Regulators of the integrated stress response pathway

Abstract

The present invention relates to a compound of formula (I) [Formula 1] TIFF2023511616000070.tif27105[where, R 1 , R 2 , R 2a , R 3 , R a1 , R a2 , R a4、 R a5 , X 1 , X 1a , A 1 and A 2 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. The invention further relates to pharmaceutical compositions comprising said compounds, their use as medicaments, and their use in methods for the treatment and prevention of one or more diseases or disorders associated with the integrated stress response.

Description

Technical Field

[0001] The present invention relates to a compound of formula (I)

Chem.

Background Art

[0002] The integrated stress response (ISR) is a cellular stress response common to all eukaryotes (1). Dysregulation of ISR signaling has significant pathological consequences associated, inter alia, with inflammation, viral infection, diabetes, cancer and neurodegenerative diseases.

[0003] The integrated stress response (ISR) is a common denominator of diverse types of cellular stress that results in the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) at serine 51, leading to the inhibition of normal protein synthesis and the expression of stress response genes (2). In mammalian cells, phosphorylation is carried out by a family of four eIF2α kinases, each of which responds to distinct environmental and physiological stresses, namely: protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), double-stranded RNA-dependent protein kinase (PKR), heme-regulated eIF2α kinase (HRI), and general control non-derepressible 2 (GCN2) (3).

[0004] eIF2α, together with eIF2β and eIF2γ, forms the eIF2 complex, which plays an important role in the initiation of normal mRNA translation (4). The eIF2 complex binds GTP and Met-tRNA i to form a ternary complex (eIF2-GTP-Met-tRNA i ), which is recruited by ribosomes for translation initiation (5, 6).

[0005] eIF2B is a hetero-decameric complex consisting of five subunits (alpha, beta, gamma, delta, epsilon) that form a dimeric GEF-active decamer (7).

[0006] In response to ISR activation, phosphorylated eIF2 alpha inhibits the GDP-GTP exchange of eIF2B, resulting in decreased ternary complex formation and, consequently, inhibition of the translation of normal mRNAs characterized by ribosome binding to the 5'AUG start codon (8). Under these conditions of decreased ternary complex abundance, the translation of several specific mRNAs, including the mRNA encoding the transcription factor ATF4, is activated via a mechanism involving altered translation of upstream open reading frames (uORFs) (7, 9, 10). These mRNAs typically contain one or more uORFs that function normally in unstressed cells to restrict the flow of ribosomes to the main coding ORF. For example, during normal conditions, the uORF in the 5'UTR of ATF occupies ribosomes and prevents the translation of the coding sequence of ATF4. However, during stress conditions, i.e., under conditions of decreased ternary complex formation, ribosomes scan past these upstream ORFs, and the probability of initiating translation in the ATF4 coding ORF increases. The ATF4 and other stress response factors thus expressed then govern the expression of a further series of stress response genes. The acute phase is in the expression of proteins aimed at restoring homeostasis, while the chronic phase leads to the expression of apoptosis-promoting factors (1, 11, 12, 13).

[0007] Upregulation of markers of ISR signaling has been demonstrated in various conditions in these cancers and neurodegenerative diseases. In cancer, ER stress-regulated translation increases resistance to hypoxia and promotes tumor growth (14, 15, 16), and deletion of PERK by gene targeting has been shown to slow the growth of tumors derived from mouse embryonic fibroblasts (14, 17). Furthermore, recent reports have provided evidence for the concept that activators of eIF2B are effective in treating the morphology of high-grade metastatic prostate cancer using patient-derived xenograft modeling in mice (28). Collectively, prevention of cytoprotective ISR signaling may represent an effective anti-proliferative strategy for the treatment of at least some cancer morphologies. - / -

[0008] ​Furthermore, regulation of ISR signaling has been found to be effective in preserving synaptic function and reducing neuronal decline, and also in neurodegenerative diseases 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 Creutzfeldt-Jakob (prion) disease (18, 19, 20). There are examples of neurodegenerative diseases in which it has been shown that not only pharmacological but also genetic inhibition of ISR signaling can normalize protein translation levels, rescue synaptic function, and prevent neuronal deficits (21). Specifically, reduction of phosphorylated eIF2α levels by overexpression of a phosphatase that controls phosphorylated eIF2α levels increased the survival of prion-infected mice, while persistent eIF2α phosphorylation decreased survival (22).

[0009] Furthermore, direct evidence regarding the importance of controlling protein expression levels for proper brain function exists in the form of rare genetic diseases that affect the functions of eIF2 and eIF2B. Mutations in eIF2γ that disrupt the complex integrity of eIF2 and result in decreased normal protein expression levels are associated with intellectual disability syndrome (ID) (23). Partial deficiencies in functional mutations in subunits of eIF2B have been shown to cause the rare leukodystrophy Vanishing White Matter Disease (VWMD) (24, 25). Specifically, stabilization of the functional eIF2B partial deficiency in a VWMD mouse model by small molecules related to ISRIB has been shown to reduce ISR markers and also improve functionally and pathologically relevant endpoints (26, 27).

[0010] Regulatory factors of the eIF2α pathway are described in Patent Document 1. Patent Documents 2, 3, 4, and 5 describe regulatory factors of the integrated stress pathway. Patent Documents 6, 7, 8, 9, and 10 describe inhibitors of the ATF4 pathway. Patent Documents 11 and 12 relate to eukaryotic translation initiation factor 2B regulatory factors.

[0011] Further documents describing regulatory factors of the integrated stress pathway are Patent Documents 13, 14, 15, 16, 17, 18, 19, 20, and 21. Regulatory factors of eukaryotic translation initiation factors are described in Patent Document 22. Patent Document 23 describes inhibitors of the integrated stress response pathway. Heteroaryl derivatives as ATF4 inhibitors are described in Patent Document 24. Bicyclic aromatic ring derivatives as ATF4 inhibitors are described in Patent Document 25.

Prior Art Documents

Patent Documents

[0012]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Patent Document 8

Patent Document 9

Patent Document 10

Patent Document 11

Patent Document 12

Patent Document 13

Patent Document 14

Patent Document 15

Patent Document 16

Patent Document 17

Patent Document 18

Patent Document 19

Patent Document 20

Patent Document 21

Patent Document 22

Patent Document 23

Patent Document 24

Patent Document 25

Summary of the Invention

Problems to be Solved by the Invention

[0013] However, there is a continuing need for novel compounds useful as modulators of the integrated stress response pathway having good pharmacokinetic properties.

[0014] Accordingly, an object of the present invention is to provide a new class of compounds as modulators of the integrated stress response pathway that can be effective in the treatment of integrated stress response pathway-related diseases and that can exhibit improved pharmaceutically relevant properties including activity, solubility, selectivity, ADMET properties and / or reduced side effects.

Means for Solving the Problems

[0015] Accordingly, the present invention provides a compound of formula (I)

Chemical formula

[0016] X 1 is C(R a6 ) or N; X 1a is a covalent single bond; CH(R a3 ), O, N(R a7 ), or CH(R a3 )CH2; R a1 , R a2 , R a3 are independently selected from the group consisting of H; halogen; OH; O-C 1-4 alkyl; C 1-4 alkyl; and A 2a ; and R a4 , R a5 , R a6 are independently selected from the group consisting of H; halogen; C 1-4 alkyl; and A 2a ; provided that only one of R a1 , R a2 , R a3 , R a4 , R a5 , R a6 is A 2a ; optionally R a1 and R a2 form a covalent single bond; Optionally, R a2 and R a4 form a methylene group; Optionally, R a4 and R a6 form an ethylene group; Optionally, R a4 and R a5 join to form an oxo group; R a7 is H, C(O)OC 1-4 alkyl, or C 1-4 alkyl, where C(O)OC 1-4 alkyl and C 1-4 alkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, OH, and O-C 1-3 alkyl, where the substituents are the same or different, and preferably R a7 is H; A 1 is C5 cycloalkylene, C5 cycloalkenylene, a 5-membered heterocycle containing a nitrogen ring atom, or a 7- to 12-membered heterobicyclene containing a 5-membered heterocycle containing a nitrogen ring atom, where the heterocycle is bonded to the nitrogen ring atom shown in formula (I), and where A 1 is optionally substituted with one or more R 4 that are the same or different; Each R 4 is independently oxo (=O) [when the ring is at least partially saturated], thioxo (=S) [when the ring is at least partially saturated], halogen, CN, OR 5 or C 1-6 alkyl, where C 1-6 alkyl is optionally substituted with one or more halogens that are the same or different; R 5 is H or C 1-6 alkyl, where C 1-6 alkyl is optionally substituted with one or more halogens that 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, where 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 ; and A 2a wherein the substituents are the same or different; R 6a1 、R 6a2 is 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 ; and A 2a wherein the substituents are the same or different; R 6a3 is H; or C 1-4 alkyl, where C 1-4 alkyl is optionally substituted with one or more halogens which are the same or different; A 2a is phenyl; or a 3- to 7-membered heterocyclyl, where 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, where R 6b is cyclopropyl, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6is alkynyl, and here R 6b is optionally substituted with one or more of the same or different halogens; or two Rs 6 are joined to form ring A together with the atoms to which they are attached 2b ; A 2b is phenyl; or 3- to 7-membered heterocyclyl, where A 2b is optionally substituted with one or more of the same or different Rs 7 ; each R 7 is independently C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, where C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are optionally substituted with one or more of the same or different halogens;

[0017] R 1 is H or C 1-4 alkyl, preferably H, where C 1-4 alkyl is optionally substituted with one or more of the same or different halogens; R 2 is H; F; or C 1-4 alkyl, where C 1-4 alkyl is optionally substituted with one or more of the same or different halogens; and R 3 is A 3 , C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, where C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are optionally substituted with one or more of the same or different Rs 8 ; or R 2 and R 3join to form ring A together with the oxygen and carbon atoms to which they are attached 3a where A 3a is a 7- to 12-membered heterobicyclic group, where the 7- to 12-membered heterobicyclic group is optionally substituted with one or more R 10 ; R 2a is H or F, preferably H; each R 8 is independently halogen; CN, C(O)OR 9 , OR 9 , C(O)R 9 , C(O)N(R 9 R 9a ), S(O)2N(R 9 R 9a ), S(O)N(R 9 R 9a ), S(O)2R 9 , S(O)R 9 , N(R 9 )S(O)2N(R 9a R 9b ), SR 9 , N(R 9 R 9a ), NO2, OC(O)R 9 , N(R 9 )C(O)R 9a , N(R 9 )SO2R 9a , N(R 9 )S(O)R 9a , N(R 9 )C(O)N(R 9a R 9b ), N(R 9 )(O)C(R 9a ), OC(O)N(R 9 R 9a ), or A 3 ; R 9 , R 9a , R 9b is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, where C 1-6 alkyl, C 2-6Alkenyl, and C 2-6 Alkynyl is optionally substituted with one or more of the same or different halogens, or one OH, or one OC 1-4 Alkyl, or one A 3 ; Each A 3 is independently phenyl, naphthyl, 3- to 7-membered heterocyclyl, or 7- to 12-membered heterobicyclic, where A 3 is optionally substituted with one or more of the same or different R 10 ; Each R 10 is independently halogen, CN, C(O)OR 11 , OR 11 , C(O)R 11 , C(O)N(R 11 R 11a ), S(O)2N(R 11 R 11a ), S(O)N(R 11 R 11a ), S(O)2R 11 , S(O)R 11 , N(R 11 ), S(O)2N(R 11a R 11b ), SR 11 , N(R 11 R 11a ), NO2, OC(O)R 11 , N(R 11 ), C(O)R 11a , N(R 11 ), S(O)2R 11a , N(R 11 ), S(O)R 11a , N(R 11 ), C(O)OR 11a , N(R 11 ), C(O)N(R 11a R 11b ), OC(O)N(R 11 R 11a ), oxo (=O) [when the ring is at least partially saturated], C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl, and C2-6 The alkynyl is optionally substituted with one or more R's which may be the same or different 12 ; R 11 、R 11a 、R 11b is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, where C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are optionally substituted with one or more halogens which may be the same or different; Each R 12 is independently halogen, CN, C(O)OR 13 、OR 13 、C(O)R 13 、C(O)N(R 13 R 13a )、S(O)2N(R 13 R 13a )、S(O)N(R 13 R 13a )、S(O)2R 13 、S(O)R 13 、N(R 13 )S(O)2N(R 13a R 13b )、SR 13 、N(R 13 R 13a )、NO2、OC(O)R 13 、N(R 13 )C(O)R 13a 、N(R 13 )SO2R 13a 、N(R 13 )S(O)R 13a 、N(R 13 )C(O)N(R 13a R 13b )、N(R 13 )C(O)OR 13a 、or OC(O)N(R 13 R 13a ); R 13 、R 13a 、R 13b is independently H, C 1-6 alkyl, C 2-6Alkenyl, and C 2-6 independently selected from the group consisting of alkynyl, wherein C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more of the same or different halogens.

