Novel tricyclic heterocyclic carbaldehyde compounds and pharmaceutical compositions containing the same for inhibiting IRE1α

Abstract

The present invention relates to novel tricyclic heterocyclic carbaldehyde compounds and pharmaceutical compositions containing the same for inhibiting IRE1α, and more specifically to novel tricyclic heterocyclic carbaldehyde compounds and pharmaceutical compositions containing the same for treating or preventing IRE1α-related diseases.

Description

[Technical Field]

[0001] The present invention relates to novel tricyclic heterocyclic carbaldehyde compounds and pharmaceutical compositions containing the same for inhibiting inositol-requiring enzyme 1α (IRE1α), and more specifically to novel tricyclic heterocyclic carbaldehyde compounds and pharmaceutical compositions containing the same for treating or preventing IRE1α-related diseases. [Background technology]

[0002] A delicate balance exists between cell survival and death depending on how protein folding stress is managed by cells, and imbalances in proteostasis can lead to many metabolic, neoplastic, neurodegenerative, inflammatory, cardiovascular, and infectious diseases.

[0003] Cancer cells utilize the unfolded protein response (UPR) to alleviate endoplasmic reticulum (ER) stress (ER stress) caused by cellular oncogene activation and a hostile tumor microenvironment (TME) (Non-Patent Document 1). The UPR is activated in many human cancers and plays an important role in tumor initiation, progression, and treatment resistance. ER stress caused by unfolded proteins in the ER of cells initiates the UPR signaling cascade. Inositol-requiring enzyme 1α (IRE1α) is an endoRNase present in the ER membrane. Under stress-free conditions, it exists in an inactive state bound to binding immunoglobulin protein (BIP). Upon ER stress, it becomes activated through phosphorylation upon dissociation of the bound BIP. Activated IRE1α splices the mRNA of a transcription factor called X-box binding protein 1 (XBP1) to induce its activated form, XBP-1, which then binds to the ER stress response element and induces transcriptional activity. Therefore, inositol-requiring enzyme 1α (IRE1α), a key enzyme in the UPR, alleviates protein folding stress and protects cells from stress-induced apoptosis.

[0004] The IRE1α gene is frequently amplified and overexpressed in aggressive luminal B breast cancer cells, which is significantly associated with poor prognosis in breast cancer patients (Non-Patent Document 2). Triple-negative breast cancer (TNBC) is a highly aggressive malignant tumor with poor prognosis and limited treatment options due to the lack of effective targeted therapeutics to date. XBP1 is activated in TNBC and plays a central role in the tumorigenesis and progression of breast cancer subtypes (Non-Patent Document 3). Oncogenic MYC is known to regulate the IRE1α / XBP1 pathway of the UPR in breast cancer through multiple mechanisms. Anticancer efficacy studies in IRE1α or XBP1 knockout transgenic MYC-amplified TNBC mouse models showed selective suppression of MYC-overexpressing tumor growth (Non-Patent Document 4). Meanwhile, research is underway to develop substances that inhibit IRE1α to treat diseases associated with unfolded protein reactions (Patent Documents 1 and 2), but the current situation is incomplete.

[0005] The present inventors have completed the present invention by developing novel tricyclic heterocyclic carbaldehyde compounds capable of inhibiting IRE1α. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Patent Publication No. WO2011 / 127070 [Patent Document 2] International Patent Publication No. WO2011 / 056744 [Non-patent literature]

[0007] [Non-Patent Document 1] Cancer Res. 2020, 80(11), 2368 [Non-patent document 2] iScience. 2020, 23(9), 101503 [Non-patent document 3] Nature 2014, 508(7494), 103 [Non-patent document 4] Cancer Res 2020, 80(11), 2368. Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide novel tricyclic heterocyclic carbaldehyde compounds that have excellent inhibitory activity against inositol-requiring enzyme 1α (IRE1α).

[0009] Another object of the present invention is to provide a pharmaceutical composition for treating or preventing IRE1α-related diseases, which comprises the compound as an active ingredient.

[0010] Other objects and advantages of the present application will become more apparent from the following detailed description, taken in conjunction with the claims. Contents not described in this specification are fully understood and can be inferred by those skilled in the art in the present application or in a similar technical field, and therefore, the description thereof will be omitted. [Means for solving the problem]

[0011] An embodiment of the present invention provides a compound selected from the group consisting of compounds of the following Chemical Formula 1, optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof: [ka]

[0012] Another embodiment of the present invention provides a pharmaceutical composition for treating or preventing an IRE1α-related disease, comprising as an active ingredient a compound selected from the compound of Formula 1, its optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof. [Effects of the Invention]

[0013] Tricyclic heterocyclic carbaldehyde compounds having the structure of Chemical Formula 1 according to one embodiment of the present invention and pharmaceutical compositions containing them have excellent IRE1α protein inhibitory activity, are effective against IRE1α-related diseases, and can be usefully used as therapeutic agents therefor. DETAILED DESCRIPTION OF THE INVENTION

[0014] The present invention will now be described in further detail. Unless otherwise defined, all technical terms used herein have the meanings commonly understood by those of ordinary skill in the art in the field of the present invention. In addition, although preferred methods and samples are described herein, similar or equivalent methods and samples are also included within the scope of the present invention.

[0015] An embodiment of the present invention provides a compound selected from the group consisting of compounds of the following Chemical Formula 1, optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof: [ka] In the above Chemical Formula 1, R1 is hydrogen, halogen, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, HaloC 1-6 Alkyl, -(CH2) a -C 1-6 Alkoxy, -(CH2) a -NR6R7, substituted or unsubstituted -(CH2) a -C 3-6 Cyclyl, substituted or unsubstituted -(CH2) a -C 6-10 Aryl or -(CH2) a -C 2-6 is heterocyclyl; R2 and R3 are each independently hydrogen, halogen, or C1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 alkoxy, oxo(=O), or hydroxy; a is an integer from 0 to 2; n and m are each independently an integer from 0 to 3; Z and Y are each independently -CH2-, -O-, -S-, or -NR8-; Dotted lines indicate the presence or absence of a bond; R4 and R5 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 2-9 Heterocycloalkyl, C 8-16 Spirocycloalkyl, C 8-16 Fused cycloalkyl, C 8-16 Bridged cycloalkyl, C 6-14 Heterospirocycloalkyl, C 6-14 fused heterocycloalkyl or C 6-14 Bridged heterocycloalkyls include halogen, nitro, oxo (=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR9R 10 , -C(O)OR9, -OR9, and -NR9R 10 or unsubstituted with one or more substituents selected from; Alternatively, R4 and R5 may be linked together and together with the amide nitrogen of Formula 1, form C 2-9 Heterocyclyl, C 6-14Heterospirocyclyl, C 6-14 Fused Heterocyclyl, C 6-14 Bridged heterocyclyl or C 4-10 Forming heteroaryl, they are halogen, nitro, oxo (=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, -C(O)R 11 , -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR 11 R 12 , -C(O)OR 11 , -OR 11 , and -NR 11 R 12 or unsubstituted with one or more substituents selected from; R6, R7, R8, R9, R 10 , R 11 , and R 12 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, HaloC 1-6 Alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, C 4-10 Heteroaryl or C 2-9 heterocycloalkyl, or R1 is -(CH2) a -NR6R7, or R4 and R5 are C(O)-NR9R 10 or -NR9R 10 When R6 and R7, or R9 and R 10 are linked together with the amide nitrogen and substituted or unsubstituted C 2-9 Heterocyclyl or substituted or unsubstituted C 4-10 A heteroaryl can be formed.

[0016] The term "halogen" as used herein can be F, Cl, Br, or I. The term "alkyl," as used herein, unless otherwise specified, refers to a substituted or unsubstituted straight-chain or branched hydrocarbon residue, such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, or t-butyl.

[0017] As used herein, unless otherwise specified, the term "alkenyl" refers to a substituted or unsubstituted alkyl group containing one or more double bonds, such as, but not limited to, prop-1-ene, but-1-ene, but-2-ene, 3-methylbut-1-ene, or pent-1-ene.

[0018] As used herein, unless otherwise specified, the term "alkynyl" refers to a substituted or unsubstituted alkyl group containing one or more triple bonds, such as, but not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, or branched-chain alkynyl groups.

[0019] The term "cycloalkyl," as used herein, unless otherwise specified, refers to saturated monocyclic and polycyclic hydrocarbon rings, generally having the specified number of carbon atoms, including substituted and unsubstituted rings, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0020] As used herein, unless otherwise specified, the term "heterocycloalkyl" refers to a substituted or unsubstituted monocyclic cyclic alkyl containing one or more heteroatoms selected from B, N, O, S, P(=O), Si, and P. Examples of the heterocycloalkyl group include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, thiomorpholinyl, imidazolidinyl, tetrahydrofuryl, or similar groups.

[0021] As used herein, unless otherwise specified, the term "spiro" refers to two rings that share one atom and are not connected by a bridge. As used herein, the term "spiro-linked" refers to a linking group that shares one atom, unless otherwise specified.

[0022] As used herein, unless otherwise specified, the term "spirocycloalkyl" refers to a saturated carbocycle compound, including two rings, in which both rings share only one carbon atom as part of the ring. The spirocycloalkyl may be, for example, [ka] There are also, but are not limited to, these.

[0023] As used herein, unless otherwise specified, the term "heterospirocycloalkyl" refers to a spirocycloalkyl containing one or more heteroatoms selected from B, N, O, S, P(=O), Si, and P. The heterospirocycloalkyl includes, for example, [ka] There are also, but are not limited to, these.

[0024] As used herein, the term "bridged cycloalkyl" refers to two rings that share two common ring atoms that are not adjacent, unless otherwise specified. Bridged cycloalkyls are classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyls depending on the number of rings. The bridged cycloalkyls include, for example: [ka] There are also, but are not limited to, these.

[0025] The term "bridged heterocycloalkyl," as used herein, unless otherwise specified, refers to a bridged cycloalkyl containing one or more heteroatoms selected from B, N, O, S, P(=O), Si, and P.

