WO2022231377A1 - Novel compound and pharmaceutical composition comprising same for prevention or treatment of cancer, and use thereof - Google Patents

Novel compound and pharmaceutical composition comprising same for prevention or treatment of cancer, and use thereof Download PDF

Info

Publication number
WO2022231377A1
WO2022231377A1 PCT/KR2022/006181 KR2022006181W WO2022231377A1 WO 2022231377 A1 WO2022231377 A1 WO 2022231377A1 KR 2022006181 W KR2022006181 W KR 2022006181W WO 2022231377 A1 WO2022231377 A1 WO 2022231377A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
cancer
alkyl
unsubstituted
aryl
Prior art date
Application number
PCT/KR2022/006181
Other languages
French (fr)
Korean (ko)
Inventor
윤여진
김형남
Original Assignee
홀로스메딕 주식회사
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 홀로스메딕 주식회사 filed Critical 홀로스메딕 주식회사
Publication of WO2022231377A1 publication Critical patent/WO2022231377A1/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present application relates to a novel compound and a pharmaceutical composition for preventing or treating cancer comprising the compound or a pharmaceutically acceptable salt thereof, a method for preventing or treating cancer, and a use for preventing or treating cancer.
  • Cancer is one of the most common causes of death worldwide, accounting for about 12% of deaths.
  • Chemotherapy which is a representative anticancer therapy, is currently used as the most effective treatment for cancer, either alone or in combination with other therapies such as radiotherapy.
  • the efficacy of a cancer treatment drug in chemotherapy depends on its ability to kill cancer cells, but there is a problem that it can act not only on cancer cells but also normal cells when the drug is used.
  • One aspect of the present application is to provide a novel compound.
  • Another aspect of the present application is to provide a pharmaceutical composition for preventing or treating cancer comprising a novel compound.
  • Another aspect of the present application is to provide a pharmaceutical composition for preventing or treating resistant cancer comprising a novel compound.
  • Another aspect of the present application is to provide a use for preventing or treating cancer of the novel compound.
  • Another aspect of the present application is to provide a use for preventing or treating resistant cancer of the novel compound.
  • Another aspect of the present application is to provide a method for preventing or treating cancer of a novel compound.
  • Another aspect of the present application is to provide a method for preventing or treating resistant cancer of a novel compound.
  • One embodiment of the present application provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • R 1 is hydrogen, straight or branched chain alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl may be substituted with at least one of;
  • R 3 is hydrogen, straight or branched chain alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy may be substituted with at least one of , C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
  • L 1 is C 1 -C 10 alkylene, wherein the alkylene may be substituted with at least one of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxyl, oxo or halogen. and wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy may be unsubstituted or substituted with substituted aryl;
  • Q is S, Se, NR, P, P(O), P(O) 2 or P(O)OR , wherein R is hydrogen, straight or branched chain alkyl, cycloalkyl, bi or tricyclo alkyl, alkoxy , haloalkyl, haloalkoxy, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 halo may be substituted with at least one of alkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
  • R 2 is hydrogen, straight chain alkyl, cycloalkyl, alkoxy, haloalkoxy, haloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C of 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, oxo, nitro, cyano or trifluoromethyl at least one may be substituted;
  • R 4 and R 4 ′ are each independently hydrogen, straight or branched chain alkyl, cycloalkyl, alkenyl, alkynyl, alkylthio, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydrogen hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, oxo , may be substituted with at least one of nitro, cyano or trifluoromethyl;
  • n is an integer from 1 to 4.
  • X, Y, Z are each independently hydrogen, straight or branched chain alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, oxo, nitro, cyano, or trifluoro It may be substituted with at least one of methyl.
  • One embodiment of the present application provides a pharmaceutical composition for treating or preventing cancer comprising at least one of the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof.
  • One embodiment of the present application provides a pharmaceutical composition for treating or preventing resistant cancer comprising at least one of the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof.
  • One embodiment of the present application provides a therapeutically effective amount of the compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer/isomer, or a combination thereof. It provides a method of treating cancer, resistant cancer, or stem cell cancer comprising administering.
  • the administration may include simultaneous, separate, or sequential administration of an anticancer agent useful for the treatment of cancer or proliferative disease.
  • One embodiment of the present application provides a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, and structure thereof for preparing a medicament for the treatment of cancer, resistant cancer, or stem cell cancer isomers, optical isomers, stereoisomers, or combinations thereof.
  • a pharmaceutical composition comprising a compound according to an embodiment of the present application or a pharmaceutically acceptable salt thereof may exhibit excellent anticancer effect.
  • a composition comprising a compound according to an embodiment of the present application or a pharmaceutically acceptable salt thereof can enhance the anticancer activity of an anticancer agent or radiation, and can effectively treat cancer by inducing proliferation inhibition and apoptosis of cancer cells.
  • a composition comprising a compound or a pharmaceutically acceptable salt thereof according to an embodiment of the present application can effectively treat resistant cancer by overcoming the resistance of cancer with resistance to anticancer drugs or radiation, and side effects of anticancer treatment can reduce
  • a composition comprising the compound according to an embodiment of the present application or a pharmaceutically acceptable salt thereof can effectively treat stem cell cancer.
  • FIG. 1 shows the IC 50 values of paclitaxel and docetaxel anticancer drugs of SKOV3
  • FIG. 2 shows the IC 50 values of paclitaxel and docetaxel anticancer drugs of SKOV3-TR.
  • 5 to 8 show the results of WST-1 analysis of SKOV3-TR and SKOV3 for paclitaxel and 47 compounds.
  • 9 to 12 show the results of WST-1 analysis of SKOV3-TR and SKOV3 for docetaxel and 47 kinds of compounds.
  • 17 to 20 show the results of WST-1 analysis of MCF7-BC19 and MCF7 for paclitaxel and 47 compounds.
  • the term "independently” means that an independently applied variable independently changes from application to application.
  • R a XYR a if R a is "independently carbon or nitrogen,” then both R a can be carbon, both R a can be nitrogen, or one R a is carbon and , other R a may be nitrogen.
  • alkyl typically means a C 1 -C 10 saturated straight chain or branched hydrocarbon chain, and more specifically, a C 1 -C 6 alkyl saturated straight chain or C 3 .
  • ⁇ C 6 means a branched hydrocarbon chain.
  • C 1 -C 10 alkyl means straight chain or branched alkyl having 1 to 10 carbon atoms, specifically methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl , neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethyl butyl, and 2,3-dimethylbutyl, and the like.
  • the term includes both substituted and unsubstituted alkyl groups.
  • the alkyl group may be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate, or phosphonate.
  • One or more hydrogen atoms attached to the carbon atoms of the alkyl may be substituted with one or more halogen atoms such as, for example, fluorine or chlorine or both, such as trifluoromethyl, difluoromethyl, fluorochloromethyl and the like.
  • the hydrocarbon chain may also contain heteroatoms such as N, O or S in the middle.
  • alkaryl or “alkylaryl” refers to an alkyl group having an aryl substituent.
  • aralkyl or arylalkyl refers to an aryl group having an alkyl substituent such as benzyl.
  • halo or “halogen” includes chloro, bromo, iodo and fluoro.
  • alkoxy means “C 1 -C 6 alkoxy” unless otherwise specified, and "C 1 -C 6 alkoxy” is a straight or branched chain having 1 to 6 carbon atoms. It means alkoxy, and includes, but is not limited to, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group.
  • alkenyl means “C 2 -C 6 alkenyl” unless otherwise specified, and "C 2 -C 6 alkenyl” is one having 2 to 6 carbon atoms. refers to a straight or branched chain alkenyl containing a double bond of, vinyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl and the like, but are not limited thereto.
  • alkynyl means “C 2 -C 6 alkynyl” unless otherwise specified, and "C 2 -C 6 alkynyl” is one having 2 to 6 carbon atoms. It refers to a straight-chain or branched alkynyl containing a triple bond of, including, but not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.
  • cycloalkyl means “C 3 -C 10 cycloalkyl” unless otherwise specified, and "C 3 -C 10 cycloalkyl” has 3 to 10 carbon atoms in the ring. means cyclic alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, etc. includes The terms “C 3 -C 8 cycloalkyl”, “C 3 -C 7 cycloalkyl” and "C 3 -C 6 cycloalkyl” have similar connotations.
  • the cycloalkyl group may have a ring substituted with an alkyl group such as cyclopropylmethyl.
  • aryl means a “C 6 to C 12 aryl group” unless otherwise specified, and "C 6 to C 12 aryl group” refers to 6 to C 12 aryl groups that do not contain a hetero atom in the ring. phenyl, biphenyl (biphenyl), or naphthyl having 12 carbon atoms, preferably phenyl. The term includes both substituted and unsubstituted moieties.
  • substituted aryl is optionally unprotected or protected hydroxyl, halogen, amino, alkylamino, arylamino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, may be substituted with one or more substituents including C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate, or phosphonate,
  • C 6 -C 10 aryl group has a similar connotation.
  • heteroaryl or “heterocyclic” means “3 to 12 membered heterocyclic", and “3 to 12 membered heterocyclic” is selected from among oxygen, sulfur and nitrogen in the ring. It means a saturated or unsaturated 3-12 membered ring group containing 1 to 3 hetero atoms, for example, dioxol (dioxol).
  • dioxol dioxol
  • 3-7 membered heterocyclic has a similar connotation.
  • substituted heteroaryl refers to unprotected or protected hydroxyl, halogen, amino, alkylamino, arylamino, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 3 to C 6 as needed. substituted with one or more substituents including cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 halo alkoxy, oxo, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate, or phosphonate can, but is not limited thereto.
  • alkylene refers to a divalent hydrocarbyl group, since it is divalent and thus can be linked with two other groups. In general, it is -(CH 2 )n-, where n is 1 to 8 and preferably n is 1 to 4, but in certain instances the alkylene may be substituted by other groups and may be of different lengths, The open atoms do not necessarily have to be on opposite sides of the chain.
  • any alkyl, alkenyl, alkynyl, or aryl, alkylaryl or arylalkyl contained within a substituent may itself be optionally substituted by other additional substituents.
  • the nature of these substituents is similar to that recited for the primary substituents themselves, unless the substituents are otherwise stated.
  • heteroatom refers to an atom other than carbon or hydrogen, such as nitrogen, oxygen, or sulfur. If it is part of the backbone or backbone of a chain or ring, the heteroatom must be at least divalent and will generally be selected from N, O, P, and S.
  • the term "which may be substituted” or "substituted” means that the particular group or groups referred to as being optionally substituted does not have non-hydrogen substituents, or that the group or groups does not contain the chemistry of the resulting molecule. and one or more non-hydrogen substituents consistent with pharmacological activity. Unless otherwise specified, the total number of such substituents that may be present is equal to the total number of hydrogen atoms present in the unsubstituted form of the group being described; There may be fewer than the maximum number of such substituents.
  • the group takes on the two valencies available on the carbon atom to which the optional substituent is attached, so that the total number of substituents that can be included is equal to the available valence. decreases with the number of
  • substituted whether used as part of the term "which may be substituted," or otherwise, when used to modify a particular group, moiety, or radical, means that one or more hydrogen atoms are each independently to each other, means to be replaced by the same or different substituents or substituents.
  • the compounds described herein may contain one or more chiral centers and/or double bonds, they may be treated as stereoisomers, such as double-bond isomers (i.e. geometric isomers such as E and Z), enantiomers, or diastereomers. may exist.
  • stereoisomers such as double-bond isomers (i.e. geometric isomers such as E and Z), enantiomers, or diastereomers.
  • the present application also encompasses mixtures of stereoisomers that differ in chiral purity and percentages of E and Z, respectively, as isolated stereoisomeric forms (such as enantiomerically pure isomers, E and Z isomers, and other replacements of stereoisomers). unless limited to a specific stereoisomer).
  • stereoisomerically pure forms eg, geometrically pure, enantiomerically pure, or diastereomerically pure
  • enantiomer mixtures and stereoisomeric mixtures It encompasses all possible enantiomers and stereoisomers of the specified compounds.
  • Mixtures of enantiomers and mixtures of stereoisomers can be resolved into their corresponding enantiomeric or stereoisomeric components using separation techniques or chiral synthesis techniques well known in the art.
  • the present application includes mixtures of stereoisomers of varying chiral purity, including racemic mixtures as well as individual isolated stereoisomeric forms. This application also encompasses the various diastereomers.
  • One embodiment of the present application provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • One embodiment of the present application provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • Formula 1 may be represented by Formula 2 or Formula 3 below.
  • R 1 is hydrogen, straight or branched chain alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, alkylaryl or alkyl heteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or It may be substituted with at least one of unsubstituted or substituted heteroaryl.
  • R 1 is hydrogen, C 1 ⁇ C 10 straight or branched chain alkyl, C 1 ⁇ C 10 alkoxy, C 1 ⁇ C 10 haloalkyl, C 1 ⁇ C 10 haloalkoxy, C 6 ⁇ C 12 aryl, C 5 ⁇ C 12 heteroaryl, alkyl(C 1 ⁇ C 10 )aryl(C 6 ⁇ C 12 ) or alkyl(C 1 ⁇ C 10 )heteroaryl(C 5 ⁇ C 12 ), each of which is independently hydroxyl, halogen , C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl, C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, oxo, cyano, unsubstituted or substituted C It may be substituted with at least one of 6 -C 12 aryl, or unsubstituted or substituted C 5 -C
  • the R 1 is specifically hydrogen, C 1 -C 6 straight or branched chain alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 6 -C 12 aryl, C 5 ⁇ C 12 heteroaryl, alkyl(C 1 ⁇ C 6 )aryl(C 6 ⁇ C 12 ) or alkyl(C 1 ⁇ C 6 )heteroaryl(C 5 ⁇ C 12 ), each of which is independently hydroxyl , halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted It may be substituted with at least one of C 6 -C 12 aryl, or unsubstituted or substituted C 5 -
  • R 1 is hydrogen, unsubstituted or substituted C 1 -C 6 straight chain alkyl, unsubstituted or substituted benzyl, or unsubstituted or substituted 2-phenylethyl, wherein the substituted C 1 -C 6
  • the straight chain alkyl is substituted with C 3 -C 6 cycloalkyl
  • the substituted benzyl or substituted 2-phenylethyl may be one in which at least one of ortho, meta and para positions is substituted with halogen or phenyl.
  • the R 1 is more specifically hydrogen, C 1 -C 6 straight-chain alkyl, C 3 -C 6 branched chain alkyl, C 3 -C 6 cycloalkyl, , , or
  • X 1 may be hydrogen, halogen, C 1 to C 3 straight-chain alkyl, CF 3 , CN, NO 2 or phenyl.
  • R 3 is hydrogen, straight or branched chain alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 to C 6 be substituted with at least one of alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl can
  • R 3 is hydrogen, C 1 ⁇ C 10 straight or branched chain alkyl, C 3 ⁇ C 10 cycloalkyl, C 6 ⁇ C 12 aryl, C 5 ⁇ C 12 heteroaryl, alkyl (C 1 ⁇ C 10 ) aryl ( C 6 -C 12 ) or alkyl (C 1 -C 10 )heteroaryl (C 5 -C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, It may be substituted with at least one of C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted C 5 -C 12 heteroaryl.
  • R 3 is hydrogen, C 1 ⁇ C 6 straight or branched chain alkyl, C 3 ⁇ C 6 cycloalkyl, C 6 ⁇ C 12 aryl, C 5 ⁇ C 12 heteroaryl, alkyl (C 1 ⁇ C 6 ) aryl ( C 6 -C 12 ) or alkyl (C 1 -C 6) heteroaryl (C 5 -C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, It may be substituted with at least one of C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted C 5 -C 12 heteroaryl.
  • R 3 is specifically hydrogen, unsubstituted or substituted C 1 -C 3 straight chain alkyl, unsubstituted or substituted C 1 -C 3 alkoxy, halogen, or unsubstituted or substituted 2-phenylethyl, wherein the substituted In the 2-phenylethyl group, at least one of ortho, meta, and para positions is substituted with halogen, and the substituted C 1 -C 6 alkoxy may be substituted with phenyl or benzyl.
  • R 3 may be hydrogen, unsubstituted or substituted C 1 -C 3 straight-chain alkyl, unsubstituted or substituted C 1 -C 3 alkoxy, or halogen.
  • the R 3 may be more specifically hydrogen, C 1 -C 3 alkoxy, or halogen.
  • the halogen may be bromine.
  • R 2 is hydrogen, straight chain alkyl, cycloalkyl, alkoxy, haloalkoxy, haloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, oxo, nitro, cya may be substituted with at least one of no or trifluoromethyl.
  • R 2 is hydrogen, C 1 -C 10 straight chain alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkoxy, C 1 -C 10 haloalkyl, C 6 -C 12 aryl, C 5 -C 12 heteroaryl, alkyl (C 1 -C 10 )aryl (C 6 -C 12 ) or alkyl (C 1 -C 10 )heteroaryl (C 5 -C 12 ), each of which is independently with hydroxyl, halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, unsubstituted or substituted C 6 -C 12 aryl, unsubstituted or substituted C 5 -C 12 heteroaryl, oxo, nitro, cyano or at least one of trifluor
  • the R 2 is specifically hydrogen, C 1 ⁇ C 6 straight chain alkyl, C 3 ⁇ C 6 cycloalkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 haloalkoxy, C 1 ⁇ C 6 haloalkyl, C 6 ⁇ C 12 aryl, C 5 -C 12 heteroaryl, alkyl (C 1 -C 6 )aryl (C 6 -C 12 ) or alkyl (C 1 -C 6) heteroaryl (C 5 -C 12 ), each of is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted C 6 -C 12 aryl, It may be substituted with at least one of unsubstituted or substituted C 5 -C 12 heteroaryl, oxo, nitro, cyano or tri
  • R 2 is more specifically hydrogen, unsubstituted or substituted C 1 -C 6 straight chain alkyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted benzyl, unsubstituted or substituted 2-phenylethyl, unsubstituted or substituted biphenyl, 2-naphthylmethyl or 1-naphthylmethyl, wherein the substituted straight chain alkyl is substituted with halogen, and the substituted benzyl is at least one of ortho, meta and para positions of halogen, C 1 -C 3 straight chain alkyl, trifluoromethyl, cyano, nitro, C 1 -C 3 alkoxy or C 6 -C 12 aryl, wherein 2-phenylethyl is at least one of ortho, meta and para positions is substituted with halogen, and the substituted biphenyl may be substituted with C 1 -C 3 straight-chain alkyl.
  • the R 2 is more specifically hydrogen, C 1 ⁇ C 6 straight chain alkyl, , , , , , , , , , , , , , or can be
  • R 4 and R 4 ' are each independently hydrogen, straight or branched chain alkyl, cycloalkyl, alkenyl, alkynyl, alkylthio, aryl, heteroaryl, alkylaryl or alkylheteroaryl; , each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted aryl, unsubstituted or may be substituted with at least one of substituted heteroaryl, oxo, nitro, cyano or trifluoromethyl.
  • R 4 and R 4 ' are each independently C 1 -C 10 straight or branched chain alkyl, C 3 -C 10 cycloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 Alkylthio, C 6 ⁇ C 12 aryl, C 5 ⁇ C 12 heteroaryl, alkyl (C 1 ⁇ C 10 ) aryl (C 6 ⁇ C 12 ) or alkyl (C 1 ⁇ C 10 ) heteroaryl (C 5 ⁇ C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, unsubstituted or substituted It may be substituted with at least one of C 6 -C 12 aryl, unsubstituted or substituted C 5 -C 12 heteroaryl, oxo
  • R 4 and R 4 ' are each independently C 1 ⁇ C 6 straight or branched chain alkyl, C 3 ⁇ C 6 cycloalkyl, C 2 ⁇ C 6 alkenyl, C 2 ⁇ C 6 alkynyl, C 1 ⁇ C 6 alkylthio, C 6 -C 12 aryl, C 5 -C 12 heteroaryl, alkyl (C 1 -C 6 )aryl (C 6 -C 12 ) or alkyl (C 1 -C 6) heteroaryl (C 5 -C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted It may be substituted with at least one of C 6 -C 12 aryl, unsubstituted or substituted C 5 -C 12 heteroaryl, oxo,
  • the R 4 and R 4 ' are each independently specifically C 1 -C 6 straight or branched chain alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 ⁇ C 6 alkylthio, unsubstituted or substituted benzyl, 2-naphthylmethyl or 1-naphthylmethyl, wherein the substituted straight chain alkyl is substituted with methylthio, alkynyl or benzyloxycarbonylamino ,
  • the substituted benzyl may be substituted with at least one of ortho, meta and para positions with halogen, aryl, nitro, cyano, C 1 -C 3 alkoxy, trifluoromethyl or benzyloxy.
  • R 4 and R 4 ' may be each independently C 1 to C 3 straight-chain alkyl.
  • L 1 is a direct linkage or C 1 -C 10 alkylene, wherein the alkylene is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 7 alkoxy, hydroxy may be substituted with at least one of hydroxyl, oxo or halogen, wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 7 alkoxy is unsubstituted or substituted C 6 -C 12 aryl or C 3 -C 6 cycloalkyl may be substituted.
  • the L 1 is specifically C 1 -C 4 alkylene, wherein the alkylene is at least one of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxyl, or oxo. may be substituted, wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy is unsubstituted or substituted with C 6 -C 12 aryl or C 3 -C 6 cycloalkyl.
  • the alkylene is at least one of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxyl, or oxo.
  • the L 1 is specifically C 1 -C 3 alkylene, wherein the C 1 -C 3 alkylene is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, unsubstituted or substituted C 1 -C 6 It may be substituted with at least one of alkoxy, hydroxyl, or oxo, and the substituted C 1 -C 6 alkoxy may be substituted with cyclohexyl, phenyl, naphthyl, or biphenyl.
  • L 1 is specifically methylene, ethylene, or propylene, wherein the methylene, ethylene, or propylene is methyl, ethyl, propyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, hydroxyl, Or it may be substituted with at least one of oxo, and the methoxy may be substituted with cyclohexyl, phenyl, naphthyl, or biphenyl.
  • Q may be S, Se, NR, P, P(O), P(O) 2 or P(O)OR.
  • R is hydrogen, C 1 ⁇ C 6 straight or branched chain alkyl, C 3 ⁇ C 6 cycloalkyl, bi or tri C 3 ⁇ C 6 cycloalkyl, C 1 ⁇ C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 6 -C 12 aryl, C 5 -C 12 heteroaryl, alkyl(C 1 -C 6 )aryl(C 6 -C 12 ) or alkyl (C 1 -C 6) heteroaryl (C 5 -C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 It may be substituted with at least one of ⁇ C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted C 6 ⁇ C 12 aryl,
  • R is, specifically hydrogen, unsubstituted or substituted C 1 ⁇ C 4 straight chain alkyl, , , , , or can be
  • n is an integer of 1 to 4, and specifically, n may be 1.
  • X, Y, and Z are each independently hydrogen, C 1 ⁇ C 6 straight or branched chain alkyl, C 3 ⁇ C 6 cycloalkyl, C 6 ⁇ C 12 aryl, C 5 ⁇ C 12 heteroaryl, Alkyl (C 1 -C 6 )aryl (C 6 -C 12 ) or alkyl (C 1 -C 6) heteroaryl (C 5 -C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted C 6 -C 12 aryl, unsubstituted or substituted C 5 -C 12 heteroaryl , oxo, nitro, cyano, or at least one of trifluoromethyl.
  • the compound according to the present application may be at least one compound selected from the group consisting of Chemical Formulas shown in Table 1 below, but is not limited thereto.
  • the terms “treat” or “treatment” refer to a therapeutic, prophylactic, curative, or prophylactic method.
  • prevention refers to any action of inhibiting cancer or delaying the onset of cancer by administering the pharmaceutical composition.
  • beneficial or desired clinical outcomes include, but are not limited to, detectable or undetectable, symptom relief, attenuation of disease severity, stable (i.e., not attenuated) state of disease, delayed or gradual disease progression progression, amelioration or temporary treatment of the disease state, and remission (whether partial or total).
  • Treatment can also mean sustained survival when compared to expected survival if not receiving treatment.
  • Those in need of treatment include those prone to have the condition or disorder, as well as those already having the condition or disorder or in which the condition or disorder has been prevented.
  • the expression "therapeutically effective amount” or “effective amount” refers to (i) treating or preventing a particular disease, condition, or disorder, (ii) one of the particular disease, condition, or disorder described herein. an amount of the compound of formula (I), when administered to a mammal in need thereof, sufficient to attenuate, ameliorate or alleviate the symptoms, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, it means.
  • the amount of compound corresponding to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (eg weight) of the mammal in need of treatment, but nevertheless is within the skill of the artisan. can be determined routinely.
  • cancer refers to or express a physiological condition in a mammal that is typically characterized by abnormal or unregulated cell growth.
  • a “tumor” includes one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancy. More specific examples of such cancers include squamous cell carcinoma (eg, epithelial squamous cell carcinoma), lung cancer (small cell lung cancer, non-small cell lung cancer (“NSCLC”)), adenocarcinoma of the lung and squamous cell carcinoma of the lung.
  • NSCLC non-small cell lung cancer
  • peritoneal cancer hepatocellular cancer, gastric or gastric cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver tumor, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma , salivary adenocarcinoma, kidney or kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatocarcinoma, anal carcinoma, penile carcinoma, skin cancer including melanoma, as well as head and neck cancer.
  • “Pharmaceutically acceptable” as used herein refers to that the substance or composition is chemically and/or animal compatible with the mammal and/or other ingredients, including formulations, being treated thereby.
  • pharmaceutically acceptable salt refers to a pharmaceutically acceptable organic or inorganic salt of the compound of the present application.
  • salts refers to a pharmaceutically acceptable organic or inorganic salt of a compound described herein.
  • Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, Acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, phor Mate, benzoate, glutamate, methanesulfonate, ethylate, ethanesulfonate, ethanedisulfonate, benzenesulfonate, p- toluenesulfonate, and pamonate (i.e.
  • a pharmaceutically acceptable salt may contain an inclusion body of another molecule, such as an acetate ion, a succinate ion or other counter ion.
  • the counter ion can be any organic or inorganic moiety that stabilizes the charge of the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure.
  • An example where multiple charged atoms are part of a pharmaceutically acceptable salt may have multiple counter ions.
  • a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counter ions.
  • One embodiment of the present application is a pharmaceutical for preventing or treating cancer comprising a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or a combination thereof A composition is provided.
  • a pharmaceutically acceptable salt a pharmaceutically acceptable salt thereof
  • hydrate solvate
  • structural isomer a pharmaceutically acceptable salt thereof
  • optical isomer a pharmaceutically acceptable salt thereof
  • One embodiment of the present application is a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or a combination thereof for preventing or treating resistant cancer
  • a pharmaceutical composition is provided.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is administered in combination with an anticancer drug or radiation therapy to resistant cancer, there is an effect of inhibiting the activity of resistant cancer.
  • One embodiment of the present application is a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or stem cell cancer prevention or A therapeutic pharmaceutical composition is provided.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof acts as an inhibitor targeting the SERCA protein, thereby inhibiting stem cell cancer activity.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof When the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is administered in combination with an anticancer drug or radiation therapy to cancer or resistant cancer, it may be administered simultaneously, individually, or sequentially.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered before or after an anticancer drug or radiation therapy.
  • the cancer or resistant cancer is ovarian cancer, colorectal cancer, pancreatic cancer, stomach cancer, liver cancer, breast cancer, cervical cancer, thyroid cancer, parathyroid cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, Biliary tract cancer, blood cancer, bladder cancer, kidney cancer, melanoma, colon cancer, bone cancer, skin cancer, head and neck cancer, uterine cancer, rectal cancer, brain cancer, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, Endocrine adenocarcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, leukemia, central nervous system (CNS) tumor, spinal cord tumor, brainstem glioma and pituitary adenoma It may be at least one selected from the group.
  • CNS central nervous system
  • the anticancer drug or anticancer agent is nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasa Nib, bosutinib, axitinib, masitinib, cediranib, restaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, pazopanib, toceranib, nintedanib, regorafenib, Semaxanib, tivozanib, ponatinib, caboxantinib, carboplatin, sorafenib, lenvatinib, bevacizumab, cisplatin, cetuximab, viscumalbum, asparaginase, tretin, aminox
  • the pharmaceutical composition according to an embodiment of the present application contains a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof and an anticancer agent from 1:0.001 to 1:1000, 1:0.01 to 1:100, 1:0.1 to 1 It may be included in a molar concentration ratio of :50 or 1:0.1 to 1:20.
  • the pharmaceutical composition according to one embodiment of the present application may be in the form of a capsule, tablet, granule, injection, ointment, powder or beverage.
  • compositions according to an embodiment of the present application may be formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and injections.
  • the pharmaceutical composition according to one embodiment of the present application may include a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers may be binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, coloring agents, flavoring agents, etc., in the case of oral administration, and in the case of injections, buffers, preservatives, analgesics, Solubilizers, isotonic agents, stabilizers, etc. can be mixed and used, and for topical administration, bases, excipients, lubricants, preservatives, etc. can be used.
  • the dosage form of the pharmaceutical composition according to one embodiment of the present application may be prepared in various ways by mixing with a pharmaceutically acceptable carrier, for example, tablets, troches, capsules, elixirs, It may be prepared in the form of a suspension, syrup, wafer, etc., and in the case of an injection, it may be prepared in the form of unit dose ampoules or multiple doses.
  • a pharmaceutically acceptable carrier for example, tablets, troches, capsules, elixirs
  • It may be prepared in the form of a suspension, syrup, wafer, etc., and in the case of an injection, it may be prepared in the form of unit dose ampoules or multiple doses.
  • the formulation of the pharmaceutical composition of the present application may be prepared as a solution, suspension, tablet, capsule, sustained-release formulation, and the like.
  • Carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, filler, anticoagulant, lubricant, wetting agent, flavoring, emulsifying agent or preservative and the like.
  • One embodiment of the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention together with a pharmaceutically applicable adjuvant and/or excipient as an active ingredient. will be.
  • adjuvant refers to any substance capable of producing, exacerbating or modifying a particular reaction to the active ingredient of the present invention if administered simultaneously, at the same time or sequentially.
  • adjuvants for injectable solutions are, for example, aluminum compositions such as aluminum hydroxide or aluminum phosphate, saponins such as QS21, muramyldipeptide or muramyltripeptide, proteins such as gamma-interferon or TNF, M59, squalene or polyol.
  • the route of administration of the pharmaceutical composition according to one embodiment of the present application is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal , enteral, topical, sublingual or rectal.
  • the pharmaceutical composition according to an embodiment of the present application may be administered orally or parenterally, and when administered parenterally, external application to the skin or intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection A method may be selected.
  • the dosage of the pharmaceutical composition according to one embodiment of the present application varies depending on the patient's condition and weight, the degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art.
  • the pharmaceutical composition according to one embodiment of the present application may be administered at 0.0001 to 1000 mg/kg or 0.001 to 500 mg/kg per day.
  • Administration of the pharmaceutical composition according to an embodiment of the present application may be administered once a day, may be administered in divided several times.
  • the above dosage does not limit the scope of the present application in any way.
  • the present application provides the use of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.
  • the present application provides the use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in the treatment of resistant cancer.
  • the present application provides the use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in the treatment of stem cell cancer.
  • Resistant cancer and the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof are the same as those described above, and detailed descriptions thereof will be omitted.
  • the present application relates to a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or Provided is a method of treating cancer, resistant cancer, or stem cell cancer comprising administering a therapeutically effective amount of a combination thereof.
  • the administration may include simultaneous, separate, or sequential administration of a chemotherapeutic agent or anticancer drug useful for the treatment of cancer or proliferative disease.
  • administration means introducing a given substance into a subject by an appropriate method.
  • Subject with resistant cancer refers to an individual who has developed or has a high probability of developing resistant cancer and requires appropriate treatment. It may be an individual who has received radiation therapy or immunotherapy, but has developed resistance to it and has relapsed.
  • Subjects with resistant cancer may include humans, cattle, dogs, guinea pigs, rabbits, chickens, or insects. Specifically, it may be a mammal such as a human, a cow, a horse, a pig, a dog, a sheep, a goat, or a cat. The subject may be an individual who has or is likely to have cancer.
  • the present application relates to a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or administering a therapeutically effective amount of a combination thereof; And irradiating radiation; provides a radiation treatment method comprising a.
  • Resistant cancer a subject with resistant cancer, the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof is the same as described above, and detailed descriptions thereof will be omitted.
  • Radiation irradiation can be applied to any radiation method conventionally used for radiation treatment of cancer or radiation method for cancer to be developed later.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present application When the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present application is administered in combination with irradiation, it gives a synergistic effect on growth inhibition and/or death induction of cancer cells, resistant cancer cells or cancer stem cells. Thus, it is possible not only to effectively prevent or treat cancer, but also to prevent resistance to radiation, metastasis of cancer, or recurrence of cancer.
  • Piperazine-2-carboxylic acid (1.0 eq.) was cooled to 5° C. or less in a dioxane/distilled water solvent, and sodium carbonate (3.0 eq.) was added.
  • Di-tertiary -butyl dicarbonate (2.2 equivalents) was added dropwise while maintaining 5° C. or less, followed by stirring at room temperature overnight. After confirming the completion of the reaction, it was concentrated under reduced pressure, dissolved in methylene chloride, and neutralized with hydrochloric acid. The organic layer was washed with sodium chloride, dehydrated over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified with n -hexane to obtain 1,4-bis( tertiary -butoxycarbonyl)piperazine-2-carboxylic acid.
  • Step 4 d - turkey Preparation of -butyl 2-((1-methoxy-2-methyl-1-oxopropan-2-yl)carbamoyl)piperazine-1,4-dicarboxylate
  • Step 5 Preparation of methyl 2-methyl-2-(piperazine-2-carboxamido)propanoate-2-trifluoroacetic acid
  • Step 6 7,7-dimethylhexahydro-2 H -Pyrazino[1,2- a ]Preparation of pyrazine-6,9-dione/2 trifluoroacetic acid
  • Step 7 2-((2-ethyl-1-benzo[ b ]Thiophen-3-yl)methyl)-7,7-dimethylhexahydro-2 H -Pyrazino[1,2- a ] Preparation of pyrazine-6,9-dione (S801)
  • step 7 of Preparation Example 1 benzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethyl-1-benzo[ b ]thiophen-3-carbaaldehyde, and after concentration in the purification process after the reaction The residue was purified by silica gel column chromatography without solidifying with n -hexane.
  • the rest of the preparation method is 2-(benzo[ b ]thiophen-3-ylmethyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ] in the same manner as in step 7 of Preparation Example 1.
  • Pyrazine-6,9-dione (S822) was prepared.
  • step 7 of Preparation Example 1 2-methylbenzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethyl-1-benzo[ b ]thiophen-3-carbaaldehyde, and the purification process after the reaction After concentration in , the residue was solidified with ethyl acetate instead of n -hexane.
  • the rest of the preparation method is 7,7-dimethyl-2-((2-methylbenzo[ b ]thiophen-3-yl)methyl)hexahydro- 2H -pyrazino[1] in the same manner as in step 7 of Preparation Example 1.
  • 2- a ]pyrazine-6,9-dione was prepared.
  • step 7 of Preparation Example 1 2-butylbenzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophene-3-carbaaldehyde, and after concentration in the purification process after the reaction The residue was solidified with ethyl acetate instead of n -hexane.
  • the rest of the preparation method is 2-((2-butylbenzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1] in the same manner as in step 7 of Preparation Example 1.
  • 2-butylbenzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1] in the same manner as in step 7 of Preparation Example 1.
  • 2-butylbenzo[ b ]thiophen-3-yl)methyl -7,
  • Step 7 of Preparation Example 1 2-hexylbenzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophene-3-carbaaldehyde, and the same as in Step 7 of Preparation Example 1 Method 2-((2-hexylbenzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S825) was prepared.
  • step 7 of Preparation Example 1 2-benzylbenzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophene-3-carbaaldehyde, and the same as in Step 7 of Preparation Example 1 Method 2-((2-benzylbenzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S827) was prepared.
  • step 7 of Preparation Example 1 2-(4-methylbenzylbenzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophene-3-carbaaldehyde, and In the same manner as in step 7, 7,7-dimethyl-2-((2-(4-methylbenzyl)benzo[ b ]thiophen-3-yl)methyl)hexahydro- 2H -pyrazino[1,2- a ] Pyrazine-6,9-dione (S828) was prepared.
  • step 7 of Preparation Example 1 2-(4-chlorobenzyl)benzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and after the reaction After concentration in the purification process, the residue was purified by silica gel column chromatography without solidifying with n -hexane.
  • the rest of the preparation method is 2-((2-(4-chlorobenzyl)benzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H in the same manner as in step 7 of Preparation Example 1.
  • -Pyrazino[1,2- a ]pyrazine-6,9-dione (S829) was prepared.
  • step 7 of Preparation Example 1 2-(4-bromobenzyl)benzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and the reaction After concentration in the subsequent purification process, the residue was solidified with ethyl acetate instead of n -hexane.
  • the rest of the preparation method is 2-((2-(4-bromobenzyl)benzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro-2 in the same manner as in step 7 of Preparation Example 1.
  • H -pyrazino[1,2- a ]pyrazine-6,9-dione (S830) was prepared.
  • step 7 of Preparation Example 1 2-(4-fluorobenzyl)benzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and after the reaction After concentration in the purification process, the residue was purified by silica gel column chromatography without solidifying with n -hexane.
  • the rest of the preparation method is 2-((2-(4-fluorobenzyl)benzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H in the same manner as in step 7 of Preparation Example 1.
  • -Pyrazino[1,2- a ]pyrazine-6,9-dione (S831) was prepared.
  • Step 7 of Preparation Example 1 1-methyl- 1H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and the same method as in Step 7 of Preparation Example 1 to 7,7-dimethyl-2-((1-methyl- 1H -indol-3-yl)methyl)hexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S833 ) was prepared.
  • step 7 of Preparation Example 1 1-(cyclohexylmethyl)-1H-indole-3- carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and the step of Preparation Example 1 In the same manner as 7, 2-((1-cyclohexylmethyl)-1H-indol-3-yl)methyl) -7,7 -dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine- 6,9-dione (S834) was prepared.
  • step 7 of Preparation Example 1 1-benzyl- 1H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and the same method as in Step 7 of Preparation Example 1 as 2-((1-benzyl- 1H -indol-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S835 ) was prepared.
  • step 7 of Preparation Example 1 1-(naphthalen-2-yl)methyl- 1H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and Preparation Example 7,7-dimethyl-2-((1-naphthalen-2-ylmethyl)-1H-indol-3-yl)methyl)hexahydro- 2H - pyrazino [1, 2- a ]pyrazine-6,9-dione (S836) was prepared.
  • step 7 of Preparation Example 1 1-benzyl-2-methyl- 1H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and the step of Preparation Example 1 In the same manner as in 7, 2-((1-benzyl-2-methyl- 1H -indol-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine -6,9-dione (S839) was prepared.
  • step 7 of Preparation Example 1 1-benzyl-5-bromo- 1H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde and In the same manner as in step 7, 2-((1-benzyl-5-bromo- 1H -indol-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]Pyrazine-6,9-dione (S840) was prepared.
  • step 7 of Preparation Example 1 1-benzyl-5-methoxy- 1H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde and In the same manner as in step 7, 2-((1-benzyl-5-methoxy-1 H -indol-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]Pyrazine-6,9-dione (S841) was prepared.
  • step 7 of Preparation Example 1 1 H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde and 2-( ( 1H -indol-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S842) was prepared.
  • Hela a cervical cancer epithelial cell line
  • Hela-PTX-R which was derived therefrom and produced as a resistant cancer cell line having resistance to the anticancer drug Paclitaxel, were prepared.
  • MCF7 a breast cancer epithelial cell line
  • MCF7-BC19 prepared as a resistant cancer cell line having resistance to the anticancer drug Paclitaxel by overexpressing P-gp therefrom were prepared.
  • FIGS. 1 to 4 Cell experiments were performed with these cell lines, and are shown in FIGS. 1 to 4 .
  • 1 shows the IC 50 values of paclitaxel and docetaxel anticancer drugs of SKOV3
  • FIG. 2 shows the IC 50 values of paclitaxel and docetaxel anticancer drugs of SKOV3-TR.
  • Figure 3 shows the IC 50 value of the anticancer agent Paclitaxel of Hela and Hela-PTX-R
  • Figure 4 shows the IC 50 value of the anticancer agent Paclitaxel of MCF7 and MCF7-BC19.
  • paclitaxel treatment induced a decrease in metabolism in SKOV3, SKOV3-TR, Hela, Hela-PTX-R, MCF7, and MCF7-BC19.
  • DMSO paclitaxel, S-form solvent
  • paclitaxel Paclitaxel
  • 47 kinds of S-forms were co-treated with WST-1 analysis 3 days later, and are shown in FIGS. 5 to 8 .
  • 5 and 7 show DMSO, paclitaxel, S801 (10 ⁇ M), S802 (10 ⁇ M), S803 (10 ⁇ M), S804 (10 ⁇ M), S806 (10 ⁇ M), S807 (10 ⁇ M), S808 (10 ⁇ M), S809 (10 ⁇ M), S810 (10 ⁇ M), S811 (10 ⁇ M), S812 (10 ⁇ M), S813 (10 ⁇ M), S815 (10 ⁇ M), S816 (10 ⁇ M), S819 (10 ⁇ M), S820 (10 ⁇ M), S821 (10 ⁇ M), S845 (10 ⁇ M), S855 (10 ⁇ M), S805 (10 ⁇ M), S822 (10 ⁇ M), S833 (10 ⁇ M), S834 (10 ⁇ M), S835 (10 ⁇ M) are shown in the order.
  • 6 and 8 show DMSO, paclitaxel, S836 (10 ⁇ M), S838 (10 ⁇ M), S840 (10 ⁇ M), S841 (10 ⁇ M), S842 (10 ⁇ M), S857 (10 ⁇ M), S858 (10 ⁇ M), S860 (10 ⁇ M), S823 (10 ⁇ M), S824 (10 ⁇ M), S825 (10 ⁇ M), S826 (10 ⁇ M), S856 (10 ⁇ M), S859 (10 ⁇ M), S839 (10 ⁇ M), S827 (10 ⁇ M), S828 (10 ⁇ M), S814 (10 ⁇ M), S830 (10 ⁇ M), S832 (10 ⁇ M), S829 (10 ⁇ M), S831 (10 ⁇ M), and S847 (10 ⁇ M) are shown in this order.
  • the absorbance at 450 nm was decreased compared to the DMSO-treated group due to phenomena such as apoptosis induction and cell growth inhibition in SKOV3-TR and SKOV3.
  • S-forms were treated in combination with paclitaxel, SKOV3-TR, a resistant cancer cell line, enhanced the anticancer effect of paclitaxel and showed lower absorbance compared to the paclitaxel-treated group.
  • a baseline was included in the absorbance of the paclitaxel-treated group, which is a comparative example.
  • the absorbance (OD Value at 450nm) was significantly decreased in the WST-1 analysis when paclitaxel + S-forms was treated compared to the paclitaxel-treated group.
  • docetaxel treatment induced a decrease in metabolism in SKOV3-TR and SKOV3.
  • SKOV3-TR and SKOV3 cancer cell lines were treated with 47 types of S-forms, then treated with docetaxel, and WST-1 analysis was performed.
  • 10 and 12 show DMSO, docetaxel, S836 (2 ⁇ M), S838 (2 ⁇ M), S840 (2 ⁇ M), S841 (2 ⁇ M), S842 (2 ⁇ M), S857 (2 ⁇ M), S858 (2 ⁇ M), S860 (2 ⁇ M), S823 (2 ⁇ M), S824 (2 ⁇ M), S825 (2 ⁇ M), S826 (2 ⁇ M), S856 (2 ⁇ M), S859 (2 ⁇ M), S839 (2 ⁇ M), S827 (2 ⁇ M), S828 (2 ⁇ M), S814 (2 ⁇ M), S830 (2 ⁇ M), S832 (2 ⁇ M), S829 (2 ⁇ M), S831 (2 ⁇ M), and S847 (2 ⁇ M) are shown in this order.
  • the docetaxel (Doxetaxel) treatment group had a decrease in absorbance at 450 nm compared to the DMSO treatment group due to phenomena such as apoptosis induction and cell growth inhibition in SKOV3-TR and SKOV3.
  • the resistant cancer cell line, SKOV3-TR enhanced the anticancer effect of docetaxel and showed lower absorbance compared to the docetaxel-treated group.
  • a reference line was put in the absorbance of the comparative example docetaxel (Doxetaxel) treatment group.
  • the anticancer enhancing efficacy of docetaxel was significantly reduced in the WST-1 analysis when docetaxel+S-forms were treated compared to docetaxel (Doxetaxel) in absorbance (OD Value at 450nm).
  • Hela-PTX-R and Hela cancer cell lines were treated with 47 types of compounds, then treated with paclitaxel, and WST-1 analysis was performed.
  • paclitaxel paclitaxel, S-form solvent
  • paclitaxel Paclitaxel
  • 47 kinds of S-forms were co-treated 3 days after WST-1 analysis was performed and shown in FIGS. 13 to 16 .
  • FIG. 13 and 15 show DMSO, paclitaxel, S801 (10 ⁇ M), S802 (10 ⁇ M), S803 (10 ⁇ M), S804 (10 ⁇ M), S806 (10 ⁇ M), S807 (10 ⁇ M), S808 (10 ⁇ M), S809 (10 ⁇ M), S810 (10 ⁇ M), S811 (10 ⁇ M), S812 (10 ⁇ M), S813 (10 ⁇ M), S815 (10 ⁇ M), S816 (10 ⁇ M), S819 (10 ⁇ M), S820 (10 ⁇ M), S821 (10 ⁇ M), S845 (10 ⁇ M), S855 (10 ⁇ M), S805 (10 ⁇ M), S822 (10 ⁇ M), S833 (10 ⁇ M), S834 (10 ⁇ M), S835 (10 ⁇ M) are shown in the order.
  • 14 and 16 show DMSO, paclitaxel, S836 (10 ⁇ M), S838 (10 ⁇ M), S840 (10 ⁇ M), S841 (10 ⁇ M), S842 (10 ⁇ M), S857 (10 ⁇ M), S858 (10 ⁇ M), S860 (10 ⁇ M), S823 (10 ⁇ M), S824 (10 ⁇ M), S825 (10 ⁇ M), S826 (10 ⁇ M), S856 (10 ⁇ M), S859 (10 ⁇ M), S839 (10 ⁇ M), S827 (10 ⁇ M), S828 (10 ⁇ M), S814 (10 ⁇ M), S830 (10 ⁇ M), S832 (10 ⁇ M), S829 (10 ⁇ M), S831 (10 ⁇ M), and S847 (10 ⁇ M) are shown in this order.
  • the paclitaxel-treated group had a decrease in absorbance at 450 nm compared to the DMSO-treated group due to phenomena such as apoptosis induction and cell growth inhibition in Hela-PTX-R and Hela.
  • S-forms were treated in combination with paclitaxel, Hela-PTX-R, a resistant cancer cell line, enhanced the anticancer effect of paclitaxel and showed lower absorbance compared to the paclitaxel-treated group.
  • a baseline was included in the absorbance of the paclitaxel-treated group, which is a comparative example.
  • the absorbance (OD Value at 450nm) was significantly decreased in the WST-1 analysis when paclitaxel + S-forms was treated compared to the paclitaxel-treated group.
  • MCF7-BC19 and MCF7 cancer cell lines were treated with 47 types of compounds and then treated with paclitaxel, and WST-1 analysis was performed.
  • paclitaxel paclitaxel, S-form solvent
  • paclitaxel Paclitaxel
  • WST-1 analysis was performed 3 days later and shown in FIGS. 17 to 20 .
  • FIG. 17 Figure 17, Figure 19 DMSO, paclitaxel, S801 (10 ⁇ M), S802 (10 ⁇ M), S803 (10 ⁇ M), S804 (10 ⁇ M), S806 (10 ⁇ M), S807 (10 ⁇ M), S808 (10 ⁇ M), S809 (10 ⁇ M), S810 (10 ⁇ M), S811 (10 ⁇ M), S812 (10 ⁇ M), S813 (10 ⁇ M), S815 (10 ⁇ M), S816 (10 ⁇ M), S819 (10 ⁇ M), S820 (10 ⁇ M), S821 (10 ⁇ M), S845 (10 ⁇ M), S855 (10 ⁇ M), S805 (10 ⁇ M), S822 (10 ⁇ M), S833 (10 ⁇ M), S834 (10 ⁇ M), S835 (10 ⁇ M) are shown in the order.
  • 18 and 20 show DMSO, paclitaxel, S836 (10 ⁇ M), S838 (10 ⁇ M), S840 (10 ⁇ M), S841 (10 ⁇ M), S842 (10 ⁇ M), S857 (10 ⁇ M), S858 (10 ⁇ M), S860 (10 ⁇ M), S823 (10 ⁇ M), S824 (10 ⁇ M), S825 (10 ⁇ M), S826 (10 ⁇ M), S856 (10 ⁇ M), S859 (10 ⁇ M), S839 (10 ⁇ M), S827 (10 ⁇ M), S828 (10 ⁇ M), S814 (10 ⁇ M), S830 (10 ⁇ M), S832 (10 ⁇ M), S829 (10 ⁇ M), S831 (10 ⁇ M), and S847 (10 ⁇ M) are shown in this order.
  • the absorbance at 450 nm was decreased compared to the DMSO-treated group due to phenomena such as apoptosis induction and cell growth inhibition in MCF7-BC19 and MCF7.
  • the resistant cancer cell line MCF7-BC19 enhanced the anticancer effect of paclitaxel and showed lower absorbance compared to the paclitaxel-treated group.
  • a baseline was included in the absorbance of the paclitaxel-treated group, which is a comparative example.
  • the absorbance (OD Value at 450nm) was significantly decreased in the WST-1 analysis when paclitaxel + S-forms was treated compared to the paclitaxel-treated group.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a pharmaceutical composition comprising a novel compound or a pharmaceutically acceptable salt thereof for prevention or treatment of refractory cancer. When administered together with an anticancer agent, the composition of the present invention can exhibit an excellent anticancer effect.

