Modulators of the integrated stress response pathway

Abstract

The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, wherein R 1 , R 2 , R 2a , R 3 , R 4 , R4 a , R4 b , R4 c , R 4d , R 4e , R 5 , R 6 has the meaning as indicated in the description and claims. The invention further relates to pharmaceutical compositions comprising said compounds, their use as medicaments and in methods for the treatment or prevention of one or more diseases or disorders associated with the integrated stress response. [Formula 1] TIFF2023546225000046.tif54105

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 important pathological consequences leading to, inter alia, inflammation, viral infections, diabetes, cancer and neurodegenerative diseases.

[0003] ISR is a common factor of different types of cellular stress that results in phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2 alpha) on serine 51, leading to the suppression of normal protein synthesis and the expression of stress response genes (2). In mammalian cells, this phosphorylation is carried out by a family of four eIF2 alpha kinases, each responding to distinct environmental and physiological stresses: PKR-like ER kinase (PERK), double-stranded RNA-dependent protein kinase (PKR), heme-regulated eIF2 alpha kinase (HRI), and general control non-derepressible (GCN2) (3).

[0004] eIF2 alpha, along with eIF2 beta and eIF2 gamma, forms the eIF2 complex, a key player in the initiation of normal mRNA translation (4). The eIF2 complex connects GTP and Met-tRNA i The ternary complex (eIF2-GTP-Met-tRNA) is formed by binding to the ribosome and being recruited for translation initiation. i ) forms (5, 6).

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

[0006] In response to ISR activation, phosphorylated eIF2-alpha inhibits the eIF2B-mediated exchange of GDP with GTP, resulting in reduced ternary complex formation and, therefore, inhibition of translation of normal mRNAs characterized by ribosomes binding to the 5'AUG start codon (8). Under these conditions of reduced ternary complex abundance, translation of certain mRNAs, including mRNA encoding the transcription factor ATF4, is activated via a mechanism involving alteration of upstream ORF (uORF) translation (7, 9, 10). These mRNAs typically contain one or more uORFs that function normally in non-stress cells to restrict ribosome flow to the main coding ORF. For example, under normal conditions, the uORF at the 5'UTR of ATF occupies the ribosome and prevents translation of the ATF4 coding sequence. However, under stress conditions, i.e., under reduced ternary complex formation, the probability of ribosomes scanning through these upstream ORFs and initiating translation at the ATF4 coding ORF is increased. The ATF4 and other stress response factors expressed in this manner subsequently control the expression of an array of further stress response genes. In the acute phase, the expression of proteins aimed at restoring homeostasis is involved, while in the chronic phase, it leads to the expression of pro-apoptotic factors (1, 11, 12, 13).

[0007] Upregulation of ISR signaling markers has been demonstrated in various conditions among these cancers and neurodegenerative diseases. In cancer, ER stress-modulating translation increases tolerance to hypoxic conditions and promotes tumor growth (14, 15, 16), and deletion of PERK by gene targeting leads to transformed PERK - / - It has been shown to slow tumor growth induced from mouse embryonic fibroblasts (14, 17). Furthermore, recent reports have provided proof of concept that activators of eIF2B are effective in treating morphologies of invasive metastatic prostate cancer using patient-derived xenograft models in mice (28). Taken together, inhibition of cytoprotective ISR signaling may represent an effective antiproliferative strategy for treating at least some morphologies of cancer.

[0008] Furthermore, modulation of ISR signaling has been shown to be effective in preserving synaptic function and reducing neuronal decline, as well as in neurodegenerative diseases characterized by the activation of misfolded and unfolded protein responses (UPRs), such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD), and Jacobukureutzfeldt (prion) diseases (18, 19, 20). Regarding prion diseases, there are examples of neurodegenerative diseases in which pharmacological inhibition, as well as genetic inhibition, of ISR signaling has been shown to normalize protein translation levels, rescue synaptic function, and prevent neuronal loss (21). Specifically, reduction of phosphorylated eIF2 alpha levels by overexpression of a phosphatase that controls phosphorylated eIF2 alpha levels increased survival time in prion-infected mice, while maintained eIF2 alpha phosphorylation decreased survival time (22).

[0009] Furthermore, direct evidence exists regarding the importance of regulating protein expression levels for proper brain function in the form of rare genetic disorders affecting the function of eIF2 and eIF2B. Mutations in eIF2 gamma that disrupt the complex integrity of eIF2 and thus result in reduced normal protein expression levels lead to intellectual disability syndrome (ID) (23). Partial loss of functional mutations in the eIF2B subunit has been shown to be the cause of rare leukodystrophy-disappearing white matter disease (VWMD) (24, 25). Specifically, stabilization of partial loss of function of eIF2B in a VWMD mouse model with ISRIB-related small molecules has been shown to reduce ISR markers and improve functional endpoints, as well as pathological endpoints (26, 27).

[0010] A modulator of the eIF2 alpha pathway is described in Patent Document 1. Patent Documents 2, 3, 4, and 5 describe modulators of the integrated stress pathway. Patent Documents 6, 7, 8, 9, and 10 describe inhibitors of the ATF4 pathway. Patent Documents 11, 12, 13, 14, and 15 relate to eukaryotic initiation factor 2B modulators. Patent Document 16 describes compounds, compositions, and methods useful for modulating the integrated stress response (ISR) and for treating related diseases, disorders, and conditions.

[0011] Further literature describing modulators of integrated stress pathways can be found in Patent Documents 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, and 36.

[0012] A modulator of eukaryotic initiation factors is described in Patent Document 37. Patent Documents 38, 39, and 40 describe inhibitors of the integrated stress response pathway. Heteroaryl derivatives as ATF4 inhibitors are described in Patent Document 41. Bicyclic aromatic ring derivatives as ATF4 inhibitors are described in Patent Document 42. Patent Documents 43 and 44 describe inhibitors of the ATF4 pathway.

[0013] However, there is still a need for novel compounds that are useful as modulators of integrated stress response pathways with favorable pharmacokinetic properties. [Prior art documents] [Patent Documents]

[0014] [Patent Document 1] WO2014 / 144952A2 [Patent Document 2] WO2017 / 193030A1 [License 3] WO2017 / 193034A1 [License 4] WO2017 / 193041A1 [Patent Document 5] WO2017 / 193063A1 [License 6] WO2017 / 212423A1 [License 7] WO2017 / 212425A1 [License 8] WO2018 / 225093A1 [License 9] WO2019 / 008506A1 [License 10] WO2019 / 008507A1 [License 11] WO2019 / 032743A1 [License 12] WO2019 / 046779A1 [License 13] WO2020 / 167994A1 [License 14] WO2020 / 168011A1 [License 15] WO2020 / 181247A1 [License 16] WO2020 / 77217A1 [License 17] WO2019 / 090069A1 [License 18] WO2019 / 090074A1 [License 19] WO2019 / 090076A1 [Patent Document 20] WO2019 / 090078A1 [License 21] WO2019 / 090081A1 [License 22] WO2019 / 090082A1 [Patent Document 23] WO2019 / 090085A1 [Patent Document 24] WO2019 / 090088A1 [Patent Document 25] WO2019 / 090090A1 [Patent Document 26] WO2020 / 223536A1 [Patent Document 27] WO2020 / 223538A1 [Patent Document 28] WO2020 / 252207A1 [Patent Document 29] WO2020 / 252205A1 [Patent Document 30] European Patent Application 20203312.2 [Patent Document 31] European Patent Application 20203311.4 [Patent Document 32] European Patent Application 21192154.9 [Patent Document 33] WO2021 / 180774A1 [Patent Document 34] WO2021 / 151865A1 [Patent Document 35] WO2020 / 216764A1 [Patent Document 36] WO2020 / 216766A1 [Patent Document 37] WO2019 / 183589A1 [Patent Document 38] WO2019 / 118785A2 [Patent Document 39] WO2019 / 236710A1 [Patent Document 40] WO2020 / 176428A1 [Patent Document 41] WO2019 / 193540A1 [Patent Document 42] WO2019 / 193541A1 [Patent Document 43] WO2020 / 031107A1 [Patent Document 44] WO2020 / 012339A1 [Overview of the project] [Problems that the invention aims to solve]

[0015] Therefore, an object of the present invention is to provide a novel class of compounds as integrated stress response pathway modulators that may be effective in treating integrated stress response pathway-related disorders and may improve pharmaceutically relevant properties, including activity, solubility, selectivity, ADMET properties, and / or reduction of side effects. [Means for solving the problem]

[0016] Therefore, the present invention relates to formula (I) [ka] Compounds thereof, or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof (in the formula, R 1 is H or C 1~4 Alkyl, preferably H, where C 1~4 Alkyls are sometimes substituted with one or more halogens, one or more of the same or different; R 2 is H, F, or C 1~4 It is alkyl, and here, C 1~4 Alkyl atoms are sometimes substituted with one or more halogens, either the same or different; R 2a is H or F, preferably H; R 3 R is a phenyl or a 6-membered aromatic heterocycline, where R 3 This refers to one or more R, whether the same or different. 7 It is sometimes replaced by; R 7 These are halogen, CN, C(O)OR8 , OR 8 , C(O)R 8 , C(O)N(R 8 R 8a ), S(O)2N(R 8 R 8a ), S(O)N(R 8 R 8a ), S(O)2R 8 , S(O)R 8 , N(R 8 )S(O)2N(R 8a R 8b ), SR 8 , N(R 8 R 8a ), NO2, O(O)R 8 , N(R 8 )C(O)R 8a , N(R 8 )S(O)2R 8a , N(R 8 )S(O)R 8a , N(R 8 )C(O)OR 8a , N(R 8 )C(O)N(R 8a R 8b ), OCN(R 8 R 8a ), C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 It is an alkinyl, and here, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkinyl is the same or different one or more R 9 It is sometimes replaced by; R 8 , R 8a , R 8b H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Independently selected from the group consisting of alkynnyls, where C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynnyls are sometimes substituted with one or more halogens, one or more of the same or different; R 9is halogen, CN, C(O)OR 10 、OR 10 、C(O)R 10 、C(O)N(R 10 R 10a )、S(O)2N(R 10 R 10a )、S(O)N(R 10 R 10a )、S(O)2R 10 、S(O)R 10 、N(R 10 )S(O)2N(R 10a R 10b )、SR 10 、N(R 10 R 10a )、NO2、OC(O)R 10 、N(R 10 )C(O)R 10a 、N(R 10 )SO2R 10a 、N(R 10 )S(O)R 10a 、N(R 10 )C(O)N(R 10a R 10b )、N(R 10 )C(O)OR 10a 、or OC(O)N(R 10 R 10a ) and; R 10 、R 10a 、R 10b 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 the same or different one or more halogens; R 4 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 halogen, OH, and O-C 1~3Optionally substituted with one or more substituents selected from the group consisting of alkyl groups, where the substituents are the same or different; R 4a , R 4b , R 4c , R 5 H, halogen and C 1~4 Independently selected from the group consisting of alkyl groups; R 4d , R 4e H, OH, OC 1~4 Alkyl, halogen and C 1~4 Independently selected from the group consisting of alkyl groups; or R 4 Furthermore, R 4d and R 4e One of them forms a methylene or ethylene group; or R 4 and R 4c Does it form an ethylene group? or R 4b and R 4d It forms a covalent single bond; R 6 These are heterobisicrills with 7 to 12 members, where R 6 This refers to one or more R, whether the same or different. 11 It is sometimes replaced by; R 11 R 12 , OH, OR 12 , halogen or CN; R 12 is cyclopropyl, C 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 It is alkinyl, and here, R 12 This refers to one or more R, whether the same or different. 13 It is sometimes replaced by; R 13 is halogen, CN or OR 14 and; R 14 is H or C 1~4 It is alkyl, and here, C 1~4The alkyl group is provided (which may be substituted with one or more halogens, either the same or different). [Modes for carrying out the invention]

[0017] Surprisingly, the example compounds disclosed according to the present invention, when combined, possess desirable physicochemical properties and / or selectivity that help achieve beneficial therapeutic efficacy while limiting unintended reliability.

