Novel indenone derivative and use thereof

Abstract

One aspect provides a novel indenone derivative or a salt thereof, and use thereof. According to one aspect, the novel indenone derivative exhibits excellent efficacy of inhibiting aggregation of amyloid-beta protein and / or degrading aggregates of amyloid-beta protein, efficacy of inhibiting aggregation of tau protein and / or degrading aggregates of tau protein, and / or efficacy of inhibiting phosphorylation of tau protein, and thus can be utilized for the prevention or treatment of degenerative brain diseases.

Description

Novel indenone derivatives and their uses

[0001] The present invention relates to a novel indenone derivative or salt thereof; and uses thereof for (i) inhibiting aggregation of amyloid-beta protein and / or dissolving aggregates of amyloid-beta protein, (ii) inhibiting aggregation of tau protein, dissolving aggregates of tau protein and / or inhibiting phosphorylation of tau protein; and uses thereof for preventing or treating neurodegenerative brain diseases.

[0002]

[0003] Degenerative brain diseases are conditions characterized by degenerative changes in the neurons of the central nervous system, resulting in various symptoms, including impaired motor and sensory functions, and impairments in higher-order functions such as memory, learning, and arithmetic reasoning. Representative examples include Alzheimer's disease, Parkinson's disease, and memory impairment. Degenerative brain diseases are characterized by neuronal death through rapid or slow-onset necrosis or apoptosis. Therefore, understanding the mechanisms of neuronal death is crucial for the prevention, control, and development of treatments for central nervous system diseases.

[0004] Two types of proteins, amyloid-beta and tau, are attracting attention as causative agents of degenerative brain diseases.

[0005] Human amyloid-beta (Aβ) is a peptide molecule containing approximately 36-43 amino acids, and its self-assembly into oligomers or aggregates is known to be involved in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease. Specifically, amyloid-beta peptide molecules are obtained by cleavage of amyloid precursor protein (APP; UniProtKB P05067) by beta secretase and gamma secretase, and these amyloid-beta peptide molecules cause degenerative brain diseases by aggregating to form neurotoxic oligomers.

[0006] In addition, Tau protein is composed of four parts: N-terminal protrusion, proline aggregation domain, microtubule binding domain, and C-terminus, and it is known that abnormal hyperphosphorylation or aggregation of Tau protein in nerve cells of the central nervous system causes degenerative brain diseases such as Parkinson's disease and tauopathy.

[0007] Therefore, a substance that inhibits the aggregation of amyloid-beta protein or disintegrates amyloid-beta protein aggregates, inhibits the aggregation of tau protein or disintegrates tau protein aggregates, or inhibits the phosphorylation of tau protein can be proposed as a treatment for degenerative brain diseases.

[0008]

[0009] One aspect is to provide a compound of the following formula 1 or a salt thereof:

[0010] [Chemical Formula 1]

[0011]

[0012] In the above chemical formula 1,

[0013] R 1 and R 2are each independently hydrogen, halogen, CN, OR a , SR a , CO2R a , CH2CO2R a , CONR b R c , NR b R c , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0014] X 1 is carbon or nitrogen;

[0015] Above X 1 If this is carbon, R 3 Silver hydrogen, halogen, CN, OR a , SR a , CO2R a , CH2CO2R a , CONR b R c , NR b R c , 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, and X 1 If this is nitrogen, R 3 does not exist;

[0016] R 4 and R 5 are each independently 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 , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0017] R a , R b , R c and R d are each independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0018] X a and X b are each independently a direct bond, oxygen, nitrogen or sulfur;

[0019] p and q are each independently integers selected from 0 to 2.

[0020] Another aspect is to provide a composition comprising a compound of the above formula 1; or a salt thereof.

[0021] Another aspect is to provide a pharmaceutical composition comprising a compound of the above formula 1; or a pharmaceutically acceptable salt thereof.

[0022] Another aspect provides a use of a compound of formula 1; or a pharmaceutically acceptable salt thereof.

[0023] Another aspect provides the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament.

[0024] Another aspect is to provide a pharmaceutical composition for preventing or treating a degenerative brain disease, comprising a compound of the above chemical formula 1; or a pharmaceutically acceptable salt thereof.

[0025] Another aspect provides the use of the compound of formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of a degenerative disease.

[0026] Another aspect provides the use of the compound of formula 1; or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of a degenerative disease.

[0027] Another aspect provides a method for preventing or treating a degenerative brain disease, comprising administering to a subject in need thereof a compound of the above chemical formula 1; or a pharmaceutically acceptable salt thereof.

[0028] Another aspect is to provide a pharmaceutical composition for inhibiting aggregation of amyloid-beta protein or for decomposing aggregates of amyloid-beta protein, comprising a compound of the above formula 1; or a pharmaceutically acceptable salt thereof.

[0029] Another aspect provides a use of the compound of formula 1 or a pharmaceutically acceptable salt thereof for inhibiting aggregation of amyloid-beta protein or disintegrating aggregates of amyloid-beta protein.

[0030] Another aspect provides the use of the compound of formula 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a drug for inhibiting the aggregation of amyloid-beta protein or for disintegrating aggregates of amyloid-beta protein.

[0031] Another aspect provides a method for inhibiting aggregation of amyloid-beta protein or decomposing aggregates of amyloid-beta protein, comprising administering to a subject in need thereof a compound of the above formula 1; or a pharmaceutically acceptable salt thereof.

[0032] Another aspect is to provide a pharmaceutical composition for inhibiting aggregation of tau protein, disintegrating aggregates of tau protein, or inhibiting phosphorylation of tau protein, comprising a compound of the above chemical formula 1; or a pharmaceutically acceptable salt thereof.

[0033] Another aspect provides a use of the compound of formula 1 for inhibiting aggregation of tau protein, disaggregation of tau protein aggregates or inhibition of phosphorylation of tau protein; or a pharmaceutically acceptable salt thereof.

[0034] Another aspect provides the use of a compound of formula 1 for the manufacture of a drug for inhibiting aggregation of tau protein, disintegrating aggregates of tau protein or inhibiting phosphorylation of tau protein; or a pharmaceutically acceptable salt thereof.

[0035] Another aspect provides a method for inhibiting aggregation of tau protein, disintegrating aggregates of tau protein, or inhibiting phosphorylation of tau protein, comprising administering to a subject in need thereof a compound of the above-described chemical formula 1; or a pharmaceutically acceptable salt thereof.

[0036] Another aspect is to provide a health functional food comprising a compound of the above chemical formula 1; or a food-wise acceptable salt thereof.

[0037] Another aspect is to provide a health functional food for preventing or improving degenerative brain diseases, comprising a compound of the above chemical formula 1 or a food-wise acceptable salt thereof.

[0038] Another aspect is to provide a health functional food for inhibiting aggregation of amyloid-beta protein or decomposing aggregates of amyloid-beta protein, comprising a compound of the above chemical formula 1 or a food-wise acceptable salt thereof.

[0039] Another aspect is to provide a health functional food for inhibiting aggregation of tau protein, decomposing aggregates of tau protein, or inhibiting phosphorylation of tau protein, comprising the compound of the above chemical formula 1 or a food-wise acceptable salt thereof.

[0040]

[0041] One aspect provides a compound of formula 1 or a salt thereof:

[0042] [Chemical Formula 1]

[0043]

[0044] In the above chemical formula 1,

[0045] R 1 and R 2 are each independently hydrogen, halogen, CN, OR a , SR a , CO2R a , CH2CO2R a , CONR b R c , NR b R c , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0046] X 1 is carbon or nitrogen;

[0047] Above X 1 If this is carbon, R 3 Silver hydrogen, halogen, CN, OR a , SR a , CO2Ra , CH2CO2R a , CONR b R c , NR b R c , 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, and X 1 If this is nitrogen, R 3 does not exist;

[0048] R 4 and R 5 are each independently 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 , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0049] R a , R b , R c and R d are each independently hydrogen, halogen, substituted or unsubstituted C 1-6Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0050] X a and X b are each independently a direct bond, oxygen, nitrogen or sulfur;

[0051] p and q are each independently integers selected from 0 to 2.

[0052] The compound or its salt may have one or more chiral carbon centers and may therefore exist as R or S isomers, racemates, mixtures of diastereoisomers and individual diastereoisomers.

[0053] Additionally, the compound of the above formula 1 may include a hydrate or solvate of the compound. The hydrate and solvate may be prepared using a known method, and are preferably non-toxic and water-soluble.

[0054] The term “salt” means a salt prepared using a specific compound and a relatively non-toxic acid or base, depending on the nature of the compound.

[0055] The term "Cm - n" (where m and n are each independently integers greater than or equal to 1) means having m to n carbon atoms.

[0056] The term "halogen" refers to an element in Group 17 of the periodic table. Examples include fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0057] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group. For example, "C 1-6 "Alkyl" means a straight or branched chain saturated hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. Specifically, C1-6 Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc. In addition, the alkyl may be unsubstituted or substituted with one or more same or different substituents. For example, it may be substituted with a substituted or unsubstituted 3- to 7-membered cycloalkyl, a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, a substituted or unsubstituted 5- to 10-membered aryl, a substituted or unsubstituted 5- to 10-membered heteroaryl, etc.

[0058] The term "cycloalkyl" means a monocyclic or polycyclic saturated hydrocarbon ring. Polycyclic ring structures may include multiple ring structures such as spiro, bridged, and fused ring structures. For example, "3- to 7-membered cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In addition, the cycloalkyl may be unsubstituted or substituted with one or more identical or different substituents. For example, substituted or unsubstituted C 1-6 It can be substituted with alkyl, etc.

[0059] The term "heterocycloalkyl" refers to a monocyclic or polycyclic ring in which at least one carbon atom forming the ring in a saturated hydrocarbon ring is replaced with a heteroatom. The heteroatom may be nitrogen (N), oxygen (O), or sulfur (S). At this time, the heteroatom contained in the ring of the heterocycloalkyl may be one type or two or more types, one type of heteroatom may be included one or two or more times, and two or more types of heteroatoms may be included at least one each. The heterocycloalkyl may include a carbon atom as the atom connected to the parent nuclear structure and a heteroatom within the ring, or the atom connected to the parent nuclear structure may be a heteroatom (at this time, if there are two or more heteroatoms, the heteroatom is also included within the ring). For example, heterocycloalkyl may include azetidinyl, azepanyl, oxiranyl, oxetanyl, morpholinyl, pyrrolidonyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, etc. In addition, the heterocycloalkyl may be unsubstituted or substituted with one or more identical or different substituents. For example, substituted or unsubstituted C 1-6 It may be substituted with alkyl, substituted or unsubstituted 5- to 10-membered aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, etc.

[0060] The term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon ring. Examples thereof include phenyl, naphthyl, biaryl, etc. In addition, the aryl may be unsubstituted or substituted with one or more identical or different substituents. For example, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 1-3 Alkoxy, -CONH(C 1-3 It can be substituted with alkyl, etc.

[0061] The term "heteroaryl" refers to a monocyclic or polycyclic ring in which at least one carbon atom in the aryl is replaced with a heteroatom such as nitrogen (N), oxygen (O), or sulfur (S). At this time, the heteroatom contained in the heteroaryl ring may be one type or two or more types, one type of heteroatom may be included one or two or more times, and two or more types of heteroatoms may each be included at least one or more times. In addition, the heteroaryl may include a carbon atom that is connected to the parent nuclear structure and a heteroatom within the ring, or the atom that is connected to the parent nuclear structure may be a heteroatom (at this time, if there are two or more heteroatoms, the heteroatom is also included within the ring).For example, heteroaryl can be pyridinyl, thiophenyl, triazolyl, tetrazolyl, benzothiazolyl, benzothiophenyl, quinolinyl, indolyl, isoindolyl, benzofuranyl, benzopyrrolyl, furanyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazinyl, Pyridazinyl, pyrimidinyl, isoquinolinyl, benzoxazolyl, benzimidazolyl, dihydro benzohiophenyl, purinyl, indolizinyl, chromenyl, pyrrolopyridinyl, pyrazolopyridinyl, thiadiazolo pyridinyl, triazinyl, triazolopyrimidinyl, triazolopyridinyl, triazolopyridazinyl, indazolyl, It may include imidazopyridinyl, imidazopyridazinyl, oxadiazolopyridinyl, benzothiadiazolyl, benzotriazolyl, etc.The above heteroaryl may be unsubstituted or substituted with one or more identical or different substituents. For example, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 1-3 Alkoxy, -CONH(C 1-3 It can be substituted with alkyl, etc.

[0062] The term "C 1-3 Alcohol" has the chemical formula -C 1-3 It means alkyl-OH and includes methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, etc. The above C 1-3 Alcohols may be unsubstituted or substituted with one or more identical or different substituents. For example, substituted or unsubstituted C 1-6 It can be substituted with alkyl, etc.

[0063] The term "C 1-3 "Alkoxy" has the chemical formula -OC 1-3 It means alkyl, and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, etc. The above C 1-3 Alkoxy may be unsubstituted or substituted with one or more identical or different substituents. For example, substituted or unsubstituted C 1-6 It can be substituted with alkyl, etc.

[0064] The term "substitution" refers to the replacement of a hydrogen atom within a molecular structure with a substituent, such that the resulting compound is chemically stable without exceeding the valence of the designated atom. For example, "group A is replaced with substituent B" may mean that a hydrogen atom bonded to an atom such as carbon constituting the backbone of group A is replaced with substituent B, so that group A and substituent B form a covalent bond.

[0065] In one specific example, in the chemical formula 1, R 1and R 2 are each independently hydrogen, halogen, CN, substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0066] Above X 1 is carbon or nitrogen;

[0067] Above X 1 If this is carbon, the above R 3 Silver hydrogen, halogen, OR a or substituted or unsubstituted C 1-6 Alkyl, and the above X 1 If this is nitrogen, the above R 3 does not exist;

[0068] The above R 4 and R 5 are each independently 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 , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl or a substituted or unsubstituted 3-7 membered heterocycloalkyl;

[0069] The above R a , R b , R c and R d are each independently hydrogen, halogen, substituted or unsubstituted C 1-6It may be alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl.

[0070] In one specific example, in the chemical formula 1, R 1 and R 2 are each independently hydrogen, halogen, CN, a substituted or unsubstituted 5- to 7-membered cycloalkyl, a substituted or unsubstituted 5- to 7-membered heterocycloalkyl, a substituted or unsubstituted 5- to 6-membered aryl, or a substituted or unsubstituted 5- to 6-membered heteroaryl;

[0071] Above X 1 is carbon or nitrogen;

[0072] Above X 1 If this is carbon, the above R 3 are each independently hydrogen, halogen, OR a or substituted or unsubstituted C 1-3 Alkyl, and the above X 1 If this is nitrogen, the above R 3 does not exist;

[0073] The above R 4 is 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 , substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted 5-7 membered cycloalkyl, or substituted or unsubstituted 5-7 membered heterocycloalkyl;

[0074] The above R a , Rb , R c and R d are each independently hydrogen, halogen, substituted or unsubstituted C 1-4 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-6 membered aryl, or a substituted or unsubstituted 5-6 membered heteroaryl;

[0075] The above R 5 can be hydrogen or halogen.

[0076] In one specific example, in the chemical formula 1, R 1 and R 2 are each independently hydrogen, halogen, CN, a substituted or unsubstituted 5- to 7-membered cycloalkyl, a substituted or unsubstituted 5- to 7-membered heterocycloalkyl, a substituted or unsubstituted 5- to 6-membered aryl, or a substituted or unsubstituted 5- to 6-membered heteroaryl,

[0077] The above R 1 and R 2 Substituted 5- to 7-membered cycloalkyl, substituted 5- to 7-membered heterocycloalkyl, substituted 5- to 6-membered aryl and substituted 5- to 6-membered heteroaryl are each independently selected from halogen, C 1-4 Alkyl, 5-6 membered heterocycloalkyl, (C 1-6 Alkyl)-(5-6 membered heterocycloalkyl), (5-6 membered heterocycloalkyl)-(C 1-6 alkyl), O-(C 1-6 alkyl), (C 1-6 Alkyl)-(5- to 6-membered heterocycloalkyl)-(C 1-6 alkyl) and (CO)HN(C 1-6 is substituted with one or more selected from the group consisting of alkyl;

[0078] Above X 1 is carbon or nitrogen;

[0079] Above X 1 If this is carbon, R 3 Silver hydrogen, halogen, OH, O-(C 1-3 alkyl) or unsubstituted C 1-3 Alkyl, and the above X 1 If this is nitrogen, R 3 does not exist;

[0080] The above R 4 is 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 , substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted 5-7 membered cycloalkyl or substituted or unsubstituted 5-7 membered heterocycloalkyl,

[0081] The above R 4 C substituted in 1-4 Alkyl, substituted 5-7 membered cycloalkyl and substituted 5-7 membered heterocycloalkyl are each independently halogen, C 1-4 Alkyl, C 1-4 Alcohol, (C 1-4 is substituted with at least one selected from the group consisting of (5- to 6-membered aryl), (5- to 6-membered heterocycloalkyl)-(5- to 6-membered aryl), and (5- to 6-membered heteroaryl)-(5- to 6-membered aryl);

[0082] The above R a , R b , R c and R d are each independently hydrogen, halogen, substituted or unsubstituted C 1-4Alkyl, 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,

[0083] The above R a , R b , R c and R d C substituted in 1-4 Alkyl, substituted 3- to 7-membered cycloalkyl, substituted 3- to 7-membered heterocycloalkyl, substituted 5- to 6-membered aryl and substituted 5- to 6-membered heteroaryl may each be independently substituted with one or more selected from the group consisting of halogen, OH, 5- to 6-membered heterocycloalkyl, 5- to 6-membered aryl and 5- to 6-membered heteroaryl.

[0084] In one specific example, in the chemical formula 1, R 1 and R 2 are each independently hydrogen, halogen, CN, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or and;

[0085] Above X 1 is carbon or nitrogen;

[0086] Above X 1 If this is carbon, the above R 3 is hydrogen, halogen, -CH3, -OH or and the above X 1 If this is nitrogen, the above R 3 does not exist;

[0087] The above R 4 is hydrogen, halogen, -OH, -NH2, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or It could be.

[0088] In one specific example, in the following chemical formula 1,

[0089] [Chemical Formula 1]

[0090]

[0091] The above R 1 Silver hydrogen, CN, OR a , SRa , CO2R a , CH2CO2R a , CONR b R c , NR b R c , a substituted or unsubstituted 3- to 7-membered cycloalkyl, a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, a 5- to 10-membered aryl substituted with a substituted or unsubstituted 6-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl substituted with a substituted or unsubstituted 6-membered heterocycloalkyl;

[0092] The above R 2 is hydrogen, halogen, CN, OR a , SR a , CO2R a , CH2CO2R a , CONR b R c , NR b R c , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0093] Above X 1 is carbon or nitrogen;

[0094] Above X 1 If this is carbon, the above R 3 Silver hydrogen, halogen, CN, OR a , SR a , CO2R a , CH2CO2R a , CONR b R c , NR b R c , substituted or unsubstituted C 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, and X 1 If this is nitrogen, the above R 3 does not exist;

[0095] The above R 4 is 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 , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0096] The above R 5 is 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 , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0097] The above R a , R b , R c and R d are each independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0098] X a and X b are each independently a direct bond, oxygen, nitrogen or sulfur;

[0099] p and q can each be an integer independently selected from 0 to 2.

[0100] In one specific example, in the following chemical formula 1,

[0101] [Chemical Formula 1]

[0102]

[0103] The above R 1 Silver hydrogen, halogen, CN, OR a , SR a , CO2R a , CH2CO2R a , CONR b R c , NR b R c , substituted or unsubstituted C 1-6Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0104] The above R 2 is hydrogen, halogen, CN, OR a , SR a , CO2R a , CH2CO2R a , CONR b R c , NR b R c , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3- to 7-membered cycloalkyl, a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, or a substituted or unsubstituted 5- to 10-membered aryl;

[0105] Above X 1 is carbon or nitrogen;

[0106] Above X 1 If this is carbon, the above R 3 Silver hydrogen, halogen, CN, OR a , SR a , CO2R a , CH2CO2R a , CONR b R c , NR b R c , 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, and X 1 If this is nitrogen, the above R 3 does not exist;

[0107] The above R 4 is hydrogen, halogen, CN, OR a , SRa , 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 , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0108] The above R 5 is 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 , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0109] The above R a , R b, R c and R d are each independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0110] X a and X b are each independently a direct bond, oxygen, nitrogen or sulfur;

[0111] p and q can each be an integer independently selected from 0 to 2.

[0112] In one specific example, in the following chemical formula 1,

[0113] [Chemical Formula 1]

[0114]

[0115] The above R 1 Silver hydrogen, halogen, CN, OR a , SR a , CO2R a , CH2CO2R a , CONR b R c , NR b R c , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0116] The above R 2 is hydrogen, halogen, CN, OR a , SR a , CO2R a , CH2CO2R a , CONR b R c , NR bR c , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0117] Above X 1 is carbon or nitrogen;

[0118] Above X 1 If this is carbon, the above R 3 Silver halogen, CN, OR a , SR a , CO2R a , CH2CO2R a , CONR b R c , NR b R c , 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, and X 1 If this is nitrogen, the above R 3 does not exist;

[0119] The above R 4 is 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=CHRd , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0120] The above R 5 is 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 , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0121] The above R a , R b , R c and R d are each independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0122] X a and X bare each independently a direct bond, oxygen, nitrogen or sulfur;

[0123] p and q can each be an integer independently selected from 0 to 2.

[0124] In one specific example, in the following chemical formula 1,

[0125] [Chemical Formula 1]

[0126]

[0127] The above R 1 Silver hydrogen, halogen, CN, OR a , SR a , CO2R a , CH2CO2R a , CONR b R c , NR b R c , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0128] The above R 2 is hydrogen, halogen, CN, OR a , SR a , CO2R a , CH2CO2R a , CONR b R c , NR b R c , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0129] Above X 1 is carbon or nitrogen;

[0130] Above X1 If this is carbon, the above R 3 Silver hydrogen, halogen, CN, OR a , SR a , CO2R a , CH2CO2R a , CONR b R c , NR b R c , 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, and X 1 If this is nitrogen, the above R 3 does not exist;

[0131] The above R 4 is hydrogen, halogen, CN, O-(C 1-3 alkyl), OH, O-(C 1-3 Alcohol), O-(C 1-3 alkyl)-(C 1-3 alkoxy), O-(substituted or unsubstituted 5- to 6-membered aryl), 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 , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0132] The above R 5 is 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 , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0133] The above R a , R b , R c and R d are each independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl;

[0134] X a and X b are each independently a direct bond, oxygen, nitrogen or sulfur;

[0135] p and q can each be an integer independently selected from 0 to 2.

[0136] In one specific example, the compound or salt thereof may be one selected from the group consisting of (1) to (101):

[0137] (1) 2,3-diphenylindene-1-one,

[0138] (2) 6-methoxy-2,3-diphenyl-1H-indene-1-one,

[0139] (3) 2,3-diphenyl-6-propoxy-1H-indene-1-one,

[0140] (4) Isopropoxy-2,3-iphenyl-1H-indene-1-one,

[0141] (5) 2-phenyl-3-(o-tolyl)-1H-inden-1-one,

[0142] (6) 3-phenyl-2-(o-tolyl)-1H-inden-1-one,

[0143] (7) 3-phenyl-2-(pyridin-3-yl)-1H-inden-1-one,

[0144] (8) 2-morpholino-3-phenyl-1H-inden-1-one,

[0145] (9) 2-phenyl-3-(pyridin-3-yl)-1H-inden-1-one,

[0146] (10) 3-cyclohexyl-2-phenyl-1H-inden-1-one,

[0147] (11) 2-cyclohexyl-3-phenyl-1H-inden-1-one,

[0148] (12) 6-morpholino-2,3-diphenyl-1H-indene-1-one,

[0149] (13) 6-(4-methylpiperazin-1-yl)-2,3-diphenyl-1H-inden-1-one,

[0150] (14) 3-(4-morpholinophenyl)-2-phenyl-1H-inden-1-one,

[0151] (15) 3-(3-morpholinophenyl)-2-phenyl-1H-inden-1-one,

[0152] (16) 3-(4-(morpholinomethyl)phenyl)-2-phenyl-1H-inden-1-one,

[0153] (17) 2-(4-morpholinophenyl)-3-phenyl-1H-inden-1-one,

[0154] (18) 2-(3-morpholinophenyl)-3-phenyl-1H-inden-1-one,

[0155] (19) 3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one,

[0156] (20) 3-(4-methylthiazol-5-yl)-6-((3-phenylpropyl)amino)-2-(pyridin-3-yl)-1H-inden-1-one,

[0157] (21) 2-(4-methylpyridin-3-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one,

[0158] (22) 6-methoxy-2-(4-methylpyridin-3-yl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one,

[0159] (23) 3-(5-methylthiazol-4-yl)-2-(pyridin-3-yl)-6-(3-(pyridin-4-yl)propoxy)-1H-inden-1-one,

[0160] (24) 2-Bromo-3-(1-methyl-1H-pyrazol-3-yl)-1-oxo-1H-indene-6-yl acetate,

[0161] (25) 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(1H-pyrazol-3-yl)-1H-inden-1-one,

[0162] (26) 2-(1-methyl-1H-pyrazol-3-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one,

[0163] (27) 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(1H-pyrazol-4-yl)-1H-inden-1-one,

[0164] (28) 2-(1-methyl-1H-pyrazol-4-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one,

[0165] (29) 2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one,

[0166] (30) 2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one,

[0167] (31) 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(1H-1,2,3-triazol-4-yl)-1H-inden-1-one,

[0168] (32) 2-(1-methyl-1H-1,2,3-triazol-4-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one,

[0169] (33) 2-(2-methyl-2H-1,2,3-triazol-4-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one,

[0170] (34) 3-(4-methylthiazol-5-yl)-1-oxo-6-(3-phenylpropoxy)-1H-indene-2-carbonitrile,

[0171] (35) 6-hydroxy-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one,

[0172] (36) 6-(2-hydroxyethoxy)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one,

[0173] (37) 6-(2-methoxyethoxy)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one,

[0174] (38) 6-(Methyl(3-phenylpropyl)amino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one,

[0175] (39) 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-4-yl)-1H-inden-1-one,

[0176] (40) 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-2-yl)-1H-inden-1-one,

[0177] (41) 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyrazin-2-yl)-1H-inden-1-one,

[0178] (42) 3-(1-methyl-1H-pyrazol-4-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one,

[0179] (43) 6-(3-phenylpropoxy)-3-(1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one,

[0180] (44) 3-(2-methoxyphenyl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one,

[0181] (45) 3-(2,6-dimethoxyphenyl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one,

[0182] (46) 4-methyl-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one,

[0183] (47) 4-methoxy-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one,

[0184] (48) 4-hydroxy-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one,

[0185] (49) 6-(Cyclopentylamino)-3-(4-methylthiizol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one,

[0186] (50) 6-(methylamino)-3-(4-methylthiizol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one,

[0187] (51) 6-((1-methylpiperidin-4-yl)amino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one,

[0188] (52) 3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-6-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1H-inden-1-one,

[0189] (53) 6-((2-hydroxyethyl)amino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one,

[0190] (54) 6-((2-methoxyethyl)amino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one,

[0191] (55) 3-(4-methylthiazol-5-yl)-6-((2-phenoxyethyl)amino)-2-(pyridin-3-yl)-1H-inden-1-one,

[0192] (56) 3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-6-((tetrahydro-2H-pyran-4-yl)amino)-1H-inden-1-one,

[0193] (57) 3-(4-methylthiazol-5-yl)-6-((3-phenylpropyl)thio)-2-(pyridin-3-yl)-1H-inden-1-one,

[0194] (58) 3-(4-methylthiazol-5-yl)-6-((1-phenylpiperidin-3-yl)amino)-2-(pyridin-3-yl)-1H-inden-1-one,

[0195] (59) 6-amino-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one,

[0196] (60) N-(3-(4-methylthiazol-5-yl)-1-oxo-2-(pyridin-3-yl)-1H-inden-6-yl)-3-phenylpropanamide,

[0197] (61) N-(3-(4-methylthiazol-5-yl)-1-oxo-2-(pyridin-3-yl)-1H-inden-6-yl)tetrahydro-2H-pyran-4-carboxamide,

[0198] (62) 6-(Dimethylamino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one,

[0199] (63) 6-(Cyclopropylamino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one,

[0200] (64) 6-(4-methylpiperazin-1-yl)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one,

[0201] (65) 6-(Methyll(3-phenylpropyl)amino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one,

[0202] (66) 3-(4-methylthiazol-5-yl)-6-phenoxy-2-(pyridin-3-yl)-1H-inden-1-one,

[0203] (67) 6-(methylamino)-2,3-diphenyl-1H-inden-1-one,

[0204] (68) 6-amino-2,3-diphenyl-1H-inden-1-one,

[0205] (69) 6-(dimethylamino)-2,3-diphenyl-1H-inden-1-one,

[0206] (70) 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2,3-diphenyl-1H-inden-1-one,

[0207] (71) 4-methyl-6-(4-methylpiperazin-1-yl)-2,3-diphenyl-1H-inden-1-one,

[0208] (72) 3-(2,6-dimethylphenyl)-6-(4-methylpiperazin-1-yl)-2-phenyl-1H-inden-1-one,

[0209] (73) 6-(4-methylpiperazin-1-yl)-2-(3-morpholinophenyl)-3-phenyl-1H-inden-1-one,

[0210] (74) 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one,

[0211] (75) 6-(4-methylpiperazin-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one,

[0212] (76) 2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one,

[0213] (77) 2,3-bis(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one,

[0214] (78) 2,3-diphenyl-6-(3-phenylpropoxy)-1H-indene-1-one,

[0215] (79) 6-(4-methylpiperazin-1-yl)-2,3-bis(4-methylthiazol-5-yl)-1H-inden-1-one,

[0216] (80) 6-(4-methylpiperazin-1-yl)-2,3-bis(3-morpholinophenyl)-1H-inden-1-one,

[0217] (81) 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2,3-bis(4-methylthiazol-5-yl)-1H-inden-1-one,

[0218] (82) 6-hydroxy-2,3-di-o-tolyl-1H-indene-1-one,

[0219] (83) 6-(3-phenylpropoxy)-2,3-di(thiazol-5-yl)-1H-inden-1-one,

[0220] (84) 3-(2,6-dimethylphenyl)-6-hydroxy-2-(o-tolyl)-1H-inden-1-one,

[0221] (85) 2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one,

[0222] (86) 2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one,

[0223] (87) 3-(4-methylthiazol-5-yl)-2-(4-(morpholinomethyl)phenyl)-1H-inden-1-one,

[0224] (88) 2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one,

[0225] (89) 3-(4-methylthiazol-5-yl)-2-(3-(morpholinomethyl)phenyl)-1H-inden-1-one,

[0226] (90) 2-(4-(4-methylpiperazin-1-yl)phenyl)-3-phenyl-1H-inden-1-one,

[0227] (91) 2-(3-(4-methylpiperazin-1-yl)phenyl)-3-phenyl-1H-inden-1-one,

[0228] (92) 3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(4-methylthiazol-5-yl)-1H-inden-1-one,

[0229] (93) 3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(4-methylthiazol-5-yl)-1H-inden-1-one,

[0230] (94) 3-(4-(4-methylpiperazin-1-yl)phenyl)-2-phenyl-1H-inden-1-one,

[0231] (95) 3-(3-(4-methylpiperazin-1-yl)phenyl)-2-phenyl-1H-inden-1-one,

[0232] (96) 3-(3,5-di-tert-butylphenyl)-2-phenyl-1H-inden-1-one,

[0233] (97) 4,6-dimethoxy-2,3-diphenyl-1H-indene-1-one,

[0234] (98) 6,7-diphenyl-5H-cyclopenta[b]pyridin-5-one,

[0235] (99) N-methyl-2-(1-oxo-3-(o-tolyl)-1H-inden-2-yl)benzamide,

[0236] (100) 6-(4-Benzylpiperazin-1-yl)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one and

[0237] (101) 3-(4-methylthiazol-5-yl)-6-((3-phenylpiperidin-1-yl)methyl)-2-(pyridin-3-yl)-1H-inden-1-one.

