i) an oligonucleotide described herein, wherein the oligonucleotide comprises a nucleotide sequence substantialy complementary to a nucleotide sequence of the target gene.

[0315] 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 substantialy complementary to a nucleotide sequence of the target gene; and / or (i) an oligonucleotide described herein, wherein the oligonucleotide comprises a nucleotide sequence substantialy complementary to a nucleotide sequence of the target gene. BRIEF DESCRIPTION OF THE DRAWINGS

[0316] FIG.1 shows mTTR levels at diferent timepoints for exemplary siRNAs (AD-2680451 and AD-2680453) containing a phosphate analog at the 5’-end of the antisense strand versus the parent siRNA (AD-64958) and siRNA comprising a 5’- vinylphosphonate (VP) in the antisense strand (AD-286913) in rat.

[0317] FIG.2 shows knockdown at 0.6 mg / Kg with another exemplary siRNA (AD-2756735) versus the parent siRNA (AD-401825) and siRNA comprising a 5’- vinylphosphonate (VP) in the antisense strand (AD-401824).

[0318] FIG.3 shows knockdown at 0.6 mg / Kg with an exemplary siRNA (AD-2756740) versus the parent siRNA (AD-2629355) and siRNA comprising a 5’- vinylphosphonate (VP) in the antisense strand (AD-890098). 115Docket No.: 051058-000105WOP2

[0319] FIG.4 shows SOD1 mRNA levels after in vivo intracerebroventricular administration of exemplary siRNAs (AD-3116182, AD-2756735, AD-3116173, AD-3116174, AD-3116175) versus the parent siRNA (AD-401825) and siRNA comprising a 5’- vinylphosphonate (VP) in the antisense strand (AD-401824) in rat.

[0320] FIG.5 shows brain TA concentration after in vivo intracerebroventricular administration of exemplary siRNAs (AD-3116182, AD-3116173, AD-3116174, AD-2756735 and AD-3116175) versus the parent siRNA (AD-960499) and siRNA comprising a 5’- vinylphosphonate (VP) in the antisense strand (AD-454844) in mice at day 28.

[0321] FIG.6 shows SOD1 mRNA levels after in vivo intracerebroventricular administration of an exemplary siRNA (AD-2919287) versus the parent siRNA (AD-401825) and siRNA comprising a 5’- vinylphosphonate (VP) in the antisense strand (AD-401824) in mice.

[0322] FIG.7 shows amyloid precursor protein (APP) protein levels at diferent timepoints after in vivo intrathecal administration of an exemplary siRNA (AD-2905747) versus the parent siRNA (AD-960498) and siRNA comprising a 5’- vinylphosphonate (VP) in the antisense strand (AD-454844) in non-human primate.

[0323] FIG.8 shows APP mRNA levels in various parts organs after in vivo intrathecal administration of an exemplary siRNA (AD-2905747) versus the parent siRNA (AD-960498) and siRNA comprising a 5’- vinylphosphonate (VP) in the antisense strand (AD-454844) in non-human primate at day 91.

[0324] FIG.9 shows Microtubule-associated protein 2 (MAP2) mRNA after in vivo intrathecal administration of an exemplary siRNA (AD-2912414) versus the parent siRNA (AD-476454) and siRNA comprising a 5’- vinylphosphonate (VP) in the antisense strand (AD-2912412) in non-human primate at day 91.

[0325] FIG.10 shows APP mRNA levels after in vivo intrathecal administration of exemplary siRNAs (AD-2905747 and AD-3216840) versus the parent siRNA (AD-445844) in non-human primate at day 1.

[0326] FIG.11 shows APP mRNA levels in brain after in vivo intrathecal administration of exemplary siRNAs (AD-3189915, AD-3367263, AD-3367264, AD-3367265and AD-3367268) versus siRNAs comprising a 5’- vinylphosphonate (VP) in the antisense strand (AD-1271086 and AD-3367267) in mice. DETAILED DESCRIPTION

[0327] It is to be understood that both the foregoing general description and the folowing 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 specificaly stated otherwise. As used herein, the use of “or” means “and / or” unless stated otherwise. Furthermore, the use of the term 116Docket No.: 051058-000105WOP2“including” as wel 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 specificaly stated otherwise.

[0328] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject mater described. Al 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. Ring G

[0329] Compounds of Formula (B) have the structure:. In compounds of Formula (B) the ring G can be a 5- or 6- membered ring. For example, ring G can be a 5- or 6- membered 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, alopyranose, 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 atached to any atom, e.g., any carbon atom of the ring G, e.g., of the sugar moiety.

[0330] In some embodiments, ring G 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 atached to C1, R2 is atached to C2 or is absent, R3’ is atached to C3, and the phosphate moiety is atached to C4 of the furanose. In some embodiments, ring G 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 atached to C1, R2 is absent, R3’ is atached to C2, and the phosphate moiety is atached to C3 of the furanose. In some embodiments, ring G 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 atached to C1, R2 is absent, R3’ is atached to C4, and the phosphate moiety is atached to C3 of the furanose. In some embodiments, ring G is a furanose (e.g., ribofuranose, arabinofuranose, lyxofuranose, xylofuranose, ribulofuranose or 117Docket No.: 051058-000105WOP2 xylulofuranose, including alpha and beta, D and L, deoxy, and modified derivates thereof), and B is atached to C1, R2 is absent, and both of R3’ and the phosphate moiety are atached 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 atached to. When the phosphate moiety is atached to C4 of the furanose, it can replace the -CH2OH group at the C4 of the ribose. The atachment of the B can be in the alpha or beta configuration. The atachment of the R2’, R3’ and the phosphate moiety independently can be in the R or S configuration.

[0331] In some embodiments, ring G is cycloepentane. In some embodiments, ring G is cycloepentane, and B is atached to C1, R2 is atached to C2 or is absent, R3’ is atached to C3, and the phosphate moiety is atached to C4 of the cycloepentane. In some embodiments, ring G is cycloepentane and B is atached to C1, R2 is absent, R3’ is atached to C2, and the phosphate moiety is atached to C3 of the cycloepentane. In some embodiments, ring G is cycloepentane, and B is atached to C1, R2 is absent, R3’ is atached to C4, and the phosphate moiety is atached to C3 of the cycloepentane. In some embodiments, ring G is cycloepentane, and B is atached to C1, R2 is absent, and both of R3’ and the phosphate moiety are atached to C3 of the cyclopentyl. It is noted that carbon of the cycloepentane to which the B is atached is denotated as C1. It is noted that atachment of the B, R2’, R3’ and the phosphate moiety independently can be in the R or S configuration.

[0332] In some embodiments, ring G is a pyranose (e.g., glucopyranose, galactopyranose, mannopyranose, alopyranose, altropyranose, gulopyranose, idopyranose, and talopyranose, including alpha and beta, D and L, deoxy, and modified derivates thereof), and B is atached to C1 of the pyranose, R2’ is absent, R3’ is atached to C4 and the phosphate moiety is atached 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 atached to. The atachment of the B can be in the alpha or beta configuration. The atachment of the R2’, R3’ and the phosphate moiety independently can be in the R or S configuration.

[0333] In some embodiments, ring G is tetrahydofuran, and B is atached to C1, R2 is atached to C2 or is absent, R3’ is atached to C3, and the phosphate moiety is atached to C4 of the tetrahydofuran. In some embodiments, ring G is tetrahydofuran, and B is atached to C1, R2 is absent, R3’ is atached to C2, and the phosphate moiety is atached to C3 of the tetrahydofuran. In some embodiments, ring G is tetrahydofuran, and B is atached to C1, R2 is absent, R3’ is atached to C4, and the phosphate moiety is atached to C3 of the tetrahydofuran. In some embodiments, ring G is tetrahydofuran, and B is atached to C1, R2 is absent, and both of R3’ and the phosphate moiety are atached to C3 of the tetrahydofuran. It is noted that atachment of the B, R2’, R3’ and the phosphate moiety independently can be in the R or S configuration. The tetrahydropyran may comprise 118Docket No.: 051058-000105WOP2 additional groups (e.g., one or more of hydroxyl, halogen and alkoxy), in addition to B, R2’, R3’ and the phosphate moiety.

[0334] In some embodiments, ring G is tetrahydropyran, and B is atached to C1 of the pyranose, R2’ is absent, R3’ is atached to C4 and the phosphate moiety is atached to C5 of the tetrahydropyran. It is noted that atachment of the B, R2’, R3’ and the phosphate moiety independently can be in the R or S configuration. The tetrahydropyran may comprise additional groups (e.g., one or more of hydroxyl, halogen and alkoxy), in addition to B, R2’, R3’ and the phosphate moiety.

[0335] DNA typicaly 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 G is in the south conformation (i.e., C2’-endo). On the other hand, RNA typicaly 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 G is in the north conformation (i.e., C3’-endo) R3’

[0336] In the various aspects described herein, R3’ can be hydrogen, halogen, -OR20, or -OR30.

[0337] In some embodiments, R3’ is -OR30, where R30 is 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 -OR30 and R30 is hydrogen or hydroxyl protecting group.

