1′-alkyl modified ribose derivatives and methods of use
The present disclosure provides linker compounds of Formula (I) or (II): pharmaceutically acceptable salts thereof, and related scaffolds and conjugates. The present disclosure also relates to uses of the linker compounds, scaffolds, and conjugates, e.g., in delivering nucleic acid and/or treating or preventing diseases.
1 . A conjugate or a pharmaceutically acceptable salt thereof, wherein the conjugate comprises:
(i) one or more Nucleic Acid Agents;
(ii) one or more Ligands; and
(iii) one or more Linker Units, wherein each Linker Unit independently is:
wherein:
X is —OR X ;
R 1 is H, C 1 -C 6 alkyl, or —(C 1 -C 6 alkyl)-(C 6 -C 10 aryl), wherein the C 1 -C 6 alkyl or —(C 1 -C 6 alkyl)-(C 6 -C 10 aryl) is optionally substituted with one or more R Xa ;
each R Xa independently is halogen, C 1 -C 6 alkyl, or —O—(C 1 -C 6 alkyl), wherein the C 1 -C 6 alkyl or —O—(C 1 -C 6 alkyl) is optionally substituted with one or more halogen;
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, C 1 -C 6 alkyl optionally substituted with one or more halogen, —P(R Z ), —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;
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 2 to 6; and
# indicates a direct or indirect attachment to the Ligand, and each ##independently indicates a direct or indirect attachment to the Nucleic Acid Agent or another Linker Unit.
2 . The conjugate of claim 1 , wherein Y is H.
3 . The conjugate of claim 1 , wherein Y is C 1 -C 6 alkyl optionally substituted with one or more halogen.
4 . The conjugate of claim 1 , 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 .
5 . The conjugate of claim 1 , wherein Y is a hydroxy protecting group.
6 . The conjugate of claim 1 , wherein Z is H.
7 . The conjugate of claim 1 , wherein Z is C 1 -C 6 alkyl optionally substituted with one or more halogen.
8 . The conjugate of claim 1 , 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 ), —P(═O)(SR Z ) 2 , or —P(═S)(SR Z ) 2 .
9 . The conjugate of claim 1 , wherein Z is a hydroxy protecting group.
10 . The conjugate of claim 1 , wherein R 1 , R 2 , R 3 , and R 4 are each H.
11 . The conjugate of claim 1 , wherein each R 5 is H.
12 . The conjugate of claim 1 , wherein each R is H and each R a is H.
13 . The conjugate of claim 12 , wherein n is 2.
14 . The conjugate of claim 1 , wherein R 1 , R 2 , R 3 , and R 4 are each H, each R 5 is H, each R is H, and each R b is H.
15 . The conjugate of claim 1 , wherein n is 2.
16 . The conjugate of claim 1 , wherein the Nucleic Acid Agent comprises an oligonucleotide.
17 . The conjugate of claim 1 , wherein the Ligand comprises
18 . The conjugate of claim 1 , wherein the Ligand comprises a lipid, a peptide moiety, or an antibody moiety.
19 . The conjugate of claim 14 , wherein the Ligand comprises
or
20 . The conjugate of claim 15 , wherein the Ligand comprises
21 . The conjugate of claim 1 , wherein the conjugate comprises a moiety selected from
22 . The conjugate of claim 1 , wherein the conjugate comprises
23 . The conjugate of claim 1 , wherein the conjugate comprises
24 . A pharmaceutical composition comprising the conjugate of claim 1 .
25 . A method of modulating the expression of a target gene in a subject in need thereof, comprising administering to the subject an effective amount of the conjugate or the pharmaceutically acceptable salt of claim 1 .