[0238] In one embodiment, it was confirmed that when compounds 1 to 99 (compounds of chemical formulae 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, the amyloid-beta aggregation disintegration and / or tau aggregation disintegration effects were exhibited (see Example 1).

[0239] In addition, when compounds 13 (compound of chemical formula 14), 30 (compound of chemical formula 31), 63 (compound of chemical formula 64), 65 (compound of chemical formula 66), 70 (compound of chemical formula 71), 72 (compound of chemical formula 73), 74 (compound of chemical formula 75), 74-7 (intermediate compound of compound 74), 75 (compound of chemical formula 76), 76-1 (intermediate compound of compound 76), and 90 (compound of chemical formula 91) were each treated to amyloid beta oligomer-expressing cells, it was confirmed that the compounds exhibited an amyloid beta oligomer reducing effect through amyloid beta oligomer aggregation decomposition (see Example 2).

[0240] Accordingly, it was confirmed that the compounds of the above chemical formula 1 can be effectively utilized for the prevention, improvement, or treatment of degenerative brain diseases, as they exhibit a decomposition effect on amyloid beta protein aggregates and / or tau protein aggregates in superior brain cells or tissues.

[0241] The compound or its salt according to the aspect can be used for inhibiting aggregation of amyloid-beta protein and / or disassembling aggregates of amyloid-beta protein, inhibiting aggregation of tau protein and / or disassembling aggregates of tau protein, and / or inhibiting phosphorylation of tau protein, and can be effectively utilized for preventing, improving, or treating degenerative brain diseases.

[0242]

[0243] Another aspect provides a composition comprising a compound of the above formula 1; or a salt thereof.

[0244] The above terms “halogen”, “alkyl”, “heterocycloalkyl”, “cycloalkyl”, “aryl”, “heteroaryl”, etc. may be within the scope mentioned above.

[0245] A composition comprising a compound or a salt thereof according to one aspect can be used for inhibiting aggregation of amyloid-beta protein and / or disassembling aggregates of amyloid-beta protein, inhibiting aggregation of tau protein and / or disassembling aggregates of tau protein, and / or inhibiting phosphorylation of tau protein, and can be effectively utilized for preventing, improving, or treating degenerative brain diseases.

[0246]

[0247] Another aspect provides a pharmaceutical composition comprising a compound of the above formula 1; or a pharmaceutically acceptable salt thereof.

[0248] The above terms “halogen”, “alkyl”, “heterocycloalkyl”, “cycloalkyl”, “aryl”, “heteroaryl”, etc. may be within the scope mentioned above.

[0249] The term "pharmaceutically acceptable" means that a compound exhibits the property of being non-toxic to cells or humans when exposed to it under certain conditions.

[0250] 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 a base in a pure solution or in 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 an acid in a pure solution or in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate ion, phosphoric acid, monohydrogen phosphate ion, dihydrogen phosphate ion, sulfuric acid, hydrogen sulfate ion, hydroiodic acid or phosphorous acid, and salts of organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and further include salts of amino acids (e.g., arginine) and salts of organic acids such as glucuronic acid.

[0251] A pharmaceutical composition comprising a compound according to one aspect or a pharmaceutically acceptable salt thereof can be used for inhibiting aggregation of amyloid-beta protein and / or disassembling aggregates of amyloid-beta protein, inhibiting aggregation of tau protein and / or disassembling aggregates of tau protein, and / or inhibiting phosphorylation of tau protein, and can be effectively utilized for preventing, improving, or treating degenerative brain diseases.

[0252]

[0253] Another aspect provides a use of a compound of formula 1; or a pharmaceutically acceptable salt thereof.

[0254] The above terms “halogen”, “alkyl”, “heterocycloalkyl”, “cycloalkyl”, “aryl”, “heteroaryl”, “pharmaceutically acceptable salt”, etc. may be within the scope mentioned above.

[0255] The compound or a pharmaceutically acceptable salt thereof according to the aspect can be used for the purpose of inhibiting aggregation of amyloid-beta protein and / or disassembling aggregates of amyloid-beta protein, inhibiting aggregation of tau protein and / or disassembling aggregates of tau protein, and / or inhibiting phosphorylation of tau protein, and can be utilized for the purpose of preventing, improving, or treating degenerative brain diseases.

[0256]

[0257] Another aspect provides the use of a compound of formula 1; or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament.

[0258] The above terms “halogen”, “alkyl”, “heterocycloalkyl”, “cycloalkyl”, “aryl”, “heteroaryl”, “pharmaceutically acceptable salt”, etc. may be within the scope mentioned above.

[0259] The compound according to one aspect or a pharmaceutically acceptable salt thereof can be used for the manufacture of a drug for inhibiting aggregation of amyloid-beta protein and / or disassembling aggregates of amyloid-beta protein, inhibiting aggregation of tau protein and / or disassembling aggregates of tau protein, and / or inhibiting phosphorylation of tau protein, and can be effectively utilized for the manufacture of a drug for preventing, improving, or treating degenerative brain diseases.

[0260]

[0261] Another aspect provides a pharmaceutical composition for preventing or treating a degenerative brain disease, comprising a compound of the above chemical formula 1; or a pharmaceutically acceptable salt thereof.

[0262] The above terms “halogen”, “alkyl”, “heterocycloalkyl”, “cycloalkyl”, “aryl”, “heteroaryl”, “pharmaceutically acceptable salt”, etc. may be within the scope mentioned above.

[0263] The term "prevention" may mean any act of inhibiting or delaying a degenerative brain disease in an individual by administering a pharmaceutical composition according to one aspect.

[0264] The term "treatment" may mean any action by which the symptoms of a degenerative brain disease in an individual are improved or beneficially altered by administration of a pharmaceutical composition according to one aspect.

[0265] Additionally, the pharmaceutical composition may be provided as a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, excipients or diluents.

[0266] Specifically, the carrier may be, for example, a colloidal suspension, a powder, a saline solution, a lipid, a liposome, microspheres, or nano-spheres. These may be complexed or associated with a carrier vehicle and may be transported in vivo using carrier systems known in the art, such as lipids, liposomes, microparticles, gold, nanoparticles, polymers, condensation agents, polysaccharides, polyamino acids, dendrimers, saponins, adsorption enhancing substances, or fatty acids.

[0267] When the above pharmaceutical composition is formulated, it can be prepared using diluents or excipients such as lubricants, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, fillers, bulking agents, binders, wetting agents, disintegrating agents, and surfactants that are commonly used. Solid preparations for oral administration may include tablets, pills, powders, granules, capsules, etc., and such solid preparations can be prepared by mixing at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc., with the above composition. In addition to simple excipients, lubricants such as magnesium stearate and talc can also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, they may contain various excipients such as wetting agents, sweeteners, fragrances, and preservatives. Preparations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include witepsol, macrogol, Tween 61, cacao butter, laurin butter, and glycerogelatin. When manufacturing in the form of eye drops, known diluents or excipients may be used.

[0268] In one specific example, the pharmaceutical composition for preventing or treating a degenerative brain disease is used in (1) an individual having a level of amyloid-beta aggregation higher than normal or at risk of being higher than normal without a degenerative brain disease;

[0269] (2) Individuals with or at risk of having higher than normal levels of tau protein aggregation than those without a degenerative brain disease;

[0270] (3) Individuals with or at risk of having higher than normal levels of phosphorylation of tau protein without a degenerative brain disease; and

[0271] (4) It may be administered to an individual selected from among individuals corresponding to one or more of (1) to (3) above.

[0272] The term “degenerative brain disease” means any disease associated with degenerative changes in the brain, in particular any disease that can be caused by one or more factors selected from the group consisting of aggregation of amyloid-beta protein, aggregation of tau protein and phosphorylation of tau protein in the brain and / or in brain neurons.

[0273] The level of aggregation of the above amyloid-beta or tau protein refers to the amount (concentration) of aggregates of amyloid-beta protein or aggregates of tau protein or the ratio of aggregates of amyloid-beta protein or aggregates of tau protein to the total amyloid-beta protein or total tau protein.

[0274] The phosphorylation level of the above tau protein refers to the amount (concentration) of phosphorylated tau protein or the ratio of phosphorylated tau protein to total tau protein.

[0275] The above “normal” may be an individual of the same species as the subject (patient) to whom the pharmaceutical composition is applied and does not have the “degenerative brain disease” defined above, or brain tissue or brain cells (brain nerve cells) isolated and / or cultured from the individual.

[0276] In one specific example, the degenerative brain disease is 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 amyloid disease, Dutch amyloidosis, Niemann-Pick disease, senile dementia, amyotrophic lateral sclerosis, spinocerebellar atrophy, Tourette's syndrome, Friedrich's ataxia, Machado-Joseph's disease, Lewy body dementia It may be one or more selected from the group consisting of dementia, dystonia, progressive supranuclear palsy, and frontotemporal dementia.

[0277] The above pharmaceutical composition is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment. The effective dosage level may be determined based on the type and severity of the patient's disease, the activity and sensitivity of the drug, the time of administration, the route of administration and excretion rate, the duration of treatment, concomitant medications, and other factors well known in the medical field. The above administration may be administered once a day or in several divided doses. For example, it may be administered every other day or once a week.

[0278] 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. Specifically, it may be administered at a dose of 1 mg / kg to 50 mg / kg, and more specifically, it may be administered at a dose of 1 mg / kg to 10 mg / kg.

[0279] The term "administration" above refers to introducing a given substance into an individual through an appropriate method, and "individual" refers to any living organism, including rats, mice, pigs, horses, cows, and livestock, including humans, that may have a degenerative brain disease. A specific example may be a mammal, including humans.

[0280] The above pharmaceutical composition may be administered orally or parenterally, and when administered parenterally, the injection method may be selected from external application to the skin or intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection, intraarterial injection, intramedullary injection, intracardiac injection, intrathecal injection, percutaneous injection, intranasal injection, intraenteric injection, local injection, sublingual injection, rectal injection, or intrathoracic injection.

[0281] In one aspect, the pharmaceutical composition may further comprise another degenerative brain disease treatment agent in addition to the compound or a pharmaceutically acceptable salt thereof.

[0282] The above other degenerative brain disease treatment agent may be included in the pharmaceutical composition in the minimum amount that can achieve the maximum effect without side effects, which can be easily determined by a person skilled in the art.

[0283] Additionally, in one aspect, the pharmaceutical composition may be administered alone or in combination with other degenerative brain disease treatments. That is, the pharmaceutical composition may be administered in combination with other degenerative brain disease treatments, and may be administered simultaneously, separately, or sequentially, and may be administered singly or in multiple doses.

[0284] When the above-mentioned other degenerative brain disease treatment agent is administered in combination with the above-mentioned pharmaceutical composition, it may be administered in an amount or ratio that can achieve the maximum effect without side effects, which can be easily determined by a person skilled in the art.

[0285] The above-mentioned other degenerative brain disease treatment agent may be a conventionally known degenerative brain disease treatment agent or a newly developed degenerative brain disease treatment agent.

[0286] A pharmaceutical composition comprising a compound according to one aspect or a pharmaceutically acceptable salt thereof exhibits a decomposing effect on amyloid beta protein aggregates and / or tau protein aggregates in superior brain cells or tissues, and can be effectively utilized for the prevention, improvement, or treatment of degenerative brain diseases.

[0287]

[0288] Another aspect provides the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of a degenerative disease.

[0289] The above terms “halogen”, “alkyl”, “heterocycloalkyl”, “cycloalkyl”, “aryl”, “heteroaryl”, “pharmaceutically acceptable salt”, “prevention”, “treatment”, etc. may be within the scope mentioned above.

[0290] The compound or a pharmaceutically acceptable salt thereof according to the present invention exhibits a decomposing effect on amyloid beta protein aggregates and / or tau protein aggregates in superior brain cells or tissues, and can be effectively utilized for the prevention, improvement, or treatment of degenerative brain diseases.

[0291]

[0292] Another aspect provides the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of a degenerative disease.

[0293] The above terms “halogen”, “alkyl”, “heterocycloalkyl”, “cycloalkyl”, “aryl”, “heteroaryl”, “pharmaceutically acceptable salt”, “prevention”, “treatment”, etc. may be within the scope mentioned above.

[0294] The compound or a pharmaceutically acceptable salt thereof according to the present invention exhibits a decomposing effect on amyloid beta protein aggregates and / or tau protein aggregates in superior brain cells or tissues, and can be effectively utilized in the manufacture of a drug for preventing, improving, or treating degenerative brain diseases.

[0295]

[0296] Another aspect provides a method for preventing or treating a degenerative brain disease, comprising administering to a subject in need thereof a compound of the above-described chemical formula 1; or a pharmaceutically acceptable salt thereof.

[0297] The above terms “halogen”, “alkyl”, “heterocycloalkyl”, “cycloalkyl”, “aryl”, “heteroaryl”, “pharmaceutically acceptable salt”, “administration”, etc. may be within the scope mentioned above.

[0298] The compound or a pharmaceutically acceptable salt thereof according to the present invention exhibits a decomposing effect on amyloid beta protein aggregates and / or tau protein aggregates in superior brain cells or tissues, and can be effectively utilized for the prevention, improvement, or treatment of degenerative brain diseases.

[0299]

[0300] Another aspect provides a pharmaceutical composition for inhibiting aggregation of amyloid-beta protein or disintegrating aggregates of amyloid-beta protein, comprising a compound of the above formula 1; or a pharmaceutically acceptable salt thereof.

[0301] The above terms “halogen”, “alkyl”, “heterocycloalkyl”, “cycloalkyl”, “aryl”, “heteroaryl”, “pharmaceutically acceptable salt”, etc. may be within the scope mentioned above.

[0302] The term "amyloid beta (Aβ)" means a polypeptide derived from amyloid precursor protein (APP) or a fragment thereof, and may include a polynucleotide sequence encoding the same or a fragment thereof.

[0303] The term "inhibition" means inhibition of any step during transcription, mRNA processing, translation, translocation, and maturation of a gene, or inhibition of protein-protein binding, protein activation, or signal transduction through it.

[0304] The term "aggregate of protein" may include polymers of proteins, fibril precursors, fibrils, plaques, protein monomers and polymers associated with homologous proteins. The fibrils may include oligomers of amyloid-beta proteins. For example, they may be aggregates of soluble amyloid-beta proteins and / or aggregates of insoluble amyloid-beta proteins, amyloid-beta oligomers, amyloid-beta protofibrils, amyloid-beta fibrils, and amyloid-beta plaques.

[0305] The term "disaggregation" refers to the process of reducing the formed aggregates to a state of low aggregation, i.e., lower-order aggregates. For example, it refers to the breakdown of amyloid-beta fibrils into amyloid-beta oligomers, or amyloid-beta oligomers into amyloid-beta monomers.

[0306] A pharmaceutical composition comprising a compound according to one aspect or a pharmaceutically acceptable salt thereof exhibits a decomposing effect on amyloid-beta protein aggregates and / or tau protein aggregates in superior brain cells or tissues, and can be utilized for inhibiting aggregation of amyloid-beta protein and / or decomposing aggregates of amyloid-beta protein.

[0307]

[0308] Another aspect provides the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof for inhibiting aggregation of amyloid-beta protein or disaggregating aggregates of amyloid-beta protein.

[0309] The above terms “halogen”, “alkyl”, “heterocycloalkyl”, “cycloalkyl”, “aryl”, “heteroaryl”, “pharmaceutically acceptable salt”, etc. may be within the scope mentioned above.

[0310] The compound or a pharmaceutically acceptable salt thereof according to one aspect exhibits a decomposing effect on amyloid-beta protein aggregates and / or tau protein aggregates in superior brain cells or tissues, and can be used for inhibiting aggregation of amyloid-beta protein and / or decomposing aggregates of amyloid-beta protein.

[0311]

[0312] Another aspect provides the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a drug for inhibiting aggregation of amyloid-beta protein or for disintegrating aggregates of amyloid-beta protein.

[0313] The above terms “halogen”, “alkyl”, “heterocycloalkyl”, “cycloalkyl”, “aryl”, “heteroaryl”, “pharmaceutically acceptable salt”, etc. may be within the scope mentioned above.

[0314] The compound or a pharmaceutically acceptable salt thereof according to one aspect exhibits an effect of decomposing amyloid-beta protein aggregates and / or tau protein aggregates in excellent brain cells or tissues, and can be used for the manufacture of a drug for inhibiting the aggregation of amyloid-beta protein and / or decomposing amyloid-beta protein aggregates.

[0315]

[0316] Another aspect provides a method for inhibiting aggregation of amyloid-beta protein or disintegrating aggregates of amyloid-beta protein, comprising administering to a subject in need thereof a compound of the above formula 1; or a pharmaceutically acceptable salt thereof.

[0317] The above terms “halogen”, “alkyl”, “heterocycloalkyl”, “cycloalkyl”, “aryl”, “heteroaryl”, “pharmaceutically acceptable salt”, etc. may be within the scope mentioned above.

[0318] The compound or a pharmaceutically acceptable salt thereof according to one aspect exhibits a decomposing effect on amyloid-beta protein aggregates and / or tau protein aggregates in superior brain cells or tissues, and can be used for inhibiting aggregation of amyloid-beta protein and / or decomposing aggregates of amyloid-beta protein.

[0319]

[0320] Another aspect provides a pharmaceutical composition for inhibiting aggregation of tau protein, disintegrating aggregates of tau protein, or inhibiting phosphorylation of tau protein, comprising a compound of the above formula 1; or a pharmaceutically acceptable salt thereof.

[0321] The above terms “halogen”, “alkyl”, “heterocycloalkyl”, “cycloalkyl”, “aryl”, “heteroaryl”, “pharmaceutically acceptable salt”, etc. may be within the scope mentioned above.

[0322] A pharmaceutical composition comprising a compound according to one aspect or a pharmaceutically acceptable salt thereof exhibits a decomposing effect on amyloid beta protein aggregates and / or tau protein aggregates in superior brain cells or tissues, and can be used for inhibiting tau protein aggregation and / or decomposing tau protein aggregates and / or inhibiting tau protein phosphorylation.

[0323]

[0324] Another aspect provides the use of a compound of formula 1; or a pharmaceutically acceptable salt thereof, for inhibiting aggregation of tau protein, disaggregation of tau protein, or inhibition of phosphorylation of tau protein.

[0325] The above terms “halogen”, “alkyl”, “heterocycloalkyl”, “cycloalkyl”, “aryl”, “heteroaryl”, “pharmaceutically acceptable salt”, etc. may be within the scope mentioned above.

[0326] The compound or a pharmaceutically acceptable salt thereof according to one aspect exhibits a decomposing effect on amyloid beta protein aggregates and / or tau protein aggregates in superior brain cells or tissues, and can be used for inhibiting tau protein aggregation and / or decomposing tau protein aggregates and / or inhibiting tau protein phosphorylation.

[0327]

[0328] Another aspect provides the use of a compound of formula 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a drug for inhibiting aggregation of tau protein, disintegrating aggregates of tau protein, or inhibiting phosphorylation of tau protein.

[0329] The above terms “halogen”, “alkyl”, “heterocycloalkyl”, “cycloalkyl”, “aryl”, “heteroaryl”, “pharmaceutically acceptable salt”, etc. may be within the scope mentioned above.

[0330] The compound or a pharmaceutically acceptable salt thereof according to one aspect exhibits a decomposing effect on amyloid beta protein aggregates and / or tau protein aggregates in superior brain cells or tissues, and can be used for the manufacture of a drug for inhibiting tau protein aggregation and / or decomposing tau protein aggregates and / or inhibiting tau protein phosphorylation.

[0331]

[0332] Another aspect provides a method for inhibiting aggregation of tau protein, disintegrating aggregates of tau protein, or inhibiting phosphorylation of tau protein, comprising administering to a subject in need thereof a compound of the above-described chemical formula 1; or a pharmaceutically acceptable salt thereof.

[0333] The above terms “halogen”, “alkyl”, “heterocycloalkyl”, “cycloalkyl”, “aryl”, “heteroaryl”, “pharmaceutically acceptable salt”, etc. may be within the scope mentioned above.

[0334] The compound or a pharmaceutically acceptable salt thereof according to one aspect exhibits a decomposing effect on amyloid beta protein aggregates and / or tau protein aggregates in superior brain cells or tissues, and can be used for inhibiting tau protein aggregation and / or decomposing tau protein aggregates and / or inhibiting tau protein phosphorylation.

[0335]

[0336] Another aspect provides a health functional food comprising a compound of the above chemical formula 1; or a food-wise acceptable salt thereof.

[0337] The above terms “halogen”, “alkyl”, “heterocycloalkyl”, “cycloalkyl”, “aryl”, “heteroaryl”, etc. may be within the scope mentioned above.

[0338] The term "improvement" can refer to any action that at least reduces a parameter associated with the condition being treated, such as the severity of symptoms. In this case, the health functional food can be used to prevent or improve a degenerative brain disease, either before or after the onset of the disease, or simultaneously with or separately from a treatment medication.

[0339] The above “health functional food” includes health functional foods, health foods, and health supplements.

[0340] The term "functional food" is synonymous with "food for special health use" (FoSHU). It refers to foods with high medical and therapeutic effects, processed to effectively demonstrate bioregulatory functions in addition to providing nutrition. "Functionality" here refers to regulating nutrients or achieving beneficial health effects, such as physiological effects, on the structure and function of the human body.

[0341] Additionally, “health food” refers to food that has a more active health maintenance or promotion effect than general food, and “health supplement food” refers to food for health supplement purposes.

[0342] In the above health functional food, the compound or its food-scientifically acceptable salt can be added directly to the food or mixed with other foods or food ingredients and used, and can be used appropriately according to a conventional method. The mixing amount of the compound or its food-scientifically acceptable salt can be appropriately determined depending on the intended use (prevention or improvement of degenerative brain diseases). Generally, when manufacturing a food or beverage, the compound or its food-scientifically acceptable salt can be added in an amount of about 15 wt% or less, more specifically about 10 wt% or less, based on the raw material. However, in the case of long-term intake for the purpose of health and hygiene or health control, the amount may be below the above range.

[0343] The above health functional food may be formulated into one selected from the group consisting of tablets, pills, powders, granules, powders, capsules, and liquid formulations, further comprising one or more of a carrier, diluent, excipient, and additive. Foods to which compounds according to one aspect may be added include various foods, powders, granules, tablets, capsules, syrups, beverages, gum, tea, vitamin complexes, and health functional foods.

[0344] Specific examples of the carrier, excipient, diluent and additive may include at least one selected from the group consisting of lactose, dextrose, sucrose, sorbitol, mannitol, erythritol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium phosphate, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, polyvinylpyrrolidone, methylcellulose, water, sugar syrup, methylcellulose, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate and mineral oil.

[0345] The above health functional food, in addition to containing the compound or its food-related acceptable salt, may contain other ingredients as essential ingredients without special limitations. For example, it may contain various flavoring agents or natural carbohydrates as additional ingredients, just like a typical beverage. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose, etc.; disaccharides such as maltose, sucrose, etc.; and polysaccharides such as dextrin, cyclodextrin, etc., and conventional sugars, and sugar alcohols such as xylitol, sorbitol, erythritol, etc. In addition to the above-mentioned flavoring agents, natural flavoring agents (thaumatin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the above-mentioned natural carbohydrates can be appropriately determined by a person skilled in the art.

[0346] In addition to the above, health functional foods according to the aspect may contain various nutrients, vitamins, minerals (electrolytes), flavorings such as synthetic flavorings and natural flavorings, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. These ingredients may be used independently or in combination, and the ratio of these additives may also be appropriately selected by those skilled in the art.

[0347] In one specific example, the compound or a food-acceptable salt thereof may be ingested at a dose of 0.1 mg / kg to 100 mg / kg. Specifically, it may be ingested at a dose of 1 mg / kg to 50 mg / kg, and more specifically, it may be ingested at a dose of 1 mg / kg to 10 mg / kg.

[0348] In one specific example, the health functional food may further include a health functional food for preventing or improving other degenerative brain diseases in addition to the compound or a food-related acceptable salt thereof.

[0349] The health functional food for preventing or improving the above-mentioned other degenerative brain diseases may be included in the health functional food in the minimum amount that can achieve the maximum effect without side effects, and this can be easily determined by a person skilled in the art.

[0350] In addition, in one specific example, the health functional food may be consumed alone or in combination with a health functional food for preventing or improving the degenerative brain disease. That is, the health functional food for preventing or improving the degenerative brain disease may be consumed in combination with another health functional food for preventing or improving the degenerative brain disease, and may be consumed simultaneously, separately, or sequentially, and may be consumed singly or in multiple doses.

[0351] When taken in combination with other health functional foods for preventing or improving the above-mentioned degenerative brain diseases, it can be taken in an amount or ratio that can achieve maximum effect without side effects, which can be easily determined by a person skilled in the art.

[0352] The above health functional food for preventing or improving other degenerative brain diseases may be a health functional food for preventing or improving degenerative brain diseases known in the past or a health functional food for preventing or improving degenerative brain diseases that is newly developed.

[0353] A health functional food containing a compound according to one aspect or a food-related acceptable salt thereof can be used to inhibit aggregation of amyloid-beta protein and / or to break up aggregates of amyloid-beta protein, to inhibit aggregation of tau protein and / or to break up aggregates of tau protein, and / or to inhibit phosphorylation of tau protein, and can be effectively utilized for the prevention, improvement, or treatment of degenerative brain diseases.

[0354]

[0355] Another aspect provides a health functional food for preventing or improving degenerative brain diseases, comprising a compound of the above chemical formula 1 or a food-wise acceptable salt thereof.

[0356] The above terms “halogen”, “alkyl”, “heterocycloalkyl”, “cycloalkyl”, “aryl”, “heteroaryl”, etc. may be within the scope mentioned above.

[0357] A health functional food containing a compound according to one aspect or a food-related acceptable salt thereof exhibits a decomposing effect on amyloid beta protein aggregates and / or tau protein aggregates in superior brain cells or tissues, and can be effectively utilized for the prevention or improvement of degenerative brain diseases.

[0358]

[0359] Another aspect provides a health functional food for inhibiting aggregation of amyloid-beta protein or decomposing aggregates of amyloid-beta protein, comprising a compound of the above chemical formula 1 or a food-wise acceptable salt thereof.

[0360] The above terms “halogen”, “alkyl”, “heterocycloalkyl”, “cycloalkyl”, “aryl”, “heteroaryl”, etc. may be within the scope mentioned above.

[0361] A health functional food containing a compound according to one aspect or a food-related acceptable salt thereof exhibits an excellent effect of decomposing amyloid-beta protein aggregates and / or tau protein aggregates in brain cells or tissues, and can be used for inhibiting aggregation of amyloid-beta protein and / or decomposing amyloid-beta protein aggregates.

[0362]

[0363] Another aspect provides a health functional food for inhibiting aggregation of tau protein, decomposing aggregates of tau protein, or inhibiting phosphorylation of tau protein, comprising a compound of the above chemical formula 1 or a food-wise acceptable salt thereof.

[0364] The above terms “halogen”, “alkyl”, “heterocycloalkyl”, “cycloalkyl”, “aryl”, “heteroaryl”, etc. may be within the scope mentioned above.

[0365] A health functional food containing a compound according to one aspect or a food-related acceptable salt thereof exhibits an effect of decomposing amyloid beta protein aggregates and / or tau protein aggregates in excellent brain cells or tissues, and can be used for inhibiting tau protein aggregation and / or decomposing tau protein aggregates and / or inhibiting tau protein phosphorylation.

[0366]

[0367] According to one aspect, the novel indenone derivative exhibits excellent aggregation inhibition and / or aggregate disintegration efficacy of amyloid-beta protein, aggregation inhibition and / or aggregate disintegration efficacy of tau protein, and / or phosphorylation inhibition efficacy of tau protein, and thus can be usefully utilized for the prevention or treatment of degenerative brain diseases.

[0368]

[0369] Figure 1 is a graph showing the change in amyloid beta oligomers caused by each compound and each compound intermediate and the relative change compared to a control group in which no compound was treated in transfected HEK293 cells:

[0370] #: Compound and intermediate number of each compound

[0371]

[0372] The present invention will be described in more detail below through examples. However, these examples are intended to exemplify the present invention and the scope of the present invention is not limited to these examples.

[0373]

[0374] Manufacturing example

[0375] Compounds 1 to 101 shown in Table 1 below were prepared according to Manufacturing Examples 1 to 100.

