Novel indanone derivative and use thereof

Abstract

The present invention relates to a novel indanone derivative, an isomer thereof or a pharmaceutically acceptable salt thereof, and a use thereof, the indanone derivative according to the present invention (i) inhibits aggregation and / or decomposition of aggregates of beta-amyloid protein, ii) inhibits aggregation and / or decomposition of aggregates of Tau protein, and / or iii) inhibits excessive phosphorylation of tau protein, therefore, the compound provided by the invention can be effectively used for preventing or treating a degenerative encephalopathy (neurogenerative brain disease), and can be used for preventing or treating the neurogenerative brain disease (neurogenerative brain disease).

Description

Technical Field

[0001] The present invention relates to a novel indanone derivative, an isomer thereof or a pharmaceutically acceptable salt thereof, and use thereof in (i) inhibiting the aggregation and / or decomposing aggregates of β-amyloid protein, (ii) inhibiting the aggregation and / or decomposing aggregates of Tau protein, and / or (iii) inhibiting the hyperphosphorylation of tau protein, as well as use thereof in preventing or treating neurodegenerative brain disease. Background Art

[0002] Degenerative brain diseases are diseases with various symptoms, such as impaired motor and sensory functions, and obstruction of higher-order causal functions such as memory, learning, and computational reasoning, due to degenerative changes in nerve cells in the central nervous system. Representative diseases include Alzheimer's disease, Parkinson's disease, and memory impairment. Degenerative brain diseases cause nerve cells to die due to rapid or slow necrosis or apoptosis. Therefore, the death mechanism of nerve cells should be understood in order to prevent and regulate central nervous system diseases and develop treatment methods.

[0003] As substances that cause degenerative brain diseases, two proteins, amyloid-beta and Tau protein, have attracted attention.

[0004] Human β-amyloid is a peptide molecule containing about 36 to 43 amino acids, and its self-assembly into oligomers or aggregates is known to be associated with brain neurological diseases such as Alzheimer's disease. Specifically, β-amyloid peptide molecules are obtained by cleaving amyloid precursor protein (APP; UniProtKB P05067) into β-secretase (betasecretase) and γ-secretase (gamma secretase). Such β-amyloid peptide molecules aggregate to form neuronal cell toxic oligomers, thereby causing degenerative brain diseases.

[0005] In addition, it is known that Tau protein is composed of four parts: the N-terminal (amino) protruding region, the proline-rich domain, the microtubule binding domain, and the C-terminal (carboxyl) region. When Tau protein is abnormally overphosphorylated or aggregated in the nerve cells of the central nervous system, it causes degenerative brain diseases such as Parkinson's disease and Tauopathy.

[0006] Therefore, as therapeutic drugs for degenerative brain diseases, substances that inhibit the aggregation or decomposition of β-amyloid protein, or inhibit the aggregation or decomposition of Tau protein, or inhibit the hyperphosphorylation of Tau protein can be proposed. Summary of the invention

[0007] Technical issues

[0008] One object of the present invention is to provide a novel indanone derivative, its isomer or a pharmaceutically acceptable salt thereof, which is effective in (i) inhibiting the aggregation and / or decomposing aggregates of β-amyloid protein, (ii) inhibiting the aggregation and / or decomposing aggregates of Tau protein, and / or (iii) inhibiting the hyperphosphorylation of tau protein.

[0009] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating degenerative brain diseases, comprising the novel indanone derivative, its isomer or a pharmaceutically acceptable salt thereof as an active ingredient.

[0010] Another object of the present invention is to provide a health functional food for preventing or improving degenerative brain diseases, which comprises the novel indanone derivative, its isomer or a food-acceptable salt thereof as an active ingredient.

[0011] Another object of the present invention is to provide a composition comprising the novel indanone derivative, its isomer or an acceptable salt thereof.

[0012] Another object of the present invention is to provide a pharmaceutical composition comprising the novel indanone derivative, its isomer or a pharmaceutically acceptable salt thereof.

[0013] Another object of the present invention is to provide a method for (i) inhibiting the aggregation and / or disintegration of β-amyloid protein, (ii) inhibiting the aggregation or disintegration of Tau protein, and / or inhibiting the hyperphosphorylation of tau protein, or (iii) treating or preventing degenerative brain diseases, the method comprising administering the novel indanone derivative, its isomer or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0014] Another object of the present invention is to provide a novel indanone derivative, its isomer or a pharmaceutically acceptable salt thereof for use in (i) inhibiting the aggregation and / or decomposing aggregates of β-amyloid protein, (ii) inhibiting the aggregation or decomposing aggregates of Tau protein, and / or inhibiting the hyperphosphorylation of tau protein, or (iii) treating or preventing degenerative brain diseases.

[0015] Technical Solution

[0016] Hereinafter, the present invention is described in further detail.

[0017] Throughout the specification, “comprising” a certain constituent element means being able to further include other constituent elements, rather than excluding other constituent elements, unless otherwise specified.

[0018] In the present invention, the term "isomer" refers to a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but different structural or stereogenic properties. Such isomers include structural isomers such as tautomers, stereoisomers such as R or S isomers with asymmetric carbon centers, geometric isomers (trans, cis), and enantiomers. All of the above isomers and mixtures thereof are also included within the scope of the present invention.

[0019] The term "halogen" refers to F, Cl, Br or I, unless otherwise indicated.

[0020] The term "C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon residue having 1 to 6 carbon atoms. Specifically, C 1-6 Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, and the like. In one embodiment, the alkyl group may be substituted with one or more substituents, such as 1 to 3 halogen or C 1-6 alkyl.

[0021] The term "C 1-6 "Alkoxy" refers to the chemical formula -OC 1-6 Alkyl groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentyloxy, tert-pentyloxy, sec-pentyloxy, neopentyloxy, hexyloxy, and the like. In one embodiment, the alkoxy group may be substituted with one or more substituents, such as 1 to 3 halogen or C 1-6 alkyl.

[0022] The term "aryl" refers to a monocyclic or bicyclic aromatic ring having a hydrocarbon. That is, in the present specification, 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 a substituent.

[0023] The term "heteroaryl" refers to an aromatic 5- to 10-membered monocyclic or bicyclic heterocyclic ring comprising 1 to 4 heteroatoms selected from N, O and S. That is, heteroaryl refers to a 5- or 6-membered aromatic heterocyclic ring comprising 1 to 4 heteroatoms selected from N, O and S, or a bicyclic ring fused to a benzene ring or other heteroaryl rings. In one embodiment, 0, 1, 2, 3 or 4 atoms of each ring of heteroaryl can be substituted with a substituent. Examples of monocyclic heteroaryl include, but are not limited to, thiazolyl, oxazolyl, thiophenyl, furyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, triazolyl, triazinyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, azaindolyl, indolinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolyl, isoquinolyl, quinoxalinyl, purinyl, furopyridinyl, and the like.

[0024] The term "heterocyclyl" refers to a saturated or partially unsaturated carbocyclic ring having 5 to 10 ring atoms, which, in addition to carbon atoms, contains 1 to 4 heteroatoms selected from N, O and S. In one embodiment, the heterocyclyl may be a 5-membered or 6-membered aliphatic heterocyclic ring, or a bicyclic ring in which the heterocyclyl ring is fused to a benzene ring or other heterocyclyl ring. In one embodiment, 0, 1, 2, 3 or 4 atoms of each ring of the heterocyclyl may be substituted with a substituent. For example, heterocyclic groups include azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, dioxolanyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, indolyl, isoindolyl, dihydroindolinyl, dioxoisoindolinyl, dihydrofuranyl, dihydroimidazolinyl, dihydrooxazolyl, dihydrobenzodioxyacyl, tetrahydropyridinyl, dihydropyranyl, dihydrobenzofuranyl, benzodioxolanyl, or benzodioxanyl.

[0025] The term "substitution" refers to replacing a hydrogen atom in a molecular structure with a substituent, thereby producing a chemically stable compound by such substitution without exceeding the valence on the designated atom. For example, "group A is substituted with substituent B" means that a hydrogen atom bonded to an atom of carbon or the like constituting the skeleton of group A is replaced with substituent B, whereby group A and substituent B form a covalent bond.

[0026] The present invention provides a compound of the following Chemical Formula 1, an isomer thereof or a pharmaceutically acceptable salt thereof:

[0027] [Chemical formula 1]

[0028]

[0029] In the above formula,

[0030] X is a direct bond or O;

[0031] Y is O or S;

[0032] n is an integer from 0 to 5;

[0033] m is an integer from 1 to 5;

[0034] R1 is halogen, C 1-6 Alkyl, C 6-10 Aryl, -C 1-6 Alkyl-C 6-10 Aryl or 5-6 membered heteroaryl, in which case the C 1-6 Alkyl, C 6-10 Aryl, -C 1-6 Alkyl-C 6-10 The aryl and 5-6 membered heteroaryl groups may be independently unsubstituted or substituted with 1 to 4 halogen, hydroxy, CN, -NH2, -CF3, C 1-6 Alkyl, -C 1-6 Alkyl-CN, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl or -N(C 1-6 Alkyl)2 substituted;

[0035] R2 is a 5-6 membered heteroaryl group, in which case the 5-6 membered heteroaryl group may be unsubstituted or substituted with 1 to 4 halogens, -CF3 or C 1-6 Alkyl substitution;

[0036] R3 is C 6-10 aryl, 5-6 membered heteroaryl or 5-10 membered heterocyclic group, in which case the C 6-10 The aryl, 5-6 membered heteroaryl and 5-10 membered heterocyclic radicals may be independently unsubstituted or substituted with 1 to 4 halogen, hydroxyl, CN, -NH2, -CF3, C 1-6 Alkyl, -C 1-6 Alkyl-CN, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl or -N(C 1-6 Alkyl)2 substituted;

[0037] The heteroaryl group is an aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from N, O and S, and the heterocyclic group is an aliphatic heterocyclic ring containing 1 to 4 heteroatoms selected from N, O and S.

[0038] In a specific embodiment, in the compound of the chemical formula 1, the R1 is a halogen, a phenyl, a pyridyl, a pyrimidyl or a phenylthio group, and the phenyl, pyridyl, pyrimidyl and phenylthio groups may be independently unsubstituted or substituted with 1 to 4 halogen, hydroxyl, CN, -CF3, C 1-6 Alkyl, -C 1-6 Alkyl-CN, or -OC 1-6 Alkyl substitution.

[0039] Specifically, the R1 can be, for example, bromine

[0040] But it is not limited to this.

[0041] In a specific embodiment, in the compound of the chemical formula 1, R2 is furanyl, phenylthio, thiazolyl or pyrazolyl, and the thiazolyl, furanyl, phenylthio and pyrazolyl can be independently unsubstituted or substituted with 1 to 4 halogens, -CF3 or C 1-6 Alkyl substitution.

[0042] Specifically, the R2 can be, for example But it is not limited to this.

[0043] In a specific embodiment, in the compound of the chemical formula 1, the R3 is phenyl, pyridyl, morpholinyl or benzodioxolanyl, and the phenyl, pyridyl, morpholinyl and benzodioxolanyl can be independently unsubstituted or substituted with 1 to 4 halogens, hydroxyl, -NH2, -CF3, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl or -N(C 1-6 alkyl)2 substituted.

[0044] Specifically, the R3 can be, for example

[0045] But it is not limited to this.

[0046] In a specific embodiment, in the compound of the chemical formula 1, the R1 is a halogen, a phenyl, a pyridyl, a pyrimidyl or a phenylthio group, and the phenyl, pyridyl, pyrimidyl and phenylthio groups may be independently unsubstituted or substituted with 1 to 4 halogen, hydroxyl, CN, -CF3, C 1-6 Alkyl, -C 1-6 Alkyl-CN, or -OC 1-6 Alkyl substitution;

[0047] R2 is furanyl, phenylthio, thiazolyl or pyrazolyl, in which case the thiazolyl, furanyl, phenylthio and pyrazolyl may each independently be unsubstituted or substituted with 1 to 4 halogens, -CF3 or C 1-6 Alkyl substitution;

[0048] R3 is phenyl, pyridyl, morpholinyl or benzodioxolanyl, in which case the phenyl, pyridyl, morpholinyl and benzodioxolanyl groups may be independently unsubstituted or substituted with 1 to 4 halogens, hydroxyl, -NH2, -CF3, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl or -N(C 1-6 alkyl)2 substituted.

[0049] Specific examples of the compounds in the chemical formula 1 according to the present invention are as follows, but are not limited thereto:

[0050] (1) 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one;

[0051] (2) 2-(2-(3-(4-methylthiazol-5-yl)-1-oxo-6-(3-phenylpropoxy)-1H-inden-2-yl)phenyl)acetonitrile;

[0052] (3) 2-bromo-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one;

[0053] (4) 3-(5-methylthiazol-4-yl)-6-(3-morpholinopropoxy)-2-(pyridin-3-yl)-1H-inden-1-one;

[0054] (5) 2-bromo-3-(5-methylthiazol-4-yl)-6-(3-morpholinopropoxy)-1H-inden-1-one;

[0055] (6) 6-(3-phenylpropoxy)-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one;

[0056] (7) 6-(3-phenylpropoxy)-3-(1H-pyrazol-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one;

[0057] (8) 3-(5-methylthiazol-4-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one;

[0058] (9) 3-(Furan-3-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one;

[0059] (10) 3-(4-methylthiazol-5-yl)-2-phenyl-6-(3-phenylpropoxy)-1H-inden-1-one;

[0060] (11) 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyrimidin-5-yl)-1H-inden-1-one;

[0061] (12) 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(thiophen-2-yl)-1H-inden-1-one;

[0062] (13) 3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-6-(3-(pyridin-4-yl)propoxy)-1H-inden-1-one;

[0063] (14) 3-(4-methylthiazol-5-yl)-6-phenethoxy-2-(pyridin-3-yl)-1H-inden-1-one;

[0064] (15) 3-(4-methylthiazol-5-yl)-6-(4-phenylbutoxy)-2-(pyridin-3-yl)-1H-inden-1-one;

[0065] (16) 6-((Benzyloxy)methoxy)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one;

[0066] (17) 3-(4-methylthiazol-5-yl)-6-(2-phenoxyethoxy)-2-(pyridin-3-yl)-1H-inden-1-one;

[0067] (18) 2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-phenethoxy-1H-inden-1-one;

[0068] (19) 2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-(4-phenylbutoxy)-1H-inden-1-one;

[0069] (20) 6-((Benzyloxy)methoxy)-2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-1H-inden-1-one;

[0070] (21) 2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-(2-phenoxyethoxy)-1H-inden-1-one;

[0071] (22) 2-(4-fluorophenyl)-6-(2-(4-methoxyphenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one;

[0072] (23) 6-(2-(3,4-dimethoxyphenoxy)ethoxy)-2-(4-fluorophenyl)-3-(5-methylthiazol-4-yl)-1H-inden-1-one;

[0073] (24) 6-(2-(Benzo[d][1,3]dioxolan-5-yloxy)ethoxy)-2-(4-fluorophenyl)-3-(5-methylthiazol-4-yl)-1H-inden-1-one;

[0074] (25) 2-(4-fluorophenyl)-3-(5-methylthiazol-4-yl)-6-(2-(pyridin-4-yloxy)ethoxy-1H-inden-1-one;

[0075] (26) 6-(2-(3,4-dichlorophenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(pyrimidin-5-yl)-1H-inden-1-one;

[0076] (27) 6-(2-(3,4-difluorophenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(pyrimidin-5-yl)-1H-inden-1-one;

[0077] (28) 3-(5-methylthiazol-4-yl)-6-phenethoxy-2-(thiophen-2-yl)-1H-inden-1-one;

[0078] (29) 3-(5-methylthiazol-4-yl)-6-(4-phenylbutoxy)-2-(thiophen-2-yl)-1H-inden-1-one;

[0079] (30) 6-((Benzyloxy)methoxy)-3-(5-methylthiazol-4-yl)-2-(thiophen-2-yl)-1H-inden-1-one;

[0080] (31) 3-(5-methylthiazol-4-yl)-6-(2-phenoxyethoxy)-2-(thiophen-2-yl)-1H-inden-1-one;

[0081] (32) 6-(2-(4-methoxyphenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one;

[0082] (33) 6-(2-(3,4-dimethoxyphenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one;

[0083] (34) 6-(2-(Benzo[d][1,3]dioxolan-5-yloxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one;

[0084] (35) 3-(5-methylthiazol-4-yl)-6-(2-(pyridin-4-yloxy)ethoxy)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one;

[0085] (36) 6-(2-(3,4-dichlorophenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(thiophen-2-yl)-1H-inden-1-one;

[0086] (37) 6-(2-(3,4-difluorophenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(thiophen-2-yl)-1H-inden-1-one;

[0087] (38) 3-(Furan-3-yl)-6-phenethoxy-2-(pyridin-3-yl)-1H-inden-1-one;

[0088] (39) 3-(Furan-3-yl)-6-(4-phenylbutoxy)-2-(pyridin-3-yl)-1H-inden-1-one;

[0089] (40) 6-((Benzyloxy)methoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one;

[0090] (41) 3-(Furan-3-yl)-6-(2-phenoxyethoxy)-2-(pyridin-3-yl)-1H-inden-1-one;

[0091] (42) 3-(Furan-3-yl)-6-(2-(4-methoxyphenoxy)ethoxy)-2-(pyridin-3-yl)-1H-inden-1-one;

[0092] (43) 6-(2-(3,4-dimethoxyphenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one;

[0093] (44) 6-(2-(Benzo[d][1,3]dioxolan-5-yloxy)ethoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one;

[0094] (45) 3-(Furan-3-yl)-2-(pyridin-3-yl)-6-(2-(pyridin-4-yloxy)ethoxy)-1H-inden-1-one;

[0095] (46) 6-(2-(3,4-dichlorophenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one;

[0096] (47) 6-(2-(3,4-difluorophenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one;

[0097] (48) 6-(2-(4-(dimethylamino)phenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one;

[0098] (49) 3-(Furan-3-yl)-6-(2-(4-isopropylphenoxy)ethoxy)-2-(pyridin-3-yl)-1H-inden-1-one;

[0099] (50) 3-(furan-3-yl)-6-(((4-methoxybenzyl)oxy)methoxy)-2-(pyridin-3-yl)1H-inden-1-one;

[0100] or a pharmaceutically acceptable salt thereof.

[0101] The present invention includes pharmaceutically acceptable salts of the compound of Chemical Formula 1.

[0102] The pharmaceutically acceptable salts should have low toxicity to humans and should not have any negative effects on the biological activity and physicochemical properties of the parent compound.

[0103] For example, the pharmaceutically acceptable salt may be an acid addition salt formed from a pharmaceutically acceptable free acid.

[0104] The free acid can use an inorganic acid or an organic acid. In this case, the inorganic acid can be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, etc., and the organic acid can 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, pamoic acid, aspartic acid, glutamic acid, etc.

[0105] The acid addition salt can be prepared by conventional methods, for example, by dissolving the compound of Chemical Formula 1 with an excess of an aqueous acid solution and precipitating the salt with a water-soluble organic solvent (eg, methanol, ethanol, acetone, or acetonitrile).

[0106] Furthermore, the pharmaceutically acceptable salt may be an alkali metal salt (sodium salt, etc.) or an alkaline earth metal salt (potassium salt, etc.).

[0107] The alkali metal salt or alkaline earth metal salt can be obtained, for example, by dissolving the compound of Chemical Formula 1 in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate.

[0108] In addition, the compounds of the present invention may have a chiral carbon center and thus may exist as R or S isomers, racemic compounds, individual enantiomers or mixtures, individual diastereomers or mixtures, and all of these stereoisomers and mixtures thereof may fall within the scope of the present invention.

[0109] In addition, the compound of the present invention may include hydrates and solvates of the compound in the chemical formula 1. The hydrates and solvates may be prepared by known methods and are preferably non-toxic and water-soluble. In particular, it is preferred that the hydrates and solvates are a combination of water and 1 to 5 alcohol solvents (particularly ethanol, etc.), respectively.

[0110] In addition, the present invention provides a method for preparing the compound of Chemical Formula 1.

[0111] Specifically, the compound of the chemical formula 1 can be prepared by the methods shown in the following reaction formulas 1 to 5, but is not limited thereto. In particular, those skilled in the art can fully understand that the compound of the chemical formula 1 in the present invention can be prepared by various methods using known techniques in the art.

[0112] The following reaction formulas 1 to 5 show the preparation method of the representative compound according to the present invention in each preparation step. Various compounds of the present invention can be prepared by changing the reagents and solvents in the following preparation steps or changing the reaction order.

[0113] [Reaction 1]

[0114]

[0115] [Reaction 2]

[0116]

[0117] [Reaction 3]

[0118]

[0119] [Reaction 4]

[0120]

[0121] [Reaction 5]

[0122]

[0123] The target compound generated by the above reaction formula can be separated and purified by conventional methods, such as column chromatography, recrystallization, etc.

[0124] The present invention provides a composition comprising the compound of Chemical Formula 1, its isomer or an acceptable salt thereof.

[0125] The present invention provides a composition comprising the compound of Chemical Formula 1, its isomer or an acceptable salt thereof as an active ingredient.

[0126] In addition, the present invention provides a pharmaceutical composition for preventing or treating degenerative brain diseases, comprising the compound of Chemical Formula 1, its isomer or a pharmaceutically acceptable salt thereof as an active ingredient.