[0026] As used herein, unless otherwise specified, the term "fused cycloalkyl" refers to a ring in which each ring shares an adjacent pair of carbon atoms with another ring, and one or more rings may share one or more double bonds, but none of the rings has a completely conjugated π-electron system. Fused cycloalkyls are classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyls depending on the number of rings. The fused cycloalkyls include, for example, [ka] There are also, but are not limited to, these.

[0027] The term "fused heterocycloalkyl," as used herein, unless otherwise stated, refers to a fused cycloalkyl containing one or more heteroatoms selected from B, N, O, S, P(=O), Si, and P.

[0028] As used herein, unless otherwise stated, the term "haloalkyl" is meant to include substituted and unsubstituted monohaloalkyl and polyhaloalkyl, where the terms halogen and alkyl are as defined above.

[0029] The term "alkoxy," as used herein, unless otherwise specified, refers to a substituted or unsubstituted straight-chain or branched hydrocarbon residue linked by an oxygen atom, such as, but not limited to, methoxy, ethoxy, propoxy, and butoxy, or isopropoxy, isobutoxy, or t-butoxy.

[0030] As used herein, unless otherwise specified, the term "alkoxyalkyl" refers to a substituted or unsubstituted straight-chain or branched alkyl group substituted with an alkoxy group. Examples of the alkoxyalkyl include, but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, methoxyethyl, ethoxyethyl, and methoxypropyl groups.

[0031] As used herein, unless otherwise specified, the term "aryl" refers to a substituted or unsubstituted aromatic group, e.g., C-C 10 This also includes aryl, C3-C8 aryl, or C3-C6 aryl, where double bonds alternate (resonate) between adjacent carbon atoms or suitable heteroatoms, such as, but not limited to, phenyl, biphenyl, naphthyl, toluyl, or naphthalenyl.

[0032] As used herein, unless otherwise specified, the term "heteroaryl" refers to a monocyclic or bicyclic or higher cyclic, substituted or unsubstituted aromatic group containing one or more heteroatoms selected from B, N, O, S, P(=O), Si, and P.

[0033] As used herein, the term "heterocyclyl" refers to a substituted or unsubstituted monocyclic hydrocarbon containing one or more heteroatoms selected from B, N, O, S, P(=O), Si, and P, unless otherwise specified. As used herein, the term "heterocycloalkyl" is included in one embodiment of "heterocyclyl." The heterocyclyl can be, for example, a substituted or unsubstituted [ka] or groups similar thereto, but are not limited thereto.

[0034] As used herein, the term "heterospirocyclyl" refers to a saturated or carbocyclic ring compound, including two rings, in which both rings share only one carbon atom as part of the ring, unless otherwise specified. As used herein, the term "heterospirocycloalkyl" is included in one embodiment of "heterospirocyclyl." The heterospirocyclyl includes, for example, [ka] or groups similar thereto, but are not limited thereto.

[0035] As used herein, unless otherwise specified, the term "fused heterocyclyl" refers to a heterocyclic ring containing one or more heteroatoms selected from B, N, O, S, P(=O), Si, and P, each ring sharing an adjacent pair of carbon atoms with another ring, and one or more rings may share one or more double bonds, but none of the rings have a completely conjugated π-electron system, and is classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl depending on the number of rings. As used herein, the term "fused heterocycloalkyl" is an embodiment of the term "fused heterocyclyl."

[0036] As used herein, unless otherwise specified, the term "bridged heterocyclyl" refers to two or more rings containing one or more heteroatoms selected from B, N, O, S, P(=O), Si, and P, which are saturated or unsaturated and share two common ring atoms that are not adjacent, and is classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl depending on the number of rings. The bridged heterocyclyl includes, for example, [ka] As used herein, the term "bridged heterocycloalkyl" includes, but is not limited to, one form of the term "bridged heterocyclyl."

[0037] As used herein, the term "stereoisomer" means a compound of the present invention or a salt thereof that has the same chemical or molecular formula but is optically or sterically different, and includes optical isomers or diastereomers. As used herein, the term "enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0038] As used herein, the term "diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. The compounds of the present invention contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, such as diastereomers, enantiomers, and racemic mixtures, are considered to be part of the present invention. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate.

[0039] As used herein, the term "solvate" refers to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Such a solvent may be volatile, non-toxic, and / or suitable for administration to humans. The "solvate" may include a molecular complex containing the compound and one or more pharmaceutically acceptable solvent molecules, such as ethanol.

[0040] The term "hydrate" as used herein refers to a complex where the solvent molecule is water. As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt, which may be prepared by any suitable method available to those skilled in the art. For example, if the compound of the present invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available to those skilled in the art, such as treating the free base with an inorganic or organic acid.

[0041] In one embodiment, R1 is C 1-6 Alkyl, HaloC 1-6 Alkyl, -(CH2) a -C 1-6 Alkoxy, -(CH2) a -NR6R7, or substituted or unsubstituted -(CH2) a -C 3-6 It can be cyclyl.

[0042] In one embodiment, R2 and R3 are each independently hydrogen, halogen, or C 1-6 It can be alkyl. In one embodiment, Z and Y may each independently be —CH 2 — or —O—.

[0043] In one embodiment, R and R are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, HaloC 1-6 Alkyl, C 1-6 Alkoxyalkyl, C 3-10 Cycloalkyl or C 2-9 heterocycloalkyl or C 2-9 Heterocycloalkyl-substituted C 1-6 In one embodiment, R4 and R5 may each independently be hydrogen, methyl, ethyl, propyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, morpholinomethyl, or morpholinoethyl. In one embodiment, R4 and R5 may be linked together to form, together with the amide nitrogen of Formula 1, [ka] C is one of the following: 2-9 Heterocyclyl, C 6-14 Heterospirocyclyl, C 6-14 Bridged heterocyclyl, or C 4-10 Forming a heteroaryl, wherein C 2-9Heterocyclyl, C 6-14 Heterospirocyclyl, C 6-14 Bridged heterocyclyl, or C 4-10 Heteroaryl is hydrogen, halogen, nitro, cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C(O)R 11 , Haro C 1-6 Alkoxy, and C 2-6 The heterocyclyl may be substituted with one or more substituents selected from the group consisting of aryl, ...

[0044] In one embodiment, R4 and R5 are linked together to form a group with the amide nitrogen of Formula 1. [ka] Any one selected from the above can be formed.

[0045] In one embodiment, R1 is C 1-6 is alkyl, R2 and R3 are each independently hydrogen, halogen, or C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 alkoxy, oxo(=O), or hydroxy; n and m are each independently an integer of 0 or 1; Z and Y are each independently -CH2- or -O-; R4 and R5 are linked together and together with the amide nitrogen of Formula 1, [ka] C is one of the following: 2-9 Heterocyclyl, C 6-14 Heterospirocyclyl, C 6-14 Bridged heterocyclyl, or C 4-10forming a heteroaryl, At this time, C 2-9 Heterocyclyl, C 6-14 Heterospirocyclyl, C 6-14 Bridged heterocyclyl, or C 4-10 Heteroaryl is hydrogen, halogen, nitro, cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C(O)R 11 , Haro C 1-6 Alkoxy, and C 2-6 Heterocyclyl may be substituted or unsubstituted with one or more substituents selected from the group consisting of aryl, ...

[0046] In one embodiment, R1 is methyl, ethyl, propyl, or isopropyl; R2 and R3 are hydrogen; R4 and R5 are linked together and together with the amide nitrogen of Formula 1, [ka] C is one of the following: 2-9 Heterocyclyl, C 6-14 Heterospirocyclyl, C 6-14 Bridged heterocyclyl, or C 4-10 forming a heteroaryl, At this time, C 2-9 Heterocyclyl, C 6-14 Heterospirocyclyl, C 6-14 Bridged heterocyclyl, or C 4-10 Heteroaryl is a group consisting of hydrogen, halogen, C 1-6 Alkyl, and -C(O)(C 1-6 alkyl) or unsubstituted.

[0047] Or, the above C 2-9 Heterocyclyl, C 6-14Heterospirocyclyl, C 6-14 Bridged heterocyclyl, or C 4-10 Heteroaryl is unsubstituted or substituted with one or more substituents selected from hydrogen, halogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, and acetyl.

[0048] In one embodiment, The compound may be a compound selected from the group consisting of compounds of the following Chemical Formula 2, optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof: [ka] In the above Chemical Formula 2, V and W each independently represent -CH2-, -S-, -O-, or -NR 14 - and; p, q, and r are each independently an integer of 0 or 1; R 13 is hydrogen, halogen, nitro, cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy or HaloC 1-6 is alkoxy; R 14 are each independently hydrogen, C 1-6 Alkyl, HaloC 1-6 Alkyl, or -C(O)(C 1-6 alkyl).

[0049] In one embodiment, R 13 can be hydrogen, halogen, methyl, ethyl, propyl, butyl, or isopropyl.

[0050] In one embodiment, R 14can be hydrogen, halogen, methyl, ethyl, propyl, butyl, isopropyl, or acetyl.