[0018] Compounds and pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof which are not restricted to use as agents as defined above having a preference tendency as defined below are also within the scope of the present invention, provided that the following compounds or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof are excluded:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0019] The excluded compounds represent commercial compounds with no indication of use.

[0020] A variable or substituent may be selected from a group of different variables and, if such a variable or substituent occurs more than once, each variable may be the same or different.

Modes for Carrying Out the Invention

[0021] Within the meaning of the present invention, the terms are used as follows: The term "optionally substituted" means unsubstituted or substituted. Generally, but not limited to, "one or more substituents" means 1, 2, or 3 substituents, preferably 1 or 2 substituents, and more preferably 1 substituent. Generally, these substituents may be the same or different.

[0022] "Alkyl" means a straight-chain or branched hydrocarbon chain. Each hydrogen of the alkyl carbon may be replaced with a substituent as further specified.

[0023] "Alkenyl" means a straight-chain or branched hydrocarbon chain containing at least one carbon-carbon double bond. Each hydrogen of the alkenyl carbon may be replaced with a substituent as further specified.

[0024] "Alkynyl" means a straight-chain or branched hydrocarbon containing at least one carbon-carbon triple bond. Each hydrogen of the alkynyl carbon may be replaced with a substituent as further specified.

[0025] "C 1-4 alkyl", when present at the end of a molecule for example, means an alkyl chain having 1 to 4 carbon atoms: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or, for example, when two parts of a molecule are linked by an alkyl group, -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. C 1-4 Each hydrogen of the C 1-3 alkyl carbon may be replaced with a substituent as further specified. The term "C

[0026] "C 1-6 alkyl" means an alkyl chain having 1 to 6 carbon atoms and, for example, when present at the end of a molecule: C 1-4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or, when two parts of a molecule are linked by an alkyl group, for example, -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. C 1-6Each hydrogen of the alkyl carbon may be replaced by a substituent as further specified.

[0027] “C 2-6 “Alkenyl” means an alkenyl chain having 2 to 6 carbon atoms. For example, when present at the end of a molecule: -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, -CH=CH-CH=CH2, or when two parts of a molecule are linked by an alkenyl group, for example, -CH=CH-. C 2-6 Each hydrogen of the alkenyl carbon may be replaced by a substituent as further specified.

[0028] “C 2-6 “Alkynyl” means an alkynyl chain having 2 to 6 carbon atoms. For example, when present at the end of a molecule: -C≡CH, -CH2-C≡CH, CH2-CH2-C≡CH, CH2-C≡C-CH3, or when two parts of a molecule are linked by an alkynyl group, for example -C≡C-. C 2-6 Each hydrogen of the alkynyl carbon may be replaced by a substituent as further specified.

[0029] “C 3-7 “Cycloalkyl” or “C 3-7 “Cycloalkyl ring” means a cyclic alkyl chain having 3 to 7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. Preferably, cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Each hydrogen of the cycloalkyl carbon may be replaced by a substituent as further specified herein. The term “C 3-5 “Cycloalkyl” or “C 3-5 “Cycloalkyl ring” is defined accordingly.

[0030] “C5 cycloalkylene” refers to a divalent cycloalkyl having 5 carbon atoms, i.e., a divalent cyclopentyl ring.

[0031] "C5 cycloalkenylene" refers to a divalent cycloalkenylene, i.e., divalent cyclopentene or cyclopentadiene.

[0032] "C 4-12 bicycloalkyl" or "C 4-12 bicycloalkyl ring" means a bicyclic fused, bridged or spiroalkyl chain having 4 to 12 carbon atoms, for example, hexahydroindane, octahydropentalene, bicyclo[2.2.1]heptane or spiro(3.2)hexane. Each hydrogen of the bicycloalkyl carbon may be replaced by a substituent as further specified herein.

[0033] "Halogen" means fluoro, chloro, bromo or iodo. It is generally preferred that the halogen is fluoro or chloro.

[0034] "3- to 7-membered heterocyclyl" or "3- to 7-membered heterocyclic ring" means a ring (aromatic or non-aromatic, fully, partially or unsaturated) having 3, 4, 5, 6 or 7 ring atoms which may contain double bonds up to the maximum number, where at least one ring atom of up to 4 ring atoms is replaced by a heteroatom selected from the group consisting of sulfur (-S(O)-, -S(O)2- included), oxygen and nitrogen (=N(O)- included), and where the ring is linked to the remainder of the molecule via a carbon or nitrogen atom. Examples of 3- to 7-membered heterocyclic rings are aziridine, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine or homopiperazine. The terms "5- to 6-membered heterocyclyl" or "5- to 6-membered heterocyclic ring" are defined accordingly and include 5- to 6-membered aromatic heterocyclyl or heterocyclic rings. The terms "5-membered heterocyclyl" or "5-membered heterocyclic ring" are defined accordingly and include 5-membered aromatic heterocyclyl or heterocyclic rings.

[0035] The term "5-membered heterocyclene containing a nitrogen ring atom" refers to a divalent 5-membered heterocyclic ring where at least one of the 5 ring atoms is a nitrogen atom and where the ring is linked to the remainder of the molecule via a carbon atom or a nitrogen atom.

[0036] "Saturated 4- to 7-membered heterocyclyl" or "saturated 4- to 7-membered heterocyclic ring" means a fully saturated "4- to 7-membered heterocyclyl" or "4- to 7-membered heterocyclic ring".

[0037] "At least partially saturated 4- to 7-membered heterocyclyl" or "at least partially saturated 4- to 7-membered heterocyclic ring" means an at least partially saturated "4- to 7-membered heterocyclyl" or "4- to 7-membered heterocyclic ring".

[0038] "5- to 6-membered aromatic heterocyclyl" or "5- to 6-membered aromatic heterocyclic ring" means a heterocyclic ring derived from cyclopentadienyl or benzene in which at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (-S(O)-, -S(O)2- included), oxygen and nitrogen (=N(O)- included). Examples of such heterocyclic rings are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine.

[0039] "5-membered aromatic heterocyclyl" or "5-membered aromatic heterocyclic ring" means a heterocyclic ring derived from cyclopentadienyl in which at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (-S(O)-, -S(O)2- included), oxygen and nitrogen (=N(O)- included). Examples of such heterocyclic rings are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole.

[0040] "7- to 12-membered heterobicyclic" or "7- to 12-membered heterobicycle" means a bicyclic heterocyclic system having 7 to 12 ring atoms, where at least one ring atom is shared by both rings and may contain up to the maximum number of double bonds (fully, partially or unsaturated aromatic or non-aromatic rings), where at least one of up to 6 ring atoms is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-), and where the ring is linked to the rest of the molecule via a carbon atom or a nitrogen atom. Examples of 7- to 12-membered heterobicycles are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine. The term 7- to 12-membered heterobicycle also includes spiro structures of two rings such as 6-oxa-2-azaspiro[3,4]octane, 2-oxa-6-azaspiro[3.3]heptan-6-yl or 2,6-diazaspiro[3.3]heptan-6-yl or bridged heterocycles such as 8-aza-bicyclo[3.2.1]octane or 2,5-diazabicyclo[2.2.2]octan-2-yl or 3,8-diazabicyclo[3.2.1]octane.

[0041] "Saturated 7- to 12-membered heterobicyclic" or "saturated 7- to 12-membered heterobicycle" means a fully saturated 7- to 12-membered heterobicyclic or 7- to 12-membered heterobicycle.

[0042] "At least partially saturated 7- to 12-membered heterobicyclic" or "at least partially saturated 7- to 12-membered heterobicycle" means an "7- to 12-membered heterobicyclic" or "7- to 12-membered heterobicycle" that is at least partially saturated.

[0043] "9- to 11-membered aromatic heterobicyclic" or "9- to 11-membered aromatic heterocycle" means a bicyclic heterocyclic system where at least one of the rings is aromatic and the heterocyclic ring system has 9 to 11 ring atoms, where two ring atoms are shared by both rings and may contain up to the maximum number of double bonds (fully or partially aromatic), where at least one of up to 6 ring atoms is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and where the ring is linked to the remainder of the molecule via a carbon atom or a nitrogen atom. Examples of 9- to 11-membered aromatic heterocycles are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, dihydro-isoquinoline, benzazepine, purine, or pteridine. The terms "9- to 10-membered aromatic heterobicyclic" or "9- to 10-membered aromatic heterocycle" are defined accordingly.

[0044] "7- to 12-membered heterobicyclene" refers to a divalent 7- to 12-membered heterocycle.

[0045] Preferred compounds of formula (I) are those in which one or more of the residues contained therein have the following meanings, and all combinations of the definitions of the preferred substituents are the subject of the present invention. For all preferred compounds of formula (I), the present invention also includes all tautomers and stereoisomeric forms, and mixtures thereof in all ratios, as well as their pharmaceutically acceptable salts.

[0046] In a preferred embodiment of the present invention, the substituents described below independently have the following meanings. Accordingly, one or more of these substituents may have the preferred or more preferred meanings shown below.

[0047] Preferably, X1 is CH.

[0048] Preferably, X 1a is a shared single bond; CH(R a3 ), or CH(R a3 ), and more preferably, CH(R a3 ) or CH(R a3 )CH2, and even more preferably CH(R a3 ).

[0049] Preferably, R a1 , R a2 , R a3 , R a4 , R a5 , R a6 is H; or R a1 is OH, and R a2 , R a3 , R a4 , R a5 , R a6 is H; or R a1 , R a3 , R a5 , R a6 is H, and R a2 and R a4 form a methylene group; or R a1 and R a2 form a shared single bond, and R a3 , R a4 , R a5 , R a6 is H; more preferably, R a1 , R a2 , R a3 , R a4 , R a5 , R a6 is H.

[0050] Preferably, A 1 is a 5-membered heterocycle containing a nitrogen ring atom, and A 1 is optionally substituted with one or more R 4 s that are the same or different.

[0051] Preferably, A 1is a 5-membered nitrogen-containing heterocycle selected from the group of divalent heterocycles consisting of oxadiazole, imidazole, imidazolidine, pyrazole and triazole, preferably oxadiazole, and here A 1 is optionally substituted with one or more R 4 which are the same or different.

[0052] Preferably, A 1 is unsubstituted or substituted with one or two R 4 which are the same or different, and more preferably A 1 is unsubstituted.

[0053] Preferably, R 4 is oxo [when the ring is at least partially saturated] or methyl.

