Tetrahydro-benzo[f]isoindole-dione compound and use thereof

Abstract

The present specification relates to a tetrahydro-benzo[f]isoindole-dione compound and, more specifically, to a compound represented by chemical formula I, an isomer thereof, a solvate thereof, a hydrate thereof, or a salt thereof, which can inhibit tankyrase. In chemical formula I, A is a substituted or unsubstituted arylene group, a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted heteroarylene group, a substituted or unsubstituted heterocycloalkylene group, or a substituted or unsubstituted bicycloalkylene group, B is a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, X is absent, -CH2-, -O-, -S-, a substituted or unsubstituted arylene group, or a substituted or unsubstituted heteroarylene group, and M1, M2, M3, and M4 are each independently N or CR1, where R1 is hydrogen, an alkoxy group, a halogen group, an acetamido group, a hydroxy group, an alkoxycarbonyl group, a carboxyl group, a hydroxyalkyl group, an alkyl group, or a haloalkyl group.

Description

Tetrahydro-benzo[f]isoindole-dione compounds and their uses

[0001] Cross-reference regarding related applications

[0002] This application claims priority to Korean Patent Application No. 10-2025-0026553 filed on February 28, 2025, the entire contents of which are incorporated by reference into this specification. This application claims priority to Korean Patent Application No. 10-2026-0033147 filed on February 23, 2026, the entire contents of which are incorporated by reference into this specification.

[0003] This specification relates to novel tetrahydro-benzo[f]isoindole-dione compounds and their uses.

[0004] [National R&D projects that supported this invention]

[0005] [Project ID] 2710089353

[0006] [Assignment No.] 00449468

[0007] [Ministry Name] Ministry of Science and ICT

[0008] [Name of Project Management (Specialized) Agency] National Research Foundation of Korea

[0009] [Research Project Name] Individual Basic Research (Ministry of Science and ICT)

[0010] [Project Title] Discovery of the Mechanism of Substrate Protein Inhibition by Tankyrase Polymers

[0011] [Name of Project Performing Organization] Lifeflex Science Co., Ltd.

[0012] [Research Period] 2025.09.01 ~ 2026.08.31

[0013]

[0014] [National R&D projects that supported this invention]

[0015] [Project ID] 2710092943

[0016] [Assignment No.] 00217266

[0017] [Ministry Name] Ministry of Science and ICT

[0018] [Name of Project Management (Specialized) Agency] National Drug Development Foundation

[0019] [Research Project Name] National New Drug Development Project (R&D) (Ministry of Science and ICT)

[0020] [Project Title] Development of a Tankyrase Degradation Inducer for Osteoarthritis Treatment Inducing Cartilage Regeneration Based on PROTAC Technology

[0021] [Name of Project Performing Organization] Seoul National University Industry-Academic Cooperation Foundation

[0022] [Research Period] 2026.01.01 ~ 2026.03.31

[0023] Osteoarthritis (OA), also known as degenerative arthritis, is a disease that affects more than 7% of the world's population (approximately 528 million people), and the incidence of osteoarthritis is on the rise globally due to population aging. Conventional treatments for osteoarthritis primarily consist of artificial joint replacement surgery or pain relief through the prescription of chondroprotective agents such as hyaluronic acid and anti-inflammatory drugs; however, the development of direct treatments for osteoarthritis beyond such simple pain relief is still lacking. Recently, research has been conducted on factors that inhibit the progression of osteoarthritis using disease-modifying OA drugs (DMOADs) that target regulators of enzymes in the anabolic / catabolic pathways of osteoarthritis cartilage proteins (KR10-2142775B1). This study suggested the possibility of developing a direct treatment for osteoarthritis by showing that the use of a tankyrase (TNKS) inhibitor stabilizes the SOX9 protein, which is important for chondrocyte differentiation, and increases the concentration of the protein, thereby promoting chondrocyte differentiation.

[0024] TNKS is an enzyme belonging to the poly(ADP-ribose; PARP) family, characterized by its catalyzing the poly(ADP-ribosyl)ation (PARylation) process, which transfers ADP-ribose units from nicotinamide adenine dinucleotide (NAD+) to target proteins. TNKS contains an ankyrin repeat domain that mediates protein-protein interactions and a PARP domain responsible for enzymatic activity, playing a crucial role in various biological processes within cells. For example, it is involved in diverse biological functions such as the regulation of Wnt / β-catenin signaling, telomere maintenance, glucose metabolism, and cell division. Among these, its involvement in the regulation of Wnt / β-catenin signaling involves Axin, a key protein of the β-catenin destruction complex. It is known that TNKS stabilizes β-catenin and induces transcription of Wnt target genes by promoting degradation through poly(ADP-ribosylation). When TNKS is inhibited to stabilize axin and reduce β-catenin activity, the expression of cartilage-forming genes SOX9 and COL2A1 increases, which induces cartilage regeneration by promoting the differentiation of mesenchymal stem cells (MSCs) into chondrocytes. Considering this, there is a need to develop novel compounds that inhibit the activity of TNKS as a direct treatment for osteoarthritis.

[0025] One aspect of the present specification aims to provide a compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a salt thereof that inhibits the activity of TNKS.

[0026] One aspect of the present specification aims to provide a composition for preventing, improving, or treating osteoarthritis.

[0027] One aspect of the present specification aims to provide a composition for the prevention, improvement, or treatment of colorectal cancer.

[0028] A compound, its isomer, its solvate, its hydrate, or its salt according to one aspect of the present specification is a compound, its isomer, its solvate, its hydrate, or its salt represented by the following formula I:

[0029] [Chemical Formula I]

[0030]

[0031] In the above chemical formula I,

[0032] A is a substituted or unsubstituted arylene group, a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted heteroarylene group, a substituted or unsubstituted heterocycloalkylene group, or a substituted or unsubstituted bicycloalkylene group, and

[0033] B is a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and

[0034] X is absence, -CH2-, -O-, -S-, a substituted or unsubstituted arylene group, or a substituted or unsubstituted heteroarylene group, and

[0035] M1, M2, M3 and M4 are each independently N or CR1, where R1 is hydrogen, an alkoxy group, a halogen group, an acetamido group, a hydroxyl group, an alkoxycarbonyl group, a carboxyl group, a hydroxyalkyl group, an alkyl group, or a haloalkyl group.

[0036] A composition for preventing, improving, or treating osteoarthritis according to one aspect of the present specification comprises, as an active ingredient, a compound represented by Formula I according to one aspect, an isomer thereof, a solvate thereof, a hydrate thereof, or a salt thereof.

[0037] A composition for preventing, improving, or treating colorectal cancer according to one aspect of the present specification comprises, as an active ingredient, a compound represented by Formula I according to one aspect, an isomer thereof, a solvate thereof, a hydrate thereof, or a salt thereof.

[0038] A compound, its isomer, its solvate, its hydrate, or its salt, and / or composition according to one aspect of the present specification, can inhibit TNKS.

[0039] A compound, its isomer, its solvate, its hydrate, or its salt, and / or composition according to one aspect of the present specification, can prevent, improve, or treat osteoarthritis (e.g., degenerative arthritis) by inhibiting TNKS, thereby inducing increased expression of the SOX9 protein and its target genes, collagen type 2 and Aggrecan.

[0040] A compound, its isomer, its solvate, its hydrate, or its salt, and / or composition according to one aspect of the present specification may exhibit an effect of preventing and / or treating osteoarthritis.

[0041] A compound, its isomer, its solvate, its hydrate, or its salt, and / or composition according to one aspect of the present specification may exhibit a preventive and / or therapeutic effect against colorectal cancer.

[0042] Figure 1 is a scatter plot showing Imax (%) versus -log(IC50[mM]) for the TNKS inhibitory effects of XAV-939, IWR-1, and the compound.

[0043] Figures 2a and 2b are graphs showing the change in cell viability according to the drug concentration (μM) of each compound.

[0044] Figure 3 is a graph showing the change in luciferase activity according to the treatment of each compound.

[0045] Figure 4 is a graph showing the relative mRNA levels of Sox9, Col9a1, and Acan according to each compound treatment under Wnt3a treatment conditions.

[0046] Figure 5a shows the GSEA results for the cartilage signature gene set.

[0047] Figure 5b shows the GSEA results for the Wnt signaling gene set.

[0048] Figure 5c is a diagram illustrating the overlapping relationship between genes downregulated in Wnt treatment and genes upregulated in IB-12 treatment as a Venn diagram, and the path analysis performed using the corresponding gene set.

[0049] Figure 5d is a bar graph showing the results of Reactome pathway analysis in Rank and -log(Adj Pval), illustrating that significant pathways such as extracellular matrix organization, glycosaminoglycan metabolism, and collagen formation are identified at the top.

[0050] Figure 6 is a figure showing the colony formation results when treated with IB-12 at different concentrations compared with the vehicle, where the top is an image of colony formation under each condition and the bottom is a graph showing the number of colonies (% vehicle) quantified.

[0051] FIGS. 7 to 9 show the chemical structural formulas of a compound (preparation example) according to one aspect of the present specification.

[0052] The various embodiments of this document and the terms used therein are not intended to limit the technical features described in this document to specific embodiments, and should be understood to include various modifications, equivalents, or substitutions of said embodiments.

[0053] Each description and embodiment disclosed in this application may be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in this application fall within the scope of this application. Furthermore, the scope of this application should not be considered limited by the specific descriptions provided below.

[0054] Definition of Terms

[0055] The terms used in this specification have been selected based on currently widely used general terms whenever possible, taking into account their functions in the present invention; however, these terms may vary depending on the intent of those skilled in the art, case law, the emergence of new technologies, etc. Additionally, in specific cases, terms have been arbitrarily selected by the applicant, and in such cases, their meanings will be described in detail in the relevant description of the invention. Therefore, the terms used in this invention should be defined not merely by their names, but based on their meanings and the overall content of the invention.

[0056] In this specification, "substituted" means that a hydrogen atom bonded to a compound is substituted with another substituent. The substitution site is sufficient as long as it is a site where a hydrogen atom can be substituted and is not limited to a specific site. The number of substitutions is also not limited, and if two or more substitutions are made, the substituents may be the same or different from each other.

[0057] For example, “substituted” may be in which at least one hydrogen atom in the compound is independently substituted with one or more substituents selected from the group consisting of deuterium, halogen group, hydroxyl group, cyano group, nitro group, amino group, alkyl group, hydroxyalkyl group, cycloalkyl group, alkenyl group, alkynyl group, alkoxy group, alkoxycarbonyl group, carboxyl group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group, alkylcarbonyl group, alkylcarbonyloxy group, alkylcarbonylamino (e.g., acetamido) group, hydroxyalkyl group, haloalkyl group, aryl group, aryloxy group, heteroaryl group, and heterocyclyl group, but is not limited thereto.

[0058] In this specification, "alkyl group" means a fully saturated straight-chain or branched-chain hydrocarbon group, for example, a C1-C6 alkyl group means a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms. For example, the alkyl group may include, but is not limited to, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, or an n-hexyl group.

[0059] In this specification, "hydroxyalkyl group" means an alkyl group in which one or more hydrogen atoms are substituted with hydroxyl groups. For example, hydroxyalkyl groups may include, but are not limited to, hydroxymethyl groups, hydroxyethyl groups, or hydroxypropyl groups.

[0060] In this specification, "alkoxy group" means an alkyl group bonded through an oxygen atom, for example, C1-C6 alkoxy means an alkyloxy group having 1 to 6 carbon atoms. For example, the alkoxy group may include, but is not limited to, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, or a tert-butoxy group.

[0061] In this specification, "alkoxycarbonyl group" means an alkoxy group connected through a carbonyl group. For example, the alkoxycarbonyl group may include, but is not limited to, a methoxycarbonyl group, an ethoxycarbonyl group, or a propoxycarbonyl group.

[0062] In this specification, "alkyl carbonyl group" means an alkyl group bonded through a carbonyl group. For example, the alkyl carbonyl group may include, but is not limited to, a methyl carbonyl group, an ethyl carbonyl group, or a propyl carbonyl group. The methyl carbonyl group is also referred to as an acetyl group.

[0063] In this specification, "alkyl carbonylamino group" refers to a group in which an alkyl carbonyl group is bonded to the nitrogen atom of an amino group. For example, the alkyl carbonylamino group may include, but is not limited to, an acetamido group (-NHCOCH3, -NHAc), a propionylamino group (-NHCOC2H5), or a butyrylamino group (-NHCOC3H7).

[0064] In this specification, "halogen group" includes a fluoro group (-F), a chloro group (-Cl), a bromo group (-Br), or an iodo group (-I).

[0065] In this specification, "haloalkyl group" means an alkyl group in which one or more hydrogen atoms are substituted with a halogen. For example, haloalkyl groups may include, but are not limited to, trifluoromethyl groups, difluoromethyl groups, fluoromethyl groups, trichloromethyl groups, 2,2,2-trifluoroethyl groups, or pentafluoroethyl groups.

[0066] In this specification, "cycloalkyl group" means a non-aromatic saturated or unsaturated cyclic hydrocarbon group, for example, a C3-C8 cycloalkyl group means a cycloalkyl group having 3 to 8 carbon atoms. For example, the cycloalkyl group may include, but is not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexenyl group, a cycloheptyl group, or a cyclooctyl group.

[0067] In this specification, "cycloalkylene group" means a divalent cycloalkyl group having two bonding positions. For example, the cycloalkylene group may include, but is not limited to, a cyclopropylene group, a cyclobutylene group, a cyclopentylene group, or a cyclohexylene group.

[0068] In this specification, "bicycloalkyl group" means a polycyclic hydrocarbon group having a cross-linked structure in which two-phase rings share one or more carbon atoms. For example, the bicycloalkyl group may include, but is not limited to, a bicyclo[1.1.1]pentane group, a bicyclo[2.2.1]heptane group, or a bicyclo[2.2.2]octane group.

[0069] In this specification, "bicycloalkylene group" means a divalent bicycloalkyl group having two bonding positions. For example, the bicycloalkylene group may include, but is not limited to, a bicyclo[1.1.1]pentane-1,3-diyl group or a bicyclo[2.2.1]heptane-1,4-diyl group.

[0070] In this specification, "aryl group" refers to a hydrocarbon group comprising an aromatic ring system, and includes a single ring or a fused ring. For example, a C6-C14 aryl group refers to an aryl group having 6 to 14 carbon atoms. For example, an aryl group may include, but is not limited to, a phenyl group, a naphthyl group, anthracenyl group, or a phenanthrenyl group.

[0071] In this specification, "arylene group" means a divalent aryl group having two bonding positions. For example, an arylene group may include, but is not limited to, a phenylene group (e.g., o-phenylene, m-phenylene, p-phenylene), a naphthylene group, or anthracenylene group.

[0072] In this specification, "heteroaryl group" means an aromatic ring system comprising one or more heteroatoms selected from the group consisting of N, O, S, and P. For example, a heteroaryl group may include, but is not limited to, a pyridyl group, a quinolinyl group, an isoquinolinyl group, a pyrimidinyl group, a pyrazinyl group, a pyrazolyl group, an imidazoleyl group, a thiazoleyl group, an oxazoleyl group, a furanyl group, or a thiophenyl group.

[0073] In this specification, "heteroarylene group" means a divalent heteroaryl group having two bonding sites. For example, a heteroarylene group may include, but is not limited to, a pyridinylene group, a pyrimidinylene group, a pyrazinylene group, a furanilene group, or a thiophenylene group.

[0074] In this specification, "heterocyclyl group" means a non-aromatic ring system comprising one or more heteroatoms selected from the group consisting of N, O, S, and P. For example, heterocyclyl groups include, but are not limited to, piperidinyl groups, piperazinyl groups, morpholinyl groups, thiomomorpholinyl groups, pyrrolidinyl groups, or tetrahydrofuranyl groups.

[0075] In this specification, "heterocycloalkylene group" means a divalent heterocyclyl group having two bonding positions.

[0076] In this specification, "absence" means that a substituent is not present at the corresponding position. For example, if X is absent in Formula I, it represents the structure of Formula II in which there is no substituent at the position of X.

[0077] In this specification, "salt" means a salt according to one aspect of the present disclosure that is acceptable in medicines, cosmetics, and foods and has desirable activity of a parent compound. For example, the salt is an inorganic acid such as hydrochloric acid, hydrobromide, sulfuric acid, nitric acid, phosphoric acid, etc.; Acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvate, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2,2,2]oct-2-en-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, Acid addition salt formed from organic acids such as lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid; or may include, but is not limited to, a salt formed when an acidic proton present in the parent compound is substituted. Additionally, the salt may be a pharmaceutically acceptable salt.

[0078] In this specification, “pharmaceuticalally acceptable” means that it does not exhibit significant toxicity when used at a normal medicinal dosage and is therefore eligible for approval by a government or equivalent regulatory body for use in animals, specifically humans, or is listed in a pharmacopoeia or recognized by other general pharmacopoeias.

[0079] In this specification, "solvent" refers to a crystalline form containing stoichiometric or non-stoichiometric amounts of solvent, for example, a higher-order compound formed between solute molecules or ions and solvent molecules in a solution. A solvent in which the solvent is water may be commonly referred to as a hydrate.

[0080] In this specification, "isomer" refers to a compound having the same chemical formula but different arrangements of atoms. Isomers may include structural isomers and stereoisomers. Stereoisomers may include geometric isomers, optical isomers, enantiomers, diastereomers, etc. Compounds of the present invention may have one or more chiral centers, in which case they may exist as a racemic mixture, a single enantiomer, or a diastereomer, all of which are included within the scope of the present invention.

[0081] Exemplary implementation examples

[0082] Compound, its isomer, its solvate, its hydrate, or its salt

[0083] One aspect of the present specification provides a compound, its isomer, its solvate, its hydrate, or its salt.

[0084] The compound may be represented by the following chemical formula I:

[0085] [Chemical Formula I]

[0086]

[0087] In Formula I, A may be a substituted or unsubstituted arylene group, a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted heteroarylene group, a substituted or unsubstituted heterocycloalkylene group, or a substituted or unsubstituted bicycloalkylene group. In Formula I, B may be a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. In Formula I, X may be absence, -CH2-, -O-, -S-, a substituted or unsubstituted arylene group, or a substituted or unsubstituted heteroarylene group. In Formula I, M1, M2, M3 and M4 are each independently N or CR1, where R1 may be hydrogen, an alkoxy group, a halogen group, an acetamido group, a hydroxyl group, an alkoxycarbonyl group, a carboxyl group, a hydroxyalkyl group, an alkyl group, or a haloalkyl group.

[0088] In one embodiment, A may be a substituted or unsubstituted arylene group, a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted heteroarylene group, a substituted or unsubstituted heterocycloalkylene group, or a substituted or unsubstituted bicycloalkylene group.

[0089] In one embodiment, A may be a substituted or unsubstituted C6-C14 arylene group, a substituted or unsubstituted C3-C10 cycloalkylene group, a substituted or unsubstituted 5- to 10-membered heteroarylene group, a substituted or unsubstituted 5- to 10-membered heterocycloalkylene group, or a substituted or unsubstituted C5-C10 bicycloalkylene group.

[0090] In one embodiment, A may be a substituted or unsubstituted phenylene group, a substituted or unsubstituted cyclohexylene group, a substituted or unsubstituted bicyclo[1.1.1]pentane-1,3-diyl group, or a substituted or unsubstituted bicyclo[2.2.1]heptane-1,4-diyl group, but is not limited thereto.

[0091] In one specific example, A may be unsubstituted.

[0092] In one embodiment, when A is substituted, the substituent of A may be selected from the group consisting of a halogen group, a hydroxyl group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, an acetamido group, and a hydroxyalkyl group, but is not limited thereto. Additionally, when A is substituted with a plurality of substituents, the plurality of substituents may each be independently identical or different.

[0093] In one embodiment, A may be an arylene group or a cycloalkylene group. For example, A may be a phenylene group or a cyclohexylene group. A compound satisfying this may have a superior effect in inhibiting tankyrase activity compared to IWR-1.

[0094] In one embodiment, B may be a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

[0095] In one embodiment, B may be a substituted or unsubstituted C6-C14 aryl group, or a substituted or unsubstituted 5- to 14-membered heteroaryl group. The position of the heteroatom in the heteroaryl group is not limited.

[0096] In one embodiment, B may be a substituted or unsubstituted quinolinyl group, a substituted or unsubstituted isoquinolinyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted pyridinyl group, but is not limited thereto.

[0097] In one specific example, B may be unsubstituted.

[0098] In one embodiment, when B is substituted, the substituent of B may be selected from the group consisting of, but not limited to, a halogen group, a hydroxyl group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group (e.g., methoxycarbonyl group), an alkylcarbonyl group (e.g., methylcarbonyl group), an acetamido group, and a hydroxyalkyl group. Additionally, when B is substituted with multiple substituents, the multiple substituents may each be independently the same or different.

[0099] In one embodiment, B may be a quinolinyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted pyridinyl group. For example, B may be a quinolinyl group, a phenyl group substituted with an alkoxycarbonyl group (e.g., methoxycarbonyl group) or an alkylcarbonyl group (e.g., methylcarbonyl group), or a pyridinyl group substituted with an alkoxycarbonyl group (e.g., methoxycarbonyl group). In one embodiment, in B, there may be only one substituent. A compound satisfying this may have a superior effect in inhibiting tankyrase activity compared to IWR-1.

[0100] In one embodiment, X may be an atom, -CH2-, -O-, -S-, a substituted or unsubstituted arylene group, or a substituted or unsubstituted heteroarylene group. The position of the heteroatom in the heteroarylene group is not limited.

[0101] In one embodiment, X may be a component, -CH2-, -O-, -S-, a substituted or unsubstituted C6-C14 arylene group, or a substituted or unsubstituted 5- to 10-membered heteroarylene group.

[0102] In one embodiment, X may be a component, -CH2-, -O-, -S-, a substituted or unsubstituted phenylene group, a substituted or unsubstituted pyridinylene group, a substituted or unsubstituted pyrimidinylene group, or a substituted or unsubstituted pyrazinylene group, but is not limited thereto.

[0103] In one specific example, X may be unsubstituted.

[0104] In one embodiment, the substituent of X may be selected from the group consisting of a halogen group (e.g., bromo group), a hydroxyl group, a hydroxyalkyl group (e.g., hydroxymethyl group), an alkyl group, an alkoxy group (e.g., methoxy group), a carboxyl group, an alkoxycarbonyl group (e.g., methoxycarbonyl group), an alkylcarbonylamino group (e.g., acetamido) group, a cyano group, and a nitro group, but is not limited thereto. Additionally, when X is substituted with a plurality of substituents, the plurality of substituents may each be independently the same or different.

[0105] In one embodiment, X may be a substitute, -CH2-, -S-, a substituted or unsubstituted phenylene group, a substituted or unsubstituted pyridinylene group, or a substituted or unsubstituted pyrimidinylene group. For example, if X is a substituted phenylene group, the substituent may be an alkoxy group (e.g., methoxy group), an alkyl carbonylamino (e.g., acetamido) group, a hydroxyl group, or a hydroxyalkyl group (e.g., hydroxymethyl group). In one embodiment, if X is a substituted phenylene group, there may be only one substituent. In this case, the inhibitory effect on tankyrase activity may be superior to that of IWR-1.

[0106] In one embodiment, M1, M2, M3, and M4 may each independently be N or CR1. R1 may be hydrogen, an alkoxy group (e.g., methoxy group), a halogen group (e.g., fluoro group, bromo group), an alkyl carbonylamino (e.g., acetamido) group, a hydroxyl group, an alkoxycarbonyl group (e.g., methoxycarbonyl group), a carboxyl group, a hydroxyalkyl group (e.g., hydroxymethyl group), an alkyl group (e.g., methyl group), or a haloalkyl group (e.g., trifluoromethyl group).

[0107] In one embodiment, M1, M2, M3 and M4 may each independently be CH, C-OCH3, C-OH, C-Br, CF, C-NHCOCH3, C-COOCH3, C-COOH, C-CH2OH, C-CF3 or N.

[0108] In one embodiment, at least one of M1, M2, M3 and M4 is CH, and the others may each independently be C-OCH3, C-OH, C-Br, CF, C-NHCOCH3, C-COOCH3, C-COOH, or C-CF3.

[0109] In one embodiment, i) M1, M2, M3, and M4 are all CH, ii) three of M1, M2, M3, and M4 are CH and one is N, iii) two of M1, M2, M3, and M4 are CH and two are N, or iv) three of M1, M2, M3, and M4 are CH and one is CR1, where R1 may be an alkoxy group (e.g., methoxy group), an alkyl carbonylamino group (e.g., acetamido), a hydroxyl group, or a hydroxyalkyl group (e.g., hydroxymethyl group). In this case, the inhibitory effect on tankyrase activity may be superior to that of IWR-1.

[0110] In one embodiment, where X is absent, the compound may be represented by the following chemical formula II.

[0111] [Chemical Formula II]

[0112]

[0113] In the above formula II, A may be a substituted or unsubstituted arylene group, a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted heteroarylene group, a substituted or unsubstituted heterocycloalkylene group, or a substituted or unsubstituted bicycloalkylene group. In the above formula II, B may be a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. In the above formula II, M1, M2, M3, and M4 are each independently N or CR1, where R1 may be hydrogen, an alkoxy group, a halogen group, an acetamido group, a hydroxyl group, an alkoxycarbonyl group, a carboxyl group, a hydroxyalkyl group, an alkyl group, or a haloalkyl group.

[0114] More specifically, in the above Chemical Formula II, A, B, M1, M2, M3, and M4 are identical to A, B, M1, M2, M3, and M4 defined in Chemical Formula I above, so a detailed explanation is omitted.

[0115] In one embodiment, the compound may be at least one selected from the group consisting of the following compounds, but is not limited thereto:

[0116]

[0117]

[0118]

[0119]

[0120] A compound or isomer thereof according to one aspect of this specification may be used in the form of a salt, for example, the salt may be an acid addition salt formed by a pharmaceutically acceptable free acid. For example, pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphate chloride, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, malieates, butin-1,4-dioate, hexane-1,6-dioate, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, It may be terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, or mandelate, but is not limited thereto.

[0121] A salt according to one aspect of the present specification or an isomer thereof may be prepared by a conventional method, for example, by dissolving a compound in an excess amount of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent, for example, methanol, ethanol, acetone, or acetonitrile. Alternatively, the salt may be prepared by heating an equal molar amount of the compound and an acid or alcohol in water, and then evaporating the mixture to dry it, or by suction filtration of the precipitated salt.

[0122] Salts according to one aspect of this specification or isomers thereof may be prepared as metal salts. Alkali metal or alkaline earth metal salts may be obtained, for example, by dissolving a compound in an excess amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. For example, the metal salt may be a sodium salt, a potassium salt, or a calcium salt.

