IP Library › Granted Patent US 12,258,564
Granted Patent B2
US 12,258,564 · App. 18/378,097 · Granted Mar 25, 2025

GalNAc compositions for improving siRNA bioavailability

Inventors: Darren H. Wakefield (Fitchburg, WI); David Rozema (Cross Plains, WI); Omri Gottesman (San Diego, CA)
Assignee: Empirico Inc.
C12N15/113C07H15/18C12N2310/14C12N2310/315C12N2310/32
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Quick Facts
Patent No.
US 12,258,564
App. No.
18/378,097
Granted
Mar 25, 2025
Kind
B2
Abstract

Provided herein, are compositions comprising GalNAc moieties that may be conjugated to an oligonucleotide. The oligonucleotide may be a small interfering RNA or an antisense oligonucleotide. Also provided herein are methods of treatment that include administering the composition to a subject.

Claims (110)

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):

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 CR 6 , or

if z is 1, Y is C(R 6 ) 2 ;

Q is selected from:

C 3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, —CN, —NO 2 , —OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 ) C(O)R 7 , —N(R 7 ) C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , —S(O)R 7 , and C 1-6 alkyl, wherein the C 1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO 2 , and —NH 2 ;

R 1 is a linker selected from:

—O—, —S—, —N(R 7 )—, —C(O)—, —C(O)N(R 7 )—, —N(R 7 )C(O)—, —N(R 7 )C(O)N(R 7 )—, —OC(O)N(R 7 )—, —N(R 7 )C(O)O—, —C(O)O—, —OC(O)—, —S(O)—, —S(O) 2 —, —OS(O) 2 —, —OP(O)(OR 7 )O—, —SP(O)(OR 7 )O—, —OP(S)(OR 7 )O—, —OP(O)(SR 7 )O—, —OP(O)(OR 7 )S—, —OP(O)(O − )O—, —SP(O)(O − )O—, —OP(S)(O − )O—, —OP(O)(S − )O—, —OP(O)(O − )S—, —OP(O)(OR 7 )NR 7 —, —OP(O)(N(R 7 ) 2 )NR 7 —, —OP(OR 7 )O—, —OP(N(R 7 ) 2 )O—, —OP(OR 7 )N(R 7 )—, and —OPN(R 7 ) 2 NR 7 —;

each R 2 is independently selected from:

C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , and —S(O)R 7 ;

R 3 and R 4 are each independently selected from:

—OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , and —S(O)R 7 ;

each R 5 is independently selected from:

—OC(O)R 7 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)R 7 , —C(O)OR 7 , and —C(O)N(R 7 ) 2 ;

each R 6 is independently selected from:

hydrogen;

halogen, —CN, —NO 2 , —OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , and —S(O)R 7 ; and

C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —CN, —NO 2 , —OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , and —S(O)R 7 ;

each R 7 is independently selected from:

hydrogen;

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , ═O, ═S, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —N(C 1-6 alkyl) 2 , —NH(C 1-6 alkyl), C 3-10 carbocycle, and 3- to 10-membered heterocycle; and

C 3-10 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, —NO 2 , —NH 2 , ═O, ═S, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —N(C 1-6 alkyl) 2 , —NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, and C 1-6 haloalkyl.

2. The method of claim 1 , wherein each w, v, n, and m is independently selected from any value from 1 to 5.

3. The method of claim 1 , wherein Q is selected from C 5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO 2 , and —NH 2 .

4. The method of claim 1 , wherein:

R 1 is selected from —OP(O)(OR 7 )O—, —OP(S)(OR 7 )O—, —OP(O)(O − )O—, —OP(S)(O − )O—, —OP(O)(S − )O—, and —OP(OR 7 )O—; and

R 2 is selected from C 1-3 alkyl substituted with one or more substituents independently selected from —OR 7 , —OC(O)R 7 , —SR 7 , and —N(R 7 ) 2 .

