Novel quinoline derivatives having inhibitory activity against c-myc transcription factor protein

Abstract

The present invention provides a novel quinoline derivative, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The present invention, as a novel compound, exhibits inhibitory activity against a c-Myc transcription factor protein and has a significant effect in preventing, alleviating, or treating diseases (particularly cancer) associated with the c-Myc transcription factor.

Description

Novel quinoline derivatives with inhibitory activity against C-MYC transcription factor protein

[0001] The present invention relates to novel quinoline derivatives, pharmaceutical compositions comprising said quinoline derivatives, and uses of said quinoline derivatives. More specifically, the present invention relates to novel quinoline derivatives that inhibit the activity of the c-Myc transcription factor protein, and pharmaceutical compositions comprising the same for the prevention or treatment of cancer.

[0002] This study was supported by the National New Drug Development Project of the National Drug Development Fund (Project No. RS-2023-00283511) funded by the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, and the Ministry of Health and Welfare, and by the Korea Invention Promotion Association's IP Startup Package for Middle-Aged and Older Idea Commercialization.

[0003] The c-Myc transcription factor is a protein that regulates cell transformation, growth, differentiation, apoptosis, and cell cycle progression. c-Myc is a proto-oncogene that encodes the c-Myc transcription factor. The c-Myc transcription factor is involved in the induction of most cancers, and its gain-of-function is observed in almost all human cancers. Overexpression of c-Myc has also been observed in a wide range of human cancers, and it has been reported to be related to the induction of various cancers, including lung cancer, breast cancer, bladder cancer, and lymphoma, by inducing the overexpression of many genes involved in cell proliferation.

[0004] Many efforts have been made to develop anticancer or antitumor agents by modulating c-Myc expression. However, due to technical difficulties in developing compounds that directly inhibit c-Myc function, most attempts have focused on indirectly controlling c-Myc function. However, these indirect c-Myc inhibitors cause various unexpected side effects.

[0005] Therefore, there is a need for the development of a direct inhibitor that directly inhibits the c-Myc transcription factor protein and has a low possibility of causing side effects.

[0006] The present invention provides a novel quinoline derivative, an optical isomer thereof, or a pharmaceutically acceptable salt thereof that inhibits the activity of c-Myc transcription factor protein.

[0007] The present invention also provides a pharmaceutical composition for preventing or treating cancer comprising a novel quinoline derivative, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0008] The terminology used in this application is merely used to describe specific embodiments and is not intended to limit the present invention. The singular expression includes the plural expression unless the context clearly indicates otherwise. In this application, terms such as "comprise" or "have" should be understood to indicate the presence of a feature, step, structure, or combination thereof described above, but do not preclude the presence or addition of one or more other features, steps, structures, or combinations thereof.

[0009] The meanings of terms and symbols used in this document are as follows.

[0010] In the present invention, the term "quinoline" refers to the following structure:

[0011]

[0012] In the present invention, the term “unsubstituted” means a state in which no substituent is substituted and is absent or hydrogen.

[0013] In the present invention, the term "substituted" refers to a moiety having a substituent that replaces a hydrogen atom on one or more carbon atoms of the main chain. "Substituted" or "substituted with" is defined to include the implicit condition that the substitution leads to a stable compound, for example, a compound that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, etc., depending on the substituted atom and whether the substitution is permitted.

[0014] In the present invention, "single bond" means that two connected radicals are directly connected. For example, if L represents a single bond in ALZ, this structure is essentially AZ.

[0015] In the present invention, the terms “halogen” and “halo” mean a substituent selected from fluorine (F), chloro (Cl), bromo (Br), or iodo (I).

[0016] In the present invention, "C x-y " means having carbon number x or more and y or less.

[0017] In the present invention, the term "alkyl" means a straight or branched chain saturated hydrocarbon, for example, "C 1-6"Alkyl" means a straight or branched saturated hydrocarbon having 1 to 6 carbon atoms. Representative saturated straight-chain alkyls may include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl, and saturated branched-chain alkyls may include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylhexyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-deethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and 3,3-diethylhexyl. "Alkyl" may be unsubstituted or Alternatively, it may be optionally substituted by one or more substituents, which may be the same or different. Each substituent may be halogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, carboxy, etc. Each of these substituents may follow any of the definitions for each substituent mentioned herein.

[0018] In the present invention, the term "haloalkyl" means a straight-chain or branched-chain saturated hydrocarbon in which at least one hydrogen atom of the straight-chain or branched-chain saturated hydrocarbon is replaced with a halogen atom (i.e., F, Cl, Br, or I). For example, "C 1-6"Haloalkyl" means a straight or branched chain saturated hydrocarbon having 1 to 6 carbon atoms, wherein one or more hydrogen atoms are replaced by a halogen atom. Specifically, haloalkyl may be, but is not limited to, CF3, CHF2, CH2F, CBr3, CHBr2, CH2Br, CCl3, CHCl2, CH2Cl, CI3, CHI2, CH2I, CH2-CF3, CH2-CHF2, CH2-CH2F, CH2-CBr3, CH2-CHBr2, CH2-CH2Br, CH2-CCl3, CH2-CHCl2, CH2-CH2Cl, CH2-CI3, CH2-CHI2, CH2-CH2I, etc.

[0019] The term "alkenyl" as used herein refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon double bond obtained by removing one hydrogen atom from a single carbon atom of a parent alkene. The radical may be in the cis or trans form with respect to the double bond. Representative straight-chain or branched-chain alkenyl groups include, but are not limited to, ethenyl (CH=CH2), 1-propenyl (CH2CH=CH2), isopropenyl [C(CH3)=CH2], 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, and the like.

[0020] The term "alkynyl" as used herein refers to an unsaturated branched, straight-chain, or cyclic alkyl radical having at least one carbon-carbon triple bond obtained by removing one hydrogen atom from a single carbon atom of a parent alkyne. Representative straight-chain or branched-chain alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl, and the like.

[0021] As used herein, the term “haloalkenyl” or “haloalkynyl” refers to an alkenyl or alkynyl group, respectively, in which one or more hydrogen atoms are replaced by a halogen atom. For example, haloalkenyl may be C=CHCl2 and C=CCl3, but is not limited thereto. “Haloalkynyl” may be C≡CF, C≡CCl, and C≡CBr, but is not limited thereto.

[0022] In the present invention, the term “cyano” means a CN group, and the term “nitro” means a NO2 group.

[0023] The term "alkoxy" in the present invention refers to an oxygen group bonded to a straight or branched chain saturated hydrocarbon group with a single bond. Examples thereof include, but are not limited to, methoxy, ethoxy, propoxy, and 1-methylpropoxy.

[0024] In the present invention, the term "haloalkoxy" refers to a functional group in which at least one hydrogen of an oxygen group bonded to a straight-chain or branched-chain saturated hydrocarbon is replaced with a halogen atom (i.e., F, Cl, Br, or I). Examples thereof include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy, 2,2,2-trichloroethoxy, and the like.

[0025] In the present invention, the term “alkoxycarbonyl” means a straight-chain or branched alkoxy group bonded to C(=O). For example, C(O)OCH3, C(O)OCH2CH 3, and C(O)OCH2CH2CH3, but is not limited thereto.

[0026] In the present invention, the term “amino” means NH2 group, and the term “alkylamino” means NR a R b It means Qi, where R a and Rb are each independently hydrogen or alkyl. For example, the term “di(C 1-6 Alkyl)amino” is NR a R b R in Ki a and R b Each C 1-6 It means an alkyl group.

[0027] In the present invention, the term “amino (C 1-6 )alkyl” is C substituted with an amino group 1-6 It means alkyl group.

[0028] In the present invention, the term “(C 1-6 )alkylamino(C 1-6 ) “Alkyl” refers to an alkyl group substituted with an alkylamino group, wherein the alkyl group and the alkylamino group have the meanings defined herein. Examples thereof include, but are not limited to, methylaminomethyl, methylaminoethyl, ethylaminomethyl, ethylaminoethyl, propylaminomethyl, methylaminopropyl, and propylaminoethyl.

[0029] In the present invention, the term “alkanoyl” means a group having a carbonyl such as RC(O), where R represents hydrogen or an alkyl group. Examples thereof include, but are not limited to, C(O)H, C(O)CH3, and C(O)H2CH3.

[0030] In the present invention, the term “alkylsulfonyl” means SO2-(alkyl) obtained by removing one hydrogen atom from an alkyl group and replacing it with a sulfonyl group (SO₂), wherein alkyl is as defined above. Representative alkylsulfonyl groups may include, but are not limited to, methylsulfonyl (SO2-CH3), ethylsulfonyl (SO2-CH2CH3), propylsulfonyl (SO2-(CH2)2CH3), isopropylsulfonyl (SO2-(CH2)3CH3), butylsulfonyl (SO2-(CH2)3CH3).

[0031] In the present invention, the term "alkylsulfinyl" means SO-(alkyl) obtained by removing one hydrogen atom from an alkyl group and replacing it with a sulfinyl group (SO), wherein alkyl is as defined above. Representative alkylsulfinyl groups include, but are not limited to, methylsulfinyl (SO-CH3), ethylsulfinyl (SOCH2CH3), propylsulfinyl (SO-(CH2)2CH3), isopropylsulfinyl (SO-(CH2)3CH3), butylsulfinyl (SO-(CH2)4CH3), etc.

[0032] In the invention, the term “halosulfanyl” refers to sulfur having one or more halogen substituents.

[0033] In the present invention, the term “C 1-6 “Alkylamine” is a C obtained by removing one hydrogen atom from an alkyl group and replacing it with an amine group (NH₂). 1-6 It refers to an amine containing a straight-chain, branched-chain or cyclic radical. Representative alkylamines include, but are not limited to, methylamine, ethylamine, propylamine, isopropylamine, butylamine, pentylamine, hexylamine, etc.

[0034] In the present invention, the term "C 1-6 "Alkylene" refers to an alkyl group having a specified number of carbons, e.g., 1 to 6 carbon atoms, which includes two points of attachment to the rest of the compound in the longest carbon chain. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), and the like. The alkylene group may be a cyclic or acyclic, branched or unbranched carbon chain moiety, and may optionally be substituted with one or more substituents.

[0035] In the present invention, the term "C 3-10"Cycloalkyl" means a saturated hydrocarbon ring containing 3 to 10 carbon atoms, and the saturated hydrocarbon ring includes both monocyclic and polycyclic rings, and ring structures in which two or more rings share one or more pairs of carbon atoms (e.g., fused ring, spiro ring, bridged ring, etc.). Representative cycloalkyls may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0036] In the present invention, the term "C 3-10 "Heterocycloalkyl" refers to a saturated monocyclic or polycyclic heterocycle containing 3 to 10 carbon atoms, wherein at least one of the ring carbon atoms is replaced by a heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S), or a ring structure in which two or more rings share one or more pairs of carbon atoms (e.g., a fused ring, a spiro ring, a bridged ring, etc.), each of which may have an optional substituent. Heterocycloalkyl is oxetanyl, morpholinyl, thiomorpholinyl, furyl, piperazinyl, pyranyl, 1,3-dioxanyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, thietanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, Hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one-yl, tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-yl, 3-oxa-8-azabicyclo[3.2.1]octan-yl, hexahydro-2H-furo[3,2-b]pyrrole, azetidinyl, etc., but are not limited thereto. In addition, the heterocycloalkyl may be substituted or unsubstituted, and when substituted, may be halogen, C 1-6 Alkyl, C 1-6Haloalkyl, OH, NO2, CN, and NH2, etc. When nitrogen is present in the heterocycloalkyl ring, it may exist in an oxidized state (i.e., N+-O-) as long as the properties of adjacent atoms and groups permit. Examples include piperidinyl N-oxide and morpholinyl-N-oxide. In addition, when sulfur is present in the heterocycloalkyl ring, it may exist in an oxidized state (i.e., S+-O- or -SO2-) as long as the properties of adjacent atoms and groups permit. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. In addition, one ring of the polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl) if the polycyclic heterocycloalkyl group is attached to the parent structure through a non-aromatic carbon or nitrogen atom.

[0037] In the present invention, the term "C 6-12 "Aryl" refers to an aromatic hydrocarbon containing 6 to 12 carbon atoms. For example, it can refer to a ring system such as monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, pentarenyl, azulenyl, tetrahydronaphthyl, tetrahydroindenyl). Preferably, aryl can be a phenyl group having the chemical formula C6H5 and having 6 carbon atoms arranged in a cyclic ring structure. Phenyl group is very stable and is a type of aromatic hydrocarbon found in many organic compounds. In addition, the aryl can be substituted or unsubstituted, and when substituted, the hydrogen at the ortho, meta, or para position of the phenyl ring can be replaced by a halogen, C 1-6 Alkyl, C 1-6 It can be substituted with haloalkyl, OH, NO2, CN, and NH2.

[0038] The term "5- to 10-membered heteroaryl" as used herein refers to an aromatic hydrocarbon containing 5- to 10-carbon atoms, wherein at least one carbon atom in the ring is substituted with a heteroatom such as oxygen (O), nitrogen (N), or sulfur (S). In addition, it may include an aromatic ring (e.g., a bicyclic or tricyclic ring system) in which one or more rings, such as a heteroaryl ring, an aryl ring, a heterocyclic ring, or a carbocyclic ring, are bonded, and each ring may have an optional substituent. For example, pyrans (e.g., 2H-pyran, 4H-pyran), pyrroles, pyrazoles, imidazoles, triazoles (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), furans, isoxazoles, oxazoles, oxadiazoles (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophenes, isothiazoles, thiazoles, thiadiazoles (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridines, pyridazines, pyrimidines, pyrazines, triazines (e.g., 1,2,4-triazine, 1,3,5-triazine), tetrazines, It may include monocyclic heteroaryl including pyridone (e.g., 2-pyridone, 4-pyridone), and polycyclic heteroaryl including pyrrolopyridine, indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, isobenzofuran, benzoxazole, benzisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole, benzodioxazole, imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole, and imidazo[2,1-b]thiazole, but is not limited thereto.

[0039] In the present invention, the term "8 to 12-membered biheteroaryl" refers to an aromatic hydrocarbon having a structure in which two heteroaryl rings are bonded, and at least one carbon atom in the ring is substituted with a heteroatom such as oxygen (O), nitrogen (N), or sulfur (S). For example, “8 to 12 membered biheteroaryl” includes pyrrolopyridine, indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, isobenzofuran, benzoxazole, benzisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole, benzodioxazole, carbazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (e.g., 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), imidazo[1,2-a]pyridine, Polycyclic heteroaryls may include, but are not limited to, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole, and imidazo[2,1-b]thiazole.

[0040] In addition, the above "5 to 10 membered heteroaryl" or "8 to 12 membered biheteroaryl" may be substituted or unsubstituted, and when substituted, may be halogen, C 1-6 Alkyl, C 1-6 It can be substituted with haloalkyl, OH, NO2, CN, and NH2, etc. In addition, the polycyclic heteroaryl group may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to the heteroaryl ring when the polycyclic heteroaryl group is bonded to the parent structure through an aromatic ring.

[0041] In the present invention, the term "enantiomer" refers to a case where two molecules having optical activity form a mirror-symmetric relationship. It is generally used synonymously with mirror image isomers, and includes the R-form, S-form, or racemic compound forms, respectively.

