Novel Dioxoisoquinolinone Derivatives and Their Uses

Abstract

The present invention relates to novel dioxoisoquinolinone derivative compounds and their uses. More specifically, the present invention relates to novel dioxoisoquinolinone derivative compounds having inhibitory activity against the activity of EZH1 (enhancer of zeste homolog 1) and / or EZH2 (enhancer of zeste homolog 2), pharmaceutically acceptable salts thereof, and / or pharmaceutical compositions containing the same.

Description

Technical Field

[0001] The present invention relates to novel dioxoisoquinolinone derivative compounds and their uses. More specifically, the present invention relates to novel dioxoisoquinolinone derivative compounds having inhibitory activity against the activity of EZH1 (enhancer of zeste homolog 1) and / or EZH2 (enhancer of zeste homolog 2), pharmaceutically acceptable salts thereof, and / or pharmaceutical compositions containing the same. Background Art

[0002] Chromosomes change their higher-order structures through methylation of DNA and its components or through various additions and subtractions (acetylation, methylation, phosphorylation, ubiquitination, etc.) of histones (histones H2A, H2B, H3, and H4), thereby dynamically controlling gene replication or transcription.

[0003] Generally, trimethylation of the fourth lysine at the N-terminus of histone H3 (H3K4me3) plays a role in activating transcription, and trimethylation of the 27th lysine (H3K27me3) can inhibit transcription. The former is added and subtracted by the trithorax complex, and the latter is added and subtracted by the polycomb repressive complex 2 (PRC2) (Cell 2007, 128, 735-745; Nat. Rev. Cancer 2010, 10, 669-682).

[0004] The polycomb genome was identified as a gene controlling Drosophila embryogenesis and is conserved in chordates (Nat. Rev. Genet., 2007, 8, 9-22). In Drosophila, the enhancer of the zeste protein is the catalytic subunit responsible for H3K27 methylation of PRC2, and both EZH1 (enhancer of zeste homolog 1 (Drosophila)) and EZH2 (enhancer of zeste homolog 2 (Drosophila)) are mammalian homologs of the Drosophila zeste enhancer (EMBO J. 1997, 16, 3219-3232; Mamm. Genome. 1999, 10, 311-314). The enzymatic active domains (SET domains) of EZH1 and EZH2 have high homology, and in humans and mice, there are two types of PRC2 (PRC2-EZH1 and PRC2-EZH2), where EZH1 or EZH2 is the catalytic subunit (PRC2-EZH1, PRC2-EZH2) (Mol. Cell 2008, 32, 491-502; Mol. Cell 2008, 32, 503-518).

[0005] In embryonic stem cells (ES cells), EZH1 and EZH2 function synergistically or complementarily and are involved in the maintenance of ES cells (Mol. Cell 2008, 32, 491 - 502). It has been reported that EZH1 and EZH2 play a synergistic role in the formation and maintenance of hair follicles and the differentiation of Merkel cells (Genes Dev. 2011, 25, 485 - 498; EMBO J. 2013, 32, 1990 - 2000; Blood 2011, 118, 6553 - 6561; Cell Stem Cell 2012, 11, 649 - 662; Cell Stem Cell 2014, 14, 68 - 80).

[0006] It has been reported that high expression of EZH2 exists in a variety of cancers, including prostate cancer, breast cancer, gastric cancer, lung cancer, ovarian cancer, pancreatic cancer, and head and neck cancer, and some of them have reported that high expression of EZH2 is associated with poor prognosis (Nature 2002, 419, 624 - 629; Proc. Natl. Acad. Sci. USA 2003, 100, 11606 - 11611; Asian Pac. J. Cancer Prev. 2012, 13, 3173 - 3178; Clin. Cancer Res. 2013, 19, 6556 - 6565; Cancer Cell 2010, 18, 185 - 197; Hum. Pathol. 2010, 41, 1205 - 1209; BMC Cancer 2010, 10, 524; Cancer 2012, 118, 2858 - 2871; Mutat. Res. 2008, 647, 21 - 29).

[0007] Based on the confirmation that the novel dioxoisoquinolinone derivative compounds have inhibitory activity against EZH1 and / or EZH2, the present inventors have completed the present invention.

[0008] [Disclosure of the Invention]

[0009] [Technical Problem]

[0010] An object of the present invention is to provide novel dioxoisoquinolinone derivative compounds having excellent inhibitory activity against EZH1 and / or EZH2.

[0011] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the above - mentioned derivative.

[0012] [Technical Solution]

[0013] One embodiment of the present invention provides a compound selected from the group consisting of dioxoisoquinolinone derivative compounds represented by Formula 1a or Formula 1b below, and pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof:

[0014] [Formula 1a]

[0015]

[0016] In Formula 1a,

[0017] R 1 is H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, nitrile, aryl, a 5- to 6-membered aromatic heterocyclic group containing 1 to 3 heteroatoms independently selected from N, O and S, or an aliphatic heterocyclic group containing or not containing an unsaturated bond in a moiety of a 5- to 6-membered ring containing 1 to 2 heteroatoms independently selected from N, O and S; the C 3-6 cycloalkyl, C 3-6 cycloalkenyl, aryl, or a 5- to 6-membered aromatic heterocyclic group containing 1 to 3 heteroatoms independently selected from N, O and S, or an aliphatic heterocyclic group containing or not containing an unsaturated bond in a 5- to 6-membered ring moiety containing 1 to 2 heteroatoms independently selected from N, O and S is substituted with 1 to 3 groups independently selected from the following Group A or is unsubstituted;

[0018] L is a bond or C 1-6 alkylene;

[0019] R a is substituted C 5-9 bicycloalkyl, and the substituted C 5-9 bicycloalkyl is substituted with NR 5 R 6 wherein R 5 and R 6 are each independently H or C 1-6 alkyl;

[0020] R 2 is H or C 1-6 alkyl;

[0021] R 3 is H, halogen or C 1-6 alkyl;

[0022] R 4is C 1-6 alkyl, C 1-6 alkoxy or thio-C 1-6 alkyl;

[0023] Group A includes halogen, C 1-6 alkyl, C 1-6 alkoxy, a 5- to 6-membered aliphatic heterocyclic group containing 1 to 2 heteroatoms each independently selected from N, O, and S in the ring, wherein the C 1-6 alkyl, C 1-6 alkoxy, and the 5- to 6-membered aliphatic heterocyclic group are either unsubstituted or substituted by 1 to 3 groups each independently selected from the following Group B;

[0024] Group B includes halogen, C 1-6 alkyl, C 1-6 alkoxy, a 5- to 6-membered aliphatic heterocyclic group containing 1 to 2 heteroatoms each independently selected from N, O, and S in the ring, wherein the C 1-6 alkyl, C 1-6 alkoxy, and the 5- to 6-membered aliphatic heterocyclic group are either unsubstituted or substituted by 1 to 3 groups each independently selected from the following Group C; and,

[0025] Group C is halogen, C 1-6 alkyl or a 5- to 6-membered aliphatic heterocyclic group containing 1 to 2 heteroatoms each independently selected from N, O, and S in the ring.

[0026] Another embodiment of the present invention provides a compound selected from the following group: a dioxoisoquinolinone derivative compound represented by Formula 1b, its pharmaceutically acceptable salts, optical isomers, hydrates, and solvates:

[0027] [Formula 1b]

[0028]

[0029] In Formula 1b,

[0030] R b is a substituted cyclohexyl;

[0031] R 7 is selected from the following group: H, furan-2-yl, furan-3-yl, 5-methylfuran-2-yl, thiophene-2-yl, thiophene-3-yl, 5-methylthiophene-2-yl, 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrrol-2-yl, thiazol-5-yl, 1H-imidazol-1-yl, pyridin-3-yl, pyridin-4-yl, 6-fluoropyridin-3-yl, and pyrimidin-5-yl;

[0032] L is a bond; and,

[0033] R8 is C 1-6 alkyl, C 1-6 alkoxy or thio-C 1-6 alkyl.

[0034] According to another embodiment of the present invention, there is provided a pharmaceutical composition and a pharmaceutical preparation for preventing or treating various diseases related to EZH1 and / or EZH2 as described above, and the pharmaceutical composition or preparation contains a therapeutically effective dose of the above compound.

[0035] [Advantages of the Invention]

[0036] The dioxoisoquinolinone derivatives represented by Formula 1a or Formula 1b provided by the present invention have outstanding EZH1 and / or EZH2 inhibitory activities, and thus have anti-cancer activities against cancers related to the activities of EZH1, EZH2 or both EZH1 and EZH2, and can be used as therapeutic agents therefor.

[0037] [Best Mode for Carrying Out the Invention]

[0038] The definitions of various terms used to describe the present invention are as follows. Unless otherwise restricted, these definitions shall apply to this specification as a whole, either alone or as part of the terms containing them.

[0039] Unless otherwise specified, the term "halogen" used in this specification refers to fluorine, chlorine, bromine or iodine.

[0040] Unless otherwise specified, the term "hydroxyl" used in this specification refers to the -O group.

[0041] Unless otherwise specified, the term "alkyl" used in this specification refers to a saturated, straight-chain or branched hydrocarbon group represented by C n H 2n+1 Specifically, it refers to a saturated, straight-chain or branched hydrocarbon group containing 1 to 6, 1 to 8, 1 to 10 or 1 to 20 carbon atoms respectively. Non-limiting examples of these groups include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl (oxyl). For example, unless otherwise mentioned, the term "C 1-6 alkyl" refers to a straight-chain or branched hydrocarbon residue having 1 to 6 carbon atoms. Non-limiting examples of such alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.

[0042] Unless otherwise indicated, the term "alkenyl" as used in this specification refers to a monovalent group derived from an unsaturated, straight-chain or branched hydrocarbon moiety having at least one carbon-carbon double bond, specifically, an unsaturated, straight-chain or branched monovalent group containing 2 to 6, 2 to 8, 2 to 10, or 2 to 20 carbon atoms, respectively. Non-limiting examples of such alkenyl groups include vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, and octenyl.

[0043] Unless otherwise indicated, the term "alkynyl" as used in this specification refers to a monovalent group derived from an unsaturated, straight-chain or branched hydrocarbon moiety having at least one carbon-carbon triple bond.

[0044] Unless otherwise indicated, the term "alkoxy" as used in this specification refers to an oxygen group represented by OC n H 2n+1 and having a monovalent group (containing 1 to 6, 1 to 8, 1 to 10, or 1 to 20 carbon atoms, respectively) derived from a saturated, straight-chain or branched hydrocarbon moiety. For example, unless otherwise indicated, "C 1-6 alkoxy" refers to an oxygen group having a straight-chain or branched hydrocarbon group residue with 1 to 6 carbon atoms. Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, pentyloxy, and hexyloxy, etc.

[0045] Unless otherwise indicated, the term "cycloalkyl" as used in this specification refers to a monovalent group derived from a saturated monocyclic or partially unsaturated monocyclic carbocyclic compound. For example, unless otherwise specified, the term "C 3-7 cycloalkyl" as used in this specification refers to a monocyclic saturated or partially unsaturated hydrocarbon functional group having 3 to 7 carbon atoms. Non-limiting examples of saturated cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, etc.

[0046] Unless otherwise specified, the term "heterocyclic group" as used in this specification refers to a 3- to 7-membered monocyclic monovalent group containing 1 to 3 heteroatoms or functional groups selected from N, O, S, SO, and SO 2 Non-limiting examples include oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, oxacyclohex-4-yl, oxacyclohex-3-yl, piperidin-1-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, 1,1-dioxothiomorpholin-4-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, azetidin-1-yl, azetidin-3-yl, aziridin-1-yl, azepan-1-yl, azepan-3-yl, and azepan-4-yl.

[0047] Unless otherwise specified, the term "aryl" as used in this specification refers to a monocyclic or polycyclic carbocyclic system having at least one fused or unfused aromatic ring, and non-limiting examples of aryl include phenyl, naphthyl, tetrahydronaphthyl, indenyl, anthracenyl, etc.

[0048] Unless otherwise specified, the term "heteroaryl" as used in this specification refers to a monocyclic, bicyclic or polycyclic 5- to 12-membered (preferably 5- to 7-membered) aryl containing at least 1 (e.g., 1 to 4, and preferably 1 to 3) heteroatoms selected from O, N, and S. Non-limiting examples of monocyclic heteroaryl include thiazolyl, oxazolyl, thiophenyl, furyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxathiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Non-limiting examples of bicyclic heteroaryl include indolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, purinyl, puropyridinyl, etc.

[0049] Unless otherwise specified, the term "C 5-9 bicycloalkyl" refers to a group of aliphatic hydrocarbon compounds derived from two cycloalkyl rings sharing two atoms, and may preferably include, but are not limited to, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, or bicyclo[3.3.2]decyl, all of which may be substituted or unsubstituted.

[0050] Unless otherwise specified, the term "optical isomer" or "enantiomer" as used in this specification refers to a pair of stereoisomers that are non-overlapping mirror images of each other. Specifically, a mixture of stereoisomers may be a mixture of stereoisomers of a compound having an asymmetric carbon atom. More specifically, the compound having an asymmetric carbon atom may be a compound having the structure of Formula 1a or Formula 1b below. At the same time, a 1:1 mixture of a pair of enantiomers should be called a "racemic" mixture.

[0051] Unless otherwise mentioned, the term "asymmetric carbon atom" as used in this specification refers to the situation where a carbon atom in a molecule is bonded to four different types of atoms, groups or atoms, or functional groups. A compound containing such an asymmetric carbon atom has chirality or optical isomers.