[0127] The compound of Chemical Formula 1, its isomer or pharmaceutically acceptable salt thereof not only inhibits the aggregation or decomposition of β-amyloid protein, inhibits the aggregation or decomposition of Tau protein, but also has an excellent effect of inhibiting the phosphorylation of Tau protein. Therefore, the compound or a pharmaceutical composition containing the compound can be effectively used for preventing or treating diseases related to inhibiting the aggregation and / or decomposition of β-amyloid protein, inhibiting the aggregation or decomposition of Tau protein, and / or inhibiting the phosphorylation of tau protein, such as degenerative brain disease.

[0128] The term "prevention" as used in the present invention refers to all actions to hinder or delay the occurrence, spread and recurrence of the disease by administering the compound or pharmaceutical composition according to the present invention, and "treatment" refers to all actions to improve or make the symptoms of the disease better by administering the compound or pharmaceutical composition according to the present invention.

[0129] The term "degenerative brain disease" as used herein refers to all diseases associated with degenerative changes in the brain, and in particular encompasses all diseases (brain diseases) caused by at least one selected from the group consisting of aggregation of β-amyloid protein, aggregation of Tau protein, and hyperphosphorylation of Tau protein in the brain and / or brain nerve cells.

[0130] As a specific embodiment, the degenerative brain disease that can be prevented or treated by the compound or pharmaceutical composition according to the present invention can be selected from dementia, Alzheimer's disease, preclinical Alzheimer's disease, Parkinson's disease, Huntington's disease, mild cognitive impairment, cerebral amyloid angiopathy, Down syndrome, amyloidosis stroke, systemic amyloidosis, Dutch amyloidosis, Niemann-Pick disease, senile dementia, amyotrophic lateral sclerosis, spinocerebellar atrophy, Tourette's syndrome, Friedrich's ataxia, Machado-Joseph's disease, Lewy body dementia, Any of the group consisting of, but not limited to, dystonia, progressive supranuclear palsy, and frontotemporal dementia, and diseases caused by aggregation of β-amyloid protein, aggregation of Tau protein, and / or phosphorylation of Tau protein can be targets.

[0131] As one embodiment, the present invention provides a pharmaceutical composition for inhibiting the aggregation of β-amyloid protein and / or decomposing aggregates, comprising the compound of Chemical Formula 1, its isomer or a pharmaceutically acceptable salt thereof as an active ingredient.

[0132] As one embodiment, the present invention provides a pharmaceutical composition for inhibiting the aggregation or decomposing aggregates of Tau protein, and / or inhibiting the phosphorylation of Tau protein, comprising the compound of Chemical Formula 1, its isomer or a pharmaceutically acceptable salt thereof as an active ingredient.

[0133] The present invention provides a use of the compound of Chemical Formula 1, its isomer or a pharmaceutically acceptable salt thereof in preventing or treating diseases related to inhibiting the aggregation and / or decomposing aggregates of β-amyloid protein (eg, degenerative brain disease).

[0134] The present invention provides a use of the compound of Chemical Formula 1, its isomer, or a pharmaceutically acceptable salt thereof in inhibiting the aggregation of β-amyloid protein and / or decomposing aggregates.

[0135] The present invention provides a use of the compound of Chemical Formula 1, its isomer, or its pharmaceutically acceptable salt in inhibiting Tau protein aggregation or decomposing aggregates, and / or inhibiting the phosphorylation of Tau protein.

[0136] The present invention provides a use of the compound of Chemical Formula 1, its isomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease (such as degenerative brain disease) related to inhibiting the aggregation and / or decomposing aggregates of β-amyloid protein.

[0137] The present invention provides a use of the compound of Chemical Formula 1, its isomer, or its pharmaceutically acceptable salt in the preparation of a medicament for inhibiting the aggregation of β-amyloid protein and / or decomposing aggregates.

[0138] The present invention provides a use of the compound of Chemical Formula 1, its isomer, or its pharmaceutically acceptable salt in the preparation of a drug for inhibiting Tau protein aggregation or decomposing aggregates, and / or inhibiting Tau protein phosphorylation.

[0139] In addition, the present invention provides a method for preventing or treating a disease (e.g., degenerative encephalopathy) related to inhibiting the aggregation and / or decomposing aggregates of β-amyloid protein, comprising administering the compound of Chemical Formula 1, its isomer, or a pharmaceutically acceptable salt thereof to a subject in need of preventing or treating degenerative encephalopathy. Prior to the administering step, the method may further include confirming a subject in need of preventing and / or treating degenerative encephalopathy.

[0140] In addition, the present invention provides a method for inhibiting the aggregation and / or decomposing aggregates of β-amyloid protein, which comprises applying the compound of Chemical Formula 1, its isomer, or its pharmaceutically acceptable salt to an object that needs to inhibit the aggregation and / or decompose the aggregates of β-amyloid protein. Prior to the administering step, the method may further include confirming the object that needs to inhibit the aggregation and / or decompose the aggregates of β-amyloid protein.

[0141] The present invention provides a method for inhibiting the aggregation or decomposition of Tau protein, and / or inhibiting the phosphorylation of tau protein, which comprises applying the compound of Chemical Formula 1, its isomer, or its pharmaceutically acceptable salt to an object that needs to inhibit the aggregation and / or decomposition of Tau protein, and / or inhibit the phosphorylation of tau protein. Before the application step, the method may further include confirming the object that needs to inhibit the aggregation, decomposition of Tau protein, and / or inhibit the phosphorylation of tau protein.

[0142] In one embodiment,

[0143] The pharmaceutical composition according to the present invention can be used for administration to a subject (patient) selected from the group consisting of:

[0144] (1) Subjects (patients) whose β-amyloid aggregation level is higher than normal or who are at risk of higher than normal levels;

[0145] (2) Subjects (patients) whose Tau protein aggregation levels are higher than normal or are at risk of higher than normal levels;

[0146] (3) Subjects (patients) whose phosphorylation level of Tau protein is higher than normal or is at risk of being higher than normal; and

[0147] (4) A subject (patient) corresponding to two or more of (1) to (3) above.

[0148] The aggregation level of β-amyloid protein or Tau protein may refer to the amount (concentration) of β-amyloid protein aggregates or tau protein aggregates or the ratio of β-amyloid protein aggregates or Tau protein aggregates to total β-amyloid protein or total tau protein.

[0149] The phosphorylation level of the Tau protein may refer to the amount (concentration) of the phosphorylated Tau protein or the ratio of the phosphorylated Tau protein to the total Tau protein.

[0150] The "normal" may refer to a subject who does not have the "degenerative brain disease" as defined above in an allogeneic subject (patient) to which the pharmaceutical composition is applicable, or brain tissue or brain cells (brain nerve cells) isolated and / or cultured from the subject.

[0151] The term "inhibit" as used in the present invention refers to inhibiting any step in gene transcription, mRNA processing, translation, translocation and maturation, or inhibiting the binding between proteins, protein activation, or signal transduction caused by them.

[0152] In addition to the active ingredient, the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier. At this point, the pharmaceutically acceptable carrier may include but is not limited to conventionally used lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talcum powder, magnesium stearate and mineral oil etc. In addition, in addition to the above-mentioned components, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives etc. may be further included.

[0153] The pharmaceutical composition of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage varies depending on the patient's state and weight, degree of illness, drug form, administration route and time, but can be appropriately selected by a technician in the field.

[0154] The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" refers to an amount sufficient to treat with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level can be determined based on factors including the patient's disease type, severity, drug activity, sensitivity to the drug, administration time, administration route and excretion rate, treatment time, drugs used simultaneously, and other factors known in the medical field.

[0155] The pharmaceutical composition according to the present invention can be administered as a single therapeutic agent or in combination with other therapeutic agents, can be administered sequentially or simultaneously with existing therapeutic agents, and can be administered singly or in multiples. It is important to administer the amount that can achieve the maximum effect with the minimum amount while taking into account all of the above factors and without side effects, which can be easily determined by a person skilled in the art.

[0156] Specifically, the effective amount of the pharmaceutical composition of the present invention can be different according to the patient's age, sex, state, body weight, absorbability, inactivation rate and excretion rate of the active ingredient in the body, disease type, and drugs administered in combination. Usually, 0.001 to 150 mg is administered per kg of body weight, preferably 0.01 to 100 mg is administered every day or every two days or once or three times a day. However, the dosage can be increased or decreased according to the administration route, the severity of obesity, sex, body weight, age, etc., so the dosage does not limit the scope of the present invention in any way.

[0157] In addition, the present invention provides a method for preventing, regulating or treating degenerative brain diseases, comprising administering the pharmaceutical composition to a subject. In the present invention, "subject" refers to an object for which a disease needs to be treated, more specifically, a mammal such as a human or non-human primate, mouse, dog, cat, horse, cow, etc.

[0158] In addition, the present invention provides a health functional food for preventing and / or improving degenerative brain diseases, which comprises the compound of Chemical Formula 1, its isomer or a food-acceptable salt thereof as an active ingredient.

[0159] The present invention provides a health functional food for inhibiting the aggregation of β-amyloid protein and / or decomposing aggregates, which comprises the compound of Chemical Formula 1, its isomer or a food-acceptable salt thereof as an active ingredient.

[0160] In addition, the present invention provides a health functional food for inhibiting the aggregation of Tau protein, decomposing Tau protein aggregates, and / or inhibiting the phosphorylation of Tau protein, which comprises the compound of Chemical Formula 1, its isomer or a food-acceptable salt thereof as an active ingredient.

[0161] The health functional food refers to food made from nutrients that are easily lacking in daily diet or raw materials or ingredients that have beneficial functions to the human body, and includes all foods that help maintain health or prevent and / or improve predetermined diseases or symptoms, and the final product form is not particularly limited. For example, the health functional food can be selected from the group consisting of various foods, beverage compositions, food additives, etc., but is not limited thereto.

[0162] The content of the active ingredient (ie, the compound of Chemical Formula 1, its isomer or a food-acceptable salt thereof) contained in the health functional food can be appropriately adjusted according to the food form, the desired use, etc., and is not particularly limited.

[0163] The health functional food may further contain at least one selected from the group consisting of various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents or natural flavoring agents, coloring agents, flavor enhancers (cheese, chocolate, etc.), pectin acid or its salts, alginic acid or its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerol, alcohol, carbonating agents for carbonated beverages, etc. The proportion of the above additives is generally selected in the range of 0.001 parts by weight to about 20 parts by weight based on 100 parts by weight of the overall health functional food, but is not limited thereto.

[0164] Beneficial Effects

[0165] The indenone derivatives according to the present invention can be effectively used for preventing or treating neurodegenerative brain diseases by (i) inhibiting the aggregation and / or disintegrating aggregates of β-amyloid protein, (ii) inhibiting the aggregation and / or disintegrating aggregates of Tau protein, and / or (iii) inhibiting the hyperphosphorylation of tau protein. BRIEF DESCRIPTION OF THE DRAWINGS

[0166] Figure 1 : is a graph showing the results of confirming the β-amyloid aggregation decomposition (Aβ disaggregation) of indenone derivative compounds 1 to 9 according to the present invention by analyzing Thioflavin T.

[0167] Figure 2 : is a graph showing the results of confirming the decomposition of β-amyloid aggregation of the indenone derivative compounds 10, 12 to 19 according to the present invention by analyzing Thioflavin T.

[0168] Figure 3 : is a graph showing the results of confirming the decomposition of β-amyloid aggregation of indenone derivative compounds 20 to 28 according to the present invention by analyzing Thioflavin T.

[0169] Figure 4 : is a graph showing the results of confirming the decomposition of β-amyloid aggregation of indenone derivative compounds 29 to 37 according to the present invention by analyzing Thioflavin T.

[0170] Figure 5 : is a graph showing the results of confirming the decomposition of β-amyloid aggregation of indenone derivative compounds 38 to 46 according to the present invention by analyzing Thioflavin T.

[0171] Figure 6 : is a graph showing the results of confirming the decomposition of β-amyloid aggregation of indenone derivative compounds 47 to 50 according to the present invention by analyzing Thioflavin T.

[0172] Figure 7 : is a graph showing the results of confirming Tau disaggregation of indenone derivative compounds 1 to 9 according to the present invention by analyzing Thioflavin T.

[0173] Figure 8 : is a graph showing the results of confirming the decomposition of Tau aggregation of the indenone derivative compounds 10, 12 to 19 according to the present invention by analyzing Thioflavin T.

[0174] Fig. 9 : is a graph showing the results of confirming the decomposition of Tau aggregation of indenone derivative compounds 20 to 28 according to the present invention by analyzing Thioflavin T.

[0175] Fig.10 : is a graph showing the results of confirming the decomposition of Tau aggregation of indenone derivative compounds 29 to 37 according to the present invention by analyzing Thioflavin T.

[0176] Fig.11 : is a graph showing the results of confirming the decomposition of Tau aggregation of indenone derivative compounds 38 to 46 according to the present invention by analyzing Thioflavin T.

[0177] Fig.12 : is a graph showing the results of confirming the decomposition of Tau aggregation of indenone derivative compounds 47 to 50 according to the present invention by analyzing Thioflavin T.

[0178] Fig.13 is a graph showing the effect of reducing amyloid plaques due to treatment of indanone derivative compounds in a 5xFAD TG mouse Alzheimer's disease model according to one aspect.

[0179] Fig.14 is a graph showing the effect of reducing Tau aggregates due to treatment with an indanone derivative compound in a PS19 TG mouse Alzheimer's disease model according to one aspect. DETAILED DESCRIPTION

[0180] Hereinafter, preferred embodiments are proposed to help understand the present invention. However, the following embodiments are only used to further easily understand the present invention, and the content of the present invention is not limited thereto. Various modifications can be made to the embodiments, and the embodiments are not limited to the embodiments disclosed below, and they can be implemented in various forms.

[0181] The meanings of the abbreviations used in this embodiment are as follows.

[0182] LCMS (liquid chromatography mass spectrometry)

[0183] HPLC (high-performance liquid chromatography)

[0184] TLC thin layer chromatography

[0185] NMR (nuclear magnetic resonance)

[0186] M+ parent molecular ion

[0187] EtEthyl

[0188] W Watt

[0189] TTemperature

[0190] eq equivalent

[0191] N normal (equivalents per liter)

[0192] N2 Nitrogen

[0193] Psi Pounds per Square inch

[0194] PdCL2Palladium(II) chloride

[0195] Pd2(dba)3Tris(debenzylideneacetone)dipalladium(0)

[0196] Pd(dtbpf)Cl2[1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)

[0197] Pd(dppf)Cl2[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0198] PdCl2(PPh3)2dichloropalladium(triphenylphosphine)

[0199] [(t-Bu)3PH]BF4[tri(tert-butyl)phosphonium]tetrafluoroborate

[0200] ACN acetonitrile

[0201] Ac2O Acetic anhydride

[0202] AIBN (2,2-azobis(2-methylpropionitrile)

[0203] DCM dichloromethane

[0204] DIAD diisopropyl azodicarboxylate

[0205] DMAP 4-dimethylaminopyridine

[0206] DMF dimethylformamide

[0207] DMSO dimethyl sulfoxide

[0208] HOAcacetic acid

[0209] TBAB Tetrabutylammonium bromide

[0210] MTBE methyl tertiary butyl ether

[0211] TFA trifluoroacetic acid

[0212] THF Tetrahydrofuran

[0213] PE petroleum ether

[0214] Pypyridine

[0215] EAethyl acetate = EtOAc

[0216] Conventional experimental methods

[0217] 1H NMR spectra were recorded on a 400 MHz NMR instrument (Varian Mercury 400 MHz) using TMS (trimethylsilyl) as an internal standard.

[0218] LCMS was measured using an Agilent LC / MSD 1200 series quadrupole mass spectrometer (column: Ultimate XB-C18 (50×4.6 mm, 5 μm)) operating in ES (+) or (−) ionization mode: T=30° C.; flow rate=1.5 mL / min; detected wavelengths: 214 nm and 254 nm.

[0219] Preparation of compounds

[0220] Example 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)

[0221] [Reaction 1]

[0222]

[0223] Step 1: Synthesis of (E)-1-(3-hydroxyphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one (1-3)

[0224] 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), NaOH (2.36 g, 58.9 mmol) was added to H2O (20.0 mL) under a nitrogen environment at 0°C. The mixture was stirred at 20°C for 12 hours. TLC (DCM: methanol = 10 / 1) confirmed that the reactants were completely consumed. The mixture was adjusted to pH 7 with 1N HCl, the mixture was filtered and concentrated under vacuum to obtain compound 1-3 (6.00 g, 24.46 mmol, yield: 62.21%) as a yellow solid.

[0225] Step 2: Synthesis of 6-hydroxy-3-(4-methylthiazol-5-yl)-2,3-dihydro-1H-inden-1-one (1-4)

[0226] After dissolving compound 1-3 (6.00 g, 24.5 mmol) in trifluoromethanesulfonic acid (30.0 mL), the mixture was stirred at 80°C for 16 hours. TLC (PE:EA=1 / 1) confirmed that the reactant was completely consumed. NaHCO3 aqueous solution was added to the mixture to adjust the pH to 8, the mixture was filtered and concentrated under vacuum to obtain compound 1-4 (5.1 g, 20.8 mmol, yield: 85.00%) as a brown solid.

[0227] Step 3: Synthesis of 1-(4-methylthiazol-5-yl)-3-oxo-2,3-dihydro-1H-inden-5-yl acetate (1-5)

[0228] After mixing compound 1-4 (2.00 g, 8.15 mmol) and Ac2O (4.16 g, 40.77 mmol, 3.82 mL) in DCM (20 mL), pyridine (3.22 g, 40.77 mmol, 3.29 mL) was added under a nitrogen environment at 0 ° C. The mixture was stirred at 20 ° C for 12 hours. 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 mLX3). After drying with anhydrous Na2SO4, it was concentrated under vacuum to obtain a residue. The residue was purified by flash silica gel chromatography to obtain compound 1-5 (850 mg, 2.96 mmol, yield: 36.28%) as a yellow solid.

[0229] Step 4: Synthesis of 2-bromo-3-(4-methylthiazol-5-yl)-1-oxo-1H-inden-6-yl acetate (1-6)

[0230] After mixing compound 1-5 (650 mg, 2.26 mmol) and NBS (886 mg, 4.98 mmol) in carbon tetrachloride (5.00 mL), AIBN (37.1 mg, 226 umol) was added under a nitrogen environment. The mixture was stirred at 80 ° C for 1 hour. Then, the reaction mixture was stirred at 80 ° C for 1.5 hours at 400 W. It was confirmed by LCMS that the reactant was completely consumed, and it was confirmed that compound 1-6 had been synthesized. The mixture was diluted with DCM (100 mL) and extracted with brine (30 mL×3). After drying and filtering with anhydrous Na2SO4 and concentrating under vacuum, compound 1-6 (890 mg) as a brown oil was obtained.

[0231] Step 5: Synthesis of 2-bromo-6-hydroxy-3-(4-methylthiazol-5-yl)inden-1-one (1-7)

[0232] After mixing compound 1-6 (780 mg, 2.14 mmol) in DCM (4.00 mL), DBU (326 mg, 2.14 mmol, 322 uL) was added under nitrogen. The mixture was stirred at 20 ° C for 12 hours. TLC (PE: EA = 1 / 1) confirmed that the reactant was completely consumed. The mixture was diluted with DCM (100 mL) and extracted with brine (30 mL X3). After drying and filtering with anhydrous Na2SO4, it was concentrated under vacuum to obtain a residue. The residue was purified by flash silica gel chromatography to obtain compound 1-7 (110 mg, 341 umol, yield: 15.9%) as a red oil.

[0233] Step 6: Synthesis of 2-bromo-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one (Compound 3)

[0234] After mixing compound 1-7 (110 mg, 341 umol) and (3-bromopropyl)benzene (81.5 mg, 409 umol, 61.8 uL) as RX in the above [reaction formula 1] in acetonitrile (2.00 mL), K2CO3 (141 mg, 1.02 mmol) was added. The mixture was stirred at 40°C for 12 hours. The reactants were confirmed to be completely consumed by LCMS, and compound 3 was confirmed to be synthesized by MS. The mixture was diluted with EA (50.0 mL) and extracted with brine (10 mLX3). After drying and filtering with anhydrous Na2SO4, it was concentrated under vacuum to obtain a residue. The residue was purified by reverse-phase HPLC to obtain compound 3 (10.0 mg, 22.7 umol, yield: 6.65%) as a red oil.

[0235] Step 7: Synthesis of 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 1)

[0236] Compound 3 (40.0 mg, 90.8 umol) and pyridin-3-ylboronic acid (13.4 mg, 109 umol) as R1-B(OH)2 in the above [Reaction Formula 1] were mixed in dioxane (2.00 mL) and H2O (0.5 mL), and K3PO4 (57.8 mg, 272 umol) and Pd(dppf)Cl2 (5.92 mg, 9.08 umol) were added under a nitrogen environment. The mixture was stirred at 100°C for 2 hours in a microwave. The reactants were completely consumed by LCMS, and 36.1% of compound 1 was detected. The mixture was filtered and concentrated under vacuum to obtain a residue. The residue was purified by reverse-phase HPLC to obtain compound 1 (6.00 mg, 13.68 umol, yield: 15.06%) as a red solid.