[0054] Preferably, A 1 is

Chemical formula

[0055] More preferably, A 1 is

Chemical formula

[0056] In one embodiment, A 2 is R 6a as follows.

[0057] Preferably, R 6a is OR 6a1 as follows.

[0058] R 6a1 is preferably alkyl which is optionally substituted with one or more halogens and / or one A 2a and / or one OR 6a3 and / or A 2a or C 1-6 substituted by the above. More preferably, R6a1 is C alkyl optionally substituted by one or more F and / or one OR 6a3 1-6 alkyl.

[0059] Preferably, R 6a is C alkyl optionally substituted by one or more halogen and / or one A 2a and / or OR 6a3 1-6 alkyl. More preferably, R 6a is C alkyl optionally substituted by one or more halogen and / or one OR 6a3 1-6 alkyl.

[0060] In one preferred embodiment, R 6a1 is unsubstituted C 4-6 alkyl; more preferably 3-methylbut-1-yl or n-butyl. In another preferred embodiment, R 6a1 is C alkyl substituted by one or more halogen, the same or different, preferably one or more fluoro 2-6 alkyl; more preferably, R 6a1 is 3,3,3-trifluoropropyl, 2-methyl-3,3,3-trifluoropropyl, 4,4,4-trifluorobut-2-yl, 2,2,3,3,3-pentafluoropropyl, 3,3-difluorobutyl or 3,3,3-trifluorobutyl.

[0061] In another preferred embodiment, R 6a1 is A 2a , CH2A 2a , CH2CH2A 2a wherein A 2a is unsubstituted or substituted by one or more halogen, the same or different, preferably one or more fluoro.

[0062] Preferably, R 6a2 is H.

[0063] ​​​Preferably, R 6a is OC 1-4 alkyl; OC 1-4 alkyl-OC 1-4 alkyl, where each C 1-4 alkyl is optionally substituted with 1 to 3 F; or OCH2A 2a in some cases.

[0064] In another embodiment, A 2 is A 2a is.

[0065] Preferably, A 2a is phenyl, or a 5- to 6-membered aromatic heterocyclyl, preferably pyridyl, pyrazinyl, pyridazinyl, pyrazolyl or 1,2,4-oxadiazolyl, and here A 2a is optionally substituted with one or more R 6 which are the same or different.

[0066] Preferably, A 2a is substituted with one or two R 6 which are the same or different.

[0067] Preferably, each R 6 is independently F, Cl, CF3, OCH3, OCF3, CH3, CH2CH3, or cyclopropyl.

[0068] Preferably, R 2 is H.

[0069] Preferably, R 3 is A 3 is.

[0070] Preferably, A 3 is phenyl, pyridyl, pyrazinyl or pyrimidazyl, and here A 3 is optionally substituted with one or more R 10 which are the same or different.

[0071] Preferably, A 3is replaced by one or two Rs which may be the same or different 10 is substituted with

[0072] Preferably, R 2 and R 3 together with the oxygen and carbon atoms to which they are attached form a dihydrobenzopyran ring, where the ring is optionally substituted with one or more Rs which may be the same or different, and preferably the ring is substituted with one or two Rs 10 is substituted with 10 is substituted with

[0073] Preferably, R 10 is independently F, Cl, CF3, CH=O, CH2OH or CH3

[0074] Compounds of formula (I) in which some or all of the above groups have the preferred or more preferred meanings are also an object of the present invention

[0075] Preferred specific compounds of the present invention are selected from the group consisting of: 2-(4-chloro-3-fluorophenoxy)-N-{1-[5-(5-chloropyridin-2-yl)-1,3,4-oxadiazol-2-yl]piperidin-4-yl}acetamide; 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]-N-{1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-4-yl}acetamide; 2-(4-chloro-3-fluorophenoxy)-N-[(3R*,4R*)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]acetamide; 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-4-piperidyl]acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-{1-[5-(4,4,4-trifluorobutyl)-1,3,4-oxadiazol-2-yl]piperidin-4-yl}acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-[(1R,5S,6R)-3-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.0]hexan-6-yl]acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-{4-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperazin-1-yl}acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-{1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]azepan-4-yl}acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-[(3R,4R)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-[(3S,4S)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-[(4S)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]azepan-4-yl]acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-[(4R)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]azepan-4-yl]acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-(1-{5-[3-(trifluoromethoxy)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-4-yl)acetamide; or 2-(4-Chloro-3-fluorophenoxy)-N-(1-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-4-yl)acetamide.

[0076] When tautomerism such as keto-enol tautomerism may exist in the compounds of formula (I), for example, the individual forms such as the keto form and the enol form are included separately and together as a mixture in any ratio. The same applies to stereoisomers such as enantiomers, cis / trans isomers, conformational isomers, etc.

[0077] In particular, when enantiomers or diastereoisomers occur in the compounds according to formula (I), each pure form is included separately and any mixture of at least two pure forms in any ratio is included according to formula (I) and is the subject of the present invention.

[0078] Isotopically labeled compounds of formula (I) are also within the scope of the present invention. Methods for isotopic labeling are known in the art. Preferred isotopes are isotopes of the elements H, C, N, O and S. Solvates and hydrates of the compounds of formula (I) are also within the scope of the present invention.

[0079] If desired, the isomers can be separated by methods well known in the art, such as liquid chromatography. The same applies to enantiomers, for example by using a chiral stationary phase. Furthermore, enantiomers can be isolated by converting them into diastereomers, i.e., by coupling them with a diastereomerically pure auxiliary compound, then separating the resulting diastereomers, and then cleaving the auxiliary group. Alternatively, any enantiomer of the compound of formula (I) can be obtained from a stereoselective synthesis using optically pure starting materials, reagents and / or catalysts.

[0080] If the compound according to formula (I) contains one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, a compound of formula (I) containing an acidic group can be used according to the present invention, for example, as an alkali metal salt, an alkaline earth metal salt or an ammonium salt. More detailed examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine or amino acids. A compound of formula (I) containing one or more basic groups, i.e., groups that can be protonated, can exist in the form of their addition salts with inorganic or organic acids and can be used according to the present invention. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compound of formula (I) contains both an acidic group and a basic group in the molecule, the present invention also includes inner salts or betaines (zwitterions) in addition to the salt forms mentioned. Each salt according to formula (I) can be obtained by the usual methods known to those skilled in the art, for example, by contacting them with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compound of formula (I) which, due to their low physiological compatibility, are not directly suitable for use in pharmaceuticals but can be used, for example, as intermediates for chemical reactions or for the production of pharmaceutically acceptable salts.

[0081] As shown below, the compounds of the present invention are considered to be suitable for modulating the integrated stress response pathway.

[0082] The integrated stress response (ISR) is a cellular stress response common to all eukaryotes (1). Dysregulation of ISR signaling has significant pathological consequences associated with, among other things, inflammation, viral infection, diabetes, cancer, and neurodegenerative diseases.

[0083] The ISR is a common factor of various types of cellular stress that results in the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2 alpha) at serine 51, leading to the suppression of normal protein synthesis and the expression of stress response genes (2). In mammalian cells, phosphorylation is carried out by a family of four eIF2 alpha kinases, namely: PKR-like ER kinase (PERK), double-stranded RNA-dependent protein kinase (PKR), heme-regulated eIF2 alpha kinase (HRI), and general control non-derepressible 2 (GCN2), which respond to individual environmental and physiological stresses respectively (3).

[0084] eIF2 alpha, together with eIF2 beta and eIF2 gamma, forms an eIF2 complex that plays an important role in the initiation of normal mRNA translation. i The eIF2 complex binds to GTP and Met-tRNA i to form a ternary complex (eIF2-GTP-Met-tRNA

[0085] ), which is recruited by ribosomes for translation initiation (5, 6).

[0086] In response to ISR activation, phosphorylated eIF2 alpha inhibits the GDP-GTP exchange of eIF2B, resulting in a decrease in ternary complex formation, and as a result, inhibits the translation of normal mRNAs characterized by ribosome 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 encoding the transcription factor ATF4, is activated via a mechanism involving altered translation of upstream open reading frames (uORFs) (7, 9, 10). These mRNAs typically contain one or more uORFs that normally function to restrict the flow of ribosomes to the main coding ORF in unstressed cells. For example, during normal conditions, the uORF in the 5'UTR of ATF occupies ribosomes and prevents the translation of the coding sequence of ATF4. However, during stress conditions, i.e., under conditions of reduced ternary complex formation, ribosomes scan past these upstream ORFs, and the probability of initiating translation in the ATF4 coding ORF increases. The ATF4 and other stress response factors expressed in this way then govern the expression of a series of further stress response genes. The acute phase is in the expression of proteins aimed at restoring homeostasis, while the chronic phase leads to the expression of apoptosis-promoting factors (1, 11, 12, 13).

[0087] Upregulation of markers of ISR signaling has been demonstrated in various states among these cancers and neurodegenerative diseases. In cancer, ER stress-regulated translation increases resistance to hypoxia and promotes tumor growth (14, 15, 16), and deletion of PERK by gene targeting has been shown to slow the growth of tumors derived from mouse embryonic fibroblasts (14, 17). Furthermore, recent reports have provided evidence for the concept that activators of eIF2B are effective in treating the morphology of high-grade metastatic prostate cancer using patient-derived xenograft modeling in mice (28). Collectively, prevention of cytoprotective ISR signaling may represent an effective anti-proliferative strategy for the treatment of at least some cancer morphologies. - / -

[0088] ​Furthermore, regulation of ISR signaling has been found to be effective in preserving synaptic function and reducing neuronal loss, and also in neurodegenerative diseases 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 Creutzfeldt-Jakob (prion) disease (18, 19, 20). There are examples of neurodegenerative diseases in which it has been shown that not only pharmacological inhibition but also genetic inhibition of ISR signaling can normalize protein translation levels, rescue synaptic function, and prevent neuronal deficits (21). Specifically, reduction of phosphorylated eIF2α levels by overexpression of a phosphatase that controls phosphorylated eIF2α levels increased the survival of prion-infected mice, while persistent eIF2α phosphorylation decreased survival (22).

[0089] Furthermore, direct evidence regarding the importance of controlling protein expression levels for proper brain function exists in the form of rare genetic diseases that affect the functions of eIF2 and eIF2B. Mutations in eIF2γ that disrupt the complex integrity of eIF2 and result in decreased normal protein expression levels are associated with intellectual disability syndrome (ID) (23). Partial deficiencies in functional mutations in the subunits of eIF2B have been shown to cause a rare leukoencephalopathy (VWMD) (24, 25). Specifically, stabilization of the functional eIF2B partial deficiency in a VWMD mouse model by small molecules related to ISRIB has been shown to reduce ISR markers and also improve functionally and pathologically relevant endpoints (26, 27).

[0090] The present invention provides the compounds of the present invention in free form or in the form of a pharmaceutically acceptable salt or solvate, hydrate, tautomer or stereoisomer for use in the treatment of the diseases or disorders mentioned herein.

[0091] Accordingly, an aspect of the present invention is a compound of the present invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof for use as a medicament as described above.

[0092] The described treatment methods can be applied to mammals such as dogs, cats, cows, horses, rabbits, monkeys and humans. Preferably, the mammalian patient is a human patient.

[0093] Accordingly, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof for use in the treatment or prevention of one or more diseases or disorders associated with the integrated stress response.

[0094] A further aspect of the present invention is a compound of the present invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof for use in a method for the treatment or prevention of one or more disorders or diseases associated with the integrated stress response.

[0095] A further aspect of the present invention is the use of a compound of the present invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof for the manufacture of a medicament for the treatment or prevention of one or more disorders or diseases associated with the integrated stress response.

