Novel heterotricyclic derivative compound and use of same

Abstract

The present invention relates to a novel heterocyclic derivative compound and a use of same, and more specifically, to a novel heterotricyclic derivative compound having inhibitory activity on enhancer of zeste homolog 1 (EZH1) and / or enhancer of zeste homolog 2 (EZH2), a pharmacologically acceptable salt thereof, or a pharmaceutical composition comprising said compound.

Description

Novel heterotriclic derivative compounds and uses thereof

[0001] The present invention relates to novel heterotriclic derivative compounds and their uses, and more specifically, to novel heterotriclic derivative compounds having inhibitory activity of EZH1 (Enhancer of zeste homolog 1) and / or EZH2 (Enhancer of zeste homolog 2), pharmacologically acceptable salts thereof, or pharmaceutical compositions comprising such compounds.

[0002] Chromosomes dynamically control gene replication and transcription by changing their higher-order structures through methylation of their constituent DNA or various additions and subtractions (acetylation, methylation, phosphorylation, ubiquitination, etc.) of histones (histones H2A, H2B, H3, H4).

[0003] Generally, trimethylation of the 4th lysine from the N-terminus of histone H3 (H3K4me3) functions to activate transcription, while trimethylation of the 27th lysine (H3K27me3) functions to inhibit transcription, with the former being modified by the Trisolax complex and the latter by the Polycomb Repressive Complex 2 (PRC2) (Cell 2007, 128, 735-745; Nat. Rev. Cancer 2010, 10, 669-682).

[0004] The Polycomb gene family has been identified as genes controlling embryonic development in Drosophila, and these genes are also conserved in vertebrates (Nat. Rev. Genet. 2007, 8, 9-22). In Drosophila, the Enhancer of zeste protein is the catalytic subunit responsible for H3K27 methylation of PRC2, and EZH1 (Enhancer of zeste homolog 1 (Drosophila)) and EZH2 (Enhancer of zeste homolog 2 (Drosophila)) are together mammalian homologs of Drosophila Enhancer of zeste (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, PRC2-EZH2) with EZH1 or EZH2 as catalytic subunits (Mol. Cell 2008, 32, 491-502; Mol. Cell 2008, 32, 503-518).

[0005] In embryonic stem cells (ES cells), EZH1 and EZH2 function cooperatively or complementarily and are involved in the maintenance of ES cells (Mol. Cell 2008, 32, 491-502). Furthermore, it has been reported that EZH1 and EZH2 act cooperatively in the formation and maintenance of hair follicles and the differentiation of Merkel cells, and that both are important for the maintenance of hematopoietic stem 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] To date, upexpression of EZH2 has been reported in numerous cancer types, including prostate, breast, gastric, lung, ovarian, pancreatic, renal, and head and neck cancers, and among these cancers, a correlation between upexpression of EZH2 and poor prognosis has been reported in some cases (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;Cancer2012,118, 2858-2871;Mutat. Res.2008,647, 21-29). There are also reports that knocking down EZH2 in such cancer-derived cell lines inhibits cell proliferation (Nature2002,419, 624-629;Oncogene2009,28, 843-853), and that overexpressing EZH2 in non-cancer cell lines of the epithelial system leads to characteristic cancer phenotypes, such as increased invasiveness or cell proliferation on soft agar medium (Proc. Natl. Acad. Sci. USA2003,100, 11606-11611).

[0007] It has been reported that in follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL) of the follicular center B-cell type, somatic mutations (Y641F, Y641N, Y641S, Y641H, Y641C, A677G, A687V) have been found in the 641st tyrosine, 677th alanine, and 687th alanine of EZH2, and that these mutations cause EZH2 to become hyperfunctional, leading to a significant increase in the amount of H3K27me3 within the cell (Nat. Genet. 2010, 42, 181-185; FEBS Lett. 2011, 585, 3011-3014; Proc. Natl. Acad. Sci. USA2012,109, 2989-2994;FEBS Lett.2012,586, 3448-3451). Compounds that specifically inhibit the enzymatic activity of EZH2 inhibit the proliferation of cancer cell lines with somatic mutations in such EZH2 in vitro and in vivo (genograft model) (Nature2012,492, 108-112; Nat. Chem. Biol.2012,8, 890-896).

[0008] In this regard, knockdown of EZH2 or inhibition of enzyme activity is considered useful for the treatment of cancers in which EZH2 expression is over-expressed or somatic mutations occur.

[0009] While there are many findings regarding the carcinogenesis of EZH2, there has been little interpretation regarding the relationship between EZH1 and carcinogenesis. However, recently, it has been revealed that inhibiting PRC2 overall suppresses the progression of acute myeloid leukemia (AML) caused by the MLL-AF9 fusion gene, but inhibiting EZH2 alone is not sufficient for such suppression (Proc. Natl. Acad. Sci. USA2012,109, 5028-5033). This implies that inhibition of PRC2-EZH2 alone is insufficient for suppressing acute myeloid leukemia caused by the MLL-AF9 fusion gene, and that it is necessary to inhibit both PRC2-EZH1 and PRC2-EZH2 simultaneously.

[0010] While researching materials of the concept described above, the inventors confirmed that novel heterotriclic derivative compounds have inhibitory activity against EZH1 and / or EZH2, thereby completing the present invention.

[0011] One objective of the present invention is to provide a novel heterotriclic derivative compound having excellent inhibitory activity against EZH1 and / or EZH2.

[0012] Another objective of the present invention is to provide a pharmaceutical composition comprising the above compound in a therapeutically effective amount.

[0013] According to one embodiment of the present invention, a compound selected from heterotricic derivative compounds of Formula 1 below, pharmaceutically acceptable salts, optical isomers, hydrates, and solvates thereof is provided:

[0014] [Chemical Formula 1]

[0015]

[0016] In the above chemical formula 1,

[0017] R 1C containing H, halogen, cyano, and 0 to 3 halogen atoms 1-6 Alkyl, C containing 0 to 3 halogen atoms 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Alkyl carbonyl C 2-6 Alkenyl, C 2-6 Alkinil, C 3-6 It is a 5 to 6-membered aromatic heterocyclil containing 1 to 3 heteroatoms independently selected from the group consisting of cycloalkenyl, aryl, N, O, and S within the ring, or an aliphatic heterocyclil containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S within the ring, having or not containing unsaturated bonds in a portion of the ring;

[0018] The above C 3-6 A 5- to 6-membered aromatic heterocyclyl containing 1 to 3 heteroatoms independently selected from the group consisting of cycloalkyl, aryl, N, O, and S in the ring, or an aliphatic heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S in the ring and having or not containing unsaturated bonds in a portion of the 5- to 6-membered ring, is substituted or unsubstituted with 1 to 3 types independently selected from the following group A;

[0019] L is bonding, C 1-6 Alkylene, or oxyC 1-6 It is an alkylene;

[0020] R 2 H, C 1-6 Alkyl, C 3-6A 5 to 6-membered aliphatic heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of cycloalkyl, N, O, and S in the ring, a 5 to 6-membered aromatic heterocyclyl containing 1 to 3 heteroatoms independently selected from the group consisting of aryl, N, O, and S in the ring, or a 5 to 12-membered bicyclic heteroaryl;

[0021] The above C 1-6 Alkyl, C 3-6 The cycloalkyl, 5 to 6-membered aliphatic heterocyclyl, aryl, 5 to 6-membered aromatic heterocyclyl, or 5 to 12-membered non-cyclic heteroaryl is substituted or unsubstituted with 1 to 3 types independently selected from the following Group C;

[0022] R 3 is C 1-6 It is alkyl;

[0023] R 4 is H, a halogen, or C containing 0 to 3 halogen atoms. 1-6 It is alkyl;

[0024] R 5 is C 1-6 alkyl, or C 1-6 It is an alkoxy;

[0025] R 6 is C 1-6 It is alkyl;

[0026] Group A contains halogen, C 1-6 Alkyl, C 1-6 A 5 to 6-membered aliphatic heterocycly containing 1 to 2 heteroatoms independently selected from the group consisting of alkoxy, N, O, and S within a ring, wherein C 1-6 Alkyl, C 1-6 The alkoxy, and the 5 to 6-membered aliphatic heterocyclyl are substituted or unsubstituted with 1 to 3 types independently selected from Group B below;

[0027] Group B consists of halogens, C 1-6It is a 5 to 6-membered aliphatic heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of alkyl, N, O, and S within the ring;

[0028] Group C consists of hydroxyl, formyl, and C substituted with 0 to 3 halogen atoms. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl carbonyl, C 1-6 Alkoxy, C 1-6 Alkylsulfonyl, -NR 20 R 21 , C 1-6 Alkoxy C 1-6 Alkyl, DiC 1-6 Alkylamino C 1-6 A 4 to 6-membered aliphatic heterocycly containing 1 to 2 heteroatoms independently selected from the group consisting of alkyl, N, O, and S within the ring, wherein R 20 and R 21 H, formyl, and C are each independently 1-6 Alkyl, substituted or unsubstituted C 1-6 It is an alkyl carbonyl.

