Novel indanone derivatives and uses thereof

Abstract

In one embodiment, a novel indanone derivative or a salt thereof and its uses are provided. According to one embodiment, the novel indanone derivative exhibits excellent efficacy in inhibiting and / or depolymerizing β-amyloid protein aggregates, inhibiting and / or depolymerizing Tau protein aggregates, and / or inhibiting Tau protein phosphorylation, and therefore can be effectively used for the prevention or treatment of degenerative brain diseases.

Description

Technical Field

[0001] It relates to a novel indanone derivative or a salt thereof; and its use in (i) inhibiting the aggregation and / or depolymerizing β-amyloid protein aggregates, (ii) inhibiting the aggregation, depolymerizing Tau protein aggregates and / or inhibiting Tau protein phosphorylation; and its use in the prevention or treatment of neurodegenerative brain diseases. Background Technology

[0002] Degenerative brain diseases are illnesses characterized by progressive changes in nerve cells within the central nervous system, leading to impairments in motor and sensory functions, as well as various symptoms such as impaired higher cognitive functions like memory, learning, and reasoning. Representative diseases include Alzheimer's disease, Parkinson's disease, and memory disorders. These diseases involve nerve cell death caused by rapidly or slowly progressing necrosis or apoptosis. Therefore, understanding the mechanisms of nerve cell apoptosis is crucial for developing methods to prevent, regulate, and treat central nervous system diseases.

[0003] Two proteins that have attracted much attention as pathogens that cause degenerative brain diseases are β-amyloid-beta and Tau protein.

[0004] Human β-amyloid protein is a peptide molecule containing approximately 36-43 amino acids. Its self-assembly oligomers or aggregates are believed to be associated with the pathogenesis of neurodegenerative diseases such as Alzheimer's disease. Specifically, β-amyloid peptide molecules are obtained by cleaving amyloid precursor protein (APP; UniProtKB P05067) with beta-secretase and gamma-secretase. These β-amyloid peptide molecules trigger degenerative brain diseases by aggregating to form neurotoxic oligomers.

[0005] In addition, Tau protein is composed of four parts: an N-terminal overhang, a proline aggregation domain, an organelle binding domain, and a C-terminus. It is known that abnormal hyperphosphorylation or aggregation of Tau protein in nerve cells of the central nervous system can lead to degenerative brain diseases such as Parkinson's disease and tauopathy.

[0006] Therefore, substances that can inhibit the aggregation or deaggregation of β-amyloid protein, inhibit the aggregation or deaggregation of Tau protein, or inhibit the phosphorylation of Tau protein have been proposed as therapeutic agents for degenerative brain diseases. Summary of the Invention

[0007] Technical problems to be solved On the one hand, compounds of the following chemical formula 1 or salts thereof are provided: [Chemical Formula 1]

[0008] In the chemical formula 1, R 1 and R 2 Each independently represents hydrogen, halogen, CN, OR a SR a CO2R a CH2CO2R a CONR b R c NR b R c C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; X 1 It is carbon or nitrogen; The X 1 When it is carbon, R 3 For hydrogen, halogen, CN, OR a SR a CO2R a CH2CO2R a CONR b R c NR b R c C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; X 1 When it is nitrogen, R 3 It does not exist; R 4 and R 5 Each independently represents hydrogen, halogen, CN, OR a SR a O(CO)R a CO2Ra NHR a NH(CO)R a CH2CO2R a CONR b R c NR b R c X a (CH2) p X b (CH2) q R d OCH2CH=CHR d C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; R a R b R c and R d Each is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; X a and X b Each can be a direct bond, oxygen, nitrogen, or sulfur; p and q are each an independent integer selected from 0 to 2.

[0009] On the other hand, a composition comprising a compound of said chemical formula 1; or a salt thereof is provided.

[0010] In another aspect, a pharmaceutical composition comprising a compound of said chemical formula 1; or a pharmaceutically acceptable salt thereof is provided.

[0011] On the other hand, there is the use of a compound of the stated chemical formula 1; or a pharmaceutically acceptable salt thereof.

[0012] In another aspect, there is the use of a compound of the stated chemical formula 1, or a pharmaceutically acceptable salt thereof, in the preparation of a medicine.

[0013] In another aspect, a pharmaceutical composition for the prevention or treatment of degenerative brain diseases is provided, comprising a compound of the chemical formula 1; or a pharmaceutically acceptable salt thereof.

[0014] In another aspect, there is the use of a compound of the stated chemical formula 1, or a pharmaceutically acceptable salt thereof, for the prevention or treatment of degenerative brain diseases.

[0015] In another aspect, there is the use of a compound of the stated chemical formula 1, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention or treatment of degenerative brain diseases.

[0016] On another front, a method for preventing or treating degenerative brain diseases is provided, comprising the step of administering a compound of said chemical formula 1, or a pharmaceutically acceptable salt thereof, to a desired individual.

[0017] In another aspect, a pharmaceutical composition is provided for inhibiting or depolymerizing β-amyloid protein aggregates, comprising a compound of said chemical formula 1; or a pharmaceutically acceptable salt thereof.

[0018] In another aspect, there is the use of a compound of the stated chemical formula 1, or a pharmaceutically acceptable salt thereof, in the inhibition of aggregation or deaggregation of β-amyloid protein aggregates.

[0019] In another aspect, there is the use of a compound of the stated chemical formula 1, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for inhibiting or depolymerizing aggregates of β-amyloid protein.

[0020] In another aspect, a method is provided for inhibiting or depolymerizing β-amyloid protein aggregates, comprising the step of administering a compound of said chemical formula 1, or a pharmaceutically acceptable salt thereof, to a desired individual.

[0021] In another aspect, a pharmaceutical composition is provided for inhibiting the aggregation of Tau protein, depolymerizing Tau protein aggregates, or inhibiting the phosphorylation of Tau protein, comprising a compound of said chemical formula 1; or a pharmaceutically acceptable salt thereof.

[0022] In another aspect, there is the use of a compound of the stated chemical formula 1, or a pharmaceutically acceptable salt thereof, for inhibiting the aggregation of Tau protein, depolymerizing Tau protein aggregates, or inhibiting the phosphorylation of Tau protein.

[0023] In another aspect, there is the use of a compound of the stated chemical formula 1, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for inhibiting the aggregation of Tau protein, depolymerizing Tau protein aggregates, or inhibiting the phosphorylation of Tau protein.

[0024] In another aspect, a method is provided for inhibiting the aggregation of Tau protein, depolymerizing Tau protein aggregates, or inhibiting the phosphorylation of Tau protein, comprising the step of administering a compound of said chemical formula 1, or a pharmaceutically acceptable salt thereof, to a desired individual.

[0025] On the other hand, a health food comprising a compound of said chemical formula 1; or a food science-acceptable salt thereof is provided.

[0026] On the other hand, a health food for the prevention or improvement of degenerative brain diseases is provided, comprising a compound of said chemical formula 1; or a food-grade acceptable salt thereof.

[0027] On the other hand, a health food is provided for inhibiting or depolymerizing β-amyloid protein aggregates, comprising a compound of said chemical formula 1; or a food-grade acceptable salt thereof.

[0028] On the other hand, a health food is provided for inhibiting the aggregation of Tau protein, depolymerizing Tau protein aggregates, or inhibiting the phosphorylation of Tau protein, comprising a compound of said chemical formula 1; or a food-grade acceptable salt thereof.

[0029] Technical solutions to the problem On the one hand, compounds of the following chemical formula 1 or salts thereof are provided: [Chemical Formula 1]

[0030] In the chemical formula 1, R 1 and R 2 Each independently represents hydrogen, halogen, CN, OR a SR a CO2R a CH2CO2R a CONR b R c NR b R c C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; X 1 It is carbon or nitrogen; The X 1 When it is carbon, R 3 For hydrogen, halogen, CN, OR a SR a CO2R a CH2CO2R a CONR b R c NR b R c C, substituted or unsubstituted 1-6Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; X 1 When it is nitrogen, R 3 It does not exist; R 4 and R 5 Each independently represents hydrogen, halogen, CN, OR a SR a O(CO)R a CO2R a NHR a NH(CO)R a CH2CO2R a CONR b R c NR b R c X a (CH2) p X b (CH2) q R d OCH2CH=CHR d C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; R a R b R c and R d Each is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; X a and X b Each can be a direct bond, oxygen, nitrogen, or sulfur; p and q are each an independent integer selected from 0 to 2.

[0031] The compound or its salt may have more than one chiral carbon center and thus may exist as an R or S isomer, a racemic mixture, a mixture of diastereomers, or a single diastereomer.

[0032] Furthermore, the compound of Formula 1 may comprise a hydrate or a solvate of the compound. The hydrate and solvate may be prepared using known methods, and are preferably non-toxic and water-soluble.

[0033] The term "salt" refers to a salt prepared using a specific compound according to a scheme and a relatively non-toxic acid or base.

[0034] The term "Cm" - n (where m and n are each an integer greater than or equal to 1) refers to a number of carbon atoms from m to n.

[0035] The term "halogen" refers to elements belonging to Group 17 of the periodic table. Examples include fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0036] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group. For example, "C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. Specifically, C 1-6 Alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc. Furthermore, the alkyl group may be unsubstituted or substituted with one or more identical or different substituents. For example, it may be substituted with substituted or unsubstituted 3-7 membered cycloalkyl groups, substituted or unsubstituted 3-7 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered aryl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, etc.

[0037] The term "cycloalkyl" refers to a monocyclic or polycyclic saturated hydrocarbon ring. Polycyclic structures can include multiple ring structures such as spiro, bridged, and fused rings. For example, "3-7 membered cycloalkyl" can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Furthermore, the cycloalkyl group can be unsubstituted or substituted with one or more of the same or different substituents. For example, substituted or unsubstituted C-membered groups... 1-6 Alkyl groups, etc., are substituted.

[0038] The term "heterocyclic alkyl" refers to a monocyclic or polycyclic ring in which at least one or more carbon atoms forming the ring are replaced by heteroatoms. The heteroatoms can be nitrogen (N), oxygen (O), or sulfur (S). The heterocyclic alkyl ring may contain one or more heteroatoms; it may contain one or more heteroatoms of one type, or each type may contain at least one heteroatom of two or more types. The heterocyclic alkyl group may have a carbon atom attached to the parent nucleus and contain heteroatoms within the ring, or an atom attached to the parent nucleus may be a heteroatom (in which case, if there are two or more heteroatoms, the ring also contains heteroatoms). For example, heterocyclic alkyl groups may include azetidinyl, azepanyl, oxiranyl, oxetanyl, morpholinyl, pyrrolidonyl, piperidinyl, pipeazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, etc. Furthermore, the heterocyclic alkyl group may be unsubstituted or substituted with one or more of the same or different substituents. For example, substituted or unsubstituted C... 1-6 Alkyl groups, substituted or unsubstituted 5-10 aryl groups, substituted or unsubstituted 5-10 heteroaryl groups, etc.

[0039] The term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon ring. For example, it can include phenyl, naphthyl, biaryl, etc. Furthermore, the aryl group can be unsubstituted or substituted with one or more of the same or different substituents. For example, it can be a substituted or unsubstituted C-shaped group. 1-6 Alkyl, substituted or unsubstituted 5-10 aryl, substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C 1-3 Alkyloxy group, -CONH(C 1-3 Alkyl groups, etc., are substituted.

[0040] The term "heteroaryl" refers to a monocyclic or polycyclic aromatic hydrocarbon in which at least one carbon atom of the aryl group is replaced by a heteroatom, namely nitrogen (N), oxygen (O), or sulfur (S). In this case, the heteroatom contained in the heteroaryl ring can be one or more types of heteroatoms, or it can contain one or more heteroatoms of one type, or each type can contain at least one heteroatom of two or more types. Furthermore, the heteroaryl group can be a carbon atom attached to the parent nucleus and contain heteroatoms within the ring, or an atom attached to the parent nucleus can be a heteroatom (in which case, if there are two or more heteroatoms, the ring also contains heteroatoms).For example, heteroaryl groups can include pyridinyl, thiophenyl, triazolyl, tetrazolyl, benzothiazolyl, benzothiophenyl, quinolinyl, indolyl, isoindolyl, benzofuranyl, benzopyrrolyl, furanyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, and oxazolyl. azolyl), oxadiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, benzoxazolyl, benzimidazolyl, dihydrobenzothiophenyl, purinyl, indolizinyl, chromenyl, pyrrolopyridinyl, pyrazolopyridinyl, thiadiazolyl The heteroaryl group can be unsubstituted or substituted with one or more identical or different substituents. For example, it can be a substituted or unsubstituted C group. 1-6 Alkyl, substituted or unsubstituted 5-10 aryl, substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C 1-3 Alkyloxy group, -CONH(C 1-3Alkyl groups, etc., are substituted.

[0041] Term "C" 1-3 "Alcohol" refers to the chemical formula -C 1-3 Alkyl-OH, including methanol, ethanol, n-propanol, isopropanol, etc. The C 1-3 Alcohols can be unsubstituted or substituted with one or more of the same or different substituents. For example, C14 can be substituted or unsubstituted. 1-6 Alkyl groups, etc., are substituted.

[0042] Term "C" 1-3 "Alkoxy" refers to the chemical formula -OC 1-3 Alkyl groups, including, for example, methoxy, ethoxy, n-propoxy, isopropoxy, etc. The C 1-3 The alkoxy group can be unsubstituted or substituted with one or more identical or different substituents. For example, the C group can be substituted or unsubstituted. 1-6 Alkyl groups, etc., are substituted.

[0043] The term "substitution" refers to replacing a hydrogen atom in a molecule with a substituent, such that, without exceeding the valence of the specified atom, this substitution produces a chemically stable compound. For example, "group A is substituted by substituent B" can mean that the hydrogen atom bonded to the carbon atoms or other atoms constituting the skeleton of group A is replaced by substituent B, causing group A to form a covalent bond with substituent B.

[0044] In one specific example, in chemical formula 1, the R 1 and R 2 Each is independently hydrogen, halogen, CN, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; The X 1 It is carbon or nitrogen; The X 1 When R is carbon, 3 For hydrogen, halogen, OR a or C that is substituted or not substituted 1-6 Alkyl; the X 1 When it is nitrogen, the R 3 It does not exist; The R 4 and R 5 Each independently represents hydrogen, halogen, and OR a SR a O(CO)R a NHR a NH(CO)R a NRb R c X a (CH2) p X b (CH2) q R d C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, or substituted or unsubstituted 3-7 membered heterocycloalkyl; The R a R b R c and R d Each can be independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl.

[0045] In one specific example, in chemical formula 1, the R 1 and R 2 Each of the following is independently hydrogen, halogen, CN, substituted or unsubstituted 5-7 membered cycloalkyl, substituted or unsubstituted 5-7 membered heterocycloalkyl, substituted or unsubstituted 5-6 membered aryl, or substituted or unsubstituted 5-6 membered heteroaryl; The X 1 It is carbon or nitrogen; The X 1 When R is carbon, 3 Each independently represents hydrogen, halogen, and OR a or C that is substituted or not substituted 1-3 Alkyl; the X 1 When it is nitrogen, the R 3 It does not exist; The R 4 For hydrogen, halogen, OR a SR a O(CO)R a NHR a NH(CO)R a NR b R c X a (CH2) p X b (CH2) q R d C, substituted or unsubstituted 1-4 Alkyl, substituted or unsubstituted 5-7 membered cycloalkyl, or substituted or unsubstituted 5-7 membered heterocycloalkyl; The R a R b Rc and R d Each is independently hydrogen, halogen, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-6 membered aryl, or substituted or unsubstituted 5-6 membered heteroaryl; The R 5 It can be hydrogen or halogen.

[0046] In one specific example, in chemical formula 1, the R 1 and R 2 Each of these can be independently hydrogen, halogen, CN, substituted or unsubstituted 5-7 membered cycloalkyl, substituted or unsubstituted 5-7 membered heterocycloalkyl, substituted or unsubstituted 5-6 membered aryl, or substituted or unsubstituted 5-6 membered heteroaryl. The R 1 and R 2 In this context, the substituted 5-7 membered cycloalkyl, substituted 5-7 membered heterocycloalkyl, substituted 5-6 membered aryl, and substituted 5-6 membered heteroaryl are each independently substituted by one or more members selected from the group consisting of: halogen, C 1-4 Alkyl, 5-6 membered heterocyclic alkyl, (C 1-6 (alkyl)-(5-6 membered heterocyclic alkyl), (5-6 membered heterocyclic alkyl)-(C 1-6 Alkyl), O-(C) 1-6 Alkyl), (C 1-6 alkyl)-(5-6 membered heterocyclic alkyl)-(C 1-6 alkyl), and (CO)HN(C 1-6 alkyl); The X 1 It is carbon or nitrogen; The X 1 When it is carbon, R 3 Hydrogen, halogen, OH, O- (C 1-3 Alkyl), or unsubstituted C 1-3 Alkyl; the X 1 When it is nitrogen, R 3 It does not exist; The R 4 For hydrogen, halogen, OR a SR a O(CO)R a NHR a NH(CO)R a NR b R c X a (CH2) p X b (CH2) q Rd C, substituted or unsubstituted 1-4 Alkyl, substituted or unsubstituted 5-7 membered cycloalkyl, or substituted or unsubstituted 5-7 membered heterocycloalkyl; The R 4 In, replacing C 1-4 Alkyl groups, substituted 5-7 membered cycloalkyl groups, and substituted 5-7 membered heterocycloalkyl groups are each independently substituted by one or more of the following groups: halogen, C 1-4 Alkyl, C 1-4 alcohol, (C 1-4 Alkyl)-(5-6 aryl), (5-6 heterocyclic alkyl)-(5-6 aryl), and (5-6 heterocyclic aryl)-(5-6 aryl); The R a R b R c and R d Each is independently hydrogen, halogen, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-6 membered aryl, or substituted or unsubstituted 5-6 membered heteroaryl; The R a R b R c and R d In, replacing C 1-4 Alkyl groups, substituted 3-7-membered cycloalkyl groups, substituted 3-7-membered heterocycloalkyl groups, substituted 5-6-membered aryl groups, and substituted 5-6-membered heteroaryl groups can each be independently substituted by one or more of the following groups: halogen, OH, 5-6-membered heterocycloalkyl groups, 5-6-membered aryl groups, and 5-6-membered heteroaryl groups.

[0047] In one specific example, in chemical formula 1, the R 1 and R 2 Each is independently hydrogen, halogen, CN, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; The X 1 It is carbon or nitrogen; The X 1 When R is carbon, 3 It can be hydrogen, halogen, -CH3, -OH or The X 1 When it is nitrogen, the R 3 It does not exist; The R 4 It can be hydrogen, halogen, -OH, -NH2, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0048] In a specific example, in the following chemical formula 1, [Chemical Formula 1]

[0049] The R 1 For hydrogen, halogen, CN, OR a SR a CO2Ra CH2CO2R a CONR b R c NR b R c substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 6 membered heterocycloalkyl substituted 5-10 membered aryl, or substituted or unsubstituted 6 membered heterocycloalkyl substituted 5-10 membered heteroaryl; The R 2 For hydrogen, halogen, CN, OR a SR a CO2R a CH2CO2R a CONR b R c NR b R c C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; The X 1 It is carbon or nitrogen; The X 1 When R is carbon, 3 For hydrogen, halogen, CN, OR a SR a CO2R a CH2CO2R a CONR b R c NR b R c C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; X 1 When it is nitrogen, the R 3 It does not exist; The R 4 For hydrogen, halogen, CN, OR a SR a O(CO)R a CO2R a NHR a NH(CO)R a CH2CO2R a CONR b R c NRb R c X a (CH2) p X b (CH2) q R d OCH2CH=CHR d C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; The R 5 For hydrogen, halogen, CN, OR a SR a O(CO)R a CO2R a NHR a NH(CO)R a CH2CO2R a CONR b R c NR b R c X a (CH2) p X b (CH2) q R d OCH2CH=CHR d C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; The R a R b R c and R d Each is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; X a and X b Each can be a direct bond, oxygen, nitrogen, or sulfur; p and q can each be an integer selected from 0 to 2 independently.

[0050] In a specific example, in the following chemical formula 1, [Chemical Formula 1]

[0051] The R 1 For hydrogen, halogen, CN, OR a SR a CO2R a CH2CO2R a CONR b R c NR b R c C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; The R 2 For hydrogen, halogen, CN, OR a SR a CO2R a CH2CO2R a CONR b R c NR b R c C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, or substituted or unsubstituted 5-10 membered aryl; The X 1 It is carbon or nitrogen; The X 1 When R is carbon, 3 For halogen, CN, OR a SR a CO2R a CH2CO2R a CONR b R c NR b R c C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; X 1 When it is nitrogen, the R 3 It does not exist; The R 4 For hydrogen, halogen, CN, OR a SR a O(CO)R a CO2R a NHR a NH(CO)R aCH2CO2R a CONR b R c NR b R c X a (CH2) p X b (CH2) q R d OCH2CH=CHR d C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; The R 5 For hydrogen, halogen, CN, OR a SR a O(CO)R a CO2R a NHR a NH(CO)R a CH2CO2R a CONR b R c NR b R c X a (CH2) p X b (CH2) q R d OCH2CH=CHR d C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; The R a R b R c and R d Each is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; X a and X b Each can be a direct bond, oxygen, nitrogen, or sulfur; p and q can each be an integer selected from 0 to 2 independently.

[0052] In a specific example, in the following chemical formula 1, [Chemical Formula 1]

[0053] The R 1 For hydrogen, halogen, CN, OR a SR a CO2R a CH2CO2R a CONR b R c NR b R c C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; The R 2 For hydrogen, halogen, CN, OR a SR a CO2R a CH2CO2R a CONR b R c NR b R c C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; The X 1 It is carbon or nitrogen; The X 1 When R is carbon, 3 For halogen, CN, OR a SR a CO2R a CH2CO2R a CONR b R c NR b R c C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; X 1 When it is nitrogen, the R 3 It does not exist; The R 4 For hydrogen, halogen, CN, OR a SR a O(CO)Ra CO2R a NHR a NH(CO)R a CH2CO2R a CONR b R c NR b R c X a (CH2) p X b (CH2) q R d OCH2CH=CHR d C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; The R 5 For hydrogen, halogen, CN, OR a SR a O(CO)R a CO2R a NHR a NH(CO)R a CH2CO2R a CONR b R c NR b R c X a (CH2) p X b (CH2) q R d OCH2CH=CHR d C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; The R a R b R c and R d Each is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; X a and X b Each can be a direct bond, oxygen, nitrogen, or sulfur; p and q can each be an integer selected from 0 to 2 independently.

[0054] In a specific example, in the following chemical formula 1, [Chemical Formula 1]

[0055] The R 1 For hydrogen, halogen, CN, OR a SR a CO2R a CH2CO2R a CONR b R c NR b R c C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; The R 2 For hydrogen, halogen, CN, OR a SR a CO2R a CH2CO2R a CONR b R c NR b R c C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; The X 1 It is carbon or nitrogen; The X 1 When R is carbon, 3 For hydrogen, halogen, CN, OR a SR a CO2R a CH2CO2R a CONR b R c NR b R c C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; X 1 When it is nitrogen, the R 3It does not exist; The R 4 Hydrogen, halogen, CN, O-(C) 1-3 Alkyl), OH, O-(C) 1-3 alcohol), O-(C 1-3 alkyl)-(C 1-3 Alkyl group), O- (substituted or unsubstituted 5-6 aryl group), N(CH2) p X b (CH2) q R d O(CO)R a CO2R a NHR a NH(CO)R a CH2CO2R a CONR b R c NR b R c OCH2CH=CHR d C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; The R 5 For hydrogen, halogen, CN, OR a SR a O(CO)R a CO2R a NHR a NH(CO)R a CH2CO2R a CONR b R c NR b R c X a (CH2) p X b (CH2) q R d OCH2CH=CHR d C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; The R a R b R c and R d Each is independently hydrogen, halogen, substituted or unsubstituted C1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; X a and X b Each can be a direct bond, oxygen, nitrogen, or sulfur; p and q can each be an integer selected from 0 to 2 independently.

[0056] In one specific instance, the compound or a salt thereof may be selected from one of (1) to (101): (1) 2,3-Diphenyl-1-indanone, (2) 6-Methoxy-2,3-diphenyl-1H-inden-1-one, (3) 2,3-Diphenyl-6-propoxy-1H-inden-1-one, (4) Isopropoxy-2,3-diphenyl-1H-inden-1-one, (5) 2-Phenyl-3-(o-tolyl)-1H-inden-1-one, (6) 3-Phenyl-2-(o-tolyl)-1H-inden-1-one, (7) 3-Phenyl-2-(pyridin-3-yl)-1H-inden-1-one, (8) 2-morpholino-3-phenyl-1H-inden-1-one, (9) 2-Phenyl-3-(pyridin-3-yl)-1H-inden-1-one, (10) 3-Cyclohexyl-2-phenyl-1H-inden-1-one, (11) 2-Cyclohexyl-3-phenyl-1H-inden-1-one, (12) 6-morpholino-2,3-diphenyl-1H-inden-1-one, (13) 6-(4-methylpiperazin-1-yl)-2,3-diphenyl-1H-inden-1-one, (14) 3-(4-morpholinophenyl)-2-phenyl-1H-inden-1-one, (15) 3-(3-morpholinophenyl)-2-phenyl-1H-inden-1-one, (16) 3-(4-(morpholinylmethyl)phenyl)-2-phenyl-1H-inden-1-one, (17) 2-(4-morpholinophenyl)-3-phenyl-1H-inden-1-one, (18) 2-(3-morpholinophenyl)-3-phenyl-1H-inden-1-one, (19) 3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (20) 3-(4-methylthiazolyl-5-yl)-6-((3-phenylpropyl)amino)-2-(pyridin-3-yl)-1H-inden-1-one, (21) 2-(4-methylpyridin-3-yl)-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (22) 6-Methoxy-2-(4-methylpyridin-3-yl)-3-(4-methylthiazo-5-yl)-1H-inden-1-one, (23) 3-(5-methylthiazolyl-4-yl)-2-(pyridin-3-yl)-6-(3-(pyridin-4-yl)propoxy)-1H-inden-1-one, (24) 2-Bromo-3-(1-methyl-1H-pyrazol-3-yl)-1-oxo-1H-indene-6-yl acetate, (25) 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(1H-pyrazol-3-yl)-1H-inden-1-one, (26) 2-(1-methyl-1H-pyrazol-3-yl)-3-(4-methylthiazo-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (27) 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(1H-pyrazol-4-yl)-1H-inden-1-one, (28) 2-(1-methyl-1H-pyrazol-4-yl)-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (29) 2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (30) 2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (31) 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(1H-1,2,3-triazol-4-yl)-1H-inden-1-one, (32) 2-(1-methyl-1H-1,2,3-triazol-4-yl)-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (33) 2-(2-methyl-2H-1,2,3-triazol-4-yl)-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (34) 3-(4-methylthiazolyl-5-yl)-1-oxo-6-(3-phenylpropoxy)-1H-indene-2-carboxynitrile, (35) 6-Hydroxy-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (36) 6-(2-hydroxyethoxy)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (37) 6-(2-methoxyethoxy)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (38) 6-(methyl(3-phenylpropyl)amino)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (39) 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-4-yl)-1H-inden-1-one, (40) 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-2-yl)-1H-inden-1-one, (41) 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(pyrazin-2-yl)-1H-inden-1-one, (42) 3-(1-methyl-1H-pyrazol-4-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (43) 6-(3-phenylpropoxy)-3-(1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (44) 3-(2-methoxyphenyl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (45) 3-(2,6-dimethoxyphenyl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (46) 4-Methyl-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (47) 4-Methoxy-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (48) 4-Hydroxy-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (49) 6-(cyclopentylamino)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (50) 6-(methylamino)-3-(4-methylthiazo-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (51) 6-((1-methylpiperidin-4-yl)amino)-3-(4-methylthiazo-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (52) 3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-6-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1H-inden-1-one, (53) 6-((2-hydroxyethyl)amino)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (54) 6-((2-methoxyethyl)amino)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (55) 3-(4-methylthiazolyl-5-yl)-6-((2-phenoxyethyl)amino)-2-(pyridin-3-yl)-1H-inden-1-one, (56) 3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-6-((tetrahydro-2H-pyran-4-yl)amino)-1H-inden-1-one, (57) 3-(4-methylthiazolyl-5-yl)-6-((3-phenylpropyl)thio)-2-(pyridin-3-yl)-1H-inden-1-one, (58) 3-(4-methylthiazolyl-5-yl)-6-((1-phenylpiperidin-3-yl)amino)-2-(pyridin-3-yl)-1H-inden-1-one, (59) 6-Amino-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (60)N-(3-(4-methylthiazo-5-yl)-1-oxo-2-(pyridin-3-yl)-1H-inden-6-yl)-3-phenylpropionamide, (61) N-(3-(4-methylthiazolyl-5-yl)-1-oxo-2-(pyridin-3-yl)-1H-inden-6-yl)tetrahydro-2H-pyran-4-carboxamide, (62) 6-(dimethylamino)-3-(4-methylthiazo-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (63) 6-(cyclopropylamino)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (64) 6-(4-methylpiperazin-1-yl)-3-(4-methylthiazo-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (65) 6-(methyl(3-phenylpropyl)amino)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (66) 3-(4-methylthiazolyl-5-yl)-6-phenoxy-2-(pyridin-3-yl)-1H-inden-1-one, (67) 6-(methylamino)-2,3-diphenyl-1H-inden-1-one, (68) 6-Amino-2,3-diphenyl-1H-inden-1-one, (69) 6-(dimethylamino)-2,3-diphenyl-1H-inden-1-one, (70) 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2,3-diphenyl-1H-inden-1-one, (71) 4-Methyl-6-(4-methylpiperazin-1-yl)-2,3-diphenyl-1H-inden-1-one, (72) 3-(2,6-dimethylphenyl)-6-(4-methylpiperazin-1-yl)-2-phenyl-1H-inden-1-one, (73) 6-(4-methylpiperazin-1-yl)-2-(3-morpholinylphenyl)-3-phenyl-1H-inden-1-one, (74) 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazo-5-yl)-1H-inden-1-one, (75) 6-(4-methylpiperazin-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazo-5-yl)-1H-inden-1-one, (76) 2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazo-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (77) 2,3-Bis(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (78) 2,3-Diphenyl-6-(3-phenylpropoxy)-1H-inden-1-one, (79) 6-(4-methylpiperazin-1-yl)-2,3-bis(4-methylthiazo-5-yl)-1H-inden-1-one, (80) 6-(4-methylpiperazin-1-yl)-2,3-bis(3-morpholinylphenyl)-1H-inden-1-one, (81) 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2,3-bis(4-methylthiazo-5-yl)-1H-inden-1-one, (82) 6-Hydroxy-2,3-di-o-tolyl-1H-inden-1-one, (83) 6-(3-phenylpropoxy)-2,3-bis(thiazolyl-5-yl)-1H-inden-1-one, (84) 3-(2,6-dimethylphenyl)-6-hydroxy-2-(o-tolyl)-1H-inden-1-one, (85)2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazo-5-yl)-1H-inden-1-one, (86)2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(4-methylthiazo-5-yl)-1H-inden-1-one, (87) 3-(4-methylthiazolyl-5-yl)-2-(4-(morpholinylmethyl)phenyl)-1H-inden-1-one, (88)2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(4-methylthiazo-5-yl)-1H-inden-1-one, (89) 3-(4-methylthiazolyl-5-yl)-2-(3-(morpholinylmethyl)phenyl)-1H-inden-1-one, (90)2-(4-(4-methylpiperazin-1-yl)phenyl)-3-phenyl-1H-inden-1-one, (91)2-(3-(4-methylpiperazin-1-yl)phenyl)-3-phenyl-1H-inden-1-one, (92) 3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(4-methylthiazo-5-yl)-1H-inden-1-one, (93) 3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(4-methylthiazo-5-yl)-1H-inden-1-one, (94) 3-(4-(4-methylpiperazin-1-yl)phenyl)-2-phenyl-1H-inden-1-one, (95) 3-(3-(4-methylpiperazin-1-yl)phenyl)-2-phenyl-1H-inden-1-one, (96) 3-(3,5-di-tert-butylphenyl)-2-phenyl-1H-inden-1-one, (97) 4,6-Dimethoxy-2,3-diphenyl-1H-indene, (98) 6,7-Diphenyl-5H-cyclopentano[b]pyridin-5-one (99) N-methyl-2-(1-oxo-3-(o-tolyl)-1H-inden-2-yl)benzamide, (100)6-(4-benzylpiperazin-1-yl)-3-(4-methylthiazo-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, and (101)3-(4-methylthiazolyl-5-yl)-6-((3-phenylpiperidin-1-yl)methyl)-2-(pyridin-3-yl)-1H-indone.

[0057] In one embodiment, when compounds 1 to 99 (compounds of formulas 2 to 100) and their intermediates (compounds 5-4, 6-2, 12-3, 23-10, 39-3, 40-4, 41-4, 42-6, 42-7, 44-8, 45-8, 72-7, 73-7, 74-7, 76-1, 83-5, 83-6, 99-7, and 99-8) were treated, it was confirmed that they exhibited the effect of depolymerizing β-amyloid protein aggregation and / or depolymerizing Tau protein aggregation (see Example 1).

[0058] Furthermore, when compounds 13 (compound of formula 14), 30 (compound of formula 31), 63 (compound of formula 64), 65 (compound of formula 66), 70 (compound of formula 71), 72 (compound of formula 73), 74 (compound of formula 75), 74-7 (intermediate compound of compound 74), 75 (compound of formula 76), 76-1 (intermediate compound of compound 76), and 90 (compound of formula 91) were treated into cells expressing β-amyloid oligomers, it was confirmed that the compounds reduced the aggregation of β-amyloid oligomers by depolymerizing them (see Example 2).

[0059] This confirms that the compound of Formula 1 exhibits excellent depolymerization effects on β-amyloid protein aggregates and / or Tau protein aggregates in brain cells or tissues, and therefore can be effectively applied to the prevention, improvement or treatment of degenerative brain diseases.

[0060] According to one scheme, the compound or its salt can be used to inhibit the aggregation and / or deaggregation of β-amyloid protein, inhibit the aggregation and / or deaggregation of Tau protein, and / or inhibit the phosphorylation of Tau protein, and can be effectively applied to the prevention, improvement or treatment of degenerative brain diseases.

[0061] On the other hand, a composition comprising a compound of said chemical formula 1; or a salt thereof is provided.

[0062] The terms “halogen,” “alkyl,” “heterocyclic alkyl,” “cycloalkyl,” “aryl,” “heteroaryl,” etc., can be within the above range.

[0063] Compositions comprising a compound or a salt thereof according to a scheme can be used to inhibit the aggregation and / or depolymerization of β-amyloid protein, inhibit the aggregation and / or depolymerization of Tau protein, and / or inhibit the phosphorylation of Tau protein, and can be effectively applied to the prevention, improvement or treatment of degenerative brain diseases.

[0064] In another aspect, a pharmaceutical composition comprising a compound of said chemical formula 1; or a pharmaceutically acceptable salt thereof is provided.

[0065] The terms “halogen,” “alkyl,” “heterocyclic alkyl,” “cycloalkyl,” “aryl,” “heteroaryl,” etc., can be within the above range.

[0066] The term "pharmaceutically acceptable" means that the substance exhibits non-toxic properties when exposed to a specific compound according to a protocol in cells or the human body.

[0067] When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include salts of sodium, potassium, calcium, ammonium, organic amines, or magnesium, or similar salts. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Pharmaceutically acceptable acid addition salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, or phosphorous acid; as well as salts of organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, succinic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and further include salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid.

[0068] Pharmaceutical compositions comprising a compound according to a scheme or a pharmaceutically acceptable salt thereof can be used to inhibit the aggregation and / or depolymerization of β-amyloid protein, inhibit the aggregation and / or depolymerization of Tau protein, and / or inhibit the phosphorylation of Tau protein, and can be effectively applied to the prevention, improvement or treatment of degenerative brain diseases.

[0069] On the other hand, there is the use of a compound of the stated chemical formula 1; or a pharmaceutically acceptable salt thereof.

[0070] The terms “halogen,” “alkyl,” “heterocyclic alkyl,” “cycloalkyl,” “aryl,” “heteroaryl,” “pharmaceuticalally acceptable salt,” etc., may be used within the above-mentioned range.

[0071] According to one embodiment, the compound or a pharmaceutically acceptable salt thereof may be used for the purposes of inhibiting the aggregation and / or depolymerization of β-amyloid protein, inhibiting the aggregation and / or depolymerization of Tau protein, and / or inhibiting the phosphorylation of Tau protein, and may be used for the prevention, improvement or treatment of degenerative brain diseases.

[0072] In another aspect, there is the use of a compound of the stated chemical formula 1, or a pharmaceutically acceptable salt thereof, in the preparation of a medicine.

[0073] The terms “halogen,” “alkyl,” “heterocyclic alkyl,” “cycloalkyl,” “aryl,” “heteroaryl,” “pharmaceuticalally acceptable salt,” etc., may be used within the above-mentioned range.

[0074] According to one scheme, the compound or its pharmaceutically acceptable salt can be used to prepare drugs that inhibit the aggregation and / or deaggregation of β-amyloid protein, inhibit the aggregation and / or deaggregation of Tau protein, and / or inhibit the phosphorylation of Tau protein, and can be effectively used to prepare drugs for the prevention, improvement or treatment of degenerative brain diseases.

[0075] In another aspect, a pharmaceutical composition for the prevention or treatment of degenerative brain diseases is provided, comprising a compound of the chemical formula 1; or a pharmaceutically acceptable salt thereof.

[0076] The terms “halogen,” “alkyl,” “heterocyclic alkyl,” “cycloalkyl,” “aryl,” “heteroaryl,” “pharmaceuticalally acceptable salt,” etc., may be used within the above-mentioned range.

[0077] The term "prevention" can refer to all behaviors that inhibit or delay an individual's degenerative brain disease by administering a pharmaceutical composition according to a regimen.

[0078] The term "treatment" can refer to all actions that improve or bring about beneficial changes in the symptoms of an individual's degenerative brain disease by administering a drug composition according to a regimen.

[0079] In addition, the pharmaceutical composition may contain one or more pharmaceutically acceptable carriers, excipients or diluents, thereby being provided as a pharmaceutical composition.

[0080] Specifically, the carrier can be, for example, a colloidal suspension, powder, saline, lipid, liposome, microspheres, or nanospheres. These can form complexes with or be associated with the delivery carrier and can be delivered in vivo using delivery systems known in the art, such as lipids, liposomes, microparticles, gold, nanoparticles, polymers, condensing agents, polysaccharides, polyamino acids, dendritic polymers, saponins, absorption enhancers, or fatty acids.

[0081] When the pharmaceutical composition is formulated, it can be prepared using commonly used lubricants, sweeteners, flavorings, emulsifiers, suspending agents, preservatives, fillers, extenders, binders, wetting agents, disintegrants, surfactants, and other diluents or excipients. Solid dosage forms for oral administration can include tablets, pills, powders, granules, capsules, etc., which can be prepared by mixing the composition with at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc can also be used. Liquid dosage forms for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and can include various excipients such as wetting agents, sweeteners, flavorings, preservatives, etc., in addition to commonly used simple diluents such as water and liquid paraffin. Dosage forms for non-oral administration can include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, and suppositories. As a non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate can be used. As a suppository base, witepsol, polyethylene glycol, Tween 61, cocoa butter, lauryl resin, glycerin gelatin, etc. can be used, and when formulated into eye drops, known diluents or excipients can be used.