[0096] A still further aspect of the present invention is a method for treating, managing, delaying or preventing in a mammalian patient in need of treatment of one or more diseases or disorders associated with the integrated stress response, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0097] The present invention provides a compound of the present invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof for use in the treatment or prevention of one or more diseases or disorders mentioned below.

[0098] A further aspect of the invention is the use of a compound of the invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof for use in a method of treating or preventing one or more of the disorders or diseases described below.

[0099] A further aspect of the invention is the use of a compound of the invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof for the manufacture of a medicament for the treatment or prevention of one or more of the disorders or diseases described below.

[0100] Yet another aspect of the invention is a method for treating, managing, delaying or preventing in a mammalian patient in need of treatment of one or more of the diseases or disorders described below, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0101] Diseases or disorders include, but are not limited to, leukodystrophy, intellectual disability syndrome, neurodegenerative diseases and disorders, neoplastic diseases, infectious diseases, inflammatory diseases, musculoskeletal diseases, metabolic diseases, eye diseases, and further 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 diseases, arrhythmias, atherosclerosis, spinal cord injury, ischemic stroke, and neuropathic pain. Diseases selected from the group consisting of

[0102] Leukodystrophy Examples of leukodystrophy include, but are not limited to, vanishing white matter disease (VWMD) and childhood ataxia with CNS hypomyelination (e.g., associated with dysfunction of components in the signal transduction or signal transduction pathway including eIF2 or eIF2).

[0103] Intellectual disability syndrome Intellectual disability refers to a state in which a person has specific limitations in intellectual functions such as communication and self-care, and / or has a social disability. Examples of intellectual disability syndromes include, but are not limited to, intellectual disability states associated with dysfunction of components in eIF2 or signal transduction or signal transduction pathways including eIF2.

[0104] Neurodegenerative disease / disorder Examples of neurodegenerative diseases and disorders include, but are not limited to, Alexander disease, Alpers disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjögren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, kuru, Lewy body dementia, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion disease, progressive supranuclear palsy, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (numerous types with various characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, spinal syphilis, and tauopathy.

[0105] In particular, the neurodegenerative disease or disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

[0106] Neoplastic disease Neoplastic diseases can be understood in the broadest sense as any tissue resulting from mis-controlled cell proliferation. In many cases, a neoplasm results in at least a swollen mass of tissue, optionally innervated by blood vessels. This may or may not include one or more metastases. The neoplastic diseases of the present invention can be any neoplasm classified by the 10th Revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10), classes C00-D48.

[0107] Exemplarily, a neoplastic disease according to the present invention can be the presence of one or more malignant neoplasms (tumors) (ICD-10 classes C00-C97), the presence of one or more in situ neoplasms (ICD-10 classes D00-D09), the presence of one or more benign neoplasms (ICD-10 classes D10-D36), or the presence of one or more neoplasms of uncertain or unknown behavior (ICD-10 classes D37-D48). Preferably, a neoplastic disease according to the present invention refers to the presence of one or more malignant neoplasms, i.e., malignant tumors (ICD-10 classes C00-C97).

[0108] In a more preferred embodiment, the neoplastic disease is cancer.

[0109] Cancer can be understood in the broadest sense as the presence of one or more malignant neoplastic diseases, i.e., one or more malignant neoplasms in a patient. Cancer can be solid or hematological. Without limitation, leukemia, lymphoma, carcinoma, and sarcoma are contemplated herein.

[0110] In particular, neoplastic diseases such as cancer characterized by upregulated ISR markers are included herein.

[0111] Examples of cancers that may be used include, but are not limited to, thyroid cancer, endocrine cancers, kidney cancer, brain cancer (e.g., glioblastoma multiforme, glioma), breast cancer (e.g., ER positive, ER negative, chemotherapy resistant, Herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), cervical cancer, ovarian cancer, uterine cancer, colon cancer, head and neck cancer, liver cancer (e.g., hepatocellular carcinoma), kidney cancer, lung cancer (e.g., non-small cell lung cancer, squamous cell lung cancer, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid, sarcoma), colon cancer, esophageal cancer, stomach cancer, bladder cancer, bone cancer, stomach cancer, prostate cancer, and skin cancer (e.g., melanoma).

[0112] Further examples include, but are not limited to, myeloma, leukemia, mesothelioma, and sarcoma.

[0113] Additional examples include, but are not limited to, medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, rhabdomyosarcoma, essential thrombocythemia, Waldenström's macroglobulinemia, primary brain tumors, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, pre-malignant skin lesions, testicular cancer, lymphoma, genitourinary cancers, hypercalcemia of malignancy, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic neoplasms, medullary thyroid cancer, medullary carcinoma of the thyroid, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget's disease of the nipple, phyllodes tumor, lobular carcinoma, ductal carcinoma, pancreatic stellate cell carcinoma, and hepatic stellate cell carcinoma.

[0114] Examples of leukemia include, but are not limited to, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophilic leukemia, blast leukemia, bovine leukemia, chronic myelogenous leukemia, cutaneous leukemia, embryonal leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic acute leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphoid leukemia, lymphotropic leukemia, lymphoid-like leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micro myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelogenous leukemia, myelogenous granulocytic leukemia, myelomonocytic leukemia, Naegeli type leukemia, plasmacytic leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, leader cell leukemia, Schilling leukemia, stem cell leukemia, subaleukemic leukemia, and undifferentiated cell leukemia.

[0115] Examples of sarcoma include, but are not limited to, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanoma, myxosarcoma, osteosarcoma, Abemethy’s sarcoma, adipose sarcoma, liposarcoma, cystosarcoma phyllodes, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, fetal sarcoma, Wilms tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin sarcoma, multiple idiopathic pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T cells, Jensen sarcoma, Kaposi sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma, parosteal sarcoma, reticuloendotheliosarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and angiectatic sarcoma.

[0116] Examples of melanomas include, but are not limited to, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, malignant lentigo-derived melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma.

[0117] Examples of carcinomas include, but are not limited to, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, cutaneous carcinoma, cylindrical carcinoma, columnar cell carcinoma, duct carcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epidermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, fibroid carcinoma, gelatiniform carcinoma, colloid carcinoma, giant cell carcinoma, carcinoma gigantocellulare, adenocarcinoma, granulosa cell carcinoma, pilomatrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher’s carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanoma, carcinoma molle, mucinous carcinoma, carcinomamuciparum), mucocellular carcinoma, mucoepidermoid carcinoma, mucous carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, spinous cell carcinoma, pultaceous carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, spongy carcinoma, squamous cell carcinoma, squamous epithelial cell carcinoma, string carcinoma, telangiectatic carcinoma, telangiectoid carcinoma, transitional cell carcinoma, tuberosum carcinoma, tubulocystic carcinoma, tuberous carcinoma, verrucous carcinoma, and villosum carcinoma.

[0118] Infectious disease Examples include, but are not limited to, infections caused by viruses (e.g., HIV-1: human immunodeficiency virus type 1; IAV: influenza A virus; HCV: hepatitis C virus; DENV: dengue virus; ASFV: African swine fever virus; EBV: Epstein-Barr virus; HSV1: herpes simplex virus type 1; CHIKV: chikungunya virus; HCMV: human cytomegalovirus; SARS-CoV: severe acute respiratory syndrome coronavirus) and infections caused by bacteria (e.g., infections by Legionella, Brucella, Simkania, Chlamydia, Helicobacter, and Campylobacter).

[0119] Inflammatory disease Examples of inflammatory diseases include, but are not limited to, postoperative cognitive dysfunction (decrease in postoperative cognitive function), traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes, type 1 diabetes, Guillain-Barré syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, graft rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis.

[0120] Musculoskeletal disease Examples of musculoskeletal diseases include, but are not limited to, muscular dystrophy, multiple sclerosis, Friedreich's ataxia, muscle wasting disorders (e.g., muscular atrophy, sarcopenia, cachexia), inclusion body myopathy, progressive muscular atrophy, motor neuron disease, carpal tunnel syndrome, maxillary sinusitis, tendinitis, back pain, muscle pain, muscle soreness, repetitive strain injury, and paralysis.

[0121] Metabolic disease Examples of metabolic diseases include, but are not limited to, diabetes (especially type II diabetes), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), Niemann-Pick disease, liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, and Kearns-Sayre syndrome.

[0122] Eye disease Examples of eye diseases include, but are not limited to, edema or angiogenesis related to any obstructive or inflammatory retinal vascular disorder, such as iris angiogenesis, neovascular glaucoma, pterygium, neovascular glaucoma filtering bleb, conjunctival papilloma; choroidal angiogenesis, such as age-related macular degeneration (AMD) with neovascularization, myopia, prior uveitis, trauma, or idiopathic; macular edema, such as postoperative macular edema, macular edema secondary to uveitis including inflammation of the retina and / or choroid, macular edema secondary to diabetes, and macular edema secondary to retinal vascular occlusion diseases (i.e., retinal vein branch and central retinal vein occlusion); retinal angiogenesis due to diabetes, such as retinal vein occlusion, uveitis, ocular ischemia syndrome from carotid artery disease, ophthalmic artery or retinal artery occlusion, sickle cell retinopathy, other ischemic or obstructive neovascular retinopathy, retinopathy of prematurity, or Eales' disease; and genetic disorders such as von Hippel-Lindau syndrome.

[0123] Additional diseases Further diseases include, but are not limited to, organ fibrosis (e.g., liver fibrosis, pulmonary fibrosis, or renal fibrosis), chronic and acute diseases of the liver (e.g., fatty liver disease, or fatty liver), chronic and acute diseases of the lung, chronic and acute diseases of the kidney, myocardial infarction, cardiovascular disease, arrhythmia, atherosclerosis, spinal cord injury, ischemic stroke, and neuropathic pain.

[0124] Yet another aspect of the present invention is a pharmaceutical composition comprising at least one compound of the present invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.

[0125] Preferably, one or more bioactive compounds are regulators of the integrated stress response pathway other than the compounds of formula (I).

[0126] "Pharmaceutical composition" means one or more active ingredients, and one or more inert ingredients constituting a carrier, and also any product directly or indirectly resulting from the combination, complexation or aggregation of any two or more ingredients, or from the dissociation of one or more of the ingredients, or from other types of reaction or interaction of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention include any composition produced by mixing a compound of the present invention with a pharmaceutically acceptable carrier.

[0127] The pharmaceutical compositions of the present invention may contain one or more additional compounds as active ingredients, such as a mixture of a compound of formula (I) or other regulators of the integrated stress response pathway in the composition.

[0128] The active ingredient may be included in one or more different pharmaceutical compositions (combination of pharmaceutical compositions).

[0129] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.

[0130] The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ophthalmic (ocular), pulmonary (nasal or buccal inhalation), or intranasal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and the nature of the active ingredient. These can be provided in convenient unit dosage forms and can be manufactured by any of the methods well known in the pharmaceutical art.

[0131] In actual use, the compounds of formula (I) can be combined as active ingredients in intimate mixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the dosage form desired for administration, e.g., oral or parenteral (including intravenous). In the manufacture of compositions for oral dosage forms, in the case of oral liquid preparations such as suspensions, elixirs, and solutions, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc.; or in the case of oral solid preparations such as powders, hard and soft capsules, and tablets, any of the usual pharmaceutical vehicles such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. can be used, and solid oral preparations are preferred over liquid preparations.

[0132] For ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case a solid pharmaceutical carrier is of course used. If desired, the tablets can be coated by standard aqueous or non-aqueous techniques. Such compositions and formulations should contain at least 0.1 percent of the active compound. The percentage of the active compound in these compositions can of course vary and can conveniently be between about 2 percent and about 60 percent of the mass of the unit. The amount of the active compound in such therapeutically useful compositions is an amount such that an effective dosage is obtained. The active compound can also be administered intranasally, for example, as a nasal spray or drops.

