Regulators of the integrated stress response pathway

Abstract

The present invention relates to a compound of formula (I) [Formula 1] TIFF2023517944000046.tif29102[where, R 1 , R 2 , R 2a , R 3 , R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , A 1 and A 2 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof. The present invention further relates to pharmaceutical compositions comprising said compounds, their use as medicaments, and their use in methods of treating and preventing one or more diseases or disorders associated with the integrated stress response.

Description

Technical Field

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

Chem.

Background Art

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

[0003] ISR is a common factor in various types of cellular stress that results in phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2 alpha) at serine 51, leading to the suppression of normal protein synthesis and the expression of stress response genes (2). In mammalian cells, phosphorylation is carried out by a family of four eIF2 alpha kinases, each responding to different 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, together with eIF2 beta and eIF2 gamma, forms the eIF2 complex, which plays a crucial role in the initiation of normal mRNA translation (4). The eIF2 complex is linked to GTP and Met-tRNA i It binds to the ternary complex (eIF2-GTP-Met-tRNA i ) are formed, which are recruited by ribosomes for translation initiation (5, 6).

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

[0006] In response to ISR activation, phosphorylated eIF2-alpha inhibits eIF2B-mediated exchange of GDP with GTP, resulting in reduced ternary complex formation and consequently inhibiting the translation of normal mRNA characterized by ribosome binding to the 5'AUG start codon (8). Under these reduced ternary complex abundance conditions, the translation of certain mRNAs, including the mRNA encoding the transcription factor ATF4, is activated via a mechanism involving altered translation of upstream ORFs (uORFs) (7, 9, 10). These mRNAs typically contain one or more uORFs that function normally in stress-free cells, restricting 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, during stress conditions, i.e., under reduced ternary complex formation conditions, the probability of ribosomes scanning beyond these upstream ORFs and initiating translation at the ATF4 coding ORF increases. The ATF4 and other stress response factors expressed in this manner subsequently govern the expression of a series of further stress response genes. In the acute phase, this involves the expression of proteins aimed at restoring homeostasis, 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 states among these cancers and neurodegenerative diseases. In cancer, ER stress-modulating translation increases tolerance to hypoxia and promotes tumor growth (14, 15, 16), and deletion of PERK by gene targeting transforms PERK - / - It has been shown to slow tumor growth derived from mouse embryonic fibroblasts (14, 17). Furthermore, recent reports using patient-derived xenograft modeling in mice have provided conceptual evidence that the activator of eIF2B is effective in treating morphologies of high-grade metastatic prostate cancer (28). Taken together, inhibition of cytoprotective ISR signaling may represent an effective antiproliferative strategy for treating at least some cancer morphologies.

[0008] Furthermore, modulation of ISR signaling has been found to be effective in preserving synaptic function and reducing neuronal decline, as well as in neurodegenerative diseases characterized by 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 Creutzfeldt-Jakob (prion) disease (18, 19, 20). In prion diseases, there are examples of neurodegenerative diseases in which not only pharmacological but also genetic inhibition of ISR signaling has been shown to normalize protein translation levels, rescue synaptic function, and prevent neuronal loss (21). Specifically, reducing phosphorylated eIF2 alpha levels by overexpression of a phosphatase that controls phosphorylated eIF2 alpha levels increased survival in prion-infected mice, while persistent eIF2 alpha phosphorylation decreased survival (22).

[0009] Furthermore, direct evidence regarding the importance of regulating protein expression levels for proper brain function exists 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, resulting in reduced normal protein expression levels, have been associated with intellectual disability syndrome (ID) (23). Partial deletion of functional mutations in the eIF2B subunit has been shown to be the cause of the rare leukodystrophy vanishing white matter disease (VWMD) (24, 25). In detail, stabilization of partial deletion of eIF2B function in a VWMD mouse model with ISRIB-related small molecules has been shown to reduce ISR markers and improve both functional and pathological endpoints (26, 27).

[0010] Regulators of the eIF2 alpha pathway are described in Patent Document 1. Patent Documents 2, 3, 4, and 5 describe regulators of the integrative 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 translation initiation factor 2B regulators. Patent Document 16 describes compounds, compositions, and methods useful for regulating the integrative stress response (ISR) and for treating related diseases, disorders, and conditions.

[0011] Further literature describing modifiers of the integrative stress pathway is Patent Documents 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, and 34. Modifiers of eukaryotic translation initiation factors are described in Patent Document 35. Patent Documents 36, 37, 38, and 39 describe inhibitors of the integrative stress response pathway. Heteroaryl derivatives as ATF4 inhibitors are described in Patent Document 40. Bicyclic aromatic ring derivatives as ATF4 inhibitors are described in Patent Document 41. Patent Documents 42 and 43 describe inhibitors of the ATF4 pathway. [Prior art documents] [Patent Documents]

[0012] [Patent Document 1] WO 2014 / 144952 A2 [Patent Document 2] WO 2017 / 193030 A1 [Patent Document 3] WO 2017 / 193034 A1 [Patent Document 4] WO 2017 / 193041 A1 [Patent Document 5] WO 2017 / 193063 A1 [Patent Document 6] WO 2017 / 212423 A1 [Patent Document 7] WO 2017 / 212425 A1 [Patent Document 8] WO 2018 / 225093 A1 [Patent Document 9] WO 2019 / 008506 A1 [Patent Document 10] WO 2019 / 008507 A1 [Patent Document 11] WO 2019 / 032743 A1 [Patent Document 12] WO 2019 / 046779 A1 [Patent Document 13] WO 2020 / 167994 A1 [Patent Document 14] WO 2020 / 168011 A1 [Patent Document 15] WO 2020 / 181247 A1 [Patent Document 16] WO 2020 / 77217 A1 [Patent Document 17] WO 2019 / 090069 A1 [Patent Document 18] WO 2019 / 090074 A1 [Patent Document 19] WO 2019 / 090076 A1 [Patent Document 20] WO 2019 / 090078 A1 [Patent Document 21] WO 2019 / 090081A1 [Patent Document 22] WO 2019 / 090082 A1 [Patent Document 23] WO 2019 / 090085 A1 [Patent Document 24] WO 2019 / 090088 A1 [Patent Document 25] WO 2019 / 090090A1 [Patent Document 26] WO 2020 / 223536 A1 [Patent Document 27] WO 2020 / 223538 A1 [Patent Document 28] WO 2020 / 252207 A1 [Patent Document 29] WO 2020 / 216764 A1 [Patent Document 30] WO 2020 / 216766 A1 [Patent Document 31] International Patent Application No. PCT / EP2021 / 051697 [Patent Document 32] European Patent Application No. 20203312.2 [Patent Document 33] European Patent Application No. 20203311.4 [Patent Document 34] European Patent Application No. 20203309.8 [Patent Document 35] WO 2019 / 183589 A1 [Patent Document 36] WO 2019 / 118785 A2 [Patent Document 37] WO 2019 / 236710 A1 [Patent Document 38] WO 2020 / 176428 A1 [Patent Document 39] WO 2020 / 252205 A1 [Patent Document 40] WO 2019 / 193540 A1 [Patent Document 41] WO 2019 / 193541 A1 [Patent Document 42] WO 2020 / 031107 A1 [Patent Document 43] WO 2020 / 012339 A1 [Overview of the project] [Problems that the invention aims to solve]

[0013] However, there is a continued need for novel compounds that are useful as modifiers of integrated stress response pathways and possess favorable pharmacokinetic properties.

[0014] Therefore, an object of the present invention is to provide a new class of compounds as modifiers of the integrated stress response pathway that may be effective in treating integrated stress response pathway-related diseases and may exhibit improved pharmaceutically relevant properties, including activity, solubility, selectivity, ADMET properties, and / or reduced side effects. [Means for solving the problem]

[0015] Therefore, the present invention relates to formula (I) [ka] The compound or its pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer is provided, in which, R a1 , R a2 , R a3 , R a4 , R a5 , R a6 H; halogen; C 1-4 Alkyl; and A 2a Independently selected from the group consisting of, where C 1-4 Alkyls are halogens, OH, and OC. 1-3 Optionally substituted with one or more substituents selected from the group consisting of alkyl groups, wherein the substituents are the same or different. However, R a1 , R a2 , R a3 , R a4 , R a5 , R a6 Only one of them is A 2a and; A 1This is a C5 cycloalkylene, a C5 cycloalkenylene, or a nitrogen ring atom-containing 5-membered heterocyclene, provided that the ring A is marked with an asterisk. 1 The ring atom is carbon, and here A 1 is one or more R, either the same or different. 4 It may be replaced in some cases; Each R 4 These are independently oxo (=O) [when the ring is at least partially saturated], thioxo (=S) [when the ring is at least partially saturated], halogens, CN, OR 5 , or C 1-6 It is alkyl, and here C 1-6 Alkyl is optionally substituted with one or more halogens, either the same or different; R 5 is H or C 1-6 It is alkyl, and here C 1-6 Alkyl is optionally substituted with one or more halogens, either the same or different; A 2 is R 6a Or A 2a and; R 6a is OR 6a1 , SR 6a1 , N(R 6a1 R 6a2 );C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 It is alkinyl, and here C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkinyl is a halogen; OR 6a3 ;CN; and A 2a Optionally substituted with one or more substituents selected from the group consisting of, where the substituents are the same or different; R 6a1 , R 6a2 H;C 1-6 Alkyl; C 2-6 Alkenil; C 2-6 Alkinyl; and A 2a Independently selected from the group consisting of, where C 1-6 Alkyl; C 2-6Alkenyl; and C 2-6 Alkynyl is optionally substituted with one or more substituents selected from the group consisting of halogen; CN; OR 6a3 ; A 2a ; and OA 2a wherein the substituents are the same or different; R 6a3 is H; or C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with one or more of the same or different halogens; A 2a is phenyl; C 3-7 cycloalkyl; C 4-12 bicycloalkyl; or 3- to 7-membered heterocyclyl, wherein A 2a is optionally substituted with one or more of the same or different R 6 ; Each R 6 is independently R 6b ; OH; OR 6b ; halogen; or CN, wherein R 6b is cyclopropyl, C 1-6 alkyl; C 2-6 alkenyl; or C 2-6 alkynyl, wherein R 6b is optionally substituted with one or more of the same or different halogens; or two R 6 are joined together with the atom to which they are attached to form ring A 2b ; A 2b is phenyl; C 3-7 cycloalkyl; or 3- to 7-membered heterocyclyl, wherein A 2b is optionally substituted with one or more of the same or different R 7 ; Each R 7 is independently C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein C 1-6 alkyl, C 2-6 alkenyl, and C 2-6Alkynnyls may be substituted with one or more halogens, either the same or different; R 1 is H or C 1-4 It is alkyl, preferably H, where C 1-4 Alkyl is optionally substituted with one or more halogens, either the same or different; R 2 is H;F; or C 1-4 It is alkyl, and here C 1-4 Alkyl is optionally substituted with one or more halogens, and R 3 is, A 3 , C 1-6 Alkyl, C 2-6 Alkenil, or C 2-6 It is alkinyl, and here C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkinyl is one or more R, either the same or different. 8 It may be replaced by; or R 2 and R 3 They bond together with the oxygen and carbon atoms to which they are bonded to form ring A 3a Forms A 3a These are 7-12 member heterobisicrills, where each 7-12 member heterobisicrill is one or more identical or different R groups. 10 It may be replaced in some cases; R 2a is H or F, preferably H; Each R 8 These are independently halogens; CN, C(O)OR 9 , OR 9 , C(O)R 9 , C(O)N(R 9 R 9a ), S(O)2N(R 9 R 9a ), S(O)N(R 9 R 9a ), S(O)2R 9 , S(O)R 9 , N(R 9)S(O)2N(R 9a R 9b ), SR 9 , N(R 9 R 9a ), NO2, O(O)R 9 , N(R 9 )C(O)R 9a , N(R 9 )SO2R 9a , N(R 9 )S(O)R 9a , N(R 9 )C(O)N(R 9a R 9b ), N(R 9 )C(O)OR 9a , OCN(R) 9 R 9a ), or A 3 and; R 9 , R 9a , R 9b H, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Independently selected from the group consisting of alkinyls, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynnyl is one or more halogens, one OH group, or one OC group, either the same or different. 1-4 Alkyl, or one A 3 It may be replaced in some cases; Each A 3 These are independently phenyl, naphthyl, and C 3-7 It is a cycloalkyl, a 3- to 7-membered heterocyclyl, or a 7- to 12-membered heterobicyclyl, where A 3 is one or more R, either the same or different. 10 It may be replaced in some cases; Each R 10 These are independently halogen, CN, and C(O)OR 11 , OR 11 , C(O)R 11 , C(O)N(R 11 R 11a ), S(O)2N(R 11 R 11a ), S(O)N(R 11R 11a ), S(O)2R 11 , S(O)R 11 , N(R 11 )S(O)2N(R 11a R 11b ), SR 11 , N(R 11 R 11a ), NO2, O(O)R 11 , N(R 11 )C(O)R 11a , N(R 11 )S(O)2R 11a , N(R 11 )S(O)R 11a , N(R 11 )C(O)OR 11a , N(R 11 )C(O)N(R 11a R 11b ), OCN(R 11 R 11a ), oxo (=O) [if the ring is at least partially saturated], C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 It is 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 12 It may be replaced in some cases; R 11 , R 11a , R 11b H, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Independently selected from the group consisting of alkinyls, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynnyls may be substituted with one or more halogens, either the same or different; Each R 12 These are independently halogen, CN, and C(O)OR 13 , OR 13 , C(O)R 13 , C(O)N(R 13 R 13a ), S(O)2N(R13 R 13a ), S(O)N(R 13 R 13a ), S(O)2R 13 , S(O)R 13 , N(R 13 )S(O)2N(R 13a R 13b ), SR 13 , N(R 13 R 13a ), NO2, O(O)R 13 , N(R 13 )C(O)R 13a , N(R 13 )SO2R 13a , N(R 13 )S(O)R 13a , N(R 13 )C(O)N(R 13a R 13b ), N(R 13 )C(O)OR 13a , or OCN(R) 13 R 13a ) and; R 13 , R 13a , R 13b H, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Independently selected from the group consisting of alkinyls, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynnyls may be substituted with one or more halogens, either the same or different. [Modes for carrying out the invention]

[0016] The compounds of the present invention represent 1,3-dioxane derivatives, which can be produced according to the routes and methods described herein or elsewhere, for example, in WO 98 / 56788 A2.

[0017] If a variable or substituent can be selected from a group of different variables, and such a variable or substituent appears more than once, each variable may be the same or different.

[0018] Within the meaning of this invention, the terms are used as follows: The term "optionally substituted" means either unsubstituted or substituted. Generally, but not limited to, "one or more substituents" means one, two, or three substituents, preferably one or two, and more preferably one substituent. Generally, these substituents may be the same or different.

[0019] "Alkyl" refers to a straight or branched hydrocarbon chain. Each hydrogen atom of an alkyl carbon can be replaced with a substituent as further specified.

[0020] "Alkenyl" refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond. Each hydrogen atom of the alkenyl carbon may be replaced by a substituent as further specified.

[0021] "Alkynyl" refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond. Each hydrogen atom of the alkynyl carbon may be replaced by a substituent as further specified.

[0022] "C 1-4 "Alkyl" refers to an alkyl chain having 1 to 4 carbon atoms, for example, when present at the end of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or, for example, when two parts of a molecule are linked by an alkyl group: -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. 1-4 Each hydrogen atom of an alkyl carbon can be replaced with a substituent as further specified. 1-3 "Alkyl" is defined accordingly.

[0023] "C 1-6 "Alkyl" refers to an alkyl chain having 1 to 6 carbon atoms, for example, when present at the end of a molecule: C 1-4Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or when two parts of a molecule are linked by an alkyl group, for example -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. 1-6 Each hydrogen atom of the alkyl carbon can be replaced by a substituent as further specified.