[0052] Unless otherwise mentioned, the term "enantiomeric excess (ee)" used in this specification generally refers to all increases in the enantiomeric ratio, including not only the enantiomeric excess relative to the racemic mixture, but also cases where the enantiomeric ratio in the racemic mixture is not 1:1 and the proportion of one enantiomer is greater than the other. Specifically, the enantiomeric excess may be an enantiomeric excess with an optical purity ("%ee") of at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%.

[0053] Unless otherwise mentioned, the term "EZH1 and / or EZH2 enzyme activity" used in this specification refers to the enzyme activity of introducing a methyl group at lysine 27 of histone H3 possessed by EZH1 and / or EZH2, and "high expression of EZH1 and / or EZH2" refers to an increase in the expression level of EZH1 protein and / or EZH2 protein through enhancement of gene transcription activity, promotion of gene translation, inhibition of protein degradation or improvement of protein stability, etc.

[0054] Unless otherwise specified, the term "EZH1 and / or EZH2 has a mutation" used in this specification means that there is a mutation in the base sequence and / or amino acid sequence of EZH2 and / or EZH2. Examples include somatic mutations (Y641F, Y641N, Y641S, Y641C, A677G and A687V) at tyrosine 641, alanine 677 and alanine 687 of EZH2.

[0055] The present invention will be further described in detail below.

[0056] The present invention relates to novel dioxoisoquinolinone derivative compounds and their uses. More specifically, the present invention relates to novel dioxoisoquinolinone derivative compounds having inhibitory activity against EZH1 (enhancer of zeste homolog 1) and / or EZH2 (enhancer of zeste homolog 2), pharmaceutically acceptable salts thereof and / or pharmaceutical compositions containing the same.

[0057] Specifically, one embodiment of the present invention provides dioxoisoquinolinone derivatives selected from Formula 1a or Formula 1b below, and pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof:

[0058] [Formula 1a]

[0059]

[0060] In Formula 1a,

[0061] R 1 is H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, nitrile, aryl, containing 1 to 3 heteroatoms independently selected from N, O, and S 5- to 6-membered aromatic heterocyclic group , or an aliphatic heterocyclic group containing or not containing an unsaturated bond in a 5- to 6-membered ring portion, wherein the ring contains 1 to 2 heteroatoms independently selected from N, O, and S each;

[0062] C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, aryl, or a 5- to 6-membered aromatic heterocyclic group containing 1 to 3 heteroatoms independently selected from N, O, and S each, or an aliphatic heterocyclic group containing or not containing an unsaturated bond in a 5- to 6-membered ring portion containing 1 to 2 heteroatoms independently selected from N, O, and S each, is substituted or unsubstituted by 1 to 3 groups independently selected from the following Group A;

[0063] L is a bond or C 1-6 Alkylene;

[0064] R a Is substituted C 5-9 Bicycloalkyl, and the substituted C 5-9 Bicycloalkyl is substituted by NR 5 R 6 Substituted, wherein R 5 And R 6 Are each independently H or C 1-6 Alkyl;

[0065] R 2 Is H or C 1-6 Alkyl;

[0066] R 3 Is H, halogen, or C 1-6 Alkyl;

[0067] R 4 Is C 1-6 Alkyl, C 1-6 Alkoxy, or thio-C 1-6 Alkyl;

[0068] Group A includes halogen, C 1-6 Alkyl, C 1-6 Alkoxy, 5- to 6-membered aliphatic heterocyclic group , the ring of which contains 1 to 2 heteroatoms independently selected from N, O, and S each, wherein C 1-6 Alkyl, C 1-6 Alkoxy, and the 5- to 6-membered aliphatic heterocyclic group are substituted or unsubstituted by 1 to 3 groups independently selected from the following Group B;

[0069] Group B includes halogen, C 1-6Alkyl, C 1-6 Alkoxy, a 5- to 6-membered aliphatic heterocyclic group containing 1 to 2 heteroatoms each independently selected from N, O, and S in the ring, where C 1-6 alkyl, C 1-6 alkoxy, and the 5- to 6-membered aliphatic heterocyclic group are either unsubstituted or substituted with 1 to 3 groups each independently selected from the following group C; and,

[0070] Group C is halogen, C 1-6 alkyl, or a 5- to 6-membered aliphatic heterocyclic group containing 1 to 2 heteroatoms each independently selected from N, O, and S in the ring.

[0071] Preferably, the compound selected from the dioxoisoquinolinone derivative compounds of formula 1a shown in the present invention and their pharmaceutically acceptable salts, optical isomers, hydrates, and solvates may be a compound in which R a is bicyclo[2.2.2]octyl, and more preferably, the bicyclo[2.2.2]octyl may be substituted by NR 5 R 6 , where R 5 and R 6 are each independently H or C 1-6 alkyl.

[0072] Preferably, the compound selected from the dioxoisoquinolinone derivative compounds of formula 1a shown in the present invention and their pharmaceutically acceptable salts, optical isomers, hydrates, and solvates may be a compound in which R 1 is H, halogen, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-5 cycloalkyl, or C 3-5 cycloalkenyl.

[0073] Preferably, the compound selected from the dioxoisoquinolinone derivative compounds of formula 1a shown in the present invention and their pharmaceutically acceptable salts, optical isomers, hydrates, and solvates may be a compound in which R 2 is methyl.

[0074] Preferably, the compound selected from the dioxoisoquinolinone derivative compounds of formula 1a shown in the present invention and their pharmaceutically acceptable salts, optical isomers, hydrates, and solvates may be a compound in which R 3 is methyl or halogen.

[0075] Preferably, the compound selected from the dioxoisoquinolinone derivative compounds of formula 1a shown in the present invention and their pharmaceutically acceptable salts, optical isomers, hydrates, and solvates may be a compound in which R 4A compound where it is methyl, propyl, methoxy or thiomethyl.

[0076] Further preferred embodiments of the compound of formula 1a according to the present invention include, but are not limited to, the following:

[0077] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0078] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer A;

[0079] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer B;

[0080] 9-chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,4-dimethyl-7,8-dihydro[1,3]dioxolo

[0081] [4,5-g]isoquinolin-5(6H)-one;

[0082] 9-chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,4-dimethyl-7,8-dihydro[1,3]dioxolo

[0083] [4,5-g]isoquinolin-5(6H)-one isomer A;

[0084] 9-chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,4-dimethyl-7,8-dihydro[1,3]dioxolo

[0085] [4,5-g]isoquinolin-5(6H)-one isomer B;

[0086] 9-Chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-6-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0087] 9-Chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-6-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer A;

[0088] 9-Chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-6-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer B;

[0089] 9-Bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0090] 9-Bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer A;

[0091] 9-Bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer B;

[0092] 9-Cyclopropyl-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo

[0093] [4,5-g]isoquinolin-5(6H)-one;

[0094] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0095] 9-(cyclopent-1-en-1-yl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0096] 9-cyclopentyl-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo

[0097] [4,5-g]isoquinolin-5(6H)-one;

[0098] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-9-ethenyl-7,8-dihydro-[1,3]dioxolo

[0099] [4,5-g]isoquinolin-5(6H)-one;

[0100] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-9-ethyl-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo

[0101] [4,5-g]isoquinolin-5(6H)-one;

[0102] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-9-(prop-1-en-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0103] 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-9-isopropyl-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo

[0104] [4,5-g]isoquinolin-5(6H)-one;

[0105] 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-9-ethynyl-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo

[0106] [4,5-g]isoquinolin-5(6H)-one;

[0107] 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0108] 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer A;

[0109] 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer B;

[0110] 2-(4-(Dimethylamino)bicyclo[2.2.2]octan-1-yl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0111] 2-(4-(Dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4,9-trimethyl-6-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-7,8-dihydro[1,3]dioxolo[4,5-g]

[0112] Isoquinolin-5(6H)-one;

[0113] 4-Chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,9-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0114] 4,9-Dichloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; and

[0115] 9-Chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-4-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0116] Specifically, another embodiment of the present invention provides a compound selected from the dioxoisoquinolinone derivatives represented by Formula 1b below and their pharmaceutically acceptable salts, optical isomers, hydrates and solvates:

[0117] [Formula 1b]

[0118]

[0119] In Formula 1b,

[0120] R b is a substituted cyclohexyl;

[0121] R 7 is selected from the group consisting of: H, furan-2-yl, furan-3-yl, 5-methylfuran-2-yl, thiophene-2-yl, thiophene-3-yl, 5-methylthiophene-2-yl, 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrrol-2-yl, thiazol-5-yl, 1H-imidazol-1-yl, pyridin-3-yl, pyridin-4-yl, 6-fluoropyridin-3-yl and pyrimidin-5-yl;

[0122] L is a bond; and,

[0123] R 8 is C 1-6 alkyl, C 1-6 alkoxy or thio-C 1-6 alkyl.

[0124] Preferred examples of the compound of formula 1b according to the present invention are, but not limited to, the following:

[0125] (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(furan-2-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0126] (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(thiophen-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0127] (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(pyridin-4-yl)-7,8-dihydro-[1,3]dioxolo

[0128] [4,5-g]isoquinolin-5(6H)-one;

[0129] (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(6-fluoropyridin-3-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0130] (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0131] (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(5-methylfuran-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0132] (R)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(5-methylthiophen-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0133] (R)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(pyridin-3-yl)-7,8-dihydro-[1,3]dioxolo

[0134] [4,5-g]isoquinolin-5(6H)-one;

[0135] (R)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(pyrimidin-5-yl)-7,8-dihydro-[1,3]dioxolo

[0136] [4,5-g]isoquinolin-5(6H)-one;

[0137] (R)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(1-methyl-1H-pyrrol-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0138] (R)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(thiophen-3-yl)-7,8-dihydro-[1,3]dioxolo

[0139] [4,5-g]isoquinolin-5(6H)-one;

[0140] (R)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(thiazol-5-yl)-7,8-dihydro-[1,3]dioxolo

[0141] [4,5-g]isoquinolin-5(6H)-one;

[0142] (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(1H-imidazol-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0143] (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(furan-3-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo

[0144] [4,5-g]isoquinolin-5(6H)-one;

[0145] (R)-2-(trans-4-Aminocyclohexyl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-9-(furan-2-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0146] (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-9-(furan-2-yl)-2,4-dimethyl-2-(trans-4-(methylamino)cyclohexyl)-7,8-dihydro-[1,3]dioxolo

[0147] [4,5-g]isoquinolin-5(6H)-one; and,

[0148] (S)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0149] Further preferred embodiments of the compound of formula 1b of the present invention include, but are not limited to, the following:

[0150] 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(thiophen-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0151] 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(pyridin-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0152] 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(6-fluoropyridin-3-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo

[0153] [4,5-g]isoquinolin-5(6H)-one;

[0154] 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(5-methylfuran-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0155] 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(5-methylthiophen-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0156] 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(pyrimidin-5-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0157] 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(1-methyl-1H-pyrrol-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0158] 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(thiophen-3-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0159] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(1H-imidazol-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0160] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(furan-3-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0161] 2-(trans-4-aminocyclohexyl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-9-(furan-2-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; and,

[0162] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-9-(furan-2-yl)-2,4-dimethyl-2-(trans-4-(methylamino)cyclohexyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one;

[0163] In the present invention, although there is no particular limitation on the preparation method of the compound represented by Formula 1a, the compound can be synthesized, for example, by the preparation method represented by the following Reaction Scheme 1 or Reaction Scheme 2:

[0164] [Reaction Scheme 1]

[0165]

[0166] In the above Reaction Scheme 1, R 1 , R 2 , R 3 , R 4 and R a are as defined in Formula 1a.

[0167] In Reaction 1, the ketalization reaction in Step 1 was carried out under the conditions set in the following literature (Ming Li et al., Journal of Organic Chemistry (J. Org. Chem.) 2008, 73, 8658 - 8660). In this method, the compound of Formula 7 was stirred in an inert solvent under heating for 1 to 24 hours, using an equal amount or an excess amount of an acetylene derivative and 0.01 to 0.03 equivalents of a Ru catalyst to produce the compound of Formula 6. The iodination reaction in Step 2 was carried out by stirring iodine and an equal amount or an excess amount of silver trifluoroacetate in a reaction-inert solvent at room temperature for 1 to 24 hours to obtain the compound of Formula 5. The Suzuki-Miyaura reaction in Step 3 was carried out by stirring an equal amount or an excess amount of (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 0.01 to 0.3 equivalents of a Pd catalyst under heating for 1 to 24 hours to obtain the compound of Formula 4. The reduction reaction in Step 4 was carried out by stirring in a reaction-inert solvent and in the presence of an acid under cooling for 0.5 to 24 hours to obtain the compound of Formula 3. The cyclization reaction in Step 5 was carried out by stirring an equal amount or an excess amount of aminoalkyl and borohydride in a reaction-inert solvent at room temperature for 1 to 72 hours to obtain the compound of Formula 2. The Suzuki-Miyaura reaction in Step 6 was carried out by stirring an equal amount or an excess amount of boric acid or pinacol borate ester and 0.01 to 0.3 equivalents of a Pd catalyst under heating for 1 to 24 hours to obtain the compound of Formula 1a.

[0168] [Reaction 2]

[0169]

[0170] In Reaction 2, R 1 、R 2 、R 3 、R 4 and R a are defined as in Formula 1a.

[0171] In Reaction 2, Step 1 is a method for obtaining the compound of Formula 9 using the same method as in Step 1 of Reaction 2. The condensation reaction in Step 2 is a process of stirring an equal amount or an excess amount of an alkyl halide and a salt such as potassium tert-butoxide in a reaction-inert solvent under cooling for 1 to 24 hours to obtain the compound of Formula 8. The deprotection reaction in Step 3 is a process of stirring the compound of Formula 8 including a benzyl group in a reaction-inert solvent in a hydrogen atmosphere with a Pd catalyst for 0.5 to 24 hours to obtain the compound of Formula 1a.

