Novel indenone derivatives and their applications

Abstract

The present invention relates to a novel indenone derivative, an isomer thereof or a pharmaceutically acceptable salt thereof, and uses thereof. The indenone derivative according to the present invention can be usefully used for the prevention or treatment of neurodegenerative brain diseases by (i) suppressing the aggregation of amyloid β and / or decomposing aggregates, (ii) suppressing the aggregation of tau protein and / or decomposing aggregates, and / or (iii) suppressing the hyperphosphorylation of tau protein.

Description

Technical Field

[0001] The present invention relates to a novel indenone derivative, an isomer thereof or a pharmaceutically acceptable salt thereof, and its use for (i) inhibiting the aggregation of amyloid β and / or disaggregating aggregates, (ii) inhibiting the aggregation of tau protein and / or disaggregating aggregates, and / or (iii) inhibiting the hyperphosphorylation of tau protein, and its use for preventing or treating neurodegenerative brain diseases.

Background Art

[0002] Neurodegenerative brain diseases are diseases in which degenerative changes appear in nerve cells of the central nervous system, inducing various symptoms such as damage to motor and sensory functions and suppression of higher-order causal functions such as memory, learning, calculation, and reasoning. Representative diseases include Alzheimer's disease, Parkinson's disease, and memory disorders. Neurodegenerative brain diseases exhibit cell death of nerve cells due to necrosis or apoptosis that progresses rapidly or slowly. Therefore, understanding the cell death mechanism of nerve cells should be made for the development of preventive, regulatory, and therapeutic methods for central nervous system diseases.

[0003] As causative substances for neurodegenerative brain diseases, two types of proteins, namely amyloid-β and Tau protein, have attracted attention.

[0004] Human amyloid-beta is a peptide molecule containing about 36 to 43 amino acids, and its self-assembly into oligomers or aggregates is known to be involved in the onset of neurodegenerative diseases such as Alzheimer's disease. Specifically, amyloid-beta peptide molecules are obtained by cleaving amyloid precursor protein (APP; UniProtKB P05067) with beta secretase and gamma secretase, and such amyloid-beta peptide molecules aggregate to form neurotoxic oligomers, thereby inducing degenerative brain diseases.

[0005] In addition, Tau protein is composed of four parts: an N-terminal protruding part, an aggregation domain of proline, a microtubule-binding domain, and a C-terminal. When Tau protein is abnormally hyperphosphorylated or aggregated in neurons of the central nervous system, it is known to induce degenerative brain diseases such as Parkinson's disease and tauopathy.

[0006] Therefore, substances that inhibit the aggregation of amyloid-beta, or decompose aggregates, inhibit the aggregation of Tau protein, or decompose aggregates, or inhibit the hyperphosphorylation of Tau protein can be proposed as therapeutic agents for degenerative brain diseases. Summary of the Invention Problems to be Solved by the Invention

[0007] One object of the present invention is to provide a novel indenone derivative, its isomer, or its pharmaceutically acceptable salt useful for (i) inhibiting the aggregation of amyloid-beta and / or decomposing aggregates, (ii) inhibiting the aggregation of Tau protein and / or decomposing aggregates, and / or (iii) inhibiting the hyperphosphorylation of Tau protein.

[0008] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating degenerative brain diseases, comprising the novel indenone derivative, its isomer, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0009] A further object of the present invention is to provide a health functional food for preventing or improving degenerative brain diseases, comprising the novel indenone derivative, its isomer, or a food-safe salt thereof as an active ingredient.

[0010] A further object of the present invention is to provide compositions comprising the novel indenone derivative, its isomers, or pharmaceutically acceptable salts thereof.

[0011] A further object of the present invention is to provide a pharmaceutical composition comprising the novel indenone derivative, its isomer, or a pharmaceutically acceptable salt thereof.

[0012] A further object of the present invention is to provide a method for treating or preventing a degenerative brain disease, comprising the step of administering the novel indenone derivative, its isomer, or a pharmaceutically acceptable salt thereof to an individual requiring (i) amyloid-beta aggregation and / or degradation of aggregates, (ii) tau protein aggregation or degradation of aggregates and / or inhibition of tau protein phosphorylation, or (iii) a degenerative brain disease.

[0013] A further object of the present invention is to provide uses for the novel indenone derivatives, their isomers or pharmaceutically acceptable salts thereof for (i) inhibiting amyloid-beta aggregation and / or degrading aggregates, (ii) inhibiting tau protein aggregation or degrading aggregates and / or inhibiting tau protein phosphorylation, or (iii) treating or preventing degenerative brain diseases. [Means for solving the problem]

[0014] The present invention will be described in more detail below.

[0015] Throughout the specification, "including" a component means, unless otherwise stated, that it may include other components rather than excluding them.

[0016] In this invention, the term "isomer" refers to a compound or salt thereof of the present invention that has the same chemical or molecular formula but is structurally or sterically different. Such isomers include structural isomers such as tautomers, stereoisomers such as R or S isomers with asymmetric carbon centers, geometric isomers (trans, cis), and optical isomers. All of these isomers and mixtures thereof are also within the scope of this invention.

[0017] The term "halogen" refers to F, Cl, Br, or I unless otherwise specified.

[0018] "C 1-6 The term "alkyl" refers to a linear or branched saturated hydrocarbon residue having 1 to 6 carbon atoms. Specifically, C 1-6 Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, and the like. In one embodiment, the alkyl group may be substituted with one or more substituents, for example, 1 to 3 halogens or C 1-6 It may be substituted with alkyl.

[0019] "C 1-6 The term "alkoxy" refers to the chemical formula -OC. 1-6Alkyl means, and includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, tert-pentoxy, sec-pentoxy, neopentoxy, hexyloxy, etc. In one embodiment, the alkoxy group may be substituted with one or more substituents, for example, 1 to 3 halogens or C 1-6 It may be substituted with alkyl.

[0020] The term "aryl" refers to a monocyclic or bicyclic aromatic ring of a hydrocarbon. That is, unless otherwise defined herein, aryl may include phenyl, naphthyl, and biaryls. In one embodiment of the present invention, C 6-10 The aryl group refers to an aromatic ring having 6 to 10 carbon atoms. In one embodiment, 0, 1, 2, 3, 4, 5, or 6 atoms in each ring of the aryl group may be substituted with substituents.

[0021] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic heterocycle with 5 to 10 members containing 1 to 4 heteroatoms selected from N, O, and S. That is, a heteroaryl refers to a 5- or 6-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, or a bicyclic ring in which the heteroaryl ring is fused to a benzene ring or other heteroaryl ring. In one embodiment, 0, 1, 2, 3, or 4 atoms in each ring of the heteroaryl group may be substituted with substituents. Examples of monocyclic heteroaryls include, but are not limited to, thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, triazolyl, triazinyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and similar groups. Examples of noncyclic heteroaryl groups include, but are not limited to, indolyl, azaindolyl, indolinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, prinyl, propyridinyl, and similar groups.

[0022] The term "heterocyclyl" refers to a saturated or partially unsaturated carbonate cyclic ring having 5 to 10 ring atoms, including 1 to 4 heteroatoms selected from N, O, and S in addition to carbon atoms. In one embodiment, the heterocyclyl may be a 5-membered or 6-membered aliphatic heteroring, or a bicyclic ring in which the heterocyclyl ring is fused to a benzene ring or other heterocyclyl ring. In one embodiment, 0, 1, 2, 3, or 4 atoms in each ring of the heterocyclyl group may be substituted with substituents. For example, heterocyclyls include azetidinil, pyrrolidinil, tetrahydrofuranil, tetrahydrothienyl, pyrazolidinil, imidazolidinil, oxazolidinil, isoxazolidinil, thiazolidinil, dioxolyl, piperidinil, tetrahydropyranil, tetrahydrothiopyranil, piperazinil, morpholinil, thiomorpholinil, 1,1-dioxo-thiomorpholin-4-yl, azepanil, diazepanil, homopiperazinil, oxazepanil, indolyl, isoindolyl, dihydroindolyl, dioxoisoindolinil, dihydrofuryl, dihydroimidazolinil, dihydrooxazolyl, dihydrobenzodioxinil, tetrahydropyridinil, dihydropyranil, dihydrobenzofuranil, benzodioxolyl, or benzodioxanil.

[0023] The term "substitution" refers to replacing a hydrogen atom in a molecular structure with a substituent so that the atoms on a specified atom do not exceed the valence, resulting in a chemically stable compound from such substitution. For example, "group A is substituted with substituent B" means that a hydrogen atom bonded to an atom such as carbon that makes up the skeleton of group A is replaced by substituent B, and group A and substituent B form a covalent bond.

[0024] The present invention provides a compound of the following chemical formula 1, its isomers, or pharmaceutically acceptable salts thereof. [ka]

[0025] In the above formula,

[0026] X is either a direct bond or O,

[0027] Y is O or S,

[0028] n is an integer from 0 to 5,

[0029] m is an integer from 1 to 5,

[0030] R1 is halogen, C 1-6 alkyl, C 6-10 aryl, -C 1-6 alkyl-C 6-10 aryl or 5- to 6-membered heteroaryl, where the C 1-6 alkyl, C 6-10 aryl, -C 1-6 alkyl-C 6-10 aryl and 5- to 6-membered heteroaryl are each independently unsubstituted or substituted with 1 to 4 halogens, hydroxy, CN, -NH2, -CF3, C 1-6 alkyl, -C 1-6 alkyl-CN, -O-C 1-6 alkyl, -NH-C 1-6 alkyl or -N(C 1-6 alkyl)2 and may be substituted,

[0031] R2 is 5- to 6-membered heteroaryl, where the 5- to 6-membered heteroaryl is unsubstituted or substituted with 1 to 4 halogens, -CF3 or C 1-6 alkyl and may be substituted,

[0032] R3 is C 6-10 aryl, 5- to 6-membered heteroaryl or 5- to 10-membered heterocyclyl, where the C 6-10 aryl, 5- to 6-membered heteroaryl and 5- to 10-membered heterocyclyl are each independently unsubstituted or substituted with 1 to 4 halogens, hydroxy, CN, -NH2, -CF3, C 1-6 alkyl, -C 1-6 alkyl-CN, -O-C 1-6 alkyl, -NH-C1-6 Alkyl or -N(C) 1-6 It may also be substituted with alkyl)2,

[0033] The heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, and the heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from N, O, and S.

[0034] In one embodiment, in the compound of formula 1, R1 is a halogen, phenyl, pyridinyl, pyrimidinyl, or thiophenyl, where each of the phenyl, pyridinyl, pyrimidinyl, and thiophenyl is independently unsubstituted or has 1 to 4 halogens, hydroxy, CN, -CF3, or C 1-6 Alkyl, -C 1-6 Alkyl-CN, or -OC 1-6 It may be substituted with alkyl.

[0035] Specifically, R1 is, for example, bromo, [ka] This may also be the case, but is not limited to this.

[0036] In one embodiment, R2 in the compound of formula 1 is furanyl, thiophenyl, thiazolyl, or pyrazolyl, where thiazolyl, furanyl, thiophenyl, and pyrazolyl are each independently unsubstituted or have 1 to 4 halogens, -CF3, or C 1-6 It may be substituted with alkyl.

[0037] Specifically, R2 is, for example, [ka] This may also be the case, but is not limited to this.

[0038] In one embodiment, R3 in the compound of formula 1 is phenyl, pyridinyl, morpholinyl, or benzodioxolyl, where phenyl, pyridinyl, morpholinyl, and benzodioxolyl are each independently unsubstituted or have 1 to 4 halogens, hydroxyl, -NH2, -CF3, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl or -N(C) 1-6 It may be substituted with alkyl(2).

[0039] Specifically, R3 is, for example, [ka] This may also be the case, but is not limited to this.

[0040] In one embodiment, in the compound of formula 1, R1 is a halogen, phenyl, pyridinyl, pyrimidinyl, or thiophenyl, where each of the phenyl, pyridinyl, pyrimidinyl, and thiophenyl is independently unsubstituted or has 1 to 4 halogens, hydroxy, CN, -CF3, C 1-6 Alkyl, -C 1-6 Alkyl-CN, or -OC 1-6 It may be substituted with alkyl,

[0041] R2 is furanyl, thiophenyl, thiazolyl, or pyrazolyl, where thiazolyl, furanyl, thiophenyl, and pyrazolyl are each independently unsubstituted or have 1 to 4 halogens, -CF3, or C 1-6 It may be substituted with alkyl,

[0042] R3 is phenyl, pyridinyl, morpholinyl, or benzodioxolyl, where each of the phenyl, pyridinyl, morpholinyl, and benzodioxolyl is independently unsubstituted or has 1 to 4 halogens, hydroxyl, -NH2, -CF3, or C 1-6 Alkyl, -OC 1-6Alkyl, -NH-C 1-6 Alkyl or -N(C) 1-6 It may be substituted with alkyl(2).

[0043] Specific examples of the compound of Formula 1 according to the present invention are as follows, but are not limited thereto.

[0044] (1) 3-(4-methylthiazole-5-yl)-6-(3-phenylpropoxy)-2-(pyridine-3-yl)-1H-inden-1-one,

[0045] (2) 2-(2-(3-(4-methylthiazole-5-yl)-1-oxo-6-(3-phenylpropoxy)-1H-inden-2-yl)phenyl)acetonitrile,

[0046] (3) 2-bromo-3-(4-methylthiazole-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one,

[0047] (4) 3-(5-methylthiazole-4-yl)-6-(3-morpholinopropoxy)-2-(pyridine-3-yl)-1H-inden-1-one,

[0048] (5) 2-bromo-3-(5-methylthiazole-4-yl)-6-(3-morpholinopropoxy)-1H-inden-1-one,

[0049] (6) 6-(3-phenylpropoxy)-2-(pyridine-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one,

[0050] (7) 6-(3-phenylpropoxy)-3-(1H-pyrazole-3-yl)-2-(pyridine-3-yl)-1H-inden-1-one,

[0051] (8) 3-(5-methylthiazole-4-yl)-6-(3-phenylpropoxy)-2-(pyridine-3-yl)-1H-inden-1-one,

[0052] (9) 3-(furan-3-yl)-6-(3-phenylpropoxy)-2-(pyridine-3-yl)-1H-inden-1-one,

[0053] (10)3-(4-methylthiazole-5-yl)-2-phenyl-6-(3-phenylpropoxy)-1H-inden-1-one,

[0054] (11)3-(4-methylthiazole-5-yl)-6-(3-phenylpropoxy)-2-(pyrimidine-5-yl)-1H-inden-1-one,

[0055] (12)3-(4-methylthiazole-5-yl)-6-(3-phenylpropoxy)-2-(thiophen-2-yl)-1H-inden-1-one,

[0056] (13)3-(4-methylthiazole-5-yl)-2-(pyridine-3-yl)-6-(3-(pyridine-4-yl)propoxy)-1H-inden-1-one,

[0057] (14)3-(4-methylthiazole-5-yl)-6-pentoxy-2-(pyridine-3-yl)-1H-inden-1-one,

[0058] (15)3-(4-methylthiazole-5-yl)-6-(4-phenylbutoxy)-2-(pyridine-3-yl)-1H-inden-1-one,

[0059] (16)6-((benzyloxy)methoxy)-3-(4-methylthiazole-5-yl)-2-(pyridine-3-yl)-1H-inden-1-one,

[0060] (17)3-(4-methylthiazole-5-yl)-6-(2-phenoxyethoxy)-2-(pyridine-3-yl)-1H-inden-1-one,

[0061] (18) 2-(4-methoxyphenyl)-3-(5-methylthiazole-4-yl)-6-pentoxy-1H-inden-1-one,

[0062] (19) 2-(4-methoxyphenyl)-3-(5-methylthiazole-4-yl)-6-(4-phenylbutoxy)-1H-inden-1-one,

[0063] (20)6-((benzyloxy)methoxy)-2-(4-methoxyphenyl)-3-(5-methylthiazole-4-yl)-1H-inden-1-one,

[0064] (21) 2-(4-methoxyphenyl)-3-(5-methylthiazole-4-yl)-6-(2-phenoxyethoxy)-1H-inden-1-one,

[0065] (22) 2-(4-fluorophenyl)-6-(2-(4-methoxyphenoxy)ethoxy)-3-(5-methylthiazole-4-yl)-1H-inden-1-one,

[0066] (23)6-(2-(3,4-dimethoxyphenoxy)ethoxy)-2-(4-fluorophenyl)-3-(5-methylthiazole-4-yl)-1H-inden-1-one,

[0067] (24)6-(2-(benzo[d][1,3]dioxol-5-yloxy)ethoxy)-2-(4-fluorophenyl)-3-(5-methylthiazole-4-yl)-1H-inden-1-one,

[0068] (25) 2-(4-fluorophenyl)-3-(5-methylthiazole-4-yl)-6-(2-(pyridine-4-yloxy)ethoxy)-1H-inden-1-one,

[0069] (26)6-(2-(3,4-dichlorophenoxy)ethoxy)-3-(5-methylthiazole-4-yl)-2-(pyrimidine-5-yl)-1H-inden-1-one,

[0070] (27)6-(2-(3,4-difluorophenoxy)ethoxy)-3-(5-methylthiazole-4-yl)-2-(pyrimidine-5-yl)-1H-inden-1-one,

[0071] (28)3-(5-methylthiazole-4-yl)-6-pentoxy-2-(thiophen-2-yl)-1H-inden-1-one,

[0072] (29)3-(5-methylthiazole-4-yl)-6-(4-phenylbutoxy)-2-(thiophen-2-yl)-1H-inden-1-one,

[0073] (30)6-((benzyloxy)methoxy)-3-(5-methylthiazole-4-yl)-2-(thiophen-2-yl)-1H-inden-1-one,

[0074] (31)3-(5-methylthiazole-4-yl)-6-(2-phenoxyethoxy)-2-(thiophen-2-yl)-1H-inden-1-one,

[0075] (32)6-(2-(4-methoxyphenoxy)ethoxy)-3-(5-methylthiazole-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one,

[0076] (33)6-(2-(3,4-dimethoxyphenoxy)ethoxy)-3-(5-methylthiazole-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one,

[0077] (34)6-(2-(benzo[d][1,3]dioxol-5-yloxy)ethoxy)-3-(5-methylthiazole-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one,

[0078] (35)3-(5-methylthiazole-4-yl)-6-(2-(pyridine-4-yloxy)ethoxy)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one,

[0079] (36)6-(2-(3,4-dichlorophenoxy)ethoxy)-3-(5-methylthiazole-4-yl)-2-(thiophen-2-yl)-1H-inden-1-one,

[0080] (37)6-(2-(3,4-difluorophenoxy)ethoxy)-3-(5-methylthiazole-4-yl)-2-(thiophen-2-yl)-1H-inden-1-one,

[0081] (38)3-(furan-3-yl)-6-pentethoxy-2-(pyridine-3-yl)-1H-indene-1-one,

[0082] (39)3-(furan-3-yl)-6-(4-phenylbutoxy)-2-(pyridine-3-yl)-1H-inden-1-one,

[0083] (40)6-((benzyloxy)methoxy)-3-(furan-3-yl)-2-(pyridine-3-yl)-1H-inden-1-one,

[0084] (41)3-(furan-3-yl)-6-(2-phenoxyethoxy)-2-(pyridine-3-yl)-1H-indene-1-one,

[0085] (42)3-(furan-3-yl)-6-(2-(4-methoxyphenoxy)ethoxy)-2-(pyridine-3-yl)-1H-inden-1-one,

[0086] (43)6-(2-(3,4-dimethoxyphenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridine-3-yl)-1H-inden-1-one,

[0087] (44)6-(2-(benzo[d][1,3]dioxol-5-yloxy)ethoxy)-3-(furan-3-yl)-2-(pyridine-3-yl)-1H-inden-1-one,

[0088] (45)3-(furan-3-yl)-2-(pyridine-3-yl)-6-(2-(pyridine-4-yloxy)ethoxy)-1H-inden-1-one,

[0089] (46)6-(2-(3,4-dichlorophenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridine-3-yl)-1H-inden-1-one,

[0090] (47)6-(2-(3,4-difluorophenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridine-3-yl)-1H-inden-1-one,

[0091] (48)6-(2-(4-(dimethylamino)phenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridine-3-yl)-1H-inden-1-one,

[0092] (49)3-(furan-3-yl)-6-(2-(4-isopropylphenoxy)ethoxy)-2-(pyridine-3-yl)-1H-inden-1-one,

[0093] (50)3-(furan-3-yl)-6-(((4-methoxybenzyl)oxy)methoxy)-2-(pyridine-3-yl)-1H-inden-1-one,

[0094] or a pharmaceutically acceptable salt thereof.

[0095] The present invention comprises pharmaceutically acceptable salts of the compound of formula 1.

[0096] The aforementioned pharmaceutically acceptable salts must have low toxicity to humans and should not have any adverse effects on the biological activity or physicochemical properties of the parent compound.

[0097] For example, the pharmaceutically acceptable salt may be an acid addition salt formed by a pharmaceutically acceptable free acid.

[0098] The free acid can be an inorganic acid or an organic acid, where the inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromate, etc., and the organic acid may be acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, emponic acid, aspartic acid, glutamic acid, etc.

[0099] The acid addition salt can be produced by conventional methods, for example, by dissolving the compound of formula 1 in an excess aqueous acid solution and precipitating the salt using a water-miscible organic solvent, such as methanol, ethanol, acetone, or acetonitrile.

[0100] Furthermore, the pharmaceutically acceptable salt may be an alkali metal salt (such as a sodium salt) or an alkaline earth metal salt (such as a potassium salt).

[0101] The alkali metal salt or alkaline earth metal salt can be obtained, for example, by dissolving the compound of formula 1 in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and then evaporating and drying the filtrate.

[0102] Furthermore, the compounds of the present invention may have a chiral carbon center and therefore may exist in the form of R or S isomers, racemic compounds, individual enantiomers or mixtures, individual diastereoisomers or mixtures, and all such stereoisomers and mixtures thereof may fall within the scope of the present invention.

[0103] Furthermore, the compounds of the present invention may include hydrates and solvates of the compound of Formula 1. The hydrates and solvates can be produced using known methods and are preferably non-toxic and water-soluble. Particularly preferably, the hydrates and solvates may each consist of 1 to 5 molecules of water and an alcoholic solvent (especially ethanol).

[0104] Furthermore, the present invention provides a method for producing the compound of formula 1.

[0105] Specifically, the compound of formula 1 can be produced by the methods shown in reaction formulas 1 to 5 below, but is not limited to those produced by such methods. In particular, those skilled in the art will understand that the compound of formula 1 of the present invention can be produced by various methods using the ordinary art in this field.

[0106] The reaction equations 1 to 5 below show the production methods for representative compounds according to the present invention, step by step. Some of the compounds of the present invention can be produced by changing the reagents and solvents used in the following production steps or by changing the reaction order.

[0107] [Reaction Equation 1]

[0108] [ka] [Reaction Equation 2]

[0109] [ka] [Reaction Equation 3]

[0110] [ka] [Reaction Equation 4]

[0111] [ka] [Reaction Equation 5]

[0112] [ka] The target compound produced by the above reaction can be separated and purified using conventional methods, such as chromatography or recrystallization.

[0113] The present invention provides a composition comprising the compound of formula 1, its isomers, or acceptable salts thereof.

[0114] The present invention provides a composition comprising the compound of formula 1, its isomer, or an acceptable salt thereof as an active ingredient.

[0115] Furthermore, the present invention provides a pharmaceutical composition for preventing or treating degenerative brain diseases, comprising the compound of Formula 1, its isomer, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0116] The compound of Formula 1, its isomers, or pharmaceutically acceptable salts are excellent at inhibiting or degrading amyloid-beta aggregation and tau protein aggregation, as well as inhibiting tau protein phosphorylation. Therefore, the compound or pharmaceutical composition containing it can be usefully used for the prevention or treatment of diseases related to the inhibition of amyloid-beta aggregation and / or degradation of amyloid-beta aggregates, the inhibition of tau protein aggregation and / or degradation of tau protein aggregates, and / or the inhibition of tau protein phosphorylation, such as degenerative brain diseases.