[0133] Tablets, pills, capsules, etc. may also contain binders such as tragacanth, gum arabic, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose or saccharin. When the dosage unit form is a capsule, it may contain, in addition to materials of the above types, a liquid carrier such as a fatty oil.

[0134] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar or both. Syrups or elixirs may contain, in addition to the active ingredient, sucrose as a sweetener, methyl and propyl parabens as preservatives, a dye, and flavoring agents such as cherry or orange flavor.

[0135] The compounds of formula (I) may also be administered parenterally. Solutions or suspensions of these active compounds may be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0136] Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form should be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyhydric alcohols (for example, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0137] Any suitable route of administration can be used to provide a mammalian, particularly human, subject with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, etc. can be used. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. Preferably, the compound of formula (I) is administered orally.

[0138] The effective dosage of the active ingredient used can vary depending on the particular compound used, the mode of administration, the condition being treated, and the severity of the condition being treated. Such dosages can be readily ascertained by one of ordinary skill in the art. Starting materials for the synthesis of preferred embodiments of the present invention can be purchased from commercial sources such as Array, Sigma Aldrich, Acros, Fisher, Fluka, ABCR, or can be synthesized using methods known to those of ordinary skill in the art.

[0139] In general, several methods are applicable for producing the compounds of the present invention. In some cases, various strategies can be combined. Sequential or convergent routes can be used. Illustrative synthetic routes are described below.

Example

[0140] I Chemical Synthesis Experimental procedures : The following abbreviations and acronyms are used: ACN Acetonitrile AgSO3CF3 Silver-trifluoromethanesulfonate aq Aqueous BOP reagent Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate Brine Saturated aqueous solution of NaCl CDI Carbonyldiimidazole CV Column volume δ Chemical shift (parts per million) DCM Dichloromethane DMSO Dimethyl Sulfoxide DMSO-d6 Deuterated Dimethyl Sulfoxide DIPEA Diisopropylethylamine DMF Dimethylformamide ESI+ Positive Ionization Mode ESI- Negative Ionization Mode Et3N Triethylamine EtOAc Ethyl Acetate Et2O Diethyl Ether h Hour H2 Hydrogen Atmosphere HATU 1-[Bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium-3-oxide·Hexafluorophosphate HCl Hydrochloric Acid HPLC High Performance Liquid Chromatography J NMR Coupling Constant K2CO3 Potassium Carbonate KF Potassium Fluoride MgSO4 Magnesium Sulfate mL Milliliter min Minute N2 Nitrogen Atmosphere Na2SO4 Sodium Sulfate NaHCO3 Sodium Bicarbonate NaOH Sodium Hydroxide NMR Nuclear Magnetic Resonance Pd / C Palladium on Carbon r.t. Room Temperature RT Retention Time satd Saturated TBAHS Tetrabutylammonium Hydrogen Sulfate T3P Propylphosphonic Anhydride TBME tert-Butyl-Methyl Ether TFA Trifluoroacetic Acid THF Tetrahydrofuran TMS-CF3 (Trifluoromethyl)trimethylsilane TsCl Tosyl Chloride Selectfluor 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane; ditetrafluoroborate

[0141] NMR conditions Unless otherwise stated 1 1H NMR spectra were recorded at 500 MHz or 400 MHz on a Bruker Avance III HD 500 MHz or Bruker Avance III HD 400 MHz spectrometer, respectively. Chemical shifts δ are quoted in parts per million (ppm) and referenced to the residual solvent peak. The following abbreviations are used to indicate multiplicity and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (septet), m (multiplet), pent (pentuplet), td (triplet of doublets), qd (quartet of doublets), app. (apparent) and br. (broad). Coupling constants J are quoted to the nearest 0.1 Hz.

[0142] The LCMS conditions for analysis are as follows: System 1 (S1): Acidic IPC method S1 HPLC-MS for analysis was performed on a Shimadzu LCMS-2010EV system using a reversed-phase Kinetex core-shell C18 column (2.1 mm x 50 mm, 5 μm; temperature: 40 °C) and a gradient of 5 - 100% B (A = 0.1% formic acid in H2O; B = 0.1% formic acid in ACN) for 1.2 min, then 100% B for 0.1 min, with an injection volume of 3 μL and a flow rate of 1.2 mL / min. The UV spectrum was recorded at 215 nm using an SPD-M20A photodiode array detector. The mass spectrum was obtained using LCMS2010EV with a sampling rate of 2 scans per second over the m / z range 150 - 850. Data were integrated and recorded using Shimadzu LCMS-Solutions and PsiPort software.

[0143] System 2 (S2): Acidic IPC method (MSQ2 and MSQ4): Analysis of S2 was performed using a Waters Acquity uPLC system, column: Waters UPLC® CSHTM C18 2.1 x 100 mm, 1.7 μm; mobile phase A: water + 0.1% v / v formic acid, mobile phase B: acetonitrile + 0.1% v / v formic acid; gradient: 0 - 1.1 min 5 - 100% B, 1.1 - 1.35 min 100% B, 1.35 - 1.4 min 100 - 5% B, 1.4 - 1.5 min 5% B; flow rate 0.9 mL / min; injection volume 2 μL; temperature: 40 °C; UV scan: 215 nm; PDA spectral range: 200 - 400 nm step: 1 nm; MSD signal setting - scan positive: 150 - 850. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0144] System 3 (S3): Basic IPC method: Column: Waters UPLC® BEH C18 2.1 x 30 mm, 1.7 μm; mobile phase A: 2 mM ammonium bicarbonate, buffered to pH 10, mobile phase B: acetonitrile; gradient: 0 - 0.75 min 5 - 100% B, 0.75 - 0.85 min 100% B, 0.85 - 0.9 min 100 - 5% B, 0.9 - 1.0 min 5% B; flow rate 1 mL / min; injection volume 2 μL; temperature: 40 °C; UV scan: 215 nm; PDA spectral range: 200 - 400 nm step: 1 nm; MSD signal setting - scan positive: 100 - 1000. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0145] System 4 (S4): Acidic final method (MSQ1 and MSQ2): For analysis, S4 was performed on a Waters Acquity uPLC system using a Waters PDA and ELS detectors with a Phenomenex Kinetex-XB C18 column (2.1 mm × 100 mm, 1.7 μM; temperature: 40 °C) and a gradient of 5 to 100% B (A = 0.1% formic acid in H2O; B = 0.1% formic acid in ACN) for 5.3 minutes, then 100% B for 0.5 minute, with a 3 μL injection volume at a flow rate of 0.6 mL / min. The UV spectrum was recorded using a Waters Acquity photodiode array detector at 215 nm. The mass spectrum was obtained using a Waters SQD with a sampling rate of 5 scans per second over the m / z range of 150 to 850. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0146] System 5 (S5): Acidic final method (Shimadzu) 5% solvent B for 1 minute, then a linear gradient of 5 to 100% solvent B in 5.5 min + 2.5 min of 100% solvent B at a flow rate of 1.0 mL / min. Column: ATLANTIS dC18 (50 X 3.0 mm). Solvent A = 0.1% formic acid in H2O, solvent B = 0.1% formic acid in ACN. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0147] System 6 (S6): Basic final method For the METCR1603 HPLC-MS analysis, a Phenomenex Gemini-NX C18 column (2.0×100 mm, 3 μm column; temperature: 40 °C) and a gradient of 5 - 100% (A = 2 mM ammonium bicarbonate, buffered to pH 10; B = ACN) for 5.5 minutes followed by 100% B for 0.4 minutes were used with an injection volume of 3 μL and a flow rate of 0.6 mL / min on an Agilent G1312A system using a Waters 2996 PDA detector and a Waters 2420 ELS detector. The UV spectrum was recorded at 215 nm using a Waters Acquity photodiode array detector. The mass spectrum was obtained using a Waters ZQ mass detector with a sampling rate of 5 scans per second over the m / z range 150 - 850. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0148] The purification methods are as follows: Method 1: Acidic initial method Purification by preparative LC (acidic pH, initial elution method) was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 100 mm, 10 μM; temperature: r.t.) and a gradient of 10 - 95% B (A = 0.1% formic acid in H2O; B = 0.1% formic acid in ACN) for 14.44 minutes followed by 95% B for 2.11 minutes with an injection volume of 1500 μL and a flow rate of 40 mL / min. The UV spectrum was recorded at 215 nm using a Gilson detector.

[0149] Method 2: Acidic standard method Purification by preparative LC (acidic pH, standard elution method) was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 10 mm, 10 μM; temperature: r.t.) and a gradient of 30 - 95% B (A = 0.1% formic acid in water; B = 0.1% formic acid in ACN) for 11.00 minutes followed by 95% B for 2.10 minutes with an injection volume of 1500 μL and a flow rate of 40 mL / min. The UV spectrum was recorded at 215 nm using a Gilson detector.

[0150] Method 3: Basic Initial Method Equipment: Pumps: Gilson 331 and 332; Autoinjector: Gilson GX281; UV Detector: Gilson 159; Collector: Gilson GX281 or Pumps: Gilson 333 and 334; Autoinjector: Gilson GX281; UV Detector: Gilson 155; Collector: Gilson GX281; Column: Waters Xbridge C18 30 x 100mm, 10μm; Eluent A: Water + 0.2% by volume ammonium hydroxide, Eluent B: Acetonitrile + 0.2% by volume ammonium hydroxide; Gradient: 0 - 0.8 min 10% B, 0.8 - 14.5 min 10 - 95% B, 14.5 - 16.7 min 95% B; Flow rate 40 mL / min; Injection volume 1500 μL; Temperature: 25°C; UV Scan: 215 nm.

[0151] Method 4: Basic Standard Method Equipment: Pumps: Gilson 331 and 332; Autoinjector: Gilson GX281; UV Detector: Gilson 159; Collector: Gilson GX281 or Pumps: Gilson 333 and 334; Autoinjector: Gilson GX281; UV Detector: Gilson 155; Collector: Gilson GX281; Column: Waters Xbridge C18 30 x 100mm, 10μm; Eluent A: Water + 0.2% by volume ammonium hydroxide, Eluent B: Acetonitrile + 0.2% by volume ammonium hydroxide; Gradient: 0 - 1.1 min 30% B, 1.1 - 10.05 min 30 - 95% B, 10.05 - 11.5 min 95% B; Flow rate 40 mL / min; Injection volume 1500 μL; Temperature: 25°C; UV Scan: 215 nm.

[0152] Method 5: Reverse Phase Chromatography Using Acidic pH, Standard Elution Method Purification by FCC on reverse-phase silica (acidic pH, standard elution method) was performed on a Biotage Isolera system using a suitable SNAP C18 cartridge and a gradient of 10% B (A = 0.1% formic acid in H2O; B = 0.1% formic acid in ACN) for 1.7 CV, then 10 - 100% B for 19.5 CV, and then 100% B for 2 CV.

[0153] Chiral separation method: Method C1 Purification method = 15% IPA: 85% heptane; Chiralcel OD-H, 20 × 250 mm, 5 μm, 18 mL / min. Sample diluent: MeOH, ACN.

[0154] Method C2 Purification method = ethanol, using a Cellulose-4, 21.2 × 250 mm, 5 μm column at 9 mL / min. Sample dilution: EtOH, MeOH.

[0155] General synthesis: Unless otherwise specified, all compounds were synthesized with a purity > 95%. 2-(4-Chlorophenyl)-5-methanesulfonyl-1,3,4-oxadiazole was prepared according to the reference Ger. Offen. (1992), DE 4033412 A1.