[0029] According to another embodiment of the present invention, a pharmaceutical composition and a pharmaceutical preparation for the prevention or treatment of various diseases associated with EZH1 and / or EZH2 are provided, comprising the above-described compound in a therapeutically effective amount.

[0030] The heterotriclic derivative compound represented by Formula 1 provided in the present invention has excellent inhibitory activity against EZH1 and / or EZH2, and thus has an anticancer effect against cancer associated with the activity of EZH1, EZH2, or both EZH1 and EZH2, and can be usefully used as a therapeutic agent.

[0031] The heterotriclic derivative compound represented by Formula 1 provided in the present invention has excellent inhibitory activity against EZH1 and / or EZH2, and thus has an anticancer effect against cancer associated with the activity of EZH1, EZH2, or both EZH1 and EZH2, and can be usefully used as a therapeutic agent.

[0032] The definitions listed below are definitions of various terms used to describe the present invention. Unless otherwise limited, these definitions apply throughout this specification, individually or as part of terms including them.

[0033] The term 'halogen' as used in this specification means fluorine, chlorine, bromine, or iodine unless otherwise noted.

[0034] As used herein, the term 'hydroxy' means -OH group unless otherwise noted.

[0035] As used in this specification, the term 'alkyl' refers to C unless otherwise noted. n H 2n+1 It refers to saturated, straight-chain or branched hydrocarbon radicals represented by, specifically, saturated, straight-chain or branched hydrocarbon radicals comprising between 1 and 6, between 1 and 8, between 1 and 10, or between 1 and 20 carbon atoms, respectively. Examples of these radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl, n-hexyl, heptyl, and octyl radicals. For example, the term 'C' as used herein 1-6 Unless otherwise noted, 'alkyl' means a straight-chain or branched hydrocarbon residue having 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, etc.

[0036] Unless otherwise noted, the term “alkenyl” as used herein 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 comprising between 2 and 6, between 2 and 8, between 2 and 10, or between 2 and 20 carbon atoms, respectively. Examples of these include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-butene-1-yl, heptenyl, and octenyl radicals.

[0037] Unless otherwise noted, 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.

[0038] As used herein, the term 'alkoxy' refers to OC n H 2n+1 It refers to an oxygen radical having a monovalent group derived from a saturated, straight-chain or branched hydrocarbon moiety containing between 1 and 6, between 1 and 8, between 1 and 10, or between 1 and 20 carbon atoms, respectively, represented by . For example, 'C 1-6 Unless otherwise noted, 'alkoxy' means an oxygen radical having a straight-chain or branched hydrocarbon residue having 1 to 6 carbon atoms. Examples thereof include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, pentoxy, hexoxy, etc.

[0039] The term 'cycloalkyl' as used herein refers to a monovalent group derived from a saturated monocyclic or partially unsaturated single-ring carbocyclic ring compound unless otherwise noted. For example, the term 'C' as used herein 3-7Unless otherwise noted, 'cycloalkyl' means a saturated or partially unsaturated hydrocarbon functional group having 3 to 7 carbon atoms in a single ring structure. Examples of saturated cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0040] Unless otherwise noted, the term 'heterocyclil' as used in this specification means a 3 to 7-membered single-ring monovalent group containing 1 to 3 heteroatoms or functional groups selected from N, O, S, SO, and SO2. Examples of these include oxetane-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, oxephan-4-yl, oxephan-3-yl, piperidine-1-yl, piperidine-3-yl, piperidine-4-yl, piperazine-1-yl, morpholine-4-yl, thiomorpholine-4-yl, 1,1-dioxide thiomorpholine-4-yl, pyrrolidine-1-yl, pyrrolidine-3-yl, azetidin-1-yl, azetidin-3-yl, aziridine-1-yl, azephan-1-yl, azephan-3-yl, azephan-4-yl, etc., but are not limited to these.

[0041] Unless otherwise noted, the term 'aryl' as used in this specification refers to a mono- or poly-cyclic carbocyclic ring system having 6 to 14 carbon atoms having one or more fused or unfused aromatic rings, and examples of aryls include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indenyl, andracenyl.

[0042] Unless otherwise noted, the term 'heteroaryl' as used in this specification means a monocyclic or noncyclic aromatic group of 5 to 12, preferably 5 to 7, containing one or more heteroatoms selected from O, N, and S, for example, 1 to 4, preferably 1 to 3 heteroatoms. Examples of monocyclic heteroaryls include, but are not limited to, thiazolyl, oxazolyl, thiopheneyl, furanyl, pyrroleyl, imidazoleyl, isooxazolyl, pyrazolyl, triazoleyl, thiadiazoleyl, tetrazolyl, oxadiazoleyl, pyridineyl, pyridazineyl, pyrimidineyl, pyrazineyl, and similar groups. Examples of noncyclic heteroaryls include, but are not limited to, indole yl, benzothiophenyl, benzofuran yl, benzimidazole yl, benzoxazole yl, benzisoxazole yl, benzthiazazole yl, benzthiadiazole yl, benztriazole yl, quinoline yl, isoquinoline yl, purine yl, puropyridine yl, and similar groups.

[0043] The term 'EZH1 and / or EZH2 enzyme activity' used in the present invention refers to the enzyme activity of EZH1 and / or EZH2 that introduces a methyl group to the 27th lysine of histone H3, and 'enhanced expression of EZH1 and / or EZH2' means that the expression level of EZH1 protein and / or EZH2 protein is increased by enhancing gene transcription activity, promoting translation, inhibiting protein degradation, enhancing protein stabilization, etc.

[0044] The term 'variation exists in EZH1 and / or EZH2' as used in the present invention means that a variation exists in the base sequence and / or amino acid sequence of EZH1 and / or EZH2. For example, somatic mutations (Y641F, Y641N, Y641S, Y641C, A677G, A687V) exist in the 641st tyrosine, 677th alanine, and 687th alanine of EZH2.

[0045] The present invention will be described in more detail below.

[0046] The present invention relates to novel heterotricic derivative compounds of the following chemical formula 1 and their uses, and more specifically, to novel heterotricic derivative compounds having inhibitory activity of EZH1 (Enhancer of zeste homolog 1) and / or EZH2 (Enhancer of zeste homolog 2), pharmacologically acceptable salts thereof, or pharmaceutical compositions comprising such compounds.

[0047] Specifically, according to one embodiment of the present invention, a compound selected from heterotriclic derivative compounds of Formula 1 below, pharmaceutically acceptable salts, optical isomers, hydrates, and solvates thereof is provided:

[0048] [Chemical Formula 1]

[0049]

[0050] In the above chemical formula 1,

[0051] R 1 C containing H, halogen, cyano, and 0 to 3 halogen atoms 1-6 Alkyl, C containing 0 to 3 halogen atoms 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Alkyl carbonyl C 2-6 Alkenyl, C 2-6 Alkinil, C 3-6 A 5- to 6-membered aromatic heterocyclil containing 1 to 3 heteroatoms independently selected from the group consisting of cycloalkenyl, aryl, N, O, and S within the ring, or an aliphatic heterocyclil containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S within the ring, having or not containing unsaturated bonds in a portion of the ring;

[0052] The above C 3-6A 5- to 6-membered aromatic heterocyclyl containing 1 to 3 heteroatoms independently selected from the group consisting of cycloalkyl, aryl, N, O, and S in the ring, or an aliphatic heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S in the ring and having or not containing unsaturated bonds in a portion of the 5- to 6-membered ring, is substituted or unsubstituted with 1 to 3 types independently selected from the following group A;

[0053] L is bonding, C 1-6 Alkylene, or oxyC 1-6 It is an alkylene;

[0054] R 2 H, C 1-6 Alkyl, C 3-6 A 5 to 6-membered aliphatic heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of cycloalkyl, N, O, and S in the ring, a 5 to 6-membered aromatic heterocyclyl containing 1 to 3 heteroatoms independently selected from the group consisting of aryl, N, O, and S in the ring, or a 5 to 12-membered bicyclic heteroaryl;