[0018] A variable or substituent can be selected from a group of different variants, and if such a variable or substituent appears more than once, each variant may be the same or different.

[0019] Within the meaning of this invention, the terms are used as follows:

[0020] The term "optionally substituted" means either unsubstituted or substituted. Generally, "one or more substituents" means one, two or three substituents, preferably one or two substituents, more preferably one substituent, although not limited to the above. Generally, these substituents may be the same or different. The term "one or more substituents" also means, for example, one, two, three, four or five substituents, preferably one, two, three or four substituents.

[0021] "Alkyl" refers to a straight or branched hydrocarbon chain. Each hydrogen atom of an alkyl carbon can be replaced by a substituent as further specified.

[0022] "Alkenyl" refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond. Each hydrogen atom of the alkenyl carbon can be replaced by substituents as further specified.

[0023] "Alkynyl" refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond. Each hydrogen atom of the alkynyl carbon can be replaced by a substituent as further specified.

[0024] "C 1~4 "Alkyl" refers to alkyl chains that, if present, have 1 to 4 carbon atoms at the ends of the molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or, when two parts of the molecule are linked by an alkyl group, for example, -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. 1~4 Each hydrogen atom of the alkyl carbon can be replaced by substituents as further specified. 1~3 The term "alkyl" is defined as appropriate.

[0025] "C 1~6 "Alkyl" refers to an alkyl chain, for example, one that has 1 to 6 carbon atoms at the ends of the molecule if present: C 1~4 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or, if two parts of the molecule are linked by an alkyl group, for example, -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. 1~6 Each hydrogen atom of the alkyl carbon can be replaced by substituents as further specified.

[0026] "C 2~6 "Alkenyl" refers to an alkenyl chain, for example, one that has 2 to 6 carbon atoms at the ends of the molecule if present: -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, -CH=CH-CH=CH2, or, if two parts of the molecule are linked by an alkenyl group, for example, -CH=CH-. 2~6Each hydrogen atom of the alkenyl carbon can be replaced by substituents as further specified.

[0027] "C 2~6 "Alkynyl" refers to, for example, an alkynyl chain having 2 to 6 carbon atoms at the ends of the molecule if present: -C≡CH, -CH2-C≡CH, CH2-CH2-C≡CH, CH2-C≡C-CH3, or, if two parts of the molecule are linked by an alkynyl group, for example, -C≡C-. 2~6 Each hydrogen atom of the alkynyl carbon can be replaced by substituents as further specified.

[0028] "C 3~7 "Cycloalkyl" or "C 3~7 "Cycloalkyl ring" means a cyclic alkyl chain having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, or cycloheptyl. Preferably, cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Each hydrogen atom of the cycloalkyl carbon can be replaced by substituents as further specified herein. 3~5 "Cycloalkyl" or "C 3~5 The term "cycloalkyl ring" is defined as appropriate.

[0029] "C5 cycloalkylene" refers to a divalent cycloalkyl group having five carbon atoms, i.e., a divalent cyclopentyl ring.

[0030] "C5 cycloalkenylene" refers to a divalent cycloalkenylene, i.e., a divalent cyclopentene or cyclopentadiene.

[0031] "C 4~12 "Bicycloalkyl" or "C 4~12The term "bicycloalkyl ring" means a bicyclic condensation, bridge, or spiroalkyl chain having 4 to 12 carbon atoms, such as hexahydroindan, octahydropentalene, bicyclic[2.2.1]heptane, or spiro(3.2)hexane. Each hydrogen atom of the bicycloalkyl carbon may be replaced by substituents as further specified herein.

[0032] "Halogen" refers to fluoro, chloro, bromo, or iodine. Generally, halogens are preferred to be fluoro or chloro.

[0033] A "3- to 7-membered heterocyclyl" or "3- to 7-membered heterocycle" means a ring having 3, 4, 5, 6, or 7 ring atoms, which can contain up to a maximum number of double bonds (aromatic or non-aromatic rings that are fully, partially, or unsaturated), where at least 1 to 4 ring atoms are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and the ring is linked to the rest of the molecule via carbon or nitrogen atoms. Examples of heterocycles with 3 to 7 members include aziridine, azetidine, oxetane, thietan, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazole, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidin, isothiazolidin, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidin, diazepane, azepine, or homopiperazine. The terms “5-membered to 6-membered heterocyclyl” or “5-membered to 6-membered heterocycle” are defined as appropriate and include 5-membered to 6-membered aromatic heterocyclyl or heterocycle.

[0034] The term "nitrogen ring atom-containing five-membered heterocyclene" refers to a divalent five-membered heterocycle in which at least one of the five ring atoms is a nitrogen atom and the ring is linked to the rest of the molecule via a carbon or nitrogen atom.

[0035] A "saturated 4- to 7-membered heterocyclyl" or "saturated 4- to 7-membered heterocycle" means a "4- to 7-membered heterocyclyl" or "4- to 7-membered heterocycle."

[0036] "A 4- to 7-membered heterocyclyl or a 4- to 7-membered heteroring" means a 4- to 7-membered heterocyclyl or a 4- to 7-membered heteroring that is at least partially saturated.

[0037] A "5- to 6-membered aromatic heterocyclyl" or "5- to 6-membered aromatic heterocycle" refers to a heterocycle derived from cyclopentadienyl or benzene, where at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-). Examples of such heterocycles include furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, and triazine.

[0038] A "five-membered aromatic heterocyclyl" or "five-membered aromatic heterocycle" refers to a heterocycle derived from cyclopentadienyl, where at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)- and -S(O)2-), oxygen, and nitrogen (including =N(O)-). Examples of such heterocycles include furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, and tetrazole.

[0039] A "six-membered aromatic heterocyclyl" or "six-membered aromatic heterocycle" refers to a heterocycle derived from benzene in which at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)- and -S(O)2-), oxygen, and nitrogen (including =N(O)-). Examples of such heterocycles are pyridine, pyrimidine, pyridazine, pyrazine, and triazine.

[0040] A "7- to 12-membered heterobicyryl" or "7- to 12-membered heterobicyclic" means a heterocyclic system of two rings having 7 to 12 ring atoms, where at least one ring atom is shared by both rings and the system may contain up to a maximum number of double bonds (aromatic or non-aromatic rings that are fully, partially, or unsaturated), and at least one ring atom, up to six ring atoms, are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and the ring is linked to the rest of the molecule via carbon or nitrogen atoms. Examples of heterobicyclic compounds with 7 to 12 members include indole, indoline, benzofuran, benzothiophene, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzimidazole, benzimidazolin, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine, or pteridine. The term seven- to twelve-membered heterobicycle includes spirostructures of two rings such as 6-oxa-2-azaspiro[3,4]octane, 2-oxa-6-azaspiro[3.3]heptane-6-yl, or 2,6-diazaspiro[3.3]heptane-6-yl, or bridging heterocycles such as 8-azabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane-2-yl, or 3,8-diazabicyclo[3.2.1]octane.

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

[0042] "7- to 12-membered heterobisicrills or 7- to 12-membered heterobicyclic rings" means at least partially saturated "7- to 12-membered heterobisicrills" or "7- to 12-membered heterobicyclic rings".

[0043] A "9- to 11-membered aromatic heterobisicryl" or "9- to 11-membered aromatic heterobicyclic" means a heterocyclic system of two rings, where at least one ring is aromatic, the heterocyclic system has 9 to 11 ring atoms, where two ring atoms are shared by both rings, and the system may contain up to a maximum number of double bonds (fully or partially aromatic), where at least one ring atom and up to six ring atoms are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and the ring is linked to the rest of the molecule via carbon or nitrogen atoms. Examples of 9- to 11-membered aromatic heterobicycles include indole, indoline, benzofuran, benzothiophene, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzimidazole, benzimidazolin, quinoline, quinazoline, dihydroquinazoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, dihydro-isoquinoline, benzazepine, purine, or pteridine. The terms "9- to 10-membered aromatic heterobicyclyl" or "9- to 10-membered aromatic heterobicycle" are defined as appropriate.

[0044] A preferred compound of formula (I) is a compound in which one or more residues contained herein have the meanings given above or below, and all combinations of the preferred substituent definitions are subject to the present invention. With respect to all preferred compounds of formula (I), the present invention also includes all tautomers and stereoisomers, mixtures thereof in all ratios, and pharmaceutically acceptable salts thereof.

[0045] In preferred embodiments of the present invention, the substituents described below independently have the following meanings. Therefore, one or more of these substituents may have the preferred or more preferred meanings given below.

[0046] Preferably, R 4 is H, CH3, CH2CH3, or CH2CH2OCH3; more preferably H or CH3; even more preferably H.

[0047] Preferably, R 4a , R 4b , R 4c , R 5 H, halogen and C 1~4 Independently selected from the group consisting of alkyl, R 4d , R 4e H, OH, OC 1~4 Alkyl, halogen and C 1~4 Independently selected from the group consisting of alkyl; more preferably, R 4a , R 4b , R 4c , R 5 , R 4d , R 4e is independently selected from the group consisting of H, F, and CH3; more preferably, R 4a , R 4b , R 4c , R 5 , R 4d , R 4e H is H.

[0048] Preferably, R 1 is H or CH3; more preferably H.

[0049] Preferably, R 2 is H, F, or CH3, more preferably H.

[0050] Preferably, R in formula (I) 1 , R 2 , R 2a , R 4 , R 4a , R 4b , R 4c , R 5 , R 4d , R 4e If is H, then we obtain equation (Ia): [ka]

[0051] Preferably, R 3 R is phenyl or pyridyl, preferably phenyl, where R 3 This refers to one or more R, whether the same or different. 7 It is sometimes replaced.

[0052] Preferably, R 3 R is one, two, or three, preferably one or two, more preferably two, the same or different R 7 It has been replaced with.

[0053] Preferably, R 9 It is a halogen.

[0054] Preferably, R 7 is F, Cl, Br, CN, CHF2, CF3, OCH3, OCF3, CH=O, CH2OH, or CH3; more preferably, R 7 is CF3, F, or Cl; more preferably F or Cl.

[0055] Preferably, R in formula (I) 1 , R 2 , R 2a , R 3 , R4 , R 4a , R 4b , R 4c , R 4d , R 4e , R 5 Equation (Ib): [ka] (In the formula, each R 7 (is selected independently from the group consisting of halogens and CF3).

[0056] Preferably, R 7 The base is selected in equation (Ib) such that we obtain equation (Ib1): [ka]

[0057] Preferably, R 6 These are quinazolinil, pyrrolo[1,2-a]pyradinil, 1,3-benzoxazolyl, pyrido[2,3-d]pyrimidinil, pyrido[3,4-d]pyrimidinil, pyrido[5,4-d]pyrimidinil, 1,2,3,4-tetrahydroquinolinil, chromanil, oxazolo[4,5-c]pyridinil, imidazo[1,2-a]pyridinil, [1,2,4]triazolo[1,5-a]pyridinil, imidazo[1,2-b]pyridadinil, or 6,7-dihydro-4H-pyrano[4,3-d]oxazolyl, where R 6 This refers to one or more R, whether the same or different. 11 It is sometimes replaced by R. 6 R is 1,3-benzoxazolyl or imidazo[1,2-a]pyridinyl, where R 6 This refers to one or more R, whether the same or different. 11 It is sometimes replaced by R. 6 is 1,3-benzoxazolyl, where R 6 This refers to one or more R, whether the same or different. 11 It is sometimes replaced.

[0058] Preferably, R 6 is either unsubstituted or one or two identical or different R 11 It has been replaced with.