[0051] In one embodiment, the compound may be selected from the group consisting of the following compounds, their optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof: 1) 4-hydroxy-9-methyl-8-(2-morpholino-2-oxoethyl)-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromene-5-carbaldehyde; 2) 4-hydroxy-9-methyl-8-(2-morpholino-2-oxoethyl)-7-oxo-7H-[1,3]dioxolo[4,5-f]chromene-5-carbaldehyde; 3) 6-hydroxy-1-methyl-2-(2-morpholino-2-oxoethyl)-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 4) 6-hydroxy-1-methyl-2-(2-(4-methylpiperidin-1-yl)-2-oxoethyl)-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 5) 6-hydroxy-1-methyl-3-oxo-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 6) 6-hydroxy-1-methyl-2-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 7) 6-hydroxy-2-(2-(4-isopropylpiperazin-1-yl)-2-oxoethyl)-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 8) N-ethyl-2-(5-formyl-4-hydroxy-9-methyl-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromen-8-yl)acetamide; 9) N,N-diethyl-2-(5-formyl-4-hydroxy-9-methyl-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromen-8-yl)acetamide; 10) 2-(2-(3,3-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 11) 6-hydroxy-1-methyl-2-(2-(3-methylpyrrolidin-1-yl)-2-oxoethyl)-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 12) 2-(2-(3,3-dimethylpyrrolidin-1-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 13) 2-(2-(azetidin-1-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 14) 6-Hydroxy-2-(2-(3-methoxypyrrolidin-1-yl)-2-oxoethyl)-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 15) 6-Hydroxy-2-(2-(3-methoxyazetidin-1-yl)-2-oxoethyl)-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 16) 2-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 17) N-ethyl-2-(5-formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromen-2-yl)acetamide; 18) 1-Ethyl-6-hydroxy-3-oxo-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 19) 2-(2-(3-fluoroazetidin-1-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 20) 6-Hydroxy-1-methyl-3-oxo-2-(2-oxo-2-(5-azaspiro[2.4]heptan-5-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 21) 6-Hydroxy-1-methyl-3-oxo-2-(2-oxo-2-(piperidin-1-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 22) 2-(5-formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromen-2-yl)acetamide; 23) 6-Hydroxy-1-isopropyl-3-oxo-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 24) 2-(5-formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydrapyrano[3,2-f]chromen-2-yl)-N-(2-methoxyethyl)acetamide; 25) N,N-Diethyl-2-(5-formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromen-2-yl)acetamide; 26) 2-(2-(4-acetylpiperazin-1-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 27) 2-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 28) 6-Hydroxy-1-methyl-3-oxo-2-(2-oxo-2-thiomorpholinoethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 29) 2-(5-formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromen-2-yl)-N-(2-morpholinoethyl)acetamide; 30) 6-hydroxy-1-methyl-3-oxo-2-(2-oxo-2-(thiazolidin-3-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; and 31) 6-Hydroxy-1-methyl-3-oxo-2-(2-oxo-2-(piperazin-1-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde.

[0052] Another embodiment of the present invention provides a pharmaceutical composition for treating or preventing an inositol-requiring enzyme 1α (IRE1α)-related disease, comprising, as an active ingredient, a compound selected from the compound of Formula 1, its optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof.

[0053] In one embodiment, the composition may exhibit IRE1α inhibitory activity. In one embodiment, the composition may be for treating treatable cancers or tumors by exhibiting IRE1α inhibitory activity.

[0054] The compound or composition according to one embodiment exhibits IRE1α inhibitory activity and can be used to inhibit IRE1α activity, for example, RNA or mRNA cleavage, RNA or mRNA splicing.

[0055] In one embodiment, the cancer may be selected from the group consisting of, but not limited to, breast cancer, liver cancer, ovarian cancer, pancreatic cancer, head and neck cancer, non-small cell lung cancer, glioblastoma, and multiple myeloma. In one embodiment, the pharmaceutical composition may comprise a therapeutically effective amount of a compound selected from the compound of Formula 1, its optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof.

[0056] As used herein, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that will treat or prevent a particular disease, condition or disorder, or that will attenuate, ameliorate or eliminate one or more symptoms of a particular disease, condition or disorder, or that will prevent or delay the onset of one or more symptoms of a particular disease, condition or disorder. A physician skilled in the art can easily determine and prescribe the effective required dosage for the pharmaceutical composition. For example, the pharmaceutical composition may contain the compound in an amount of 0.0001 mg to 10 g, but is not limited thereto.

[0057] In one embodiment, the pharmaceutical composition may further contain pharmaceutically acceptable additives other than the active ingredient, such as, but not limited to, diluents, disintegrants, binders, lubricants, surfactants, suspending agents, or emulsifiers.

[0058] The pharmaceutical compositions of the present invention can be formulated by conventional methods and manufactured into various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, etc., or parenteral dosage forms such as intramuscular, intravenous, or subcutaneous administration.

[0059] Another embodiment of the present invention provides a method for treating an IRE1α-related disease, comprising administering a compound selected from the compound of Formula 1, its optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition containing the same as an active ingredient, to a subject suffering from an IRE1α-related disease. As used herein, the term "treat" or "treatment" refers to inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting pathology or symptoms of the disease, condition, or disorder, i.e., preventing further development of or reversing the pathology and / or symptoms, or ameliorating the disease, e.g., reducing disease severity.

[0060] As used herein, the term "preventing" or "prevention" refers to preventing a disease, e.g., preventing a disease, condition, or disorder in an individual who is also predisposed to the disease, condition, or disorder, but who has not yet experienced or exhibited the pathology or symptoms of the disease.

[0061] As used herein, the term "subject" or "individual" can refer to a vertebrate, such as a mammal, fish, bird, reptile, or amphibian. For example, the subject can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent.

[0062] As used herein, the terms "administer" and "administration" refer to any method of providing the disclosed compositions to a subject. The dosage, frequency, and method of administration of a compound or pharmaceutical composition according to an embodiment may vary depending on the subject being treated, the severity of the disease or condition, the rate of administration, and the discretion of the prescribing physician. For example, the dosage for a normal 70 kg human may be 0.0001 mg to 10 g, e.g., 1 mg to 1 g, per day. The dosage may be one to several times, e.g., 1 to 4 times, or on an on / off schedule, and may be administered orally or parenterally. For example, a compound or pharmaceutical composition according to an embodiment may be administered orally or parenterally in an amount ranging from 0.1 to 100 mg / kg body weight.

[0063] A physician may start at a level lower than that required to produce the desired therapeutic effect and gradually increase the dose of a compound or pharmaceutical composition of the present invention administered to a subject until the intended effect is achieved.

[0064] Another embodiment of the present invention provides a kit comprising, as an active ingredient, a compound selected from the compound of Formula 1, its optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof. In one embodiment, the therapeutic agent may be a drug for treating an IRE1α-related disease, such as a drug for treating cancer. For example, the therapeutic agent may be a chemotherapy drug for treating cancer.

[0065] In one embodiment, the compounds, compositions, and kits of the present invention may be administered alone or simultaneously with at least one other therapeutic agent, either separately or sequentially. In the context of the present invention, the singular forms of words include the plural and vice versa, unless the context clearly dictates otherwise.

[0066] Numerical values ​​described herein are considered to include the meaning of "about" even if not explicitly stated. As used herein, the term "about" means within 5%, preferably within 1% to 2%, of a given value or range. In this specification, numerical ranges expressed using the term "to" refer to ranges that include the numerical values ​​stated before and after the term "to" as the lower and upper limits, respectively.

[0067] As used herein, the terms "have," "can have," "include," or "can include" indicate the presence of a given feature (e.g., a value or a component such as a component) and do not exclude the presence of additional features. The contents of all publications referenced herein are hereby incorporated by reference in their entirety.

[0068] Hereinafter, the method for preparing the compound of Formula 1 will be described in detail. The compound of Formula 1 according to an embodiment of the present invention can be easily prepared by synthesizing an intermediate according to the synthesis methods shown in Reaction Scheme 1 and Reaction Scheme 2, and then by the method shown in Reaction Scheme 3. [Anti 1] [ka]

[0069] ●[Stage-1] (Diacetoxyiodo)benzene (1.1 equivalents) and potassium carbonate (1.2 equivalents) are added to the haloalcohol or haloamine. 3,4-Dimethoxyphenol (1 equivalent, reference equivalent) is slowly added dropwise. After the addition is complete, the mixture is stirred at room temperature. After the reaction is complete, the reaction solvent is distilled off under reduced pressure, followed by the addition of saturated aqueous sodium bicarbonate and extraction with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtered organic layer is concentrated under reduced pressure. The resulting residue is purified by MPLC (ethyl acetate:hexane) to obtain the target compound A.

[0070] ●[Stage-2] Add A (1 equivalent, reference equivalent) prepared in [Step 1] and sodium iodide (10 equivalents) to acetone and stir under reflux overnight. After the reaction is complete, remove the acetone by distillation under reduced pressure, add water, and then extract with dichloromethane. The organic layer is dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtered organic layer is concentrated under reduced pressure. The resulting residue is purified by MPLC (ethyl acetate:hexane) to obtain the title compound B.

[0071] ●[Stage-3] B (1 equivalent, reference equivalent) obtained in [Step-2] above is dissolved in toluene, and azobisisobutyronitrile (1 equivalent) is added. Tri-n-butyltin hydride (Bu3SnH) (5 equivalents) is dissolved in toluene and added dropwise, and the reaction solution is stirred at 90°C overnight. After the reaction is complete, the toluene is removed by distillation under reduced pressure, water is added, and the mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtered organic layer is concentrated under reduced pressure. The resulting residue is purified by MPLC (ethyl acetate:hexane) to obtain the title compound C.

[0072] ●[Stage-4] C (1 equivalent, reference equivalent) obtained in [Step-3], p-toluenesulfonic acid (0.5 equivalents), and 4A molecular sieves (5 v / v) are added to dichloromethane and stirred at room temperature. After the reaction is complete, the reaction solution is filtered through a filter filled with Celite and washed with dichloromethane. The filtered organic layer is concentrated under reduced pressure, and the resulting residue is purified by MPLC (ethyl acetate:hexane) to obtain the title compound D.

[0073] [Anti 2] [ka]

[0074] ●[Stage-1] 3-Methoxy-1,3-benzodioxole-5-carbaldehyde (1 equivalent, reference equivalent) was dissolved in dichloromethane and cooled to 0°C. Sodium bicarbonate (2 equivalents) was added to the reaction mixture, and 3-chloroperoxybenzoic acid (2 equivalents) was added and stirred at room temperature overnight. After confirming the completion of the reaction, methanol and saturated deuterium solution were added and the mixture was stirred at room temperature. The resulting solid was dissolved in water, and the methanol was removed by distillation under reduced pressure. The reaction mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by MPLC (ethyl acetate:hexane) to obtain the title compound E. [Anti 3] [ka]

[0075] ●[Stage-1] Add D or E (1 equivalent, reference equivalent) obtained in Reaction Scheme 1 and 2 above and diethylacetylsuccinate (1.2 equivalents) to methanesulfonic acid. Stir the reaction mixture overnight at room temperature. After the reaction is complete, add water and extract with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and then filtered under reduced pressure. The filtered organic layer is concentrated under reduced pressure. The resulting residue is purified by MPLC (ethyl acetate:hexane) to obtain the title compound F.