Description

신규한 화합물 및 이를 포함하는 암 예방 또는 치료용 약학 조성물 및 그의 용도Novel compound and pharmaceutical composition for preventing or treating cancer comprising same, and use thereof
본 출원은 2021년 4월 29일에 한국 특허청에 제출한 출원 10-2021-0056108호의 출원일의 이익을 주장하며, 그 내용 전부는 본 명세서에 포함된다. This application claims the benefit of the filing date of Application No. 10-2021-0056108, filed with the Korean Intellectual Property Office on April 29, 2021, the entire contents of which are incorporated herein by reference.
본 출원은 신규한 화합물 및 상기 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 암 예방 또는 치료용 약학 조성물, 암 예방 또는 치료 방법, 암 예방 또는 치료 용도에 관한 것이다.The present application relates to a novel compound and a pharmaceutical composition for preventing or treating cancer comprising the compound or a pharmaceutically acceptable salt thereof, a method for preventing or treating cancer, and a use for preventing or treating cancer.
암은 전세계적으로 가장 보편적인 사망 원인 중의 하나로, 사망 원인의 약 12%를 차지하고 있다. 대표적인 항암 요법인 화학 요법(chemotherapy)은, 단독으로 또는 방사능 요법과 같은 다른 치료법과 조합하여 현재 암을 치료하기 위한 가장 효율적인 치료법으로 사용되고 있다. 그러나, 화학 요법에서 암 치료 약물의 효능은 암세포를 죽일 수 있는 능력에 따르나, 약물 사용 시 암 세포 뿐만 아니라 일반적인 세포에도 작용할 수 있다는 문제가 있다. Cancer is one of the most common causes of death worldwide, accounting for about 12% of deaths. Chemotherapy, which is a representative anticancer therapy, is currently used as the most effective treatment for cancer, either alone or in combination with other therapies such as radiotherapy. However, the efficacy of a cancer treatment drug in chemotherapy depends on its ability to kill cancer cells, but there is a problem that it can act not only on cancer cells but also normal cells when the drug is used.
일반 암세포는 항암제를 투여하면 과도한 스트레스가 유발되고 소포체(endoplasmic reticulum, ER)에서 칼슘 이온이 과다 분비되며 분비된 칼슘이온이 미토콘드리아에 쌓이면서 암 세포의 자살로 이어지는 반면, 암 줄기세포는 항암제 투여 시 과도한 칼슘 이온의 분비를 줄이고, 동시에 과도하게 분비된 칼슘이온을 다시 소포체로 되돌려 넣을 수 있는 SERCA 발현을 늘려 칼슘이온 농도를 조절하면서 생존하는 것으로 밝혀졌다. 즉, SERCA 단백질은 소포체 스트레스 신호전달 과정에서 생존 신호전달을 위한 역할을 할 수 있다.In general, when anticancer drugs are administered, excessive stress is induced, calcium ions are excessively secreted from the endoplasmic reticulum (ER), and the secreted calcium ions accumulate in mitochondria, leading to cancer cell suicide. It was found to survive while controlling the calcium ion concentration by decreasing the secretion of calcium ions and increasing the expression of SERCA, which can return the excessively secreted calcium ions back to the endoplasmic reticulum. That is, the SERCA protein may play a role for survival signaling in the endoplasmic reticulum stress signaling process.
암 줄기세포가 갖는 항암제 저항성을 나타나게 하는 원인인 SERCA 단백질을 타겟으로 하는 억제제로 작용할 수 있는 물질을 개발하여 암 줄기세포의 성장을 선택적으로 억제할 수 있다면, 항암 약물에 의한 화학 요법의 효능을 증가시켜 더 낮은 용량의 약물로도 우수한 항암 효과를 나타나게 할 수 있을 것이다.If it is possible to selectively inhibit the growth of cancer stem cells by developing a substance that can act as an inhibitor that targets the SERCA protein, which is the cause of the anticancer drug resistance of cancer stem cells, increase the efficacy of chemotherapy by anticancer drugs. Therefore, it will be possible to show excellent anticancer effect even with a lower dose of the drug.
본 출원의 일측면은 신규한 화합물을 제공하는 것이다. One aspect of the present application is to provide a novel compound.
또한, 본 출원의 다른 일측면은 신규한 화합물을 포함하는 암 예방 또는 치료용 약학 조성물을 제공하는 것이다.In addition, another aspect of the present application is to provide a pharmaceutical composition for preventing or treating cancer comprising a novel compound.
또한, 본 출원의 다른 일측면은 신규한 화합물을 포함하는 내성암 예방 또는 치료용 약학 조성물을 제공하는 것이다.In addition, another aspect of the present application is to provide a pharmaceutical composition for preventing or treating resistant cancer comprising a novel compound.
또한, 본 출원의 다른 일측면은 신규한 화합물의 암 예방 또는 치료 용도를 제공하는 것이다.In addition, another aspect of the present application is to provide a use for preventing or treating cancer of the novel compound.
또한, 본 출원의 다른 일측면은 신규한 화합물의 내성암 예방 또는 치료 용도를 제공하는 것이다.In addition, another aspect of the present application is to provide a use for preventing or treating resistant cancer of the novel compound.
또한, 본 출원의 다른 일측면은 신규한 화합물의 암 예방 또는 치료 방법을 제공하는 것이다.In addition, another aspect of the present application is to provide a method for preventing or treating cancer of a novel compound.
또한, 본 출원의 다른 일측면은 신규한 화합물의 내성암 예방 또는 치료 방법을 제공하는 것이다.In addition, another aspect of the present application is to provide a method for preventing or treating resistant cancer of a novel compound.
본 출원의 해결 과제는 이상에서 언급된 것들에 한정되지 않으며, 언급되지 아니한 다른 해결과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.The problems to be solved in the present application are not limited to those mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.
본 출원의 하나의 실시예는, 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다.One embodiment of the present application provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2022006181-appb-img-000001
Figure PCTKR2022006181-appb-img-000001
상기 화학식 1에서In Formula 1 above
R1은 수소, 직쇄 또는 분지쇄알킬, 알콕시, 할로알킬, 할로알콕시, 아릴, 헤테로아릴, 알킬아릴 또는 알킬헤테로아릴이고, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C6알킬, C1~C6알콕시, C3~C6사이클로알킬, C1~C6할로알킬, C1~C6할로알콕시, 옥소, 시아노, 비치환되거나 치환된 아릴, 또는 비치환되거나 치환된 헤테로아릴 중 적어도 하나로 치환될 수 있고;R 1 is hydrogen, straight or branched chain alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl may be substituted with at least one of;
R3은 수소, 직쇄 또는 분지쇄알킬, 사이클로알킬, 아릴, 헤테로아릴, 알킬아릴 또는 알킬헤테로아릴이며, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C6알킬, C1~C6알콕시, C1~C6할로알킬, C1~C6할로알콕시, 옥소, 시아노, 비치환되거나 치환된 아릴, 또는 비치환되거나 치환된 헤테로아릴 중 적어도 하나로 치환될 수 있으며;R 3 is hydrogen, straight or branched chain alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy may be substituted with at least one of , C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
L1은 C1~C10 알킬렌이며, 이때 상기 알킬렌은 C1~C6알킬, C3~C6 사이클로알킬, C1~C6알콕시, 히드록실, 옥소 또는 할로겐 중 적어도 하나로 치환될 수 있고, 상기 C1~C6알킬, C3~C6 사이클로알킬, C1~C6알콕시는 비치환되거나 치환된 아릴로 치환될 수 있고;L 1 is C 1 -C 10 alkylene, wherein the alkylene may be substituted with at least one of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxyl, oxo or halogen. and wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy may be unsubstituted or substituted with substituted aryl;
Q는 S, Se, NR, P, P(O), P(O)2 또는 P(O)OR 이며, 이때 상기 R은 수소, 직쇄 또는 분지쇄알킬, 사이클로알킬, 바이 또는 트라이사이클로 알킬, 알콕시, 할로알킬, 할로알콕시, 아릴, 헤테로아릴, 알킬아릴 또는 알킬헤테로아릴이고, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C6 알킬, C1~C6알콕시, C1~C6할로알킬, C1~C6할로알콕시, 옥소, 시아노, 비치환되거나 치환된 아릴, 또는 비치환되거나 치환된 헤테로아릴 중 적어도 하나로 치환될 수 있으며;Q is S, Se, NR, P, P(O), P(O) 2 or P(O)OR , wherein R is hydrogen, straight or branched chain alkyl, cycloalkyl, bi or tricyclo alkyl, alkoxy , haloalkyl, haloalkoxy, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 halo may be substituted with at least one of alkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
R2는 수소, 직쇄알킬, 사이클로알킬, 알콕시, 할로알콕시, 할로알킬, 아릴, 헤테로아릴, 알킬아릴 또는 알킬헤테로아릴이고, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C6알킬, C1~C6알콕시, C1~C6할로알킬, C1~C6할로알콕시, 비치환되거나 치환된 아릴, 비치환되거나 치환된 헤테로아릴, 옥소, 나이트로, 시아노 또는 트리플루오로메틸 중 적어도 하나로 치환될 수 있고;R 2 is hydrogen, straight chain alkyl, cycloalkyl, alkoxy, haloalkoxy, haloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C of 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, oxo, nitro, cyano or trifluoromethyl at least one may be substituted;
R4 및 R4’은 각각 독립적으로 수소, 직쇄 또는 분지쇄알킬, 사이클로알킬, 알케닐, 알키닐, 알킬싸이오, 아릴, 헤테로아릴, 알킬아릴 또는 알킬헤테로아릴이며, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C6알킬, C1~C6알콕시, C1~C6할로알킬, C1~C6할로알콕시, 비치환되거나 치환된 아릴, 비치환되거나 치환된 헤테로아릴, 옥소, 나이트로, 시아노 또는 트리플루오로메틸 중 적어도 하나로 치환될 수 있으며;R 4 and R 4 ′ are each independently hydrogen, straight or branched chain alkyl, cycloalkyl, alkenyl, alkynyl, alkylthio, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydrogen hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, oxo , may be substituted with at least one of nitro, cyano or trifluoromethyl;
n은 1 내지 4의 정수이고;n is an integer from 1 to 4;
X, Y, Z는 각각 독립적으로 수소, 직쇄 또는 분지쇄알킬, 사이클로알킬, 아릴, 헤테로아릴, 알킬아릴 또는 알킬헤테로아릴이며, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C6알킬, C1~C6알콕시, C1~C6할로알킬, C1~C6할로알콕시, 비치환되거나 치환된 아릴, 비치환되거나 치환된 헤테로아릴, 옥소, 나이트로, 시아노, 또는 트리플루오로메틸 중 적어도 하나로 치환될 수 있다. X, Y, Z are each independently hydrogen, straight or branched chain alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, oxo, nitro, cyano, or trifluoro It may be substituted with at least one of methyl.
본 출원의 하나의 실시예는, 상기 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용 가능한 염 중 적어도 하나를 포함하는 암 치료 또는 예방용 약학 조성물을 제공한다.One embodiment of the present application provides a pharmaceutical composition for treating or preventing cancer comprising at least one of the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof.
본 출원의 하나의 실시예는, 상기 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용 가능한 염 중 적어도 하나를 포함하는 내성암 치료 또는 예방용 약학 조성물을 제공한다.One embodiment of the present application provides a pharmaceutical composition for treating or preventing resistant cancer comprising at least one of the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof.
본 출원의 하나의 실시예는, 상기 화학식 1로 표시되는 화합물, 이의 약학적으로 허용 가능한 염, 수화물, 용매화물, 구조 이성질체, 광학 이성질체, 입체이/성질체, 또는 이들의 조합의 치료적 유효량을 투여하는 단계를 포함하는 암, 내성암, 또는 줄기세포성 암의 치료 방법을 제공한다. One embodiment of the present application provides a therapeutically effective amount of the compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer/isomer, or a combination thereof. It provides a method of treating cancer, resistant cancer, or stem cell cancer comprising administering.
본 출원의 하나의 실시예에서 상기 투여는 암 또는 증식성 질병의 치료에 유용한 항암제를 동시에, 개별적으로, 또는 순차적으로 투여할 수 있다. In one embodiment of the present application, the administration may include simultaneous, separate, or sequential administration of an anticancer agent useful for the treatment of cancer or proliferative disease.
본 출원의 하나의 실시예는, 암, 내성암, 또는 줄기세포성 암의 치료를 위한 약제를 제조하기 위한 상기 화학식 1로 표시되는 화합물, 이의 약학적으로 허용 가능한 염, 수화물, 용매화물, 구조 이성질체, 광학 이성질체, 입체이성질체, 또는 이들의 조합의 용도를 제공한다. One embodiment of the present application provides a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, and structure thereof for preparing a medicament for the treatment of cancer, resistant cancer, or stem cell cancer isomers, optical isomers, stereoisomers, or combinations thereof.
본 출원의 하나의 실시예에 따른 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 약학 조성물은 우수한 항암 효과를 나타낼 수 있다.A pharmaceutical composition comprising a compound according to an embodiment of the present application or a pharmaceutically acceptable salt thereof may exhibit excellent anticancer effect.
본 출원의 하나의 실시예에 따른 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물은 항암제 또는 방사선의 항암 활성을 증진시킬 수 있으며, 암세포의 증식억제 및 세포 사멸 등을 유도하여 효과적으로 암을 치료할 수 있다.A composition comprising a compound according to an embodiment of the present application or a pharmaceutically acceptable salt thereof can enhance the anticancer activity of an anticancer agent or radiation, and can effectively treat cancer by inducing proliferation inhibition and apoptosis of cancer cells. can
본 출원의 하나의 실시예에 따른 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물은 항암제 또는 방사선에 대한 내성을 갖는 암의 내성을 극복하게 하여 효과적으로 내성암을 치료할 수 있고, 항암치료의 부작용을 줄일 수 있다.A composition comprising a compound or a pharmaceutically acceptable salt thereof according to an embodiment of the present application can effectively treat resistant cancer by overcoming the resistance of cancer with resistance to anticancer drugs or radiation, and side effects of anticancer treatment can reduce
본 출원의 하나의 실시예에 따른 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물은 줄기세포성 암을 효과적으로 치료할 수 있다.A composition comprising the compound according to an embodiment of the present application or a pharmaceutically acceptable salt thereof can effectively treat stem cell cancer.
본 출원에 따른 효과는 이상에서 예시된 내용에 의해 제한되지 않으며, 더욱 다양한 효과들이 본 명세서 내에 포함되어 있다.Effects according to the present application are not limited by the contents exemplified above, and more various effects are included in the present specification.
도 1은 SKOV3의 파클리탁셀과 도세탁셀 항암제 IC50값을 나타낸 것이고, 도 2는 SKOV3-TR의 파클리탁셀과 도세탁셀 항암제 IC50값을 나타낸 것이다. 1 shows the IC 50 values of paclitaxel and docetaxel anticancer drugs of SKOV3, and FIG. 2 shows the IC 50 values of paclitaxel and docetaxel anticancer drugs of SKOV3-TR.
도 3은 Hela와 Hela-PTX-R의 파클리탁셀 항암제 IC50값을 나타낸 것이다.3 shows the IC 50 values of Hela and Hela-PTX-R for paclitaxel anticancer drugs.
도 4는 MCF7과 MCF7-BC19의 파클리탁셀 항암제 IC50값을 나타낸 것이다.4 shows the IC 50 values of the paclitaxel anticancer agent of MCF7 and MCF7-BC19.
도 5 내지 도 8은 파클리탁셀과 47종의 화합물에 대한 SKOV3-TR과 SKOV3의 WST-1 분석 결과를 나타낸 것이다. 5 to 8 show the results of WST-1 analysis of SKOV3-TR and SKOV3 for paclitaxel and 47 compounds.
도 9 내지 도 12는 도세탁셀과 47종의 화합물에 대한 SKOV3-TR과 SKOV3의 WST-1 분석 결과를 나타낸 것이다. 9 to 12 show the results of WST-1 analysis of SKOV3-TR and SKOV3 for docetaxel and 47 kinds of compounds.
도 13 내지 도 16은 파클리탁셀과 47종의 화합에 대한 Hela-PTX-R과 Hela의 WST-1 분석 결과를 나타낸 것이다. 13 to 16 show the results of WST-1 analysis of Hela-PTX-R and Hela for 47 compounds with paclitaxel.
도 17 내지 도 20은 파클리탁셀과 47종의 화합물에 대한 MCF7-BC19와 MCF7의 WST-1 분석 결과를 나타낸 것이다. 17 to 20 show the results of WST-1 analysis of MCF7-BC19 and MCF7 for paclitaxel and 47 compounds.
본 출원의 이점 및 특징, 그리고 그것들을 달성하는 방법은 상세하게 후술되어 있는 실시 예들을 참조하면 명확해질 것이다. 그러나 본 출원은 이하에서 개시되는 실시예들에 한정되는 것이 아니라 서로 다른 다양한 형태로 구현될 수 있으며, 단지 본 실시예들은 본 출원의 개시가 완전하도록 하고, 본 출원이 속하는 기술분 야에서 통상의 지식을 가진 자에게 발명의 범주를 완전하게 알려주기 위해 제공되 는 것이며, 본 출원은 청구항의 범주에 의해 정의될 뿐이다. Advantages and features of the present application, and a method for achieving them will become apparent with reference to the embodiments described below in detail. However, the present application is not limited to the embodiments disclosed below, but may be implemented in various different forms, and only the present embodiments allow the disclosure of the present application to be complete, and are common in the art to which the present application belongs. It is provided to fully inform those with knowledge of the scope of the invention, and the present application is only defined by the scope of the claims.
본 명세서에서, "독립적으로"란 용어는 독립적으로 적용되는 변수가 적용시 마다 독립적으로 변한다는 것을 의미한다. 따라서, RaXYRa와 같은 화합물에 있어서, Ra가 "독립적으로 탄소 또는 질소"이면, 양 쪽 Ra 모두 탄소일 수 있고, 양쪽 Ra 모두 질소일 수 있고, 또는 한 Ra는 탄소이고, 다른 Ra는 질소일 수 있다.As used herein, the term "independently" means that an independently applied variable independently changes from application to application. Thus, for compounds such as R a XYR a , if R a is "independently carbon or nitrogen," then both R a can be carbon, both R a can be nitrogen, or one R a is carbon and , other R a may be nitrogen.
본 명세서에서 "알킬"이란 용어는 달리 특정하지 않는 한 전형적으로 C1~C10의 포화된 직쇄 또는 분지된 탄화수소 사슬을 의미하며, 더욱 구체적으로 C1~C6 알킬의 포화된 직쇄 또는 C3~C6 분지된 탄화수소 사슬을 의미한다. "C1~C10 알킬"은 1개 내지 10개의 탄소 원자를 구비하는 직쇄 또는 분쇄 알킬를 의미하고, 구체적으로 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, t-부틸, 펜틸, 이소펜틸, 네오 펜틸, 헥실, 이소헥실, 사이클로헥실, 사이클로헥실메틸, 3-메틸펜틸, 2,2-디메틸 부틸, 및 2,3-디메틸부틸 등을 포함한다. 상기 용어는 치환 및 비치환된알킬기 모두를 포함한다. 알킬기는 선택적으로 하이드록실, 아미노, 알킬아미노, 아릴아미노, 알콕시, 아릴옥시, 니트로, 시아노, 술폰산, 설페이트, 인산, 포스페이트, 또는 포스포네이트로 이루어진 군으로부터 선택된 하나 이상의 모이어티로 치환될 수 있다. 알킬의 탄소 원자에 부착된 하나 이상의 수소 원자는 트리플루오로메틸, 디플루오로메틸, 플루오로클로로메틸 등과 같이 예를 들면 불소 또는 염소 또는 이들 모두와 같은 하나 이상의 할로겐 원자로 치환될 수 있다. 상기 탄화수소 사슬은 또한 중간에 N, O 또는 S와 같은 헤테로원자를 포함할 수 있다.As used herein, unless otherwise specified, the term "alkyl" typically means a C 1 -C 10 saturated straight chain or branched hydrocarbon chain, and more specifically, a C 1 -C 6 alkyl saturated straight chain or C 3 . ~C 6 means a branched hydrocarbon chain. "C 1 -C 10 alkyl" means straight chain or branched alkyl having 1 to 10 carbon atoms, specifically methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl , neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethyl butyl, and 2,3-dimethylbutyl, and the like. The term includes both substituted and unsubstituted alkyl groups. The alkyl group may be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate, or phosphonate. have. One or more hydrogen atoms attached to the carbon atoms of the alkyl may be substituted with one or more halogen atoms such as, for example, fluorine or chlorine or both, such as trifluoromethyl, difluoromethyl, fluorochloromethyl and the like. The hydrocarbon chain may also contain heteroatoms such as N, O or S in the middle.
"알카릴" 또는 "알킬아릴"이란 용어는 아릴 치환체를 갖는 알킬기를 의미한다. "아랄킬" 또는 "아릴알킬"이란 용어는 알킬 치환체, 예를 들면 벤질을 갖는 아릴기를 의미한다.The term "alkaryl" or "alkylaryl" refers to an alkyl group having an aryl substituent. The term “aralkyl” or “arylalkyl” refers to an aryl group having an alkyl substituent such as benzyl.
본 명세서에서 사용된 "할로" 또는 “할로겐"이란 용어는 클로로, 브로모, 아이오도 및 플루오로를 포함한다. As used herein, the term “halo” or “halogen” includes chloro, bromo, iodo and fluoro.
본 명세서에서 사용된 "알콕시"란 용어는 달리 특정하지 않는 한 "C 1~C6 알콕시"를 의미하고, "C1 ~C6 알콕시"는 1개 내지 6개의 탄소원자를 구비하는 직쇄 또는 분지쇄 알콕시를 의미하고, 메톡시기(methoxy), 에톡시기(ethoxy), 프로폭시(propoxy), 이소프로폭시(isopropoxy)와 부톡시기(butoxy) 등을 포함하나 이에 한정되는 것은 아니다.As used herein, the term "alkoxy" means "C 1 -C 6 alkoxy" unless otherwise specified, and "C 1 -C 6 alkoxy" is a straight or branched chain having 1 to 6 carbon atoms. It means alkoxy, and includes, but is not limited to, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group.
본 명세서에서 사용된 "알케닐"이란 용어는 달리 특정하지 않는 한 "C2 ~C6 알케닐"을 의미하고, "C2~C6 알케닐"는 2개 내지 6개의 탄소원자를 구비하는 한개의 이중 결합을 함유하는 직쇄 또는 분지쇄 알케닐을 의미하고, 비닐(vinyl), 프로페닐(propenyl), 부테닐(Butenyl), 이소부테닐(isobutenyl), 펜테닐(pentenyl)과 헥세닐(hexenyl) 등을 포함하나 이에 한정되는 것은 아니다.As used herein, the term "alkenyl" means "C 2 -C 6 alkenyl" unless otherwise specified, and "C 2 -C 6 alkenyl" is one having 2 to 6 carbon atoms. refers to a straight or branched chain alkenyl containing a double bond of, vinyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl and the like, but are not limited thereto.
본 명세서에서 사용된 "알키닐"이란 용어는 달리 특정하지 않는 한 "C2~C6 알키닐"을 의미하고, "C2~C6 알키닐"은 2 개 내지 6 개의 탄소원자를 구비하는 한개의 3중 결합을 함유하는 직쇄 또는 분지쇄 알키닐를 의미하고, 에티닐, 프로피닐, 부 티닐, 이소부티닐, 펜티닐과 헥시닐 등을 포함하나 이에 한정되는 것은 아니다.As used herein, the term "alkynyl" means "C 2 -C 6 alkynyl" unless otherwise specified, and "C 2 -C 6 alkynyl" is one having 2 to 6 carbon atoms. It refers to a straight-chain or branched alkynyl containing a triple bond of, including, but not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.
본 명세서에서 사용된 "사이클로알킬"이란 용어는 달리 특정하지 않는 한 "C3 ~C10 사이클로알킬"을 의미하고, "C3~C10 사이클로알킬"은 고리에 3 개 내지 10 개의 탄소원자를 구비하는 고리형 알킬를 의미하고, 사이클로프로필(cyclopropyl), 사이클로부틸(cyclobutyl), 사이클로펜틸(cyclopentyl), 사이클로헥실(cyclohexyl), 사이클로헵틸(cyclohe ptyl), 사이클로옥틸(cyclooctyl)과 사이클로데실(cyclodecyl) 등을 포함한다. 용어 "C3~C8 사이클로알킬", "C3~C7 사이클로알킬"과 "C3~C6 사이클로알킬"은 유사한 함의를 가지고 있다. 상기 사이클로알킬기는 사이클로프로필메틸 등과 같이 알킬기에 의해 고리가 치환될 수 있다.As used herein, the term "cycloalkyl" means "C 3 -C 10 cycloalkyl" unless otherwise specified, and "C 3 -C 10 cycloalkyl" has 3 to 10 carbon atoms in the ring. means cyclic alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, etc. includes The terms "C 3 -C 8 cycloalkyl", "C 3 -C 7 cycloalkyl" and "C 3 -C 6 cycloalkyl" have similar connotations. The cycloalkyl group may have a ring substituted with an alkyl group such as cyclopropylmethyl.
본 명세서에서 사용된 "아릴"이란 용어는 달리 특정하지 않는 한 "C6 내지 C12 아릴기"를 의미하고, "C6~C12 아릴기"는 고리에 헤테로 원자를 함유하지 않은 6개 내지 12개의 탄소 원자를 구비하는 페닐, 비페닐 (바이페닐), 또는 나프틸을 의미하며, 바람직하게는 페닐이다. 상기 용어는 치환 및 비치환된 모이어티 모두를 포함한다. 상기 "치환된 아릴"은 필요에 따라 비보호되거나 또는 보호된 하이드록실, 할로겐, 아미노, 알킬아미노, 아릴아미노, C1~C6 알킬, C1~C6 알콕시, C3~C6 사이클로알킬, C1~C6 할로알킬, C1~C6 할로알콕시, 옥소, 아릴옥시, 니트로, 시아노, 술폰산, 설페이트, 인산, 포스페이트, 또는 포스포네이트를 포함하는 하나 이상의 치환기로 치환될 수 있지만, 이에 한정되지는 않는다. 용어 "C6~C10 아릴기"는 유사한 함의를 가지고 있다. As used herein, the term "aryl" means a "C 6 to C 12 aryl group" unless otherwise specified, and "C 6 to C 12 aryl group" refers to 6 to C 12 aryl groups that do not contain a hetero atom in the ring. phenyl, biphenyl (biphenyl), or naphthyl having 12 carbon atoms, preferably phenyl. The term includes both substituted and unsubstituted moieties. The "substituted aryl" is optionally unprotected or protected hydroxyl, halogen, amino, alkylamino, arylamino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, may be substituted with one or more substituents including C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate, or phosphonate, However, the present invention is not limited thereto. The term "C 6 -C 10 aryl group" has a similar connotation.
본 명세서에서 사용된 용어 "헤테로아릴" 또는 "헤테로사이클릭"은 "3~12원 헤테로사이클릭"을 의미하고, "3~12원 헤테로사이클릭"은 고리에 산소, 유황과 질소 중에서 선택되는 헤테로 원자를 1~3개 함유하는 포화 또는 불포화된 3~12원 고리기를 의미하는 바, 예를 들면 디옥솔(dioxol)이다. 용어 "3~7원 헤테로사이클릭" 은 유사한 함의를 가지고 있다. 본 명세서에서 "치환된 헤테로아릴"은 필요에 따라 비보호되거나 또는 보호된 하이드록실, 할로겐, 아미노, 알킬아미노, 아릴아미노, C1~C6 알킬, C1~C6 알콕시, C3~C 6 사이클로알킬, C1~C6 할로알킬, C1~C6 할로 알콕시, 옥소, 아릴옥시, 니트로, 시아노, 술폰산, 설페이트, 인산, 포스페이트, 또는 포스포네이트를 포함하는 하나 이상의 치환기로 치환될 수 있지만, 이에 한정되지는 않는다. As used herein, the term "heteroaryl" or "heterocyclic" means "3 to 12 membered heterocyclic", and "3 to 12 membered heterocyclic" is selected from among oxygen, sulfur and nitrogen in the ring. It means a saturated or unsaturated 3-12 membered ring group containing 1 to 3 hetero atoms, for example, dioxol (dioxol). The term "3-7 membered heterocyclic" has a similar connotation. As used herein, "substituted heteroaryl" refers to unprotected or protected hydroxyl, halogen, amino, alkylamino, arylamino, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 3 to C 6 as needed. substituted with one or more substituents including cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 halo alkoxy, oxo, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate, or phosphonate can, but is not limited thereto.
본 명세서에서 사용된 "알킬렌"은 2가의 히드로카르빌기를 가리키는데, 이는 이것이 2가이므로 2개의 다른 기들과 함께 링크될 수 있기 때문이다. 일반적으로, 이것은 -(CH2)n-이며 여기서 n은 1 내지 8이고 바람직하게는 n은 1 내지 4이지만, 특정한 경우, 알킬렌은 다른 기들에 의해 치환될 수도 있으며, 길이가 다를 수도 있고, 오픈 원자가들이 반드시 사슬의 반대쪽에 있어야 할 필요도 없다.As used herein, “alkylene” refers to a divalent hydrocarbyl group, since it is divalent and thus can be linked with two other groups. In general, it is -(CH 2 )n-, where n is 1 to 8 and preferably n is 1 to 4, but in certain instances the alkylene may be substituted by other groups and may be of different lengths, The open atoms do not necessarily have to be on opposite sides of the chain.
일반적으로, 치환기 내에 함유된 모든 알킬, 알케닐, 알키닐, 또는 아릴,알킬아릴 또는 아릴알킬은 그 자체가 다른 부가적인 치환기들에 의해 선택적으로 치환될 수 있다. 이들 치환기들의 성질은 치환기들이 달리 설명되지 않는 한, 일차 치환기들 자체에 대하여 인용된 것과 유사하다.In general, any alkyl, alkenyl, alkynyl, or aryl, alkylaryl or arylalkyl contained within a substituent may itself be optionally substituted by other additional substituents. The nature of these substituents is similar to that recited for the primary substituents themselves, unless the substituents are otherwise stated.
본 명세서에서 사용된 "헤테로원자"라는 용어는 질소, 산소 또는 황처럼 탄소나 수소가 아닌 원자를 가리킨다. 이것이 사슬이나 고리의 백본 또는 골격의 일부이면, 헤테로원자는 적어도 2가여야 하며, 일반적으로 N, O, P, 및 S로부터 선택될 것이다.As used herein, the term "heteroatom" refers to an atom other than carbon or hydrogen, such as nitrogen, oxygen, or sulfur. If it is part of the backbone or backbone of a chain or ring, the heteroatom must be at least divalent and will generally be selected from N, O, P, and S.
본 명세서에서 사용된 "치환될 수 있는" 또는 “치환된”이라는 용어는 선택적으로 치환되는 것으로 칭해지는 특정 기 또는 기들이 비-수소 치환기들을 갖지 않거나, 또는 상기 기 또는 기들이 결과적인 분자의 화학 및 약리학적 활성과 부합 하는 1개 이상의 비-수소 치환기들을 가질 수 있음을 나타낸다. 달리 특정되지 않는 한, 존재할 수 있는 이러한 치환기들의 총 개수는 설명되는 기의 치환되지 않은 형태에 존재하는 수소 원자들의 총 개수와 같으며; 이러한 치환기들의 최대 개수보다 적은 수로 존재할 수 있다. 선택적 치환기가 이중 결합 예컨대 카르보닐 산소(C=O)를 통해 결합되는 경우, 그 기는 그 선택적 치환기가 부착되는 탄소 원자 상에서 이용 가능한 2 원자가를 취함으로써, 포함될 수 있는 치환기들의 총 개수는 이용가능한 원자가의 수에 따라 감소된다. 본 출원에서, "치환된"이라는 용어는 "치환될 수 있는"이라는 용어의 일부로 사용되든 또는 달리 사용되든, 특정한 기, 모이어티 또는 래디칼을 변형시키도록 사용될 경우, 1개 이상의 수소 원자들이 각각 독립적으로 서로, 같거나 다른 치환기 또는 치환기들에 의해 대체됨을 의미한다.As used herein, the term "which may be substituted" or "substituted" means that the particular group or groups referred to as being optionally substituted does not have non-hydrogen substituents, or that the group or groups does not contain the chemistry of the resulting molecule. and one or more non-hydrogen substituents consistent with pharmacological activity. Unless otherwise specified, the total number of such substituents that may be present is equal to the total number of hydrogen atoms present in the unsubstituted form of the group being described; There may be fewer than the maximum number of such substituents. When an optional substituent is attached via a double bond such as a carbonyl oxygen (C=O), the group takes on the two valencies available on the carbon atom to which the optional substituent is attached, so that the total number of substituents that can be included is equal to the available valence. decreases with the number of In this application, the term "substituted", whether used as part of the term "which may be substituted," or otherwise, when used to modify a particular group, moiety, or radical, means that one or more hydrogen atoms are each independently to each other, means to be replaced by the same or different substituents or substituents.
본 명세서에서 설명된 화합물들은 1개 이상의 키랄 중심 및/또는 이중 결합을 함유할 수 있으므로, 입체이성질체, 예컨대 이중-결합 이성질체(즉, 기하 이성질체 예컨대 E 및 Z), 에난티오머 또는 부분입체이성질체로서 존재할 수 있다. 본 출원은 각각 분리된 입체이성질 형태(예컨대 에난티오머적으로 순수한 이성질체, E 및 Z 이성질체, 및 입체 이성질체의 기타 대체물) 및 키랄 순도와 E 및 Z의 백분율을 달리하는 입체이성질체들의 혼합물도 포괄한다(특정 입체이성질체로 한정되지 않는 한). 따라서, 본 출원에 설명된 화학 구조들은 입체이성질체적으로 순수한 형태(예컨대 기하적으로 순수하거나, 에난티오머적으로 순수하거나 부분입체이성질체적으로 순수한) 및 에난티오머 혼합물 및 입체이성질체 혼합물을 비롯하여, 설명된 화합물의 가능한 모든 에난티오머와 입체이성질체를 모두 포괄한다. 에난티오머 혼합물과 입체이성질체 혼합물은 당업계에 잘 알려진 분리 기술 또는 키랄 합성 기술을 이용하여 그들의 대응하는 에난티오머 또는 입체이성질체 성분으로 분할될 수 있다. 본 출원은 각각의 분리된 입체이성질체 형태뿐 아니라 라세미 혼합물을 비롯, 키랄 순도를 달리하는 입체이성질체의 혼합물도 포함한다. 본 출원은 또한 다양한 부분입체이성질체도 포괄한다. 기타 구조들이 특정 이성질체를 묘사하는 것으로 보일 수 있으나, 이는 편의상 그러한 것일 뿐, 본 출원이 그와 같이 특정하게 설명된 이성질체로 한정되는 것은 아니다. 화학명칭이 화합물의 이성질체 형태를 명시하지 않을 경우, 화합물의 이성질체 형태들의 가능한 모든 이성질체 형태 또는 그들의 혼합물을 가리키는 것이다.Since the compounds described herein may contain one or more chiral centers and/or double bonds, they may be treated as stereoisomers, such as double-bond isomers (i.e. geometric isomers such as E and Z), enantiomers, or diastereomers. may exist. The present application also encompasses mixtures of stereoisomers that differ in chiral purity and percentages of E and Z, respectively, as isolated stereoisomeric forms (such as enantiomerically pure isomers, E and Z isomers, and other replacements of stereoisomers). unless limited to a specific stereoisomer). Accordingly, the chemical structures described in this application are described, including stereoisomerically pure forms (eg, geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomer mixtures and stereoisomeric mixtures. It encompasses all possible enantiomers and stereoisomers of the specified compounds. Mixtures of enantiomers and mixtures of stereoisomers can be resolved into their corresponding enantiomeric or stereoisomeric components using separation techniques or chiral synthesis techniques well known in the art. The present application includes mixtures of stereoisomers of varying chiral purity, including racemic mixtures as well as individual isolated stereoisomeric forms. This application also encompasses the various diastereomers. Other structures may appear to depict specific isomers, but this is for convenience only and is not intended to limit the present application to the isomers specifically described as such. When a chemical name does not specify an isomeric form of a compound, it refers to all possible isomeric forms of the isomeric forms of the compound or mixtures thereof.
본 명세서 및 하기 청구범위에서 사용되는 경우, 단어 "~를 포 함하다", "~를 포함하는", "~를 포괄하다" 및 "~를 포괄하는"은 언급 된 특징, 정수, 성분, 또는 단계를 구체화하기 위한 것이나, 이것이 하나 이상의 다른 특징, 정수, 성분, 단계, 또는 이들의 그룹의 존재 또는 부가를 불가능하게 하는 것은 아니다.As used herein and in the claims that follow, the words "comprises", "comprising Although it is intended to specify a step, it is not intended to preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.
이하, 본 출원의 실시예들을 설명하도록 한다.Hereinafter, embodiments of the present application will be described.
본 출원의 하나의 실시예는, 하기 화학식 1로 표시되는 화합물 또는 이의 약 학적으로 허용 가능한 염을 제공한다.One embodiment of the present application provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
본 출원의 하나의 실시예는, 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다.One embodiment of the present application provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2022006181-appb-img-000002
Figure PCTKR2022006181-appb-img-000002
상기 화학식 1은, 하기 화학식 2 또는 화학식 3으로 표시될 수 있다. Formula 1 may be represented by Formula 2 or Formula 3 below.
[화학식 2][Formula 2]
Figure PCTKR2022006181-appb-img-000003
Figure PCTKR2022006181-appb-img-000003
[화학식 3][Formula 3]
Figure PCTKR2022006181-appb-img-000004
Figure PCTKR2022006181-appb-img-000004
화학식 1 내지 화학식 3에서, R1은 수소, 직쇄 또는 분지쇄알킬, 알콕시, 할로알킬, 할로알콕시, 아릴, 헤테로아릴, 알킬아릴 또는 알킬 헤테로아릴이고, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C6 알킬, C1~C6 알콕시, C3~C6 사이클로알킬, C1~C6 할로알킬, C 1~C6 할로알콕시, 옥소, 시아노, 비치환되거나 치환된 아릴, 또는 비치환되거나 치환된 헤테로아릴 중 적어도 하나로 치환될 수 있다.In Formulas 1 to 3, R 1 is hydrogen, straight or branched chain alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, alkylaryl or alkyl heteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or It may be substituted with at least one of unsubstituted or substituted heteroaryl.
상기 R1은 수소, C1~C10 직쇄 또는 분지쇄알킬, C1~C10 알콕시, C1~C10 할로알킬, C1~C10 할로알콕시, C6~C12 아릴, C5~C12 헤테로아릴, 알킬(C1~C10)아릴(C6~C12) 또는 알킬(C1~C10)헤테로아릴(C5~C12)이고, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C10 알킬, C1~C10 알콕시, C3~C10 사이클로알킬, C1~C10 할로알킬, C1~C10 할로알콕시, 옥소, 시아노, 비치환되거나 치환된 C6~C12 아릴, 또는 비치환되거나 치환된 C5~C12 헤테로아릴중 적어도 하나로 치환될 수 있다. Wherein R 1 is hydrogen, C 1 ~ C 10 straight or branched chain alkyl, C 1 ~ C 10 alkoxy, C 1 ~ C 10 haloalkyl, C 1 ~ C 10 haloalkoxy, C 6 ~ C 12 aryl, C 5 ~ C 12 heteroaryl, alkyl(C 1 ~C 10 )aryl(C 6 ~C 12 ) or alkyl(C 1 ~C 10 )heteroaryl(C 5 ~C 12 ), each of which is independently hydroxyl, halogen , C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl, C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, oxo, cyano, unsubstituted or substituted C It may be substituted with at least one of 6 -C 12 aryl, or unsubstituted or substituted C 5 -C 12 heteroaryl.
상기 R1은 구체적으로 수소, C1~C6 직쇄 또는 분지쇄알킬, C1~C6 알콕시, C1~C6 할로알킬, C1~C6 할로알콕시, C6~C12 아릴, C5~C12 헤테로아릴, 알킬(C1~C6)아릴(C6~C12) 또는 알킬(C1~C6)헤테로아릴(C5~C12)이고, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C6 알킬, C1~C6 알콕시, C3~C6 사이클로알킬, C1~C6 할로알킬, C1~C6 할로알콕시, 옥소, 시아노, 비치환되거나 치환된 C6~C12 아릴, 또는 비치환되거나 치환된 C5~C12 헤테로아릴중 적어도 하나로 치환될 수 있다.The R 1 is specifically hydrogen, C 1 -C 6 straight or branched chain alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 6 -C 12 aryl, C 5 ~C 12 heteroaryl, alkyl(C 1 ~C 6 )aryl(C 6 ~C 12 ) or alkyl(C 1 ~C 6 )heteroaryl(C 5 ~C 12 ), each of which is independently hydroxyl , halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted It may be substituted with at least one of C 6 -C 12 aryl, or unsubstituted or substituted C 5 -C 12 heteroaryl.
상기 R1은 더욱 구체적으로 수소, 비치환되거나 치환된 C1~C6직쇄알킬,비치환되거나 치환된 벤질, 또는 비치환되거나 치환된 2-페닐에틸이고, 이때 상기 치환된 C1~C6 직쇄알킬은 C3~C6 사이클로알킬로 치환된 것이고, 상기 치환된 벤질 또는 상기 치환된 2-페닐에틸은 오쏘, 메타 및 파라 위치 중 적어도 하나가 할로겐으로 치환되거나 페닐로 치환된 것일 수 있다.More specifically, R 1 is hydrogen, unsubstituted or substituted C 1 -C 6 straight chain alkyl, unsubstituted or substituted benzyl, or unsubstituted or substituted 2-phenylethyl, wherein the substituted C 1 -C 6 The straight chain alkyl is substituted with C 3 -C 6 cycloalkyl, and the substituted benzyl or substituted 2-phenylethyl may be one in which at least one of ortho, meta and para positions is substituted with halogen or phenyl.
상기 R1은 더욱 더 구체적으로 수소, C1~C6 직쇄알킬, C3~C6 분지쇄알킬, C3~C6 사이클로알킬,
Figure PCTKR2022006181-appb-img-000005
,
Figure PCTKR2022006181-appb-img-000006
,
Figure PCTKR2022006181-appb-img-000007
또는
Figure PCTKR2022006181-appb-img-000008
이며,이때 상기 X1은 수소, 할로겐, C1~C3 직쇄알킬, CF3, CN, NO2 또는 페닐일 수 있다.The R 1 is more specifically hydrogen, C 1 -C 6 straight-chain alkyl, C 3 -C 6 branched chain alkyl, C 3 -C 6 cycloalkyl,
Figure PCTKR2022006181-appb-img-000005
,
Figure PCTKR2022006181-appb-img-000006
,
Figure PCTKR2022006181-appb-img-000007
or
Figure PCTKR2022006181-appb-img-000008
In this case, X 1 may be hydrogen, halogen, C 1 to C 3 straight-chain alkyl, CF 3 , CN, NO 2 or phenyl.
화학식 1 내지 화학식 3에서, 상기 R3은 수소, 직쇄 또는 분지쇄알킬, 사이클로알킬, 아릴, 헤테로아릴, 알킬아릴 또는 알킬헤테로아릴이며, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C6알킬, C1~C6알콕시, C1~C6할로알킬, C1~C6할로알콕시, 옥소, 시아노, 비치환되거나 치환된 아릴, 또는 비치환되거나 치환된 헤테로아릴중 적어도 하나로 치환될 수 있다. In Formulas 1 to 3, R 3 is hydrogen, straight or branched chain alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 to C 6 be substituted with at least one of alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl can
상기 R3은 수소, C1~C10 직쇄 또는 분지쇄알킬, C3~C10 사이클로알킬, C6~C12 아릴, C5~C12 헤테로아릴, 알킬(C1~C10)아릴(C6~C12) 또는 알킬(C1~C10)헤테로아릴(C5~C12)이며, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C10 알킬, C1~C10 알콕시, C1~C10 할로알킬, C1~C10 할로알콕시, 옥소, 시아노, 비치환되거나 치환된아릴, 또는 비치환되거나 치환된 C5~C12 헤테로아릴중 적어도 하나로 치환될 수 있다.Wherein R 3 is hydrogen, C 1 ~ C 10 straight or branched chain alkyl, C 3 ~ C 10 cycloalkyl, C 6 ~ C 12 aryl, C 5 ~ C 12 heteroaryl, alkyl (C 1 ~C 10 ) aryl ( C 6 -C 12 ) or alkyl (C 1 -C 10 )heteroaryl (C 5 -C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, It may be substituted with at least one of C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted C 5 -C 12 heteroaryl.
상기 R3은 수소, C1~C6 직쇄 또는 분지쇄알킬, C3~C6 사이클로알킬, C6~C12 아릴, C5~C12 헤테로아릴, 알킬(C1~C6)아릴(C6~C12) 또는 알킬(C1~C6)헤테로아릴(C5~C12)이며, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C6 알킬, C1~C6 알콕시, C1~C6 할로알킬, C1~C6 할로알콕시, 옥소, 시아노, 비치환되거나 치환된아릴, 또는 비치환되거나 치환된 C5~C12 헤테로아릴중 적어도 하나로 치환될 수 있다.Wherein R 3 is hydrogen, C 1 ~ C 6 straight or branched chain alkyl, C 3 ~ C 6 cycloalkyl, C 6 ~ C 12 aryl, C 5 ~ C 12 heteroaryl, alkyl (C 1 ~C 6 ) aryl ( C 6 -C 12 ) or alkyl (C 1 -C 6) heteroaryl (C 5 -C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, It may be substituted with at least one of C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted C 5 -C 12 heteroaryl.
상기 R3은 구체적으로 수소, 비치환되거나 치환된 C1~C3 직쇄알킬,비치환되거나 치환된 C1~C3 알콕시, 할로겐, 또는 비치환되거나 치환된 2-페닐에틸이며, 이때 상기 치환된 2-페닐에틸은 오쏘, 메타 및 파라 위치 중 적어도 하나가 할로겐으로 치환된 것이고,상기 치환된 C1~C6알콕시는 페닐 또는 벤질로 치환된것일 수 있다.R 3 is specifically hydrogen, unsubstituted or substituted C 1 -C 3 straight chain alkyl, unsubstituted or substituted C 1 -C 3 alkoxy, halogen, or unsubstituted or substituted 2-phenylethyl, wherein the substituted In the 2-phenylethyl group, at least one of ortho, meta, and para positions is substituted with halogen, and the substituted C 1 -C 6 alkoxy may be substituted with phenyl or benzyl.
상기 R3은 더욱 구체적으로 수소, 비치환되거나 치환된 C1~C3 직쇄알킬, 비치환되거나 치환된 C1~C3 알콕시, 또는 할로겐일 수 있다. More specifically, R 3 may be hydrogen, unsubstituted or substituted C 1 -C 3 straight-chain alkyl, unsubstituted or substituted C 1 -C 3 alkoxy, or halogen.
상기 R3은 더욱 더 구체적으로 수소, C1~C3 알콕시, 또는 할로겐일 수 있다. 상기 할로겐은 브롬일 수 있다.The R 3 may be more specifically hydrogen, C 1 -C 3 alkoxy, or halogen. The halogen may be bromine.
화학식 1 내지 화학식 3에서, R2는 수소, 직쇄알킬, 사이클로알킬, 알콕시, 할로알콕시, 할로알킬, 아릴, 헤테로아릴, 알킬아릴 또는 알킬헤테로아릴이고, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C6 알킬, C1~C6 알콕시, C1~C6 할로알킬, C1~C6 할로알콕시, 비치환되거나 치환된 아릴, 비치환되거나 치환된 헤테로아릴, 옥소, 나이트로, 시아노 또는 트리플루오로메틸 중 적어도 하나로 치환될 수 있다.In Formulas 1 to 3, R 2 is hydrogen, straight chain alkyl, cycloalkyl, alkoxy, haloalkoxy, haloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, oxo, nitro, cya may be substituted with at least one of no or trifluoromethyl.
상기 R2는 수소, C1~C10 직쇄알킬, C3~C10 사이클로알킬, C1~C10 알콕시, C1~C10 할로알콕시, C1~C10 할로알킬, C6~C12 아릴, C5~C12 헤테로아릴, 알킬(C1~C10)아릴(C6~C12) 또는 알킬(C1~C10)헤테로아릴(C5~C12)이고, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C10 알킬, C1~C10 알콕시, C1~C10 할로알킬, C1~C10 할로알콕시, 비치환되거나 치환된 C6~C12아릴, 비치환되거나 치환된 C5~C12 헤테로아릴, 옥소, 나이트로, 시아노 또는 트리플루오로메틸 중 적어도 하나로 치환될 수 있다.wherein R 2 is hydrogen, C 1 -C 10 straight chain alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkoxy, C 1 -C 10 haloalkyl, C 6 -C 12 aryl, C 5 -C 12 heteroaryl, alkyl (C 1 -C 10 )aryl (C 6 -C 12 ) or alkyl (C 1 -C 10 )heteroaryl (C 5 -C 12 ), each of which is independently with hydroxyl, halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, unsubstituted or substituted C 6 -C 12 aryl, unsubstituted or substituted C 5 -C 12 heteroaryl, oxo, nitro, cyano or at least one of trifluoromethyl.
상기 R2는 구체적으로 수소, C1~C6 직쇄알킬, C3~C6 사이클로알킬, C1~C6 알콕시, C1~C6 할로알콕시, C1~C6 할로알킬, C6~C12 아릴, C5~C12 헤테로아릴, 알킬(C1~C6)아릴(C6~C12) 또는 알킬(C1~C6)헤테로아릴(C5~C12)이고, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C6 알킬, C1~C6 알콕시, C1~C6 할로알킬, C1~C6 할로알콕시, 비치환되거나 치환된 C6~C12아릴, 비치환되거나 치환된 C5~C12 헤테로아릴, 옥소, 나이트로, 시아노 또는 트리플루오로메틸 중 적어도 하나로 치환될 수 있다.The R 2 is specifically hydrogen, C 1 ~ C 6 straight chain alkyl, C 3 ~ C 6 cycloalkyl, C 1 ~ C 6 alkoxy, C 1 ~ C 6 haloalkoxy, C 1 ~ C 6 haloalkyl, C 6 ~ C 12 aryl, C 5 -C 12 heteroaryl, alkyl (C 1 -C 6 )aryl (C 6 -C 12 ) or alkyl (C 1 -C 6) heteroaryl (C 5 -C 12 ), each of is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted C 6 -C 12 aryl, It may be substituted with at least one of unsubstituted or substituted C 5 -C 12 heteroaryl, oxo, nitro, cyano or trifluoromethyl.
상기 R2는 더욱 구체적으로 수소, 비치환되거나 치환된 C1~C6 직쇄알킬, 비치환되거나 치환된 사이클로헥실, 비치환되거나 치환된 벤질, 비치환되거나 치환된 2-페닐에틸, 비치환되거나 치환된 바이페닐, 2-나프틸메틸 또는 1-나프틸메틸이고, 이때 상기 치환된 직쇄알킬은 할로겐으로 치환된 것이고, 상기 치환된 벤질은 오쏘, 메타 및 파라 위치 중 적어도 하나가 할로겐, C1~C3 직쇄알킬, 트리플루오로메틸, 사이아노, 나이트로, C1~C3 알콕시 또는 C6~C12 아릴로 치환된 것이며, 상기 2-페닐에틸은 오쏘, 메타 및 파라 위치 중 적어도 하나가 할로겐으로 치환된 것이고, 상기 치환된 바이페닐은 C1~C3 직쇄알킬로 치환될 수 있다.R 2 is more specifically hydrogen, unsubstituted or substituted C 1 -C 6 straight chain alkyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted benzyl, unsubstituted or substituted 2-phenylethyl, unsubstituted or substituted biphenyl, 2-naphthylmethyl or 1-naphthylmethyl, wherein the substituted straight chain alkyl is substituted with halogen, and the substituted benzyl is at least one of ortho, meta and para positions of halogen, C 1 -C 3 straight chain alkyl, trifluoromethyl, cyano, nitro, C 1 -C 3 alkoxy or C 6 -C 12 aryl, wherein 2-phenylethyl is at least one of ortho, meta and para positions is substituted with halogen, and the substituted biphenyl may be substituted with C 1 -C 3 straight-chain alkyl.
상기 R2는 더욱 더 구체적으로 수소, C1~C6 직쇄알킬,
Figure PCTKR2022006181-appb-img-000009
,
Figure PCTKR2022006181-appb-img-000010
,
Figure PCTKR2022006181-appb-img-000011
,
Figure PCTKR2022006181-appb-img-000012
,
Figure PCTKR2022006181-appb-img-000013
,
Figure PCTKR2022006181-appb-img-000014
,
Figure PCTKR2022006181-appb-img-000015
,
Figure PCTKR2022006181-appb-img-000016
,
Figure PCTKR2022006181-appb-img-000017
,
Figure PCTKR2022006181-appb-img-000018
,
Figure PCTKR2022006181-appb-img-000019
,
Figure PCTKR2022006181-appb-img-000020
,
Figure PCTKR2022006181-appb-img-000021
,
Figure PCTKR2022006181-appb-img-000022
,
Figure PCTKR2022006181-appb-img-000023
,
Figure PCTKR2022006181-appb-img-000024
또는
Figure PCTKR2022006181-appb-img-000025
일 수 있다.The R 2 is more specifically hydrogen, C 1 ~ C 6 straight chain alkyl,
Figure PCTKR2022006181-appb-img-000009
,
Figure PCTKR2022006181-appb-img-000010
,
Figure PCTKR2022006181-appb-img-000011
,
Figure PCTKR2022006181-appb-img-000012
,
Figure PCTKR2022006181-appb-img-000013
,
Figure PCTKR2022006181-appb-img-000014
,
Figure PCTKR2022006181-appb-img-000015
,
Figure PCTKR2022006181-appb-img-000016
,
Figure PCTKR2022006181-appb-img-000017
,
Figure PCTKR2022006181-appb-img-000018
,
Figure PCTKR2022006181-appb-img-000019
,
Figure PCTKR2022006181-appb-img-000020
,
Figure PCTKR2022006181-appb-img-000021
,
Figure PCTKR2022006181-appb-img-000022
,
Figure PCTKR2022006181-appb-img-000023
,
Figure PCTKR2022006181-appb-img-000024
or
Figure PCTKR2022006181-appb-img-000025
can be
화학식 1 내지 화학식 3에서, R4 및 R4’은 각각 독립적으로 수소, 직쇄 또는 분지쇄알킬, 사이클로알킬, 알케닐, 알키닐, 알킬싸이오, 아릴, 헤테로아릴, 알킬아릴 또는 알킬헤테로아릴이며, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C6알킬, C1~C6알콕시, C1~C6할로알킬, C1~C6할로알콕시, 비치환되거나 치환된 아릴, 비치환되거나 치환된 헤테로아릴, 옥소, 나이트로, 시아노 또는 트리플루오로메틸 중 적어도 하나로 치환될 수 있다.In Formulas 1 to 3, R 4 and R 4 ' are each independently hydrogen, straight or branched chain alkyl, cycloalkyl, alkenyl, alkynyl, alkylthio, aryl, heteroaryl, alkylaryl or alkylheteroaryl; , each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted aryl, unsubstituted or may be substituted with at least one of substituted heteroaryl, oxo, nitro, cyano or trifluoromethyl.
R4 및 R4’은 각각 독립적으로 C1~C10 직쇄 또는 분지쇄알킬, C3~C10 사이클로알킬, C2~C10 알케닐, C2~C10 알키닐, C1~C10 알킬싸이오, C6~C12 아릴, C5~C12 헤테로아릴, 알킬(C1~C10)아릴(C6~C12) 또는 알킬(C1~C10)헤테로아릴(C5~C12)이며, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C10 알킬, C1~C10 알콕시, C1~C10 할로알킬, C1~C10 할로알콕시, 비치환되거나 치환된 C6~C12 아릴, 비치환되거나 치환된 C5~C12 헤테로아릴, 옥소, 나이트로, 시아노 또는 트리플루오로메틸 중 적어도 하나로 치환될 수 있다.R 4 and R 4 ' are each independently C 1 -C 10 straight or branched chain alkyl, C 3 -C 10 cycloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 Alkylthio, C 6 ~ C 12 aryl, C 5 ~ C 12 heteroaryl, alkyl (C 1 ~ C 10 ) aryl (C 6 ~ C 12 ) or alkyl (C 1 ~C 10 ) heteroaryl (C 5 ~ C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, unsubstituted or substituted It may be substituted with at least one of C 6 -C 12 aryl, unsubstituted or substituted C 5 -C 12 heteroaryl, oxo, nitro, cyano or trifluoromethyl.
