Novel tricyclic heterocyclic aldehyde compound and pharmaceutical composition for inhibiting IRE1 alpha comprising same

Abstract

The present invention provides a novel tricyclic heterocyclic aldehyde compound and a pharmaceutical composition for inhibiting inositol-demanding enzyme 1 alpha (IRE1 alpha) comprising the same. More specifically, the present invention provides a novel tricyclic heterocyclic aldehyde compound for treating or preventing IRE1 [alpha]-related diseases and a pharmaceutical composition comprising the same.

Description

Technical Field

[0001] The present invention relates to a novel tricyclic heterocyclic aldehyde compound and a pharmaceutical composition comprising the same for inhibiting inositol requiring enzyme 1α (IRE1α), and more particularly to a novel tricyclic heterocyclic aldehyde compound for treating or preventing IRE1α-related diseases and a pharmaceutical composition comprising the same. Background Art

[0002] There is a delicate balance between cell survival and death, depending on how cells manage protein folding stress. Imbalances in protein homeostasis give rise to many metabolic diseases, tumors, neurodegenerative diseases, inflammation, cardiovascular diseases, and infectious diseases.

[0003] Cancer cells use the unfolded protein response (UPR) to alleviate endoplasmic reticulum stress (ER stress) caused by cellular oncogene activation and a hostile tumor microenvironment (TME) (Non-Patent Literature 1). The UPR is activated in many human cancers and is crucial for tumor initiation, tumor progression, and tumor therapy resistance. Endoplasmic reticulum stress caused by unfolded proteins in the cellular endoplasmic reticulum initiates the signaling cascade of the UPR. Inositol-requiring enzyme 1α (IRE1α) is an endoRNase present in the endoplasmic reticulum membrane. Under stress-free conditions, IRE1α binds to binding immunoglobulin protein (BIP) and remains inactive, but when endoplasmic reticulum stress occurs, it is phosphorylated and activated by disengaging from bound BIP. Activated IRE1α splices the mRNA of a transcription factor called X-box binding protein 1 (XBP1) to induce the activated XBP-1 form, and activated XBP1 binds to the ER stress response element and induces transcriptional activity. Thus, inositol-requiring enzyme 1α (IRE1α), a key enzyme of the UPR, alleviates protein folding stress and protects cells from stress-induced apoptosis.

[0004] The IRE1α gene is often amplified and overexpressed in invasive luminal B breast cancer cells, which is significantly associated with poor prognosis in breast cancer patients (non-patent document 2). In addition, triple-negative breast cancer (TNBC) is a highly invasive malignant tumor with poor prognosis and has limited treatment options due to the lack of effective targeted therapies to date. XBP1 is activated in TNBC and plays a key role in tumorigenesis and progression of breast cancer subtypes (non-patent document 3). It is known that oncogenic MYC regulates the IRE1α / XBP1 pathway of the UPR in breast cancer via multiple mechanisms. In the anti-cancer efficacy test of the MYC-amplified TNBC mouse model engineered for IRE1α or XBP1 gene knockout, the growth of tumors that overexpress MYC was selectively inhibited (non-patent document 4). At the same time, research (patent documents 1 and patent documents 2) is being conducted to develop substances that inhibit IRE1α to treat diseases associated with the unfolded protein response, but the research is limited.

[0005] The inventors of the present application have developed a novel tricyclic heterocyclic aldehyde compound capable of inhibiting IRE1α, thereby completing the present disclosure.

[0006] [Prior art literature]

[0007] [Patent Document]

[0008] (Patent Document 1) International Publication Patent WO2011 / 127070

[0009] (Patent Document 2) International Publication Patent WO2011 / 056744

[0010] [Non-patent literature]

[0011] (Non-patent document 1) Cancer Res. 2020, 80(11), 2368

[0012] (Non-patent document 2) "iScience." 2020, 23(9), 101503

[0013] (Non-patent document 3) Nature, 2014, 508(7494), 103

[0014] (Non-patent document 4) Cancer Research, 2020, 80(11), 2368. Summary of the invention

[0015] Technical issues

[0016] The object of the present invention is to provide a novel tricyclic heterocyclic aldehyde compound having excellent inhibitory activity against inositol requiring enzyme 1α (IRE1α).

[0017] Another object of the present invention is to provide a pharmaceutical composition comprising the compound as an active ingredient for treating or preventing IRE1α-related diseases.

[0018] According to the following detailed description combined with the attached claims, other objects and advantages of the present application will become more apparent. Matters not described in this specification are sufficiently obvious to be recognized and inferred by those skilled in the art of this application or its similar technology, so their description will be omitted.

[0019] Technical Solutions

[0020] One embodiment of the present disclosure provides a compound selected from the group consisting of a compound of Formula 1, optical isomers, diastereomers, solvates and hydrates thereof, and pharmaceutically acceptable salts thereof.

[0021] [Formula 1]

[0022]

[0023] Another embodiment of the present disclosure provides a pharmaceutical composition for treating or preventing IRE1α-related diseases, comprising a compound selected from Formula 1, its optical isomers, diastereomers, solvates and hydrates, and pharmaceutically acceptable salts thereof as an active ingredient.

[0024] Advantageous Effects of the Present Disclosure

[0025] According to one embodiment of the present disclosure, the tricyclic heterocyclic aldehyde compound having the structure of Formula 1 and the pharmaceutical composition comprising the same effectively inhibit IRE1α protein and can be used as a therapeutic agent thereof. DETAILED DESCRIPTION

[0026] Hereinafter, the present disclosure will be described in more detail.

[0027] Unless otherwise defined, all technical terms used in this disclosure are used with the same meanings as those commonly understood by those skilled in the art related to the present invention. In addition, although preferred methods or samples are described in this specification, methods or samples similar or equivalent thereto are also included in the scope of this disclosure.

[0028] One embodiment of the present disclosure provides a compound selected from the group consisting of a compound of Formula 1, optical isomers, diastereomers, solvates and hydrates thereof, and pharmaceutically acceptable salts thereof.

[0029] [Formula 1]

[0030]

[0031] Among them, in formula 1,

[0032] R1 can be hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halide C 1-6 Alkyl, -(CH2) a -C 1-6 Alkoxy, -(CH2) a -NR6R7, substituted or unsubstituted -(CH2) a -C 3-6 Cyclic group, substituted or unsubstituted -(CH2) a -C 6-10 Aryl or -(CH2) a -C 2-6 Heterocyclic group;

[0033] R2 and R3 can be independently hydrogen, halogen, C 1-6 Alkyl, halogen C 1-6 Alkyl, C 1-6 Alkoxy, pendant oxygen (=O) or hydroxyl;

[0034] a can be an integer from 0 to 2;

[0035] n and m can each independently be an integer from 0 to 3;

[0036] Z and Y can each independently be -CH2-, -O-, -S- or -NR8-;

[0037] Dashed lines indicate the presence or absence of bonds;

[0038] R4 and R5 can each independently be 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 Cross-linked cycloalkyl, C 6-14 Heterospirocycloalkyl, C 6-14 Fused heterocycloalkyl or C 6-14The cross-linked heterocycloalkyl radicals, each of which may be unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, nitro, pendant oxy (=O), cyano, halogen C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogen C 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 ;

[0039] Alternatively, R4 and R5 may be linked to each other and to the amide nitrogen of Formula 1 to form C 2-9 Heterocyclic group, C 6-14 Heterospirocyclic group, C 6-14 Condensed heterocyclic group, C 6-14 Cross-linked heterocyclic group or C 4-10 heteroaryl, each of which may be unsubstituted or substituted with one or more than one substituent selected from the group consisting of halogen, nitro, oxo (=O), cyano, halogen C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogen C 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 ;

[0040] R6, R7, R8, R9, R 10 , R 11 and R 12 can be independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, halogen C 1-6 Alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, C 4-10 Heteroaryl or C 2-9Heterocycloalkyl, or, when R1 is -(CH2) a -NR6R7 or when R4 and R5 are C(O)-NR9R 10 or -NR9R 10 When a pair of R6 and R7 or a pair of R9 and R 10 can be linked to each other and to the amide nitrogen to form a substituted or unsubstituted C 2-9 Heterocyclic or substituted or unsubstituted C 4-10 Heteroaryl.

[0041] The term "halogen" herein may be F, Cl, Br or I.

[0042] Unless otherwise specified, as used herein, the term "alkyl" refers to a straight or branched hydrocarbon moiety which may be substituted or unsubstituted. The alkyl group may be, for example, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl or tertiary butyl, but is not limited thereto.