[0172] In addition, in the present invention, there is no particular limitation on the preparation method of the compound represented by Formula 1b. For example, the compound can be synthesized using the preparation method of Reaction 3:

[0173] [Reaction 3]

[0174]

[0175] In Reaction Scheme 3, R 7 、 R 8 and R b are as defined in Formula 1b.

[0176] In Reaction Scheme 3, Step 1 is a method for obtaining the compound of Formula 14 using the same method as Step 1 in Reaction Scheme 1. The bromination reaction in Step 2 is a process of obtaining the compound of Formula 13 by stirring an equal amount or an excess amount of N-bromosuccinimide in a reaction-inert solvent under heating for 1 to 24 hours. The Suzuki-Miyaura reaction in Step 3 is a process of obtaining the compound of Formula 12 by stirring an equal amount or an excess amount of boric acid or boronic acid pinacol ester and 0.01 to 0.3 equivalents of a Pd catalyst under heating for 1 to 24 hours. The condensation reaction in Step 4 is a process of obtaining the compound of Formula 11 by stirring an equal amount or an excess amount of an alkyl halide and a salt such as potassium tert-butoxide in a reaction-inert solvent under cooling for 1 to 24 hours. The deprotection reaction in Step 5 is a process of obtaining the compound of Formula 1b by stirring the compound of Formula 11 including benzyl in a reaction-inert solvent in a hydrogen atmosphere with a Pd catalyst for 0.5 - 24 hours.

[0177] The compounds according to the present invention can further form pharmaceutically acceptable salts. There are no particular limitations on such pharmaceutically acceptable salts as long as they are acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions. Examples include acid addition salts formed from inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid; acid addition salts formed from organic carbonic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, and maleic acid; acid addition salts formed from sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid.

[0178] Meanwhile, the compounds represented by Formula 1a or Formula 1b of the present invention may have asymmetric carbon centers and thus can exist in the form of different enantiomers. Specifically, the compounds represented by Formula 1a or Formula 1b can exist in the form of all optical isomers and R or S enantiomers, racemic mixtures, diastereomeric mixtures, or individual diastereomers, and all these isomers and their mixtures are included within the scope of the present invention. In addition, the present invention includes the use of racemic mixtures, one or more enantiomeric forms or mixtures thereof, and includes methods for separating or preparing isomers known in the art.

[0179] In addition, solvate and hydrate forms of Formula 1a and Formula 1b are also included within the scope of the present invention.

[0180] Another embodiment of the present invention provides a pharmaceutical composition containing a therapeutically effective dose of a compound selected from the compounds of formula 1a or formula 1b and their pharmaceutically acceptable salts.

[0181] The compound represented by formula 1a or formula 1b contained in the pharmaceutical composition of the present invention inhibits the activities of EZH1 and / or EZH2, and thus the pharmaceutical composition of the present invention can be used for preventing or treating various diseases related thereto.

[0182] According to another embodiment of the present invention, the pharmaceutical composition is a pharmaceutical composition for preventing or treating cancer or tumor, and it can be treated by inhibiting the activities of EZH1 and / or EZH2 enzymes.

[0183] According to still another embodiment of the present invention, there is provided a pharmaceutical preparation containing the above-mentioned pharmaceutical composition.

[0184] The pharmaceutical preparation of the present invention can be in various forms for oral administration, such as pills, tablets, powders, capsules, syrups or emulsions, or can be in a form for non-oral administration, such as intramuscular, intravenous or subcutaneous injection. Preferably, it is in a form for oral administration.

[0185] In addition, the pharmaceutical composition can be formulated by conventional methods, and in addition to the active ingredient, conventional non-toxic and pharmaceutically acceptable additives are added, specifically, at least one additive selected from carriers, enhancers and excipients.

[0186] Excipients that can be used in the pharmaceutical preparation of the present invention include but are not limited to sweeteners, binders, solubilizers, solubilizing agents, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers and fragrances. For example, as excipients, lactose, glucose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, aluminum magnesium silicate, starch, gelatin, tragacanth, alginic acid, sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence and vanilla can be used.

[0187] In the case where the pharmaceutical preparation of the present invention is in a form for oral administration, non-limiting examples of carriers that can be used include cellulose, calcium silicate, corn starch, lactose, sucrose, glucose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin and talc.

[0188] In the case where the pharmaceutical preparation of the present invention is in the form of an injection, non-limiting examples of carriers can include water, saline solution, glucose aqueous solution, similar sugar aqueous solutions, alcohols, ethylene glycol, ethers, oils, fatty acids, fatty acid esters and glycerol esters.

[0189] Regarding the use of the compounds according to the present invention as medicaments, the latter are prepared in the form of pharmaceutical preparations which, in addition to the active ingredient for oral or parenteral administration, also include pharmaceutically suitable inert organic or inorganic carrier substances, such as water, gelatin, gum arabic, lactose, starch, vegetable oils, polyalkylene glycols and the like. The pharmaceutical preparations can exist in solid form, for example, as tablets, dragees, suppositories or capsules, or in liquid form, for example, as solutions, suspensions or emulsions. In addition, these optionally contain auxiliaries, such as preservatives, stabilizers, wetting agents, emulsifiers, osmotic regulating salts or buffering agents.

[0190] In particular, for parenteral administration, injectable solutions or suspensions are preferred.

[0191] As carrier systems, surfactant auxiliaries can be used, such as bile salts, animal or vegetable phospholipids, or combinations thereof, liposomes and their components.

[0192] For oral administration, tablets, dragees or capsules containing talc and / or hydrocarbon carriers or binders (such as lactose or corn or potato starch) are suitable. In addition, administration can also be in liquid form, for example, in the form of fruit juices to which sweeteners are added.

[0193] For adult patients weighing 70 kg, the human dose of the compound of formula 1a or formula 1b according to the present invention is preferably in the range of 0.1 mg / day to 2,000 mg / day. The compounds according to the present invention can be administered once a day or multiple times a day. The administered dose can vary depending on the patient's health condition, age, weight, gender, form of administration and severity of the disease, and thus the scope of the present invention is not limited to the administered doses given above.

[0194] According to another embodiment of the present invention, there is provided the use of a compound selected from the dioxoisoquinolinone derivative compounds of formula 1a or formula 1b and their pharmaceutically acceptable salts, enantiomers, hydrates and solvates for the treatment of cancer or tumors.

[0195] Hereinafter, the present invention will be described in more detail with examples and embodiments. These are only intended to illustrate the present invention, and the scope of the present invention is not limited thereto.

[0196] Embodiments

[0197] Examples of intermediate synthesis

[0198] [Intermediate 1] 6,7-Dihydroxy-5,8-dimethyl-3,4-dihydroisoquinolin-1(2H)-one

[0199]

[0200] Step 1. Preparation of methyl 3,4-dimethoxy-2,5-dimethylbenzoate

[0201]

[0202] Methyl 3,4-dihydroxy-2,5-dimethylbenzoate (1.97 g, 10.0 mmol), potassium carbonate (6.94 g, 50.2 mmol) and methyl iodide (1.88 mL, 30.1 mmol) were successively added to acetone (20 mL), and the reaction mixture was stirred at room temperature for 24 h. The reaction product was diluted with ethyl acetate and water, and the organic layer was extracted. The extracted organic layer was dried over anhydrous sodium sulfate and then distilled in vacuo. The product was used without further purification.

[0203] Step 2. Preparation of 3,4-dimethoxy-2,5-dimethylbenzoic acid

[0204]

[0205] Methyl 3,4-dimethoxy-2,5-dimethylbenzoate (2.25 g, 10.4 mmol) synthesized in the above [Step 1] and sodium hydroxide (1.2 g, 30.1 mmol) were added to a methanol / water (1 / 1, 50 mL) mixture, and the reaction solution was refluxed at 100 °C for 12 h. The reaction solution was cooled to 0 °C and then acidified to about pH 1 using 6.0 N hydrochloric acid solution. The resulting solid was stirred cold for 1 h and then collected and washed with water to give the compound shown in the title (2.06 g).

[0206] Step 3. Preparation of N-(2,2-dimethoxyethyl)-3,4-dimethoxy-2,5-dimethylbenzamide

[0207]

[0208] 3,4-Dimethoxy-2,5-dimethylbenzoic acid (2.06 g, 9.8 mmol) synthesized in the above [Step 2] was added to N,N-dimethylformamide (20 mL), and then 1-hydroxybenzotriazole (1.72 g, 12.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.44 g, 12.7 mmol) and triethylamine (1.78 mL, 12.7 mmol) were successively added, and the mixture was stirred at room temperature for 0.5 h. A mixture of aminoacetaldehyde dimethyl acetal (1.38 mL, 12.7 mmol) and triethylamine (1.78 mL, 12.7 mmol) was added dropwise within about 5 min, and the mixture was stirred at room temperature for 12 h. The reaction product was diluted with dichloromethane and water, and the organic layer was extracted. The extracted organic layer was washed with water and brine and dried over anhydrous sodium sulfate, and then distilled in vacuo to obtain the compound shown in the title, which was used without further purification.

[0209] Step 4. Preparation of 6,7-dihydroxy-5,8-dimethylisoquinolin-1-(2H)-one

[0210]

[0211] The N-(2,2-dimethoxyethyl)-3,4-dimethoxy-2,5-dimethylbenzamide (2.9 g, 9.8 mmol) synthesized in the above [Step 3] was added to concentrated sulfuric acid (15 mL), and the reaction solution was stirred at 60 °C for 24 hours. The reaction solution was cooled to room temperature and then poured into ice water and stirred for 30 minutes. The resulting solid was collected by filtration, washed with excess water and dried to obtain the compound indicated in the title, which can be used without further purification.

[0212] Step 5. Preparation of 6,7-dihydroxy-5,8-dimethyl-3,4-dihydroisoquinolin-1-(2H)-one

[0213]

[0214] The 6,7-dihydroxy-5,8-dimethylisoquinolin-1(2H)-one (1.8 g, 8.8 mmol) and 10% palladium / carbon (885 mg) synthesized in the above [Step 4] were added to a methanol / ethanol (1 / 1, 36 mL) mixture, and a hydrogen balloon was installed. The reaction solution was heated to 60 °C, stirred for 48 hours, then cooled to room temperature, filtered through diatomaceous earth, and vacuum distilled. Dichloromethane was added to the residue and stirred. The resulting solid was collected by filtration, rinsed with dichloromethane, and then dried to obtain the compound shown in the title (776 mg).

[0215] [Intermediate 2] 8-Chloro-6,7-dihydroxy-5-methyl-3,4-dihydroisoquinolin-1(2H)-one

[0216]

[0217] Step 1. Preparation of methyl 5-chloro-3,4-dihydroxy-2-methylbenzoate

[0218]

[0219] Methyl 3,4-dihydroxy-2-methylbenzoate (2.0 g, 11.0 mmol) was dissolved in ethyl acetate (44 mL), and N-chlorosuccinimide (2.2 g, 16.5 mmol) was added. The reaction solution was stirred at room temperature for 1 hour, then anisole (1.2 mL, 11.0 mmol) was added. After stirring for an additional 15 minutes, the reaction product was diluted with ethyl acetate and water, and the organic layer was extracted. The resulting organic layer was dried over sodium sulfate and vacuum distilled. Dichloromethane (5 mL) was added to the residue and stirred for 30 minutes. The resulting solid was collected by filtration and then washed with dichloromethane to obtain the compound shown in the title (1.1 g).

[0220] Step 1. Preparation of methyl 5-chloro-3,4-dimethoxy-2-methylbenzoate

[0221]

[0222] By carrying out the same reaction as in [Step 2] with [Intermediate 1], the compound shown in the title (2.6 g) was obtained, except that methyl 5-chloro-3,4-dihydroxy-2-methylbenzoate (2.3 g, 10.6 mmol) prepared in the above [Step 1] was used instead of methyl 3,4-dihydroxy-2-methylbenzoate.

[0223] Step 3. Preparation of (5-chloro-3,4-dimethoxy-2-methylphenyl)methanol

[0224]

[0225] Methyl 5-chloro-3,4-dimethoxy-2-methylbenzoate (2.6 g, 10.63 mmol) synthesized in the above [Step 2] was dissolved in tetrahydrofuran (26 mL) and purged with argon, then cooled to 0 °C. Lithium aluminum hydride (403 mg, 10.63 mmol) was added to the reaction solution, and then the mixture was stirred at room temperature for 1 hour. The reaction product was cooled to 0 °C, and then an excess of water and 15% sodium hydroxide solution (2.5 mL) were added dropwise. After stirring at room temperature for another two hours, filtration through diatomaceous earth was carried out. The residue was extracted with ethyl acetate, dried over anhydrous material, and then distilled under vacuum to obtain the compound shown in the title (2.3 g), which could be used without further purification.

[0226] Step 4. Preparation of 1-chloro-5-(chloromethyl)-2,3-dimethoxy-4-methylbenzene

[0227]

[0228] (5-Chloro-3,4-dimethoxy-2-methylphenyl)methanol (2.1 g, 9.69 mmol) synthesized in the above [Step 3] was dissolved in ethyl acetate (50 mL), and then cooled to 0 °C. Thionyl chloride (1.1 mL, 14.53 mmol) was added dropwise to the reaction solution, and the mixture was stirred at 0 °C for 1 hour. An excess of water was added dropwise to the reaction product, and then extraction was carried out using ethyl acetate. The resulting organic layer was dried over anhydrous material, and then distilled under vacuum to obtain the compound shown in the title (2.3 g), which could be used without further purification.