상기 R4 및 R4’은 각각 독립적으로 C1~C6 직쇄 또는 분지쇄알킬, C3~C6 사이클로알킬, C2~C6 알케닐, C2~C6 알키닐, C1~C6 알킬싸이오, C6~C12 아릴, C5~C12 헤테로아릴, 알킬(C1~C6)아릴(C6~C12) 또는 알킬(C1~C6)헤테로아릴(C5~C12)이며, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C6 알킬, C1~C6 알콕시, C1~C6 할로알킬, C1~C6 할로알콕시, 비치환되거나 치환된 C6~C12 아릴, 비치환되거나 치환된 C5~C12 헤테로아릴, 옥소, 나이트로, 시아노 또는 트리플루오로메틸 중 적어도 하나로 치환될 수 있다.Wherein R 4 and R 4 ' are each independently C 1 ~ C 6 straight or branched chain alkyl, C 3 ~ C 6 cycloalkyl, C 2 ~ C 6 alkenyl, C 2 ~ C 6 alkynyl, C 1 ~ C 6 alkylthio, C 6 -C 12 aryl, C 5 -C 12 heteroaryl, alkyl (C 1 -C 6 )aryl (C 6 -C 12 ) or alkyl (C 1 -C 6) heteroaryl (C 5 -C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted It may be substituted with at least one of C 6 -C 12 aryl, unsubstituted or substituted C 5 -C 12 heteroaryl, oxo, nitro, cyano or trifluoromethyl.
상기 R4 및 R4’은 구체적으로 각각 독립적으로 C1~C6 직쇄 또는 분지쇄알킬, C3~C6 사이클로알킬, C2~C6 알케닐, C2~C6 알키닐, C1~C6 알킬싸이오, 비치환되거나 치환된 벤질, 2-나프틸메틸 또는 1-나프틸메틸이고, 이때 상기 치환된 직쇄알킬은 메틸싸이오, 알카이닐 또는 벤질옥시카보닐아미노로 치환된 것이고, 상기 치환된 벤질은 오쏘, 메타 및 파라 위치 중 적어도 하나가 할로겐, 아릴, 나이트로, 시아노, C1~C3 알콕시, 트리플루오로메틸 또는 벤질옥시로 치환될 수 있다.The R 4 and R 4 ' are each independently specifically C 1 -C 6 straight or branched chain alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 ~C 6 alkylthio, unsubstituted or substituted benzyl, 2-naphthylmethyl or 1-naphthylmethyl, wherein the substituted straight chain alkyl is substituted with methylthio, alkynyl or benzyloxycarbonylamino , The substituted benzyl may be substituted with at least one of ortho, meta and para positions with halogen, aryl, nitro, cyano, C 1 -C 3 alkoxy, trifluoromethyl or benzyloxy.
상기 R4 및 R4’은 더욱 구체적으로 각각 독립적으로 C1~C3 직쇄알킬일 수 있다.More specifically, R 4 and R 4 ' may be each independently C 1 to C 3 straight-chain alkyl.
화학식 1 내지 화학식 3에서, L1은 직접 연결 또는 C1~C10 알킬렌이며, 이때 상기 알킬렌은 C1~C6 알킬, C3~C6 사이클로알킬, C1~C7 알콕시, 히드록실, 옥소 또는 할로겐 중 적어도 하나로 치환될 수 있고, 상기 C1~C6 알킬, C3~C6 사이클로알킬, C1~C7 알콕시는 비치환되거나 치환된 C6~C12 아릴 또는 C3~C6 사이클로알킬로 치환될 수 있다.In Formulas 1 to 3, L 1 is a direct linkage or C 1 -C 10 alkylene, wherein the alkylene is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 7 alkoxy, hydroxy may be substituted with at least one of hydroxyl, oxo or halogen, wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 7 alkoxy is unsubstituted or substituted C 6 -C 12 aryl or C 3 -C 6 cycloalkyl may be substituted.
상기 L1은 구체적으로 C1~C4 알킬렌이며, 이때 상기 알킬렌은 C1~C6 알킬, C3~C6 사이클로알킬, C1~C6 알콕시, 히드록실, 또는 옥소 중 적어도 하나로 치환될 수 있고, 상기 C1~C6 알킬, C3~C6 사이클로알킬, C1~C6 알콕시는 비치환되거나 치환된 C6~C12 아릴 또는 C3~C6 사이클로알킬로 치환될 수 있다.The L 1 is specifically C 1 -C 4 alkylene, wherein the alkylene is at least one of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxyl, or oxo. may be substituted, wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy is unsubstituted or substituted with C 6 -C 12 aryl or C 3 -C 6 cycloalkyl. can
상기 L1은 구체적으로 C1~C3 알킬렌이며, 이때 상기 C1~C3 알킬렌은 C1~C6 알킬, C3~C6 사이클로알킬, 비치환되거나 치환된 C1~C6 알콕시, 히드록실, 또는 옥소 중 적어도 하나로 치환될 수 있고, 상기 치환된 C1~C6 알콕시는 사이클로헥실, 페닐, 나프틸, 또는 바이페닐로 치환될 수 있다.The L 1 is specifically C 1 -C 3 alkylene, wherein the C 1 -C 3 alkylene is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, unsubstituted or substituted C 1 -C 6 It may be substituted with at least one of alkoxy, hydroxyl, or oxo, and the substituted C 1 -C 6 alkoxy may be substituted with cyclohexyl, phenyl, naphthyl, or biphenyl.
상기 L1은 구체적으로 메틸렌, 에틸렌, 또는 프로필렌이며, 이때 상기 메틸렌, 에틸렌, 또는 프로필렌은 메틸, 에틸, 프로필, 메톡시, 에톡시, 프로폭시, 부톡시, 펜톡시, 헥소시, 히드록실, 또는 옥소 중 적어도 하나로 치환될 수 있고, 상기 메톡시는 사이클로헥실, 페닐, 나프틸, 또는 바이페닐로 치환될 수 있다.Wherein L 1 is specifically methylene, ethylene, or propylene, wherein the methylene, ethylene, or propylene is methyl, ethyl, propyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, hydroxyl, Or it may be substituted with at least one of oxo, and the methoxy may be substituted with cyclohexyl, phenyl, naphthyl, or biphenyl.
화학식 1에서, Q는 S, Se, NR, P, P(O), P(O)2 또는 P(O)OR일 수 있다.In Formula 1, Q may be S, Se, NR, P, P(O), P(O) 2 or P(O)OR.
화학식 1 내지 화학식 3에서, 상기 R은 수소, C1~C6 직쇄 또는 분지쇄 알킬, C3~C6 사이클로알킬, 바이 또는 트라이 C3~C6 사이클로알킬, C1~C6 알콕시, C1~C6 할로알킬, C1~C6 할로알콕시, C6~C12 아릴, C5~C12 헤테로아릴, 알킬(C1~C6)아릴(C6~C12) 또는 알킬(C1~C6)헤테로아릴(C5~C12)이고, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C6 알킬, C1~C6 알콕시, C1~C6 할로알킬, C1~C6 할로알콕시, 옥소, 시아노, 비치환되거나 치환된 C6~C12 아릴, 또는 비치환되거나 치환된 C5~C12 헤테로아릴 중 적어도 하나로 치환될 수 있다.In Formulas 1 to 3, R is hydrogen, C 1 ~C 6 straight or branched chain alkyl, C 3 ~C 6 cycloalkyl, bi or tri C 3 ~C 6 cycloalkyl, C 1 ~C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 6 -C 12 aryl, C 5 -C 12 heteroaryl, alkyl(C 1 -C 6 )aryl(C 6 -C 12 ) or alkyl (C 1 -C 6) heteroaryl (C 5 -C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 It may be substituted with at least one of ~C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted C 6 ~C 12 aryl, or unsubstituted or substituted C 5 ~C 12 heteroaryl.
상기 R은, 구체적으로 수소, 비치환되거나 치환된 C1~C4 직쇄알킬,
Figure PCTKR2022006181-appb-img-000026
,
Figure PCTKR2022006181-appb-img-000027
,
Figure PCTKR2022006181-appb-img-000028
,
Figure PCTKR2022006181-appb-img-000029
,
Figure PCTKR2022006181-appb-img-000030
또는
Figure PCTKR2022006181-appb-img-000031
일 수 있다.Wherein R is, specifically hydrogen, unsubstituted or substituted C 1 ~ C 4 straight chain alkyl,
Figure PCTKR2022006181-appb-img-000026
,
Figure PCTKR2022006181-appb-img-000027
,
Figure PCTKR2022006181-appb-img-000028
,
Figure PCTKR2022006181-appb-img-000029
,
Figure PCTKR2022006181-appb-img-000030
or
Figure PCTKR2022006181-appb-img-000031
can be
화학식 1 내지 화학식 3에서, 상기 n은 1 내지 4의 정수이며,구체적으로 상기 n은 1일 수 있다.In Formulas 1 to 3, n is an integer of 1 to 4, and specifically, n may be 1.
화학식 1에서, 상기 X, Y, Z는 각각 독립적으로 수소, C1~C6 직쇄 또는 분지쇄알킬, C3~C6 사이클로알킬, C6~C12 아릴, C5~C12 헤테로아릴, 알킬(C1~C6)아릴(C6~C12) 또는 알킬(C1~C6)헤테로아릴(C5~C12)이며, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C6 알킬, C1~C6 알콕시, C1~C6 할로알킬, C1~C6 할로알콕시, 비치환되거나 치환된 C6~C12 아릴, 비치환되거나 치환된 C5~C12 헤테로아릴, 옥소, 나이트로, 시아노, 또는 트리플루오로메틸 중 적어도 하나로 치환될 수 있다. In Formula 1, X, Y, and Z are each independently hydrogen, C 1 ~ C 6 straight or branched chain alkyl, C 3 ~ C 6 cycloalkyl, C 6 ~ C 12 aryl, C 5 ~ C 12 heteroaryl, Alkyl (C 1 -C 6 )aryl (C 6 -C 12 ) or alkyl (C 1 -C 6) heteroaryl (C 5 -C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted C 6 -C 12 aryl, unsubstituted or substituted C 5 -C 12 heteroaryl , oxo, nitro, cyano, or at least one of trifluoromethyl.
본 출원에 따른 화합물은 하기 표 1의 화학식으로 이루어진 군에서 선택된 적어도 하나의 화합물일 수 있으나, 이에 제한되지 않는다. The compound according to the present application may be at least one compound selected from the group consisting of Chemical Formulas shown in Table 1 below, but is not limited thereto.
Figure PCTKR2022006181-appb-img-000032
Figure PCTKR2022006181-appb-img-000032
Figure PCTKR2022006181-appb-img-000033
Figure PCTKR2022006181-appb-img-000033
Figure PCTKR2022006181-appb-img-000034
Figure PCTKR2022006181-appb-img-000034
Figure PCTKR2022006181-appb-img-000035
Figure PCTKR2022006181-appb-img-000035
Figure PCTKR2022006181-appb-img-000036
Figure PCTKR2022006181-appb-img-000036
Figure PCTKR2022006181-appb-img-000037
Figure PCTKR2022006181-appb-img-000037
Figure PCTKR2022006181-appb-img-000038
Figure PCTKR2022006181-appb-img-000038
Figure PCTKR2022006181-appb-img-000039
Figure PCTKR2022006181-appb-img-000039
Figure PCTKR2022006181-appb-img-000040
Figure PCTKR2022006181-appb-img-000040
Figure PCTKR2022006181-appb-img-000041
Figure PCTKR2022006181-appb-img-000041
본 명세서에서 사용된 용어들 "~를 치료하다" 또는 "치료"는 치료제, 예방적, 일시적 처방의 또는 예방적 방법을 말한다. 본 명세서에서 사용된 용어 "예방"은 상기 약학적 조성물의 투여에 의해 암을 억제하거나 암의 발병을 지연시키는 모든 행위를 말한다. 본 출원을 위해, 유익한 또는 원하는 임상 결과는 비제한적으로, 검출가능하거나 또는 검출불가능하거나, 증상 완화, 질환 정도의 약화, 질환의 안정 (즉, 약화되지 않는) 상태, 질환 진행의 지연 또는 서서한 진행, 질환 상태의 개선 또는 일시적 처방 및 차도 (부분적이든 또는 전체적이든)를 포함한다. "치료"는 또한, 치료를 받지 않는다면 기대되는 생존과 비교하는 경우, 지속적 생존을 의미할 수 있다. 치료가 필요한 것들에는, 병태 또는 장애를 가지기 쉬운 것들뿐만 아니라, 이미 병태 또는 장애를 가지는 것 또는, 병태 또는 장애가 예방된 것들이 포함된다.As used herein, the terms “treat” or “treatment” refer to a therapeutic, prophylactic, curative, or prophylactic method. As used herein, the term “prevention” refers to any action of inhibiting cancer or delaying the onset of cancer by administering the pharmaceutical composition. For purposes of this application, beneficial or desired clinical outcomes include, but are not limited to, detectable or undetectable, symptom relief, attenuation of disease severity, stable (i.e., not attenuated) state of disease, delayed or gradual disease progression progression, amelioration or temporary treatment of the disease state, and remission (whether partial or total). "Treatment" can also mean sustained survival when compared to expected survival if not receiving treatment. Those in need of treatment include those prone to have the condition or disorder, as well as those already having the condition or disorder or in which the condition or disorder has been prevented.
본 명세서에서 사용된 표현 "치료적으로 효과적인 양" 또는 "효과적인 양"은, 본원에 기재된 (i) 특정한 질환, 병태, 또는 장애의 치료 또는 예방, (ii) 특정한 질환, 병태, 또는 장애의 하나 이상의 증상의 약화, 개선 또는 완화, 또는 (iii) 특정한 질환, 병태의 하나 이상의 증상의 개시의 예방 또는 지연에 충분한, 그와 같은 치료가 필요한 포유동물에 투여되는 경우, 화학식 I의 화합물의 양을 의미한다. 그와 같은 양에 해당하는 화합물의 양은 인자 예컨대 특정한 화합물, 질환 상태 및 그것의 중증도, 치료가 필요한 포유동물의 동일성 (예를 들면, 중량)에 따라 다를 것이나, 그럼에도 불구하고, 당해 분야의 숙련가에 의해 일상적으로 결정될 수 있다.As used herein, the expression "therapeutically effective amount" or "effective amount" refers to (i) treating or preventing a particular disease, condition, or disorder, (ii) one of the particular disease, condition, or disorder described herein. an amount of the compound of formula (I), when administered to a mammal in need thereof, sufficient to attenuate, ameliorate or alleviate the symptoms, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, it means. The amount of compound corresponding to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (eg weight) of the mammal in need of treatment, but nevertheless is within the skill of the artisan. can be determined routinely.
본 명세서에서 사용된 용어들 "암" 및 "암성"은, 전형적으로 비정상 또는 조절되지 않은 세포 성장을 특징으로 하는 포유동물의 생리적 조건을 말하거나 또는 표현한다. "종양"은 하나 이상의 암성 세포를 포함한다. 암의 예에는 비제한적으로, 암종, 림프종, 모세포종, 육종, 및 백혈병 또는 림프모양 악성종양이 포함된다. 그와 같은 암의 더욱 특정한 예에는 편평상피세포 암 (예를 들면, 상피성편평상피세포 암), 폐암 (소세포 폐암, 비-소세포 폐암 ("NSCLC"), 폐의 선암종 및 폐의 편평상피암종 포함), 복막암, 간세포 암, 위장 암을 포함한 위 또는 위암, 췌장암, 교모세포종, 자궁경부암, 난소암, 간암, 방광암, 간종양, 유방암, 결장암, 직장암, 결장직장 암, 자궁내막 또는 자궁암종, 타액샘암종, 신장 또는 신장암, 전립선암, 외음부암, 갑상선암, 간암종, 항문 암종, 음경 암종, 흑색종을 포함한 피부암뿐만 아니라 두경부암이 포함된다.As used herein, the terms “cancer” and “cancerous” refer to or express a physiological condition in a mammal that is typically characterized by abnormal or unregulated cell growth. A “tumor” includes one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancy. More specific examples of such cancers include squamous cell carcinoma (eg, epithelial squamous cell carcinoma), lung cancer (small cell lung cancer, non-small cell lung cancer (“NSCLC”)), adenocarcinoma of the lung and squamous cell carcinoma of the lung. peritoneal cancer, hepatocellular cancer, gastric or gastric cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver tumor, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma , salivary adenocarcinoma, kidney or kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatocarcinoma, anal carcinoma, penile carcinoma, skin cancer including melanoma, as well as head and neck cancer.
본 명세서에서 사용되는 "약학적으로 허용 가능한"은, 상기 물질 또는 조성물이 그에 의해 치료되는 포유동물 및/또는 제형을 포함한 기타 성분과 화학적으로 및/또는 동물학적으로 양립 가능한 것을 가리킨다."Pharmaceutically acceptable" as used herein refers to that the substance or composition is chemically and/or animal compatible with the mammal and/or other ingredients, including formulations, being treated thereby.
본 명세서에서 사용되는 "약학적으로 허용 가능한 염"은 약학적으로 허용 가능한 본 출원의 화합물의 유기 또는 무기 염을 말한다.As used herein, "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of the compound of the present application.
본 명세서에서 사용되는 "약학적으로 허용 가능한 염"은 본 명세서에 기재된 화합물의 약제학적으로 허용 가능한 유기 또는 무기 염을 의미한다. 예시적인 염으로는 비제한적으로, 설페이트, 시트레이트, 아세테이트, 옥살레이트, 클로라이드, 브로마이드, 아이오다이드, 니트레이트, 바이설페이트, 포스페이트, 산 포스페이트, 이소니코티네이트, 락테이트, 살리실레이트, 산 시트레이트, 타르트레이트, 올레이트, 탄네이트, 판토테네이트, 바이타르트레이트, 아스코르베이트, 석시네이트, 말레에이트, 젠티시네이트, 푸마레이트, 글루코네이트, 글루쿠로네이트, 사카레이트, 포르메이트, 벤조에이트, 글루타메이트, 메탄설포네이트, 에실레이트, 에탄설포네이트, 에탄디설포네이트, 벤젠설포네이트, p-톨루엔설포네이트, 및 파모네이트(즉, 1,1'-메틸렌-bis -(2-하이드록시-3-나프토네이트)) 염이 포함된다. 약제학적으로 허용 가능한 염은 또 하나의 분자의 봉입체, 예컨대 아세테이트 이온, 석시네이트 이온 또는 다른 반대 이온을 포함할 수 있다. 반대 이온은, 모 화합물의 전하를 안정화시키는 임의의 유기 또는 무기 모이어티일 수 있다. 더욱이, 약제학적으로 허용 가능한 염은 그 구조에 1 초과 충전된 원자를 가질 수 있다. 다중 충전된 원자가 약학적으로 허용 가능한 염의 일부인 경우의 예는 다중 반대 이온을 가질 수 있다. 그러므로, 약학적으로 허용 가능한 염은 하나 이상의 충전된 원자 및/또는 하나 이상의 반대 이온을 가질 수 있다.As used herein, "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound described herein. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, Acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, phor Mate, benzoate, glutamate, methanesulfonate, ethylate, ethanesulfonate, ethanedisulfonate, benzenesulfonate, p- toluenesulfonate, and pamonate (i.e., 1,1'-methylene-bis-(2 -hydroxy-3-naphtonate)) salts. A pharmaceutically acceptable salt may contain an inclusion body of another molecule, such as an acetate ion, a succinate ion or other counter ion. The counter ion can be any organic or inorganic moiety that stabilizes the charge of the parent compound. Moreover, a pharmaceutically acceptable salt may have more than one charged atom in its structure. An example where multiple charged atoms are part of a pharmaceutically acceptable salt may have multiple counter ions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counter ions.
본 출원의 하나의 실시예는 화학식 1로 표시되는 화합물, 이의 약학적으로 허용 가능한 염, 수화물, 용매화물, 구조 이성질체, 광학 이성질체, 입체이성질체, 또는 이들의 조합을 포함하는 암 예방 또는 치료용 약학 조성물을 제공한다. 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 단독으로 투여한 경우 암 활성이 억제되는 효과가 있다.One embodiment of the present application is a pharmaceutical for preventing or treating cancer comprising a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or a combination thereof A composition is provided. When the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is administered alone, there is an effect of inhibiting cancer activity.
본 출원의 하나의 실시예는 화학식 1로 표시되는 화합물, 이의 약학적으로 허용 가능한 염, 수화물, 용매화물, 구조 이성질체, 광학 이성질체, 입체이성질체, 또는 이들의 조합을 포함하는 내성암 예방 또는 치료용 약학 조성물을 제공한다. 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 내성암에 항암 약물이나, 방사선 요법 등과 병용으로 투여한 경우 내성암 활성이 억제되는 효과가 있다.One embodiment of the present application is a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or a combination thereof for preventing or treating resistant cancer A pharmaceutical composition is provided. When the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is administered in combination with an anticancer drug or radiation therapy to resistant cancer, there is an effect of inhibiting the activity of resistant cancer.
본 출원의 하나의 실시예는 화학식 1로 표시되는 화합물, 이의 약학적으로 허용 가능한 염, 수화물, 용매화물, 구조 이성질체, 광학 이성질체, 입체이성질체, 또는 이들의 조합을 포함하는 줄기세포성 암 예방 또는 치료용 약학 조성물을 제공한다. 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 투여한 경우 SERCA 단백질을 타겟으로 하는 억제제로 작용하므로 줄기세포성 암 활성이 억제되는 효과가 있다. One embodiment of the present application is a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or stem cell cancer prevention or A therapeutic pharmaceutical composition is provided. When the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is administered, it acts as an inhibitor targeting the SERCA protein, thereby inhibiting stem cell cancer activity.
상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 암 또는 내성암에 항암 약물이나, 방사선 요법 등과 병용으로 투여시에는 동시에, 개별적으로, 또는 순차적으로 투여할 수 있다. 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 항암 약물이나, 방사선 요법보다 먼저 투여하거나, 나중에 투여할 수도 있다. When the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is administered in combination with an anticancer drug or radiation therapy to cancer or resistant cancer, it may be administered simultaneously, individually, or sequentially. The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered before or after an anticancer drug or radiation therapy.
본 출원의 하나의 실시예에서, 상기 암 또는 내성암은, 난소암, 대장암, 췌장암, 위암, 간암, 유방암, 자궁경부암, 갑상선암, 부갑상선암, 폐암, 비소세포성폐암, 전립선암, 담낭암, 담도암, 혈액암, 방광암, 신장암, 흑색종, 결장암, 골암, 피부암, 두경부암, 자궁암, 직장암, 뇌암, 항문부근암, 나팔관암종, 자궁내막암종, 질암, 음문암종, 식도암, 소장암, 내분비선암, 부신암, 연조직 육종, 요도암, 음경암, 수뇨관암, 신장세포 암종, 신장골반암종, 백혈병, 중추신경계(central nervous system; CNS) 종양, 척수 종양, 뇌간 신경교종 및 뇌하수체 선종으로 이루어진 군에서 선택된 적어도 하나일 수 있다. In one embodiment of the present application, the cancer or resistant cancer is ovarian cancer, colorectal cancer, pancreatic cancer, stomach cancer, liver cancer, breast cancer, cervical cancer, thyroid cancer, parathyroid cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, Biliary tract cancer, blood cancer, bladder cancer, kidney cancer, melanoma, colon cancer, bone cancer, skin cancer, head and neck cancer, uterine cancer, rectal cancer, brain cancer, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, Endocrine adenocarcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, leukemia, central nervous system (CNS) tumor, spinal cord tumor, brainstem glioma and pituitary adenoma It may be at least one selected from the group.
본 출원의 하나의 실시예에에서 상기 항암 약물 또는 항암제는, 나이트로젠머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 마시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 파조파닙, 토세라닙, 닌테다닙, 레고라페닙, 세막사닙, 티보자닙, 포나티닙, 카보잔티닙, 카보플라틴, 소라페닙, 렌바티닙, 베바시주맙, 시스플라틴, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라실, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 5-플루오로우라실, 플루다라빈, 에노시타빈, 플루타미드, 케페시타빈, 데시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 도세탁셀, 파클리탁셀, 카바지탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레타민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레티노인, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 올라파립, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴, 보리노스텟, 엔티노스텟 및 카르무스틴으로 이루어진 군에서 선택된 적어도 하나일 수 있다.In one embodiment of the present application, the anticancer drug or anticancer agent is nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasa Nib, bosutinib, axitinib, masitinib, cediranib, restaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, pazopanib, toceranib, nintedanib, regorafenib, Semaxanib, tivozanib, ponatinib, caboxantinib, carboplatin, sorafenib, lenvatinib, bevacizumab, cisplatin, cetuximab, viscumalbum, asparaginase, tretinoin, hydroxycarba amide, dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomab tuccetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate Chitosan, gemcitabine, doxyfluridine, pemetrexed, tegafur, capecitabine, gimeracil, oteracil, azacitidine, methotrexate, uracil, cytarabine, 5-fluorouracil, fludarabine , enocitabine, flutamide, kepecitabine, decitabine, mercaptopurine, thioguanine, cladribine, carmofer, raltitrexed, docetaxel, paclitaxel, cabazitaxel, irinotecan, velotecan, topotecan, vino Relvin, etoposide, vincristine, vinblastine, teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleromycin, daunorubicin, dactinomycin, pyrarubicin, Aclarubicin, pepromycin, temsirolimus, temozolomide, busulfan, ifosfamide, cyclophosphamide, melparan, altretamine, dacarbazine, thiotepa, nimustine, chlorambucil, mito Lactol, leucovorin, tretinoin, exemestane, aminoglutethimide, anagrelide, olaparib, nabelbine, fadrazole, tamoxifen, toremifene, testolactone, anastrozole, letrozole, vorozole , may be at least one selected from the group consisting of bicalutamide, lomustine, vorinostat, entinostat, and carmustine.
본 출원의 하나의 실시예에 따른 약학 조성물은 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염과 항암제를 1:0.001 내지 1:1000, 1:0.01 내지 1:100, 1:0.1 내지 1:50 또는 1:0.1 내지 1:20 몰 농도비로 포함할 수 있다.The pharmaceutical composition according to an embodiment of the present application contains a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof and an anticancer agent from 1:0.001 to 1:1000, 1:0.01 to 1:100, 1:0.1 to 1 It may be included in a molar concentration ratio of :50 or 1:0.1 to 1:20.
본 출원의 하나의 실시예에 따른 약학 조성물은 캡슐, 정제, 과립, 주사제, 연고제, 분말 또는 음료 형태일 수 있다.The pharmaceutical composition according to one embodiment of the present application may be in the form of a capsule, tablet, granule, injection, ointment, powder or beverage.
본 출원의 하나의 실시예에 따른 약학 조성물은 산제, 과립제, 캡슐, 정제, 수성 현탁액 등의 경구형 제형, 외용제, 좌제 및 주사제의 형태로 제형화하여 사용될 수 있다.The pharmaceutical composition according to an embodiment of the present application may be formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and injections.
본 출원의 하나의 실시예에 따른 약학 조성물은 약학적으로 허용 가능한 담체를 포함할 수 있다. 약학적으로 허용 가능한 담체는 경구 투여 시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등일 수 있으며, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등을 혼합하여 사용할 수 있으며, 국소투여용의 경우는 기제, 부형제, 윤활제, 보존제 등을 사용할 수 있다.The pharmaceutical composition according to one embodiment of the present application may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may be binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, coloring agents, flavoring agents, etc., in the case of oral administration, and in the case of injections, buffers, preservatives, analgesics, Solubilizers, isotonic agents, stabilizers, etc. can be mixed and used, and for topical administration, bases, excipients, lubricants, preservatives, etc. can be used.
본 출원의 하나의 실시예에 따른 약학 조성물의 제형은 약학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있으며, 예를 들어, 경구 투여시에는 정제, 트로키, 캡슐, 엘릭서(elixir), 서스펜션, 시럽, 웨이퍼 등의 형태로 제조될 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수회 투약 형태로 제조될 수 있다. 또한, 본 출원의 약학 조성물의 제형은 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제조될 수 있다.The dosage form of the pharmaceutical composition according to one embodiment of the present application may be prepared in various ways by mixing with a pharmaceutically acceptable carrier, for example, tablets, troches, capsules, elixirs, It may be prepared in the form of a suspension, syrup, wafer, etc., and in the case of an injection, it may be prepared in the form of unit dose ampoules or multiple doses. In addition, the formulation of the pharmaceutical composition of the present application may be prepared as a solution, suspension, tablet, capsule, sustained-release formulation, and the like.
제제화를 위한 담체, 부형제 및 희석제는 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말디톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸셀룰로즈, 미정질셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트, 광물유, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제 또는 방부제 등일 수 있다.Carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, filler, anticoagulant, lubricant, wetting agent, flavoring, emulsifying agent or preservative and the like.
본 출원의 하나의 실시예는 약학적으로 적용가능한 어주반트 및/또는 부형제와 함께 본 발명에 따른 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 활성 성분으로 포함하는 약제학적 조성물에 관한 것이다. One embodiment of the present application relates to a pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention together with a pharmaceutically applicable adjuvant and/or excipient as an active ingredient. will be.
본 출원에서, "어주반트"는 동시에, 동시간대에 또는 연속해서 투여된다면 본 발명의 활성 성분에 대하여 특정 반응을 할 수 있거나, 심해지거나 또는 변형할 수 있는 모든 물질을 나타낸다. 주사 용액용 공지 아주반트는 예를 들어, 알루미늄 조성물, 예를 들어 알루미늄 히드록시드 또는 알루미늄 포스페이트, 사포닌, 예를 들어 QS21, 무라밀디펩티드 또는 무라밀트리펩티드, 단백질, 예를 들어 감마-인터페론 또는 TNF, M59, 스쿠알렌 또는 폴리올이 있다.In the present application, "adjuvant" refers to any substance capable of producing, exacerbating or modifying a particular reaction to the active ingredient of the present invention if administered simultaneously, at the same time or sequentially. Known adjuvants for injectable solutions are, for example, aluminum compositions such as aluminum hydroxide or aluminum phosphate, saponins such as QS21, muramyldipeptide or muramyltripeptide, proteins such as gamma-interferon or TNF, M59, squalene or polyol.
본 출원의 하나의 실시예에 따른 약학 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다. The route of administration of the pharmaceutical composition according to one embodiment of the present application is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal , enteral, topical, sublingual or rectal.
본 출원의 하나의 실시예에 따른 약학 조성물은 경구 또는 비경구로 투여될 수 있으며, 비경구 투여 시 피부 외용 또는 복강내주사, 직장내주사, 피하주사, 정맥주사, 근육내 주사 또는 흉부내 주사 주입방식이 선택될 수 있다.The pharmaceutical composition according to an embodiment of the present application may be administered orally or parenterally, and when administered parenterally, external application to the skin or intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection A method may be selected.
본 출원의 하나의 실시예에 따른 약학 조성물의 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 예를 들어, 본 출원의 하나의 실시예에 따른 약학 조성물은 1일 0.0001 내지 1000mg/kg 또는 0.001 내지 500mg/kg으로 투여될 수 있다. 본 출원의 하나의 실시예에 따른 약학 조성물의 투여는 하루에 한번 투여할 수도 있고, 수 회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 출원의 범위를 한정하는 것은 아니다.The dosage of the pharmaceutical composition according to one embodiment of the present application varies depending on the patient's condition and weight, the degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art. For example, the pharmaceutical composition according to one embodiment of the present application may be administered at 0.0001 to 1000 mg/kg or 0.001 to 500 mg/kg per day. Administration of the pharmaceutical composition according to an embodiment of the present application may be administered once a day, may be administered in divided several times. The above dosage does not limit the scope of the present application in any way.
또한, 본 출원은 암 치료에 사용하기 위한 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염의 용도를 제공한다.In addition, the present application provides the use of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.
또한, 본 출원은 내성암 치료에 사용하기 위한 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염의 용도를 제공한다.In addition, the present application provides the use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in the treatment of resistant cancer.
또한, 본 출원은 줄기세포성 암 치료에 사용하기 위한 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염의 용도를 제공한다.In addition, the present application provides the use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in the treatment of stem cell cancer.
내성암과, 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염은 전술한 내용과 동일하여, 구체적인 설명은 생략한다.Resistant cancer and the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof are the same as those described above, and detailed descriptions thereof will be omitted.
또한, 본 출원은 암, 내성암 또는 줄기세포성 암이 있는 개체에게 전술한 화학식 1로 표시되는 화합물, 이의 약학적으로 허용 가능한 염, 수화물, 용매화물, 구조 이성질체, 광학 이성질체, 입체이성질체, 또는 이들의 조합의 치료적 유효량을 투여하는 단계를 포함하는 암, 내성암 또는 줄기세포성 암의 치료 방법을 제공한다. 상기 투여는 암 또는 증식성 질병의 치료에 유용한 화학요법제나 항암 약물을 동시에, 개별적으로, 또는 순차적으로 투여할 수 있다. In addition, the present application relates to a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or Provided is a method of treating cancer, resistant cancer, or stem cell cancer comprising administering a therapeutically effective amount of a combination thereof. The administration may include simultaneous, separate, or sequential administration of a chemotherapeutic agent or anticancer drug useful for the treatment of cancer or proliferative disease.
용어 "투여"는 적절한 방법으로 개체에게 소정의 물질을 도입하는 것을 의미한다. The term “administration” means introducing a given substance into a subject by an appropriate method.
“내성암이 있는 대상”은 내성암 암이 발병하였거나 발병 가능성이 높아 적절한 치료를 필요로 하는 개체를 의미하는 것으로, 항암 치료 요법으로, 예를 들면, 외과적 절제 치료법, 항암제를 이용한 화학적 치료법, 방사선 치료법 또는 면역 치료법을 받았지만, 이에 대하여 내성을 가져 재발한 개체일 수 있다.“Subject with resistant cancer” refers to an individual who has developed or has a high probability of developing resistant cancer and requires appropriate treatment. It may be an individual who has received radiation therapy or immunotherapy, but has developed resistance to it and has relapsed.
내성암이 있는 대상은 인간, 소, 개, 기니아, 피그, 토끼, 닭 또는 곤충 등을 포함할 수 있다. 구체적으로, 인간, 소, 말, 돼지, 개, 양, 염소, 또는 고양이 등의 포유동물일 수 있다. 상기 개체는 암을 앓거나 앓을 가능성이 큰 개체일 수 있다.Subjects with resistant cancer may include humans, cattle, dogs, guinea pigs, rabbits, chickens, or insects. Specifically, it may be a mammal such as a human, a cow, a horse, a pig, a dog, a sheep, a goat, or a cat. The subject may be an individual who has or is likely to have cancer.
또한, 본 출원은 암, 내성암 또는 줄기세포성 암이 있는 대상에게 전술한 화학식 1로 표시되는 화합물, 이의 약학적으로 허용 가능한 염, 수화물, 용매화물, 구조 이성질체, 광학 이성질체, 입체이성질체, 또는 이들의 조합의 치료적 유효량을 투여하는 단계; 및 방사선을 조사하는 단계;를 포함하는 방사선 치료 방법을 제공한다.In addition, the present application relates to a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or administering a therapeutically effective amount of a combination thereof; And irradiating radiation; provides a radiation treatment method comprising a.
내성암, 내성암이 있는 대상, 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염은 전술한 내용과 동일하여, 구체적인 설명은 생략한다.Resistant cancer, a subject with resistant cancer, the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof is the same as described above, and detailed descriptions thereof will be omitted.
방사선 조사는 암의 방사선 치료를 위해 종래 사용되었던 임의의 방사선 조사 방법 또는 추후 개발되는 암에 대한 방사선 조사 방법이 모두 적용될 수 있다.Radiation irradiation can be applied to any radiation method conventionally used for radiation treatment of cancer or radiation method for cancer to be developed later.
본 출원에 따른 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염의 투여와 방사선 조사를 병용하는 경우 암 세포, 내성암 세포 또는 암 줄기세포의 성장억제 및/또는 사멸 유도에 상승적인 효과를 부여하여 암을 효과적으로 예방 또는 치료할 수 있을 뿐만 아니라, 더 나아가서는 방사선에 대한 내성이나, 암의 전이 또는 암의 재발을 방지할 수 있다.When the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present application is administered in combination with irradiation, it gives a synergistic effect on growth inhibition and/or death induction of cancer cells, resistant cancer cells or cancer stem cells. Thus, it is possible not only to effectively prevent or treat cancer, but also to prevent resistance to radiation, metastasis of cancer, or recurrence of cancer.
제조예production example
하기 제조예 1의 방법으로 표 1의 화합물들을 제조하였다.The compounds of Table 1 were prepared by the method of Preparation Example 1 below.
제조예 1Preparation Example 1
아래 기재된 7단계 반응을 거쳐 2-((2-에틸-1-벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온을 제조하였다. 각 단계에서의 합성 방법을 아래에서 구체적으로 설명한다.2-((2-ethyl-1-benzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a through the 7-step reaction described below ]Pyrazine-6,9-dione was prepared. The synthesis method in each step will be described in detail below.
1) 단계 1:　2-에틸 벤조[1) Step 1: 　 2-ethyl benzo [ bb ]싸이오펜의 제조]Production of thiophene
[반응식 1][Scheme 1]
Figure PCTKR2022006181-appb-img-000042
Figure PCTKR2022006181-appb-img-000042
반응식 1과 같이 벤조[b]싸이오펜(1.0당량)을 테트라하이드로퓨란용매하에서 -78℃로 냉각하고 2.5M n-부틸리튬(1.2당량) 용액을 첨가하였다. -78℃를 유지하면서 1시간 교반하고 에틸아이오다이드(2.0당량)를 적가한 후, 0℃에서 1시간 교반하였다. 반응완결을 확인하고, 암모늄클로라이드수용액과 에틸아세테이트를 사용하여 반응을 종료하였다. 유기층을 증류수로 세정하고, 무수 마그네슘설페이트로 건조 후, 감압농축하였다. 잔사를실리카크로마토그래피로 정제하여 2-에틸 벤조[b]싸이오펜을 수득하였다.As shown in Scheme 1, benzo[ b ]thiophene (1.0 equiv.) was cooled to -78°C in a tetrahydrofuran solvent, and 2.5M n-butyllithium (1.2 equiv) solution was added thereto. After stirring for 1 hour while maintaining -78°C, ethyl iodide (2.0 equivalents) was added dropwise, followed by stirring at 0°C for 1 hour. After confirming the completion of the reaction, the reaction was terminated using an aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica chromatography to obtain 2-ethyl benzo[ b ]thiophene.
2) 단계 2: 2-에틸벤조[2) Step 2: 2-ethylbenzo[ bb ]싸이오펜-3-카르바알데히드의 제조]Preparation of thiophene-3-carbaaldehyde
[반응식 2][Scheme 2]
Figure PCTKR2022006181-appb-img-000043
Figure PCTKR2022006181-appb-img-000043
2-에틸 벤조[b]싸이오펜(1.0당량)을 메틸렌클로라이드(MC)에 투입한 후, 0℃로 냉각하고, 0℃를 유지하며 틴(Ⅳ)클로라이드(1.5당량), 디클로로메틸 메틸에테르(1.5당량)를 순서대로 투입한 후, 1시간 교반하였다. 반응완결을 확인하고, 암모늄클로라이드수용액과 메틸렌클로라이드를 사용하여 반응을 종료하였다. 유기층을 증류수로 세정하고, 무수 마그네슘설페이트로 건조하고, 감압농축하였다. 잔사를 실리카크로마토그래피로 정제하여 2-에틸-1-벤조[b]싸이오펜-3-카르바알데히드 를 수득하였다.2-ethyl benzo [ b ] thiophene (1.0 equivalent) was added to methylene chloride (MC), cooled to 0 ° C, maintained at 0 ° C, and tin (IV) chloride (1.5 equivalents), dichloromethyl methyl ether ( 1.5 equivalents) were added in order, and then stirred for 1 hour. After confirming the completion of the reaction, the reaction was terminated using an aqueous ammonium chloride solution and methylene chloride. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica chromatography to obtain 2-ethyl-1-benzo[ b ]thiophene-3-carbaaldehyde.
3) 단계 3:　1,4-비스(3) Step 3: 　 1,4-bis ( 터셔리turkey -부톡시카르보닐)피페라진-2-카르복실산의 제조Preparation of -butoxycarbonyl)piperazine-2-carboxylic acid
[반응식 3][Scheme 3]
Figure PCTKR2022006181-appb-img-000044
Figure PCTKR2022006181-appb-img-000044
피페라진-2-카르복실산(1.0당량)을 다이옥세인/증류수 용매하에서 5℃ 이하로 냉각하고 소듐카보네이트(3.0당량)를 첨가하였다. 5℃ 이하를 유지하면서 디-터셔리-부틸 디카보네이트(2.2당량)를 적가한 후, 실온에서 철야 교반하였다. 반응완결을 확인하고, 감압 농축한 후 염화메틸렌에 녹여 염산으로 중화하였다. 유기층을 소듐 클로라이드로 세정하고 무수 마그네슘 설페이트로 탈수 후, 감압 농축하였다. 잔사를 n-헥산으로 정제하여 1,4-비스(터셔리-부톡시카르보닐)피페라진-2-카르복실산을 수득하였다.Piperazine-2-carboxylic acid (1.0 eq.) was cooled to 5° C. or less in a dioxane/distilled water solvent, and sodium carbonate (3.0 eq.) was added. Di-tertiary -butyl dicarbonate (2.2 equivalents) was added dropwise while maintaining 5° C. or less, followed by stirring at room temperature overnight. After confirming the completion of the reaction, it was concentrated under reduced pressure, dissolved in methylene chloride, and neutralized with hydrochloric acid. The organic layer was washed with sodium chloride, dehydrated over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified with n -hexane to obtain 1,4-bis( tertiary -butoxycarbonyl)piperazine-2-carboxylic acid.
4) 단계 4: 4) Step 4: 디d -- 터셔리turkey -부틸 2-((1-메톡시-2-메틸-1-옥소프로판-2-일)카르바모일)피페라진-1,4-디카르복실레이트의 제조Preparation of -butyl 2-((1-methoxy-2-methyl-1-oxopropan-2-yl)carbamoyl)piperazine-1,4-dicarboxylate
[반응식 4][Scheme 4]
Figure PCTKR2022006181-appb-img-000045
Figure PCTKR2022006181-appb-img-000045
실온에서 1,4-비스(터셔리-부톡시카르보닐)피페라진-2-카르복실산(1.0당량)과 메틸 α-아미노이소부틸레이트 하이드로클로라이드(1.1당량), N,N’-디사이클로헥실카보디이미드(1.1당량), N,N-디메틸아미노피리딘(0.3당량)을 메틸렌클로라이드로 용해 시킨 후, N,N-디이소프로필에틸아민(1.1당량)을 첨가하고 실온에서 한 시간 교반하였다. 물을 투입하여 반응을 종료시킨 후 여과를 통해 부산물을 제거하였다. 얻어진 유기층을 brine으로 세정 후, 무수 마그네슘 설페이트로 탈수하고 감압 농축하였다. 잔사를 실리카크로마토그래피로 정제하여 디-터셔리-부틸 2-((1-메톡시-2-메틸-1-옥소프로판-2-일)카르바모일)피페라진-1,4-디카르복실레이트를 수득하였다.1,4-bis( tertiary -butoxycarbonyl)piperazine-2-carboxylic acid (1.0 equiv) with methyl α-aminoisobutylate hydrochloride (1.1 equiv) at room temperature, N,N' -dicyclo Hexylcarbodiimide (1.1 equivalents) and N,N -dimethylaminopyridine (0.3 equivalents) were dissolved in methylene chloride, then N,N -diisopropylethylamine (1.1 equivalents) was added and stirred at room temperature for 1 hour. . After the reaction was terminated by adding water, by-products were removed through filtration. The obtained organic layer was washed with brine, dehydrated over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica chromatography and di-tert -butyl 2-((1-methoxy-2-methyl-1-oxopropan-2-yl)carbamoyl)piperazine-1,4-dicarboxyl rate was obtained.
5) 단계 5: 메틸 2-메틸-2-(피페라진-2-카르복사미도)프로판오에이트·2트리플루오로아세트산의 제조 5) Step 5: Preparation of methyl 2-methyl-2-(piperazine-2-carboxamido)propanoate-2-trifluoroacetic acid
[반응식 5][Scheme 5]
Figure PCTKR2022006181-appb-img-000046
Figure PCTKR2022006181-appb-img-000046
반응식 5와 같이, 실온에서 2-((1-메톡시-2-메틸-1-옥소프로판-2-일)카르바모일)피페라진-1,4-디카르복실레이트를 메틸렌클로라이드(10.0볼륨)에 용해시킨 후, 트리플루오로아세트산(TFA) (2.5볼륨)을 첨가하고 실온에서 1 시간동안 교반하였다. 반응이 완료된 후, 감압 농축하고, 잔사에 디에틸이써를 투입, 교반, 여과하여 메틸 2-메틸-2-(피페라진-2-카르복사미도)프로판오에이트·2트리플루오로아세트산을 수득하였다.As in Scheme 5, 2-((1-methoxy-2-methyl-1-oxopropan-2-yl)carbamoyl)piperazine-1,4-dicarboxylate was mixed with methylene chloride (10.0 volume ), trifluoroacetic acid (TFA) (2.5 vol) was added and stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, diethyl ether was added to the residue, stirred, and filtered to obtain methyl 2-methyl-2-(piperazine-2-carboxamido)propanoate-2-trifluoroacetic acid. did.
6) 단계 6: 7,7-디메틸헥사하이드로-26) Step 6: 7,7-dimethylhexahydro-2 HH -피라지노[1,2--Pyrazino[1,2- aa ]피라진-6,9-디온·2트리플루오로아세트산의 제조]Preparation of pyrazine-6,9-dione/2 trifluoroacetic acid
[반응식 6][Scheme 6]
Figure PCTKR2022006181-appb-img-000047
Figure PCTKR2022006181-appb-img-000047
실온에서 단계 5를 통해 수득한 메틸 2-메틸-2-(피페라진-2-카르복사미도)프로판오에이트·2트리플루오로아세트산을 메틸알코올에 녹인 후 1,8-디아자바이사이클로[5,4,0]언덱-7-엔을 적가하고 실온에서 철야 교반하였다. 반응 완결 확인 후 감압농축하고, 헥산을 투입하여 교반 후 헥산을을 걸러내었다. 디에틸이써를 넣고 가열 교반하면서 메틸알코올을 소량씩 투입하여 고체를 생성한 후 냉동 보관하였다. 여과 후 건조하여 7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온·2트리플루오로아세트산을 수득하였다.After dissolving methyl 2-methyl-2-(piperazine-2-carboxamido)propanoate·2-trifluoroacetic acid obtained in step 5 in methyl alcohol at room temperature, 1,8-diazabicyclo[5, 4,0]Undec-7-ene was added dropwise and stirred overnight at room temperature. After confirming the completion of the reaction, the mixture was concentrated under reduced pressure, hexane was added and stirred, and the hexane was filtered off. Diethyl ether was added and methyl alcohol was added little by little while heating and stirring to form a solid, and then stored frozen. After filtration and drying, 7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione/2trifluoroacetic acid was obtained.
7) 단계 7: 2-((2-에틸-1-벤조[7) Step 7: 2-((2-ethyl-1-benzo[ bb ]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2]Thiophen-3-yl)methyl)-7,7-dimethylhexahydro-2 HH -피라지노[1,2--Pyrazino[1,2- aa ]피라진-6,9-디온(S801)의 제조] Preparation of pyrazine-6,9-dione (S801)
[반응식 7][Scheme 7]
Figure PCTKR2022006181-appb-img-000048
Figure PCTKR2022006181-appb-img-000048
실온에서 단계 2를 통해 수득한 2-에틸벤조[b]싸이오펜-3-카르바알데히드(1.0당량)와 단계 6을 통해 수득한 7,7-디메틸헥사히드로-2H-피라지노[1,2-a]피라진-6,9-디온·2트리플루오로아세트산(1.0당량)를 메틸렌클로라이드(MC)에 투입 후, 트리에틸아민(TEA)(3.0당량)을 부가한 다음 30분간 교반하였다. 소듐 트리아세톡시보로하이드(2.0당량)를 넣고, 실온에서 6시간 교반하였다. 포화 소듐 바이카보네이트 수용액으로 중화한 후에 반응액에 메틸렌클로라이드를 넣고 유기층을 분리하였다. 분리된 유기층을 포화 염화나트륨 수용액으로 세정하고, 무수 마그네슘 설페이트로 건조하고 농축 후 n-헥산으로 고체화하고 여과하여 2-((2-에틸-1-벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S801)을 수득하였다.2-ethylbenzo[ b ]thiophen-3-carbaaldehyde (1.0 equivalent) obtained through step 2 at room temperature and 7,7-dimethylhexahydro- 2H -pyrazino[1, obtained through step 6 2- a ]Pyrazine-6,9-dione/2trifluoroacetic acid (1.0 equiv.) was added to methylene chloride (MC), followed by addition of triethylamine (TEA) (3.0 equiv.), followed by stirring for 30 minutes. Sodium triacetoxyborohydr (2.0 equivalents) was added, and the mixture was stirred at room temperature for 6 hours. After neutralization with a saturated aqueous sodium bicarbonate solution, methylene chloride was added to the reaction solution, and the organic layer was separated. The separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated, solidified with n -hexane, filtered, and 2-((2-ethyl-1-benzo[ b ]thiophen-3-yl)methyl) -7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S801) was obtained.
[화학식 4] [Formula 4]
S801S801
Figure PCTKR2022006181-appb-img-000049
Figure PCTKR2022006181-appb-img-000049
1H NMR (400 MHz, CDCl3)δ 7.845 - 7.826 (d, J = 7.6 Hz, 1H), 7.777 - 7.758 (d, J = 7.6 Hz, 1H), 7.346 - 7.256 (m, 2H), 7.180 (s, 1H), 4.501 - 4.468 (m, 1H), 4.090 - 4.054 (dd, J = 3.6, 10.8 Hz, 1H), 3.804 - 3.645 (m, 2H), 3.517 - 3.489 (m, 1H), 2.970 - 2.913 (q, J = 7.6 Hz, 2H), 2.866 - 2.838 (m, 1H), 2.737 - 2.666 (td, J = 3.2, 12.8 Hz, 1H), 2.153 - 2.097 (t, J = 11.2 Hz, 1H), 2.078 - 2.012 (td, J = 3.2, 12.8 Hz, 1H), 1.517 (s, 3H), 1.469 (s, 3H), 1.349 - 1.312 (t, J = 7.2 Hz, 3H) 1 H NMR (400 MHz, CDCl 3 )δ 7.845 - 7.826 (d, J = 7.6 Hz, 1H), 7.777 - 7.758 (d, J = 7.6 Hz, 1H), 7.346 - 7.256 (m, 2H), 7.180 ( s, 1H), 4.501 - 4.468 (m, 1H), 4.090 - 4.054 (dd, J = 3.6, 10.8 Hz, 1H), 3.804 - 3.645 (m, 2H), 3.517 - 3.489 (m, 1H), 2.970 - 2.913 (q, J = 7.6 Hz, 2H), 2.866 - 2.838 (m, 1H), 2.737 - 2.666 (td, J = 3.2, 12.8 Hz, 1H), 2.153 - 2.097 (t, J = 11.2 Hz, 1H) , 2.078 - 2.012 (td, J = 3.2, 12.8 Hz, 1H), 1.517 (s, 3H), 1.469 (s, 3H), 1.349 - 1.312 (t, J = 7.2 Hz, 3H)
13C NMR (126 MHz, CDCl3)δ 168.15, 165.60, 146.30, 140.48, 137.99, 125.78, 123.88, 123.64, 122.19, 122.05, 77.31, 77.05, 76.80, 57.51, 56.62, 56.06, 53.25, 51.53, 41.77, 29.22, 29.01, 22.00, 16.11. 13 C NMR (126 MHz, CDCl 3 )δ 168.15, 165.60, 146.30, 140.48, 137.99, 125.78, 123.88, 123.64, 122.19, 122.05, 77.31, 77.05, 76.80, 57.51, 56.62, 56.53, 41.77, 29.22. , 29.01, 22.00, 16.11.
MS (ESI) m/z for C20H25N3O2S[M+H]+:calcd371.50,found372.17.MS (ESI) m/z for C 20 H 25 N 3 O 2 S[M+H] + :calcd371.50,found372.17.
제조예 2-1Preparation 2-1
