N-(BENZHYDRYL)CYCLOALKYLCARBOXAMIDE DERIVATIVES AS INHIBITORS OF GLYCOGEN SYNTHASE 1 (GYS1) AND METHODS OF USE THEREOF
Provided herein are compounds of formula (I) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, n, R 1 , R 2 , R 3 , R 4 , Y 1 , Y 2 , X 1 , X 2 , L, and Q 1 are as defined elsewhere herein. Also provided herein CN are methods of preparing compounds of formula (I). Also provided herein are methods of inhibiting GYSI and methods of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.
1 . A compound of formula (I):
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
Y 1 and Y 2 are each CH, or
one of Y 1 and Y 2 is N and the other of Y 1 and Y 2 is CH;
X 1 and X 2 are each independently H or halo;
R 3 and R 4 are each —CH 3 , or
R 3 and R 4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl;
either
(1) L is absent; and
Q 1 is:
(i) C 6-20 aryl, wherein the C 6-20 aryl of Q 1 is optionally substituted with one or more —OH, —NH 2 , halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 5-20 membered heteroaryl, —NH—C(O)—NH 2 , —NH—C(O)—NH(C 1-6 alkyl), —NH—C(O)—C 1-6 alkyl, —NH—C(O)—C 3-10 cycloalkyl, —NH—C(O)-(3-15 membered heterocyclyl), —NH—C(═N—CN)—NH 2 , —NH—S(O) 2 —C 1-6 alkyl, —NH(C 1-6 alkyl), —NH-(3-15 membered heterocyclyl), or —NH-(5-20 membered heteroaryl), wherein
the 3-15 membered heterocyclyl of the —NH—C(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more —C(O)—C 1-6 alkyl or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, C 1-6 alkoxy, or C 3-10 cycloalkyl, and
the 3-15 membered heterocyclyl of the —NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C 1-6 alkyl, or
(ii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q 1 is optionally substituted with one or more oxo, or
(iii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q 1 comprises at least one annular N atom and is optionally substituted with one or more —NH 2 , halo, C 1-6 alkyl, or C 3-10 cycloalkyl;
or
(2) L is —CH 2 —; and
Q 1 is C 3-10 cycloalkyl;
m is 0 or 1;
n is 0 or 1;
R 1 is H, halo, —CN, —C(O)—NH 2 , —C(O)—NH(CN), —C(O)—NH(C 1-6 alkyl), —NH—C(O)—NH 2 , or —NH—C(O)—C 1-6 alkyl, wherein
the C 1-6 alkyl of the —C(O)—NH(C 1-6 alkyl) of R 1 is optionally substituted with one or more —C(O)—C 1-6 alkoxy, and
the C 1-6 alkyl of the —NH—C(O)—C 1-6 alkyl of R 1 is optionally substituted with one or more —NH—C(O)—C 1-6 alkyl or —C(O)—NH 2 ; and
R 2 is H, halo, or —OH.
2 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compounds of formula (I) has a stereochemical configuration of
3 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 is H.
4 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 is halo.
5 . The compound of claim 1 or claim 4 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 is fluoro.
6 . The compound of any one of claims 1-5 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 2 is H.
7 . The compound of any one of claims 1-5 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 2 is halo.
8 . The compound of any one of claims 1-5 and 7 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 2 is fluoro.
9 . The compound of any one of claims 1-8 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 and R 4 are each independently —CH 3 .
10 . The compound of any one of claims 1-8 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 and R 4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl.
11 . The compound of any one of claims 1-8 and 10 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 and R 4 are taken, together with the atoms to which they are attached, to form cyclopropyl.
12 . The compound of any one of claims 1-8 and 10 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 and R 4 are taken, together with the atoms to which they are attached, to form cyclobutyl.
13 . The compound of any one of claims 1-12 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is absent.
14 . The compound of any one of claims 1-13 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is C 6-20 aryl, wherein the C 6-20 aryl of Q 1 is optionally substituted with one or more NH 2 , halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 5-20 membered heteroaryl, —NH—C(O)—NH 2 , —NH—C(O)—NH(C 1-6 alkyl), —NH—C(O)—C 1-6 alkyl, —NH—C(O)—C 3-10 cycloalkyl, —NH—C(O)-(3-15 membered heterocyclyl), or —NH—C(═N—CN)—NH 2 , —NH(C 1-6 alkyl), wherein
the 3-15 membered heterocyclyl of the —NH—C(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more —C(O)—C 1-6 alkyl or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, C 1-6 alkoxy, or C 3-10 cycloalkyl, and
the 3-15 membered heterocyclyl of the —NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C 1-6 alkyl.