[0042] As used herein, the term "tautomer" refers to isomeric forms of a compound that can exist in equilibrium with each other. The concentration of the isomeric forms will depend on the environment in which the compound is found, and may vary, for example, depending on whether the compound is a solid or in an organic or aqueous solution. Although not explicitly indicated in the structural formulas shown herein, tautomers are intended to be included within the scope of the present invention. For example, the enamine form and the imine form, or the enol form and the keto form, are referred to as tautomers of each other, and these compounds can exist as tautomers of each other through resonance as follows:

[0043]

[0044] As shown in the above diagram, some compounds of the present invention may exist as tautomers of enamine and imine forms, or as tautomers of enol and keto forms, and all of these forms are included in the scope of the present invention.

[0045] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and will not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0046]

[0047] Novel quinoline derivatives, optical isomers thereof, or pharmaceutically acceptable salts thereof

[0048] To solve the above-mentioned technical problem, the present invention provides a compound represented by the following chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[0049] [Chemical Formula 1]

[0050]

[0051] In the above chemical formula 1,

[0052] R1 and R4 are each independently OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-10 Haloalkenyl, C 2-6 alkynyl, C 2-10 Haloalkynyl, cyano, nitro, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxycarbonyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, amino(C 1-6 )alkyl, (C 1-6 )alkylamino(C 1-6 )alkyl, C 1-6 Alkanoyl, C 1-6 Alkylsulfonyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 6-12 Any one selected from the group consisting of aryl and 5 to 10 membered heteroaryl,

[0053] R2 and R3 are each independently hydrogen, OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-10 Haloalkenyl, C 2-6 alkynyl, C 2-10 Haloalkynyl, cyano, nitro, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6Alkoxycarbonyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, amino(C 1-6 )alkyl, (C 1-6 )alkylamino(C 1-6 )alkyl, C 1-6 Alkanoyl, C 1-6 Alkylsulfonyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 6-12 Any one selected from the group consisting of aryl and 5 to 10 membered heteroaryl,

[0054] R5 is NR a R b And,

[0055] Here, the above R a and R b are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-C 1-6 Haloalkyl, C 6-12 Aryl, C 3-10 Cycloalkyl, 5 to 10 membered heteroaryl, C 3-10 Heterocycloalkyl, C 1-6 alkylene-C 6-12 Aryl, C 1-6 alkylene-C 3-10 Cycloalkyl, C 1-6 Alkylene-5 to 10 membered heteroaryl, C 1-6 alkylene-C 3-10 Heterocycloalkyl, C 6-12 Aryl-C 1-6 alkylene-C 6-12 Aryl, and C 6-12 Aryl-OC 1-6 alkylene-C 6-12 Any one selected from the group consisting of aryl, or

[0056] or the above NR a R b R of a Wow R b are bonded to each other to form 5 to 10 membered heteroaryl or C 3-10Forming a heterocycloalkyl,

[0057] Here, the above C 6-12 Aryl, C 3-10 Cycloalkyl, 5 to 10 membered heteroaryl, and C 3-10 Heterocycloalkyl is C 1-6 Alkyl, OH, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, amino, COOH, C 1-6 Alkylsulfonyl, C 6-12 which may be substituted with any one selected from the group consisting of arylsulfonyl, sulfanyl and halosulfanyl,

[0058] R6 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, and NR c R d is one selected from the group consisting of , where R c and R d are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkylene-OC 1-6 It is alkyl,

[0059] n is 1 or 2,

[0060] L is a bond, or unsubstituted or substituted C 1-6 It is alkylene,

[0061] Het is an unsubstituted or substituted 5 to 10-membered heteroaryl or an unsubstituted or substituted 8 to 12-membered biheteroaryl,

[0062] The above L and Het are each independently halogen, C 1-6 Alkyl, C 1-6 It may be substituted with one or more selected from the group consisting of haloalkyl, OH, NO2, CN and NH2.

[0063] Specifically, R1 and R4 are each independently OH, halogen, C 1-6Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, cyano, nitro, C 1-6 Alkoxy, C 1-6 Haloalkoxy, amino, C 1-6 Alkylamino, amino(C 1-6 )alkyl, C 1-6 Alkylsulfonyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 6-12 Any one selected from the group consisting of aryl and 5 to 10 membered heteroaryl,

[0064] The above R2 and R3 are each independently hydrogen, OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, cyano, nitro, C 1-6 Alkoxy, C 1-6 Haloalkoxy, amino, C 1-6 Alkylamino, amino(C 1-6 )alkyl, C 1-6 Alkylsulfonyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 6-12 Any one selected from the group consisting of aryl and 5 to 10 membered heteroaryl,

[0065] The above R5 is NH2, NH-C 1-6 Alkyl, N-(C 1-6 alkyl)2, NH-(C 1-6 alkylene)-(C 1-6 Haloalkyl), NH-(C 6-12 Aryl), NH-C 3-10 Cycloalkyl, NH-5 to 10 membered heteroaryl, NH-C 3-10 Heterocycloalkyl, NH-(C 1-6 alkylene)-C 3-10 Cycloalkyl, NH-(C 1-6 alkylene)-(5 to 10 membered heteroaryl), NH-(C 1-6 alkylene)- C 3-10Heterocycloalkyl, NH-(C 6-12 Aryl)-O-(C 1-6 alkylene)-(C 6-12 aryl), 5 to 10 membered heteroaryl containing 1 or more N, and C containing 1 or more N 3-10 Any one selected from the group consisting of heterocycloalkyl,

[0066] Here, the above C 6-12 Aryl, C 3-10 Cycloalkyl, 5 to 10 membered heteroaryl, and C 3-10 Heterocycloalkyl is C 1-6 Alkyl, OH, C 1-6 Haloalkyl, amino, COOH, C 1-6 which may be substituted with any one selected from the group consisting of alkylsulfonyl, and halosulfanyl,

[0067] The above R6 is C 1-6 Alkyl or C 1-6 It is haloalkyl,

[0068] n can be 1.

[0069] Specifically, the Het may be any one selected from the group consisting of piperazinyl, pyrrolidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, and pyrrolopyridinyl.

[0070] More specifically, the L-Het may be any one selected from the group consisting of piperazinyl, pyrrolidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, oxadiazolyl, and pyrimidinyl.

[0071] More specifically, R1 and R4 can each independently be Cl or Br.

[0072] More specifically, R2 and R3 may be hydrogen.

[0073] More specifically, the above R5 is , , , , , , , , , , , , , , , , , , , , , and is one selected from the group consisting of,

[0074] The above R6 may be CH3 or C(CH3)2.

[0075] According to a specific example of the present invention, the compound represented by the above chemical formula 1 may be any one selected from the group consisting of compounds described below:

[0076] (1) 1-(4-amino-8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one,

[0077] (2) 1-(8-bromo-5-chloro-4-(methylamino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one,

[0078] (3) 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-((2,2,2-trifluoroethyl)amino)quinolin-3-yl)ethan-1-one,

[0079] (4) 1-(8-bromo-5-chloro-4-((1-methyl-1H-1,2,4-triazol-3-yl)amino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one,

[0080] (5) 1-(8-bromo-5-chloro-4-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one,

[0081] (6) 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-(pyridazin-4-ylamino)quinolin-3-yl)ethan-1-one,

[0082] (7) 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-((((R)-oxetan-2-ylmethyl)amino)quinolin-3-yl)ethan-1-one,

[0083] (8) 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-((((S)-oxetan-2-ylmethyl)amino)quinolin-3-yl)ethan-1-one,

[0084] (9) 1-(8-bromo-5-chloro-4-((cyclobutylmethyl)amino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one,

[0085] (10) 1-(8-bromo-5-chloro-4-(cyclobutylamino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one,

[0086] (11) 1-(8-bromo-5-chloro-4-((cyclopentylmethyl)amino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one,

[0087] (12) 1-(8-bromo-5-chloro-4-(((1-hydroxycyclopropyl)methyl)amino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one,

[0088] (13) 1-(8-bromo-5-chloro-4-(dimethylamino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one,

[0089] (14) 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-(phenylamino)quinolin-3-yl)ethan-1-one,

[0090] (15) 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-((4-(trifluoromethyl)phenyl)amino)quinolin-3-yl)ethan-1-one,

[0091] (16) 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-((4-(pentafluoro-lambda6-sulfanyl)phenyl)amino)quinolin-3-yl)ethan-1-one,

[0092] (17) 1-(4-((4-(benzyloxy)phenyl)amino)-8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one,

[0093] (18) 1-(4-((4-aminophenyl)amino)-8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one,

[0094] (19) 4-((5,8-dichloro-3-isobutyryl-2-((pyrimidin-5-ylmethyl)sulfinyl)quinolin-4-yl)amino)benzoic acid,

[0095] (20) 1-(5,8-dichloro-4-((4-(methylsulfonyl)phenyl)amino)-2-((pyrimidin-5-ylmethyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one,

[0096] (21) 1-(5,8-dichloro-4-((4-(pentafluoro-lambda6-sulfanyl)phenyl)amino)-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)ethan-1-one,

[0097] (22) 1-(5,8-dichloro-2-(pyrimidin-5-ylsulfinyl)-4-((3-(trifluoromethyl)cyclobutyl)amino)quinolin-3-yl)ethan-1-one,

[0098] (23) 1-(5,8-dichloro-4-((4-(methylsulfonyl)phenyl)amino)-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)ethan-1-one,

[0099] (24) 1-(5,8-dichloro-2-(pyrimidin-5-ylsulfinyl)-4-(1H-pyrrol-1-yl)quinolin-3-yl)ethan-1-one,

[0100] (25) 1-(5,8-dichloro-4-morpholino-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)ethan-1-one,

[0101] (26) 1-(5,8-dichloro-2-(pyrimidin-5-ylsulfinyl)-4-((4-(trifluoromethyl)phenyl)amino)quinolin-3-yl)ethan-1-one, and

[0102] (27) 1-(5,8-dichloro-2-((pyrimidin-5-ylmethyl)sulfinyl)-4-(1H-pyrrol-1-yl)quinolin-3-yl)ethan-1-one.

[0103]

[0104] The compound represented by Chemical Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid can be used. The acid addition salt is obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, and organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid and fumaric acid. These pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphate chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyn-1,4-dioate, hexane-1,6-dioate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, Including, but not limited to, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

[0105] The acid addition salt according to the present invention can be prepared by a conventional method, for example, dissolving the compound represented by Chemical Formula 1 in an organic solvent, for example, methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess acid under reduced pressure and then drying or crystallizing the same in an organic solvent.

[0106] Furthermore, pharmaceutically acceptable metal salts can be prepared using bases. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and evaporating and drying the filtrate. In this case, sodium, potassium, or calcium salts are pharmaceutically suitable as metal salts. In addition, the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate). Furthermore, the present invention encompasses not only the compound represented by Chemical Formula 1 and its pharmaceutically acceptable salts, but also all possible solvates, hydrates, stereoisomers, etc. that can be prepared therefrom.

[0107]

[0108] pharmaceutical composition

[0109] In another aspect of the present invention, a pharmaceutical composition is provided comprising a compound represented by formula 1 as defined in any embodiment described herein, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0110] In another aspect of the present invention, a pharmaceutical composition is provided comprising a compound represented by formula 1 as defined in any embodiment described herein, an optical isomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0111] The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier, and may be formulated in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods.

[0112] The pharmaceutically acceptable carriers include, but are not limited to, those commonly used in the art, such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, the pharmaceutical composition of the present invention may include, but is not limited to, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants, and other pharmaceutically acceptable additives.

[0113] In another aspect of the present invention, a pharmaceutical composition for preventing or treating cancer is provided, comprising a compound represented by formula 1 as defined in any embodiment described herein, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0114] The compound represented by Chemical Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof can exhibit a significant effect in preventing, improving, or treating diseases related to the c-Myc transcription factor by inhibiting the activity of the c-Myc transcription factor protein. Specifically, according to the present invention, by inhibiting the activity of the c-Myc transcription factor protein, cancer growth can be effectively controlled.

[0115] The cancer may be any one selected from the group consisting of lung cancer, colon cancer, colon cancer, rectal cancer, breast cancer, bladder cancer, blood cancer, leukemia, myeloid leukemia, lymphoma, cervical carcinoma, osteosarcoma, glioblastoma, melanoma, pancreatic cancer, stomach cancer, liver cancer, kidney cancer, gallbladder cancer, bile duct cancer, prostate cancer, esophageal cancer, ovarian cancer, and neuroblastoma, but is not limited thereto.

[0116] In the present invention, the term “prevention” means any act of suppressing or inhibiting cancer or delaying its onset by administering a composition.

[0117] In the present invention, the term “treatment” means any action by which the symptoms of the disease are improved or beneficially changed by administration of the composition.

[0118] The pharmaceutical composition according to one embodiment of the present invention can be formulated and used in various forms, such as oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, and injections of sterile injection solutions, according to conventional methods according to the intended use, and can be administered orally or through various routes, including intravenous, intraperitoneal, subcutaneous, rectal, and topical administration.

[0119] The pharmaceutical composition of the present invention can be administered orally, and solid preparations for oral administration include tablets, pills, powders, granules, capsules, troches, etc., and these solid preparations are prepared by mixing one or more compounds of the present invention with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, or syrups, and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included.

[0120] Formulations for oral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solutions and suspensions can include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include witepsol, macrogol, Tween 61, cocoa butter, laurin, glycerol, and gelatin.

[0121] Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solutions and suspending agents can include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include withepsol, macrogol, Tween 61, cacao butter, laurin, and glycerogelatin. Meanwhile, injections can include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.

[0122] The pharmaceutical composition of the present invention may be sterilized, or may further contain auxiliary agents such as preservatives, stabilizers, thickeners, wetting agents or emulsifying agents, salts for osmotic pressure control, and / or buffers, and may further contain other therapeutically useful substances, and may be formulated according to conventional methods such as dissolving, dispersing, and gelling.

[0123] The pharmaceutical composition of the present invention may contain 0.0001 to 99 wt%, preferably 0.01 to 80 wt%, of the compound represented by Chemical Formula 1, its optical isomer, or its pharmaceutically acceptable salt, based on the total weight of the composition.

[0124] The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount, and the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or in multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that achieves the maximum effect with the minimum amount without side effects, and this can be easily determined by those skilled in the art. The appropriate dosage of the pharmaceutical composition of the present invention can be prescribed in various ways depending on factors such as the formulation method, administration method, patient age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and response sensitivity.

[0125] Specifically, the effective amount of the compound in the composition of the present invention may vary depending on the patient's age, sex, and weight, and is generally 0.0001 to 100 mg per kg of body weight, preferably 1 to 90 mg, administered daily, every other day, or weekly, or divided into 1 to 3 times a day. However, the dosage may increase or decrease depending on the route of administration, severity of the disease, sex, body weight, age, etc., and thus the above dosage does not limit the scope of the present invention in any way.

[0126] In one aspect of the present invention, a c-Myc transcription factor protein inhibitor is provided, comprising a compound represented by formula 1 as defined in any embodiment described herein, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0127] In another aspect of the present invention, a method for preventing or treating cancer is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by formula 1 as defined in any embodiment described herein, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0128] Additionally, the method for preventing or treating cancer of the present invention can be used in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.

[0129] The term "subject" of the present invention refers to any animal that has developed or may develop cancer, and typically may be an animal that can exhibit a beneficial effect by treatment with a compound represented by Chemical Formula 1 of the present invention, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, but includes, without limitation, any subject that has symptoms of cancer or is likely to have such symptoms. As described above, by administering the pharmaceutical composition of the present invention to a subject, the above-described disease can be effectively prevented or treated. The pharmaceutical composition of the present invention can be administered as an individual therapeutic agent, or in combination with an existing cancer therapeutic agent (anticancer agent), and can be administered sequentially or simultaneously with the existing therapeutic agent.

