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US 10,836,725 B2Granted
Modulators of the integrated stress pathway
AssigneeAbbVie Inc.
InventorsMarina 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
Life of this patent
Estimating the term…
Abstract
Provided herein are compounds, compositions, and methods useful for modulating the integrated stress response (ISR) and for treating related diseases; disorders and conditions.
Claims13
A compound of Formula (I):
- or a pharmaceutically acceptable salt thereof, wherein:
- D is
- L1 is 2-7-membered heteroalkylene and L2 is selected from C1-C6 alkylene or 2-7-membered heteroalkylene, wherein each alkylene and heteroalkylene is optionally substituted by 1-5 RX;
- R1 and R2 are each hydrogen or 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, —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.
18 more elements
A compound represented by Formula (I-b):
- or a pharmaceutically acceptable salt thereof, wherein:
- L1 is selected from CH2O—* or CH2CH2O—*, L2 is selected from —CH2—*, —CH2CH2—*, CH2CH2CH2—*, —CH2(CH3)—*, —CH2(CH3)CH2—*, CH2O—* or CH2CH2O—*, and “—*” indicates the attachment point to A and W, respectively;
- R1 and R2 are each hydrogen or C1-C6 alkyl;
- A is phenyl substituted with 1-2 RY;
- W is phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1-5 RY,
- each RX is oxo or —ORA;
- each RY is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo, cyano, —ORA, —NRBRC, —S(O)2RD, —S(RF)m, or 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;
- G1 is phenyl optionally substituted with 1-3 RZ;
- each RZ is independently C1-C6 alkyl;
- RA is, at each occurrence, independently hydrogen, C1-C6 alkyl, or halo-C1-C6 alkyl;
- each of RB and RC is independently hydrogen or C1-C6 alkyl;
- each RD is independently C1-C6 alkyl, halo-C1-C6 alkyl, or —NRB1RC1;
- each RF is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, or halo;
- each of RB1 and RC1 is independently hydrogen or C1-C6 alkyl;
- and
- m is 1, 3, or 5.
15 more elements
A compound selected from the group consisting of:
- and a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.