[0117] As used in this invention, the term "prevention" means all actions that suppress or delay the onset, spread, and recurrence of the disease by administering the compound or pharmaceutical composition according to the present invention, and "treatment" means all actions that improve or favorably alter the symptoms of the disease by administering the compound or pharmaceutical composition according to the present invention.

[0118] As used herein, the term “degenerative brain disease” encompasses all diseases related to degenerative changes in the brain, in particular all diseases (brain diseases) that can be triggered by one or more factors selected from amyloid-beta aggregation, tau protein aggregation, and tau protein hyperphosphorylation in the brain and / or brain nerve cells.

[0119] In one embodiment, degenerative brain diseases that can be prevented or treated with the compounds or pharmaceutical compositions according to the present invention include dementia, Alzheimer's disease, preclinical Alzheimer's disease, Parkinson's disease, Huntington's disease, mild cognitive impairment, cerebral amyloid vascular disease, Down syndrome, amyloid stroke, systemic amyloid disease, Dutch amyloidosis, Niemann-Pick disease, senile dementia, amyotrophic lateral sclerosis, spinocerebellar atrophy, Tourette's syndrome, Friedrich's ataxia, and Machado-Joseph's disease. The disease may be selected from the group consisting of amyloid-beta aggregation, tau protein aggregation, and / or tau protein phosphorylation, but is not limited to these, and any disease resulting from amyloid-beta aggregation, tau protein aggregation, and / or tau protein phosphorylation may be included.

[0120] As one embodiment, the present invention provides a pharmaceutical composition for inhibiting amyloid-beta aggregation and / or degrading aggregates, comprising the compound of formula 1, its isomer, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0121] As one embodiment, the present invention provides a pharmaceutical composition for inhibiting the aggregation of tau protein, or for degrading aggregates and / or inhibiting the phosphorylation of tau protein, comprising the compound of Formula 1, its isomer, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0122] The present invention provides applications for the prevention or treatment of diseases related to the inhibition of amyloid-beta aggregation and / or the degradation of amyloid-beta aggregates, such as degenerative brain diseases, of the compound of Formula 1, its isomers, or pharmaceutically acceptable salts thereof.

[0123] The present invention provides applications for inhibiting amyloid-beta aggregation and / or degrading aggregates of the compound of Formula 1, its isomers, or pharmaceutically acceptable salts thereof.

[0124] The present invention provides applications for inhibiting the aggregation of tau protein by the compound of Formula 1, its isomers, or pharmaceutically acceptable salts thereof, or for degrading aggregates and / or inhibiting the phosphorylation of tau protein.

[0125] The present invention provides applications for the manufacture of agents for the prevention or treatment of diseases related to the inhibition of amyloid-beta aggregation and / or the degradation of amyloid-beta aggregates, such as degenerative brain diseases, of the compound of Formula 1, its isomers, or pharmaceutically acceptable salts thereof.

[0126] The present invention provides applications for the production of agents for inhibiting amyloid-beta aggregation and / or degrading amyloid-beta aggregates, using the compound of Formula 1, its isomers, or pharmaceutically acceptable salts thereof.

[0127] The present invention provides applications for the production of agents for inhibiting tau protein aggregation or degrading aggregates and / or inhibiting tau protein phosphorylation, using the compound of Formula 1, its isomers, or pharmaceutically acceptable salts thereof.

[0128] The present invention also provides a method for preventing or treating diseases related to the inhibition of amyloid-beta aggregation and / or the degradation of amyloid-beta aggregates, such as degenerative brain diseases, comprising the step of administering a compound of Formula 1, its isomer, or a pharmaceutically acceptable salt thereof to a subject in need of prevention or treatment of a degenerative brain disease. The method may further include a step of identifying a subject in need of prevention and / or treatment of a degenerative brain disease prior to the administration step.

[0129] The present invention also provides a method for inhibiting amyloid-beta aggregation and / or degrading amyloid-beta aggregates, comprising the step of administering a compound of formula 1, its isomer, or a pharmaceutically acceptable salt thereof to a target requiring inhibition of amyloid-beta aggregation and / or degradation of aggregates. The method may further include a step of identifying a target requiring inhibition of amyloid-beta aggregation and / or degradation of aggregates prior to the administration step.

[0130] The present invention provides a method for inhibiting tau protein aggregation or degrading aggregates and / or inhibiting tau protein phosphorylation, comprising the step of administering a compound of Formula 1, its isomer, or a pharmaceutically acceptable salt thereof to a subject requiring inhibition of tau protein aggregation and / or degradation of aggregates and / or inhibition of tau protein phosphorylation. The method may further include a step of identifying a subject requiring inhibition of tau protein aggregation, degradation of aggregates, and / or inhibition of tau protein phosphorylation before the administration step.

[0131] In one embodiment, the pharmaceutical composition according to the present invention is

[0132] (1) Individuals (patients) whose amyloid-beta aggregation level is higher than normal or at high risk,

[0133] (2) Individuals (patients) whose tau protein aggregation levels are higher than normal or at high risk,

[0134] (3) Individuals (patients) whose tau protein phosphorylation levels are higher than normal or at high risk, and

[0135] (4) Individuals (patients) that fall under two or more of the above (1) to (3)

[0136] It may be intended for administration to individuals (patients) selected from a group consisting of the following.

[0137] The amyloid-beta or tau protein aggregation level can refer to the amount (concentration) of amyloid-beta aggregates or tau protein aggregates, or the ratio of amyloid-beta aggregates or tau protein aggregates to total amyloid-beta or total tau protein.

[0138] The phosphorylation level of the tau protein can refer to the amount (concentration) of phosphorylated tau protein, or the ratio of phosphorylated tau protein to total tau protein.

[0139] The term "normal" refers to an individual of the same species as the target of application of the pharmaceutical composition (patient) that does not have the "degenerative brain disease" defined above, or brain tissue or brain cells (brain nerve cells) isolated and / or cultured from such an individual.

[0140] As used in this invention, the term "suppression" means inhibiting any step among gene transcription, mRNA processing, translation, translocation, and maturation, or suppressing protein-protein binding, protein activation, or signal transduction mediated thereby.

[0141] The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier in addition to the active ingredient. Here, the pharmaceutically acceptable carrier is one that is commonly used in formulation and includes, but is not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above components, the composition may further contain lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, and the like.

[0142] The pharmaceutical composition of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) according to the intended method, and the dosage can be appropriately selected by those skilled in the art, depending on the patient's condition and weight, the severity of the disease, the form of the drug, the route of administration, and the time of administration.

[0143] The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, “pharmaceutically effective amount” means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the level of the effective dose may be determined according to factors including the type and severity of the patient’s disease, the activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and elimination rate, the duration of treatment, drugs used concurrently, and other factors well known in the medical field.

[0144] The pharmaceutical compositions according to the present invention can be administered as individual therapeutic agents or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple times. Considering all the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art.

[0145] Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, weight, absorption rate of the active ingredient into the body, inactivation rate and excretion rate, type of disease, and concomitant drugs. Generally, 0.001 to 150 mg, preferably 0.01 to 100 mg per kg of body weight, can be administered daily or every other day, or divided into 1 to 3 doses per day. However, the dosage may increase or decrease depending on the route of administration, the severity of obesity, sex, weight, age, etc., and therefore, the aforementioned dosage, regardless of the method, does not limit the scope of the present invention.

[0146] Furthermore, the present invention provides a method for preventing, regulating, or treating a degenerative brain disease, comprising the step of administering the pharmaceutical composition to an individual. In the present invention, “individual” means a subject requiring treatment for a disease, and more specifically, a mammal such as a human or non-human primate, mouse, dog, cat, horse, or cattle.

[0147] Furthermore, the present invention provides a health functional food for preventing and / or improving degenerative brain diseases, comprising the compound of Formula 1, its isomer, or a food-grade salt thereof as an active ingredient.

[0148] The present invention provides a health-functional food for inhibiting amyloid-beta aggregation and / or decomposing aggregates, comprising the compound of formula 1, its isomer, or a food-safe salt thereof as an active ingredient.

[0149] Furthermore, the present invention provides a health-functional food for inhibiting tau protein aggregation, decomposition of tau protein aggregates, and / or phosphorylation of tau protein, comprising the compound of Formula 1, its isomer, or a food-grade salt thereof as an active ingredient.

[0150] The aforementioned health functional foods are foods manufactured using nutrients that are often lacking in daily diets or raw materials or components that have functions useful to the human body, and mean all foods that help maintain health or prevent and / or improve certain diseases or symptoms, and there are no special restrictions on the final product form. For example, the aforementioned health functional foods may be selected from the group consisting of various foods, beverage compositions, food additives, etc., but are not limited to these.

[0151] The amount of active ingredients (i.e., the compound of Formula 1, its isomers, or food-grade salts) contained in the aforementioned health functional food can be appropriately adjusted depending on the form of the food, the desired use, etc., and there are no special restrictions.

[0152] The aforementioned functional health food may further contain one or more substances selected from the group consisting of various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic or natural flavoring agents, coloring agents, enhancers (such as cheese and chocolate), pectic acid or its salts, alginic acid or its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, and carbonating agents used in carbonated beverages. The proportion of such additives is generally selected from a range of 0.001 to about 20 parts by weight per 100 parts by weight of the total functional health food, but is not limited thereto. [Effects of the Invention]

[0153] The indenone derivatives according to the present invention can be usefully used for the prevention or treatment of neurodegenerative brain disease by (i) inhibiting amyloid-beta aggregation and / or degrading aggregates, (ii) inhibiting tau protein aggregation and / or degrading aggregates, and / or (iii) inhibiting tau protein hyperphosphorylation. [Brief explanation of the drawing]

[0154] [Figure 1]This graph shows the results of confirming the amyloid-beta disaggregation of indenone derivative compounds 1-9 according to the present invention by thioflavin-T analysis. [Figure 2] This graph shows the results of confirming the amyloid-beta disaggregation of indenone derivative compounds 10, 12-19 according to the present invention by thioflavin-T analysis. [Figure 3] This graph shows the results of confirming the amyloid-beta disaggregation of indenone derivative compounds 20-28 according to the present invention by thioflavin-T analysis. [Figure 4] This graph shows the results of confirming the amyloid-beta disaggregation of indenone derivative compounds 29-37 according to the present invention by thioflavin-T analysis. [Figure 5] This graph shows the results of confirming the amyloid-beta disaggregation of indenone derivative compounds 38-46 according to the present invention by thioflavin-T analysis. [Figure 6] This graph shows the results of confirming the amyloid-beta disaggregation of indenone derivative compounds 47-50 according to the present invention by thioflavin-T analysis. [Figure 7] This graph shows the results of tau disaggregation of indenone derivative compounds 1-9 according to the present invention, as confirmed by thioflavin-T analysis. [Figure 8] This graph shows the results of confirming the tau disaggregation of indenone derivative compounds 10, 12-19 according to the present invention by thioflavin-T analysis. [Figure 9]This graph shows the results of confirming the tau disaggregation of indenone derivative compounds 20-28 according to the present invention by thioflavin-T analysis. [Figure 10] This graph shows the results of confirming the tau disaggregation of indenone derivative compounds 29-37 according to the present invention by thioflavin-T analysis. [Figure 11] This graph shows the results of confirming the tau disaggregation of indenone derivative compounds 38-46 according to the present invention by thioflavin-T analysis. [Figure 12] This graph shows the results of tau disaggregation of indenone derivative compounds 47-50 according to the present invention, as confirmed by thioflavin-T analysis. [Figure 13] This graph shows the effect of indenone derivative compound treatment on reducing amyloid plaque in a 5xFAD TG mouse Alzheimer's model according to one embodiment. [Figure 14] This graph shows the effect of indenone derivative compound treatment on reducing tau aggregates in a PS19 TG mouse Alzheimer's model according to one embodiment. [Modes for carrying out the invention]

[0155] The following describes preferred embodiments to facilitate understanding of the present invention. However, the following embodiments are provided to make the present invention easier to understand, and the scope of the present invention is not limited by these embodiments. The embodiments can be modified in various ways, and the embodiments are not limited to those disclosed below and may be realized in various forms.

[0156] The abbreviations used in this embodiment are as follows:

[0157] LCMS (Liquid Chromatography Mass Spectrometry)

[0158] HPLC (High-Performance Liquid Chromatography)

[0159] TLC (Thin-Layer Chromatography)

[0160] NMR nuclear magnetic resonance

[0161] M+ Parent molecular ion

[0162] Et Ethyl

[0163] W (watt)

[0164] T temperature

[0165] eq equivalent

[0166] N normal (liter equivalent; equivalents per liter)

[0167] N2 nitrogen

[0168] Psi Pounds per Square inch

[0169] PdCl2 Palladium(II) chloride

[0170] Pd2(dba)3 Tris(debenzylideneacet1one)dipalladium(0)

[0171] Pd(dtbpf)Cl2[1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)

[0172] Pd(dppf)Cl2[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0173] PdCl2(PPh3)2 dichloropalladium (triphenylphosphine)

[0174] [(t-Bu)3PH]BF4[tri(tert-butyl)phosphonium]tetrafluoroborate]

[0175] ACN (acetonitrile)

[0176] Ac2O Acetic anhydride

[0177] AIBN Azobisisobutyronitrile (2,2-azobis(2-methylpropionitrile))

[0178] DCM (Dichloromethane)

[0179] DIAD (Diisopropyl Azodicarboxylate)

[0180] DMAP 4-dimethylaminopyridine

[0181] DMF (Dimethylformamide)

[0182] DMSO (Dimethyl Sulfoxide)

[0183] HOAc Acetic acid (acetic acid)

[0184] TBAB Tetrabutylammonium bromide

[0185] MTBE (Methyl Tertiary Butyl Ether)

[0186] TFA (trifluoroacetic acid)

[0187] THF (Tetrahydrofuran)

[0188] PE (Petroleum ether)

[0189] Py pyridine

[0190] EA Ethyl acetate = hydroxy

[0191] General experimental methods

[0192] ¹H NMR spectra were recorded on a Varian Mercury 400 MHz system, using TMS (trimethylsilyl) as the internal standard.

[0193] LC-MS was measured using an Agilent LC / MSD 1200 series quadrupole mass spectrometer (Column: Ultimate XB-C18 (50 × 4.6 mm, 5 μm)) operating in ES(+) or (-) ionization mode: T=30°C; flow rate=1.5 mL / min; detected wavelengths: 214 nm and 254 nm.

[0194] Manufacturing of compounds

[0195] Embodiment 1: 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 1)

[0196] [Reaction Equation 1]

[0197] [ka]

[0198] Step 1: Synthesis of (E)-1-(3-hydroxyphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one (1-3)

[0199] Compound 1-1 (5.00 g, 39.3 mmol) and Compound 1-2 (5.35 g, 39.3 mmol, 4.87 mL) were mixed in ethanol (50.0 mL). Then, NaOH (2.36 g, 58.9 mmol) was added to H2O (20.0 mL) under a nitrogen atmosphere at 0°C. The mixture was stirred at 20°C for 12 hours. Complete consumption of the reactants was confirmed by TLC (DCM: methanol = 10 / 1). After adjusting the pH of the mixture to 7 with 1N HCl, the mixture was filtered and concentrated under vacuum to obtain the yellow solid Compound 1-3 (6.00 g, 24.46 mmol, yield: 62.21%).

[0200] Step 2: Synthesis of 6-hydroxy-3-(4-methylthiazol-5-yl)-2,3-dihydro-1H-inden-1-one (1-4)

[0201] Compound 1-3 (6.00 g, 24.5 mmol) was dissolved in triflic acid (30.0 mL), and the mixture was stirred at 80°C for 16 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA = 1 / 1). After adjusting the pH of the mixture to 8 by adding an aqueous solution of NaHCO3, the mixture was filtered and concentrated under vacuum to obtain the brown solid compound 1-4 (5.1 g, 20.8 mmol, yield: 85.00%).

[0202] Step 3: Synthesis of 1-(4-methylthiazol-5-yl)-3-oxo-2,3-dihydro-1H-inden-5-yl acetate (1-5)

[0203] Compounds 1-4 (2.00 g, 8.15 mmol) and Ac2O (4.16 g, 40.77 mmol, 3.82 mL) were mixed in DCM (20 mL), and then pyridine (3.22 g, 40.77 mmol, 3.29 mL) was added under a nitrogen atmosphere at 0°C. The mixture was stirred at 20°C for 12 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA = 1 / 1). The mixture was diluted with DCM (100 mL) and extracted with brine (30 mL x 3). After drying with anhydrous Na2SO4, the residue was concentrated under vacuum to obtain the residue. The residue was purified by flash silica gel chromatography to obtain the yellow solid compound 1-5 (850 mg, 2.96 mmol, yield: 36.28%).

[0204] Step 4: Synthesis of 2-bromo-3-(4-methylthiazol-5-yl)-1-oxo-1H-inden-6-yl acetate (1-6)

[0205] Compounds 1-5 (650 mg, 2.26 mmol) and NBS (886 mg, 4.98 mmol) were mixed in carbon tetrachloride (5.00 mL), and then AIBN (37.1 mg, 226 mmol) was added under a nitrogen atmosphere. The mixture was stirred at 80°C for 1 hour. Subsequently, the reaction mixture was stirred at 80°C for 1.5 hours under 400 W. LC-MS confirmed that the reactants were completely consumed and that compounds 1-6 had been synthesized. The mixture was diluted with DCM (100 mL) and extracted with brine (30 mL x 3). After drying and filtering with anhydrous Na2SO4, the mixture was concentrated under vacuum to obtain compound 1-6 (890 mg) as a brown oil.

[0206] Step 5: Synthesis of 2-bromo-6-hydroxy-3-(4-methylthiazol-5-yl)inden-1-one (1-7)

[0207] Compounds 1-6 (780 mg, 2.14 mmol) were mixed in DCM (4.00 mL), and then DBU (326 mg, 2.14 mmol, 322 μL) was added under a nitrogen atmosphere. The mixture was stirred at 20°C for 12 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA = 1 / 1). The mixture was diluted with DCM (100 mL) and extracted with brine (30 mL x 3). After drying and filtering with anhydrous Na2SO4, the residue was concentrated under vacuum to obtain the residue. The residue was purified by flash silica gel chromatography to obtain compound 1-7 (110 mg, 341 μL, yield: 15.9%) as a red oil.

[0208] Step 6: Synthesis of 2-bromo-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one (Compound 3)

[0209] Compounds 1-7 (110 mg, 341 μL) and (3-bromopropyl)benzene (81.5 mg, 409 μL, 61.8 μL) from [Reaction Formula 1] were mixed in acetonitrile (2.00 mL), and then K2CO3 (141 mg, 1.02 mmol) was added. The mixture was stirred at 40°C for 12 hours. LC-MS confirmed that the reactants were completely consumed, and MS confirmed that compound 3 had been synthesized. The mixture was diluted with EA (50.0 mL) and extracted with brine (10 mL x 3). After drying and filtering over anhydrous Na2SO4, the residue was concentrated under vacuum. The residue was purified by reversed-phase HPLC to obtain compound 3 (10.0 mg, 22.7 μL, yield: 6.65%) as a red oil.

[0210] Step 7: Synthesis of 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 1)

[0211] Dioxane (2.00 mL) and H2O (0.5 mL) were mixed with compound 3 (40.0 mg, 90.8 umol) and pyrimidin-3-ylboronic acid (13.4 mg, 109 umol) in the reaction formula 1 above, with R1-B(OH)2. Then, K3PO4 (57.8 mg, 272 umol) and Pd(dppf)Cl2 (5.92 mg, 9.08 umol) were added under a nitrogen atmosphere. The mixture was stirred in a microwave at 100°C for 2 hours. Complete consumption of the reactants was confirmed by LC-MS, and it was confirmed that compound 1 was detected at 36.1%. The mixture was filtered and concentrated under vacuum to obtain the residue. The residue was purified by reversed-phase HPLC to obtain compound 1 (6.00 mg, 13.68 umol, yield: 15.06%) as a red solid.

[0212] 1H NMR (400MHz, CD3OD): δ9.19(s, 1H), 8.4-8.5(m, 2H), 7.70-7.78(m, 1H), 7.37-7.45(m, 1H), 7.13-7.30(m, 6H), 7.11(d, J = 8.4 Hz, 1H), 6.94(dd, J = 2.4, 8.0 Hz, 1H), 4.03(t, J = 6.4 Hz, 2H), 2.81(t, J = 7.6 Hz, 2H,), 2.07-2.15(m, 2H), 2.05(s, 3H)

[0213] MS measured value: 439.1 [M+H] +

[0214] Embodiment 2: 2-(2-(3-(4-methylthiazol-5-yl)-1-oxo-6-(3-phenylpropoxy)-1H-inden-2-yl)phenyl)acetonitrile (Compound 2)

[0215] THF (2.00 mL) and H2O (0.50 mL) were mixed with compound 3 (20.0 mg, 45.4 umol) synthesized in Embodiment 1, and 2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)acetonitrile (13.2 mg, 54.5 umol) and Pd2(dba)3 (4.16 mg, 4.54 umol) in R1-B(OH)2 in [Reaction Scheme 1]. Then, KF (7.92 mg, 136 umol) and [(t-Bu)3PH]BF4 (1.32 mg, 4.54 umol) were added under a nitrogen atmosphere. The mixture was stirred at 20°C for 4 hours. Complete consumption of the reactants was confirmed by LC-MS, and synthesis of compound 2 was confirmed by MS. The mixture was diluted with H2O (20.0 mL) and extracted with EA (20.0 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and filtered, then concentrated under vacuum to obtain the residue. The residue was purified by reversed-phase HPLC to obtain compound 2 (3.80 mg, 7.97 umol, yield: 17.5%) as a red oil.

[0216] 1H NMR (400 MHz, CD3OD): δ9.09(s, 1H), 7.5-7.5(m, 1H), 7.40(t, J = 7.6 Hz, 1H, ), 7.21-7.32(m, 5H), 7.15- 7.20(m, 3H), 7.05(d, J = 7.2 Hz, 1H), 6.93-6.97(m, 1H), 4.05(t, J=6.4 Hz, 2H), 3.75(s, 2H), 2.82(t, J=7.6Hz, 2H), 2.08-2.18(m, 2H), 2.07(s, 3H)

[0217] MS measured value: 477.0 [M+H] +

[0218] Embodiment 3: 2-bromo-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one (Compound 3)

[0219] Compound 3 was synthesized in the above embodiment 1.

[0220] 1H NMR (400 MHz, CD3OD): δ9.20(s, 1H), 7.24-7.30(m, 2H), 7.13-7.22(m, 4H), 7.00(d, J = 8.0 Hz, 1H), 6.88(dd, J = 2.4, 8.4 Hz, 1H), 4.01(t, J = 6.4 Hz, 2H), 2.80(t, J = 7.6 Hz, 2H), 2.49(s, 3H), 2.05-2.14(m, 2H)

[0221] MS measured value: 439.9 [M+H] +

[0222] Embodiment 4: 3-(4-methylthiazol-5-yl)-2-phenyl-6-(3-phenylpropoxy)-1H-inden-1-one (Compound 10)

[0223] Step 1: Synthesis of 2-bromo-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one (10-1)

[0224] Compounds 1-7 (30.0 g, 1.0 eq) synthesized in Embodiment 1 and (3-bromopropyl)benzene (22.3 g, 1.2 eq) in the reaction formula 1 were mixed in DMF (300 mL). Then, K2CO3 (23.2 g, 1.8 eq) and NaI (1.40 g, 0.1 eq) were added under a nitrogen atmosphere at 20-25°C. The mixture was stirred for 2 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA = 1 / 1). Water (300 mL) was added to the mixture, and the pH was adjusted to 3 with 1 M HCl, after which it was extracted with SiO (100 mL x 2). The organic layer was dried over Na2SO4, and a concentrated organic phase residue was obtained under reduced pressure at 40-45°C. The residue was purified by flash silica gel chromatography (PE / EA = 20 / 1, 1 / 1) to obtain a red oily compound 10-1 (25.0 g).