[0082] In one specific instance, the pharmaceutical composition for the prevention or treatment of degenerative brain diseases may be administered to individuals selected from those who do not have degenerative brain diseases and whose β-amyloid aggregation levels are higher than normal or who are at risk of elevation. (2) The aggregation level of Tau protein was higher than that of normal individuals or individuals at risk of elevation who did not have degenerative brain diseases; (3) Tau protein phosphorylation levels were higher than normal or in individuals at risk of elevated levels who did not have degenerative brain diseases; and (4) Corresponding to one or more of the individuals mentioned in (1) to (3).

[0083] The term “degenerative brain disease” refers to all diseases associated with degenerative changes in the brain, particularly those that can be caused by one or more factors selected from the group consisting of: aggregation of β-amyloid protein, aggregation of Tau protein, and phosphorylation of Tau protein in brain and / or brain nerve cells.

[0084] The aggregation level of β-amyloid protein or Tau protein refers to the amount (concentration) of β-amyloid protein aggregates or Tau protein aggregates, or the proportion of β-amyloid protein aggregates or Tau protein aggregates to total β-amyloid protein or total Tau protein.

[0085] The phosphorylation level of Tau protein refers to the amount (concentration) of phosphorylated Tau protein, or the proportion of phosphorylated Tau protein to total Tau protein.

[0086] The term "normal" can refer to a subject (patient) of the pharmaceutical composition and an individual of the same species who does not suffer from the "degenerative brain disease" as defined above, or brain tissue or brain cells (brain nerve cells) isolated and / or cultured from said individual.

[0087] In one specific instance, the degenerative brain disease may be one or more selected from the group consisting of: dementia, Alzheimer's disease, preclinical Alzheimer's disease, Parkinson's disease, Huntington's disease, mild cognitive impairment, cerebral amyloid angiopathy, Down syndrome, amyloid stroke, systemic amyloidosis, Dutch amyloidosis, Niemann-Pick disease, senile dementia, amyotrophic lateral sclerosis, spinocerebellar ataxia, Tourette's syndrome, Friedrich's ataxia, Machado-Joseph's disease, and Lewy body dementia. Body dementia, dystonia, progressive supranuclear palsy, and frontotemporal dementia.

[0088] The pharmaceutical composition is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease with a reasonable benefit / risk ratio suitable for medical treatment. Effective dose levels can depend on factors including the type and severity of the patient's disease, the activity of the drug, the patient's sensitivity to the drug, the timing of administration, the route of administration and excretion rate, the duration of treatment, factors of concomitant medications, and other factors well known in the medical field. Administration may be once daily or in multiple divided doses. For example, it may be administered every other day or once a week.

[0089] In one specific example, the compound or a pharmaceutically acceptable salt thereof may be administered at a dose of 0.1 mg / kg to 100 mg / kg. More specifically, it may be administered at a dose of 1 mg / kg to 50 mg / kg, and even more specifically, at a dose of 1 mg / kg to 10 mg / kg.

[0090] The term "administration" refers to the introduction of a prescribed substance into an individual in an appropriate manner. "Individual" means any living organism, including humans, that may be susceptible to a degenerative brain disease, such as rats, mice, pigs, horses, cattle, and livestock. As a specific example, it can include mammals, including humans.

[0091] The pharmaceutical composition can be administered orally or non-orally. When administered non-orally, the injection methods can include topical application, intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, arterial injection, intramedullary injection, intracardiac injection, intrathecal injection, percutaneous injection, intranasal injection, enteral injection, local injection, sublingual injection, rectal injection, or pleural injection.

[0092] On the one hand, in addition to the compound or its pharmaceutically acceptable salt, the pharmaceutical composition may also contain other therapeutic agents for degenerative brain diseases.

[0093] The other therapeutic agents for degenerative brain diseases may be included in the pharmaceutical composition in the minimum amount that can achieve maximum effect without side effects, which can be readily determined by those skilled in the art.

[0094] Furthermore, the pharmaceutical composition can be administered alone or in combination with other treatments for degenerative brain diseases. That is, the pharmaceutical composition can be administered in combination with other treatments for degenerative brain diseases, simultaneously, alone, or sequentially, and can be administered once or multiple times.

[0095] When the other treatment agents for degenerative brain diseases are administered in combination with the pharmaceutical composition, they can be administered at an amount or proportion that can achieve the maximum effect without side effects, which can be readily determined by those skilled in the art.

[0096] The other degenerative brain disease treatment agents may be known degenerative brain disease treatment agents or newly developed degenerative brain disease treatment agents.

[0097] Pharmaceutical compositions comprising a compound according to a scheme or a pharmaceutically acceptable salt thereof exhibit excellent effects in disaggregating β-amyloid and / or Tau protein aggregates in brain cells or tissues, and can be effectively used for the prevention, improvement, or treatment of degenerative brain diseases.

[0098] In another aspect, there is the use of a compound of the stated chemical formula 1, or a pharmaceutically acceptable salt thereof, for the prevention or treatment of degenerative brain diseases.

[0099] The terms “halogen,” “alkyl,” “heterocyclic alkyl,” “cycloalkyl,” “aryl,” “heteroaryl,” “pharmaceutically acceptable salt,” “prevention,” “treatment,” etc., may be used within the above-mentioned scope.

[0100] According to one formulation, the compound or its pharmaceutically acceptable salt exhibits excellent depolymerization effects on β-amyloid and / or Tau protein aggregates in brain cells or tissues, and can be effectively applied to the prevention, improvement, or treatment of degenerative brain diseases.

[0101] In another aspect, there is the use of a compound of the stated chemical formula 1, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention or treatment of degenerative brain diseases.

[0102] The terms “halogen,” “alkyl,” “heterocyclic alkyl,” “cycloalkyl,” “aryl,” “heteroaryl,” “pharmaceutically acceptable salt,” “prevention,” “treatment,” etc., may be used within the above-mentioned scope.

[0103] According to one scheme, the compound or its pharmaceutically acceptable salt exhibits excellent depolymerization effects on β-amyloid and / or Tau protein aggregates in brain cells or tissues, and can be effectively used in the preparation of drugs for the prevention, improvement or treatment of degenerative brain diseases.

[0104] On another front, a method for preventing or treating degenerative brain diseases is provided, comprising the step of administering a compound of said chemical formula 1, or a pharmaceutically acceptable salt thereof, to a desired individual.

[0105] The terms “halogen,” “alkyl,” “heterocyclic alkyl,” “cycloalkyl,” “aryl,” “heteroaryl,” “pharmaceutically acceptable salt,” “administration,” etc., may be used within the above-mentioned range.

[0106] According to one formulation, the compound or its pharmaceutically acceptable salt exhibits excellent depolymerization effects on β-amyloid and / or Tau protein aggregates in brain cells or tissues, and can be effectively applied to the prevention, improvement, or treatment of degenerative brain diseases.

[0107] In another aspect, a pharmaceutical composition is provided for inhibiting or depolymerizing β-amyloid protein aggregates, comprising a compound of said chemical formula 1; or a pharmaceutically acceptable salt thereof.

[0108] The terms “halogen,” “alkyl,” “heterocyclic alkyl,” “cycloalkyl,” “aryl,” “heteroaryl,” “pharmaceuticalally acceptable salt,” etc., may be used within the above-mentioned range.

[0109] The term "β-amyloid (Aβ)" refers to a polypeptide or fragment thereof derived from APP (amyloid precursor protein), which may contain a polynucleotide sequence or fragment thereof encoding it.

[0110] The term "inhibition" refers to any stage in gene transcription, mRNA processing, translation, transport, and maturation, or the inhibition of protein-protein binding, protein activation, or signal transduction through proteins.

[0111] The term "protein aggregate" can include protein polymers, fibril precursors, fibrils, plaques, protein monomers and polymers bound to the same protein. The fibrils can include oligomers of β-amyloid protein. For example, they can be aggregates of water-soluble and / or insoluble β-amyloid protein, β-amyloid oligomers, β-amyloid protofibrils, β-amyloid fibrils, and β-amyloid plaques.

[0112] The term "depolymerization" refers to transforming an existing aggregate into a state with lower aggregation degree, i.e., a lower-order aggregate. For example, transforming β-amyloid fibrils into β-amyloid oligomers, and β-amyloid oligomers into β-amyloid monomers.

[0113] Pharmaceutical compositions comprising a compound according to a scheme or a pharmaceutically acceptable salt thereof exhibit excellent effects in disaggregating β-amyloid aggregates and / or Tau protein aggregates in brain cells or tissues, and can be used to inhibit the aggregation and / or disaggregate β-amyloid aggregates.

[0114] In another aspect, there is the use of a compound of the stated chemical formula 1, or a pharmaceutically acceptable salt thereof, in the inhibition of aggregation or deaggregation of β-amyloid protein aggregates.

[0115] The terms “halogen,” “alkyl,” “heterocyclic alkyl,” “cycloalkyl,” “aryl,” “heteroaryl,” “pharmaceuticalally acceptable salt,” etc., may be used within the above-mentioned range.

[0116] According to one formulation, the compound or its pharmaceutically acceptable salt exhibits excellent depolymerization effects on β-amyloid aggregates and / or Tau protein aggregates in brain cells or tissues, and can be used to inhibit the aggregation and / or depolymerize β-amyloid aggregates.

[0117] In another aspect, there is the use of a compound of the stated chemical formula 1, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for inhibiting or depolymerizing aggregates of β-amyloid protein.

[0118] The terms “halogen,” “alkyl,” “heterocyclic alkyl,” “cycloalkyl,” “aryl,” “heteroaryl,” “pharmaceuticalally acceptable salt,” etc., may be used within the above-mentioned range.

[0119] According to one formulation, the compound or its pharmaceutically acceptable salt exhibits excellent depolymerization effects on β-amyloid aggregates and / or Tau protein aggregates in brain cells or tissues, and can be used to prepare a drug that inhibits the aggregation and / or depolymerizes β-amyloid aggregates.

[0120] In another aspect, a method is provided for inhibiting or depolymerizing β-amyloid protein aggregates, comprising the step of administering a compound of said chemical formula 1, or a pharmaceutically acceptable salt thereof, to a desired individual.

[0121] The terms “halogen,” “alkyl,” “heterocyclic alkyl,” “cycloalkyl,” “aryl,” “heteroaryl,” “pharmaceuticalally acceptable salt,” etc., may be used within the above-mentioned range.

[0122] According to one formulation, the compound or its pharmaceutically acceptable salt exhibits excellent depolymerization effects on β-amyloid aggregates and / or Tau protein aggregates in brain cells or tissues, and can be used to inhibit the aggregation and / or depolymerize β-amyloid aggregates.

[0123] In another aspect, a pharmaceutical composition is provided for inhibiting the aggregation of Tau protein, depolymerizing Tau protein aggregates, or inhibiting the phosphorylation of Tau protein, comprising a compound of said chemical formula 1; or a pharmaceutically acceptable salt thereof.

[0124] The terms “halogen,” “alkyl,” “heterocyclic alkyl,” “cycloalkyl,” “aryl,” “heteroaryl,” “pharmaceuticalally acceptable salt,” etc., may be used within the above-mentioned range.

[0125] Pharmaceutical compositions comprising a compound according to a scheme or a pharmaceutically acceptable salt thereof exhibit excellent effects in disaggregating β-amyloid aggregates and / or Tau protein aggregates in brain cells or tissues, and can be used to inhibit Tau protein aggregation and / or disaggregate Tau protein aggregates and / or inhibit Tau protein phosphorylation.

[0126] In another aspect, there is the use of a compound of the stated chemical formula 1, or a pharmaceutically acceptable salt thereof, for inhibiting the aggregation of Tau protein, depolymerizing Tau protein aggregates, or inhibiting the phosphorylation of Tau protein.

[0127] The terms “halogen,” “alkyl,” “heterocyclic alkyl,” “cycloalkyl,” “aryl,” “heteroaryl,” “pharmaceuticalally acceptable salt,” etc., may be used within the above-mentioned range.

[0128] According to one formulation, the compound or its pharmaceutically acceptable salt exhibits excellent depolymerization effects on β-amyloid aggregates and / or Tau protein aggregates in brain cells or tissues, and can be used to inhibit Tau protein aggregation and / or depolymerize Tau protein aggregates and / or inhibit Tau protein phosphorylation.

[0129] In another aspect, there is the use of a compound of the stated chemical formula 1, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for inhibiting the aggregation of Tau protein, depolymerizing Tau protein aggregates, or inhibiting the phosphorylation of Tau protein.

[0130] The terms “halogen,” “alkyl,” “heterocyclic alkyl,” “cycloalkyl,” “aryl,” “heteroaryl,” “pharmaceuticalally acceptable salt,” etc., may be used within the above-mentioned range.

[0131] According to one formulation, the compound or its pharmaceutically acceptable salt exhibits excellent depolymerization effects on β-amyloid aggregates and / or Tau protein aggregates in brain cells or tissues, and can be used to prepare drugs that inhibit Tau protein aggregation and / or depolymerize Tau protein aggregates and / or inhibit Tau protein phosphorylation.

[0132] In another aspect, a method is provided for inhibiting the aggregation of Tau protein, depolymerizing Tau protein aggregates, or inhibiting the phosphorylation of Tau protein, comprising the step of administering a compound of said chemical formula 1, or a pharmaceutically acceptable salt thereof, to a desired individual.

[0133] The terms “halogen,” “alkyl,” “heterocyclic alkyl,” “cycloalkyl,” “aryl,” “heteroaryl,” “pharmaceuticalally acceptable salt,” etc., may be used within the above-mentioned range.

[0134] According to one formulation, the compound or its pharmaceutically acceptable salt exhibits excellent depolymerization effects on β-amyloid aggregates and / or Tau protein aggregates in brain cells or tissues, and can be used to inhibit Tau protein aggregation and / or depolymerize Tau protein aggregates and / or inhibit Tau protein phosphorylation.

[0135] On the other hand, a health food comprising a compound of said chemical formula 1; or a food science-acceptable salt thereof is provided.

[0136] The terms “halogen,” “alkyl,” “heterocyclic alkyl,” “cycloalkyl,” “aryl,” “heteroaryl,” etc., can be within the above range.

[0137] The term "improvement" can refer to all behaviors that at least reduce parameters associated with the treated state, such as the severity of symptoms. In this context, the health food product can be used concurrently with or alone with medications used for treatment, before or after the onset of the disease, to prevent or improve degenerative brain diseases.

[0138] The term "health functional food" includes health functional food, health food, and health supplement food.

[0139] The term "functional food" is the same as "food for special health use" (FoSHU), referring to processed foods that, in addition to providing nutrition, effectively exert biological regulatory functions and have high medical or therapeutic effects. "Functional" here refers to the beneficial effects on the structure and function of the human body for health purposes, such as regulating nutrients or physiological processes.

[0140] In addition, "health food" refers to food that has a more positive effect on maintaining or promoting health compared to ordinary food, while "health supplement food" refers to food intended to assist in health maintenance.

[0141] In the aforementioned health functional foods, the compound or its food-grade acceptable salt can be added directly to the food or mixed with other foods or food ingredients, and can be used appropriately according to conventional methods. The amount of the compound or its food-grade acceptable salt mixed in can be appropriately determined according to its intended use (for the prevention or improvement of degenerative brain diseases). Generally, when producing food or beverages, the compound or its food-grade acceptable salt can be added specifically at an amount of about 15% by weight or less, more specifically about 10% by weight or less, of the raw materials. However, in cases of long-term intake for health and hygiene purposes or health control purposes, the amount can be below the aforementioned range.

[0142] The health functional foods also include one or more of the following: carriers, diluents, excipients, and additives, and can be formulated into one of the following dosage forms: tablets, pills, powders, granules, capsules, and liquids. Foods that may contain compounds according to a scheme include various food categories, powders, granules, tablets, capsules, syrups, beverages, chewing gum, tea, vitamin complexes, and health functional foods.

[0143] Specific examples of the carrier, excipient, diluent, and additive may be selected from one or more of the following groups: lactose, glucose, sucrose, sorbitol, mannitol, erythritol, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium phosphate, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, polyvinylpyrrolidone, methylcellulose, water, syrup, methylcellulose, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil.

[0144] In addition to containing the aforementioned compound or its food-grade acceptable salt, the health functional food may contain other ingredients as essential components without particular limitation. For example, like ordinary beverages, it may contain various flavoring agents or natural carbohydrates as additional ingredients. Examples of natural carbohydrates may be monosaccharides, such as glucose and fructose; disaccharides, such as maltose and sucrose; and polysaccharides, such as dextrin and cyclodextrin; as well as sugar alcohols such as xylitol, sorbitol, and erythritol. As flavor enhancers other than those mentioned above, natural flavor enhancers (such as sematriene and stevia extract (e.g., rebaudioside A, glycyrrhizic acid, etc.)) and synthetic flavor enhancers (such as saccharin and aspartame) may be advantageously used. The proportion of the natural carbohydrates can be appropriately determined by those skilled in the art.

[0145] In addition to the above, the health functional food according to one embodiment may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and flavor enhancers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, and carbonating agents used in carbonated beverages. These components may be used alone or in combination, and the proportions of these additives may be appropriately selected by those skilled in the art.

[0146] In one specific instance, the compound or its food-grade acceptable salt can be ingested at a rate of 0.1 mg / kg to 100 mg / kg. More specifically, it can be ingested at a rate of 1 mg / kg to 50 mg / kg, and even more specifically, at a rate of 1 mg / kg to 10 mg / kg.

[0147] In one specific instance, in addition to the compound or its food-grade acceptable salt, the health food may also contain other health foods for the prevention or improvement of degenerative brain diseases.

[0148] The other health food products used to prevent or improve degenerative brain diseases may be included in the health food product in the minimum amount that can achieve the maximum effect without side effects, which can be easily determined by those skilled in the art.

[0149] Furthermore, in a specific example, the health functional food can be taken alone or in combination with the health functional food for the prevention or improvement of degenerative brain diseases. That is, the health functional food for the prevention or improvement of degenerative brain diseases can be taken in combination with other health functional foods for the prevention or improvement of degenerative brain diseases, and can be taken simultaneously, alone, or sequentially, and can be taken once or multiple times.

[0150] When taken in combination with other health functional foods for the prevention or improvement of degenerative brain diseases, the amount or proportion in which the maximum effect can be obtained without side effects can be readily determined by those skilled in the art.

[0151] The other health functional foods mentioned can be known health functional foods for the prevention or improvement of degenerative brain diseases, or newly developed health functional foods for the prevention or improvement of degenerative brain diseases.

[0152] Health functional foods containing a compound according to a scheme or a food science-acceptable salt thereof may be used to inhibit the aggregation and / or deaggregation of β-amyloid protein, inhibit the aggregation and / or deaggregation of Tau protein, and / or inhibit the phosphorylation of Tau protein, and may be effectively used for the prevention, improvement or treatment of degenerative brain diseases.

[0153] On the other hand, a health food for the prevention or improvement of degenerative brain diseases is provided, comprising a compound of said chemical formula 1; or a food-grade acceptable salt thereof.

[0154] The terms “halogen,” “alkyl,” “heterocyclic alkyl,” “cycloalkyl,” “aryl,” “heteroaryl,” etc., can be within the above range.

[0155] Health foods containing a compound according to a scheme or its food-grade acceptable salt exhibit excellent effects in disaggregating β-amyloid and / or Tau protein aggregates in brain cells or tissues, and can be effectively applied to the prevention or improvement of degenerative brain diseases.

[0156] On the other hand, a health food is provided for inhibiting or depolymerizing β-amyloid protein aggregates, comprising a compound of said chemical formula 1; or a food-grade acceptable salt thereof.

[0157] The terms “halogen,” “alkyl,” “heterocyclic alkyl,” “cycloalkyl,” “aryl,” “heteroaryl,” etc., can be within the above range.

[0158] Health foods containing a compound according to a scheme or a food science-acceptable salt thereof exhibit excellent effects in depolymerizing β-amyloid protein aggregates and / or Tau protein aggregates in brain cells or tissues, and can be used to inhibit the aggregation and / or depolymerize β-amyloid protein aggregates.

[0159] On the other hand, a health food is provided for inhibiting the aggregation of Tau protein, depolymerizing Tau protein aggregates, or inhibiting the phosphorylation of Tau protein, comprising a compound of said chemical formula 1; or a food-grade acceptable salt thereof.

[0160] The terms “halogen,” “alkyl,” “heterocyclic alkyl,” “cycloalkyl,” “aryl,” “heteroaryl,” etc., can be within the above range.

[0161] Health foods containing a compound according to a scheme or a food science-acceptable salt thereof exhibit excellent effects in depolymerizing β-amyloid protein aggregates and / or Tau protein aggregates in brain cells or tissues, and can be used to inhibit Tau protein aggregation and / or depolymerize Tau protein aggregates and / or inhibit Tau protein phosphorylation.

[0162] Invention Effects According to one approach, novel indanone derivatives exhibit excellent efficacy in inhibiting and / or depolymerizing β-amyloid protein aggregates, inhibiting and / or depolymerizing Tau protein aggregates, and / or inhibiting Tau protein phosphorylation, and therefore can be effectively applied for the prevention or treatment of degenerative brain diseases. Attached Figure Description

[0163] Figure 1 A graph showing the relative changes in β-amyloid oligomers caused by each compound and its intermediates, compared to the changes in HEK293 cells transfected without the compound as a control group.

[0164] #: Compound and intermediate number Detailed Implementation The present invention will be described in more detail below through embodiments. However, these embodiments are intended to illustrate the invention, and the scope of the invention is not limited to these embodiments.

[0165] Preparation Example Compounds 1 to 101 shown in Table 1 were prepared according to Preparation Examples 1 to 100.

[0166] Table 1

[0167] Preparation Example 1. 2,3-Diphenyl-1-indanone (Compound 1) [Reaction Formula 1]

[0168] Under CO2 conditions, tetrabutylammonium bromide (361.76 mg, 1.12 mmol), Na2CO3 (237.88 mg, 2.24 mmol), 1-bromo-2-iodobenzene (634.95 mg, 2.24 mmol), and PdCl2 (19.90 mg, 0.11 mmol) were sequentially added to a 5 mL solution of (2-phenylethynyl)benzene (200 mg, 1.12 mmol) in 1,4-dioxane. The reaction mixture was stirred at 100 °C under CO2 conditions for 24 hours. Water (15 mL) was added to the resulting mixture, and extraction was performed using EtOAc (15 mL x 3). The organic layer was washed with brine, dried and concentrated with sodium sulfate, and purified by silica gel column chromatography (0%-4% EtOAc / PE) to give 2,3-diphenyl-1-indanone (191.4 mg, 0.67 mmol, 59.9%) as a red solid.

[0169] By confirming the MS (ESI) of the obtained compound 1 (hereinafter chemical formula 2) and 1 H NMR yielded the following data: [Chemical Formula 2]

[0170] MS(ESI): C 21 H 14 O 282.1 m / z, measured value 282.7 [M+1] + .

[0171] 1 H NMR (400 MHz, DMSO-d6) δ 7.57 - 7.55 (m, 1H), 7.53 - 7.45 (m, 4H), 7.43 - 7.36 (m, 3H), 7.30 - 7.28 (m, 3H), 7.20 - 7.15 (m, 3H).

[0172] Preparation Example 2. 6-Methoxy-2,3-diphenyl-1H-inden-1-one, (6-methoxy-2,3-diphenyl-1H- inden-1-one) (compound 2) [Reaction 2]

[0173] A round-bottom flask containing a mixture of (2-phenylethynyl)benzene (3.56 g, 0.02 mmol), 2-bromo-5-methoxybenzaldehyde (4.30 g, 0.02 mol), Pd(OAc)₂ (0.23 g, 0.001 mol), TBACl (5.56 g, 0.02 mol), NaOAc (6.56 g, 0.08 mol), and DMF (100 mL) was stirred in an oil bath heated to 100 °C for 24 hours. H₂O (500 mL) was added to the resulting mixture, and extraction was performed using EtOAc (300 mL x 3). The resulting organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% EtOAc / PE) to give 6-methoxy-2,3-diphenyl-1H-indone (3.60 g, 11.54 mmol, yield 57.7%) as a red solid.

[0174] By confirming the MS (ESI) of the obtained compound 2 (hereinafter chemical formula 3) and 1 H NMR yielded the following data: [Chemical Formula 3]

[0175] MS(ESI): C 22 H 16 O2 312.1 m / z, measured value 312.8 [M+1] + .

[0176] 1 H NMR (400 MHz, DMSO-d6) δ 7.47 - 7.46 (m, 3H), 7.39 - 7.37 (m, 2H), 7.31 - 7.23 (m, 3H), 7.17 - 7.14 (m, 3H), 7.07 (d, J = 8.1 Hz, 1H), 6.97 (dd,J = 8.1, 2.4 Hz, 1H), 3.83 (s, 3H).

[0177] Preparation Example 3. 2,3-Diphenyl-6-propoxy-1H-inden-1-one (2,3-diphenyl-6-propoxy-1H- inden-1-one) (compound 3) [Reaction 3]

[0178] Step 1: Synthesis of 6-hydroxy-2,3-diphenyl-1H-inden-1-one A mixture of 6-methoxy-2,3-diphenyl-1H-inden-1-one (100 mg, 0.3201 mol) and Py·HCl (147.96 mg, 1.2804 mol) was stirred at 160 °C under N2 for 24 hours. After cooling to room temperature, the residue was diluted with water and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (5%, MeOH / DCM) to give 6-hydroxy-2,3-diphenyl-1H-inden-1-one (60 mg, 0.1911 mol, 59.70%) as a white solid.

[0179] MS (ESI): C 21 H 14 O2 298.1 m / z, measured value 299.1 [M+1] + .

[0180] 1 H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 7.48 - 7.42 (m, 3H), 7.39 -7.33 (m, 2H), 7.29 - 7.22 (m, 3H), 7.14 (d, J = 6.9 Hz, 2H), 6.96 (d, J = 7.6Hz, 2H), 6.78 (dd, J = 7.7, 1.9 Hz, 1H).

[0181] Step 2: Synthesis of 2,3-diphenyl-6-propoxy-1H-inden-1-one (Compound 3) A mixture of 6-hydroxy-2,3-diphenyl-1H-indene-1-one (50 mg, 0.1676 mmol), 1-iodopropane (42.74 mg, 0.2514 mmol), K₂CO₃ (69.49 mg, 0.5028 mmol), and acetone (4 mL) was stirred at 60 °C for 5 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (10% EA / PE) to give 2,3-diphenyl-6-propoxy-1H-indene-1-one (30 mg, 0.0837 mmol, yield 49.94%).

[0182] By confirming the MS (ESI) of the obtained compound 3 (hereinafter chemical formula 4) and 1 H NMR yielded the following data: [Chemical Formula 4]

[0183] MS (ESI): C 24 H 20 O2 340.1 m / z, measured value 341.1 [M+1] + .

[0184] 1 H NMR (400 MHz, DMSO-d6) δ 7.49 - 7.43 (m, 3H), 7.38 (dt, J = 6.0, 3.2 Hz, 2H), 7.31 - 7.23 (m, 3H), 7.16 (dd, J = 7.6, 1.7 Hz, 2H), 7.11 (d, J= 2.3 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.96 (dd, J = 8.1, 2.4 Hz, 1H), 4.01(t, J = 6.5 Hz, 2H), 1.81 - 1.65 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).

[0185] Preparation Example 4. 6-Isopropoxy-2,3-diphenyl-1H-inden-1-one (6-isopropoxy-2,3-diphenyl- 1H-inden-1-one) (compound 4) [Reaction 4]

[0186] Acetone (4 mL) was added to 6-hydroxy-2,3-diphenyl-1H-indene-1-one (50 mg, 0.1676 mmol), 2-iodopropane (42.74 mg, 0.2514 mmol), and K₂CO₃ (69.49 mg, 0.5028 mmol), and the reaction mixture was reacted at 60 °C for 5 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% EA / PE) to give 6-isopropoxy-2,3-diphenyl-1H-indene-1-one (30 mg, 0.0837 mmol, yield 49.94%).

[0187] By confirming the MS (ESI) of the obtained compound 4 (hereinafter chemical formula 5) and 1 H NMR yielded the following data: [Chemical Formula 5]

[0188] MS (ESI): C 24 H 20 O2 340.1 m / z, measured value 340.8 [M+1] + .

[0189] 1 H NMR (400 MHz, DMSO-d6) δ 7.49 - 7.42 (m, 3H), 7.38 (dd, J = 6.6,3.0 Hz, 2H), 7.31 - 7.23 (m, 3H), 7.19 - 7.12 (m, 2H), 7.10 (d, J = 2.3 Hz,1H), 7.04 (d, J = 8.1 Hz, 1H), 6.95 (dd, J = 8.1, 2.3 Hz, 1H), 4.72 (dt, J =12.0, 6.0 Hz, 1H), 1.28 (d, J = 6.0 Hz, 6H).

[0190] Preparation Example 5. 2-Phenylacetyl-3-(o-tolyl)-1H-inden-1-one (2-phenyl-3-(o-tolyl)-1H- inden-1-one) (compound 5) [Reaction 5]

[0191] Step 1: Synthesis of 2-phenyl-3-(trimethylsilyl)-1H-inden-1-one 200 mL of ACN was added to trimethyl(2-phenylethynyl)silane (10 g, 57 mmol), methyl 2-(dihydroxyboranyl)benzoate (15.4 g, 85 mmol), and 1,2-bis(diphenylphosphino)ethane (2.3 g, 5 mmol), along with Co(acac)₂ (2 g, 5 mmol). The reaction mixture was stirred at 80 °C under N₂ for 16 hours. After cooling to room temperature, the residue was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc (20 mL x 3). The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The concentrated residue was purified by silica gel column chromatography (10% EtOAc / PE) to give 2-phenyl-3-(trimethylsilyl)-1H-indone (12 g, 43 mmol, 75.44%) as a white solid.

[0192] MS (ESI): Calculated value is C 18 H 18 OSi 278.1 m / z, measured value 279.1 [M+1]+.

[0193] Step 2: Synthesis of 3-bromo-2-phenyl-1H-inden-1-one Br2 (4.14 g, 25.9 mmol) was added to a solution of 2-phenyl-3-(trimethylsilyl)-1H-inden-1-one (6.0 g, 21.6 mmol) in 100 mL of DCM. The reaction mixture was stirred at room temperature for 2 hours, then extracted with DCM (100 mL x 3). The combined organic layers were washed with water and brine, dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (15% EtOAc / PE) to give 3-bromo-2-phenyl-1H-inden-1-one (4.1 g, 14.3 mmol, yield 66.60%) as a yellow solid.

[0194] MS (ESI): C 15 H9BrO 284.0 m / z, measured value 285.0 [M+1] + .

[0195] 1H NMR (400 MHz, DMSO-d6) δ 7.70 - 7.56 (m, 3H), 7.55 - 7.41 (m, 5H), 7.35 - 7.33 (m, 1H).

[0196] Step 3: Synthesis of 2-phenyl-3-(o-tolyl)-1H-inden-1-one (Compound 5) 1,4-Dioxane / water (5 mL; 4:1) was added to 3-bromo-2-phenyl-1H-indene-1-one (200 mg, 0.7014 mmol), (2-methylphenyl)boranediol (143.04 mg, 1.0521 mmol), and tetrakis(triphenylphosphine)palladium (40.53 mg, 0.035 mmol), followed by the addition of K₂CO₃ (387.76 mg, 2.8056 mmol). The reaction mixture was stirred at 45 °C for 5 hours. The mixture was extracted with EtOAc (30 mL x 3). The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The resulting concentrated residue was analyzed by prep-HPLC (Gemini 5). C 18 Purification was performed using a chromatographic column (150 x 21.2 mm, 30%–90% ACN / H₂O w / 0.1% FA) to obtain 2-phenyl-3-(o-tolyl)-1H-inden-1-one (70 mg, 0.2364 mmol, 33.72%) as a white solid.

[0197] The MS (ESI) of the obtained compound 5 (hereinafter chemical formula 6) was confirmed. 1 H NMR yielded the following data: [Chemical Formula 6]

[0198] MS (ESI): C 22 H 16 O 296.1 m / z, measured value 297.1 [M+1] + .

[0199] 1H NMR (400 MHz, DMSO-d6) δ 7.56 (d, J = 6.8 Hz, 1H), 7.47 (t, J = 7.2Hz, 1H), 7.42- 7.23 (m, 8H), 7.19 (dd, J = 7.2, 2.4 Hz, 2H), 6.79 (d, J = 7.2Hz, 1H), 2.02 (s, 3H).

[0200] Preparation Example 6. 3-Phenylacetyl-2-(o-tolyl)-1H-inden-1-one (3-phenyl-2-(o-tolyl)-1H- inden-1-one) (compound 6) [Reaction Formula 6]

[0201] Step 1: Synthesis of 2-bromo-3-phenyl-1H-inden-1-one A mixture containing 3-phenyl-2,3-dihydro-1H-inden-1-one (500 mg, 2.40 mmol), PPh3·HBr (1647.98 mg, 4.80 mmol), and DMSO (10 mL) was stirred at 50 °C for 9 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EA (20 mL x 3). The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The concentrated residue was purified by silica gel column chromatography (10% EA / PE) to give 2-bromo-3-phenyl-1H-inden-1-one (500 mg, 1.6659 mmol, 69.39%).

[0202] MS (ESI): C 15 H9BrO 284.0 m / z, measured value 284.6 [M+1] + .

[0203] 1 H NMR (400 MHz, DMSO-d6) δ 7.74 - 7.55 (m, 6H), 7.50 (t, J = 8.0 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H).

[0204] Step 2: Synthesis of 3-phenyl-2-(o-tolyl)-1H-inden-1-one (compound 6) A mixture of 2-bromo-3-phenyl-1H-indene-1-one (100 mg, 0.3507 mmol), o-tolylboronic acid (71.52 mg, 0.5260 mmol), Pd(PPh3)4 (40.53 mg, 0.0350 mmol), K2CO3 (96.94 mg, 0.7014 mmol), and 1,4-dioxane / water (5 mL / 1 mL) was stirred at 70 °C for 6 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (10% EA / PE) to give 3-phenyl-2-(o-tolyl)-1H-indene-1-one (40 mg, 0.1282 mmol, 36.56%).

[0205] By confirming the MS (ESI) of the obtained compound 6 (hereinafter chemical formula 7) and 1 H NMR yielded the following data: [Chemical Formula 7]

[0206] MS (ESI): C 22 H 16 O 296.1 m / z, measured value 296.7 [M+1] + .

[0207] 1 H NMR (400 MHz, DMSO-d6) δ 7.54 (dd, J = 14.8, 7.2 Hz, 2H), 7.41 (t,J = 5.7 Hz, 4H), 7.34 (dd, J = 6.0, 2.6 Hz, 2H), 7.30 (d, J = 7.4 Hz, 1H), 7.19 (qd, J = 14.8, 7.3 Hz, 3H), 7.05 (d, J = 7.5 Hz, 1H), 1.97 (s, 3H).

[0208] Preparation Example 7. 3-Phenylacetonate 2-(pyridin-3-yl)-1H-inden-1-one (3-phenyl-2-(pyridin-3-yl)- 1H-inden-1-one) (compound 7) [Reaction Formula 7]

[0209] A mixture of 2-bromo-3-phenyl-1H-indene-1-one (100 mg, 0.3507 mmol), pyridin-3-ylboronic acid (64.66 mg, 0.5260 mmol), Pd(PPh3)4 (40.53 mg, 0.0350 mmol), K2CO3 (96.94 mg, 0.7014 mmol), and 1,4-dioxane / water (5 mL / 1 mL) was stirred at 70 °C for 6 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (10% EA / PE) to give 3-phenyl-2-(pyridin-3-yl)-1H-indene-1-one (40 mg, 0.1341 mmol, 38.24%).

[0210] By confirming the MS (ESI) of the obtained compound 7 (hereinafter chemical formula 8) and 1 H NMR yielded the following data: [Chemical Formula 8]

[0211] MS (ESI): C 20 H 13 NO 283.1 m / z, measured value 283.7 [M+1] + .

[0212] 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (dd, J = 4.8, 1.6 Hz, 1H), 8.34 (d, J= 1.6 Hz, 1H), 7.64 - 7.59 (m, 2H), 7.53 (ddd, J = 10.0, 7.1, 1.7 Hz, 4H), 7.47 - 7.40 (m, 3H), 7.37 (dd, J = 7.9, 4.8 Hz, 1H), 7.21 (d, J = 7.3 Hz, 1H).

[0213] Preparation Example 8. 2-morpholino-3-phenyl-1H-inden-1-one one)(Compound 8) [Reaction Equation 8]

[0214] A mixture of 2-bromo-3-phenyl-1H-indanone (50 mg, 0.1754 mmol), morpholine (76.4 mg, 0.877 mmol), and toluene (3 mL) was stirred at 110 °C for 6 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (10% EA / PE) to give 2-morpholino-3-phenyl-1H-indanone (40 mg, 0.1304 mmol, yield 74.34%).

[0215] The MS (ESI) of the obtained compound 8 (hereinafter chemical formula 9) was confirmed. 1 H NMR yielded the following data: [Chemical Formula 9]

[0216] MS (ESI): C 19 H 17 NO2 291.1 m / z, measured value 292.0 [M+1] + .

[0217] 1 H NMR (400 MHz, DMSO-d6) δ 7.54 - 7.46 (m, 2H), 7.41 (dd, J = 14.9,7.1 Hz, 3H), 7.24 (t, J = 7.5 Hz, 2H), 7.02 (t, J = 7.3 Hz, 1H), 6.65 (d, J =7.2 Hz, 1H), 3.59 - 3.42 (m, 4H), 3.11 - 2.97 (m, 4H).

[0218] Preparation Example 9. 2-Phenylacetyl-3-(pyridin-3-yl)-1H-inden-1-one (2-phenyl-3-(pyridin-3-yl)- 1H-inden-1-one) (compound 9) [Reaction Formula 9]

[0219] Potassium carbonate (290.82 mg, 2.1042 mmol) was added to a mixture of 3-bromo-2-phenyl-1-indone (200 mg, 0.7014 mmol), pyridin-3-ylboranediol (129.32 mg, 1.0521 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (51.32 mg, 0.0701 mmol) in 1,4-dioxane / water (5 mL; 4:1). The reaction mixture was stirred at 45 °C for 5 hours. The mixture was extracted with EtOAc (25 mL x 3), the organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The concentrated residue was analyzed by prep-HPLC (Gemini 5). C 18 Purification was performed using a chromatographic column (150x21.2 mm, 0.1% FA 40%-90% ACN / H2O) to obtain 2-phenyl-3-(pyridin-3-yl)-1H-inden-1-one (26 g, 0.0919 mmol, 13.10%) as a yellow solid.

[0220] The MS (ESI) of the obtained compound 9 (hereinafter chemical formula 10) was confirmed. 1 H NMR yielded the following data: [Chemical Formula 10]

[0221] MS (ESI): C 20 H 13 NO 283.1 m / z, measured value 284.1 [M+1] + .