[0156] Scheme for Route 1

Chemical formula

[0157] Intermediate 1: 5-(5-Chloropyridin-2-yl)-2,3-dihydro-1,3,4-oxadiazol-2-one

Chemical formula

[0158] Scheme for Route 2

Chem.

[0159] Step 2.a: tert-Butyl N-{1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-4-yl}carbamate

Chem.

[0160] Intermediate 2 (Step 2.b): 1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-4-amine; trifluoroacetic acid

Chemical Structure

[0161] Scheme for Route 3

Chem.

[0162] Intermediate 3 (Step 3.a) 2-(4-Chloro-3-fluorophenoxy)acetyl chloride

Chem.

[0163] Scheme for Route 4

Chem.

[0164] Step 4.a: tert-Butyl 4-[2-(4-Chloro-3-fluorophenoxy)acetamido]piperidine-1-carboxylate [Chem.] To a solution of 2-(4-chloro-3-fluorophenoxy)acetyl chloride (500 mg, 2.24 mmol, Intermediate 3) in DCM (15 mL) were added tert-butyl 4-aminopiperidine-1-carboxylate (458 mg, 2.24 mmol) and DIPEA (0.78 mL, 4.48 mmol), and the resulting mixture was stirred at r.t. for 2 h. H2O (25 mL) was added, and the resulting solution was extracted with DCM (2 × 50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give the title compound (purity 83%, 1.05 g, 2.24 mmol, 100% yield) as a brown oily substance; 1 1H NMR (500 MHz, DMSO-d6) δ 8.04 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.06 (dd, J = 11.4, 2.8 Hz, 1H), 6.84 (ddd, J = 9.0, 2.8, 1.1 Hz, 1H), 4.50 (s, 2H), 3.93 - 3.74 (m, 3H), 2.85 (d, J = 35.4 Hz, 2H), 1.74 - 1.62 (m, 2H), 1.39 (s, 9H), 1.36 - 1.26 (m, 2H); M / Z: 287, 289 [M - Boc + H]+, ESI+, RT = 1.22 min (S1).

[0165] Intermediate 4 (Step 4.b): 2-(4-chloro-3-fluorophenoxy)-N-(piperidin-4-yl)acetamide [Chem.] tert-Butyl 4-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1-carboxylate (867 mg, 2.24 mmol) was dissolved in 4 M HCl in 1,4-dioxane (10 mL), and the resulting mixture was stirred at r.t. for 17 h. The reaction mixture was concentrated in vacuo, and the resulting residue was dissolved in satd aq NaHCO3 solution (25 mL) and extracted with DCM (2 × 50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give the title compound (531 mg, 1.85 mmol, 83% yield) as an off-white solid; 1 1H NMR (500 MHz, chloroform-d) δ 7.32 (t, J = 8.6 Hz, 1H), 6.76 (dd, J = 10.3, 2.8 Hz, 1H), 6.68 (ddd, J = 8.9, 2.8, 1.2 Hz, 1H), 6.34 (d, J = 7.4 Hz, 1H), 4.44 (s, 2H), 3.97 (ddp, J = 11.6, 8.4, 4.2 Hz, 1H), 3.10 (d, J = 12.6 Hz, 2H), 2.72 (t, J = 9.7 Hz, 2H), 1.98 - 1.91 (m, 4H), 1.40 (td, J = 15.2, 7.8 Hz, 1H); M / Z: 287, 289 [M+H] + , ESI+, RT = 0.82 min (S1).

[0166] Scheme for Route 5

Chem.

[0167] Step 5.a: (1R,5S,6S)-6-[2-(4-chloro-3-fluorophenoxy)acetamido]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl

Chem.

[0168] Intermediate 5 (Step 5.b): N-[(1R,5S,6S)-3-azabicyclo[3.1.0]hexan-6-yl]-2-(4-chloro-3-fluorophenoxy)acetamide

Chemical Structure

[0169] Scheme for Route 6

Chem.

[0170] Step 6.a: tert-Butyl 4-[2-(4-chloro-3-fluorophenoxy)acetamido]piperazine-1-carboxylate

Chem.

[0171] Intermediate 6 (Step 6.b): 2-(4-chloro-3-fluorophenoxy)-N-(piperazin-1-yl)acetamide dihydrochloride

Chemical Structure

[0172] Scheme for Route 7

Chem.

[0173] Step 7.a: tert-Butyl 4-[2-(4-chloro-3-fluorophenoxy)acetamido]azepane-1-carboxylate

Chem.

[0174] Intermediate 7 (Step 7.b): N-(Azepan-4-yl)-2-(4-chloro-3-fluorophenoxy)acetamide [Chem.] To a solution of tert-butyl 4-[2-(4-chloro-3-fluorophenoxy)acetamido]azepane-1-carboxylate (purity 84%, 242 mg, 0.507 mmol) in DCM (5 mL) was added TFA (0.20 mL, 2.69 mmol), and the resulting mixture was stirred at r.t. for 24 h. The reaction mixture was washed with satd aq NaHCO3 solution (20 mL) and extracted with DCM (2 × 25 mL). The combined organic extracts were concentrated in vacuo to afford the title compound (purity 92%, 132 mg, 0.404 mmol, 80% yield) as a yellow oil; 1 H NMR (500 MHz, chloroform-d) δ 7.31 (t, J = 8.6 Hz, 1H), 7.13 (d, J = 8.5 Hz, 1H), 6.76 (dd, J = 10.4, 2.8 Hz, 1H), 6.68 (ddd, J = 8.9, 2.8, 1.2 Hz, 1H), 4.45 (s, 2H), 4.28 - 4.34 (m, 1H), 3.01 - 2.93 (m, 2H), 2.87 - 2.80 (m, 1H), 2.79 - 2.71 (m, 1H), 1.94 (dq, J = 15.1, 4.7 Hz, 2H), 1.83 - 1.69 (m, 2H), 1.68 - 1.60 (m, 2H); M / Z: 301, 303 [M+H] + , ESI+, RT = 0.81 min (S1).

[0175] Scheme for Route 8 [Chem.]

[0176] Step 8.a: tert-Butyl N-[1-(hydrazinecarbonyl)piperidin-4-yl]carbamate [Chem.] To a solution of tert-butyl N-(4-piperidyl)carbamate (5.00 g, 25.0 mmol) in anhydrous THF (50 mL) were added CDI (8.10 g, 49.9 mmol) and DIPEA (8.7 mL, 49.9 mmol), and the resulting mixture was stirred at r.t. for 2 h. Then hydrazine (1.86 mL, 60.0 mmol) was added, and the mixture was stirred at 45 °C for 24 h. The reaction mixture was cooled to r.t., concentrated in vacuo, and triturated with H2O to afford the title compound (purity 94%, 5.28 g, 19.2 mmol, 77% yield) as a white solid; 1 H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 1H), 6.81 (d, J = 7.6 Hz, 1H), 3.88 - 3.77 (m, 4H), 3.45 - 3.34 (m, 1H), 2.75 - 2.65 (m, 2H), 1.69 - 1.60 (m, 2H), 1.38 (s, 9H), 1.19 (qd, J = 12.2, 4.0 Hz, 2H); M / Z: 203 [M+H] + , ESI+, RT = 0.73 min (S1).

[0177] Step 8.b: tert-Butyl N-{1-[N'-(5,5,5-trifluoropentanoyl)hydrazinecarbonyl]piperidin-4-yl}carbamate [Chemical formula] A solution of 5,5,5-trifluoropentanoic acid (121 mg, 0.774 mmol) in DMF (1.5 mL) was treated with DIPEA (0.54 mL, 3.10 mmol) and T3P (50%, 0.51 mL, 0.852 mmol), and the resulting mixture was stirred at r.t. for 15 min. A solution of tert-butyl N-[1-(hydrazinecarbonyl)piperidin-4-yl]carbamate (200 mg, 0.774 mmol) in DMF (1.5 mL) was added, and the resulting mixture was stirred at r.t. for 45 min. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, and concentrated in vacuo to afford the title compound (108 mg, 0.272 mmol, 35% yield) as a white solid; 1 H NMR (500 MHz, DMSO-d6) δ 9.40 (d, J = 1.7 Hz, 1H), 8.38 (d, J = 1.6 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 3.86 (d, J = 13.4 Hz, 2H), 3.40 (s, 1H), 2.83 - 2.72 (m, 2H), 2.39 - 2.23 (m, 2H), 2.19 (t, J = 7.2 Hz, 2H), 1.70 (ddd, J = 23.3, 15.6, 8.6 Hz, 4H), 1.38 (s, 9H), 1.23 (td, J = 13.0, 11.3, 6.4 Hz, 2H); M / Z: 419 [M+Na] + , ESI+, RT = 0.99 min (S1).

[0178] Step 8.c: tert-Butyl N-{1-[5-(4,4,4-trifluorobutyl)-1,3,4-oxadiazol-2-yl]piperidin-4-yl}carbamate

Chem.

[0179] Intermediate 8 (Step 8.d): 1-[5-(4,4,4-trifluorobutyl)-1,3,4-oxadiazol-2-yl]piperidin-4-amine hydrochloride

Chem.

[0180] Scheme for Route 9

Chem.

[0181] Step 9.a: tert-Butyl N-[(3R*,4R*)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]carbamate

Chem.

[0182] Intermediate 9 (Step 9.b): (3R*,4R*)-4-Amino-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-ol

Chem.

[0183] Scheme for Route 10

Chem.

[0184] Step 10.a: 2-(4-Chloro-3-fluorophenoxy)-N-[1-(hydrazinecarbonyl)piperidin-4-yl]acetamide

Chem.

[0185] Step 10.b: N-[1-(5-amino-1,3,4-oxadiazol-2-yl)piperidin-4-yl]-2-(4-chloro-3-fluorophenoxy)acetamide

Chemical Structure

[0186] Intermediate 10 (Step 10.c): N-[1-(5-bromo-1,3,4-oxadiazol-2-yl)piperidin-4-yl]-2-(4-chloro-3-fluorophenoxy)acetamide

Chemical Structure

[0187] Scheme for Route 11

Chemical formula

[0188] Step 11.a: tert-Butyl 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetate

Chemical formula

[0189] Step 11.b: 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetic acid

Chem.

[0190] Scheme for Route 12 [Chemical formula]

[0191] Example 1: 2-(4-Chloro-3-fluorophenoxy)-N-{1-[5-(5-chloropyridin-2-yl)-1,3,4-oxadiazol-2-yl]piperidin-4-yl}acetamide [Chemical formula] To a solution of 5-(5-chloropyridin-2-yl)-2,3-dihydro-1,3,4-oxadiazol-2-one (purity 90%, 70 mg, 0.319 mmol, Intermediate 1) in anhydrous DMF (1.5 mL) were added DIPEA (0.14 mL, 0.797 mmol) and BOP reagent (169 mg, 0.383 mmol), and the mixture was stirred at r.t. for 30 min under N2. 2-(4-Chloro-3-fluorophenoxy)-N-(piperidin-4-yl)acetamide (91 mg, 0.319 mmol, Intermediate 4) was added, and the reaction mixture was stirred at r.t. for 1 h. H2O (25 mL) was added, and the resulting solution was extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo. The obtained residue was purified by preparative HPLC (Method 3) and triturated with Et2O to give the title compound (59 mg, 0.123 mmol, 39% yield) as a grayish white solid; 11H NMR (500 MHz, DMSO-d6) δ 8.76 (d, J = 2.4 Hz, 1H), 8.12 (dd, J = 8.5, 2.4 Hz, 2H), 8.06 (d, J = 8.5 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.89 - 6.83 (m, 1H), 4.54 (s, 2H), 4.00 - 3.89 (m, 3H), 3.31 - 3.22 (m, 2H), 1.89 - 1.81 (m, 2H), 1.58 (qd, J = 12.5, 4.2 Hz, 2H); M / Z: 466, 468, 470 [M+H] + , ESI+, RT = 3.18 min (S4).

