Novel indenone derivatives and their uses

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 indene 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 disease.

Background Art

[0002] Neurodegenerative brain disease is a disease 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 disease shows the death of nerve cells due to necrosis or apoptosis that progresses rapidly or slowly. Therefore, understanding the mechanism of nerve cell death should be made for the development of preventive, regulatory, and therapeutic methods for central nervous system diseases.

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

[0004] Human amyloid-beta is a peptide molecule containing approximately 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 novel indenone derivatives, their isomers, or pharmaceutically acceptable salts thereof that are 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, which contains the novel indene derivative, its isomer or its pharmaceutically acceptable salt as an active ingredient.

[0009] Still another object of the present invention is to provide a health functional food for preventing or improving degenerative brain diseases, which contains the novel indene derivative, its isomer or its food scientifically acceptable salt as an active ingredient.

[0010] Still another object of the present invention is to provide a composition containing the novel indene derivative, its isomer or its pharmaceutically acceptable salt.

[0011] Still another object of the present invention is to provide a pharmaceutical composition containing the novel indene derivative, its isomer or its pharmaceutically acceptable salt.

[0012] Still another object of the present invention is to provide a method comprising the step of administering to an individual in need of the novel indene derivative, its isomer or its pharmaceutically acceptable salt, (i) suppressing the aggregation of amyloid β and / or decomposing aggregates, (ii) suppressing the aggregation of tau protein or decomposing aggregates and / or suppressing the phosphorylation of tau protein, or (iii) treating or preventing degenerative brain diseases.

[0013] Still another object of the present invention is to provide the use of the novel indene derivative, its isomer or its pharmaceutically acceptable salt for (i) suppressing the aggregation of amyloid β and / or decomposing aggregates, (ii) suppressing the aggregation of tau protein or decomposing aggregates and / or suppressing the phosphorylation of tau protein, or (iii) treating or preventing degenerative brain diseases.

Means for Solving the Problems

[0014] Hereinafter, the present invention will be described more specifically.

[0015] Throughout the specification, the term "comprising" a certain component means, unless otherwise stated to the contrary, that other components are not excluded but may further include other components.

[0016] The term "isomer" in the present invention means a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but different structurally or stereochemically. Such isomers include structural isomers such as tautomers, and stereoisomers such as R or S isomers having an asymmetric carbon center, geometric isomers (trans, cis), and optical isomers (enantiomers). All these isomers and mixtures thereof are also included within the scope of the present invention.

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

[0018] "C 1-6 alkyl" means the residue of a straight-chain or branched saturated hydrocarbon 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, etc. In one embodiment, the alkyl group may be substituted with one or more substituents, for example, 1 to 3 halogens or C 1-6 alkyl.

[0019] "C 1-6 alkoxy" means the chemical formula -O-C 1-6means alkyl and includes, but is not limited to, for example, 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, such as 1 to 3 halogens or C 1-6 alkyl.

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

[0021] The term "heteroaryl" refers to an aromatic 5- to 10-membered monocyclic or bicyclic heterocyclic ring containing 1 to 4 heteroatoms selected from N, O, and S. That is, heteroaryl is a 5- or 6-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from N, O, and S, or the heteroaryl ring refers to a bicyclic ring condensed with a benzene ring or another heteroaryl ring. In one embodiment, 0, 1, 2, 3, or 4 atoms of 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 bicyclic heteroaryls include, but are not limited to, indolyl, azaindolyl, indolinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, purinyl, propyridinyl, and similar groups.

[0022] The term "heterocyclyl" refers to a saturated or partially unsaturated carbocyclic 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 is a 5- or 6-membered aliphatic heterocycle, or the heterocyclyl ring can be a bicyclic ring fused to a benzene ring or another heterocyclyl ring. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of the heterocyclyl group may be substituted with substituents. For example, heterocyclyl includes azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, dioxolyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, indolyl, isoindolyl, dihydroindolyl, dioxoisoindolinyl, dihydrofuryl, dihydroimidazolinyl, dihydrooxazolyl, dihydrobenzodioxinyl, tetrahydropyridinyl, dihydropyranyl, dihydrobenzofuranyl, benzodioxolyl, or benzodioxanyl.

[0023] The term "substituted" refers to replacing a hydrogen atom in a molecular structure with a substituent such that the atom on the specified atom does not exceed its valence and results in a chemically stable compound. For example, "group A is substituted with substituent B" means that a hydrogen atom bonded to an atom such as carbon constituting the backbone of group A is replaced with 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, an isomer thereof, or a pharmaceutically acceptable salt thereof.

Chemical Formula

[0025] In the above formula,

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

[0027] Y is either O or S,

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

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

[0030] 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,

[0031] R 2 is 5- to 6-membered heteroaryl, where the 5- to 6-membered heteroaryl is unsubstituted or substituted with 1 to 4 halogens, -CF 3 or C 1-6 alkyl and may be substituted,

[0032] R 3 is C 6-10 aryl, 5- to 6-membered heteroaryl or 5- to 10-membered heterocyclyl, where the C 6-10Aryl, 5- to 6-membered heteroaryl, and 5- to 10-membered heterocyclyl 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 with,

[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, the R 1 is halogen, phenyl, pyridinyl, pyrimidinyl, or thiophenyl, where the phenyl, pyridinyl, pyrimidinyl, and thiophenyl are each independently unsubstituted or substituted with 1 to 4 halogens, hydroxy, CN, -CF 3 , C 1-6 alkyl, -C 1-6 alkyl-CN, or -O-C 1-6 alkyl and may be substituted with.

[0035] Specifically, the R 1 is, for example, bromo,

Chemical formula

[0036] In one embodiment, the R 2 in the compound of Formula 1 is furanyl, thiophenyl, thiazolyl, or pyrazolyl, where the thiazolyl, furanyl, thiophenyl, and pyrazolyl are each independently unsubstituted or substituted with 1 to 4 halogens, -CF 3 or C1-6 It may be substituted with alkyl.

[0037] Specifically, the R 2 is, for example,

Chemical formula

[0038] In one embodiment, in the compound of Formula 1, the R 3 is phenyl, pyridinyl, morpholinyl or benzodioxolyl, where the phenyl, pyridinyl, morpholinyl and benzodioxolyl are each independently unsubstituted or substituted with 1 to 4 halogens, hydroxy, -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 It may be substituted.

[0039] Specifically, the R 3 is, for example,

Chemical formula

[0040] In one embodiment, in the compound of Formula 1, the R 1 is halogen, phenyl, pyridinyl, pyrimidinyl or thiophenyl, where the phenyl, pyridinyl, pyrimidinyl and thiophenyl are each independently unsubstituted or substituted with 1 to 4 halogens, hydroxy, CN, -CF 3 , C 1-6 alkyl, -C 1-6 alkyl-CN, or -O-C 1-6 alkyl, and may be substituted.

[0041] R 2is furanyl, thiophenyl, thiazolyl or pyrazolyl, where the thiazolyl, furanyl, thiophenyl and pyrazolyl are each independently unsubstituted or substituted with 1 to 4 halogens, -CF 3 or C 1-6 alkyl,

[0042] R 3 is phenyl, pyridinyl, morpholinyl or benzodioxolyl, where the phenyl, pyridinyl, morpholinyl and benzodioxolyl are each independently unsubstituted or substituted with 1 to 4 halogens, hydroxy, -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 and may be substituted with.

[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-Methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one,

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

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

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

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

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

[0050] (7) 6-(3-Phenylpropoxy)-3-(1H-pyrazol-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one,

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

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

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

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

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

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

[0057] (14) 3-(4-Methylthiazol-5-yl)-6-pentethoxy-2-(pyridin-3-yl)-1H-inden-1-one,

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

[0059] (16) 6-((Benzyloxy)methoxy)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one,

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

[0061] (18) 2-(4-Methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-pentethoxy-1H-inden-1-one,

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

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

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

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

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

[0067] (24) 6-(2-(Benzo[d][1,3]dioxol-5-yloxy)ethoxy)-2-(4-fluorophenyl)-3-(5-methylthiazol-4-yl)-1H-indene-1-one,

[0068] (25) 2-(4-fluorophenyl)-3-(5-methylthiazol-4-yl)-6-(2-(pyridin-4-yloxy)ethoxy)-1H-indene-1-one,

[0069] (26) 6-(2-(3,4-dichlorophenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(pyrimidin-5-yl)-1H-indene-1-one,

[0070] (27) 6-(2-(3,4-difluorophenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(pyrimidin-5-yl)-1H-indene-1-one,

[0071] (28) 3-(5-methylthiazol-4-yl)-6-pentethoxy-2-(thiophen-2-yl)-1H-indene-1-one,

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

[0073] (30) 6-((Benzyloxy)methoxy)-3-(5-methylthiazol-4-yl)-2-(thiophen-2-yl)-1H-indene-1-one,

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

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

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

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

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

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

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

[0081] (38) 3-(Furan-3-yl)-6-pentethoxy-2-(pyridin-3-yl)-1H-inden-1-one,

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

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

[0084] (41) 3-(Furan-3-yl)-6-(2-phenoxyethoxy)-2-(pyridin-3-yl)-1H-inden-1-one,

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

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

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

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

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

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

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

[0092] (49) 3-(Furan-3-yl)-6-(2-(4-isopropylphenoxy)ethoxy)-2-(pyridin-3-yl)-1H-inden-1-one, and

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

[0094] or a pharmaceutically acceptable salt thereof.

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

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

[0097] For example, the pharmaceutically acceptable salts can be acid addition salts formed by a pharmaceutically acceptable free acid.

[0098] The free acid can be an inorganic acid or an organic acid. Here, the inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, 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, embonic acid, aspartic acid, glutamic acid, etc.

[0099] The acid addition salts can be prepared by conventional methods, for example, by dissolving the compound of formula 1 in an excess of 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 salts can be alkali metal salts (such as sodium salts) or alkaline earth metal salts (such as potassium salts).

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

[0102] Furthermore, the compounds of the present invention can have chiral carbon centers and can thus 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 can fall within the scope of the present invention.

[0103] In addition, the compounds of the present invention can include hydrates and solvates of the compounds of Formula 1 above. The hydrates and solvates can be produced using known methods and are preferably non-toxic and water-soluble. In particular, preferably, the hydrates and solvates can each be those in which 1 to 5 molecules of water and alcoholic solvents (especially, ethanol, etc.) are bonded.

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

[0105] Specifically, the compound of Formula 1 above can be produced by the methods shown in Reaction Schemes 1 to 5 below, but is not limited to those produced by such methods. In particular, those skilled in the art will fully understand that the compound of Formula 1 of the present invention can be produced by various methods using ordinary techniques in the art.

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

[0107] [Reaction Scheme 1]

[0108] [Chemical Formula] [Reaction Scheme 2]

[0109] [Chemical Formula] [Reaction Scheme 3]

[0110] [Chemical formula] [Reaction formula 4]

[0111] [Chemical formula] [Reaction formula 5]

[0112] [Chemical formula] The target compound produced in the above reaction formula can be separated and purified using conventional methods, such as methods using a chromatography column, recrystallization, etc.

[0113] The present invention provides a composition comprising the compound of formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.

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

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

[0116] The compound of formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof not only suppresses the aggregation of amyloid-β or decomposes aggregates, suppresses the aggregation of tau protein or decomposes aggregates, but also has an excellent effect of suppressing the phosphorylation of tau protein. Therefore, the compound or a pharmaceutical composition containing the same can be usefully used for the prevention or treatment of diseases related to the suppression of amyloid-β aggregation and / or decomposition of aggregates, the suppression of tau protein aggregation and / or decomposition of aggregates, and / or the suppression of tau protein phosphorylation, such as degenerative brain diseases.

[0117] As used herein, the term "prevention" means all acts of suppressing or delaying the occurrence, spread and recurrence of the disease by administration of the compounds or pharmaceutical compositions according to the present invention, and "treatment" means all acts of improving or favorably changing the symptoms of the disease by administration of the compounds or pharmaceutical compositions according to the present invention.

[0118] As used herein, the term "degenerative brain disease" comprehensively means all diseases related to degenerative changes in the brain, in particular, all diseases (brain diseases) that can be induced by one or more factors selected from the aggregation of amyloid β, the aggregation of tau protein, and the hyperphosphorylation of tau protein in the brain and / or brain nerve cells.

[0119] In one embodiment, the 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 angiopathy, Down syndrome, amyloid stroke, systemic amyloidosis, Dutch-type amyloidosis, Niemann-Pick disease, senile dementia, amyotrophic lateral sclerosis, spinocerebellar atrophy, Tourette's syndrome, Friedrich's ataxia, Machado-Joseph's disease, Lewy body dementia, dystonia, progressive supranuclear palsy, and frontotemporal dementia. However, the diseases are not limited thereto, and any disease caused by the aggregation of amyloid β, the aggregation of tau protein, and / or the phosphorylation of tau protein can be a target.

[0120] As one embodiment, the present invention provides a pharmaceutical composition for suppressing the aggregation of amyloid β and / or decomposing 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 suppressing the aggregation of tau protein, decomposing aggregates and / or suppressing the phosphorylation of tau protein, which contains the compound of formula 1, its isomer or its pharmaceutically acceptable salt as an active ingredient.

[0122] The present invention provides the use of the compound of formula 1, its isomer or its pharmaceutically acceptable salt for the prevention or treatment of diseases related to the suppression of amyloid-β aggregation and / or the decomposition of aggregates, such as neurodegenerative diseases.

[0123] The present invention provides the use of the compound of formula 1, its isomer or its pharmaceutically acceptable salt for suppressing the aggregation of amyloid-β and / or decomposing aggregates.

[0124] The present invention provides the use of the compound of formula 1, its isomer or its pharmaceutically acceptable salt for suppressing the aggregation of tau protein, decomposing aggregates and / or suppressing the phosphorylation of tau protein.

[0125] The present invention provides the use of the compound of formula 1, its isomer or its pharmaceutically acceptable salt for the production of a medicament for the prevention or treatment of diseases related to the suppression of amyloid-β aggregation and / or the decomposition of aggregates, such as neurodegenerative diseases.

[0126] The present invention provides the use of the compound of formula 1, its isomer or its pharmaceutically acceptable salt for the production of a medicament for suppressing the aggregation of amyloid-β and / or decomposing aggregates.

[0127] The present invention provides the use of the compound of formula 1, its isomer or its pharmaceutically acceptable salt for the production of a medicament for suppressing the aggregation of tau protein or decomposing aggregates and / or suppressing the phosphorylation of tau protein.

[0128] In addition, the present invention provides a method for preventing or treating a disease associated with suppressing the aggregation of amyloid-β and / or degrading aggregates, such as a degenerative brain disease, which includes administering the compound of formula 1, its isomer, or a pharmaceutically acceptable salt thereof to a subject in need of preventing or treating a degenerative brain disease. The method may further include a step of identifying a subject in need of preventing and / or treating a degenerative brain disease before the step of administering.

[0129] In addition, the present invention provides a method for suppressing the aggregation of amyloid-β and / or degrading aggregates, which includes administering the compound of formula 1, its isomer, or a pharmaceutically acceptable salt thereof to a subject in need of suppressing the aggregation of amyloid-β and / or degrading aggregates. The method may further include a step of identifying a subject in need of suppressing the aggregation of amyloid-β and / or degrading aggregates before the step of administering.

[0130] The present invention provides a method for suppressing the aggregation of tau protein, degrading aggregates, and / or suppressing the phosphorylation of tau protein, which includes administering the compound of formula 1, its isomer, or a pharmaceutically acceptable salt thereof to a subject in need of suppressing the aggregation of tau protein, degrading aggregates, and / or suppressing the phosphorylation of tau protein. The method may further include a step of identifying a subject in need of suppressing the aggregation of tau protein, degrading aggregates, and / or suppressing the phosphorylation of tau protein before the step of administering.