[0055] The above C 1-6 Alkyl, C 3-6 The cycloalkyl, 5 to 6-membered aliphatic heterocyclyl, aryl, 5 to 6-membered aromatic heterocyclyl, or 5 to 12-membered non-cyclic heteroaryl is substituted or unsubstituted with 1 to 3 types independently selected from the following Group C;

[0056] R 3 is C 1-6 It is alkyl;

[0057] R 4 is H, a halogen, or C containing 0 to 3 halogen atoms. 1-6 It is alkyl;

[0058] R 5 is C 1-6alkyl, or C 1-6 It is an alkoxy;

[0059] R 6 is C 1-6 It is alkyl;

[0060] Group A contains halogen, C 1-6 Alkyl, C 1-6 A 5 to 6-membered aliphatic heterocycly containing 1 to 2 heteroatoms independently selected from the group consisting of alkoxy, N, O, and S within a ring, wherein C 1-6 Alkyl, C 1-6 The alkoxy, and the 5 to 6-membered aliphatic heterocyclyl are substituted or unsubstituted with 1 to 3 types independently selected from Group B below;

[0061] Group B consists of halogens, C 1-6 It is a 5 to 6-membered aliphatic heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of alkyl, N, O, and S within the ring;

[0062] Group C consists of hydroxyl, formyl, and C containing 0 to 3 halogen atoms. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl carbonyl, C 1-6 Alkoxy, C 1-6 Alkylsulfonyl, -NR 20 R 21 , C 1-6 Alkoxy C 1-6 Alkyl, DiC 1-6 Alkylamino C 1-6 A 4 to 6-membered aliphatic heterocycly containing 1 to 2 heteroatoms independently selected from the group consisting of alkyl, N, O, and S within the ring, wherein R 20 and R 21 H, formyl, and C are each independently 1-6 Alkyl, substituted or unsubstituted C 1-6 It is an alkyl carbonyl.

[0063] Preferably, a compound selected from the heterotriclic derivative compound of Formula 1 of the present invention, pharmaceutically acceptable salts, optical isomers, hydrates, and solvates thereof is

[0064] R 1 This H, halogen, C containing 0 to 3 halogen atoms 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkinil, C 3-6 It may be a compound that is a 5 to 6-membered aromatic heterocyclyl containing 1 to 3 heteroatoms independently selected from the group consisting of cycloalkenyl, aryl, N, O, and S, or an aliphatic heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S, and having or not containing unsaturated bonds in a portion of the 5 to 6-membered ring.

[0065] Preferably, a compound selected from the heterotriclic derivative compound of Formula 1 of the present invention, pharmaceutically acceptable salts, optical isomers, hydrates, and solvates thereof is

[0066] R 1 This may be a compound that is H, halogen, methyl, ethyl, nitrile, methoxy, ethoxy, cyclopropyl, vinyl, acetylenyl, phenyl, isopropenyl, isopropyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, furanyl, pyridine, pyrazolyl, dihydropyranyl, or thiazolyl.

[0067] Preferably, a compound selected from the heterotriclic derivative compound of Formula 1 of the present invention, pharmaceutically acceptable salts, optical isomers, hydrates, and solvates thereof is

[0068] R 2 Ga C 1-6 Alkyl, C 3-6A 5 to 6-membered aliphatic heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of cycloalkyl, N, O, and S in the ring, a 5 to 6-membered aromatic heterocyclyl containing 1 to 3 heteroatoms independently selected from the group consisting of aryl, N, O, and S in the ring, or a 5 to 12-membered bicyclic heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, and 5 to 6-membered aliphatic heterocyclyls, aryls, 5 to 6-membered aromatic heterocyclyls, or 5 to 12-membered bicyclic heteroaryls, are C 1-6 Alkyl, C 1-6 Alkylsulfonyl, hydroxy, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, DiC 1-6 It may be a compound substituted or unsubstituted with 1 to 3 types independently selected from the group consisting of alkylaminos, 3 to 6 aliphatic heterocyclyls containing 1 to 2 heteroatoms in the ring, or alkylamides.

[0069] Preferably, a compound selected from the heterotriclic derivative compound of Formula 1 of the present invention, pharmaceutically acceptable salts, optical isomers, hydrates, and solvates thereof is

[0070] L is bonded, or methylene;

[0071] R 2 ga butyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranil, piperidyl, phenyl, pyridine, indole, or isooxazole;

[0072] R 3The butyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, piperidyl, phenyl, pyridine, indole, or isooxazole may be a compound substituted or unsubstituted with one independently selected from the group consisting of methyl, ethyl, ethylsulfonyl, hydroxy, methoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, ethylmethylamino, piperidyl, pyrrolidyl, trifluoroethyl, or (R)-2-hydroxybutanamide.

[0073] Preferably, a compound selected from the heterotriclic derivative compound of Formula 1 of the present invention, pharmaceutically acceptable salts, optical isomers, hydrates, and solvates thereof is

[0074] L is a combination;

[0075] R 1 and R 4 Each is independently H, a halogen, or a methyl;

[0076] R 2 Ga C 3-6 Cycloalkyl or NR 20 R 21 C substituted with 3-6 It is cycloalkyl;

[0077] R 3 , R 5 and R 6 This is methyl;

[0078] At this time, the above NR 20 R 21 It is amino, C 1-6 Alkylamino and diC 1-6 It may be a compound selected from the group consisting of alkylaminos.

[0079]

[0080] Preferred examples of the compound of Formula 1 according to the present invention are as follows, but are not limited thereto:

[0081] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0082] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0083] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,9-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0084] 4-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,9-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0085] 4-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,9-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one isomer A;

[0086] 4-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,9-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one isomer B;

[0087] 4,9-dichloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0088] 2-(trans-4-aminocyclohexyl)-9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0089] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0090] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one isomer A;

[0091] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one isomer B;

[0092] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(cis-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0093] 9-chloro-2-(trans-4-(dimethylamino)cyclohexyl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0094] 9-chloro-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-6-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridine-3-yl)methyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0095] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(ethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0096] 9-chloro-2-(trans-4-(diethylamino)cyclohexyl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0097] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-2-(trans-4-(piperidine-1-yl)cyclohexyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0098] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-2-(trans-4-(pyrrolidin-1-yl)cyclohexyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0099] (2S)-N-(trans-4-(9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)-2-hydroxybutanamide;

[0100] 2-((trans-4-aminocyclohexyl)methyl)-9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0101] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-((trans-4-(dimethylamino)cyclohexyl)methyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0102] 9-chloro-2-cyclohexyl-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0103] 9-chloro-2-cyclopentyl-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0104] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0105] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(4-(dimethylamino)phenyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0106] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(4-(dimethylamino)butyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0107] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(3,5-(dimethylisoxazole-4-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0108] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-2-(piperidine-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0109] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-2-(1-methylpiperidine-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0110] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(1-((R)-2-hydroxybutanoyl)piperidin-4-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0111] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-2-(1-(2,2,2-trifluoroethyl)piperidine-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0112] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-2-(1-methyl-1H-indole-5-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0113] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-methoxycyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0114] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-2-(trans-4-(methylamino)cyclohexyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0115] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-3-(dimethylamino)cyclobutyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0116] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(cis-3-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0117] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(cis-3-(dimethylamino)cyclopentyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0118] 2-(trans-4-aminocyclohexyl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0119] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0120] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one isomer A;

[0121] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one isomer B;

[0122] 2-(trans-4-(dimethylamino)cyclohexyl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0123] 2-(trans-4-(dimethylamino)cyclohexyl)-2,4,9-trimethyl-6-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridine-3-yl)methyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0124] 2-cyclohexyl-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0125] 2-(trans-4-(ethylamino)cyclohexyl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0126] 2-(trans-4-(diethylamino)cyclohexyl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0127] 2-(trans-4-(ethyl(methyl)amino)cyclohexyl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0128] 9-bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0129] 9-bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one isomer A;

[0130] 9-bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one isomer B;

[0131] 9-bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-2-(trans-4-(methylamino)cyclohexyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

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

[0133] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-ethynyl-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0134] 9-cyclopropyl-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0135] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(4-(morpholinomethyl)phenyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0136] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-phenyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0137] 9-(cyclopent-1-en-1-yl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0138] 9-cyclopentyl-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0139] 9-(cyclohex-1-en-1-yl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0140] 9-cyclohexyl-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0141] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(prop-1-en-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0142] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-isopropyl-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0143] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-ethyl-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0144] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(furan-2-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0145] 9-(3,6-dihydro-2H-pyran-4-yl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0146] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(pyridine-3-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0147] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(thiazole-5-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one;

[0148] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(1-methyl-1H-pyrazole-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one; and

[0149] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-9-carbonitrile;

[0150]

[0151] In the present invention, the method for preparing the compound represented by Chemical Formula 1 is not particularly limited, but, for example, it can be synthesized by the preparation method of Reaction Scheme 1 below:

[0152] [Reaction Equation 1]

[0153]

[0154]

[0155]

[0156] In the above reaction equation 1, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Each is as defined in Chemical Formula 1 above.