15 . The compound of any one of claims 1-14 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is phenyl, wherein the phenyl of Q 1 is optionally substituted with one or more NH 2 , halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 5-20 membered heteroaryl, —NH—C(O)—NH 2 , —NH—C(O)—NH(C 1-6 alkyl), —NH—C(O)—C 1-6 alkyl, —NH—C(O)—C 3-10 cycloalkyl, —NH—C(O)-(3-15 membered heterocyclyl), or —NH—C(═N—CN)—NH 2 , —NH(C 1-6 alkyl), wherein
the 3-15 membered heterocyclyl of the —NH—C(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more —C(O)—C 1-6 alkyl or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, C 1-6 alkoxy, or C 3-10 cycloalkyl, and
the 3-15 membered heterocyclyl of the —NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C 1-6 alkyl.
16 . The compound of any one of claims 1-15 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is selected from the group consisting of
17 . The compound of any one of claims 1-13 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q 1 is optionally substituted with one or more oxo.
18 . The compound of any one of claims 1-13 and 17 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is 9-10 membered heterocyclyl, wherein the 9-10 membered heterocyclyl of Q 1 is optionally substituted with one or more oxo.
19 . The compound of any one of claims 1-13, 17, and 18 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is selected from the group consisting of
20 . The compound of any one of claims 1-13 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q 1 comprises at least one annular N atom and is optionally substituted with one or more —NH 2 , halo, C 1-6 alkyl, or C 3-10 cycloalkyl.
21 . The compound of any one of claims 1-13 and 20 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is 6-10 membered heteroaryl, wherein the 6-10 membered heteroaryl of Q 1 comprises at least one annular N atom and is optionally substituted with one or more —NH 2 , halo, C 1-6 alkyl, or C 3-10 cycloalkyl.
22 . The compound of any one of claims 1-13, 20, and 21 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is selected from the group consisting of
23 . The compound of any one of claims 1-12 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is —CH 2 — and Q 1 is C 3-10 cycloalkyl.
24 . The compound of claim any one of claims 1-23 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m and n are each independently 0.
25 . The compound of any one of claims 1-23 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m and n are each independently 1.
26 . The compound of any one of claims 1-25 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is selected from the group consisting of H, —CN, —C(O)—NH 2 , —C(O)—NH(CN), —C(O)—NH(C 1-6 alkyl), —NH—C(O)—NH 2 , and —NH—C(O)—C 1-6 alkyl, wherein
the C 1-6 alkyl of the —C(O)—NH(C 1-6 alkyl) is optionally substituted with one or more —C(O)—C 1-6 alkoxy, and
the C 1-6 alkyl of the —NH—C(O)—C 1-6 alkyl is optionally substituted with one or more —NH—C(O)—C 1-6 alkyl or —C(O)—NH 2 .
27 . The compound of any one of claims 1-26 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is H.
28 . The compound of any one of claims 1-26 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is selected from the group consisting of —CN, —C(O)—NH 2 , —C(O)—NH(CN), —C(O)—NH(C 1-6 alkyl), —NH—C(O)—NH 2 , and —NH—C(O)—C 1-6 alkyl, wherein
the C 1-6 alkyl of the —C(O)—NH(C 1-6 alkyl) is optionally substituted with one or more —C(O)—C 1-6 alkoxy, and
the C 1-6 alkyl of the —NH—C(O)—C 1-6 alkyl is optionally substituted with one or more —NH—C(O)—C 1-6 alkyl or —C(O)—NH 2 .
29 . The compound of any one of claims 1-26 and 28 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is selected from the group consisting of —CN,
30 . The compound of any one of claims 1-25 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is H or halo.
31 . The compound of any one of claims 1-25 and 30 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is H or fluoro.
32 . The compound of any one of claims 1-25, 30, and 31 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is fluoro.
33 . The compound of any one of claims 1-32 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is H.
34 . The compound of any one of claims 1-32 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is halo.
35 . The compound of any one of claims 1-32, and 34 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is fluoro.
36 . The compound of any one of claims 1-32 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is —OH.