[0123] A compound or isomer thereof according to one aspect of this specification may be used in the form of a solvate and / or a hydrate. A solvate refers to a compound in which the compound is bonded to a solvent molecule by a non-covalent bond, and a hydrate may refer to the case where the solvent is water.

[0124] A compound, its isomer, its solvate, its hydrate, or its salt according to one aspect of the present specification can inhibit Tankyrase (TNKS) activity.

[0125] A compound, its isomer, its solvate, its hydrate, or its salt, and / or composition according to one aspect of the present specification, may induce increased expression of SOX9 protein, type 2 collagen, and / or Aggrecan.

[0126] A compound, its isomer, its solvate, its hydrate, or its salt, and / or composition according to one aspect of the present specification may exhibit an effect of preventing, improving, or treating osteoarthritis.

[0127] A compound, its isomer, its solvate, its hydrate, or its salt, and / or composition according to one aspect of the present specification may exhibit an effect of preventing, improving, or treating colorectal cancer.

[0128] Method for preparing a compound

[0129] The aforementioned compounds (e.g., the compound represented by Formula I above, the compound represented by Formula II above) can each be prepared independently using chemical transformations well known to those skilled in the art of organic / medicinal chemistry. For example, the aforementioned compounds can each be prepared independently according to the method represented by the following examples.

[0130] In one embodiment, the compound represented by chemical formula I can be synthesized according to [Reaction Scheme 1] below.

[0131] [Reaction Equation 1]

[0132]

[0133] In step 1 of the above reaction scheme 1, intermediate a is synthesized by reacting a substituted anthracene compound with maleic anhydride (CAS: 108-31-6). Then, intermediate a is reacted with 4-aminobenzoic acid (CAS: 150-13-0) to obtain intermediate b, and then reacted with 8-aminoquinoline (CAS: 578-66-5) to synthesize a structure represented by chemical formula I.

[0134] In one embodiment, the compound represented by chemical formula I can be synthesized according to [Reaction Scheme 2] below.

[0135] [Reaction Equation 2]

[0136]

[0137] In step 1 of the above reaction scheme 2, intermediate c can be synthesized by reacting 4-nitrobenzoyl chloride (CAS: 122-04-3) with 8-aminoquinoline (CAS: 578-66-5) and then reducing the nitro group. Subsequently, intermediate c can be reacted with maleic anhydride (CAS: 108-31-6) to obtain intermediate d, and then reacted with a substituted anthracene compound at high temperature to synthesize a structure represented by chemical formula I.

[0138] In one embodiment, the compound represented by chemical formula I can be synthesized according to [Reaction Scheme 3] below.

[0139] [Reaction Equation 3]

[0140]

[0141] In step 1 of reaction scheme 3 above, intermediate e can be synthesized by reacting an N-Boc-aminocarboxylic acid compound with 8-aminoquinoline (CAS: 578-66-5). Subsequently, intermediate e can be synthesized by reacting it with trifluoroacetic acid (CAS: 76-05-1) to remove the protecting group, and then reacting it with a substituted anthracene compound to synthesize a structure represented by chemical formula I.

[0142] In one embodiment, a compound represented by Chemical Formula I or Chemical Formula II can be synthesized according to [Reaction Scheme 4] below.

[0143] [Reaction Equation 4]

[0144]

[0145] In step 1 of the above reaction scheme 4, intermediate f can be synthesized by reacting a dihalide compound with Rongalite (CAS: 6035-47-8). Then, intermediate f can be reacted with maleic anhydride (CAS: 108-31-6) to obtain intermediate g, and then heated with intermediate c of reaction scheme 2 to synthesize a structure represented by chemical formula I or chemical formula II.

[0146] The specific synthesis method of the compound represented by the above chemical formula I and / or chemical formula II is explained in more detail in the synthesis method of I-V described below.

[0147] Composition for prevention, improvement, or treatment

[0148] 1) Composition for the prevention, improvement, or treatment of osteoarthritis

[0149] One aspect of the present specification provides a composition for preventing, improving, or treating osteoarthritis comprising, as an active ingredient, a compound represented by Formula I, an isomer thereof, a solvate thereof, a hydrate thereof, or a salt thereof.

[0150] The compound represented by Chemical Formula I, its isomers, its solvates, its hydrates, or its salts have been described above, so a detailed explanation is omitted.

[0151] In one embodiment, the composition for preventing, improving, or treating osteoarthritis may include the following compound as an active ingredient:

[0152] .

[0153] In one embodiment, osteoarthritis may be degenerative arthritis, traumatic arthritis, or inflammatory arthritis, but is not limited thereto.

[0154] In one embodiment, the composition can promote the differentiation of mesenchymal stem cells into chondrocytes.

[0155] In one embodiment, the composition can promote chondrocyte differentiation through the stabilization of SOX9 protein.

[0156] 2) Composition for the prevention, improvement, or treatment of colorectal cancer

[0157] One aspect of the present specification provides a composition for the prevention, improvement, or treatment of colorectal cancer comprising, as an active ingredient, a compound represented by Formula I, an isomer thereof, a solvate thereof, a hydrate thereof, or a salt thereof.

[0158] The compound represented by Chemical Formula I, its isomers, its solvates, its hydrates, or its salts have been described above, so a detailed explanation is omitted.

[0159] In one embodiment, the composition for preventing, improving, or treating colorectal cancer may include the following compound as an active ingredient:

[0160] .

[0161] 3) Common composition

[0162] In one embodiment, the composition can inhibit tankyrase activity.

[0163] In one embodiment, the composition may be a pharmaceutical composition, a health functional food composition, a food composition, or a feed composition.

[0164] In one embodiment, the composition may further comprise a pharmaceutically acceptable carrier, excipient, or diluent. For example, in addition to the above components, the composition may further comprise a lubricant, wetting agent, sweetener, flavoring agent, emulsifier, suspending agent, preservative, etc.

[0165] In one embodiment, the pharmaceutically acceptable carrier is one that is commonly used in formulations and may include, but is not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0166] In one embodiment, the composition may be administered orally or parenterally. For example, parenteral administration may be, but is not limited to, intravenous infusion, subcutaneous infusion, intramuscular infusion, intraperitoneal infusion, endodermal administration, topical administration, intranasal administration, intrapulmonary administration, or rectal administration.

[0167] In one embodiment, the composition may be used by being formulated into the form of a powder, granule, tablet, capsule, suspension, emulsion, syrup, aerosol, etc. for oral administration according to the intended method, or by being formulated into the form of an injectable or sterile injectable solution for parenteral administration.

[0168] In one embodiment, the dosage of the composition may vary depending on the age, gender, body weight, severity of the disease, route of administration, time of administration, etc. In one embodiment, the composition of the present invention may be administered to an adult at a dose of 0.001 to 1000 mg / kg of the active ingredient per day, preferably 0.01 to 100 mg / kg. The administration may be performed once a day or divided into several doses. The above dosage does not limit the scope of the present invention in any way.

[0169] In one embodiment, a compound according to one aspect of the present specification may be administered at an effective concentration that exhibits a pharmacological effect without causing cytotoxicity.

[0170] For example, a compound according to one aspect of the present specification may be administered at an exposure concentration of less than 1 μM in a cell or tissue environment (e.g., chondrocytes, cartilage tissue, colon cancer cells, colon cancer tissue). For example, a compound according to one aspect of the present specification has an exposure concentration in an environment of cells or tissues (e.g., chondrocytes, cartilage tissue, colorectal cancer cells, colorectal cancer tissue) of less than 1 μM, 0.999 μM or less, 0.9 μM or less, 0.8 μM or less, 0.7 μM or less, 0.6 μM or less, 0.5 μM or less, 0.4 μM or less, 0.3 μM or less, 0.2 μM or less, 0.1 μM or less, 0.05 μM or less, 0.01 μM or less, 0.005 μM or less, 0.001 μM or less, 0.999 μM or more, 0.9 μM or more, 0.8 μM or more, 0.7 μM or more, 0.6 μM or more, 0.5 μM or more, 0.4 μM or more, 0.3 μM or more, 0.2 μM or more, 0.1 μM or more, It may be administered in a range of 0.05 μM or more, 0.01 μM or more, 0.005 μM or more, 0.001 μM or more, greater than 0, or a combination thereof (e.g., 0.01 to 0.999 μM).

[0171] In one embodiment, the composition may include food additives. For example, the composition may contain various flavoring agents or natural carbohydrates as additional ingredients. The natural carbohydrates mentioned above may be monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As a sweetener, natural sweeteners such as taumatin and stevia extract, or synthetic sweeteners such as saccharin and aspartame may be used.

[0172] In one embodiment, the composition may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and fillers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.

[0173] In one embodiment, the composition may be manufactured as a health functional food, and when manufactured as a health functional food, it may be manufactured in the same way as a conventional health functional food, and may be manufactured as a health functional food by mixing the above raw material with a raw material used in the manufacture of a conventional health functional food. For example, a health functional food using the composition according to the present invention may be manufactured in the form of tablets, capsules, powder, granules, liquid, pills, etc.

[0174] Prevention, improvement, or treatment methods

[0175] 1) Methods for the prevention, improvement, or treatment of osteoarthritis

[0176] One aspect of the present specification provides a method for preventing, improving, or treating osteoarthritis, comprising the step of administering to an individual a composition comprising as an active ingredient a compound represented by Formula I, an isomer thereof, a solvate thereof, a hydrate thereof, or a salt thereof.

[0177] In one embodiment, the object may be a subject requiring treatment for a disease.

[0178] In one embodiment, the individual may include, but is not limited to, mammals. The mammal may be, but is not limited to, humans, mice, cattle, dogs, rabbits, and cats.

[0179] The compound represented by Chemical Formula I, its isomers, its solvates, its hydrates, its salts, compositions, osteoarthritis, routes of administration, and dosages have been described above, so a detailed explanation is omitted.

[0180] In one embodiment, the step may be to administer the composition to an individual in an effective amount that exhibits an effect of preventing, improving, or treating osteoarthritis.

[0181] In one embodiment, the composition may include the following compound as an active ingredient:

[0182] .

[0183] 2) Methods for the prevention, improvement, or treatment of colorectal cancer

[0184] One aspect of the present specification provides a method for preventing, improving, or treating colorectal cancer, comprising the step of administering to an individual a composition comprising as an active ingredient a compound represented by Formula I, an isomer thereof, a solvate thereof, a hydrate thereof, or a salt thereof.

[0185] In one embodiment, the object may be a subject requiring treatment for a disease.

[0186] In one embodiment, the individual may include, but is not limited to, mammals. The mammal may be, but is not limited to, humans, mice, cattle, dogs, rabbits, and cats.

[0187] The compound represented by Chemical Formula I, its isomers, its solvates, its hydrates, its salts, compositions, colorectal cancer, routes of administration, and dosages have been described above, so a detailed explanation is omitted.

[0188] In one embodiment, the step may be to administer the composition to an individual in an effective amount that exhibits an effect of preventing, improving, or treating colorectal cancer.

[0189] In one embodiment, the composition may include the following compound as an active ingredient:

[0190] .

[0191] Use for preparing compositions for prevention, improvement, or treatment

[0192] 1) Use for manufacturing a composition for the prevention, improvement, or treatment of osteoarthritis

[0193] One aspect of the present specification provides a use for preparing a composition for the prevention, improvement, or treatment of osteoarthritis of a compound represented by Formula I, its isomer, its solvate, its hydrate, or its salt.

[0194] Compounds represented by Chemical Formula I, their isomers, their solvates, their hydrates, their salts, compositions, osteoarthritis, etc., have been described above, so a detailed explanation is omitted.

[0195] In one embodiment, the compound may be the following compound:

[0196] .

[0197] 2) Methods for the prevention, improvement, or treatment of colorectal cancer

[0198] One aspect of the present specification provides a use for preparing a composition for the prevention, improvement, or treatment of colorectal cancer of a compound represented by Formula I, its isomers, its solvates, its hydrates, or its salts.

[0199] Compounds represented by Chemical Formula I, their isomers, their solvates, their hydrates, their salts, compositions, colorectal cancer, etc., have been described above, so a detailed explanation is omitted.

[0200] In one embodiment, the compound may be the following compound:

[0201] .

[0202] For prevention, improvement, or treatment purposes

[0203] 1) Use for the prevention, improvement, or treatment of osteoarthritis

[0204] One aspect of the present specification provides a use for a composition comprising a compound represented by Formula I, an isomer thereof, a solvate thereof, a hydrate thereof, or a salt thereof for the prevention, improvement, or treatment of osteoarthritis.

[0205] Compounds represented by Chemical Formula I, their isomers, their solvates, their hydrates, their salts, compositions, osteoarthritis, etc., have been described above, so a detailed explanation is omitted.

[0206] In one embodiment, the compound may be the following compound:

[0207] .

[0208] 2) Use for the prevention, improvement, or treatment of colorectal cancer

[0209] One aspect of the present specification provides a use for a composition comprising a compound represented by Formula I, an isomer thereof, a solvate thereof, a hydrate thereof, or a salt thereof for the prevention, improvement, or treatment of colorectal cancer.

[0210] Compounds represented by Chemical Formula I, their isomers, their solvates, their hydrates, their salts, compositions, colorectal cancer, etc., have been described above, so a detailed explanation is omitted.

[0211] In one embodiment, the compound may be the following compound:

[0212] .

[0213] Hereinafter, the present invention will be described in detail with reference to examples to specifically explain the invention. However, the following examples are merely illustrative of the invention, and the scope of the invention is not limited by the following examples.

[0214] I. Synthesis of Intermediate Compounds

[0215] 1. Preparation Example A1: Synthesis of 4-amino-N-(quinolin-8-yl)benzamide (4-amino-N-(quinolin-8-yl)benzamide, I-2)

[0216]

[0217] (1) Step 1: Synthesis of 4-nitro-N-(quinolin-8-yl)benzamide (4-nitro-N-(quinolin-8-yl)benzamide, I-1)

[0218] 4-nitrobenzoyl chloride (940.7 mg, 5.1 mmol) was added to a solution of 8-aminoquinoline (586.7 mg, 4.0 mmol) and triethylamine (676 μL, 4.9 mmol) in anhydrous dichloromethane (5 mL) at 0 °C and stirred overnight at room temperature (RT). The mixture was extracted with DCM, washed with water and brine, dried with sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM / ethyl acetate (EA) = 10 / 1). The target product was obtained as yellow solids (827.0 mg, 3.46 mmol, 69%).

[0219] 1 H NMR (400 MHz, CDCl3) δ 10.84 (s, 1H), 8.97 - 8.85 (m, 2H), 8.45 - 8.38 (m, 2H), 8.29 - 8.20 (m, 3H), 7.68 - 7.58 (m, 2H), 7.53 (dd, J = 8.3, 4.2 Hz, 1H).

[0220] (2) Step 2: Synthesis of 4-amino-N-(quinoline-8-yl)benzamide(I-2)

[0221] Ammonium formate (334.5 mg, 5.3 mmol) and 10% palladium on activated carbon (56 mg) were added to a dimethylformamide / methanol (DMF / MeOH) (2:1, 18 mL) solution of 4-nitro-N-(quinoline-8-yl)benzamide (279.0 mg, 0.95 mmol) obtained in Step 1. The mixture was stirred for 1 hour (1 h) under an argon (Ar) atmosphere. The reaction mixture was filtered through Celite, and the solvent was evaporated to obtain the target compound as pale beige solids (146 mg, 0.55 mmol, 58%).

[0222] 1 H NMR (400 MHz, CDCl3) δ 10.63 (s, 1H), 8.92 (dd,J= 7.6, 1.4 Hz, 1H), 8.85 (dd,J= 4.2, 1.7 Hz, 1H), 8.18 (dd,J= 8.3, 1.7 Hz, 1H), 7.97 - 7.89 (m, 2H), 7.58 (t,J= 7.9 Hz, 1H), 7.54 - 7.43 (m, 2H), 6.80 - 6.73 (m, 2H), 4.05 (s, 2H).

[0223] 2. Preparation Example A2: Synthesis of 4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(quinolin-8-yl)benzamide (4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(quinolin-8-yl)benzamide, I-3)

[0224]

[0225] Maleic anhydride (55.1 mg, 0.55 mmol) was added to the 4-amino-N-(quinoline-8-yl)benzamide (146.0 mg, 0.56 mmol) obtained in Step 2 in DCM (3 mL), and the mixture was stirred overnight at room temperature (RT). The precipitated solid was filtered, washed with DCM and acetone, and dried to obtain an intermediate, which was used in the next step without purification.

[0226] The above intermediate and sodium acetate (38.3 mg, 0.47 mmol) were dissolved in acetic anhydride (1 mL) and stirred at 140 °C until a homogeneous solution was formed. After cooling the reaction mixture to room temperature (RT), an excess amount of cold deionized water (DI) was added and stirred for 1 hour (1 h). The resulting precipitate was filtered and washed with DI to obtain the target compound, 4-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)-N-(quinoline-8-yl)benzamide, as dark brown solids (143 mg, 0.42 mmol, 76%).

[0227] 1 H NMR (300 MHz, DMSO) δ 10.62 (s, 1H), 9.00 (dd,J= 4.2, 1.7 Hz, 1H), 8.74 (dd,J= 7.6, 1.5 Hz, 1H), 8.47 (dd,J= 8.3, 1.7 Hz, 1H), 8.03 (d,J= 8.7 Hz, 2H), 7.85 (d,J= 8.6 Hz, 2H), 7.79 - 7.62 (m, 3H), 6.34 (s, 2H).

[0228] 3. Preparation Example A3: Synthesis of (9S,10S,11R,15S)-2,6-dihydroxy-9,10-dihydro-9,10-[3,4]furanoanthracene-12,14-dione ((9S,10S,11R,15S)-2,6-dihydroxy-9,10-dihydro-9,10-[3,4]furanoanthracene-12,14-dione, I-4)

[0229]

[0230] Maleic anhydride (112.0 mg, 1.1 mmol) was added under stirring to a solution of 2,6-dihydroxyanthracene (211.0 mg, 1.0 mmol, CAS: 101488-73-7) in xylene (2 mL), and the mixture was heated at 140 °C overnight. After cooling the reaction mixture to room temperature, the solid was washed with hexane and recovered by filtration to obtain the target product as reddish-brown solids (274.0 mg, 0.89 mmol, 89%).

[0231] 1 H NMR (400 MHz, DMSO) δ 9.39 (s, 2H), 7.20 (d,J= 8.0 Hz, 1H), 7.07 (d,J= 8.0 Hz, 1H), 6.86 (d,J= 2.4 Hz, 1H), 6.69 (d,J= 2.4 Hz, 1H), 6.52 (ddd,J= 8.3, 6.0, 2.4 Hz, 2H), 4.61 (d,J= 1.6 Hz, 2H), 3.58 - 3.52 (m, 2H).

[0232] II. Synthesis of Compounds

[0233] 1. Synthesis of Compound (= IB-3) of Preparation Example 1

[0234]

[0235] (1) Step 1: Synthesis of (9R,10S,11R,15S)-9,10-dihydro-9,10-[3,4]furanoanthracene-12,14-dione

[0236] Maleic anhydride (98.1 mg, 1.0 mmol) was added to a solution of anthracene (178.2 mg, 1.0 mmol, CAS: 120-12-7) in xylene (1 mL) under stirring, and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature, then transferred to a refrigerator and left until crystals formed (~3 hours). The precipitate was filtered, washed with cold hexane, and dried to obtain the desired product as a white solid (229.0 mg, 0.82 mmol, 81%).

[0237] 1 H NMR (400 MHz, CDCl3) δ 7.44 - 7.29 (m, 4H), 7.21 (td,J= 5.4, 3.2 Hz, 4H), 4.83 (t,J= 1.7 Hz, 2H), 3.53 (dd,J= 2.1, 1.5 Hz, 2H).

[0238] (2) Step 2: Synthesis of 4-((9R,10S,11R,15S)-12,14-dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl)benzoic acid

[0239] 4-aminobenzoic acid (30.0 mg, 0.17 mmol) was added under stirring to the solution of (9R,10S,11R,15S)-9,10-dihydro-9,10-[3,4]furanoanthracene-12,14-dione (46.0 mg, 0.17 mmol) obtained in Step 1 in acetic acid (1 mL), and the mixture was heated at 120 °C for 5 hours. After cooling the reaction mixture to room temperature, an excess amount of DI was added to the solution until a precipitate was formed. The precipitate was filtered and dried to obtain the target product as a white solid (45.3 mg, 0.12 mmol, 69%).

[0240] 1 H NMR (300 MHz, DMSO) δ 7.93 - 7.84 (m, 2H), 7.52 (dd,J= 5.4, 3.2 Hz, 2H), 7.32 (dd,J= 5.4, 3.3 Hz, 2H), 7.26 - 7.16 (m, 4H), 6.62 (d,J= 8.3 Hz, 2H), 4.88 (t,J= 1.7 Hz, 2H), 3.47 - 3.40 (m, 2H).

[0241] (3) Step 3: Synthesis of 4-((9R,10S,11R,15S)-12,14-Dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl)-N-(quinolin-8-yl)benzamide

[0242] 8-aminoquinoline (17.7 mg, 0.12 mmol) was added to the solution of 4-((9R,10S,11R,15S)-12,14-dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl)benzoic acid (45.3 mg, 0.12 mmol), HATU (137.4 mg, 0.35 mmol), and DIPEA (105 μL, 0.60 mmol) obtained in Step 2 in anhydrous DMF (1 mL), and the mixture was stirred overnight at room temperature. The mixture was washed with a saturated sodium bicarbonate solution, extracted with EA, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure (in vacuo). The residue was purified by column chromatography (hexane (Hex) / EA = 1 / 1) to obtain a product as a white solid (38.0 mg, 0.073 mmol, 63%).

[0243] 1 H NMR (400 MHz, CDCl3) δ 10.65 (s, 1H), 8.89 (dd,J= 7.3, 1.8 Hz, 1H), 8.83 (dd,J= 4.2, 1.7 Hz, 1H), 8.18 (dd,J= 8.3, 1.7 Hz, 1H), 8.04 - 7.97 (m, 2H), 7.63 - 7.51 (m, 2H), 7.51 - 7.42 (m, 3H), 7.42 - 7.31 (m, 2H), 7.29 - 7.18 (m, 4H), 6.81 - 6.73 (m, 2H), 4.92 (t,J= 1.8 Hz, 2H), 3.43 (t,J= 1.7 Hz, 2H).

[0244] 2. Synthesis of Compound (= IB-6) of Preparation Example 2

[0245]

[0246] (1) Step 1: Synthesis of (3aR,4R,9S,9aS)-3a,4,9,9a-tetrahydro-4,9-methanonaphtho[2,3-]furan-1,3-dione

[0247] A solution of maleic anhydride (981.6 mg, 10.0 mmol) and p-hydroquinone (396.9 mg, 3.4 mmol) in 1H-indene (1632 uL, 14.0 mmol, CAS: 95-13-6) was heated at 190 °C for 3 hours. The reaction mixture was cooled to 60 °C and then poured into toluene (100 mL). Insoluble byproducts were removed by filtration, and the filtrate was concentrated under reduced pressure (in vacuo). The product was recovered by filtration and recrystallized from EA to obtain a white crystalline solid (59 mg, 0.28 mmol, 3%).

[0248] 1 H NMR (300 MHz, CDCl3) δ 7.32 - 7.17 (m, 4H), 3.92 (dq,J= 3.3, 1.6 Hz, 2H), 3.79 (dd,J= 3.2, 1.8 Hz, 2H), 2.16 (dt,J= 9.5, 1.6 Hz, 1H), 1.95 (dt,J= 9.5, 1.5 Hz, 1H).

[0249] (2) Step 2: Synthesis of 4-((3aR,4R,9S,9aS)-1,3-dioxo-1,3,3a,4,9,9a-hexahydro-2H-4,9-methanobenzo[f]isoindol-2-yl)benzoic acid

[0250] 4-aminobenzoic acid (20.1 mg, 0.12 mmol) was added under stirring to the solution of (3aR,4R,9S,9aS)-3a,4,9,9a-tetrahydro-4,9-methanonaphth[2,3-]furan-1,3-dione (25.0 mg, 0.12 mmol) obtained in Step 1 in acetic acid (1 mL), and the mixture was heated at 120 °C overnight. After cooling the reaction mixture to 0 °C, an excess amount of DI was added to the solution until a precipitate was formed. The precipitate was filtered and dried to obtain the desired product as a white solid (22.0 mg, 0.067 mmol, 58%).

[0251] 1 H NMR (300 MHz, CDCl3) δ 8.02 - 7.93 (m, 2H), 7.32 - 7.16 (m, 4H), 6.63 - 6.54 (m, 2H), 3.95 (dd,J= 3.2, 1.7 Hz, 2H), 3.68 (dd,J= 3.1, 1.8 Hz, 2H), 2.19 (d,J= 9.4 Hz, 1H), 2.02 (d,J= 9.4 Hz, 1H).

[0252] (2) Step 3: Synthesis of 4-((3aR,4R,9S,9aS)-1,3-dioxo-1,3,3a,4,9,9a-hexahydro-2H-4,9-methanobenzo[f]isoindol-2-yl)-N-(quinolin-8-yl)benzamide

[0253] 8-aminoquinoline (8.5 mg, 0.06 mmol) was added to the solution of 4-((3aR,4R,9S,9aS)-1,3-dioxo-1,3,3a,4,9,9a-hexahydro-2H-4,9-methanobenzo[f]isoindole-2-yl)benzoic acid (18.9 mg, 0.06 mmol), HATU (69.0 mg, 0.18 mmol), and DIPEA (32.0 μL, 0.18 mmol) obtained in Step 2 in anhydrous DMF (1 mL), and the mixture was stirred overnight at room temperature. The mixture was washed with a saturated sodium bicarbonate solution, extracted with EA, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Hex / EA = 1 / 1) to obtain the target product as a white solid (15.0 mg, 0.03 mmol, 54%).

[0254] 1 H NMR (300 MHz, CDCl3) δ 10.63 (s, 1H), 8.92 - 8.78 (m, 2H), 8.18 (dd,J= 8.3, 1.7 Hz, 1H), 8.01 - 7.91 (m, 2H), 7.64 - 7.49 (m, 2H), 7.47 (dd,J= 8.3, 4.2 Hz, 1H), 7.36 - 7.19 (m, 4H), 6.72 - 6.61 (m, 2H), 3.97 (dq,J= 3.3, 1.6 Hz, 2H), 3.70 (dd,J= 3.1, 1.8 Hz, 2H), 2.20 (dt,J= 9.4, 1.6 Hz, 1H), 2.04 (s, 1H).

