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 11,814,367
App. No.: 17/694,311
Granted: Nov 14, 2023
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 (65)

1. 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 compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the moiety represented by

has a stereochemical configuration of the formula:

3. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the moiety represented by

is selected from the group consisting

4. The compound of claim 3 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the moiety represented by

is selected from the group consisting

5. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, 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 compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R k is H or halo.

7. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is selected from the group consisting of

8. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is

9. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from the group consisting of

10. A pharmaceutical composition comprising (i) a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

11. A method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

12. A kit, comprising (i) a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 10 , and (ii) instructions for use in treating an GYS1-mediated disease, disorder, or condition in an individual in need thereof.

13. A method of modulating GYS1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

14. A method of inhibiting GYS1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

15. A method of reducing tissue glycogen stores in an individual in need thereof, comprising administering to the individual an effective amount of a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

16. A method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of a pharmaceutical composition of claim 10 .

17. The compound of claim 1 , wherein the compound 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.

18. The compound of claim 1 , wherein the compound 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