[0237] 1 H NMR (400MHz, CD3OD): δ9.19 (s, 1H), 8.4-8.5 (m, 2H), 7.70-7.78 (m, 1H), 7.37-7.45 (m, 1H), 7.13-7.30 (m, 6H), 7.11 (d, J =8.4Hz, 1H), 6.94 (dd, J = 2.4, 8.0Hz, 1H), 4.03 (t, J = 6.4Hz, 2H), 2.81 (t, J = 7.6Hz, 2H,), 2.07-2.15 (m, 2H), 2.05 (s, 3H)

[0238] MS found value: 439.1[M+H] +

[0239] Example 2. 2-(2-(3-(4-methylthiazol-5-yl)-1-oxo-6-(3-phenylpropoxy)-1H-inden-2-yl)phenyl)acetonitrile (Compound 2)

[0240] The compound 3 (20.0 mg, 45.4 umol) synthesized in Example 1 above, 2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)acetonitrile (13.2 mg, 54.5 umol) as R1-B(OH)2 in the above [Reaction Formula 1], and Pd2(dba)3 (4. 16mg, 4.54umol), KF (7.92mg, 136umol) and [(t-Bu)3PH]BF4 (1.32mg, 4.54umol) were added under nitrogen environment. The mixture was stirred at 20°C for 4 hours. LCMS confirmed that the reactants were completely consumed, and MS confirmed that compound 2 had been synthesized. The mixture was diluted with H2O (20.0ml) and extracted with EA (20.0mLX3). The combined organic phase was dried over anhydrous Na2SO4 and filtered, and then concentrated under vacuum to obtain a residue. The residue was purified by reverse-phase HPLC to obtain compound 2 (3.80mg, 7.97umol, yield: 17.5%) as a red oil.

[0241] 1 H NMR (400MHz, CD3OD): δ9.09 (s, 1H), 7.5-7.5 (m, 1H), 7.40 (t, J=7.6Hz, 1H,), 7.21-7.32 (m, 5H), 7.15-7.20 (m, 3H), 7.05 (d, J=7.2Hz, 1H), 6.93-6.97 (m, 1H), 4.05 (t, J=6.4Hz, 2H), 3.75 (s, 2H), 2.82 (t, J=7.6Hz, 2H), 2.08-2.18 (m, 2H), 2.07 (s, 3H)

[0242] MS found: 477.0 [M+H] +

[0243] Example 3. 2-bromo-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one (Compound 3)

[0244] In the above Example 1, compound 3 was synthesized.

[0245] 1H NMR (400MHz, CD3OD): δ9.20 (s, 1H), 7.24-7.30 (m, 2H), 7.13-7.22 (m, 4H), 7.00 (d, J=8.0Hz, 1H), 6.8 8(dd, J=2.4, 8.4Hz, 1H), 4.01 (t, J=6.4Hz, 2H), 2.80 (t, J=7.6Hz, 2H), 2.49 (s, 3H), 2.05-2.14 (m, 2H)

[0246] MS found value: 439.9[M+H] +

[0247] Example 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)

[0248] Step 1: Synthesis of 2-bromo-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one (10-1)

[0249] After mixing the compound 1-7 (30.0 g, 1.0 eq) synthesized by the above Example 1 and (3-bromopropyl) benzene (22.3 g, 1.2 eq) as RX in the above [reaction formula 1] in DMF (300 mL), K2CO3 (23.2 g, 1.8 eq) and NaI (1.40 g, 0.1 eq) were added under a nitrogen environment at 20°C to 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, adjusted to pH 3 with 1M HCl, and then extracted with EtOAc (100 mLX2). After drying the organic layer with Na2SO4, a concentrated organic phase residue was obtained under reduced pressure conditions at 40°C to 45°C. 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 oil.

[0250] Step 2: Synthesis of 3-(4-methylthiazol-5-yl)-2-phenyl-6-(3-phenylpropoxy)-1H-inden-1-one (Compound 10)

[0251] After mixing compound 10-1 (100 mg, 220 umol, 1 eq) and phenylboronic acid (41.5 mg, 340 umol, 1.5 eq) as R1-B(OH)2 in the above [reaction formula 1], K2CO3 (94.0 mg, 681 umol, 3.0 eq), Pd(t-Bu3P)2 (11.0 mg, 21 umol, 0.1 eq), dioxane (0.8 mL) and water (0.2 mL) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 80°C to 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 mLX3). After drying the organic layer over Na2SO4, the concentrated organic phase residue was obtained under reduced pressure at 40° C. to 45° C. The residue was purified by column chromatography (SiO2, PE / EA=10 / 1 to 1 / 1) to obtain compound 10 (82.0 mg, 179 umol, yield: 79.1%) as a red solid.

[0252] 1 H NMR (400MHz, DMSO-d6): δ9.28 (s, 1H), 7.37-7.26 (m, 5H), 7.25-7.16 (m, 5H), 7.15-7.06 (m, 2H), 6.99 (dd, J=2.4, 8.0Hz, 1H), 4.04 (t, J=6.4Hz, 2H), 2.74 (t, J=7.6Hz, 2H), 2.10-1.98 (m, 2H), 1.91 (s, 3H)

[0253] MS found value: 438.1[M+H] +

[0254] Example 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)

[0255] After mixing the compound 10-1 (100 mg, 220 umol, 1 eq) synthesized by the above Example 4 and pyrimidin-5-ylboronic acid (42.2 mg, 340 umol, 1.5 eq) as R1-B(OH)2 in the above [reaction formula 1], K2CO3 (94.0 mg, 681 umol, 3.0 eq), Pd(t-Bu3P)2 (11.0 mg, 21 umol, 0.1 eq), dioxane (0.8 mL) and water (0.2 mL) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 80°C to 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 mLX3). After drying the organic layer over Na2SO4, the concentrated organic phase residue was obtained under reduced pressure at 40° C. to 45° C. The residue was purified by column chromatography (SiO2, PE / EA=10 / 1 to 1 / 1) to obtain compound 11 (23.0 mg, 179 umol, yield: 22.1%) as a red solid.

[0256] 1 H NMR (400MHz, DMSO-d6): δ9.29 (s, 1H), 9.08 (s, 1H), 8.62 (s, 2H), 7.34-7.11 (m, 7H), 7.03 (m, 1H), 4.11 (brt, J=6.4Hz, 2H), 2.77 (brt, J=7.6Hz, 2H), 2.08 (s, 3H), 2.06 (brd, J=7.2Hz, 2H)

[0257] MS found value: 440 [M+H] +

[0258] Example 6. 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(thiophen-2-yl)-1H-inden-1-one (3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(thiophen-2-yl)-1H-inden-1-one) (Compound 12)

[0259] After mixing the compound 10-1 (100 mg, 220 umol, 1 eq) synthesized by the above Example 4 and thiophene-2-ylboronic acid (43.6 mg, 340 umol, 1.5 eq) as R1-B(OH)2 in the above [reaction formula 1], K2CO3 (94.0 mg, 681 umol, 3.0 eq), Pd(t-Bu3P)2 (11.0 mg, 21 umol, 0.1 eq), dioxane (0.8 mL) and water (0.2 mL) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 80°C to 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 mLX3). After the organic layer was dried over Na2SO4, the concentrated organic phase residue was obtained under reduced pressure at 40° C. to 45° C. The residue was purified by column chromatography (SiO2, PE / EA=10 / 1 to 1 / 1) to obtain compound 12 (23.0 mg, 179 umol, yield: 22.08%) as a red solid.

[0260] 1 H NMR (400MHz, DMSO-d6): δ9.38 (s, 1H), 7.59 (d, J=5.2Hz, 1H), 7.40 (d, J=3.6Hz, 1H), 7.31-7.25 (m, 2H), 7.25-7.17 (m, 3H), 7.12-7.0 5 (m, 2H), 6.97-6.91 (m, 1H), 6.85 (d, J=8.0Hz, 1H), 4.02 (brt, J=6.4Hz, 2H), 2.74 (brt, J=7.6Hz, 2H), 2.18 (s, 3H), 2.06-1.97 (m, 2H)

[0261] MS found: 444.1 ([M+H] + )

[0262] Example 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)

[0263] Step 1: Synthesis of 2-bromo-3-(4-methylthiazol-5-yl)-6-(3-(pyridin-4-yl)propoxy)-1H-inden-1-one (13-1)

[0264] After mixing the compound 1-7 (300 mg, 745 umol, 1.00 eq) synthesized by the above Example 1 and 4-(3-bromopropyl)pyridine (557 mg, 2.24 mmol, 3.00 eq) as RX in the above [Reaction Formula 1] in DMF (3.00 mL), K2CO3 (190 mg, 1.35 mmol, 1.80 eq) and NaI (13.0 mg, 85.8 umol, 0.10 eq) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 40°C to 45°C for 18 hours. 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 1M HCl, and then extracted with EtOAc (10.0 mLX3). The residue was purified by reverse phase HPLC under HCl conditions to obtain compound 13-1 (47.0 mg, 97.9 umol, yield: 13.1%) as a red solid.

[0265] 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)

[0266] After mixing the above compound 13-1 (45.0 mg, 93.8 umol, 1.00 eq) and pyridin-3-ylboronic acid (18.0 mg, 145 umol, 1.45 eq) as R1-B(OH)2 in the above [reaction formula 1], K2CO3 (40.0 mg, 283 umol, 3.00 eq), Pd(t-Bu3P)2 (6.00 mg, 11.1 umol, 0.10 eq), dioxane (0.80 mL) and water (0.20 mL) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 80°C to 85°C for 12 hours. It was confirmed by LCMS that the reactant was completely consumed. Water (10 mL) was added to the mixture, adjusted to pH 7 with 1M HCl, and then extracted with EtOAc (10 mLX3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure at 40 to 45°C to obtain a residue. The residue was purified by prep-HPLC to obtain Compound 13 (36.0 mg, 79.4 umol, yield: 84.7%) as a red solid.

[0267] 1 H NMR (400MHz, DMSO-d6): δ9.31 (s, 1H), 8.44-8.50 (m, 3H), 8.35 (d, J=1.2Hz, 1H), 7.61 (m, 1H), 7. 40 (m, 1H), 7.28 (d, J = 5.6Hz, 2H), 7.11-7.18 (m, 2H), 7.02 (m, 1H), 4.07 (t, J = 6.4Hz, 2H), 2.77 (br t, J=7.6Hz, 2H), 2.02-2.11(m, 2H), 1.96(s, 3H)

[0268] MS found: 440.0 ([M+H] + )

[0269] Example 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)

[0270] Step 1: Synthesis of 2-bromo-3-(4-methylthiazol-5-yl)-6-phenethoxy-1H-inden-1-one (14-1)

[0271] After mixing compound 1-7 (3.00 g, 9.31 mmol, 1.00 eq) synthesized by the above Example 1 and (2-bromoethyl)benzene (2.58 g, 13.97 mmol, 1.5 eq) as RX in the above [Reaction Formula 1] in DMF (30 mL), K2CO3 (2.32 g, 16.76 mmol, 1.5 eq) and NaI (139 mg, 931.17 umol, 0.2 eq) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 20°C to 25°C for 12 hours. It was confirmed by TLC (PE:EA=1 / 1) that the reactants were completely consumed. Water (20 mL) was added to the mixture, adjusted to pH 3 with 1M HCl, and then extracted with EtOAc (5 mL). The residue was purified by column chromatography (SiO 2 , PE / EA=10 / 1 to 1 / 1) to obtain compound 14-1 (2.3 mg, 508 umol, yield: 32.76%) as a red solid.

[0272] Step 2: Synthesis of 3-(4-methylthiazol-5-yl)-6-phenethoxy-2-(pyridin-3-yl)-1H-inden-1-one (Compound 14)

[0273] After mixing compound 14-1 (500 mg, 220 umol, 1 eq) and pyridin-3-ylboronic acid (209 mg, 1.70 mmol, 1.5 eq) as R1-B(OH)2 in the above [reaction formula 1], K2CO3 (470 mg, 681 umol, 3.0 eq), Pd(t-Bu3P)2 (57.9 mg, 113 umol, 0.1 eq), dioxane (8 mL) and water (2 mL) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 80°C to 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 mLX3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure at 40 to 45°C to obtain a residue. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 1 / 1) to obtain compound 14 (300 mg, 692 umol, yield: 61.07%) as a red solid.

[0274] 1H NMR (400MHz, DMSO-d6): δ9.36 (s, 1H), 8.53 (dd, J=1.2, 4.8Hz, 1H), 8.40 (d, J=1.6Hz, 1H), 7.65 (m, 1H), 7.44 (dd, J=4.8, 7.8Hz, 1H), 7.41-7.34 (m, 4H), 7.31-7.26 (m, 1H), 7.21 (d, J=2.4Hz, 1H), 7.17 (d, J=8.0Hz, 1H), 7.1 0-7.05 (m, 1H), 4.34 (t, J=6.8Hz, 2H), 3.10 (t, J=6.8Hz, 2H), 2.00 (s, 3H)

[0275] MS found: 425[M+H] +

[0276] Example 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)

[0277] Step 1: Synthesis of 2-bromo-3-(4-methylthiazol-5-yl)-6-(4-phenylbutoxy)-1H-inden-1-one (15-1)

[0278] After mixing compound 1-7 (500 mg, 1.55 mmol, 1 eq) synthesized by the above Example 1 and (4-bromobutyl)benzene (396 mg, 1.86 mmol, 1.2 eq) as RX in the above [Reaction Formula 1] in DMF (5 mL), K2CO3 (321 mg, 2.33 mmol, 1.5 eq) and NaI (46.0 mg, 310 umol, 0.2 eq) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 20°C to 25°C for 12 hours. It was confirmed by TLC (PE:EA=1 / 1) that the reactants were completely consumed. Water (20 mL) was added to the mixture, adjusted to pH 3 with 1M HCl, and then extracted with EtOAc (5 mL). The residue was purified by column chromatography (SiO 2 , PE / EA=10 / 1 to 1 / 1) to obtain compound 15-1 (231 mg, 508 umol, yield: 32.7%) as a red solid.

[0279] Step 2: Synthesis of 3-(4-methylthiazol-5-yl)-6-(4-phenylbutoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 15)

[0280] After mixing compound 15-1 (100 mg, 220 umol, 1 eq) and pyridin-3-ylboronic acid (40.0 mg, 325 umol, 1.48 eq) as R1-B(OH)2 in the above [reaction formula 1], K2CO3 (91.0 mg, 658 umol, 2.99 eq), Pd(t-Bu3P)2 (11.00 mg, 21 umol, 0.10 eq), dioxane (0.8 mL) and water (0.2 mL) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 80°C to 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 mLX3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure at 40 to 45°C to obtain a residue. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 1 / 1) to obtain compound 15 (14.9 mg, 26 umol, yield: 12.1%) as a red solid.

[0281] 1 H NMR (400MHz, DMSO-d6): δ9.30 (s, 1H), 8.52-8.39 (m, 2H), 7.61 -7.59 (d, J=8.0Hz, 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)

[0282] MS found: 453.3[M+H] +

[0283] Example 10. 6-((benzyloxy)methoxy)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 16)

[0284] Step 1: Synthesis of 6-((benzyloxy)methoxy)-2-bromo-3-(4-methylthiazol-5-yl)-1H-inden-1-one (16-1)

[0285] After mixing compound 1-7 (1.00 g, 3.10 mmol, 1.00 eq) synthesized by Example 1 above and ((chloromethoxy)methyl)benzene (614 mg, 3.72 mmol, 1.20 eq) as RX in the above [reaction formula 1] in DMF (10.0 mL), K2CO3 (657 mg, 4.66 mmol, 1.50 eq) and NaI (94 mg, 620 umol, 0.20 eq) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 40°C to 45°C for 18 hours. It was confirmed by LCMS that the reactants were completely consumed. Water (20 mL) was added to the mixture, adjusted to pH 3 with 1M HCl, and then extracted with EtOAc (30.0 mLX3). The residue was purified by column chromatography (SiO 2 , PE / EA=20 / 1 to 5 / 1) to obtain compound 16-1 (270 mg, 568 umol, yield: 18.3%) as a red solid.

[0286] Step 2: Synthesis of 6-((benzyloxy)methoxy)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 16)

[0287] After mixing compound 16-1 (250 mg, 525 umol, 1.00 eq) and pyridin-3-ylboronic acid (98.0 mg, 789 umol, 1.50 eq) as R1-B(OH)2 in the above [reaction formula 1], K2CO3 (224 mg, 4.59 mmol, 3.02 eq), Pd(t-Bu3P)2 (29.0 mg, 53.9 umol, 0.10 eq), dioxane (2.00 mL) and water (0.50 mL) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 80°C to 85°C for 12 hours. It was confirmed by LCMS 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 Na2SO4 and concentrated under reduced pressure at 40 to 45°C to obtain a residue. The residue was purified by column chromatography (SiO2, PE / EA = 20 / 1 to 1 / 1) to obtain compound 16 (67.4 mg, 26 umol, yield: 12.1%) as a red solid.

[0288] 1 H NMR (400MHz, DMSO-d6): δ8.86 (s, 1H), 8.37-8.50 (m, 2H), 7.55-7.64 (m, 1H), 7.30 (br d, J=1.2Hz, 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)

[0289] MS found: 441.0 [M+H] +

[0290] Example 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)

[0291] Step 1: Synthesis of 2-bromo-3-(4-methylthiazol-5-yl)-6-(2-phenoxyethoxy)-1H-inden-1-one (17-1)

[0292] After mixing compound 1-7 (500 mg, 1.55 mmol, 1 eq) synthesized by the above Example 1 and (2-bromoethoxy)benzene (374 mg, 1.86 mmol, 1.2 eq) as RX in the above [Reaction Formula 1] in DMF (5 mL), K2CO3 (321 mg, 2.33 mmol, 1.5 eq) and NaI (46.0 mg, 310 umol, 0.2 eq) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 20°C to 25°C for 12 hours. It was confirmed by LCMS that the reactants were completely consumed. Water (20 mL) was added to the mixture, adjusted to pH 3 with 1M HCl, and then extracted with EtOAc (5 mL). The residue was purified by column chromatography (SiO 2 , PE / EA=10 / 1 to 1 / 1) to obtain compound 16-1 (179 mg, 404 umol, yield: 26.1%) as a red solid.

[0293] Step 2: Synthesis of 3-(4-methylthiazol-5-yl)-6-(2-phenoxyethoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 17)

[0294] After mixing compound 17-1 (100 mg, 220 umol, 1 eq) and pyridin-3-ylboronic acid (40.0 mg, 325 umol, 1.48 eq) as R1-B(OH)2 in the above [reaction formula 1], K2CO3 (91.0 mg, 658 umol, 2.99 eq), Pd(t-Bu3P)2 (11.00 mg, 21 umol, 9.78e-2 eq), dioxane (0.8 mL) and water (0.2 mL) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 80°C to 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 mLX3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure at 40 to 45°C to obtain a residue. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 1 / 1) to obtain compound 17 (22.86 mg, 37 umol, yield: 16.44%) as a red solid.

[0295] 1H NMR (400MHz, DMSO-d6): δ9.31 (s, 1H), 8.49-8.49 (d, J=1.2Hz, 1H), 8.48-8.47 (d, J=1.2Hz, 1H), 8.36-8.35 (d, J=1.6Hz, 1H), 7.62-7.60 (d, J=8Hz, 1H), 7.39-6.95 (m, 9H), 4.44-4.42 (m, 2H), 4.34-4.32 (m, 2H), 1.96 (s, 1H).

[0296] MS found value: 441.3 [M+H] +

[0297] Example 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)

[0298] [Reaction 2]

[0299]

[0300] Step 1: Synthesis of 3-bromo-6-methoxy-1H-inden-1-one (9-2)

[0301] After mixing the compound 9-1 (50.0 g, 308 mmol, 1.00 eq) of the above [Reaction Formula 2] and NBS (109 g, 616 mmol, 2.00 eq) and AIBN (1.02 g, 6.20 mmol, 2.01 eq) in CCl4 (1.00 L), add under a nitrogen environment at 20°C to 25°C. Stir the mixture at 85°C for 2 hours. Confirm that the reactant is completely consumed by TLC (PE: EA = 1: 1). After adding TEtOAc (93.5 g, 924 mmol, 128 mL, 3.00 eq) to the mixture, stir at 25°C for 12 hours. Confirm that the reactant is synthesized into the desired compound by LCMS. Cool the mixture with water (1000 mL) and extract with DCM (800 mLX2). Wash the organic layer with NaCl (500 mLX3) and dry with Na2SO4. After filtration, the mixture was concentrated under reduced pressure to obtain a residue, which was a red solid compound 9-2 (70.0 g, 201 mmol, yield: 65.4%, purity: 68.9%).

[0302] Step 2: Synthesis of 2,3-dibromo-6-methoxy-1H-inden-1-one (9-3)

[0303] Compound 9-2 (65.0 g, 271.8 mmol, 1.00 eq) was dissolved in HOAc (850 mL), and the mixture was stirred at 22 to 25 ° C. After Br2 (130 g, 815 mmol, 42.0 mL, 3.00 eq) was added dropwise, the mixture was stirred at 22 to 25 ° C for 12 hours. The reactants were completely consumed as confirmed by TLC (PE: EA = 3: 1). The mixture was extracted with 10% NaS2O3 aqueous solution (1000 mL), and the aqueous phase was extracted with MTBE (500 mLX2). After washing the organic phase with NaHCO3 (1000 mLX2), it was washed with brine (500 mLX2) and dried with anhydrous Na2SO4. Concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (SiO2, PE / EA=3:1, P1=0.49) to obtain compound 9-3 (15.0 g, 39.8 nmol, yield: 14.6%, purity: 84.5%) as a red solid.