[0338] In some embodiments, R3’ is -OR30 and R30 is a reactive phosphorus group. For example, R30 is a phosphoramidite, H-phosphonate, alkyl-phosphonate, or phosphate triester. In some embodiments, R3’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 P1 P2 2, -P(SR )N(R )2, -P(O)(OR )N(R )2, - P(S)(ORP1)N(RP2) P3 P2 P1 P2 P1 P1 2, -P(R )N(R )2, -P(O)(SR )N(R )2, -P(O)(OR )H, -P(S)(OR )H, - P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1 is C1-6alkyl, optionaly 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(C1-4)alkyl, N[(C1- 4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-8)alkyl, O(C1-8)alkyl (i.e., C1- 8alkoxy), O(C1-8)haloalkyl, (C2-8)alkenyl, (C2-8)alkynyl, C1-8haloalkyl, C1-8thioalkyl, cyanomethylene, aminoC1-8alkyl, aryl, heteroaryl, substituted aryl, -C1- 8alkylC(O)NH2, -C1-8alkylC(O)N(H)Me, -CH2C(O)-C1-8alkyl, -C(O)-C1-8alkyl, - N(H)C(O)C1-8alkyl, CH2—[CH(OH)]m—(CH2)p—OH, CH2—[CH(OH)]m— 119Docket No.: 051058-000105WOP2(CH2)p—NH2 or CH2-aryl-alkoxy, where “m” and “p” are independently 1, 2, 3, 4, 5 or 6; each RP2 is independently C1-6alkyl, optionaly 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(C1-4)alkyl, N[(C1-4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-8)alkyl, O(C1-8)alkyl (i.e., C1-8alkoxy), O(C1-8)haloalkyl, (C2-8)alkenyl, (C2-8)alkynyl, C1-8haloalkyl, C1- 8thioalkyl, cyanomethylene, aminoC1-8alkyl, aryl, heteroaryl, substituted aryl, -C1- 8alkylC(O)NH2, -C1-8alkylC(O)N(H)Me, -CH2C(O)-C1-8alkyl, -C(O)-C1-8alkyl, - N(H)C(O)C1-8alkyl, CH2—[CH(OH)]m—(CH2)p—OH, CH2—[CH(OH)]m— (CH2)p—NH2 or CH2-aryl-alkoxy, where “m” and “p” are independently 1, 2, 3, 4, 5 or 6, optionaly each RP2 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, preferably each RP2 is isopropyl; or both RP2 taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; or RP1 and one of RP2 taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl; and each RP3 is independently C1-30alkyl, C2-C30alkenyl, or C2-C30alkynyl, each optionaly independently 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(C1-4)alkyl, N[(C1-4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-8)alkyl, O(C1-8)alkyl (i.e., C1-8alkoxy), O(C1- 8)haloalkyl, (C2-8)alkenyl, (C2-8)alkynyl, C1-8haloalkyl, C1-8thioalkyl, cyanomethylene, aminoC1-8alkyl, aryl, heteroaryl, substituted aryl, -C1- 8alkylC(O)NH2, -C1-8alkylC(O)N(H)Me, -CH2C(O)-C1-8alkyl, -C(O)-C1-8alkyl, - N(H)C(O)C1-8alkyl, CH2—[CH(OH)]m—(CH2)p—OH, CH2—[CH(OH)]m— (CH2)p—NH2 or CH2-aryl-alkoxy, where “m” and “p” are independently 1, 2, 3, 4, 5 or 6, optionaly each RP3 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionaly substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-6alkoxy.

[0339] In some embodiments, R3’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR )N(R )2, - P(O)(ORP1)N(RP2), -P(S) P1 P2 P3 P2 P1 P2 P1 2 (OR )N(R )2, -P(R )N(R )2, -P(O)(SR )N(R )2, -P(O)(OR )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 C alkyl, op P2 1-6 tionaly substituted with a CN or –SC(O)Ph; each R is independently optionaly substituted C P3 1-6alkyl; and each R is independently optionaly substituted C1-6alkyl. 120Docket No.: 051058-000105WOP2

[0340] In some embodiments, R3’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR)N(R)2, - P(O)(ORP1)N(RP2), -P(S)(ORP1)N(RP2), -P(RP3)N(RP2), -P(O)(SRP1)N(P2 P1 2 2 2 R)2, -P(O)(OR)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, optionaly substituted with a CN or –SC(O)Ph; each RP2 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl; and each RP3 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionaly substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-6alkoxy.

[0341] In some embodiments, R3’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR)N(R)2, - P(O)(ORP1)N(RP2) P1 P2 P3 P2 P1 P2 P1 2, -P(S)(OR)N(R)2, -P(R)N(R)2, -P(O)(SR)N(R)2, -P(O)(OR)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 (-CHCH P2 2 2CN); each R is independently optionaly substituted C1-6alkyl; and each RP3 is independently optionaly substituted C1-6alkyl.

[0342] In some embodiments, R3’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR)N(R)2, - P(O)(ORP1)N(RP2), -P(S)(ORP1)N(RP2), -P(RP3)N(RP2), -P(O)(SRP1)N(RP2 P1 2 2 2 )2, -P(O)(OR)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 RP2 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl; and each RP3 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionaly substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-6alkoxy.

[0343] In some embodiments, R3’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR)N(R)2, - P(O)(ORP1)N(RP2), -P(S)(ORP1)N(RP2), -P(P3 P2 P1 P2 P1 2 2 R)N(R)2, -P(O)(SR)N(R)2, -P(O)(OR)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 (-CHCHCN); each RP2 is independentl P3 2 2 y isopropyl; and each R is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionaly substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-6alkoxy.

[0344] In some embodiments, R3’ is -OR30 and R30 is -P(ORP1)N(RP2)2, where: RP1 is 2- cyanoethyl (-CH2CH2CN); each RP2 is independently isopropyl.

[0345] In some embodiments, R3’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR)N(R)2, - P(O)(ORP1)N(RP2), -P(S)(ORP1 P2 P3 P2 P1 P2 P1 2 )N(R)2, -P(R)N(R)2, -P(O)(SR)N(R)2, -P(O)(OR)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 C alkyl, optionaly substituted with a CN o P2 1-6 r –SC(O)Ph; both R taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; and each RP3 is independently optionaly substituted C1-6alkyl.

[0346] In some embodiments, R3’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR)N(R)2, - P(O)(ORP1)N(RP2), -P(S)(ORP1)N(RP2), P3 P2 P1 P2 P1 2 2 -P(R)N(R)2, -P(O)(SR)N(R)2, -P(O)(OR)H, - 121Docket No.: 051058-000105WOP2P(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, optionaly substituted with a CN or –SC(O)Ph; both RP2 taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; and each RP3 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionaly substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-6alkoxy.

[0347] In some embodiments, R3’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR)N(R)2, - P(O)(ORP1)N(RP2), -P(S)(ORP1)N(RP2), -P P3 P2 P1 P2 P1 2 2 (R)N(R)2, -P(O)(SR)N(R)2, -P(O)(OR)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 (-CH P2 2CH2CN); both R taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; and each RP3 is independently optionaly substituted C1-6alkyl.

[0348] In some embodiments, R3’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR)N(R)2, - P(O)(ORP1)N(RP2), -P(S)(ORP1)N(RP2), -P P3 P2 P1 P2 P1 2 2 (R)N(R)2, -P(O)(SR)N(R)2, -P(O)(OR)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 (-CH P2 2CH2CN); both R taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; and each RP3 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionaly substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-6alkoxy.

[0349] In some embodiments, R3’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR)N(R)2, - P(O)(ORP1)N(RP2), -P(S)(ORP1)N(RP2), -P(RP3)N(RP2), -P(O)( P1 P2 P1 2 2 2 SR)N(R)2, -P(O)(OR)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 RP2 taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl; other RP2 is independently optionaly substituted C1-6alkyl; and each RP3 is independently optionaly substituted C1-6alkyl.

[0350] In some embodiments, R3’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR)N(R)2, - P(O)(ORP1)N(RP2), -P(S)(ORP1)N P2 P3 P2 P1 P2 P1 2 (R)2, -P(R)N(R)2, -P(O)(SR)N(R)2, -P(O)(OR)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 RP2 taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl; other RP2 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso- butyl, pentyl or hexyl; and each RP3 is independently optionaly substituted C1-6alkyl.

[0351] In some embodiments, R3’ is -OR30 and R30 is -P(ORP1)N(RP2), -P( P1 P2 2 SR)N(R)2, - P(O)(ORP1)N(RP2), -P(S)(ORP1)N(RP2), -P(RP3)N(RP2), -P(O)(SRP1)N(RP2), -P(O)(OP1 2 2 2 2 R)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 RP2 taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl; other RP2 is independently optionaly substituted C P3 1-6alkyl; and each R 122Docket No.: 051058-000105WOP2 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionaly substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-6alkoxy.

[0352] In some embodiments, R3’ is -OR30 and R30 is -P(ORP1)N(RP2), -P(SRP1) P2 2 N(R )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 RP2 taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl; other RP2 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso- butyl, pentyl or hexyl; and each RP3 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso- butyl, pentyl or hexyl, each of which can be optionaly substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-6alkoxy.

[0353] In some embodiments, R3’ is -OR30 and R30 is a bond to a nucleoside or a nucleotide, or an oligonucleotide. When R30 is a bond to a nucleoside, a nucleotide, or an oligonucleotide, the internucleoside linkage between compound of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A- IC, A-I, A-IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B- IIA – B-IIF and the nucleoside, nucleotide, or oligonucleotide can be an unmodified (e.g., phosphodiester) internucleoside linkage or a modified (e.g., phosphorothioate or N- mesylphosphoramidate) internucleoside linkage.

[0354] In some embodiments, R3’ is -OR30 and R30 is linked to 5’-position of a nucleoside, nucleotide, or oligonucleotide by an unmodified (e.g., phosphodiester) internucleoside linkage (e.g., or a modified (e.g., phosphorothioate or N-mesylphosphoramidate) internucleoside linkage. For example, R30 is linked to the 5’-terminal (e.g., 5’-OH) of the oligonucleotide. In some embodiments, R30 is linked to the 5’-terminal (e.g., 5’-OH) of the oligonucleotide by an unmodified (e.g., phosphodiester) internucleoside linkage. In some other embodiments, R30 is linked to the 5’-terminal (e.g., 5’-OH) of the oligonucleotide by a modified (e.g., phosphorothioate or N- mesylphosphoramidate) internucleoside linkage.

[0355] In some embodiments, R3’is -OR30 and R30 is a hydroxyl protecting group. For example, R3’is -OR30 and R30 is 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, alyl, p-chlorophenyl, p-methoxyphenyl, 2,4- 123Docket No.: 051058-000105WOP2 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), Fmoc, C1-6alkyl carbonate (e.g., methyl, ethyl, or isobutyl), Troc, TMSEC, Psec, Peoc, C2-6alkenyl carbonate (e.g., vinyl or alyl), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, 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, N,N,N′,N′-tetramethylphosphorodiamidate, N- phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate.

[0356] In some embodiments, R3’is -OR30 and R30 is TBDMS, TBDPS, TMS, TES, TIPS, IPDMS, DEIPS, TBMPS, DPMS, dimethylthexylsilyl, tribenzylsilyl, tri-p-xylylsilyl, or triphenylsilyl, optionaly, R30 is TBDMS.

[0357] In some embodiments, R3’ is hydrogen or halogen. For example, R3’ is H or F.

