Novel quinoline derivative 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 is a novel compound that inhibits the activity of a c-Myc transcription factor protein, and has a significant effect in preventing, alleviating, or treating diseases (in particular, 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” refers to a straight-chain or branched alkoxy group bonded to C(=O). Examples thereof include, but are not limited to, C(O)OCH3, C(O)OCH2CH3, and C(O)OCH2CH2CH3.

[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 R bare 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 present invention, the term "tree (C 1-6 Alkyl)silylethynyl" is a silyl group in which three hydrogen atoms are connected to a straight or branched C 1-6 It represents an ethynyl group (HC≡C) substituted with an alkyl group and connected to an alkylsilyl group. Examples thereof include, but are not limited to, a trimethylsilylethynyl group, a tert-butyldimethylsilylethynyl group, a triethylsilylethynyl group, an isopropyldimethylsilylethynyl group, and a triisopropylsilylethynyl group.

[0033] In the present invention, the term “halosulfanyl” refers to sulfur having one or more halogen substituents.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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, etc.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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:

[0044]

[0045] 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.

[0046] 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.

[0047]

[0048] Novel quinoline derivatives, optical isomers thereof, or pharmaceutically acceptable salts thereof

[0049] 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:

[0050] [Chemical Formula 1]

[0051]

[0052] In the above chemical formula 1,

[0053] R1 to R4 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 Aryl, 5- to 10-membered heteroaryl and tri(C 1-6 Any one selected from the group consisting of alkyl)silylethynyl,

[0054] R5 is hydrogen, OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 1-6 Alkoxy, C 1-6 Haloalkoxy and -OC 6-12 Any one selected from the group consisting of aryl-halosulfanyl,

[0055] R6 is hydrogen, halogen, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Any one selected from the group consisting of alkylene-O-amine and C(O)-R7, wherein R7 is C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, and NR a R b is one selected from the group consisting of , where R a and R b are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkylene-OC 1-6 It is alkyl,

[0056] n is 1 or 2,

[0057] L is a bond, or unsubstituted or substituted C 1-6 It is alkylene,

[0058] Het is an unsubstituted or substituted 5 to 10-membered heteroaryl or an unsubstituted or substituted 8 to 12-membered biheteroaryl,

[0059] Here, L and Het are each independently halogen, C 1-6 Alkyl, C 1-6 which may be substituted with one or more selected from the group consisting of haloalkyl, OH, NO2, CN and NH2,

[0060] However, if R5 is OH, R7 is NR a R b am.

[0061] Specifically, the above R1 to R4 are each independently hydrogen, 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, C1-6 Alkylsulfonyl, C 3-10 Cycloalkyl and tri(C 1-6 Any one selected from the group consisting of alkyl)silylethynyl,

[0062] The above R6 is C 1-6 Alkyl, C 1-6 Alkylene-O-amine, C(O)-C 1-10 Alkyl, C(O)-C 1-6 Alkylamine, C(O)-C 3-10 Cycloalkyl, C(O)-N-(C 1-6 alkyl)2, C(O)-NH-(C 1-6 alkylene)-O-(C 1-6 alkyl) and C(O)-NH-(C 1-6 Any one selected from the group consisting of alkyl),

[0063] n can be 1.

[0064] 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.

[0065] 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.

[0066] More specifically, each of R1 to R4 may be independently any one selected from the group consisting of hydrogen, CH3, C≡CH, Cl, Br, cyano, C≡C-Si(CH3)3, and SO2CH3.

[0067] More specifically, the above R5 is hydrogen, OH, Cl, CH3, CF3, CN, OCH3, OCH2CH3, and is one selected from the group consisting of,

[0068] The above R6 is CH3, , , , , , and It can be any one selected from the group consisting of .

[0069]

[0070] 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:

[0071]

[0072] (1) 1-(8-bromo-4,5-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one,

[0073] (2) 1-(8-bromo-4,5-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one,

[0074] (3) 1-(4,5-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-8-((trimethylsilyl)ethynyl)quinolin-3-yl)-2-methylpropan-1-one,

[0075] (4) 1-(4,5-dichloro-8-ethynyl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one,

[0076] (5) 4,5,8-Trichloro-N,N-dimethyl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinoline-3-carboxamide,

[0077] (6) 1-(4,5,8-trichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one,

[0078] (7) 4,5,8-Trichloro-N,N-dimethyl-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfinyl)quinoline-3-carboxamide,

[0079] (8) 1-(4,5,8-trichloro-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1one,

[0080] (9) 4,5,8-Trichloro-N-(2-methoxyethyl)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinoline-3-carboxamide,

[0081] (10) 1-(4,5,8-trichloro-2-((pyrimidin-5-ylmethyl)sulfinyl)quinolin-3-yl)ethan-1-one,

[0082] (11) Cyclopropyl(4,5,8-trichloro-2-((pyrimidin-5-ylmethyl)sulfinyl)quinolin-3-yl)methan-1-one,

[0083] (12) 2-methyl-1-(4,5,8-trichloro-2-((2-(pyrimidin-5-yl)ethyl)sulfinyl)quinolin-3-yl)propan-1-one,

[0084] (13) Cyclopropyl(4,5,8-trichloro-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)methan-1-one,

[0085] (14) 4,8-dichloro-3-isobutyryl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinoline-5-carbonitrile,

[0086] (15) 1-(4,8-dichloro-5-methyl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one,

[0087] (16) 1-(4,5,8-trichloro-2-((1-methyl-1H-pyrazol-3-yl)sulfinyl)quinolin-3-yl)ethan-1-one,

[0088] (17) 1-(4,8-dichloro-5-methyl-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)ethan-1-one,

[0089] (18) 4,5,8-trichloro-3-methyl-2-(pyrimidin-5-ylsulfinyl)quinoline,

[0090] (19) 3-(1-(aminooxy)-2-methylpropyl)-8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-4-ol,

[0091] (20) 8-bromo-5-chloro-4-hydroxy-N-methyl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinoline-3-carboxamide,

[0092] (21) 5,8-dichloro-3-methyl-2-(pyrimidin-5-ylsulfinyl)quinolin-4-ol,

[0093] (22) 1-(8-bromo-5-chloro-4-methoxy-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one,

[0094] (23) 1-(8-bromo-5-chloro-4-(difluoromethoxy)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one,

[0095] (24) 1-(5,8-dichloro-4-ethoxy-2-((3-(pyrimidin-5-yl)propyl)sulfinyl)quinolin-3-yl)ethan-1-one,

[0096] (25) 1-(5,8-dichloro-4-(4-(pentafluoro-lambda 6 -sulfanyl)phenoxy)-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)ethan-1-one,

[0097] (26) 1-(5,8-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one,

[0098] (27) 1-(5,8-dichloro-4-methyl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one,

[0099] (28) 1-(5,8-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-(trifluoromethyl)quinolin-3-yl)-2-methylpropan-1-one,

[0100] (29) 1-(8-chloro-5-methyl-2-(pyrimidin-5-ylsulfinyl)-4-(trifluoromethyl)quinolin-3-yl)ethan-1-one,

[0101] (30) 5,8-dichloro-3-isobutyryl-2-((pyrimidin-5-ylmethyl)sulfinyl)quinoline-4-carbonitrile, and

[0102] (31) 1-(8-chloro-4-hydroxy-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-5-(methylsulfonyl)quinolin-3-yl)-2-methylpropan-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] In addition, 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 alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and evaporating and drying the filtrate. At this time, 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). In addition, the present invention includes not only the compound represented by Chemical Formula 1 and a pharmaceutically acceptable salt thereof, 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] [Example]

[0143] Example 1. Preparation of 1-(8-bromo-4,5-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethanone (compound 1)

[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)sulfinyl)quinolin-3-yl)ethan-1-one (compound 1)

[0148]

[0149] Compound 1a (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 the mixture is stirred at 15 °C for 12 h. The mixture is additionally prepared in four vials in the same manner as above. The five vial batches are combined, filtered, and washed with sodium bicarbonate (100 mL) and brine (100 mL). The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1b (20 g, yield 66.46%) as a yellow oil.

[0150] Dissolve sodium hydride (3.86 g, 96.57 mmol, purity 60%, 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) dissolved in THF (90 mL) dropwise to the above reaction mixture at 0 to 3 °C, and stir at 0 °C for 0.5 h. Add a solution of compound 1b (20 g, 80.47 mmol, 1 eq) dissolved in THF (90 mL) dropwise to the above reaction mixture at 0 to 5 °C, and stir for 0.5 h.

[0151] Compound 1c (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 0–3 °C, and the mixture was stirred at 15 °C for 12 h. 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 compound 1d (30 g, yield 63.07%) as a yellow oil.

[0152] Compound 1d (1 g, 2.18 mmol, 1 eq) was dissolved in 1,2-dichlorobenzene (7.5 mL) and stirred at 180 °C for 15 minutes. 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 obtain compound 1e (500 mg, yield 17.92%) as a yellow solid.

[0153] Compound 1e (500 mg, 1.17 mmol, 1 eq) was dissolved in phosphoryl trichloride (POCl3; 5 mL), stirred at 110 °C for 0.5 h, and concentrated under reduced pressure to obtain compound 1f (500 mg, yield 67.11%, purity 70%) as a brown oil. Compound 1f (100 mg) was purified by column chromatography to obtain a white solid (21 mg, yield 21.00%).

[0154] Compound 1f (100 mg, 224.14 μmol, 1 eq) was dissolved in dichloromethane (2 mL), and meta-chloroperoxybenzoic acid (45.51 mg, 224.14 μmol, purity 85%, 1 eq) was added at 0 °C and stirred for 15 min. Sodium thiosulfate solution (20 mL) was added at 0 °C, 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 purified by column chromatography to obtain compound 1 (29 mg, yield 28.00%) as a yellow solid.

[0155] 1 H NMR: 400 MHz, CDCl3

[0156] δ = 8.07 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 6.08 (s, 1H), 4.69 - 4.53 (m, 2H), 2.67 (s, 3H), 2.42 (s, 3H)

[0157] Example 2. Preparation of 1-(8-bromo-4,5-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one (Compound 2)

[0158] (1) Preparation of (5-methylisoxazol-3-yl)methyl methanesulfonate

[0159]

[0160] (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.

[0161] (2) Preparation of 1-(8-bromo-4,5-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one (compound 2)

[0162]

[0163] Compound 2f (50 mg, 105.44 μmol, 1 eq) obtained in the same manner as compound 1 was dissolved in dichloromethane (1 mL), and meta-chloroperoxybenzoic acid (21.41 mg, 105.44 μmol, purity 85%, 1 eq) was added at 0 °C and stirred for 15 minutes. An additional mixture was prepared in one vial in the same manner as above. The two vial batches were combined, and 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 2 (18 mg, yield 17.41%) as a white solid.

[0164] 1H NMR: 400 MHz, CDCl3

[0165] δ = 8.08 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 6.08 (s, 1H), 4.68 - 4.53 (m, 2H), 3.16 (td, J = 7.1, 14.0 Hz, 1H), 2.40 (s, 3H), 1.27 (dd, J = 4.8, 7.0 Hz, 6H)

[0166] Example 3. Preparation of 1-(4,5-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-8-((trimethylsilyl)ethynyl)quinolin-3-yl)-2-methylpropan-1-one (Compound 3)

[0167]

[0168] Compound 3a (50 mg, 105.44 μmol, 1 eq) and ethynyl(trimethyl)silane (51.78 mg, 527.21 μmol, 73.03 μL, 5 eq) obtained in the same manner as compound 2f described in Example 2 were dissolved in toluene (1 mL), degassed and purged with nitrogen three times, and then copper iodide (2.01 mg, 10.54 μmol, 0.1 eq), methanesulfonate; [2-[2-(methylamino)phenyl]phenyl]palladium(1+); tri-tert-butylphosphane (6.18 mg, 10.54 μmol, 0.1 eq) and triethylamine (213.39 mg, 2.11 mmol, 293.52 μL, 20 eq) were added under nitrogen. Stir at 100°C for 12 hours. Prepare the mixture in 19 additional vials in the same manner as above. Combine the batches of 20 vials, filter, concentrate under reduced pressure, and then purify by column chromatography (PE:EtOAc = 4:1, Rf = 0.66) to obtain compound 3b (80 mg, yield 7.72%) as a brown solid.

[0169] Compound 3b (100 mg, 203.46 μmol, 1 eq) was dissolved in dichloromethane (3 mL) and methyl alcohol (0.3 mL), and meta-chloroperoxybenzoic acid (61.96 mg, 305.19 μmol, purity 85%, 1.5 eq) was added at 0 °C, and the mixture was stirred at 25 °C for 12 h. Saturated sodium bisulfite solution (8 mL) was added at 0 °C, stirred for 0.5 h, separated, and washed with sodium bicarbonate solution (8 mL). Drying over sodium sulfate, filtering, and concentrating were performed, and the residue was purified by column chromatography to obtain compound 3 (5 mg, yield 4.84%) as a yellow solid.

[0170] 1 H NMR: 400 MHz, CDCl3

[0171] δ = 7.90 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 6.01 (s, 1H), 4.73 - 4.57 (m, 2H), 3.14 (quin, J = 7.0 Hz, 1H), 2.39 (s, 3H), 1.26 (dd, J = 4.4, 6.9 Hz, 6H), 0.32 (s, 9H)

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

[0173]

[0174] Compound 4a, obtained in the same manner as compound 3 described in Example 3, was dissolved in dichloromethane (0.5 mL) and methyl alcohol (0.5 mL), potassium fluoride (8.24 mg, 141.87 μmol, 3.32 μL, 3 eq) was added, and the mixture was stirred at 25°C for 1.5 hours. The mixture was partitioned between water (3 mL) and dichloromethane (3 mL), and the organic layer was separated, washed with brine (3 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 4 (0.5 mg, yield 17.01%) as a white solid.

[0175] 1 H NMR: 400 MHz, CDCl3

[0176] δ = 7.92 (dd, J = 1.2, 7.9 Hz, 2H), 7.77 (dd, J = 3.3, 8.0 Hz, 2H), 6.03 (d, J = 6.4 Hz, 2H), 5.34 (s, 1H), 4.86 (s, 1H), 3.62 (s, 2H), 3.23 - 3.13 (m, 1H), 2.84 - 2.76 (m, 1H), 2.43 (s, 3H), 2.40 (s, 3H), 1.19 (d, J = 3.3 Hz, 3H), 1.18 (d, J = 3.4 Hz, 3H), 1.14 (d, J = 6.9 Hz, 3H), 0.91 (d, J = 7.0 Hz, 3H)

[0177] Example 5. Preparation of 4,5,8-trichloro-N,N-dimethyl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinoline-3-carboxamide (Compound 5)

[0178]

[0179] Compound 5a (5 g, 30.86 mmol, 1 eq) was dissolved in dichloromethane (50 mL), and sodium carbonate (6.54 g, 61.72 mmol, 2 eq) and thiocarbonyl dichloride (5.32 g, 46.29 mmol, 3.55 mL, 1.5 eq) were added at 0–3 °C, and the mixture was stirred at 15 °C for 12 h. The mixture was filtered, diluted with sodium bicarbonate solution (100 mL), and extracted with dichloromethane (40 mL × 3). The organic layer was washed with brine (100 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 5b (12.5 g, yield 99.24%) as a yellow oil.