[0130] The term "therapeutically effective amount" as used herein means an amount sufficient to prevent or treat a disease at a reasonable benefit / risk ratio applicable to medical prevention or treatment, and refers to an amount of the compound represented by Chemical Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof that is effective for the prevention or treatment of the disease. The effective dosage level may be determined according to factors including the severity of the disease, the activity of the drug, the age, weight, health, and sex of the patient, the patient's sensitivity to the drug, the time of administration of the composition of the present invention used, the route of administration and the excretion rate, the duration of treatment, drugs combined with or used concurrently with the composition of the present invention used, and other factors well known in the medical field. For example, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof may be administered at 0.0001 to 100 mg / kg per day, and the administration may be administered once a day or in several divided doses.

[0131] The term "administration" in the present invention means introducing a predetermined substance into a patient by an appropriate method, and the route of administration of the composition may be administered through any common route as long as it can reach the target tissue. In addition, the pharmaceutical composition of the present invention may be administered by any device that allows the active substance to move to the target tissue. For example, it may be administered by oral administration, intrathecal administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, topical administration, intranasal administration, intrapulmonary administration, rectal administration, inner ear administration, intrauterine epidural administration, sublingual administration, and intracerebrovascular injection, but is not limited thereto. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories.

[0132] The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with another therapeutic agent, and may be administered sequentially or simultaneously with conventional therapeutic agents. Taking all of the above factors into account, the pharmaceutical composition may be administered in an amount that achieves maximum efficacy with minimal side effects, as can be readily determined by those skilled in the art.

[0133] The therapeutic method of the present invention includes not only treating the disease itself before the onset of symptoms, but also inhibiting or avoiding its symptoms by administering the compound represented by the above chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. In the management of a disease, the prophylactic or therapeutic dosage of a particular active ingredient will vary depending on the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The dosage and frequency of administration will vary depending on the age, weight, and response of the individual patient. An appropriate dosage regimen can be readily selected by one skilled in the art, taking these factors into account. In addition, the treatment method of the present invention may further include administration of a therapeutically effective amount of an additional active agent helpful in treating a disease together with the compound represented by the above chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the additional active agent may exhibit a synergistic or auxiliary effect together with the compound represented by the above chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0134] In addition, the present invention provides a use of a compound represented by the above chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a drug for treating cancer.

[0135] In addition, the present invention provides a compound represented by the above chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the treatment of cancer.

[0136] In addition, the present invention provides a pharmaceutical composition comprising a compound represented by the above chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the treatment of cancer.

[0137] The present invention also provides the use of a compound represented by the above chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the treatment of cancer.

[0138] The present invention is a novel quinoline derivative that inhibits the activity of c-Myc transcription factor protein and thus has a significant effect in preventing, improving, or treating diseases (particularly, cancer) related to c-Myc transcription factor.

[0139] Hereinafter, the present invention will be described in detail using examples to aid understanding. However, the examples according to the present invention may be modified in various ways, and the scope of the present invention should not be construed as being limited to the following examples. The examples of the present invention are provided to more fully explain the present invention to those of average skill in the art.

[0140] The compound of the above chemical formula 1 according to one embodiment of the present invention can be prepared by various known methods depending on the type of its substituent. It will be apparent to those skilled in the art that this can be done by using a method known in the art or by appropriately modifying it.

[0141] Reagents and solvents used below are available from Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) unless otherwise noted. 1 H NMR spectra were measured using a Bruker 400 MHz NMR spectrometer.

[0142] [Manufacturing example]

[0143] Manufacturing Example 1. Manufacturing of 1-(8-bromo-4,5-dichloro-2-(((5-methylisoxazol-3-yl)methyl)thio)quinolin-3-yl)ethan-1-one

[0144] (1) Preparation of (5-methylisoxazol-3-yl)methyl methanesulfonate

[0145]

[0146] (5-Methylisoxazol-3-yl)methanol (7.2 g, 63.65 mmol, 1 eq) was dissolved in 25 mL of tetrahydrofuran (THF). Triethylamine (9.66 g, 95.48 mmol, 13.29 mL, 1.5 eq) and methylsulfonyl chloride (7.29 g, 63.65 mmol, 4.93) were added at 0–5 °C under nitrogen, and the mixture was stirred for 2 h. Sodium bicarbonate solution (20 mL) was added, cooled, and extracted with ethyl acetate (20 mL × 3). The organic layer was washed with brine (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain (5-methylisoxazol-3-yl)methyl methanesulfonate (12.1 g) as a yellow oil.

[0147] (2) Preparation of 1-(8-bromo-4,5-dichloro-2-(((5-methylisoxazol-3-yl)methyl)thio)quinolin-3-yl)ethan-1-one

[0148]

[0149] 2-Bromo-5-chloro-aniline (5 g, 24.22 mmol, 1 eq) is dissolved in dichloromethane (175 mL) and sodium carbonate (5.13 g, 48.43 mmol, 2 eq) is added at 0 °C. Thiocarbonyl dichloride (4.18 g, 36.33 mmol, 2.78 mL, 1.5 eq) is added dropwise at 0–3 °C and stirred at 15 °C for 12 h. The mixture is prepared in four additional vials in the same manner. The five vial batches are combined, filtered, and washed with sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1-bromo-4-chloro-2-isothiocyanatobenzene (20 g, yield 66.46%) as a yellow oil.

[0150] Dissolve sodium hydride (3.86 g, 96.57 mmol, 60% purity, 1.2 eq) in THF (90 mL), cool to 0 °C, add a solution of methyl 3-oxobutanoate (11.21 g, 96.57 mmol, 10.41 mL, 1.2 eq) in THF (90 mL) dropwise to the reaction mixture at 0 to 3 °C, and stir for 0.5 h at 0 °C. Add a solution of 1-bromo-4-chloro-2-isothiocyanatobenzene (20 g, 80.47 mmol, 1 eq) in THF (90 mL) dropwise to the reaction mixture at 0 to 5 °C, and stir for 0.5 h.

[0151] Sodium(E)-1-((2-bromo-5-chlorophenyl)amino)-2-(methoxycarbonyl)-3-oxobut-1-ene-1-thiolate (5 g, 12.93 mmol, 1 eq) was dissolved in THF (25 mL) and (5-methylisoxazol-3-yl)methyl methanesulfonate (2.47 g, 12.93 mmol, 1 eq) was added dropwise at 0 to 3 °C, and the mixture was stirred at 15 °C for 12 hours. An additional 7 vials were prepared in the same manner as above. The 8 vial batches were combined, sodium thiosulfate solution (100 mL) was added at 0 °C, cooled, and extracted with ethyl acetate (100 mL × 3). The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (Petroleum ether / Ethyl acetate (PE / EtOAc) = 5 / 1 to 3 / 1) to obtain (E)-methyl 2-(((2-bromo-5-chlorophenyl)amino)(((5-methylisoxazol-3-yl)methyl)thio)methylene)-3-oxobutanoate (30 g, yield 63.07%) as a yellow oil.

[0152] (E)-methyl 2-(((2-bromo-5-chlorophenyl)amino)(((5-methylisoxazol-3-yl)methyl)thio)methylene)-3-oxobutanoate (1 g, 2.18 mmol, 1 eq) was dissolved in 1,2-dichlorobenzene (7.5 mL) and stirred at 180 °C for 15 min. Two additional vials were prepared with the same method as above. The three vial batches were combined and purified by column chromatography (PE / EtOAc = 5 / 1 to 1 / 1) to give 3-acetyl-8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)thio)quinolin-4(1H)-one (500 mg, yield 17.92%) as a yellow solid.

[0153] 3-acetyl-8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)thio)quinolin-4(1H)-one (500 mg, 1.17 mmol, 1 eq) was dissolved in phosphoryl trichloride (5 mL), stirred at 110 °C for 0.5 h, and concentrated under reduced pressure to obtain 1-(8-bromo-4,5-dichloro-2-(((5-methylisoxazol-3-yl)methyl)thio)quinolin-3-yl)ethan-1-one (500 mg, yield 67.11%, purity 70%) as a brown oil. 1-(8-bromo-4,5-dichloro-2-(((5-methylisoxazol-3-yl)methyl)thio)quinolin-3-yl)ethan-1-one (100 mg) was purified by column chromatography. It was purified by chromatography and obtained as a white solid (21 mg, yield 21.00%).

[0154] 1 H NMR: 400 MHz, CDCl3

[0155] δ = 7.96 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 6.09 (s, 1H), 4.72 (s, 2H), 2.65 (s, 3H), 2.37 (s, 3H)

[0156] Manufacturing Example 2. Manufacturing of 1-(8-bromo-4,5-dichloro-2-(((5-methylisoxazol-3-yl)methyl)thio)quinolin-3-yl)-2-methylpropan-1-one

[0157] (1) Preparation of (5-methylisoxazol-3-yl)methyl methanesulfonate

[0158]

[0159] (5-Methylisoxazol-3-yl)methanol (7.2 g, 63.65 mmol, 1 eq) was dissolved in THF (25 mL), and triethylamine (9.66 g, 95.48 mmol, 13.29 mL, 1.5 eq) and methylsulfonyl chloride (7.29 g, 63.65 mmol, 4.93) were added at 0–5 °C under nitrogen, and stirred for 2 h. Sodium bicarbonate solution (20 mL) was added, cooled, and extracted with ethyl acetate (20 mL × 3). The organic layer was washed with brine (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain (5-methylisoxazol-3-yl)methyl methanesulfonate (12.1 g) as a yellow oil.

[0160] (2) Preparation of 1-(8-bromo-4,5-dichloro-2-(((5-methylisoxazol-3-yl)methyl)thio)quinolin-3-yl)-2-methylpropan-1-one

[0161]

[0162] 1-(8-bromo-4,5-dichloro-2-(((5-methylisoxazol-3-yl)methyl)thio)quinolin-3-yl)-2-methylpropan-1-one (50 mg, 105.44 μmol, 1 eq) was obtained in the same manner as the compound according to Manufacturing Example 1.

[0163] 1 H NMR: 400 MHz, CDCl3

[0164] δ = 7.96 (d, J = 8.3 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 6.06 (s, 1H), 4.72 (s, 2H), 3.23 (td, J = 7.0, 13.9 Hz, 1H), 2.37 (s, 3H), 1.29 (d, J = 7.0 Hz, 6H)

[0165] [Example]

[0166] Example 1. Preparation of 1-(4-amino-8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one (Compound 1)

[0167]

[0168] Compound 1a (200 mg, 421.76 μmol, 1 eq) was dissolved in ammonia aqueous solution (4 M, 10 mL, 50 eq) in tetrahydrofuran (THF), and stirred at 25 °C for 2 hours. In another vial, the reaction mixture was prepared in the same manner as above. Both reaction mixtures were concentrated under reduced pressure, and then purified by column chromatography (SiO2, Petroleum ether: ethyl acetate (PE:EtOAc) = 1:1, Rf = 0.4) to obtain compound 1b (135 mg, yield 35.19%) as a yellow solid.

[0169] Compound 1b (130 mg, 285.86 μmol, 1 eq) was dissolved in dichloromethane (1 mL) and methanol (0.1 mL), and meta-chloroperoxybenzoic acid (58.03 mg, 285.86 μmol, purity 85%, 1 eq) was added at 0 °C, and the mixture was stirred at 25 °C for 5 min. Sodium thiosulfate solution (2.5 mL) was added at 0 °C, cooled, stirred for 5 min, and extracted with dichloromethane (5 mL × 3). The mixture was washed with sodium bicarbonate solution (2.5 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 1 (92.0 mg, 68.36%) as a white solid.

[0170] 1 H NMR: 400 MHz, DMSO-d6

[0171] δ = 8.12 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.39 (s, 2H), 6.02 (s, 1H), 4.72 (d, J = 13.6 Hz, 1H), 4.53 (d, J = 13.5 Hz, 1H), 2.99 (quin, J = 6.8 Hz, 1H), 2.34 (s, 3H), 1.12 - 0.95 (m, 6H)

[0172] Example 2. Preparation of 1-(8-bromo-5-chloro-4-(methylamino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one (Compound 2)

[0173]

[0174] Compound 2a (100 mg, 210.88 μmol, 1 eq) was dissolved in THF (0.5 mL), and triethylamine (21.34 mg, 210.88 μmol, 29.35 μL, 1 eq) and methylamine (2 M, 1.05 mL, 10 eq) dissolved in THF were added, and the mixture was stirred at 25 °C for 1 h. After cooling with 1 N aqueous hydrochloric acid solution (20 mL), the mixture was extracted with ethyl acetate (10 mL × 3). The organic layer was washed with 10 mL of brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (PE:EtOAc = 3:1, Rf = 0.29) to obtain compound 2b (75 mg, yield 75.86%) as a yellow oil.

[0175] Compound 2b (75 mg, 159.98 μmol, 1 eq) was dissolved in dichloromethane (1 mL) and methanol (0.1 mL), and meta-chloroperoxybenzoic acid (32.48 mg, 159.98 μmol, purity 85%, 1 eq) was added at 0 °C, and the mixture was stirred at 0 °C for 10 min. Sodium thiosulfate solution (20 mL) was added, cooled, and extracted with ethyl acetate (10 mL × 3). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and extracted with ethyl acetate (5 mL) to obtain compound 2 (30 mg, yield 38.68%) as a white solid.

[0176] 1 H NMR: 400 MHz, CDCl3

[0177] δ = 7.93 (d, J = 8.1 Hz, 1H), 7.47 (br s, 1H), 7.38 (d, J = 8.1 Hz, 1H), 6.30 (s, 1H), 4.65 (d, J = 13.4 Hz, 1H), 4.47 (d, J = 13.5 Hz, 1H), 3.27 (td, J = 6.8, 13.6 Hz, 1H), 3.10 (d, J = 5.0 Hz, 3H), 2.39 (s, 3H), 1.23 (d, J = 6.5 Hz, 3H), 1.04 (d, J = 7.1 Hz, 3H)

[0178] Example 3. Preparation of 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-((2,2,2-trifluoroethyl)amino)quinolin-3-yl)ethanone (Compound 3)

[0179]

[0180] Compound 3a (250 mg, 560.36 μmol, 1 eq) was dissolved in THF (15 mL), and N,N-diethylethanamine (850.53 mg, 8.41 mmol, 1.17 mL, 15 eq) and 2,2,2-trifluoroethanamine (1.11 g, 11.21 mmol, 879.65 μL, 20 eq) were added, and the mixture was stirred at 75 °C for 12 h. The mixture was concentrated under reduced pressure to remove the solvent, and then purified by column chromatography (PE:EtOAc = 3:1) to obtain compound 3b (180 mg, yield 63.14%) as a yellow solid.

[0181] Compound 3b (100 mg, 196.56 μmol, 1 eq) was dissolved in dichloromethane (1 mL) and methanol (0.1 mL), and meta-chloroperoxybenzoic acid (39.91 mg, 196.56 μmol, purity 85%, 1 eq) was added at 0 °C, and stirred for 0.25 h. Sodium thiosulfate solution (20 mL) was added at 0 °C, cooled, and extracted with dichloromethane (10 mL × 3). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 3 (24 mg, yield 23.27%) as a white solid.