[0043] Unless otherwise specified, as used herein, the term "alkenyl" refers to an alkyl group which may be substituted or unsubstituted and contains one or more than one double bond. The alkenyl group may be, for example, prop-1-ene, but-1-ene, but-2-ene, 3-methylbut-1-ene or pent-1-ene, but is not limited thereto.

[0044] Unless otherwise specified, as used herein, the term "alkynyl" refers to an alkyl group which may be substituted or unsubstituted and contains one or more than one triple bond. The alkynyl group may be, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl or a branched chain alkynyl group, but is not limited thereto.

[0045] Unless otherwise specified, as used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon ring generally having a specified number of carbon atoms, which may be substituted or unsubstituted. The cycloalkyl group may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but is not limited thereto.

[0046] Unless otherwise specified, as used herein, the term "heterocycloalkyl" refers to a substituted or unsubstituted monocyclic alkyl group containing one or more heteroatoms selected from B, N, O, S, P(=O), Si and P. The heterocycloalkyl group may be, for example, a piperidinyl group, a piperazinyl group, a morpholinyl group, a pyrrolidinyl group, a thiomorpholinyl group, an imidazolidinyl group, a tetrahydrofuranyl group or the like, but is not limited thereto.

[0047] Unless otherwise specified, as used herein, the term "spiro" refers to two rings sharing one atom, and refers to the situation where the two rings are not connected to each other by a crosslink (bridge). Unless otherwise specified, as used herein, the term "spiro linkage" refers to a linking group sharing one atom.

[0048] Unless otherwise specified, as used herein, the term "spirocycloalkyl" refers to a saturated carbocyclic compound comprising two rings, wherein the two rings share only one carbon atom as part of the ring. A spirocycloalkyl group may be, for example

[0049] But it is not limited to this.

[0050] Unless otherwise specified, as used herein, the term "heterospirocycloalkyl" refers to a spirocycloalkyl group containing one or more than one heteroatom selected from B, N, O, S, P(=O), Si and P. The heterospirocycloalkyl group may be, for example But it is not limited to this.

[0051] Unless otherwise specified, as used herein, the term "cross-linked cycloalkyl" refers to two rings that share two common non-adjacent ring atoms. Cross-linked cycloalkyls can be classified as bicyclic, tricyclic, tetracyclic or polycyclic cross-linked cycloalkyls according to the number of rings. Cross-linked cycloalkyls can be, for example But it is not limited to this.

[0052] As used herein, the term "crosslinked heterocycloalkyl" refers to a crosslinked cycloalkyl group comprising one or more than one heteroatom selected from B, N, O, S, P(=O), Si and P, unless otherwise specified.

[0053] Unless otherwise specified, as used herein, the term "fused cycloalkyl" refers to a group in which each ring shares a pair of carbon atoms adjacent to different rings, and one or more than one ring may share one or more than one double bond, but none of these rings has a completely conjugated π electron system. Fused cycloalkyls can be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyls according to the number of rings. Fused cycloalkyls can be, for example, But it is not limited to this.

[0054] As used herein, the term "fused heterocycloalkyl" refers to a fused cycloalkyl group comprising one or more than one heteroatom selected from B, N, O, S, P(=O), Si and P, unless otherwise specified.

[0055] Unless otherwise specified, as used herein, the term "haloalkyl" includes monohaloalkyl and polyhaloalkyl which may be substituted or unsubstituted. The terms "halogen" and "alkyl" are the same as defined above.

[0056] Unless otherwise specified, as used herein, the term "alkoxy" refers to a group in which a straight or branched hydrocarbon portion is attached to oxygen, and the group is substituted or unsubstituted. The alkoxy group may be, for example, methoxy, ethoxy, propoxy and butoxy, or isopropoxy, isobutoxy or tertiary butoxy, but is not limited thereto.

[0057] Unless otherwise specified, as used herein, the term "alkoxyalkyl" refers to a substituted or unsubstituted group in which a straight or branched alkyl group is substituted with an alkoxy group. The alkoxyalkyl group may be, for example, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, methoxyethyl, ethoxyethyl or methoxypropyl, but is not limited thereto.

[0058] Unless otherwise specified, as used herein, the term "aryl" refers to an aromatic group which may be substituted or unsubstituted, and may include, for example, C3-C 10 Aryl, C3-C8 aryl or C3-C6 aryl, wherein the double bonds alternate (resonance) between adjacent carbon atoms or suitable heteroatoms. For example, the aryl group may be phenyl, biphenyl, naphthyl, toluoyl or naphthyl, but is not limited thereto.

[0059] As used herein, unless otherwise specified, the term "heteroaryl" refers to a substituted or unsubstituted aromatic group containing one or more than one heteroatom selected from B, N, O, S, P(=O), Si and P, or a monocyclic or bicyclic or multicyclic ring.

[0060] Unless otherwise specified, 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. As used herein, the term "heterocycloalkyl" is an example of a "heterocyclyl". A heterocyclyl group may be, for example, substituted or unsubstituted or the like, but not limited thereto.

[0061] Unless otherwise specified, as used herein, the term "heterospirocyclyl" refers to a saturated or carbocyclic compound containing two rings, wherein the two rings share only one carbon atom as part of the ring. As used herein, the term "heterospirocycloalkyl" is an example of a "heterospirocyclyl". A heterospirocyclyl group can be, for example, or the like, but not limited thereto.

[0062] Unless otherwise specified, as used herein, the term "fused heterocyclyl" refers to a group containing one or more than one heteroatom selected from B, N, O, S, P(=O), Si and P, wherein each ring shares a pair of carbon atoms adjacent to different rings, and one or more than one ring may share one or more than one double bond, but none of these rings has a completely conjugated π electron system, and can be 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 example of the term "fused heterocyclyl".

[0063] Unless otherwise specified, as used herein, the term "crosslinked heterocyclic group" refers to two or more rings that contain one or more heteroatoms selected from B, N, O, S, P(=O), Si and P, may be saturated or unsaturated, and share two non-adjacent common ring atoms, and may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic crosslinked heterocyclic group depending on the number of rings. The crosslinked heterocyclic group may be, for example and similar groups thereof, but are not limited thereto. The term "cross-linked heterocycloalkyl group" may be an example of the term "cross-linked heterocyclic group".

[0064] As used herein, the term "stereoisomer" refers to a compound of the present disclosure or a salt thereof that has the same chemical formula or molecular formula and is optically or sterically different, and includes optical isomers or diastereomers.

[0065] As used herein, the term "optical isomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0066] As used herein, the term "diastereoisomer" refers to stereoisomers having two or more chiral centers, whose molecules are not mirror images of one another.

[0067] The compounds of the present disclosure may contain asymmetric or chiral centers and may therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present disclosure, such as diastereoisomers, optical isomers and racemic mixtures, are considered to form part of the present disclosure. A 50:50 mixture of optical isomers is called a racemic mixture or a racemate.

[0068] As used herein, the term "solvate" refers to a compound of the present disclosure or a salt thereof, comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. In this regard, preferred solvents may be volatile, non-toxic and / or suitable for administration to humans. A "solvate" may include a molecular complex comprising a compound and one or more than one pharmaceutically acceptable solvent molecule, such as ethanol.

[0069] As used herein, the term "hydrate" refers to a complex in which the solvent molecule is water.

[0070] As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt that can be prepared by any suitable method applicable to those skilled in the art. For example, when the compound of the present disclosure is a base, a pharmaceutically acceptable salt can be prepared by any suitable method applicable to those skilled in the art, such as by treating the free base with an inorganic acid or an organic acid or the like.

[0071] In one embodiment, R1 may be C1-6 Alkyl, halogen C 1-6 Alkyl, -(CH2) a -C 1-6 Alkoxy, -(CH2) a -NR6R7 or substituted or unsubstituted -(CH2) a -C 3-6 Cyclic group.

[0072] In one embodiment, R2 and R3 can each independently be hydrogen, halogen or C 1-6 alkyl.

[0073] In one embodiment, Z and Y may each independently be -CH2- or -O-.

[0074] In one embodiment, R4 and R5 can be independently: hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halide C 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 alkyl.

[0075] In one embodiment, R4 and R5 may each independently be hydrogen, methyl, ethyl, propyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, morpholinomethyl or (N-morpholino)ethyl.

[0076] In one embodiment, R4 and R5 can be connected to each other and together with the amide nitrogen of Formula 1 to form C 2-9 Heterocyclic group, C 6-14 Heterospirocyclic group, C 6-14 Cross-linked heterocyclic group or C 4-10 Heteroaryl, which is one of: Among them C 2-9 Heterocyclic group, C 6-14 Heterospirocyclic group, C 6-14 Cross-linked heterocyclic group or C 4-10 The heteroaryl group may be substituted with at least one substituent selected from the group consisting of hydrogen, halogen, nitro, cyano, halogen, 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C(O)R 11 , halogen C 1-6 Alkoxy and C 2-6 Heterocyclic group.