[0180] Sodium hydride (2.94 g, 73.50 mmol, purity 60%, 1.2 eq) was dissolved in THF (35 mL), cooled to 0-5 °C, dimethyl malonate (9.71 g, 73.50 mmol, 8.42 mL, 1.2 eq) dissolved in THF (35 mL) at 0-3 °C was added dropwise, and stirred at 0-5 °C for 0.5 h. Compound 5b (12.5 g, 61.25 mmol, 1 eq) was dissolved in THF (35 mL), added dropwise to the mixture, and stirred for 1 h to obtain compound 5c (21.5 g, yield 98.00%) as a yellow oil.

[0181] Compound 5c was dissolved in THF (35 mL), and added dropwise to a solution of (5-methylisoxazol-3-yl)methyl methanesulfonate (12.1 g, 63.28 mmol, 1.05 eq) in THF (35 mL) at 0 to 5 °C, and stirred at 0 to 15 °C for 12 h. Water (60 mL) was added at 0 to 5 °C, cooled, and extracted with ethyl acetate (50 mL × 3). The organic layer was washed with brine (25 mL × 2), dried over sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (PE / EtOAc = 100 / 60 ~ 0 / 40, Rf = 0.60) to obtain compound 5d (23.5 g, yield 90.77%) as a yellow solid.

[0182] Compound 5d (5 g, 11.59 mmol, 1 eq) was dissolved in 1,2-dichlorobenzene (32 mL) and stirred at 180 °C for 15 min. Cooled to room temperature, filtered, and filtered (ethyl acetate / methyl tert-butyl ether (EtOAc / MTBE) = 1 / 1) (15.00 mL) at 15 °C for 5 min to obtain compound 5e (10 g, yield 54.01%) as a white solid.

[0183] Compound 5e (1 g, 2.50 mmol, 1 eq) was dissolved in dimethylamine tetrahydrofuran (13 mL) and stirred at 110 °C for 12 h. Two additional vials were prepared using the same method as above. The three vial batches were combined, diluted with water (40 mL), and extracted with ethyl acetate (25 mL × 3). The organic layer was washed with brine (15 mL × 2), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 5f (1 g, yield 32.28%) as a white solid.

[0184] Compound 5f (500 mg, 1.21 mmol, 1 eq) was dissolved in phosphoryl trichloride (10 mL) and stirred at 110 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove phosphoryl trichloride, and compound 5g (520 mg, yield 99.55%) was obtained as a yellow oil.

[0185] Compound 5 g (235 mg, 545.58 μmol, 1 eq) was dissolved in dichloromethane (7 mL), and meta-chloroperoxybenzoic acid (55.38 mg, 272.79 μmol, purity 85%, 1 eq) was added at 0–3 °C, and stirred at 25 °C for 0.5 min. Sodium thiosulfate solution (10 mL) was added at 0 °C, cooled, stirred for 5 min, and extracted with dichloromethane (10 mL × 3). 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 (34.4 mg, yield 7.06%) as a white solid.

[0186] 1 H NMR: 400 MHz, CDCl3

[0187] δ = 7.86 (dd, J = 8.3, 11.8 Hz, 1H), 7.74 (dd, J = 5.4, 8.3 Hz, 1H), 6.11 (d, J = 10.5 Hz, 1H), 4.79 - 4.71 (m, 1H), 4.71 - 4.56 (m, 1H), 3.20 (d, J = 2.9 Hz, 3H), 2.90 (d, J = 17.4 Hz, 3H), 2.44 - 2.37 (m, 3H)

[0188] Example 6. Preparation of 1-(4,5,8-trichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one (compound 6)

[0189]

[0190] Methyl 3-oxobutanoate (1.28 g, 11.03 mmol, 1.19 mL) is dissolved in THF (10 mL), and sodium hydride (588 mg, 14.70 mmol, purity 60%) is added at 0°C under nitrogen and stirred for 0.5 h. A solution of compound 6a (1.5 g, 7.35 mmol) dissolved in THF (10 mL) at 0°C under nitrogen is added to the mixture and stirred for 1 h.

[0191] Compound 6b (2.52 g, 7.36 mmol, 1 eq) was dissolved in THF (20 mL), 3-(chloromethyl)-5-methylisoxazole (969 mg, 7.36 mmol, 1 eq) was added at 0 °C, and the mixture was stirred at 15 °C for 12 h. Saturated ammonium chloride (40 mL) was added at 0 °C, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (PE:EtOAc = 1:0 to 1:1) to obtain compound 6c (1.2 g, yield 39%) as a yellow solid.

[0192] Compound 6c (1.2 g, 2.89 mmol, 1 eq) was dissolved in 1,2-dichlorobenzene (10 mL) and heated at 170 °C for 2 hours. The solvent was removed by blowing nitrogen, and the residue was purified by column chromatography (PE:EtOAc = 20:1 to 5:1) to obtain compound 6d (0.55 g, yield 49.67%) as a yellow solid.

[0193] Compound 6d (550 mg, 1.44 mmol, 1 eq) was dissolved in phosphoryl trichloride (9.87 g, 64.37 mmol, 6 mL, 44.85 eq) at 20 °C and stirred at 100 °C for 1 h. The reaction mixture was slowly poured into water (10 mL) at 20 °C, the pH was adjusted to 7–8 by adding saturated sodium carbonate, and extracted with ethyl acetate (3 × 10 mL). The organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (PE:EtOAc = 1:0 to 3:1) to obtain compound 6e (400 mg, yield 69.39%) as a yellow solid.

[0194] Compound 6e (400 mg, 995.78 μmol, 1 eq) was dissolved in dichloromethane (5 mL), and meta-chloroperoxybenzoic acid (243 mg, 1.19 mmol, purity 85%, 1.2 eq) was added at 0 °C and stirred for 0.5 h. The reaction mixture was poured into saturated sodium sulfite (6 mL), stirred for 10 min, and extracted with ethyl acetate (2 mL × 3). The organic phase was dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 6 (32.91 mg, yield 7.9%) as a white solid.

[0195] 1 H NMR: 400 MHz, CDCl3

[0196] δ = 7.87 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 6.09 (s, 1H), 4.67-4.52 (m, 2H), 2.68 (s, 3H), 2.42 (s, 3H)

[0197] Example 7. Preparation of 4,5,8-trichloro-N,N-dimethyl-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfinyl)quinoline-3-carboxamide (Compound 7)

[0198]

[0199] Dimethyl malonate (776.85 mg, 5.88 mmol, 673.77 μL, 1.2 eq) was dissolved in THF (10 mL), and sodium hydride (235.18 mg, 5.88 mmol, purity 60%, 1.2 eq) was added at 0 °C under nitrogen and stirred for 0.5 h. Compound 7a (1 g, 4.90 mmol, 1 eq) was added to the reaction mixture at 0-5 °C under nitrogen and stirred for 0.5 h to obtain compound 7b (1.76 g, yield 100.00%) as a yellow oil.

[0200] Compound 7b (1.76 g, 4.91 mmol, 1 eq) was dissolved in THF (20 mL), and 3-(chloromethyl)-1-methyl-1H-pyrazole (641.62 mg, 4.91 mmol, 1 eq) was added at 0 °C and stirred at 15 °C under nitrogen for 16 h. Saturated ammonium chloride (30 mL) was added, the reaction mixture was 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 then purified by column chromatography (PE:EtOAc = 1:0 to 1:1) to obtain compound 7c (1.05 g, yield 49.66%) as a colorless oil.

[0201] Compound 7c (0.75 g, 1.74 mmol, 1 eq) was dissolved in 1,2-dichlorobenzene (8 mL), degassed, purged with nitrogen three times, and stirred at 175 °C under nitrogen for 1 h. The reaction mixture was filtered and concentrated to obtain compound 7d (0.43 g, yield 61.95%) as a light yellow solid.

[0202] Compound 7d (240 mg, 602.62 μmol, 1 eq) was dissolved in dimethylamine (2 M, 24.00 mL, 79.65 eq) and stirred in a 100 mL sealed tube at 70 °C under nitrogen for 12 h. The mixture was concentrated under reduced pressure and filtered (EtOAc:MTBE = 1:3) (10 mL) at 20 °C for 30 min to obtain compound 7e (0.16 g, yield 52.37%) as an off-white solid.

[0203] Compound 7e (0.1 g, 243.13 μmol, 1 eq) was dissolved in phosphoryl trichloride (5.48 g, 35.76 mmol, 3.33 mL, 147.09 eq) and stirred at 100 °C under nitrogen for 1 h. The reaction mixture was concentrated under reduced pressure, poured into water (20 mL), stirred for 2 min, and extracted with ethyl acetate (10 mL × 3). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7f (100 mg) as an orange solid.

[0204] Compound 7f (0.1 g, 232.69 μmol, 1 eq) was dissolved in dichloromethane (3 mL), and meta-chloroperoxybenzoic acid (60.23 mg, 279.23 μmol, purity 80%, 1.2 eq) was added at 0 °C and stirred for 0.5 h. The reaction mixture was added dropwise to sodium bisulfite solution (10 mL), stirred for 5 minutes, and extracted with dichloromethane (5 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 7 (32.18 mg, yield 30.48%) as a white solid.

[0205] 1 H NMR: 400 MHz, CDCl3

[0206] δ = 7.89 - 7.80 (m, 1H), 7.76 - 7.69 (m, 1H), 7.26 - 7.21 (m, 1H), 6.17 (t, J = 2.3 Hz, 1H), 4.89 - 4.71 (m, 1H), 4.65 - 4.59 (m, 1H), 3.88 - 3.82 (m, 3H), 3.20 (d, J = 2.0 Hz, 3H), 2.91 - 2.85 (m, 3H)

[0207] Example 8. Preparation of 1-(4,5,8-trichloro-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one (Compound 8)

[0208]

[0209] Methyl 3-oxobutanoate (854 mg, 7.35 mmol, 792.45 μL, 1.5 eq) is dissolved in THF (10 mL), and sodium hydride (391.97 mg, 9.80 mmol, purity 60%, 2 eq) is added at 0 °C under nitrogen, and the mixture is stirred for 0.5 h. Compound 8a (1 g, 4.90 mmol, 1 eq) is dissolved in THF (10 mL), and the mixture is added at 0 °C under nitrogen, and the mixture is stirred for 1 h.

[0210] Compound 8b (1.68 g, 4.91 mmol, 1 eq) was dissolved in THF (20 mL), and 3-(chloromethyl)-1-methyl-1H-pyrazole (641.10 mg, 4.91 mmol, 1 eq) was added at 0 °C, and the mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into saturated ammonium chloride (40 mL) at 0 °C, and extracted with ethyl acetate (10 mL × 3). The organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (PE:EtOAc = 1:0 to 1:1) to obtain compound 8c (1 g, yield 49%) as a yellow solid.

[0211] Compound 8c (0.64 g, 1.54 mmol, 1 eq) was dissolved in 1,2-dichlorobenzene (5 mL) at 20 °C and heated at 170 °C for 1 h. The mixture was blown with nitrogen to remove the solvent, and the resultant was purified by column chromatography (PE:EtOAc = 20:1 to 5:1) to obtain compound 8d (0.27 g, yield 45.7%) as a yellow solid.

[0212] Compound 8d (270 mg, 706.32 μmol, 1 eq) was dissolved in phosphoryl trichloride (822.50 mg, 5.36 mmol, 0.5 mL, 7.59 eq) at 20 °C and stirred at 100 °C for 1 h. The reaction mixture was slowly poured into water (3 mL) at 20 °C, saturated sodium carbonate was added to adjust the pH to 7–8, and extracted with ethyl acetate (1 mL × 3). The organic layer was washed with brine (1.5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 8e (160 mg, yield 56.53%) as a yellow solid.

[0213] Compound 8e (160 mg, 399.29 μmol, 1 eq) was dissolved in dichloromethane (3 mL), and meta-chloroperoxybenzoic acid (97.28 mg, 479.15 μmol, purity 85%, 1.2 eq) was added at 0 °C, followed by stirring for 1.5 h. The mixture was poured into water (6 mL), then extracted with ethyl acetate (2 mL × 3). The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 8 (60 mg, yield 14.43%) as a white solid.

[0214] 1 H NMR: 400 MHz, CDCl3

[0215] δ = 7.85 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 6.14 (d, J = 2.0 Hz, 1H), 4.63-4.52 (m, 2H), 3.83 (s, 3H), 2.66 (s, 3H)

[0216] Example 9. Preparation of 4,5,8-trichloro-N-(2-methoxyethyl)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinoline-3-carboxamide (Compound 9)

[0217]

[0218] A mixture of compound 9a (250 mg, 626.18 µmol, 1 eq) and 2-methoxyethanamine (2.16 g, 28.76 mmol, 2.50 mL, 45.93 eq) was stirred at 110 °C for 1.5 h. An additional batch of the mixture was prepared in the same manner as above, and the two mixtures were combined and concentrated under reduced pressure to obtain compound 9b (850 mg) as a yellow oil.

[0219] Compound 9b (450 mg, 1.02 mmol, 1 eq) was dissolved in phosphoryl trichloride (9 mL), stirred at 110 °C for 1.5 h, concentrated under reduced pressure, and purified by column chromatography (PE / EtOAc = 100 / 0 ~ 85 / 15, Rf = 0.60) to obtain compound 9c (150 mg, yield 32.00%) as a yellow solid.

[0220] Compound 9c (150 mg, 325.55 μmol, 1 eq) was dissolved in dichloromethane (1.5 mL), and meta-chloroperoxybenzoic acid (66.09 mg, 325.557 μmol, purity 85%, 1 eq) was added at 0–3 °C, and the mixture was stirred at 25 °C for 1 h. Sodium thiosulfate solution (2.5 mL) was added at 0 °C, the mixture was stirred for 5 minutes, and then extracted with dichloromethane (2 mL × 3). The extracted mixture was washed with sodium bicarbonate solution (2.5 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 9 (54 mg, yield 34.79%) as a white solid.

[0221] 1 H NMR: 400 MHz, CDCl3

[0222] δ = 7.86 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 6.63 - 6.35 (m, 1H), 6.13 (s, 1H), 4.78 - 4.67 (m, 1H), 4.66 - 4.56 (m, 1H), 3.80 - 3.67 (m, 2H), 3.66 - 3.54 (m, 2H), 3.39 (s, 3H), 2.39 (s, 3H)

[0223] Example 10. Preparation of 1-(4,5,8-trichloro-2-((pyrimidin-5-ylmethyl)sulfinyl)quinolin-3-yl)ethan-1-one (Compound 10)

[0224] (1) Preparation of pyrimidin-5-ylmethanethiol

[0225]

[0226] Pyrimidin-5-ylmethanol (5 g, 45.41 mmol, 1 eq) was dissolved in THF (50 mL), and triethylamine (6.89 g, 68.11 mmol, 9.48 mL, 1.5 eq) and methylsulfonyl chloride (6.24 g, 54.49 mmol, 4.22 mL, 1.2 eq) were added dropwise at 0-5 °C under nitrogen, and the mixture was stirred at 0 °C for 2 h. The reaction mixture was treated with water (50 mL) to stop the reaction and extracted with ethyl acetate (50 mL × 3). The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain pyrimidin-5-ylmethyl methanesulfonate (8 g) as a yellow oil.

[0227] Pyrimidin-5-ylmethyl methanesulfonate (4 g, 21.25 mmol, 1 eq) was dissolved in acetone (20 mL), potassium ethanethioate (4.85 g, 42.51 mmol, 2 eq) was added, and the mixture was stirred at 25 °C for 1 h. An additional batch of the mixture was prepared in the same manner as above. The two mixtures were combined, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain S-(pyrimidin-5-ylmethyl)ethanethioate (3.27 g, yield 45.73%) as a white solid.

