modulators of the integrated stress response pathway

Abstract

The present invention relates to compounds of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein R 1 , R 2 , R 2a , R 3 , R 4 , R 4a , R 4b , R 4c , R 4d , R 4e , R 5 , R 6 have the meanings as indicated in the description and claims. The present invention also relates to pharmaceutical compositions comprising said compounds, their use as medicaments and use in methods of treating or preventing one or more diseases or disorders associated with integrated stress response

Description

[0001] This invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof.

[0002]

[0003] Where R 1 ,R 2 ,R 2a ,R 3 ,R 4 ,R 4a ,R 4b ,R 4c ,R 4d ,R 4e ,R 5 ,R 6 It has the meaning as indicated in the specification and claims. The invention further relates to pharmaceutical compositions comprising the said compounds, their use as medicines, and their use in methods for treating or preventing one or more diseases or disorders related to integrated stress responses.

[0004] Integrated stress response (ISR) is a cellular stress response common to all eukaryotes (1). Abnormal regulation of ISR signaling has important pathological consequences, particularly those associated with inflammation, viral infections, diabetes, cancer, and neurodegenerative diseases.

[0005] ISR is a common feature of different types of cellular stress, leading to phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) at ​​serine 51, thereby inhibiting normal protein synthesis and the expression of stress-response genes (2). In mammalian cells, this phosphorylation is carried out by four families of eIF2α kinases: PKR-like ER kinase (PERK), double-stranded RNA-dependent protein kinase (PKR), heme-regulated eIF2α kinase (HRI), and generalized regulatory repressor protein kinase 2 (GCN2), each responding to different environmental and physiological stresses (3).

[0006] eIF2α, together with eIF2β and eIF2γ, forms the eIF2 complex, a key player in the initiation of normal mRNA translation (4). The eIF2 complex binds GTP and Met-tRNA. i This forms a ternary complex (eIF2-GTP-Met-tRNA). i ), which is recruited by ribosomes for translation initiation (5,6).

[0007] eIF2B is a heterodecame complex composed of five subunits (α, β, γ, δ, ε), which are formed in duplicate to form a GEF active decamer (7).

[0008] In response to ISR activation, phosphorylated eIF2α inhibits eIF2B-mediated GDP-GTP exchange, leading to reduced ternary complex formation and thus inhibiting the translation of normal mRNAs characterized by ribosome binding to the 5'AUG start codon (8). Under these conditions of reduced ternary complex abundance, the translation of several specific mRNAs, including the mRNA encoding the transcription factor ATF4, is activated through mechanisms involving translational alterations in upstream ORFs (uORFs) (7,9,10). These mRNAs typically contain one or more uORFs, which normally function in unstressed cells to restrict ribosome flow to the major encoding ORF. For example, under normal conditions, uORFs in the 5'UTR of ATF occupy ribosomes and prevent translation of the ATF4 coding sequence. However, under stress conditions, i.e., conditions of reduced ternary complex formation, the likelihood of ribosome scanning across these upstream ORFs and initiating translation at the ATF4-encoding ORF increases. ATF4 and other stress response factors expressed in this manner subsequently control the expression of a range of other stress response genes. The acute phase involves the expression of proteins aimed at restoring homeostasis, while the chronic phase leads to the expression of pro-apoptotic factors (1,11,12,13).

[0009] Upregulation of markers of ISR signaling has been confirmed in a variety of diseases, including cancer and neurodegenerative diseases. In cancer, ER stress-regulated translation increases tolerance to hypoxia and promotes tumor growth (14,15,16), and gene-targeted deletion of PERK has been shown to slow the transformation of PERK. - / - Growth of tumors derived from mouse embryonic fibroblasts (14,17). Furthermore, a recent report has provided evidence of concept that activators of eIF2B are effective in treating an aggressive metastatic prostate cancer using a patient-derived xenograft model in mice (28). In conclusion, the prevention of cell-protective ISR signaling may represent an effective antiproliferative strategy for the treatment of at least some forms of cancer.

[0010] Furthermore, regulation of ISR signaling has demonstrated effectiveness in maintaining synaptic function and reducing neuronal degeneration, as has been shown in neurodegenerative diseases characterized by activation of misfolded proteins and the unfolded protein response (UPR), such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD), and Jakob Creutzfeld (prion) disease (18,19,20). In prion diseases (an example of existing neurodegenerative diseases), pharmacological and genetic repression of ISR signaling has been shown to normalize protein translation levels, salvage synaptic function, and prevent neuronal loss (21). Specifically, reducing phosphorylated eIF2α levels by overexpressing phosphatases that control phosphorylated eIF2α levels increases survival in prion-infected mice, while persistent eIF2α phosphorylation decreases survival (22).

[0011] Furthermore, direct evidence of the importance of controlling protein expression levels for proper brain function exists in the form of rare genetic disorders affecting the function of eIF2 and eIF2B. Mutations in eIF2γ that disrupt the complex integrity of eIF2 and thus lead to reduced levels of normal protein expression are associated with intellectual disability syndrome (ID) (23). Partial loss-of-function mutations in subunits of eIF2B have been shown to be a cause of the rare leukodystrophy leukoablation disease (VWMD) (24,25). Specifically, stabilization of partial loss-of-function eIF2B by small molecules associated with ISRIB in VWMD mouse models has been shown to reduce ISR markers and improve function and pathological endpoints (26,27).

[0012] Modulators of the eIF2α pathway are described in WO 2014 / 144952 A2. Modulators of the integrated stress pathway are described in WO 2017 / 193030 A1, WO 2017 / 193034 A1, WO 2017 / 193041 A1, and WO 2017 / 193063 A1. Inhibitors of the ATF4 pathway are described in WO 2017 / 212423 A1, WO 2017 / 212425 A1, WO 2018 / 225093 A1, WO 2019 / 008506 A1, and WO 2019 / 008507 A1. WO 2019 / 032743 A1, WO 2019 / 046779 A1, WO2020 / 167994 A1, WO 2020 / 168011 A1 and WO 2020 / 181247 A1 relate to eukaryotic initiation factor 2B modulators. WO 2020 / 77217 A1 describes compounds, compositions and methods for modulating integrated stress response (ISR) and for treating related diseases, disorders and conditions.

[0013] Other literature describing modulators of integrated stress pathways includes WO 2019 / 090069 A1, WO 2019 / 090074A1, WO 2019 / 090076A1, WO 2019 / 090078A1, WO 2019 / 090081A1, WO 2019 / 090082A1, WO 2019 / 090085 A1, WO 2019 / 090088 A1, WO 2019 / 090090 A1, WO 2020 / 223536 A1, WO2020 / 223538 A1, WO 2020 / 252207 A1, and WO 2020 / 252205. A1, European patent applications 20203312.2, 20203311.4 and 21192154.9, WO 2021 / 180774 A1, WO 2021 / 151865 A1, WO 2020 / 216764 A1 and WO 2020 / 216766 A1.

[0014] Regulators of eukaryotic initiation factors are described in WO 2019 / 183589 A1. Inhibitors of the integrated stress response pathway are described in WO 2019 / 118785 A2, WO 2019 / 236710 A1, and WO 2020 / 176428 A1. Heteroaryl derivatives as ATF4 inhibitors are described in WO 2019 / 193540 A1. Bicyclic aromatic ring derivatives as ATF4 inhibitors are described in WO 2019 / 193541 A1. Inhibitors of the ATF4 pathway are described in WO 2020 / 031107 A1 and WO 2020 / 012339 A1.

[0015] However, there is still a need for new compounds with good pharmacokinetic properties that can be used as modulators of integrated stress response pathways.

[0016] Therefore, one object of the present invention is to provide a new class of compounds that serve as modulators of integrated stress response pathways, which can effectively treat diseases associated with integrated stress response pathways and can exhibit improved pharmaceutically relevant properties, including activity, solubility, selectivity, ADMET performance and / or reduced side effects.

[0017] Therefore, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof.

[0018]

[0019] in

[0020] R 1 For H or C 1-4 Alkyl, preferably H, wherein C 1-4 Alkyl groups may optionally be substituted with one or more identical or different halogens;

[0021] R 2 For H, F or C 1-4 Alkyl, wherein C 1-4 Alkyl groups may optionally be substituted with one or more identical or different halogens;

[0022] R 2a It can be H or F, preferably H;

[0023] R 3 It is a phenyl or a 6-membered aromatic heterocyclic group, wherein R 3 Optional by one or more identical or different R 7 replace;

[0024] R 7 Halogen, CN, C(O)OR 8 OR 8C(O)R 8 C(O)N(R) 8 R 8a ), S(O)2N(R 8 R 8a ), S(O)N(R 8 R 8a ), S(O)2R 8 S(O)R 8 、N(R 8 )S(O)2N(R 8a R 8b ), SR 8 、N(R 8 R 8a NO2, OC(O)R 8 、N(R 8 )C(O)R 8a 、N(R 8 )S(O)2R 8a 、N(R 8 )S(O)R 8a 、N(R 8 )C(O)OR 8a 、N(R 8 )C(O)N(R 8a R 8b ), OC(O)N(R 8 R 8a C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group, where C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally surrounded by one or more identical or different R groups. 9 replace;

[0025] R 8 R 8a R 8b Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group, where C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group may be optionally substituted by one or more identical or different halogens;

[0026] R 9 It is halogen, CN, C(O)OR 10 OR 10 C(O)R 10 C(O)N(R) 10 R 10a), S(O)2N(R 10 R 10a ), S(O)N(R 10 R 10a ), S(O)2R 10 S(O)R 10 、N(R 10 )S(O)2N(R 10a R 10b ), SR 10 、N(R 10 R 10a NO2, OC(O)R 10 、N(R 10 )C(O)R 10a 、N(R 10 SO2R 10a 、N(R 10 )S(O)R 10a 、N(R 10 )C(O)N(R 10a R 10b ), N(R 10 )C(O)OR 10a orOC(O)N(R 10 R 10a );

[0027] R 10 R 10a R 10b Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group, where C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group may be optionally substituted by one or more identical or different halogens.

[0028] R 4 It is H, C(O)OC 1-4 Alkyl or C 1-4 Alkyl, wherein C(O)OC 1-4 Alkyl and C 1-4 The alkyl group may optionally be substituted by one or more substituents selected from the following: halogen, OH, and OC. 1-3 Alkyl groups, wherein the substituents are the same or different;

[0029] R 4a R 4b R 4c R 5 Independently selected from H, halogens and C 1-4 Alkyl; and

[0030] R 4dR 4e Independently selected from H, OH, OC 1-4 Alkyl, halogen and C 1-4 alkyl;

[0031] Or R 4d and R 4e One of them and R 4 Forms methylene or ethylene;

[0032] Or R 4 With R 4c Formation of ethylene;

[0033] Or R 4b With R 4d Forming covalent single bonds;

[0034] R 6 It is a 7- to 12-membered heterobicyclic group, in which R 6 Optional by one or more identical or different R 11 replace;

[0035] R 11 It is R 12 OH, OR 12 halogen or CN, and

[0036] R 12 Cyclopropyl, C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group, wherein R 12 Optional by one or more identical or different R 13 replace;

[0037] R 13 Halogen, CN or OR 14 ;

[0038] R 14 For H or C 1-4 Alkyl, wherein C 1-4 The alkyl group may optionally be substituted with one or more of the same or different halogens.

[0039] Surprisingly, the compounds of the embodiments disclosed in this invention have advantageous physicochemical properties and / or selectivity, which, when combined, contribute to achieving beneficial therapeutic efficacy while limiting unintended consequences.

[0040] Where the variable or substituent can be selected from a set of different variants and such variable or substituent appears more than once, the variants can be the same or different.

