Modulators of the integrated stress pathway

A compound of Formula (I):

• or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof, wherein:
• D is a bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, bridged bicyclic cycloalkenyl, or cubanyl, wherein each bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, bridged bicyclic cycloalkenyl, or cubanyl is optionally substituted with 1-4 RX groups;
• and wherein if the bridged bicyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen moiety may be optionally substituted by RN1;
• L1 and L2 are each independently C1-C6 alkylene, C2-C6 alkenylene, 2-7-membered heteroalkylene, O, or NRC, wherein each C1-C6 alkylene, C2-C6 alkenylene, or 2-7-membered heteroalkylene is optionally substituted with 1-5 RL;
• R1 and R2 are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C2-C6 alkyl, hydroxy-C2-C6 alkyl, silyloxy-C2-C6 alkyl, G1-O—C2-C6 alkyl, HO2C—C1-C6 alkyl, or C1-C6 alkyl-C(O)2—C1-C6 alkyl;
• each RL is independently selected from the group consisting of C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, HO2C—C1-C6 alkyl, C1-C6 alkyl-C(O)2—C1-C6 alkyl, oxo, halo, cyano, —ORA, —NRBRC, —NBRCC, 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 G2;
• or
• 2 geminal RL groups together with the carbon to which they are attached form a cyclopropyl moiety;
• RN1 is selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C2-C6 alkyl, amino-C2-C6 alkyl, cyano-C2-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, HO2C—C1-C6 alkyl, C1-C6 alkyl-C(O)2—C1-C6 alkyl, phenoxy-C1-C6 alkyl (wherein phenoxy is optionally substituted with 1-3 halogens), —C(O)NRBRC, —C(O)RD, —C(O)ORD, and —S(O)2RD;
• 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, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkoxy, oxo, halo, cyano, —ORA, —NRBRC—NBRCC, —NRBC(O)RD, —C(O)NRBRC, —C(O)RD, —C(O)OH, —C(O)ORD, ═CHC(O)ORD, ═CHC(O)OH, —SRE, —S(O)RD, —S(O)2RD, —OS(O)RD, —OS(O)2RD, and G2;
• or
• 2 geminal RX groups together with the carbon to which they are attached form an oxirane moiety;
• each RY is independently selected from the group consisting of hydrogen, C1-C6 alkyl, O—C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, —ORA, —NRBRC, —NRBRCC, —NRBRC(O)RD, —C(O)NRBRC, —C(O)RD, —C(O)OH, —C(O)ORD, —S(RF)m, —S(O)RD, —S(O)2RD, and G;
• or
• 2 RY groups on adjacent atoms, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl, heterocyclyl, aryl, or heteroaryl ring optionally substituted with 1-5 RX;
• each G1 and G2 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;
• each RA is independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, —C(O)NRBRC, —C(O)RD, or —C(O)ORD;
• each of RB and RC is independently hydrogen, C1-C6 alkyl, or halo-C1-C6 alkyl;
• 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 RCC is independently selected from the group consisting of hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, HO2C—C1-C6 alkyl, C1-C6 alkyl-C(O)2—C1-C6 alkyl, (CO)—C1-C6alkyl-OH, (CO)—C1-C6alkyl-C1-C6alkoxy and 4-6 membered heterocyclyl;
• wherein the heterocyclyl may optionally be substituted with 1-3 RZ:
• each RD is independently C1-C6 alkyl, 2-7-membered heteroalkyl, hydroxy-C1-C6 alkyl, or halo-C1-C6 alkyl, wherein each C1-C6 alkyl, 2-7-membered heteroalkyl, hydroxy-C1-C6 alkyl, or halo-C1-C6 alkyl is optionally substituted with 1-5 RG;
• each RE is independently hydrogen, C1-C6 alkyl, or halo-C1-C6 alkyl;
• each RF is independently hydrogen, C1-C6 alkyl, or halo;
• each RG is independently aryl or 5-6 membered heteroaryl, wherein each aryl or 5-6 membered heteroaryl is optionally substituted with 1-5 RH;
• each RH is independently C1-C6 alkyl or halo-C1-C6 alkyl;
• m is 1 when RF is hydrogen or C1-C6 alkyl, 3 when RF is C1-C6 alkyl, or 5 when RF is halo;
• t is 0 or 1;
• and
• s is 0 or 1.