[0228] S-(pyrimidin-5-ylmethyl)ethanethiol (1 g, 5.94 mmol, 1 eq) was dissolved in methanol (10 mL), potassium carbonate (2.05 g, 14.86 mmol, 2.5 eq) was added, and the mixture was stirred at 25 °C for 0.5 h to obtain pyrimidin-5-ylmethanethiol (750 mg, yield 99.99%) as a yellow oil.

[0229] (2) Preparation of 1-(4,5,8-trichloro-2-((pyrimidin-5-ylmethyl)sulfinyl)quinolin-3-yl)ethan-1-one (compound 10)

[0230]

[0231] Compound 10e (0.5 g, 1.57 mmol, 1 eq) obtained by the above manufacturing process or a known method (PCT Publication No. WO 2018 / 021810) was dissolved in methanol (10 mL), potassium carbonate (217.18 mg, 1.57 mmol, 1 eq) and pyrimidin-5-ylmethanethiol (375.00 mg, 2.97 mmol, 1.89 eq) were added, and the mixture was stirred at 25°C for 0.5 h. The mixture was treated with water (5 mL), acidified to pH = 8 with saturated ammonium chloride, filtered, and the filter cake was dried under vacuum to obtain a crude product, which was then triturated with PE (Petroleum ether; 20 mL) to obtain compound 10f (850 mg, yield 71.12%) as a white solid.

[0232] Compound 10f (850 mg, 2.24 mmol, 1 eq) was dissolved in phosphoryl trichloride (8.5 mL) and stirred at 80 °C for 12 h. The mixture was cooled to 20 °C, treated with water (50 mL), and extracted with ethyl acetate (20 mL × 3). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 10g (45 mg, yield 5.05%) as a white solid.

[0233] Compound 10 g (40 mg, 100.33 μmol, 1 eq) was dissolved in dichloromethane (1 mL), and meta-chloroperoxybenzoic acid (20.37 mg, 100.33 μmol, purity 85%, 1 eq) was added at 0 °C and stirred for 0.5 h. Sodium thiosulfate solution (5 mL) was added at 0 °C, and the mixture was stirred for 5 minutes and extracted with dichloromethane (5 mL × 3). The extracted mixture was washed with sodium bicarbonate solution (5 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 10 (17 mg, yield 40.86%) as a white solid.

[0234] 1 H NMR: 400 MHz, CDCl3

[0235] δ = 9.15 (s, 1H), 8.51 (s, 2H), 7.90 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 4.68 (d, J = 13.5 Hz, 1H), 4.49 (d, J = 13.4 Hz, 1H), 2.53 (s, 3H)

[0236] Example 11. Preparation of cyclopropyl(4,5,8-trichloro-2-((pyrimidin-5-ylmethyl) sulfinyl)quinolin-3-yl)methanone (Compound 11)

[0237]

[0238] After mixing NaH (296.33 mg, 7.41 mmol, purity 60%, 1.2 eq) in THF (10 mL), cooled to 0 to 5 °C, a solution of compound 11b (877.67 mg, 6.17 mmol, 1 eq) mixed in THF (1 mL) was added dropwise between 0 and 3 °C. After stirring the mixture at 0 to 5 °C for 0.5 h, a solution of compound 11a (1.26 g, 6.17 mmol, 1 eq) mixed in THF (1 mL) was added dropwise, and stirred at 0 to 5 °C for 1 h to obtain compound 11c (2.27 g) as a yellow solution.

[0239] Compound 11c (750 mg, 2.04 mmol, 1 eq) was dissolved in THF (5 mL), and compound 11d (see Example 10; 498.35 mg, 2.65 mmol, 1.3 eq) dissolved in THF (1 mL) was added dropwise between 0 and 5 °C, and stirred at 15 °C for 12 h. Water (10 mL) was added between 0 and 5 °C, and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with brine (10 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, 0–15% EtOAc / PE) to obtain compound 11e (500 mg, 992.41 μmol, yield 48.72%, purity 87%) as a yellow solid.

[0240] Compound 11e (500 mg, 1.14 mmol, 1 eq) was stirred with 1,2-dichlorobenzene (10 mL) at 179 °C under nitrogen for 1.5 h, and then evaporated under an oil pump to obtain a crude product. DMSO (2 mL) was added, stirred for 10 min, filtered, and washed with dichloromethane / methanol (3:1, 6 mL) to obtain compound 11f (10.8 mg, 26.49 μmol, yield 2.32%, purity 99.66%) as a white solid.

[0241] Compound 11f (500 mg, 1.23 mmol, 1 eq) and phosphoryl trichloride (10 mL) were mixed and stirred at 100°C under nitrogen for 5 hours. The mixture was evaporated to remove phosphoryl trichloride, toluene (20 mL × 3) was added, evaporated, and the residue was purified by column chromatography to obtain compound 11g (160 mg, 376.71 μmol, yield 30.61%, purity 100%) as a white solid.

[0242] Compound 11 g (90 mg, 211.90 μmol, 1 eq) was dissolved in dichloromethane (5 mL), meta-chloroperoxybenzoic acid (42.51 mg, 211.90 μmol, 1 eq) was added, and the mixture was stirred for 1.5 hours while maintaining the temperature below 20 °C. After cooling the mixture to 0 °C, water (2 mL) was added, stirred for 10 minutes, filtered, and purified by column chromatography to obtain compound 11 (12.7 mg, 28.82 μmol, yield 13.60%, purity 100%) as a white solid.

[0243] 1 H NMR: 400 MHz, DMSO

[0244] δ = 9.05 (s, 1H), 8.40 (s, 2H), 8.16 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 4.71 (d, J = 13.2 Hz, 1H), 4.50 (d, J = 13.2 Hz, 1H), 2.30 - 2.18 (m, 1H), 1.30 - 1.12 (m, 4H)

[0245] Example 12. Preparation of 2-methyl-1-(4,5,8-trichloro-2-((2-(pyrimidin-5-yl)ethyl) sulfinyl)quinolin-3-yl)propan-1-one (Compound 12)

[0246] (1) Preparation of 2-(pyrimidin-5-yl)ethane-1-thiol

[0247]

[0248] 5-Bromopyrimidine (3.0 g, 18.87 mmol, 1 eq), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (4.36 g, 28.30 mmol, 4.80 mL, 1.5 eq), Pd(dppf)Cl2 (690.36 mg, 943.49 μmol, 0.05 eq), sodium carbonate (5.00 g, 47.17 mmol, 2.5 eq), dioxane (60 mL), and water (12 mL) are mixed. The mixture is purged with nitrogen for 4 min, stirred at 90 °C for 16 h, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (SiO2, 0-30%EtOAc / PE) to obtain 5-vinylpyrimidine (1.4 g, 13.19 mmol, yield 69.91%) as a brown liquid.

[0249] 5-Vinylpyrimidine (533.8 mg, 5.03 mmol, 1 eq), ethyl acetate (5 mL), 2,2-dimethoxy-1,2-diphenyl-ethan-1-one (128.91 mg, 502.99 μmol, 0.1 eq), and 1-(4-methoxyphenyl)ethan-1-one (75.54 mg, 502.99 μmol, 0.1 eq) were mixed, degassed, and backfilled with nitrogen three times. AcSH (1.15 g, 15.09 mmol, 1.08 mL, 3 eq) was added via syringe, and the mixture was stirred at 25 °C under UV irradiation for 16 h. The mixture was diluted with ethyl acetate (10 mL) and washed with sodium bicarbonate solution (50 mL), and the aqueous layer was extracted with ethyl acetate (10 mL × 5). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, 0–20% EtOAc / PE) to give S-(2-(pyrimidin-5-yl)ethyl)ethanethioate (990 mg, 5.43 mmol, yield 46.96%) as a brown oil.

[0250] S-(2-(pyrimidin-5-yl)ethyl)ethanethioate (250 mg, 1.37 mmol, 1 eq) was dissolved in methanol (2.5 mL), sodium methoxide (5.4 M, 2.54 mL, 10 eq) was added, and the mixture was stirred at 25 °C for 1 h. The mixture was neutralized to pH 7–8 with 1 M HCl solution and concentrated in vacuo to obtain 2-(pyrimidin-5-yl)ethane-1-thiol (192 mg) as a white solid.

[0251] (2) Preparation of 2-methyl-1-(4,5,8-trichloro-2-((2-(pyrimidin-5-yl)ethyl)sulfinyl) quinolin-3-yl)propan-1-one (compound 12)

[0252]

[0253] To a solution of 2-(pyrimidin-5-yl)ethane-1-thiol (144.18 mg, 1.03 mmol, 1.5 eq) in MeCN (6 mL), TEA (138.74 mg, 1.37 mmol, 190.84 μL, 2 eq) and compound 12a (see Example 10 or the preparation method of published Korean Patent No. 10-1879992, etc.) (250 mg, 685.54 μmol, 1 eq) were added, and the mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuo and then purified by column chromatography (SiO2, 0-30% EtOAc / PE) to obtain compound 12b (163 mg, 240.37 μmol, yield 35.06%, purity 65%) as a white solid.

[0254] Compound 12b (140 mg, 317.62 μmol, 1 eq) was dissolved in dichloromethane (3.5 mL), and meta-chloroperoxybenzoic acid (135.42 mg, 667.01 μmol, purity 85%, 2.1 eq) was added and stirred at 25 °C for 1 h. The reaction was stopped by adding aqueous sodium bicarbonate solution (20 mL) at 25 °C, then diluted with dichloromethane (10 mL) and extracted with dichloromethane (10 mL × 3). The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, 5-60% MeCN / H2O (0.0225% FA)) to obtain compound 12 (39.1 mg, 80.46 μmol, yield 25.33%, purity 94.3%) as a white solid.

[0255] 1 H NMR: 400 MHz, DMSO-d6

[0256] δ = 8.90 (s, 1 H), 8.70 - 8.61 (m, 2 H), 8.16 (d, J=8.31 ​​Hz, 1 H), 8.04 - 7.93 (m, 1 H), 3.79 - 3.67 (m, 1 H), 3.53 (s, 1 H), 3.21 - 3.03 (m, 2 H), 3.01 - 2.89 (m, 1 H), 1.24 - 1.15 (m, 6 H)

[0257] Example 13. Preparation of Cyclopropyl(4,5,8-trichloro-2-(pyrimidin-5-ylsulfinyl) quinoline-3-yl)methan-1-one (Compound 13)

[0258] (1) Preparation of sodium pyrimidine-5-thiolate

[0259]

[0260] To a solution of 5-bromopyrimidine (1 g, 6.29 mmol, 1 eq) in pre-degassed dioxane (5 mL) is added Xantphos (727.90 mg, 1.26 mmol, 0.2 eq) and Pd2(dba)3 (575.98 mg, 628.99 μmol, 0.1 eq) under nitrogen, followed by 2-ethylhexyl 3-mercaptopropanoate (1.51 g, 6.92 mmol, 1.1 eq) and DIEA (1.63 g, 12.58 mmol, 2.19 mL, 2 eq). The reaction mixture was stirred at 100°C for 12 h, cooled to room temperature, filtered through a pad of Celite, concentrated under reduced pressure, and purified by column chromatography (SiO2, 0-15%EtOAc / PE) to obtain 2-ethylhexyl 3-(pyrimidin-5-ylthio)propanoate (1.84 g, 5.77 mmol, yield 91.78%, purity 93%) as a yellow oil.

[0261] 2-Ethylhexyl 3-(pyrimidin-5-ylthio)propanoate (3.6 g, 12.14 mmol, 1 eq) was dissolved in methanol (80 mL), NaOH (582.90 mg, 14.57 mmol, 1.2 eq) was added, and the mixture was stirred at 20 °C for 3 h. The reaction solution was concentrated by rotary evaporation to remove approximately 70 mL of methanol, and then water (20 mL) was added to the residue and extracted with ethyl acetate (20 mL × 3). The aqueous layer was lyophilized to obtain compound 13e (2 g) as a yellow solid.

[0262] (2) Preparation of Cyclopropyl(4,5,8-trichloro-2-(pyrimidin-5-ylsulfinyl)quinoline-3-yl)methan-1-one (Compound 13)

[0263]

[0264] Compound 13a (4.5 g, 12.22 mmol, 1 eq) was dissolved in THF (30 mL), and MeI (1.91 g, 13.44 mmol, 836.91 μL, 1.1 eq) was added dropwise at 20 °C and stirred at 20 °C for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered, evaporated, and purified by column chromatography (SiO2, 0–3% EtOAc / PE) to obtain compound 13b (3.2 g, 7.82 mmol, yield 63.96%, purity 88%) as a yellow solid.

[0265] Compound 13b (1.6 g, 4.44 mmol, 1 eq) was dissolved in 1,2-dichlorobenzene (25 mL) and stirred at 179 °C under nitrogen for 1 h. One more batch was prepared in the same manner as above, combined, and 1,2-dichlorobenzene was removed by evaporation under an oil pump. Then, PE / dichloromethane (DCM) (3:1, 20 mL) was added, stirred for 10 minutes, and filtered. The filter cake was washed with PE / DCM (3:1, 9 mL) to obtain compound 13c (740 mg) as a white solid.

[0266] Compound 13c (740 mg, 2.25 mmol, 1 eq) is dissolved in dichloromethane (30 mL), and meta-chloroperoxybenzoic acid (457.73 mg, 2.25 mmol, purity 85%, 1 eq) is added in one portion and stirred for 2 hours while maintaining the temperature below 20 °C. Another portion of meta-chloroperoxybenzoic acid (311.26 mg, 1.80 mmol, purity 85%, 0.8 eq) is added and stirring is continued for 1 hour. A third batch of meta-chloroperoxybenzoic acid (38.91 mg, 225.46 μmol, 0.1 eq) is added and stirring is continued for 3 hours. The reaction mixture was treated with 15% aqueous potassium carbonate solution (10 mL), the layers were separated, the organic layer was washed with 15% potassium carbonate and brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to obtain compound 13d (640 mg, 1.77 mmol, yield 78.67%, purity 95.4%) as a white solid.

[0267] Compound 13d (50 mg, 145.26 μmol, 1 eq) is dissolved in acetonitrile (1 mL), and compound 13e (39.26 mg, 290.52 μmol, 2 eq) and cesium carbonate (94.66 mg, 290.52 μmol, 2 eq) are added and stirred at 20 °C for 5 h. DMA (1 mL) is added and stirred at 50 °C for another 12 h. DMSO (1 mL) is added and stirred at 90 °C for 12 h. The reaction mixture is diluted with water (5 mL) and extracted with ethyl acetate (10 mL × 3). The organic layer was washed with water (5 mL × 3) and brine (10 mL), dried over sodium sulfate, filtered, and evaporated to obtain compound 13f (50 mg, 76.48 μmol, yield 52.65%, purity 60%) as a yellow solid.

[0268] Compound 13f (100 mg, 254.93 μmol, 1 eq) was dissolved in phosphoryl trichloride (2 mL) and stirred at 100 °C under nitrogen for 2 hours. The reaction mixture was evaporated to remove phosphoryl trichloride, toluene (20 mL × 3) was added, and the evaporation resulted in a residue that was purified by column chromatography (SiO2, 0-20% EtOAc / PE) to obtain compound 13g (69 mg, 163.90 μmol, yield 64.29%, purity 97.56%) as a yellow solid.

