Folate conjugates

1. An iRNA agent comprising at least one monomer having the structure shown in formula (I′)

wherein:

A and B are each independently for each occurrence O, N(R N ) or S;

X is H, a protecting group, a phosphate group, a phosphodiester group, an activated phosphate group, an activated phosphite group, a phosphoramidite, a solid support, —P(Z′)(Z″)O-nucleoside, —P(Z′)(Z″)O-oligonucleotide, a lipid, a PEG, a steroid, a polymer, —P(Z′)(Z″)O-L 6 -Q′-L 7 -P(Z′″)(Z″″)O-oligonucleotide, a nucleotide, or an oligonucleotide;

Y is H, a protecting group, a phosphate group, a phosphodiester group, an activated phosphate group, an activated phosphite group, a phosphoramidite, a solid support, —P(Z′)(Z″)O-nucleoside, —P(Z′)(Z″)O-oligonucleotide, a lipid, a PEG, a steroid, a lipophile, a polymer, —P(Z′)(Z″)O-L 6 -Q′-L 7 -OP(Z′″)(Z″″)O-oligonucleotide, a nucleotide, or an oligonucleotide;

R is folate, a folate analog a folate mimic or a folate receptor binding ligand;

L 6 and L 7 are each independently for each occurrence —(CH 2 ) n —, —C(R′)(R″)(CH 2 ) n —, —(CH 2 ) n C(R′)(R″)—, —(CH 2 CH 2 O) m CH 2 CH 2 —, or —(CH 2 CH 2 O) m CH 2 CH 2 NH—;

Q′ is NH, O, S, CH 2 , C(O)O, C(O)NH, —NH—CH(R a )—C(O)—, —C(O)—CH(R a )—NH—, CO,

R a is H or amino acid side chain;

R′ and R″ are each independently H, CH 3 , OH, SH, NH 2 , NH(Alkyl) or N(diAlkyl);

Z′, Z″, Z′″ and Z″″ are independently O or S;

n represent independently for each occurrence 1-20; and

m represent independently for each occurrence 0-50.

2. An iRNA agent comprising at least one monomer having the structure shown in formula (I)

wherein:

X is H, a hydroxyl protecting group, a phosphate group, a phosphodiester group, an activated phosphate group, an activated phosphite group, a phosphoramidite, a solid support, —P(Z′)(Z″)O-nucleoside, —P(Z′)(Z″)O-oligonucleotide, a lipid, a PEG, a steroid, a polymer, —P(Z′)(Z″)O-L 6 -Q′-L 7 -OP(Z′″)(Z″″)O-oligonucleotide, a nucleotide, or an oligonucleotide;

Y is H, a hydroxyl protecting group, a phosphate group, a phosphodiester group, an activated phosphate group, an activated phosphite group, a phosphoramidite, a solid support, —P(Z′)(Z″)O-nucleoside, —P(Z′)(Z″)O-oligonucleotide, a lipid, a PEG, a steroid, a lipophile, a polymer, —P(Z′)(Z″)O-L 6 -Q′-L 7 -OP(Z′″)(Z″″)O- ligonucleotide, a nucleotide, or an oligonucleotide;

Q is a tether;

R is folate, a folate analog a folate mimic or a folate receptor binding ligand;

L 6 and L 7 are each independently for each occurrence —(CH 2 ) n —, —C(R′)(R″)(CH 2 ) n —, —(CH 2 ) n C(R′)(R″)—, —(CH 2 CH 2 O) m CH 2 CH 2 —, or —(CH 2 CH 2 O) m CH 2 CH 2 NH—;

Q′ is NH, O, S, CH 2 , C(O)O, C(O)NH, —NH—CH(R a )—C(O)—, —C(O)—CH(R a )—NH—, CO,

R a is H or amino acid side chain;

R′ and R″ are each independently H, CH 3 , OH, SH, NH 2 , NH(Alkyl) or N(diAlkyl);

Z′, Z″, Z′″ and Z″″ are independently O or S;

n represent independently for each occurrence 1-20; and

m represent independently for each occurrence 0-50.