[0077] In one embodiment, R4 and R5 may be connected to each other and together with the amide nitrogen of Formula 1 to form one selected from the following:

[0078] In one embodiment,

[0079] R1 can be C 1-6 alkyl,

[0080] R2 and R3 can be independently hydrogen, halogen, C 1-6 Alkyl, halogen C 1-6 Alkyl, C 1-6 Alkoxy, pendant oxygen (=O) or hydroxyl;

[0081] n and m can each independently be an integer of 0 or 1;

[0082] Z and Y may each independently be -CH2- or -O-;

[0083] R4 and R5 can be connected to each other and together with the amide nitrogen of formula 1 to form C 2-9 Heterocyclic group, C 6-14 Heterospirocyclic group, C 6-14 Cross-linked heterocyclic group or C 4-10 Heteroaryl, which is one of:

[0084] Among them C 2-9 Heterocyclic group, C 6-14 Heterospirocyclic group, C 6-14 Cross-linked heterocyclic group or C 4-10 The heteroaryl group may be unsubstituted or substituted with one or more than one substituent selected from the group consisting of hydrogen, halogen, nitro, cyano, halo 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C(O)R 11 , halogen C 1-6 Alkoxy and C 2-6 Heterocyclic group.

[0085] In one embodiment,

[0086] R1 can be methyl, ethyl, propyl or isopropyl;

[0087] R2 and R3 may be hydrogen;

[0088] R4 and R5 can be connected to each other and together with the amide nitrogen of formula 1 to form C 2-9 Heterocyclic group, C 6-14Heterospirocyclic group, C 6-14 Cross-linked heterocyclic group or C 4-10 Heteroaryl, which is one of:

[0089] Among them C 2-9 Heterocyclic group, C 6-14 Heterospirocyclic group, C 6-14 Cross-linked heterocyclic group or C 4-10 The heteroaryl group may be unsubstituted or substituted with at least one substituent selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl and -C(O)(C 1-6 alkyl).

[0090] In some embodiments, C 2-9 Heterocyclic group, C 6-14 Heterospirocyclic group, C 6-14 Cross-linked heterocyclic group or C 4-10 The heteroaryl group may be unsubstituted or substituted with at least one substituent selected from the group consisting of hydrogen, halogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl and acetyl.

[0091] In one embodiment,

[0092] The compound may be a compound selected from the group consisting of a compound of Formula 2, an optical isomer, a diastereomer, a solvate and a hydrate thereof, and a pharmaceutically acceptable salt thereof.

[0093] [Formula 2]

[0094]

[0095] Among them, in formula 2,

[0096] V and W can each independently be -CH2-, -S-, -O- or -NR 14 -;

[0097] p, q and r may each independently be an integer of 0 or 1;

[0098] R 13 Can be hydrogen, halogen, nitro, cyano, halogen C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy or halogen C 1-6 Alkoxy; and

[0099] Each R 14 can be independently hydrogen, C 1-6 Alkyl, halogen C 1-6 Alkyl or -C(O)(C1-6 alkyl).

[0100] In one embodiment,

[0101] R 13 It may be hydrogen, halogen, methyl, ethyl, propyl, butyl or isopropyl.

[0102] In one embodiment,

[0103] R 14 It may be hydrogen, halogen, methyl, ethyl, propyl, butyl, isopropyl or acetyl.

[0104] In one embodiment, the compound can be selected from the group consisting of the following compounds, their optical isomers, diastereomers, solvates and hydrates, and pharmaceutically acceptable salts thereof:

[0105] 1) 4-Hydroxy-9-methyl-8-(2-(N-morpholinyl)-2-oxoethyl)-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromene-5-carbaldehyde;

[0106] 2) 4-Hydroxy-9-methyl-8-(2-(N-morpholinyl)-2-oxoethyl)-7-oxo-7H-[1,3]dioxol[4,5-f]chromene-5-carbaldehyde;

[0107] 3) 6-hydroxy-1-methyl-2-(2-(N-morpholinyl)-2-oxoethyl)-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde;

[0108] 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;

[0109] 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;

[0110] 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;

[0111] 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;

[0112] 8) N-ethyl-2-(5-formyl-4-hydroxy-9-methyl-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromen-8-yl)acetamide;

[0113] 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;

[0114] 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;

[0115] 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;

[0116] 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;

[0117] 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;

[0118] 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;

[0119] 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;

[0120] 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;

[0121] 17) N-ethyl-2-(5-formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromen-2-yl)acetamide;

[0122] 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;

[0123] 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;

[0124] 20) 6-hydroxy-1-methyl-3-oxo-2-(2-oxo-2-(5-azaspiro[2.4]hept-5-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde;

[0125] 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;

[0126] 22) 2-(5-Formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromen-2-yl)acetamide;

[0127] 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;

[0128] 24) 2-(5-Formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromen-2-yl)-N-(2-methoxyethyl)acetamide;

[0129] 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;

[0130] 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;

[0131] 27) 2-(2-(2-Oxa-5-azabicyclo[2.2.1]hept-5-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde;

[0132] 28) 6-hydroxy-1-methyl-3-oxo-2-(2-oxo-2-thio(N-morpholinyl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde;

[0133] 29) 2-(5-Formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromen-2-yl)-N-(2-(N-morpholinyl)ethyl)acetamide;

[0134] 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

[0135] 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.

[0136] Another embodiment of the present disclosure provides a pharmaceutical composition for treating or preventing diseases related to inositol-requiring enzyme 1α (IRE1α), comprising a compound selected from the group consisting of a compound of Formula 1, its optical isomers, diastereomers, solvates and hydrates, and pharmaceutically acceptable salts thereof as an active ingredient.

[0137] In one embodiment, the composition can exhibit IRE1α inhibitory activity.

[0138] In one embodiment, the composition exhibits IRE1α inhibitory activity and is used to treat a cancer or tumor that is treatable by IRE1α inhibitory activity.

[0139] The compound or composition according to one embodiment may exhibit IRE1α inhibitory activity and may be used to inhibit IRE1α activity, such as RNA or mRNA cleavage or RNA or mRNA splicing.

[0140] In one embodiment, the cancer can be selected from the group consisting of: breast cancer, liver cancer, ovarian cancer, pancreatic cancer, head and neck cancer, non-small cell lung cancer, glioblastoma and multiple myeloma, but is not limited thereto. In one embodiment, the pharmaceutical composition can include a therapeutically effective amount of a compound selected from the group consisting of a compound of Formula 1, its optical isomers, diastereoisomers, solvates and hydrates, and a pharmaceutically acceptable salt thereof.

[0141] As used herein, the term "therapeutically effective amount" refers to an amount of a compound of the present disclosure that treats or prevents a particular disease, condition or disorder, attenuates, ameliorates or eliminates one or more than one symptom of a particular disease, condition or disorder, or prevents or delays one or more than one symptom of a particular disease, condition or disorder.

[0142] A skilled physician in the art can readily determine the effective, required dosage of the pharmaceutical composition and prescribe it. For example, the pharmaceutical composition may contain 0.0001 mg to 10 g of the compound, but is not limited thereto.

[0143] In one embodiment, in addition to the active ingredient, the pharmaceutical composition may further include a pharmaceutically acceptable additive, such as a diluent, a disintegrant, a binder, a lubricant, a surfactant, a suspending agent or an emulsifier, but is not limited thereto.

[0144] The pharmaceutical composition of the present disclosure can be formulated according to existing methods and can be administered in various oral dosage forms, such as tablets, pills, powders, capsules, syrups, emulsions and microemulsions; or can be administered in parenteral dosage forms, such as intramuscular administration, intravenous administration or subcutaneous administration.

[0145] Another embodiment of the present disclosure provides a therapeutic method of administering a pharmaceutical composition to an individual suffering from an IRE1α-related disease, wherein the pharmaceutical composition comprises a compound selected from the group consisting of a compound of Formula 1, its optical isomers, diastereomers, solvates and hydrates, and pharmaceutically acceptable salts thereof as an active ingredient.

[0146] As used herein, the terms "treating" or "treatment" refer to inhibiting a disease in an individual experiencing or displaying the pathology or symptoms of a disease, condition or disorder, such as inhibiting the disease, condition or disorder, that is, preventing or reversing further development of the pathology and / or symptoms, or ameliorating the disease, such as reducing the severity of the disease.

