REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED AS AN ASCII TEXT FILE

The Sequence Listing written in file 048536-539C02US_SL_ST25.TXT, created May 21, 2019, 3,608 bytes, machine format IBM-PC, MS-Windows operating system, is hereby incorporated by reference.

BACKGROUND OF THE INVENTION

In metazoa, diverse stress signals converge at a single phosphorylation event at serine 51 of a common effector, the translation initiation factor eIF2α. This step is carried out by four eIF2α kinases in mammalian cells: PERK, which responds to an accumulation of unfolded proteins in the endoplasmic reticulum (ER), GCN2 to amino acid starvation and UV light, PKR to viral infection, and HRI to heme deficiency. This collection of signaling pathways has been termed the “integrated stress response” (ISR), as they converge on the same molecular event. eIF2α phosphorylation results in an attenuation of translation with consequences that allow cells to cope with the varied stresses (1).

eIF2 (which is comprised of three subunits, α, β and γ) binds GTP and the initiator Met-tRNA to form the ternary complex (eIF2-GTP-Met-tRNAi), which, in turn, associates with the 40S ribosomal subunit scanning the 5′UTR of mRNAs to select the initiating AUG codon. Upon phosphorylation of its α-subunit, eIF2 becomes a competitive inhibitor of its GTP-exchange factor (GEF), eIF2B (2). The tight and nonproductive binding of phosphorylated eIF2 to eIF2B prevents loading of the eIF2 complex with GTP thus blocking ternary complex formation and reducing translation initiation (3). Because eIF2B is less abundant than eIF2, phosphorylation of only a small fraction of the total eIF2 has a dramatic impact on eIF2B activity in cells.

Paradoxically, under conditions of reduced protein synthesis, a small group of mRNAs that contain upstream open reading frames (uORFs) in their 5′UTR are translationally upregulated (4,5). These include mammalian ATF4 (a cAMP element binding (CREB) transcription factor) and CHOP (a pro-apoptotic transcription factor) (6-8). ATF4 regulates the expression of many genes involved in metabolism and nutrient uptake and additional transcription factors, such as CHOP, which is under both translational and transcriptional control (9). Phosphorylation of eIF2α thus leads to preferential translation of key regulatory molecules and directs diverse changes in the transcriptome of cells upon cellular stress.

One of the eIF2α kinases, PERK, lies at the intersection of the ISR and the unfolded protein response (UPR) that maintains homeostasis of protein folding in the ER (10). The UPR is activated by unfolded or misfolded proteins that accumulate in the ER lumen because of an imbalance between protein folding load and protein folding capacity, a condition known as “ER stress”. In mammals, the UPR is comprised of three signaling branches mediated by ER-localized transmembrane sensors, PERK, IRE1, and ATF6. These sensor proteins detect the accumulation of unfolded protein in the ER and transmit the information across the ER membrane, initiating unique signaling pathways that converge in the activation of an extensive transcriptional response, which ultimately results in ER expansion (11). The lumenal stress-sensing domains of PERK and IRE1 are homologous and likely activated in analogous ways by direct binding to unfolded peptides (12). This binding event leads to oligomerization and trans-autophosphorylation of their cytosolic kinase domains, and, for PERK, phosphorylation of its only known substrate, eIF2α. In this way, PERK activation results in a quick reduction in the load of newly synthesized proteins that are translocated into the ER-lumen (13).

Upon ER stress, both the transcription factor XBP1s, produced as the consequence of a non-conventional mRNA splicing reaction initiated by IRE1, and the transcription factor ATF6, produced by proteolysis and release from the ER membrane, collaborate with ATF4 to induce the vast UPR transcriptional response. Transcriptional targets of the UPR include the ER protein folding machinery, the ER-associated degradation machinery, and many other components functioning in the secretory pathway (14). Although the UPR initially mitigates ER stress and as such confers cytoprotection, persistent and severe ER stress leads to activation of apoptosis that eliminates damaged cells (15,16).

Small-molecule therapeutics that inhibit the UPR and/or the Integrated Stress Response could be used in cancer as a single agent or in combination with other chemotherapeutics [1] [2][3], for enhancement of long-term memory [5] [6], in neurodegenerative and prion associated diseases [4], in white matter disease (VWM) [7] and in biotechnology applications that would benefit from increased protein translation.

Disclosed herein, inter alia, are solutions to these and other problems in the art.

BRIEF SUMMARY OF THE INVENTION

In a first aspect is provided a method of treating an integrated stress response-associated disease in a patient in need of such treatment, the method including administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, to the patient, wherein the compound has the formula:


Ring A is substituted or unsubstituted cycloalkylene or substituted or unsubstituted arylene. L1, L2, L3, and L4are independently a bond, —NH—, —O—, —S—, —S(O)—, —S(O)2—, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene; R1, R3, R5, R6and R7are 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; R2and R4are 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.

In another aspect is provided a method of treating a disease associated with phosphorylation of eIF2α in a patient in need of such treatment, the method including administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, to the patient, wherein the compound has the formula:


Ring A is substituted or unsubstituted cycloalkylene or substituted or unsubstituted arylene. L1, L2, L3, and L4are independently a bond, —NH—, —O—, —S—, —S(O)—, —S(O)2—, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene; R1, R3, R5, R6and R7are 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; R2and R4are 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.

In another aspect is provided a method of treating a disease in a patient in need of such treatment, the method including administering a therapeutically effective amount of a compound to the patient, wherein the disease is selected from the group consisting of cancer, a neurodegenerative disease, vanishing white matter disease, childhood ataxia with CNS hypo-myelination, and an intellectual disability syndrome; and wherein the compound has the formula:


Ring A is substituted or unsubstituted cycloalkylene or substituted or unsubstituted arylene. L1, L2, L3, and L4are independently a bond, —NH—, —O—, —S—, —S(O)—, —S(O)2—, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene; R1, R3, R5, R6and R7are 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; R2and R4are 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.

In another aspect is provided a method of treating an inflammatory disease in a patient in need of such treatment, the method including administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, to the patient, wherein the compound has the formula:


Ring A is substituted or unsubstituted cycloalkylene or substituted or unsubstituted arylene. L1, L2, L3, and L4are independently a bond, —NH—, —O—, —S—, —S(O)—, —S(O)2—, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene; R1, R3, R5, R6and R7are 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; R2and R4are 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.

In another aspect is provided a method of improving long-term memory in a patient, the method including administering a therapeutically effective amount of a compound to the patient, wherein the compound is a compound described herein.

In another aspect is provided a method of increasing protein expression of a cell or in vitro expression system, the method including administering an effective amount of a compound to the cell or expression system, wherein the compound is a compound described herein.

In another aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula:


wherein. ring A, L1, L2, L3, L4, R1, R2, R3, R4, R5, R6, R7, z2, z4, z5 and z6, are as described herein, including embodiments and in the method of treatment section herein above. In embodiments, Ring A is substituted or unsubstituted cycloalkylene or substituted or unsubstituted arylene. In embodiments, L1, L2, L3, and L4are independently a bond, —NH—, —O—, —S—, —S(O)—, —S(O)2—, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. In embodiments, R1, R3, R5, R6and R7are 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. In embodiments, R2and R4are independently ═NR7, ═O, or ═S. The symbols z2 and z4 are each independently 0 or 1. The symbols z5 and z6 are each independently an integer from 0 to 5.

In another aspect is provided a pharmaceutical composition including a pharmaceutically acceptable excipient and a compound, or pharmaceutically acceptable salt thereof, as described herein.