단계 7에서 제조된 2-((2-에틸-1-벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S801)을 디메틸포름아미드(DMF)로 용해하고 60% NaH(오일분산)를 가하였다. 여기에 아이오도메탄(2당량)를 부가 한 다음 실온에서 1일 동안 교반 하였다. 반응액을 아세트산 에틸로 희석한 다음 물로 세정하였다. 유기층을 탈수시키고 감압 증발기로 농축시켜 얻어진 잔사를 실리카겔 관 크로마토그래피로 정제하여 2-((2-에틸-1-벤조[b]싸이오펜-3-일)메틸)-7,7,8-트리메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S802)을 제조하였다.2-((2-ethyl-1-benzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine prepared in step 7 -6,9-dione (S801) was dissolved in dimethylformamide (DMF), and 60% NaH (oil dispersion) was added thereto. Iodomethane (2 equivalents) was added thereto, followed by stirring at room temperature for 1 day. The reaction solution was diluted with ethyl acetate and washed with water. The organic layer was dehydrated and concentrated with a vacuum evaporator, and the obtained residue was purified by silica gel column chromatography, and 2-((2-ethyl-1-benzo[ b ]thiophen-3-yl)methyl)-7,7,8-trimethyl Hexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S802) was prepared.
[화학식 5] [Formula 5]
S802S802
Figure PCTKR2022006181-appb-img-000050
Figure PCTKR2022006181-appb-img-000050
1H NMR (400 MHz, CDCl3)δ 7.845 - 7.826 (d, J = 7.6 Hz, 1H), 7.777 - 7.758 (d, J = 7.6 Hz, 1H), 7.351 - 7.253 (m, 2H), 4.499 - 4.454 (m, 1H), 4.077 - 4.042 (dd, J = 3.2, 10.8 Hz, 1H), 3.814 - 3.623 (m, 2H), 3.582 - 3.543 (m, 1H), 2.969 (s, 3H), 2.969 - 2.916 (q, J = 6.0 Hz, 2H), 2.843 - 2.811 (m, 1H), 2.733 - 2.662 (td, J = 3.2, 12.8 Hz, 1H), 2.106 - 2.050 (t, J = 11.2 Hz, 1H), 2.056 - 1.990 (td, J = 3.2, 12.8 Hz, 1H), 1.578 (s, 3H), 1.513 (s, 3H), 1.349 - 1.312 (t, J = 7.2 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 )δ 7.845 - 7.826 (d, J = 7.6 Hz, 1H), 7.777 - 7.758 (d, J = 7.6 Hz, 1H), 7.351 - 7.253 (m, 2H), 4.499 - 4.454 (m, 1H), 4.077 - 4.042 (dd, J = 3.2, 10.8 Hz, 1H), 3.814 - 3.623 (m, 2H), 3.582 - 3.543 (m, 1H), 2.969 (s, 3H), 2.969 - 2.916 (q, J = 6.0 Hz, 2H), 2.843 - 2.811 (m, 1H), 2.733 - 2.662 (td, J = 3.2, 12.8 Hz, 1H), 2.106 - 2.050 (t, J = 11.2 Hz, 1H) , 2.056 - 1.990 (td, J = 3.2, 12.8 Hz, 1H), 1.578 (s, 3H), 1.513 (s, 3H), 1.349 - 1.312 (t, J = 7.2 Hz, 3H).
13C NMR (126 MHz, CDCl3)δ 167.70, 163.70, 146.09, 140.42, 137.87, 125.79, 123.79, 123.52, 122.15, 121.93, 60.54, 57.04, 56.95, 53.11, 51.29, 41.69, 27.95, 25.98, 25.30, 21.92, 16.05. 13 C NMR (126 MHz, CDCl 3 )δ 167.70, 163.70, 146.09, 140.42, 137.87, 125.79, 123.79, 123.52, 122.15, 121.93, 60.54, 57.04, 56.95, 53.11, 51.29, 41.69, 27.30, 21.98, 25.30, 25.92 , 16.05.
MS (ESI) m/z for C21H27N3O2S[M+H]+:calcd385.53,found386.18.MS (ESI) m/z for C 21 H 27 N 3 O 2 S[M+H]+:calcd385.53,found386.18.
제조예 2-2Preparation 2-2
제조예 2-1에서 아이오도메탄대신 아이오도에탄을 사용하고 제조예 2-1과 동일한 방법으로 8-에틸-2-((2-에틸-1-벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S803)을 제조하였다.8-ethyl-2-((2-ethyl-1-benzo[ b ]thiophen-3-yl) in Preparation Example 2-1 using iodoethane instead of iodomethane and in the same manner as in Preparation Example 2-1 Methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S803) was prepared.
[화학식 6] [Formula 6]
S803S803
Figure PCTKR2022006181-appb-img-000051
Figure PCTKR2022006181-appb-img-000051
1H NMR (400 MHz, CDCl3)δ 7.856 - 7.837 (d, J = 7.6 Hz, 1H), 7.773 - 7.753 (d, J = 8.0 Hz, 1H), 7.346 - 7.252 (m, 2H), 4.477 - 4.444 (m, 1H), 4.058 - 4.023 (dd, J = 3.2, 10.8 Hz, 1H), 3.823 - 3.621 (m, 2H), 3.581 - 3.551 (m, 1H), 3.470 - 3.372 (m, 3H), 2.973 - 2.916 (q, J = 6.0 Hz, 2H), 2.833 - 2.805 (m, 1H), 2.725 - 2.654 (td, J = 3.2, 12.8 Hz, 1H), 2.105 - 2.050 (t, J = 11.2 Hz, 1H), 2.056 - 1.986 (td, J = 3.2, 12.8 Hz, 1H), 1.577 (s, 3H), 1.511 (s, 3H), 1.348 - 1.311 (t, J = 7.2 Hz, 3H), 1.227 - 1.192 (t, J = 6.8 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 )δ 7.856 - 7.837 (d, J = 7.6 Hz, 1H), 7.773 - 7.753 (d, J = 8.0 Hz, 1H), 7.346 - 7.252 (m, 2H), 4.477 - 4.444 (m, 1H), 4.058 - 4.023 (dd, J = 3.2, 10.8 Hz, 1H), 3.823 - 3.621 (m, 2H), 3.581 - 3.551 (m, 1H), 3.470 - 3.372 (m, 3H), 2.973 - 2.916 (q, J = 6.0 Hz, 2H), 2.833 - 2.805 (m, 1H), 2.725 - 2.654 (td, J = 3.2, 12.8 Hz, 1H), 2.105 - 2.050 (t, J = 11.2 Hz, 1H), 2.056 - 1.986 (td, J = 3.2, 12.8 Hz, 1H), 1.577 (s, 3H), 1.511 (s, 3H), 1.348 - 1.311 (t, J = 7.2 Hz, 3H), 1.227 - 1.192 (t, J = 6.8 Hz, 3H).
13C NMR (126 MHz, CDCl3)δ 167.92, 163.37, 146.12, 140.49, 137.95, 125.90, 123.85, 123.59, 122.23, 121.99, 61.11, 57.14, 56.90, 53.19, 51.30, 41.75, 37.79, 26.61, 26.17, 21.99, 16.11, 14.53. 13 C NMR (126 MHz, CDCl 3 )δ 167.92, 163.37, 146.12, 140.49, 137.95, 125.90, 123.85, 123.59, 122.23, 121.99, 61.11, 57.14, 56.90, 53.19, 51.30, 41.75, 37.79, 26.61, , 16.11, 14.53.
MS (ESI) m/z for C22H29N3O2S[M+H]+:calcd399.55,found386.19.MS (ESI) m/z for C 22 H 29 N 3 O 2 S[M+H] + :calcd399.55,found386.19.
제조예 2-3Preparation 2-3
제조예 2-1에서 아이오도메탄대신 1-브로모부탄을 사용하고 제조예 2-1과 동일한 방법으로 8-부틸-2-((2-에틸-1-벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S804)을 제조하였다.In Preparation Example 2-1, 1-bromobutane was used instead of iodomethane, and in the same manner as in Preparation Example 2-1, 8-butyl-2-((2-ethyl-1-benzo[ b ]thiophene-3- yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S804) was prepared.
[화학식 7] [Formula 7]
S804S804
Figure PCTKR2022006181-appb-img-000052
Figure PCTKR2022006181-appb-img-000052
1H NMR (400 MHz, CDCl3)δ 7.859 - 7.839 (d, J = 8.0 Hz, 1H), 7.774 - 7.755 (d, J = 7.6 Hz 1H), 7.349 - 7.253 (m, 2H), 4.475 - 4.441 (m, 1H), 4.150 - 4.096 (q, J = 7.2 Hz, 1H), 4.051 - 4.016 (dd, J = 3.2, 10.8 Hz, 1H), 3.818 - 3.624 (m, 2H), 3.572 - 3.541 (m, 1H), 3.373 - 3.232 (m, 2H), 2.972 - 2.916 (q, J = 7.6 Hz, 2H), 2.839 - 2.811 (m, 1H), 2.731 -2.660 (td, J = 3.2, 12.4 Hz, 1H), 2.098 - 1.996 (m, 3H), 1.572 (s, 3H), 1.498 (s, 3H), 1.373 - 1.309 (m, 5H), 1.281 - 1.245 (m, 1H), 0.960 - 0.923 (t, J = 7.2 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 )δ 7.859 - 7.839 (d, J = 8.0 Hz, 1H), 7.774 - 7.755 (d, J = 7.6 Hz 1H), 7.349 - 7.253 (m, 2H), 4.475 - 4.441 (m, 1H), 4.150 - 4.096 (q, J = 7.2 Hz, 1H), 4.051 - 4.016 (dd, J = 3.2, 10.8 Hz, 1H), 3.818 - 3.624 (m, 2H), 3.572 - 3.541 (m , 1H), 3.373 - 3.232 (m, 2H), 2.972 - 2.916 (q, J = 7.6 Hz, 2H), 2.839 - 2.811 (m, 1H), 2.731 -2.660 (td, J = 3.2, 12.4 Hz, 1H) ), 2.098 - 1.996 (m, 3H), 1.572 (s, 3H), 1.498 (s, 3H), 1.373 - 1.309 (m, 5H), 1.281 - 1.245 (m, 1H), 0.960 - 0.923 (t, J = 7.2 Hz, 3H).
13C NMR (126 MHz, CDCl3)δ 168.10, 163.79, 146.22, 140.51, 138.00, 125.88, 123.87, 123.61, 122.24, 122.04, 61.15, 57.21, 56.94, 53.26, 51.30, 43.05, 41.82, 31.33, 26.65, 26.28, 22.03, 20.48, 16.11, 13.77. 13 C NMR (126 MHz, CDCl 3 )δ 168.10, 163.79, 146.22, 140.51, 138.00, 125.88, 123.87, 123.61, 122.24, 122.04, 61.15, 57.21, 56.94, 53.26, 51.30, 43.05, 41.65, 31.28, , 22.03, 20.48, 16.11, 13.77.
MS (ESI) m/z for C24H33N3O2S[M+H]+:calcd427.61,found400.2.MS (ESI) m/z for C 24 H 33 N 3 O 2 S[M+H]+:calcd427.61,found400.2.
제조예 2-4Preparation 2-4
제조예 2-1에서 아이오도메탄대신 1-브로모헥산을 사용하고 제조예 2-1과 동일한 방법으로 2-((2-에틸-1-벤조[b]싸이오펜-3-일)메틸)-8-헥실-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S805)을 제조하였다.In Preparation Example 2-1, 1-bromohexane was used instead of iodomethane, and in the same manner as in Preparation Example 2-1, 2-((2-ethyl-1-benzo[ b ]thiophen-3-yl)methyl) -8-hexyl-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S805) was prepared.
[화학식 8] [Formula 8]
S805S805
Figure PCTKR2022006181-appb-img-000053
Figure PCTKR2022006181-appb-img-000053
1H NMR (400 MHz, CDCl3)δ 7.857 - 7.837 (d, J = 8.0 Hz, 1H), 7.774 - 7.754 (d, J = 7.6 Hz 1H), 7.347 - 7.253 (m, 2H), 4.473 - 4.440 (m, 1H), 4.051 - 4.016 (dd, J = 3.2, 10.8 Hz, 1H), 3.817 - 3.624 (m, 2H), 3.570 - 3.542 (m, 1H), 3.356 - 3.226 (m, 2H), 2.971 - 2.889 (m, 2H), 2.839 - 2.810 (m, 1H), 2.730 - 2.659 (td, J = 3.2, 12.4 Hz, 1H), 2.096 - 1.988 (m, 2H), 1.569 (s, 3H), 1.497 (s, 3H), 1.346 - 1.302 (m, 9H), 0.903 - 0.871 (t, J = 7.2 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 )δ 7.857 - 7.837 (d, J = 8.0 Hz, 1H), 7.774 - 7.754 (d, J = 7.6 Hz 1H), 7.347 - 7.253 (m, 2H), 4.473 - 4.440 (m, 1H), 4.051 - 4.016 (dd, J = 3.2, 10.8 Hz, 1H), 3.817 - 3.624 (m, 2H), 3.570 - 3.542 (m, 1H), 3.356 - 3.226 (m, 2H), 2.971 - 2.889 (m, 2H), 2.839 - 2.810 (m, 1H), 2.730 - 2.659 (td, J = 3.2, 12.4 Hz, 1H), 2.096 - 1.988 (m, 2H), 1.569 (s, 3H), 1.497 (s, 3H), 1.346 - 1.302 (m, 9H), 0.903 - 0.871 (t, J = 7.2 Hz, 3H).
13C NMR (126 MHz, CDCl3)δ 168.09, 163.75, 146.21, 140.51, 138.00, 125.88, 123.87, 123.61, 122.24, 122.03, 61.13, 57.20, 56.95, 53.25, 51.31, 43.29, 41.81, 31.43, 29.16, 26.91, 26.66, 26.28, 22.59, 22.03, 16.10, 14.01. 13 C NMR (126 MHz, CDCl 3 )δ 168.09, 163.75, 146.21, 140.51, 138.00, 125.88, 123.87, 123.61, 122.24, 122.03, 61.13, 57.20, 56.95, 53.25, 51.31, 43.29, 41.81, 31.43, 29.16, 31.91 , 26.66, 26.28, 22.59, 22.03, 16.10, 14.01.
MS (ESI) m/z for C26H37N3O2S[M+H]+:calcd455.66,found456.26.MS (ESI) m/z for C 26 H 37 N 3 O 2 S[M+H] + :calcd455.66,found456.26.
제조예 2-5Preparation 2-5
제조예 2-1에서 아이오도메탄대신 브로모메틸사이클로헥산을 사용하고 제조예 2-1과 동일한 방법으로 8-(사이클로메틸)-2-((2-에틸-1-벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S806)을 제조하였다.In Preparation Example 2-1, bromomethylcyclohexane was used instead of iodomethane, and in the same manner as in Preparation Example 2-1, 8-(cyclomethyl)-2-((2-ethyl-1-benzo[ b ]thiophene) -3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S806) was prepared.
[화학식 9] [Formula 9]
S806S806
Figure PCTKR2022006181-appb-img-000054
Figure PCTKR2022006181-appb-img-000054
1H NMR (500 MHz, CDCl3)δ 7.84 (d, J = 7.9 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 7.1 Hz, 1H), 7.27 (dd, J = 11.2, 3.7 Hz, 1H), 4.44 (d, J = 13.1 Hz, 1H), 4.02 (dd, J = 10.9, 3.3 Hz, 1H), 3.80 (d, J = 13.0 Hz, 1H), 3.65 (d, J = 13.0 Hz, 1H), 3.61 - 3.51 (m, 1H), 3.29 (dd, J = 13.7, 7.3 Hz, 1H), 3.14 (dd, J = 13.7, 6.8 Hz, 1H), 2.94 (q, J = 7.6 Hz, 2H), 2.82 (d, J = 11.4 Hz, 1H), 2.70 (td, J = 12.8, 3.3 Hz, 1H), 2.13 - 1.97 (m, 2H), 1.80 - 1.61 (m, 6H), 1.56 (s, 3H), 1.46 (s, 3H), 1.33 (t, J = 7.5 Hz, 3H), 1.22 - 1.08 (m, 3H), 1.03 - 0.91 (m, 2H). 1 H NMR (500 MHz, CDCl 3 )δ 7.84 (d, J = 7.9 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 7.1 Hz, 1H), 7.27 (dd , J = 11.2, 3.7 Hz, 1H), 4.44 (d, J = 13.1 Hz, 1H), 4.02 (dd, J = 10.9, 3.3 Hz, 1H), 3.80 (d, J = 13.0 Hz, 1H), 3.65 (d, J = 13.0 Hz, 1H), 3.61 - 3.51 (m, 1H), 3.29 (dd, J = 13.7, 7.3 Hz, 1H), 3.14 (dd, J = 13.7, 6.8 Hz, 1H), 2.94 ( q, J = 7.6 Hz, 2H), 2.82 (d, J = 11.4 Hz, 1H), 2.70 (td, J = 12.8, 3.3 Hz, 1H), 2.13 - 1.97 (m, 2H), 1.80 - 1.61 (m) , 6H), 1.56 (s, 3H), 1.46 (s, 3H), 1.33 (t, J = 7.5 Hz, 3H), 1.22 - 1.08 (m, 3H), 1.03 - 0.91 (m, 2H).
13C NMR (126 MHz, CDCl3)δ 168.50, 165.71, 146.18, 140.50, 138.00, 125.89, 123.86, 123.60, 122.25, 122.03, 77.30, 77.04, 76.79, 61.26, 57.23, 56.85, 53.27, 51.22, 48.51, 41.80, 37.88, 31.20, 31.09, 29.70, 26.56, 26.41, 26.35, 26.06, 22.02, 16.11. 13 C NMR (126 MHz, CDCl 3 )δ 168.50, 165.71, 146.18, 140.50, 138.00, 125.89, 123.86, 123.60, 122.25, 122.03, 77.30, 77.04, 76.79, 61.26, 57.23, 56.85, 53.27, 51.22, 48.51, 51.22 , 37.88, 31.20, 31.09, 29.70, 26.56, 26.41, 26.35, 26.06, 22.02, 16.11.
MS (ESI) m/z for C27H37N3O2S[M+H]+:calcd467.67,found468.26.MS (ESI) m/z for C 27 H 37 N 3 O 2 S[M+H]+:calcd467.67,found468.26.
제조예 2-6Preparation 2-6
제조예 2-1에서 아이오도메탄대신 브로모메틸벤젠을 사용하고 제조예 2-1과 동일한 방법으로 8-벤질-2-((2-에틸-1-벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S807)을 제조하였다.In Preparation Example 2-1, using bromomethylbenzene instead of iodomethane, and in the same manner as in Preparation Example 2-1, 8-benzyl-2-((2-ethyl-1-benzo[ b ]thiophen-3-yl )methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S807) was prepared.
[화학식 10] [Formula 10]
S807S807
Figure PCTKR2022006181-appb-img-000055
Figure PCTKR2022006181-appb-img-000055
1H NMR (400 MHz, CDCl3)δ 7.870 - 7.851 (d, J = 7.6 Hz, 1H), 7.776 - 7.757 (d, J = 7.6 Hz, 1H), 7.352 - 7.199 (m, 7H), 4.488 - 4.455 (m, 1H), 4.185 - 4.149 (dd, J = 3.2, 10.8 Hz, 1H), 3.850 - 3.628 (m, 3H), 2.986 - 2.930 (q, J = 6.0 Hz, 2H), 2.871 - 2.843 (m, 1H), 2.783 - 2.712 (td, J = 3.2, 12.8 Hz, 1H), 2.212 - 2.156 (t, J = 11.2 Hz, 1H), 2.105 - 2.047 (td, J = 3.2, 12.8 Hz, 1H), 1.517 (s, 3H), 1.445 (s, 3H), 1.357 - 1.320 (t, J = 7.2 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 )δ 7.870 - 7.851 (d, J = 7.6 Hz, 1H), 7.776 - 7.757 (d, J = 7.6 Hz, 1H), 7.352 - 7.199 (m, 7H), 4.488 - 4.455 (m, 1H), 4.185 - 4.149 (dd, J = 3.2, 10.8 Hz, 1H), 3.850 - 3.628 (m, 3H), 2.986 - 2.930 (q, J = 6.0 Hz, 2H), 2.871 - 2.843 ( m, 1H), 2.783 - 2.712 (td, J = 3.2, 12.8 Hz, 1H), 2.212 - 2.156 (t, J = 11.2 Hz, 1H), 2.105 - 2.047 (td, J = 3.2, 12.8 Hz, 1H) , 1.517 (s, 3H), 1.445 (s, 3H), 1.357 - 1.320 (t, J = 7.2 Hz, 3H).
13C NMR (126 MHz, CDCl3)δ 168.21, 165.11, 146.24, 140.49, 138.00, 128.57, 127.10, 126.83, 125.84, 123.87, 123.62, 122.23, 122.04, 61.68, 57.18, 56.92, 53.27, 51.25, 45.61, 41.92, 29.68, 26.63, 26.51, 22.03, 16.11. 13 C NMR (126 MHz, CDCl 3 )δ 168.21, 165.11, 146.24, 140.49, 138.00, 128.57, 127.10, 126.83, 125.84, 123.87, 123.62, 122.23, 122.04, 61.68, 57.18, 56.92, 53.27, 51.25. , 29.68, 26.63, 26.51, 22.03, 16.11.
MS (ESI) m/z for C27H31N3O2S[M+H]+:calcd461.62,found462.22.MS (ESI) m/z for C 27 H 31 N 3 O 2 S[M+H] + :calcd461.62,found462.22.
제조예 2-7Preparation 2-7
제조예 2-1에서 아이오도메탄대신 1-(브로모메틸)-4-메틸벤젠을 사용하고 제조예 2-1과 동일한 방법으로 2-((2-에틸-1-벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸-8-(4-메틸벤질)헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S808)을 제조하였다.In Preparation Example 2-1, 1-(bromomethyl)-4-methylbenzene was used instead of iodomethane, and in the same manner as in Preparation Example 2-1, 2-((2-ethyl-1-benzo[ b ]thiophene) -3-yl)methyl)-7,7-dimethyl-8-(4-methylbenzyl)hexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S808) was prepared .
[화학식 11] [Formula 11]
S808S808
Figure PCTKR2022006181-appb-img-000056
Figure PCTKR2022006181-appb-img-000056
1H NMR (500 MHz, CDCl3)δ 7.85 (d, J = 7.7 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.36 - 7.23 (m, 2H), 7.18 - 7.05 (m, 4H), 4.69 (d, J = 15.6 Hz, 1H), 4.60 (d, J = 15.6 Hz, 1H), 4.46 (ddd, J = 13.1, 3.0, 1.8 Hz, 1H), 4.14 (dd, J = 10.9, 3.4 Hz, 1H), 3.82 (d, J = 13.0 Hz, 1H), 3.70 - 3.59 (m, 2H), 3.00 - 2.91 (m, 2H), 2.89 - 2.81 (m, 1H), 2.78 - 2.68 (m, 1H), 2.31 (s, 3H), 2.16 (t, J = 11.1 Hz, 1H), 2.06 (td, J = 11.7, 3.2 Hz, 1H), 1.52 (s, 3H), 1.43 (s, 3H), 1.34 (t, J = 7.6 Hz, 3H). 1 H NMR (500 MHz, CDCl 3 )δ 7.85 (d, J = 7.7 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.36 - 7.23 (m, 2H), 7.18 - 7.05 (m, 4H), 4.69 (d, J = 15.6 Hz, 1H), 4.60 (d, J = 15.6 Hz, 1H), 4.46 (ddd, J = 13.1, 3.0, 1.8 Hz, 1H), 4.14 (dd, J = 10.9) , 3.4 Hz, 1H), 3.82 (d, J = 13.0 Hz, 1H), 3.70 - 3.59 (m, 2H), 3.00 - 2.91 (m, 2H), 2.89 - 2.81 (m, 1H), 2.78 - 2.68 ( m, 1H), 2.31 (s, 3H), 2.16 (t, J = 11.1 Hz, 1H), 2.06 (td, J = 11.7, 3.2 Hz, 1H), 1.52 (s, 3H), 1.43 (s, 3H) ), 1.34 (t, J = 7.6 Hz, 3H).
13C NMR (126 MHz, CDCl3)δ 168.25, 165.04, 146.22, 140.49, 138.00, 136.71, 135.01, 129.24, 126.87, 125.86, 123.87, 123.61, 122.23, 122.04, 61.65, 57.17, 56.92, 53.27, 51.26, 45.41, 41.90, 26.63, 26.54, 22.03, 21.04, 16.12. 13 C NMR (126 MHz, CDCl 3 )δ 168.25, 165.04, 146.22, 140.49, 138.00, 136.71, 135.01, 129.24, 126.87, 125.86, 123.87, 123.61, 122.23, 122.04, 61.65, 57.41, 51.26, 53.27, 51.26 , 41.90, 26.63, 26.54, 22.03, 21.04, 16.12.
MS (ESI) m/z for C28H33N3O2S[M+H]+:calcd475.65,found476.23.MS (ESI) m/z for C 28 H 33 N 3 O 2 S[M+H]+:calcd475.65,found476.23.
제조예 2-8Preparation 2-8
제조예 2-1에서 아이오도메탄대신 1-(브로모메틸)-4-클로로벤젠을 사용하고, 반응 후 농축시켜 얻어진 잔사를 메탄올 슬러리, 아이소프로필에테르 슬러리를 연속으로 한 다음 실리카겔 관 크로마토그래피로 정제하였다. 나머지 제조방법은 제조예 2-1과 동일한 방법으로 8-(4-클로로벤질)-2-((2-에틸-1-벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S809)을 제조하였다.In Preparation Example 2-1, 1-(bromomethyl)-4-chlorobenzene was used instead of iodomethane, and the residue obtained by concentration after the reaction was continuously subjected to methanol slurry and isopropyl ether slurry, followed by silica gel column chromatography. Purified. 8-(4-chlorobenzyl)-2-((2-ethyl-1-benzo[ b ]thiophen-3-yl)methyl)-7,7- Dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S809) was prepared.
[화학식 12] [Formula 12]
S809S809
Figure PCTKR2022006181-appb-img-000057
Figure PCTKR2022006181-appb-img-000057
1H NMR (400 MHz, CDCl3)δ 7.874 - 7.855 (d, J = 8.0 Hz, 1H), 7.778 - 7.759 (d, J = 7.6 Hz, 1H), 7.357 - 7.263 (m, 4H), 7.165 - 7.144 (m, 2H), 4.728 - 4.688 (m, 2H), 4.489 - 4.453 (m, 1H), 4.489 - 4.453 (dd, J = 3.2, 10.8 Hz, 1H), 3.845 - 3.665 (m, 2H), 3.640 - 3.600 (m, 1H), 2.984 - 2.927 (q, J = 6.0 Hz, 2H), 2.877 - 2.849 (m, 1H), 2.786 - 2.715 (td, J = 3.2, 12.8 Hz, 1H), 2.188 - 2.133 (t, J = 11.2 Hz, 1H), 2.105 - 2.038 (td, J = 3.2, 12.8 Hz, 1H), 1.518 (s, 3H), 1.443 (s, 3H), 1.357 - 1.319 (t, J = 7.2 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 )δ 7.874 - 7.855 (d, J = 8.0 Hz, 1H), 7.778 - 7.759 (d, J = 7.6 Hz, 1H), 7.357 - 7.263 (m, 4H), 7.165 - 7.144 (m, 2H), 4.728 - 4.688 (m, 2H), 4.489 - 4.453 (m, 1H), 4.489 - 4.453 (dd, J = 3.2, 10.8 Hz, 1H), 3.845 - 3.665 (m, 2H), 3.640 - 3.600 (m, 1H), 2.984 - 2.927 (q, J = 6.0 Hz, 2H), 2.877 - 2.849 (m, 1H), 2.786 - 2.715 (td, J = 3.2, 12.8 Hz, 1H), 2.188 - 2.133 (t, J = 11.2 Hz, 1H), 2.105 - 2.038 (td, J = 3.2, 12.8 Hz, 1H), 1.518 (s, 3H), 1.443 (s, 3H), 1.357 - 1.319 (t, J = 7.2 Hz, 3H).
13C NMR (126 MHz, CDCl3)δ 168.01, 165.19, 146.27, 140.47, 138.01, 136.56, 132.92, 128.74, 128.32, 125.79, 123.88, 123.64, 122.21, 122.06, 61.71, 57.11, 56.90, 53.25, 51.24, 45.09, 41.94, 26.67, 26.52, 22.02, 16.12. 13 C NMR (126 MHz, CDCl 3 )δ 168.01, 165.19, 146.27, 140.47, 138.01, 136.56, 132.92, 128.74, 128.32, 125.79, 123.88, 123.64, 122.21, 122.06, 61.71, 57.11, 56.90, 53.25. , 41.94, 26.67, 26.52, 22.02, 16.12.
MS (ESI) m/z for C27H30ClN3O2S[M+H]+:calcd496.07,found496.18.MS (ESI) m/z for C 27 H 30 ClN 3 O 2 S[M+H] + :calcd496.07,found496.18.
제조예 2-9Preparation 2-9
제조예 2-1에서 아이오도메탄대신 1-(브로모메틸)-4-브로모벤젠을 사용하고, 반응 후 농축시켜 얻어진 잔사를 메탄올 슬러리, 아이소프로필에테르 슬러리를 연속으로 한 다음 실리카겔 관 크로마토그래피로 정제하였다. 나머지 제조방법은 제조예 2-1과 동일한 방법으로 8-(4-브로모벤질)-2-((2-에틸-1-벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S810)을 제조하였다.In Preparation Example 2-1, 1-(bromomethyl)-4-bromobenzene was used instead of iodomethane, and the residue obtained by concentration after the reaction was continuously subjected to methanol slurry and isopropyl ether slurry, followed by silica gel column chromatography. was purified with The rest of the preparation method is 8-(4-bromobenzyl)-2-((2-ethyl-1-benzo[ b ]thiophen-3-yl)methyl)-7,7 in the same manner as in Preparation Example 2-1. -Dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S810) was prepared.
[화학식 13] [Formula 13]
S810S810
Figure PCTKR2022006181-appb-img-000058
Figure PCTKR2022006181-appb-img-000058
1H NMR (400 MHz, CDCl3)δ 7.866 - 7.845 (d, J = 8.0 Hz, 1H), 7.781 - 7.761 (d, J = 7.6 Hz, 1H), 7.443 - 7.416 (m, 2H), 7.356 - 7.263 (m, 2H), 7.108 - 7.087 (m, 2H), 4.709 - 4.537 (m, 2H), 4.488 - 4.452 (m, 1H), 4.173 - 4.138 (dd, J = 3.2, 10.8 Hz, 1H), 3.844 - 3.664 (m, 2H), 3.633 - 3.601 (m, 1H), 2.983 - 2.927 (q, J = 6.0 Hz, 2H), 2.877 - 2.848 (m, 1H), 2.785 - 2.714 (td, J = 3.2, 12.8 Hz, 1H), 2.185 - 2.130 (t, J = 11.2 Hz, 1H), 2.104 - 2.038 (td, J = 3.2, 12.8 Hz, 1H), 1.517 (s, 3H), 1.442 (s, 3H), 1.356 - 1.319 (t, J = 7.2 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 )δ 7.866 - 7.845 (d, J = 8.0 Hz, 1H), 7.781 - 7.761 (d, J = 7.6 Hz, 1H), 7.443 - 7.416 (m, 2H), 7.356 - 7.263 (m, 2H), 7.108 - 7.087 (m, 2H), 4.709 - 4.537 (m, 2H), 4.488 - 4.452 (m, 1H), 4.173 - 4.138 (dd, J = 3.2, 10.8 Hz, 1H), 3.844 - 3.664 (m, 2H), 3.633 - 3.601 (m, 1H), 2.983 - 2.927 (q, J = 6.0 Hz, 2H), 2.877 - 2.848 (m, 1H), 2.785 - 2.714 (td, J = 3.2) , 12.8 Hz, 1H), 2.185 - 2.130 (t, J = 11.2 Hz, 1H), 2.104 - 2.038 (td, J = 3.2, 12.8 Hz, 1H), 1.517 (s, 3H), 1.442 (s, 3H) , 1.356 - 1.319 (t, J = 7.2 Hz, 3H).
13C NMR (126 MHz, CDCl3)δ 168.01, 165.19, 146.28, 140.47, 138.01, 137.09, 131.69, 128.68, 125.78, 123.88, 123.64, 122.20, 122.06, 121.00, 61.72, 57.12, 56.90, 53.26, 51.24, 45.16, 41.95, 26.68, 26.53, 22.03, 16.12. 13 C NMR (126 MHz, CDCl 3 )δ 168.01, 165.19, 146.28, 140.47, 138.01, 137.09, 131.69, 128.68, 125.78, 123.88, 123.64, 122.20, 122.06, 121.00, 61.72, 57.12, 56.90, 53.26, 56.90, 53.26 , 41.95, 26.68, 26.53, 22.03, 16.12.
MS (ESI) m/z for C27H30BrN3O2S[M+H]+:calcd540.52,found540.13.MS (ESI) m/z for C 27 H 30 BrN 3 O 2 S[M+H]+:calcd540.52,found540.13.
제조예 2-10Preparation Example 2-10
제조예 2-1에서 아이오도메탄대신 1-(브로모메틸)-4-플루오르벤젠을 사용하고, 반응 후 농축시켜 얻어진 잔사를 메탄올 슬러리, 아이소프로필에테르 슬러리를 연속으로 한 다음 실리카겔 관 크로마토그래피로 정제하였다. 나머지 제조방법은 제조예 2-1과 동일한 방법으로 2-((2-에틸-1-벤조[b]싸이오펜-3-일)메틸)-8-(4-플루오르벤질)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S811)을 제조하였다.In Preparation Example 2-1, 1-(bromomethyl)-4-fluorobenzene was used instead of iodomethane, and the residue obtained by concentration after the reaction was continuously subjected to methanol slurry and isopropyl ether slurry, followed by silica gel column chromatography. Purified. The rest of the preparation method was 2-((2-ethyl-1-benzo[ b ]thiophen-3-yl)methyl)-8-(4-fluorobenzyl)-7,7- in the same manner as in Preparation Example 2-1. Dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S811) was prepared.
[화학식 14][Formula 14]
S811S811
Figure PCTKR2022006181-appb-img-000059
Figure PCTKR2022006181-appb-img-000059
1H NMR (400 MHz, CDCl3)δ 7.867 - 7.848 (d, J = 8.0 Hz, 1H), 7.781 - 7.761 (d, J = 7.6 Hz, 1H), 7.356 - 7.263 (m, 2H), 7.213 - 7.178 (m, 2H), 7.027 - 6.976 (m, 2H), 4.730 - 4.565 (m, 2H), 4.484 - 4.451 (m, 1H), 4.173 - 4.137 (dd, J = 3.2, 10.8 Hz, 1H), 3.847 - 3.664 (m, 2H), 3.639 - 3.611 (m, 1H), 2.984 - 2.928 (q, J = 6.0, 2H), 2.875 - 2.844 (m, 1H), 2.783 - 2.712 (td, J = 3.2, 12.8 Hz, 1H), 2.191 - 2.136 (t, J = 11.2 Hz, 1H), 2.103 - 2.044 (td, J = 3.2, 12.8 Hz, 1H), 1.521 (s, 3H), 1.444 (s, 3H), 1.357 - 1.319 (t, J = 7.2 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 )δ 7.867 - 7.848 (d, J = 8.0 Hz, 1H), 7.781 - 7.761 (d, J = 7.6 Hz, 1H), 7.356 - 7.263 (m, 2H), 7.213 - 7.178 (m, 2H), 7.027 - 6.976 (m, 2H), 4.730 - 4.565 (m, 2H), 4.484 - 4.451 (m, 1H), 4.173 - 4.137 (dd, J = 3.2, 10.8 Hz, 1H), 3.847 - 3.664 (m, 2H), 3.639 - 3.611 (m, 1H), 2.984 - 2.928 (q, J = 6.0, 2H), 2.875 - 2.844 (m, 1H), 2.783 - 2.712 (td, J = 3.2, 12.8 Hz, 1H), 2.191 - 2.136 (t, J = 11.2 Hz, 1H), 2.103 - 2.044 (td, J = 3.2, 12.8 Hz, 1H), 1.521 (s, 3H), 1.444 (s, 3H), 1.357 - 1.319 (t, J = 7.2 Hz, 3H).
13C NMR (126 MHz, CDCl3)δ 168.09, 165.20, 162.87, 160.92, 146.27, 140.48, 138.01, 133.78, 128.60, 125.81, 123.88, 123.64, 122.21, 122.06, 115.53, 115.36, 61.70, 57.12, 56.90, 53.26, 51.25, 45.02, 41.94, 26.66, 26.52, 22.03, 16.11. 13 C NMR (126 MHz, CDCl 3 )δ 168.09, 165.20, 162.87, 160.92, 146.27, 140.48, 138.01, 133.78, 128.60, 125.81, 123.88, 123.64, 122.21, 122.06, 115.53, 115.26, 61.70, 57.12, 56.70, 57.12 , 51.25, 45.02, 41.94, 26.66, 26.52, 22.03, 16.11.
MS (ESI) m/z for C27H30FN3O2S[M+H]+:calcd479.61,found480.2.MS (ESI) m/z for C 27 H 30 FN 3 O 2 S[M+H] + :calcd479.61,found480.2.
제조예 2-11Preparation 2-11
제조예 2-1에서 아이오도메탄대신 1-(브로모메틸)-4-(트리플루오로메틸)벤젠을 사용하고, 반응 후 농축시켜 얻어진 잔사를 메탄올 슬러리, 아이소프로필에테르 슬러리를 연속으로 한 다음 실리카겔 관 크로마토그래피로 정제하였다. 나머지 제조방법은 제조예 2-1과 동일한 방법으로 2-((2-에틸-1-벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸-8-(4-(트리플루오로메틸)벤질)헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S812)을 제조하였다.In Preparation Example 2-1, 1- (bromomethyl) -4- (trifluoromethyl) benzene was used instead of iodomethane, and the residue obtained by concentration after the reaction was continuously subjected to methanol slurry and isopropyl ether slurry. Purified by silica gel column chromatography. The rest of the preparation method was 2-((2-ethyl-1-benzo[ b ]thiophen-3-yl)methyl)-7,7-dimethyl-8-(4-(tri Fluoromethyl) benzyl) hexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S812) was prepared.
[화학식 15] [Formula 15]
S812S812
Figure PCTKR2022006181-appb-img-000060
Figure PCTKR2022006181-appb-img-000060
1H NMR (400 MHz, CDCl3)δ 7.868 - 7.847 (d, J = 8.0 Hz, 1H), 7.783 - 7.763 (d, J = 7.6 Hz, 1H), 7.587 - 7.567 (m, 2H), 7.359 - 7.265 (m, 4H), 4.832 - 4.615 (m, 2H), 4.502 - 4.462 (m, 1H), 4.194 - 4.159 (dd, J = 3.2, 10.8 Hz, 1H), 3.850 - 3.672 (m, 2H), 3.642 - 3.607 (m, 1H), 2.986 - 2.930 (q, J = 6.0 Hz, 2H), 2.890 - 2.861 (m, 1H), 2.801 - 2.730 (td, J = 3.2, 12.8 Hz, 1H), 2.200 - 2.144 (t, J = 11.2 Hz, 1H), 2.117 - 2.054 (td, J = 3.2, 12.8 Hz, 1H), 1.528 (s, 3H), 1.467 (s, 3H), 1.358 - 1.320 (t, J = 7.2 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 )δ 7.868 - 7.847 (d, J = 8.0 Hz, 1H), 7.783 - 7.763 (d, J = 7.6 Hz, 1H), 7.587 - 7.567 (m, 2H), 7.359 - 7.265 (m, 4H), 4.832 - 4.615 (m, 2H), 4.502 - 4.462 (m, 1H), 4.194 - 4.159 (dd, J = 3.2, 10.8 Hz, 1H), 3.850 - 3.672 (m, 2H), 3.642 - 3.607 (m, 1H), 2.986 - 2.930 (q, J = 6.0 Hz, 2H), 2.890 - 2.861 (m, 1H), 2.801 - 2.730 (td, J = 3.2, 12.8 Hz, 1H), 2.200 - 2.144 (t, J = 11.2 Hz, 1H), 2.117 - 2.054 (td, J = 3.2, 12.8 Hz, 1H), 1.528 (s, 3H), 1.467 (s, 3H), 1.358 - 1.320 (t, J = 7.2 Hz, 3H).
13C NMR (126 MHz, CDCl3)δ 167.92, 165.27, 146.32, 142.03, 140.48, 138.03, 129.63, 129.37, 127.03, 125.77, 125.60, 125.15, 123.90, 123.63, 122.98, 122.21, 122.08, 61.77, 57.16, 56.94, 53.26, 51.22, 45.39, 41.97, 26.66, 26.55, 22.04, 16.14. 13 C NMR (126 MHz, CDCl 3 )δ 167.92, 165.27, 146.32, 142.03, 140.48, 138.03, 129.63, 129.37, 127.03, 125.77, 125.60, 125.15, 123.90, 123.63, 122.98, 122.21, 122.08, 61.77, 122.08, 122.21, 122.08 , 53.26, 51.22, 45.39, 41.97, 26.66, 26.55, 22.04, 16.14.
MS (ESI) m/z for C28H30F3N3O2S[M+H]+:calcd529.62,found530.2.MS (ESI) m/z for C 28 H 30 F 3 N 3 O 2 S[M+H]+:calcd529.62,found530.2.
제조예 2-12Preparation Example 2-12
제조예 2-1에서 아이오도메탄대신 1-(브로모메틸)-4-시아노벤젠을 사용하고, 반응 후 농축시켜 얻어진 잔사를 메탄올 슬러리, 아이소프로필에테르 슬러리를 연속으로 한 다음 실리카겔 관 크로마토그래피로 정제하였다. 나머지 제조방법은 제조예 2-1과 동일한 방법으로 4-((8-((2-에틸-1-벤조[b]싸이오펜-3-일)메틸)-3,3-디메틸-1,4-디옥소옥타하이드로-2H-피라지노[1,2-a]피라진-2-일)메틸)벤조니트릴(S813)을 제조하였다.In Preparation Example 2-1, 1-(bromomethyl)-4-cyanobenzene was used instead of iodomethane, and the residue obtained by concentration after the reaction was continuously subjected to methanol slurry and isopropyl ether slurry, followed by silica gel column chromatography. was purified with The rest of the preparation method was 4-((8-((2-ethyl-1-benzo[ b ]thiophen-3-yl)methyl)-3,3-dimethyl-1,4 in the same manner as in Preparation Example 2-1. -Dioxooctahydro- 2H -pyrazino[1,2- a ]pyrazin-2-yl)methyl)benzonitrile (S813) was prepared.
[화학식 16] [Formula 16]
S813S813
Figure PCTKR2022006181-appb-img-000061
Figure PCTKR2022006181-appb-img-000061
1H NMR (400 MHz, CDCl3)δ 7.860 - 7.841 (d, J = 8.0 Hz, 1H), 7.783 - 7.764 (d, J = 7.6 Hz, 1H), 7.630 - 7.610 (m, 2H), 7.357 - 7.266 (m, 4H), 4.816 - 4.598 (m, 2H), 4.498 - 4.465 (m, 1H), 4.189 - 4.154 (dd, J = 3.2, 10.8 Hz, 1H), 3.847 - 3.676 (m, 2H), 3.619 - 3.588 (m, 1H), 2.984 - 2.927 (q, J = 6.0, 2H), 2.894 - 2.866 (m, 1H), 2.803 - 2.732 (td, J = 3.2, 12.8 Hz, 1H), 2.190 - 2.134 (t, J = 11.2 Hz, 1H), 2.122 - 2.055 (td, J = 3.2, 12.8 Hz, 1H), 1.519 (s, 3H), 1.463 (s, 3H), 1.357 - 1.319 (t, J = 7.2 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 )δ 7.860 - 7.841 (d, J = 8.0 Hz, 1H), 7.783 - 7.764 (d, J = 7.6 Hz, 1H), 7.630 - 7.610 (m, 2H), 7.357 - 7.266 (m, 4H), 4.816 - 4.598 (m, 2H), 4.498 - 4.465 (m, 1H), 4.189 - 4.154 (dd, J = 3.2, 10.8 Hz, 1H), 3.847 - 3.676 (m, 2H), 3.619 - 3.588 (m, 1H), 2.984 - 2.927 (q, J = 6.0, 2H), 2.894 - 2.866 (m, 1H), 2.803 - 2.732 (td, J = 3.2, 12.8 Hz, 1H), 2.190 - 2.134 (t, J = 11.2 Hz, 1H), 2.122 - 2.055 (td, J = 3.2, 12.8 Hz, 1H), 1.519 (s, 3H), 1.463 (s, 3H), 1.357 - 1.319 (t, J = 7.2) Hz, 3H).
13C NMR (126 MHz, CDCl3)δ 167.75, 165.30, 146.31, 143.40, 140.44, 138.01, 132.44, 127.39, 125.71, 123.89, 123.67, 122.17, 122.07, 118.61, 111.13, 61.76, 57.04, 56.90, 53.23, 51.20, 45.51, 41.98, 26.72, 26.67, 26.50, 26.45, 22.02, 16.13. 13 C NMR (126 MHz, CDCl 3 )δ 167.75, 165.30, 146.31, 143.40, 140.44, 138.01, 132.44, 127.39, 125.71, 123.89, 123.67, 122.17, 122.07, 118.61, 111.13, 61.76, 53.04, 56.90, 57.04 , 45.51, 41.98, 26.72, 26.67, 26.50, 26.45, 22.02, 16.13.
MS (ESI) m/z for C28H30N4O2S[M+H]+:calcd486.63,found487.21.MS (ESI) m/z for C 28 H 30 N 4 O 2 S[M+H] + :calcd486.63,found487.21.
제조예 2-13Preparation Example 2-13
제조예 2-1에서 아이오도메탄대신 1-(브로모메틸)-4-니트로벤젠을 사용하고 제조예 2-1과 동일한 방법으로 2-((2-에틸벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸-8-(4-니트로벤질)헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S814)을 제조하였다.In Preparation Example 2-1, 1-(bromomethyl)-4-nitrobenzene was used instead of iodomethane, and in the same manner as in Preparation Example 2-1, 2-((2-ethylbenzo[ b ]thiophene-3- yl)methyl)-7,7-dimethyl-8-(4-nitrobenzyl)hexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S814) was prepared.
[화학식 17] [Formula 17]
S814S814
Figure PCTKR2022006181-appb-img-000062
Figure PCTKR2022006181-appb-img-000062
1H NMR (500 MHz, CDCl3)δ 8.21 - 8.14 (m, 2H), 7.85 (dd, J = 7.4, 0.6 Hz, 1H), 7.79 - 7.73 (m, 1H), 7.40 - 7.24 (m, 4H), 4.83 (d, J = 16.3 Hz, 1H), 4.65 (d, J = 16.3 Hz, 1H), 4.48 (ddd, J = 13.2, 3.1, 1.8 Hz, 1H), 4.15 (ddd, J = 21.4, 12.6, 5.3 Hz, 1H), 3.83 (d, J = 13.0 Hz, 1H), 3.70 (d, J = 13.0 Hz, 1H), 3.60 (ddd, J = 11.2, 3.3, 1.7 Hz, 1H), 2.96 (q, J = 7.6 Hz, 2H), 2.91 - 2.85 (m, 1H), 2.82 - 2.72 (m, 1H), 2.21 - 2.02 (m, 2H), 1.53 (s, 3H), 1.47 (s, 3H), 1.34 (t, J = 7.6 Hz, 3H). 1 H NMR (500 MHz, CDCl 3 )δ 8.21 - 8.14 (m, 2H), 7.85 (dd, J = 7.4, 0.6 Hz, 1H), 7.79 - 7.73 (m, 1H), 7.40 - 7.24 (m, 4H) ), 4.83 (d, J = 16.3 Hz, 1H), 4.65 (d, J = 16.3 Hz, 1H), 4.48 (ddd, J = 13.2, 3.1, 1.8 Hz, 1H), 4.15 (ddd, J = 21.4, 12.6, 5.3 Hz, 1H), 3.83 (d, J = 13.0 Hz, 1H), 3.70 (d, J = 13.0 Hz, 1H), 3.60 (ddd, J = 11.2, 3.3, 1.7 Hz, 1H), 2.96 ( q, J = 7.6 Hz, 2H), 2.91 - 2.85 (m, 1H), 2.82 - 2.72 (m, 1H), 2.21 - 2.02 (m, 2H), 1.53 (s, 3H), 1.47 (s, 3H) , 1.34 (t, J = 7.6 Hz, 3H).
13C NMR (126 MHz, CDCl3)δ 167.73, 165.36, 147.15, 146.35, 145.44, 140.45, 138.04, 127.53, 125.71, 123.91, 123.67, 122.18, 122.09, 77.30, 77.04, 76.79, 61.83, 57.08, 56.92, 53.25, 51.25, 45.37, 42.02, 26.73, 26.51, 22.04, 16.13. 13 C NMR (126 MHz, CDCl 3 )δ 167.73, 165.36, 147.15, 146.35, 145.44, 140.45, 138.04, 127.53, 125.71, 123.91, 123.67, 122.18, 122.09, 77.30, 77.04, 53.25, 56.83, 57.08, 61.83 , 51.25, 45.37, 42.02, 26.73, 26.51, 22.04, 16.13.
MS (ESI) m/z for C27H30N4O4S[M+H]+:calcd506.62,found507.2.MS (ESI) m/z for C 27 H 30 N 4 O 4 S[M+H]+:calcd506.62,found507.2.
제조예 2-14Preparation Example 2-14
제조예 2-1에서 아이오도메탄대신 1-(브로모메틸)-4-메톡시벤젠을 사용하고 제조예 2-1과 동일한 방법으로 2-((2-에틸벤조[b]싸이오펜-3-일)메틸)-8-(4-메톡시벤질)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S815)을 제조하였다.In Preparation Example 2-1, 1-(bromomethyl)-4-methoxybenzene was used instead of iodomethane, and in the same manner as in Preparation Example 2-1, 2-((2-ethylbenzo[ b ]thiophene-3 -yl)methyl)-8-(4-methoxybenzyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S815) was prepared.
[화학식 18][Formula 18]
S815S815
Figure PCTKR2022006181-appb-img-000063
Figure PCTKR2022006181-appb-img-000063
1H NMR (400 MHz, CDCl3)δ 7.869 - 7.850 (d, J = 8.0 Hz, 1H), 7.779 - 7.760 (d, J = 7.6 Hz, 1H), 7.356 - 7.264 (m, 2H), 7.173 - 7.152 (m, 2H), 6.850 - 6.828 (m, 2H), 4.693 - 4.569 (m, 2H), 4.479 - 4.446 (m, 1H), 4.165 - 4.130 (dd, J = 3.2, 10.8 Hz, 1H), 3.846 - 3.790 (m, 4H), 3.690 - 3.621 (m, 2H), 2.985 - 2.929 (q, J = 6.0, 2H), 2.866 - 2.838 (m, 1H), 2.774 - 2.703 (td, J = 3.2, 12.8 Hz, 1H), 2.194 - 2.139 (t, J = 11.2 Hz, 1H), 2.093 - 2.027 (td, J = 3.2, 12.8 Hz, 1H), 1.626 (s, 1H), 1.527 (s, 3H), 1.438 (s, 3H), 1.357 - 1.319 (t, J = 7.2 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 )δ 7.869 - 7.850 (d, J = 8.0 Hz, 1H), 7.779 - 7.760 (d, J = 7.6 Hz, 1H), 7.356 - 7.264 (m, 2H), 7.173 - 7.152 (m, 2H), 6.850 - 6.828 (m, 2H), 4.693 - 4.569 (m, 2H), 4.479 - 4.446 (m, 1H), 4.165 - 4.130 (dd, J = 3.2, 10.8 Hz, 1H), 3.846 - 3.790 (m, 4H), 3.690 - 3.621 (m, 2H), 2.985 - 2.929 (q, J = 6.0, 2H), 2.866 - 2.838 (m, 1H), 2.774 - 2.703 (td, J = 3.2, 12.8 Hz, 1H), 2.194 - 2.139 (t, J = 11.2 Hz, 1H), 2.093 - 2.027 (td, J = 3.2, 12.8 Hz, 1H), 1.626 (s, 1H), 1.527 (s, 3H), 1.438 (s, 3H), 1.357 - 1.319 (t, J = 7.2 Hz, 3H).
13C NMR (126 MHz, CDCl3)δ 168.26, 168.26, 165.08, 158.67, 146.22, 140.49, 138.00, 130.17, 128.38, 128.31, 125.85, 123.87, 123.63, 122.23, 122.04, 113.95, 77.30, 77.05, 76.79, 61.63, 57.15, 56.92, 55.23, 53.27, 51.24, 45.09, 41.90, 26.62, 26.57, 22.02, 16.12. 13 C NMR (126 MHz, CDCl 3 )δ 168.26, 168.26, 165.08, 158.67, 146.22, 140.49, 138.00, 130.17, 128.38, 128.31, 125.85, 123.87, 123.63, 122.23, 122.04, 113.95, 77.76. , 57.15, 56.92, 55.23, 53.27, 51.24, 45.09, 41.90, 26.62, 26.57, 22.02, 16.12.
MS (ESI) m/z for C28H33N3O3S[M+H]+:calcd491.65,found492.23.MS (ESI) m/z for C 28 H 33 N 3 O 3 S[M+H] + :calcd491.65,found492.23.
제조예 2-15Preparation Example 2-15
제조예 2-1에서 아이오도메탄대신 1-(브로모메틸)-3,5-디메톡시벤젠을 사용하고 제조예 2-1과 동일한 방법으로 8-(3,5-디메톡시벤질)-2-((2-에틸벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S816)을 제조하였다.In Preparation Example 2-1, 1-(bromomethyl)-3,5-dimethoxybenzene was used instead of iodomethane, and 8-(3,5-dimethoxybenzyl)-2 was used in the same manner as in Preparation Example 2-1. -((2-ethylbenzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S816) was prepared.
[화학식 19][Formula 19]
S816S816
Figure PCTKR2022006181-appb-img-000064
Figure PCTKR2022006181-appb-img-000064
1H NMR (400MHz, CDCl3)δ 7.856 (d, J = 8.0 Hz, 1H), 7.770 (d, J = 8.0 Hz, 1H), 7.356 - 7.260 (m, 2H), 7.173 - 7.152 (m, 2H), 6.347 (dd, J = 9.6, 2.0 Hz, 3H), 4.702 (d, J = 16.0 Hz, 1H), 4.546 (d, J = 15.6 Hz, 1H), 4.476 (d, J = 13.2 Hz, 1H), 4.156 (dd, J = 11.2, 3.4 Hz, 1H), 3.835 - 3.803 (m, 2H), 3.728 - 3.658 (m, 2H), 3.644 - 3.617 (m, 1H), 2.953 (q, J = 7.6, 2H), 2.887 - 2.847 (m, 1H), 2.749 (td, J = 12.8, 3.1 Hz, 1H), 2.167 (t, J = 11.0 Hz, 1H), 2.072 (td, J = 11.6, 3.2, Hz, 1H), 1.682 (s, 1H), 1.536 (s, 3H), 1.460 (s, 3H), 1.336 (t, J = 7.6 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 )δ 7.856 (d, J = 8.0 Hz, 1H), 7.770 (d, J = 8.0 Hz, 1H), 7.356 - 7.260 (m, 2H), 7.173 - 7.152 (m, 2H) ), 6.347 (dd, J = 9.6, 2.0 Hz, 3H), 4.702 (d, J = 16.0 Hz, 1H), 4.546 (d, J = 15.6 Hz, 1H), 4.476 (d, J = 13.2 Hz, 1H) ), 4.156 (dd, J = 11.2, 3.4 Hz, 1H), 3.835 - 3.803 (m, 2H), 3.728 - 3.658 (m, 2H), 3.644 - 3.617 (m, 1H), 2.953 (q, J = 7.6 , 2H), 2.887 - 2.847 (m, 1H), 2.749 (td, J = 12.8, 3.1 Hz, 1H), 2.167 (t, J = 11.0 Hz, 1H), 2.072 (td, J = 11.6, 3.2, Hz) , 1H), 1.682 (s, 1H), 1.536 (s, 3H), 1.460 (s, 3H), 1.336 (t, J = 7.6 Hz, 3H).
13C NMR (126 MHz, CDCl3)δ 168.18, 165.09, 160.96, 146.27, 140.47, 138.00, 125.83, 123.88, 123.66, 122.22, 122.04, 105.03, 98.61, 77.31, 77.05, 76.80, 61.70, 57.18, 56.94, 55.29, 53.25, 51.25, 45.63, 41.92, 26.57, 26.51, 26.45, 22.03, 16.13. 13 C NMR (126 MHz, CDCl 3 )δ 168.18, 165.09, 160.96, 146.27, 140.47, 138.00, 125.83, 123.88, 123.66, 122.22, 122.04, 105.03, 98.61, 77.31, 77.05, 76.18, 61.70, 57.18, 56.70, 57.18 , 53.25, 51.25, 45.63, 41.92, 26.57, 26.51, 26.45, 22.03, 16.13.
MS (ESI) m/z for C29H35N3O4S[M+H]+:calcd521.68,found522.24.MS (ESI) m/z for C 29 H 35 N 3 O 4 S[M+H]+:calcd521.68,found522.24.
제조예 2-16Preparation Example 2-16
제조예 2-1에서 아이오도메탄대신 1-(브로모메틸)나프탈렌을 사용하고 제조예 2-1과 동일한 방법으로 2-((2-에틸벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸-8-(나프탈렌-1-일메틸)헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S819)을 제조하였다.In Preparation Example 2-1, 1-(bromomethyl)naphthalene was used instead of iodomethane, and in the same manner as in Preparation Example 2-1, 2-((2-ethylbenzo[ b ]thiophen-3-yl)methyl) -7,7-dimethyl-8-(naphthalen-1-ylmethyl)hexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S819) was prepared.
[화학식 20][Formula 20]
S819S819
Figure PCTKR2022006181-appb-img-000065
Figure PCTKR2022006181-appb-img-000065
1H NMR (400 MHz, CDCl3)δ 7.975 (d, J = 8.0 Hz, 1H), 7.902 - 7.867 (m, 2H), 7.782 - 7.753 (m, 2H), 7.587 - 7.502 (m, 2H), δ 7.426 (t, J = 7.6 Hz, 1H), 7.363 - 7.260 (m, 2H), 7.159 (d, J = 7.2 Hz, 1H), 5.280 - 5.019 (m, 2H), 4.548 - 4.516 (m, 1H), 4.256 (dd, J = 7.6, 3.2 Hz, 1H), 3.860 (d, J = 13.2 Hz, 1H), 3.744 - 3.662 (m, 2H), 2.998 - 2.772 (m, 4H), 2.307 - 2.238 (m, 1H), 2.133 (td, J = 11.6, 3.2 Hz, 1H), 1.530 (d, J = 11.2 Hz, 6H), 1.344 (t, J = 7.60 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 )δ 7.975 (d, J = 8.0 Hz, 1H), 7.902 - 7.867 (m, 2H), 7.782 - 7.753 (m, 2H), 7.587 - 7.502 (m, 2H), δ 7.426 (t, J = 7.6 Hz, 1H), 7.363 - 7.260 (m, 2H), 7.159 (d, J = 7.2 Hz, 1H), 5.280 - 5.019 (m, 2H), 4.548 - 4.516 (m, 1H) ), 4.256 (dd, J = 7.6, 3.2 Hz, 1H), 3.860 (d, J = 13.2 Hz, 1H), 3.744 - 3.662 (m, 2H), 2.998 - 2.772 (m, 4H), 2.307 - 2.238 ( m, 1H), 2.133 (td, J = 11.6, 3.2 Hz, 1H), 1.530 (d, J = 11.2 Hz, 6H), 1.344 (t, J = 7.60 Hz, 3H).
13C NMR (126 MHz, CDCl3)δ 169.84, 166.66, 147.84, 142.05, 139.56, 135.27, 133.46, 131.91, 130.57, 129.11, 127.80, 127.38, 126.86, 125.44, 124.25, 124.14, 123.79, 123.68, 123.61, 78.85, 78.59, 78.34, 63.32, 58.88, 58.62, 58.59, 54.81, 52.75, 44.68, 43.52, 27.88, 27.80, 23.59, 17.72. 13 C NMR (126 MHz, CDCl 3 )δ 169.84, 166.66, 147.84, 142.05, 139.56, 135.27, 133.46, 131.91, 130.57, 129.11, 127.80, 127.38, 126.86, 125.44, 124.25, 124.79, 123.68 123. , 78.59, 78.34, 63.32, 58.88, 58.62, 58.59, 54.81, 52.75, 44.68, 43.52, 27.88, 27.80, 23.59, 17.72.
MS (ESI) m/z for C31H33N3O2S[M+H]+:calcd511.68,found512.23.MS (ESI) m/z for C 31 H 33 N 3 O 2 S[M+H] + :calcd511.68,found512.23.
제조예 2-17Preparation Example 2-17
제조예 2-1에서 아이오도메탄대신 2-(브로모메틸)나프탈렌을 사용하고 제조예 2-1과 동일한 방법으로 2-((2-에틸벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸-8-(나프탈렌-2-일메틸)헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S820)을 제조하였다.In Preparation Example 2-1, 2-(bromomethyl)naphthalene was used instead of iodomethane, and in the same manner as in Preparation Example 2-1, 2-((2-ethylbenzo[ b ]thiophen-3-yl)methyl) -7,7-dimethyl-8-(naphthalen-2-ylmethyl)hexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S820) was prepared.
[화학식 21][Formula 21]
S820S820
Figure PCTKR2022006181-appb-img-000066
Figure PCTKR2022006181-appb-img-000066
1H NMR (400 MHz, CDCl3)δ 7.873 (d, J = 7.6 Hz, 1H), 7.821 - 7.761 (m, 4H), 7.638 (s, 1H), 7.497 - 7.430 (m, 2H), 7.373 - 7.260 (m, 3H), 4.880 - 4.845 (m, 2H), 4.503 - 4.471 (m, 1H), 4.215 (dd, J = 10.8, 3.2 Hz, 1H), 3.864 - 3.663 (m, 3H), 2.969 (q, J = 6.0 Hz, 2H), 2.888 - 2.859 (m, 1H), 2.771 (td, J = 12.8, 3.2 Hz, 1H), 2.221 (t, J = 10.8 Hz, 1H), 2.093 (td, J = 12.0, 3.2 Hz, 1H), 1.557 (s, 3H), 1.460 (s, 3H), 1.346 (t, J = 7.2 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 )δ 7.873 (d, J = 7.6 Hz, 1H), 7.821 - 7.761 (m, 4H), 7.638 (s, 1H), 7.497 - 7.430 (m, 2H), 7.373 - 7.260 (m, 3H), 4.880 - 4.845 (m, 2H), 4.503 - 4.471 (m, 1H), 4.215 (dd, J = 10.8, 3.2 Hz, 1H), 3.864 - 3.663 (m, 3H), 2.969 ( q, J = 6.0 Hz, 2H), 2.888 - 2.859 (m, 1H), 2.771 (td, J = 12.8, 3.2 Hz, 1H), 2.221 (t, J = 10.8 Hz, 1H), 2.093 (td, J ) = 12.0, 3.2 Hz, 1H), 1.557 (s, 3H), 1.460 (s, 3H), 1.346 (t, J = 7.2 Hz, 3H).
13C NMR (126 MHz, CDCl3)δ 168.21, 165.26, 146.26, 140.50, 138.01, 135.60, 133.30, 132.60, 128.42, 127.68, 127.65, 126.19, 125.84, 125.54, 125.14, 123.89, 123.64, 122.23, 122.05, 61.77, 57.20, 57.00, 56.97, 53.28, 51.26, 45.78, 41.94, 26.71, 26.66, 26.61, 26.56, 22.04, 16.11. 13 C NMR (126 MHz, CDCl 3 )δ 168.21, 165.26, 146.26, 140.50, 138.01, 135.60, 133.30, 132.60, 128.42, 127.68, 127.65, 126.19, 125.84, 125.54, 125.14, 123.89, 123.64 , 57.20, 57.00, 56.97, 53.28, 51.26, 45.78, 41.94, 26.71, 26.66, 26.61, 26.56, 22.04, 16.11.
MS (ESI) m/z for C31H33N3O2S[M+H]+:calcd511.68,found512.23.MS (ESI) m/z for C 31 H 33 N 3 O 2 S[M+H] + :calcd511.68,found512.23.
제조예 2-18Preparation Example 2-18
제조예 2-1에서 아이오도메탄대신 4-(브로모메틸)-1,1‘-비페닐을 사용하고 제조예 2-1과 동일한 방법으로 8-([1,1'-비페닐]-4-일메틸)-2-((2-에틸벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S821)을 제조하였다.In Preparation Example 2-1, using 4-(bromomethyl)-1,1'-biphenyl instead of iodomethane, and in the same manner as in Preparation Example 2-1, 8-([1,1'-biphenyl]- 4-ylmethyl)-2-((2-ethylbenzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6 , 9-dione (S821) was prepared.
[화학식 22][Formula 22]
S821S821
Figure PCTKR2022006181-appb-img-000067
Figure PCTKR2022006181-appb-img-000067
1H NMR (400 MHz, CDCl3)δ 7.865 (d, J = 7.6 Hz, 1H), 7.778 - 7.758 (m, 1H), 7.579 - 7.525 (m, 4H), 7.452 - 7.414 (m, 2H), 7.359 - 7.276 (m, 5H), 4.810 - 4.648 (m, 2H), 4.503 - 4.468 (m, 1H), 4.184 (dd, J = 10.8, 3.2 Hz, 1H), 3.856 - 3.638 (m, 3H), 2.962 (q, J = 6.0 Hz, 2H), 2.880 - 2.852 (m, 1H), 2.760 (td, J = 12.8, 3.2 Hz, 1H), 2.200 (t, J = 11.2 Hz, 1H), 2.085 (td, J = 12.8, 3.2 Hz, 1H), 1.565 (s, 3H), 1.484 (s, 3H), 1.341 (t, J = 7.2 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 )δ 7.865 (d, J = 7.6 Hz, 1H), 7.778 - 7.758 (m, 1H), 7.579 - 7.525 (m, 4H), 7.452 - 7.414 (m, 2H), 7.359 - 7.276 (m, 5H), 4.810 - 4.648 (m, 2H), 4.503 - 4.468 (m, 1H), 4.184 (dd, J = 10.8, 3.2 Hz, 1H), 3.856 - 3.638 (m, 3H), 2.962 (q, J = 6.0 Hz, 2H), 2.880 - 2.852 (m, 1H), 2.760 (td, J = 12.8, 3.2 Hz, 1H), 2.200 (t, J = 11.2 Hz, 1H), 2.085 (td) , J = 12.8, 3.2 Hz, 1H), 1.565 (s, 3H), 1.484 (s, 3H), 1.341 (t, J = 7.2 Hz, 3H).