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

[0132] (1) an individual (patient) with a higher amyloid-β aggregation level than normal or at high risk of having a higher amyloid-β aggregation level,

[0133] (2) an individual (patient) with a higher tau protein aggregation level than normal or at high risk of having a higher tau protein aggregation level,

[0134] (3) Individuals (patients) in whom the phosphorylation level of tau protein is higher than normal or there is a high risk thereof, and

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

[0136] It may be for administration to an individual (patient) selected from the group consisting of.

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

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

[0139] The "normal" can be an individual without the "degenerative brain disease" defined above among individuals of the same species as the application target (patient) of the pharmaceutical composition, or brain tissue or brain cells (brain nerve cells) isolated and / or cultured from the individual.

[0140] The term "inhibition" used in the present invention 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 can contain a pharmaceutically acceptable carrier in addition to the active ingredient. Here, the pharmaceutically acceptable carrier is one commonly used in formulation, including but not limited to lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above components, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc. can further be included.

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

[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 dosage 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 administration time, the administration route and excretion rate, the treatment period, factors including drugs used simultaneously, and other factors well-known in the medical field.

[0144] The pharmaceutical composition according to the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or plurally. Considering all the above elements, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, and this 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 degree of the active ingredient into the body, inactivation rate and excretion rate, type of disease, and drugs used in combination. Generally, it can be administered daily or every other day at 0.001 to 150 mg per kg of body weight, preferably 0.01 to 100 mg, or divided into 1 to 3 doses per day. However, since the dosage may increase or decrease depending on the administration route, severity of obesity, sex, weight, age, etc., the above dosage does not limit the scope of the present invention in any way.

[0146] Furthermore, the present invention provides a method for preventing, regulating, or treating a degenerative brain disease, which includes the step of administering the pharmaceutical composition to an individual. In the present invention, "individual" means a subject in need of treatment for a disease, and more specifically, means mammals such as humans or non-human primates, mice, dogs, cats, horses, and cows.

[0147] In addition, the present invention provides a health functional food for preventing and / or improving a degenerative brain disease, which contains the compound of formula 1, its isomer, or its pharmaceutically acceptable salt as an active ingredient.

[0148] The present invention provides a health functional food for suppressing the aggregation of amyloid-β and / or decomposing aggregates, which contains the compound of formula 1, its isomer, or its pharmaceutically acceptable salt as an active ingredient.

[0149] In addition, the present invention provides a health functional food for suppressing the aggregation of tau protein, decomposing aggregates of tau protein, and / or suppressing the phosphorylation of tau protein, which contains the compound of formula 1, its isomer, or its pharmaceutically acceptable salt as an active ingredient.

[0150] The above-mentioned health functional food is a food manufactured using nutrients that are likely to be lacking in daily diet, raw materials or components having functions useful to the human body, and means all foods that are useful for maintaining health or preventing and / or improving predetermined diseases or symptoms, and there is no special restriction on the final product form. For example, the above-mentioned health functional food may be selected from the group consisting of various foods, beverage compositions, food additives, etc., but is not limited thereto.

[0151] The content of the active ingredient (i.e., the compound of Formula 1, its isomer or its food-acceptable salt) contained in the above-mentioned health functional food can be appropriately adjusted according to the form of the food, the desired use, etc., and there is no special restriction.

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

Advantages of the Invention

[0153] The indene derivative according to the present invention can be usefully used for the preventive or therapeutic use of neurodegenerative brain disease 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.

Brief Description of the Drawings

[0154]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Mode for Carrying Out the Invention

[0155] Hereinafter, preferred embodiments are presented to facilitate the understanding of the present invention. However, the following embodiments are provided to more easily understand the present invention, and the content of the present invention is not limited by the following embodiments. The embodiments can be subjected to various conversions, but the embodiments are not limited to the embodiments disclosed below and may be realized in various forms.

[0156] The abbreviations used in this embodiment are shown below.

[0157] LCMS Liquid Chromatography Mass Spectrometer

[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] N 2 Nitrogen

[0168] Psi Pounds per Square inch

[0169] PdCL 2 Palladium(II) chloride

[0170] Pd 2 (dba) 3Tris(dibenzylideneacetone)dipalladium(0)

[0171] Pd(dtbpf)Cl 2 [1,1’-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)

[0172] Pd(dppf)Cl 2 [1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0173] PdCl 2 (PPh 3 ) 2 Dichloropalladium(triphenylphosphine)

[0174] [(t-Bu) 3 PH]BF 4 [Tri(tert-butyl)phosphonium]tetrafluoroborate

[0175] ACN Acetonitrile

[0176] Ac 2 O Acetic anhydride

[0177] AIBN 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

[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 = EtOAc

[0191] General experimental methods

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

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

[0194] Manufacture of the compound

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

[0196] [Reaction Scheme 1]

[0197] [Chemical Formula]

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

[0199] After mixing Compound 1-1 (5.00 g, 39.3 mmol) and Compound 1-2 (5.35 g, 39.3 mmol, 4.87 mL) in ethanol (50.0 mL), H 2NaOH (2.36 g, 58.9 mmol) was added to O (20.0 mL) under a nitrogen atmosphere at 0 °C. The mixture was stirred at 20 °C for 12 h. It was confirmed by TLC (DCM: methanol = 10 / 1) that the reactants were completely consumed. After adjusting the mixture to pH 7 with 1N HCl, the mixture was filtered and concentrated in vacuo 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 then the mixture was stirred at 80 °C for 16 h. It was confirmed by TLC (PE: EA = 1 / 1) that the reactants were completely consumed. After adding an aqueous solution of NaHCO 3 to adjust the pH to 8, the mixture was filtered and concentrated in vacuo 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] Compound 1-4 (2.00 g, 8.15 mmol) and Ac 2After mixing O (4.16 g, 40.77 mmol, 3.82 mL), 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 h. It was confirmed by TLC (PE:EA = 1 / 1) that the reactants were completely consumed. The mixture was diluted with DCM (100 mL) and extracted with brine (30 mL × 3). Anhydrous Na 2 SO 4 After drying over and then concentrating in vacuo, a residue was obtained. The residue was purified by flash silica gel chromatography to give 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] Compound 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 μmol) was added under a nitrogen atmosphere. The mixture was stirred at 80 °C for 1 h. Then, the reaction mixture was stirred at 80 °C for 1.5 h under 400 W. LCMS confirmed that the reactants were completely consumed and that compound 1-6 was synthesized. The mixture was diluted with DCM (100 mL) and extracted with brine (30 mL × 3). Anhydrous Na 2 SO 4 After drying and filtering over and then concentrating in vacuo, compound 1-6 (890 mg) was obtained as a brown oil.

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

[0207] After mixing compound 1-6 (780 mg, 2.14 mmol) with DCM (4.00 mL), DBU (326 mg, 2.14 mmol, 322 μL) was added under a nitrogen atmosphere. The mixture was stirred at 20 °C for 12 hours. It was confirmed by TLC (PE:EA = 1 / 1) that the reactants were completely consumed. The mixture was diluted with DCM (100 mL) and extracted with brine (30 mL × 3). Anhydrous Na 2 SO 4 After drying and filtering with it, it was concentrated in vacuo to obtain a residue. The residue was purified by flash silica gel chromatography to obtain compound 1-7 (110 mg, 341 μmol, 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] Compound 1-7 (110 mg, 341 μmol) and RX from the above [Reaction Scheme 1] (3-bromopropyl)benzene (81.5 mg, 409 μmol, 61.8 μL) were mixed in acetonitrile (2.00 mL), and then K 2 CO 3 (141 mg, 1.02 mmol) was added. The mixture was stirred at 40 °C for 12 hours. It was confirmed by LCMS that the reactants were completely consumed and by MS that compound 3 was synthesized. The mixture was diluted with EA (50.0 mL) and extracted with brine (10 mL × 3). Anhydrous Na 2 SO 4 After drying and filtering with it, it was concentrated in vacuo to obtain a residue. The residue was purified by reversed-phase HPLC to obtain compound 3 (10.0 mg, 22.7 μmol, 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 H 2 O (0.5 mL) were mixed with Compound 3 (40.0 mg, 90.8 μmol) and pyridin-3-ylboronic acid (13.4 mg, 109 μmol) where R 1 -B(OH) 2 in [Reaction Scheme 1]. After mixing, K 3 PO 4 (57.8 mg, 272 μmol) and Pd(dppf)Cl 2 (5.92 mg, 9.08 μmol) were added under a nitrogen atmosphere. The mixture was stirred in a microwave at 100 °C for 2 hours. It was confirmed by LCMS that the reactants were completely consumed and that Compound 1 was detected at 36.1%. The mixture was filtered and concentrated in vacuo to obtain a residue. The residue was purified by reversed-phase HPLC to obtain Compound 1 (6.00 mg, 13.68 μmol, yield: 15.06%) as a red solid.

[0212] 1H NMR (400 MHz, CD3OD): δ 9.19 (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 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 H 2 O (0.50 mL) were charged with Compound 3 (20.0 mg, 45.4 μmol) synthesized in Embodiment 1 above, and 2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (13.2 mg, 54.5 μmol) and Pd 1 -B(OH) 2 represented by 2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile, and Pd 2 (dba) 3 (4.16 mg, 4.54 μmol) were mixed, and then KF (7.92 mg, 136 μmol) and [(t-Bu) 3 PH]BF 4 (1.32 mg, 4.54 μmol) were added under a nitrogen atmosphere. The mixture was stirred at 20 °C for 4 hours. It was confirmed by LCMS that the reactants were completely consumed, and it was confirmed by MS that Compound 2 was synthesized. The mixture was diluted with H 2 O (20.0 mL) and extracted with EA (20.0 mL × 3). The combined organic phases were dried over anhydrous Na 2 SO 4 and filtered, and then concentrated in vacuo to obtain a residue. The residue was purified by reversed-phase HPLC to obtain Compound 2 (3.80 mg, 7.97 μmol, yield: 17.5%) as a red oil.

[0216] 1H NMR (400 MHz, CD3OD): δ 9.09 (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 = 7.6 Hz, 2H), 2.08ー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 (2 - bromo - 3 - (4 - methylthiazol - 5 - yl) - 6 - (3 - phenylpropoxy) - 1H - inden - 1 - one) (Compound 3)

[0219] In the above - mentioned Embodiment 1, Compound 3 was synthesized.

[0220] 1H NMR (400 MHz, CD3OD): δ 9.20 (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 (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] Compound 1-7 (30.0 g, 1.0 eq) synthesized in Embodiment 1 and (3-bromopropyl)benzene ((3-bromopropyl)benzene, 22.3 g, 1.2 eq) as RX in [Reaction Scheme 1] were mixed in DMF (300 mL), and then K 2 CO 3 (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. It was confirmed by TLC (PE:EA = 1 / 1) that the reactants were completely consumed. Water (300 mL) was added to the mixture, the pH was adjusted to 3 with 1M HCl, and then extracted with EtOAc (100 mL × 2). The organic layer was dried over Na 2 SO 4 and then the organic phase residue concentrated under reduced pressure at 40 - 45°C was obtained. The residue was purified by flash silica gel chromatography (PE / EA = 20 / 1, 1 / 1) to obtain compound 10-1 (25.0 g) as a red oily substance.

[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 μmol, 1 eq) and R 1 -B(OH) 2After mixing with phenylboronic acid (41.5 mg, 340 μmol, 1.5 eq), K 2 CO 3 (94.0 mg, 681 μmol, 3.0 eq), Pd(t-Bu 3 P) 2 (11.0 mg, 21 μmol, 0.1 eq), and dioxane (0.8 mL) and water (0.2 mL) were added under a nitrogen atmosphere at 20 - 25 °C. The mixture was stirred at 80 - 85 °C for 3 hours. It was confirmed by TLC (PE:EA = 1 / 1) that the reactants were completely consumed. Water (10 mL) was added to the mixture, adjusted to pH 3 with 1M HCl, and then extracted with EtOAc (10 mL × 3). The organic layer was dried over Na 2 SO 4 , and the residue of the concentrated organic phase was obtained under reduced pressure conditions at 40 - 45 °C. The residue was purified by column chromatography (SiO 2 , PE / EA = 10 / 1 - 1 / 1) to obtain compound 10 (82.0 mg, 179 μmol, yield: 79.1%) as a red solid.

[0227] 1H NMR (400 MHz, DMSO-d6): δ 9.28 (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 (3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyrimidin-5-yl)-1H-inden-1-one) (Compound 11)

[0230] The compound 10-1 (100 mg, 220 μmol, 1 eq) synthesized in the above Embodiment 4 and R in the above [Reaction Formula 1] 1 -B(OH) 2 were mixed with pyrimidin-5-ylboronic acid (42.2 mg, 340 μmol, 1.5 eq). Then, K 2 CO 3 (94.0 mg, 681 μmol, 3.0 eq), Pd(t-Bu 3 P) 2 (11.0 mg, 21 μmol, 0.1 eq) and dioxane (0.8 mL) and water (0.2 mL) were added under a nitrogen atmosphere at 20-25 °C. The mixture was stirred at 80-85 °C for 3 hours. It was confirmed by TLC (PE:EA = 1 / 1) that the reactants were completely consumed. Water (10 mL) was added to the mixture, and the pH was adjusted to 3 with 1 M HCl, followed by extraction with EtOAc (10 mL × 3). The organic layer was dried over Na 2 SO 4 , and the residue of the concentrated organic phase was obtained under reduced pressure conditions at 40-45 °C. The residue was purified by column chromatography (SiO 2 , PE / EA = 10 / 1 - 1 / 1) to obtain compound 11 (23.0 mg, 179 μmol, yield: 22.1%) as a red solid.

[0231] 1H NMR (400 MHz, DMSO-d6): δ 9.29 (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] Compound 10-1 (100 mg, 220 μmol, 1 eq) synthesized in the said Embodiment 4 and R in the said [Reaction Formula 1] 1 -B(OH) 2 were mixed with thiophen-2-ylboronic acid (43.6 mg, 340 μmol, 1.5 eq), and then K 2 CO 3 (94.0 mg, 681 μmol, 3.0 eq), Pd(t-Bu 3 P) 2 (11.0 mg, 21 μmol, 0.1 eq) and dioxane (0.8 mL) and water (0.2 mL) were added under a nitrogen atmosphere at 20 - 25°C. The mixture was stirred at 80 - 85°C for 3 hours. It was confirmed by TLC (PE:EA = 1 / 1) that the reactants were completely consumed. Water (10 mL) was added to the mixture, the pH was adjusted to 3 with 1M HCl, and then extracted with EtOAc (10 mL × 3). The organic layer was dried over Na 2 SO 4 , and then an organic phase residue concentrated under reduced pressure conditions at 40 - 45°C was obtained. The residue was purified by column chromatography (SiO 2 , PE / EA = 10 / 1 - 1 / 1) to obtain compound 12 (23.0 mg, 179 μmol, yield: 22.08%) as a red solid.

[0235] 1H NMR (400 MHz, DMSO-d6): δ 9.38 (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 = 8.0 Hz, 1H), 4.02 (brt, J = 6.4 Hz, 2H), 2.74 (brt, J = 7.6 Hz, 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 (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-1H-inden-1-one (2-bromo-3-(4-methylthiazol-5-yl)-6-(3-(pyridin-4-yl)propoxy)-1H-inden-1-one) (13-1)

[0239] The compound 1-7 (300 mg, 745 μmol, 1.00 eq) synthesized in Embodiment 1 and 4-(3-bromopropyl)pyridine (557 mg, 2.24 mmol, 3.00 eq) as RX in [Reaction Formula 1] were mixed in DMF (3.00 mL), and then K 2 CO 3(190 mg, 1.35 mmol, 1.80 eq) and NaI (13.0 mg, 85.8 μmol, 0.10 eq) were added under a nitrogen atmosphere at 20 - 25 °C. The mixture was stirred at 40 - 45 °C for 18 h. It was confirmed by TLC (PE:EA = 1 / 1) that the reactants were completely consumed. Water (10.0 mL) was added to the mixture, adjusted to pH 3 with 1 M HCl, and then extracted with EtOAc (10.0 mL × 3). The residue was purified by reversed-phase HPLC under HCl conditions to obtain the red solid compound 13-1 (47.0 mg, 97.9 μmol, yield: 13.1%).