[0358] In some embodiments, R3’ is -OR20, where R20 is hydrogen, hydroxyl protecting group, optionaly 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 R20 is hydrogen or hydroxyl protecting group. 124Docket No.: 051058-000105WOP2

[0359] In some embodiments, R3’ is -OR20, and R20 is C1-6alkyl, optionaly 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(C1-4)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), C1-8alkyl, C1-8alkoxy, O(C1-8)haloalkyl, C2-8alkenyl, C2-8alkynyl, C1-8haloalkyl, C1-8thioalkyl, cyanomethylene, aminoC1-8alkyl, aryl, heteroaryl, substituted aryl, -C1- 8alkylC(O)NH2, -C1-8alkylC(O)N(H)Me, -CH2C(O)-C1-8alkyl, -C(O)-C1-8alkyl, -N(H)C(O)C1-8alkyl, CH2—[CH(OH)]m—(CH2)p—OH, CH2—[CH(OH)]m—(CH2)p—NH2 or CH2-aryl-alkoxy, where “m” and “p” are independently 1, 2, 3, 4, 5 or 6. For example, R3’ is -OR20, and R20 is methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, optionaly, R20 is methyl.

[0360] In some embodiments, R3’ is -OR20, and R20 is C alkoxyC al 3’ 1-6 1-6 kyl. For example, R is -OR20, and R20 is 2-methoxyethyl.

[0361] In some embodiments, R3’is -OR20 and R20 is a hydroxyl protecting group. For example, R3’is -OR20 and R20 is 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, alyl, 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 125Docket No.: 051058-000105WOP2(levulinoyldithioacetal), adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), Fmoc, C1-6alkyl carbonate (e.g., methyl, ethyl, or isobutyl), Troc, TMSEC, Psec, Peoc, C2-6alkenyl carbonate (e.g., vinyl or alyl), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, 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.

[0362] In some embodiments, R3’is -OR20 and R20 is TBDMS (or TBS), TBDPS, TMS, TES, TIPS, IPDMS, DEIPS, TBMPS, DPMS, dimethylthexylsilyl, tribenzylsilyl, tri-p-xylylsilyl, or triphenylsilyl, optionaly, R20 is TBDMS (or TBS). R2’

[0363] In the various aspects described herein, R2’ can be hydrogen, halogen, -OR20, or -OR30.

[0364] In some embodiments, R2’ is hydrogen or halogen. For example, R2’ is H or F.

[0365] In some embodiments, R2’ is -OR20, where R20 is hydrogen, hydroxyl protecting group, optionaly 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 R20 is hydrogen or hydroxyl protecting group. In other examples, R2’ is -OR20, where R20 is an optionaly substituted C1-6alkyl.

[0366] In some embodiments, R2’ is -OR20, and R20 is C1-6alkyl, optionaly 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(C1-4)alkyl, N[(C1- 4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-8)alkyl, O(C1-8)alkyl (i.e., C1-8alkoxy), O(C1- C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, C1-8haloalkyl, C1-8thioalkyl, cyanomethylene, aminoC1-8alkyl, aryl, heteroaryl, substituted aryl, -C1-8alkylC(O)NH2, -C1-8alkylC(O)N(H)Me, - CH2C(O)-C1-8alkyl, -C(O)-C1-8alkyl, -N(H)C(O)C1-8alkyl, CH2—[CH(OH)]m—(CH2)p—OH, CH2—[CH(OH)]m—(CH2)p—NH2 or CH2-aryl-alkoxy, where “m” and “p” are independently 1, 2, 3, 4, 5 or 6. For example, R2’ is -OR20, and R20 is methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, optionaly, R20 is methyl. 126Docket No.: 051058-000105WOP2

[0367] In some embodiments, R2’ is -OR20, and R20 is C1-6alkoxyC1-6alkyl, optionaly 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(C1-4)alkyl, N[(C1-4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-8)alkyl, O(C1-8)alkyl (i.e., C1-8alkoxy), O(C1-8)haloalkyl, (C2-8)alkenyl, (C2-8)alkynyl, C1-8haloalkyl, C1-8thioalkyl, cyanomethylene, aminoC1-8alkyl, aryl, heteroaryl, substituted aryl, -C1-8alkylC(O)NH2, -C1-8alkylC(O)N(H)Me, - CH2C(O)-C1-8alkyl, -C(O)-C1-8alkyl, -N(H)C(O)C1-8alkyl, CH2—[CH(OH)]m—(CH2)p—OH, CH2—[CH(OH)]m—(CH2)p—NH2 or CH2-aryl-alkoxy, where “m” and “p” are independently 1, 2, 3, 4, 5 or 6. For example, R2’ is -OR20, and R20 is 2-methoxyethyl.

[0368] In some embodiments, R2’is -OR20 and R20 is a hydroxyl protecting group. For example, R2’is -OR20 and R20 is 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, alyl, 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), Fmoc, C1-6alkyl carbonate (e.g., methyl, ethyl, or isobutyl), Troc, TMSEC, Psec, Peoc, C2-6alkenyl carbonate (e.g., vinyl or alyl), p-nitrophenyl carbonate, 127Docket No.: 051058-000105WOP2 benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, 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.

[0369] In some embodiments, R2’is -OR20 and R20 is TBDMS, TBDPS, TMS, TES, TIPS, IPDMS, DEIPS, TBMPS, DPMS, dimethylthexylsilyl, tribenzylsilyl, tri-p-xylylsilyl, or triphenylsilyl, optionaly, R20 is TBDMS.

[0370] In some embodiments, R2’ is -OR30, where R30 is 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 -OR30 and R30 is hydrogen or hydroxyl protecting group.

[0371] In some embodiments, R2’ is -OR30 and R30 is a reactive phosphorus group. For example, R30 is a phosphoramidite, H-phosphonate, alkyl-phosphonate, or phosphate triester. In some embodiments, R2’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 P1 P2 2, -P(SR )N(R )2, -P(O)(OR )N(R )2, - P(S)(ORP1)N(RP2), -P(RP3)N(RP2), -P(O) P1 P2 P1 P1 2 2 (SR )N(R )2, -P(O)(OR )H, -P(S)(OR )H, - P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(SRP1)RP3, where: each RP1 is C1-6alkyl, optionaly 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(C1-4)alkyl, N[(C1- 4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-8)alkyl, O(C1-8)alkyl (i.e., C1- 8alkoxy), O(C1-8)haloalkyl, (C2-8)alkenyl, (C2-8)alkynyl, C1-8haloalkyl, C1-8thioalkyl, cyanomethylene, aminoC1-8alkyl, aryl, heteroaryl, substituted aryl, -C1- 8alkylC(O)NH2, -C1-8alkylC(O)N(H)Me, -CH2C(O)-C1-8alkyl, -C(O)-C1-8alkyl, - N(H)C(O)C1-8alkyl, CH2—[CH(OH)]m—(CH2)p—OH, CH2—[CH(OH)]m— (CH2)p—NH2 or CH2-aryl-alkoxy, where “m” and “p” are independently 1, 2, 3, 4, 5 or 6; each RP2 is independently C1-6alkyl, optionaly 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(C1-4)alkyl, 128Docket No.: 051058-000105WOP2N[(C1-4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-8)alkyl, O(C1-8)alkyl (i.e., C1-8alkoxy), O(C1-C8)haloalkyl, (C2-8)alkenyl, (C2-8)alkynyl, C1-8haloalkyl, C1- 8thioalkyl, cyanomethylene, aminoC1-8alkyl, aryl, heteroaryl, substituted aryl, -C1- 8alkylC(O)NH2, -C1-8alkylC(O)N(H)Me, -CH2C(O)-C1-8alkyl, -C(O)-C1-8alkyl, - N(H)C(O)C1-8alkyl, CH2—[CH(OH)]m—(CH2)p—OH, CH2—[CH(OH)]m— (CH2)p—NH2 or CH2-aryl-alkoxy, where “m” and “p” are independently 1, 2, 3, 4, 5 or 6, optionaly each RP2 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, preferably each RP2 is isopropyl; or both RP2 taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; or RP1 and one of RP2 taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl; and each RP3 is independently C1-30alkyl, C2-C30alkenyl, or C2-C30alkynyl (e.g.,C1-10alkyl, C2- C10alkenyl, or C2-C10alkynyl , each optionaly independently 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(C1-4)alkyl, N[(C1-4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-8)alkyl, O(C1-8)alkyl (i.e., C1-8alkoxy), O(C1-8)haloalkyl, (C2-8)alkenyl, (C2-8)alkynyl, C1- 8haloalkyl, C1-8thioalkyl, cyanomethylene, aminoC1-8alkyl, aryl, heteroaryl, substituted aryl, -C1-8alkylC(O)NH2, -C1-8alkylC(O)N(H)Me, -CH2C(O)-C1-8alkyl, - C(O)-C1-8alkyl, -N(H)C(O)C1-8alkyl, CH2—[CH(OH)]m—(CH2)p—OH, CH2— [CH(OH)]m—(CH2)p—NH2 or CH2-aryl-alkoxy, where “m” and “p” are independently 1, 2, 3, 4, 5 or 6, optionaly each RP3 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionaly substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-6alkoxy.

[0372] In some embodiments, R2’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR )N(R )2, - P(O)(ORP1)N(RP2), -P(S)(ORP1)N(RP2), -P(RP3)N(RP2), -P(O)( P1 P2 P1 2 2 2 SR )N(R )2, -P(O)(OR )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 C alkyl, optionaly substituted with a CN or –SC( P2 1-6 O)Ph; each R is independently optionaly substituted C1-6alkyl; and each RP3 is independently optionaly substituted

[0373] In some embodiments, R2’ is -OR30 and R30 is -P(ORP1)N( - P(O)(ORP1)N(RP2), -P(S)(ORP1 P2 P3 P2 P1 2 )N(R )2, -P(R )N(R )2, -P(O)(SR )N - P(S)(ORP1)H, -P(O)(SRP1)H, -P(O)(ORP1)RP3, -P(S)(ORP1)RP3, or -P(O)(Sis C alkyl, optionaly s P2 1-6 ubstituted with a CN or –SC(O)Ph; each R is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl; and each RP3 is independently methyl, ethyl, 129Docket No.: 051058-000105WOP2 propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionaly substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-6alkoxy.

[0374] In some embodiments, R2’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR )N(R )2, - P(O)(ORP1)N(RP2), -P(S)(ORP1)N(RP2), -P(RP3)N(RP2), -P(O P1 P2 P1 2 2 2 )(SR )N(R )2, -P(O)(OR )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 (-CH P2 2CH2CN); each R is independently optionaly substituted C1-6alkyl; and each RP3 is independently optionaly substituted C1-6alkyl.

[0375] In some embodiments, R2’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR )N(R )2, - P(O)(ORP1)N(RP2), -P(S)(ORP1)N(RP2), -P(RP3)N(RP2), -P(O)(SP1 P2 P1 2 2 2 R )N(R )2, -P(O)(OR )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 RP2 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl; and each RP3 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionaly substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-6alkoxy.