[0225] Step 2: Synthesis of 3-(4-methylthiazol-5-yl)-2-phenyl-6-(3-phenylpropoxy)-1H-inden-1-one (Compound 10)

[0226] Compound 10-1 (100 mg, 220 umol, 1 eq) and phenylboronic acid (41.5 mg, 340 umol, 1.5 eq) were mixed with R1-B(OH)2 in [Reaction Formula 1]. This mixture was then added to K2CO3 (94.0 mg, 681 umol, 3.0 eq), Pd(t-Bu3P)2 (11.0 mg, 21 umol, 0.1 eq), dioxane (0.8 mL), and water (0.2 mL) under a nitrogen atmosphere at 20-25°C. The mixture was stirred at 80-85°C for 3 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA=1 / 1). Water (10 mL) was added to the mixture, and the pH was adjusted to 3 with 1 M HCl, followed by extraction with SiO (10 mL x 3). The organic layer was dried over Na2SO4, and a concentrated organic phase residue was obtained under reduced pressure at 40-45°C. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 1 / 1) to obtain compound 10 (82.0 mg, 179 umol, yield: 79.1%) as a red solid.

[0227] 1H NMR (400 MHz, DMSO-d6): δ9.28(s, 1H), 7.37~7.26(m, 5H), 7.25~7.16(m, 5H), 7.15~7.06(m, 2H), 6.99 (dd, J = 2.4, 8.0 Hz, 1H), 4.04 (t, J = 6.4 Hz, 2H), 2.74 (t, J = 7.6 Hz, 2H), 2.10 - 1.98 (m, 2H), 1.91 (s, 3H)

[0228] MS measured value: 438.1 [M+H] +

[0229] Embodiment 5: 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyrimidin-5-yl)-1H-inden-1-one (Compound 11)

[0230] In Embodiment 4, compound 10-1 (100 mg, 220 umol, 1 eq) synthesized was mixed with pyrimidin-5-ylboronic acid (42.2 mg, 340 umol, 1.5 eq) in R1-B(OH)2 in [Reaction Formula 1]. This mixture was then added to K2CO3 (94.0 mg, 681 umol, 3.0 eq), Pd(t-Bu3P)2 (11.0 mg, 21 umol, 0.1 eq), dioxane (0.8 mL), and water (0.2 mL) under a nitrogen atmosphere at 20-25°C. The mixture was stirred at 80-85°C for 3 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA=1 / 1). Water (10 mL) was added to the mixture, the pH was adjusted to 3 with 1 M HCl, and then extracted with SiO (10 mL x 3). The organic layer was dried over Na2SO4, and a concentrated organic phase residue was obtained under reduced pressure at 40-45°C. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1-1 / 1) to obtain compound 11 (23.0 mg, 179 umol, yield: 22.1%) as a red solid.

[0231] 1H NMR (400MHz, DMSO-d6): δ9.29(s, 1H), 9.08(s, 1H), 8.62(s, 2H), 7.34-7.11(m, 7H), 7.03(m, 1H), 4.11 (brt, J = 6.4 Hz, 2H), 2.77 (brt, J = 7.6 Hz, 2H), 2.08 (s, 3H), 2.06 (brd, J = 7.2 Hz, 2H)

[0232] MS measured value: 440 [M+H] +

[0233] Embodiment 6 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(thiophen-2-yl)-1H-inden-1-one (Compound 12)

[0234] In Embodiment 4, compound 10-1 (100 mg, 220 umol, 1 eq) synthesized was mixed with thiophene-2-ylboronic acid (43.6 mg, 340 umol, 1.5 eq) in R1-B(OH)2 in [Reaction Formula 1]. This mixture was then added to K2CO3 (94.0 mg, 681 umol, 3.0 eq), Pd(t-Bu3P)2 (11.0 mg, 21 umol, 0.1 eq), dioxane (0.8 mL), and water (0.2 mL) under a nitrogen atmosphere at 20-25°C. The mixture was stirred at 80-85°C for 3 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA=1 / 1). Water (10 mL) was added to the mixture, the pH was adjusted to 3 with 1 M HCl, and then extracted with SiO (10 mL x 3). The organic layer was dried over Na2SO4, and a concentrated organic phase residue was obtained under reduced pressure at 40-45°C. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1-1 / 1) to obtain compound 12 (23.0 mg, 179 umol, yield: 22.08%) as a red solid.

[0235] 1H NMR (400 MHz, DMSO-d6): δ9.38(s, 1H), 7.59(d, J = 5.2 Hz, 1H), 7.40(d, J = 3.6 Hz, 1H), 7.31 - 7.25(m, 2H), 7.25~7.17(m, 3H), 7.12~7.05(m, 2H), 6.97~6.91(m, 1H), 6.85(d, J=8.0Hz, 1H), 4.02(brt, J=6.4Hz) 2H), 2.74(brt, J=7.6Hz, 2H), 2.18(s, 3H), 2.06~1.97(m, 2H)

[0236] MS measured value: 444.1 ([M+H] + )

[0237] Embodiment 7 3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-6-(3-(pyridin-4-yl)propoxy)-1H-inden-1-one (Compound 13)

[0238] Step 1: Synthesis of 2-bromo-3-(4-methylthiazol-5-yl)-6-(3-(pyridin-4-yl)propoxy-inden-1-one)(13-1)

[0239] Compounds 1-7 (300 mg, 745 ml, 1.00 eq) synthesized in Embodiment 1 and 4-(3-bromopropyl)pyridine (557 mg, 2.24 mmol, 3.00 eq) were mixed in DMF (3.00 mL) using RX in [Reaction Formula 1]. Then, K2CO3 (190 mg, 1.35 mmol, 1.80 eq) and NaI (13.0 mg, 85.8 ml, 0.10 eq) were added under a nitrogen atmosphere at 20-25°C. The mixture was stirred at 40-45°C for 18 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA = 1 / 1). Water (10.0 mL) was added to the mixture, the pH was adjusted to 3 with 1 M HCl, and then extracted with SiO (10.0 mL x 3). The residue was purified under HCl conditions by reversed-phase HPLC to obtain compound 13-1 (47.0 mg, 97.9 umol, yield: 13.1%), which was a red solid.

[0240] Step 2: Synthesis of 3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-6-(3-(pyridin-4-yl)propoxy)-1H-inden-1-one (Compound 13)

[0241] Compound 13-1 (45.0 mg, 93.8 umol, 1.00 eq) and pyridine-3-ylboronic acid (18.0 mg, 145 umol, 1.45 eq) were mixed with R1-B(OH)2 in [Reaction Formula 1]. This mixture was then added to K2CO3 (40.0 mg, 283 umol, 3.00 eq), Pd(t-Bu3P)2 (6.00 mg, 11.1 umol, 0.10 eq), dioxane (0.80 mL), and water (0.20 mL) under a nitrogen atmosphere at 20-25°C. The mixture was stirred at 80-85°C for 12 hours. LC-MS confirmed that the reactants were completely consumed. Water (10 mL) was added to the mixture, the pH was adjusted to 7 with 1 M HCl, and then extracted with ELISA (10 mL x 3). The organic layer was dried over Na2SO4, and a concentrated residue was obtained under reduced pressure at 40-45°C. The residue was purified by prep-HPLC to obtain compound 13 (36.0 mg, 79.4 umol, yield: 84.7%) as a red solid.

[0242] 1H NMR (400 MHz, DMSO-d6): δ9.31 (s, 1H), 8.44~8.50 (m, 3H), 8.35 (d, J = 1.2 Hz, 1H), 7.61 (m, 1H), 7.40 (m, 1H), 7.28 (d, J = 5.6 Hz, 2H), 7.11 - 7.18 (m, 2H), 7.02 (m, 1H), 4.07 (t, J = 6.4 Hz, 2H), 2.77 (br t, J = 7.6 Hz, 2H), 2.02 - 2.11(m, 2H), 1.96 (s, 3H)

[0243] MS measured value: 440.0 ([M+H] + )

[0244] Embodiment 8 3-(4-Methylthiazol-5-yl)-6-phenethoxy-2-(pyridin-3-yl)-1H-inden-1-one (3-(4-methylthiazol-5-yl)-6-phenethoxy-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 14)

[0245] Step 1: Synthesis of 2-bromo-3-(4-methylthiazol-5-yl)-6-phenethoxy-1H-inden-1-one (14-1)

[0246] The compound 1-7 (3.00 g, 9.31 mmol, 1.00 eq) synthesized in Embodiment 1 and (2-bromoethyl)benzene ((2-bromoethyl)benzene, 2.58 g, 13.97 mmol, 1.5 eq) as RX in [Reaction Formula 1] were mixed in DMF (30 mL), and then K2CO3 (2.32 g, 16.76 mmol, 1.5 eq) and NaI (139 mg, 931.17 μmol, 0.2 eq) were added under a nitrogen atmosphere at 20 - 25°C. The mixture was stirred at 20 - 25°C for 12 hours. It was confirmed by TLC (PE:EA = 1 / 1) that the reactants were completely consumed. Water (20 mL) was added to the mixture, adjusted to pH 3 with 1M HCl, and then extracted with EtOAc (5 mL). The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1 - 1 / 1) to obtain the red solid compound 14-1 (2.3 mg, 508 μmol, yield: 32.76%).

[0247] Step 2: Synthesis of 3-(4-Methylthiazol-5-yl)-6-phenethoxy-2-(pyridin-3-yl)-1H-inden-1-one (3-(4-methylthiazol-5-yl)-6-phenethoxy-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 14)

[0248] Compound 14-1 (500 mg, 220 umol, 1 eq) and pyridine-3-ylboronic acid (209 mg, 1.70 mmol, 1.5 eq) were mixed with R1-B(OH)2 in [Reaction Formula 1]. This mixture was then added to K2CO3 (470 mg, 681 umol, 3.0 eq), Pd(t-Bu3P)2 (57.9 mg, 113 umol, 0.1 eq), dioxane (8 mL), and water (2 mL) under a nitrogen atmosphere at 20-25°C. The mixture was stirred at 80-85°C for 3 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA=1 / 1). Water (10 mL) was added to the mixture, the pH was adjusted to 3 with 1 M HCl, and then extracted with SiO2CO3 (10 mL x 3). The organic layer was dried over Na2SO4, and a concentrated residue was obtained under reduced pressure at 40-45°C. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1-1 / 1) to obtain compound 14 (300 mg, 692 umol, yield: 61.07%) as a red solid.

[0249] 1H NMR (400 MHz, DMSO-d6): δ9.36(s, 1H), 8.53(dd, J = 1.2, 4.8 Hz, 1H), 8.40(d, J = 1.6 Hz, 1H), 7.65(m, 1H), 7.44(dd, J=4.8, 7.8Hz, 1H), 7.41~7.34(m, 4H), 7.31~7.26(m, 1H), 7.21(d, J=2.4Hz, 1H), 7.17(d, J = 8.0 Hz, 1H), 7.10 - 7.05 (m, 1H), 4.34 (t, J = 6.8 Hz, 2H), 3.10 (t, J = 6.8 Hz, 2H), 2.00 (s, 3H)

[0250] MS measured value: 425 [M+H] +

[0251] Embodiment 9 3-(4-methylthiazol-5-yl)-6-(4-phenylbutoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 15)

[0252] Step 1: Synthesis of 2-bromo-3-(4-methylthiazol-5-yl)-6-(4-phenylbutoxy)-1H-inden-1-one)(15-1)

[0253] Compounds 1-7 (500 mg, 1.55 mmol, 1 eq) synthesized in Embodiment 1 and (4-bromobutyl)benzene (396 mg, 1.86 mmol, 1.2 eq) in the reaction formula 1 were mixed in DMF (5 mL). Then, K2CO3 (321 mg, 2.33 mmol, 1.5 eq) and NaI (46.0 mg, 310 µm, 0.2 eq) were added under a nitrogen atmosphere at 20-25°C. The mixture was stirred at 20-25°C for 12 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA = 1 / 1). Water (20 mL) was added to the mixture, the pH was adjusted to 3 with 1 M HCl, and then extracted with SiO (5 mL). The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 1 / 1) to obtain compound 15-1 (231 mg, 508 umol, yield: 32.7%), which was a red solid.

[0254] Step 2: Synthesis of 3-(4-methylthiazol-5-yl)-6-(4-phenylbutoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 15)

[0255] Compound 15-1 (100 mg, 220 umol, 1 eq) and pyridine-3-ylboronic acid (40.0 mg, 325 umol, 1.48 eq) were mixed with R1-B(OH)2 in [Reaction Formula 1]. This mixture was then added to K2CO3 (91.0 mg, 658 umol, 2.99 eq), Pd(t-Bu3P)2 (11.00 mg, 21 umol, 0.10 eq), dioxane (0.8 mL), and water (0.2 mL) under a nitrogen atmosphere at 20-25°C. The mixture was stirred at 80-85°C for 3 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA=1 / 1). Water (10 mL) was added to the mixture, the pH was adjusted to 3 with 1 M HCl, and then extracted with ELISA (10 mL x 3). The organic layer was dried over Na2SO4, and a concentrated residue was obtained under reduced pressure at 40-45°C. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1-1 / 1) to obtain compound 15 (14.9 mg, 26 umol, yield: 12.1%) as a red solid.

[0256] 1H NMR (400 MHz, DMSO-d6): δ9.30(s, 1H), 8.52~8.39(m, 2H), 7.61~7.59(d, J = 8.0 Hz, 1H), 7.30(s, 1H), 7.28 - 7.11(m, 7H), 7.02(s, 1H), 4.09 - 4.07(t, J = 10.8, 2H), 2.66 - 2.62(t, J = 14, 2H), 1.95(s, 3H), 1.74 ~1.73(d, J=3.6, 4H)

[0257] MS measured value: 453.3 [M+H] +

[0258] Embodiment 10 6-((benzyloxy)methoxy)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (compound 16)

[0259] Step 1: Synthesis of 6-((benzyloxy)methoxy)-2-bromo-3-(4-methylthiazol-5-yl)-inden-1-one (16-1)

[0260] Compounds 1-7 (1.00 g, 3.10 mmol, 1.00 eq) synthesized in the above embodiment and ((chloromethoxy)methyl)benzene (((chloromethoxy)methyl)benzene (((chloromethoxy)methyl)benzene (((chloromethoxy)methyl)) (614 mg, 3.72 mmol, 1.20 eq)) were mixed in DMF (10.0 mL) with RX in [Reaction Formula 1]. Then, K2CO3 (657 mg, 4.66 mmol, 1.50 eq) and NaI (94 mg, 620 µm, 0.20 eq) were added under a nitrogen atmosphere at 20-25°C. The mixture was stirred at 40-45°C for 18 hours. LCMS confirmed that the reactants were completely consumed. Water (20 mL) was added to the mixture, and the pH was adjusted to 3 with 1 M HCl, after which it was extracted with SiO (30.0 mL × 3). The residue was purified by column chromatography (SiO2, PE / EA = 20 / 1 to 5 / 1) to obtain compound 16-1 (270 mg, 568 umol, yield: 18.3%), which was a red solid.

[0261] Step 2: Synthesis of 6-((benzyloxy)methoxy)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 16)

[0262] Compound 16-1 (250 mg, 525 umol, 1.00 eq) and pyridine-3-ylboronic acid (98.0 mg, 789 umol, 1.50 eq) were mixed with R1-B(OH)2 in [Reaction Formula 1]. This mixture was then added to K2CO3 (224 mg, 4.59 mmol, 3.02 eq), Pd(t-Bu3P)2 (29.0 mg, 53.9 umol, 0.10 eq), dioxane (2.00 mL), and water (0.50 mL) under a nitrogen atmosphere at 20-25°C. The mixture was stirred at 80-85°C for 12 hours. LC-MS confirmed that the reactants were completely consumed. Water (10 mL) was added to the mixture, the pH was adjusted to 3 with 1 M HCl, and then extracted with Â(10 mL × 3). The organic layer was dried over Na2SO4, and a concentrated residue was obtained under reduced pressure at 40-45°C. The residue was purified by column chromatography (SiO2, PE / EA = 20 / 1-1 / 1) to obtain compound 16 (67.4 mg, 26 umol, yield: 12.1%) as a red solid.

[0263] 1H NMR (400 MHz, DMSO-d6): δ8.86 (s, 1H), 8.37~8.50 (m, 2H), 7.55~7.64 (m, 1H), 7.30 (br d, J = 1.2 Hz, 3H), 7.18~7.27(m, 4H), 6.96~7.05(m, 2H), 5.26(s, 2H), 4.66(s, 2H), 2.03(s, 3H)

[0264] MS measured value: 441.0 [M+H] +

[0265] Embodiment 11 3-(4-methylthiazol-5-yl)-6-(2-phenoxyethoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 17)

[0266] Step 1: Synthesis of 2-bromo-3-(4-methylthiazol-5-yl)-6-(2-phenoxyethoxy)-1H-inden-1-one (17-1)

[0267] Compound 1-7 (500 mg, 1.55 mmol, 1 eq) synthesized in Embodiment 1 above and (2-bromoethoxy)benzene (374 mg, 1.86 mmol, 1.2 eq) as RX in [Reaction Scheme 1] were mixed in DMF (5 mL). Then, K2CO3 (321 mg, 2.33 mmol, 1.5 eq) and NaI (46.0 mg, 310 μmol, 0.2 eq) were added under a nitrogen atmosphere at 20 - 25°C. The mixture was stirred at 20 - 25°C for 12 hours. LCMS confirmed that the reactants were completely consumed. Water (20 mL) was added to the mixture, and after adjusting the pH to 3 with 1M HCl, it was extracted with EtOAc (5 mL). The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1 - 1 / 1) to obtain red solid Compound 16-1 (179 mg, 404 μmol, yield: 26.1%).

[0268] Step 2: Synthesis of 3-(4-methylthiazol-5-yl)-6-(2-phenoxyethoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 17)

[0269] Compound 17-1 (100 mg, 220 umol, 1 eq) and pyridine-3-ylboronic acid (40.0 mg, 325 umol, 1.48 eq) were mixed with R1-B(OH)2 in [Reaction Formula 1]. This mixture was then added to K2CO3 (91.0 mg, 658 umol, 2.99 eq), Pd(t-Bu3P)2 (11.00 mg, 21 umol, 9.78 e-2 eq), dioxane (0.8 mL), and water (0.2 mL) under a nitrogen atmosphere at 20-25°C. The mixture was stirred at 80-85°C for 3 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA=1 / 1). Water (10 mL) was added to the mixture, the pH was adjusted to 3 with 1 M HCl, and then extracted with SiO2CO3 (10 mL x 3). The organic layer was dried over Na2SO4, and a concentrated residue was obtained under reduced pressure at 40-45°C. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1-1 / 1) to obtain compound 17 (22.86 mg, 37 umol, yield: 16.44%) as a red solid.

[0270] 1H NMR (400 MHz, DMSO-d6): δ9.31(s, 1H), 8.49 - 8.49 (d, J = 1.2 Hz, 1H), 8.48 - 8.47 (d, J = 1.2 Hz, 1H), 8.36-8.35 (d, J = 1.6 Hz, 1H), 7.62 - 7.60 (d, J = 8Hz, 1H), 7.39 - 6.95 (m, 9H), 4.44 - 4.42 (m, 2H), 4.34 - 4.32 (m, 2H), 1.96(s, 1H)

[0271] MS measured value: 441.3 [M+H] +

[0272] Embodiment 12 3-(furan-3-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 9)

[0273] [Reaction Equation 2]

[0274] [ka]

[0275] Step 1: Synthesis of 3-bromo-6-methoxy-1H-inden-1-one (9-2)

[0276] Compound 9-1 (50.0 g, 308 mmol, 1.00 eq) from [Reaction Scheme 2], NBS (109 g, 616 mmol, 2.00 eq), and AIBN (1.02 g, 6.20 mmol, 2.01 eq) were mixed in CCl4 (1.00 L) and added under a nitrogen atmosphere at 25°C. The mixture was stirred at 85°C for 2 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA = 1:1). TsiRNA (93.5 g, 924 mmol, 128 mL, 3.00 eq) was added to the mixture and stirred at 25°C for 12 hours. Synthesis of the desired compound was confirmed by LC-MS. The mixture was cooled with water (1000 mL) and extracted with DCM (800 mL x 2). The organic layer was washed with NaCl (500 mL x 3) and then dried over Na2SO4. After filtration, the mixture was concentrated under reduced pressure, and the residue yielded compound 9-2 (70.0 g, 201 mmol, yield: 65.4%, purity: 68.9%), a red solid.

[0277] Step 2: Synthesis of 2,3-dibromo-6-methoxy-1H-inden-1-one (9-3)

[0278] Compound 9-2 (65.0 g, 271.8 mmol, 1.00 eq) was dissolved in HOAc (850 mL), and the mixture was stirred at 22-25°C. Br2 (130 g, 815 mmol, 42.0 mL, 3.00 eq) was added dropwise, and the mixture was stirred at 22-25°C for 12 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA = 3:1). The mixture was extracted with 10% NaS2O3 aqueous solution (1000 mL), and the aqueous phase was extracted with MTBE (500 mL x 2). The organic phase was washed with NaHCO3 (1000 mL x 2), then with brine (500 mL x 2), and dried over anhydrous Na2SO4. The residue was obtained by concentration under vacuum. The residue was purified by column chromatography (SiO2, PE / EA=3:1, P1=0.49) to obtain compound 9-3 (15.0 g, 39.8 nmol, yield: 14.6%, purity: 84.5%) as a red solid.

[0279] Step 3: Synthesis of 2-bromo-3-(furan-3-yl)-6-methoxy-1H-inden-1-one (9-4)

[0280] Dioxane (120 mL) and H2O (30.0 mL) were mixed with compound 9-3 (11.9 g, 37.4 mmol, 1.00 eq) and 2A (5.03 g, 44.9 mmol, 1.20 eq) from [Reaction Scheme 2] above. Then, K2CO3 (15.5 g, 112 mmol, 3.00 eq) and Pd(PPh3)4 (4.32 g, 3.74 mmol, 0.10 eq) were added under a nitrogen atmosphere at 25°C. The mixture was stirred under a nitrogen atmosphere at 40°C for 12 hours. ACN (1 mL) was added dropwise, and the reaction was confirmed to be completely consumed by LC-MS, and the reaction was cooled to 22-25°C. Water (200 mL) was added to the mixture and extracted with SiO (100 mL x 2). The organic layer was washed with NaCl (100 mL x 2) and then dried with Na2SO4. The mixture was filtered and concentrated under vacuum to obtain the residue. After filtration, the residue was concentrated under reduced pressure, and the residue yielded the red solid compound 9-4 (5.20 g, 4.67 mmol, yield: 12.4%, purity: 27.4%).

[0281] Step 4: Synthesis of 3-(furan-3-yl)-6-methoxy-2-(pyridin-3-yl)-1H-inden-1-one (9-5)

[0282] Dioxane (120 mL) and H2O (30.0 mL) were mixed with compound 9-4 (5.00 g, 16.3 mmol, 1.00 eq) and pyridine-3-ylboronic acid (2.42 g, 19.7 mmol, 1.20 eq) in the above [Reaction Scheme 2] via R1-B(OH)2. Then, K2CO3 (6.78 g, 49.0 mmol, 2.99 eq) and Pd(t-Bu3P)2 (875 mg, 1.71 mq, 1.04 eq) were added under a nitrogen atmosphere. The mixture was stirred at 85°C for 12 hours. After cooling the reaction to 22-25°C, ACN (1 mL) was added dropwise, and the complete consumption of the reaction was confirmed by LC-MS. Water (30.0 mL) was added to the mixture and extracted with siRNA (30.0 mL × 2). The organic layer was washed with NaCl (20.0 mL × 2) and then dried over Na2SO4. The mixture was filtered and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, PE:EA=3:1, P1=0.20) to obtain the red solid compound 9-5 (2.50 g, 5.17 mmol, yield: 31.5%, purity: 62.7%).

