| abstract |
Compounds, compositions and useful methods for modulating the integrated stress response (ISR) and for treating related diseases, disorders and conditions are provided herein. Claim 1: A compound of the formula (1), or one of its pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers, wherein: D is a monocyclic bridge cycloalkyl, monocyclic bridge or cubanyl heterocycle, wherein each cycloalkyl bridge monocyclic, bridge monocyclic heterocycle or cubanyl is optionally substituted with 1-4 RX groups; L¹ and L² are each independently C₁₋₆ alkylene, C₂₋₆ alkenylene or 2-7 membered heteroalkylene, wherein each C₁₋₆ alkylene, C₂₋₆ alkenylene or 2-7 membered heteroalkylene is optionally substituted with 1-5 RX; R¹ and R² are each, independently, hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, hydroxy-C₁₋₆ alkyl, silyloxy-C₁₋₆ alkyl; A and W are each, independently, 5-6 membered phenyl or heteroaryl, wherein each 5-6 membered phenyl or heteroaryl is optionally substituted with 1-5 RY; each RX is independently selected from the group consisting of C₁₋₆ alkyl, hydroxy-C₁₋₆ alkyl, halo-C₁₋₆ alkyl, amino-C₁₋₆ alkyl, cyano-C₁₋₆ 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, -S (O) ₂RD, OS (O) RD, -OS (O) ₂RD and 5-6 membered heteroaryl; each RY is independently selected from the group consisting of hydrogen, C₁₋₆ alkyl, hydroxyC₁₋₆ alkyl, haloC₁₋₆ alkyl, haloC₁₋₆ alkoxy, aminoC₁₋₆ alkyl, cyano -C₁₋₆ 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 in adjacent atoms, together with the atoms to which they are attached, form a fused 3-7 membered cycloalkyl ring, heterocyclyl, aryl or heteroaryl optionally substituted with 1-5 RX; each G¹ is, independently, C₃₋₆ cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered aryl or heteroaryl, wherein each C ciclo cycloalkyl, 4-7 membered heterocyclyl, 5- aryl or heteroaryl 6 members is optionally substituted with 1-3 RZ; each RZ is independently selected from the group consisting of C₁₋₆ alkyl, hydroxy-C₁₋₆ alkyl, halo-C₁₋₆ alkyl, halo, cyano, -ORA, -NRBRC, -NRBC (O) RD, -C (O) NRBRC, -C (O) RD, -C (O) OH, -C (O) ORD and -S (O) ₂RD; each RA is, independently, hydrogen, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, -C (O) NRBRC, -C (O) RD, -C (O) OH or -C (O) ORD; each of RB and RC is, independently, hydrogen or C₁₋₆ alkyl; or RB and RC together with the atom to which they are attached form a 3-7 membered heterocyclyl ring optionally substituted with 1-3 RZ; each RD is independently C₁₋₆ alkyl, 2-7 membered heteroalkyl or halo-C-alkyl, wherein each C₁₋₆ alkyl, 2-7 membered heteroalkyl or halo-C- alkyl is optionally substituted with 1-5 RG; each RE is independently hydrogen, C₁₋₆ alkyl or halo-C-alkyl; each RF is, independently, hydrogen, C₁₋₆ alkyl or halo; each RG is, independently, 5-6 membered aryl or heteroaryl, wherein each 5-6 membered aryl or heteroaryl is optionally substituted with 1-5 RH; each RH is independently C₁₋₆ alkyl or halo-C-alkyl; m is 1, 3 or 5; and t is 0 or 1. |