[0059] Preferably, R 11 is Cl, CH3, CF3, CH2CF3, OCF3, OCHF2, or OCH2CF3. Preferably, R 11 These are Cl, CH3, CF3, CH2CF3, OCF3, or OCH2CF3.

[0060] Compounds of formula (I) in which some or all of the above-described groups have a preferred or more preferred meaning are also subject to the present invention.

[0061] In the preferred specific compounds of the present invention, or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers, R in formula (I) 1 , R 2 , R 2a , R 3 , R 4 , R 4a , R 4b , R 4c , R 4d , R 4e , R 5 , R 6 The following is selected: tert-butyl(2R,5S)-2-(6-chloro-1,3-benzoxazol-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-1-carboxylate; N-[(3S,6R)-6-(6-chloro-1,3-benzoxazole-2-yl)piperidine-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide; tert-butyl(2R,5S)-2-(5-chloro-1,3-benzoxazol-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-1-carboxylate; N-[(3S,6R)-6-(5-chloro-1,3-benzoxazole-2-yl)piperidine-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide; tert-butyl(2R,5S)-5-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-yl]piperidine-1-carboxylate; 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-yl]-3-piperidyl]acetamide; tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[7-(trifluoromethyl)imidazo[1,2-a]pyridine-2-yl]piperidine-1-carboxylate; 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[7-(trifluoromethyl)imidazo[1,2-a]pyridine-2-yl]-3-piperidyl]acetamide; tert-butyl(2R,5S)-2-(7-chloro-1,3-benzoxazol-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-1-carboxylate; N-[(3S,6R)-6-(7-chloro-1,3-benzoxazole-2-yl)piperidine-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide; tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[6-(trifluoromethoxy)-1,3-benzoxazole-2-yl]piperidine-1-carboxylate; 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[6-(trifluoromethoxy)-1,3-benzoxazole-2-yl]piperidine-3-yl]acetamide; tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[6-(difluoromethoxy)-1,3-benzoxazole-2-yl]piperidine-1-carboxylate; 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[6-(difluoromethoxy)-1,3-benzoxazole-2-yl]piperidine-3-yl]acetamide; tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[6-(trifluoromethyl)-1,3-benzoxazole-2-yl]piperidine-1-carboxylate; 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[6-(trifluoromethyl)-1,3-benzoxazole-2-yl]piperidine-3-yl]acetamide; tert-butyl(2R,5S)-2-(4-chloro-1,3-benzoxazol-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-1-carboxylate; or N-[(3S,6R)-6-(4-chloro-1,3-benzoxazole-2-yl)piperidine-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide.

[0062] If tautomerism can occur in a compound of formula (I), such as keto-enol tautomerism, then the individual forms, such as keto and enol forms, are included separately and together as mixtures in any ratio. The same applies to stereoisomers, such as enantiomers, cis / trans isomers, and conformational isomers.

[0063] In particular, when an enantiomer or diastereomer form is shown in a compound according to formula (I), each pure form separately, and any mixture of at least two pure forms in any ratio, are included by formula (I) and are the subject of the present invention.

[0064] A preferred compound is formula (Ic) [ka] The compound of formula (I) having the relative stereoconfiguration as shown, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0065] Isotope-labeled compounds of formula (I) are also within the scope of the present invention. Methods for isotope labeling are known in the art. Preferred isotopes are those of the elements H, C, N, O, and S. Solvates and hydrates of compounds of formula (I) are also within the scope of the present invention.

[0066] If desired, isomers can be separated by methods well known in the art, for example, by liquid chromatography. The same applies to enantiomers, for example, by using a chiral stationary phase. Additionally, enantiomers can be isolated by converting them to diastereomers, i.e., by coupling with an enantiomerically pure auxiliary compound, followed by separation of the resulting diastereomer and cleavage of the auxiliary residue. Alternatively, any enantiomer of the compound of formula (I) can be obtained by stereoselective synthesis using optically pure starting materials, reagents and / or catalysts.

[0067] Where a compound according to formula (I) contains one or more acidic or basic groups, the present invention also includes corresponding pharmaceutically or toxicologically acceptable salts thereof, in particular pharmaceutically usable salts thereof. Thus, compounds of formula (I) containing acidic groups can be used according to the present invention, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More precise 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. Compounds of formula (I) containing one or more basic groups, i.e., protonable groups, can exist and can be used according to the present invention in the form of addition salts thereof with inorganic or organic acids. 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, vivariic 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 acidic and basic groups in its molecule, the present invention also includes internal salts or betaines (amphoteric ions) in addition to the salt forms described. Each salt according to formula (I) can be obtained by conventional 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) that, 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.

[0068] As shown below, the compounds of the present invention are considered suitable for modulating the integrated stress response pathway.

[0069] The integrated stress response (ISR) is a cellular stress response common to all eukaryotes (1). Dysregulation of ISR signaling has significant pathological consequences, particularly leading to inflammation, viral infections, diabetes, cancer, and neurodegenerative diseases.

[0070] ISR is a common factor of different types of cellular stress that results in phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2 alpha) on serine 51, leading to the suppression of normal protein synthesis and the expression of stress response genes (2). In mammalian cells, this phosphorylation is carried out by a family of four eIF2 alpha kinases, each responding to distinct environmental and physiological stresses: PKR-like ER kinase (PERK), double-stranded RNA-dependent protein kinase (PKR), heme-regulated eIF2 alpha kinase (HRI), and generalized unrepressive 2 (GCN2) (3).

[0071] eIF2 alpha, along with eIF2 beta and eIF2 gamma, forms the eIF2 complex, a key player in the initiation of normal mRNA translation (4). The eIF2 complex connects GTP and Met-tRNA i The ternary complex (eIF2-GTP-Met-tRNA) is formed by binding to the ribosome and being recruited for translation initiation. i ) forms (5, 6).

[0072] eIF2B is a heterodecameric complex consisting of five subunits (alpha, beta, gamma, delta, and epsilon) that duplicate and form a GEF-active decamer (7).

[0073] In response to ISR activation, phosphorylated eIF2-alpha inhibits the eIF2B-mediated exchange of GDP with GTP, resulting in reduced ternary complex formation and, therefore, inhibition of translation of normal mRNAs characterized by ribosomes bound to the 5'AUG start codon (8). Under these conditions of reduced ternary complex abundance, the translation of several specific mRNAs, including mRNA encoding the transcription factor ATF4, is activated via a mechanism involving alteration of translation of upstream ORFs (uORFs) (7, 9, 10). These mRNAs typically contain one or more uORFs that function normally in non-stress cells, restricting ribosome flow to the primary encoding ORF. For example, under normal conditions, the uORF at the 5'UTR of ATF occupies the ribosome, preventing translation of the ATF4 coding sequence. However, under stress conditions, i.e., under reduced ternary complex formation, the probability of ribosomes scanning these upstream ORFs and initiating translation at the ATF4 coding ORF increases. ATF4 and other stress response factors expressed in this manner subsequently govern the expression of an array of further stress response genes. The acute phase involves the expression of proteins aimed at restoring homeostasis, while the chronic phase leads to the expression of pro-apoptotic factors (1, 11, 12, 13).

[0074] Upregulation of ISR signaling markers has been demonstrated in various conditions among these cancers and neurodegenerative diseases. In cancer, ER stress-modulating translation increases tolerance to hypoxic conditions and promotes tumor growth (14, 15, 16), and deletion of PERK by gene targeting leads to transformed PERK - / -It has been shown to slow tumor growth induced from mouse embryonic fibroblasts (14, 17). Furthermore, recent reports have provided proof of concept that activators of eIF2B are effective in treating morphologies of invasive metastatic prostate cancer using patient-derived xenograft models in mice (28). Taken together, inhibition of cytoprotective ISR signaling may represent an effective antiproliferative strategy for treating at least some morphologies of cancer.

[0075] Furthermore, modulation of ISR signaling has been shown to be effective in preserving synaptic function and reducing neuronal decline, as well as in neurodegenerative diseases characterized by the activation of misfolded and unfolded protein responses (UPRs), such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD), and Jacobukureutzfeldt (prion) diseases (18, 19, 20). Regarding prion diseases, there are examples of neurodegenerative diseases in which pharmacological inhibition, as well as genetic inhibition, of ISR signaling has been shown to normalize protein translation levels, rescue synaptic function, and prevent neuronal loss (21). Specifically, reduction of phosphorylated eIF2 alpha levels by overexpression of a phosphatase that controls phosphorylated eIF2 alpha levels increased survival time in prion-infected mice, while maintained eIF2 alpha phosphorylation decreased survival time (22).

[0076] Furthermore, direct evidence exists regarding the importance of regulating protein expression levels for proper brain function in the form of rare genetic disorders affecting the function of eIF2 and eIF2B. Mutations in eIF2 gamma that disrupt the complex integrity of eIF2 and thus result in reduced normal protein expression levels lead to intellectual disability syndrome (ID) (23). Partial loss of functional mutations in the eIF2B subunit has been shown to be the cause of rare leukodystrophy-disappearing white matter disease (VWMD) (24, 25). Specifically, stabilization of partial loss of function of eIF2B in a VWMD mouse model with ISRIB-related small molecules has been shown to reduce ISR markers and improve functional endpoints, as well as pathological endpoints (26, 27).

[0077] The present invention provides the compounds of the present invention in free form, pharmaceutically acceptable salt form, or in the form of solvates, hydrates, tautomers, or stereoisomers for use in the treatment of diseases or disorders described herein. The same applies to the pharmaceutical compositions of the present invention.

[0078] Accordingly, one 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 pharmaceutical. The same applies to a pharmaceutical composition of the present invention.

[0079] The treatment methods described can be applied to mammals such as dogs, cats, cattle, horses, rabbits, monkeys, and humans. Preferably, the mammalian patient is a human patient.

[0080] Accordingly, the present invention provides compounds of the present invention, or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, or pharmaceutical compositions for use in the treatment or prevention of one or more diseases or disorders associated with the integrated stress response.

[0081] Further aspects of the present invention include the compounds of the present invention, or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, or pharmaceutical compositions for use in methods of treating or preventing one or more disorders or diseases associated with integrated stress response.

[0082] A further aspect of the present invention is the use of the compounds of the present invention, or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, or pharmaceutical compositions for the manufacture of pharmaceuticals for the treatment or prevention of one or more disorders or diseases associated with integrated stress response.

[0083] Another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient requiring treatment of one or more diseases or disorders related to the integrated stress response, the method comprising administering to the patient a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition thereof.

[0084] The present invention provides compounds of the present invention, or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, or pharmaceutical compositions for use in the treatment or prevention of one or more diseases or disorders described below.

[0085] Further aspects of the present invention are compounds of the present invention, or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, or pharmaceutical compositions for use in methods of treating or preventing one or more disorders or diseases described below.

[0086] A further aspect of the present invention is the use of the compounds of the present invention, or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, or pharmaceutical compositions for the manufacture of pharmaceuticals for the treatment or prevention of one or more disorders or diseases described below.

[0087] Further aspects of the present invention are methods for treating, controlling, delaying or preventing in a mammalian patient requiring treatment of one or more of the diseases or disorders described below, the methods comprising administering to the patient a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition thereof.

[0088] Diseases or disorders include, but are not limited to, leukodystrophy, intellectual disability syndromes, neurodegenerative diseases and disorders, neoplasms, infectious diseases, inflammatory diseases, musculoskeletal diseases, metabolic diseases, ocular diseases, as well as organ fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lungs, chronic and acute diseases of the kidneys, myocardial infarction, cardiovascular diseases, arrhythmias, atherosclerosis, spinal cord injury, ischemic stroke, and neuropathic pain.

[0089] Leukodystrophy Examples of leukodystrophy include, but are not limited to, vanishing white matter disease (VWMD) with CNS hypomyelination and childhood ataxia (e.g., associated with a deficiency in the function of eIF2 or a component in signaling or signaling pathways including eIF2).