[0283] Step 5: Synthesis of 3-(furan-3-yl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one (9-6)

[0284] Compound 9-5 (3.00 g, 9.89 mmol, 1.00 eq) was mixed with DCM (90.0 mL) under a nitrogen atmosphere at 22-25°C, and then BBr3 (7.44 g, 29.7 mmol, 2.86 mL, 3.00 eq) was mixed under a nitrogen atmosphere at -78°C. The mixture was stirred at -78°C for 2 hours, and then stirred under a nitrogen atmosphere at 22-25°C for 6 hours. The reaction was confirmed to be completely consumed by LC-MS while adding ACN (1 mL) dropwise. Water (100 mL) was added to the mixture at 0°C and stirred for 10 minutes. The mixture was adjusted to pH 7 with 5% NaHCO3 / H2O, and then extracted with siRNA (50.0 mL x 3). The organic layer was washed with brine (100 mL), dried over Na2SO4, and the mixture was filtered and concentrated. THF (20.0 mL) and PE (80.0 mL) were added to this mixture, and the mixture was stirred at 25°C for 30 minutes. After filtration, the mixture was washed with PE (50.0 mL) and dried in vacuum to obtain a pale red solid compound. The solution was removed from this to obtain compound 9-6 (3.30 g, 7.41 mmol, yield: 74.9%, purity: 65.0%) as a red solid.

[0285] Step 6: Synthesis of 3-(furan-3-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (compound 9)

[0286] Compound 9-6 (50.0 mg, 172.84 umol, 1 eq) and (3-bromopropyl)benzene (1 eq) in the above [Reaction Formula 2] were mixed in DMF (1 mL), and then K2CO3 (35.8 mg, 259.26 umol, 1.5 eq) and NaI (5.18 mg, 34.57 umol, 0.2 eq) were added at 25°C. The mixture was stirred at 45°C for 12 hours. LCMS confirmed that the reactants were completely consumed. The mixture was diluted with water (5 mL) and extracted with SiO (5 mL x 3). The organic layer was washed with brine (5 mL x 2), dried over Na2SO4, and the mixture was filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC to obtain compound 9 (12.18 mg, 28.93 umol, yield: 16.74%, purity: 96.78%) as an orange solid.

[0287] 1H NMR(400 MHz, DMSO-d6): δ8.56 (dd, J=1.6, 4.8Hz, 1H), 8.50-8.41 (m, 2H), 7.83 (t, J=1.6Hz, 1H), 7.72 (td, J=2.0, 8.0Hz, 1H), 7.55-7.44 (m, 2H) , 7.36~7.13(m, 6H), 7.04(dd, J=2.4, 8.0Hz, 1H), 6.23(d, J=1.2Hz, 1H), 4.09(t, J=6.4Hz, 2H), 2.78(t, J=8.0Hz, 2H), 2.14~2.02(m, 2H)

[0288] MS measured value: 408.2 [M+H] +

[0289] Embodiment 13 3-(furan-3-yl)-6-phenethoxy-2-(pyridin-3-yl)-1H-inden-1-one (compound 38)

[0290] Compound 9-6 (50.0 mg, 172 umol, 1 eq) synthesized in Embodiment 12 and (2-bromoethoxy)benzene (31.9 mg, 172 umol, 23.38 uL, 1 eq) in [Reaction Scheme 2] were mixed in DMF (1 mL), and then K2CO3 (35.8 mg, 259 umol, 1.5 eq) and NaI (5.18 mg, 34.5 umol, 0.2 eq) were added at 25°C. The mixture was stirred at 50°C for 14 hours. DCM (1.00 mL) was added dropwise, and the reaction products were confirmed to be completely consumed by TLC (PE:EA = 1 / 1). The mixture was diluted with water (5 mL) and extracted with SiO (5 mL × 3). The organic layer was washed with brine (5 mL × 2), dried over Na2SO4, and the mixture was filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC to obtain compound 38 (12 mg, 30.50 umol, yield: 17.65%) as a red solid.

[0291] 1H NMR (400MHz, DMSO-d6): δ8.54(d, J=4.8Hz, 1H), 8.45(s, 2H), 7.81(s, 1H), 7.70(br d, J=8.0Hz, 1H), 7.52-7.40(m, 2H), 7.37-7.30(m, 4H), 7.28-7.20(m, 1H), 7.13(d, J=2.0Hz , 1H), 7.04(dd, J=2.0, 8.0Hz, 1H), 6.20(s, 1H), 4.31(t, J=6.8Hz, 2H), 3.06(t, J=6.8Hz, 2H)

[0292] MS measured value: 394.1 [M+H] +

[0293] Embodiment 14 3-(furan-3-yl)-6-(4-phenylbutoxy)-2-(pyridin-3-yl)-1H-inden-1-one (compound 39)

[0294] Compound 9-6 (54.3 mg, 187.69 umol, 1 eq) synthesized in Embodiment 12 was mixed with (4-bromobutyl)benzene ((4-bromoethoxy)benzene, 40.0 mg, 187.69 umol, 1 eq) in RX as in [Reaction Scheme 2]. Then, K2CO3 (38.9 mg, 281 umol, 1.5 eq) and NaI (5.63 mg, 37.5 umol, 0.2 eq) were added at 25°C. The mixture was stirred at 50°C for 14 hours. The synthesis of the desired compound was confirmed by LC-MS. The mixture was diluted with water (5 mL) and extracted with SiO (5 mL x 3). The organic layer was washed with brine (5 mL x 2), dried over Na2SO4, and the mixture was filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC to obtain compound 39 (15 mg, 34.95 umol, yield: 18.62%, purity: 98.2%) as a red solid.

[0295] 1H NMR (400MHz, DMSO-d6): δ8.55(dd, J=1.6, 4.8 Hz, 1H), 8.46(s, 2H), 7.83-7.80(m, 1H), 7.71(td, J=2.0, 8.0Hz, 1H), 7.49(d, J=8.0Hz, 1H), 7.45(m, 1H), 7.32~7.26(m, 2H), 7.26~ 7.16(m, 3H), 7.13(d, J=2.4Hz, 1H), 7.02(dd, J=2.4, 8.0Hz, 1H), 6.20(d, J=1.6Hz, 1H), 4.13~4.06(m, 2H), 2.73~2.61(m, 2H), 1.75 (br d, J=3.6Hz, 4H)

[0296] MS measured value: 422.2 [M+H] +

[0297] Embodiment 15 6-((benzyloxy)methoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one (compound 40)

[0298] After mixing compound 9-6 (80.0 mg, 276.54 umol, 1 eq) synthesized in Embodiment 12 with NaH (13.3 mg, 331 umol, purity: 60%, 1.2 eq) in DMF (1 mL), ((chloromethoxy)methyl)benzene (((chloromethoxy)methyl)benzene, 86.6 mg, 553 umol, 76.4 uL, 2 eq) in RX as in [Reaction Scheme 2] was added dropwise to DMF (0.1 mL) and mixed, and the mixture was stirred at 25°C for 1 hour. The synthesis of the desired compound was confirmed by LC-MS. The mixture was cooled with NH4Cl (5 mL), diluted with water (5 mL), and extracted with SiO (5 mL × 3). The organic layer was washed with brine (5 mL × 2), dried with Na2SO4, and the mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (SiO2, PE:EA = 1:2) to obtain compound 40 (9.72 mg, 20.58 umol, yield: 7.44%, purity: 86.7%) as a red, gum-like substance.

[0299] 1H NMR (400MHz, CHLOROFORM-d): δ8.55-8.43(m, 2H), 7.79(s, 1H), 7.65(br d, J=8.0Hz, 1H), 7.41(s, 1H), 7.28(br s, 3H), 7.25-7.13(m, 5H), 7.02(dd, J=2.4, 8.0Hz, 1H), 6.19(s, 1H), 5.26 (s, 2H), 4.72~4.61(s, 2H)

[0300] MS measured value: 410.1 [M+H] +

[0301] Embodiment 16 3-(furan-3-yl)-6-(2-phenoxyethoxy)-2-(pyridin-3-yl)-1H-inden-1-one (compound 41)

[0302] Compound 9-6 (54.7 mg, 189 umol, 1 eq) synthesized in Embodiment 12 was mixed with (2-bromoethoxy)benzene (38.0 mg, 189 umol, 1 eq) in RX as described in [Reaction Scheme 2]. Then, K2CO3 (39.2 mg, 283 umol, 1.5 eq) and NaI (5.67 mg, 37.8 umol, 0.2 eq) were added at 25°C. The mixture was stirred at 45°C for 12 hours. The synthesis of the desired compound was confirmed by LC-MS. The mixture was diluted with water (5 mL) and extracted with SiO (5 mL x 3). The organic layer was washed with brine (5 mL x 2), dried over Na2SO4, and the mixture was filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC to obtain compound 41 (20 mg, 48.26 umol, yield: 25.54%, purity: 98.8%) as a red solid.

[0303] 1H NMR (400MHz, METHANOL-d): δ8.53-8.47(m, 2H), 8.18(s, 1H), 7.85(td, J=2.0, 8.0Hz, 1H), 7.66(t, J=1.6Hz, 1H), 7.51-7.41(m, 2H), 7.3 1(t, J=7.2Hz, 2H), 7.24(d, J=2.4Hz, 1H), 7.08(dd, J=2.4, 8.0Hz, 1H), 7.03~6.94(m, 3H), 6.30(dd, J=0.8, 2.0Hz, 1H), 4.49~4.31(m, 4H)

[0304] MS measured value: 410.1 [M+H] +

[0305] Embodiment 17 3-(furan-3-yl)-6-(2-(4-methoxyphenoxy)ethoxy)-2-(pyridin-3-yl)-1H-inden-1-one (compound 42)

[0306] Compound 9-6 (50.0 mg, 172 umol, 1 eq) synthesized in Embodiment 12 and 1-(2-bromoethoxy)-4-methoxybenzene (40.7 mg, 176 umol, 1.02 eq) from Reaction Scheme 2 were mixed in DMF (3.00 mL) with RX. Then, K2CO3 (36.0 mg, 260 umol, 1.51 eq) and NaI (5.00 mg, 33.3 umol, 1.93 eq) were added at 25°C. The mixture was stirred at 45-50°C for 12 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA = 3:1). The mixture was cooled with water (10.0 mL). Extraction was performed with ethyl acetate (10.0 mL x 2). The organic layer was washed with NaCl (10.0 mL x 2), dried over Na2SO4, and the mixture was filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC to obtain compound 42 (11.0 mg, 24.6 umol, yield: 14.2%, purity: 98.4%).

[0307] 1H NMR (400MHz, DMSO-d6): δppm 3.70(s, 3H), 4.24-4.32(m, 2H), 4.38-4.44(m, 2H), 6.20(d, J =1.2Hz, 1H), 6.84-6.89 (m, 2H), 6.90-6.96 (m, 2 H), 7.06-7.11 (m, 1 H), 7.17-7.22 (m, 1 H), 7.45 (dd, J=8.0, 4.8Hz, 1H), 7.51 (d, J=8.0Hz, 1H), 7.67-7.74 (m, 1H), 7.77-7.86 (m, 1H), 8.44-8.50(m, 2H), 8.54(dd, J=4.8, 1.2Hz, 1H).

[0308] MS measured value: 440.1 (M+1)

[0309] Embodiment 18 6-(2-(3,4-dimethoxyphenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one (compound 43)

[0310] Compound 9-6 (20.0 mg, 69.1 umol, 1.00 eq) synthesized in Embodiment 12 was mixed with 4-(2-bromoethoxy)-1,2-dimethoxybenzene (18.4 mg, 70.5 umol, 1.02 eq) in RX as described in [Reaction Scheme 2]. Then, K2CO3 (14.4 mg, 104 umol, 1.51 eq) and NaI (20.0 mg, 133 umol, 1.93 eq) were added at 25°C. The mixture was stirred at 40°C for 12 hours. The reaction products were completely consumed by TLC (PE:EA=1:0) while adding HCl (1 mL) dropwise. The mixture was cooled to 22-25°C. It was diluted with water (30.0 mL) and extracted with HCl (10.0 mL × 3). The organic layer was washed with brine (15.0 mL), dried over Na2SO4, and the mixture was filtered and concentrated under reduced pressure. Compound 43 (12.1 mg, 25.33 umol, yield: 36.64%, purity: 98.3%) was obtained as a red solid.

[0311] 1H NMR (400MHz, DMSO-d6): δppm 8.54 (s, 1H), 8.46 (s, 2H) 7.81 (s, 1H), 7.71 (s, 1H), 7.48 (d, J =21.6Hz, 2H), 7.19 (s, 1H), 7.11 (s, 1H), 6.86 (d, J=4.8Hz, 1H), 6.62 (s, 1H), 6.50 (s, 1H), 6.20 (s, 1H), 4.21~4.48 (d, J=52Hz, 4H) 3.71 (d, J=19.2Hz, 6H).

[0312] MS measured value: 470.2 [M+H] +

[0313] Embodiment 19 6-(2-(benzo[d][1,3]dioxol-5-yloxy)ethoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one)(Compound 44)

[0314] Compound 9-6 (50.0 mg, 172 umol, 1.00 eq) synthesized in Embodiment 12 and 5-(2-bromoethoxy)benzo[d][1,3]dioxole (40.7 mg, 176 umol, 1.02 eq) in RX as described in [Reaction Scheme 2] were mixed in DMF (3.0 mL). Then, K2CO3 (36.0 mg, 260 umol, 1.51 eq) and NaI (5.00 mg, 33.3 umol, 1.93 eq) were added at 25°C. The mixture was stirred at 45-50°C for 12 hours. The synthesis of the desired compound was confirmed by LC-MS. The mixture was cooled with water (10.0 mL). Extraction was performed with RINKAN (10.0 mL x 2). The organic layer was washed with NaCl (10.0 mL x 2), dried over Na2SO4, and the mixture was filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC to obtain compound 44 (15.9 mg, 31.4 umol, yield: 18.1%, purity: 89.6%) as a red solid.

[0315] 1H NMR (400MHz, DMSO-d6): δppm 8.54 (dd, J=4.8, 1.6Hz, 1H), 8.45-8.49 (m, 2H), 7.82 (t, J=2.0 Hz, 1H), 7.71 (dt, J=8.0, 2.0Hz, 1H), 7.51 (d, J =8.4Hz, 1H), 7.42-7.47(m, 1H), 7.19(d, J=2.4 Hz, 1H), 7.09(dd, J=8.4, 2.4Hz, 1H), 6.82(d, J =8.0Hz, 1H), 6.69(d, J =2.4Hz, 1H), 6.43(dd, J =8.4, 2.8Hz, 1H), 6.20(dd, J=2.0, 0.8Hz, 1H), 5.96(s, 2H), 4.38~4.40(m, 2H), 4.21~4.30(m, 2H).

[0316] MS measured value: 454 (M+1)

[0317] Embodiment 20 3-(furan-3-yl)-2-(pyridin-3-yl)-6-(2-(pyridin-4-yloxy)ethoxy)-1H-inden-1-one (compound 45)

[0318] Compound 9-6 (50.0 mg, 172 umol, 1.00 eq) synthesized in Example 12 and 4-(2-bromoethoxy)pyridine (35.6 mg, 176 umol, 1.02 eq) were mixed in DMF (3.00 mL) using RX in [Reaction Scheme 2]. Then, K2CO3 (60.0 mg, 434 umol, 2.51 eq) and NaI (5.18 mg, 34.5 umol, 0.20 eq) were added at 25°C. The mixture was stirred at 40°C for 12 hours. The reaction products were completely consumed by TLC (PE:EA=1:0) while adding HCl (1 mL) dropwise. The mixture was cooled to 22-25°C. It was diluted with water (30.0 mL) and extracted with HCl (10.0 mL x 3). The organic layer was washed with brine (15.0 mL), dried over Na2SO4, and the mixture was filtered and concentrated under reduced pressure. Compound 45 (8 mg, 18.7 umol, yield: 10.8%, purity: 96.2%) was obtained as a red solid.

[0319] 1H NMR (400 MHz, CHLOROFORM-d): δppm 8.58 (s, 2 H), 8.50 (s, 1 H), 7.88 (s, 1 H), 7.74 (d, J=8.4 Hz, 1 H), 7.50 (s, 1 H), 7.31~7.34 (m, 1 H), 7.30(s, 1H), 6.89~6.98(m, 3H), 6.27(s, 1H), 4.43(s, 4H).

[0320] MS measured value: 411.2 [M+H] +

[0321] Embodiment 21 6-(2-(3,4-dichlorophenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one (compound 46)

[0322] Compound 9-6 (50.0 mg, 173 umol, 1.00 eq) synthesized in Embodiment 12 was mixed with 4-(2-bromoethoxy)-1,2-dichlorobenzene (46.0 mg, 194 umol, 1.12 eq) in RX as described in [Reaction Scheme 2]. Then, K2CO3 (36.0 mg, 260 umol, 1.51 eq) and NaI (5.00 mg, 33.4 umol, 0.20 eq) were added at 25°C. The mixture was stirred at 40°C for 12 hours. The synthesis of the desired compound was confirmed by LC-MS while MeOH (1.00 mL) was added dropwise. The mixture was cooled to 25°C. It was diluted with water (30.0 mL) and extracted with ethyl acetate (10.0 mL x 3). The organic layer was washed with brine (15.0 mL), dried over Na2SO4, and the mixture was filtered and concentrated under vacuum. The residue was purified by reversed-phase HPLC to obtain compound 46 (34.0 mg, purity: 90.1%) as a red solid.

[0323] 1H NMR (400 MHz, DMSO-d6): δ ppm 8.54 (dd, J =4.8, 1.6 Hz, 1 H), 8.48 (s, 1 H), 8.46 (d, J =2.0 Hz, 1 H), 7.82 (t, J=2.0 Hz, 1 H), 7.71 (dt, J=8.0, 2.0 Hz, 1 H), 7.53(dd, J=11.6, 9.2 Hz, 2 H), 7.45(dd, J=7.6, 4.8 Hz, 1 H), 7.33(d, J=3.2 Hz, 1 H), 7.19(d, J=2.4 Hz, 1 H), 7.08(dd, J=8.4, 2.4 Hz, 1 H), 7.04(dd, J=9.2, 3.2 Hz, 1 H), 6.20(d, J=1.2 Hz, 1 H), 4.41(dd, J= 16.0, 1.2 Hz, 4 H).

[0324] MS measured value: 478.1 (M)

[0325] Embodiment 22 6-(2-(3,4-difluorophenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one (compound 47)

[0326] Compound 9-6 (50.0 mg, 172 umol, 1.00 eq) synthesized in Embodiment 12 was mixed with 4-(2-bromoethoxy)-1,2-difluorobenzene (46.0 mg, 194 umol, 1.12 eq) in RX as described in [Reaction Scheme 2]. Then, K2CO3 (36.0 mg, 260 umol, 1.51 eq) and NaI (5.00 mg, 33.3 umol, 0.20 eq) were added at 25°C. The mixture was stirred at 40°C for 12 hours. The synthesis of the desired compound was confirmed by LC-MS while MeOH (1.00 mL) was added dropwise. The mixture was cooled to 25°C. It was diluted with water (50.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The organic layer was washed with brine (15.0 mL), dried over Na2SO4, and the mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography (P1=0.30) to obtain compound 47 (21.0 mg, purity: 98.5%) as a red solid.

[0327] 1H NMR (400 MHz, METHANOL-d): δ ppm 8.54 (d, J=4.4 Hz, 1 H), 8.46 (s, 2 H), 7.81 (s, 1 H), 7.71 (d, J=8.0 Hz), 1 H), 7.51(d, J = 8.0 Hz, 1 H), 7.44 (dd, J = 8.0, 5.2 Hz, 1 H), 7.36 (q, J = 9.6 Hz, 1 H), 7.11-7.24 (m, 2 H), 7.08 (dd, J=8.0, 2.4 Hz, 1 H), 6.83 (d, J=8.8 Hz, 1 H), 6.20 (s, 1H), 4.39-4.49 (m, 2 H) ), 4.34(d, J=4.4Hz, 2H).

[0328] MS measured value: 446.1 (M)

[0329] Embodiment 23 6-(2-(4-(dimethylamino)phenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 48)

[0330] Compound 9-6 (50.0 mg, 172 umol, 1.00 eq) synthesized in Embodiment 12 was mixed with 4-(2-bromoethoxy)-N,N-dimethylaniline (43.0 mg, 176 umol, 1.02 eq) in RX as described in [Reaction Scheme 2]. Then, K2CO3 (36.0 mg, 260 umol, 1.51 eq) and NaI (5.00 mg, 33.3 umol, 1.93 eq) were added at 25°C. The mixture was stirred at 45-50°C for 12 hours. The synthesis of the desired compound was confirmed by LC-MS. The mixture was cooled with water (10.0 mL) and extracted with RINKAN (10.0 mL x 2). The organic layer was washed with NaCl (10.0 mL x 2), dried over Na2SO4, and the mixture was filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC to obtain compound 48 (7.00 mg, 13.8 umol, yield: 8.03%, purity: 89.7%) as a red gum.

[0331] 1H NMR (400 MHz, CHLOROFORM-d): δppm 8.52-8.61 (m, 2 H), 7.88 (s, 1 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.49 (s, 1 H) ), 7.31-7.42 (m, 2 H), 6.87-7.01 (m, 3 H), 6.76(d, J = 9.2 Hz, 2 H), 6.27(s, 1 H), 4.28-4.42(m, 4 H), 2.89(s, 6 H).

[0332] MS measured value: 453.2 (M+1)

[0333] Embodiment 24 3-(furan-3-yl)-6-(2-(4-isopropylphenoxy)ethoxy)-2-(pyridin-3-yl)-1H-inden-1-one (compound 49)

[0334] Compound 9-6 (50.0 mg, 172 umol, 1.00 eq) synthesized in Embodiment 12 and 1-(2-bromoethoxy)-4-isopropylbenzene (43.0 mg, 176 umol, 1.02 eq) in [Reaction Scheme 2] were mixed in DMF (3.00 mL) with RX. Then, K2CO3 (36.0 mg, 260 umol, 1.51 eq) and NaI (5.00 mg, 33.3 umol, 1.93 eq) were added at 25°C. The mixture was stirred at 45-50°C for 12 hours. The synthesis of the desired compound was confirmed by LC-MS while MeOH (1.00 mL) was added dropwise. The mixture was cooled with water (10.0 mL) and extracted with ethyl acetate (10.0 mL x 2). The organic layer was washed with NaCl (10.0 mL x 2), dried over Na2SO4, and the mixture was filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC to obtain compound 49 (13.00 mg, 26.1 umol, yield: 15.11%, purity: 90.7%) as a red gum.

[0335] 1H NMR (400 MHz, DMSO-d6): δppm 8.53-8.60 (m, 2 H), 7.88 (s, 1 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.49 (s, 1 H) ), 7.30-7.39 (m, 2 H), 6.88-7.00 (m, 3 H), 6.76(d, J = 9.2 Hz, 2H), 6.27(s, 1H), 4.25-4.48(m, 4H), 2.89(s, 6H), 1.23(brs, 3H), 1.16(s, 3H).