[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] The compound 13-1 (45.0 mg, 93.8 μmol, 1.00 eq) and R in the above [Reaction Scheme 1] 1 -B(OH) 2 were mixed with pyridin-3-ylboronic acid (18.0 mg, 145 μmol, 1.45 eq), and then K 2 CO 3 (40.0 mg, 283 μmol, 3.00 eq), Pd(t-Bu 3 P) 2 (6.00 mg, 11.1 μmol, 0.10 eq) and dioxane (0.80 mL) and water (0.20 mL) were added under a nitrogen atmosphere at 20 - 25 °C. The mixture was stirred at 80 - 85 °C for 12 h. LCMS confirmed that the reactants were completely consumed. Water (10 mL) was added to the mixture, adjusted to pH 7 with 1 M HCl, and then extracted with EtOAc (10 mL × 3). The organic layer was Na 2 SO 4After drying, a residue concentrated under reduced pressure at 40 - 45 °C was obtained. The residue was purified by prep-HPLC to obtain Compound 13 (36.0 mg, 79.4 μmol, yield: 84.7%) as a red solid.

[0242] 1H NMR (400 MHz, DMSO-d6): δ 9.31 (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] Compound 1-7 (3.00 g, 9.31 mmol, 1.00 eq) synthesized in Embodiment 1 above and (2-bromoethyl)benzene ((2-bromoethyl)benzene, 2.58 g, 13.97 mmol, 1.5 eq) in RX in [Reaction Formula 1] were mixed in DMF (30 mL), and then K 2 CO 3(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 h. 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 1 M HCl, and then extracted with EtOAc (5 mL). The residue was purified by column chromatography (SiO 2 , 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 (compound 14)

[0248] Compound 14 - 1 (500 mg, 220 μmol, 1 eq) and pyridin-3-ylboronic acid (209 mg, 1.70 mmol, 1.5 eq) where R 1 -B(OH) 2 in the above [Reaction Scheme 1] were mixed, and then K 2 CO 3 (470 mg, 681 μmol, 3.0 eq), Pd(t-Bu 3 P) 2 (57.9 mg, 113 μmol, 0.1 eq) and dioxane (8 mL) and water (2 mL) were added under a nitrogen atmosphere at 20 - 25 °C. The mixture was stirred at 80 - 85 °C for 3 h. It was confirmed by TLC (PE:EA = 1 / 1) that the reactants were completely consumed. Water (10 mL) was added to the mixture, adjusted to pH 3 with 1 M HCl, and then extracted with EtOAc (10 mL × 3). The organic layer was dried over Na 2 SO 4 , and the residue concentrated under reduced pressure at 40 - 45 °C was obtained. The residue was purified by column chromatography (SiO 2, purified with PE / EA = 10 / 1 to 1 / 1), to obtain Compound 14 (300 mg, 692 μmol, yield: 61.07%) as a red solid.

[0249] 1H NMR (400 MHz, DMSO-d6): δ 9.36 (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, 7.8 Hz, 1H), 7.41 - 7.34 (m, 4H), 7.31 - 7.26 (m, 1H), 7.21 (d, J = 2.4 Hz, 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 (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)-inden-1-one (2-bromo-3-(4-methylthiazol-5)-yl)-6-(4-phenylbutoxy)-1H-inden-1-one) (15-1)

[0253] The compound 1-7 (500 mg, 1.55 mmol, 1 eq) synthesized in the above Embodiment 1 and (4-bromobutyl)benzene ((4-bromobutyl)benzene, 396 mg, 1.86 mmol, 1.2 eq) in RX in the above [Reaction Formula 1] were mixed in DMF (5 mL), and then K 2 CO3 (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. 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 1 M HCl, and then extracted with EtOAc (5 mL). The residue was purified by column chromatography (SiO 2 , PE / EA = 10 / 1 - 1 / 1) to obtain the red solid compound 15 - 1 (231 mg, 508 μmol, yield: 32.7%).

[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 μmol, 1 eq) and pyridin-3-ylboronic acid (40.0 mg, 325 μmol, 1.48 eq) with R 1 -B(OH) 2 in the above [Reaction Scheme 1] were mixed, and then K 2 CO 3 (91.0 mg, 658 μmol, 2.99 eq), Pd(t-Bu 3 P) 2 (11.00 mg, 21 μmol, 0.10 eq) and dioxane (0.8 mL) and water (0.2 mL) were added under a nitrogen atmosphere at 20 - 25 °C. The mixture was stirred at 80 - 85 °C for 3 hours. It was confirmed by TLC (PE:EA = 1 / 1) that the reactants were completely consumed. Water (10 mL) was added to the mixture, adjusted to pH 3 with 1 M HCl, and then extracted with EtOAc (10 mL × 3). The organic layer was dried over Na 2 SO 4 and then concentrated under reduced pressure at 40 - 45 °C to obtain a residue. The residue was purified by column chromatography (SiO2 Purified with PE / EA = 10 / 1 to 1 / 1) to obtain Compound 15 (14.9 mg, 26 μmol, yield: 12.1%) as a red solid.

[0256] 1H NMR (400 MHz, DMSO-d6): δ 9.30 (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 (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)-1H-inden-1-one (16-1)

[0260] Compound 1-7 (1.00 g, 3.10 mmol, 1.00 eq) synthesized in the above embodiment and ((chloromethoxy)methyl)benzene (614 mg, 3.72 mmol, 1.20 eq) in RX in [Reaction Formula 1] were mixed in DMF (10.0 mL), and then K 2 CO 3(657 mg, 4.66 mmol, 1.50 eq) and NaI (94 mg, 620 μmol, 0.20 eq) were added under a nitrogen atmosphere at 20 - 25 °C. The mixture was stirred at 40 - 45 °C for 18 h. LCMS confirmed that the reactants were completely consumed. Water (20 mL) was added to the mixture, and after adjusting the pH to 3 with 1 M HCl, it was extracted with EtOAc (30.0 mL × 3). The residue was purified by column chromatography (SiO 2 , PE / EA = 20 / 1 - 5 / 1) to obtain the red solid compound 16 - 1 (270 mg, 568 μmol, yield: 18.3%).

[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 μmol, 1.00 eq) and pyridin - 3 - ylboronic acid (98.0 mg, 789 μmol, 1.50 eq) where R 1 - B(OH) 2 in the above [Reaction Scheme 1] were mixed, and then K 2 CO 3 (224 mg, 4.59 mmol, 3.02 eq), Pd(t - Bu 3 P) 2 (29.0 mg, 53.9 μmol, 0.10 eq) and dioxane (2.00 mL) and water (0.50 mL) were added under a nitrogen atmosphere at 20 - 25 °C. The mixture was stirred at 80 - 85 °C for 12 h. LCMS confirmed that the reactants were completely consumed. Water (10 mL) was added to the mixture, and after adjusting the pH to 3 with 1 M HCl, it was extracted with EtOAc (10 mL × 3). The organic layer was dried over Na 2 SO 4 , and then the residue concentrated under reduced pressure at 40 - 45 °C was obtained. The residue was purified by column chromatography (SiO 2Purified with PE / EA = 20 / 1 to 1 / 1) to obtain Compound 16 (67.4 mg, 26 μmol, yield: 12.1%) as a red solid.

[0263] 1H NMR (400 MHz, DMSO-d6): δ 8.86 (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 (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 ((2-bromoethoxy)benzene, 374 mg, 1.86 mmol, 1.2 eq) in RX in [Reaction Scheme 1] were mixed in DMF (5 mL), and then K 2 CO 3(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 h. LCMS confirmed that the reactants were completely consumed. Water (20 mL) was added to the mixture, adjusted to pH 3 with 1 M HCl, and then extracted with EtOAc (5 mL). The residue was purified by column chromatography (SiO 2 , PE / EA = 10 / 1 - 1 / 1) to obtain the 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 μmol, 1 eq) and pyridin-3-ylboronic acid (40.0 mg, 325 μmol, 1.48 eq) with R 1 -B(OH) 2 in the above [Reaction Scheme 1] were mixed, and then K 2 CO 3 (91.0 mg, 658 μmol, 2.99 eq), Pd(t-Bu 3 P) 2 (11.00 mg, 21 μmol, 9.78×10⁻² eq) and dioxane (0.8 mL) and water (0.2 mL) were added under a nitrogen atmosphere at 20 - 25 °C. The mixture was stirred at 80 - 85 °C for 3 h. TLC (PE:EA = 1 / 1) confirmed that the reactants were completely consumed. Water (10 mL) was added to the mixture, adjusted to pH 3 with 1 M HCl, and then extracted with EtOAc (10 mL×3). The organic layer was dried over Na 2 SO 4 , and the residue concentrated under reduced pressure at 40 - 45 °C was obtained. The residue was purified by column chromatography (SiO 2Purified with PE / EA = 10 / 1 to 1 / 1) to obtain Compound 17 (22.86 mg, 37 μmol, yield: 16.44%) as a red solid.

[0270] 1H NMR (400 MHz, DMSO-d6): δ 9.31 (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 = 8 Hz, 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 (3-(furan-3-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 9)

[0273] [Reaction Scheme 2]

[0274]

Chemical Structure

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

[0276] CCl 4(1.00 L), the compound 9-1 (50.0 g, 308 mmol, 1.00 eq) of [Reaction Formula 2], NBS (109 g, 616 mmol, 2.00 eq), and AIBN (1.02 g, 6.20 mmol, 2.01 eq) were mixed and then added under a nitrogen atmosphere at 25 °C. The mixture was stirred at 85 °C for 2 hours. It was confirmed by TLC (PE:EA = 1:1) that the reactants were completely consumed. After adding TEtOAc (93.5 g, 924 mmol, 128 mL, 3.00 eq) to the mixture, it was stirred at 25 °C for 12 hours. It was confirmed by LCMS that the desired compound was synthesized. The mixture was cooled with water (1000 mL) and extracted with DCM (800 mL × 2). The organic layer was washed with NaCl (500 mL × 3) and then dried over Na 2 SO 4 . After filtration, it was concentrated under reduced pressure, and the residue was obtained as a red solid compound 9-2 (70.0 g, 201 mmol, yield: 65.4%, purity: 68.9%).

[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 then the mixture was stirred at 22 - 25 °C. After dropwise adding Br 2 (130 g, 815 mmol, 42.0 mL, 3.00 eq), it was stirred at 22 - 25 °C for 12 hours. It was confirmed by TLC (PE:EA = 3:1) that the reactants were completely consumed. The mixture was extracted with 10% aqueous NaS 2 O 3 solution (1000 mL), and the aqueous phase was extracted with MTBE (500 mL × 2). The organic phase was washed with NaHCO 3 (1000 mL × 2), then washed with brine (500 mL × 2), and dried over anhydrous Na 2 SO 4 . It was concentrated in vacuo to obtain a residue. The residue was subjected to column chromatography (SiO 2 , PE / EA = 3:1, P 1Purified with (yield: 14.6%, purity: 84.5%) to obtain Compound 9-3 (15.0 g, 39.8 nmol) as a red solid.

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

[0280] Dissolve Compound 9-3 (11.9 g, 37.4 mmol, 1.00 eq) and 2A (5.03 g, 44.9 mmol, 1.20 eq) in [Reaction Formula 2] in dioxane (120 mL) and H 2 O (30.0 mL). After mixing, add K 2 CO 3 (15.5 g, 112 mmol, 3.00 eq) and Pd(PPh 3 ) 4 (4.32 g, 3.74 mmol, 0.10 eq) under a nitrogen atmosphere at 25 °C. Stir the mixture under a nitrogen atmosphere at 40 °C for 12 hours. While dropping ACN (1 mL), confirm by LCMS that the reactants are completely consumed, and cool the reactants to 22 - 25 °C. Add water (200 mL) to the mixture and extract with EtOAc (100 mL × 2). Wash the organic layer with NaCl (100 mL × 2), and then dry with Na 2 SO 4 . Filter the mixture and concentrate in vacuo to obtain a residue. After filtration, concentrate under reduced pressure to obtain Compound 9-4 (5.20 g, 4.67 mmol, yield: 12.4%, purity: 27.4%) as a red solid.

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

[0282] Dissolve in dioxane (120 mL) and H 2To O (30.0 mL) were added compound 9-4 (5.00 g, 16.3 mmol, 1.00 eq) and pyridin-3-ylboronic acid (2.42 g, 19.7 mmol, 1.20 eq) where R 1 -B(OH) 2 in [Reaction Scheme 2]. After mixing, K 2 CO 3 (6.78 g, 49.0 mmol, 2.99 eq) and Pd(t-Bu 3 P) 2 (875 mg, 1.71 mmol, 1.04 eq) were added under a nitrogen atmosphere. The mixture was stirred at 85 °C for 12 h. After cooling the reaction mixture to 22 - 25 °C, while dropping ACN (1 mL), it was confirmed by LCMS that the reactants were completely consumed. It was confirmed by LCMS that the reactants were completely consumed. Water (30.0 mL) was added to the mixture, and the mixture was extracted with EtOAc (30.0 mL × 2). The organic layer was washed with NaCl (20.0 mL × 2), and then dried over Na 2 SO 4 . The mixture was filtered and concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (SiO 2 , PE:EA = 3:1, P 1 = 0.20) to obtain a 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 in DCM (90.0 mL) at 22 - 25 °C under a nitrogen atmosphere. Then BBr 3(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 at 22 - 25 °C under a nitrogen atmosphere for 6 hours. While dropping ACN (1 mL), it was confirmed by LCMS that the reactant was completely consumed. Water (100 mL) was added to the mixture at 0 °C and stirred for 10 minutes. After adjusting the pH of the mixture to 7 with 5% NaHCO 3 / H 2 O, it was extracted with EtOAc (50.0 mL × 3). The organic layer was washed with brine (100 mL) and then dried over Na 2 SO 4 . The mixture was filtered and concentrated. THF (20.0 mL) and PE (80.0 mL) were added thereto and stirred at 25 °C for 30 minutes. After filtration, it was washed with PE (50.0 mL) and then dried in vacuo to obtain a light red solid compound. After removing the solution therefrom, Compound 9-6 (3.30 g, 7.41 mmol, yield: 74.9%, purity: 65.0%) was obtained 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 μmol, 1 eq) and (3-bromopropyl)benzene (1 eq) as RX in the above [Reaction Scheme 2] were mixed in DMF (1 mL), and then K 2 CO 3 (35.8 mg, 259.26 μmol, 1.5 eq) and NaI (5.18 mg, 34.57 μmol, 0.2 eq) were added at 25 °C. The mixture was stirred at 45 °C for 12 hours. LCMS confirmed that the reactant was completely consumed. The mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL × 3). The organic layer was washed with brine (5 mL × 2) and then dried over Na 2 SO 4It was dried 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 μmol, yield: 16.74%, purity: 96.78%) as an orange solid.

