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EP-4117780-B1 - MODULATORS OF THE INTEGRATED STRESS RESPONSE PATHWAY

EP4117780B1EP 4117780 B1EP4117780 B1EP 4117780B1EP-4117780-B1

Inventors

  • ATTON, HOLLY VICTORIA
  • BROWN, CHRISTOPHER JOHN
  • CARR, JAMES LINDSAY
  • SADLER, Scott Alexander
  • SHINE, Jonathan Paul
  • WALTER, DARYL SIMON

Dates

Publication Date
20260506
Application Date
20210310

Claims (16)

  1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein R a1 , R a2 , R a3 , R a4 , R a5 , and R a6 are H; A 1 is triazole or oxadiazole, provided that the ring atom of ring A 1 marked with an asterisk is a carbon atom, wherein A 1 is optionally substituted with one or more R 4 , which are the same or different; each R 4 is independently oxo (=O) where the ring is at least partially saturated, thiooxo (=S) where the ring is at least partially saturated, halogen, CN, OR 5 , or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; R 5 is H or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; A 2 is R 6a or A 2a ; R 6a is OR 6a1 , SR 6a1 , N(R 6a1 R 6a2 ), C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, OR 6a3 , CN, and A 2a , wherein the substituents are the same or different; R 6a1 and R 6a2 are independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and A 2a , wherein C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OR 6a3 , A 2a , and OA 2a , wherein the substituents are the same or different; R 6a3 is H, or C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with one or more halogen, which are the same or different; A 2a is phenyl, cyclobutyl, azetidinyl, or 5- to 6-membered aromatic heterocyclyl, wherein A 2a is optionally substituted with one or more R 6 , which are the same or different; each R 6 is independently R 6b , OH, OR 6b , halogen, or CN, wherein R 6b is cyclopropyl, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein R 6b is optionally substituted with one or more halogen, which are the same or different; or two R 6 are joined to form together with the atoms to which they are attached a ring A 2b ; A 2b is phenyl, C 3-7 cycloalkyl, or 3 to 7 membered heterocyclyl, wherein A 2b is optionally substituted with one or more R 7 , which are the same or different; each R 7 is independently C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different; R 1 is H; R 2 is H; R 3 is A 3 ; R 2a is H; each A 3 is independently phenyl, pyridyl, pyrazinyl, pyrimidazyl, cyclopropyl, cyclobutyl or cyclohexyl, wherein A 3 is optionally substituted with one or more R 10 , which are the same or different; each R 10 is independently F, Cl, Br, CHF 2 , CF 3 , OCF 3 , CH=O, CH 2 OH or CH 3 .
  2. The compound of claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein A 1 is unsubstituted or substituted with one or two R 4 , which are the same or different, preferably A 1 is unsubstituted.
  3. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein R 4 is oxo, where the ring is at least partly saturated.
  4. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein A 1 is
  5. The compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein A 2 is R 6a .
  6. The compound of claim 5 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein R 6a is OR 6a1 and R 6a1 is preferably A 2a or C 1-6 alkyl, optionally substituted with one or more halogen and/or one A 2a and/or one OR 6a3 ; or R 6a is C 1-6 alkyl, optionally substituted with one or more halogen and/or one A 2a and/or one OR 6a3 .
  7. The compound of claim 5 or 6 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein R 6a is OR 6a1 and R 6a1 is preferably C 1-6 alkyl, optionally substituted with one or more F and/or one OR 6a3 ; or R 6a is C 1-6 alkyl, optionally substituted with one or more halogen and/or one OR 6a3 .
  8. The compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein A 2 is A 2a .
  9. The compound of any one of claims 1 to 6 and 8 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein A 2a is substituted with one or two R 6 , which are the same or different.
  10. The compound of any one of claims 1 to 6, 8 and 9 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein each R 6 is independently F, Cl, CF 3 , OCH 3 , OCF 3 , CH 3 , CH 2 CH 3 , or cyclopropyl.
  11. The compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein A 3 is substituted with one or two R 10 , which are the same or different.
  12. The compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein the compound is 2-(4-chloro-3-fluorophenoxy)- N -[ trans -2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1,3-dioxan-5-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)- N -[ trans -2-{5-[ cis -3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-1,3-dioxan-5-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)- N -[ cis -2-[1-(4-chlorophenyl)-1 H -1,2,3-triazol-4-yl]-1,3-dioxan-5-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)- N- [ trans -2-[1-(4-chlorophenyl)-1 H -1,23-triazol-4-yl]-1,3-dioxan-5-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)- N -[ trans -2-[5-(4,4,4-trifluorobutoxy)-1,3,4-oxadiazol-2-yl]-1,3-dioxan-5-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)- N -[ trans- 2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}-1,3-dioxan-5-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)- N -[ trans- 2-{5-[3-(trifluoromethoxy)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}-1,3-dioxan-5-yl]acetamide; 2-[(6-chloro-5-fluoro-3-pyridyl)oxy]- N -[ trans -2-[5-[ cis -3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1,3-dioxan-5-yl]acetamide; 2-[3-chloro-4-(difluoromethyl)phenoxy]- N -[ trans -2-{5-[3-(trifluoromethoxy)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}-1,3-dioxan-5-yl]acetamide; or 2-(3,4-dichlorophenoxy)- N -[ trans- 2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}-1,3-dioxan-5-yl]acetamide.
  13. The compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein the compound is of formula (Ia)
  14. A pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof as defined in any one of claims 1 to 13 together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.
  15. A compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof of any one of claims 1 to 13 for use as a medicament.
  16. A compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof of any one of claims 1 to 13 or a pharmaceutical composition of claim 14 for use in a method of treating or preventing of one or more diseases or disorders selected from the group consisting of leukodystrophies, intellectual disability syndrome, neurodegenerative diseases and disorders, neoplastic diseases, infectious diseases, inflammatory diseases, musculoskeletal diseases, metabolic diseases, ocular diseases as well as diseases selected from the group consisting of organ fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, myocardial infarction, cardiovascular disease, arrhythmias, atherosclerosis, spinal cord injury, ischemic stroke, and neuropathic pain.