[0376] In some embodiments, R2’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR )N(R )2, - P(O)(ORP1)N(RP2), -P(S)(ORP1)N(P2 P3 P2 P1 P2 P1 2 R )2, -P(R )N(R )2, -P(O)(SR )N(R )2, -P(O)(OR )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 (-CHCHCN); each RP2 is indepen P3 2 2 dently isopropyl; and each R is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionaly substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-6alkoxy.

[0377] In some embodiments, R2’ is -OR30 and R30 is -P(ORP1)N(RP2)2, where: RP1 is 2- cyanoethyl (-CH2CH2CN); each RP2 is independently isopropyl.

[0378] In some embodiments, R2’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR )N(R )2, - P(O)(ORP1)N(RP2), -P P1 P2 P3 P2 P1 P2 P1 2 (S)(OR )N(R )2, -P(R )N(R )2, -P(O)(SR )N(R )2, -P(O)(OR )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 C alkyl, optionaly substituted wi P2 1-6 th a CN or –SC(O)Ph; both R taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; and each RP3 is independently optionaly substituted C1-6alkyl.

[0379] In some embodiments, R2’ is -OR30 and R30 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, where: each RP1 is C1-6alkyl, optionaly substituted with a CN or –SC(O)Ph; both RP2 taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; and each RP3 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionaly substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-6alkoxy. 130Docket No.: 051058-000105WOP2

[0380] In some embodiments, R2’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR)N(R)2, - P(O)(ORP1)N(RP2), -P(S)(ORP1)N(RP2), -P(RP3)N(RP2), -P(O)(SRP1)N(RP2), -P P1 2 2 2 2 (O)(OR)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 RP2 taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; and each RP3 is independently optionaly substituted C1-6alkyl.

[0381] In some embodiments, R2’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR)N(R)2, - P(O)(ORP1)N(RP2), -P(S)(ORP1)N(RP2), -P(RP3)N(RP2), -P(O)(SRP1)N(RP2), P1 2 2 2 2 -P(O)(OR)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 RP2 taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl; and each RP3 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionaly substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-6alkoxy.

[0382] In some embodiments, R2’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR)N(R)2, - P(O)(ORP1)N(RP2), -P(S)( P1 P2 P3 P2 P1 P2 P1 2 OR)N(R)2, -P(R)N(R)2, -P(O)(SR)N(R)2, -P(O)(OR)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 RP2 taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl; other RP2 is independently optionaly substituted C1-6alkyl; and each RP3 is independently optionaly substituted C1-6alkyl.

[0383] In some embodiments, R2’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR)N(R)2, - P(O)(ORP1)N(RP2), -P(S)(ORP1)N(RP2), -P(RP3)N(RP2), -P(O P1 P2 P1 2 2 2 )(SR)N(R)2, -P(O)(OR)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 RP2 taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl; other RP2 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso- butyl, pentyl or hexyl; and each RP3 is independently optionaly substituted C1-6alkyl.

[0384] In some embodiments, R2’ is -OR30 and R30 is -P(ORP1)N(RP2) P1 P2 2, -P(SR)N(R)2, - P(O)(ORP1)N(RP2), -P(S)(ORP1)N(RP2), -P(RP3 P2 P1 P2 P1 2 2 )N(R)2, -P(O)(SR)N(R)2, -P(O)(OR)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 RP2 taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl; other RP2 is independently optionaly substituted C P3 1-6alkyl; and each R is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, pentyl or hexyl, each of which can be optionaly substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-6alkoxy.

[0385] In some embodiments, R2’ is -OR30 and R30 is -P(ORP1)N(RP2)2, -P(SRP1)N(RP2)2, - P(O)(ORP1)N(RP2), -P(S)(ORP1) P2 P3 P2 P1 P2 P1 2 N(R)2, -P(R)N(R)2, -P(O)(SR)N(R)2, -P(O)(OR)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 131Docket No.: 051058-000105WOP2 one of RP2 taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl; other RP2 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso- butyl, pentyl or hexyl; and each RP3 is independently methyl, ethyl, propyl, isopropyl, n-butyl, iso- butyl, pentyl or hexyl, each of which can be optionaly substituted with a NH2, OH, C(O)NH2, COOH, halogen, SH, or C1-6alkoxy.

[0386] In some embodiments, R2’ is -OR30 and R30 is a bond to a nucleoside or a nucleotide, or an oligonucleotide. When R30 is a bond to a nucleoside, a nucleotide, or an oligonucleotide, the internucleoside linkage between compound of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A- IC, A-I, A-IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B- IIA – B-IIF and the nucleoside, nucleotide, or oligonucleotide can be an unmodified (e.g., phosphodiester) internucleoside linkage or a modified (e.g., phosphorothioate or N- mesylphosphoramidate) internucleoside linkage.

[0387] In some embodiments, R2’ is -OR30 and R30 is linked to 5’-position of a nucleoside, nucleotide, or oligonucleotide by an unmodified (e.g., phosphodiester) internucleoside linkage (e.g., or a modified (e.g., phosphorothioate or N-mesylphosphoramidate) internucleoside linkage. For example, R30 is linked to the 5’-terminal (e.g., 5’-OH) of the oligonucleotide. In some embodiments, R30 is linked to the 5’-terminal (e.g., 5’-OH) of the oligonucleotide by an unmodified (e.g., phosphodiester) internucleoside linkage. In some other embodiments, R30 is linked to the 5’-terminal (e.g., 5’-OH) of the oligonucleotide by a modified (e.g., phosphorothioate or N- mesylphosphoramidate) internucleoside linkage.

[0388] In some embodiments, R2’is -OR30 and R30 is a hydroxyl protecting group. For example, R2’is -OR30 and R30 is 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, alyl, 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- 132Docket No.: 051058-000105WOP2 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), Fmoc, C1-6alkyl carbonate (e.g., methyl, ethyl, or isobutyl), Troc, TMSEC, Psec, Peoc, C2-6alkenyl carbonate (e.g., vinyl or alyl), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, 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.

[0389] In some embodiments, R2’is -OR30 and R30 is TBDMS, TBDPS, TMS, TES, TIPS, IPDMS, DEIPS, TBMPS, DPMS, dimethylthexylsilyl, tribenzylsilyl, tri-p-xylylsilyl, or triphenylsilyl, optionaly, R30 is TBDMS. RP

[0390] In various aspects described herein, each RP is independently -ORO, -SRS, -N(RN)2, or - N(RN)S(O)R2S. In some embodiments, at least one RP is -ORO, e.g., b P 2 oth R are independently - ORO. When RP is -ORO, each RO can be independently hydrogen, C1-3alkyl, or a hydroxyl protecting group. In some embodiments, at least one RP is -ORO, e.g., both RP are independently -ORO and each RO is independently hydrogen or C alkyl (e.g., C alkyl). For example, at least on P 1-6 1-3 e R is - ORO, e.g., both RP are independently -ORO and each RO is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. For example, at least one RP is -ORO, e.g., both RP are independently -ORO and each RO is hydrogen. In another example, at least one RP is -ORO, e.g., both RP are independently - ORO and each RO is methyl. In yet another example, at least one RP is -ORO, e.g., both RP are 133Docket No.: 051058-000105WOP2 independently -ORO and each RO is ethyl. In yet another example, at least one RP is -ORO, e.g., both RP are independently -ORO and each RO is tert-butyl.

[0391] In some embodiments, at least one RP is -ORO, e.g., both RP are independently -ORO and each RO is independently a hydroxyl protecting group. For example, at least one RP is -ORO, e.g., both RP are independently -ORO and each RO is 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, alyl, 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), Fmoc, C1-6alkyl carbonate (e.g., methyl, ethyl, or isobutyl), Troc, TMSEC, Psec, Peoc, C2-6alkenyl carbonate (e.g., vinyl or alyl), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, 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- 134Docket No.: 051058-000105WOP2 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, N,N,N′,N′-tetramethylphosphorodiamidate, N- phenylcarbamate, borate, dimethylphosphinothioyl, 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate, preferably the protecting group is POM. Thus, in some embodiments, at least one RP is -ORO, e.g., both RP are independently -ORO and each RO is independently pivaloyloxymethyl (POM).

[0392] In some embodiments, at least one RP is -SRS, e.g., both RP are independently -SRS. When RP is - SRS, each RS can be independently hydrogen, C1-3alkyl, or a thiol protecting group. In some embodiments, at least one RP is -SRS, e.g., both RP are independently -SRS and each RS is independently hydrogen or C a P S P 1-3lkyl. For example, at least one R is -SR, e.g., both R are independently -SRS and each RS is hydrogen, methyl, ethyl, or propyl. For example, at least one RP is -SRS, e.g., both RP are independently -SRS and each RS is hydrogen. In another example, at least one RP is -SRS, e.g., both RP are independently -SRS and each RS is methyl. In yet another example, at least one RP is -SRS, e.g., both RP are independently -SRS and each RS is ethyl. In some embodiments, at least one RP is -SRS, e.g., both RP are independently -SRS and each RS is independently a thiol protecting group. In some embodiments, at least one RP is -SRS, e.g., both RP are independently -SRS and each RS is independently pivaloyloxymethyl.

[0393] In some embodiments, at least one RP is -N(RN) N 2, e.g., both R are independently - N(RN)S. When RP is - N N 2 N(R)2, each R can be independently hydrogen, C1-3alkyl, or a thiol protecting group. In some embodiments, at least one RP is -N(RN) P 2, e.g., both R are independently -N(RN) and each RN is independent P N 2 ly hydrogen or C1-3alkyl. For example, at least one R is -N(R)2, e.g., both RP are independently -N(RN) N 2 and each R is hydrogen, methyl, ethyl, or propyl. For example, at least one RP is -N(RN), e.g. P N N 2 , both R are independently -N(R)2 and each R is hydrogen. In another example, at least one RP is -N(RN) P N N 2, e.g., both R are independently -N(R)2 and each R is methyl. In yet another example, at least one RP is -N(RN) P N 2, e.g., both R are independently -N(R)2 and each RN is ethyl. In some embodiments, at least one RP is -N(RN) P 2, e.g., both R are independently -N(RN)2 and each RN is independently an amine protecting group.