[0269] After dissolving compound 13 g (58 mg, 141.22 μmol, 1 eq) in dichloromethane (0.5 mL), meta-chloroperoxybenzoic acid (37.27 mg, 183.59 μmol, purity 85%, 1.3 eq) is added, and the mixture is stirred at 25 °C for 1 hour. The reaction mixture is stopped by adding aqueous sodium bicarbonate solution (20 mL) at 25 °C, diluted with dichloromethane (10 mL), and extracted with dichloromethane (10 mL × 3). The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, 5-60% MeCN / H2O (0.05% FA)) to obtain compound 13 (34.6 mg, 79.30 μmol, yield 56.16%, purity 97.8%) as a white solid.

[0270] 1 H NMR: 400 MHz, DMSO-d6

[0271] δ = 9.35 (s, 1 H), 9.13 (s, 2 H), 8.15 (d, J=8.38 Hz, 1 H), 7.97 (d, J=8.38 Hz, 1 H), 2.61 (br d, J=4.38 Hz, 1 H), 1.25 - 1.42 (m, 4 H)

[0272] Example 14. Preparation of 4,8-dichloro-3-isobutyryl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinoline-5-carbonitrile (Compound 14)

[0273]

[0274] To a solution of compound 14a (25 g, 163.85 mmol) and sodium bicarbonate (137.64 g, 1640 mmol) in dichloromethane (200 mL) and water (200 mL) at 0 °C, add thiocarbonyl dichloride (20.72 g, 180.23 mmol, 13.82 mL) and stir at 20 °C for 6 h. Filter the reaction mixture, dilute the filtrate with water (100 mL), and extract with dichloromethane (100 mL × 3). Wash the organic layer with brine (200 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a yellow solid compound 14b (32 g).

[0275] Methyl 4-methyl-3-oxopentanoate (444.41 mg, 3.08 mmol) was dissolved in THF (5 mL), and NaH (246.58 mg, 6.17 mmol, purity 60%) was added at 0 °C under nitrogen, and the mixture was stirred for 0.5 h. The mixture was added to compound 14b (600 mg, 3.08 mmol) dissolved in THF (3 mL) at 0 °C, and stirred for 1 h to obtain compound 14c.

[0276] Compound 14c (1.11 g, 3.08 mmol) was dissolved in THF (5 mL), and 3-(chloromethyl)-5-methylisoxazole (404.75 mg, 3.08 mmol) was added at 20 °C and stirred for 3 hours. Saturated NH4Cl (8 mL) was added to the reaction mixture at 0 °C to stop the reaction and extracted with ethyl acetate (5 mL × 3). The organic layer was washed with brine (5 mL × 2), dried over sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 ~ 20 / 1) to obtain compound 14d (800 mg, yield 59.93%) as a yellow solid.

[0277] Compound 14d (700 mg, 1.61 mmol) was dissolved in 1,2-dichlorobenzene (7 mL) and stirred at 175 °C under nitrogen for 1 h. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 1 / 1) to obtain compound 14e (350 mg, yield 53.99%) as a yellow solid.

[0278] Compound 14e (200 mg, 0.498 mmol) and phosphoryl trichloride (2 mL) were mixed and stirred at 110 °C for 2 h, then cooled to room temperature. The reaction mixture was stopped by adding saturated sodium bicarbonate solution (10 mL), then extracted with ethyl acetate (10 mL × 3). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 14f (200 mg) as a brown oil.

[0279] Compound 14f (180 mg, 0.428 mmol) was dissolved in dichloromethane (2 mL), and meta-chloroperoxybenzoic acid (86.94 mg, 0.428 mmol) was added at 0 °C under nitrogen, and the mixture was stirred for 0.5 h. The reaction was stopped by adding saturated sodium sulfate solution (5 mL) to the reaction mixture, and then extracted with dichloromethane (3 mL × 3). The organic layer was washed with sodium bicarbonate (8 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 14 (10.5 mg, yield 5.62%) as a white solid.

[0280] 1 H NMR: 400 MHz, CDCl3

[0281] δ: 8.15 (d, J=8.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 6.11 (s, 1H), 4.65-4.52 (m, 2H), 3.14 (spt, J=6.8 Hz, 1H), 2.41 (s, 3H), 1.27 (t, J=6.8 Hz, 6H)

[0282] Example 15. Preparation of 1-(4,8-dichloro-5-methyl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one (Compound 15)

[0283]

[0284] Compound 15a (1 g, 7.06 mmol) and sodium bicarbonate (5.93 g, 70.62 mmol, 2.75 mL) were mixed in dichloromethane (10 mL) and water (20 mL), then CSCl2 (893.23 mg, 7.77 mmol, 0.6 mL) was added at 0 °C and stirred at 20 °C for 2 h. The reaction mixture was filtered, the filtrate was diluted with water (10 mL), and then extracted with dichloromethane (20 mL × 3). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 15b (1.1 g) as a yellow oil.

[0285] Methyl 4-methyl-3-oxopentanoate (588.74 mg, 4.08 mmol, 0.58 mL) was dissolved in THF (3 mL), and NaH (217.78 mg, 5.44 mmol, purity 60%) was added at 0 °C under nitrogen, and stirred for 0.5 h. Compound 15b (500 mg, 2.72 mmol) was added to the reaction mixture at 0 °C, and stirred for 1 h to obtain compound 15c.

[0286] Compound 15c (760 mg, 2.17 mmol) was dissolved in THF (10 mL), and 3-(chloromethyl)-5-methylisoxazole (285.83 mg, 2.17 mmol) was added at 20 °C under nitrogen, and stirred for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, PE / EtOAc=1 / 0~0 / 1) to obtain compound 15d (740 mg, yield 80.53%) as a yellow oil.

[0287] Compound 15d (640 mg, 1.51 mmol) was dissolved in 1, 2-dichlorobenzene (3 mL) and stirred at 175 °C under nitrogen for 1 hour. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography (SiO2, PE / EtOAc=1 / 0~0 / 1) to obtain compound 15e (260 mg, yield 43.96%) as a yellow oil.

[0288] Compound 15e (260 mg, 0.67 mmol) was mixed with phosphoryl trichloride (3 mL), stirred at 110 °C for 2 hours, and cooled to room temperature. The reaction mixture was stopped by adding saturated sodium bicarbonate solution (15 mL), and then extracted with ethyl acetate (10 mL × 3). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, PE / EtOAc=1 / 0~0 / 1) to obtain compound 15f (200 mg, yield 73.46%) as a brown solid.

[0289] Compound 15f (200 mg, 0.49 mmol) was dissolved in dichloromethane (3 mL), and meta-chloroperoxybenzoic acid (101.18 mg, 0.59 mmol) was added at 0 °C under nitrogen, and the mixture was stirred for 0.5 h. The reaction mixture was quenched by adding saturated sodium bisulfite solution (10 mL) and extracted with dichloromethane (5 mL × 3). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 15 (22.53 mg, yield 10.46%) as a white solid.

[0290] 1 H NMR: 400 MHz, CDCl3

[0291] δ = 7.83 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 6.09 (s, 1H), 4.68 - 4.50 (m, 2H), 3.15 (td, J = 6.8, 14.0 Hz, 1H), 3.04 (s, 3H), 2.40 (s, 3H), 1.27 (dd, J = 3.6, 7.2 Hz, 6H)

[0292] Example 16. Preparation of 1-(4,5,8-trichloro-2-((1-methyl-1H-pyrazol-3-yl)sulfinyl) quinolin-3-yl)ethan-1-one (Compound 16)

[0293] (1) Preparation of 1-methyl-1H-pyrazole-3-thiol

[0294]

[0295] A mixture of 3-bromo-1-methyl-pyrazole (2 g, 12.42 mmol, 1 eq), 2-ethylhexyl 3-sulfanyl propanoate (2.71 g, 12.42 mmol, 1 eq), Xantphos (1.44 g, 2.48 mmol, 0.2 eq), DIEA (3.21 g, 24.84 mmol, 4.33 mL, 2 eq), and Pd2(dba)3 (1.14 g, 1.24 mmol, 0.1 eq) in dioxane (20 mL) was degassed and purged with nitrogen three times, and the mixture was stirred at 100 °C under nitrogen for 16 h. The reaction mixture was concentrated under reduced pressure to remove dioxane, water (100 mL) was added, and extracted with EA (100 mL × 3). The organic layer was washed with brine (50 mL × 2), filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, 0–20% EtOAc / PE) to give 2-ethylhexyl 3-((1-methyl-1H-pyrazol-3-yl)thio)propanoate (975 mg, 3.16 mmol, yield 25.40%, purity 96.6%) as a yellow oil.

[0296] 2-Ethylhexyl 3-((1-methyl-1H-pyrazol-3-yl)thio)propanoate (300 mg, 1.01 mmol, 1 eq) was dissolved in methanol (2 mL), NaOH (48.25 mg, 1.21 mmol, 1.2 eq) was added, and the mixture was stirred at 25°C for 1 h. The mixture was neutralized to pH 7–8 with HCl solution (2 M) and concentrated in vacuo to obtain 1-methyl-1H-pyrazole-3-thiol (114 mg) as a brown oil.

[0297] (2) Preparation of 1-(4,5,8-trichloro-2-((1-methyl-1H-pyrazol-3-yl)sulfinyl) quinolin-3-yl)ethan-1-one (compound 16)

[0298]

[0299] Compound 16a (63.6 mg, 190.32 μmol, 1 eq), obtained in the same manner as compound 10e, was dissolved in MeCN (1 mL), and TEA (38.52 mg, 380.64 μmol, 52.98 μL, 2 eq) and compound 16b (32.59 mg, 285.48 μmol, 1.5 eq) were added, and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and then purified by column chromatography (SiO2, 5-80% MeCN / H2O (0.0025% FA)) to obtain compound 16c (68 mg, 184.66 μmol, yield 97.03%, purity 100%) as a white solid.

[0300] Compound 16c (63 mg, 171.09 μmol, 1 eq) was dissolved in DCE (3.2 mL), (COCl)2 (86.86 mg, 684.34 μmol, 59.90 μL, 4 eq) was added, and the mixture was stirred at 60 °C for 5 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, 0–7% EtOAc / DCM) to obtain compound 16d (48.8 mg, 109.29 μmol, yield 63.88%, purity 86.6%) as a white solid.

[0301] Compound 16d (43 mg, 111.20 μmol, 1 eq) was dissolved in dichloromethane (2.2 mL), and meta-chloroperoxybenzoic acid (31.61 mg, 155.68 μmol, purity 85%, 1.4 eq) was added and stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-20% EtOAc / PE) to obtain compound 16 (30.7 mg, 74.45 μmol, 66.95% yield, 97.65% purity) as a white solid.

[0302] 1 H NMR: 400 MHz, CDCl3

[0303] δ = 7.81 (d, J=8.14 Hz, 1 H), 7.69 (d, J=8.14 Hz, 1 H), 7.40 (d, J=2.20 Hz, 1 H), 6.78 (d, J=2.42 Hz, 1 H), 3.95 (s, 3 H), 2.80 (s, 3 H)

[0304] Example 17. Preparation of 1-(4,8-dichloro-5-methyl-2-(pyrimidin-5-ylsulfinyl) quinolin-3-yl)ethan-1-one (Compound 17)

[0305]

[0306] To a solution of compound 17a (5 g, 35.31 mmol, 1 eq) and TEA (7.15 g, 70.62 mmol, 9.83 mL, 2 eq) in THF (100 mL) was added thiocarbonyl dichloride (4.47 g, 38.84 mmol, 2.98 mL, 1.1 eq) dropwise at 0 °C and stirred at 25 °C for 1 h. The reaction mixture was diluted with water and saturated sodium bicarbonate solution (50 mL), then extracted with ethyl acetate (100 mL × 3). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 17b (6.49 g) as a yellow oil.

[0307] To a solution of methyl 3-oxobutanoate (4.10 g, 35.34 mmol, 3.81 mL, 1 eq) and potassium carbonate (4.88 g, 35.34 mmol, 1 eq) in DMF (50 mL) at 25 °C, a solution of compound 17b (6.49 g, 35.34 mmol, 1 eq) in DMF (10 mL) is slowly added, and the mixture is stirred at 25 °C for 16 h. Then, MeI (5.02 g, 35.34 mmol, 2.20 mL, 1 eq) is added dropwise to the mixture at 0 °C, and the mixture is stirred at 25 °C for 2 h. The reaction mixture is treated with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic layer was washed with water (200 mL × 3), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, 0-5% EtOAc / PE) to obtain compound 17c (10 g, 31.87 mmol, yield 75.15%) as a yellow oil.

[0308] Compound 17c (2.5 g, 7.97 mmol, 1 eq) was dissolved in 1,2-dichlorobenzene (30 mL) and stirred at 175 °C for 1 h. The reaction mixture was concentrated under reduced pressure, then triturated with PE / DCM (30 mL, 3 / 1) at 25 °C for 30 min to obtain compound 17d (2.8 g, 9.94 mmol, 62.37% yield) as a yellow solid.

[0309] Compound 17d (500.00 mg, 1.77 mmol, 1 eq) was dissolved in dichloromethane (5 mL), MeCN (5 mL), and water (2.5 mL), and then NaIO4 (1.14 g, 5.32 mmol, 295.00 μL, 3 eq) and RuCl3 (36.81 mg, 177.46 μmol, 11.84 μL, 0.1 eq) were added and stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography (SiO2, 0-5% EtOAc / DCM) to obtain compound 17e (280 mg, 892.41 μmol, yield 50.29%) as a yellow solid.

[0310] Compound 17e (35 mg, 111.55 μmol, 1 eq) was dissolved in MeCN (1 mL), and sodium pyrimidine-5-thiolate (37.69 mg, 278.88 μmol, 2.5 eq) and TEA (33.86 mg, 334.65 μmol, 46.58 μL, 3 eq) were added and 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 / DCM) to obtain compound 17f (26.7 mg, 63.67 μmol, yield 29.20%, purity 95.69%) as a white solid.

[0311] Compound 17f (70 mg, 202.43 μmol, 1 eq) was dissolved in DCE (2 mL), and (COCl)2 (102.77 mg, 809.71 μmol, 70.88 μL, 4 eq) was added at 0 °C and stirred at 60 °C for 3 h. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography (SiO2, 0-5% EtOAc / DCM) to obtain compound 17g (35 mg, 96.09 μmol, yield 47.47%) as a white solid.

[0312] Compound 17 g (34 mg, 93.34 μmol, 1 eq) was dissolved in dichloromethane (1 mL), and meta-chloroperoxybenzoic acid (18.95 mg, 93.34 μmol, purity 85%, 1 eq) was added and stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography (SiO2, 0-5% EtOAc / DCM) to obtain compound 17 (20.5 mg, 53.91 μmol, yield 57.76%, purity 100%) as a white solid.