[0255] 3. Synthesis of Compound (= IB-8) of Preparation Example 3

[0256]

[0257] (1) Step 1: Synthesis of (9S,10S,11R,15S)-2,6-dimethoxy-9,10-dihydro-9,10-[3,4]furanoanthracene-12,14-dione

[0258] Maleic anhydride (40.0 mg, 0.41 mmol) was added to a solution of 2,6-dimethoxycyanthracene (95.8 mg, 0.40 mmol) in xylene (0.5 mL) under stirring, and the mixture was heated in a pressure tube at 180 °C for 30 minutes. The reaction mixture was cooled to room temperature and filtered. The precipitate was washed with hexane and dried to obtain the target product as a white solid (101.0 mg, 0.3 mmol, 75%).

[0259] 1 H NMR (300 MHz, CDCl3) δ 7.31 - 7.18 (m, 2H), 6.95 (d,J= 2.5 Hz, 1H), 6.88 (d,J= 2.5 Hz, 1H), 6.69 (ddd,J= 7.9, 5.1, 2.5 Hz, 2H), 4.71 (s, 2H), 3.77 (d,J= 7.7 Hz, 6H), 3.50 (t,J= 1.7 Hz, 2H).

[0260] (2) Step 2: Synthesis of 4-((9S,10S,11R,15S)-2,6-dimethoxy-12,14-dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl)benzoic acid

[0261] 4-aminobenzoic acid (14.7 mg, 0.11 mmol) was added under stirring to the solution of (9S,10S,11R,15S)-2,6-dimethoxy-9,10-dihydro-9,10-[3,4]furanoanthracene-12,14-dione (34.1 mg, 0.10 mmol) obtained in Step 1 in acetic acid (1 mL), and the mixture was heated at 120 °C overnight. After cooling the reaction mixture to 0 °C, an excess amount of DI was added to the solution until a precipitate was formed. The precipitate was filtered and dried to obtain the target product as a white solid (32.0 mg, 0.07 mmol, 69%).

[0262] 1 H NMR (300 MHz, CDCl3) δ 8.08 - 7.99 (m, 2H), 7.31 (d,J= 8.2 Hz, 1H), 7.23 (d,J= 8.1 Hz, 1H), 6.99 (d,J= 2.5 Hz, 1H), 6.90 (d,J= 2.5 Hz, 1H), 6.80 - 6.66 (m, 4H), 4.78 (s, 2H), 3.78 (d,J= 15.7 Hz, 6H), 3.38 (t,J= 1.7 Hz, 2H).

[0263] (2) Step 3: Synthesis of 4-((9S,10S,11R,15S)-2,6-dimethoxy-12,14-dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl)-N-(quinolin-8-yl)benzamide

[0264] 8-aminoquinoline (10.4 mg, 0.07 mmol) was added to a solution of 4-((9S,10S,11R,15S)-2,6-dimethoxy-12,14-dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl)benzoic acid (32.0 mg, 0.07 mmol), HATU (80.3 mg, 0.21 mmol), and DIPEA (38 μL, 0.21 mmol) obtained in Step 2 in anhydrous DMF (1 mL), and the mixture was stirred overnight at room temperature. The mixture was washed with a saturated sodium bicarbonate solution, extracted with DCM, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude residue was dissolved in DCM and purified by preparative thin layer chromatography (DCM / MeOH = 50 / 1). The target product was obtained as off-white solids (14.0 mg, 0.024 mmol, 34%).

[0265] 1 H NMR (300 MHz, CDCl3) δ 10.69 (s, 1H), 8.95 - 8.82 (m, 2H), 8.21 (dd,J= 8.3, 1.6 Hz, 1H), 8.10 - 7.99 (m, 2H), 7.67 - 7.54 (m, 2H), 7.50 (dd,J= 8.3, 4.2 Hz, 1H), 7.31 (dd,J= 18.6, 8.2 Hz, 3H), 7.03 (d,J= 2.5 Hz, 1H), 6.95 (d,J= 2.5 Hz, 1H), 6.92 - 6.82 (m, 2H), 6.75 (td,J=8.5, 2.5 Hz, 2H), 4.83 (d,J= 2.0 Hz, 2H), 3.81 (d,J= 10.7 Hz, 6H), 3.48 - 3.36 (m, 2H).

[0266] 4. Synthesis of Compound (= IB-3-A2) of Preparation Example 4

[0267]

[0268] (1) Step 1: Synthesis of 3-((9R,10S,11R,15S)-12,14-dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl)bicyclo[1.1.1]pentane-1-carboxylic acid

[0269] 3-Aminobicyclo[1.1.1]pentane-1-carboxylic acid hydrochloride (67.4 mg, 0.41 mmol, CAS: 1172097-47-0) was added under stirring to a solution of (9R,10S,11R,15S)-9,10-dihydro-9,10-[3,4]furanoanthracen-12,14-dione) (56.0 mg, 0.20 mmol) prepared in the preparation process of Preparation Example 1 (IB-3) in acetic acid (1 mL), and the mixture was heated at 120 °C for 5 hours. After cooling the reaction mixture to room temperature, an excess amount of DI was added to the solution until a precipitate was formed. The precipitate was filtered and dried to obtain the target product as a white solid (44.0 mg, 0.11 mmol, 57%).

[0270] 1 H NMR (300 MHz, CDCl3) δ 7.38 (dd,J= 5.4, 3.3 Hz, 2H), 7.16 (ddd,J= 7.2, 5.4, 3.2 Hz, 4H), 4.75 (t,J= 1.8 Hz, 2H), 3.13 (dd,J= 2.1, 1.3 Hz, 2H), 2.22 (s, 6H).

[0271] (2) Step 2: Synthesis of 4-((9R,10S,11R,15S)-12,14-Dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl)-N-(quinolin-8-yl)benzamide

[0272] 8-aminoquinoline (16.4 mg, 0.11 mmol) was added to a solution of 3-((9R,10S,11R,15S)-12,14-dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (36.5 mg, 0.095 mmol), HATU (113.5 mg, 0.30 mmol), and DIPEA (80 μL, 0.45 mmol) obtained in Step 1 in anhydrous DMF (1 mL), and the mixture was stirred overnight at room temperature. The mixture was washed with a saturated sodium bicarbonate solution, extracted with EA, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Hex / EA = 1 / 1) to obtain a product as a white solid (11.4 mg, 0.022 mmol, 22%).

[0273] 1H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 8.81 (dd,J= 4.3, 1.6 Hz, 1H), 8.70 (dd,J= 5.9, 3.1 Hz, 1H), 8.15 (dd,J= 8.3, 1.7 Hz, 1H), 7.50 (q,J= 3.9 Hz, 2H), 7.46 (dd,J= 8.3, 4.2 Hz, 1H), 7.40 (dd,J= 5.4, 3.3 Hz, 2H), 7.30 (dt,J= 7.7, 3.8 Hz, 2H), 7.19 (dt,J= 5.6, 2.8 Hz, 4H), 4.78 (s, 2H), 3.17 (t,J= 1.7 Hz, 2H), 2.37 (s, 6H).

[0274] 5. Synthesis of Compound (= IB-3-A3) of Preparation Example 5

[0275]

[0276] (1) Step 1: Synthesis of (1R,4r)-4-((9R,10S,11R,15S)-12,14-dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl)cyclohexane-1-carboxylic acid

[0277] Trans-4-aminocyclohexanecarboxylic acid (76.7 mg, 0.54 mmol, CAS: 3685-25-4) was added under stirring to a solution of (9R,10S,11R,15S)-9,10-dihydro-9,10-[3,4]furanoanthracen-12,14-dione) (69.3 mg, 0.25 mmol) prepared in the preparation process of Preparation Example 1 (IB-3) in acetic acid (1 mL), and the mixture was heated at 120 °C overnight. After cooling the reaction mixture to room temperature, an excess amount of DI was added to the solution until a precipitate was formed. The precipitate was filtered and dried to obtain the desired product as a white solid (67.0 mg, 0.17 mmol, 67%).

[0278] 1 H NMR (300 MHz, CDCl3) δ 7.37 (dd,J= 5.4, 3.2 Hz, 2H), 7.26 (d,J= 8.6 Hz, 2H), 7.15 (ddd,J= 13.7, 5.4, 3.2 Hz, 4H), 4.76 (s, 2H), 3.60 - 3.47 (m, 1H), 3.13 (dd,J= 2.1, 1.4 Hz, 2H), 2.28 - 2.15 (m, 1H), 1.94 (d,J= 13.5 Hz, 2H), 1.87 - 1.69 (m, 2H), 1.40 - 1.21 (m, 2H), 0.91 (d,J= 12.9 Hz, 2H).

[0279] (2) Step 2: Synthesis of (1R,4R)-4-((9R,10S,11R,15S)-12,14-Dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl)-N-(quinolin-8-yl)cyclohexane-1-carboxamide

[0280] 8-aminoquinoline (15.5 mg, 0.11 mmol) was added to the solution of (1R,4r)-4-((9R,10S,11R,15S)-12,14-dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl)cyclohexane-1-carboxylic acid (38.6 mg, 0.096 mmol), HATU (122.8 mg, 0.32 mmol), and DIPEA (80 μL, 0.45 mmol) obtained in Step 1 in anhydrous DMF (1 mL), and the mixture was stirred overnight at room temperature. The mixture was washed with a saturated sodium bicarbonate solution, extracted with DCM, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude raw material residue was resuspended in EA, and the precipitated solid was recovered to obtain the target product as a white solid (24.5 mg, 0.046 mmol, 48%).

[0281] 1 H NMR (300 MHz, CDCl3) δ 9.83 (s, 1H), 8.80 (dd,J= 4.2, 1.7 Hz, 1H), 8.73 (dd,J= 6.7, 2.3 Hz, 1H), 8.15 (dd,J= 8.3, 1.7 Hz, 1H), 7.57 - 7.33 (m, 5H), 7.29 (dd,J= 5.4, 3.3 Hz, 2H), 7.16 (ddd,J= 9.5, 5.4, 3.2 Hz, 4H), 4.79 (t,J= 1.7 Hz, 2H), 3.75 - 3.56 (m, 1H), 3.16 (dd,J=2.1, 1.3 Hz, 2H), 2.38 (tt,J= 12.2, 3.4 Hz, 1H), 2.03 (d,J= 13.3 Hz, 2H), 1.99 - 1.80 (m, 2H), 1.65 - 1.40 (m, 3H), 1.00 (dd,J= 13.0, 3.6 Hz, 2H).

[0282] 6. Synthesis of Compound (= IB-10) of Preparation Example 6

[0283]

[0284] I-3 (34.3 mg, 0.10 mmol) was added to a solution of 2,6-dibromoanthracene (35.2 mg, 0.10 mmol, CAS: 186517-01-1) in xylene (1 mL) under stirring, and the mixture was heated at 140 °C overnight. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure. The residue was resuspended in hexane, and the insoluble solid was recovered by filtration. The solid was dissolved in chloroform and purified by preparative thin-layer chromatography (Hex / EA = 1 / 1), followed by further purification by column chromatography (DCM / MeOH = 50 / 1) to obtain the target product as off-white solids (13.0 mg, 0.021 mmol, 21%).

[0285] 1 H NMR (300 MHz, CDCl3) δ 10.67 (s, 1H), 8.94 - 8.80 (m, 2H), 8.19 (dd,J= 8.3, 1.7 Hz, 1H), 8.09 - 7.98 (m, 2H), 7.65 - 7.53 (m, 2H), 7.53 - 7.40 (m, 4H), 7.37 (d,J= 7.4 Hz, 1H), 7.19 - 7.06 (m, 2H), 6.92 - 6.82 (m, 2H), 5.52 - 5.45 (m, 1H), 5.39 (t,J= 1.7 Hz, 1H), 3.50 - 3.38 (m, 2H).

[0286] 7. Synthesis of Compound (= IB-11a / b) of Preparation Example 7

[0287]

[0288] (1) Step 1: Synthesis of N-(anthracen-2-yl)acetamide

[0289] Acetic anhydride (60 μL, 0.63 mmol) was added to a solution of 1-aminoanthracene (101.9 mg, 0.53 mmol, CAS: 610-49-1) in DCM (1 mL) and stirred overnight at room temperature. After removing the solvent under reduced pressure, the solid was triturated with Et2O. The precipitate was recovered by filtration to obtain the target product as pale-yellow solids (88.0 mg, 0.37 mmol, 70%).

[0290] 1 H NMR (300 MHz, DMSO) δ 10.07 (s, 1H), 8.76 (s, 1H), 8.61 (s, 1H), 8.10 (d,J= 7.9 Hz, 3H), 7.93 (d,J= 8.4 Hz, 1H), 7.76 (d,J= 7.1 Hz, 1H), 7.60 - 7.44 (m, 3H), 2.27 (s, 3H).

[0291] (2) Step 2: Synthesis of 4-((9R,10S,11R,15S)-4-acetamide-12,14-dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl)-N-(quinolin-8-yl)benzamide

[0292] I-3 (17.3 mg, 0.05 mmol) was added under stirring to the solution of N-(anthracen-2-yl)acetamide (12.4 mg, 0.05 mmol) obtained in Step 1 in xylene (1 mL), and the mixture was heated at 140 °C overnight. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure. The residue was resuspended in MeOH, and the insoluble solid was obtained by filtration. The insoluble solid contains 4-((9R,10S,11R,15S)-4-acetamide-12,14-dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl)-N-(quinoline-8-yl)benzamide and / or its isomers. The solid was dissolved in DCM and purified by thin-layer chromatography for preparation (DCM / MeOH = 10 / 1) to obtain two isomers IB-11a and IB-11b in a ratio of 4:1 (15 mg, 0.026 mmol, 52%).

[0293] IB-11a: 1 H NMR (300 MHz, CDCl3) δ 10.66 (s, 1H), 8.93 - 8.80 (m, 2H), 8.19 (dd,J= 8.3, 1.7 Hz, 1H), 8.08 - 7.98 (m, 2H), 7.65 - 7.39 (m, 6H), 7.34 (d,J= 8.6 Hz, 1H), 7.31 - 7.19 (m, 4H), 6.83 - 6.73 (m, 2H), 5.09 (d,J= 3.6 Hz, 1H), 4.92 (d,J= 3.2 Hz, 1H), 3.53 - 3.36 (m, 2H), 2.27 (s, 3H),IB-11b: 1H NMR (300 MHz, CDCl3) δ 10.65 (s, 1H), 8.93 - 8.79 (m, 2H), 8.19 (dd,J= 8.3, 1.7 Hz, 1H), 8.05 - 7.95 (m, 2H), 7.64 - 7.53 (m, 2H), 7.48 (dd,J= 8.3, 4.2 Hz, 1H), 7.40 - 7.28 (m, 3H), 7.28 - 7.14 (m, 4H), 6.81 - 6.71 (m, 2H), 4.94 (dd,J= 7.2, 3.4 Hz, 2H), 3.61 (dd,J=8.5, 3.5 Hz, 1H), 3.42 (dd,J= 8.5, 3.5 Hz, 1H), 2.35 (s, 3H).

[0294] 8. Synthesis of Compound (= IB-12) in Preparation Example 8

[0295]

[0296] I-3 (34.3 mg, 0.10 mmol) was added to a solution of 2,6-dihydroxyanthracene (15.2 mg, 0.072 mmol, CAS: 101488-73-7) in toluene (1 mL) under stirring, and the mixture was heated at 120 °C overnight. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure. The residue was resuspended in a chloroform:MeOH (2:1 v / v) mixture and purified by preparative thin-layer chromatography (chloroform / MeOH = 10 / 1) to obtain the target product as off-white solids (22.5 mg, 0.041 mmol, 57%).

[0297] 1H NMR (300 MHz, DMSO) δ 10.63 (s, 1H), 9.38 (s, 2H), 8.98 (dd,J= 4.2, 1.7 Hz, 1H), 8.74 - 8.66 (m, 1H), 8.47 (dd,J= 8.3, 1.7 Hz, 1H), 8.02 (d,J= 8.5 Hz, 2H), 7.80 - 7.74 (m, 1H), 7.72 - 7.63 (m, 2H), 7.25 (d,J= 8.0 Hz, 1H), 7.09 (d,J= 8.0 Hz, 1H), 6.91 (d,J= 2.4 Hz, 1H), 6.82 (d,J= 8.4 Hz, 2H), 6.71 (d,J= 2.4 Hz, 1H), 6.57 (ddd,J= 13.9, 8.0, 2.4 Hz, 2H), 4.64 (s, 2H), 3.37 (d,J= 2.4 Hz, 2H).

[0298] 9. Synthesis of Compound (= IB-15) of Preparation Example 9

[0299]

[0300] (1) Step 1: Synthesis of N,N'-(anthracene-2,6-diyl)diacetamide

[0301] Acetic anhydride (150 μL, 1.59 mmol) was added to a solution of anthracene-2,6-diamine (74.8 mg, 0.36 mmol, CAS: 46710-42-3) in DCM (1 mL), and stirred overnight at room temperature. After removing the solvent under reduced pressure, the solid was treated with Et2O. The precipitate was recovered by filtration to obtain the target product as khaki brown solids (97.0 mg, 0.33 mmol, 92%).

[0302] 1H NMR (300 MHz, DMSO) δ 10.15 (s, 2H), 8.44 (d,J= 2.0 Hz, 2H), 8.34 (s, 2H), 7.97 (d,J= 9.1 Hz, 2H), 7.52 (dd,J= 9.1, 2.0 Hz, 2H), 2.13 (s, 6H).

[0303] (2) Step 2: Synthesis of N,N'-((9S,10S,11R,15S)-12,14-dioxo-13-(4-(quinolin-8-ylcarbamoyl)phenyl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-2,6-diyl)diacetamide

[0304] I-3 (24.2 mg, 0.07 mmol) was added to the solution of N,N'-(anthracene-2,6-diyl)diacetamide (20.7 mg, 0.07 mmol) obtained in Step 1 in xylene (1 mL), and the mixture was heated at 140 °C overnight. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure. The residue was resuspended in acetone, and the insoluble solid was recovered by filtration. The solid was dissolved in a mixture of DCM and MeOH and purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain the target product as pale brown solids (7 mg, 0.011 mmol, 16%).

[0305] 1H NMR (400 MHz, CDCl3) δ 10.65 (s, 1H), 8.90 - 8.80 (m, 2H), 8.18 (dd,J= 8.3, 1.7 Hz, 1H), 8.02 - 7.96 (m, 2H), 7.70 (s, 1H), 7.61 - 7.40 (m, 6H), 7.34 (d,J= 8.0 Hz, 1H), 7.25 (d,J= 9.8 Hz, 2H), 7.17 (dd,J= 7.9, 2.0 Hz, 1H), 6.84 (d,J= 8.4 Hz, 2H), 4.80 (d,J= 10.4 Hz, 2H), 3.36 (s, 2H), 2.18 (s, 3H), 2.13 (s, 3H).

[0306] 10. Synthesis of Compound (= IB-16) of Preparation Example 10

[0307]

[0308] (1) Step 1: Synthesis of N,N'-(anthracene-1,5-diyl)diacetamide

[0309] Acetic anhydride (150 μL, 1.59 mmol) was added to a solution of anthracene-1,5-diamine (75.6 mg, 0.36 mmol, CAS: 79015-49-9) in DCM (1 mL), and stirred overnight at room temperature. After removing the solvent under reduced pressure, the solid was treated with Et2O. The precipitate was recovered by filtration to obtain the target product as khaki solids (101.0 mg, 0.35 mmol, 96%).

[0310] 1H NMR (300 MHz, DMSO) δ 10.08 (s, 2H), 8.78 (s, 2H), 7.95 (d,J= 8.5 Hz, 2H), 7.79 (d,J= 7.2 Hz, 2H), 7.52 (dd,J= 8.5, 7.2 Hz, 2H), 2.27 (s, 6H).

[0311] (2) Step 2: Synthesis of N,N'-((9S,10S,11R,15S)-12,14-dioxo-13-(4-(quinolin-8-ylcarbamoyl)phenyl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-1,5-diyl)diacetamide

[0312] I-3 (15.0 mg, 0.04 mmol) was added to the solution of N,N'-(anthracene-1,5-diyl)diacetamide (15.7 mg, 0.05 mmol) obtained in Step 1 in xylene (1 mL), and the mixture was heated at 140 °C overnight. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure. The residue was resuspended in DCM, and the solid was removed by centrifugation. The soluble fraction was recovered by centrifugation and purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain the target product as pale brown solids (8 mg, 0.013 mmol, 30%).

[0313] 1H NMR (400 MHz, Acetone) δ 10.75 (s, 1H), 8.97 (dd,J= 4.2, 1.7 Hz, 2H), 8.91 (dd,J= 7.5, 1.5 Hz, 1H), 8.44 (dd,J= 8.3, 1.7 Hz, 1H), 8.08 - 8.01 (m, 2H), 7.77 - 7.62 (m, 3H), 7.56 (d,J= 7.9 Hz, 1H), 7.42 (d,J= 7.4 Hz, 1H), 7.33 (d,J= 7.4 Hz, 1H), 7.23 - 7.14 (m, 2H), 7.09 (d,J= 7.4 Hz, 1H), 6.98 (d,J= 8.3 Hz, 2H), 5.37 (d,J= 3.5 Hz, 1H), 5.09 (s, 1H), 3.66 (dd,J= 8.4, 3.4 Hz, 1H), 3.48 (dd,J= 8.5, 3.7 Hz, 1H), 2.21 (d,J= 14.2 Hz, 6H).

[0314] 11. Synthesis of Compound (= IB-17) in Preparation Example 11

[0315]

[0316] I-3 (24.1 mg, 0.070 mmol) was added to a solution of 2,6-dihydroxyanthracene (17.6 mg, 0.074 mmol, CAS: 16294-32-9) in xylene (1 mL) under stirring, and the mixture was heated at 140 °C overnight. After cooling the reaction mixture to room temperature, the solid was removed by centrifugation. The soluble fraction was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain the target product as off-white solids (22.5 mg, 0.041 mmol, 57%).

[0317] 1H NMR (400 MHz, CDCl3) δ 10.66 (s, 1H), 8.89 (dt,J= 7.2, 1.9 Hz, 1H), 8.83 (dt,J= 4.0, 1.8 Hz, 1H), 8.19 (dt,J= 8.3, 1.9 Hz, 1H), 8.05 - 7.97 (m, 2H), 7.64 - 7.56 (m, 2H), 7.56 - 7.45 (m, 1H), 7.17 (dtd,J= 10.0, 8.1, 1.8 Hz, 2H), 7.09 (d,J= 7.3 Hz, 1H), 7.03 (d,J= 7.3 Hz, 1H), 6.79 (ddd,J= 15.6, 8.3, 1.7 Hz, 4H), 5.42 (ddd,J= 16.4, 3.3, 1.7 Hz, 2H), 3.85 (dd,J= 24.8, 1.9 Hz, 6H), 3.37 (qdd,J= 8.5, 3.3, 1.8 Hz, 2H).

[0318] 12. Synthesis of Compound (= IB-18) of Preparation Example 12

[0319]

[0320] (1) Step 1: Synthesis of dimethyl anthracene-2,6-dicarboxylate

[0321] Methyl iodide (130 μL, 2.1 mmol, CAS: 74-88-4) was dropwise added to a mixture of anthracene-2,6-dicarboxylic acid (53.4 mg, 0.2 mmol, CAS: 138308-89-1) and lithium carbonate (147.4 mg, 2.0 mmol, CAS: 554-13-2) in anhydrous DMF (1 mL), and the mixture was stirred overnight at room temperature. A 1 M aqueous hydrochloric acid solution (9.8 mL) was added, and the resulting yellow precipitate was recovered by filtration to obtain the target product (47.0 mg, 0.16 mmol, 80%).

[0322] 1 H NMR (400 MHz, DMSO) δ 8.96 (s, 2H), 8.89 (s, 2H), 8.25 (d,J= 8.9 Hz, 2H), 8.00 (dd,J= 8.9, 1.7 Hz, 2H), 3.97 (s, 3H), 3.96 (s, 3H).

[0323] (2) Step 2: Synthesis of dimethyl (9S,10S,11R,15S)-12,14-dioxo-13-(4-(quinolin-8-ylcarbamoyl)phenyl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-2,6-dicarboxylate

[0324] I-3 (23.8 mg, 0.070 mmol) was added under stirring to the solution of dimethyl anthracene-2,6-dicarboxylate (20.5 mg, 0.07 mmol) obtained in Step 1 in DMF (1 mL), and the mixture was heated overnight at 120 °C in a sealed tube. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure. The crude residue was dissolved in DCM and purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain the target product as off-white solids (20 mg, 0.031 mmol, 44%).

[0325] 1H NMR (400 MHz, CDCl3) δ 10.66 (s, 1H), 8.91 - 8.80 (m, 2H), 8.19 (dd,J= 8.3, 1.7 Hz, 1H), 8.12 (d,J= 1.6 Hz, 1H), 8.05 (d,J= 1.6 Hz, 1H), 8.03 - 7.92 (m, 4H), 7.64 - 7.43 (m, 5H), 6.85 - 6.72 (m, 2H), 5.06 (t,J= 2.6 Hz, 2H), 3.92 (d,J= 10.9 Hz, 6H), 3.52 - 3.41 (m, 2H).

[0326] 13. Synthesis of Compound (= IB-19a / b) of Preparation Example 13

[0327]

[0328] I-3 (27.8 mg, 0.08 mmol) was added to a solution of benzo[g]isoquinone (14.3 mg, 0.08 mmol, CAS: 260-32-2) in xylene (1 mL) under stirring, and the mixture was heated at 140 °C overnight. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure. The crude residue was dispersed in acetone, and the solid was removed by centrifugation. The soluble fraction was purified by preparative thin-layer chromatography (DCM / MeOH = 15 / 1) to obtain 4-((5R,10S,11R,15S)-12,14-dioxo-5,10-dihydro-5,10-[3,4]epipyrrolobenzo[g]isoquinolin-13-yl)-N-(quinolin-8-yl)benzamide and / or its isomers in a ratio of 1.2:1 (26 mg, 0.05 mmol, 63%). One of the two isomers was named IB-19a and the other was named IB-19b.

[0329] IB-19a: 1H NMR (400 MHz, CDCl3) δ 10.71 (s, 1H), 8.94 - 8.82 (m, 2H), 8.66 (s, 1H), 8.55 (d,J= 4.8 Hz, 1H), 8.21 (dd,J= 8.3, 1.6 Hz, 1H), 8.09 - 8.00 (m, 2H), 7.65 - 7.54 (m, 2H), 7.50 (ddd,J= 8.7, 6.8, 3.5 Hz, 3H), 7.35 (d,J= 4.8 Hz, 1H), 7.34 - 7.24 (m, 2H), 6.87 - 6.78 (m, 2H), 5.05 (d,J= 2.5 Hz, 1H), 4.98 (d,J= 2.5 Hz, 1H), 3.55 - 3.45 (m, 2H),IB-19b: 1 H NMR (400 MHz, CDCl3) δ 10.66 (s, 1H), 8.88 (dd,J= 7.1, 1.9 Hz, 1H), 8.83 (dd,J= 4.2, 1.6 Hz, 1H), 8.69 (s, 1H), 8.52 (d,J= 4.8 Hz, 1H), 8.19 (dd,J= 8.3, 1.7 Hz, 1H), 8.05 - 7.97 (m, 2H), 7.63 - 7.54 (m, 2H), 7.49 (dd,J= 8.3, 4.2 Hz, 1H), 7.41 (tq,J= 4.8, 2.8 Hz, 3H), 7.36 - 7.25 (m, 2H), 6.81 - 6.73 (m, 2H), 5.03 (d,J= 3.2 Hz, 1H), 4.95 (d,J= 3.1 Hz, 1H), 3.43 (qd,J= 8.5, 3.2 Hz, 2H).

