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US 2019/0160176 A1Published application
Targeted nucleic acid conjugate compositions
AssigneeArbutus Biopharma Corporation
InventorsJames HEYES, Richard J. HOLLAND, Alan D. MARTIN, Mark WOOD
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Abstract
The invention provides conjugates that comprise a targeting moiety, a nucleic acid, and optional linking groups as well as synthetic intermediates and synthetic methods useful for preparing the conjugates. The conjugates are useful to target therapeutic nucleic acids to the liver and to treat liver diseases including hepatitis (e.g. hepatitis B and hepatitis D).
Claims158
A compound of formula (I):
- wherein:
- R1 a is targeting ligand;
- L1 is absent or a linking group;
- L2 is absent or a linking group;
- R2 is a nucleic acid;
- the ring A is absent, a 3-20 membered cycloalkyl, a 5-20 membered aryl, a 5-20 membered heteroaryl, or a 3-20 membered heterocycloalkyl;
- each RA is independently selected from the group consisting of hydrogen, hydroxy, CN, F, Cl, Br, I, —C1-2 alkyl-ORB, C1-10 alkyl C2-10 alkenyl, and C2-10 alkynyl;
- wherein the C1-10 alkyl C2-10 alkenyl, and C2-10 alkynyl are optionally substituted with one or more groups independently selected from halo, hydroxy, and C1-3 alkoxy;
- RB is hydrogen, a protecting group, a covalent bond to a solid support, or a bond to a linking group that is bound to a solid support;
- and
- n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
- or a salt thereof.
9 more elements
A compound of formula (I):
- wherein:
- R1 is H or a synthetic activating group;
- L1 is absent or a linking group;
- L2 is absent or a linking group;
- R2 is a nucleic acid;
- the ring A is absent, a 3-20 membered cycloalkyl, a 5-20 membered aryl, a 5-20 membered heteroaryl, or a 3-20 membered heterocycloalkyl;
- each RA is independently selected from the group consisting of hydrogen, hydroxy, CN, F, Cl, Br, I, —C1-2 alkyl-ORB, C1-10 alkyl C2-10 alkenyl, and C2-10 alkynyl;
- wherein the C1-10 alkyl C2-10 alkenyl, and C2-10 alkynyl are optionally substituted with one or more groups independently selected from halo, hydroxy, and C1-3 alkoxy;
- RB is hydrogen, a protecting group, a covalent bond to a solid support, or a bond to a linking group that is bound to a solid support;
- and
- n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
- or a salt thereof.
9 more elements
A compound of formula (I):
- wherein:
- R1 a is targeting ligand;
- L1 is absent or a linking group;
- L2 is absent or a linking group;
- R2 is H or a synthetic activating group;
- the ring A is absent, a 3-20 membered cycloalkyl, a 5-20 membered aryl, a 5-20 membered heteroaryl, or a 3-20 membered heterocycloalkyl;
- each RA is independently selected from the group consisting of hydrogen, hydroxy, CN, F, Cl, Br, I, —C1-2 alkyl-ORB, C1-10 alkyl C2-10 alkenyl, and C2-10 alkynyl;
- wherein the C1-10 alkyl C2-10 alkenyl, and C2-10 alkynyl are optionally substituted with one or more groups independently selected from halo, hydroxy, and C1-3 alkoxy;
- RB is hydrogen, a protecting group, a covalent bond to a solid support, or a bond to a linking group that is bound to a solid support;
- and
- n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
- or a salt thereof.
9 more elements
A compound of formula (Ig):
- wherein:
- B is —N— or —CH—;
- L1 is absent or a linking group;
- L2 is C1-4 alkylene-O— that is optionally substituted with hydroxyl or halo;
- n is 0, 1, 2, 3, 4, 5, 6, or 7;
- R1 is H or a synthetic activating group;
- and
- R2 is H or a synthetic activating group;
- or a salt thereof.
6 more elements
A compound selected from the group consisting of:
- wherein Q is -L1-R1;
- L1 is absent or a linking group;
- R1 is C1-9 alkyl, C2-9 alkenyl or C2-9 alkynyl;
- wherein the C1-9 alkyl, C2-9 alkenyl or C2-9 alkynyl are optionally substituted with halo or hydroxyl;
- R1 is H or a synthetic activating group;
- and
- R2 is H or a synthetic activating group;
- or a salt thereof.
5 more elements
A compound selected from the group consisting of:
- wherein:
- Q is -L1-R1;
- L1 is absent or a linking group;
- R1 is H or a synthetic activating group;
- and
- R2 is H or a synthetic activating group;
- or a salt thereof.
4 more elements
A compound of formula (XX):
- wherein:
- R1 a is targeting ligand;
- L1 is absent or a linking group;
- L2 is absent or a linking group;
- R2 is a nucleic acid;
- B is divalent and is selected from the group consisting of:
- wherein:
- each R1 is independently C1-9 alkyl, C2-9 alkenyl or C2-9 alkynyl;
- wherein the C1-9 alkyl, C2-9 alkenyl or C2-9 alkynyl are optionally substituted with halo or hydroxyl;
- the valence marked with * is attached to L1 or is attached to R1 if L1 is absent;
- and
- the valence marked with ** is attached to L2 or is attached to R2 if L2 is absent;
- or a salt thereof.
10 more elements
The compound,
- or a salt thereof.
Dependencies are inferred from the claim text.