[0182] 1 H NMR: 400 MHz, DMSO

[0183] δ = 8.21 (d, J = 8.3 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.16 (t, J = 6.8 Hz, 1H), 6.09 (s, 1H), 4.70 - 4.38 (m, 2H), 4.17 - 3.93 (m, 2H), 2.52 (br s, 3H), 2.34 (s, 3H)

[0184] Example 4. Preparation of 1-(8-bromo-5-chloro-4-((1-methyl-1H-1,2,4-triazol-3-yl)amino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethanone (Compound 4)

[0185]

[0186] 1-Methyl-1H-1,2,4-triazol-3-amine (10.00 mg, 101.93 μmol, 1 eq) is dissolved in THF (1 mL), sodium hydride (12.23 mg, 305.79 μmol, purity 60%, 3 eq) is added at 0-3 °C, and the mixture is stirred at 0-5 °C for 5 minutes. Compound 4a (9.10 mg, 20.39 μmol, 0.2 eq) is dissolved in THF (1 mL), and the mixture is added dropwise to the stirred mixture at 0-5 °C, and the mixture is stirred at 40 °C for 2.5 hours. Additionally, the reaction mixture is prepared in the same manner as above in 19 vials. After cooling to 25°C, all 20 reaction mixtures were combined, cooled by adding ice water (50 mL) at 25°C, and extracted with ethyl acetate (100 mL × 3). The organic layer was washed with brine (25 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 4b (60.00 mg, yield 5.80%) as a yellow solid.

[0187] Compound 4b (60 mg, 118.16 μmol, 1 eq) was dissolved in dichloromethane (1 mL) and methanol (0.1 mL), and meta-chloroperoxybenzoic acid (23.99 mg, 118.16 μmol, purity 85%, 1 eq) was added at 0 °C, and the mixture was stirred at 25 °C for 0.5 h. Sodium thiosulfate solution (2.5 mL) was added at 0 °C, cooled, stirred for 5 min, and extracted with dichloromethane (2 mL × 3). The mixture was washed with sodium bicarbonate solution (2.5 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 4 (3.3 mg, yield 5.33%) as a yellow solid.

[0188] 1 H NMR: 400 MHz, CDCl3

[0189] δ = 8.79 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.77 (s, 1H), 7.50 (d, J = 8.3 Hz, 1H), 6.27 (s, 1H), 4.74 (d, J = 13.5 Hz, 1H), 4.38 (d, J = 13.4 Hz, 1H), 3.79 (s, 3H), 2.41 (d, J = 2.3 Hz, 6H)

[0190] Example 5. Preparation of 1-(8-bromo-5-chloro-4-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethanone (Compound 5)

[0191]

[0192] Compound 5a (100 mg, 224.14 μmol, 1 eq) was dissolved in THF (1 mL), and triethylamine (226.81 mg, 2.24 mmol, 311.98 μL, 10 eq) and (1-methyl-1H-pyrazol-3-yl)methanamine (498.24 mg, 4.48 mmol, 20 eq) were added, and the mixture was stirred at 75 °C for 12 h. The reaction mixture was prepared in the same manner in another vial. Cooled to room temperature and concentrated under reduced pressure to remove the solvent, diluted with water (15 mL), and extracted with ethyl acetate (15 mL). The two combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 5b (200 mg) as a brown solid.

[0193] Compound 5b (200 mg, 384.00 μmol, 1 eq) was dissolved in dichloromethane (2 mL) and methanol (0.2 mL), and meta-chloroperoxybenzoic acid (77.96 mg, 384.00 μmol, purity 85%, 1 eq) was added at 0 °C, and the mixture was stirred at 25 °C for 2 h. Sodium thiosulfate solution (5 mL) was added at 0 °C, cooled, stirred for 5 min, and extracted with dichloromethane (5 mL × 3). The mixture was washed with sodium bicarbonate solution (5 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 5 (8.0 mg, yield 25.00%) as a white solid.

[0194] 1 H NMR: 400 MHz, DMSO-d6

[0195] δ = 8.14 (d, J = 8.3 Hz, 1H), 8.10 (br s, 1H), 7.67 - 7.58 (m, 2H), 6.21 (s, 1H), 6.16 (d, J = 2.1 Hz, 1H), 4.62 (d, J = 13.4 Hz, 1H), 4.52 (dd, J = 3.4, 14.4 Hz, 1H), 4.32 (br d, J = 5.0 Hz, 1H), 4.27 (d, J = 13.4 Hz, 1H), 3.77 (s, 3H), 2.53 (s, 3H), 2.37 (s, 3H)

[0196] Example 6. Preparation of 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-(pyridazin-4-ylamino)quinolin-3-yl)ethan-1-one (compound 6)

[0197]

[0198] Pyridazin-4-amine (40 mg, 420.60 μmol, 1 eq) was dissolved in THF (5 mL) and sodium hydride (100.93 mg, 2.52 mmol, 60% purity, 6 eq) was added at 0 °C and stirred for 10 min. Compound 6a (37.53 mg, 84.12 μmol, 0.2 eq) was dissolved in THF (5 mL) and added dropwise to the stirred mixture and stirred at 0 °C for 10 min. The reaction mixtures were prepared in the same manner as above in three other vials. All four reaction mixtures were combined, cooled by adding water (30 mL) at 0 °C, and extracted with dichloromethane (20 mL × 3). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 6b (40 mg, yield 23.55%) as a white solid.

[0199] Compound 6b (20 mg, 39.62 μmol, 1 eq) was dissolved in THF (1 mL) and meta-chloroperoxybenzoic acid (8.04 mg, 39.62 μmol, purity 85%, 1 eq) was added at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was prepared in the same manner as above in another vial. The two reaction mixtures were combined, and sodium thiosulfate (10 mL) solution was added at 0 °C, cooled, and extracted with dichloromethane (5 mL × 3). Washed with brine (5 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 6 (13 mg, yield 66.81%) as a yellow solid.

[0200] 1 H NMR: 400 MHz, DMSO

[0201] δ = 12.98 (br s, 1H), 8.15 (br d, J = 8.1 Hz, 1H), 7.86 (br dd, J = 6.8, 18.1 Hz, 1H), 7.79 (br s, 1H), 7.56 (br d, J = 8.0 Hz, 1H), 6.09 (s, 1H), 5.78 (br s, 1H), 4.73 - 4.56 (m, 1H), 4.55 - 4.43 (m, 1H), 2.35 (s, 3H), 2.29 (br s, 3H)

[0202] Example 7. Preparation of 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-((((R)-oxetan-2-ylmethyl)amino)quinolin-3-yl)ethanone (Compound 7)

[0203]

[0204] Compound 7a (10.00 mg, 224.14 μmol, 1 eq) was dissolved in THF (1 mL), and triethylamine (340.21 mg, 3.36 mmol, 467.97 μL, 15 eq) and oxetan-2-ylmethanamine (97.64 mg, 1.12 mmol, 5 eq) were added at 25 °C, and the mixture was stirred at 75 °C for 12 h. Cooled to 25 °C, diluted with water (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic layer was washed with brine (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7b (110 mg) as a yellow solid.

[0205] Compound 7b (110 mg, 221.42 μmol, 1 eq) was dissolved in dichloromethane (1 mL) and methanol (0.1 mL), and meta-chloroperoxybenzoic acid (44.95 mg, 221.42 μmol, purity 85%, 1 eq) was added at 0 °C, and the mixture was stirred at 25 °C for 0.5 h. Sodium thiosulfate solution (2.5 mL) was added at 0 °C, cooled, stirred for 5 min, and extracted with dichloromethane (2 mL × 3). The mixture was washed with sodium bicarbonate solution (2.5 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 7 (23.1 mg, yield 20.34%) as a white solid.

[0206] 1 H NMR: 400 MHz, CDCl3

[0207] δ = 8.56 - 8.11 (m, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 6.27 (s, 1H), 5.09 (td, J = 3.7, 7.1 Hz, 1H), 4.78 - 4.69 (m, 1H), 4.65 (d, J = 13.5 Hz, 1H), 4.58 - 4.51 (m, 1H), 4.51 - 4.44 (m, 1H), 3.68 (br dd, J = 2.7, 13.4 Hz, 1H), 3.35 (br d, J = 12.1 Hz, 1H), 2.61 (br s, 1H), 2.61 - 2.54 (m, 3H), 2.46 - 2.39 (m, 1H), 2.37 (s, 3H)

[0208] Example 8. Preparation of 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-((((S)-oxetan-2-ylmethyl)amino)quinolin-3-yl)ethanone (compound 8)

[0209]

[0210] Compound 8a (10.00 mg, 224.14 μmol, 1 eq) was dissolved in THF (1 mL), and triethylamine (340.21 mg, 3.36 mmol, 467.97 μL, 15 eq) and oxetan-2-ylmethanamine (97.64 mg, 1.12 mmol, 5 eq) were added at 25 °C, and the mixture was stirred at 75 °C for 12 h. Cooled to 25 °C, diluted with water (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic layer was washed with brine (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 8b (110 mg) as a yellow solid.

[0211] Compound 8b (110 mg, 221.42 μmol, 1 eq) was dissolved in dichloromethane (1 mL) and methanol (0.1 mL), and meta-chloroperoxybenzoic acid (44.95 mg, 221.42 μmol, purity 85%, 1 eq) was added at 0 °C, and the mixture was stirred at 25 °C for 0.5 h. Sodium thiosulfate solution (2.5 mL) was added at 0 °C, cooled, stirred for 5 min, and extracted with dichloromethane (2 mL × 3). The mixture was washed with sodium bicarbonate solution (2.5 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 8 (19.5 mg, yield 17.17%) as a white solid.

[0212] 1 H NMR: 400 MHz, CDCl3

[0213] δ = 8.27 - 8.00 (m, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 6.23 (s, 1H), 4.98 (br s, 1H), 4.79 - 4.72 (m, 1H), 4.69 (d, J = 13.5 Hz, 1H), 4.64 - 4.56 (m, 1H), 4.48 (br d, J = 13.5 Hz, 1H), 3.78 - 3.54 (m, 1H), 3.45 (br d, J = 12.1 Hz, 1H), 2.77 - 2.66 (m, 1H), 2.61 (s, 3H), 2.50 - 2.40 (m, 1H), 2.37 (s, 3H)

[0214] Example 9. Preparation of 1-(8-bromo-5-chloro-4-((cyclobutylmethyl)amino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethanone (compound 9)

[0215]

[0216] Compound 9a (100 mg, 224.14 μmol, 1 eq) was dissolved in THF (10 mL), triethylamine (340.21 mg, 3.36 mmol, 467.97 μL, 15 eq) and cyclobutylmethanamine (381.70 mg, 4.48 mmol, 20 eq) were added, and the mixture was stirred at 75 °C for 12 h. The mixture was concentrated under reduced pressure to remove THF, dissolved in water (15 mL), and extracted with ethyl acetate (10 mL × 3). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 9b (100 mg) as a black oil.

[0217] Compound 9b (100 mg, 202.09 μmol, 1 eq) was dissolved in dichloromethane (1 mL) and methanol (0.1 mL), and meta-chloroperoxybenzoic acid (41.03 mg, 202.09 μmol, purity 85%, 1 eq) was added at 0 °C, and stirred for 0.25 h. Sodium thiosulfate (20 mL) was added at 0 °C, cooled, and extracted with dichloromethane (10 mL × 3). Washed with brine (10 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 9 (21 mg, yield 20.34%) as a white solid.

[0218] 1 H NMR: 400 MHz, CDCl3

[0219] δ = 8.13 (d, J = 8 Hz, 1H), 7.61 (d, J = 8 Hz, 1H), 7.50 (t, 1H), 6.22 (s, 1H), 4.64 (d, J = 13.6 Hz, 1H), 4.33 (d, J = 13.6 Hz, 1H), 3.48 - 3.38 (m, 1H), 3.21 - 3.16 (m, 1H), 2.68 - 2.51 (m, 1H), 2.52 (s, 3H), 2.37 (s, 3H), 2.21 - 1.98 (m, 2H), 1.87 - 1.79 (m, 2H), 1.71 – 1.63 (m, 2H)

[0220] Example 10. Preparation of 1-(8-bromo-5-chloro-4-(cyclobutylamino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethanone (Compound 10)

[0221]

[0222] Cyclobutanamine (15.94 mg, 224.14 μmol, 19.21 μL, 1 eq) was dissolved in THF (1 mL), and triethylamine (340.21 mg, 3.36 mmol, 467.97 μL, 15 eq) and compound 10a (100 mg, 224.14 μmol, 1 eq) were added, and the mixture was stirred at 25 °C for 2 h. Water (5 mL) was added, cooled, and extracted with ethyl acetate (2 mL × 3). The organic layer was washed with brine (2 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 10b (75 mg) as a brown solid.

[0223] Compound 10b (37.5 mg, 77.99 μmol, 1 eq) was dissolved in dichloromethane (0.5 mL), and meta-chloroperoxybenzoic acid (15.83 mg, 77.99 μmol, purity 85%, 1 eq) was added at 0 °C and stirred for 0.5 h. The reaction mixture was prepared in the same manner as above in another vial. The two reaction mixtures were combined, and sodium thiosulfate (20 mL) solution was added at 0 °C, cooled, and extracted with dichloromethane (10 mL × 3). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 10 (29 mg, yield 37.42%) as a white solid.

[0224] 1 H NMR: 400 MHz, DMSO

[0225] δ = 8.12 (d, J = 8.3 Hz, 1H), 7.74 (br d, J = 7.8 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 6.21 (d, J = 0.6 Hz, 1H), 4.62 (d, J = 13.4 Hz, 1H), 4.32 (d, J = 13.4 Hz, 1H), 3.96 - 3.85 (m, 1H), 2.46 (s, 3H), 2.41 - 2.30 (m, 4H), 2.28 - 2.15 (m, 2H), 2.14 - 2.02 (m, 1H), 1.70 - 1.51 (m, 2H)

[0226] Example 11. Preparation of 1-(8-bromo-5-chloro-4-((cyclopentylmethyl)amino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethanone (Compound 11)

[0227]

[0228] Compound 11a (100 mg, 224.14 μmol, 1 eq) was dissolved in THF (1.5 mL), and triethylamine (340.21 mg, 3.36 mmol, 467.97 μL, 15 eq) and cyclopentylmethanamine (444.58 mg, 4.48 mmol, 20 eq) were added at 25 °C, and the mixture was stirred at 75 °C for 12 h. After cooling to 25 °C, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic layer was washed with brine (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 11b (110 mg) as a yellow solid.

[0229] Compound 11b (110 mg, 216.17 μmol, 1 eq) was dissolved in dichloromethane (1 mL) and methanol (0.1 mL), and meta-chloroperoxybenzoic acid (43.89 mg, 216.17 μmol, 2.60 μL, purity 85%, 1 eq) was added between 0 and 3 °C, and stirred at 25 °C for 1 h. Sodium thiosulfate solution (2.5 mL) was added, cooled, and extracted with dichloromethane (2 mL × 3). Washed with sodium bicarbonate solution (2.5 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 11 (21.9 mg, yield 19.30%) as a yellow solid.

[0230] 1 H NMR: 400 MHz, DMSO-d6

[0231] δ = 8.13 (d, J = 8.3 Hz, 1H), 7.67 (br t, J = 4.9 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 6.22 (s, 1H), 4.62 (d, J = 13.4 Hz, 1H), 4.30 (d, J = 13.4 Hz, 1H), 3.34 - 3.28 (m, 1H), 3.10 - 3.01 (m, 1H), 2.48 (br s, 3H), 2.36 (s, 3H), 2.25 - 2.17 (m, 1H), 1.75 - 1.64 (m, 2H), 1.56 - 1.44 (m, 4H), 1.20 - 1.06 (m, 2H)

[0232] Example 12. Preparation of 1-(8-bromo-5-chloro-4-(((1-hydroxycyclopropyl)methyl)amino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethanone (Compound 12)

[0233]

[0234] 1-(Aminomethyl)cyclopropan-1-ol (19.53 mg, 224.14 μmol, 1 eq) was dissolved in THF (1 mL), and triethylamine (226.81 mg, 2.24 mmol, 311.98 μL, 10 eq) and compound 12a (100 mg, 224.14 μmol, 1 eq) were added, and the mixture was stirred at 40 °C for 12 h. Water (20 mL) was added, cooled, and extracted with ethyl acetate (20 mL × 3). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 12b (80 mg, yield 71.84%) as a brown solid.