[0313] 1 H NMR: 400 MHz, CDCl3

[0314] δ = 9.30 (s, 1H), 9.23 (s, 2H), 7.83 (d, J=7.9 Hz, 1H), 7.44 (d, J=7.7 Hz, 1H), 3.01 (s, 3H), 2.83 (s, 3H)

[0315] Example 18. Preparation of 4,5,8-trichloro-3-methyl-2-(pyrimidin-5-ylsulfinyl) quinoline (Compound 18)

[0316]

[0317] Compound 18a (11 g, 69.55 mmol, 1 eq) and compound 18b (101.42 g, 625.98 mmol, 9 eq) were mixed and stirred at 65 °C for 15 h and then at 80 °C for 5 h. After cooling, diluted with water (100 mL), made alkaline with 50% NaOH (w / v) aqueous solution, and extracted with ethyl acetate (100 mL × 3) to remove excess aniline. The alkaline solution was acidified with HCl solution (6 M, 100 mL), extracted with ethyl acetate (100 mL × 3), dried over magnesium sulfate, filtered, evaporated to dryness, and recrystallized from ethyl acetate to obtain compound 18c (8.8 g) as a white solid.

[0318] Compound 18c (6 g, 22.89 mmol, 1 eq) was mixed with PPA (62.82 g, 160.25 mmol, 7 eq) and stirred at 105 °C for 1 hour. One more batch was prepared in the same manner as above, combined, cooled to room temperature, and ice water (100 mL) was slowly added. The resulting precipitate was filtered, washed with water, and dried under reduced pressure in a desiccator to obtain compound 18d (2.1 g, 6.63 mmol, yield 28.94%, purity 77%) as a white solid.

[0319] Compound 18d (1 g, 4.10 mmol, 1 eq) and phosphoryl trichloride (18.85 g, 122.91 mmol, 11.46 mL, 30 eq) were mixed and stirred at 100 °C under nitrogen for 1 h. One more batch was prepared in the same manner as above, combined, and evaporated to remove phosphoryl trichloride. Toluene (10 mL × 3) was added and evaporated. The product was dissolved in dichloromethane (3 mL) and purified by column chromatography (SiO2, 0–5% EtOAc / PE) to obtain compound 18e (1.9 g, purity 98.5%) as a yellow solid.

[0320] Compound 18e (100 mg, 355.92 μmol, 1 eq) was dissolved in AcOH (3 mL), NaOAc (58.39 mg, 711.83 μmol, 2 eq) was added, and the mixture was stirred at 120 °C for 6 h. One more batch was prepared in the same manner as above, combined, and water (5 mL) was added. The solid was filtered, washed with a small amount of water (1 mL × 3), and dried under high vacuum to obtain compound 18f (90 mg, 330.15 μmol, yield 92.76%, purity 96.3%) as a white solid.

[0321] Compound 18f (60 mg, 228.55 μmol, 1 eq), compound 18g (153.29 mg, 1.14 mmol, 5 eq), and Et3N (69.38 mg, 685.66 μmol, 95.44 μL, 3 eq) were mixed in CH3CN (4 mL) and stirred at 70 °C for 2 h. One more batch was prepared in the same manner as above, combined, and evaporated. The crude product was purified by column chromatography (SiO2, 0-1.5% MeOH / DCM) to obtain compound 18h ​​(110 mg) as a yellow solid.

[0322] To a solution of compound 18h ​​(200 mg, 591.35 μmol, 1 eq) in dichloromethane (10 mL) and THF (10 mL) was added (COCl)2 (375.29 mg, 2.96 mmol, 258.82 μL, 5 eq), followed by the addition of DMF (10 drops). The reaction mixture was stirred at 25 °C for 16 h and at 45 °C for 16 h. The reaction mixture was evaporated to obtain the crude product, which was purified by column chromatography (SiO2, 0–40% EtOAc / PE) to obtain compound 18i (80 mg) as a white solid.

[0323] Compound 18i (60 mg, 168.23 μmol, 1 eq) was dissolved in dichloromethane (5 mL), and meta-chloroperoxybenzoic acid (40.98 mg, 201.87 μmol, purity 85%, 1.2 eq) was added in portions and stirred at 25 °C for 2 h. The reaction mixture was evaporated, and the product was dissolved in dichloromethane (2 mL) and purified by column chromatography (SiO2, 0-15% EtOAc / PE) to obtain compound 18 (9.3 mg, 24.41 μmol, yield 14.51%) as a white solid.

[0324] 1 H NMR: 400 MHz, CDCl3

[0325] δ = 9.37 (s, 1H), 9.08 (s, 2H), 7.86 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 2.60 (s, 3H)

[0326] Example 19. Preparation of 3-(1-(aminooxy)-2-methylpropyl)-8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-4-ol (Compound 19)

[0327]

[0328] To a solution of compound 19a (0.2 g, 423.95 μmol, 1 eq) dissolved in tetrahydrofuran (2 mL) and ethanol (2 mL) (see compound 2e described in Example 2 or the preparation method of published Korean Patent No. 10-1879992, etc.), sodium borohydride (48.12 mg, 1.27 mmol, 3 eq) and cerium chloride (156.74 mg, 635.93 μmol, 39.98 μL, 1.5 eq) are added at 0 °C, and the mixture is stirred at 25 °C for 3 hours. The mixture is treated with 1 N hydrochloric acid, extracted with dichloromethane (25 mL × 3), and washed with saturated sodium bicarbonate solution (25 mL × 3). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 19b (160 mg, yield 79.66%) as a white solid.

[0329] Diethylazodicarboxylate (153.65 mg, 882.29 μmol, 160.39 μL, 1.1 eq) was added to a solution of compound 19b (380 mg, 802.08 μmol, 1 eq), 2-hydroxyisoindole-1,3-dione (130.84 mg, 802.08 μmol, 1 eq), and triphenylphosphane (210.37 mg, 802.08 μmol, 1 eq) in THF (6 mL) at 0 °C, and the mixture was stirred for 2 hours to obtain compound 19c.

[0330] At 0 °C, hydrazine hydrate (4.13 g, 82.46 mmol, 4.00 mL, 255.17 eq) was added to compound 19c (200 mg, 323.16 μmol, 1 eq) and stirred at 0 °C for 0.5 h. The reaction mixture was concentrated with nitrogen to obtain a crude product, which was then purified by column chromatography to obtain compound 19 (12 mg, yield 7.60%) as a white solid.

[0331] 1 H NMR: 400 MHz, CDCl3

[0332] δ = 10.37 - 10.02 (m, 2H), 7.90 (br s, 2H), 7.38 - 7.27 (m, 2H), 6.65 (br s, 2H), 5.94 - 5.68 (m, 2H), 4.61 (br d, J = 9.4 Hz, 2H), 3.90 - 3.17 (m, 2H), 2.52 (br s, 6H), 2.31 (br s, 2H), 1.26 (br d, J = 5.4 Hz, 6H), 0.77 (br d, J = 5.6 Hz, 6H)

[0333] Example 20. Preparation of 8-bromo-5-chloro-4-hydroxy-N-methyl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinoline-3-carboxamide (Compound 20)

[0334]

[0335] Compound 20a (100 mg, 484.34 μmol, 1 eq) was dissolved in dichloromethane (7 mL), and sodium carbonate (102.67 mg, 968.68 μmol, 2 eq) and thiocarbonyl dichloride (83.54 mg, 726.51 μmol, 55.69 μL, 1.5 eq) were added at 0–3 °C and stirred at 15 °C for 12 h. Nine additional batches were prepared in the same manner as above, and all ten mixtures were combined and filtered. The filtrate was diluted with sodium bicarbonate solution (100 mL) and extracted with dichloromethane (40 mL × 3). The organic layer was washed with brine (100 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 20b (1.12 g) as a yellow oil.

[0336] Dissolve NaH (216.29 mg, 5.41 mmol, purity 60%, 1.2 eq) in THF (10 mL) and cool to 0-5 °C. Add compound 20c (714.46 mg, 5.41 mmol, 619.65 μL, 1.2 eq) dissolved in THF (10 mL) dropwise to the mixture at 0-3 °C and stir at 0-5 °C for 0.5 h. Then, add compound 20b (1.12 g, 4.51 mmol, 1 eq) dissolved in THF (10 mL) dropwise to the mixture at 0-5 °C and stir for 1 h to obtain compound 20d (1.80 g, yield 94.70%) as a yellow oil.

[0337] Compound 20e (983.04 mg, 5.14 mmol, 1.15 eq) dissolved in THF (10 mL) was added dropwise to compound 20d (1.80 g, 4.47 mmol, 1 eq) dissolved in THF (10 mL) at 0–5 °C and stirred at 0–15 °C for 12 h. The reaction mixture was quenched with water (60 mL) at 0–5 °C and extracted with ethyl acetate (50 mL × 3). The organic layer was washed with brine (25 mL × 2), dried over sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (PE / EtOAc = 10 / 1–1 / 1, Rf = 0.60) to obtain compound 20f (1.60 g, yield 75.23%) as a yellow solid.

[0338] Compound 20f (1 g, 2.10 mmol, 1 eq) was dissolved in 1,2-dichlorobenzene (7 mL), stirred at 180 °C for 15 minutes, cooled to room temperature, and filtered. The filter cake was triturated with MTBE / EtOAc (1 / 1) (10.00 mL) at 15 °C for 5 minutes to obtain compound 20g (600 mg, yield 64.33%) as a white solid.

[0339] Compound 20 g (75 mg, 169.03 μmol, 1 eq) was dissolved in THF (0.75 mL), purged three times with nitrogen, and a solution of methanamine (2 M, 253.55 μL, 3 eq) and a solution of trimethylalumin (2 M, 126.78 μL, 1.5 eq) were added at 0 °C and stirred for 2 h at 25 °C under nitrogen. The reaction mixture was diluted with water (5 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 20h (95 mg) as a white solid.

[0340] Compound 20h (90 mg, 203.29 μmol, 1 eq) was dissolved in dichloromethane (1 mL) and methanol (0.1 mL), and then meta-chloroperoxybenzoic acid (41.27 mg, 203.29 μmol, purity 85%, 1 eq) was added at 0–3 °C and stirred at 25 °C for 0.5 min. The reaction was stopped by adding sodium thiosulfate solution (2.5 mL) to the reaction mixture at 0 °C, the mixture was stirred for 5 min, and then 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 20 (30 mg, yield 32.17%) as a white solid.

[0341] 1 H NMR: 400 MHz, CDCl3

[0342] δ = 9.93 - 9.84 (m, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 6.15 (s, 1H), 4.70 - 4.61 (m, 1H), 4.57 - 4.48 (m, 1H), 3.01 (d, J = 5.0 Hz, 3H), 2.36 (s, 3H)

[0343] Example 21. Preparation of 5,8-dichloro-3-methyl-2-(pyrimidin-5-ylsulfinyl)quinolin-4-ol (Compound 21)

[0344]

[0345] Compound 21a (96 mg, 283.85 μmol, 1 eq) obtained in the same manner as compound 18h ​​described in Example 18 was dissolved in DMF (15 mL), meta-chloroperoxybenzoic acid (74.91 mg, 369.00 μmol, purity 85%, 1.3 eq) was added, and the mixture was stirred at 25 °C for 16 hours. Meta-chloroperoxybenzoic acid (299.66 mg, 1.48 mmol, purity 85%, 5.2 eq) was added, and the mixture was stirred for another 5 hours. One more batch was prepared in the same manner, combined, treated with a 15% aqueous potassium carbonate solution (5 mL), and extracted with dichloromethane (30 mL × 5). The organic layer was washed with water (20 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to obtain a DMF residue (20 mL). The DMF residue was evaporated with an oil pump to less than 5 mL, then the residue was cooled with ice water, filtered, washed with ethyl acetate (2 mL × 3), and dried under high vacuum to obtain compound 21 (20 mg, 56.46 μmol, yield 19.89%, purity 100%) as a white solid.

[0346] 1 H NMR: 400 MHz, DMSO-d6

[0347] δ = 11.54 (br s, 1H), 9.39 (s, 1H), 9.21 (s, 2H), 7.72 (d, J = 8.6 Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), 2.12 (s, 3H)

[0348] Example 22. Preparation of 1-(8-bromo-5-chloro-4-methoxy-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one (Compound 22)

[0349]

[0350] Compound 22a (50.00 mg, 105.44 μmol, 1 eq), obtained in the same manner as compound 2f described in Example 2, was dissolved in methanol (1 mL), sodium methoxide (18.99 mg, 105.44 μmol, purity 30%, 1 eq) was added, and the mixture was stirred at 25 °C for 1 hour. Reaction mixtures were prepared in four vials in the same manner as above. Five reaction mixtures were combined, concentrated under reduced pressure to remove the solvent, diluted with water (12 mL), and extracted with ethyl acetate (15 mL). The organic layer was washed with brine (12 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE:EtOAc = 4:1, Rf = 0.49) to obtain compound 22b (60 mg, yield 24.23%) as a yellow solid.

[0351] Compound 22b was dissolved in dichloromethane (1 mL) and methanol (0.1 mL), and meta-chloroperoxybenzoic acid (25.93 mg, 127.72 μmol, purity 85%, 1 eq) was added at 0 °C and stirred for 2 h. Sodium thiosulfate solution (4 mL) was added at 0 °C and stirred for 0.5 h, after which the mixture was separated. The mixture was washed with sodium bicarbonate solution (4 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 22 (13.8 mg, yield 22.24%) as a white solid.

[0352] 1 H NMR: 400 MHz, CDCl3

[0353] δ = 8.04 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 6.11 (s, 1H), 4.72 - 4.62 (m, 1H), 4.60 - 4.50 (m, 1H), 3.92 (s, 3H), 3.09 (td, J = 6.9, 13.9 Hz, 1H), 2.40 (s, 3H), 1.22 (dd, J = 6.9, 16.3 Hz, 6H)

[0354] Example 23. Preparation of 1-(8-bromo-5-chloro-4-(difluoromethoxy)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one (Compound 23)

[0355]

[0356] Compound 23a (400 mg, 877.67 μmol, 1 eq) obtained in the same manner as compound 2e described in Example 2 was dissolved in acetonitrile (5 mL), and then [bromo(difluoro)methyl]-trimethyl-silane (356.51 mg, 1.76 mmol, 2 eq) and sodium carbonate (3.8 M, 1.39 mL, 6 eq) were added, and the mixture was stirred at 60 °C for 12 h. The reaction mixture was partitioned between water (15 mL) and ethyl acetate (15 mL) to separate the organic layer. The organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (PE:EtOAc = 3:1, Rf = 0.67) to obtain compound 23b (42 mg, yield 9.46%) as a white solid.

[0357] Compound 23b (42 mg, 83.04 μmol, 1 eq) was dissolved in dichloromethane (2 mL) and methanol (0.2 mL), and then meta-chloroperoxybenzoic acid (16.86 mg, 83.04 μmol, purity 85%, 1 eq) was added at 0 °C and stirred for 15 min. Saturated sodium bisulfite solution (4 mL) was added at 0 °C and stirred for 0.5 h, and then the mixture was separated. The organic layer was washed with sodium bicarbonate solution (4 mL) and extracted with dichloromethane (6 mL). Drying over sodium sulfate, filtering, and concentrating under reduced pressure, the residue was purified by column chromatography to obtain compound 23 (13.4 mg, yield 30.93%) as a white solid.