[0336] MS measured value: 452.2 (M+1)

[0337] Embodiment 25 3-(furan-3-yl)-6-(((4-methoxybenzyl)oxy)methoxy)-2-(pyridin-3-yl)-1H-inden-1-one (compound 50)

[0338] [Reaction Equation 2-1]

[0339] [ka]

[0340] Step 1: Synthesis of (((4-methoxybenzyl)oxy)methyl)(methyl)sulfane ((((4-methoxybenzyl)oxy)methyl)(methyl)sulfane)(50-2)

[0341] THF (100 mL), NaI (10.8 g, 72.4 mmol, 1 eq), and NaH (5.79 g, 144.76 mmol, purity: 60%, 2 eq) were mixed at 25°C. After cooling the mixture to 0°C, compound 50-1 (10.0 g, 72.4 mmol, 9.03 mL, 1 eq) of [Reaction Scheme 2-1] was added and the reaction was carried out at 25-30°C. The mixture was stirred at 25-30°C for 1 hour. Chloro(methylsulfanyl)methane (6.99 g, 72.38 mmol, 6.06 mL, 1 eq) was added and the reaction was carried out at 25-30°C. The mixture was stirred under a nitrogen atmosphere at 25-30°C for 12 hours. The synthesis of the desired compound was confirmed by TLC (PE / EA = 3 / 1) while adding DCM (0.5 mL) dropwise. The mixture was cooled at 0°C with NH4Cl (300 mL), diluted with water (100 mL), and extracted with siRNA (100 mL x 3). The organic layer was washed with brine (100 mL x 2), dried over Na2SO4, and the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE:EA = 50:1, 10:1 P1 = 0.20) to obtain a white oily compound 50-2 (9.2 g, 46.40 mmol, yield: 64.11%).

[0342] Step 2: Synthesis of 1-((chloromethoxy)methyl)-4-methoxybenzene (50-3)

[0343] Compound 50-2 (500 mg, 2.52 mmol, 1 eq) was dissolved in DMF (1 mL), then acetyl chloride (178 mg, 2.27 mmol, 161 μL, 0.9 eq) was mixed and stirred under a nitrogen atmosphere at 25-30°C for 12 hours. The desired compound was confirmed to be synthesized by TLC (PE:EA = 5:1) while adding DCM (1.00 mL) dropwise. The mixture was concentrated under vacuum and extracted with EA (5 mL). Diluted with water (10 mL), extracted with dimethyl (10 mL x 2), the organic layer was washed with water (10 mL x 3), dried over Na2SO4, and the mixture was filtered and concentrated under reduced pressure. The residue yielded a white oily compound 50-3 (400 mg, 2.14 mmol, yield: 84.99%).

[0344] Step 3: Synthesis of 3-(furan-3-yl)-6-(((4-methoxybenzyl)oxy)methoxy)-2-(pyridin-3-yl)-1H-inden-1-one (compound 50)

[0345] Compound 9-6 (60.0 mg, 207 umol, 1 eq) synthesized in Embodiment 12 and NaH (5.97 g, 248 umol, 1.2 eq) were mixed in DMF (1 mL). Compound 50-3 (77.4 mg, 414 umol, 2 eq) was added dropwise to DMF (0.2 mL) and added to the mixture. The mixture was stirred for 2 hours under a nitrogen atmosphere at 25-30°C. A mixture of DCM (1.00 mL) and water (1.00 mL) was added dropwise, and the complete consumption of the reactants was confirmed by TLC (PE:EA = 1:1). The mixture was cooled with NH4Cl (30 mL) at 0°C, diluted with water (10 mL), and extracted with HCl (10 mL × 3). The organic layer was washed with brine (5.00 mL × 2), dried over Na2SO4, and the mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (SiO2, PE:EA = 1:1) to obtain compound 50 (11.0 mg, 34.9 umol, yield: 11.1%, purity: 92.1%) as a red solid.

[0346] 1H NMR (400 MHz, CHLOROFORM-d): δ8.50 (br s, 2H), 7.80 (s, 1H), 7.68 (br d, J = 8.0 Hz, 1H), 7.31 - 7.23 (m, 2H), 7.22 - 7.15(m, 4H), 7.02(dd, J=8.0, 2.4Hz, 1H), 6.81(d, J=8.4Hz, 2H), 6.19(d, J=1.2Hz, 1H), 5.23(s, 2H), 4.59(s, 2H), 3.73(s, 3H)

[0347] MS measured value: 440.1 [M+H] +

[0348] Embodiment 26 3-(5-methylthiazol-4-yl)-6-(3-morpholinopropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 4)

[0349] [Reaction Equation 3]

[0350] [ka]

[0351] Step 1: Synthesis of (E)-1-(3-hydroxyphenyl)-3-(5-methylthiazol-4-yl)prop-2-en-1-one (4-3)

[0352] Compound 4-1 (500 mg, 3.93 mmol) and Compound 4-2 (535 mg, 3.93 mmol, 486 μL) from the above [Reaction Scheme 3] were mixed with ethanol (5.00 mL). Then, NaOH (235 mg, 5.90 mmol) was added to H2O (2.00 mL) under a nitrogen atmosphere at 0°C. The mixture was stirred at 20°C for 12 hours. Complete consumption of the reactants was confirmed by TLC (DCM: methanol = 10 / 1). Complete consumption of the reactants was confirmed by LCMS, and synthesis of compound 4-3 was confirmed by MS. After adjusting the pH of the mixture to 7 with 1N HCl, the mixture was filtered and concentrated under vacuum to obtain the yellow solid compound 4-3 (700 mg, 2.85 mmol, yield: 72.5%).

[0353] Step 2: Synthesis of 6-hydroxy-3-(5-methylthiazol-4-yl)indan-1-one(4-4)

[0354] Compound 4-3 (700 mg, 2.85 mmol) was dissolved in triflic acid (10 mL), and the mixture was stirred at 80°C for 16 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA = 1 / 1). Water (30.0 mL) was added to the mixture, and an aqueous solution of NaHCO3 was added to adjust the pH to 8. The mixture was then filtered and concentrated under vacuum to obtain a brown solid compound 4-4 (700 mg, 2.85 mmol, yield: 100.00%).

[0355] Step 3: Synthesis of [1-(5-methylthiazol-4-yl)-3-oxo-indan-5-yl]acetate (4-5)

[0356] Compound 4-4 (200 mg, 815 umol) was dissolved in DCM (10.0 mL), and then Ac2O (416.18 mg, 4.08 mmol, 381.82 μL, 5 eq), pyridine (322 mg, 4.08 mmol, 329 μL, 5 eq), and DMAP (99.6 mg, 815 umol) were added at 0°C. The mixture was stirred at 20°C for 24 hours. Complete consumption of the reaction products was confirmed by TLC (PE:EA = 1 / 1). The mixture was diluted with DCM (100 mL) and extracted with brine (30.0 mL x 3). After drying with anhydrous Na2SO4, the residue was concentrated in vacuum to obtain a residue. The residue was purified by flash silica gel chromatography to obtain compound 4-5 (130 mg, 452 umol, yield: 55.4%) as a white solid.

[0357] Step 4: Synthesis of (2-bromo-1-(5-methylthiazol-4-yl)-3-oxo-inden-5-yl)acetate (4-6)

[0358] Compounds 4-5 (130 mg, 452 umol) and NBS (177 mg, 995 umol) were mixed in carbon tetrachloride (5.00 mL), and then AIBN (7.43 mg, 45.2 umol) was added under a nitrogen atmosphere. The reaction mixture was stirred at 400 W and 80°C for 2 hours. Complete consumption of the reaction products was confirmed by TLC (PE:EA = 2 / 1). The mixture was diluted with DCM (100 mL) and extracted with brine (30 mL x 3). After drying and filtering with anhydrous Na2SO4, the mixture was concentrated under vacuum to obtain compound 4-6 (200 mg) as a brown oil.

[0359] Step 5: Synthesis of 2-bromo-6-hydroxy-3-(5-methylthiazol-4-yl)inden-1-one (4-7)

[0360] Compound 4-6 (200 mg, 549 umol) was mixed with DCM (4.00 mL), and then DBU (83.6 mg, 549 umol, 82.7 μL) was added. The mixture was stirred at 20°C for 12 hours. Complete consumption of the reaction products was confirmed by TLC (PE:EA = 1 / 1). The mixture was diluted with DCM (100 mL) and extracted with brine (30 mL x 3). After drying and filtering with anhydrous Na2SO4, the residue was concentrated under vacuum to obtain the residue. The residue was purified by flash silica gel chromatography to obtain compound 4-7 (50.0 mg, 155 umol, yield: 28.26%) as a red oil.

[0361] Step 6: Synthesis of 2-bromo-3-(5-methylthiazol-4-yl)-6-(3-morpholinopropoxy)-1H-inden-1-one (Compound 5)

[0362] Compounds 4-7 (50.0 mg, 155 umol) and 4-(3-chloropropyl)morpholine (30.5 mg, 186 umol, 61.7 uL) were mixed in acetonitrile (2.00 mL) using the RX method in [Reaction Formula 3], and then K2CO3 (64.3 mg, 465 umol) and KI (25.7 mg, 155 umol) were added. The mixture was stirred at 60°C for 2 hours. Complete consumption of the reactants was confirmed by LC-MS, and synthesis of compound 5 was confirmed by MS. The mixture was diluted with  (50.0 mL) and extracted with brine (10 mL x 3). After drying and filtering over anhydrous Na2SO4, the residue was concentrated under vacuum. The residue was purified by reversed-phase HPLC to obtain compound 5 (5.60 mg, 11.7 umol, yield: 7.58%) as a red solid.

[0363] Step 7: Synthesis of 3-(5-methylthiazol-4-yl)-6-(3-morpholinopropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 4)

[0364] Dioxane (2.00 mL) and H2O (0.50 mL) were mixed with compound 5 (30.0 mg, 66.7 umol) and pyridine-3-ylboronic acid (8.21 mg, 66.7 umol) in the reaction formula 3 above, with R1-B(OH)2. Then, K3PO4 (42.5 mg, 200 umol) and Pd(dtbpf)Cl2 (4.35 mg, 6.68 umol) were added under a nitrogen atmosphere. The mixture was stirred in a microwave at 100°C for 2 hours. Complete consumption of the reactants was confirmed by LC-MS, and synthesis of compound 4 was confirmed by MS. The mixture was filtered and concentrated under vacuum to obtain the residue. The residue was purified by reversed-phase HPLC to obtain compound 4 (5.40 mg, 12.1 umol, yield: 18.0%) as a red solid.

[0365] 1H NMR (400 MHz, CD3OD): δ9.13(s, 1H), 8.88(s, 1H), 8.76(d, J = 6.0 Hz, 1H), 8.38(d, J = 8.4 Hz, 1H), 8.03( dd, J = 6.0, 8.4 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.06 (dd, J = 2.54, 8.4 Hz, 1H), 4.23(t, J=5.6Hz, 2H), 4.06-4.11(m, 2H), 3.83(t, J=12.0Hz, 2H), 3.58(d, J=12.4Hz, 2H), 3.38-3.44(m) , 2H), 3.17-3.26(m, 2H), 2.29-2.36(m, 2H), 2.24(s, 3H)

[0366] MS measured value: 448.0 [M+H] +

[0367] Embodiment 27 2-bromo-3-(5-methylthiazol-4-yl)-6-(3-morpholinopropoxy)-1H-inden-1-one (Compound 5)

[0368] Compound 5 was synthesized in the above embodiment 26.

[0369] 1 H NMR (400 MHz, CD3OD): δ9.04(s, 1H), 7.14(d, J = 2.4 Hz, 1H), 6.95-7.01(m, 1H), 6.89(dd, J = 2.4, 8.0 Hz, 1 ), 4.09(t, J=6.0Hz, 2H), 3.72(t, J=4.8Hz, 4H), 2.52-2.65(m, 9H), 1.96-2.08(m, 2H)

[0370] MS measured value: 448.9 [M+H] +

[0371] Embodiment 28 3-(5-methylthiazol-4-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 8)

[0372] Step 1: Synthesis of 2-bromo-3-(5-methylthiazol-4-yl)-6-(3-phenylpropoxy)-1H-inden-1-one (8-1)

[0373] Compounds 4-7 (100 mg, 1.00 eq) synthesized in Embodiment 26 and (3-bromopropyl)benzene (88.0 mg, 1.5 eq) in RX as shown in [Reaction Formula 3] were mixed in DMF (1.00 mL). Then, K2CO3 (70.0 mg, 1.83 eq) and NaI (5.00 mg, 0.01 eq) were added under a nitrogen atmosphere at 20-25°C. The mixture was stirred at 40-45°C for 12 hours. Complete consumption of the reactants was confirmed by LC-MS. Water (10.0 mL) was added to the mixture, and the pH was adjusted to 3 with 1 M HCl, after which it was extracted with HCl (10.0 mL x 3). The mixture was washed with brine (10.0 mL), dried over Na2SO4, and then filtered and concentrated under reduced pressure at 45°C. The residue was purified by column chromatography (SiO2, PE / EA = 50 / 1 to 20 / 1) to obtain compound 8-1 (78.0 mg, yield: 61.5%, purity: 97.4%) as a red gel.

[0374] Step 2: Synthesis of 3-(5-methylthiazol-4-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 8)

[0375] Compound 8-1 (78.0 mg, 1.00 eq) and pyridine-3-ylboronic acid (32.0 mg, 1.5 eq) were mixed with R1-B(OH)2 in [Reaction Formula 3]. This mixture was then added to K2CO3 (73.0 mg, 3.01 eq), Pd(t-Bu3P)2 (10.0 mg, 0.01 eq), dioxane (0.80 mL), and water (0.20 mL) under a nitrogen atmosphere at 20-25°C. The mixture was stirred at 80-85°C for 12 hours. Complete consumption of the reactants was confirmed by LC-MS. Water (10.0 mL) was added to the mixture, and the pH was adjusted to 7 with 1 M HCl. The mixture was then extracted with SiO2 (1.00 mL x 3). The organic layer was washed with brine (10.0 mL), dried over Na2SO4, and concentrated under reduced pressure at 45°C to obtain the organic phase residue. The residue was purified by prep-HPLC to obtain compound 8 (21.0 mg, yield: 26.2%, purity: 94.2%) as a red gum.

[0376] 1H NMR (400 MHz, DMSO-d6): δppm 9.23(s, 1H), 8.72(br d, J = 4.8 Hz, 1H), 8.61(s, 1H), 7.98 - 8.07(m, 1H), 7.77 - 7.85(m, 1H), 7.18 - 7.30(m, 7H), 7.00 - 7.04(m, 1H), 4.07(br t, J = 6.0 Hz, 2H), 2.75 (br t, J = 7.6 Hz, 2H), 2.07(s, 2H), 1.98(s, 3H)

[0377] MS measured value: 439.2 [M+H] +

[0378] Embodiment 29 2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-phenethoxy-1H-inden-1-one (Compound 18)

[0379] Step 1: Synthesis of 2-bromo-3-(5-methylthiazol-4-yl)-6-phenethoxy-1H-inden-1-one (18-1)

[0380] Compounds 4-7 (1.5 g, 1.00 eq) synthesized in Embodiment 26 and (2-bromoethyl)benzene (9.00 g, 6.58 mL, 11.0 eq) were mixed in DMF (15.0 mL) with RX in [Reaction Formula 3]. Then, K2CO3 (1.83 g, 3.00 eq) and NaI (133 mg, 0.20 eq) were added under a nitrogen atmosphere at 15-20°C. The mixture was stirred at 65-70°C for 37 hours. The synthesis of the desired compound was confirmed by TLC (PE:EA = 3:1). Water (45.0 mL) was added to the mixture at 15-20°C and cooled, and the mixture was diluted with HCl (40.0 mL x 3) and extracted. The mixture was washed with brine (40.0 mL), dried over Na2SO4, and then filtered and concentrated under reduced pressure at 45°C. The residue was purified by column chromatography (SiO2, PE / EA = 50 / 1 to 10 / 1) to obtain compound 18-1 as a red solid.

[0381] Step 2: Synthesis of 2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-phenethoxy-1H-inden-1-one (Compound 18)

[0382] Compound 18-1 (100.0 mg, 1.00 eq) and (4-methoxyphenyl)boronic acid (67.0 mg, 2.05 eq) were mixed with R1-B(OH)2 in [Reaction Scheme 3]. This mixture was then added to K2CO3 (90.0 mg, 3.02 eq), Pd(t-Bu3P)2 (11.0 mg, 0.10 eq), dioxane (2.0 mL), and water (0.5 mL) under a nitrogen atmosphere at 20-25°C. The mixture was stirred at 80-85°C for 19 hours. Complete consumption of the reactants was confirmed by LC-MS. The mixture was cooled by adding water (10.0 mL) at 15-20°C, diluted with ELISA (10.0 mL x 3), and extracted. The organic layer was washed with brine (10.0 mL), dried over Na2SO4, and then filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain compound 18 as a red solid.

[0383] 1H NMR (400 MHz, DMSO-d6): δppm 1.85(s, 3H)3.05(t, J = 6.8 Hz, 2H)3.75(s, 3H)4.27(t, J = 6.8 Hz, 2H) 6.91 (d, J = 8.8 Hz, 2H) 6.96 (dd, J = 8.0, 2.38 Hz, 1 H) 7.06 (d, J = 8.0 Hz, 1 H) 7.09 (d, J = 2.4 Hz, 1 H) ) 7.13(d, J = 8.8 Hz, 2 H) 7.21 - 7.25 (m, 1 H) 7.31 - 7.35 (m, 4 H) 9.17 (s, 1H)

[0384] MS measured value: 454.2 [M+H] +

[0385] Embodiment 30 2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-(4-phenylbutoxy)-1H-inden-1-one (Compound 19)

[0386] Step 1: Synthesis of 2-bromo-3-(5-methylthiazol-4-yl)-6-(4-phenylbutoxy)-1H-inden-1-one (19-1)

[0387] Compound 4-7 (300 mg, 1.00 eq) synthesized in Embodiment 26 was mixed with (4-bromobutyl)benzene (239 mg, 1.20 eq) in RX as in [Reaction Formula 3]. Then, K2CO3 (194 mg, 1.51 eq) and NaI (28.0 mg, 0.02 eq) were added under a nitrogen atmosphere at 20-25°C. The mixture was stirred at 40-45°C for 12 hours. The synthesis of the desired compound was confirmed by TLC (PE:EA = 1:1). The mixture was diluted with water (20.0 mL), adjusted to pH 3 with 1 M HCl, and extracted with SiO (30.0 mL × 3). The mixture was separated, the organic layer was washed with brine (30.0 mL), dried over Na2SO4, and then filtered and concentrated under reduced pressure at 45°C. The residue was purified by column chromatography (SiO2, PE / EA = 100 / 1 to 20 / 1) to obtain compound 19-1 (275 mg, yield: 64.0%, purity: 97.9%) as a red gum.

[0388] Step 2: Synthesis of 2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-(4-phenylbutoxy)-1H-inden-1-one (Compound 19)

[0389] Compound 19-1 (130 mg, 1.00 eq) and (4-methoxyphenyl)boronic acid (66.0 mg, 1.52 eq) were mixed with R1-B(OH)2 in [Reaction Scheme 3]. This mixture was then added to K2CO3 (118 mg, 3.01 eq), Pd(t-Bu3P)2 (15.0 mg, 0.10 eq), dioxane (0.8 mL), and water (0.2 mL) under a nitrogen atmosphere at 20-25°C. The mixture was stirred at 80-85°C for 12 hours. Complete consumption of the reactants was confirmed by LC-MS. Water (10.0 mL) was added to the mixture, and the pH was adjusted to 7 with 1 M HCl. The mixture was then extracted with SiO2 (10.0 mL x 3). The organic layer was washed with brine (10.0 mL), dried over Na2SO4, and then filtered and concentrated under reduced pressure at 45°C. The residue was purified by prep-HPLC to obtain compound 19 (58.0 mg, yield: 42.0%, purity: 97.5%) as a red gum.

[0390] 1H NMR (400 MHz, DMSO-d6): δ9.11 - 9.23 (m, 1H), 7.04 - 7.30 (m, 9H), 6.85 - 6.97 (m, 3H), 4.00 - 4.11(m, 2H), ms, 3H), 2.61~2.68(m, 2H), 1.85(s, 3H), 1.73(br s, 4H)

[0391] MS measured value: 482.2 [M+H] +

[0392] Embodiment 31 6-((benzyloxy)methoxy)-2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-1H-inden-1-one (Compound 20)

[0393] Step 1: Synthesis of 6-((benzyloxy)methoxy)-2-bromo-3-(5-methylthiazol-4-yl)-1H-inden-1-one (20-1)

[0394] Compound 4-7 (500 mg, 1.00 eq) synthesized in Embodiment 26 was mixed with ((chloromethoxy)methyl)benzene (((chloromethoxy)methyl)benzene, 1.16 g, 5.02 eq) in RX as shown in [Reaction Formula 3] in DMF (5.0 mL). Then, K2CO3 (618 mg, 3.03 eq) and NaI (48 mg, 0.20 eq) were added under a nitrogen atmosphere at 25°C. The mixture was stirred at 40-45°C for 12 hours. The synthesis of the desired compound was confirmed by TLC (PE:EA=3:1). Water (5.00 mL) was added to the mixture and extracted with HCl (2 mL × 1). The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EA=20 / 1~10 / 1) to obtain compound 20-1 (300 mg, yield: 34.0%, purity: 74.4%) as a red solid.

[0395] Step 2: Synthesis of 6-((benzyloxy)methoxy)-2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-1H-inden-1-one (Compound 20)

[0396] Compound 20-1 (100.0 mg, 1.00 eq) and (4-methoxyphenyl)boronic acid (52.0 mg, 1.51 eq) were mixed with R1-B(OH)2 in [Reaction Scheme 3]. This mixture was then added to K2CO3 (94.0 mg, 3.01 eq), Pd(t-Bu3P)2 (12.0 mg, 0.10 eq), dioxane (0.80 mL), and water (0.20 mL) under a nitrogen atmosphere at 25°C. The mixture was stirred under a nitrogen atmosphere at 80-85°C for 12 hours. Complete consumption of the reactants was confirmed by LC-MS. The mixture was diluted with water (3.00 mL), extracted with SiO (1.00 mL), dried over Na2SO4, and then filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain compound 20 (36.87 mg, yield: 34.5%, purity: 99.5%) as a red gum.

[0397] 1H NMR (400 MHz, DMSO-d6): δ 9.06 - 9.31 (m, 1 H), 7.25 - 7.41 (m, 5 H), 7.23 (s, 1 H), 7.04 - 7.18 (m, 4 H), 6.91 (d, J=8.8Hz, 2H) 5.40(s, 2H), 4.70(s, 2H), 3.75(s, 3H), 1.86(s, 3H)

[0398] MS measured value: 470.1 (M+1)

[0399] Embodiment 32 2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-(2-phenoxyethoxy)-1H-inden-1-one (Compound 21)

[0400] Step 1: Synthesis of 2-bromo-3-(5-methylthiazol-4-yl)-6-(2-phenoxyethoxy)-1H-inden-1-one (21-1)

[0401] Compounds 4-7 (500 mg, 1.00 eq) synthesized in Embodiment 26 and (2-bromoethoxy)benzene (1.78 g, 6.00 eq) were mixed in DMF (5.00 mL) with RX in [Reaction Scheme 3]. Then, K2CO3 (306 mg, 1.50 eq) and NaI (45.0 mg, 0.20 eq) were added under a nitrogen atmosphere at 15-20°C. The mixture was stirred at 55-60°C for 37 hours. The synthesis of the desired compound was confirmed by TLC (PE:EA = 3:1). The mixture was cooled with water (20.0 mL) at 15-20°C, then diluted with ₹ (20.0 mL × 3) and extracted. The organic layer was washed with brine (20 mL), dried over Na2SO4, and then filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EA = 50 / 1~2 / 1) to obtain compound 21-1 as a red solid.