[0376] Compound No. Chemical Formula No. Compound Structure Korean Name 12 2,3-diphenylindene-1-one 23 6-methoxy-2,3-diphenyl-1H-indene-1-one 34 2,3-diphenyl-6-propoxy-1H-indene-1-one 45 Isopropoxy-2,3-diphenyl-1H-indene-1-one 56 2-phenyl-3-(o-tolyl)-1H-indene-1-one 67 3-phenyl-2-(o-tolyl)-1H-indene-1-one 78 3-phenyl-2-(pyridin-3-yl)-1H-inden-1-one 89 2-Morpholino-3-phenyl-1H-indene-1-one 910 2-phenyl-3-(pyridin-3-yl)-1H-inden-1-one 1011 3-Cyclohexyl-2-phenyl-1H-indene-1-one 1112 2-Cyclohexyl-3-phenyl-1H-indene-1-one 1213 6-morpholino-2,3-diphenyl-1H-indene-1-one 1314 6-(4-methylpiperazin-1-yl)-2,3-diphenyl-1H-indene-1-one 1415 3-(4-morpholinophenyl)-2-phenyl-1H-indene-1-one 1516 3-(3-morpholinophenyl)-2-phenyl-1H-indene-1-one 1617 3-(4-(morpholinomethyl)phenyl)-2-phenyl-1H-inden-1-one 1718 2-(4-morpholinophenyl)-3-phenyl-1H-inden-1-one 1819 2-(3-morpholinophenyl)-3-phenyl-1H-indene-1-one 1920 3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-indene-1-one2021 3-(4-methylthiazol-5-yl)-6-((3-phenylpropyl)amino)-2-(pyridin-3-yl)-1H-inden-1-one 2122 2-(4-methylpyridin-3-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one 2223 6-Methoxy-2-(4-methylpyridin-3-yl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one 2324 3-(5-methylthiazol-4-yl)-2-(pyridin-3-yl)-6-(3-(pyridin-4-yl)propoxy)-1H-indene-1-one 2425 2-Bromo-3-(1-methyl-1H-pyrazol-3-yl)-1-oxo-1H-indene-6-yl acetate 2526 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(1H-pyrazol-3-yl)-1H-inden-1-one 2627 2-(1-Methyl-1H-pyrazol-3-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one 2728 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(1H-pyrazol-4-yl)-1H-inden-1-one 2829 2-(1-Methyl-1H-pyrazol-4-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one2930 2-(1-(1-Methylpiperidin-4-yl)-1H-pyrazol-3-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one 3031 2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one 3132 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(1H-1,2,3-triazol-4-yl)-1H-inden-1-one 3233 2-(1-Methyl-1H-1,2,3-triazol-4-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one 3334 2-(2-Methyl-2H-1,2,3-triazol-4-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one 3435 3-(4-methylthiazol-5-yl)-1-oxo-6-(3-phenylpropoxy)-1H-indene-2-carbonitrile3536 6-Hydroxy-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one 3637 6-(2-Hydroxyethoxy)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-indene-1-one 3738 6-(2-methoxyethoxy)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one 3839 6-(Methyl(3-phenylpropyl)amino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one 3940 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-4-yl)-1H-inden-1-one 4041 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-2-yl)-1H-inden-1-one 4142 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyrazin-2-yl)-1H-inden-1-one 4243 3-(1-Methyl-1H-pyrazol-4-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one 4344 6-(3-phenylpropoxy)-3-(1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one 4445 3-(2-methoxyphenyl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one 4546 3-(2,6-dimethoxyphenyl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-indene-1-one 4647 4-Methyl-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one 4748 4-Methoxy-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one 4849 4-Hydroxy-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one 4950 6-(Cyclopentylamino)-3-(4-methylthiizol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one 5051 6-(Methylamino)-3-(4-methylthiizol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one 5152 6-((1-methylpiperidin-4-yl)amino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one 5253 3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-6-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1H-inden-1-one 5354 6-((2-hydroxyethyl)amino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one 5455 6-((2-methoxyethyl)amino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one 5556 3-(4-methylthiazol-5-yl)-6-((2-phenoxyethyl)amino)-2-(pyridin-3-yl)-1H-inden-1-one 5657 3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-6-((tetrahydro-2H-pyran-4-yl)amino)-1H-inden-1-one 5758 3-(4-methylthiazol-5-yl)-6-((3-phenylpropyl)thio)-2-(pyridin-3-yl)-1H-inden-1-one 5859 3-(4-methylthiazol-5-yl)-6-((1-phenylpiperidin-3-yl)amino)-2-(pyridin-3-yl)-1H-inden-1-one 5960 6-Amino-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one 6061 N-(3-(4-methylthiazol-5-yl)-1-oxo-2-(pyridin-3-yl)-1H-inden-6-yl)-3-phenylpropanamide 6162 N-(3-(4-methylthiazol-5-yl)-1-oxo-2-(pyridin-3-yl)-1H-indene-6-yl)tetrahydro-2H-pyran-4-carboxamide 6263 6-(Dimethylamino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one 6364 6-(Cyclopropylamino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one 6465 6-(4-methylpiperazin-1-yl)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one 6566 6-(Methyl l(3-phenylpropyl)amino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one 6667 3-(4-methylthiazol-5-yl)-6-phenoxy-2-(pyridin-3-yl)-1H-inden-1-one 6768 6-(methylamino)-2,3-diphenyl-1H-indene-1-one 6869 6-Amino-2,3-diphenyl-1H-indene-1-one 6970 6-(Dimethylamino)-2,3-diphenyl-1H-indene-1-one 7071 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2,3-diphenyl-1H-inden-1-one 7172 4-Methyl-6-(4-methylpiperazin-1-yl)-2,3-diphenyl-1H-inden-1-one 7273 3-(2,6-dimethylphenyl)-6-(4-methylpiperazin-1-yl)-2-phenyl-1H-inden-1-one 7374 6-(4-methylpiperazin-1-yl)-2-(3-morpholinophenyl)-3-phenyl-1H-inden-1-one 7475 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one 7576 6-(4-methylpiperazin-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one 7677 2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one 7778 2,3-Bis(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-indene-1-one 7879 2,3-diphenyl-6-(3-phenylpropoxy)-1H-indene-1-one 7980 6-(4-methylpiperazin-1-yl)-2,3-bis(4-methylthiazol-5-yl)-1H-indene-1-one 8081 6-(4-methylpiperazin-1-yl)-2,3-bis(3-morpholinophenyl)-1H-indene-1-one 8182 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2,3-bis(4-methylthiazol-5-yl)-1H-inden-1-one 8283 6-Hydroxy-2,3-di-o-tolyl-1H-indene-1-one 8384 6-(3-phenylpropoxy)-2,3-di(thiazol-5-yl)-1H-indene-1-one 8485 3-(2,6-dimethylphenyl)-6-hydroxy-2-(o-tolyl)-1H-indene-1-one 8586 2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one 8687 2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one 8788 3-(4-methylthiazol-5-yl)-2-(4-(morpholinomethyl)phenyl)-1H-inden-1-one 8889 2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one 8990 3-(4-methylthiazol-5-yl)-2-(3-(morpholinomethyl)phenyl)-1H-inden-1-one 9091 2-(4-(4-methylpiperazin-1-yl)phenyl)-3-phenyl-1H-inden-1-one 9192 2-(3-(4-methylpiperazin-1-yl)phenyl)-3-phenyl-1H-inden-1-one 9293 3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(4-methylthiazol-5-yl)-1H-inden-1-one 9394 3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(4-methylthiazol-5-yl)-1H-inden-1-one 9495 3-(4-(4-methylpiperazin-1-yl)phenyl)-2-phenyl-1H-inden-1-one 9596 3-(3-(4-methylpiperazin-1-yl)phenyl)-2-phenyl-1H-inden-1-one 9697 3-(3,5-di-tert-butylphenyl)-2-phenyl-1H-indene-1-one 9798 4,6-Dimethoxy-2,3-diphenyl-1H-indene-1-one 9899 6,7-diphenyl-5H-cyclopenta[b]pyridin-5-one 99100 N-methyl-2-(1-oxo-3-(o-tolyl)-1H-inden-2-yl)benzamide 100101 6-(4-Benzylpiperazin-1-yl)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one 101102 3-(4-methylthiazol-5-yl)-6-((3-phenylpiperidin-1-yl)methyl)-2-(pyridin-3-yl)-1H-inden-1-one

[0377]

[0378] Manufacturing Example 1. 2,3-diphenylinden-1-one (Compound 1)

[0379] [Reaction Formula 1]

[0380]

[0381] To a solution of (2-phenylethynyl)benzene (200 mg, 1.12 mmol) in 1,4-dioxane (5 mL) were added tetrabutylammoni㎛ 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) sequentially under CO. The reaction mixture was stirred at 100 °C under CO for 24 h. Water (15 mL) was added to the obtained mixture, and the mixture was extracted with EtOAc (15 mL x 3). The organic layer was washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (0% - 4% EtOAc / PE) to give 2,3-diphenylinden-1-one (191.4 mg, 0.67 mmol, 59.9%) as a red solid.

[0382] MS (ESI) and of the compound 1 (chemical formula 2) obtained above1 As a result of H NMR analysis, the following data were obtained:

[0383] [Chemical Formula 2]

[0384]

[0385] MS(ESI): C 21 H 14 O 282.1 m / z, found 282.7 [M+1] + .

[0386] 1 H NMR (400 MHz, DMSO-d6) δ7.57 - 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).

[0387]

[0388] Manufacturing Example 2. 6-methoxy-2,3-diphenyl-1H-inden-1-one (6-methoxy-2,3-diphenyl-1H-inden-1-one) (Compound 2)

[0389] [Reaction Formula 2]

[0390]

[0391] A round-bottomed flask containing a mixture of (2-phenylethylnyl)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 h. H2O (500 mL) was added to the resulting mixture, and extracted with EtOAc (300 mL x 3). The obtained 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-inden-1-one (3.60 g, 11.54 mmol, 57.7% yield) as a red solid.

[0392] MS (ESI) and of the compound 2 (chemical formula 3) obtained above 1 As a result of H NMR analysis, the following data were obtained:

[0393] [Chemical Formula 3]

[0394]

[0395] MS(ESI): C 22 H 16 O2312.1 m / z, found 312.8 [M+1] + .

[0396] 1 H NMR (400 MHz, DMSO-d6) δ7.47 - 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).

[0397]

[0398] Manufacturing Example 3. 2,3-diphenyl-6-propoxy-1H-inden-1-one (Compound 3)

[0399] [Reaction Formula 3]

[0400]

[0401] Step 1: Synthesis of 6-hydroxy-2,3-diphenyl-1H-inden-1-one

[0402] 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 ℃ under N2 for 24 h. 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 obtain 6-hydroxy-2,3-diphenyl-1H-inden-1-one (60 mg, 0.1911 mol, 59.70%) as a white solid.

[0403] MS (ESI): C 21 H 14 O2298.1 m / z, found 299.1 [M+1] + .

[0404] 1H NMR (400 MHz, DMSO-d6) δ10.13 (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 = 7.6 Hz, 2H), 6.78 (dd, J = 7.7, 1.9 Hz, 1H).

[0405]

[0406] Step 2: Synthesis of 2,3-diphenyl-6-propoxy-1H-inden-1-one (Compound 3)

[0407] A mixture of 6-hydroxy-2,3-diphenyl-1H-inden-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 h. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (10% EA / PE) to give 2,3-diphenyl-6-propoxy-1H-inden-1-one (30 mg, 0.0837 mmol, 49.94% yield).

[0408] MS (ESI) and of the compound 3 (chemical formula 4) obtained above 1 As a result of H NMR analysis, the following data were obtained:

[0409] [Chemical Formula 4]

[0410]

[0411] MS (ESI): C 24 H 20 O2340.1 m / z, found 341.1 [M+1] + .

[0412] 1H NMR (400 MHz, DMSO-d6) δ7.49 - 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).

[0413]

[0414] Manufacturing Example 4. 6-isopropoxy-2,3-diphenyl-1H-inden-1-one (6-isopropoxy-2,3-diphenyl-1H-inden-1-one) (Compound 4)

[0415] [Reaction Formula 4]

[0416]

[0417] Acetone (4 mL) was added to 6-hydroxy-2,3-diphenyl-1H-inden-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 mixture was reacted at 60 °C for 5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% EA / PE) to obtain 6-isopropoxy-2,3-diphenyl-1H-inden-1-one (30 mg, 0.0837 mmol, 49.94% yield).

[0418] MS (ESI) and of the compound 4 (chemical formula 5) obtained above 1 As a result of H NMR analysis, the following data were obtained:

[0419] [Chemical Formula 5]

[0420]

[0421] MS (ESI): C 24 H 20 O2340.1 m / z, found 340.8 [M+1] + .

[0422] 1 H NMR (400 MHz, DMSO-d6) δ7.49 - 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).

[0423]

[0424] Manufacturing Example 5. 2-phenyl-3-(o-tolyl)-1H-inden-1-one (2-phenyl-3-(o-tolyl)-1H-inden-1-one (Compound 5)

[0425] [Reaction Formula 5]

[0426]

[0427] Step 1: Synthesis of 2-phenyl-3-(trimethylsilyl)-1H-inden-1-one

[0428] 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) was added ACN (200 mL), followed by the addition of Co(acac)2 (2 g, 5 mmol). The reaction mixture was stirred at 80 °C under N2 for 16 h. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated in vacuo. 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 in vacuo. The concentrated residue was purified by silica gel column chromatography (10% EtOAc / PE) to obtain 2-phenyl-3-(trimethylsilyl)-1H-inden-1-one (12 g, 43 mmol, 75.44%) as a white solid.

[0429] MS (ESI): Mass calculation C 18 H 18 OSi 278.1 m / z, found 279.1 [M+1]+.

[0430]

[0431] Step 2: Synthesis of 3-bromo-2-phenyl-1H-inden-1-one

[0432] 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 DCM (100 mL). The reaction mixture was stirred at room temperature for 2 h and then extracted with DCM (100 mL x 3). The combined organic layers were washed with water and brine, dried over sodium sulfate, concentrated in vacuo 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, 66.60% yield) as a yellow solid.

[0433] MS (ESI): C 15 H9BrO 284.0 m / z, found 285.0 [M+1] + .

[0434] 1 H NMR (400 MHz, DMSO-d6) δ7.70 - 7.56 (m, 3H), 7.55 - 7.41 (m, 5H), 7.35 - 7.33 (m, 1H).

[0435]

[0436] Step 3: Synthesis of 2-phenyl-3-(o-tolyl)-1H-inden-1-one (compound 5)

[0437] 3-Bromo-2-phenyl-1H-inden-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) were added to dioxane / water (5 ml; 4:1), followed by the addition of K2CO3 (387.76 mg, 2.8056 mmol). The reaction mixture was stirred at 45 °C for 5 h. 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 in vacuo. The obtained concentrated residue was purified by prep-HPLC (Gemini 5 μm C). 18 The residue was purified by column, 150 x 21.2 mm, 30% to 90% ACN / H2O w / 0.1% FA) to give 2-phenyl-3-(o-tolyl)-1H-inden-1-one (70 mg, 0.2364 mmol, 33.72%) as a white solid.

[0438] MS (ESI) and of the compound 5 (chemical formula 6) obtained above 1 As a result of H NMR analysis, the following data were obtained:

[0439] [Chemical Formula 6]

[0440]

[0441] MS (ESI): C 22 H 16 O 296.1 m / z, found 297.1 [M+1] + .

[0442] 1H NMR (400 MHz, DMSO-d6) δ7.56 (d, J = 6.8 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.42-7.23 (m, 8H), 7.19 (dd, J = 7.2, 2.4 Hz, 2H), 6.79 (d, J = 7.2 Hz, 1H), 2.02 (s, 3H).

[0443]

[0444] Manufacturing Example 6. 3-phenyl-2-(o-tolyl)-1H-inden-1-one (3-phenyl-2-(o-tolyl)-1H-inden-1-one) (Compound 6)

[0445] [Reaction Formula 6]

[0446]

[0447] Step 1: Synthesis of 2-bromo-3-phenyl-1H-inden-1-one

[0448] 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 h. 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 in vacuo. 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%).

[0449] MS (ESI): C 15 H9BrO 284.0 m / z, found 284.6 [M+1] + .

[0450] 1H NMR (400 MHz, DMSO-d6) δ7.74 - 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).

[0451]

[0452] Step 2: Synthesis of 3-phenyl-2-(o-tolyl)-1H-inden-1-one (compound 6)

[0453] A mixture of 2-bromo-3-phenyl-1H-inden-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 h. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (10% EA / PE) to give 3-phenyl-2-(o-tolyl)-1H-inden-1-one (40 mg, 0.1282 mmol, 36.56%).

[0454] MS (ESI) and of the compound 6 (chemical formula 7) obtained above 1 As a result of H NMR analysis, the following data were obtained:

[0455] [Chemical Formula 7]

[0456]

[0457] MS (ESI): C 22 H 16 O 296.1 m / z, found 296.7 [M+1] + .

[0458] 1H NMR (400 MHz, DMSO-d6) δ7.54 (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).

[0459]

[0460] Manufacturing Example 7. 3-phenyl-2-(pyridin-3-yl)-1H-inden-1-one (3-phenyl-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 7)

[0461] [Reaction Formula 7]

[0462]

[0463] A mixture of 2-bromo-3-phenyl-1H-inden-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 h. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (10% EA / PE) to give 3-phenyl-2-(pyridin-3-yl)-1H-inden-1-one (40 mg, 0.1341 mmol, 38.24%).

[0464] MS (ESI) and of the compound 7 (chemical formula 8) obtained above 1 As a result of H NMR analysis, the following data were obtained:

[0465] [Chemical Formula 8]

[0466]

[0467] MS (ESI): C 20 H 13 NO 283.1 m / z, found 283.7 [M+1] + .

[0468] 1 H NMR (400 MHz, DMSO-d6) δ8.46 (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).

[0469]

[0470] Manufacturing Example 8. 2-morpholino-3-phenyl-1H-inden-1-one (Compound 8)

[0471] [Reaction Formula 8]

[0472]

[0473] A mixture of 2-bromo-3-phenyl-1H-inden-1-one (50 mg, 0.1754 mmol), morpholine (76.4 mg, 0.877 mmol), and toluene (3 mL) was stirred at 110 °C for 6 h. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (10% EA / PE) to give 2-morpholino-3-phenyl-1H-inden-1-one (40 mg, 0.1304 mmol, 74.34% yield).

[0474] MS (ESI) and of the compound 8 (chemical formula 9) obtained above 1 As a result of H NMR analysis, the following data were obtained:

[0475] [Chemical Formula 9]

[0476]

[0477] MS (ESI): C 19 H 17 NO2291.1 m / z, found 292.0 [M+1] + .

[0478] 1 H NMR (400 MHz, DMSO-d6) δ7.54 - 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).

[0479]

[0480] Manufacturing Example 9. 2-phenyl-3-(pyridin-3-yl)-1H-inden-1-one (2-phenyl-3-(pyridin-3-yl)-1H-inden-1-one) (Compound 9)

[0481] [Reaction Formula 9]

[0482]

[0483] To a dioxane / water (5 ml; 4:1) mixture of 3-bromo-2-phenyl-1-inden-1-one (200 mg, 0.7014 mmol), pyridin-3-ylboranediol (129.32 mg, 1.0521 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladi㎛dichloride (51.32 mg, 0.0701 mmol) was added potassium carbonate (290.82 mg, 2.1042 mmol). The reaction mixture was stirred at 45 °C for 5 h. The mixture was extracted with EtOAc (25 mL x 3), and the organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The concentrated residue was purified by prep-HPLC (Gemini 5 ㎛ C 18 Column, 150 x 21.2 mm, 0.1% FA 40% - 90% ACN / H2O) was purified to give 2-phenyl-3-(pyridin-3-yl)-1H-inden-1-one (26 mg, 0.0919 mmol, 13.10%) as a yellow solid.

[0484] MS (ESI) and of the compound 9 (chemical formula 10) obtained above 1 As a result of H NMR analysis, the following data were obtained:

[0485] [Chemical Formula 10]

[0486]

[0487] MS (ESI): C 20 H 13 NO 283.1 m / z, found 284.1 [M+1] + .

[0488] 1H NMR (400 MHz, DMSO-d6) δ8.64 (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).

[0489]

[0490] Manufacturing Example 10. 3-cyclohexyl-2-phenyl-1H-inden-1-one (Compound 10)

[0491] [Reaction Formula 10]

[0492]

[0493] Step 1: Synthesis of (cyclohexylethynyl)benzene

[0494] 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) were added THF (50 mL) and TEA (1.87 g, 18.488 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. 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 over sodium sulfate, concentrated in vacuo and purified by silica gel column chromatography (1% PE / EtOAc) to give (cyclohexylethynyl)benzene (800 mg, 4.348 mol, 47.03%) as a white oil.

[0495]

[0496] Step 2: Synthesis of 3-cyclohexyl-2-phenyl-1H-inden-1-one (Compound 10)

[0497] (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 ACN (10 mL). The reaction mixture was stirred at 80 °C for 16 h. 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 purified by prep-HPLC (Gemini 5 μm C). 18 Column, 150 x 21.2 mm, 0.1% FA 60%- 90% ACN / H2O) was purified to obtain 3-cyclohexyl-2-phenyl-1H-inden-1-one (100 mg, 0.3472 mmol, 25.59%).

[0498] MS (ESI) and of the compound 10 (chemical formula 11) obtained above 1 As a result of H NMR analysis, the following data were obtained:

[0499] [Chemical Formula 11]

[0500]

[0501] MS (ESI): C 21 H 20 O 288.2 m / z, found 289.2 [M+1] + .

[0502] 1H NMR (400 MHz, DMSO-d6) δ7.61 (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).

[0503]

[0504] Manufacturing Example 11. 2-cyclohexyl-3-phenyl-1H-inden-1-one (Compound 11)

[0505] [Reaction Formula 11]

[0506]

[0507] 2-Bromo-3-phenyl-1H-inden-1-one (300 mg, 1.052 mmol), cyclohexylboranediol (269.3 mg, 2.104 mmol), and Pd(OAc)2 (23.6 mg, 0.105 mmol) were sequentially added THF (20 ml), P(o-tol)3 (64.2 mg, 0.210 mmol), and Ag2O (1219.1 mg, 5.26 mmol). The reaction mixture was stirred at 85 °C for 16 h. The mixture was extracted with DCM (60 mL x 3). The obtained organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The concentrated residue was purified by prep-HPLC (Gemini 5 μm C). 18 Column, 150 x 21.2 mm, 0.1% FA 60 - 90% ACN / H2O) was purified to give 2-cyclohexyl-3-phenyl-1H-inden-1-one (23 mg, 0.0799 mmol, 7.81%) as a white solid.

[0508] MS (ESI) and of the compound 11 (chemical formula 12) obtained above 1As a result of H NMR analysis, the following data were obtained:

[0509] [Chemical Formula 12]

[0510]

[0511] MS (ESI): C 21 H 20 O 288.2 m / z, found 289.2 [M+1]+.

[0512] 1 H NMR (400 MHz, CDCl3) δ7.58 - 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).

[0513]

[0514] Manufacturing Example 12. 6-morpholino-2,3-diphenyl-1H-inden-1-one (Compound 12)

[0515] [Reaction Formula 12]

[0516]

[0517] Step 1: Synthesis of 6-chloro-2,3-diphenyl-1H-inden-1-one

[0518] 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) were added dioxane (60 mL), sodium carbonate (1.78 g, 0.0168 mol), and tetrabutylammoni㎛ bromide (1.81 g, 0.0056 mol). The reaction mixture was stirred at 100 °C under CO. After cooling to room temperature, the mixture was passed through Celite, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and it was extracted with EtOAc (100 mL x 3). The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% PE / EtOAc) to obtain 6-chloro-2,3-diphenyl-1H-inden-1-one (320 mg, 1.0126 mmol, 18.08%) as a white solid.

[0519]

[0520] Step 2: Synthesis of 6-morpholino-2,3-diphenyl-1H-inden-1-one (Compound 12)

[0521] 6-Chloro-2,3-diphenyl-1H-inden-1-one (150 mg, 0.4735 mmol), morpholine (82.5 mg, 0.947 mmol) and xphosPdG3 (40.06 mg, 0.0473 mmol) were added dioxane (6 ml) and Cs2CO3 (308.55 mg, 0.947 mmol). was added. The reaction mixture was stirred at 100°C for 16 h. 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. prep-HPLC (Gemini 5 μm C18 Column, 150 x 21.2 mm, 0.1% TFA 30 - 90% ACN / H2O) was purified to give 6-morpholino-2,3-diphenyl-1H-inden-1-one (41 mg, 0.1117 mmol, 23.59%) as a yellow solid.

[0522] MS (ESI) and of the compound 12 (chemical formula 13) obtained above 1 As a result of H NMR analysis, the following data were obtained:

[0523] [Chemical Formula 13]

[0524]

[0525] MS (ESI): C 25 H 21 NO2367.2 m / z, found 368.2 [M+1] + .

[0526] 1 H NMR (400 MHz, DMSO-d6) δ7.50 - 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).

[0527]

[0528] Manufacturing 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)

[0529] [Reaction Formula 13]

[0530]

[0531] To 6-chloro-2,3-diphenylinden-1-one (150 mg, 0.4735 mmol), 1-methylpiperazine (94.7 mg, 0.947 mmol), and xphosPdG3 (40.06 mg, 0.0473 mmol) were added dioxane (6 mL) and Cs2CO3 (308.55 mg, 0.947 mmol). The reaction mixture was stirred at 100 °C for 16 h. The mixture was extracted with EtOAc (30 mL x 3), and the organic layer was washed with water and brine, dried over sodium sulfate, concentrated under reduced pressure, and purified by prep-HPLC (Gemini 5 μm C). 18 Column, 150 x 21.2 mm, 0.1% FA 30-90% ACN / H2O) was purified to give 6-(4-methylpiperazin-1-yl)-2,3-diphenyl-1H-inden-1-one (35 mg, 0.0921 mmol, 19.45%) as a yellow solid.

[0532] MS (ESI) and of the compound 13 (chemical formula 14) obtained above 1 As a result of H NMR analysis, the following data were obtained:

[0533] [Chemical Formula 14]

[0534]

[0535] MS (ESI): C 26 H 24 N2O 380.2 m / z, found 381.2 [M+1] + .

[0536] 1 H NMR (400 MHz, DMSO-d6) δ7.49 - 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, 2.0 Hz, 1H), 3.34 - 3.16 (m, 4H), 2.48 - 2.35 (m, 4H), 2.22 (s, 3H).

[0537]

[0538] Manufacturing Example 14. 3-(4-morpholinophenyl)-2-phenyl-1H-inden-1-one (3-(4-morpholinophenyl)-2-phenyl-1H-inden-1-one) (Compound 14)

[0539] [Reaction Formula 14]

[0540]

[0541] To a solution of 3-bromo-2-phenyl-1H-inden-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) were added dioxane / water (5 ml; 4:1) and potassium carbonate (290.82 mg, 2.1042 mmol). The reaction mixture was stirred at 45 °C for 5 h. The mixture was extracted with EtOAc (30 mL x 3), and the organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. Then, it was purified by prep-HPLC (Gemini 5 μm C18 column, 150 x 21.2 mm, 0.1% FA 40 - 90% ACN / H2O) to obtain 3-(4-morpholinophenyl)-2-phenyl-1H-inden-1-one (70 mg, 0.1907 mmol, 27.19% yield).

[0542] MS (ESI) and of the compound 14 (chemical formula 15) obtained above 1 As a result of H NMR analysis, the following data were obtained:

[0543] [Chemical Formula 15]

[0544]

[0545] MS (ESI): Mass calculation C 25 H 21NO2367.2 m / z, found 368.2 [M+1]+.

[0546] 1 H NMR (400 MHz, DMSO-d6) δ7.51 (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).

[0547]

[0548] Manufacturing Example 15. 3-(3-morpholinophenyl)-2-phenyl-1H-inden-1-one (3-(3-morpholinophenyl)-2-phenyl-1H-inden-1-one) (Compound 15)

[0549] [Reaction Formula 15]

[0550]

[0551] To a solution of 3-bromo-2-phenyl-1H-inden-1-one (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) were added dioxane / water (5 ml; 4:1) and potassium carbonate (290.82 mg, 2.1042 mmol). The reaction mixture was stirred at 45 °C for 5 h. 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, it was purified by prep-HPLC (Gemini 5 μm C18 column, 150 x 21.2 mm, 0.1% FA 40% - 90% ACN / H2O) to obtain 3-(3-morpholinophenyl)-2-phenyl-1H-inden-1-one (135 mg, 0.3678 mmol, 52.44%).

[0552] MS (ESI) and of the compound 15 (chemical formula 16) obtained above 1 As a result of H NMR analysis, the following data were obtained:

[0553] [Chemical Formula 16]

[0554]

[0555] MS (ESI): C 25 H 21 NO2367.2 m / z, found 368.2 [M+1]+.

[0556] 1 H NMR (400 MHz, DMSO-d6) δ7.58 - 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).

[0557]

[0558] Manufacturing Example 16. 3-(4-(morpholinomethyl)phenyl)-2-phenyl-1H-inden-1-one (3-(4-(morpholinomethyl)phenyl)-2-phenyl-1H-inden-1-one) (Compound 16)

[0559] [Reaction Formula 16]

[0560]

[0561] 3-Bromo-2-phenyl-1H-inden-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) were added to potassium carbonate (290.82 mg, 2.1042 mmol) in dioxane / water (5 ml; 4:1). The reaction mixture was stirred at 45 °C for 5 h. 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 in vacuo. Then, it was purified by prep-HPLC (Gemini 5 μm C18 column, 150 x 21.2 mm, 40% to 90% ACN / H2O containing 0.1% FA) to give 3-(4-(morpholinomethyl)phenyl)-2-phenyl-1H-inden-1-one (100 mg, 0.2625 mmol, 37.42% yield).

[0562] MS (ESI) and of the compound 16 (chemical formula 17) obtained above 1 As a result of H NMR analysis, the following data were obtained:

[0563] [Chemical Formula 17]

[0564]

[0565] MS (ESI): C 26 H 23 NO2381.2 m / z, found 382.2 [M+1]+.

[0566] 1H NMR (400 MHz, DMSO-d6) δ7.55 (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).

[0567]

[0568] Manufacturing Example 17. 2-(4-morpholinophenyl)-3-phenyl-1H-inden-1-one (2-(4-morpholinophenyl)-3-phenyl-1H-inden-1-one) (Compound 17)

[0569] [Reaction Formula 17]

[0570]

[0571] A mixture of 2-bromo-3-phenyl-1H-inden-1-one (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 h. The mixture was passed through Celite, 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-inden-1-one (60 mg, 0.1551 mmol, 44.23%).

[0572] MS (ESI) and of the compound 17 (chemical formula 18) obtained above 1 As a result of H NMR analysis, the following data were obtained:

[0573] [Chemical Formula 18]

[0574]

[0575] MS (ESI): C 25 H 21 NO2367.2 m / z, found 368.1 [M+1]+

[0576] 1 H NMR (400 MHz, DMSO-d6) δ7.53 - 7.44 (m, 5H), 7.41 (dd,J= 7.7, 1.6 Hz, 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).

[0577]

[0578] Manufacturing Example 18. 2-(3-morpholinophenyl)-3-phenyl-1H-inden-1-one (2-(3-morpholinophenyl)-3-phenyl-1H-inden-1-one) (Compound 18)

[0579] [Reaction Formula 18]

[0580]

[0581] A mixture of 2-bromo-3-phenyl-1H-inden-1-one (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 h. The mixture was passed through Celite, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (20% EA / PE) to obtain 2-(3-morpholinophenyl)-3-phenyl-1H-inden-1-one (50 mg, 0.1293 mmol, 36.87%).

[0582] MS (ESI) and of the compound 18 (chemical formula 19) obtained above 1As a result of H NMR analysis, the following data were obtained:

[0583] [Chemical Formula 19]

[0584]

[0585] MS (ESI): C 25 H 21 NO2367.2 m / z, found 367.7 [M+1]+.

[0586] 1 H NMR (400 MHz, DMSO-d6) δ7.54 (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).

[0587]

[0588] Manufacturing Example 19. 3-(4-methylthiazol-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)

[0589] [Reaction Formula 19]

[0590]

[0591] Step 1: Synthesis of 4-methyl-5-((trimethylsilyl)ethynyl)thiazole

[0592] To a solution of 5-bromo-4-methyl-1,3-thiazole (1 g, 0.0056 mol), ethynyltrimethylsilane (1.1 g, 0.0112 mmol), and copper(I) iodide (0.11 g, 0.0005 mol) were added TEA (20 mL) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (0.41 g, 0.0005 mol). The reaction mixture was stirred at 60 °C for 12 h under N2. After cooling to room temperature, the reaction mixture was passed through Celite, and the 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 over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (10% EtOAc / PE) to give 4-methyl-5-((trimethylsilyl)ethynyl)thiazole (800 mg, 4.1026 mmol, 73.26% yield) as a red oil.

[0593] MS (ESI): C9H 13 NSSi 195.1 m / z, found 196.1 [M+1]+.

[0594]

[0595] Step 2: Synthesis of 3-(4-methylthiazol-5-yl)-2-(trimethylsilyl)-1H-inden-1-one

[0596] 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) were added dioxane (40 mL), sodium carbonate (813.7 mg, 7.677 mmol), and tetrabutylammoni㎛ bromide (824.9 mg, 2.559 mmol). The reaction mixture was stirred at 100 °C under CO. 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. The residue was then purified by silica gel column chromatography (15% EtOAc / PE) to afford 3-(4-methylthiazol-5-yl)-2-(trimethylsilyl)-1H-inden-1-one (200 mg, 0.6667 mol, 26.05%) as a yellow solid.

[0597]

[0598] Step 3: Synthesis of 2-bromo-3-(4-methylthiazol-5-yl)-1H-inden-1-one

[0599] To 3-(4-methyl-thiazol-5-yl)-2-(trimethylsilyl)inden-1-one (200 mg, 0.668 mmol) was added DCM (5 ml) and N-bromosuccinimide (237.8 mg, 1.336 mmol). The reaction mixture was stirred at 40 °C for 1 h. 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-methylthiazol-5-yl)-1H-inden-1-one (160 mg, 0.5246 mol, 78.53%) as a yellow solid.

[0600]

[0601] Step 4: Synthesis of 3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 19)

[0602] To a solution of 2-bromo-3-(4-methyl-thiazol-5-yl)-1H-inden-1-one (160 mg, 0.5232 mmol), pyridin-3-ylboranediol (128.64 mg, 1.0464 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (38.24 mg, 0.0512 mmol) were added dioxane / water (8 mL; 4:1) and potassium carbonate (216.96 mg, 1.5696 mmol). The reaction mixture was stirred at 70 °C for 6 h. 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 purified by prep-HPLC (Gemini 5 ㎛ C 18Column, 150 x 21.2 mm, 0.1% FA 30 - 90% ACN / H2O) was purified to give 3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (30 mg, 0.0986 mmol, 18.86%) as a yellow solid.

[0603] MS (ESI) and of the compound 19 (chemical formula 20) obtained above 1 As a result of H NMR analysis, the following data were obtained:

[0604] [Chemical Formula 20]

[0605]

[0606] MS (ESI): C 18 H 12 N2OS 304.1 m / z, found 305.1 [M+1]+.

[0607] 1 H NMR (400 MHz, DMSO) δ9.32 (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).