13C NMR (126 MHz, CDCl3)δ 168.20, 165.15, 146.27, 140.71, 140.50, 140.10, 138.02, 137.00, 128.76, 127.33, 127.29, 127.03, 125.84, 123.89, 123.64, 122.24, 122.06, 61.74, 57.21, 56.97, 53.29, 51.27, 45.45, 41.95, 26.71, 26.60, 22.04, 16.13. 13 C NMR (126 MHz, CDCl 3 )δ 168.20, 165.15, 146.27, 140.71, 140.50, 140.10, 138.02, 137.00, 128.76, 127.33, 127.29, 127.03, 125.84, 123.89, 123.64, 122.24, 122.06, 61.74, 57.06, , 53.29, 51.27, 45.45, 41.95, 26.71, 26.60, 22.04, 16.13.
MS (ESI) m/z for C33H35N3O2S[M+H]+:calcd537.72,found538.25.MS (ESI) m/z for C 33 H 35 N 3 O 2 S[M+H] + :calcd537.72,found538.25.
제조예 3-1Preparation 3-1
제조예 1의 단계 7에서 2-에틸-1-벤조[b]싸이오펜-3-카르바알데히드 대신에 벤조[b]싸이오펜-3-카르바알데히드를 사용하고, 반응 후 정제 과정에서 농축 후 잔사를 n-헥산으로 고체화하지 않고 실리카겔 관 크로마토그래피로 정제하였다. 나머지 제조방법은 제조예 1의 단계 7과 동일한 방법으로 2-(벤조[b]싸이오펜-3-일메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S822)을 제조하였다.In step 7 of Preparation Example 1, benzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethyl-1-benzo[ b ]thiophen-3-carbaaldehyde, and after concentration in the purification process after the reaction The residue was purified by silica gel column chromatography without solidifying with n -hexane. The rest of the preparation method is 2-(benzo[ b ]thiophen-3-ylmethyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ] in the same manner as in step 7 of Preparation Example 1. Pyrazine-6,9-dione (S822) was prepared.
[화학식 23][Formula 23]
S822S822
Figure PCTKR2022006181-appb-img-000068
Figure PCTKR2022006181-appb-img-000068
1H NMR (500 MHz, CDCl3)δ 7.99 - 7.91 (m, 1H), 7.89 - 7.81 (m, 1H), 7.41 - 7.31 (m, 3H), 7.27 (d, J = 12.9 Hz, 1H), 4.50 (ddd, J = 13.2, 3.0, 1.9 Hz, 1H), 4.10 (dd, J = 11.0, 3.3 Hz, 1H), 3.87 (dd, J = 13.4, 0.6 Hz, 1H), 3.78 - 3.71 (m, 1H), 3.52 (ddd, J = 11.3, 3.2, 1.8 Hz, 1H), 2.95 - 2.88 (m, 1H), 2.76 (ddd, J = 13.1, 12.2, 3.3 Hz, 1H), 2.16 - 2.01 (m, 2H), 1.48 (d, J = 19.3 Hz, 6H). 1 H NMR (500 MHz, CDCl 3 )δ 7.99 - 7.91 (m, 1H), 7.89 - 7.81 (m, 1H), 7.41 - 7.31 (m, 3H), 7.27 (d, J = 12.9 Hz, 1H), 4.50 (ddd, J = 13.2, 3.0, 1.9 Hz, 1H), 4.10 (dd, J = 11.0, 3.3 Hz, 1H), 3.87 (dd, J = 13.4, 0.6 Hz, 1H), 3.78 - 3.71 (m, 1H), 3.52 (ddd, J = 11.3, 3.2, 1.8 Hz, 1H), 2.95 - 2.88 (m, 1H), 2.76 (ddd, J = 13.1, 12.2, 3.3 Hz, 1H), 2.16 - 2.01 (m, 2H), 1.48 (d, J = 19.3 Hz, 6H).
13C NMR (126 MHz, CDCl3)δ 168.21, 165.52, 140.70, 138.66, 132.09, 124.94, 124.46, 123.96, 122.76, 122.62, 57.44, 56.51, 56.31, 56.04, 51.75, 41.72, 29.16, 28.99. 13 C NMR (126 MHz, CDCl 3 )δ 168.21, 165.52, 140.70, 138.66, 132.09, 124.94, 124.46, 123.96, 122.76, 122.62, 57.44, 56.51, 56.31, 56.04, 51.75, 41.72, 29.16, 28.99.
MS (ESI) m/z for C18H21N3O2S[M+H]+:calcd344.2,found343.45.MS (ESI) m/z for C 18 H 21 N 3 O 2 S[M+H]+:calcd344.2,found343.45.
제조예 3-2Production Example 3-2
제조예 1의 단계 7에서 2-에틸-1-벤조[b]싸이오펜-3-카르바알데히드 대신에 2-메틸벤조[b]싸이오펜-3-카르바알데히드를 사용하고, 반응 후 정제 과정에서 농축 후 잔사를 n-헥산 대신 아세트산 에틸로 고체화하였다. 나머지 제조방법은 제조예 1의 단계 7과 동일한 방법으로 7,7-디메틸-2-((2-메틸벤조[b]싸이오펜-3-일)메틸)헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S823)을 제조하였다.In step 7 of Preparation Example 1, 2-methylbenzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethyl-1-benzo[ b ]thiophen-3-carbaaldehyde, and the purification process after the reaction After concentration in , the residue was solidified with ethyl acetate instead of n -hexane. The rest of the preparation method is 7,7-dimethyl-2-((2-methylbenzo[ b ]thiophen-3-yl)methyl)hexahydro- 2H -pyrazino[1] in the same manner as in step 7 of Preparation Example 1. ,2- a ]pyrazine-6,9-dione (S823) was prepared.
[화학식 24][Formula 24]
S823S823
Figure PCTKR2022006181-appb-img-000069
Figure PCTKR2022006181-appb-img-000069
1H NMR (500 MHz, CDCl3)δ 7.84 - 7.78 (m, 1H), 7.77 - 7.71 (m, 1H), 7.36 - 7.23 (m, 3H), 4.48 (ddd, J = 13.2, 3.1, 1.9 Hz, 1H), 4.06 (dd, J = 11.0, 3.3 Hz, 1H), 3.77 (d, J = 13.0 Hz, 1H), 3.65 (d, J = 13.0 Hz, 1H), 3.49 (ddd, J = 11.2, 3.2, 1.7 Hz, 1H), 2.88 - 2.81 (m, 1H), 2.70 (ddd, J = 13.2, 12.1, 3.3 Hz, 1H), 2.53 (s, 3H), 2.17 - 2.00 (m, 2H), 1.51 (s, 3H), 1.46 (s, 3H). 1 H NMR (500 MHz, CDCl 3 )δ 7.84 - 7.78 (m, 1H), 7.77 - 7.71 (m, 1H), 7.36 - 7.23 (m, 3H), 4.48 (ddd, J = 13.2, 3.1, 1.9 Hz) , 1H), 4.06 (dd, J = 11.0, 3.3 Hz, 1H), 3.77 (d, J = 13.0 Hz, 1H), 3.65 (d, J = 13.0 Hz, 1H), 3.49 (ddd, J = 11.2, 3.2, 1.7 Hz, 1H), 2.88 - 2.81 (m, 1H), 2.70 (ddd, J = 13.2, 12.1, 3.3 Hz, 1H), 2.53 (s, 3H), 2.17 - 2.00 (m, 2H), 1.51 (s, 3H), 1.46 (s, 3H).
13C NMR (126 MHz, CDCl3)δ 168.08, 165.52, 140.45, 138.47, 137.93, 126.75, 123.88, 123.62, 121.97, 121.83, 77.27, 77.01, 76.76, 57.47, 56.54, 56.02, 53.22, 51.46, 41.69, 29.21, 28.96, 14.01. 13 C NMR (126 MHz, CDCl 3 )δ 168.08, 165.52, 140.45, 138.47, 137.93, 126.75, 123.88, 123.62, 121.97, 121.83, 77.27, 77.01, 76.76, 57.47, 56.54, 56.02, 53.69, 29.21. , 28.96, 14.01.
MS (ESI) m/z for C19H23N3O2S[M+H]+:calcd357.47,found358.2.MS (ESI) m/z for C 19 H 23 N 3 O 2 S[M+H] + :calcd357.47,found358.2.
제조예 3-3Production Example 3-3
제조예 1의 단계 7에서 2-에틸벤조[b]싸이오펜-3-카르바알데히드 대신에 2-부틸벤조[b]싸이오펜-3-카르바알데히드를 사용하고, 반응 후 정제 과정에서 농축 후 잔사를 n-헥산 대신 아세트산 에틸로 고체화하였다. 나머지 제조방법은 제조예 1의 단계 7과 동일한 방법으로 2-((2-부틸벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S824)을 제조하였다.In step 7 of Preparation Example 1, 2-butylbenzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophene-3-carbaaldehyde, and after concentration in the purification process after the reaction The residue was solidified with ethyl acetate instead of n -hexane. The rest of the preparation method is 2-((2-butylbenzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1] in the same manner as in step 7 of Preparation Example 1. ,2- a ]pyrazine-6,9-dione (S824) was prepared.
[화학식 25][Formula 25]
S824S824
Figure PCTKR2022006181-appb-img-000070
Figure PCTKR2022006181-appb-img-000070
1H NMR (500 MHz, CDCl3)δ 7.87 - 7.81 (m, 1H), 7.75 (dd, J = 7.4, 0.6 Hz, 1H), 7.38 - 7.23 (m, 3H), 4.48 (ddd, J = 13.2, 2.9, 1.9 Hz, 1H), 4.06 (dd, J = 11.0, 3.3 Hz, 1H), 3.79 (d, J = 13.0 Hz, 1H), 3.65 (d, J = 13.0 Hz, 1H), 3.50 (ddd, J = 11.2, 3.1, 1.6 Hz, 1H), 2.90 (dd, J = 8.4, 6.8 Hz, 2H), 2.87 - 2.80 (m, 1H), 2.74 - 2.64 (m, 1H), 2.13 (t, J = 11.2 Hz, 1H), 2.03 (td, J = 11.7, 3.2 Hz, 1H), 1.69 (dt, J = 15.3, 7.6 Hz, 2H), 1.51 (d, J = 4.7 Hz, 3H), 1.48 - 1.36 (m, 5H), 0.95 (t, J = 7.4 Hz, 3H). 1 H NMR (500 MHz, CDCl 3 )δ 7.87 - 7.81 (m, 1H), 7.75 (dd, J = 7.4, 0.6 Hz, 1H), 7.38 - 7.23 (m, 3H), 4.48 (ddd, J = 13.2) , 2.9, 1.9 Hz, 1H), 4.06 (dd, J = 11.0, 3.3 Hz, 1H), 3.79 (d, J = 13.0 Hz, 1H), 3.65 (d, J = 13.0 Hz, 1H), 3.50 (ddd , J = 11.2, 3.1, 1.6 Hz, 1H), 2.90 (dd, J = 8.4, 6.8 Hz, 2H), 2.87 - 2.80 (m, 1H), 2.74 - 2.64 (m, 1H), 2.13 (t, J = 11.2 Hz, 1H), 2.03 (td, J = 11.7, 3.2 Hz, 1H), 1.69 (dt, J = 15.3, 7.6 Hz, 2H), 1.51 (d, J = 4.7 Hz, 3H), 1.48 - 1.36 (m, 5H), 0.95 (t, J = 7.4 Hz, 3H).
13C NMR (126 MHz, CDCl3)δ 168.14, 165.57, 144.88, 140.46, 138.10, 126.20, 123.84, 123.63, 122.21, 121.99, 57.53, 56.67, 56.06, 53.32, 51.46, 41.77, 33.71, 29.24, 29.02, 28.31, 22.47, 13.92. 13 C NMR (126 MHz, CDCl 3 )δ 168.14, 165.57, 144.88, 140.46, 138.10, 126.20, 123.84, 123.63, 122.21, 121.99, 57.53, 56.67, 56.06, 53.32, 51.46, 41.77, 33.71, 29.24, 29.02, 28.31, 29.02 , 22.47, 13.92.
MS (ESI) m/z for C22H29N3O2S[M+H]+:calcd399.55,found400.4.MS (ESI) m/z for C 22 H 29 N 3 O 2 S[M+H] + :calcd399.55,found400.4.
제조예 3-4Preparation 3-4
제조예 1의 단계 7에서 2-에틸벤조[b]싸이오펜-3-카르바알데히드 대신에 2-헥실벤조[b]싸이오펜-3-카르바알데히드를 사용하고 제조예 1의 단계 7과 동일한 방법으로 2-((2-헥실벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S825)을 제조하였다. In Step 7 of Preparation Example 1, 2-hexylbenzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophene-3-carbaaldehyde, and the same as in Step 7 of Preparation Example 1 Method 2-((2-hexylbenzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S825) was prepared.
[화학식 26][Formula 26]
S825S825
Figure PCTKR2022006181-appb-img-000071
Figure PCTKR2022006181-appb-img-000071
1H NMR (500 MHz, CDCl3)δ 7.87 - 7.81 (m, 1H), 7.78 - 7.72 (m, 1H), 7.33 - 7.25 (m, 3H), 4.48 (ddd, J = 13.2, 3.0, 1.9 Hz, 1H), 4.07 (dd, J = 11.0, 3.3 Hz, 1H), 3.79 (d, J = 13.0 Hz, 1H), 3.65 (d, J = 13.0 Hz, 1H), 3.50 (ddd, J = 11.2, 3.2, 1.6 Hz, 1H), 2.93 - 2.80 (m, 3H), 2.74 - 2.64 (m, 1H), 2.13 (t, J = 11.2 Hz, 1H), 2.03 (td, J = 11.7, 3.1 Hz, 1H), 1.70 (dt, J = 15.3, 7.5 Hz, 2H), 1.52 (s, 3H), 1.47 (s, 3H), 1.44 - 1.17 (m, 6H), 0.92 - 0.81 (m, 3H). 1 H NMR (500 MHz, CDCl 3 )δ 7.87 - 7.81 (m, 1H), 7.78 - 7.72 (m, 1H), 7.33 - 7.25 (m, 3H), 4.48 (ddd, J = 13.2, 3.0, 1.9 Hz) , 1H), 4.07 (dd, J = 11.0, 3.3 Hz, 1H), 3.79 (d, J = 13.0 Hz, 1H), 3.65 (d, J = 13.0 Hz, 1H), 3.50 (ddd, J = 11.2, 3.2, 1.6 Hz, 1H), 2.93 - 2.80 (m, 3H), 2.74 - 2.64 (m, 1H), 2.13 (t, J = 11.2 Hz, 1H), 2.03 (td, J = 11.7, 3.1 Hz, 1H) ), 1.70 (dt, J = 15.3, 7.5 Hz, 2H), 1.52 (s, 3H), 1.47 (s, 3H), 1.44 - 1.17 (m, 6H), 0.92 - 0.81 (m, 3H).
13C NMR (126 MHz, CDCl3)δ 168.13, 165.55, 144.96, 140.46, 138.10, 126.18, 123.84, 123.62, 122.20, 122.00, 77.30, 77.05, 76.79, 57.54, 56.68, 56.07, 53.32, 51.45, 41.77, 31.60, 31.57, 29.26, 29.06, 29.02, 28.61, 22.56, 14.08. 13 C NMR (126 MHz, CDCl 3 )δ 168.13, 165.55, 144.96, 140.46, 138.10, 126.18, 123.84, 123.62, 122.20, 122.00, 77.30, 77.05, 76.79, 57.60.54, 56.68, 56.07, 53.77, 31.45, 53.77, 51.45 , 31.57, 29.26, 29.06, 29.02, 28.61, 22.56, 14.08.
MS (ESI) m/z for C24H33N3O2S[M+H]+:calcd427.61,found428.4.MS (ESI) m/z for C 24 H 33 N 3 O 2 S[M+H]+:calcd427.61,found428.4.
제조예 3-5Preparation 3-5
제조예 1의 단계 7에서 2-에틸벤조[b]싸이오펜-3-카르바알데히드 대신에 2-(사이클로헥실메틸)벤조[b]싸이오펜-3-카르바알데히드를 사용하고 제조예 1의 단계 7과 동일한 방법으로 2-((2-(사이클로헥실메틸)벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S826)을 제조하였다.Using 2-(cyclohexylmethyl)benzo[ b ]thiophene-3-carbaaldehyde instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde in step 7 of Preparation Example 1, In the same manner as in step 7, 2-((2-(cyclohexylmethyl)benzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]Pyrazine-6,9-dione (S826) was prepared.
[화학식 27][Formula 27]
S826S826
Figure PCTKR2022006181-appb-img-000072
Figure PCTKR2022006181-appb-img-000072
1H NMR (500 MHz, CDCl3)δ 7.89 - 7.83 (m, 1H), 7.78 - 7.72 (m, 1H), 7.35 - 7.23 (m, 3H), 4.48 (ddd, J = 13.1, 2.8, 1.9 Hz, 1H), 4.07 (dd, J = 11.0, 3.3 Hz, 1H), 3.79 (d, J = 13.0 Hz, 1H), 3.64 (d, J = 13.0 Hz, 1H), 3.50 (ddd, J = 11.2, 3.0, 1.5 Hz, 1H), 2.87 - 2.75 (m, 3H), 2.68 (td, J = 13.1, 3.3 Hz, 1H), 2.14 (t, J = 11.2 Hz, 1H), 2.08 - 1.98 (m, 1H), 1.82 - 1.61 (m, 6H), 1.52 (s, 3H), 1.47 (s, 3H), 1.28 - 1.11 (m, 3H), 1.05 - 0.92 (m, 2H). 1 H NMR (500 MHz, CDCl 3 )δ 7.89 - 7.83 (m, 1H), 7.78 - 7.72 (m, 1H), 7.35 - 7.23 (m, 3H), 4.48 (ddd, J = 13.1, 2.8, 1.9 Hz) , 1H), 4.07 (dd, J = 11.0, 3.3 Hz, 1H), 3.79 (d, J = 13.0 Hz, 1H), 3.64 (d, J = 13.0 Hz, 1H), 3.50 (ddd, J = 11.2, 3.0, 1.5 Hz, 1H), 2.87 - 2.75 (m, 3H), 2.68 (td, J = 13.1, 3.3 Hz, 1H), 2.14 (t, J = 11.2 Hz, 1H), 2.08 - 1.98 (m, 1H) ), 1.82 - 1.61 (m, 6H), 1.52 (s, 3H), 1.47 (s, 3H), 1.28 - 1.11 (m, 3H), 1.05 - 0.92 (m, 2H).
13C NMR (126 MHz, CDCl3)δ 168.12, 165.54, 143.50, 140.42, 138.26, 126.99, 123.79, 123.66, 122.29, 121.91, 77.30, 77.04, 76.79, 57.54, 56.69, 56.08, 53.43, 51.42, 41.77, 40.29, 36.27, 33.28, 33.25, 29.28, 29.04, 26.37, 26.20. 13 C NMR (126 MHz, CDCl 3 )δ 168.12, 165.54, 143.50, 140.42, 138.26, 126.99, 123.79, 123.66, 122.29, 121.91, 77.30, 77.04, 76.79, 57.54, 56.69, 56.08, 53.77, 51.42, 53.77, 51.42 , 36.27, 33.28, 33.25, 29.28, 29.04, 26.37, 26.20.
MS (ESI) m/z for C25H33N3O2S[M+H]+:calcd439.62,found440.4.MS (ESI) m/z for C 25 H 33 N 3 O 2 S[M+H] + :calcd439.62,found440.4.
제조예 3-6Preparation 3-6
제조예 1의 단계 7에서 2-에틸벤조[b]싸이오펜-3-카르바알데히드 대신에 2-벤질벤조[b]싸이오펜-3-카르바알데히드를 사용하고 제조예 1의 단계 7과 동일한 방법으로 2-((2-벤질벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S827)을 제조하였다.In step 7 of Preparation Example 1, 2-benzylbenzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophene-3-carbaaldehyde, and the same as in Step 7 of Preparation Example 1 Method 2-((2-benzylbenzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S827) was prepared.
[화학식 28][Formula 28]
S827S827
Figure PCTKR2022006181-appb-img-000073
Figure PCTKR2022006181-appb-img-000073
1H NMR (500 MHz, CDCl3)δ 7.90 - 7.84 (m, 1H), 7.73 - 7.72 (m, 1H), 7.37 - 7.14 (m, 8H), 4.46 (ddd, J = 13.1, 2.9, 1.9 Hz, 1H), 4.32 - 4.21 (m, 2H), 4.02 (dd, J = 11.0, 3.3 Hz, 1H), 3.83 (d, J = 13.1 Hz, 1H), 3.71 (d, J = 13.1 Hz, 1H), 3.48 (ddd, J = 11.2, 3.1, 1.6 Hz, 1H), 2.83 (dd, J = 10.1, 1.5 Hz, 1H), 2.70 - 2.60 (m, 1H), 2.09 (t, J = 11.1 Hz, 1H), 2.05 - 1.97 (m, 1H), 1.51 (s, 3H), 1.46 (s, 3H). 1 H NMR (500 MHz, CDCl 3 )δ 7.90 - 7.84 (m, 1H), 7.73 - 7.72 (m, 1H), 7.37 - 7.14 (m, 8H), 4.46 (ddd, J = 13.1, 2.9, 1.9 Hz) , 1H), 4.32 - 4.21 (m, 2H), 4.02 (dd, J = 11.0, 3.3 Hz, 1H), 3.83 (d, J = 13.1 Hz, 1H), 3.71 (d, J = 13.1 Hz, 1H) , 3.48 (ddd, J = 11.2, 3.1, 1.6 Hz, 1H), 2.83 (dd, J = 10.1, 1.5 Hz, 1H), 2.70 - 2.60 (m, 1H), 2.09 (t, J = 11.1 Hz, 1H) ), 2.05 - 1.97 (m, 1H), 1.51 (s, 3H), 1.46 (s, 3H).
13C NMR (126 MHz, CDCl3)δ 168.13, 165.47, 142.60, 140.34, 139.51, 138.61, 128.58, 128.55, 127.26, 126.67, 123.98, 123.94, 122.28, 122.09, 77.30, 77.04, 76.79, 57.47, 56.56, 56.06, 53.38, 51.49, 41.70, 34.49, 29.25, 29.00. 13 C NMR (126 MHz, CDCl 3 )δ 168.13, 165.47, 142.60, 140.34, 139.51, 138.61, 128.58, 128.55, 127.26, 126.67, 123.98, 123.94, 122.28, 122.09, 77.30, 06.04, 76.56, 57.47, 56.79 , 53.38, 51.49, 41.70, 34.49, 29.25, 29.00.
MS (ESI) m/z for C25H27N3O2S[M+H]+:calcd433.57,found434.18.MS (ESI) m/z for C 25 H 27 N 3 O 2 S[M+H] + :calcd433.57,found434.18.
제조예 3-7Preparation 3-7
제조예 1의 단계 7에서 2-에틸벤조[b]싸이오펜-3-카르바알데히드 대신에 2-(4-메틸벤질벤조[b]싸이오펜-3-카르바알데히드를 사용하고 제조예 1의 단계 7과 동일한 방법으로 7,7-디메틸-2-((2-(4-메틸벤질)벤조[b]싸이오펜-3-일)메틸)헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S828)을 제조하였다.In step 7 of Preparation Example 1, 2-(4-methylbenzylbenzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophene-3-carbaaldehyde, and In the same manner as in step 7, 7,7-dimethyl-2-((2-(4-methylbenzyl)benzo[ b ]thiophen-3-yl)methyl)hexahydro- 2H -pyrazino[1,2- a ] Pyrazine-6,9-dione (S828) was prepared.
[화학식 29][Formula 29]
S828S828
Figure PCTKR2022006181-appb-img-000074
Figure PCTKR2022006181-appb-img-000074
1H NMR (500 MHz, CDCl3)δ 7.86 (d, J = 7.7 Hz, 1H), 7.74 - 7.68 (m, 1H), 7.35 - 7.29 (m, 1H), 7.29 - 7.23 (m, 1H), 7.21 (s, 1H), 7.12 - 7.08 (m, 4H), 4.46 (ddd, J = 13.1, 2.9, 1.9 Hz, 1H), 4.21 (t, J = 9.9 Hz, 2H), 4.03 (dt, J = 10.3, 5.2 Hz, 1H), 3.83 (d, J = 13.1 Hz, 1H), 3.71 (d, J = 13.1 Hz, 1H), 3.49 (ddd, J = 11.2, 3.1, 1.6 Hz, 1H), 2.84 (dd, J = 10.1, 1.5 Hz, 1H), 2.72 - 2.62 (m, 1H), 2.33 - 2.27 (m, 3H), 2.14 - 1.96 (m, 2H), 1.53 - 1.44 (m, 6H). 1 H NMR (500 MHz, CDCl 3 )δ 7.86 (d, J = 7.7 Hz, 1H), 7.74 - 7.68 (m, 1H), 7.35 - 7.29 (m, 1H), 7.29 - 7.23 (m, 1H), 7.21 (s, 1H), 7.12 - 7.08 (m, 4H), 4.46 (ddd, J = 13.1, 2.9, 1.9 Hz, 1H), 4.21 (t, J = 9.9 Hz, 2H), 4.03 (dt, J = 10.3, 5.2 Hz, 1H), 3.83 (d, J = 13.1 Hz, 1H), 3.71 (d, J = 13.1 Hz, 1H), 3.49 (ddd, J = 11.2, 3.1, 1.6 Hz, 1H), 2.84 ( dd, J = 10.1, 1.5 Hz, 1H), 2.72 - 2.62 (m, 1H), 2.33 - 2.27 (m, 3H), 2.14 - 1.96 (m, 2H), 1.53 - 1.44 (m, 6H).
13C NMR (126 MHz, CDCl3)δ 168.13, 165.47, 143.11, 140.38, 138.60, 136.45, 136.26, 129.27, 128.46, 127.04, 123.95, 123.88, 122.27, 122.09, 57.50, 56.58, 56.08, 53.39, 51.52, 41.73, 34.11, 29.27, 29.02, 21.04. 13 C NMR (126 MHz, CDCl 3 )δ 168.13, 165.47, 143.11, 140.38, 138.60, 136.45, 136.26, 129.27, 128.46, 127.04, 123.95, 123.88, 122.27, 122.09, 57.50, 56.58, 51.52, 53.39, 51.52, 53.39 , 34.11, 29.27, 29.02, 21.04.
MS (ESI) m/z for C26H29N3O2S[M+H]+:calcd447.6,found448.2.MS (ESI) m/z for C 26 H 29 N 3 O 2 S[M+H]+:calcd447.6,found448.2.
제조예 3-8Preparation 3-8
제조예 1의 단계 7에서 2-에틸벤조[b]싸이오펜-3-카르바알데히드 대신에 2-(4-클로로벤질)벤조[b]싸이오펜-3-카르바알데히드를 사용하고, 반응 후 정제 과정에서 농축 후 잔사를 n-헥산으로 고체화하지 않고 실리카겔 관 크로마토그래피로 정제하였다. 나머지 제조방법은 제조예 1의 단계 7과 동일한 방법으로 2-((2-(4-클로로벤질)벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S829)을 제조하였다.In step 7 of Preparation Example 1, 2-(4-chlorobenzyl)benzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and after the reaction After concentration in the purification process, the residue was purified by silica gel column chromatography without solidifying with n -hexane. The rest of the preparation method is 2-((2-(4-chlorobenzyl)benzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H in the same manner as in step 7 of Preparation Example 1. -Pyrazino[1,2- a ]pyrazine-6,9-dione (S829) was prepared.
[화학식 30][Formula 30]
S829S829
Figure PCTKR2022006181-appb-img-000075
Figure PCTKR2022006181-appb-img-000075
1H NMR (500 MHz, CDCl3)δ 7.86 (d, J = 7.8 Hz, 1H), 7.77 - 7.71 (m, 1H), 7.38 - 7.22 (m, 4H), 7.17 (dd, J = 6.4, 4.5 Hz, 2H), 6.84 (s, 1H), 4.48 (ddd, J = 13.2, 2.9, 1.9 Hz, 1H), 4.30 - 4.18 (m, 2H), 4.00 (dd, J = 11.0, 3.3 Hz, 1H), 3.80 (d, J = 13.1 Hz, 1H), 3.71 (d, J = 13.1 Hz, 1H), 3.45 (ddd, J = 11.2, 3.1, 1.6 Hz, 1H), 2.85 (dd, J = 10.1, 1.5 Hz, 1H), 2.72 - 2.62 (m, 1H), 2.10 - 1.99 (m, 2H), 1.51 (s, 3H), 1.47 (s, 3H). 1 H NMR (500 MHz, CDCl 3 )δ 7.86 (d, J = 7.8 Hz, 1H), 7.77 - 7.71 (m, 1H), 7.38 - 7.22 (m, 4H), 7.17 (dd, J = 6.4, 4.5 Hz, 2H), 6.84 (s, 1H), 4.48 (ddd, J = 13.2, 2.9, 1.9 Hz, 1H), 4.30 - 4.18 (m, 2H), 4.00 (dd, J = 11.0, 3.3 Hz, 1H) , 3.80 (d, J = 13.1 Hz, 1H), 3.71 (d, J = 13.1 Hz, 1H), 3.45 (ddd, J = 11.2, 3.1, 1.6 Hz, 1H), 2.85 (dd, J = 10.1, 1.5) Hz, 1H), 2.72 - 2.62 (m, 1H), 2.10 - 1.99 (m, 2H), 1.51 (s, 3H), 1.47 (s, 3H).
13C NMR (126 MHz, CDCl3)δ 168.07, 165.25, 141.84, 140.26, 138.59, 138.00, 132.51, 129.89, 128.73, 127.54, 124.13, 122.32, 122.16, 57.48, 56.47, 56.15, 53.39, 51.67, 41.72, 33.84, 29.32, 29.10. 13 C NMR (126 MHz, CDCl 3 )δ 168.07, 165.25, 141.84, 140.26, 138.59, 138.00, 132.51, 129.89, 128.73, 127.54, 124.13, 122.32, 122.16, 57.48, 56.47, 56.15, 53.39, 51.67, 41.72, 33.67 , 29.32, 29.10.
MS (ESI) m/z for C25H26ClN3O2S[M+H]+:calcd468.01,found468.15.MS (ESI) m/z for C 25 H 26 ClN 3 O 2 S[M+H] + :calcd468.01,found468.15.
제조예 3-9Preparation 3-9
제조예 1의 단계 7에서 2-에틸벤조[b]싸이오펜-3-카르바알데히드 대신에 2-(4-브로모벤질)벤조[b]싸이오펜-3-카르바알데히드를 사용하고, 반응 후 정제 과정에서 농축 후 잔사를 n-헥산 대신 아세트산 에틸로 고체화하였다. 나머지 제조방법은 제조예 1의 단계 7과 동일한 방법으로 2-((2-(4-브로모벤질)벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S830)을 제조하였다.In step 7 of Preparation Example 1, 2-(4-bromobenzyl)benzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and the reaction After concentration in the subsequent purification process, the residue was solidified with ethyl acetate instead of n -hexane. The rest of the preparation method is 2-((2-(4-bromobenzyl)benzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro-2 in the same manner as in step 7 of Preparation Example 1. H -pyrazino[1,2- a ]pyrazine-6,9-dione (S830) was prepared.
[화학식 31][Formula 31]
S830S830
Figure PCTKR2022006181-appb-img-000076
Figure PCTKR2022006181-appb-img-000076
1H NMR (500 MHz, CDCl3)δ 7.89 - 7.83 (m, 1H), 7.74 (dd, J = 7.4, 0.6 Hz, 1H), 7.44 - 7.23 (m, 4H), 7.14 - 7.08 (m, 3H), 4.48 (ddd, J = 13.1, 2.9, 1.9 Hz, 1H), 4.28 - 4.16 (m, 2H), 4.00 (dd, J = 11.0, 3.3 Hz, 1H), 3.79 (d, J = 13.1 Hz, 1H), 3.70 (d, J = 13.1 Hz, 1H), 3.44 (ddd, J = 11.2, 3.1, 1.6 Hz, 1H), 2.84 (dd, J = 10.1, 1.5 Hz, 1H), 2.72 - 2.62 (m, 1H), 2.09 - 1.99 (m, 2H), 1.51 (s, 3H), 1.46 (s, 3H). 1 H NMR (500 MHz, CDCl 3 )δ 7.89 - 7.83 (m, 1H), 7.74 (dd, J = 7.4, 0.6 Hz, 1H), 7.44 - 7.23 (m, 4H), 7.14 - 7.08 (m, 3H) ), 4.48 (ddd, J = 13.1, 2.9, 1.9 Hz, 1H), 4.28 - 4.16 (m, 2H), 4.00 (dd, J = 11.0, 3.3 Hz, 1H), 3.79 (d, J = 13.1 Hz, 1H), 3.70 (d, J = 13.1 Hz, 1H), 3.44 (ddd, J = 11.2, 3.1, 1.6 Hz, 1H), 2.84 (dd, J = 10.1, 1.5 Hz, 1H), 2.72 - 2.62 (m) , 1H), 2.09 - 1.99 (m, 2H), 1.51 (s, 3H), 1.46 (s, 3H).
13C NMR (126 MHz, CDCl3)δ 168.09, 165.37, 141.70, 140.23, 138.57, 138.51, 131.67, 130.26, 127.56, 124.13, 122.31, 122.15, 120.53, 57.44, 56.45, 56.10, 53.36, 51.66, 41.69, 33.89, 29.27, 29.03. 13 C NMR (126 MHz, CDCl 3 )δ 168.09, 165.37, 141.70, 140.23, 138.57, 138.51, 131.67, 130.26, 127.56, 124.13, 122.31, 122.15, 120.53, 57.44, 56.45, 56.10, 53.69, 31.89, 41.69, 31.89, , 29.27, 29.03.
MS (ESI) m/z for C25H26BrN3O2S[M+H]+:calcd512.47,found512.09.MS (ESI) m/z for C 25 H 26 BrN 3 O 2 S[M+H] + :calcd512.47,found512.09.
제조예 3-10Preparation 3-10
제조예 1의 단계 7에서 2-에틸벤조[b]싸이오펜-3-카르바알데히드 대신에 2-(4-플루오르벤질)벤조[b]싸이오펜-3-카르바알데히드를 사용하고, 반응 후 정제 과정에서 농축 후 잔사를 n-헥산으로 고체화하지 않고 실리카겔 관 크로마토그래피로 정제하였다. 나머지 제조방법은 제조예 1의 단계 7과 동일한 방법으로 2-((2-(4-플루오르벤질)벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S831)을 제조하였다.In step 7 of Preparation Example 1, 2-(4-fluorobenzyl)benzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and after the reaction After concentration in the purification process, the residue was purified by silica gel column chromatography without solidifying with n -hexane. The rest of the preparation method is 2-((2-(4-fluorobenzyl)benzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H in the same manner as in step 7 of Preparation Example 1. -Pyrazino[1,2- a ]pyrazine-6,9-dione (S831) was prepared.
[화학식 32][Formula 32]
S831S831
Figure PCTKR2022006181-appb-img-000077
Figure PCTKR2022006181-appb-img-000077
1H NMR (500 MHz, CDCl3)δ 7.87 (dd, J = 7.5, 0.6 Hz, 1H), 7.73 (dd, J = 7.5, 0.7 Hz, 1H), 7.37 - 7.23 (m, 2H), 7.23 - 7.13 (m, 3H), 7.01 - 6.94 (m, 2H), 4.48 (ddd, J = 13.2, 2.9, 1.9 Hz, 1H), 4.30 - 4.18 (m, 2H), 4.02 (dd, J = 11.0, 3.3 Hz, 1H), 3.81 (d, J = 13.1 Hz, 1H), 3.71 (d, J = 13.1 Hz, 1H), 3.46 (ddd, J = 11.2, 3.1, 1.6 Hz, 1H), 2.84 (dd, J = 10.1, 1.5 Hz, 1H), 2.72 - 2.62 (m, 1H), 2.12 - 1.99 (m, 2H), 1.51 (s, 3H), 1.46 (s, 3H). 1 H NMR (500 MHz, CDCl 3 )δ 7.87 (dd, J = 7.5, 0.6 Hz, 1H), 7.73 (dd, J = 7.5, 0.7 Hz, 1H), 7.37 - 7.23 (m, 2H), 7.23 - 7.13 (m, 3H), 7.01 - 6.94 (m, 2H), 4.48 (ddd, J = 13.2, 2.9, 1.9 Hz, 1H), 4.30 - 4.18 (m, 2H), 4.02 (dd, J = 11.0, 3.3) Hz, 1H), 3.81 (d, J = 13.1 Hz, 1H), 3.71 (d, J = 13.1 Hz, 1H), 3.46 (ddd, J = 11.2, 3.1, 1.6 Hz, 1H), 2.84 (dd, J ) = 10.1, 1.5 Hz, 1H), 2.72 - 2.62 (m, 1H), 2.12 - 1.99 (m, 2H), 1.51 (s, 3H), 1.46 (s, 3H).
13C NMR (126 MHz, CDCl3)δ 168.13, 165.38, 162.64, 160.69, 142.40, 140.30, 138.57, 135.20, 130.06, 129.99, 127.34, 124.08, 122.31, 122.14, 115.50, 115.33, 57.48, 56.53, 56.10, 53.37, 51.62, 41.71, 33.70, 29.27, 29.02. 13 C NMR (126 MHz, CDCl 3 )δ 168.13, 165.38, 162.64, 160.69, 142.40, 140.30, 138.57, 135.20, 130.06, 129.99, 127.34, 124.08, 122.31, 122.14, 115.50, 115.33, 56.48, 56.53, 56.48, 56.53 , 51.62, 41.71, 33.70, 29.27, 29.02.
MS (ESI) m/z for C25H26FN3O2S[M+H]+:calcd451.56,found452.18.MS (ESI) m/z for C 25 H 26 FN 3 O 2 S[M+H]+:calcd451.56,found452.18.
제조예 3-11Production Example 3-11
제조예 1의 단계 7에서 2-에틸벤조[b]싸이오펜-3-카르바알데히드 대신에 2-([1,1'-비페닐]-4-일메틸)벤조[b]싸이오펜-3-카르바알데히드를 사용하고, 반응 후 정제 과정에서 농축 후 잔사를 n-헥산으로 고체화하지 않고 실리카겔 관 크로마토그래피로 정제하였다. 나머지 제조방법은 제조예 1의 단계 7과 동일한 방법으로 2-(([1,1'-비페닐]-4-일메틸)벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S832)을 제조하였다.2-([1,1'-biphenyl]-4-ylmethyl)benzo[b]thiophene-3 instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde in step 7 of Preparation Example 1 -Carbaaldehyde was used, and the residue after concentration in the purification process after reaction was purified by silica gel column chromatography without solidifying with n -hexane. The rest of the preparation method is 2-(([1,1'-biphenyl]-4-ylmethyl)benzo[ b ]thiophen-3-yl)methyl)-7,7 in the same manner as in Step 7 of Preparation Example 1. -Dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S832) was prepared.
[화학식 33][Formula 33]
S832S832
Figure PCTKR2022006181-appb-img-000078
Figure PCTKR2022006181-appb-img-000078
1H NMR (500 MHz, CDCl3)δ 7.91 - 7.85 (m, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.59 - 7.49 (m, 4H), 7.44 - 7.38 (m, 2H), 7.36 - 7.23 (m, 5H), 7.06 (s, 1H), 4.47 (ddd, J = 13.0, 2.7, 1.9 Hz, 1H), 4.36 - 4.25 (m, 2H), 4.01 (dd, J = 11.0, 3.3 Hz, 1H), 3.84 (d, J = 13.1 Hz, 1H), 3.74 (d, J = 13.1 Hz, 1H), 3.47 (ddd, J = 11.1, 2.9, 1.5 Hz, 1H), 2.90 - 2.83 (m, 1H), 2.68 (td, J = 13.1, 3.3 Hz, 1H), 2.05 (dt, J = 12.5, 7.2 Hz, 2H), 1.48 (s, 3H), 1.44 (s, 3H). 1 H NMR (500 MHz, CDCl 3 )δ 7.91 - 7.85 (m, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.59 - 7.49 (m, 4H), 7.44 - 7.38 (m, 2H), 7.36 - 7.23 (m, 5H), 7.06 (s, 1H), 4.47 (ddd, J = 13.0, 2.7, 1.9 Hz, 1H), 4.36 - 4.25 (m, 2H), 4.01 (dd, J = 11.0, 3.3 Hz, 1H), 3.84 (d, J = 13.1 Hz, 1H), 3.74 (d, J = 13.1 Hz, 1H), 3.47 (ddd, J = 11.1, 2.9, 1.5 Hz, 1H), 2.90 - 2.83 (m , 1H), 2.68 (td, J = 13.1, 3.3 Hz, 1H), 2.05 (dt, J = 12.5, 7.2 Hz, 2H), 1.48 (s, 3H), 1.44 (s, 3H).
13C NMR (126 MHz, CDCl3)δ 168.09, 165.36, 142.44, 140.69, 140.36, 139.58, 138.62, 138.59, 128.97, 128.74, 127.36, 127.28, 127.22, 126.99, 124.03, 124.00, 122.31, 122.13, 57.48, 56.48, 56.07, 53.41, 51.63, 41.72, 34.14, 29.25, 29.02. 13 C NMR (126 MHz, CDCl 3 )δ 168.09, 165.36, 142.44, 140.69, 140.36, 139.58, 138.62, 138.59, 128.97, 128.74, 127.36, 127.28, 127.22, 126.99, 124.03, 124.00, 122.31, 122.13, 57.48 , 56.07, 53.41, 51.63, 41.72, 34.14, 29.25, 29.02.
MS (ESI) m/z for C31H31N3O2S[M+H]+:calcd509.67,found510.22.MS (ESI) m/z for C 31 H 31 N 3 O 2 S[M+H] + :calcd509.67,found510.22.
제조예 3-12Production Example 3-12
제조예 1의 단계 7에서 2-에틸벤조[b]싸이오펜-3-카르바알데히드 대신에 1-메틸-1H-인돌-3-카르바알데히드를 사용하고 제조예 1의 단계 7과 동일한 방법으로 7,7-디메틸-2-((1-메틸-1H-인돌-3-일)메틸)헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S833)을 제조하였다.In Step 7 of Preparation Example 1, 1-methyl- 1H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and the same method as in Step 7 of Preparation Example 1 to 7,7-dimethyl-2-((1-methyl- 1H -indol-3-yl)methyl)hexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S833 ) was prepared.
[화학식 34][Formula 34]
S833S833
Figure PCTKR2022006181-appb-img-000079
Figure PCTKR2022006181-appb-img-000079
1H NMR (400 MHz, CDCl3)δ 7.694 (d, J = 8.0 Hz, 1H), 7.318 - 7.197 (m, 3H), 7.135 - 7.098 (m, 1H), 6.975 (s, 1H), 4.491 (d, J = 13.2 Hz, 1H), 4.090 (dd, J = 10.8, 3.2 Hz, 1H), 3.850 - 3.702 (m, 5H), 3.537 -3.506 (m, 1H), 2.964 (d, J = 10.6 Hz, 1H), 2.767 (td, J = 12.8, 3.2 Hz, 1H), 2.097 - 1.998 (m, 2H), 1.472 (d, J = 10 Hz, 6H). 1 H NMR (400 MHz, CDCl 3 )δ 7.694 (d, J = 8.0 Hz, 1H), 7.318 - 7.197 (m, 3H), 7.135 - 7.098 (m, 1H), 6.975 (s, 1H), 4.491 ( d, J = 13.2 Hz, 1H), 4.090 (dd, J = 10.8, 3.2 Hz, 1H), 3.850 - 3.702 (m, 5H), 3.537 -3.506 (m, 1H), 2.964 (d, J = 10.6 Hz) , 1H), 2.767 (td, J = 12.8, 3.2 Hz, 1H), 2.097 - 1.998 (m, 2H), 1.472 (d, J = 10 Hz, 6H).
13C NMR (126 MHz, CDCl3)δ 168.15, 165.68, 137.12, 128.49, 128.17, 121.73, 119.53, 119.13, 109.93, 109.22, 57.53, 56.28, 56.01, 53.23, 51.52, 41.80, 32.69, 29.16, 29.00. 13 C NMR (126 MHz, CDCl 3 )δ 168.15, 165.68, 137.12, 128.49, 128.17, 121.73, 119.53, 119.13, 109.93, 109.22, 57.53, 56.28, 56.01, 53.23, 51.52, 41.80, 32.69, 29.16, 29.00.
MS (ESI) m/z for C19H24N4O2[M+H]+:calcd340.43,found341.2.MS (ESI) m/z for C 19 H 24 N 4 O 2 [M+H] + :calcd340.43,found341.2.
제조예 4-1Preparation 4-1
제조예 1의 단계 7에서 2-에틸벤조[b]싸이오펜-3-카르바알데히드 대신에 1-(사이클로헥실메틸)-1H-인돌-3-카르바알데히드를 사용하고 제조예 1의 단계 7과 동일한 방법으로 2-((1-사이클로헥실메틸)-1H-인돌-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S834)을 제조하였다.In step 7 of Preparation Example 1, 1-(cyclohexylmethyl)-1H-indole-3- carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and the step of Preparation Example 1 In the same manner as 7, 2-((1-cyclohexylmethyl)-1H-indol-3-yl)methyl) -7,7 -dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine- 6,9-dione (S834) was prepared.
[화학식 35][Formula 35]
S834S834
Figure PCTKR2022006181-appb-img-000080
Figure PCTKR2022006181-appb-img-000080
1H NMR (400 MHz, CDCl3)δ 7.696 (d, J = 8.0 Hz, 1H), 7.316 (d, J = 8.4 Hz, 1H), 7.210 (td, J = 7.2, 1.2 Hz, 1H), 7.101 (td, J = 7.2, 0.8 Hz, 1H) 7.007 (s, 1H), 6.976 (s, 1H), 4.503 - 4.471 (m, 1H), 4.103 (dd, J = 11.2, 3.4 Hz, 1H), 3.898 (d, J = 7.2 Hz, 2H), 3.856 (d, J = 13.6 Hz, 1H), 3.710 (d, J = 13.2 Hz, 1H), 3.545 - 3.513 (m, 1H), 2.964 - 2.936 (m, 1H), 2.767 (td, J = 12.8, 3.2 Hz, 1H), 2.107 - 1.984 (m, 2H), 1.882 - 1.808 (m, 1H), 1.708 - 1.604 (m, 5H), 1.475 (d, J = 8.8 Hz, 6H), 1.192 - 1.146 (m, 3H), 1.024 - 0.936 (m, 2H). 1 H NMR (400 MHz, CDCl 3 )δ 7.696 (d, J = 8.0 Hz, 1H), 7.316 (d, J = 8.4 Hz, 1H), 7.210 (td, J = 7.2, 1.2 Hz, 1H), 7.101 (td, J = 7.2, 0.8 Hz, 1H) 7.007 (s, 1H), 6.976 (s, 1H), 4.503 - 4.471 (m, 1H), 4.103 (dd, J = 11.2, 3.4 Hz, 1H), 3.898 (d, J = 7.2 Hz, 2H), 3.856 (d, J = 13.6 Hz, 1H), 3.710 (d, J = 13.2 Hz, 1H), 3.545 - 3.513 (m, 1H), 2.964 - 2.936 (m, 1H), 2.767 (td, J = 12.8, 3.2 Hz, 1H), 2.107 - 1.984 (m, 2H), 1.882 - 1.808 (m, 1H), 1.708 - 1.604 (m, 5H), 1.475 (d, J = 8.8 Hz, 6H), 1.192 - 1.146 (m, 3H), 1.024 - 0.936 (m, 2H).
13C NMR (126 MHz, CDCl3)δ 168.14, 165.70, 136.76, 128.26, 128.16, 121.51, 119.58, 118.97, 109.68, 109.55, 57.56, 56.35, 56.02, 53.32, 52.88, 51.45, 41.82, 38.73, 31.08, 29.20, 29.00, 26.28, 25.70. 13 C NMR (126 MHz, CDCl 3 )δ 168.14, 165.70, 136.76, 128.26, 128.16, 121.51, 119.58, 118.97, 109.68, 109.55, 57.56, 56.35, 56.02, 53.32, 52.88, 51.45, 41.82, 29.73, 31.08 , 29.00, 26.28, 25.70.
MS (ESI) m/z for C25H34N4O2[M+H]+:calcd422.57,found423.4.MS (ESI) m/z for C 25 H 34 N 4 O 2 [M+H]+:calcd422.57,found423.4.
제조예 4-2Preparation 4-2
제조예 1의 단계 7에서 2-에틸벤조[b]싸이오펜-3-카르바알데히드 대신에 1-벤질-1H-인돌-3-카르바알데히드를 사용하고 제조예 1의 단계 7과 동일한 방법으로 2-((1-벤질-1H-인돌-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S835)을 제조하였다.In step 7 of Preparation Example 1, 1-benzyl- 1H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and the same method as in Step 7 of Preparation Example 1 as 2-((1-benzyl- 1H -indol-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S835 ) was prepared.
[화학식 36][Formula 36]
S835S835
Figure PCTKR2022006181-appb-img-000081
Figure PCTKR2022006181-appb-img-000081
1H NMR (400 MHz, CDCl3)δ 7.730 (d, J = 7.6 Hz, 1H), 7.332 - 7.258 (m, 4H), 7.186 (td, J = 7.6, 0.8 Hz, 1H), 7.141 - 7.100 (m, 3H) 7.048 (s, 1H), 6.853 (s, 1H), 5.296 (s, 2H), 4.511 - 4.478 (m, 1H), 4.106 (dd, J = 11.2, 3.4 Hz, 1H), 3.858 (d, J = 13.6 Hz, 1H), 3.726 (d, J = 13.2 Hz, 1H), 3.554 - 3.523 (m, 1H), 2.969 (d, J = 11.2 Hz, 1H), 2.776 (td, J = 12.8, 3.2 Hz, 1H), 2.112 - 1.997 (m, 2H), 1.480 (d, J = 9.6 Hz, 6H). 1 H NMR (400 MHz, CDCl 3 )δ 7.730 (d, J = 7.6 Hz, 1H), 7.332 - 7.258 (m, 4H), 7.186 (td, J = 7.6, 0.8 Hz, 1H), 7.141 - 7.100 ( m, 3H) 7.048 (s, 1H), 6.853 (s, 1H), 5.296 (s, 2H), 4.511 - 4.478 (m, 1H), 4.106 (dd, J = 11.2, 3.4 Hz, 1H), 3.858 ( d, J = 13.6 Hz, 1H), 3.726 (d, J = 13.2 Hz, 1H), 3.554 - 3.523 (m, 1H), 2.969 (d, J = 11.2 Hz, 1H), 2.776 (td, J = 12.8) , 3.2 Hz, 1H), 2.112 - 1.997 (m, 2H), 1.480 (d, J = 9.6 Hz, 6H).
13C NMR (126 MHz, CDCl3)δ 168.14, 165.68, 137.38, 136.81, 128.76, 128.38, 127.84, 127.62, 126.77, 121.97, 119.71, 119.41, 110.69, 109.73, 57.53, 56.34, 56.01, 53.32, 51.50, 49.94, 41.79, 29.19, 28.99. 13 C NMR (126 MHz, CDCl 3 )δ 168.14, 165.68, 137.38, 136.81, 128.76, 128.38, 127.84, 127.62, 126.77, 121.97, 119.71, 119.41, 110.69, 109.73, 57.53, 56.34, 56.01, 53.32, 51.50, 53.32 , 41.79, 29.19, 28.99.
MS (ESI) m/z for C25H28N4O2[M+H]+:calcd416.53,found417.2.MS (ESI) m/z for C 25 H 28 N 4 O 2 [M+H] + :calcd416.53,found417.2.
제조예 4-3Preparation 4-3
제조예 1의 단계 7에서 2-에틸벤조[b]싸이오펜-3-카르바알데히드 대신에 1-(나프탈렌-2-일)메틸-1H-인돌-3-카르바알데히드를 사용하고 제조예 1의 단계 7과 동일한 방법으로 7,7-디메틸-2-((1-나프탈렌-2-일메틸)-1H-인돌-3-일)메틸)헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S836)을 제조하였다.In step 7 of Preparation Example 1, 1-(naphthalen-2-yl)methyl- 1H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and Preparation Example 7,7-dimethyl-2-((1-naphthalen-2-ylmethyl)-1H-indol-3-yl)methyl)hexahydro- 2H - pyrazino [1, 2- a ]pyrazine-6,9-dione (S836) was prepared.
[화학식 37][Formula 37]
S836S836
Figure PCTKR2022006181-appb-img-000082
Figure PCTKR2022006181-appb-img-000082
1H NMR (400 MHz, CDCl3)δ 7.809 - 7.734 (m, 4H), 7.561 (s, 1H), 7.467 - 7.443 (m, 2H), 7.307 (d, J = 7.6 Hz, 1H), 7.238 (dd, J = 8.4, 1.6 Hz, 1H), 7.197 - 7.108 (m, 3H) 7.079 (s, 1H), 5.430 (s, 2H), 4.514 - 4.481 (m, 1H), 4.104 (dd, J = 11.2, 3.2 Hz, 1H), 3.864 (d, J = 13.6 Hz, 1H), 3.726 (d, J = 13.6 Hz, 1H), 3.565 - 3.537 (m, 1H), 2.971 (d, J = 11.2 Hz, 1H), 2.774 (td, J = 12.8, 3.2 Hz, 1H), 2.115 - 1.996 (m, 2H), 1.470 (d, J = 9.2 Hz, 6H). 1 H NMR (400 MHz, CDCl 3 )δ 7.809 - 7.734 (m, 4H), 7.561 (s, 1H), 7.467 - 7.443 (m, 2H), 7.307 (d, J = 7.6 Hz, 1H), 7.238 ( dd, J = 8.4, 1.6 Hz, 1H), 7.197 - 7.108 (m, 3H) 7.079 (s, 1H), 5.430 (s, 2H), 4.514 - 4.481 (m, 1H), 4.104 (dd, J = 11.2) , 3.2 Hz, 1H), 3.864 (d, J = 13.6 Hz, 1H), 3.726 (d, J = 13.6 Hz, 1H), 3.565 - 3.537 (m, 1H), 2.971 (d, J = 11.2 Hz, 1H) ), 2.774 (td, J = 12.8, 3.2 Hz, 1H), 2.115 - 1.996 (m, 2H), 1.470 (d, J = 9.2 Hz, 6H).
13C NMR (126 MHz, CDCl3)δ 168.13, 165.63, 136.90, 134.79, 133.27, 132.81, 128.68, 128.44, 127.86, 127.79, 127.68, 126.37, 126.05, 125.65, 124.81, 122.01, 119.75, 119.46, 110.81, 109.76, 57.53, 56.36, 56.02, 53.35, 51.51, 50.16, 41.80, 29.19, 29.01. 13 C NMR (126 MHz, CDCl 3 )δ 168.13, 165.63, 136.90, 134.79, 133.27, 132.81, 128.68, 128.44, 127.86, 127.79, 127.68, 126.37, 126.05, 125.65, 124.81, 109.75, 119.46, 110. , 57.53, 56.36, 56.02, 53.35, 51.51, 50.16, 41.80, 29.19, 29.01.
MS (ESI) m/z for C29H30N4O2[M+H]+:calcd466.59,found467.4.MS (ESI) m/z for C 29 H 30 N 4 O 2 [M+H] + :calcd466.59,found467.4.
제조예 4-4Preparation 4-4
제조예 1의 단계 7에서 2-에틸벤조[b]싸이오펜-3-카르바알데히드 대신에 1-([1,1'-비페닐]-4-일메틸)-1H-인돌-3-카르바알데히드를 사용하고 제조예 1의 단계 7과 동일한 방법으로 2-((1-[1,1'-비페닐]-4-일메틸)-1H-인돌-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S838)을 제조하였다.1-([1,1'-biphenyl]-4-ylmethyl)-1H-indole-3- instead of 2-ethylbenzo[ b ]thiophen-3- carbaaldehyde in step 7 of Preparation Example 1 2-((1-[1,1'-biphenyl]-4-ylmethyl) -1H -indol-3-yl)methyl)- in the same manner as in Step 7 of Preparation Example 1 using carbaaldehyde 7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S838) was prepared.
[화학식 38][Formula 38]
S838S838
Figure PCTKR2022006181-appb-img-000083
Figure PCTKR2022006181-appb-img-000083
1H NMR (400 MHz, CDCl3)δ 7.745 (d, J = 7.6 Hz, 1H), 7.556 - 7.511 (m, 4H), 7.422 (t, J = 7.6 Hz, 2H), 7.353 - 7.296 (m, 2H), 7.223 -7.116 (m, 4H), 7.084 (s, 1H), 6.775 (s, 1H), 5.336 (s, 2H), 4.516 - 4.483 (m, 1H), 4.112 (dd, J = 10.8, 3.2 Hz, 1H), 3.872 (d, J = 13.2 Hz, 1H), 3.738 (d, J = 13.2 Hz, 1H), 3.566 - 3.538 (m, 1H), 2.980 (d, J = 11.6 Hz, 1H), 2.781 (td, J = 12.7, 2.9 Hz, 1H), 2.123 - 2.002 (m, 2H), 1.490 (s, 3H), 1.466 (s, 3H). 1 H NMR (400 MHz, CDCl 3 )δ 7.745 (d, J = 7.6 Hz, 1H), 7.556 - 7.511 (m, 4H), 7.422 (t, J = 7.6 Hz, 2H), 7.353 - 7.296 (m, 2H), 7.223 -7.116 (m, 4H), 7.084 (s, 1H), 6.775 (s, 1H), 5.336 (s, 2H), 4.516 - 4.483 (m, 1H), 4.112 (dd, J = 10.8, 3.2 Hz, 1H), 3.872 (d, J = 13.2 Hz, 1H), 3.738 (d, J = 13.2 Hz, 1H), 3.566 - 3.538 (m, 1H), 2.980 (d, J = 11.6 Hz, 1H) , 2.781 (td, J = 12.7, 2.9 Hz, 1H), 2.123 - 2.002 (m, 2H), 1.490 (s, 3H), 1.466 (s, 3H).
13C NMR (126 MHz, CDCl3)δ 168.12, 165.62, 140.60, 140.51, 136.82, 136.37, 128.77, 128.42, 127.82, 127.49, 127.37, 127.23, 127.00, 122.02, 119.76, 119.46, 110.79, 109.75, 77.29, 77.04, 76.79, 57.54, 56.37, 56.04, 53.35, 51.51, 49.68, 41.81, 29.20, 29.02. 13 C NMR (126 MHz, CDCl 3 )δ 168.12, 165.62, 140.60, 140.51, 136.82, 136.37, 128.77, 128.42, 127.82, 127.49, 127.37, 127.23, 127.00, 122.02, 77.76, 119.46, 110.79, 109. , 76.79, 57.54, 56.37, 56.04, 53.35, 51.51, 49.68, 41.81, 29.20, 29.02.
MS (ESI) m/z for C31H32N4O2[M+H]+:calcd492.62,found493.4.MS (ESI) m/z for C 31 H 32 N 4 O 2 [M+H]+:calcd492.62,found493.4.
제조예 4-5Preparation 4-5
제조예 1의 단계 7에서 2-에틸벤조[b]싸이오펜-3-카르바알데히드 대신에 1-벤질-2-메틸-1H-인돌-3-카르바알데히드를 사용하고 제조예 1의 단계 7과 동일한 방법으로 2-((1-벤질-2-메틸-1H-인돌-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S839)을 제조하였다.In step 7 of Preparation Example 1, 1-benzyl-2-methyl- 1H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and the step of Preparation Example 1 In the same manner as in 7, 2-((1-benzyl-2-methyl- 1H -indol-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine -6,9-dione (S839) was prepared.
[화학식 39][Formula 39]
S839S839
Figure PCTKR2022006181-appb-img-000084
Figure PCTKR2022006181-appb-img-000084
1H NMR (500 MHz, CDCl3)δ 7.68 - 7.63 (m, 1H), 7.29 - 7.17 (m, 5H), 7.13 - 7.08 (m, 2H), 6.95 (d, J = 6.9 Hz, 2H), 5.30 (s, 2H), 4.48 (ddd, J = 13.0, 2.9, 1.9 Hz, 1H), 4.07 (dd, J = 11.0, 3.3 Hz, 1H), 3.83 (d, J = 13.2 Hz, 1H), 3.69 (d, J = 13.2 Hz, 1H), 3.52 (ddd, J = 11.0, 2.9, 1.5 Hz, 1H), 2.92 (dd, J = 10.2, 1.4 Hz, 1H), 2.73 (td, J = 12.9, 3.3 Hz, 1H), 2.32 (s, 3H), 2.13 - 1.97 (m, 2H), 1.49 (s, 3H), 1.46 (s, 3H). 1 H NMR (500 MHz, CDCl 3 )δ 7.68 - 7.63 (m, 1H), 7.29 - 7.17 (m, 5H), 7.13 - 7.08 (m, 2H), 6.95 (d, J = 6.9 Hz, 2H), 5.30 (s, 2H), 4.48 (ddd, J = 13.0, 2.9, 1.9 Hz, 1H), 4.07 (dd, J = 11.0, 3.3 Hz, 1H), 3.83 (d, J = 13.2 Hz, 1H), 3.69 (d, J = 13.2 Hz, 1H), 3.52 (ddd, J = 11.0, 2.9, 1.5 Hz, 1H), 2.92 (dd, J = 10.2, 1.4 Hz, 1H), 2.73 (td, J = 12.9, 3.3) Hz, 1H), 2.32 (s, 3H), 2.13 - 1.97 (m, 2H), 1.49 (s, 3H), 1.46 (s, 3H).
13C NMR (126 MHz, CDCl3) δ 168.09, 165.73, 137.76, 136.47, 135.25, 128.78, 128.47, 127.28, 125.91, 121.10, 119.44, 118.62, 109.03, 107.19, 57.65, 56.52, 56.04, 52.40, 51.44, 46.52, 41.85, 29.28, 29.01. 13 C NMR (126 MHz, CDCl 3 ) δ 168.09, 165.73, 137.76, 136.47, 135.25, 128.78, 128.47, 127.28, 125.91, 121.10, 119.44, 118.62, 109.03, 46.52.19, 57.65, 56.52, 56.04, 52.40, 56.04, , 41.85, 29.28, 29.01.
MS (ESI) m/z for C26H30N4O2[M+H]+:calcd430.55,found429.8.MS (ESI) m/z for C 26 H 30 N 4 O 2 [M+H]+:calcd430.55,found429.8.
제조예 4-6Preparation 4-6
제조예 1의 단계 7에서 2-에틸벤조[b]싸이오펜-3-카르바알데히드 대신에 1-벤질-5-브로모-1H-인돌-3-카르바알데히드를 사용하고 제조예 1의 단계 7과 동일한 방법으로 2-((1-벤질-5-브로모-1H-인돌-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S840)을 제조하였다.In step 7 of Preparation Example 1, 1-benzyl-5-bromo- 1H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde and In the same manner as in step 7, 2-((1-benzyl-5-bromo- 1H -indol-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]Pyrazine-6,9-dione (S840) was prepared.
[화학식 40][Formula 40]
S840S840
Figure PCTKR2022006181-appb-img-000085
Figure PCTKR2022006181-appb-img-000085
1H NMR (500 MHz, CDCl3)δ 7.86 (s, 1H), 7.34 - 7.21 (m, 4H), 7.14 - 7.01 (m, 4H), 6.85 (s, 1H), 5.25 (s, 2H), 4.51 (d, J = 12.9 Hz, 1H), 4.10 (d, J = 9.0 Hz, 1H), 3.76 (d, J = 13.2 Hz, 1H), 3.66 (d, J = 13.2 Hz, 1H), 3.50 (d, J = 10.8 Hz, 1H), 2.94 (d, J = 11.2 Hz, 1H), 2.79 (t, J = 11.6 Hz, 1H), 2.03 (dd, J = 25.0, 12.3 Hz, 2H), 1.50 (s, 3H), 1.47 (s, 3H). 1 H NMR (500 MHz, CDCl 3 )δ 7.86 (s, 1H), 7.34 - 7.21 (m, 4H), 7.14 - 7.01 (m, 4H), 6.85 (s, 1H), 5.25 (s, 2H), 4.51 (d, J = 12.9 Hz, 1H), 4.10 (d, J = 9.0 Hz, 1H), 3.76 (d, J = 13.2 Hz, 1H), 3.66 (d, J = 13.2 Hz, 1H), 3.50 ( d, J = 10.8 Hz, 1H), 2.94 (d, J = 11.2 Hz, 1H), 2.79 (t, J = 11.6 Hz, 1H), 2.03 (dd, J = 25.0, 12.3 Hz, 2H), 1.50 ( s, 3H), 1.47 (s, 3H).
13C NMR (126 MHz, CDCl3)δ 168.08, 165.45, 136.85, 135.51, 129.95, 128.82, 127.78, 126.65, 124.84, 122.36, 112.81, 111.24, 110.57, 77.24, 76.98, 76.73, 57.44, 56.22, 56.06, 53.28, 51.63, 50.13, 41.74, 29.21, 29.06. 13 C NMR (126 MHz, CDCl 3 )δ 168.08, 165.45, 136.85, 135.51, 129.95, 128.82, 127.78, 126.65, 124.84, 122.36, 112.81, 111.24, 110.57, 77.24, 76.98, 53.28, 76.73, 57.06 , 51.63, 50.13, 41.74, 29.21, 29.06.
MS (ESI) m/z for C25H27BrN4O2[M+H]+:calcd495.42,found495.13.MS (ESI) m/z for C 25 H 27 BrN 4 O 2 [M+H] + :calcd495.42,found495.13.
제조예 4-7Preparation 4-7
제조예 1의 단계 7에서 2-에틸벤조[b]싸이오펜-3-카르바알데히드 대신에 1-벤질-5-메톡시-1H-인돌-3-카르바알데히드를 사용하고 제조예 1의 단계 7과 동일한 방법으로 2-((1-벤질-5-메톡시-1H-인돌-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S841)을 제조하였다.In step 7 of Preparation Example 1, 1-benzyl-5-methoxy- 1H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde and In the same manner as in step 7, 2-((1-benzyl-5-methoxy-1 H -indol-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]Pyrazine-6,9-dione (S841) was prepared.
[화학식 41][Formula 41]
S841S841
Figure PCTKR2022006181-appb-img-000086
Figure PCTKR2022006181-appb-img-000086
1H NMR (500 MHz, CDCl3)δ 7.32 - 7.21 (m, 3H), 7.18 - 7.08 (m, 5H), 7.01 (s, 1H), 6.83 (dd, J = 8.9, 2.4 Hz, 1H), 5.24 (s, 2H), 4.50 (ddd, J = 13.0, 2.8, 1.9 Hz, 1H), 4.10 (dd, J = 11.0, 3.3 Hz, 1H), 3.87 - 3.80 (m, 4H), 3.66 (d, J = 13.3 Hz, 1H), 3.55 (ddd, J = 11.2, 3.0, 1.6 Hz, 1H), 2.99 - 2.93 (m, 1H), 2.76 (td, J = 13.0, 3.3 Hz, 1H), 2.12 - 1.96 (m, 2H), 1.49 (s, 3H), 1.47 (s, 3H). 1 H NMR (500 MHz, CDCl 3 )δ 7.32 - 7.21 (m, 3H), 7.18 - 7.08 (m, 5H), 7.01 (s, 1H), 6.83 (dd, J = 8.9, 2.4 Hz, 1H), 5.24 (s, 2H), 4.50 (ddd, J = 13.0, 2.8, 1.9 Hz, 1H), 4.10 (dd, J = 11.0, 3.3 Hz, 1H), 3.87 - 3.80 (m, 4H), 3.66 (d, J = 13.3 Hz, 1H), 3.55 (ddd, J = 11.2, 3.0, 1.6 Hz, 1H), 2.99 - 2.93 (m, 1H), 2.76 (td, J = 13.0, 3.3 Hz, 1H), 2.12 - 1.96 (m, 2H), 1.49 (s, 3H), 1.47 (s, 3H).
13C NMR (126 MHz, CDCl3)δ 168.13, 165.66, 154.01, 137.48, 132.15, 128.76, 128.49, 127.61, 126.71, 111.98, 110.52, 110.18, 101.74, 77.31, 77.05, 76.80, 57.59, 56.46, 56.05, 55.94, 53.46, 51.46, 50.16, 41.86, 29.24, 29.02. 13 C NMR (126 MHz, CDCl 3 )δ 168.13, 165.66, 154.01, 137.48, 132.15, 128.76, 128.49, 127.61, 126.71, 111.98, 110.52, 110.18, 101.74, 77.31, 77.05, 76.80, 56.05, 56.46, 57.05, 56.46 , 53.46, 51.46, 50.16, 41.86, 29.24, 29.02.