[0041] Within the meaning of this invention, the following terms are used:

[0042] The term "optionally substituted" refers to either unsubstituted or substituted components. Generally, but not limited to, "one or more substituents" refers to one, two, or three substituents, preferably one or two, and more preferably one substituent. These substituents can generally be the same or different. The term "one or more substituents" also indicates, for example, one, two, three, four, or five, preferably, for example, one, two, three, or four.

[0043] "Alkyl" refers to a straight-chain or branched hydrocarbon chain. Each hydrogen atom on an alkyl carbon can be replaced by a further specified substituent.

[0044] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain containing at least one carbon-carbon double bond. Each hydrogen atom of an alkenyl carbon may be replaced by a further specified substituent.

[0045] "Alynyl" refers to a straight-chain or branched hydrocarbon chain containing at least one carbon-carbon triple bond. Each hydrogen atom in the alkynyl carbon can be replaced by a further specified substituent.

[0046] “C 1-4 "Alkyl" refers to an alkyl chain having 1-4 carbon atoms, if present at the end of the molecule, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or when two parts of the molecule are connected by an alkyl group, such as -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. 1-4 Each hydrogen atom in an alkyl carbon can be replaced by a further specified substituent. The term "C" is defined accordingly. 1-3 alkyl".

[0047] “C 1-6 "Alkyl" refers to an alkyl chain having 1-6 carbon atoms, if present at the end of the molecule, for example: C 1-4 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or, when two parts of the molecule are connected by an alkyl group, such as -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. C 1-6 Each hydrogen atom in an alkyl carbon can be replaced by a further specified substituent.

[0048] “C 2-6"Alkenyl" refers to an alkenyl chain with 2-6 carbon atoms, if present at the end of a molecule, such as: -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, -CH=CH-CH=CH2, or when two parts of a molecule are connected by an alkenyl group, such as -CH=CH-. 2-6 Each hydrogen atom of the alkenyl carbon can be replaced by a further specified substituent.

[0049] “C 2-6 "Alkyne" refers to an alkynyl chain with 2-6 carbon atoms, if present at the end of a molecule, such as -C≡CH, -CH2-C≡CH, CH2-CH2-C≡CH, CH2-C≡C-CH3, or when two parts of a molecule are connected by an alkynyl group, such as -C≡C-. 2-6 Each hydrogen atom in the alkynyl carbon can be replaced by a further specified substituent.

[0050] “C 3-7 "Cycloalkyl" or "C" 3-7 "Cycloalkyl ring" refers to a cycloalkyl chain having 3-7 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 further specified herein. The term "C" is defined accordingly. 3-5 "Cycloalkyl" or "C" 3-5 Cycloalkyl rings.

[0051] "C5 cycloalkylene" refers to a divalent cycloalkylene ring with 5 carbon atoms, namely a divalent cyclopentyl ring.

[0052] "C5 cycloene group" refers to a divalent cycloene group, namely divalent cyclopentene or cyclopentadiene.

[0053] “C 4-12 "Bicycloalkyl" or "C" 4-12 "Bicycloalkyl ring" refers to a bicyclic fused, bridged, or spiroalkyl chain having 4-12 carbon atoms, such as hexahydroindane, octahydrocyclopentadiene, bicyclo[2.2.1]heptane, or spiro(3.2)hexane. Each hydrogen atom of the bicycloalkyl carbon may be replaced by a substituent further specified herein.

[0054] "Halogen" refers to fluorine, chlorine, bromine, or iodine. Fluorine or chlorine is usually preferred as the halogen.

[0055] "3-7 membered heterocyclic group" or "3-7 membered heterocycle" refers to a ring having 3, 4, 5, 6 or 7 ring atoms, which may contain up to a maximum number of double bonds (aromatic rings or fully saturated, partially saturated or unsaturated non-aromatic rings), wherein at least one ring atom up to 4 ring atoms are replaced by heteroatoms selected from sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-), and wherein said ring is connected to the rest of the molecule via a carbon or nitrogen atom. Examples of 3-7 membered heterocycles are azirropropane, azirrobutane, oxacyclobutane, thioheterobutane, furan, thiophene, pyrrole, pyrrolin, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazazole, isothiazoline, thiadiazole, thiadizoline, tetrahydrofuran, tetrahydrothiophene, pyrrole, imidazoline, pyrazoline, oxazoline, isoxazoline, thiazoline, isothiazoline, thiazoline, thiadizoline, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazoline, pyridine, pyrazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetraazole, triazole, triazolidine, tetrazolidine, diazirroheptane, azirroheptane, or homopiperazine. The terms "5-6 membered heterocyclic group" or "5-6 membered heterocycle" are defined accordingly and include 5-6 membered aromatic heterocyclic groups or heterocycles. The terms "5 membered heterocyclic group" or "5 membered heterocycle" are defined accordingly and include 5 membered aromatic heterocyclic groups or heterocycles.

[0056] The term "5-membered subheterocyclic group containing nitrogen ring atoms" refers to a divalent 5-membered heterocycle in which at least one of the five ring atoms is a nitrogen atom and said ring is attached to the rest of the molecule via a carbon or nitrogen atom.

[0057] "Saturated 4-7 membered heterocyclic group" or "saturated 4-7 membered heterocyclic ring" refers to a fully saturated "4-7 membered heterocyclic group" or "4-7 membered heterocyclic ring".

[0058] "4-7 member heterocyclic group at least partially saturated" or "4-7 member heterocyclic ring at least partially saturated" refers to a "4-7 member heterocyclic group" or "4-7 member heterocyclic ring" that is at least partially saturated.

[0059] "5-6 membered aromatic heterocyclic group" or "5-6 membered aromatic heterocycle" refers to a heterocycle derived from cyclopentadienyl or benzene, wherein at least one carbon atom is replaced by a heteroatom selected from sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-). Examples of such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiazolium, thiadiazole, triazole, tetraazole, pyridine, pyrimidine, pyridazine, pyrazine, and triazine.

[0060] "5-membered aromatic heterocyclic group" or "5-membered aromatic heterocycle" refers to a heterocycle derived from cyclopentadienyl, in which at least one carbon atom is replaced by a heteroatom selected from sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-). Examples of such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiaazole, thiadiazole, triazole, and tetraazole.

[0061] "Six-membered aromatic heterocyclic group" or "six-membered aromatic heterocycle" refers to a heterocycle derived from benzene in which at least one carbon atom is replaced by a heteroatom selected from sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-). Examples of such heterocycles are pyridine, pyrimidine, pyridazine, pyrazine, and triazine.

[0062] "7-12 membered heterobicyclic group" or "7-12 membered heterobicyclic" refers to a heterocyclic system of two rings having 7-12 ring atoms, wherein the two rings share at least one ring atom and may contain at most a maximum number of double bonds (aromatic rings or fully saturated, partially saturated or unsaturated non-aromatic rings), wherein at least one ring atom up to 6 ring atoms are replaced by heteroatoms selected from sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-), and wherein said rings are connected to the rest of the molecule via carbon or nitrogen atoms. Examples of 7-12 membered heterobicyclic compounds include indole, indoline, benzofuran, benzothiophene, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzoimidazolium, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzodiazepine heptatriene, purine, or pteridine. The term 7-12-membered heterobicyclic also includes spiro structures with two rings such as 6-oxa-2-azaspiro[3,4]octane, 2-oxa-6-azaspiro[3.3]heptane-6-yl or 2,6-diazaspiro[3.3]heptane-6-yl, or bridged heterocycles such as 8-azabicyclic[3.2.1]octane or 2,5-diazabicyclic[2.2.2]octane-2-yl or 3,8-diazabicyclic[3.2.1]octane.

[0063] "Saturated 7-12 member heterobicyclic group" or "saturated 7-12 member heterobicyclic group" refers to a fully saturated "7-12 member heterobicyclic group" or "7-12 member heterobicyclic group".

[0064] "7-12 member heterobicyclic group at least partially saturated" or "7-12 member heterobicyclic group at least partially saturated" refers to a "7-12 member heterobicyclic group" or "7-12 member heterobicyclic group" that is at least partially saturated.

[0065] "9-11-membered aromatic heterobicyclic group" or "9-11-membered aromatic heterobicyclic" refers to a heterocyclic system of two rings, wherein at least one ring is aromatic, and wherein the heterocyclic system has 9-11 ring atoms, wherein the two rings share two ring atoms, and may contain at most a maximum number of double bonds (fully or partially aromatic), wherein at least one ring atom up to six ring atoms are replaced by heteroatoms selected from sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-), and wherein the ring is connected to the rest of the molecule via a carbon or nitrogen atom. Examples of 9-11 quinacrine heterobicyclic compounds are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzoimidazolium, quinoline, quinazoline, dihydroquinazoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzo[a]heptatriene, purine, or pteridine. The terms "9-10 quinacrine heterobicyclic group" or "9-10 quinacrine heterobicyclic" are defined accordingly.

[0066] Preferred compounds of formula (I) are those containing one or more residues having the meanings given above or below, wherein all combinations defined by preferred substituents are the subject of this invention. With respect to all preferred compounds of formula (I), this invention also includes all tautomers and stereoisomers and mixtures thereof in all ratios, as well as pharmaceutically acceptable salts thereof.

[0067] In a preferred embodiment of the invention, the substituents mentioned below independently have the following meanings. Therefore, one or more of these substituents may have the preferred or more preferred meanings given below.

[0068] Preferably, R 4 It is H, CH3, CH2CH3 or CH2CH2OCH3; more preferably H or CH3; even more preferably H.

[0069] Preferably, R 4a R 4b R 4c R 5 Independently selected from H, halogens and C 1-4 Alkyl and R 4d R 4e Independently selected from H, OH, OC 1-4 Alkyl, halogen and C 1-4 Alkyl; more preferably R 4a R 4b R 4c R 5 R 4d R 4e Independently selected from H, F, and CH3; even more preferably, R 4a R4b R 4c R 5 R 4d R 4e It is H.

[0070] Preferably, R 1 It is H or CH3; H is preferred.

[0071] Preferably, R 2 It is H, F, or CH3, with H being more preferred.

[0072] Preferably, R in formula (I) 1 R 2 R 2a R 4 R 4a R 4b R 4c R 5 R 4d R 4e If we have H, we obtain equation (Ia).

[0073]

[0074] Preferably, R 3 It is phenyl or pyridyl, preferably phenyl, wherein R 3 Optionally by one or more identical or different R 7 replace.

[0075] Preferably, R 3 By one, two or three, preferably one or two, more preferably two identical or different R 7 replace.

[0076] Preferably, R 9 It is halogen.

[0077] Preferably, R 7 For F, Cl, Br, CN, CHF2, CF3, OCH 3、 OCF3, CH=O, CH2OH or CH3; more preferably R 7 It is CF3, F, or Cl; or even more preferably F or Cl.

[0078] Preferably, R in formula (I) 1 R 2 R 2a R 3 R 4 R 4a R 4b R 4c R 4d R 4e R5 Equation (Ib) is obtained.

[0079]

[0080] Each R 7 It is independently selected from halogens and CF3.

[0081] Preferably, R in formula (Ib) 7 The group yields formula (Ib1).

[0082]

[0083] Preferably, R 6 The derivatives are quinazolinyl, pyrrolo[1,2-a]pyrazinyl, 1,3-benzoxazolyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrimido[5,4-d]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, benzodihydropyranyl, oxazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-b]pyridazinyl, or 6,7-dihydro-4H-pyrano[4,3-d]oxazolyl, wherein R 6 Optional by one or more identical or different R 11 Replacement. More preferably, R 6 It is 1,3-benzoxazolyl or imidazo[1,2-a]pyridyl, wherein R 6 Optional by one or more identical or different R 11 Replacement. Even more preferably, R 6 It is 1,3-benzoxazolyl, where R 6 Optional by one or more identical or different R 11 replace.

[0084] Preferably, R 6 Not replaced or replaced by one or two identical or different R 11 replace.

