2'-ALKYL OR 3'- ALKYL MODIFIED RIBOSE DERIVATIVES AND METHODS OF USE

1 . A compound of Formula (I) or (II):

or a pharmaceutically acceptable salt thereof, wherein:

B is H or a nucleobase moiety;

W is H, C 1 -C 6 alkyl optionally substituted with one or more halogen, or an amino substitution group;

Y is H, C 1 -C 6 alkyl optionally substituted with one or more halogen, —P(R Y ) 2 , —P(OR Y )(N(R Y ) 2 ), —P(═O)(OR Y )R Y , —P(═S)(OR Y )R Y , —P(═O)(SR Y )R Y , —P(═S)(SR Y )R Y , —P(═O)(OR Y ) 2 , —P(═S)(OR Y ) 2 , —P(═O)(SR Y ) 2 , —P(═S)(SR Y ) 2 , or a hydroxy protecting group;

each R Y independently is H or C 1 -C 6 alkyl optionally substituted with one or more halogen or cyano;

Z is H, or C 1 -C 6 alkyl optionally substituted with one or more halogen, —P(R Z ) 2 , —P(OR z )(N(R Z ) 2 ), —P(═O)(OR Z )R Z , —P(═S)(OR Z )R Z , —P(═O)(SR Z )R Z , —P(═S)(SR Z )R Z , —P(═O)(OR Z ) 2 , —P(═S)(OR Z ) 2 , —P(═O)(SR Z ) 2 , —P(═S)(SR Z ) 2 , or a hydroxy protecting group;

each R Z independently is H or C 1 -C 6 alkyl optionally substituted with one or more halogen or cyano;

or Y and Z in Formula (I) together form —Si(R L ) 2 —O—Si(R L ) 2 —, wherein each R L independently is H or C 1 -C 6 , alkyl;

each R a independently is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen; or two R a on two adjacent carbon atoms, together with the two adjacent carbon atoms, form a double bond;

each R b independently is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

R 1 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

R 2 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

R 3 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

R 4 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

each R 5 independently is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen; and

n is an integer ranging from about 0 to about 10.

2 . A scaffold or a pharmaceutically acceptable salt thereof, wherein the scaffold comprises:

(i) one or more Ligands, or one or more Nucleic Acid Agents; and

(ii) one or more Linker Units, wherein each Linker Unit independently is:

wherein:

B is H or a nucleobase moiety;

W is H. C 1 -C 6 alkyl optionally substituted with one or more halogen, or an amino substitution group;

Y is H. C 1 -C 6 alkyl optionally substituted with one or more halogen, —P(R Y ) 2 , —P(OR Y )(N(R Y ) 2 ), —P(═O)(OR Y )R Y , —P(═S)(OR Y )R Y ,—P(═O)(SR Y )R Y , —P(═S)(SR Y )R Y , ~ P(═O)(OR Y ) 2 , —P(═S)(OR Y ) 2 , —P(═O)(SR Y ) 2 . —P(═S)(SR Y ) 2 , or a hydroxy protecting group;

each R Y independently is H or C 1 -C 6 alkyl optionally substituted with one or more halogen or cyano;

Z is H, or C 1 -C 6 alkyl optionally substituted with one or more halogen, —P(R z ) 2 , —P(OR z )(N(R Z ) 2 ), —P(═O)(OR z )R z , —P(═S)(OR z )R z . —P(═O)(SR z )R z , —P(═S)(SR z )R z , —P(═O)(OR Z ) 2 , —P(═S)(OR Z ) 2 ,—P(═O)(SR Z ) 2 , —P(═S)(SR z ) 2 , or a hydroxy protecting group;

each R Z independently is H or C 1 -C 6 alkyl optionally substituted with one or more halogen or cyano;

or Y and Z in Formula (I) together form —Si(R L )2—0—Si(R L ) 2 —, wherein each R L independently is H or C 1 -C 6 alkyl;

each R a independently is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen: or two R a on two adjacent carbon atoms, together with the two adjacent carbon atoms, form a double bond;

each R b independently is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

R 1 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

R 2 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

R 3 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

R 4 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

each R 5 independently is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen:

n is an integer ranging from about 0 to about 10;

# indicates an attachment to the Ligand, and ## indicates an attachment to the Nucleic Acid Agent.

3 . (canceled)

4 . A conjugate or a pharmaceutically acceptable salt thereof, wherein the conjugate comprises:

(i) one or more Nucleic Acid Agent;

(ii) one or more Ligand; and

(iii) one or more Linker Unit, wherein each Linker Unit independently is:

or

wherein:

B is H or a nucleobase moiety;

Y is H. C 1 -C 6 alkyl optionally substituted with one or more halogen, —P(R Y ) 2 , —P(OR Y )(N(R Y ) 2 ), —P(═O)(OR Y )R Y , —P(═S)(OR Y )R Y , —P(═O)(SR Y )R Y , —P(═S)(SR Y )R Y , —P(═O)(OR Y )2 , —P(═S)(OR Y ) 2 , —P(═O)(SR Y ) 2 , —P(═S)(SR Y ) 2 , or a hydroxy protecting group;

each R Y independently is H or C 1 -C 6 alkyl optionally substituted with one or more halogen or cyano;

Z is H, or C 1 -C 6 alkyl optionally substituted with one or more halogen. —P(R Z ) 2 , —P(OR z )(N(R z ) 2 ), —P(═O)(OR z )R z , —P(═S)(OR z )R z , —P(═O)(SR z )R z , —P(═S)(SR Z )R Z , —P(═O)(OR Z ) 2 , —P(═S)(OR Z ) 2 , —P(═O)(SR Z ) 2 , —P(═S)(SR z ) 2 , or a hydroxy protecting group;

each R Z independently is H or C 1 -C 6 alkyl optionally substituted with one or more halogen or cyano;

or Y and Z in Formula (I) together form —Si(R L ) 2 —O—Si(R L ) 2 —, wherein each R L independently is H or C 1 -C 6 alkyl;

each R a independently is H. halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen; or two R a on two adjacent carbon atoms, together with the two adjacent carbon atoms, form a double bond;

each R b independently is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

R 1 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

R 2 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

R 3 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

R 4 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

each R 5 independently is H. halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;

n is an integer ranging from about 0 to about 10;

# indicates an attachment to the Ligand, and ## indicates an attachment to the Nucleic Acid Agent.

5 . The conjugate of claim 4 , wherein B is H.

6 . The conjugate of claim 4 , wherein B is a nucleobase moiety.

7 . The conjugate of claim 4 , wherein the nucleobase moiety is adenine (A), cytosine (C), guanine (G), thymine (T), or uracil (U).

8 - 11 . (canceled)

12 . The conjugate of claim 4 , wherein Y is C 1 -C 6 alkyl optionally substituted with one or more halogen.

13 . The conjugate of claim 4 , wherein Y is —P(R Y ) 2 , —P(OR Y )(N(R Y ) 2 ), —P(═O)(OR Y )R Y , —P(═S)(OR Y )R Y , —P(═O)(SR Y )R Y , —P(═S)(SR Y )R Y , —P(═O)(OR Y ) 2 , —P(═S)(OR Y ) 2 , —P(═O)(SR Y ) 2 , or —P(═S)(SR Y ) 2 .

14 . The conjugate of claim 4 , wherein Y is a hydroxy protecting group.

15 . The conjugate of claim 4 , wherein Z is H.

16 . The conjugate of claim 4 , wherein Z is C 1 -C 6 alkyl optionally substituted with one or more halogen.

17 . The conjugate of claim 4 , wherein Z is —P(R Z ) 2 , —P(OR Z )(N(R Z ) 2 ), —P(═O)(OR Z )R Z , —P(═S)(OR Z )R Z , —P(═O)(SR Z )R Z , —P(═S)(SR Z )R Z , —P(═O)(OR Z ) 2 , —P(═S)(OR Z ) 2 , —P(═O)(SR Z ) 2 , or —P(═S)(SR z ) 2 .

18 . The conjugate of claim 4 , wherein Z is a hydroxy protecting group.

19 . The conjugate of claim 4 , wherein Y and Z in Formula (I) together form —Si(R L ) 2 —O—Si(R L ) 2 —.

20 - 31 . (canceled)

32 . The conjugate of claim 4 , wherein the conjugate is selected from the conjugates described in Table C.

33 . The conjugate of claim 4 , wherein the ligand comprises

or

.

34 . (canceled)

35 . The conjugate of claim 4 , wherein the ligand comprises a lipid, a peptide moiety, or an antibody moiety.

36 . The conjugate of claim 4 , wherein the Nucleic Acid Agent comprises an oligonucleotide.

37 . A pharmaceutical composition comprising the conjugate of claim 4 .

38 . A method of modulating the expression of a target gene in a subject, delivering a Nucleic Acid Agent to a subject, or treating or preventing a disease in a subject in need thereof, comprising administering to the subject the conjugate of claim 4 .

39 - 40 . (canceled)