Chemical modifications of monomers and oligonucleotides with cycloaddition

1. A compound of formula (II), or pharmaceutically acceptable salts thereof:

wherein A and B are each independently hydrogen, a protecting group, optionally substituted aliphatic, optionally substituted aryl, 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, or —P(Z 1 )(Z 2 )—O-oligonucleotide; wherein Z 1 and Z 2 are each independently for each occurrence O, S or optionally substituted alkyl, provided that either one or both of A and B is independently —P(Z 1 )(Z 2 )—O-nucleoside, or —P(Z 1 )(Z 2 )—O-oligonucleotide;

J 1 and J 2 are each independently O, S, NR N , optionally substituted alkyl, OC(O)NH, NHC(O)O, C(O)NH, NHC(O), OC(O), C(O)O, OC(O)O, NHC(O)NH, NHC(S)NH, OC(S)NH, OP(N(R P ) 2 )O, or OP(N(R P ) 2 );

is a cyclic group selected from the group consisting of pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3]dioxolane, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, and decalin; or

is an acyclic group containing a serinol backbone or a diethanolamine backbone;

R N is 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 H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;

Q is

L 10 and L 11 are independently absent or a linker; and

the ligand is selected from the group consisting of thyrotropin, melanotropin, lectin, glycoprotein, surfactant protein A, Mucin carbohydrate, multivalent lactose, multivalent galactose, multivalent N-acetyl-galactosamine, multivalent N-acetyl-glucosamine, multivalent mannose, multivalent fucose, glycosylated polyaminoacids, transferrin, bisphosphonate, polyglutamate, polyaspartate, a lipid, cholesterol, a steroid, bile acid, folate, vitamin B12, biotin, and an RGD peptide.

2. The compound of claim 1 , wherein

is a cyclic group selected from the group consisting of pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3]dioxolane, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, and decalin.

3. The compound of claim 1 , wherein either one or both of A and B is independently —P(Z 1 )(Z 2 )—O-oligonucleotide.

4. The compound of claim 3 , wherein the oligonucleotide is a single-stranded oligonucleotide.

5. The compound of claim 4 , wherein the single-stranded oligonucleotide is a single-stranded siRNA.

6. The compound of claim 4 , wherein the single-stranded oligonucleotide is a micro RNA.

7. The compound of claim 3 , wherein the oligonucleotide is a double-stranded oligonucleotide.

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

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

10. A compound of claim 1 , wherein the linker is represented by structure

—[P-Q 1 -R] q -T-,

wherein:

P, R and T are each independently absent, CO, NH, O, 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,

Q 1 is 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 H, CH 3 , OH, SH or N(R X ) 2 ;

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

q is an integer from 0-20;

n is an integer from 1-20; and

m is an integer from 0-50;

provided that at least one of P, R, T, and Q 1 is present in the linker.

11. The compound of claim 1 , wherein

is an acyclic group containing a serinol backbone or a diethanolamine backbone.