[0085] Preferably, R 11 It is Cl, CH3, CF3, CH2CF3, OCF3, OCHF2, or OCH2CF3. Preferably, R 11 It is Cl, CH3, CF3, CH2CF3, OCF3, or OCH2CF3.

[0086] Compounds of formula (I) in which some or all of the above groups have preferred or more preferred meanings are also objects of this invention.

[0087] For the preferred specific compounds of the present invention or their pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers, R in formula (I) is selected. 1 ,R 2 ,R 2a ,R 3 ,R 4 ,R 4a ,R 4b ,R 4c ,R 4d ,R 4e ,R 5 ,R 6 get

[0088] (2R,5S)-2-(6-chloro-1,3-benzoxazol-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1-carboxylic acid tert-butyl ester;

[0089] N-[(3S,6R)-6-(6-chloro-1,3-benzoxazol-2-yl)piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide;

[0090] (2R,5S)-2-(5-chloro-1,3-benzoxazol-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1-carboxylic acid tert-butyl ester;

[0091] N-[(3S,6R)-6-(5-chloro-1,3-benzoxazol-2-yl)piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide;

[0092] (2R,5S)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylic acid tert-butyl ester;

[0093] 2-(4-chloro-3-fluoro-phenoxy)-N-[(3S,6R)-6-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-3-piperidinyl]acetamide;

[0094] (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]piperidin-1-carboxylic acid tert-butyl ester;

[0095] 2-(4-chloro-3-fluoro-phenoxy)-N-[(3S,6R)-6-[7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-3-piperidinyl]acetamide;

[0096] (2R,5S)-2-(7-chloro-1,3-benzoxazol-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1-carboxylic acid tert-butyl ester;

[0097] N-[(3S,6R)-6-(7-chloro-1,3-benzoxazol-2-yl)piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide;

[0098] (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[6-(trifluoromethoxy)-1,3-benzoxazol-2-yl]piperidine-1-carboxylic acid tert-butyl ester;

[0099] 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[6-(trifluoromethoxy)-1,3-benzoxazol-2-yl]piperidin-3-yl]acetamide;

[0100] (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[6-(difluoromethoxy)-1,3-benzoxazol-2-yl]piperidine-1-carboxylic acid tert-butyl ester;

[0101] 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[6-(difluoromethoxy)-1,3-benzoxazol-2-yl]piperidin-3-yl]acetamide;

[0102] (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[6-(trifluoromethyl)-1,3-benzoxazol-2-yl]piperidine-1-carboxylic acid tert-butyl ester;

[0103] 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[6-(trifluoromethyl)-1,3-benzoxazol-2-yl]piperidin-3-yl]acetamide;

[0104] (2R,5S)-2-(4-chloro-1,3-benzoxazol-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1-carboxylic acid tert-butyl ester; or

[0105] N-[(3S,6R)-6-(4-chloro-1,3-benzoxazol-2-yl)piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide.

[0106] In cases where tautomerism of a compound of formula (I) can occur (e.g., keto-enol tautomerism), the compounds include, and mixtures in any ratio include, various forms such as, for example, ketone and enol forms. This also applies to stereoisomers, such as, for example, enantiomers, cis / trans isomers, conformational isomers, etc.

[0107] In particular, when an enantiomer or diastereomer is given in a compound according to formula (I), any mixture of each pure form alone and any ratio of at least two pure forms is included in formula (I) and is the subject of this invention.

[0108] A preferred compound is a compound of formula (I) having the relative configuration shown in formula (Ic), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0109]

[0110] Isotopically labeled compounds of formula (I) are also within the scope of this invention. Methods for isotopic labeling are known in the art. Preferred isotopes are isotopes of the elements H, C, N, O, and S. Solvates and hydrates of compounds of formula (I) are also within the scope of this invention.

[0111] If desired, isomers can be separated by methods well-known in the art, such as liquid chromatography. This also applies to enantiomers by using, for example, a chiral stationary phase. Alternatively, enantiomers can be separated by converting them to diastereomers, i.e., by coupling them with an enantiomerically pure auxiliary compound, followed by separation of the resulting diastereomer and cleavage of 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.

[0112] Where the compounds according to formula (I) contain one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically or toxicologically acceptable salts, especially their pharmaceutically usable salts. Therefore, according to the present invention, compounds of formula (I) containing acidic groups can be used, for example, as alkali metal salts, alkaline earth metal salts, or as ammonium salts. More specific 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 that can be protonated) can be present, and according to the present invention, they can be used in the form of addition salts formed with inorganic or organic acids. Examples of suitable acids include: hydrochloric acid, hydrobromic acid, 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, neopentanoic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compound of formula (I) contains both acidic and basic groups in its molecule, the invention also includes, in addition to the salt forms mentioned, internal salts or internal ammonium salts (zwitterions). Various salts according to formula (I) can be obtained by conventional methods known to those skilled in the art, such as, for example, by contacting these with organic or inorganic acids or bases in a solvent or dispersant, or by anion or cation exchange with other salts. The present invention also includes all salts of compounds of formula (I), which are not directly applicable to pharmaceuticals due to low physiological compatibility, but can be used, for example, as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0113] As shown below, the compounds of the present invention are believed to be suitable for modulating integrated stress response pathways.

[0114] Integrated stress response (ISR) is a cellular stress response common to all eukaryotes (1). Abnormal regulation of ISR signaling has important pathological consequences, particularly those associated with inflammation, viral infections, diabetes, cancer, and neurodegenerative diseases.

[0115] ISR is a common feature of different types of cellular stress, leading to phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) at ​​serine 51, thereby inhibiting normal protein synthesis and the expression of stress-response genes (2). In mammalian cells, this phosphorylation is carried out by four families of eIF2α kinases: PKR-like ER kinase (PERK), double-stranded RNA-dependent protein kinase (PKR), heme-regulated eIF2α kinase (HRI), and generalized regulatory repressor protein kinase 2 (GCN2), each responding to different environmental and physiological stresses (3).

[0116] eIF2α, together with eIF2β and eIF2γ, forms the eIF2 complex, a key player in the initiation of normal mRNA translation (4). The eIF2 complex binds GTP and Met-tRNA. i This forms a ternary complex (eIF2-GTP-Met-tRNA). i ), which is recruited by ribosomes for translation initiation (5,6).

[0117] eIF2B is a heterodecame complex composed of five subunits (α, β, γ, δ, ε), which are formed in duplicate to form a GEF active decamer (7).

[0118] In response to ISR activation, phosphorylated eIF2α inhibits eIF2B-mediated GDP-GTP exchange, leading to reduced ternary complex formation and thus inhibiting the translation of normal mRNAs characterized by ribosome binding to the 5'AUG start codon (8). Under these conditions of reduced ternary complex abundance, the translation of several specific mRNAs, including the mRNA encoding the transcription factor ATF4, is activated through mechanisms involving translational alterations in upstream ORFs (uORFs) (7,9,10). These mRNAs typically contain one or more uORFs, which normally function in unstressed cells to restrict ribosome flow to the major encoding ORF. For example, under normal conditions, uORFs in the 5'UTR of ATF occupy ribosomes and prevent translation of the ATF4 coding sequence. However, under stress conditions, i.e., conditions of reduced ternary complex formation, the likelihood of ribosome scanning across these upstream ORFs and initiating translation at the ATF4-encoding ORF increases. ATF4 and other stress response factors expressed in this manner subsequently control the expression of a range of other stress response genes. The acute phase involves the expression of proteins aimed at restoring homeostasis, while the chronic phase leads to the expression of pro-apoptotic factors (1,11,12,13).

[0119] Upregulation of markers of ISR signaling has been confirmed in a variety of diseases, including cancer and neurodegenerative diseases. In cancer, ER stress-regulated translation increases tolerance to hypoxia and promotes tumor growth (14,15,16), and gene-targeted deletion of PERK has been shown to slow the transformation of PERK. - / -Growth of tumors derived from mouse embryonic fibroblasts (14,17). Furthermore, a recent report has provided evidence of concept that activators of eIF2B are effective in treating an aggressive metastatic prostate cancer using a patient-derived xenograft model in mice (28). In conclusion, the prevention of cell-protective ISR signaling may represent an effective antiproliferative strategy for the treatment of at least some forms of cancer.

[0120] Furthermore, regulation of ISR signaling has demonstrated effectiveness in maintaining synaptic function and reducing neuronal degeneration, as has been shown in neurodegenerative diseases characterized by activation of misfolded proteins and the unfolded protein response (UPR), such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD), and Jakob Creutzfeld (prion) disease (18,19,20). In prion diseases (an example of existing neurodegenerative diseases), pharmacological and genetic repression of ISR signaling has been shown to normalize protein translation levels, salvage synaptic function, and prevent neuronal loss (21). Specifically, reducing phosphorylated eIF2α levels by overexpressing phosphatases that control phosphorylated eIF2α levels increases survival in prion-infected mice, while persistent eIF2α phosphorylation decreases survival (22).

[0121] Furthermore, direct evidence of the importance of controlling protein expression levels for proper brain function exists in the form of rare genetic disorders affecting the function of eIF2 and eIF2B. Mutations in eIF2γ that disrupt the complex integrity of eIF2 and thus lead to reduced levels of normal protein expression are associated with intellectual disability syndrome (ID) (23). Partial loss-of-function mutations in subunits of eIF2B have been shown to be a cause of the rare leukodystrophy leukoablation disease (VWMD) (24,25). Specifically, stabilization of partial loss-of-function eIF2B by small molecules associated with ISRIB in VWMD mouse models has been shown to reduce ISR markers and improve function and pathological endpoints (26,27).

[0122] This invention provides compounds of the invention in free or pharmaceutically acceptable salt form, or in solvated, hydrated, tautomer, or stereoisomer form, for the treatment of the diseases or disorders mentioned herein. This also applies to the pharmaceutical compositions of the invention.

[0123] Therefore, one aspect of the invention is the use of the compounds of the invention as pharmaceuticals, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof. This also applies to the pharmaceutical compositions of the invention.

[0124] The described treatment method can be applied to mammals such as dogs, cats, cattle, horses, rabbits, monkeys, and humans. Preferably, the mammalian patient is a human patient.

[0125] Therefore, the present invention provides compounds of the present invention, or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers or pharmaceutical compositions thereof, for the treatment or prevention of one or more diseases or disorders related to integrated stress responses.

[0126] Another aspect of the invention is a compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer or pharmaceutical composition thereof, for the treatment or prevention of one or more disorders or diseases related to integrated stress response.

[0127] Another aspect of the invention is the use of the compounds of the invention or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers or pharmaceutical compositions thereof in the preparation of a medicament for the treatment or prevention of one or more disorders or diseases associated with integrated stress responses.

[0128] Another aspect of the invention is a method for treating, controlling, delaying, or preventing one or more diseases or disorders related to integrated stress responses in a mammalian patient requiring treatment, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or pharmaceutical composition thereof.

[0129] The present invention provides compounds of the present invention, or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers or pharmaceutical compositions thereof, for the treatment or prevention of one or more of the following diseases or disorders.

[0130] Another aspect of the invention is a compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer or pharmaceutical composition thereof, for the treatment or prevention of one or more of the following disorders or diseases.

[0131] Another aspect of the invention is the use of the compounds of the invention or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers or pharmaceutical compositions thereof in the preparation of a medicament for the treatment or prevention of one or more of the following disorders or diseases.

[0132] Another aspect of the invention is a method for treating, controlling, delaying, or preventing one or more of the following diseases or disorders in a mammalian patient requiring treatment, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or pharmaceutical composition thereof.