[0330] 14. 제조예 14 화합물(= IB-20)의 합성

[0331]

[0332] LiCl (8.7 mg, 0.21 mmol) was added to IB-18 (6.0 mg, 0.0094 mmol) in DMF (1 mL), and heated in a microwave reactor at 110 °C for 10 minutes. After cooling the mixture to room temperature, the reaction was terminated with 1 N aqueous hydrochloric acid solution (1 mL). The organic extract was extracted with DCM, dried with sodium sulfate, and then concentrated under reduced pressure. The crude raw material was dissolved in DCM and centrifuged to remove the insoluble solid. The soluble fraction was concentrated under reduced pressure (in vacuum) to obtain the target product as a white solid (3.0 mg, 0.005 mmol, 53%).

[0333] 1 H NMR (400 MHz, Acetone) δ 11.43 (s, 2H), 10.73 (s, 1H), 8.95 (dd,J= 4.2, 1.7 Hz, 1H), 8.89 (dd,J= 7.6, 1.4 Hz, 1H), 8.43 (dd,J= 8.3, 1.7 Hz, 1H), 8.24 (d,J= 1.7 Hz, 1H), 8.12 - 8.05 (m, 2H), 8.05 - 8.01 (m, 1H), 8.01 - 7.95 (m, 2H), 7.79 - 7.57 (m, 5H), 6.95 - 6.87 (m, 2H), 5.23 (t,J= 3.5 Hz, 2H), 3.67 (qd,J= 8.6, 3.2 Hz, 2H).

[0334] 15. Synthesis of Compound (= IB-21a / b) of Preparation Example 15

[0335]

[0336] I-3 (34.7 mg, 0.10 mmol) was added under stirring to a solution of benzo[g]quinoxaline (17.8 mg, 0.10 mmol, CAS: 260-50-4) in xylene (1 mL), and the mixture was heated at 140 °C overnight. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure. The crude residue was dissolved in DCM and purified by thin-layer chromatography for preparation (DCM / MeOH = 49 / 1) to obtain 4-((5R,10S,11R,15S)-12,14-Dioxo-5,10-dihydro-5,10-[3,4]epipyrrolobenzo[g]quinoxalin-13-yl)-N-(quinolin-8-yl)benzamide and / or its isomers in a ratio of 1:3.3 (26 mg, 0.05 mmol, 50%). One of the two isomers was named IB-21a and the other was named IB-21b.

[0337] IB-21a: 1 H NMR (400 MHz, CDCl3) δ 10.68 (s, 1H), 8.92 - 8.80 (m, 2H), 8.37 (s, 2H), 8.20 (dd,J= 8.3, 1.7 Hz, 1H), 8.08 - 8.01 (m, 2H), 7.64 - 7.45 (m, 5H), 7.30 (dd,J= 5.4, 3.2 Hz, 2H), 6.98 - 6.92 (m, 2H), 5.16 (t,J= 1.8 Hz, 2H), 3.64 - 3.59 (m, 2H),IB-21b: 1H NMR (400 MHz, CDCl3) δ 10.67 (s, 1H), 8.89 (dd,J= 7.1, 1.8 Hz, 1H), 8.83 (dd,J= 4.2, 1.7 Hz, 1H), 8.34 (s, 2H), 8.20 (dd,J= 8.3, 1.7 Hz, 1H), 8.06 - 7.98 (m, 2H), 7.64 - 7.53 (m, 2H), 7.53 - 7.42 (m, 3H), 7.33 (dd,J= 5.4, 3.2 Hz, 2H), 6.83 - 6.75 (m, 2H), 5.11 (s, 2H), 3.59 (dd,J= 2.1, 1.3 Hz, 2H).

[0338] 16. Synthesis of Compound (= IB-22) in Preparation Example 16

[0339]

[0340] I-3 (34.2 mg, 0.10 mmol) was added to a solution of 1,8-bis(hydroxymethyl)anthracene (23.8 mg, 0.10 mmol, CAS: 34824-20-9) in toluene (1 mL), and the mixture was heated overnight at 140 °C in a pressure tube. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure. The crude residue was dissolved in DCM, and the insoluble solid was removed by centrifugation. The soluble fraction was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain the target product as off-white solids (19.0 mg, 0.033 mmol, 33%).

[0341] 1H NMR (400 MHz, CDCl3) δ 10.66 (s, 1H), 8.91 - 8.80 (m, 2H), 8.19 (dd,J= 8.3, 1.7 Hz, 1H), 8.05 - 7.97 (m, 2H), 7.63 - 7.52 (m, 2H), 7.49 (dd,J= 8.3, 4.3 Hz, 1H), 7.46 - 7.39 (m, 1H), 7.35 (q,J= 4.2 Hz, 1H), 7.27 - 7.18 (m, 4H), 6.79 - 6.72 (m, 2H), 5.72 (d,J= 2.8 Hz, 1H), 5.14 (dd,J= 12.2, 4.6 Hz, 1H), 5.05 (dd,J= 12.2, 6.5 Hz, 1H), 4.94 (d,J= 2.7 Hz, 1H), 4.73 - 4.60 (m, 2H), 3.52 - 3.40 (m, 2H), 2.82 (s, 1H), 2.76 (s, 1H).

[0342] 17. Synthesis of Compound (= IB-23) of Preparation Example 17

[0343]

[0344] (1) Step 1: Synthesis of anthracene-2,6-diyldimethanol

[0345] The product obtained in Step 1 (22.0 mg, 0.075 mmol) was slowly added to a lithium aluminum hydride suspension (23.0 mg, 0.061 mmol, CAS: 16853-85-3) in anhydrous THF at 0 °C. The mixture was heated to room temperature and stirred overnight. After terminating the reaction of the unreacted lithium aluminum hydride by adding EA, the mixture was extracted with brine, dried with MgSO4, and concentrated under reduced pressure (in vacuum) to obtain the target product as a yellow solid (17.0 mg, 0.070 mmol, 93%).

[0346] 1H NMR (400 MHz, DMSO) δ 8.50 (s, 2H), 8.03 (d,J= 8.8 Hz, 2H), 7.95 (s, 2H), 7.45 (d,J= 8.9 Hz, 2H), 5.37 (t,J= 5.7 Hz, 2H), 4.69 (d,J= 5.7 Hz, 4H).

[0347] (2) Step 2: Synthesis of 4-((9S,10S,11R,15S)-2,6-bis(hydroxymethyl)-12,14-dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl)-N-(quinolin-8-yl)benzamide

[0348] I-3 (11.7 mg, 0.03 mmol) was added to the anthracene-2,6-diyldimethanol (8.0 mg, 0.03 mmol) solution obtained in Step 1 in xylene (1 mL), and the mixture was heated overnight at 140 °C in a pressure tube. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure. The crude residue was dissolved in a mixture of DCM and MeOH and purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain the target product as off-white solids (7.0 mg, 0.012 mmol, 35%).

[0349] 1H NMR (400 MHz, DMSO) δ 10.62 (s, 1H), 8.97 (dd,J= 4.2, 1.6 Hz, 1H), 8.70 (dd,J= 7.6, 1.3 Hz, 1H), 8.48 (dd,J= 8.3, 1.7 Hz, 1H), 8.04 - 7.96 (m, 2H), 7.77 (dd,J= 8.3, 1.4 Hz, 1H), 7.73 - 7.62 (m, 2H), 7.50 - 7.43 (m, 2H), 7.32 - 7.23 (m, 2H), 7.15 (td,J= 7.5, 1.6) Hz, 2H), 6.77 - 6.69 (m, 2H), 5.21 (dt,J= 21.9, 5.7 Hz, 2H), 4.86 (t,J= 2.7 Hz, 2H), 4.48 (dd,J= 5.6, 2.0 Hz, 4H), 3.50 - 3.37 (m, 2H).

[0350] 13. Synthesis of Compound (= IB-24a / b) of Preparation Example 18

[0351]

[0352] I-3 (48.7 mg, 0.14 mmol) was added to a solution of benzo[g]quinazoline (27.2 mg, 0.15 mmol) in xylene (1 mL) under stirring, and the mixture was heated at 140 °C overnight. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure. The crude residue was dissolved in a mixture of DCM and MeOH and purified by thin-layer chromatography for preparation (DCM / MeOH = 20 / 1) to obtain 4-((5R,10S,11R,15S)-12,14-dioxo-5,10-dihydro-5,10-[3,4]epipyrrolobenzo[g]quinazolin-13-yl)-N-(quinolin-8-yl)benzamide and / or its isomers in a ratio of 1:1.4 (24.0 mg, 0.046 mmol, 31%). One of the two isomers was named IB-24a and the other was named IB-24b.

[0353] IB-24a: 1 H NMR (400 MHz, CDCl3) δ 10.69 (s, 1H), 9.08 (s, 1H), 8.92 - 8.81 (m, 2H), 8.67 (s, 1H), 8.19 (dd,J= 8.3, 1.7 Hz, 1H), 8.09 - 8.01 (m, 2H), 7.63 - 7.45 (m, 5H), 7.34 - 7.28 (m, 2H), 6.96 - 6.88 (m, 2H), 5.12 - 5.06 (m, 1H), 5.06 - 5.00 (m, 1H), 3.60 - 3.51 (m, 2H),IB-24b: 1 H NMR (400 MHz, CDCl3) δ 10.65 (s, 1H), 9.06 (s, 1H), 8.91 - 8.79 (m, 2H), 8.72 (s, 1H), 8.18 (dd,J= 8.3, 1.7 Hz, 1H), 8.05 - 7.97 (m, 2H), 7.62 - 7.52 (m, 2H), 7.51 - 7.39 (m, 3H), 7.37 - 7.29 (m, 2H), 6.81 - 6.74 (m, 2H), 5.04 (dd,J= 10.0, 3.4 Hz, 2H), 3.53 (dd,J= 8.6, 3.3 Hz, 1H), 3.46 (dd,J= 8.6, 3.4 Hz, 1H).

[0354] 19. Synthesis of Compound (= IB-26) of Preparation Example 19

[0355]

[0356] (1) Step 1: Synthesis of pyrido[3,4-g]isoquinoline-5,10-dione

[0357] N,N-diethylnicotinamide (840.7 μL, 5.0 mmol, CAS: 59-26-7) in anhydrous THF (1.3 mL) was dropwise added to a solution of hexamethylphosphorus triamide (1580 μL, 8.7 mmol) and lithium diisopropylamide solution (1.0 M in THF) (15 mL, 15.0 mmol) at -78 °C under an argon atmosphere. The temperature of the stirred solution was allowed to rise to room temperature overnight. The reaction of the mixture was terminated with water (26 mL), and the mixture was extracted with Et2O (15 mL x 3) and DCM (15 mL x 2). The bound organic layer was washed with water (2 x 15 mL) and dried with sodium sulfate. The crude residue was purified by column chromatography (DCM / Et2O = 7 / 3) to obtain the product as off-white solids (334.0 mg, 1.6 mmol, 64%).

[0358] 1 H NMR (400 MHz, CDCl3) δ 9.59 (s, 2H), 9.19 (d,J= 5.0 Hz, 2H), 8.11 (dd,J= 5.1, 0.9 Hz, 2H).

[0359] (2) Step 2: Synthesis of 5,10-dihydropyrido[3,4-g]isoquinoline

[0360] A 57% hydroiodic acid solution of pyrido[3,4-g]isoquinoline-5,10-dione (289.0 mg, 1.4 mmol) obtained in Step 1 was heated under reflux in an argon atmosphere. After cooling the mixture to room temperature, it was carefully added to a solution of sodium bisulfite (1 M, pH 8, 20 mL) that had been chilled to ice under stirring. The mixture was extracted with DCM, brine, and water. The organic extract was concentrated under reduced pressure to obtain a product as red solids (157.0 mg, 0.86 mmol, 63%).

[0361] 1 H NMR (400 MHz, CDCl3) δ 8.54 (s, 2H), 8.45 (d,J= 5.0 Hz, 2H), 7.25 (d,J= 4.9 Hz, 2H), 3.95 (s, 4H).

[0362] (3) Step 3: Synthesis of pyrido[3,4-g]isoquinoline

[0363] The 5,10-dihydropyrido[3,4-g]isoquinoline (78.0 mg, 0.43 mmol) and 10% Pd / C (20.7 mg) obtained in Step 2 were suspended in diglyme (1 mL) and heated under reflux for 0.5 hours under an argon atmosphere. After cooling the mixture to room temperature, it was filtered through a pad of Celite. The solvent was removed by vacuum distillation at 100 °C. The crude residue was purified by column chromatography (EA / MeOH = 100 / 0 -> 10 / 1) to obtain the product as yellow solids (29.0 mg, 0.16 mmol, 37%).

[0364] 1H NMR (400 MHz, CDCl3) δ 9.56 (s, 2H), 8.60 (s, 2H), 8.54 (d,J= 6.1 Hz, 2H), 7.87 (d,J= 6.0 Hz, 2H).

[0365] (4) Step 4: Synthesis of 4-((5S,10S,11R,15S)-12,14-dioxo-5,10-dihydro-5,10-[3,4]epipyrrolopyrido[3,4-g]isoquinolin-13-yl)-N-(quinolin-8-yl)benzamide

[0366] I-3 (11.9 mg, 0.035 mmol) was added to the pyrido[3,4-g]isoquinoline (6.0 mg, 0.033 mmol) solution obtained in Step 3 in xylene (1 mL), and the mixture was heated at 120 °C overnight under stirring. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure. The crude residue was dissolved in DCM and purified by preparative thin-layer chromatography (DCM / MeOH = 15 / 1) to obtain the target product as a white solid (9.0 mg, 0.017 mmol, 52%).

[0367] 1 H NMR (400 MHz, CDCl3) δ 10.68 (s, 1H), 8.91 - 8.81 (m, 2H), 8.73 (s, 1H), 8.67 (s, 1H), 8.58 (t,J= 5.1 Hz, 2H), 8.19 (dd,J= 8.3, 1.7 Hz, 1H), 8.07 - 7.99 (m, 2H), 7.63 - 7.42 (m, 4H), 7.37 (d,J= 4.8 Hz, 1H), 6.84 - 6.77 (m, 2H), 5.06 (t,J= 2.8 Hz, 2H), 3.53 - 3.41 (m, 2H).

[0368] 20. Synthesis of Compound (= IB-27) of Preparation Example 20

[0369]

[0370] (1) Step 1: Synthesis of (3aR,4S,9R,9aS)-3a,4,9,9a-tetrahydro-4,9-epoxynaphtho[2,3-c]furan-1,3-dione

[0371] A mixture of 1,3-dihydro-1-methoxyisobenzofuran (152.4 mg, 1.0 mmol, CAS: 67536-29-2), maleic anhydride (108.5 mg, 1.1 mmol), and acetic anhydride (104 μL, 1.1 mmol) in chlorobenzene (2 mL) was refluxed for 24 hours. The solvent was removed under reduced pressure and washed with cold chloroform to obtain the product as white crystals (108.0 mg, 0.5 mmol, 50%).

[0372] 1 H NMR (400 MHz, DMSO) δ 7.49 (dd,J= 5.3, 3.1 Hz, 2H), 7.27 (dd,J= 5.4, 3.0 Hz, 2H), 5.88 (s, 2H), 3.42 (s, 2H).

[0373] (2) Step 2: Synthesis of 4-((3aR,4S,9R,9aS)-1,3-dioxo-1,3,3a,4,9,9a-hexahydro-2H-4,9-epoxybenzo[f]isoindol-2-yl)-N-(quinolin-8-yl)benzamide)).

[0374] I-2 (26.2 mg, 0.10 mmol) was added to the solution of (3aR,4S,9R,9aS)-3a,4,9,9a-tetrahydro-4,9-epoxynaphtho[2,3-c]furan-1,3-dione (21.8 mg, 0.10 mmol) obtained in Step 1 in acetic acid (1 mL), and the mixture was heated overnight at 110 °C under stirring. After cooling the reaction mixture to RT, an excess amount of cold DI was added and stirred for 1 hour (1 h). The solid was recovered by filtration, dissolved in chloroform, and then purified by column chromatography (DCM / MeOH = 50 / 1) to obtain the product as a white solid (29.0 mg, 0.063 mmol, 63%).

[0375] 1 H NMR (400 MHz, CDCl3) δ 10.77 (s, 1H), 8.92 (dd,J= 7.3, 1.7 Hz, 1H), 8.85 (dd,J= 4.2, 1.7 Hz, 1H), 8.20 (dd,J= 8.5, 2.0 Hz, 3H), 7.65 - 7.58 (m, 1H), 7.57 (dt,J= 6.9, 1.9 Hz, 3H), 7.49 (dd,J= 8.3, 4.2 Hz, 1H), 7.42 (dd,J= 5.3, 3.0 Hz, 2H), 7.29 (dd,J= 5.3, 3.0 Hz, 2H), 5.84 (s, 2H), 3.18 (s, 2H).

[0376] 21. Synthesis of Compound (= IB-28) of Preparation Example 21

[0377]

[0378] (1) Step 1: Synthesis of 9,10-diethyl-2,3,6,7-tetramethoxy-9,10-dihydroanthracene

[0379] Veratrol (635 μL, 5.0 mmol, CAS: 91-16-7) and propionaldehyde (1800 μL, 25.0 mmol, CAS: 123-38-6) in chloroform (3.0 mL) were dropwise added to concentrated sulfuric acid (5 mL) at 0 °C and stirred at room temperature for 6 hours. The mixture was then poured into cold MeOH (75 mL), the precipitate was recovered by filtration, and the product was washed with water and MeOH to obtain a white solid (452 ​​mg, 1.28 mmol, 26%).

[0380] 1 H NMR (400 MHz, CDCl3) δ 7.41 (s, 4H), 4.07 (s, 12H), 3.47 (d,J= 7.7 Hz, 4H), 1.44 (t,J= 7.6 Hz, 6H).

[0381] (2) Step 2: Synthesis of 2,3,6,7-tetramethoxyanthracene-9,10-dione

[0382] 9,10-diethyl-2,3,6,7-tetramethoxy-9,10-dihydroanthracene (113.0 mg, 0.30 mmol) and potassium dichromate (442.1 mg, 1.5 mmol) obtained in Step 1 were suspended in acetic acid (7.5 mL) and heated at 90 °C for 30 minutes. After cooling the mixture to room temperature, the solid was recovered by filtration and washed with water and Et2O to obtain a yellow solid product (37.0 mg, 0.11 mmol, 35%).

[0383] 1 H NMR (400 MHz, CDCl3) δ 7.69 (s, 4H), 4.07 (s, 12H).

[0384] (3) Step 3: Synthesis of 2,3,6,7-tetramethoxyanthracene

[0385] Under an argon atmosphere, zinc (182.1 mg, 2.7 mmol) and sodium hydroxide (58.5 mg, 1.5 mmol) were added to the 2,3,6,7-tetramethoxycyanthracene-9,10-dione (30.0 mg, 0.10 mmol) obtained in Step 2, dissolved in distilled water (1 mL). The mixture was stirred at 100 °C for 2 days. After cooling the mixture to room temperature, 1 N hydrochloric acid (4 mL) was added. The mixture was stirred until a pale yellow mixture was observed. The solid was recovered by filtration and washed with water and acetone to obtain a product as a yellow solid (16.0 mg, 0.054 mmol, 54%).

[0386] 1 H NMR (400 MHz, CDCl3) δ 8.03 (s, 2H), 7.15 (s, 4H), 4.03 (s, 12H).

[0387] (4) Step 4: Synthesis of N-(quinolin-8-yl)-4-((9R,10S,11R,15S)-2,3,6,7-tetramethoxy-12,14-dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl)benzamide

[0388] I-3 (17.6 mg, 0.051 mmol) was added to the 2,3,6,7-tetramethoxycyanthracene (14.1 mg, 0.047 mmol) solution obtained in Step 3 in toluene (1 mL), and the mixture was heated overnight at 120 °C under stirring in a pressure tube. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure. The crude residue was dissolved in a mixture of DCM and MeOH and purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain the target product as off-white solids (8.0 mg, 0.012 mmol, 26%).

[0389] 1 H NMR (400 MHz, CDCl3) δ 10.68 (s, 1H), 8.92 - 8.83 (m, 2H), 8.19 (dd,J= 8.3, 1.6 Hz, 1H), 8.07 - 7.99 (m, 2H), 7.63 - 7.45 (m, 3H), 7.01 (s, 2H), 6.94 (s, 2H), 6.88 - 6.80 (m, 2H), 4.77 (t,J= 1.7 Hz, 2H), 3.88 (d,J= 12.7 Hz, 12H), 3.43 - 3.36 (m, 2H).

[0390] 22. Synthesis of Compound (= IB-29) of Preparation Example 22

[0391]

[0392] (1) Step 1: Synthesis of 2,3,6,7-Tetrahydroxyanthracene

[0393] 2,3,6,7-tetramethoxycyanthracene was added to an oven-dried Schlenk flask equipped with a stirring bar. The flask was sealed with a rubber Septum, and after reducing the pressure, the air was purged with argon three times. Anhydrous DCM (200 μL) was added, and the mixture was cooled to 0 °C. Boron tribromide (20 μL, 0.42 mmol) was dropwise added to the mixture, and stirring was continued at 0 °C for 30 minutes; subsequently, the temperature was raised to room temperature and stirred until a white precipitate was observed. The solvent was removed under reduced pressure, and the solid was washed with water to obtain the product as pale brown solids (9.9 mg, 0.041 mmol, 76%).

[0394] 1 H NMR (400 MHz, Acetone) δ 8.41 (s, 4H), 7.89 (s, 2H), 7.21 (s, 4H).

[0395] (2) Step 2: Synthesis of N-(quinolin-8-yl)-4-((9R,10S,11R,15S)-2,3,6,7-tetrahydroxy-12,14-dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl)benzamide

[0396] I-3 (13.2 mg, 0.038 mmol) was added to the 2,3,6,7-tetrahydroxyanthracene (9.9 mg, 0.033 mmol) solution obtained in Step 1 in toluene (1 mL), and the mixture was heated overnight at 120 °C under stirring in a pressure tube. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure. The crude residue was dissolved in a mixture of DCM and MeOH and purified by preparative thin-layer chromatography (DCM / MeOH = 8 / 1) to obtain the target product as off-white solids (4.5 mg, 0.0077 mmol, 23%).

[0397] 1 H NMR (400 MHz, DMSO) δ 10.63 (s, 1H), 8.98 (dd,J= 4.2, 1.7 Hz, 1H), 8.77 (s, 2H), 8.74 - 8.67 (m, 3H), 8.48 (dd,J= 8.3, 1.7 Hz, 1H), 8.05 - 8.00 (m, 2H), 7.77 (dd,J= 8.4, 1.4 Hz, 1H), 7.71 - 7.66 (m, 2H), 6.87 - 6.81 (m, 4H), 6.67 (s, 2H), 4.45 (t,J= 1.7 Hz, 2H), 3.29 (t,J= 1.8 Hz, 2H).

[0398] 23. Synthesis of Compound (= IB-30a / b) of Preparation Example 23

[0399]

[0400] (1) Step 1: Synthesis of 1,3-dihydrobenzo[c]thiophene 2-oxide

[0401] 1,3-Dihydrobenzo[c]thiophene (155.7 mg, 1.14 mmol, CAS: 2471-92-3) was added dropwise to a 50 v / v% aqueous solution of sodium periodate in MeOH. After stirring at room temperature for 12 hours, the mixture was filtered and concentrated, and then recrystallized from EA and hexane to obtain the target product as brown crystals (155.0 mg, 1.02 mmol, 89%).

[0402] 1 H NMR (400 MHz, CDCl3) δ 7.40 - 7.27 (m, 4H), 4.28 (d,J= 16.1 Hz, 2H), 4.14 (d,J= 16.1 Hz, 2H).

[0403] (2) Step 2: Synthesis of 4-((4R,9S)-1,3-dioxo-1,3,3a,4,9,9a-hexahydro-2H-4,9-epithiobenzo[f]isoindol-2-yl)-N-(quinolin-8-yl)benzamide

[0404] I-3 (27.0 mg, 0.079 mmol) was added to the solution of 1,3-dihydrobenzo[c]thiophene 2-oxide (12.0 mg, 0.079 mmol) obtained in Step 1 in acetic anhydride (1 mL), and the mixture was heated at 140 °C overnight. After cooling the reaction mixture to room temperature, it was extracted with brine and DCM, dried with anhydrous MgSO4, and then concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (DCM / MeOH = 100 / 1) to obtain two isomers IB-30a (compound name: 4-((3aR,4S,9R,9aS)-1,3-dioxo-1,3,3a,4,9,9a-hexahydro-2H-4,9-epithiobenzo[f]isoindol-2-yl)-N-(quinolin-8-yl)benzamide) and IB-30b (compound name: 4-((3aR,4R,9S,9aS)-1,3-dioxo-1,3,3a,4,9,9a-hexahydro-2H-4,9-epithiobenzo[f]isoindol-2-yl)-N-(quinolin-8-yl)benzamide) in a 1:1 ratio (19.0 mg, 0.04 mmol, 51%).

[0405] IB-30a: 1 H NMR (400 MHz, CDCl3) δ 10.77 (s, 1H), 8.93 (dd,J= 7.3, 1.7 Hz, 1H), 8.85 (dd,J= 4.2, 1.7 Hz, 1H), 8.24 - 8.16 (m, 3H), 7.65 - 7.46 (m, 5H), 7.28 (dd,J= 5.3, 3.1 Hz, 2H), 7.17 - 7.07 (m, 2H), 5.04 (s, 2H), 3.50 (s, 2H),IB-30b: 1H NMR (400 MHz, CDCl3) δ 10.63 (s, 1H), 8.87 (dd,J= 7.1, 1.8 Hz, 1H), 8.82 (dd,J= 4.2, 1.6 Hz, 1H), 8.19 (dd,J= 8.3, 1.7 Hz, 1H), 8.02 - 7.93 (m, 2H), 7.61 - 7.53 (m, 2H), 7.48 (dd,J= 8.3, 4.2 Hz, 1H), 7.29 - 7.23 (m, 2H), 7.18 (dd,J= 5.4, 3.2 Hz, 2H), 6.73 - 6.65 (m, 2H), 5.02 (dd,J= 2.8, 1.7 Hz, 2H), 4.25 (dd,J= 2.8, 1.6 Hz, 2H).