[0287] 1H NMR (400 MHz, DMSO-d6): δ 8.56 (dd, J = 1.6, 4.8 Hz, 1H), 8.50 - 8.41 (m, 2H), 7.83 (t, J = 1.6 Hz, 1H), 7.72 (td, J = 2.0, 8.0 Hz, 1H), 7.55~7.44 (m, 2H), 7.36~7.13 (m, 6H), 7.04 (dd, J = 2.4, 8.0 Hz, 1H), 6.23 (d, J = 1.2 Hz, 1H), 4.09 (t, J = 6.4 Hz, 2H), 2.78 (t, J = 8.0 Hz, 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 (3-(furan-3-yl)-6-phenethoxy-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 38)

[0290] To DMF (1 mL), Compound 9-6 (50.0 mg, 172 μmol, 1 eq) synthesized in Embodiment 12 above and (2-bromoethoxy)benzene (31.9 mg, 172 μmol, 23.38 μL, 1 eq) in RX in [Reaction Scheme 2] were mixed, and then K 2 CO 3(35.8 mg, 259 μmol, 1.5 eq) and NaI (5.18 mg, 34.5 μmol, 0.2 eq) were added at 25 °C. The mixture was stirred at 50 °C for 14 h. While dropping DCM (1.00 mL), it was confirmed by TLC (PE:EA = 1 / 1) that the reactants were completely consumed. The mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL × 3). The organic layer was washed with brine (5 mL × 2), then dried over Na 2 SO 4 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 μmol, yield: 17.65%) as a red solid.

[0291] 1H NMR (400 MHz, DMSO-d6): δ 8.54 (d, J = 4.8 Hz, 1H), 8.45 (s, 2H), 7.81 (s, 1H), 7.70 (br d, J = 8.0 Hz, 1H), 7.52 - 7.40 (m, 2H), 7.37 - 7.30 (m, 4H), 7.28 - 7.20 (m, 1H), 7.13 (d, J = 2.0 Hz, 1H), 7.04 (dd, J = 2.0, 8.0 Hz, 1H), 6.20 (s, 1H), 4.31 (t, J = 6.8 Hz, 2H), 3.06 (t, J = 6.8 Hz, 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 (3-(furan-3-yl)-6-(4-phenylbutoxy)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 39)

[0294] In DMF (1 mL), the compound 9-6 (54.3 mg, 187.69 μmol, 1 eq) synthesized in Embodiment 12 above and (4-bromoethoxy)benzene ((4-bromoethoxy)benzene, 40.0 mg, 187.69 μmol, 1 eq) in RX in [Reaction Scheme 2] were mixed, then K2 CO 3 (38.9 mg, 281 μmol, 1.5 eq) and NaI (5.63 mg, 37.5 μmol, 0.2 eq) were added at 25 °C. The mixture was stirred at 50 °C for 14 hours. It was confirmed by LCMS that the desired compound was synthesized. The mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL × 3). The organic layer was washed with brine (5 mL × 2), and then dried over Na 2 SO 4 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 μmol, yield: 18.62%, purity: 98.2%) as a red solid.

[0295] 1H NMR (400 MHz, DMSO-d6): δ 8.55 (dd, J = 1.6, 4.8 Hz, 1H), 8.46 (s, 2H), 7.83 - 7.80 (m, 1H), 7.71 (td, J = 2.0, 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.45 (m, 1H), 7.32 - 7.26 (m, 2H), 7.26 - 7.16 (m, 3H), 7.13 (d, J = 2.4 Hz, 1H), 7.02 (dd, J = 2.4, 8.0 Hz, 1H), 6.20 (d, J = 1.6 Hz, 1H), 4.13 - 4.06 (m, 2H), 2.73 - 2.61 (m, 2H), 1.75 (br d, J = 3.6 Hz, 4H)

[0296] MS found: 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] To DMF (1 mL), the compound 9-6 (80.0 mg, 276.54 μmol, 1 eq) synthesized in the above Embodiment 12 and NaH (13.3 mg, 331 μmol, purity: 60%, 1.2 eq) were mixed. Then, in the above [Reaction Formula 2], ((chloromethoxy)methyl)benzene (86.6 mg, 553 μmol, 76.4 μL, 2 eq) was dissolved in DMF (0.1 mL), added dropwise and mixed. After that, the mixture was stirred at 25 °C for 1 hour. It was confirmed by LCMS that the desired compound was synthesized. The mixture was cooled with NH 4 Cl (5 mL), diluted with water (5 mL), and extracted with EtOAc (5 mL × 3). The organic layer was washed with brine (5 mL × 2), and then dried over Na 2 SO 4 . The mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (SiO 2 , PE:EA = 1:2) to obtain Compound 40 (9.72 mg, 20.58 μmol, yield: 7.44%, purity: 86.7%) as a red gum.

[0299] 1H NMR (400 MHz, CHLOROFORM-d): δ 8.55 - 8.43 (m, 2H), 7.79 (s, 1H), 7.65 (br d, J = 8.0 Hz, 1H), 7.41 (s, 1H), 7.28 (br s, 3H), 7.25 - 7.13 (m, 5H), 7.02 (dd, J = 2.4, 8.0 Hz, 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] To DMF (1 mL), the compound 9-6 (54.7 mg, 189 μmol, 1 eq) synthesized in the above Embodiment 12 and (2-bromoethoxy)benzene ((2-bromoethoxy)benzene, 38.0 mg, 189 μmol, 1 eq) in the above [Reaction Formula 2] were mixed, and then K 2 CO 3 (39.2 mg, 283 μmol, 1.5 eq) and NaI (5.67 mg, 37.8 μmol, 0.2 eq) were added at 25 °C. The mixture was stirred at 45 °C for 12 hours. It was confirmed by LCMS that the desired compound was synthesized. The mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL × 3). The organic layer was washed with brine (5 mL × 2), and then dried over Na 2 SO 4 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 μmol, yield: 25.54%, purity: 98.8%) as a red solid.

[0303] 1H NMR (400 MHz, METHANOL-d): δ 8.53 - 8.47 (m, 2H), 8.18 (s, 1H), 7.85 (td, J = 2.0, 8.0 Hz, 1H), 7.66 (t, J = 1.6 Hz, 1H), 7.51~7.41 (m, 2H), 7.31 (t, J = 7.2 Hz, 2H), 7.24 (d, J = 2.4 Hz, 1H), 7.08 (dd, J = 2.4, 8.0 Hz, 1H), 7.03~6.94 (m, 3H), 6.30 (dd, J = 0.8, 2.0 Hz, 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] To DMF (3.00 mL), the compound 9-6 (50.0 mg, 172 μmol, 1 eq) synthesized in the above Embodiment 12 and 1-(2-bromoethoxy)-4-methoxybenzene (40.7 mg, 176 μmol, 1.02 eq) represented by RX in the above [Reaction Formula 2] were mixed, and then K 2 CO 3 (36.0 mg, 260 μmol, 1.51 eq) and NaI (5.00 mg, 33.3 μmol, 1.93 eq) were added at 25 °C. The mixture was stirred at 45 - 50 °C for 12 hours. It was confirmed by TLC (PE:EA = 3:1) that the reactants were completely consumed. The mixture was cooled with water (10.0 mL). It was extracted with EtOAc (10.0 mL × 2). The organic layer was washed with NaCl (10.0 mL × 2), and then dried over Na 2 SO 4 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 μmol, yield: 14.2%, purity: 98.4%).

[0307] 1H NMR (400 MHz, DMSO-d6): δ ppm 3.70 (s, 3H), 4.24 - 4.32 (m, 2H), 4.38 - 4.44 (m, 2H), 6.20 (d, J = 1.2 Hz, 1H), 6.84 - 6.89 (m, 2H), 6.90 - 6.96 (m, 2H), 7.06 - 7.11 (m, 1H), 7.17 - 7.22 (m, 1H), 7.45 (dd, J = 8.0, 4.8 Hz, 1H), 7.51 (d, J = 8.0 Hz, 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, 1.2 Hz, 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 (6-(2-(3,4-dimethoxyphenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 43)

[0310] To DMF (3.00 mL), Compound 9-6 (20.0 mg, 69.1 μmol, 1.00 eq) synthesized in Embodiment 12 and 4-(2-bromoethoxy)-1,2-dimethoxybenzene (18.4 mg, 70.5 μmol, 1.02 eq) represented by RX in [Reaction Formula 2] were mixed, and then K 2 CO 3 (14.4 mg, 104 μmol, 1.51 eq) and NaI (20.0 mg, 133 μmol, 1.93 eq) were added at 25°C. The mixture was stirred at 40°C for 12 hours. While dropping EtOAc (1 mL), it was confirmed by TLC (PE:EA = 1:0) that the reactants were completely consumed. The mixture was cooled to 22 - 25°C. It was diluted with water (30.0 mL) and extracted with EtOAc (10.0 mL × 3). The organic layer was washed with brine (15.0 mL), and then dried over Na 2 SO 4 and the mixture was filtered and concentrated under reduced pressure. Compound 43 (12.1 mg, 25.33 μmol, yield: 36.64%, purity: 98.3%) was obtained as a red solid.

[0311] 1H NMR (400 MHz, DMSO-d6): δ ppm 8.54 (s, 1H), 8.46 (s, 2H), 7.81 (s, 1H), 7.71 (s, 1H), 7.48 (d, J = 21.6 Hz, 2H), 7.19 (s, 1H), 7.11 (s, 1H), 6.86 (d, J = 4.8 Hz, 1H), 6.62 (s, 1H), 6.50 (s, 1H), 6.20 (s, 1H), 4.21 - 4.48 (d, J = 52 Hz, 4H), 3.71 (d, J = 19.2 Hz, 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 (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] To DMF (3.0 mL), Compound 9-6 (50.0 mg, 172 μmol, 1.00 eq) synthesized in Embodiment 12 above and 5-(2-bromoethoxy)benzo[d][1,3]dioxole (40.7 mg, 176 μmol, 1.02 eq) in [Reaction Formula 2] were mixed, and then K 2 CO 3 (36.0 mg, 260 μmol, 1.51 eq) and NaI (5.00 mg, 33.3 μmol, 1.93 eq) were added at 25 °C. The mixture was stirred at 45 - 50 °C for 12 hours. It was confirmed by LCMS that the desired compound was synthesized. The mixture was cooled with water (10.0 mL). It was extracted with EtOAc (10.0 mL × 2). The organic layer was washed with NaCl (10.0 mL × 2), and then dried over Na 2 SO 4 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 μmol, yield: 18.1%, purity: 89.6%) as a red solid.

[0315] 1H NMR (400 MHz, DMSO-d6): δ ppm 8.54 (dd, J = 4.8, 1.6 Hz, 1H), 8.45 - 8.49 (m, 2H), 7.82 (t, J = 2.0 Hz, 1H), 7.71 (dt, J = 8.0, 2.0 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.42 - 7.47 (m, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.09 (dd, J = 8.4, 2.4 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 8.4, 2.8 Hz, 1H), 6.20 (dd, J = 2.0, 0.8 Hz, 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] To DMF (3.00 mL), the compound 9-6 (50.0 mg, 172 μmol, 1.00 eq) synthesized in Example 12 above and 4-(2-bromoethoxy)pyridine (35.6 mg, 176 μmol, 1.02 eq) as RX in [Reaction Formula 2] were mixed, and then K 2 CO 3 (60.0 mg, 434 μmol, 2.51 eq) and NaI (5.18 mg, 34.5 μmol, 0.20 eq) were added at 25 °C. The mixture was stirred at 40 °C for 12 hours. While dropping EtOAc (1 mL), it was confirmed by TLC (PE:EA = 1:0) that the reactants were completely consumed. The mixture was cooled to 22 - 25 °C. Diluted with water (30.0 mL) and extracted with EtOAc (10.0 mL × 3). The organic layer was washed with brine (15.0 mL), and then Na2 SO 4 It was dried with SO, and the mixture was filtered and concentrated under reduced pressure. Compound 45 (8 mg, 18.7 μmol, yield: 10.8%, purity: 96.2%) was obtained as a red solid.

[0319] 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 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, 1 H), 6.89 - 6.98 (m, 3 H), 6.27 (s, 1 H), 4.43 (s, 4 H).

[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 (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 μmol, 1.00 eq) synthesized in Embodiment 12 and 4-(2-bromoethoxy)-1,2-dichlorobenzene (46.0 mg, 194 μmol, 1.12 eq) in RX in [Reaction Formula 2] were mixed in DMF (3.0 mL), and then K 2 CO 3(36.0 mg, 260 μmol, 1.51 eq) and NaI (5.00 mg, 33.4 μmol, 0.20 eq) were added at 25 °C. The mixture was stirred at 40 °C for 12 h. While dropping MeOH (1.00 mL), it was confirmed by LCMS that the desired compound was synthesized. The mixture was cooled to 25 °C. It was diluted with water (30.0 mL) and extracted with EtOAc (10.0 mL × 3). The organic layer was washed with brine (15.0 mL), then dried over Na 2 SO 4 and the mixture was filtered and concentrated under vacuum conditions. 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 (6-(2-(3,4-difluorophenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 47)

[0326] To DMF (3.00 mL), the compound 9-6 (50.0 mg, 172 μmol, 1.00 eq) synthesized in the above Embodiment 12 and 4-(2-bromoethoxy)-1,2-difluorobenzene (46.0 mg, 194 μmol, 1.12 eq) represented by RX in the above [Reaction Formula 2] were mixed, and then K 2 CO 3 (36.0 mg, 260 μmol, 1.51 eq) and NaI (5.00 mg, 33.3 μmol, 0.20 eq) were added at 25 °C. The mixture was stirred at 40 °C for 12 hours. While dropping MeOH (1.00 mL), it was confirmed by LCMS that the desired compound was synthesized. The mixture was cooled to 25 °C. It was diluted with water (50.0 mL) and extracted with EtOAc (30.0 mL × 3). The organic layer was washed with brine (15.0 mL), and then dried over Na 2 SO 4 . The mixture was filtered and concentrated under vacuum conditions. The residue was purified by column chromatography (P 1 = 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, 1 H), 4.39 - 4.49 (m, 2 H)), 4.34 (d, J = 4.4 Hz, 2 H).

[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] To DMF (3.00 mL), Compound 9-6 (50.0 mg, 172 μmol, 1.00 eq) synthesized in Embodiment 12 and 4-(2-bromoethoxy)-N,N-dimethylaniline (43.0 mg, 176 μmol, 1.02 eq) in [Reaction Formula 2] were mixed, and then K 2 CO 3 (36.0 mg, 260 μmol, 1.51 eq) and NaI (5.00 mg, 33.3 μmol, 1.93 eq) were added at 25 °C. The mixture was stirred at 45 - 50 °C for 12 hours. It was confirmed by LCMS that the desired compound was synthesized. The mixture was cooled with water (10.0 mL) and extracted with EtOAc (10.0 mL × 2). The organic layer was washed with NaCl (10.0 mL × 2), and then dried over Na 2 SO 4 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 μmol, yield: 8.03%, purity: 89.7%) as a red gum.

[0331] 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 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 (3-(furan-3-yl)-6-(2-(4-isopropylphenoxy)ethoxy)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 49)

[0334] To DMF (3.00 mL), Compound 9-6 (50.0 mg, 172 μmol, 1.00 eq) synthesized in Embodiment 12 and 1-(2-bromoethoxy)-4-isopropylbenzene (43.0 mg, 176 μmol, 1.02 eq) in [Reaction Scheme 2] were mixed, and then K 2 CO 3 (36.0 mg, 260 μmol, 1.51 eq) and NaI (5.00 mg, 33.3 μmol, 1.93 eq) were added at 25 °C. The mixture was stirred at 45 - 50 °C for 12 hours. While dropping MeOH (1.00 mL), it was confirmed by LCMS that the desired compound was synthesized. The mixture was cooled with water (10.0 mL) and extracted with EtOAc (10.0 mL × 2). The organic layer was washed with NaCl (10.0 mL × 2), and then dried over Na 2 SO 4 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 μmol, yield: 15.11%, purity: 90.7%) as a red gum.