[0133] Diseases or disorders include, but are not limited to, leukodystrophy, intellectual disability syndromes, neurodegenerative diseases and disorders, neoplastic diseases, infectious diseases, inflammatory diseases, musculoskeletal diseases, metabolic diseases, eye diseases, and diseases selected from organ fibrosis, chronic and acute liver disease, chronic and acute lung disease, chronic and acute kidney disease, myocardial infarction, cardiovascular disease, arrhythmia, atherosclerosis, spinal cord injury, ischemic stroke, and neuropathic pain.

[0134] Leukodystrophy

[0135] Examples of leukodystrophy include, but are not limited to, white matter ablation disorders (VWMD) and childhood ataxia with insufficient myelination of the CNS (e.g., associated with impaired function of eIF2 or components of signal transduction or signaling pathways including eIF2).

[0136] Intellectual Disability Syndrome

[0137] Intellectual disability specifically refers to conditions in which a person has certain limitations in intellectual functions such as communication, self-care, and / or impaired social skills. Intellectual disability syndromes include, but are not limited to, intellectual disability conditions associated with impairment of function in eIF2 or components of signal transduction or signaling pathways that include eIF2.

[0138] Neurodegenerative diseases / disorders

[0139] Examples of neurodegenerative diseases and disorders include, but are not limited to, Alexander disease, Alpert disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia-telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, cortical-basal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-related dementia, Kennedy disease, Clab disease, Kuru disease, and Louisiana disease. Dementia, Machado-Joseph disease (type 3 spinocerebellar ataxia), multiple sclerosis, multiple system atrophy, narcolepsy, spirochete disease, Parkinson's disease, Peyrenia, Pick's disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy, Reversomnia, Sandhof's disease, Sheld's disease, subacute mixed degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (multiple types with different characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, tabes dorsalis, and Tau lesions.

[0140] Neurodegenerative diseases or disorders, especially those of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

[0141] neoplastic diseases

[0142] Oncological diseases can be understood most broadly as any tissue arising from uncontrolled cell growth. In many cases, a tumor results in at least a large mass of tissue, optionally innervated by blood vessels. It may or may not include the formation of one or more metastases / metastatic foci. The oncological disease of this invention can be any tumor classified under categories C00-D48 of the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10).

[0143] Exemplarily, the neoplastic disease according to the present invention can be the presence of one or more malignant tumors (ICD-10 categories C00-C97), the presence of one or more tumors in situ (ICD-10 categories D00-D09), the presence of one or more benign tumors (ICD-10 categories D10-D36), or the presence of one or more tumors with indeterminate or unknown behavior (ICD-10 categories D37-D48). Preferably, the neoplastic disease according to the present invention refers to the presence of one or more malignant tumors, that is, malignant tumor formation (ICD-10 categories C00-C97).

[0144] In a more preferred embodiment, the neoplastic disease is cancer.

[0145] Cancer can be understood in the broadest sense as any malignant neoplastic disease, that is, the presence of one or more malignant tumors in a patient. Cancer can be a solid or hematologic malignancy. This article covers, but is not limited to, leukemia, lymphoma, carcinoma, and sarcoma.

[0146] This article includes, in particular, neoplastic diseases characterized by upregulated ISR markers, such as cancer.

[0147] Exemplary cancers include, but are not limited to, thyroid cancer, endocrine system 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, ductal carcinoma, lobular carcinoma, primary, metastatic), cervical cancer, ovarian cancer, uterine cancer, colon cancer, head and neck cancer, liver cancer (e.g., hepatocellular carcinoma), kidney cancer, lung cancer (e.g., non-small cell lung cancer, squamous cell lung cancer, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid, sarcoma), colon cancer, esophageal cancer, gastric cancer, bladder cancer, bone cancer, stomach cancer, prostate cancer, and skin cancer (e.g., melanoma).

[0148] Other examples include, but are not limited to, myeloma, leukemia, mesothelioma, and sarcoma.

[0149] Other examples include, but are not limited to, medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, malignant pancreatic islet tumors, malignant carcinoid tumors, bladder cancer, pre-exacerbating skin lesions, testicular cancer, lymphoma, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic tumors, medullary thyroid carcinoma, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, Paget's papillary lesion, phyllodes tumor, lobular carcinoma, ductal carcinoma, pancreatic astrocytoma, and hepatic astrocytoma.

[0150] Exemplary leukemias include, but are not limited to, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, leukopenic leukemia, leukocytic leukemia, basophilic leukemia, embryonic cell leukemia, bovine leukemia, chronic myeloid leukemia, cutaneous leukemia, embryonic cell leukemia, eosinophilic leukemia, Gross's leukemia, hairy cell leukemia, hemoblastic leukemia, and hemocytoblastic leukemia. Leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloid leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Shilling's leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated leukemia.

[0151] Exemplary sarcomas include, but are not limited to, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Ebernathy's sarcoma, liposarcoma, liposarcoma, soft tissue alveolar sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, nephroblastoma sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant mesenchymal sarcoma, extraperiosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and capillary hemangiosarcoma.

[0152] Exemplary melanomas include, but are not limited to, acral lentigines melanoma, amelanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harper-Parot II melanoma, juvenile melanoma, malignant lentigines melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial diffuse melanoma.

[0153] Exemplary cancers include, but are not limited to, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinar-like carcinoma, cystic adenoid carcinoma, adenoid cystic carcinoma, adenocarcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal epithelial cell carcinoma, basal cell-like carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchial carcinoma, cerebral carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, uterine corpus cancer, cribriform carcinoma, armored carcinoma, skin cancer, columnar carcinoma, columnar cell carcinoma, tubular carcinoma, ductal carcinoma, sclerocarcinoma, embryonal carcinoma, cerebral carcinoma, epidermoid carcinoma, adenoid epithelial carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrocarcinoma, colloid carcinoma, colloid sclerocarcinoma, giant cell carcinoma, and giant cell carcinoma. gigantocellulare), adenocarcinoma, granulocytic carcinoma, pilostromal carcinoma, hemangioma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, adrenal carcinoma, embryonic carcinoma, carcinoma in situ, intraepithelial carcinoma, intraepithelial carcinoma, Krompecher carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular carcinoma, lipoma-like carcinoma, lobular carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanoma, molluscum carcinoma, mucinous carcinoma, mucinous muciparum, mucinous cell carcinoma, mucinous epidermoid carcinoma, mucinous mucosum, mucous carcinoma Carcinoma, myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, Schneider carcinoma, sclerosing carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato-shaped carcinoma, spherical cell carcinoma, spindle cell carcinoma, medullary carcinoma, squamous carcinoma, squamous cell carcinoma, cord carcinoma, telangiectatic carcinoma, telangiectodes carcinoma, transitional cell carcinoma, tuberosum carcinoma, tubular carcinoma, tuberous carcinoma, verrucous carcinoma, and villous carcinoma.

[0154] Infectious diseases

[0155] Examples include, but are not limited to, infections caused by viruses (such as those caused by the following viruses: HIV-1; IAV; HCV; DENV; ASFV; EBV; HSV1; CHIKV; HCMV; SARS-CoV; SARS-CoV-2) and infections caused by bacteria (such as those caused by Legionella, Brucella, Simkania, Chlamydia, Helicobacter, and Campylobacter).

[0156] Inflammatory diseases

[0157] Examples of inflammatory diseases include, but are not limited to, postoperative cognitive impairment (cognitive decline after surgery), traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile diabetes mellitus, type 1 diabetes mellitus, Graves-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Bechtel's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis.

[0158] Musculoskeletal diseases

[0159] Examples of musculoskeletal disorders include, but are not limited to, muscular dystrophy, multiple sclerosis, Freidrich's ataxia, muscle atrophy disorders (e.g., muscle atrophy, sarcopenia, cachexia), inclusion body myopathy, progressive muscle atrophy, motor neuron disease, carpal tunnel syndrome, epicondylitis, tendinitis, back pain, myalgia, muscle soreness, repetitive strain disorder, and paralysis.

[0160] Metabolic diseases

[0161] Examples of metabolic diseases include, but are not limited to, diabetes (especially type II diabetes), nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), Niemann-Pick disease, liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, and Kearns-Sayre disease.

[0162] Eye diseases

[0163] Examples of eye diseases include, but are not limited to, any occlusive or inflammatory retinal vascular disease with edema or neovascularization, such as iris redness, neovascular glaucoma, pterygium, vascularized glaucoma follicles, and conjunctival papilloma; choroidal neovascularization, such as neovascular age-related macular degeneration (AMD), myopia, and anterior uveitis. (e.g., uveitis), traumatic or idiopathic macular edema; macular edema, such as postoperative macular edema, macular edema secondary to uveitis (including inflammation of the retina and / or choroid), macular edema secondary to diabetes, and macular edema secondary to retinal vascular occlusive diseases (i.e., occlusion of retinal branches and central veins); retinal neovascularization caused by diabetes, such as retinal vein occlusion, uveitis, ocular ischemia syndrome caused by carotid artery disease, ocular or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathy, retinopathy of prematurity, or Ills' disease; and genetic disorders, such as Von Hippel-Lindau syndrome.

[0164] Other diseases

[0165] Other conditions include, but are not limited to, organ fibrosis (such as liver fibrosis, pulmonary fibrosis, or kidney fibrosis), chronic and acute liver diseases (such as fatty liver disease or hepatocellular carcinoma), chronic and acute lung diseases, chronic and acute kidney diseases, myocardial infarction, cardiovascular diseases, arrhythmias, atherosclerosis, spinal cord injury, ischemic stroke, and neuropathic pain.

[0166] Another aspect of the invention is a pharmaceutical composition comprising at least one compound of the invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, and a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.

[0167] Preferably, the one or more bioactive compounds are modulators of integrated stress response pathways other than those of formula (I).

[0168] "Pharmaceutical composition" means one or more active ingredients and one or more inert ingredients constituting a carrier, as well as any product formed directly or indirectly by combination, complexation, or aggregation of any two or more ingredients, or any product formed directly or indirectly by decomposition of one or more ingredients, or any product formed directly or indirectly by other types of reactions or interactions of one or more ingredients. Therefore, the pharmaceutical compositions of the present invention include any composition prepared by mixing the compounds of the present invention with a pharmaceutically acceptable carrier.

[0169] The pharmaceutical compositions of the present invention may contain one or more other compounds as active ingredients, such as a mixture of compounds of formula (I) in the composition or other modulators that integrate stress response pathways.

[0170] The active ingredient may be contained in one or more different pharmaceutical compositions (a combination of pharmaceutical compositions).

[0171] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic base or acid (including inorganic bases or acids and organic bases or acids).

[0172] The compositions include those suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (eye), pulmonary (nasal or sublingual inhalation), or nasal administration, although the most appropriate route in any given case depends on the nature and severity of the condition being treated and the nature of the active ingredient. They can be conveniently present in unit dosage forms and can be prepared by any method well known in the pharmaceutical field.

[0173] In practical applications, the compound of formula (I) can be combined with a drug carrier as an active ingredient into a close mixture using conventional drug formulation techniques. The carrier can take various forms, depending on the intended form of the formulation, such as oral or parenteral (including intravenous). In preparing oral dosage forms, in the case of oral liquid formulations (e.g., suspensions, elixirs, and solutions), any commonly used pharmaceutical medium, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., can be used; or in the case of oral solid formulations (e.g., powders, hard and soft capsules, and tablets), carriers such as starch, sugar, microcrystalline cellulose, diluents, granulators, lubricants, binders, disintegrants, etc., can be used, with solid oral formulations preferred over liquid formulations.

[0174] Because tablets and capsules are easy to administer, and represent the most advantageous form of oral dosage unit, solid pharmaceutical carriers are obviously used in such cases. Tablets can be coated using standard aqueous or non-aqueous techniques if desired. Such compositions and formulations should contain at least 0.1% of the active compound. The percentage of the active compound in these compositions can, of course, vary and can conveniently range from about 2% to about 60% of the unit's weight. The amount of the active compound in the composition useful for this treatment is the amount at which an effective dose is obtained. The active compound can also be administered intranasally, for example, as liquid drops or sprays.

