Polyhydroxylated cyclopentane 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; and
(ii) one or more moieties selected from:
wherein:
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;
and each ## independently indicates an attachment to the rest of the conjugate.
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 ) 2 , —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 the conjugate further comprises a lipid moiety, a peptide moiety, or an antibody moiety.
11 . The conjugate of claim 1 , wherein each Nucleic Acid Agent independently comprises an oligonucleotide.
12 . A pharmaceutical composition comprising the conjugate of claim 1 , and at least one pharmaceutically acceptable excipient or carrier.
13 . A method of reducing the expression of a target gene in a subject or delivering a Nucleic Acid Agent to a subject, comprising administering to the subject the conjugate of claim 1 .
14 . The conjugate of claim 1 , wherein the conjugate comprises
15 . The conjugate of claim 1 , wherein the conjugate comprises
16 . The conjugate of claim 1 , wherein the conjugate comprises
17 . The conjugate of claim 1 , wherein the conjugate comprises
18 . The conjugate of claim 1 , wherein the conjugate comprises
19 . The conjugate of claim 1 , wherein the conjugate comprises