[0076] ●[Stage-2] The F (1 equivalent, reference equivalent) obtained in [Step-1] above is dissolved in tetrahydrofuran / methanol / water, and sodium hydroxide (5 equivalents) is added. The reaction mixture is stirred at room temperature. After the reaction is complete, the mixture is acidified with 6N hydrochloric acid to a pH of 3-4 to obtain a solid product. The obtained solid is filtered under reduced pressure and washed with water. The filtered solid is dried to obtain the title compound G.

[0077] ●[Stage-3] Dissolve G (1 equivalent, reference equivalent) obtained in [Step 2], R4R5 amine (1.2 equivalents), and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.2 equivalents) in DMF, and slowly add N,N-diisopropylethylamine (1.2 equivalents). The reaction mixture is stirred overnight at room temperature, and upon completion of the reaction, water is added and the mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtered organic layer is concentrated under reduced pressure. The resulting residue is purified by MPLC (ethyl acetate:hexane) to obtain the title compound H.

[0078] ●[Stage-4] The H (1 equivalent, reference equivalent) obtained in [Step-3] is dissolved in dichloromethane, and a solution of boron tribromide (BBr3, 7 equivalents) is slowly added dropwise at room temperature. The reaction mixture is stirred at room temperature, and after the reaction is complete, water is added and the mixture is extracted with a methanol / dichloromethane solution. The organic layer is dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtered organic layer is concentrated under reduced pressure. The resulting residue is purified by MPLC (dichloromethane:methanol) to obtain the title compound I.

[0079] ●[Stage-5] The I (1 equivalent, reference equivalent) obtained in [Step-4] and hexamethylenetetramine (HMTA, 4 equivalents) are dissolved in trifluoroacetic acid and stirred at 90°C. After the reaction is complete, the mixture is cooled to room temperature and neutralized by adding aqueous sodium bicarbonate solution dropwise. The mixture is extracted with a methanol / dichloromethane solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by MPLC (dichloromethane:methanol) to obtain Formula 1.

[0080] In the above Reaction Schemes 1 to 3, R1, R2, R3, R4, R5, Y, Z, n, and m are as defined in the above Chemical Formula 1, but are not limited thereto. The compound of Formula 1 according to an embodiment of the present invention can be prepared by, but is not limited to, the methods illustrated in Reaction Schemes 1 to 3. Those skilled in the art of organic compounds can appropriately adjust the specific reaction route, reaction conditions, reaction amounts, etc.

[0081] The present invention will be explained in more detail below with reference to the following examples and experimental examples, which are intended to aid in the understanding of the present invention and are not intended to limit the scope of the present invention in any way.

[0082] Example 1: 4-hydroxy-9-methyl-8-(2-morpholino-2-oxoethyl)-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromene-5-carbaldehyde

[0083] [Step 1] Preparation of 4-(2-chloroethoxy)-3,4-dimethoxycyclohexa-2,5-dien-1-one [ka]

[0084] (Diacetoxyiodo)benzene (PhI(OAc)2, 25.3 g, 78.55 mmol) and potassium carbonate (11.8 g, 85.38 mmol) were added to 200 mL of 2-chloroethanol, followed by the slow dropwise addition of 3,4-dimethoxyphenol (11 g, 71.35 mmol) dissolved in 100 mL of 2-chloroethanol at room temperature. After the dropwise addition, the mixture was stirred at room temperature for 3 hours to complete the reaction, after which the 2-chloroethanol was removed by distillation under reduced pressure. 300 mL of saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The organic layer was filtered under reduced pressure and concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate:hexane = 1:4 (v / v) to 1:1 (v / v)) to give 15 g of the title compound (90%, yield).

[0085] 1 H-NMR (300 MHz, CDCl3): δ 6.59 (d, J= 10.2 Hz, 1H), 6.29 (dd, J= 10.2, 3.7 Hz, 1H), 5.62 (d, J= 1.8 Hz, 1H), 3.81 (s, 3H), 3.78-3.74 (m, 2H), 3.63-3.58 (m, 2H), 3.34 (s, 3H).

[0086] [Step-2] Preparation of 4-(2-iodoethoxy)-3,4-dimethoxycyclohexa-2,5-dien-1-one [ka]

[0087] 4-(2-chloroethoxy)-3,4-dimethoxycyclohexa-2,5-dien-1-one (15 g, 64.47 mmol) and sodium iodide (96.64 g, 644.72 mmol) prepared in [Step 1] were added to 300 mL of acetone (4.35 g, 108.63 mmol) and stirred at reflux for 48 hours. After the reaction was completed, the acetone was removed by distillation under reduced pressure, and the mixture was extracted three times with dichloromethane after adding 200 mL of water. The organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The residue obtained by concentrating the filtered organic layer under reduced pressure was purified by MPLC (ethyl acetate:hexane = 1:1 (v / v)) to obtain 17 g of the title compound (81%, yield).

[0088] 1 H-NMR (300 MHz, CDCl3): δ6.62 (d, J= 10.2 Hz, 1H), 6.32 (dd, J= 10.2, 1.8 Hz, 1H), 5.64 (d, J= 1.8 Hz, 1H), 3.81 (s, 3H), 3.79-3.75 (m, 2H), 3.37 (s, 3H), 3.31-3.23 (m, 2H).

[0089] [Step-3] Preparation of 7,7a-dimethoxy-2,3,3a,7a-tetrahydrobenzofuran-5(4H)-one [ka]

[0090] 4-(2-iodoethoxy)-3,4-dimethoxycyclohexa-2,5-dien-1-one (17 g, 52.45 mmol) obtained in [Step 2] was dissolved in 300 mL of toluene and azobisisobutyronitrile (AIBN, 8.6 g, 52.45 mmol) was added. Tri-n-butyltin hydride (Bu3SnH, 76.33 g, 262.26 mmol) was dissolved in 50 mL of toluene and added dropwise over 30 minutes. The reaction mixture was stirred at 90°C overnight. After the reaction was complete, the toluene was removed by distillation under reduced pressure. 200 mL of water was added and the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure. The resulting residue was purified by MPLC (ethyl acetate:hexane = 1:3 (v / v)) to obtain 4.7 g (45%, yield) of the title compound.

[0091] 1 H-NMR (300 MHz, CDCl3): δ5.38 (s, 1H), 4.16-4.09 (m, 2H), 3.77 (s, 3H), 3.38 (s, 3H) 2.85-2.78 (m, 1H), 2.59-2.57(m, 1H), 2.47-2.39(m, 1H), 2.18-2.06 (m, 1H), 1.69-1.81 (m, 1H)

[0092] [Step-4] Preparation of 7-methoxy-2,3-dihydrobenzofuran-5-ol [ka]

[0093] 7,7a-Dimethoxy-2,3,3a,7a-tetrahydrobenzofuran-5(4H)-one (4.2 g, 21.19 mmol) obtained in [Step-3], p-toluenesulfonic acid (2.02 g, 10.59 mmol), and 4A molecular sieves (20 g) were added to 200 mL of dichloromethane and stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was filtered through a filter filled with Celite and washed with 200 mL of dichloromethane. The filtered organic layer was concentrated under reduced pressure, and the resulting residue was purified by MPLC (ethyl acetate:hexane = 1:4 (v / v) to 1:1 (v / v)) to obtain 3.2 g (91%, yield) of the title compound.

[0094] 1 H-NMR (300 MHz, CDCl3): δ6.35-6.32 (m, 2H), 4.69 (brs, 1H), 4.58 (t, J= 8.7 Hz, 2H), 3.82 (s, 3H), 3.17 (t, J= 8.7 Hz, 2H).

[0095] [Step-5] Preparation of ethyl 2-(4-methoxy-9-methyl-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromen-8-yl)acetate [ka]

[0096] 7-Methoxy-2,3-dihydrobenzofuran-5-ol (520 mg, 3.13 mmol) prepared in [Step 4] and diethylacetylsuccinate (855 mg, 3.76 mmol) were added to 5 mL of methanesulfonic acid, and the reaction mixture was stirred overnight at room temperature. After the reaction was completed, 100 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure, and the resulting residue was purified by MPLC (ethyl acetate:hexane = 1:3 (v / v)) to obtain 780 mg (78%, yield) of the title compound.

[0097] 1H-NMR (300 MHz, DMSO-d6): δ 6.97 (s, 1H), 4.62-4.56 (m, 2H), 4.12-4.02 (m, 2H), 3.86 (s, 3H), 3.71-3.63 (m, 4H), 2.42 (s, 3H), 1.21-1.16 (m, 3H).

[0098] [Step-6] Preparation of 2-(4-methoxy-9-methyl-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromen-8-yl)acetic acid [ka]

[0099] Ethyl 2-(4-methoxy-9-methyl-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromen-8-yl)acetate (780 mg, 2.45 mmol) obtained in [Step-5] was dissolved in tetrahydrofuran / methanol / water (20 mL / 5 mL / 5 mL), and sodium hydroxide (490 mg, 12.25 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was acidified with 6N hydrochloric acid to a pH of 3-4 to obtain a solid product. The resulting solid was filtered under reduced pressure and washed with distilled water. The filtered solid was dried in an oven at 55°C to obtain 510 mg (72%, yield) of the title compound.

[0100] 1 H-NMR (300 MHz, DMSO-d6): δ 6.96 (s, 1H), 4.61-4.56 (m, 2H), 3.86 (s, 3H), 3.71-3.65 (m, 2H), 3.59 (s, 2H), 2.42 (s, 3H).

[0101] [Step-7] Preparation of 4-methoxy-9-methyl-8-(2-morpholino-2-oxoethyl)-1,2-dihydro-7H-furo[3,2-f]chromen-7-one [ka]

[0102] 2-(4-Methoxy-9-methyl-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromen-8-yl)acetic acid (510 mg, 1.76 mmol), morpholine (183 mg, 2.11 mmol), and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP, 1.1 g, 2.11 mmol) were dissolved in 30 mL of DMF, and N,N-diisopropylethylamine (273 mg, 2.11 mmol) was slowly added. The reaction mixture was stirred overnight at room temperature, and then 100 mL of water was added. The mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtered organic layer was concentrated under reduced pressure. The resulting residue was purified by MPLC (ethyl acetate:hexane=1:1 (v / v)) to give 470 mg (74%, yield) of the title compound.

