Modulators of the integrated stress pathway
AssigneesCalico Life Sciences LLC, AbbVie Inc.
InventorsCarmela Sidrauski, Marina Pliushchev, Jennifer M. Frost, Lawrence A. Black, Xiangdong Xu, Ramzi Farah Sweis, Lei Shi, Qingwei I. Zhang, Yunsong Tong, Charles W. Hutchins, Seungwon Chung, Michael J. Dart
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Abstract
Provided herein are compounds, compositions, and methods useful for modulating the integrated stress response (ISR) and for treating related diseases; disorders and conditions.
Claims40
A compound of Formula (I):
- or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:
- D is a bridged monocyclic cycloalkyl, bridged monocyclic heterocyclyl, or cubanyl, wherein each bridged monocyclic cycloalkyl, bridged monocyclic heterocyclyl, or cubanyl is optionally substituted with 1-4 RX;
- L1 and L2 are each independently C1-C6 alkylene or 2-7-membered heteroalkylene, wherein each C1-C6 alkylene or 2-7-membered heteroalkylene is optionally substituted with 1-5 RX;
- R1 and R2 are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, silyloxy-C1-C6 alkyl;
- A and W are each independently phenyl or 5-6 membered heteroaryl, wherein each phenyl or 5-6-membered heteroaryl is optionally substituted with 1-5 RY;
- each RX is independently selected from the group consisting of C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, —ORA, —NRBRC, —NRBC(O)RD, —C(O)NRBRC, —C(O)RD, —C(O)OH,—C(O)ORD, —SRE, —S(O)RD, and —S(O)2RD;
- each RY is independently selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, —ORA, —NRBRC, —NRBC(O)RD, —C(O)NRBRC, —C(O)RD, —C(O)OH, —C(O)ORD, —S(RF)m, —S(O)RD, —S(O)2RD, and G1;
- or
- 2 RY groups on adjacent atoms, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl, 3-7 membered heterocyclyl, aryl, or 5-6 membered heteroaryl, optionally substituted with 1-5 RX;
- each G1 is independently C3-C6 cycloalkyl, 4-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl, wherein each C3-C6 cycloalkyl, 4-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl is optionally substituted with 1-3 RZ;
- each RZ is independently selected from the group consisting of C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, —ORA, —NRBRC, —NRBC(O)RD, —C(O)NRBRC, —C(O)RD, —C(O)OH, —C(O)ORD, and —S(O)2RD;
- RA is, at each occurrence, independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, —C(O)NRBRC, —C(O)RD, —C(O)OH, or —C(O)ORD;
- each of RB and RC is independently hydrogen or C1-C6 alkyl;
- or RB and RC together with the atom to which they are attached form a 3-7-membered heterocyclyl optionally substituted with 1-3 RZ;
- each RD is independently C1-C6 alkyl, halo-C1-C6 alkyl, or —NRB1RC1;
- each RE is independently hydrogen, C1-C6 alkyl, or halo-C1-C6 alkyl;
- each RF is independently hydrogen, C1-C6 alkyl, halo, or halo-C1-C6 alkyl;
- each of RB1 and RC1 is independently hydrogen or C1-C6 alkyl;
- and
- m is 1, 3, or 5.
The compound of any one of the preceding claims, wherein the compound is selected from any compound set forth in Table 1 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.
A pharmaceutically acceptable composition comprising a compound of any one of the preceding claims and a pharmaceutically acceptable carrier.
A composition for use in treating a neurodegenerative disease, a leukodystrophy, cancer, an inflammatory disease, a musculoskeletal disease, or a metabolic disease in a subject, wherein composition comprises a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof as described in any one of the preceding claims.
A composition for use in treating a disease related to a modulation of eIF2B activity or levels, eIF2α activity or levels, or the activity or levels of a component of the eIF2 pathway or the ISR pathway, wherein the composition comprises a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof as described in any one of the preceding claims.
Dependencies are inferred from the claim text.