[0358] 1 H NMR: 400 MHz, CDCl3

[0359] δ = 8.11 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 6.60 (dd, J = 72.5, 74.8 Hz, 1H), 6.11 (s, 1H), 4.72 - 4.65 (m, 1H), 4.61 - 4.54 (m, 1H), 3.17 (td, J = 6.9, 13.9 Hz, 1H), 2.40 (s, 3H), 1.25 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 7.1 Hz, 3H)

[0360] Example 24. Preparation of 1-(5,8-dichloro-4-ethoxy-2-((3-(pyrimidin-5-yl)propyl)sulfinyl)quinolin-3-yl)ethan-1-one (Compound 24)

[0361]

[0362] Compound 24a (750 mg, 5.59 mmol, 1 eq) was dissolved in methanol (10 mL), and Pd / C (595.03 mg, 559.14 μmol, 10% purity, 0.1 eq) was added under nitrogen. The suspension was degassed and purged three times with H2. The mixture was stirred at 15°C under H2 (15 psi.) for 15 h. The mixture was filtered through Celite and evaporated to obtain compound 24b (700 mg) as a yellow gum.

[0363] Compound 24b (700 mg, 5.07 mmol, 1 eq) was dissolved in dichloromethane (20 mL), and TEA (1.54 g, 15.20 mmol, 2.12 mL, 3 eq) and methylsulfonyl methanesulfonate (1.77 g, 10.13 mmol, 2 eq) were added and stirred at 15 °C for 1 h. The mixture was diluted with saturated brine (10 mL) and extracted with dichloromethane (20 mL × 3). The organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to obtain compound 24c (1.1 g) as a yellow oil.

[0364] Compound 24c (500 mg, 2.31 mmol, 1 eq) was dissolved in THF (5 mL), potassium ethanethioate (528.11 mg, 4.62 mmol, 2 eq) was added, and the mixture was stirred at 50 °C for 1 h. The mixture was filtered, evaporated, and purified by column chromatography (SiO2, 0–70% EtOAc / PE) to obtain compound 24d (350 mg, 1.69 mmol, yield 73.27%, purity 95%) as a yellow oil.

[0365] To a solution of compound 24d (69.97 mg, 356.48 μmol, 1.2 eq) dissolved in EtOH (2 mL), cesium carbonate (193.58 mg, 594.14 μmol, 2 eq) and compound 24e (see Example 10 or the preparation method of published Korean Patent No. 10-1879992, etc.) (100 mg, 297.07 μmol, 1 eq) were added, and the mixture was stirred at 15 °C for 1 h. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography (SiO2, 0-50% EtOAc / PE) to obtain compound 24f (45 mg, 61.88 μmol, 20.83% yield, 60% purity) as a light yellow oil.

[0366] Compound 24f (45 mg, 103.13 μmol, 1 eq) was dissolved in dichloromethane (1 mL), and meta-chloroperoxybenzoic acid (20.94 mg, 103.13 μmol, purity 85%, 1 eq) was added and stirred at 15 °C for 1 h. The mixture was filtered, concentrated in vacuo, and purified by column chromatography to obtain compound 24 (6.9 mg, 14.20 μmol, 13.77% yield, 93.09% purity) as a white solid.

[0367] 1 H NMR: 400 MHz, CDCl3

[0368] δ = 9.11 (s, 1 H), 8.63 (s, 2 H), 7.73 (d, 1 H), 7.43 (d, 1 H), 4.50 - 4.82 (m, 2 H), 3.25 - 3.57 (m, 2 H), 2.84 (br t, 2 H), 2.63 (s, 3) H), 2.14 - 2.40 (m, 2 H), 1.48 (t, 3 H)

[0369] Example 25.1-(5,8-dichloro-4-(4-(pentafluoro-λ 6Preparation of -sulfaneyl)phenoxy)-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)ethan-1-one (compound 25)

[0370]

[0371] Potassium carbonate (143.68 mg, 623.79 μmol, 197.64 μL, 2 eq) and compound 25b (103.00 mg, 467.84 μmol, 1.5 eq) were added to a solution of compound 25a (see Example 10 or the preparation method of published Korean Patent No. 10-1879992, etc.) dissolved in DMF (1 mL), and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with water (1 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 (100 mg, 198.29 μmol, yield 63.57%) as a yellow solid.

[0372] Compound 25c (85 mg, 168.54 μmol, 1 eq) was dissolved in dichloromethane (2 mL), and meta-chloroperoxybenzoic acid (68.44 mg, 337.09 μmol, 85% purity, 2 eq) was added and stirred at 25 °C for 1 h. The reaction mixture was diluted with water (3 mL) and extracted with dichloromethane (3 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (SiO2, 0-15% EtOAc / PE) to obtain compound 25d (100 mg, 186.46 μmol, yield 88.50%) as a white solid.

[0373] Compound 25d (50 mg, 93.23 μmol, 1 eq) was dissolved in MeCN (2 mL), and TEA (28.30 mg, 279.68 μmol, 38.93 μL, 3 eq) and compound 25e (22.51 mg, 167.81 μmol, 1.8 eq) were added and stirred at 25 °C for 2 h. The reaction mixture was diluted with water (1 mL) and extracted with ethyl acetate (1 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, 0–4% EtOAc / PE) to give compound 25f (35 mg, 61.58 μmol, 66.05% yield) as a white solid.

[0374] Compound 25f (31 mg, 54.54 μmol, 1 eq) was dissolved in dichloromethane (0.7 mL), and meta-chloroperoxybenzoic acid (16.61 mg, 81.81 μmol, 85% purity, 1.5 eq) was added and stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, 5–60% MeCN / H2O (0.05% FA)) to obtain compound 25 (16 mg, 27.13 μmol, 49.74% yield, 99.08% purity) as a white solid.

[0375] 1 H NMR: 400 MHz, CDCl3

[0376] δ = 9.35 (s, 1H), 9.30 (s, 2H), 7.91 (d, J=8.4 Hz, 1H), 7.70 - 7.64 (m, 2H), 7.62 (d, J=8.3 Hz, 1H), 6.69 (d, J=9.1 Hz, 2H), 2.69 (s, 3H)

[0377] Example 26. Preparation of 1-(5,8-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one (Compound 26)

[0378]

[0379] Compound 26a (2 g, 6.62 mmol, 1 eq) and POBr3 (2.20 g, 9.93 mmol, 1.5 eq), obtained in the same manner as compound 10d, were dissolved in DCE (20 mL), DMF (48.38 mg, 661.87 μmol, 50.92 μL, 0.1 eq) was added, and the mixture was stirred at 50 °C under nitrogen for 3 hours. The reaction mixture was added to saturated sodium bicarbonate (30 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography (PE:EtOAc=1:0~30:1) to obtain compound 26b (1.3 g, 3.43 mmol, yield 51.86%, purity 96.388%) as a yellow solid.

[0380] Compound 26b (0.5 g, 1.37 mmol, 1 eq) was dissolved in THF (30 mL), and n-BuLi (2.5 M, 602.62 μL, 1.1 eq) was added at -70 °C and stirred for 15 min. NH4Cl (25 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (3 × 20 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography (PE:EtOAc=1:0∼30:1) to obtain compound 26c (0.2 g, 566.92 μmol, yield 41.39%, purity 81.120%) as a yellow solid.

[0381] Compound 26c (200 mg, 698.87 μmol, 1 eq) was dissolved in dichloromethane (15 mL), and then meta-chloroperoxybenzoic acid (203.52 mg, 943.47 μmol, purity 80%, 1.35 eq) was added and stirred at 25 °C for 1 h. Dichloromethane (30 mL) was added to the reaction mixture, and the resulting mixture was washed with saturated sodium sulfite (2 × 15 mL), saturated sodium carbonate (15 mL), and brine (15 mL), dried over sodium sulfate, filtered, and concentrated to obtain compound 26d (0.2 g) as a yellow solid.

[0382] To a solution of S-[(5-methylisoxazol-3-yl)methyl]ethanethioate (42.50 mg, 248.20 μmol, 1.5 eq) and compound 26d (50 mg, 165.47 μmol, 1 eq) in EtOH (5 mL) was added cesium carbonate (107.82 mg, 330.93 μmol, 2 eq) and stirred at 25 °C for 2 h. Ethyl acetate (50 mL) was added to the reaction mixture, and the resulting mixture was washed with brine (3 × 15 mL), dried over sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography (PE:EtOAc = 50:1∼10:1) to obtain compound 26e (50 mg, purity 79.162%) as a yellow solid.

[0383] Compound 26e (25 mg, 40.08 μmol, 1 eq) was dissolved in dichloromethane (1 mL), and then meta-chloroperoxybenzoic acid (9.51 mg, 44.09 μmol, purity 80%, 1.1 eq) was added and stirred at 25 °C for 1 h. Dichloromethane (30 mL) was added to the resulting mixture, and the resulting mixture was washed with saturated sodium sulfite (2 × 15 mL), saturated sodium carbonate (15 mL), and brine (15 mL), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 26 (14.2 mg, purity 100%) as a white solid.

[0384] 1 H NMR: 400 MHz, DMSO-d6

[0385] δ = 9.16 (s, 1H), 8.22 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 6.30 (d, J = 0.6 Hz, 1H), 4.53 (d, J = 13.4 Hz, 1H), 4.10 (d, J = 13.6 Hz, 1H), 2.84 (s, 3H), 2.39 (s, 3H)

[0386] Example 27. Preparation of 1-(5,8-dichloro-4-methyl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one (Compound 27)

[0387] (1) Preparation of (5-methylisoxazol-3-yl)methanethiol

[0388]

[0389] S-((5-methylisoxazol-3-yl)methyl)ethanethiol (112.57 mg) was obtained as a yellow oil by dissolving S-((5-methylisoxazol-3-yl)methyl)ethanethiol (150 mg, 876.08 μmol, 1 eq) in methanol (2 mL), adding potassium carbonate (242.17 mg, 1.75 mmol, 2 eq) and stirring at 25 °C for 10 minutes.

[0390] (2) Preparation of 1-(5,8-dichloro-4-methyl-2-(((5-methylisoxazol-3-yl)methyl) sulfinyl)quinolin-3-yl)-2-methylpropan-1-one (Compound 27)

[0391]

[0392] Compound 27a (2 g, 9.71 mmol, 1 eq) was dissolved in dimethylformamide (100 mL), then 4-methylmorpholine (4.42 g, 43.68 mmol, 4.80 mL, 4.5 eq), [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium; hexafluorophosphate (5.52 g, 14.56 mmol, 1.5 eq), and N-methoxymethanamine (889.40 mg, 14.56 mmol, 1.5 eq) were added and stirred at 25 °C for 12 h. After preparing four other vials in the same manner as above, all five mixtures were combined, cooled by adding water (150 mL) at 25 °C, and extracted with ethyl acetate (150 mL × 3). The organic layer was washed with brine (25 mL × 2), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EtOAc = 100 / 0~4 / 1, Rf = 0.40) to obtain compound 27b (7 g, yield 57.90%) as a yellow solid.

[0393] Compound 27b (5 g, 20.07 mmol, 1 eq) was dissolved in THF (50 mL), and a solution of lithium methide (1 M in THF, 160.58 mL, 8 eq) was added at -78 °C and stirred at 25 °C for 3 h. A 2N aqueous hydrochloride solution (150 mL) was added dropwise to the mixture at 0 °C to stop the reaction, and the mixture was stirred at 25 °C for 30 min. The mixture was extracted with ethyl acetate (200 mL × 3). The organic layer was washed with brine (200 mL × 3), dried over sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (PE / EtOAc = 100 / 0~17 / 3, Rf = 0.40) to obtain compound 27c (1 g, yield 24.41%) as a yellow oil.

[0394] Compound 27c (500 mg, 2.45 mmol, 1 eq) was dissolved in methyl 4-methyl-3-oxopentanoate (3 mL), CeCl3 (120.79 mg, 490.07 μmol, 30.81 μL, 0.2 eq) was added, and the mixture was stirred at 160 °C for 15 minutes. After preparing one vial in the same manner as above, the two mixtures were combined, filtered, and the filter cake was ground with PE (10.00 mL) at 15 °C for 10 minutes to obtain compound 27d (1 g, yield 68.44%) as a yellow solid.

[0395] Compound 27d (500 mg, 1.68 mmol, 1 eq) was dissolved in phosphoryl trichloride (5 mL) and stirred at 100 °C for 3 hours. After preparing one vial in the same manner as above, the two mixture solutions were combined, cooled to 15 °C, treated with water (50 mL), and extracted with ethyl acetate (3 × 20 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 27e (800 mg) as a yellow solid.

[0396] Compound 27e (600 mg, 1.90 mmol, 1 eq) was dissolved in 1-methylpyrrolidin-2-one (6 mL), sodium thiomethoxide (199.24 mg, 2.84 mmol, 181.12 μL, 1.5 eq) was added, and the mixture was stirred at 90 °C for 0.5 h. The reaction mixture was cooled to 15 °C, treated with water (30 mL), and extracted with ethyl acetate (10 mL 3 × 3). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (PE:EtOAc = 3:1, Rf = 0.6) to obtain compound 27f (240 mg, yield 38.58%) as a yellow solid.

[0397] Compound 27f (100 mg, 304.64 μmol, 1 eq) was dissolved in dichloromethane (1 mL), and meta-chloroperoxybenzoic acid (61.85 mg, 304.64 μmol, purity 85%, 1 eq) was added at 0 °C and stirred for 0.5 h. After making two vials in the same way as above, all three mixtures were combined and sodium thiosulfate solution (10 mL) was added at 0 °C to stop the reaction, and the mixture was stirred for 5 minutes and then 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 triturated with methyl tert-butyl ether (MTBE) at 15 °C for 15 minutes to obtain 27 g (300 mg, yield 95.35%) of the compound as a white solid.

[0398] Compound 27g (250 mg, 726.20 μmol, 1 eq) was dissolved in methanol (3 mL), potassium carbonate (100.37 mg, 726.20 μmol, 1 eq) and (5-methylisoxazol-3-yl)methanethiol (112.57 mg, 871.45 μmol, 1.2 eq) were added, and the mixture was stirred at 25 °C for 10 minutes. The reaction mixture was treated with water (10 mL) to stop the reaction, and then extracted with ethyl acetate (5 mL × 3). The mixture was washed with sodium bicarbonate solution (5 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (PE:EtOAc = 3:1, Rf = 0.7) to obtain compound 27h (110 mg, yield 37.01%).

[0399] Compound 27h (90 mg, 219.87 μmol, 1 eq) was dissolved in dichloromethane (2.5 mL), and meta-chloroperoxybenzoic acid (44.64 mg, 219.87 μmol, purity 85%, 1 eq) was added at 0 °C and stirred for 0.5 h. The reaction mixture was stopped by adding sodium thiosulfate solution (5 mL) at 0 °C, stirred for 5 minutes, 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 27 (59.2 mg, yield 63.30%) as a white solid.

[0400] 1 H NMR: 400 MHz, CDCl3

[0401] δ = 7.81 (br d, J = 8.1 Hz, 1H), 7.68 (br d, J = 8.2 Hz, 1H), 6.08 (s, 1H), 4.69 - 4.59 (m, 1H), 4.58 - 4.47 (m, 1H), 3.04 (td, J = 6.9, 13.8 Hz, 1H), 2.96 (s, 3H), 2.40 (s, 3H), 1.23 (br dd, J = 7.0, 14.0 Hz, 6H)

[0402] Example 28. Preparation of 1-(5,8-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-(trifluoromethyl)quinolin-3-yl)-2-methylpropan-1-one (Compound 28)

[0403]

[0404] DMF (22.13 mg, 302.82 μmol, 23.30 μL, 0.1 eq) is added to a DCE (10 mL) solution of compound 28a (see Examples 2, 10 or the preparation method of published Korean Patent No. 10-1879992, etc.) (1 g, 3.03 mmol, 1 eq) and POBr3 (1.30 g, 4.54 mmol, 461.78 μL, 1.5 eq), heated to 50 °C, and stirred at 50 °C under nitrogen for 3 h. The reaction mixture is added to saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography (PE:EtOAc=1:0~30:1) to obtain compound 28b (0.65 g, 1.65 mmol, yield 54.60%) as a yellow solid.