[0394] In some embodiments, at least one RP is -N(RN)S(O)2R2S, e.g., each RP is independently -N(RN)S(O)2R2S. For example, at least one RP is -N(RN)S(O)2R2S, e.g., both RP are independently - N(RN)S(O)2R2S, and each RN is independently hydrogen, methyl, ethyl, propyl, or isopropyl, and each R2S is independently methyl, ethyl, propyl, or isopropyl. In some embodiments, at least one RP is -N(RN)S(O)2R2S, e.g., both RP are independently -N(RN)S(O)2R2S, and each RN is independently an amine protecting group, and each R2S is independently methyl, ethyl, propyl, or isopropyl. 135Docket No.: 051058-000105WOP2B (nucleobase)

[0395] In some embodiments of the various aspects described herein, B is an optionaly 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 alyl 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-alyl-uracil, N3-methyluracil, substituted 1,2,4-triazoles, 2-pyridinone, 5-nitroindole, 3- nitropyrole, 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 al which is incorporated herein by reference.

[0396] 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-(aminoalkyl)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, 136Docket No.: 051058-000105WOP23-(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-(alylamino)uracil, 5-(aminoalyl)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, pyrolopyrimidinyl, 3- 137Docket No.: 051058-000105WOP2(methyl)isocarbostyrilyl, 5-(methyl)isocarbostyrilyl, 3-(methyl)-7-(propynyl)isocarbostyrilyl, 7- (aza)indolyl, 6-(methyl)-7-(aza)indolyl, imidizopyridinyl, 9-(methyl)-imidizopyridinyl, pyrolopyrizinyl, 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-nitropyrole, 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.

[0397] 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.

[0398] 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 al of adenine, cytosine, guanine and uracil without substantialy afecting the melting behavior, recognition by intracelular enzymes or activity of the oligonucleotide comprising the universal nucleobase. Some exemplary universal nucleobases include, but are not limited to, 2,4-difluorotoluene, nitropyrolyl, 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, pyrolopyrizinyl, 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.

[0399] 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. Examples of protected nucleobases include, but are not limited to, N3-acetyluracil, N3-acetyl-5-methyluracil, N3- isobutyryluracil, N3-isobutyryl-5-methyluracil, N3-pivaloyluracil, N3-pivaloyl-5-methyluracil, N3- benzoyluracil, N3-benzoyl-5-methyluracil, N3-(pivaloyloxymethyl)uracil, N3-(pivaloyloxymethyl)- 5-methyluracil, N3-(t-butyloxymethyl)uracil, N3-(t-butyloxymethyl)-5-methyluracil, N4- 138Docket No.: 051058-000105WOP2(alyloxycarbonyl)cytosine, N4-(alyloxycarbonyl)-5-methylcytosine, N4-acetylcytosine, N4- acetyl-5-methylcytosine, N4-isobutyrylcytosine, N4-isobutyryl-5-methylcytosine, N4- pivaloylcytosine, N4-pivaloyl-5-methylcytosine, N4-benzoylcytosine, N4-benzoyl-5- methylcytosine, N4-(2-phenoxyacetyl)cytosine, N4-(2-phenoxyacetyl)-5-methylcytosine, N4-(2-(4- (2-propyl)phenoxy)acetyl)cytosine, N4-(2-(4-(2-propyl)phenoxy)acetyl)-5-methylcytosine, N4-(2- (4-(1,1-dimethylethyl)phenoxy)acetyl)cytosine, N4-(2-(4-(1,1-dimethylethyl)phenoxy)acetyl)-5- methylcytosine, N4-(dimethylaminomethylene)cytosine, N4-(dimethylaminomethylene)-5- methylcytosine, N4-(1-methyl-2-pyrolidinylidene)cytosine, N4-(1-methyl-2-pyrolidinylidene)5- methylcytosine, 2,6-di(benzoylamino)purine, 2,6-di(isobutanoylamino)purine, N6-benzyladenine,

[0400] N6-acetyladenine, N6-isobutyryladenine, N6-pivaloyladenine, N6-benzoyladenine, N6- (2-phenoxyacetyl)adenine, N6-(2-(4-(2-propyl)phenoxy)acetyl)adenine, N6-(2-(4-(1,1- dimethylethyl)phenoxy)acetyl)adenine, N2-benzylguanine, N2-(dimethylaminomethylene)guanine, N2-acetylguanine, N2-isobutyrylguanine, N2-pivaloylguanine, N2-benzoylguanine, N2-(2- phenoxyacetyl)guanine, N2-(2-(4-(2-propyl)phenoxy)acetyl)guanine, and N2-(2-(4-(1,1- dimethylethyl)phenoxy)acetyl)guanine.

[0401] 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.

[0402] 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 deazapurine, optionaly modified at the N7 position.

[0403] 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, optionaly each independently comprising a hydroxyl, or amine protecting group. Double-stranded RNA

[0404] The skiled person is wel aware that double-stranded RNAs comprising a duplex structure of between 19 and 24, but specificaly 21, base pairs have been hailed as particularly efective in inducing RNA interference (RNAi). However, others have found that shorter or longer double-stranded oligonucleotides can be efective as wel. 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 139Docket No.: 051058-000105WOP2 the expression of a target nucleic acid, e.g., a target RNA such as a mRNA in a sequence specific manner.

[0405] Accordingly, in another aspect provided herein is a double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand substantialy or 100% (e.g., exactly) complementary to the sense strand, and wherein one of the sense and antisense strand has a 5’- terminal phosphate mimic modification comprising the structure: ,wherein: X is O or S; R71 and R72 are independently hydrogen or halogen (e.g., fluoro) , or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73A and R74A are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73A and R74A together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); 140Docket No.: 051058-000105WOP2R73B and R74B are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73B and R74B together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R75 and R76 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C alkyl, -ORO, -SRS, -N(RN) N 2S 1-3 2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, prov P 1-3 ided no more than one R is C1-3alkyl.

[0406] Generaly, the 5’-terminal phosphate mimic modification replaces a CH2OH group on the sugar moiety of the 5’-terminal nucleotide of the sense or antisense strand. For example, the , , .,e 4’-CH2OH group on a 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, alopyranose, altropyranose, gulopyranose, idopyranose, or talopyranose, preferably glucopyranose, galactopyranose, or mannopyranose) of the 5’-terminal nucleotide of the sense or antisense strand. In other embodiments, the 5’-terminal phosphate mimic 141Docket No.: 051058-000105WOP2

[0407] In other words, one of the sense and antisense strand comprises at its 5’-end a compound of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A-IA – A-IE, A-II, A-IIA – A- IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF described herein. For example, the 5’-terminal nucleotide of one of the sense and antisense strand is of the structure: ,, , , 142Docket No.: 051058-000105WOP2, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); Ring G 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; 143Docket No.: 051058-000105WOP2X is O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73A and R74A are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73A and R74A together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73B and R74B are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73B and R74B together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R75 and R76 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); one of R2’and R3’ is hydrogen, halogen, or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is a bond to an oligonucleotide (e.g., to an internucleoside linkage that connects to the subsequent nucleotide of the oligonucleotide).

[0408] In certain embodiments, at least one of R71 and R72 is halogen (e.g., fluoro). In another embodiment, both of R71 and R72 are halogen (e.g., fluoro). In certain embodiments, at least one of R71 and R72 is methyl. In another embodiment, both of R71 and R72 are methyl. In certain embodiments, R71 and R72 together with the carbon they are atached to, form cyclopropyl.

[0409] In certain embodiments, at least one of R73 and R74 is halogen (e.g., fluoro). In another embodiment, both of R73 and R74 are halogen (e.g., fluoro). In certain embodiments, at least one of R73 and R74 is methyl. In another embodiment, both of R73 and R74 are methyl. In certain embodiments, R73 and R74 together with the carbon they are atached to, form cyclopropyl.

[0410] In certain embodiments, at least one of R73A and R74A is halogen (e.g., fluoro). In another embodiment, both of R73A and R74A are halogen (e.g., fluoro). In certain embodiments, at least one 144Docket No.: 051058-000105WOP2 of R73A and R74A is methyl. In another embodiment, both of R73A and R74A are methyl. In certain embodiments, R73A and R74A together with the carbon they are atached to, form cyclopropyl.

[0411] In certain embodiments, at least one of R73B and R74B is halogen (e.g., fluoro). In another embodiment, both of R73B and R74B are halogen (e.g., fluoro). In certain embodiments, at least one of R73B and R74B is methyl. In another embodiment, both of R73B and R74B are methyl. In certain embodiments, R73B and R74B together with the carbon they are atached to, form cyclopropyl.

[0412] In certain embodiments, at least one of R75 and R76 is halogen (e.g., fluoro). In another embodiment, both of R75 and R76 are halogen (e.g., fluoro). In certain embodiments, at least one of R75 and R76 is methyl. In another embodiment, both of R75 and R76 are methyl. In certain embodiments, R75 and R76 together with the carbon they are atached to, form cyclopropyl.

[0413] In another embodiment, the double-stranded RNA (dsRNA) herein comprises a sense strand and an antisense strand substantialy or 100% (e.g., exactly) complementary to the sense strand, and wherein the antisense strand has a 5’-terminal nucleotide of the structure selected from the group consisting of:145Docket No.: 051058-000105WOP2, , , , , , , 146Docket No.: 051058-000105WOP2

[0414] Preferably, the antisense strand of the dsRNA is an oligonucleotide described herein.

[0415] As used herein, the term “antisense strand” refers to an oligonucleotide that is substantialy 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.

[0416] 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 147Docket No.: 051058-000105WOP2 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.

[0417] 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 of the 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.

[0418] 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.

[0419] 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.

[0420] 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.

[0421] 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. Generaly, the antisense strand of the dsRNA has a nucleotide overhang at the 3’-end, and the 5’-end is blunt. While not bound by 148Docket No.: 051058-000105WOP2 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.

[0422] 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.

[0423] 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.

[0424] In some embodiments, sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length. Nucleic acid modifications

[0425] 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.

[0426] 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. 149Docket No.: 051058-000105WOP2Thermaly destabilizing modifications

[0427] In some embodiments of any one of the aspects described herein, the dsRNA comprises a thermaly destabilizing modification. By a “thermaly destabilizing modification” is meant modification that result in a dsRNA having a lower overal melting temperature (Tm), preferably a Tm with one, two, three or four degrees lower, than the Tm of the dsRNA without having such a modification. Exemplary thermaly 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 internucleoside linkages that decrease the thermal stability of dsRNA duplexes; or nucleobases with impaired W-C H-bonding to complementary base on the opposite strand.