[0175] Tablets, pills, capsules, etc., may also contain: binders such as gum arabic, 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. When the dosage unit is in capsule form, in addition to the above types of substances, it may also contain a liquid carrier such as fatty oils.

[0176] Various other substances can exist as coatings or be used to change the physical form of dosage units. For example, tablets can be coated with shellac, sugar, or both. In addition to the active ingredient, syrups or elixirs may also contain: sucrose as a sweetener, methylparaben and propylparaben as preservatives, dyes, and flavorings such as cherry or orange flavorings.

[0177] Compounds of formula (I) can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water appropriately mixed with surfactants such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Under normal storage and use conditions, these products contain preservatives to inhibit microbial growth.

[0178] Suitable drug forms for injection 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 should flow to a degree that facilitates injection. It should be stable under manufacturing and storage conditions and should be preserved against contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0179] The compounds of the present invention can be administered to mammals, particularly humans, using any suitable route of administration. Routes of administration include, for example, oral, rectal, topical, parenteral, ocular, pulmonary, and nasal routes. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, and aerosols. Oral administration of compounds of formula (I) is preferred.

[0180] The effective dosage of the active ingredient used can vary depending on the specific compound used, the administration method, the condition to be treated, and the severity of the condition. Such dosage can be readily determined by those skilled in the art.

[0181] The starting materials used to synthesize the preferred embodiments of the present invention may be purchased from commercially available sources such as Array, Sigma Aldrich, Acros, Fisher, Fluka, ABCR, or may be synthesized by those skilled in the art using known methods.

[0182] Generally, several methods can be used to prepare the compounds of the present invention. In some cases, various strategies can be combined. Sequential or convergent pathways can be used. Exemplary synthetic pathways are described below. Example

[0183] Chemical Synthesis

[0184] Experimental Procedure :

[0185] Use the following abbreviations and acronyms:

[0186] aq (water-based)

[0187] ACN Acetonitrile

[0188] AcOH (acetic acid)

[0189] A saturated solution of NaCl in water

[0190] BnONH2·HCl O-benzylhydroxyamine hydrochloride

[0191] Boc tert-butoxycarbonyl

[0192] Boc2O ditert-butyl dicarbonate

[0193] CDCl3 (deuterated chloroform)

[0194] CV column volume

[0195] DCM dichloromethane

[0196] DCE 1,2-Dichloroethane

[0197] DIAD (Diisopropyl Azodicarbonate)

[0198] DMSO (dimethyl sulfoxide)

[0199] DMSO-d6-deuterated dimethyl sulfoxide

[0200] DIPEA N,N-Diisopropylethylamine

[0201] DMF (dimethylformamide)

[0202] DMAP N,N-dimethylpyridine-4-amine

[0203] ESI + Positive ionization mode

[0204] ESI - Negative ionization mode

[0205] EtOAc (ethyl acetate)

[0206] EtOH (ethanol)

[0207] Et2O diethyl ether

[0208] FCC rapid column chromatography

[0209] H2O water

[0210] H2SO4 sulfuric acid

[0211] HATU 1-[bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridine-1-onium 3-oxide hexafluorophosphate

[0212] HCl hydrochloric acid

[0213] HPLC (High Performance Liquid Chromatography)

[0214] h hours

[0215] KHCO3 (potassium bicarbonate)

[0216] LiOH·H2O Lithium hydroxide hydrate

[0217] LiHMDS bis(trimethylsilyl)aminolithium

[0218] m multiplet

[0219] MeOH (methanol)

[0220] MeMgBr methyl magnesium bromide

[0221] MgSO4 Magnesium sulfate

[0222] MHz

[0223] min minutes

[0224] MsOH (methanesulfonic acid)

[0225] mL

[0226] N2 nitrogen atmosphere

[0227] Na2SO4 Sodium sulfate

[0228] NaHCO3 (sodium bicarbonate)

[0229] NBS N-bromosuccinimide

[0230] NH4Cl ammonium chloride

[0231] NMR (Nuclear Magnetic Resonance)

[0232] PPh3 triphenylphosphine

[0233] prep. preparative

[0234] rt room temperature

[0235] RT Retention Time

[0236] satd saturated TBME 2-methoxy-2-methylpropane

[0237] THF Tetrahydrofuran

[0238] TMSOI (trimethylsulfonium iodide)

[0239] TMSCl Trimethylsilane

[0240] ZnBr2 Zinc dibromide

[0241] The conditions for analytical LCMS are as follows:

[0242] System 1 (S1): Acidic IPC methods (MS18 and MS19)

[0243] Analytical HPLC-MS was performed on a Shimadzu LCMS system using a Kinetex Core shell C18 column (2.1 mm × 50 mm, 5 μm; temperature: 40 °C) and a gradient of 5–100% B (A = 0.1% formic acid / H₂O; B = 0.1% formic acid / ACN) for 1.2 min, followed by a hold at 100% B for 0.1 min. A second gradient of 100–5% B was then applied for 0.01 min at a flow rate of 1.2 mL / min with an injection volume of 3 μL. UV spectra were recorded at 215 nm using an SPD-M20A photodiode array detector (spectral range: 200–400 nm). Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0244] System 2 (S2): Acidic IPC methods (MSQ1, MSQ2, MSQ4 and MSQ6)

[0245] Using Waters BEH TM 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 / H₂O; B = 0.1% formic acid / ACN) were applied for 1.1 min, followed by a hold at 100% B for 0.25 min, and then analyzed using uHPLC-MS on a Waters Acquity uPLC system (MET / uPLC / 1704). A second gradient of 100–5% B was then applied for 0.05 min and held for 0.1 min, with an injection volume of 1 μL and a flow rate of 0.9 mL / min. UV spectra were recorded at 215 nm on a Waters Acquity PDA with a 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.

[0246] System 3 (S3): Alkaline IPC Method (MS16)

[0247] Using Waters BEH TMA 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) were applied for 0.75 min, followed by a hold at 100% B for 0.1 min, and then analyzed using uHPLC-MS (MET / CR / 1602) on a Waters Acquity uPLC system. A second gradient of 100–5% B was then applied for 0.05 min and held for 0.1 min, with an injection volume of 1 μL and a flow rate of 1 mL / min. UV spectra were recorded at 215 nm on 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.

[0248] System 4 (S4): Acidic final methods (MSQ1 and MSQ2)

[0249] Analytical HPLC-MS was performed on a Waters Acquity uPLC system (MET / uPLC / AB101) using a Phenomenex Kinetex-XB C18 column (2.1 mm × 100 mm, 1.7 μM; temperature: 40 °C) with a gradient of 5–100% B (A = 0.1% formic acid / H₂O; B = 0.1% formic acid / ACN) for 5.3 min, followed by a hold at 100% B for 0.5 min. A second gradient of 100–5% B was then applied for 0.02 min and held for 1.18 min, with an injection volume of 1 μL and a flow rate of 0.6 mL / min. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector (spectral range: 200–400 nm). Mass spectra were obtained using a Waters SQD (MSQ1) or Waters Acquity QDA (MSQ2) detector. Use Waters MassLynx and OpenLynx software to integrate and report data.

[0250] System 5 (S5): Acidic final method (MS18, MS19)

[0251] Analytical HPLC-MS (MET / CR / 1416) was performed on a Shimadzu LCMS system using a Waters Atlantis dC18 column (2.1 mm × 100 mm, 3 μm; temperature: 40 °C) with a gradient of 5–100% B (A = 0.1% formic acid / H₂O; B = 0.1% formic acid / ACN) for 5 min, followed by a hold at 100% B for 0.4 min. A second gradient of 100–5% B was then applied for 0.02 min and held for 1.58 min, with an injection volume of 3 μL and a flow rate of 0.6 mL / min. UV spectra were recorded at 215 nm using an SPD-M20A photodiode array detector (spectral range: 200–400 nm). Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0252] System 6 (S6): Alkaline Final Method (MS16)

[0253] Using Waters BEH TM A C18 column (2.1 mm × 100 mm, 1.7 μm column; temperature: 40 °C) and a 5–100% gradient (A = 2 mM ammonium bicarbonate, buffered to pH 10; B = ACN) were applied for 5.3 min, followed by a 0.5 min hold at 100% B, and then analyzed using a Waters Acquity uPLC system (MET / uHPLC / AB105) uPLC-MS. A second gradient of 100–5% B was then applied for 0.02 min and held for 1.18 min, with an injection volume of 1 μL and a flow rate of 0.6 mL / min. UV spectra were recorded at 215 nm using a Waters Acquity photodiode array detector (spectral range: 200–400 nm). Mass spectra were obtained using a Waters Quattro Premier XE mass detector. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0254] The purification method is as follows:

[0255] Method 1: Early Acidity Method

[0256] Purification was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm × 100 mm, 10 μM; temperature: room temperature) with a gradient of 10–95% B (A = 0.1% formic acid / H₂O; B = 0.1% formic acid / ACN) for 14.44 min, followed by a 2.11 min hold at 95% B. A second gradient of 95–10% B was then applied over 0.2 min at a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0257] Method 2: Acidic Standard Method

[0258] Purification was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm × 10 mm, 10 μM; temperature: room temperature) with a gradient of 30–95% B (A = 0.1% formic acid / water; B = 0.1% formic acid / ACN) for 11.00 min, followed by a 2.10 min hold at 95% B. A second gradient of 95–30% B was then applied over 0.2 min at an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0259] Method 3: Early Alkaline Method

[0260] Purification was performed on a Gilson LC system using a Waters X-Bridge C18 column (30 mm × 100 mm, 10 μM; temperature: room temperature) with a gradient of 10–95% B (A = 0.2% NH4OH / H2O; B = 0.2% NH4OH / ACN) for 14.44 min, followed by a 2.11 min hold at 95% B. A second gradient of 95–10% B was then applied for 0.2 min at a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0261] Method 4: Alkaline Standard Method

[0262] Purification was performed on a Gilson LC system using a Waters X-Bridge C18 column (30 mm × 10 mm, 10 μM; temperature: room temperature) with a gradient of 30–95% B (A = 0.2% NH4OH / water; B = 0.2% NH4OH / ACN) for 11.00 min, followed by a 2.10 min hold at 95% B. A second gradient of 95–30% B was then applied over 0.21 min at a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0263] Method 5: Reversed-phase chromatography using acidic pH and standard elution method

[0264] FCC purification on reversed-phase silica gel (acidic pH, standard elution method) was performed on a Biotage Isolera system using a suitable SNAP C18 column and a gradient of 10% B (A = 0.1% formic acid / H2O; B = 0.1% formic acid / ACN) at 1.7 CV, followed by 10-100% B at 19.5 CV and 100% B at 2 CV.

[0265] Method 6: Reversed-phase chromatography using alkaline pH and standard elution method

[0266] FCC purification on reversed-phase silica gel (alkaline pH, standard elution method) was performed on a Biotage Isolera system using a suitable SNAP C18 column and a gradient of 10% B (A = 0.1% NH3 / H2O; B = 0.1% NH3 / ACN) at 1.7 CV, followed by 10-100% B at 19.5 CV and 100% B at 2 CV.

[0267] NMR conditions

[0268] Unless otherwise specified, records were made at 500 MHz, 400 MHz, or 250 MHz on a Bruker Avance III HD 500 MHz spectrometer, a Bruker Avance III HD 400 MHz spectrometer, or a Bruker Avance III HD 250 MHz spectrometer, respectively. 11H NMR spectra. Chemical shifts δ are cited in parts per million (ppm) and referenced to residual solvent peaks. The following abbreviations and general designations are used to denote multiplicity: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet), ddd (doublet of doublet), dt (doublet), dq (doublet of quartet), hep (septet), m (multiplet), pent (quintet), td (triplet), qd (quadruplet), app. (obvious), and br. (broad peak). The coupling constant J is cited to the nearest 0.1 Hz.