[0192] Scheme for Route 13

Chem.

[0193] Example 2: 2-[(6-Chloro-5-fluoropyridin-3-yl)oxy]-N-{1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-4-yl}acetamide

Chem.

[0194] Scheme for Route 14

Chemical Structure

[0195] Example 3: 2-(4-Chloro-3-fluorophenoxy)-N-[(3R*,4R*)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]acetamide

Chemical Structure

[0196] Scheme for Route 15

Chemical Structure

[0197] Example 4: 2-(4-Chloro-3-fluoro-phenoxy)-N-[1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-4-piperidyl]acetamide

Chemical Structure

[0198] The compound of Example 5 in Table 1 was synthesized according to the general route 15 as exemplified in Example 4, using the corresponding intermediates and purification methods.

[0199]

Table 1

[0200] Scheme for Route 16

Chem.

[0201] Example 6: 2-(4-Chloro-3-fluorophenoxy)-N-{1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]azepan-4-yl}acetamide

Chem.

[0202] The example compounds in Table 2 were synthesized using the corresponding intermediates and purification methods according to General Route 16 as exemplified in Example 6.

[0203] [Table 2]

[0204] Scheme for Route 17 [Chemical Formula]

[0205] Example 9: 2-(4-Chloro-3-fluorophenoxy)-N-(1-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-4-yl)acetamide [Chemical Formula] To a solution of 2-(trifluoromethoxy)ethan-1-ol (28 mg, 0.219 mmol) in anhydrous THF (1 mL) was added NaH (5.3 mg, 0.219 mmol) at 0 °C, and the resulting mixture was stirred at 0 °C for 10 min. N-[1-(5-Bromo-1,3,4-oxadiazol-2-yl)piperidin-4-yl]-2-(4-chloro-3-fluorophenoxy)acetamide (50 mg, 0.110 mmol, Intermediate 10) in anhydrous THF (1 mL) was added, and the resulting mixture was stirred at r.t. for 1 h. H2O (0.5 mL) was added, then concentrated in vacuo, and purified by preparative HPLC (Method 4) to give the title compound (22 mg, 0.0456 mmol, 42% yield) as a white powder; 11H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 7.9 Hz, 1H), 7.58 - 7.42 (m, 1H), 7.14 - 7.01 (m, 1H), 6.94 - 6.79 (m, 1H), 4.61 - 4.55 (m, 2H), 4.53 (s, 2H), 4.48 - 4.41 (m, 2H), 3.98 - 3.81 (m, 1H), 3.74 - 3.63 (m, 2H), 3.14 - 3.00 (m, 2H), 1.84 - 1.71 (m, 2H), 1.62 - 1.46 (m, 2H); M / Z: 483, 485 [M+H] + , ESI+, RT = 3.32 min (S4).

[0206] Scheme for Route 18

Chem.

[0207] Example 10: 2-(4-Chloro-3-fluorophenoxy)-N-(1-{5-[3-(trifluoromethoxy)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-4-yl)acetamide

Chem.

[0208] Scheme for Route 19 [Chemical Structure]

[0209] Examples 11 and 12: Chiral Separation of 2-(4-Chloro-3-fluorophenoxy)-N-[(3R*,4R*)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]acetamide 2-(4-Chloro-3-fluorophenoxy)-N-[(3R*,4R*)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]acetamide (48 mg, 0.0997 mmol) was subjected to chiral separation using Method C1 to give the enantiomers 2-(4-chloro-3-fluorophenoxy)-N-[(3R,4R)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]acetamide (chiral purity 100%, 18.5 mg, 0.0369 mmol, 37% yield) and 2-(4-chloro-3-fluorophenoxy)-N-[(3S,4S)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]acetamide (chiral purity 98%, 17.5 mg, 0.0345 mmol, 35% yield) as white powders. The stereochemistry of each enantiomer was arbitrarily assigned.

[0210] The example compounds in Table 3 were chiral purified using the corresponding intermediates and methods according to General Route 19 as illustrated in Examples 11 and 12.

[0211]

Table 3-1

Table 3-2

[0212] II Biological Assays HEK-ATF4 high-content imaging assay The example compounds were tested in a HEK-ATF4 high-content imaging assay to evaluate their pharmacological efficacy in preventing tunicamycin-induced ISR. Wild-type HEK293 cells were plated at a density of 12,000 cells per well in growth medium (containing DMEM / F12, 10% FBS, 2 mM L-glutamine, 100 U / mL penicillin - 100 μg / mL streptomycin) in 384-well imaging assay plates and incubated at 37 °C, 5% CO2. After 24 hours, the medium was changed to 50 μL per well of assay medium (DMEM / F12, 0.3% FBS, 2 mM L-glutamine, 100 U / mL penicillin - 100 μg / mL streptomycin). The example compounds were serially diluted in dimethyl sulfoxide (DMSO), spotted onto an intermediate plate, and pre-diluted with assay medium containing 3.3 μM tunicamycin to obtain an 11-fold excess final assay concentration. In addition to the example compound test areas, the plates included multiple control wells for assay normalization purposes, wells containing tunicamycin but no example compound (high control), and wells containing neither the example compound nor tunicamycin (low control). The assay was initiated by transferring 5 μL from the intermediate plate to the assay plate, followed by incubation at 37 °C, 5% CO2 for 6 hours. The cells were then fixed (4% PFA in PBS, 20 minutes at room temperature) and subjected to indirect ATF4 immunofluorescence staining (primary antibody rabbit anti-ATF4, clone D4B8, Cell Signaling Technologies; secondary antibody Alexa Fluor 488 goat anti-rabbit IgG(H+L), Thermofisher Scientific). The nuclei were stained using Hoechst dye (Thermofisher Scientific), and the plates were imaged on an Opera Phenix high-content imaging platform equipped with 405 nm and 488 nm excitation. Finally, the images were analyzed using a script-based algorithm. The primary readout, HEK-ATF4, monitored the ATF4 signal ratio between the nucleus and cytoplasm. Tunicamycin induced an increase in the overall ATF4 ratio signal, which was prevented by the example compounds that modulate ISR.Furthermore, the HEK-CellCount readout was derived from counting the number of stained nuclei corresponding to healthy cells. This readout served as an internal toxicity control. The example compounds herein did not produce a significant decrease in CellCount.

[0213] The activities of the tested example compounds are shown in Table 4 as follows: +++=IC50 1 - 500 nM; ++=IC50 > 500 - 2000 nM; +=IC50 > 2000 - 15000 nM

[0214] [Table 4]

[0215] References (1) Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM. The integrated stress response. EMBO Rep. October 2016;17(10):1374 - 1395. Epub September 14, 2016. (2) Wek RC, Jiang HY, Anthony TG. Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans. February 2006;34(Pt 1):7 - 11. (3) Donnelly N, Gorman AM, Gupta S, Samali A. The eIF2alpha kinases: their structures and functions. Cell Mol Life Sci. October 2013;70(19):3493 - 511 (4) Jackson RJ, Hellen CU, Pestova TV. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat Rev Mol Cell Biol. February 2010;11(2):113-27 (5) Lomakin IB, Steitz TA. The initiation of mammalian protein synthesis and mRNA scanning mechanism. Nature. August 15, 2013;500(7462):307-11 (6) Pain VM. Initiation of protein synthesis in eukaryotic cells. Eur J Biochem. March 15, 1996;236(3):747-71 (7) Pavitt GD. Regulation of translation initiation factor eIF2B at the hub of the integrated stress response. Wiley Interdiscip Rev RNA. November 2018;9(6):e1491. (8) Krishnamoorthy T, Pavitt GD, Zhang F, Dever TE, Hinnebusch AG. Tight binding of the phosphorylated alpha subunit of initiation factor 2 (eIF2alpha) to the regulatory subunits of guanine nucleotide exchange factor eIF2B is required for inhibition of translation initiation. Mol Cell Biol. August 2001;21(15):5018-30. (9) Hinnebusch, A.G., Ivanov, I.P., & Sonenberg, N. (2016). Translational control by 5’-untranslated regions of eukaryotic mRNAs. Science, 352(6292), 1413-1416. (10) Young, S.K., & Wek, R.C. (2016). Upstream open reading frames differentially regulate gene-specific translation in the integrated stress response. The Journal of Biological Chemistry, 291(33), 16927 -16935. (11) Lin JH, Li H, Zhang Y, Ron D, Walter P (2009) Divergent effects of PERK and IRE1 signaling on cell viability. PLoS ONE 4:e4170 (12) Tabas I, Ron D. Nat Cell Biol. 2011 Mar;13(3):184-90. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. (13) Shore GC, Papa FR, Oakes SA. Curr Opin Cell Biol. 2011 Apr;23(2):143-9. Signaling cell death from the endoplasmic reticulum stress response. (14) Bi M, Naczki C, Koritzinsky M, Fels D, Blais J, Hu N, Harding H, Novoa I, Varia M, Raleigh J, Scheuner D, Kaufman RJ, Bell J, Ron D, Wouters BG, Koumenis C. EMBO J. October 5, 2005; 24(19): 3470 - 81. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. (15) Bobrovnikova-Marjon E, Grigoriadou C, Pytel D, Zhang F, Ye J, Koumenis C, Cavener D, Diehl JA. Oncogene. July 8, 2010; 29(27): 3881 - 95. PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage. (16) Avivar-Valderas A, Salas E, Bobrovnikova-Marjon E, Diehl JA, Nagi C, Debnath J, Aguirre-Ghiso JA. Mol Cell Biol. September 31, 2011 (17): 3616 - 29. PERK integrates autophagy and oxidative stress responses to promote survival during extracellular matrix detachment. (17) Blais, J.D.; Addison, C.L.; Edge, R.; Falls, T.; Zhao, H.; Kishore, W.; Koumenis, C.; Harding, H.P.; Ron, D.; Holcik, M.; Bell, J.C. Mol. Cell. Biol. 2006, 26, 9517 - 9532. PERK-dependent translational regulation promotes tumor cell adaptation and angiogenesis in response to hypoxic stress. (18) Taalab YM, Ibrahim N, Maher A, Hassan M, Mohamed W, Moustafa AA, Salama M, Johar D, Bernstein L. Rev Neurosci. June 27, 2018; 29(4): 387 - 415. Mechanisms of disordered neurodegenerative function: concepts and facts about the different roles of the protein kinase RNA-like endoplasmic reticulum kinase (PERK). (19) Remondelli P, Renna M. Front Mol Neurosci. June 16, 2017; 10: 187. The Endoplasmic Reticulum Unfolded Protein Response in Neurodegenerative Disorders and Its Potential Therapeutic Significance. (20) Halliday M, Mallucci GR. Neuropathol Appl Neurobiol. June 2015; 41(4): 414 - 27. Review: Modulating the unfolded protein response to prevent neurodegeneration and enhance memory. (21) Halliday M, Radford H, Sekine Y, Moreno J, Verity N, le Quesne J, Ortori CA, Barrett DA, Fromont C, Fischer PM, Harding HP, Ron D, Mallucci GR. Cell Death Dis. March 5, 2015; 6: e1672. Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. (22) Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Martin MG, Halliday M, Morgan J, Dinsdale D, Ortori CA, Barrett DA, Tsaytler P, Bertolotti A, Willis AE, Bushell M, Mallucci GR. Nature 2012; 485: 507-11. Sustained translational repression by eIF2alpha-P mediates prion neurodegeneration. (23) Skopkova M, Hennig F, Shin BS, Turner CE, Stanikova D, Brennerova K, Stanik J, Fischer U, Henden L, Mueller U, Steinberger D, Leshinsky-Silver E, Bottani A, Kurdiova T, Ukropec J, Nyitrayova O, Kolnikova M, Klimes I, Borck G, Bahlo M, Haas SA, Kim JR, Lotspeich-Cole LE, Gasperikova D, Dever TE, Kalscheuer VM. Hum Mutat. 2017 Apr;38(4):409-425. EIF2S3 Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO. (24) Hamilton EMC, van der Lei HDW, Vermeulen G, Gerver JAM, Lourenco CM, Naidu S, Mierzewska H, Gemke RJBJ, de Vet HCW, Uitdehaag BMJ, Lissenberg-Witte BI; VWM Research Group, van der Knaap MS. Ann Neurol. 2018 Aug;84(2):274-288. Natural History of Vanishing White Matter. (25) Bugiani M, Vuong C, Breur M, van der Knaap MS. Brain Pathol. 2018 May;28(3):408-421. Vanishing white matter: a leukodystrophy due to astrocytic dysfunction. (26) Wong YL, LeBon L, Edalji R, Lim HB, Sun C, Sidrauski C. Elife. February 28, 2018;7. 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Claims