[0402] Step 2: 2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-(2-phenoxyethoxy)-1H-inden-1-one (Compound 21)

[0403] Compound 21-1 (100.0 mg, 1.00 eq) and (4-methoxyphenyl)boronic acid (61.0 mg, 2.01 eq) were mixed with R1-B(OH)2 in [Reaction Scheme 3]. This mixture was then added to K2CO3 (83.0 mg, 3.01 eq), Pd(t-Bu3P)2 (11.0 mg, 0.10 eq), dioxane (1.60 mL), and water (0.40 mL) under a nitrogen atmosphere at 20-25°C. The mixture was stirred under a nitrogen atmosphere at 80-85°C for 18 hours. Complete consumption of the reactants was confirmed by LC-MS. The mixture was cooled by adding water (10.0 mL) at 15-20°C and diluted with SiO2 (10.0 mL x 3) for extraction. The organic layer was washed with brine (10.0 mL), dried over Na2SO4, and then filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain compound 21 as a red solid.

[0404] 1H NMR (400 MHz, DMSO-d6): δppm 1.85(s, 3H)3.05(t, J = 6.8 Hz, 2H)3.75(s, 3H)4.27(t, J = 6.8 Hz, 2H) 6.91 (d, J = 8.8 Hz, 2H) 6.96 (dd, J = 8.0, 2.4 Hz, 1 H) 7.06 (d, J = 8.0 Hz, 1 H) 7.09 (d, J = 2.4 Hz, 1 H) ) 7.13(d, J = 8.8 Hz, 2 H) 7.21 - 7.25 (m, 1 H) 7.31 - 7.35 (m, 4 H) 9.17 (s, 1H)

[0405] MS measured value: 454.2 [M+H] +

[0406] Embodiment 33 6-(2-(3,4-dichlorophenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(pyrimidin-5-yl)-1H-inden-1-one (Compound 26)

[0407] Step 1: Synthesis of 2-bromo-6-(2-(3,4-dichlorophenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one)(26-1)

[0408] Compound 4-7 (0.50 g, 1.00 eq) synthesized in Embodiment 26 was mixed with 4-(2-bromoethoxy)-1,2-dichlorobenzene (503 mg, 1.20 eq) in RX as shown in [Reaction Scheme 3]. Then, K2CO3 (322 mg, 1.50 eq) and NaI (47 mg, 2.02 e-1 eq) were added under a nitrogen atmosphere at 15-20°C. The mixture was stirred at 40-45°C for 18 hours. The synthesis of the desired compound was confirmed by TLC (PE:EA = 3:1). Water (20 mL) was added to the mixture, and the pH was adjusted to 3 with 1 M HCl, followed by extraction with SiO (30 mL x 3). The organic layer was washed with brine (30 mL), dried over Na2SO4, and then filtered and concentrated under reduced pressure at 45°C. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 3 / 1) to obtain compound 26-1 (401 mg, yield: 43.3%, purity: 85.7%) as a red solid.

[0409] Step 2: Synthesis of 6-(2-(3,4-dichlorophenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(pyrimidin-5-yl)-1H-inden-1-one (Compound 26)

[0410] Compound 26-1 (100 mg, 1.00 eq) and pyrimidin-5-ylboronic acid (37 mg, 1.53 eq) were mixed with R1-B(OH)2 in [Reaction Scheme 3]. This mixture was then added to K2CO3 (81.0 mg, 586.08 umol, 3 eq), Pd(t-Bu3P)2 (10 mg, 0.10 eq), dioxane (2 mL), and water (0.5 mL) under a nitrogen atmosphere at 15-25°C. The mixture was stirred under a nitrogen atmosphere at 80-85°C for 12 hours. The synthesis of the desired compound was confirmed by LC-MS. Water (20 mL) was added to the mixture and extracted with RINKAN (30 mL x 3). The organic layer was washed with brine (30 mL), dried over Na2SO4, and then filtered and concentrated under reduced pressure at 45°C. The residue was purified by reversed-phase HPLC to obtain compound 26 (17.04 mg, yield: 19.17%, purity: 95.2%) as an orange solid.

[0411] 1H NMR (400 MHz, DMSO-d6): δ 9.22 (s, 1H), 9.10 (s, 1H), 8.60 (s, 2H), 7.54 (d, J = 8.8 Hz, 1H), 7.32 (d, J) = 2.8 Hz, 1H), 7.26-7.20(m, 2H), 7.06(ddd, J=2.8, 8.4, 17.2 Hz, 2H), 4.41(br dd, J=5.2, 14.4 Hz, 4H), 2, 3H)

[0412] MS measured value: 510.1 (M+1)

[0413] Embodiment 34 6-(2-(3,4-difluorophenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(pyrimidin-5-yl)-1H-inden-1-one (Compound 27)

[0414] Step 1: Synthesis of 2-bromo-6-(2-(3,4-difluorophenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one)(27-1)

[0415] Compound 4-7 (1.00 g, 3.10 mmol, 1.00 eq) synthesized in Embodiment 26 was mixed with 4-(2-bromoethoxy)-1,2-difluorobenzene (883 mg, 1.20 eq) in RX as shown in [Reaction Scheme 3]. Then, K2CO3 (644 mg, 1.50 eq) and NaI (94 mg, 0.20 eq) were added under a nitrogen atmosphere at 15-20°C. The mixture was stirred at 40-45°C for 18 hours. The synthesis of the desired compound was confirmed by TLC (PE:EA = 3:1). Water (20 mL) was added to the mixture, and the pH was adjusted to 3 with 1 M HCl. The mixture was then extracted with SiO2 (30 mL x 3). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure at 45°C. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 3 / 1) to obtain compound 27-1 (690 mg, yield: 42.8%, purity: 92.1%) as a red solid.

[0416] Step 2: Synthesis of 6-(2-(3,4-difluorophenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(pyrimidin-5-yl)-1H-inden-1-one (Compound 27)

[0417] Compound 27-1 (100 mg, 1.00 eq) and pyrimidin-5-ylboronic acid (39.0 mg, 1.51 eq) were mixed with R1-B(OH)2 in [Reaction Formula 3]. This mixture was then added to K2CO3 (87.0 mg, 3.01 eq), Pd(t-Bu3P)2 (11 mg, 1.03 e-1 eq), dioxane (2 mL), and water (0.5 mL) under a nitrogen atmosphere at 15-25°C. The mixture was stirred under a nitrogen atmosphere at 80-85°C for 12 hours. The synthesis of the desired compound was confirmed by TLC (PE:EA = 1:1). Water (20 mL) was added to the mixture and extracted with HCl (30 mL x 3). The organic layer was washed with brine (30 mL), dried over Na2SO4, and then filtered and concentrated under reduced pressure at 45°C. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 2 / 1) to obtain compound 27 (31.0 mg, yield: 28.5%, purity: 91.9%) as a reddish-brown solid.

[0418] 1H NMR (400 MHz, DMSO-d6): δ9.22(s, 1H), 9.10(s, 1H), 8.60(s, 2H), 7.42-7.32(m, 1H), 7.27-7.20(m, 2H), 7.16 (ddd, J = 2.8, 6.8, 12.8 Hz, 1H), 7.07 (dd, J = 2.4, 8.0 Hz, 1H), 6.87-6.80 (m, 1H), 4.46-4.01 (m, 4) (s, 3H)

[0419] MS measured value: 478.1 (M+1)

[0420] Embodiment 35 6-(2-(4-methoxyphenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one (Compound 32)

[0421] Step 1: Synthesis of 2-bromo-6-(2-(4-methoxyphenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one)(32-1)

[0422] Compounds 4-7 (200 mg, 1.00 eq) synthesized in Embodiment 26 and 1-(2-bromoethoxy)-4-methoxybenzene (164 mg, 1.20 eq) were mixed in DMF (1.00 mL) using RX in [Reaction Scheme 3]. Then, K2CO3 (124 mg, 1.52 eq) and NaI (19.0 mg, 0.02 eq) were added under a nitrogen atmosphere at 20-25°C. The mixture was stirred at 40-45°C for 18 hours. The synthesis of the desired compound was confirmed by TLC (PE:EA = 3:1). Water (10.0 mL) was added to the mixture, and the pH was adjusted to 3-4 with 1 M HCl. The mixture was then extracted with ELISA (20.0 mL x 2). After drying over Na2SO4, the mixture was concentrated. The residue was purified by column chromatography (SiO2, PE / EA = 30 / 1 to 3 / 1) to obtain compound 32-1 (199 mg, yield: 70%, purity: 100%) as a red solid.

[0423] Step 2: Synthesis of 6-(2-(4-methoxyphenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one (Compound 32)

[0424] Compound 32-1 (90.0 mg, 1.00 eq) and (4-(trifluoromethyl)phenyl)boronic acid (54.0 mg, 1.49 eq) were mixed with R1-B(OH)2 in [Reaction Scheme 3]. This mixture was then added to K2CO3 (79.0 mg, 3.00 eq), Pd(t-Bu3P)2 (10.0 mg, 0.02 eq), dioxane (2.00 mL), and water (0.5 mL) under a nitrogen atmosphere at 20-25°C. The mixture was stirred under a nitrogen atmosphere at 80-85°C for 8 hours. The synthesis of the desired compound was confirmed by LC-MS. Water (20 mL) was added to the mixture and extracted with SiO (10.0 mL × 2). The organic layer was washed with brine (10.0 mL × 2), dried over anhydrous Na2SO4, and then filtered and concentrated under vacuum conditions. The mixture was titrated with ACN / MeOH = 5 / 1 (3.00 mL) at 20-25°C for 30 minutes, and the residue was filtered to obtain the residue. Compound 32 (26.4 mg, yield: 24.54%, purity: 95.2%) was obtained as a red solid from the residue.

[0425] 1H NMR (400 MHz, DMSO-d6): δppm 9.21 (s, 1 H), 8.40 (br d, J = 6.0 Hz, 2 H), 7.72 (br d, J = 8.0 Hz, 2 H), 7.40 (br d, J = 8.0 Hz, 2 H), 7.12 - 7.29 (m, 2 H), 6.94 - 7.11 (m, 3 H), 4.44 (s, 4 H), 1.85 (s, 3 H).

[0426] MS measured value: 509.3 (M+1)

[0427] Embodiment 36 2-(4-fluorophenyl)-6-(2-(4-methoxyphenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one (Compound 22)

[0428] Compound 32-1 (100 mg, 1.00 eq) synthesized in Embodiment 35 was mixed with (4-fluorophenyl)boronic acid (45.0 mg, 1.52 eq) in R1-B(OH)2 in [Reaction Scheme 3]. This mixture was then added to K2CO3 (88.0 mg, 3.01 eq), Pd(t-Bu3P)2 (11.0 mg, 0.1 eq), dioxane (2 mL), and water (0.5 mL) under a nitrogen atmosphere at 15-20°C. The mixture was stirred under a nitrogen atmosphere at 80-85°C for 14 hours. The synthesis of the desired compound was confirmed by LC-MS. Water (20 mL) was added to the mixture and extracted with SiO2. The organic layer was washed with brine, dried over Na2SO4, and then filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to obtain compound 22 (12.05 mg, yield: 11.59%, purity: 99.3%) as a red solid.

[0429] 1H NMR (400 MHz, DMSO-d6): δ ppm 9.20 (s, 1 H), 7.18 - 7.24 (m, 5 H), 7.12 - 7.16 (m, 1 H), 7.01 - 7.06 (m, 1 H) , 6.91~6.95(m, 2H), 6.85~6.90(m, 2H), 4.36~4.41(m, 2H), 4.24~4.29(m, 2H), 3.71(s, 3H), 1.86 (s, 3H).

[0430] MS measured value: 488.3 (MS +1)

[0431] Embodiment 37 6-(2-(3,4-dimethoxyphenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one (Compound 33)

[0432] Step 1: Synthesis of 2-bromo-6-(2-(3,4-dimethoxyphenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one)(33-1)

[0433] Compound 4-7 (500 mg, 1.00 eq) synthesized in Embodiment 26 and 4-(2-bromoethoxy)-1,2-dimethoxybenzene (642 mg, 1.50 eq) were mixed in DMF (5.00 mL) using RX in [Reaction Scheme 3]. Then, K2CO3 (306 mg, 1.50 eq) and NaI (44.0 mg, 0.02 eq) were added under a nitrogen atmosphere at 20-25°C. The mixture was stirred at 40-45°C for 18 hours. The synthesis of the desired compound was confirmed by LC-MS. Water (10.0 mL) was added to the mixture, and the pH was adjusted to 3-4 with 1 M HCl. After extraction with ELISA (20.0 mL x 2), the mixture was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (SiO2, EA / DCM = 0 / 1 to 1 / 20), and then concentrated to obtain compound 33-1 (172 mg, yield: 22.0%, purity: 95.0%) as a red solid.

[0434] Step 2: Synthesis of 6-(2-(3,4-dimethoxyphenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one (Compound 33)

[0435] Compound 33-1 (80.0 mg, 1.00 eq) and (4-(trifluoromethyl)phenyl)boronic acid (45.0 mg, 1.49 eq) in R1-B(OH)2 in [Reaction Scheme 3] were mixed. This mixture was then added to a solution of K2CO3 (66.0 mg, 3.00 eq) dissolved in water (0.25 mL), Pd(t-Bu3P)2 (16.0 mg, 0.02 eq), and dioxane (1.00 mL) under a nitrogen atmosphere at 20-25°C. The mixture was stirred under a nitrogen atmosphere at 80-85°C for 8 hours. The synthesis of the desired compound was confirmed by LC-MS. Water (20.0 mL) was added to the mixture and extracted with ELISA (10.0 mL × 2). The organic layer was washed with brine (10.0 mL x 2), dried over anhydrous Na₂SO₄, and then filtered and concentrated under vacuum. The residue was purified by reversed-phase HPLC under 0.10% HCl conditions to obtain compound 33 (17.3 mg, yield: 18.6%, purity: 97.4%) as a red solid.

[0436] 1H NMR (400 MHz, DMSO-d6): δppm 9.21 (s, 1 H), 7.72 (d, J = 8.4 Hz, 2 H), 7.41 (d, J = 8.0 Hz, 2 H), 7.15 - 7.25 (m, 2 H), 7.06 (dd, J = 8.4, 2.4 Hz, 1 H), 6.86 (d, J = 9.2 Hz, 1 H), 6.62 (d, J = 2.8 Hz, 1 H), 6.48 (dd, J = 8.8, 3.2 Hz, 1 H), 4.40(dd, J = 5.6, 2.8 Hz, 2 H), 4.20 - 4.33(m, 2 H), 3.74(s, 3 H), 3.69(s, 3H), 1.85(s, 3H).

[0437] MS measured value: 568.3 (M+1)

[0438] Embodiment 38 6-(2-(3,4-dimethoxyphenoxy)ethoxy)-2-(4-fluorophenyl)-3-(5-methylthiazol-4-yl)-1H-inden-1-one (Compound 23)

[0439] Compound 33-1 (80.0 mg, 1.00 eq) synthesized in Embodiment 37 was mixed with (4-fluorophenyl)boronic acid (34.0 mg, 1.53 eq) in R1-B(OH)2 in [Reaction Scheme 3]. This mixture was then added to K2CO3 (67.0 mg, 3.04 eq), Pd(t-Bu3P)2 (10.0 mg, 0.12 eq), dioxane (2 mL), and water (0.5 mL) under a nitrogen atmosphere at 15-20°C. The mixture was stirred under a nitrogen atmosphere at 80-85°C for 14 hours. The synthesis of the desired compound was confirmed by LC-MS. Water (20 mL) was added to the mixture and extracted with SiO2. The organic layer was washed with brine, dried over Na2SO4, and then filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain compound 23 (13.60 mg, purity: 95.4%) as a red solid.

[0440] 1H NMR (400 MHz, DMSO-d6): δppm 9.20 (s, 1 H), 7.17 - 7.27 (m, 5 H), 7.15 (d, J = 8.0 Hz, 1 H), 7.04 (dd, J = 8.0, 2.4 Hz, 1 H), 6.86 (d, J = 8.8 Hz, 1 H), 6.63 (d, J = 2.4 Hz, 1 H), 6.49 (dd, J = 8.8, 2.75 Hz, 1 H), 4.38(br d, J = 4.4 Hz, 2 H), 4.27 (br d, J = 2.4 Hz, 2 H), 3.74 (s, 3 H), 3.69 (s, 3H), 1.86 (s, 3 H)

[0441] MS measured value: 518.3 (MS +1)

[0442] Embodiment 39 6-(2-(benzo[d][1,3]dioxol-5-yloxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one)(Compound 34)

[0443] Step 1: Synthesis of 6-(2-(benzo[d][1,3]dioxol-5-yloxy)ethoxy)-2-bromo-3-(5-methylthiazol-4-yl)-1H-inden-1-one)(34-1)

[0444] Compounds 4-7 (200 mg, 1.00 eq) synthesized in Embodiment 26 and 5-(2-bromoethoxy)benzo[d][1,3]dioxole (173 mg, 1.19 eq) were mixed in DMF (1.00 mL) with RX in [Reaction Scheme 3]. Then, K2CO3 (124 mg, 1.52 eq) and NaI (18.0 mg, 0.02 eq) were added under a nitrogen atmosphere at 20-25°C. The mixture was stirred at 40-45°C for 18 hours. The synthesis of the desired compound was confirmed by TLC (PE / EA = 3 / 1). Water (10.0 mL) was added to the mixture, and the pH was adjusted to 3-4 with 1 M HCl. After extraction with SiO2 (20.0 mL × 2), the mixture was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (SiO2, PE / EA = 30 / 1 to 3 / 1), and then concentrated to obtain compound 34-1 (150 mg, yield: 48.0%, purity: 91.8%) as a red solid.

[0445] Step 2: Synthesis of 6-(2-(benzo[d][1,3]dioxol-5-yloxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one) (Compound 34)

[0446] Compound 34-1 (40.0 mg, 1.00 eq) and (4-(trifluoromethyl)phenyl)boronic acid (24.0 mg, 1.54 eq) in R1-B(OH)2 in [Reaction Scheme 3] were mixed. This mixture was then added to a solution of K2CO3 (34.0 mg, 2.99 eq) dissolved in water (0.25 mL), Pd(t-Bu3P)2 (5.00 mg, 0.02 eq), and dioxane (1.00 mL) under a nitrogen atmosphere at 20-25°C. The mixture was stirred under a nitrogen atmosphere at 80-85°C for 8 hours. The synthesis of the desired compound was confirmed by LC-MS. Water (20.0 mL) was added to the mixture, and it was extracted with SiO2 (10.0 mL × 2). The organic layer was washed with brine (10.0 mL x 2), dried over anhydrous Na₂SO₄, and then filtered and concentrated under vacuum. The residue was purified by reversed-phase HPLC under 0.10% HCl conditions to obtain compound 34 (24.1 mg, yield: 53.1%, purity: 99.6%) as a red solid.

[0447] 1H NMR (400 MHz, DMSO-d6): δppm 9.21 (s, 1 H), 7.72 (d, J = 8.4 Hz, 2 H), 7.41 (d, J = 8.0 Hz, 2 H), 7.15 - 7.25 (m, 2 H), 7.06 (dd, J = 8.4, 2.4 Hz, 1 H), 6.86 (d, J = 9.2 Hz, 1 H), 6.62 (d, J = 2.8 Hz, 1 H), 6.48 (dd, J = 8.8, 3.2 Hz, 1 H), 4.40(dd, J = 5.6, 2.8 Hz, 2 H), 4.20 - 4.33(m, 2 H), 3.74(s, 3 H), 3.69(s, 3H), 1.85(s, 3H).

[0448] MS measured value: 552.3 (M+1)

[0449] Embodiment 40 6-(2-(benzo[d][1,3]dioxol-5-yloxy)ethoxy)-2-(4-fluorophenyl)-3-(5-methylthiazol-4-yl)-1H-inden-1-one (6-(2-(benzo[d][1,3]dioxol-5-yloxy)ethoxy)-2-(4-fluorophenyl)-3-(5-methylthiazol-4-yl)-1H-inden-1-one) (Compound 24)

[0450] Compound 34-1 (90.0 mg, 1.00 eq) synthesized in Embodiment 39 was mixed with (4-fluorophenyl)boronic acid (40.0 mg, 1.54 eq) in R1-B(OH)2 in [Reaction Scheme 3]. This mixture was then added to K2CO3 (78.0 mg, 3.05 eq), Pd(t-Bu3P)2 (10.0 mg, 0.1 eq), dioxane (2 mL), and water (0.5 mL) under a nitrogen atmosphere at 15-20°C. The mixture was stirred under a nitrogen atmosphere at 80-85°C for 14 hours. The synthesis of the desired compound was confirmed by LC-MS. Water (20 mL) was added to the mixture and extracted with SiO2. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography to obtain compound 24 (14.72 mg, yield: 15.8%, purity: 99.8%) as a red solid.

[0451] 1H NMR (400 MHz, DMSO-d6): δ ppm 9.20 (s, 1 H), 7.17 - 7.24 (m, 5 H), 7.14 (d, J=8.0 Hz, 1 H), 7.03 (dd, J= 8.0, 2.4 Hz, 1 H), 6.83 (d, J=8.4 Hz, 1 H), 6.69 (d, J=2.8 Hz, 1 H), 6.43 (dd, J=8.8, 2.8 Hz, 1 H), 5.97(s, 2H), 4.37(m, 2H), 4.23~4.28(m, 2H), 1.86(s, 3H)

[0452] MS measured value: 502.2 (MS +1)

[0453] Embodiment 41 3-(5-methylthiazol-4-yl)-6-(2-(pyridin-4-yloxy)ethoxy)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one (Compound 35)

[0454] Step 1: Synthesis of 2-bromo-6-(2-((t-butyldimethylsilyl)oxy)ethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one)(35-1)

[0455] Compounds 4-7 (1.00 g, 1.00 eq) synthesized in Embodiment 26 and (2-bromoethoxy)(tert-butyl)dimethylsilane (1.06 g, 1.50 eq) were mixed in DMF (10.0 mL). Then, K2CO3 (613 mg, 1.50 eq) and NaI (89.0 mg, 0.02 eq) were added under a nitrogen atmosphere at 20-25°C. The mixture was stirred at 40-45°C for 18 hours. The synthesis of the desired compound was confirmed by LC-MS. Water (50.0 mL) was added to the mixture, and the pH was adjusted to 3-4 with 1 M HCl. After extraction with ELISA (50.0 mL x 2), the mixture was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (SiO2, PE / EA = 30 / 1 to 3 / 1), and then concentrated to obtain compound 35-1 (723 mg, yield: 50.9%) as a red solid.

[0456] Step 2: Synthesis of 2-bromo-6-(2-hydroxyethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one (Compound 35-2)

[0457] Compound 35-1 (723 mg, 1.00 eq) and HCl (2.00 M, 1.50 mL, 2.00 eq) were added to THF (4.00 mL), and the mixture was stirred at 20-25°C for 12 hours. The synthesis of the desired compound was confirmed by TLC (PE / EA = 1 / 1). Water (10.0 mL) was added to the mixture, and the pH was adjusted to 8-9 with NaHCO3, after which it was extracted with ELISA (20.0 mL x 2). After concentration, compound 35-2 (521 mg, yield: 94.5%) was obtained as a red solid without purification.

[0458] Step 3: Synthesis of 6-(2-hydroxyethoxy)-3-(5-methylthiazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one (Compound 35-3)

[0459] Compound 35-2 (270 mg, 1.00 eq) and (4-(trifluoromethyl)phenyl)boronic acid (210 mg, 1.50 eq) in R1-B(OH)2 in [Reaction Scheme 3] were mixed. This mixture was then added to a solution of K2CO3 (307 mg, 3.01 eq) dissolved in water (0.7 mL), Pd(t-Bu3P)2 (75.0 mg, 0.02 eq), and dioxane (2.70 mL) under a nitrogen atmosphere at 20-25°C. The mixture was stirred under a nitrogen atmosphere at 80-85°C for 8 hours. TLC confirmed that the desired compound was synthesized. Water (20.0 mL) was added to the mixture and extracted with SiO (10.0 mL × 2). The organic layer was washed with brine (10.0 mL × 2), dried over anhydrous Na2SO4, and then filtered and concentrated under vacuum conditions. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 0 / 1), and then concentrated to obtain compound 35-3 (219 mg, yield: 62.4%, purity: 90.6%) as a red solid.