[0608]

[0609] Manufacturing Example 20. 3-(4-methylthiazol-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)

[0610] [Reaction Formula 20]

[0611]

[0612] Step 1: Synthesis of (E)-1-(2-bromo-5-chlorophenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one

[0613] 5-Methyl-1,3-thiazole-4-carbaldehyde (2 g, 0.0086 mol) and 1-(3-hydroxyphenyl)ethanone (1.2 g, 0.0094 mol) were added to EtOH (30 mL) and stirred at 20-25 °C for 10 minutes. After cooling the solution to 0-5 °C, H2O (5 mL) and NaOH (516 mg, 0.0129 mol) were added. Then, the mixture was stirred at room temperature for 4 hours, the pH was adjusted to 7 with 1 N HCl, and the obtained solid was filtered to obtain (E)-1-(2-bromo-5-chlorophenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one (2.1 g, 0.0061 mmol, 70.93%).

[0614]

[0615] Step 2: Synthesis of 6-chloro-3-(4-methylthiazol-5-yl)-1H-inden-1-one

[0616] (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) were added DMF (50 mL) and potassium carbonate (1.6 g, 11.6744 mmol). The reaction mixture was stirred at 100 °C for 4 h. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and it was extracted 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 by silica gel column chromatography (2% MeOH / DCM) afforded 6-chloro-3-(4-methylthiazol-5-yl)-1H-inden-1-one (550 mg, 2.1072 mmol, 36.33%) as a yellow solid.

[0617]

[0618] Step 3: Synthesis of 2-bromo-6-chloro-3-(4-methylthiazol-5-yl)-1H-inden-1-one

[0619] To 6-chloro-3-(4-methylthiazol-5-yl)-1H-inden-1-one (400 mg, 1.5283 mmol) was added DCM (5 ml) and Br2 (268.66 mg, 1.6811 mmol). The reaction mixture was stirred at 0 °C for 2 h. Water was added to the reaction mixture, and 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, 67.37% yield) as a yellow solid.

[0620]

[0621] Step 4: Synthesis of 6-chloro-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one

[0622] To a solution of 2-bromo-6-chloro-3-(4-methylthiazol-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) was added dioxane / water (10 ml; 4:1) and Na2CO3 (124.4 mg, 1.174 mmol). The reaction mixture was stirred at 90 °C for 5 h. The mixture was passed through Celite, 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 over sodium sulfate, concentrated in vacuo and purified by silica gel column chromatography (10% MEOH / DCM) to obtain 6-chloro-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (170 mg, 0.5060 mmol, 86.20%).

[0623]

[0624] Step 5: Synthesis of 3-(4-methylthiazol-5-yl)-6-((3-phenylpropyl)amino)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 20)

[0625] To a solution of 6-chloro-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (100 mg, 0.2951 mmol), 2-phenylethanamine (71.52 mg, 0.5902 mmol), and xphosPdG3 (24.97 mg, 0.0295 mmol) were added dioxane (7 ml) and Cs2CO3 (288.45 mg, 0.8853 mmol). The reaction mixture was stirred at 100 °C for 16 h under N2. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. 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 in vacuo and purified by prep-HPLC (Gemini 5 μm C18 column, 150 x 21.2 mm, 0.1% FA 30 - 90% ACN / H2O) to afford 3-(4-methylthiazol-5-yl)-6-((3-phenylpropyl)amino)-2-(pyridin-3-yl)-1H-inden-1-one (40 mg, 0.0915 mmol, 31.01%) as a red solid.

[0626] MS (ESI) and of the compound 20 (chemical formula 21) obtained above 1 As a result of H NMR analysis, the following data were obtained:

[0627] [Chemical Formula 21]

[0628]

[0629] MS (ESI): C 27 H 23 N3OS 437.2 m / z, found 438.2 [M+1]+.

[0630] 1H NMR (400 MHz, DMSO-d6) δ9.28 (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).

[0631]

[0632] Manufacturing Example 21. 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)

[0633] [Reaction Formula 21]

[0634]

[0635] Step 1: Synthesis of (E)-1-(3-hydroxyphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one

[0636] To a solution of 1-(3-hydroxyphenyl)ethanone (4.50 g, 33.1 mmol) and 4-methyl-1,3-thiazole-5-carbaldehyde (6.31 g, 49.6 mmol) in ethanol (100 mL) was added NaOH solution (2.65 g, 66.2 mmol, 20 mL H2O) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. 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), and the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain (E)-1-(3-hydroxyphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one (2.8 g, 90% purity, 10.3 mmol, 31.1% yield) as a yellow solid.

[0637] MS (ESI): C 13 H 11 NO2S 245.1 m / z, found 246.1 [M+1]+.

[0638]

[0639] Step 2: Synthesis of 6-hydroxy-3-(4-methylthiazol-5-yl)-2,3-dihydro-1H-inden-1-one

[0640] (E)-1-(3-Hydroxyphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one (2.2 g, 9.00 mol) was added portionwise to HOTf (25 mL) at 0 to 5 °C. The resulting mixture was stirred at 25 °C for 16 h and concentrated. Then, it was dissolved in DCM / water (50 mL / 50 mL) and extracted with DCM (2 x 50 mL). The residue was dried and concentrated under reduced pressure to afford 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) as a yellow solid.

[0641] MS (ESI): C 13 H 11 NO2S 245.1 m / z, found 246.1 [M+1]+.

[0642]

[0643] Step 3: Synthesis of 1-(4-methylthiazol-5-yl)-3-oxo-2,3-dihydro-1H-inden-5-yl acetate

[0644] To a solution of 6-hydroxy-3-(4-methylthiazol-5-yl)-2,3-dihydro-1H-inden-1-one (2.2 g, 8.98 mmol) and pyridine (2.14 g, 26.9 mmol) in DCM (30 mL) at 0°C was added Ac2O (2.76 g, 26.9 mmol). The reaction mixture was stirred at 25°C for 3 h, and water (50 mL) was added. Afterwards, extraction 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 obtain 1-(4-methylthiazol-5-yl)-3-oxo-2,3-dihydro-1H-inden-5-yl acetate (2.4 g, 95% purity, 7.94 mmol, 88.4% yield) as a yellow solid.

[0645] MS (ESI): C 15 H 13 NO3S 287.1 m / z, found 288.1 [M+1]+.

[0646]

[0647] Step 4: Synthesis of 2-bromo-3-(4-methylthiazol-5-yl)-1-oxo-1H-inden-6-yl acetate

[0648] A mixture of 1-(4-methylthiazol-5-yl)-3-oxo-2,3-dihydro-1H-inden-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 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (15% EtOAc / PE) to afford 2-bromo-3-(4-methylthiazol-5-yl)-1-oxo-1H-inden-6-yl acetate (1.42 g, 80% purity, 3.12 mmol, 73.4%) as a red oil.

[0649] MS (ESI): C 15 H 10 BrNO3S 363.0 m / z, found 364.1 [M+1]+.

[0650]

[0651] Step 5: Synthesis of 6-hydroxy-2-(4-methylpyridin-3-yl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one

[0652] 2-Bromo-3-(4-methylthiazol-5-yl)-1-oxo-1H-inden-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), K2CO3 (1.62 g, 1.17 mmol) were added with dioxane (15 mL) and water (3 mL), and the mixture was stirred at 90 °C for 16 h. Water (30 mL) was added to the obtained mixture, and the mixture was extracted with 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-methylthiazol-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 compound with 70% purity was purified by prep-HPLC (Gemini 5 μm C 18 Secondary purification using column, 150 x 21.2 mm, 0.1% FA 22 - 55% ACN / H2O) gave 20 mg of the title compound with 98% purity.

[0653] MS (ESI): C 19 H 14 N2O2S 334.1 m / z, found 349.1 [M+1]+.

[0654] 1 H NMR (400 MHz, DMSO-d6) δ10.37 (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).

[0655]

[0656] Step 6: Synthesis of 2-(4-methylpyridin-3-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one (Compound 21)

[0657] 6-Hydroxy-2-(4-methylpyridin-3-yl)-3-(4-methylthiazol-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 h. The resulting mixture was added with water (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated, and purified by prep-HPLC (Gemini 5 μm C). 18 Column, 150 x 21.2 mm, 0.1% NH3H2O ​​65 - 95% ACN / H2O) was purified to give 2-(4-methylpyridin-3-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one (Compound 21) (60 mg, 95.6% purity, 0.126 mmol, 17.5% yield).

[0658] MS (ESI) and of the compound 21 (chemical formula 22) obtained above 1 As a result of H NMR analysis, the following data were obtained:

[0659] [Chemical Formula 22]

[0660]

[0661] MS (ESI): C 28 H 24 N2O2S 452.2 m / z, found 453.2 [M+1]+.

[0662] 1 H NMR (400 MHz, DMSO-d6) δ9.24 (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).

[0663]

[0664] Manufacturing Example 22. 6-methoxy-2-(4-methylpyridin-3-yl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one (6-methoxy-2-(4-methylpyridin-3-yl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one) (Compound 22)

[0665] [Reaction Formula 22]

[0666]

[0667] Step 1: Synthesis of (E)-1-(2-bromo-5-methoxyphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one

[0668] 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 ethanol (50 mL) at 0°C was added NaOH solution (2.39 g, 0.06 mol in H2O (10 mL)). The resulting mixture was stirred at 25°C for 16 h, and water (100 mL) was added. Then, the organic layer was extracted with DCM (100 x 3), washed with brine, dried over Na2SO4, concentrated and purified by silica gel column chromatography (5 -10% MeOH / DCM) to give (E)-1-(2-bromo-5-methoxyphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one (3) (6.6 g, 80% purity, 0.157 mol, 78.1% yield) as a yellow solid.

[0669] MS (ESI): C 14 H 12 BrNO2337.0 m / z, found 338.1 [M+1]+.

[0670]

[0671] Step 2: Synthesis of 6-methoxy-3-(4-methylthiazol-5-yl)-1H-inden-1-one

[0672] (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), K2CO3 (6.12 g, 44.3 mmol) was added DMF (60 mL) and stirred at 110 °C for 16 h. After cooling to room temperature, water (200 mL) was added to the obtained mixture and extracted with EtOAc (150 mL x 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-methylthiazol-5-yl)-1H-inden-1-one (22-4) (600 mg, 95% purity, 2.22 mmol, 12.5% ​​yield) as a yellow solid.

[0673] MS (ESI): C 14 H 11 NO2S 257.1 m / z, found 258.1 [M+1]+.

[0674]

[0675] Step 3: Synthesis of 2-bromo-6-methoxy-3-(4-methylthiazol-5-yl)-1H-inden-1-one

[0676] 6-Methoxy-3-(4-methylthiazol-5-yl)-1H-inden-1-one (22-4) (600 mg, 2.33 mmol), NBS (498 mg, 2.80 mmol), AIBN (76.6 mg, 0.466 mmol) was added CCl4 (12 mL), and the mixture was stirred at 70 °C for 3 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (15% EtOAc / PE) to obtain 2-bromo-6-methoxy-3-(4-methylthiazol-5-yl)-1H-inden-1-one (22-5) (400 mg, 80% purity, 0.952 mmol, 40.8% yield).

[0677] MS (ESI): C 14 H 10 BrNO2S 335.0 m / z, found 336.1 [M+1]+.

[0678]

[0679] Step 4: Synthesis of 6-methoxy-2-(4-methylpyridin-3-yl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one (Compound 22)

[0680] 2-Bromo-6-methoxy-3-(4-methylthiazol-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, 0.595 mmol), K2CO3 (493 mg, 3.57 mmol) were added with dioxane (8 mL) and water (2 mL), and stirred at 85°C for 16 h. Water (30 mL) was added to the obtained mixture, and extracted with EtOAc (30 mL x 3). The combined organic phase was 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-methylthiazol-5-yl)-1H-inden-1-one (compound 22) (300 mg, 90% purity, 0.776 mmol, 65.1% yield) as a yellow solid. 190 mg of compound 22 with 90% purity was purified by prep-HPLC (Gemini 5 μm C 18 column, 150 x 21.2 mm, 0.1% FA 25 - 70% ACN / H2O) and obtained 91 mg (99% purity).

[0681] MS (ESI) and of the compound 22 (chemical formula 23) obtained above 1 As a result of H NMR analysis, the following data were obtained:

[0682] [Chemical Formula 23]

[0683]

[0684] MS (ESI): C 20 H 16 N2O2S 348.1 m / z, found 349.1 [M+1]+.

[0685] 1H NMR (400 MHz, DMSO-d6) δ9.26 (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).

[0686]

[0687] Manufacturing Example 23. 3-(5-methylthiazol-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)

[0688] [Reaction Formula 23]

[0689]

[0690] Step 1: Synthesis of methyl 5-methylthiazole-4-carboxylate

[0691] To a solution of tert-butyl nitrite (31 mL, 290.7 mmol) in 1,4-dioxane (240 mL) was added a solution of methyl 2-amino-5-methylthiazole-4-carboxylate (10 g, 58.1 mmol) in 1,4-dioxane (90 mL). The solution was stirred at 60 °C for 1 h. After cooling to room temperature, the solvent was evaporated, and the residue was purified by flash chromatography (0-20% EtOAc / hexanes) to obtain methyl 5-methylthiazole-4-carboxylate (5.0 g, 31.8 mmol, 55% yield).

[0692]

[0693] Step 2: Synthesis of 5-methylthiazole-4-carbaldehyde (23-3)

[0694] A -78 °C solution of methyl 5-methylthiazole-4-carboxylate (5 g, 31.8 mmol) in DCM (100 mL) was added to a solution of diisobutylaluminum hydride (1 M in THF, 34 mL, 34 mmol). The mixture was stirred at -78 °C for 2 h. Diisobutylaluminum hydride (1 M in toluene, 10 mL, 10 mmol) was added and stirred for 2 h at -78 °C. The reaction mixture was quenched by adding Rochelle's salt solution (500 mL), and DCM (200 mL) was further added. The mixture was stirred very rapidly until the layers were well separated. After separating the organic layer, it was dried over MgSO4, filtered, evaporated, and dried in vacuo to obtain 5-methylthiazole-4-carbaldehyde (2.5 g, 19.7 mmol, 61.95% yield).

[0695]

[0696] Step 3: Synthesis of (E)-1-(3-hydroxyphenyl)-3-(5-methylthiazol-4-yl)prop-2-en-1-one

[0697] A solution of 5-methylthiazole-4-carbaldehyde (2.5 g, 19.69 mmol) and 1-(3-hydroxyphenyl)ethan-1-one (2.9 g, 21.65 mmol) in EtOH (30 mL) was stirred at 20-25 °C for 10 min. The above solution was stirred at 0-5 ℃) with NaOH solution (1.2 g, 29.52 mmol in H2O (12.5 mL). Then, the mixture was stirred at room temperature for 12 hours, and the pH was adjusted to 7 with 1 N HCl, and then filtered to obtain (E)-1-(3-hydroxyphenyl)-3-(5-methylthiazol-4-yl)prop-2-en-1-one (2.0 g, 8.16 mmol, 41.43% yield).

[0698] MS (ESI): C 13 H 11 NO2S 245.1 m / z, found 246.1 [M+1]+.

[0699]

[0700] Step 4: Synthesis of 6-hydroxy-3-(5-methylthiazol-4-yl)-2,3-dihydro-1H-inden-1-one

[0701] (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) at 0 °C. The mixture was stirred at room temperature for 16 h, and the pH was adjusted to 8 with aqueous NaHCO3 solution. The mixture was filtered to obtain 6-hydroxy-3-(5-methylthiazol-4-yl)-2,3-dihydro-1H-inden-1-one (1.3 g, 5.3 mmol, 64.71% yield).

[0702]

[0703] Step 5: Synthesis of 1-(5-methylthiazol-4-yl)-3-oxo-2,3-dihydro-1H-inden-5-yl acetate

[0704] To a solution of 6-hydroxy-3-(5-methylthiazol-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, 1.0582 mmol) was added DCM (40 ml), and Ac2O (1.6 g, 15.8964 mmol) was added. The reaction mixture was stirred at 25 °C for 3 h. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and it was extracted with DCM (90 mL x 3). The organic layer was washed with water and brine, dried over sodium sulfate, concentrated in vacuo and purified by silica gel column chromatography (50% EtOAc / PE) to give 1-(5-methylthiazol-4-yl)-3-oxo-2,3-dihydro-1H-inden-5-yl acetate (1.2 g, 4.1811 mmol, 78.91% yield) as a yellow solid.

[0705] MS (ESI): C 15 H 13 NO3S 287.1 m / z, found 288.1 [M+1]+.

[0706]

[0707] Step 6: Synthesis of 2-bromo-3-(5-methylthiazol-4-yl)-1-oxo-1H-inden-6-yl acetate

[0708] CCl4 (20 ml) was added to 1-(5-methylthiazol-4-yl)-3-oxo-2,3-dihydro-1H-inden-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 h. Water was added to the residue, and it was extracted with DCM (40 mL x 3). The organic layer was washed with water and brine, dried over sodium sulfate, concentrated in vacuo and purified by silica gel column chromatography (50% EtOAc / PE) to give 2-bromo-3-(5-methylthiazol-4-yl)-1-oxo-1H-inden-6-yl acetate (500 mg, 0.0014 mol, 39.25% yield) as a yellow solid.

[0709]

[0710] Step 7: Synthesis of 6-hydroxy-3-(5-methylthiazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one

[0711] To a solution of 2-bromo-3-(5-methylthiazol-4-yl)-1-oxo-1H-inden-6-yl acetate (500 mg, 1.3725 mmol), pyridin-3-ylboranediol (253 mg, 2.0575 mmol), and Pd(dppf)Cl2DCM (112 mg, 0.135 mmol) were added dioxane / water (20 ml; 4:1) and potassium carbonate (380 mg, 2.745 mmol). The reaction mixture was stirred at 80 °C for 5 h under N2. The residue was diluted with water and extracted with EtOAc (60 mL x 3). The organic layer was washed with water and brine, dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (10% MEOH / DCM) to afford 6-hydroxy-3-(5-methylthiazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one (250 mg, 0.7813 mol, 56.92% yield) as a red solid.

[0712]

[0713] 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)

[0714] 6-Hydroxy-3-(5-methylthiazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one (200 mg, 0.624 mmol), 4-(3-bromopropyl)pyridine (187.3 mg, 0.936 mmol) and potassium carbonate (172.5 mg, 1.248 mmol) were added DMF (8 ml). The reaction mixture was stirred at 40 °C for 8 h. The mixture was extracted with EtOAc (40 mL x 3), and the organic layer was washed with water and brine. The mixture was dried over sodium sulfate and concentrated in vacuo. Prep-HPLC (Gemini 5 μm C) 18 The residue was purified by column chromatography (150 x 21.2 mm, 0.1% FA 30 - 90% ACN / H2O) to afford 3-(5-methylthiazol-4-yl)-2-(pyridin-3-yl)-6-(3-(pyridin-4-yl)propoxy)-1H-inden-1-one (25 mg, 0.0569 mmol, 9.12% yield) as a red solid.

[0715] MS (ESI) and of the compound 23 (chemical formula 24) obtained above 1 As a result of H NMR analysis, the following data were obtained:

[0716] [Chemical Formula 24]

[0717]

[0718] MS (ESI): C 26 H 21 N3O2S 439.1 m / z, found 440.1 [M+1]+.

[0719] 1H NMR (400 MHz, CDCl3) δ8.86 (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).

[0720]

[0721] Manufacturing 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)

[0722] [Reaction Formula 24]

[0723]

[0724] Step 1: Synthesis of (E)-1-(3-hydroxyphenyl)-3-(1-methyl-1H-pyrazol-3-yl)prop-2-en-1-one

[0725] 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 in H2O (11 ml)) was added at 0-5 ℃, stirred at room temperature for 16 hours, adjusted to pH 7 with 1 N HCl, and filtered to obtain (E)-1-(3-hydroxyphenyl)-3-(1-methyl-1H-pyrazol-3-yl)prop-2-en-1-one (7.2 g, 31.57 mmol, 85.91% yield).

[0726]

[0727] Step 2: Synthesis of 6-hydroxy-3-(1-methyl-1H-pyrazol-3-yl)-2,3-dihydro-1H-inden-1-one

[0728] (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) at 0°C, the solution was stirred at room temperature for 12 h, the pH was adjusted to 8 with aqueous NaHCO3 solution, and then filtered to obtain 6-hydroxy-3-(1-methyl-1H-pyrazol-3-yl)-2,3-dihydro-1H-inden-1-one (3.1 g, 13.60 mmol, 77.51% yield).

[0729] MS (ESI): C 13 H 12 N2O2228.1 m / z, found 229.1 [M+1]+.

[0730]

[0731] Step 3: Synthesis of 1-(1-methyl-1H-pyrazol-3-yl)-3-oxo-2,3-dihydro-1H-inden-5-yl acetate

[0732] 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) were added to DCM (30 ml), and 4-dimethylaminopyridine (0.27 g, 0.0022 mol) was added. The reaction mixture was stirred at room temperature for 4 h. 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 in vacuo. Then, the residue 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-inden-5-yl acetate (2.0 g, 0.0074 mmol, 66.73% yield).

[0733] MS (ESI): C 15 H 14 N2O3270.1 m / z, found 271.1 [M+1]+.

[0734]

[0735] Step 4: Synthesis of 2-bromo-3-(1-methyl-1H-pyrazol-3-yl)-1-oxo-1H-inden-6-yl acetate (Compound 24)

[0736] To 1-(1-methyl-1H-pyrazol-3-yl)-3-oxo-2,3-dihydro-1H-inden-5-yl acetate (1 g, 3.7 mmol), AIBN (0.120 g, 0.7 mmol), and NBS (0.79 g, 4.4 mmol) was added CCl4 (20 ml). The reaction mixture was stirred at 80 °C for 2 h. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. Water was added to the residue, and the mixture was extracted with DCM (60 mL x 3). The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. 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-inden-6-yl acetate (400 mg, 1.1527 mmol, 31.55% yield) as a white solid.

[0737] MS (ESI) of the above-obtained compound 24 (chemical formula 25 below) and 1 As a result of H NMR analysis, the following data were obtained:

[0738] [Chemical Formula 25]

[0739]

[0740] MS (ESI): C 15 H 11 BrN2O3346.0 m / z, found 347.0 [M+1]+.

[0741] 1 H NMR (400 MHz, DMSO-d6) δ8.32 (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).

[0742]

[0743] Manufacturing Example 25. 3-(4-methylthiazol-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)

[0744] [Reaction Formula 25]

[0745]

[0746] Step 1: Synthesis of 2-bromo-6-hydroxy-3-(4-methylthiazol-5-yl)-1H-inden-1-one

[0747] K2CO3 (11 g, 0.08 mmol) was added to a methanol (260 mL) solution of 2-bromo-3-(4-methylthiazol-5-yl)-1-oxo-1H-inden-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 extracted with DCM (200 mL x 3). The organic layer was washed by a conventional method, dried, and concentrated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (3% MeOH / DCM) to obtain the desired title compound (12 g, 93%) as a white solid.

[0748]

[0749] Step 2: Synthesis of 2-bromo-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one

[0750] To a solution of 2-bromo-6-hydroxy-3-(4-methylthiazol-5-yl)- 1H-inden-1-one (12 g, 0.04 mol), 3-phenylpropan-1-ol (11 g, 0.08 mmol) and triphenylphosphine (21 g, 0.08 mmol) in THF (500 mL) was added diisopropyl azodicarboxylate (16 g, 0.08 mmol) and stirred at room temperature for 16 h. Water (200 mL) was added to the reaction mixture and extracted with DCM (300 mL x 3). The organic layer was washed by a conventional method, dried and concentrated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (1% MeOH / DCM) to obtain the desired title compound (8 g, 45%) as a red solid.

[0751] 1 H NMR (400 MHz, DMSO-d6) δ9.37 (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).

[0752]

[0753] Step 3: Synthesis of 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(1H-pyrazol-3-yl)-1H-inden-1-one (Compound 25)

[0754] The desired title compound (170 mg, 57% yield) was obtained as a yellow solid in the same manner as step 5 of Manufacturing Example 21.

[0755] LCMS (ESI-MS) of the above-obtained compound 25 (chemical formula 26 below) and 1 As a result of H NMR analysis, the following data were obtained:

[0756] [Chemical Formula 26]

[0757]

[0758] LCMS (ESI-MS): mass calcd. C 25 H 21 N3O2S 427.1 m / z, found 427.9 [M+H] + .

[0759] 1 H NMR (400 MHz, DMSO-d6) 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= 6.0 Hz, 2H), 2.81 - 2.71 (m, 2H), 2.18 - 1.94 (m, 5H).

[0760]

[0761] Manufacturing Example 26. 2-(1-methyl-1H-pyrazol-3-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-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)

[0762] [Reaction Formula 26]

[0763]

[0764] 2-Bromo-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one was prepared in the same manner as in step 5 of Preparation Example 21, to obtain the desired title compound ((23.0 mg, 23% yield) as a yellow solid.

[0765] LCMS (ESI-MS) of the above-obtained compound 26 (chemical formula 27 below) and 1 As a result of H NMR analysis, the following data were obtained:

[0766] [Chemical Formula 27]

[0767]

[0768] LCMS (ESI-MS): mass calcd. C 26 H 23 N3O2S 441.2 m / z, found 441.8 [M+H] + .

[0769] 1 H NMR (400 MHz, DMSO-d6) δ9.25 (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= 2.0 Hz, 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).

[0770]

[0771] Manufacturing Example 27. 3-(4-methylthiazol-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)

[0772] [Reaction Formula 27]

[0773]

[0774] 2-Bromo-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one was prepared in the same manner as in step 5 of Preparation Example 21 to obtain the desired title compound (60 mg, 35%) as a red solid.

[0775] LCMS (ESI-MS) of the above-obtained compound 27 (chemical formula 28 below) and 1 As a result of H NMR analysis, the following data were obtained:

[0776] [Chemical Formula 28]

[0777]

[0778] LCMS (ESI-MS): mass calcd. C 25 H 21 N3O2S 427.1 m / z, found 427.8 [M+H] + .

[0779] 1 H NMR (400 MHz, DMSO-d6) δ13.08 (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).

[0780]

[0781] Manufacturing Example 28. 2-(1-methyl-1H-pyrazol-4-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-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)

[0782] [Reaction Formula 28]

[0783]

[0784] 2-Bromo-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one was prepared in the same manner as in step 5 of Preparation Example 21, to obtain the desired title compound (60 mg, 53%) as a red solid.

[0785] LCMS (ESI-MS) of the above-obtained compound 28 (chemical formula 29) and 1 As a result of H NMR analysis, the following data were obtained:

[0786] [Chemical Formula 29]

[0787]

[0788] LCMS (ESI-MS): mass calcd. C 26 H 23 N3O2S 441.2 m / z, found 441.9 [M+H] + .

[0789] 1 H NMR (400 MHz, DMSO-d6) δ9.34 (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= 8.0 Hz, 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).

[0790]

[0791] Manufacturing Example 29. 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)

[0792] [Reaction Formula 29]

[0793]

[0794] Step 1: Synthesis of tert-butyl 4-(3-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0795] A mixture of 3-bromo-1H-pyrazole (2 g, 13.61 mmol), tert-butyl 4-bromopiperidine-1-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 h. After cooling the reaction mixture to room temperature, water (50 mL) was added and extracted with EA (100 mL x 3). The organic layer was washed by a conventional method, dried and concentrated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (20% EtOAc / PE) to obtain the desired title compound (1 g, 22%) as a white solid.

[0796] 1 H NMR (400 MHz, DMSO-d6) δ7.83 (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).

[0797]

[0798] 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

[0799] A mixture of tert-butyl 4-(3-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate (500 mg, 1.52 mmol), bis(pinatolato)diboron (767 mg, 3.04 mmol), [1,1'-bas(diphenylphosphino)ferrocene]dichloropalladium(II) (110 mg, 0.15 mmol) and KOAc (298 mg, 3.04 mmol) in dioxane (15 mL) was stirred at 100°C for 16 h.

[0800] After the reaction mixture was cooled to room temperature, water (10 mL) was added and extracted with EA (20 mL x 3). The organic layer was washed in a conventional manner, dried, and concentrated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (30% EtOAc / PE) to obtain the desired title compound (400 mg, 69.8%).

[0801]

[0802] 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

[0803] The desired title compound (190 mg, 33%) was obtained as a blue solid in the same manner as in Step 5 of Preparation Example 21 using tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and 2-bromo-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one.

[0804] 1H NMR (400 MHz, DMSO-d6) δ9.23 (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= 2.4 Hz, 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).

[0805]

[0806] 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

[0807] To a solution 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 (180 mg, 0.29 mmol) was added DCM / TFA (3 ml / 1 ml) and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to obtain the desired title compound (150 mg, crude) as a yellow solid.

[0808]

[0809] 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 (Compound 29)

[0810] 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(1-(piperidin-4-yl)-1H-pyrazol-3-yl)-1H-inden-1-one (150 mg, 0.29 mmol), aqueous CH2O (0.3 ml, 2.90 mmol), NaBH3CN (37 mg, 0.58 mmol), and AcOH (34.8 mg, 0.58 mmol) were stirred at room temperature for 6 h in a mixture of MeOH (3 ml). Water (5 mL) was added to the reaction mixture, and extracted with EA (10 mL x 3). The organic layer was washed by a conventional method, dried, and concentrated under reduced pressure. The obtained concentrated residue was purified by prep-HPLC (Gemini 5 ㎛ C 18 The residue was purified by column, 150 x 21.2 mm, 30 - 90% ACN / H2O 0.1% FA) to obtain the desired title compound (5.5 mg, 4%) as a red solid.

[0811] LCMS (ESI-MS) of the above-obtained compound 29 (chemical formula 30 below) and 1 As a result of H NMR analysis, the following data were obtained:

[0812] [Chemical Formula 30]

[0813]

[0814] LCMS (ESI-MS): mass calcd. C 31 H 32 N4O2S 524.2 m / z, found 525.0 [M+H] + .

[0815] 1H NMR (400 MHz, DMSO-d6) δ9.26 (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).

[0816]

[0817] Manufacturing Example 30. 2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-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)

[0818] [Reaction Formula 30]

[0819]

[0820] 3-(4-Methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(1H-pyrazol-4-yl)-1H-inden-1-one (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) were added DMF (10 mL) and stirred for 16 h at 120 °C under nitrogen. Water (30 mL) was added to the reaction mixture and extracted with EA (30 mL x 3). The organic layer was washed by a conventional method, dried, and concentrated under reduced pressure. The obtained concentrated residue was purified by prep-HPLC (Gemini 5 ㎛ C 18The crude product was purified by column chromatography (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.

[0821] LCMS (ESI-MS) of the above-obtained compound 30 (chemical formula 31 below) and 1 As a result of H NMR analysis, the following data were obtained:

[0822] [Chemical Formula 31]

[0823]

[0824] LCMS (ESI-MS): mass calcd. C 31 H 32 N4O2S 524.2 m / z, found 525.0 [M+H] + .

[0825] 1 H NMR (400 MHz, DMSO-d6) δ9.34 (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).

[0826]

[0827] Manufacturing Example 31. 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(1H-1,2,3-triazol-4-yl)-1H-inden-1-one (3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(1H-1,2,3-triazol-4-yl)-1H-inden-1-one) (Compound 31)

[0828] [Reaction Formula 31]

[0829]

[0830] Step 1: Synthesis of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazole

[0831] 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 h. Water (300 mL) was added to the reaction mixture, and extracted with EA (400 mL x 3). The organic layer was washed by a conventional method, dried, and concentrated under reduced pressure. The obtained concentrated residue was purified by flash chromatography (10% EtOAc / Hexanes) to obtain the desired title compound (1.5 g, 23%) as a white oil.

[0832] LCMS (ESI-MS): mass calcd. C8H 16 BrN3OSi 277.0 m / z, found 278.0 [M+H] + .

[0833]

[0834] Step 2: Synthesis of (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-4-yl)boronic acid

[0835] To a mixture of 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'-bi(1,3,2-dioxaborolane) (1.65 g, 0.0065 mol), Pd(dppf)Cl2 (0.4 g, 0.0005 mol) and KOAc (1.59 g, 0.0162 mol) was added dioxane (20 mL), and the mixture was stirred at 90°C for 16 h under nitrogen. Water (100 mL) was added to the reaction mixture, and extracted with EA (100 mL x 3). The organic layer was washed in a conventional manner, dried, and concentrated under reduced pressure. The obtained concentrated residue was purified by flash chromatography (20% EtOAc / Hexanes) to obtain the desired title compound (0.4 g, 20%) as a white oil.