[0024] "C 2-6 "Alkenyl" refers to an alkenyl chain having 2 to 6 carbon atoms, for example, when present at the end of a molecule: -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, -CH=CH-CH=CH2, or when two parts of a molecule are linked by an alkenyl group, for example, -CH=CH-. 2-6 Each hydrogen atom of the alkenyl carbon can be replaced by a substituent that can be further specified.

[0025] "C 2-6 "Alkynyl" refers to an alkynyl chain having 2 to 6 carbon atoms, for example, when it is at the end of a molecule: -C≡CH, -CH2-C≡CH, CH2-CH2-C≡CH, CH2-C≡C-CH3, or when two parts of a molecule are linked by an alkynyl group, for example, -C≡C-. 2-6 Each hydrogen atom of the alkynyl carbon can be replaced by a substituent that can be further specified.

[0026] "C 3-7 "Cycloalkyl" or "C 3-7 The term "cycloalkyl ring" refers to 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 may be replaced by a substituent as further specified herein. 3-5"Cycloalkyl" or "C 3-5 A "cycloalkyl ring" is defined accordingly.

[0027] "C5 cycloalkylene" refers to a divalent cycloalkyl group having five carbon atoms, i.e., a divalent cyclopentyl ring.

[0028] "C5 cycloalkenylene" refers to divalent cycloalkenylene, that is, divalent cyclopentene or cyclopentadiene.

[0029] "C 4-12 "Bicycloalkyl" or "C 4-12 The term "bicycloalkyl ring" means a bicyclic condensation, crosslinking, or spiroalkyl chain having 4 to 12 carbon atoms, such as hexahydroindan, octahydropentalene, bicyclo[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.

[0030] "Halogen" refers to fluoro, chloro, bromo, or iodine. Generally, fluoro or chloro halogens are preferred.

[0031] A "3- to 7-membered heterocyclyl" or "3- to 7-membered heterocycle" means a ring (a fully, partially, or unsaturated aromatic or aromatic ring) having 3, 4, 5, 6, or 7 ring atoms, which may contain up to a maximum number of double bonds, where at least one of up to four ring atoms is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and where the ring is linked to the rest of the molecule via carbon or nitrogen atoms. Examples of 3- to 7-membered heterocycles 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, isooxazolidine, 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 “5-6 membered heterocyclyl” or “5-6 membered heterocycle” are defined accordingly and include 5-6 membered aromatic heterocyclyls or heterocycles. The terms “5 membered heterocyclyl” or “5 membered heterocycle” are defined accordingly and include 5 membered aromatic heterocyclyls or heterocycles.

[0032] The term "nitrogen ring atom-containing five-membered heterocyclene" refers to a divalent five-membered heterocycle, where 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.

[0033] A "saturated 4-7 member heterocyclyl" or "saturated 4-7 member heterocycle" refers to a "4-7 member heterocyclyl" or "4-7 member heterocycle" that is completely saturated.

[0034] "At least partially saturated 4- to 7-membered heterocyclyl" or "at least partially saturated 4- to 7-membered heterocycle" means at least partially saturated "4- to 7-membered heterocyclyl" or "4- to 7-membered heterocycle".

[0035] A "5-6 membered aromatic heterocyclyl" or "5-6 membered aromatic heterocycle" refers to a heterocycle derived from cyclopentadienyl or benzene in which 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.

[0036] A "five-membered aromatic heterocyclyl" or "five-membered aromatic heterocycle" refers to a heterocycle derived from cyclopentadienyl in which 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, and tetrazole.

[0037] A "7-12 membered heterobisicryl" or "heterobicycle" refers to a heterocyclic system of two rings having 7 to 12 ring atoms, where at least one ring atom is shared by both rings and may contain up to a maximum number of double bonds (fully, partially, or unsaturated aromatic or aromatic rings), where at least one of up to six ring atoms is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), where the ring is linked to the rest of the molecule via carbon or nitrogen atoms. Examples of 7-12 member heterobiscules 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 7- to 12-membered heterobiscules also includes two-ring spirostructures such as 6-oxa-2-azaspiro[3,4]octane, 2-oxa-6-azaspiro[3.3]heptan-6-yl or 2,6-diazaspiro[3.3]heptan-6-yl, or 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.

[0038] "Saturated 7-12 member heterobicyryl" or "saturated 7-12 member heterobicyl" means a 7-12 member heterobicyryl or 7-12 member heterobicyl that is completely saturated.

[0039] "At least partially saturated 7-12 member heterobisicrill" or "at least partially saturated 7-12 member heterobisicle" means at least partially saturated "7-12 member heterobisicrill" or "7-12 member heterobisicle".

[0040] A "9-11 member aromatic heterobisicryl" or "9-11 member aromatic heterobisicle" means a heterocyclic system of two rings, where at least one ring is aromatic, and the heterocyclic system has 9-11 ring atoms, where two ring atoms are shared by both rings, and may contain up to a maximum number of double bonds (fully or partially aromatic), where at least one of up to six ring atoms is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and where the ring is linked to the rest of the molecule via carbon or nitrogen atoms. Examples of 9-11 member aromatic heterobisicles 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 "9-10 member aromatic heterobisicril" or "9-10 member aromatic heterobisicle" are defined accordingly.

[0041] A preferred compound of formula (I) is a compound in which one or more residues contained herein have the following meaning, and all combinations of the definition of preferred substituents are the subject of 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.

[0042] In preferred embodiments of the present invention, the substituents described below have the following meanings independently. Therefore, one or more of these substituents may have the preferred or more preferred meanings shown below.

[0043] Preferably, R a1 , R a2 , R a3 , R a4 , R a5 , Ra6 H is H.

[0044] Preferably, A 1 This is a 5-membered heterocyclene containing a nitrogen ring atom, and here A 1 is one or more R, either the same or different. 4 It may be replaced depending on the circumstances.

[0045] more, A 1 This is a nitrogen ring atom-containing 5-membered heterocyclene selected from the group of divalent heterocycles consisting of oxadiazole, imidazole, imidazolidine, pyrazole, and triazole, more preferably triazole or oxadiazole, and more preferably oxadiazole. 1 is one or more R, either the same or different. 4 It may be replaced depending on the circumstances.

[0046] Preferably, A 1 is either unsubstituted, or one or two R's that are the same or different. 4 Replaced with , farA 1 This is a non-substitution.

[0047] Preferably, R 4 These are independently oxo (=O) [if the ring is at least partially saturated], halogens, CN, OR 5 or C 1-6 It is alkyl, and here C 1-6 Alkyl atoms may be substituted with one or more halogens, either the same or different.

[0048] Preferably, R 4 It is oxo if the ring is at least partially saturated.

[0049] Preferably, A 1 teeth, [ka] That is the case.

[0050] more, A 1 teeth, [ka] That is the case.

[0051] Furthermore, A 1 teeth, [ka] That is the case.

[0052] In one embodiment, A 2 is R 6a In another embodiment, A 2 is A 2a That is the case.

[0053] Preferably, R 6a is one or more halogens and / or one A 2a and / or one OR 6a3 C which may be replaced depending on the case 1-6 It is alkyl. More preferably, R 6a is one or more halogens and / or one OR 6a3 C which may be replaced depending on the case 1-6 It is alkyl.

[0054] Preferably, R 6a is OR 6a1 That is the case.

[0055] R 6a1 Preferably A 2a or C 1-6 It is alkyl, and here C 1-6 Alkyl is one or more halogens and / or one A 2a and / or one OR 6a3 It is replaced depending on the circumstances. More preferably, R 6a1 is one or more F and / or one OR 6a3 C which may be replaced depending on the case 1-6 It is alkyl.

[0056] Preferably, R 6a2 H is H.

[0057] Preferably, R 6a OC 1-4 Alkyl; OC 1-4 Alkyl-OC 1-4 It is alkyl, where each C 1-4 Alkyl groups consist of 1-3 F groups; or OCH2A groups. 2a It is replaced depending on the circumstances. More preferably, R 6a This is O(CH2)3CF3 or O(CH2)2OCF3.

[0058] Preferably, A 2a is phenyl; C 3-7 Cycloalkyl; or 3- to 7-membered heterocyclyl, where A 2a is one or more R, either the same or different. 6 It may be replaced depending on the circumstances.

[0059] Preferably, A 2a A is a phenyl or 5-6 member aromatic heterocycline, where A 2a is one or more R, either the same or different. 6 These may be substituted depending on the circumstances. Preferred 5-6 member aromatic heterocyclyls are preferably pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, or 1,2,4-oxadiazolyl.

[0060] Preferably, A 2a is C 3-7 It is a cycloalkyl, more preferably a cyclobutyl, where A 2a is one or more R, either the same or different. 6 It may be replaced depending on the circumstances.

[0061] Preferably, A 2a It is azetidinyl.

[0062] Preferably, A 2a is one or two R's that are the same or different. 6It will be replaced with.

[0063] Preferably, R 6 The elements are independently F, Cl, CF3, OCH3, OCF3, CH3, CH2CH3, or cyclopropyl, preferably F, Cl, CF3, OCH3, CH3, CH2CH3, or cyclopropyl.

[0064] Furthermore, A 2 These are 4-chlorophenyl, 3-trifluoromethoxycyclobutyl, 3-trifluoromethoxy-azetidine-1-yl, 4,4,4-trifluorobutyl-1-oxy, or 2-trifluoromethoxyethoxy.

[0065] Preferably, R 2 H is H.

[0066] Preferably, R 3 is A 3 That is the case.

[0067] Preferably, A 3 is phenyl, pyridyl, pyrazinyl, pyrimidadyl, cyclopropyl, cyclobutyl or cyclohexyl, more preferably phenyl or pyridyl, and here A 3 is one or more R, either the same or different. 10 It may be replaced depending on the circumstances.

[0068] Preferably, A 3 is one or two R's that are the same or different. 10 It will be replaced with.

[0069] Preferably, R 2 and R 3 These, together with the oxygen and carbon atoms to which they are bonded, form a dihydrobenzopyran ring, where the ring is composed of one or more identical or different R atoms. 10 The ring may be replaced in some cases, preferably with one or two R 10 It will be replaced with.

[0070] Preferably, R 10 It is CHF2. Preferably, R 10 These are independently F, Cl, Br, CF3, OCF3, CH=O, CH2OH, or CH3; preferably F, Cl, CF3, CH=O, CH2OH, or CH3. More preferably F or Cl.

[0071] Furthermore, R 3 This is 3-chloro-4-difluoromethylphenyl or 3,4-dichlorophenyl. Furthermore, R 3 The compound is 4-chloro-3-fluorophenyl or 2-chloro-3-fluoropyridine-5-yl, and more preferably 4-chloro-3-fluorophenyl.

[0072] Compounds of formula (I) having some or all of the above-mentioned groups in a preferred or more preferred sense are also objects of the present invention.

[0073] Preferred specific compounds of the present invention are: 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]-1,3-dioxan-5-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl}-1,3-dioxan-5-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)-N-[cis-2-[1-(4-chlorophenyl)-1H-1,2,3-triazole-4-yl]-1,3-dioxan-5-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-[1-(4-chlorophenyl)-1H-1,2,3-triazole-4-yl]-1,3-dioxan-5-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-[5-(4,4,4-trifluorobutoxy)-1,3,4-oxadiazole-2-yl]-1,3-dioxan-5-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}-1,3-dioxan-5-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-{5-[3-(trifluoromethoxy)azetidine-1-yl]-1,3,4-oxadiazole-2-yl}-1,3-dioxan-5-yl]acetamide; 2-[(6-chloro-5-fluoro-3-pyridyl)oxy]-N-[trans-2-[5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl]-1,3-dioxan-5-yl]acetamide; 2-[3-chloro-4-(difluoromethyl)phenoxy]-N-[trans-2-{5-[3-(trifluoromethoxy)azetidine-1-yl]-1,3,4-oxadiazole-2-yl}-1,3-dioxan-5-yl]acetamide; or 2-(3,4-dichlorophenoxy)-N-[trans-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}-1,3-dioxan-5-yl]acetamide It is selected from the group consisting of the following.

[0074] If tautomerisms, such as keto-enol tautomerism, can exist in the compounds of formula (I), then individual forms, such as the keto and enol forms, may be contained separately and together as mixtures in any ratio. The same applies to enantiomers, cis / trans isomers, conformational isomers, and so on.

[0075] In particular, when enantiomers or diastereoisomers arise in a compound according to formula (I), each pure form is included separately, and any mixture of at least two pure forms in any ratio is included by formula (I), and is the subject of the present invention.

[0076] A preferred compound is formula (Ia) [ka] The compound of formula (I) having the relative configuration shown, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0077] 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.

[0078] If desired, isomers can be separated by methods well known in the art, such as liquid chromatography. The same applies to enantiomers, for example, by using a chiral stationary phase. Furthermore, enantiomers can be isolated by converting them to diastereomers, i.e., by coupling them with enantiomerically pure auxiliary compounds, then separating the resulting diastereomers, and cleaving the auxiliary residues. Alternatively, any enantiomer of the compound of formula (I) can be obtained by stereoselective synthesis using optically pure starting materials, reagents, and / or catalysts.

[0079] If the compounds according to formula (I) contain one or more acidic or basic groups, also included in the present invention are their corresponding pharmaceutically or toxicologically acceptable salts, especially their pharmaceutically available salts. 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 detailed examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of formula (I) containing one or more basic groups, i.e., groups capable of being protonated, can exist in the form of their addition salts with inorganic or organic acids and can be used according to the present invention. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compounds of formula (I) contain both acidic and basic groups in the molecule, the present invention also includes inner salts or betaines (zwitterions) in addition to the salt forms mentioned. Each salt according to formula (I) can be obtained by 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 compounds of formula (I) which, due to their low physiological compatibility, are not directly suitable for use in pharmaceuticals but can be used, for example, as intermediates for chemical reactions or for the production of pharmaceutically acceptable salts.

[0080] As shown below, the compounds of the present invention are considered to be suitable for modulating the integrated stress response pathway.

[0081] The integrated stress response (ISR) is a cellular stress response common to all eukaryotes (1). Dysregulation of ISR signaling has significant pathological consequences associated with, among other things, inflammation, viral infection, diabetes, cancer, and neurodegenerative diseases.

[0082] The ISR is a common factor of various types of cellular stress that results in the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2 alpha) at serine 51, leading to the suppression of normal protein synthesis and the expression of stress response genes (2). In mammalian cells, phosphorylation is carried out by a family of four eIF2 alpha kinases, namely: PKR-like ER kinase (PERK), double-stranded RNA-dependent protein kinase (PKR), heme-regulated eIF2 alpha kinase (HRI), and general control non-derepressible 2 (GCN2), each responding to individual environmental and physiological stresses (3).

[0083] eIF2 alpha forms an eIF2 complex with eIF2 beta and eIF2 gamma that plays an important role in the initiation of normal mRNA translation (4). The eIF2 complex binds to GTP and Met-tRNA i to form a ternary complex (eIF2-GTP-Met-tRNA i ), which is recruited by ribosomes for translation initiation (5, 6).

[0084] eIF2B is a hetero-decameric complex consisting of five subunits (alpha, beta, gamma, delta, epsilon) that form a dimeric GEF-active decamer (7).

[0085] In response to ISR activation, phosphorylated eIF2-alpha inhibits eIF2B-mediated exchange of GDP with GTP, resulting in reduced ternary complex formation and consequently, inhibition of translation of normal mRNA characterized by ribosome 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 altered translation of upstream ORFs (uORFs) (7, 9, 10). These mRNAs typically contain one or more uORFs that function normally to restrict ribosome flow to the major coding ORF in stress-free cells. 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, during stress conditions, i.e., under conditions of reduced ternary complex formation, the probability of ribosomes scanning beyond these upstream ORFs and initiating translation at the ATF4 coding ORF increases. The ATF4 and other stress response factors expressed in this manner subsequently govern the expression of a series of further stress response genes. In the acute phase, this involves the expression of proteins aimed at restoring homeostasis, while in the chronic phase, it leads to the expression of pro-apoptotic factors (1, 11, 12, 13).