[0406] 24. Synthesis of Compound (= IB-3-A12) of Preparation Example 24

[0407]

[0408] (1) Step 1: Synthesis of tert-butyl (4-(quinolin-8-ylcarbamoyl)bicyclo[2.2.1]heptan-1-yl)carbamate

[0409] 8-aminoquinoline (51.0 mg, 0.35 mmol) was added to a solution of 4-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid) (89.4 mg, 0.35 mmol, CAS: 1201186-86-8), HATU (389.0 mg, 1.0 mmol), and DIPEA (200 μL, 1.2 mmol) in anhydrous DMF (2 mL), and the mixture was stirred overnight at room temperature. The mixture was washed with a saturated sodium bicarbonate solution, extracted with DCM, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Hex / EA = 1 / 1) to obtain a product as a white solid (107.0 mg, 0.28 mmol, 80%).

[0410] 1 H NMR (300 MHz, CDCl3) δ 10.08 (s, 1H), 8.85 - 8.71 (m, 2H), 8.15 (dd,J= 8.3, 1.7 Hz, 1H), 7.59 - 7.40 (m, 3H), 4.84 (s, 1H), 2.22 (d,J= 15.9 Hz, 4H), 2.14 - 1.79 (m, 6H), 1.47 (s, 9H).

[0411] (2) Step 2: Synthesis of 4-((9R,10S,11R,15S)-12,14-dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl)-N-(quinolin-8-yl)bicyclo[2.2.1]heptane-1-carboxamide

[0412] The tert-butyl (4-(quinoline-8-ylcarbamoyl)bicyclo[2.2.1]heptane-1-yl)carbamate (40.0 mg, 0.11 mmol) obtained in Step 1 was dissolved in DCM and cooled to 0 °C, after which TFA (200 μL, 2.63 mmol) was added dropwise. The mixture was stirred for 2 hours, and volatile components were removed using a rotary evaporator to obtain a crude intermediate salt, which was used immediately in the next step.

[0413] The crude raw material intermediate salt, TEA (500 μL, 3.6 mmol), and (9R,10S,11R,15S)-9,10-dihydro-9,10-[3,4]furanoanthracene-12,14-dione (29.1 mg, 0.11 mmol) prepared during the preparation process of Preparation Example 1 (IB-3) were dissolved in DMF (1 mL) and stirred overnight at 120 °C. The mixture was washed with a saturated sodium bicarbonate solution, extracted with DCM, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude raw material residue was resuspended in acetone, and the precipitate was recovered to obtain the target product as off-white solids (45.8 mg, 0.085 mmol, 81%).

[0414] 1 H NMR (300 MHz, CDCl3) δ 10.02 (s, 1H), 8.85 - 8.72 (m, 2H), 8.15 (dd,J= 8.3, 1.7 Hz, 1H), 7.58 - 7.24 (m, 7H), 7.17 (ddd,J= 5.4, 3.9, 3.2 Hz, 4H), 4.78 (t,J= 1.8 Hz, 2H), 3.14 (dd,J= 2.1, 1.4 Hz, 2H), 2.33 (s, 2H), 2.19 - 1.90 (m, 4H), 1.83 - 1.69 (m, 2H), 1.17 (td,J= 11.7, 4.0 Hz, 2H).

[0415] 25. Synthesis of Compound (= IB-12-A3) of Preparation Example 25

[0416]

[0417] (1) Step 1: Synthesis of tert-butyl ((1r,4r)-4-(quinolin-8-ylcarbamoyl)cyclohexyl)carbamate

[0418] 8-aminoquinoline (51.0 mg, 0.35 mmol) was added to a solution of trans-4-(tert-butoxycarbonylamino)cyclohexanoic acid (122.3 mg, 0.50 mmol, CAS: 53292-89-0), HATU (560.8 mg, 1.5 mmol), and DIPEA (260 μL, 1.5 mmol) in anhydrous DMF (2 mL), and the mixture was stirred overnight at room temperature. The mixture was washed with a saturated sodium bicarbonate solution, extracted with DCM, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Hex / EA = 1 / 1) to obtain a white solid product (130.0 mg, 0.35 mmol, 70%).

[0419] 1 H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 8.84 - 8.74 (m, 2H), 8.16 (dd,J= 8.3, 1.6 Hz, 1H), 7.57 - 7.42 (m, 3H), 4.51 - 4.33 (m, 1H), 3.52 (s, 1H), 2.43 (tt,J= 12.1, 3.4 Hz, 1H), 2.17 (tt,J= 9.2, 3.7 Hz, 4H), 1.78 (qd,J= 13.6, 3.8 Hz, 2H), 1.46 (s, 9H), 1.23 (qd,J= 13.0, 3.9 Hz, 2H).

[0420] (2) Step 2: Synthesis of (1S,4r)-4-((9S,10S,11R,15S)-2,6-dihydroxy-12,14-dioxo-9,10-dihydro-9,10-[3,4]epipyrroloanthracen-13-yl)-N-(quinolin-8-yl)cyclohexane-1-carboxamide

[0421] The tert-butyl ((1r,4r)-4-(quinoline-8-ylcarbamoyl)cyclohexyl)carbamate (54.0 mg, 0.15 mmol) obtained in Step 1 was dissolved in DCM and cooled to 0 °C, after which TFA (500 μL, 6.6 mmol) was added dropwise. The mixture was stirred for 2 hours, and volatile components were removed using a rotary evaporator to obtain a crude intermediate salt, which was used immediately in the next step.

[0422] The crude intermediate salt, I-4 (75.0 mg, 0.24 mmol), and TEA (500 μL, 3.6 mmol) were dissolved in DMF (1 mL) and stirred overnight at 120 °C. The mixture was washed with a saturated sodium bicarbonate solution, extracted with DCM, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude residue was dissolved in a mixture of DCM and MeOH and purified by column chromatography (DCM / MeOH = 10 / 1) to obtain the target product as off-white solids (15.0 mg, 0.027 mmol, 15%).

[0423] 1H NMR (400 MHz, DMSO) δ 10.09 (s, 1H), 9.33 (s, 2H), 8.94 (dd,J= 4.2, 1.7 Hz, 1H), 8.59 (dd,J= 7.7, 1.4 Hz, 1H), 8.40 (dd,J= 8.4, 1.7 Hz, 1H), 7.69 - 7.60 (m, 2H), 7.55 (t,J= 7.9 Hz, 1H), 7.19 (d,J= 8.0 Hz, 1H), 6.98 (d,J= 8.0 Hz, 1H), 6.85 (d,J= 2.4 Hz, 1H), 6.63 (d,J= 2.4 Hz, 1H), 6.49 (ddd,J= 8.0, 4.3, 2.4 Hz, 2H), 4.51 (q,J= 2.0 Hz, 2H), 3.48 (s, 1H), 3.17 (d,J= 3.2 Hz, 1H), 3.15 - 3.07 (m, 1H), 2.65 - 2.52 (m, 1H), 1.91 - 1.76 (m, 4H), 1.37 (dd,J= 14.2, 10.6 Hz, 2H), 0.94 (t,J= 14.6 Hz, 2H).

[0424] 26. Synthesis of Compound (= IB-12-C2) of Preparation Example 26 and Compound (= IB-12-C3) of Preparation Example 27

[0425] [General Procedure for IB-12-C2 and IB-12-C3]

[0426]

[0427] (1) Step 1:

[0428] Starting amine (1.1 equivalents) was added to 4-Boc-aminobenzoic acid (1 equivalent), HATU (2 equivalents), and DIPEA (3 equivalents) in anhydrous DMF (1 mL), and stirred overnight at room temperature. The crude mixture was washed with a saturated sodium bicarbonate solution, extracted with DCM, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Hex / EA = 4 / 1) to obtain the product.

[0429] (2) Step 2:

[0430] The product (1 equivalent) obtained in Step 1 was dissolved in DCM and cooled to 0°C, after which TFA (500 μL, excess) was added dropwise. The mixture was stirred for 2 hours, and volatile components were removed using a rotary evaporator to obtain a crude intermediate salt, which was used immediately in the next step.

[0431] I-4 was added to the crude intermediate salt solution in acetic acid (1 mL) and stirred at 110 °C overnight. After cooling the reaction mixture to room temperature, an excess amount of cold DI was added and stirred for 1 hour (1 h). The solid was recovered by filtration, dissolved in DCM, and then purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain the target product.

[0432]

[0433] Starting amine: methyl anthranilate (166.3 mg, 1.1 mmol, CAS: 134-20-3)

[0434] N-Boc-4-aminobenzoic acid (237.2 mg, 1.0 mmol, CAS: 66493-39-8)

[0435] Product obtained in Step 1: 94.0 mg, 0.25 mmol, 25%

[0436] Product obtained in Step 2: 9.8 mg, 0.017 mmol, 11%

[0437]

[0438] Starting amine: 2'-Aminoacetophenone (148.7 mg, 1.1 mmol, CAS: 551-93-9)

[0439] N-Boc-4-aminobenzoic acid (237.2 mg, 1.0 mmol, CAS: 66493-39-8)

[0440] Product obtained in Step 1: 100 mg, 0.28 mmol, 28%

[0441] Product obtained in Step 2: 8.0 mg, 0.015 mmol, 21%

[0442] 27. Synthesis of Compound of Preparation Example 28 (= IB-12-C4), Compound of Preparation Example 29 (= IB-12-C5), Compound of Preparation Example 30 (= IB-12-C6), and Compound of Preparation Example 31 (= IB-12-C7)

[0443] [General Procedures for IB-12-C4 through IB-12-C7]

[0444]

[0445] (1) Step 1:

[0446] Starting amine (2 equivalents) was added to 4-Boc-aminobenzoic acid (1 equivalent), HATU (2 equivalents), and DIPEA (3 equivalents) in dioxane anhydride (1 mL), and stirred overnight under reflux. The precipitated solid was recovered by filtration and washed with DCM to obtain the target product.

[0447] (2) Step 2:

[0448] After cooling the product (1 equivalent) obtained in Step 1 to 0 ℃, TFA (200 μL, excess) was added dropwise. The mixture was stirred for 2 hours, and volatile components were removed using a rotary evaporator to obtain a crude intermediate salt, which was immediately used in the next step.

[0449] I-4 was added to a crude intermediate salt solution in acetic acid (1 mL) and stirred under reflux for 16 to 120 hours. After cooling the reaction mixture to room temperature, an excess amount of cold DI was added and stirred for 1 hour (1 h). The solid was recovered by filtration, dissolved in DCM, and then purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain the target product.

[0450]

[0451] Starting amine: Methyl 4-aminonicotinate (302.5 mg, 2.0 mmol, CAS: 16135-36-7)

[0452] N-Boc-4-aminobenzoic acid (238.4 mg, 1.0 mmol, CAS: 66493-39-8)

[0453] Product obtained in Step 1: 152.0 mg, 0.41 mmol, 41%

[0454] Product obtained in Step 2: 3 mg, 0.005 mmol, 7%

[0455]

[0456] Starting amine: Methyl 2-aminonicotinate (309.8 mg, 2.0 mmol, CAS: 14667-47-1)

[0457] N-Boc-4-aminobenzoic acid (240.2 mg, 1.0 mmol, CAS: 66493-39-8)

[0458] Product obtained in Step 1: 51.0 mg, 0.14 mmol, 27%

[0459] Product obtained in Step 2: 9.0 mg, 0.016 mmol, 23%

[0460]

[0461] Starting amine: Methyl 3-aminoisonicotinate (329.4 mg, 2.2 mmol, CAS: 55279-30-6)

[0462] N-Boc-4-aminobenzoic acid (234.9 mg, 1.5 mmol, CAS: 66493-39-8)

[0463] Product obtained in Step 1: 28.0 mg, 0.075 mmol, 5%

[0464] Product obtained in Step 2: 9.0 mg, 0.016 mmol, 28%

[0465]

[0466] Starting amine: Methyl 3-aminopicolinate (36.0 mg, 0.24 mmol, CAS: 36052-27-4)

[0467] N-Boc-4-aminobenzoic acid (24.1 mg, 0.1 mmol, CAS: 66493-39-8)

[0468] Product obtained in Step 1: 12.0 mg, 0.032 mmol, 32%

[0469] Product obtained in Step 2: 9.0 mg, 0.016 mmol, 27%

[0470] 28. Synthesis of Compound (= IB-25) of Preparation Example 32

[0471]

[0472] (1) Step 1: Synthesis of 1,4-dihydrobenzo[d][1,2]oxathiine 3-oxide

[0473] Dichloro-o-xylene (1.745 g, 10.0 mmol, CAS: 612-12-4) and tetrabutylammonium bromide (0.664 g, 2.0 mmol) were dissolved in anhydrous DMF (10 mL). The suspension was cooled to 0 °C, and then Rongalite (3.848 g, 25.0 mmol) was added. The mixture was heated to room temperature over 18 hours, and the reaction was terminated with water. The aqueous layer was extracted with DCM, dried with MgSO4, and then concentrated under reduced pressure. The crude residue was purified by column chromatography (Hex / EA = 2 / 1) to obtain the target product as a colorless clear oil (1.084 g, 6.44 mmol, 64%).

[0474] 1 H NMR (400 MHz, CDCl3) δ 7.40 - 7.29 (m, 2H), 7.23 (ddd,J= 12.1, 6.0, 2.2 Hz, 2H), 5.30 (d,J= 13.7 Hz, 1H), 4.96 (d,J= 13.7 Hz, 1H), 4.41 (d,J= 15.3 Hz, 1H), 3.55 (d,J= 15.4 Hz, 1H).

[0475] (2) Step 2: Synthesis of 3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1,3-dione

[0476] 1,4-dihydrobenzo[d][1,2]oxatiin 3-oxide (336.4 mg, 2.0 mmol) and maleic anhydride (298.5 mg, 3.0 mmol) obtained in Step 1 were dissolved in toluene (1 mL) and stirred overnight at 80 °C. The solvent was removed under reduced pressure, and the solid was triturated with MeOH to obtain the product as pale beige crystals (248.0 mg, 1.23 mmol, 62%).

[0477] 1 H NMR (400 MHz, CDCl3) δ 7.28 - 7.15 (m, 4H), 3.59 (dtd,J= 4.6, 2.1, 1.3 Hz, 2H), 3.22 - 3.13 (m, 2H), 2.95 (ddd,J= 14.8, 4.2, 2.2 Hz, 2H).

[0478] (3) Step 3: Synthesis of 4-(1,3-dioxo-1,3,3a,4,9,9a-hexahydro-2H-benzo[f]isoindol-2-yl)benzoic acid

[0479] 4-aminobenzoic acid (20.0 mg, 0.20 mmol) and 3a,4,9,9a-tetrahydronaphth[2,3-c]furan-1,3-dione (40.0 mg, 0.20 mmol) obtained in step 2 were dissolved in acetic acid (1 mL) and stirred overnight at 110 °C. After cooling the mixture to room temperature, ice-cold water was added under stirring. The solid was recovered by filtration and then triturated with MeOH to obtain the target product as a white solid (55.0 mg, 0.17 mmol, 86%).

[0480] 1H NMR (400 MHz, DMSO) δ 7.99 - 7.91 (m, 2H), 7.19 (s, 4H), 7.03 - 6.95 (m, 2H), 3.52 (dq,J= 3.7, 2.0 Hz, 2H), 3.11 - 2.92 (m, 4H).

[0481] (4) Step 4: Synthesis of 4-(1,3-dioxo-1,3,3a,4,9,9a-hexahydro-2H-benzo[f]isoindol-2-yl)-N-(quinolin-8-yl)benzamide

[0482] 8-aminoquinoline (11.2 mg, 0.078 mmol) was added to a solution of 4-(1,3-dioxo-1,3,3a,4,9,9a-hexahydro-2H-benzo[f]isoindole-2-yl)benzoic acid (24.0 mg, 0.075 mmol), HATU (78.3 mg, 0.21 mmol), and DIPEA (40 μL, 0.23 mmol) obtained in Step 3 in anhydrous DMF (1 mL), and the mixture was stirred overnight at room temperature. The mixture was washed with a saturated sodium bicarbonate solution, extracted with DCM, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Hex / EA = 1 / 1). The target product was obtained as a white solid (13.0 mg, 0.0029 mmol, 39%).

[0483] 1H NMR (400 MHz, CDCl3) δ 10.68 (s, 1H), 8.89 (dd,J= 7.3, 1.7 Hz, 1H), 8.82 (dd,J= 4.2, 1.7 Hz, 1H), 8.18 (dd,J= 8.3, 1.7 Hz, 1H), 8.09 - 8.00 (m, 2H), 7.63 - 7.51 (m, 2H), 7.47 (dd,J= 8.3, 4.2 Hz, 1H), 7.27 - 7.17 (m, 4H), 7.13 - 7.05 (m, 2H), 3.57 - 3.47 (m, 2H), 3.33 - 3.24 (m, 2H), 3.02 (ddd,J= 14.6, 4.0, 2.0 Hz, 2H).

[0484] 29. Synthesis of Compound (= IB-31) of Preparation Example 33

[0485]

[0486] (1) Step 1: Synthesis of 5,6,7,8-tetrafluoro-1,4-dihydrobenzo[d][1,2]oxathiine 3-oxide

[0487] 1,2-Bis(bromomethyl)-3,4,5,6-tetrafluorobenzene (102.7 mg, 0.31 mmol, CAS: 13719-82-9) and tetrabutylammonium bromide (9.7 mg, 0.03 mmol) were dissolved in anhydrous DMF (1 mL). The suspension was cooled to 0 °C, and then Rongalite (231.2 mg, 1.5 mmol) was added. The mixture was heated to room temperature over 4 hours, and the reaction was terminated with water. The aqueous layer was extracted with DCM, dried with MgSO4, and then concentrated under reduced pressure. The crude residue was purified by column chromatography (Hex / EA = 4 / 1) to obtain the target product as colorless clear crystals (118.0 mg, 0.31 mmol, quant.).

[0488] 1 H NMR (400 MHz, CDCl3) δ 5.20 - 5.06 (m, 2H), 4.07 (d,J= 16.2 Hz, 1H), 3.61 (d,J= 16.2 Hz, 1H).

[0489] (2) Step 2: Synthesis of 5,6,7,8-tetrafluoro-3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1,3-dione

[0490] 5,6,7,8-tetrafluoro-1,4-dihydrobenzo[d][1,2]oxatiin 3-oxide (62.9 mg, 0.26 mmol) and maleic anhydride (40.3 mg, 0.41 mmol) obtained in Step 1 were dissolved in toluene (1 mL) and stirred overnight at 80 °C. The solvent was removed under reduced pressure, and the solid was triturated with MeOH to obtain the target product as a white solid (27.0 mg, 0.10 mmol, 38%).

[0491] 1 H NMR (400 MHz, CDCl3) δ 3.63 (dt,J= 5.2, 2.3 Hz, 2H), 3.54 - 3.42 (m, 2H), 2.88 - 2.72 (m, 2H).

[0492] (3) Step 3: Synthesis of N-(quinolin-8-yl)-4-(5,6,7,8-tetrafluoro-1,3-dioxo-1,3,3a,4,9,9a-hexahydro-2H-benzo[f]isoindol-2-yl)benzamide

[0493] I-2 (20.5 mg, 0.08 mmol) was added to the solution of 5,6,7,8-tetrafluoro-3a,4,9,9a-tetrahydronaphth[2,3-c]furan-1,3-dione (19.8 mg, 0.07 mmol) obtained in Step 2 in acetic acid (1 mL), and the mixture was heated at 110 °C overnight. After cooling the reaction mixture to room temperature, an excess amount of cold DI was added and stirred for 1 hour (1 h). The solid was recovered by filtration, dissolved in a mixture of DCM and MeOH, and then purified by preparative thin-layer chromatography (DCM / MeOH = 30 / 1) to obtain the target product as a white solid (20.4 mg, 0.04 mmol, 56%).

[0494] 1H NMR (400 MHz, CDCl3) δ 10.72 (s, 1H), 8.89 (dd,J= 7.2, 1.8 Hz, 1H), 8.83 (dd,J= 4.3, 1.7 Hz, 1H), 8.19 (dd,J= 8.3, 1.7 Hz, 1H), 8.16 - 8.09 (m, 2H), 7.63 - 7.52 (m, 2H), 7.48 (dd,J= 8.3, 4.2 Hz, 1H), 7.36 - 7.29 (m, 2H), 3.54 (dp,J= 8.3, 3.5 Hz, 4H), 2.91 - 2.81 (m, 2H).

[0495] 30. Synthesis of Compound (= IB-32) of Preparation Example 34

[0496]

[0497] (1) Step 1: Synthesis of dimethyl 4,5-difluorophthalate

[0498] Dimethyl 4,5-difluorophthalate was synthesized as described in EP3628672A1. Briefly, concentrated sulfuric acid (670 μL, 12.5 mmol) was added dropwise to a solution of 4,5-difluorophthalic acid (202.5 mg, 1.0 mmol, CAS: 18959-31-4) at 0 °C and refluxed at 65 °C for 4 hours. The cooled mixture was neutralized with a saturated sodium bicarbonate solution and extracted with EA, then dried with sodium sulfate, filtered, and concentrated under reduced pressure to obtain the desired product as a colorless oil (231.0 mg, 1.0 mmol, quant.).

[0499] 1 H NMR (400 MHz, CDCl3) δ 7.57 - 7.49 (m, 2H), 3.89 (d, J= 1.2 Hz, 6H).

[0500] (2) Step 2: Synthesis of (4,5-difluoro-1,2-phenylene)dimethanol

[0501] Dimethyl 4,5-difluorophthalate (231.0 mg, 1.0 mmol) obtained in Step 1 in anhydrous THF (1.7 mL) was dropwise added to a lithium aluminum hydride suspension (154.9 mg, 4.1 mmol) in anhydrous THF (4 mL) at 0 °C and stirred for 30 minutes, then stirred for 16 hours at room temperature. The mixture was cooled to 0 °C and the reaction was terminated by adding water (0.15 mL), 15% NaOH aqueous solution (0.15 mL), and water (0.5 mL). The mixture was filtered through Celite, washed with THF, and concentrated under reduced pressure to obtain the crude raw material as white solids (223.0 mg, 1.0 mmol, quant.).

[0502] 1 H NMR (400 MHz, CDCl3) δ 7.21 (t,J= 9.3 Hz, 2H), 4.69 (d,J= 4.7 Hz, 4H).

[0503] (3) Step 3: Synthesis of 1,2-bis(bromomethyl)-4,5-difluorobenzene

[0504] A mixture of (4,5-difluoro-1,2-phenylene)dimethanol (223.0 mg, 1.28 mmol) obtained in Step 2 and 48% hydrobromic acid (1 mL) was stirred at 80 °C for 3 hours. The cooled reaction mixture was diluted with water and extracted with Et2O. The bound organic layer was washed with H2O and brine, dried with MgSO4, filtered, and concentrated under reduced pressure to obtain the target product as brown oil (151.6 mg, 0.51 mmol, 45%).

[0505] 1 H NMR (400 MHz, CDCl3) δ 7.20 (t, J= 9.1 Hz, 2H), 4.55 (s, 4H).

[0506] (4) Step 4: Synthesis of 6,7-difluoro-1,4-dihydrobenzo[d][1,2]oxathiine 3-oxide

[0507] 1,2-bis(bromomethyl)-4,5-difluorobenzene (151.6 mg, 0.51 mmol) and tetrabutylammonium bromide (49.3 mg, 0.15 mmol) obtained in Step 3 were dissolved in anhydrous DMF (1 mL). The suspension was cooled to 0 °C, and then rongalite (154.1 mg, 1.02 mmol) was added. The mixture was heated to room temperature over 4 hours, and the reaction was terminated with water. The aqueous layer was extracted with DCM, dried with MgSO4, and then concentrated under reduced pressure. The crude residue was purified by column chromatography (Hex / EA = 2 / 1) to obtain the target product as colorless clear crystals (45.8 mg, 0.22 mmol, 44%).

[0508] 1 H NMR (400 MHz, CDCl3) δ 7.07 (td,J= 10.2, 7.5 Hz, 2H), 5.22 (d,J= 13.9 Hz, 1H), 4.90 (d,J= 13.9 Hz, 1H), 4.29 (d,J= 15.6 Hz, 1H), 3.51 (d,J= 15.5 Hz, 1H).

[0509] (5) Step 5: Synthesis of 6,7-difluoro-3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1,3-dione

[0510] 6,7-difluoro-1,4-dihydrobenzo[d][1,2]oxatiin 3-oxide (45.8 mg, 0.22 mmol) and maleic anhydride (25.5 mg, 0.26 mmol) obtained in Step 4 were dissolved in toluene (1 mL) and stirred overnight at 80 °C. The solvent was removed under reduced pressure, and the solid was triturated with MeOH to obtain the target product as a white solid (11.0 mg, 0.046 mmol, 21%).

[0511] 1 H NMR (400 MHz, Acetone) δ 7.11 (t,J= 9.9 Hz, 2H), 3.33 - 3.23 (m, 4H), 3.15 - 3.05 (m, 2H).

[0512] (6) Step 6: Synthesis of 4-(6,7-difluoro-1,3-dioxo-1,3,3a,4,9,9a-hexahydro-2H-benzo[f]isoindol-2-yl)-N-(quinolin-8-yl)benzamide

[0513] I-2 (11.4 mg, 0.048 mmol) was added to the solution of 6,7-difluoro-3a,4,9,9a-tetrahydronaphth[2,3-c]furan-1,3-dione (11.0 mg, 0.046 mmol) obtained in Step 5 in acetic acid (1 mL), and the mixture was heated at 110 °C overnight. After cooling the reaction mixture to room temperature, an excess amount of cold DI was added and stirred for 1 hour (1 h). The solid was recovered by filtration, dissolved in a mixture of DCM and MeOH, and then purified by preparative thin-layer chromatography (DCM / MeOH = 30 / 1) to obtain the target product as a white solid (11.1 mg, 0.023 mmol, 50%).

[0514] 1H NMR (400 MHz, CDCl3) δ 10.70 (s, 1H), 8.89 (dd,J= 7.2, 1.8 Hz, 1H), 8.83 (dd,J= 4.3, 1.7 Hz, 1H), 8.19 (dd,J= 8.3, 1.7 Hz, 1H), 8.13 - 8.05 (m, 2H), 7.59 (dd,J= 8.3, 7.2 Hz, 1H), 7.55 (dd,J= 8.3, 1.8 Hz, 1H), 7.48 (dd,J= 8.3, 4.2 Hz, 1H), 7.22 - 7.12 (m, 2H), 7.06 (t,J=8.9 Hz, 2H), 3.57 - 3.47 (m, 2H), 3.26 (dd,J= 14.8, 2.1 Hz, 2H), 2.94 (dt,J= 14.4, 3.7 Hz, 2H).