[0103] 1 H-NMR (300 MHz, DMSO-d6): δ 6.95 (s, 1H), 4.61-4.55 (m, 2H), 3.69 (s, 3H), 3.67-3.56 (m, 10H), 3.45-3.42 (m, 2H), 2.36 (s, 3H). [Step-8] Preparation of 4-hydroxy-9-methyl-8-(2-morpholino-2-oxoethyl)-1,2-dihydro-7H-furo[3,2-f]chromen-7-one [ka]

[0104] 4-Methoxy-9-methyl-8-(2-morpholino-2-oxoethyl)-1,2-dihydro-7H-furo[3,2-f]chromen-7-one (300 mg, 0.83 mmol) obtained in [Step-7] was dissolved in 10 mL of dichloromethane, and 1.0 M boron tribromide tetrahydrofuran (BBr3, 5.84 mL) solution was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was cooled to 0°C, 10 mL of water was added, and the mixture was extracted three times with a 20% methanol / dichloromethane solution. The organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure, and the resulting residue was purified by MPLC (dichloromethane:methanol = 10:1 (v / v)) to give 200 mg (69%, yield) of the title compound.

[0105] 1 H-NMR (300 MHz, CDCl3): δ 6.48 (s, 1H), 4.29-4.25 (m, 2H), 3.76-3.65 (m, 10H), 3.18-3.14 (m, 2H), 2.57 (s, 3H)

[0106] [Step-9] Preparation of 4-hydroxy-9-methyl-8-(2-morpholino-2-oxoethyl)-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromene-5-carbaldehyde [ka]

[0107] 4-Hydroxy-9-methyl-8-(2-morpholino-2-oxoethyl)-1,2-dihydro-7H-furo[3,2-f]chromen-7-one (200 mg, 0.57 mmol) obtained in [Step-8] above and hexamethylenetetramine (HMTA, 328 mg, 2.31 mmol) were dissolved in 10 mL of trifluoroacetic acid and stirred at 90°C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and neutralized by adding aqueous sodium bicarbonate solution dropwise. The mixture was extracted three times with a 20% methanol / dichloromethane solution, dried over anhydrous sodium sulfate, and filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure, and the resulting residue was purified by MPLC (dichloromethane:methanol = 20:1 (v / v)) to obtain 10 mg of the title compound (5%, yield).

[0108] 1 H-NMR (300 MHz, CD3OD): δ 10.42 (s, 1H), 4.67-4.61 (m, 2H), 3.76-3.66 (m, 10H), 3.61-3.58 (m, 2H), 2.41 (s, 3H). MS (ESI + , m / z): 374.2 [M+H] +

[0109] Example 2: 4-hydroxy-9-methyl-8-(2-morpholino-2-oxoethyl)-7-oxo-7H-[1,3]dioxolo[4,5-f]chromene-5-carbaldehyde

[0110] [Step 1] Preparation of 7-methoxybenzo[d][1,3]dioxol-5-ol [ka]

[0111] 7-Methoxy-1,3-benzodioxole-5-carbaldehyde (5 g, 27.75 mmol, eNovation) was dissolved in 143 mL of dichloromethane and cooled to 0 °C. Sodium bicarbonate (4.66 g, 55.48 mmol) was added. 3-Chloroperoxybenzoic acid (mCPBA, 9.58 g, 55.51 mmol) was added to the reaction mixture and stirred overnight at room temperature. After confirming completion of the reaction, 143 mL of methanol was added, followed by 72 mL of saturated deuterium oxide solution, and the mixture was stirred for an additional hour. The resulting solid was dissolved in water, and the methanol was concentrated under reduced pressure. The reaction mixture was extracted three times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure, and the resulting residue was purified by MPLC (ethyl acetate:hexane = 1:4 (v / v)) to yield 3.5 g of the title compound (75%, yield).

[0112] 1 H-NMR (300 MHz, CDCl3): δ6.13-6.07 (m, 2H), 3.86 (s, 2H), 2.32 (s, 3H).

[0113] [Step 2] Preparation of ethyl 2-(4-methoxy-9-methyl-7-oxo-7H-[1,3]dioxolo[4,5-f]chromen-8-yl)acetate [ka]

[0114] In step 5) of Example 1, instead of 7-methoxy-2,3-dihydrobenzofuran-5-ol, 7-methoxybenzo[d][1,3]dioxol-5-ol (1 g, 5.95 mmol) prepared in step 1 was used, and the procedure was carried out in the same manner as in step 5) of Example 1 to obtain 310 mg (16%, yield) of the target compound.

[0115] 1H-NMR (300 MHz, CDCl3): δ 6.53 (s, 1H), 6.09 (s, 2H), 4.23-4.16 (m, 2H), 3.95 (s, 3H), 3.69 (s, 2H), 2.49 (s, 3H), 1.31-1.27 (m, 3H).

[0116] [Step 3] Preparation of 2-(4-methoxy-9-methyl-7-oxo-7H-[1,3]dioxolo[4,5-f]chromen-8-yl)acetic acid [ka]

[0117] In step 6) of Example 1, ethyl 2-(4-methoxy-9-methyl-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromen-8-yl)acetate was replaced with ethyl 2-(4-methoxy-9-methyl-7-oxo-7H-[1,3]dioxolo[4,5-f]chromen-8-yl)acetate (310 mg, 5.95 mmol) prepared in step 2, and the procedure was carried out in the same manner as in step 6) of Example 1 to obtain 160 mg of the target compound (57%, yield).

[0118] 1 H-NMR (300 MHz, CD3OD): δ 6.66 (s, 1H), 6.11 (s, 2H), 3.96 (s, 3H), 3.67 (s, 2H), 2.52 (s, 3H).

[0119] [Step 4] Preparation of 4-methoxy-9-methyl-8-(2-morpholino-2-oxoethyl)-7H-[1,3]dioxolo[4,5-f]chromen-7-one [ka]

[0120] In step 7) of Example 1, instead of ethyl 2-(4-methoxy-9-methyl-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromen-8-yl)acetate, 2-(4-methoxy-9-methyl-7-oxo-7H-[1,3]dioxolo[4,5-f]chromen-8-yl)acetate (485 mg, 1.66 mmol) obtained in [Step-3] was used, and the procedure was carried out in the same manner as in step 7) of Example 1 to obtain 425 mg of the target compound (71%, yield).

[0121] 1 H-NMR (300 MHz, CDCl3): δ 6.53 (s, 1H), 6.09 (s, 2H), 3.96 (s, 3H), 3.76-3.65 (m, 10H), 2.56 (s, 3H).

[0122] [Step 5] Preparation of 4-hydroxy-9-methyl-8-(2-morpholino-2-oxoethyl)-7H-[1,3]dioxolo[4,5-f]chromen-7-one [ka]

[0123] In step 8) of Example 1, 4-hydroxy-9-methyl-8-(2-morpholino-2-oxoethyl)-1,2-dihydro-7H-furo[3,2-f]chromen-7-one was replaced with 4-methoxy-9-methyl-8-(2-morpholino-2-oxoethyl)-7H-[1,3]dioxolo[4,5-f]chromen-7-one (300 mg, 0.83 mmol) prepared in step 4, and the procedure was carried out in the same manner as in step 8) of Example 1 to obtain 75 mg of the target compound (26%, yield).

[0124] 1 H-NMR (300 MHz, CD3OD): δ 6.38 (s, 1H), 6.06 (s, 2H), 3.73-3.65 (m, 8H), 3.60-3.57 (m, 2H), 2.47 (s, 3H).

[0125] [Step 6] Preparation of 4-hydroxy-9-methyl-8-(2-morpholino-2-oxoethyl)-7H-[1,3]dioxolo[4,5-f]chromene-5-carbaldehyde [ka]

[0126] In step 9) of Example 1, 4-hydroxy-9-methyl-8-(2-morpholino-2-oxoethyl)-1,2-dihydro-7H-furo[3,2-f]chromen-7-one was replaced with 4-hydroxy-9-methyl-8-(2-morpholino-2-oxoethyl)-7H-[1,3]dioxolo[4,5-f]chromen-7-one (75 mg, 0.21 mmol) prepared in step 5, and the procedure was carried out in the same manner as in step 9) of Example 1 to obtain 4 mg of the target compound (5%, yield).

[0127] 1 H-NMR (300 MHz, CD3OD): δ 10.35 (s, 1H), 6.16 (s, 2H), 3.74-3.58 (m, 10H), 2.46 (s, 3H). MS (ESI + , m / z): 376.2 [M+H] +

[0128] Example 3: 6-Hydroxy-1-methyl-2-(2-morpholino-2-oxoethyl)-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0129] The procedure of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, to obtain 16 mg (6%, yield) of the title compound.

[0130] 1 H-NMR (300 MHz, CDCl3): δ 12.55 (s, 1H), 10.59 (s, 1H), 4.35 (t, J= 5.0 Hz, 2H), 3.79-3.66 (m, 10H), 3.19 (t, J= 6.3 Hz, 2H), 2.59 (s, 3H), 2.09-2.01 (m, 2H). MS (ESI + , m / z): 388.2 [M+H] +

[0131] Example 4: 6-Hydroxy-1-methyl-2-(2-(4-methylpiperidin-1-yl)-2-oxoethyl)-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0132] The procedure of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and 4-methylpiperidine (219 mg, 2.16 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 4 mg of the title compound (2%, yield).

[0133] 1 H-NMR (300 MHz, CDCl3): δ10.56 (s, 1H), 4.56-4.51 (m, 1H), 4.33-4.30 (m, 1H), 4.10-4.04 (m, 1H), 3.80-3.66 (m, 5H), 3.17-3.13 (m, 2H), 2.65-2.57 (m, 1H), 2.56 (s, 3H), 2.05-2.00 (m, 2H), 1.98-1.66 (m, 2H), 1.23-1.09 (m, 2H), 0.98-0.96 (m, 3H) MS (ESI + , m / z): 400.2 [M+H] +

[0134] Example 5: 6-Hydroxy-1-methyl-3-oxo-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0135] The process of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and pyrrolidine (44 mg, 0.62 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 76 mg (47%, yield) of the title compound.