MS (ESI) m/z for C26H30N4O3[M+H]+:calcd446.55,found447.2.MS (ESI) m/z for C 26 H 30 N 4 O 3 [M+H] + :calcd446.55,found447.2.
제조예 4-8Preparation 4-8
제조예 1의 단계 7에서 2-에틸벤조[b]싸이오펜-3-카르바알데히드 대신에 1H-인돌-3-카르바알데히드를 사용하고 제조예 1의 단계 7과 동일한 방법으로 2-((1H-인돌-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S842)을 제조하였다.In step 7 of Preparation Example 1, 1 H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde and 2-( ( 1H -indol-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S842) was prepared.
[화학식 42][Formula 42]
S842S842
Figure PCTKR2022006181-appb-img-000087
Figure PCTKR2022006181-appb-img-000087
1H NMR (400 MHz, CDCl3)δ 8.491 (s, 1H), 7.713 (d, J = 7.6 Hz, 1H), 7.355 (d, J = 8.0 Hz, 1H), 7.278 (s, 1H), 7.200 (t, J = 7.6 Hz, 1H), 7.122 (t, J = 7.6 Hz, 1H) 7.056 (d, J = 2.0 Hz, 1H), 4.499 (d, J = 12.8 Hz, 1H), 4.097 (dd, J = 11.2, 3.6 Hz, 1H), 3.830 (d, J = 13.2 Hz, 1H), 3.741 (d, J = 13.6 Hz, 1H), 3.534 (d, J = 10.0 Hz, 1H), 2.968 (d, J = 12.8 Hz, 1H), 2.777 (td, J = 12.8, 3.2 Hz, 1H), 2.104 - 2.016 (m, 2H), 1.466 (d, J = 11.6 Hz, 6H). 1 H NMR (400 MHz, CDCl 3 )δ 8.491 (s, 1H), 7.713 (d, J = 7.6 Hz, 1H), 7.355 (d, J = 8.0 Hz, 1H), 7.278 (s, 1H), 7.200 (t, J = 7.6 Hz, 1H), 7.122 (t, J = 7.6 Hz, 1H) 7.056 (d, J = 2.0 Hz, 1H), 4.499 (d, J = 12.8 Hz, 1H), 4.097 (dd, J = 11.2, 3.6 Hz, 1H), 3.830 (d, J = 13.2 Hz, 1H), 3.741 (d, J = 13.6 Hz, 1H), 3.534 (d, J = 10.0 Hz, 1H), 2.968 (d, J = 12.8 Hz, 1H), 2.777 (td, J = 12.8, 3.2 Hz, 1H), 2.104 - 2.016 (m, 2H), 1.466 (d, J = 11.6 Hz, 6H).
13C NMR (126 MHz, CDCl3)δ 168.53, 166.00, 136.73, 128.00, 124.23, 122.46, 119.91, 119.79, 111.75, 111.52, 57.85, 56.57, 56.40, 53.71, 51.96, 42.16, 29.51, 29.35. 13 C NMR (126 MHz, CDCl 3 )δ 168.53, 166.00, 136.73, 128.00, 124.23, 122.46, 119.91, 119.79, 111.75, 111.52, 57.85, 56.57, 56.40, 53.71, 51.96, 42.16, 29.51, 29.35.
MS (ESI) m/z for C18H22N4O2[M+H]+:calcd326.4,found327.2.MS (ESI) m/z for C 18 H 22 N 4 O 2 [M+H]+:calcd326.4,found327.2.
제조예 4-9Preparation 4-9
제조예 1의 단계4에서 1,4-비스(터셔리-부톡시카르보닐)피페라진-2-카르복실산 대신에 제조예 1의 단계 6에서 제조된 7,7-디메틸헥사히드로-2H-피라지노[1,2-a]피라진-6,9-디온을 사용하고, 또한 제조예 1의 단계 4에서 2-에틸벤조[b]싸이오펜-3-카르바알데히드 대신에 벤조[b]싸이오펜-3-아세틱애시드(0.9당량)를 사용하며 제조예 1의 단계 4와 동일한 방법으로 2-(2-(벤조[b]싸이오펜-3-일)아세틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S845)을 제조하였다.7,7-dimethylhexahydro- 2H prepared in step 6 of Preparation Example 1 instead of 1,4-bis( tertiary -butoxycarbonyl)piperazine-2-carboxylic acid in Step 4 of Preparation Example 1 -Pyrazino[1,2- a ]pyrazine-6,9-dione, and also 2-ethylbenzo[ b ]thiophene-3-carbaaldehyde in step 4 of Preparation Example 1 instead of benzo[ b ] 2-(2-(benzo[ b ]thiophen-3-yl)acetyl)-7,7-dimethyl in the same manner as in step 4 of Preparation Example 1 using thiophene-3-acetic acid (0.9 equivalents) Hexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S845) was prepared.
[화학식 43][Formula 43]
S845S845
Figure PCTKR2022006181-appb-img-000088
Figure PCTKR2022006181-appb-img-000088
1H NMR (400 MHz, CDCl3)δ 8.491 (s, 1H), 7.713 (d, J = 7.6 Hz, 1H), 7.355 (d, J = 8.0 Hz, 1H), 7.278 (s, 1H), 7.200 (t, J = 7.6 Hz, 1H), 7.122 (t, J = 7.6 Hz, 1H) 7.056 (d, J = 2.0 Hz, 1H), 4.499 (d, J = 12.8 Hz, 1H), 4.097 (dd, J = 11.2, 3.6 Hz, 1H), 3.830 (d, J = 13.2 Hz, 1H), 3.741 (d, J = 13.6 Hz, 1H), 3.534 (d, J = 10.0 Hz, 1H), 2.968 (d, J = 12.8 Hz, 1H), 2.777 (td, J = 12.8, 3.2 Hz, 1H), 2.104 - 2.016 (m, 2H), 1.466 (d, J = 11.6 Hz, 6H). 1 H NMR (400 MHz, CDCl 3 )δ 8.491 (s, 1H), 7.713 (d, J = 7.6 Hz, 1H), 7.355 (d, J = 8.0 Hz, 1H), 7.278 (s, 1H), 7.200 (t, J = 7.6 Hz, 1H), 7.122 (t, J = 7.6 Hz, 1H) 7.056 (d, J = 2.0 Hz, 1H), 4.499 (d, J = 12.8 Hz, 1H), 4.097 (dd, J = 11.2, 3.6 Hz, 1H), 3.830 (d, J = 13.2 Hz, 1H), 3.741 (d, J = 13.6 Hz, 1H), 3.534 (d, J = 10.0 Hz, 1H), 2.968 (d, J = 12.8 Hz, 1H), 2.777 (td, J = 12.8, 3.2 Hz, 1H), 2.104 - 2.016 (m, 2H), 1.466 (d, J = 11.6 Hz, 6H).
13C NMR (126 MHz, CDCl3)δ 163.61, 156.75, 124.71, 124.45, 124.37, 122.84, 122.13, 56.88, 56.37, 49.16, 49.03, 41.25, 41.14, 34.92, 33.96, 29.70, 29.15, 25.63, 24.95. 13 C NMR (126 MHz, CDCl 3 )δ 163.61, 156.75, 124.71, 124.45, 124.37, 122.84, 122.13, 56.88, 56.37, 49.16, 49.03, 41.25, 41.14, 34.92, 33.96, 29.70, 29.15, 25.63, 24.95.
MS (ESI) m/z for C18H22N4O2[M+H]+:calcd371.46,found372.13.MS (ESI) m/z for C 18 H 22 N 4 O 2 [M+H]+:calcd371.46,found372.13.
제조예 4-10Preparation 4-10
제조예 1의 단계6에서 제조한 7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온·2트리플루오로아세트산(1.0당량)과 파라포름알데히드(2.0당량)를 에탄올에 용해시킨 후, 염산 메탄올용액을 첨가하고 실온에서 20분 교반하였다. 1-(1-벤질-1H-인돌-3-일)에탄-1-온(1.0당량)을 투입한 뒤 2시간동안 환류교반하였다. 반응액을 감압 증발기로 농축시킨 다음 메틸렌클로라이드로 희석하고 소듐 바이카보네이트로 중화하였다. 유기층을 탈수시키고 감압 증발기로 농축시켜 얻어진 잔사를 실리카겔 관 크로마토그래피로 정제하여 2-(3-(1-벤질-1H-인돌-3-일)-3-옥소프로필)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S847)을 제조하였다.7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione/2trifluoroacetic acid (1.0 equivalent) and paraformaldehyde prepared in step 6 of Preparation Example 1 (2.0 equivalents) was dissolved in ethanol, and then a methanol solution of hydrochloric acid was added, followed by stirring at room temperature for 20 minutes. 1-(1-benzyl- 1H -indol-3-yl)ethan-1-one (1.0 equivalent) was added, followed by reflux stirring for 2 hours. The reaction solution was concentrated with a vacuum evaporator, diluted with methylene chloride, and neutralized with sodium bicarbonate. The organic layer was dehydrated and concentrated with a reduced pressure evaporator, and the obtained residue was purified by silica gel column chromatography to 2-(3-(1-benzyl-1 H -indol-3-yl)-3-oxopropyl)-7,7-dimethyl Hexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S847) was prepared.
[화학식 44][Formula 44]
S847S847
Figure PCTKR2022006181-appb-img-000089
Figure PCTKR2022006181-appb-img-000089
1H NMR (500 MHz, CDCl3)δ 8.43 - 8.37 (m, 1H), 7.80 (s, 1H), 7.38 - 7.22 (m, 6H), 7.19 - 7.13 (m, 3H), 5.34 (s, 2H), 4.51 (ddd, J = 13.1, 3.0, 1.8 Hz, 1H), 4.03 (dd, J = 11.1, 3.3 Hz, 1H), 3.48 (ddd, J = 11.3, 3.1, 1.7 Hz, 1H), 3.13 - 3.04 (m, 2H), 3.03 - 2.84 (m, 3H), 2.81 - 2.71 (m, 1H), 2.19 - 2.04 (m, 2H), 1.51 (s, 3H), 1.48 (s, 3H). 1 H NMR (500 MHz, CDCl 3 )δ 8.43 - 8.37 (m, 1H), 7.80 (s, 1H), 7.38 - 7.22 (m, 6H), 7.19 - 7.13 (m, 3H), 5.34 (s, 2H) ), 4.51 (ddd, J = 13.1, 3.0, 1.8 Hz, 1H), 4.03 (dd, J = 11.1, 3.3 Hz, 1H), 3.48 (ddd, J = 11.3, 3.1, 1.7 Hz, 1H), 3.13 - 3.04 (m, 2H), 3.03 - 2.84 (m, 3H), 2.81 - 2.71 (m, 1H), 2.19 - 2.04 (m, 2H), 1.51 (s, 3H), 1.48 (s, 3H).
13C NMR (126 MHz, CDCl3)δ 193.77, 168.30, 165.59, 137.29, 135.89, 134.80, 129.27, 128.47, 127.24, 126.60, 123.81, 123.01, 122.85, 117.23, 110.37, 57.55, 56.32, 56.28, 53.39, 52.57, 50.94, 41.81, 37.50, 29.44, 29.21. 13 C NMR (126 MHz, CDCl 3 )δ 193.77, 168.30, 165.59, 137.29, 135.89, 134.80, 129.27, 128.47, 127.24, 126.60, 123.81, 123.01, 122.85, 117.23, 110.37, 57.55, 53.32, 56.28, 56.32, , 50.94, 41.81, 37.50, 29.44, 29.21.
MS (ESI) m/z for C27H30N4O3[M+H]+:calcd458.56,found459.23.MS (ESI) m/z for C 27 H 30 N 4 O 3 [M+H] + :calcd458.56,found459.23.
제조예 4-11Preparation 4-11
제조예 4-9에서 벤조[b]싸이오펜-3-아세틱애시드 대신에 1-벤질-2-메틸-1H-인돌-3-카르복실애시드(0.9당량)를 사용하고 제조예 4-9와 동일한 방법으로 2-((1-벤질-2-메틸-1H-인돌-3-카르보닐)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S855)을 제조하였다.In Preparation Example 4-9, 1-benzyl-2-methyl- 1H -indole-3-carboxyl acid (0.9 equivalents) was used instead of benzo[ b ]thiophene-3-acetic acid, and Preparation Example 4-9 In the same manner as 2-((1-benzyl-2-methyl- 1H -indole-3-carbonyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6 , 9-dione (S855) was prepared.
[화학식 45][Formula 45]
S855S855
Figure PCTKR2022006181-appb-img-000090
Figure PCTKR2022006181-appb-img-000090
1H NMR (500 MHz, CDCl3)δ 8.43 - 8.37 (m, 1H), 7.80 (s, 1H), 7.38 - 7.22 (m, 6H), 7.19 - 7.13 (m, 3H), 5.34 (s, 2H), 4.51 (ddd, J = 13.1, 3.0, 1.8 Hz, 1H), 4.03 (dd, J = 11.1, 3.3 Hz, 1H), 3.48 (ddd, J = 11.3, 3.1, 1.7 Hz, 1H), 3.13 - 3.04 (m, 2H), 3.03 - 2.84 (m, 3H), 2.81 - 2.71 (m, 1H), 2.19 - 2.04 (m, 2H), 1.51 (s, 3H), 1.48 (s, 3H). 1 H NMR (500 MHz, CDCl 3 )δ 8.43 - 8.37 (m, 1H), 7.80 (s, 1H), 7.38 - 7.22 (m, 6H), 7.19 - 7.13 (m, 3H), 5.34 (s, 2H) ), 4.51 (ddd, J = 13.1, 3.0, 1.8 Hz, 1H), 4.03 (dd, J = 11.1, 3.3 Hz, 1H), 3.48 (ddd, J = 11.3, 3.1, 1.7 Hz, 1H), 3.13 - 3.04 (m, 2H), 3.03 - 2.84 (m, 3H), 2.81 - 2.71 (m, 1H), 2.19 - 2.04 (m, 2H), 1.51 (s, 3H), 1.48 (s, 3H).
13C NMR (126 MHz, CDCl3)δ 193.77, 168.30, 165.59, 137.29, 135.89, 134.80, 129.27, 128.47, 127.24, 126.60, 123.81, 123.01, 122.85, 117.23, 110.37, 57.55, 56.32, 56.28, 53.39, 52.57, 50.94, 41.81, 37.50, 29.44, 29.21. 13 C NMR (126 MHz, CDCl 3 )δ 193.77, 168.30, 165.59, 137.29, 135.89, 134.80, 129.27, 128.47, 127.24, 126.60, 123.81, 123.01, 122.85, 117.23, 110.37, 57.55, 53.32, 56.28, 56.32, , 50.94, 41.81, 37.50, 29.44, 29.21.
MS (ESI) m/z for C27H30N4O3[M+H]+:calcd430.51,found391.12.MS (ESI) m/z for C 27 H 30 N 4 O 3 [M+H] + :calcd430.51,found391.12.
제조예 5-1Preparation 5-1
제조예 2-1에서 2-((2-에틸-1-벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S801)의 사용 대신에 제조예 4-2에서 제조된 2-((1-벤질-1H-인돌-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S835)을 사용하고, 또한 제조예 2-1에서 아이오도메탄대신 4-(브로모메틸)-1,1‘-비페닐을 사용하며 제조예 2-1과 동일한 방법으로 8-([1,1'-비페닐]-4-일메틸)-2-((1-벤질-1H-인돌-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S856)을 합성하였다. 2-((2-ethyl-1-benzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ] in Preparation Example 2-1 2-((1-benzyl-1 H -indol-3-yl)methyl)-7,7-dimethylhexahydro- prepared in Preparation Example 4-2 instead of using pyrazine-6,9-dione (S801) 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S835) was used, and 4-(bromomethyl)-1,1'- instead of iodomethane in Preparation Example 2-1 8-([1,1'-biphenyl]-4-ylmethyl)-2-((1-benzyl-1 H -indol-3-yl) in the same manner as in Preparation Example 2-1 using biphenyl Methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S856) was synthesized.
[화학식 46][Formula 46]
S856S856
Figure PCTKR2022006181-appb-img-000091
Figure PCTKR2022006181-appb-img-000091
1H NMR (500 MHz, CDCl3)δ 7.78 - 7.72 (m, 1H), 7.58 - 7.49 (m, 4H), 7.47 - 7.38 (m, 2H), 7.36 - 7.21 (m, 7H), 7.21 - 7.08 (m, 4H), 7.05 (s, 1H), 5.28 (s, 2H), 4.79 (d, J = 15.8 Hz, 1H), 4.63 (d, J = 15.8 Hz, 1H), 4.50 (ddd, J = 13.0, 3.0, 1.8 Hz, 1H), 4.19 (dd, J = 10.9, 3.4 Hz, 1H), 3.88 (d, J = 13.4 Hz, 1H), 3.75 (d, J = 15.0 Hz, 1H), 3.70 - 3.65 (m, 1H), 3.02 - 2.95 (m, 1H), 2.88 - 2.78 (m, 1H), 2.14 (t, J = 11.2 Hz, 1H), 2.11 - 2.03 (m, 1H), 1.53 (s, 3H), 1.47 (s, 3H). 1 H NMR (500 MHz, CDCl 3 )δ 7.78 - 7.72 (m, 1H), 7.58 - 7.49 (m, 4H), 7.47 - 7.38 (m, 2H), 7.36 - 7.21 (m, 7H), 7.21 - 7.08 (m, 4H), 7.05 (s, 1H), 5.28 (s, 2H), 4.79 (d, J = 15.8 Hz, 1H), 4.63 (d, J = 15.8 Hz, 1H), 4.50 (ddd, J = 13.0, 3.0, 1.8 Hz, 1H), 4.19 (dd, J = 10.9, 3.4 Hz, 1H), 3.88 (d, J = 13.4 Hz, 1H), 3.75 (d, J = 15.0 Hz, 1H), 3.70 - 3.65 (m, 1H), 3.02 - 2.95 (m, 1H), 2.88 - 2.78 (m, 1H), 2.14 (t, J = 11.2 Hz, 1H), 2.11 - 2.03 (m, 1H), 1.53 (s, 3H), 1.47 (s, 3H).
13C NMR (126 MHz, CDCl3)δ 168.20, 165.29, 140.71, 140.02, 137.41, 137.07, 136.87, 128.76, 128.74, 128.45, 128.40, 127.84, 127.61, 127.30, 127.26, 127.10, 127.07, 127.01, 126.79, 126.72, 121.97, 119.77, 119.63, 119.41, 110.80, 109.74, 66.57, 61.67, 57.75, 56.96, 56.90, 56.75, 55.45, 53.42, 53.24, 51.40, 49.96, 45.41, 41.99, 31.57, 30.10, 29.15, 26.64, 26.54, 22.64, 14.12. 13 C NMR (126 MHz, CDCl 3 )δ 168.20, 165.29, 140.71, 140.02, 137.41, 137.07, 136.87, 128.76, 128.74, 128.45, 128.40, 127.84, 127.61, 127.30, 127.26, 127.10, 127.07, 127.72. , 121.97, 119.77, 119.63, 119.41, 110.80, 109.74, 66.57, 61.67, 57.75, 56.96, 56.90, 56.75, 55.45, 53.42, 53.24, 51.40, 49.96, 45.41, 41.99, 31.57, 30.64, 26.15, 26.64, 29.15, 26.64 , 14.12.
MS (ESI) m/z for C38H38N4O2[M+H]+:calcd582.75,found583.3.MS (ESI) m/z for C 38 H 38 N 4 O 2 [M+H] + :calcd582.75,found583.3.
제조예 5-2Preparation 5-2
제조예 2-1에서 2-((2-에틸-1-벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S801)의 사용 대신에 제조예 4-2에서 제조된 2-((1-벤질-1H-인돌-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S835)을 사용하고, 또한 제조예 2-1에서 아이오도메탄대신 2-(클로로메틸)퀴놀린·염산을 사용하며 제조예 2-1과 동일한 방법으로 2-((1-벤질-1H-인돌-3-일)메틸)-7,7-디메틸-8-(퀴놀린-2-일메틸)헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S857)을 합성하였다. 2-((2-ethyl-1-benzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ] in Preparation Example 2-1 2-((1-benzyl-1 H -indol-3-yl)methyl)-7,7-dimethylhexahydro- prepared in Preparation Example 4-2 instead of using pyrazine-6,9-dione (S801) 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S835) was used, and prepared using 2-(chloromethyl)quinoline hydrochloric acid instead of iodomethane in Preparation Example 2-1 In the same manner as in Example 2-1, 2-((1-benzyl- 1H -indol-3-yl)methyl) -7,7 -dimethyl-8-(quinolin-2-ylmethyl)hexahydro-2H- Pyrazino [1,2- a ] pyrazine-6,9-dione (S857) was synthesized.
[화학식 47][Formula 47]
S857S857
Figure PCTKR2022006181-appb-img-000092
Figure PCTKR2022006181-appb-img-000092
1H NMR (400 MHz, CDCl3)δ 8.101 (d, J = 8.8 Hz, 1H), 8.026 - 8.005 (m, 1H), 7.794 (d, J = 8.4 Hz, 1H), 7.740 - 7.690 (m, 2H), 7.527 (td, J = 7.6, 1.0 Hz, 1H), 7.352 - 7.261 (m, 5H), 7.202 (td, J = 7.4, 1.1 Hz, 1H), 7.159 - 7.109 (m, 3H), 7.076 (s, 1H), 5.302 (s, 2H), 5.219 (d, J = 16.0 Hz, 1H), 4.836 (d, J = 16.4 Hz, 1H), 4.158 - 4.095 (m, 2H), 3.891 (q, J = 10.7 Hz, 2H), 3.736 - 3.684 (m, 1H), 3.234 (td, J = 12.6, 4.5 Hz, 1H), 3.130 - 3.096 (m, 1H), 2.408 (d, J = 11.6 Hz, 1H), 2.295 - 2.220 (m, 1H), 1.528 (d, J = 8.4 Hz, 6H). 1 H NMR (400 MHz, CDCl 3 )δ 8.101 (d, J = 8.8 Hz, 1H), 8.026 - 8.005 (m, 1H), 7.794 (d, J = 8.4 Hz, 1H), 7.740 - 7.690 (m, 2H), 7.527 (td, J = 7.6, 1.0 Hz, 1H), 7.352 - 7.261 (m, 5H), 7.202 (td, J = 7.4, 1.1 Hz, 1H), 7.159 - 7.109 (m, 3H), 7.076 (s, 1H), 5.302 (s, 2H), 5.219 (d, J = 16.0 Hz, 1H), 4.836 (d, J = 16.4 Hz, 1H), 4.158 - 4.095 (m, 2H), 3.891 (q, J = 10.7 Hz, 2H), 3.736 - 3.684 (m, 1H), 3.234 (td, J = 12.6, 4.5 Hz, 1H), 3.130 - 3.096 (m, 1H), 2.408 (d, J = 11.6 Hz, 1H) ), 2.295 - 2.220 (m, 1H), 1.528 (d, J = 8.4 Hz, 6H).
13C NMR (126 MHz, CDCl3)δ 171.80, 165.23, 162.51, 158.05, 147.46, 137.29, 136.96, 136.92, 129.65, 128.86, 128.78, 128.17, 128.08, 127.65, 127.55, 127.22, 126.79, 126.35, 122.12, 119.69, 119.40, 119.31, 110.25, 109.96, 79.70, 62.12, 60.13, 53.07, 51.10, 49.95, 48.57, 38.88, 36.42, 31.55, 31.39, 29.67, 27.37, 25.93, 22.63, 14.12. 13 C NMR (126 MHz, CDCl 3 )δ 171.80, 165.23, 162.51, 158.05, 147.46, 137.29, 136.96, 136.92, 129.65, 128.86, 128.78, 128.17, 128.08, 127.65, 127.55, 127.22, 126.35, 122.12, 126.35, 122.12. , 119.40, 119.31, 110.25, 109.96, 79.70, 62.12, 60.13, 53.07, 51.10, 49.95, 48.57, 38.88, 36.42, 31.55, 31.39, 29.67, 27.37, 25.93, 22.63, 14.12.
MS (ESI) m/z for C35H35N5O2[M+H]+:calcd557.7,found574.28.MS (ESI) m/z for C 35 H 35 N 5 O 2 [M+H]+:calcd557.7,found574.28.
제조예 5-3Production Example 5-3
제조예 2-1에서 2-((2-에틸-1-벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S801)의 사용 대신에 제조예 4-2에서 제조된 2-((1-벤질-1H-인돌-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S835)을 사용하고, 또한 제조예 2-1에서 아이오도메탄대신 1-(브로모메틸)나프탈렌을 사용하며 제조예 2-1과 동일한 방법으로 2-((1-벤질-1H-인돌-3-일)메틸)-7,7-디메틸-8-(나프탈렌-1-일메틸)헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S858)을 합성하였다.2-((2-ethyl-1-benzo[b]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ] in Preparation Example 2-1 2-((1-benzyl-1 H -indol-3-yl)methyl)-7,7-dimethylhexahydro- prepared in Preparation Example 4-2 instead of using pyrazine-6,9-dione (S801) 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S835) is used, and 1-(bromomethyl)naphthalene is used instead of iodomethane in Preparation Example 2-1, and Preparation Example In the same manner as in 2-1, 2-((1-benzyl- 1H -indol-3-yl)methyl)-7,7-dimethyl-8-(naphthalen-1-ylmethyl)hexahydro- 2H -pyra Zino [1,2- a ] pyrazine-6,9-dione (S858) was synthesized.
[화학식 48][Formula 48]
S858S858
Figure PCTKR2022006181-appb-img-000093
Figure PCTKR2022006181-appb-img-000093
1H NMR (400 MHz, CDCl3)δ 8.101 (d, J = 8.8 Hz, 1H), 8.026 - 8.005 (m, 1H), 7.794 (d, J = 8.4 Hz, 1H), 7.740 - 7.690 (m, 2H), 7.527 (td, J = 7.6, 1.0 Hz, 1H), 7.352 - 7.261 (m, 5H), 7.202 (td, J = 7.4, 1.1 Hz, 1H), 7.159 - 7.109 (m, 3H), 7.076 (s, 1H), 5.302 (s, 2H), 5.219 (d, J = 16.0 Hz, 1H), 4.836 (d, J = 16.4 Hz, 1H), 4.158 - 4.095 (m, 2H), 3.891 (q, J = 10.7 Hz, 2H), 3.736 - 3.684 (m, 1H), 3.234 (td, J = 12.6, 4.5 Hz, 1H), 3.130 - 3.096 (m, 1H), 2.408 (d, J = 11.6 Hz, 1H), 2.295 - 2.220 (m, 1H), 1.528 (d, J = 8.4 Hz, 6H). 1 H NMR (400 MHz, CDCl 3 )δ 8.101 (d, J = 8.8 Hz, 1H), 8.026 - 8.005 (m, 1H), 7.794 (d, J = 8.4 Hz, 1H), 7.740 - 7.690 (m, 2H), 7.527 (td, J = 7.6, 1.0 Hz, 1H), 7.352 - 7.261 (m, 5H), 7.202 (td, J = 7.4, 1.1 Hz, 1H), 7.159 - 7.109 (m, 3H), 7.076 (s, 1H), 5.302 (s, 2H), 5.219 (d, J = 16.0 Hz, 1H), 4.836 (d, J = 16.4 Hz, 1H), 4.158 - 4.095 (m, 2H), 3.891 (q, J = 10.7 Hz, 2H), 3.736 - 3.684 (m, 1H), 3.234 (td, J = 12.6, 4.5 Hz, 1H), 3.130 - 3.096 (m, 1H), 2.408 (d, J = 11.6 Hz, 1H) ), 2.295 - 2.220 (m, 1H), 1.528 (d, J = 8.4 Hz, 6H).
13C NMR (126 MHz, CDCl3)δ 171.80, 165.23, 162.51, 158.05, 147.46, 137.29, 136.96, 136.92, 129.65, 128.86, 128.78, 128.17, 128.08, 127.65, 127.55, 127.22, 126.79, 126.35, 122.12, 119.69, 119.40, 119.31, 110.25, 109.96, 79.70, 62.12, 60.13, 53.07, 51.10, 49.95, 48.57, 38.88, 36.42, 31.55, 31.39, 29.67, 27.37, 25.93, 22.63, 14.12. 13 C NMR (126 MHz, CDCl 3 )δ 171.80, 165.23, 162.51, 158.05, 147.46, 137.29, 136.96, 136.92, 129.65, 128.86, 128.78, 128.17, 128.08, 127.65, 127.55, 127.22, 126.35, 122.12, 126.35, 122.12. , 119.40, 119.31, 110.25, 109.96, 79.70, 62.12, 60.13, 53.07, 51.10, 49.95, 48.57, 38.88, 36.42, 31.55, 31.39, 29.67, 27.37, 25.93, 22.63, 14.12.
MS (ESI) m/z for C35H35N5O2[M+H]+:calcd556.71,found557.29.MS (ESI) m/z for C 35 H 35 N 5 O 2 [M+H]+:calcd556.71,found557.29.
제조예 5-4Preparation 5-4
제조예 2-1에서 2-((2-에틸-1-벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S801)의 사용 대신에 제조예 4-2에서 제조된 2-((1-벤질-1H-인돌-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S835)을 사용하고, 또한 제조예 2-1에서 아이오도메탄대신 2-(브로모메틸)나프탈렌을 사용하며 제조예 2-1과 동일한 방법으로 2-((1-벤질-1H-인돌-3-일)메틸)-7,7-디메틸-8-(나프탈렌-2-일메틸)헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S859)을 합성하였다.2-((2-ethyl-1-benzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ] in Preparation Example 2-1 2-((1-benzyl-1 H -indol-3-yl)methyl)-7,7-dimethylhexahydro- prepared in Preparation Example 4-2 instead of using pyrazine-6,9-dione (S801) 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S835) is used, and 2-(bromomethyl)naphthalene is used instead of iodomethane in Preparation Example 2-1, and Preparation Example In the same manner as in 2-1, 2-((1-benzyl- 1H -indol-3-yl)methyl)-7,7-dimethyl-8-(naphthalen-2-ylmethyl)hexahydro- 2H -pyra Zino [1,2- a ] pyrazine-6,9-dione (S859) was synthesized.
[화학식 49][Formula 49]
S859S859
Figure PCTKR2022006181-appb-img-000094
Figure PCTKR2022006181-appb-img-000094
1H NMR (500 MHz, CDCl3)δ 7.81 - 7.72 (m, 4H), 7.62 (s, 1H), 7.46 - 7.39 (m, 2H), 7.34 (dd, J = 8.5, 1.7 Hz, 1H), 7.30 - 7.06 (m, 8H), 7.04 (s, 1H), 5.25 (s, 2H), 4.88 (d, J = 15.8 Hz, 1H), 4.77 (d, J = 15.8 Hz, 1H), 4.50 (ddd, J = 13.0, 2.9, 1.7 Hz, 1H), 4.22 (dd, J = 10.9, 3.4 Hz, 1H), 3.88 (d, J = 13.3 Hz, 1H), 3.75 (d, J = 13.3 Hz, 1H), 3.70 (ddd, J = 11.3, 3.1, 1.6 Hz, 1H), 2.98 (dd, J = 10.2, 1.5 Hz, 1H), 2.81 (d, J = 3.4 Hz, 1H), 2.16 (t, J = 11.1 Hz, 1H), 2.06 (ddd, J = 19.7, 14.1, 6.4 Hz, 1H), 1.51 (s, 3H), 1.44 (s, 3H). 1 H NMR (500 MHz, CDCl 3 )δ 7.81 - 7.72 (m, 4H), 7.62 (s, 1H), 7.46 - 7.39 (m, 2H), 7.34 (dd, J = 8.5, 1.7 Hz, 1H), 7.30 - 7.06 (m, 8H), 7.04 (s, 1H), 5.25 (s, 2H), 4.88 (d, J = 15.8 Hz, 1H), 4.77 (d, J = 15.8 Hz, 1H), 4.50 (ddd , J = 13.0, 2.9, 1.7 Hz, 1H), 4.22 (dd, J = 10.9, 3.4 Hz, 1H), 3.88 (d, J = 13.3 Hz, 1H), 3.75 (d, J = 13.3 Hz, 1H) , 3.70 (ddd, J = 11.3, 3.1, 1.6 Hz, 1H), 2.98 (dd, J = 10.2, 1.5 Hz, 1H), 2.81 (d, J = 3.4 Hz, 1H), 2.16 (t, J = 11.1) Hz, 1H), 2.06 (ddd, J = 19.7, 14.1, 6.4 Hz, 1H), 1.51 (s, 3H), 1.44 (s, 3H).
13C NMR (126 MHz, CDCl3) δ 168.19, 165.36, 162.44, 137.39, 136.84, 135.64, 133.27, 132.54, 128.72, 128.37, 127.83, 127.67, 127.60, 127.57, 126.75, 126.66, 126.14, 125.88, 125.75, 125.47, 125.15, 121.94, 119.74, 119.39, 110.75, 109.72, 61.68, 56.95, 56.87, 53.38, 51.36, 49.90, 45.72, 45.28, 41.96, 36.34, 31.53, 31.33, 26.60, 26.49, 22.60, 14.11. 13 C NMR (126 MHz, CDCl 3 ) δ 168.19, 165.36, 162.44, 137.39, 136.84, 135.64, 133.27, 132.54, 128.72, 128.37, 127.83, 127.67, 127.60, 127.57, 126.75, 125.75, 125.47 126.14, 125.88 , 125.15, 121.94, 119.74, 119.39, 110.75, 109.72, 61.68, 56.95, 56.87, 53.38, 51.36, 49.90, 45.72, 45.28, 41.96, 36.34, 31.53, 31.33, 26.60, 26.49, 22.60, 14.11.
MS (ESI) m/z for C36H36N4O2[M+H]+:calcd556.71,found557.4.MS (ESI) m/z for C 36 H 36 N 4 O 2 [M+H] + :calcd556.71,found557.4.
제조예 5-5Preparation 5-5
제조예 2-1에서 2-((2-에틸-1-벤조[b]싸이오펜-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S801)의 사용 대신에 제조예 4-2에서 제조된 2-((1-벤질-1H-인돌-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S835)을 사용하고, 또한 제조예 2-1에서 아이오도메탄대신 브로모메틸벤젠을 사용하며 제조예 2-1과 동일한 방법으로 8-벤질-2-((1-벤질-1H-인돌-3-일)메틸)-7,7-디메틸헥사하이드로-2H-피라지노[1,2-a]피라진-6,9-디온(S860)을 합성하였다.2-((2-ethyl-1-benzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ] in Preparation Example 2-1 2-((1-benzyl-1 H -indol-3-yl)methyl)-7,7-dimethylhexahydro- prepared in Preparation Example 4-2 instead of using pyrazine-6,9-dione (S801) 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S835) is used, and in Preparation Example 2-1, bromomethylbenzene is used instead of iodomethane, and Preparation Example 2-1 and In the same manner, 8-benzyl-2-((1-benzyl- 1H -indol-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6 ,9-dione (S860) was synthesized.
[화학식 50][Formula 50]
S860S860
Figure PCTKR2022006181-appb-img-000095
Figure PCTKR2022006181-appb-img-000095
1H NMR (500 MHz, CDCl3)δ 7.81 - 7.72 (m, 4H), 7.62 (s, 1H), 7.46 - 7.39 (m, 2H), 7.34 (dd, J = 8.5, 1.7 Hz, 1H), 7.30 - 7.06 (m, 8H), 7.04 (s, 1H), 5.25 (s, 2H), 4.88 (d, J = 15.8 Hz, 1H), 4.77 (d, J = 15.8 Hz, 1H), 4.50 (ddd, J = 13.0, 2.9, 1.7 Hz, 1H), 4.22 (dd, J = 10.9, 3.4 Hz, 1H), 3.88 (d, J = 13.3 Hz, 1H), 3.75 (d, J = 13.3 Hz, 1H), 3.70 (ddd, J = 11.3, 3.1, 1.6 Hz, 1H), 2.98 (dd, J = 10.2, 1.5 Hz, 1H), 2.81 (d, J = 3.4 Hz, 1H), 2.16 (t, J = 11.1 Hz, 1H), 2.06 (ddd, J = 19.7, 14.1, 6.4 Hz, 1H), 1.51 (s, 3H), 1.44 (s, 3H). 1 H NMR (500 MHz, CDCl 3 )δ 7.81 - 7.72 (m, 4H), 7.62 (s, 1H), 7.46 - 7.39 (m, 2H), 7.34 (dd, J = 8.5, 1.7 Hz, 1H), 7.30 - 7.06 (m, 8H), 7.04 (s, 1H), 5.25 (s, 2H), 4.88 (d, J = 15.8 Hz, 1H), 4.77 (d, J = 15.8 Hz, 1H), 4.50 (ddd , J = 13.0, 2.9, 1.7 Hz, 1H), 4.22 (dd, J = 10.9, 3.4 Hz, 1H), 3.88 (d, J = 13.3 Hz, 1H), 3.75 (d, J = 13.3 Hz, 1H) , 3.70 (ddd, J = 11.3, 3.1, 1.6 Hz, 1H), 2.98 (dd, J = 10.2, 1.5 Hz, 1H), 2.81 (d, J = 3.4 Hz, 1H), 2.16 (t, J = 11.1) Hz, 1H), 2.06 (ddd, J = 19.7, 14.1, 6.4 Hz, 1H), 1.51 (s, 3H), 1.44 (s, 3H).
13C NMR (126 MHz, CDCl3) δ 168.19, 165.36, 162.44, 137.39, 136.84, 135.64, 133.27, 132.54, 128.72, 128.37, 127.83, 127.67, 127.60, 127.57, 126.75, 126.66, 126.14, 125.88, 125.75, 125.47, 125.15, 121.94, 119.74, 119.39, 110.75, 109.72, 61.68, 56.95, 56.87, 53.38, 51.36, 49.90, 45.72, 45.28, 41.96, 36.34, 31.53, 31.33, 26.60, 26.49, 22.60, 14.11. 13 C NMR (126 MHz, CDCl 3 ) δ 168.19, 165.36, 162.44, 137.39, 136.84, 135.64, 133.27, 132.54, 128.72, 128.37, 127.83, 127.67, 127.60, 127.57, 126.75, 125.75, 125.47 126.14, 125.88 , 125.15, 121.94, 119.74, 119.39, 110.75, 109.72, 61.68, 56.95, 56.87, 53.38, 51.36, 49.90, 45.72, 45.28, 41.96, 36.34, 31.53, 31.33, 26.60, 26.49, 22.60, 14.11.
MS (ESI) m/z for C36H36N4O2[M+H]+:calcd506.65,found507.27.MS (ESI) m/z for C 36 H 36 N 4 O 2 [M+H] + :calcd506.65,found507.27.
실험예Experimental example
1. SKOV3와 SKOV3-TR, Hela, Hela-PTX-R, MCF7, MCF7-BC19의 준비1. Preparation of SKOV3 and SKOV3-TR, Hela, Hela-PTX-R, MCF7, MCF7-BC19
상피성 난소암 세포주인 SKOV3와, 이로부터 유래하여 파클리탁셀(Paclitaxel) 항암제에 저항성을 갖는 내성 암세포주로 제작된 SKOV3-TR를 준비하였다. SKOV3, an epithelial ovarian cancer cell line, and SKOV3-TR, which was derived from this and produced as a resistant cancer cell line having resistance to the anticancer agent of Paclitaxel, were prepared.
또한, 자궁경부암 상피 세포주인 Hela와, 이로부터 유래하여 파클리탁셀(Paclitaxel) 항암제에 저항성을 갖는 내성 암세포주로 제작된 Hela-PTX-R를 준비하였다. In addition, Hela, a cervical cancer epithelial cell line, and Hela-PTX-R, which was derived therefrom and produced as a resistant cancer cell line having resistance to the anticancer drug Paclitaxel, were prepared.
또한, 유방암 상피 세포주인 MCF7과, 이로부터 P-gp를 과발현시켜 파클리탁셀(Paclitaxel) 항암제에 저항성을 갖는 내성 암세포주로 제작된 MCF7-BC19를 준비하였다. In addition, MCF7, a breast cancer epithelial cell line, and MCF7-BC19 prepared as a resistant cancer cell line having resistance to the anticancer drug Paclitaxel by overexpressing P-gp therefrom were prepared.
이 세포주들로 세포실험을 진행하여 도 1 내지 도 4에 나타내었다. 도 1은 SKOV3의 파클리탁셀과 도세탁셀 항암제 IC50값을 나타낸 것이고, 도 2는 SKOV3-TR의 파클리탁셀과 도세탁셀 항암제 IC50값을 나타낸 것이다. 도 3은 Hela와 Hela-PTX-R의 파클리탁셀 항암제 IC50값을 나타낸 것이고, 도 4는 MCF7과 MCF7-BC19의 파클리탁셀 항암제 IC50값을 나타낸 것이다. Cell experiments were performed with these cell lines, and are shown in FIGS. 1 to 4 . 1 shows the IC 50 values of paclitaxel and docetaxel anticancer drugs of SKOV3, and FIG. 2 shows the IC 50 values of paclitaxel and docetaxel anticancer drugs of SKOV3-TR. Figure 3 shows the IC 50 value of the anticancer agent Paclitaxel of Hela and Hela-PTX-R, Figure 4 shows the IC 50 value of the anticancer agent Paclitaxel of MCF7 and MCF7-BC19.
2. WST-1 분석2. WST-1 Analysis
세포증식이나 생존을 측정하는 WST-1 분석 결과에 의하면, 파클리탁셀 처리에 의해 SKOV3, SKOV3-TR, Hela, Hela-PTX-R, MCF7, MCF7-BC19에서 물질대사의 감소를 유발하였다. According to the results of the WST-1 assay measuring cell proliferation or survival, paclitaxel treatment induced a decrease in metabolism in SKOV3, SKOV3-TR, Hela, Hela-PTX-R, MCF7, and MCF7-BC19.
2-1. SKOV3, SKOV3-TR의 WST-1 분석2-1. WST-1 analysis of SKOV3, SKOV3-TR
SKOV3, SKOV3-TR에 대하여 각각 47종의 화합물과 파클리탁셀(Paclitaxel)과 병용처리한 후 WST-1 분석을 실시하였다.For SKOV3 and SKOV3-TR, 47 compounds and paclitaxel were co-treated, respectively, and then WST-1 analysis was performed.
구체적으로 96-Well에서 자라고 있는 암세포주들에 47종류의 S-forms을 10μM을 처리한 후 파클리탁셀을 병용 처리하였고, 파클리탁셀 농도는 SKOV3-TR 세포주에는 3μM, SKOV3 세포주에는 0.002μM로 처리하였다. Specifically, 47 types of S-forms were treated with 10 μM of cancer cell lines growing in 96-Well, and then paclitaxel was co-treated, and the concentration of paclitaxel was 3 μM for the SKOV3-TR cell line and 0.002 μM for the SKOV3 cell line.
세포독성 분석을 위해 DMSO (파클리탁셀, S-form 용매), 파클리탁셀(Paclitaxel)과 47종의 S-forms을 병용처리한지 3일 후에 WST-1 분석을 실시하여 도 5 내지 도 8에 나타내었다.For cytotoxicity analysis, DMSO (paclitaxel, S-form solvent), paclitaxel (Paclitaxel) and 47 kinds of S-forms were co-treated with WST-1 analysis 3 days later, and are shown in FIGS. 5 to 8 .
도 5, 도 7은 DMSO, 파클리탁셀, S801(10μM), S802(10μM), S803(10μM), S804(10μM), S806(10μM), S807(10μM), S808(10μM), S809(10μM), S810(10μM), S811(10μM), S812(10μM), S813(10μM), S815(10μM), S816(10μM), S819(10μM), S820(10μM), S821(10μM), S845(10μM), S855(10μM), S805(10μM), S822(10μM), S833(10μM), S834(10μM), S835(10μM)의 순서로 나타낸 것이다.5 and 7 show DMSO, paclitaxel, S801 (10 μM), S802 (10 μM), S803 (10 μM), S804 (10 μM), S806 (10 μM), S807 (10 μM), S808 (10 μM), S809 (10 μM), S810 (10 μM), S811 (10 μM), S812 (10 μM), S813 (10 μM), S815 (10 μM), S816 (10 μM), S819 (10 μM), S820 (10 μM), S821 (10 μM), S845 (10 μM), S855 (10 μM), S805 (10 μM), S822 (10 μM), S833 (10 μM), S834 (10 μM), S835 (10 μM) are shown in the order.
도 6, 도 8은 DMSO, 파클리탁셀, S836(10μM), S838(10μM), S840(10μM), S841(10μM), S842(10μM), S857(10μM), S858(10μM), S860(10μM), S823(10μM), S824(10μM), S825(10μM), S826(10μM), S856(10μM), S859(10μM), S839(10μM), S827(10μM), S828(10μM), S814(10μM), S830(10μM), S832(10μM), S829(10μM), S831(10μM), S847(10μM)의 순으로 나타낸 것이다.6 and 8 show DMSO, paclitaxel, S836 (10 μM), S838 (10 μM), S840 (10 μM), S841 (10 μM), S842 (10 μM), S857 (10 μM), S858 (10 μM), S860 (10 μM), S823 (10 μM), S824 (10 μM), S825 (10 μM), S826 (10 μM), S856 (10 μM), S859 (10 μM), S839 (10 μM), S827 (10 μM), S828 (10 μM), S814 (10 μM), S830 (10 μM), S832 (10 μM), S829 (10 μM), S831 (10 μM), and S847 (10 μM) are shown in this order.
즉, 파클리탁셀 처리군은 SKOV3-TR 및 SKOV3에서 세포사멸 유발 및 세포성장 억제 등의 현상으로 인해 DMSO 처리군에 비해 450nm의 흡광도가 감소하였다. S-forms을 파클리탁셀과 병용처리 시 내성 암세포주인 SKOV3-TR에서는 파클리탁셀의 항암효능을 증강하여 파클리탁셀 처리군에 비해 더 낮은 흡광도를 보였다. 비교예인 파클리탁셀 처리군의 흡광도에 기준선을 넣었다. 파클리탁셀 항암증강 효능은 파클리탁셀 처리군에 비해 파클리탁셀+S-forms 처리시 WST-1 분석에서 흡광도(OD Value at 450nm)가 유의하게 감소하였다. That is, in the paclitaxel-treated group, the absorbance at 450 nm was decreased compared to the DMSO-treated group due to phenomena such as apoptosis induction and cell growth inhibition in SKOV3-TR and SKOV3. When S-forms were treated in combination with paclitaxel, SKOV3-TR, a resistant cancer cell line, enhanced the anticancer effect of paclitaxel and showed lower absorbance compared to the paclitaxel-treated group. A baseline was included in the absorbance of the paclitaxel-treated group, which is a comparative example. As for the anticancer enhancing efficacy of paclitaxel, the absorbance (OD Value at 450nm) was significantly decreased in the WST-1 analysis when paclitaxel + S-forms was treated compared to the paclitaxel-treated group.
또한, 세포증식이나 생존을 측정하는 WST-1 분석 결과에 의하면, 도세탁셀 처리에 의해 SKOV3-TR 및 SKOV3에서 물질대사의 감소를 유발하였다. In addition, according to the results of WST-1 analysis to measure cell proliferation or survival, docetaxel treatment induced a decrease in metabolism in SKOV3-TR and SKOV3.
SKOV3-TR과 SKOV3 암세포주들에 47종류의 S-forms을 처리한 후 도세탁셀을 병용 처리하였고, WST-1 분석을 실시하였다.SKOV3-TR and SKOV3 cancer cell lines were treated with 47 types of S-forms, then treated with docetaxel, and WST-1 analysis was performed.
구체적으로, 96-well에서 자라고 있는 두 세포주에 47종류의 S-form을 2μM로 도세탁셀을 함께 처리하였고, 도세탁셀 농도는 SKOV3-TR 세포주에는 1μM, SKOV3 세포주에는 0.75nM 처리하였다. 세포독성 분석을 위해 DMSO (도세탁셀, S-form 용매), 도세탁셀(Docetaxel)과 47종의 S-forms을 병용처리한지 3일 후에 WST-1 분석을 실시하여 도 9 내지 도 12에 나타내었다.Specifically, two cell lines grown in 96-well were treated with docetaxel at 2 μM of 47 types of S-form, and docetaxel concentrations were 1 μM in the SKOV3-TR cell line and 0.75 nM in the SKOV3 cell line. For cytotoxicity analysis, DMSO (docetaxel, S-form solvent), docetaxel (Docetaxel) and 47 types of S-forms were co-treated with WST-1 analysis 3 days later, and are shown in FIGS. 9 to 12 .
도 9, 도 11은 DMSO, 도세탁셀, S801(2μM), S802(2μM), S803(2μM), S804(2μM), S806(2μM), S807(2μM), S808(2μM), S809(2μM), S810(2μM), S811(2μM), S812(2μM), S813(2μM), S815(2μM), S816(2μM), S819(2μM), S820(2μM), S821(2μM), S845(2μM), S855(2μM), S805(2μM), S822(2μM), S833(2μM), S834(2μM), S835(2μM)의 순서로 나타낸 것이다.9 and 11 show DMSO, docetaxel, S801 (2 μM), S802 (2 μM), S803 (2 μM), S804 (2 μM), S806 (2 μM), S807 (2 μM), S808 (2 μM), S809 (2 μM), S810 (2 μM), S811 (2 μM), S812 (2 μM), S813 (2 μM), S815 (2 μM), S816 (2 μM), S819 (2 μM), S820 (2 μM), S821 (2 μM), S845 (2 μM), S855 (2 μM), S805 (2 μM), S822 (2 μM), S833 (2 μM), S834 (2 μM), S835 (2 μM) are shown in the order.
도 10, 도 12는 DMSO, 도세탁셀, S836(2μM), S838(2μM), S840(2μM), S841(2μM), S842(2μM), S857(2μM), S858(2μM), S860(2μM), S823(2μM), S824(2μM), S825(2μM), S826(2μM), S856(2μM), S859(2μM), S839(2μM), S827(2μM), S828(2μM), S814(2μM), S830(2μM), S832(2μM), S829(2μM), S831(2μM), S847(2μM)의 순으로 나타낸 것이다.10 and 12 show DMSO, docetaxel, S836 (2 μM), S838 (2 μM), S840 (2 μM), S841 (2 μM), S842 (2 μM), S857 (2 μM), S858 (2 μM), S860 (2 μM), S823 (2 μM), S824 (2 μM), S825 (2 μM), S826 (2 μM), S856 (2 μM), S859 (2 μM), S839 (2 μM), S827 (2 μM), S828 (2 μM), S814 (2 μM), S830 (2 μM), S832 (2 μM), S829 (2 μM), S831 (2 μM), and S847 (2 μM) are shown in this order.
즉, 도세탁셀(Doxetaxel)처리군은 SKOV3-TR 및 SKOV3에서 세포사멸 유발 및 세포성장 억제 등의 현상으로 인해 DMSO 처리군에 비해 450nm의 흡광도가 감소하였다. S-forms을 도세탁셀(Doxetaxel)과 병용처리 시 내성 암세포주인 SKOV3-TR에서는 도세탁셀의 항암효능을 증강하여 도세탁셀 (Doxetaxel) 처리군에 비해 더 낮은 흡광도를 보였다. 비교예인 도세탁셀(Doxetaxel) 처리군의 흡광도에 기준선을 넣었다. 도세탁셀 항암증강 효능은 도세탁셀 (Doxetaxel)에 비해 도세탁셀+S-forms 처리시 WST-1 분석에서 흡광도(OD Value at 450nm)가 유의하게 감소하였다. That is, the docetaxel (Doxetaxel) treatment group had a decrease in absorbance at 450 nm compared to the DMSO treatment group due to phenomena such as apoptosis induction and cell growth inhibition in SKOV3-TR and SKOV3. When S-forms were treated in combination with docetaxel (Doxetaxel), the resistant cancer cell line, SKOV3-TR, enhanced the anticancer effect of docetaxel and showed lower absorbance compared to the docetaxel-treated group. A reference line was put in the absorbance of the comparative example docetaxel (Doxetaxel) treatment group. The anticancer enhancing efficacy of docetaxel was significantly reduced in the WST-1 analysis when docetaxel+S-forms were treated compared to docetaxel (Doxetaxel) in absorbance (OD Value at 450nm).
2-2. Hela, Hela-PTX-R의 WST-1 분석2-2. WST-1 analysis of Hela, Hela-PTX-R
세포증식이나 생존을 측정하는 WST-1 분석 결과에 의하면, 파클리탁셀 처리에 의해 Hela-PTX-R 및 Hela에서 물질대사의 감소를 유발하였다. According to the results of the WST-1 assay measuring cell proliferation or survival, paclitaxel treatment induced a decrease in metabolism in Hela-PTX-R and Hela.
Hela-PTX-R과 Hela 암세포주들에 47종류의 화합물을 처리한 후 파클리탁셀을 병용 처리하였고, WST-1 분석을 실시하였다.Hela-PTX-R and Hela cancer cell lines were treated with 47 types of compounds, then treated with paclitaxel, and WST-1 analysis was performed.
구체적으로, 96-well에서 자라고 있는 두 세포주에 47종류의 S-form을 10μM로 파클리탁셀을 함께 처리하였고, 파클리탁셀 농도는 Hela-PTX-R 세포주에는 0.015μM, Hela 세포주에는 0.002μM 처리하였다. 세포독성 분석을 위해 DMSO (파클리탁셀, S-form 용매), 파클리탁셀(Paclitaxel)과 47종의 S-forms을 병용처리한지 3일 후에 WST-1 분석을 실시하여 도 13 내지 도 16에 나타내었다.Specifically, two cell lines grown in 96-well were treated with paclitaxel at 10 μM of 47 types of S-form, and the concentration of paclitaxel was 0.015 μM in the Hela-PTX-R cell line and 0.002 μM in the Hela cell line. For cytotoxicity analysis, DMSO (paclitaxel, S-form solvent), paclitaxel (Paclitaxel) and 47 kinds of S-forms were co-treated 3 days after WST-1 analysis was performed and shown in FIGS. 13 to 16 .
도 13, 도 15는 DMSO, 파클리탁셀, S801(10μM), S802(10μM), S803(10μM), S804(10μM), S806(10μM), S807(10μM), S808(10μM), S809(10μM), S810(10μM), S811(10μM), S812(10μM), S813(10μM), S815(10μM), S816(10μM), S819(10μM), S820(10μM), S821(10μM), S845(10μM), S855(10μM), S805(10μM), S822(10μM), S833(10μM), S834(10μM), S835(10μM)의 순서로 나타낸 것이다.13 and 15 show DMSO, paclitaxel, S801 (10 μM), S802 (10 μM), S803 (10 μM), S804 (10 μM), S806 (10 μM), S807 (10 μM), S808 (10 μM), S809 (10 μM), S810 (10 μM), S811 (10 μM), S812 (10 μM), S813 (10 μM), S815 (10 μM), S816 (10 μM), S819 (10 μM), S820 (10 μM), S821 (10 μM), S845 (10 μM), S855 (10 μM), S805 (10 μM), S822 (10 μM), S833 (10 μM), S834 (10 μM), S835 (10 μM) are shown in the order.
도 14, 도 16은 DMSO, 파클리탁셀, S836(10μM), S838(10μM), S840(10μM), S841(10μM), S842(10μM), S857(10μM), S858(10μM), S860(10μM), S823(10μM), S824(10μM), S825(10μM), S826(10μM), S856(10μM), S859(10μM), S839(10μM), S827(10μM), S828(10μM), S814(10μM), S830(10μM), S832(10μM), S829(10μM), S831(10μM), S847(10μM)의 순으로 나타낸 것이다.14 and 16 show DMSO, paclitaxel, S836 (10 μM), S838 (10 μM), S840 (10 μM), S841 (10 μM), S842 (10 μM), S857 (10 μM), S858 (10 μM), S860 (10 μM), S823 (10 μM), S824 (10 μM), S825 (10 μM), S826 (10 μM), S856 (10 μM), S859 (10 μM), S839 (10 μM), S827 (10 μM), S828 (10 μM), S814 (10 μM), S830 (10 μM), S832 (10 μM), S829 (10 μM), S831 (10 μM), and S847 (10 μM) are shown in this order.
즉, 파클리탁셀 처리군은 Hela-PTX-R 및 Hela에서 세포사멸 유발 및 세포성장 억제 등의 현상으로 인해 DMSO 처리군에 비해 450nm의 흡광도가 감소하였다. S-forms을 파클리탁셀과 병용처리 시 내성 암세포주인 Hela-PTX-R에서는 파클리탁셀의 항암효능을 증강하여 파클리탁셀 처리군에 비해 더 낮은 흡광도를 보였다. 비교예인 파클리탁셀 처리군의 흡광도에 기준선을 넣었다. 파클리탁셀 항암증강 효능은 파클리탁셀 처리군에 비해 파클리탁셀+S-forms 처리시 WST-1 분석에서 흡광도(OD Value at 450nm)가 유의하게 감소하였다.That is, the paclitaxel-treated group had a decrease in absorbance at 450 nm compared to the DMSO-treated group due to phenomena such as apoptosis induction and cell growth inhibition in Hela-PTX-R and Hela. When S-forms were treated in combination with paclitaxel, Hela-PTX-R, a resistant cancer cell line, enhanced the anticancer effect of paclitaxel and showed lower absorbance compared to the paclitaxel-treated group. A baseline was included in the absorbance of the paclitaxel-treated group, which is a comparative example. As for the anticancer enhancing efficacy of paclitaxel, the absorbance (OD Value at 450nm) was significantly decreased in the WST-1 analysis when paclitaxel + S-forms was treated compared to the paclitaxel-treated group.
2-3. MCF7, MCF7-BC19의 WST-1 분석2-3. WST-1 analysis of MCF7, MCF7-BC19
세포증식이나 생존을 측정하는 WST-1 분석 결과에 의하면, 파클리탁셀 처리에 의해 MCF7-BC19 및 MCF7에서 물질대사의 감소를 유발하였다. According to the results of WST-1 assay measuring cell proliferation or survival, paclitaxel treatment induced a decrease in metabolism in MCF7-BC19 and MCF7.
MCF7-BC19과 MCF7 암세포주들에 47종류의 화합물을 처리한 후 파클리탁셀을 병용 처리하였고, WST-1 분석을 실시하였다.MCF7-BC19 and MCF7 cancer cell lines were treated with 47 types of compounds and then treated with paclitaxel, and WST-1 analysis was performed.
구체적으로, 96-well에서 자라고 있는 두 세포주에 47종류의 S-form을 10μM로 파클리탁셀을 함께 처리하였고, 파클리탁셀 농도는 MCF7-BC19 세포주에는 0.2μM, MCF7 세포주에는 0.001μM 처리하였다. 세포독성 분석을 위해 DMSO (파클리탁셀, S-form 용매), 파클리탁셀(Paclitaxel)과 47종의 S-forms을 병용처리한지 3일 후에 WST-1 분석을 실시하여 도 17 내지 도 20에 나타내었다.Specifically, two cell lines grown in 96-well were treated with paclitaxel at 10 μM of 47 types of S-form, and the concentration of paclitaxel was 0.2 μM for MCF7-BC19 cell line and 0.001 μM for MCF7 cell line. For cytotoxicity analysis, DMSO (paclitaxel, S-form solvent), paclitaxel (Paclitaxel) and 47 kinds of S-forms were co-treated, and WST-1 analysis was performed 3 days later and shown in FIGS. 17 to 20 .
도 17, 도 19는 DMSO, 파클리탁셀, S801(10μM), S802(10μM), S803(10μM), S804(10μM), S806(10μM), S807(10μM), S808(10μM), S809(10μM), S810(10μM), S811(10μM), S812(10μM), S813(10μM), S815(10μM), S816(10μM), S819(10μM), S820(10μM), S821(10μM), S845(10μM), S855(10μM), S805(10μM), S822(10μM), S833(10μM), S834(10μM), S835(10μM)의 순서로 나타낸 것이다.Figure 17, Figure 19 DMSO, paclitaxel, S801 (10 μM), S802 (10 μM), S803 (10 μM), S804 (10 μM), S806 (10 μM), S807 (10 μM), S808 (10 μM), S809 (10 μM), S810 (10 μM), S811 (10 μM), S812 (10 μM), S813 (10 μM), S815 (10 μM), S816 (10 μM), S819 (10 μM), S820 (10 μM), S821 (10 μM), S845 (10 μM), S855 (10 μM), S805 (10 μM), S822 (10 μM), S833 (10 μM), S834 (10 μM), S835 (10 μM) are shown in the order.
도 18, 도 20은 DMSO, 파클리탁셀, S836(10μM), S838(10μM), S840(10μM), S841(10μM), S842(10μM), S857(10μM), S858(10μM), S860(10μM), S823(10μM), S824(10μM), S825(10μM), S826(10μM), S856(10μM), S859(10μM), S839(10μM), S827(10μM), S828(10μM), S814(10μM), S830(10μM), S832(10μM), S829(10μM), S831(10μM), S847(10μM)의 순으로 나타낸 것이다.18 and 20 show DMSO, paclitaxel, S836 (10 μM), S838 (10 μM), S840 (10 μM), S841 (10 μM), S842 (10 μM), S857 (10 μM), S858 (10 μM), S860 (10 μM), S823 (10 μM), S824 (10 μM), S825 (10 μM), S826 (10 μM), S856 (10 μM), S859 (10 μM), S839 (10 μM), S827 (10 μM), S828 (10 μM), S814 (10 μM), S830 (10 μM), S832 (10 μM), S829 (10 μM), S831 (10 μM), and S847 (10 μM) are shown in this order.
즉, 파클리탁셀 처리군은 MCF7-BC19 및 MCF7에서 세포사멸 유발 및 세포성장 억제 등의 현상으로 인해 DMSO 처리군에 비해 450nm의 흡광도가 감소하였다. S-forms을 파클리탁셀과 병용처리 시 내성 암세포주인 MCF7-BC19에서는 파클리탁셀의 항암효능을 증강하여 파클리탁셀 처리군에 비해 더 낮은 흡광도를 보였다. 비교예인 파클리탁셀 처리군의 흡광도에 기준선을 넣었다. 파클리탁셀 항암증강 효능은 파클리탁셀 처리군에 비해 파클리탁셀+S-forms 처리시 WST-1 분석에서 흡광도(OD Value at 450nm)가 유의하게 감소하였다.That is, in the paclitaxel-treated group, the absorbance at 450 nm was decreased compared to the DMSO-treated group due to phenomena such as apoptosis induction and cell growth inhibition in MCF7-BC19 and MCF7. When S-forms were co-treated with paclitaxel, the resistant cancer cell line MCF7-BC19 enhanced the anticancer effect of paclitaxel and showed lower absorbance compared to the paclitaxel-treated group. A baseline was included in the absorbance of the paclitaxel-treated group, which is a comparative example. As for the anticancer enhancing efficacy of paclitaxel, the absorbance (OD Value at 450nm) was significantly decreased in the WST-1 analysis when paclitaxel + S-forms was treated compared to the paclitaxel-treated group.
본 출원이 속하는 기술분야의 통상의 지식을 가진 자는 본 출원이 그 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. 본 출원의 범위는 상기 상세한 설명보다는 후술하는 청구범위에 의하여 나타내어지며, 청구범위의 의미 및 범위 그리고 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 출원의 범위에 포함되는 것으로 해석되어야 한다.Those of ordinary skill in the art to which the present application pertains will understand that the present application may be implemented in other specific forms without changing the technical spirit or essential features thereof. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present application is indicated by the following claims rather than the above detailed description, and all changes or modifications derived from the meaning and scope of the claims and their equivalents should be construed as being included in the scope of the present application.