[0405] To a solution of compound 28b (0.65 g, 1.65 mmol, 1 eq) and compound 28c (635.29 mg, 3.31 mmol, 420.72 μL, 2 eq) dissolved in DMF (10 mL) was added CuI (629.79 mg, 3.31 mmol, 2 eq), heated to 125 °C, and stirred at 125 °C under nitrogen for 16 h. Ethyl acetate (50 mL) was added to the reaction mixture, and the resulting mixture was washed with brine (4 × 15 mL), dried over sodium sulfate, filtered, concentrated to dryness, and then purified by column chromatography (PE:EtOAc=1:0∼30:1) to obtain compound 28d (0.6 g, 1.57 mmol, yield 94.94%) as a yellow solid.

[0406] Compound 28d (0.3 g, 784.87 μmol, 1 eq) was dissolved in dichloromethane (10 mL), and then meta-chloroperoxybenzoic acid (203.16 mg, 941.85 μmol, purity 80%, 1.2 eq) was added and stirred at 25 °C for 1 h. Dichloromethane (30 mL) was added to the reaction mixture, and the resulting mixture was washed with saturated sodium sulfite (2 × 15 mL), saturated sodium carbonate (15 mL), and brine (15 mL), dried over sodium sulfate, filtered, and concentrated to obtain compound 28e (0.37 g) as a yellow solid.

[0407] To a solution of compound 28f (257.97 mg, 1.51 mmol, 2 eq) and compound 28e (0.3 g, 753.34 μmol, 1 eq) dissolved in DMF (10 mL) was added cesium carbonate (490.90 mg, 1.51 mmol, 2 eq) and stirred at 70 °C for 16 h. Ethyl acetate (50 mL) was added to the reaction mixture, and the resulting mixture was washed with brine (3 × 15 mL), dried over sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography (PE:EtOAc=15:1) to obtain compound 28g (152 mg, 193.15 μmol, yield 25.64%, purity 58.874%) as a yellow solid.

[0408] After dissolving 28 g (72 mg, 91.49 μmol, 1 eq) of the compound in dichloromethane (3 mL), meta-chloroperoxybenzoic acid (21.71 mg, 100.64 μmol, purity 80%, 1.1 eq) is added and stirred at 25 °C for 1 hour. Dichloromethane (30 mL) was added to the reaction mixture, and the resulting mixture was washed with saturated sodium sulfite (2 × 15 mL), saturated sodium carbonate (15 mL), and brine (15 mL), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to give two isomeric forms of compound 28-1 (11.2 mg, 22.08 μmol, yield 24.13%, purity 94.470%) as a yellow solid and compound 28-2 (18.3 mg, 36.87 μmol, yield 40.29%, purity 96.559%) as a yellow solid.

[0409] 1 H NMR: 400 MHz, CDCl3 (compound 28-1)

[0410] δ = 8.21 (s, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 6.01 (s, 1H), 4.50 - 4.40 (m, 1H), 4.33 - 4.24 (m, 1H), 2.35 (s, 3H), 1.55 (d, J = 1.0 Hz, 3H), 1.35 (s, 3H)

[0411] 1 H NMR: 400 MHz, CDCl3 (compound 28-2)

[0412] δ = 8.19 (br s, 1H), 7.35 - 7.30 (m, 1H), 7.27 - 7.22 (m, 1H), 6.14 (s, 1H), 4.45 - 4.37 (m, 1H), 4.32 - 4.25 (m, 1H), 2.34 (s, 3H), 1.64 (s, 6H)

[0413] Example 29. Preparation of 1-(8-chloro-5-methyl-2-(pyrimidin-5-ylsulfinyl)-4-(trifluoromethyl)quinolin-3-yl)ethan-1-one (Compound 29)

[0414]

[0415] Compound 29a (500 mg, 1.77 mmol, 1 eq), obtained in the same manner as compound 17d, was dissolved in DCE (10 mL), POBr3 (763.12 mg, 2.66 mmol, 270.61 μL, 1.5 eq) and DMF (12.97 mg, 177.46 μmol, 13.65 μL, 0.1 eq) were added, and the mixture was stirred at 25 °C for 16 hours. The reaction was stopped by treating the reaction mass with water (10 mL) at 25 °C, and extracted with dichloromethane (20 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 29b (50 mg, 145.07 μmol, yield 8.18%) as a yellow solid.

[0416] After mixing compound 29b (20 mg, 58.03 μmol, 1 eq), compound 29c (22.30 mg, 116.06 μmol, 14.77 μL, 2 eq), and CuI (22.10 mg, 116.06 μmol, 2 eq) in DMF (0.5 mL), degassed and purged with nitrogen three times, the mixture was stirred at 100 °C under nitrogen for 1 h. The reaction mixture was diluted with water (1 mL) and NH4OH (0.05 mL), and extracted with dichloromethane (2 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 29d (10 mg, 29.96 μmol, yield 51.63%) as a white solid.

[0417] Compound 29d (73 mg, 218.72 μmol, 1 eq) was dissolved in dichloromethane (2 mL), and meta-chloroperoxybenzoic acid (111.01 mg, 546.81 μmol, purity 85%, 2.5 eq) was added and stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-10% EtOAc / PE) to obtain compound 29e (80 mg, 218.73 μmol, yield 95.24%) as a white solid.

[0418] Compound 29f (48.03 mg, 355.43 μmol, 2 eq) and TEA (53.95 mg, 533.14 μmol, 74.21 μL, 3 eq) were added to a solution of compound 29e (65 mg, 177.71 μmol, 1 eq) dissolved in MeCN (2 mL), and the mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography (SiO2, 0-10% EtOAc / DCM) to obtain compound 29g (50 mg, 125.69 μmol, 70.73% yield) as a white solid.

[0419] Compound 29 g (40 mg, 100.55 μmol, 1 eq) was dissolved in dichloromethane (1 mL), and meta-chloroperoxybenzoic acid (24.50 mg, 120.66 μmol, purity 85%, 1.2 eq) was added and stirred at 0 °C for 3 h. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography (SiO2, 0-15% EtOAc / PE) to obtain compound 29 (21.3 mg, 48.67 μmol, yield 48.40%, purity 94.55%) as a white solid.

[0420] 1 H NMR: 400 MHz, CDCl3

[0421] δ = 9.33 (s, 1H), 9.28 (s, 2H), 7.87 (d, J=7.9 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 2.88 (d, J=1.1 Hz, 3H), 2.77 (d, J=2.4 Hz, 3H)

[0422] Example 30. 5,8-dichloro-3-isobutyryl-2-((pyrimidin-5-ylmethyl)

[0423] Preparation of sulfinyl)quinoline-4-carbonitrile (compound 30)

[0424] (1) Preparation of 5,8-dichloro-3-(isobutyryl)-2-(methylsulfinyl)quinoline-4-carbonitrile (compound 30d)

[0425]

[0426] To a solution of 1-(5,8-dichloro-4-hydroxy-2-(methylthio)quinolin-3-yl)-2-methylpropan-1-one (2 g, 6.06 mmol, 1 eq) and POBr3 (2.60 g, 9.08 mmol, 923.55 μL, 1.5 eq) in DCE (20 mL) was added DMF (44.27 mg, 605.64 μmol, 46.60 μL, 0.1 eq), heated to 50 °C, and stirred at 50 °C under nitrogen for 2 h. The reaction mixture was added to saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography (PE:EtOAc=1:0~30:1) to obtain 1-(4-bromo-5,8-dichloro-2-(methylthio)quinolin-3-yl)-2-methylpropan-1-one (1.65 g, 3.90 mmol, yield 64.38%, purity 92.905%) as a yellow solid.

[0427] To a solution of 1-(4-bromo-5,8-dichloro-2-(methylthio)quinolin-3-yl)-2-methylpropan-1-one (500 mg, 1.27 mmol, 1 eq) and cyanocopper (227.82 mg, 2.54 mmol, 555.67 μL, 2 eq) in NMP (5 mL) was added CuI (24.22 mg, 127.19 μmol, 0.1 eq), heated to 120 °C, and stirred at 120 °C for 5 h under nitrogen. Ethyl acetate (50 mL) was added to the reaction mixture, and the resulting mixture was washed with brine (4 × 15 mL), dried over sodium sulfate, filtered, and concentrated to dryness to obtain a yellow gum (1.2 g). The yellow gum was purified by column chromatography (PE:EtOAc=1:0~30:1) to obtain 5,8-dichloro-3-isobutyryl-2-(methylthio)quinoline-4-carbonitrile (380 mg, purity 78.298%) as a yellow solid.

[0428] 5,8-Dichloro-3-isobutyryl-2-(methylthio)quinoline-4-carbonitrile (280 mg, 825.38 μmol, 1 eq) was dissolved in dichloromethane (5 mL), and then meta-chloroperoxybenzoic acid (240.36 mg, 1.11 mmol, 80% purity, 1.35 eq) was added and stirred at 25 °C for 1 h. Dichloromethane (50 mL) was added to the reaction mixture, and the resulting mixture was washed with saturated sodium sulfite (2 × 15 mL), saturated sodium carbonate (15 mL), and brine (15 mL), dried over sodium sulfate, filtered, and concentrated to obtain compound 30d (0.3 g) as a yellow solid.

[0429] (2) Preparation of 5,8-dichloro-3-isobutyryl-2-((pyrimidin-5-ylmethyl)sulfinyl)quinoline-4-carbonitrile (Compound 30)

[0430]

[0431] To a solution of compound 30a (1 g, 9.08 mmol, 1 eq) and methylsulfonyl methanesulfonate (2.37 g, 13.62 mmol, 1.5 eq) in dichloromethane (10 mL) was added TEA (1.84 g, 18.16 mmol, 2.53 mL, 2 eq) and stirred at 25 °C under nitrogen for 3 h. The reaction mixture was added to saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography (PE:EtOAc=10:1∼1:1) to obtain compound 30b (1.65 g, 8.77 mmol, yield 96.54%) as a yellow solid.

[0432] Compound 30b (1.65 g, 8.77 mmol, 1 eq) was dissolved in THF (30 mL), potassium ethanethiolate (2.00 g, 17.53 mmol, 2 eq) was added, heated to 50 °C, and stirred at 50 °C under nitrogen for 1 h. The reaction mixture was concentrated to dryness, and then purified by column chromatography (PE:EtOAc = 10:1~1:1) to obtain compound 30c (0.8 g, 4.48 mmol, yield 51.12%, purity 94.244%) as a yellow oil.

[0433] Compound 30c (84.29 mg, 501.07 μmol, 2 eq) is dissolved in EtOH (3 mL), cesium carbonate (163.26 mg, 501.07 μmol, 2 eq) is added, and the mixture is stirred at 25 °C for 1 hour. A solution of compound 30d (89 mg, 250.54 μmol, 1 eq) dissolved in DMF (1 mL) is added to the reaction mixture, and the resulting mixture is stirred at 25 °C for another hour. After adding ethyl acetate (50 mL) to the resulting mixture, the resulting mixture was washed with brine (3 × 15 mL), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography (PE:EtOAc=15:1~2:1) to obtain compound 30e (25 mg, 19.40 μmol, yield 7.74%, purity 32.388%) as a yellow solid.

[0434] Compound 30e (25 mg, 19.40 μmol, 1 eq) was dissolved in dichloromethane (1 mL), and then meta-chloroperoxybenzoic acid (5.65 mg, 26.19 μmol, purity 80%, 1.35 eq) was added and stirred at 0 °C for 0.5 h. Dichloromethane (20 mL) was added to the reaction mixture, and the resulting mixture was washed with saturated sodium sulfite (2 × 15 mL), saturated sodium carbonate (15 mL), and brine (15 mL), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 30 (0.5 mg, 1.01 μmol, yield 5.20%, purity 87.397%) as a yellow solid.

[0435] 1 H NMR: 400 MHz, CDCl3

[0436] δ = 9.16 (s, 1H), 8.52 (s, 2H), 8.03 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 4.75 - 4.62 (m, 1H), 4.57 - 4.46 (m, 1H), 3.30 - 3.17 (m, 1H), 1.27 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 7.0 Hz, 3H)

[0437] Example 31. Preparation of 1-(8-chloro-4-hydroxy-2-(((5-methylisoxazol-3-yl)methyl) sulfinyl)-5-(methylsulfonyl)quinolin-3-yl)-2-methylpropan-1-one

[0438]

[0439] Compound 31a (9.5 g, 46.88 mmol) was dissolved in THF (100 mL), and DPPA (14.19 g, 51.56 mmol, 11.13 mL) and TEA (6.17 g, 60.94 mmol, 8.48 mL, 1.3 eq) were added and stirred at 70 °C for 1 h. After cooling to room temperature, water (35 mL) was added and stirred at 70 °C for 2 h. The reaction was stopped by adding water (30 mL) at 25 °C and extracted with ethyl acetate (50 mL × 3). The organic layer was washed with brine (50 mL × 2), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, PE / EtOAc=1 / 0~20 / 1) to obtain compound 31b (5 g, yield 61.42%) as a colorless oil.

[0440] Compound 31b (5 g, 28.79 mmol) was dissolved in dichloromethane (30 mL) and water (60 mL), and CSCl2 (3.64 g, 31.67 mmol, 2.43 mL) and sodium bicarbonate (24.19 g, 287.91 mmol, 11.20 mL) were added at 0 °C, and the mixture was stirred at 20 °C for 2 h. The reaction mixture was filtered, the filtrate was diluted with water (30 mL), and then extracted with dichloromethane (30 mL × 3). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 31c (5.9 g) as a yellow solid.

[0441] After dissolving compound 31c (5 g, 23.18 mmol) in DMF (30 mL), methyl 4-methyl-3-oxopentanoate (3.34 g, 23.18 mmol, 3.30 mL) and potassium carbonate (3.20 g, 23.18 mmol) are added at 20 °C and stirred at 20 °C for 12 hours.

[0442] Methyl (E)-2-(((2-chloro-5-(methylthio)phenyl)amino)(mercapto)methylene)-4-methyl-3-oxopentanoate (8.34 g, 23.17 mmol) was dissolved in DMF (30 mL), MeI (3.29 g, 23.17 mmol, 1.44 mL) was added at 0 °C, and the mixture was stirred at 20 °C for 2 h. Water (30 mL) was added to the reaction mixture to stop the reaction, and then extracted with ethyl acetate (20 mL × 3). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (SiO2, PE / EtOAc=1 / 0~0 / 1) to obtain compound 31d (8.2 g, yield 94.63%) as a yellow oil.

[0443] Compound 31d (7.7 g, 20.59 mmol) was dissolved in 1,2-dichlorobenzene (50 mL), stirred at 175°C under nitrogen for 1 hour, concentrated under reduced pressure, and purified by column chromatography (SiO2, PE / EtOAc=1 / 0~1 / 1) to obtain compound 31e (5 g, yield 71.02%) as a yellow solid.