[0157] In the above reaction scheme 1, the step 1 ketalization reaction can be carried out under the conditions shown in the following literature (Ming Liet. al., J. Org. Chem. 2008, 73, 8658-8660). For the compound of formula 4, the process is to obtain the compound of formula 3 by using an equal or excess amount of acetylene derivative and an equal amount of Ru catalyst (0.01 to 0.3) in a solvent inert to the reaction, and stirring for 1 to 24 hours under heating conditions. The step 2 condensation reaction is a process to obtain the compound of formula 2 by using an equal or excess amount of the corresponding alkyl halide and a salt such as t-potassium butoxylide in a solvent inert to the reaction, and stirring for 1 to 24 hours under low temperature conditions. The deprotection reaction of step 3 is a process of obtaining a compound of formula 1 by stirring a compound of formula 2 containing a benzyl group in a solvent inert to the reaction for 0.5 to 24 hours in the presence of acid, under cooling or heating.

[0158] The compound according to the present invention may also form a pharmaceutically acceptable salt. Such pharmaceutically acceptable salts are not particularly limited to acids that form a non-toxic acid addition salt containing a pharmaceutically acceptable anion. Examples include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromide, hydroiodide, etc.; organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc.; and acid addition salts formed by sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.

[0159] Meanwhile, since the compounds according to the present invention may have asymmetric carbon centers, they may exist as R or S isomers, racemic compounds, mixtures of diastereomers, or individual diastereomers, and all such isomers and mixtures are included within the scope of the present invention.

[0160] In addition, solvates and hydrates of Chemical Formula 1 are also included within the scope of the present invention.

[0161] According to another embodiment of the present invention, a pharmaceutical composition is provided containing a therapeutically effective amount of a compound selected from the compound of Formula 1 and a pharmaceutically acceptable salt thereof.

[0162] The pharmaceutical composition of the present invention is also useful for preventing or treating various diseases related thereto by inhibiting the activity of EZH1 and / or EZH2 by the compound represented by Formula 1 included therein.

[0163] According to another embodiment of the present invention, the pharmaceutical composition is a pharmaceutical composition for preventing or treating cancer or tumors that can be treated by inhibiting EZH1 and / or EZH2 enzyme activity.

[0164] According to another embodiment of the present invention, a pharmaceutical formulation comprising the above-described pharmaceutical composition is provided.

[0165] The pharmaceutical formulation of the present invention may be in various forms of oral administration such as tablets, pills, powders, capsules, syrups, or emulsions, or in forms of parenteral administration such as intramuscular, intravenous, or subcutaneous administration such as injections, and preferably in an oral form.

[0166] In addition, the above pharmaceutical formulation may be formulated according to conventional methods by adding one or more of the usual non-toxic, pharmaceutically acceptable additives, specifically examples selected from the group consisting of carriers, reinforcing agents, and excipients, in addition to the active ingredient.

[0167] Excipients that can be used in the pharmaceutical formulation of the present invention may include, but are not limited to, sweeteners, binders, solubilizers, solubilizing agents, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, etc. For example, as excipients, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, magnesium aluminum silicate, starch, gelatin, tragacanth gum, arginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla scent, etc.

[0168] When the pharmaceutical formulation of the present invention is in the form of oral administration, examples of carriers used include, but are not limited to, cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, etc.

[0169] When the pharmaceutical preparation of the present invention is in the form of an injectable, the carrier may include, but is not limited to, water, saline solution, glucose aqueous solution, similar sugar aqueous solution, alcohol, glycol, ether, oil, fatty acid, fatty acid ester, glyceride, etc.

[0170] To use the compound according to the present invention as a pharmaceutical, the latter is prepared in the form of a pharmaceutical formulation, which contains, in addition to an active ingredient for oral or parenteral administration, a suitable pharmaceutical organic or inorganic inert carrier material, e.g., water, gelatin, gum arabic, lactose, starch, vegetable oil, polyalkylene glycol, etc. The pharmaceutical formulation may exist in a solid form, e.g., tablets, coated tablets, suppositories, or capsules, or in a liquid form, e.g., liquids, suspensions, or emulsions. Additionally, they may optionally contain adjuvants, e.g., preservatives, stabilizers, wetting agents, or emulsifiers; or salts or buffers for osmotic pressure alteration.

[0171] For parenteral administration, injectable liquids or suspensions are particularly preferred.

[0172] As a carrier system, surfactant adjuvants, for example, bile acid salts or animal or plant phospholipids, as well as mixtures thereof, and liposomes or their components may also be used.

[0173] For oral administration, tablets, coated tablets, or capsules containing talc and / or hydrocarbon vehicles or binders, for example, lactose, corn or potato starch, are particularly suitable. In addition, it may be administered in liquid form, for example, as juice to which a sweetener has been added.

[0174] In addition, the dosage of the compound of Formula 1 according to the present invention for the human body is generally preferably in the range of 0.1 mg / day to 2,000 mg / day based on an adult patient with a body weight of 70 kg. The compound according to the present invention may be administered once or several times per day. However, the above dosage may vary depending on the patient's health condition, age, body weight, and gender, as well as the form of administration and the severity of the disease, and accordingly, the scope of the present invention is not limited to the dosage presented above.

[0175]

[0176] The present invention will be explained in more detail below based on the following manufacturing examples and embodiments, but this is merely illustrative of the present invention and the scope of the present invention is not limited thereto.

[0177]

[0178] Examples

[0179] Intermediate synthesis example

[0180] [Intermediate 1] 6,7-dihydroxy-8-methyl-3,4-dihydroisoquinoline-1(2H)-one

[0181]

[0182] Step 1. Preparation of Methyl 3,4-Dimethoxy-2-Methylbenzoate

[0183]

[0184] Methyl 3,4-dihydroxy-2-methylbenzoate (5.0 g, 27.4 mmol) was dissolved in acetone (50 ml), and then potassium carbonate (18.9 g, 137.0 mmol) and iodomethane (5.1 ml, 82.3 mmol) were added sequentially. After the addition was completed, the mixture was stirred at room temperature for 24 hours. The reaction product was diluted with dichloromethane and water, and the organic layer was extracted. The extracted organic layer was dried using anhydrous sodium sulfate and subjected to vacuum distillation to obtain the title compound (5.4 g), which was used without further purification.

[0185] Step 2. Preparation of 3,4-Dimethoxy-2-Methylbenzoic Acid

[0186]

[0187] Methyl 3,4-dimethoxy-2-methylbenzoate (5.4 g, 27.4 mmol) synthesized in [Step 1] above was added to a methanol / water (1 / 1, 54 ml) mixture, and then sodium hydroxide (3.3 g, 82.2 mmol) was added. After the addition was completed, the reaction was completed by heating and refluxing for 4 hours. The reaction mixture was cooled to a low temperature and acidified to a pH of about 1 using 6.0 N aqueous hydrochloric acid. The resulting solid was stirred at a low temperature for 1 hour, collected by filtration, washed with water, and dried to obtain the title compound (5.4 g), which was used without further purification.

[0188] Step 3. Preparation of N-(2,2-Dimethoxyethyl)-3,4-Dimethoxy-2-Methylbenzamide

[0189]

[0190] 3,4-dimethoxy-2-methylbenzoic acid (5.4 g, 27.4 mmol) synthesized in [Step 2] above was dissolved in N,N-dimethylformamide (54 ml), and then 1-hydroxybenzotriazole (4.8 g, 35.6 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.8 g, 35.6 mmol), and triethylamine (5 ml, 35.6 mmol) were added sequentially and stirred at room temperature for 1 hour. A mixture of aminoacetaldehyde dimethylacetal (3.9 ml, 35.6 mmol) and triethylamine (5 ml, 35.6 mmol) was added dropwise over approximately 5 minutes, and the mixture was stirred overnight at room temperature. 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, dried using anhydrous sodium sulfate, and subjected to vacuum distillation to obtain the title compound (7.8g), which was used without further purification.