[0428] 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 thermaly destabilizing modifications. The thermaly destabilizing modification can be present at any position of the dsRNA. Further, the thermaly destabilizing modifications al 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 thermaly destabilizing modifications. In some embodiments, only the sense strand comprises at least one, e.g., two, three, four or more thermaly destabilizing modifications. In some embodiments, both the sense and the antisense strands comprise at least one, e.g., two, three, four or more thermaly destabilizing modifications.

[0429] The thermaly destabilizing modification can occur on any nucleotide of the sense strand or antisense strand. For instance, the thermaly destabilizing modification can occur on every nucleotide on the sense strand and / or antisense strand; each thermaly destabilizing modification can occur in an alternating patern on the sense strand or antisense strand; or the sense strand and antisense strand both comprise thermaly destabilizing modifications in an alternating patern. The alternating patern of the thermaly destabilizing modifications on the sense strand can be the same or diferent from the antisense strand, and the alternating patern of the thermaly destabilizing modifications on the sense strand can have a shift relative to the alternating patern of the thermaly destabilizing modifications on the antisense strand.

[0430] In some embodiments, thermaly 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 thermaly destabilizing modification is located at position 2, 3, 150Docket No.: 051058-000105WOP24, 5 or 9 from the 5’-end of the antisense strand. In some other embodiments, the thermaly destabilizing modification is located at position 6, 7 or 8 from the 5’-end of the antisense strand. In some particular embodiments, the thermaly destabilizing modification is located at position 7 from the 5’-end of the antisense strand.

[0431] In some embodiments, only the antisense strand comprises a thermaly destabilizing modification. For example, only the antisense strand comprises a thermaly destabilizing modification and said thermaly destabilizing modification is located at position 4, 5, 6, 7, or 8, counting from the 5’-end of the antisense strand, preferably the thermaly destabilizing modification is located at position 5, 6, 7, or 8; more preferably the thermaly destabilizing modification is located at position 6, 7, or 8. In some embodiments, only the antisense strand comprises a thermaly destabilizing modification and the thermaly destabilizing modification is located at position 7 of the antisense strand, counting from the 5’-end of the antisense strand.

[0432] Similar to the antisense strand, a thermaly 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 thermaly 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 thermaly destabilizing modification is located at position 6, 7 or 8 from the 5’-end of the longer- ssNA. In some particular embodiments, the thermaly destabilizing modification is located at position 7 from the 5’-end of the longer-ssNA. Thermaly stabilizing modifications

[0433] In some embodiments, dsRNA comprises a thermaly destabilizing modification. By a “thermaly stabilizing modification” is meant modification that result in a dsRNA having a higher overal 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 thermaly 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 prefered embodiments, the thermaly stabilizing modification is a 2’-fluoro nucleotide. Exemplary, thermaly 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.

[0434] 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 thermaly stabilizing (e.g., 2’- F) modifications. Without limitations, the thermaly stabilizing (e.g., 2’-F) modifications al can be 151Docket No.: 051058-000105WOP2 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 thermaly stabilizing (e.g., 2’-F) modifications. In some embodiments, the antisense strand comprises at least one, e.g., two, three, four or more thermaly 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 thermaly stabilizing (e.g., 2’-F) modifications. The thermaly stabilizing (e.g., 2’-F) modification can occur on any nucleotide of the sense strand or antisense strand. For instance, the thermaly stabilizing (e.g., 2’-F) modification can occur on every nucleotide on the sense strand and / or antisense strand; each thermaly stabilizing (e.g., 2’-F) modification can occur in an alternating patern on the sense strand or antisense strand; or the sense strand and antisense strand both comprise thermaly stabilizing (e.g., 2’-F) modifications in an alternating patern. The alternating patern of the thermaly stabilizing (e.g., 2’-F) modifications on the sense strand can be the same or diferent from the antisense strand, and the alternating patern of the thermaly stabilizing (e.g., 2’-F) modifications on the sense strand can have a shift relative to the alternating patern of the thermaly stabilizing (e.g., 2’-F) modifications on the antisense strand.

[0435] 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 thermaly stabilizing (e.g., 2’-F) modifications. In some embodiments, the sense strand comprises two, three, four, or five thermaly stabilizing (e.g., 2’-F) modifications. For example, the sense strand comprises three or four thermaly stabilizing (e.g., 2’-F) modifications. Without limitations, a thermaly 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 thermaly stabilizing (e.g., 2’-F) modifications. For example, the sense comprises thermaly 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 thermaly stabilizing (e.g., 2’-F) modifications. For example, the sense comprises thermaly stabilizing (e.g., 2’-F) modification at least at positions 7, 9, 10 and 11, counting from the 5’-end of the sense strand.

[0436] In some embodiments, the sense strand comprises thermaly 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 thermaly 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 thermaly stabilizing (e.g., 2’-F) modification.

[0437] In some embodiments, the sense strand comprises thermaly 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 152Docket No.: 051058-000105WOP2 antisense strand comprises thermaly 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 thermaly 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 thermaly 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 thermaly 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 thermaly 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.

[0438] In some embodiments, the sense strand comprises thermaly 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 thermaly 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 thermaly 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 thermaly 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 thermaly 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 thermaly 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.

[0439] In some embodiments, the sense strand does not comprise a thermaly stabilizing (e.g., 2’-F) modification in position opposite or complimentary to the thermaly destabilizing modification of the duplex in the antisense strand.

[0440] 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 thermaly stabilizing (e.g., 2’-F) modifications. In some embodiments, the antisense strand comprises two, three, four, five or six thermaly stabilizing (e.g., 2’-F) modifications. Without limitations, a thermaly 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 thermaly stabilizing (e.g., 2’-F) modifications. For example, the antisense strand comprises thermaly 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 thermaly stabilizing (e.g., 2’-F) modifications. For example, the antisense comprises thermaly 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 thermaly stabilizing (e.g., 2’-F) modifications. For example, the antisense 153Docket No.: 051058-000105WOP2 strand comprises thermaly 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 stil some further embodiments, the antisense strand comprises at least six thermaly stabilizing (e.g., 2’-F) modifications. For example, the antisense strand comprises thermaly 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.

[0441] In some embodiments, the antisense strand comprises at least one thermaly stabilizing (e.g., 2’-F) modification adjacent to a stabilizing destabilizing modification. For example, the thermaly stabilizing (e.g., 2’-F) modification can be the nucleotide at the 5’-end or the 3’-end of the thermaly destabilizing modification, i.e., at position -1 or +1 from the position of the thermaly destabilizing modification. In some embodiments, the antisense strand comprises a thermaly stabilizing (e.g., 2’-F) modification at each of the 5’-end and the 3’-end of the thermaly destabilizing modification, i.e., positions -1 and +1 from the position of the destabilizing modification.

[0442] 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.

[0443] In some embodiments, the sense strand does not comprise a thermaly stabilizing (e.g., 2’-F) modification in position opposite or complimentary to the thermaly destabilizing modification of the duplex in the antisense strand. 2’-OMe nucleotides

[0444] 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 al 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 patern on the sense strand or antisense strand; or the sense strand and antisense strand both comprise 2’-OMe modifications in an alternating patern. The alternating patern of the 2’-OMe modifications on the sense strand can be the same or diferent from the antisense strand, and the alternating patern of the 2’-OMe modifications on the sense strand can have a shift relative to the alternating patern of the 2’-OMe modifications on the antisense strand.

[0445] 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 154Docket No.: 051058-000105WOP2 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., thermaly destabilizing modification(s), thermaly stabilizing modification(s), and / or 2’-deoxy (2’-H) modification(s) of the antisense strand is independently a 2’-O-methyl nucleotide.

[0446] 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., thermaly stabilizing modification(s), lipophilic modification(s), inverted nucleotide(s), thermaly 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

[0447] 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.

[0448] A 2’-deoxy nucleotide can be present in any position of the sense or antisense strand. Further, 2’-deoxy nucleotides al can be present in one strand or both strands of the dsRNA.

[0449] 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.

[0450] 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. 155Docket No.: 051058-000105WOP2 Lipophilic modifications

[0451] 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-C30 alkyl, or a C10-C30 alkenyl group, such as a C16 alkyl, a C16 alkenyl, a C18 alkyl, a C18 alkenyl, a C20alkyl, a C20 alkenyl, a C22 alkyl, a C22 alkenyl, a C24 alkyl, a C24 alkenyl; C15 alkyl, a C15 alkenyl, a C17 alkyl, a C17 alkenyl, a C19alkyl, a C19 alkenyl, a C21 alkyl, a C21 alkenyl, a C23 alkyl, or a C23 alkenyl) 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).

[0452] A lipophilic modification can be present in any position of the sense or antisense strand. Further, lipophilic modifications al 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.

[0453] 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-alyl, or 2’-C-alyl, 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 thermaly destabilizing modification of the duplex present in the antisense strand) of dsRNA molecule.

[0454] In some embodiments, at least two diferent modifications are typicaly present on the sense strand and antisense strand. Those two modifications may be the 2’-deoxy, 2’-O-methyl or 2’- fluoro modifications, thermaly destabilizing modifications. In some embodiments, the sense strand and antisense strand each comprises two diferently 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 156Docket No.: 051058-000105WOP2 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 thermaly destabilizing modification of the duplex present in the antisense strand.

[0455] In some embodiments, the antisense strand comprises at least one thermaly 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 thermaly 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 thermaly destabilizing modification at position 5, 6, 7, or 8, counting from the 5’-end of the antisense strand; (i) at least two, e.g., 3, 4, 5 or 62’-fluoro nucleotides; and (ii) the remaining nucleotides are independently a 2’-O-methyl nucleotide or 2’-deoxy nucleotide.

[0456] 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 62’-fluoro nucleotides, and the remaining nucleotides are independently a 2’-O-methyl nucleotide or 2’-deoxy nucleotide.

[0457] 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 the duplex 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. 157Docket No.: 051058-000105WOP2Modified internucleoside linkages

[0458] 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, phosphodiesetrs, phosphorothioates (R, S, or racemic), phosphorodithioates, methylenemethylimino (MMI, 3'-CH2-N(CH3)-O-5'), phosphotriesters, C1-6alkylphosphonates (e.g., methylphosphonates), phosphoramidates (e.g., or N- mesylphosphoramidate), 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, optionaly the modified internucleoside linkage is phosphorothioate, methylphosphonate, or N-mesylphosphoramidate, imidp or MMI, more preferably the modified internucleoside linkage is phosphorothioate (PS).

