Inhibitors of integrated stress response pathway

A compound of formula (I)

• or a pharmaceutically acceptable salt thereof,
• wherein:
• X is N or CR12;
• Y is a bond, NRa, or NRaNRa;
• provided that:
• (a) when X is N, then Y is a bond or NRa;
• and
• (b) when X is CR12, then Y is NRa or NRaNRa;
• Z is a bond, C(═O), CR11R11, or NRa;
• L1 is selected from the group consisting of *1-C(═O)-#1, *1-CH2-#1, *1-CH2CH2-#1, *1-CH2CH2CH2-#1, *1-OCH2C(═O)-#1, *1-OCH2CH2C(═O)-#1, *1-OCH2CH2CH2C(═O)-#1, *1-OCH2CH(OH)CH2-#1, *1-OCH2-#1, *1-OCH2CH2-#1, and *1-OCH2CH2CH2-#1;
• wherein *1 represents the attachment point to R1 and #1 represents the attachment point to the remainder of the molecule;
• L2 is selected from the group consisting of #2-C(═O)-*2, #2-CH2-*2, #2-CH2CH2-*2, #2-CH2CH2CH2-*2, #2-C(═O)CH2O—*2, #2-C(═O)CH2CH2O—*2, #2-C(═O)CH2CH2CH2O-*2, #2-CH2CH(OH)CH2O—*2, #2-CH2O-*2, #2-CH2CH2O-*2, and #2-CH2CH2CH2O-*2;
• wherein *2 represents the attachment point to R2 and #2 represents the attachment point to the remainder of the molecule;
• R1 is selected from the group consisting of:
• C6-C14 aryl substituted with one or more halo groups and optionally substituted with one or more Rb;
• and
• 5-14 membered heteroaryl substituted with one or more halo groups and optionally substituted with one or more Rb;
• R2 is selected from the group consisting of:
• C6-C14 aryl substituted with one or more halo groups and optionally substituted one or more Rb;
• and
• 5-14 membered heteroaryl substituted with one or more halo groups and optionally substituted one or more Rb;
• R3 is hydrogen, halogen, or C1-C6 alkyl;
• or R3 and R12 are taken together to form a CR13R14 group;
• R4, R5, R6, R7, R8, and R9, independently of each other, are selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl;
• R10 and R11, independently of each other, are selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl;
• R12 is hydrogen, halogen, or C1-C6 alkyl;
• or R3 and R12 are taken together to form a CR13R14 group;
• R13 and R14, independently of each other, are selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl;
• Ra, independently at each occurrence, is hydrogen or C1-C6 alkyl;
• Rb, independently at each occurrence, is selected from the group consisting of NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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, NRcRd, 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)2NRcRd, 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 Rc and Rd are taken together with the nitrogen atom to which they are attached to form a 3-10 membered heterocycle;
• and
• provided that:
• (i) when X is CR12, Y is NRa, Z is a bond, L1 is *1-CH2-#1, and L2 is #2-CH2-*2;
• then either:
• (i-1) at least one of R3, R4, and R5 is hydrogen or halogen;
• or
• (i-2) R3 and R12 are taken together to form a CR13R14 group;
• (ii) when X is CR12, Y is NRa, Z is a bond, and R3 and R12 are taken together to form CR13R14;
• then either:
• (ii-1) L1 is selected from the group consisting of *1-C(═O)-#1, *1-CH2-#1, *1-CH2CH2-#1, *1-CH2CH2CH2-#1, *1-OCH2CH2C(═O)-#1, *1-OCH2CH2CH2C(═O)-#1, *1-OCH2CH(OH)CH2-#1, *1-OCH2-#1, *1-OCH2CH2-#1, and *1-OCH2CH2CH2-#1;
• or
• (ii-2) L2 is selected from the group consisting of #2-C(═O)-*2, #2-CH2-*2, #2-CH2CH2-*2, #2-CH2CH2CH2-*2, #2-C(═O)CH2CH2O—*2, #2-C(═O)CH2CH2CH2O-*2, #2-CH2CH(OH)CH2O—*2, #2-CH2O-*2, #2-CH2CH2O-*2, and #2-CH2CH2CH2O-*2;
• and
• (iii) when X is N and Y is a bond;
• then:
• L1 is selected from the group consisting of *1-OCH2CH(OH)CH2-#1, *1-OCH2-#1, *1-OCH2CH2-#1, and *1-OCH2CH2CH2-#1;
• and
• further provided that, when Z is CR10R11, then at least one of R1 and R2 is substituted by two or more halo groups.