[0229] Step 5. Preparation of 2-(5-chloro-3,4-dimethoxy-2-methylphenyl)acetonitrile

[0230]

[0231] Dissolve 1-chloro-5-(chloromethyl)-2,3-dimethoxy-4-methylbenzene (2.3 g, 9.78 mmol) synthesized in the above [Step 4] in dimethyl sulfoxide (23 mL), and then add sodium cyanide (576 mg, 11.74 mmol) at room temperature. After stirring the reaction solution at room temperature for 2 hours, add an excess of water dropwise to the reaction product, and then extract with ethyl acetate. Dry the obtained organic layer with anhydrous sodium sulfate, and then distill under vacuum to obtain the compound shown in the title (2.2 g), which can be used without further purification.

[0232] Step 6. Preparation of 2-(5-chloro-3,4-dimethoxy-2-methylphenyl)ethan-1-amine

[0233]

[0234] Dissolve 2-(5-chloro-3,4-dimethoxy-2-methylphenyl)acetonitrile (2.2 g, 9.75 mmol) synthesized in the above [Step 5] and an excess of Raney nickel in ethyl acetate (45 mL), and install a hydrogen balloon. Stir the reaction solution at room temperature for 18 hours, filter through diatomaceous earth and distill under vacuum to obtain the compound shown in the title (2.0 g), which can be used without further filtration.

[0235] Step 7. Preparation of 4-nitrophenyl(5-chloro-3,4-dimethoxy-2-methylphenyl)carbamate

[0236]

[0237] Dissolve 2-(5-chloro-3,4-dimethoxy-2-methylphenyl)ethan-1-amine (2.0 g, 8.71 mmol) synthesized in the above [Step 6] and sodium carbonate (2.77 g, 26.12 mmol) in 1,2-dichloroethane (40 mL), and add 4-nitrophenyl chloroformate (2.63 g, 13.06 mmol). After stirring the reaction solution at room temperature for 18 hours, add an excess of water dropwise to the reaction product, and then extract with dichloromethane. Dry the obtained organic layer with anhydrous sodium sulfate, and then distill under vacuum. Purify the residue by silica gel column chromatography to obtain the compound shown in the title (3.0 g).

[0238] Step 8. Preparation of 8-chloro-6,7-dimethoxy-5-methyl-3,4-dihydroisoquinolin-1-(2H)-one

[0239]

[0240] Dissolve the 4-nitrophenyl (5-chloro-3,4-dimethoxy-2-methylphenyl) carbamate (3.0 g, 7.60 mmol) synthesized in the above [Step 7] in 1,2-dichloroethane (50 mL), and then cool it to 0 °C. Slowly add trifluoromethanesulfonic acid (7.3 mL, 81.1 mmol) to the reaction solution, and then stir at 70 °C for 2 hours. After cooling the reaction product to room temperature, slowly add it dropwise to excess ice water, and then stir for 1 hour until all the ice melts. Neutralize the organic layer obtained by dichloromethane extraction with 2N aqueous sodium hydroxide solution. Dry the organic layer with sodium sulfate and distill it under vacuum. Purify the residue by silica gel column chromatography to obtain the compound shown in the title (1.6 g).

[0241] Step 9. Preparation of 8-chloro-6,7-dihydroxy-5-methyl-3,4-dihydroisoquinolin-1(2H)-one

[0242]

[0243] Add the 8-chloro-6,7-dimethoxy-5-methyl-3,4-dihydroisoquinolin-1(2H)-one (1.6 g, 6.14 mmol) synthesized in the above [Step 8] to dichloromethane (20 mL) under a nitrogen atmosphere, and cool the reaction solution to 0 °C. Add boron tribromide (1.3 mL, 13.51 mmol), and then slowly warm to room temperature and stir for 12 hours. Add ice water to the reaction solution, stir the resulting solid for 1 hour, collect it by filtration, and then wash it with excess water and dichloromethane, and dry it to obtain the compound shown in the title (1.2 g).

[0244] [Intermediate 3] 5,8-Dichloro-6,7-dihydroxy-3,4-dihydroisoquinolin-1(2H)-one

[0245]

[0246] Add 3,4-dihydrobenzoic acid (10.0 g, 64.88 mmol) to acetic acid (44 mL), and then add sulfuryl chloride (12.6 mL, 155.72 mmol). Heat the reaction solution to 50 °C and stir for 14 hours. Cool the reaction solution to 0 °C, filter the resulting solid, and recrystallize it with an ethyl acetate / hexane solvent to obtain 2,5-dichloro-3,4-dihydrobenzoic acid (4.2 g).

[0247] By repeating [Step 9] in [Intermediate 2], the compound shown in the title (55 mg) was obtained, except that in [Step 2] of [Intermediate 2], the above-synthesized 2,5-dichloro-3,4-dihydrobenzoic acid (4.2 g, 18.92 mmol) was used instead of methyl 3,4-dihydroxy-2-methylbenzoate.

[0248] [Intermediate 4] 6,7-Dihydroxy-8-methyl-3,4-dihydroisoquinolin-1(2H)-one

[0249]

[0250] Step 1. Preparation of 7-hydroxy-6-methoxy-8-methylisoquinolin-1(2H)-one

[0251]

[0252] By repeating [Step 4] in [Intermediate 1], the compound shown in the title (5.7 g) was obtained, except that in [Step 1] of [Intermediate 1], methyl 3,4-dihydroxy-2-methylbenzoate was used instead of methyl 3,4-dihydroxy-2,5-dimethylbenzoate.

[0253] Step 2. Preparation of 7-hydroxy-6-methoxy-8-methyl-3,4-dihydroisoquinolin-1(2H)-one

[0254]

[0255] The compound shown in the title (3.39 g) was obtained by repeating the process of [Intermediate 1], except that in [Step 5] of [Intermediate 1], 7-hydroxy-6-methoxy-8-methylisoquinolin-1(2H)-one synthesized in the above [Step 1] was used instead of 6,7-dihydroxy-5,8-dimethylisoquinolin-1(2H)-one.

[0256] Step 3. Preparation of 6,7-dihydroxy-8-methyl-3,4-dihydroisoquinolin-1(2H)-one

[0257]

[0258] 7-Hydroxy-6-methoxy-8-methyl-3,4-dihydroisoquinolin-1(2H)-one (100 mg, 0.482 mmol) synthesized in the above [Step 2] was added to dichloromethane (2 mL) under a nitrogen atmosphere, and the reaction solution was cooled to 0 °C. Boron tribromide (1 mL, 0.96 mmol, 1 M solution in dichloromethane) was added thereto, and then the temperature was slowly raised to room temperature and stirred overnight. Ice water was added to the reaction solution, the resulting solid was stirred for 1 hour and collected by filtration. It was washed with excess water and dichloromethane, and then dried to obtain the compound shown in the title (53 mg).

[0259] [Synthesis Example 1] 9-Chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 1]

[0260]

[0261] Step 1. Preparation of methyl 2-(4-((tert-butoxycarbonyl)amino)bicyclo)[2.2.2]oct-1-yl)-7-chloro-2,4-dimethylbenzo [d][1,3]dioxole-5-carboxylate

[0262]

[0263] Methyl 5-chloro-3,4-dihydroxy-2-methylbenzoate (1.5 g, 6.92 mmol), tert-butyl (4-ethynylbicyclo[2.2.2]octan-1-yl)carbamate (2.07 g, 8.31 mmol), Ru 3 (CO) 12 (111 mg, 0.173 mmol) and Bippyphos (263 mg, 0.519 mmol) were added to toluene (37.5 mL), the mixture was purged with nitrogen, and then the mixture was refluxed at 120 °C for 12 hours. The reaction solution was cooled to room temperature and then concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (2.0 g).

[0264] Step 2. Preparation of ethyl 2-(4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]oct-1-yl)-7-chloro-6-iodo-2,4-dimethylbenzo [d][1,3]dioxole-5-carboxylate

[0265]

[0266] Methyl 2-(4-((tert-butoxycarbonyl)amino)bicyclo)[2.2.2]octan-1-yl)-7-chloro-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate (1.85 g, 3.97 mmol) synthesized in the above [Step 1] was added to chloroform (18.5 mL). Iodine (2.02 g, 7.97 mmol) and silver trifluoroacetate (1.75 g, 3.97 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction product was diluted with dichloromethane and an aqueous solution of sodium thiosulfate, and then the organic layer was extracted. The extracted organic layer was washed with brine, dried over anhydrous sodium sulfate, and distilled in vacuo. The residue was purified by basic silica gel column chromatography to give the title compound (1.7 g).

[0267] Step 3. Preparation of methyl (2-(4-aminobicyclo[2.2.2]oct-1-yl)-7-chloro-6-iodo-2,4-dimethylbenzo[d][1,3] dioxole-5-carboxylate

[0268]

[0269] Ethyl 2-(4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octan-1-yl)-7-chloro-6-iodo-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate (1.7 g, 2.9 mmol), which was synthesized in the above [Step 2], and trifluoroacetic acid (3.4 mL) were successively added to dichloromethane (17 mL), and then the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, saturated aqueous sodium bicarbonate was added for neutralization, and extraction was carried out using dichloromethane. The extracted organic layer was dried over anhydrous sodium sulfate. The dried organic layer was concentrated under vacuum, and the residue was purified by basic silica gel column chromatography to obtain the compound shown in the title (1.1 g).

[0270] Step 4. Preparation of methyl 7-chloro-2-(4-(dimethylamino)bicyclo[2.2.2]oct-1-yl)-6-iodo-2,4-dimethylbenzo [d][1,3]dioxole-5-carboxylate

[0271]

[0272] Methyl (2-(4-aminobicyclo[2.2.2]octan-1-yl))-7-chloro-6-iodo-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate (1.1 g, 2.2 mmol), which was synthesized in the above [Step 3], and 37% aqueous formaldehyde solution (0.68 mL, 8.9 mmol) were successively added to methanol (22 mL) at 5 °C, and then the mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (2.84 g, 13 mmol) was added and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, neutralization was carried out with saturated aqueous calcium carbonate, and extraction was carried out using dichloromethane. The extracted organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then distilled under vacuum. The residue was purified by basic silica gel column chromatography to obtain the compound shown in the title (1 g).

[0273] Step 5. (E)-7-chloro-2-(4-(dimethylamino)bicyclo[2.2.2]oct-1-yl))-6-(2-ethoxyvinyl Preparation of Methyl (2,4-dimethylbenzo[d][1,3]dioxol-5-yl)acetate

[0274]

[0275] The methyl 7-chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-6-iodo-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate (1 g, 1.9 mmol) synthesized in the above [Step 4], (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.572 g, 2.9 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.176 g, 0.19 mmol), triphenylphosphine (50 mg, 0.19 mmol) and cesium carbonate (1.25 g, 3.8 mmol) were added to dimethoxyethane (10 mL). The mixture was purged with nitrogen and then refluxed and stirred at 84 °C for 5 hours. After completion of the reaction, it was filtered through silica sand and then washed with saturated aqueous sodium chloride solution. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by basic silica gel column chromatography to give the title compound (900 mg).

[0276] Step 6. Preparation of Methyl 7-chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-6-(2-oxoethyl)benzo[d][1,3]dioxole-5-carboxylate Step 7. Preparation of Methyl 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one

[0277]

[0278] The methyl (E)-7-chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl))-6-(2-ethoxyvinyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate (300 mg, 0.65 mmol) synthesized in the above [Step 5] was added to dichloromethane (3 mL). Trifluoroacetic acid (0.12 mL, 1.6 mmol) was added at 5 °C and then stirred for 1 hour. After completion of the reaction, it was neutralized with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The extracted organic layer was washed with saturated aqueous sodium chloride solution. The washed organic layer was dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue (280 mg) was used for the next reaction without purification.

[0279] Step 1. Preparation of 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-9-carbaldehyde Step 2. Preparation of 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-9-ethynyl-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one Step 1. Preparation of tert-Butyl (4-(2,4,9-trimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate

[0280]

[0281] Methyl 7-chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl))-2,4-dimethyl-6-(2-oxoethyl)benzo[d][1,3]dioxole-5-carboxylate (280 mg, 0.65 mmol) synthesized in the above [Step 6] and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (118 mg, 0.78 mmol) were added to methanol (3 mL). The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, sodium borohydride (98 mg, 2.6 mmol) was added, and then stirred for 30 minutes. After 30 minutes, the reaction mixture was warmed to room temperature and then stirred for 68 hours. After completion of the reaction, saturated aqueous sodium bicarbonate was added for neutralization, and extraction was performed using dichloromethane. The extracted organic layer was dried over anhydrous magnesium sulfate and then concentrated under vacuum. The residue was purified by basic silica gel column chromatography to obtain the compound shown in the title (150 mg).

[0282] [Synthesis Example 2] 9-Chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl))-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one Isomers A and B [Compound 2 and Compound 3]

[0283]

[0284] The 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl))-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 1] synthesized in [Example 1] was separated into isomers under the following conditions. The absolute stereochemistry of each isomer was not measured.

[0285] Column: Daicel Chiralcel OZ-H, 10 x 250 mm

[0286] Temperature: 35 °C

[0287] Flow rate: 1.8 mL / min

[0288] Wavelength: 270 nm

[0289] Elution solvent: Ethanol:n-Hexane:Diethylamine = 800:200:0.2 (v / v%)

[0290] First peak: 21 minutes - Isomer A (>99.0% ee) [Compound 2]

[0291] Second peak: 27 minutes - Isomer B (>99.0% ee) [Compound 3]

[0292] [Synthesis Example 3] 9-Chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,4-dimethyl-7,8-dihydro[1,3]

[0293] dioxolane[4,5-g]isoquinolin-5(6H)-one [Compound 4]

[0294]

[0295] By conducting the same reaction as in [Synthesis Example 1], the title compound (98 mg) was obtained, except that in [Step 7] of [Synthesis Example 1], 3-(aminomethyl)-4-methoxy-6-methylpyridin-2(1H)-one was used instead of 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one.