[0147] The terms "preventing" or "prevention" refer to preventing a disease in an individual who may be predisposed to the disease, pathology or disorder but has not yet experienced or displayed the pathology or symptoms of the disease, such as preventing a disease, condition or disorder.

[0148] As used herein, the term "subject" or "individual" may be a vertebrate, such as a mammal, fish, bird, reptile, or amphibian. For example, the subject may be a human, a non-human primate, a horse, a pig, a rabbit, a dog, a sheep, a goat, a cow, a cat, a guinea pig, or a rodent.

[0149] As used herein, the terms "administering" and "administration" refer to any method of providing a disclosed composition to a subject.

[0150] The dosage, frequency of administration or method of administration of a compound or pharmaceutical composition according to one embodiment may vary depending on the individual to be treated, the severity of the disease or condition, the speed of administration and the judgment of the prescribing physician. For example, a dose for a person weighing 70 kg can be administered in an amount of 0.0001 mg to 10 g per day, for example, 1 mg to 1 g per day. The number of administrations may be one to several times, such as 1 to 4 times, or a dosing / withdrawal schedule, and the method of administration may use an oral or parenteral route. For example, a compound or pharmaceutical composition according to one embodiment may be administered in an amount ranging from 0.1 mg / kg to 100 mg / kg (body weight) via an oral or parenteral route.

[0151] The physician can gradually increase the dosage of the compound or pharmaceutical composition of the disclosure administered to a subject, starting from levels below that required to achieve the desired therapeutic effect to a level that achieves the desired effect.

[0152] Another embodiment of the present disclosure provides a kit comprising a compound selected from the group consisting of a compound of Formula 1, optical isomers, diastereomers, solvates and hydrates thereof, and pharmaceutically acceptable salts thereof as an active ingredient.

[0153] 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 chemotherapeutic drug for treating cancer.

[0154] In one embodiment, the compounds, compositions, and kits of the present disclosure may be administered alone or simultaneously, separately, or sequentially with at least one other therapeutic agent.

[0155] In the context of the present disclosure, unless the context clearly indicates otherwise, the singular form of a word may include the plural form and vice versa.

[0156] Numerical values ​​described herein are deemed to include the meaning of "about" even if not explicitly stated. As used herein, the term "about" means a stated value or within 5%, such as within 1% to 2%.

[0157] The numerical range expressed using the term "to" means that the numerical values ​​described before and after the term "to" are included as the lower limit and the upper limit, respectively.

[0158] The terms “having”, “may have”, “including” or “may comprise” indicate the presence of corresponding features (eg ingredients, such as values ​​or components) and do not exclude the presence of additional features.

[0159] The contents of all publications cited herein are hereby incorporated by reference in their entirety.

[0160] Hereinafter, a method for preparing the compound of Formula 1 will be described in detail.

[0161] After synthesizing the intermediates according to the synthesis methods shown in Reaction Scheme 1 and Reaction Scheme 2, the compound of Formula 1 according to one embodiment of the present disclosure can be more easily prepared by the method of Reaction Scheme 3.

[0162] [Reaction Scheme 1]

[0163]

[0164] [Step-1]

[0165] (Di(acetyloxy)iodo)benzene (1.1 equivalents) and potassium carbonate (1.2 equivalents) are added to the haloalcohol or haloamine. 3,4-dimethoxyphenol (1 equivalent, standard equivalent) is slowly added dropwise thereto. After the dropwise addition is completed, the mixture is stirred at room temperature, and when the reaction is complete, the reaction solvent is distilled off under reduced pressure, a saturated solution of sodium bicarbonate is added thereto, and ethyl acetate is used for extraction. The organic layer is dried over anhydrous sodium sulfate and 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 compound A as the target compound.

[0166] [STEP-2]

[0167] Compound A (1 equivalent, standard equivalent) prepared in [Step-1] and sodium iodide (10 equivalents) were added to acetone, and then the mixture was stirred under reflux overnight. After the reaction was completed, acetone was removed by distillation under reduced pressure, water was added thereto, and extraction was performed using dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure, and the filtered organic layer was concentrated under reduced pressure. The resulting residue was purified by MPLC (ethyl acetate: hexane) to obtain compound B.

[0168] [STEP-3]

[0169] The compound B (1 equivalent, standard equivalent) obtained in [Step-2] is dissolved in toluene, and azobisisobutyronitrile (1 equivalent) is added thereto. Tri-n-butyltin hydride (Bu3SnH) (5 equivalents) is dissolved in toluene, and then added dropwise thereto, and the reaction solution is stirred at 90°C overnight. After the reaction is completed, toluene is removed by distillation under reduced pressure, and water is added thereto to extract with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and 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 compound C.

[0170] [STEP-4]

[0171] Compound C (1 equivalent, standard equivalent) obtained in [Step-3], p-toluenesulfonic acid (0.5 equivalent) and 4A molecular sieves (5 v / v) were added to dichloromethane and stirred at room temperature. After the reaction was complete, the reaction solution was filtered through a filter filled with diatomaceous earth and washed with dichloromethane. The filtered organic layer was concentrated under reduced pressure, and the resulting residue was purified by MPLC (ethyl acetate: hexane) to obtain compound D.

[0172] [Reaction Scheme 2]

[0173]

[0174] [Step-1]

[0175] 3-Methoxy-1,3-benzodioxole-5-carboxaldehyde (1 equivalent, standard equivalent) was dissolved in dichloromethane and the temperature was lowered to 0°C. 3-Chloroperoxybenzoic acid (2 equivalents) was added to the reaction solution to which sodium bicarbonate (2 equivalents) had been added, followed by stirring at room temperature overnight. After confirming the completion of the reaction, methanol and a saturated deuterium solution were added thereto and stirred at room temperature, and the resulting solid was dissolved in water, and then methanol was distilled off under reduced pressure. The reaction solution was extracted with dichloromethane, and the organic layer was dried with anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by MPLC (ethyl acetate: hexane) to give compound E.

[0176] [Reaction Scheme 3]

[0177]

[0178] [Step-1]

[0179] Compound D or compound E (1 equivalent, standard equivalent) obtained in reaction scheme 1 and reaction scheme 2 and diethyl acetyl succinate (1.2 equivalents) were added to methanesulfonic acid. After the reaction solution was stirred at room temperature overnight to complete the reaction, water was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure, and the filtered organic layer was concentrated under reduced pressure. The resulting residue was purified by MPLC (ethyl acetate: hexane) to obtain compound F.

[0180] [STEP-2]

[0181] The compound F (1 equivalent, standard equivalent) obtained in [step-1] is dissolved in tetrahydrofuran / methanol / water, and sodium hydroxide (5 equivalents) is added thereto. The reaction solution is stirred at room temperature. When the reaction is complete, 6N hydrochloric acid is used for acidification until the pH of the resulting solution reaches a range of pH 3 to pH 4 to obtain a solid product. The obtained solid is filtered under reduced pressure, and the filtered solid is washed with water. The filtered solid is dried to obtain compound G.

[0182] [STEP-3]

[0183] The compound G (1 equivalent, standard equivalent) obtained in [Step-2], R4R5 amine (1.2 equivalents) and (benzotriazol-1-yloxy)tripyrrolidinephosphonium hexafluorophosphate (1.2 equivalents) were dissolved in DMF, and N,N-diisopropylethylamine (1.2 equivalents) was slowly added thereto. After the reaction solution was stirred at room temperature overnight to complete the reaction, water was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure, and the filtered organic layer was concentrated under reduced pressure. The resulting residue was purified by MPLC (ethyl acetate: hexane) to obtain compound H.

[0184] [STEP-4]

[0185] The compound H (1 equivalent, standard equivalent) obtained in [Step-3] was dissolved in dichloromethane, and a boron tribromide solution (BBr3, 7 equivalents) was slowly added dropwise thereto at room temperature. After the reaction was completed by stirring the reaction solution at room temperature, water was added thereto, and an extraction process was performed using a methanol / dichloromethane solution. The organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure, and the filtered organic layer was concentrated under reduced pressure. The resulting residue was purified by MPLC (dichloromethane: methanol) to obtain compound I.

[0186] [STEP-5]

[0187] The compound I (1 equivalent, standard equivalent) obtained in [Step-4] and hexamethylenetetramine (HMTA, 4 equivalents) were dissolved in trifluoroacetic acid and stirred at 90°C. After the reaction was completed, the reaction product was cooled to room temperature and then neutralized by adding sodium bicarbonate aqueous solution dropwise thereto. The resulting product was extracted with a methanol / dichloromethane solution, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by MPLC (dichloromethane: methanol) to obtain Formula 1.

[0188] In Reaction Schemes 1 to 3, R1, R2, R3, R4, R5, Y, Z, n and m are as defined in Formula 1, but are not limited thereto.