[0090] Intellectual disability syndrome Intellectual disability refers specifically to a condition in which a person has certain limitations in intellectual functions such as communicating and caring for oneself, and / or has a deficit in social skills. Intellectual disability syndromes include, but are not limited to, intellectual disability conditions associated with a deficit in the function of eIF2 or signaling or components in signaling pathways including eIF2.

[0091] Neurodegenerative diseases / disorders Examples of neurodegenerative diseases and disorders include, but are not limited to, Alexander disease, Alpers disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxic telangiectasia, Batten disease (also known as Spielmeier-Voigt-Sjögren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Streussler-Scheinker syndrome, Huntington's disease, HIV-related dementia, Kennedy disease, Krabbe disease, and Coeurl. These include Lou, Lewy body dementia, Machad-Joseph disease (spinocerebellar degeneration type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar degeneration (multiple types with fluctuating characteristics), spinal muscular atrophy, Steele-Richardson-Olsewski disease, spinal fistula, and tauopathy.

[0092] In particular, neurodegenerative diseases and disorders are selected from the group consisting of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

[0093] Neoplastic disease Neoplastic diseases can be understood in their broadest sense as any tissue resulting from misregistration of cell growth. Often, neoplasms progress to at least bulky tissue tumors, sometimes innervated by blood vessels. They may or may not involve the formation of one or more metastases. The neoplastic diseases of this invention may be any neoplasm as classified by the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) Classification C00-D48.

[0094] For example, the neoplastic disease according to the present invention may be the presence of one or more malignant neoplasms (single or multiple) (tumors) (ICD-10 classification C00-C97), one or more in situ neoplasms (single or multiple) (ICD-10 classification D00-D09), one or more benign neoplasms (single or multiple) (ICD-10 classification D10-D36), or one or more neoplasms (single or multiple) exhibiting uncertain or unknown behavior (ICD-10 classification D37-D48). Preferably, the neoplastic disease according to the present invention refers to the presence of one or more malignant neoplasms (single or multiple), i.e., malignant neoplasms (ICD-10 classification C00-C97).

[0095] In a more preferred embodiment, the neoplasm is cancer.

[0096] Cancer, in its broadest sense, can be understood as any malignant neoplasm in a patient, i.e., the presence of one or more malignant neoplasms. Cancer can be solid or hematological malignancies. The cancers discussed herein are, without limitation, leukemia, lymphoma, carcinoma, and sarcoma.

[0097] In particular, neoplasms such as cancers characterized by upwardly modulated ISR markers are included in this specification.

[0098] Illustrative cancers include, but are not limited to, thyroid cancer, endocrine cancer, pancreatic 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, tubular 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 carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), colon cancer, esophageal cancer, gastric cancer, bladder cancer, bone cancer, prostate cancer, and skin cancer (e.g., melanoma).

[0099] Further examples include, but are not limited to, myeloma, leukemia, mesothelioma, and sarcoma.

[0100] Additional examples include, but are not limited to, medulloblastoma, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumor, malignant pancreatic insulinoma, malignant carcinoid, urinary vesicle cancer, pre-malignant skin lesions, testicular cancer, lymphoma, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, Paget's disease of the nipple, phyllodes tumor, lobular carcinoma, tubular carcinoma, pancreatic stellate cell carcinoma, and hepatic stellate cell carcinoma.

[0101] Illustrative leukemias include, but are not limited to, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, nonleukocytic leukemia, basophilic leukemia, blastocyte leukemia, bovine leukemia, chronic myelocytic leukemia, cutaneous leukemia, embryonic leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, and acute monocytic leukemia. These include leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphotropic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocyte leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli's leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, leader cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemia, and anaplastic cell leukemia.

[0102] Illustrative sarcomas include, but are not limited to, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemesy's sarcoma, liposarcoma, lipid sarcoma, alveolar soft tissue sarcoma, ameloblastic sarcoma, staphyloid sarcoma, greenish sarcoma, choriocarcinoma, embryonic sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fasciosarcoma, fibroblastic sarcoma, and giant sarcoma. These include cell sarcomas, granulocytic sarcomas, Hodgkin's sarcomas, idiopathic multiple pigmented hemorrhagic sarcomas, B-cell immunoblastic sarcomas, lymphomas, T-cell immunoblastic sarcomas, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemosarcoma, malignant mesenchymal sarcoma, paraosteal sarcoma, reticular sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and peripheral telangiectatic sarcomas.

[0103] Illustrative melanomas include, but are not limited to, acral lentiginous melanoma, achromatic melanoma, benign juvenile melanoma, Cloudmann melanoma, S91 melanoma, Harding-Passé melanoma, juvenile melanoma, lentigo malignant melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma.

[0104] Symptomatic carcinomas include, but are not limited to, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenal cortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell carcinoma, basal basal carcinoma, basal squamous cell carcinoma, bronchoalveolar carcinoma, bronchiololar carcinoma, bronchogenic lung carcinoma, cerebral carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedone carcinoma, corpus carcinoma, cribriform carcinoma, armory carcinoma, skin carcinoma, cylindrical carcinoma, cylindrical cell carcinoma, tubular carcinoma, tubular carcinoma, compact carcinoma (carcinoma) Durum carcinoma, embryonic carcinoma, cerebral carcinoma, epidermal carcinoma, epithelial adenoid carcinoma, extrinsic carcinoma, preulative ulcer carcinoma (carcinoma ex ulcere), fibrous carcinoma, gelatinous carcinoma, gelatinous carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, piloma carcinoma, hematoid carcinoma, hepatocellular carcinoma, Haasle cell carcinoma, hyaline carcinoma, high renal carcinoma, infantile carcinoma, carcinoma in situ, carcinoma in epidermis, carcinoma in situ Carcinoma, Krompecher carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma, mucinous adenocarcinoma (carcinoma muciparum), mucocellular carcinoma (carcinoma mucocellulare), mucoepidermal carcinoma, mucinous carcinoma, mucinous carcinoma, myxomatous carcinoma (carcinoma Myxomatodes include nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, gooey 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, solenoid carcinoma, bulbous cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous carcinoma, squamous cell carcinoma, linear carcinoma, telangiectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma, tubular carcinoma, nodular carcinoma, verrucous carcinoma, and choriocarcinoma.

[0105] infectious disease Examples include, but are not limited to, infections caused by viruses (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 1; CHIKV: chikungunya virus; HCMV: human cytomegalovirus; SARS-CoV: severe acute respiratory syndrome coronavirus; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2 infections, etc.), and infections caused by bacteria (Legionella, Brucella, Simkania, Chlamydia, Helicobacter, and Campylobacter infections, etc.).

[0106] inflammatory diseases Examples of inflammatory diseases include, but are not limited to, postoperative cognitive impairment (decline in cognitive function after surgery), traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes mellitus, type 1 diabetes mellitus, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, and glomeruli. These include nephritis, 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, transplant rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis.

[0107] Musculoskeletal disorders Examples of musculoskeletal disorders include, but are not limited to, muscular dystrophy, multiple sclerosis, ataxia Friedrich, muscle wasting disorders (e.g., muscle atrophy, sarcopenia, cachexia), inclusion body myopathy, progressive muscular atrophy, motor neuron disease, carpal tunnel syndrome, epicondylitis, tendinitis, back pain, muscle pain, muscle soreness, repetitive tonic disorders, and paralysis.

[0108] metabolic disease Examples of metabolic diseases include, but are not limited to, diabetes mellitus (especially type II diabetes mellitus), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), Niemann-Pick disease, hepatic fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, and Kearns-Thayer disease.

[0109] eye disease Examples of ocular diseases include, but are not limited to, edema or neovascularization related to any obstructive or inflammatory retinal vascular disorder, e.g., iris neovascularization, neovascular glaucoma, pterygium, neovascularization of glaucoma filtering vesicles, conjunctival papilloma; choroidal neovascularization, e.g., neovascular age-related macular degeneration (AMD), myopia, pre-uveitis, trauma, or idiopathic; macular edema, e.g., postoperative macular edema, secondary to uveitis, including retinal and / or choroidal inflammation. Macular edema, macular edema secondary to diabetes, and macular edema secondary to retinal vascular occlusive disease (i.e., retinal branch and central retinal vein occlusion); retinal neovascularization due to diabetes, e.g., retinal vein occlusion, uveitis, ischemic syndrome of the eye originating from carotid artery disease, ocular or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathy, retinopathy of prematurity, or Eels disease; and genetic disorders, e.g., von Hippel-Lindau syndrome.

[0110] Further diseases Further conditions include, but are not limited to, organ fibrosis (such as hepatic fibrosis, pulmonary fibrosis, or renal fibrosis), chronic and acute diseases of the liver (such as fatty liver disease or hepatic steatohepatosis), chronic and acute diseases of the lungs, chronic and acute diseases of the kidneys, myocardial infarction, cardiovascular disease, arrhythmias, atherosclerosis, spinal cord injury, ischemic stroke, and neuropathic pain.

[0111] 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 biologically active compounds or pharmaceutical compositions.

[0112] Preferably, one or more bioactive compounds are modulators of integrated stress response pathways other than the compound of formula (I).

[0113] "Pharmaceutical composition" means one or more active ingredients, one or more inactive ingredients constituting a carrier, as well as any products directly or indirectly resulting from any combination of two or more ingredients, complexation or aggregation, or dissociation of one or more ingredients, or other types of reactions or interactions of one or more ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition prepared by adding and mixing the compounds of the present invention with a pharmaceutically acceptable carrier.

[0114] The pharmaceutical compositions of the present invention may include one or more additional compounds as active ingredients, such as a mixture of compounds of formula (I) in the composition or other modulators of the integrated stress response pathway.

[0115] The active ingredient may be contained in one or more different pharmaceutical compositions (combinations of pharmaceutical compositions).

[0116] The term "pharmaceutically acceptable salt" refers to a salt produced from a pharmaceutically acceptable, non-toxic base or acid, including inorganic and organic bases or acids.

[0117] Examples of compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (intranasal or buccal inhalation), or intranasal administration include those suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), etc., but the most appropriate route in any given case depends on the nature and severity of the condition being treated and the nature of the active ingredient. Conveniently, they exist in unit dosage forms and can be manufactured by any method well known in the art of pharmaceuticals.

[0118] In practical use, the compound of formula (I) can be combined as an active ingredient in a closely compounded mixture with a pharmaceutical carrier, according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms, depending on the desired form of the product for administration, e.g., orally or parenterally (including intravenously). When preparing compositions for oral dosage forms, any of the usual pharmaceutical media, such as water, glycol, oil, alcohol, flavoring agents, preservatives, and colorants, can be used in the case of oral liquid products such as suspensions, elixirs, and solutions; or carriers, such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants, can be used in the case of oral solid products such as powders, hard and soft capsules, and tablets, with solid oral products being preferred over liquid products.

[0119] Due to their ease of administration, tablets and capsules represent the most advantageous oral dose unit forms, in which case solid pharmaceutical carriers are obviously used. If desired, tablets can be coated by standard aqueous or non-aqueous techniques. Such compositions and products 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 may, conveniently, be between about 2 percent and about 60 percent of the weight of the unit. The amount of the active compound in such therapeutically useful compositions is such that an effective dose is obtained. The active compound can also be administered intranasally, for example, as liquid drops or sprays.

[0120] Tablets, pills, capsules, etc. may also contain a binder, such as tragacanth gum, acacia, corn starch, or gelatin; an excipient, such as dicalcium phosphate; a disintegrant, such as corn starch, potato starch, or alginic acid; a lubricant, such as magnesium stearate; and a sweetener, such as sucrose, lactose, or saccharin. If the dosage unit form is a capsule, it may contain a liquid carrier, such as fatty oil, in addition to the materials of the above types.