[0222] 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (dd, J = 4.8, 1.6 Hz, 1H), 8.54 (d, J= 1.6 Hz, 1H), 7.89 (dt, J = 8.0, 2.0 Hz, 1H), 7.59 (d, J = 6.8 Hz, 1H), 7.53(m, 2H), 7.42 (t, J = 7.2 Hz, 1H), 7.32 (m, 3H), 7.24 - 7.14 (m, 3H).

[0223] Preparation Example 10. 3-Cyclohexyl-2-phenyl-1H-inden-1-one 1-one)(Compound 10) [Reaction Formula 10]

[0224] Step 1: Synthesis of (cyclohexylethynyl)benzene THF (50 mL) and TEA (1.87 g, 18.488 mmol) were added to ethynylcyclohexane (1 g, 9.244 mmol), iodobenzene (2.07 g, 10.168 mmol), copper(I)iodide (175 mg, 0.924 mmol), and Pd(PPh3)2Cl2 (645 mg, 0.924 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with water and brine, dried with sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (1% PE / EtOAc) to obtain (cyclohexylethynyl)benzene (800 mg, 4.348 mol, 47.03%), which was a white oil.

[0225] Step 2: Synthesis of 3-cyclohexyl-2-phenyl-1H-inden-1-one (Compound 10) (2-Cyclohexylethynyl)benzene (250 mg, 1.3567 mmol), methyl 2-(dihydroxyboranyl)benzoate (366.24 mg, 2.035 mmol), and Co(acac)2 (48.3 mg, 0.1356 mmol) were added to 1,2-bis(diphenylphosphino)ethane (108.11 mg, 0.2713 mmol) in 10 mL of ACN. The reaction mixture was stirred at 80 °C for 16 hours. The mixture was extracted with EtOAc (30 mL x 3). The organic layer was washed with water and brine, dried over sodium sulfate, concentrated under reduced pressure, and analyzed by prep-HPLC (Gemini 5). C 18 Purification was performed using a chromatographic column (150x21.2 mm, 0.1% FA 60%-90% ACN / H2O) to obtain 3-cyclohexyl-2-phenyl-1H-indanone (100 mg, 0.3472 mmol, 25.59%).

[0226] The MS (ESI) of the obtained compound 10 (hereinafter chemical formula 11) was confirmed. 1 H NMR yielded the following data: [Chemical Formula 11]

[0227] MS (ESI): C 21 H 20 O 288.2 m / z, measured value 289.2 [M+1] + .

[0228] 1 H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 7.2 Hz, 1H), 7.57 - 7.43 (m,4H), 7.39 (d, J = 7.2 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.29 - 7.21 (m, 2H), 3.15 - 2.77 (m, 1H), 2.02 - 1.59 (m, 7H), 1.52 - 1.13 (m, 3H).

[0229] Preparation Example 11. 2-Cyclohexyl-3-phenyl-1H-inden-1-one 1-one)(Compound 11) [Reaction Formula 11]

[0230] THF (20 mL), P(o-tol)3 (64.2 mg, 0.210 mmol), and Ag2O (1219.1 mg, 5.26 mmol) were added sequentially to 2-bromo-3-phenyl-1H-indanone (300 mg, 1.052 mmol), cyclohexylboranediol (269.3 mg, 2.104 mmol), and Pd(OAc)2 (23.6 mg, 0.105 mmol). The reaction mixture was stirred at 85 °C for 16 hours. The mixture was extracted with DCM (60 mL x 3). The resulting organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The concentrated residue was analyzed by prep-HPLC (Gemini 5). C 18 Purification was performed using a chromatographic column (150x21.2 mm, 0.1% FA 60-90% ACN / H2O) to obtain 2-cyclohexyl-3-phenyl-1H-inden-1-one (23 mg, 0.0799 mmol, 7.81%) as a white solid.

[0231] The MS (ESI) of the obtained compound 11 (hereinafter chemical formula 12) was confirmed. 1 H NMR yielded the following data: [Chemical Formula 12]

[0232] MS (ESI): C 21 H 20 O 288.2 m / z, measured value 289.2 [M+1]+.

[0233] 1 H NMR (400 MHz, CDCl3) δ 7.58 - 7.41 (m, 4H), 7.41 - 7.35 (m, 2H), 7.30 - 7.23 (m, 1H), 7.18 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H), 2.47(m, 1H), 1.85 (m, 2H), 1.74 (d, J = 12.8 Hz, 2H), 1.69 - 1.51 (m, 3H), 1.35 -1.01 (m, 3H).

[0234] Preparation Example 12. 6-morpholino-2,3-diphenyl-1H-inden-1-one (6-morpholino-2,3-diphenyl- 1H-inden-1-one) (compound 12) [Reaction 12]

[0235] Step 1: Synthesis of 6-chloro-2,3-diphenyl-1H-inden-1-one 1,4-Dioxane (60 mL), sodium carbonate (1.78 g, 0.0168 mol), and tetrabutylammonium bromide (1.81 g, 0.0056 mol) were added to (2-phenylethynyl)benzene (1 g, 0.0056 mol), 2-bromo-4-chloro-1-iodobenzene (3.55 g, 0.0112 mmol), and PdCl2 (0.1 g, 0.0005 mol). The reaction mixture was stirred at 100 °C under CO2 conditions. After cooling the mixture to room temperature, it was filtered through diatomaceous earth, and the resulting filtrate was concentrated under reduced pressure. Water was added to the residue, and extraction was performed with EtOAc (100 mL x 3). The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification was performed by silica gel column chromatography (30% PE / EtOAc) to obtain 6-chloro-2,3-diphenyl-1H-indan-1-one (320 mg, 1.0126 mmol, 18.08%) as a white solid.

[0236] Step 2: Synthesis of 6-morpholino-2,3-diphenyl-1H-inden-1-one (Compound 12) 1,4-Dioxane (6 mL) and Cs₂CO₃ (308.55 mg, 0.947 mmol) were added to 6-chloro-2,3-diphenyl-1H-indene-1-one (150 mg, 0.4735 mmol), morpholine (82.5 mg, 0.947 mmol), and xphosPdG₃ (40.06 mg, 0.0473 mmol). The reaction mixture was stirred at 100 °C for 16 hours. The mixture was extracted with EtOAc (20 mL x 3). The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The solution was then analyzed by prep-HPLC (Gemini 5). C 18 Purification was performed using a chromatographic column (150x21.2 mm, 0.1% TFA 30-90% ACN / H2O) to obtain 6-morpholino-2,3-diphenyl-1H-indanone (41 mg, 0.1117 mmol, 23.59%) as a yellow solid.

[0237] The MS (ESI) of the obtained compound 12 (hereinafter chemical formula 13) was confirmed. 1 H NMR yielded the following data: [Chemical Formula 13]

[0238] MS (ESI): C25 H 21 NO2 367.2 m / z, measured value 368.2 [M+1] + .

[0239] 1 H NMR (400 MHz, DMSO-d6) δ 7.50 - 7.43 (m, 3H), 7.36 (m, 2H), 7.30 -7.21 (m, 4H), 7.15 (dd, J = 7.6, 1.6 Hz, 2H), 6.98 (d, J = 8.0 Hz, 1H), 6.86 (dd, J = 8.4, 2.4 Hz, 1H), 3.77 - 3.69 (m, 4H), 3.28 - 3.06 (m, 4H).

[0240] Preparation Example 13. 6-(4-methylpiperazin-1-yl)-2,3-diphenyl-1H-inden-1-one (6-(4- methylpiperazin-1-yl)-2,3-diphenyl-1H-inden-1-one) (compound 13) [Reaction Formula 13]

[0241] 1,4-Dioxane (6 mL) and Cs₂CO₃ (308.55 mg, 0.947 mmol) were added to 6-chloro-2,3-diphenyl-1-indanone (150 mg, 0.4735 mmol), 1-methylpiperazine (94.7 mg, 0.947 mmol), and xphosPdG₃ (40.06 mg, 0.0473 mmol). The reaction mixture was stirred at 100 °C for 16 hours. The mixture was extracted with EtOAc (30 mL x 3), the organic layer was washed with water and brine, dried over sodium sulfate, concentrated under reduced pressure, and analyzed by prep-HPLC (Gemini 5). C 18 Purification was performed using a chromatographic column (150x21.2 mm, 0.1% FA, 30~90% ACN / H2O) to obtain 6-(4-methylpiperazin-1-yl)-2,3-diphenyl-1H-indone (35 mg, 0.0921 mmol, 19.45%), as a yellow solid.

[0242] The MS (ESI) of the obtained compound 13 (hereinafter chemical formula 14) was confirmed. 1 H NMR yielded the following data: [Chemical Formula 14]

[0243] MS (ESI): C 26 H24 N₂O 380.2 m / z, measured value 381.2 [M+1] + .

[0244] 1 H NMR (400 MHz, DMSO-d6) δ 7.49 - 7.42 (m, 3H), 7.36 (m, 2H), 7.31 -7.20 (m, 4H), 7.14 (m, 2H), 6.96 (d, J = 8.0 Hz, 1H), 6.85 (dd, J = 8.0, 2.0Hz, 1H), 3.34 - 3.16 (m, 4H), 2.48 - 2.35 (m, 4H), 2.22 (s, 3H).

[0245] Preparation Example 14. 3-(4-morpholinophenyl)-2-phenyl-1H-inden-1-one (3-(4-morpholinophenyl)- 2-phenyl-1H-inden-1-one) (compound 14) [Reaction Formula 14]

[0246] 1,4-Dioxane / water (5 mL; 4:1) and potassium carbonate (290.82 mg, 2.1042 mmol) were added to 3-bromo-2-phenyl-1H-indene-1-one (200 mg, 0.7014 mmol), [4-(morpholin-4-yl)phenyl]boranediol (290.43 mg, 1.4028 mmol), and tetrakis(triphenylphosphine)palladium (81.05 mg, 0.0701 mmol). The reaction mixture was stirred at 45 °C for 5 hours. The mixture was extracted with EtOAc (30 mL x 3), the organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The final product was then analyzed by prep-HPLC (Gemini 5). Purification was performed using a C18 column (150x21.2mm, 0.1% FA 40-90% ACN / H2O) to obtain 3-(4-morpholinylphenyl)-2-phenyl-1H-indone (70mg, 0.1907mmol, yield 27.19%).

[0247] The MS (ESI) of the obtained compound 14 (hereinafter chemical formula 15) was confirmed. 1 H NMR yielded the following data: [Chemical Formula 15]

[0248] MS (ESI): Calculated value is C 25 H21 NO2 367.2 m / z, measured value 368.2 [M+1]+.

[0249] 1 H NMR (400 MHz, DMSO-d6) δ 7.51 (m, 2H), 7.39 (d, J = 7.2 Hz, 1H), 7.29 (m, 6H), 7.21 (d, J = 7.6 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 3.95 - 3.63(m, 4H), 3.27 - 3.17(m, 4H).

[0250] Preparation Example 15. 3-(3-morpholinophenyl)-2-phenyl-1H-inden-1-one (3-(3-morpholinophenyl)- 2-phenyl-1H-inden-1-one) (compound 15) [Reaction Formula 15]

[0251] 1,4-Dioxane / water (5 mL; 4:1) and potassium carbonate (290.82 mg, 2.1042 mmol) were added to 3-bromo-2-phenyl-1H-indanone (200 mg, 0.7014 mmol), [3-(morpholin-4-yl)phenyl]boranediol (290.43 mg, 1.4028 mmol), and tetrakis(triphenylphosphine)palladium (81.05 mg, 0.0701 mmol). The reaction mixture was stirred at 45 °C for 5 hours. The mixture was extracted with EtOAc (30 mL x 3). The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. Then, the mixture was analyzed by prep-HPLC (Gemini 5). Purification was performed using a C18 column (150x21.2mm, 0.1% FA 40%-90% ACN / H2O) to obtain 3-(3-morpholinylphenyl)-2-phenyl-1H-indone (135mg, 0.3678mmol, 52.44%).

[0252] The MS (ESI) of the obtained compound 15 (hereinafter chemical formula 16) was confirmed. 1 H NMR yielded the following data: [Chemical Formula 16]

[0253] MS (ESI): C 25 H 21 NO2 367.2 m / z, measured value 368.2 [M+1]+.

[0254] 1 H NMR (400 MHz, DMSO-d6) δ 7.58 - 7.45 (m, 2H), 7.38 (t, J = 7.2 Hz,1H), 7.34 - 7.25 (m, 4H), 7.24 - 7.17 (m, 3H), 7.04 (d, J = 8.4 Hz, 1H), 6.90(s, 1H), 6.80 (d, J = 7.2 Hz, 1H), 4.01 - 3.54 (m, 4H), 3.09 - 2.90 (m, 4H).

[0255] Preparation Example 16. 3-(4-(morpholinylmethyl)phenyl)-2-phenyl-1H-inden-1-one (3-(4- (morpholinomethyl)phenyl)-2-phenyl-1H-inden-1-one) (compound 16) [Reaction Formula 16]

[0256] A mixture of 1,4-dioxane / water (5 mL; 4:1) and potassium carbonate (290.82 mg, 2.1042 mmol) was added to a mixture of 3-bromo-2-phenyl-1H-indene-1-one (200 mg, 0.7014 mmol), [4-(morpholin-4-ylmethyl)phenyl]boranediol (310.10 mg, 1.4028 mmol), and tetrakis(triphenylphosphine)palladium (81.05 mg, 0.701 mmol). The reaction mixture was stirred at 45 °C for 5 hours. The mixture was extracted with EtOAc (30 mL x 3). The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The final product was then analyzed by prep-HPLC (Gemini 5). Purification was performed using a C18 column (150x21.2mm, 0.1% FA, 40%-90% ACN / H2O) to obtain 3-(4-(morpholinylmethyl)phenyl)-2-phenyl-1H-indone (100mg, 0.2625mmol, yield 37.42%).

[0257] The MS (ESI) of the obtained compound 16 (hereinafter chemical formula 17) was confirmed. 1 H NMR yielded the following data: [Chemical Formula 17]

[0258] MS (ESI): C 26 H 23NO2 381.2 m / z, measured value 382.2 [M+1]+.

[0259] 1 H NMR (400 MHz, DMSO-d6) δ 7.55 (d, J = 6.8 Hz, 1H), 7.51 (m, 1H), 7.43 - 7.33 (m, 5H), 7.33 - 7.26 (m, 3H), 7.23 - 7.15 (m, 3H), 3.64 - 3.55(m, 4H), 3.51(s, 2H), 2.37(s, 4H).

[0260] Preparation Example 17. 2-(4-morpholinophenyl)-3-phenyl-1H-inden-1-one (2-(4-morpholinophenyl)- 3-phenyl-1H-inden-1-one) (compound 17) [Reaction Formula 17]

[0261] A mixture of 2-bromo-3-phenyl-1H-indone (100 mg, 0.3507 mmol), (4-morpholinophenyl)boronic acid (108.91 mg, 0.5260 mmol), Pd(PPh3)4 (40.53 mg, 0.0350 mmol), K2CO3 (96.94 mg, 0.7014 mmol), and 1,4-dioxane / water (5 mL / 1 mL) was stirred at 70 °C for 6 hours. The mixture was passed through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% EA / PE) to give 2-(4-morpholinophenyl)-3-phenyl-1H-indone (60 mg, 0.1551 mmol, 44.23%).

[0262] The MS (ESI) of the obtained compound 17 (hereinafter chemical formula 18) was confirmed. 1 H NMR yielded the following data: [Chemical Formula 18]

[0263] MS (ESI): C 25 H 21 NO2367.2 m / z, measured value is 368.1 [M+1]+.

[0264] 1 H NMR (400 MHz, DMSO-d6) δ 7.53 - 7.44 (m, 5H), 7.41 (dd, J= 7.7, 1.6Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.09 (dd, J = 11.5, 8.1 Hz, 3H), 6.84 (d, J =8.9 Hz, 2H), 3.76 - 3.61 (m, 4H), 3.16 - 3.06 (m, 4H).

[0265] Preparation Example 18. 2-(3-morpholinophenyl)-3-phenyl-1H-inden-1-one (2-(3-morpholinophenyl)- 3-phenyl-1H-inden-1-one) (compound 18) [Reaction Formula 18]

[0266] A mixture of 2-bromo-3-phenyl-1H-indone (100 mg, 0.3507 mmol), (3-morpholinophenyl)boronic acid (108.91 mg, 0.5260 mmol), Pd(PPh3)4 (40.53 mg, 0.0350 mmol), K2CO3 (96.94 mg, 0.7014 mmol), and 1,4-dioxane / water (5 mL / 1 mL) was stirred at 70 °C for 6 hours. The mixture was passed through diatomaceous earth, and the resulting filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (20% EA / PE) to give 2-(3-morpholinophenyl)-3-phenyl-1H-indone (50 mg, 0.1293 mmol, 36.87%).

[0267] The MS (ESI) of the obtained compound 18 (hereinafter chemical formula 19) was confirmed. 1 H NMR yielded the following data: [Chemical Formula 19]

[0268] MS (ESI): C 25 H 21 NO2 367.2 m / z, measured value 367.7 [M+1]+.

[0269] 1 H NMR (400 MHz, DMSO-d6) δ 7.54 (d, J = 6.9 Hz, 1H), 7.48 (dt, J = 8.0,5.0 Hz, 4H), 7.43 - 7.35 (m, 3H), 7.15 (dd,J = 9.7, 7.6 Hz, 2H), 6.87 (dd, J =8.2, 2.2 Hz, 1H), 6.72 (s, 1H), 6.67 (d, J = 7.6 Hz, 1H), 3.72 - 3.57 (m, 4H), 2.96 - 2.84 (m, 4H).

[0270] Preparation Example 19. 3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (3-(4-) methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one) (compound 19) [Reaction Formula 19]

[0271] Step 1: Synthesis of 4-methyl-5-((trimethylsilyl)ethynyl)thiazole TEA (20 mL) and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.41 g, 0.0005 mol) were added to 5-bromo-4-methyl-1,3-thiazole (1 g, 0.0056 mol), ethynyltrimethylsilane (1.1 g, 0.0112 mmol), and cuprous iodide (0.11 g, 0.0005 mol). The reaction mixture was stirred at 60 °C under N2 for 12 hours. After cooling the reaction mixture to room temperature, it was filtered through diatomaceous earth, and the resulting filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc (60 mL x 3). The organic layer was washed with water and brine, dried with sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (10% EtOAc / PE) to obtain 4-methyl-5-((trimethylsilyl)ethynyl)thiazole (800 mg, 4.1026 mmol, yield 73.26%), which was a red oil.

[0272] MS (ESI): C9H 13 NSSi 195.1 m / z, measured value 196.1 [M+1]+.

[0273] Step 2: Synthesis of 3-(4-methylthiazol-5-yl)-2-(trimethylsilyl)-1H-inden-1-one 1,4-Dioxane (40 mL), sodium carbonate (813.7 mg, 7.677 mmol), and tetrabutylammonium bromide (824.9 mg, 2.559 mmol) were added to 4-methyl-5-[2-(trimethylsilyl)ethynyl]-1,3-thiazole (500 mg, 2.559 mmol), 1-bromo-2-iodobenzene (1447.9 mg, 5.118 mmol), and PdCl2 (45.4 mg, 0.255 mmol). The reaction mixture was stirred at 100 °C under CO2 conditions. After the reaction mixture was cooled to room temperature, it was extracted with DCM (100 mL x 3). The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. Then, it was purified by silica gel column chromatography (15% EtOAc / PE) to obtain 3-(4-methylthiazolyl-5-yl)-2-(trimethylsilyl)-1H-indone (200 mg, 0.6667 mol, 26.05%) as a yellow solid.

[0274] Step 3: Synthesis of 2-bromo-3-(4-methylthiazol-5-yl)-1H-inden-1-one Add DCM (5 mL) and N-bromosuccinimide ( N Bromosuccinimide (237.8 mg, 1.336 mmol) was added to 3-(4-methyl-thiazolyl-5-yl)-2-(trimethylsilyl)indone (200 mg, 0.668 mmol). The reaction mixture was stirred at 40 °C for 1 hour. The mixture was extracted with DCM (25 mL x 3). The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (35% EtOAc / PE) to give 2-bromo-3-(4-methylthiazolyl-5-yl)-1H-indone (160 mg, 0.5246 mol, 78.53%) as a yellow solid.

[0275] Step 4: Synthesis of 3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (compound 19) 1,4-Dioxane / water (8 mL; 4:1) and potassium carbonate (216.96 mg, 1.5696 mmol) were added to 2-bromo-3-(4-methyl-thiazolyl-5-yl)-1H-inden-1-one (160 mg, 0.5232 mmol), pyridin-3-ylboranediol (128.64 mg, 1.0464 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (38.24 mg, 0.0512 mmol). The reaction mixture was stirred at 70 °C for 6 hours. The mixture was extracted with EtOAc (40 mL x 3). The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The concentrated residue was analyzed by prep-HPLC (Gemini 5). C 18 Purification was performed using a chromatographic column (150x21.2 mm, 0.1% FA 30-90% ACN / H2O) to obtain 3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-indone (30 mg, 0.0986 mmol, 18.86%), as a yellow solid.

[0276] The MS (ESI) of the obtained compound 19 (hereinafter chemical formula 20) was confirmed. 1 H NMR yielded the following data: [Chemical Formula 20]

[0277] MS (ESI): C 18 H 12 N2OS 304.1 m / z, measured value 305.1 [M+1]+.

[0278] 1 H NMR (400 MHz, DMSO) δ 9.32 (s, 1H), 8.51 (dd, J = 4.8, 1.6 Hz, 1H), 8.38 (d, J = 1.6 Hz, 1H), 7.72 - 7.55 (m, 3H), 7.52 - 7.39 (m, 2H), 7.25 (d, J =7.6 Hz, 1H), 1.97 (s, 3H).

[0279] Preparation Example 20. 3-(4-methylthiazolyl-5-yl)-6-((3-phenylpropyl)amino)-2-(pyridin-3-yl)-1H- Inden-1-one(3-(4-methylthiazol-5-yl)-6-((3-phenylpropyl)amino)-2-(pyridin-3-yl)- 1H-inden-1-one) (compound 20) [Reaction 20]

[0280] Step 1: Synthesis of (E)-1-(2-bromo-5-chlorophenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one EtOH (30 mL) was added to 5-methyl-1,3-thiazolyl-4-carboxaldehyde (2 g, 0.0086 mol) and 1-(3-hydroxyphenyl)ethanone (1.2 g, 0.0094 mol), and stirred at 20 to 25 °C for 10 minutes. The solution was cooled to 0 to 5 °C, and H₂O (5 mL) and NaOH (516 mg, 0.0129 mol) were added. The mixture was then stirred at room temperature for 4 hours, adjusted to pH 7 with 1 N HCl, and the resulting solid was filtered to give (E)-1-(2-bromo-5-chlorophenyl)-3-(4-methylthiazolyl-5-yl)prop-2-en-1-one (2.1 g, 0.0061 mmol, 70.93%).

[0281] Step 2: Synthesis of 6-chloro-3-(4-methylthiazol-5-yl)-1H-inden-1-one DMF (50 mL) and potassium carbonate (1.6 g, 11.6744 mmol) were added to (E)-1-(2-bromo-5-chlorophenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one (2 g, 5.8372 mmol), PdCl2 (103.52 mg, 0.2536 mmol), and PPh3 (306.2 mg, 1.1672 mmol). The reaction mixture was stirred at 100 °C for 4 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and extraction was performed with DCM (120 mL x 3). The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification was performed by silica gel column chromatography (2% MeOH / DCM) to obtain 6-chloro-3-(4-methylthiazolyl-5-yl)-1H-indone (550 mg, 2.1072 mmol, 36.33%) as a yellow solid.

[0282] Step 3: Synthesis of 2-bromo-6-chloro-3-(4-methylthiazol-5-yl)-1H-inden-1-one DCM (5 mL) and Br2 (268.66 mg, 1.6811 mmol) were added to 6-chloro-3-(4-methylthiazol-5-yl)-1H-inden-1-one (400 mg, 1.5283 mmol). The reaction mixture was stirred at 0 °C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM (20 mL x 3). The organic layer was washed with water and brine, dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (2% MeOH / DCM) to give 2-bromo-6-chloro-3-(4-methylthiazol-5-yl)-1H-inden-1-one (350 mg, 1.0294 mmol, yield 67.37%) as a yellow solid.

[0283] Step 4: Synthesis of 6-chloro-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one 1,4-Dioxane / water (10 mL; 4:1) and Na₂CO₃ (124.4 mg, 1.174 mmol) were added to 2-bromo-6-chloro-3-(4-methylthiazolyl-5-yl)-1H-inden-1-one (200 mg, 0.587 mmol), pyridin-3-ylboranediol (108.2 mg, 0.88 mmol), and tetrakis(triphenylphosphine)palladium (67.8 mg, 0.058 mmol). The reaction mixture was stirred at 90 °C for 5 hours. The mixture was passed through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with DCM (90 mL x 3). The organic layer was washed with water and brine, dried with sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (10% MEOH / DCM) to give 6-chloro-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-indone (170 mg, 0.5060 mmol, 86.20%).

[0284] Step 5: Synthesis of 3-(4-methylthiazol-5-yl)-6-((3-phenylpropyl)amino)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 20) 1,4-Dioxane (7 mL) and Cs₂CO₃ (288.45 mg, 0.8853 mmol) were added to 6-chloro-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-indene-1-one (100 mg, 0.2951 mmol), 2-phenylethanamine (71.52 mg, 0.5902 mmol), and xphosPdG₃ (24.97 mg, 0.0295 mmol). The reaction mixture was stirred at 100 °C under N₂ for 16 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc (40 mL x 3). The organic layer was washed with water and brine, dried over sodium sulfate, concentrated under vacuum, and analyzed by prep-HPLC (Gemini 5). Purification was performed using a C18 column (150x21.2 mm, 0.1% FA 30-90% ACN / H2O) to obtain 3-(4-methylthiazolyl-5-yl)-6-((3-phenylpropyl)amino)-2-(pyridin-3-yl)-1H-indone (40 mg, 0.0915 mmol, 31.01%) as a red solid.

[0285] The MS (ESI) of the obtained compound 20 (hereinafter chemical formula 21) was confirmed. 1 H NMR yielded the following data: [Chemical Formula 21]

[0286] MS (ESI): C 27 H 23 N3OS 437.2 m / z, measured value 438.2 [M+1]+.

[0287] 1 H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.43 (dd, J = 4.8, 1.2 Hz, 1H), 8.31 (d, J = 1.2 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.42 - 7.13 (m, 6H), 7.01 - 6.86 (m, 2H), 6.62 (t, J = 5.2 Hz, 1H), 6.44 (dd, J = 8.4, 2.0 Hz, 1H), 3.10 (dd, J= 12.8, 6.8 Hz, 2H), 2.75 - 2.60 (m, 2H), 1.94 (s, 3H), 1.86 (m, 2H).

[0288] Preparation Example 21. 2-(4-methylpyridin-3-yl)-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)- 1H-Inden-1-one(2-(4-methylpyridin-3-yl)-3-(4-methylthiazol-5-yl)-6-(3- (phenylpropoxy)-1H-inden-1-one)(compound 21) [Reaction 21]

[0289] Step 1: Synthesis of (E)-1-(3-hydroxyphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one At 0 °C, a NaOH solution (2.65 g, 66.2 mmol, 20 mL H₂O) was added to a solution of 1-(3-hydroxyphenyl)ethyl ketone (4.50 g, 33.1 mmol) and 4-methyl-1,3-thiazol-5-carboxaldehyde (6.31 g, 49.6 mmol) in 100 mL of ethanol. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated, dissolved in ethyl acetate, and adjusted to pH 3 with 1 N HCl solution. Then, it was extracted with EtOAc (200 mL x 3), the organic layer was washed with brine, dried over Na₂SO₄, and concentrated to give (E)-1-(3-hydroxyphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one (2.8 g, 90% purity, 10.3 mmol, yield 31.1%) as a yellow solid.

[0290] MS (ESI): C 13 H 11 NO2S 245.1 m / z, measured value 246.1 [M+1]+.

[0291] Step 2: Synthesis of 6-hydroxy-3-(4-methylthiazol-5-yl)-2,3-dihydro-1H-inden-1-one (E)-1-(3-hydroxyphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one (2.2 g, 9.00 mol) was added in portions to HOTf (25 mL) at 0 to 5 °C. The resulting mixture was stirred at 25 °C for 16 hours and concentrated. It was then dissolved in DCM / water (50 mL / 50 mL) and extracted with DCM (2 x 50 mL). By drying and concentration under reduced pressure, 6-hydroxy-3-(4-methylthiazol-5-yl)-2,3-dihydro-1H-inden-1-one (2.2 g, 95% purity, 8.53 mmol, 94.4% yield) was given as a yellow solid.

[0292] MS (ESI): C 13 H 11 NO2S 245.1 m / z, measured value 246.1 [M+1]+.

[0293] Step 3: Synthesis of 1-(4-methylthiazol-5-yl)-3-oxo-2,3-dihydro-1H-inden-5-yl acetate At 0 °C, Ac₂O (2.76 g, 26.9 mmol) was added to a solution of 6-hydroxy-3-(4-methylthiazol-5-yl)-2,3-dihydro-1H-indene-1-one (2.2 g, 8.98 mmol) and pyridine (2.14 g, 26.9 mmol) in DCM (30 mL). The reaction mixture was stirred at 25 °C for 3 hours, and water (50 mL) was added. The mixture was then extracted with DCM (50 mL x 3), the organic layer was washed with brine, dried over Na₂SO₄, concentrated, and purified by silica gel column chromatography (6% MeOH / DCM) to give 1-(4-methylthiazol-5-yl)-3-oxo-2,3-dihydro-1H-indene-5-yl acetate (2.4 g, 95% purity, 7.94 mmol, yield 88.4%) as a yellow solid.

[0294] MS (ESI): C 15 H 13 NO3S 287.1 m / z, measured value 288.1 [M+1]+.

[0295] Step 4: Synthesis of 2-bromo-3-(4-methylthiazol-5-yl)-1-oxo-1H-inden-6-yl acetate A mixture of 1-(4-methylthiazol-5-yl)-3-oxo-1H-indene-5-yl acetate (1.22 g, 4.25 mmol), NBS (1.64 g, 9.24 mmol), AIBN (0.07 g, 0.42 mol), CCl4 (20 mL), and ACN (4 mL) was stirred at 70 °C for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (15% EtOAc / PE) to give 2-bromo-3-(4-methylthiazol-5-yl)-1-oxo-1H-indene-6-yl acetate (1.42 g, 80% purity, 3.12 mmol, 73.4%) as a red oil.

[0296] MS (ESI): C 15 H 10 BrNO3S 363.0 m / z, measured value 364.1 [M+1]+.

[0297] Step 5: Synthesis of 6-hydroxy-2-(4-methylpyridin-3-yl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one 1,4-Dioxane (15 mL) and water (3 mL) were added to 2-bromo-3-(4-methylthiazo-5-yl)-1-oxo-1H-indene-6-yl acetate (1.42 g, 3.90 mmol), (4-methylpyridin-3-yl)boranediol (641 mg, 4.68 mmol), Pd(dppf)Cl2CH2Cl2 (159 mg, 0.195 mmol), and K2CO3 (1.62 g, 1.17 mmol), and stirred at 90 °C for 16 hours. Water (30 mL) was added to the resulting mixture, and extraction was performed using EtOAc (30 mL x 3). The organic layer was washed with brine, dried over Na₂SO₄, concentrated, and purified by silica gel column chromatography (6% MeOH / DCM) to give 6-hydroxy-2-(4-methylpyridin-3-yl)-3-(4-methylthiazolyl-5-yl)-1H-inden-1-one (21-8) (600 mg, 70% purity, 1.26 mmol, 32.2%), as a yellow solid. 260 mg of the 70% pure compound was then purified by prep-HPLC (Gemini 5). C 18The chromatographic column (150x21.2mm, 0.1% FA 22-55% ACN / H2O) was used for secondary purification to obtain 20 mg of the title compound with a purity of 98%.

[0298] MS (ESI): C 19 H 14 N2O2S 334.1 m / z, measured value 349.1 [M+1]+.

[0299] 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (br, 1H), 9.23 (s, 1H), 8.36 (d, J =4.8Hz, 1H), 8.12 (s, 1H), 7.27 - 7.26 (m, 1H), 7.11 - 7.09 (m, 1H), 6.99 -6.98 (m, 1H), 6.85 - 6.83 (m, 1H), 2.03 (s, 3H), 1.95 (s, 3H).

[0300] Step 6: Synthesis of 2-(4-methylpyridin-3-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one (2-(4-methylpyridin-3-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one) (Compound 21) 6-hydroxy-2-(4-methylpyridin-3-yl)-3-(4-methylthiazolyl-5-yl)-1H-inden-1-one (21-8) (240 mg, 0.718 mmol), (3-bromopropyl)benzene (286 mg, 1.44 mmol), K₂CO₃ (297 mg, 2.15 mmol), and DMF (8 mL) were stirred at 25 °C for 3 hours. Water (20 mL) was added to the resulting mixture, and extraction was performed using EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, concentrated, and analyzed using prep-HPLC (Gemini 5). C 18 The chromatographic column (150x21.2 mm, 0.1% NH3H2O, 65-95% ACN / H2O) was used for purification to obtain 2-(4-methylpyridin-3-yl)-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-1H-indone (compound 21) (60 mg, purity 95.6%, 0.126 mmol, yield 17.5%).

[0301] By confirming the MS (ESI) of the obtained compound 21 (hereinafter chemical formula 22) and 1 H NMR yielded the following data: [Chemical Formula 22]

[0302] MS (ESI): C 28 H 24 N2O2S 452.2 m / z, measured value 453.2 [M+1]+.

[0303] 1 H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.36 (d, J = 4.8Hz, 1H), 8.14(s, 1H), 7.30 - 7.17 (m, 8H), 7.04 - 7.01 (m, 1H), 4.06 (t, J = 6.4Hz, 2H), 2.75 (t, J = 7.6Hz, 2H), 2.07 - 2.01 (m, 5H), 1.96 (s, 3H).

[0304] Preparation Example 22. 6-Methoxy-2-(4-methylpyridin-3-yl)-3-(4-methylthiazolyl-5-yl)-1H-inden-1-one (6-methoxy-2-(4-methylpyridin-3-yl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one) (Compound 22) [Reaction 22]

[0305] Step 1: Synthesis of (E)-1-(2-bromo-5-methoxyphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one At 0°C, a NaOH solution (2.39 g, 0.06 mol, dissolved in H₂O (10 mL)) was added to a mixture of 1-(2-bromo-5-methoxyphenyl)ethenone (4.56 g, 0.02 mol) and 4-methyl-1,3-thiazole-5-carbaldehyde (3.81 g, 0.03 mol) in 50 mL of ethanol. The resulting mixture was stirred at 25°C for 16 hours, and then water (100 mL) was added. Then, the mixture was extracted with DCM (100x3), the organic layer was washed with brine, dried with Na2SO4 and concentrated, and purified by silica gel column chromatography (5-10% MeOH / DCM) to obtain (E)-1-(2-bromo-5-methoxyphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one (3) (6.6 g, purity 80%, 0.157 mol, yield 78.1%), as a yellow solid.

[0306] MS (ESI): C 14 H 12 BrNO2 337.0 m / z, measured value 338.1 [M+1]+.

[0307] Step 2: Synthesis of 6-methoxy-3-(4-methylthiazol-5-yl)-1H-inden-1-one DMF (60 mL) was added to (E)-1-(2-bromo-5-methoxyphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one (6.00 g, 17.7 mmol), PdCl2 (160 mg, 0.885 mmol), PPh3 (460 mg, 1.77 mmol), and K2CO3 (6.12 g, 44.3 mmol), and stirred at 110 °C for 16 hours. After cooling to room temperature, water (200 mL) was added to the resulting mixture, and extraction was performed using EtOAc (150 mL × 3). The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (15% EtOAc / PE) to give 6-methoxy-3-(4-methylthiazolyl-5-yl)-1H-indone (22-4) (600 mg, purity 95%, 2.22 mmol, yield 12.5%), as a yellow solid.

[0308] MS (ESI): C 14 H 11NO2S 257.1 m / z, measured value 258.1 [M+1]+.

[0309] Step 3: Synthesis of 2-bromo-6-methoxy-3-(4-methylthiazol-5-yl)-1H-inden-1-one CCl4 (12 mL) was added to 6-methoxy-3-(4-methylthiazol-5-yl)-1H-inden-1-one (22-4) (600 mg, 2.33 mmol), NBS (498 mg, 2.80 mmol), and AIBN (76.6 mg, 0.466 mmol), and the mixture was stirred at 70 °C for 3 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (15% EtOAc / PE) to give 2-bromo-6-methoxy-3-(4-methylthiazol-5-yl)-1H-inden-1-one (22-5) (400 mg, 80% purity, 0.952 mmol, yield 40.8%).

[0310] MS (ESI): C 14 H 10 BrNO2S 335.0 m / z, measured value 336.1 [M+1]+.

[0311] Step 4: Synthesis of 6-methoxy-2-(4-methylpyridin-3-yl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one (Compound 22) 1,4-Dioxane (8 mL) and water (2 mL) were added to 2-bromo-6-methoxy-3-(4-methylthiazolyl-5-yl)-1H-inden-1-one (22-5) (400 mg, 1.19 mmol), (4-methylpyridin-3-yl)boranediol (196 mg, 1.43 mmol), Pd(dppf)Cl2CH2Cl2 (48.6 mg, 0.059 mmol), and K2CO3 (493 mg, 3.57 mmol), and stirred at 85 °C for 16 hours. Water (30 mL) was added to the resulting mixture, and extraction was performed using EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, concentrated, and purified by silica gel column chromatography (6% MeOH / DCM) to give 6-methoxy-2-(4-methylpyridin-3-yl)-3-(4-methylthiazolyl-5-yl)-1H-inden-1-one (compound 22) (300 mg, 90% purity, 0.776 mmol, yield 65.1%), as a yellow solid. 190 mg of compound 22 (90% purity) was further purified by prep-HPLC (Gemini 5). C 18 Purification was performed using a chromatographic column (150x21.2mm, 0.1% FA 25-70% ACN / H2O) to obtain 91mg (purity 99%).

[0312] By confirming the MS (ESI) of the obtained compound 22 (hereinafter chemical formula 23) and 1 H NMR yielded the following data: [Chemical Formula 23]

[0313] MS (ESI): C 20 H 16 N2O2S 348.1 m / z, measured value 349.1 [M+1]+.

[0314] 1 H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.38 (d, J = 4.8Hz, 1H), 8.14(s, 1H), 7.28 - 7.18 (m, 3H), 7.05 - 7.02 (m, 1H), 3.85 (s, 3H), 2.04 (s, 3H), 1.98 (s, 3H).

[0315] Preparation Example 23. 3-(5-methylthiazolyl-4-yl)-2-(pyridin-3-yl)-6-(3-(pyridin-4-yl)propoxy)- 1H-Inden-1-one(3-(5-methylthiazol-4-yl)-2-(pyridin-3-yl)-6-(3-(pyridin-4-yl) propoxy)-1H-inden-1-one) (compound 23) [Reaction 23]

[0316] Step 1: Synthesis of methyl 5-methylthiazole-4-carboxylate 2 amino 5 Methylthiazole 4 A solution of methyl 2-amino-5-methylthiazole-4-carboxylate (10 g, 58.1 mmol) / 1,4-dioxane (90 mL) was added to a solution of tert-butyl nitrite (31 mL, 290.7 mmol) / 1,4-dioxane (240 mL). The solution was stirred at 60 °C for 1 hour. After cooling to room temperature, the solvent was evaporated, and the solution was purified by rapid column chromatography (0-20% EtOAc / hexane) to give methyl 5-methylthiazole-4-carboxylate (5.0 g, 31.8 mmol, yield 55%).