[0086] Upregulation of ISR signaling markers has been demonstrated in various states among these cancers and neurodegenerative diseases. In cancer, ER stress-modulating translation increases tolerance to hypoxia and promotes tumor growth (14, 15, 16), and deletion of PERK by gene targeting transforms PERK - / - It has been shown to slow tumor growth derived from mouse embryonic fibroblasts (14, 17). Furthermore, recent reports using patient-derived xenograft modeling in mice have provided conceptual evidence that the activator of eIF2B is effective in treating morphologies of high-grade metastatic prostate cancer (28). Taken together, inhibition of cytoprotective ISR signaling may represent an effective antiproliferative strategy for treating at least some cancer morphologies.

[0087] Furthermore, modulation of ISR signaling has been found to be effective in preserving synaptic function and reducing neuronal decline, as well as in neurodegenerative diseases characterized by 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 Creutzfeldt-Jakob (prion) disease (18, 19, 20). In prion diseases, there are examples of neurodegenerative diseases in which not only pharmacological but also genetic inhibition of ISR signaling has been shown to normalize protein translation levels, rescue synaptic function, and prevent neuronal loss (21). Specifically, reducing phosphorylated eIF2 alpha levels by overexpression of a phosphatase that controls phosphorylated eIF2 alpha levels increased survival in prion-infected mice, while persistent eIF2 alpha phosphorylation decreased survival (22).

[0088] Furthermore, direct evidence regarding the importance of regulating protein expression levels for proper brain function exists 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, resulting in reduced normal protein expression levels, have been associated with intellectual disability syndrome (ID) (23). Partial deletion of functional mutations in the eIF2B subunit has been shown to be the cause of rare white matter disappearance disease (VWMD) (24, 25). More specifically, stabilization of partial deletion of eIF2B function in a VWMD mouse model with ISRIB-related small molecules has been shown to reduce ISR markers and improve both functional and pathological endpoints (26, 27).

[0089] The present invention provides compounds of the present invention, in the form of free salts, solvates, hydrates, tautomers, or stereoisomers, for use in the treatment of diseases or disorders referred to herein.

[0090] Accordingly, aspects of the present invention are the compounds of the present invention or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers for use as pharmaceuticals, as described above.

[0091] The treatment methods described may be applicable to mammals such as dogs, cats, cattle, horses, rabbits, monkeys, and humans. Preferably, the mammalian patient is a human patient.

[0092] Accordingly, the present invention provides the compound of the present invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition of the present invention for use in the treatment or prevention of one or more diseases or disorders related to the integrated stress response.

[0093] 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 of the present invention for use in methods of treating or preventing one or more disorders or diseases related to the integrated stress response.

[0094] A further aspect of the present invention is the use of the compounds of the present invention or their pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers, or pharmaceutical compositions of the present invention, for the manufacture of agents for the treatment or prevention of one or more disorders or diseases related to the integrated stress response.

[0095] A further aspect of the present invention is a method for treating, managing, delaying or preventing in a mammalian patient requiring treatment for 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 of the present invention.

[0096] The present invention provides compounds of the present invention or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof for use in the treatment or prevention of one or more diseases or disorders described below.

[0097] 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 of the present invention, for use in methods of treating or preventing one or more disorders or diseases described below.

[0098] A further aspect of the present invention is the use of the compounds of the present invention or their pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers, or pharmaceutical compositions of the present invention, for the manufacture of agents for the treatment or prevention of one or more disorders or diseases described below.

[0099] A further aspect of the present invention is a method for treating, managing, delaying or preventing in a mammalian patient requiring treatment for one or more of the diseases or disorders described below, 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 of the present invention.

[0100] 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, eye diseases, and also include 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.

[0101] Leukodystrophy Examples of leukodystrophy include, but are not limited to, vanishing white matter disease (VWMD) and pediatric ataxia with CNS hypomyelination (e.g., associated with dysfunction of components in the eIF2 or signal transduction or signal transduction pathways that include eIF2).

[0102] Intellectual disability syndrome Intellectual disability refers to a condition in which a person has specific limitations in intellectual functions such as communication and self-care, and / or has a social disability. Examples of intellectual disability syndromes include, but are not limited to, intellectual disability conditions associated with dysfunction of components in the eIF2 or signal transduction or signal transduction pathways that include eIF2.

[0103] 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, ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjögren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, Kuru disease, Lewy body dementia, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion disease, progressive supranuclear palsy, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (many types with various characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, spinal syphilis, and tauopathy.

[0104] In particular, the neurodegenerative disease or disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

[0105] Neoplastic disease In its broadest sense, a neoplasm can be understood as any tissue arising from miscontrolled cell proliferation. Often, the neoplasm progresses to at least a bulky tissue mass, sometimes innervated by blood vessels. This may or may not include the formation of one or more metastases. The neoplasms of this invention may be any neoplasm classified by the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10), Class C00-D48.

[0106] Exemplary, a neoplastic disease according to the present invention may be the presence of one or more malignant neoplasms (tumors) (ICD-10 classes C00-C97), one or more in situ neoplasms (ICD-10 classes D00-D09), one or more benign neoplasms (ICD-10 classes D10-D36), or one or more neoplasms (ICD-10 classes D37-D48) with uncertain or unknown behavior. Preferably, a neoplastic disease according to the present invention refers to the presence of one or more malignant neoplasms, i.e., malignant tumors (ICD-10 classes C00-C97).

[0107] In a more preferred embodiment, the neoplasm is cancer.

[0108] Cancer can be understood in its broadest sense as any malignant neoplasm, i.e., the presence of one or more malignant neoplasms in a patient. Cancer may be solid or hematological. Without limitation, leukemia, lymphoma, carcinoma and sarcoma are intended herein.

[0109] In particular, neoplasms such as cancers characterized by upregulated ISR markers are included herein.

[0110] Examples of 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 cancer, squamous cell lung carcinoma, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid, sarcoma), colon cancer, esophageal cancer, gastric cancer, bladder cancer, bone cancer, prostate cancer, and skin cancer (e.g., melanoma).

[0111] Further examples include, but are not limited to, myeloma, leukemia, mesothelioma, and sarcoma.

[0112] 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, bladder 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 carcinoma, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, Paget's disease of the papillary thyroid, phyllodes tumor, lobular carcinoma, tubular carcinoma, pancreatic stellate cell carcinoma, and hepatic stellate cell carcinoma.

[0113] Examples of leukemia include, but are not limited to, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemia, aleukocythemic leukemia, basophilic leukemia, blast leukemia, bovine leukemia, chronic myeloid leukemia, cutaneous leukemia, and embryonal leukemia. Leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphotropic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, Mass Examples include trepanic cell leukemia, megakaryocyte leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli 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.

[0114] Examples of sarcomas include, but are not limited to, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, hydatidiform soft tissue sarcoma, ameloblastic sarcoma, botryoid sarcoma, and green sarcoma. Examples include sarcoma, choriocarcinoma, embryonal sarcoma, Wilms tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, multiple idiopathic pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemosarcoma, malignant mesenchymal sarcoma, paraosteal sarcoma, reticular sarcoma, Rouss sarcoma, serocystic sarcoma, synovial sarcoma, and pyelodactyl sarcoma.

[0115] Examples of melanoma 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.

[0116] Examples of carcinomas include, but are not limited to, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, carcinoma of the adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basal cell carcinoma, basal squamous cell carcinoma, bronchoalveolar carcinoma, bronchiolar carcinoma, bronchogenic lung carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, gelatinous carcinoma, comedone carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, skin carcinoma, columnar carcinoma, columnar cell carcinoma, duct carcinoma, ductal carcinoma Carcinoma, carcinoma durum, embryonic carcinoma, cerebral carcinoma, epidermal carcinoma, epithelial adenoides, carcinoma ex ulcere, fibrous carcinoma, gelatinous carcinoma, glial carcinoma, giant cell carcinoma, giant cell carcinoma (carcinoma gigantocellulare), adenocarcinoma, granulosa cell carcinoma, hair matrix cell carcinoma, hematoid carcinoma, hepatocellular carcinoma, Haasle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, carcinoma in epidermis, intraepithelial carcinoma, Krompecher's carcinoma Carcinoma, Krutskyi cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, black carcinoma, soft carcinoma (carcinoma molle), mucinous carcinoma, musipalm carcinomaMuciparum carcinoma, mucocellular carcinoma, mucoepidermoid carcinoma, mucinoma mucosum, mucinous carcinoma, myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, ossificans carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, pre-invasive carcinoma, squamous cell carcinoma, medullary carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma Examples include carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, cavernous carcinoma (carcinoma spongiosum), squamous cell carcinoma, string carcinoma, telangiectaticum, telangiectodes, transitional cell carcinoma, tuberosum, tubular carcinoma, tuberous carcinoma, verrucous carcinoma, and choriocarcinoma (carcinoma villosum).

[0117] infectious disease Examples include, but are not limited to, infections caused by viruses (e.g., HIV-1: human immunodeficiency virus type 1; IAV: influenza A virus; HCV: hepatitis C virus; DENV: dengue virus; ASFV: African swine fever virus; EBV: Epstein-Barr virus; HSV1: herpes simplex virus type 1; CHIKV: chikungunya virus; HCMV: human cytomegalovirus; SARS-CoV: severe acute respiratory syndrome coronavirus; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2) and infections caused by bacteria (e.g., infections caused by Legionella, Brucella, Symkania, Chlamydia, Helicobacter, and Campylobacter).

[0118] 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, type 1 diabetes, Guillain-Barré syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, and autoimmune diseases. Examples include autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, graft rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis.

[0119] Musculoskeletal disorders Examples of musculoskeletal disorders include, but are not limited to, muscular dystrophy, multiple sclerosis, Friedreich's ataxia, muscle wasting disorders (e.g., muscular atrophy, muscle loss, 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.

[0120] Metabolic diseases 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 syndrome. eye disease Examples of eye diseases include, but are not limited to, edema or neovascularization related to any obstructive or inflammatory retinal vascular disorder, such as iris neovascularization, neovascular glaucoma, pterygium, neovascular glaucoma filtration bleb, conjunctival papilloma; choroidal neovascularization, such as age-related macular degeneration (AMD) with neovascularization, myopia, prior uveitis. Macular edema can be caused by uveitis, trauma, or idiopathic conditions; macular edema, such as postoperative macular edema, macular edema secondary to uveitis including inflammation of the retina and / or choroid, macular edema secondary to diabetes mellitus, and macular edema secondary to retinal vascular occlusion diseases (i.e., retinal vein branch and central retinal vein occlusion); retinal neovascularization resulting from diabetes mellitus, such as retinal vein occlusion, uveitis, ocular ischemic syndrome from carotid artery disease, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathy, retinopathy of prematurity, or Eels disease; and hereditary disorders such as von Hippel-Lindau syndrome.

[0121] Further diseases Further conditions include, but are not limited to, organ fibrosis (e.g., hepatic fibrosis, pulmonary fibrosis, or renal fibrosis), chronic and acute diseases of the liver (e.g., fatty liver disease or fatty liver), chronic and acute diseases of the lungs, chronic and acute diseases of the kidneys, myocardial infarction, cardiovascular disease, arrhythmias, atherosclerosis, spinal cord injury, ischemic stroke, and neuropathic pain.

[0122] A further 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 physiologically active compounds or pharmaceutical compositions.

[0123] Preferably, one or more physiologically active compounds are modifiers of integrated stress response pathways other than the compound of formula (I).

[0124] "Pharmaceutical composition" means any product that directly or indirectly arises from one or more active ingredients, one or more inactive ingredients constituting a carrier, or any combination, complexation or aggregation of any two or more ingredients, or from the dissociation of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. Accordingly, the pharmaceutical composition of the present invention includes any composition produced by mixing the compound of the present invention with a pharmaceutically acceptable carrier.

[0125] The pharmaceutical composition of the present invention may contain one or more further compounds as active ingredients, such as a compound of formula (I) in the composition or a mixture of other moduloents of the integrated stress response pathway.

[0126] The active ingredient may be contained in one or more different pharmaceutical compositions (combinations of pharmaceutical compositions).

[0127] The term "pharmaceutically acceptable salt" refers to a salt produced from a pharmaceutically acceptable, non-toxic base or acid, including inorganic bases or acids and organic bases or acids.

[0128] The compositions include those suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ophthalmic (eye), pulmonary (nasal or buccal inhalation), or intranasal administration, but the most suitable route in any given case depends on the nature and severity of the condition being treated and the nature of the active ingredient. These may be provided in convenient unit dosage forms and may be manufactured by any method well known in the pharmaceutical art.

[0129] In practical use, the compound of formula (I) can be combined as an active ingredient in a thorough mixture with a pharmaceutical carrier according to conventional pharmaceutical formulation techniques. The carrier can take a wide variety of forms depending on the desired dosage form for administration, e.g., oral or parenteral (including intravenous). In the preparation of compositions for oral administration, any of the usual pharmaceutical media can be used, such as water, glycol, oil, alcohol, flavoring agents, preservatives, coloring agents, etc., for oral liquid formulations such as suspensions, elixirs, and solutions; or, for oral solid formulations such as powders, hard and soft capsules, and tablets, carriers such as starch, sugars, microcrystalline cellulose, diluents, granulators, lubricants, binders, disintegrants, etc., with solid oral formulations being preferred over liquid formulations.

[0130] Due to their ease of administration, tablets and capsules represent the most advantageous forms of oral medication, in which case solid drug carriers are naturally used. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and formulations should contain at least 0.1 percent of the active compound. The percentage of the active compound in these compositions can, of course, vary and may conveniently be between about 2 percent and about 60 percent of the mass of the unit. The amount of the active compound in such therapeutically useful compositions is such that an effective dose is obtained. The active compound may also be administered intranasally, for example, as a nasal drop or spray.

[0131] Tablets, pills, capsules, etc., may also contain binders such as tragacanth gum, gum arabic, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, or alginic acid; lubricants such as magnesium stearate; and sweeteners 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 above types of materials.

[0132] Various other materials may be present as coatings or to modify the physical form of the medication 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, colorants, and flavorings such as cherry or orange flavoring.

[0133] The compounds of formula (I) may also be administered parenterally. Liquid or suspension formulations of these active compounds may be prepared in water appropriately mixed with a surfactant such as hydroxypropyl cellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Under normal storage and use conditions, these formulations contain preservatives to prevent microbial growth.

[0134] Suitable pharmaceutical forms for injectable applications 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 enough to allow for easy syringability. 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, polyhydric alcohols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0135] Any suitable route of administration may be used to deliver an effective dose of the compound of the present invention to a mammal, particularly a human. For example, oral, rectal, topical, parenteral, ocular, pulmonary, or nasal administration may be used. Dosage forms include tablets, lozenges, dispersions, suspensions, liquids, capsules, creams, ointments, and aerosols. Preferably, the compound of formula (I) is administered orally.

[0136] The effective dosage of the active ingredient used may vary depending on the specific compound used, the mode of administration, the condition being treated, and the severity of the condition. Such dosages can be easily determined by those skilled in the art.

[0137] 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 they can be synthesized using methods known to those skilled in the art.