[0191] Step 4. Preparation of 7-hydroxy-6-methoxy-8-methylisoquinoline-1(2H)-one

[0192]

[0193] N-(2,2-dimethoxyethyl)-3,4-dimethoxy-2-methylbenzamide (7.8g, 27.4mmol) synthesized in [Step 3] above was added to concentrated sulfuric acid (35ml), heated to 60°C, and stirred for 4 hours. The reaction mixture was cooled to room temperature, 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 title compound (5.7g), which was used without further purification.

[0194] Step 5. Preparation of 7-hydroxy-6-methoxy-8-methyl-3,4-dihydroisoquinoline-1(2H)-one

[0195]

[0196] 7-hydroxy-6-methoxy-8-methylisoquinoline-1(2H)-one (5.7 g, 27.4 mmol) synthesized in [Step 4] above and 10% palladium / carbon (2.7 g) were added to a methanol / ethanol (1 / 1, 57 ml) mixture, and a hydrogen balloon was attached. The reaction mixture was heated to 60°C and stirred overnight, then cooled to room temperature, filtered with Celite, and distilled under reduced pressure. The resulting product was stirred in dichloromethane, collected by filtration, washed with dichloromethane, and dried to obtain the title compound (3.39 g).

[0197] Step 6. Preparation of 6,7-dihydroxy-8-methyl-3,4-dihydroisoquinoline-1(2H)-one

[0198]

[0199] 7-hydroxy-6-methoxy-8-methyl-3,4-dihydroisoquinoline-1(2H)-one (100 mg, 0.482 mmol) synthesized in [Step 5] above was added to dichloromethane (2 ml) under nitrogen, and the reaction mixture was cooled to 0°C. Tribromoboron (1 ml, 0.96 mmol, 1 M dichloromethane solution) was added to this, and the temperature was slowly raised to room temperature and stirred overnight. Ice water was added to the reaction mixture, and the resulting solid was stirred for 1 hour, collected by filtration, washed with excess water and dichloromethane, and dried to obtain the title compound (53 mg).

[0200]

[0201] [Intermediate 2] 6,7-dihydroxy-3,4-dihydroisoquinoline-1(2H)-one

[0202]

[0203] Using 6,7-dimethoxy-3,4-dihydroisoquinoline-1(2H)-one (500 mg, 15.6 mmol) synthesized according to the method described in Asian Journal of Organic Chemistry, 5(2), 287-292; 2016, the same reaction as [Step 6] of [Intermediate 1] was carried out, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (190 mg).

[0204]

[0205] [Intermediate 3] 6,7-dihydroxy-5,8-dimethyl-3,4-dihydroisoquinoline-1(2H)-one

[0206]

[0207] Step 1. Preparation of Methyl 3,4-Dimethoxy-2,5-Dimethyl Benzoate

[0208]

[0209] The same reaction was carried out except that methyl 3,4-dihydroxy-2,5-dimethylbenzoate (2.0 g, 10.1 mmol) was used instead of methyl 3,4-dihydroxy-2-methylbenzoate in [Step 1] of [Intermediate 1], and the title compound (2.3 g) was obtained.

[0210] Step 2. Preparation of 3,4-Dimethoxy-2,5-Dimethylbenzoic Acid

[0211]

[0212] Using the methyl 3,4-dimethoxy-2,5-dimethylbenzoate (2.3g, 10.1mmol) synthesized in [Step 1] above, the same reaction as [Step 2] of [Intermediate 1] was carried out to obtain the title compound (2.1g).

[0213] Step 3. Preparation of N-(2,2-Dimethoxyethyl)-3,4-Dimethoxy-2,5-Dimethylbenzamide

[0214]

[0215] Using the 3,4-dimethoxy-2,5-dimethylbenzoic acid (2.1 g, 10.1 mmol) synthesized in [Step 2] above, the same reaction as [Step 3] of [Intermediate 1] was carried out to obtain the title compound (3.0 g).

[0216] Step 4. Preparation of 6,7-dihydroxy-5,8-dimethylisoquinoline-1(2H)-one

[0217]

[0218] Using N-(2,2-dimethoxyethyl)-3,4-dimethoxy-2,5-dimethylbenzamide (3.0 g, 10.1 mmol) synthesized in [Step 3] above, the same reaction as [Step 4] of [Intermediate 1] was carried out for 24 hours to obtain the title compound (1.8 g).

[0219] Step 5. Preparation of 6,7-dihydroxy-5,8-dimethyl-3,4-dihydroisoquinoline-1(2H)-one

[0220]

[0221] Using 6,7-dihydroxy-5,8-dimethylisoquinoline-1(2H)-one (1.8g, 8.8mmol) synthesized in [Step 4] above, the same reaction as [Step 5] of [Intermediate 1] was carried out for 48 hours to obtain the title compound (780mg).

[0222]

[0223] [Intermediate 4] 5-chloro-6,7-dihydroxy-8-methyl-3,4-dihydroisoquinoline-1(2H)-one

[0224]

[0225] Step 1. Preparation of 5-chloro-7-hydroxy-6-methoxy-8-methyl-3,4-dihydroisoquinoline-1(2H)-one

[0226]

[0227] 7-hydroxy-6-methoxy-8-methyl-3,4-dihydroisoquinoline-1(2H)-one (938 mg, 4.53 mmol) synthesized in [Step 5] of [Intermediate 1] was dissolved in acetic acid (20 ml), and then N-chlorosuccinimide (1.2 g, 9.05 mmol) was added. The reaction mixture was heated to 70°C and stirred for 1 hour. The reaction mixture was cooled to room temperature, neutralized by adding saturated sodium bicarbonate water, and extracted using 20% ​​methanol-chloroform. The extracted organic layer was washed with brine, dried using anhydrous sodium sulfate, and subjected to vacuum distillation. The resulting residue was purified by silica gel column chromatography, and the residue was stirred in diethyl ether for 1 hour. The resulting solid was filtered and washed to obtain the title compound (380 mg).

[0228] Step 2. Preparation of 5-chloro-6,7-dihydroxy-8-methyl-3,4-dihydroisoquinoline-1(2H)-one

[0229]

[0230] Using 5-chloro-7-hydroxy-6-methoxy-8-methyl-3,4-dihydroisoquinoline-1(2H)-one (377 mg, 1.56 mmol) synthesized in [Step 1] above, the same reaction as [Step 6] of [Intermediate 1] was carried out to obtain the title compound (293 mg).

[0231]

[0232] [Intermediate 5] 8-chloro-6,7-dihydroxy-5-methyl-3,4-dihydroisoquinoline-1(2H)-one

[0233]

[0234] Step 1. Preparation of Methyl 5-chloro-3,4-dihydroxy-2-methylbenzoate

[0235]

[0236] Methyl 3,4-dihydroxy-2-methylbenzoate (2.0 g, 10.98 mmol) was dissolved in ethyl acetate (44 mL), and N-chlorosuccinimide (2.2 g, 16.47 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, after which p-anisole (1.2 mL, 10.98 mmol) was added. After stirring for an additional 15 minutes, extraction was performed using ethyl acetate. The organic layer was dried using anhydrous sodium sulfate and then subjected to vacuum distillation. Dichloromethane (5 mL) was added to the resulting residue and stirred for 30 minutes, after which the solution was filtered to obtain the title compound (1.1 g), which was used without further purification.

[0237] Step 2. Preparation of Methyl 5-Chloro-3,4-Dimethoxy-2-Methylbenzoate

[0238]

[0239] The same reaction was carried out except that the methyl 5-chloro-3,4-dihydroxy-2-methylbenzoate (2.3g, 10.59mmol) synthesized in [Step 1] above was used instead of the methyl 3,4-dihydroxy-2-methylbenzoate in [Step 1] of [Intermediate 1], and the title compound (2.6g) was obtained.

[0240] Step 3. Preparation of (5-chloro-3,4-dimethoxy-2-methylphenyl)methanol

[0241]

[0242] Methyl 5-chloro-3,4-dimethoxy-2-methylbenzoate (2.6 g, 10.63 mmol) synthesized in [Step 2] above was dissolved in tetrahydrofuran (26 mL), argon-substituted, and cooled to 0°C. LiAlH4 (403 mg, 10.63 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction product was cooled to 0°C, and excess water and a 15% aqueous sodium hydroxide solution (2.5 mL) were added dropwise. After stirring for 2 hours at room temperature, the mixture was filtered using Celite. The resulting residue was extracted with ethyl acetate, dried using anhydrous sodium sulfate, and then subjected to vacuum distillation to obtain the title compound (2.3 g).