[0136] 1 H-NMR (300 MHz, CDCl3): δ12.53 (s, 1H), 10.59 (s, 1H), 4.34 (t, J= 5.0 Hz, 2H), 3.71-3.66 (m, 4H), 3.53- 3.48 (m, 2H), 3.19 (t, J= 6.3 Hz, 2H), 2.59 (s, 3H), 2.07-1.89 (m, 6H). MS (ESI + , m / z): 372.2 [M+H] +

[0137] Example 6: 6-Hydroxy-1-methyl-2-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0138] The process of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and 1-methylpiperazine (40 mg, 0.40 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 20 mg (21%, yield) of the title compound.

[0139] 1 H-NMR (300 MHz, CDCl3): δ12.55 (s, 1H), 10.59 (s, 1H), 4.34 (t, J= 5.1 Hz, 2H), 3.82-3.71 (m, 8H), 3.18 (t, J= 6.3 Hz, 2H), 2.64 (s, 3H), 2.57-2.42 (m, 2H), 2.44 (s, 3H), 2.08-1.98 (m, 2H). MS (ESI + , m / z): 401.2 [M+H] +

[0140] Example 7: 6-Hydroxy-2-(2-(4-isopropylpiperazin-1-yl)-2-oxoethyl)-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0141] The procedure of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and 1-isopropylpiperazine (257 mg, 1.97 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 2 mg of the title compound (1%, yield).

[0142] 1H-NMR (300 MHz, CDCl3): δ10.38 (s, 1H), 4.24-4.19 (m, 2H), 3.75-3.72 (m, 2H), 3.66-3.35 (m, 4H), 3.34-3.06 (m, 2H), 2.76-2.70 (m, 1H), 2.65-2.53 (m, 4H), 2.45 (s, 3H), 1.97-1.89 (m, 2H), 1.10-1.08 (m, 6H). MS (ESI + , m / z): 429.2 [M+H] +

[0143] Example 8: N-ethyl-2-(5-formyl-4-hydroxy-9-methyl-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromen-8-yl)acetamide [ka]

[0144] The procedure of Example 1 was repeated, except that 2.0 M ethylamine tetrahydrofuran solution (39 mg, 0.86 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 5 mg (10%, yield) of the title compound.

[0145] 1 H-NMR (300 MHz, CDCl3): δ10.60 (s, 1H), 6.25 (brs, 1H), 4.79-4.72 (m, 2H), 3.85-3.68 (m, 2H), 3.58 (s, 2H), 3.32-3.22 (m, 2H), 2.67 (s, 3H), 1.18-1.12 (m, 3H). MS (ESI + , m / z): 332.1 [M+H] +

[0146] Example 9: N,N-Diethyl-2-(5-formyl-4-hydroxy-9-methyl-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromen-8-yl)acetamide [ka]

[0147] The procedure of Example 1 was repeated, except that diethylamine (126 mg, 1.72 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 18 mg (25%, yield) of the title compound.

[0148] 1 H-NMR (300 MHz, CDCl3): δ12.04 (brs, 1H), 10.59 (s, 1H), 4.78-4.71 (m, 2H), 3.75 (s, 2H), 3.74-3.67 (m, 2H), 3.59-3.38 (m, 4H), 2.51 (s, 3H), 1.37-1.13 (m, 6H). MS (ESI + , m / z): 360.1 [M+H] +

[0149] Example 10: 2-(2-(3,3-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0150] The process of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and 3,3-difluoropyrrolidine hydrochloride (193 mg, 1.31 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 5 mg of the title compound (19%, yield).

[0151] 1 H-NMR (300 MHz, CDCl3): δ12.58 (brs, 1H), 10.59 (s, 1H), 4.37-4.33 (m, 2H), 4.14-3.64 (m, 6H), 3.22-3.16 (m, 2H), 2.61 (s, 3H), 2.58-2.02 (m, 4H). MS (ESI + , m / z): 408.1 [M+H] +

[0152] Example 11: 6-Hydroxy-1-methyl-2-(2-(3-methylpyrrolidin-1-yl)-2-oxoethyl)-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0153] The process of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and 3-methylpyrrolidine hydrochloride (98 mg, 0.79 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 12 mg (19%, yield) of the title compound.

[0154] 1 H-NMR (300 MHz, CD3OD): δ 10.46 (s, 1H), 4.84-4.24 (m, 2H), 3.89-2.57 (m, 4H), 3.30- 3.17 (m, 4H), 2.51(s, 3H), 2.48-2.01 (m, 4H), 1.99-1.51 (m, 1H), 1.15-0.91 (m, 3H). MS (ESI + , m / z): 386.2 [M+H] +

[0155] Example 12: 2-(2-(3,3-dimethylpyrrolidin-1-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0156] The process of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and 3,3-dimethylpyrrolidine (206 mg, 1.97 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 13 mg (8%, yield) of the title compound.

[0157] 1 H-NMR (300 MHz, CDCl3): δ12.50 (brs, 1H), 10.59 (s, 1H), 4.37-4.32 (m, 2H), 3.82-3.55 (m, 4H), 3.44-3.16 (m, 4H), 2.60 (s, 3H), 1.86-1.60 (m, 4H), 1.28 (s, 3H), 1.18 (s, 3H). MS (ESI + , m / z): 400.2 [M+H] +

[0158] Example 13: 2-(2-(azetidin-1-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0159] The process of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and azetidine (79 mg, 1.31 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 2 mg of the title compound (3%, yield).

[0160] 1 H-NMR (300 MHz, CD3OD): δ 10.47 (s, 1H), 4.41-4.36 (m, 2H), 4.28-4.22 (m, 2H), 4.06-4.01 (m, 2H), 3.52 (s, 2H), 3.21-3.14 (m, 2H), 2.55 (s, 3H), 2.40-2.29 (m, 2H), 2.00-1.97 (m, 2H). MS (ESI + , m / z): 358.1 [M+H] +

[0161] Example 14: 6-Hydroxy-2-(2-(3-methoxypyrrolidin-1-yl)-2-oxoethyl)-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0162] The procedure of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and 3-methoxypyrrolidine (98 mg, 0.69 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 3 mg of the title compound (3%, yield).

[0163] 1H-NMR (300 MHz, CD3OD): δ 10.49 (s, 1H), 4.29-4.25 (m, 2H), 4.14-4.02 (m, 1H), 3.83-3.60 (m, 5H), 3.57-3.54 (m, 1H), 3.47 (s, 3H), 3.34-3.21 (m, 2H), 2.54 (s, 3H), 2.24-2.11 (m, 4H). MS (ESI + , m / z): 402.2 [M+H] +

[0164] Example 15: 6-Hydroxy-2-(2-(3-methoxyazetidin-1-yl)-2-oxoethyl)-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0165] The process of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and 3-methoxyazetidine hydrochloride (90 mg, 0.69 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 3 mg of the title compound (10%, yield).

[0166] 1 H-NMR (300 MHz, CD3OD): δ 10.49 (s, 1H), 4.57-4.52 (m, 1H), 4.29-4.15 (m, 5H), 3.85-3.80 (m, 1H), 3.57 (s, 2H), 3.31 (s, 3H), 3.26-3.19 (m, 2H), 2.56 (s, 3H), 2.04-1.95 (m, 2H). MS (ESI + , m / z): 388.1 [M+H] +

[0167] Example 16: 2-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0168] The process of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and 3-fluoropyrrolidine hydrochloride (116 mg, 0.90 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 4 mg of the title compound (2%, yield).

[0169] 1 H-NMR (300 MHz, CD3OD): δ 10.48 (s, 1H), 5.47-5.21 (m, 2H), 4.28-4.22 (m, 2H), 4.01-3.89 (m, 2H), 3.85-3.66 (m, 4H), 3.64-3.42 (m, 1H), 3.23-3.19 (m, 2H), 2.53 (s, 3H), 2.00-1.98 (m, 2H). MS (ESI + , m / z): 390.1 [M+H] +

[0170] Example 17: N-ethyl-2-(5-formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromen-2-yl)acetamide [ka]

[0171] The process of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and 2.0 M ethylamine tetrahydrofuran solution (4.1 mL, 8.22 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 19 mg (7%, yield) of the title compound.

[0172] 1 H-NMR (300 MHz, CDCl3): δ12.56 (brs, 1H), 10.60 (s, 1H), 6.29 (s, 1H), 4.37-4.32 (m, 2H), 3.59 (s, 2H), 3.32-3.16 (m, 4H), 2.75 (s, 3H), 2.11-2.01 (m, 2H), 1.18-1.12 (m, 3H). MS (ESI + , m / z): 346.1 [M+H] +

[0173] Example 18: 1-Ethyl-6-hydroxy-3-oxo-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0174] The process of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, diethyl 2-propanoylbutanedioate (4.6 g, 19.99 mmol) was used instead of diethylacetylsuccinic acid in [Step-5] of Example 1, and pyrrolidine (137 mg, 1.88 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 120 mg (49%, yield) of the title compound.

[0175] 1H-NMR (300 MHz, CDCl3): δ 12.56 (s, 1H), 10.56 (s, 1H), 4.33-4.29 (m, 2H), 3.73-3.69 (m, 4H), 3.55-3.50 (m, 2H), 3.20-3.16 (m, 2H), 3.04-2.97 (m, 2H), 2.09-2.03 (m, 4H), 1.97-1.24 (m, 2H), 1.24-1.19 (m, 3H). MS (ESI + , m / z): 386.2 [M+H] +

[0176] Example 19: 2-(2-(3-fluoroazetidin-1-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0177] The process of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and 3-fluoroazetidine hydrochloride (367 mg, 3.29 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 81 mg (19%, yield) of the title compound.

