US 12,258,564 B2
GalNAc compositions for improving siRNA bioavailability
Darren H. Wakefield, Fitchburg, WI (US); David Rozema, Cross Plains, WI (US); and Omri Gottesman, San Diego, CA (US)
Assigned to Empirico Inc., San Diego, CA (US)
Filed by Empirico Inc., San Diego, CA (US)
Filed on Oct. 9, 2023, as Appl. No. 18/378,097.
Application 18/378,097 is a continuation of application No. 18/184,528, filed on Mar. 15, 2023, granted, now 11,879,125.
Claims priority of provisional application 63/430,542, filed on Dec. 6, 2022.
Claims priority of provisional application 63/354,359, filed on Jun. 22, 2022.
Claims priority of provisional application 63/320,431, filed on Mar. 16, 2022.
Prior Publication US 2024/0175023 A1, May 30, 2024
This patent is subject to a terminal disclaimer.
Int. Cl. C12N 15/113 (2010.01); C07H 15/18 (2006.01)
CPC C12N 15/113 (2013.01) [C07H 15/18 (2013.01); C12N 2310/14 (2013.01); C12N 2310/315 (2013.01); C12N 2310/32 (2013.01)] 20 Claims
 
1. A method of decreasing a target mRNA or target protein in a subject in need thereof, comprising administering an effective amount of a compound represented by Formula (I) or (II):

OG Complex Work Unit Chemistry
or a salt thereof, wherein
J is an oligonucleotide;
each w is independently selected from any value from 1 to 20;
each v is independently selected from any value from 1 to 20;
n is selected from any value from 1 to 20;
m is selected from any value from 0 to 20;
z is selected from any value from 1 to 3, wherein
if z is 3, Y is C
if z is 2, Y is CR6, or
if z is 1, Y is C(R6)2;
Q is selected from:
C3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, —CN, —NO2, —OR7, —SR7, —N(R7)2, —C(O)R7, —C(O)N(R7)2, —N(R7) C(O)R7, —N(R7) C(O)N(R7)2, —OC(O)N(R7)2, —N(R7)C(O)OR7, —C(O)OR7, —OC(O)R7, —S(O)R7, and C1-6 alkyl, wherein the C1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO2, and —NH2;
R1 is a linker selected from:
—O—, —S—, —N(R7)—, —C(O)—, —C(O)N(R7)—, —N(R7)C(O)—, —N(R7)C(O)N(R7)—, —OC(O)N(R7)—, —N(R7)C(O)O—, —C(O)O—, —OC(O)—, —S(O)—, —S(O)2—, —OS(O)2—, —OP(O)(OR7)O—, —SP(O)(OR7)O—, —OP(S)(OR7)O—, —OP(O)(SR7)O—, —OP(O)(OR7)S—, —OP(O)(O−)O—, —SP(O)(O−)O—, —OP(S)(O−)O—, —OP(O)(S−)O—, —OP(O)(O−)S—, —OP(O)(OR7)NR7—, —OP(O)(N(R7)2)NR7—, —OP(OR7)O—, —OP(N(R7)2)O—, —OP(OR7)N(R7)—, and —OPN(R7)2NR7—;
each R2 is independently selected from:
C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR7, —SR7, —N(R7)2, —C(O)R7, —C(O)N(R7)2, —N(R7)C(O)R7, —N(R7)C(O)N(R7)2, —OC(O)N(R7)2, —N(R7)C(O)OR7, —C(O)OR7, —OC(O)R7, and —S(O)R7;
R3 and R4 are each independently selected from:
—OR7, —SR7, —N(R7)2, —C(O)R7, —C(O)N(R7)2, —N(R7)C(O)R7, —N(R7)C(O)N(R7)2, —OC(O)N(R7)2, —N(R7)C(O)OR7, —C(O)OR7, —OC(O)R7, and —S(O)R7;
each R5 is independently selected from:
—OC(O)R7, —OC(O)N(R7)2, —N(R7)C(O)R7, —N(R7)C(O)N(R7)2, —N(R7)C(O)OR7, —C(O)R7, —C(O)OR7, and —C(O)N(R7)2;
each R6 is independently selected from:
hydrogen;
halogen, —CN, —NO2, —OR7, —SR7, —N(R7)2, —C(O)R7, —C(O)N(R7)2, —N(R7)C(O)R7, —N(R7)C(O)N(R7)2, —OC(O)N(R7)2, —N(R7)C(O)OR7, —C(O)OR7, —OC(O)R7, and —S(O)R7; and
C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —CN, —NO2, —OR7, —SR7, —N(R7)2, —C(O)R7, —C(O)N(R7)2, —N(R7)C(O)R7, —N(R7)C(O)N(R7)2, —OC(O)N(R7)2, —N(R7)C(O)OR7, —C(O)OR7, —OC(O)R7, and —S(O)R7;
each R7 is independently selected from:
hydrogen;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO2, —NH2, ═O, ═S, —O—C1-6 alkyl, —S—C1-6 alkyl, —N(C1-6 alkyl)2, —NH(C1-6 alkyl), C3-10 carbocycle, and 3- to 10-membered heterocycle; and
C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO2, —NH2, ═O, ═S, —O—C1-6 alkyl, —S—C1-6 alkyl, —N(C1-6 alkyl)2, —NH(C1-6 alkyl), C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, and C1-6 haloalkyl.