[0243] Step 4. Preparation of 1-chloro-5-(chloromethyl)-2,3-dimethoxy-4-methylbenzene

[0244]

[0245] (5-chloro-3,4-dimethoxy-2-methylphenyl)methanol (2.1 g, 9.69 mmol) synthesized in [Step 3] above was dissolved in ethyl acetate (50 mL) and cooled to 0°C. Thionyl chloride (1.1 mL, 14.53 mmol) was added dropwise to the reaction mixture and stirred at 0°C for 1 hour. Excess water was added dropwise to the reaction product and extracted with ethyl acetate. The obtained organic layer was dried using anhydrous sodium sulfate and subjected to vacuum distillation to obtain the title compound (2.3 g), which was used without further purification.

[0246] Step 5. Preparation of 2-(5-chloro-3,4-dimethoxy-2-methylphenyl)acetonitrile

[0247]

[0248] 1-chloro-5-(chloromethyl)-2,3-dimethoxy-4-methylbenzene (2.3g, 9.78mmol) synthesized in [Step 4] above was dissolved in dimethyl sulfoxide (23mL), and sodium cyanide (576mg, 11.74mmol) was added at room temperature. After stirring the reaction mixture at room temperature for 2 hours, excess water was added dropwise to the reaction product and extracted with ethyl acetate. The obtained organic layer was dried using anhydrous sodium sulfate and subjected to vacuum distillation to obtain the title compound (2.2g), which was used without further purification.

[0249] Step 6. Preparation of 2-(5-chloro-3,4-dimethoxy-2-methylphenyl)ethane-1-amine

[0250]

[0251] 2-(5-chloro-3,4-dimethoxy-2-methylphenyl)acetonitrile (2.2 g, 9.75 mmol) synthesized in [Step 5] above and an excess amount of Raney-nickel were dissolved in ethyl acetate (45 mL), and a hydrogen balloon was installed. The reaction mixture was stirred at room temperature for 18 hours, filtered with Celite, and subjected to vacuum distillation to obtain the title compound (2.0 g), which was used without further purification.

[0252] Step 7. Preparation of 4-Nitrophenyl(5-chloro-3,4-dimethoxy-2-methylphenethyl)carbamate

[0253]

[0254] 2-(5-chloro-3,4-dimethoxy-2-methylphenyl)ethane-1-amine (2.0 g, 8.71 mmol) and sodium carbonate (2.77 g, 26.12 mmol) synthesized in [Step 6] above were dissolved in 1,2-dichloroethane (40 mL), and then 4-nitrophenylchloroformate (2.63 g, 13.06 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours, after which excess water was added dropwise to the reaction product and extracted with dichloromethane. The obtained organic layer was dried using anhydrous sodium sulfate and subjected to vacuum distillation. The resulting residue was purified by silica gel column chromatography to obtain the title compound (3.0 g).

[0255] Step 8. Preparation of 8-chloro-6,7-dimethoxy-5-methyl-3,4-dihydroisoquinoline-1(2H)-one

[0256]

[0257] The 4-nitrophenyl (5-chloro-3,4-dimethoxy-2-methylphenethyl)carbamate (3.0 g, 7.60 mmol) synthesized in [Step 7] above was dissolved in 1,2-dichloroethane (50 mL) and cooled to 0°C. Triflic acid (7.3 mL, 81.1 mmol) was slowly added dropwise to the reaction mixture and stirred at 70°C for 2 hours. After cooling the reaction product to room temperature, it was slowly added dropwise to an excess amount of ice water and stirred for 1 hour until the ice completely melted. The organic layer obtained was extracted with dichloromethane and neutralized with a 2N aqueous sodium hydroxide solution. The organic layer was dried using anhydrous sodium sulfate and subjected to vacuum distillation. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1.6 g).

[0258] Step 9. Preparation of 8-chloro-6,7-dihydroxy-5-methyl-3,4-dihydroisoquinoline-1(2H)-one

[0259]

[0260] The same reaction was carried out except that 8-chloro-6,7-dimethoxy-5-methyl-3,4-dihydroisoquinoline-1(2H)-one (1.6 g, 6.14 mmol) synthesized in [Step 8] above was used instead of 7-hydroxy-6-methoxy-8-methyl-3,4-dihydroisoquinoline-1(2H)-one in [Step 6] of [Intermediate 1], and the title compound (1.2 g) was obtained.

[0261]

[0262] [Intermediate 6] 6,7-dihydroxy-5-methyl-3,4-dihydroisoquinoline-1(2H)-one

[0263]

[0264] The same reaction was carried out up to [Step 9] of [Intermediate 5], except that 3,4-dimethoxy-2-methylbenzoic acid (5.3 g, 27.01 mmol) was used instead of methyl 5-chloro-3,4-dimethoxy-2-methylbenzoate in [Step 3] of [Intermediate 5], to obtain the title compound (220 mg).

[0265]

[0266] [Intermediate 7] 5,8-Dichloro-6,7-Dihydroxy-3,4-Dihydroisoquinoline-1(2H)-on

[0267]

[0268] 3,4-dihydrobenzoic acid (10.0 g, 64.88 mmol) was added to acetic acid (44 mL), and sulfuryl chloride (12.6 mL, 155.72 mmol) was added. The reaction mixture was heated to 50°C and stirred overnight. After lowering the reaction mixture to 0°C, the resulting solid was filtered and recrystallized using ethyl acetate-hexane solvent to obtain 2,5-dichloro-3,4-dihydrobenzoic acid (4.2 g).

[0269] The same method was followed up to [Step 9] of [Intermediate 5], except that 2,5-dichloro-3,4-dihydrobenzoic acid (4.2 g, 18.92 mmol) synthesized above was used instead of methyl 3,4-dihydroxy-2-methylbenzoate in [Step 2] of [Intermediate 5], to obtain the title compound (55 mg).

[0270]

[0271]

[0272] [Intermediate 8] Trans-4-ethynyl-N,N-dimethylcyclohexane-1-amine

[0273]

[0274] Step 1. Preparation of trans-4-ethynylcyclohexane-1-amine

[0275]

[0276] t-butyl-(trans-4-ethynylcyclohexyl)carbamate (2.5 g, 11.2 mmol) was added to methanol (25 ml), followed by the addition of 4 M hydrochloric acid-1,4-dioxane solution (24 ml, 95.2 mmol) and stirring at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate was added to neutralize the mixture, and extraction was performed using 20% ​​methanol-chloroform. The extracted organic layer was washed with brine, dried using anhydrous sodium sulfate, and subjected to vacuum distillation to obtain the title compound (1.3 g).

[0277] Step 2. Preparation of trans-4-ethynyl-N,N-dimethylcyclohexane-1-amine

[0278]

[0279] Trans-4-ethynylcyclohexane-1-amine (1.3 g, 10.6 mmol) synthesized in [Step 1] above was added to methanol (110 ml), and a 37% aqueous formaldehyde solution (1.8 ml, 23.5 mmol) was added. After stirring at room temperature for 10 minutes, sodium hydroxide triacetoxyborohydride (11.9 g, 56.0 mmol) was added and stirred at room temperature for 18 hours. After the reaction was finished, the mixture was neutralized with a 1 M aqueous sodium hydroxide solution and extracted using 20% ​​methanol-chloroform. The extracted organic layer was washed with brine, dried using anhydrous sodium sulfate, and subjected to vacuum distillation. The resulting residue was purified by basic silica gel column chromatography to obtain the title compound (1.4 g).

[0280]

[0281] [Intermediate 9]t-butyl-(cis-4-ethynylcyclohexyl)carbamate

[0282]

[0283] t-butyl-(cis-4-formylcyclohexyl)carbamate (800 mg, 3.52 mmol) was added to methanol (14 ml), followed by the addition of potassium carbonate (967 mg, 7.04 mmol) and dimethyl(1-diazo-2-oxopropyl)phosphonate (0.94 ml, 3.52 mmol). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, and the mixture was washed with saturated saline solution. The resulting organic layer was dried using anhydrous sodium sulfate and subjected to vacuum distillation. The resulting residue was purified by basic silica gel column chromatography to obtain the title compound (735 mg).

[0284]

[0285] [Intermediate 10]t-butyl-(cis-4-ethynylcyclohexyl)carbamate

[0286]

[0287] The same reaction was carried out except that t-butyl-(trans-4-(2-oxoethyl)cyclohexyl)carbamate (1 g, 4.1 mmol) was used instead of t-butyl-(cis-4-formylcyclohexyl)carbamate in [Intermediate 9], and the title compound (720 mg) was obtained.

