Inhibitors of integrated stress response pathway

A compound of formula (1-2):

• or a pharmaceutically acceptable salt thereof;
• wherein:
• X2 is CH;
• RY1 is hydrogen or C1-C6 alkyl;
• Y2 is selected from the group consisting of NRY2 and O;
• RY2 is hydrogen or C1-C6 alkyl;
• q2 is 1;
• r and s, independently of each other, are 0, 1, or 2;
• A1 is a substituent of formula (A1-a)
• wherein
• represents the attachment point to the remainder of the molecule;
• Z1 is selected from the group consisting of CRZ1-1RZ1-2, NRZ1-2, O, S, and —CRZ1-1═CRZ1-1;
• wherein RZ1-1 is H or R14;
• and RZ1-2 is H or R14;
• Z2 is selected from the group consisting of CRZ2-1RZ2-2, NRZ2-2;
• and —CRZ2-1═CRZ2-1;
• wherein RZ2-1 is H or R14;
• and RZ2-2 is H or R14;
• Z3, independently at each occurrence, is C or N, provided that at least one Z3 is C;
• R13 is hydrogen or R14, or R13 and RZ1-2 are taken together to form a double bond between the carbon atom bearing R13 and Z1, or R13 and RZ2-2 are taken together to form a double bond between the carbon atom bearing R13 and Z2;
• and
• x1 is 1, 2, 3, or 4, and at least one R14 is halogen;
• R14 is selected, independently at each occurrence, from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —O(C1-C6 alkyl), —O(C1-C6 haloalkyl), —SH, —S(C1-C6 alkyl), —S(C1-C6 haloalkyl), —NH2, —NH(C1-C6 alkyl), —NH(C1-C6 haloalkyl), —N(C1-C6 alkyl)2, —N(C1-C6 haloalkyl)2, —NR14-aR14-b, —CN, —C(O)OH, —C(O)O(C1-C6 alkyl), —C(O)O(C1-C6 haloalkyl), —C(O)NH2, —C(O)NH(C1-C6 alkyl), —C(O)NH(C1-C6 haloalkyl), —C(O)N(C1-C6 alkyl)2, —C(O)N(C1-C6 haloalkyl)2, —C(O)NR14-aR14-b—S(O)2OH, —S(O)2O(C1-C6 alkyl), —S(O)2O(C1-C6 haloalkyl), —S(O)2NH2, —S(O)2NH(C1-C6 alkyl), —S(O)2NH(C1-C6 haloalkyl), —S(O)2N(C1-C6 alkyl)2, —S(O)2N(C1-C6 haloalkyl)2, —S(O)2NR14-aR14-b, —OC(O)H, —OC(O)(C1-C6 alkyl), —OC(O)(C1-C6 haloalkyl), —N(H)C(O)H, —N(H)C(O)(C1-C6 alkyl), —N(H)C(O)(C1-C6 haloalkyl), —N(C1-C6 alkyl)C(O)H, —N(C1-C6 alkyl)C(O)(C1-C6 alkyl), —N(C1-C6 alkyl)C(O)(C1-C6 haloalkyl), —N(C1-C6 haloalkyl)C(O)H, —N(C1-C6 haloalkyl)C(O)(C1-C6 alkyl), —N(C1-C6 haloalkyl)C(O)(C1-C6 haloalkyl), —OS(O)2(C1-C6 alkyl), —OS(O)2(C1-C6 haloalkyl), —N(H)S(O)2(C1-C6 alkyl), —N(H)S(O)2(C1-C6 haloalkyl), —N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), —N(C1-C6 alkyl)S(O)2(C1-C6 haloalkyl), —N(C1-C6 haloalkyl)S(O)2(C1-C6 alkyl), and —N(C1-C6 haloalkyl)S(O)2(C1-C6 haloalkyl);
• wherein R14-a and R14-b are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;
• A2 is C6-C10 aryl substituted by at least one halogen substituent and optionally further substituted with one or more R16 substituents, or 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R16 substituents;
• R16 is selected, independently at each occurrence, from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —O(C1-C6 alkyl), —O(C1-C6 haloalkyl), —SH, —S(C1-C6 alkyl), —S(C1-C6 haloalkyl), —NH2, —NH(C1-C6 alkyl), —NH(C1-C6 haloalkyl), —N(C1-C6 alkyl)2, —N(C1-C6 haloalkyl)2, —NR16-aR16-b, —CN, —C(O)OH, —C(O)O(C1-C6 alkyl), —C(O)O(C1-C6 haloalkyl), —C(O)NH2, —C(O)NH(C1-C6 alkyl), —C(O)NH(C1-C6 haloalkyl), —C(O)N(C1-C6 alkyl)2, —C(O)N(C1-C6 haloalkyl)2, —C(O)NR16-aR16-b—S(O)2OH, —S(O)2O(C1-C6 alkyl), —S(O)2O(C1-C6 haloalkyl), —S(O)2NH2, —S(O)2NH(C1-C6 alkyl), —S(O)2NH(C1-C6 haloalkyl), —S(O)2N(C1-C6 alkyl)2, —S(O)2N(C1-C6 haloalkyl)2, —S(O)2NR16-aR16-b, —OC(O)H, —OC(O)(C1-C6 alkyl), —OC(O)(C1-C6 haloalkyl), —N(H)C(O)H, —N(H)C(O)(C1-C6 alkyl), —N(H)C(O)(C1-C6 haloalkyl), —N(C1-C6 alkyl)C(O)H, —N(C1-C6 alkyl)C(O)(C1-C6 alkyl), —N(C1-C6 alkyl)C(O)(C1-C6 haloalkyl), —N(C1-C6 haloalkyl)C(O)H, —N(C1-C6 haloalkyl)C(O)(C1-C6 alkyl), —N(C1-C6 haloalkyl)C(O)(C1-C6 haloalkyl), —OS(O)2(C1-C6 alkyl), —OS(O)2(C1-C6 haloalkyl), —N(H)S(O)2(C1-C6 alkyl), —N(H)S(O)2(C1-C6 haloalkyl), —N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), —N(C1-C6 alkyl)S(O)2(C1-C6 haloalkyl), —N(C1-C6 haloalkyl)S(O)2(C1-C6 alkyl), and —N(C1-C6 haloalkyl)S(O)2(C1-C6 haloalkyl);
• wherein R16-a and R16-b are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;
• R1a and R1b are independently selected from the group consisting of hydrogen, C1-C6 alkyl, and halogen;
• R2a and R2b are independently selected from the group consisting of hydrogen, C1-C6 alkyl, and halogen;
• when present, R3a and R3b are independently at each occurrence selected from the group consisting of hydrogen, C1-C6 alkyl, and halogen;
• when present, R4a and R4b are independently at each occurrence selected from the group consisting of hydrogen, C1-C6 alkyl, and halogen;
• or alternatively, R1a and R2a are taken together to form a C1-C6 alkylene moiety;
• or alternatively, R1a and an R3a moiety, when present, are taken together to form a C1-C6 alkylene moiety, and R1b and the R3b in the geminal position to the R3a taken together with Ria, are both hydrogen;
• or alternatively, an R3a moiety, when present, and an R4a moiety, when present, are taken together to form a C1-C6 alkylene moiety, and the R3b in the geminal position to the R3a taken together with the R4a moiety and the R4b in the geminal position to the R4a taken together with the R3a moiety, are both hydrogen;
• R9a and R9b are taken together to form an oxo (═O) substituent or an imido (═NH) substituent, or alternatively, R9a and R9b are both hydrogen;
• R10a is hydrogen;
• and
• R10b is hydrogen.