[0460] Step 4: Synthesis of 3-(5-methylthiazol-4-yl)-6-(2-(pyridin-4-yloxy)ethoxy)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one (Compound 35)

[0461] Compound 35-3 (110 mg, 1.00 eq) and pyridin-4-ol (29.0 mg, 1.50 eq) were added to DCM (0.50 mL) in place of RX in [Reaction Equation 3], and then PPh3 (118 mg, 1.76 eq) was added under a nitrogen atmosphere at 20-25°C. After cooling the mixture to 0-5°C, DIAD (91.0 mg, 1.77 eq) was added, and the mixture was stirred under a nitrogen atmosphere for 2 hours. The synthesis of the desired compound was confirmed by TLC (PE / EA=1 / 2). Water (20.0 mL) was added to the mixture and extracted with ethyl acetate (50.0 mL × 3). After drying over Na2SO4, the mixture was concentrated. The residue was purified by prep-TLC (EA:THF=1:1) and titrated in 3 mL of PE / MTBE=10 / 1 for 30 minutes at 20-25°C. After filtration and concentration processes, compound 35 was obtained as an orange solid.

[0462] 1H NMR (400 MHz, DMSO-d6): δppm 9.21 (s, 1 H), 8.40 (br d, J = 6.0 Hz, 2 H), 7.72 (br d, J = 8.0 Hz, 2 H), 7.40 (br d, J = 8.0 Hz, 2 H), 7.12 - 7.29 (m, 2 H), 6.94 - 7.11 (m, 3 H), 4.44 (s, 4 H), 1.85 (s, 3 H).

[0463] MS measured value: 509.3 (M+1)

[0464] Example Form 42: 2-(4-fluorophenyl)-3-(5-methylthiazol-4-yl)-6-(2-(pyridin-4-yloxy)ethoxy)-1H-inden-1-one (Compound 25)

[0465] Step 1: Synthesis of 2-(4-fluorophenyl)-6-(2-hydroxyethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one (25-1)

[0466] Compound 35-2 (250 mg, 1.00 eq) synthesized in Embodiment 41 was mixed with (4-fluorophenyl)boronic acid (146 mg, 1.53 eq) in R1-B(OH)2 in [Reaction Scheme 3]. This mixture was then added to a solution of K2CO3 (287 mg, 3.04 eq) dissolved in water (1 mL), Pd(t-Bu3P)2 (43.0 mg, 0.12 eq), and dioxane (4 mL) under a nitrogen atmosphere at 15-20°C. The mixture was stirred under a nitrogen atmosphere at 80-85°C for 14 hours. The synthesis of the desired compound was confirmed by LC-MS. Water (20.0 mL) was added to the mixture and extracted with SiO2. The organic layer was washed with brine, dried over Na2SO4, and then filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 3 / 1), and then concentrated to obtain compound 25-1 (103 mg, yield: 35.9%, purity: 90.8%) as a red solid.

[0467] Step 2: Synthesis of 2-(4-fluorophenyl)-3-(5-methylthiazol-4-yl)-6-(2-(pyridin-4-yloxy)ethoxy)-1H-inden-1-one (Compound 25)

[0468] Compound 25-1 (100.0 mg, 1.00 eq) and pyridin-4-ol (25.0 mg, 1.00 eq) were added to THF (5 mL) in place of RX in [Reaction Formula 3]. Then, PPh3 (103 mg, 1.50 eq) and DIAD (80.0 mL, 1.51 eq) were added under a nitrogen atmosphere at 0-10°C. The mixture was stirred under a nitrogen atmosphere at 15-25°C for 14 hours. The synthesis of the desired compound was confirmed by LC-MS. Water (20.0 mL) was added to the mixture and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. After drying over Na2SO4, the mixture was concentrated. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 3 / 1), after which compound 25 (27.58 mg, yield: 20.72%, purity: 90.3%) was obtained as a red gum.

[0469] 1H NMR (400 MHz, DMSO-d6): δ ppm 9.20 (s, 1 H), 8.39 - 8.43 (m, 2 H), ppm 7.13 - 7.25 (m, 6 H), 7.02 - 7.06 (m, 3 H) ), 4.44 (s, 4 H), 1.87 (s, 3 H)

[0470] MS measured value: 459.1 (MS +1)

[0471] Embodiment 43.3-(5-methylthiazol-4-yl)-6-phenethoxy-2-(thiophen-2-yl)-1H-inden-1-one (Compound 28)

[0472] Compound 18-1 (150 mg, 1.00 eq) synthesized in Embodiment 29 was mixed with tributyl(thiophen-2-yl)stannane (157 mg, 1.30 eq) in place of R1-B(OH)2 in [Reaction Scheme 3]. This mixture was then added to Pd2(dba)3 (60.0 mg, 0.20 eq) and dioxane (4.00 mL) under a nitrogen atmosphere at 20-25°C. The mixture was stirred under a nitrogen atmosphere at 115-120°C for 2 hours. Complete consumption of the reactants was confirmed by LC-MS. Water (15.0 mL) was added to the mixture at 15-20°C to cool it, and it was extracted with ethyl acetate (15.0 mL x 3). The organic layer was washed with brine (15.0 mL), dried over Na2SO4, filtered under reduced pressure, and concentrated to obtain the residue. The residue was purified by prep-HPLC to obtain compound 28 as a dark brown solid.

[0473] 1H NMR (400 MHz, DMSO-d6): δ ppm 2.17 (s, 3 H) 3.04 (t, J = 6.8 Hz, 2 H) 4.26 (t, J = 6.8 Hz, 2 H) 6.85 - 6.89 (m, 1 H) 6.92 - 6.96 (m, 1H) 7.04 - 7.10 (m, 2 H) 7.26 - 7.36 (m, 6 H) 7.56 (m, 1 H) 9.21 (s, 1 H)

[0474] MS measured value: 430.1 [M+H] +

[0475] Embodiment 44 3-(5-methylthiazol-4-yl)-6-(4-phenylbutoxy)-2-(thiophen-2-yl)-1H-inden-1-one (Compound 29)

[0476] Compound 19-1 (50.0 mg, 1.00 eq) synthesized in Embodiment 30 was mixed with tributyl(thiophen-2-yl)stannane (55.0 mg, 1.31 eq) in place of R1-B(OH)2 in [Reaction Scheme 3]. This mixture was then added to Pd2(dba)3 (20.0 mg, 0.02 eq) and dioxane (1.50 mL) under a nitrogen atmosphere at 25-30°C. The mixture was stirred in a microwave at 115-120°C for 2 hours. Complete consumption of the reactants was confirmed by LC-MS. Water (10.0 mL) was added to the mixture at 15-20°C and extracted with ELISA (10.0 mL x 3). The organic layer was washed with brine (10.0 mL), dried over Na2SO4, and then filtered and concentrated under reduced pressure at 45°C to obtain the residue. The residue was purified by prep-HPLC to obtain compound 29 (58.0 mg, yield: 58.7%, purity: 99.5%) as a red oil.

[0477] 1H NMR (400 MHz, DMSO-d6): δ 9.22(s, 1H), 7.55~7.57(m, 1H), 7.18~7.31(m, 6H), 7.05~7.10(m, 2H), 6.85~6.85 m, 2H), 4.03~4.07(m, 2H), 2.62~2.67(m, 2H), 2.18(s, 3H), 1.70~1.75(m, 4H)

[0478] MS measured value: 458.1 [M+H] +

[0479] Embodiment 45 6-((benzyloxy)methoxy)-3-(5-methylthiazol-4-yl)-2-(thiophen-2-yl)-1H-inden-1-one (compound 30)

[0480] Compound 20-1 (100 mg, 1.00 eq) synthesized in Embodiment 31 was mixed with tributyl(thiophen-2-yl)stannane (110 mg, 1.30 eq) in place of R1-B(OH)2 in Reaction Scheme 3. This mixture was then added to Pd2(dba)3 (42.0 mg, 0.20 eq) and dioxane (1.00 mL) under a nitrogen atmosphere at 20-25°C. The mixture was stirred under a nitrogen atmosphere at 120°C for 2 hours. LC-MS confirmed that the reactants were completely consumed. Water (3.0 mL) was added to the mixture and extracted with  (1.0 mL × 1). After drying over Na2SO4, the residue was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to obtain compound 30 (51.82 mg, yield: 51.0%, purity: 99.3%) as a dark purple solid.

[0481] 1H NMR (400 MHz, DMSO-d6): δ 9.23 (s, 1 H), 7.58 (dd, J = 5.2, 1.2 Hz, 1 H), 7.26 - 7.39 (m, 6 H), 7.23 (d, J = 2.4 Hz, 1 H), 7.02 - 7.14 (m, 2 H), 6.91 (d, J = 8.0 Hz, 1 H), 5.40 (s, 2 H), 4.70 (s, 2 H), 2.12 - 2.28 (m, 3 H)

[0482] MS measured value: 446.0 (M+1)

[0483] Embodiment 46 3-(5-methylthiazol-4-yl)-6-(2-phenoxyethoxy)-2-(thiophen-2-yl)-1H-inden-1-one (Compound 31)

[0484] Compound 21-1 (150 mg, 1.00 eq) synthesized in Embodiment 32 was mixed with tributyl(thiophen-2-yl)stannane (146 mg, 1.30 eq) in place of R1-B(OH)2 in [Reaction Formula 3]. This mixture was then added to Pd2(dba)3 (55.0 mg, 0.20 eq) and dioxane (4.50 mL) under a nitrogen atmosphere at 20-25°C. The mixture was stirred under a nitrogen atmosphere at 115-120°C for 2 hours. Complete consumption of the reactants was confirmed by LC-MS. Water (15.0 mL) was added to the mixture at 15-20°C to cool it, and it was extracted with ethyl acetate (15.0 mL x 3). The organic layer was washed with brine (15.0 mL), dried over Na2SO4, filtered under reduced pressure, and concentrated to obtain the residue. The residue was purified by prep-HPLC to obtain compound 31 as a dark brown solid.

[0485] 1H NMR (400 MHz, DMSO-d6): δppm 2.19 (s, 3 H) 4.29 - 4.34 (m, 2 H) 4.40 (dd, J = 5.6, 2.8 Hz, 2 H) 6.89 - 7.02 (m, 5 H) 7.07 (m, 1 H) 7.17 (d, J=2.4 Hz, 1 H) 7.27 - 7.33 (m, 3 H) 7.57 (dd, J = 5.2, 1.2 Hz, 1 H) 9.23 (s, 1 H)

[0486] MS measured value: 446.0 [M+H] +

[0487] Embodiment 47 6-(2-(3,4-dichlorophenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(thiophen-2-yl)-1H-inden-1-one (Compound 36)

[0488] Compound 26-1 (100 mg, 1.00 eq) synthesized in Embodiment 33 was mixed with tributyl(thiophen-2-yl)stannane (96.0 mg, 1.32 eq) in place of R1-B(OH)2 in [Reaction Scheme 3]. This mixture was then added to Pd2(dba)3 (36.0 mg, 39.31 umol, 0.20 eq) and dioxane (3 mL) under a nitrogen atmosphere at 15-25°C. The mixture was stirred with microwaves under a nitrogen atmosphere at 145-150°C for 2 hours. The synthesis of the desired compound was confirmed by LC-MS. Water (20 mL) was added to the mixture and extracted with RINKAN (30 mL x 3). The organic layer was washed with brine (30 mL), dried over Na2SO4, and then filtered and concentrated under reduced pressure at 45°C to obtain the residue. The residue was purified by reversed-phase HPLC to obtain compound 36 (50.2 mg, yield: 49.5%, purity: 99.4%) as a dark purple solid.

[0489] 1H NMR (400 MHz, DMSO-d6): δ9.23(s, 1H), 7.64 - 7.48(m, 2H), 7.36-7.25(m, 2H), 7.16(d, J = 2.4 Hz, 1H), 7.09 -6.97(m, 3H), 6.90(d, J=8.0Hz, 1H), 4.38(br d, J=2.8Hz, 4H), 2.19(s, 3H)

[0490] MS measured value: 514.0 (M+1)

[0491] Embodiment 48 6-(2-(3,4-difluorophenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(thiophen-2-yl)-1H-inden-1-one (Compound 37)

[0492] Compound 27-1 (100 mg, 1.00 eq) synthesized in Embodiment 34 was mixed with tributyl(thiophen-2-yl)stannane (103 mg, 1.32 eq) in place of R1-B(OH)2 in [Reaction Formula 3]. This mixture was then added to Pd2(dba)3 (39 mg, 0.20 eq) and dioxane (3 mL) under a nitrogen atmosphere at 15-25°C. The mixture was stirred with microwaves under a nitrogen atmosphere at 145-150°C for 2 hours. The synthesis of the desired compound was confirmed by LC-MS. Water (20 mL) was added to the mixture and extracted with RINKAN (30 mL x 3). The organic layer was washed with brine (30 mL), dried over Na2SO4, and then filtered and concentrated under reduced pressure at 45°C to obtain the residue. The residue was purified by reversed-phase HPLC to obtain compound 37 (30.4 mg, yield: 29.9%, purity: 99.0%) as a dark purple solid.

[0493] 1H NMR (400 MHz, DMSO-d6): δ9.22(s, 1H), 9.10(s, 1H), 8.60(s, 2H), 7.42-7.32(m, 1H), 7.27-7.20(m, 2H), 7.16 (ddd, J = 2.8, 6.8, 12.8 Hz, 1H), 7.07 (dd, J = 2.4, 8.0 Hz, 1H), 6.87-6.80 (m, 1H), 4.46-4.01 (m, 4) (s, 3H)

[0494] MS measured value: 478.1 (M+1)

[0495] Embodiment 49 6-(3-phenylpropoxy)-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one (Compound 6)

[0496] [Reaction Equation 4]

[0497] [ka]

[0498] Step 1: Synthesis of 3-(thiophen-2-ylethynyl)pyridin (6-3)

[0499] Compound 6-1 (1.70 g, 8.08 mmol, 823 μL) from [Reaction Scheme 4] was mixed with 3-ethynylpyridine (1.00 g, 9.70 mmol, 558 μL) as compound 6-2(A) in [Reaction Scheme 4], where R1 is pyridine. Then, Et3N (2.45 g, 24.2 mmol, 3.37 mL), CuI (769 mg, 4.04 mmol), and PdCl2(PPh3)2 (567 mg, 808 μL) were added under a nitrogen atmosphere at 25°C. The mixture was stirred at 25°C for 12 hours. The synthesis of compound 6-3 was confirmed by LC-MS, and the complete consumption of the reactants was confirmed by TLC (PE:EA=3 / 1). The residue was diluted with RINKAN (200 mL). The bound organic phase layer was extracted with brine (20 mL x 3). After drying and filtering with anhydrous Na2SO4, the residue was concentrated under low pressure conditions to obtain the residue. The residue was purified by flash silica gel chromatography, and compound 6-3 yielded 3-(thiophen-2-ylethynyl)pyridine (1.16 g, 6.26 mmol, yield: 77.49%) as a yellow oil.

[0500] Step 2: Synthesis of 6-methoxy-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one (6-5)

[0501] Dioxane (5.00 mL) was mixed with 3-(thiophene-2-ylethinyl)pyridine (600 mg, 3.24 mmol), which is compound 6-3 synthesized in step 1, and compound 6-4A (2.03 g, 6.48 mmol). Then, TBAB (1.04 g, 3.24 mmol), Na2CO3 (686 mg, 6.48 mmol), and PdCl2 (57.4 mg, 323 mmol) were added at 25°C under carbon monoxide (15 psi) conditions. The mixture was stirred at 100°C for 12 hours. Complete consumption of the reaction products was confirmed by TLC (PE:EA = 1 / 1). The residue was diluted with ELISA (200 mL). The bound organic phase layer was extracted with brine (20.0 mL x 3). After drying and filtering with anhydrous Na2SO4, the residue was concentrated under low pressure conditions. The residue was purified by flash silica gel chromatography, followed by prep-HPLC to obtain compound 6-5 (6-methoxy-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one, 100 mg, 313 umol, yield: 9.67%) as a red solid and compound 6-5(B) (6-methoxy-3-(pyridin-3-yl)-2-(thiophen-2-yl)-1H-inden-1-one, 140 mg, 438.35 umol, yield: 13.53%) as a purple solid.

[0502] Step 3: Synthesis of 6-hydroxy-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one (6-6)

[0503] Compound 6-5, 6-methoxy-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one (70.0 mg, 219.18 umol), was mixed with DCM (2.00 mL), and then BBr3 (55.0 mg, 219 umol, 21.1 uL) was added under a nitrogen atmosphere at 0°C. The mixture was stirred at 25°C for 12 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA=1 / 1). The reaction mixture was cooled with aqueous NaHCO3 (10.0 mL), and no further reaction (work-up) occurred, yielding compound 6-6 (6-hydroxy-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one, 150 mg) as a red oil.

[0504] Step 4: Synthesis of 6-(3-phenylpropoxy)-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one (compound 6)

[0505] 6-hydroxy-2-(pyridine-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one (70.0 mg, 229 umol), compound 6-6, and (3-bromopropyl)benzene ((3-bromopropyl)benzene (68.5 mg, 343 umol, 51.8 uL) in RX of [Reaction Scheme 4] were mixed in acetonitrile (3.00 mL), and then K2CO3 (79.2 mg, 573 umol) was added under a nitrogen atmosphere at 25°C. The mixture was stirred at 60°C for 12 hours. Complete consumption of the reactants was confirmed by LC-MS. The residue was diluted with  (200 mL). The bound organic phase layer was extracted with brine (20.0 mL x 3). After drying and filtering with anhydrous Na2SO4, the residue was concentrated under low pressure conditions. The residue was purified by prep-HPLC to obtain compound 6 (5.00 mg, 11.6 umol, yield: 5.05%, purity: 98.15%) as a red solid.

[0506] 1H NMR (400 MHz, CD3OD): δ8.53-8.56(m, 2H), 7.97-8.0(m, 1H), 7.74(dd, J = 8.0, 5.2 Hz, 1H), 7.59-7.62(m, 1H), 7.48-7.55(m, 2H), 7.15-7.33(m, 7H), 6.97(dd, J=2.4, 8.0Hz, 1H), 4.04(t, J=6.0Hz, 2H), 2.82(t, J=7.6 Hz, 2H), 2.04-2.18(m, 2H)

[0507] MS measured value: 424.1 [M+H] +

[0508] Embodiment 50 6-(3-phenylpropoxy)-3-(1H-pyrazol-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 7)

[0509] [Reaction Equation 5]

[0510] [ka]

[0511] Step 1: Synthesis of (E)-1-(3-hydroxyphenyl)-3-(1H-pyrazol-5-yl)prop-2-en-1-one (7-3)

[0512] Compound 7-1 (5.00 g, 52.0 mmol) from [Reaction Formula 5] and compound 7-2 (7.08 g, 52.0 mmol) from [Chemical Formula 5] were mixed in ethanol (75.0 mL). Then, NaOH (3.12 g, 78.05 mmol) was added to H2O (30.0 mL) at 0°C. The reaction mixture was stirred at 25°C for 16 hours. Complete consumption of the reaction products was confirmed by TLC (PE:EA=3 / 1). The residue was diluted with H2O (50 mL) and extracted with ELISA (50.0 mL × 2). The bound organic phase layer was extracted with brine (50 mL × 2). After drying with Na2SO4 and filtering, the residue was concentrated under low pressure conditions. The residue was purified by column chromatography (SiO2, PE / EA=1 / 0~3 / 1) to obtain compound 7-3 (1.25 g) as a yellow solid.

[0513] Step 2: Synthesis of 6-hydroxy-3-(1H-pyrazol-5-yl)-2,3-dihydro-1H-inden-1-one (7-4)

[0514] Compound 7-3 (1.10 g, 5.13 mmol) was mixed with triflic acid (10.0 mL), and the mixture was stirred at 80°C for 16 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA = 1 / 1). The residue was diluted with H2O (50.0 mL) and extracted with ELISA (50.0 mL × 2). The bound organic phase layer was extracted with brine (50.0 mL × 2). After drying with Na2SO4 and filtration, the residue was concentrated under low pressure conditions. The residue was purified by column chromatography (SiO2, PE / EA = 1 / 0 to 1 / 1) to obtain compound 7-4 (0.80 g, 3.73 mmol, yield: 72.7%) as a dark brown solid.

[0515] Step 3: Synthesis of [1-(1-acetylpyrazol-3-yl)-3-oxo-indan-5-yl]acetate (7-5)

[0516] Compound 7-4 (500 mg, 2.33 mmol) and Ac2O (1.19 g, 11.6 mmol) were mixed in DCM (10 mL), and then pyridine (923 mg, 11.6 mmol) and DMAP (285 mg, 2.33 mmol) were added under a nitrogen atmosphere at 0°C. The mixture was stirred at 20°C for 12 hours. Complete consumption of the reaction products was confirmed by TLC (PE:EA = 1 / 1). The reaction mixture was diluted with DCM (100 mL) and extracted with brine (30.0 mL x 3). After drying with anhydrous Na2SO4, the residue was concentrated under vacuum to obtain the residue. The residue was purified by flash silica gel chromatography to obtain the yellow solid compound 7-5 (540 mg, 1.81 mmol, yield: 77.5%).

[0517] Step 4: Synthesis of [1-(1-acetylpyrazol-3-yl)-2-bromo-3-oxo-inden-5-yl]acetate (7-6)

[0518] Compound 7-5 (540 mg, 1.81 mmol) and NBS (708 mg, 3.98 mmol) were dissolved in carbon tetrachloride (10.0 mL), and then AIBN (29.7 mg, 181 µl) was added under a nitrogen atmosphere. The mixture was stirred at 400 W and 80°C for 2 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA = 1 / 1). The mixture was diluted with DCM (100 mL) and extracted with brine (30.0 mL x 3). After drying and filtering with anhydrous Na2SO4, the mixture was concentrated under vacuum to obtain compound 7-6 (800 mg) as a red oil.

[0519] Step 5: Synthesis of 3-(1-acetylpyrazol-3-yl)-2-bromo-6-hydroxy-inden-1-one (7-7)

[0520] Compound 7-6 (800 mg, 2.13 mmol) was dissolved in DCM (10.0 mL), and then DBU (324 mg, 2.13 mmol) was added at 0°C. The mixture was stirred at 20°C for 12 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA = 2 / 1). The mixture was adjusted to pH 6 with 1N HCl, and then extracted with DCM (50.0 mL × 3). The bound organic phase layer was dried with anhydrous Na2SO4 and filtered, and then concentrated in vacuum to obtain the residue. The residue was purified by flash silica gel chromatography to obtain compound 7-7 (40.0 mg, 120 µl, yield: 5.63%) as a red solid.

[0521] Step 6: Synthesis of 3-(1-acetyl-1H-pyrazol-3-yl)-2-bromo-6-(3-phenylpropoxy)-1H-inden-1-one (compounds 7-8)

[0522] Compound 7-7 (40.0 mg, 120 umol) and (3-bromopropyl)benzene (35.8 mg, 180 umol) were mixed in acetonitrile (3.00 mL) at RX in the reaction formula 5 above. Then, K2CO3 (49.8 mg, 360 umol) was added at 20°C, and the mixture was stirred at 20°C for 3 hours. Complete consumption of the reactants was confirmed by TLC (PE:EA = 2 / 1). The mixture was diluted with ethyl acetate (50.0 mL) and extracted with brine (20.0 mL x 3). After drying and filtering with anhydrous sodium 2SO4, the residue was concentrated in vacuum to obtain the residue. The residue was purified by flash silica gel chromatography to obtain compound 7-8(3-(1-acetyl-1H-pyrazol-3-yl)-2-bromo-6-(3-phenylpropoxy)-1H-inden-1-one, 6.00 mg, 12.37 umol, yield: 10.30%) as a yellow oil.