[0121] 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. In addition to the active ingredient, syrups or elixirs may contain sucrose as a sweetener, methyl and propylparabens as preservatives, and dyes and flavorings such as cherry or orange flavoring.

[0122] The compounds of formula (I) can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water appropriately mixed with a surfactant such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerin, liquid polyethylene glycol, and mixtures thereof in oil. Under normal storage and use conditions, these preparations contain preservatives to prevent microbial growth.

[0123] Suitable pharmaceutical forms for injectable use include sterile aqueous solutions or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. In all cases, the form should be sterile and fluid to the extent that it is readily available for syringe injection. It should be stable under manufacturing and storage conditions and protected against contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerin, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0124] Any suitable route of administration can be used to provide an effective dose of the compound of the present invention to mammals, particularly humans. For example, oral, rectal, topical, parenteral, ocular, lung, or nasal administration may be used. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, and aerosols. Preferably, the compound of formula (I) is administered orally.

[0125] The effective dose of the active ingredient used can vary depending on the specific compound used, the mode of administration, the condition being treated, and the severity of the condition being treated. Such doses can be easily determined by those skilled in the art.

[0126] Starting materials for the synthesis of preferred embodiments of the present invention can be purchased from commercially available sources such as Array, Sigma Aldrich, Acros, Fisher, Fluka, and ABCR, or can be synthesized using methods known to those skilled in the art.

[0127] In general, several methods are applicable to the preparation of the compounds of the present invention. In some cases, various strategies are combined. Sequential or convergent pathways are used. Illustrative synthetic pathways are described below. [Examples]

[0128] I Chemical Synthesis Experimental procedure: The following abbreviations and acronyms are used: AQ water-based ACN Acetonitrile Acetic acid (ACOH) Brine: A saturated solution of NaCl in water. BnONH2·HCl O-benzylhydroxylamine hydrochloride Boc tert-butoxycarbonyl Boc2O di-tert-butyl dicarbonate CDCl3 (deuterated chloroform) CV column volume DCM Dichloromethane DCE 1,2-Dichloroethane DIAD Diisopropyl Azodicarboxylate DMSO (Dimethyl Sulfoxide) DMSO-d6 Deuterated Dimethyl Sulfoxide DIPEA N,N-diisopropylethylamine DMF Dimethylformamide DMAP N,N-dimethylpyridine-4-amine ESI + Positive ionization mode ESI - Negative ionization mode HCl ethyl acetate EtOH Ethanol Et2O Diethyl ether FCC Flash column chromatography H2O Water H2SO4 Sulfuric acid HATU 1-[Bis(dimethylamino)methylidene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate HCl Hydrochloric acid HPLC High-performance liquid chromatography h Hour(s) (singular or plural) KHCO3 Potassium bicarbonate LiOH·H2O Lithium hydroxide hydrate LiHMDS Lithium bis(trimethylsilyl)amide m Multiplet MeOH Methanol MeMgBr Methylmagnesium bromide MgSO4 Potassium sulfate MHz Megahertz min Minute(s) MsOH Methanesulfonic acid mL Milliliter(s) (singular or plural) N2 Nitrogen atmosphere Na2SO4 Sodium sulfate NaHCO3 Sodium bicarbonate NBS N-Bromosuccinimide NH4Cl Ammonium chloride NMR Nuclear magnetic resonance PPh3 Triphenylphosphine prep. Preparative r.t. Room temperature RT Retention time satd Saturated TBME 2-Methoxy-2-methylpropane THF Tetrahydrofuran TMSOI Trimethylsulfoxonium iodide TMSCI Chlorotrimethylsilane ZnBr2 Zinc bromide

[0129] The LCMS conditions for analysis are as follows:

[0130] System 1 (S1): Acidic IPC method (MS18 and MS19) Analytical HPLC-MS (MET / CR / 1410) was performed on a Shimadzu LCMS system using a Kinetex Core shell C18 column (2.1 mm × 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) over 1.2 minutes, followed by a gradient of 100% B over 0.1 minutes. A second gradient of 100–5% B was then applied over 0.01 minutes with an injection volume of 3 μL at a flow rate of 1.2 mL / min. The UV spectrum was recorded at 215 nm using an SPD-M20A photodiode array detector with a spectral range of 200–400 nm. The mass spectrum was obtained using a 2010 EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0131] System 2 (S2): Acidic IPC methods (MSQ1, MSQ2, MSQ4 and MSQ6): Analytical (MET / uPLC / 1704) uHPLC-MS was performed on a Waters Acquity uPLC system using a Waters UPLC® BEH® C18 column (2.1 mm × 50 mm, 1.7 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) over 1.1 minutes, followed by a gradient of 100% B over 0.25 minutes. A second gradient of 100–5% B was then applied over 0.05 minutes and held at a flow rate of 0.9 mL / min with an injection volume of 1 μL for 0.1 minutes. The UV spectrum was recorded at 215 nm on a Waters Acquity PDA using the spectral range of 200–400 nm. Mass spectra were obtained using Waters QDa. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0132] System 3 (S3): Basic IPC method (MS16) Analytical (MET / CR / 1602) uHPLC-MS was performed on a Waters Acquity uPLC system using a Waters UPLC® BEH® C18 column (2.1 mm × 30 mm, 1.7 μm; temperature 40°C) and a gradient of 5–100% B (A: 2 mM ammonium bicarbonate, buffered to pH 10, B: ACN) over 0.75 minutes, followed by a gradient of 100% B over 0.1 minutes. A second gradient of 100–5% B was then applied over 0.05 minutes and held at a flow rate of 1 mL / min with an injection volume of 1 μL for 0.1 minutes. The UV spectrum was recorded at 215 nm on a Waters Acquity PDA using the spectral range of 200–400 nm. Mass spectra were obtained using a Waters Quattro Premier XE. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0133] System 4 (S4): Acidic final method (MSQ1 and MSQ2) Analytical (MET / uPLC / AB101) uHPLC-MS was performed on a Waters Acquity uPLC system using a Phenomenex Kinetex-XB C18 column (2.1 mm × 100 mm, 1.7 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) over 5.3 minutes, followed by a gradient of 100% B over 0.5 minutes. A second gradient of 100–5% B was then applied over 0.02 minutes and held at a flow rate of 0.6 mL / min with an injection volume of 1 μL for 1.18 minutes. The UV spectrum was recorded at 215 nm using a Waters Acquity PDA detector with a spectral range of 200–400 nm. Mass spectra were obtained using Waters SQD (MSQ1) or Waters Acquity QDA (MSQ2). Waters MassLynx and OpenLynx software were used to integrate and report the data.

[0134] System 5 (S5): Acidic final method (MS18, MS19) Analytical (MET / CR / 1416) HPLC-MS was performed on a Shimadzu LCMS system using a Waters Atlantis dC18 column (2.1 mm × 100 mm, 3 μm; temperature: 40°C) with a gradient of 5–100% B (A = 0.1% formic acid in H2O; B = 0.1% formic acid in ACN) over 5 minutes, followed by 100% B for 0.4 minutes. A second gradient of 100–5% B was then applied over 0.02 minutes and held for 1.58 minutes at a flow rate of 0.6 mL / min with an injection volume of 3 μL. The UV spectrum was recorded at 215 nm using an SPD-M20A photodiode array detector with a spectral range of 200–400 nm. The mass spectrum was obtained using a 2010 EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0135] System 6 (S6): Basic final method (MS16) Analytical (MET / uHPLC / AB105) uPLC-MS was performed on a Waters Acquity uPLC system using a Waters UPLC® BEH® C18 column (2.1 mm × 100 mm, 1.7 μm column; temperature: 40°C) and a gradient of 5–100% (A = 2 mM ammonium bicarbonate, buffered at pH 10; B = ACN) over 5.3 minutes, followed by a 100% B gradient over 0.5 minutes. A second gradient of 100–5% B was then applied over 0.02 minutes and held for 1.18 minutes at an injection volume of 1 μL and a flow rate of 0.6 mL / min. The UV spectrum was recorded at 215 nm using a Waters Acquity photodiode array detector with a spectral range of 200–400 nm. The mass spectrum was obtained using a Waters Quattro Premier XE mass detector. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0136] The purification method is as follows: Method 1: Acidic initial method On a Gilson LC system, purification (P1) LC was performed using a Waters Sunfire C18 column (30 mm × 100 mm, 10 μM; temperature: room temperature), and a gradient of 10 - 95% B (A = 0.1% formic acid in H2O; B = 0.1% formic acid in ACN) over 14.44 minutes followed by 95% B for 2.11 minutes. A second gradient of 95 - 10% B was then applied over 0.2 minutes at a flow rate of 40 mL / min with an injection volume of 1500 μL. The UV spectrum was recorded at 215 nm using a Gilson detector.

[0137] Method 2: Acidic Standard Method On a Gilson LC system, purification (P2) LC was performed using a Waters Sunfire C18 column (30 mm × 10 mm, 10 μM; temperature: room temperature), and a gradient of 30 - 95% B (A = 0.1% formic acid in water; B = 0.1% formic acid in ACN) over 11.00 minutes followed by 95% B for 2.10 minutes. A second gradient of 95 - 30% B was then applied over 0.2 minutes at a flow rate of 40 mL / min with an injection volume of 1500 μL. The UV spectrum was recorded at 215 nm using a Gilson detector.

[0138] Method 3: Basic Initial Method On a Gilson LC system, purification (P3) LC was performed using a Waters X - Bridge C18 column (30 mm × 100 mm, 10 μM; temperature: room temperature), and a gradient of 10 - 95% B (A = 0.2% NH4OH in H2O; B = 0.2% NH4OH in ACN) over 14.44 minutes followed by 95% B for 2.11 minutes. A second gradient of 95 - 10% B was then applied over 0.2 minutes at a flow rate of 40 mL / min with an injection volume of 1500 μL. The UV spectrum was recorded at 215 nm using a Gilson detector.

[0139] Method 4: Basic Standard Method Purification (P4) LC was performed on a Gilson LC system using a Waters X-Bridge C18 column (30 mm × 10 mm, 10 μM; temperature: room temperature) and a gradient of 30–95% B (A = 0.2% NH4OH in water; B = 0.2% NH4OH in ACN) over 11.00 minutes, followed by a gradient of 95% B over 2.10 minutes. A second gradient of 95–30% B was then applied over 0.21 minutes with an injection volume of 1500 μL at a flow rate of 40 mL / min. The UV spectrum was recorded at 215 nm using a Gilson detector.

[0140] Method 5: Reverse-phase chromatography using acidic pH, standard elution method Purification by FCC on reversed-phase silica (acidic pH, standard elution method) was performed on a Biotage Isolera system using a suitable SNAP C18 cartridge and gradients of 10% B (A = 0.1% formic acid in H2O; B = 0.1% formic acid in ACN) above 1.7 CV, followed by 10-100% B above 19.5 CV, and 100% B above 2 CV.

[0141] Method 6: Reverse-phase chromatography using basic pH, standard elution method Purification by FCC on reversed-phase silica (basic pH, standard elution method) was performed on a Biotage Isolera system using an appropriate SNAP C18 cartridge and gradients of 10% B (A = 0.1% NH3 in H2O; B = 0.1% NH3 in ACN) above 1.7 CV, followed by 10-100% B above 19.5 CV, and 100% B for 2 CV.

[0142] NMR conditions Unless otherwise specified, 1¹H NMR spectra were recorded at 500 MHz, 400 MHz, or 250 MHz using one of the following Bruker Avance III HD 500 MHz, Bruker Avance III HD 400 MHz, or Bruker Avance III HD 250 MHz spectrometers, respectively. Chemical shift δ is expressed in parts per million (ppm), with the residual solvent peak as the reference. The following abbreviations are used to indicate multiplicity and general assignment: s (singlet), d (doublet), t (triplet of doublets), ddd (doublet of doublets), dt (triplet of doublets), dq (quartet of doublets), hep (heptet), m (multiplet), pent (pentet), td (doublet of triplets), qd (doublet of quartet), app. (apparent), and br. (broad). The coupling constant J is shown at the closest frequency, 0.1 Hz.