Claims (16)

  1. 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염:A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2022006181-appb-img-000096
    Figure PCTKR2022006181-appb-img-000096
    상기 화학식 1에서,In Formula 1,
    R1은 수소, C1~C10 직쇄 또는 분지쇄알킬, C1~C10 알콕시, C1~C10 할로알킬, C1~C10 할로알콕시, C6~C12 아릴, C5~C12 헤테로아릴, 알킬(C1~C10)아릴(C6~C12) 또는 알킬(C1~C10)헤테로아릴(C5~C12)이고, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C10 알킬, C1~C10 알콕시, C3~C10 사이클로알킬, C1~C10 할로알킬, C1~C10 할로알콕시, 옥소, 시아노, 비치환되거나 치환된 C6~C12 아릴, 또는 비치환되거나 치환된 C5~C12 헤테로아릴중 적어도 하나로 치환될 수 있고;R 1 is hydrogen, C 1 -C 10 straight or branched chain alkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, C 6 -C 12 aryl, C 5 -C 12 heteroaryl, alkyl (C 1 -C 10 )aryl (C 6 -C 12 ) or alkyl (C 1 -C 10 )heteroaryl (C 5 -C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl, C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, oxo, cyano, unsubstituted or substituted C 6 can be substituted with at least one of -C 12 aryl, or unsubstituted or substituted C 5 -C 12 heteroaryl;
    R3은 수소, C1~C10 직쇄 또는 분지쇄알킬, C3~C10 사이클로알킬, C6~C12 아릴, C5~C12 헤테로아릴, 알킬(C1~C10)아릴(C6~C12) 또는 알킬(C1~C10)헤테로아릴(C5~C12)이며, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C10 알킬, C1~C10 알콕시, C1~C10 할로알킬, C1~C10 할로알콕시, 옥소, 시아노, 비치환되거나 치환된아릴, 또는 비치환되거나 치환된 C5~C12 헤테로아릴중 적어도 하나로 치환될 수 있으며;R 3 is hydrogen, C 1 -C 10 straight or branched chain alkyl, C 3 -C 10 cycloalkyl, C 6 -C 12 aryl, C 5 -C 12 heteroaryl, alkyl (C 1 -C 10 ) aryl (C 6 -C 12 ) or alkyl (C 1 -C 10 )heteroaryl (C 5 -C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C may be substituted with at least one of 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted C 5 -C 12 heteroaryl;
    L1은 직접 연결 또는 C1~C10 알킬렌이며, 이때 상기 알킬렌은 C1~C10 알킬, C3~C10 사이클로알킬, C1~C10 알콕시, 히드록실, 옥소 또는 할로겐 중 적어도 하나로 치환될 수 있고, 상기 C1~C10 알킬, C3~C10 사이클로알킬, C1~C10 알콕시는 비치환되거나 치환된 C6~C12 아릴 또는 C3~C10 사이클로알킬로 치환될 수 있고;L 1 is a direct linkage or C 1 -C 10 alkylene, wherein the alkylene is at least one of C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy, hydroxyl, oxo or halogen. may be substituted with one, wherein the C 1 ~C 10 alkyl, C 3 ~C 10 cycloalkyl, C 1 ~C 10 alkoxy is unsubstituted or substituted with C 6 ~C 12 aryl or C 3 ~C 10 cycloalkyl can be;
    Q는 S, Se, NR, P, P(O), P(O)2 또는 P(O)OR 이며, 이때 상기 R은 수소, C1~C10 직쇄 또는 분지쇄 알킬, C3~C10 사이클로알킬, 바이 또는 트라이 C3~C10 사이클로알킬, C1~C10 알콕시, C1~C10 할로알킬, C1~C10 할로알콕시, C6~C12 아릴, C5~C12 헤테로아릴, 알킬(C1~C10)아릴(C6~C12) 또는 알킬(C1~C10)헤테로아릴(C5~C12)이고, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C10 알킬, C1~C10 알콕시, C1~C10 할로알킬, C1~C10 할로알콕시, 옥소, 시아노, 비치환되거나 치환된 C6~C12 아릴, 또는 비치환되거나 치환된 C5~C12 헤테로아릴 중 적어도 하나로 치환될 수 있으며;Q is S, Se, NR, P, P(O), P(O) 2 or P(O)OR , wherein R is hydrogen, C 1 -C 10 straight or branched chain alkyl, C 3 -C 10 Cycloalkyl, bi or tri C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, C 6 -C 12 aryl, C 5 -C 12 hetero aryl, alkyl (C 1 -C 10 )aryl (C 6 -C 12 ) or alkyl (C 1 -C 10 )heteroaryl (C 5 -C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, oxo, cyano, unsubstituted or substituted C 6 -C 12 aryl, or unsubstituted or substituted may be substituted with at least one of C 5 -C 12 heteroaryl;
    R2는 수소, C1~C10 직쇄알킬, C3~C10 사이클로알킬, C1~C10 알콕시, C1~C10 할로알콕시, C1~C10 할로알킬, C6~C12 아릴, C5~C12 헤테로아릴, 알킬(C1~C10)아릴(C6~C12) 또는 알킬(C1~C10)헤테로아릴(C5~C12)이고, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C10 알킬, C1~C10 알콕시, C1~C10 할로알킬, C1~C10 할로알콕시, 비치환되거나 치환된 C6~C12아릴, 비치환되거나 치환된 C5~C12 헤테로아릴, 옥소, 나이트로, 시아노 또는 트리플루오로메틸 중 적어도 하나로 치환될 수 있고;R 2 is hydrogen, C 1 -C 10 straight chain alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkoxy, C 1 -C 10 haloalkyl, C 6 -C 12 aryl , C 5 -C 12 heteroaryl, alkyl (C 1 -C 10 )aryl (C 6 -C 12 ) or alkyl (C 1 -C 10 )heteroaryl (C 5 -C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, unsubstituted or substituted C 6 -C 12 aryl, unsubstituted or may be substituted with at least one of substituted C 5 -C 12 heteroaryl, oxo, nitro, cyano or trifluoromethyl;
    R4 및 R4’은 각각 독립적으로 C1~C10 직쇄 또는 분지쇄알킬, C3~C10 사이클로알킬, C2~C10 알케닐, C2~C10 알키닐, C1~C10 알킬싸이오, C6~C12 아릴, C5~C12 헤테로아릴, 알킬(C1~C10)아릴(C6~C12) 또는 알킬(C1~C10)헤테로아릴(C5~C12)이며, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C10 알킬, C1~C10 알콕시, C1~C10 할로알킬, C1~C10 할로알콕시, 비치환되거나 치환된 C6~C12 아릴, 비치환되거나 치환된 C5~C12 헤테로아릴, 옥소, 나이트로, 시아노 또는 트리플루오로메틸 중 적어도 하나로 치환될 수 있으며;R 4 and R 4 ' are each independently C 1 -C 10 straight or branched chain alkyl, C 3 -C 10 cycloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 Alkylthio, C 6 ~ C 12 aryl, C 5 ~ C 12 heteroaryl, alkyl (C 1 ~ C 10 ) aryl (C 6 ~ C 12 ) or alkyl (C 1 ~C 10 ) heteroaryl (C 5 ~ C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, unsubstituted or substituted may be substituted with at least one of C 6 -C 12 aryl, unsubstituted or substituted C 5 -C 12 heteroaryl, oxo, nitro, cyano or trifluoromethyl;
    n은 1 내지 4의 정수이고;n is an integer from 1 to 4;
    X, Y, Z는 각각 독립적으로 수소, C1~C10 직쇄 또는 분지쇄알킬, C3~C10 사이클로알킬, C6~C12 아릴, C5~C12 헤테로아릴, 알킬(C1~C10)아릴(C6~C12) 또는 알킬(C1~C10)헤테로아릴(C5~C12)이며, 이들 각각은 독립적으로 히드록실, 할로겐, C1~C10알킬, C1~C10알콕시, C1~C10 할로알킬, C1~C10 할로알콕시, 비치환되거나 치환된 C6~C12 아릴, 비치환되거나 치환된 C5~C12헤테로아릴, 옥소, 나이트로, 시아노, 또는 트리플루오로메틸 중 적어도 하나로 치환될 수 있다. X, Y, Z are each independently hydrogen, C 1 ~ C 10 straight or branched chain alkyl, C 3 ~ C 10 cycloalkyl, C 6 ~ C 12 aryl, C 5 ~ C 12 heteroaryl, alkyl (C 1 ~ C 10 )aryl (C 6 -C 12 ) or alkyl (C 1 -C 10 )heteroaryl (C 5 -C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, unsubstituted or substituted C 6 -C 12 aryl, unsubstituted or substituted C 5 -C 12 heteroaryl, oxo, nitro , cyano, or trifluoromethyl.
  2. 청구항 1에 있어서, The method according to claim 1,
    상기 n은 1인 화합물 또는 이의 약학적으로 허용 가능한 염.wherein n is 1, or a pharmaceutically acceptable salt thereof.
  3. 청구항 1 내지 2 중 어느 한 항에 있어서,The method according to any one of claims 1 to 2,
    상기 R1은 수소, 비치환되거나 치환된 C1~C6 직쇄알킬, 비치환되거나 치환된 벤질, 또는 비치환되거나 치환된 2-페닐에틸이고, 이때 상기 치환된 C1~C6 직쇄알킬은 C3~C6 사이클로알킬로 치환된 것이고, 상기 치환된 벤질 또는 상기 치환된 2-페닐에틸은 오쏘, 메타 및 파라 위치 중 적어도 하나가 할로겐으로 치환되거나 페닐로 치환된 것이며;wherein R 1 is hydrogen, unsubstituted or substituted C 1 -C 6 straight chain alkyl, unsubstituted or substituted benzyl, or unsubstituted or substituted 2-phenylethyl, wherein the substituted C 1 -C 6 straight chain alkyl is substituted with C 3 -C 6 cycloalkyl, wherein the substituted benzyl or the substituted 2-phenylethyl is at least one of the ortho, meta and para positions substituted with halogen or substituted with phenyl;
    상기 R3은 수소, 비치환되거나 치환된 C1~C3 직쇄알킬, 비치환되거나 치환된 C1~C3 알콕시, 또는 할로겐이고;wherein R 3 is hydrogen, unsubstituted or substituted C 1 -C 3 straight chain alkyl, unsubstituted or substituted C 1 -C 3 alkoxy, or halogen;
    상기 L1은 C1~C4 알킬렌이며, 이때 상기 알킬렌은 C1~C6 알킬, C3~C6 사이클로알킬, C1~C6 알콕시, 히드록실, 또는 옥소 중 적어도 하나로 치환될 수 있고, 상기 C1~C6 알킬, C3~C6 사이클로알킬, C1~C6 알콕시는 비치환되거나 치환된 C6~C12 아릴 또는 C3~C6 사이클로알킬로 치환된 것이고;wherein L 1 is C 1 -C 4 alkylene, wherein the alkylene may be substituted with at least one of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxyl, or oxo may, wherein the C 1 ~C 6 alkyl, C 3 ~C 6 cycloalkyl, C 1 ~C 6 alkoxy is unsubstituted or substituted with substituted C 6 ~C 12 aryl or C 3 ~C 6 cycloalkyl;
    상기 R2는 수소, 비치환되거나 치환된 C1~C6 직쇄알킬, 비치환되거나 치환된 사이클로헥실, 비치환되거나 치환된 벤질, 비치환되거나 치환된 2-페닐에틸, 비치환되거나 치환된 바이페닐, 2-나프틸메틸 또는 1-나프틸메틸이고, 이때 상기 치환된 직쇄알킬은 할로겐으로 치환된 것이고, 상기 치환된 벤질은 오쏘, 메타 및 파라 위치 중 적어도 하나가 할로겐, C1~C3 직쇄알킬, 트리플루오로메틸, 사이아노, 나이트로, C1~C3 알콕시 또는 C6~C12 아릴로 치환된 것이며, 상기 2-페닐에틸은 오쏘, 메타 및 파라 위치 중 적어도 하나가 할로겐으로 치환된 것이고, 상기 치환된 바이페닐은 C1~C3 직쇄알킬로 치환된 것이며;wherein R 2 is hydrogen, unsubstituted or substituted C 1 -C 6 straight chain alkyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted benzyl, unsubstituted or substituted 2-phenylethyl, unsubstituted or substituted bi phenyl, 2-naphthylmethyl or 1-naphthylmethyl, wherein the substituted straight-chain alkyl is substituted with halogen, and the substituted benzyl is at least one of ortho, meta and para positions of halogen, C 1 -C 3 straight chain alkyl, trifluoromethyl, cyano, nitro, C 1 -C 3 alkoxy or C 6 -C 12 aryl, wherein at least one of the ortho, meta and para positions is halogen substituted, wherein the substituted biphenyl is substituted with C 1 -C 3 straight chain alkyl;
    상기 R4 및 R4’은 각각 독립적으로 C1~C6 직쇄 또는 분지쇄알킬, C3~C6 사이클로알킬, C2~C6 알케닐, C2~C6 알키닐, C1~C6 알킬싸이오, 비치환되거나 치환된 벤질, 2-나프틸메틸 또는 1-나프틸메틸이고, 이때 상기 치환된 직쇄알킬은 메틸싸이오, 알카이닐 또는 벤질옥시카보닐아미노로 치환된 것이고, 상기 치환된 벤질은 오쏘, 메타 및 파라 위치 중 적어도 하나가 할로겐, 아릴, 나이트로, 시아노, C1~C3 알콕시, 트리플루오로메틸 또는 벤질옥시로 치환될 수 있는 화합물 또는 이의 약학적으로 허용 가능한 염.Wherein R 4 and R 4 ' are each independently C 1 ~ C 6 straight or branched chain alkyl, C 3 ~ C 6 cycloalkyl, C 2 ~ C 6 alkenyl, C 2 ~ C 6 alkynyl, C 1 ~ C 6 alkylthio, unsubstituted or substituted benzyl, 2-naphthylmethyl or 1-naphthylmethyl, wherein the substituted straight-chain alkyl is substituted with methylthio, alkynyl or benzyloxycarbonylamino, Substituted benzyl is a compound in which at least one of ortho, meta and para positions may be substituted with halogen, aryl, nitro, cyano, C 1 -C 3 alkoxy, trifluoromethyl or benzyloxy, or a pharmaceutically acceptable compound thereof possible salts.
  4. 청구항 1 내지 3 중 어느 한 항에 있어서, 4. The method according to any one of claims 1 to 3,
    상기 R1은 수소, C1~C6 직쇄알킬, C3~C6 분지쇄알킬, C3~C6 사이클로알킬,
    Figure PCTKR2022006181-appb-img-000097
    ,
    Figure PCTKR2022006181-appb-img-000098
    ,
    Figure PCTKR2022006181-appb-img-000099
    또는
    Figure PCTKR2022006181-appb-img-000100
    이며, 이때 상기 X1은 수소, 할로겐, C1~C3 직쇄알킬, CF3, CN, NO2 또는 C6~C12 아릴이고;    The R 1 is hydrogen, C 1 -C 6 straight chain alkyl, C 3 -C 6 branched chain alkyl, C 3 -C 6 cycloalkyl,
    Figure PCTKR2022006181-appb-img-000097
    ,
    Figure PCTKR2022006181-appb-img-000098
    ,
    Figure PCTKR2022006181-appb-img-000099
    or
    Figure PCTKR2022006181-appb-img-000100
    and wherein X 1 is hydrogen, halogen, C 1 -C 3 straight-chain alkyl, CF 3 , CN, NO 2 or C 6 -C 12 aryl;
    상기 R3은 수소, C1~C3 직쇄알킬, 비치환되거나 치환된 C1~C3 알콕시, 또는 할로겐이고;wherein R 3 is hydrogen, C 1 -C 3 straight chain alkyl, unsubstituted or substituted C 1 -C 3 alkoxy, or halogen;
    상기 L1은 C1~C3 알킬렌이며, 이때 상기 C1~C3 알킬렌은 C1~C6 알킬, C3~C6 사이클로알킬, 비치환되거나 치환된 C1~C6 알콕시, 히드록실, 또는 옥소 중 적어도 하나로 치환될 수 있고, 상기 치환된 C1~C6 알콕시는 사이클로헥실, 페닐, 나프틸, 또는 바이페닐로 치환된 것이고;Wherein L 1 is C 1 -C 3 alkylene, wherein the C 1 -C 3 alkylene is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, unsubstituted or substituted C 1 -C 6 alkoxy, may be substituted with at least one of hydroxyl, or oxo, wherein the substituted C 1 -C 6 alkoxy is substituted with cyclohexyl, phenyl, naphthyl, or biphenyl;
    상기 R2는 수소, C1~C6 직쇄알킬,
    Figure PCTKR2022006181-appb-img-000101
    ,
    Figure PCTKR2022006181-appb-img-000102
    ,
    Figure PCTKR2022006181-appb-img-000103
    ,
    Figure PCTKR2022006181-appb-img-000104
    ,
    Figure PCTKR2022006181-appb-img-000105
    ,
    Figure PCTKR2022006181-appb-img-000106
    ,
    Figure PCTKR2022006181-appb-img-000107
    ,
    Figure PCTKR2022006181-appb-img-000108
    ,
    Figure PCTKR2022006181-appb-img-000109
    ,
    Figure PCTKR2022006181-appb-img-000110
    ,
    Figure PCTKR2022006181-appb-img-000111
    ,
    Figure PCTKR2022006181-appb-img-000112
    ,
    Figure PCTKR2022006181-appb-img-000113
    ,
    Figure PCTKR2022006181-appb-img-000114
    ,
    Figure PCTKR2022006181-appb-img-000115
    ,
    Figure PCTKR2022006181-appb-img-000116
    ,
    Figure PCTKR2022006181-appb-img-000117
    또는
    Figure PCTKR2022006181-appb-img-000118
    이고;     The R 2 is hydrogen, C 1 ~ C 6 straight chain alkyl,
    Figure PCTKR2022006181-appb-img-000101
    ,
    Figure PCTKR2022006181-appb-img-000102
    ,
    Figure PCTKR2022006181-appb-img-000103
    ,
    Figure PCTKR2022006181-appb-img-000104
    ,
    Figure PCTKR2022006181-appb-img-000105
    ,
    Figure PCTKR2022006181-appb-img-000106
    ,
    Figure PCTKR2022006181-appb-img-000107
    ,
    Figure PCTKR2022006181-appb-img-000108
    ,
    Figure PCTKR2022006181-appb-img-000109
    ,
    Figure PCTKR2022006181-appb-img-000110
    ,
    Figure PCTKR2022006181-appb-img-000111
    ,
    Figure PCTKR2022006181-appb-img-000112
    ,
    Figure PCTKR2022006181-appb-img-000113
    ,
    Figure PCTKR2022006181-appb-img-000114
    ,
    Figure PCTKR2022006181-appb-img-000115
    ,
    Figure PCTKR2022006181-appb-img-000116
    ,
    Figure PCTKR2022006181-appb-img-000117
    or
    Figure PCTKR2022006181-appb-img-000118
    ego;
    상기 R4 및 R4’은 각각 독립적으로 C1~C3 직쇄알킬이고;wherein R 4 and R 4 ′ are each independently C 1 -C 3 straight-chain alkyl;
    상기 X, Y, Z는 수소인 화합물 또는 이의 약학적으로 허용 가능한 염.wherein X, Y, and Z are hydrogen; or a pharmaceutically acceptable salt thereof.
  5. 청구항 1 내지 4 중 어느 한 항에 있어서, 5. The method according to any one of claims 1 to 4,
    상기 Q는 S 또는 NR이고,Wherein Q is S or NR,
    상기 R은,wherein R is,
    수소, 비치환되거나 치환된 C1~C4 직쇄알킬,
    Figure PCTKR2022006181-appb-img-000119
    ,
    Figure PCTKR2022006181-appb-img-000120
    ,
    Figure PCTKR2022006181-appb-img-000121
    , 또는
    Figure PCTKR2022006181-appb-img-000122
    인 화합물 또는 이의 약학적으로 허용 가능한 염.    hydrogen, unsubstituted or substituted C 1 -C 4 straight chain alkyl,
    Figure PCTKR2022006181-appb-img-000119
    ,
    Figure PCTKR2022006181-appb-img-000120
    ,
    Figure PCTKR2022006181-appb-img-000121
    , or
    Figure PCTKR2022006181-appb-img-000122
    A phosphorus compound or a pharmaceutically acceptable salt thereof.
  6. 청구항 1 내지 5 중 어느 한 항에 있어서,6. The method according to any one of claims 1 to 5,
    상기 화학식 1은, Formula 1 is,
    하기 화학식 2 또는 화학식 3으로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염:A compound represented by Formula 2 or Formula 3 or a pharmaceutically acceptable salt thereof:
    [화학식 2][Formula 2]
    Figure PCTKR2022006181-appb-img-000123
    Figure PCTKR2022006181-appb-img-000123
    [화학식 3][Formula 3]
    Figure PCTKR2022006181-appb-img-000124
    Figure PCTKR2022006181-appb-img-000124
    상기 R1은 수소, C1~C6 직쇄알킬, C3~C6 분지쇄알킬, C3~C6 사이클로알킬,
    Figure PCTKR2022006181-appb-img-000125
    , 또는
    Figure PCTKR2022006181-appb-img-000126
    또는
    Figure PCTKR2022006181-appb-img-000127
    이며, 이때 상기 X1은 수소, 할로겐, C1~C3 직쇄알킬, CF3, CN, NO2 또는 페닐이고;    The R 1 is hydrogen, C 1 -C 6 straight chain alkyl, C 3 -C 6 branched chain alkyl, C 3 -C 6 cycloalkyl,
    Figure PCTKR2022006181-appb-img-000125
    , or
    Figure PCTKR2022006181-appb-img-000126
    or
    Figure PCTKR2022006181-appb-img-000127
    and wherein X 1 is hydrogen, halogen, C 1 -C 3 straight-chain alkyl, CF 3 , CN, NO 2 or phenyl;
    상기 R3는 수소, C1~C3 알콕시, 또는 할로겐이고;wherein R 3 is hydrogen, C 1 -C 3 alkoxy, or halogen;
    상기 L1은 C1~C3 알킬렌이며, 이때 상기 C1~C3 알킬렌은 C1~C6 알킬, C3~C6 사이클로알킬, 비치환되거나 치환된 C1~C6 알콕시, 히드록실, 또는 옥소 중 적어도 하나로 치환될 수 있고, 상기 치환된 C1~C6 알콕시는 사이클로헥실, 페닐, 나프틸, 또는 바이페닐로 치환된 것이고;Wherein L 1 is C 1 -C 3 alkylene, wherein the C 1 -C 3 alkylene is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, unsubstituted or substituted C 1 -C 6 alkoxy, may be substituted with at least one of hydroxyl, or oxo, wherein the substituted C 1 -C 6 alkoxy is substituted with cyclohexyl, phenyl, naphthyl, or biphenyl;
    상기 R2는 수소, C1~C6 직쇄알킬,
    Figure PCTKR2022006181-appb-img-000128
    ,
    Figure PCTKR2022006181-appb-img-000129
    ,
    Figure PCTKR2022006181-appb-img-000130
    ,
    Figure PCTKR2022006181-appb-img-000131
    ,
    Figure PCTKR2022006181-appb-img-000132
    ,
    Figure PCTKR2022006181-appb-img-000133
    ,
    Figure PCTKR2022006181-appb-img-000134
    ,
    Figure PCTKR2022006181-appb-img-000135
    ,
    Figure PCTKR2022006181-appb-img-000136
    ,
    Figure PCTKR2022006181-appb-img-000137
    ,
    Figure PCTKR2022006181-appb-img-000138
    ,
    Figure PCTKR2022006181-appb-img-000139
    ,
    Figure PCTKR2022006181-appb-img-000140
    ,
    Figure PCTKR2022006181-appb-img-000141
    ,
    Figure PCTKR2022006181-appb-img-000142
    ,
    Figure PCTKR2022006181-appb-img-000143
    또는
    Figure PCTKR2022006181-appb-img-000144
    이고;     The R 2 is hydrogen, C 1 ~ C 6 straight chain alkyl,
    Figure PCTKR2022006181-appb-img-000128
    ,
    Figure PCTKR2022006181-appb-img-000129
    ,
    Figure PCTKR2022006181-appb-img-000130
    ,
    Figure PCTKR2022006181-appb-img-000131
    ,
    Figure PCTKR2022006181-appb-img-000132
    ,
    Figure PCTKR2022006181-appb-img-000133
    ,
    Figure PCTKR2022006181-appb-img-000134
    ,
    Figure PCTKR2022006181-appb-img-000135
    ,
    Figure PCTKR2022006181-appb-img-000136
    ,
    Figure PCTKR2022006181-appb-img-000137
    ,
    Figure PCTKR2022006181-appb-img-000138
    ,
    Figure PCTKR2022006181-appb-img-000139
    ,
    Figure PCTKR2022006181-appb-img-000140
    ,
    Figure PCTKR2022006181-appb-img-000141
    ,
    Figure PCTKR2022006181-appb-img-000142
    ,
    Figure PCTKR2022006181-appb-img-000143
    or
    Figure PCTKR2022006181-appb-img-000144
    ego;
    상기 R4 및 R4’은 각각 독립적으로 C1~C3 직쇄알킬이고;wherein R 4 and R 4 ′ are each independently C 1 -C 3 straight-chain alkyl;
    상기 R은, wherein R is,
    수소, 비치환되거나 치환된 C1~C4 직쇄알킬,
    Figure PCTKR2022006181-appb-img-000145
    ,
    Figure PCTKR2022006181-appb-img-000146
    ,
    Figure PCTKR2022006181-appb-img-000147
    또는
    Figure PCTKR2022006181-appb-img-000148
    이다.    hydrogen, unsubstituted or substituted C 1 -C 4 straight chain alkyl,
    Figure PCTKR2022006181-appb-img-000145
    ,
    Figure PCTKR2022006181-appb-img-000146
    ,
    Figure PCTKR2022006181-appb-img-000147
    or
    Figure PCTKR2022006181-appb-img-000148
    to be.
  7. 청구항 1 내지 6 중 어느 한 항에 있어서,7. The method of any one of claims 1 to 6,
    상기 화학식 1은, Formula 1 is,
    하기 표 1의 화합물 중 어느 하나인 화합물 또는 이의 약학적으로 허용 가능한 염.Any one of the compounds of Table 1 below, or a pharmaceutically acceptable salt thereof.
    [표 1][Table 1]
    Figure PCTKR2022006181-appb-img-000149
    Figure PCTKR2022006181-appb-img-000149
    Figure PCTKR2022006181-appb-img-000150
    Figure PCTKR2022006181-appb-img-000150
    Figure PCTKR2022006181-appb-img-000151
    Figure PCTKR2022006181-appb-img-000151
    Figure PCTKR2022006181-appb-img-000152
    Figure PCTKR2022006181-appb-img-000152
    Figure PCTKR2022006181-appb-img-000153
    Figure PCTKR2022006181-appb-img-000153
    Figure PCTKR2022006181-appb-img-000154
    Figure PCTKR2022006181-appb-img-000154
    Figure PCTKR2022006181-appb-img-000155
    Figure PCTKR2022006181-appb-img-000155
    Figure PCTKR2022006181-appb-img-000156
    Figure PCTKR2022006181-appb-img-000156
    Figure PCTKR2022006181-appb-img-000157
    Figure PCTKR2022006181-appb-img-000157
    Figure PCTKR2022006181-appb-img-000158
    Figure PCTKR2022006181-appb-img-000158
  8. 청구항 1 내지 7 중 어느 한 항의 화합물, 이의 약학적으로 허용 가능한 염, 수화물, 용매화물, 구조 이성질체, 광학 이성질체, 입체이성질체, 또는 이들의 조합을 포함하는 암 또는 내성암의 예방 또는 치료용 약학 조성물.A pharmaceutical composition for the prevention or treatment of cancer or resistant cancer, comprising the compound of any one of claims 1 to 7, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or a combination thereof .
  9. 청구항 8에 있어서, 9. The method of claim 8,
    상기 내성암은, The resistant cancer is
    항암 약물에 대한 내성을 가지거나 방사능에 대한 내성을 가지는, 암 또는 내성암의 예방 또는 치료용 약학 조성물.Having resistance to anticancer drugs or having resistance to radiation, a pharmaceutical composition for the prevention or treatment of cancer or resistant cancer.
  10. 청구항 8 내지 9 중 어느 한 항에 있어서, 10. The method according to any one of claims 8 to 9,
    상기 내성암은, The resistant cancer is
    난소암, 대장암, 췌장암, 위암, 간암, 유방암, 자궁경부암, 갑상선암, 부갑상선암, 폐암, 비소세포성폐암, 전립선암, 담낭암, 담도암, 혈액암, 방광암, 신장암, 흑색종, 결장암, 골암, 피부암, 두경부암, 자궁암, 직장암, 뇌암, 항문부근암, 나팔관암종, 자궁내막암종, 질암, 음문암종, 식도암, 소장암, 내분비선암, 부신암, 연조직 육종, 요도암, 음경암, 수뇨관암, 신장세포 암종, 신장골반암종, 중추신경계(central nervous system; CNS) 종양, 척수 종양, 뇌간 신경교종 및 뇌하수체 선종으로 이루어진 군에서 선택된 적어도 하나인, 암 또는 내성암의 예방 또는 치료용 약학 조성물.Ovarian cancer, colon cancer, pancreatic cancer, stomach cancer, liver cancer, breast cancer, cervical cancer, thyroid cancer, parathyroid cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, biliary tract cancer, blood cancer, bladder cancer, kidney cancer, melanoma, colon cancer, Bone cancer, skin cancer, head and neck cancer, uterine cancer, rectal cancer, brain cancer, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine adenocarcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, ureter Cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumor, spinal cord tumor, at least one selected from the group consisting of brain stem glioma and pituitary adenoma, cancer or resistant cancer prevention or treatment pharmaceutical composition .
  11. 청구항 8 내지 10 중 어느 한 항에 있어서, 11. The method according to any one of claims 8 to 10,
    상기 항암 약물은, The anticancer drug is
    나이트로젠머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 보수티닙, 악시티닙, 마시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 파조파닙, 토세라닙, 닌테다닙, 레고라페닙, 세막사닙, 티보자닙, 포나티닙, 카보잔티닙, 카보플라틴, 소라페닙, 렌바티닙, 베바시주맙, 시스플라틴, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라실, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 5-플루오로우라실, 플루다라빈, 에노시타빈, 플루타미드, 케페시타빈, 데시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 도세탁셀, 파클리탁셀, 카바지탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레타민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레티노인, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 올라파립, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴, 보리노스텟, 엔티노스텟 및 카르무스틴으로 이루어진 군에서 선택된 적어도 하나인, 암 또는 내성암의 예방 또는 치료용 약학 조성물.Nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, bosutinib, axitinib, masitinib, cediranib, lestaurtinib, Trastuzumab, gefitinib, bortezomib, sunitinib, pazopanib, toceranib, nintedanib, regorafenib, semaxanib, tivozanib, ponatinib, caboxantinib, carboplatin, Sorafenib, lenvatinib, bevacizumab, cisplatin, cetuximab, viscumalbum, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomab Cetane, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmchitosan nitrate, gemcitabine, doxyfluridine, pemetrexed, tegafur, capeci Tabine, gimeracil, oteracil, azacitidine, methotrexate, uracil, cytarabine, 5-fluorouracil, fludarabine, enocitabine, flutamide, kepecitabine, decitabine, mercaptopurine, Thioguanine, cladribine, carmopher, raltitrexed, docetaxel, paclitaxel, cabazitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, teniposide, doxorubicin, ida Rubicin, epirubicin, mitoxantrone, mitomycin, bleromycin, daunorubicin, dactinomycin, pyrarubicin, aclarubicin, pepromycin, temsirolimus, temozolomide, busulfan, Ifosfamide, cyclophosphamide, melpharan, altretamine, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, tretinoin, exemestane, aminoglutethimide, anag with Lelide, olaparib, nabelbine, fadrazole, tamoxifen, toremifene, testolactone, anastrozole, letrozole, vorozole, bicalutamide, lomustine, vorinostat, entinostat and carmustine At least one selected from the group consisting of, a pharmaceutical composition for the prevention or treatment of cancer or resistant cancer.
  12. 청구항 1 내지 7 중 어느 한 항의 화합물, 이의 약학적으로 허용 가능한 염, 수화물, 용매화물, 구조 이성질체, 광학 이성질체, 입체이성질체, 또는 이들의 조합을 포함하는 줄기세포성 암의 예방 또는 치료용 약학 조성물.A pharmaceutical composition for preventing or treating stem cell cancer, comprising the compound of any one of claims 1 to 7, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or a combination thereof .
  13. 청구항 1 내지 7 중 어느 한 항의 화합물, 이의 약학적으로 허용 가능한 염, 수화물, 용매화물, 구조 이성질체, 광학 이성질체, 입체이성질체, 또는 이들의 조합의 치료학적 유효량을 암 또는 내성암이 있는 개체에게 투여하는 것을 포함하는, 종양학적 요법에 대해 내성을 나타내는 암을 치료하는 방법.A therapeutically effective amount of the compound of any one of claims 1 to 7, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or a combination thereof, is administered to an individual having cancer or resistant cancer. A method of treating cancer that is resistant to oncological therapy, comprising:
  14. 청구항 13에 있어서, 14. The method of claim 13,
    암 또는 증식성 질병의 치료에 유용한 화합요법제를 동시에, 개별적으로, 또는 순차적으로 투여하는 것을 포함하는, 종양학적 요법에 대해 내성을 나타내는 암을 치료하는 방법.A method of treating cancer that is resistant to oncological therapy, comprising administering simultaneously, separately, or sequentially, a chemotherapeutic agent useful for the treatment of cancer or a proliferative disease.
  15. 암 또는 내성암의 치료를 위한 약제를 제조하기 위한 청구항 1 내지 7 중 어느 한 항의 화합물 또는 이의 약학적으로 허용가능한 염의 용도.Use of the compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer or resistant cancer.
  16. 줄기세포성 암의 치료를 위한 약제를 제조하기 위한 청구항 1 내지 7 중 어느 한 항의 화합물 또는 이의 약학적으로 허용가능한 염의 용도. Use of the compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of stem cell cancer.
PCT/KR2022/006181 2021-04-29 2022-04-29 Novel compound and pharmaceutical composition comprising same for prevention or treatment of cancer, and use thereof WO2022231377A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2021-0056108 2021-04-29
KR20210056108 2021-04-29