[0296] [Synthesis Example 4] 9-Chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,4-dimethyl-7,8-dihydro[1,3]dioxolane[4,5-g]isoquinolin-5(6H)-one Isomers A and B [Compound 5, Compound 6]

[0297]

[0298] The 9-chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,4-dimethyl-7,8-dihydro[1,3]dioxolane[4,5-g]isoquinolin-5(6H)-one synthesized in [Synthesis Example 3] was separated into isomers under the following conditions. The absolute stereochemistry of each isomer was not measured.

[0299] Column: Daicel Chiralpak Daicel Chiralpak OZ-H, 10 x 250 mm

[0300] Temperature: 35 °C

[0301] Flow rate: 2.2 mL / min

[0302] Wavelength: 270 nm

[0303] Elution solvent: Ethanol:n-Hexane:Diethylamine = 990:10:1 (v / v%)

[0304] First peak: 50 minutes - Isomer A (>99.0% ee) [Compound 5]

[0305] Second peak: 61 minutes - Isomer B (>99.0% ee) [Compound 6]

[0306] [Synthesis Example 5] 9-Chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-6-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 7]

[0307]

[0308] By carrying out the same reaction as in [Synthesis Example 1], the title compound (90 mg) was obtained, except that in [Step 7] of [Synthesis Example 1], 3-(aminomethyl)-6-methyl-4-(methylthio)pyridin-2(1H)-one was used instead of 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one.

[0309] [Synthesis Example 6] 9-Chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-6-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one Isomers A and B [Compound 8, Compound 9]

[0310]

[0311] The 9-chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-6-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one synthesized in [Synthesis Example 5] was separated into isomers under the following conditions. The absolute stereochemistry of each isomer was not measured.

[0312] Column: Daicel Chiralpak Daicel Chiralpak OZ-H, 10 x 250 mm

[0313] Temperature: 35 °C

[0314] Flow rate: 2.2 mL / min

[0315] Wavelength: 270 nm

[0316] Elution solvent: ethanol: n-hexane: diethylamine = 990:10:1 (v / v%)

[0317] The first peak: 49 minutes - isomer A (>99.0% ee) [Compound 8]

[0318] The second peak: 60 minutes - isomer B (>99.0% ee) [Compound 9]

[0319] [Synthesis Example 7] 9-Bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 10]

[0320]

[0321] By carrying out the same reaction as in [Synthesis Example 1], the title compound (48 mg) was obtained, except that in [Step 1] of [Synthesis Example 1], methyl 5-bromo-3,4-dihydroxy-2-methylbenzoate was used instead of methyl 5-chloro-3,4-dihydroxy-2-methylbenzoate.

[0322] [Synthesis Example 8] 9-Bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomers A and B [Compound 11, Compound 12]

[0323]

[0324] The 9-bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one synthesized in [Synthesis Example 7] was separated into isomers under the following conditions. The absolute stereochemistry of each isomer was not measured.

[0325] Column: Daicel chiral column OZ-H, 10 x 250 mm

[0326] Temperature: 35 °C

[0327] Flow rate: 1.8 mL / min

[0328] Wavelength: 270 nm

[0329] Elution solvent: ethanol:n-hexane:diethylamine = 800:200:0.2 (v / v%)

[0330] The first peak: 22 minutes - isomer A (>99.0% ee) [compound 11]

[0331] The second peak: 27 minutes - isomer B (>99.0% ee) [compound 12]

[0332] [Synthesis Example 9] 9-Cyclopropyl-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [compound 13] and 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [compound 14]

[0333]

[0334] 9-Bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one (40 mg, 0.07 mmol, [compound 10]) synthesized in [Synthesis Example 7], cyclopropylboronic acid (29 mg, 0.34 mmol), potassium phosphate (36 mg, 0.17 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (7 mg, 0.01 mmol) were successively added to a mixture of 1,4-dioxane:water (0.5 mL, 4:1). After purging with argon, the mixture was refluxed at 90 °C for 13 hours. After cooling the reaction solution to room temperature, dichloromethane and water were added, and the organic layer was extracted. The extracted organic layer was dried over anhydrous sodium sulfate and then distilled under vacuum. The residue was purified by basic silica gel column chromatography to obtain compound 13 (14 mg) and compound 14 (8 mg).

[0335] [Synthesis Example 10] 9-(Cyclopent-1-en-1-yl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 15]

[0336]

[0337] By conducting the same reaction as in [Synthesis Example 9], the title compound (35 mg) was obtained, except that 1-cyclopentenylboronic acid was used instead of cyclopropylboronic acid in [Synthesis Example 9].

[0338] [Synthesis Example 11] 9-Cyclopentyl-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 16]

[0339]

[0340] 9-(Cyclopent-1-en-1-yl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-1 (20 mg, 0.035 mmol) synthesized in [Synthesis Example 10] and 10% palladium / carbon (30 mg) were dissolved in ethyl acetate / methanol (1:1, 2 mL), and then a hydrogen balloon was installed. The reaction solution was stirred at room temperature for 18 hours, and then filtered through diatomaceous earth and distilled under vacuum. The residue was purified by silica gel column chromatography to obtain the title compound (9 mg).

[0341] [Synthesis Example 12] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-9-ethenyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 17]

[0342]

[0343] By carrying out the same reaction as in [Synthesis Example 9], the title compound (160 mg) was obtained, except that 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane was used instead of cyclopropylboronic acid used in [Synthesis Example 9].

[0344] [Synthesis Example 13] 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-9-ethyl-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 18]

[0345]

[0346] By carrying out the same reaction as in [Synthesis Example 11], the title compound (25.5 mg) was obtained, except that 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-9-vinyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 17] was used instead of 9-(cyclopent-1-en-1-yl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 15] in [Synthesis Example 11].

[0347] [Synthesis Example 14] 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-9-(prop-1-en-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 19]

[0348]

[0349] By carrying out the same reaction as in [Synthesis Example 10], the title compound (35 mg) was obtained, except that 2-isopropenylboronic acid pinacol ester was used instead of cyclopropylboronic acid used in [Synthesis Example 10].

[0350] [Synthesis Example 15] 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-9-isopropyl-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 20]

[0351]

[0352] By carrying out the same reaction as in [Synthesis Example 11], the title compound (10 mg) was obtained, except that 6-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-dimethylaminobicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-9-(prop-1-en-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 19] was used instead of 9-(cyclopent-1-en-1-yl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]

[0353] dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 15].

[0354] [Synthesis Example 16] 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-9-ethynyl-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 21]

[0355]

[0356] Step 2. Preparation of tert-Butyl (4-(6-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-2,4,9-trimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate Step 3. Preparation of tert-Butyl (4-(6-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,4,9-trimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate , 6,7 , Step 4. Preparation of 2-(4-Aminobicyclo[2.2.2]octan-1-yl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one Step 5. 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5-one

[0357]

[0358] 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-9-ethenyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one (106 mg, 0.199 mmol, [Compound 17]) synthesized in [Synthesis Example 12] was added to a mixture of tetrahydrofuran (2.0 mL) and water (1.0 mL), and then 4% osmium tetroxide (63 μL, 0.01 mmol) and sodium periodate (85 mg, 0.398 mmol) were added successively. The reaction solution was stirred at room temperature for 17 hours, and the insoluble solid was removed by filtration. Saturated sodium nitrite was added to the filtrate, and extraction was performed with dichloromethane. The extracted organic layer was dried over anhydrous sodium sulfate and then distilled under vacuum to obtain the compound shown in the title (53 mg).

[0359] ​ ​ ​

[0360]

[0361] 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-9-carbaldehyde (50 mg, 0.09 mmol) synthesized in [Step 1] above was added to methanol (1.0 mL), and then potassium carbonate (20 mg, 0.149 mmol) and dimethyl (1-thiazol-2-ylpropyl)phosphonate (12.3 mg, 0.187 mmol) diluted in dichloromethane (1.0 mL) were added successively. The reaction solution was stirred at room temperature for 16 hours, neutralized with saturated ammonium chloride, and then a salt solution was added and the organic layer was extracted with dichloromethane. The extracted organic layer was dried over anhydrous sodium sulfate and then distilled under vacuum. The residue was purified by basic silica gel column chromatography to obtain the compound shown in the title (8 mg).

[0362] [Table 1]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372] [Synthesis Example 17] 6 - ((4,6 - dimethyl - 2 - oxo - 1,2 - dihydropyridin - 3 - yl)methyl) - 2 - (4 - (dimethylamino)bicyclo[2.2.2]octan - 1 - yl) - 2,4,9 - trimethyl - 7,8 - dihydro - [1,3]dioxolo[4,5 - g]isoquinolin - 5(6H) - one [Compound 22]

[0373]

[0374] ​ ​

[0375]

[0376] 6,7 - Dihydroxy - 5,8 - dimethyl - 3,4 - dihydroisoquinolin - 1(2H) - one (570 mg, 2.77 mmol, [Intermediate 1]), tert - butyl (4 - ethynylbicyclo[2.2.2]octan - 1 - yl)carbamate (1.38 g, 5.53 mmol), Ru 3 (CO) 12 (176 mg, 0.277 mmol) and Bippyphos (420 mg, 0.828 mmol) were added to acetonitrile (28 mL). After purging with argon, the mixture was refluxed at 120 °C for 12 hours. The reaction solution was cooled to room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain the compound shown in the title (350 mg).

[0377] ​ ​ ​

[0378]

[0379] The tert-butyl (4-(2,4,9-trimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate (350 mg, 0.77 mmol) synthesized in the above [Step 1] was added to N,N-dimethylformamide (5.0 mL). The reaction solution was cooled to 0 °C, then 1.0 M potassium tert-butoxide (1.0 mL, 0.1 mmol) was added dropwise, and then stirred for 5 minutes. A solution of 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (260 mg, 0.1 mmol) synthesized by the method described in WO2014097041 dissolved in tetrahydrofuran (4.0 mL) was added, and the mixture was stirred at 0 °C for 4 hours. After the reaction, ammonium chloride solution was added, and extraction was carried out using 10% methanol-chloroform. The extracted organic layer was dried over anhydrous sodium sulfate and then distilled under vacuum. The residue was purified by basic silica gel column chromatography to obtain the compound shown in the title (320 mg).

[0380] ​ ​ ​

[0381]

[0382] The tert-butyl (4-(6-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-2,4,9-trimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate (319 mg, 0.47 mmol) and 10% palladium / carbon (30 mg) synthesized in the above [Step 2] were added to methanol (3 mL) and ethyl acetate (3 mL), and then a hydrogen balloon was installed. The reaction solution was stirred at room temperature for 1 hour, filtered through diatomaceous earth, and then distilled under vacuum to obtain the compound shown in the title (200 mg).

[0383] ​ ​ ​

[0384]

[0385] (4-(6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,4,9-trimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-2-yl)bicyclo[2.2.2]octan-1-yl)carbamic acid tert-butyl ester (200 mg, 0.34 mmol) synthesized in the above [Step 3] and 4N hydrochloric acid - 1,4-dioxane solution (1.7 mL) were sequentially added to methanol (mL), and the reaction solution was stirred at room temperature for 1 hour. After the reaction, saturated aqueous sodium bicarbonate was added for neutralization, and extraction was performed with 20% methanol - chloroform. The extracted organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo to obtain the compound shown in the title (166 mg).

[0386] ​ ​ , ​ (6H)-Ketone Preparation

[0387]

[0388] 2-(4-Aminobicyclo[2.2.2]octan-1-yl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one (166 mg, 0.34 mmol) synthesized in the above [Step 4] and 37% aqueous formaldehyde solution (0.2 mL, 2.67 mmol) were sequentially added to methanol (3 mL). After stirring at room temperature for 10 minutes, sodium triacetoxyborohydride (530 mg, 2.5 mmol) was added, and then the mixture was stirred at room temperature for 18 hours. After the reaction, neutralization was carried out using sodium bicarbonate, and then extraction was performed with 20% methanol - chloroform. The extracted organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by basic silica gel column chromatography to obtain the compound shown in the title (168 mg).

[0389] [Synthesis Example 18] 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one Isomers A and B [Compound 23, Compound 24]

[0390]

[0391] The 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one synthesized in [Synthesis Example 17] was separated into isomers under the following conditions. The absolute stereochemistry of each isomer was not measured.

[0392] Column: Daicel Chiralpak OZ-H, 10 x 250 mm

[0393] Temperature: 35 °C

[0394] Flow rate: 1.8 mL / min

[0395] Wavelength: 270 nm

[0396] Elution solvent: ethanol: n-hexane: diethylamine = 800:200:0.2 (v / v%)

[0397] First peak: 20 minutes - Isomer A (>99.0% ee) [Compound 23]

[0398] Second peak: 25 minutes - Isomer B (>99.0% ee) [Compound 24]

[0399] [Synthesis Example 19] 2-(4-(Dimethylamino)bicyclo[2.2.2]octan-1-yl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 25]

[0400]

[0401] By carrying out the same reaction as in [Synthesis Example 17], except that in [Step 2] of [Synthesis Example 17], 2-(benzyloxy)-3-(chloromethyl)-4-methoxy-6-methylpyridine was used instead of 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine, the title compound (81 mg) was obtained.