[0317] Step 2: Synthesis of 5-methylthiazole-4-carbaldehyde (23-3) A solution of methyl 5-methylthiazolium-4-carboxylate (5 g, 31.8 mmol) dissolved in DCM (100 mL) at -78 °C was added to a solution of diisobutylaluminum hydride (1 M THF solution, 34 mL, 34 mmol). The mixture was stirred at -78 °C for 2 hours. Diisobutylaluminum hydride (1 M toluene solution, 10 mL, 10 mmol) was added, and the mixture was stirred at -78 °C for 2 hours. The reaction was terminated by adding Rochelle's salt solution (500 mL), followed by the addition of DCM (200 mL). The mixture was rapidly stirred until clear layers were formed. The organic layer was separated, dried over MgSO4, filtered, evaporated, and dried under vacuum to give 5-methylthiazolium-4-carboxaldehyde (2.5 g, 19.7 mmol, yield 61.95%).

[0318] Step 3: Synthesis of (E)-1-(3-hydroxyphenyl)-3-(5-methylthiazol-4-yl)prop-2-en-1-one A solution of 5-methylthiazol-4-carboxaldehyde (2.5 g, 19.69 mmol) and 1-(3-hydroxyphenyl)ethan-1-one (2.9 g, 21.65 mmol) dissolved in EtOH (30 mL) was stirred at 20–25 °C for 10 minutes. At 0–5 °C, a solution of NaOH (1.2 g, 29.52 mmol, dissolved in H₂O (12.5 mL)) was added to the solution. The mixture was then stirred at room temperature for 12 hours, and the pH was adjusted to 7 with 1 N HCl before filtration to give (E)-1-(3-hydroxyphenyl)-3-(5-methylthiazol-4-yl)prop-2-en-1-one (2.0 g, 8.16 mmol, yield 41.43%).

[0319] MS (ESI): C 13 H 11 NO2S 245.1 m / z, measured value 246.1 [M+1]+.

[0320] Step 4: Synthesis of 6-hydroxy-3-(5-methylthiazol-4-yl)-2,3-dihydro-1H-inden-1-one At 0 °C, (E)-1-(3-hydroxyphenyl)-3-(5-methylthiazol-4-yl)prop-2-en-1-one (2 g, 8.2 mmol) was added to CF3SO3H (20 mL). The mixture was then stirred at room temperature for 16 hours, and the pH was adjusted to 8 with an aqueous NaHCO3 solution before filtration to obtain 6-hydroxy-3-(5-methylthiazol-4-yl)-2,3-dihydro-1H-inden-1-one (1.3 g, 5.3 mmol, yield 64.71%).

[0321] Step 5: Synthesis of 1-(5-methylthiazol-4-yl)-3-oxo-2,3-dihydro-1H-inden-5-yl acetate DCM (40 mL) was added to 6-hydroxy-3-(5-methylthiazolyl-4-yl)-2,3-dihydro-1H-inden-1-one (1.3 g, 5.2988 mmol), pyridine (1.2 g, 15.8964 mmol), and 4-dimethylaminopyridine (129.5 mg, 1.0582 mmol), along with Ac₂O (1.6 g, 15.8964 mmol). The reaction mixture was stirred at 25 °C for 3 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and extraction was performed with DCM (90 mL x 3). The organic layer was washed with water and brine, dried with sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (50% EtOAc / PE) to give 1-(5-methylthiazolyl-4-yl)-3-oxo-2,3-dihydro-1H-indene-5-ylacetate (1.2 g, 4.1811 mmol, yield 78.91%) as a yellow solid.

[0322] MS (ESI): C 15 H 13 NO3S 287.1 m / z, measured value 288.1 [M+1]+.

[0323] Step 6: Synthesis of 2-bromo-3-(5-methylthiazol-4-yl)-1-oxo-1H-inden-6-yl acetate CCl4 (20 mL) was added to 1-(5-methylthiazol-4-yl)-3-oxo-2,3-dihydro-1H-indene-5-yl acetate (1 g, 0.0035 mol), NBS (1.25 g, 0.007 mol), and AIBN (110 mg, 0.7 mmol). The reaction mixture was stirred at 80 °C for 2 hours. Water was added to the residue, and the mixture was extracted with DCM (40 mL x 3). The organic layer was washed with water and brine, dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (50% EtOAc / PE) to give 2-bromo-3-(5-methylthiazol-4-yl)-1-oxo-1H-indene-6-yl acetate (500 mg, 0.0014 mol, yield 39.25%) as a yellow solid.

[0324] Step 7: Synthesis of 6-hydroxy-3-(5-methylthiazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one 1,4-Dioxane / water (20 mL; 4:1) and potassium carbonate (380 mg, 2.745 mmol) were added to 2-bromo-3-(5-methylthiazo-4-yl)-1-oxo-1H-indene-6-ylacetate (500 mg, 1.3725 mmol), pyridin-3-ylboranediol (253 mg, 2.0575 mmol), and Pd(dppf)Cl2DCM (112 mg, 0.135 mmol). The reaction mixture was stirred at 80 °C under N2 for 5 hours. The residue was diluted with water and extracted with EtOAc (60 mL x 3). The organic layer was washed with water and brine, dried with sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (10% MEOH / DCM) to give 6-hydroxy-3-(5-methylthiazolyl-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one (250 mg, 0.7813 mol, yield 56.92%) as a red solid.

[0325] Step 8: Synthesis of 3-(5-methylthiazol-4-yl)-2-(pyridin-3-yl)-6-(3-(pyridin-4-yl)propoxy)-1H-inden-1-one (compound 23) DMF (8 mL) was added to 6-hydroxy-3-(5-methylthiazo-4-yl)-2-(pyridin-3-yl)-1H-indone (200 mg, 0.624 mmol), 4-(3-bromopropyl)pyridine (187.3 mg, 0.936 mmol), and potassium carbonate (172.5 mg, 1.248 mmol). The reaction mixture was stirred at 40 °C for 8 hours. The mixture was extracted with EtOAc (40 mL x 3), and the organic layer was washed with water and brine. After drying with sodium sulfate, the mixture was concentrated under vacuum and analyzed by prep-HPLC (Gemini 5). Purification was performed using a C18 column (150x21.2 mm, 0.1% FA 30-90% ACN / H2O) to obtain 3-(5-methylthiazolyl-4-yl)-2-(pyridin-3-yl)-6-(3-(pyridin-4-yl)propoxy)-1H-indone (25 mg, 0.0569 mmol, yield 9.12%) as a red solid.

[0326] The MS (ESI) of the obtained compound 23 (hereinafter chemical formula 24) was confirmed. 1 H NMR yielded the following data: [Chemical Formula 24]

[0327] MS (ESI): C 26 H 21 N3O2S 439.1 m / z, measured value 440.1 [M+1]+.

[0328] 1 H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.50 (m, 3H), 7.72 (d, J = 8.0 Hz, 1H), 7.33- 7.25(m, 2H), 7.23-7.12(m, 4H), 6.82(dd, J = 8.0, 2.4 Hz, 1H), 4.02(t, J = 6.0 Hz, 2H), 2.86(t, J = 7.6 Hz, 2H), 2.38 - 2.07 (m, 2H), 1.93 (s, 3H).

[0329] Preparation Example 24. 2-Bromo-3-(1-methyl-1H-pyrazol-3-yl)-1-oxo-1H-inden-6-yl acetate (2- bromo-3-(1-methyl-1H-pyrazol-3-yl)-1-oxo-1H-inden-6-yl acetate) (compound 24) [Reaction 24]

[0330] Step 1: Synthesis of (E)-1-(3-hydroxyphenyl)-3-(1-methyl-1H-pyrazol-3-yl)prop-2-en-1-one EtOH (100 mL) was added to 1-(3-hydroxyphenyl)ethan-1-one (5 g, 36.76 mmol) and 1-methyl-1H-pyrazole-3-carbaldehyde (4.5 g, 40.44 mmol), and stirred at 20–25 °C for 30 minutes. Then, NaOH solution (2.2 g, 55.14 mmol, dissolved in H₂O (11 mL)) was added at 0–5 °C, and stirred at room temperature for 16 hours. After adjusting the pH to 7 with 1 N HCl, the mixture was filtered to obtain (E)-1-(3-hydroxyphenyl)-3-(1-methyl-1H-pyrazole-3-yl)prop-2-en-1-one (7.2 g, 31.57 mmol, yield 85.91%).

[0331] Step 2: Synthesis of 6-hydroxy-3-(1-methyl-1H-pyrazol-3-yl)-2,3-dihydro-1H-inden-1-one At 0 °C, (E)-1-(3-hydroxyphenyl)-3-(1-methyl-1H-pyrazol-3-yl)prop-2-en-1-one (4 g, 17.54 mmol) was added to CF3SO3H (40 mL), and the solution was stirred at room temperature for 12 hours. After adjusting the pH to 8 with NaHCO3 aqueous solution, the solution was filtered to obtain 6-hydroxy-3-(1-methyl-1H-pyrazol-3-yl)-2,3-dihydro-1H-indone (3.1 g, 13.60 mmol, yield 77.51%).

[0332] MS (ESI): C 13 H 12 N2O2 228.1 m / z, measured value 229.1 [M+1]+.

[0333] Step 3: Synthesis of 1-(1-methyl-1H-pyrazol-3-yl)-3-oxo-2,3-dihydro-1H-inden-5-yl acetate DCM (30 mL) was added to 6-hydroxy-3-(1-methyl-1H-pyrazol-3-yl)-2,3-dihydro-1H-inden-1-one (2.5 g, 0.0111 mol) and Ac₂O (3.4 g, 0.0333 mol), and 4-dimethylaminopyridine (0.27 g, 0.0022 mol) was added. The reaction mixture was stirred at room temperature for 4 hours. The residue was diluted with water and extracted with DCM (60 mL x 3). The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. Then, the product was purified by silica gel column chromatography (50% EtOAc / PE) to obtain 1-(1-methyl-1H-pyrazol-3-yl)-3-oxo-2,3-dihydro-1H-indene-5-yl acetate (2.0 g, 0.0074 mmol, yield 66.73%).

[0334] MS (ESI): C 15 H 14 N2O3 270.1 m / z, measured value 271.1 [M+1]+.

[0335] Step 4: Synthesis of 2-bromo-3-(1-methyl-1H-pyrazol-3-yl)-1-oxo-1H-inden-6-yl acetate (compound 24) CCl4 (20 mL) was added to 1-(1-methyl-1H-pyrazol-3-yl)-3-oxo-2,3-dihydro-1H-indene-5-yl acetate (1 g, 3.7 mmol), AIBN (0.120 g, 0.7 mmol), and NBS (0.79 g, 4.4 mmol). The reaction mixture was stirred at 80 °C for 2 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. Water was added to the residue, and extraction was performed using DCM (60 mL x 3). The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. Then, the product was purified by silica gel column chromatography (5% MeOH / DCM) to obtain 2-bromo-3-(1-methyl-1H-pyrazol-3-yl)-1-oxo-1H-indene-6-yl acetate (400 mg, 1.1527 mmol, yield 31.55%) as a white solid.

[0336] The MS (ESI) of the obtained compound 24 (hereinafter chemical formula 25) was confirmed. 1 H NMR yielded the following data: [Chemical Formula 25]

[0337] MS (ESI): C 15 H 11 BrN2O3 346.0 m / z, measured value 347.0 [M+1]+.

[0338] 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.28 (m, 1H), 4.06 (s, 3H), 2.29 (s, 3H).

[0339] Preparation Example 25. 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(1H-pyrazol-3-yl)-1H- Inden-1-one (3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(1H-pyrazol-3-yl)-1H- inden-1-one) (compound 25) [Reaction 25]

[0340] Step 1: Synthesis of 2-bromo-6-hydroxy-3-(4-methylthiazol-5-yl)-1H-inden-1-one K₂CO₃ (11 g, 0.08 mmol) was added to a methanol (260 mL) solution of 2-bromo-3-(4-methylthiazo-5-yl)-1-oxo-1H-indene-6-yl acetate (21-6) (15 g, 0.04 mol) obtained in step 4 of Preparation Example 21, and the mixture was stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with DCM (200 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (3% MeOH / DCM) to give the desired title compound (12 g, 93%) as a white solid.

[0341] Step 2: Synthesis of 2-bromo-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one Diisopropyl azodicarbonate (16 g, 0.08 mmol) was added to a THF (500 mL) solution of 2-bromo-6-hydroxy-3-(4-methylthiazolyl-5-yl)-1H-inden-1-one (12 g, 0.04 mol), 3-phenylpropane-1-ol (11 g, 0.08 mmol), and triphenylphosphine (21 g, 0.08 mmol), and stirred at room temperature for 16 hours. Water (200 mL) was added to the reaction mixture, and extraction was performed using DCM (300 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (1% MeOH / DCM) to give the desired title compound (8 g, 45%) as a red solid.

[0342] 1 H NMR (400 MHz, DMSO- d 6) δ 9.37 (s, 1H), 7.41 – 7.11 (m, 6H), 7.04(d, J = 8.0 Hz, 1H), 6.95 (dd, J = 8.0, 2.4 Hz, 1H), 4.09 – 3.94 (m, 2H), 2.79 –2.67 (m, 2H), 2.44 (s, 3H), 2.14 – 1.83 (m, 3H).

[0343] Step 3: Synthesis of 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(1H-pyrazol-3-yl)-1H-inden-1-one (Compound 25) Following the same method as step 5 of Preparation Example 21, the desired title compound (170 mg, yield 57%) was obtained as a yellow solid.

[0344] The LCMS (ESI-MS) results of the obtained compound 25 (hereinafter chemical formula 26) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 26]

[0345] LCMS (ESI-MS): Calculated mass value. C 25 H 21 N3O2S 427.1 m / z, measured value 427.9 [M+H]+ .

[0346] 1 H NMR (400 MHz, DMSO- d 6) δ12.99 - 12.83 (m, 1H), 9.28 - 9.23 (m, 1H), 7.74 - 7.48 (m, 1H), 7.37 - 6.90 (m, 8H), 6.61 - 6.05 (m, 1H), 4.04 (t, J = 6.0Hz, 2H), 2.81 – 2.71 (m, 2H), 2.18 – 1.94 (m, 5H).

[0347] Preparation Example 26. 2-(1-methyl-1H-pyrazole-3-yl)-3-(4-methylthiazo-5-yl)-6-(3-phenylpropoxy) methyl)-1H-inden-1-one (2-(1-methyl-1H-pyrazol-3-yl)-3-(4-methylthiazol-5-yl)-6-(3- (phenylpropoxy)-1H-inden-1-one)(compound 26) [Reaction 26]

[0348] Following the same method as step 5 of Preparation Example 21, 2-bromo-3-(4-methylthiazolyl)-6-(3-phenylpropoxy)-1H-indone was used to give the desired title compound (23.0 mg, yield 23%) as a yellow solid.

[0349] The LCMS (ESI-MS) results of the obtained compound 26 (hereinafter chemical formula 27) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 27]

[0350] LCMS (ESI-MS): Calculated mass value. C 26 H 23 N3O2S 441.2 m / z, measured value 441.8 [M+H] + .

[0351] 1 H NMR (400 MHz, DMSO- d 6) δ 9.25 (s, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.37– 7.15 (m, 5H), 7.08 (d, J = 2.0 Hz, 1H), 7.02 – 6.89 (m, 2H), 6.48 (d, J = 2.0Hz, 1H), 4.03 (t,J = 6.4 Hz, 2H), 3.76 (s, 3H), 2.79 – 2.67 (m, 2H), 2.12 (s, 3H), 2.10 – 1.94 (m, 2H).

[0352] Preparation Example 27. 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(1H-pyrazol-4-yl)-1H- Inden-1-one (3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(1H-pyrazol-4-yl)-1H- inden-1-one) (compound 27) [Reaction 27]

[0353] Following the same method as step 5 of Preparation Example 21, 2-bromo-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-1H-indone was used to obtain the desired title compound (60 mg, 35%) as a red solid.

[0354] The LCMS (ESI-MS) results of the obtained compound 27 (hereinafter chemical formula 28) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 28]

[0355] LCMS (ESI-MS): Calculated mass value. C 25 H 21 N3O2S 427.1 m / z, measured value 427.8 [M+H] + .

[0356] 1 H NMR (400 MHz, DMSO- d 6) δ 13.08 (s, 1H), 9.34 (s, 1H), 7.87 (s, 1H), 7.34 – 7.14 (m, 6H), 7.07 (d, J = 2.4 Hz, 1H), 6.93 – 6.91 (m, 1H), 6.84 (d, J =8.0 Hz, 1H), 4.02 (t, J = 6.2 Hz, 2H), 2.81 – 2.71 (m, 2H), 2.17 (s, 3H), 2.06 – 1.96 (m, 2H).

[0357] Preparation Example 28. 2-(1-methyl-1H-pyrazole-4-yl)-3-(4-methylthiazo-5-yl)-6-(3-phenylpropoxy) methyl)-1H-inden-1-one (2-(1-methyl-1H-pyrazol-4-yl)-3-(4-methylthiazol-5-yl)-6-(3- (phenylpropoxy)-1H-inden-1-one)(compound 28) [Reaction 28]

[0358] Following the same method as step 5 of Preparation Example 21, 2-bromo-3-(4-methylthiazolyl)-6-(3-phenylpropoxy)-1H-indone was used to give the desired title compound (60 mg, yield 53%) as a red solid.

[0359] The LCMS (ESI-MS) results of the obtained compound 28 (hereinafter chemical formula 29) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 29]

[0360] LCMS (ESI-MS): Calculated mass value. C 26 H 23 N3O2S 441.2 m / z, measured value 441.9 [M+H] + .

[0361] 1 H NMR (400 MHz, DMSO- d 6) δ 9.34 (s, 1H), 7.91 (s, 1H), 7.33 – 7.16 (m, 6H), 7.07 (d, J = 2.4 Hz, 1H), 6.91 (dd, J = 8.2, 2.4 Hz, 1H), 6.83 (d, J = 8.0Hz, 1H), 4.01 (t, J = 6.2 Hz, 2H), 3.83 (s, 3H), 2.78 – 2.69 (m, 2H), 2.19 (s, 3H), 2.09 – 1.96 (m, 2H).

[0362] Preparation Example 29. 2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)-3-(4-methylthiazolyl-5-yl)-6- (3-Phenylacetoxy)-1H-inden-1-one (2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)-3- (4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one) (Compound 29) [Reaction 29]

[0363] Step 1: Synthesis of tert-butyl 4-(3-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate 3-bromo-1H-pyrazole (2g, 13.61mmol), 4 Brompiperidine 1 A mixture of tert-butyl carboxylate (3.59 g, 13.61 mmol) and Cs₂CO₃ (8.85 g, 27.22 mmol) in DMF (100 mL) was stirred at 80 °C for 16 hours. After cooling to room temperature, water (50 mL) was added, and the mixture was extracted with EA (100 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (20% EtOAc / PE) to give the desired title compound (1 g, 22%) as a white solid.

[0364] 1 H NMR (400 MHz, DMSO- d 6) δ 7.83 (d, J = 2.4 Hz, 1H), 6.37 (d, J = 2.4 Hz,1H), 4.37 - 4.31 (m, 1H), 4.04 - 4.01 (m, 2H), 2.87 (s, 2H), 1.97 (dd, J =12.8, 2.4 Hz, 2H), 1.78 - 1.68 (m, 2H), 1.41 (s, 9H).

[0365] Step 2: Synthesis of tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate A mixture of tert-butyl 4-(3-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylic acid (500 mg, 1.52 mmol), bis(pinacolyl)diboron (767 mg, 3.04 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (110 mg, 0.15 mmol) and KOAc (298 mg, 3.04 mmol) in 1,4-dioxane (15 mL) was stirred at 100 °C for 16 hours.

[0366] After cooling the reactants to room temperature, water (10 mL) was added, and extraction was performed using EA (20 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (30% EtOAc / PE) to obtain the desired title compound (400 mg, 69.8%).

[0367] Step 3: Synthesis of tert-butyl 4-(3-(3-(4-methylthiazol-5-yl)-1-oxo-6-(3-phenylpropoxy)-1H-inden-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate Following the same method as in step 5 of Preparation Example 21, 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester and 2-bromo-3-(4-methylthiazolyl)-6-(3-phenylpropoxy)-1H-indone were used to give the desired title compound (190 mg, 33%) as a blue solid.

[0368] 1 H NMR (400 MHz, DMSO- d 6) δ 9.23 (s, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.39– 7.15 (m, 5H), 7.08 (d, J = 2.0 Hz, 1H), 7.02 – 6.89 (m, 2H), 6.58 (d, J = 2.4Hz, 1H), 4.27 (s, 1H), 4.03 (t, J = 6.4 Hz, 3H), 3.91 (d, J = 15.6 Hz, 3H), 2.87(s, 2H), 2.82 – 2.66 (m, 2H), 2.09 (s, 3H), 2.04 – 1.98 (m, 2H), 1.86 (d, J =10.4 Hz, 2H), 1.63 - 1.59 (m, 2H), 1.41 (s, 9H), 1.07 (s, 5H).

[0369] Step 4: Synthesis of 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(1-(piperidin-4-yl)-1H-pyrazol-3-yl)-1H-inden-1-one DCM / TFA (3 mL / 1 mL) was added to tert-butyl 4-(3-(3-(4-methylthiazolyl-5-yl)-1-oxo-6-(3-phenylpropoxy)-1H-inden-2-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylic acid (180 mg, 0.29 mmol), and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the desired title compound (150 mg, crude product) as a yellow solid.

[0370] Step 5: Synthesis of 2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one (2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one) (Compound 29) A mixture of 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(1-(piperidin-4-yl)-1H-pyrazol-3-yl)-1H-inden-1-one (150 mg, 0.29 mmol), CH2O aqueous solution (0.3 mL, 2.90 mmol), NaBH3CN (37 mg, 0.58 mmol), and AcOH (34.8 mg, 0.58 mmol) and MeOH (3 mL) was added and stirred at room temperature for 6 hours. Water (5 mL) was added to the reaction mixture, and extraction was performed with EA (10 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The resulting concentrated residue was analyzed by prep-HPLC (Gemini 5). C 18 Purification was performed using a chromatographic column (150x21.2 mm, 30-90% ACN / H2O, 0.1% FA) to obtain the desired title compound (5.5 mg, yield 4%) as a red solid.

[0371] The LCMS (ESI-MS) results of the obtained compound 29 (hereinafter chemical formula 30) were confirmed by... 1H NMR yielded the following data: [Chemical Formula 30]

[0372] LCMS (ESI-MS): Calculated mass value. C 31 H 32 N4O2S 524.2 m / z, measured value 525.0 [M+H] + .

[0373] 1 H NMR (400 MHz, DMSO- d 6) δ 9.26 (s, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.37– 7.16 (m, 5H), 7.08 (d, J = 2.0 Hz, 1H), 6.96 (dt, J = 8.0, 5.2 Hz, 2H), 6.59(d, J = 2.4 Hz, 1H), 4.05 - 3.99 (m, 3H), 2.75 (t, J = 7.6 Hz, 4H), 2.16 (s, 3H), 2.10 (s, 3H), 2.05 - 1.96 (m, 4H), 1.89 - 1.71 (m, 4H).

[0374] Preparation Example 30. 2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(4-methylthiazolyl-5-yl)-6- (3-Phenylacetoxy)-1H-inden-1-one (2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3- (4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one) (Compound 30) [Reaction 30]

[0375] DMF (10 mL) was added to 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(1H-pyrazol-4-yl)-1H-indone (170 mg, 0.3976 mmol), 4-bromo-1-methylpiperidine (106.2 mg, 0.5964 mmol), Cs₂CO₃ (388.64 mg, 1.1928 mmol), and KI (33 mg, 0.1988 mmol), and stirred at 120 °C under nitrogen for 16 hours. Water (30 mL) was added to the reaction mixture, and extraction was performed using EA (30 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was analyzed by prep-HPLC (Gemini 5). C 18Purification was performed using a chromatographic column (150 x 21.2 mm, 25-95% ACN / H2O, 0.1% NH3H2O) to obtain the desired title compound (30 mg, 14%) as a red solid.

[0376] The LCMS (ESI-MS) results of the obtained compound 30 (hereinafter chemical formula 31) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 31]

[0377] LCMS (ESI-MS): Calculated mass value. C 31 H 32 N4O2S 524.2 m / z, measured value 525.0 [M+H] + .

[0378] 1 H NMR (400 MHz, DMSO- d 6) δ 9.34 (s, 1H), 7.89 (s, 1H), 7.31 – 7.17 (m, 6H), 7.07 (s, 1H), 6.92 (dd, J = 8.0, 2.2 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H),4.22 – 4.11 (m, 1H), 4.01 (t, J = 6.2 Hz, 2H), 2.82 (d, J = 11.2 Hz, 2H), 2.74(t, J = 7.6 Hz, 2H), 2.18 (s, 6H), 2.07 – 1.97 (m, 4H), 1.91 – 1.86 (m, 4H).

[0379] Preparation Example 31. 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(1H-1,2,3-triazol-4- 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(1H-1,2,3-) triazol-4-yl)-1H-inden-1-one)(compound 31) [Reaction Formula 31]

[0380] Step 1: Synthesis of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazole Anhydrous DMF (100 mL) and 2-(trimethylsilyl)ethoxymethyl chloride (5.08 g, 0.0304 mol) were added to 4-bromo-1H-1,2,3-triazole (3 g, 0.0203 mol) and Cs₂CO₃ (7.94 g, 0.0243 mol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. Water (300 mL) was added to the reaction mixture, and the mixture was extracted with EA (400 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by rapid column chromatography (10% EtOAc / hexane) to give the desired title compound (1.5 g, 23%) as a white oil.

[0381] LCMS (ESI-MS): Calculated mass value. C8H 16 BrN3OSi 277.0 m / z, measured value 278.0 [M+H] + .

[0382] Step 2: Synthesis of (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-4-yl)boronic acid 1,4-Dioxane (20 mL) was added to 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazole (1.5 g, 0.0054 mol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhexacyclopentene) (1.65 g, 0.0065 mol), Pd(dppf)Cl2 (0.4 g, 0.0005 mol), and KOAc (1.59 g, 0.0162 mol), and stirred at 90 °C under nitrogen for 16 hours. Water (100 mL) was added to the reactants, and the mixture was extracted with EA (100 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by rapid column chromatography (20% EtOAc / hexane) to obtain the desired title compound (0.4 g, 20%) as a white oil.

[0383] LCMS (ESI-MS): Calculated mass value. C8H 18 BN3O3Si has a m / z of 243.1, with a measured value of 243.6 [M+H]. + .

[0384] Step 3: Synthesis of 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-4-yl)-1H-inden-1-one Following the same method as step 5 of Preparation Example 21, 2-bromo-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-1H-indone and (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-4-yl)boronic acid were used to obtain the desired title compound (220 mg, 71%) as a red solid.

[0385] LCMS (ESI-MS): Calculated mass value. C 30 H 34 N4O3SSi 558.2 m / z, measured value 559.0 [M+H] + .

[0386] Step 4: Synthesis of 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(1H-1,2,3-triazol-4-yl)-1H-inden-1-one (compound 31) HCl / 1,4-dioxane (15 mL) was added to 3-(4-methylthiazo-5-yl)-6-(3-phenylpropoxy)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-4-yl)-1H-inden-1-one (260 mg, 0.4645 mmol), and stirred at room temperature under nitrogen for 16 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with EA (50 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (5% MeOH / DCM) to give the desired title compound (90 mg, 40%) as a red solid.

[0387] The LCMS (ESI-MS) results of the obtained compound 31 (hereinafter chemical formula 32) were confirmed. 1H NMR yielded the following data: [Chemical Formula 32]

[0388] LCMS (ESI-MS): Calculated mass value. C 24 H 20 N4O2S 428.1 m / z, measured value 428.8 [M+H] + .

[0389] 1 H NMR (400 MHz, DMSO- d 6) δ 9.30 (s, 1H), 8.43 – 7.95 (m, 1H), 7.34 –7.12 (m, 6H), 7.06 – 6.98 (m, 2H), 4.06 – 4.03 (m, 2H), 2.77 – 2.75 (m, 2H), 2.11 (s, 3H), 2.11 – 1.98 (m, 2H).

[0390] Preparation Example 32. 2-(1-methyl-1H-1,2,3-triazol-4-yl)-3-(4-methylthiazolyl-5-yl)-6-(3-phenyl) (propoxy)-1H-indone (2-(1-methyl-1H-1,2,3-triazol-4-yl)-3-(4-methylthiazol-5-) yl)-6-(3-phenylpropoxy)-1H-inden-1-one)(compound 32); and 2-(2-methyl-2H-1,2,3-triazol-4-yl)-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)- 1H-Inden-1-one(2-(2-methyl-2H-1,2,3-triazol-4-yl)-3-(4-methylthiazol-5-yl)-6-(3- (phenylpropoxy)-1H-inden-1-one)(compound 33) [Reaction 32]

[0391] DMF (10 mL) was added to 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(1H-1,2,3-triazol-4-yl)-1H-inden-1-one (200 mg, 0.4667 mmol), dimethyl carbonate (92.49 mg, 1.0267 mmol), and K₂CO₃ (161.26 mg, 1.1667 mmol), and stirred at 145 °C under nitrogen for 4 hours. Water (70 mL) was added to the reaction mixture, and the mixture was extracted with EA (100 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was analyzed by prep-HPLC (Gemini 5). C 18 Purification was performed using a chromatographic column (150 x 21.2 mm, 60-95% ACN / H2O 0.1% FA) to give the desired title compound 32 (3.7 mg, 2%) and compound 32-1 (6.4 mg, 3%) as red solids.

[0392] The LCMS (ESI-MS) results of the obtained compound 32 (hereinafter chemical formula 33) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 33]

[0393] LCMS (ESI-MS): Calculated mass value. C 25 H 22 N4O2S 442.1 m / z, measured value 443.1 [M+H] + .

[0394] 1 H NMR (400 MHz, DMSO- d 6) δ 9.28 (s, 1H), 8.42 (s, 1H), 7.31 – 7.18 (m, 5H), 7.13 (d, J = 2.2 Hz, 1H), 7.02 – 6.97 (m, 2H), 4.12 – 4.01 (m, 5H), 2.82 – 2.72 (m, 2H), 2.14 (s, 3H), 2.08 – 1.98 (m, 2H).

[0395] The LCMS (ESI-MS) results of the obtained compound 33 (hereinafter chemical formula 34) were confirmed. 1 H NMR yielded the following data: [Chemical Formula 34]

[0396] LCMS (ESI-MS): Calculated mass value. C 25 H 22 N4O2S 442.1 m / z, measured value 443.1 [M+H] + .

[0397] 1 H NMR (400 MHz, DMSO- d 6) δ 9.30 (s, 1H), 7.95 (s, 1H), 7.32 – 7.16 (m, 5H), 7.13 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.98 (dd, J= 8.2, 2.4Hz, 1H), 4.08 (s, 3H), 4.07 – 4.01 (m, 2H), 2.81 – 2.71 (m, 2H), 2.14 (s, 3H), 2.10 – 1.99 (m, 2H).

[0398] Preparation Example 33. 3-(4-methylthiazolyl-5-yl)-1-oxo-6-(3-phenylpropoxy)-1H-inden-2-carboxynitrile (3- (4-methylthiazol-5-yl)-1-oxo-6-(3-phenylpropoxy)-1H-indene-2-carbonitrile)(chemical Compound 34) [Reaction 33]

[0399] DMF (10 mL) was added to 2-bromo-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-1H-indone (500 mg, 1.14 mmol) and CuCN (303 mg, 3.41 mmol), and stirred at 150 °C for 3 hours. The resulting concentrated residue was analyzed by prep-HPLC (Gemini 5). C 18 Purification was performed using a chromatographic column (150x21.2mm, 30-90% ACN / H2O 0.1% FA) to obtain the desired title compound (200mg, 45%) as a yellow solid.

[0400] The LCMS (ESI-MS) results of the obtained compound 34 (hereinafter chemical formula 35) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 35]

[0401] LCMS (ESI-MS): Calculated mass value. C 23 H 18 N₂O₂S 386.1 m / z, measured value 386.7 [M+H] + .

[0402] 1 H NMR (400 MHz, DMSO- d 6) δ 9.52 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.35– 7.16 (m, 6H), 7.13 (dd, J = 8.0, 2.4 Hz, 1H), 4.10 (t, J = 6.4 Hz, 2H), 2.75(t, J= 7.2 Hz, 2H), 2.58 (s, 3H), 2.14 – 1.96 (m, 2H).

[0403] Preparation Example 34. 6-Hydroxy-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (6- Hydroxy-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 35) [Reaction Formula 34]

[0404] Following the same method as step 5 of Preparation Example 21, 2-bromo-3-(4-methylthiazo-5-yl)-1-oxo-1H-indene-6-yl acetate and pyridin-3-ylboronic acid were used to give the desired title compound (17.3 mg, 16%) as a red solid.

[0405] The MS (ESI) of the obtained compound 35 (hereinafter chemical formula 36) was confirmed. 1 H NMR yielded the following data: [Chemical Formula 36]

[0406] MS(ESI): Calculated mass index. C 18 H 12 N₂O₂S 320.1 m / z, measured value 321.0 [M+H] + . 1 H NMR (400 MHz, DMSO-) d 6) δ 10.33 (s, 1H), 9.30 (s, 1H), 8.48 – 8.47 (m, 1H), 8.34 –8.33 (m, 1H), 7.60 – 7.58 (m, 1H), 7.41 – 7.37 (m, 1H), 7.06 – 6.99 (m, 2H), 6.85 – 6.83 (m, 1H), 1.95 (s, 3H).

[0407] Preparation Example 35. 6-(2-hydroxyethoxy)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-indene-1- Ketone(6-(2-hydroxyethoxy)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1- one)(Compound 36) [Reaction Formula 35]

[0408] DMF (3 mL) and K₂CO₃ (86 mg, 0.62 mmol) were added to 6-hydroxy-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (100 mg, 0.31 mmol) and 2-bromoethane-1-ol (78 mg, 0.62 mmol), and stirred at 80 °C for 16 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was analyzed by prep-HPLC (Gemini 5). C 18 Purification was performed using a chromatographic column (150x21.2 mm, 30-90% ACN / H2O 0.1% FA) to obtain the desired title compound (5.6 mg, yield 5%) as a yellow solid.

[0409] The LCMS (ESI-MS) results of the obtained compound 36 (hereinafter chemical formula 37) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 37]

[0410] LCMS (ESI-MS): Calculated mass value. C 20 H 16 N₂O₃S 364.1 m / z, measured value 364.7 [M+H] + .

[0411] 1 H NMR (400 MHz, DMSO- d 6) δ 9.31 (s, 1H), 8.49 (dd, J = 4.8, 1.2 Hz, 1H), 8.36 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.40 (dd, J = 8.0, 4.8 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.04 (dd, J = 8.0, 2.4 Hz, 1H), 4.92 (t, J = 5.2 Hz, 1H), 4.09 (t, J= 4.8 Hz, 2H), 3.75 - 3.71 (m, 2H), 1.96 (s, 3H).

[0412] Preparation Example 36. 6-(2-methoxyethoxy)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-indene 1-keto(6-(2-methoxyethoxy)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden- 1-one)(compound 37) [Reaction Formula 36]

[0413] The reaction was carried out at room temperature, using the same method as in Preparation Example 35, with 1-bromo-2-methoxyethane, to give the desired title compound (20.1 mg, 28%) as a yellow solid.

[0414] The LCMS (ESI-MS) results of the obtained compound 37 (hereinafter chemical formula 38) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 38]

[0415] LCMS (ESI-MS): Calculated mass value. C 21 H 18 N₂O₃S 378.1 m / z, measured value 378.7 [M+H] + .

[0416] 1 H NMR (400 MHz, DMSO- d 6) δ 9.31 (s, 1H), 8.49 (dd, J = 4.8, 1.6 Hz, 1H), 8.36 (d, J = 1.2Hz, 1H), 7.61 (dt, J = 8.0, 2.0 Hz, 1H), 7.40 (dd, J = 7.6, 4.8 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.04 (dd, J = 8.4,2.4 Hz, 1H), 4.21 - 4.19 (m, 2H), 3.80 - 3.57 (m, 2H), 3.31 (s, 3H), 1.96 (s, 3H).

[0417] Preparation Example 37. 6-(methyl(3-phenylpropyl)amino)-3-(4-methylthiazo-5-yl)-2-(pyridin-3-yl)- 1H-Inden-1-one(6-(methyl(3-phenylpropyl)amino)-3-(4-methylthiazol-5-yl)-2- (pyridin-3-yl)-1H-inden-1-one) (Compound 38) [Reaction Formula 37]

[0418] Following the same method as step 5 of Preparation Example 29, 3-(4-methylthiazolyl-5-yl)-6-((3-phenylpropyl)amino)-2-(pyridin-3-yl)-1H-indone was used to obtain the desired title compound (50 mg, 75%) as a purple solid.

[0419] The LCMS (ESI-MS) results of the obtained compound 38 (hereinafter chemical formula 39) were confirmed. 1 H NMR yielded the following data: [Chemical Formula 39]

[0420] LCMS (ESI-MS): Calculated mass value. C 21 H 17 N3OS 451.2 m / z, measured value 451.8 [M+H] + .

[0421] 1 H NMR (400 MHz, DMSO- d 6) δ 9.29 (s, 1H), 8.44 (dd, J = 4.8, 1.6 Hz, 1H), 8.32 (d, J = 1.6 Hz, 1H), 7.58 – 7.55 (m, 1H), 7.39 – 7.34 (m, 1H), 7.30 –7.27 (m, 2H), 7.24 – 7.16 (m, 3H), 7.00 – 6.96 (m, 2H), 6.57 (dd, J = 8.4, 2.4Hz, 1H), 3.52 – 3.41 (m, 2H), 3.00 (s, 3H), 2.65 – 2.58 (m, 2H), 1.95 (s,3H), 1.89 – 1.77 (m, 2H).

[0422] Preparation Example 38. 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-4-yl)-1H-inden-1- Ketone(3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-4-yl)-1H-inden-1- one)(compound 39) [Reaction Formula 38]

[0423] Step 1: Synthesis of 6-hydroxy-3-(4-methylthiazol-5-yl)-2-(pyridin-4-yl)-1H-inden-1-one Following the same method as step 5 of Preparation Example 21, using 2-bromo-3-(4-methylthiazo-5-yl)-1-oxo-1H-indene-6-ylacetate (21-6) and pyridin-4-ylboronic acid from Preparation Example 21, the desired title compound (87.2 mg, yield 39%) was obtained as a red solid.

[0424] LCMS (ESI-MS): Calculated mass value. C 18 H 12 N₂O₂S 320.4 m / z, measured value 321.0 [M+H] + .

[0425] 1 H NMR (400 MHz, DMSO- d 6) δ 10.38 (s, 1H), 9.32 (s, 1H), 8.53 – 8.52 (m, 2H), 7.15 – 7.14 (m, 2H), 7.07 – 7.05 (m, 1H), 7.00 – 6.99 (m, 1H), 6.86– 6.83 (m, 1H), 2.00 (s, 3H).