[0836] LCMS (ESI-MS): mass calcd. C8H 18 BN3O3Si 243.1 m / z, found 243.6 [M+H] + .

[0837]

[0838] 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

[0839] Using 2-bromo-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one and (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-4-yl)boronic acid, the desired title compound (220 mg, 71%) was obtained as a red solid in the same manner as in step 5 of Preparation Example 21.

[0840] LCMS (ESI-MS): mass calcd. C 30 H 34 N4O3SSi 558.2 m / z, found 559.0 [M+H] + .

[0841]

[0842] 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)

[0843] 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 (260 mg, 0.4645 mmol) was added HCl / dioxane (15 mL) and stirred at room temperature under nitrogen for 16 h. Water (50 mL) was added to the reaction mixture and extracted with EA (50 mL x 3). The organic layer was washed by a conventional method, dried, and concentrated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (5% MeOH / DCM) to obtain the desired title compound (90 mg, 40%) as a red solid.

[0844] LCMS (ESI-MS) of the above-obtained compound 31 (chemical formula 32 below) and 1 As a result of H NMR analysis, the following data were obtained:

[0845] [Chemical Formula 32]

[0846]

[0847] LCMS (ESI-MS): mass calcd. C 24 H 20 N4O2S 428.1 m / z, found 428.8 [M+H] + .

[0848] 1 H NMR (400 MHz, DMSO-d6) δ9.30 (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).

[0849]

[0850] Manufacturing Example 32. 2-(1-methyl-1H-1,2,3-triazol-4-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one (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

[0851] 2-(2-methyl-2H-1,2,3-triazol-4-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one (Compound 33)

[0852] [Reaction Formula 32]

[0853]

[0854] 3-(4-Methylthiazol-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) were added DMF (10 mL) and stirred for 4 h at 145°C under nitrogen. Water (70 mL) was added to the reaction mixture and extracted with EA (100 mL x 3). The organic layer was washed by a conventional method, dried and concentrated under reduced pressure. The obtained concentrated residue was purified by prep-HPLC (Gemini 5 ㎛ C 18 The residue was purified by 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 a red solid.

[0855] LCMS (ESI-MS) of the above-obtained compound 32 (chemical formula 33 below) and 1 As a result of H NMR analysis, the following data were obtained:

[0856] [Chemical Formula 33]

[0857]

[0858] LCMS (ESI-MS): mass calcd. C 25 H 22 N4O2S 442.1 m / z, found 443.1 [M+H] + .

[0859] 1 H NMR (400 MHz, DMSO-d6) δ9.28 (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).

[0860]

[0861] LCMS (ESI-MS) of the above-obtained compound 33 (chemical formula 34 below) and 1 As a result of H NMR analysis, the following data were obtained:

[0862] [Chemical Formula 34]

[0863]

[0864] LCMS (ESI-MS): mass calcd. C 25 H 22 N4O2S 442.1 m / z, found 443.1 [M+H] + .

[0865] 1 H NMR (400 MHz, DMSO-d6) δ9.30 (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, 2.4 Hz, 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).

[0866]

[0867] Manufacturing Example 33. 3-(4-methylthiazol-5-yl)-1-oxo-6-(3-phenylpropoxy)-1H-indene-2-carbonitrile (3-(4-methylthiazol-5-yl)-1-oxo-6-(3-phenylpropoxy)-1H-indene-2-carbonitrile) (Compound 34)

[0868] [Reaction Formula 33]

[0869]

[0870] 2-Bromo-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one (500 mg, 1.14 mmol, CuCN (303 mg, 3.41 mmol) was added DMF (10 ml) and stirred at 150°C for 3 hours. The obtained concentrated residue was purified by prep-HPLC (Gemini 5 μm C 18 The residue was purified by column, 150 x 21.2 mm, 30 - 90% ACN / H2O 0.1% FA) to obtain the desired title compound (200 mg, 45%) as a yellow solid.

[0871] LCMS (ESI-MS) of the above-obtained compound 34 (chemical formula 35 below) and 1 As a result of H NMR analysis, the following data were obtained:

[0872] [Chemical Formula 35]

[0873]

[0874] LCMS (ESI-MS): mass calcd. C 23 H 18 N2O2S 386.1 m / z, found 386.7 [M+H] + .

[0875] 1 H NMR (400 MHz, DMSO-d6) δ9.52 (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).

[0876]

[0877] Manufacturing Example 34. 6-hydroxy-3-(4-methylthiazol-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)

[0878] [Reaction Formula 34]

[0879]

[0880] The desired title compound (17.3 mg, 16%) was obtained as a red solid in the same manner as in step 5 of Preparation Example 21 using 2-bromo-3-(4-methylthiazol-5-yl)-1-oxo-1H-indene-6-yl acetate and pyridin-3-ylboronic acid.

[0881] MS (ESI) of the above-obtained compound 35 (chemical formula 36 below) and 1 As a result of H NMR analysis, the following data were obtained:

[0882] [Chemical Formula 36]

[0883]

[0884] MS (ESI): mass calcd. C 18 H 12 N2O2S 320.1 m / z, found 321.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ10.33 (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).

[0885]

[0886] Manufacturing Example 35. 6-(2-hydroxyethoxy)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (6-(2-hydroxyethoxy)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 36)

[0887] [Reaction Formula 35]

[0888]

[0889] DMF (3 ml) and K2CO3 (86 mg, 0.62 mmol) were added to 6-hydroxy-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (100 mg, 0.31 mmol) and 2-bromoethanol-1-ol (78 mg, 0.62 mmol), and the mixture was stirred at 80 °C for 16 h. Water (5 mL) was added to the reaction mixture, and extracted with EA (10 mL x 3). The organic layer was washed by a conventional method, dried, and concentrated under reduced pressure. The obtained concentrated residue was purified by prep-HPLC (Gemini 5 ㎛ C 18 The residue was purified by column, 150 x 21.2 mm, 30 - 90% ACN / H2O 0.1% FA) to obtain the desired title compound (5.6 mg, 5%) as a yellow solid.

[0890] LCMS (ESI-MS) of the above-obtained compound 36 (chemical formula 37 below) and 1 As a result of H NMR analysis, the following data were obtained:

[0891] [Chemical Formula 37]

[0892]

[0893] LCMS (ESI-MS): mass calcd. C 20 H 16 N2O3S 364.1 m / z, found 364.7 [M+H] + .

[0894] 1H NMR (400 MHz, DMSO-d6) δ9.31 (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).

[0895]

[0896] Manufacturing Example 36. 6-(2-methoxyethoxy)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (6-(2-methoxyethoxy)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 37)

[0897] [Reaction Formula 36]

[0898]

[0899] The reaction temperature was carried out at room temperature and the desired title compound (20.1 mg, 28%) was obtained as a yellow solid in the same manner as in Manufacturing Example 35 using 1-bromo-2-methoxyethane.

[0900] LCMS (ESI-MS) of the above-obtained compound 37 (chemical formula 38 below) and 1 As a result of H NMR analysis, the following data were obtained:

[0901] [Chemical Formula 38]

[0902]

[0903] LCMS (ESI-MS): mass calcd. C 21 H 18 N2O3S 378.1 m / z, found 378.7 [M+H]+ .

[0904] 1 H NMR (400 MHz, DMSO-d6) δ9.31 (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).

[0905]

[0906] Manufacturing Example 37. 6-(methyl(3-phenylpropyl)amino)-3-(4-methylthiazol-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)

[0907] [Reaction Formula 37]

[0908]

[0909] The desired title compound (50 mg, 75%) was obtained as a purple solid in the same manner as in step 5 of Preparation Example 29 using 3-(4-methylthiazol-5-yl)-6-((3-phenylpropyl)amino)-2-(pyridin-3-yl)-1H-inden-1-one.

[0910] LCMS (ESI-MS) of the above-obtained compound 38 (chemical formula 39 below) and 1 As a result of H NMR analysis, the following data were obtained:

[0911] [Chemical Formula 39]

[0912]

[0913] LCMS (ESI-MS): mass calcd. C 21 H 17 N3OS 451.2 m / z, found 451.8 [M+H] + .

[0914] 1 H NMR (400 MHz, DMSO-d6) δ9.29 (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, 2.4 Hz, 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).

[0915]

[0916] Manufacturing Example 38. 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-4-yl)-1H-inden-1-one (3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-4-yl)-1H-inden-1-one) (Compound 39)

[0917] [Reaction Formula 38]

[0918]

[0919] Step 1: Synthesis of 6-hydroxy-3-(4-methylthiazol-5-yl)-2-(pyridin-4-yl)-1H-inden-1-one

[0920] Using 2-bromo-3-(4-methylthiazol-5-yl)-1-oxo-1H-inden-6-yl acetate (21-6) and pyridin-4-ylboronic acid of Preparation Example 21, the desired title compound (87.2 mg, 39% yield) was obtained as a red solid in the same manner as in Step 5 of Preparation Example 21.

[0921] LCMS (ESI-MS): mass calcd. C 18 H 12 N2O2S 320.4 m / z, found 321.0 [M+H] + .

[0922] 1 H NMR (400 MHz, DMSO-d6) δ10.38 (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).

[0923]

[0924] Step 2: Synthesis of 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-4-yl)-1H-inden-1-one (Compound 39)

[0925] The desired title compound (18.6 mg, 19%) was obtained as a red solid in the same manner as in Preparation Example 36 using 6-hydroxy-3-(4-methylthiazol-5-yl)-2-(pyridin-4-yl)-1H-inden-1-one and (3-bromopropyl)benzene.

[0926] LCMS (ESI-MS) of the above-obtained compound 39 (chemical formula 40) and 1 As a result of H NMR analysis, the following data were obtained:

[0927] [Chemical Formula 40]

[0928]

[0929] LCMS (ESI-MS): mass calcd. C 27 H 22 N2O2S 438.1 m / z, found 439.1 [M+H] + .

[0930] 1 H NMR (400 MHz, DMSO-d6) δ9.33 (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).

[0931]

[0932] Manufacturing Example 39. 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-2-yl)-1H-inden-1-one (3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-2-yl)-1H-inden-1-one) (Compound 40)

[0933] [Reaction Formula 39]

[0934]

[0935] Step 1: Synthesis of 3-(4-methylthiazol-5-yl)-1-oxo-2-(pyridin-2-yl)-1H-inden-6-yl acetate

[0936] To 2-bromo-3-(4-methylthiazol-5-yl)-1-oxo-1H-inden-6-yl acetate (21-6) (278 mg, 0.7633 mmol), 2-(tributylstannyl)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, toluene (10 mL) was added and the mixture was stirred at 110 °C for 16 hours under nitrogen. Water (30 mL) was added to the reaction mixture and extracted with EA (25 mL x 3). The organic layer was washed in a conventional manner, dried and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (3% MeOH / DCM) to obtain the desired title compound (100 mg, 36%) as a red solid.

[0937] LCMS (ESI-MS): mass calcd. C 20 H 14 N2O3S 362.1 m / z, found 363.0 [M+H] + .

[0938]

[0939] Step 2: Synthesis of 6-hydroxy-3-(4-methylthiazol-5-yl)-2-(pyridin-2-yl)-1H-inden-1-one

[0940] 3-(4-methylthiazol-5-yl)-1-oxo-2-(pyridin-2-yl)-1H-indene-6-yl acetate was prepared in the same manner as in step 1 of Preparation Example 25 to obtain the desired title compound (76 mg, 86% yield) as a red solid.

[0941] LCMS (ESI-MS): mass calcd. C 18 H 12 N2O2S 320.4 m / z, found 321.0 [M+H] + .

[0942] 1H NMR (400 MHz, DMSO-d6) δ10.35 (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).

[0943]

[0944] Step 3: Synthesis of 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-2-yl)-1H-inden-1-one (Compound 40)

[0945] 6-Hydroxy-3-(4-methylthiazol-5-yl)-2-(pyridin-2-yl)-1H-inden-1-one was prepared by the same method as in step 2 of Preparation Example 38, to obtain the desired title compound (20.9 mg, 22%) as a red solid.

[0946] LCMS (ESI-MS) of the above-obtained compound 40 (chemical formula 41) and 1 As a result of H NMR analysis, the following data were obtained:

[0947] [Chemical Formula 41]

[0948]

[0949] LCMS (ESI-MS): mass calcd. C 27 H 22 N2O2S 438.1 m / z, found 439.1 [M+H] + .

[0950] 1H NMR (400 MHz, DMSO-d6) δ9.24 (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).

[0951]

[0952] Manufacturing Example 40. 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyrazin-2-yl)-1H-inden-1-one (3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyrazin-2-yl)-1H-inden-1-one) (Compound 41)

[0953] [Reaction Formula 40]

[0954]

[0955] Step 1: Synthesis of 3-(4-methylthiazol-5-yl)-1-oxo-2-(pyrazin-2-yl)-1H-inden-6-yl acetate

[0956] Using 2-bromo-3-(4-methylthiazol-5-yl)-1-oxo-1H-inden-6-yl acetate (21-6) and 2-(tributylstannyl)pyrazine of Preparation Example 21, the desired title compound (100 mg, 40%) was obtained as a red solid in the same manner as in Step 1 of Preparation Example 39.

[0957] LCMS (ESI-MS): mass calcd. C 19 H 13 N3O3S 363.1 m / z, found 363.7 [M+H] + .

[0958]

[0959] Step 2: Synthesis of 6-hydroxy-3-(4-methylthiazol-5-yl)-2-(pyridin-2-yl)-1H-inden-1-one

[0960] 3-(4-methylthiazol-5-yl)-1-oxo-2-(pyrazin-2-yl)-1H-inden-6-yl acetate was prepared in the same manner as in step 1 of Preparation Example 25 to obtain the desired title compound (84 mg, 94%) as a red solid.

[0961] LCMS (ESI-MS): mass calcd. C 17 H 11 N3O2S 321.1 m / z, found 322.0 [M+H] + .

[0962] 1 H NMR (400 MHz, DMSO-d6) δ10.52 (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).

[0963]

[0964] Step 3: Synthesis of 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyrazin-2-yl)-1H-inden-1-one (Compound 41)

[0965] The desired title compound (20.8 mg, 19%) was obtained as a red solid using the same method as in step 2 of Preparation Example 38 using 6-hydroxy-3-(4-methylthiazol-5-yl)-2-(pyrazin-2-yl)-1H-inden-1-one.

[0966] LCMS (ESI-MS) of the above-obtained compound 41 (chemical formula 42) and 1 As a result of H NMR analysis, the following data were obtained:

[0967] [Chemical Formula 42]

[0968]

[0969] LCMS (ESI-MS): mass calcd. C 26 H 21 N3O2S 439.1 m / z, found 440.1 [M+H] + .

[0970] 1 H NMR (400 MHz, DMSO-d6) δ9.28 (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).

[0971]

[0972] Manufacturing Example 41. 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)

[0973] [Reaction Formula 41]

[0974]

[0975] Step 1: Synthesis of 2,3-dibromo-6-methoxy-1H-inden-1-one

[0976] CCl4 was added to 6-methoxy-2,3-dihydroindene-1-one (1 g, 0.0062 mol), NBS (3.31 g, 0.0186 mol), and AIBN (0.1 g, 0.00062 mol), and the mixture was 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 obtain the desired title compound (1.8 g, 92%) as a red solid.

[0977] 1 H NMR (400 MHz, CDCl3) δ7.09 - 7.06 (m, 2H), 6.85 - 6.83 (m, 1H), 3.84 (s, 3H).

[0978]

[0979] Step 2: Synthesis of 2-bromo-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-inden-1-one

[0980] To a mixture of 2,3-dibromo-6-methoxy-1H-indene-1-one (800 mg, 2.5160 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) was added dioxane (24 mL) / H2O (8 mL) and stirred for 16 h 40 o C was stirred under nitrogen. Water (50 mL) was added to the reaction mixture and extracted with EA (30 mL x 3). The organic layer was washed in a conventional manner, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (MeOH / DCM) to obtain the desired title compound (500 mg, 62%) as a red solid.

[0981] LCMS (ESI-MS): mass calcd. C 14H 11 BrN2O2318.0 m / z, found 318.7 [M+H] + .

[0982]

[0983] Step 3: Synthesis of 6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one

[0984] The desired title compound (390 mg, 89%) was obtained as a red solid in the same manner as in step 5 of Preparation Example 21 using 2-bromo-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-inden-1-one and pyridine-3-boronic acid.

[0985] LCMS (ESI-MS): mass calcd. C 19 H 15 N3O2317.1 m / z, found 318.0 [M+H] + .

[0986] 1 H NMR (400 MHz, DMSO-d6) δ8.56 - 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).

[0987]

[0988] Step 4: Synthesis of 6-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one

[0989] 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) was added BBr3 (4 mL) and 25 o The mixture was stirred at C for 16 h. Water (5 mL) was added to the reaction mixture to quench the reaction, and the pH was adjusted to 7 with aqueous NaHCO3 solution, followed by extraction with DCM (40 mL x 3). The organic layer was washed in a conventional manner, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (3% MeOH / DCM) to obtain the desired title compound (300 mg, 85%) as a red solid.

[0990] LCMS (ESI-MS): mass calcd. C 18 H 13 N3O2303.1 m / z, found 301.8 [MH] - .

[0991] 1 H NMR (400 MHz, DMSO-d6) δ10.17 (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).

[0992]

[0993] Step 5: Synthesis of 3-(1-methyl-1H-pyrazol-4-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 42)

[0994] The desired title compound (20.9 mg, 14%) was obtained as a red solid using the same method as in step 2 of Preparation Example 38 using 6-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one.

[0995] LCMS (ESI-MS) of the above-obtained compound 42 (chemical formula 43) and 1 As a result of H NMR analysis, the following data were obtained:

[0996] [Chemical Formula 43]

[0997]

[0998] LCMS (ESI-MS): mass calcd. C 27 H 23 N3O2421.2 m / z, found 422.2 [M+H] + .

[0999] 1 H NMR (400 MHz, DMSO-d6) δ8.56 - 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).

[1000]

[1001] Manufacturing 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) (Compound 43)

[1002] [Reaction Formula 42]

[1003]

[1004] Step 1: Synthesis of tert-butyl 4-(2-bromo-6-methoxy-1-oxo-1H-inden-3-yl)-1H-pyrazole-1-carboxylate

[1005] The desired title compound (300 mg, 22%) was obtained as a yellow solid in the same manner as in step 2 of Manufacturing Example 41.

[1006] LCMS (ESI-MS): mass calcd. C 18 H 17 BrN2O4404.0 m / z, found 404.6 [M+H] + .

[1007]

[1008] Step 2: Synthesis of 6-methoxy-3-(1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one

[1009] The desired title compound (170 mg, 76%) was obtained as a white solid in the same manner as step 5 of Manufacturing Example 21.

[1010] 1 H NMR (400 MHz, DMSO-d6) δ13.51 (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).

[1011]

[1012] Step 3: Synthesis of 6-hydroxy-3-(1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one

[1013] The desired title compound (60 mg, 37%) was obtained as a blue solid in the same manner as in step 4 of Manufacturing Example 41.

[1014] LCMS (ESI-MS): mass calcd. C 17 H 11 N3O2289.1 m / z, found 289.7 [M+H] + .

[1015]

[1016] Step 4: Synthesis of 6-(3-phenylpropoxy)-3-(1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 43)

[1017] In the same manner as in step 5 of Manufacturing 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-inden-1-one (compound 42-1, 5.7 mg, 7%) as a reaction by-product were obtained as a red solid.

[1018] LCMS (ESI-MS) of the above-obtained compound 43 (chemical formula 44 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1019] [Chemical Formula 44]

[1020]

[1021] LCMS (ESI-MS): mass calcd. C 26 H 21 N3O2407.2 m / z, found 407.8 [M+H]+ .

[1022] 1 H NMR (400 MHz, DMSO-d6) δ13.51 (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).

[1023] LCMS (ESI-MS) of the above-obtained compound 43-1 and 1 As a result of H NMR analysis, the following data were obtained:

[1024] LCMS (ESI-MS): mass calcd. C 26 H 21 N3O2407.2 m / z, found 407.9 [M+H] + .

[1025] 1 H NMR (400 MHz, DMSO-d6) δ10.19 (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).

[1026]

[1027] Manufacturing 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) (Compound 44)

[1028] [Reaction Formula 43]

[1029]

[1030] Step 1: Synthesis of (E)-1-(5-(benzyloxy)-2-bromophenyl)-3-(2-methoxyphenyl)prop-2-en-1-one

[1031] The desired title compound (1.3 g, 84%) was obtained as a yellow solid using the same method as step 1 of Manufacturing Example 21.

[1032] LCMS (ESI-MS): mass calcd. C 23 H 19 BrO3422.1 m / z, found 422.7 [M+H] + .

[1033]

[1034] Step 2: Synthesis of 6-(benzyloxy)-3-(2-methoxyphenyl)-1H-inden-1-one

[1035] (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) were added DMF (28 mL) and stirred for 16 h at 100°C under nitrogen. Water (50 mL) was added to the reaction mixture, and extracted with EA (80 mL x 3). The organic layer was washed by the usual method, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (10% EtOAc / hexane) to obtain the desired title compound (900 mg, 77%) as a yellow solid.

[1036] LCMS (ESI-MS): mass calcd. C 23 H 18 O3342.1 m / z, found 342.8 [M+H] + .

[1037]

[1038] Step 3: Synthesis of 6-(benzyloxy)-2-bromo-3-(2-methoxyphenyl)-1H-inden-1-one

[1039] To a solution of 6-(benzyloxy)-3-(2-methoxyphenyl)-1H-inden-1-one (880 mg, 2.56 mmol) in CHCl3 (35 ml) was added NBS (478.9 mg, 2.69 mmol) at -45°C and stirred at the same temperature for 2 hours. Water (50 mL) was added to the reaction mixture and extracted with EA (80 mL x 3). The organic layer was washed in a conventional manner, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (2% EtOAc / hexane) to obtain the desired title compound (350 mg, 26%) as a yellow solid.

[1040] LCMS (ESI-MS): mass calcd. C 23 H 17 BrO3420.0 m / z, found 420.7 [M+H] + .

[1041] 1 H NMR (400 MHz, DMSO-d6) δ7.60 - 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).

[1042]

[1043] Step 4: Synthesis of 6-(benzyloxy)-3-(2-methoxyphenyl)-2-(pyridin-3-yl)-1H-inden-1-one

[1044] The desired title compound (270 mg, 71%) was obtained as a yellow solid in the same manner as in step 5 of Manufacturing Example 21.

[1045] LCMS (ESI-MS): mass calcd. C 28 H 21 NO3419.2m / z, found 419.9 [M+H] + .

[1046]

[1047] Step 5: Synthesis of 6-hydroxy-3-(2-methoxyphenyl)-2-(pyridin-3-yl)-1H-inden-1-one

[1048] 6-(Benzyloxy)-3-(2-methoxyphenyl)-2-(pyridin-3-yl)-1H-inden-1-one (270 mg, 0.6421 mmol) and Pd / C (10 mg) were added to MeOH (13 mL) and stirred at room temperature for 2 hours under hydrogen. The reaction mixture was concentrated using Celite and the resulting filtrate was concentrated. The concentrated residue was purified by silica gel column chromatography (50% EtOAc / hexane) to obtain the desired title compound (70 mg, 31%) as an orange solid.

[1049] LCMS (ESI-MS): mass calcd. C 21 H 15 NO3329.1 m / z, found 329.7 [M+H] + .

[1050] 1 H NMR (400 MHz, DMSO-d6) δ10.26 (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).

[1051]

[1052] Step 6: Synthesis of 3-(2-methoxyphenyl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 44)

[1053] The desired title compound (5.0 mg, 6%) was obtained as a red solid in the same manner as in step 2 of Manufacturing Example 38.

[1054] LCMS (ESI-MS) of the above-obtained compound 44 (chemical formula 45 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1055] [Chemical Formula 45]

[1056]

[1057] LCMS (ESI-MS): mass calcd. C 30 H 25 NO3447.2 m / z, found 447.9 [M+H] + .

[1058] 1 H NMR (400 MHz, DMSO-d6) δ8.41 - 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).

[1059]

[1060] Manufacturing Example 44. 3-(2,6-dimethoxyphenyl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (3-(2,6-dimethoxyphenyl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 45)

[1061] [Reaction Formula 44]

[1062]

[1063] Step 1: Synthesis of (E)-1-(5-(benzyloxy)-2-bromophenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one

[1064] The desired title compound (1.81 g, 95%) was obtained as a yellow solid using the same method as step 1 of Manufacturing Example 21.

[1065] LCMS (ESI-MS): mass calcd. C 24 H 21 BrO4452.1 m / z, found 453.1 [M+H] + .

[1066]

[1067] Step 2: Synthesis of 6-(benzyloxy)-3-(2,6-dimethoxyphenyl)-1H-inden-1-one

[1068] The desired title compound (1.04 g, 70%) was obtained as a yellow solid using the same method as step 2 of Manufacturing Example 43.

[1069] LCMS (ESI-MS): mass calcd. C 24 H 20 O4372.1 m / z, found 372.7 [M+H] + .

[1070]

[1071] Step 3: Synthesis of 6-(benzyloxy)-2-bromo-3-(2,6-dimethoxyphenyl)-1H-inden-1-one

[1072] The desired title compound (415 mg, 91%) was obtained as a yellow solid in the same manner as in step 3 of Manufacturing Example 43.

[1073] LCMS (ESI-MS): mass calcd. C 24 H 19 BrO4450.0 m / z, found 451.0 [M+H] + .

[1074]

[1075] Step 4: Synthesis of 6-(benzyloxy)-2-bromo-3-(2,6-dimethoxyphenyl)-2-(pyridin-3-yl)-1H-inden-1-one

[1076] The desired title compound (200 mg, 60%) was obtained as a red oil in the same manner as in step 5 of Manufacturing Example 21.

[1077] LCMS (ESI-MS): mass calcd. C 29 H 23 NO4449.2m / z, found 450.1 [M+H] + .

[1078]

[1079] Step 5: Synthesis of 3-(2,6-dimethoxyphenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one

[1080] The desired title compound (120 mg, 75%) was obtained as a red solid in the same manner as in step 5 of Manufacturing Example 43.

[1081] LCMS (ESI-MS): mass calcd. C 22 H 17 NO4359.1 m / z, found 360.0 [M+H] + .

[1082] 1H NMR (400 MHz, DMSO-d6) δ10.07 (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).

[1083]

[1084] Step 6: Synthesis of 3-(2,6-dimethoxyphenyl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 45)

[1085] The desired title compound (20 mg, 16%) was obtained as a red solid in the same manner as in step 2 of Manufacturing Example 38.

[1086] LCMS (ESI-MS) of the above-obtained compound 45 (chemical formula 46 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1087] [Chemical Formula 46]

[1088]

[1089] LCMS (ESI-MS): mass calcd. C 31 H 27 NO4477.2 m / z, found 478.3 [M+H] + .

[1090] 1H NMR (400 MHz, DMSO-d6) δ8.41 - 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).

[1091]

[1092] Manufacturing Example 45. 4-methyl-3-(4-methylthiazol-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)

[1093] [Reaction Formula 45]

[1094]

[1095] Step 1: Synthesis of (E)-1-(3-hydroxy-5-methylphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one

[1096] The desired title compound (800 mg, 46%) was obtained as a yellow solid using the same method as step 1 of Manufacturing Example 21.

[1097] LCMS (ESI-MS): mass calcd. C 14 H 13 NO2S 259.1 m / z, found 260.0 [M+H] + .

[1098]

[1099] Step 2: Synthesis of 6-hydroxy-4-methyl-3-(4-methylthiazol-5-yl)-2,3-dihydro-1H-inden-1-one

[1100] The desired title compound (0.4 g, 76%) was obtained as a yellow solid in the same manner as in step 2 of Manufacturing Example 21.

[1101] LCMS (ESI-MS): mass calcd. C 14 H 13 NO2S 259.1 m / z, found 259.7[M+H] + .

[1102]

[1103] Step 3: Synthesis of 7-methyl-1-(4-methylthiazol-5-yl)-3-oxo-2,3-dihydro-1H-inden-5-yl acetate

[1104] The desired title compound (0.9 g, 69%) was obtained as a yellow oil in the same manner as in step 3 of Manufacturing Example 21.

[1105] LCMS (ESI-MS): mass calcd. C 16 H 15 NO3S 301.1 m / z, found 301.7 [M+H] + .

[1106]

[1107] Step 4: Synthesis of 2-bromo-4-methyl-3-(4-methylthiazol-5-yl)-1-oxo-1H-inden-6-yl acetate

[1108] The desired title compound (180 mg, 38%) was obtained as a yellow solid in the same manner as step 4 of Manufacturing Example 21.

[1109] LCMS (ESI-MS): mass calcd. C 16 H 12 BrNO3S 377.0 m / z, found 377.6 [M+H] + .

[1110]

[1111] Step 5: Synthesis of 6-hydroxy-4-methyl-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one

[1112] The desired title compound (50 mg, 72%) was obtained as a red solid in the same manner as in step 5 of Manufacturing Example 21.

[1113] LCMS (ESI-MS): mass calcd. C 19 H 14 N2O2S 334.1 m / z, found 335.0 [M+H] + .

[1114]

[1115] Step 6: Synthesis of 4-methyl-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 46)

[1116] The desired title compound (40 mg, 53% yield) was obtained as a red solid using the same method as step 2 of Manufacturing Example 38.

[1117] LCMS (ESI-MS) of the above-obtained compound 46 (chemical formula 47 below) and 1As a result of H NMR analysis, the following data were obtained:

[1118] [Chemical Formula 47]

[1119]

[1120] LCMS (ESI-MS): mass calcd. C 28 H 24 N2O2S 452.2 m / z, found 452.9 [M+H] + .

[1121] 1 H NMR (400 MHz, DMSO-d6) δ9.23 (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).

[1122]

[1123] Manufacturing Example 46. 4-methoxy-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (4-methoxy-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one) (Compound 47)

[1124] [Reaction Formula 46]

[1125]

[1126] Step 1: Synthesis of (E)-1-(3-(hydroxy-5-methoxyphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one

[1127] The desired title compound ((0.95 g, 57%) was obtained as a yellow solid in the same manner as in step 1 of Manufacturing Example 21.

[1128] 1 H NMR (400 MHz, DMSO-d6) δ9.85 (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= 2.4 Hz, 1H), 3.79 (s, 3H), 2.55 (s, 3H).

[1129]

[1130] 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

[1131] In the same manner as in step 2 of Manufacturing Example 21, two structural isomers (650 mg, 68%) of the desired title compound were obtained as a yellow solid and used in the next reaction without purification.

[1132] LCMS (ESI-MS): mass calcd. C 14 H 13 NO3S 275.1 m / z, found 275.6 [M+H] + .

[1133]

[1134] 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

[1135] In the same manner as in step 3 of Manufacturing Example 21, two structural isomers (260 mg, 35%) of the desired title compound were obtained as a yellow solid and used in the next reaction without purification.

[1136] LCMS (ESI-MS): mass calcd. C 16 H 15 NO4S 317.1 m / z, found 317.6 [M+H] + .

[1137]

[1138] 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-6-yl acetate

[1139] By reacting and purifying in the same manner as step 4 of Manufacturing Example 21, the title compounds A (130 mg, 42%) and B (150 mg, 50%) were obtained as yellow solids.

[1140] Compound 46-8 1The results of the H NMR measurements are as follows:

[1141] 1 H NMR (400 MHz, DMSO-d6) δ9.24 (s, 1H), 7.08 (s, 1H), 7.04 (s, 1H), 3.64 (s, 3H), 2.35 (s, 3H), 2.28 (s, 3H).

[1142]

[1143] Step 5: Synthesis of 6-hydroxy-4-methoxy-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one

[1144] The desired title compound (70 mg, 67%) was obtained as a yellow solid in the same manner as in step 5 of Manufacturing Example 21.

[1145]

[1146] Step 6: Synthesis of 4-methoxy-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 47)

[1147] The desired title compound (30 mg, 38%) was obtained as a red solid in the same manner as in step 2 of Manufacturing Example 38.