[0402] [Synthesis Example 20] 2-(4-(Dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4,9-trimethyl-6-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 26]

[0403]

[0404] By carrying out the same reaction as in [Synthesis Example 17], except that in [Step 2] of [Synthesis Example 17], 2-(benzyloxy)-3-(chloromethyl)-6-methyl-4-propylpyridine was used instead of 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine, the compound shown in the title (11 mg) was obtained.

[0405] [Table 2]

[0406]

[0407]

[0408]

[0409] [Synthesis Example 21] 4-Chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,9-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 27]

[0410]

[0411] By carrying out the same reaction as in [Synthesis Example 17], except that in [Step 1] of [Synthesis Example 17], 8-chloro-6,7-dihydroxy-5-methyl-3,4-dihydroisoquinolin-1(2H)-one [Intermediate 2] was used instead of 6,7-dihydroxy-5,8-dimethyl-3,4-dihydroisoquinolin-1(2H)-one, the compound shown in the title (76 mg) was obtained.

[0412] [Synthesis Example 22] 4,9-Dichloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 28]

[0413]

[0414] By carrying out the same reaction as in [Synthesis Example 17], except that in [Step 1] of [Synthesis Example 17], 5,8-dichloro-6,7-dihydroxy-3,4-dihydroisoquinolin-1(2H)-one [Intermediate 3] was used instead of 6,7-dihydroxy-5,8-dimethyl-3,4-dihydroisoquinolin-1(2H)-one, the compound shown in the title (10 mg) was obtained.

[0415] [Synthesis Example 23] 9-Chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-4-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 29]

[0416] Step 1 Preparation of Methyl 4-(4-methyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-2- yl)bicyclo[2.2.2]octane-1-carboxylate

[0417]

[0418] 6,7-Dihydroxy-8-methyl-3,4-dihydroisoquinolin-1(2H)-one (600 mg, 3.106 mmol), methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate (914 mg, 4.659 mmol) and 4-methylbenzenesulfonate monohydrate (118 mg, 0.621 mmol) were added to toluene (6 mL), and the mixture was refluxed at 120 °C for 12 hours using a Dean-Stark trap. The reaction solution was cooled to room temperature, and then dichloromethane was added. The insoluble solid was filtered off, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to give the title compound (452 mg).

[0419] Step 2 Preparation of Methyl 4-(9-chloro-4-methyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]iso quinolin-2-yl)bicyclo[2.2.2]octane-1-carboxylate

[0420]

[0421] The compound synthesized in the above [Step 1] (400 mg, 1.077 mmol) and N-chlorosuccinimide (173 mg, 1.292 mmol) were successively added to acetic acid (11 mL). The reaction mixture was stirred at 50 °C for 1 hour and then cooled to 0 °C. Excess water was added, and extraction was performed using dichloromethane. The organic layer was washed with brine, then dried over anhydrous material and distilled under vacuum. The residue was purified by silica gel column chromatography to give the title compound (140 mg).

[0422] Step 3 Preparation of 4-(9-chloro-4-methyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]iso quinolin-2-yl)bicyclo[2.2.2]octane-1-carboxylate salt

[0423]

[0424] Methyl 4-(9-chloro-4-methyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-2-yl)bicyclo[2.2.2]octane-1-carboxylate (140 mg, 0.345 mmol) and lithium hydroxide monohydrate (58 mg, 1.380 mmol) synthesized in the above [Step 2] were successively added to tetrahydrofuran (2 mL) and water (0.5 mL). The reaction solution was stirred at 60 °C for 14 hours, then cooled to room temperature, and then tetrahydrofuran was distilled off under vacuum. The residue was neutralized with 1 N hydrochloric acid and then extracted with chloroform and isopropanol. The organic layer was dried over anhydrous sodium sulfate and then distilled under vacuum. The next reaction was carried out without further purification.

[0425] Step 4 Preparation of tert-Butyl (4-(9-chloro-4-methyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]iso quinolin-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate

[0426]

[0427] 4-(9-Chloro-4-methyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-2-yl)bicyclo[2.2.2]octane-1-carboxylate (100 mg, 0.255 mmol), diphenylphosphoryl azide (0.07 mL, 0.306 mmol) and triethylamine (0.04 mL, 0.306 mmol) synthesized in the above [Step 3] were added to tert-butanol (0.5 mL) and toluene (0.5 mL), then stirred at room temperature for 30 minutes, heated to 80 °C, and then stirred for 24 hours. The reaction solution was cooled to room temperature and then distilled under vacuum. The residue was purified by silica gel column chromatography to give the compound shown in the title (19 mg).

[0428] Step 5 Preparation of 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethyl amino)bicyclo[2.2.2]octan-1-yl)-4-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5 (6H)-Ketone

[0429]

[0430] By carrying out the same reaction as in [Synthesis Example 17], except that in [Step 2] of [Synthesis Example 17], tert-butyl (4-(9-chloro-4-methyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate was used instead of tert-butyl (4-(2,4,9-trimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate synthesized in the above [Step 4], the compound shown in the title (2.8 mg) was obtained.

[0431] [Table 3]

[0432]

[0433]

[0434]

[0435] [Synthesis Example 24] (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(furan-2-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 30] and (S)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(furan-2-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 31]

[0436]

[0437] Step 1 Preparation of Methyl 3,4-dimethoxy-2-methylbenzoate

[0438]

[0439] Methyl 3,4-dihydroxy-2-methylbenzoate (20 g, 110 mmol), potassium carbonate (45.6 g, 330 mmol), dimethyl sulfate (26 mL, 270 mmol) and tetrabutylammonium iodide (0.4 mL, 1.1 mmol) were added to acetone (200 mL), and the reaction mixture was refluxed at 65 °C for 12 h. The reaction solution was cooled to room temperature, the solid was filtered off and washed with acetone. The filtrate was distilled in vacuo and used without further purification.

[0440] Step 2 Preparation of 3,4-dimethoxy-2-methylbenzoic acid

[0441]

[0442] Methyl 3,4-dimethoxy-2-methylbenzoate (23.1 g, 110 mmol) synthesized in the above [Step 1] and sodium hydroxide (13.2 g, 330 mmol) were added to a methanol / water (1 / 1, 300 mL) mixture, and the reaction mixture was refluxed at 80 °C for 4 h. The reaction solution was cooled and then acidified to about pH 1 with 6.0 N aqueous hydrochloric acid. The resulting solid was collected by filtration after stirring at low temperature for 1 h, washed with water and then dried to obtain the title compound (21 g), which was used without further purification.

[0443] Step 3 Preparation of N-(2,2-dimethoxyethyl)-3,4-dimethoxy-2-methylbenzamide

[0444]

[0445] The 3,4-dimethoxy-2-methylbenzoic acid (21. g, 107 mmol), 1-hydroxybenzotriazole (18.8 g, 139 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (26.6 g, 139 mmol), aminoacetaldehyde dimethyl acetal (15 mL, 139 mmol) and triethylamine (38.7 mL, 278 mmol) synthesized in the above [Step 2] were successively added to N,N-dimethylformamide (147 mL), and the mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with dichloromethane and water, and then the organic layer was extracted. The extracted organic layer was washed with water and brine, dried using sodium sulfate, distilled under vacuum, and used without further purification.

[0446] Step 4 Preparation of 7-hydroxy-6-methoxy-8-methylisoquinolin-1(2H)-one

[0447]

[0448] The N-(2,2-dimethoxyethyl)-3,4-dimethoxy-2-methylbenzamide (30.3 g, 107 mmol) synthesized in the above [Step 3] was added to concentrated sulfuric acid (140 mL), and the mixture was stirred at 60 °C for 4 hours. The reaction solution was cooled to room temperature, then poured into ice water and stirred for 30 minutes. The resulting solid was collected by filtration, washed with excess water, and then dried to obtain the compound shown in the title (17 g), which was used without further purification.

[0449] Step 5 Preparation of 7-hydroxy-6-methoxy-8-methyl-3,4-dihydroisoquinolin-1(2H)-one

[0450]

[0451] The 7-hydroxy-6-methoxy-8-methylisoquinolin-1(2H)-one (30 g, 0.146 mol) and 10% palladium / carbon (15 g) synthesized in the above [Step 4] were added to ethanol (600 mL), and a hydrogen balloon was installed. The reaction solution was stirred at 60 °C for 12 hours, then cooled to room temperature, filtered through diatomaceous earth, and distilled under vacuum to obtain the compound shown in the title (30 g).

[0452] Step 6 Preparation of 6,7-dihydroxy-8-methyl-3,4-dihydroisoquinolin-1(2H)-one

[0453]

[0454] The 7-hydroxy-6-methoxy-8-methyl-3,4-dihydroisoquinolin-1(2H)-one (31.9 g, 0.154 mol) synthesized in the above [Step 5] was added to dichloromethane (320 mL) under a nitrogen atmosphere, and the reaction solution was cooled to 0 °C. Boron tribromide (37 mL, 0.38 mol) was added, and then the reaction solution was slowly heated to room temperature and stirred for 12 hours. Ice water was added to the reaction solution. The resulting solid was stirred for 1 hour, collected by filtration, washed with excess water and dichloromethane, and then dried to obtain the compound shown in the title (21.9 g).

[0455] Step 7 Preparation of tert-Butyl ((trans-4-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]iso quinolin-2-yl)cyclohexyl)carbamate

[0456]

[0457] The 6,7-dihydroxy-8-methyl-3,4-dihydroisoquinolin-1(2H)-one (7.12 g, 36.85 mmol) synthesized in the above [Step 6], tert-butyl (trans-4-ethynylcyclohexyl)carbamate (12.34 g, 55.28 mmol), Ru 3 (CO) 12 (1.17 g, 1.84 mmol) and Bippyphos (2.8 g, 5.52 mmol) were successively added to acetonitrile (350 mL), purged with argon, and then refluxed at 130 °C for 17 hours. The reaction solution was cooled to room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain the compound shown in the title (13.4 g).

[0458] Step 8 Preparation of tert-Butyl ((trans-4-(9-bromo-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4, 5-g]isoquinolin-2-yl)cyclohexyl)carbamate

[0459]

[0460] The tert-butyl (trans-4-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-2-yl)cyclohexyl)carbamate (48.7 g, 0.117 mmol) synthesized in the above [Step 7] was added to acetonitrile (550 mL), and then N-bromosuccinimide (25.0 g, 0.14 mmol) was added. The reaction solution was stirred at room temperature for 12 hours, then saturated sodium thiosulfate was added and extraction was carried out with ethyl acetate. The extracted organic layer was dried over anhydrous sodium sulfate and then distilled under vacuum. The residue was purified by silica gel column chromatography to obtain the compound shown in the title (38.7 g).

[0461] Step 9 Preparation of tert-Butyl ((trans-4-(9-(furan-2-yl)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxo l[4,5-g]isoquinolin-2-yl)cyclohexyl)carbamate

[0462]

[0463] tert-Butyl (trans-4-(9-bromo-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-2-yl)cyclohexyl)carbamate (0.3 g, 0.606 mmol) synthesized in the above [Step 8], furan-2-boronic acid (280 mg, 3.028 mmol), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (115 mg, 0.1 mmol) and potassium carbonate (420 mg, 3.028 mmol) were added to 1,4-dioxane (20 mL) and water (5 mL), purged with argon, and then refluxed at 100 °C for 15 hours. The reaction solution was cooled to room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain the compound shown in the title (180 mg).

[0464] Step 10 Preparation of tert-Butyl ((trans-4-(6-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-9-(furan-2-yl)- 2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-2-yl)cyclohexyl)amino carbamate

[0465]

[0466] tert-Butyl (trans-4-(9-(furan-2-yl)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-2-yl)cyclohexyl)carbamate (180 mg, 0.373 mmol) synthesized in the above [Step 9] was added to N,N-dimethylformamide (1.5 mL). The reaction solution was cooled to 0 °C, then tert-butanol (0.5 mL, 0.485 mmol) was added dropwise and stirred for 5 minutes. A solution of 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (127 mg, 0.485 mmol) synthesized according to the method described in WO2014097041 dissolved in N,N-dimethylformamide (1.5 mL) was added, and then stirred at 0 °C for 3 hours. After completion of the reaction, ammonium chloride solution was added, and extraction was carried out with 10% methanol-chloroform. The extracted organic layer was dried over anhydrous material and then distilled under vacuum. The residue was purified by basic silica gel column chromatography to obtain the compound shown in the title (170 mg).

[0467] Step 11. Preparation of 2-(trans-4-aminocyclohexyl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl)-9-(furan-2-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one Preparation

[0468]

[0469] tert-Butyl (trans-4-(6-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-9-(furan-2-yl)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-2-yl)cyclohexyl)carbamate (170 mg, 0.24 mmol) synthesized in the above [Step 10] was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.18 mL, 2.4 mmol) was added. The reaction solution was stirred at room temperature for 11 hours. After the reaction was completed, saturated sodium bicarbonate water was added for neutralization, and extraction was carried out with 20% methanol-chloroform. The extracted organic layer was dried over anhydrous sodium sulfate, then concentrated under vacuum and purified by basic silica gel column chromatography to obtain the compound shown in the title (43 mg).

[0470] Step 12. Preparation of 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-trans-4-(dimethyl amino)cyclohexyl-9-(furan-2-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5 (6H)-one

[0471]

[0472] 2-(trans-4-Aminocyclohexyl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-9-(furan-2-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one (40 mg, 0.077 mmol) synthesized in the above [Step 11] and aqueous formaldehyde solution (25 μL, 0.231 mmol) were successively added to methanol (0.8 mL), and then stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (81 mg, 0.385 mmol) was added, and then stirred at room temperature for 12 hours. After the reaction was completed, saturated sodium bicarbonate water was added for neutralization, and extraction was carried out with 20% methanol-chloroform. The extracted organic layer was washed with brine, dried over anhydrous sodium sulfate, and then distilled under vacuum. The residue was purified by basic silica gel column chromatography to obtain the compound shown in the title (33 mg).