[0426] Step 2: Synthesis of 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-4-yl)-1H-inden-1-one (compound 39) Following the same method as in Preparation Example 36, 6-hydroxy-3-(4-methylthiazolyl-5-yl)-2-(pyridin-4-yl)-1H-inden-1-one and (3-bromopropyl)benzene were used to give the desired title compound (18.6 mg, 19%) as a red solid.

[0427] The LCMS (ESI-MS) results of the obtained compound 39 (hereinafter chemical formula 40) were confirmed. 1 H NMR yielded the following data: [Chemical Formula 40]

[0428] LCMS (ESI-MS): Calculated mass value. C 27 H 22 N₂O₂S 438.1 m / z, measured value 439.1 [M+H] + .

[0429] 1 H NMR (400 MHz, DMSO- d 6) δ 9.33 (s, 1H), 8.55 – 8.53 (m, 2H), 7.31 –7.23 (m, 4H), 7.21 – 7.14 (m, 5H), 7.04 – 7.02 (m, 1H), 4.08 – 4.05 (m, 2H), 2.77 – 2.73 (m, 2H), 2.07 – 2.00 (m, 2H), 1.97 (s, 3H).

[0430] Preparation Example 39. 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-2-yl)-1H-inden-1- Ketone(3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-2-yl)-1H-inden-1- one)(compound 40) [Reaction Formula 39]

[0431] Step 1: Synthesis of 3-(4-methylthiazol-5-yl)-1-oxo-2-(pyridin-2-yl)-1H-inden-6-yl acetate Toluene (10 mL) was added to the mixture of 2-bromo-3-(4-methylthiazo-5-yl)-1-oxo-1H-indene-6-yl acetate (21-6) (278 mg, 0.7633 mmol), 2-(tributyltinyl)pyridine (337.21 mg, 0.916 mmol), and tetrakis(triphenylphosphine)palladium (88.2 mg, 0.07633 mol) obtained in step 4 of Preparation Example 21, and stirred at nitrogen and 110 °C for 16 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with EA (25 mL x 3). The organic layer was washed by conventional methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (3% MeOH / DCM) to give the desired title compound (100 mg, 36%) as a red solid.

[0432] LCMS (ESI-MS): Calculated mass value. C20 H 14 N₂O₃S 362.1 m / z, measured value 363.0 [M+H] + .

[0433] Step 2: Synthesis of 6-hydroxy-3-(4-methylthiazol-5-yl)-2-(pyridin-2-yl)-1H-inden-1-one Following the same method as in step 1 of Preparation Example 25, 3-(4-methylthiazo-5-yl)-1-oxo-2-(pyridin-2-yl)-1H-indene-6-yl acetate was used to give the desired title compound (76 mg, yield 86%) as a red solid.

[0434] LCMS (ESI-MS): Calculated mass value. C 18 H 12 N₂O₂S 320.4 m / z, measured value 321.0 [M+H] + .

[0435] 1 H NMR (400 MHz, DMSO- d 6) δ 10.35 (s, 1H), 9.49 (s, 1H), 8.70 (s, 1H), 7.84 – 7.80 (m, 1H), 7.52 – 7.50 (m, 1H), 7.27 – 7.26 (m, 1H), 7.07 – 6.97(m, 2H), 6.85 – 6.82 (m, 1H), 1.92 (s, 3H).

[0436] Step 3: Synthesis of 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-2-yl)-1H-inden-1-one (compound 40) Following the same method as step 2 of Preparation Example 38, 6-hydroxy-3-(4-methylthiazolyl-5-yl)-2-(pyridin-2-yl)-1H-inden-1-one was used to give the desired title compound (20.9 mg, 22%) as a red solid.

[0437] The LCMS (ESI-MS) results of the obtained compound 40 (hereinafter chemical formula 41) were confirmed by...1 H NMR yielded the following data: [Chemical Formula 41]

[0438] LCMS (ESI-MS): Calculated mass value. C 27 H 22 N₂O₂S 438.1 m / z, measured value 439.1 [M+H] + .

[0439] 1 H NMR (400 MHz, DMSO- d 6) δ 9.24 (s, 1H), 8.48 – 8.46 (m, 1H), 7.86 –7.82 (m, 1H), 7.54 – 7.52 (m, 1H), 7.31 – 7.19 (m, 6H), 7.16 – 7.14 (m, 2H),7.03 – 7.00 (m, 1H), 4.08 – 4.05 (m, 2H), 2.77 – 2.74 (m, 2H), 2.06 – 2.00 (m, 2H), 1.93 (s, 3H).

[0440] Preparation Example 40. 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(pyrazin-2-yl)-1H-indene-1- Ketone(3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyrazin-2-yl)-1H-inden-1- one)(Compound 41) [Reaction Formula 40]

[0441] Step 1: Synthesis of 3-(4-methylthiazol-5-yl)-1-oxo-2-(pyrazin-2-yl)-1H-inden-6-yl acetate Following the same method as step 1 of Preparation Example 39, 2-bromo-3-(4-methylthiazolyl-5-yl)-1-oxo-1H-indene-6-yl acetate (21-6) and 2-(tributylstannyl)pyrazine from Preparation Example 21 were used to obtain the desired title compound (100 mg, 40%) as a red solid.

[0442] LCMS (ESI-MS): Calculated mass value. C 19 H 13 N3O3S 363.1 m / z, measured value 363.7 [M+H]+ .

[0443] Step 2: Synthesis of 6-hydroxy-3-(4-methylthiazol-5-yl)-2-(pyridin-2-yl)-1H-inden-1-one Following the same method as in step 1 of Preparation Example 25, 3-(4-methylthiazo-5-yl)-1-oxo-2-(pyrazin-2-yl)-1H-indene-6-yl acetate was used to give the desired title compound (84 mg, 94%) as a red solid.

[0444] LCMS (ESI-MS): Calculated mass value. C 17 H 11 N3O2S 321.1 m / z, measured value 322.0 [M+H] + .

[0445] 1 H NMR (400 MHz, DMSO- d 6) δ 10.52 (s, 1H), 9.27 (s, 1H), 8.77 – 8.76 (m, 1H), 8.55 – 8.51 (m, 2H), 7.12 – 7.01 (m, 2H), 6.86 – 6.84 (m, 1H), 1.96 (s, 3H).

[0446] Step 3: Synthesis of 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyrazin-2-yl)-1H-inden-1-one (compound 41) Following the same method as step 2 of Preparation Example 38, 6-hydroxy-3-(4-methylthiazolyl-5-yl)-2-(pyrazin-2-yl)-1H-indone was used to give the desired title compound (20.8 mg, 19%) as a red solid.

[0447] The LCMS (ESI-MS) results of the obtained compound 41 (hereinafter chemical formula 42) were confirmed. 1 H NMR yielded the following data: [Chemical Formula 42]

[0448] LCMS (ESI-MS): Calculated mass value. C 26 H 21 N3O2S 439.1 m / z, measured value 440.1 [M+H] + .

[0449] 1 H NMR (400 MHz, DMSO- d 6) δ 9.28 (s, 1H), 8.78 – 8.77 (m, 1H), 7.57 –7.53 (m, 2H), 7.31 – 7.23 (m, 4H), 7.20 – 7.18 (m, 3H), 7.06 – 7.03 (m, 1H), 4.09 – 4.06 (m, 2H), 2.78 – 2.74 (m, 2H), 2.08 – 2.01 (m, 2H), 1.97 (s, 3H).

[0450] Preparation Example 41. 3-(1-methyl-1H-pyrazole-4-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H- Inden-1-one (3-(1-methyl-1H-pyrazol-4-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H- inden-1-one) (compound 42) [Reaction Formula 41]

[0451] Step 1: Synthesis of 2,3-dibromo-6-methoxy-1H-inden-1-one CCl4 was added to 6-methoxy-2,3-dihydroindanone (1 g, 0.0062 mol), NBS (3.31 g, 0.0186 mol), and AIBN (0.1 g, 0.00062 mol), and stirred at 80 °C for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (2% EtOAc / hexane) to give the desired title compound (1.8 g, 92%) as a red solid.

[0452] 1 H NMR (400 MHz, CDCl3) δ 7.09 – 7.06 (m, 2H), 6.85 – 6.83 (m, 1H), 3.84 (s, 3H).

[0453] Step 2: Synthesis of 2-bromo-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-inden-1-one 1,4-Dioxane (24 mL) / H₂O (8 mL) was added to a mixture of 2,3-dibromo-6-methoxy-1H-inden-1-one (800 mg, 2.5160 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazole (523.49 mg, 2.516 mmol), Pd(PPh₃)₄ (145.37 mg, 0.1258 mmol), and K₂CO₃ (1041.62 mg, 7.548 mmol), and then added to a solution at 40 mL. o C. Stir under nitrogen for 16 hours. Add water (50 mL) to the reactants and extract with EA (30 mL x 3). Wash the organic layer using standard methods, dry, and concentrate under reduced pressure. Purify the concentrated residue by silica gel column chromatography (MeOH / DCM) to obtain the desired title compound (500 mg, 62%) as a red solid.

[0454] LCMS (ESI-MS): Calculated mass value. C 14 H 11 BrN₂O₂ 318.0 m / z, measured value 318.7 [M+H] + .

[0455] Step 3: Synthesis of 6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one Following the same method as step 5 of Preparation Example 21, 2-bromo-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-indone and pyridine-3-boronic acid were used to obtain the desired title compound (390 mg, 89%) as a red solid.

[0456] LCMS (ESI-MS): Calculated mass value. C 19 H 15 N3O2 has a m / z value of 317.1 and a measured value of 318.0 [M+H]. + .

[0457] 1 H NMR (400 MHz, DMSO- d6) δ 8.56 – 8.54 (m, 1H), 8.47 – 8.46 (m, 1H), 8.31 (s, 1H), 7.72 – 7.69 (m, 1H), 7.57 – 7.55 (m, 1H), 7.46 – 7.43 (m, 2H), 7.12 – 7.11 (m, 1H), 7.03 – 7.01 (m, 1H), 3.90 (s, 3H), 3.86 (s, 3H).

[0458] Step 4: Synthesis of 6-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one BBr3 (4 mL) was added to a solution of 6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one (370 mg, 1.1659 mmol) in DCM (8 mL), and the solution was heated to 25 °C. o The mixture was stirred at C for 16 hours. Water (5 mL) was added to the reactants to terminate the reaction, and the pH was adjusted to 7 with NaHCO3 aqueous solution. Extraction was then performed using DCM (40 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (3% MeOH / DCM) to give the desired title compound (300 mg, 85%) as a red solid.

[0459] LCMS (ESI-MS): Calculated mass value. C 18 H 13 N₃O₂ has a measured value of 301.8 m / z (303.1 m / z) [M–H]. - .

[0460] 1 H NMR (400 MHz, DMSO- d 6) δ 10.17 (s, 1H), 8.54 – 8.52 (m, 1H), 8.45 –8.44 (m, 1H), 8.27 (s, 1H), 7.70 – 7.67 (m, 1H), 7.46 – 7.40 (m, 3H), 6.94 –6.93 (m, 1H), 6.85 – 6.82 (m, 1H), 3.89 (s, 3H).

[0461] Step 5: Synthesis of 3-(1-methyl-1H-pyrazol-4-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (3-(1-methyl-1H-pyrazol-4-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 42) Following the same method as step 2 of Preparation Example 38, 6-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1H-indone was used to give the desired title compound (20.9 mg, 14%) as a red solid.

[0462] The LCMS (ESI-MS) results of the obtained compound 42 (hereinafter chemical formula 43) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 43]

[0463] LCMS (ESI-MS): Calculated mass value. C 27 H 23 N3O2 has a measured value of 422.2 m / z (421.2 m / z) and a measured value of 422.2 [M+H]. + .

[0464] 1 H NMR (400 MHz, DMSO- d 6) δ 8.56 – 8.54 (m, 1H), 8.47 – 8.46 (m, 1H), 8.31 (s, 1H), 7.72 – 7.70 (m, 1H), 7.56 – 7.54 (m, 1H), 7.46 – 7.42 (m, 2H), 7.32 – 7.17 (m, 5H), 7.11 – 7.10 (m, 1H), 7.03 – 7.00 (m, 1H), 4.09 – 4.06(m, 2H), 3.90 (s, 3H), 2.78 – 2.74 (m, 2H), 2.08 – 2.02 (m, 2H).

[0465] Preparation Example 42. 6-(3-phenylpropoxy)-3-(1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one (6-(3-phenylpropoxy)-3-(1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one)(chem. Compound 43) [Reaction 42]

[0466] Step 1: Synthesis of tert-butyl 4-(2-bromo-6-methoxy-1-oxo-1H-inden-3-yl)-1H-pyrazole-1-carboxylate Following the same method as step 2 of Preparation Example 41, the desired title compound (300 mg, 22%) was obtained as a yellow solid.

[0467] LCMS (ESI-MS): Calculated mass value. C 18 H 17 BrN₂O₄ 404.0 m / z, measured value 404.6 [M+H] + .

[0468] Step 2: Synthesis of 6-methoxy-3-(1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one Following the same method as step 5 of Preparation Example 21, the desired title compound (170 mg, 76%) was obtained as a white solid.

[0469] 1 H NMR (400 MHz, DMSO- d 6) δ 13.51 (s, 1H), 8.54 (dd, J = 4.8, 1.6 Hz, 1H), 8.46 (d, J = 1.6 Hz, 1H), 8.29 (s, 1H), 7.71 (dt, J = 8.0, 2.0 Hz, 1H), 7.64– 7.37 (m, 3H), 7.12 (d, J = 2.4 Hz, 1H), 7.02 (dd, J = 8.0, 2.4 Hz, 1H), 3.85(s, 3H).

[0470] Step 3: Synthesis of 6-hydroxy-3-(1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one Following the same method as step 4 of Preparation Example 41, the desired title compound (60 mg, 37%) was obtained as a blue solid.

[0471] LCMS (ESI-MS): Calculated mass value. C 17 H 11 N3O2 has a measured value of 289.1 m / z, while the actual value is 289.7 [M+H]. + .

[0472] Step 4: Synthesis of 6-(3-phenylpropoxy)-3-(1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one (compound 43) Following the same method as step 5 of Preparation Example 41, the desired title compound (2.9 mg, 4%) and 6-hydroxy-3-(1-(3-phenylpropyl)-1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1H-indone (compound 42-1, 5.7 mg, 7%) as a reaction byproduct were obtained as a red solid.

[0473] The LCMS (ESI-MS) results of the obtained compound 43 (hereinafter chemical formula 44) were confirmed. 1 H NMR yielded the following data: [Chemical Formula 44]

[0474] LCMS (ESI-MS): Calculated mass value. C 26 H 21 N3O2 has a measured value of 407.2 m / z and a measured value of 407.8 [M+H]. + .

[0475] 1 H NMR (400 MHz, DMSO- d 6) δ 13.51 (s, 1H), 8.54 (dd, J = 4.8, 1.6 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.31 - 8.23 ​​(m, 1H), 7.71 (dt, J = 8.0, 1.6 Hz,1H), 7.64 – 7.40 (m, 3H), 7.36 – 7.17 (m, 5H), 7.11 (d, J= 2.4 Hz, 1H), 7.01(dd, J = 8.0, 2.4 Hz, 1H), 4.07 (t, J = 6.4 Hz, 2H), 2.92 – 2.72 (m, 2H), 2.15 –1.93 (m, 2H).

[0476] The LCMS (ESI-MS) results of the obtained compound 43-1 were confirmed by... 1 H NMR yielded the following data: LCMS (ESI-MS): Calculated mass value. C 26 H 21 N₃O₂ has a measured value of 407.2 m / z and a measured value of 407.9 [M+H]. + .

[0477] 1 H NMR (400 MHz, DMSO- d 6) δ 10.19 (s, 1H), 8.53 (dd, J = 4.8, 1.6 Hz, 1H), 8.46 (d, J = 1.6 Hz, 1H), 8.28 (s, 1H), 7.70 (dt, J = 8.0, 2.0 Hz, 1H), 7.56– 7.40 (m, 3H), 7.36 – 7.24 (m, 2H), 7.19 (dd, J = 7.2, 3.2 Hz, 3H), 6.94 (d, J =2.4 Hz, 1H), 6.84 (dd, J = 8.0, 2.4 Hz, 1H), 4.16 (t, J = 6.8 Hz, 2H), 2.55 (s, 2H), 2.17 – 1.94 (m, 2H).

[0478] Preparation Example 43. 3-(2-methoxyphenyl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (3-(2-methoxyphenyl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one)(chem. Compound 44) [Reaction Formula 43]

[0479] Step 1: Synthesis of (E)-1-(5-(benzyloxy)-2-bromophenyl)-3-(2-methoxyphenyl)prop-2-en-1-one Following the same method as step 1 of Preparation Example 21, the desired title compound (1.3 g, 84%) was obtained as a yellow solid.

[0480] LCMS (ESI-MS): Calculated mass value. C 23 H 19 BrO3 422.1 m / z, measured value 422.7 [M+H] + .

[0481] Step 2: Synthesis of 6-(benzyloxy)-3-(2-methoxyphenyl)-1H-inden-1-one DMF (28 mL) was added to (E)-1-(5-(benzyloxy)-2-bromophenyl)-3-(2-methoxyphenyl)prop-2-en-1-one (1.3 g, 0.0031 mol), PdCl2 (0.0274 g, 0.000155 mol), PPh3 (0.16 g, 0.0006 mol), and K2CO3 (1.29 g, 0.0093 mol), and stirred at 100 °C under nitrogen for 16 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with EA (80 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (10% EtOAc / hexane) to give the desired title compound (900 mg, 77%) as a yellow solid.

[0482] LCMS (ESI-MS): Calculated mass value. C 23 H 18 O3342.1 m / z, measured value 342.8 [M+H] + .

[0483] Step 3: Synthesis of 6-(benzyloxy)-2-bromo-3-(2-methoxyphenyl)-1H-inden-1-one NBS (478.9 mg, 2.69 mmol) was added to a CHCl3 (35 mL) solution of 6-(benzyloxy)-3-(2-methoxyphenyl)-1H-inden-1-one (880 mg, 2.56 mmol) at -45 °C, and stirred for 2 hours at the same temperature. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with EA (80 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (2% EtOAc / hexane) to give the desired title compound (350 mg, 26%) as a yellow solid.

[0484] LCMS (ESI-MS): Calculated mass value. C 23 H 17 BrO3 420.0 m / z, measured value 420.7 [M+H] + .

[0485] 1 H NMR (400 MHz, DMSO- d 6) δ 7.60 – 7.51 (m, 1H), 7.45 (d, J = 6.8 Hz, 2H), 7.40 (t, J = 7.2Hz, 3H), 7.35 (d, J = 7.2 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 6.99 (dd, J = 8.0, 2.4 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 5.17 (s, 2H), 3.80 (s, 3H).

[0486] Step 4: Synthesis of 6-(benzyloxy)-3-(2-methoxyphenyl)-2-(pyridin-3-yl)-1H-inden-1-one Following the same method as step 5 of Preparation Example 21, the desired title compound (270 mg, 71%) was obtained as a yellow solid.

[0487] LCMS (ESI-MS): Calculated mass value. C28 H 21 NO3 419.2 m / z, measured value 419.9 [M+H] + .

[0488] Step 5: Synthesis of 6-hydroxy-3-(2-methoxyphenyl)-2-(pyridin-3-yl)-1H-inden-1-one MeOH (13 mL) was added to 6-(benzyloxy)-3-(2-methoxyphenyl)-2-(pyridin-3-yl)-1H-inden-1-one (270 mg, 0.6421 mmol) and Pd / C (10 mg), and stirred at room temperature under hydrogen atmosphere for 2 hours. The reaction mixture was passed through diatomaceous earth, and the resulting filtrate was concentrated. The concentrated residue was purified by silica gel column chromatography (50% EtOAc / hexane) to give the desired title compound (70 mg, 31%) as an orange solid.

[0489] LCMS (ESI-MS): Calculated mass value. C 21 H 15 NO3 329.1 m / z, measured value 329.7 [M+H] + .

[0490] 1 H NMR (400 MHz, DMSO- d 6) δ 10.26 (s, 1H), 8.39 (d, J = 3.2 Hz, 1H), 8.27 (d, J = 1.6 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.51 – 7.44 (m, 1H), 7.32 –7.29 (m, 1H), 7.24 (dd, J = 7.6, 1.6 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.95 (s, 1H), 6.76 (s, 2H), 3.56 (s, 3H).

[0491] Step 6: Synthesis of 3-(2-methoxyphenyl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (compound 44) Following the same method as step 2 of Preparation Example 38, the desired title compound (5.0 mg, 6%) was obtained as a red solid.

[0492] The LCMS (ESI-MS) results of the obtained compound 44 (hereinafter chemical formula 45) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 45]

[0493] LCMS (ESI-MS): Calculated mass value. C 30 H 25 NO3 447.2 m / z, measured value 447.9 [M+H] + .

[0494] 1 H NMR (400 MHz, DMSO- d 6) δ 8.41 – 8.40 (m, 1H), 8.29 (s, 1H), 7.55(dd, J = 6.0, 4.0 Hz, 1H), 7.50 – 7.46 (m, 1H), 7.34 – 7.31 (m, 1H), 7.31 –7.27 (m, 2H), 7.24 (d, J = 7.2 Hz, 3H), 7.19 (t, J = 8.4 Hz, 2H), 7.13 – 7.12 (m,1H), 7.04 (t, J = 7.4 Hz, 1H), 6.95 (dd, J = 8.0, 2.4 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 4.04 (t, J = 6.4 Hz, 2H), 3.58 (s, 3H), 2.78 – 2.73 (m, 2H), 2.08 – 2.00 (m, 2H).

[0495] Preparation Example 44. 3-(2,6-dimethoxyphenyl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-indene 1-keto(3-(2,6-dimethoxyphenyl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1- one)(Compound 45) [Reaction Formula 44]

[0496] Step 1: Synthesis of (E)-1-(5-(benzyloxy)-2-bromophenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one Following the same method as step 1 of Preparation Example 21, the desired title compound (1.81 g, 95%) was obtained as a yellow solid.

[0497] LCMS (ESI-MS): Calculated mass value. C 24 H 21 BrO4 452.1 m / z, measured value 453.1 [M+H] + .

[0498] Step 2: Synthesis of 6-(benzyloxy)-3-(2,6-dimethoxyphenyl)-1H-inden-1-one Following the same method as step 2 of Preparation Example 43, the desired title compound (1.04 g, 70%) was obtained as a yellow solid.

[0499] LCMS (ESI-MS): Calculated mass value. C 24 H 20 O4372.1 m / z, measured value 372.7 [M+H] + .

[0500] Step 3: Synthesis of 6-(benzyloxy)-2-bromo-3-(2,6-dimethoxyphenyl)-1H-inden-1-one Following the same method as step 3 of Preparation Example 43, the desired title compound (415 mg, 91%) was obtained as a yellow solid.

[0501] LCMS (ESI-MS): Calculated mass value. C 24 H 19 BrO4 450.0 m / z, measured value 451.0 [M+H] + .

[0502] Step 4: Synthesis of 6-(benzyloxy)-2-bromo-3-(2,6-dimethoxyphenyl)-2-(pyridin-3-yl)-1H-inden-1-one Following the same method as step 5 of Preparation Example 21, the desired title compound (200 mg, 60%) was obtained as a red oil.

[0503] LCMS (ESI-MS): Calculated mass value. C 29 H 23 NO4449.2 m / z, measured value 450.1 [M+H] + .

[0504] Step 5: Synthesis of 3-(2,6-dimethoxyphenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one Following the same method as step 5 of Preparation Example 43, the desired title compound (120 mg, 75%) was obtained as a red solid.

[0505] LCMS (ESI-MS): Calculated mass value. C 22 H 17 NO4 359.1 m / z, measured value 360.0 [M+H] + .

[0506] 1 H NMR (400 MHz, DMSO- d 6) δ 10.07 (s, 1H), 8.38 – 8.30 (m, 2H), 7.57 –7.54 (m, 1H), 7.45 – 7.41 (m, 1H), 7.31 – 7.28 (m, 1H), 6.92 – 6.91 (m, 1H), 6.78 – 6.72 (m, 3H), 6.58 – 6.56 (m, 1H), 3.58 (s, 6H).

[0507] Step 6: Synthesis of 3-(2,6-dimethoxyphenyl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (compound 45) Following the same method as step 2 of Preparation Example 38, the desired title compound (20 mg, 16%) was obtained as a red solid.

[0508] The LCMS (ESI-MS) results of the obtained compound 45 (hereinafter chemical formula 46) were confirmed. 1 H NMR yielded the following data: [Chemical Formula 46]

[0509] LCMS (ESI-MS): Calculated mass value. C 31 H 27 NO4477.2 m / z, measured value 478.3 [M+H] + .

[0510] 1 H NMR (400 MHz, DMSO- d 6) δ 8.41 – 8.31 (m, 2H), 7.59 – 7.56 (m, 1H), 7.46 – 7.42 (m, 1H), 7.33 – 7.17 (m, 6H), 7.10 – 7.09 (m, 1H), 6.93 – 6.90(m, 1H), 6.79 – 6.77 (m, 2H), 6.68 – 6.66 (m, 1H), 4.05 – 4.02 (m, 2H), 3.58(s, 6H), 2.77 – 2.73 (m, 2H), 2.06 – 2.01 (m, 2H).

[0511] Preparation Example 45. 4-Methyl-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)- 1H-Inden-1-one(4-methyl-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin- 3-yl)-1H-inden-1-one) (Compound 46) [Reaction Formula 45]

[0512] Step 1: (E)-1-(3-hydroxy-5-methylphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one (( ESynthesis of )-1-(3-hydroxy-5-methylphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one) Following the same method as step 1 of Preparation Example 21, the desired title compound (800 mg, 46%) was obtained as a yellow solid.

[0513] LCMS (ESI-MS): Calculated mass value. C 14 H 13 NO₂S 259.1 m / z, measured value 260.0 [M+H] + .

[0514] Step 2: Synthesis of 6-hydroxy-4-methyl-3-(4-methylthiazol-5-yl)-2,3-dihydro-1H-inden-1-one Following the same method as step 2 of Preparation Example 21, the desired title compound (0.4 g, 76%) was obtained as a yellow solid.

[0515] LCMS (ESI-MS): Calculated mass value. C 14 H 13 NO₂S 259.1 m / z, measured value 259.7 [M+H] + .

[0516] Step 3: Synthesis of 7-methyl-1-(4-methylthiazol-5-yl)-3-oxo-2,3-dihydro-1H-inden-5-yl acetate Following the same method as step 3 of Preparation Example 21, the desired title compound (0.9 g, 69%) was obtained as a yellow oil.

[0517] LCMS (ESI-MS): Calculated mass value. C 16 H 15 NO3S 301.1 m / z, measured value 301.7 [M+H] + .

[0518] Step 4: Synthesis of 2-bromo-4-methyl-3-(4-methylthiazol-5-yl)-1-oxo-1H-inden-6-yl acetate Following the same method as step 4 of Preparation Example 21, the desired title compound (180 mg, 38%) was obtained as a yellow solid.

[0519] LCMS (ESI-MS): Calculated mass value. C 16 H 12 BrNO3S 377.0 m / z, measured value 377.6 [M+H] + .

[0520] Step 5: Synthesis of 6-hydroxy-4-methyl-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one Following the same method as step 5 of Preparation Example 21, the desired title compound (50 mg, 72%) was obtained as a red solid.

[0521] LCMS (ESI-MS): Calculated mass value. C 19 H 14 N₂O₂S 334.1 m / z, measured value 335.0 [M+H] + .

[0522] Step 6: Synthesis of 4-methyl-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (compound 46) Following the same method as step 2 of Preparation Example 38, the desired title compound (40 mg, yield 53%) was obtained as a red solid.

[0523] The LCMS (ESI-MS) results of the obtained compound 46 (hereinafter chemical formula 47) were confirmed. 1 H NMR yielded the following data: [Chemical Formula 47]

[0524] LCMS (ESI-MS): Calculated mass value. C 28 H 24 N₂O₂S 452.2 m / z, measured value 452.9 [M+H] + .

[0525] 1 H NMR (400 MHz, DMSO- d 6) δ 9.23 (s, 1H), 8.44 – 8.43 (m, 1H), 8.30 (s, 1H), 7.57 – 7.52 (m, 1H), 7.41 – 7.16 (m, 6H), 7.02 – 7.01 (m, 1H), 6.78(s, 1H), 4.04 (t, J = 6.4 Hz, 2H), 2.79 – 2.70 (m, 2H), 2.24 (s, 3H), 2.07 –1.98 (m, 2H), 1.84 (s, 3H).

[0526] Preparation Example 46. 4-Methoxy-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(pyridine-3- base)-1H-inden-1-one (4-methoxy-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2- (pyridin-3-yl)-1H-inden-1-one) (Compound 47) [Reaction Formula 46]

[0527] Step 1: ( E )-1-(3-hydroxy-5-methoxyphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one(( E Synthesis of )-1-(3-hydroxy-5-methoxyphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one) Following the same method as step 1 of Preparation Example 21, the desired title compound ((0.95 g, 57%), as a yellow solid, was obtained.

[0528] 1 H NMR (400 MHz, DMSO- d 6) δ 9.85 (s, 1H), 9.14 (s, 1H), 7.88 (d, J =15.2 Hz, 1H), 7.37 (d, J = 15.2 Hz, 1H), 7.06 (d, J = 1.2 Hz, 2H), 6.62 (t,J = 2.4Hz, 1H), 3.79 (s, 3H), 2.55 (s, 3H).

[0529] Step 2: Synthesis of 6-hydroxy-4-methoxy-3-(4-methylthiazol-5-yl)-2,3-dihydro-1H-inden-1-one (47-4) and 4-hydroxy-6-methoxy-3-(4-methylthiazol-5-yl)-2,3-dihydro-1H-inden-1-one Following the same method as step 2 of Preparation Example 21, two structural isomers of the desired title compound (650 mg, 68%) were obtained as yellow solids and used directly in the next reaction without purification.

[0530] LCMS (ESI-MS): Calculated mass value. C 14 H 13 NO3S 275.1 m / z, measured value 275.6 [M+H] + .

[0531] Step 3: Synthesis of 7-methoxy-1-(4-methylthiazol-5-yl)-3-oxo-2,3-dihydro-1H-inden-5-yl acetate and 6-methoxy-3-(4-methylthiazol-5-yl)-1-oxo-2,3-dihydro-1H-inden-4-yl acetate Following the same method as step 3 of Preparation Example 21, two structural isomers of the desired title compound (260 mg, 35%) were obtained as yellow solids and used directly in the next reaction without purification.

[0532] LCMS (ESI-MS): Calculated mass value. C 16 H 15 NO4S 317.1 m / z, measured value 317.6 [M+H] + .

[0533] Step 4: Synthesis of 2-bromo-4-methoxy-3-(4-methylthiazol-5-yl)-1-oxo-1H-inden-6-yl acetate and 2-bromo-6-methoxy-3-(4-methylthiazol-5-yl)-1-oxo-1H-inden-4-yl acetate The reaction and purification were carried out in the same manner as in step 4 of Preparation Example 21 to obtain title compounds A (130 mg, 42%) and B (150 mg, 50%) as yellow solids.

[0534] Compound 46-8 1 The H NMR results are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 9.24 (s, 1H), 7.08 (s, 1H), 7.04 (s, 1H), 3.64 (s, 3H), 2.35 (s, 3H), 2.28 (s, 3H).

[0535] Step 5: Synthesis of 6-hydroxy-4-methoxy-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one Following the same method as step 5 of Preparation Example 21, the desired title compound (70 mg, 67%) was obtained as a yellow solid.

[0536] Step 6: Synthesis of 4-methoxy-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (compound 47) Following the same method as step 2 of Preparation Example 38, the desired title compound (30 mg, 38%) was obtained as a red solid.

[0537] The LCMS (ESI-MS) results of the obtained compound 47 (hereinafter chemical formula 48) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 48]

[0538] LCMS (ESI-MS): Calculated mass value. C 28 H 24 N₂O₃S 468.2 m / z, measured value 468.9 [M+H] + .

[0539] 1 H NMR (400 MHz, DMSO- d 6) δ 9.16 (s, 1H), 8.43 (dd, J = 4.8, 1.6 Hz, 1H), 8.22 (d, J = 1.6 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.39 – 7.14 (m, 6H), 6.84 (d, J = 2.0 Hz, 1H), 6.71 (d, J = 1.6 Hz, 1H), 4.11 (t, J = 6.4 Hz, 2H), 3.67(s, 3H), 2.82 – 2.72 (m, 2H), 2.14 – 1.96 (m, 5H).

[0540] Preparation Example 47. 4-Hydroxy-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)- 1H-Inden-1-one(4-hydroxy-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin- 3-yl)-1H-inden-1-one) (Compound 48) [Reaction Formula 47]

[0541] Step 1: Synthesis of 4-hydroxy-6-methoxy-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one Following the same method as step 5 of Preparation Example 46, the desired title compound (100 mg, 71%) was obtained as a yellow solid.

[0542] Step 2: Synthesis of 4,6-dihydroxy-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one Add 1 mL of HBr aqueous solution to 95 mg of 4-hydroxy-6-methoxy-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-indone (95 mg, 0.27 mmol) and stir at 100 °C for 6 hours.

[0543] By concentration, the desired title compound (100 mg, crude product) was obtained as a yellow solid.

[0544] Step 3: Synthesis of 4-hydroxy-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (compound 48) Following the same method as step 2 of Preparation Example 38, the desired title compound (3 mg, 3%) was obtained as a yellow solid.

[0545] The LCMS (ESI-MS) results of the obtained compound 48 (hereinafter chemical formula 49) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 49]

[0546] LCMS (ESI-MS): Calculated mass value. C 27 H 22 N₂O₃S 454.1 m / z, measured value 454.9 [M+H] + .

[0547] 1 H NMR (400 MHz, DMSO- d 6) δ 9.25 (s, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.35– 7.16 (m, 5H), 7.09 (s, 1H), 6.97 (d, J = 4.4 Hz, 2H), 6.60 (d, J= 2.0 Hz, 1H),4.03 (s, 3H), 3.74 (s, 2H), 2.87 – 2.70 (m, 4H), 2.35 – 2.20 (m, 2H), 2.10(s, 3H), 2.07 – 1.97 (m, 2H), 1.97 – 1.72 (m, 4H).

[0548] Preparation Example 48. 6-(cyclopentylamino)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (6-(cyclopentylamino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1- one)(Compound 49) [Reaction Formula 48]

[0549] 1,4-Dioxane / H₂O (5 mL / 1 mL) was added to 6-chloro-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (100 mg, 0.30 mmol), cyclopentylamine (51 mg, 0.60 mmol), and Pd-PEPPSI-IPent. Cl The mixture was prepared in 28 mg (0.03 mmol) and Cs₂CO₃ (195 mg, 0.60 mmol) and stirred at 100 °C under nitrogen for 16 hours. After cooling to room temperature, water (5 mL) was added to the reaction mixture, and extraction was performed using EA (10 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was analyzed by prep-HPLC (Gemini 5). C 18 Purification was performed using a chromatographic column (150 x 21.2 mm, 30-90% ACN / H2O 0.1% FA) to obtain the desired title compound (38 mg, 33%) as a blue solid.

[0550] The LCMS (ESI-MS) results of the obtained compound 49 (hereinafter chemical formula 50) were confirmed. 1 H NMR yielded the following data: [Chemical Formula 50]

[0551] LCMS (ESI-MS): Calculated mass value. C 23 H 21 N3OS 387.1 m / z, measured value 387.7 [M+H] + .

[0552] 1 H NMR (400 MHz, DMSO- d 6) δ 9.28 (s, 1H), 8.43 (dd,J = 4.8, 1.6 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.55 (dt, J = 8.0, 2.0 Hz, 1H), 7.36 (dd, J = 8.0, 4.8 Hz, 1H), 6.91 (dd, J = 5.2, 3.6 Hz, 2H), 6.56 (d, J = 6.8 Hz, 1H), 6.46 (dd, J = 8.0, 2.0 Hz, 1H), 3.93 – 3.66 (m, 1H), 2.02 – 1.84 (m, 5H), 1.79 – 1.31 (m, 6H).

[0553] Preparation Example 49. 6-(methylamino)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (6-(methylamino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one)(chemical Compound 50) [Reaction Formula 49]

[0554] Following the same method as in Preparation Example 48, methylamine was used to obtain the desired title compound (11.9 mg, 12%) as a blue solid.

[0555] The LCMS (ESI-MS) results of the obtained compound 50 (hereinafter chemical formula 51) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 51]

[0556] LCMS (ESI-MS): Calculated mass value. C 19 H 15 N3OS 333.1 m / z, measured value 333.7 [M+H] + .

[0557] 1 H NMR (400 MHz, DMSO- d 6) δ 9.28 (s, 1H), 8.44 (dd, J = 4.8, 1.6 Hz, 1H), 8.31 (d, J = 1.6 Hz, 1H), 7.56 (dt, J = 8.0, 2.0 Hz, 1H), 7.36 (dd,J = 8.0, 4.8 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.60 (d, J = 5.2Hz, 1H), 6.42 (dd, J = 8.0, 2.0 Hz, 1H), 2.76 (d, J = 5.2 Hz, 3H), 1.95 (s, 3H).

[0558] Preparation Example 50. 6-((1-methylpiperidin-4-yl)amino)-3-(4-methylthiazo-5-yl)-2-(pyridine-3-yl) methyl)-1H-inden-1-one(6-((1-methylpiperidin-4-yl)amino)-3-(4-methylthiazol-5-yl)-2- (pyridin-3-yl)-1H-inden-1-one) (Compound 51) [Reaction Formula 50]

[0559] Following the same method as in Preparation Example 48, the desired title compound (37 mg, 35%) was obtained as a blue solid using 1-methylpiperidin-4-amine.

[0560] The LCMS (ESI-MS) results of the obtained compound 51 (hereinafter chemical formula 52) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 52]

[0561] LCMS (ESI-MS): Calculated mass value. C 24 H 24 N4OS 416.2 m / z, measured value 416.8 [M+H] + .

[0562] 1 H NMR (400 MHz, DMSO- d 6) δ 9.28 (s, 1H), 8.44 (dd, J = 4.8, 1.6 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.20 (s, 1H), 7.56 – 7.53 (m, 1H), 7.37 – 7.34(m, 1H), 6.93 – 6.89 (m, 2H), 6.54 – 6.41 (m, 2H), 3.35 (s, 1H), 2.81 (d, J=11.6 Hz, 2H), 2.25 (s, 3H), 2.17 (t, J = 10.6 Hz, 2H), 1.94 – 1.89 (m, 5H), 1.44 (q, J = 13.4 Hz, 2H).

[0563] Preparation Example 51. 3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-6-(((tetrahydro-2H-pyran-4-yl)methyl) (3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-6-yl)-1H-indone (((tetrahydro-2H-pyran-4-yl)methyl)amino)-1H-inden-1-one)(Compound 52) [Reaction Formula 51]

[0564] Following the same method as in Preparation Example 48, the desired title compound (35 mg, 33%) was obtained as a blue solid using (tetrahydro-2H-pyran-4-yl)methanamine.