[0178] 1 H-NMR (300 MHz, CDCl3): δ 12.55 (brs, 1H), 10.58 (s, 1H), 4.96-4.88 (m, 1H), 4.69-4.11 (m, 6H), 3.59-3.45 (m, 2H), 3.21-3.15 (m, 2H), 2.64 (s, 3H), 2.10-2.01 (m, 2H). MS (ESI + , m / z): 376.1 [M+H] +

[0179] Example 20: 6-Hydroxy-1-methyl-3-oxo-2-(2-oxo-2-(5-azaspiro[2.4]heptan-5-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0180] The process of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and 5-azaspiro[2.4]heptane (141 mg, 1.38 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 3 mg (1%, yield) of the title compound.

[0181] 1 H-NMR (300 MHz, CDCl3): δ12.54 (brs, 1H), 10.59 (s, 1H), 4.37-4.32 (m, 2H), 3.88-3.39 (m, 6H), 3.22-3.17 (m, 2H), 2.60 (s, 3H), 2.10-1.80 (m, 4H), 0.80-0.50 (m, 4H). MS (ESI + , m / z): 398.2 [M+H] +

[0182] Example 21: 6-hydroxy-1-methyl-3-oxo-2-(2-oxo-2-(piperidin-1-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0183] The process of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and piperidine (226 mg, 2.63 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 155 mg (39%, yield) of the title compound.

[0184] 1 H-NMR (300 MHz, CDCl3): δ 12.52 (brs, 1H), 10.58 (s, 1H), 4.36-4.31 (m, 2H), 3.76 (s, 2H), 3.61-3.57 (m, 4H), 3.21-3.15 (m, 2H), 2.54 (s, 3H), 2.08-2.00 (m, 2H), 1.70-1.58 (m, 6H). MS (ESI + , m / z): 386.2 [M+H] +

[0185] Example 22: 2-(5-formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromen-2-yl)acetamide [ka]

[0186] The procedure of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and ammonia water (0.5 mL) was used instead of morpholine in [Step-7] of Example 1, to obtain 4 mg (2%, yield) of the title compound.

[0187] 1 H-NMR (300 MHz, DMSO-d6): δ 10.20 (s, 1H), 4.07-4.02 (m, 2H), 3.44 (s, 2H), 2.90-2.86 (m, 2H), 2.33 (s, 3H), 1.85-1.76 (m, 2H). MS (ESI + , m / z): 318.1 [M+H] +

[0188] Example 23: 6-Hydroxy-1-isopropyl-3-oxo-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0189] The process of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, diethyl 2-(2-methylpropanoyl)butanedioate (2.76 g, 11.32 mmol) was used instead of diethylacetylsuccinic acid in [Step-5] of Example 1, and pyrrolidine (46 mg, 0.63 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 2 mg of the title compound (4%, yield).

[0190] 1 H-NMR (300 MHz, CDCl3): δ 12.48 (s, 1H), 10.53 (s, 1H), 4.39-4.36 (m, 2H), 3.70-3.60 (m, 5H), 3.57-3.38 (m, 2H), 3.12-3.08 (m, 2H), 2.08-1.85 (m, 6H), 1.44 (s, 3H), 1.41 (s, 3H). MS (ESI + , m / z): 400.2 [M+H] +

[0191] Example 24: 2-(5-formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydrapyrano[3,2-f]chromen-2-yl)-N-(2-methoxyethyl)acetamide [ka]

[0192] The process of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and 2-methoxyethylamine (504 mg, 6.57 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 55 mg (21%, yield) of the title compound.

[0193] 1 H-NMR (300 MHz, CDCl3): δ12.56 (brs, 1H), 10.60 (s, 1H), 6.52 (s, 1H), 4.37-4.32 (m, 2H), 3.62 (s, 2H), 3.50-3.40 (m, 4H), 3.38 (s, 3H), 3.21-3.16 (m, 2H), 2.72 (s, 3H), 2.10-2.01 (m, 2H). MS (ESI + , m / z): 376.1 [M+H] +

[0194] Example 25: N,N-Diethyl-2-(5-formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromen-2-yl)acetamide [ka]

[0195] The process of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and diethylamine (385 mg, 5.26 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 140 mg (19%, yield) of the title compound.

[0196] 1 H-NMR (300 MHz, CDCl3): δ12.53 (brs, 1H), 10.59 (s, 1H), 4.37-4.32 (m, 2H), 3.76 (s, 2H), 3.55-3.38 (m, 4H), 3.21-3.16 (m, 2H), 2.56 (s, 3H), 2.10-2.00 (m, 2H), 1.36-1.31 (m, 3H), 1.19-1.13 (m, 3H). MS (ESI + , m / z): 374.2 [M+H] +

[0197] Example 26: 2-(2-(4-acetylpiperazin-1-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0198] The process of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and 1-piperazin-1-ylethenone (258 mg, 1.97 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 100 mg (28%, yield) of the title compound.

[0199] 1 H-NMR (300 MHz, CDCl3): δ 12.52 (s, 1H), 10.55 (s, 1H), 4.34-4.30 (m, 2H), 3.75-3.49 (m, 10H), 3.18-3.14 (m, 2H), 2.60-2.55 (m, 3H), 2.14 (s, 3H), 2.07-1.99 (m, 2H). MS (ESI + , m / z): 429.2 [M+H] +

[0200] Example 27: 2-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0201] The process of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and 2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (273 mg, 1.97 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 15 mg (7%, yield) of the title compound.

[0202] 1 H-NMR (300 MHz, CDCl3): δ12.55 (brs, 1H), 10.58 (s, 1H), 4.97-4.92 (m, 1H), 4.76-4.68 (m, 1H), 4.37-4.33 (m, 2H), 3.99-3.40 (m, 6H), 3.22-3.17 (m, 2H), 2.68-2.60 (m, 3H), 2.10-1.95 (m, 4H). MS (ESI + , m / z): 400.1 [M+H] +

[0203] Example 28: 6-Hydroxy-1-methyl-3-oxo-2-(2-oxo-2-thiomorpholinoethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0204] The procedure of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and thiomorpholine (109 mg, 1.03 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 1.5 mg (1%, yield) of the title compound.

[0205] 1 H-NMR (300 MHz, CDCl3): δ12.55 (brs, 1H), 10.59 (s, 1H), 4.37-4.32 (m, 2H), 3.99-3.90 (m, 4H), 3.75 (s, 2H), 3.21-3.16 (m, 2H), 2.79-2.64 (m, 4H), 2.57 (s, 3H), 2.10-2.00 (m, 2H). MS (ESI + , m / z): 404.1 [M+H] +

[0206] Example 29: 2-(5-formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromen-2-yl)-N-(2-morpholinoethyl)acetamide [ka]

[0207] The process of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and 4-(2-aminoethyl)morpholine (343 mg, 2.58 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 15 mg of the title compound (7%, yield).

[0208] 1H-NMR (300 MHz, CDCl3): δ 12.55 (brs, 1H), 10.60 (s, 1H), 6.69 (s, 1H), 4.37-4.32 (m, 2H), 3.74-3.70 (m, 4H), 3.62 (s, 2H), 3.38-3.31 (m, 2H), 3.22-3.16 (m, 2H), 2.73 (s, 3H), 2.51-2.43 (m, 6H), 2.10-2.01 (m, 2H). MS (ESI + , m / z): 431.2 [M+H] +

[0209] Example 30: 6-Hydroxy-1-methyl-3-oxo-2-(2-oxo-2-(thiazolidin-3-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0210] The procedure of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and thiazolidine (125 mg, 1.38 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 11 mg (4%, yield) of the title compound.

[0211] 1 H-NMR (300 MHz, CDCl3): δ 12.55 (s, 1H), 10.57 (s, 1H), 4.34-4.31 (m, 2H), 3.60 (s, 2H), 3.46-3.40(m, 2H), 3.21-3.14 (m, 2H), 2.70 (s, 3H), 2.66-2.61 (m, 2H), 2.21 (s, 2H), 2.05-2.02 (m, 2H). MS (ESI + , m / z): 390.2 [M+H] +

[0212] Example 31: 6-hydroxy-1-methyl-3-oxo-2-(2-oxo-2-(piperazin-1-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde [ka]

[0213] The procedure of Example 1 was repeated, except that 3-chloropropan-1-ol (60 mL) was used instead of 2-chloroethanol in [Step-1] of Example 1, and piperazine (55 mg, 0.63 mmol) was used instead of morpholine in [Step-7] of Example 1, to obtain 2 mg of the title compound (7%, yield).

[0214] 1 H-NMR (300 MHz, CD3OD): δ 10.51 (s, 1H), 4.29-4.26 (m, 2H), 3.81 (s, 2H), 3.76-3.67 (m, 6H), 3.62-3.59 (m, 2H), 3.25-3.21 (m, 2H), 2.52 (s, 3H), 2.05-1.97 (m, 2H). MS (ESI + , m / z): 387.2 [M+H] +

[0215] According to an embodiment of the present invention, the compound of Formula 1 may be a compound selected from the group consisting of the compounds listed in Table 1 below.

[0216] Table 1 [Table 1-1]

[0217] [Table 1-2]

[0218] [Table 1-3]

[0219] [Table 1-4]

[0220] [Table 1-5]

[0221] [Table 1-6]

[0222] [Table 1-7]

[0223] [Table 1-8]

[0224] Experimental Example 1: Spliced ​​XBP1 mRNA measurement test To confirm the effect of the synthetic compounds on the mRNA and protein levels of spliced ​​XBP1, the target of IRE endonuclease, a reverse transcription polymerase chain reaction (RT-PCR) experiment was performed on MCF-7 cancer cells. RT-PCR is a test method in which RNA is extracted from cells, cDNA is created using reverse transcriptase, and then relative mRNA expression levels are measured through RT-PCR.