[0143] General synthesis: All compounds were synthesized with a purity of >95% unless otherwise specified.

[0144] Scheme for Route 1 [ka]

[0145] Step 1.a: Ethyl(2R)-5-[(benzyloxy)imino]-2-{[(tert-butoxy)carbonyl]amino}-6-chlorohexanoate [ka] DMSO (75 mL) is used to dissolve TMSOI (12.89 g, 58.3 mmol) in THF (anhydrous, 60 mL) and tThe mixture was added to a solution of BuOK (6.27 g, 55.9 mmol) and stirred at room temperature for 1 hour. The reaction mixture was cooled to -12°C, and a solution of ethyl Boc-D-pyroglutamate (12.5 g, 48.6 mmol) in THF (anhydrous, 38 mL) was added and stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous NH4Cl (80 mL), H2O (15 mL), and HCl (200 mL), the organic layer was isolated, washed with brine, and concentrated to approximately 100 mL under vacuum. A solution of BnONH2·HCl (8.14 g, 51.0 mmol) in HCl (62 mL) was added and the mixture was stirred under reflux for 2 hours. The reaction mixture was cooled to room temperature, washed with H2O and brine, and the organic layer was concentrated under vacuum to obtain the title compound as a colorless oil (85% purity, 19.5 g, 40.1 mmol, 83% yield); 1 H NMR (400 MHz, chloroform-d) δ 7.16 - 7.33 (m, 5H), 5.01 - 5.06 (m, 2H), 3.95 - 4.30 (m, 5H), 2.32 - 2.50 (m, 2H), 1.98 - 2.13 (m, 1H), 1.75 - 1.92 (m, 1H),1.30 - 1.40 (m, 9H), 1.12 - 1.24 (m, 3H),

[0146] Step 1.b: Ethyl(2R)-5-[(benzyloxy)imino]piperidine-2-carboxylate [ka] To a solution of ethyl(2R)-5-[(benzyloxy)imino]-2-{[(tert-butoxy)carbonyl]amino}-6-chlorohexanoate (85% purity, 19.5 g, 40.1 mmol) in SiO2 (157 mL), MsOH (7.8 mL, 0.12 mol) was added, and the mixture was stirred at 42°C for 2 hours. The resulting mixture was added to a solution of KHCO3 (20.1 g, 0.201 mol) in H2O (100 mL), and the mixture was stirred at 52°C for 2 hours. The reaction mixture was cooled to room temperature, the organic layer was isolated, washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain the title compound as a dark orange oil in a quantitative yield of 13.0 g, 40.0 mmol (85% purity). 1 H NMR (400 MHz, chloroform-d) δ 7.20 - 7.34 (m, 5H), 4.99 (d, J = 4.8 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.45 - 3.56 (m, 1H), 3.25 (dd, J = 14.9, 9.8 Hz, 1H), 3.08 (dt, J = 14.5, 4.3 Hz, 1H), 2.01 - 2.32 (m, 3H), 1.55 - 1.80 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H).

[0147] Step 1.c: Ethyl(2R,5S)-5-[(benzyloxy)amino]piperidine-2-carboxylate oxalate [ka] Propanic acid (23 mL, 0.240 mol) was added to a suspension of NaBH4 (3.03 g, 80.0 mmol) in toluene (95 mL), and the mixture was stirred at room temperature for 1 hour. The resulting mixture was added at -20°C to a solution of ethyl(2R)-5-[(benzyloxy)imino]piperidine-2-carboxylate (85% purity, 13.0 g, 40.0 mmol) in toluene (95 mL) and H2SO4 (11 mL, 0.20 mol), and the mixture was stirred at room temperature for 60 hours. The reaction mixture was diluted with H2O (75 mL) and neutralized with aqueous NH4OH. The organic layer was isolated, washed with brine, dried over Na2SO4, and concentrated to approximately 75 mL in vacuum. The solution was heated to 45°C, and MeOH (30 mL) was added, followed by a solution of oxalic acid (3.60 g, 40.0 mmol) in MeOH (15 mL). The mixture was cooled to 0°C, and the resulting precipitate was isolated by vacuum filtration and washed with MeOH:EtOH (1:4) and HCl to obtain the title compound (7.17 g, 19.1 mmol, 48% yield); 1 H NMR (500 MHz, DMSO-d6) δ 7.25 - 7.42 (m, 5H), 4.59 (s, 2H), 4.17 - 4.24 (m, 2H), 3.92 (dd, J = 12.3, 3.2 Hz, 1H), 3.34 - 3.40 (m, 1H), 3.10 (ddd, J = 15.1, 7.6, 3.9 Hz, 1H), 2.64 (t, J = 11.5 Hz, 1H), 2.13 (dt, J = 10.2, 3.4 Hz, 1H), 1.87 (dd, J = 9.0, 3.8 Hz, 1H), 1.65 (qd, J = 13.2, 3.6 Hz, 1H), 1.40 (qd, J = 12.8, 3.9 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H); M / Z: 279, [M+H] + , ESI + RT = 0.81 (S1).

[0148] Intermediate 1 (Step 1.d): 1-tert-butyl 2-ethyl (2R,5S)-5-[(benzyloxy)amino]piperidine-1,2-dicarboxylate [ka] To a solution of ethyl(2R,5S)-5-[(benzyloxy)amino]piperidine-2-carboxylate oxalic acid (2.22 g, 6.03 mmol) in anhydrous DCM (30 mL), Et3N (3.6 mL, 25.8 mmol), DMAP (76 mg, 0.622 mmol), and Boc2O (4.2 mL, 18.3 mmol) were added at 0°C, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with saturated aqueous NH4Cl and DCM, the organic layer was isolated, washed with H2O and brine, dried over Na2SO4, and concentrated under vacuum. Purification by FCC on silica gel (0-20% RINKAN in heptane) yielded the title compound as a colorless oil (86% purity, 1.40 g, 3.18 mmol, 53% yield); 1 H NMR (500 MHz, chloroform-d) δ 7.40 - 7.26 (m, 5H), 5.51 - 5.41 (m, 1H), 4.92 - 4.80 (m, 1H), 4.79 - 4.62 (m, 2H), 4.19 (q, J = 7.0 Hz, 3H), 3.11 (d, J = 45.4 Hz, 2H), 1.96 (s, 2H), 1.73 - 1.60 (m, 1H), 1.55 - 1.49 (m, 1H), 1.46 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H); M / Z: 379, [M+H] + , ESI + RT = 1.09 (S2).

[0149] Scheme for Route 2 [ka]

[0150] Intermediate 2 (Step 2.a): 2-(4-chloro-3-fluorophenoxy)acetyl chloride [ka] To a solution of 2-(4-chloro-3-fluorophenoxy)acetic acid (5.16 g, 22.7 mmol) in DCM (45 mL), dichloride oxalate (10 mL, 0.115 mol), followed by DMF (81 μL, 1.11 mmol), was added at 0°C, and the mixture was stirred at room temperature for 17 hours. By concentrating the reaction mixture under vacuum, the title compound was obtained as an orange oil (90% purity, 5.30 g, 21.4 mmol, 94% yield); 1 H NMR (400 MHz, chloroform-d) δ 7.31 (t, J = 8.6 Hz, 1H), 6.75 (dt, J = 10.2, 2.9 Hz, 1H), 6.66 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 4.96 (s, 2H).

[0151] Scheme for Route 3 [ka]

[0152] Step 3.a: 1-tert-butyl2-ethyl(2R,5S)-5-aminoaminopiperidine-1,2-dicarboxylate [ka] To a solution of 1-tert-butyl 2-ethyl (2R,5S)-5-[(benzyloxy)amino]piperidine-1,2-dicarboxylate (93% purity, 8.7 g, 21.3 mmol, intermediate 2) in EtOH (anhydrous, 200 mL), Pd / C (10%, 2.28 g, 2.14 mmol) was added under N2, and the mixture was stirred under H2 at room temperature for 17 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under vacuum. The residue was purified using an SCX-2 cartridge that flushed first with MeOH and then eluted second with 3 M NH3 in MeOH, yielding the title compound (4.88 g, 17.0 mmol, 80% yield) as a pale yellow oily substance; 1 H NMR (400 MHz, chloroform-d) δ 4.98 - 4.57 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.87 - 3.64 (m, 1H), 3.35 - 2.99 (m, 2H), 2.14 - 1.92 (m, 2H), 1.64 - 1.52 (m, 2H), 1.45 (s, 11H), 1.26 (t, J = 7.1 Hz, 3H).

[0153] Step 3.b: 1-tert-butyl2-ethyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-1,2-dicarboxylate [ka] A mixture of 1-tert-butyl 2-ethyl (2R,5S)-5-aminoaminopiperidine-1,2-dicarboxylate (4.88 g, 17.0 mmol) and Et3N (14 mL, 0.103 mol) in DCM (170 mL) was added dropwise at 0°C to a solution of 2-(4-chloro-3-fluorophenoxy)acetyl chloride (4.19 g, 18.8 mmol, intermediate 2) in DCM (10 mL), and the mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted in DCM (250 mL), washed with saturated NaHCO3 aqueous solution (2 × 100 mL) and brine (100 mL), dried over Na2SO4, and concentrated under vacuum. Purification by FCC on silica gel (0-50% ethyl phosphate in heptane) yielded the title compound (7.14 g, 15.6 mmol, 91% yield) as a colorless oil; 1 H NMR (400 MHz, chloroform-d) δ 7.32 (t, J = 8.6 Hz, 1H), 6.86 - 6.72 (m, 2H), 6.69 - 6.63 (m, 1H), 4.98 - 4.66 (m, 1H), 4.45 (s, 2H), 4.29 - 4.13 (m, 3H), 4.09 - 3.87 (m, 1H), 3.33 - 3.10 (m, 1H), 2.23 - 2.02 (m, 1H), 2.00 - 1.71 (m, 2H), 1.56 (s, 1H), 1.44 (s, 9H), 1.28 (t, J = 7.2 Hz, 3H); M / Z: 459, 461 [M+H] + , ESI + RT = 3.83 (S4).

[0154] Intermediate 3 (Step 3.c): (2R,5S)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-2-carboxylic acid [ka] LiOH (0.78 g, 31.1 mmol) was added to a solution of 1-tert-butyl 2-ethyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-1,2-dicarboxylate (7.1 g, 15.6 mmol) in EtOH (80 mL) and H2O (20 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum, dissolved in H2O (50 mL), and extracted with DCM (2 × 100 mL). The aqueous layer was then acidified to pH 2 using a 2 M aqueous HCl solution and extracted with ELISA (3 × 100 mL). The combined organic extracts were washed with brine (100 mL), dried on anhydrous Na2SO4, and concentrated under vacuum to obtain the title compound as a white solid (87% purity, 5.60 g, 11.3 mmol, 73% yield); 1 H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 7.3 Hz, 1H), 7.47 (t, J = 8.9 Hz, 1H), 7.03 (dd, J = 11.4, 2.8 Hz, 1H), 6.83 - 6.75 (m, 1H), 4.59 - 4.54 (m, 2H), 3.93 (s, 1H), 3.73 (d, J = 54.2 Hz, 1H), 3.13 - 2.94 (m, 1H), 2.06 - 1.87 (m, 2H), 1.61 (d, J = 12.2 Hz, 1H), 1.56 - 1.43 (m, 1H), 1.37 (s, 10H); M / Z: 429, 431 [M+H], ESI + RT = 0.91 min (S1).