37 . The compound of any one of claims 1-21, and 24-36 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-A):
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein
either:
i. X 4-8 are each independently H, —OH, —NH 2 , halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 5-20 membered heteroaryl, —NH—C(O)—NH 2 , —NH—C(O)—NH(C 1-6 alkyl), —NH—C(O)—C 1-6 alkyl, —NH—C(O)—C 3-10 cycloalkyl, —NH—C(O)-(3-15 membered heterocyclyl), —NH—C(═N—CN)—NH 2 , —NH—S(O)2-C 1-6 alkyl, —NH(C 1-6 alkyl), —NH-(3-15 membered heterocyclyl), or —NH-(5-20 membered heteroaryl), wherein
the 3-9 membered heterocyclyl of the —NH—C(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more —C(O)—C 1-6 alkyl or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, C 1-6 alkoxy, or C 3-10 cycloalkyl, and
the 3-9 membered heterocyclyl of the —NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C 1-6 alkyl; or
ii. X 6 is taken together with either of X 4 or X 8 , and the atoms to which they are attached, to form ring A, wherein ring A is
3-9 membered heterocyclyl, and wherein the 3-9 membered heterocyclyl of ring A is optionally substituted with one or more oxo, wherein X 5 , X 7 , and the other of X 4 or X 8 are each independently H, or oxo, or
5-14 membered heteroaryl, and wherein the 5-14 membered heteroaryl of ring A comprises at least one annular N atom and is optionally substituted with one or more —NH 2 , halo, C 1-6 alkyl, or C 3-10 cycloalkyl, wherein X 5 , X 7 , and the other of X 4 or X 8 are each independently H, —NH 2 , halo, C 1-6 alkyl, or C 3-10 cycloalkyl; or
iii. X 7 is taken together with either of X 5 or X 8 , and the atoms to which they are attached, to form ring A, wherein ring A is
3-9 membered heterocyclyl, and wherein the 3-9 membered heterocyclyl of ring A is optionally substituted with one or more oxo, and wherein X 4 , X 6 , and the other of X 5 or X 8 are each independently H, or oxo, or 5-14 membered heteroaryl, and wherein the 5-14 membered heteroaryl of ring A comprises at least one annular N atom and is optionally substituted with one or more —NH 2 , halo, C 1-6 alkyl, or C 3-10 cycloalkyl, and wherein X 4 , X 6 , and the other of X 5 or X 8 are
each independently H, —NH 2 , halo, C 1-6 alkyl, or C 3-10 cycloalkyl.
38 . The compound of any one of claims 1-10, 13, 15, or 20-23 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-C):
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A is
3-9 membered heterocyclyl, and wherein the 3-9 membered heterocyclyl of ring A is optionally substituted with one or more oxo,
5-14 membered heteroaryl, and wherein the 5-14 membered heteroaryl of ring A comprises at least one annular N atom and is optionally substituted with one or more —NH 2 , halo, C 1-6 alkyl, or C 3-10 cycloalkyl.
39 . 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 Table 1.
40 . A process for preparing a compound of any one of claims 1-39 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the process comprises:
(a) reacting a compound of formula (I-1):
or a salt thereof, wherein
Y 1 and Y 2 are each CH, or
one of Y 1 and Y 2 is N and the other of Y 1 and Y 2 is CH;
X 1 and X 2 are each independently H or halo;
R 3 and R 4 are each —CH 3 , or
R 3 and R 4 are taken, together with the atoms to which they are attached, to form cyclopropyl or cyclobutyl;
either
(1) L is absent; and
Q 1 is:
(i) C 6-20 aryl, wherein the C 6-20 aryl of Q 1 is optionally substituted with one or more —OH, —NH 2 , halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 5-20 membered heteroaryl, —NH—C(O)—NH 2 , —NH—C(O)—NH(C 1-6 alkyl), —NH—C(O)—C 1-6 alkyl, —NH—C(O)—C 3-10 cycloalkyl, —NH—C(O)-(3-15 membered heterocyclyl), —NH—C(═N—CN)—NH 2 , —NH—S(O) 2 —C 1-6 alkyl, —NH(C 1-6 alkyl), —NH-(3-15 membered heterocyclyl), or —NH-(5-20 membered heteroaryl), wherein
the 3-15 membered heterocyclyl of the —NH—C(O)-(3-15 membered heterocyclyl) is optionally substituted with one or more —C(O)—C 1-6 alkyl or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, C 1-6 alkoxy, or C 3-10 cycloalkyl, and
the 3-15 membered heterocyclyl of the —NH-(3-15 membered heterocyclyl) is optionally substituted with one or more oxo or C 1-6 alkyl, or
(ii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q 1 is optionally substituted with one or more oxo, or
(iii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q 1 comprises at least one annular N atom and is optionally substituted with one or more —NH 2 , halo, C 1-6 alkyl, or C 3-10 cycloalkyl;
or
(2) L is —CH 2 —; and
Q 1 is C 3-10 cycloalkyl,
with a compound of formula (I-2):
wherein,
m is 0 or 1;
n is 0 or 1;
R 1 is H, halo, —CN, —C(O)—NH 2 , —C(O)—NH(CN), —C(O)—NH(C 1-6 alkyl), —NH—C(O)—NH 2 , or —NH—C(O)—C 1-6 alkyl, wherein
the C 1-6 alkyl of the —C(O)—NH(C 1-6 alkyl) of R 1 is optionally substituted with one or more —C(O)—C 1-6 alkoxy, and
the C 1-6 alkyl of the —NH—C(O)—C 1-6 alkyl of R 1 is optionally substituted with one or more —NH—C(O)—C 1-6 alkyl or —C(O)—NH 2 ; and
R 2 is H, halo, or —OH
in the presence of a coupling reagent to provide a compound of formula (I).