[0235] Compound 12b (40 mg, 80.51 μmol, 1 eq) was dissolved in dichloromethane (0.5 mL) and meta-chloroperoxybenzoic acid (16.35 mg, 80.51 μmol, purity 85%, 1 eq) was added at 0 °C, and the mixture was stirred for 0.5 h. The reaction mixture was prepared in the same manner as above in another vial. After combining the two reaction mixtures, sodium thiosulfate (20 mL) aqueous solution was added at 0 °C, cooled, and extracted with dichloromethane (10 mL × 3). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 12 (14 mg, yield 16.95%) as a white solid.

[0236] 1 H NMR: 400 MHz, DMSO

[0237] δ = 8.15 (d, J = 8.3 Hz, 1H), 8.04 - 7.96 (m, 1H), 7.63 (d, J = 8.3 Hz, 1H), 6.22 (s, 1H), 5.66 (s, 1H), 4.63 (d, J = 13.4 Hz, 1H), 4.28 (d, J = 13.4 Hz, 1H), 3.40 (dd, J = 3.1, 12.8 Hz, 1H), 3.18 (dd, J = 5.8, 12.8 Hz, 1H), 2.47 (s, 3H), 2.37 (s, 3H), 0.71 - 0.53 (m, 4H)

[0238] Example 13. Preparation of 1-(8-bromo-5-chloro-4-(dimethylamino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one (Compound 13)

[0239]

[0240] Compound 13a (200 mg, 421.76 μmol, 1 eq) was dissolved in THF (1.5 mL), N-methylmethanamine (2 M, 2.11 mL, 10 eq) was added at 25 °C, and the mixture was stirred at 75 °C for 2 h. After cooling to 25 °C, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic layer was washed with brine (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 13b (110 mg) as a yellow solid.

[0241] Compound 13b (71 mg, 147.05 μmol, 1 eq) was dissolved in dichloromethane (1 mL), and meta-chloroperoxybenzoic acid (29.85 mg, 147.05 μmol, purity 85%, 1 eq) was added, and the mixture was stirred at 25 °C for 0.5 h. Sodium thiosulfate solution (2.5 mL) was added at 0 °C, cooled, stirred for 5 min, and extracted with dichloromethane (2 mL × 3). The mixture was washed with sodium bicarbonate solution (2.5 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 13 (25.5 mg, yield 34.76%) as a white solid.

[0242] 1 H NMR: 400 MHz, CDCl3

[0243] δ = 7.96 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 6.18 (s, 1H), 4.62 - 4.49 (m, 1H), 4.40 (d, J = 13.5 Hz, 1H), 3.03 (s, 6H), 2.99 - 2.89 (m, 1H), 2.38 (s, 3H), 1.25 (d, J = 6.8 Hz, 3H), 1.17 (d, J = 7.0 Hz, 3H)

[0244] Example 14. Preparation of 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-(phenylamino)quinolin-3-yl)ethan-1-one (Compound 14)

[0245]

[0246] Compound 14a (300 mg, 672.43 μmol, 1 eq) was dissolved in dichloromethane (10 mL). At 20 °C, under nitrogen, meta-chloroperoxybenzoic acid (195.81 mg, 907.78 μmol, purity 80%, 1.35 eq) and methylsulfonyl chloride (9.72 g, 84.87 mmol, 6.57 mL, 1.2 eq) were added dropwise, and the mixture was stirred at 20 °C for 1 h. Water (20 mL) was added to the reaction mixture at 20 °C to stop the reaction, then diluted with EA (20 mL) and extracted with EA (20 mL × 2). The organic layer was washed with water (20 mL × 2), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, 0-20% EtOAc / PE) to obtain compound 14b (220 mg, 428.44 μmol, yield 63.72%, purity 90%) as a white solid.

[0247] Compound 14b (50 mg, 108.19 μmol, 1 eq) was dissolved in DMSO (1 mL), and DIEA (55.93 mg, 432.76 μmol, 75.38 μL, 4 eq) and aniline (60.45 mg, 649.15 μmol, 59.15 μL, 6 eq) were added, and the mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 14 (3.0 mg, yield 6.11%) as a yellow solid.

[0248] 1 H NMR: 400 MHz, CDCl3

[0249] δ = 8.39 (s, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.31 (br s, 1H), 7.22 (t, J = 8.0 Hz, 2H), 7.07 - 7.01 (m, 1H), 6.81 - 6.64 (m, 2H), 6.17 (s, 1H), 4.88 (s, 1H), 4.67 (s, 1H), 2.45 (s, 3H), 2.09 (s, 3H)

[0250] Example 15. Preparation of 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-((4-(trifluoromethyl)phenyl)amino)quinolin-3-yl)ethan-1-one (Compound 15)

[0251]

[0252] Compound 15a (200 mg, 448.28 μmol, 1 eq) is dissolved in DMSO (8 mL), and 4-(trifluoromethyl)aniline (288.92 mg, 1.79 mmol, 222.93 μL, 4 eq), DIEA (289.69 mg, 2.24 mmol, 390.41 μL, 5 eq), and CsF (136.19 mg, 896.57 μmol, 2 eq) are added to the mixture, and the mixture is stirred at 140 °C for 2 h. The reaction mixture is stopped by adding water (20 mL) at 20 °C, diluted with EA (20 mL), and extracted with EA (20 mL × 2). The organic layer was washed with water (20 mL × 2), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, 0–11% EtOAc / PE) to obtain compound 15b (220 mg, 428.44 μmol, yield 63.72%, purity 90%) as a yellow solid.

[0253] Compound 15b (50 mg, 87.60 μmol, 1 eq) was dissolved in dichloromethane (1 mL), and meta-chloroperoxybenzoic acid (24.56 mg, 113.87 μmol, purity 80%, 1.3 eq) was added, followed by stirring at 25 °C for 1 h. The reaction mixture was filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 15 (7.0 mg, yield 13.21%) as a yellow solid.

[0254] 1 H NMR: 400 MHz, CDCl3

[0255] δ = 8.10 - 7.97 (m, 1H), 7.58 - 7.46 (m, 3H), 7.32 - 7.29 (m, 1H), 6.98 - 6.81 (m, 2H), 6.24 (s, 1H), 4.69 - 4.56 (m, 2H), 2.40 (s, 3H), 2.33 (br s, 3H)

[0256] Example 16. 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-((4-(pentafluoro-λ 6 Preparation of -sulfaneyl)phenyl)amino)quinolin-3-yl)ethan-1-one (compound 16)

[0257]

[0258] Toluene (1 mL) was added to compound 16a (30 mg, 0.067 mmol, 1 eq) and 4-Aminophenylsulfur pentafluoride (88 mg, 0.403 mmol, 6 eq) and stirred at 150 °C for 4 hours. After cooling to room temperature, 4-Aminophenylsulfurpentafluoride (59 mg, 0.269 mmol, 4 eq) was added and stirred at 150 °C overnight. After the reaction was completed, extraction was performed with EA, dried over magnesium sulfate, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain compound 16b (22 mg, yield 52%).

[0259] Dichloromethane (1 mL) was added to compound 16b (8 mg, 0.013 mmol, 1 eq), meta-chloroperoxybenzoic acid (3.2 mg, 0.019 mmol, 1.5 eq), and potassium carbonate (2.6 mg, 0.019 mmol, 1.5 eq), and the mixture was stirred at 0 °C for 4 hours. After quenching the reaction with water, the mixture was extracted with EA, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to obtain compound 16 (7.8 mg, yield 95%).

[0260] 1 H NMR: 300 MHz, CDCl3

[0261] δ = 8.06 (d, 8.2 Hz), 7.73 (s, 1H), 7.63 (d, 9.2 Hz, 2H), 7.52 (d, 8.2 Hz, 1H), 6.77 (d, 8.7 Hz, 2H), 6.20 (s, 1H)

[0262] Example 17. Preparation of 1-(4-((4-(benzyloxy)phenyl)amino)-8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one (Compound 17)

[0263]

[0264] To a solution of 4-benzyloxyaniline (100.48 mg, 504.32 μmol, 1.5 eq) in DMF (2 mL) were added DIEA (130.36 mg, 1.01 mmol, 175.68 μL, 3 eq), compound 17a (150 mg, 336.21 μmol, 1 eq), and CsF (153.21 mg, 1.01 mmol, 3 eq), and the mixture was stirred at 100 °C for 2 h. The solid was filtered and dried in vacuo to obtain compound 17b (230 mg) as a yellow solid.

[0265] Compound 17b (180 mg, 295.60 μmol, 1 eq) was dissolved in dichloromethane (2 mL), and meta-chloroperoxybenzoic acid (108.02 mg, 532.08 μmol, purity 85%, 1.8 eq) was added, and the mixture was stirred at 15 °C for 1 h. The mixture was treated with brine (10 mL) and extracted with ethyl acetate (20 mL × 3). The organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, concentrated in vacuo, and purified by column chromatography to obtain compound 17 (18.4 mg, 27.05 μmol, yield 56.35%, purity 91.88%) as a yellow solid.

[0266] 1 H NMR: 400 MHz, CDCl3

[0267] δ = 8.68 - 9.03 (m, 1 H), 8.22 (d, 1 H), 7.97 (br d, 1 H), 7.31 - 7.47 (m, 7 H), 6.80 - 7.09 (m, 5 H), 6.29 (s, 1 H), 4.90 - 5.12 (m, 2) H), 4.35 - 4.64 (m, 2 H), 2.38 (s, 3 H), 2.16 (br s, 3 H)

[0268] Example 18. Preparation of 1-(4-((4-aminophenyl)amino)-8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one (Compound 18)

[0269]

[0270] tert-butyl N-(4-aminophenyl)carbamate (280.07 mg, 1.34 mmol, 5 eq) was dissolved in DMF (3 mL), and DIEA (104.29 mg, 806.91 μmol, 140.55 μL, 3 eq), compound 18a (120 mg, 268.97 μmol, 1 eq), and CsF (122.57 mg, 806.91 μmol, 3 eq) were added to the mixture, and the mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, diluted with brine (10 mL), and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, 0-30% EtOAc / PE) to obtain compound 18b (40 mg, 64.73 μmol, yield 24.07%, purity 100%) as a yellow solid.

[0271] Compound 18b (250 mg, 404.57 μmol, 1 eq) was dissolved in dichloromethane (3 mL), and meta-chloroperoxybenzoic acid (87.27 mg, 404.57 μmol, purity 80%, 1 eq) was added, and the mixture was stirred at 15 °C for 1 h. The mixture was treated with brine (10 mL) and extracted with ethyl acetate (20 mL × 3). The organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to obtain compound 18c (250 mg) as a dark brown solid.

[0272] Compound 18c (250 mg, 394.36 μmol, 1 eq) was dissolved in dichloromethane (5 mL), and TFA (44.97 mg, 394.36 μmol, 29.29 μL, 1 eq) was added, followed by stirring at 15 °C for 5 h. The mixture was evaporated and purified by column chromatography to obtain compound 18 (1.9 mg, 3.39 μmol, yield 1.51%, purity 95.17%) as a yellow solid.

[0273] 1 H NMR: 400 MHz, CDCl3

[0274] δ = 8.75 - 9.06 (m, 1 H), 7.90 - 8.19 (m, 1 H), 7.42 (d, 1 H), 6.93 (d, 2 H), 6.64 (d, 2 H), 6.30 (s, 1 H), 4.39 - 4.67 (m, 2 H), 2.40 (s, 3 H), 2.17 (br s, 3 H)

[0275] Example 19. Preparation of 4-((5,8-dichloro-3-isobutyryl-2-((pyrimidin-5-ylmethyl) sulfinyl)quinolin-4-yl)amino)benzoic acid (Compound 19)

[0276]

[0277] Dissolve tert-Butyl 4-aminobenzoate (997.59 mg, 5.16 mmol, 6 eq) in THF (10 mL), add NaHMDS (2 M, 1.72 mL, 4 eq) at 0 to 3 °C, and stir at 0 to 5 °C for 10 minutes. A solution of compound 19a (refer to Preparation Example 2 and the preparation method of published Korean Patent No. 10-1879992, etc.) (300 mg, 860.40 μmol, 1 eq) dissolved in THF (10 mL) is added dropwise to the mixture at 0 to 5 °C, and stirred at 25 °C under nitrogen for 1 hour. Treat the reaction mixture with water (50 mL) and extract with dichloromethane (50 mL × 3). The organic layer was concentrated under reduced pressure and then purified by column chromatography (SiO2, 0-30% EtOAc / PE) to obtain compound 19b (980 mg, 810.44 μmol, yield 94.19%, purity 41.8%) as a yellow solid.

[0278] Compound 19b (480 mg, 396.95 μmol, 1 eq) was dissolved in dichloromethane (5 mL), and meta-chloroperoxybenzoic acid (120.88 mg, 595.42 μmol, purity 85%, 1.5 eq) was added, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL × 3). The organic layer was concentrated under reduced pressure and then purified by column chromatography (SiO2, 0-25% EtOAc / PE) to obtain compound 19c (108 mg, 207.11 μmol, yield 52.18%) as a yellow oil.

[0279] Compound 19c (108 mg, 207.11 μmol, 1 eq) was dissolved in MeCN (2 mL), and TEA (62.87 mg, 621.34 μmol, 86.48 μL, 3 eq) and compound 19d (61.79 mg, 414.23 μmol, 2 eq, sodium salt) were added to the mixture, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography (SiO2, 0-30% EtOAc / PE) to obtain compound 19e (120 mg, 205.65 μmol, yield 99.29%) as a yellow solid.

[0280] Compound 19e (56 mg, 95.97 μmol, 1 eq) was dissolved in dichloromethane (2 mL), and meta-chloroperoxybenzoic acid (25.33 mg, 124.76 μmol, purity 85%, 1.3 eq) was added, and the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL × 3). The organic layer was concentrated under reduced pressure and then purified by column chromatography (SiO2, 0-50% EtOAc / PE) to obtain compound 19f (58.8 mg, 75.42 μmol, yield 78.59%, purity 76.9%) as a yellow solid.

[0281] Compound 19f (58.8 mg, 98.08 μmol, 1 eq) was dissolved in dichloromethane (3 mL), TFA (1 mL) was added, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was treated with water (10 mL) and extracted with dichloromethane (10 mL × 3). The organic layer was concentrated under reduced pressure and then purified by column chromatography (SiO2, 5–30% MeCN / H2O (0.0025% FA)) to obtain compound 19 (15.3 mg, 26.33 μmol, yield 26.84%, purity 93.51%) as a yellow solid.