[0304] Step 3: Synthesis of 2-bromo-3-(furan-3-yl)-6-methoxy-1H-inden-1-one (9-4)

[0305] After mixing compound 9-3 (11.9 g, 37.4 mmol, 1.00 eq) and 2A (5.03 g, 44.9 mmol, 1.20 eq) in the above [Reaction Formula 2] in dioxane (120 mL) and H2O (30.0 mL), K2CO3 (15.5 g, 112 mmol, 3.00 eq) and Pd(PPh3)4 (4.32 g, 3.74 mmol, 0.10 eq) were added under a nitrogen environment at 25°C. The mixture was stirred for 12 hours at 40°C under a nitrogen environment. While ACN (1 mL) was added dropwise, it was confirmed by LCMS that the reactants were completely consumed, and the reactants were cooled to 22°C to 25°C. Water (200 mL) was added to the mixture, and extracted with EtOAc (100 mLX2). The organic layer was washed with NaCl (100 mLX2) and dried with Na2SO4. The mixture was filtered and concentrated under vacuum to obtain a residue. After filtration, the mixture was concentrated under reduced pressure to obtain a residue, which was compound 9-4 (5.20 g, 4.67 mmol, yield: 12.4%, purity: 27.4%) as a red solid.

[0306] Step 4: Synthesis of 3-(furan-3-yl)-6-methoxy-2-(pyridin-3-yl)-1H-inden-1-one (9-5)

[0307] 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) as R1-B(OH)2 in the above [Reaction Formula 2] were mixed in dioxane (120 mL) and H2O (30.0 mL), and K2CO3 (6.78 g, 49.0 mmol, 2.99 eq) and Pd(t-Bu3P)2 (875 mg, 1.71 mmol, 1.04 eq) were added under nitrogen atmosphere. The mixture was stirred at 85°C for 12 hours. After the reactant was cooled to 22°C to 25°C, ACN (1 mL) was added dropwise, and the reactant was confirmed to be completely consumed by LCMS. The reactant was confirmed to be completely consumed by LCMS. Water (30.0 mL) was added to the mixture and extracted with EtOAc (30.0 mL×2). The organic layer was washed with NaCl (20.0 mL×2) and dried with Na2SO4. The mixture was filtered and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (SiO2, PE:EA=3:1, P1=0.20) to obtain compound 9-5 (2.50 g, 5.17 mmol, yield: 31.5%, purity: 62.7%) as a red solid.

[0308] Step 5: Synthesis of 3-(furan-3-yl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one (9-6)

[0309] After compound 9-5 (3.00 g, 9.89 mmol, 1.00 eq) was mixed into DCM (90.0 mL) under a nitrogen environment at 20°C to 25°C, BBr3 (7.44 g, 29.7 mmol, 2.86 mL, 3.00 eq) was mixed under a nitrogen environment at -78°C. The mixture was stirred for 2 hours at -78°C and for 6 hours at 22°C to 25°C under a nitrogen environment. While ACN (1 mL) was added dropwise, 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. The mixture was adjusted to pH 7 with 5% NaHCO3 / H2O, and then extracted with EtOAc (50.0 mLX3). The organic layer was washed with brine (100 mL), dried with Na2SO4, and 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, the mixture was washed with PE (50.0 mL) and dried under vacuum to obtain a light red solid compound. The solution was removed to obtain compound 9-6 (3.30 g, 7.41 mmol, yield: 74.9%, purity: 65.0%) as a red solid.

[0310] Step 6: Synthesis of 3-(furan-3-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 9)

[0311] After mixing compound 9-6 (50.0 mg, 172.84 umol, 1 eq) and (3-bromopropyl)benzene (3-bromopropyl)benzene, 1 eq) as RX in the above [reaction formula 2] in DMF (1 mL), K2CO3 (35.8 mg, 259.26 umol, 1.5 eq) and NaI (5.18 mg, 34.57 umol, 0.2 eq) were added at 25 ° C. The mixture was stirred at 45 ° C for 12 hours. It was confirmed by LCMS 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), dried with Na2SO4, and filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to obtain Compound 9 (12.18 mg, 28.93 umol, yield: 16.74%, purity: 96.78%) as an orange solid.

[0312] 1H NMR (400MHz, DMSO-d6): δ8.56 (dd, J=1.6, 4.8Hz, 1H), 8.50-8.41 (m, 2H), 7.83 (t, J=1.6Hz, 1H), 7.72 (td, J=2.0, 8.0Hz, 1H), 7.55-7.44 (m, 2H), 7.36-7.13 (m, 6H), 7.04 (dd, J=2.4, 8.0Hz, 1H), 6.23 (d, J=1.2Hz, 1H), 4.09 (t, J=6.4Hz, 2H), 2.78 (t, J=8.0Hz, 2H), 2.14-2.02 (m, 2H)

[0313] MS found value: 408.2[M+H] +

[0314] Example 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)

[0315] After mixing compound 9-6 (50.0 mg, 172 umol, 1 eq) synthesized by the above Example 12 and (2-bromoethyl)benzene (31.9 mg, 172 umol, 23.38 uL, 1 eq) as RX in the above [Reaction Formula 2] in DMF (1 mL), K2CO3 (35.8 mg, 259 umol, 1.5 eq) and NaI (5.18 mg, 34.5 umol, 0.2 eq) were added at 25°C. The mixture was stirred at 50°C for 14 hours. While DCM (1.00 mL) was added dropwise, 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 x 3). The organic layer was washed with brine (5 mL x 2), dried with Na2SO4, and filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to obtain Compound 38 (12 mg, 30.50 umol, yield: 17.65%) as a red solid.

[0316] 1H NMR (400MHz, DMSO-d6): δ8.54 (d, J=4.8Hz, 1H), 8.45 (s, 2H), 7.81 (s, 1H), 7.70 (br d, J=8.0Hz, 1H), 7.52-7.40 (m, 2H), 7.37-7.30 (m, 4H), 7.28-7.20 (m, 1H), 7.13 (d, J=2.0Hz , 1H), 7.04 (dd, J=2.0, 8.0Hz, 1H), 6.20 (s, 1H), 4.31 (t, J=6.8Hz, 2H), 3.06 (t, J=6.8Hz, 2H)

[0317] MS found value: 394.1[M+H] +

[0318] Example 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)

[0319] After mixing the compound 9-6 (54.3 mg, 187.69 umol, 1 eq) synthesized by the above Example 12 and (4-bromobutyl)benzene (40.0 mg, 187.69 umol, 1 eq) as RX in the above [Reaction Formula 2] in DMF (1 mL), K2CO3 (38.9 mg, 281 umol, 1.5 eq) and NaI (5.63 mg, 37.5 umol, 0.2 eq) were added at 25°C. The mixture was stirred at 50°C for 14 hours. The synthesis of the desired compound was confirmed by LCMS. 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), dried with Na2SO4, and filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to obtain Compound 39 (15 mg, 34.95 umol, yield: 18.62%, purity: 98.2%) as a red solid.

[0320] 1H NMR (400MHz, DMSO-d6): δ8.55 (dd, J=1.6, 4.8Hz, 1H), 8.46 (s, 2H), 7.83-7.8 0 (m, 1H), 7.71 (td, J=2.0, 8.0Hz, 1H), 7.49 (d, J=8.0Hz, 1H), 7.45 (m, 1H), 7.3 2-7.26 (m, 2H), 7.26-7.16 (m, 3H), 7.13 (d, J=2.4Hz, 1H), 7.02 (dd, J=2.4, 8.0 Hz, 1H), 6.20 (d, J=1.6Hz, 1H), 4.13-4.06 (m, 2H), 2.73-2.61 (m, 2H), 1.75 (br d, J = 3.6 Hz, 4H)

[0321] MS found value: 422.2[M+H] +

[0322] Example 15. 6-((benzyloxy)methoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 40)

[0323] After mixing the compound 9-6 (80.0 mg, 276.54 umol, 1 eq) synthesized by the above Example 12 and NaH (13.3 mg, 331 umol, purity: 60%, 1.2 eq) in DMF (1 mL), ((chloromethoxy)methyl)benzene (86.6 mg, 553 umol, 76.4 uL, 2 eq) as RX in the above [Reaction Formula 2] was dissolved in DMF (0.1 mL) and added dropwise thereto and mixed, and the mixture was stirred at 25° C. for 1 hour. The synthesis of the desired compound was confirmed by LCMS. The mixture was cooled with NH4Cl (5 mL), diluted with water (5 mL), and extracted with EtOAc (5 mL). The organic layer was washed with brine (5 mL×2), dried with Na2SO4, and the mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (SiO 2 , PE:EA=1:2) to obtain compound 40 (9.72 mg, 20.58 umol, yield: 7.44%, purity: 86.7%) as a red gum.

[0324] 1H NMR (400MHz, CHLOROFORM-d): δ8.55-8.43 (m, 2H), 7.79 (s, 1H), 7.65 (br d, J=8.0Hz, 1H), 7.41 (s, 1H), 7.28 (br s, 3H), 7.25-7.13 (m, 5H), 7.02 (dd, J=2.4, 8.0Hz, 1H), 6.19 (s, 1H), 5.26 (s, 2H), 4.72-4.61 (s, 2H)

[0325] MS found: 410.1[M+H] +

[0326] Example 16. 3-(furan-3-yl)-6-(2-phenoxyethoxy)-2-(pyridin-3-yl)-1H-inden-1-one (3-(furan-3-yl)-6-(2-phenoxyethoxy)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 41)

[0327] After mixing compound 9-6 (54.7 mg, 189 umol, 1 eq) synthesized by the above Example 12 and (2-bromoethoxy)benzene (38.0 mg, 189 umol, 1 eq) as RX in the above [Reaction Formula 2] in DMF (1 mL), K2CO3 (39.2 mg, 283 umol, 1.5 eq) and NaI (5.67 mg, 37.8 umol, 0.2 eq) were added at 25°C. The mixture was stirred at 45°C for 12 hours. The synthesis of the desired compound was confirmed by LCMS. 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), dried with Na2SO4, and the mixture was filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to obtain Compound 41 (20 mg, 48.26 umol, yield: 25.54%, purity: 98.8%) as a red solid.

[0328] 1H NMR (400MHz, METHANOL-d): δ8.53-8.47 (m, 2H), 8.18 (s, 1H), 7.85 (td, J=2.0, 8.0Hz, 1H), 7.66 (t, J=1.6Hz, 1H), 7.51-7.41 (m, 2H), 7.3 1(t, J=7.2Hz, 2H), 7.24 (d, J=2.4Hz, 1H), 7.08 (dd, J=2.4, 8.0Hz, 1H), 7.03-6.94 (m, 3H), 6.30 (dd, J=0.8, 2.0Hz, 1H), 4.49-4.31 (m, 4H)

[0329] MS found: 410.1[M+H] +

[0330] Example 17. 3-(furan-3-yl)-6-(2-(4-methoxyphenoxy)ethoxy)-2-(pyridin-3-yl)-1H-inden-1-one (3-(furan-3-yl)-6-(2-(4-methoxyphenoxy)ethoxy)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 42)

[0331] After mixing compound 9-6 (50.0 mg, 172 umol, 1 eq) synthesized by the above Example 12 and 1-(2-bromoethoxy)-4-methoxybenzene (40.7 mg, 176 umol, 1.02 eq) as RX in the above [Reaction Formula 2] in DMF (3.00 mL), K2CO3 (36.0 mg, 260 umol, 1.51 eq) and NaI (5.00 mg, 33.3 umol, 1.93 eq) were added at 25°C. The mixture was stirred at 45°C to 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). Extraction was performed with EtOAc (10.0 mLX2). The organic layer was washed with NaCl (10.0 mL x 2), dried with Na2SO4, and filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to obtain compound 42 (11.0 mg, 24.6 umol, yield: 14.2%, purity: 98.4%).

[0332] 1H NMR (400MHz, DMSO-d6): δppm 3.70(s, 3H), 4.24-4.32(m, 2H), 4.38-4.44(m, 2H), 6.20(d, J=1.2Hz, 1H ), 6.84-6.89(m, 2H), 6.90-6.96(m, 2H), 7.06-7.11(m, 1H), 7.17-7.22( m, 1H), 7.45 (dd, J=8.0, 4.8Hz, 1H), 7.51 (d, J=8.0Hz, 1H), 7.67-7.74 (m, 1H), 7.77-7.86 (m, 1H), 8.44-8.50 (m, 2H), 8.54 (dd, J=4.8, 1.2Hz, 1H).

[0333] MS measured value: 440.1 (M+1)

[0334] Example 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)

[0335] Compound 9-6 (20.0 mg, 69.1 umol, 1.00 eq) synthesized by Example 12 and 4-(2-bromoethoxy)-1,2-dimethoxybenzene (18.4 mg, 70.5 umol, 1.02 eq) as RX in [Reaction Formula 2] were mixed in DMF (3.00 mL), and K2CO3 (14.4 mg, 104 umol, 1.51 eq) and NaI (20.0 mg, 133 umol, 1.93 eq) were added at 25°C. The mixture was stirred at 40°C for 12 hours. While dropping EtOAc (1 mL), it was confirmed by TLC (PE:EA=1:0) that the reactant was completely consumed. The mixture was cooled to 22°C to 25°C. Dilute with water (30.0 mL) and extract with EtOAc (10.0 mL x 3). Wash the organic layer with brine (15.0 mL), dry with Na2SO4, and filter and concentrate the mixture under reduced pressure. Compound 43 (12.1 mg, 25.33 umol, yield: 36.64%, purity: 98.3%) was obtained as a red solid.

[0336] 1H NMR (400MHz, DMSO-d6): δppm 8.54 (s, 1H), 8.46 (s, 2H) 7.81 (s, 1H), 7.71 (s, 1H), 7.48 (d, J=21.6Hz, 2H), 7.19 (s, 1H), 7.11 (s, 1H), 6.86 (d, J=4.8Hz, 1H) 6.62 (s, 1H), 6.50 (s, 1H), 6.20 (s, 1H), 4.21-4.48 (d, J=52Hz, 4H) 3.71 (d, J=19.2Hz, 6H).

[0337] MS found value: 470.2[M+H] +

[0338] Example 19. 6-(2-(Benzo[d][1,3]dioxol-5-yloxy)ethoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 44)

[0339] Compound 9-6 (50.0 mg, 172 umol, 1.00 eq) synthesized by Example 12 and 5-(2-bromoethoxy)benzo[d][1,3]dioxole (40.7 mg, 176 umol, 1.02 eq) as RX in [Reaction Formula 2] were mixed in DMF (3.0 mL), and K2CO3 (36.0 mg, 260 umol, 1.51 eq) and NaI (5.00 mg, 33.3 umol, 1.93 eq) were added at 25°C. The mixture was stirred at 45°C to 50°C for 12 hours. The desired compound was confirmed to be synthesized by LCMS. The mixture was cooled with water (10.0 mL). Extraction was performed with EtOAc (10.0 mLX2). The organic layer was washed with NaCl (10.0 mL x 2), dried with Na2SO4, and filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to obtain compound 44 (15.9 mg, 31.4 umol, yield: 18.1%, purity: 89.6%) as a red solid.

[0340] 1H NMR (400MHz, DMSO-d6): δppm 8.54 (dd, J=4.8, 1.6Hz, 1H), 8.45-8.49 (m, 2H), 7.82 (t, J=2.0Hz, 1H), 7.71 (dt, J=8.0 , 2.0Hz, 1H), 7.51 (d, J=8.4Hz, 1H), 7.42-7.47 (m, 1H), 7.19 (d, J=2.4Hz, 1H), 7.09 (dd, d, 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). MS found: 454 (M+1)

[0341] Example 20. 3-(Furan-3-yl)-2-(pyridin-3-yl)-6-(2-(pyridin-4-yloxy)ethoxy)-1H-inden-1-one (3-(furan-3-yl)-2-(pyridin-3-yl)-6-(2-(pyridin-4-yloxy)ethoxy)-1H-inden-1-one) (Compound 45)

[0342] After mixing compound 9-6 (50.0 mg, 172 umol, 1.00 eq) synthesized by the above Example 12 and 4-(2-bromoethoxy)pyridine (35.6 mg, 176 umol, 1.02 eq) as RX in the above [Reaction Formula 2] in DMF (3.00 mL), K2CO3 (60.0 mg, 434 umol, 2.51 eq) and NaI (5.18 mg, 34.5 umol, 0.20 eq) were added at 25°C. The mixture was stirred at 40°C for 12 hours. While dropping EtOAc (1 mL), it was confirmed by TLC (PE: EA = 1: 0) that the reactant was completely consumed. The mixture was cooled to 22°C to 25°C. Dilute with water (30.0 mL) and extract with EtOAc (10.0 mLX3). The organic layer was washed with brine (15.0 mL), dried over Na2SO4, and filtered and the mixture was concentrated under reduced pressure to obtain Compound 45 (8 mg, 18.7 umol, yield: 10.8%, purity: 96.2%) as a red solid.

[0343] 1H NMR (400MHz, CHLOROFORM-d): δppm 8.58(s, 2H), 8.50(s, 1H), 7.88(s, 1H), 7.74(d, J=8.4Hz, 1H), 7.50(s, 1H), 7 .31-7.34(m, 1H), 7.30(s, 1H), 6.89-6.98(m, 3H), 6.27(s, 1H), 4.43(s, 4H).

[0344] MS found: 411.2[M+H] +

[0345] Example 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)

[0346] Compound 9-6 (50.0 mg, 173 umol, 1.00 eq) synthesized by Example 12 and 4-(2-bromoethoxy)-1,2-dichlorobenzene (46.0 mg, 194 umol, 1.12 eq) as RX in [Reaction Formula 2] were mixed in DMF (3.0 mL), and K2CO3 (36.0 mg, 260 umol, 1.51 eq) and NaI (5.00 mg, 33.4 umol, 0.20 eq) were added at 25°C. The mixture was stirred at 40°C for 12 hours. While MeOH (1.00 mL) was added dropwise, the synthesis of the desired compound was confirmed by LCMS. The mixture was cooled to 25°C. Diluted with water (30.0 mL) and extracted with EtOAc (10.0 mLX3). The organic layer was washed with brine (15.0 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by reverse-phase HPLC to obtain Compound 46 (34.0 mg, purity: 90.1%) as a red solid.

[0347] 1H NMR (400MHz, DMSO-d6): δppm 8.54 (dd, J=4.8, 1.6Hz, 1H), 8.48 (s, 1H), 8.46 (d, J=2.0Hz, 1H), 7.82 (t, J=2.0Hz, 1H), 7.71 (dt, J=8.0, 2.0Hz, 1H), 7.53 (dd, J=11.6, 9.2Hz, 2H), 7.45 (dd, J=7.6, 4. 8Hz, 1H), 7.33 (d, J=3.2Hz, 1H), 7.19 (d, J=2.4Hz, 1H), 7.08 (dd, J=8.4, 2.4Hz, 1H) , 7.04 (dd, J=9.2, 3.2Hz, 1H), 6.20 (d, J=1.2Hz, 1H), 4.41 (dd, J=16.0, 1.2Hz, 4H).

[0348] MS measured value: 478.1 (M)

[0349] Example 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)

[0350] Compound 9-6 (50.0 mg, 172 umol, 1.00 eq) synthesized by Example 12 and 4-(2-bromoethoxy)-1,2-difluorobenzene (46.0 mg, 194 umol, 1.12 eq) as RX in [Reaction Formula 2] were mixed in DMF (3.00 mL), and K2CO3 (36.0 mg, 260 umol, 1.51 eq) and NaI (5.00 mg, 33.3 umol, 0.20 eq) were added at 25°C. The mixture was stirred at 40°C for 12 hours. While MeOH (1.00 mL) was added dropwise, the synthesis of the desired compound was confirmed by LCMS. The mixture was cooled to 25°C. Diluted with water (50.0 mL) and extracted with EtOAc (30.0 mLX3). The organic layer was washed with brine (15.0 mL), dried over Na2SO4, and the mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography (P1=0.30) to obtain Compound 47 (21.0 mg, purity: 98.5%) as a red solid.

[0351] 1H NMR (400MHz, METHANOL-d): δppm 8.54 (d, J=4.4Hz, 1H), 8.46 (s, 2H), 7.81 (s, 1H), 7.71 (d, J=8.0Hz, 1H), 7.51 (d, J=8.0Hz, 1H), 7.44 (dd, J=8.0, 5.2Hz, 1H), 7.36 (q, J=9 .6Hz, 1H), 7.11-7.24 (m, 2H), 7.08 (dd, J=8.0, 2.4Hz, 1H), 6.83 (d, J=8.8Hz, 1H), 6.20 (s, 1H), 4.39-4.49 (m, 2H), 4.34 (d, J=4.4Hz, 2H).

[0352] MS measured value: 446.1 (M)

[0353] Example 23. 6-(2-(4-(dimethylamino)phenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one (6-(2-(4-(dimethylamino)phenoxy)ethoxy)-3-(furan-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 48)

[0354] Compound 9-6 (50.0 mg, 172 umol, 1.00 eq) synthesized by Example 12 and 4-(2-bromoethoxy)-N,N-dimethylaniline (43.0 mg, 176 umol, 1.02 eq) as RX in [Reaction Formula 2] were mixed in DMF (3.00 mL), and K2CO3 (36.0 mg, 260 umol, 1.51 eq) and NaI (5.00 mg, 33.3 umol, 1.93 eq) were added at 25°C. The mixture was stirred at 45°C to 50°C for 12 hours. The desired compound was confirmed to be synthesized by LCMS. The mixture was cooled with water (10.0 mL) and extracted with EtOAc (10.0 mLX2). The organic layer was washed with NaCl (10.0 mL x 2), dried with Na2SO4, and filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to obtain compound 48 (7.00 mg, 13.8 umol, yield: 8.03%, purity: 89.7%) as a red colloid.