[0269] General synthesis:

[0270] All compounds have been synthesized with a purity of >95%, unless otherwise indicated.

[0271] Route 1 plan

[0272]

[0273] Step 1.a: Ethyl (2R)-5-[(benzyloxy)imino]-2-{[(tert-butoxy)carbonyl]amino}-6-chlorohexanoate

[0274]

[0275] Add DMSO (75 mL) to TMSOI (12.89 g, 58.3 mmol) and t BuOK (6.27 g, 55.9 mmol) was added to a solution of THF (anhydrous, 60 mL), and the mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to -12 °C, and a solution of Boc-D-pyroglutamic acid ethyl ester (12.5 g, 48.6 mmol) in THF (anhydrous, 38 mL) was added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated aqueous NH4Cl solution (80 mL), H2O (15 mL), and EtOAc (200 mL), the organic layer was separated, washed with brine, and concentrated under vacuum to about 100 mL. A solution of BnONH2·HCl (8.14 g, 51.0 mmol) in EtOAc (62 mL) was added, and the mixture was stirred under reflux for 2 h. The reaction mixture was cooled to room temperature, washed with H2O and brine, and the organic layer was concentrated under vacuum to give the title compound (85% purity, 19.5 g, 40.1 mmol, 83% yield) as a colorless oil. 1¹H NMR (400MHz, chloroform-d) δ 7.16–7.33 (m, 5H), 5.01–5.06 (m, 2H), 3.95–4.30 (m, 5H), 2.32–2.50 (m, 2H), 1.98–2.13 (m, 1H), 1.75–1.92 (m, 1H), 1.30–1.40 (m, 9H), 1.12–1.24 (m, 3H).

[0276] Step 1.b: (2R)-5-[(benzyloxy)imino]piperidine-2-carboxylic acid ethyl ester

[0277]

[0278] MsOH (7.8 mL, 0.12 mol) was added to a solution of ethyl (2R)-5-[(benzyloxy)imino]-2-{[(tert-butoxy)carbonyl]amino}-6-chlorohexanoate (85% purity, 19.5 g, 40.1 mmol) in EtOAc (157 mL), and the mixture was stirred at 42 °C for 2 h. The resulting mixture was added to a solution of KHCO3 (20.1 g, 0.201 mol) in H2O (100 mL), and stirred at 52 °C for 2 h. The reaction mixture was cooled to room temperature, the organic layer was separated, washed with brine, dried over Na2SO4, and concentrated under vacuum to give a quantitative yield of the title compound (85% purity, 13.0 g, 40.0 mmol) as a deep orange oil; 1 ¹H NMR (400 MHz, chloroform-d) δ 7.20–7.34 (m, 5H), 4.99 (d, J = 4.8 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.45–3.56 (m, 1H), 3.25 (dd, J = 14.9, 9.8 Hz, 1H), 3.08 (dt, J = 14.5, 4.3 Hz, 1H), 2.01–2.32 (m, 3H), 1.55–1.80 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H).

[0279] Step 1.c: (2R,5S)-5-[(benzyloxy)amino]piperidine-2-carboxylic acid ethyl ester oxalic acid

[0280]

[0281] Propionic acid (23 mL, 0.240 mol) was added to a suspension of NaBH4 (3.03 g, 80.0 mmol) in EtOAc (95 mL), and the mixture was stirred at room temperature for 1 hour. The resulting mixture was added at -20 °C to a solution of (2R)-5-[(benzyloxy)imino]piperidine-2-carboxylate (85% purity, 13.0 g, 40.0 mmol) in EtOAc (95 mL) and H2SO4 (11 mL, 0.20 mol), and stirred at room temperature for 60 hours. The reaction mixture was diluted with H2O (75 mL) and neutralized with aqueous NH4OH. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated under vacuum to ~75 mL. The solution was heated to 45 °C, MeOH (30 mL) was added, followed by a MeOH (15 mL) solution of oxalic acid (3.60 g, 40.0 mmol). The mixture was cooled to 0°C, and the precipitate was separated by vacuum filtration. The precipitate was washed with MeOH:EtOH (1:4) and EtOAc to give the title compound (7.17 g, 19.1 mmol, 48% yield). 1 H NMR(500MHz,DMSO-d6)δ7.25–7.42(m,5H),4.59(s,2H),4.17–4.24(m,2H),3.92(dd, J=12.3,3.2Hz,1H),3.34–3.40(m,1H),3.10(ddd,J=15.1,7.6,3.9Hz,1H),2.64(t,J =11.5Hz,1H),2.13(dt,J=10.2,3.4Hz,1H),1.87(dd,J=9.0,3.8Hz,1H),1.65(qd,J= 13.2, 3.6Hz, 1H), 1.40 (qd, J=12.8, 3.9Hz, 1H), 1.23 (t, J=7.1Hz, 3H); M / Z: 279, [M+H] + ESI + RT = 0.81(S1).

[0282] Intermediate 1 (Step 1.d): (2R,5S)-5-[(benzyloxy)amino]piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester

[0283]

[0284] Et3N (3.6 mL, 25.8 mmol), DMAP (76 mg, 0.622 mmol), and Boc2O (4.2 mL, 18.3 mmol) were added to a solution of (2R,5S)-5-[(benzyloxy)amino]piperidine-2-carboxylic acid ethyl ester oxalic acid (2.22 g, 6.03 mmol) in DCM (anhydrous, 30 mL) at 0 °C, and the mixture was stirred at room temperature for 17 h. The reaction mixture was diluted with saturated aqueous NH4Cl solution and DCM, the organic layer was separated, washed with H2O and brine, dried over Na2SO4, and concentrated under vacuum. Purification by silica gel FCC (0-20% EtOAc / heptane) gave the title compound (86% purity, 1.40 g, 3.18 mmol, 53% yield) as a colorless oil. 1 ¹H NMR (500MHz, chloroform-d) δ 7.40–7.26 (m, 5H), 5.51–5.41 (m, 1H), 4.92–4.80 (m, 1H), 4.79–4.62 (m, 2H), 4.19 (q, J = 7.0Hz, 3H), 3.11 (d, J = 45.4Hz, 2H), 1.96 (s, 2H), 1.73–1.60 (m, 1H), 1.55–1.49 (m, 1H), 1.46 (s, 9H), 1.27 (t, J = 7.1Hz, 3H); M / Z: 379, [M+H] + ESI + RT = 1.09(S2).

[0285] Route 2 plan

[0286]

[0287] Intermediate 2 (step 2.a): 2-(4-chloro-3-fluorophenoxy)acetyl chloride

[0288]

[0289] Oxaloyl chloride (10 mL, 0.115 mol) was added to a solution of 2-(4-chloro-3-fluorophenoxy)acetic acid (5.16 g, 22.7 mmol) in DCM (45 mL) at 0 °C, followed by the addition of DMF (81 μL, 1.11 mmol), and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under vacuum to give the title compound (90% purity, 5.30 g, 21.4 mmol, 94% yield) as an orange oil. 1¹H NMR (400MHz, chloroform-d) δ 7.31 (t, J = 8.6 Hz, 1H), 6.75 (dt, J = 10.2, 2.9 Hz, 1H), 6.66 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 4.96 (s, 2H).

[0290] Route 3 plan

[0291]

[0292] Step 3.a: (2R,5S)-5-aminopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester

[0293]

[0294] Pd / C (10%, 2.28 g, 2.14 mmol) was added to a solution of (2R,5S)-5-[(benzyloxy)amino]piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (93% purity, 8.7 g, 21.3 mmol, intermediate 1) in EtOH (anhydrous, 200 mL) under N2 conditions, and the mixture was stirred at room temperature under H2 for 17 hours. The reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under vacuum. The residue was purified using an SCX-2 column, first by washing with MeOH and then eluting with 3M NH3 / MeOH, to give the title compound (4.88 g, 17.0 mmol, 80% yield) as a pale yellow oil. 1 ¹H NMR (400MHz, chloroform-d) δ 4.98–4.57 (m, 1H), 4.18 (q, J = 7.1Hz, 2H), 3.87–3.64 (m, 1H), 3.35–2.99 (m, 2H), 2.14–1.92 (m, 2H), 1.64–1.52 (m, 2H), 1.45 (s, 11H), 1.26 (t, J = 7.1Hz, 3H).

[0295] Step 3.b: (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester

[0296]

[0297] A solution of 2-(4-chloro-3-fluoro-phenoxy)acetyl chloride (4.19 g, 18.8 mmol, intermediate 2) in DCM (10 mL) was added dropwise to a mixture of (2R,5S)-5-aminopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (4.88 g, 17.0 mmol) and Et3N (14 mL, 0.103 mol) in DCM (170 mL) and stirred at room temperature for 48 h. The reaction mixture was diluted with DCM (250 mL) and washed with saturated NaHCO3 aqueous solution (2 × 100 mL) and brine (100 mL), dried over Na2SO4 and concentrated under vacuum. Purification by silica gel FCC (0-50% EtOAc / heptane) gave the title compound (7.14 g, 15.6 mmol, 91% yield) as a colorless oil. 1 H NMR (400MHz, chloroform-d) δ7.32(t,J=8.6Hz,1H),6.86–6.72(m,2H),6.69–6.63(m,1H),4.98–4.66(m,1H),4.45(s,2H),4.29–4.13(m,3H),4.09– 3.87(m,1H),3.33–3.10(m,1H),2.23–2.02(m,1H),2.00–1.71(m,2H),1.56(s,1H),1.44(s,9H),1.28(t,J=7.2Hz,3H); M / Z:459,461[M+H] + ESI + RT = 3.83 (S4).

[0298] Intermediate 3 (step 3.c): (2R,5S)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-2-carboxylic acid

[0299]

[0300] LiOH (0.78 g, 31.1 mmol) was added to a solution of (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (7.1 g, 15.6 mmol) in EtOH (80 mL) and H2O (20 mL), and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under vacuum, dissolved in H2O (50 mL), and extracted with DCM (2 × 100 mL). The aqueous layer was then acidified to pH 2 with 2 M hydrochloric acid aqueous solution and extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to provide the title compound (87% purity, 5.60 g, 11.3 mmol, 73% yield) as a white solid; 1 H NMR (400MHz, DMSO-d6) δ8.02(d,J=7.3Hz,1H),7.47(t,J=8.9Hz,1H),7.03(dd,J=11.4,2.8Hz,1H),6.83–6.75(m,1H),4.59–4.54(m,2H),3.9 3(s,1H),3.73(d,J=54.2Hz,1H),3.13–2.94(m,1H),2.06–1.87(m,2H) ,1.61(d,J=12.2Hz,1H),1.56–1.43(m,1H),1.37(s,10H);M / Z:429,431

[0301] [M+H],ESI + RT = 0.91 min (S1).

[0302] Route 4

[0303]

[0304] Step 4.a: 5-(difluoromethoxy)-2-nitrophenol

[0305]

[0306] At 0 °C, nitric acid (0.43 mL, 10.3 mmol) was slowly added to a solution of 3-(difluoromethoxy)phenol (1.50 g, 9.37 mmol) in acetic acid (8.0 mL, 9.37 mmol). The reaction mixture was stirred for 10 min, then diluted with H2O (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over MgSO4, concentrated under vacuum, and purified by silica gel FCC (0–100% EtOAc / heptane) to give the title compound (90% purity, 780 mg, 3.42 mmol, 37% yield) as a brown gel. 1 H NMR (500MHz, DMSO-d6) δ 11.31 (s, 1H), 8.04 (d, J = 9.1Hz, 1H), 7.31 (t, J = 72.9Hz, 1H), 6.82 (dd, J = 9.1, 2.5Hz, 1H), 6.77 (d, J = 2.4Hz, 1H).