[0189] The compound of Formula 1 according to one embodiment of the present disclosure can be prepared according to the methods shown in Reaction Schemes 1 to 3, but is not limited thereto. Those skilled in the art of organic compounds can appropriately adjust the specific reaction pathway, reaction conditions, reaction amounts, and the like.

[0190] Hereinafter, the present disclosure will be described in more detail by the following examples and experimental examples. However, these examples and experimental examples are only used to help understand the present disclosure, and the scope of the present disclosure is not limited by these examples and experimental examples in any sense.

[0191] Example 1: 4-Hydroxy-9-methyl-8-(2-(N-morpholinyl)-2-oxoethyl)-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromene-5-carbaldehyde

[0192] [Step-1] Preparation of 4-(2-chloroethoxy)-3,4-dimethoxycyclohexa-2,5-dien-1-one

[0193]

[0194] (Bis(acetoxy)iodo)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, and then 3,4-dimethoxyphenol (11 g, 71.35 mmol) was dissolved in 100 ml of 2-chloroethanol and slowly added dropwise at room temperature. After the dropwise addition was completed, the mixture was stirred at room temperature for 3 hours. After the reaction was completed, 2-chloroethanol was removed by distillation under reduced pressure. 300 ml of a saturated sodium bicarbonate solution was added to the reaction solution and extracted three times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The organic layer filtered under reduced pressure was concentrated under reduced pressure, and the residue was purified by MPLC (ethyl acetate:hexane=1:4 (v / v) to 1:1 (v / v)) to obtain 15 g (90%, yield) of the target compound.

[0195] 1 H-NMR (300MHz, CDCl3): δ6.59 (d, J=10.2Hz, 1H), 6.29 (dd, J=10.2, 3.7Hz, 1H), 5.6 2(d,J=1.8Hz,1H),3.81(s,3H),3.78-3.74(m,2H),3.63-3.58(m,2H),3.34(s,3H).

[0196] [Step-2] Preparation of 4-(2-iodoethoxy)-3,4-dimethoxycyclohexa-2,5-dien-1-one

[0197]

[0198] 4-(2-Chloroethoxy)-3,4-dimethoxycyclohexa-2,5-diene-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 (4.35 g, 108.63 mmol) of acetone and stirred under reflux for 48 hours. After the reaction was completed, acetone was removed by distillation under reduced pressure, and 200 ml of water was added thereto, followed by extraction three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and 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 obtain 17 g (81%, yield) of the target compound.

[0199] 1 H-NMR (300MHz, CDCl3): δ6.62 (d, J=10.2Hz, 1H), 6.32 (dd, J=10.2, 1.8Hz, 1H), 5.6 4(d,J=1.8Hz,1H),3.81(s,3H),3.79-3.75(m,2H),3.37(s,3H),3.31-3.23(m,2H).

[0200] [Step-3] Preparation of 7,7a-dimethoxy-2,3,3a,7a-tetrahydrobenzofuran-5(4H)-one

[0201]

[0202] 4-(2-iodoethoxy)-3,4-dimethoxycyclohexa-2,5-diene-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 thereto. Tri-n-butyl hydride (Bu3SnH, 76.33 g, 262.26 mmol) was dissolved in 50 ml of toluene and added dropwise for 30 minutes, and then the reactant was stirred at 90°C overnight. After the reaction was completed, toluene was removed by distillation under reduced pressure, and water was removed therefrom, and in this state, extraction was performed three times with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and filtered under reduced pressure, and the filtered organic layer was concentrated under reduced pressure. The obtained residue was purified by MPLC (ethyl acetate: hexane = 1: 3 (v / v)) to obtain 4.7 g (45%, yield) of the target compound.

[0203] 1H-NMR (300MHz, 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)

[0204] [Step-4] Preparation of 7-methoxy-2,3-dihydrobenzofuran-5-ol

[0205]

[0206] 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 the mixture was stirred at room temperature for 3 hours. After the reaction was completed, 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 obtained 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 target compound.

[0207] 1 H-NMR (300MHz, CDCl3): δ6.35-6.32 (m, 2H), 4.69 (brs, 1H), 4.58 (t, J = 8.7Hz, 2H), 3.82 (s, 3H), 3.17 (t, J = 8.7Hz, 2H).

[0208] [Step-5] Preparation of 2-(4-methoxy-9-methyl-7-oxo-1,7-dihydro-2H-furo[3,2 -f ]color Ethyl 2-(4-(4-ene-8-yl)acetate

[0209]

[0210] 7-Methoxy-2,3-dihydrobenzofuran-5-ol (520 mg, 3.13 mmol) and diethyl acetosuccinate (855 mg, 3.76 mmol) prepared in [Step-4] were added to 5 ml of methanesulfonic acid. The reaction solution was stirred at room temperature overnight. After the reaction was completed, 100 ml of water was added and extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and 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: 3 (v / v)) to obtain 780 mg of the target compound (78%, yield).

[0211] 1H-NMR (300MHz, DMSO-d6): δ6.97(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).

[0212] [Step-6] Preparation of 2-(4-methoxy-9-methyl-7-oxo-1,7-dihydro-2H-furo[3,2 -f ]color 8-enyl)acetic acid

[0213]

[0214] The ethyl 2-(4-methoxy-9-methyl-7-oxo-1,7-dihydro-2H-furano[3,2-f]chromen-8-yl)acetate (780 mg, 2.45 mmol) obtained in [Step-5] was dissolved in a mixture containing tetrahydrofuran / methanol / water=20 ml / 5 ml / 5 ml, and sodium hydroxide (490 mg, 12.25 mmol) was added thereto. After stirring the reaction solution at room temperature for 3 hours, when the reaction was completed, 6N hydrochloric acid was used for acidification until the pH of the resulting solution reached a range of pH 3 to pH 4 to obtain a solid product. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with distilled water. The filtered solid was dried in an oven dryer at 55°C to obtain 510 mg (72%, yield) of the target compound.

[0215] 1 H-NMR (300MHz, DMSO-d6): δ6.96(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).

[0216] [Step-7] Preparation of 4-methoxy-9-methyl-8-(2-(N-morpholinyl)-2-oxoethyl)-1,2-dihydro- 7H-Furo[3,2-f]chromen-7-one

[0217]

[0218] 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)tripyrrolidiniumphosphonium hexafluorophosphate (PyBOP, 1.1 g, 2.11 mmol) obtained in [Step-6] were dissolved in 30 mL of DMF, and N,N-diisopropylethylamine (273 mg, 2.11 mmol) was slowly added thereto. After the reaction solution was stirred at room temperature overnight to complete the reaction, 100 mL of water was added thereto, followed by extraction three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure, and the filtered organic layer was concentrated under reduced pressure. The obtained residue was purified by MPLC (ethyl acetate:hexane=1:1 (v / v)) to obtain 470 mg (74%, yield) of the target compound.

[0219] 1 H-NMR (300MHz, DMSO-d6): δ6.95(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).

[0220] [Step-8] Preparation of 4-hydroxy-9-methyl-8-(2-(N-morpholinyl)-2-oxoethyl)-1,2-dihydro-7H- Furo[3,2-f]chromen-7-one

[0221]

[0222] 4-Methoxy-9-methyl-8-(2-(N-morpholinyl)-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 a 1.0 M solution of boron tribromide in tetrahydrofuran (BBr3, 5.84 ml) was slowly added dropwise thereto at room temperature. After the reaction was completed by stirring at room temperature for 4 hours, the mixture was cooled at 0°C, and 10 ml of water was added thereto, followed by extraction three times with a 20% methanol / dichloromethane solution. The organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure, and the filtered organic layer was concentrated under reduced pressure. The obtained residue was purified by MPLC (dichloromethane:methanol=10:1 (v / v)) to obtain 200 mg (69%, yield) of the target compound.

[0223] 1 H-NMR (300MHz, CDCl3): δ6.48(s,1H),4.29-4.25(m,2H),3.76-3.65(m,10H),3.18-3.14(m,2H),2.57(s,3H)

[0224] [Step-9] Preparation of 4-hydroxy-9-methyl-8-(2-(N-morpholinyl)-2-oxoethyl)-7-oxo-1,7- Dihydro-2H-furo[3,2 -f ]chromene-5-carboxaldehyde

[0225]

[0226] 4-Hydroxy-9-methyl-8-(2-(N-morpholinyl)-2-oxoethyl)-1,2-dihydro-7H-furo[3,2-f]chromen-7-one (200 mg, 0.57 mmol) obtained in [Step-8] and hexamethylenetetramine (HMTA, 328 mg, 2.31 mmol) were dissolved in 10 ml of trifluoroacetic acid, and the mixture was stirred at 90° C. for 2 hours. After the reaction was completed, the reaction product was cooled to room temperature, and then neutralized by dropwise adding an aqueous sodium bicarbonate solution thereto. The obtained product was extracted three times with a 20% methanol / dichloromethane solution, dried with anhydrous sodium sulfate, and then filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure, and the obtained residue was purified by MPLC (dichloromethane: methanol = 20: 1 (v / v)) to obtain 10 mg (5%, yield) of the target compound.