[0565] The LCMS (ESI-MS) results of the obtained compound 52 (hereinafter chemical formula 53) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 53]

[0566] LCMS (ESI-MS): Calculated mass value. C 24 H 23 N3O2S 417.2 m / z, measured value 417.9 [M+H] + .

[0567] 1 H NMR (400 MHz, DMSO- d 6) δ 9.28 (s, 1H), 8.43 (dd, J = 4.8, 1.6 Hz, 1H), 8.30 (d, J = 1.6 Hz, 1H), 7.56 – 7.54 (m, 1H), 7.36 (dd, J = 7.4, 4.8 Hz,1H), 6.94 – 6.90 (m, 2H), 6.64 (t, J = 5.6 Hz, 1H), 6.53 – 6.47 (m, 1H), 3.86(dd, J = 11.2, 3.2 Hz, 2H), 3.28 (t, J= 10.8 Hz, 2H), 3.01 (t, J = 6.2 Hz, 2H),1.94 (s, 3H), 1.89 – 1.74 (m, 1H), 1.66 (d, J = 12.8 Hz, 2H), 1.31 – 1.15 (m, 2H).

[0568] Preparation Example 52. 6-((2-hydroxyethyl)amino)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H- Inden-1-one(6-((2-hydroxyethyl)amino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)- 1H-inden-1-one) (compound 53) [Reaction Formula 52]

[0569] Following the same method as in Preparation Example 48, the desired title compound (20.0 mg, 22%) was obtained as a blue solid using 2-aminoethanol (2-aminoethan-1-ol).

[0570] The LCMS (ESI-MS) results of the obtained compound 53 (hereinafter chemical formula 54) were confirmed. 1 H NMR yielded the following data: [Chemical Formula 54]

[0571] LCMS (ESI-MS): Calculated mass value. C 20 H 17 N3O2S 363.1 m / z, measured value 363.7 [M+H] + .

[0572] 1 H NMR (400 MHz, DMSO- d 6) δ 9.28 (s, 1H), 8.43 (dd, J = 4.8, 1.7 Hz, 1H), 8.31 (d, J = 1.6 Hz, 1H), 7.55 (dt, J = 8.0, 2.0 Hz, 1H), 7.36 (dd, J = 8.0,4.8 Hz, 1H), 6.93 (m, 2H), 6.59 – 6.46 (m, 2H), 4.78 (s, 1H), 3.56 (d, J = 5.2Hz, 2H), 3.18 (q, J = 6.0 Hz, 2H), 1.95 (s, 3H).

[0573] Preparation Example 53. 6-((2-methoxyethyl)amino)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)- 1H-Inden-1-one(6-((2-methoxyethyl)amino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3- yl)-1H-inden-1-one) (compound 54) [Reaction Formula 53]

[0574] Following the same method as in Preparation Example 48, the desired title compound (5.3 mg, 5%) was obtained as a blue solid using 2-methoxyethan-1-amine.

[0575] The LCMS (ESI-MS) results of the obtained compound 54 (hereinafter chemical formula 55) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 55]

[0576] LCMS (ESI-MS): Calculated mass value. C 21 H 19 N3O2S 377.1 m / z, measured value 377.7 [M+H] + .

[0577] 1 H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.48 (d, J = 6.4 Hz, 2H), 7.69(d, J = 7.6 Hz, 1H), 7.34 – 7.28 (m, 1H), 6.94 (dd, J = 6.8, 5.2 Hz, 2H), 6.48(dd, J = 8.0, 2.3 Hz, 1H), 3.63 (t, J = 5.2 Hz, 2H), 3.41 (s, 3H), 3.36 (t, J = 5.2Hz, 2H), 2.10 (s, 3H).

[0578] Preparation Example 54. 3-(4-methylthiazolyl-5-yl)-6-((2-phenoxyethyl)amino)-2-(pyridin-3-yl)-1H- Inden-1-one(3-(4-methylthiazol-5-yl)-6-((2-phenoxyethyl)amino)-2-(pyridin-3-yl)- 1H-inden-1-one) (compound 55) [Reaction Formula 54]

[0579] Following the same method as in Preparation Example 48, the desired title compound (28.0 mg, 25%) was obtained as a blue solid using 2-phenoxyethan-1-amine.

[0580] The LCMS (ESI-MS) results of the obtained compound 55 (hereinafter chemical formula 56) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 56]

[0581] LCMS (ESI-MS): Calculated mass value. C 26 H 21 N3O2S 439.1 m / z, measured value 439.8 [M+H] + .

[0582] 1 H NMR (400 MHz, DMSO- d 6) δ 9.29 (s, 1H), 8.44 (dd, J = 4.8, 1.6 Hz, 1H), 8.31 (d, J = 1.6 Hz, 1H), 7.56 (dt, J = 8.0, 1.9 Hz, 1H), 7.35 – 7.28 (m,3H), 7.04 – 6.92 (m, 5H), 6.79 (t, J = 5.6 Hz, 1H), 6.58 (dd, J = 8.0, 2.4 Hz, 1H), 4.13 (t, J = 5.2 Hz, 2H), 3.53 (q, J = 5.2 Hz, 2H), 1.95 (s, 3H).

[0583] Preparation Example 55. 3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-6-((tetrahydro-2H-pyran-4-yl)amino (3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-6-((tetrahydro-2H-))-1H-indone pyran-4-yl)amino)-1H-inden-1-one) (compound 56) [Reaction Formula 55]

[0584] Following the same method as in Preparation Example 48, the desired title compound (22.6 mg, 19%) was obtained as a blue solid using tetrahydro-2H-pyran-4-amine.

[0585] The LCMS (ESI-MS) results of the obtained compound 56 (hereinafter chemical formula 57) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 57]

[0586] LCMS (ESI-MS): Calculated mass value. C 23 H 21 N3O2S 403.1 m / z, measured value 403.8 [M+H] + .

[0587] 1 H NMR (400 MHz, DMSO- d 6) δ 9.28 (s, 1H), 8.44 (d, J = 4.8 Hz, 1H), 8.31(s, 1H), 7.60 – 7.51 (m, 1H), 7.36 (dd, J = 8.0, 4.8 Hz, 1H), 7.03 – 6.88 (m,2H), 6.56 – 6.47 (m, 2H), 3.88 – 3.86 (m, 2H), 3.59 (s, 1H), 3.44 (t, J = 11.2Hz, 2H), 2.03 – 1.78 (m, 5H), 1.43 – 1.36 (m, 2H).

[0588] Preparation Example 56. 3-(4-methylthiazolyl-5-yl)-6-((3-phenylpropyl)thio)-2-(pyridin-3-yl)-1H- Inden-1-one(3-(4-methylthiazol-5-yl)-6-((3-phenylpropyl)thio)-2-(pyridin-3-yl)- 1H-inden-1-one) (compound 57) [Reaction Formula 56]

[0589] Following the same method as in Preparation Example 48, the desired title compound (16 mg, 30%) was obtained as a red solid using 3-phenylpropane-1-thiol.

[0590] The LCMS (ESI-MS) results of the obtained compound 57 (hereinafter chemical formula 58) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 58]

[0591] LCMS (ESI-MS): Calculated mass value. C 27 H22 N2OS 2454.1 m / z, measured value 455.1 [M+H] + .

[0592] 1 H NMR (400 MHz, DMSO- d 6) δ 8.95 (s, 1H), 8.51 – 8.50 (m, 2H), 7.72 –7.70 (m, 1H), 7.53 – 7.52 (m, 1H), 7.35 – 7.28 (m, 4H), 7.23 – 7.18 (m, 3H),7.06 – 7.04 (m, 1H), 2.99 (t, J = 7.2 Hz, 2H), 2.78 (t, J = 7.2 Hz, 2H), 2.10 (s, 3H), 2.05 – 1.97 (m, 2H).

[0593] Preparation Example 57. 3-(4-methylthiazolyl-5-yl)-6-((1-phenylpiperidin-3-yl)amino)-2-(pyridine-3-yl) methyl)-1H-inden-1-one (3-(4-methylthiazol-5-yl)-6-((1-phenylpiperidin-3-yl)amino)-2- (pyridin-3-yl)-1H-inden-1-one) (Compound 58) [Reaction Formula 57]

[0594] Following the same method as in Preparation Example 48, the desired title compound (20.0 mg, 22%) was obtained as a blue solid using 1-phenylpiperidin-3-amine.

[0595] The LCMS (ESI-MS) results of the obtained compound 58 (hereinafter chemical formula 59) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 59]

[0596] LCMS (ESI-MS): Calculated mass value. C 29 H 26 N4OS 478.2 m / z, measured value 479.0 [M+H] + .

[0597] 1 H NMR (400 MHz, DMSO- d 6) δ 9.29 (s, 1H), 8.44 – 8.43 (m, 1H), 8.31 –8.30 (m, 1H), 7.56 (d, J= 8.0 Hz, 1H), 7.36 (dd, J = 8.0, 4.8 Hz, 1H), 7.22 –7.20 (m, 2H), 7.00 (s 1H), 6.96 – 6.94 (m, 3H), 6.77 (t, J = 7.2 Hz, 1H), 6.60– 6.52 (m, 2H), 3.68 – 3.65 (m, 1H), 3.60 (s, 1H), 3.51 – 3.48 (m, 1H), 2.80(t, J = 10.0 Hz, 1H), 2.66 – 2.63 (m, 1H), 2.02 – 1.99 (m, 1H), 1.95 (s, 3H), 1.82 – 1.81 (m, 1H), 1.68 – 1.67 (m, 1H), 1.43 – 1.41 (m, 1H).

[0598] Preparation Example 58. 6-Amino-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (6- amino-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 59) [Reaction Formula 58]

[0599] 1,4-Dioxane (30 mL) was added to 6-chloro-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (600 mg, 1.78 mmol), diphenylamine (642 mg, 3.55 mmol), Cs₂CO₃ (1153 mg, 3.55 mmol), and XphosPdG₃ (152 mg, 0.18 mmol), and stirred at 100 °C under nitrogen for 16 hours. HCl / 1,4-dioxane (3 mL) was then added to the reactants, and the mixture was stirred at room temperature for 2 hours.

[0600] Water (20 mL) was added to the reactants, and the mixture was extracted with EA (30 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (5% MeOH / DCM) to give the desired title compound (180 mg, 32%) as a blue solid.

[0601] The LCMS (ESI-MS) results of the obtained compound 59 (hereinafter chemical formula 60) were confirmed. 1 H NMR yielded the following data: [Chemical Formula 60]

[0602] LCMS (ESI-MS): Calculated mass value. C 18 H 13 N3OS 319.1 m / z, measured value 319.6 [M+H] + .

[0603] 1 H NMR (400 MHz, DMSO- d 6) δ 9.28 (s, 1H), 8.43 – 8.42 (m, 1H), 8.30 –8.29 (m, 1H), 7.55 – 7.54 (m, 1H), 7.36 – 7.34 (m, 1H), 6.86 – 6.84 (m, 2H), 6.52 – 6.50 (m, 1H), 5.97 (s, 2H), 1.94 (s, 3H).

[0604] Preparation Example 59. N -(3-(4-methylthiazolyl-5-yl)-1-oxo-2-(pyridin-3-yl)-1H-inden-6-yl)-3-benzene Propanamide( N -(3-(4-methylthiazol-5-yl)-1-oxo-2-(pyridin-3-yl)-1H-inden-6-yl)-3- phenylpropanamide) (compound 60) [Reaction Formula 59]

[0605] 6-Amino-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (120 mg, 0.38 mmol) was added to a DMF (6 mL) solution of 3-phenylpropionic acid (86 mg, 0.57 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (217 mg, 0.57 mmol), and DIPEA (98 mg, 0.76 mmol), and stirred at room temperature for 16 hours. Water (6 mL) was added to the reaction mixture, and extraction was performed using EA (15 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was analyzed by prep-HPLC (Gemini 5). C 18 Purification was performed using a chromatographic column (150x21.2 mm, 30-90% ACN / H2O 0.1% FA) to obtain the desired title compound (23.1 mg, 13%) as a yellow solid.

[0606] The LCMS (ESI-MS) results of the obtained compound 60 (hereinafter chemical formula 61) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 61]

[0607] LCMS (ESI-MS): Calculated mass value. C 27 H 21 N3O2S 451.1 m / z, measured value 452.2 [M+H] + .

[0608] 1 H NMR (400 MHz, DMSO- d 6) δ 10.28 (s, 1H), 9.32 (s, 1H), 8.49 – 8.48 (m, 1H), 8.36 (s, 1H), 7.92 (s, 1H), 7.70 – 7.65 (m, 2H), 7.42 – 7.39 (m,1H), 9.31 - 7.17 (m, 6H), 2.93 (t, J = 7.2 Hz, 2H), 2.67 (t, J = 7.2 Hz, 2H), 1.97 (s, 3H).

[0609] Preparation Example 60. N-(3-(4-methylthiazo-5-yl)-1-oxo-2-(pyridin-3-yl)-1H-inden-6-yl)tetramethyl Hydrogen-2H-pyran-4-carboxamide (N-(3-(4-methylthiazol-5-yl)-1-oxo-2-(pyridin-3-yl)-1H-) (inden-6-yl)tetrahydro-2H-pyran-4-carboxamide)(compound 61) [Reaction Formula 60]

[0610] Following the same method as in Preparation Example 59, tetrahydro-2H-pyran-4-carboxylic acid was used to obtain the desired title compound (18.7 mg, 29%) as a white solid.

[0611] The LCMS (ESI-MS) results of the obtained compound 61 (hereinafter chemical formula 62) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 62]

[0612] LCMS (ESI-MS): Calculated mass value. C 24 H 21 N3O3S 431.1 m / z, measured value 431.8 [M+H] + .

[0613] 1 H NMR (400 MHz, DMSO -d6) δ 10.26 (s, 1H), 9.32 (s, 1H), 8.50 – 8.49 (m, 1H), 8.36 (s, 1H), 7.92 (s, 1H), 7.77 – 7.56 (m, 2H), 7.41 – 7.39 (m,1H), 7.19 (d, J = 8.0 Hz, 1H), 3.98 – 3.85 (m, 2H), 3.38 – 3.36 (m, 2H), 2.66 –2.56 (m, 1H), 1.99 (s, 3H), 1.77 – 1.61 (m, 4H).

[0614] Preparation Example 61. 6-(dimethylamino)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (6-(dimethylamino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 62) [Reaction Formula 61]

[0615] Following the same method as in Preparation Example 58, dimethylamine was used to obtain the desired title compound (60 mg, 65%) as a purple solid.

[0616] The LCMS (ESI-MS) results of the obtained compound 62 (hereinafter chemical formula 63) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 63]

[0617] LCMS (ESI-MS): Calculated mass value. C 20 H 17 N₃O 347.1 m / z, measured value 347.7 [M+H] + .

[0618] 1 H NMR (400 MHz, DMSO- d 6) δ 9.29 (s, 1H), 8.45 (dd, J = 4.8, 1.6 Hz, 1H), 8.33 (d, J = 1.8 Hz, 1H), 7.59 – 7.56 (m, 1H), 7.39 – 7.35 (m, 1H), 7.04 –7.00 (m, 2H), 6.63 – 6.61 (m, 1H), 3.03 (s, 6H), 1.96 (s, 3H).

[0619] Preparation Example 62. 6-(cyclopropylamino)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (6-(cyclopropylamino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1- one)(Compound 63) [Reaction 62]

[0620] Following the same method as in Preparation Example 58, the desired title compound (80 mg, 67%) was obtained as a purple solid using cyclopropanamine.

[0621] The LCMS (ESI-MS) results of the obtained compound 63 (hereinafter chemical formula 64) were confirmed. 1 H NMR yielded the following data: [Chemical Formula 64]

[0622] LCMS (ESI-MS): Calculated mass value. C 21 H 17 N3OS 359.1 m / z, measured value 359.7 [M+H] + .

[0623] 1 H NMR (400 MHz, DMSO- d 6) δ 9.28 (s, 1H), 8.44 (dd, J = 4.8, 1.6 Hz, 1H), 8.31 (d, J = 1.6 Hz, 1H), 7.61 – 7.52 (m, 1H), 7.36 (dd, J = 7.6, 5.2 Hz,1H), 7.02 – 6.90 (m, 3H), 6.67 (dd, J = 8.2, 2.2 Hz, 1H), 2.47 – 2.41 (m, 1H), 0.80 – 0.69 (m, 2H), 0.44 – 0.41 (m, 2H).

[0624] Preparation Example 63. 6-(4-methylpiperazin-1-yl)-3-(4-methylthiazo-5-yl)-2-(pyridin-3-yl)-1H- Inden-1-one(6-(4-methylpiperazin-1-yl)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)- 1H-inden-1-one) (compound 64) [Reaction Formula 63]

[0625] Following the same method as in Preparation Example 58, the desired title compound (15.1 mg, 16%) was obtained as a yellow solid using 1-methylpiperazine.

[0626] The LCMS (ESI-MS) results of the obtained compound 64 (hereinafter chemical formula 65) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 65]

[0627] LCMS (ESI-MS): Calculated mass value. C 23 H 22 N4OS 402.2 m / z, measured value 403.1 [M+H] + .

[0628] 1 H NMR (400 MHz, DMSO- d 6) δ 9.30 (s, 1H), 8.46 (dd, J = 4.8, 1.6 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 7.59 (dt, J = 8.0, 2.0 Hz, 1H), 7.38 (dd, J = 8.0, 4.8 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.90 (dd, J = 8.4,2.4 Hz, 1H), 3.31 – 3.24 (m, 4H), 2.47 – 2.41 (m, 4H), 2.22 (s, 3H), 1.95 (s, 3H).

[0629] Preparation Example 64. 6-(methyl(3-phenylpropyl)amino)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)- 1H-Inden-1-one(6-(methyl(3-phenylpropyl)amino)-3-(4-methylthiazol-5-yl)-2- (pyridin-3-yl)-1H-inden-1-one) (Compound 65) [Reaction Formula 64]

[0630] Step 1: Synthesis of 3-(4-methylthiazol-5-yl)-6-((3-phenylpropyl)amino)-2-(pyridin-3-yl)-1H-inden-1-one Following the same method as in Preparation Example 58, the desired title compound (220 mg, 34%) was obtained as a yellow solid using 3-phenylpropan-1-amine.

[0631] LCMS (ESI-MS): Calculated mass value. C 27 H 23 N3OS 437.2 m / z, measured value 437.8 [M+H] + .

[0632] Step 2: Synthesis of 6-(methyl(3-phenylpropyl)amino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (compound 65) Following the same method as step 5 of Preparation Example 29, the desired title compound (12 mg, 12%) was obtained as a yellow solid.

[0633] The LCMS (ESI-MS) results of the obtained compound 65 (hereinafter chemical formula 66) were confirmed. 1 H NMR yielded the following data: [Chemical Formula 66]

[0634] LCMS (ESI-MS): Calculated mass value. C 28 H 25 N3OS 451.2 m / z, measured value 452.0 [M+H] + .

[0635] 1 H NMR (400 MHz, DMSO- d 6) δ 9.29 (s, 1H), 8.44 (dd, J = 4.8, 1.2 Hz, 1H), 8.32 (d, J= 2.0 Hz, 1H), 7.62 – 7.51 (m, 1H), 7.39 – 7.36 (m, 1H), 7.31 –7.17 (m, 5H), 7.04 – 6.91 (m, 2H), 6.57 (dd, J = 8.4, 2.4 Hz, 1H), 3.51 – 3.42(m, 2H), 3.01 (s, 3H), 2.67 – 2.59 (m, 2H), 1.95 (s, 3H), 1.90 – 1.77 (m, 2H).

[0636] Preparation Example 65. 3-(4-methylthiazolyl-5-yl)-6-phenoxy-2-(pyridin-3-yl)-1H-inden-1-one (3-(4- methylthiazol-5-yl)-6-phenoxy-2-(pyridin-3-yl)-1H-inden-1-one (compound 66) [Reaction Formula 65]

[0637] Toluene (5 mL) was added to 6-chloro-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (40 mg, 0.1181 mmol), phenol (16.67 mg, 0.17715 mmol), Pd(OAc)₂ (2.65 mg, 0.01181 mmol), Me₄t-BuXPhos (11.36 mg, 0.02362 mmol), and K₃PO₄ (75.21 mg, 0.3543 mmol), and stirred at 100 °C under nitrogen for 16 hours. After cooling to room temperature, water (20 mL) was added to the reaction mixture, and extraction was performed using EA (15 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (40% EA / hexane) to give the desired title compound (5.62 mg, yield 12%) as a red solid.

[0638] The LCMS (ESI-MS) results of the obtained compound 66 (hereinafter chemical formula 67) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 67]

[0639] LCMS (ESI-MS): Calculated mass value. C 24 H 16 N₂O₂S 396.1 m / z, measured value 397.1 [M+H] + .

[0640] 1 H NMR (400 MHz, DMSO- d6) δ 8.96 (s, 1H), 8.54 – 8.52 (m, 2H), 7.74 –7.72 (m, 1H), 7.42 – 7.36 (m, 4H), 7.22 – 7.18 (m, 1H), 7.13 – 7.01 (m, 4H), 2.12 (s, 3H).

[0641] Preparation Example 66. 6-(methylamino)-2,3-diphenyl-1H-inden-1-one (6-(methylamino)-2,3- diphenyl-1H-inden-1-one) (compound 67) [Reaction Formula 66]

[0642] Step 1: Synthesis of 6-((2,4-dimethoxybenzyl)(methyl)amino)-2,3-diphenyl-1H-inden-1-one Following the same method as in Preparation Example 58, the desired title compound (70 mg, 38%) was obtained as a yellow solid using 1-(2,4-dimethoxyphenyl)-N-methylmethanamine.

[0643] LCMS (ESI-MS): Calculated mass value. C 31 H 27 NO3 461.2 m / z, measured value 461.8 [M+H] + .

[0644] Step 2: Synthesis of 6-(methylamino)-2,3-diphenyl-1H-inden-1-one (compound 67) Add 6-((2,4-dimethoxybenzyl)(methyl)amino)-2,3-diphenyl-1H-indone (70 mg, 0.15 mmol) and DCM / TFA (1 mL / 0.3 mL), and stir at room temperature. Add water (3 mL) to the reaction mixture and extract with DCM (80 mL x 3). Wash the organic layer using standard methods, dry, and concentrate under reduced pressure. Analyze the concentrated residue using prep-HPLC (Gemini 5). C 18 Purification was performed using a chromatographic column (150x21.2 mm, 30-90% ACN / H2O, 0.1% NH3H2O) to obtain the desired title compound (20.2 mg, 43%) as a blue solid.

[0645] The LCMS (ESI-MS) results of the obtained compound 67 (hereinafter chemical formula 68) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 68]

[0646] LCMS (ESI-MS): Calculated mass value. C 22 H 17 NO 311.1 m / z, measured value 311.8 [M+H] + .

[0647] 1 H NMR (400 MHz, DMSO- d 6) δ 7.47 – 7.40 (m, 3H), 7.37 – 7.31 (m, 2H), 7.28 – 7.16 (m, 3H), 7.12 (d, J = 6.8 Hz, 2H), 6.89 – 6.80 (m, 2H), 6.48 – 6.33(m, 2H), 2.75 (d, J = 5.2 Hz, 3H).

[0648] Preparation Example 67. 6-Amino-2,3-diphenyl-1H-inden-1-one 1-one)(Compound 68) [Reaction Formula 67]

[0649] Following the same method as in Preparation Example 58, the desired title compound (200 mg, 27%) was obtained as a white solid using diphenylmethanimine.

[0650] The LCMS (ESI-MS) results of the obtained compound 68 (hereinafter chemical formula 69) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 69]

[0651] LCMS (ESI-MS): Calculated mass value. C 21 H 15 NO 297.1 m / z, measured value 298.1 [M+H] + .

[0652] 1H NMR (400 MHz, DMSO- d 6) δ 7.46 – 7.41 (m, 3H), 7.35 – 7.33 (m, 2H), 7.30 – 7.17 (m, 3H), 7.11 (d, J = 6.4 Hz, 2H), 6.83 (d, J = 2.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.47 (dd, J = 7.6, 2.0 Hz, 1H), 5.82 (s, 2H).

[0653] Preparation Example 68. 6-(dimethylamino)-2,3-diphenyl-1H-inden-1-one (6-(dimethylamino)-2,3- diphenyl-1H-inden-1-one) (compound 69) [Reaction Formula 68]

[0654] Following the same method as step 5 of Preparation Example 29, using an aqueous solution of NaBH4 and H2SO4, the desired title compound (20 mg, 20%) was obtained as a white solid.

[0655] The LCMS (ESI-MS) results of the obtained compound 69 (hereinafter chemical formula 70) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 70]

[0656] LCMS (ESI-MS): Calculated mass value. C 23 H 19 NO 325.1 m / z, measured value 325.7 [M+H]+.

[0657] 1 H NMR (400 MHz, DMSO- d 6) δ 7.48 – 7.41 (m, 3H), 7.37 – 7.35 (m, 2H), 7.30 – 7.19 (m, 3H), 7.16 – 7.10 (m, 2H), 7.00 (d, J = 2.4 Hz, 1H), 6.93 (d, J =8.0 Hz, 1H), 6.58 (dd, J = 8.4, 2.4 Hz, 1H), 3.01 (s, 6H).

[0658] Preparation Example 69. 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2,3-diphenyl-1H-inden-1-one (6-(4-(2-) hydroxyethyl)piperazin-1-yl)-2,3-diphenyl-1H-inden-1-one) (Compound 70) [Reaction Formula 69]

[0659] Following the same method as in Preparation Example 58, the desired title compound (8.9 mg, 4%) was obtained as a yellow solid using 2-(piperazin-1-yl)ethan-1-ol.

[0660] The LCMS (ESI-MS) results of the obtained compound 70 (hereinafter chemical formula 71) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 71]

[0661] LCMS (ESI-MS): Calculated mass value. C 27 H 26 N₂O₂ 410.2 m / z, measured value 411.0 [M+H] + .

[0662] 1 H NMR (400 MHz, DMSO- d 6) δ 7.50 – 7.39 (m, 3H), 7.39 – 7.34 (m, 2H), 7.31 – 7.19 (m, 4H), 7.17 – 7.11 (m, 2H), 6.96 (d, J = 8.0 Hz, 1H), 6.85 (dd, J =8.0, 2.0 Hz, 1H), 4.44 (t, J = 5.6 Hz, 1H), 3.54 (q, J = 6.0 Hz, 2H), 3.27 – 3.20(m, 4H), 2.58 – 2.52 (m, 4H), 2.44 (t, J = 6.0 Hz, 2H).

[0663] Preparation Example 70. 4-Methyl-6-(4-methylpiperazin-1-yl)-2,3-diphenyl-1H-inden-1-one (4-methyl- 6-(4-methylpiperazin-1-yl)-2,3-diphenyl-1H-inden-1-one) (Compound 71) [Reaction Formula 70]

[0664] Step 1: Synthesis of 1-bromo-5-chloro-2-iodo-3-methylbenzene 2-Bromo-4-chloro-6-methylaniline (3 g, 0.0136 mol) was dissolved in HCl (18 mL) and H2O (24 mL) at -5 °C, followed by the addition of NaNO2 aqueous solution (1.03 g / 5 mL H2O) and stirring at the same temperature for 30 minutes. KI (2.71 g, 0.0163 mol) was added to the reactants, and the mixture was heated to room temperature and stirred for 16 hours. Water (50 mL) was added to the reactants, and extraction was performed using EA (50 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (5% EtOAc / hexane) to give the desired title compound (1.6 g, 31%) as a yellow solid.

[0665] Step 2: Synthesis of 6-chloro-4-methyl-2,3-diphenyl-1H-inden-1-one 1,4-Dioxane (10 mL) was added to 1-bromo-5-chloro-2-iodo-3-toluene (300 mg, 0.9258 mmol), 1,2-diphenylacetylene (110 mg, 0.6172 mmol), PdCl2 (10.94 mg, 0.06172 mmol), tetrabutylammonium bromide (198.97 mg, 0.6172 mmol), and Na2CO3 (196.25 mg, 1.8516 mmol), and stirred at CO2 and 100 °C for 24 hours. The reaction mixture was filtered, washed with EtOAc (10 mL), and the combined filtrates were concentrated. The concentrated residue was purified by silica gel column chromatography (5% EtOAc / hexane) to give the desired title compound (130 mg, 39%) as a yellow solid.

[0666] LCMS (ESI-MS): Calculated mass value. C 22 H 15 ClO 330.1 m / z, measured value 330.6 [M+H] + .

[0667] Step 3: Synthesis of 4-methyl-6-(4-methylpiperazin-1-yl)-2,3-diphenyl-1H-inden-1-one (compound 71) Following the same method as in Preparation Example 58, the desired title compound (50 mg, 37%) was obtained as a white solid.

[0668] The LCMS (ESI-MS) results of the obtained compound 71 (hereinafter chemical formula 72) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 72]

[0669] LCMS (ESI-MS): Calculated mass value. C 27 H 26 N₂O 394.2 m / z, measured value 395.1 [M+H] + .

[0670] 1 H NMR (400 MHz, DMSO- d 6) δ 7.48 – 7.32 (m, 5H), 7.24 – 7.03 (m, 6H), 6.56 (d, J = 2.2 Hz, 1H), 3.27 – 3.19 (m, 4H), 2.45 – 2.39 (m, 4H), 2.21 (s, 3H), 1.66 (s, 3H).

[0671] Preparation Example 71. 3-(2,6-dimethylphenyl)-6-(4-methylpiperazin-1-yl)-2-phenyl-1H-inden-1-one (3- (2,6-dimethylphenyl)-6-(4-methylpiperazin-1-yl)-2-phenyl-1H-inden-1-one)(compound Object 72) [Reaction Formula 71]

[0672] Step 1: ( E )-1-(2-bromo-5-chlorophenyl)-3-(2,6-dimethylphenyl)prop-2-en-1-one(( E Synthesis of )-1-(2-bromo-5-chlorophenyl)-3-(2,6-dimethylphenyl)prop-2-en-1-one) Following the same method as step 1 of Preparation Example 21, the desired title compound (2.8 g, 83%) was obtained as a yellow oil.

[0673] LCMS (ESI-MS): Calculated mass value. C 17 H 14 BrClO 350.0 m / z, measured value 350.6 [M+H] + .

[0674] Step 2: Synthesis of 6-chloro-3-(2,6-dimethylphenyl)-1H-inden-1-one Add DMF (20 mL) to ( E The mixture was prepared in a nitrogen atmosphere at 100°C for 4 hours with 2.5 g (7.1 mmol) of 1-(2-bromo-5-chlorophenyl)-3-(2,6-dimethylphenyl)prop-2-en-1-one, PdCl2 (0.08 g, 0.355 mmol), PPh3 (0.19 g, 0.72 mmol), and K2CO3 (2.96 g, 21.4 mmol). Water (80 mL) was added to the mixture, and the mixture was extracted with EA (100 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (10% EtOAc / hexane) to give the desired title compound (1 g, 26%) as a yellow solid.

[0675] LCMS (ESI-MS): Calculated mass value. C 17 H 13 ClO 268.1 m / z, measured value 268.7 [M+H] + .

[0676] Step 3: Synthesis of 2-bromo-6-chloro-3-(2,6-dimethylphenyl)-1H-inden-1-one At 0 °C, Br2 (0.89 g, 0.0055 mol) was added to a DCM (30 mL) solution of 6-chloro-3-(2,6-dimethylphenyl)-1H-inden-1-one (1 g, 0.0037 mol), and the mixture was stirred for 2 hours at the same temperature. Water (80 mL) was added to the reactants, and the mixture was extracted with DCM (100 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (5% EtOAc / hexane) to give the desired title compound (0.8 g, 56%) as a yellow oil.

[0677] LCMS (ESI-MS): Calculated mass value. C 17 H 12 BrClO 348.0 m / z, measured value 348.6 [M+H] + .

[0678] Step 4: Synthesis of 6-chloro-3-(2,6-dimethylphenyl)-2-phenyl-1H-inden-1-one Following the same method as step 5 of Preparation Example 21, the desired title compound (80 mg, 40%) was obtained as a white solid.

[0679] LCMS (ESI-MS): Calculated mass value. C 23 H 17 ClO 344.1 m / z, measured value 344.7 [M+H] + .

[0680] 1 H NMR (400 MHz, DMSO- d 6) δ 7.57– 7.44 (m, 1H), 7.42 – 7.39 (m, 2H), 7.26 – 7.20 (m, 4H), 7.16 – 7.10 (m, 4H), 2.11 (s, 6H).

[0681] Step 5: Synthesis of 3-(2,6-dimethylphenyl)-6-(4-methylpiperazin-1-yl)-2-phenyl-1H-inden-1-one (compound 72) Following the same method as in Preparation Example 58, the desired title compound (20.2 mg, 27%) was obtained as a purple solid.

[0682] The LCMS (ESI-MS) results of the obtained compound 72 (hereinafter chemical formula 73) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 73]

[0683] LCMS (ESI-MS): Calculated mass value. C 28 H 28 N₂O 408.2 m / z, measured value 409.1 [M+H] + .

[0684] 1 H NMR (400 MHz, DMSO- d6) δ 7.21 – 7.11 (m, 9H), 6.82 – 6.80 (m, 1H), 6.61 – 6.59 (m, 1H), 3.32 – 3.24 (m, 4H), 2.48 – 2.47 (m, 4H), 2.33 (s, 3H), 2.24 (s, 3H), 1.96 (s, 3H).

[0685] Preparation Example 72. 6-(4-methylpiperazin-1-yl)-2-(3-morpholinylphenyl)-3-phenyl-1H-inden-1-one (6- (4-methylpiperazin-1-yl)-2-(3-morpholinophenyl)-3-phenyl-1H-inden-1-one)(compound Object 73) [Reaction Formula 72]

[0686] Step 1: ( E )-1-(2-bromo-5-chlorophenyl)-3-phenylprop-2-en-1-one(( E Synthesis of 1-(2-bromo-5-chlorophenyl)-3-phenylprop-2-en-1-one Following the same method as step 1 of Preparation Example 21, the desired title compound (4 g, 65%) was obtained as a yellow solid.

[0687] LCMS (ESI-MS): Calculated mass value. C 15 H 10 BrClO 322.0 m / z, measured value 322.6 [M+H] + .

[0688] Step 2: Synthesis of 6-chloro-3-phenyl-1H-inden-1-one Following the same method as step 2 of Preparation Example 22, the desired title compound (2.6 g, 74%) was obtained as a yellow solid.

[0689] LCMS (ESI-MS): Calculated mass value. C 15 H9ClO 240.0 m / z, measured value 240.6 [M+H] + .

[0690] Step 3: Synthesis of 2-bromo-6-chloro-3-phenyl-1H-inden-1-one Following the same method as step 3 of Preparation Example 22, the desired title compound (0.8 g, 38%) was obtained as a yellow oil.

[0691] LCMS (ESI-MS): Calculated mass value. C 15 H8BrClO has a m / z of 319.9 and a measured value of 320.5 [M+H]. + .

[0692] Step 4: Synthesis of 6-chloro-2-(3-morpholinophenyl)-3-phenyl-1H-inden-1-one Following the same method as step 5 of Preparation Example 21, the desired title compound (220 mg, 52%) was obtained as a red solid.

[0693] LCMS (ESI-MS): Calculated mass value. C 25 H 20 ClNO2 401.1 m / z, measured value 402.0 [M+H] + .

[0694] Step 5: Synthesis of 6-(4-methylpiperazin-1-yl)-2-(3-morpholinophenyl)-3-phenyl-1H-inden-1-one (compound 73) Following the same method as in Preparation Example 58, the desired title compound (70 mg, 45%) was obtained as a red solid.

[0695] The LCMS (ESI-MS) results of the obtained compound 73 (hereinafter chemical formula 74) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 74]

[0696] LCMS (ESI-MS): Calculated mass value. C 30 H 31 N₃O₂ has a measured value of 466.2 m / z (465.2 m / z, measured value is 466.2 [M+H]). + .

[0697] 1 H NMR (400 MHz, DMSO- d 6) δ 7.47 – 7.45 (m, 3H), 7.38 – 7.36 (m, 2H), 7.20 (d, J= 2.2 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.85– 6.81 (m, 2H), 6.68 – 6.62 (m, 2H), 3.69 – 3.61 (m, 4H), 3.27 – 3.21 (m,4H), 2.92 – 2.84 (m, 4H), 2.49 – 2.44 (m, 4H), 2.22 (s, 3H).

[0698] Preparation Example 73. 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4- (6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(4-(4-) methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one)(Compound 74) [Reaction Formula 73]

[0699] Step 1: ( E )-1-(2-bromo-5-chlorophenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one(( E Synthesis of )-1-(2-bromo-5-chlorophenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one) Following the same method as step 1 of Preparation Example 21, the desired title compound (6 g, 73%) was obtained as a yellow solid.

[0700] LCMS (ESI-MS): Calculated mass value. C 13 H9BrClNOS 342.9 m / z, measured value 343.6 [M+H] + .

[0701] Step 2: Synthesis of 6-chloro-3-(4-methylthiazol-5-yl)-1H-inden-1-one Following the same method as step 2 of Preparation Example 22, the desired title compound (2.7 g, 63%) was obtained as a yellow solid.

[0702] LCMS (ESI-MS): Calculated mass value. C 13 H8ClNOS 261.0 m / z, measured value 261.6 [M+H] + .

[0703] Step 3: Synthesis of 2-bromo-6-chloro-3-(4-methylthiazol-5-yl)-1H-inden-1-one Following the same method as step 3 of Preparation Example 22, the desired title compound (2.7 g, 58%) was obtained as a yellow solid.

[0704] LCMS (ESI-MS): Calculated mass value. C 13 H7BrClNOS 340.9 m / z, measured value 341.5 [M+H] + .

[0705] Step 4: Synthesis of 6-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one Following the same method as step 5 of Preparation Example 21, the desired title compound (200 mg, 81%) was obtained as a red solid.

[0706] LCMS (ESI-MS): Calculated mass value. C 24 H 22 ClN3OS 435.1 m / z, measured value 435.8 [M+H] + .

[0707] Step 5: Synthesis of 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one (6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one) (Compound 74) Following the same method as in Preparation Example 58, the desired title compound (60 mg, 55%) was obtained as a purple solid.

[0708] The LCMS (ESI-MS) results of the obtained compound 74 (hereinafter chemical formula 75) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 75]

[0709] LCMS (ESI-MS): Calculated mass value. C 30 H 35 N₅O₂S 529.3 m / z, measured value 530.1 [M+H] + .

[0710] 1 H NMR (400 MHz, DMSO- d 6) δ 9.24 (s, 1H), 7.18 (d, J = 2.2 Hz, 1H), 7.07(d, J = 8.8 Hz, 2H), 6.93 – 6.78 (m, 4H), 4.43 (s, 1H), 3.53 (d, J = 5.6 Hz, 2H), 3.27 – 3.11 (m, 8H), 2.59 – 2.53 (m, 4H), 2.45 – 2.39 (m, 6H), 2.20 (s, 3H), 1.99 (s, 3H).

[0711] Preparation Example 74. 6-(4-methylpiperazin-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazolyl) Azol-5-yl)-1H-inden-1-one (6-(4-methylpiperazin-1-yl)-2-(4-(4-methylpiperazin-1-yl) phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one) (Compound 75) [Reaction Formula 74]

[0712] Step 1: Synthesis of 6-hydroxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one Following the same method as step 5 of Preparation Example 21, the desired title compound (324 mg, 45%) was obtained as a purple solid.