[0515] 31. Synthesis of Compound (= IB-33) of Preparation Example 35

[0516]

[0517] (1) Step 1: Synthesis of 6,7-dimethoxy-1,4-dihydrobenzo[d][1,2]oxathiine 3-oxide

[0518] 1,2-Bis(bromomethyl)-4,5-dimethoxybenzene (321.8 mg, 1.0 mmol, CAS: 26726-81-8) and sodium iodide (53.8 mg, 0.36 mmol) were dissolved in anhydrous DMF (2 mL). The suspension was cooled to 0 °C, and then Rongalite (310.5 mg, 2.0 mmol) was added. The mixture was heated to room temperature over 2 hours, and the reaction was terminated with water. The aqueous layer was extracted with DCM, dried with MgSO4, and then concentrated under reduced pressure. The crude residue was washed with EA, and the solid was removed by filtration to obtain the crude product as pink crystals (113.0 mg, 0.50 mmol, 50%). Purification by column chromatography was attempted, but since decomposition occurred, the crude product was used as is in the subsequent reaction.

[0519] 1 H NMR (400 MHz, CDCl3) δ 6.72 (d,J= 16.5 Hz, 2H), 5.23 (d,J= 13.5 Hz, 1H), 4.89 (d,J= 13.5 Hz, 1H), 4.35 - 4.27 (m, 6H), 4.11 (q,J= 7.1 Hz, 1H), 3.51 (d,J= 15.2 Hz, 1H).

[0520] (2) Step 2: Synthesis of 6,7-dimethoxy-3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1,3-dione

[0521] The crude raw materials obtained in Step 1, 6,7-dimethoxy-1,4-dihydrobenzo[d][1,2]oxathine 3-oxide (30.6 mg, 0.13 mmol) and maleic anhydride (19.9 mg, 0.20 mmol), were dissolved in toluene (1 mL) and stirred overnight at 80 °C. The solvent was removed under reduced pressure, and the solid was treated with MeOH to obtain the target product as a white solid (9.0 mg, 0.034 mmol, 25%).

[0522] 1 H NMR (400 MHz, CDCl3) δ 6.70 (s, 2H), 3.85 (s, 6H), 3.58 (dp,J= 4.3, 1.3 Hz, 2H), 3.17 - 3.08 (m, 2H), 2.92 - 2.80 (m, 2H).

[0523] (3) Step 3: Synthesis of 4-(6,7-dimethoxy-1,3-dioxo-1,3,3a,4,9,9a-hexahydro-2H-benzo[f]isoindol-2-yl)-N-(quinolin-8-yl)benzamide

[0524] I-2 (6.6 mg, 0.025 mmol) was added to the solution of 6,7-dimethoxy-3a,4,9,9a-tetrahydronaphth[2,3-c]furan-1,3-dione (6.1 mg, 0.023 mmol) obtained in Step 2 in acetic acid (1 mL), and the mixture was heated at 110 °C overnight. After cooling the reaction mixture to room temperature, an excess amount of cold DI was added and stirred for 1 hour (1 h). The solid was recovered by filtration, dissolved in a mixture of DCM and MeOH, and then purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain the target product as a white solid (4.5 mg, 0.0089 mmol, 39%).

[0525] 1 H NMR (400 MHz, CDCl3) δ 10.70 (s, 1H), 8.92 - 8.85 (m, 1H), 8.85 - 8.80 (m, 1H), 8.19 (dd,J= 8.3, 2.2 Hz, 1H), 8.10 - 8.03 (m, 2H), 7.63 - 7.52 (m, 2H), 7.52 - 7.44 (m, 1H), 7.17 - 7.10 (m, 2H), 6.74 (d,J= 1.9 Hz, 2H), 3.87 (d,J= 1.9 Hz, 6H), 3.55 - 3.47 (m, 2H), 3.23 (d,J= 14.5 Hz, 2H), 2.94 (d,J= 14.4 Hz, 2H).

[0526] 32. Synthesis of Compound (= IB-34) of Preparation Example 36

[0527]

[0528] (1) Step 1: Synthesis of (4-methoxy-1,2-phenylene)dimethanol

[0529] 4-Methoxyphthalic acid (197.5 mg, 1.0 mmol, CAS: 1885-13-8) was added to a lithium aluminum hydride suspension (104.8 mg, 2.8 mmol) in anhydrous THF (2 mL) at 0 °C and stirred for 30 minutes, then heated under reflux for 2 hours. The mixture was cooled to 0 °C, and the reaction was terminated by adding water (0.1 mL), 15% aqueous NaOH solution (0.1 mL), and water (0.3 mL). The mixture was filtered through Celite, washed with DCM, and concentrated under reduced pressure (in vacuo). The crude residue was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain a yellow oil product (109.0 mg, 0.65 mmol, 65%).

[0530] 1H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 6.91 (d,J= 2.7 Hz, 1H), 6.81 (dd,J= 8.3, 2.7 Hz, 1H), 4.67 (dt,J= 8.3, 1.8 Hz, 4H), 3.81 (s, 3H).

[0531] (2) Step 2: Synthesis of 1,2-bis(bromomethyl)-4-methoxybenzene

[0532] A mixture of (4-methoxy-1,2-phenylene)dimethanol (109.0 mg, 0.65 mmol) and phosphorus tribromide (216 μL, 2.3 mmol) obtained in Step 1 was stirred overnight at room temperature. The reaction mixture was cooled, the pH was adjusted to pH 8 with a saturated sodium bicarbonate solution, extracted with DCM, dried with MgSO4, filtered, and concentrated under reduced pressure to obtain the target product as a colorless clear oil (143.0 mg, 0.49 mmol, 75%).

[0533] 1 H NMR (400 MHz, CDCl3) δ 7.29 (d,J= 8.4 Hz, 1H), 6.90 (d,J= 2.7 Hz, 1H), 6.83 (dd,J= 8.4, 2.7 Hz, 1H), 4.64 (d,J= 14.2 Hz, 4H), 3.82 (s, 3H).

[0534] (3) Step 3: Synthesis of 6-methoxy-1,4-dihydrobenzo[d][1,2]oxathiine 3-oxide

[0535] 1,2-bis(bromomethyl)-4-methoxybenzene (69.0 mg, 0.23 mmol) and tetrabutylammonium bromide (26.7 mg, 0.08 mmol) obtained in Step 2 were dissolved in anhydrous DMF (1 mL). The suspension was cooled to 0 °C, and then Rongalite (95.8 mg, 0.62 mmol) was added. The mixture was heated to room temperature over 3 hours, and the reaction was terminated with water. The aqueous layer was extracted with DCM, dried with MgSO4, and then concentrated under reduced pressure. The crude residue was purified by column chromatography (Hex / EA = 3 / 1) to obtain the target product as a white solid (38.3 mg, 0.14 mmol, 61%).

[0536] 1 H NMR (400 MHz, CDCl3) δ 7.15 (dd,J= 20.1, 8.4 Hz, 1H), 6.89 (td,J= 7.8, 2.7 Hz, 1H), 6.78 (dd,J= 8.0, 2.6 Hz, 1H), 5.26 (ddd,J= 13.4, 1.9, 1.1 Hz, 1H), 4.91 (d,J= 13.9 Hz, 1H), 4.37 (dd,J= 15.2, 12.5 Hz, 1H), 3.81 (s, 3H), 3.52 (dd,J= 15.3, 8.9 Hz, 1H).

[0537] (4) Step 4: Synthesis of 6-methoxy-3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1,3-dione

[0538] 6-methoxy-1,4-dihydrobenzo[d][1,2]oxatiin 3-oxide (11.3 mg, 0.057 mmol) and maleic anhydride (13.3 mg, 0.14 mmol) obtained in Step 3 were dissolved in toluene (1 mL) and stirred overnight at 80 °C. The solvent was removed under reduced pressure, and the solid was treated with MeOH to obtain the target product as a white solid (12.3 mg, 0.053 mmol, 93%).

[0539] 1 H NMR (400 MHz, CDCl3) δ 7.14 - 7.05 (m, 1H), 6.81 - 6.70 (m, 2H), 3.78 (s, 3H), 3.57 (ddd,J= 4.7, 2.9, 1.4 Hz, 2H), 3.14 (dt,J= 14.6, 3.1 Hz, 2H), 2.90 (ddt,J= 16.3, 13.8, 3.0 Hz, 2H).

[0540] (5) Step 5: Synthesis of 4-(6-methoxy-1,3-dioxo-1,3,3a,4,9,9a-hexahydro-2H-benzo[f]isoindol-2-yl)-N-(quinolin-8-yl)benzamide

[0541] I-2 (16.2 mg, 0.062 mmol) was added to the solution of 6-methoxy-3a,4,9,9a-tetrahydronaphth[2,3-c]furan-1,3-dione (11.8 mg, 0.051 mmol) obtained in Step 4 in acetic acid (1 mL), and the mixture was heated at 110 °C overnight. After cooling the reaction mixture to room temperature, an excess amount of cold DI was added and stirred for 1 hour (1 h). The solid was recovered by filtration, dissolved in DCM, and then purified by preparative thin-layer chromatography (DCM / MeOH = 30 / 1) to obtain the target product as a white solid (10.6 mg, 0.022 mmol, 43%).

[0542] 1 H NMR (400 MHz, CDCl3) δ 10.68 (s, 1H), 8.89 (dd,J= 7.3, 1.7 Hz, 1H), 8.82 (dd,J= 4.2, 1.7 Hz, 1H), 8.18 (dd,J= 8.3, 1.7 Hz, 1H), 8.11 - 8.02 (m, 2H), 7.63 - 7.54 (m, 2H), 7.47 (dd,J= 8.3, 4.2 Hz, 1H), 7.18 - 7.09 (m, 3H), 6.80 - 6.73 (m, 2H), 3.79 (s, 3H), 3.55 - 3.44 (m, 2H), 3.24 (ddd,J= 14.7, 4.8, 2.1 Hz, 2H), 3.05 - 2.87 (m, 2H).

[0543] 33. Synthesis of Compound (= IB-35) of Preparation Example 37

[0544]

[0545] (1) Step 1: Synthesis of 6,7-dimethyl-1,4-dihydrobenzo[d][1,2]oxathiine 3-oxide

[0546] 1,2-Bis(bromomethyl)-4,5-dimethylbenzene (146.0 mg, 0.5 mmol, CAS: 60070-06-6) and TBAB (75.0 mg, 0.23 mmol) were dissolved in anhydrous DMF (1 mL). The suspension was cooled to 0 °C, and then rongalite (159.8 mg, 1.0 mmol) was added. The mixture was heated to room temperature over 5.5 hours, and the reaction was terminated with water. The aqueous layer was extracted with Et2O, dried with MgSO4, and then concentrated under reduced pressure. The crude residue was purified by column chromatography (Hex / EA = 2 / 1) to obtain the target product as a white solid (57.0 mg, 0.29 mmol, 58%).

[0547] 1 H NMR (400 MHz, CDCl3) δ 7.00 (d,J= 10.5 Hz, 2H), 5.23 (d,J= 13.5 Hz, 1H), 4.88 (d,J= 13.5 Hz, 1H), 4.31 (d,J= 15.4 Hz, 1H), 3.50 (d,J= 15.2 Hz, 1H), 2.26 (d,J= 1.4 Hz, 6H).

[0548] (2) Step 2: Synthesis of 6,7-dimethyl-3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1,3-dione

[0549] 6,7-dimethyl-1,4-dihydrobenzo[d][1,2]oxatiin 3-oxide (57.0 mg, 0.29 mmol) and maleic anhydride (34.4 mg, 0.35 mmol) obtained in Step 1 were dissolved in toluene (1 mL) and stirred overnight at 80 °C. The solvent was removed under reduced pressure, and the solid was treated with MeOH to obtain the target product as a white solid (44.7 mg, 0.19 mmol, 67%).

[0550] 1 H NMR (400 MHz, CDCl3) δ 6.95 (s, 2H), 3.56 (ddt,J= 4.5, 2.7, 1.4 Hz, 2H), 3.11 (dd,J= 14.9, 2.3 Hz, 2H), 2.95 - 2.81 (m, 2H), 2.21 (s, 6H).

[0551] (3) Step 3: Synthesis of 4-(6,7-dimethyl-1,3-dioxo-1,3,3a,4,9,9a-hexahydro-2H-benzo[f]isoindol-2-yl)-N-(quinolin-8-yl)benzamide

[0552] I-2 (30.3 mg, 0.12 mmol) was added to the solution of 6,7-dimethyl-3a,4,9,9a-tetrahydronaphth[2,3-c]furan-1,3-dione (26.7 mg, 0.12 mmol) obtained in Step 2 in acetic acid (1 mL), and the mixture was heated at 110 °C overnight. After cooling the reaction mixture to room temperature, an excess amount of cold DI was added and stirred for 1 hour (1 h). The solid was recovered by filtration, dissolved in a mixture of DCM and MeOH, and then purified by preparative thin-layer chromatography (chloroform / MeOH = 40 / 1) to obtain the target product as a white solid (16.9 mg, 0.036 mmol, 31%).

[0553] 1H NMR (400 MHz, CDCl3) δ 10.68 (s, 1H), 8.89 (dd,J= 7.3, 1.7 Hz, 1H), 8.82 (dd,J= 4.2, 1.6 Hz, 1H), 8.18 (dd,J= 8.3, 1.7 Hz, 1H), 8.10 - 8.02 (m, 2H), 7.63 - 7.51 (m, 2H), 7.47 (dd,J= 8.2, 4.2 Hz, 1H), 7.20 - 7.13 (m, 2H), 6.97 (s, 2H), 3.47 (dd,J= 5.3, 2.6 Hz, 2H), 3.24 - 3.16 (m, 2H), 3.02 - 2.90 (m, 2H), 2.22 (s, 6H).

[0554] 34. Synthesis of Compound (= IB-36) of Preparation Example 38

[0555]

[0556] (1) Step 1: Synthesis of (3-methoxy-1,2-phenylene)dimethanol

[0557] 3-Methoxyphthalic acid (348.3 mg, 1.8 mmol, CAS: 14963-97-4) was added to a lithium aluminum hydride suspension (286.1 mg, 7.5 mmol) in anhydrous THF (4 mL) at 0 °C and stirred for 30 minutes, then heated under reflux for 2 hours. The mixture was cooled to 0 °C, and the reaction was terminated by adding water (0.2 mL), 15% aqueous NaOH solution (0.2 mL), and water (0.6 mL). The mixture was filtered through Celite, washed with DCM, and concentrated under reduced pressure to obtain the product as white solids (269.0 mg, 1.6 mmol, 90%).

[0558] 1H NMR (400 MHz, CDCl3) δ 7.27 (ddd,J= 8.5, 7.6, 0.9 Hz, 1H), 6.96 (d,J= 7.6 Hz, 1H), 6.90 (d,J= 8.3 Hz, 1H), 4.83 (d,J= 2.5 Hz, 2H), 4.72 (d,J= 2.3 Hz, 2H), 3.86 (d,J= 1.0 Hz, 3H).

[0559] (2) Step 2: Synthesis of 1,2-bis(bromomethyl)-3-methoxybenzene

[0560] A mixture of (3-methoxy-1,2-phenylene)dimethanol (175.0 mg, 1.04 mmol) and phosphorus tribromide (240 μL, 2.6 mmol) obtained in Step 1 was stirred overnight at room temperature. The reaction mixture was cooled, the pH was adjusted to pH 8 with a saturated sodium bicarbonate solution, extracted with DCM, dried with MgSO4, filtered, and concentrated under reduced pressure to obtain the target product as white crystals (278.0 mg, 0.95 mmol, 91%).

[0561] 1 H NMR (400 MHz, CDCl3) δ 7.27 (dd,J= 8.4, 7.7 Hz, 1H), 6.97 (dd,J= 7.7, 1.1 Hz, 1H), 6.87 (dd,J= 8.4, 1.1 Hz, 1H), 4.78 (s, 2H), 4.62 (s, 2H), 3.90 (s, 3H).

[0562] (3) Step 3: Synthesis of 5-methoxy-1,4-dihydrobenzo[d][1,2]oxathiine 3-oxide

[0563] 1,2-bis(bromomethyl)-3-methoxybenzene (188.8 mg, 0.64 mmol) and tetrabutylammonium bromide (107.0 mg, 0.33 mmol) obtained in Step 2 were dissolved in anhydrous DMF (1 mL). The suspension was cooled to 0 °C, and then rongalite (299.0 mg, 1.94 mmol) was added. The mixture was heated to room temperature over 6 hours, and the reaction was terminated with water. The aqueous layer was extracted with DCM, dried with MgSO4, and then concentrated under reduced pressure. The crude residue was purified by column chromatography (Hex / EA = 3 / 1) to obtain the target product as white solids (116.0 mg, 0.59 mmol, 92%).

[0564] 1 H NMR (400 MHz, CDCl3) δ 7.29 (d,J= 7.7 Hz, 1H), 6.91 - 6.83 (m, 2H), 5.29 (d,J= 13.9 Hz, 1H), 4.92 (d,J= 13.9 Hz, 1H), 4.45 (d,J= 16.2 Hz, 1H), 3.87 (s, 3H), 3.52 (d,J= 16.2 Hz, 1H).

[0565] (4) Step 4: Synthesis of 5-methoxy-3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1,3-dione

[0566] 5-methoxy-1,4-dihydrobenzo[d][1,2]oxatiin 3-oxide (76.0 mg, 0.38 mmol) and maleic anhydride (94.2 mg, 0.96 mmol) obtained in Step 3 were dissolved in toluene (1 mL) and stirred overnight at 80 °C. The solvent was removed under reduced pressure, and the solid was treated with MeOH to obtain the target product as a white solid (30.2 mg, 0.13 mmol, 34%).

[0567] 1 H NMR (400 MHz, CDCl3) δ 7.23 - 7.12 (m, 1H), 6.80 (d,J= 8.4 Hz, 2H), 3.81 (s, 3H), 3.64 - 3.48 (m, 3H), 3.19 - 3.10 (m, 1H), 2.97 - 2.84 (m, 1H), 2.75 - 2.63 (m, 1H).

[0568] (5) Step 5: Synthesis of 4-(5-methoxy-1,3-dioxo-1,3,3a,4,9,9a-hexahydro-2H-benzo[f]isoindol-2-yl)-N-(quinolin-8-yl)benzamide

[0569] I-2 (22.2 mg, 0.084 mmol) was added to the solution of 5-methoxy-3a,4,9,9a-tetrahydronaphth[2,3-c]furan-1,3-dione (19.1 mg, 0.082 mmol) obtained in Step 4 in acetic acid (1 mL), and the mixture was heated at 110 °C overnight. After cooling the reaction mixture to room temperature, an excess amount of cold DI was added and stirred for 1 hour (1 h). The solid was recovered by filtration, dissolved in DCM, and then purified by preparative thin-layer chromatography (DCM / MeOH = 50 / 1) to obtain the target product as a white solid (16.5 mg, 0.035 mmol, 43%).

[0570] 1H NMR (400 MHz, CDCl3) δ 10.70 (s, 1H), 8.91 (dd,J= 7.3, 1.7 Hz, 1H), 8.84 (dd,J= 4.2, 1.7 Hz, 1H), 8.20 (dd,J= 8.3, 1.7 Hz, 1H), 8.13 - 8.05 (m, 2H), 7.61 (dd,J= 8.3, 7.3 Hz, 1H), 7.56 (dd,J= 8.3, 1.7 Hz, 1H), 7.49 (dd,J= 8.3, 4.3 Hz, 1H), 7.25 - 7.15 (m, 3H), 6.85 (dd,J=11.6, 7.9 Hz, 2H), 3.84 (s, 3H), 3.75 - 3.66 (m, 1H), 3.52 - 3.48 (m, 2H), 3.30 - 3.21 (m, 1H), 3.07 - 2.94 (m, 1H), 2.85 - 2.71 (m, 1H).

[0571] 35. Synthesis of Compound (= IB-37) of Preparation Example 39

[0572]

[0573] (1) Step 1: Synthesis of (3-fluoro-1,2-phenylene)dimethanol

[0574] 3-(Fluoromethyl)phthalic acid (185.1 mg, 1.0 mmol, CAS: 1583-67-1) in anhydrous THF (0.5 mL) was added to a lithium aluminum hydride suspension (98.0 mg, 2.6 mmol) in anhydrous THF (4 mL) at 0 °C, stirred for 16 hours, and then heated under reflux for 2 hours. The mixture was cooled to 0 °C, and the reaction was terminated by adding water (0.2 mL), 15% NaOH aqueous solution (0.2 mL), and water (0.6 mL). The mixture was filtered through Celite, washed with DCM, and concentrated under reduced pressure to obtain the product as white solids (65.0 mg, 0.42 mmol, 42%).

[0575] 1 H NMR (400 MHz, CDCl3) δ 7.28 (ddd,J= 8.3, 7.5, 5.6 Hz, 1H), 7.15 (dd,J= 7.5, 1.2 Hz, 1H), 7.06 (ddd,J= 9.6, 8.2, 1.3 Hz, 1H), 4.83 (s, 2H), 4.75 (s, 2H).

[0576] (2) Step 2: Synthesis of 1,2-bis(bromomethyl)-3-fluorobenzene

[0577] A mixture of (3-fluoro-1,2-phenylene)dimethanol (52.5 mg, 0.34 mmol) and phosphorus tribromide (60 μL, 0.64 mmol) obtained in Step 1 was stirred overnight at room temperature. The reaction mixture was cooled, the pH was adjusted to pH 8 with a saturated sodium bicarbonate solution, extracted with DCM, dried with MgSO4, filtered, and concentrated under reduced pressure to obtain the target product as a colorless clear oil (50.0 mg, 0.18 mmol, 53%).

[0578] 1 H NMR (400 MHz, CDCl3) δ 7.34 - 7.24 (m, 1H), 7.16 (s, 1H), 7.06 (td,J= 8.9, 1.3 Hz, 1H), 4.70 (d,J= 1.9 Hz, 2H), 4.63 (s, 2H).

[0579] (3) Step 3: Synthesis of 5-fluoro-1,4-dihydrobenzo[d][1,2]oxathiine 3-oxide

[0580] 1,2-bis(bromomethyl)-3-fluorobenzene (52.9 mg, 0.19 mmol) and tetrabutylammonium bromide (20.4 mg, 0.06 mmol) obtained in Step 2 were dissolved in anhydrous DMF (1 mL). The suspension was cooled to 0 °C, and then rongalite (62.8 mg, 0.41 mmol) was added. The mixture was heated to room temperature over 6 hours, and the reaction was terminated with water. The aqueous layer was extracted with DCM, dried with MgSO4, and then concentrated under reduced pressure. The crude residue was purified by column chromatography (Hex / EA = 3 / 1) to obtain the target product as a colorless clear oil (22.4 mg, 0.12 mmol, 63%).

[0581] 1 H NMR (400 MHz, CDCl3) δ 7.31 (td,J= 8.0, 5.6 Hz, 1H), 7.08 (t,J= 8.7 Hz, 1H), 7.03 (d,J= 7.6 Hz, 1H), 5.30 (dq,J= 14.1, 0.9 Hz, 1H), 4.95 (d,J= 14.2 Hz, 1H), 4.34 (d,J= 16.1 Hz, 1H), 3.56 (d,J= 16.1 Hz, 1H).

[0582] (4) Step 4: Synthesis of 5-fluoro-3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1,3-dione

[0583] 5-fluoro-1,4-dihydrobenzo[d][1,2]oxatiin 3-oxide (29.1 mg, 0.11 mmol) and maleic anhydride (12.6 mg, 0.13 mmol) obtained in Step 3 were dissolved in toluene (1 mL) and stirred overnight at 80 °C. The solvent was removed under reduced pressure, and the solid was treated with MeOH to obtain the target product as a white solid (18.7 mg, 0.069 mmol, 63%).

[0584] 1 H NMR (400 MHz, CDCl3) δ 7.24 - 7.14 (m, 1H), 7.06 - 6.91 (m, 2H), 3.61 (dq,J= 5.0, 1.6 Hz, 2H), 3.56 - 3.47 (m, 1H), 3.20 (dq,J= 15.1, 1.4 Hz, 1H), 3.00 - 2.91 (m, 1H), 2.85 - 2.71 (m, 1H).

[0585] (5) Step 5: Synthesis of 4-(5-fluoro-1,3-dioxo-1,3,3a,4,9,9a-hexahydro-2H-benzo[f]isoindol-2-yl)-N-(quinolin-8-yl)benzamide

[0586] I-2 (18.2 mg, 0.069 mmol) was added to the solution of 5-fluoro-3a,4,9,9a-tetrahydronaphth[2,3-c]furan-1,3-dione (18.7 mg, 0.069 mmol) obtained in Step 4 in acetic acid (1 mL), and the mixture was heated at 110 °C overnight. After cooling the reaction mixture to room temperature, an excess amount of cold DI was added and stirred for 1 hour (1 h). The solid was recovered by filtration, dissolved in DCM, and then purified by preparative thin-layer chromatography (DCM / MeOH = 30 / 1) to obtain the target product as a white solid (20.3 mg, 0.039 mmol, 57%).

[0587] 1 H NMR (400 MHz, CDCl3) δ 10.68 (s, 1H), 8.88 (dd,J= 7.3, 1.7 Hz, 1H), 8.81 (dd,J= 4.2, 1.7 Hz, 1H), 8.20 - 8.13 (m, 1H), 8.06 (d,J= 8.2 Hz, 2H), 7.62 - 7.50 (m, 2H), 7.46 (ddd,J= 8.3, 4.3, 1.5 Hz, 1H), 7.19 (d,J= 7.4 Hz, 2H), 7.16 (d,J= 2.2 Hz, 1H), 7.05 - 6.94 (m, 2H), 3.61 (dd,J= 14.9, 2.4 Hz, 1H), 3.55 - 3.45 (m, 2H), 3.34 - 3.25 (m, 1H), 3.00 (dd,J= 13.2, 4.1 Hz, 1H), 2.82 (dd,J= 13.6, 4.1 Hz, 1H).

[0588] 36. Synthesis of Compound (= IB-38) of Preparation Example 40

[0589]

[0590] (1) Step 1: Synthesis of (4-(trifluoromethyl)-1,2-phenylene)dimethanol

[0591] 4-(Trifluoromethyl)phthalic acid (222.7 mg, 0.95 mmol, CAS: 835-58-5) in anhydrous THF (0.5 mL) was added to a lithium aluminum hydride suspension (286.1 mg, 7.5 mmol) in anhydrous THF (1 mL) at 0 °C, stirred for 30 minutes, and then heated under reflux for 16 hours. The mixture was cooled to 0 °C, and the reaction was terminated by adding water (0.2 mL), 15% aqueous NaOH solution (0.2 mL), and water (0.6 mL). The mixture was filtered through Celite, washed with DCM, and concentrated under reduced pressure to obtain the product as white solids (187.0 mg, 0.91 mmol, 96%).