[0282] 1 H NMR: 400 MHz, CDCl3

[0283] δ = 9.15 (s, 1 H), 8.64 (s, 2 H), 8.19 (s, 1 H), 7.99 (d, J=8.80 Hz, 2 H), 7.84 - 7.91 (m, 1 H), 7.58 (s, 1 H), 6.76 (br d, J=8.36 Hz, 2 H), 4.57 (br d, J=10.78 Hz, 2 H), 3.06 - 3.20 (m, 1 H), 0.89 (br d, J=7.04 Hz, 3 H), 0.74 (br d, J=6.60 Hz, 3 H)

[0284] Example 20. Preparation of 1-(5,8-dichloro-4-((4-(methylsulfonyl)phenyl)amino)-2-((pyrimidin-5-ylmethyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one (Compound 20)

[0285]

[0286] 4-Methylsulfonylaniline (220.97 mg, 1.29 mmol, 1.5 eq), compound 20a (300 mg, 860.40 μmol, 1 eq), XantPhos Pd G3 (81.60 mg, 86.04 μmol, 0.1 eq), Cs2CO3 (841.01 mg, 2.58 mmol, 3 eq) were mixed in toluene (3 mL), degassed, and purged with nitrogen three times, and the mixture was stirred at 100 °C under nitrogen for 16 h. The reaction mixture was treated with water (20 mL) at 25 °C to stop the reaction, diluted with water (50 mL), and extracted with EA (100 mL × 3). The organic layer was washed with brine (50 mL × 2), concentrated under reduced pressure, and purified by column chromatography (SiO2, 0–25% EtOAc / PE) to obtain compound 20b (193 mg, 399.23 μmol, yield 23.20%) as a white solid.

[0287] Compound 20b (220 mg, 455.08 μmol, 1 eq) was dissolved in dichloromethane (3 mL), and meta-chloroperoxybenzoic acid (138.59 mg, 682.62 μmol, purity 85%, 1.5 eq) was added, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL × 3). The organic layer was concentrated under reduced pressure and then purified by column chromatography (SiO2, 5–50% MeCN / H20 (0.0025% FA)) to obtain compound 20c (110 mg, 214.97 μmol, yield 47.24%, purity 97.6%) as a white solid.

[0288] Compound 20c (60 mg, 120.14 μmol, 1 eq) was dissolved in MeCN (1.5 mL), and TEA (36.47 mg, 360.41 μmol, 50.17 μL, 3 eq) and compound 20d (35.84 mg, 240.27 μmol, 2 eq, sodium salt) were added to the mixture, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography (SiO2, 0-35% EtOAc / PE) to obtain compound 20e (60 mg, 97.67 μmol, yield 81.30%, purity 91.4%) as a yellow solid.

[0289] Compound 20e (55 mg, 97.95 μmol, 1 eq) was dissolved in dichloromethane (2 mL), and meta-chloroperoxybenzoic acid (25.85 mg, 127.34 μmol, purity 85%, 1.3 eq) was added, and the mixture was stirred at 0 °C for 1 h. The reaction mixture was treated with water (10 mL) to stop the reaction, and then extracted with dichloromethane (10 mL × 3). The organic layer was concentrated under reduced pressure and purified by column chromatography (SiO2, 5–29% MeCN / H2O (0.0025% FA)) to obtain compound 20 (17.6 mg, 29.97 μmol, yield 30.60%, purity 98.338%) as a yellow solid.

[0290] 1 H NMR: 400 MHz, CDCl3

[0291] δ = 9.13 (s, 1 H), 8.57 (s, 2 H), 7.90 (d, J=8.36 Hz, 1 H), 7.85 (s, 1 H), 7.79 (d, J=8.58 Hz, 2 H), 7.59 (d, J=8.14 Hz, 1 H), 6.73 (d, J=8.58 Hz, 2 H), 4.58 (s, 2 H), 3.01 - 3.08 (m, 4 H), 0.86 (dd, J=9.13, 6.93 Hz, 6 H)

[0292] Example 21. 1-(5,8-dichloro-4-((4-(pentafluoro-λ 6 Preparation of -sulfaneyl)phenyl)amino)-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)ethan-1-one (compound 21)

[0293]

[0294] 4-(Pentafluoro-sulfanyl)aniline (410.16 mg, 1.87 mmol, 3 eq) is dissolved in DMF (3 mL) and NaH (62.38 mg, 1.56 mmol, purity 60%, 2.5 eq) is added at 0 to 3 °C, and the mixture is stirred at 0 to 5 °C for 10 minutes. To the mixture, a solution of compound 21a (refer to Preparation Example 1 and the preparation method of published Korean Patent No. 10-1879992, etc.) (200 mg, 623.79 μmol, 1 eq) dissolved in DMF (2.5 mL) is added dropwise at 0 to 5 °C and stirred at 25 °C under nitrogen for 1 hour. The reaction mixture was treated with water (20 mL) at 25 °C to stop the reaction, then diluted with water (50 mL) and extracted with EA (100 mL × 3). The organic layer was washed with brine (50 mL × 2), concentrated under reduced pressure, and purified by column chromatography (SiO2, 0–13% DCM / PE) to obtain compound 21b (169 mg, 335.76 μmol, yield 35.88%) as a yellow solid.

[0295] Compound 21b (149 mg, 296.02 μmol, 1 eq) was dissolved in dichloromethane (3.75 mL), and meta-chloroperoxybenzoic acid (150.25 mg, 740.06 μmol, purity 85%, 2.5 eq) was added, and the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (20 mL × 3). The organic layer was concentrated under reduced pressure and then purified by column chromatography (SiO2, 0–30% EtOAc / PE) to obtain compound 21c (34.7 mg, 54.01 μmol, yield 18.25%, purity 83.33%) as a white solid.

[0296] Compound 21c (34.7 mg, 64.82 μmol, 1 eq) was dissolved in MeCN (0.5 mL), and TEA (19.68 mg, 194.46 μmol, 27.07 μL, 3 eq) and compound 21d (17.52 mg, 129.64 μmol, 2 eq, sodium salt) were added, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography (SiO2, 0-30% EtOAc / PE) to obtain compound 21e (24.7 mg, 41.86 μmol, yield 64.57%, purity 96.15%) as a white solid.

[0297] Compound 21e (24.7 mg, 43.53 μmol, 1 eq) was dissolved in dichloromethane (1 mL), and meta-chloroperoxybenzoic acid (11.49 mg, 56.59 μmol, purity 85%, 1.3 eq) was added, and the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-30% EtOAc / DCM) to obtain compound 21 (12.2 mg, 20.29 μmol, yield 46.60%, purity 97%) as a yellow solid.

[0298] 1 H NMR: 400 MHz, CDCl3

[0299] δ = 9.25 - 9.42 (m, 3 H), 7.89 - 7.94 (m, 1 H), 7.85 - 7.89 (m, 1 H), 7.57 - 7.64 (m, 3 H), 6.64 - 6.74 (m, 2 H), 2.41 - 2.51 (m, 3 H)

[0300] Example 22. Preparation of 1-(5,8-dichloro-2-(pyrimidin-5-ylsulfinyl)-4-((3-(trifluoromethyl)cyclobutyl)amino)quinolin-3-yl)ethan-1-one (Compound 22)

[0301]

[0302] Compound 22a (see Preparation Example 1 and the preparation method of published Korean Patent No. 10-1879992, etc.) (1.6 g, 5.29 mmol, 1 eq) was added in portions to phosphoryl trichloride (13.16 g, 85.83 mmol, 8.00 mL, 16.21 eq), and the mixture was stirred at 100 °C under nitrogen for 1 hour. The reaction mixture was evaporated to remove phosphoryl trichloride, and then toluene (10 mL × 3) was added and evaporated to obtain a crude product. The crude product was dissolved in dichloromethane (3 mL) and purified by column chromatography (SiO2, 0-5% PE / EtOAc) to obtain compound 22b (1.5 g, 4.51 mmol, yield 85.09%, purity 96.3%) as a yellow solid.

[0303] A mixture of compound 22b (400 mg, 1.25 mmol, 1 eq), compound 22c (219.05 mg, 1.25 mmol, 1 eq, HCl), and Et3N (631.20 mg, 6.24 mmol, 868.23 μL, 5 eq) in THF (4 mL) and DMF (4 mL) was stirred at 55 °C for 20 h. The reaction mixture was evaporated and then purified by column chromatography (SiO2, 0–3% ethyl acetate / hexane) to obtain compound 22d (140 mg, 320.83 μmol, yield 25.72%, purity 97%) as a white solid.

[0304] Compound 22d (360 mg, 850.50 μmol, 1 eq) was dissolved in dichloromethane (10 mL) and treated portionwise with meta-chloroperoxybenzoic acid (431.67 mg, 2.13 mmol, purity 85%, 2.5 eq), and stirred at 25 °C for 2 h. The reaction mixture was treated with 15% aqueous potassium carbonate solution (15 mL) and water (5 mL), stirred for 30 min, filtered, and dried under high vacuum to obtain compound 22e (250 mg, 477.73 μmol, yield 56.17%, purity 87%) as a white solid.

[0305] A mixture of compound 22e (50 mg, 109.82 μmol, 1 eq), compound 22f (73.66 mg, 549.11 μmol, 5 eq), and Et3N (55.56 mg, 549.11 μmol, 76.43 μL, 5 eq) was added to CH3CN (0.5 mL) and DMF (1 mL) and stirred at 25 °C for 20 h. The reaction mixture was combined with another batch prepared in the same manner as above, evaporated, and purified by column chromatography (SiO2, 0-20% ethyl acetate / hexane) to give compound 22g (57 mg) as a yellow solid.

[0306] Compound 22 g (27 mg, 42.66 μmol, 1 eq) was dissolved in dichloromethane (1.5 mL) and treated portionwise with meta-chloroperoxybenzoic acid (9.53 mg, 46.93 μmol, purity 85%, 1.1 eq), and stirred at 25°C for 2 h. The reaction mixture was combined with another batch prepared in the same manner as above, treated with 15% aqueous potassium carbonate solution (5 mL) and water (5 mL), and stirred for 30 min. The mixture was filtered, washed with water (5 mL), dried under high vacuum, and purified by column chromatography (SiO2, 0-1.8% MeOH / DCM) to obtain compound 22 (20.8 mg, 40.53 μmol, purity 98.07%) as a white solid.

[0307] 1 H NMR: 400 MHz, CDCl3

[0308] δ = 9.31 (s, 2H), 9.28 (s, 1H), 7.80 - 7.73 (m, 1H), 7.68 - 7.54 (m, 1H), 7.52 - 7.46 (m, 1H), 4.19 - 3.74 (m, 1H), 2.99 - 2.75 (m, 1H), 2.74 - 2.67 (m, 1H), 2.67 - 2.64 (m, 3H), 2.62 - 2.53 (m, 1H), 2.45 - 2.23 (m, 1H), 2.21 - 2.00 (m, 1H)

[0309] Example 23. Preparation of 1-(5,8-dichloro-4-((4-(methylsulfonyl)phenyl)amino)-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)ethan-1-one (Compound 23)

[0310]

[0311] Compound 23b (320.41 mg, 1.87 mmol, 2 eq) is dissolved in THF (10 mL) and NaH (56.14 mg, 1.40 mmol, purity 60%, 1.5 eq) is added at 0–3 °C, and the mixture is stirred at 0–5 °C for 10 minutes. A solution of compound 23a (300 mg, 935.68 μmol, 1 eq) in THF (10 mL) is added dropwise to the mixture at 0–5 °C, and the mixture is stirred at 25 °C under nitrogen for 1 h. The reaction mixture is treated with water (20 mL) at 25 °C to stop the reaction, diluted with water (50 mL), and extracted with EA (100 mL × 3). The organic layer was washed with brine (50 mL × 2), concentrated under reduced pressure, and purified by column chromatography (SiO2, 5–70% MeCN / H2O (0.0025% FA)) to obtain compound 23c (70 mg, 139.15 μmol, yield 14.87%, purity 90.52%) as a yellow solid.

[0312] Compound 23c (70 mg, 153.72 μmol, 1 eq) was dissolved in dichloromethane (1 mL), and meta-chloroperoxybenzoic acid (62.42 mg, 307.44 μmol, purity 85%, 2 eq) was added, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (20 mL × 3). The organic layer was concentrated under reduced pressure and then purified by column chromatography (SiO2, 0-50% EtOAc / PE) to obtain compound 23d (56.2 mg, 114.48 μmol, yield 74.47%, purity 99.28%) as a white solid.

[0313] Compound 23d (56 mg, 114.90 μmol, 1 eq) was dissolved in MeCN (2 mL), and TEA (34.88 mg, 344.70 μmol, 47.98 μL, 3 eq) and compound 23e (31.06 mg, 229.80 μmol, 2 eq, sodium salt) were added, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography (SiO2, 0-60% EtOAc / PE) to obtain compound 23f (40 mg, 58.22 μmol, yield 50.67%, purity 75.6%) as a yellow solid.

[0314] Compound 23f (26 mg, 50.06 μmol, 1 eq) was dissolved in dichloromethane (3 mL), and meta-chloroperoxybenzoic acid (13.21 mg, 65.07 μmol, purity 85%, 1.3 eq) was added, and the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-30% EtOAc / DCM) to obtain compound 23 (18.4 mg, 32.04 μmol, yield 64.00%, purity 93.224%) as a yellow solid.

[0315] 1 H NMR: 400 MHz, CDCl3

[0316] δ = 9.33 (d, J=3.30 Hz, 3 H), 7.85 - 7.91 (m, 1 H), 7.79 (d, J=8.80 Hz, 2 H), 7.72 (br s, 1 H), 7.60 (d, J=8.14 Hz, 1 H), 6.74 (d, J=8.80) Hz, 2 H), 3.05 (s, 3 H), 2.50 (s, 3 H)

[0317] Example 24. Preparation of 1-(5,8-dichloro-2-(pyrimidin-5-ylsulfinyl)-4-(1H-pyrrol-1-yl)quinolin-3-yl)ethan-1-one (Compound 24)

[0318]

[0319] To a solution of pyrrole (125.55 mg, 1.87 mmol, 6 eq) in THF (5 mL) was added NaH (49.90 mg, 1.25 mmol, purity 60%, 4 eq.) at 0–3 °C, and the mixture was stirred at 0–5 °C for 10 minutes. A solution of compound 24a (100 mg, 311.89 μmol, 1 eq) in DMF (5 mL) was added dropwise to the mixture at 0–5 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was treated with water (10 mL) at 25 °C to stop the reaction, diluted with water (5 mL), and extracted with ethyl acetate (10 mL × 3). The organic layer was concentrated under reduced pressure by adding an aqueous NaCl solution (20 mL × 2), and then purified by column chromatography (SiO2, 0-1% EtOAc / PE) to obtain compound 24b (73 mg, 207.46 μmol, yield 66.51%, purity 99.82%) as a white solid.

[0320] Compound 24b (63 mg, 179.36 μmol, 1 eq.) was dissolved in dichloromethane (1 mL), and meta-chloroperoxybenzoic acid (91.04 mg, 448.40 μmol, purity 85%, 2.5 eq.) was added, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was stopped by adding water (10 mL) at 25 °C, diluted with water (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, 0-20% EtOAc / PE) to obtain compound 24c (56.8 mg, 148.21 μmol, yield 82.63%) as a white solid.

[0321] Compound 24c (51 mg, 133.07 μmol, 1 eq.) was dissolved in MeCN (2 mL), and TEA (40.40 mg, 399.22 μmol, 55.57 μL, 3 eq) and compound 24d (32.37 mg, 239.53 μmol, 1.8 eq, sodium salt) were added, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography (SiO2, 0-17% EtOAc / PE) to obtain compound 24e (42.8 mg, 103.06 μmol, yield 77.45%, purity 100%) as a white solid.

[0322] Compound 24e (37.8 mg, 91.02 μmol, 1 eq.) was dissolved in dichloromethane (1 mL), and meta-chloroperoxybenzoic acid (25.87 mg, 127.43 μmol, purity 85%, 1.4 eq.) was added, and the mixture was stirred at 0 °C for 1 h. The reaction mixture was treated with water (10 mL) and extracted with dichloromethane (10 mL × 3). The organic layer was concentrated under reduced pressure and then purified by column chromatography (SiO2, 5–50% MeCN / H2O (0.0025% FA)) to obtain compound 24 (22.4 mg, 51.94 μmol, yield 57.06%, purity 100%) as a white solid.

