Granted Patent B2

US 12,258,332 · App. 18/301,025 · Granted Mar 25, 2025

Inventors: Brett Bradley Busch (San Diego, CA); Justin Thomas Ernst (San Diego, CA); Garrick K. Packard (San Diego, CA); Jason G. Lewis (Castro Valley, CA); Eric D. Turtle (Belmont, CA)

Assignee: Lycia Therapeutics, Inc.

C07D405/04C07D405/12C07D405/14C07D493/08

Abstract

Claims (105)

1. A compound of formula (I):

X n -L-Y   (I)

or a prodrug thereof, or a salt thereof,

wherein:

Y is an antibody or antibody fragment that binds a target protein;

n is 1 to 500;

L is a linker; and

X is a moiety that binds to a cell surface asialoglycoprotein receptor (ASGPR) of formula:

wherein:

R 1 is selected from —OH, —OC(O)R, —C(O)NHR, and triazole, where R is C 1-6 alkyl or aryl;

R 2 is selected from —NHCOCH 3 , —NHCOCF 3 , —NHCOCH 2 CF 3 , —OH, and triazole;

wherein “*” represents a point of attachment of Z 1 to the linker (L);

R 4 and R 5 are H;

each Z 1 is a linking moiety selected from Z 11 , Z 11 -heteroaryl, Z 11 -aryl, and alkyl;

Z 11 is —C(R 22 ) 2 —; and

each R 22 is independently selected from H, halogen, and (C 1 -C 6 ) alkyl.

2. The compound of claim 1 , wherein each X is independently of formula:

3. The compound of claim 1 , wherein Z 1 is Z 11 -Ar, wherein Ar is heteroaryl or aryl.

4. The compound of claim 3 , wherein each X is

5. The compound of claim 1 , wherein n is 1, and L comprises a linear linker having a backbone of 20 to 50 consecutive atoms covalently linking X to Y via Z 1 .

6. The compound of claim 1 , wherein n is 2 or 3, and L is a branched linker that covalently links each X moiety to Y via the linking moiety Z 1 and a chain of 21 to 50 consecutive atoms.

7. The compound of claim 1 , wherein L is of formula (II):

wherein

n is 1 to 20;

L 1 and L 3 are independently a linker, and L 2 is a branched linking moiety, wherein L 1 to L 3 together provide a linear or branched linker between X and Y;

a is 1;

b is 0 or 1;

c is 1;

** represents the point of attachment to L 1 of X via Z 1 ; and

*** represents the point of attachment to Y;

wherein:

when n is 1, then b is 0;

when n is >1, then b is 1.

8. The compound of claim 7 , wherein L 1 to L 3 each independently comprise one or more linking moieties independently selected from —C 1-20 -alkylene-, —NHCO—C 1-6 -alkylene-, —CONH—C 1-6 -alkylene-, —NH—C 1-6 -alkylene-, —NHCONH—C 1-6 -alkylene-, —NHCSNH—C 1-6 -alkylene-, —C 1-6 -alkylene-NHCO—, —C 1-6 -alkylene-CONH—, —C 1-6 -alkylene-NH—, —C 1-6 -alkylene-NHCONH—, —C 1-6 -alkylene-NHCSNH—, —O(CH 2 ) p —, —(OCH 2 CH 2 ) p —, —NHCO—, —CONH—, —NHSO 2 —, —SO 2 NH—, —CO—, —SO 2 —, —O—, —S—, pyrrolidine-2,5-dione, 1,2,3-triazole, —NH—, and —NMe-, wherein each p is independently 1 to 50;

L 2 is a polypeptide, or is selected from:

wherein each x and y is independently 1 to 10.

9. The compound of claim 7 , wherein —Z 1 -L 1 - comprises a group selected from:

wherein p, q, and z1 are each independently 1 to 6.

10. A conjugate of formula (III):

wherein:

n is 1 to 20;

m is an average loading of 1 to 80;

each X is a moiety that binds to a cell surface ASGPR of formula:

wherein:

R 1 is selected from —OH, —OC(O)R, —C(O)NHR, and triazole, where R is C 1-6 alkyl or aryl;

R 2 is selected from —NHCOCH 3 , —NHCOCF 3 , —NHCOCH 2 CF 3 , —OH, and triazole;

wherein “*” represents a point of attachment of Z 1 to the linker (L);

R 4 and R 5 are each H;

Z 1 is a linking moiety selected from Z 11 , Z 11 -heteroaryl, Z 11 -aryl, and alkyl;

Z 11 is —C(R 22 ) 2 —; and

each R 22 is independently selected from H, halogen, and (C 1 -C 6 ) alkyl;

each L is a linker;

each Z is a residual moiety resulting from the covalent linkage of a chemoselective ligation group to a compatible group of Ab; and

Ab is an antibody or antibody fragment that binds a target protein.

11. The compound of claim 10 , wherein n is 1 to 6, and m is 1 to 20.

12. The compound of claim 10 , wherein Z is a residual moiety resulting from the covalent linkage of a thiol-reactive chemoselective ligation group to one or more cysteine residue(s) of Ab; or Z is a residual moiety resulting from the covalent linkage of an amine-reactive chemoselective ligation group to one or more lysine residue(s) of Ab.

13. The compound of claim 10 , wherein L is of the formula:

wherein

n is 1, 2, or 3;

each L 11 to L 15 is independently a linking moiety which together provide a linear or branched linker between Z 1 and Ab;

a, b, c, d, and e are each independently 0, 1, or 2;

** represents the point of attachment to L 1 to X via Z 1 ; and

* represents the point of attachment to Ab.

14. The compound of claim 13 , wherein:

each linking moiety of L 11 , L 12 , L 14 and L 15 is independently selected from —C 1-20 -alkylene-, —NHCO—C 1-6 -alkylene-, —CONH—C 1-6 -alkylene-, —NH C 1-6 -alkylene-, —NHCONH—C 1-6 -alkylene-, —NHCSNH—C 1-6 -alkylene-, —C 1-6 -alkylene-NHCO—, —C 1-6 -alkylene-CONH—, —C 1-6 -alkylene-NH—, —C 1-6 -alkylene-NHCONH—, —C 1-6 -alkylene-NHCSNH—, —O(CH 2 ) p —, —(OCH 2 CH 2 ) p —, —NHCO—, —CONH—, —NHSO 2 —, —SO 2 NH—, —CO—, —SO 2 —, —O—, —S—, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocycle, amino acid residue, —NH—, and —NMe-, wherein each p is independently 1 to 50; and

each L 13 is a branched linking moiety independently selected from amino acid residue, polypeptide,

wherein each x and y is independently 1 to 10.

15. The compound of claim 13 , wherein n is 1 and the linker comprises a linking moiety selected from:

L1

L1.1

L1.2

L1.3

L1.4

L1.5

L1.6

L1.7

L1.8

L1.9

L1.10

L1.11

L2

L2.1

L3

L4

L5

L5.1

L6

L7

L7.1

L7.2

L7.3

L8

L9

L10

L11

16. The compound of claim 14 , wherein:

n is 2 or 3;

c is 1; and

L 13 is

17. The compound of claim 10 , wherein each X moiety is covalently linked to Ab via L-Z having a chain of 21 to 50 consecutive atoms.

18. The compound of claim 10 , wherein the linker is selected from:

wherein:

each r is independently 0 to 10;

each s is independently 0 or 1; and

each q and p is independently 0 to 20.

Assignments (3)

Continuity (3)

References Cited (259)