[0138] In general, several methods are applicable to the production of the compounds of the present invention. In some cases, various approaches can be combined. Sequential or intensive routes may be used. An example of a synthetic route is described below. [Examples]

[0139] I Chemical synthesis Experimental Procedure : The following abbreviations and acronyms are used: AQ water-based ACN Acetonitrile BF3· / OEt2 Boron trifluoride diethyl ether complex Saturated aqueous solution of brine (NaCl) Burgess reagent 1-methoxy-N-triethylammoniosulfonyl methaneimidate CDI di-1H-imidazole-1-ylmethanone CSA (Camphor Sulfonic Acid) CV column volume δ chemical shift (1 in 1,000,000) DAST N,N-diethylaminosulfur trifluoride DCM Dichloromethane DMSO (Dimethyl Sulfoxide) DMSO-d6 Deuterated Dimethyl Sulfoxide DIPEA Diisopropylethylamine DMF Dimethylformamide EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride ELS evaporative light scattering ESI+ Positive Ionization Mode ESI - Negative Ionization Mode HCl ethyl acetate EtOH Ethanol FCC Flash Column Chromatography g grams HATU 1-[bis(dimethylamino)methylidene]-1H-[1,2,3]triazolo[4,5-b]pyridine-1-ium 3-oxide hexafluorophosphate HCl (hydrochloric acid) HOAt 1-hydroxy-7-azabenzotriazole HPLC (High-Performance Liquid Chromatography) h time H2 hydrogen atmosphere J NMR coupling constant LC (Reset Chromatography) LCMS (Liquid Chromatography Mass Spectrometry) MgSO4 Magnesium Sulfate M molar concentration mg milligrams MHz (megahertz) mL (milliliter) min mm (millimeters) mM millimolar concentration mole nm (nanometer) MW microwave MTBE methyl tert-butyl ether M / Z mass-to-charge ratio N2 nitrogen atmosphere Sodium sulfate (Na2SO4) NaBH4 Sodium borohydride NaClO2 (sodium chlorite) NaHCO3 (sodium bicarbonate) NH4Cl (Ammonium Chloride) NaH2PO4 sodium dihydrogen phosphate NMM 4-methylmorpholine NMR nuclear magnetic resonance NaOCl sodium hypochlorite PDA Photometric Diode Array Pd / C carbon-supported palladium prep.for preparative separation PTSA para-toluenesulfonic acid monohydrate rt room temperature RT retention time satd saturation sec seconds TEMPO(2,2,6,6-tetramethylpiperidine-1-yl)oxydanyl THF (Tetrahydrofuran) Tol TsCl 4-toluenesulfonyl chloride uPLC Ultra-High Performance Liquid Chromatography UV ultraviolet μL (microliter)

[0140] The LCMS conditions for analysis are as follows:

[0141] System 1 (S1): Acidic IPC method (MS18 and MS19) Analytical (MET / CR / 1410) HPLC-MS was performed using a Shimadzu LCMS system with 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) for 1.2 minutes, followed by 100% B for 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.

[0142] System 2 (S2): Acidic IPC method (MSQ2 and MSQ4): Analytical (MET / uPLC / 1704) uHPLC-MS is performed using the Waters Acquity uPLC system with Waters UPLC® BEH TM The procedure was performed using a 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) for 1.1 minutes, followed by 100% B for 0.25 minutes. A second gradient of 100–5% B for 0.05 minutes, followed by a 0.1 minute hold, was then applied at a flow rate of 0.9 mL / min using an injection volume of 1 μL. UV spectra were recorded at 215 nm using a Waters Acquity PDA in the spectral range of 200–400 nm. Mass spectra were obtained using a Waters QDa. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0143] System 3 (S3): Basic IPC method (MS16): Analytical (MET / CR / 1602) uHPLC-MS using the Waters Acquity uPLC system with Waters UPLC® BEH TMThe procedure was performed using a 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) for 0.75 minutes, followed by 100% B for 0.1 minutes. A second gradient of 100–5% B for 0.05 minutes and a 0.1 minute retention was then applied using an injection volume of 1 μL at a flow rate of 1 mL / min. UV spectra were recorded at 215 nm using a Waters Acquity PDA with a 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.

[0144] System 4 (S4): Acidic final method (MSQ1 and MSQ2): Analytical uHPLC-MS (MET / uPLC / AB101) was performed using a Waters Acquity uPLC system with 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) for 5.3 minutes, followed by 100% B for 0.5 minutes. A second gradient of 100–5% B for 0.02 minutes, followed by a 1.18 minute retention, was applied at a flow rate of 0.6 mL / min using an injection volume of 1 μL. 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). Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0145] System 5 (S5): Acidic final treatment (MS18, MS19) Analytical (MET / CR / 1416) HPLC-MS was performed using a Shimadzu LCMS system with a Waters Atlantis dC18 column (2.1 mm × 100 mm, 3 μm; temperature: 40°C) and a gradient of 5–100% B (A = 0.1% formic acid in H2O; B = 0.1% formic acid in ACN) for 5 minutes, followed by 100% B for 0.4 minutes. A second gradient of 100–5% B for 0.02 minutes, followed by a 1.58 minute retention, was applied at a flow rate of 0.6 mL / min using an injection volume of 3 μL. UV spectra were recorded at 215 nm using an SPD-M20A photodiode array detector with a spectral range of 200–400 nm. Mass spectra were obtained using a 2010 EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0146] System 6 (S6): Basic final method (MS16) Analytical (MET / uHPLC / AB105) uPLC-MS is performed using the Waters Acquity uPLC system with Waters UPLC® BEH TM The procedure was performed using a 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 to pH 10; B = ACN) for 5.3 minutes, followed by 100% B for 0.5 minutes. A second gradient of 100–5% B for 0.02 minutes, held for 1.18 minutes, was then applied at a flow rate of 0.6 mL / min using an injection volume of 1 μL. The UV spectrum was recorded at 215 nm using a Waters Acquit 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.

[0147] System 7 (S7): Basic final method (MS10) Analytical HPLC-MS (MET / CR / 1603)(M6) was performed on an Agilent G1312A system using a Phenomenex Gemini NX C18 column (2.0 mm × 100 mm, 3 μm; temperature: 40°C) and a gradient of 5–100% B (A = 2 mM ammonium bicarbonate, buffered to pH 10; B = ACN) for 5.5 minutes, followed by 100% B for 0.4 minutes. A second gradient of 100–5% B for 0.02 minutes, followed by a 1.08 minute retention, was applied at a flow rate of 0.6 mL / min using an injection volume of 3 μL. UV spectra were recorded at 215 nm using a Waters 2996 photodiode array detector with a spectral range of 200–400 nm. ELS data were collected using a Water 2420 detector, where reported. Mass spectra were obtained using a Waters ZQ mass detector. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0148] The purification method is as follows: Method 1: Acidic initial method Purification (P1) LC was performed using a Gilson LC system with a Waters Sunfire C18 column (30 mm × 100 mm, 10 μM; temperature: rt) and a gradient of 10–95% B (A = 0.1% formic acid in H2O; B = 0.1% formic acid in ACN) for 14.44 minutes, followed by 95% B for 2.11 minutes. A second gradient of 95–10% B for 0.2 minutes was then applied at a flow rate of 40 mL / min using an injection volume of 1500 μL. The UV spectrum was recorded at 215 nm using a Gilson detector.

[0149] Method 2: Acidic standard method Purification (P2) LC was performed using a Gilson LC system with a Waters Sunfire C18 column (30 mm × 10 mm, 10 μM; temperature: rt) and a gradient of 30–95% B (A = 0.1% formic acid in water; B = 0.1% formic acid in ACN) for 11.00 minutes, followed by 95% B for 2.10 minutes. A second gradient of 95–30% B was then applied over 0.2 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.

[0150] Method 3: Basic initial method Purification (P3) LC was performed using a Gilson LC system with a Waters X-Bridge C18 column (30 mm × 100 mm, 10 μM; temperature: rt) and a gradient of 10–95% B (A = 0.2% ammonium hydroxide in H2O; B = 0.2% ammonium hydroxide in ACN) for 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 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.

[0151] Method 4: Basic standard method Purification (P4) LC was performed using a Gilson LC system with a Waters X-Bridge C18 column (30 mm × 10 mm, 10 μM; temperature: rt) and a gradient of 30-95% B (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in ACN) for 11.00 minutes, followed by 95% B for 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.

[0152] Method 5: Reverse-phase chromatography using acidic pH and standard elution method Purification by FCC using reversed-phase silica (acidic pH, standard elution method) was performed using a Biotage Isolera system with an appropriate SNAP C18 cartridge and a gradient of 1.7 CV of 10% B (A = 0.1% formic acid in H2O; B = 0.1% formic acid in ACN), followed by 19.5 CV of 10-100% B, and then 2 CV of 100% B.

[0153] Method 6: Reverse-phase chromatography using neutral pH and standard elution method Purification by FCC using reversed-phase silica (neutral pH, standard elution method) was performed using a Biotage Isolera system with an appropriate SNAP C18 cartridge and a gradient of 1.7 CV of 10% B (A=H2O; B=ACN), followed by 19.5 CV of 10-100% B, and then 2 CV of 100% B.

[0154] NMR conditions Unless otherwise stated, 1 ¹H NMR spectra were recorded at 500 MHz, 400 MHz, or 250 MHz using either a Bruker Avance III HD 500 MHz, Bruker Avance III HD 400 MHz, or Bruker Avance III HD 250 MHz spectrometer, respectively. Chemical shifts, δ, were cited in parts per million (ppm), and residual solvent peaks were referenced. The following abbreviations are used to indicate multiplicity and general assignments: s (singular), d (double), t (tripular), q (quadular), dd (double-double), ddd (double-double-double), dt (double-tripular), dq (double-quadular), hep (septuplicate), m (multiple), pent (quintular), td (triple-double), qd (quaduplicate), app. (apparent), and br. (broad). The coupling constant J is cited at the nearest 0.1 Hz.

[0155] general synthesis Unless otherwise stated, all compounds were synthesized with a purity of >95%.

[0156] Scheme for Route 1 [ka]

[0157] Intermediate 1 (Step 1.a): 2-[2-hydroxy-1-(hydroxymethyl)ethyl]isoindoline-1,3-dione A solution of isobenzofuran-1,3-dione (854 mg, 5.8 mmol) and 2-aminopropane-1,3-diol (521 mg, 5.7 mmol) in toluene (20 mL) was heated at 110°C for 24 hours. The reaction mixture was cooled to 62°C and treated with MTBE (20 mL), resulting in a white powder precipitate. After stirring this suspension for 1 hour, the precipitate was collected by hot filtration. The precipitate was washed with warm MTBE (20 mL) and vacuum-dried to obtain the title compound (786 mg, 3.45 mmol, 60% yield) as a white powder; 1 H NMR (500MHz, DMSO-d6) δ 7.87-7.81(m, 4H), 4.89-4.84(m, 2H), 4.27-4.20(m, 1H), 3.83-3.76(m, 2H), 3.69-3.62(m, 2H);M / Z:222[M+H] + ESI + RT=0.73(S1).

[0158] Scheme for Route 2 [ka]

[0159] Intermediate 2 (Step 2.a): 2-(4-chloro-3-fluorophenoxy)acetyl chloride To a solution of 2-(4-chloro-3-fluorophenoxy)acetic acid (5.16 g, 22.7 mmol) in DCM (45 mL), oxalyl dichloride (10 mL, 0.12 mol) was added at 0°C, followed by DMF (81 μL, 1.11 mmol), and the mixture was stirred at rt for 17 hours. The reaction mixture was concentrated under vacuum to obtain the title compound (purity 90%, 5.30 g, 21.4 mmol, yield 94%) as an orange oil; 1¹H NMR (400MHz, chloroform-d) δ 7.31 (t, J=8.6Hz, 1H), 6.75 (dt, J=10.2, 2.9Hz, 1H), 6.66 (ddd, J=8.9, 2.9, 1.2Hz, 1H), 4.96 (s, 2H).

[0160] The intermediates shown in Table 1 were synthesized using the corresponding starting materials according to general pathway 2, as exemplified by intermediate 2.

[0161] [Table 1]

[0162] Scheme for Route 3 [ka]

[0163] Step 3.a: 4-Chloro-N'-(2,2-diethoxyacetyl)benzohydrazide A suspension of 4-chlorobenzohydrazide (250 mg, 1.47 mmol) in 2,2-diethoxyethyl acetate (2.7 mL, 14.7 mmol) was stirred at 110°C for 16 hours. The reaction mixture was cooled to rt, diluted with MeOH, and the precipitate was removed by filtration. The filtrate was concentrated under vacuum and purified by chromatography on silica gel (0-100% ethyl acetate in heptane) to obtain the title compound (purity 80%, 135 mg, 0.36 mmol, yield 25%) as a pale yellow oil. 1 H NMR (400MHz, chloroform-d) δ 9.24(d, J=5.3Hz, 1H), 8.93(d, J=4.8Hz, 1H), 7.81-7.76(m, 2H), 7.48-7.41(m, 2H) 3.82-3.64(m, 4H), 1.32-1.24(m, 6H);M / Z:299, 301, [MH] - ESI - RT=0.98(S1).

[0164] Intermediate 4 (Step 3.b): 2-(4-chlorophenyl)-5-(diethoxymethyl)-1,3,4-oxadiazole A suspension of 4-chloro-N'-(2,2-diethoxyacetyl)benzohydrazide (135 mg, 0.45 mmol) and methoxycarbonyl-(triethylammonio)sulfonyl azanide (0.43 g, 1.80 mmol) in anhydrous THF (4.4 mL) was stirred under microwave irradiation at 120°C for 10 minutes. The reaction mixture was partitioned between RINKAN and a solution of saturated aq NaHCO3, and the organic layer was isolated, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (0-100% RINKAN in heptane) to obtain the title compound (purity 92%, 68 mg, 0.22 mmol, yield 49%) as a grayish-white solid; 1 ¹H NMR (400 MHz, chloroform-d) δ 8.10-8.03 (m, 2H), 7.54-7.49 (m, 2H), 5.79 (s, 1H), 3.90-3.70 (m, 4H), 1.32 (t, J=7.1, 6H); M / Z: 283, 285 [M+H] + ESI + RT=1.21(S1).

[0165] Scheme for Route 4 [ka]

[0166] Step 4.a: 2-[trans-2-[(benzyloxy)methyl]-1,3-dioxan-5-yl]-2,3-dihydro-1H-isoindole-1,3-dione A solution of benzyloxyacetaldehyde (0.25 mL, 1.77 mmol), PTSA (28 mg, 0.15 mmol), and 2-[2-hydroxy-1-(hydroxymethyl)ethyl]isoindoline-1,3-dione (336 mg, 1.47 mmol, intermediate 1) in toluene (30 mL) was heated under Dean-Stark conditions for 18 hours under reflux. The reaction mixture was cooled to rt and subsequently washed with satd aq NaHCO3 solution (2 × 10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, concentrated under vacuum, and purified by chromatography on silica gel (0-35% HCl in heptane) to obtain the title compound (303 mg, 0.82 mmol, yield 55%) as a colorless oil; 1 H NMR (400MHz, chloroform-d) δ 7.90-7.82(m, 2H), 7.79-7.71(m, 2H), 7.41-7.34(m, 4H), 7.34-7.29(m, 1H), 4.91(t, J=4.5Hz, 1H), 4. 74-4.66(m, 1H), 4.64(s, 2H), 4.52-4.43(m, 2H), 4.09(dd, J=10.8, 4.9Hz, 2H), 3.60(d, J=4.5Hz, 2H).

[0167] Intermediate 5 (Step 4.b): 2-[trans-2-(hydroxymethyl)-1,3-dioxan-5-yl]-2,3-dihydro-1H-isoindole-1,3-dione A suspension of 2-[trans-2-[(benzyloxy)methyl]-1,3-dioxan-5-yl]-2,3-dihydro-1H-isoindole-1,3-dione (393 mg, 1.06 mmol) and Pd / C (10%, 112 mg, 0.11 mmol) in EtOH (10 mL) and siRNA (6 mL) was stirred under H2 for 5 hours. The reaction mixture was purged with N2, heated to near reflux temperature, and then filtered through a Celite® pad. The filtrate was concentrated under vacuum to obtain the title compound (purity 94%, 260 mg, 0.93 mmol, yield 88%) as a white solid; 1H NMR (400MHz, chloroform-d) δ 7.90-7.80(m, 2H), 7.79-7.66(m, 2H), 4.78(t, J=4.3Hz, 1H), 4.69-4.58(m, 1H), 4.47 (dd, J=10.8Hz, 2H), 4.07(dd, J=10.7, 4.8Hz, 2H), 3.68(d, J=4.2Hz, 2H), 1.92(s, 1H).