[0713] LCMS (ESI-MS): Calculated mass value. C 24 H 23 N3O2S 417.2 m / z, measured value 418.0 [M+H] + .

[0714] Step 2: Synthesis of 2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1-oxo-1H-inden-6-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate At 0 °C, NaH (57.48 mg, 1.437 mmol, 60% mineral oil dispersion) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (434.1 mg, 1.437 mmol) were added to a THF (10 mL) solution of 6-hydroxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazolyl-5-yl)-1H-indone (240 mg, 0.5748 mmol) and stirred at the same temperature for 2 hours.

[0715] Water (20 mL) was added to the reactants, and the mixture was extracted with EA (20 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (3% MeOH / DCM) to give the desired title compound (324 mg, 45%) as a purple solid.

[0716] LCMS (ESI-MS): Calculated mass value. C 28 H 22 F9N3O4S2699.1 m / z, measured value 700.1 [M+H] + .

[0717] Step 3: Synthesis of 6-(4-methylpiperazin-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one (compound 75) Following the same method as in Preparation Example 58, the desired title compound (36 mg, 18%) was obtained as a purple solid.

[0718] The LCMS (ESI-MS) results of the obtained compound 75 (hereinafter chemical formula 76) were confirmed by... 1H NMR yielded the following data: [Chemical Formula 76]

[0719] LCMS (ESI-MS): Calculated mass value. C 29 H 33 N5OS 499.2 m / z, measured value 500.3 [M+H] + .

[0720] 1 H NMR (400 MHz, DMSO- d 6) δ 9.24 (s, 1H), 7.18 – 7.17 (m, 1H), 7.08 –7.16 (m, 2H), 6.92 – 6.83 (m, 4H), 3.24 – 3.22 (m, 4H), 3.17 – 3.15 (m, 4H), 2.45 – 2.40 (m, 8H), 2.22 – 2.20 (m, 6H), 1.99 (s, 3H).

[0721] Preparation Example 75. 2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropane) 2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5- yl)-6-(3-phenylpropoxy)-1H-inden-1-one) (Compound 76) [Reaction Formula 75]

[0722] Following the same method as in Preparation Example 35, the desired title compound (11.1 mg, 5%) was obtained as a purple solid.

[0723] The LCMS (ESI-MS) results of the obtained compound 76 (hereinafter chemical formula 77) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 77]

[0724] LCMS (ESI-MS): Calculated mass value. C 33 H 33 N3O2S 535.2 m / z, measured value 536.2 [M+H] + .

[0725] 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 7.31 – 7.29 (m, 2H), 7.22 – 7.18 (m, 5H), 7.16 – 7.15 (m, 1H), 6.96 – 6.94 (m, 1H), 6.83 – 6.78 (m, 3H), 4.01 – 3.98 (m, 2H), 3.37 (s, 4H), 2.83 – 2.77 (m, 6H), 2.49 (s, 3H), 2.13 –2.10 (m, 5H).

[0726] Preparation Example 76. 2,3-Bis(4-methylthiazolyl)-6-(3-phenylpropoxy)-1H-inden-1-one (2,3-bis) (4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one) (Compound 77) [Reaction Formula 76]

[0727] Step 1: Synthesis of 6-hydroxy-2,3-bis(4-methylthiazol-5-yl)-1H-inden-1-one Following the same method as step 5 of Preparation Example 21, the desired title compound (149 mg, 69%) was obtained as a yellow solid.

[0728] LCMS (ESI-MS): Calculated mass value. C 17 H 12 The measured value of N₂O₂S₂ at 340.0 m / z is 341.0 [M+H]. + .

[0729] Step 2: Synthesis of 2,3-bis(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one (compound 77) Following the same method as in Preparation Example 35, the desired title compound (19 mg, 9%) was obtained as a yellow solid.

[0730] The LCMS (ESI-MS) results of the obtained compound 77 (hereinafter chemical formula 78) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 78]

[0731] LCMS (ESI-MS): Calculated mass value. C 26 H 22 The measured value of N₂O₂S₂ at 458.1 m / z is 459.1 [M+H]. + .

[0732] 1 H NMR (400 MHz, DMSO- d 6) δ 9.32 (s, 1H), 9.08 (s, 1H), 7.31 – 7.16 (m, 7H), 7.04 – 7.01 (m, 1H), 4.06 (t, J = 6 Hz, 2H), 2.75 (t, J = 8 Hz, 2H), 2.07 – 2.00 (m, 2H), 1.98 (s, 3H), 1.91 (s, 3H).

[0733] Preparation Example 77. 2,3-Diphenyl-6-(3-phenylpropoxy)-1H-inden-1-one (2,3-diphenyl-6-(3- (phenylpropoxy)-1H-inden-1-one)(compound 78) [Reaction Formula 77]

[0734] Following the same method as in Preparation Example 35, the desired title compound (70 mg, 47%) was obtained as a white solid.

[0735] The LCMS (ESI-MS) results of the obtained compound 78 (hereinafter chemical formula 79) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 79]

[0736] LCMS (ESI-MS): Calculated mass value. C 30 H 24 O2 416.2 m / z, measured value 417.2 [M+H] + .

[0737] 1 H NMR (400 MHz, DMSO- d 6) δ 7.47 – 7.44 (m, 3H), 7.40 – 7.37 (m, 2H), 7.32 – 7.24 (m, 7H), 7.18 – 7.13 (m, 4H), 7.06 – 7.04 (m, 1H), 6.98 – 6.95(m, 1H), 4.05 (t, J= 6.4 Hz, 2H), 2.80 – 2.71 (m, 2H), 2.09 – 2.00 (m, 2H).

[0738] Preparation Example 78. 6-(4-methylpiperazin-1-yl)-2,3-bis(4-methylthiazo-5-yl)-1H-inden-1-one (6- (4-methylpiperazin-1-yl)-2,3-bis(4-methylthiazol-5-yl)-1H-inden-1-one)(Compound 79) [Reaction Formula 78]

[0739] Step 1: Synthesis of 5-ethynyl-4-methylthiazole MeOH (50 mL) was added to 4-methylthiazol-5-carboxaldehyde (5.0 g, 0.0393 mol), dimethyl (1-diazo-2-oxopropyl)phosphonate (8.3 g, 0.04323 mol), and Cs₂CO₃ (14.09 g, 0.04323 mol), and stirred at room temperature for 16 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with EA (100 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (10% EtOAc / hexane) to give the desired title compound (5 g, 50%) as a yellow oil.

[0740] LCMS (ESI-MS): Calculated mass value. C6H5NS 123.0 m / z, measured value 124.0 [M+H] + .

[0741] Step 2: Synthesis of 1,2-bis(4-methylthiazol-5-yl)ethyne DMF (15 mL) was added to 5-ethynyl-4-methylthiazole (1.2 g, 0.0097 mol), 5-bromo-4-methylthiazole (1.73 g, 0.0097 mol), Pd(PPh3)2Cl2 (0.34 g, 0.0005 mol), CuI (0.09 g, 0.0005 mol), and TEA (2.94 g, 0.0291 mol). The mixture was stirred at 90 °C under nitrogen atmosphere for 16 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with EA (100 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (20% EtOAc / hexane) to give the desired title compound (0.8 g, 34%) as a yellow oil.

[0742] LCMS (ESI-MS): Calculated mass value. C10 H8N2S2220.0 m / z, measured value 220.6 [M+H] + .

[0743] Step 3: Synthesis of 6-(4-methylpiperazin-1-yl)-2,3-bis(4-methylthiazol-5-yl)-1H-inden-1-one (compound 79) DMF (4 mL) was added to 1,2-bis(4-methylthiazolyl-5-yl)acetylene (77.8 mg, 0.3532 mmol), 2-bromo-5-(4-methylpiperazin-1-yl)benzaldehyde (100 mg, 0.3532 mmol), Pd(OAc)₂ (3.96 mg, 0.0177 mmol), TBACl (98.16 mg, 0.3532 mmol), and NaOAc (115.8 mg, 1.4128 mmol), and stirred at 100 °C under nitrogen for 24 hours. Water (30 mL) was added to the reactants, and the mixture was extracted with EA (40 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was analyzed by prep-HPLC (Gemini 5). C 18 Purification was performed using a chromatographic column (150x21.2mm, 30-95% ACN / H2O, 0.1% NH3H2O) to obtain the desired title compound (50mg, 30%) as a purple solid.

[0744] The LCMS (ESI-MS) results of the obtained compound 79 (hereinafter chemical formula 80) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 80]

[0745] LCMS (ESI-MS): Calculated mass value. C 22 H 22 N4OS2422.1 m / z, measured value 423.1 [M+H] + .

[0746] 1 H NMR (400 MHz, DMSO- d 6) δ 9.30 (s, 1H), 9.05 (s, 1H), 7.25 (d, J = 2.4Hz, 1H), 7.10 (d,J = 8.2 Hz, 1H), 6.89 (dd, J = 8.2, 2.4 Hz, 1H), 3.30 – 3.25(m, 4H), 2.46 – 2.41 (m, 4H), 2.22 (s, 3H), 1.98 (s, 3H), 1.90 (s, 3H).

[0747] Preparation Example 79. 6-(4-methylpiperazin-1-yl)-2,3-bis(3-morpholinylphenyl)-1H-inden-1-one (6-(4- methylpiperazin-1-yl)-2,3-bis(3-morpholinophenyl)-1H-inden-1-one) (Compound 80) [Reaction Formula 79]

[0748] Step 1: Synthesis of 4-(3-((trimethylsilyl)ethynyl)phenyl)morpholine Following the same method as step 2 of Preparation Example 78, the desired title compound (4.2 g, purity 75%, yield 97%) was obtained as a yellow oil.

[0749] LCMS (ESI-MS): Calculated mass value. C 15 H 21 NOSi 259.1 m / z, measured value 259.7 [M+H] + .

[0750] Step 2: Synthesis of 4-(3-ethynylphenyl)morpholine MeOH (100 mL) was added to 4-(3-((trimethylsilyl)ethynyl)phenyl)morpholine (4.12 g, 0.0159 mol) and K2CO3 (3.29 g, 0.02385 mmol) and stirred at room temperature for 3 hours.

[0751] Water (200 mL) was added to the reactants, and the mixture was extracted with DCM (100 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (5% EtOAc / hexane) to give the desired title compound (2.87 g, 90% purity, 87% yield) as a yellow oil.

[0752] LCMS (ESI-MS): Calculated mass value. C 12 H 13 NO 187.1 m / z, measured value 187.7 [M+H] + .

[0753] Step 3: Synthesis of 1,2-bis(3-morpholinophenyl)ethyne Following the same method as step 2 of Preparation Example 78, the desired title compound (340 mg, 45%) was obtained as a yellow oil.

[0754] LCMS (ESI-MS): Calculated mass value. C 22 H 24 N₂O₂ 348.2 m / z, measured value 349.2 [M+H] + .

[0755] Step 4: Synthesis of 2-bromo-5-(4-methylpiperazin-1-yl)benzaldehyde DCM (10 mL) was added to 3-(4-methylpiperazin-1-yl)benzaldehyde (408 mg, 1.9974 mmol) and NBS (710.99 mg, 3.9948 mmol), and stirred at room temperature for 2 hours. The residue obtained by concentrating the reaction mixture was purified by silica gel column chromatography (15% EtOAc / hexane) to give the desired title compound (400 mg, 71%) as a yellow oil.

[0756] LCMS (ESI-MS): Calculated mass value. C 12 H 15 BrN₂O 282.0 m / z, measured value 282.9 [M+H] + .

[0757] Step 5: Synthesis of 6-(4-methylpiperazin-1-yl)-2,3-bis(3-morpholinophenyl)-1H-inden-1-one (compound 80) Following the same method as step 3 of Preparation Example 78, the desired title compound (55.4 mg, 22%) was obtained as a yellow oil.

[0758] The LCMS (ESI-MS) results of the obtained compound 80 (hereinafter chemical formula 81) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 81]

[0759] LCMS (ESI-MS): Calculated mass value. C 34 H 38 N4O3 550.3 m / z, measured value 551.73 [M+H] + .

[0760] 1 H NMR (400 MHz, DMSO- d 6) δ 7.33 – 7.29 (m, 1H), 7.19 – 7.12 (m, 2H), 7.04 – 6.95 (m, 2H), 6.87 – 6.79 (m, 4H), 6.71 – 6.69 (m, 2H), 3.69 – 3.65(m, 8H), 3.24 (t, J = 4.8 Hz, 4H), 3.01 (t, J = 4.8 Hz, 4H), 2.90 (t, J = 4.8 Hz, 4H), 2.44 (d, J = 4.8 Hz, 4H), 2.22 (s, 3H).

[0761] Preparation Example 80. 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2,3-bis(4-methylthiazo-5-yl)-1H-indene-1- Ketone(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2,3-bis(4-methylthiazol-5-yl)-1H- inden-1-one) (compound 81) [Reaction Formula 80]

[0762] Step 1: Synthesis of tert-butyl 4-(4-bromo-3-formylphenyl)piperazine-1-carboxylate Following the same method as step 4 of Preparation Example 79, the desired title compound (500 mg, 70%) was obtained as a yellow solid.

[0763] LCMS (ESI-MS): Calculated mass value. C 16 H 21 BrN₂O₃ has a m / z of 368.1, while the measured value is 368.7 [M+H]. + .

[0764] Step 2: Synthesis of tert-butyl 4-(2,3-bis(4-methylthiazol-5-yl)-1-oxo-1H-inden-6-yl)piperazine-1-carboxylate Following the same method as step 3 of Preparation Example 78, the desired title compound (0.6 g, 40%) was obtained as a yellow solid.

[0765] LCMS (ESI-MS): Calculated mass value. C 26 H 28 N4O3S2 508.2 m / z, measured value 509.1 [M+H] + .

[0766] Step 3: Synthesis of 2,3-bis(4-methylthiazol-5-yl)-6-(piperazin-1-yl)-1H-inden-1-one Following the same method as step 4 of Preparation Example 29, the desired title compound (180 mg, 67%) was obtained as a purple solid.

[0767] LCMS (ESI-MS): Calculated mass value. C 21 H 20 N4OS2408.1 m / z, measured value 409.0 [M+H] + .

[0768] Step 4: Synthesis of 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2,3-bis(4-methylthiazol-5-yl)-1H-inden-1-one (compound 81) DCM (10 mL) was added to 2,3-bis(4-methylthiazolyl-5-yl)-6-(piperazin-1-yl)-1H-indone (100 mg, 0.2448 mmol), 2-bromoethanol (458.8 mg, 3.67 mmol), and DIEA (632.8 mg, 4.89 mmol), and stirred at 50 °C under nitrogen for 16 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was analyzed by prep-HPLC (Gemini 5). C18 Purification was performed using a chromatographic column (150x21.2 mm, 5-95% ACN / H2O 0.1% FA) to obtain the desired title compound (20 mg, 18%) as a purple solid.

[0769] The LCMS (ESI-MS) results of the obtained compound 81 (hereinafter chemical formula 82) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 82]

[0770] LCMS (ESI-MS): Calculated mass value. C 23 H 24 N4O2S2 has a m / z value of 452.1 m / z and a measured value of 452.8 [M+H]. + .

[0771] 1 H NMR (400 MHz, DMSO- d 6) δ 9.30 (s, 1H), 9.04 (s, 1H), 8.17 (s, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.89 (dd, J = 8.2, 2.4 Hz, 1H), 3.54 (t, J = 6.2 Hz, 2H), 3.31 – 3.25 (m, 4H), 2.59 – 2.53 (m, 4H), 2.44 (t, J =6.2 Hz, 2H), 1.98 (s, 3H), 1.91 (s, 3H).

[0772] Preparation Example 81. 6-hydroxy-2,3-di-o-tolyl-1H-inden-1-one (6-hydroxy-2,3-di-o-tolyl- 1H-inden-1-one) (compound 82) [Reaction Formula 81]

[0773] Step 1: Synthesis of 1,2-di-o-tolylethyne DMSO (100 mL) was added to propynic acid (3 g, 0.0428 mol), 1-iodo-2-methylbenzene (18.6 g, 0.0856 mol), Pd(PPh3)2Cl2 (1.5 g, 0.0021 mol), DPPB (1.83 g, 0.0042 mol), and DBU (13.0 g, 0.0856 mol), and stirred at 80 °C for 3 hours under nitrogen atmosphere. Water (300 mL) was added to the reaction mixture, and extraction was performed with EA (400 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (5% EtOAc / hexane) to give the desired title compound (5 g, 50%) as a yellow solid.

[0774] 1 H NMR (400 MHz, CDCl3) δ 7.52–7.50 (m, 2H), 7.26–7.23 (m, 6H), 2.53 (s, 6H).

[0775] Step 2: Synthesis of 6-methoxy-2,3-di-o-tolyl-1H-inden-1-one Following the same method as step 3 of Preparation Example 78, the desired title compound (0.4 g, 7%) was obtained as a yellow solid.

[0776] LCMS (ESI-MS): Calculated mass value. C 24 H 20 O2 340.1 m / z, measured value 340.8 [M+H] + .

[0777] Step 3: Synthesis of 6-hydroxy-2,3-di-o-tolyl-1H-inden-1-one (Compound 82) 6-Methoxy-2,3-bis(o-tolyl)-1H-inden-1-one (200 mg, 0.5875 mmol) and Py HCl (271.57 mg, 2.35 mmol) were stirred at 160 °C under nitrogen for 24 hours. Water (20 mL) was added to the reaction mixture, and extraction was performed with EA (30 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was analyzed by prep-HPLC (Gemini 5). C 18Purification was performed using a chromatographic column (150x21.2 mm, 55-95% ACN / H2O 0.1% FA) to obtain the desired title compound (80 mg, 37%) as a white solid.

[0778] The LCMS (ESI-MS) results of the obtained compound 82 (hereinafter chemical formula 83) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 83]

[0779] LCMS (ESI-MS): Calculated mass value. C 23 H 18 O2 326.1 m / z, measured value 327.1 [M+H] + .

[0780] 1 H NMR (400 MHz, DMSO- d 6) δ 10.12 (s, 1H), 7.28– 7.14 (m, 6H), 7.02 –6.94 (m, 1H), 6.93 – 6.89 (m, 2H), 6.75 – 6.73 (m, 1H), 6.64 – 6.62 (m, 1H), 2.07 (s, 6H).

[0781] Preparation Example 82. 6-(3-phenylpropoxy)-2,3-bis(thiazol-5-yl)-1H-inden-1-one (6-(3- (phenylpropoxy)-2,3-di(thiazol-5-yl)-1H-inden-1-one (compound 83) [Reaction Equation 82]

[0782] Step 1: Synthesis of 1,2-di(thiazol-5-yl)ethyne Following the same method as step 2 of Preparation Example 78, the desired title compound (0.9 g, 53%) was obtained as a white solid.

[0783] LCMS (ESI-MS): Calculated mass value. C8H4N2S2 192.0 m / z, measured value 192.6 [M+H] + .

[0784] Step 2: Synthesis of 6-methoxy-2,3-di(thiazol-5-yl)-1H-inden-1-one Following the same method as step 3 of Preparation Example 78, the desired title compound (0.35 g, 39%) was obtained as a purple solid.

[0785] LCMS (ESI-MS): Calculated mass value. C 16 H 10 N₂O₂S₂ = 326.0 m / z, measured value is 326.6 [M+H] + .

[0786] Step 3: Synthesis of 6-hydroxy-2,3-di(thiazol-5-yl)-1H-inden-1-one Following the same method as step 4 of Preparation Example 41, the desired title compound (180 mg, 74%) was obtained as a red solid.

[0787] LCMS (ESI-MS): Calculated mass value. C 15 H8N2O2S2 312.0 m / z, measured value 312.6 [M+H] + .

[0788] Step 4: Synthesis of 6-(3-phenylpropoxy)-2,3-di(thiazol-5-yl)-1H-inden-1-one (compound 83) Following the same method as step 2 of Preparation Example 38, the desired title compound (60 mg, 39%) was obtained as a purple solid.

[0789] The LCMS (ESI-MS) results of the obtained compound 83 (hereinafter chemical formula 84) were confirmed. 1 H NMR yielded the following data: [Chemical Formula 84]

[0790] LCMS (ESI-MS): Calculated mass value. C 24 H 18 N₂O₂S₂ 430.1 m / z, measured value 430.7 [M+H] + .

[0791] 1 H NMR (400 MHz, DMSO- d6) δ 9.44 (s, 1H), 9.15 (s, 1H), 8.42 (s, 1H), 8.10 (s, 1H), 7.34 – 7.14 (m, 7H), 7.02 (dd, J = 8.2, 2.4 Hz, 1H), 4.06 (t, J =6.4 Hz, 2H), 2.75 (t, J = 7.6 Hz, 2H), 2.11 – 1.98 (m, 2H).

[0792] Preparation Example 83. 3-(2,6-dimethylphenyl)-6-hydroxy-2-(o-tolyl)-1H-inden-1-one (3-(2,6- dimethylphenyl)-6-hydroxy-2-(o-tolyl)-1H-inden-1-one) (Compound 84) [Reaction Formula 83]

[0793] Step 1: ( E )-3-( 2,6-Dimethylphenyl )-1-(3- Hydroxyphenyl )prop-2-en-1-one(( E Synthesis of )-3-(2,6-dimethylphenyl)-1-(3-hydroxyphenyl)prop-2-en-1-one) Following the same method as step 1 of Preparation Example 21, the desired title compound (10.8 g, 53%) was obtained as a yellow solid.

[0794] 1 H NMR (400 MHz, DMSO- d 6) δ 9.84 (s, 1H), 7.82 (d, J = 16.0 Hz, 1H), 7.53(d, J = 8.0 Hz, 1H), 7.43 – 7.40 (m, 1H), 7.40 – 7.29 (m, 2H), 7.20 – 7.13 (m,3H), 7.07 (dd, J = 8.0, 2.4 Hz, 1H), 2.38 (s, 6H).

[0795] Step 2: Synthesis of 3-(2,6-dimethylphenyl)-6-hydroxy-2,3-dihydro-1H-inden-1-one Add MsOH (3 ml) to ( EThe mixture was placed in a DCM (15 mL) solution of 2 g (7.94 mmol) of 3-(2,6-dimethylphenyl)-1-(3-hydroxyphenyl)prop-2-en-1-one and stirred at 50 °C for 12 hours.

[0796] The reactants were adjusted to pH 6 with an aqueous NaOH solution (1N) and filtered to give a mixture (1.2 g, 60%) of 3-(2,6-dimethylphenyl)-4-hydroxy-2,3-dihydro-1H-inden-1-one, an isomer of the title compound, as a yellow solid. This mixture was used directly in the next reaction without purification.

[0797] LCMS (ESI-MS): Calculated mass value. C 17 H 16 O2 252.1 m / z, measured value 252.7 [M+H] + .

[0798] Step 3: Synthesis of 1-(2,6-dimethylphenyl)-3-oxo-2,3-dihydro-1H-inden-5-yl acetate Following the same method as step 3 of Preparation Example 21, a mixture (500 mg, 36%) of the desired title compound and 3-(2,6-dimethylphenyl)-1-oxo-2,3-dihydro-1H-indene-4-yl acetate was obtained as a white solid.

[0799] LCMS (ESI-MS): Calculated mass value. C 19 H 18 O3294.1 m / z, measured value 294.8 [M+H] + .

[0800] Step 4: Synthesis of 2-bromo-3-(2,6-dimethylphenyl)-1-oxo-1H-inden-6-yl acetate Following the same method as step 4 of Preparation Example 21, the desired title compound (70 mg, 11%) was obtained as a red solid.

[0801] LCMS (ESI-MS): Calculated mass value. C 19 H 15 BrO3 370.0 m / z, measured value 370.8 [M+H] + .

[0802] Step 5: Synthesis of 3-(2,6-dimethylphenyl)-6-hydroxy-2-(o-tolyl)-1H-inden-1-one (compound 84) and 3-(2,6-dimethylphenyl)-4-hydroxy-2-(o-tolyl)-1H-inden-1-one (compounds 84-11). Following the same method as step 5 of Preparation Example 21, the desired title compounds 83 (15.4 mg, 15%) and 84-11 (5.4 mg, 5%) were obtained as yellow solids.

[0803] The LCMS (ESI-MS) results of the obtained compound 84-11 were confirmed by... 1 H NMR yielded the following data: LCMS (ESI-MS): Calculated mass value. C 24 H 20 O2 340.1 m / z, measured value 340.8 [M+H] + .

[0804] 1 H NMR (400 MHz, DMSO- d 6) δ 10.09 (s, 1H), 7.25 – 7.06 (m, 4H), 7.04 –6.97 (m, 2H), 6.93 (d, J = 2.0 Hz, 1H), 6.89 (s, 2H), 6.79 (dd, J = 8.0, 2.0 Hz,1H), 2.17 (s, 6H), 1.97 (s, 3H).

[0805] The LCMS (ESI-MS) results of the obtained compound 84 (hereinafter chemical formula 85) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 85]

[0806] LCMS (ESI-MS): Calculated mass value. C 24 H 20 O2 340.1 m / z, measured value 341.1 [M+H] + .

[0807] 1 H NMR (400 MHz, DMSO- d 6) δ 10.04 (s, 1H), 7.15 - 7.03 (m, 6H), 6.92 -6.89 (m, 2H), 6.74 - 6.72 (m, 1H), 6.64 (d, J = 8.0 Hz, 1H), 2.26 (s, 3H), 2.05- 1.99 (m, 6H).

[0808] Preparation Example 84. 2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazo-5-yl)-1H-inden-1-one (2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1- one)(Compound 85) [Reaction Formula 84]

[0809] Following the same method as step 5 of Preparation Example 21, the desired title compound (23.6 mg, 18%) was obtained as a red solid.

[0810] The LCMS (ESI-MS) results of the obtained compound 85 (hereinafter chemical formula 86) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 86]

[0811] LCMS (ESI-MS): Calculated mass value. C 24 H 23 N3OS 401.2 m / z, measured value 401.8 [M+H] + .

[0812] 1 H NMR (400 MHz, DMSO- d 6) δ 9.27 (s, 1H), 7.58 – 7.43 (m, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.14 - 7.09 (m, 3H), 6.89 (d, J = 8.8 Hz, 2H), 3.23 – 3.11 (m,4H), 2.45 – 2.39 (m, 4H), 2.21 (s, 3H), 2.01 (s, 3H).

[0813] Preparation Example 85. 2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(4-methylthiazo-5-yl)-1H- Inden-1-one (2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(4-methylthiazol-5- yl)-1H-inden-1-one) (compound 86) [Reaction Formula 85]

[0814] Following the same method as step 5 of Preparation Example 21, the desired title compound (24.2 mg, 17%) was obtained as a yellow solid.

[0815] The LCMS (ESI-MS) results of the obtained compound 86 (hereinafter chemical formula 87) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 87]

[0816] LCMS (ESI-MS): Calculated mass value. C 25 H 25 N3OS 415.2 m / z, measured value 416.1 [M+H] + .

[0817] 1 H NMR (400 MHz, DMSO- d 6) δ 9.29 (s, 1H), 7.58 - 7.53 (m, 2H), 7.43 –7.38 (m, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.21 - 7.16 (m, 3H), 3.45 (s, 2H), 2.36 (s, 8H), 2.18 (s, 3H), 1.92 (s, 3H).

[0818] Preparation Example 86. 3-(4-methylthiazolyl-5-yl)-2-(4-(morpholinylmethyl)phenyl)-1H-inden-1-one (3-(4- methylthiazol-5-yl)-2-(4-(morpholinomethyl)phenyl)-1H-inden-1-one) (Compound 87) [Reaction Formula 86]

[0819] Following the same method as step 5 of Preparation Example 21, the desired title compound (23.8 mg, 18%) was obtained as a yellow solid.

[0820] The LCMS (ESI-MS) results of the obtained compound 87 (hereinafter chemical formula 88) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 88]

[0821] LCMS (ESI-MS): Calculated mass value. C 24 H 22 N₂O₂S 402.1 m / z, measured value 403.1 [M+H] + .

[0822] 1 H NMR (400 MHz, DMSO- d 6) δ 9.30 (s, 1H), 7.63 – 7.50 (m, 2H), 7.41 (t, J = 7.2 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.19 (t, J = 8.0 Hz, 3H), 3.63 – 3.53(m, 4H), 3.45 (s, 2H), 2.34 (d, J = 4.4 Hz, 4H), 1.91 (s, 3H).

[0823] Preparation Example 87. 2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(4-methylthiazo-5-yl)-1H- Inden-1-one (2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(4-methylthiazol-5- yl)-1H-inden-1-one) (compound 88) [Reaction Equation 87]

[0824] Following the same method as step 5 of Preparation Example 21, the desired title compound (24.6 mg, 18%) was obtained as a yellow solid.

[0825] The LCMS (ESI-MS) results of the obtained compound 88 (hereinafter chemical formula 89) were confirmed. 1 H NMR yielded the following data: [Chemical Formula 89]

[0826] LCMS (ESI-MS): Calculated mass value. C 25 H 25 N3OS 415.2 m / z, measured value 416.2 [M+H] + .

[0827] 1 H NMR (400 MHz, DMSO- d 6) δ 9.29 (s, 1H), 7.64 – 7.50 (m, 2H), 7.41 (t, J= 7.2 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.27 – 7.12 (m, 3H), 7.08 (s, 1H), 3.36 (s, 2H), 2.25 (s, 8H), 2.18 (s, 3H), 1.91 (s, 3H).

[0828] Preparation Example 88. 3-(4-methylthiazolyl-5-yl)-2-(3-(morpholinylmethyl)phenyl)-1H-inden-1-one (3-(4-) methylthiazol-5-yl)-2-(3-(morpholinomethyl)phenyl)-1H-inden-1-one) (Compound 89) [Reaction Formula 88]

[0829] Following the same method as step 5 of Preparation Example 21, the desired title compound (24.7 mg, 19%) was obtained as a yellow solid.

[0830] The LCMS (ESI-MS) results of the obtained compound 89 (hereinafter chemical formula 90) were confirmed. 1 H NMR yielded the following data: [Chemical Formula 90]

[0831] LCMS (ESI-MS): Calculated mass value. C 24 H 22 N₂O₂S 402.1 m / z, measured value 403.1 [M+H] + .

[0832] 1 H NMR (400 MHz, DMSO- d 6) δ 9.30 (s, 1H), 7.65 – 7.50 (m, 2H), 7.46 –7.39 (m, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.27 – 7.15 (m, 3H), 7.08 (s, 1H), 3.62– 3.44 (m, 4H), 3.37 (s, 2H), 2.21 (d, J = 4.4 Hz, 4H), 1.91 (s, 3H).

[0833] Preparation Example 89. 2-(4-(4-methylpiperazin-1-yl)phenyl)-3-phenyl- 1H-indanone (2-(4-(4- methylpiperazin-1-yl)phenyl)-3-phenyl-1H-inden-1-one) (Compound 90) [Reaction Equation 89]

[0834] Following the same method as in Preparation Example 14, the desired title compound (60 mg, 46%) was obtained as a red solid.

[0835] The LCMS (ESI-MS) results of the obtained compound 90 (hereinafter chemical formula 91) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 91]

[0836] LCMS (ESI-MS): Calculated mass value. C 26 H 24 N₂O 380.2 m / z, measured value 380.9 [M+H] + .

[0837] 1 H NMR (400 MHz, DMSO- d 6) δ 7.51 – 7.45 (m, 5H), 7.42 – 7.38 (m, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.09 – 7.06 (m, 3H), 6.83 (d, J = 8.8 Hz, 2H), 3.17 –3.12 (m, 4H), 2.43 – 2.38 (m, 4H), 2.20 (s, 3H).

[0838] Preparation Example 90. 2-(3-(4-methylpiperazin-1-yl)phenyl)-3-phenyl-1H-inden-1-one (2-(3-(4-) methylpiperazin-1-yl)phenyl)-3-phenyl-1H-inden-1-one) (Compound 91) [Reaction Formula 90]

[0839] Following the same method as in Preparation Example 14, the desired title compound (60 mg, 40%) was obtained as a yellow solid.

[0840] The LCMS (ESI-MS) results of the obtained compound 91 (hereinafter chemical formula 92) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 92]

[0841] LCMS (ESI-MS): Calculated mass value. C 26 H 24 N₂O 380.2 m / z, measured value 380.9 [M+H] + .

[0842] 1 H NMR (400 MHz, DMSO- d 6) δ 7.56 – 7.45 (m, 5H), 7.42 – 7.36 (m, 3H), 7.16 – 7.09 (m, 2H), 6.85 (dd, J = 8.4, 2.2 Hz, 1H), 6.70 (s, 1H), 6.65 (d, J =7.6 Hz, 1H), 2.97 – 2.90 (m, 4H), 2.40 – 2.32 (m, 4H), 2.18 (s, 3H).

[0843] Preparation Example 91. 3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(4-methylthiazo-5-yl)-1H- Inden-1-one (3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(4-methylthiazol-5- yl)-1H-inden-1-one) (compound 92) [Reaction Formula 91]

[0844] Step 1: Synthesis of 3-bromo-1H-inden-1-one Following the same method as step 4 of Preparation Example 21, the desired title compound (1.6 g, 17%) was obtained as a yellow solid.

[0845] LCMS (ESI-MS): Calculated mass value. C9H5BrO 208.0 m / z, measured value 208.5 [M+H] + .

[0846] Step 2: Synthesis of 3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-inden-1-one Following the same method as step 5 of Preparation Example 21, the desired title compound (510 mg, 22%) was obtained as a yellow solid.

[0847] 1 H NMR (400 MHz, DMSO- d 6) δ 7.77 (d, J = 8.0 Hz, 2H), 7.65 – 7.47 (m, 6H), 7.45 – 7.38 (m, 1H), 3.54 (s, 2H), 2.40 – 2.34 (m, 8H), 2.16 (s, 3H).

[0848] Step 3: Synthesis of 2-bromo-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-inden-1-one CCl4 was added to 3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-inden-1-one (510 mg, 1.6 mmol), NBS (570 mg, 3.2 mmol), and AIBN (262 mg, 1.6 mmol), and stirred at 80 °C for 4 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (35% EtOAc / PE) to give the desired title compound (210 mg, 33%) as a red solid.

[0849] LCMS (ESI-MS): Calculated mass value. C 21 H 21 BrN₂O 396.1 m / z, measured value 396.2 [M+H] + .

[0850] Step 4: Synthesis of 3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(4-methylthiazol-5-yl)-1H-inden-1-one (Compound 92) 1,4-Dioxane (1.5 mL) was added to 2-bromo-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-inden-1-one (162 g, 0.0004 mol), 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopenten-2-yl)thiazole (0.1 g, 0.0005 mol), Pd(dppf)Cl2 (30 mg, 0.00004 mol), and K2CO3 (118 mg, 0.0012 mol), and the mixture was heated under nitrogen and 100 mL of oxygen. °Stir at C for 3 hours. Add water (10 mL) to the reaction mixture and extract with EA (10 mL x 3). Wash the organic layer using standard methods, dry, and concentrate under reduced pressure. Purify the concentrated residue by rapid column chromatography (50% EtOAc / PE) to obtain the desired title compound (5.1 mg, 3%) as a red solid.

[0851] The LCMS (ESI-MS) results of the obtained compound 92 (hereinafter chemical formula 93) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 93]

[0852] LCMS (ESI-MS): Calculated mass value. C 25 H 25 N3OS 415.2 m / z, measured value 415.9 [M+H] + .

[0853] 1 H NMR (400 MHz, DMSO- d 6) δ 9.06 (s, 1H), 7.64 – 7.50 (m, 2H), 7.48 –7.26 (m, 6H), 3.52 (s, 2H), 2.38 (s, 8H), 2.17 (s, 3H), 1.80 (s, 3H).

[0854] Preparation Example 92. 3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(4-methylthiazo-5-yl)-1H- Inden-1-one (3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(4-methylthiazol-5- yl)-1H-inden-1-one) (compound 93) [Reaction Formula 92]

[0855] Step 1: Synthesis of 2-(4-(4-methylpiperazin-1-yl)methyl)phenyl)-1H-inden-1-one Following the same method as step 5 of Preparation Example 21, the desired title compound (190 mg, 31%) was obtained as a yellow solid.

[0856] 1 H NMR (400 MHz, DMSO- d 6) δ 7.68 (d, J= 8.8 Hz, 2H), 7.57 – 7.46 (m, 5H), 7.42 (d, J = 7.2 Hz, 1H), 6.24 (s, 1H), 3.56 (s, 2H), 2.41 - 2.33 (m, 8H), 2.15 (s, 3H).

[0857] Step 2: Synthesis of 2-bromo-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-inden-1-one Following the same method as step 3 of Preparation Example 22, the desired title compound (100 mg, crude product) was obtained as a yellow solid.

[0858] Step 3: Synthesis of 3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(4-methylthiazol-5-yl)-1H-inden-1-one (Compound 93) Following the same method as step 5 of Preparation Example 21, the desired title compound (8.2 mg, 13%) was obtained as a red solid.

[0859] The LCMS (ESI-MS) results of the obtained compound 93 (hereinafter chemical formula 94) were confirmed. 1 H NMR yielded the following data: [Chemical Formula 94]

[0860] LCMS (ESI-MS): Calculated mass value. C 25 H 25 N3OS 415.2 m / z, measured value 416.0 [M+H] + .

[0861] 1 H NMR (400 MHz, DMSO- d 6) δ9.05 (s, 1H), 7.63 – 7.35 (m, 6H), 7.33 –7.23 (m, 2H), 3.44 (s, 2H), 2.24 (s, 8H), 2.13 (s, 3H), 1.81 (s, 3H).

[0862] Preparation Example 93. 3-(4-(4-methylpiperazin-1-yl)phenyl)-2-phenyl-1H-inden-1-one (3-(4-(4-) methylpiperazin-1-yl)phenyl)-2-phenyl-1H-inden-1-one) (Compound 94) [Reaction Formula 93]

[0863] Following the same method as step 5 of Preparation Example 21, the desired title compound (80 mg, 35%) was obtained as a white solid.

[0864] The LCMS (ESI-MS) results of the obtained compound 94 (hereinafter chemical formula 95) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 95]

[0865] LCMS (ESI-MS): Calculated mass value. C 26 H 24 N₂O 380.2 m / z, measured value 381.1 [M+H] + .

[0866] 1 H NMR (400 MHz, DMSO- d 6) δ 7.51 (t, J = 7.2 Hz, 2H), 7.40 – 7.36 (m,1H), 7.34 – 7.30 (m, 3H), 7.27 – 7.26 (m, 3H), 7.22 – 7.19 (m, 2H), 6.98 –6.96 (m, 2H), 3.33 – 3.24 (m, 4H), 2.51 – 2.44 (m, 4H), 2.22 (s, 3H).

[0867] Preparation Example 94. 3-(3-(4-methylpiperazin-1-yl)phenyl)-2-phenyl-1H-inden-1-one (3-(3-(4-) methylpiperazin-1-yl)phenyl)-2-phenyl-1H-inden-1-one) (Compound 95) [Reaction Formula 94]

[0868] Following the same method as step 5 of Preparation Example 21, the desired title compound (60 mg, 46%) was obtained as a white solid.