5. The method of claim 1 , wherein:

R 3 is selected from —OR 7 —SR 7 , —OC(O)R 7 , and —N(R 7 ) 2 ; and

R 4 is selected from —OR 7 —SR 7 , —OC(O)R 7 , and —N(R 7 ) 2 .

6. The method of claim 1 , wherein:

R 5 is selected from —OC(O)R 7 and —N(R 7 )C(O)R 7 ; and

each R 7 is independently selected from hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , ═O, ═S, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —N(C 1-6 alkyl) 2 , —NH(C 1-6 alkyl), C 3-10 carbocycle, or 3- to 10-membered heterocycle.

7. The method of claim 1 , wherein the compound comprises:

8. The method of claim 1 , wherein the oligonucleotide (J) is attached to R 1 at a 5′ end of the oligonucleotide.

9. The method of claim 1 , wherein the oligonucleotide comprises at least one phosphorothioate linkage, 2′-O-methyl modified nucleoside, or 2′-fluoro modified nucleoside.

10. The method of claim 1 , wherein the effective amount decreases a measurement of the target mRNA or target protein in the subject, relative to a baseline target mRNA or target protein measurement.

11. The method of claim 1 , wherein the effective amount treats a disorder in the subject.

12. The method of claim 11 , wherein the effective amount decreases a measurement of a symptom or parameter related to the disorder in the subject, relative to a baseline symptom or parameter measurement.

13. The method of claim 12 , wherein the measurement of the symptom or the parameter related to the disorder in the subject is decreased for at least 10 days.

14. The method of claim 11 , wherein the disorder comprises a metabolic disorder.

15. The method of claim 11 , wherein the disorder comprises a liver disorder.

16. The method of claim 15 , wherein the liver disorder is selected from the group consisting of liver inflammation, liver cancer, liver fibrosis, cholestasis, a gall bladder disease, a biliary tree disease, alcoholic liver disease, non-alcoholic steatohepatitis, a liver infection, or an inherited liver disorder, and liver infection.

17. The method of claim 16 , wherein the liver infection comprises hepatitis A, hepatitis B, or hepatitis C.

18. The method of claim 16 , wherein the inherited liver disorder comprises hemochromatosis or Wilson disease.

19. A compound represented by Formula (A) or (B):

or a salt thereof, wherein

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 CR 6 , or

if z is 1, Y is C(R 6 ) 2 ;

Q is selected from:

C 3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, —CN, —NO 2 , —OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , —S(O)R 7 , and C 1-6 alkyl, wherein the C 1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO 2 , and —NH 2 ;

R 1 is selected from:

—OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , —S(O)R 7 , —S(O) 2 R 7 , —OS(O) 2 R 7 , —OP(O)(OR 7 ) 2 , —OP(S)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , —OP(O)(SR 7 )(OR 7 ), —OP(O)(OR 7 )N(R 7 ) 2 , —OP(S)(OR 7 )N(R 7 ) 2 , —SP(O)(OR 7 )N(R 7 ) 2 , —OP(O)(SR 7 )N(R 7 ) 2 , —OP(O)(N(R 7 ) 2 ) 2 , —OP(S)(N(R 7 ) 2 ) 2 , —SP(O)(N(R 7 ) 2 ) 2 , —OP(OR 7 ) 2 , —SP(OR 7 ) 2 , —OP(OR 7 )(SR 7 ), —OP(OR 7 )N(R 7 ) 2 , —OP(SR 7 )N(R 7 ) 2 , —SP(OR 7 )N(R 7 ) 2 , —OP(N(R 7 ) 2 ) 2 , and —SP(N(R 7 ) 2 ) 2 ;

each R 2 is independently selected from:

C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , and —S(O)R 7 ;

R 3 and R 4 are each independently selected from:

—OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , and —S(O)R 7 ;

each R 5 is independently selected from:

—OC(O)R 7 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)R 7 , —C(O)OR 7 , and —C(O)N(R 7 ) 2 ;

each R 6 is independently selected from:

hydrogen;

halogen, —CN, —NO 2 , —OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , and —S(O)R 7 ; and

C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —CN, —NO 2 , —OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , and —S(O)R 7 ;

each R 7 is independently selected from:

hydrogen;

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , ═O, ═S, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —N(C 1-6 alkyl) 2 , —NH(C 1-6 alkyl), C 3-10 carbocycle, and 3- to 10-membered heterocycle; and

C 3-10 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, —NO 2 , —NH 2 , ═O, ═S, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —N(C 1-6 alkyl) 2 , —NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, and C 1-6 haloalkyl.

20. A method of synthesizing a compound represented by Formula (I) or (II):

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 CR 6 , or

if z is 1, Y is C(R 6 ) 2 ;

Q is selected from:

C 3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, —CN, —NO 2 , —OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , —S(O)R 7 , and C 1-6 alkyl, wherein the C 1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO 2 , and —NH 2 ;

R 1 is a linker selected from:

—O—, —S—, —N(R 7 )—, —C(O)—, —C(O)N(R 7 )—, —N(R 7 )C(O)—, —N(R 7 )C(O)N(R 7 )—, —OC(O)N(R 7 )—, —N(R 7 )C(O)O—, —C(O)O—, —OC(O)—, —S(O)—, —S(O) 2 —, —OS(O) 2 —, —OP(O)(OR 7 )O—, —SP(O)(OR 7 )O—, —OP(S)(OR 7 )O—, —OP(O)(SR 7 )O—, —OP(O)(OR 7 )S—, —OP(O)(O − )O—, —SP(O)(O − )O—, —OP(S)(O − )O—, —OP(O)(S − )O—, —OP(O)(O − )S—, —OP(O)(OR 7 )NR 7 , —OP(O)(N(R 7 ) 2 )NR 7 , —OP(OR 7 )O—, —OP(N(R 7 ) 2 )O—, —OP(OR 7 )N(R 7 )—, and —OPN(R 7 ) 2 NR 7 —;

each R 2 is independently selected from:

C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , and —S(O)R 7 ;

R 3 and R 4 are each independently selected from:

—OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , and —S(O)R 7 ;

each R 5 is independently selected from:

—OC(O)R 7 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)R 7 , —C(O)OR 7 , and —C(O)N(R 7 ) 2 ;

each R 6 is independently selected from:

hydrogen;

halogen, —CN, —NO 2 , —OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , and —S(O)R 7 ; and

C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —CN, —NO 2 , —OR 7 , —SR 7 , —N(R 7 ) 2 , —C(O)R 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , and —S(O)R 7 ;

each R 7 is independently selected from:

hydrogen;

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , ═O, ═S, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —N(C 1-6 alkyl) 2 , —NH(C 1-6 alkyl), C 3-10 carbocycle, and 3- to 10-membered heterocycle; and

C 3-10 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, —NO 2 , —NH 2 , ═O, ═S, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —N(C 1-6 alkyl) 2 , —NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, and C 1-6 haloalkyl;

comprising reacting a compound of Formula (A) or (B) of claim 19 with an oligonucleotide.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 26, 2025
From: WAKEFIELD, DARREN H.; ROZEMA, DAVID; GOTTESMAN, OMRI
To: EMPIRICO INC.
Reel/Frame 072562/0151 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 17, 2024
From: WAKEFIELD, DARREN H.; ROZEMA, DAVID; GOTTESMAN, OMRI
To: EMPIRICO INC.
Reel/Frame 066342/0498 →
Continuity (5)
Continuation 18184528 · Mar 15, 2023
Provisional Application 63430542 · Dec 6, 2022
Provisional Application 63354359 · Jun 22, 2022
Provisional Application 63320431 · Mar 16, 2022
Related Publication 20240175023A1 · May 30, 2024
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