[0168] Scheme for Route 5 [ka]

[0169] Intermediate 6 (Step 5.a): trans-5-(1,3-dioxo-2,3-dihydro-1H-isoindole-2-yl)-1,3-dioxan-2-carboxylic acid TEMPO (0.13 g, 0.80 mmol) was added to the solution of 2-[trans-2-(hydroxymethyl)-1,3-dioxan-5-yl]-2,3-dihydro-1H-isoindole-1,3-dione (89% purity, 2.37 g, 8.01 mmol, intermediate 5) in ACN (66 mL) and 0.67 M aq NaH2PO4 solution (66 mL). The reaction mixture was heated to 35°C. A solution of NaClO2 (80%, 1.83 g, 16.0 mmol) in H2O (15 mL) was added, followed by NaOCl (5.0%, 0.5 mL, 0.41 mmol). The reaction mixture was stirred at 35°C for 20 hours. Additional TEMPO (0.13 g, 0.80 mmol), NaClO2 (80%, 1.83 g, 16.0 mmol), and NaOCl (5.0%, 0.5 mL, 0.41 mmol) were added, and the reaction mixture was stirred at 35°C for 24 hours. The reaction mixture was concentrated under vacuum. The aqueous residue was basicized to pH 9 using a satd aq NaHCO3 solution and washed with pharmaceutically acceptable HCl (2 × 20 mL). The aqueous layer was cooled to 0°C and acidified to pH 2 by slowly adding a 1 M aq HCl solution. The aqueous layer was re-extracted with HCl (3 × 20 mL). The combined organic extracts were washed with H2O (50 mL), dried over Na2SO4, and then vacuum concentrated to obtain the title compound (2.10 g, 7.50 mmol, 94% yield) as a grayish-white powder; 1 ¹H NMR (400 MHz, methanol-d) δ 7.90-7.86 (m, 2H), 7.85-7.81 (m, 2H), 5.11 (s, 1H), 4.63-4.56 (m, 1H), 4.56-4.49 (m, 2H), 4.20-4.14 (m, 2H).

[0170] Scheme for Route 6 [ka]

[0171] Intermediate 7 (Step 6.a): [trans-5-amino-1,3-dioxan-2-yl]methanol A suspension of 2-[trans-2-(hydroxymethyl)-1,3-dioxan-5-yl]-2,3-dihydro-1H-isoindole-1,3-dione (93% purity, 904 mg, 3.19 mmol, intermediate 5) and hydrazine hydrate (0.6 mL, 12.8 mmol) in EtOH (49 mL) was stirred at 50°C for 2 hours. The reaction mixture was cooled to rt and then concentrated under vacuum. The residue was suspended in MeOH (20 mL), and a white solid precipitate was formed. This solid was filtered under vacuum, and the filtrate was concentrated under vacuum. The residue was dissolved in MeOH and loaded onto an SCX cartridge (2 g). The product was washed with MeOH and then eluted with 7 M NH3 in MeOH. The eluate was collected and concentrated under vacuum to obtain the title compound (299 mg, 2.25 mmol, 70% yield) as a viscous yellow oil; 1 H NMR (500MHz, DMSO-d6) δ 4.76(s, 1H), 4.34(t, J=4.7Hz, 1H), 3.98-3.86(m, 2H), 3.41-3.19(m, 2H), 3.19-3.07(m, 2H), 2.75 (tt, J=10.2, 5.0Hz, 1H).

[0172] Step 6.b: 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-(hydroxymethyl)-1,3-dioxan-5-yl]acetamide A solution of 2-(4-chloro-3-fluorophenoxy)acetic acid (459 mg, 2.3 mmol) and DIPEA (1.2 mL, 6.7 mmol) in anhydrous DMF (10 mL) was treated with HATU (807 mg, 2.1 mmol). The reaction mixture was stirred at rt for 10 minutes. [trans-5-amino-1,3-dioxan-2-yl]methanol (299 mg, 2.25 mmol, intermediate 7) was added, and the reaction mixture was stirred at rt for 19 hours. The reaction mixture was diluted with H2O (30 mL) and then extracted with ethyl acetate (30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium 2SO4, and then concentrated under vacuum. Purification by chromatography on silica gel (0-100% ethyl acetate in heptane) yielded the title compound (393 mg, 1.20 mmol, yield 54%) as a grayish-white solid; 1 H NMR (400MHz, chloroform-d) δ 7.35(t, J=8.6Hz, 1H), 6.76(dd, J=10.2, 2.9Hz, 1H), 6.71-6.63(m, 1H), 6.12(d, J=8.0Hz, 1H), 4.61(t, J=4.4Hz, 1H), 4.45(s, 2H), 4.42-4.31(m , 1H), 4.28(dd, J=11.2, 4.8Hz, 2H), 3.67(dd, J=6.6, 4.4Hz, 2H), 3.51(t, J=10.7Hz, 2H), 2.81(s, 4H), 1.80(t, J=6.6Hz, 1H);M / Z:320, 322[M+H] + ESI + RT=0.74(S2).

[0173] Intermediate 8 (Step 6.c): trans-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-1,3-dioxane-2-carboxylic acid NaOCl (5%, 0.23 mL, 0.18 mmol), NaClO2 (80%, 843 mg, 7.38 mmol), and TEMPO (58 mg, 0.369 mmol) were added at rt to a solution of 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-(hydroxymethyl)-1,3-dioxan-5-yl]acetamide (393 mg, 1.23 mmol) in ACN (10 mL) and NaH2PO4 (0.67 M, 10 mL, 6.8 mmol). The reaction mixture was heated at 35 °C for 22 hours. The reaction mixture was cooled to rt and diluted with siRNA (30 mL) and H2O (30 mL). The aqueous layer was acidified to pH 2 using a 2 M aq HCl solution and extracted with siRNA (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and then concentrated under vacuum to obtain the title compound (purity 88%, 274 mg, 0.723 mmol, yield 59%) as a grayish-white solid; 1 H NMR (500MHz, DMSO-d6) δ 8.12(d, J=7.8Hz, 1H), 7.49(t, J=8.9Hz, 1H), 7.07(dd, J=11.4, 2.8Hz, 1H), 6.85(ddd, J=9.0, 2.8 , 1.2Hz, 1H), 4.91(s, 1H), 4.54(s, 2H), 4.12-3.91(m, 3H), 3.66-3.53(m, 2H);M / Z:334, 336[M+H] + ESI + RT=0.76(S2).

[0174] The intermediates shown in Table 2 were synthesized using the corresponding starting materials according to the general pathway 6, as exemplified by intermediate 8.

[0175] [Table 2]

[0176] Scheme for Route 7 [ka]

[0177] Step 7.a: cis-3-hydroxycyclobutane-1-carboxylate benzyl NaBH4 (0.51 g, 13.5 mmol) was added to a solution of benzyl 3-oxocyclobutanecarboxylate (2.76 g, 13.5 mmol) in MeOH (25 mL) under N2 at -40°C, and the mixture was stirred for 1 hour. The reaction mixture was heated to 0°C and quenched with satd aq NH4Cl solution (10 mL). The reaction mixture was heated to rt and then vacuum concentrated. The residue was dissolved in H2O (50 mL) and extracted with ELISA (2 × 50 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, and vacuum concentrated to obtain the title compound (2.73 g, 13.2 mmol, 98% yield) as a colorless oil; 1 ¹H NMR (400MHz, chloroform-d) δ 7.41-7.29 (m, 5H), 5.14 (s, 2H), 4.27-4.15 (m, 1H), 2.74-2.53 (m, 3H), 2.28-2.12 (m, 2H), 1.86 (d, J=7.6Hz, 1H).

[0178] Step 7.b: cis-3-(trifluoromethoxy)cyclobutane-1-carboxylate benzyl 2-Fluoropyridine (3.5 mL, 40.4 mmol) and trifluoromethyltrimethylsilane (6.0 mL, 40.4 mmol) were successively added dropwise to a solution of benzyl cis-3-hydroxycyclobutane-1-carboxylate (2.78 g, 13.5 mmol), silver trifluoromethanesulfonate (10.43 g, 40.4 mmol), Selectfluor (7.16 g, 20.2 mmol), and potassium fluoride (3.13 g, 53.9 mmol) in HCl (120 mL) under N2 at rt in a foil-covered flask. The reaction mixture was stirred at rt for 20 hours, filtered through Celite®, and washed with HCl (50 mL). The filtrate was concentrated under vacuum and purified by chromatography on silica gel (5-30% HCl in heptane) to obtain the title compound (1.69 g, 6.16 mmol, yield 46%) as a colorless oil; 1¹H NMR (400MHz, chloroform-d) δ 7.44-7.29 (m, 5H), 5.15 (s, 2H), 4.58 (p, J=7.6Hz, 1H), 2.83-2.73 (m, 1H), 2.65 (dtd, J=10.0, 7.3, 2.6Hz, 2H), 2.60-2.47 (m, 2H).

[0179] Intermediate 10 (Step 7.c): cis-3-(trifluoromethoxy)cyclobutanecarboxylic acid A suspension of benzyl cis-3-(trifluoromethoxy)cyclobutane-1-carboxylate (1.70 g, 6.20 mmol) and Pd / C (10%, 0.66 g, 0.31 mmol) in EtOH (50 mL) was stirred under H2 at rt for 18 hours. The reaction mixture was purged with N2, then filtered through Celite®, and washed with EtOH (50 mL). The filtrate was concentrated under vacuum to obtain the title compound (1.06 g, 5.64 mmol, 91% yield) as a pale yellow oil. 1 ¹H NMR (400MHz, chloroform-d): δ 9.11 (s, 1H), 4.60 (p, J=7.4Hz, 1H), 2.84-2.62 (m, 3H), 2.55 (q, J=10.2, 9.5Hz, 2H). 1 Observation by 1H NMR revealed that it contains 10% trans-isomers.

[0180] Scheme for Route 8 [ka]

[0181] Step 8.a: Imidazole-1-carboxylic acid 4,4,4-trifluorobutyl A solution of 4,4,4-trifluorobutan-1-ol (3.0 g, 23.4 mmol) in DCM (50 mL) was added to a solution of CDI (5.70 g, 35.1 mmol) in THF (100 mL) at 0°C under N2 conditions, and the mixture was stirred for 1 hour. The reaction mixture was heated to rt and stirred for 19 hours. The reaction mixture was concentrated under vacuum and purified by chromatography on silica gel (5-50% ethyl acetate in heptane) to obtain the title compound (4.92 g, 22.1 mmol, 95% yield) as a colorless oil. 1 ¹H NMR (400MHz, chloroform-d) δ 8.14 (s, 1H), 7.42 (t, J=1.4Hz, 1H), 7.14-7.04 (m, 1H), 4.50 (t, J=6.4Hz, 2H), 2.37-2.19 (m, 2H), 2.11 (dq, J=10.3, 6.6Hz, 2H); 19 F{ 1 ¹H NMR (376 MHz, chloroform-d) δ -66.31 (3F, s); M / Z: 223 [M+H] + ESI + RT=0.73(S2).

[0182] Intermediate 11 (Step 8.b): N-aminocarbamic acid 4,4,4-trifluorobutyl A solution of imidazole-1-carboxylic acid 4,4,4-trifluorobutyl (4.92 g, 22.1 mmol) and hydrazine hydrate (4.4 mL, 88.6 mmol) in DCM (70 mL) was stirred at rt for 1.5 hours. Isopropanol (15 mL) was added, and the organic layer was washed with H2O (100 mL), satd aq NaHCO3 solution (100 mL), and brine (100 mL). The mixture was dried over Na2SO4 and then concentrated under vacuum to obtain the title compound (2.54 g, 13.7 mmol, 62% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ 8.15(s, 1H), 4.15-3.89(m, 4H), 2.40-2.15(m, 2H), 1.84-1.67(m, 2H); 19 F{ 1 ¹H NMR (376 MHz, chloroform-d) δ -64.89 (3F, s).

[0183] The following intermediates were produced using route 8.

[0184] Intermediate 12: 2-(trifluoromethoxy)ethyl N-aminocarbamate [ka] 1 H NMR (400MHz, DMSO-d6) δ 8.30(s, 1H), 4.23(s, 4H), 4.07(s, 2H); 19 F{ 1 H}NMR (376MHz, DMSO-d6) δ -58.99(3F, s).

[0185] Intermediate 13: 3-(trifluoromethoxy)azetidine-1-carbohydrazide [ka] 1 H NMR (400MHz, DMSO-d6) δ 9.92(s, 2H), 9.45(s, 1H), 5.22(tt, J=6.9, 4.0Hz, 1H), 4.33(dd, J=10.1, 6.7Hz, 2H), 4.01(dd, J=10.1, 3.8Hz, 2H); 19 F{ 1 ¹H NMR (376 MHz, chloroform-d) δ -58.43 (3F, s).

[0186] Scheme for route 9 [ka]

[0187] Step 9.a: 2-(3-chloro-4-formylphenoxy) tert-butyl acetate [ka] To a solution of 2-chloro-4-hydroxybenzaldehyde (1.50 g, 9.58 mmol) in anhydrous DMF (15 mL), tert-butyl bromoacetate (1.6 mL, 10.5 mmol), followed by K2CO3 (2.65 g, 19.2 mmol), was added, and the mixture was stirred at 65°C for 2 hours. The reaction mixture was cooled to rt and then poured into water (100 mL). The resulting solution was extracted with Depositphotos (2 × 70 mL), and the combined organic extract was washed with brine (100 mL), dried over MgSO4, and concentrated under vacuum to obtain the title compound (2.76 g, 9.89 mmol) as a grayish-white solid in quantitative yield; 1 ¹H NMR (400MHz, chloroform-d) δ 10.34 (s, 1H), 7.90 (d, J=8.7Hz, 1H), 6.93 (d, J=2.4Hz, 1H), 6.88 (dd, J=8.7, 2.2Hz, 1H), 4.58 (s, 2H), 1.49 (s, 9H); M / Z: 271, 273 [M+H] + ESI + RT=0.98(S2).

[0188] Step 9.b: 2-[3-chloro-4-(difluoromethyl)phenoxy]tert-butyl acetate [ka] To a solution of 2-(3-chloro-4-formylphenoxy)acetate tert-butyl (2.76 g, 9.89 mmol) in anhydrous DCM (20 mL), DAST (2.6 mL, 19.8 mmol) was added dropwise at 0°C, and the mixture was stirred at rt for 3 hours. Satd aq NaHCO3 solution (50 mL) was slowly added, and the mixture was stirred at rt for 1 hour. This solution was extracted with DCM (2 × 50 mL), and the combined organic extract was washed with satd aq NaHCO3 solution, dried over MgSO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (5-40% toluene in heptane) to obtain the title compound (2.02 g, 6.62 mmol, yield 67%) as a yellow oil; 1¹H NMR (400 MHz, chloroform-d) δ 7.58 (d, J=8.6 Hz, 1H), 7.05-6.73 (m, 3H), 4.53 (s, 2H), 1.49 (s, 9H); M / Z: 291, 293 [MH] - ESI - RT=1.06(S2).