[1148] LCMS (ESI-MS) of the above-obtained compound 47 (chemical formula 48 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1149] [Chemical Formula 48]

[1150]

[1151] LCMS (ESI-MS): mass calcd. C 28 H24 N2O3S 468.2 m / z, found 468.9 [M+H] + .

[1152] 1 H NMR (400 MHz, DMSO-d6) δ9.16 (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).

[1153]

[1154] Manufacturing Example 47. 4-hydroxy-3-(4-methylthiazol-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)

[1155] [Reaction Formula 47]

[1156]

[1157] Step 1: Synthesis of 4-hydroxy-6-methoxy-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one

[1158] The desired title compound (100 mg, 71%) was obtained as a yellow solid in the same manner as step 5 of Manufacturing Example 46.

[1159]

[1160] Step 2: Synthesis of 4,6-dihydroxy-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one

[1161] To 4-hydroxy-6-methoxy-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (95 mg, 0.27 mmol) was added HBr aqueous solution (1 ml) and stirred at 100 °C for 6 hours.

[1162] The mixture was concentrated to obtain the desired title compound (100 mg, crude) as a yellow solid.

[1163]

[1164] Step 3: Synthesis of 4-hydroxy-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 48)

[1165] The desired title compound (3 mg, 3%) was obtained as a yellow solid using the same method as step 2 of Manufacturing Example 38.

[1166] LCMS (ESI-MS) of the above-obtained compound 48 (chemical formula 49 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1167] [Chemical Formula 49]

[1168]

[1169] LCMS (ESI-MS): mass calcd. C 27 H 22 N2O3S 454.1 m / z, found 454.9 [M+H] + .

[1170] 1H NMR (400 MHz, DMSO-d6) δ9.25 (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).

[1171]

[1172] Manufacturing Example 48. 6-(cyclopentylamino)-3-(4-methylthiazol-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)

[1173] [Reaction Formula 48]

[1174]

[1175] 6-Chloro-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (100 mg, 0.30 mmol), cyclopentylamine (51 mg, 0.60 mmol), Pd-PEPPSI-IPent Cl (28 mg, 0.03 mmol) and Cs2CO3 (195 mg, 0.60 mmol) were added with dioxane / H2O (5 ml / 1 ml) 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 extracted with EA (10 mL x 3). The organic layer was washed in a conventional manner, dried, and concentrated under reduced pressure. The concentrated residue was purified by prep-HPLC (Gemini 5 ㎛ C 18The crude product was purified by 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.

[1176] LCMS (ESI-MS) of the above-obtained compound 49 (chemical formula 50 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1177] [Chemical Formula 50]

[1178]

[1179] LCMS (ESI-MS): mass calcd. C 23 H 21 N3OS 387.1 m / z, found 387.7 [M+H] + .

[1180] 1 H NMR (400 MHz, DMSO-d6) δ9.28 (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).

[1181]

[1182] Manufacturing Example 49. 6-(methylamino)-3-(4-methylthiazol-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) (Compound 50)

[1183] [Reaction Formula 49]

[1184]

[1185] The desired title compound (11.9 mg, 12%) was obtained as a blue solid using methanamine in the same manner as in Manufacturing Example 48.

[1186] LCMS (ESI-MS) of the above-obtained compound 50 (chemical formula 51 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1187] [Chemical Formula 51]

[1188]

[1189] LCMS (ESI-MS): mass calcd. C 19 H 15 N3OS 333.1 m / z, found 333.7 [M+H] + .

[1190] 1 H NMR (400 MHz, DMSO-d6) δ9.28 (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= 5.2 Hz, 1H), 6.42 (dd,J= 8.0, 2.0 Hz, 1H), 2.76 (d,J= 5.2 Hz, 3H), 1.95 (s, 3H).

[1191]

[1192] Manufacturing Example 50. 6-((1-methylpiperidin-4-yl)amino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-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)

[1193] [Reaction Formula 50]

[1194]

[1195] The desired title compound (37 mg, 35%) was obtained as a blue solid using 1-methylpiperidin-4-amine in the same manner as in Manufacturing Example 48.

[1196] LCMS (ESI-MS) of the above-obtained compound 51 (chemical formula 52 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1197] [Chemical Formula 52]

[1198]

[1199] LCMS (ESI-MS): mass calcd. C 24 H 24 N4OS 416.2 m / z, found 416.8 [M+H] + .

[1200] 1 H NMR (400 MHz, DMSO-d6) δ9.28 (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).

[1201]

[1202] Manufacturing Example 51. 3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-6-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1H-inden-1-one (3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-6-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1H-inden-1-one) (Compound 52)

[1203] [Reaction Formula 51]

[1204]

[1205] The desired title compound (35 mg, 33%) was obtained as a blue solid using (tetrahydro-2H-pyran-4-yl)methanamine in the same manner as in Manufacturing Example 48.

[1206] LCMS (ESI-MS) of the above-obtained compound 52 (chemical formula 53 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1207] [Chemical Formula 53]

[1208]

[1209] LCMS (ESI-MS): mass calcd. C 24 H 23 N3O2S 417.2 m / z, found 417.9 [M+H] + .

[1210] 1H NMR (400 MHz, DMSO-d6) δ9.28 (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).

[1211]

[1212] Manufacturing Example 52. 6-((2-hydroxyethyl)amino)-3-(4-methylthiazol-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)

[1213] [Reaction Formula 52]

[1214]

[1215] Using 2-aminoethan-1-ol in the same manner as in Manufacturing Example 48, the desired title compound (20.0 mg, 22%) was obtained as a blue solid.

[1216] LCMS (ESI-MS) of the above-obtained compound 53 (chemical formula 54 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1217] [Chemical Formula 54]

[1218]

[1219] LCMS (ESI-MS): mass calcd. C 20 H 17 N3O2S 363.1 m / z, found 363.7 [M+H] + .

[1220] 1 H NMR (400 MHz, DMSO-d6) δ9.28 (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= 5.2 Hz, 2H), 3.18 (q,J= 6.0 Hz, 2H), 1.95 (s, 3H).

[1221]

[1222] Manufacturing Example 53. 6-((2-methoxyethyl)amino)-3-(4-methylthiazol-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)

[1223] [Reaction Formula 53]

[1224]

[1225] The desired title compound (5.3 mg, 5%) was obtained as a blue solid using 2-methoxyethan-1-amine in the same manner as in Manufacturing Example 48.

[1226] LCMS (ESI-MS) of the above-obtained compound 54 (chemical formula 55 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1227] [Chemical Formula 55]

[1228]

[1229] LCMS (ESI-MS): mass calcd. C 21 H 19 N3O2S 377.1 m / z, found 377.7 [M+H] + .

[1230] 1 H NMR (400 MHz, CDCl3) δ8.92 (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= 5.2 Hz, 2H), 2.10 (s, 3H).

[1231]

[1232] Manufacturing Example 54. 3-(4-methylthiazol-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)

[1233] [Reaction Formula 54]

[1234]

[1235] Using 2-phenoxyethan-1-amine in the same manner as in Manufacturing Example 48, the desired title compound (28.0 mg, 25%) was obtained as a blue solid.

[1236] LCMS (ESI-MS) of the above-obtained compound 55 (chemical formula 56 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1237] [Chemical Formula 56]

[1238]

[1239] LCMS (ESI-MS): mass calcd. C 26 H 21 N3O2S 439.1 m / z, found 439.8 [M+H] + .

[1240] 1 H NMR (400 MHz, DMSO-d6) δ9.29 (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).

[1241]

[1242] Manufacturing Example 55. 3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-6-((tetrahydro-2H-pyran-4-yl)amino)-1H-inden-1-one (3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-6-((tetrahydro-2H-pyran-4-yl)amino)-1H-inden-1-one) (Compound 56)

[1243] [Reaction Formula 55]

[1244]

[1245] The desired title compound (22.6 mg, 19%) was obtained as a blue solid using tetrahydro-2H-pyran-4-amine in the same manner as in Manufacturing Example 48.

[1246] LCMS (ESI-MS) of the above-obtained compound 56 (chemical formula 57 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1247] [Chemical Formula 57]

[1248]

[1249] LCMS (ESI-MS): mass calcd. C 23 H 21 N3O2S 403.1 m / z, found 403.8 [M+H] + .

[1250] 1 H NMR (400 MHz, DMSO-d6) δ9.28 (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= 11.2 Hz, 2H), 2.03 - 1.78 (m, 5H), 1.43 - 1.36 (m, 2H).

[1251]

[1252] Manufacturing Example 56.3-(4-methylthiazol-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)

[1253] [Reaction Formula 56]

[1254]

[1255] The desired title compound (16 mg, 30%) was obtained as a red solid using 3-phenylpropane-1-thiol in the same manner as in Manufacturing Example 48.

[1256] LCMS (ESI-MS) of the above-obtained compound 57 (chemical formula 58 below) and 1As a result of H NMR analysis, the following data were obtained:

[1257] [Chemical Formula 58]

[1258]

[1259] LCMS (ESI-MS): mass calcd. C 27 H 22 N2OS2454.1 m / z, found 455.1 [M+H] + .

[1260] 1 H NMR (400 MHz, DMSO-d6) δ8.95 (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).

[1261]

[1262] Manufacturing Example 57.3-(4-methylthiazol-5-yl)-6-((1-phenylpiperidin-3-yl)amino)-2-(pyridin-3-yl)-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)

[1263] [Reaction Formula 57]

[1264]

[1265] Using the same method as in Manufacturing Example 48, 1-phenylpiperidin-3-amine was used to obtain the desired title compound (20.0 mg, 22%) as a blue solid.

[1266] LCMS (ESI-MS) of the above-obtained compound 58 (chemical formula 59 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1267] [Chemical Formula 59]

[1268]

[1269] LCMS (ESI-MS): mass calcd. C 29 H 26 N4OS 478.2 m / z, found 479.0 [M+H] + .

[1270] 1 H NMR (400 MHz, DMSO-d6) δ9.29 (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).

[1271]

[1272] Manufacturing Example 58. 6-amino-3-(4-methylthiazol-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)

[1273] [Reaction Formula 58]

[1274]

[1275] To a solution of 6-chloro-3-(4-methylthiazol-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) was added dioxane (30 mL), and the mixture was stirred at 100°C for 16 h under nitrogen. HCl / dioxane (3 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 h.

[1276] Water (20 mL) was added to the reaction mixture and extracted with EA (30 mL x 3). The organic layer was washed in a conventional manner, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (5% MeOH / DCM) to obtain the desired title compound (180 mg, 32%) as a blue solid.

[1277] LCMS (ESI-MS) of the above-obtained compound 59 (chemical formula 60 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1278] [Chemical Formula 60]

[1279]

[1280] LCMS (ESI-MS): mass calcd. C 18 H 13 N3OS 319.1 m / z, found 319.6 [M+H] + .

[1281] 1H NMR (400 MHz, DMSO-d6) δ9.28 (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).

[1282]

[1283] Manufacturing Example 59. N-(3-(4-methylthiazol-5-yl)-1-oxo-2-(pyridin-3-yl)-1H-inden-6-yl)-3-phenylpropanamide (N-(3-(4-methylthiazol-5-yl)-1-oxo-2-(pyridin-3-yl)-1H-inden-6-yl)-3-phenylpropanamide) (Compound 60)

[1284] [Reaction Formula 59]

[1285]

[1286] 6-Amino-3-(4-methylthiazol-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-phenylpropanoic acid (86 mg, 0.57 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (217 mg, 0.57 mmol) and DIPEA (98 mg, 0.76 mmol), and the mixture was stirred at room temperature for 16 h. Water (6 mL) was added to the reaction mixture, and extracted with EA (15 mL x 3). The organic layer was washed by a conventional method, dried, and concentrated under reduced pressure. The concentrated residue was purified by prep-HPLC (Gemini 5 ㎛ C). 18 The residue was purified by column, 150 x 21.2 mm, 30 - 90% ACN / H2O 0.1% FA) to obtain the desired title compound (23.1 mg, 13%) as a yellow solid.

[1287] LCMS (ESI-MS) of the above-obtained compound 60 (chemical formula 61 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1288] [Chemical Formula 61]

[1289]

[1290] LCMS (ESI-MS): mass calcd. C 27 H 21 N3O2S 451.1 m / z, found 452.2 [M+H] + .

[1291] 1 H NMR (400 MHz, DMSO-d6) δ10.28 (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).

[1292]

[1293] Manufacturing Example 60. N-(3-(4-methylthiazol-5-yl)-1-oxo-2-(pyridin-3-yl)-1H-inden-6-yl)tetrahydro-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)

[1294] [Reaction Formula 60]

[1295]

[1296] The desired title compound (18.7 mg, 29%) was obtained as a white solid using tetrahydro-2H-pyran-4-carboxylic acid in the same manner as in Manufacturing Example 59.

[1297] LCMS (ESI-MS) of the above-obtained compound 61 (chemical formula 62 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1298] [Chemical Formula 62]

[1299]

[1300] LCMS (ESI-MS): mass calcd. C 24 H 21 N3O3S 431.1 m / z, found 431.8 [M+H] + .

[1301] 1 H NMR (400 MHz, DMSO-d6) δ10.26 (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).

[1302]

[1303] Manufacturing Example 61. 6-(dimethylamino)-3-(4-methylthiazol-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)

[1304] [Reaction Formula 61]

[1305]

[1306] The desired title compound (60 mg, 65%) was obtained as a purple solid using dimethylamine in the same manner as in Manufacturing Example 58.

[1307] LCMS (ESI-MS) of the above-obtained compound 62 (chemical formula 63 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1308] [Chemical Formula 63]

[1309]

[1310] LCMS (ESI-MS): mass calcd. C 20 H 17 N3O 347.1 m / z, found 347.7 [M+H] + .

[1311] 1 H NMR (400 MHz, DMSO-d6) δ9.29 (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).

[1312]

[1313] Manufacturing Example 62. 6-(cyclopropylamino)-3-(4-methylthiazol-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)

[1314] [Reaction Formula 62]

[1315]

[1316] The desired title compound (80 mg, 67%) was obtained as a purple solid using cyclopropanamine in the same manner as in Manufacturing Example 58.

[1317] LCMS (ESI-MS) of the above-obtained compound 63 (chemical formula 64 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1318] [Chemical Formula 64]

[1319]

[1320] LCMS (ESI-MS): mass calcd. C 21 H 17 N3OS 359.1 m / z, found 359.7 [M+H] + .

[1321] 1 H NMR (400 MHz, DMSO-d6) δ9.28 (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).

[1322]

[1323] Manufacturing Example 63. 6-(4-methylpiperazin-1-yl)-3-(4-methylthiazol-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)

[1324] [Reaction Formula 63]

[1325]

[1326] Using 1-methylpiperazine in the same manner as in Manufacturing Example 58, the desired title compound (15.1 mg, 16%) was obtained as a yellow solid.

[1327] LCMS (ESI-MS) of the above-obtained compound 64 (chemical formula 65 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1328] [Chemical Formula 65]

[1329]

[1330] LCMS (ESI-MS): mass calcd. C 23 H 22 N4OS 402.2 m / z, found 403.1 [M+H] + .

[1331] 1 H NMR (400 MHz, DMSO-d6) δ9.30 (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).

[1332]

[1333] Manufacturing Example 64. 6-(methyl(3-phenylpropyl)amino)-3-(4-methylthiazol-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)

[1334] [Reaction Formula 64]

[1335]

[1336] Step 1: Synthesis of 3-(4-methylthiazol-5-yl)-6-((3-phenylpropyl)amino)-2-(pyridin-3-yl)-1H-inden-1-one

[1337] Using 3-phenylpropan-1-amine in the same manner as in Manufacturing Example 58, the desired title compound (220 mg, 34%) was obtained as a yellow solid.

[1338] LCMS (ESI-MS): mass calcd. C 27 H 23 N3OS 437.2 m / z, found 437.8 [M+H] + .

[1339]

[1340] Step 2: Synthesis of 6-(methyl(3-phenylpropyl)amino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (65)

[1341] The desired title compound (12 mg, 12%) was obtained as a yellow solid in the same manner as step 5 of Manufacturing Example 29.

[1342] LCMS (ESI-MS) of the above-obtained compound 65 (chemical formula 66 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1343] [Chemical Formula 66]

[1344]

[1345] LCMS (ESI-MS): mass calcd. C 28 H 25 N3OS 451.2 m / z, found 452.0 [M+H] + .

[1346] 1 H NMR (400 MHz, DMSO-d6) δ9.29 (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).

[1347]

[1348] Manufacturing Example 65. 3-(4-methylthiazol-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 65)

[1349] [Reaction Formula 65]

[1350]

[1351] To a solution of 6-chloro-3-(4-methylthiazol-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) was added toluene (5 mL), and the mixture was stirred at 100 °C for 16 h under nitrogen. After cooling to room temperature, water (20 mL) was added to the reaction mixture, and extracted with EA (15 mL x 3). The organic layer was washed in a conventional manner, dried, and concentrated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (40% EA / Hexane) to obtain the desired title compound (5.62 mg, 12% yield) as a red solid.

[1352] LCMS (ESI-MS) of the above-obtained compound 66 (chemical formula 67 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1353] [Chemical Formula 67]

[1354]

[1355] LCMS (ESI-MS): mass calcd. C 24 H 16 N2O2S 396.1 m / z, found 397.1 [M+H] + .

[1356] 1 H NMR (400 MHz, DMSO-d6) δ8.96 (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).

[1357]

[1358] Manufacturing Example 66. 6-(methylamino)-2,3-diphenyl-1H-inden-1-one (6-(methylamino)-2,3-diphenyl-1H-inden-1-one) (Compound 67)

[1359] [Reaction Formula 66]

[1360]

[1361] Step 1: Synthesis of 6-((2,4-dimethoxybenzyl)(methyl)amino)-2,3-diphenyl-1H-inden-1-one

[1362] Using the same method as in Manufacturing Example 58, 1-(2,4-dimethoxyphenyl)-N-methylmethanamine was used to obtain the desired title compound (70 mg, 38%) as a yellow solid.

[1363] LCMS (ESI-MS): mass calcd. C 31 H 27 NO3461.2 m / z, found 461.8 [M+H] + .

[1364]

[1365] Step 2: Synthesis of 6-(methylamino)-2,3-diphenyl-1H-inden-1-one (67)

[1366] 6-((2,4-Dimethoxybenzyl)(methyl)amino)-2,3-diphenyl-1H-inden-1-one (70 mg, 0.15 mmol) and DCM / TFA (1 ml / 0.3 ml) were added and stirred at room temperature. Water (3 mL) was added to the reaction mixture and extracted with DCM (80 mL x 3). The organic layer was washed in a conventional manner, dried, and concentrated under reduced pressure. The concentrated residue was purified by prep-HPLC (Gemini 5 ㎛ C 18The crude product was purified by column chromatography (150 x 21.2 mm, 30 - 90% ACN / H2O 0.1% NH3H2O) to obtain the desired title compound (20.2 mg, 43%) as a blue solid.

[1367] LCMS (ESI-MS) of the above-obtained compound 67 (chemical formula 68 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1368] [Chemical Formula 68]

[1369]

[1370] LCMS (ESI-MS): mass calcd. C 22 H 17 NO 311.1 m / z, found 311.8 [M+H] + .

[1371] 1 H NMR (400 MHz, DMSO-d6) δ7.47 - 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).

[1372]

[1373] Manufacturing Example 67. 6-amino-2,3-diphenyl-1H-inden-1-one (6-amino-2,3-diphenyl-1H-inden-1-one) (Compound 68)

[1374] [Reaction Formula 67]

[1375]

[1376] The desired title compound (200 mg, 27%) was obtained as a white solid using diphenylmethanimine in the same manner as in Manufacturing Example 58.

[1377] LCMS (ESI-MS) of the above-obtained compound 68 (chemical formula 69 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1378] [Chemical Formula 69]

[1379]

[1380] LCMS (ESI-MS): mass calcd. C 21 H 15 NO 297.1 m / z, found 298.1 [M+H] + .

[1381] 1 H NMR (400 MHz, DMSO-d6) δ7.46 - 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).

[1382]

[1383] Manufacturing Example 68. 6-(dimethylamino)-2,3-diphenyl-1H-inden-1-one (6-(dimethylamino)-2,3-diphenyl-1H-inden-1-one) (Compound 69)

[1384] [Reaction Formula 68]

[1385]

[1386] The desired title compound (20 mg, 20%) was obtained as a white solid using an aqueous solution of NaBH4 and H2SO4 in the same manner as step 5 of Manufacturing Example 29.

[1387] LCMS (ESI-MS) of the above-obtained compound 69 (chemical formula 70 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1388] [Chemical Formula 70]

[1389]

[1390] LCMS (ESI-MS): mass calcd. C 23 H 19 NO 325.1 m / z, found 325.7 [M+H]+.

[1391] 1 H NMR (400 MHz, DMSO-d6) δ7.48 - 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).

[1392]

[1393] Manufacturing 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)

[1394] [Reaction Formula 69]

[1395]

[1396] Using the same method as in Manufacturing Example 58, 2-(piperazin-1-yl)ethan-1-ol, the desired title compound (8.9 mg, 4%) was obtained as a yellow solid.

[1397] LCMS (ESI-MS) of the above-obtained compound 70 (chemical formula 71 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1398] [Chemical Formula 71]

[1399]

[1400] LCMS (ESI-MS): mass calcd. C 27 H 26 N2O2410.2 m / z, found 411.0 [M+H] + .

[1401] 1 H NMR (400 MHz, DMSO-d6) δ7.50 - 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).

[1402]

[1403] Manufacturing 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)

[1404] [Reaction Formula 70]

[1405]

[1406] Step 1: Synthesis of 1-bromo-5-chloro-2-iodo-3-methylbenzene

[1407] 2-Bromo-4-chloro-6-methylaniline (3 g, 0.0136 mol) was dissolved in HCl (18 mL) and H2O (24 mL), and then NaNO2 aqueous solution (1.03 g / 5 mL H2O) was added at -5℃ and stirred at the same temperature for 30 minutes. KI (2.71 g, 0.0163 mol) was added to the reaction mixture, the mixture was warmed to room temperature, and stirred 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 according to the usual method, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (5% EtOAc / hexane) to obtain the desired title compound (1.6 g, 31%) as a yellow solid.

[1408]

[1409] Step 2: Synthesis of 6-chloro-4-methyl-2,3-diphenyl-1H-inden-1-one

[1410] To 1-bromo-5-chloro-2-iodo-3-methylbenzene (300 mg, 0.9258 mmol), 1,2-diphenylethene (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) was added dioxane (10 mL), and the mixture was stirred at 100°C for 24 h under CO. 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 obtain the desired title compound (130 mg, 39%) as a yellow solid.

[1411] LCMS (ESI-MS): mass calcd. C 22 H 15 ClO 330.1 m / z, found 330.6 [M+H] + .

[1412]

[1413] Step 3: Synthesis of 4-methyl-6-(4-methylpiperazin-1-yl)-2,3-diphenyl-1H-inden-1-one (Compound 71)

[1414] The desired title compound (50 mg, 37%) was obtained as a white solid in the same manner as in Manufacturing Example 58.

[1415] LCMS (ESI-MS) of the above-obtained compound 71 (chemical formula 72 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1416] [Chemical Formula 72]

[1417]

[1418] LCMS (ESI-MS): mass calcd. C 27 H 26 N2O 394.2 m / z, found 395.1 [M+H] + .

[1419] 1 H NMR (400 MHz, DMSO-d6) δ7.48 - 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).

[1420]

[1421] Manufacturing 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 72)

[1422] [Reaction Formula 71]

[1423]

[1424] Step 1: Synthesis of (E)-1-(2-bromo-5-chlorophenyl)-3-(2,6-dimethylphenyl)prop-2-en-1-one

[1425] The desired title compound (2.8 g, 83%) was obtained as a yellow oil in the same manner as in step 1 of Manufacturing Example 21.

[1426] LCMS (ESI-MS): mass calcd. C 17 H 14 BrClO 350.0 m / z, found 350.6 [M+H] + .

[1427]

[1428] Step 2: Synthesis of 6-chloro-3-(2,6-dimethylphenyl)-1H-inden-1-one

[1429] (E)-1-(2-Bromo-5-chlorophenyl)-3-(2,6-dimethylphenyl)prop-2-en-1-one (2.5 g, 7.1 mmol), PdCl2 (0.08 g, 0.355 mmol), PPh3 (0.19 g, 0.72 mmol), and K2CO3 (2.96 g, 21.4 mmol) were added DMF (20 mL) and stirred at 100 °C for 4 h under nitrogen. Water (80 mL) was added to the reaction mixture and extracted with EA (100 mL x 3). The organic layer was washed by a conventional method, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (10% EtOAc / hexane) to obtain the desired title compound (1 g, 26%) as a yellow solid.

[1430] LCMS (ESI-MS): mass calcd. C 17 H 13ClO 268.1 m / z, found 268.7 [M+H] + .

[1431]

[1432] Step 3: Synthesis of 2-bromo-6-chloro-3-(2,6-dimethylphenyl)-1H-inden-1-one

[1433] Br2 (0.89 g, 0.0055 mol) was added to a solution of 6-chloro-3-(2,6-dimethylphenyl)-1H-inden-1-one (1 g, 0.0037 mol) in DCM (30 mL) at 0℃ and stirred at the same temperature for 2 hours. Water (80 mL) was added to the reaction mixture and extracted with DCM (100 mL x 3). The organic layer was washed in a conventional manner, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (5% EtOAc / hexane) to obtain the desired title compound (0.8 g, 56%) as a yellow oil.

[1434] LCMS (ESI-MS): mass calcd. C 17 H 12 BrClO 348.0 m / z, found 348.6 [M+H] + .

[1435]

[1436] Step 4: Synthesis of 6-chloro-3-(2,6-dimethylphenyl)-2-phenyl-1H-inden-1-one

[1437] The desired title compound (80 mg, 40%) was obtained as a white solid in the same manner as step 5 of Manufacturing Example 21.

[1438] LCMS (ESI-MS): mass calcd. C 23 H 17 ClO 344.1 m / z, found 344.7 [M+H] +.

[1439] 1 H NMR (400 MHz, DMSO-d6) δ7.57 - 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).

[1440]

[1441] Step 5: Synthesis of 3-(2,6-dimethylphenyl)-6-(4-methylpiperazin-1-yl)-2-phenyl-1H-inden-1-one (Compound 72)

[1442] The desired title compound (20.2 mg, 27%) was obtained as a purple solid using the same method as in Manufacturing Example 58.

[1443] LCMS (ESI-MS) of the above-obtained compound 72 (chemical formula 73 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1444] [Chemical Formula 73]

[1445]

[1446] LCMS (ESI-MS): mass calcd. C 28 H 28 N2O 408.2 m / z, found 409.1 [M+H] + .

[1447] 1 H NMR (400 MHz, DMSO-d6) δ7.21 - 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).

[1448]

[1449] Manufacturing Example 72. 6-(4-methylpiperazin-1-yl)-2-(3-morpholinophenyl)-3-phenyl-1H-inden-1-one (6-(4-methylpiperazin-1-yl)-2-(3-morpholinophenyl)-3-phenyl-1H-inden-1-one) (Compound 73)

[1450] [Reaction Formula 72]

[1451]

[1452] Step 1: Synthesis of (E)-1-(2-bromo-5-chlorophenyl)-3-phenylprop-2-en-1-one

[1453] The desired title compound (4 g, 65%) was obtained as a yellow solid in the same manner as step 1 of Manufacturing Example 21.

[1454] LCMS (ESI-MS): mass calcd. C 15 H 10 BrClO 322.0 m / z, found 322.6 [M+H] + .

[1455]

[1456] Step 2: Synthesis of 6-chloro-3-phenyl-1H-inden-1-one

[1457] The desired title compound (2.6 g, 74%) was obtained as a yellow solid in the same manner as in step 2 of Manufacturing Example 22.

[1458] LCMS (ESI-MS): mass calcd. C 15 H9ClO 240.0 m / z, found 240.6 [M+H] + .

[1459]

[1460] Step 3: Synthesis of 2-bromo-6-chloro-3-phenyl-1H-inden-1-one

[1461] The desired title compound (0.8 g, 38%) was obtained as a yellow oil in the same manner as step 3 of Manufacturing Example 22.

[1462] LCMS (ESI-MS): mass calcd. C 15 H8BrClO 319.9 m / z, found 320.5 [M+H] + .

[1463]

[1464] Step 4: Synthesis of 6-chloro-2-(3-morpholinophenyl)-3-phenyl-1H-inden-1-one

[1465] The desired title compound (220 mg, 52%) was obtained as a red solid in the same manner as in step 5 of Manufacturing Example 21.

[1466] LCMS (ESI-MS): mass calcd. C 25 H 20 ClNO2401.1 m / z, found 402.0 [M+H] + .

[1467]

[1468] Step 5: Synthesis of 6-(4-methylpiperazin-1-yl)-2-(3-morpholinophenyl)-3-phenyl-1H-inden-1-one (Compound 73)

[1469] The desired title compound (70 mg, 45%) was obtained as a red solid using the same method as in Manufacturing Example 58.

[1470] LCMS (ESI-MS) of the above-obtained compound 73 (chemical formula 74 below) and 1As a result of H NMR analysis, the following data were obtained:

[1471] [Chemical Formula 74]

[1472]

[1473] LCMS (ESI-MS): mass calcd. C 30 H 31 N3O2465.2 m / z, found 466.2 [M+H] + .

[1474] 1 H NMR (400 MHz, DMSO-d6) δ7.47 - 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).

[1475]

[1476] Manufacturing Example 73. 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)

[1477] [Reaction Formula 73]

[1478]

[1479] Step 1: Synthesis of (E)-1-(2-bromo-5-chlorophenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one

[1480] The desired title compound (6 g, 73%) was obtained as a yellow solid using the same method as step 1 of Manufacturing Example 21.

[1481] LCMS (ESI-MS): mass calcd. C 13 H9BrClNOS 342.9 m / z, found 343.6 [M+H] + .

[1482]

[1483] Step 2: Synthesis of 6-chloro-3-(4-methylthiazol-5-yl)-1H-inden-1-one

[1484] The desired title compound (2.7 g, 63%) was obtained as a yellow solid using the same method as step 2 of Manufacturing Example 22.

[1485] LCMS (ESI-MS): mass calcd. C 13 H8ClNOS 261.0 m / z, found 261.6 [M+H] + .

[1486]

[1487] Step 3: Synthesis of 2-bromo-6-chloro-3-(4-methylthiazol-5-yl)-1H-inden-1-one

[1488] The desired title compound (2.7 g, 58%) was obtained as a yellow solid in the same manner as step 3 of Manufacturing Example 22.

[1489] LCMS (ESI-MS): mass calcd. C 13H7BrClNOS 340.9 m / z, found 341.5 [M+H] + .

[1490]

[1491] Step 4: Synthesis of 6-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one

[1492] The desired title compound (200 mg, 81%) was obtained as a red solid in the same manner as in step 5 of Manufacturing Example 21.

[1493] LCMS (ESI-MS): mass calcd. C 24 H 22 ClN3OS 435.1 m / z, found 435.8 [M+H] + .

[1494]

[1495] 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 (Compound 74)

[1496] The desired title compound (60 mg, 55%) was obtained as a purple solid using the same method as in Manufacturing Example 58.

[1497] LCMS (ESI-MS) of the above-obtained compound 74 (chemical formula 75 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1498] [Chemical Formula 75]

[1499]

[1500] LCMS (ESI-MS): mass calcd. C 30 H 35 N5O2S 529.3 m / z, found 530.1 [M+H] + .

[1501] 1 H NMR (400 MHz, DMSO-d6) δ9.24 (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).

[1502]

[1503] Manufacturing Example 74. 6-(4-methylpiperazin-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-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)

[1504] [Reaction Formula 74]

[1505]

[1506] Step 1: Synthesis of 6-hydroxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one

[1507] The desired title compound (324 mg, 45%) was obtained as a purple solid in the same manner as in step 5 of Manufacturing Example 21.

[1508] LCMS (ESI-MS): mass calcd. C 24 H 23 N3O2S 417.2 m / z, found 418.0 [M+H] + .