[0335] 1H NMR (400 MHz, DMSO-d6): δ ppm 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, 2 H), 6.27 (s, 1 H), 4.25 - 4.48 (m, 4 H), 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 (3-(furan-3-yl)-6-(((4-methoxybenzyl)oxy)methoxy)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 50)

[0338] [Reaction Scheme 2-1]

[0339] [Chemical Structure]

[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 the [Reaction Formula 2-1] was mixed, and then the reaction mixture was reacted 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 reacted at 25 - 30 °C. The mixture was stirred for 12 hours under a nitrogen atmosphere at 25 - 30 °C. While dropping DCM (0.5 mL), it was confirmed by TLC (PE / EA = 3 / 1) that the desired compound was synthesized. The mixture was cooled with NH 4 Cl (300 mL) at 0 °C, diluted with water (100 mL), and extracted with EtOAc (100 mL × 3). The organic layer was washed with brine (100 mL × 2), and then dried over Na 2 SO 4 . The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , PE:EA = 50:1 with a gradient of 10:1 P 1 = 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] After dissolving the compound 50-2 (500 mg, 2.52 mmol, 1 eq) in DMF (1 mL), acetyl chloride (178 mg, 2.27 mmol, 161 μL, 0.9 eq) was mixed, and the mixture was stirred for 12 hours under a nitrogen atmosphere at 25 - 30 °C. While dropping DCM (1.00 mL), it was confirmed by TLC (PE:EA = 5:1) that the desired compound was synthesized. The mixture was concentrated under vacuum and extracted with EA (5 mL). It was diluted with water (10 mL), extracted with EtOAc (10 mL × 2), and the organic layer was washed with water (10 mL × 3), and then dried over Na 2 SO 4 and the mixture was filtered and concentrated under reduced pressure conditions. The residue gave the compound 50-3 as a white oil (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 (3-(furan-3-yl)-6-(((4-methoxybenzyl)oxy)methoxy)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 50)

[0345] The compound 9-6 (60.0 mg, 207 μmol, 1 eq) synthesized in Embodiment 12 and NaH (5.97 g, 248 μmol, 1.2 eq) were mixed in DMF (1 mL). The compound 50-3 (77.4 mg, 414 μmol, 2 eq) was added to DMF (0.2 mL) and dropped into the mixture. The mixture was stirred for 2 hours under a nitrogen atmosphere at 25 - 30 °C. While dropping a mixture of DCM (1.00 mL) and water (1.00 mL), it was confirmed by TLC (PE:EA = 1:1) that the reactant was completely consumed. The mixture was cooled with NH 4 Cl (30 mL) at 0 °C, diluted with water (10 mL), and extracted with EtOAc (10 mL × 3). The organic layer was washed with brine (5.00 mL × 2), and then dried over Na 2 SO 4 and the mixture was filtered and concentrated under reduced pressure conditions. The residue was purified by prep-HPLC (SiO 2Purified with PE:EA = 1:1) to obtain Compound 50 (11.0 mg, 34.9 μmol, yield: 11.1%, purity: 92.1%) as a red solid.

[0346] 1H NMR (400 MHz, CHLOROFORM-d): δ 8.50 (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, 2.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 2H), 6.19 (d, J = 1.2 Hz, 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 (3-(5-methylthiazol-4-yl)-6-(3-morpholinopropoxy)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 4)

[0349] [Reaction Scheme 3]

[0350]

Chemical Formula

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

[0352] Ethanol (5.00 mL) was mixed with Compound 4-1 (500 mg, 3.93 mmol) of [Reaction Formula 3] and Compound 4-2 (535 mg, 3.93 mmol, 486 μL) of [Reaction Formula 3], and then H 2 O (2.00 mL) was added with NaOH (235 mg, 5.90 mmol) under a nitrogen atmosphere at 0 °C. The mixture was stirred at 20 °C for 12 hours. It was confirmed by TLC (DCM:methanol = 10 / 1) that the reactants were completely consumed. It was confirmed by LCMS that the reactants were completely consumed, and it was confirmed by MS that Compound 4-3 was synthesized. After adjusting the pH of the mixture to 7 with 1N HCl, the mixture was filtered and concentrated in vacuo to obtain Compound 4-3 (700 mg, 2.85 mmol, yield: 72.5%) as a yellow solid.

[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 then the mixture was stirred at 80 °C for 16 hours. It was confirmed by TLC (PE:EA = 1 / 1) that the reactants were completely consumed. Water (30.0 mL) was added to the mixture, and an aqueous NaHCO 3 solution was added to adjust the pH to 8. Then the mixture was filtered and concentrated in vacuo to obtain Compound 4-4 (700 mg, 2.85 mmol, yield: 100.00%) as a brown solid.

[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 μmol) was dissolved in DCM (10.0 mL), and then Ac 2O (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 μmol) were added at 0 °C. The mixture was stirred at 20 °C for 24 h. It was confirmed by TLC (PE:EA = 1 / 1) that the reactants were completely consumed. The mixture was diluted with DCM (100 mL) and extracted with brine (30.0 mL × 3). After drying over anhydrous Na 2 SO 4 and concentrating in vacuo to give a residue. The residue was purified by flash silica gel chromatography to give the white solid compound 4-5 (130 mg, 452 μmol, yield: 55.4%).

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

[0358] Compound 4-5 (130 mg, 452 μmol) and NBS (177 mg, 995 μmol) were mixed in carbon tetrachloride (5.00 mL), and then AIBN (7.43 mg, 45.2 μmol) was added under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 2 h under 400 W. It was confirmed by TLC (PE:EA = 2 / 1) that the reactants were completely consumed. The mixture was diluted with DCM (100 mL) and extracted with brine (30 mL × 3). After drying and filtering over anhydrous Na 2 SO 4 and concentrating in vacuo to give 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] After mixing compound 4-6 (200 mg, 549 μmol) with DCM (4.00 mL), DBU (83.6 mg, 549 μmol, 82.7 μL) was added. The mixture was stirred at 20 °C for 12 h. It was confirmed by TLC (PE:EA = 1 / 1) that the reactant was completely consumed. The mixture was diluted with DCM (100 mL) and extracted with brine (30 mL × 3). After drying and filtering with anhydrous Na 2 SO 4 and concentrating in vacuo to obtain a residue. The residue was purified by flash silica gel chromatography to obtain compound 4-7 (50.0 mg, 155 μmol, 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] Compound 4-7 (50.0 mg, 155 μmol) and 4-(3-chloropropyl)morpholine (4-(3-chloropropyl)morpholine, 30.5 mg, 186 μmol, 61.7 μL) as RX in the above [Reaction Scheme 3] were mixed in acetonitrile (2.00 mL), and then K 2 CO 3 (64.3 mg, 465 μmol) and KI (25.7 mg, 155 μmol) were added. The mixture was stirred at 60 °C for 2 h. It was confirmed by LCMS that the reactant was completely consumed and by MS that compound 5 was synthesized. The mixture was diluted with EtOAc (50.0 mL) and extracted with brine (10 mL × 3). After drying and filtering with anhydrous Na 2 SO 4 and concentrating in vacuo to obtain a residue. The residue was purified by reversed-phase HPLC to obtain compound 5 (5.60 mg, 11.7 μmol, 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] To dioxane (2.00 mL) and H 2 O (0.50 mL) were added Compound 5 (30.0 mg, 66.7 μmol) and pyridin-3-ylboronic acid (8.21 mg, 66.7 μmol) where R 1 -B(OH) 2 in [Reaction Scheme 3]. After mixing, K 3 PO 4 (42.5 mg, 200 μmol) and Pd(dtbpf)Cl 2 (4.35 mg, 6.68 μmol) were added under a nitrogen atmosphere. The mixture was stirred in a microwave at 100 °C for 2 hours. It was confirmed by LCMS that the reactants were completely consumed and by MS that Compound 4 was synthesized. The mixture was filtered and concentrated in vacuo to obtain a residue. The residue was purified by reversed-phase HPLC to obtain Compound 4 (5.40 mg, 12.1 μmol, yield: 18.0%) as a red solid.

[0365] 1H NMR (400 MHz, CD3OD): δ 9.13 (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 = 5.6 Hz, 2H), 4.06 - 4.11 (m, 2H), 3.83 (t, J = 12.0 Hz, 2H), 3.58 (d, J = 12.4 Hz, 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 (2 - bromo - 3 - (5 - methylthiazol - 4 - yl) - 6 - (3 - morpholinopropoxy) - 1H - inden - 1 - one) (Compound 5)

[0368] In Embodiment 26 described above, Compound 5 was synthesized.

[0369] 1 1H NMR (400 MHz, CD3OD): δ 9.04 (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 = 6.0 Hz, 2H), 3.72 (t, J = 4.8 Hz, 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 (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 (2-bromo-3-(5-methylthiazol-4-yl)-6-(3-phenylpropoxy)-1H-inden-1-one) (8-1)

[0373] Compound 4-7 (100 mg, 1.00 eq) synthesized in Embodiment 26 above and (3-bromopropyl)benzene ((3-bromopropyl)benzene, 88.0 mg, 1.5 eq) as RX in [Reaction Formula 3] were mixed in DMF (1.00 mL), and then K 2 CO 3 (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. It was confirmed by LCMS that the reactants were completely consumed. Water (10.0 mL) was added to the mixture, the pH was adjusted to 3 with 1M HCl, and then the mixture was extracted with EtOAc (10.0 mL × 3). The mixture was washed with brine (10.0 mL) and dried over Na 2 SO 4 and then filtered and concentrated under reduced pressure at 45°C. The residue was purified by column chromatography (SiO 2 , PE / EA = 50 / 1 - 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 R in the above [Reaction Scheme 3] 1 -B(OH) 2 were mixed with pyridin-3-ylboronic acid (32.0 mg, 1.5 eq), and then K 2 CO 3 (73.0 mg, 3.01 eq), Pd(t-Bu 3 P) 2 (10.0 mg, 0.01 eq) and dioxane (0.80 mL) and water (0.20 mL) were added under a nitrogen atmosphere at 20 - 25 °C. The mixture was stirred at 80 - 85 °C for 12 hours. It was confirmed by LCMS that the reactants were completely consumed. Water (10.0 mL) was added to the mixture, adjusted to pH 7 with 1M HCl, and then extracted with EtOAc (1.00 mL × 3). The organic layer was washed with brine (10.0 mL), dried over Na 2 SO 4 , and then concentrated under reduced pressure at 45 °C to obtain an 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): δ ppm 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 (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] Compound 4-7 (1.5 g, 1.00 eq) synthesized in Embodiment 26 above and (2-bromoethyl)benzene ((2-bromoethyl)benzene, 9.00 g, 6.58 mL, 11.0 eq) in RX in [Reaction Formula 3] were mixed in DMF (15.0 mL), and then K 2 CO 3 (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. It was confirmed by TLC (PE:EA = 3:1) that the desired compound was synthesized. Water (45.0 mL) was added to the mixture at 15-20 °C for cooling, and it was diluted and extracted with EtOAc (40.0 mL × 3). The mixture was washed with brine (40.0 mL) and dried over Na 2 SO 4 and then filtered and concentrated under reduced pressure at 45 °C. The residue was purified by column chromatography (SiO 2 , PE / EA = 50 / 1 - 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 R in the above [Reaction Scheme 3] 1 -B(OH) 2 were mixed with (4-methoxyphenyl)boronic acid (67.0 mg, 2.05 eq), and then K 2 CO 3 (90.0 mg, 3.02 eq), Pd(t-Bu 3 P) 2 (11.0 mg, 0.10 eq) and dioxane (2.0 mL) and water (0.5 mL) were added under a nitrogen atmosphere at 20 - 25 °C. The mixture was stirred at 80 - 85 °C for 19 h. It was confirmed by LCMS that the reactants were completely consumed. Water (10.0 mL) was added to the mixture at 15 - 20 °C for cooling, and diluted and extracted with EtOAc (10.0 mL × 3). The organic layer was washed with brine (10.0 mL), dried over Na 2 SO 4 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): δ ppm 1.85 (s, 3 H) 3.05 (t, J = 6.8 Hz, 2 H) 3.75 (s, 3 H) 4.27 (t, J = 6.8 Hz, 2 H ) 6.91 (d, J = 8.8 Hz, 2 H) 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, 1 H)

[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 (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 (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 above and (4-bromobutyl)benzene ((4-bromobutyl)benzene, 239 mg, 1.20 eq) as RX in [Reaction Formula 3] were mixed in DMF (3.00 mL), and then K 2 CO 3 (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. It was confirmed by TLC (PE:EA = 1:1) that the desired compound was synthesized. The mixture was diluted with water (20.0 mL), adjusted to pH 3 with 1M HCl, and then extracted with EtOAc (30.0 mL × 3). The mixture was separated, the organic layer was washed with brine (30.0 mL), dried over Na 2 SO 4 and then filtered and concentrated under reduced pressure at 45 °C. The residue was purified by column chromatography (SiO 2 , PE / EA = 100 / 1 - 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 R in the above [Reaction Scheme 3] 1 -B(OH) 2 were mixed with (4-methoxyphenyl)boronic acid (66.0 mg, 1.52 eq), and then K 2 CO 3 (118 mg, 3.01 eq), Pd(t-Bu 3 P) 2 (15.0 mg, 0.10 eq) and dioxane (0.8 mL) and water (0.2 mL) were added under a nitrogen atmosphere at 20 - 25 °C. The mixture was stirred at 80 - 85 °C for 12 h. It was confirmed by LCMS that the reactants were completely consumed. Water (10.0 mL) was added to the mixture, adjusted to pH 7 with 1 M HCl, and then extracted with EtOAc (10.0 mL × 3). The organic layer was washed with brine (10.0 mL), dried over Na 2 SO 4 , 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): δ 9.11 - 9.23 (m, 1H), 7.04 - 7.30 (m, 9H), 6.85 - 6.97 (m, 3H), 4.00 - 4.11 (m, 2H), m s, 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 (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 (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 above and ((chloromethoxy)methyl)benzene (1.16 g, 5.02 eq) as RX in [Reaction Formula 3] were mixed in DMF (5.0 mL), and then K 2 CO 3 (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. It was confirmed by TLC (PE:EA = 3:1) that the desired compound was synthesized. Water (5.00 mL) was added to the mixture, and the mixture was extracted with EtOAc (2 mL × 1). It was concentrated under reduced pressure conditions. The residue was purified by column chromatography (SiO 2 , 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 R in the above [Reaction Scheme 3] 1 -B(OH) 2 were mixed with (4-methoxyphenyl)boronic acid (52.0 mg, 1.51 eq), and then K 2 CO 3 (94.0 mg, 3.01 eq), Pd(t-Bu 3 P) 2 (12.0 mg, 0.10 eq) and dioxane (0.80 mL) and water (0.20 mL) were added under a nitrogen atmosphere at 25 °C. The mixture was stirred under a nitrogen atmosphere at 80 - 85 °C for 12 hours. It was confirmed by LCMS that the reactants were completely consumed. Water (3.00 mL) was added to the mixture for dilution, and it was extracted with EtOAc (1.00 mL), dried over Na 2 SO 4 , 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 = 8.8 Hz, 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] Compound 4-7 (500 mg, 1.00 eq) synthesized in Embodiment 26 above and (2-bromoethoxy)benzene (1.78 g, 6.00 eq) represented by RX in [Reaction Formula 3] were mixed in DMF (5.00 mL), and then K 2 CO 3 (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. It was confirmed by TLC (PE:EA = 3:1) that the desired compound was synthesized. After cooling the mixture with water (20.0 mL) at 15 - 20°C, it was diluted with EtOAc (20.0 mL × 3) and extracted. The organic layer was washed with brine (20 mL) and dried over Na 2 SO 4 and then filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , 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 R in the above [Reaction Scheme 3] 1 -B(OH) 2 were mixed with (4-methoxyphenyl)boronic acid (61.0 mg, 2.01 eq), and then K 2 CO 3 (83.0 mg, 3.01 eq), Pd(t-Bu 3 P) 2 (11.0 mg, 0.10 eq) and dioxane (1.60 mL) and water (0.40 mL) were added under a nitrogen atmosphere at 20 - 25 °C. The mixture was stirred under a nitrogen atmosphere at 80 - 85 °C for 18 hours. It was confirmed by LCMS that the reactants were completely consumed. Water (10.0 mL) was added to the mixture at 15 - 20 °C for cooling, and it was diluted with EtOAc (10.0 mL × 3) and extracted. The organic layer was washed with brine (10.0 mL), dried over Na 2 SO 4 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): δ ppm 1.85 (s, 3 H) 3.05 (t, J = 6.8 Hz, 2 H) 3.75 (s, 3 H) 4.27 (t, J = 6.8 Hz, 2 H) 6.91 (d, J = 8.8 Hz, 2 H) 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, 1 H)