[0225] Briefly, MCF-7 cells were seeded into 12-well plates and cultured in a 5% CO2 incubator for one day. The following day, cells were pretreated for one hour with compounds serially diluted 10-fold starting from 10,000 nM. To induce endoplasmic reticulum stress, cells were treated with 2 μg / mL tunicamycin for six or 24 hours, after which cells were lysed for RNA isolation. RNA was isolated according to the protocol of the RNeasy Kits (Qiagen, 74106). 5 μg of RNA was dissolved in a sample containing reverse transcriptase and dNTPs, and the reverse transcription reaction was carried out in a thermal cycler. The amounts of spliced ​​and total XBP1 mRNA were determined by polymerase chain reaction (PCR) using real-time PCR in which each cDNA sample was mixed with a PCR reaction mixture containing a primer pair specifically binding to each target and SYBR green dye. The expression level of spliced ​​XBP1 was normalized to the expression level of total XBP1, and the relative expression levels of spliced ​​XBP1 between samples were compared. The relative amounts of spliced ​​XBP1 RNA in compound-treated cells were normalized to the tunicamycin-treated (100%) and untreated (0%) samples, and a dose-response curve and IC were plotted based on the percentage values ​​of each sample. 50 The values ​​were calculated. MKC8866 (MedChemExpress, Cat# HY-104040), an IRE1α RNase inhibitor, was used as a control. The results, which show the inhibitory ability of the compounds on spliced ​​XBP1 expression, are shown in Table 2 below.

[0226] I C 50 Values ​​were marked A if they were less than 100 nM, B if they were between 100 nM and 200 nM, and C if they were 200 nM or greater.

[0227] [Table 2]

[0228] The present invention has been described above with reference to specific embodiments. Those skilled in the art will recognize that the present invention can be embodied in various modified forms without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the claims, not the foregoing description, and all variations within the scope of the claims should be construed as being within the scope of the present invention.

Claims

1. A compound selected from the group consisting of compounds of the following formula 1, their optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof: [Chemical 1] In the above Chemical Formula 1, R １ is hydrogen, halogen, hydroxy, cyano, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, HaloC １－６ Alkyl, -(CH ２ ) ａ -C １－６ Alkoxy, -(CH ２ ) ａ -NR ６ R ７ , substituted or unsubstituted -(CH ２ ) ａ -C ３－６ Cyclyl, substituted or unsubstituted -(CH ２ ) ａ -C ６－１０ Aryl, or -(CH ２ ) ａ -C ２－６ is heterocyclyl; R ２ and R ３ are each independently hydrogen, halogen, or C １－６ Alkyl, haloC １－６ Alkyl, C １－６ alkoxy, oxo (=O), or hydroxy; a is an integer from 0 to 2; n and m are each independently an integer from 0 to 2; Z and Y each independently represent —CH ２ -, -O-, -S-, or -NR ８ - and; Dotted lines indicate the presence or absence of a bond; R ４ and R ５ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C １－６ Alkoxyalkyl, C ３－１０ Cycloalkyl, C ６－１０ Aryl, C ４－１０ Heteroaryl, C ２－９ Heterocycloalkyl, C ８－１６ Spirocycloalkyl, C ８－１６ Fused Cycloalkyl, C ８－１６ Bridged cycloalkyl, C ６－１４ Heterospirocycloalkyl, C ６－１４ fused heterocycloalkyl or C ６－１４ bridged heterocycloalkyl, which are halogen, nitro, oxo (=O), cyano, haloC １－６ Alkyl, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, HaloC １－６ Alkoxy, —S(O)—C １－４ Alkyl, —S(O) ２ -C １－４ Alkyl, —C(O)—NR ９ R １０ , -C(O)OR ９ , -OR ９ , and -NR ９ R １０ or unsubstituted with one or more substituents selected from: Alternatively, the R ４ and R ５ are linked together to form a C ２－９ Heterocyclyl, C ６－１４ Heterospirocyclyl, C ６－１４ Fused Heterocyclyl, C ６－１４ Bridged heterocyclyl or C ４－１０ Form heteroaryl, which are halogen, nitro, oxo (=O), cyano, haloC １－６ Alkyl, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, HaloC １－６ Alkoxy, —C(O)R １１ , -S(O)-C １－４ Alkyl, —S(O) ２ -C １－４ Alkyl, —C(O)—NR １１ R １２ , -C(O)OR １１ , -OR １１ , and -NR １１ R １２ or unsubstituted with one or more substituents selected from: R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , and R １２ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C １－６ Alkoxyalkyl, haloC １－６ Alkyl, C ６－１０ Aryl, C ３－１０ Cycloalkyl, C ４－１０ Heteroaryl, or C ２－９ heterocycloalkyl, or R １ Ga-(CH ２ ) ａ -NR ６ R ７ or R ４ and R ５ is C(O)-NR ９ R １０ or -NR ９ R １０ When ６ and R ７ , or R ９ and R １０ are linked together with the amide nitrogen and form a substituted or unsubstituted C ２－９ Heterocyclyl or substituted or unsubstituted C ４－１０ A heteroaryl can be formed.

2. R １ is C １－６ Alkyl, haloC １－６ Alkyl, -(CH ２ ) ａ -C １－６ Alkoxy, -(CH ２ ) ａ -NR ６ R ７ or substituted or unsubstituted -(CH ２ ) ａ -C ３－６ The compound of claim 1 which is cyclyl.

3. R ２ and R ３ are each independently hydrogen, halogen, or C １－６ The compound of claim 1 , wherein the aryl group is alkyl.

4. Z and Y each independently represent —CH ２ The compound of claim 1, wherein the aryl group is - or -O-.

5. R ４ and R ５ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, HaloC １－６ Alkyl, C １－６ Alkoxyalkyl, C ３－１０ cycloalkyl, or C ２－９ heterocycloalkyl or C ２－９ C substituted with heterocycloalkyl １－６ The compound of claim 1 , wherein the aryl group is alkyl.

6. R ４ and R ５ are linked together and form a group with the amide nitrogen of Formula 1. 【Chemistry 2】 C is any one selected from ２－９ Heterocyclyl, C ６－１４ Heterospirocyclyl, C ６－１４ Bridged heterocyclyl, or C ４－１０ forming a heteroaryl, At this time, C ２－９ Heterocyclyl, C ６－１４ Heterospirocyclyl, C ６－１４ Bridged heterocyclyl, or C ４－１０ Heteroaryl is hydrogen, halogen, nitro, cyano, haloC １－６ Alkyl, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, —C(O)R １１ , Halo C １－６ Alkoxy, and C ２－６ 10. The compound of claim 1 , substituted with one or more substituents selected from heterocyclyl.

7. R ４ and R ５ are linked together to form, together with the amide nitrogen of Formula 1, 【Chemistry 3】 The compound according to claim 1, which forms any one selected from the following:

8. The compound according to claim 1, wherein the compound is selected from the group consisting of compounds of the following formula 2, their optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof: 【Chemistry 4】 In the above Chemical Formula 2, V and W each independently represent —CH ２ -, -S-, -O- or -NR １４ - and; p, q, and r are each independently an integer of 0 or 1; R １３ is hydrogen, halogen, nitro, cyano, haloC １－６ Alkyl, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy or halo C １－６ is alkoxy; R １４ are each independently hydrogen, C １－６ Alkyl, haloC １－６ Alkyl, or —C(O)(C １－６ alkyl).

9. The compound of claim 1, wherein the compound is selected from the group consisting of the following compounds, their optical isomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof: 1) 4-hydroxy-9-methyl-8-(2-morpholino-2-oxoethyl)-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromene-5-carbaldehyde; 2) 4-hydroxy-9-methyl-8-(2-morpholino-2-oxoethyl)-7-oxo-7H-[1,3]dioxolo[4,5-f]chromene-5-carbaldehyde; 3) 6-hydroxy-1-methyl-2-(2-morpholino-2-oxoethyl)-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 4) 6-hydroxy-1-methyl-2-(2-(4-methylpiperidin-1-yl)-2-oxoethyl)-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 5) 6-hydroxy-1-methyl-3-oxo-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 6) 6-hydroxy-1-methyl-2-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 7) 6-hydroxy-2-(2-(4-isopropylpiperazin-1-yl)-2-oxoethyl)-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 8) N-ethyl-2-(5-formyl-4-hydroxy-9-methyl-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromen-8-yl)acetamide; 9) N,N-diethyl-2-(5-formyl-4-hydroxy-9-methyl-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromen-8-yl)acetamide; 10) 2-(2-(3,3-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 11) 6-hydroxy-1-methyl-2-(2-(3-methylpyrrolidin-1-yl)-2-oxoethyl)-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 12) 2-(2-(3,3-dimethylpyrrolidin-1-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 13) 2-(2-(azetidin-1-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 14) 6-hydroxy-2-(2-(3-methoxypyrrolidin-1-yl)-2-oxoethyl)-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 15) 6-hydroxy-2-(2-(3-methoxyazetidin-1-yl)-2-oxoethyl)-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 16) 2-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 17) N-ethyl-2-(5-formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromen-2-yl)acetamide; 18) 1-ethyl-6-hydroxy-3-oxo-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 19) 2-(2-(3-fluoroazetidin-1-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 20) 6-hydroxy-1-methyl-3-oxo-2-(2-oxo-2-(5-azaspiro[2.4]heptan-5-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 21) 6-hydroxy-1-methyl-3-oxo-2-(2-oxo-2-(piperidin-1-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 22) 2-(5-formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromen-2-yl)acetamide; 23) 6-hydroxy-1-isopropyl-3-oxo-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 24) 2-(5-formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydrapyrano[3,2-f]chromen-2-yl)-N-(2-methoxyethyl)acetamide; 25) N,N-diethyl-2-(5-formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromen-2-yl)acetamide; 26) 2-(2-(4-acetylpiperazin-1-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 27) 2-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 28) 6-hydroxy-1-methyl-3-oxo-2-(2-oxo-2-thiomorpholinoethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; 29) 2-(5-formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromen-2-yl)-N-(2-morpholinoethyl)acetamide; 30) 6-hydroxy-1-methyl-3-oxo-2-(2-oxo-2-(thiazolidin-3-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde; and 31) 6-hydroxy-1-methyl-3-oxo-2-(2-oxo-2-(piperazin-1-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde.

10. A pharmaceutical composition for treating or preventing an inositol-requiring enzyme 1α (IRE1α)-associated disease, comprising as an active ingredient a compound selected from the group consisting of the compound according to any one of claims 1 to 9, its optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof.

11. The pharmaceutical composition of claim 10 , wherein the composition exhibits IRE1α inhibitory activity.

12. The pharmaceutical composition of claim 10, wherein the composition exhibits IRE1α inhibitory activity and is for treating a treatable cancer or tumor.

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