1. The compound of formula (I) 【Chemical 1】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein X １ is C(R ａ６ ) or N; X １ａ is a shared single bond, CH(R ａ３ ), O, N(R ａ７ ), or CH(R ａ３ ),CH ２ ; R a1, R a2, R a3, R a4, R a5, R a6 are independently H; or, R a1 is OH and R a2, R a3, R a4, R a5, R a6 are independently H; or, R a1, R a3, R a5, R a6 are independently H and R a2 and R a4 form a methylene group; or, R a1 and R a2 form a shared single bond and R a3, R a4, R a5, R a6 are independently H; R ａ７ is H, C(O)OC １－４ alkyl, or C １－４ alkyl, where C(O)OC １－４ alkyl and C １－４ alkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, OH, and O-C １－３ alkyl, where the substituents are the same or different; A １ is an oxadiazole, and here A １ is optionally substituted with one or more R ４ which may be the same or different; Each R ４ is independently oxo (=O) [when the ring is at least partially saturated], thioxo (=S) [when the ring is at least partially saturated], halogen, CN, OR ５ , or C １－６ alkyl [where C １－６ alkyl is optionally substituted with one or more of the same or different halogens]; R ５ is H or C １－６ alkyl, where C １－６ alkyl is optionally substituted with one or more of the same or different halogen; A ２ is R ６ａ or A ２ａ and; 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, where 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 , and A ２ａ , where 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 , and A ２ａ wherein the substituents are the same or different; R ６ａ３ is H, or C １－４ alkyl, where C １－４ alkyl is optionally substituted with one or more of the same or different halogen; A ２ａ is phenyl or 3- to 7-membered heterocyclyl, where A ２ａ is optionally substituted by one or more of the same or different R ６ groups; Each R ６ is independently R ６ｂ , OH, OR ６ｂ , halogen, or CN, where R ６ｂ is cyclopropyl, C １－６ alkyl, C ２－６ alkenyl, or C ２－６ alkynyl, and where R ６ｂ is optionally substituted with one or more of the same or different halogens; or Two Rs ６ are joined to together with the atoms to which they are attached to form ring A ２ｂ ; A ２ｂ is phenyl or 3- to 7-membered heterocyclyl, where A ２ｂ is optionally substituted by one or more of the same or different R ７ groups; Each R ７ is independently C １－６ alkyl, C ２－６ alkenyl or C ２－６ alkynyl, where C １－６ alkyl, C ２－６ alkenyl, and C ２－６ alkynyl are optionally substituted with the same or different one or more halogens; R １ is H or C １－４ alkyl, where C １－４ alkyl is optionally substituted with one or more of the same or different halogen; R ２ is H, F, or C １－４ alkyl, where C １－４ alkyl is optionally substituted with one or more of the same or different halogens; and R ３ is A ３ ; R ２ａ is H or F; Each A ３ is independently phenyl or 6-membered heterocyclyl, where A ３ is optionally substituted by one or more of the same or different R １０ groups; Each R １０ is independently halogen, CN, C(O)OR １１ , OR １１ , C(O)R １１ , C(O)N(R １１ R １１ａ ), S(O) ２ N(R １１ R １１ａ ), S(O)N(R １１ R １１ａ ), S(O) ２ R １１ , S(O)R １１ , N(R １１ ), S(O) ２ N(R １１ａ R １１ｂ , SR １１ , N(R １１ R １１ａ ), NO ２ , OC(O)R １１ , N(R １１ ), C(O)R １１ａ , N(R １１ ), S(O) ２ R １１ａ , N(R １１ ), S(O)R １１ａ , N(R １１ ), C(O)OR １１ａ , N(R １１ ), C(O)N(R １１ａ R １１ｂ ), OC(O)N(R １１ R １１ａ ), oxo(=O) [when the ring is at least partially saturated], C １－６ alkyl, C ２－６ alkenyl, or C ２－６ alkynyl, where C １－６ alkyl, C ２－６ alkenyl, and C ２－６ alkynyl are optionally substituted with one or more of the same or different R １２ ; R １１ 、R １１ａ 、R １１ｂ are independently selected from the group consisting of H, C １－６ alkyl, C ２－６ alkenyl, and C ２－６ alkynyl, wherein C １－６ alkyl, C ２－６ alkenyl, and C ２－６ alkynyl are optionally substituted with the same or different one or more halogens; Each R １２ is independently halogen, CN, C(O)OR １３ OR １３ C(O)R １３ C(O)N(R １３ R １３ａ ), S(O) ２ N(R １３ R １３ａ ), S(O)N(R １３ R １３ａ ), S(O) ２ R １３ S(O)R １３ N(R １３ ), N(R ２ N(R １３ａ R １３ｂ SR １３ N(R １３ R １３ａ ), NO ２ OC(O)R １３ N(R １３ ), N(R １３ａ ), N(R １３ ), N(R ２ R １３ａ ), N(R １３ ), N(R １３ａ ), N(R １３ ), N(R １３ａ R １３ｂ ), N(R １３ ), N(R １３ａ ), or OC(O)N(R １３ R １３ａ ); R １３ 、R １３ａ 、R １３ｂ is independently selected from the group consisting of H, C １－６ alkyl, C ２－６ alkenyl, and C ２－６ alkynyl, wherein C １－６ alkyl, C ２－６ alkenyl, and C ２－６ alkyl, alkenyl, and alkynyl are optionally substituted with the same or different one or more halogens, provided that provided that the following compounds: 【Chemical 2】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof are excluded, the above compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

2. The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof according to Claim 1, wherein R a7 is H.

3. The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof according to Claim 1 or 2, wherein R 1 is H.

4. The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof according to any one of Claims 1 to 3, wherein R 2a is H.

5. X １ The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein X is CH.

6. X １ａ is a shared single bond, CH(R ａ３ ), or CH(R ａ３ ), CH ２ is the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

7. The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof according to Claim 6, wherein X 1a is CH(R a3) or CH(R a3)CH 2.

8. The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof according to Claim 7, wherein X 1a is CH(R a3).

9. R ａ１ 、 R ａ２ 、 R ａ３ 、 R ａ４ 、 R ａ５ 、 R ａ６ is H, the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

10. A １ which is unsubstituted or substituted with one or two Rs which may be the same or different ４ is a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

11. The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof according to Claim 10, wherein A 1 is unsubstituted.

12. R ４ is oxo [when the ring is at least partially saturated] or methyl, Claim The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof according to any one of Claims 1 to 11.

13. A １ is [Chemical 3] The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof according to any one of Claims 1 to 12, which is

14. A ２ is R ６ａ which is the compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof according to any one of claims 1 to 13.

15. R ６ａ is OR ６ａ１ ; or R ６ａ is one or more halogens and / or one A ２ａ and / or one OR ６ａ３ optionally substituted C １－６ alkyl, the compound according to claim 14 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

16. R6a1 is C1-6 alkyl optionally substituted by A2a, or one or more halogens and / or one A2a and / or one OR6a3, a compound according to claim 15 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

17. R ６ａ is OR ６ａ１ ; or R ６ａ is one or more halogens and / or one OR ６ａ３ optionally substituted C １－６ alkyl, a compound according to any one of claims 14 to 16 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

18. R6a1 is C1-6 alkyl optionally substituted by one or more F and / or one OR6a3, a compound according to claim 17 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

19. A ２ is A ２ａ which is the compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof according to any one of claims 1 to 13.

20. A ２ａ is phenyl, or 5- to 6-membered aromatic heterocyclyl, and here A ２ａ is one or more R, which are the same or different ６ and which is optionally substituted, of the compound according to claim 19 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

21. A2a is pyridyl, pyrazinyl, pyridazinyl, pyrazolyl or 1,2,4-oxadiazolyl, and wherein A2a is optionally substituted by one or more R6 which are the same or different, a compound according to claim 20 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

22. A ２ａ is the compound or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 13, 19 to 21, optionally substituted with one or two R ６ which are the same or different solvate, hydrate, tautomer or stereoisomer.

23. Each R ６ is independently F, Cl, CF ３ , OCH ３ , OCF ３ , CH ３ , CH ２ CH ３ or cyclopropyl, a compound according to any one of claims 1 to 13, 19 to 22 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

24. R ２ which is H, the compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof,

25. A ３ is phenyl, pyridyl, pyrazinyl or pyrimidazyl, and wherein A ３ is optionally substituted with one or more R １０ which are the same or different, of the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

26. A ３ is the compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof according to any one of claims 1 to 25, which is substituted with one or two R １０ that are the same or different.

27. R １０ is independently F, Cl, CF ３ , CH=O, CH ２ OH or CH ３ and is a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

28. The compound is 2-(4-chloro-3-fluorophenoxy)-N-{1-[5-(5-chloropyridin-2-yl)-1,3,4-oxadiazol-2-yl]piperidin-4-yl}acetamide; 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]-N-{1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-4-yl}acetamide; 2-(4-chloro-3-fluorophenoxy)-N-[(3R*,4R*)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]acetamide; 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-4-piperidyl]acetamide; 2-(4-chloro-3-fluorophenoxy)-N-{1-[5-(4,4,4-trifluorobutyl)-1,3,4-oxadiazol-2-yl]piperidin-4-yl}acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-[(1R,5S,6R)-3-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.0]hexan-6-yl]acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-{4-[5-(4-chlorophenyl )-1,3,4-oxadiazol-2-yl]piperazin-1-yl}acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-{1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]azepan-4-yl}acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-[(3R,4R)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-[(3S,4S)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-[(4S)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]azepan-4-yl]acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-[(4R)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]azepan-4-yl]acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-(1-{5-[3-(trifluoromethoxy)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-4-yl)acetamide; or 2-(4-Chloro-3-fluorophenoxy)-N-(1-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-4-yl)acetamide which is the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

29. At least one compound defined in any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, in combination with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions, a pharmaceutical composition.

30. Use of a compound defined in any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, in the manufacture of a medicament for the treatment or prevention of one or more diseases or disorders associated with the integrated stress response.

31. Use of a compound defined in any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, in the manufacture of a medicament for the treatment or prevention of one or more diseases or disorders selected from the group consisting of leukodystrophy, intellectual disability syndrome, neurodegenerative diseases and disorders, neoplastic diseases, infectious diseases, inflammatory diseases, musculoskeletal diseases, metabolic diseases, eye diseases, and further including 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 diseases, arrhythmias, atherosclerosis, spinal cord injury, ischemic stroke, and neuropathic pain.

32. Use of a compound defined in any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, in the manufacture of a medicament.

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