[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 (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] The compound 4-7 (0.50 g, 1.00 eq) synthesized in Embodiment 26 above and 4-(2-bromoethoxy)-1,2-dichlorobenzene (4-(2-bromoethoxy)-1,2-dichlorobenzene, 503 mg, 1.20 eq) represented by RX in [Reaction Formula 3] were mixed in DMF (5 mL), and then K 2 CO 3(322 mg, 1.50 eq) and NaI (47 mg, 2.02e-1 eq) were added under a nitrogen atmosphere at 15 - 20 °C. The mixture was stirred at 40 - 45 °C for 18 hours. It was confirmed by TLC (PE:EA = 3:1) that the desired compound was synthesized. Water (20 mL) was added to the mixture, and after adjusting the pH to 3 with 1 M HCl, it was extracted with EtOAc (30 mL × 3). The organic layer was washed with brine (30 mL) and dried over Na 2 SO 4 , and then filtered and concentrated under reduced pressure at 45 °C. The residue was purified by column chromatography (SiO 2 , PE / EA = 10 / 1 - 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) with R 1 -B(OH) 2 in the above [Reaction Scheme 3] were mixed, and then K 2 CO 3 (81.0 mg, 586.08 μmol, 3 eq), Pd(t-Bu 3 P) 2 (10 mg, 0.10 eq) and dioxane (2 mL) and water (0.5 mL) were added under a nitrogen atmosphere at 15 - 25 °C. The mixture was stirred at 80 - 85 °C for 12 hours under a nitrogen atmosphere. It was confirmed by LCMS that the desired compound was synthesized. Water (20 mL) was added to the mixture, and it was extracted with EtOAc (30 mL × 3). The organic layer was washed with brine (30 mL) and dried over Na 2 SO 4After drying, it was 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 (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] To DMF (10 mL), the compound 4-7 (1.00 g, 3.10 mmol, 1.00 eq) synthesized in the above Embodiment 26 and 4-(2-bromoethoxy)-1,2-difluorobenzene (883 mg, 1.20 eq) in the above [Reaction Formula 3] were mixed, and then K 2 CO 3 (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. It was confirmed by TLC (PE:EA = 3:1) that the desired compound was synthesized. Water (20 mL) was added to the mixture, adjusted to pH 3 with 1 M HCl, and then extracted with EtOAc (30 mL×3). The organic layer was washed with brine (30 mL) and dried over Na 2 SO 4 , filtered and concentrated under reduced pressure at 45 °C. The residue was purified by column chromatography (SiO 2 , PE / EA = 10 / 1 - 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) in the above [Reaction Formula 3] with R 1 -B(OH) 2 were mixed, and then K 2 CO 3 (87.0 mg, 3.01 eq), Pd(t-Bu 3 P) 2(11 mg, 1.03e-1 eq) and dioxane (2 mL) and water (0.5 mL) were added under a nitrogen atmosphere at 15 - 25 °C. The mixture was stirred under a nitrogen atmosphere at 80 - 85 °C for 12 hours. It was confirmed that the desired compound was synthesized by TLC (PE:EA = 1:1). Water (20 mL) was added to the mixture, and it was extracted with EtOAc (30 mL × 3). The organic layer was washed with brine (30 mL) and dried over Na 2 SO 4 , and then filtered and concentrated under reduced pressure at 45 °C. The residue was purified by column chromatography (SiO 2 , PE / EA = 10 / 1 - 2 / 1) to obtain Compound 27 (31.0 mg, yield: 28.5%, purity: 91.9%) as a brownish-red solid.

[0418] 1H NMR (400 MHz, DMSO-d6): δ 9.22 (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 (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] To DMF (1.00 mL), the compound 4-7 (200 mg, 1.00 eq) synthesized in the above Embodiment 26 and 1-(2-bromoethoxy)-4-methoxybenzene (164 mg, 1.20 eq) in RX in the above [Reaction Formula 3] were mixed, and then K 2 CO 3 (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. It was confirmed by TLC (PE:EA = 3:1) that the desired compound was synthesized. Water (10.0 mL) was added to the mixture, adjusted to pH 3 - 4 with 1M HCl, and then extracted with EtOAc (20.0 mL × 2). After drying with Na 2 SO 4 , it was concentrated. The residue was purified by column chromatography (SiO 2 , PE / EA = 30 / 1 - 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 R 1 -B(OH)2 was mixed with (4-(trifluoromethyl)phenyl)boronic acid (54.0 mg, 1.49 eq), and then K 2 CO 3 (79.0 mg, 3.00 eq), Pd(t-Bu 3 P) 2 (10.0 mg, 0.02 eq) and added to 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. It was confirmed by LCMS that the desired compound was synthesized. Water (20 mL) was added to the mixture, and it was extracted with EtOAc (10.0 mL × 2). The organic layer was washed with brine (10.0 mL × 2) and dried over anhydrous Na 2 SO 4 . After drying, it was 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 filtered to obtain a residue. The residue gave compound 32 (26.4 mg, yield: 24.54%, purity: 95.2%) as a red solid.

[0425] 1H NMR (400 MHz, DMSO-d6): δ ppm 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] In the above Embodiment 35, the synthesized compound 32-1 (100 mg, 1.00 eq) and R in the above [Reaction Formula 3] 1 -B(OH) 2 were mixed with (4-fluorophenyl)boronic acid (45.0 mg, 1.52 eq), and then K 2 CO 3 (88.0 mg, 3.01 eq), Pd(t-Bu 3 P) 2 (11.0 mg, 0.1 eq) and dioxane (2 mL) and water (0.5 mL) were added under a nitrogen atmosphere at 15 - 20 °C. The mixture was stirred under a nitrogen atmosphere at 80 - 85 °C for 14 hours. It was confirmed by LCMS that the desired compound was synthesized. Water (20 mL) was added to the mixture, and it was extracted with EtOAc. The organic layer was washed with brine and dried over Na 2 SO 4 . After that, it was filtered and concentrated under reduced pressure conditions. 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, 3 H).

[0430] Measured value of MS: 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 (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 (2-bromo-6-(2-(3,4-dimethoxyphenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one) (33-1)

[0433] To DMF (5.00 mL), the compound 4-7 (500 mg, 1.00 eq) synthesized in Embodiment 26 and 4-(2-bromoethoxy)-1,2-dimethoxybenzene (4-(2-bromoethoxy)-1,2-dimethoxybenzene, 642 mg, 1.50 eq) represented by RX in [Reaction Formula 3] were mixed, and then K 2 CO 3 (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. It was confirmed by LCMS that the desired compound was synthesized. Water (10.0 mL) was added to the mixture, the pH was adjusted to 3 - 4 with 1M HCl, and then extracted with EtOAc (20.0 mL × 2). After drying with Na 2 SO 4 and concentrated. The residue was purified by column chromatography (SiO 2 , EA / DCM = 0 / 1 - 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 R in the above [Reaction Formula 3] 1 -B(OH) 2 The (4-(trifluoromethyl)phenyl)boronic acid ((4-(trifluoromethyl)phenyl)boronic acid, 45.0 mg, 1.49 eq) was mixed, and then a solution of K 2 CO 3 (66.0 mg, 3.00 eq) dissolved in water (0.25 mL), Pd(t-Bu 3 P) 2 (16.0 mg, 0.02 eq) and dioxane (1.00 mL) were added under a nitrogen atmosphere at 20 - 25 °C. The mixture was stirred under a nitrogen atmosphere at 80 - 85 °C for 8 hours. It was confirmed by LCMS that the desired compound was synthesized. Water (20.0 mL) was added to the mixture, and it was extracted with EtOAc (10.0 mL × 2). The organic layer was washed with brine (10.0 mL × 2), dried over anhydrous Na 2 SO 4 and then filtered and concentrated under vacuum conditions. 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): δ ppm 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 (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 above and R 1 -B(OH) 2 in (4-Fluorophenyl)boronic acid (34.0 mg, 1.53 eq) were mixed, and then K 2 CO 3 (67.0 mg, 3.04 eq), Pd(t-Bu 3 P) 2(10.0 mg, 0.12 eq) and dioxane (2 mL) and water (0.5 mL) were added under a nitrogen atmosphere at 15 - 20 °C. The mixture was stirred under a nitrogen atmosphere at 80 - 85 °C for 14 hours. It was confirmed by LCMS that the desired compound was synthesized. Water (20 mL) was added to the mixture, and it was extracted with EtOAc. The organic layer was washed with brine and dried over Na 2 SO 4 . After filtration and concentration 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): δ ppm 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, 3 H), 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 (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] Compound 4-7 (200 mg, 1.00 eq) synthesized in Embodiment 26 above and 5-(2-bromoethoxy)benzo[d][1,3]dioxole (173 mg, 1.19 eq) as RX in [Reaction Formula 3] were mixed in DMF (1.00 mL), and then K 2 CO 3 (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. It was confirmed by TLC (PE / EA = 3 / 1) that the desired compound was synthesized. Water (10.0 mL) was added to the mixture, the pH was adjusted to 3 - 4 with 1M HCl, and then extracted with EtOAc (20.0 mL × 2). After drying with Na 2 SO 4 and concentrated. The residue was purified by column chromatography (SiO 2 , PE / EA = 30 / 1 - 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 R in the above [Reaction Scheme 3] 1 -B(OH) 2 was mixed with (4-(trifluoromethyl)phenyl)boronic acid (24.0 mg, 1.54 eq). After that, a solution of K 2 CO 3 (34.0 mg, 2.99 eq) dissolved in water (0.25 mL), Pd(t-Bu 3 P) 2 (5.00 mg, 0.02 eq) and dioxane (1.00 mL) were added under a nitrogen atmosphere at 20 - 25 °C. The mixture was stirred under a nitrogen atmosphere at 80 - 85 °C for 8 hours. It was confirmed by LCMS that the desired compound was synthesized. Water (20.0 mL) was added to the mixture, and the mixture was extracted with EtOAc (10.0 mL × 2). The organic layer was washed with brine (10.0 mL × 2), dried over anhydrous Na 2 SO 4 , and then filtered and concentrated under vacuum conditions. 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): δ ppm 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 (Compound 24)

[0450] Compound 34-1 (90.0 mg, 1.00 eq) synthesized in Embodiment 39 above and R 1 -B(OH) 2 of (4-fluorophenyl)boronic acid (40.0 mg, 1.54 eq) were mixed, and then K 2 CO 3 (78.0 mg, 3.05 eq), Pd(t-Bu 3 P) 2 (10.0 mg, 0.1 eq) and dioxane (2 mL) and water (0.5 mL) were added under a nitrogen atmosphere at 15 - 20°C. The mixture was stirred under a nitrogen atmosphere at 80 - 85°C for 14 hours. It was confirmed by LCMS that the desired compound was synthesized. Water (20 mL) was added to the mixture, and it was extracted with EtOAc. The organic layer was washed with brine and dried over Na 2 SO 4 . After drying, it was filtered and concentrated under reduced pressure to obtain a 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 (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 (2-bromo-6-(2-((t-butyldimethylsilyl)oxy)ethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one) (35-1)

[0455] The compound 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), and then K 2 CO 3(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. It was confirmed by LCMS that the desired compound was synthesized. Water (50.0 mL) was added to the mixture, adjusted to pH 3 - 4 with 1 M HCl, and then extracted with EtOAc (50.0 mL × 2). 2 SO 4 After drying over Na 2 2SO4 and concentrating, the residue was purified by column chromatography (SiO2, PE / EA = 30 / 1 - 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] HCl (2.00 M, 1.50 mL, 2.00 eq) was added to Compound 35 - 1 (723 mg, 1.00 eq) in THF (4.00 mL), and the mixture was stirred at 20 - 25 °C for 12 hours. It was confirmed by TLC (PE / EA = 1 / 1) that the desired compound was synthesized. Water (10.0 mL) was added to the mixture, adjusted to pH 8 - 9 with NaHCO 3 3, and then extracted with EtOAc (20.0 mL × 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 R in the above [Reaction Scheme 3] 1 -B(OH) 2 was mixed with (4-(trifluoromethyl)phenyl)boronic acid (210 mg, 1.50 eq). After that, a solution of K 2 CO 3 (307 mg, 3.01 eq) dissolved in water (0.7 mL), Pd(t-Bu 3 P) 2 (75.0 mg, 0.02 eq) and dioxane (2.70 mL) were added under a nitrogen atmosphere at 20 - 25 °C. The mixture was stirred under a nitrogen atmosphere at 80 - 85 °C for 8 hours. It was confirmed by TLC that the desired compound was synthesized. Water (20.0 mL) was added to the mixture, and it was extracted with EtOAc (10.0 mL × 2). The organic layer was washed with brine (10.0 mL × 2), dried over anhydrous Na 2 SO 4 , and then filtered and concentrated under vacuum conditions. The residue was purified by column chromatography (SiO 2 , PE / EA = 10 / 1 - 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 (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) in place of RX in the above [Reaction Scheme 3] were mixed in DCM (0.50 mL). After that, PPh 3(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 then the mixture was stirred for 2 hours under a nitrogen atmosphere. It was confirmed that the desired compound was synthesized by TLC (PE / EA = 1 / 2). Water (20.0 mL) was added to the mixture, and it was extracted with EtOAc (50.0 mL × 3). Na 2 SO 4 After drying and concentrating, the residue was purified by prep-TLC (EA:THF = 1:1), and this was titrated with 3 mL of PE / MTBE = 10 / 1 at 20 - 25 °C for 30 minutes. Through the filtration and concentration processes, Compound 35 was obtained as an orange solid.