[0227] 1 H-NMR (300MHz, CD3OD): δ10.42(s,1H),4.67-4.61(m,2H),3.76-3.66(m,10H),3.61-3.58(m,2H),2.41(s,3H).

[0228] MS (ESI + ,m / z):374.2[M+H] +

[0229] Example 2: 4-Hydroxy-9-methyl-8-(2-(N-morpholinyl)-2-oxoethyl)-7-oxo-7H-[1,3]dioxol[4,5-f]chromene-5-carbaldehyde

[0230] [Step 1] Preparation of 7-methoxybenzo[d][1,3]dioxolane-5-ol

[0231]

[0232] 7-Methoxy-1,3-benzodioxole-5-carbaldehyde (5 g, 27.75 mmol, eNovation) was dissolved in 143 ml of dichloromethane, and its temperature was lowered to 0°C, and sodium bicarbonate (4.66 g, 55.48 mmol) was added thereto. 3-Chloroperoxybenzoic acid (mCPBA, 9.58 g, 55.51 mmol) was added to the reaction mixture, and then the mixture was stirred at room temperature overnight. After confirming the completion of the reaction, 143 ml of methanol was added, and 72 ml of a saturated deuterium solution was added, followed by additional stirring for 1 hour. The obtained solid was dissolved in water, the methanol was concentrated under reduced pressure, and the reaction solution was extracted 3 times with dichloromethane, and the organic layer was dried using anhydrous sodium sulfate and filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure, and the obtained residue was purified by MPLC (ethyl acetate: hexane = 1: 4 (v / v)) to obtain 3.5 g (75%, yield) of the target compound.

[0233] 1 H-NMR (300MHz, CDCl3): δ6.13-6.07(m,2H),3.86(s,2H),2.32(s,3H).

[0234] [Step 2] Preparation of ethyl 2-(4-methoxy-9-methyl-7-oxo-7H-[1,3]dioxolane[4,5- f]chromen-8-yl)acetic acid ethyl ester

[0235]

[0236] 310 mg (16%, yield) of the target compound was obtained in the same manner as in Step 5 of Example 1), except that 7-methoxybenzo[d][1,3]dioxole-5-ol (1 g, 5.95 mmol) prepared in Step 1 of this Example was used instead of 7-methoxy-2,3-dihydrobenzofuran-5-ol in Step 5 of Example 1.

[0237] 1 H-NMR (300MHz, CDCl3): δ6.53(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).

[0238] [Step 3] Preparation of 2-(4-methoxy-9-methyl-7-oxo-7H-[1,3]dioxolane[4,5 -f ]color 8-enyl)acetic acid

[0239]

[0240] 160 mg (57% yield) of the target compound was obtained in the same manner as in step 6) of Example 1, except that ethyl 2-(4-methoxy-9-methyl-7-oxo-7H-[1,3]dioxol[4,5-f]chromen-8-yl)acetic acid (310 mg, 5.95 mmol) prepared in step 2 of this example was used instead of ethyl 2-(4-methoxy-9-methyl-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromen-8-yl)acetic acid in step 6) of Example 1.

[0241] 1 H-NMR (300MHz, CD3OD): δ6.66(s,1H), 6.11(s,2H), 3.96(s,3H), 3.67(s,2H), 2.52(s,3H).

[0242] [Step 4] Preparation of 4-methoxy-9-methyl-8-(2-(N-morpholinyl)-2-oxoethyl)-7H-[1,3]dioxadiazole Heterocyclopenta[4,5-f]chromen-7-one

[0243]

[0244] 425 mg (71%, yield) of the target compound was obtained in the same manner as in step 7) of Example 1, except that 2-(4-methoxy-9-methyl-7-oxo-7H-[1,3]dioxol[4,5-f]chromen-8-yl)acetic acid (485 mg, 1.66 mmol) obtained in [step-3] of this example was used instead of ethyl 2-(4-methoxy-9-methyl-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromen-8-yl)acetic acid in step 7) of Example 1.

[0245] 1 H-NMR (300MHz, CDCl3): δ6.53(s,1H),6.09(s,2H),3.96(s,3H),3.76-3.65(m,10H),2.56(s,3H).

[0246] [Step 5] Preparation of 4-hydroxy-9-methyl-8-(2-(N-morpholinyl)-2-oxoethyl)-7H-[1,3]dioxazoline Cyclopenta[4,5-f]chromen-7-one

[0247]

[0248] 75 mg (26% yield) of the target compound was obtained in the same manner as in Step 8) of Example 1, except that 4-methoxy-9-methyl-8-(2-(N-morpholinyl)-2-oxoethyl)-7H-[1,3]dioxol[4,5-f]chromen-7-one (300 mg, 0.83 mmol) prepared in Step 4 of this Example was used instead of 4-hydroxy-9-methyl-8-(2-(N-morpholinyl)-2-oxoethyl)-1,2-dihydro-7H-furo[3,2-f]chromen-7-one in Step 8) of Example 1.

[0249] 1 H-NMR (300MHz, CD3OD): δ6.38(s,1H),6.06(s,2H),3.73-3.65(m,8H),3.60-3.57(m,2H),2.47(s,3H).

[0250] [Step 6] Preparation of 4-hydroxy-9-methyl-8-(2-(N-morpholinyl)-2-oxoethyl)-7H-[1,3]dioxazoline Cyclopenta[4,5-f]chromene-5-carbaldehyde

[0251]

[0252] 4 mg (5%, yield) of the target compound was obtained in the same manner as in step 9) of Example 1, except that 4-hydroxy-9-methyl-8-(2-(N-morpholinyl)-2-oxoethyl)-7H-[1,3]dioxol[4,5-f]chromen-7-one (75 mg, 0.21 mmol) prepared in step 5 of this example was used instead of 4-hydroxy-9-methyl-8-(2-(N-morpholinyl)-2-oxoethyl)-1,2-dihydro-7H-furo[3,2-f]chromen-7-one in step 9) of Example 1.

[0253] 1 H-NMR (300MHz, CD3OD): δ10.35(s,1H),6.16(s,2H),3.74-3.58(m,10H),2.46(s,3H).

[0254] MS (ESI + ,m / z):376.2[M+H] +

[0255] Example 3: 6-Hydroxy-1-methyl-2-(2-(N-morpholinyl)-2-oxoethyl)-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde

[0256]

[0257] 16 mg (6%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropan-1-ol (60 ml) was used instead of 2-chloroethanol in [Step-1] of Example 1.

[0258] 1 H-NMR (300MHz, CDCl3): δ12.55(s,1H),10.59(s,1H),4.35(t,J=5.0Hz,2H) ,3.79-3.66(m,10H),3.19(t,J=6.3Hz,2H),2.59(s,3H),2.09-2.01(m,2H).

[0259] MS (ESI + ,m / z):388.2[M+H] +

[0260] 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

[0261]

[0262] 4 mg (2%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0263] 1 H-NMR (300MHz, 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)

[0264] MS (ESI + ,m / z):400.2[M+H] +

[0265] 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

[0266]

[0267] 76 mg (47% yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0268] 1 H-NMR (300MHz, CDCl3): δ12.53 (s, 1H), 10.59 (s, 1H), 4.34 (t, J = 5.0Hz, 2H), 3.71-3. 66(m,4H),3.53-3.48(m,2H),3.19(t,J=6.3Hz,2H),2.59(s,3H),2.07-1.89(m,6H).

[0269] MS (ESI + ,m / z):372.2[M+H] +

[0270] 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

[0271]

[0272] 20 mg of the target compound (21%, yield) was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0273] 1 H-NMR (300MHz, CDCl3): δ12.55(s,1H),10.59(s,1H),4.34(t,J=5.1Hz,2H),3.82-3.71(m, 8H), 3.18 (t, J = 6.3Hz, 2H), 2.64 (s, 3H), 2.57-2.42 (m, 2H), 2.44 (s, 3H), 2.08-1.98 (m, 2H).

[0274] MS (ESI + ,m / z):401.2[M+H] +

[0275] 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

[0276]

[0277] 2 mg (1%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0278] 1 H-NMR (300MHz, 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).