[0473] Step 13. Preparation of (R)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-trans-4-(dimethyl amino)cyclohexyl-9-(furan-2-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin- 5(6H)-one [Compound 30] and (S)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-trans- 4-(dimethylamino)cyclohexyl-9-(furan-2-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g] isoquinolin-5(6H)-one [Compound 31]

[0474]

[0475] The 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-trans-4-(dimethylamino)cyclohexyl-9-(furan-2-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one synthesized in [Step 12] was separated into isomers under the following conditions.

[0476] Column: Daicel Chiralpak OZ-H, 10x250 mm

[0477] Temperature: 40 °C

[0478] Flow rate: 1.8 mL / min

[0479] Wavelength: 270 nm

[0480] Elution solvent: ethanol:n-hexane:diethylamine = 800:200:0.2 (v / v%)

[0481] The first peak: 18 minutes (specific rotation [α] 20 D : -39.81 (C = 0.5, methanol:dichloromethane) [Compound 30]

[0482] The second peak: 24 minutes (specific rotation [α] 20 D : +39.57 (C = 0.5, methanol:dichloromethane) [Compound 31]

[0483] [Synthesis Example 25] Preparation of (R)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(thiophen-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 32] and (S)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(thiophen-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 33]

[0484]

[0485] By performing the same reaction as in [Synthesis Example 24], except that in [Step 9] of [Synthesis Example 24], thiophene-2-boronic acid was used instead of furan-2-boronic acid, the synthesized 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(thiophen-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one (53 mg) was obtained.

[0486]

[0487] The above-synthesized 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(thiophen-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one was separated into isomers under the following conditions.

[0488] Column: Daicel Chiralpak OZ-H, 10 x 250 mm

[0489] Temperature: 40 °C

[0490] Flow rate: 1.8 mL / min

[0491] Wavelength: 270 nm

[0492] Elution solvent: ethanol: n-hexane: diethylamine = 800:200:0.2 (v / v%)

[0493] First peak: 18 minutes [Compound 32]

[0494] Second peak: 24 minutes [Compound 33]

[0495] [Synthesis Example 26] (R)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(pyridin-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 34] and (S)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(pyridin-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 35]

[0496]

[0497] By conducting the same reaction as in [Synthesis Example 24], except that pyridine-4-boronic acid was used instead of furan-2-boronic acid in [Step 9] of [Synthesis Example 24], 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(pyridin-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one (55 mg) was obtained.

[0498]

[0499] The above-synthesized 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(pyridin-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one was separated into isomers under the following conditions.

[0500] Column: Daicel Chiralpak OZ-H, 10 x 250 mm

[0501] Temperature: 40 °C

[0502] Flow rate: 1.8 mL / min

[0503] Wavelength: 270 nm

[0504] Elution solvent: ethanol:n-hexane:diethylamine = 800:200:0.2 (v / v%)

[0505] First peak: 22 minutes [Compound 34]

[0506] Second peak: 35 minutes [Compound 35]

[0507] [Synthesis Example 27] (R)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(6-fluoropyridin-3-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 36] and (S)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(6-fluoropyridin-3-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 37]

[0508]

[0509] By carrying out the same reaction as in [Synthesis Example 24], except that in [Step 9] of [Synthesis Example 24], furan-2-boronic acid was replaced with 6-fluoropyridine-3-boronic acid, 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(6-fluoropyridin-3-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one (36 mg) was obtained.

[0510]

[0511] The 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(6-fluoropyridin-3-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one synthesized above was separated into isomers under the following conditions.

[0512] Column: Daicel Chiralpak OZ-H, 10 x 250 mm

[0513] Temperature: 40 °C

[0514] Flow rate: 1.8 mL / min

[0515] Wavelength: 270 nm

[0516] Elution solvent: ethanol: n-hexane: diethylamine = 800:200:0.2 (v / v%)

[0517] First peak: 22 minutes [Compound 36]

[0518] Second peak: 35 minutes [Compound 37]

[0519] [Synthesis Example 28] (R)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 38] and (S)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 39]

[0520]

[0521] By conducting the same reaction as in [Synthesis Example 24], except that 1-methylpyrazole-4-boronic acid pinacol ester was used instead of furan-2-boronic acid in [Step 9] of [Synthesis Example 24], 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one (68 mg) was obtained.

[0522]

[0523] The 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one synthesized above was separated into isomers under the following conditions.

[0524] Column: Daicel Chiralpak OZ-H, 10x250 mm

[0525] Temperature: 40 °C

[0526] Flow rate: 1.8 mL / min

[0527] Wavelength: 270 nm

[0528] Elution solvent: ethanol: n-hexane: diethylamine = 800:200:0.2 (v / v%)

[0529] First peak: 26 minutes [Compound 38]

[0530] Second peak: 38 minutes [Compound 39]

[0531] [Synthesis Example 29] (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(5-methylfuran-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 40] and (S)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(5-methylfuran-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 41]

[0532]

[0533] By performing the same reaction as in [Synthesis Example 24], except that in [Step 9] of [Synthesis Example 24], pinacol 5-methylfuran-2-borate was used instead of furan-2-boronic acid, 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(5-methylfuran-2-yl)-7,8-dihydro-[1,3]dioxolo

[0534] [4,5-g]isoquinolin-5(6H)-one (48 mg) was obtained.

[0535]

[0536] The 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(5-methylfuran-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one synthesized above was separated into isomers under the following conditions.

[0537] Column: Daicel Chiralpak OZ-H, 10 x 250 mm

[0538] Temperature: 40 °C

[0539] Flow rate: 1.8 mL / min

[0540] Wavelength: 270 nm

[0541] Elution solvent: Ethanol:n-Hexane:Diethylamine = 800:200:0.2 (v / v%)

[0542] First peak: 19 minutes [Compound 40]

[0543] Second peak: 24 minutes [Compound 41]

[0544] [Synthesis Example 30] (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(5-methylthiophen-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 42] and (S)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(5-methylthiophen-2-yl)-7,8-dihydro-[1,3]dioxolo

[0545] Isoquinolin-5(6H)-one [Compound 43]

[0546]

[0547] By conducting the same reaction as in [Synthesis Example 24], except that in [Step 9] of [Synthesis Example 24], pinacol 5-methylthiophene-2-borate is used instead of furan-2-boronic acid, 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(5-methylthiophen-2-yl)-7,8-dihydro-[1,3]dioxolo

[0548] [4,5-g]Isoquinolin-5(6H)-one (49 mg).

[0549]

[0550] The 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(5-methylthiophen-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one synthesized above was separated into isomers under the following conditions.

[0551] Column: Daicel Chiralpak OZ-H, 10 x 250 mm

[0552] Temperature: 40 °C

[0553] Flow rate: 1.8 mL / min

[0554] Wavelength: 270 nm

[0555] Elution solvent: ethanol:n-hexane:diethylamine = 800:200:0.2 (v / v%)

[0556] First peak: 19 minutes [Compound 42]

[0557] Second peak: 24 minutes [Compound 43]

[0558] [Synthesis Example 31] (R)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(pyridin-3-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 44] and (S)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(pyridin-3-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 45]

[0559]

[0560] By carrying out the same reaction as in [Synthesis Example 24], except that pyridine-3-boronic acid was used instead of furan-2-boronic acid in [Step 9] of [Synthesis Example 24], 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(pyridin-3-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one (49 mg) was obtained.

[0561]

[0562] The 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(pyridin-3-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one synthesized above was separated into isomers under the following conditions.

[0563] Column: Daicel Chiralpak OZ-H, 10 x 250 mm

[0564] Temperature: 40 °C

[0565] Flow rate: 1.8 mL / min

[0566] Wavelength: 270 nm

[0567] Elution solvent: ethanol:n - hexane:diethylamine = 800:200:0.2 (v / v%)

[0568] The first peak: 22 minutes [Compound 44]

[0569] The second peak: 35 minutes [Compound 45]

[0570] [Synthesis Example 32] (R)-6-((4,6 - dimethyl - 2 - oxo - 1,2 - dihydropyridin - 3 - yl)methyl)-2-(trans - 4-(dimethylamino)cyclohexyl)-2,4 - dimethyl - 9-(pyrimidin - 5 - yl)-7,8 - dihydro - [1,3]dioxolo[4,5 - g]isoquinolin - 5(6H)-one [Compound 46] and (S)-6-((4,6 - dimethyl - 2 - oxo - 1,2 - dihydropyridin - 3 - yl)methyl)-2-(trans - 4-(dimethylamino)cyclohexyl)-2,4 - dimethyl - 9-(pyrimidin - 5 - yl)-7,8 - dihydro - [1,3]dioxolo[4,5 - g]isoquinolin - 5(6H)-one [Compound 47]

[0571]

[0572] By conducting the same reaction as in [Synthesis Example 24], except that pyrimidin - 5 - boronic acid was used instead of furan - 2 - boronic acid in [Step 9] of [Synthesis Example 24], 6-((4,6 - dimethyl - 2 - oxo - 1,2 - dihydropyridin - 3 - yl)methyl)-2-(trans - 4-(dimethylamino)cyclohexyl)-2,4 - dimethyl - 9-(pyrimidin - 5 - yl)-7,8 - dihydro - [1,3]dioxolo[4,5 - g]isoquinolin - 5(6H)-one (58 mg) was obtained.

[0573]

[0574] The 6-((4,6 - dimethyl - 2 - oxo - 1,2 - dihydropyridin - 3 - yl)methyl)-2-(trans - 4-(dimethylamino)cyclohexyl)-2,4 - dimethyl - 9-(pyrimidin - 5 - yl)-7,8 - dihydro - [1,3]dioxolo[4,5 - g]isoquinolin - 5(6H)-one synthesized above was separated into isomers under the following conditions.

[0575] Column: Daicel chiral column OZ - H, 10x250 mm

[0576] Temperature: 40 °C

[0577] Flow rate: 1.8 mL / min

[0578] Wavelength: 270 nm

[0579] Elution solvent: ethanol:n-hexane:diethylamine = 800:200:0.2 (v / v%)

[0580] The first peak: 28 minutes [Compound 46]

[0581] The second peak: 35 minutes [Compound 47]

[0582] [Synthesis Example 33] (R)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(1-methyl-1H-pyrrol-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 48] and (S)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(1-methyl-1H-pyrrol-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 49]

[0583]

[0584] By conducting the same reaction as in [Synthesis Example 24], except that N-methylpyrrole-2-boronic acid pinacol ester was used instead of furan-2-boronic acid in [Step 9] of [Synthesis Example 24], 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(1-methyl-1H-pyrrol-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one (9 mg) was obtained.

[0585]

[0586] The 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(1-methyl-1H-pyrrol-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one synthesized above was separated into isomers under the following conditions.

[0587] Column: Daicel chiral column OZ-H, 10x250 mm

[0588] Temperature: 40 °C

[0589] Flow rate: 1.8 mL / min

[0590] Wavelength: 270 nm

[0591] Elution solvent: ethanol:n-hexane:diethylamine = 800:200:0.2 (v / v%)

[0592] The first peak: 25 minutes [Compound 48]

[0593] The second peak: 36 minutes [Compound 49]

[0594] [Synthesis Example 34] (R)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(thiophen-3-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 50] and (S)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(thiophen-3-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 51]

[0595]

[0596] By conducting the same reaction as in [Synthesis Example 24], except that in [Step 9] of [Synthesis Example 24], thiophene-3-boronic acid was used instead of furan-2-boronic acid, 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(thiophen-3-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one (66 mg) was obtained.

[0597]

[0598] The 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(thiophen-3-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one synthesized above was separated into isomers under the following conditions.

[0599] Column: Daicel chiral column OZ-H, 10 x 250 mm

[0600] Temperature: 40 °C

[0601] Flow rate: 1.8 mL / min

[0602] Wavelength: 270 nm

[0603] Elution solvent: ethanol:n - hexane:diethylamine = 800:200:0.2 (v / v%)

[0604] First peak: 18 minutes [Compound 50]

[0605] Second peak: 24 minutes [Compound 51]

[0606] [Synthesis Example 35] (R)-6-((4,6 - dimethyl - 2 - oxo - 1,2 - dihydropyridin - 3 - yl)methyl)-2-(trans - 4-(dimethylamino)cyclohexyl)-2,4 - dimethyl - 9-(thiazol - 5 - yl)-7,8 - dihydro - [1,3]dioxolo[4,5 - g]isoquinolin - 5(6H)-one [Compound 52] and (S)-6-((4,6 - dimethyl - 2 - oxo - 1,2 - dihydropyridin - 3 - yl)methyl)-2-(trans - 4-(dimethylamino)cyclohexyl)-2,4 - dimethyl - 9-(thiazol - 5 - yl)-7,8 - dihydro - [1,3]dioxolo[4,5 - g]isoquinolin - 5(6H)-one [Compound 53]

[0607]

[0608] By conducting the same reaction as in [Synthesis Example 24], except that 5-(tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)-1,3 - thiazole was used instead of furan - 2 - boronic acid in [Step 9] of [Synthesis Example 24], 6-((4,6 - dimethyl - 2 - oxo - 1,2 - dihydropyridin - 3 - yl)methyl)-2-(trans - 4-(dimethylamino)cyclohexyl)-2,4 - dimethyl - 9-(thiazol - 5 - yl)-7,8 - dihydro - [1,3]dioxolo

[0609] [4,5 - g]isoquinolin - 5(6H)-one (7 mg) was obtained.