[0189] Intermediate 14 (Step 9.c): 2-[3-chloro-4-(difluoromethyl)phenoxy]acetic acid [ka] To a solution of tert-butyl 2-[3-chloro-4-(difluoromethyl)phenoxy]acetate (2.02 g, 6.62 mmol) in 1,4-dioxane (5 mL), 4 M HCl (17 mL, 66.2 mmol) was added to the 1,4-dioxane, and the mixture was stirred at 60°C for 4 hours. The reaction mixture was cooled to rt and then concentrated under vacuum. H2O was added, and the resulting precipitate was filtered under vacuum and washed with H2O. This solid was then dissolved in MeCN, filtered under vacuum, and the filtrate was concentrated under vacuum to obtain the title compound (1.51 g, 6.26 mmol, yield 95%) as a cream-colored solid; 1 ¹H NMR (400 MHz, chloroform-d): δ 7.61 (d, J=8.7 Hz, 1H), 7.05-6.74 (m, 3H), 4.73 (s, 2H); 19 F NMR (376 MHz, chloroform-d) δ -113.69; M / Z: 235, 237 [MH] - ESI - RT=0.74(S2).

[0190] Scheme for route 10 [ka]

[0191] Step 10.a: 2-(3,4-dichlorophenoxy)-N-[trans-2-(hydroxymethyl)-1,3-dioxan-5-yl]acetamide and 2-(3,4-dichlorophenoxy)acetic acid [trans-5-[2-(3,4-dichlorophenoxy)acetamide]-1,3-dioxan-2-yl]methyl A solution of [trans-5-amino-1,3-dioxan-2-yl]methanol (495 mg, 3.72 mmol, intermediate 7) and DIPEA (3.9 mL, 22.3 mmol) in DCM (10 mL) was cooled to 0°C, and a solution of 2-(3,4-dichlorophenoxy)acetyl chloride (1.87 g, 7.81 mmol, intermediate 3) in DCM (15 mL) was added dropwise and treated. The mixture was heated to rt and stirred for 3 hours. The reaction mixture was cooled to 0°C and slowly quenched with H2O (10 mL). The organic layer was separated and washed with satd aq NaHCO3 solution (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by chromatography using silica gel (20-100% ethyl acetate in heptane) to obtain the title compounds 2-(3,4-dichlorophenoxy)-N-[trans-2-(hydroxymethyl)-1,3-dioxan-5-yl]acetamide (405 mg, 1.14 mmol, yield 31%) and 2-(3,4-dichlorophenoxy)acetic acid [trans-5-[2-(3,4-dichlorophenoxy)acetamide]-1,3-dioxan-2-yl]methyl (purity 92%, 800 mg, 1.37 mmol, yield 37%) as grayish-white solids.

[0192] 2-(3,4-dichlorophenoxy)-N-[trans-2-(hydroxymethyl)-1,3-dioxan-5-yl]acetamide [ka] (405 mg, 1.14 mmol, yield 31%); 1H NMR (400MHz, chloroform-d) δ 7.39(d, J=8.9Hz, 1H), 7.04(d, J=2.9Hz, 1H), 6.78(dd, J=8.9, 2.9Hz, 1H), 6.11(d, J=8.1Hz, 1H), 4.60(t, J=4.4Hz, 1H), 4 .44(s, 2H), 4.40-4.30(m, 1H), 4.30-4.23(m, 2H), 3.66(dd, J=6.6, 4.4Hz, 2H), 3.54-3.46(m, 2H), 1.81(t, J=6.6Hz, 1H).

[0193] 2-(3,4-dichlorophenoxy)acetic acid [trans-5-[2-(3,4-dichlorophenoxy)acetamide]-1,3-dioxan-2-yl]methyl [ka] (Purity 92%, 800 mg, 1.37 mmol, yield 37%); 1 H NMR (500MHz, chloroform-d) δ 7.36(m, 2H), 7.02(m, 2H), 6.81-6.75(m, 2H), 6.14(d,J=8.1Hz, 1H), 4.71(t,J=4.4Hz, 1 H), 4.66(s, 2H), 4.44(s, 2H), 4.38-4.30(m, 1H), 4.30-4.21(m, 4H), 3.52-3.44(m, 2H).

[0194] Step 10.b: 2-(3,4-dichlorophenoxy)-N-[trans-2-(hydroxymethyl)-1,3-dioxan-5-yl]acetamide [ka] A solution of 2-(3,4-dichlorophenoxy)acetic acid [trans-5-[2-(3,4-dichlorophenoxy)acetamide]-1,3-dioxan-2-yl]methyl (92% purity, 800 mg, 1.37 mmol) in H2O (2.8 mL), THF (2.8 mL), and MeOH (2.8 mL) was treated with LiOH (43 mg, 1.78 mmol) and stirred at rt for 1 hour. The organic solvent was removed under vacuum to obtain an aqueous residue, which was diluted with H2O (10 mL) and extracted with siRNA (2 × 10 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, and concentrated under vacuum to obtain the title compound (385 mg, 1.09 mmol, yield 73%) as a grayish-white solid; 1 H NMR (400MHz, chloroform-d) δ 7.39(d, J=8.9Hz, 1H), 7.05(d, J=2.9Hz, 1H), 6.78(dd, J=8.9, 2.9Hz, 1H), 6.11(d, J=8.2Hz, 1H), 4.60(t, J=4.4H) z, 1H), 4.44(s, 2H), 4.40-4.31(m, 1H), 4.30-4.20(m, 2H), 3.66(d, J=4.4Hz, 2H), 3.55-3.43(m, 2H), 1.80(s, 1H).

[0195] Intermediate 15 (Step 10.c): trans-5-[2-(3,4-dichlorophenoxy)acetamide]-1,3-dioxane-2-carboxylic acid [ka] NaOCl (5.0%, 0.44 mL, 0.353 mmol), NaClO2 (80%, 1.61 g, 14.1 mmol), and TEMPO (111 mg, 0.705 mmol) were added at rt to a solution of 2-(3,4-dichlorophenoxy)-N-[trans-2-(hydroxymethyl)-1,3-dioxan-5-yl]acetamide (790 mg, 2.35 mmol) and 0.67 M NaH2PO4 (19 mL, 12.9 mmol) in ACN (38 mL), and the mixture was stirred at 35°C for 48 hours. The reaction mixture was concentrated under vacuum at rt to remove the organic solvent, and the resulting aqueous solution was basicized to pH 8 / 9 using a satd aq NaHCO3 solution. The aqueous solution was washed with ELISA (2 × 30 mL), and the organic extract was discarded. The aqueous solution was then cooled to 0°C and acidified to pH 2 / 3 by slowly adding a 1 M aq HCl solution. The resulting solution was then extracted with siRNA (2 × 50 mL), and the combined organic extract was washed with H₂O (50 mL), dried over Na₂SO₄, and concentrated under vacuum to obtain the title compound (90% purity, 760 mg, 1.95 mmol, 83% yield) as a foamy grayish-white solid; 1 H NMR (400MHz, DMSO-d6) δ 8.11(d, J=7.8Hz, 1H), 7.54(d, J=8.9Hz, 1H), 7.25(d, J=2.9Hz, 1H), 6.98(dd, J=8.9, 2.9 Hz, 1H), 4.91(s, 1H), 4.55(s, 2H), 4.08-3.95(m, 3H), 3.59(m, 2H); M / Z: 348, 350, 352[MH] - ESI - RT=2.61(S4).

[0196] Scheme for Route 11 [ka]

[0197] Step 11.a: 2-[trans-2-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]-1,3-dioxan-5-yl]isoindoline-1,3-dione A solution of BF3·OEt2 (0.12 mL, 0.97 mmol) in anhydrous ACN (3 mL) was stirred at 80°C. Another solution of 2-[2-hydroxy-1-(hydroxymethyl)ethyl]isoindoline-1,3-dione (100 mg, 0.44 mmol, intermediate 1) and 2-(4-chlorophenyl)-5-(diethoxymethyl)-1,3,4-oxadiazole (94 μL, 0.44 mmol, intermediate 4) in ACN (2 mL) was added dropwise. The reaction mixture was stirred for 1 hour, then additional BF3·OEt2 (0.12 mL, 0.97 mmol) was added, and the reaction mixture was stirred for another 1 hour at 80°C. The reaction mixture was cooled to rt, quenched with satd aq NaHCO3 solution (0.1 mL), and then concentrated under vacuum. The residue was dissolved in RINKAN (10 mL) and subsequently washed with 200-3 1 1H NMR (400 MHz, chloroform-d) δ 8.12-8.08(m, 1H), 8.08-8.04(m, 2H), 7.89-7.82(m, 4H), 7.79-7.71(m, 4H), 7.54-7.49(m, 3H), 6.04(s, 1H), 4.90-4.80(m, 2H), 4.73-4.65(m, 3H) ), 4.57-4.49(m, 1H), 4.35-4.24(m, 3H), 4.19(dd, J=11.0, 5.0Hz, 1H), 4 .12(q, J=7.1Hz, 3H), 2.04(s, 4H), 1.73-1.59(m, 4H); M / Z:412, 414[M+H] + ESI + RT=3.52, 3.67(S4).

[0198] Step 11.b: trans-2-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]-1,3-dioxan-5-amine A suspension of hydrazine hydrate (0.02 mL, 0.14 mmol) and 2-[trans-2-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]-1,3-dioxan-5-yl]isoindoline-1,3-dione (33 mg, 0.06 mmol) in EtOH (0.7 mL) was stirred at rt for 2 hours. The reaction mixture was heated at 40°C for 25 hours, then at 50°C for a further 6 hours. The reaction mixture was cooled to rt, filtered through a Celite® pad, and then concentrated under vacuum to obtain the title compound (50% purity, 17 mg, 0.03 mmol, 54% yield) as a white solid; 1 H NMR (400MHz, chloroform-d) δ 8.04(m, 2H), 7.49(m, 2H), 5.80(s, 1H), 4.35(dd, J=11.4, 4.6Hz, 2H), 4.09( d, J=12.0Hz, 1H), 3.51(t, J=10.8Hz, 2H), 3.36-3.25(m, 2H);M / Z:282[M+H] + ESI + RT=0.82(S1).

[0199] Example 1 (Step 11.c): 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]-1,3-dioxan-5-yl]acetamide A solution of trans-2-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]-1,3-dioxan-5-amine (50%, 17 mg, 0.03 mmol) in DCM (0.5 mL) was treated with DIPEA (0.02 mL, 0.09 mmol) and cooled to 0°C. A solution of 2-(4-chloro-3-fluorophenoxy)acetyl chloride (7.4 mg, 0.03 mmol, intermediate 2) in DCM (0.5 mL) was slowly added. The reaction mixture was heated to rt and stirred for 1 hour. 2-(4-chloro-3-fluorophenoxy)acetyl chloride (3.0 mg, 0.01 mmol, intermediate 2) was added, and the reaction mixture was stirred at rt for 1 hour. The reaction mixture was cooled to 0°C, quenched with H2O, and concentrated under vacuum. The residue was purified by prep.HPLC (Method 4) to obtain the title compound (5.0 mg, 0.01 mmol, yield 35%) as a grayish-white powder; 1 H NMR (400MHz, chloroform-d) δ 8.07-8.01(m, 2H), 7.54-7.48(m, 2H), 7.36(t, J=8.6Hz, 1H), 6.84-6.76(m, 2H), 6.72(ddd, J=8.9, 2.9, 1.3Hz, 1H), 6.03(s, 1H), 4.53-4.44(m, 4H), 4.39-4.32(m, 1H), 3.86(dd, J=11.6, 6.6Hz, 2H);M / Z:468, 470, 472[M+H] + ESI + RT=3.65(S4).

[0200] Scheme for route 12 [ka]

[0201] Step 12.a: 2-[trans-2-[({[(benzyloxy)carbonyl]amino}amino)carbonyl]-1,3-dioxan-5-yl]-2,3-dihydro-1H-isoindole-1,3-dione A solution of trans-5-(1,3-dioxo-2,3-dihydro-1H-isoindole-2-yl)-1,3-dioxan-2-carboxylic acid (2.07 g, 7.39 mmol, intermediate 6) in anhydrous THF (49 mL) was treated by successively adding isobutyl chloroformate (0.9 mL, 7.02 mmol) and NMM (0.8 mL, 7.39 mmol) at 0°C under N2. Benzyl N-aminocarbamate (1.17 g, 7.02 mmol) was added, and the reaction mixture was stirred at 0°C for 30 minutes, then stirred at rt for 1 hour. The reaction mixture was cooled to 0°C and quenched with H2O (1 mL). The resulting mixture was concentrated under vacuum, and the residue was partitioned between RINKAN (50 mL) and H2O (50 mL). The layers were separated, and the aqueous layer was re-extracted with RINKAN (20 mL). The combined organic extracts were washed with a solution of satd aq NaHCO3 (80 mL) and brine (80 mL), dried over anhydrous Na2SO4, and then vacuum concentrated to obtain the title compound (86%, 2.86 g, 5.78 mmol, yield 78%) as a grayish-white powder; 1 H NMR (400MHz, DMSO-d6) δ 10.16-9.91(m, 1H), 9.27(s, 1H), 7.93-7.82(m, 4H), 7.44-7.27(m, 5H), 5.09(s, 2H), 5.03(s, 1H), 4.44-4.28(m, 3H), 4.22-4.12(m, 2H).

[0202] Step 12.b: trans-5-(1,3-dioxo-2,3-dihydro-1H-isoindole-2-yl)-1,3-dioxan-2-carbozide A suspension of 2-[trans-2-[({[(benzyloxy)carbonyl]amino}amino)carbonyl]-1,3-dioxan-5-yl]-2,3-dihydro-1H-isoindole-1,3-dione (86% purity, 2.86 g, 5.78 mmol) and Pd / C (10%, 0.62 g, 0.578 mmol) in EtOH (160 mL) and siRNA (50 mL) was stirred under H2 for 3 hours. Additional Pd / C (10%, 0.62 g, 0.578 mmol) was added, and the reaction mixture was stirred under H2 for a further 4 hours. N2 was passed through the reaction vessel. The reaction mixture was heated to near reflux temperature, filtered through a Celite® pad, and washed with hot EtOH. The reaction mixture was concentrated under vacuum and purified by chromatography on silica gel (0-7% MeOH in DCM) to obtain the title compound (90% purity, 290 mg, 0.90 mmol, 15% yield) as a pale yellow powder; 1 H NMR (500MHz, DMSO-d6) δ 9.32(s, 1H), 7.93-7.79(m, 4H), 4.93(s, 1H), 4.41-4.25(m, 5H), 4.17-4.08(m, 2H).

[0203] Step 12.c: trans-5-(1,3-dioxo-2,3-dihydro-1H-isoindole-2-yl)-N'-[cis-3-(trifluoromethoxy)cyclobutanecarbonyl]-1,3-dioxane-2-carbozide A solution of cis-3-(trifluoromethoxy)cyclobutanecarboxylic acid (170 mg, 0.90 mmol, intermediate 10) in anhydrous THF (7.5 mL) was treated by successively adding isobutyl chloroformate (0.11 mL, 0.85 mmol) and NMM (0.1 mL, 0.90 mmol) at 0°C. The mixture was stirred for 15 minutes, and then a suspension of trans-5-(1,3-dioxo-2,3-dihydro-1H-isoindole-2-yl)-1,3-dioxan-2-carbohydrazide (90% purity, 290 mg, 0.90 mmol) in anhydrous THF (5 mL) was added. The reaction mixture was heated to rt and stirred for 3 hours. The reaction mixture was cooled to 0°C and quenched by slowly adding H2O (5 mL). The reaction mixture was concentrated under vacuum, and the resulting residue was partitioned between H2O and ethyl acetate. The aqueous layer was re-extracted with ethyl acetate. The combined organic extracts were washed with satd aq NaHCO3 solution and brine, and then vacuum concentrated to obtain the title compound (purity 90%, 382 mg, 0.75 mmol, yield 84%) as a grayish-white powder; 1 H NMR (500MHz, DMSO-d6) δ 10.04(s, 1H), 9.96(s, 1H), 7.88(s, 4H), 5.04(s, 1H), 4.89-4.71(m, 1H), 4 .46-4.26(m, 3H), 4.26-4.10(m, 2H), 2.77-2.63(m, 2H), 2.36-2.18(m, 4H).

