Inhibitors of glycogen synthase 1 (GYS1) and methods of use thereof

Inventors: David John Morgans, Jr. (Los Altos, CA); Kevin Mellem (Redwood City, CA); Hannah L. Powers (San Diego, CA); Patrick Sang Tae Lee (Walnut Creek, CA); Walter Won (San Diego, CA); Christopher Joseph Sinz (Walnut Creek, CA)

Assignee: Maze Therapeutics, Inc.

C07D403/12 C07D207/16 C07D401/06 C07D401/12 C07D401/14 C07D403/06 C07D405/06 C07D413/06 C07D413/14 C07D417/06 C07D471/04 C07D487/04 C07D487/10 C07D491/048 C07D491/08 C07D498/10

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Quick Facts

Patent No.: US 12,534,453
App. No.: 18/243,973
Granted: Jan 27, 2026
Kind: B2

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Abstract

Provided herein are compounds of formula (I′): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y 2 , Y 3 , L 1 , L 2 , X 1 , X 2 , X 3 , X 4 , X 5 , Q 1 , R 1 , R 2 , R k , R m , and R n are as defined elsewhere herein. Also provided herein are methods of preparing compounds of formula (I′). Also provided herein are methods of inhibiting GYS1 and methods of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

Claims (61)

1 . A method of treating a disease, disorder, or condition selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease, or condition in an individual in need thereof, comprising administering to the individual an effective amount of a compound of formula (I-A):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

Y 1 is CH or N;

R x and R z are independently H, halo, C 1-6 alkyl, or —NH 2 , wherein, when Y 1 is CH, the C 1-6 alkyl of R x or R z may be optionally substituted with one or more halo;

R y is (i) C 1-6 alkyl, or (ii) C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl;

R k is H, halo, —OH, —NH 2 , or —NH—C(O)C 1-6 alkyl;

R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R a is optionally substituted with one or more R b ; and

R b is halo, C 1-6 alkyl, C 1-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , C 3-10 cycloalkyl, 3-15 membered heterocyclyl, or —C(O)—C 1-6 alkoxy, wherein the C 1-6 alkyl of R b is optionally substituted with one or more halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy, and the 3-15-membered heterocyclyl of R b is optionally substituted with one or more halo or —C(O)—C 1-6 alkoxy.

2 . The method of claim 1 , wherein the moiety represented by

has a stereochemical configuration of the formula:

3 . The method of claim 1 , wherein the moiety represented by

is selected from the group consisting of

4 . The method of claim 3 , wherein the moiety represented by

is selected from the group consisting of

5 . The method of claim 1 , wherein R x is H, fluoro, or methyl, and

R y is (i) isopropyl, or (ii) C 3-4 cycloalkyl, wherein the C 3-4 cycloalkyl is optionally substituted with one or more fluoro or methyl.

6 . The method of claim 1 , wherein R k is H or halo.

7 . The method of claim 1 , wherein R 2 is selected from the group consisting of

8 . The method of claim 1 , wherein R 2 is

9 . The method of claim 1 , wherein the compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from the group consisting of

or a pharmaceutically acceptable salt of any of the foregoing.

10 . The method of claim 1 , wherein the compound of formula (I-A) is a compound of formula (I-A3):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R x is H, halo, C 1-6 alkyl, or —NH 2 , wherein the C 1-6 alkyl is optionally substituted with one or more halo.

11 . The method of claim 1 , wherein the disease, disorder, or condition is Pompe disease.

12 . The method of claim 11 , wherein the disease, disorder, or condition is late-onset Pompe disease.

13 . The method of claim 11 , wherein the compound of formula (I-A) is (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoro-N—((S)-(4-isopropylphenyl)(phenyl)methyl)pyrrolidine-2-carboxamide having the structure