[0155] Scheme for Route 4 [ka]

[0156] Step 4.a: 5-(difluoromethoxy)-2-nitrophenol [ka] Nitric acid (0.43 mL, 10.3 mmol) was slowly added at 0°C to a solution of 3-(difluoromethoxy)phenol (1.50 g, 9.37 mmol) in acetic acid (8.0 mL, 9.37 mmol). The reaction mixture was stirred for 10 minutes, then diluted with H2O (50 mL) and extracted with HCl (3 × 50 mL). The combined organic extract was dried over MgSO4, concentrated under vacuum, and purified by FCC on silica gel (0-100% HCl in heptane) to obtain the title compound as a brown gum (90% purity, 780 mg, 3.42 mmol, 37% yield); 1 H NMR (500 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.04 (d, J = 9.1 Hz, 1H), 7.31 (t, J = 72.9 Hz, 1H), 6.82 (dd, J = 9.1, 2.5 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H).

[0157] Intermediate 4 (Step 4.b): 2-amino-5-(difluoromethoxy)phenol [ka] To a solution of 5-(difluoromethoxy)-2-nitrophenol (90% purity, 780 mg, 3.42 mmol) in EtOH (14 mL), AcOH (7 mL) and iron (1.91 g, 34.2 mmol) were added, and the mixture was stirred at 100°C for 1 hour. The reaction mixture was diluted with H2O (25 mL) and basicized to pH 8 using 1 M NaOH aqueous solution. The resulting solution was extracted with ELISA (50 mL), and the combined organic extract was washed with H2O (25 mL) and brine (25 mL), dried on MgSO4, and concentrated under vacuum to obtain the title compound (50% purity, 800 mg, 2.28 mmol, 67% yield) as a black oily substance; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 6.97 (t, J = 74.8 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 6.48 - 6.42 (m, 2H), 4.34 (s, 2H).

[0158] Scheme for Route 5 [ka]

[0159] Step 5.a: tert-butyl(2R,5S)-2-[(4-chloro-2-hydroxyphenyl)carbamoyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-1-carboxylate [ka] To a solution of 2-amino-5-chlorophenol (167 mg, 1.16 mmol, intermediate 3), DIPEA (0.61 mL, 3.48 mmol), and (2R,5S)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-2-carboxylic acid (500 mg, 1.16 mmol, intermediate 3) in DMF (anhydrous, 16 mL), HATU (441 mg, 1.16 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with HCl (30 mL), washed with water (2 × 20 mL), and the combined organic extract was dried over MgSO4 and concentrated under vacuum. By purification by FCC over silica gel (10-100% HCl in heptane), the title compound was obtained as a brown oily substance (90% purity, 256 mg, 0.414 mmol, 36% yield); 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.37 - 7.30 (m, 1H), 7.14 - 7.04 (m, 1H), 7.01 - 6.98 (m, 1H), 6.87 - 6.65 (m, 3H), 4.93 (s, 1H), 4.53 - 4.41 (m, 2H), 4.30 - 4.13 (m, 2H), 3.21 - 3.10 (m, 1H), 2.41 - 2.13 (m, 1H), 1.97 - 1.57 (m, 5H), 1.52 - 1.40 (m, 9H); M / Z: 556, 558 [M+H] + , ESI + RT = 4.24 min (S4).

[0160] Example 1 (Step 5.b): tert-butyl(2R,5S)-2-(6-chloro-1,3-benzoxazol-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-1-carboxylate [ka] To a solution of tert-butyl(2R,5S)-2-[(4-chloro-2-hydroxyphenyl)carbamoyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-1-carboxylate (90% purity, 200 mg, 0.324 mmol) and DIAD (76 μL, 0.388 mmol) in THF (anhydrous, 4 mL), PPh3 (110 mg, 0.421 mmol) was added at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ELISA (10 mL), washed with H2O (2 × 10 mL), and the organic extract was dried over MgSO4 and concentrated under vacuum. By purification by FCC on silica gel (0-100% ELISA in heptane), the title compound was obtained as a colorless oil (90% purity, 170 mg, 0.284 mmol, 88% yield); 1H NMR (500 MHz, CDCl3) δ 7.64 - 7.59 (m, 1H), 7.55 - 7.51 (m, 1H), 7.37 - 7.31 (m, 2H), 6.96 - 6.80 (m, 1H), 6.80 - 6.75 (m, 1H), 6.72 - 6.66 (m, 1H), 4.54 - 4.43 (m, 2H), 4.20 - 4.15 (m, 1H), 2.34 (s, 1H), 2.07 - 1.75 (m, 6H), 1.47 (s, 9H); M / Z: 438, 440 [M-Boc+H] + , ESI + RT = 1.16 min (S2).

[0161] Example 2 (Step 5.c): N-[(3S,6R)-6-(6-chloro-1,3-benzoxazole-2-yl)piperidine-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide [ka] To a solution of tert-butyl(2R,5S)-2-(6-chloro-1,3-benzoxazole-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-1-carboxylate (90% purity, 80 mg, 0.134 mmol, Example 1) in DCM (anhydrous, 2.5 mL), ZnBr2 (90 mg, 0.401 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with RINKAN (15 mL), washed with H2O (2 × 8 mL), and the organic extract was dried over MgSO4 and concentrated under vacuum. Purification by preparative HPLC (Method 3) yielded the title compound (8.2 mg, 0.0187 mmol, 14% yield) as a white solid; 1H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J = 8.1 Hz, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.42 (dd, J = 8.5, 2.0 Hz, 1H), 7.07 (dd, J = 11.4, 2.8 Hz, 1H), 6.86 (ddd, J = 9.0, 2.8, 1.1 Hz, 1H), 4.53 (s, 2H), 3.98 - 3.90 (m, 1H), 3.78 - 3.69 (m, 1H), 3.09 - 3.00 (m, 1H), 2.93 - 2.84 (m, 1H), 2.16 - 2.06 (m, 1H), 1.99 - 1.89 (m, 1H), 1.81 - 1.69 (m, 1H), 1.62 - 1.49 (m, 1H); M / Z: 438, 440 [M+H] + , ESI + RT = 2.27 min (S4).

[0162] Following general route 5, the example compounds in Table 1 were synthesized using the corresponding intermediates, as illustrated in Examples 1 and 2.

[0163] [Table 1-1] [Table 1-2] [Table 1-3]

[0164] Scheme for Route 6 [ka]

[0165] Step 6.a: tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-{[2-hydroxy-4-(trifluoromethyl)phenyl]carbamoyl}piperidine-1-carboxylate [ka] To a solution of 2-amino-5-(trifluoromethyl)phenol (164 mg, 0.928 mmol), DIPEA (0.49 mL, 2.79 mmol), and (2R,5S)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-2-carboxylic acid (intermediate 3, 400 mg, 0.928 mmol) in anhydrous DMF (8 mL), HATU (353 mg, 0.928 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with Depositphotos (30 mL) and washed with H2O (2 × 20 mL). The combined organic extracts were dried on MgSO4, concentrated under vacuum, and purified by FCC on silica gel (10-100% toluene in heptane) to obtain the title compound as a colorless oil (53% purity, 507 mg, 0.456 mmol, 49% yield); M / Z: 590, 592 [M+H] + ESI + RT=4.19min(S4).

[0166] Example 15 (Step 6.b): tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[6-(trifluoromethyl)-1,3-benzoxazole-2-yl]piperidine-1-carboxylate [ka] To a solution of tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-{[2-hydroxy-4-(trifluoromethyl)phenyl]carbamoyl}piperidine-1-carboxylate (53% purity, 507 mg, 0.456 mmol) and DIAD (0.11 mL, 0.547 mmol) in anhydrous THF (6 mL), PPh3 (155 mg, 0.592 mmol) was added at 0°C, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with H2O (2 × 10 mL). The organic extract was dried over MgSO4, concentrated under vacuum, and purified by FCC on silica gel (0-100% ethyl acetate in heptane) to obtain the title compound as a white solid (54% purity, 430 mg, 0.406 mmol, 89% yield); 1 H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 8.13 (d, J = 7.1 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.06 (dd, J = 11.4, 2.8 Hz, 1H), 6.84 (dd, J = 9.0, 2.0 Hz, 1H), 5.75 (s, 2H), 4.64 - 4.54 (m, 2H), 4.03 - 3.87 (m, 2H), 2.35 - 2.18 (m, 2H), 1.80 - 1.64 (m, 2H), 1.39 - 1.34 (m, 9H); M / Z: 472, 474 [M-Boc+H] + , ESI + RT = 1.17 min (S2).

[0167] Example 16 (Step 6.c): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[6-(trifluoromethyl)-1,3-benzoxazole-2-yl]piperidine-3-yl]acetamide [ka] tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[6-(trifluoromethyl)-1,3-benzoxazole-2-yl]piperidine-1-carboxylate (Example 15, 54% purity, 430 mg, 0.406 mmol) was dissolved in 4 M HCl in 1,4-dioxane (50 mL) and stirred at room temperature for 3 hours. The reaction mixture was diluted with toluene (30 mL) and washed with saturated aqueous NaHCO3 solution. The organic extract was dried over MgSO4, concentrated under vacuum, and purified by preparative HPLC (Method 3) to obtain the title compound (90 mg, 0.186 mmol, 46% yield) as a white solid; 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.97 (dd, J = 19.4, 8.2 Hz, 2H), 7.73 (dd, J = 8.3, 1.2 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.86 (ddd, J = 9.0, 2.8, 1.0 Hz, 1H), 4.54 (s, 2H), 4.05 - 3.96 (m, 1H), 3.82 - 3.70 (m, 1H), 3.11 - 3.03 (m, 1H), 2.94 (s, 1H), 2.56 - 2.52 (m, 1H), 2.19 - 2.09 (m, 1H), 2.00 - 1.91 (m, 1H), 1.85 - 1.51 (m, 2H); M / Z: 472, 474 [M+H] + , ESI + RT = 2.31 min (S4).

[0168] Following general route 6, the example compounds in Table 2 were synthesized using the corresponding intermediates, as illustrated in Examples 15 and 16.

[0169] [Table 2]

[0170] Scheme for Route 7 [ka]

[0171] Step 7.a: tert-butyl(2R,5S)-5-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]-2-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate [ka] To a solution of N-methoxymethaneamine hydrochloride (340 mg, 3.48 mmol), DIPEA (1.8 mL, 10.4 mmol), and (2R,5S)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-2-carboxylic acid (1.50 g, 3.48 mmol, intermediate 3) in DMF (anhydrous, 49.2 mL), HATU (1324 mg, 3.48 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (2 × 30 mL). The combined organic extracts were dried (Na2SO4) and concentrated under vacuum to obtain the title compound as a colorless oil (95% purity, 1.58 g, 3.17 mmol, 91% yield). The product was used in the next reaction without further purification; 1 H NMR (500 MHz, CDCl3) δ 7.31 (t, J = 8.6 Hz, 1H), 6.74 (dd, J = 10.3, 2.8 Hz, 2H), 6.66 (ddd, J = 8.9, 2.8, 1.1 Hz, 1H), 5.17 - 4.83 (m, M / Z: 496 [M+Na] + , ESI + RT = 0.94 min (S2).

[0172] Step 7. b: tert-butyl(2R,5S)-2-acetyl-5-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]piperidine-1-carboxylate [ka] To a solution of tert-butyl(2R,5S)-5-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]-2-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (1.58 g, 3.17 mmol) in THF (anhydrous, 20 mL), 3 M MeMgBr (3 M in Et2O) (1.4 mL, 4.12 mmol) was added at 0°C. The reaction mixture was heated to room temperature over 1 hour. The reaction mixture was diluted with ELISA, and the organic layer was washed three times with saturated aqueous NH4Cl solution. The organic layer was dried over (MgSO4) and concentrated under vacuum. Purification by FCC on silica gel (10-100% ELISA in heptane) yielded the title compound as a pale yellow oily substance (89% purity, 622 mg, 1.29 mmol, 41% yield); 1 H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 8.6 Hz, 1H), 6.87 - 6.63 (m, 3H), 4.85 - 4.53 (m, 1H), 4.48 - 4.41 (m, 2H), 4.15 - 4.08 (m, 1H), 2.17 (s, 3H), 2.15 - 2.06 (m, 1H), 1.84 - 1.56 (m, 5H), 1.45 (s, 9H); M / Z: 429 [M+H] + , ESI + RT = 3.46 min (S4).