Publications (1)

Publication Number Publication Date
WO2022231377A1 true WO2022231377A1 (en) 2022-11-03

Family

ID=83848400

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2022/006181 WO2022231377A1 (en) 2021-04-29 2022-04-29 Novel compound and pharmaceutical composition comprising same for prevention or treatment of cancer, and use thereof

Country Status (2)

Country Link
KR (1) KR20220148758A (en)
WO (1) WO2022231377A1 (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008157500A1 (en) * 2007-06-17 2008-12-24 Kalypsys, Inc. Aminoquinazoline cannabinoid receptor modulators for treatment of disease
KR20140020224A (en) * 2010-10-14 2014-02-18 제이더블유중외제약 주식회사 Novel compound of a reverse-turn mimetic and a production method and use therefor
WO2020037079A1 (en) * 2018-08-14 2020-02-20 Epizyme, Inc. Substituted indoles and methods of use thereof
KR20200081320A (en) * 2018-12-27 2020-07-07 홀로스메딕 주식회사 Novel compounds for enhancing anti-cancer activity and pharmaceutical composition thereof
WO2021086038A1 (en) * 2019-10-31 2021-05-06 홀로스메딕 주식회사 Novel compound and pharmaceutical composition for prevention or treatment of cancer comprising same

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20060127413A (en) 2003-11-25 2006-12-12 카이론 코포레이션 Quinazolinone compounds as anticancer agents

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008157500A1 (en) * 2007-06-17 2008-12-24 Kalypsys, Inc. Aminoquinazoline cannabinoid receptor modulators for treatment of disease
KR20140020224A (en) * 2010-10-14 2014-02-18 제이더블유중외제약 주식회사 Novel compound of a reverse-turn mimetic and a production method and use therefor
WO2020037079A1 (en) * 2018-08-14 2020-02-20 Epizyme, Inc. Substituted indoles and methods of use thereof
KR20200081320A (en) * 2018-12-27 2020-07-07 홀로스메딕 주식회사 Novel compounds for enhancing anti-cancer activity and pharmaceutical composition thereof
WO2021086038A1 (en) * 2019-10-31 2021-05-06 홀로스메딕 주식회사 Novel compound and pharmaceutical composition for prevention or treatment of cancer comprising same

Also Published As

Publication number Publication date
KR20220148758A (en) 2022-11-07

Similar Documents

Publication Publication Date Title
WO2018182341A1 (en) Pyrrolobenzodiazepine dimer precursor and ligand-linker conjugate compound thereof
WO2017160116A9 (en) Novel compound for inhibiting nicotinamide phosphoribosyltransferase and composition containing same
WO2017188694A1 (en) Heteroaryl compound comprising nitrogen, and use thereof
WO2015030514A1 (en) Tetrahydrocyclopentapyrrole derivative and preparation method therefor
WO2020149723A1 (en) Pyrrolopyrimidine derivative, and pharmaceutical composition for preventing or treating protein kinase-related disease comprising same as active ingredient
WO2021125803A1 (en) Novel pyrimidin derivative and use thereof
WO2016032209A2 (en) Substituted n-(pyrrolidine-3-yl)-7h-pyrrolo[2,3-d]pyrimidine-4-amine as janus kinase inhibitor
WO2022010150A1 (en) Novel tnf activity inhibitor compound, and pharmaceutically acceptable salt thereof
WO2020096372A1 (en) Novel piperidine-2,6-dione derivative and use of same
WO2022035303A1 (en) Novel dioxoloisoquinolinone derivatives and use thereof
WO2019054766A1 (en) Pyrazole derivative compound and use thereof
WO2020036386A1 (en) Isoindolin-1-on derivative, method for preparing same, and pharmaceutical composition comprising same as effective component for preventing or treating cancer
WO2012030170A2 (en) Novel compound acting as a cannabinoid receptor-1 inhibitor
WO2018021826A1 (en) Novel pyrimidine-2,4-diamine derivative and pharmaceutical composition for prevention or treatment of cancer containing same as active ingredient
WO2016006974A2 (en) Novel triazolopyrimidinone or triazolopyridinone derivatives, and use thereof
WO2016006975A2 (en) Novel imidazotriazinone or imidazopyrazinone derivatives, and use thereof
WO2021096112A1 (en) Pyrrolopyrimidine, pyrrolopyridine and indazole compound derivative, and therapeutic pharmaceutical composition containing same
WO2022231377A1 (en) Novel compound and pharmaceutical composition comprising same for prevention or treatment of cancer, and use thereof
WO2021086038A1 (en) Novel compound and pharmaceutical composition for prevention or treatment of cancer comprising same
WO2021261970A1 (en) Novel compound, and pharmaceutical composition for preventing or treating resistant cancer, comprising same
WO2022103149A1 (en) Novel carbazole derivative and pharmaceutical composition for prevention or treatment of cancer comprising same as active ingredient
WO2022086110A1 (en) Thiobenzimidazole derivative or pharmaceutically acceptable salt thereof and use thereof
WO2021040422A1 (en) Novel pyrimido[4,5-d]pyrimidine-2-one derivative having protein kinase inhibitory activity
WO2020139044A1 (en) Novel compound and pharmaceutical composition comprising same for enhancing anticancer activity
WO2019212256A1 (en) Novel heterocycle derivative

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22796209

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22796209

Country of ref document: EP

Kind code of ref document: A1