[0355] 1H NMR (400MHz, CHLOROFORM-d): δppm 8.52-8.61 (m, 2H), 7.88 (s, 1H), 7.74 (d, J=8.0Hz, 1H), 7.49 (s, 1H), 7.31-7.42 (m, 2H), 6.87-7.01 (m, 3H), 6.76 (d, J=9.2Hz, 2H), 6.27 (s, 1H), 4.28-4.42 (m, 4H), 2.89 (s, 6H).

[0356] MS measured value: 453.2 (M+1)

[0357] Example 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)

[0358] Compound 9-6 (50.0 mg, 172 umol, 1.00 eq) synthesized by Example 12 and 1-(2-bromoethoxy)-4-isopropylbenzene (43.0 mg, 176 umol, 1.02 eq) as RX in [Reaction Formula 2] were mixed in DMF (3.00 mL), and K2CO3 (36.0 mg, 260 umol, 1.51 eq) and NaI (5.00 mg, 33.3 umol, 1.93 eq) were added at 25°C. The mixture was stirred at 45°C to 50°C for 12 hours. While MeOH (1.00 mL) was added dropwise, the synthesis of the desired compound was confirmed by LCMS. The mixture was cooled with water (10.0 mL) and extracted with EtOAc (10.0 mLX2). The organic layer was washed with NaCl (10.0 mL x 2), dried with Na2SO4, and filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to obtain compound 49 (13.00 mg, 26.1 umol, yield: 15.11%, purity: 90.7%) as a red colloid.

[0359] 1H NMR (400MHz, DMSO-d6): δppm 8.53-8.60 (m, 2H), 7.88 (s, 1H), 7.74 (d, J=8.0Hz, 1H), 7.49 (s, 1H), 7.30-7.39 (m, 2H), 6.8 8-7.00 (m, 3H), 6.76 (d, J=9.2Hz, 2H), 6.27 (s, 1H), 4.25-4.48 (m, 4H), 2.89 (s, 6H), 1.23 (br s, 3H), 1.16 (s, 3H).

[0360] MS measured value: 452.2 (M+1)

[0361] Example 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)

[0362] [Reaction formula 2-1]

[0363]

[0364] Step 1: Synthesis of (((4-methoxybenzyl)oxy)methyl)(methyl)sulfane (50-2)

[0365] 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. The mixture was cooled to 0°C, and the compound 50-1 (10.0 g, 72.4 mmol, 9.03 mL, 1 eq) of the above [Reaction Formula 2-1] was mixed, and the reactants were reacted at 25°C to 30°C. The mixture was stirred at 25°C to 30°C for 1 hour. Chloromethyl methyl sulfide (chloro(methylsulfanyl)methane, 6.99 g, 72.38 mmol, 6.06 mL, 1 eq) was added, and the mixture was reacted at 25°C to 30°C. Stirred for 12 hours at 25°C to 30°C under a nitrogen atmosphere. While DCM (0.5 mL) was added dropwise, TLC (PE / EA=3 / 1) confirmed the synthesis of the desired compound. The mixture was cooled at 0°C with NH4Cl (300 mL), diluted with water (100 mL), and extracted with EtOAc (100 mL×3). The organic layer was washed with brine (100 mL×2), dried with Na2SO4, and filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE:EA=50:1 to 10:1, P1=0.20) to obtain compound 50-2 (9.2 g, 46.40 mmol, yield: 64.11%) as a white oil.

[0366] Step 2: Synthesis of 1-((chloromethoxy)methyl)-4-methoxybenzene (50-3)

[0367] The compound 50-2 (500 mg, 2.52 mmol, 1 eq) was dissolved in DMF (1 mL), and then mixed with acetyl chloride (178 mg, 2.27 mmol, 161 uL, 0.9 eq), and stirred for 12 hours at 25°C to 30°C under a nitrogen environment. While DCM (1.00 mL) was added dropwise, the synthesis of the desired compound was confirmed by TLC (PE: EA = 5: 1). The mixture was concentrated under vacuum and extracted with EA (5 mL). Diluted with water (10 mL), extracted with EtOAc (10 mLX2), washed with water (10 mLX3) and dried with Na2SO4, and the mixture was filtered and concentrated under reduced pressure. Compound 50-3 (400 mg, 2.14 mmol, yield: 84.99%) was obtained as a white oil from the residue.

[0368] Step 3: Synthesis of 3-(furan-3-yl)-6-(((4-methoxybenzyl)oxy)methoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 50)

[0369] Compound 9-6 (60.0 mg, 207 umol, 1 eq) synthesized by the above Example 12 and NaH (5.97 g, 248 umol, 1.2 eq) were mixed in DMF (1 mL). The mixture 50-3 (77.4 mg, 414 umol, 2 eq) was added to DMF (0.2 mL) and added dropwise to the mixture. The mixture was stirred for 2 hours at 25°C to 30°C under a nitrogen environment. While a mixture of DCM (1.00 mL) and water (1.00 mL) was added dropwise, it was confirmed by TLC (PE: EA = 1: 1) that the reactant was completely consumed. The mixture was cooled at 0°C with NH4Cl (30 mL), diluted with water (10 mL), and extracted with EtOAc (10 mLX3). The organic layer was washed with brine (5.00 mLX2), dried with Na2SO4, and filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (SiO 2 , PE:EA=1:1) to obtain Compound 50 (11.0 mg, 34.9 umol, yield: 11.1%, purity: 92.1%) as a red solid.

[0370] 1 H NMR (400MHz, CHLOROFORM-d): δ8.50 (br s, 2H), 7.80 (s, 1H), 7.68 (br d, J=8.0Hz, 1H), 7.31-7.23 (m, 2H), 7.22-7.15 (m, 4H), 7.02 (dd, J=8.0, 2.4Hz, 1H), 6.81 (d, J=8.4Hz, 2H), 6.19 (d, J=1.2Hz, 1H), 5.23 (s, 2H), 4.59 (s, 2H), 3.73 (s, 3H)

[0371] MS found: 440.1[M+H] +

[0372] Example 26. 3-(5-methylthiazol-4-yl)-6-(3-morpholinopropoxy)-2-(pyridin-5-yl)-1H-inden-1-one (3-(5-methylthiazol-4-yl)-6-(3-morpholinopropoxy)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 4)

[0373] [Reaction 3]

[0374]

[0375] Step 1: Synthesis of (E)-1-(3-hydroxyphenyl)-3-(5-methylthiazol-4-yl)prop-2-en-1-one (4-3)

[0376] After mixing the compound 4-1 (500 mg, 3.93 mmol) of the above [Reaction Formula 3] and the compound 4-2 (535 mg, 3.93 mmol, 486 uL) of the above [Reaction Formula 3] in ethanol (5.00 mL), NaOH (235 mg, 5.90 mmol) was added to H2O (2.00 mL) under a nitrogen environment 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 had been synthesized. The mixture was adjusted to pH 7 with 1N HCl, the mixture was filtered and concentrated under vacuum to obtain compound 4-3 (700 mg, 2.85 mmol, yield: 72.5%) as a yellow solid.

[0377] Step 2: Synthesis of 6-hydroxy-3-(5-methylthiazol-4-yl)indan-1-one (4-4)

[0378] After dissolving compound 4-3 (700 mg, 2.85 mmol) in trifluoromethanesulfonic acid (10 mL), the mixture was stirred at 80 ° C for 16 hours. TLC (PE: EA = 1 / 1) confirmed that the reactant was completely consumed. Water (30.0 mL) was added to the mixture, and NaHCO3 aqueous solution was added to adjust the pH to 8. The mixture was filtered and concentrated under vacuum to obtain compound 4-4 (700 mg, 2.85 mmol, yield: 100%) as a brown solid.

[0379] Step 3: Synthesis of [1-(5-methylthiazol-4-yl)-3-oxo-indan-5-yl]acetate (4-5)

[0380] After compound 4-4 (200 mg, 815 umol) was dissolved in DCM (10.0 mL), Ac2O (416.18 mg, 4.08 mmol, 381.82 uL, 5 eq), pyridine (322 mg, 4.08 mmol, 329 uL, 5 eq) and DMAP (99.6 mg, 815 umol) were added at 0 ° C. The mixture was stirred at 20 ° C for 24 hours. 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 (30.0 mLX3). After drying with anhydrous Na2SO4, it was concentrated under vacuum to obtain a residue. The residue was purified by flash silica gel chromatography to obtain compound 4-5 (130 mg, 452 umol, yield: 55.4%) as a white solid.

[0381] Step 4: Synthesis of 2-bromo-1-(5-methylthiazol-4-yl)-3-oxo-inden-5-yl]acetate (4-6)

[0382] After mixing compound 4-5 (130 mg, 452 umol) and NBS (177 mg, 995 umol) in carbon tetrachloride (5.00 mL), AIBN (7.43 mg, 45.2 umol) was added under nitrogen. The reaction mixture was stirred at 80 ° C for 2 hours at 400 W. It was confirmed by TLC (PE: EA = 2 / 1) that the reactant was completely consumed. The mixture was diluted with DCM (100 ml) and extracted with brine (30 mLX3). After drying and filtering with anhydrous Na2SO4 and concentrating under vacuum, a brown oily compound 4-6 (200 mg) was obtained.

[0383] Step 5: Synthesis of 2-bromo-6-hydroxy-3-(5-methylthiazol-4-yl)inden-1-one (4-7)

[0384] After mixing compound 4-6 (200 mg, 549 umol) in DCM (4.00 mL), DBU (83.6 mg, 549 umol, 82.7 uL) was added. The mixture was stirred at 20 ° C for 12 hours. TLC (PE: EA = 1 / 1) confirmed that the reactant was completely consumed. The mixture was diluted with DCM (100 ml) and extracted with brine (30 mLX3). After drying and filtering with anhydrous Na2SO4, it was concentrated under vacuum to obtain a residue. The residue was purified by flash silica gel chromatography to obtain compound 4-7 (50.0 mg, 155 umol, yield: 28.26%) as a red oil.

[0385] Step 6: Synthesis of 2-bromo-3-(5-methylthiazol-4-yl)-6-(3-morpholinopropoxy)-1H-inden-1-one (Compound 5)

[0386] Compound 4-7 (50.0 mg, 155 umol) and 4-(3-chloropropyl)morpholine (30.5 mg, 186 umol, 61.7 uL) as RX in the above reaction formula 3 were mixed in acetonitrile (2.00 mL), and K2CO3 (64.3 mg, 465 umol) and KI (25.7 mg, 155 umol) were added. The mixture was stirred at 60°C for 2 hours. The reactants were completely consumed by LCMS, and compound 5 was synthesized by MS. The mixture was diluted with EtOAc (50.0 mL) and extracted with brine (10 mL×3). After drying and filtering with anhydrous Na2SO4, the residue was concentrated under vacuum to obtain a residue. The residue was purified by reverse-phase HPLC to obtain compound 5 (5.60 mg, 11.7 umol, yield: 7.58%) as a red solid.

[0387] Step 7: Synthesis of 3-(5-methylthiazol-4-yl)-6-(3-morpholinopropoxy)-2-(pyridin-5-yl)-1H-inden-1-one (Compound 4)

[0388] Compound 5 (30.0 mg, 66.7 umol) and pyridin-3-ylboronic acid (8.21 mg, 66.7 umol) as R1-B(OH)2 in the above [Reaction Formula 3] were mixed in dioxane (2.00 mL) and H2O (0.50 mL), and then K3PO4 (42.5 mg, 200 umol) and Pd(dtbpf)Cl2 (4.35 mg, 6.68 umol) were added under a nitrogen environment. The mixture was stirred at 100°C for 2 hours in a microwave. The reactants were completely consumed by LCMS, and compound 4 was confirmed to be synthesized by MS. The mixture was filtered and concentrated under vacuum to obtain a residue. The residue was purified by reverse-phase HPLC to obtain compound 4 (5.40 mg, 12.1 umol, yield: 18.0%) as a red solid.

[0389] 1 H NMR (400MHz, CD3OD): δ9.13 (s, 1H), 8.88 (s, 1H), 8.76 (d, J=6.0Hz, 1H), 8.38 (d, J=8.4Hz , 1H), 8.03 (dd, J=6.0, 8.4Hz, 1H), 7.29 (d, J=2.4Hz, 1H), 7.24 (d, J=8.0Hz, 1H), 7.06 (dd, J=2.54, 8.4Hz, 1H), 4.23 (t, J=5.6Hz, 2H), 4.06-4.11 (m, 2H), 3.83 (t, J=12.0Hz, 2H), 3.5 8(d, J=12.4Hz, 2H), 3.38-3.44(m, 2H), 3.17-3.26(m, 2H), 2.29-2.36(m, 2H), 2.24(s, 3H)

[0390] MS found: 448.0 [M+H] +

[0391] Example 27. 2-bromo-3-(5-methylthiazol-4-yl)-6-(3-morpholinopropoxy)-1H-inden-1-one (Compound 5)

[0392] In the above Example 26, Compound 5 was synthesized.

[0393] 1H NMR (400MHz, CD3OD): δ9.04 (s, 1H), 7.14 (d, J=2.4Hz, 1H), 6.95-7.01 (m, 1H), 6.89 (dd, J=2.4, 8.0Hz, 1H)), 4.09 (t, J=6.0Hz, 2H), 3.72 (t, J=4.8Hz, 4H), 2.52-2.65 (m, 9H), 1.96-2.08 (m, 2H)

[0394] MS found value: 448.9[M+H] +

[0395] Example 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)

[0396] Step 1: Synthesis of 2-bromo-3-(5-methylthiazol-4-yl)-6-(3-phenylpropoxy)-1H-inden-1-one (8-1)

[0397] After mixing compound 4-7 (100 mg, 1.00 eq) synthesized by the above Example 26 and (3-bromopropyl)benzene (88.0 mg, 1.5 eq) as RX in the above [Reaction Formula 3] in DMF (1.00 mL), K2CO3 (70.0 mg, 1.83 eq) and NaI (5.00 mg, 0.01 eq) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 40°C to 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, adjusted to pH 3 with 1M HCl, and then extracted with EtOAc (10.0 mLX3). The mixture was washed with brine (10.0 mL), dried with Na2SO4, and filtered and concentrated under reduced pressure at 45°C. The residue was purified by column chromatography (SiO 2 , PE / EA=50 / 1 to 20 / 1) to obtain compound 8-1 (78.0 mg, yield: 61.5%, purity: 97.4%) as a red gel.

[0398] Step 2: Synthesis of 3-(5-methylthiazol-4-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 8)

[0399] After mixing compound 8-1 (78.0 mg, 1.00 eq) and pyridin-3-ylboronic acid (32.0 mg, 1.5 eq) as R1-B(OH)2 in the above [reaction formula 3], K2CO3 (73.0 mg, 3.01 eq), Pd(t-Bu3P)2 (10.0 mg, 0.01 eq), dioxane (0.80 mL) and water (0.20 mL) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 80°C to 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 with Na2SO4, and concentrated organic phase residues were obtained under reduced pressure at 45°C. The residue was purified by prep-HPLC to obtain Compound 8 (21.0 mg, yield: 26.2%, purity: 94.2%) as a red colloid.

[0400] 1 H NMR (400MHz, DMSO-d6): δppm 9.23 (s, 1H), 8.72 (br d, J=4.8Hz, 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 (brt, J=6.0Hz, 2H), 2.75 (br t, J=7.6Hz, 2H), 2.07(s, 2H), 1.98(s, 3H)

[0401] MS found: 439.2[M+H] +

[0402] Example 29. 2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-phenethoxy-1H-inden-1-on (Compound 18)

[0403] Step 1: Synthesis of 2-bromo-3-(5-methylthiazol-4-yl)-6-phenethoxy-1H-inden-1-one (18-1)

[0404] After mixing compound 4-7 (1.5 g, 1.00 eq) synthesized by the above Example 26 and (2-bromoethyl)benzene (9.00 g, 6.58 mL, 11.0 eq) as RX in the above [Reaction Formula 3] in DMF (15.0 mL), K2CO3 (1.83 g, 3.00 eq) and NaI (133 mg, 0.20 eq) were added under a nitrogen environment at 15°C to 20°C. The mixture was stirred at 65°C to 70°C for 37 hours. The synthesis of the desired compound was confirmed by TLC (PE:EA=3:1). Water (45.0 mL) was added to the mixture at 15°C to 20°C for cooling, and diluted and extracted with EtOAc (40.0 mLX3). The mixture was washed with brine (40.0 mL), dried with Na2SO4, and filtered and concentrated under reduced pressure at 45°C. The residue was purified by column chromatography (SiO 2 , PE / EA=50 / 1 to 10 / 1) to give compound 18-1 as a red solid.

[0405] Step 2: Synthesis of 2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-phenethoxy-1H-inden-1-on (Compound 18)

[0406] After mixing compound 18-1 (100.0 mg, 1.00 eq) and (4-methoxyphenyl)boronic acid (67.0 mg, 2.05 eq) as R1-B(OH)2 in the above [reaction formula 3], K2CO3 (90.0 mg, 3.02 eq), Pd(t-Bu3P)2 (11.0 mg, 0.10 eq), dioxane (2.0 mL) and water (0.5 mL) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 80°C to 85°C for 19 hours. It was confirmed by LCMS that the reactants were completely consumed. Water (10.0 mL) was added to the mixture at 15°C to 20°C for cooling, and diluted and extracted with EtOAc (10.0 mLX3). The organic layer was washed with brine (10.0 mL), dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford compound 18 as a red solid.

[0407] 1 H NMR (400MHz, DMSO-d6): δppm 1.85 (s, 3H) 3.05 (t, J = 6.8Hz, 2H) 3.75 (s, 3H) 4.27 (t, J = 6.8Hz, 2H) 6.91 (d, J = 8.8Hz, 2H) 6.96 (dd, J = 8.0, 2.38Hz, 1 H) 7.06 (d, J = 8.0Hz, 1H) 7.09 (d, J = 2.4Hz, 1H) 7.13 (d, J = 8.8Hz, 2H) 7.21-7.25 (m, 1H) 7.31-7.35 (m, 4H) 9.17 (s, 1H)

[0408] MS found value: 454.2[M+H] +

[0409] Example 30. 2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-(4-phenylbutoxy)-1H-inden-1-one (Compound 19)

[0410] Step 1: Synthesis of 2-bromo-3-(5-methylthiazol-4-yl)-6-(4-phenylbutoxy)-1H-inden-1-one (19-1)

[0411] After mixing compound 4-7 (300 mg, 1.00 eq) synthesized by the above Example 26 and (4-bromobutyl)benzene (239 mg, 1.20 eq) as RX in the above [Reaction Formula 3] in DMF (3.00 mL), K2CO3 (194 mg, 1.51 eq) and NaI (28.0 mg, 0.02 eq) were added under nitrogen atmosphere at 20°C to 25°C. The mixture was stirred at 40°C to 45°C for 12 hours. Synthesis of the desired compound was confirmed by TLC (PE:EA=1:1). The mixture was diluted with water (20.0 mL), adjusted to pH 3 with 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 with Na2SO4, and filtered and concentrated under reduced pressure at 45°C. The residue was purified by column chromatography (SiO 2 , PE / EA=100 / 1 to 20 / 1) to obtain compound 19-1 (275 mg, yield: 64.0%, purity: 97.9%) as a red colloid.

[0412] Step 2: Synthesis of 2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-(4-phenylbutoxy)-1H-inden-1-one (Compound 19)

[0413] After mixing compound 19-1 (130 mg, 1.00 eq) and (4-methoxyphenyl)boronic acid (66.0 mg, 1.52 eq) as R1-B(OH)2 in the above [reaction formula 3], K2CO3 (118 mg, 3.01 eq), Pd(t-Bu3P)2 (15.0 mg, 0.10 eq), dioxane (0.8 mL) and water (0.2 mL) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 80°C to 85°C for 12 hours. LCMS confirmed 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 (10.0 mLX3). The organic layer was washed with brine (10.0 mL), dried with Na2SO4, and 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 colloid.

[0414] 1 H NMR (400MHz, DMSO-d6): δ9.11-9.23(m, 1H), 7.04-7.30(m, 9H), 6.85-6.97(m, 3H), 4.00-4.11(m, 2H), 3.75(s, 3H), 2.61-2.68(m, 2H), 1.85(s, 3H), 1.73(br s, 4H)

[0415] MS measured value: 482.2[M+H] +

[0416] Example 31. 6-((benzyloxy)methoxy)-2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-1H-inden-1-one (Compound 20)

[0417] Step 1: Synthesis of 6-((benzyloxy)methoxy)-2-bromo-3-(5-methylthiazol-4-yl)-1H-inden-1-one (20-1)

[0418] After mixing compound 4-7 (500 mg, 1.00 eq) synthesized by the above Example 26 and ((chloromethoxy)methyl)benzene (1.16 g, 5.02 eq) as RX in the above [Reaction Formula 3] in DMF (5.0 mL), K2CO3 (618 mg, 3.03 eq) and NaI (48 mg, 0.20 eq) were added under a nitrogen environment at 25°C. The mixture was stirred at 40°C to 45°C for 12 hours. The synthesis of the desired compound was confirmed by TLC (PE:EA=3:1). Water (5.00 mL) was added to the mixture, and extraction was performed with EtOAc (2 mLX1). Concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EA=20 / 1 to 10 / 1) to obtain compound 20-1 (300 mg, yield: 34.0%, purity: 74.4%) as a red solid.