[0288]

[0289] [Intermediate 11]t-butyl-(trans-4-ethynylcyclohexyl)(methyl)carbamate

[0290]

[0291] t-butyl-(trans-4-ethynylcyclohexyl)carbamate (1.0 g, 4.48 mmol) was added to N,N-dimethylformamide (4 ml). After switching to argon gas, sodium hydride (60%) (0.54 g, 13.44 mmol) was added at 0°C and stirred at room temperature for 30 minutes, after which methyl iodide (2.8 mL, 44.8 mmol) was slowly added at 0°C. The reaction mixture was stirred at room temperature for 16 hours, and dichloromethane was added to the resulting residue to separate the organic layer. The resulting organic layer was dried using anhydrous sodium sulfate and subjected to vacuum distillation. The resulting residue was purified by basic silica gel column chromatography to obtain the title compound (0.55 g).

[0292]

[0293] [Intermediate 12] Trans-1-ethynyl-4-methoxycyclohexane

[0294]

[0295] The same reaction was carried out except that trans-4-ethynylcyclohexan-1-ol (300 mg, 2.42 mmol) was used instead of t-butyl-(trans-4-ethynylcyclohexyl)carbamate in [Intermediate 11] to obtain the title compound (250 mg).

[0296]

[0297] [Synthetic Example 1] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 1]

[0298]

[0299] Step 1. Preparation of 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one

[0300]

[0301] 6,7-Dihydroxy-8-methyl-3,4-dihydroisoquinoline-1(2H)-one(61 mg, 0.3 mmol, [Intermediate 1]), Ru3(CO) 12 (5 mg, 0.008 mmol) and Bippyphos (12 mg, 0.02 mmol) were added to 1,4-dioxane (1 ml), and after argon gas exchange, the mixture was refluxed at 120°C for 10 minutes. A solution of trans-4-ethynyl-N,N-dimethylcyclohexane-1-amine (95 mg, 0.6 mmol, [Intermediate 8]) dissolved in 1,4-dioxane (0.3 ml) was added dropwise, and the mixture was refluxed at 120°C for 36 hours. After cooling the reaction mixture to room temperature, it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (24 mg).

[0302] Step 2. Preparation of 6-((2-(benzyloxy)-4,6-dimethylpyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one

[0303]

[0304] 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one (24 mg, 0.07 mmol) synthesized in [Step 1] above was added to N,N-dimethylformamide (0.7 ml). After cooling the reaction mixture to 0°C, 1.0 M potassium t-butoxide (90 µl, 0.09 mmol) was added dropwise and stirred for 5 minutes. A solution of 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (24 mg, 0.09 mmol) synthesized according to the method described in WO2014097041 and dissolved in N,N-dimethylformamide (0.3 ml) was added and stirred at 0°C for 1 hour. After the reaction was finished, an ammonium chloride solution was added and extracted using 10% methanol-chloroform. The extracted organic layer was dried using anhydrous sodium sulfate and subjected to vacuum distillation. The resulting residue was purified by basic silica gel column chromatography to obtain the title compound (20 mg).

[0305] Step 3. Preparation of 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one

[0306]

[0307] 6-((2-(benzyloxy)-4,6-dimethylpyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one (20 mg, 0.03 mmol) synthesized in [Step 2] above was added to dichloromethane (0.5 ml). 4 M hydrochloric acid-1,4-dioxane solution (0.2 ml, 0.8 mmol) was added to the reaction mixture and stirred at room temperature for 3 hours. After the reaction was finished, saturated sodium bicarbonate was added to neutralize the mixture, and extraction was performed using 20% ​​methanol-chloroform. The extracted organic layer was dried using anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography to obtain the title compound (9 mg).

[0308]

[0309] [Synthetic Example 2] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2(trans-4-(dimethylamino)cyclohexyl)-2-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 2]

[0310]

[0311] Step 1. Preparation of t-butyl(trans-4-(2-methyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate

[0312]

[0313] 6,7-Dihydroxy-3,4-Dihydroisoquinoline-1(2H)-one (190 mg, 1.06 mmol, [Intermediate 2]) and t-butyl-(trans-4-ethynylcyclohexyl)carbamate (355 mg, 1.59 mmol), Ru3(CO) 12(34 mg, 0.05 mmol) and Bippyphos (81 mg, 0.16 mmol) were sequentially added to 1,4-dioxane (9.5 ml), and after argon gas exchange, the mixture was refluxed at 120°C for 16 hours. After cooling the reaction mixture to room temperature, it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (320 mg).

[0314] Step 2. Preparation of t-butyl(trans-4-(6-((2-(benzyloxy)-4,6-dimethylpyridine-3-yl)methyl)-2-methyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate

[0315]

[0316] The same reaction was carried out except that the t-butyl(trans-4-(2-methyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate (320 mg, 0.77 mmol) synthesized in [Step 1] above was used instead of 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate (320 mg, 0.77 mmol) synthesized in [Step 1] above was used in [Step 2] of [Synthesis Example 1], and the title compound (225 mg) was obtained.

[0317] Step 3. Preparation of t-butyl(trans-4-(6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-methyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate

[0318]

[0319] t-butyl (trans-4-(6-((2-(benzyloxy)-4,6-dimethylpyridine-3-yl)methyl)-2-methyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate (225 mg, 0.36 mmol) synthesized in [Step 2] above and 10% palladium / carbon (25 mg) were added to methanol (5 ml) and a hydrogen balloon was fitted. The reaction mixture was stirred at room temperature for 2 hours, filtered in Celite, and subjected to vacuum distillation to obtain the title compound (212 mg).

[0320] Step 4. Preparation of 2-(trans-4-aminocyclohexyl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one

[0321]

[0322] t-butyl (trans-4-(6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-methyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate (200 mg, 0.37 mmol) synthesized in [Step 3] above and 4 M hydrochloric acid-1,4-dioxane solution (2 ml) were sequentially added to methanol (5 ml), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was finished, saturated sodium bicarbonate was added to neutralize the mixture, and it was extracted using 20% ​​methanol-chloroform. The extracted organic layer was dried using anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography to obtain the title compound (182 mg).

[0323] Step 5. 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 3]

[0324]

[0325] 2-(trans-4-aminocyclohexyl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one (160 mg, 0.37 mmol) synthesized in [Step 4] above and 37% aqueous formaldehyde solution (67 µl, 0.8 mmol) were sequentially added to methanol (4 ml) and stirred at room temperature for 10 minutes, after which sodium triacetoxyboron hydrogen (388 mg, 1.83 mmol) was added and stirred at room temperature for 18 hours. After the reaction was finished, the mixture was neutralized with baking soda and extracted using 20% ​​methanol-chloroform. The extracted organic layer was washed with brine, dried using anhydrous sodium sulfate, and distilled under reduced pressure. The resulting residue was purified by basic silica gel column chromatography to obtain the title compound (112 mg).

[0326]

[0327] [Synthetic Example 3] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,9-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 3]

[0328] The same reaction as in [Synthetic Example 2] was carried out, except that 6,7-dihydroxy-5-methyl-3,4-dihydroxyisoquinoline-1(2H)-one [intermediate 6] was used instead of 6,7-dihydroxy-3,4-dihydroxyisoquinoline-1(2H)-one in [Step 1] of [Synthetic Example 2], and the title compound (30 mg) was obtained.

[0329]

[0330] [Synthetic Example 4] 4-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,9-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 4]

[0331] The same reaction as in [Synthetic Example 2] was carried out, except that 8-chloro-6,7-dihydroxy-5-methyl-3,4-dihydroisoquinoline-1(2H)-one [intermediate 5] was used instead of 6,7-dihydroxy-3,4-dihydroisoquinoline-1(2H)-one in [Step 1] of [Synthetic Example 2], and the title compound (160 mg) was obtained.

[0332]

[0333] [Synthetic Example 5]. Preparation of 4-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,9-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one isomers A and B [Compound 5, Compound 6]

[0334] Each enantiomer of 4-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,9-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 4] synthesized in [Synthesizing Example 4] was separated under the following conditions. The absolute stereochemistry of each isomer was not measured.