[0523] Step 7: Synthesis of 6-(3-phenylpropoxy)-3-(1H-pyrazol-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 7)

[0524] Dioxane (1.50 mL) and H2O (0.50 mL) were mixed with compound 7-8 (6.00 mg, 12.37 umol) and pyridine-3-ylboronic acid (1.82 mg, 14.8 umol) in the above [Chemical Formula 5] B(OH)2-R1, where R1 is pyridine. Then, K3PO4 (7.88 mg, 37.11 umol) and Pd(dtbpf)Cl2 (806 ug, 1.24 umol) were added. The mixture was stirred for 10 hours under a nitrogen atmosphere at 100°C. Complete consumption of the reactants was confirmed by TLC (DCM: methanol = 10 / 1). The mixture was diluted with H2O (10.0 mL) and extracted with SiO2 (20.0 mL × 3). The bound organic phase layer was dried with anhydrous Na2SO4 and filtered, then concentrated in vacuum to obtain the residue. The residue was purified by prep-TLC (SiO2, DCM:methanol = 10 / 1) to obtain compound 7 (3.50 mg, 8.59 umol, yield: 64.61%, purity: 89.36%) as a red solid.

[0525] 1H NMR (400 MHz, CD3OD): δ8.45-8.52(m, 2H), 7.80-7.90(m, 2H), 7.63(d, J = 2.4 Hz, 1H), 7.41-7.49(m, 1H), 7. -7.33(m, 2H, ), 7.13-7.22(m, 3H), 7.00(d, J=2.4Hz, 1H), 6.83(dd, J=2.4, 8.0Hz, 1H), 6.18(d, J= 2.4 Hz, 1H), 4.24 (t, J = 6.8 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 2.18-2.25 (m, 2H)

[0526] MS measured value: 452.8 [M+H] +

[0527] Experimental example

[0528] Experimental Example 1: Amyloid-beta disaggregation test

[0529] 1.1. Sample Preparation

[0530] Each compound was dissolved in DMSO to a concentration of 10 mM. The compounds were then diluted with 6% DMSO (in DW) before use.

[0531] Specifically, amyloid-beta and tau solutions are used for Aβ 1~42 Alternatively, Tau-RD3 (Tau repeat domain 3) monomer was prepared by dissolving it in DMSO to a concentration of 10 mM. This was then diluted to 100 μM using DW and stored on ice. Meanwhile, thioflavin-T was dissolved in 50 mM glycine buffer (pH 8.5) to a concentration of 5 mM. This was then diluted to 5 μM using 50 mM glycine buffer (pH 8.5) and stored in a dark room, protected from light.

[0532] 1.2. Amyloid-β and Tau Aggregation and Degradation Test by Thioflavin-T Analysis

[0533] The amyloid-β and tau solutions prepared in Experimental Example 1.1 were placed in 1.5 mL microcentrifuge tubes to concentrations of 50 μM and 35 μM, respectively, and reacted at 37°C for 24 hours. Each of the 1.5 mL microcentrifuge tubes containing the completed amyloid-β and tau aggregation was then subjected to serial dilution from 500 μM down to 0 μM, and reacted further at 37°C for 48 hours. 25 μL of the reaction solution was placed in each well of a 96-well fluorescence analysis plate, and 75 μL of the previously prepared thioflavin-T solution was added to each well. After reacting in a dark room at room temperature for 5 minutes, the fluorescence values ​​were measured using a multi-mode microplate reader at excitation 450 nm and emission 485 nm.

[0534] The fluorescence values ​​of the group (control group) treated with amyloid-beta or tau alone and aggregated for 72 hours were converted to percentage values ​​and expressed as 100. After the amyloid-beta and tau aggregates had been reacted for 24 hours and aggregated, each compound was treated at different concentrations and reacted for a further 48 hours. The measured fluorescence values ​​were then converted to relative values, and the results are shown in Figures 1-6 and 7-12, respectively. Furthermore, the EC250 of each compound of the present invention against amyloid-beta and tau was also measured. 50 The values ​​are summarized in Table 1.

[0535] [Table 1] JPEG0007860640000017.jpg121140

[0536] Figures 1-6 show the amyloid-beta aggregation and degradation effects of each indenone derivative compound 1-50 at treatment concentrations (0-500 μM) (control group: Aβ). 1-42 Aggregation occurred in the 50 μM treatment group after 72 hours. Treatment group: Aβ 1-42 (50 μM amyloid-beta aggregates for 24 hours + treatment with each derivative compound at its respective concentration for 48 hours) and concentrations (EC2) that can decompose 50% of amyloid-beta aggregates compared to the control group during each compound treatment. 50This indicates that each compound exhibits a concentration-dependent aggregation and decomposition effect.

[0537] Figures 7-12 show the tau agglutination decomposition effect of each compound at different treatment concentrations (0-500 μM) (control group: Tau-RD3 35 μM treatment group with 72 hours of agglutination; treatment group: Tau-RD3 35 μM with 24 hours of agglutination + treatment at the respective concentrations of derivative compounds for 48 hours of reaction) and the concentration (EC) required to decompose 50% of tau agglutination compared to the control group at each compound treatment. 50 This indicates that each compound exhibits a concentration-dependent aggregation and decomposition effect.

[0538] Experimental Example 2: Confirmation of the effect of compound treatment on reducing amyloid plaques in 5xFAD TG mice.

[0539] 2.1 Preparing the 5xFAD TG Mouse Model

[0540] Transgenic mice (5×FAD TG, an animal model of Alzheimer's disease, B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas / Mmjax) and wild-type mice were derived from Jackson Laboratory (Bar Harbor, Maine, USA). 5×FAD TG mice were cross-retained with wild-type mice to maintain double hemizygotes. All genotypes were confirmed by PCR analysis using tail DNA according to Jackson Laboratory's standard PCR conditions. The TG mice used in this study were selected because they represent a model of cognitive decline caused by amyloid-beta deposition in the brain, and the amyloid-beta deposition patterns are known to be similar to those of actual Alzheimer's patients, making interpretation and evaluation of the study results easier. The mice were housed individually in plastic cages in the animal enclosure, maintained at 21±1°C with a 12-hour light-dark cycle, and given free access to food and water.

[0541] 2.2 Administration of compounds to mouse models

[0542] The compounds were administered orally daily at various concentrations to 10-month-old 5×FAD TG mice.

[0543] The test group consisted of a total of six groups: one wildtype (WT) group and five 5xFAD (TG) groups. The TG mouse groups included a negative control group administered via vehicle and groups administered compound 1 at 3 mg / kg, 10 mg / kg, 30 mg / kg, and 100 mg / kg.

[0544] 2.3 Preparation of brain tissue samples

[0545] After 4 weeks of administration, mice were anesthetized with 2% aveltin (20 mg / g, ip). The mice were perfused with 0.9% NaCl, their brains were removed, and the hemibrains were fixed overnight in 4% paraformaldehyde (pH 7.4) at 4°C.

[0546] 2.4 Immunohistochemical staining

[0547] In Experimental Example 2.3, fixed brain tissue was prepared into 30 μm thick sections and subjected to immunohistochemical staining. The fixed tissue was reacted with a 0.5% thioflavin-S solution for 10 minutes to stain amyloid plaques. After washing twice with 50% ethanol and once with DPBS, the stained tissue was mounted on a glass slide and observed with a laser scanning confocal microscope. Immunostaining was also performed using the 6E10 antibody, a specific antibody against amyloid-beta.

[0548] Figure 13 is a graph showing the effect of indenone derivative compound treatment on reducing amyloid plaque in a 5xFAD TG mouse Alzheimer's model according to one embodiment.

[0549] As shown in the graph in Figure 13, the total area of ​​amyloid-beta aggregation in the cerebral hemispheres was calculated, and compared to the control group of mice (Vehicle), it was confirmed that the plaque area decreased significantly in a dose-dependent manner in mice administered with the compound.

[0550] Experimental Example 3: Confirmation of the effect of compound treatment on reducing tau aggregates in PS19 TG mice.

[0551] 3.1 Preparing the PS19 TG Mouse Model

[0552] Transgenic mice (PS19 TG, an animal model of Alzheimer's disease, B6;C3-Tg(Prnp-MAPT*P301S)PS19Vle / J) and wild-type mice were derived from Jackson Laboratory (Bar Harbor, Maine, USA). PS19 TG mice were cross-pollinated with wild-type mice to maintain double hemizygotes. All genotypes were confirmed by PCR analysis using tail DNA according to Jackson Laboratory's standard PCR conditions. The TG mice used in this study were selected because they represent a model in which cognitive decline occurs due to tau aggregate deposition in the brain, and the deposition patterns of tau aggregates, which are deposited in the brains of actual Alzheimer's patients, are known to have a similar morphology to those of patients, making it easier to interpret and evaluate the test results. The mice were housed individually in plastic cages in the animal housing room, maintained at 21±1°C with a 12-hour light-dark cycle, and had free access to food and water.

[0553] 3.2 Administration of compounds to mouse models

[0554] The compounds were administered orally daily at various concentrations to 6-month-old PS19 TG mice.

[0555] There were a total of four test groups: one wildtype (WT) group and three PS19 (TG) groups. The TG mouse groups consisted of a negative control group administered via vehicle and groups administered compound 1 at 3 mg / kg and 10 mg / kg.

[0556] 3.3 Preparation of brain tissue samples

[0557] After 12 weeks of administration, mice were anesthetized with 2% aveltin (20 mg / g, ip). The mice were perfused with 0.9% NaCl, their brains were removed, and the hemibrains were fixed overnight in 4% paraformaldehyde (pH 7.4) at 4°C.

[0558] 3.4 Immunohistochemical staining

[0559] The fixed brain tissue prepared in Experimental Example 3.3 was sectioned to a thickness of 30 μm and subjected to immunohistochemical staining. The fixed tissue was reacted with 0.5% thioflavin-S solution for 10 minutes to stain tau aggregates. After washing twice with 50% ethanol and once with DPBS, the stained tissue was mounted on a glass slide and observed with a laser scanning confocal microscope. Immunostaining was also performed using NFT (Neurofibrillary tangles) antibody bodies, which are specific antibodies against tau aggregates.

[0560] Figure 14 is a graph showing the effect of indenone derivative compound treatment on reducing tau aggregates in a PS19 TG mouse Alzheimer's model according to one embodiment.

[0561] As shown in the graph in Figure 14, the total area of ​​tau aggregates in the cerebral hemispheres was calculated, and when compared with control mice (Vehicle), it was confirmed that the area of ​​the tau aggregates decreased significantly in a dose-dependent manner in mice administered the compound.

[0562] The above description of the present invention is illustrative, and a person with ordinary skill in the art will understand that the invention can be easily modified into other specific forms without altering the technical idea or essential features of the invention. Therefore, the embodiments described above should be understood to be illustrative in all respects and not limiting.

Claims

1. Compounds of the following chemical formula 1 or their pharmaceutically acceptable salts: 【Chemistry 1】 In the above formula, X is either directly bonded or O, Y is either O or S, n is an integer between 0 and 5. m is an integer from 1 to 5. R 1 is halogen, C 1-6 alkyl, C 6-10 aryl, -C 1-6 alkyl-C 6-10 aryl or 5- to 6-membered heteroaryl, where the C 1-6 alkyl, C 6-10 aryl, -C 1-6 alkyl-C 6-10 aryl and 5- to 6-membered heteroaryl are each independently unsubstituted or substituted with 1 to 4 halogens, hydroxy, CN, -NH 2 , -CF 3 , C 1-6 alkyl, -C 1-6 alkyl-CN, -O-C 1-6 alkyl, -NH-C 1-6 alkyl or -N(C 1-6 alkyl) 2 and may be substituted, R 2 is a 5-6 member heteroaryl, where the 5-6 member heteroaryl is either unsubstituted or has 1-4 halogens, -CF 3 or C 1-6 It may be substituted with alkyl, R 3 is C 6-10 The aryl, 5-6 membered heteroaryl, or 5-10 membered heterocyclyl, where C 6-10 The aryl, 5-6 membered heteroaryl, and 5-10 membered heterocyclyl compounds are each independently unsubstituted or have 1-4 halogens, hydroxyls, CNs, or -NHs. 2 , -CF 3 , C 1-6 Alkyl, -C 1-6 Alkyl-CN,-O-C 1-6 Alkyl, -NH-C 1-6 Alkyl or -N(C) 1-6 Alkyl) 2 It may be replaced with, The heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, and the heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from N, O, and S.

2. R 1 is a halogen, phenyl, pyridinyl, pyrimidinyl, or thiophenyl, where each of the phenyl, pyridinyl, pyrimidinyl, and thiophenyl is independently unsubstituted or has 1 to 4 halogens, hydroxyl, CN, or -CF 3 , C 1-6 Alkyl, -C 1-6 Alkyl-CN, or -O-C 1-6 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with an alkyl group.

3. R 2 is furanyl, thiophenyl, thiazolyl, or pyrazolyl, where thiazolyl, furanyl, thiophenyl, and pyrazolyl are each independently unsubstituted or have 1 to 4 halogens, -CF 3 or C 1-6 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with an alkyl group.

4. R 3 is phenyl, pyridinyl, morpholinyl, or benzodioxolyl, where each of the phenyl, pyridinyl, morpholinyl, and benzodioxolyl is independently unsubstituted or has 1 to 4 halogens, hydroxy, or -NH 2 , -CF 3 , C 1-6 Alkyl, -O-C 1-6 Alkyl, -NH-C 1-6 Alkyl or -N(C) 1-6 Alkyl) 2 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with.

5. R 1 is a halogen, phenyl, pyridinyl, pyrimidinyl, or thiophenyl, where each of the phenyl, pyridinyl, pyrimidinyl, and thiophenyl is independently unsubstituted or has 1 to 4 halogens, hydroxyl, CN, or -CF 3 , C 1-6 Alkyl, -C 1-6 Alkyl-CN, or -O-C 1-6 It may be substituted with alkyl, R 2 is furanyl, thiophenyl, thiazolyl, or pyrazolyl, where thiazolyl, furanyl, thiophenyl, and pyrazolyl are each independently unsubstituted or have 1 to 4 halogens, -CF 3 or C 1-6 It may be substituted with alkyl, R 3 is phenyl, pyridinyl, morpholinyl, or benzodioxolyl, where each of the phenyl, pyridinyl, morpholinyl, and benzodioxolyl is independently unsubstituted or has 1 to 4 halogens, hydroxy, or -NH 2 , -CF 3 , C 1-6 Alkyl, -O-C 1-6 Alkyl, -NH-C 1-6 Alkyl or -N(C) 1-6 Alkyl) 2 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the following: (1) 3-(4-methylthiazole-5-yl)-6-(3-phenylpropoxy)-2-(pyridine-3-yl)-1H-inden-1-one, (2) 2-(2-(3-(4-methylthiazole-5-yl)-1-oxo-6-(3-phenylpropoxy)-1H-inden-2-yl)phenyl)acetonitrile, (3) 2-bromo-3-(4-methylthiazole-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (4) 3-(5-methylthiazole-4-yl)-6-(3-morpholinopropoxy)-2-(pyridine-3-yl)-1H-inden-1-one, (5) 2-bromo-3-(5-methylthiazole-4-yl)-6-(3-morpholinopropoxy)-1H-inden-1-one, (6) 6-(3-phenylpropoxy)-2-(pyridine-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one, (7) 6-(3-phenylpropoxy)-3-(1H-pyrazole-3-yl)-2-(pyridine-3-yl)-1H-inden-1-one, (8) 3-(5-methylthiazole-4-yl)-6-(3-phenylpropoxy)-2-(pyridine-3-yl)-1H-inden-1-one, (9) 3-(furan-3-yl)-6-(3-phenylpropoxy)-2-(pyridine-3-yl)-1H-inden-1-one, (10) 3-(4-methylthiazole-5-yl)-2-phenyl-6-(3-phenylpropoxy)-1H-inden-1-one, (11) 3-(4-methylthiazole-5-yl)-6-(3-phenylpropoxy)-2-(pyrimidine-5-yl)-1H-inden-1-one, (12) 3-(4-methylthiazole-5-yl)-6-(3-phenylpropoxy)-2-(thiophen-2-yl)-1H-inden-1-one, (13) 3-(4-methylthiazole-5-yl)-2-(pyridine-3-yl)-6-(3-(pyridine-4-yl)propoxy)-1H-inden-1-one, (14) 3-(4-methylthiazole-5-yl)-6-penethoxy-2-(pyridine-3-yl)-1H-inden-1-one, (15) 3-(4-methylthiazole-5-yl)-6-(4-phenylbutoxy)-2-(pyridine-3-yl)-1H-inden-1-one, (16) 6-((benzyloxy)methoxy)-3-(4-methylthiazole-5-yl)-2-(pyridine-3-yl)-1H-inden-1-one, (17) 3-(4-methylthiazole-5-yl)-6-(2-phenoxyethoxy)-2-(pyridine-3-yl)-1H-inden-1-one, (18) 2-(4-methoxyphenyl)-3-(5-methylthiazole-4-yl)-6-pentoxy-1H-inden-1-one, (19) 2-(4-methoxyphenyl)-3-(5-methylthiazole-4-yl)-6-(4-phenylbutoxy)-1H-inden-1-one, (20) 6-((benzyloxy)methoxy)-2-(4-methoxyphenyl)-3-(5-methylthiazole-4-yl)-1H-inden-1-one, (21) 2-(4-methoxyphenyl)-3-(5-methylthiazole-4-yl)-6-(2-phenoxyethoxy)-1H-inden-1-one, (22) 2-(4-fluorophenyl)-6-(2-(4-methoxyphenoxy)ethoxy)-3-(5-methylthiazole-4-yl)-1H-inden-1-one, (23) 6-(2-(3,4-dimethoxyphenoxy)ethoxy)-2-(4-fluorophenyl)-3-(5-methylthiazole-4-yl)-1H-inden-1-one, (24) 6-(2-(benzo[d][1,3]dioxol-5-yloxy)ethoxy)-2-(4-fluorophenyl)-3-(5-methylthiazole-4-yl)-1H-inden-1-one, (25) 2-(4-fluorophenyl)-3-(5-methylthiazole-4-yl)-6-(2-(pyridine-4-yloxy)ethoxy)-1H-inden-1-one, (26) 6-(2-(3,4-dichlorophenoxy)ethoxy)-3-(5-methylthiazole-4-yl)-2-(pyrimidine-5-yl)-1H-inden-1-one, (27) 6-(2-(3,4-difluorophenoxy)ethoxy)-3-(5-methylthiazole-4-yl)-2-(pyrimidine-5-yl)-1H-inden-1-one, (28) 3-(5-methylthiazole-4-yl)-6-pentoxy-2-(thiophen-2-yl)-1H-inden-1-one, (29) 3-(5-methylthiazole-4-yl)-6-(4-phenylbutoxy)-2-(thiophen-2-yl)-1H-inden-1-one, (30) 6-((benzyloxy)methoxy)-3-(5-methylthiazole-4-yl)-2-(thiophen-2-yl)-1H-inden-1-one, (31) 3-(5-methylthiazole-4-yl)-6-(2-phenoxyethoxy)-2-(thiophen-2-yl)-1H-inden-1-one, (32) 6-(2-(4-methoxyphenoxy)ethoxy)-3-(5-methylthiazole-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one, (33) 6-(2-(3,4-dimethoxyphenoxy)ethoxy)-3-(5-methylthiazole-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one, (34) 6-(2-(benzo[d][1,3]dioxol-5-yloxy)ethoxy)-3-(5-methylthiazole-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one, (35) 3-(5-methylthiazole-4-yl)-6-(2-(pyridine-4-yloxy)ethoxy)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one, (36) 6-(2-(3,4-dichlorophenoxy)ethoxy)-3-(5-methylthiazole-4-yl)-2-(thiophen-2-yl)-1H-inden-1-one, (37) 6-(2-(3,4-difluorophenoxy)ethoxy)-3-(5-methylthiazole-4-yl)-2-(thiophen-2-yl)-1H-inden-1-one, (38) 3-(furan-3-yl)-6-pentethoxy-2-(pyridine-3-yl)-1H-indene-1-one, (39) 3-(furan-3-yl)-6-(4-phenylbutoxy)-2-(pyridine-3-yl)-1H-inden-1-one, (40) 6-((benzyloxy)methoxy)-3-(furan-3-yl)-2-(pyridine-3-yl)-1H-inden-1-one, (41) 3-(furan-3-yl)-6-(2-phenoxyethoxy)-2-(pyridine-3-yl)-1H-indene-1-one, (42) 3-(furan-3-yl)-6-(2-(4-methoxyphenoxy)ethoxy)-2-(pyridine-3-yl)-1H-inden-1-one, (43) 6-(2-(3,4-dimethoxyphenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridine-3-yl)-1H-inden-1-one, (44) 6-(2-(benzo[d][1,3]dioxol-5-yloxy)ethoxy)-3-(furan-3-yl)-2-(pyridine-3-yl)-1H-inden-1-one, (45) 3-(furan-3-yl)-2-(pyridine-3-yl)-6-(2-(pyridine-4-yloxy)ethoxy)-1H-inden-1-one, (46) 6-(2-(3,4-dichlorophenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridine-3-yl)-1H-inden-1-one, (47) 6-(2-(3,4-difluorophenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridine-3-yl)-1H-inden-1-one, (48) 6-(2-(4-(dimethylamino)phenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridine-3-yl)-1H-inden-1-one, (49) 3-(furan-3-yl)-6-(2-(4-isopropylphenoxy)ethoxy)-2-(pyridine-3-yl)-1H-inden-1-one, and (50) 3-(furan-3-yl)-6-(((4-methoxybenzyl)oxy)methoxy)-2-(pyridine-3-yl)-1H-indene-1-one.

7. A pharmaceutical composition for preventing or treating a degenerative brain disease, comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

8. (1) Individuals whose amyloid-beta aggregation level is higher than normal or at high risk of developing degenerative brain disease, (2) Individuals whose tau protein aggregation level is higher than normal or at high risk of having degenerative brain disease, (3) Individuals whose tau protein phosphorylation levels are higher than normal or at high risk of developing degenerative brain disease, and (4) Individuals that fall under one or more of the above (1) to (3) A pharmaceutical composition according to claim 7 for administration to an individual selected from among.

9. The aforementioned degenerative brain diseases include dementia, Alzheimer's disease, preclinical Alzheimer's disease, Parkinson's disease, Huntington's disease, mild cognitive impairment, cerebral amyloid vascular disease, Down syndrome, amyloid stroke, systemic amyloid disease, Dutch amyloidosis, Niemann-Pick disease, senile dementia, and amyotrophic lateral sclerosis. The pharmaceutical composition according to claim 7, which is selected from the group consisting of sclerosis, spinocerebellar degeneration, Tourette's syndrome, Friedrich's ataxia, Machado-Joseph's disease, Lewy body dementia, dystonia, progressive supranuclear palsy, and frontotemporal dementia.

10. A pharmaceutical composition for inhibiting amyloid-beta aggregation or for degrading amyloid-beta aggregates, A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

11. A pharmaceutical composition for inhibiting the aggregation of tau protein, degrading tau protein aggregates, or inhibiting the phosphorylation of tau protein, A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

12. A composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof.

13. A health functional food for preventing or improving degenerative brain diseases, comprising the compound described in claim 1 or a food-grade salt thereof as an active ingredient.

14. A health functional food for inhibiting amyloid-beta aggregation or for degrading amyloid-beta aggregates, A health functional food comprising the compound described in claim 1 or a food-grade salt thereof as an active ingredient.

15. A health functional food for inhibiting the aggregation of tau protein, degrading tau protein aggregates, or inhibiting the phosphorylation of tau protein, A health functional food comprising the compound described in claim 1 or a food-grade salt thereof as an active ingredient.

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