[0419] Step 2: Synthesis of 6-((benzyloxy)methoxy)-2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-1H-inden-1-one (Compound 20)

[0420] After mixing compound 20-1 (100.0 mg, 1.00 eq) and (4-methoxyphenyl)boronic acid (52.0 mg, 1.51 eq) as R1-B(OH)2 in the above [reaction formula 3], K2CO3 (94.0 mg, 3.01 eq), Pd(t-Bu3P)2 (12.0 mg, 0.10 eq), dioxane (0.80 mL) and water (0.20 mL) were added under a nitrogen environment at 25°C. The mixture was stirred at 80°C to 85°C under a nitrogen environment for 12 hours. It was confirmed by LCMS that the reactants were completely consumed. The mixture was diluted by adding water (3.00 mL), extracted with EtOAc (1.00 mL), dried with Na2SO4, and 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 colloid.

[0421] 1 H NMR (400MHz, DMSO-d6): δ9.06-9.31 (m, 1H), 7.25-7.41 (m, 5H), 7.23 (s, 1H), 7.04-7 .18(m, 4H), 6.91(d, J=8.8Hz, 2H) 5.40(s, 2H), 4.70(s, 2H), 3.75(s, 3H), 1.86(s, 3H)

[0422] MS measured value: 470.1 (M+1)

[0423] Example 32. 2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-(2-phenoxyethoxy)-1H-inden-1-one (Compound 21)

[0424] Step 1: Synthesis of 2-bromo-3-(5-methylthiazol-4-yl)-6-(2-phenoxyethoxy)-1H-inden-1-one (21-1)

[0425] After mixing compound 4-7 (500 mg, 1.00 eq) synthesized by the above Example 26 and (2-bromoethoxy)benzene (1.78 g, 6.00 eq) as RX in the above [Reaction Formula 3] in DMF (5.00 mL), K2CO3 (306 mg, 1.50 eq) and NaI (45.0 mg, 0.20 eq) were added under a nitrogen environment at 15°C to 20°C. The mixture was stirred at 55°C to 60°C for 37 hours. The synthesis of the desired compound was confirmed by TLC (PE:EA=3:1). Water (20.0 mL) was added to the mixture at 15°C to 20°C for cooling, and diluted and extracted with EtOAc (20.0 mLX3). The organic layer was washed with brine (20 mL), dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , PE / EA=50 / 1 to 2 / 1) to give compound 21-1 as a red solid.

[0426] Step 2: 2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-(2-phenoxyethoxy)-1H-inden-1-one (Compound 21)

[0427] After mixing compound 21-1 (100.0 mg, 1.00 eq) and (4-methoxyphenyl)boronic acid (61.0 mg, 2.01 eq) as R1-B(OH)2 in the above [reaction formula 3], K2CO3 (83.0 mg, 3.01 eq), Pd(t-Bu3P)2 (11.0 mg, 0.10 eq), dioxane (1.6. mL) and water (0.40 mL) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 80°C to 85°C under a nitrogen environment 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°C to 20°C for cooling, and diluted and extracted with EtOAc (10.0 mLX3). The organic layer was washed with brine (10.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford Compound 21 as a red solid.

[0428] 1 H NMR (400MHz, DMSO-d6): δppm 1.85 (s, 3H) 3.05 (t, J = 6.8Hz, 2H) 3.75 (s, 3H) 4.27 (t, J = 6.8Hz, 2H) 6.91 (d, J = 8.8Hz, 2H) 6.96 (dd, J = 8.0, 2.4Hz, 1 H) 7.06 (d, J = 8.0Hz, 1H) 7.09 (d, J = 2.4Hz, 1H) 7.13 (d, J = 8.8Hz, 2H) 7.21-7.25 (m, 1H) 7.31-7.35 (m, 4H) 9.17 (s, 1H)

[0429] MS found: 454.2[M+H] +

[0430] Example 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)

[0431] Step 1: Synthesis of 2-bromo-6-(2-(3,4-dichlorophenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one (26-1)

[0432] After mixing compound 4-7 (0.50 g, 1.00 eq) synthesized by the above Example 26 and 4-(2-bromoethoxy)-1,2-dichlorobenzene (503 mg, 1.20 eq) as RX in the above [Reaction Formula 3] in DMF (5 mL), K2CO3 (322 mg, 1.50 eq) and NaI (47 mg, 2.02e-1 eq) were added under a nitrogen atmosphere. The mixture was stirred at 40°C to 45°C for 18 hours. The synthesis of the desired compound was confirmed by TLC (PE:EA=3:1). Water (20 mL) was added to the mixture, adjusted to pH 3 with 1M HCl, and then extracted with EtOAc (30 mLX3). The organic layer was washed with brine (30 mL), dried with Na2SO4, and filtered and concentrated under reduced pressure at 45°C. The residue was purified by column chromatography (SiO 2 , PE / EA=10 / 1 to 3 / 1) to obtain compound 26-1 (401 mg, yield: 43.3%, purity: 85.7%) as a red solid.

[0433] 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)

[0434] After mixing compound 26-1 (100 mg, 1.00 eq) and pyrimidin-5-ylboronic acid (37 mg, 1.53 eq) as R1-B(OH)2 in the above [reaction formula 3], K2CO3 (81.0 mg, 586.08 umol, 3 eq), Pd(t-Bu3P)2 (10 mg, 0.10 eq), dioxane (2 mL) and water (0.5 mL) were added under a nitrogen environment at 15°C to 25°C. The mixture was stirred for 12 hours at 80°C to 85°C under a nitrogen environment. The synthesis of the desired compound was confirmed by LCMS. Water (20 mL) was added to the mixture, and extracted with EtOAc (30 mL×3). The organic layer was washed with brine (30 mL), dried with Na2SO4, filtered and concentrated under reduced pressure at 45°C. The residue was purified by reverse-phase HPLC to obtain Compound 26 (17.04 mg, yield: 19.17%, purity: 95.2%) as an orange solid.

[0435] 1 H NMR (400MHz, DMSO-d6): δ9.22 (s, 1H), 9.10 (s, 1H), 8.60 (s, 2H), 7.54 (d, J=8.8Hz, 1H) , 7.32 (d, J=2.8Hz, 1H), 7.26-7.20 (m, 2H), 7.06 (ddd, J=2.8, 8.4, 17.2Hz, 2H), 4.41 (br dd, J=5.2, 14.4Hz, 4H), 2.00 (s, 3H)

[0436] MS measured value: 510.1 (M+1)

[0437] Example 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)

[0438] Step 1: Synthesis of 2-bromo-6-(2-(3,4-difluorophenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one (27-1)

[0439] After mixing compound 4-7 (1.00 g, 3.10 mmol, 1.00 eq) synthesized by the above Example 26 and 4-(2-bromoethoxy)-1,2-difluorobenzene (883 mg, 1.20 eq) as RX in the above [Reaction Formula 3] in DMF (10 mL), K2CO3 (644 mg, 1.50 eq) and NaI (94 mg, 0.20 eq) were added under a nitrogen environment. The mixture was stirred at 40°C to 45°C for 18 hours. The synthesis of the desired compound was confirmed by TLC (PE:EA=3:1). Water (20 mL) was added to the mixture, adjusted to pH 3 with 1M HCl, and then extracted with EtOAc (30 mLX3). The organic layer was washed with brine (30 mL), dried with Na2SO4, and filtered and concentrated under reduced pressure at 45°C. The residue was purified by column chromatography (SiO 2 , PE / EA=10 / 1 to 3 / 1) to obtain compound 27-1 (690 mg, yield: 42.8%, purity: 92.1%) as a red solid.

[0440] 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)

[0441] After mixing compound 27-1 (100 mg, 1.00 eq) and pyrimidin-5-ylboronic acid (39.0 mg, 1.51 eq) as R1-B(OH)2 in the above [reaction formula 3], K2CO3 (87.0 mg, 3.01 eq), Pd(t-Bu3P)2 (11 mg, 1.03e-1 eq), dioxane (2 mL) and water (0.5 mL) were added under a nitrogen environment at 15°C to 25°C. The mixture was stirred for 12 hours at 80°C to 85°C under a nitrogen environment. The synthesis of the desired compound was confirmed by TLC (PE:EA=1:1). Water (20 mL) was added to the mixture, and it was extracted with EtOAc (30 mLX3). The organic layer was washed with brine (30 mL), dried with Na2SO4, filtered and concentrated under reduced pressure at 45°C. The residue was purified by column chromatography (SiO 2 , PE / EA=10 / 1 to 2 / 1) to obtain Compound 27 (31.0 mg, yield: 28.5%, purity: 91.9%) as a brown-red solid.

[0442] 1 H NMR (400MHz, DMSO-d6): δ9.22 (s, 1H), 9.10 (s, 1H), 8.60 (s, 2H), 7.42-7.32 (m, 1H), 7.27-7.20 (m, 2H), 7.16 ( ddd, J=2.8, 6.8, 12.8Hz, 1H), 7.07 (dd, J=2.4, 8.0Hz, 1H), 6.87-6.80 (m, 1H), 4.46-4.31 (m, 4H), 2.00 (s, 3H)

[0443] MS measured value: 478.1 (M+1)

[0444] Example 35. 6-(2-(4-methoxyphenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one (Compound 32)

[0445] Step 1: Synthesis of 2-bromo-6-(2-(4-methoxyphenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one (32-1)

[0446] After mixing compound 4-7 (200 mg, 1.00 eq) synthesized by the above Example 26 and 1-(2-bromoethoxy)-4-methoxybenzene (1-(2-bromoethoxy)-4-methoxybenzene, 164 mg, 1.20 eq) as RX in the above [Reaction Formula 3] in DMF (1.00 mL), K2CO3 (124 mg, 1.52 eq) and NaI (19.0 mg, 0.02 eq) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 40°C to 45°C for 18 hours. The synthesis of the desired compound was confirmed by TLC (PE:EA=3:1). Water (10.0 mL) was added to the mixture, adjusted to pH 3 to 4 with 1M HCl, and then extracted with EtOAc (20.0 mLX2). After drying with Na2SO4, it was concentrated. The residue was purified by column chromatography (SiO 2 , PE / EA=30 / 1 to 3 / 1) to obtain compound 32-1 (199 mg, yield: 70%, purity: 100%) as a red solid.

[0447] Step 2: Synthesis of 6-(2-(4-methoxyphenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one (Compound 32)

[0448] After mixing compound 32-1 (90.0 mg, 1.00 eq) and (4-(trifluoromethyl)phenyl)boronic acid (54.0 mg, 1.49 eq) as R1-B(OH)2 in the above [reaction formula 3], K2CO3 (79.0 mg, 3.00 eq), Pd(t-Bu3P)2 (10.0 mg, 0.02 eq), dioxane (2.00 mL) and water (0.5 mL) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred and mixed for 8 hours at 80°C to 85°C under a nitrogen environment. The synthesis of the desired compound was confirmed by LCMS. Water (20 mL) was added to the mixture, and it was extracted with EtOAc (10.0 mLX2). The organic layer was washed with brine (10.0 mLX2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum conditions. The mixture was titrated with ACN / MeOH=5 / 1 (3.00 mL) at 20-25°C for 30 minutes, and the residue was obtained by filtration. Compound 32 (26.4 mg, yield: 24.54%, purity: 95.2%) was obtained from the residue as a red solid.

[0449] 1 H NMR (400MHz, DMSO-d6): δppm 9.21 (s, 1H), 8.40 (br d, J=6.0Hz, 2H), 7.72 (brd, J=8.0Hz, 2H), 7.40 (br d, J=8.0Hz, 2H), 7.12-7.29(m, 2H), 6.94-7.11(m, 3H), 4.44(s, 4H), 1.85(s, 3H).

[0450] MS measured value: 509.3 (M+1)

[0451] Example 36. 2-(4-fluorophenyl)-6-(2-(4-methoxyphenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one (Compound 22)

[0452] After mixing the compound 32-1 (100 mg, 1.00 eq) synthesized by the above-mentioned Example 35 and (4-fluorophenyl)boronic acid ((4-(trifluoromethyl)phenyl)boronic acid, 45.0 mg, 1.52 eq) as R1-B(OH)2 in the above-mentioned [reaction formula 3], K2CO3 (88.0 mg, 3.01 eq), Pd(t-Bu3P)2 (11.0 mg, 0.1 eq), dioxane (2 mL) and water (0.5 mL) were added under a nitrogen environment at 15°C to 20°C. The mixture was stirred for 14 hours at 80°C to 85°C under a nitrogen environment. The synthesis of the desired compound was confirmed by LCMS. Water (20 mL) was added to the mixture, and extraction was performed with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to obtain Compound 22 (12.05 mg, yield: 11.59%, purity: 99.3%) as a red solid.

[0453] 1 H NMR (400MHz, DMSO-d6): δppm 9.20(s, 1H), 7.18-7.24(m, 5H), 7.12-7.16(m, 1H), 7.01-7.06(m, 1H), 6.91-6.95(m, 2 H), 6.85-6.90 (m, 2H), 4.36-4.41 (m, 2H), 4.24-4.29 (m, 2H), 3.71 (s, 3H), 1.86 (s, 3H).

[0454] MS measured value: 488.3 (MS+1)

[0455] Example 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)

[0456] Step 1: Synthesis of 2-bromo-6-(2-(3,4-dimethoxyphenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one (33-1)

[0457] After mixing compound 4-7 (500 mg, 1.00 eq) synthesized by the above Example 26 and 4-(2-bromoethoxy)-1,2-dimethoxybenzene (4-(2-bromoethoxy)-1,2-dimethoxybenzene, 642 mg, 1.50 eq) as RX in the above [Reaction Formula 3] in DMF (5.00 mL), K2CO3 (306 mg, 1.50 eq) and NaI (44.0 mg, 0.02 eq) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 40°C to 45°C for 18 hours. The synthesis of the desired compound was confirmed by LCMS. Water (10.0 mL) was added to the mixture, adjusted to pH 3 to 4 with 1M HCl, and then extracted with EtOAc (20.0 mLX2). After drying with Na2SO4, it was concentrated. After the residue was purified by column chromatography (SiO 2 , EA / DCM=0 / 1 to 1 / 20), compound 33-1 (172 mg, yield: 22.0%, purity: 95.0%) was obtained as a red solid by concentration.

[0458] 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)

[0459] After mixing compound 33-1 (80.0 mg, 1.00 eq) and (4-(trifluoromethyl)phenyl)boronic acid (45.0 mg, 1.49 eq) as R1-B(OH)2 in the above [reaction formula 3], add K2CO3 (66.0 mg, 3.00 eq) dissolved in water (0.25 mL), Pd(t-Bu3P)2 (16.0 mg, 0.02 eq) and dioxane (1.00 mL) at 20°C to 25°C in a nitrogen environment. Stir and mix for 8 hours at 80°C to 85°C in a nitrogen environment. The synthesis of the desired compound was confirmed by LCMS. Water (20.0 mL) was added to the mixture, and extracted with EtOAc (10.0 mLX2). The organic layer was washed with brine (10.0 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by reverse-phase HPLC under 0.10% HCl to give compound 33 (17.3 mg, yield: 18.6%, purity: 97.4%) as a red solid.

[0460] 1 H NMR (400MHz, DMSO-d6): δppm 9.21 (s, 1H), 7.72 (d, J = 8.4Hz, 2H), 7.41 (d, J = 8.0Hz, 2H), 7.15-7.25 (m, 2H), 7.06 (dd, J = 8.4, 2.4Hz, 1H), 6.86 (d, J = 9.2Hz, 1H), 6.62 (d, J=2.8Hz, 1H), 6.48 (dd, J=8.8, 3.2Hz, 1H), 4.40 (dd, J=5.6, 2.8Hz, 2H), 4.20-4.33 (m, 2H), 3.74 (s, 3H), 3.69 (s, 3H), 1.85 (s, 3H).

[0461] MS measured value: 568.3 (M+1)

[0462] Example 38. 6-(2-(3,4-dimethoxyphenoxy)ethoxy)-2-(4-fluorophenyl)-3-(5-methylthiazol-4-yl)-1H-inden-1-one (Compound 23)

[0463] After mixing the compound 33-1 (80 mg, 1.00 eq) synthesized by the above-mentioned Example 37 and (4-fluorophenyl)boronic acid ((4-(trifluoromethyl)phenyl)boronic acid, 34.0 mg, 1.53 eq) as R1-B(OH)2 in the above-mentioned [reaction formula 3], K2CO3 (67.0 mg, 3.04 eq), Pd(t-Bu3P)2 (10.0 mg, 0.12 eq), dioxane (2 mL) and water (0.5 mL) were added under a nitrogen environment at 15°C to 20°C. The mixture was stirred for 14 hours at 80°C to 85°C under a nitrogen environment. The synthesis of the desired compound was confirmed by LCMS. Water (20 mL) was added to the mixture, and extraction was performed with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain Compound 23 (13.60 mg, purity: 95.4%) as a red solid.

[0464] 1 H NMR (400MHz, DMSO-d6): δppm 9.20 (s, 1H), 7.17-7.27 (m, 5H), 7.15 (d, J=8.0Hz, 1H), 7.04 (dd, J=8.0, 2.4Hz, 1H), 6.86 (d, J=8.8Hz, 1H), 6.63 (d, J=2.4Hz, 1H), 6.49 (dd, J=8.8, 2.75Hz, 1H), 4.38 (br d, J=4.4Hz, 2H), 4.27 (br d, J=2.4Hz, 2H), 3.74 (s, 3H), 3.69 (s, 3H), 1.86 (s, 3H)

[0465] MS measured value: 518.3 (MS+1)

[0466] Example 39. 6-(2-(Benzo[d][1,3]dioxol-5-yloxy)ethoxy)-3-(5-methylthiazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one (Compound 34)

[0467] 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)

[0468] Compound 4-7 (200 mg, 1.00 eq) synthesized by Example 26 above and 5-(2-bromoethoxy)benzo[d][1,3]dioxole (173 mg, 1.19 eq) as RX in the above [Reaction Formula 3] were mixed in DMF (1.00 mL), and K2CO3 (124 mg, 1.52 eq) and NaI (18.0 mg, 0.02 eq) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 40°C to 45°C for 18 hours. The synthesis of the desired compound was confirmed by TLC (PE / EA=3 / 1). Water (10.0 mL) was added to the mixture, adjusted to pH 3 to 4 with 1M HCl, and then extracted with EtOAc (20.0 mLX2). After drying with Na2SO4, it was concentrated. The residue was purified by column chromatography (SiO 2 , PE / EA=30 / 1 to 3 / 1) and concentrated to obtain compound 34-1 (150 mg, yield: 48.0%, purity: 91.8%) as a red solid.

[0469] 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)

[0470] After mixing compound 34-1 (40.0 mg, 1.00 eq) and (4-(trifluoromethyl)phenyl)boronic acid (24.0 mg, 1.54 eq) as R1-B(OH)2 in the above [reaction formula 3], add K2CO3 (34.0 mg, 2.99 eq) dissolved in water (0.25 mL), Pd(t-Bu3P)2 (5.00 mg, 0.02 eq) and dioxane (1.00 mL) at 20°C to 25°C in a nitrogen environment. Stir and mix for 8 hours at 80°C to 85°C in a nitrogen environment. The synthesis of the desired compound was confirmed by LCMS. Water (20.0 mL) was added to the mixture, and it was extracted with EtOAc (10.0 mLX2). The organic layer was washed with brine (10.0 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by reverse-phase HPLC under 0.10% HCl to give compound 34 (24.1 mg, yield: 53.1%, purity: 99.6%) as a red solid.

[0471] 1 H NMR (400MHz, DMSO-d6): δppm 9.21 (s, 1H), 7.72 (d, J = 8.4Hz, 2H), 7.41 (d, J = 8.0Hz, 2H), 7.15-7.25 (m, 2H), 7.06 (dd, J = 8.4, 2.4Hz, 1H), 6.86 (d, J = 9.2Hz, 1H), 6.62 (d, J=2.8Hz, 1H), 6.48 (dd, J=8.8, 3.2Hz, 1H), 4.40 (dd, J=5.6, 2.8Hz, 2H), 4.20-4.33 (m, 2H), 3.74 (s, 3H), 3.69 (s, 3H), 1.85 (s, 3H).

[0472] MS measured value: 552.3 (M+1)

[0473] Example 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)

[0474] After mixing the compound 34-1 (90.0 mg, 1.00 eq) synthesized by the above-mentioned Example 39 and (4-fluorophenyl)boronic acid ((4-(trifluoromethyl)phenyl)boronic acid, 40.0 mg, 1.54 eq) as R1-B(OH)2 in the above-mentioned [reaction formula 3], K2CO3 (78.0 mg, 3.05 eq), Pd(t-Bu3P)2 (10.0 mg, 0.1 eq), dioxane (2 mL) and water (0.5 mL) were added under a nitrogen environment at 15°C to 20°C. The mixture was stirred at 80°C to 85°C under a nitrogen environment for 14 hours. The synthesis of the desired compound was confirmed by LCMS. Water (20 mL) was added to the mixture, and extraction was performed with EtOAc. The organic layer was washed with brine, dried over Na2SO4, 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.