[0610]

[0611] The 6-((4,6 - dimethyl - 2 - oxo - 1,2 - dihydropyridin - 3 - yl)methyl)-2-(trans - 4-(dimethylamino)cyclohexyl)-2,4 - dimethyl - 9-(thiazol - 5 - yl)-7,8 - dihydro - [1,3]dioxolo[4,5 - g]isoquinolin - 5(6H)-one synthesized above was separated into isomers under the following conditions.

[0612] Column: Daicel Chiralpak OZ - H, 10 x 250 mm

[0613] Temperature: 40 °C

[0614] Flow rate: 1.8 mL / min

[0615] Wavelength: 270 nm

[0616] Elution solvent: ethanol:n-hexane:diethylamine = 800:200:0.2 (v / v%)

[0617] The first peak: 26 minutes [Compound 52]

[0618] The second peak: 38 minutes [Compound 53]

[0619] [Synthesis Example 36] (R)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(1H-imidazol-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 54] and (S)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(1H-imidazol-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 55]

[0620]

[0621] tert-Butyl (trans-4-(9-bromo-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-2-yl)cyclohexyl)carbamate (0.7 g, 1.125 mmol), iron(II) acetylacetonate (44 mg, 0.125 mmol), copper(II) acetate hydrate (25 mg, 0.125 mmol), potassium carbonate (346 mg, 2.506 mmol) and imidazole (1.28 g, 1.879 mmol) synthesized in [Step 8] of [Synthesis Example 24] were successively added to N,N-dimethylacetamide (7 mL). After purging with nitrogen, the mixture was refluxed at 80 °C for 13 hours. The reaction solution was cooled to room temperature and filtered through a layer of diatomaceous earth. The residue obtained by vacuum distillation of the filtrate was purified by basic silica column chromatography to obtain tert-butyl (trans-4-(9-(1H-imidazol-1-yl)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-2-yl)cyclohexyl)carbamate (100 mg).

[0622] Using the tert-butyl ((trans-4-(9-(1H-imidazol-1-yl)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-2-yl)cyclohexyl)carbamate synthesized above, and using the method in [Step 10] of [Synthesis Example 24] above, 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(1H-imidazol-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one (10 mg) was obtained.

[0623]

[0624] The synthesized 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(1H-imidazol-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one was separated into isomers under the following conditions.

[0625] Column: Daicel Chiralpak OZ-H, 10 x 250 mm

[0626] Temperature: 40 °C

[0627] Flow rate: 1.8 mL / min

[0628] Wavelength: 270 nm

[0629] Elution solvent: ethanol: n-hexane: diethylamine = 800:200:0.2 (v / v%)

[0630] First peak: 28 minutes [Compound 54]

[0631] Second peak: 40 minutes [Compound 55]

[0632] [Synthesis Example 37] (R)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(furan-3-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 56] and (S)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(furan-3-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one

[0633] [Compound 57]

[0634]

[0635] By carrying out the same reaction as in [Synthesis Example 24], except that furan-3-boronic acid was used instead of furan-2-boronic acid in [Step 9] of [Synthesis Example 24], 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(furan-3-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one (50 mg) was obtained.

[0636]

[0637] The 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(furan-3-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one synthesized above was separated into isomers under the following conditions.

[0638] Column: Daicel Chiralpak OZ-H, 10x250 mm

[0639] Temperature: 40 °C

[0640] Flow rate: 1.8 mL / min

[0641] Wavelength: 270 nm

[0642] Elution solvent: ethanol:n-hexane:diethylamine = 800:200:0.2 (v / v%)

[0643] The first peak: 18 minutes [Compound 56]

[0644] The second peak: 24 minutes [Compound 57]

[0645] [Synthesis Example 38](R)-2-(trans-4-Aminocyclohexyl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-9-(furan-2-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 58] and (S)-2-(trans-4-Aminocyclohexyl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-9-(furan-2-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 59]

[0646]

[0647] The 2-(trans-4-aminocyclohexyl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-9-(furan-2-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one synthesized in [Step 11] of [Synthesis Example 24] was separated into isomers under the following conditions. The absolute stereochemistry of each isomer was not measured.

[0648] Column: Daicel Chiralpak OZ-H, 10x250 mm

[0649] Temperature: 40 °C

[0650] Flow rate: 1.8 mL / min

[0651] Wavelength: 270 nm

[0652] Elution solvent: Ethanol:n-Hexane:Diethylamine = 800:200:0.2 (v / v%)

[0653] First peak: 24 minutes [Compound 58]

[0654] Second peak: 37 minutes [Compound 59]

[0655] [Synthesis Example 39](R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-9-(furan-2-yl)-2,4-dimethyl-2-(trans-4-(methylamino)cyclohexyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 60] and (S)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-9-(furan-2-yl)-2,4-dimethyl-2-(trans-4-(methylamino)cyclohexyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 61]

[0656]

[0657] By carrying out the reaction of [Step 11] of [Synthesis Example 24], except that in [Step 7] of [Synthesis Example 24], tert-butyl (trans-4-ethynylcyclohexyl)(methyl)carbamate was used instead of tert-butyl (trans-4-ethynylcyclohexyl)carbamate, 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-9-(furan-2-yl)-2,4-dimethyl-2-(trans-4-(methylamino)cyclohexyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one (250 mg) was obtained.

[0658]

[0659] The 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-9-(furan-2-yl)-2,4-dimethyl-2-(trans-4-(methylamino)cyclohexyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one synthesized above was separated into isomers under the following conditions.

[0660] Column: Daicel Chiralpak OZ-H, 10x250 mm

[0661] Temperature: 40 °C

[0662] Flow rate: 1.8 mL / min

[0663] Wavelength: 270 nm

[0664] Elution solvent: Ethanol: n-Hexane: Diethylamine = 800:200:0.2 (v / v%)

[0665] First peak: 18 minutes [Compound 60]

[0666] Second peak: 24 minutes [Compound 61]

[0667] [Synthesis Example 40] (S)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 62] and (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one [Compound 63]

[0668]

[0669] By conducting the same reaction as in [Synthesis Example 24], except for [Steps 8] and [9] of [Synthesis Example 24], 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one (50 mg) was obtained.

[0670]

[0671] The above-synthesized 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one was separated into isomers under the following conditions.

[0672] Column: Daicel Chiralpak OZ-H, 10 x 250 mm

[0673] Temperature: 40 °C

[0674] Flow rate: 1.8 mL / min

[0675] Wavelength: 270 nm

[0676] Elution solvent: Ethanol:n-Hexane:Diethylamine = 800:200:0.2 (v / v%)

[0677] First peak: 18 minutes [Compound 62]

[0678] Second peak: 24 minutes [Compound 63]

[0679] [Table 4]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695]

[0696] Experimental Example 1: Evaluation of EZH1 / EZH2 Methyltransferase Inhibitory Activity

[0697] The inhibitory activity of the above-synthesized compounds against EZH1 or EZH2 methyltransferase was measured. The experiment was entrusted to Reaction Biology, and the EZH1 or EZH2 activity was measured using a scintillation proximity assay. To measure the IC 50 of the synthesized compounds against EZH1 or EZH2, 2.3 nmol / L EZH1 or EZH2, 1 μmol / L histone H3(21-44)-lys(biotin), 1.5 μmol / L S-adenosylmethionine (SAM), and 500 nmol / L 3H-SAM was added to a buffer solution of the compound or DMSO and reacted at room temperature for 90 minutes. The buffer solution consisted of 50 mmol / L Tris-HCl pH 8.0, 50 mmol / L NaCl, 1 mmol / L EDTA, 1 mmol / L DTT, 1 mmol / L PMSF, and 1% DMSO. The reaction was terminated by adding trichloroacetic acid, and SPA beads coated with PVT streptavidin were added, followed by reaction at room temperature for 1 hour. The methylation value of the substrate peptide was measured using a TopCount NXT microplate reader. The measured values were converted to percentage of activity, with the average value of the wells treated with DMSO set as 100% and the background average value set as 0%. The IC 50 value was obtained using the "log(inhibitor) vs. normalized response - variable slope" analysis method of the GraphPad PRISM v6 program.

[0698] Experimental Example 2: Cell Growth Inhibition Assay

[0699] The cell growth inhibitory effect of the synthesized compound on KARPAS - 422 cells was verified. Cultured cell lines were prepared at 1.8×10 4 cells / 400 μL and placed in 48 - well plates. RPMI 1640 medium containing 20% fetal bovine serum was treated with the test compound serially diluted to the specified concentrations (0.001 to 1000 nM, 1 / 10 dilution), and then cultured for 7 days. The cell viability was determined by the CTG method, and the concentration (GI 50 ) that inhibited the growth of the cell line by 50% was calculated using GraphPad Prism software.

[0700] The results of Experimental Example 1 and Experimental Example 2 are shown in [Table 5] below.

[0701] [Table 5]

[0702]

[0703]

[0704]

[0705] Comparative Example

[0706] Control A was N - ((4,6 - dimethyl - 2 - oxo - 1,2 - dihydropyridin - 3 - yl)methyl)-5-(ethyl(tetrahydro - 2H - pyran - 4 - yl)amino)-4 - methyl - 4'-(morpholinomethyl)-[1,1'-biphenyl]-3 - carboxamide (Tazemetostat). The synthesis of this compound was as described in Example 44 on page 220 of International Patent Application WO2012 / 142504, and its structure was as follows:

[0707]

[0708] Control B is (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide (Valemetostat). The synthesis of this compound is as described in Example 35 on page 137 of International Patent Application WO2014 / 141616, and its structure is as follows:

[0709]

[0710] Comparative experimental example: EZH1 / EZH2 methyltransferase inhibitory activity and cell growth inhibition experiments were carried out using blood malignant cell lines

[0711] Using control A [N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide (Tazemetostat)] and control B [(2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide (Valemetostat)] synthesized by the method described in the comparative example, the EZH1 / EZH2 methyltransferase inhibitory activity and blood malignant cell line growth inhibition experiments were carried out using the same methods as described in Experimental Example 1 and Experimental Example 2.

[0712] The results are as shown in [Table 5] above.

[0713] As shown in [Table 5], compared with the control, the compounds according to the present invention have excellent EZH1 and / or EZH2 enzyme inhibitory activity, and thus have excellent growth inhibitory activity against blood malignant cell lines.

[0714] [Industrial applicability]

[0715] The present invention relates to novel dioxoisoquinolinone derivative compounds and their uses. More specifically, the present invention relates to novel dioxoisoquinolinone derivative compounds having inhibitory activity against EZH1 (enhancer of zeste homolog 1) and / or EZH2 (enhancer of zeste homolog 2) activity, pharmaceutically acceptable salts thereof, and / or pharmaceutical compositions containing the same.

Claims

1. A compound selected from compounds of dioxoisoquinolinone derivatives, characterized in that, selected from the following compounds, their pharmaceutically acceptable salts and optical isomers: 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer A; 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer B; 9-chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,4-dimethyl-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 9-chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,4-dimethyl-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer A; 9-chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,4-dimethyl-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer B; 9-chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-6-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 9-chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-6-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer A; 9-Chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-6-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer B; 9-Bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 9-Bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer A; 9-Bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer B; 9-Cyclopropyl-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 9-(Cyclopent-1-en-1-yl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 9-Cyclopentyl-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-9-ethenyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-9-ethyl-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-9-(prop-1-en-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-9-isopropyl-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-9-ethynyl-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer A; 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer B; 2-(4-(Dimethylamino)bicyclo[2.2.2]octan-1-yl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 2-(4-(Dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4,9-trimethyl-6-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 4-Chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,9-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 4,9-Dichloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; and 9-Chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-4-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one.

2. A compound selected from the group of dioxoisoquinolinone derivative compounds, characterized in that, selected from the following compounds, their pharmaceutically acceptable salts and optical isomers: (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(furan-2-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(thiophen-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(pyridin-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(6-fluoropyridin-3-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(5-methylfuran-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(5-methylthiophen-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(pyridin-3-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(pyrimidin-5-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(1-methyl-1H-pyrrol-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(thiophen-3-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(thiazol-5-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(1H-imidazol-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(furan-3-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; (R)-2-(trans-4-Aminocyclohexyl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-9-(furan-2-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; and (R)-6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-9-(furan-2-yl)-2,4-dimethyl-2-(trans-4-(methylamino)cyclohexyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one.

3. A compound selected from the group consisting of dioxoisoquinolinone derivative compounds, pharmaceutically acceptable salts, and optical isomers thereof: 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(thiophen-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(pyridin-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(6-fluoropyridin-3-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(5-methylfuran-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(5-methylthiophen-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(pyrimidin-5-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(1-methyl-1H-pyrrol-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(thiophen-3-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(1H-imidazol-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(furan-3-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 2-(trans-4-Aminocyclohexyl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-9-(furan-2-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; and, 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-9-(furan-2-yl)-2,4-dimethyl-2-(trans-4-(methylamino)cyclohexyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one.

4. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.

5. The pharmaceutical composition according to claim 4, wherein, it is for treating cancer or tumor, and the cancer or tumor can be treated by inhibiting the enzyme activities of EZH1 (enhancer of zeste homolog 1) and / or EZH2 (enhancer of zeste homolog 2).

6. A pharmaceutical preparation comprising the pharmaceutical composition according to claim 4.

7. The pharmaceutical preparation according to claim 6, wherein, it has the form of tablets, pills, powders, capsules, syrups or emulsions.

8. The pharmaceutical preparation according to claim 6, wherein, it further comprises one or more components selected from the group consisting of pharmaceutically acceptable carriers, adjuvants and vehicles.

Images