[0444] Compound 31e (500 mg, 1.46 mmol) was dissolved in dichloromethane (6 mL), and meta-chloroperoxybenzoic acid (1.19 g, 5.85 mmol, purity 85%) was added and stirred at 0 °C for 3 hours. After cooling the reaction mixture to room temperature, sodium sulfite (5 mL) was added at 20 °C to stop the reaction, and extracted with ethyl acetate (5 mL × 3). The organic layer was washed with sodium bicarbonate (5 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 31f (500 mg, yield 87.69%) as a yellow solid.

[0445] S-((5-methylisoxazol-3-yl)methyl)ethanethioate (217 mg, 1.2 mmol) was dissolved in methanol (5 mL), potassium carbonate (290 mg, 2.12 mmol) was added, and the mixture was stirred at 25 °C for 1 h. Compound 31f (415 mg, 1.06 mmol) was added to the mixture, and the mixture was stirred at 25 °C under nitrogen for 0.5 h. Water (5 mL) was added to the reaction mixture to stop the reaction, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic layer was washed with aqueous NaCl (5 mL × 2), dried over sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (SiO2, PE / EtOAc=1 / 0~1 / 1) to obtain compound 31g (300 mg, yield 61.95%) as a yellow solid.

[0446] Compound 31 g (150 mg, 0.329 mmol) was dissolved in dichloromethane (2 mL), and meta-chloroperoxybenzoic acid (66.94 mg, 0.33 mmol, purity 85%) was added. The mixture was stirred at 0 °C under nitrogen for 2 hours. The reaction was stopped by adding sodium sulfite (4 mL) at 20 °C and extracted with dichloromethane (3 mL × 3). The organic layer was washed with sodium bicarbonate (3 mL × 2), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 31 (41.39 mg, yield 26.66%) as a white solid.

[0447] 1 H NMR: 400 MHz, CDCl3

[0448] δ = 10.63 (br s, 1H), 8.38 (d, J=8.4 Hz, 1H), 7.88 (d, J=8.4 Hz, 1H), 6.16 (s, 1H), 4.59-4.38 (m, 2H), 4.12 (dt, J=13.6, 6.8 Hz, 1H), 3.73 (s, 3H), 2.38 (s, 3H), 1.21 (dd, J=14.4, 6.8 Hz, 6H)

[0449] The compound structures and compound names of Examples 1 to 31 are as shown in Table 1 below.

[0450] Example structural compound name 1 1-(8-bromo-4,5-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one2 1-(8-Bromo-4,5-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one 3 1-(4,5-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-8-((trimethylsilyl)ethynyl)quinolin-3-yl)-2-methylpropan-1-one4 1-(4,5-dichloro-8-ethynyl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one5 4,5,8-Trichloro-N,N-dimethyl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinoline-3-carboxamide6 1-(4,5,8-Trichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one7 4,5,8-Trichloro-N,N-dimethyl-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfinyl)quinoline-3-carboxamide8 1-(4,5,8-Trichloro-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1one9 4,5,8-Trichloro-N-(2-methoxyethyl)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinoline-3-carboxamide10 1-(4,5,8-trichloro-2-((pyrimidin-5-ylmethyl)sulfinyl)quinolin-3-yl)ethan-1-one 11 Cyclopropyl(4,5,8-trichloro-2-((pyrimidin-5-ylmethyl)sulfinyl)quinolin-3-yl)methan-1-one 12 2-Methyl-1-(4,5,8-trichloro-2-((2-(pyrimidin-5-yl)ethyl)sulfinyl)quinolin-3-yl)propan-1-one13 Cyclopropyl(4,5,8-trichloro-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)methan-1-one 14 4,8-Dichloro-3-isobutyryl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinoline-5-carbonitrile15 1-(4,8-dichloro-5-methyl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one16 1-(4,5,8-Trichloro-2-((1-methyl-1H-pyrazol-3-yl)sulfinyl)quinolin-3-yl)ethan-1-one17 1-(4,8-dichloro-5-methyl-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)ethan-1-one18 4,5,8-Trichloro-3-methyl-2-(pyrimidin-5-ylsulfinyl)quinoline19 3-(1-(aminooxy)-2-methylpropyl)-8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-4-ol20 8-Bromo-5-chloro-4-hydroxy-N-methyl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinoline-3-carboxamide21 5,8-Dichloro-3-methyl-2-(pyrimidin-5-ylsulfinyl)quinolin-4-ol22 1-(8-Bromo-5-chloro-4-methoxy-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one23 1-(8-Bromo-5-chloro-4-(difluoromethoxy)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one24 1-(5,8-dichloro-4-ethoxy-2-((3-(pyrimidin-5-yl)propyl)sulfinyl)quinolin-3-yl)ethan-1-one25 1-(5,8-dichloro-4-(4-(pentafluoro-lambda 6 -sulfanyl)phenoxy)-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)ethan-1-one 26 1-(5,8-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one27 1-(5,8-dichloro-4-methyl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one28 1-(5,8-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-(trifluoromethyl)quinolin-3-yl)-2-methylpropan-1-one29 1-(8-chloro-5-methyl-2-(pyrimidin-5-ylsulfinyl)-4-(trifluoromethyl)quinolin-3-yl)ethan-1-one30 5,8-Dichloro-3-isobutyryl-2-((pyrimidin-5-ylmethyl)sulfinyl)quinoline-4-carbonitrile 31 1-(8-chloro-4-hydroxy-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-5-(methylsulfonyl)quinolin-3-yl)-2-methylpropan-1-one

[0451]

[0452] [Experimental Example]

[0453] Experimental Example 1. Stability Evaluation

[0454] 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.

[0455] Specifically, the evaluation was conducted in the following manner.

[0456] 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.

[0457] 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.

[0458] 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.

[0459] 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.

[0460] 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.

[0461] 6) Centrifuge at 13,000 rpm for 3 minutes and filter the supernatant through a 0.2 μm filter.

[0462] 7) The spectral area of ​​the introduced compound was measured using HPLC (Agilent HPLC 1260). This was used as the reference concentration.

[0463] 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.

[0464] 9) Centrifuge at 13,000 rpm for 3 minutes and filter the supernatant through a 0.2 μm filter.

[0465] 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.

[0466] 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.

[0467] 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 32) and VPC-70619 (CAS 2361742-30-3, compound 33), which are currently used as Myc transcription factor inhibitors, were used as control compounds.

[0468] [Compound 32]

[0469]

[0470] [Compound 33]

[0471]

[0472]

[0473] Example Stability Evaluation (Half-life) Plasma Stability Liver Metabolic Stability 11.4 hours 0.76 hours 21.5 hours 0.85 hours 32.6 hours 5.76 hours 47.40 hours 2.16 hours 5> 24 hours 1.37 hours 612.77 hours 0.49 hours 7> 24 hours 9.16 hours 89.71 hours 0.78 hours 915.68 hours 0.43 hours 105.11 hours 0.35 hours 112.9 hours 0.43 hours 124.7 hours 0.83 hours 132.6 hours < 0.1 hours 140.8 hours 0.36 hours 151.5 hours 1.67 hours 165.3 hours 0.16 hours 173.9 hours 0.27 hours 1810.3 hours 0.17 hours 19N / AN / A20> 24 hours 2.64 hours 21> 24 hours 1.65 hours 22> 24 hours 0.93 hours 23> 24 hours 0.54 hours 24 15.1 hours 23.46 hours 25 0.4 hours 0.18 hours 26> 24 hours 0.29 hours 27 2.23 hours < 0.1 hours 28> 24 hours 0.42 hours 29 0.32 hours 30 0.4 hours 0.22 hours 31 22.6 hours 0.57 hours 32 (control compound 10058-F4)> 24 hours> 24 hours 33 (control compound VPC-70619)> 24 hours> 24 hours

[0474]

[0475] 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 3, 4, 5, 7, 15, 20, 21, and 24.

[0476]

[0477] Experimental Example 2. Evaluation of Transcription Factor Activity

[0478] 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.

[0479] Specifically, the evaluation was conducted in the following manner.

[0480] 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.

[0481] 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.

[0482] 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.

[0483] 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.

[0484] 5) Luciferase activity was measured using a luminometer (Tecan, Spark®).

[0485] 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 32) and VPC-70619 (CAS 2361742-30-3, compound 33), which are used as Myc transcription factor inhibitors, were used.

[0486]

[0487] 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++++++29++++++30+++31+++32 (Control compound 10058-F4)++33 (Control compound VPC-70619)++

[0488]

[0489] 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.

[0490]

[0491] Experimental Example 3. Evaluation of Anticancer Activity

[0492] 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).

[0493] Specifically, the evaluation was conducted in the following manner.

[0494] 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 10 3 / 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.

[0495] 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.

[0496] 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.

[0497] 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.

[0498] 5) After shaking for 30 minutes at room temperature, ATP of viable cells was measured using a luminometer (Tecan, Spark®).

[0499] 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 32) and VPC-70619 (CAS 2361742-30-3, compound 33), which are used as Myc transcription factor inhibitors, were used.

[0500]

[0501] Example Cell Viability Assay (μM, 24 hours) LineNCI-H1299NCI-H23JurkatDaudi1+++++++++++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++++++++++++29++++++++++++30++++++++31++++++++++32 (control compound 10058-F4)++++33 (control compound VPC-70619)+++++

[0502]

[0503] Example Cell Viability Assay (μM, 72 hours) LineNCI-H1299NCI-H23JurkatDaudi1++++++++++++2++++++++++++3++++++++++++4++++++++++++5+++++++6++++++++++++7++++++++8++++++++++++++9++++++++++++10++++++++++++11++++++++++++12++++++++13++++++++++++14++++++ +++++15++++++++16++++++++++++17++++++++++++18+++++++++++19+++++++++++20++++++++21++++++++22+++++2 3++++++++++24++++25++++++++++26++++++++27++++28+++++++++++29+++++++++++30++++++31++++++++32 (control compound 10058-F4)++++33 (control compound VPC-70619)++++++

[0504]

[0505] 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.

[0506] 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 Inland R 4 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 Aryl, 5 to 10 membered heteroaryl and tri(C 1-6 Any one selected from the group consisting of alkyl)silylethynyl, R 5 is hydrogen, OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 1-6 Alkoxy, C 1-6 Haloalkoxy and -OC 6-12 Any one selected from the group consisting of aryl-halosulfanyl, R 6 Silver hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylene-O-amine and C(O)-R 7 is one selected from the group consisting of, wherein R 7 Silver C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, and NR a R b is one selected from the group consisting of , where R a and R b 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, Here, L and Het are each independently halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, OH, NO 2 , CN and NH 2 It can be substituted with one or more selected from the group consisting of, But, R 5 If R is OH, 7 Silver NR a R b am.

2. In paragraph 1, Above R 1 Inland R 4 are each independently hydrogen, 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 and tri(C 1-6 Any one selected from the group consisting of alkyl)silylethynyl, Above R 6 Silver C 1-6 Alkyl, C 1-6 Alkylene-O-amine, C(O)-C 1-10 Alkyl, C(O)-C 1-6 Alkylamine, C(O)-C 3-10 Cycloalkyl, C(O)-N-(C 1-6 alkyl) 2 , C(O)-NH-(C 1-6 alkylene)-O-(C 1-6 alkyl) and C(O)-NH-(C 1-6 Any one selected from the group consisting of alkyl, 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 Inland R 4 are each independently hydrogen, CH 3 , C≡CH, Cl, Br, cyano, C≡C-Si(CH 3 ) 3 and SO 2 CH 3 Any one selected from the group consisting of, A compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

5. In any one of paragraphs 1 to 4, Above R 5 is hydrogen, OH, Cl, CH 3 , CF 3 , CN, OCH 3 , OCH 2 CH 3 , and is one selected from the group consisting of, Above R 6 is CH 3 , , , , , , and Any one selected from the group consisting of, A compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

6. In any one of paragraphs 1 to 5, 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.

7. 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-(8-bromo-4,5-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one, (2) 1-(8-bromo-4,5-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one, (3) 1-(4,5-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-8-((trimethylsilyl)ethynyl)quinolin-3-yl)-2-methylpropan-1-one, (4) 1-(4,5-dichloro-8-ethynyl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one, (5) 4,5,8-Trichloro-N,N-dimethyl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinoline-3-carboxamide, (6) 1-(4,5,8-trichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one, (7) 4,5,8-Trichloro-N,N-dimethyl-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfinyl)quinoline-3-carboxamide, (8) 1-(4,5,8-trichloro-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1one, (9) 4,5,8-Trichloro-N-(2-methoxyethyl)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinoline-3-carboxamide, (10) 1-(4,5,8-trichloro-2-((pyrimidin-5-ylmethyl)sulfinyl)quinolin-3-yl)ethan-1-one, (11) Cyclopropyl(4,5,8-trichloro-2-((pyrimidin-5-ylmethyl)sulfinyl)quinolin-3-yl)methan-1-one, (12) 2-Methyl-1-(4,5,8-trichloro-2-((2-(pyrimidin-5-yl)ethyl)sulfinyl)quinolin-3-yl)propan-1-one, (13) Cyclopropyl(4,5,8-trichloro-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)methan-1-one, (14) 4,8-dichloro-3-isobutyryl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinoline-5-carbonitrile, (15) 1-(4,8-dichloro-5-methyl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one, (16) 1-(4,5,8-trichloro-2-((1-methyl-1H-pyrazol-3-yl)sulfinyl)quinolin-3-yl)ethan-1-one, (17) 1-(4,8-dichloro-5-methyl-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)ethan-1-one, (18) 4,5,8-Trichloro-3-methyl-2-(pyrimidin-5-ylsulfinyl)quinoline, (19) 3-(1-(aminooxy)-2-methylpropyl)-8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-4-ol, (20) 8-bromo-5-chloro-4-hydroxy-N-methyl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinoline-3-carboxamide, (21) 5,8-dichloro-3-methyl-2-(pyrimidin-5-ylsulfinyl)quinolin-4-ol, (22) 1-(8-bromo-5-chloro-4-methoxy-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one, (23) 1-(8-bromo-5-chloro-4-(difluoromethoxy)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one, (24) 1-(5,8-dichloro-4-ethoxy-2-((3-(pyrimidin-5-yl)propyl)sulfinyl)quinolin-3-yl)ethan-1-one, (25) 1-(5,8-dichloro-4-(4-(pentafluoro-lambda 6 -sulfanyl)phenoxy)-2-(pyrimidin-5-ylsulfinyl)quinolin-3-yl)ethan-1-one, (26) 1-(5,8-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)ethan-1-one, (27) 1-(5,8-dichloro-4-methyl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-3-yl)-2-methylpropan-1-one, (28) 1-(5,8-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-4-(trifluoromethyl)quinolin-3-yl)-2-methylpropan-1-one, (29) 1-(8-chloro-5-methyl-2-(pyrimidin-5-ylsulfinyl)-4-(trifluoromethyl)quinolin-3-yl)ethan-1-one, (30) 5,8-dichloro-3-isobutyryl-2-((pyrimidin-5-ylmethyl)sulfinyl)quinoline-4-carbonitrile, and (31) 1-(8-chloro-4-hydroxy-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)-5-(methylsulfonyl)quinolin-3-yl)-2-methylpropan-1-one.

8. A compound according to any one of claims 1 to 7, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition for inhibition of c-Myc transcription factor protein.

9. A compound according to any one of claims 1 to 7, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition for preventing or treating cancer.

10. In paragraph 9, The above cancer is caused by overexpression or overactivation of the c-Myc transcription factor protein. A pharmaceutical composition for preventing or treating cancer.

11. In clause 9 or 10, 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.

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