[0173] Step 7. c:tert-butyl(2R,5S)-2-(2-bromoacetyl)-5-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]piperidine-1-carboxylate [ka] To a solution of tert-butyl(2R,5S)-2-acetyl-5-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]piperidine-1-carboxylate (89% purity, 431 mg, 0.894 mmol) in THF (anhydrous, 8 mL), 1 M LiHMDS in THF (2.7 mL, 2.68 mmol) was added at -78°C, and the reaction mixture was stirred for 30 minutes. TMSCl (0.34 mL, 2.68 mmol) was added, and the mixture was stirred at -78°C for 30 minutes. A solution of NBS (239 mg, 1.34 mmol) in THF (anhydrous, 4 mL) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with RINKAN (20 mL) and washed with saturated NH4Cl aqueous solution (2 × 20 mL). The combined organic layers were dried over (MgSO4) and evaporated to dryness. Purification by FCC on silica gel (10-100% siRNA in heptane) yielded the title compound as a yellow oil (39% purity, 482 mg, 0.370 mmol, 41% yield). The product was used in the following reaction without further purification; M / Z: 407, 409 [M-Boc+H] + ESI + RT=3.78min(S4).

[0174] Example 5 (Step 7.d): tert-butyl(2R,5S)-5-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-yl]piperidine-1-carboxylate [ka] A solution of 2-amino-5-(trifluoromethyl)pyridine (27 mg, 0.165 mmol), tert-butyl(2R,5S)-2-(2-bromoacetyl)-5-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]piperidine-1-carboxylate (39%, 215 mg, 0.165 mmol), and NaHCO3 (14 mg, 0.165 mmol) in ACN (anhydrous, 2.15 mL) was stirred at 80°C for 6 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water and brine, dried, and concentrated under vacuum to obtain the title compound (35% purity, 240 mg, 0.147 mmol, 89% yield) as an orange oil. The product was used in the next reaction without further purification; M / Z: 571[M+H] + ESI + RT=3.71min(S4).

[0175] Example 6 (Step 7.e): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-yl]-3-piperidine]acetamide [ka] To a solution of tert-butyl(2R,5S)-5-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-yl]piperidine-1-carboxylate (35% purity, 240 mg, 0.147 mmol, Example 5) in 1,4-dioxane (2 mL), HCl (4 M in 1,4-dioxane) (2.0 mL, 8.00 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ELISA and washed twice with saturated aqueous NaHCO3 solution. The organic phase was dried with (MgSO4) and evaporated under vacuum. Purification by preparative HPLC (Method 3) yielded the title compound as an off-white amorphous solid (95% purity, 7.9 mg, 0.0159 mmol, 11% yield); 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 7.2 Hz, 1H), 8.09 - 7.96 (m, 3H), 7.51 (t, J = 8.9 Hz, 1H), 7.16 (dd, J = 7.1, 1.7 Hz, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.87 (dd, J = 8.9, 1.9 Hz, 1H), 4.54 (s, 2H), 3.97 - 3.76 (m, 2H), 3.17 - 3.08 (m, 1H), 2.71 - 2.59 (m, 1H), 2.21 - 2.11 (m, 1H), 2.04 - 1.88 (m, 2H), 1.71 - 1.54 (m, 2H); M / Z: 471 [M+H] + , ESI + RT = 2.08 min (S4).

[0176] Following general route 7, the example compounds in Table 3 were synthesized using the corresponding intermediates, as illustrated in Examples 5 and 6.

[0177] [Table 3]

[0178] Assay II HEK-ATF4 high-content imaging assay The example compounds were tested in a HEK-ATF4 high-content imaging assay to determine their pharmacological efficacy in preventing tunicamycin-induced ISR. Wild-type HEK293 cells were cultured in a 384-well imaging assay plate 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) and incubated at 37°C and 5% CO2. After 24 hours, the medium was changed to 50 μL of assay medium per well (DMEM / F12, 0.3% FBS, 2 mM L-glutamine, 100 U / mL penicillin-100 μg / mL streptomycin). The example compounds were sequentially diluted in 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 area, the plate also contained several control wells for assay normalization, wells containing tunicamycin but not the example compound (high control), and similarly, 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 with 5% CO2 for 6 hours. Subsequently, cells were fixed (in PBS with 4% PFA, 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). Nuclei were stained using Hoechst dye (Thermofisher Scientific), and plates were imaged on an Opera Phenix High Content imaging platform equipped with excitations at 405 nm and 488 nm. Finally, images were analyzed using a script-based algorithm. The ATF4 signal ratio between the nucleus and cytoplasm was monitored using the main readout HEK-ATF4. Tunicamycin induced an increase in the overall ATF4 ratio signal, which was prevented by the ISR-modulated example compound.In addition, HEK-CellCount readout was derived by counting the number of stained nuclei corresponding to healthy cells. This readout served as an internal toxicity control. The example compounds described herein did not produce a significant reduction in CellCount.

[0179] The HEK ATF4 activity of the tested example compounds is provided in Table 4 as follows: +++=IC 50 1~500nM;++=IC 50 >500~2000nM;+=IC50 >2000~15000nM.

[0180] [Table 4]

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Claims

1. Equation (I) 【Chemistry 1】 Compounds thereof, or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof (wherein the formula, R 1 H is; R 2 H is; R 2a is either H or F; R 3 is phenyl, and here, R 3 This is one or more R, either the same or different. 7 It is sometimes replaced by; R 7 It is a halogen; R 4 is H or C(O)OC 1 to 4 alkyl; R 4a , R 4b , R 4c , R 5 R 4d and R 4e are independently H; R 6 These are heterobisicryls with 7 to 12 members, where R 6 This is one or more R, either the same or different. 11 It is sometimes replaced by; R 11 R 12 , OR 12 or halogen; R 12 is cyclopropyl or C 1 ~ 6 It is alkyl, and here, R 12 are the same or different one or more R 13 It is sometimes replaced by; R 13 is halogen or OR 14 And; R 14 C 1 ~ 4 It is alkyl, and here, C 1 ~ 4 Alkyl atoms are sometimes substituted with one or more halogens, either the same or different.

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

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

4. R in equation (I) 1 , R 2 , R 2a , R 4 , R 4a , R 4b , R 4c , R 5 , R 4d , and R 4e The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein formula (Ia) is obtained, where is H: 【Chemistry 2】

5. R 3 This is one, two, or three identical or different R's. 7 A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, substituted with .

6. The compound according to claim 5, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein R3 is substituted with one or two identical or different R7s.

7. The compound according to claim 6, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein R3 is substituted with the same or two different R7s.

8. R 7 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein is F, Cl or Br.

9. The compound according to claim 8, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein R7 is F or Cl.

10. R in equation (I) 1 , R 2 , R 2a , R 3 , R 4 , R 4a , R 4b , R 4c , R 4d , R 4e , and R 5 Equation (Ib): 【Transformation 3】 (In the formula, each R 7 A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, selected to obtain (independently selected from the group consisting of halogens).

11. R 6 These are quinazolinil, pyrrolo[1,2-a]pyradinil, 1,3-benzoxazolyl, pyrido[2,3-d]pyrimidinil, pyrido[3,4-d]pyrimidinil, pyrido[5,4-d]pyrimidinil, 1,2,3,4-tetrahydroquinolinil, chromanil, oxazolo[4,5-c]pyridinil, imidazo[1,2-a]pyridinil, [1,2,4]triazolo[1,5-a]pyridinil, imidazo[1,2-b]pyridadinil, or 6,7-dihydro-4H-pyrano[4,3-d]oxazolyl, where R 6 This is one or more R, either the same or different. 11 A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, which may be substituted in the event of the compound.

12. The compound according to claim 11, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein R 6 is 1,3-benzoxazolyl or imidazo[1,2-a]pyridinyl, where R 6 is optionally substituted with one or more identical or different R 11s.

13. The compound according to claim 12, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein R6 is 1,3-benzoxazolyl, where R6 is optionally substituted with one or more identical or different R11s.

14. R 6 is either unsubstituted or one or two identical or different R 11 A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, substituted with .

15. R 11 Cl, CH 3 CF 3 ,CH 2 CF 3 OCF 3 , OCHF 2 or OCH 2 CF 3 The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

16. R in equation (I) 1 , R 2 , R 2a , R 4 , R 4a , R 4b , R 4c , R 4d , R 4e , R 3 , R 5 , and R 6 The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, selected to obtain the following: tert-butyl(2R,5S)-2-(6-chloro-1,3-benzoxazole-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-1-carboxylate; N-[(3S,6R)-6-(6-chloro-1,3-benzoxazole-2-yl) Peridine-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide; tert-butyl(2R,5S)-2-(5-chloro-1,3-benzoxazole-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-1-carboxylate; N-[(3S,6R)-6-(5-chloro-1,3-benzoxazole-2-yl)piperidine-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide; tert-butyl(2R,5S)-5-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-yl]piperidine-1-carboxylate; 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-yl]-3-piperidyl]acetamide; tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[7-(trifluoromethyl)imidazo[1,2-a]pyridine-2-yl]piperidine-1-carboxylate or 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[7-(trifluoromethyl)imidazo[1,2-a]pyridine-2-yl]-3-piperidyl]acetamide; tert-butyl(2R,5S)-2-(7-chloro-1,3-benzoxazole-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-1-carboxylate; N-[(3S,6R)-6-(7-chloro-1,3-benzoxazole-2-yl)piperidine-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide; tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[6-(trifluoromethoxy)-1,3-benzoxazole-2-yl]piperidine-1-carboxylate; 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[6-(trifluoromethoxy)-1,3-benzoxazole-2-yl]piperidine-3-yl]acetamide; tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[6-(difluoromethoxy)-1,3-benzoxazole-2-yl]piperidine-1-carboxylate; 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[6-(difluoromethoxy)-1,3-benzoxazole-2-yl]piperidine-3-yl]acetamide; tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[6-(trifluoromethyl)-1,3-benzoxazole-2-yl]piperidine-1-carboxylate; 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[6-(trifluoromethyl)-1,3-benzoxazole-2-yl]piperidine-3-yl]acetamide; tert-butyl(2R,5S)-2-(4-chloro-1,3-benzoxazole-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-1-carboxylate; or N-[(3S,6R)-6-(4-chloro-1,3-benzoxazole-2-yl)piperidine-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide.

17. Formula (I) is a compound according to any one of claims 1 to 16 having the stereochemistry shown in formula (Ic), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof: 【Chemistry 4】

18. A pharmaceutical composition comprising at least one compound described in any one of claims 1 to 17 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 biologically active compounds or pharmaceutical compositions.

19. A pharmaceutical composition according to claim 18 for treating or preventing one or more diseases or disorders associated with the integrated stress response.

20. The pharmaceutical composition according to claim 18 for treating or preventing one or more diseases or disorders selected from the group consisting of leukodystrophy, intellectual disability syndromes, neurodegenerative diseases and disorders, neoplasms, infectious diseases, inflammatory diseases, musculoskeletal diseases, metabolic diseases, and ocular diseases, as well as one or more diseases selected from the group consisting of organ fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lungs, chronic and acute diseases of the kidneys, myocardial infarction, cardiovascular diseases, arrhythmias, atherosclerosis, spinal cord injury, ischemic stroke, and neuropathic pain.

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