[0204] Step 12.d: 2-[trans-2-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl}-1,3-dioxan-5-yl]-2,3-dihydro-1H-isoindole-1,3-dione A suspension of trans-5-(1,3-dioxo-2,3-dihydro-1H-isoindole-2-yl)-N'-[cis-3-(trifluoromethoxy)cyclobutanecarbonyl]-1,3-dioxan-2-carbhydrazide (85%, 365 mg, 0.68 mmol) and Burgess reagent (647 mg, 2.71 mmol) in anhydrous THF (11 mL) was irradiated in a microwave vial at 120 °C for 3 minutes. The reaction mixture was concentrated under vacuum and purified by prep.HPLC (Method 6) to obtain the title compound (190 mg, 0.41 mmol, yield 61%) as a grayish-white solid; 1 H NMR (400MHz, DMSO-d6) δ 7.98-7.73(m, 4H), 6.09(s, 1H), 4.97-4.87(m, 1H), 4.55-4.39(m, 3H), 4. 29-4.20(m, 2H), 3.56-3.46(m, 1H), 2.92-2.83(m, 2H), 2.57-2.51(m, 2H).

[0205] Intermediate 16 (Step 12.e): trans-2-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl}-1,3-dioxan-5-amine A solution of 2-[trans-2-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl}-1,3-dioxan-5-yl]-2,3-dihydro-1H-isoindole-1,3-dione (90% purity, 330 mg, 0.68 mmol) and hydrazine hydrate (0.13 mL, 2.70 mmol) in EtOH (7.8 mL) was heated at 40°C for 6 hours, then cooled to rt and stirred for 18 hours. The resulting precipitate was filtered under vacuum and washed with EtOH. The combined filtrate was collected and concentrated under vacuum to obtain the title compound (77% purity, 250 mg, 0.62 mmol, 92% yield) as a grayish-white solid; 1H NMR (400MHz, DMSO-d6) δ 5.78(s, 1H), 4.97-4.83(m, 1H), 4.14-4.02(m, 2H), 3.52-3.39(m, 5H), 2.95(tt, J=10.2, 5.0Hz, 1H), 2.90-2.80(m, 2H), 2.55-2.51(m, 2H).

[0206] Example 2 (Step 12.f): 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl}-1,3-dioxan-5-yl]acetamide A solution of trans-2-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl}-1,3-dioxan-5-amine (77% purity, 255 mg, 0.64 mmol, intermediate 16) and DIPEA (0.33 mL, 1.90 mmol) in DCM (8 mL) was cooled to 0°C and treated with 2-(4-chloro-3-fluorophenoxy)acetyl chloride (90% purity, 173 mg, 0.70 mmol, intermediate 2). The reaction mixture was heated to rt and stirred for 1 hour. The reaction mixture was cooled to 0°C and quenched with H2O (0.1 mL), and then the reaction mixture was concentrated under vacuum. The residue was purified by prep.HPLC (Method 6), and the resulting solid was dissolved in ACN (10 mL) and H2O (10 mL). The turbid solution was heated to solubilize the substance, and then allowed to cool for 4 days. The resulting solid was collected and purified by prep.HPLC (Method 3) to obtain the title compound (62 mg, 0.13 mmol, yield 20%) as a white solid; 1¹H NMR (500MHz, chloroform-d) δ 7.35 (t, J=8.6Hz, 1H), 6.79 (dd, J=10.2, 2.9Hz, 1H), 6.75 (d, J=8.4Hz, 1H), 6.71 (ddd, J=8.9, 2.9, 1.2Hz, 1H), 5.93 (s, 1H), 4.72 (p, J=7.6Hz, 1H), 4.49 (s, 2H), 4.43 (dd, J= 11.6, 3.8Hz, 2H), 4.35(dtt, J=10.8, 7.4, 3.8Hz, 1H), 3.82(dd, J=11.6, 7.0Hz, 2H), 3 .38(tt, J=10.1, 7.8Hz, 1H), 2.94-2.86(m, 2H), 2.77-2.68(m, 2H);M / Z:496, 498[M+H] + ESI + RT=3.50(S4).

[0207] Scheme for Route 13 [ka]

[0208] Step 13.a: 2-(4-chloro-3-fluorophenoxy)-N-[2-hydroxy-1-(hydroxymethyl)ethyl]acetamide 2-(4-chloro-3-fluorophenoxy)acetic acid (200 mg, 0.98 mmol), 2-aminopropane-1,3-diol (107 mg, 1.17 mmol), and HOAt (160 mg, 1.18 mmol) were dissolved in anhydrous DMF (5 mL). Then, EDCI (225 mg, 1.17 mmol) was gradually added at 0°C. The reaction mixture was heated to rt and stirred for 17 hours. The reaction mixture was quenched with H2O (20 mL) and extracted with pharmaceutically acceptable phosphate (2 × 30 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4, and concentrated under vacuum. Purification by chromatography on silica gel (0-100% phosphate in heptane) yielded the title compound (278 mg, 1.0 mmol) as a white powder in quantitative yield; 1H NMR (500MHz, DMSO-d6) δ 7.67(d, J=8.3Hz, 1H), 7.49(t, J=8.9Hz, 1H), 7.08(dd, J=11.4, 2.9Hz, 1H), 6.85(ddd, J=9.0, 2.9, 1 .1Hz, 1H), 4.74-4.63(m, 2H), 4.54(s, 2H), 3.83-3.74(m, 1H), 3.46-3.40(m, 4H);M / Z:278, 280[M+H] + ESI + RT=0.88(S1).

[0209] Example 3 (Step 13.b): 2-(4-chloro-3-fluorophenoxy)-N-[cis-2-[1-(4-chlorophenyl)-1H-1,2,3-triazole-4-yl]-1,3-dioxan-5-yl]acetamide A suspension of 1-(4-chlorophenyl)-1H-1,2,3-triazole-4-carbaldehyde (50 mg, 0.241 mmol), CSA (6 mg, 0.03 mmol), and 2-(4-chloro-3-fluorophenoxy)-N-[2-hydroxy-1-(hydroxymethyl)ethyl]acetamide (67 mg, 0.24 mmol) in anhydrous toluene (2 mL) was heated at 110 °C for 18 hours. Additional 2-(4-chloro-3-fluorophenoxy)-N-[2-hydroxy-1-(hydroxymethyl)ethyl]acetamide (67 mg, 0.24 mmol) and CSA (6 mg, 0.03 mmol) were added, and the reaction mixture was heated at 110 °C for 5 hours. The reaction mixture was cooled to rt, and brine was added. The aqueous layer was extracted with ELISA (2 × 50 mL), dried over MgSO4, and concentrated under vacuum. The compound was purified by chromatography on silica gel (0-100% RINKAN in heptane), followed by prep.HPLC (Method 3), to obtain the title compound (10 mg, 0.02 mmol, yield 8.6%) as a white powder in a mixture of cis and trans isomers (93:7); 1H NMR (500MHz, chloroform-d) δ 7.93(s, 1H), 7.70-7.65(m, 2H), 7.55-7.49(m, 2H), 7.40-7.34(m, 1H), 7.30(t, J=8.6Hz, 1H), 6.78(dd, J=10.3, 2.9Hz, 1 H), 6.69(dd, J=8.9, 1.6Hz, 1H), 5.91(s, 1H), 4.53(s, 2H), 4.28-4.15(m, 4H), 4.11(d, J=8.3Hz, 1H);M / Z:467, 469[M+H] + ESI + RT=3.65(S6).

[0210] Scheme for Route 14 [ka]

[0211] Step 14.a: 2-[trans-2-[1-(4-chlorophenyl)-1H-1,2,3-triazole-4-yl]-1,3-dioxan-5-yl]-2,3-dihydro-1H-isoindole-1,3-dione A suspension of 1-(4-chlorophenyl)-1H-1,2,3-triazole-4-carbaldehyde (270 mg, 1.30 mmol), CSA (32 mg, 0.14 mmol), and 2-[2-hydroxy-1-(hydroxymethyl)ethyl]isoindoline-1,3-dione, and intermediate 1 (288 mg, 1.30 mmol) in anhydrous toluene (11 mL) was heated at 110 °C for 1 hour. The reaction mixture was allowed to cool to rt and diluted with cold DCM. The resulting precipitate was filtered under vacuum to obtain the title compound (305 mg, 0.74 mmol, yield 57%) as a colorless solid; 1 H NMR (400MHz, chloroform-d) δ 8.11(s, 1H), 7.89(dd, J=5.5, 3.1Hz, 2H), 7.79(dd, J=5.5, 3.1Hz, 2H), 7.75-7.68(m, 2H) , 7.57-7.50(m, 2H), 6.02(s, 1H), 4.86-4.67(m, 3H), 428-4.19(m, 2H);M / Z:411, 413[M+H] + ESI+ RT=1.29(S1).

[0212] Step 14.b: trans-2-[1-(4-chlorophenyl)-1H-1,2,3-triazole-4-yl]-1,3-dioxan-5-amine A suspension of hydrazine hydrate (0.46 mL, 3.71 mmol) and 2-[trans-2-[1-(4-chlorophenyl)-1H-1,2,3-triazole-4-yl]-1,3-dioxan-5-yl]-2,3-dihydro-1H-isoindole-1,3-dione (305 mg, 0.74 mmol) in EtOH (7.4 mL) was heated at 80°C for 1 hour. The reaction mixture was cooled to rt, and the resulting precipitate was filtered under vacuum. The filtrate was then concentrated under vacuum to obtain the title compound (200 mg, 0.69 mmol, 93% yield) as a colorless solid; 1 H NMR (400MHz, DMSO-d6) δ 8.88(s, 1H), 8.06-7.89(m, 2H), 7.72-7.58(m, 2H), 5.66(s, 1H), 4.09(dd, J=11.3, 5.0Hz, 2H), 3.52-3.39(m, 2H), 2.94 (tt, J=10.3, 5.0Hz, 1H);M / Z:281, 283, 285[M+H] + ESI + RT=0.66(S1).

[0213] Example 4 (Step 14.c): 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-[1-(4-chlorophenyl)-1H-1,2,3-triazole-4-yl]-1,3-dioxan-5-yl]acetamide A solution of 2-(4-chloro-3-fluorophenoxy)acetyl chloride (0.05 mL, 0.77 mmol, intermediate 2) in DCM (1 mL) was added at 0°C to a solution of trans-2-[1-(4-chlorophenyl)-1H-1,2,3-triazole-4-yl]-1,3-dioxan-5-amine (72 mg, 0.26 mmol) and Et3N (0.21 mL, 1.54 mmol) in DCM (1.2 mL). The reaction mixture was heated to rt and stirred for 15 minutes. The reaction mixture was diluted with aq NaHCO3, and the insoluble material was isolated by filtration. The organic layer was collected, dried over Na2SO4, and concentrated under vacuum. The residue (with the solid isolated by suction filtration) was triturized with ACN to obtain the title compound (87 mg, 0.18 mmol, yield 70%) as a grayish-white solid; 1 H NMR (400MHz, DMSO-d6) δ 8.94(s, 1H), 8.17(d, J=7.6Hz, 1H), 7.99(d, J=8.9Hz, 2H), 7.67(d, J=8.9Hz, 2H), 7.52(t, J=8.9Hz, 1H), 7.10(dd, J=11.3, 2. 8Hz, 1H), 6.88(dd, J=8.9, 1.8, 1H), 5.80(s, 1H), 4.57(s, 2H), 4.23-4.08(m, 3H), 3.85-3.68(m, 2H); M / Z: 511, 513, 515[M+H] + ESI + RT=3.58(S4).

[0214] Scheme for Route 15 [ka]

[0215] Step 15.a: 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-{N'-[(4,4,4-trifluorobutoxy)carbonyl]hydrazinecarbonyl}-1,3-dioxan-5-yl]acetamide NMM (80 μL, 0.7 mmol) and isobutyl chloroformate (90 μL, 0.7 mmol) were added under N2 conditions at 0°C to a solution of trans-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-1,3-dioxane-2-carboxylic acid (88%, 274 mg, 0.7 mmol, intermediate 8) in anhydrous THF (6.5 mL), and the mixture was stirred for 15 minutes. N-aminocarbamic acid 4,4,4-trifluorobutyl (135 mg, 0.7 mmol, intermediate 11) was added, and the reaction mixture was heated to rt and stirred for 17 hours. The reaction mixture was cooled to 0°C, and additional NMM (40 μL, 0.35 mmol) and isobutyl chloroformate (45 μL, 0.35 mmol) were added. The reaction mixture was heated to rt and stirred for 1 hour. The reaction mixture was diluted with RINKAN (30 mL), washed with H2O (30 mL), a solution of saturated aq NaHCO3 (30 mL), and brine (30 mL), dried over anhydrous Na2SO4, and then concentrated under vacuum. The resulting solid was triturated with ACN to obtain the title compound (222 mg, 0.442 mmol, yield 61%) as a white solid; 1 H NMR (400MHz, DMSO-d6) δ 9.92(s, 1H), 9.25-8.65(m, 1H), 8.10(d, J=7.6Hz, 1H), 7.50(t, J=8.9Hz, 1H), 7.08(dd, J=11.3, 2.8Hz, 1H), 6.85(ddd, J=9 .0, 2.8, 1.1Hz, 1H), 4.89(s, 1H), 4.54(s, 2H), 4.14-3.96(m, 5H), 3.67-3.51(m, 2H), 2.39-2.19(m, 2H), 1.87-1.61(m, 2H); 19 F{ 1 ¹H NMR (376 MHz, chloroform-d) δ -64.91- -65.02 (m, 3F), -113.96 (s, 1F); M / Z: 502, 504 [M+H] + ESI + RT=0.98(S2).

[0216] Example 5 (Step 15.b): 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-[5-(4,4,4-trifluorobutoxy)-1,3,4-oxadiazole-2-yl]-1,3-dioxan-5-yl]acetamide [ka] A suspension of 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-{N'-[(4,4,4-trifluorobutoxy)carbonyl]hydrazinecarbonyl}-1,3-dioxan-5-yl]acetamide (162 mg, 0.32 mmol) in ACN (5 mL) was to be mixed with K2CO3 (223 mg, 1.6 mmol) and TsCl (154 mg, 0.81 mmol) at rt. The resulting mixture was heated to 80°C and stirred for 1.5 hours. The reaction mixture was cooled to rt, diluted with DCM (30 mL), washed with H2O (30 mL), saturated aq NaHCO3 solution (30 mL), and brine (30 mL), dried over anhydrous Na2SO4, and then concentrated under vacuum. The title compound (65 mg, 0.13 mmol, 41% yield) was purified by prep.HPLC (Method 3) to obtain a colorless viscous substance; 1 H NMR (400MHz, DMSO-d6) δ 8.19(d, J=7.6Hz, 1H), 7.50(t, J=8.9Hz, 1H), 7.08(dd, J=11.3, 2.8Hz, 1H), 6.85(dd, J=8.9, 1.8H z, 1H), 5.82(s, 1H), 4.62-4.45(m, 4H), 4.20-3.99(m, 3H), 3.82-3.67(m, 2H), 2.10-1.92(m, 2H); 19 F{ 1 ¹H} NMR (376 MHz, chloroform-d) δ -64.89 (3F, s), -113.95 (1F, s); M / Z: 484, 486 [M+H] + ESI + RT=3.42(S4).

[0217] The following examples were manufactured using route 15.