41 . A pharmaceutical composition comprising (i) a compound of any one of claims 1-39 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.
42 . 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 any one of claims 1-39 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41 .
43 . The method of claim 42 , wherein the disease, disorder, or condition is a glycogen storage disorder (GSD).
44 . The method of claim 42 or claim 43 , wherein the disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.
45 . The method of any one of claims 42-44 , wherein the disease, disorder, or condition is Pompe disease.
46 . The method of claim 42 , wherein the disease, disorder, or condition is cancer.
47 . The method of claim 42 or claim 46 , wherein the disease, disorder, or condition is selected from the group consisting of Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma (GRCC) breast cancer, non-small-cell lung carcinoma (NSCLC), and acute myeloid leukemia (AML).
48 . The method of claim 42 , wherein the individual has a GAA mutation.
49 . The method of claim 48 , wherein the GAA mutation is a loss-of-function mutation.
50 . A kit, comprising (i) a compound of any one of claims 1-39 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41 , and (ii) instructions for use in treating an GYS1-mediated disease, disorder, or condition in an individual in need thereof.
51 . The kit of claim 50 , wherein the disease, disorder, or condition is a glycogen storage disorder (GSD).
52 . The kit of claim 50 or claim 51 , wherein the disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.
53 . The kit of any one of claims 50-52 , wherein the disease, disorder, or condition is Pompe disease.
54 . The kit of claim 50 , wherein the disease, disorder, or condition is cancer.
55 . The kit of claim 50 or claim 54 , wherein the disease, disorder, or condition is selected from the group consisting of Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma (GRCC) breast cancer, non-small-cell lung carcinoma (NSCLC), and acute myeloid leukemia (AML).
56 . The kit of claim 52 , wherein the individual has a GAA mutation.
57 . The kit of claim 56 , wherein the GAA mutation is a loss-of-function mutation.
58 . A method of modulating GYS1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of any one or claims 1-39 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41 .
59 . A method of inhibiting GYS1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of any one or claims 1-39 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41 .
60 . 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 any one of claims 1-39 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41 .
61 . A method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising subjecting the individual to glycogen substrate reduction therapy, wherein the glycogen substrate reduction therapy comprises administering to the individual an effective amount of a compound of any one of claims 1-39 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 39 .
62 . The method of claim 61 , comprising subjecting the individual to glycogen substrate reduction therapy in combination with enzyme replacement therapy.
63 . The method of claim 62 , wherein the enzyme replacement therapy is selected from the group consisting of alglucosidase alfa (human recombinant alpha-glucosidase (human GAA)) Myozyme and Lumizyme.
64 . The method of any one of claims 61-63 , wherein the disease, disorder, or condition is a glycogen storage disorder (GSD).
65 . The method of any one of claims 61-64 , wherein the disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.
66 . The method of any one of claims 61-65 , wherein the disease, disorder, or condition is Pompe disease.
67 . The method of any one of claims 61-63 , wherein the disease, disorder, or condition is cancer.
68 . The method of any one of claims 61-63, or 67 , wherein the disease, disorder, or condition is selected from the group consisting of Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma (GRCC) breast cancer, non-small-cell lung carcinoma (NSCLC), and acute myeloid leukemia (AML).
69 . The method of any one of claims 61-63 , wherein the individual has a GAA mutation.
70 . The method of claim 69 , wherein the GAA mutation comprises a loss-of-function mutation.
71 . The method of any one of claims 58-60 wherein the compound is selective for GYS1 over GYS2.
72 . The method of claim 71 , wherein the compound is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2.
73 . The method of any one of claims 42-49 or 58-72 , comprising reducing the level of glycogen in skeletal muscle.
74 . A compound of any one of claims 1-39 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41 , for use in treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.
75 . A compound of any one of claims 1-39 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41 , for use in modulating GYS1 in a cell.
76 . A compound of any one of claims 1-39 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41 , for use in inhibiting GYS1 in a cell.
77 . A compound of any one of claims 1-39 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41 , for use in reducing tissue glycogen stores in an individual in need thereof.
78 . A compound of any one of claims 1-39 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 41 , for use in a glycogen substrate reduction therapy for treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.
79 . Use of a compound of any one of claims 1-39 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41 , in the manufacture of a medicament for use in treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.
80 . Use of a compound of any one of claims 1-39 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41 , in the manufacture of a medicament for use in modulating GYS1 in a cell.
81 . Use of a compound of any one of claims 1-39 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41 , in the manufacture of a medicament for use in inhibiting GYS1 in a cell.
82 . Use of a compound of any one of claims 1-39 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41 , in the manufacture of a medicament for use in reducing tissue glycogen stores in an individual in need thereof.
83 . Use of a compound of any one of claims 1-39 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 41 , in the manufacture of a medicament for use in a glycogen substrate reduction therapy for treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.