[1509]

[1510] 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

[1511] To a THF (10 mL) solution of 6-hydroxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one (240 mg, 0.5748 mmol) at 0°C were added NaH (57.48 mg, 1.437 mmol, 60% in mineral oil) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (434.1 mg, 1.437 mmol), and the mixture was stirred at the same temperature for 2 hours.

[1512] Water (20 mL) was added to the reaction mixture and extracted with EA (20 mL x 3). The organic layer was washed in a conventional manner, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (3% MeOH / DCM) to obtain the desired title compound (324 mg, 45%) as a purple solid.

[1513] LCMS (ESI-MS): mass calcd. C 28 H 22 F9N3O4S2699.1 m / z, found 700.1 [M+H] + .

[1514]

[1515] 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)

[1516] The desired title compound (36 mg, 18%) was obtained as a purple solid in the same manner as in Manufacturing Example 58.

[1517] LCMS (ESI-MS) of the above-obtained compound 75 (chemical formula 76 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1518] [Chemical Formula 76]

[1519]

[1520] LCMS (ESI-MS): mass calcd. C 29 H 33 N5OS 499.2 m / z, found 500.3 [M+H] + .

[1521] 1 H NMR (400 MHz, DMSO-d6) δ9.24 (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).

[1522]

[1523] Manufacturing Example 75. 2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one (2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one) (Compound 76)

[1524] [Reaction Formula 75]

[1525]

[1526] The desired title compound (11.1 mg, 5%) was obtained as a purple solid in the same manner as in Manufacturing Example 35.

[1527] LCMS (ESI-MS) of the above-obtained compound 76 (chemical formula 77 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1528] [Chemical Formula 77]

[1529]

[1530] LCMS (ESI-MS): mass calcd. C 33 H 33 N3O2S 535.2 m / z, found 536.2 [M+H] + .

[1531] 1 H NMR (400 MHz, CDCl3) δ8.89 (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).

[1532]

[1533] Manufacturing Example 76. 2,3-bis(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one (2,3-bis(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one) (Compound 77)

[1534] [Reaction Formula 76]

[1535]

[1536] Step 1: Synthesis of 6-hydroxy-2,3-bis(4-methylthiazol-5-yl)-1H-inden-1-one

[1537] The desired title compound (149 mg, 69%) was obtained as a yellow solid in the same manner as in step 5 of Manufacturing Example 21.

[1538] LCMS (ESI-MS): mass calcd. C 17 H 12 N2O2S2340.0 m / z, found 341.0 [M+H] + .

[1539]

[1540] Step 2: Synthesis of 2,3-bis(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one (Compound 77)

[1541] The desired title compound (19 mg, 9%) was obtained as a yellow solid using the same method as in Manufacturing Example 35.

[1542] LCMS (ESI-MS) of the above-obtained compound 77 (chemical formula 78 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1543] [Chemical Formula 78]

[1544]

[1545] LCMS (ESI-MS): mass calcd. C 26 H 22 N2O2S2458.1 m / z, found 459.1 [M+H] + .

[1546] 1 H NMR (400 MHz, DMSO-d6) δ9.32 (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).

[1547]

[1548] Manufacturing Example 77. 2,3-diphenyl-6-(3-phenylpropoxy)-1H-inden-1-one (2,3-diphenyl-6-(3-phenylpropoxy)-1H-inden-1-one) (Compound 78)

[1549] [Reaction Formula 77]

[1550]

[1551] The desired title compound (70 mg, 47%) was obtained as a white solid using the same method as in Manufacturing Example 35.

[1552] LCMS (ESI-MS) of the above-obtained compound 78 (chemical formula 79 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1553] [Chemical Formula 79]

[1554]

[1555] LCMS (ESI-MS): mass calcd. C 30 H 24 O2416.2 m / z, found 417.2 [M+H] + .

[1556] 1 H NMR (400 MHz, DMSO-d6) δ7.47 - 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).

[1557]

[1558] Manufacturing Example 78. 6-(4-methylpiperazin-1-yl)-2,3-bis(4-methylthiazol-5-yl)-1H-inden-1-one (6-(4-methylpiperazin-1-yl)-2,3-bis(4-methylthiazol-5-yl)-1H-inden-1-one) (Compound 79)

[1559] [Reaction Formula 78]

[1560]

[1561] Step 1: Synthesis of 5-ethynyl-4-methylthiazole

[1562] 4-Methylthiazole-5-carbaldehyde (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) were added MeOH (50 mL) and stirred at room temperature for 16 hours. Water (100 mL) was added to the reaction mixture and extracted with EA (100 mL x 3). The organic layer was washed by a conventional method, dried and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (10% EtOAc / hexane) to obtain the desired title compound (5 g, 50%) as a yellow oil.

[1563] LCMS (ESI-MS): mass calcd. C6H5NS 123.0 m / z, found 124.0 [M+H]+ .

[1564]

[1565] Step 2: Synthesis of 1,2-bis(4-methylthiazol-5-yl)ethyne

[1566] 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) were added DMF (15 mL) and stirred at 90°C for 16 h under nitrogen. Water (100 mL) was added to the reaction mixture and extracted with EA (100 mL x 3). The organic layer was washed by a conventional method, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (20% EtOAc / hexane) to obtain the desired title compound (0.8 g, 34%) as a yellow oil.

[1567] LCMS (ESI-MS): mass calcd. C 10 H8N2S2220.0 m / z, found 220.6 [M+H] + .

[1568]

[1569] Step 3: Synthesis of 6-(4-methylpiperazin-1-yl)-2,3-bis(4-methylthiazol-5-yl)-1H-inden-1-one (Compound 79)

[1570] 1,2-Bis(4-methylthiazol-5-yl)ethyne (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) were added DMF (4 mL) and stirred at 100°C for 24 h under nitrogen. Water (30 mL) was added to the reaction mixture and extracted with EA (40 mL x 3). The organic layer was washed by a conventional method, dried, and concentrated under reduced pressure. The concentrated residue was purified by prep-HPLC (Gemini 5 μm C). 18 The desired title compound (50 mg, 30%) was obtained as a purple solid by purification with column, 150 x 21.2 mm, 30 - 95% ACN / H2O 0.1% NH3H2O).

[1571] LCMS (ESI-MS) of the above-obtained compound 79 (chemical formula 80 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1572] [Chemical Formula 80]

[1573]

[1574] LCMS (ESI-MS): mass calcd. C 22 H 22 N4OS2422.1 m / z, found 423.1 [M+H] + .

[1575] 1H NMR (400 MHz, DMSO-d6) δ9.30 (s, 1H), 9.05 (s, 1H), 7.25 (d,J= 2.4 Hz, 1H), 7.10 (d,J= 8.2 Hz, 1H), 6.89 (dd,J= 8.2, 2.4 Hz, 1H), 3.30 - 3.25 (m, 4H), 2.46 - 2.41 (m, 4H), 2.22 (s, 3H), 1.98 (s, 3H), 1.90 (s, 3H).

[1576]

[1577] Manufacturing Example 79. 6-(4-methylpiperazin-1-yl)-2,3-bis(3-morpholinophenyl)-1H-inden-1-one (6-(4-methylpiperazin-1-yl)-2,3-bis(3-morpholinophenyl)-1H-inden-1-one) (Compound 80)

[1578] [Reaction Formula 79]

[1579]

[1580] Step 1: Synthesis of 4-(3-((trimethylsilyl)ethynyl)phenyl)morpholine

[1581] The desired title compound (4.2 g, 75% purity, 97% yield) was obtained as a yellow oil using the same method as step 2 of Manufacturing Example 78.

[1582] LCMS (ESI-MS): mass calcd. C 15 H 21 NOSi 259.1 m / z, found 259.7 [M+H] + .

[1583]

[1584] Step 2: Synthesis of 4-(3-ethynylphenyl)morpholine

[1585] 4-(3-((trimethylsilyl)ethynyl)phenyl)morpholine (4.12 g, 0.0159 mol) and K2CO3 (3.29 g, 0.02385) mmol were added to MeOH (100 mL) and stirred at room temperature for 3 hours.

[1586] Water (200 mL) was added to the reaction mixture and extracted with DCM (100 mL x 3). The organic layer was washed in a conventional manner, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (5% EtOAc / hexane) to obtain the desired title compound (2.87 g, 90% purity, 87% yield) as a yellow oil.

[1587] LCMS (ESI-MS): mass calcd. C 12 H 13 NO 187.1 m / z, found 187.7 [M+H] + .

[1588]

[1589] Step 3: Synthesis of 1,2-bis(3-morpholinophenyl)ethyne

[1590] The desired title compound (340 mg, 45%) was obtained as a yellow oil in the same manner as step 2 of Manufacturing Example 78.

[1591] LCMS (ESI-MS): mass calcd. C 22 H 24 N2O2348.2 m / z, found 349.2 [M+H] + .

[1592]

[1593] Step 4: Synthesis of 2-bromo-5-(4-methylpiperazin-1-yl)benzaldehyde

[1594] 3-(4-methylpiperazin-1-yl)benzaldehyde (408 mg, 1.9974 mmol) and NBS (710.99 mg, 3.9948 mmol) were added DCM (10 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (15% EtOAc / hexane) to obtain the desired title compound (400 mg, 71%) as a yellow oil.

[1595] LCMS (ESI-MS): mass calcd. C 12 H 15 BrN2O 282.0 m / z, found 282.9 [M+H] + .

[1596]

[1597] Step 5: Synthesis of 6-(4-methylpiperazin-1-yl)-2,3-bis(3-morpholinophenyl)-1H-inden-1-one (Compound 80)

[1598] The desired title compound (55.4 mg, 22%) was obtained as a yellow oil in the same manner as in step 3 of Manufacturing Example 78.

[1599] LCMS (ESI-MS) of the above-obtained compound 80 (chemical formula 81 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1600] [Chemical Formula 81]

[1601]

[1602] LCMS (ESI-MS): mass calcd. C 34 H 38 N4O3550.3 m / z, found 551.73 [M+H] + .

[1603] 1H NMR (400 MHz, DMSO-d6) δ7.33 - 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).

[1604]

[1605] Manufacturing Example 80. 6-(4-(2-hydroxy)piperazin-1-yl)-2,3-bis(4-methylthiazol-5-yl)-1H-inden-1-one (6-(4-(2-hydroxyethyl)piperazin-1-yl)-2,3-bis(4-methylthiazol-5-yl)-1H-inden-1-one) (Compound 81)

[1606] [Reaction Formula 80]

[1607]

[1608] Step 1: Synthesis of tert-butyl 4-(4-bromo-3-formylphenyl)piperazine-1-carboxylate

[1609] The desired title compound (500 mg, 70%) was obtained as a yellow solid in the same manner as step 4 of Manufacturing Example 79.

[1610] LCMS (ESI-MS): mass calcd. C 16 H 21 BrN2O3368.1 m / z, found 368.7 [M+H] + .

[1611]

[1612] Step 2: Synthesis of tert-butyl 4-(2,3-bis(4-methylthiazol-5-yl)-1-oxo-1H-inden-6-yl)piperazine-1-carboxylate

[1613] The desired title compound (0.6 g, 40%) was obtained as a yellow solid in the same manner as step 3 of Manufacturing Example 78.

[1614] LCMS (ESI-MS): mass calcd. C 26 H 28 N4O3S2508.2 m / z, found 509.1 [M+H] + .

[1615]

[1616] Step 3: Synthesis of 2,3-bis(4-methylthiazol-5-yl)-6-(piperazin-1-yl)-1H-inden-1-one

[1617] The desired title compound (180 mg, 67%) was obtained as a purple solid using the same method as step 4 of Manufacturing Example 29.

[1618] LCMS (ESI-MS): mass calcd. C 21 H 20 N4OS2408.1 m / z, found 409.0 [M+H] + .

[1619]

[1620] Step 4: Synthesis of 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2,3-bis(4-methylthiazol-5-yl)-1H-inden-1-one (Compound 81)

[1621] 2,3-Bis(4-methylthiazol-5-yl)-6-(piperazin-1-yl)-1H-inden-1-one (100 mg, 0.2448 mmol), 2-bromoethane-1-ol (458.8 mg, 3.67 mmol) and DIEA (632.8 mg, 4.89 mmol) were added DCM (10 mL) and stirred at 50°C for 16 h under nitrogen. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by prep-HPLC (Gemini 5 μm C 18 The desired title compound (20 mg, 18%) was obtained as a purple solid by purification with column, 150 x 21.2 mm, 5 - 95% ACN / H2O 0.1% FA).

[1622] LCMS (ESI-MS) of the above-obtained compound 81 (chemical formula 82 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1623] [Chemical Formula 82]

[1624]

[1625] LCMS (ESI-MS): mass calcd. C 23 H 24 N4O2S2452.1 m / z, found 452.8 [M+H] + .

[1626] 1 H NMR (400 MHz, DMSO-d6) δ9.30 (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).

[1627]

[1628] Manufacturing Example 81. 6-hydroxy-2,3-di-o-tolyl-1H-inden-1-one (Compound 82)

[1629] [Reaction Formula 81]

[1630]

[1631] Step 1: Synthesis of 1,2-di-o-tolylethyne

[1632] DMSO (100 mL) was added to propiolic 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 the mixture was stirred at 80°C for 3 hours under nitrogen. Water (300 mL) was added to the reaction mixture, and extracted with EA (400 mL x 3). The organic layer was washed by a conventional method, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (5% EtOAc / hexane) to obtain the desired title compound (5 g, 50%) as a yellow solid.

[1633] 1 H NMR (400 MHz, CDCl3) δ7.52- 7.50 (m, 2H), 7.26 - 7.23 (m, 6H), 2.53 (s, 6H).

[1634]

[1635] Step 2: Synthesis of 6-methoxy-2,3-di-o-tolyl-1H-inden-1-one

[1636] The desired title compound (0.4 g, 7%) was obtained as a yellow solid in the same manner as step 3 of Manufacturing Example 78.

[1637] LCMS (ESI-MS): mass calcd. C24 H 20 O2340.1 m / z, found 340.8 [M+H] + .

[1638]

[1639] Step 3: Synthesis of 6-hydroxy-2,3-di-o-tolyl-1H-inden-1-one (Compound 82)

[1640] 6-Methoxy-2,3-di-o-tolyl-1H-indene-1-one (200 mg, 0.5875 mmol) and Py·HCl (271.57 mg, 2.35 mmol) were stirred at 160°C for 24 h under nitrogen. Water (20 mL) was added to the reaction mixture, and extracted with EA (30 mL x 3). The organic layer was washed in a conventional manner, dried, and concentrated under reduced pressure. The concentrated residue was purified by prep-HPLC (Gemini 5 ㎛ C 18 The desired title compound (80 mg, 37%) was obtained as a white solid by purification with column, 150 x 21.2 mm, 55 - 95% ACN / H2O 0.1% FA).

[1641] LCMS (ESI-MS) of the above-obtained compound 82 (chemical formula 83 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1642] [Chemical Formula 83]

[1643]

[1644] LCMS (ESI-MS): mass calcd. C 23 H 18 O2326.1 m / z, found 327.1 [M+H] + .

[1645] 1H NMR (400 MHz, DMSO-d6) δ10.12 (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).

[1646]

[1647] Manufacturing Example 82. 6-(3-phenylpropoxy)-2,3-di(thiazol-5-yl)-1H-inden-1-one (6-(3-phenylpropoxy)-2,3-di(thiazol-5-yl)-1H-inden-1-one) (Compound 83)

[1648] [Reaction Formula 82]

[1649]

[1650] Step 1: Synthesis of 1,2-di(thiazol-5-yl)ethyne

[1651] The desired title compound (0.9 g, 53%) was obtained as a white solid using the same method as step 2 of Manufacturing Example 78.

[1652] LCMS (ESI-MS): mass calcd. C8H4N2S2192.0 m / z, found 192.6 [M+H] + .

[1653]

[1654] Step 2: Synthesis of 6-methoxy-2,3-di(thiazol-5-yl)-1H-inden-1-one

[1655] The desired title compound (0.35 g, 39%) was obtained as a purple solid in the same manner as in step 3 of Manufacturing Example 78.

[1656] LCMS (ESI-MS): mass calcd. C 16 H 10N2O2S2326.0 m / z, found 326.6 [M+H] + .

[1657]

[1658] Step 3: Synthesis of 6-hydroxy-2,3-di(thiazol-5-yl)-1H-inden-1-one

[1659] The desired title compound (180 mg, 74%) was obtained as a red solid in the same manner as step 4 of Manufacturing Example 41.

[1660] LCMS (ESI-MS): mass calcd. C 15 H8N2O2S2312.0 m / z, found 312.6 [M+H] + .

[1661]

[1662] Step 4: Synthesis of 6-(3-phenylpropoxy)-2,3-di(thiazol-5-yl)-1H-inden-1-one (Compound 83)

[1663] The desired title compound (60 mg, 39%) was obtained as a purple solid in the same manner as in step 2 of Manufacturing Example 38.

[1664] LCMS (ESI-MS) of the above-obtained compound 83 (chemical formula 84 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1665] [Chemical Formula 84]

[1666]

[1667] LCMS (ESI-MS): mass calcd. C 24 H 18 N2O2S2430.1 m / z, found 430.7 [M+H] + .

[1668] 1H NMR (400 MHz, DMSO-d6) δ9.44 (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).

[1669]

[1670] Manufacturing 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)

[1671] [Reaction Formula 83]

[1672]

[1673] Step 1: Synthesis of (E)-3-(2,6-dimethylphenyl)-1-(3-hydroxyphenyl)prop-2-en-1-one

[1674] The desired title compound (10.8 g, 53%) was obtained as a yellow solid using the same method as step 1 of Manufacturing Example 21.

[1675] 1 H NMR (400 MHz, DMSO-d6)δ9.84 (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).

[1676]

[1677] Step 2: Synthesis of 3-(2,6-dimethylphenyl)-6-hydroxy-2,3-dihydro-1H-inden-1-one

[1678] To a solution of (E)-3-(2,6-dimethylphenyl)-1-(3-hydroxyphenyl)prop-2-en-1-one (2 g, 7.94 mmol) in DCM (15 mL) was added MsOH (3 ml) and stirred at 50 °C for 12 h.

[1679] The reaction mixture was adjusted to pH 6 with NaOH aqueous solution (1 N) and filtered to obtain a mixture of the title compound and its structural isomer, 3-(2,6-dimethylphenyl)-4-hydroxy-2,3-dihydro-1H-inden-1-one (1.2 g, 60%) as a yellow solid. It was used in the next reaction without purification.

[1680] LCMS (ESI-MS): mass calcd. C 17 H 16 O2252.1 m / z, found 252.7 [M+H] + .

[1681]

[1682] Step 3: Synthesis of 1-(2,6-dimethylphenyl)-3-oxo-2,3-dihydro-1H-inden-5-yl acetate

[1683] In the same manner as in step 3 of Manufacturing Example 21, a mixture of the desired title compound and 3-(2,6-dimethylphenyl)-1-oxo-2,3-dihydro-1H-inden-4-yl acetate (500 mg, 36%) was obtained as a white solid.

[1684] LCMS (ESI-MS): mass calcd. C 19 H 18 O3294.1 m / z, found 294.8 [M+H] + .

[1685]

[1686] Step 4: Synthesis of 2-bromo-3-(2,6-dimethylphenyl)-1-oxo-1H-inden-6-yl acetate

[1687] The desired title compound (70 mg, 11%) was obtained as a red solid using the same method as step 4 of Manufacturing Example 21.

[1688] LCMS (ESI-MS): mass calcd. C 19 H 15 BrO3370.0 m / z, found 370.8 [M+H] + .

[1689]

[1690] 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 (Compound 84-11)

[1691] In the same manner as in step 5 of Manufacturing Example 21, the desired title compounds 83 (15.4, 15%) and 84-11 (5.4 mg, 5%) were obtained as yellow solids.

[1692] LCMS (ESI-MS) of the above-obtained compound 84-11 and 1 As a result of H NMR analysis, the following data were obtained:

[1693] LCMS (ESI-MS): mass calcd. C 24 H 20 O2340.1 m / z, found 340.8 [M+H] + .

[1694] 1 H NMR (400 MHz, DMSO-d6)δ10.09 (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).

[1695] LCMS (ESI-MS) of the above-obtained compound 84 (chemical formula 85 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1696] [Chemical Formula 85]

[1697]

[1698] LCMS (ESI-MS): mass calcd. C 24 H 20 O2340.1 m / z, found 341.1 [M+H] + .

[1699] 1 H NMR (400 MHz, DMSO-d6)δ10.04 (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).

[1700]

[1701] Manufacturing Example 84. 2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one (2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one) (Compound 85)

[1702] [Reaction Formula 84]

[1703]

[1704] The desired title compound (23.6 mg, 18%) was obtained as a red solid in the same manner as in step 5 of Manufacturing Example 21.

[1705] LCMS (ESI-MS) of the above-obtained compound 85 (chemical formula 86 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1706] [Chemical Formula 86]

[1707]

[1708] LCMS (ESI-MS): mass calcd. C 24 H 23 N3OS 401.2 m / z, found 401.8 [M+H] + .

[1709] 1 H NMR (400 MHz, DMSO-d6)δ9.27 (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).

[1710]

[1711] Manufacturing Example 85. 2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(4-methylthiazol-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)

[1712] [Reaction Formula 85]

[1713]

[1714] The desired title compound (24.2 mg, 17%) was obtained as a yellow solid in the same manner as in step 5 of Manufacturing Example 21.

[1715] LCMS (ESI-MS) of the above-obtained compound 86 (chemical formula 87 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1716] [Chemical Formula 87]

[1717]

[1718] LCMS (ESI-MS): mass calcd. C 25 H 25 N3OS 415.2 m / z, found 416.1 [M+H] + .

[1719] 1 H NMR (400 MHz, DMSO-d6)δ9.29 (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).

[1720]

[1721] Manufacturing Example 86. 3-(4-methylthiazol-5-yl)-2-(4-(morpholinomethyl)phenyl)-1H-inden-1-one (3-(4-methylthiazol-5-yl)-2-(4-(morpholinomethyl)phenyl)-1H-inden-1-one) (Compound 87)

[1722] [Reaction Formula 86]

[1723]

[1724] The desired title compound (23.8 mg, 18%) was obtained as a yellow solid in the same manner as in step 5 of Manufacturing Example 21.

[1725] LCMS (ESI-MS) of the above-obtained compound 87 (chemical formula 88 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1726] [Chemical Formula 88]

[1727]

[1728] LCMS (ESI-MS): mass calcd. C 24 H 22 N2O2S 402.1 m / z, found 403.1 [M+H] + .

[1729] 1 H NMR (400 MHz, DMSO-d6)δ9.30 (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).

[1730]

[1731] Manufacturing Example 87. 2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(4-methylthiazol-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)

[1732] [Reaction Formula 87]

[1733]

[1734] The desired title compound (24.6 mg, 18%) was obtained as a yellow solid in the same manner as in step 5 of Manufacturing Example 21.

[1735] LCMS (ESI-MS) of the above-obtained compound 88 (chemical formula 89 below) and 1As a result of H NMR analysis, the following data were obtained:

[1736] [Chemical Formula 89]

[1737]

[1738] LCMS (ESI-MS): mass calcd. C 25 H 25 N3OS 415.2 m / z, found 416.2 [M+H] + .

[1739] 1 H NMR (400 MHz, DMSO-d6)δ9.29 (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).

[1740]

[1741] Manufacturing Example 88. 3-(4-methylthiazol-5-yl)-2-(3-(morpholinomethyl)phenyl)-1H-inden-1-one (3-(4-methylthiazol-5-yl)-2-(3-(morpholinomethyl)phenyl)-1H-inden-1-one) (Compound 89)

[1742] [Reaction Formula 88]

[1743]

[1744] The desired title compound (24.7 mg, 19%) was obtained as a yellow solid in the same manner as in step 5 of Manufacturing Example 21.

[1745] LCMS (ESI-MS) of the above-obtained compound 89 (chemical formula 90) and 1 As a result of H NMR analysis, the following data were obtained:

[1746] [Chemical Formula 90]

[1747]

[1748] LCMS (ESI-MS): mass calcd. C 24 H 22 N2O2S 402.1 m / z, found 403.1 [M+H] + .

[1749] 1 H NMR (400 MHz, DMSO-d6)δ9.30 (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).

[1750]

[1751] Manufacturing Example 89. 2-(4-(4-methylpiperazin-1-yl)phenyl)-3-phenyl-1H-inden-1-one (2-(4-(4-methylpiperazin-1-yl)phenyl)-3-phenyl-1H-inden-1-one) (Compound 89)

[1752] [Reaction Formula 89]

[1753]

[1754] The desired title compound (60 mg, 46%) was obtained as a red solid in the same manner as in Manufacturing Example 14.

[1755] LCMS (ESI-MS) of the above-obtained compound 90 (chemical formula 91) and 1 As a result of H NMR analysis, the following data were obtained:

[1756] [Chemical Formula 91]

[1757]

[1758] LCMS (ESI-MS): mass calcd. C 26 H 24 N2O 380.2 m / z, found 380.9 [M+H]+ .

[1759] 1 H NMR (400 MHz, DMSO-d6) δ7.51 - 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).

[1760]

[1761] Manufacturing 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)

[1762] [Reaction Formula 90]

[1763]

[1764] The desired title compound (60 mg, 40%) was obtained as a yellow solid in the same manner as in Manufacturing Example 14.

[1765] LCMS (ESI-MS) of the above-obtained compound 91 (chemical formula 92) and 1 As a result of H NMR analysis, the following data were obtained:

[1766] [Chemical Formula 92]

[1767]

[1768] LCMS (ESI-MS): mass calcd. C 26 H 24 N2O 380.2 m / z, found 380.9 [M+H] + .

[1769] 1H NMR (400 MHz, DMSO-d6) δ7.56 - 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).

[1770]

[1771] Manufacturing Example 91. 3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(4-methylthiazol-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)

[1772] [Reaction Formula 91]

[1773]

[1774] Step 1: Synthesis of 3-bromo-1H-inden-1-one

[1775] The desired title compound (1.6 g, 17%) was obtained as a yellow solid in the same manner as in step 4 of Manufacturing Example 21.

[1776] LCMS (ESI-MS): mass calcd. C9H5BrO 208.0 m / z, found 208.5 [M+H] + .

[1777]

[1778] Step 2: Synthesis of 3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-inden-1-one

[1779] The desired title compound (510 mg, 22%) was obtained as a yellow solid in the same manner as step 5 of Manufacturing Example 21.

[1780] 1 H NMR (400 MHz, DMSO-d6)δ7.77 (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).

[1781]

[1782] Step 3: Synthesis of 2-bromo-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-inden-1-one

[1783] 3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-inden-1-one (510 mg, 1.6 mmol), NBS (570 mg, 3.2 mmol), AIBN (262 mg, 1.6 mmol) was added CCl4 and stirred at 80°C for 4 hours. Water (5 mL) was added to the reaction mixture and extracted with EA (10 mL x 3). The organic layer was washed by a conventional method, 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 obtain the desired title compound (210 mg, 33%) as a red solid.

[1784] LCMS (ESI-MS): mass calcd. C 21 H 21 BrN2O 396.1 m / z, found 396.2 [M+H] + .

[1785]

[1786] Step 4: Synthesis of 3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(4-methylthiazol-5-yl)-1H-inden-1-one (Compound 92)

[1787] 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-dioxaborolein-2-yl)thiazole (0.1 g, 0.0005 mol), Pd(dppf)Cl2 (30 mg, 0.00004 mol) and K2CO3 (118 mg, 0.0012 mol) were added dioxane (1.5 mL) and stirred under nitrogen for 100 o The mixture was stirred at C for 3 hours. Water (10 mL) was added to the reaction mixture and extracted with EA (10 mL x 3). The organic layer was washed in a conventional manner, dried, and concentrated under reduced pressure. The obtained concentrated residue was purified by flash chromatography (50% EtOAc / PE) to obtain the desired title compound (5.1 mg, 3%) as a red solid.

[1788] LCMS (ESI-MS) of the above-obtained compound 92 (chemical formula 93) and 1 As a result of H NMR analysis, the following data were obtained:

[1789] [Chemical Formula 93]

[1790]

[1791] LCMS (ESI-MS): mass calcd. C 25 H 25 N3OS 415.2 m / z, found 415.9 [M+H] + .

[1792] 1H NMR (400 MHz, DMSO-d6) δ9.06 (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).

[1793]

[1794] Manufacturing Example 92. 3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(4-methylthiazol-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)

[1795] [Reaction Formula 92]

[1796]

[1797] Step 1: Synthesis of 2-(4-(4-methylpiperazin-1-yl)methyl)phenyl)-1H-inden-1-one

[1798] The desired title compound (190 mg, 31%) was obtained as a yellow solid using the same method as step 5 of Manufacturing Example 21.

[1799] 1 H NMR (400 MHz, DMSO-d6) δ7.68 (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).

[1800]

[1801] Step 2: Synthesis of 2-bromo-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-inden-1-one

[1802] The desired title compound (100 mg, crude) was obtained as a yellow solid in the same manner as step 3 of Manufacturing Example 22.

[1803]

[1804] Step 3: Synthesis of 3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(4-methylthiazol-5-yl)-1H-inden-1-one (Compound 93)

[1805] The desired title compound (8.2 mg, 13%) was obtained as a red solid using the same method as step 5 of Manufacturing Example 21.

[1806] LCMS (ESI-MS) of the above-obtained compound 93 (chemical formula 94 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1807] [Chemical Formula 94]

[1808]

[1809] LCMS (ESI-MS): mass calcd. C 25 H 25 N3OS 415.2 m / z, found 416.0 [M+H] + .

[1810] 1 H NMR (400 MHz, DMSO-d6) 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).

[1811]

[1812] Manufacturing 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)

[1813] [Reaction Formula 93]

[1814]

[1815] The desired title compound (80 mg, 35%) was obtained as a white solid in the same manner as step 5 of Manufacturing Example 21.

[1816] LCMS (ESI-MS) of the above-obtained compound 94 (chemical formula 95 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1817] [Chemical Formula 95]

[1818]

[1819] LCMS (ESI-MS): mass calcd. C 26 H 24 N2O 380.2 m / z, found 381.1 [M+H] + .

[1820] 1 H NMR (400 MHz, DMSO-d6) δ7.51 (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).

[1821]

[1822] Manufacturing 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)

[1823] [Reaction Formula 94]

[1824]

[1825] The desired title compound (60 mg, 46%) was obtained as a white solid using the same method as step 5 of Manufacturing Example 21.

[1826] LCMS (ESI-MS) of the above-obtained compound 95 (chemical formula 96 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1827] [Chemical Formula 96]

[1828]

[1829] LCMS (ESI-MS): mass calcd. C 26 H 24 N2O 380.2 m / z, found 381.1 [M+H] + .

[1830] 1 H NMR (400 MHz, DMSO-d6) δ7.55 - 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).

[1831]

[1832] Manufacturing 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) (Compound 96)

[1833] [Reaction Formula 95]

[1834]

[1835] The desired title compound (40 mg, 17%) was obtained as a white solid using the same method as step 5 of Manufacturing Example 21.

[1836] LCMS (ESI-MS) of the above-obtained compound 96 (chemical formula 97 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1837] [Chemical Formula 97]

[1838]

[1839] LCMS (ESI-MS): mass calcd. C 29 H 30 O 394.2 m / z, found 395.2 [M+H] + .

[1840] 1 H NMR (400 MHz, CDCl3) δ7.59 (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).

[1841]

[1842] Manufacturing Example 96. 4,6-dimethoxy-2,3-diphenyl-1H-inden-1-one (Compound 97)

[1843] [Reaction Formula 96]

[1844]

[1845] Step 1: Synthesis of 2-bromo-3,5-dimethoxybenzaldehyde

[1846] The desired title compound (400 mg, 48%) was obtained as a yellow solid in the same manner as step 4 of Manufacturing Example 79.

[1847] LCMS (ESI-MS): mass calcd. C9H9BrO3244.0 m / z, found 244.9 [M+H] + .

[1848]

[1849] Step 2: Synthesis of 4,6-dimethoxy-2,3-diphenyl-1H-inden-1-one (6-dimethoxy-2,3-diphenyl-1H-inden-1-one) (Compound 97)

[1850] The desired title compound (80 mg, 25%) was obtained as a yellow solid in the same manner as step 3 of Manufacturing Example 78.