[0218] Example 6: 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}-1,3-dioxan-5-yl]acetamide [ka] Use intermediates 8 and 12; 1 H NMR (400MHz, DMSO-d6) δ 8.22(d, J=7.7Hz, 1H), 7.51(t, J=8.9Hz, 1H), 7.08(dd, J=11.4, 2.8Hz, 1H), 6.85(ddd, J=8.9, 2.8, 1.1Hz, 1H), 5.84(s, 1H), 4.79-4.66(m, 2H), 4.56(s, 2H), 4.50-4.42(m, 2H), 4.22-4.01(m, 3H), 3.75(t, J=10.1Hz, 2H);M / Z:486, 488[M+H] + ESI + RT=3.35(S4).

[0219] Example 7: 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-{5-[3-(trifluoromethoxy)azetidine-1-yl]-1,3,4-oxadiazole-2-yl}-1,3-dioxan-5-yl]acetamide [ka] Use intermediates 8 and 13; 1 H NMR (400MHz, DMSO-d6) δ 8.18(d, J=7.6Hz, 1H), 7.50(t, J=8.9Hz, 1H), 7.08(dd, J=11.3, 2.8Hz, 1H), 6.85(ddd, J=9.0, 2.8, 1.2Hz, 1H), 5.78(s, 1H), 5.32 (tt, J=7.0, 4.1Hz, 1H), 4.59-4.43(m, 4H), 4.26(dd, J=9.7, 4.0Hz, 2H), 4.18-4.01(m, 3H), 3.74(t, J=9.6Hz, 2H);M / Z:497, 499[M+H] + ESI + RT=3.26(S4).

[0220] Example 8: 2-[3-chloro-4-(difluoromethyl)phenoxy]-N-[trans-2-{5-[3-(trifluoromethoxy)azetidine-1-yl]-1,3,4-oxadiazole-2-yl}-1,3-dioxan-5-yl]acetamide [ka] Use intermediates 9 and 13; 1 H NMR (400MHz, DMSO-d6) δ 8.21(d, J=7.5Hz, 1H), 7.63(d, J=8.8Hz, 1H), 7.28-6.97(m, 3H), 5.79(s, 1H), 5.32 (tt, J=7.0, 4.1Hz, 1H), 4.62(s, 2H), 4.51(dd, J=9.6, 6.8Hz, 2H), 4.26(dd, J=9.6, 4.0Hz, 2H), 4.18-4.01(m, 3H), 3.81-3.67(m, 2H); 19 F NMR (376 MHz, DMSO-d6) δ -58.47, -112.49(d, J=54.6Hz);M / Z:529, 531[M+H] + ESI + RT=3.38(S4).

[0221] Example 9: 2-(3,4-dichlorophenoxy)-N-[trans-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}-1,3-dioxan-5-yl]acetamide [ka] Use intermediates 15 and 12: 1H NMR (500MHz, chloroform-d) δ 7.40(d, J=8.9Hz, 1H), 7.08(d, J=2.9Hz, 1H), 6.85-6.79(m, 2H), 5.83(s, 1H), 4.77-4.71(m, 2H), 4.49(s, 2H), 4.41( M / Z: 502, 504, 506 [M+H] + ESI + RT=3.56(S4).

[0222] Scheme for Route 16 [ka]

[0223] Step 16.a: 2-[(6-chloro-5-fluoropyridine-3-yl)oxy] tert-butyl acetate To a solution of 6-chloro-5-fluoropyridine-3-ol (4.90 g, 33.2 mmol) in DMF (50 mL), tert-butyl bromoacetate (4.5 mL, 34.9 mmol) and K2CO3 (13.8 g, 0.0996 mol) were added, and the resulting mixture was stirred at 65°C for 2 hours. The reaction mixture was cooled to rt, suspended in RINKAN (100 mL), and washed with H2O (2 × 50 mL) and brine (50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under vacuum to obtain the title compound (9.00 g, 32.7 mmol, 98% yield) as a brown oil; 1 ¹H NMR (500 MHz, chloroform-d) δ 7.91 (d, J=2.6 Hz, 1H), 7.07 (dd, J=9.1, 2.6 Hz, 1H), 4.55 (s, 2H), 1.53-1.39 (m, 9H); M / Z: 262, 264 [M+H] + ESI + RT=1.00 min(S2).

[0224] Step 16.b: 2-[(6-chloro-5-fluoropyridine-3-yl)oxy]acetic acid 4M HCl (25 mL, 98.0 mmol) in 1,4-dioxane was added to tert-butyl 2-[(6-chloro-5-fluoropyridine-3-yl)oxy]acetate (9.00 g, 32.7 mmol), and the resulting mixture was stirred at rt for 2 hours. Further addition of 4M HCl (25 mL, 98.0 mmol) in 1,4-dioxane was added, and the reaction mixture was stirred at 50°C for 5 hours. The reaction mixture was concentrated under vacuum, and then triturated with Et2O and heptane. The resulting precipitate was filtered under vacuum to obtain the title compound (6.48 g, 31.2 mmol, 96% yield) as a grayish-white solid; 1 H NMR (500MHz, DMSO-d6) δ 13.22(s, 1H), 8.07(d, J=2.6Hz, 1H), 7.76(dd, J=10.4, 2.6Hz, 1H), 4.85(s, 2H); M / Z:206, 208[M+H] + ESI + RT=0.60min(S2).

[0225] Example 10 (Step 16.c): 2-[(6-chloro-5-fluoro-3-pyridyl)oxy]-N-[trans-2-[5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl]-1,3-dioxan-5-yl]acetamide [ka] A solution of 2-[(6-chloro-5-fluoropyridine-3-yl)oxy]acetic acid (34 mg, 0.163 mmol) in THF (2 mL) was cooled to 0°C and treated with isobutyl chloroformate (20 μL, 0.155 mmol) and NMM (18 μL, 0.163 mmol). The reaction mixture was stirred for 15 minutes, and then a solution of trans-2-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl}-1,3-dioxan-5-amine (50 mg, 0.163 mmol, intermediate 16, as described in route 12) in THF (1 mL) was added dropwise. The reaction mixture was stirred at rt for 1 hour, quenched with H2O (2 drops), and then concentrated under vacuum. The title compound (37 mg, 0.0745 mmol, 46% yield) was purified by prep.HPLC (Method 3) to obtain a white powder; 1 H NMR (500MHz, chloroform-d) δ 8.03(d, J=2.6Hz, 1H), 7.17(dd, J=8.8, 2.6Hz, 1H), 6.78(d, J=8.4Hz, 1H), 5.96(s, 1H), 4.77-4.67(m, 1H), 4.57(s, 2H), 4.49-4.41( M / Z:497, 499[M+H] + ESI + RT=3.15(S4).

[0226] II. Biological Assays HEK-ATF4 High-Content Imaging Assay The example compounds were tested in a HEK-ATF4 high-content imaging assay to evaluate their pharmacological efficacy in preventing tunicamycin-induced ISR. Wild-type HEK293 cells were plated at a density of 12,000 cells per well in growth medium (containing DMEM / F12, 10% FBS, 2 mM L-glutamine, 100 U / mL penicillin-100 μg / mL streptomycin) in a 384-well imaging assay plate 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 serially diluted with dimethyl sulfoxide (DMSO), spotted onto an intermediate plate, and then 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 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 and 5% CO2 for 6 hours. The cells were then fixed (4% PFA in PBS, room temperature for 20 minutes) 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 with 405 nm and 488 nm excitation. Finally, images were analyzed using a script-based algorithm. The primary readout HEK-ATF4 monitored the ATF4 signal ratio between the nucleus and cytoplasm. Tunicamycin induced an increase in the overall ATF4 ratio signal, which was prevented by example compounds that modulated the ISR.Furthermore, the 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 result in a significant decrease in CellCount.

[0227] The activity of the tested example compounds is shown in Table 3 below: +++=IC 50 1~500nM;++=IC 50 >500~2000nM;+=IC 50 >2000~15000nM.

[0228] [Table 3]

[0229] Protocol - Measurement of the effect on the hERG channel by tail current recording using in vitro Rapid ICE The efficacy of the example compounds in inhibiting human ERG potassium channel (hERG) tail current was evaluated using a Rapid ICE (rapid ion channel electrophysiology) assay in recombinant HEK293 cell lines stably transfected with hERG cDNA under an inducible promoter. Rapid ICE is an automated patch-clamp assay using the QPatch HTX system (Sophion Bioscience A / S). Briefly, inducible HEK hERG cells were cultured in minimal essential medium supplemented with 10% FBS, 1% non-essential amino acids, 1% sodium pyruvate, 2 mM l-glutamine, 15 μg / mL blastosidine, and 100 μg / mL hygromycin. hERG channel expression induction was achieved by adding 10 μg / mL tetracycline 24, 48, or 72 h prior to recording.

[0230] On the day of the experiment, cells were detached using TrypLE and prepared for loading into the instrument. The cells were resuspended in 7 mL of serum-free medium containing 25 mM Hepes and a soy trypsin inhibitor, and immediately placed into the cell storage tank of the instrument. The extracellular buffer composition was (mM): NaCl 137, KCl 4, CaCl 21.8, MgCl 21.0, d-glucose 10, N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) 10, with 1 M NaOH, and pH 7.4. The intracellular solution composition was (mM): KCl 130, MgCl 21.0, ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) 5, MgATP 5, HEPES 10, with 1 M KOH, and pH 7.2. The potential protocol included the following steps: a 200ms step from -80 to -50mV, a 4.8-second step at +20mV, a 5-second step down to -50mV, and then a step holding the potential at -80mV. The example compound was dissolved in DMSO and then diluted in extracellular buffer to achieve the final test concentrations (0.3, 3, and 30 μM) in 0.3% DMSO. The potential protocol was performed and continuously recorded throughout the experiment. A vehicle equivalent to 0.3% DMSO in extracellular buffer was then applied for 3 minutes, followed by a triple application to the example compound. The standard combined exposure time was 5 minutes. The effect of the example compound on each cell was calculated by averaging the tail current amplitude values ​​recorded from the four consecutive potential pulses and comparing them to the vehicle pretreatment to calculate the residual current (% control). The data was reported as inhibition % for each concentration tested, and IC50. 50 The values ​​were estimated using QPatch software. At least two cells were tested, and further tests were performed if the results were variable.

[0231] [Table 4]

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Claims

1. Equation (I) 【Chemistry 1】 A compound of or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein in the formula, R a1 , R a2 , R a3 , R a4 , R a5 , and R a6 H is; A 1 is a triazole or an oxadiazole, provided that the ring atoms of ring A marked with an asterisk 1 are carbon atoms, where A 1 is optionally substituted with one R 4 ; Each R 4 These are independently halogen, CN, OR 5 , or C 1-6 It is alkyl, and here C 1-6 Alkyl is optionally substituted with one or more halogens, either the same or different; R 5 is H or C 1-6 It is alkyl, and here C 1-6 Alkyl is optionally substituted with one or more halogens, either the same or different; A 2 is R 6a Or A 2a And; R 6a OR 6a1 , SR 6a1 , N(R 6a1 R 6a2 ); 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 a halogen, OR 6a3 , CN, and A 2a Optionally substituted with one or more substituents selected from the group consisting of, where the substituents are the same or different; R 6a1 and R 6a2 H, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and A 2 a Independently selected from the group consisting of, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkinyl is a halogen, CN, OR 6a3 A 2a , and OA 2a Optionally substituted with one or more substituents selected from the group consisting of, where the substituents are the same or different; R 6a3 is H, or C 1-4 It is alkyl, and here C 1-4 Alkyl is optionally substituted with one or more halogens, either the same or different; A 2a A is phenyl, cyclobutyl, azetidinyl, or a 5-6 member aromatic heterocycline, where A 2a is one or more R, either the same or different. 6 It may be replaced in some cases; Each R 6 R is independent of 6b OH, OR 6b , halogen, or CN, where R 6b is cyclopropyl, C 1-6 Alkyl, C 2-6 Alkenil, or C 2-6 It is alkinyl, and here R 6b may be replaced by one or more halogens, either the same or different; or Two R's 6 They are joined together with the atoms to which they are bonded to form ring A 2b Forming; A 2b Phenylenide, C 3-7 It is a cycloalkyl or a 3- to 7-membered heterocycline, where A 2b is one or more R, either the same or different. 7 It may be replaced in some cases; Each R 7 C is independent 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 Alkynnyls may be substituted with one or more halogens, either the same or different; R 1 is H; R 2 is H; and R 3 is A 3 And; R 2a is H; Each A 3 A is independently phenyl, pyridyl, or pyrazinyl, where A 3 is one or more R, either the same or different. 10 It may be replaced in some cases; Each R 10 These are independently F, Cl, Br, CHF 2 CF 3 OCF 3 CH=O, CH 2 OH or CH 3 That is, The above-mentioned compounds or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

2. A 1 is either unsubstituted or one R 4 A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, which is substituted with .

3. A 1 is a compound according to claim 2 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, which is unsubstituted.

4. A 1 teeth, 【Chemistry 2】 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

5. A 2 is R 6a The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

6. R 6a is OR 6a1 ; or R 6a is one or more halogens and / or one A 2a and / or one OR 6a3 and optionally substituted C 1-6 alkyl The compound described in claim 5, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

7. R 6a1 is, A 2a Either or one or more halogens and / or one A 2a and / or one OR 6a3 C which may be replaced depending on the case 1-6 The compound according to claim 6, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, which is alkyl.

8. R 6a OR 6a1 is; or R 6a is one or more halogens and / or one OR 6a3 C which may be replaced depending on the case 1-6 A compound according to any one of claims 5 to 7, which is alkyl, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

9. R 6a1 is one or more F and / or one OR 6a3 C which may be replaced depending on the case 1-6 The compound according to claim 8, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, which is alkyl.

10. A 2 is A 2a The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

11. A 2a is one or two R's that are the same or different. 6 A compound according to any one of claims 1 to 6 and 10, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, which is substituted with.

12. Each R 6 These are independently F, Cl, and CF 3 , OCH 3 OCF 3 ,CH 3 ,CH 2 CH 3 The compound according to any one of claims 1 to 6, 10 to 11, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, which is cyclopropyl.

13. A 3 is one or two R's that are the same or different. 10 A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, which is substituted with.

14. The compound is 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]-1,3-dioxan-5-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl}-1,3-dioxan-5-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)-N-[cis-2-[1-(4-chlorophenyl)-1H-1,2,3-triazole-4-yl]-1,3-dioxan-5-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-[1-(4-chlorophenyl)-1H-1,2,3-triazole-4-yl]-1,3-dioxan-5-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-[5-(4,4,4-trifluorobutoxy)-1,3,4-oxadiazole-2-yl]-1,3-dioxan-5-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}-1, 3-dioxan-5-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)-N-[trans-2-{5-[3-(trifluoromethoxy)azetidine-1-yl]-1,3,4-oxadiazole-2-yl}-1,3-dioxan-5-yl]acetamide; 2-[(6-chloro-5-fluoro-3-pyridyl)oxy]-N-[trans-2-[5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl]-1,3-dioxan-5-yl]acetamide; 2-[3-chloro-4-(difluoromethyl)phenoxy]-N-[trans-2-{5-[3-(trifluoromethoxy)azetidine-1-yl]-1,3,4-oxadiazole-2-yl}-1,3-dioxan-5-yl]acetamide; or 2-(3,4-dichlorophenoxy)-N-[trans-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}-1,3-dioxan-5-yl]acetamide The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

15. The compound is given by formula (Ia) 【Transformation 3】 The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

16. A pharmaceutical composition comprising at least one compound as defined in any one of claims 1 to 15, 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 physiologically active compounds or pharmaceutical compositions.

17. A pharmaceutical composition for use as a drug, comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition according to claim 16, which is used in a method for treating or preventing one or more diseases or disorders related to integrated stress response.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition according to claim 16, which is used in a method of treating or preventing one or more diseases or disorders selected from the group consisting of leukodystrophy, intellectual disability syndrome, neurodegenerative diseases and disorders, neoplasms, infectious diseases, inflammatory diseases, musculoskeletal diseases, metabolic diseases, eye diseases, and more specifically, 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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