[0592] 1 H NMR (400 MHz, CDCl3) δ 7.64 (d,J= 2.0 Hz, 1H), 7.60 - 7.56 (m, 1H), 7.50 (d,J= 7.9 Hz, 1H), 4.79 (d,J= 4.1 Hz, 4H).

[0593] (2) Step 2: Synthesis of 1,2-bis(bromomethyl)-4-(trifluoromethyl)benzene

[0594] A mixture of (4-(trifluoromethyl)-1,2-phenylene)dimethanol (124.9 mg, 0.61 mmol) and phosphorus tribromide (60 μL, 0.64 mmol) obtained in Step 1 was stirred overnight at room temperature. The reaction mixture was cooled, the pH was adjusted to pH 8 with a saturated sodium bicarbonate solution, extracted with DCM, dried with MgSO4, filtered, and concentrated under reduced pressure to obtain the target product as a colorless clear oil (122.0 mg, 0.37 mmol, 61%).

[0595] 1H NMR (400 MHz, CDCl3) δ 7.64 (d,J= 2.0 Hz, 1H), 7.57 (dd,J= 8.0, 1.9 Hz, 1H), 7.50 (d,J= 8.0 Hz, 1H), 4.66 (d,J= 2.7 Hz, 4H).

[0596] (3) Step 3: Synthesis of 6-(trifluoromethyl)-1,4-dihydrobenzo[d][1,2]oxathiine 3-oxide

[0597] 1,2-bis(bromomethyl)-4-(trifluoromethyl)benzene (122.0 mg, 0.37 mmol) and tetrabutylammonium bromide (78.2 mg, 0.24 mmol) obtained in Step 2 were dissolved in anhydrous DMF (1 mL). The suspension was cooled to 0 °C, and then rongalite (236.1 mg, 1.53 mmol) was added. The mixture was heated to room temperature over 6 hours, and the reaction was terminated with water. The aqueous layer was extracted with DCM, dried with MgSO4, and then concentrated under reduced pressure. The crude residue was purified by column chromatography (Hex / EA = 3 / 1) to obtain the target product as white solids (55.0 mg, 0.23 mmol, 40%).

[0598] 1 H NMR (400 MHz, CDCl3) δ 7.63 (ddd,J= 7.4, 5.2, 1.8 Hz, 1H), 7.55 - 7.48 (m, 1H), 7.38 (t,J= 7.5 Hz, 1H), 5.36 (d,J= 14.1 Hz, 1H), 5.04 (d,J= 14.2 Hz, 1H), 4.41 (dd,J= 15.7, 3.7 Hz, 1H), 3.65 (d,J= 15.6 Hz, 1H).

[0599] (4) Step 4: Synthesis of 6-(trifluoromethyl)-3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1,3-dione

[0600] 6-(trifluoromethyl)-1,4-dihydrobenzo[d][1,2]oxatiin 3-oxide (29.1 mg, 0.11 mmol) and maleic anhydride (12.6 mg, 0.13 mmol) obtained in Step 3 were dissolved in toluene (1 mL) and stirred overnight at 80 °C. The solvent was removed under reduced pressure, and the solid was treated with MeOH to obtain the target product as a white solid (18.7 mg, 0.069 mmol, 63%).

[0601] 1 H NMR (400 MHz, CDCl3) δ 7.54 - 7.44 (m, 2H), 7.33 (d,J= 7.9 Hz, 1H), 3.70 - 3.59 (m, 2H), 3.26 (dt,J= 15.1, 2.6 Hz, 2H), 3.00 (dq,J= 15.2, 3.6 Hz, 2H).

[0602] (5) Step 5: Synthesis of 4-(1,3-dioxo-6-(trifluoromethyl)-1,3,3a,4,9,9a-hexahydro-2H-benzo[f]isoindol-2-yl)-N-(quinolin-8-yl)benzamide

[0603] I-2 (18.2 mg, 0.069 mmol) was added to the solution of 6-(trifluoromethyl)-3a,4,9,9a-tetrahydronaphth[2,3-c]furan-1,3-dione (18.7 mg, 0.069 mmol) obtained in Step 4 in acetic acid (1 mL), and the mixture was heated at 110 °C overnight. After cooling the reaction mixture to room temperature, an excess amount of cold DI was added and stirred for 1 hour (1 h). The solid was recovered by filtration, dissolved in DCM, and then purified by preparative thin-layer chromatography (DCM / MeOH = 30 / 1) to obtain the target product as a white solid (20.3 mg, 0.039 mmol, 57%).

[0604] 1 H NMR (400 MHz, CDCl3) δ 10.68 (s, 1H), 8.88 (dd,J= 7.3, 1.8 Hz, 1H), 8.82 (dd,J= 4.3, 1.7 Hz, 1H), 8.18 (dd,J= 8.3, 1.7 Hz, 1H), 8.10 - 8.03 (m, 2H), 7.62 - 7.43 (m, 5H), 7.34 (d,J= 7.8 Hz, 1H), 7.17 - 7.10 (m, 2H), 3.59 - 3.51 (m, 2H), 3.36 (d,J= 14.5 Hz, 2H), 3.11 - 3.00 (m, 2H).

[0605] 37. Synthesis of Compound (= IB-39) of Preparation Example 41

[0606]

[0607] (1) Step 1: Synthesis of (4-fluoro-1,2-phenylene)dimethanol

[0608] 4-(Fluoromethyl)phthalic acid (361.2 mg, 2.0 mmol, CAS: 320-97-8) in anhydrous THF (1.0 mL) was added to a lithium aluminum hydride suspension (191.8 mg, 5.0 mmol) in anhydrous THF (8 mL) at 0 °C, stirred for 30 minutes, and then heated under reflux overnight. The mixture was cooled to 0 °C, and the reaction was terminated by adding water (0.2 mL), 15% NaOH aqueous solution (0.2 mL), and water (0.6 mL). The mixture was filtered through Celite, washed with DCM, and concentrated under reduced pressure to obtain the product as white solids (257.0 mg, 1.65 mmol, 80%).

[0609] 1 H NMR (400 MHz, CDCl3) δ 7.21 (dd,J= 8.3, 5.5 Hz, 1H), 6.99 (dd,J= 9.3, 2.9 Hz, 1H), 6.93 (td,J= 8.3, 2.8 Hz, 1H), 4.52 (d,J= 6.0 Hz, 4H).

[0610] (2) Step 2: Synthesis of 1,2-bis(bromomethyl)-4-fluorobenzene

[0611] A mixture of (4-fluoro-1,2-phenylene)dimethanol (157.3 mg, 1.0 mmol) and phosphorus tribromide (120 μL, 2 / 5 mmol) obtained in Step 1 was stirred overnight at room temperature. The reaction mixture was cooled, the pH was adjusted to pH 8 with a saturated sodium bicarbonate solution, extracted with DCM, dried with MgSO4, filtered, and concentrated under reduced pressure to obtain the target product as a white powder (205.0 mg, 0.73 mmol, 73%).

[0612] 1H NMR (400 MHz, CDCl3) δ 7.39 - 7.31 (m, 1H), 7.10 (dd,J= 9.0, 2.7 Hz, 1H), 7.05 - 6.95 (m, 1H), 4.65 - 4.58 (m, 4H).

[0613] (3) Step 3: Synthesis of 6-fluoro-1,4-dihydrobenzo[d][1,2]oxathiine 3-oxide

[0614] 1,2-Bis(bromomethyl)-4-fluorobenzene (205.0 mg, 0.73 mmol) and tetrabutylammonium bromide (71.8 mg, 0.22 mmol) obtained in Step 2 were dissolved in anhydrous DMF (1 mL). The suspension was cooled to 0 °C, and then rongalite (230.7 mg, 1.5 mmol) was added. The mixture was heated to room temperature over 6 hours, and the reaction was terminated with water. The aqueous layer was extracted with DCM, dried with MgSO4, and then concentrated under reduced pressure. The crude residue was purified by column chromatography (Hex / EA = 3 / 1) to obtain the target product as white crystals (134.0 mg, 0.72 mmol, 96%).

[0615] 1 H NMR (400 MHz, CDCl3) δ 7.26 - 7.15 (m, 1H), 7.07 (ddd,J= 8.0, 4.9, 2.7 Hz, 1H), 6.97 (ddd,J= 8.3, 5.3, 2.6 Hz, 1H), 5.27 (d,J= 13.8 Hz, 1H), 4.94 (dd,J= 13.8, 5.0 Hz, 1H), 4.36 (t,J= 14.7 Hz, 1H), 3.55 (dd,J= 15.5, 2.2 Hz, 1H).

[0616] (4) Step 4: Synthesis of 6-fluoro-3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1,3-dione

[0617] 6-fluoro-1,4-dihydrobenzo[d][1,2]oxatiin 3-oxide (85.1 mg, 0.46 mmol) and maleic anhydride (91.9 mg, 0.94 mmol) obtained in Step 3 were dissolved in toluene (1 mL) and stirred overnight at 80 °C. The solvent was removed under reduced pressure, and the solid was treated with MeOH to obtain the target product as white solids (101.0 mg, 0.46 mmol, quant.).

[0618] 1 H NMR (400 MHz, CDCl3) δ 7.16 (dd,J= 9.2, 5.2 Hz, 1H), 6.93 (d,J= 8.3 Hz, 2H), 3.63 - 3.57 (m, 2H), 3.19 (d,J= 14.9 Hz, 2H), 2.92 (t,J= 14.5 Hz, 2H).

[0619] (5) Step 5: Synthesis of 4-(6-fluoro-1,3-dioxo-1,3,3a,4,9,9a-hexahydro-2H-benzo[f]isoindol-2-yl)-N-(quinolin-8-yl)benzamide

[0620] I-2 (42.7 mg, 0.16 mmol) was added to the solution of 6-fluoro-3a,4,9,9a-tetrahydronaphth[2,3-c]furan-1,3-dione (39.6 mg, 0.18 mmol) obtained in Step 4 in acetic acid (1 mL), and the mixture was heated at 110 °C overnight. After cooling the reaction mixture to room temperature, an excess amount of cold DI was added and stirred for 1 hour (1 h). The solid was recovered by filtration, dissolved in DCM, and then purified by preparative thin-layer chromatography (DCM / MeOH = 30 / 1) to obtain the target product as a white solid (17.2 mg, 0.04 mmol, 22%).

[0621] 1 H NMR (400 MHz, CDCl3) δ 10.69 (s, 1H), 8.89 (dd,J= 7.3, 1.7 Hz, 1H), 8.82 (dd,J= 4.2, 1.7 Hz, 1H), 8.24 - 8.15 (m, 1H), 8.13 - 8.03 (m, 2H), 7.65 - 7.53 (m, 2H), 7.48 (dd,J= 8.3, 4.3 Hz, 1H), 7.22 - 7.08 (m, 3H), 7.00 - 6.89 (m, 2H), 3.57 - 3.47 (m, 2H), 3.29 (dt,J= 14.2, 2.1 Hz, 2H), 3.06 - 2.88 (m, 2H).

[0622] 38. Synthesis of Compound (= IB-40) of Preparation Example 42

[0623]

[0624] 4-(5-methoxy-1,3-dioxo-1,3,3a,4,9,9a-hexahydro-2H-benzo[f]isoindol-2-yl)-N-(quinolin-8-yl)benzamide (IB-36, 5.0 mg, 0.0105 mmol) was added to an oven-dried Schlenk flask equipped with a stirring bar. The flask was sealed with a rubber septum, and after reducing the pressure, the air was purged with argon three times. Anhydrous DCM (500 μL) was added, and the mixture was cooled to 0 °C. Boron tribromide (20 μL, 0.42 mmol) was added dropwise to the mixture, and stirring was continued at 0 °C for 1 hour. The solvent was removed under reduced pressure, and the solid was washed with water. The solid was dissolved in a mixed solvent of DCM and MeOH and purified by preparative thin-layer chromatography (DCM / MeOH = 15 / 1) to obtain the target product as white solids (3.5 mg, 0.0076 mmol, 73%).

[0625] 1H NMR (400 MHz, Acetone) δ 10.76 (s, 1H), 8.95 (dd,J= 4.2, 1.7 Hz, 1H), 8.90 (dd,J= 7.5, 1.4 Hz, 1H), 8.43 (dd,J= 8.3, 1.7 Hz, 1H), 8.15 - 8.08 (m, 2H), 7.72 (dd,J= 8.3, 1.4 Hz, 1H), 7.70 - 7.61 (m, 2H), 7.30 - 7.22 (m, 2H), 7.04 (ddd,J= 8.1, 7.3, 0.7 Hz, 1H), 6.81 (dt,J=8.2, 0.9 Hz, 1H), 6.74 (d,J= 7.4 Hz, 1H), 3.67 - 3.58 (m, 3H), 3.16 (dd,J= 14.5, 2.6 Hz, 1H), 3.08 - 2.98 (m, 1H), 2.82 - 2.78 (m, 1H).

[0626] 39. Synthesis of Compound (= IB-41) of Preparation Example 43

[0627]

[0628] 4-(6-methoxy-1,3-dioxo-1,3,3a,4,9,9a-hexahydro-2H-benzo[f]isoindole-2-yl)-N-(quinoline-8-yl)benzamide) (IB-34, 9.0 mg, 0.019 mmol) was added to an oven-dried Schlenk flask equipped with a stirring bar. The flask was sealed with a rubber septum, and after reduced pressure, the atmosphere was flushed with argon three times. Anhydrous DCM (500 μL) was added, and the mixture was cooled to 0 °C. Boron tribromide (40 μL, 0.84 mmol) was added dropwise to the mixture, and stirring was continued at 0 °C for 1 hour. The solvent was removed under reduced pressure, and the solid was washed with water. The solid was dissolved in a mixed solvent of DCM and MeOH and purified by thin-layer chromatography for preparation (DCM / MeOH = 20 / 1) to obtain the target product as white solids (3.5 mg, 0.0076 mmol, 79%).

[0629] 1 H NMR (400 MHz, DMSO) δ 10.64 (s, 1H), 9.24 (s, 1H), 8.97 (dd, J = 4.3, 1.7 Hz, 1H), 8.71 (dd, J = 7.6, 1.4 Hz, 1H), 8.47 (dd, J = 8.3, 1.7) Hz, 1H), 8.12 - 8.04 (m, 2H), 7.77 (dd, J = 8.3, 1.4 Hz, 1H), 7.73 - 7.63 (m, 2H), 7.20 - 7.11 (m, 2H), 6.99 (d, J = 7.9 Hz, 1H), 6.65 - 6.56 (m, 2H), 3.56 - 3.44 (m, 2H), 3.02 - 2.83 (m, 4H).

[0630] 40. Synthesis of Compound (= IB-42) of Preparation Example 44

[0631]

[0632] (1) Step 1: Synthesis of pyridine-2,3-diyldimethanol

[0633] Sodium borohydride (272.4 mg, 7.20 mmol) was added to a solution of dimethylpyridine-3,4-dicarboxylate (780.7 mg, 4 mmol) in ethanol (200 mL) at 0 °C. The reaction mixture was then refluxed overnight. After cooling to room temperature, the reaction was quenched with excess water and extracted with CHCl3. The combined organic layer was washed with brine and dried with MgSO4. After removing the solvent under reduced pressure (vacuo), the residue was purified by column chromatography to obtain pyridine-2,3-diyldimethanol as a white powder (140 mg, 25%).

[0634] 1H NMR (400 MHz, CDCl3) δ 8.52 - 8.45 (m, 1H), 7.76 (dd,J= 7.7, 1.6 Hz, 1H), 7.30 - 7.22 (m, 1H), 4.79 (s, 2H), 4.70 (s, 2H)

[0635] (2) Step 2: Synthesis of Bis(chloromethyl)pyridine

[0636] Thionyl chloride (1 mL) was added to a solution of pyridine-2,3-diyldimethanol (140.0 mg, 1.01 mmol) dissolved in CH2Cl2 (0.5 mL), and the mixture was reacted at 75 °C for 6 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate and an aqueous solution of NaHCO3. The combined organic layer was washed with brine and dried with MgSO4. After removing the solvent under reduced pressure (in vacuo), the residue was purified by column chromatography to obtain bis(chloromethyl)pyridine as a dark brown oil (106 mg, 60%).

[0637] 1 H NMR (400 MHz, CDCl3) δ 8.53 (dd,J= 4.9, 1.7 Hz, 1H), 7.75 (dd,J= 7.8, 1.7 Hz, 1H), 7.29 (dd,J= 7.7, 4.9 Hz, 1H), 4.82 (s, 2H), 4.73 (s, 2H).

[0638] (3) Step 3: Synthesis of 4-(6,8-dioxo-5,5a,6,8,8a,9-hexahydro-7H-pyrrolo[3,4-g]quinoline-7-yl)-N-(quinoline-8-yl)benzamide (IB-42)

[0639] I-3 (309.0 mg, 0.90 mmol) and NaI (224.8 mg, 1.50 mmol) were added to bis(chloromethyl)pyridine (52.8 mg, 0.30 mmol) in anhydrous DMF (4 mL) at room temperature under an Ar atmosphere. The reaction mixture was reacted at 60 °C under an Ar atmosphere for 20 hours. The resulting mixture was extracted with aqueous solutions of CHCl3 and NaHCO3. The combined organic layer was washed with brine and dried with MgSO4. After removing the solvent under reduced pressure (in vacuo), the residue was purified by column chromatography to obtain IB-42 as a dark brown powder (9 mg, 17%).

[0640] 1 H NMR (400 MHz, DMSO) δ 10.64 (s, 1H), 8.96 (dd,J= 4.2, 1.6 Hz, 1H), 8.70 (dd,J= 7.6, 1.3 Hz, 1H), 8.46 (dd,J= 8.3, 1.7 Hz, 1H), 8.37 (dd,J= 5.0, 1.7 Hz, 1H), 8.08 (d,J= 8.6 Hz, 2H), 7.76 (dd,J= 8.3, 1.4 Hz, 1H), 7.72 - 7.58 (m, 3H), 7.24 (dd,J= 7.5, 5.0 Hz, 1H), 7.19 (d,J=8.6 Hz, 2H), 3.69 - 3.53 (m, 2H), 3.26 - 3.02 (m, 4H).

[0641] The chemical structural formulas of the compounds (preparation examples) synthesized in I-II above are shown in FIGS. 7 to 9.

[0642] III. Synthesis of Additional Compounds

[0643] 1. Synthesis of Compound (= IB-1) of Preparation Example 45

[0644]

[0645] (1) Step 1: Synthesis of 4-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-ethanoisoindol-2-yl)benzoic acid

[0646] 4-aminobenzoic acid (67.7 mg, 0.49 mmol) was added to a solution of cis-5-norbornene-endo-2,3-dicarboxylic anhydride (90.2 mg, 0.51 mmol, CAS: 129-64-6) in acetic acid (1 mL) under stirring, and the mixture was heated at 120 °C overnight. After cooling the reaction mixture to room temperature, an excess amount of DI was added to the solution until a precipitate was formed. The precipitate was filtered and dried to obtain the desired product as white solids (111.0 mg, 0.37 mmol, 77%).

[0647] 1 H NMR (300 MHz, CDCl3) δ 8.21 - 8.12 (m, 1H), 7.40 - 7.31 (m, 1H), 6.30 (dd,J= 4.5, 3.1 Hz, 1H), 3.27 (s, 1H), 3.04 (t,J= 1.6 Hz, 1H), 1.68 (d,J= 8.1 Hz, 1H), 1.51 - 1.39 (m, 1H).

[0648] (2) Step 2: Synthesis of 4-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-ethanoisoindol-2-yl)-N-(quinolin-8-yl)benzamide

[0649] 8-Aminoquinoline (22.7 mg, 0.16 mmol) was added to a solution of 4-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-ethanoisoindole-2-yl)benzoic acid (43.5 mg, 0.16 mmol), HATU (170.0 mg, 0.45 mmol), and DIPEA (80 μL, 0.46 mmol) obtained in Step 1 in anhydrous DMF (1 mL), and the mixture was stirred overnight at room temperature. The mixture was washed with a saturated sodium bicarbonate solution, extracted with EA, and dried with anhydrous MgSO4. After filtration, it was concentrated under reduced pressure (in vacuo). The residue was purified by column chromatography (Hex / EA = 1 / 1). The target product was obtained as white solids (31.0 mg, 0.073 mmol, 46%).

[0650] 1 H NMR (300 MHz, CDCl3) δ 10.74 (s, 1H), 8.92 (dd,J= 7.1, 1.8 Hz, 1H), 8.84 (dd,J= 4.2, 1.7 Hz, 1H), 8.24 - 8.11 (m, 3H), 7.65 - 7.41 (m, 5H), 6.32 (dd,J= 4.5, 3.1 Hz, 2H), 3.29 (s, 2H), 3.06 (t,J= 1.6 Hz, 2H), 1.69 (d,J= 8.2 Hz, 2H).

[0651] 2. Synthesis of Compound (= IB-2) in Preparation Example 46

[0652]

[0653] (1) Step 1: Synthesis of 4-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)benzoic acid

[0654] 4-aminobenzoic acid (90.0 mg, 0.51 mmol) was added to a solution of cis-4-cyclohexene-1,2-dicarboxylic anhydride (77.8 mg, 0.51 mmol, CAS: 935-79-5) in acetic acid (1 mL) under stirring, and the mixture was heated at 120 °C overnight. After cooling the reaction mixture to room temperature, an excess amount of DI was added to the solution until a precipitate was formed. The precipitate was filtered and dried to obtain the target product as an off-white solid (118.0 mg, 0.44 mmol, 84%).

[0655] 1 H NMR (300 MHz, CDCl3) δ 8.22 - 8.13 (m, 2H), 7.46 - 7.37 (m, 2H), 6.07 - 5.96 (m, 2H), 3.33 - 3.25 (m, 2H), 2.71 (s, 1H), 2.64 (s, 5H), 2.34 (dd,J= 17.7, 4.8 Hz, 2H).

[0656] (2) Step 2: Synthesis of 4-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)-N-(quinolin-8-yl)benzamide

[0657] 8-Aminoquinoline (23.8 mg, 0.17 mmol) was added to a solution of 4-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-isoindole-2-yl)benzoic acid (41.3 mg, 0.15 mmol), HATU (181.7 mg, 0.48 mmol), and DIPEA (80 μL, 0.46 mmol) obtained in Step 1 in anhydrous DMF (1 mL), and the mixture was stirred overnight at room temperature. The mixture was washed with a saturated sodium bicarbonate solution, extracted with EA, and dried with anhydrous MgSO4. After filtration, it was concentrated under reduced pressure (in vacuo). The residue was purified by column chromatography (Hex / EA = 1 / 1). The target product was obtained as white solids (43.0 mg, 0.10 mmol, 71%).

[0658] 1 H NMR (300 MHz, CDCl3) δ 10.75 (s, 1H), 8.96 - 8.80 (m, 2H), 8.24 - 8.11 (m, 3H), 7.64 - 7.45 (m, 5H), 6.08 - 5.94 (m, 2H), 3.38 - 3.24 (m, 2H), 2.75 (ddt,J= 14.1, 4.4, 2.2 Hz, 2H), 2.35 (dt,J= 14.9, 4.6 Hz, 2H).

[0659] 3. Synthesis of Compound (= IB-4) of Preparation Example 47

[0660]

[0661] (1) Step 1: Synthesis of (3aR,4R,4aR,5aS,6S,6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-ethenocyclopropa[f]isobenzofuran-1,3(3aH)-dione

[0662] Maleic anhydride (425.9 mg, 4.3 mmol) was added to a solution of cycloheptatriene (415.0 μL, 4.0 mmol, CAS: 544-25-2) in o-xylene (4 mL) under stirring, and the mixture was heated at 150 °C for 12 hours. The solvent was removed under reduced pressure (in vacuo), and the crude residue was purified by column chromatography (Hex / EA = 10 / 1 to 1 / 1) to obtain the product as white solids (290.0 mg, 1.5 mmol, 38%).

[0663] 1 H NMR (300 MHz, CDCl3) δ 5.95 - 5.83 (m, 2H), 3.47 (dp,J= 6.6, 2.1 Hz, 2H), 3.24 (dd,J= 2.2, 1.6 Hz, 2H), 1.17 - 1.06 (m, 2H), 0.37 (td,J= 7.4, 6.0 Hz, 1H), 0.26 (dt,J= 6.1, 3.7 Hz, 1H).

[0664] (2) Step 2: Synthesis of 4-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-ethenocyclopropa[f]isoindol-2(1H)-yl)benzoic acid

[0665] 4-aminobenzoic acid (22.1 mg, 0.16 mmol) was added to the solution of (3aR,4R,4aR,5aS,6S,6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-etenocyclopropa[f]isobenzofuran-1,3(3aH)-dione (31.0 mg, 0.16 mmol) obtained in Step 1 in acetic acid (1 mL) under stirring, and the mixture was heated at 120 °C overnight. After cooling the reaction mixture to room temperature, an excess amount of DI was added to the solution until a precipitate was formed. The precipitate was filtered and dried to obtain the desired product as white solids (34.0 mg, 0.11 mmol, 68%).

[0666] 1 H NMR (300 MHz, CDCl3) δ 8.20 - 8.11 (m, 2H), 7.39 - 7.29 (m, 2H), 5.87 (dd,J= 4.8, 3.3 Hz, 2H), 3.51 (s, 2H), 3.21 - 3.13 (m, 2H), 1.17 (s, 2H), 0.41 - 0.25 (m, 2H).

[0667] (3) Step 3: Synthesis of 4-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-ethenocyclopropa[f]isoindol-2(1H)-yl)-N-(quinolin-8-yl)benzamide

[0668] 8-Aminoquinoline (15.7 mg, 0.11 mmol) was added to a solution of the compound obtained in Step 2 (32.0 mg, 0.10 mmol), HATU (120.0 mg, 0.32 mmol), and DIPEA (60 μL, 0.34 mmol) in anhydrous DMF (1 mL), and the mixture was stirred overnight at room temperature. The mixture was washed with a saturated sodium bicarbonate solution, extracted with EA, and dried with anhydrous MgSO4. After filtration, it was concentrated under reduced pressure (in vacuo). The residue was purified by column chromatography (Hex / EA = 1 / 1) to obtain the target product as white solids (32.0 mg, 0.073 mmol, 71%).

[0669] 1H NMR (300 MHz, CDCl3) δ 10.74 (s, 1H), 8.91 (dd,J= 7.2, 1.9 Hz, 1H), 8.84 (dd,J= 4.3, 1.7 Hz, 1H), 8.24 - 8.09 (m, 3H), 7.65 - 7.52 (m, 2H), 7.49 (dd,J= 8.3, 4.2 Hz, 1H), 7.45 - 7.38 (m, 2H), 5.89 (dd,J= 4.8, 3.3 Hz, 2H), 3.53 (s, 2H), 3.25 - 3.13 (m, 2H), 1.23 - 1.13 (m, 2H), 0.40 - 0.25 (m, 2H).