[0279] MS (ESI + ,m / z):429.2[M+H] +

[0280] 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

[0281]

[0282] 5 mg (10%, yield) of the target compound was obtained in the same manner as in Example 1, except that 2.0 M methylamine tetrahydrofuran solution (39 mg, 0.86 mmol) was used instead of morpholine in [Step-7] of Example 1.

[0283] 1 H-NMR (300MHz, 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).

[0284] MS (ESI + ,m / z):332.1[M+H]+

[0285] 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

[0286]

[0287] 18 mg (25%, yield) of the target compound was obtained in the same manner as in Example 1, except that diethylamine (126 mg, 1.72 mmol) was used instead of morpholine in [Step-7] of Example 1.

[0288] 1 H-NMR (300MHz, CDCl3): δ12.04(brs,1H),10.59(s,1H),4.78-4.71(m,2H),3.7 5(s,2H),3.74-3.67(m,2H),3.59-3.38(m,4H),2.51(s,3H),1.37-1.13(m,6H).

[0289] MS (ESI + ,m / z):360.1[M+H] +

[0290] 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

[0291]

[0292] 5 mg (19%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0293] 1 H-NMR (300MHz, 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).

[0294] MS (ESI + ,m / z):408.1[M+H]+

[0295] 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

[0296]

[0297] 12 mg (19%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0298] 1 H-NMR (300MHz, CD3OD): δ10.46(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).

[0299] MS (ESI + ,m / z):386.2[M+H] +

[0300] 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

[0301]

[0302] 13 mg (8%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0303] 1H-NMR (300MHz, 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).

[0304] MS (ESI + ,m / z):400.2[M+H] +

[0305] 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

[0306]

[0307] 2 mg (3%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0308] 1 H-NMR (300MHz, CD3OD): δ10.47(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).

[0309] MS (ESI + ,m / z):358.1[M+H] +

[0310] 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

[0311]

[0312] 3 mg of the target compound (3%, yield) was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0313] 1 H-NMR (300MHz, CD3OD): δ10.49(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).

[0314] MS (ESI + ,m / z):402.2[M+H] +

[0315] 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

[0316]

[0317] 3 mg (10%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0318] 1 H-NMR (300MHz, CD3OD): δ10.49(s,1H),4.57-4.52(m,1H),4.29-4.15(m,5H),3.85-3.8 0(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).

[0319] MS (ESI + ,m / z):388.1[M+H] +

[0320] 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

[0321]

[0322] 4 mg (2%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0323] 1 H-NMR (300MHz, CD3OD): δ10.48(s,1H),5.47-5.21(m,2H),4.28-4.22(m,2H),4.01-3.89(m,2 H),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).

[0324] MS (ESI + ,m / z):390.1[M+H] +

[0325] 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

[0326]

[0327] 19 mg (7%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0328] 1 H-NMR (300MHz, 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).

[0329] MS (ESI + ,m / z):346.1[M+H] +

[0330] 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

[0331]

[0332] 120 mg (49%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropan-1-ol (60 ml) was used instead of 2-chloroethanol in [Step-1] of Example 1, diethyl 2-propionylsuccinate (4.6 g, 19.99 mmol) was used instead of diethyl acetylsuccinate in [Step-5] of Example 1, and pyrrolidine (137 mg, 1.88 mmol) was used instead of morpholine in [Step-7] of Example 1.

[0333] 1 H-NMR (300MHz, CDCl3): δ12.56(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).

[0334] MS (ESI + ,m / z):386.2[M+H] +

[0335] 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

[0336]

[0337] 81 mg (19% yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0338] 1H-NMR (300MHz, CDCl3): δ12.55(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).

[0339] MS (ESI + ,m / z):376.1[M+H] +

[0340] Example 20: 6-Hydroxy-1-methyl-3-oxo-2-(2-oxo-2-(5-azaspiro[2.4]hept-5-yl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde

[0341]

[0342] 3 mg (1%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0343] 1 H-NMR (300MHz, 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).

[0344] MS (ESI + ,m / z):398.2[M+H] +

[0345] 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

[0346]

[0347] 155 mg (39%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0348] 1 H-NMR (300MHz, CDCl3): δ12.52(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).

[0349] MS (ESI + ,m / z):386.2[M+H] +

[0350] Example 22: 2-(5-Formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromen-2-yl)acetamide

[0351] 4 mg (2%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-1-ol (60 ml) was used instead of 2-chloroethanol in [Step-1] of Example 1, and aqueous ammonia (0.5 ml) was used instead of morpholine in [Step-7] of Example 1.

[0352] 1 H-NMR (300MHz, DMSO-d6): δ10.20(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).

[0353] MS (ESI + ,m / z):318.1[M+H] +

[0354] 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.

[0355]

[0356] 2 mg (4%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-1-ol (60 ml) was used instead of 2-chloroethanol in [Step-1] of Example 1, diethyl 2-(2-methylpropionyl)succinate (2.76 g, 11.32 mmol) was used instead of diethyl acetylsuccinate in [Step-5] of Example 1, and pyrrolidine (46 mg, 0.63 mmol) was used instead of morpholine in [Step-7] of Example 1.

[0357] 1 H-NMR (300MHz, CDCl3): δ12.48(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).

[0358] MS (ESI + ,m / z):400.2[M+H] +

[0359] Example 24: 2-(5-Formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromen-2-yl)-N-(2-methoxyethyl)acetamide

[0360]

[0361] 55 mg (21%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0362] 1 H-NMR (300MHz, CDCl3): δ12.56(brs,1H),10.60(s,1H),6.52(s,1H),4.37-4.32(m,2H),3.6 2(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).

[0363] MS (ESI + ,m / z):376.1[M+H] +

[0364] 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

[0365]

[0366] 140 mg (19% yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0367] 1 H-NMR (300MHz, CDCl3): δ12.53(brs,1H),10.59(s,1H),4.37-4.32(m,2H),3.76(s,2H),3.55-3.3 8(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).

[0368] MS (ESI + ,m / z):374.2[M+H] +

[0369] 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

[0370]

[0371] 100 mg (28%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-1-ol (60 ml) was used instead of 2-chloroethanol in [Step-1] of Example 1, and 1-piperazin-1-yl ketone (258 mg, 1.97 mmol) was used instead of morpholine in [Step-7] of Example 1.

[0372] 1 H-NMR (300MHz, CDCl3): δ12.52(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).

[0373] MS (ESI + ,m / z):429.2[M+H] +

[0374] Example 27: 2-(2-(2-Oxa-5-azabicyclo[2.2.1]hept-5-yl)-2-oxoethyl)-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde

[0375]

[0376] 15 mg (7%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0377] 1 H-NMR (300MHz, 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).

[0378] MS (ESI + ,m / z):400.1[M+H] +

[0379] Example 28: 6-Hydroxy-1-methyl-3-oxo-2-(2-oxo-2-thio(N-morpholinyl)ethyl)-3,8,9,10-tetrahydropyrano[3,2-f]chromene-5-carbaldehyde

[0380]

[0381] 1.5 mg (1%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0382] 1H-NMR (300MHz, 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).

[0383] MS (ESI + ,m / z):404.1[M+H] +

[0384] Example 29: 2-(5-Formyl-6-hydroxy-1-methyl-3-oxo-3,8,9,10-tetrahydropyrano[3,2-f]chromen-2-yl)-N-(2-(N-morpholinyl)ethyl)acetamide

[0385]

[0386] 15 mg (7% yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0387] 1 H-NMR (300MHz, CDCl3): δ12.55(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).

[0388] MS (ESI + ,m / z):431.2[M+H] +

[0389] 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

[0390]

[0391] 11 mg (4%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0392] 1 H-NMR (300MHz, CDCl3): δ12.55(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).

[0393] MS (ESI + ,m / z):390.2[M+H] +

[0394] 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

[0395]

[0396] 2 mg (7%, yield) of the target compound was obtained in the same manner as in Example 1, except that 3-chloropropane-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.

[0397] 1 H-NMR (300MHz, CD3OD): δ10.51(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).

[0398] MS (ESI + ,m / z):387.2[M+H] +

[0399] According to one embodiment of the present disclosure, the compound of Formula 1 may be a compound selected from the group consisting of the compounds listed in Table 1 below.

[0400] [Table 1]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406] Experimental Example 1: Splicing XBP1 mRNA Measurement Test

[0407] For these synthetic compounds, reverse transcription polymerase chain reaction (RT-PCR) experiments were performed on MCF-7 cancer cells to confirm their effects on the mRNA and protein levels of spliced ​​XBP1, which is the target of IRE endonuclease. RT-PCR is a test method in which RNA is extracted from cells, cDNA is prepared using reverse transcriptase, and relative mRNA expression is measured via polymerase chain reaction.

