Monomers and oligonucleotides comprising cycloaddition adduct(s)

1. A compound of formula I, or pharmaceutically acceptable salts thereof:

wherein:

X is O, S, NR N or CR P 2 ;

B is independently for each occurrence hydrogen, optionally substituted natural or non-natural nucleobase, optionally substituted triazole or optionally substituted tetrazole; NH—C(O)—O—C(CH 2 B 1 ) 3 , NH—C(O)—NH—C(CH 2 B 1 ) 3 ; where B 1 is halogen, mesylate, N 3 , CN, optionally substituted triazole or optionally substituted tetrazole;

R 1 , R 2 , R 3 , R 4 and R 5 are each independently for each occurrence H, OR 6 , F, N(R N ) 2 , N 3 , CN, -J-linker-N 3 , -J-linker-CN, -J-linker-C≡R 8 , -J-linker-cycloalkyne, -J-linker-R L , -J-Q-linker-R L , -J-linker-Q-R L , -J-linker-Q-linker-R L , -J-linker-J-Q-R L , or -J-linker-J-Q-linker-R L ;

J is independently for each occurrence absent, O, S, NR N , OC(O)NH, NHC(O)O, C(O)NH, NHC(O), NHSO, NHSO 2 , NHSO 2 NH, OC(O), C(O)O, OC(O)O, NHC(O)NH, NHC(S)NH, OC(S)NH, O—N═CH, OP(N(R N ) 2 )O, or OP(N(R N ) 2 );

R 6 is independently for each occurrence hydrogen, hydroxyl protecting group, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted alkenyl, optionally substituted heteroaryl, polyethyleneglycol (PEG), a phosphate, a diphosphate, a triphosphate, a phosphonate, a phosphonothioate, a phosphonodithioate, a phosphorothioate, a phosphorothiolate, a phosphorodithioate, a phosphorothiolothionate, a phosphodiester, a phosphotriester, an activated phosphate group, an activated phosphite group, a phosphoramidite, a solid support, —P(Z 1 )(Z 2 )—O-nucleoside, —P(Z 1 )(Z 2 )—O-oligonucleotide, —P(Z 1 )(Z 2 )-formula (I), —P(Z 1 )(O-linker-Q-linker-R L )—O-nucleoside, P(Z 1 )(O-linker-R L )—O-nucleoside, —P(Z 1 )(O-linker-N 3 )—O-nucleoside, P(Z 1 )(O-linker-CN)—O-nucleoside, P(Z 1 )(O-linker-C≡R 8 )—O-nucleoside, P(Z 1 )(O-linker-cycloalkyne)-O-nucleoside, —P(Z 1 )(O-linker-Q-linker-R L )—O-oligonucleotide, P(Z 1 )(O-linker-R L )—O-oligonucleotide, P(Z 1 )(O-linker-N 3 )—O-oligonucleotide, —P(Z 1 )(O-linker-CN)—O-oligonucleotide, P(Z 1 )(O-linker-C≡R 8 )—O-oligonucleotide, P(Z 1 )(O-linker-cycloalkyne)-O-oligonucleotide, —P(Z 1 )(-linker-Q-linker-R L )—O-nucleoside, —P(Z 1 )(-linker-Q-R L )—O-nucleoside, —P(Z 1 )(-linker-N 3 )—O-nucleoside, P(Z 1 )(-linker-CN)—O-nucleoside, P(Z 1 )(-linker-C≡R 8 )—O-nucleoside, P(Z 1 )(-linker-cycloalkyne)-O-nucleoside, —P(Z 1 )(-linker-Q-linker-R L )—O-oligonucleotide, —P(Z 1 )(-linker-R L )—O-oligonucleotide, P(Z 1 )(-linker-N 3 )—O-oligonucleotide, —P(Z 1 )(-linker-CN)—O-oligonucleotide, P(Z 1 )(-linker-C≡R 8 )—O-oligonucleotide or P(Z 1 )(-linker-cycloalkyne)-O-oligonucleotide;

R N is independently for each occurrence H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted heteroaryl or an amino protecting group;

R P is independently for each occurrence H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl or optionally substituted heteroaryl;

Q is absent or independently for each occurrence or

X 1 is O, S, CF 2 , or CH 2 ;

Y 1 , Y 2 and Y 3 are each independent CR P , N, O, or S;

W 1 is CH or N;

R 100 , R 200 , R 300 and R 400 are each independently hydrogen, halogen, OR N , CR P 2 , acyl, phosphonyl, sulfonyl; or alternatively, R 100 and R 200 or R 300 and R 400 are taken together to form an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl;

R L is hydrogen or a ligand;

R 8 is N or CR 9 ;

R 9 is H, optionally substituted alkyl or silyl; and

Z 1 and Z 2 are each independently for each occurrence O, S or optionally substituted alkyl;

provided that at least one of R 1 , R 2 , R 3 , R 4 and R 5 is -J-linker-Q-R L , -J-linker-Q-linker-R L , -J-linker-J-Q-R L , or -J-linker-J-Q-linker-R L .

2. The compound of claim 1 , represented by formula (VI)

wherein each of R 500 is independently hydroxyl, halogen, acyl, sulfonyl, phosphonyl, alkyl, haloalkyl, NO 2 , CN, N 3 , alkoxy, aminoalkyl, aminodialkyl, and thioalkyl; n is 0-4; each linker can be the same or different; and B, R 3 , R 5 , R L , J, and X are as defined in claim 1 .

3. The compound of claim 1 , represented by formula (VIa)

wherein Y 1 -Y 6 are each independently O, S, NR N , or CR P 2 ; each linker can be the same or different; and B, R 3 , R 5 , R L , R N , R P , J, and X are as defined in claim 1 .

4. The compound of claim 1 , where R L is selected from the group consisting of:

5. The compound of claim 1 , wherein each linker is represented by structure

—[P-Q 1 -R] q -T-,

wherein:

P, R and T are each independently for each occurrence absent, CO, NH, O, S, S—S, OC(O), NHC(O), CH 2 , CH 2 NH, CH 2 O; NHCH(R a )C(O), —C(O)—CH(R a )—NH—, —C(O)— (optionally substituted alkyl)-NH—, CH═N—O,

acetal, ketal,

Q 1 is independently for each occurrence absent, —(CH 2 ) n —, —C(R 100 )(R 200 )(CH 2 ) n —, —(CH 2 ) n C(R 100 )(R 200 )—, —(CH 2 CH 2 O) m CH 2 CH 2 —, or —(CH 2 CH 2 O) m CH 2 CH 2 NH—;

R a is H or an amino acid side chain;

R 100 and R 200 are each independently for each occurrence H, CH 3 , OH, SH or N(R X ) 2 ;

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

q is independently for each occurrence 0-20;

n is independently for each occurrence 1-20; and

m is independently for each occurrence 0-50.

6. The compound of claim 1 , where least one of R 1 , R 2 , R 3 , R 4 , and R 5 of formula (I) is

wherein Y 1 , Y 2 , Y 3 , R 100 , R 200 , R 300 , R 400 , and R L are as previously defined in claim 1 .

7. The compound of claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 and R 5 is OR 6 , wherein R 6 contains an oligonucleotide.

8. The compound of claim 7 , wherein the oligonucleotide is a single-stranded oligonucleotide.

9. The compound of claim 8 , wherein the single-stranded oligonucleotide is a single-stranded siRNA.

10. The compound of claim 7 , wherein the oligonucleotide is a double-stranded oligonucleotide.

11. The compound of claim 10 , wherein the double-stranded oligonucleotide is a double-stranded siRNA.

12. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.