[0323] 1 H NMR: 400 MHz, CDCl3

[0324] δ = 9.33 (s, 1 H), 9.27 (s, 2 H), 7.90 (d, J=8.0 Hz, 1 H), 7.67 (d, J=8.0 Hz, 1 H), 6.70 - 6.66 (m, 2 H), 6.42 - 6.40 (m, 2 H), 2.09 (s, 3H)

[0325] Example 25. Preparation of 1-(5,8-dichloro-4-morpholino-2-(pyrimidin-5-ylsulfinyl) quinolin-3-yl)ethan-1-one (Compound 25)

[0326]

[0327] To a solution of compound 25a (100.00 mg, 311.89 μmol, 1 eq.) in THF (1 mL) and DMF (1 mL) were added TEA (263.00 mg, 1.56 mmol, 5 eq.) and compound 25b (135.86 mg, 1.56 mmol, 5 eq.), and the mixture was stirred at 65 °C for 16 h. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (SiO2, 0–1% EtOAc / PE) to obtain compound 25c (85 mg, 228.94 μmol, yield 73.40%, purity 100%) as a yellow solid.

[0328] Compound 25c (70 mg, 188.54 μmol, 1 eq.) was dissolved in dichloromethane (2 mL), and meta-chloroperoxybenzoic acid (65.07 mg, 320.51 μmol, purity 85%, 1.7 eq.) was added at 0 °C, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (2 mL) and extracted with dichloromethane (2 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (SiO2, 0-10% EtOAc / PE) to obtain compound 25d (60 mg, 148.78 μmol, yield 78.91%) as a white solid.

[0329] Compound 25d (50 mg, 123.98 μmol, 1 eq.) was dissolved in DMSO (2 mL), and DIEA (48.07 mg, 371.95 μmol, 64.79 μL, 3 eq.) and compound 25e (99.78 mg, 743.90 μmol, 6 eq.) were added, and the mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 Ml × 3). The organic layer was washed with water (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, 0-10% EtOAc / PE) to obtain compound 25f (25 mg, 57.43 μmol, yield 46.32%) as a yellow solid.

[0330] Compound 25f (22 mg, 50.54 μmol, 1 eq) was dissolved in dichloromethane (0.5 mL), and meta-chloroperoxybenzoic acid (15.39 mg, 75.81 μmol, 85% purity, 1.5 eq) was added, and the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, 5–30% MeCN / H2O (0.05% FA)) to obtain compound 25 (6.5 mg, 13.45 μmol, yield 26.61%, purity 93.39%) as a white solid.

[0331] 1 H NMR: 400 MHz, CDCl3

[0332] δ = 9.31 (s, 1H), 9.25 (s, 2H), 7.78 (d, J=8.1 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 3.85 (br s, 4H), 3.39 (br s, 4H), 2.90 - 2.83 (m, 3H)

[0333] Example 26. Preparation of 1-(5,8-dichloro-2-(pyrimidin-5-ylsulfinyl)-4-((4-(trifluoromethyl)phenyl)amino)quinolin-3-yl)ethan-1-one (Compound 26)

[0334]

[0335] Compound 26b (753.81 mg, 4.68 mmol, 5 eq) is dissolved in DMF (10 mL) and NaH (112.27 mg, 2.81 mmol, purity 60%, 3 eq) is added at 0 °C, and the mixture is stirred for 0.5 h. Compound 26a (300 mg, 935.68 μmol, 1 eq) dissolved in DMF (10 mL) is added to the reaction mixture and stirred at 0 °C for 1 h. The reaction mixture is treated with water (15 mL) and extracted with ethyl acetate (15 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, 0-5% EtOAc / PE) to obtain compound 26c (416 mg, 653.96 μmol, yield 69.89%, purity 70%) as a yellow solid.

[0336] Compound 26c (410 mg, 920.76 μmol, 1 eq) was dissolved in dichloromethane (10 mL), and meta-chloroperoxybenzoic acid (560.81 mg, 2.76 mmol, purity 85%, 3 eq) was added, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-15% EtOAc / PE) to obtain compound 26d (90 mg, 188.57 μmol, yield 20.48%) as a yellow solid.

[0337] Compound 26d (90 mg, 188.57 μmol, 1 eq) was dissolved in MeCN (2 mL), and TEA (57.24 mg, 565.70 μmol, 78.74 μL, 3 eq) and compound 26e (50.97 mg, 377.13 μmol, 2 eq, sodium salt) were added, and the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography (SiO2, 0-20% EtOAc / PE) to obtain compound 26f (50 mg, 98.17 μmol, yield 52.06%) as a yellow solid.

[0338] Compound 26f (37 mg, 72.64 μmol, 1 eq) was dissolved in dichloromethane (1 mL), and meta-chloroperoxybenzoic acid (17.70 mg, 87.17 μmol, 85% purity, 1.2 eq) was added, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-40% EtOAc / PE) to obtain compound 26 (16.2 mg, 29.92 μmol, yield 41.19%, purity 97.02%) as a white solid.

[0339] 1 H NMR: 400 MHz, CDCl3

[0340] δ = 9.36 (s, 2H), 9.34 - 9.31 (m, 1H), 9.32 (s, 1H), 8.24 - 8.17 (m, 1H), 8.21 (s, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.58 (d, J=8.3 Hz, 1H), 7.50 (d, J=8.5 Hz, 2H), 6.79 (d, J=8.5 Hz, 2H), 2.41 (s, 3H)

[0341] Example 27. Preparation of 1-(5,8-dichloro-2-((pyrimidin-5-ylmethyl)sulfinyl)-4-(1H-pyrrol-1-yl)quinolin-3-yl)ethan-1-one (Compound 27)

[0342] (1) Preparation of Pyrimidin-5-ylmethanethiol

[0343]

[0344] S-(Pyrimidin-5-ylmethyl)ethanethiol (150 mg, 891.71 μmol, 1 eq) was dissolved in methanol (3 mL), NaOMe (5.4 M, 247.70 μL, 1.5 eq) was added, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was adjusted to pH (6-7) with 2 N HCl / dioxane, then concentrated under reduced pressure to obtain Pyrimidin-5-ylmethanethiol (110 mg) as a brown solid.

[0345] (2) Preparation of 1-(5,8-dichloro-2-((pyrimidin-5-ylmethyl)sulfinyl)-4-(1H-pyrrol-1-yl)quinolin-3-yl)ethan-1-one (compound 27)

[0346]

[0347] Pyrimidin-5-ylmethanethiol (110 mg, 871.78 μmol, 2 eq) and TEA (132.32 mg, 1.31 mmol, 182.01 μL, 3 eq) were added to a solution of compound 27a (167.05 mg, 435.89 μmol, 1 eq) in MeCN (3 mL), and the mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography (SiO2, 0-20% EtOAc / PE) to obtain compound 27b (70 mg, 163.05 μmol, yield 37.41%) as a light yellow solid.

[0348] Compound 27b (67 mg, 156.06 μmol, 1 eq) was dissolved in dichloromethane (1 mL), and meta-chloroperoxybenzoic acid (31.68 mg, 156.06 μmol, purity 85%, 1 eq) was added, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography (SiO2, 0-25% EtOAc / PE) to obtain compound 27 (30 mg, 67.17 μmol, yield 43.04%, purity 99.7%) as a white solid.

[0349] 1 H NMR: 400 MHz, CDCl3

[0350] δ = 9.15 (s, 1H), 8.57 (br s, 2H), 7.93 (d, J=8.3 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 6.69 - 6.62 (m, 2H), 6.40 (t, J=2.1 Hz, 2H), 4.71 - 4.65 (m, 1H), 4.58 - 4.51 (m, 1H), 1.85 (s, 3H)

[0351] The compound structures and compound names of Examples 1 to 27 are as shown in Table 1 below.

[0352] Example structural compound name 1 1-(4-amino-8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one2 1-(8-bromo-5-chloro-4-(methylamino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one 3 1-(8-Bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-((2,2,2-trifluoroethyl)amino)quinolin-3-yl)ethan-1-one 4 1-(8-Bromo-5-chloro-4-((1-methyl-1H-1,2,4-triazol-3-yl)amino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one5 1-(8-bromo-5-chloro-4-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one6 1-(8-Bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-(pyridazin-4-ylamino)quinolin-3-yl)ethan-1-one7 1-(8-Bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-((((R)-oxetan-2-ylmethyl)amino)quinolin-3-yl)ethan-1-one8 1-(8-Bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-((((S)-oxetan-2-ylmethyl)amino)quinolin-3-yl)ethan-1-one9 1-(8-bromo-5-chloro-4-((cyclobutylmethyl)amino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one10 1-(8-bromo-5-chloro-4-(cyclobutylamino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one 11 1-(8-bromo-5-chloro-4-((cyclopentylmethyl)amino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one12 1-(8-bromo-5-chloro-4-(((1-hydroxycyclopropyl)methyl)amino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one13 1-(8-Bromo-5-chloro-4-(dimethylamino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one14 1-(8-Bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-(phenylamino)quinolin-3-yl)ethan-1-one15 1-(8-Bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-((4-(trifluoromethyl)phenyl)amino)quinolin-3-yl)ethan-1-one16 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-((4-(pentafluoro-lambda) 6 -sulfanyl)phenyl)amino)quinolin-3-yl)ethan-1-one 17 1-(4-((4-(benzyloxy)phenyl)amino)-8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one18 1-(4-((4-aminophenyl)amino)-8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one19 4-((5,8-dichloro-3-isobutyryl-2-((pyrimidin-5-ylmethyl)sulfinyl)quinolin-4-yl)amino)benzoic acid 20 1-(5,8-dichloro-4-((4-(methylsulfonyl)phenyl)amino)-2-((pyrimidin-5-ylmethyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one21 1-(5,8-dichloro-4-((4-(pentafluoro-lambda 6 -sulfanyl)phenyl)amino)-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)ethan-1-one 22 1-(5,8-dichloro-2-(pyrimidin-5-ylsulfinyl)-4-((3-(trifluoromethyl)cyclobutyl)amino)quinolin-3-yl)ethan-1-one23 1-(5,8-dichloro-4-((4-(methylsulfonyl)phenyl)amino)-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)ethan-1-one24 1-(5,8-dichloro-2-(pyrimidin-5-ylsulfinyl)-4-(1H-pyrrol-1-yl)quinolin-3-yl)ethan-1-one25 1-(5,8-dichloro-4-morpholino-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)ethan-1-one26 1-(5,8-dichloro-2-(pyrimidin-5-ylsulfinyl)-4-((4-(trifluoromethyl)phenyl)amino)quinolin-3-yl)ethan-1-one27 1-(5,8-dichloro-2-((pyrimidin-5-ylmethyl)sulfinyl)-4-(1H-pyrrol-1-yl)quinolin-3-yl)ethan-1-one

[0353] [Experimental Example]

[0354] Experimental Example 1. Stability Evaluation

[0355] The serum and hepatocyte metabolic stability of the compound of the present invention was evaluated. The evaluation was performed by introducing the compound of the present invention into fetal bovine serum (FBS) and human hepatoma cells (HepG2) and measuring the half-life.

[0356] Specifically, the evaluation was conducted in the following manner.

[0357] 1) HepG2 cells stabilized in a cell culture medium for about a week were suspended in a culture medium containing 10% FBS and placed in 1.5 ml microtubes at a density of 2 x 10 6 Two microtubes were prepared, each containing 200 μl of cells / 200 μl and 200 μl of culture medium containing 10% FBS without cells.

[0358] 2) Each compound was dissolved in DMSO to a concentration of 10 mM, and a 100-fold diluted solution was prepared using the culture medium.

[0359] 3) 200 μl of the compound solution diluted in the culture medium was added to each microtube prepared in 1) and mixed using a vortex for 1 minute.

[0360] 4) One microtube containing a mixture of culture medium and compound solution and one microtube containing a mixture of culture medium and compound solution containing cells were placed in a cell incubator.

[0361] 5) 600 μl of cold acetonitrile was added to one microtube containing the culture medium and compound solution without cells and mixed using a vortex for 5 minutes.

[0362] 6) Centrifuge at 13,000 rpm for 3 minutes and filter the supernatant through a 0.2 μm filter.

[0363] 7) The spectral area of ​​the introduced compound was measured using HPLC (Agilent HPLC 1260). This was used as the reference concentration.

[0364] 8) After 30 minutes, the microtube placed in the incubator was removed from the incubator, 600 μl of acetonitrile was added, and vortex was used to mix for 5 minutes.

[0365] 9) Centrifuge at 13,000 rpm for 3 minutes and filter the supernatant through a 0.2 μm filter.

[0366] 10) The spectral area of ​​the introduced compound was measured using HPLC (Agilent HPLC 1260). The spectral area of ​​the microtube without cells was taken as the plasma concentration, and the spectral area of ​​the microtube with cells was taken as the hepatocyte metabolic concentration.

[0367] 11) The plasma half-life was calculated by comparing the plasma concentration with the reference concentration, and the hepatocyte metabolic half-life was calculated by comparing the hepatocyte metabolic concentration with the plasma concentration.

[0368] 12) The experimental results were calculated as the half-life of each compound, and this is shown in Table 2. A half-life of 0.1 hours or more is known to be effective, less than 0.2 hours is considered average, 0.2 to 1 hours is considered excellent, and more than 1 hour is considered very excellent. 10058-F4 (CAS 403811-55-2, compound 28) and VPC-70619 (CAS 2361742-30-3, compound 29), which are used as Myc transcription factor inhibitors, were used as control compounds.

[0369] [Compound 28]

[0370]

[0371] [Compound 29]

[0372]

[0373] Example Stability Evaluation (Half-life) Plasma Stability Liver Metabolic Stability 1> 24 hours 0.26 hours 2> 24 hours 1.78 hours 3> 24 hours 1.3 hours 412.7 hours 1.08 hours 5> 24 hours 0.62 hours 64.6 hours 1.95 hours 7> 24 hours 0.84 hours 8> 24 hours 0.5 hours 9> 24 hours 0.39 hours 115.3 hours > 24 hours 12> 24 hours 8.56 hours 13> 24 hours 0.72 hours 14> 24 hours > 24 hours 15> 24 hours 3.68 hours 16> 24 hours 5.36 hours 17> 24 hours 6.29 hours 18> 24 hours 2.2 hours 19> 24 hours > 24 hours 208.7 hours 13.4 hours 213.3 hours 0.25 Time 222.63 Time 1.09 Time 233.5 Time 0.28 Time 240.9 Time < 0.1 Time 251.2 Time 0.68 Time 263.2 Time 0.27 Time 274.6 Time 0.57 Time 28 (Control compound 10058-F4) > 24 Hours > 24 Hours 29 (Control compound VPC-70619) > 24 Hours > 24 Hours

[0374] From the results in Table 2 above, it was confirmed that most of the compounds of the present invention had effective half-lives. Specifically, the effects were notably confirmed in Examples 2, 3, 4, 6, 11, 12, 14 to 20, and 22.

[0375] Experimental Example 2. Evaluation of Transcription Factor Activity

[0376] The inhibitory effect of the compound of the present invention on c-Myc transcription factor activity in cancer cells was evaluated. The evaluation was performed by introducing the compound of the present invention into human lung cancer cells (NCI-H1299 and NCI-H23) using Lipofectamie® with pGL4.47[luc2P / MYC / Hygro] Vector and pNL[NLucP / CMVd3 / Neo] Vector (Promega, CS186807), and measuring the activity of reporter luciferase.

