Modulators of the eif2alpha pathway
AssigneeThe Regents of the University of California
InventorsPeter Walter, Carmela Sidrauski, Diego Acosta Alvear, Michelle R. Arkin, Christopher G. Wilson, Kean Hooi Ang, Brian R. Hearn, Punitha Vedantham, Adam R. Renslo, Mervyn Maze, Susana Vacas
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Abstract
Provided herein, inter alia, are compounds and methods useful for modulating the translational effects of eIF2α phosphorylation, the Integrated Stress Response (ISR), and the unfolded protein response (UPR); for treating diseases; for increasing protein production, and for improving long-term memory.
Claims33
A method of treating an integrated stress response-associated disease, disease associated with phosphorylation of eIF2α, inflammatory disease, cancer, a neurodegenerative disease, vanishing white matter disease, childhood ataxia with CNS hypo-myelination, or an intellectual disability syndrome in a patient in need of such treatment, said method comprising administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, to said patient, wherein said compound has the formula:
- wherein,
- ring A is substituted or unsubstituted cycloalkylene or substituted or unsubstituted arylene;
- L1, L2, L3, and L4 are independently a bond, —NH—, —O—, —S—, —S(O)—, —S(O)2—, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene;
- R1, R3, R5, R6 and R7 are independently hydrogen, halogen, —OCH3, —OCH2Ph, —C(O)Ph, —CH3, —CF3, —CCl3, —CN, —S(O)CH3, —OH, —NH2, —COOH, —CONH2, —NO2, —C(O)CH3, —CH(CH3)2, —CCSi(CH3)3, —C(NN)CF3, —C(NH—NH)CF3, —CCH, —CH2CCH, —SH, —SO2Cl, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O)NH2, —NHSO2H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCH3, —OCF3, —OCHF2, —N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R2 and R4 are independently ═NR7, ═O, or ═S;
- z2 and z4 are independently 0 or 1;
- and
- z5 and z6 are independently an integer from 0 to 5.
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A method of improving long-term memory in a patient, said method comprising administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, to said patient, wherein said compound has the formula:
- wherein,
- ring A is substituted or unsubstituted cycloalkylene or substituted or unsubstituted arylene;
- L1, L2, L3, and L4 are independently a bond, —NH—, —O—, —S—, —S(O)—, —S(O)2—, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene;
- R1, R3, R5, R6 and R7 are independently hydrogen, halogen, —OCH3, —OCH2Ph, —C(O)Ph, —CH3, —CF3, —CCl3, —CN, —S(O)CH3, —OH, —NH2, —COOH, —CONH2, —NO2, —C(O)CH3, —CH(CH3)2, —CCSi(CH3)3, —C(NN)CF3, —C(NH—NH)CF3, —CCH, —CH2CCH, —SH, —SO2Cl, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O)NH2, —NHSO2H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCH3, —OCF3, —OCHF2, —N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R2 and R4 are independently ═NR7, ═O, or ═S;
- z2 and z4 are independently 0 or 1;
- and
- z5 and z6 are independently an integer from 0 to 5.
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A compound, or a pharmaceutically acceptable salt thereof, having the formula:
- wherein,
- ring A is substituted or unsubstituted cycloalkylene or substituted or unsubstituted arylene;
- L1, L2, L3, and L4 are independently a bond, —NH—, —O—, —S—, —S(O)—, —S(O)2—, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene;
- R1, R3, R5, R6 and R7 are independently hydrogen, halogen, —OCH3, —OCH2Ph, —C(O)Ph, —CH3, —CF3, —CCl3, —CN, —S(O)CH3, —OH, —NH2, —COOH, —CONH2, —NO2, —C(O)CH3, —CH(CH3)2, —CCSi(CH3)3, —C(NN)CF3, —C(NH—NH)CF3, —CCH, —CH2CCH, —SH, —SO2Cl, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O)NH2, —NHSO2H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCH3, —OCF3, —OCHF2, —N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R2 and R4 are independently ═NR7, ═O, or ═S;
- z2 and z4 are independently 0 or 1;
- and
- z5 and z6 are independently an integer from 0 to 5;
- with the proviso that the compound is not
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Dependencies are inferred from the claim text.