[0462] 1H NMR (400 MHz, DMSO-d6): δ ppm 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 (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 (2-(4-fluorophenyl)-6-(2-hydroxyethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one) (25-1)

[0466] In the above Embodiment 41, the synthesized compound 35-2 (250 mg, 1.00 eq) and R in the above [Reaction Formula 3] 1 -B(OH) 2 with (4-fluorophenyl)boronic acid (146 mg, 1.53 eq) were mixed. Then, a solution of K 2 CO 3 (287 mg, 3.04 eq) dissolved in water (1 mL), Pd(t-Bu 3 P) 2 (43.0 mg, 0.12 eq) and dioxane (4 mL) were added under a nitrogen atmosphere at 15 - 20 °C. The mixture was stirred under a nitrogen atmosphere at 80 - 85 °C for 14 hours. It was confirmed by LCMS that the desired compound was synthesized. Water (20.0 mL) was added to the mixture, and it was extracted with EtOAc. The organic layer was washed with brine and dried over Na 2 SO 4 . After filtration and concentration under reduced pressure conditions, the residue was purified by column chromatography (SiO 2 , PE / EA = 10 / 1 - 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) in place of RX in the above [Reaction Formula 3] were mixed in THF (5 mL). Then, PPh 3(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. It was confirmed by LCMS that the desired compound was synthesized. Water (20.0 mL) was added to the mixture, and it was extracted with EtOAc. The organic layer was washed with brine and dried over Na 2 SO 4 , and then filtered and concentrated under reduced pressure. After drying over Na 2 SO 4 , it was concentrated. The residue was purified by column chromatography (SiO 2 , PE / EA = 10 / 1 - 3 / 1), and then 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,4H), 1.87(s,3H)

[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 (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 above and tributyl(thiophen-2-yl)stannane (157 mg, 1.30 eq) were mixed in place of R 1 -B(OH) 2 in [Reaction Formula 3], and then Pd 2 (dba) 3(60.0 mg, 0.20 eq) and dioxane (4.00 mL) were added under a nitrogen atmosphere at 20 - 25 °C. The mixture was stirred under a nitrogen atmosphere at 115 - 120 °C for 2 hours. It was confirmed by LCMS that the reactant was completely consumed. Water (15.0 mL) was added to the mixture at 15 - 20 °C to cool it, and it was extracted with EtOAc (15.0 mL × 3). The organic layer was washed with brine (15.0 mL) and dried over Na 2 SO 4 , and then filtered and concentrated under reduced pressure to obtain a 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 found: 430.1 [M+H] +

[0475] Embodiment 44 3-(5-Methylthiazol-4-yl)-6-(4-phenylbutoxy)-2-(thiophen-2-yl)-1H-inden-1-one (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 above and tributyl(thiophen-2-yl)stannane (55.0 mg, 1.31 eq) instead of R 1 -B(OH) 2 in [Reaction Scheme 3] were mixed, and then Pd 2 (dba)3 (20.0 mg, 0.02 eq) and dioxane (1.50 mL) were added under a nitrogen atmosphere at 25 - 30 °C. The mixture was stirred in a microwave at 115 - 120 °C for 2 hours. It was confirmed by LCMS that the reactant was completely consumed. Water (10.0 mL) was added to the mixture at 15 - 20 °C, and it was extracted with EtOAc (10.0 mL × 3). The organic layer was washed with brine (10.0 mL) and dried over Na 2 SO 4 and then filtered and concentrated under reduced pressure at 45 °C to obtain a 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 (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 above and tributyl(thiophen - 2 - yl)stannane (110 mg, 1.30 eq) were mixed instead of R 1 -B(OH) 2 in [Reaction Formula 3], and then Pd 2 (dba) 3(42.0 mg, 0.20 eq) and dioxane (1.00 mL) were added under a nitrogen atmosphere at 20 - 25 °C. The mixture was stirred under a nitrogen atmosphere at 120 °C for 2 hours. It was confirmed by LCMS that the reactant was completely consumed. Water (3.0 mL) was added to the mixture, and it was extracted with EtOAc (1.0 mL × 1). 2 SO 4 After drying over Na

[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 (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 above and in [Reaction Scheme 3], R 1 -B(OH) 2 were replaced with tributyl(thiophen-2-yl)stannane (146 mg, 1.30 eq), and after mixing, Pd 2 (dba) 3(55.0 mg, 0.20 eq) and dioxane (4.50 mL) were added under a nitrogen atmosphere at 20 - 25 °C. The mixture was stirred under a nitrogen atmosphere at 115 - 120 °C for 2 hours. It was confirmed by LCMS that the reactant was completely consumed. Water (15.0 mL) was added to the mixture at 15 - 20 °C for cooling, and extracted with EtOAc (15.0 mL × 3). The organic layer was washed with brine (15.0 mL), dried over Na 2 SO 4 , and then filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to obtain Compound 31 as a black-brown solid.

[0485] 1H NMR (400 MHz, DMSO-d6): δ ppm 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 found: 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 (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 above and tributyl(thiophen-2-yl)stannane (96.0 mg, 1.32 eq) in place of R 1 -B(OH) 2 in [Reaction Scheme 3] were mixed, and then Pd2 (dba) 3 (36.0 mg, 39.31 μmol, 0.20 eq) and dioxane (3 mL) were added under a nitrogen atmosphere at 15 - 25 °C. The mixture was stirred with microwave at 145 - 150 °C for 2 hours under a nitrogen atmosphere. It was confirmed by LCMS that the desired compound was synthesized. Water (20 mL) was added to the mixture, and it was extracted with EtOAc (30 mL × 3). The organic layer was washed with brine (30 mL), and 2 SO 4 dried over Na

[0489] 1H NMR (400 MHz, DMSO-d6): δ 9.23 (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 = 8.0 Hz, 1H), 4.38 (br d, J = 2.8 Hz, 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 (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 above and in [Reaction Formula 3], R 1 -B(OH) 2Instead, tributyl(thiophen-2-yl)stannane (103 mg, 1.32 eq) was mixed, and then added to Pd 2 (dba) 3 (39 mg, 0.20 eq) and dioxane (3 mL) under a nitrogen atmosphere at 15 - 25 °C. The mixture was stirred by microwave under a nitrogen atmosphere at 145 - 150 °C for 2 hours. It was confirmed by LCMS that the desired compound was synthesized. Water (20 mL) was added to the mixture, and it was extracted with EtOAc (30 mL × 3). The organic layer was washed with brine (30 mL) and dried over Na 2 SO 4 . After that, it was filtered and concentrated under reduced pressure at 45 °C to obtain a 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): δ 9.22 (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 found: 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 Scheme 4]

[0497] [Chemical Formula]

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

[0499] To THF (10.0 mL), compound 6-1 (1.70 g, 8.08 mmol, 823 μL) of [Reaction Formula 4] and, in [Reaction Formula 4], when R 1 is pyridine, 3-ethynylpyridine (1.00 g, 9.70 mmol, 558 μL) as compound 6-2 (A) were mixed, and then Et 3 N (2.45 g, 24.2 mmol, 3.37 mL), CuI (769 mg, 4.04 mmol), and PdCl 2 (PPh3) 2 (567 mg, 808 μmol) were added at 25 °C under a nitrogen atmosphere. The mixture was stirred at 25 °C for 12 hours. It was confirmed by LCMS that compound 6-3 was synthesized and by TLC (PE:EA = 3 / 1) that the reactants were completely consumed. The residue was diluted with EtOAc (200 mL). The combined organic phase layer was extracted with brine (20 mL × 3). After drying and filtering over anhydrous Na 2 SO 4 and concentrating under low pressure conditions to obtain a residue. The residue was purified by flash silica gel chromatography to obtain 3-(thiophen-2-ylethynyl)pyridine (1.16 g, 6.26 mmol, yield: 77.49%) as a yellow oil in compound 6-3.

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

[0501] To dioxane (5.00 mL), 3-(thiophen-2-ylethynyl)pyridine (600 mg, 3.24 mmol), which is Compound 6-3 synthesized in Step 1 above, and Compound 6-4A (2.03 g, 6.48 mmol) were added. After mixing, TBAB (1.04 g, 3.24 mmol), Na 2 CO 3 (686 mg, 6.48 mmol), and PdCl 2 (57.4 mg, 323 μmol) were added at 25 °C under carbon monoxide (15 psi) conditions. The mixture was stirred at 100 °C for 12 hours. It was confirmed by TLC (PE:EA = 1 / 1) that the reactants were completely consumed. The residue was diluted with EtOAc (200 mL). The combined organic phase layer was extracted with brine (20.0 mL × 3). After drying and filtering over anhydrous Na 2 SO 4 , it was concentrated under low pressure conditions to obtain a residue. The residue was purified by flash silica gel chromatography and then by prep-HPLC to obtain red solid Compound 6-5 (6-methoxy-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one, 100 mg, 313 μmol, yield: 9.67%) and purple solid Compound 6-5(B), 6-methoxy-3-(pyridin-3-yl)-2-(thiophen-2-yl)-1H-inden-1-one (6-methoxy-3-(pyridin-3-yl)-2-(thiophen-2-yl)-1H-inden-1-one, 140 mg, 438.35 μmol, yield: 13.53%).

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

[0503] To DCM (2.00 mL), 6-methoxy-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one (70.0 mg, 219.18 μmol), which is Compound 6-5, was added. Then, BBr 3 (55.0 mg, 219 μmol, 21.1 μL) was added under a nitrogen atmosphere at 0 °C. The mixture was stirred at 25 °C for 12 hours. It was confirmed by TLC (PE:EA = 1 / 1) that the reactant was completely consumed. The reaction mixture was cooled with aqueous NaHCO 3 (10.0 mL), and no further reaction (work up) occurred. Compound 6-6 (6-hydroxy-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one, 150 mg) was obtained 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] To acetonitrile (3.00 mL), 6-hydroxy-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one (70.0 mg, 229 μmol), which is Compound 6-6, and (3-bromopropyl)benzene ((3-bromopropyl)benzene, 68.5 mg, 343 μmol, 51.8 μL), which is RX in [Reaction Formula 4], were added. Then, K 2 CO 3 (79.2 mg, 573 μmol) was added under a nitrogen atmosphere at 25 °C. The mixture was stirred at 60 °C for 12 hours. It was confirmed by LCMS that the reactant was completely consumed. The residue was diluted with EtOAc (200 mL). The combined organic phase layer was extracted with brine (20.0 mL × 3). Anhydrous Na 2 SO 4After drying and filtering, it was concentrated under low pressure conditions to obtain a residue. The residue was purified by prep-HPLC to obtain Compound 6 (5.00 mg, 11.6 μmol, yield: 5.05%, purity: 98.15%) as a red solid.

[0506] 1H NMR (400 MHz, CD3OD): δ 8.53 - 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, 8.0 Hz, 1H), 4.04 (t, J = 6.0 Hz, 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 Scheme 5]

[0510]

Chemical Formula

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

[0512] To ethanol (75.0 mL), compound 7-1 (5.00 g, 52.0 mmol) of [Reaction Scheme 5] and compound 7-2 (7.08 g, 52.0 mmol) of [Figure 5] were added and mixed, and then H 2 O (30.0 mL) was added with NaOH (3.12 g, 78.05 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. It was confirmed by TLC (PE:EA = 3 / 1) that the reactants were completely consumed. The residue was diluted with H 2 O (50 mL) and extracted with EtOAc (50.0 mL × 2). The combined organic phase layer was extracted with brine (50 mL × 2). After drying and filtering with Na 2 SO 4 and concentrated under low pressure conditions to obtain a residue. The residue was purified by column chromatography (SiO 2 , PE / EA = 1 / 0 to 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 then the mixture was stirred at 80 °C for 16 hours. It was confirmed by TLC (PE:EA = 1 / 1) that the reactants were completely consumed. The residue was diluted with H 2 O (50.0 mL) and extracted with EtOAc (50.0 mL × 2). The combined organic phase layer was extracted with brine (50.0 mL × 2). After drying and filtering with Na 2 SO 4 and concentrated under low pressure conditions to obtain a residue. The residue was purified by column chromatography (SiO 2 , PE / EA = 1 / 0 to 1 / 1) to obtain compound 7-4 (0.80 g, 3.73 mmol, yield: 72.7%) as a black-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 Ac 2 O (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 h. It was confirmed by TLC (PE:EA = 1 / 1) that the reactants were completely consumed. The reaction mixture was diluted with DCM (100 mL) and extracted with brine (30.0 mL × 3). After drying over anhydrous Na 2 SO 4 and concentrating in vacuo, a residue was obtained. The residue was purified by flash silica gel chromatography to give 7-5 (540 mg, 1.81 mmol, yield: 77.5%) as a yellow solid.

[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 μmol) was added under a nitrogen atmosphere. The mixture was stirred at 80 °C for 2 h under 400 W. It was confirmed by TLC (PE:EA = 1 / 1) that the reactants were completely consumed. The mixture was diluted with DCM (100 mL) and extracted with brine (30.0 mL × 3). After drying and filtering over anhydrous Na 2 SO 4 and concentrating in vacuo, 7-6 (800 mg) was obtained as a red oil.

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

[0520] After dissolving compound 7-6 (800 mg, 2.13 mmol) in DCM (10.0 mL), DBU (324 mg, 2.13 mmol) was added at 0 °C. The mixture was stirred at 20 °C for 12 h. It was confirmed by TLC (PE:EA = 2 / 1) that the reactant was completely consumed. After adjusting the mixture to pH 6 with 1N HCl, the mixture was extracted with DCM (50.0 mL×3). The combined organic phase layers were dried over anhydrous Na 2 SO 4 and filtered, and then concentrated in vacuo to obtain a residue. The residue was purified by flash silica gel chromatography to obtain compound 7-7 (40.0 mg, 120 μmol, 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 (compound 7-8)

[0522] Compound 7-7 (40.0 mg, 120 μmol) and (3-bromopropyl)benzene (35.8 mg, 180 μmol) as RX in the above [Reaction Formula 5] were mixed in acetonitrile (3.00 mL), and then K 2 CO 3 (49.8 mg, 360 μmol) was added at 20 °C, and the mixture was stirred at 20 °C for 3 h. It was confirmed by TLC (PE:EA = 2 / 1) that the reactant was completely consumed. The mixture was diluted with EtOAc (50.0 mL) and extracted with brine (20.0 mL×3). Anhydrous Na 2 SO4 After drying and filtering with [specific drying and filtering method], it was concentrated in vacuo to obtain a 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 μmol, 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] To dioxane (1.50 mL) and H 2 O (0.50 mL) were added Compound 7-8 (6.00 mg, 12.37 μmol) and, in the above [Chemical Formula 5], B(OH) 2 -R 1 where R 1 was taken as pyridine, and pyridin-3-ylboronic acid (1.82 mg, 14.8 μmol) was mixed. Then, K 3 PO 4 (7.88 mg, 37.11 μmol) and Pd(dtbpf)Cl 2 (806 μg, 1.24 μmol) were added. The mixture was stirred under a nitrogen atmosphere at 100 °C for 10 hours. It was confirmed by TLC (DCM: methanol = 10 / 1) that the reactants were completely consumed. The mixture was diluted with H 2 O (10.0 mL) and extracted with EtOAc (20.0 mL × 3). The combined organic phase layers were dried and filtered with anhydrous Na 2 SO 4 and then concentrated in vacuo to obtain a residue. The residue was purified by prep-TLC (SiO 2, Purified with DCM:methanol = 10 / 1) to obtain Compound 7 (3.50 mg, 8.59 μmol, yield: 64.61%, purity: 89.36%) as a red solid.

[0525] 1H NMR (400 MHz, CD3OD): δ 8.45 - 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 = 2.4 Hz, 1H), 6.83 (dd, J = 2.4, 8.0 Hz, 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 β aggregation decomposition test (Aβ disaggregation test)

[0529] 1.1. Preparation of samples

[0530] Each compound was dissolved in DMSO to a concentration of 10 mM. Then, the compound was diluted with 6% DMSO (in DW) and used.

[0531] Specifically, the amyloid β and tau solutions were Aβ 1~42Alternatively, Tau-RD3 (Tau repeat domain 3) monomers were prepared by dissolving them in DMSO to a concentration of 10 mM. Subsequently, they were diluted to 100 μM using DW and stored on ice. On the other hand, Thioflavin-T was dissolved in 50 mM glycine buffer (pH 8.5) to a concentration of 5 mM. Subsequently, it was diluted to 5 μM using 50 mM glycine buffer (pH 8.5) and stored in a dark room with light blocked.

[0532] 1.2. Amyloid-β and Tau aggregation decomposition tests by Thioflavin-T analysis

[0533] The amyloid-β and Tau solutions prepared in Experimental Example 1.1 were respectively placed in 1.5 mL microcentrifuge tubes to a concentration of 50 μM or 35 μM, and then reacted at 37 °C for 24 hours. Separately for each 1.5 mL microcentrifuge tube in which the amyloid-β and Tau aggregations were completed, the compound was serially diluted from 500 μM and treated at concentrations up to 0 μM, and then further reacted at 37 °C for 48 hours. The completed reaction solutions were each placed 25 μL per well in a 96-well fluorescence analysis plate, and the previously prepared Thioflavin-T solution was placed 75 μL per well in each well. After reacting for 5 minutes in a dark room at room temperature, 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) aggregated for 72 hours by treating with only amyloid-β or Tau were converted to % values and displayed as 100. After treating the amyloid-β and Tau aggregates that had completed aggregation after reacting for 24 hours with each compound according to concentration and further reacting for 48 hours, the measured fluorescence values were converted to relative values, and the results are shown in Figures 1-6 and Figures 7-12 respectively. Furthermore, the EC 50 values of each compound of the present invention against amyloid-β and Tau were summarized in Table 1.