[0459] A modified internucleoside linkage can occur on any nucleotide of the sense strand or antisense strand or both in any position of the strand. For instance, the internucleoside linkage modification can occur on every nucleotide on the sense strand and / or antisense strand; each internucleoside linkage modification can occur in an alternating patern on the sense strand or antisense strand; or the sense strand or antisense strand comprises both internucleoside linkage modifications in an alternating patern. The alternating patern of the internucleoside linkage modification on the sense strand can be the same or diferent from the antisense strand, and the alternating patern of the internucleoside linkage modification on the sense strand can have a shift relative to the alternating patern of the internucleoside linkage modification on the antisense strand.

[0460] In some embodiments, the dsRNA comprises the modified internucleoside (e.g., phosphorothioate,methylphosphonate, or N-mesylphosphoramidate internucleoside) linkage(s) in the overhang region. For example, the overhang region comprises two nucleotides having modified internucleoside (e.g., phosphorothioate, methylphosphonate, or N-mesylphosphoramidate internucleoside) linkage between the two nucleotides. Internucleoside linkage modifications can 158Docket No.: 051058-000105WOP2 also be made to link the overhang nucleotides with the terminal paired nucleotides within duplex region. For example, at least 2, 3, 4, or al the overhang nucleotides can be linked through modified internucleoside (e.g., phosphorothioate,methylphosphonate, or N-mesylphosphoramidate internucleoside) linkage, and optionaly, there can be additional modified internucleoside (e.g., phosphorothioate, methylphosphonate, or N-mesylphosphoramidate internucleoside) 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, methylphosphonate, or N-mesylphosphoramidate internucleoside) 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.

[0461] With respect to position of an internucleoside linkage, the indicated position refers to the internucleoside linkage that links the nucleotide at said position with the nucleotide one position down stream from said position. In other word, an internucleoside linkage at position N means it is between nucleotides N and N+1. Thus, an internucleoside 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.

[0462] In some embodiments, the sense strand comprises one to five (e.g., 1, 2, 3, 4 or 5) modified internucleoside (e.g., phosphorothioate, methylphosphonate, or N-mesylphosphoramidate) 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, methylphosphonate, or N- mesylphosphoramidate) 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, methylphosphonate, or N-mesylphosphoramidate) 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, methylphosphonate, or N- mesylphosphoramidate) linkage between nucleotide positions 1 and 2, and between nucleotide positions 2 and 3, counting from the 3’-end of the sense strand.

[0463] In some embodiments, the antisense strand comprises one to five (e.g., 1, 2, 3, 4 or 5) modified internucleoside (e.g., phosphorothioate, methylphosphonate, or N-mesylphosphoramidate) 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, methylphosphonate, or N- mesylphosphoramidate) 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, methylphosphonate, or N-mesylphosphoramidate) linkage between nucleotide positions 1 and 2, and between nucleotide positions 2 and 3, counting from the 5’-end of the antisense 159Docket No.: 051058-000105WOP2 strand, and the antisense strand further comprises a modified internucleoside (e.g., phosphorothioate, methylphosphonate, or N-mesylphosphoramidate) linkage between nucleotide positions 1 and 2, and between nucleotide positions 2 and 3, counting from the 3’-end of the antisense strand.

[0464] In some embodiments, the sense strand comprises a modified internucleoside (e.g., phosphorothioate, methylphosphonate, or N-mesylphosphoramidate) linkage at positions 1 and 2 counting from the 5’-end of the sense strand, a modified internucleoside (e.g., phosphorothioate, methylphosphonate, or N-mesylphosphoramidate) 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, methylphosphonate, or N-mesylphosphoramidate) linkage at positions 1 and 2 counting from the 5’-end of the antisense strand, a modified internucleoside (e.g., phosphorothioate, methylphosphonate, or N-mesylphosphoramidate) linkage at positions 1 and 2, counting from the 3’-end of the antisense strand. Overhang modifications

[0465] 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 internucleoside linkage between the two nucleotides, where the two nucleotides in the overhang region can be the same or diferent. 5’-modifications

[0466] The 5’-end of a strand of the dsRNA lacking the 5’-terminal phosphate modification 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. 160Docket No.: 051058-000105WOP2

[0467] 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.

[0468] In some embodiments, the sense strand comprises a ligand at its 3’-end. Ligands

[0469] In some embodiments, the longer double-stranded and single-stranded oligonucleotide can comprise a ligand. Without wishing to be bound by a theory, a ligand can modify one or more properties of the atached molecule (e.g., the dsRNA described herein) including but not limited to pharmacodynamic, pharmacokinetic, binding, absorption, celular distribution, celular uptake (cel targeting), charge and clearance.

[0470] In some embodiments, the ligand is a targeting ligand. As used herein the term “targeting ligand” refers to any molecule that provides an enhanced afinity for a selected target, e.g., a cel, cel type, tissue, organ, region of the body, or a compartment, e.g., a celular, 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, transfering receptor ligands (e.g., transferin), biotin, serotonin receptor ligands, PSMA, endothelin, GCPI, somatostatin, lipoprotein receptor ligands (e.g., LDL and HDL) .

[0471] 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 scafold molecule.

[0472] 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 cels that may be utilized in order to achieve delivery of an oligonucleotide, such as to a neuronal cel, a glial cel, a microglial cel, an oligodendrocytic cel, an ependymal cel, astrocytic cel, a unipolar cel, a bipolar cel, a multipolar cel, a psuedounipolar 161Docket No.: 051058-000105WOP2 cel, a pyramidal cel, a basket cel, a stelate cel, a purkinje cel, a betz cel, an amacrine cel, a granule cel, an ovoid cel, a medium aspiny neuronal cel, and / or a large aspiny ...

Claims

Docket No.: 051058-000105WOP2 CLAIMS What is claimed is:

1. A compound of Formula (A), ,wherein: h is 1, 2 or 3 (e.g., 1 or 2); B is an optionaly modified nucleobase (e.g., uracil or thymine); Ring G 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; X is O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C al O S N N 2S 1-3 kyl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; 4912-9036-9864.8 353Docket No.: 051058-000105WOP2 each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C1-3alkyl, provided no more than one RP is C1-3alkyl; one of R2’and R3’ is hydrogen, halogen (e.g., fluoro), or -OR20, wherein: R20 is 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); and the other of R2’and R3’ is -OR30, wherein: R30 is 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.

2. The compound of claim 1, wherein h is 1.

3. The compound of claim 2, wherein the compound is of Formula (Ia),a salt thereof.

4. The compound of claim 2, wherein the compound is of Formula (Ib),a salt thereof.

5. The compound of any one of claims 1-4, wherein X is O.

6. The compound of any one of claims 1-4, wherein X is S.

7. The compound of any one of claims 1-6, wherein at least one RP is -ORO, optionaly, each RP is independently -ORO.

8. The compound of claim 7, wherein each RO is independently H, methyl, ethyl, propyl, 1- methylethyl, butyl, or tert-butyl, optionaly each RO is independently H, methyl, or ethyl. 4912-9036-9864.8 354Docket No.: 051058-000105WOP2 9. The compound of claim 7, wherein each RO is independently a hydroxyl protecting group.

10. The compound of any one of claims 1-9, wherein at least one (e.g., one) RP is -N(RN)2 or - N(RN)S(O) 2S 2R .

11. The compound of any one of claims 1-10, wherein B is an unmodified nucleobase (e.g., uracil, adenine, cytosine, guanine, or thymine).

12. The compound of any one of claims 1-10, wherein B is a modified or protected nucleobase.

13. The compound of any one of claims 1-12, wherein R2’ is hydrogen or halogen (e.g., fluoro).

14. The compound of any one of claims 1-12, wherein R2’ is -OR20.

15. The compound of claim 14, wherein R20 is optionaly substituted C1-6alkyl.

16. The compound of claim 15, wherein R20 is 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, R20 is methyl or 2-(N-methylamino)-2-oxoethyl.

17. The compound of claim 14, wherein R20 is C1-6alkoxyC1-6alkyl (e.g., 2-methoxyethyl).

18. The compound of any one of claims 1-17, wherein R3’ is -OR30, wherein R30 is hydrogen, a hydroxyl protecting group, or a reactive phosphorous group.

19. The compound of claim 18, wherein R30 is hydrogen.

20. The compound of claim 18, 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.

21. The compound of claim 18, wherein the reactive phosphorous group is a phosphoramidite, H-phosphonate, alkyl-phosphonate, or phosphate triester. 4912-9036-9864.8 355Docket No.: 051058-000105WOP2 22. The compound of any one of claims 1-17, wherein the R3’ is a bond to an oligonucleotide.

23. The compound of claim 22, wherein R3’ is connected to the oligonucleotide via a phosphodiester or modified internucleoside linkage (e.g., phosphorothioate).

24. The compound of claim 22 or 23, wherein R3’ is connected to the 5’-terminal of a oligonucleotide (e.g., 5’-hydroxyl at the 5’-terminal of the oligonucleotide).

25. The compound of any one of claims 1-24, wherein: X is O; each RP is -ORO; R2’ is hydrogen, F, or -OR20, wherein R20 is 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 R30 is hydrogen, hydroxyl protecting group, or a reactive phosphorous group.

26. The compound of claim 1, wherein the compound is of formula:wherein: R20 is C1-3alkyl or C1-3alkoxyC1-3alkyl; and R30 is hydrogen, a hydroxyl protecting group or a reactive phosphorous group.

27. The compound of any one of claims 1-26, wherein (a) R20 is methyl and R30 is a reactive phosphorous group (e.g., -P(ORP1)N(RP2)2, where RP1 –CHCHCN, and each RP2 2 2 is isopropyl); or 4912-9036-9864.8 356Docket No.: 051058-000105WOP2 (b) R20 is 2-methoxyethyl and R30 is a reactive phosphorous group (e.g., -P(ORP1)N(RP2)2, where RP1 –CH P2 2CH2CN, and each R is isopropyl; or (c) R20 is methyl and R30 is a hydroxyl protecting group (e.g., t-butyldimethylsilyl) or hydrogen; or (d) R20 is 2-methoxyethyl and R30 is a hydroxyl protecting group (e.g., t-butyldimethylsilyl) or hydrogen.

28. The compound of any one of claims 1-27, wherein X is O and each RP is -ORO, where each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl (e.g., ethyl).

29. The compound of claim 1, wherein the compound is of formula:.

30. The compound of claim 29, wherein: R20 is methyl; R30 is a reactive phosphorous group (e.g., -P(ORP1)N(RP2), w P1 2 here R –CH2CH2CN, and each RP2 is isopropyl; X is O; and each RP is -ORO, where each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl (e.g., ethyl).

