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US 2023/0104740 A1Published application
Inhibitors of glycogen synthase 1 (gys1) and methods of use thereof
AssigneeMaze Therapeutics, Inc.
InventorsDavid John MORGANS, JR., Kevin MELLEM, Hannah L. POWERS, Patrick Sang Tae LEE, Walter WON, Christopher Joseph SINZ
Life of this patent
Estimating the term…
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 Y2, Y3, L1, L2, X1, X2, X3, X4, X5, Q1, R1, R2, Rk, Rm, and Rn 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.
Claims49
1:
- A compound of formula (I-A):
- or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
- Y1 is CH or N;
- Rx and Rz are independently H, halo, C1-6alkyl, or —NH2, wherein, when Y1 is CH, the C1-6alkyl of Rx or Rz may be optionally substituted with one or more halo;
- Ry is (i) C1-6alkyl, or (ii) C3-10cycloalkyl, wherein the C3-10cycloalkyl is optionally substituted with one or more halo or C1-6alkyl;
- Rk is H, halo, —OH, —NH2, or —NH—C(O)C1-6alkyl;
- R2 is C1-6alkyl, wherein the C1-6alkyl of R2 is substituted with one or more Ra, wherein Ra is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Ra is optionally substituted with one or more Rb;
- and
- Rb is halo, C1-6alkyl, C1-6alkoxy, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, C3-10cycloalkyl, 3-15 membered heterocyclyl, or —C(O)—C1-6alkoxy, wherein the C1-6alkyl of Rb is optionally substituted with one or more halo, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —NH—C(O)C1-6alkyl, or —NH—C(O)—C1-6alkoxy, and the 3-15-membered heterocyclyl of Rb is optionally substituted with one or more halo or —C(O)—C1-6alkoxy.
6 more elements
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:
-5. (canceled)
6:
- 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 of
7:
- The compound of claim 6, 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 of
-36. (canceled)
37:
- The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Rx is H, fluoro, or methyl, and Ry is (i) isopropyl, or (ii) C3-4cycloalkyl, wherein the C3-4cycloalkyl is optionally substituted with one or more fluoro or methyl.
38:
- The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Rk is H or halo.
-41. (canceled)
42:
- The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2 is selected from the group consisting of
43:
- The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2 is
-53. (canceled)
54:
- 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
(canceled)
56:
- 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.
57:
- 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, or a pharmaceutical composition of claim 56.
-64. (canceled)
65:
- 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 56, and (ii) instructions for use in treating an GYS1-mediated disease, disorder, or condition in an individual in need thereof.
-72. (canceled)
73:
- A method of modulating GYS1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a GYS1 modulator, or a pharmaceutical composition comprising a GYS1 modulator.
74:
- A method of inhibiting GYS1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a GYS1 inhibitor, or a pharmaceutical composition comprising a GYS1 inhibitor.
75:
- A method of reducing tissue glycogen stores in an individual in need thereof, comprising administering to the individual an effective amount of a GYS1 inhibitor, or a pharmaceutical composition comprising a GYS1 inhibitor.
76:
- 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.
-90. (canceled)
91:
- 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 Rx is H, halo, C1-6alkyl, or —NH2, wherein the C1-6alkyl is optionally substituted with one or more halo.
92:
- 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
- or a pharmaceutically acceptable salt thereof.
93:
- The compound of claim 92, 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
94:
- 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)-(5-isopropylpyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide having the structure
- or a pharmaceutically acceptable salt thereof.
95:
- The compound of claim 94, wherein the compound is (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoro-N—((S)-(5-isopropylpyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide having the structure
96:
- The compound of claim 1, wherein the compound is (2S,4R)—N—((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)-1-(2-(5-(difluoromethyl)-1H-tetrazol-1-yl)acetyl)-4-fluoropyrrolidine-2-carboxamide having the structure
- or a pharmaceutically acceptable salt thereof.
97:
- The compound of claim 96, wherein the compound is (2S,4R)—N—((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)-1-(2-(5-(difluoromethyl)-1H-tetrazol-1-yl)acetyl)-4-fluoropyrrolidine-2-carboxamide having the structure
98:
- The compound of claim 1, wherein the compound is (2S,4R)-4-fluoro-N—((S)-(3-fluoro-4-isopropylphenyl)(phenyl)methyl)-1-(2-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)acetyl)pyrrolidine-2-carboxamide having the structure
- or a pharmaceutically acceptable salt thereof.
99:
- The compound of claim 98, wherein the compound is (2S,4R)-4-fluoro-N—((S)-(3-fluoro-4-isopropylphenyl)(phenyl)methyl)-1-(2-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)acetyl)pyrrolidine-2-carboxamide having the structure
100:
- 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)-(6-fluoro-5-isopropylpyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide having the structure
- or a pharmaceutically acceptable salt thereof.
101:
- The compound of claim 100, wherein the compound is (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoro-N—((S)-(6-fluoro-5-isopropylpyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide having the structure
102:
- The compound of claim 1, wherein the compound is (2S,4R)-1-(2-(1H-benzo[d]imidazol-1-yl)acetyl)-N—((S)-(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide having the structure
- or a pharmaceutically acceptable salt thereof.
103:
- The compound of claim 102, wherein the compound is (2S,4R)-1-(2-(1H-benzo[d]imidazol-1-yl)acetyl)-N—((S)-(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide having the structure
104:
- The compound of claim 1, wherein the compound is (2S,4R)—N—[(S)-[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide having the structure
- or a pharmaceutically acceptable salt thereof.
105:
- The compound of claim 104, wherein the compound is (2S,4R)—N—[(S)-[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide having the structure
106:
- The compound of claim 1, wherein the compound is (2S,4R)—N—[(S)-[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide having the structure
- or a pharmaceutically acceptable salt thereof.
107:
- The compound of claim 106, wherein the compound is (2S,4R)—N—[(S)-[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl]-4-fluoro-1l-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide having the structure
108:
- The compound of claim 1, wherein the compound is (2S,4R)—N—[(S)-[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide having the structure
- or a pharmaceutically acceptable salt thereof.
109:
- The compound of claim 108, wherein the compound is (2S,4R)—N—[(S)-[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide having the structure
110:
- The compound of claim 1, wherein the compound is (2S,4R)-4-fluoro-N—[(S)-[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl]-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide having the structure
- or a pharmaceutically acceptable salt thereof.
111:
- The compound of claim 110, wherein the compound is (2S,4R)-4-fluoro-N—[(S)-[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl]-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide having the structure
112:
- The compound of claim 1, wherein the compound is (2S,4R)-1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-4-fluoro-N—[(S)-[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl]pyrrolidine-2-carboxamide having the structure
- or a pharmaceutically acceptable salt thereof.
113:
- The compound of claim 112, wherein the compound is (2S,4R)-1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-4-fluoro-N—[(S)-[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl]pyrrolidine-2-carboxamide having the structure
114:
- The compound of claim 1, wherein the compound is (2S,4R)-1-(2-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)acetyl)-4-fluoro-N—((S)-(5-isopropyl-4-methylpyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide having the structure
- or a pharmaceutically acceptable salt thereof.
115:
- The compound of claim 114, wherein the compound is (2S,4R)-1-(2-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)acetyl)-4-fluoro-N—((S)-(5-isopropyl-4-methylpyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide having the structure
Dependencies are inferred from the claim text.