[0535]

Table 1

[0536] Figures 1 - 6 show the amyloid-β aggregation decomposition effect (control group: Aβ 1-42 aggregated for 72 hours in the 50 μM treatment group, treatment group: Aβ 1-42 aggregated for 24 hours with 50 μM + treated with the concentration of each derivative compound for 48 hours) and the concentration (EC 50 ) at which each compound can decompose 50% of amyloid-β aggregation relative to the control group at the time of each compound treatment. This means that each compound shows an aggregation decomposition effect in a concentration-dependent manner.

[0537] Figures 7 - 12 show the tau aggregation decomposition effect (control group: Tau-RD3 aggregated for 72 hours in the 35 μM treatment group, treatment group: Tau-RD3 aggregated for 24 hours with 35 μM + treated with the concentration of each derivative compound for 48 hours) and the concentration (EC 50 ) at which each compound can decompose 50% of tau aggregation relative to the control group at the time of each compound treatment. This means that each compound shows an aggregation decomposition effect in a concentration-dependent manner.

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

[0539] 2.1 Preparation of 5xFAD TG mouse model

[0540] Transgenic mice (5×FAD TG, an Alzheimer's disease animal model, B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas / Mmjax) and wild-type mice were obtained from the Jackson Laboratory (Bar Harbor, Maine, USA). The 5xFAD TG mice were maintained as double hemizygotes by crossing with wild-type mice. All genotypes were confirmed by PCR analysis using tail DNA according to the standard PCR conditions of the Jackson Laboratory. The TG mice used in this study are a model in which cognitive function decline occurs due to the deposition of amyloid-β in the brain, and it is known that the pattern of amyloid-β deposition, which is the deposited substance in the brains of actual Alzheimer's patients, has a morphology similar to that of patients, and was selected because it is easy to interpret and evaluate the test results. The mice were housed individually in plastic cages in an animal breeding room, maintained at 21±1 °C on a 12-hour light-dark cycle, and allowed free access to food and water.

[0541] 2.2 Administration of Compounds to Mouse Models

[0542] The compound was orally administered daily at each concentration to 10-month-old 5×FAD TG mice.

[0543] There were a total of 6 test groups, consisting of 1 wildtype (WT) group and 5 5xFAD (TG) groups. The TG mouse groups consisted of a vehicle administration group, which is a negative control group, 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, the mice were anesthetized using 2% avertin (20 mg / g, i.p.). The mice were perfused with 0.9% NaCl, the brains were excised, and the hemibrains were fixed overnight in 4% paraformaldehyde (pH 7.4) at 4 °C.

[0546] 2.4 Immunohistochemical staining

[0547] The fixed brain tissue prepared in Experimental Example 2.3 was sectioned into 30-μm thickness slices 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 slide glass and observed with a laser scanning confocal microscope. In addition, immunostaining was performed using the 6E10 antibody, a specific antibody against amyloid β.

[0548] FIG. 13 is a graph showing the amyloid plaque reduction effect according to indenone derivative compound treatment in a 5xFAD TG mouse Alzheimer's model according to one aspect.

[0549] As shown in the graph of FIG. 13, in terms of the value obtained by determining the total area of amyloid β aggregation in the cerebral hemisphere, when compared with the control group mice (Vehicle), it was confirmed that the plaque area significantly decreased in a dose-dependent manner in the mice administered with the compound.

[0550] Experimental Example 3 Confirmation of the tau aggregate reduction effect by compound treatment in PS19 TG mice

[0551] 3.1 Preparation of the PS19 TG mouse model

[0552] Transgenic mice (PS19 TG, an Alzheimer's disease animal model, B6;C3-Tg(Prnp-MAPT*P301S)PS19Vle / J) and wild-type mice were obtained from the Jackson Laboratory (Bar Harbor, Maine, USA). PS19 TG mice were crossed with wild-type mice and maintained as double hemizygotes. All genotypes were confirmed by PCR analysis using tail DNA according to the standard PCR conditions of the Jackson Laboratory. The TG mice used in this study are a model in which cognitive function decline occurs due to the deposition of tau aggregates in the brain, and it is known that the deposition pattern of tau aggregates, which are the deposited substances in the brains of actual Alzheimer's patients, has a similar morphology to that of patients, and was selected because it is easy to interpret and evaluate the test results. The mice were housed individually in plastic cages in an animal breeding room, maintained at 21±1°C on a 12-hour light-dark cycle, and allowed free access to food and water.

[0553] 3.2 Administration of Compounds to Mouse Models

[0554] The compound was orally administered daily at each concentration to 6-month-old PS19 TG mice.

[0555] There were a total of 4 test groups, consisting of 1 wildtype (WT) group and 3 PS19 (TG) groups. The TG mouse groups consisted of a vehicle-administered group as a negative control group 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, the mice were anesthetized using 2% avertin (20 mg / g, i.p.). The mice were perfused with 0.9% NaCl, the brains were excised, 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 into 30-μm thick slices and subjected to immunohistochemical staining. The fixed tissue was reacted with a 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 slide glass and observed with a laser scanning confocal microscope. In addition, immunostaining was performed using an NFT (Neurofibrillary tangles) antibody, which is a specific antibody against tau aggregates.

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

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

[0562] The above description of the present invention is for illustrative purposes, and those of ordinary skill in the technical field to which the present invention pertains will be able to understand that it can be easily modified into other specific forms without changing the technical idea or essential features of the present invention. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive.

Claims

1. A compound of the following chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemical 1】 In the above formula, X is a direct bond or O, Y is O or S, n is an integer from 0 to 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- or 6-membered heteroaryl, where the 5- or 6-membered heteroaryl is unsubstituted or substituted with 1 to 4 halogens, -CF ３ or C １－６ alkyl may also be substituted, R ３ 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, -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 with The heteroaryl is an aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from N, O, and S, and the heterocyclyl is an aliphatic heterocyclic ring containing 1 to 4 heteroatoms selected from N, O, and S.

2. R １ is halogen, phenyl, pyridinyl, pyrimidinyl or thiophenyl, wherein the phenyl, pyridinyl, pyrimidinyl and thiophenyl are each independently unsubstituted or substituted with 1 to 4 halogens, hydroxy, CN, -CF ３ , C １－６ alkyl, -C １－６ alkyl-CN, or -O-C １－６ alkyl, and the compound according to claim 1, its isomer or its pharmaceutically acceptable salt, which may be substituted.

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

4. R ３ is phenyl, pyridinyl, morpholinyl or benzodioxolyl, wherein said phenyl, pyridinyl, morpholinyl and benzodioxolyl are each independently unsubstituted or substituted with 1 to 4 halogens, hydroxy, -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 and may be substituted, a compound, an isomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3.

5. R １ is halogen, phenyl, pyridinyl, pyrimidinyl or thiophenyl, where said phenyl, pyridinyl, pyrimidinyl and thiophenyl are each independently unsubstituted or substituted with 1 to 4 halogens, hydroxy, CN, -CF ３ , C １－６ alkyl, -C １－６ alkyl-CN, or -O-C １－６ alkyl and may be substituted, R ２ is furanyl, thiophenyl, thiazolyl or pyrazolyl, where said thiazolyl, furanyl, thiophenyl and pyrazolyl are each independently unsubstituted or substituted with 1 to 4 halogens, -CF ３ or C １－６ alkyl may also be substituted, R ３ is phenyl, pyridinyl, morpholinyl or benzodioxolyl, where the phenyl, pyridinyl, morpholinyl and benzodioxolyl are each independently unsubstituted or substituted with 1 to 4 halogens, hydroxy, -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 and may be substituted, the compound, isomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4.

6. Any compound, isomer thereof, or pharmaceutically acceptable salt thereof according to any one of Claims 1 to 5, wherein the compound is selected from the group consisting of: (1) 3-(4-Methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (2) 2-(2-(3-(4-Methylthiazol-5-yl)-1-oxo-6-(3-phenylpropoxy)-1H-inden-2-yl)phenyl)acetonitrile, (3) 2-Bromo-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (4) 3-(5-Methylthiazol-4-yl)-6-(3-morpholinopropoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (5) 2-Bromo-3-(5-methylthiazol-4-yl)-6-(3-morpholinopropoxy)-1H-inden-1-one, (6) 6-(3-Phenylpropoxy)-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one, (7) 6-(3-Phenylpropoxy)-3-(1H-pyrazol-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (8) 3-(5-Methylthiazol-4-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (9) 3-(Furan-3-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (10) 3-(4-Methylthiazol-5-yl)-2-phenyl-6-(3-phenylpropoxy)-1H-inden-1-one, (11) 3-(4-Methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyrimidin-5-yl)-1H-inden-1-one, (12) 3-(4-Methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(thiophen-2-yl)-1H-indene-1-one, (13) 3-(4-Methylthiazol-5-yl)-2-(pyridin-3-yl)-6-(3-(pyridin-4-yl)propoxy)-1H-indene-1-one, (14) 3-(4-Methylthiazol-5-yl)-6-pentethoxy-2-(pyridin-3-yl)-1H-indene-1-one, (15) 3-(4-Methylthiazol-5-yl)-6-(4-phenylbutoxy)-2-(pyridin-3-yl)-1H-indene-1-one, (16) 6-(((Benzyloxy)methoxy))-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-indene-1-one, (17) 3-(4-Methylthiazol-5-yl)-6-(2-phenoxyethoxy)-2-(pyridin-3-yl)-1H-indene-1-one, (18) 2-(4-Methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-pentethoxy-1H-indene-1-one, (19) 2-(4-Methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-(4-phenylbutoxy)-1H-indene-1-one, (20) 6-(((Benzyloxy)methoxy))-2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-1H-indene-1-one, (21) 2-(4-Methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-(2-phenoxyethoxy)-1H-indene-1-one, (22) 2-(4-Fluorophenyl)-6-(2-(4-methoxyphenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-1H-indene-1-one, (23) 6-(2-(3,4-Dimethoxyphenoxy)ethoxy)-2-(4-fluorophenyl)-3-(5-methylthiazol-4-yl)-1H-indene-1-one, (24) 6-(2-(Benzo[d][1,3]dioxol-5-yloxy)ethoxy)-2-(4-fluorophenyl)-3-(5-methylthiazol-4-yl)-1H-indene-1-one, (25) 2-(4-Fluorophenyl)-3-(5-methylthiazol-4-yl)-6-(2-(pyridin-4-yloxy)ethoxy)-1H-indene-1-one, (26) 6-(2-(3,4-dichlorophenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(pyrimidin-5-yl)-1H-inden-1-one, (27) 6-(2-(3,4-difluorophenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(pyrimidin-5-yl)-1H-inden-1-one, (28) 3-(5-methylthiazol-4-yl)-6-pentethoxy-2-(thiophen-2-yl)-1H-inden-1-one, (29) 3-(5-methylthiazol-4-yl)-6-(4-phenylbutoxy)-2-(thiophen-2-yl)-1H-inden-1-one, (30) 6-((benzyloxy)methoxy)-3-(5-methylthiazol-4-yl)-2-(thiophen-2-yl)-1H-inden-1-one, (31) 3-(5-methylthiazol-4-yl)-6-(2-phenoxyethoxy)-2-(thiophen-2-yl)-1H-inden-1-one, (32) 6-(2-(4-methoxyphenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one, (33) 6-(2-(3,4-dimethoxyphenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one, (34) 6-(2-(benzo[d][1,3]dioxol-5-yloxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one, (35) 3-(5-methylthiazol-4-yl)-6-(2-(pyridin-4-yloxy)ethoxy)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one, (36) 6-(2-(3,4-dichlorophenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(thiophen-2-yl)-1H-inden-1-one, (37) 6-(2-(3,4-difluorophenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(thiophen-2-yl)-1H-inden-1-one, (38) 3-(furan-3-yl)-6-pentethoxy-2-(pyridin-3-yl)-1H-inden-1-one, (39)3-(Furan-3-yl)-6-(4-phenylbutoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (40)6-(((Benzyloxy)methoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (41)3-(Furan-3-yl)-6-(2-phenoxyethoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (42)3-(Furan-3-yl)-6-(2-(4-methoxyphenoxy)ethoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (43)6-(2-(3,4-Dimethoxyphenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (44)6-(2-(Benzo[d][1,3]dioxol-5-yloxy)ethoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (45)3-(Furan-3-yl)-2-(pyridin-3-yl)-6-(2-(pyridin-4-yloxy)ethoxy)-1H-inden-1-one, (46)6-(2-(3,4-Dichlorophenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (47)6-(2-(3,4-Difluorophenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (48)6-(2-(4-(Dimethylamino)phenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (49)3-(Furan-3-yl)-6-(2-(4-isopropylphenoxy)ethoxy)-2-(pyridin-3-yl)-1H-inden-1-one, and (50)3-(Furan-3-yl)-6-((((4-methoxybenzyl)oxy)methoxy)-2-(pyridin-3-yl)-1H-inden-1-one.

7. A pharmaceutical composition for preventing or treating a degenerative brain disease, comprising as an active ingredient the compound according to any one of Claims 1 to 6, an isomer thereof, or a pharmaceutically acceptable salt thereof.

8. (1)An individual in whom the aggregation level of amyloid β is higher than that of a normal individual without a degenerative brain disease or who has a high risk thereof, (2) An individual having a higher or high-risk level of tau protein aggregation than normal individuals without neurodegenerative diseases, (3) An individual having a higher or high-risk level of phosphorylated tau protein than normal individuals without neurodegenerative diseases, and (4) An individual falling under one or more of (1) to (3) above The pharmaceutical composition according to claim 7, for administration to an individual selected from the above. [

9. ] The neurodegenerative disease is any one selected from the group consisting of dementia, Alzheimer's disease, preclinical Alzheimer's disease, Parkinson's disease, Huntington's disease, mild cognitive impairment, cerebral amyloid angiopathy, Down syndrome, amyloid stroke, systemic amyloidosis, Dutch-type amyloidosis, Niemann-Pick disease, senile dementia, amyotrophic lateral sclerosis, spinocerebellar ataxia, Tourette syndrome, Friedrich's ataxia, Machado-Joseph's disease, Lewy body dementia, dystonia, progressive supranuclear palsy, and frontotemporal dementia. The pharmaceutical composition according to claims 7 to 8. [

10. ] A health functional food for preventing or improving neurodegenerative diseases, comprising as an active ingredient the compound according to any one of claims 1 to 6, its isomer, or a pharmaceutically acceptable salt thereof. [

11. ] A composition comprising the compound according to any one of claims 1 to 6, its isomer, or an acceptable salt thereof. [

12. ] A method for suppressing the aggregation of amyloid β or decomposing aggregates, comprising the step of administering to an individual in need of the compound according to any one of claims 1 to 6, an isomer thereof, or a pharmaceutically acceptable salt thereof.

13. A method for suppressing the aggregation of tau protein, decomposing aggregates, or suppressing the phosphorylation of tau protein, comprising the step of administering to an individual in need of the compound according to any one of claims 1 to 6, an isomer thereof, or a pharmaceutically acceptable salt thereof.

14. A method for treating or preventing a degenerative brain disease, comprising the step of administering to an individual in need of the compound according to any one of claims 1 to 6, an isomer thereof, or a pharmaceutically acceptable salt thereof.

15. Use of the compound according to any one of claims 1 to 6, an isomer thereof, or a pharmaceutically acceptable salt thereof, for suppressing the aggregation of amyloid β or decomposing aggregates.

16. Use of a compound according to any one of claims 1 to 6, an isomer thereof, or a pharmaceutically acceptable salt thereof, for suppressing the aggregation of tau protein, decomposing aggregates, or suppressing the phosphorylation of tau protein.

17. Use of a compound according to any one of claims 1 to 6, an isomer thereof, or a pharmaceutically acceptable salt thereof, for treating or preventing a degenerative brain disease.

Images