[0408] Briefly, MCF-7 cells were seeded in 12-well plates and cultured in an incubator containing 5% CO2 for one day. The next day, compounds were pretreated for 1 hour with 10-fold serial dilutions from 10,000 nM, and then treated with 2 μg / ml tunicamycin for 6 hours or 24 hours to induce endoplasmic reticulum stress, followed by cell lysis to obtain RNA. RNA was subjected to the procedure of the RNeasy kit (Qiagen, 74106), and 5 μg of RNA sample was dissolved in a sample containing reverse transcriptase and dNTPs, and reverse transcription reaction was performed using a thermal cycler. The amount of mRNA of each of spliced ​​XBP1 and total XBP1 was measured by polymerase chain reaction, by real-time PCR, by mixing each cDNA sample with a PCR reaction mixture containing primer pairs capable of binding specificity to each target and SYBR green dye. The expression of spliced ​​XBP1 was corrected by the total expression of XBP1, and the relative expression of spliced ​​XBP1 between samples was compared and analyzed. The relative amount of spliced ​​XBP1 RNA inside compound-treated cells was normalized to that of tunicamycin-treated samples (100%) and untreated samples (0%), and the percentage value of each sample was used to calculate the dose-response curve and IC according to the drug concentration. 50The IRE1α RNase inhibitor MKC8866 (MedChemExpress, catalog number HY-104040) was used as a control material. Accordingly, the inhibitory ability of the compounds on splicing XBP1 expression is shown in Table 2 below.

[0409] A indicates that IC 50 When the value is less than 100, B indicates that IC 50 The value is 100 nM or greater than 100 nM and less than 200 nM, and C indicates the IC 50 The value is 200 nM or greater.

[0410] [Table 2]

[0411] Synthetic compounds <![CDATA[XBP1 mRNA(IC 50 ,nM)]]> Synthetic compounds <![CDATA[XBP1 mRNA(IC 50 ,nM)]]> MKC8866 A Example 16 C Example 1 A Example 17 A Example 2 B Example 18 C Example 3 A Example 19 B Example 4 C Example 20 B Example 5 A Example 21 C Example 6 A Example 22 C Example 7 B Example 23 B Example 8 A Example 24 A Example 9 A Example 25 A Example 10 A Example 26 C Example 11 A Example 27 A Example 12 B Example 28 B Example 13 B Example 29 C Example 14 B Example 30 A Example 15 B Example 31 C

[0412] The present disclosure has been discussed with respect to the embodiments. It will be appreciated by those skilled in the art to which the present disclosure belongs that the present disclosure may be implemented in a modified form without departing from the basic features of the present disclosure. Therefore, the disclosed embodiments are considered to be illustrative rather than restrictive. The scope of the present disclosure is shown in the claims rather than in the foregoing description, and all differences within the scope of equivalents will be interpreted as being included in the present disclosure.

Claims

1. A compound selected from the group consisting of a compound of formula 1, its optical isomers, diastereoisomers, solvates and hydrates, and a pharmaceutically acceptable salt thereof: [Formula 1] in, In formula 1, R1 is hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halide C 1-6 Alkyl, -(CH2) a -C 1-6 Alkoxy, -(CH2) a -NR6R7, substituted or unsubstituted -(CH2) a -C 3-6 Cyclic group, substituted or unsubstituted -(CH2) a -C 6-10 Aryl or -(CH2) a -C 2-6 Heterocyclic group; R2 and R3 are each independently hydrogen, halogen, C 1-6 Alkyl, halogen C 1-6 Alkyl, C 1-6 Alkoxy, pendant oxygen (=O) or hydroxyl; a is an integer from 0 to 2; n and m are each independently an integer from 0 to 2; Z and Y are each independently -CH2-, -O-, -S- or -NR8-; Dashed lines indicate the presence or absence of bonds; 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 Cross-linked cycloalkyl, C 6-14 Heterospirocycloalkyl, C 6-14 Fused heterocycloalkyl or C 6-14 Cross-linked heterocycloalkyl groups, each of which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, nitro, pendant oxy (=O), cyano, halogen C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogen C 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 ; Alternatively, R4 and R5 are linked to each other and to the amide nitrogen of Formula 1 to form C 2-9 Heterocyclic group, C 6-14 Heterospirocyclic group, C 6-14 Condensed heterocyclic group, C 6-14 Cross-linked heterocyclic group or C 4-10 heteroaryl, each of which is unsubstituted or substituted with one or more than one substituent selected from the group consisting of halogen, nitro, oxo (=O), cyano, halo 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogen C 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 ; R6, R7, R8, R9, R 10 , R 11 and R 12 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, halogen C 1-6 Alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, C 4-10 Heteroaryl or C 2-9 Heterocycloalkyl, or, when R1 is -(CH2) a -NR6R7 or when R4 and R5 are C(O)-NR9R 10 or -NR9R 10 When a pair of R6 and R7 or a pair of R9 and R 10 are linked to each other and to the amide nitrogen to form a substituted or unsubstituted C 2-9 Heterocyclic or substituted or unsubstituted C 4-10 Heteroaryl.

2. The compound according to claim 1, wherein R1 is C 1-6 Alkyl, halogen C 1-6 Alkyl, -(CH2) a -C 1-6 Alkoxy, -(CH2) a -NR6R7 or substituted or unsubstituted -(CH2) a -C 3-6 Cyclic group.

3. The compound according to claim 1, wherein R2 and R3 are each independently hydrogen, halogen or C 1-6 alkyl.

4. The compound according to claim 1, wherein Z and Y are each independently -CH2- or -O-.

5. The compound according to claim 1, wherein R4 and R5 are each independently: hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halide C 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 alkyl.

6. The compound according to claim 1, wherein R4 and R5 are connected to each other and together with the amide nitrogen of formula 1 to form C 2-9 Heterocyclic group, C 6-14 Heterospirocyclic group, C 6-14 Cross-linked heterocyclic group or C 4-10 The heteroaryl groups are each one selected from the following: Wherein C 2-9 Heterocyclic group, said C 6-14 Heterospirocyclic group, said C 6-14 Cross-linked heterocyclic group or the C 4-10 The heteroaryl group is substituted with one or more than one substituent selected from the group consisting of hydrogen, halogen, nitro, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C(O)R 11 , halogen C 1-6 Alkoxy and C 2-6 Heterocyclic group.

7. The compound according to claim 1, wherein R4 and R5 are connected to each other and together with the amide nitrogen of Formula 1 to form one selected from the following:

8. The compound according to claim 1, wherein The compound is selected from the compounds of Formula 2, their optical isomers, diastereomers, solvates and hydrates, and their pharmaceutically acceptable salts: [Formula 2] in, In formula 2, V and W are each independently -CH2-, -S-, -O- or -NR 14 -; p, q and r are each independently an integer of 0 or 1; R 13 is hydrogen, halogen, nitro, cyano, halogen C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy or halogen C 1-6 Alkoxy; and Each R 14 are independently hydrogen, C 1-6 Alkyl, halogen C 1-6 Alkyl or -C(O)(C 1-6 alkyl).

9. The compound according to claim 1, wherein the compound is selected from the group consisting of the following compounds, their optical isomers, diastereoisomers and solvates, and pharmaceutically acceptable salts thereof: 1) 4-Hydroxy-9-methyl-8-(2-(N-morpholinyl)-2-oxoethyl)-7-oxo-1,7-dihydro-2H-furo[3,2-f]chromene-5-carbaldehyde; 2) 4-Hydroxy-9-methyl-8-(2-(N-morpholinyl)-2-oxoethyl)-7-oxo-7H-[1,3]dioxol[4,5-f]chromene-5-carbaldehyde; 3) 6-hydroxy-1-methyl-2-(2-(N-morpholinyl)-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]hept-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-tetrahydropyrano[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]hept-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-thio(N-morpholinyl)ethyl)-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-(N-morpholinyl)ethyl)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 diseases related to inositol requiring enzyme 1α (IRE1α), comprising as an active ingredient a compound selected from the group consisting of a compound as described in any one of claims 1 to 9, its optical isomers, diastereomers, solvates and hydrates, and pharmaceutically acceptable salts thereof. The pharmaceutical composition according to claim 10 , wherein the pharmaceutical composition exhibits IRE1α inhibitory activity. 12 . The pharmaceutical composition according to claim 10 , wherein the pharmaceutical composition exhibits IRE1α inhibitory activity and is used for treating cancer or tumor treatable by IRE1α inhibitory activity.

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