3. The iRNA agent of claim 1 , wherein said iRNA agent is double stranded.

4. The iRNA agent of claim 3 , wherein said monomer is at the 3′-end of one of the strands.

5. The iRNA agent of claim 4 , wherein said monomer is at the 3′-end of sense strand.

6. The iRNA agent of claim 1 , wherein the iRNA agent further comprises at least one monomer of formula (LI)

wherein X 6 and Y 6 are each independently H, a hydroxyl protecting group, a phosphate group, a phosphodiester group, an activated phosphate group, an activated phosphate group, a phosphoramidite, a solid support, —P(Z′)(Z″)O-nucleoside, —P(Z′)(Z″)O-oligonucleotide, a lipid, a PEG, a steroid, a polymer, —P(Z′)(Z″)O—R 1 -Q′-R 2 —OP(Z′″)(Z″″)O-oligonucleotide, a nucleotide, or an oligonucleotide, —P(Z′)(Z″)-formula (I) or —P(Z′)(Z″)—;

Q 6 is absent or —(P 6 -Q 6 -R 6 ) v -T 6 -;

P 6 and T 6 are each independently for each occurrence absent, CO, NH, O, S, OC(O), NHC(O), CH 2 , CH 2 NH or CH 2 O;

Q 6 is independently for each occurrence absent, substituted alkylene wherein one or more methylenes can be interrupted or terminated by one or more of O, S, S(O), SO 2 , N(R N ), C(R′)═C(R′), C≡C or C(O);

R 6 is independently for each occurrence absent, NH, O, S, CH 2 , C(O)O, C(O)NH, NHCH(R a )C(O), —C(O)—CH(R a )—NH—, CO, CH═N—O,

 or heterocyclyl;

R′ and R″ are each independently H, C 1 -C 6 alkyl OH, SH, N(R N ) 2 ;

R N is independently for each occurrence methyl, ethyl, propyl, isopropyl, butyl or benzyl;

R a is H or amino acid side chain;

Z′, Z″, Z′″ and Z″″ are each independently for each occurrence O or S;

v represent independently for each occurrence 0-20;

R L is a lipophile or a cationic lipid.

7. The RNAi agent of claim 6 , wherein R L is a lipophile.

8. The RNAi agent of claim 7 , wherein R L is cholesterol.

9. The RNAi agent of claim 1 , wherein R is chosen from a group consisting of

10. The RNAi agent of claim 1 , wherein said monomer is chosen from a group consisting of

11. The RNAi agent of claim 10 , wherein R is

12. A method of modulating the expression of a target gene in a cell, comprising providing to said cell an iRNA agent of claim 1 .

13. The method of claim 12 , wherein the target gene is selected from the group consisting of CD45, GFP, Factor VII, Eg5, PCSK9, TPX2, apoB, SAA, TTR, RSV, PDGF beta gene, Erb-B gene, Src gene, CRK gene, GRB2 gene, RAS gene, MEKK gene, JNK gene, RAF gene, Erk1/2 gene, PCNA(p21) gene, MYB gene, JUN gene, FOS gene, BCL-2 gene, Cyclin D gene, VEGF gene, EGFR gene, Cyclin A gene, Cyclin E gene, WNT-1 gene, beta-catenin gene, c-MET gene, PKC gene, NFKB gene, STAT3 gene, survivin gene, Her2/Neu gene, topoisomerase I gene, topoisomerase II alpha gene, mutations in the p73 gene, mutations in the p21(WAF1/CIP1) gene, mutations in the p27(KIP1) gene, mutations in the PPM1D gene, mutations in the RAS gene, mutations in the caveolin I gene, mutations in the MIB I gene, mutations in the MTAI gene, mutations in the M68 gene, mutations in tumor suppressor genes, and mutations in the p53 tumor suppressor gene.

14. A pharmaceutical composition comprising an iRNA agent of claim 1 alone or in combination with a pharmaceutically acceptable carrier or excipient.