[0475] 1 H NMR (400MHz, DMSO-d6): δppm 9.20 (s, 1H), 7.17-7.24 (m, 5H), 7.14 (d, J=8.0Hz, 1H), 7.03 (dd, J=8.0, 2.4Hz, 1H), 6.83 (d, J=8.4Hz, 1H), 6 .69 (d, J=2.8Hz, 1H), 6.43 (dd, J=8.8, 2.8Hz, 1H), 5.97 (s, 2H), 4.37 (m, 2H), 4.23-4.28 (m, 2H), 1.86 (s, 3H)

[0476] MS measured value: 502.2 (MS+1)

[0477] Example 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)

[0478] Step 1: Synthesis of 2-bromo-6-(2-((t-butyldimethylsilyl)oxy)ethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one (35-1)

[0479] After mixing compound 4-7 (1.00 g, 1.00 eq) synthesized by Example 26 above and (2-bromoethoxy)(tert-butyl)dimethylsilane (1.06 g, 1.50 eq) in DMF (10.0 mL), K2CO3 (613 mg, 1.50 eq) and NaI (89.0 mg, 0.02 eq) were added under a nitrogen environment at 20°C to 25°C. The mixture was stirred at 40°C to 45°C for 18 hours. The synthesis of the desired compound was confirmed by LCMS. Water (50.0 mL) was added to the mixture, adjusted to pH 3 to 4 with 1M HCl, and then extracted with EtOAc (50.0 mLX2). After drying with Na2SO4, it was concentrated. The residue was purified by column chromatography (SiO 2 , PE / EA=30 / 1 to 3 / 1) and concentrated to obtain compound 35-1 (723 mg, yield: 50.9%) as a red solid.

[0480] Step 2: Synthesis of 2-bromo-6-(2-hydroxyethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one (Compound 35-2)

[0481] Compound 35-1 (723 mg, 1.00 eq) and HCl (2.00 M, 1.50 mL, 2.00 eq) were placed in THF (4.00 mL) and stirred at 20°C to 25°C for 12 hours. The synthesis of the desired compound was confirmed by TLC (PE / EA=1 / 1). Water (10.0 mL) was added to the mixture, and the pH was adjusted to 8 to 9 with NaHCO3, 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.

[0482] Step 3: Synthesis of 6-(2-hydroxyethoxy)-3-(5-methylthiazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one (Compound 35-3)

[0483] After mixing compound 35-2 (270 mg, 1.00 eq) and (4-(trifluoromethyl)phenyl)boronic acid (210 mg, 1.50 eq) as R1-B(OH)2 in the above [reaction formula 3], add K2CO3 (307 mg, 3.01 eq) dissolved in water (0.7 mL), Pd(t-Bu3P)2 (75.0 mg, 0.02 eq) and dioxane (2.70 mL) at 20°C to 25°C in a nitrogen environment. Stir and mix for 8 hours at 80°C to 85°C in a nitrogen environment. The synthesis of the desired compound was confirmed by TLC. Water (20.0 mL) was added to the mixture, and extracted with EtOAc (10.0 mLX2). The organic layer was washed with brine (10.0 mLX2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO 2 , PE / EA=10 / 1 to 0 / 1) and concentrated to obtain compound 35-3 (219 mg, yield: 62.4%, purity: 90.6%) as a red solid.

[0484] Step 4: Synthesis of 3-(5-methylthiazol-4-yl)-6-(2-(pyridin-4-yloxy)ethoxy)-2-(4-(trifluoromethyl)phenyl)-1H-inden-1-one (Compound 35)

[0485] After mixing compound 35-3 (110 mg, 1.00 eq) and 4-hydroxypyridine (pyridin-4-ol, 29.0 mg, 1.50 eq) (replacing RX in the above [reaction formula 3]) in DCM (0.50 mL), PPh3 (118 mg, 1.76 eq) was added under a nitrogen environment at 20°C to 25°C. The mixture was cooled to 0°C to 5°C, DIAD (91.0 mg, 1.77 eq) was added, and stirred for 2 hours under a nitrogen environment. The synthesis of the desired compound was confirmed by TLC (PE / EA=1 / 2). Water (20.0 mL) was added to the mixture, and extracted with EtOAc (50.0 mLX3). After drying with Na2SO4, it was concentrated. The residue was purified by prep-TLC (EA:THF=1:1) and titrated into 3 mL of PE / MTBE=10 / 1 at 20°C to 25°C for 30 minutes. Filtration and concentration gave compound 35 as an orange solid.

[0486] 1 H NMR (400MHz, DMSO-d6): δppm 9.21 (s, 1H), 8.40 (br d, J=6.0Hz, 2H), 7.72 (brd, J=8.0Hz, 2H), 7.40 (br d, J=8.0Hz, 2H), 7.12-7.29(m, 2H), 6.94-7.11(m, 3H), 4.44(s, 4H), 1.85(s, 3H).

[0487] MS measured value: 509.3 (M+1)

[0488] Example 42. 2-(4-fluorophenyl)-3-(5-methylthiazol-4-yl)-6-(2-(pyridin-4-yloxy)ethoxy)-1H-inden-1-one (Compound 25)

[0489] Step 1: Synthesis of 2-(4-fluorophenyl)-6-(2-hydroxyethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one (25-1)

[0490] After mixing the compound 35-2 (250 mg, 1.00 eq) synthesized by the above-mentioned Example 41 and (4-fluorophenyl)boronic acid ((4-(trifluoromethyl)phenyl)boronic acid, 146 mg, 1.53 eq) as R1-B(OH)2 in the above-mentioned [reaction formula 3], K2CO3 (287 mg, 3.04 eq) was dissolved in water (1 mL) solution, Pd(t-Bu3P)2 (43.0 mg, 0.12 eq) and dioxane (4 mL) were added at 15°C to 20°C in a nitrogen environment. The mixture was stirred at 80°C to 85°C for 14 hours in a nitrogen environment. The synthesis of the desired compound was confirmed by LCMS. Water (20.0 mL) was added to the mixture and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , PE / EA=10 / 1 to 3 / 1) and concentrated to obtain compound 25-1 (103 mg, yield: 35.9%, purity: 90.8%) as a red solid.

[0491] Step 2: Synthesis of 2-(4-fluorophenyl)-3-(5-methylthiazol-4-yl)-6-(2-(pyridin-4-yloxy)ethoxy)-1H-inden-1-one (Compound 25)

[0492] After mixing compound 25-1 (100.0 mg, 1.00 eq) and 4-hydroxypyridine (pyridin-4-ol, 25.0 mg, 1.00 eq) (replacing RX in the above [reaction formula 3]) in THF (5 mL), PPh3 (103 mg, 1.50 eq) and DIAD (80.0 mL, 1.51 eq) were added under a nitrogen environment at 0°C to 10°C. The mixture was stirred for 14 hours at 15°C to 25°C under a nitrogen environment. The synthesis of the desired compound was confirmed by LCMS. Water (20.0 mL) was added to the mixture and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. After drying over Na2SO4, it was concentrated. The residue was purified by column chromatography (SiO 2 , PE / EA=10 / 1 to 3 / 1) to obtain Compound 25 (27.58 mg, yield: 20.72%, purity: 90.3%) as a red colloid.

[0493] 1H NMR (400MHz, DMSO-d6): δppm 9.20 (s, 1H), 8.39-8.43 (m, 2H), ppm 7.13-7.25 (m, 6H), 7.02-7.06 (m, 3H), 4.44 (s, 4H), 1.87 (s, 3H)

[0494] MS measured value: 459.1 (MS+1)

[0495] Example 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)

[0496] After mixing the compound 18-1 (150 mg, 1.00 eq) synthesized by the above-mentioned Example 29 and tributyl (2-thienyl) stannane (tributyl (thiophen-2-yl) stannane, 157 mg, 1.30 eq) (replacing R1-B (OH) 2 in the above-mentioned [reaction formula 3]), add it to Pd2 (dba) 3 (60.0 mg, 0.20 eq) and dioxane (4.00 mL) under a nitrogen environment at 20°C to 25°C. Stir the mixture for 2 hours at 115°C to 120°C under a nitrogen environment. It was confirmed by LCMS that the reactants were completely consumed. Water (15.0 mL) was added to the mixture at 15°C to 20°C for cooling, and extracted with EtOAc (15.0 mLX3). The organic layer was washed with brine (15.0 mL), dried with Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to afford compound 28 as a dark brown solid.

[0497] 1 H NMR (400MHz, DMSO-d6): δppm 2.17 (s, 3H) 3.04 (t, J = 6.8Hz, 2H) 4.26 (t, J = 6.8Hz, 2H) 6.85-6.89 (m, 1H) 6. 92-6.96(m,1H)7.04-7.10(m,2H)7.26-7.36(m,6H)7.56(m,1H)9.21(s,1H)

[0498] MS found: 430.1[M+H] +

[0499] Example 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)

[0500] After mixing the compound 19-1 (50.0 mg, 1.00 eq) synthesized by the above-mentioned Example 30 and tributyl (2-thienyl) stannane (tributyl (thiophen-2-yl) stannane, 55.0 mg, 1.31 eq) (replacing R1-B (OH) 2 of the above-mentioned [reaction formula 3]), it was added to Pd2 (dba) 3 (20.0 mg, 0.02 eq) and dioxane (1.50 mL) under a nitrogen environment at 25°C to 30°C. The mixture was stirred at 115°C to 120°C for 2 hours in a microwave. It was confirmed by LCMS that the reactants were completely consumed. Water (10.0 mL) was added to the mixture at 15°C to 20°C, and extracted with EtOAc (10.0 mLX3). The organic layer was washed with brine (10.0 mL), dried with Na2SO4, and 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.

[0501] 1 H NMR (400MHz, DMSO-d6): δ9.22 (s, 1H), 7.55-7.57 (m, 1H), 7.18-7.31 (m, 6H), 7.05-7.10 (m, 2H), 6.85-6.94(m, 2H), 4.03-4.07(m, 2H), 2.62-2.67(m, 2H), 2.18(s, 3H), 1.70-1.75(m, 4H)

[0502] MS found value: 458.1[M+H] +

[0503] Example 45. 6-((benzyloxy)methoxy)-3-(5-methylthiazol-4-yl)-2-(thiophen-2-yl)-1H-inden-1-one (Compound 30)

[0504] After mixing the compound 20-1 (100 mg, 1.00 eq) synthesized by the above-mentioned Example 31 and tributyl (2-thienyl) stannane (tributyl (thiophen-2-yl) stannane, 110 mg, 1.30 eq) (replacing R1-B (OH) 2 in the above-mentioned [reaction formula 3]), add it to Pd2 (dba) 3 (42.0 mg, 0.20 eq) and dioxane (1.00 mL) under a nitrogen environment at 20° C. to 25° C. The mixture was stirred for 2 hours at 120° C. under a nitrogen environment. It was confirmed by LCMS that the reactants were completely consumed. Water (3.0 mL) was added to the mixture, and it was extracted with EtOAc (1.0 mL×1). It was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to obtain Compound 30 (51.82 mg, yield: 51.0%, purity: 99.3%) as a purple solid.

[0505] 1 H NMR (400MHz, DMSO-d6): δ9.23 (s, 1H), 7.58 (dd, J=5.2, 1.2Hz, 1H), 7.26-7.39 (m, 6H), 7.23 (d, J= 2.4Hz, 1H), 7.02-7.14 (m, 2H), 6.91 (d, J=8.0Hz, 1H), 5.40 (s, 2H), 4.70 (s, 2H), 2.12-2.28 (m, 3H)

[0506] MS measured value: 446.0 (M+1)

[0507] Example 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)

[0508] After mixing the compound 21-1 (150 mg, 1.00 eq) synthesized by the above-mentioned Example 32 and tributyl (2-thienyl) stannane (tributyl (thiophen-2-yl) stannane, 146 mg, 1.30 eq) (replacing R1-B (OH) 2 in the above-mentioned [reaction formula 3]), add it to Pd2 (dba) 3 (55.0 mg, 0.20 eq) and dioxane (4.50 mL) under a nitrogen environment at 20°C to 25°C. Stir the mixture for 2 hours at 115°C to 120°C under a nitrogen environment. It was confirmed by LCMS that the reactants were completely consumed. Water (15.0 mL) was added to the mixture at 15°C to 20°C for cooling, and extracted with EtOAc (15.0 mLX3). The organic layer was washed with brine (15.0 mL), dried with Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to afford compound 31 as a dark brown solid.

[0509] 1 H NMR (400MHz, DMSO-d6): δppm 2.19 (s, 3H) 4.29-4.34 (m, 2H) 4.40 (dd, J = 5.6, 2.8Hz, 2H) 6.89-7.02 (m, 5H) 7.07 (m , 1H) 7.17 (d, J = 2.4Hz, 1H) 7.27-7.33 (m, 3H) 7.57 (dd, J = 5.2, 1.2Hz, 1H) 9.23 (s, 1H)

[0510] MS found: 446.0 [M+H] +

[0511] Example 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)

[0512] After mixing the compound 26-1 (100 mg, 1.00 eq) synthesized by the above-mentioned Example 33 and tributyl (2-thienyl) stannane (tributyl (thiophen-2-yl) stannane, 96 mg, 1.32 eq) (replacing R1-B (OH) 2 in the above-mentioned [reaction formula 3]), add it to Pd2 (dba) 3 (36.0 mg, 39.31 umol, 0.20 eq) and dioxane (3 mL) under a nitrogen environment at 15°C to 25°C. Stir the mixture by microwave for 2 hours at 145°C to 150°C under a nitrogen environment. The synthesis of the desired compound was confirmed by LCMS. Water (20 mL) was added to the mixture, and it was extracted with EtOAc (30 mLX3). The organic layer was washed with brine (30 mL), dried with Na2SO4, filtered and concentrated under reduced pressure at 45°C to obtain a residue. The residue was purified by reverse-phase HPLC to obtain Compound 36 (50.2 mg, yield: 49.5%, purity: 99.4%) as a dark purple solid.

[0513] 1 H NMR (400MHz, DMSO-d6): δ9.23 (s, 1H), 7.64-7.48 (m, 2H), 7.36-7.25 (m, 2H), 7.16 (d, J=2.4Hz, 1H), 7.09-6.97 (m, 3H), 6.90 (d, J=8.0Hz, 1H), 4.38 (br d, J=2.8Hz, 4H), 2.19 (s, 3H)

[0514] MS measured value: 514.0 (M+1)

[0515] Example 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)

[0516] After mixing the compound 27-1 (100 mg, 1.00 eq) synthesized by the above-mentioned Example 34 and tributyl (2-thienyl) stannane (tributyl (thiophen-2-yl) stannane, 103 mg, 1.32 eq) (replacing R1-B (OH) 2 in the above-mentioned [reaction formula 3]), add it to Pd2 (dba) 3 (39 mg, 0.20 eq) and dioxane (3 mL) under a nitrogen environment at 15°C to 25°C. Stir the mixture by microwave for 2 hours at 145°C to 150°C under a nitrogen environment. The synthesis of the desired compound was confirmed by LCMS. Water (20 mL) was added to the mixture, and it was extracted with EtOAc (30 mLX3). The organic layer was washed with brine (30 mL), dried with Na2SO4, filtered and concentrated under reduced pressure at 45°C to obtain a residue. The residue was purified by reverse-phase HPLC to obtain Compound 37 (30.4 mg, yield: 29.9%, purity: 99.0%) as a dark purple solid.

[0517] 1 H NMR (400MHz, DMSO-d6): δ9.22 (s, 1H), 9.10 (s, 1H), 8.60 (s, 2H), 7.42-7.32 (m, 1H), 7.27-7.20 (m, 2H), 7.16 ( ddd, J=2.8, 6.8, 12.8Hz, 1H), 7.07 (dd, J=2.4, 8.0Hz, 1H), 6.87-6.80 (m, 1H), 4.46-4.31 (m, 4H), 2.00 (s, 3H)

[0518] MS measured value: 478.1 (M+1)

[0519] Example 49. 6-(3-phenylpropoxy)-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one (Compound 6)

[0520] [Reaction 4]

[0521]

[0522] Step 1: Synthesis of 3-(thiophen-2-ylethynyl)pyridine (6-3)

[0523] After mixing the compound 6-1 (1.70 g, 8.08 mmol, 823 uL) of the above [reaction formula 4], pyridine as R1 in the above [reaction formula 4], and 3-ethynylpyridine (3-ethynylpyridine, 1.00 g, 9.70 mmol, 558 uL) as compound 6-2 (A) in THF (10.0 mL), Et3N (2.45 g, 24.2 mmol, 3.37 mL), CuI (769 mg, 4.04 mmol) and PdCl2 (567 mg, 808 umol) were added under nitrogen environment at 25°C. The mixture was stirred at 25°C for 12 hours. The synthesis of compound 6-3 was confirmed by LCMS, and the complete consumption of the reactant was confirmed by TLC (PE: EA = 3 / 1). The residue was diluted with EtOAc (200 mL). The combined organic phase layer was extracted with brine (20 mLX3). After drying with anhydrous Na2SO4 and filtering, the residue was concentrated under low pressure. 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 compound 6-3 as a yellow oil.

[0524] Step 2: Synthesis of 6-methoxy-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one (6-5)

[0525] After mixing 3-(thiophene-2-ylethynyl)pyridine (600 mg, 3.24 mmol) of compound 6-3 synthesized by the above step 1 and compound 6-4A (2.03 g, 6.48 mmol) in dioxane (5.00 mL), TBAB (1.04 g, 3.24 mmol), Na2CO3 (686 mg, 6.48 mmol) and PdCl2 (57.4 mg, 323 umol) were added at 25°C under a carbon monoxide (15 psi) environment. The mixture was stirred at 100°C for 12 hours. It was confirmed by TLC (PE:EA=1 / 1) 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). After drying and filtering with anhydrous Na2SO4, it was concentrated under low pressure to obtain a residue. The residue was purified by flash silica gel chromatography and then purified by prep-HPLC to obtain compound 6-5 (6-methoxy-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-on, 100 mg, 313 umol, yield: 9.67%) as a red solid and 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 umol, yield: 13.53%) as a purple solid as compound 6-5 (B).

[0526] Step 3: Synthesis of 6-hydroxy-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one (6-6)

[0527] After mixing 6-methoxy-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one (70.0 mg, 219.18 umol) as compound 6-5 in DCM (2.00 mL), BBr3 (55.0 mg, 219 umol, 21.1 uL) was added under nitrogen atmosphere at 0°C. The mixture was stirred at 25°C for 12 hours. TLC (PE:EA=1 / 1) confirmed that the reactant was completely consumed. The reaction mixture was cooled with aqueous NaHCO3 (10.0 mL) and no additional work up was performed, thereby obtaining compound 6-6 (6-hydroxy-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one; 6-hydroxy-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one, 150 mg) as a red oil.

[0528] Step 4: Synthesis of 6-(3-phenylpropoxy)-2-(pyridin-3-yl)-3-(thiophen-2-yl)-1H-inden-1-one (Compound 6)

[0529] After mixing 6-hydroxy-2-(pyridin-3-yl)-3-(thiophene-2-yl)-1H-indene-1-one (70.0 mg, 229 umol) as compound 6-6 and (3-bromopropyl)benzene (68.5 mg, 343 umol, 51.8 uL) as RX in the above [reaction formula 4] in acetonitrile (3.00 mL), K2CO3 (79.2 mg, 573 umol) was added under nitrogen environment 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). After drying and filtering with anhydrous Na2SO4, it was concentrated under low pressure to obtain a residue. The residue was purified by prep-HPLC to obtain Compound 6 (5.00 mg, 11.6 umol, yield: 5.05%, purity: 98.15%) as a red solid.

[0530] 1H NMR (400MHz, CD3OD): δ8.53-8.56 (m, 2H), 7.97-8.0 (m, 1H), 7.74 (dd, J=8.0, 5.2Hz, 1H), 7.59-7.62 (m, 1H), 7.48-7.55 (m, 2H), 7.15-7.33 (m, 7H), 6.97 (dd, J=2.4, 8.0Hz, 1H), 4.04 (t, J=6.0Hz, 2H), 2.82 (t, J=7.6Hz, 2H), 2.04-2.18 (m, 2H)

[0531] MS found: 424.1[M+H] +

[0532] Example 50. 6-(3-phenylpropoxy)-3-(1H-pyrazol-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 7)

[0533] [Reaction 5]

[0534]

[0535] Step 1: Synthesis of (E)-1-(3-hydroxyphenyl)-3-(1H-pyrazol-5-yl)prop-2-en-1-one (7-3)

[0536] After mixing the compound 7-1 (5.00 g, 52.0 mmol) of the [reaction formula 5] and the compound 7-2 (7.08 g, 52.0 mmol) of the [chemical formula 5] in ethanol (75.0 mL), NaOH (3.12 g, 78.05 mmol) was added to H2O (30.0 mL) at 0°C. The reaction mixture was stirred at 25°C for 16 hours. It was confirmed by TLC (PE: EA = 3 / 1) that the reactant was completely consumed. The residue was diluted with H2O (50 ml) and extracted with EtOAc (50.0 mLX2). The combined organic phase layer was extracted with brine (50 mLX2). After drying and filtering with Na2SO4, it was concentrated under low pressure to obtain a residue. The residue was purified by column chromatography (SiO2, PE / EA = 1 / 0 to 3 / 1) to obtain compound 7-3 (1.25 g) as a yellow solid.

[0537] Step 2: Synthesis of 6-hydroxy-3-(1H-pyrazol-5-yl)-2,3-dihydro-1H-inden-1-one (7-4)

[0538] After mixing compound 7-3 (1.10 g, 5.13 mmol) in trifluoromethanesulfonic acid (10.0 mL), the mixture was stirred at 80 ° C for 16 hours. It was confirmed by TLC (PE: EA = 1 / 1) that the reactant was completely consumed. The residue was diluted with H2O (50.0 ml) and extracted with EtOAc (50.0 mLX2). The combined organic phase layer was extracted with brine (50.0 mLX2). After drying and filtering with Na2SO4, it was concentrated under low pressure to obtain a residue. The residue was purified by column chromatography (SiO2, PE / EA = 1 / 0 to 1 / 1) to obtain compound 7-4 (0.80 g, 3.73 mmol, yield: 72.7%) as a dark brown solid.