[1851] LCMS (ESI-MS) of the above-obtained compound 97 (chemical formula 98 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1852] [Chemical Formula 98]

[1853]

[1854] LCMS (ESI-MS): mass calcd. C 23 H 18 O3342.1 m / z, found 343.1 [M+H] + .

[1855] 1 H NMR (400 MHz, DMSO-d6) δ7.37 - 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).

[1856]

[1857] Manufacturing Example 97 6,7-diphenyl-5H-cyclopenta[b]pyridin-5-one (Compound 98)

[1858] [Reaction Formula 97]

[1859]

[1860] Step 1: Synthesis of 6,7-dibromo-5H-cyclopenta[b]pyridin-5-one

[1861] The desired title compound (350 mg, 11%) was obtained as a yellow solid in the same manner as step 1 of Manufacturing Example 41.

[1862] MS (ESI): mass calcd. C8H3Br2NO 288.9 m / z, found 289.8 [M+H] + .

[1863]

[1864] Step 2: Synthesis of 6,7-diphenyl-5H-cyclopenta[b]pyridin-5-one (Compound 98)

[1865] The desired title compound (60 mg, 16%) was obtained as a yellow solid in the same manner as step 5 of Manufacturing Example 21.

[1866] LCMS (ESI-MS) of the above-obtained compound 98 (chemical formula 99) and 1 As a result of H NMR analysis, the following data were obtained:

[1867] [Chemical Formula 99]

[1868]

[1869] MS (ESI): mass calcd. C 12 H 13NO 283.1 m / z, found 284.0 [M+H] + .

[1870] 1 H NMR (400 MHz, CDCl3) δ8.58 - 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).

[1871]

[1872] Manufacturing Example 98. N-methyl-2-(1-oxo-3-(o-tolyl)-1H-inden-2-yl)benzamide (Compound 99)

[1873] [Reaction Formula 98]

[1874]

[1875] Step 1: Synthesis of (E)-1-(2-iodophenyl)-3-(o-tolyl)prop-2-en-1-one

[1876] The desired title compound (6 g, 76%) was obtained as a white solid using the same method as in step 1 of Manufacturing Example 21. LCMS (ESI-MS): mass calcd. C 16 H 13 IO 348.0 m / z, found 348.6 [M+H] + .

[1877]

[1878] Step 2: Synthesis of 3-(o-tolyl)-2,3-dihydro-1H-inden-1-one

[1879] (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 h. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with EA (300 mL x 3). The organic layer was washed according to the usual method, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (10% EtOAc / hexane) to obtain the desired title compound (2.9 g, 60%) as a yellow solid.

[1880] LCMS (ESI-MS): mass calcd. C 16 H 14 O 222.1 m / z, found 223.1 [M+H] + .

[1881]

[1882] Step 3: Synthesis of 2-bromo-3-(2-methylphenyl)inden-1-one

[1883] The desired title compound (1.8 g, 60%) was obtained as a yellow solid using the same method as step 1 of Manufacturing Example 6.

[1884] LCMS (ESI-MS): mass calcd. C 16 H 11 BrO 298.0 m / z, found 298.6 [M+H] + .

[1885]

[1886] Step 4: Synthesis of ethyl 2-(1-oxo-3-(o-tolyl)-1H-inden-2-yl)benzoate

[1887] 2-Bromo-3-(2-methylphenyl)inden-1-one (2.6 g, 0.0087 mmol), ethyl 2-(dihydroxyboranyl)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 h. Water (60 mL) was added to the reaction mixture, and extracted with EA (100 mL x 3). The organic layer was washed according to the conventional method, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (5% MeOH / DCM) to obtain the desired title compound (0.5 g, 13%) as a yellow solid.

[1888] LCMS (ESI-MS): mass calcd. C 25 H 20 O3368.1 m / z, found 368.8 [M+H] + .

[1889]

[1890] Step 5: Synthesis of 2-(1-oxo-3-(o-tolyl)-1H-inden-2-yl)benzoic acid

[1891] Ethyl 2-(1-oxo-3-(o-tolyl)-1H-indene-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 h. The pH of the mixture was adjusted to 6 by adding 1 M HCl, filtered, and the filter cake was washed with 50 ml of DCM. The organic layer was washed in a conventional manner, dried, and concentrated under reduced pressure. The obtained concentrated residue was purified by prep-HPLC (Gemini 5 ㎛ C 18The crude product was purified by column chromatography (150 x 21.2 mm, 30 - 90% ACN / H2O 0.1% NH3H2O) to obtain the desired title compound (140 mg, 34%) as a yellow solid.

[1892] LCMS (ESI-MS): mass calcd. C 23 H 16 O3340.1 m / z, found 340.8 [M+H] + .

[1893]

[1894] Step 6: Synthesis of N-methyl-2-(1-oxo-3-(o-tolyl)-1H-inden-2-yl)benzamide (Compound 99)

[1895] 2-(1-Oxo-3-(o-tolyl)-1H-indene-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 at room temperature under nitrogen for 16 h. A small amount of water was added to the reaction mixture and extracted with EA (40 mL x 3). The organic layer was washed by a conventional method, dried and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (5% MeOH / DCM) and then prep-HPLC (Gemini 5 μm C 18 The desired title compound (10 mg, 9%) was obtained as a white solid by purification with column, 150 x 21.2 mm, 50 - 95% ACN / H2O 0.05% FA).

[1896] LCMS (ESI-MS) of the above-obtained compound 99 (chemical formula 100 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1897] [Chemical Formula 100]

[1898]

[1899] LCMS (ESI-MS): mass calcd. C 24 H 19 NO2353.1 m / z, found 354.0 [M+H] + .

[1900] 1 H NMR (400 MHz, CDCl3) δ8.57 (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).

[1901]

[1902] Manufacturing Example 99. 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)

[1903] [Reaction Formula 99]

[1904]

[1905] Step 1: Synthesis of 1-benzylpiperazine

[1906] tert-Butyl 4-benzylpiperazine-1-carboxylate (200 mg, 0.721 mmol) was stirred at 25°C for 1 hour under nitrogen with HCl-1,4-dioxane (5 mL). NH3-MeOH (5 mL) was added to the reaction mixture to quench the reaction, water (10 mL) was added, and the mixture was extracted with EA (10 mL x 3). The organic layer was washed in a conventional manner, dried, and concentrated under reduced pressure to obtain the title compound (900 mg, 77%) as a white solid.

[1907] LCMS (ESI-MS): mass calcd. C 11 H 16 N2176.1 m / z, found 177.1 [M+H] + .

[1908]

[1909] Step 2: Synthesis of 6-(4-benzylpiperazin-1-yl)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (Compound 100)

[1910] 6-Chloro-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (80 mg, 0.236 mmol), 1-benzylpiperazine (62.42 mg, 0.354 mmol), Pd-PEPPSI-IPent Cl 1,4-Dioxane (4 ml) was added to (22.97 mg, 0.023 mmol) and Cs2CO3 (153.85 mg, 0.472 mmol) and stirred at 100 °C for 16 h under nitrogen. Water (10 mL) was added to the reaction mixture and extracted with EA (10 mL x 3). The organic layer was washed in a conventional manner, dried, and concentrated under reduced pressure. The concentrated residue was purified by prep-HPLC (Gemini 5 ㎛ C 18The residue was purified by column, 150 x 21.2 mm, 70 - 95% MeCN / H2O 0.1% FA) to obtain the desired title compound (35.2 mg, 29%) as a blue solid.

[1911] LCMS (ESI-MS) of the above-obtained compound 100 (chemical formula 101 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1912] [Chemical Formula 101]

[1913]

[1914] LCMS (ESI-MS): mass calcd. C 29 H 26 N4OS 478.2 m / z, found 478.9 [M+H] + .

[1915] 1 H NMR (400 MHz, CDCl3) δ8.92 (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).

[1916]

[1917] Manufacturing Example 100. 3-(4-methylthiazol-5-yl)-6-((3-phenylpiperidin-1-yl)methyl)-2-(pyridin-3-yl)-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)

[1918] [Reaction Formula 100]

[1919]

[1920] Step 1: Synthesis of 6-methyl-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one

[1921] 6-Chloro-3-(4-methylthiazol-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-trioxatrivorinane (1.66 g, 0.013 mol) and Pd-PEPPSI-IPent Cl (0.43 g, 0.0004 mol), Cs2CO3 (2.87 g, 0.008 mol) was added dioxane (70 mL) / H2O (20 mL) and stirred at 100 ℃ for 16 hours under nitrogen. Water (50 mL) was added to the reaction mixture and extracted with EA (80 mL x 3). The organic layer was washed in a conventional manner, dried and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (20% EtOAc / hexane) to obtain the desired title compound (1.1 g, 70%) as a yellow solid.

[1922] LCMS (ESI-MS): mass calcd. C 19 H 14 N2OS 318.1 m / z, found 318.7 [M+H] + .

[1923]

[1924] Step 2: Synthesis of 6-(chloromethyl)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one

[1925] 6-Methyl-3-(4-methylthiazol-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 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 for 16 h under nitrogen.

[1926] Water (30 mL) was added to the reaction mixture and extracted with EA (50 mL x 3). The organic layer was washed in a conventional manner, dried, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (50% EtOAc / hexane) to obtain the desired title compound (200 mg, 12.9%) as a yellow solid.

[1927] LCMS (ESI-MS): mass calcd. C 19 H 13 ClN2OS 352.0 m / z, found 352.7 [M+H] + .

[1928]

[1929] 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)

[1930] 6-(Chloromethyl)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one (50 mg, 0.141 mmol) was dissolved in DMF (3 ml), 3-phenylpiperidine (27.42 mg, 0.170 mol) and DIEA (54.94 mg, 0.425 mol) were added, and the mixture was stirred at 60 °C for 1 h under nitrogen. Water (5 mL) was added to the reaction mixture, and extracted with EA (8 mL x 3). The organic layer was washed by a conventional method, dried, and concentrated under reduced pressure. The concentrated residue was purified by prep-HPLC (Gemini 5 μm C 18 The residue was purified by column, 150 x 21.2 mm, 70 - 95% MeCN / H2O 0.1% FA) to obtain the desired title compound (2.7 mg, 4%) as a red solid.

[1931] LCMS (ESI-MS) of the above-obtained compound 101 (chemical formula 102 below) and 1 As a result of H NMR analysis, the following data were obtained:

[1932] [Chemical Formula 102]

[1933]

[1934] LCMS (ESI-MS): mass calcd. C 30 H 27 N3OS 477.2 m / z, found 478.0 [M+H] + .

[1935] 1H NMR (400 MHz, DMSO-d6) δ9.27 (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).

[1936]

[1937] Example 1: Amyloid-beta and tau disaggregation test

[1938] 1.1. Sample preparation

[1939] Each compound was dissolved in DMSO to a concentration of 10 mM. The compound was then diluted with 6% DMSO (in DW) and used.

[1940] Amyloid-beta and tau solutions are Aβ 1~42 Alternatively, Tau-RD3 (Tau repeat domain 3) monomer was dissolved in DMSO to prepare a concentration of 10 mM. Then, it was diluted to 100 μM using DW and stored on ice.

[1941] Meanwhile, Thioflavin-T was dissolved in 50 mM glycine buffer (pH 8.5) to a concentration of 5 mM. Then, it was diluted to 5 μM using 50 mM glycine buffer (pH 8.5) and stored in a dark room protected from light.

[1942]

[1943] 1.2. Amyloid-beta and tau aggregation dissociation test by thioflavin-T analysis

[1944] The amyloid-beta and tau solutions prepared in Example 1.1 above were each added to a 1.5 mL microcentrifuge tube at a concentration of 50 μM or 35 μM, and reacted at 37°C for 24 hours.

[1945] The compounds were serially diluted from 500 μM to 0 μM in each 1.5 mL microcentrifuge tube where the amyloid-beta and tau aggregation was completed, and then further reacted at 37°C for 48 hours.

[1946] After the reaction was completed, 25 μL of the reaction solution was added to each well of a 96-well fluorescence analysis plate, and 75 μL of thioflavin-T solution was added to each well. After the reaction was incubated for 5 minutes in a dark room at room temperature, the fluorescence values ​​were measured at 450 nm (excitation) and 485 nm (emission) using a multi-mode microplate reader.

[1947] The fluorescence value of the group (control group) that was treated with only amyloid-beta or tau and aggregated for 72 hours was converted to a % value and expressed as 100. The amyloid-beta and tau aggregates that were reacted for 24 hours and aggregated were treated with each compound at different concentrations and reacted for an additional 48 hours, and the measured fluorescence values ​​were converted to relative values, and the results are shown in Table 2.

[1948] Table 2 shows the amyloid-beta aggregation disintegration effect according to the treatment concentration (0 to 500 μM) of each compound and each compound intermediate (control group: Aβ 1-42 Aggregation for 72 hours in 50 μM treatment group; Treatment group: Aβ 1-42The effect of Tau aggregation disintegration (control group: Tau-RD3 35 μM treated group for 72 hours; treatment group: Tau-RD3 35 μM treated group for 24 hours + reaction for 48 hours with each concentration of compound) and tau aggregation disintegration (control group: Tau-RD3 35 μM treated group for 72 hours + reaction for 48 hours with each concentration of compound) was shown. The concentration (EC) that can disintegrate 50% of amyloid-beta and tau aggregation compared to the control group when treated with each compound and the intermediate of each compound 50 ) were obtained and indicated by the following symbols according to their strength, which means that each compound exhibits a coagulation-decomposition effect depending on concentration:

[1949] +++ : Strong effect (EC 50 ≤ 20 μM);

[1950] ++ : Moderate effect (20 < EC 50 ≤ 100 μM);

[1951] +: Weak effect (100 < EC) 50 ≤ 250 μM); and

[1952] -: No effect (250 μM < EC 50 ).

[1953] As shown in Table 2 below, it was confirmed that 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, the amyloid-beta aggregation disintegration and / or tau aggregation disintegration effects were exhibited.

[1954] In particular, compounds 13, 20, 21, 23, 27, 28, 30-33, 46, 47, 57, 63, 65, 66, 70, 72, 74-77, 83, 84, 90; and compounds 5-4, 74-7, 76-1, which are intermediates of the compounds, exhibited remarkably excellent aggregation-disintegrating effects on both amyloid-beta protein aggregates and tau protein aggregates.

[1955] That is, according to the above results, it was confirmed that the compounds of chemical formula 1 exhibited a remarkably excellent effect in disassembling amyloid-beta aggregates and / or tau aggregates, and thus could be utilized for preventing, improving, or treating degenerative brain diseases.

[1956] Compound number EC 50 (μM) Compound number EC 50(μM)AβTauAβTau1+++-61--2+++-62--3+++-63++++++4++-64+++5++-65++++++6++-66++++++7+++-67--8+++6 8--9++++69+++-10--70++++++11+-71+++12+++-72++++++13++++++73++14+++-74++++++15++-75++++++16++- 76++++++17+++-77++++++18+++-78+-19-+79++++20++++++80+++21++++++81++++22-++82+++++23++++++83++++++24-+++84++++++25+++-85--26+++-86+++++27++++++87+++++28++++++88+++++29--89+++30++++++90++ ++++31++++++91+++-32++++++92++++33++++++93++++34-+94+++++35++++95++-36+++96--37++++97+++-38+++-98--39+++-99--40+++-5-4++++++41+++-6-2+++++42--12-3+-43--23-10-++44+++-39-3--45++++40-4--4 6++++++41-4--47++++++42-6++++48+++-42-7-+49+++-44-8+++50--45-8+-51+++++72-7+++-52--73-7+++-53--74-7++++++54--76-1++++++55+++-83-5++++56++++83-6-+57++++++99-7+-58+++-99-8-++59++++60+++++

[1957]

[1958] Example 2: Confirmation of the effect of compound treatment on reducing aggregates in amyloid beta oligomer-expressing cell lines.

[1959] 2.1. Preparation of cell lines overexpressing amyloid beta oligomers

[1960] To observe changes in intracellular amyloid beta oligomers, we introduced the APP E693Δ (Osaka mutation) mutant plasmid from GenScript, which is known to be associated with early onset of Alzheimer's disease and induces intracellular amyloid beta oligomer formation. The plasmid was transfected into HEK293 cells via liposomes (Lipofectamine) to prepare a cell line overexpressing intracellular amyloid beta oligomers.

[1961]

[1962] 2.2. Compound treatment

[1963] HEK293 cells transfected with the APP E693Δ mutant plasmid were cultured in a 37°C, 5% CO2 incubator for 48 hours, and then treated with the compound prepared in 1.1 above, diluted in a cell culture solution at a concentration of 10 μM. The untransfected control group was treated with 0.1% DMSO, the same as the compound treatment group.

[1964] The compound-treated cell lines were cultured again in a 37°C, 5% CO2 incubator for 48 hours before being used in the experiment.

[1965]

[1966] 2.3. Confirmation of oligomer changes through dot blot

[1967] In Example 2.2, dot blot analysis was performed using cell lysates after culturing control and compound-treated cells. A 3.5 μg sample was spotted onto a nitrocellulose membrane, air-dried, and the membrane with the sample adhered to it was blocked with 5% skim milk. After incubation with A11, an amyloid oligomer antibody, to bind, the membrane was washed four times with TBST, and a secondary antibody was added. Image signals were measured using a chemiluminescent substrate.

[1968] As a result, Fig. 1 graphically shows the changes in amyloid beta oligomers caused by each compound (dot blot image) and the relative changes in transfected HEK293 cells treated with no compound as a control. It was confirmed that the amount of amyloid beta oligomers was reduced by treatment with each compound compared to the control.

[1969] That is, the results of the above Figure 1 mean that each compound exhibits an amyloid beta oligomer reduction effect through amyloid beta oligomer aggregation decomposition in amyloid beta oligomer-expressing cells.

[1970] According to the above results, it was confirmed that the compounds of chemical formula 1 exhibited a remarkably excellent effect in disassembling amyloid-beta aggregates and / or tau aggregates, and thus could be used for preventing, improving, or treating degenerative brain diseases.

Claims

1. A compound of the following chemical formula 1 or a salt thereof: [Chemical Formula 1] In the above chemical formula 1, R 1 and R 2 are each independently hydrogen, halogen, CN, OR a , SR a , CO2R a , CH2CO2R a , CONR b R c , NR b R c , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl; X 1 is carbon or nitrogen; Above X 1 If this is carbon, R 3 Silver hydrogen, halogen, CN, OR a , SR a , CO2R a , CH2CO2R a , CONR b R c , NR b R c , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3- to 7-membered cycloalkyl, a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, a substituted or unsubstituted 5- to 10-membered aryl, or a substituted or unsubstituted 5- to 10-membered heteroaryl, and wherein X 1 If this is nitrogen, R 3 does not exist; R 4 and R 5 are each independently 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 , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl; R a , R b , R c and R d are each independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl; X a and X b are each independently a direct bond, oxygen, nitrogen or sulfur; p and q are each independently integers selected from 0 to 2.

2. In claim 1, Above R 1 and R 2 are each independently hydrogen, halogen, CN, substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl; Above X 1 is carbon or nitrogen; Above X 1 If this is carbon, the above R 3 Silver hydrogen, halogen, OR a or substituted or unsubstituted C 1-6 Alkyl, and the above X 1 If this is nitrogen, the above R 3 does not exist; Above R 4 and R 5 are each independently 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 , substituted or unsubstituted C 1-6 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl or a substituted or unsubstituted 3-7 membered heterocycloalkyl; Above R a , R b , R c and R d are each independently hydrogen, halogen, substituted or unsubstituted C 1-6 A compound or a salt thereof, which is alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl.

3. In claim 1, Above R 1 and R 2 are each independently hydrogen, halogen, CN, a substituted or unsubstituted 5- to 7-membered cycloalkyl, a substituted or unsubstituted 5- to 7-membered heterocycloalkyl, a substituted or unsubstituted 5- to 6-membered aryl, or a substituted or unsubstituted 5- to 6-membered heteroaryl; Above X 1 is carbon or nitrogen; Above X 1 If this is carbon, the above R 3 are each independently hydrogen, halogen, OR a or substituted or unsubstituted C 1-3 Alkyl, and the above X 1 If this is nitrogen, the above R 3 does not exist; Above R 4 is 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 , substituted or unsubstituted C 1-4 Alkyl, a substituted or unsubstituted 5-7 membered cycloalkyl or a substituted or unsubstituted 5-7 membered heterocycloalkyl; Above R a , R b , R c and R d are each independently hydrogen, halogen, substituted or unsubstituted C 1-4 Alkyl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted 5-6 membered aryl, or a substituted or unsubstituted 5-6 membered heteroaryl; Above R 5 A compound or a salt thereof, which is hydrogen or a halogen.

4. In claim 1, Above R 1 and R 2 are each independently hydrogen, halogen, CN, a substituted or unsubstituted 5- to 7-membered cycloalkyl, a substituted or unsubstituted 5- to 7-membered heterocycloalkyl, a substituted or unsubstituted 5- to 6-membered aryl, or a substituted or unsubstituted 5- to 6-membered heteroaryl, Above R 1 and R 2 Substituted 5- to 7-membered cycloalkyl, substituted 5- to 7-membered heterocycloalkyl, substituted 5- to 6-membered aryl and substituted 5- to 6-membered heteroaryl are each independently selected from halogen, C 1-4 Alkyl, 5- to 6-membered heterocycloalkyl, (C 1-6 Alkyl)-(5- to 6-membered heterocycloalkyl), (5- to 6-membered heterocycloalkyl)-(C 1-6 Alkyl), O-(C 1-6 alkyl), (C 1-6 Alkyl)-(5- to 6-membered heterocycloalkyl)-(C 1-6 alkyl) and (CO)HN(C 1-6 is substituted with one or more selected from the group consisting of alkyl; Above X 1 is carbon or nitrogen; Above X 1 If this is carbon, R 3 Silver hydrogen, halogen, OH, O-(C 1-3 alkyl) or unsubstituted C 1-3 Alkyl, and the above X 1 If this is nitrogen, R 3 does not exist; Above R 4 is 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 , substituted or unsubstituted C 1-4 Alkyl, a substituted or unsubstituted 5- to 7-membered cycloalkyl, or a substituted or unsubstituted 5- to 7-membered heterocycloalkyl, Above R 4 C substituted in 1-4 Alkyl, substituted 5- to 7-membered cycloalkyl and substituted 5- to 7-membered heterocycloalkyl are each independently halogen, C 1-4 Alkyl, C 1-4 Alcohol, (C 1-4 is substituted with at least one selected from the group consisting of (alkyl)-(5 to 6 membered aryl), (5 to 6 membered heterocycloalkyl)-(5 to 6 membered aryl), and (5 to 6 membered heteroaryl)-(5 to 6 membered aryl); Above R a , R b , R c and R d are each independently hydrogen, halogen, substituted or unsubstituted C 1-4 Alkyl, a substituted or unsubstituted 3- to 7-membered cycloalkyl, a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, a substituted or unsubstituted 5- to 6-membered aryl, or a substituted or unsubstituted 5- to 6-membered heteroaryl, Above R a , R b , R c and R d C substituted in 1-4 A compound or a salt thereof, wherein alkyl, a substituted 3- to 7-membered cycloalkyl, a substituted 3- to 7-membered heterocycloalkyl, a substituted 5- to 6-membered aryl and a substituted 5- to 6-membered heteroaryl are each independently substituted with at least one selected from the group consisting of halogen, OH, a 5- to 6-membered heterocycloalkyl, a 5- to 6-membered aryl and a 5- to 6-membered heteroaryl.

5. In claim 1, Above R 1 and R 2 are each independently hydrogen, halogen, CN, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or and; Above X 1 is carbon or nitrogen; Above X 1 If this is carbon, the above R 3 is hydrogen, halogen, -CH3, -OH or And, the above X 1 If this is nitrogen, the above R 3 does not exist; Above R 4 is hydrogen, halogen, -OH, -NH2, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or A person, compound or salt thereof.

6. In claim 1, The compound is a compound or a salt thereof, which is selected from the group consisting of the following (1) to (101): (1) 2,3-diphenylindene-1-one, (2) 6-methoxy-2,3-diphenyl-1H-indene-1-one, (3) 2,3-diphenyl-6-propoxy-1H-indene-1-one, (4) Isopropoxy-2,3-iphenyl-1H-indene-1-one, (5) 2-Phenyl-3-(o-tolyl)-1H-indene-1-one, (6) 3-phenyl-2-(o-tolyl)-1H-indene-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-indene-1-one, (11) 2-Cyclohexyl-3-phenyl-1H-indene-1-one, (12) 6-morpholino-2,3-diphenyl-1H-indene-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-(morpholinomethyl)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-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (20) 3-(4-methylthiazol-5-yl)-6-((3-phenylpropyl)amino)-2-(pyridin-3-yl)-1H-inden-1-one, (21) 2-(4-methylpyridin-3-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (22) 6-methoxy-2-(4-methylpyridin-3-yl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one, (23) 3-(5-methylthiazol-4-yl)-2-(pyridin-3-yl)-6-(3-(pyridin-4-yl)propoxy)-1H-indene-1-one, (24) 2-Bromo-3-(1-methyl-1H-pyrazol-3-yl)-1-oxo-1H-indene-6-yl acetate, (25) 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(1H-pyrazol-3-yl)-1H-inden-1-one, (26) 2-(1-Methyl-1H-pyrazol-3-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (27) 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(1H-pyrazol-4-yl)-1H-inden-1-one, (28) 2-(1-Methyl-1H-pyrazol-4-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (29) 2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (30) 2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (31) 3-(4-methylthiazol-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-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (33) 2-(2-Methyl-2H-1,2,3-triazol-4-yl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (34) 3-(4-methylthiazol-5-yl)-1-oxo-6-(3-phenylpropoxy)-1H-indene-2-carbonitrile, (35) 6-Hydroxy-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (36) 6-(2-hydroxyethoxy)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (37) 6-(2-methoxyethoxy)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (38) 6-(Methyl(3-phenylpropyl)amino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (39) 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-4-yl)-1H-inden-1-one, (40) 3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-2-yl)-1H-inden-1-one, (41) 3-(4-methylthiazol-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-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (47) 4-methoxy-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (48) 4-Hydroxy-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-2-(pyridin-3-yl)-1H-inden-1-one, (49) 6-(Cyclopentylamino)-3-(4-methylthiizol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (50) 6-(Methylamino)-3-(4-methylthiizol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (51) 6-((1-methylpiperidin-4-yl)amino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (52) 3-(4-methylthiazol-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-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (54) 6-((2-methoxyethyl)amino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (55) 3-(4-methylthiazol-5-yl)-6-((2-phenoxyethyl)amino)-2-(pyridin-3-yl)-1H-inden-1-one, (56) 3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-6-((tetrahydro-2H-pyran-4-yl)amino)-1H-inden-1-one, (57) 3-(4-methylthiazol-5-yl)-6-((3-phenylpropyl)thio)-2-(pyridin-3-yl)-1H-inden-1-one, (58) 3-(4-methylthiazol-5-yl)-6-((1-phenylpiperidin-3-yl)amino)-2-(pyridin-3-yl)-1H-inden-1-one, (59) 6-Amino-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (60) N-(3-(4-methylthiazol-5-yl)-1-oxo-2-(pyridin-3-yl)-1H-indene-6-yl)-3-phenylpropanamide, (61) N-(3-(4-methylthiazol-5-yl)-1-oxo-2-(pyridin-3-yl)-1H-indene-6-yl)tetrahydro-2H-pyran-4-carboxamide, (62) 6-(Dimethylamino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (63) 6-(Cyclopropylamino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (64) 6-(4-methylpiperazin-1-yl)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (65) 6-(Methyl-l(3-phenylpropyl)amino)-3-(4-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one, (66) 3-(4-methylthiazol-5-yl)-6-phenoxy-2-(pyridin-3-yl)-1H-inden-1-one, (67) 6-(methylamino)-2,3-diphenyl-1H-indene-1-one, (68) 6-Amino-2,3-diphenyl-1H-indene-1-one, (69) 6-(Dimethylamino)-2,3-diphenyl-1H-indene-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-morpholinophenyl)-3-phenyl-1H-inden-1-one, (74) 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one, (75) 6-(4-methylpiperazin-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one, (76) 2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-inden-1-one, (77) 2,3-bis(4-methylthiazol-5-yl)-6-(3-phenylpropoxy)-1H-indene-1-one, (78) 2,3-diphenyl-6-(3-phenylpropoxy)-1H-indene-1-one, (79) 6-(4-methylpiperazin-1-yl)-2,3-bis(4-methylthiazol-5-yl)-1H-indene-1-one, (80) 6-(4-methylpiperazin-1-yl)-2,3-bis(3-morpholinophenyl)-1H-indene-1-one, (81) 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2,3-bis(4-methylthiazol-5-yl)-1H-inden-1-one, (82) 6-Hydroxy-2,3-di-o-tolyl-1H-indene-1-one, (83) 6-(3-phenylpropoxy)-2,3-di(thiazol-5-yl)-1H-indene-1-one, (84) 3-(2,6-dimethylphenyl)-6-hydroxy-2-(o-tolyl)-1H-indene-1-one, (85) 2-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one, (86) 2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one, (87) 3-(4-methylthiazol-5-yl)-2-(4-(morpholinomethyl)phenyl)-1H-inden-1-one, (88) 2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(4-methylthiazol-5-yl)-1H-inden-1-one, (89) 3-(4-methylthiazol-5-yl)-2-(3-(morpholinomethyl)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-methylthiazol-5-yl)-1H-inden-1-one, (93) 3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-2-(4-methylthiazol-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-indene-1-one, (97) 4,6-Dimethoxy-2,3-diphenyl-1H-indene-1-one, (98) 6,7-Diphenyl-5H-cyclopenta[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-methylthiazol-5-yl)-2-(pyridin-3-yl)-1H-inden-1-one and (101) 3-(4-Methylthiazol-5-yl)-6-((3-phenylpiperidin-1-yl)methyl)-2-(pyridin-3-yl)-1H-inden-1-one.

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 preventing or treating a degenerative brain disease, comprising the compound of claim 1; or a pharmaceutically acceptable salt thereof.

10. In claim 9, (1) Individuals with or at risk of having higher than normal levels of amyloid-beta aggregation without a degenerative brain disease; (2) Individuals with or at risk of having higher than normal levels of tau protein aggregation than those without a degenerative brain disease; (3) Individuals with or at risk of having higher than normal levels of phosphorylation of tau protein without a degenerative brain disease; and (4) A pharmaceutical composition for preventing or treating a degenerative brain disease, to be administered to an individual selected from among the individuals falling under one or more of (1) to (3) above.

11. In claim 9, The above degenerative brain diseases include dementia, Alzheimer's disease, preclinical alzheimer's disease, Parkinson's disease, Huntington's disease, mild cognitive impairment, cerebral amyloid angiopathy, Down syndrome, amyloid stroke, systemic amyloid disease, Dutch amyloidosis, Niemann-Pick disease, senile dementia, amyotrophic lateral sclerosis, spinocerebellar atrophy, Tourette's syndrome, Friedrich's ataxia, Machado-Joseph's disease, Lewy body dementia, A pharmaceutical composition for preventing or treating a degenerative brain disease, wherein the degenerative brain disease is at least one selected from the group consisting of dystonia, progressive supranuclear palsy, and frontotemporal dementia.

12. A pharmaceutical composition for inhibiting aggregation of amyloid-beta protein or decomposing aggregates of amyloid-beta protein, comprising the compound of claim 1; or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition for inhibiting aggregation of tau protein, disintegrating aggregates of tau protein, or inhibiting 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-wise acceptable salt thereof.

15. A health functional food for preventing or improving degenerative brain disease, comprising the compound of claim 1; or a food-wise acceptable salt thereof.

16. A health functional food for inhibiting aggregation of amyloid-beta protein or decomposing amyloid-beta protein aggregates, comprising the compound of claim 1; or a food-wise acceptable salt thereof.

17. A health functional food for inhibiting aggregation of tau protein, decomposing aggregates of tau protein, or inhibiting phosphorylation of tau protein, comprising the compound of claim 1; or a food-wise acceptable salt thereof.

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