[0377] Specifically, the evaluation was conducted in the following manner.

[0378] 1) After stabilizing the reporter vector-transduced cells for about 3 days, 9 x 10 were seeded in a 24-well plate (NUNC, 24well multidish 142475). 3 / 1 ml / well was added and cultured, and wells containing only culture medium without cells were set as blank.

[0379] 2) Each compound was dissolved in DMSO to prepare a concentration of 10 mM, and the culture medium did not contain each compound solution or was diluted 100,000 to 3,333 times to prepare a concentration of 0.01 to 3 μM.

[0380] 3) After 22 hours, the existing cell culture medium was removed from the 24-well plate, and 800 μl of the culture medium containing the diluted compound was treated.

[0381] 4) After culturing in a cell incubator for an additional 6 hours, the cell culture medium was removed from each well of the plate and treated with Nano-Glo®Dual-Luciferase® Reporter Assay System (Promega, N1610) solution according to the seller's instructions.

[0382] 5) Luciferase activity was measured using a luminometer (Tecan, Spark®).

[0383] 6) The experimental results are shown in Table 3. IC calculated through luciferase measurement 50 It is known to be effective when the concentration is less than 100 μM, 3 to 100 μM is considered moderate (+), 1 to 3 μM is considered good (++), and less than 1 μM is considered very good (+++). As control compounds, 10058-F4 (CAS 403811-55-2, compound 28) and VPC-70619 (CAS 2361742-30-3, compound 29), which are used as Myc transcription factor inhibitors, were used.

[0384] Example Reporter Assay (μM) Cell Line NCI-H1299 NCI-H23 1++2++3++++4++5++6++++7++8++9++10+++11+++12++13++++14++15+++++16+++++17++18++19++20++21++++++22+++23++++++24++++++25++++26++++++27+++++28 (Control compound 10058-F4)++29 (Control compound VPC-70619)++

[0385] This experimental example was conducted by introducing a vector into lung cancer cells, NCI-H1299 and NCI-H23, and measuring luciferase activity to determine whether the compounds of the present invention can directly inhibit the activity of the c-Myc transcription factor protein. From the results in Table 3 above, it was confirmed that the compounds of the present invention have the effect of directly inhibiting the activity of the c-Myc transcription factor protein.

[0386] Experimental Example 3. Evaluation of Anticancer Activity

[0387] To evaluate the anticancer activity of the compound of the present invention, two types of lung cancer cells (NCI-H1299 and NCI-H23) and two types of blood cancer cells (Daudi and jurkat) were cultured in a 96-well plate (COSTAR, 3903 white plate) and evaluated using the CellTiter-Glo® Luminescent Cell Viability Assay kit (Promega, G7570).

[0388] Specifically, the evaluation was conducted in the following manner.

[0389] 1) NCI-H1299, NCI-H23, Daudi and jurkat cancer cells stabilized in a cell culture medium for about a week were seeded at 7 x 10 each in a 96-well plate (COSTAR, 3903 white plate). 2 / 100 μl / well, 2 x 10 3 / 100 μl / well, 3 x 103 / 100 μl / well, 3 x 10 3 Culture was performed to reach / 100 μl / well, and wells containing only culture medium without cells were measured as blanks.

[0390] 2) Each compound was dissolved in DMSO to prepare a concentration of 10 mM, and the solution of each compound was not added to the culture medium or was diluted 166,666 to 500 times to prepare a concentration of 0.06 to 20 μM.

[0391] 3) After 24 hours, 100 μl of culture medium containing diluted compounds was added to the 96-well plate without removing the existing cell culture medium, so that the concentration of each compound was 0.03 to 10 μM.

[0392] 4) After culturing in a cell incubator for an additional 24 or 72 hours, the cell culture medium was removed from each well of the plate and processed using the CellTiter-Glo® Luminescent Cell Viability Assay kit according to the seller's instructions.

[0393] 5) After shaking for 30 minutes at room temperature, ATP of viable cells was measured using a luminometer (Tecan, Spark®).

[0394] 6) The experimental results are shown in Tables 4 and 5. IC for cancer cell survival inhibition calculated through ATP measurement 50 It is known to be effective when the concentration is less than 100 μM, 10 to 100 μM is considered moderate (+), 1 to 10 μM is considered good (++), and less than 1 μM is considered very good (+++). As control compounds, 10058-F4 (CAS 403811-55-2, compound 28) and VPC-70619 (CAS 2361742-30-3, compound 29), which are used as Myc transcription factor inhibitors, were used.

[0395] Example Cell Viability Assay (μM, 24 hours) Cell Line NCI-H1299 NCI-H23 Jurkat Daudi 1++++2++++++++3++++++++4++++5++++++6+++++++++7+++++++8+++++++9++++++++10+++++++++11++++++++12+++++++13++++++++14++++15+++++++16++N / A++++17+++++++18++++++++19++++20++++21++++++++++++22+++++++23+++++++++++24++++++++++++25++++++++26++++++++++27+++++++++28 (Control compound 10058-F4)++++29 (Control compound VPC-70619)+++++

[0396] Example Cell Viability Assay (μM, 72 hours) Cell Line NCI-H1299 NCI-H23 Jurkat Daudi 1++++++2++++++++3++++++++4++++5++++++++6+++++++++7++++++++8++++++9++++++++10++++++++11++++++++12++++++++13++++++++14++++15++++++++16++++++++17++++++++18++++++++19++++20++++21++++++++++++22++++++++23+++++++++++24++++++++++++25+++++++26++++++++++27++++++++28 (Control compound 10058-F4)++++29 (Control compound VPC-70619)++++++

[0397] From the results in Tables 4 and 5 above, it was confirmed that the compounds of the present invention significantly induce cell death in cell lines with specific activity toward c-Myc among solid cancer (lung cancer) and blood cancer cells.

[0398] The specification omits detailed descriptions of matters that would be readily apparent and inferred by those skilled in the art. Furthermore, various modifications, other than the specific examples described herein, are possible without altering the technical spirit or essential configuration of the invention. Therefore, the present invention may be practiced in ways other than those specifically described and exemplified herein, as will be readily apparent to those skilled in the art.

Claims

1. A compound represented by the following chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, R 1 and R 4 are each independently, OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-10 Haloalkenyl, C 2-6 Alkynyl, C 2-10 Haloalkynyl, cyano, nitro, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxycarbonyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, amino(C 1-6 )alkyl, (C 1-6 )Alkylamino(C 1-6 )alkyl, C 1-6 Alkanoyl, C 1-6 Alkylsulfonyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 6-12 Any one selected from the group consisting of aryl and 5 to 10 membered heteroaryl, R 2 and R 3 are each independently hydrogen, OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-10 Haloalkenyl, C 2-6 Alkynyl, C 2-10 Haloalkynyl, cyano, nitro, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxycarbonyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, amino(C 1-6 )alkyl, (C 1-6 )Alkylamino(C 1-6 )alkyl, C 1-6 Alkanoyl, C 1-6 Alkylsulfonyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 6-12 Any one selected from the group consisting of aryl and 5 to 10 membered heteroaryl, R 5 is NR a R b And, Here the above R a and R b are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylene-C 1-6 Haloalkyl, C 6-12 Aryl, C 3-10 Cycloalkyl, 5 to 10 membered heteroaryl, C 3-10 Heterocycloalkyl, C 1-6 Alkylene-C 6-12 Aryl, C 1-6 Alkylene-C 3-10 Cycloalkyl, C 1-6 Alkylene-5 to 10 membered heteroaryl, C 1-6 Alkylene-C 3-10 Heterocycloalkyl, C 6-12 Aryl-C 1-6 Alkylene-C 6-12 Aryl, and C 6-12 Aryl-OC 1-6 Alkylene-C 6-12 Any one selected from the group consisting of aryl, or or the above NR a R b R of a Wow R b are bonded to each other to form a 5 to 10 membered heteroaryl or C 3-10 Forming a heterocycloalkyl, Here the above C 6-12 Aryl, C 3-10 Cycloalkyl, 5 to 10 membered heteroaryl, and C 3-10 Heterocycloalkyl is C 1-6 Alkyl, OH, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, Amino, COOH, C 1-6 Alkylsulfonyl, C 6-12 which may be substituted with any one selected from the group consisting of arylsulfonyl, sulfanyl and halosulfanyl, R 6 Silver C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, and NR c R d is one selected from the group consisting of , where R c and R d are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkylene-OC 1-6 It is alkyl, n is 1 or 2, L is a bond, or unsubstituted or substituted C 1-6 It is alkylene, Het is an unsubstituted or substituted 5 to 10-membered heteroaryl or an unsubstituted or substituted 8 to 12-membered biheteroaryl, The above L and Het are each independently halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, OH, NO 2 ,CN and NH 2 may be substituted by one or more selected from the group consisting of .

2. In paragraph 1, Above R 1 and R 4 are each independently, OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Cyano, Nitro, C 1-6 Alkoxy, C 1-6 Haloalkoxy, amino, C 1-6 Alkylamino, amino(C 1-6 )alkyl, C 1-6 Alkylsulfonyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 6-12 Any one selected from the group consisting of aryl and 5 to 10 membered heteroaryl, Above R 2 and R 3 are each independently hydrogen, OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Cyano, Nitro, C 1-6 Alkoxy, C 1-6 Haloalkoxy, amino, C 1-6 Alkylamino, amino(C 1-6 )alkyl, C 1-6 Alkylsulfonyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 6-12 Any one selected from the group consisting of aryl and 5 to 10 membered heteroaryl, Above R 5 is NH 2 , NH-C 1-6 Alkyl, N-(C 1-6 alkyl) 2 , NH-(C 1-6 alkylene)-(C 1-6 Haloalkyl), NH-(C 6-12 Aryl), NH-C 3-10 Cycloalkyl, NH-5 to 10 membered heteroaryl, NH-C 3-10 Heterocycloalkyl, NH-(C 1-6 alkylene)-C 3-10 Cycloalkyl, NH-(C 1-6 alkylene)-(5 to 10 membered heteroaryl), NH-(C 1-6 alkylene)- C 3-10 Heterocycloalkyl, NH-(C 6-12 Aryl)-O-(C 1-6 alkylene)-(C 6-12 Aryl), 5 to 10 membered heteroaryl containing 1 or more N, and C containing 1 or more N 3-10 Any one selected from the group consisting of heterocycloalkyl, Here the above C 6-12 Aryl, C 3-10 Cycloalkyl, 5 to 10 membered heteroaryl, and C 3-10 Heterocycloalkyl is C 1-6 Alkyl, OH, C 1-6 Haloalkyl, amino, COOH, C 1-6 which may be substituted with any one selected from the group consisting of alkylsulfonyl, and halosulfanyl, Above R 6 Silver C 1-6 Alkyl or C 1-6 It is haloalkyl, n is 1, A compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

3. In paragraph 1 or 2, The above Het is any one selected from the group consisting of piperazinyl, pyrrolidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl and pyrrolopyridinyl. A compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

4. In any one of paragraphs 1 to 3, Above R 1 and R 4 are each independently Cl or Br, A compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

5. In any one of paragraphs 1 to 4, Above R 2 and R 3 is hydrogen, A compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

6. In any one of paragraphs 1 to 5, Above R 5 Is , , , , , , , , , , , , , , , , , , , , , and is one selected from the group consisting of, Above R 6 is CH 3 or C(CH 3 ) 2 person, A compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

7. In any one of paragraphs 1 to 6, The above L-Het , and Any one selected from the group consisting of, A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

8. In paragraph 1, The compound represented by the above chemical formula 1 is any one selected from the group consisting of the compounds described below, a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: (1) 1-(4-amino-8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one, (2) 1-(8-bromo-5-chloro-4-(methylamino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one, (3) 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-((2,2,2-trifluoroethyl)amino)quinolin-3-yl)ethan-1-one, (4) 1-(8-bromo-5-chloro-4-((1-methyl-1H-1,2,4-triazol-3-yl)amino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one, (5) 1-(8-bromo-5-chloro-4-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one, (6) 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-(pyridazin-4-ylamino)quinolin-3-yl)ethan-1-one, (7) 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-((((R)-oxetan-2-ylmethyl)amino)quinolin-3-yl)ethan-1-one, (8) 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-((((S)-oxetan-2-ylmethyl)amino)quinolin-3-yl)ethan-1-one, (9) 1-(8-bromo-5-chloro-4-((cyclobutylmethyl)amino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one, (10) 1-(8-bromo-5-chloro-4-(cyclobutylamino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one, (11) 1-(8-bromo-5-chloro-4-((cyclopentylmethyl)amino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one, (12) 1-(8-bromo-5-chloro-4-(((1-hydroxycyclopropyl)methyl)amino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one, (13) 1-(8-bromo-5-chloro-4-(dimethylamino)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one, (14) 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-(phenylamino)quinolin-3-yl)ethan-1-one, (15) 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-((4-(trifluoromethyl)phenyl)amino)quinolin-3-yl)ethan-1-one, (16) 1-(8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-((4-(pentafluoro-lambda 6 -sulfanyl)phenyl)amino)quinolin-3-yl)ethan-1-one, (17) 1-(4-((4-(benzyloxy)phenyl)amino)-8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one, (18) 1-(4-((4-aminophenyl)amino)-8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one, (19) 4-((5,8-dichloro-3-isobutyryl-2-((pyrimidin-5-ylmethyl)sulfinyl)quinolin-4-yl)amino)benzoic acid, (20) 1-(5,8-dichloro-4-((4-(methylsulfonyl)phenyl)amino)-2-((pyrimidin-5-ylmethyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one, (21) 1-(5,8-dichloro-4-((4-(pentafluoro-lambda 6 -sulfanyl)phenyl)amino)-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)ethan-1-one, (22) 1-(5,8-dichloro-2-(pyrimidin-5-ylsulfinyl)-4-((3-(trifluoromethyl)cyclobutyl)amino)quinolin-3-yl)ethan-1-one, (23) 1-(5,8-dichloro-4-((4-(methylsulfonyl)phenyl)amino)-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)ethan-1-one, (24) 1-(5,8-dichloro-2-(pyrimidin-5-ylsulfinyl)-4-(1H-pyrrol-1-yl)quinolin-3-yl)ethan-1-one, (25) 1-(5,8-dichloro-4-morpholino-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)ethan-1-one, (26) 1-(5,8-dichloro-2-(pyrimidin-5-ylsulfinyl)-4-((4-(trifluoromethyl)phenyl)amino)quinolin-3-yl)ethan-1-one, and (27) 1-(5,8-dichloro-2-((pyrimidin-5-ylmethyl)sulfinyl)-4-(1H-pyrrol-1-yl)quinolin-3-yl)ethan-1-one.

9. A compound according to any one of claims 1 to 8, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition for inhibiting c-Myc transcription factor protein.

10. A compound according to any one of claims 1 to 8, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition for preventing or treating cancer.

11. In paragraph 10, The above cancer is caused by overexpression or overactivation of the c-Myc transcription factor protein. A pharmaceutical composition for preventing or treating cancer.

12. In clause 10 or 11, The above cancer is at least one selected from the group consisting of lung cancer, colon cancer, colon cancer, rectal cancer, breast cancer, bladder cancer, blood cancer, leukemia, myeloid leukemia, lymphoma, cervical carcinoma, osteosarcoma, glioblastoma, melanoma, pancreatic cancer, stomach cancer, liver cancer, kidney cancer, gallbladder cancer, bile duct cancer, prostate cancer, esophageal cancer, ovarian cancer, and neuroblastoma. A pharmaceutical composition for preventing or treating cancer.

Images