Description

The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, wherein R1, R2, R2a, R3, Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, A1 and A2 have the meaning as indicated in the description and claims. The invention further relates to pharmaceutical compositions comprising said compounds, and said compounds and pharmaceutical compositions for use as medicament and in a method for treating and preventing of one or more diseases or disorders specified hereinafter. The Integrated Stress Response (ISR) is a cellular stress response common to all eukaryotes (1). Dysregulation of ISR signaling has important pathological consequences linked inter alia to inflammation, viral infection, diabetes, cancer and neurodegenerative diseases. ISR is a common denominator of different types of cellular stresses resulting in phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha) on serine 51 leading to the suppression of normal protein synthesis and expression of stress response genes (2). In mammalian cells the phosphorylation is carried out by a family of four eIF2alpha kinases, namely: PKR-like ER kinase (PERK), double-stranded RNA-dependent protein kinase (PKR), heme-regulated eIF2alpha kinase (HRI), and general control non-derepressible 2 (GCN2), each responding to distinct environmental and physiological stresses (3). eIF2alpha together with eIF2beta and eIF2gamma form the eIF2 complex, a key player of the initiation of normal mRNA translation (4). The eIF2 complex binds GTP and Met-tRNAi forming a ternary complex (eIF2-GTP-Met-tRNAi), which is recruited by ribosomes for translation initiation (5, 6). eIF2B is a heterodecameric complex consisting of 5 subunits (alpha, beta, gamma, delta, epsilon) which in duplicate form a GEF-active decamer (7). In response to ISR activation, phosphorylated eIF2alpha inhibits the eIF2B-mediated exchange of GDP for GTP, resulting in reduced ternary complex formation and hence in the inhibition of translation of normal mRNAs characterized by ribosomes binding to the 5' AUG start codon (8). Under these conditions of reduced ternary complex abundance the translation of several specific mRNAs including the mRNA coding for the transcription factor ATF4 is activated via a mechanism involving altered translation of upstream ORFs (uORFs) (7, 9, 10). These mRNAs typically contain one or more uORFs that normally function in unstressed cells to limit the flow of ribosomes to the main coding ORF. For example, during normal conditions, uORFs in the 5' UTR of ATF occupy the ribosomes and prevent translation of the coding sequence of ATF4. However, during stress conditions, i.e. under conditions of reduced ternary complex formation, the probability for ribosomes to scan past these upstream ORFs and initiate translation at the ATF4 coding ORF is increased. ATF4 and other stress response factors expressed in this way subsequently govern the expression of an array of further stress response genes. The acute phase consists in expression of proteins that aim to restore homeostasis, while the chronic phase leads to expression of pro-apoptotic factors (1, 11, 12, 13). Upregulation of markers of ISR signaling has been demonstrated in a variety of conditions, among these cancer and neurodegenerative diseases. In cancer, ER stress-regulated translation increases tolerance to hypoxic conditions and promotes tumor growth (14, 15, 16), and deletion of PERK by gene targeting has been shown to slow growth of tumours derived from transformed PERK-/- mouse embryonic fibroblasts (14, 17). Further, a recent report has provided proof of concept using patient derived xenograft modeling in mice for activators of eIF2B to be effective in treating a form of aggressive metastatic prostate cancer (28). Taken together, prevention of cytoprotective ISR signaling may represent an effective anti-proliferation strategy for the treatment of at least some forms of cancer. Further, modulation of ISR signaling could prove effective in preserving synaptic function and reducing neuronal decline, also in neurodegenerative diseases that are characterized by misfolded proteins and activation of the unfolded protein response (UPR), such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD) and Jakob Creutzfeld (prion) diseases (18, 19, 20). With prion disease an example of a neurodegenerative disease exists where it has been shown that pharmacological as well as genetic inhibition of ISR signaling can normalize protein translation levels, rescue synaptic function and prevent neuronal loss (21). Specifically, reduction of levels of phosphorylated eIF2alpha by overexpression of the phosphatase controlling phosphorylated eIF2alpha levels increased survival of prion-infected mice whereas sustained eIF2alpha phosphorylation decreased survival (22). Further, direct ev