[0307] Intermediate 4 (Step 4.b): 2-Amino-5-(difluoromethoxy)phenol

[0308]

[0309] To a solution of 5-(difluoromethoxy)-2-nitrophenol (90% purity, 780 mg, 3.42 mmol) in EtOH (14 mL), AcOH (7 mL) and iron (1.91 g, 34.2 mmol) were added, and the mixture was stirred at 100 °C for 1 hour. The reaction mixture was diluted with H₂O (25 mL) and alkalized to pH 8 using 1 M NaOH aqueous solution. The resulting solution was extracted with EtOAc (50 mL), and the combined organic extracts were washed with H₂O (25 mL) and brine (25 mL), dried over MgSO₄, and concentrated under vacuum to give the title compound (50% purity, 800 mg, 2.28 mmol, 67% yield) as a black oil. 1 H NMR (400MHz, DMSO-d6) δ8.76 (s, 1H), 6.97 (t, J = 74.8Hz, 1H), 6.62 (d, J = 8.4Hz, 1H), 6.48–6.42 (m, 2H), 4.34 (s, 2H).

[0310] Route 5 plan

[0311]

[0312] Step 5.a: (2R,5S)-2-[(4-chloro-2-hydroxyphenyl)carbamoyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1-carboxylic acid tert-butyl ester

[0313]

[0314] HATU (441 mg, 1.16 mmol) was added to a solution of 2-amino-5-chlorophenol (167 mg, 1.16 mmol), DIPEA (0.61 mL, 3.48 mmol), and (2R,5S)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidin-2-carboxylic acid (500 mg, 1.16 mmol, intermediate 3) in DMF (anhydrous, 16 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (30 mL), washed with water (2 × 20 mL), and the combined organic extracts were dried over MgSO4 and concentrated under vacuum. Purification by silica gel FCC (10–100% EtOAc / heptane) gave the title compound (90% purity, 256 mg, 0.414 mmol, 36% yield) as a brown oil. 1 H NMR(400MHz, CDCl3)δ8.45(s,1H),7.37–7.30(m,1H),7.14–7.04(m,1H),7.01–6.98(m,1H),6.87–6.65(m,3H),4.93(s,1H),4.53 –4.41(m,2H),4.30–4.13(m,2H),3.21–3.10(m,1H),2.41–2.13(m,1H),1.97–1.57(m,5H),1.52–1.40(m,9H); M / Z:556,558[M+H] + ESI + RT = 4.24 min (S4).

[0315] Example 1 (Step 5.b): (2R,5S)-2-(6-chloro-1,3-benzoxazol-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1-carboxylic acid tert-butyl ester

[0316]

[0317] A solution of (2R,5S)-2-[(4-chloro-2-hydroxyphenyl)carbamoyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidin-1-carboxylic acid tert-butyl ester (90% purity, 200 mg, 0.324 mmol) and DIAD (76 μL, 0.388 mmol) in THF (anhydrous, 4 mL) was added to PPh3 (110 mg, 0.421 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (10 mL), washed with H2O (2 × 10 mL), and the organic extract was dried over MgSO4 and concentrated under vacuum. Purification by silica gel FCC (0-100% EtOAc / heptane) gave the title compound (90% purity, 170 mg, 0.284 mmol, 88% yield) as a colorless oil. 1 H NMR (500MHz, CDCl3) δ7.64–7.59(m,1H),7.55–7.51(m,1H),7.37–7.31(m,2H),6.96–6.80(m,1H),6.80–6.75(m,1H),6.72 –6.66(m,1H),4.54–4.43(m,2H),4.20–4.15(m,1H),2.34(s,1H),2.07–1.75(m,6H),1.47(s,9H); M / Z:438,440[M-Boc+H] + ESI + RT = 1.16 min (S2).

[0318] Example 2 (Step 5.c): N-[(3S,6R)-6-(6-chloro-1,3-benzoxazol-2-yl)piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide

[0319]

[0320] ZnBr2 (90 mg, 0.401 mmol) was added to a solution of (2R,5S)-2-(6-chloro-1,3-benzoxazol-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamyl]piperidine-1-carboxylate (90% purity, 80 mg, 0.134 mmol, Example 1) in DCM (anhydrous, 2.5 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (15 mL), washed with H2O (2 × 8 mL), and the organic extract was dried over MgSO4 and concentrated under vacuum. Purification by preparative HPLC (Method 3) gave the title compound (8.2 mg, 0.0187 mmol, 14% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ7.99(d,J=8.1Hz,1H),7.91(d,J=1.9Hz,1H),7.74(d,J=8.5Hz,1H),7.50( t,J=8.9Hz,1H),7.42(dd,J=8.5,2.0Hz,1H),7.07(dd,J=11.4,2.8Hz,1H),6.86(ddd,J=9.0,2.8, 1.1Hz,1H),4.53(s,2H),3.98–3.90(m,1H),3.78–3.69(m,1H),3.09–3.00(m,1H),2.93–2.84(m,1 H),2.16–2.06(m,1H),1.99–1.89(m,1H),1.81–1.69(m,1H),1.62–1.49(m,1H); M / Z:438,440[M+H] + ESI + RT = 2.27 min (S4).

[0321] The compounds in Table 1 were synthesized using the corresponding intermediates according to the general route 5 exemplified in Examples 1 and 2.

[0322] Table 1

[0323]

[0324]

[0325]

[0326]

[0327]

[0328] Route 6 plan

[0329]

[0330] Step 6.a: (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{[2-hydroxy-4-(trifluoromethyl)phenyl]carbamoyl}piperidine-1-carboxylic acid tert-butyl ester

[0331]

[0332] HATU (353 mg, 0.928 mmol) was added to a solution of 2-amino-5-(trifluoromethyl)phenol (164 mg, 0.928 mmol), DIPEA (0.49 mL, 2.79 mmol), and (2R,5S)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-2-carboxylic acid (intermediate 3,400 mg, 0.928 mmol) in anhydrous DMF (8 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc (30 mL) and washed with H2O (2 × 20 mL). The combined organic extracts were dried over MgSO4, concentrated under vacuum, and purified by silica gel FCC (10–100% EtOAc / heptane) to give the title compound (53% purity, 507 mg, 0.456 mmol, 49% yield) as a colorless oil; M / Z: 590, 592 [M+H] + ESI + RT = 4.19 min (S4).

[0333] Example 15 (Step 6.b): (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[6-(trifluoromethyl)-1,3-benzoxazol-2-yl]piperidine-1-carboxylic acid tert-butyl ester

[0334]

[0335] PPh3 (155 mg, 0.592 mmol) was added to a solution of (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamitoyl]-2-{[2-hydroxy-4-(trifluoromethyl)phenyl]carbamoyl}piperidin-1-carboxylic acid tert-butyl ester (53% purity, 507 mg, 0.456 mmol) and DIAD (0.11 mL, 0.547 mmol) in anhydrous THF (6 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc (10 mL) and washed with H2O (2 × 10 mL). The organic extract was dried over MgSO4, concentrated under vacuum, and purified by silica gel FCC (0–100% EtOAc / heptane) to give the title compound (54% purity, 430 mg, 0.406 mmol, 89% yield) as a white solid. 1H NMR(400MHz,DMSO)δ8.25(s,1H),8.13(d,J=7.1Hz,1H),7.98(d,J=8.3Hz,1H), 7.75(d,J=8.3Hz,1H),7.49(t,J=8.9Hz,1H),7.06(dd,J=11.4,2.8Hz,1H),6.8 4(dd,J=9.0,2.0Hz,1H),5.75(s,2H),4.64–4.54(m,2H),4.03–3.87(m,2H),2. 35–2.18(m,2H),1.80–1.64(m,2H),1.39–1.34(m,9H); M / Z:472,474[M-Boc+H] + ESI + RT = 1.17 min (S2).

[0336] Example 16 (Step 6.c): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[6-(trifluoromethyl)-1,3-benzoxazol-2-yl]piperidin-3-yl]acetamide

[0337]

[0338] (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamyl]-2-[6-(trifluoromethyl)-1,3-benzoxazol-2-yl]piperidine-1-carboxylic acid tert-butyl ester (Example 15, 54% purity, 430 mg, 0.406 mmol) was dissolved in 4 M HCl / 1,4-dioxane (5 mL) and stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (30 mL) and washed with saturated NaHCO3 aqueous solution. The organic extract was dried over MgSO4, concentrated under vacuum, and purified by preparative HPLC (Method 3) to give the title compound (90 mg, 0.186 mmol, 46% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ8.21(s,1H),7.97(dd,J=19.4,8.2Hz,2H),7.73(dd,J=8.3,1.2Hz ,1H),7.50(t,J=8.9Hz,1H),7.08(dd,J=11.4,2.8Hz,1H),6.86(ddd,J=9.0,2.8,1.0Hz,1H ),4.54(s,2H),4.05–3.96(m,1H),3.82–3.70(m,1H),3.11–3.03(m,1H),2.94(s,1H),2.56 –2.52(m,1H),2.19–2.09(m,1H),2.00–1.91(m,1H),1.85–1.51(m,2H); M / Z:472,474[M+H] + ESI + RT = 2.31 min (S4).

[0339] The compounds in Table 2 were synthesized using the corresponding intermediates according to general route 6 as exemplified in Examples 15 and 16.

[0340] Table 2

[0341]

[0342]

[0343] Route 7 plan

[0344]

[0345] Step 7.a: (2R,5S)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-2-[methoxy(methyl)carbamoyl]piperidine-1-carboxylic acid tert-butyl ester

[0346]

[0347] HATU (1324 mg, 3.48 mmol) was added to a solution of N-methoxymethylamine hydrochloride (340 mg, 3.48 mmol), DIPEA (1.8 mL, 10.4 mmol), and (2R, 5S)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidin-2-carboxylic acid (1.50 g, 3.48 mmol, intermediate 3) in DMF (anhydrous, 49.2 mL), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were dried (Na2SO4) and concentrated under vacuum to give the title compound (95% purity, 1.58 g, 3.17 mmol, 91% yield) as a colorless oil. The product was used in the next reaction without further purification. 1 H NMR (500MHz, CDCl3) δ7.31(t,J=8.6Hz,1H),6.74(dd,J=10.3,2.8Hz,2H),6.66(ddd,J=8.9,2.8,1.1Hz,1H),5.17–4.83 (m,1H),4.45(s,2H),4.23–4.17(m,1H),3.98–3.61(m,5H),3.18(s,3H),1.95–1.81(m,4H),1.41(s,9H); M / Z:496[M+Na] + ESI + RT = 0.94 min (S2).

[0348] Step 7.b: (2R,5S)-2-acetyl-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0349]

[0350] A solution of (2R,5S)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-2-[methoxy(methyl)carbamoyl]piperidine-1-carboxylic acid tert-butyl ester (1.58 g, 3.17 mmol) in THF (anhydrous, 20 mL) was added to 3 M MeMgBr (3 M / Et2O) (1.4 mL, 4.12 mmol). The reaction was heated to room temperature over 1 hour. The reaction mixture was diluted with EtOAc, and the organic layer was washed with saturated aqueous NH4Cl solution (3x). The organic layer was dried (MgSO4) and concentrated under vacuum. Purification by silica gel FCC (10–100% EtOAc / heptane) gave the title compound (89% purity, 622 mg, 1.29 mmol, 41% yield) as a pale yellow oil. 1H NMR(400MHz, CDCl3)δ7.32(t,J=8.6Hz,1H),6.87–6.63(m,3H),4.85–4.53(m,1H),4.48–4.41(m,2H ),4.15–4.08(m,1H),2.17(s,3H),2.15–2.06(m,1H),1.84–1.56(m,5H),1.45(s,9H); M / Z:429[M+H] + ESI + RT = 3.46 min (S4).