[0539] Step 3: Synthesis of [1-(1-acetylpyrazol-3-yl)-3-oxo-indan-5-yl]acetate (7-5)

[0540] After mixing compound 7-4 (500 mg, 2.33 mmol) and Ac2O (1.19 g, 11.6 mmol) in DCM (10 mL), pyridine (923 mg, 11.6 mmol) and DMAP (285 mg, 2.33 mmol) were added under nitrogen environment at 0 ° C. The mixture was stirred at 20 ° C for 12 hours. It was confirmed by TLC (PE: EA = 1 / 1) that the reactant was completely consumed. The reaction mixture was diluted with DCM (100 ml) and extracted with brine (30.0 mLX3). After drying with anhydrous Na2SO4, it was concentrated under vacuum to obtain a residue. The residue was purified by flash silica gel chromatography to obtain compound 7-5 (540 mg, 1.81 mmol, yield: 77.5%) as a yellow solid.

[0541] Step 4: Synthesis of [1-(1-acetylpyrazol-3-yl)-2-bromo-3-oxo-inden-5-yl]acetate (7-6)

[0542] After dissolving compound 7-5 (540 mg, 1.81 mmol) and NBS (708 mg, 3.98 mmol) in carbon tetrachloride (10.0 mL), AIBN (29.7 mg, 181 umol) was added under nitrogen. The mixture was stirred at 80 ° C for 2 hours at 400 W. TLC (PE: EA = 1 / 1) confirmed that the reactant was completely consumed. The mixture was diluted with DCM (100 ml) and extracted with brine (30.0 mL x 3). After drying and filtering with anhydrous Na2SO4 and concentrating under vacuum, compound 7-6 (800 mg) was obtained as a brown oil.

[0543] Step 5: Synthesis of 3-(1-acetylpyrazol-3-yl)-2-bromo-6-hydroxy-inden-1-one (7-7)

[0544] 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 hours. TLC (PE: EA = 2 / 1) confirmed that the reactant was completely consumed. Adjust to pH 6 with 1N HCl, and then extract with DCM (50.0 mLX3). Dry and filter the combined organic phase layer with anhydrous Na2SO4, and then concentrate under vacuum to obtain a residue. The residue was purified by flash silica gel chromatography to obtain compound 7-7 (40.0 mg, 120 umol, yield: 5.63%) as a red solid.

[0545] Step 6: Synthesis of 3-(1-acetyl-1H-pyrazol-3-yl)-2-bromo-6-(3-phenylpropoxy)-1H-inden-1-one (Compound 7-8)

[0546] After mixing compound 7-7 (40.0 mg, 120 umol) and (3-bromopropyl)benzene (35.8 mg, 180 umol) as RX in the above [Reaction Formula 5] in acetonitrile (3.00 mL), K2CO3 (49.8 mg, 360 umol) was added at 20°C, and the mixture was stirred at 20°C for 3 hours. 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 mLX3). After drying and filtering with anhydrous Na2SO4, it was concentrated under vacuum 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; 3-(1-acetyl-1H-pyrazol-3-yl)-2-bromo-6-(3-phenylpropoxy)-1H-inden-1-one, 6.00 mg, 12.37 umol, yield: 10.30%).

[0547] Step 7: Synthesis of 6-(3-phenylpropoxy)-3-(1H-pyrazol-3-yl)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 7)

[0548] After mixing compound 7-8 (6.00 mg, 12.37 umol) and pyridin-3-ylboronic acid (1.82 mg, 14.8 umol) as R1 in B(OH)2-R1 of [Chemical Formula 5] in dioxane (1.50 mL) and H2O (0.50 mL), K3PO4 (7.88 mg, 37.11 umol) and Pd(dtbpf)Cl2 (806 ug, 1.24 umol) were added. The mixture was stirred for 10 hours at 100°C under nitrogen environment. It was confirmed by TLC (DCM: methanol = 10 / 1) that the reactants were completely consumed. The mixture was diluted with H2O (10.0 mL) and extracted with EtOAc (20.0 mLX3). The combined organic phase layer was dried and filtered with anhydrous Na2SO4, and then concentrated under vacuum to obtain a residue. The residue was purified by prep-TLC (SiO 2 , DCM:methanol=10 / 1) to obtain Compound 7 (3.50 mg, 8.59 umol, yield: 64.61%, purity: 89.36%) as a red solid.

[0549] 1 H NMR (400MHz, CD3OD): δ8.45-8.52 (m, 2H), 7.80-7.90 (m, 2H), 7.63 (d, J=2.4Hz, 1H), 7.41-7.49 (m, 1H), 7.26-7.33 (m, 2H,), 7.13-7.22 (m, 3H ), 7.00 (d, J=2.4Hz, 1H), 6.83 (dd, J=2.4, 8.0Hz, 1H), 6.18 (d, J=2.4Hz, 1H), 4.24 (t, J=6.8Hz, 2H), 2.63 (t, J=7.6Hz, 2H), 2.18-2.25 (m, 2H)

[0550] MS found value: 452.8[M+H] +

[0551] Experimental example

[0552] Experimental Example 1. Aβ disaggregation test

[0553] 1.1. Sample preparation

[0554] Each compound was dissolved in DMSO to a concentration of 10 mM, and then diluted with 6% DMSO (in DW) before use.

[0555] Specifically, Aβ was dissolved in DMSO. 1～42 or Tau-RD3 (Tau repeat domain 3) monomer to a concentration of 10 mM to prepare β-amyloid protein and Tau solutions. Then, dilute it to 100 μM with DW and store it on ice. In addition, dissolve Thioflavin-T in 50 mM glycine buffer (pH 8.5) to a concentration of 5 mM. Then, dilute it to 5 μM with 50 mM glycine buffer (pH 8.5) and store it in a dark room away from light.

[0556] 1.2. β-Amyloid and Tau Aggregation Decomposition Experiments by Thioflavin T Analysis

[0557] The β-amyloid protein and Tau solutions prepared in Experimental Example 1.1 were placed in 1.5 mL microcentrifuge tubes until they reached 50 μM or 35 μM, and then reacted at 37 ° C for 24 hours. In each 1.5 mL microcentrifuge tube where the aggregation of β-amyloid protein and Tau had been terminated, the compounds were serially diluted from 500 μM until the concentration reached 0 μM, and then further reacted at 37 ° C for 48 hours. 25 μL of the terminated reaction solution was placed in each well of the 96-well fluorescence analysis plate, and then 75 μL of the prepared thioflavin T solution was placed in each well. After reacting at room temperature in the dark for 5 minutes, the fluorescence value was measured at excitation 450 nm and emission 485 nm using a multi-mode microplate reader.

[0558] Only β-amyloid protein or Tau protein was treated, and the fluorescence value of the group (control group) aggregated for 72 hours was converted into a % value and represented as 100. The β-amyloid protein and Tau aggregates that had been reacted for 24 hours and terminated aggregation were treated with each compound at each concentration, and further reacted for 48 hours, and then the measured fluorescence values ​​were converted into relative values, and the results are shown in Figures 1 to 6 , Figures 7 to 12 In addition, the EC values ​​of the compounds of the present invention on β-amyloid protein and Tau were respectively 50 The values ​​are shown in Table 1.

[0559]

Table 1

[0560]

[0561]

[0562] Figures 1 to 6 The β-amyloid aggregation effect (control group: Aβ) according to the treatment concentration (0 μM to 500 μM) of each indone derivative compound 1 to 50 is shown. 1-42 50μM treatment group, aggregation for 72 hours; treatment group: Aβ 1-42

[0563] 50 μM, aggregation for 24 hours + treatment with each derivative compound concentration, reaction for 48 hours) and the concentration that can decompose 50% of β-amyloid aggregation relative to the control group when treating each compound (EC 50 ). This indicates that each compound exhibited an aggregation-decomposing effect in a concentration-dependent manner.

[0564] Figures 7 to 12The Tau aggregation decomposition effect according to the treatment concentration of each compound (0 μM to 500 μM) is shown (control group: Tau-RD3 35 μM treatment group, aggregation for 72 hours; treatment group: Tau-RD3 35 μM, aggregation for 24 hours + treatment with each derivative compound concentration, reaction for 48 hours) and the concentration that can decompose 50% of Tau aggregation relative to the control group when treating each compound (EC 50 ). This indicates that each compound exhibited an aggregation-decomposing effect in a concentration-dependent manner.

[0565] Experimental Example 2: Confirmation of the effect of treatment compounds on reducing amyloid plaques in 5xFAD TG mice

[0566] 2.1. Preparation of 5xFAD TG Mouse Model

[0567] Transgenic mice (5xFAD TG; Alzheimer's disease animal model; B6SJL-Tg (APPSwFlLon, PSEN1 * M146L * L286V) 6799Vas / Mmjax) and wild-type mice were from Jackson Laboratory (Bar Harbor, Maine, USA). 5xFAD TG mice were crossed with wild-type mice to maintain double hemizygotes. All genotypes were confirmed by PCR analysis using tail DNA according to standard PCR conditions of Jackson Laboratory. The TG mice used in this experiment are a model of cognitive decline due to the deposition of β-amyloid protein in the brain. It is known that the deposition pattern of β-amyloid protein (the substance deposited in the brain of actual Alzheimer's patients) is similar to that of patients, so it is selected to easily analyze and evaluate the experimental results. Each mouse was placed in a plastic cage in the animal breeding room, and the light and dark cycles were alternating for 12 hours to maintain at 21 ± 1 ° C, with free intake of food and water.

[0568] 2.2. Administration of compounds to mouse models

[0569] To 10-month-old 5xFAD TG mice, the compound was orally administered at each concentration daily.

[0570] There were 6 experimental groups, consisting of 1 wild type (WT) group and 5 5xFAD (TG) groups. The TG mouse group consisted of a vehicle administration group as a negative control group, and a group administered with compound 1 at 3 mg / kg, 10 mg / kg, 30 mg / kg, and 100 mg / kg.

[0571] 2.3. Preparation of brain tissue samples

[0572] After 4 weeks of administration, the mice were anesthetized with 2% avertin (20 mg / g, ip) and perfused with 0.9% NaCl, and the brains were removed and fixed in 4% paraformaldehyde (pH 7.4) at 4°C overnight.

[0573] Immunohistochemistry

[0574] The fixed brain tissue prepared in Example 2.3 was prepared into 30 μm thick slices and then subjected to immunohistochemistry. The fixed tissue was reacted with 0.5% Thioflavin-S solution for 10 minutes to stain the amyloid plaques. After washing twice with 50% ethanol and once with DPBS, the stained tissue was fixed on a slide and then observed using a confocal laser scanning microscope. In addition, immunostaining was performed using the 6E10 antibody (which is a specific antibody for β-amyloid protein).

[0575] Fig.13 is a graph showing the effect of reducing amyloid plaques due to treatment of indanone derivative compounds in a 5xFAD TG mouse Alzheimer's disease model according to one aspect.

[0576] like Fig.13 As shown in the graph in the middle, as the total area of ​​amyloid accumulation in the cerebral hemisphere, it was confirmed that the plaque area was significantly decreased in the mice administered with the compound in a dose-dependent manner compared with the control mice (vehicle).

[0577] Experimental Example 3. Confirmation of the effect of treatment compounds on reducing Tau aggregates in PS19 TG mice

[0578] 3.1. Preparation of PS19 TG Mouse Model

[0579] Transgenic mice (PS19 TG; Alzheimer's disease animal model; B6; C3-Tg (Prnp-MAPT * P301S) PS19Vle / J) and wild-type mice were from Jackson Laboratory (Bar Harbor, Maine, USA). PS19 TG mice were hybridized with wild-type mice to maintain double hemizygotes. All genotypes were confirmed by PCR analysis of tail DNA according to the standard PCR conditions of Jackson Laboratory. The TG mice used in this experiment are a model of cognitive decline due to the deposition of Tau aggregates in the brain. It is known that the deposition pattern of Tau aggregates (the substance deposited in the brain of actual Alzheimer's patients) is similar to that of patients, so it is selected to easily analyze and evaluate the experimental results. Each mouse was placed in a plastic cage in the animal breeding room, and the light and dark cycles were alternating for 12 hours to maintain at 21 ± 1 ° C, and food and water were freely available.

[0580] 3.2. Administration of compounds to mouse models

[0581] To 6-month-old PS19 TG mice, the compounds were orally administered daily at each concentration.

[0582] There were 4 experimental groups, including 1 wild type (WT) group and 3 PS19 (TG) groups. The TG mouse group consisted of a vehicle administration group as a negative control group, and a group administered with compound 1 at 3 mg / kg and 10 mg / kg.

[0583] 3.3. Preparation of brain tissue samples

[0584] After 12 weeks of administration, the mice were anesthetized with 2% avertin (20 mg / g, ip) and perfused with 0.9% NaCl, and the brains were removed and fixed in 4% paraformaldehyde (pH 7.4) at 4°C overnight.

[0585] Immunohistochemistry

[0586] The fixed brain tissue prepared in Example 3.3. was prepared into slices of 30 μm thickness and then immunohistochemistry was performed. The fixed tissue was reacted with 0.5% Thioflavin S solution for 10 minutes to stain Tau aggregates. After washing twice with 50% ethanol and once with DPBS, the stained tissue was fixed on a slide and then observed using a confocal laser scanning microscope. In addition, immunostaining was performed with a neurofibrillary tangles (NFT) antibody, which is a specific antibody for Tau aggregates.

[0587] Fig.14 is a graph showing the effect of reducing Tau aggregates due to treatment with an indanone derivative compound in a PS19 TG mouse Alzheimer's disease model according to one aspect.

[0588] like Fig.14 As shown in the graph in the figure, as the total area of ​​Tau aggregation in the cerebral hemisphere, it was confirmed that the area of ​​Tau aggregates was significantly decreased in a dose-dependent manner in mice administered with the compound compared with the control group mice (vehicle).

[0589] The above description of the present invention is intended to exemplify the present invention, and those skilled in the art will appreciate that it can be easily modified into other specific forms without changing the technical concept or essential features of the present invention. Therefore, the above embodiments are exemplary in all aspects and not restrictive.

Claims

1. A compound of the following chemical formula 1, an isomer thereof or a pharmaceutically acceptable salt thereof: [Chemical formula 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; R1 is halogen, C 1-6 Alkyl, C 6-10 Aryl, -C 1-6 Alkyl-C 6-10 Aryl or 5-6 membered heteroaryl, in which case the C 1-6 Alkyl, C 6-10 Aryl, -C 1-6 Alkyl-C 6-10 The aryl and 5-6 membered heteroaryl groups may be independently unsubstituted or substituted with 1 to 4 halogen, hydroxy, CN, -NH2, -CF3, C 1-6 Alkyl, -C 1-6 Alkyl-CN, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl or -N(C 1-6 Alkyl)2 substituted; R2 is a 5-6 membered heteroaryl group, in which case the 5-6 membered heteroaryl group may be unsubstituted or substituted with 1 to 4 halogens, -CF3 or C 1-6 Alkyl substitution; R3 is C 6-10 aryl, 5-6 membered heteroaryl or 5-10 membered heterocyclic group, in which case the C 6-10 The aryl, 5-6 membered heteroaryl and 5-10 membered heterocyclic radicals may be independently unsubstituted or substituted with 1 to 4 halogen, hydroxyl, CN, -NH2, -CF3, C 1-6 Alkyl, -C 1-6 Alkyl-CN, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl or -N(C 1-6 Alkyl)2 substituted; The heteroaryl group is an aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from N, O and S, and the heterocyclic group is an aliphatic heterocyclic ring containing 1 to 4 heteroatoms selected from N, O and S.

2. The compound according to claim 1, its isomer or a pharmaceutically acceptable salt thereof, wherein: R1 is halogen, phenyl, pyridyl, pyrimidyl or phenylthio, in which case the phenyl, pyridyl, pyrimidyl and phenylthio groups may be independently unsubstituted or substituted with 1 to 4 halogen, hydroxyl, CN, -CF3, C 1-6 Alkyl, -C 1-6 Alkyl -CN or -OC 1-6 Alkyl substitution.

3. The compound according to claim 1 or 2, its isomer or a pharmaceutically acceptable salt thereof, wherein: R2 is furanyl, phenylthio, thiazolyl or pyrazolyl, in which case the thiazolyl, furanyl, phenylthio and pyrazolyl may each independently be unsubstituted or substituted with 1 to 4 halogens, -CF3 or C 1-6 Alkyl substitution.

4. The compound according to any one of claims 1 to 3, its isomer or a pharmaceutically acceptable salt thereof, wherein: R3 is phenyl, pyridyl, morpholinyl or benzodioxolanyl, in which case the phenyl, pyridyl, morpholinyl and benzodioxolanyl groups may be independently unsubstituted or substituted with 1 to 4 halogens, Hydroxyl, -NH2, -CF3, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl or -N(C 1-6 alkyl)2 substituted.

5. The compound according to any one of claims 1 to 4, its isomer or a pharmaceutically acceptable salt thereof, wherein: R1 is halogen, phenyl, pyridyl, pyrimidyl or phenylthio, in which case the phenyl, pyridyl, pyrimidyl and phenylthio groups may be independently unsubstituted or substituted with 1 to 4 halogen, hydroxyl, CN, -CF3, C 1-6 Alkyl, -C 1-6 Alkyl -CN or -OC 1-6 Alkyl substitution; R2 is furanyl, phenylthio, thiazolyl or pyrazolyl, in which case the thiazolyl, furanyl, phenylthio and pyrazolyl may each independently be unsubstituted or substituted with 1 to 4 halogens, -CF3 or C 1-6 Alkyl substitution; R3 is phenyl, pyridyl, morpholinyl or benzodioxolanyl, in which case the phenyl, pyridyl, morpholinyl and benzodioxolanyl groups may be independently unsubstituted or substituted with 1 to 4 halogens, Hydroxyl, -NH2, -CF3, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl or -N(C 1-6 alkyl)2 substituted.

6. The compound according to any one of claims 1 to 5, its isomer or a pharmaceutically acceptable salt thereof, wherein: The compound is any one 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-inden-1-one, (13) 3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-6-(3-(pyridin-4-yl)propoxy)-1H-inden-1-one, (14) 3-(4-methylthiazol-5-yl)-6-phenethoxy-2-(pyridin-3-yl)-1H-inden-1-one, (15) 3-(4-methylthiazol-5-yl)-6-(4-phenylbutoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (16) 6-((Benzyloxy)methoxy)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (17) 3-(4-methylthiazol-5-yl)-6-(2-phenoxyethoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (18) 2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-phenethoxy-1H-inden-1-one, (19) 2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-(4-phenylbutoxy)-1H-inden-1-one, (20) 6-((Benzyloxy)methoxy)-2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-1H-inden-1-one, (21) 2-(4-methoxyphenyl)-3-(5-methylthiazol-4-yl)-6-(2-phenoxyethoxy)-1H-inden-1-one, (22) 2-(4-fluorophenyl)-6-(2-(4-methoxyphenoxy)ethoxy)-3-(5-methylthiazol-4-yl)-1H-inden-1-one, (23) 6-(2-(3,4-dimethoxyphenoxy)ethoxy)-2-(4-fluorophenyl)-3-(5-methylthiazol-4-yl)-1H-inden-1-one, (24) 6-(2-(Benzo[d][1,3]dioxolan-5-yloxy)ethoxy)-2-(4-fluorophenyl)-3-(5-methylthiazol-4-yl)-1H-inden-1-one, (25) 2-(4-fluorophenyl)-3-(5-methylthiazol-4-yl)-6-(2-(pyridin-4-yloxy)ethoxy-1H-inden-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-phenethoxy-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]dioxolan-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-phenethoxy-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]dioxolan-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 the compound, isomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 as an active ingredient.

8. The pharmaceutical composition according to claim 7, wherein It is used for administration to a subject selected from: (1) Subjects whose β-amyloid aggregation levels are higher than the normal level in patients who do not have degenerative brain diseases or who are at risk of having higher than the normal level; (2) subjects whose Tau protein aggregation levels are higher than normal levels in patients who do not have degenerative brain diseases or who are at risk of higher than normal levels; (3) subjects whose phosphorylation level of Tau protein is higher than the normal level in patients who do not have degenerative brain diseases or who are at risk of having a higher level than the normal level; as well as (4) A subject corresponding to at least one of (1) to (3) above.

9. The pharmaceutical composition according to claim 7 or 8, wherein The degenerative brain disease is 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, amyloidosis stroke, systemic amyloidosis, Dutch amyloidosis, Niemann-Pick disease, senile dementia, amyotrophic lateral sclerosis, spinocerebellar atrophy, Tourette syndrome, Friedreich's ataxia, Machado-Joseph disease, dementia with Lewy bodies, dystonia, progressive supranuclear palsy and frontotemporal dementia.

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

11. A composition comprising the compound, isomer or acceptable salt thereof according to any one of claims 1 to 6. 12 . A method for inhibiting the aggregation of β-amyloid protein or disintegrating aggregates, comprising administering the compound, isomer or pharmaceutically acceptable salt thereof according to claim 1 to a subject in need thereof.

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

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

15. Use of the compound according to any one of claims 1 to 6, its isomer or pharmaceutically acceptable salt in inhibiting the aggregation of β-amyloid protein or disintegrating aggregates.

16. Use of the compound according to any one of claims 1 to 6, its isomer or pharmaceutically acceptable salt in inhibiting Tau protein aggregation, decomposing aggregates or inhibiting Tau protein phosphorylation.

17. Use of the compound according to any one of claims 1 to 6, its isomer or pharmaceutically acceptable salt in treating or preventing degenerative brain diseases.

Images