[0670] IV. Experimental Example: Evaluation of Compound Efficacy

[0671] 1. Evaluation of the TNKS inhibitory effect of the compound

[0672] The TNKS inhibitory effects of the synthesized compounds, as well as XAV939 (Cayman, Cat no. 13596) and IWR-1 (Sigma Aldrich, Cat no. 10161), were evaluated. The specific experimental methods and results are as follows.

[0673] (1) Wnt3a conditioned media production

[0674] To activate WNT signaling, cell lines overexpressing Wnt3a were 100 mm 2 Seeds were placed in dishes to achieve 80-90% confluency, and 10 mL of growth media (DMEM, Welgene LM001-51+1% PC / ST+10 %FBS) was added to the culture medium and incubated for 3 days. Afterward, the culture medium was harvested for the first time and stored at 4°C. The same cells were then cultured for 4 days with 10 mL of growth media, followed by a second harvest. The second harvested medium and the first harvested medium were combined, filtered through a 0.2 μm syringe filter, dispensed in 10 mL aliquots, and stored at -22°C for use.

[0675] (2) TOPflash assay

[0676] A vector containing the SuperTOPflash reporter gene, capable of confirming the inhibitory effect of TNKS on WNT signaling, was overexpressed in HEK293T cells via a lentiviral system, followed by selection to construct the HEK293T SuperTOPflash cell line. The cell line was cultured in a 24-well plate at 5.0 x 10⁶ 4 Cells were seeded at the cell / well concentration. After 24 hours, the compounds to be tested were treated at various concentrations in Wnt3a-conditioned media. For the control group, a group treated with the vehicle without Wnt3a-conditioned media and a group treated with both Wnt3a-conditioned media and the vehicle were used. Subsequently, the culture medium was collected after 24 hours to measure the activities of gaussia luciferase and secretory alkaline phosphatase (SEAP). The measured values ​​were normalized by dividing the gaussian luciferase activity by the SEAP activity. The compounds were treated at concentrations of 0.001, 0.01, 0.1, 1, and 10 μM, and the IC50 for the inhibitory effect of the compounds on TNKS was determined using Graphpad Prism. 50 and I max The value was calculated.

[0677] (3) Measurement of Gaussia luciferase and SEAP activity

[0678] A substrate was prepared to measure the activity of Gaussia luciferase. The substrate consisted of a mixture of assay buffer, coelenterazine reconstitution, and BSA, with the composition of each solution as follows: Assay buffer: NaCl 1.1 M, NaEDTA 2.2 mM, KH2PO4 20 mM, NaN 3 1.3 mM, pH 5.0 (dissolved in tertiary water); Coelenterazine reconstitution: Coelenterazine 1 mg, HCl 5 mM (dissolved in 9.44 mL of methanol); BSA: 44 mg / mL (dissolved in tertiary water). After preparing each solution, 10 mL of assay buffer, 100 μL of coelenterazine reconstitution, and 100 μL of BSA were mixed to create the Gaussian luciferase substrate, which was then dispensed in 1 mL aliquots and stored at -22 ℃ for use.

[0679] Using a microplate reader capable of measuring luminescence, 10 μL of the recovered culture medium was loaded into a white 96-well plate, 50 μL of gaussia luciferase substrate was added, and the plate was immediately placed in the microplate reader to measure the signal value for 10 seconds.

[0680] To measure SEAP activity, assay buffer, 5x dilution buffer, and CSPD substrate buffer were prepared. The composition of each solution is as follows: Assay buffer: diethanolamine 2 M, MgCl2 anhydrous 1 mM, L-homoarginine 20 mM, pH 9.8 (dissolved using tertiary water); 5x dilution buffer: NaCl 0.75 M, Tris 0.2 M, pH 7.2 (dissolved using tertiary water); CSPD substrate buffer: CSPD substrate 1.25 mM (mixed with Emerald-II enhancer at a 1:20 ratio). The assay buffer and 5x dilution buffer were prepared in advance and stored at 4 ℃ for use, while the 5x dilution buffer was diluted to 1x dilution buffer using tertiary water prior to use. The CSPD substrate was prepared immediately before the experiment.

[0681] 5 μL of the recovered culture medium was loaded into a white 96-well plate, and 15 μL of 1 x dilution buffer was added. The mixture was then reacted at 65°C for 30 minutes, followed by cooling on ice for 2 minutes. Next, 20 μL of assay buffer was added, and the mixture was reacted at room temperature for 5 minutes. Afterward, 20 μL of CSPD substrate was added and the mixture was reacted at room temperature for 10 minutes, after which the signal value was measured for 1 second using a microplate reader capable of measuring luminescence.

[0682] (4) Experimental results

[0683] IC for TNKS inhibitory effect using TOPflash assay 50 and I max... was calculated, and the results for each compound are shown in [Table 1] and Figure 1. As a result of the experiment, the compounds according to one aspect of this specification exhibited TNKS inhibitory effects. In particular, some compounds (IB-12-A3, IB-26, IB-12, IB-19b, IB-12-C7, IB-12-C2, IB-8, IB-36, IB-3-A3, IB-25, IB-34, IB-24b, IB-12-C4, IB-12-C3, IB-11a, IB-6, IB-19a, IB-30b, IB-3, IB-23, IB-22, IB-17, etc.) I max With a value exceeding 50%, and simultaneously compared to IWR-1, known as an existing TNKS inhibitor, IC 50 The value was low (i.e., IC 50 (Excellent value). Some compounds IC compared to IWR-1 50 The value is IC 50 It was confirmed that the value was significantly low.

[0684] Compound IC 50 (μM)-LOG(IC 50[mM])Imax (%)IB-12-A30.0011595.93591656473.5IB-260.0013435.87192398764.4IB-120.0028685.54242085383IB-19b0.0039635.40 197592872IB-12-C70.0056735.24618721666.5IB-12-C20.0074725.12656313780.9IB-80.0090385.04392766382IB-360.010 294.98758462565.3IB-3-A30.010524.9779842692IB-250.016074.79398412361IB-340.016324.78727984664.1IB-24b0.019394.71242219160.1IB-12-C40.019854.70223948969.4IB-12-C30.021014.67757394870.4IB-11a0.02154.6675615479IB-60 022434.64917072667IB-19a0.023894.6217838568IB-30b0.026724.57316354664.5IB-30.042224.37448177183IB-230.050544.29636476261.9IB-220.052494.27992342771.59IB-170.057024.24397278776XAV9390.062424.20467623675IWR-10.068 824.16228533268IB-11b0.086764.06168045780IB-320.08784.05650548472.7IB-150.090114.0452270174IB-24a0.10513.97839728467.6IB-21a0.10993.95900230871.92IB-20.11753.92996213382IB-10.17253.76321090178IB-43.6482.4379451776

[0685] 2. Cell viability assay

[0686] (1) Mouse chondrocyte 일차 배양

[0687] Mouse articular chondrocytes were isolated from the femoral condylar and tibial barbels of 4–5 day old ICR mice by 0.2% collagen degradation. Chondrocytes were cultured in DMEM containing 10% fetal bovine serum (FBS), 100 units / mL penicillin, and 100 μg / mL streptomycin. Cells were placed in 96-well plates at a density of 1.0 x 10⁶ 4 Cells were seeded at a concentration of cells / well, and after 3 days, the drug was treated at concentrations of 0, 1, 10, 100, 1000, and 10000 nM, respectively. After 3 days, cell viability was measured using the CellTiter-Gol 2.0 Cell Viability Assay Kit (Promega, G9241).

[0688] (2) Cell viability assay

[0689] Cell viability assays were performed according to the instructions provided by the manufacturer. In summary, an equal volume (100 ul) of the CellTiter-Glo2.0 Reagent solution from the Cell Viability Assay Kit was added to cultured cells along with the growth media, and the cells were incubated at room temperature for 10 minutes. Subsequently, luminescence was measured.

[0690] (3) Cell viability assay results

[0691] Cell viability assays were performed on some drugs (compounds) with superior IC50 values ​​compared to XAV939 and IWR-1, as well as on Lorecivivint, which is currently being developed as a treatment for osteoarthritis. As a result, no cytotoxicity was observed at concentrations below 1 uM (Figs. 2a and 2b). Therefore, in subsequent experiments, the effects of the drugs were confirmed at concentrations below 1 uM.

[0692] 3. Evaluation of the increase in SOX9 activity of the compound

[0693] (1) Mouse chondrocyte primary culture

[0694] Mouse articular chondrocytes were isolated from ICR mice approximately 4 to 5 days old. Specifically, cartilage tissue was collected from the femoral condyle and tibial striae, and chondrocytes were isolated by treatment with 0.2% collagenase. Chondrocytes were cultured in DMEM medium containing 10% fetal bovine serum (FBS), 100 units / mL penicillin, and 100 μg / mL streptomycin. Cells were placed in a 24-well plate at a density of 2.0 x 10⁶ 4 Cells were inoculated at a concentration of cells / well and transfection was performed after culturing for 3 days. Transfection was carried out using METAFECTENE PRO (Biontex) reagent according to the manufacturer's protocol. The SOX9 reporter vector was inoculated into cells to a final concentration of 1 μg / mL, and after 6 hours, the medium was replaced with a medium containing 0.1 μM of the compound. 72 hours after the replacement, the culture medium was collected, and Gaussian luciferase activity and SEAP activity were measured. The measured values ​​were normalized by dividing Gaussian luciferase activity by SEAP activity.

[0695] (2) Measurement of Gaussia luciferase and SEAP activity

[0696] A substrate was prepared to measure the activity of Gaussia luciferase. The substrate consisted of a mixture of assay buffer, coelenterazine reconstitution, and BSA, with the composition of each solution as follows: Assay buffer: NaCl 1.1 M, NaEDTA 2.2 mM, KH2PO4 20 mM, NaN 3 1.3 mM, pH 5.0 (dissolved in tertiary water); Coelenterazine reconstitution: Coelenterazine 1 mg, HCl 5 mM (dissolved in 9.44 mL of methanol); BSA: 44 mg / mL (dissolved in tertiary water). After preparing each solution, 10 mL of assay buffer, 100 μL of coelenterazine reconstitution, and 100 μL of BSA were mixed to create the Gaussian luciferase substrate, which was then dispensed in 1 mL aliquots and stored at -22 ℃ for use. To measure Gaussia luciferase activity, 10 μL of the recovered culture medium was loaded into a white 96-well plate using a microplate reader capable of measuring luminescence, 50 μL of gaussia luciferase substrate was added, and the plate was immediately placed in the microplate reader to measure the signal value for 10 seconds.

[0697] To measure SEAP activity, assay buffer, 5x dilution buffer, and CSPD substrate buffer were prepared. The composition of each solution is as follows: Assay buffer: diethanolamine 2 M, MgCl2 anhydrous 1 mM, L-homoarginine 20 mM, pH 9.8 (dissolved using tertiary water); 5x dilution buffer: NaCl 0.75 M, Tris 0.2 M, pH 7.2 (dissolved using tertiary water); CSPD substrate buffer: CSPD substrate 1.25 mM (mixed with Emerald-II enhancer at a 1:20 ratio). The assay buffer and 5x dilution buffer were prepared in advance and stored at 4 ℃ for use, while the 5x dilution buffer was diluted to 1x dilution buffer using tertiary water prior to use. The CSPD substrate was prepared immediately before the experiment. To measure SEAP activity, 5 μL of the recovered culture medium was loaded into a white 96-well plate, and 15 μL of 1 x dilution buffer was added. The mixture was then reacted at 65°C for 30 minutes, followed by cooling on ice for 2 minutes. Next, 20 μL of assay buffer was added, and the mixture was reacted at room temperature for 5 minutes. Afterward, 20 μL of CSPD substrate was added and the mixture was reacted at room temperature for 10 minutes, after which the signal value was measured for 1 second using a microplate reader capable of measuring luminescence.

[0698] For statistical analysis, all quantitative data were expressed as mean ± standard error (Mean ± SEM). Statistical significance testing was performed using GraphPad Prism 10 software (version 10.4.2). One-way ANOVA was conducted in comparison with the control sample, followed by the application of Tukey's post-hoc test.

[0699] (3) Sox9 reporter gene assay results

[0700] Sox9 reporter gene assays were performed on some drugs (compounds) with better IC50 values ​​than XAV939 and IWR-1, as well as on Lorecivivint, which is currently being developed as a treatment for osteoarthritis. As a result, while some drugs (compounds) did not show a significant increase in gaussian luciferase activity compared to the control group, it was confirmed that gaussian luciferase activity increased significantly at a concentration of 0.1 uM for only some drugs (compounds) (Fig. 3).

[0701] 4. Analysis of SOX9 target gene expression of the compound

[0702] (1) Mouse chondrocyte primary culture

[0703] Mouse articular chondrocytes were isolated from ICR mice approximately 4 to 5 days old. Specifically, cartilage tissue was collected from the femoral condyle and tibial striae, and chondrocytes were isolated by treatment with 0.2% collagenase. Chondrocytes were cultured in DMEM medium containing 10% fetal bovine serum (FBS), 100 units / mL penicillin, and 100 μg / mL streptomycin. Cells were placed in 12-well plates at a density of 1.0 x 10⁶ 5Cells were inoculated at a concentration of cells / well and cultured for 3 days, after which they were treated according to each experimental condition. Wnt3a (R&D systems) and the drug (compound) were treated at concentrations of 100 ng / ml and 30 nM, respectively. 48 hours after treatment, cells were harvested and RNA was extracted.

[0704] (2) RNA extraction, reverse transcription and quantitative PCR

[0705] After 48 hours of ASO treatment, cells were harvested and total RNA was extracted using TRI Reagent (Molecular Research Center, Inc.). The extracted RNA was subjected to reverse transcription using EasyScript Reverse Transcriptionase (Transgen Biotech), and the expression levels of SOX9 target genes were measured via qPCR.

[0706] Sox9 target gene expression measurement results

[0707] As a result of the SOX9 reporter gene assay, the expression of SOX9 target genes (SOX9, Col9a1, Acan) was confirmed for drugs (compounds) that significantly increase SOX9 activity. As a result, when Wnt3a was treated, a significant decrease in SOX9 target genes was observed, and IB-12 was found to increase the reduced genes back to a significant level. In addition, IB-12-A3 and IWR-1 were found to significantly increase Col9a1 and Acan (Fig. 4).

[0708] 5. Analysis of Transcriptome Changes Caused by Compounds

[0709] (1) Mouse chondrocyte primary culture

[0710] Mouse articular chondrocytes were isolated from ICR mice approximately 4 to 5 days old. Specifically, cartilage tissue was collected from the femoral condyle and tibial striae, and chondrocytes were isolated by treatment with 0.2% collagenase. Chondrocytes were cultured in DMEM medium containing 10% fetal bovine serum (FBS), 100 units / mL penicillin, and 100 μg / mL streptomycin. Cells were placed in 12-well plates at a density of 1.0 x 10⁶ 5 Cells were inoculated at a concentration of cells / well and cultured for 3 days, after which they were treated according to each experimental condition. Wnt3a (R&D systems) and the drug (compound) were treated at concentrations of 100 ng / ml and 30 nM, respectively. 48 hours after treatment, cells were harvested and RNA was extracted.

[0711] (2) RNA extraction and RNA sequencing

[0712] 48 hours after ASO treatment, cells were harvested and total RNA was extracted using TRI Reagent (Molecular Research Center, Inc.). The extracted RNA was sent to Macrogen for RNA sequencing.

[0713] (3) Transcriptome analysis

[0714] GSEA was performed using the Cartilage signature gene set (Kim et al., Nat. Comm., 2019) and the Reactome Signaling by Wnt gene set (MsigDB). For pathway analysis, genes that decreased upon Wnt treatment (Fold change < 0.667, Adjusted P value < 0.05) and genes that increased upon IB-12 treatment (Fold change > 1.5, Adjusted P value < 0.05) were selected, and Reactome pathway analysis was performed using Enrichr.

[0715] (4) Transcriptome analysis results

[0716] GSEA was conducted to analyze the effects of IB-12 on mouse chondrocytes at the transcriptome level. As a result, WNT3A showed a decrease in genes belonging to the cartilage signature gene set, whereas the experimental group treated with IB-12 showed an increase in genes belonging to the cartilage signature gene set (Fig. 5a). Furthermore, when examining the results regarding Wnt signaling, it was confirmed that IB-12 caused transcriptome changes that significantly reduced Wnt signaling (Fig. 5b). This indicates that IB-12 has the effect of increasing the expression of genes necessary for cartilage maintenance while simultaneously reducing Wnt signaling.

[0717] Next, a reactionome pathway analysis was performed on genes that are decreased by WNT and increased by IB-12. As a result, it was confirmed that most of the pathways observed above are related to substances constituting the cartilage matrix, such as the extracellular matrix, glycosaminoglycan metabolism, collagen biosynthesis, and modifying enzymes (Figs. 5c, 5d). These results suggest that genes increased by IB-12 promote cartilage matrix synthesis.

[0718] 6. Inhibitory effect of the compound on colorectal cancer

[0719] (1) Evaluation of colony formation using colorectal cancer cell lines

[0720] To perform a colony formation assay using the human-derived colorectal adenocarcinoma cell line DLD-1, DLD-1 cells were seeded into 35 mm culture dishes at a cell density of approximately 700 cells per dish and cultured for about 24 hours. Culture was performed at 37°C, 5% CO2, and atmospheric oxygen concentrations, and RPMI medium supplemented with 10% fetal bovine serum (FBS), 100 units / mL penicillin, and 100 μg / mL streptomycin was used as the culture medium. After 24 hours of inoculation, the existing culture medium was removed, and IB-12 was diluted in the culture medium to concentrations of 0.1, 1, 2, 5, and 10 μM and applied to the cells. Drug treatment was maintained for a total of 9 days, and the existing culture medium was removed and replaced with fresh medium containing the same concentration of the compound at intervals of approximately 72 hours.

[0721] After the culture was finished, the cells were fixed in a cold 4% paraformaldehyde (PFA) solution for 2 minutes and then washed with PBS. Subsequently, permeabilization was performed using cold methanol at room temperature for approximately 20 minutes. After removing the methanol, the cells were stained with a 0.1% crystal violet solution at room temperature for approximately 20 minutes. Following staining, the cells were washed repeatedly with PBS and dried at room temperature for one day. The dried dishes were photographed, and the number of colonies was quantified using the Cell Counter function of ImageJ software.

[0722] All quantitative data were expressed as mean ± standard error (mean ± SEM). Statistical analysis was performed using GraphPad Prism software (version 10.4.2, GraphPad Software), and statistical significance was evaluated by applying Tukey's post-hoc test after conducting one-way ANOVA.

[0723] (2) Results of colony formation evaluation of colorectal cancer cell lines

[0724] As a result of performing a colony formation assay using colorectal cancer cell lines, it was observed that the number of colonies decreased in a concentration-dependent manner as the concentration of IB-12 treatment increased (Fig. 6). These results suggest that IB-12 can inhibit the proliferative ability of colorectal cancer cells and has an inhibitory effect on colorectal cancer.

[0725] The present disclosure is further explained by the following embodiments that do not limit the scope of the claims.

[0726] Embodiment 1. A compound represented by the following chemical formula I, an isomer thereof, a solvate thereof, a hydrate thereof, or a salt thereof:

[0727] [Chemical Formula I]

[0728]

[0729] In the above chemical formula I,

[0730] A is a substituted or unsubstituted arylene group, a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted heteroarylene group, a substituted or unsubstituted heterocycloalkylene group, or a substituted or unsubstituted bicycloalkylene group, and

[0731] B is a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and

[0732] X is absence, -CH2-, -O-, -S-, a substituted or unsubstituted arylene group, or a substituted or unsubstituted heteroarylene group, and

[0733] M1, M2, M3 and M4 are each independently N or CR1, where R1 is hydrogen, an alkoxy group, a halogen group, an acetamido group, a hydroxyl group, an alkoxycarbonyl group, a carboxyl group, a hydroxyalkyl group, an alkyl group, or a haloalkyl group.

[0734] Example 2. In Example 1,

[0735] If the above X is absent,

[0736] The above compound is a compound, its isomer, its solvate, its hydrate, or its salt, which is represented by the following chemical formula II:

[0737] [Chemical Formula II]

[0738]

[0739] In the above chemical formula II,

[0740] A is a substituted or unsubstituted arylene group, a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted heteroarylene group, a substituted or unsubstituted heterocycloalkylene group, or a substituted or unsubstituted bicycloalkylene group, and

[0741] B is a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and

[0742] M1, M2, M3 and M4 are each independently N or CR1, where R1 is hydrogen, an alkoxy group, a halogen group, an acetamido group, a hydroxyl group, an alkoxycarbonyl group, a carboxyl group, a hydroxyalkyl group, an alkyl group, or a haloalkyl group.

[0743] Example 3. In Example 1 or 2,

[0744] The above A is a compound, isomer thereof, solvate thereof, hydrate thereof, or salt thereof, wherein A is a substituted or unsubstituted phenylene group, a substituted or unsubstituted cyclohexylene group, a substituted or unsubstituted bicyclo[1.1.1]pentane-1,3-diyl group, or a substituted or unsubstituted bicyclo[2.2.1]heptane-1,4-diyl group.

[0745] Embodiment 4. In any one of Embodiments 1 to 3,

[0746] The above B is a compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a salt thereof, wherein B is a substituted or unsubstituted quinolinyl group, a substituted or unsubstituted isoquinolinyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted pyridinyl group.

[0747] Embodiment 5. In any one of Embodiments 1 to 4,

[0748] X is a compound, its isomer, its solvate, its hydrate, or its salt, which is absence, -CH2-, -O-, -S-, a substituted or unsubstituted phenylene group, a substituted or unsubstituted pyridinylene group, a substituted or unsubstituted pyrimidinylene group, or a substituted or unsubstituted pyrazinylene group.

[0749] Embodiment 6. In any one of Embodiments 1 to 5,

[0750] The above compound is at least one selected from the group consisting of the following compounds: a compound, its isomer, its solvate, its hydrate, or its salt:

[0751]

[0752]

[0753]

[0754]

[0755] Example 7. In any one of Examples 1 to 6, the compound, its isomer, its solvate, its hydrate, or its salt is a compound, its isomer, its solvate, its hydrate, or its salt that inhibits tankyrase activity.

[0756] Embodiment 8. A composition for preventing, improving, or treating osteoarthritis comprising, as an active ingredient, any one of the compounds in Embodiments 1 to 7, an isomer thereof, a solvate thereof, a hydrate thereof, or a salt thereof.

[0757] Embodiment 9. The composition of Embodiment 8, wherein the composition comprises the following compound as an active ingredient:

[0758]

[0759] Embodiment 10. In Embodiment 8 or 9,

[0760] A composition in which the above compound promotes the differentiation of mesenchymal stem cells into chondrocytes.

[0761] Embodiment 11. A composition for preventing, improving, or treating colorectal cancer comprising, as an active ingredient, any one of the compounds in Embodiments 1 to 7, an isomer thereof, a solvate thereof, a hydrate thereof, or a salt thereof.

[0762] Embodiment 12. The composition of Embodiment 11, wherein the composition comprises the following compound as an active ingredient:

[0763] .

Claims

1. A compound represented by the following chemical formula I, its isomer, its solvate, its hydrate, or its salt: [Chemical Formula I] In the above chemical formula I, A is a substituted or unsubstituted arylene group, a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted heteroarylene group, a substituted or unsubstituted heterocycloalkylene group, or a substituted or unsubstituted bicycloalkylene group, and B is a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and X is absence, -CH2-, -O-, -S-, a substituted or unsubstituted arylene group, or a substituted or unsubstituted heteroarylene group, and M1, M2, M3 and M4 are each independently N or CR1, where R1 is hydrogen, an alkoxy group, a halogen group, an acetamido group, a hydroxyl group, an alkoxycarbonyl group, a carboxyl group, a hydroxyalkyl group, an alkyl group, or a haloalkyl group.

2. In Paragraph 1, If the above X is absent, The above compound is a compound, its isomer, its solvate, its hydrate, or its salt, which is represented by the following chemical formula II: [Chemical Formula II] In the above chemical formula II, A is a substituted or unsubstituted arylene group, a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted heteroarylene group, a substituted or unsubstituted heterocycloalkylene group, or a substituted or unsubstituted bicycloalkylene group, and B is a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and M1, M2, M3 and M4 are each independently N or CR1, where R1 is hydrogen, an alkoxy group, a halogen group, an acetamido group, a hydroxyl group, an alkoxycarbonyl group, a carboxyl group, a hydroxyalkyl group, an alkyl group, or a haloalkyl group.

3. In Paragraph 1, The above A is a compound, isomer thereof, solvate thereof, hydrate thereof, or salt thereof, wherein A is a substituted or unsubstituted phenylene group, a substituted or unsubstituted cyclohexylene group, a substituted or unsubstituted bicyclo[1.1.1]pentane-1,3-diyl group, or a substituted or unsubstituted bicyclo[2.2.1]heptane-1,4-diyl group.

4. In Paragraph 1, The above B is a compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a salt thereof, wherein B is a substituted or unsubstituted quinolinyl group, a substituted or unsubstituted isoquinolinyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted pyridinyl group.

5. In Paragraph 1, X is a compound, its isomer, its solvate, its hydrate, or its salt, which is absence, -CH2-, -O-, -S-, a substituted or unsubstituted phenylene group, a substituted or unsubstituted pyridinylene group, a substituted or unsubstituted pyrimidinylene group, or a substituted or unsubstituted pyrazinylene group.

6. In Paragraph 1, The above compound is at least one selected from the group consisting of the following compounds: a compound, its isomer, its solvate, its hydrate, or its salt:

7. In claim 1, the compound, its isomer, its solvate, its hydrate, or its salt is a compound, its isomer, its solvate, its hydrate, or its salt that inhibits tankyrase activity.

8. A composition for preventing, improving, or treating osteoarthritis comprising, as an active ingredient, a compound of any one of claims 1 to 7, an isomer thereof, a solvate thereof, a hydrate thereof, or a salt thereof.

9. The composition of claim 8, wherein the composition comprises the following compound as an active ingredient: .

10. In Paragraph 8, A composition in which the above compound promotes the differentiation of mesenchymal stem cells into chondrocytes.

11. A composition for the prevention, improvement, or treatment of colorectal cancer comprising, as an active ingredient, a compound of any one of claims 1 to 7, an isomer thereof, a solvate thereof, a hydrate thereof, or a salt thereof.

12. The composition of claim 11, wherein the composition comprises the following compound as an active ingredient: .

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