5'-cyclo-phosphonate modified nucleotides

A compound having Formula I-b-5 or Formula II-b-5:

• wherein,
• D is O, S, CH2—CH2, CH═CH, OCH2, N(R1), C(R2)(R3), C(R2)(R3)C(R4)(R2), C(R2)═C(R4), OC(R2)(R3), OC(H)(X3) or OC(R2)(X3);
• R1 is H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, or substituted C2-C6 alkynyl;
• R2, R3, and R4 are each, independently, H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, or substituted C2-C6 alkynyl;
• when D is O, S, CH2—CH2, CH═CH, OCH2, N(R1), C(R2)(R3), C(R2)(R3)C(R4)(R2), C(R2)═C(R4), OC(R2)(R3), then X is a heterocyclic base moiety;
• when D is OC(H)(X3) or OC(R2)(X3), X is H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl and X3 is a heterocyclic base moiety;
• Z is H, —OH, F, OCH3, —O—(CH2)2—OCH3;
• halogen;
• —OCH2F, —OCHF2, —OCF3, —OCH2CH3, —O(CH2)2F, —OCH2CHF2, —OCH2CF3, —OCH2—CH═CH2, —O(CH2)2—OCH3, —O(CH2)2—SCH3, —O(CH2)2—OCF3, —O(CH2)2—O(CH2)2—N(CH3)2, —OCH2C(═O)—N(H)CH3, —OCH2C(═O)—N(H)—(CH2)2—N(CH3)2, —O(CH2)2—N(H)—C(═NH)(NH2), —O(CH2)3—N(R5)(R6), —O(CH2)2—ON(R5)(R6), —O(CH2)2—O(CH2)2—N(R5)(R6), —OCH2C(═O)—N(R5)(R6), —OCH2C(═O)—N(R7)—(CH2)2—N(R5)(R6)—O(CH2)2—N(R7)—C(═R8)[N(R5)(R6)], optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl, wherein R5, R6, R7 and R8 are each, independently, H or C1-C6 alkyl;
• Y1, Y2, Y3, and Y4 are each, independently, H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, or substituted C2-C6 alkynyl;
• or, alternatively, Y4 is linked to one of Y1 or Y2, wherein the linkage comprises a divalent group selected from O, S, NR9, C(R10)(R11), C(R10)═C(R11), C[═C(R10)(R11)] and C(═O), and the other two of Y1, Y2, and Y3, are each, independently, H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl, wherein each R9, R10 and R11 is, independently, H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, or substituted C2-C6 alkynyl;
• J is O, S, NR12, N—N(R13)2, or N—OR13, wherein:
• R12 is H, OH, halogen, C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, or
• wherein R14 is selected from H or C1-C4 alkyl optionally substituted with one to three substituents independently selected from SH, S—(C1-C4 alkyl), aryl optionally substituted with hydroxyl, heteroaryl optionally substituted with hydroxyl, amino, hydroxyl, oxo, or NH—C═(NH)NH2, wherein R11 is selected from H, C1-C18 alkyl, or aryl;
• wherein R13 is H, C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, or
• wherein R14 is selected from H or C1-C4 alkyl optionally substituted with one to three substituents independently selected from SH, S—(C1-C4 alkyl), aryl optionally substituted with hydroxyl, heteroaryl optionally substituted with hydroxyl, amino, hydroxyl, oxo, or NH—C═(NH)NH2, and wherein R15 is selected from H, C1-C18 alkyl, or aryl;
• K and L are each independently selected from OH, OR16, SR16, or NR16, wherein R16 is selected from H, C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, or
• wherein R14 is selected from H or C1-C4 alkyl optionally substituted with one to three substituents independently selected from SH, S—(C1-C4 alkyl), aryl optionally substituted with hydroxyl, heteroaryl optionally substituted with hydroxyl, amino, hydroxyl, oxo or —NH—C═(NH)NH2, and R15 is selected from H, C1-C18 alkyl, or aryl;
• and
• G1, G2, G3 and G4 are each independently selected from the group consisting of H, F, halogen, C1-C6 alkyl, CN, CH2(R33), CH2—O—(R33), C(═O)(R33), C(═S)(R33), or (R34)(R33), wherein R33 is O(R35), S(R35), N(R35)(R36), wherein R34, R35, and R36 are each independently selected from H, halogen, or C1-C6 alkyl.

An RNAi agent having Formula III-b or Formula IV-b:

• wherein:
• X is a heterocyclic base moiety;
• Z is H, —OH, F, OCH3, —O—(CH2)2—OCH3;
• halogen;
• —OCH2F, —OCHF2, —OCF3, —OCH2CH3, —O(CH2)2F, —OCH2CHF2, —OCH2CF3, —OCH2—CH═CH2, —O(CH2)2—OCH3, —O(CH2)2—SCH3, —O(CH2)2—OCF3, —O(CH2)2—O(CH2)2—N(CH3)2, —OCH2C(═O)—N(H)CH3, —OCH2C(═O)—N(H)—(CH2)2—N(CH3)2, —O(CH2)2—N(H)—C(═NH)(NH2), —O(CH2)3—N(R5)(R6), —O(CH2)2—ON(R5)(R6), —O(CH2)2—O(CH2)2—N(R5)(R6), —OCH2C(═O)—N(R5)(R6), —OCH2C(═O)—N(R7)—(CH2)2—N(R5)(R6)—O(CH2)2—N(R7)—C(═R8)[N(R5)(R6)], optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl, wherein R5, R6, R7 and R8 are each, independently, H or C1-C6 alkyl;
• J and J′ are each independently O or S;
• and
• includes the remainder of the RNAi agent.