31. The compound of claim 29, wherein: R20 is 2-methoxyethyl; R30 is a reactive phosphorous group (e.g., -P(ORP1)N(RP2) P1 2, where R –CH2CH2CN, and each RP2 is isopropyl); X is O; and each RP is -ORO, where each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl (e.g., ethyl).

32. The compound of claim 29, wherein: R20 is methyl; R30 is a hydroxyl protecting group (e.g., t-butyldimethylsilyl); X is O; and each RP is -ORO, where each RO is independently methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl (e.g., ethyl). 4912-9036-9864.8 357Docket No.: 051058-000105WOP2 33. The compound of claim 29, wherein: R20 is 2-methoxyethyl; R30 is a hydroxyl protecting group (e.g., t-butyldimethylsilyl); X is O; and each RP is -ORO, where each RO is independently, methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl (e.g., ethyl).

34. The compound of any one of claims 1-33, wherein B is uracil or thymine (e.g., uracil).

35. The compound of claim 1, wherein the compound is selected from the group consisting of:4912-9036-9864.8 358Docket No.: 051058-000105WOP24912-9036-9864.8 359Docket No.: 051058-000105WOP24912-9036-9864.8 360Docket No.: 051058-000105WOP24912-9036-9864.8 361Docket No.: 051058-000105WOP24912-9036-9864.8 362Docket No.: 051058-000105WOP24912-9036-9864.8 363Docket No.: 051058-000105WOP24912-9036-9864.8 364Docket No.: 051058-000105WOP24912-9036-9864.8 365Docket No.: 051058-000105WOP24912-9036-9864.8 366Docket No.: 051058-000105WOP24912-9036-9864.8 367Docket No.: 051058-000105WOP24912-9036-9864.8 368Docket No.: 051058-000105WOP24912-9036-9864.8 369Docket No.: 051058-000105WOP24912-9036-9864.8 370Docket No.: 051058-000105WOP236. An oligonucleotide having a 5’-terminal phosphate mimic modification comprising the structure:wherein: X is O or S; 4912-9036-9864.8 371Docket No.: 051058-000105WOP2 R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the same carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); each RP is independently C O S N N 2S 1-3alkyl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, provided n P 1-3 o more than one R is C1-3alkyl.

37. The oligonucleotide of claim 36, wherein the 5’-terminal phosphate mimic modification comprises the structure:, wherein: X is O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro), methyl, or R71 and R72, together with the carbon they are atached to form a C3-6cycloalkyl (e.g., cyclopropyl); each RP is independently C O S N N 2S 1-3alkyl, -OR, -SR, -N(R)2, or -N(R)S(O)2R , wherein: each RO is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; each RS is independently hydrogen, C1-3alkyl, or a thiol protecting group; each RN is independently hydrogen, C1-3alkyl, or an amine protecting group; and R2S is C alkyl, provided no P 1-3 more than one R is C1-3alkyl. 4912-9036-9864.8 372Docket No.: 051058-000105WOP2 38. The oligonucleotide of claim 36 or 37, wherein the 5’-terminal phosphate mimic modification is comprised in a nucleotide comprising a furanose (e.g., ribofuranose, arabinofuranose, lyxofuranose, xylofuranose, ribulofuranose or xylulofuranose, optionaly ribofuranose) or a pyranos (e.g., glucopyranose, galactopyranose, mannopyranose, alopyranose, altropyranose, gulopyranose, idopyranose, or talopyranose) sugar, and alpha and beta, D and L, deoxy, and modified derivates thereof.

39. The oligonucleotide of claim 36, wherein the 5’-terminal nucleotide has the structure:, wherein: B is an optionaly modified nucleobase (e.g., uracil or thymine); X is O or S; R71 and R72 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R71 and R72 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73A and R74A are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73A and R74A together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R73 and R74 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); R75 and R76 are independently hydrogen, halogen (e.g., fluoro), or methyl, or R73 and R74 together with the carbon they are atached to form a C3-C6cycloalkyl (e.g., cyclopropyl or cyclobutyl); one of R2’and R3’ is hydrogen, halogen, or -OR20, wherein: R20 is 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); ; and the other of R2’and R3’ is -OR30, wherein: 4912-9036-9864.8 373Docket No.: 051058-000105WOP2 R30 is a bond to an oligonucleotide (e.g., to an internucleoside linkage that connects to the subsequent nucleotide of the oligonucleotide).

40. The oligonucleotide of claim 39, wherein the 5’-terminal nucleotide has the structure:.

41. The oligonucleotide of claim 39, wherein the 5’-terminal nucleotide has the structure:.

42. The oligonucleotide of claim 36, wherein the 5’-terminal nucleotide has the formula:, wherein Z is O or S and R20 is C1-3alkyl or C1-3alkoxyC1-3alkyl.

43. The oligonucleotide of claim 42, wherein the 5’-terminal nucleotide has the formula:.

44. The oligonucleotide of claim 39 wherein the 5’-terminal nucleotide has the formula:l or C1-3alkoxyC1-3alkyl. 4912-9036-9864.8 374Docket No.: 051058-000105WOP2 45. The oligonucleotide of claim 44, wherein the 5’-terminal nucleotide has the formula:.

46. The oligonucleotide of any one of claims 39-45 wherein B is uracil or thymine (e.g., uracil).

47. The oligonucleotide of any one of claims 39-46, wherein X is O and each RP is -OH.

48. An oligonucleotide, wherein the oligonucleotide is a compound of any one of claims 22- 24.

49. The oligonucleotide of any one of claims 36-48, wherein the oligonucleotide is from 10 to 50 nucleotides (e.g., from 15 to 40 nucleotides) in length, wherein the compound of Formula (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A-IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF is one nucleotide.

50. The oligonucleotide of claim 49, 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.

51. The oligonucleotide of any one of claims 36-50, 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).

52. The oligonucleotide of claim 51, wherein the oligonucleotide comprises at least one nucleic acid modification selected from the group consisting of nucleobase modifications, sugar modifications, internucleoside linkage modifications, conjugates (e.g., ligands), and any combinations thereof.

53. The oligonucleotide of any one of claims 36-52, wherein the oligonucleotide comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2’-OMe nucleotides. 4912-9036-9864.8 375Docket No.: 051058-000105WOP2 54. The oligonucleotide of any one of claims 36-53, 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.

55. The oligonucleotide of claim 54, 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 (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A- IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF 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.

56. The oligonucleotide of any one of claims 36-55, wherein the oligonucleotide comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2’-F nucleotides.

57. The oligonucleotide of claim 56, 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 (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A-IA – A- IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B- IIF 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.

58. The compound of any one of claims 36-57, 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.

59. The oligonucleotide of claim 58, 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 (A) or (B), e.g., of formulae I, A-I, A-IB, A-IC, A-I, A-IA – A-IE, A-II, A-IIA – A-IIF, B-I, B-IA – B-ID, B-I, B-IA – B-IE, B-II and B-IIA – B-IIF 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 4912-9036-9864.8 376Docket No.: 051058-000105WOP2 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.

60. The oligonucleotide of any one of claims 36-59, 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.

61. The oligonucleotide of any one of claims 36-60, wherein the oligonucleotide comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) modified internucleoside linkages.

62. The oligonucleotide of claim 61, 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.

63. The oligonucleotide of any one of claims 36-62, wherein the oligonucleotide is covalently linked to a support, e.g., a solid support.

64. 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 36-63.

65. The dsRNA of claim 64, wherein the antisense strand is the oligonucleotide of any one of claims 87-110.

66. The dsRNA of claim 64 or 65, wherein the dsRNA is capable of inducing RNA interference.

67. 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 64-66, wherein the antisense strand is substantialy complementary to a target gene; or (i) an oligonucleotide according to any one of claims 36-63, wherein the oligonucleotide is substantialy complementary to a target gene. 4912-9036-9864.8 377Docket No.: 051058-000105WOP2 68. A composition comprising a compound of any one of claims 1-35, an oligonucleotide of any one of claims 36-63, or a dsRNA of any one of claims 64-66.

69. A kit comprising a compound of any one of claims 1-35, an oligonucleotide of any one of claims 36-63, or a dsRNA of any one of claims 64-66.

70. A cel (e.g. an in vivo cel) comprising a compound of any one of claims 1-35, an oligonucleotide of any one of claims 36-63, or a dsRNA of any one of claims 64-66.

71. A method of preparing a compound of formula,, or a salt thereof, wherein: B is an optionaly modified nucleobase (e.g., uracil); each RO is independently hydrogen,C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl) or a hydroxyl-protecting group (e.g., POM); one of R2’and R3’ is hydrogen, halogen, or -OR20, wherein: R20 is 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 the other of R2’and R3’ is -OR30, wherein: R30 is a reactive phosphorous group (e.g., a phosphoramidite), the method comprising: 4912-9036-9864.8 378Docket No.: 051058-000105WOP2 (i) reacting a compound formulaa triphenyl phosphonium ylide of formulato obtain a compound of formula, where: B is an optionaly modified nucleobase (e.g., uracil or thymine); one of R2S and R3S is hydrogen, halogen, or -OR20, wherein: R20 is 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 R30 is a hydroxyl protecting group (e.g., TBS); and RX is C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, or tert- butyl); (i) reducing the double bond (e.g., with NaBH4) and the ester (e.g., with NaBH4) in the compound obtained in step (i) to obtain the compound; (ii) reacting the compound obtained in step (i) with a halogenation agent (e.g., I2) to obtain the compound, e.g., I, Cl, Br or F, preferably I); 4912-9036-9864.8 379Docket No.: 051058-000105WOP2 (iv) reacting the compound obtained in step (ii) with P(O)(ORO)2H to obtain, where: each RO is independently hydrogen or C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl), optionaly each RO is ethyl; (v) partialy deprotecting the compound obtained in step (iv) to remove the R30 hydroxyl protecting group (e.g., TBS) to obtain the compounda hydroxyl (OH) group; (vi) reacting the partialy deprotected compound from step (v) with a phosphorylation reagent (e.g., a phosphitylation reagent) to obtain the compound, optionaly the phosphitylation reagent is reagent is P(ORP1)N(RP2) LG 2R , where: RP1 is optionaly substituted C1-6alkyl (e.g., C1-6alkyl optionaly substituted with a CN or –SC(O)Ph); each RP2 is independently optionaly substituted C1-6alkyl, or both RP2 taken together with the nitrogen atom to which they are atached form an optionaly substituted 3-8 membered heterocyclyl, or RP1 and one of RP2 taken together with the atoms to which they are atached form an optionaly substituted 4-8 membered heterocyclyl; and each RLG is halogen (e.g., Cl). 4912-9036-9864.8 380

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