5′-modified carbocyclic ribonucleotide derivatives and methods of use
The present disclosure provides phosphate mimic derivatives of Formula (I) or (II): pharmaceutically acceptable salts thereof, and related Nucleic Acid Agents and conjugates. The present disclosure also relates to uses of the phosphate mimic derivatives (e.g., in the Nucleic Acid Agents and conjugates) in treating or preventing diseases.
1 . A compound of Formula (I) or (II):
or a pharmaceutically acceptable salt thereof, wherein:
B is H or a nucleobase moiety;
X is halogen or —OR X ;
R X 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)(N(R Y ) 2 ), —P(═O)(OR Y )R Y , —P(═S)(OR)R Y , —P(═O)(SR Y )R Y , —P(═S)(SR)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 —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 ;
each R Z independently is H or C 1 -C 6 alkyl optionally substituted with one or more halogen or cyano;
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;
indicates a single bond; and
each R 6 independently is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen.
2 . The compound of claim 1 , wherein the compound is selected from:
and pharmaceutically acceptable salts thereof.
3 . The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
4 . A Nucleic Acid Agent, or a pharmaceutically acceptable salt thereof, comprising:
an oligonucleotide comprising one or two 5′-End Unit, wherein each 5′-End Unit independently is:
wherein:
B is H or a nucleobase moiety;
X is H, halogen, or —OR X ;
R X 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;
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 ;
each R Z independently is H or C 1 -C 6 alkyl optionally substituted with one or more halogen or cyano;
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;
indicates a single bond;
each R 6 independently is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen; and
## indicates attachment to the rest of the oligonucleotide.
5 . The Nucleic Acid Agent of claim 4 , comprising one or two of:
6 . The Nucleic Acid Agent of claim 2 , wherein the 5′-End Unit is
7 . A conjugate, or a pharmaceutically acceptable salt thereof, comprising:
(i) one or more Nucleic Acid Agent, wherein each Nucleic Acid Agent comprises:
an oligonucleotide comprising one or two 5′-End Unit being covalently attached to the oligonucleotide, wherein each 5′-End Unit independently is:
and
(ii) one or more Ligand being covalently attached to the one or more Nucleic Acid Agent, wherein:
B is H or a nucleobase moiety;
X is H, halogen, or —OR X ;
R X 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;
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 ;
each R Z independently is H or C 1 -C 6 alkyl optionally substituted with one or more halogen or cyano;
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;
indicates a single bond;
each R 6 independently is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen; and
## indicates an attachment to the rest of the oligonucleotide.
8 . The conjugate of claim 7 , wherein B is H.
9 . The conjugate of claim 7 , wherein B is a nucleobase moiety.
10 . The conjugate of claim 7 , wherein the nucleobase moiety is adenine (A), cytosine (C), guanine (G), thymine (T), or uracil (U).
11 . The conjugate of claim 7 , wherein X is —OR X .
12 . The conjugate of claim 7 , wherein X is —OH.
13 . The conjugate of claim 7 , wherein X is —O—(C 1 -C 6 alkyl).
14 . The conjugate of claim 7 , wherein X is —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl).
15 . The conjugate of claim 7 , wherein X is —O—(C 1 -C 6 alkyl)-(C 6 -C 10 aryl) optionally substituted with one or more R Xa .
16 . The conjugate of claim 7 , wherein X is —O—(C 1 -C 6 alkyl)-(C 6 -C 10 aryl).
17 . The conjugate of claim 7 , wherein Z is —P(R Z ) 2 , —PH 2 , or —P(OR Z )(N(R Z ) 2 ).
18 . The conjugate of claim 7 , wherein Z is —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 .
19 . The conjugate of claim 7 , comprising one or two of:
20 . The conjugate of claim 7 , wherein the one or more Ligand comprises
21 . The conjugate of claim 7 , wherein the one or more Ligand comprises a lipid moiety, a peptide moiety, or an antibody moiety.
22 . The conjugate of claim 7 , wherein the 5′-End Unit is
23 . The conjugate of claim 7 , wherein the 5′-End Unit is
24 . The conjugate of claim 7 , wherein the 5′-End Unit is
25 . A pharmaceutical composition comprising the conjugate of claim 7 , and at least one pharmaceutically acceptable excipient or carrier.
26 . A method of modulating 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 7 .