[0351] Step 7.c: (2R,5S)-2-(2-bromoacetyl)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0352]

[0353] 1 M LiHMDS / THF (2.7 mL, 2.68 mmol) was added to a solution of (2R,5S)-2-acetyl-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]piperidine-1-carboxylic acid tert-butyl ester (89% purity, 431 mg, 0.894 mmol) in anhydrous THF (8 mL), and the reaction was stirred for 30 min. TMSCl (0.34 mL, 2.68 mmol) was added, and the mixture was stirred at -78 °C for 30 min. A solution of NBS (239 mg, 1.34 mmol) in anhydrous THF (4 mL) was added, and the mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (20 mL) and washed with saturated NH4Cl aqueous solution (2 × 20 mL). The combined organic layers were dried (MgSO4) and evaporated to dryness. Purified by silica gel FCC (10-100% EtOAc / heptane), the title compound (39% purity, 482 mg, 0.370 mmol, 41% yield) was given as a yellow oil. The product was used directly in the next reaction without further purification; M / Z: 407, 409 [M-Boc+H] + ESI + RT = 3.78 min (S4).

[0354] Example 5 (Step 7.d): (2R,5S)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylic acid tert-butyl ester

[0355]

[0356] A solution of 2-amino-5-(trifluoromethyl)pyridine (27 mg, 0.165 mmol), (2R,5S)-2-(2-bromoacetyl)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]piperidine-1-carboxylic acid tert-butyl ester (39%, 215 mg, 0.165 mmol), and NaHCO3 (14 mg, 0.165 mmol) in anhydrous ACN (2.15 mL) was stirred at 80 °C for 6 hours. The reaction was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), and concentrated under vacuum to give the title compound (35% purity, 240 mg, 0.147 mmol, 89% yield) as an orange oil. The product was used directly in the next reaction without further purification; M / Z: 571[M+H] + ESI + RT = 3.71 min (S4).

[0357] Example 6 (Step 7.e): 2-(4-chloro-3-fluoro-phenoxy)-N-[(3S,6R)-6-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-3-piperidinyl]acetamide

[0358]

[0359] To a solution of (2R,5S)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]piperidin-1-carboxylic acid tert-butyl ester (35% purity, 240 mg, 0.147 mmol, Example 5) in 1,4-dioxane (2 mL), HCl (4 M / 1,4-dioxane) (2.0 mL, 8.00 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution (2x). The organic phase was dried (MgSO4) and evaporated under vacuum. Purification by preparative HPLC (Method 3) yielded the title compound (95% purity, 7.9 mg, 0.0159 mmol, 11% yield) as a grayish-white amorphous solid. 1H NMR (400MHz, DMSO-d6) δ8.76 (d, J=7.2Hz, 1H), 8.09–7.96 (m, 3H), 7.51 (t, J=8. 9Hz, 1H), 7.16 (dd, J=7.1, 1.7Hz, 1H), 7.08 (dd, J=11.4, 2.8Hz, 1H), 6.87 (dd, J= 8.9,1.9Hz,1H),4.54(s,2H),3.97–3.76(m,2H),3.17–3.08(m,1H),2.71–2.59 (m,1H),2.21–2.11(m,1H),2.04–1.88(m,2H),1.71–1.54(m,2H); M / Z:471[M+H] + ESI + RT = 2.08 min (S4).

[0360] The compounds in Table 3 were synthesized using the corresponding intermediates according to the general route 7 exemplified in Examples 5 and 6.

[0361] Table 3

[0362]

[0363]

[0364] II Measurement

[0365] HEK-ATF4 High Content Imaging Measurement

[0366] The compound examples were tested in a HEK-ATF4 high-content imaging assay to evaluate their pharmacological efficacy in inhibiting tunicamycin-induced ISR. Wild-type HEK293 cells were seeded at a density of 12,000 cells per well in growth medium (containing DMEM / F12, 10% FBS, 2 mM L-glutamine, 100 U / mL penicillin-100 μg / mL streptomycin) in 384-well imaging assay plates and incubated at 37°C and 5% CO2. After 24 hours, the medium was replaced with 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 compound examples were serially diluted in DMSO, spotted into intermediate plates, and pre-diluted with assay medium containing 3.3 μM tunicamycin to produce an 11-fold excess of the final assay concentration. In addition to the test area for the compounds in the examples, the plate also contains multiple control wells for normalization purposes, wells containing tunicamycin but not the compounds in the examples (high control), and wells containing neither the compounds in the examples nor tunicamycin (low control). Assays were initiated by transferring 5 μL from the intermediate plate into the assay plate, followed by incubation at 37°C and 5% CO2 for 6 hours. Cells were then fixed (4% PFA / PBS, at 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). Cell nuclei were stained with Hoechst dye (Thermofisher Scientific), and the plate was imaged on an Opera Phenix High Content imaging platform equipped with 405 nm and 488 nm excitation. Finally, the images were analyzed using a script-based algorithm. The primary reading, HEK-ATF4, monitors the ATF4 signal ratio between the cell nucleus and cytoplasm. Chlamydia elata induced an increase in the overall ATF4 ratio signal, which was inhibited by the example compounds that modulate ISR. Furthermore, the number of stained cell nuclei corresponding to healthy cells was counted to derive an HEK-CellCount reading. This reading serves as an internal toxicity control. The example compounds described herein did not produce a significant reduction in CellCount.

[0367] The HEK ATF4 activity of the tested example compounds is provided in Table 4 below:

[0368] +++=IC 50 1-500nM; ++ = IC 50 >500-2000nM; +=IC50 > 2000 - 15000 nM.

[0369] Table 4

[0370] Example number HEK-ATF4 activity 2 ++ 4 + 6 + 8 + 10 ++ 12 +++ 14 ++ 16 +++ 18 + .

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Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein R 1 is H; R 2 is H; R 2a R is H or F; R 3 is phenyl, wherein R 3 is optionally substituted by one or more identical or different R 7 ; R 7 R is halogen; R 4 is H or C(O)OC 1-4 alkyl; R 4a , R 4b , R 4c , and R 5 are independently selected from H; and R 4d and R 4e are independently selected from H; R 6 is 7- to 12-membered heterobicyclyl, wherein R 6 is optionally substituted with one or more R 11 identical or different; R 11 is R 12 , OR 12 or halogen, and R 12 is cyclopropyl or C 1-6 alkyl, wherein R 12 is optionally substituted by one or more, identical or different R 13 ; R 13 is halogen or OR 14 ; R 14 is C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with one or more halogen, which can be the same or different.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2a is H.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 is H.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 2a , R 4 , R 4a , R 4b , R 4c , R 5 , R 4d , R 4e is H, to give formula (la) 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 3 is substituted with one, two, or three R 7 which are the same or different.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R 3 is substituted with one or two identical or different R 7 .

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R 3 is substituted with two identical or different R 7 .

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 7 is F, Cl, or Br.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R 7 is F or Cl.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R in formula (I) is selected. 1 R 2 R 2a R 3 R 4 R 4a R 4b R 4c R 4d R 4e R 5 Equation (Ib) is obtained. wherein each R 7 is independently selected from halogen.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 6 is quinazolinyl, pyrrolo[l,2-a]pyrazinyl, 1,3-benzoxazolyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrimido[5,4-d]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, oxazolo[4,5-c]pyridinyl, imidazo[l,2-a]pyridinyl, [l,2,4]triazolo[l,5-a]pyridinyl, imidazo[l,2-b]pyridazinyl, or 6,7-dihydro-4H-pyrano[4,3-d]oxazolyl, wherein R 6 is optionally substituted with one or more R 11 which are the same or different.

12. The compound or pharmaceutically acceptable salt thereof of claim 11, wherein, R 6 is 1,3-benzoxazolyl or imidazo[1,2-a]pyridinyl, wherein R 6 is optionally substituted by one or more, identical or different R 11 substituents.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein, R 6 is 1,3-benzoxazolyl, wherein R 6 is optionally substituted by one or more, identical or different R 11 substituents.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 6 is unsubstituted or substituted with one or two of the same or different R 11 substituents.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 11 is Cl, CH3, CF3, CH2CF3, OCF3, OCHF2, or OCH2CF3.

16. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of 1 2 2a 4 4a 4b 4c 4d 4e 3 5 6 R​​​​​​​​​​​ (2R,5S)-2-(6-chloro-l,3-benzoxazol-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-l- carboxylic acid tert-butyl ester; N-[(3S,6R)-6-(6-chloro-l,3-benzoxazol-2-yl)piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide; (2R,5S)-2-(5-chloro-l,3-benzoxazol-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-l- carboxylic acid tert-butyl ester; N-[(3S,6R)-6-(5-chloro-l,3-benzoxazol-2-yl)piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide; (2R,5S)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-2-[6-(trifluoromethyl)imidazo[l,2- a]pyridin-2-yl]piperidine-l-carboxylic acid tert-butyl ester; 2-(4-chloro-3-fluoro-phenoxy)-N-[(3S,6R)-6-[6-(trifluoromethyl)imidazo[l,2-a]pyridin-2-yl]-3- piperidinyl]acetamide; (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[7-(trifluoromethyl)imidazo[l,2- a]pyridin-2-yl]piperidine-l-carboxylic acid tert-butyl ester; or 2-(4-chloro-3-fluoro-phenoxy)-N-[(3S,6R)-6-[7-(trifluoromethyl)imidazo[l,2-a]pyridin-2-yl]-3- piperidinyl]acetamide; (2R,5S)-2-(7-chloro-l,3-benzoxazol-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-l- carboxylic acid tert-butyl ester; N-[(3S,6R)-6-(7-chloro-l,3-benzoxazol-2-yl)piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide; (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[6-(trifluoromethoxy)-l,3-benzoxazol-2- yl]piperidine-l-carboxylic acid tert-butyl ester; 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[6-(trifluoromethoxy)-l,3-benzoxazol-2-yl]piperidin- 3-yl]acetamide; (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[6-(difluoromethoxy)-l,3-benzoxazol-2- yl]piperidine-l-carboxylic acid tert-butyl ester; 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[6-(difluoromethoxy)-l,3-benzoxazol-2-yl]piperidin- 3-yl]acetamide; (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[6-(trifluoromethyl)-l,3-benzoxazol-2- yl]piperidine-l-carboxylic acid tert-butyl ester; 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[6-(trifluoromethyl)-1,3-benzoxazol-2- yl]piperidin-3-yl]acetamide; (2R,5S)-2-(4-chloro-1,3-benzoxazol-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1- carboxylic acid tert-butyl ester; or N-[(3S,6R)-6-(4-chloro-1,3-benzoxazol-2-yl)piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide.

17. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Formula (I) has the stereochemistry shown in Formula (Ic) 18. A pharmaceutical composition comprising at least one compound according to any one of claims 1-17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, optionally in combination with one or more other biologically active compounds or pharmaceutical compositions.

19. Use of a compound according to any one of claims 1-17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for the manufacture of a medicament for the treatment or prevention of one or more diseases or disorders associated with integrated stress response.

20. The use according to claim 19, wherein the one or more diseases or disorders associated with integrated stress response is selected from the group consisting of a disease or disorder of white matter brain dysmyelinating syndromes, intellectual disability syndromes, infectious diseases, musculoskeletal diseases, ocular diseases and a disease selected from the group consisting of organ fibrosis, chronic and acute liver diseases, chronic and acute lung diseases, chronic and acute kidney diseases, myocardial infarction, arrhythmia, atherosclerosis, spinal cord injury, ischemic stroke and neuropathic pain.

21. The use according to claim 19, wherein the one or more diseases or disorders associated with integrated stress response is selected from the group consisting of neurodegenerative diseases and disorders, neoplastic diseases, inflammatory diseases, metabolic diseases, cardiovascular diseases.

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