[0869] The LCMS (ESI-MS) results of the obtained compound 95 (hereinafter chemical formula 96) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 96]

[0870] LCMS (ESI-MS): Calculated mass value. C 26 H 24 N₂O 380.2 m / z, measured value 381.1 [M+H] + .

[0871] 1 H NMR (400 MHz, DMSO- d 6) δ 7.55 – 7.49 (m, 2H), 7.38 (t, J = 7.4 Hz,1H), 7.33 – 7.27 (m, 4H), 7.22 – 7.20 (m, 3H), 7.04 – 7.01 (m, 1H), 6.87 (s,1H), 6.79 (d, J = 7.4 Hz, 1H), 3.07 – 3.00 (m, 4H), 2.40 – 2.35 (m, 4H), 2.19 (s, 3H).

[0872] Preparation Example 95. 3-(3,5-di-tert-butylphenyl)-2-phenyl-1H-inden-1-one (3-(3,5-di-tert-butylphenyl)-2-phenyl-1H-inden-1-one) (butylphenyl)-2-phenyl-1H-inden-1-one (compound 96) [Reaction Formula 95]

[0873] Following the same method as step 5 of Preparation Example 21, the desired title compound (40 mg, 17%) was obtained as a white solid.

[0874] The LCMS (ESI-MS) results of the obtained compound 96 (hereinafter chemical formula 97) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 97]

[0875] LCMS (ESI-MS): Calculated mass value. C 29 H 30 O 394.2 m / z, measured value 395.2 [M+H] + .

[0876] 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.0 Hz, 1H), 7.43 – 7.37 (m, 2H), 7.31 – 7.28 (m, 1H), 7.26 – 7.22 (m, 6H), 7.21 (d, J = 1.6 Hz, 2H), 1.24 (s, 18H).

[0877] Preparation Example 96. 4,6-Dimethoxy-2,3-diphenyl-1H-inden-1-one (4,6-dimethoxy-2,3- diphenyl-1H-inden-1-one) (compound 97) [Reaction Formula 96]

[0878] Step 1: Synthesis of 2-bromo-3,5-dimethoxybenzaldehyde Following the same method as step 4 of Preparation Example 79, the desired title compound (400 mg, 48%) was obtained as a yellow solid.

[0879] LCMS (ESI-MS): Calculated mass value. C9H9BrO3 244.0 m / z, measured value 244.9 [M+H] + .

[0880] Step 2: Synthesis of 4,6-dimethoxy-2,3-diphenyl-1H-inden-1-one (compound 97) Following the same method as step 3 of Preparation Example 78, the desired title compound (80 mg, 25%) was obtained as a yellow solid.

[0881] The LCMS (ESI-MS) results of the obtained compound 97 (hereinafter chemical formula 98) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 98]

[0882] LCMS (ESI-MS): Calculated mass value. C 23 H 18 O3342.1 m / z, measured value 343.1 [M+H] + .

[0883] 1 H NMR (400 MHz, DMSO- d6) δ 7.37 – 7.27 (m, 5H), 7.21 – 7.18 (m, 3H), 7.04 – 7.01 (m, 2H), 6.80 (d, J = 2.2 Hz, 1H), 6.67 (d, J = 2.2 Hz, 1H), 3.86 (s, 3H), 3.57 (s, 3H).

[0884] Preparation Example 97. 6,7-Diphenyl-5H-cyclopenta[b]pyridin-5-one (6,7-diphenyl-5H-cyclopenta) [b]pyridin-5-one)(compound 98) [Reaction Formula 97]

[0885] Step 1: 6,7-Dibromo-5H-cyclopenta[b]pyridin-5-one (6,7-dibromo-5H-cyclopenta[b]) Synthesis of pyridin-5-one Following the same method as step 1 of Preparation Example 41, the desired title compound (350 mg, 11%) was obtained as a yellow solid.

[0886] MS (ESI): Calculated mass value. C8H3Br2NO 288.9 m / z, measured value 289.8 [M+H] + .

[0887] Step 2: Synthesis of 6,7-diphenyl-5H-cyclopenta[b]pyridin-5-one (Compound 98) Following the same method as step 5 of Preparation Example 21, the desired title compound (60 mg, 16%) was obtained as a yellow solid.

[0888] The LCMS (ESI-MS) results of the obtained compound 98 (hereinafter chemical formula 99) were confirmed. 1 H NMR yielded the following data: [Chemical Formula 99]

[0889] MS(ESI): Calculated mass index. C 12 H 13 NO 283.1 m / z, measured value 284.0 [M+H] + .

[0890] 1H NMR (400 MHz, CDCl3) δ 8.58 – 8.56 (m, 1H), 7.84 – 7.82 (m, 1H), 7.64 – 7.61 (m, 2H), 7.42 – 7.40 (m, 3H), 7.33 – 7.31 (m, 5H), 7.23 – 7.20(m,1H).

[0891] Preparation Example 98. N -Methyl-2-(1-oxo-3-(o-tolyl)-1H-inden-2-yl)benzamide ( N -methyl- 2-(1-oxo-3-(o-tolyl)-1H-inden-2-yl)benzamide) (Compound 99) [Reaction Formula 98]

[0892] Step 1: ( E )-1-(2-iodophenyl)-3-(o-tolyl)prop-2-en-1-one(( E Synthesis of 1-(2-iodophenyl)-3-(o-tolyl)prop-2-en-1-one Following the same method as step 1 of Preparation Example 21, the desired title compound (6 g, 76%) was obtained as a white solid. LCMS (ESI-MS): calculated mass. 16 H 13 IO 348.0 m / z, measured value 348.6 [M+H] + .

[0893] Step 2: Synthesis of 3-(o-tolyl)-2,3-dihydro-1H-inden-1-one Will( E 1-(2-iodophenyl)-3-(o-tolyl)prop-2-en-1-one (6.7 g, 0.0192 mol), Pd(PPh3)2Cl2 (0.67 g, 0.00096 mol), TEA (5.83 g, 0.0576 mol), and DMF (100 mL) were stirred at 100 °C for 16 hours. Water (200 mL) was added to the reactants, and the mixture was extracted with EA (300 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (10% EtOAc / hexane) to give the desired title compound (2.9 g, 60%) as a yellow solid.

[0894] LCMS (ESI-MS): Calculated mass value. C 16 H 14 O 222.1 m / z, measured value 223.1 [M+H] +.

[0895] Step 3: Synthesis of 2-bromo-3-(2-methylphenyl)inden-1-one Following the same method as in step 1 of Preparation Example 6, the desired title compound (1.8 g, 60%) was obtained as a yellow solid.

[0896] LCMS (ESI-MS): Calculated mass value. C 16 H 11 BrO 298.0 m / z, measured value 298.6 [M+H] + .

[0897] Step 4: Synthesis of ethyl 2-(1-oxo-3-(o-tolyl)-1H-inden-2-yl)benzoate 2-Bromo-3-(2-methylphenyl)indene-1-one (2.6 g, 0.0087 mmol), ethyl 2-(dihydroxyboryl)benzoate (3.38 g, 0.0174 mol), Pd(dppf)Cl2 (0.32 g, 0.0004 mol), potassium acetate (2.56 g, 0.0261 mol), and DMF / H2O (20 mL / 4 mL) were stirred at 140 °C for 2 hours. Water (60 mL) was added to the reaction mixture, and the mixture was extracted with EA (100 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (5% MeOH / DCM) to give the desired title compound (0.5 g, 13%) as a yellow solid.

[0898] LCMS (ESI-MS): Calculated mass value. C 25 H 20 O3368.1 m / z, measured value 368.8 [M+H] + .

[0899] Step 5: Synthesis of 2-(1-oxo-3-(o-tolyl)-1H-inden-2-yl)benzoic acid Ethyl 2-(1-oxo-3-(o-tolyl)-1H-inden-2-yl)benzoate (400 mg, 1.0857 mmol), LiOH (234 mg, 9.7713 mmol), and EtOH / H₂O (20 mL / 2 mL) were stirred at room temperature for 3 hours. 1 M HCl was added to adjust the pH of the mixture to 6, and the mixture was filtered. The filter cake was washed with 50 mL of DCM. The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was analyzed by prep-HPLC (Gemini 5). C 18 Purification was performed using a chromatographic column (150x21.2mm, 30-90% ACN / H2O, 0.1% NH3H2O) to obtain the desired title compound (140mg, 34%) as a yellow solid.

[0900] LCMS (ESI-MS): Calculated mass value. C 23 H 16 O3340.1 m / z, measured value 340.8 [M+H] + .

[0901] Step 6: N -Methyl-2-(1-oxo-3-(o-tolyl)-1H-inden-2-yl)benzamide (N Synthesis of methyl-2-(1-oxo-3-(o-tolyl)-1H-inden-2-yl)benzamide (compound 99) 2-(1-oxo-3-(o-tolyl)-1H-inden-2-yl)benzoic acid (90 mg, 0.2644 mmol), MeNH2 (8.21 mg, 0.2644 mmol), HATU (130.69 mg, 0.3437 mmol), DIEA (102.51 mg, 0.7932 mmol), and DMF (6 mL) were stirred under nitrogen at room temperature for 16 hours. A small amount of water was added to the reaction mixture, and extraction was performed with EA (40 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (5% MeOH / DCM), followed by prep-HPLC (Gemini 5). Purification was performed using a C18 column (150x21.2mm, 50-95% ACN / H2O 0.05% FA) to obtain the desired title compound (10mg, 9%) as a white solid.

[0902] The LCMS (ESI-MS) results of the obtained compound 99 (hereinafter chemical formula 100) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 100]

[0903] LCMS (ESI-MS): Calculated mass value. C 24 H 19 NO2 353.1 m / z, measured value 354.0 [M+H] + .

[0904] 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.22– 8.20 (m, 1H), 7.72 –7.70 (m, 1H), 7.35 – 7.22 (m, 6H), 7.21 – 7.13 (m, 2H), 6.89 (s, 1H), 3.88 (s, 3H), 1.95 – 1.36 (m, 4H).

[0905] Preparation Example 99. 6-(4-benzylpiperazin-1-yl)-3-(4-methylthiazo-5-yl)-2-(pyridin-3-yl)-1H- Inden-1-one(6-(4-benzylpiperazin-1-yl)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)- 1H-inden-1-one (compound 100) [Reaction Formula 99]

[0906] Step 1: Synthesis of 1-benzylpiperazine HCl-1,4-dioxane (5 mL) was added to tert-butyl 4-benzylpiperazine-1-carboxylate (200 mg, 0.721 mmol), and the mixture was stirred at 25 °C for 1 hour under nitrogen atmosphere. The reaction was terminated by adding NH3-MeOH (5 mL), followed by the addition of water (10 mL) and extraction with EA (10 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure to give the title compound (900 mg, 77%) as a white solid.

[0907] LCMS (ESI-MS): Calculated mass value. C 11 H 16 N = 2176.1 m / z, measured value 177.1 [M+H] + .

[0908] Step 2: Synthesis of 6-(4-benzylpiperazin-1-yl)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (6-(4-benzylpiperazin-1-yl)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 100) 1,4-Dioxane (4 mL) was added to 6-chloro-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (80 mg, 0.236 mmol), 1-benzylpiperazine (62.42 mg, 0.354 mmol), and Pd-PEPPSI-IPent. Cl In a mixture of 22.97 mg (0.023 mmol) and Cs₂CO₃ (153.85 mg, 0.472 mmol), the mixture was stirred at 100 °C under nitrogen atmosphere for 16 hours. Water (10 mL) was added to the reaction mixture, and extraction was performed using EA (10 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was analyzed by prep-HPLC (Gemini 5). C 18 Purification was performed using a chromatographic column (150x21.2 mm, 70-95% MeCN / H2O 0.1% FA) to obtain the desired title compound (35.2 mg, 29%) as a blue solid.

[0909] The LCMS (ESI-MS) results of the obtained compound 100 (hereinafter chemical formula 101) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 101]

[0910] LCMS (ESI-MS): Calculated mass value. C 29 H 26 N4OS 478.2 m / z, measured value 478.9 [M+H] + .

[0911] 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.48 – 8.46 (m, 2H), 7.65 – 7.63 (m, 1H), 7.41 – 7.38 (m, 5H), 7.25 (s, 2H), 7.01 – 6.99 (m, 1H), 6.76 –6.74 (m, 1H), 3.68 (s, 2H), 3.39 (s, 4H), 2.70 (s, 4H), 1.71 (s, 3H).

[0912] Preparation Example 100. 3-(4-methylthiazolyl-5-yl)-6-((3-phenylpiperidin-1-yl)methyl)-2-(pyridine-3- base)-1H-inden-1-one (3-(4-methylthiazol-5-yl)-6-((3-phenylpiperidin-1-yl)methyl)-2- (pyridin-3-yl)-1H-inden-1-one) (Compound 101) [Reaction Formula 100]

[0913] Step 1: Synthesis of 6-methyl-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one 1,4-Dioxane (70 mL) / H₂O (20 mL) was added to 6-chloro-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (1.5 g, 0.004 mol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxaboranecyclohexane (1.66 g, 0.013 mol), and Pd-PEPPSI-IPent. Cl The mixture was stirred in nitrogen at 100°C for 16 hours with 0.43 g (0.0004 mol) and Cs₂CO₃ (2.87 g, 0.008 mol). Water (50 mL) was added to the reaction mixture, and the mixture was extracted with EA (80 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (20% EtOAc / hexane) to give the desired title compound (1.1 g, 70%) as a yellow solid.

[0914] LCMS (ESI-MS): Calculated mass value. C 19 H 14 N2OS 318.1 m / z, measured value 318.7 [M+H] + .

[0915] Step 2: Synthesis of 6-(chloromethyl)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one 6-Methyl-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (1 g, 0.003 mol) was dissolved in CCl4 (21 mL) / MeCN (7 mL), and then NCS (0.79 g, 0.003 mol) and benzoyl peroxide (0.15 g, 0.0006 mol) were added. The reaction mixture was stirred at 80 °C under nitrogen atmosphere for 16 hours.

[0916] Water (30 mL) was added to the reactants, and the mixture was extracted with EA (50 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (50% EtOAc / hexane) to give the desired title compound (200 mg, 12.9%) as a yellow solid.

[0917] LCMS (ESI-MS): Calculated mass value. C 19 H 13 ClN2OS 352.0 m / z, measured value 352.7 [M+H] + .

[0918] Step 3: Synthesis of 3-(4-methylthiazol-5-yl)-6-((3-phenylpiperidin-1-yl)methyl)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 101) 6-(chloromethyl)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-indene-1-one (50 mg, 0.141 mmol) was dissolved in DMF (3 mL), followed by the addition of 3-phenylpiperidine (27.42 mg, 0.170 mol) and DIEA (54.94 mg, 0.425 mol), and the mixture was stirred at 60 °C for 1 hour under nitrogen atmosphere. Water (5 mL) was added to the reaction mixture, and extraction was performed using EA (8 mL x 3). The organic layer was washed using standard methods, dried, and concentrated under reduced pressure. The concentrated residue was analyzed by prep-HPLC (Gemini 5). C 18Purification was performed using a chromatographic column (150x21.2 mm, 70-95% MeCN / H2O 0.1% FA) to obtain the desired title compound (2.7 mg, 4%) as a red solid.

[0919] The LCMS (ESI-MS) results of the obtained compound 101 (hereinafter chemical formula 102) were confirmed by... 1 H NMR yielded the following data: [Chemical Formula 102]

[0920] LCMS (ESI-MS): Calculated mass value. C 30 H 27 N3OS 477.2 m / z, measured value 478.0 [M+H] + .

[0921] 1 H NMR (400 MHz, DMSO- d6 ) δ 9.27 (s, 1H), 8.46 – 8.48 (m, 1H), 8.39 –8.40 (m, 1H), 7.64 – 7.62 (m, 1H), 7.47 (s, 1H), 7.39 – 7.31 (m, 2H), 7.21 –7.13 (m, 3H), 7.06 – 7.04 (m, 1H), 6.92 (s, 2H), 3.64 (s, 2H), 2.58 (s, 3H), 2.39 (s, 3H), 1.90 (s, 2H), 1.57 – 1.50 (m, 2H), 1.27 – 1.24 (m, 2H).

[0922] Example 1: Disaggregation test of β-amyloid and Tau proteins 1.1. Sample Preparation Each compound was dissolved in DMSO to a concentration of 10 mM. The compounds were then diluted with 6% DMSO (in DW) and used.

[0923] By Aβ 1~42 Alternatively, Tau-RD3 (Tau protein repeat domain 3) monomers were dissolved in DMSO to a concentration of 10 mM to prepare β-amyloid and Tau protein solutions. These solutions were then diluted to 100 μM using a dry whey method and stored on ice.

[0924] Meanwhile, thioflavin-T was dissolved in 50 mM glycine buffer (pH 8.5) to achieve a concentration of 5 mM. Subsequently, it was diluted to 5 μM with 50 mM glycine buffer (pH 8.5) and stored in a dark room protected from light.

[0925] 1.2. Depolymerization assay of β-amyloid and Tau protein by thioflavin-T analysis The β-amyloid protein and Tau protein solutions prepared in Example 1.1 were added to 1.5 mL microcentrifuge tubes to reach 50 μM or 35 μM, and then reacted at 37 °C for 24 hours.

[0926] For each 1.5 mL microcentrifuge tube that had completed the aggregation of the β-amyloid and Tau proteins, the compound was serially diluted from 500 μM to 0 μM and then reacted further at 37 °C for 48 hours.

[0927] The reaction solution was added in increments of 25 μL to each well of a 96-well plate for fluorescence analysis, and thioflavone-T solution was added in increments of 75 μL to each well. After reacting for 5 minutes at room temperature and in the dark, the fluorescence values ​​were measured at 450 nm (excitation wavelength) and 485 nm (emission wavelength) using a multi-mode microplate reader.

[0928] The fluorescence values ​​of the control group (group that aggregated after 72 hours of treatment with only β-amyloid or Tau protein) were converted into percentage (%) values ​​and expressed as 100. For the β-amyloid and Tau protein aggregates that had completed aggregation after 24 hours of reaction, different concentrations of each compound were treated and reacted for another 48 hours. The measured fluorescence values ​​were then converted into relative values, and the results are shown in Table 2.

[0929] Table 2 shows the depolymerization effect of each compound and its intermediate on β-amyloid protein according to the treatment concentration (0–500 μM) (control group: treated with 50 μM Aβ). 1-42 Treatment and aggregation for 72 hours; Treatment group: with 50 μM Aβ 1-42 The effects of Tau protein depolymerization (24 hours of aggregation followed by 48 hours of treatment with different concentrations of the compound) and (control group: treatment with 35 μM Tau-RD3 followed by 72 hours of aggregation; treatment group: 24 hours of aggregation with 35 μM Tau-RD3 followed by 48 hours of treatment with different concentrations of the compound) were calculated. The depolymerization rate of each compound and its intermediates was calculated to be 50% higher than that of the control group. Concentrations of amyloid and tau protein aggregation (EC) 50 The concentrations of each compound are represented by the following symbols according to their intensity; this indicates that each compound exhibits a concentration-dependent depolymerization effect: +++: Strong effect (EC) 50 ≤20μM); ++: Moderate effect (20) <EC 50 ≤100μM); +: Weak effect (100) <EC 50 ≤250μM); and -: No effect (250μM) <EC 50 ).

[0930] As shown in Table 2 below, when compounds 1 to 99 and their intermediates (compounds 5-4, 6-2, 12-3, 23-10, 39-3, 40-4, 41-4, 42-6, 42-7, 44-8, 45-8, 72-7, 73-7, 74-7, 76-1, 83-5, 83-6, 99-7, and 99-8) were treated, it was confirmed that they exhibited the effect of depolymerizing β-amyloid protein aggregation and / or depolymerizing Tau protein aggregation.

[0931] In particular, when compounds 13, 20, 21, 23, 27, 28, 30-33, 46, 47, 57, 63, 65, 66, 70, 72, 74-77, 83, 84, and 90, as well as their intermediate compounds 5-4, 74-7, and 76-1, showed significant and excellent depolymerization effects on β-amyloid aggregates and Tau protein aggregates.

[0932] That is, based on the results, it is confirmed that the compound of chemical formula 1 has a significant and excellent effect on depolymerizing β-amyloid protein and / or depolymerizing Tau protein, and can therefore be applied to the prevention, improvement or treatment of degenerative brain diseases.

[0933] Table 2

[0934] Example 2: Confirmation of aggregate reduction in cell lines expressing β-amyloid oligomers by compound treatment Less effective 2.1. Preparation of β-amyloid oligomer overexpression cell lines To observe changes in intracellular β-amyloid oligomers, the APP E693Δ (Osaka mutant) mutant plasmid was introduced from GenScript, a cell line known to be associated with early Alzheimer's disease and to induce the formation of intracellular β-amyloid oligomers. This plasmid was transfected into HEK293 cells using liposomes to prepare a cell line overexpressing intracellular β-amyloid oligomers.

[0935] 2.2. Compound Treatment HEK293 cells transfected with the APP E693Δ mutant plasmid were cultured at 37°C in a 5% CO2 incubator for 48 hours. The compound prepared in section 1.1 was then diluted 10 μM in the cell culture solution for treatment. The untransfected control group was treated with the same 0.1% DMSO as the compound-treated group.

[0936] The cell lines treated with the compound were cultured again at 37°C and 5% CO2 for 48 hours before being used in experiments.

[0937] 2.3. Confirming changes in oligomers using dot blot analysis. After culturing the control group and compound-treated cells from Example 2.2 above, dot blot analysis was performed using cell lysate. 3.5 μg of sample was spotted onto a nitrocellulose membrane, allowed to air dry, and then blocked with 5% skim milk powder. After incubation with amyloid oligomer antibody A11, the membrane was washed four times with TBST and then bound to a secondary antibody. The image signal was detected using a chemiluminescent substrate.

[0938] The results showed that Figure 1 Images were used to show the changes in β-amyloid oligomers induced by each compound (dot blot images), with the relative changes compared to the control group (HEK293 cells not treated with the compounds). It was confirmed that the amount of β-amyloid oligomers was reduced after treatment with each compound compared to the control group.

[0939] That is, the Figure 1 The results showed that each compound reduced the aggregation of β-amyloid oligomers in cells expressing β-amyloid oligomers by depolymerizing the aggregates of β-amyloid oligomers.

[0940] Based on the results, it was confirmed that the compound of chemical formula 1 exhibits significant and excellent effects on depolymerizing β-amyloid protein and / or depolymerizing Tau protein, and can therefore be applied to the prevention, improvement or treatment of degenerative brain diseases.

Claims

1. The compound represented by chemical formula 1 or its salt: [Chemical Formula 1] In the chemical formula 1, R 1 and R 2 Each independently represents hydrogen, halogen, CN, OR a SR a CO2R a CH2CO2R a CONR b R c NR b R c C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; X 1 It is carbon or nitrogen; The X 1 When it is carbon, R 3 For hydrogen, halogen, CN, OR a SR a CO2R a CH2CO2R a CONR b R c NR b R c C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; X 1 When it is nitrogen, R 3 It does not exist; R 4 and R 5 Each independently represents hydrogen, halogen, CN, OR a SR a O(CO)R a CO2R a NHR a NH(CO)R a CH2CO2R a CONR b R c NR b R c X a (CH2) p X b (CH2) q R d OCH2CH=CHR d C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; R a R b R c and R d Each is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; X a and X b Each can be a direct bond, oxygen, nitrogen, or sulfur; p and q are each an independent integer selected from 0 to 2.

2. The compound or a salt thereof according to claim 1, wherein, The R 1 and R 2 Each is independently hydrogen, halogen, CN, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl; The X 1 It is carbon or nitrogen; The X 1 When R is carbon, 3 For hydrogen, halogen, OR a or C that is substituted or not substituted 1-6 Alkyl; the X 1 When it is nitrogen, the R 3 It does not exist; The R 4 and R 5 Each independently represents hydrogen, halogen, and OR a SR a O(CO)R a NHR a NH(CO)R a NR b R c X a (CH2) p X b (CH2) q R d C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, or substituted or unsubstituted 3-7 membered heterocycloalkyl; The R a R b R c and R d Each is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl.

3. The compound or a salt thereof according to claim 1, wherein, The R 1 and R 2 Each is independently hydrogen, halogen, CN, substituted or unsubstituted 5-7 membered cycloalkyl, substituted or unsubstituted 5-7 membered heterocycloalkyl, substituted or unsubstituted 5-6 membered aryl, or substituted or unsubstituted 5-6 membered heteroaryl; The X 1 It is carbon or nitrogen; The X 1 When R is carbon, 3 Each independently represents hydrogen, halogen, and OR a or C that is substituted or not substituted 1-3 Alkyl; the X 1 When it is nitrogen, the R 3 It does not exist; The R 4 For hydrogen, halogen, OR a SR a O(CO)R a NHR a NH(CO)R a NR b R c X a (CH2) p X b (CH2) q R d C, substituted or unsubstituted 1-4 Alkyl, substituted or unsubstituted 5-7 membered cycloalkyl, or substituted or unsubstituted 5-7 membered heterocycloalkyl; The R a R b R c and R d Each is independently hydrogen, halogen, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-6 membered aryl, or substituted or unsubstituted 5-6 membered heteroaryl; The R 5 It is hydrogen or halogen.

4. The compound or a salt thereof according to claim 1, wherein, The R 1 and R 2 Each is independently hydrogen, halogen, CN, substituted or unsubstituted 5-7 membered cycloalkyl, substituted or unsubstituted 5-7 membered heterocycloalkyl, substituted or unsubstituted 5-6 membered aryl, or substituted or unsubstituted 5-6 membered heteroaryl; The R 1 and R 2 In this context, the substituted 5-7 membered cycloalkyl, substituted 5-7 membered heterocycloalkyl, substituted 5-6 membered aryl, and substituted 5-6 membered heteroaryl are each independently substituted by one or more members selected from the group consisting of: halogen, C 1-4 Alkyl, 5-6 membered heterocyclic alkyl, (C 1-6 (alkyl)-(5-6 membered heterocyclic alkyl), (5-6 membered heterocyclic alkyl)-(C 1-6 Alkyl), O-(C) 1-6 Alkyl), (C 1-6 alkyl)-(5-6 membered heterocyclic alkyl)-(C 1-6 alkyl), and (CO)HN(C 1-6 alkyl); The X 1 It is carbon or nitrogen; The X 1 When it is carbon, R 3 Hydrogen, halogen, OH, O- (C 1-3 Alkyl), or unsubstituted C 1-3 Alkyl; the X 1 When it is nitrogen, R 3 It does not exist; The R 4 For hydrogen, halogen, OR a SR a O(CO)R a NHR a NH(CO)R a NR b R c X a (CH2) p X b (CH2) q R d C, substituted or unsubstituted 1-4 Alkyl, substituted or unsubstituted 5-7 membered cycloalkyl, or substituted or unsubstituted 5-7 membered heterocycloalkyl; The R 4 In, replacing C 1-4 Alkyl groups, substituted 5-7 membered cycloalkyl groups, and substituted 5-7 membered heterocycloalkyl groups are each independently substituted by one or more of the following groups: halogen, C 1-4 Alkyl, C 1-4 alcohol, (C 1-4 Alkyl)-(5-6 aryl), (5-6 heterocyclic alkyl)-(5-6 aryl), and (5-6 heterocyclic aryl)-(5-6 aryl); The R a R b R c and R d Each is independently hydrogen, halogen, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted 5-6 membered aryl, or substituted or unsubstituted 5-6 membered heteroaryl; The R a R b R c and R d In, replacing C 1-4 Alkyl, substituted 3-7-membered cycloalkyl, substituted 3-7-membered heterocycloalkyl, substituted 5-6-membered aryl, and substituted 5-6-membered heteroaryl are each independently substituted by one or more of the following groups: halogen, OH, 5-6-membered heterocycloalkyl, 5-6-membered aryl, and 5-6-membered heteroaryl.

5. The compound or a salt thereof according to claim 1, wherein, The R 1 and R 2 Each is independently hydrogen, halogen, CN, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; The X 1 It is carbon or nitrogen; The X 1 When R is carbon, 3 It is hydrogen, halogen, -CH3, -OH or The X 1 When it is nitrogen, the R 3 It does not exist; The R 4 For hydrogen, halogen, -OH, -NH2, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

6. The compound or a salt thereof according to claim 1, wherein, The compound is selected from one of the following groups (1) to (101): (1) 2,3-Diphenyl-1-indanone, (2) 6-Methoxy-2,3-diphenyl-1H-inden-1-one, (3) 2,3-Diphenyl-6-propoxy-1H-inden-1-one, (4) Isopropoxy-2,3-diphenyl-1H-inden-1-one, (5) 2-Phenyl-3-(o-tolyl)-1H-inden-1-one, (6) 3-Phenyl-2-(o-tolyl)-1H-inden-1-one, (7) 3-Phenyl-2-(pyridin-3-yl)-1H-inden-1-one, (8) 2-morpholino-3-phenyl-1H-inden-1-one, (9) 2-Phenyl-3-(pyridin-3-yl)-1H-inden-1-one, (10) 3-Cyclohexyl-2-phenyl-1H-inden-1-one, (11) 2-Cyclohexyl-3-phenyl-1H-inden-1-one, (12) 6-morpholino-2,3-diphenyl-1H-inden-1-one, (13) 6-(4-methylpiperazin-1-yl)-2,3-diphenyl-1H-inden-1-one, (14) 3-(4-morpholinophenyl)-2-phenyl-1H-inden-1-one, (15) 3-(3-morpholinophenyl)-2-phenyl-1H-inden-1-one, (16) 3-(4-(morpholinylmethyl)phenyl)-2-phenyl-1H-inden-1-one, (17) 2-(4-morpholinophenyl)-3-phenyl-1H-inden-1-one, (18) 2-(3-morpholinophenyl)-3-phenyl-1H-inden-1-one, (19) 3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (20) 3-(4-methylthiazolyl-5-yl)-6-((3-phenylpropyl)amino)-2-(pyridin-3-yl)-1H-inden-1-one, (21) 2-(4-methylpyridin-3-yl)-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (22) 6-Methoxy-2-(4-methylpyridin-3-yl)-3-(4-methylthiazo-5-yl)-1H-inden-1-one, (23) 3-(5-methylthiazolyl-4-yl)-2-(pyridin-3-yl)-6-(3-(pyridin-4-yl)propoxy)-1H-inden-1-one, (24) 2-Bromo-3-(1-methyl-1H-pyrazol-3-yl)-1-oxo-1H-indene-6-yl acetate, (25) 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(1H-pyrazol-3-yl)-1H-inden-1-one, (26) 2-(1-methyl-1H-pyrazol-3-yl)-3-(4-methylthiazo-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (27) 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(1H-pyrazol-4-yl)-1H-inden-1-one, (28) 2-(1-methyl-1H-pyrazol-4-yl)-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (29) 2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (30) 2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (31) 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(1H-1,2,3-triazol-4-yl)-1H-inden-1-one, (32) 2-(1-methyl-1H-1,2,3-triazol-4-yl)-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (33) 2-(2-methyl-2H-1,2,3-triazol-4-yl)-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (34) 3-(4-methylthiazolyl-5-yl)-1-oxo-6-(3-phenylpropoxy)-1H-indene-2-carboxynitrile, (35) 6-hydroxy-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (36) 6-(2-hydroxyethoxy)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (37) 6-(2-methoxyethoxy)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (38) 6-(methyl(3-phenylpropyl)amino)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (39) 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-4-yl)-1H-inden-1-one, (40) 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-2-yl)-1H-inden-1-one, (41) 3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(pyrazin-2-yl)-1H-inden-1-one, (42) 3-(1-methyl-1H-pyrazol-4-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (43) 6-(3-phenylpropoxy)-3-(1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (44) 3-(2-methoxyphenyl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (45) 3-(2,6-dimethoxyphenyl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (46) 4-Methyl-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (47) 4-Methoxy-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (48) 4-Hydroxy-3-(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (49) 6-(cyclopentylamino)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (50) 6-(methylamino)-3-(4-methylthiazo-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (51) 6-((1-methylpiperidin-4-yl)amino)-3-(4-methylthiazo-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (52) 3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-6-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1H-inden-1-one, (53) 6-((2-hydroxyethyl)amino)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (54) 6-((2-methoxyethyl)amino)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (55) 3-(4-methylthiazolyl-5-yl)-6-((2-phenoxyethyl)amino)-2-(pyridin-3-yl)-1H-inden-1-one, (56) 3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-6-((tetrahydro-2H-pyran-4-yl)amino)-1H-inden-1-one, (57) 3-(4-methylthiazolyl-5-yl)-6-((3-phenylpropyl)thio)-2-(pyridin-3-yl)-1H-inden-1-one, (58) 3-(4-methylthiazolyl-5-yl)-6-((1-phenylpiperidin-3-yl)amino)-2-(pyridin-3-yl)-1H-inden-1-one, (59) 6-Amino-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (60)N-(3-(4-methylthiazolyl-5-yl)-1-oxo-2-(pyridin-3-yl)-1H-inden-6-yl)-3-phenylpropionamide, (61) N-(3-(4-methylthiazolyl-5-yl)-1-oxo-2-(pyridin-3-yl)-1H-inden-6-yl)tetrahydro-2H-pyran-4-carboxamide, (62) 6-(dimethylamino)-3-(4-methylthiazo-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (63) 6-(cyclopropylamino)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (64) 6-(4-methylpiperazin-1-yl)-3-(4-methylthiazo-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (65) 6-(methyl(3-phenylpropyl)amino)-3-(4-methylthiazolyl-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (66) 3-(4-methylthiazolyl-5-yl)-6-phenoxy-2-(pyridin-3-yl)-1H-inden-1-one, (67) 6-(methylamino)-2,3-diphenyl-1H-inden-1-one, (68) 6-Amino-2,3-diphenyl-1H-inden-1-one, (69) 6-(dimethylamino)-2,3-diphenyl-1H-inden-1-one, (70) 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2,3-diphenyl-1H-inden-1-one, (71) 4-Methyl-6-(4-methylpiperazin-1-yl)-2,3-diphenyl-1H-inden-1-one, (72) 3-(2,6-dimethylphenyl)-6-(4-methylpiperazin-1-yl)-2-phenyl-1H-inden-1-one, (73) 6-(4-methylpiperazin-1-yl)-2-(3-morpholinylphenyl)-3-phenyl-1H-inden-1-one, (74) 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazo-5-yl)-1H-inden-1-one, (75) 6-(4-methylpiperazin-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazo-5-yl)-1H-inden-1-one, (76) 2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazo-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (77) 2,3-Bis(4-methylthiazolyl-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (78) 2,3-Diphenyl-6-(3-phenylpropoxy)-1H-inden-1-one, (79) 6-(4-methylpiperazin-1-yl)-2,3-bis(4-methylthiazo-5-yl)-1H-inden-1-one, (80) 6-(4-methylpiperazin-1-yl)-2,3-bis(3-morpholinylphenyl)-1H-inden-1-one, (81) 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2,3-bis(4-methylthiazo-5-yl)-1H-inden-1-one, (82) 6-Hydroxy-2,3-di-o-tolyl-1H-inden-1-one, (83) 6-(3-phenylpropoxy)-2,3-bis(thiazolyl-5-yl)-1H-inden-1-one, (84) 3-(2,6-dimethylphenyl)-6-hydroxy-2-(o-tolyl)-1H-inden-1-one, (85)2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazo-5-yl)-1H-inden-1-one, (86)2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(4-methylthiazo-5-yl)-1H-inden-1-one, (87) 3-(4-methylthiazolyl-5-yl)-2-(4-(morpholinylmethyl)phenyl)-1H-inden-1-one, (88)2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(4-methylthiazo-5-yl)-1H-inden-1-one, (89) 3-(4-methylthiazolyl-5-yl)-2-(3-(morpholinylmethyl)phenyl)-1H-inden-1-one, (90)2-(4-(4-methylpiperazin-1-yl)phenyl)-3-phenyl-1H-inden-1-one, (91)2-(3-(4-methylpiperazin-1-yl)phenyl)-3-phenyl-1H-inden-1-one, (92) 3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(4-methylthiazo-5-yl)-1H-inden-1-one, (93) 3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(4-methylthiazo-5-yl)-1H-inden-1-one, (94) 3-(4-(4-methylpiperazin-1-yl)phenyl)-2-phenyl-1H-inden-1-one, (95) 3-(3-(4-methylpiperazin-1-yl)phenyl)-2-phenyl-1H-inden-1-one, (96) 3-(3,5-di-tert-butylphenyl)-2-phenyl-1H-inden-1-one, (97) 4,6-Dimethoxy-2,3-diphenyl-1H-indene, (98) 6,7-Diphenyl-5H-cyclopentano[b]pyridin-5-one (99) N-methyl-2-(1-oxo-3-(o-tolyl)-1H-inden-2-yl)benzamide, (100)6-(4-benzylpiperazin-1-yl)-3-(4-methylthiazo-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, and (101)3-(4-methylthiazolyl-5-yl)-6-((3-phenylpiperidin-1-yl)methyl)-2-(pyridin-3-yl)-1H-indone.

7. A composition comprising the compound of claim 1; or a salt thereof.

8. A pharmaceutical composition comprising the compound of claim 1; or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition for the prevention or treatment of degenerative brain diseases, comprising the compound of claim 1; or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition for the prevention or treatment of degenerative brain diseases according to claim 9, wherein, The pharmaceutical composition is administered to individuals selected from the following: (1) The aggregation level of β-amyloid protein was higher than that of individuals without degenerative brain diseases who were at risk of elevated levels. (2) The aggregation level of Tau protein was higher than that of normal individuals or individuals at risk of elevation who did not have degenerative brain diseases; (3) Tau protein phosphorylation levels were higher than normal or in individuals at risk of elevated levels who did not have degenerative brain diseases; and (4) Corresponding to one or more of the individuals mentioned in (1) to (3).

11. The pharmaceutical composition for the prevention or treatment of degenerative brain diseases according to claim 9, wherein, The degenerative brain diseases mentioned are selected from one or more of the following groups: dementia, Alzheimer's disease, preclinical Alzheimer's disease, Parkinson's disease, Huntington's disease, mild cognitive impairment, cerebral amyloid angiopathy, Down syndrome, amyloid stroke, systemic amyloidosis, Dutch amyloidosis, Niemann-Pick disease, senile dementia, amyotrophic lateral sclerosis, spinocerebellar ataxia, Tourette syndrome, Friedreich ataxia, Machado-Joseph disease, Lewy body dementia, dystonia, progressive supranuclear palsy, and frontotemporal dementia.

12. A pharmaceutical composition for inhibiting or depolymerizing β-amyloid aggregates, comprising the compound of claim 1; or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition for inhibiting the aggregation of Tau protein, depolymerizing Tau protein aggregates, or inhibiting the phosphorylation of Tau protein, comprising the compound of claim 1; or a pharmaceutically acceptable salt thereof.

14. A health functional food comprising the compound of claim 1; or a food science acceptable salt thereof.

15. A health food for preventing or improving degenerative brain diseases, comprising the compound of claim 1; or a food-grade acceptable salt thereof.

16. A health food for inhibiting or depolymerizing β-amyloid protein aggregates, comprising the compound of claim 1; or a food-grade acceptable salt thereof.

17. A health food for inhibiting the aggregation of Tau protein, depolymerizing Tau protein aggregates, or inhibiting the phosphorylation of Tau protein, comprising the compound of claim 1; or a food-grade acceptable salt thereof.

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