[0335] Column: Daicel chiralcell OZ-H, 4.6X250mm, 5μM

[0336] Temperature: 35 o C

[0337] Flow rate: 0.8 ml / min

[0338] Wavelength: 270 nM

[0339] Elution solvent: n-hexane:ethanol:diethylamine = 500:500:0.4(v / v%)

[0340] Peak 1: 17.9 min - Isomer A (99.9%ee)

[0341] Second peak: 28.3 min - Dimer B (99.9%ee)

[0342]

[0343] [Synthetic Example 6] 4,9-Dichloro-6-((4,6-Dimethyl-2-oxo-1,2-Dihydropyridine-3-yl)methyl)-2-(Trans-4-(Dimethylamino)cyclohexyl)-2-methyl-7,8-Dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 7]

[0344] The same reaction as in [Synthetic Example 2] was carried out, except that 5,8-dichloro-6,7-dihydroxy-5-methyl-3,4-dihydroisoquinoline-1(2H)-one [Intermediate 7] was used instead of 6,7-dihydroxy-3,4-dihydroisoquinoline-1(2H)-one in [Step 1] of [Synthetic Example 2], and the title compound (1.8 mg) was obtained.

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354] [Synthetic Example 7] 2-(trans-4-aminocyclohexyl)-9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 8] and 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one racemate [Compound 9]

[0355] Step 1. Preparation of t-butyl-((trans-4-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate

[0356]

[0357] 6,7-dihydroxy-8-methyl-3,4-dihydroisoquinoline-1(2H)-one (2.5 g, 12.9 mmol, [Intermediate 1]), t-butyl-(trans-4-ethynylcyclohexyl)carbamate (7.2 g, 32.2 mmol), Ru3(CO) 12 (415 mg, 0.65 mmol) and Bippyphos (985 mg, 1.94 mmol) were sequentially added to 1,4-dioxane (125 ml), and after argon gas exchange, the mixture was refluxed at 120°C for 16 hours. After cooling the reaction mixture to room temperature, it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (3.59 g).

[0358] Step 2. Preparation of t-butyl-((trans-4-(9-chloro-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate

[0359]

[0360] t-butyl-((trans-4-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate (885 mg, 2.1 mmol) synthesized in [Step 1] above was added to acetic acid (10 ml), and then N-chlorosuccinimide (567 mg, 4.3 mmol) was added. The reaction mixture was heated to 70°C and stirred for 1 hour. After the reaction was finished, it was cooled to room temperature, neutralized by adding saturated sodium bicarbonate, and extracted using ethyl acetate. The extracted organic layer was dried using anhydrous sodium sulfate and subjected to vacuum distillation. The resulting residue was purified by silica gel column chromatography to obtain the title compound (356 mg).

[0361] Step 3. Preparation of t-butyl-((trans-4-(6-((2-(benzyloxy)-4,6-dimethylpyridine-3-yl)methyl)-9-chloro-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate

[0362]

[0363] Using the t-butyl-((trans-4-(9-chloro-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate (150 mg, 0.33 mmol) synthesized in [Step 2] above, the same reaction as in [Step 2] of [Synthesis Example 2] was carried out to obtain the title compound (150 mg).

[0364] Step 4. Preparation of t-butyl-(trans-4-(9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate

[0365]

[0366] Using the t-butyl-((trans-4-(6-((2-(benzyloxy)-4,6-dimethylpyridine-3-yl)methyl)-9-chloro-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate (150 mg, 0.22 mmol) synthesized in [Step 3] above, the same reaction as in [Step 3] of [Synthesis Example 2] was carried out to obtain the title compound (120 mg).

[0367] Step 5. Preparation of 2-(trans-4-aminocyclohexyl)-9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 8]

[0368]

[0369] t-butyl-(trans-4-(9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate (120 mg, 0.20 mmol) synthesized in [Step 4] above and 4 M hydrochloric acid-1,4-dioxane solution (2 ml) were sequentially added to methanol, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was finished, saturated sodium bicarbonate was added to neutralize the mixture, and extraction was performed using 20% ​​methanol-chloroform. The extracted organic layer was dried using anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (91 mg).

[0370] Step 6. Preparation of 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 9]

[0371]

[0372] 2-(trans-4-aminocyclohexyl)-9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one (90.6 mg, 0.19 mmol) synthesized in [Step 5] above and 37% aqueous formaldehyde solution (31 µl, 0.41 mmol) were sequentially added to methanol (2 ml) and stirred at room temperature for 10 minutes, after which sodium triacetoxyboron hydride (197 mg, 0.93 mmol) was added and stirred at room temperature for 18 hours. After the reaction was finished, the mixture was neutralized with a 1M aqueous sodium hydroxide solution and extracted using 20% ​​methanol-chloroform. The extracted organic layer was washed with brine, dried using anhydrous sodium sulfate, and distilled under reduced pressure. The resulting residue was purified by basic silica gel column chromatography to obtain the title compound (50 mg).

[0373]

[0374] [Synthetic Example 8] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one isomers A, B [Compound 10, Compound 11]

[0375]

[0376] Each enantiomer of 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 9] synthesized in [Synthesizing Example 7] was separated under the following conditions. The absolute stereochemistry of each isomer was not measured.

[0377] Column: Daicel chiralcell OZ-H, 4.6X250mm, 5μM

[0378] Temperature: 35℃

[0379] Flow rate: 0.9 ml / min

[0380] Wavelength: 270 nM

[0381] Elution solvent: n-hexane:ethanol:diethylamine = 600:400:0.4(v / v%)

[0382] Peak 1: 13.7 min - Isomer A (99.9%ee)

[0383] Second peak: 22.0 min - Dimer B (99.9%ee)

[0384]

[0385] [Synthetic Example 9] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(cis-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 12]

[0386] The same reaction as in [Synthetic Example 7] was carried out, except that t-butyl-(cis-4-ethynylcyclohexyl)carbamate [intermediate 9] was used instead of t-butyl-(trans-4-ethynylcyclohexyl)carbamate in [Step 1] of [Synthetic Example 7], and the title compound (25 mg) was obtained.

[0387]

[0388] [Synthetic Example 10] 9-chloro-2-(trans-4-(dimethylamino)cyclohexyl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 13]

[0389] The same reaction as in [Synthetic Example 7] was carried out, except that 2-(benzyloxy)-3-(chloromethyl)-4-methoxy-6-methylpyridine was used instead of 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine in [Step 3] of [Synthetic Example 7], and the title compound (31 mg) was obtained.

[0390]

[0391] [Synthetic Example 11] 9-chloro-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-6-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridine-3-yl)methyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 14]

[0392] The same reaction as in [Synthetic Example 7] was carried out, except that 2-(benzyloxy)-3-(chloromethyl)-6-methyl-4-propylpyridine was used instead of 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine in [Step 3] of [Synthetic Example 7], and the title compound (50 mg) was obtained.

[0393]

[0394] [Synthetic Example 12] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(ethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 15]

[0395] The same reaction as in [Step 6] of [Synthetic Example 7] was carried out, except that acetaldehyde (1 equivalent) was used instead of 37% formaldehyde aqueous solution in [Step 6] of [Synthetic Example 7], and the title compound (12 mg) was obtained.

[0396]

[0397] [Synthetic Example 13] 9-chloro-2-(trans-4-(diethylamino)cyclohexyl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 16]

[0398] The same reaction as in [Step 6] of [Synthetic Example 7] was carried out, except that acetaldehyde (1.5 equivalents) was used instead of 37% formaldehyde aqueous solution in [Step 6] of [Synthetic Example 7], and the title compound (34 mg) was obtained.

[0399]

[0400] [Synthetic Example 14] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-2-(trans-4-(piperidine-1-yl)cyclohexyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 17]

[0401] 2-(trans-4-aminocyclohexyl)-9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one (21 mg, 0.043 mmol) synthesized in [Step 5] of [Synthesis Example 7] was added to N,N-dimethylformamide (0.5 ml), after which potassium carbonate (30 mg, 0.215 mmol) and 1,5-dibromopentane (7 μl, 0.052 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 17 hours, and then extracted using water and 20% methanol-chloroform. The extracted organic layer was dried using anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by basic silica gel column chromatography to obtain the title compound (12.2 mg).

[0402]

[0403] [Synthetic Example 15] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-2-(trans-4-(pyrrolidin-1-yl)cyclohexyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 18]

[0404] The same reaction as in [Synthetic Example 14] was carried out, except that 1,4-dibromobutane was used instead of 1,5-dibromopentane in [Synthetic Example 14], and the title compound (5.6 mg) was obtained.

[0405]

[0406] [Synthetic Example 16] (2S)-N-(trans-4-(9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)-2-hydroxybutanamide [Compound 19]

[0407] After sequentially adding 2-(trans-4-aminocyclohexyl)-9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one (21 mg, 0.043 mmol), (R)-2-hydroxybutanoic acid (4.2 mg, 0.04 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (11 mg, 0.057 mmol), and hydroxybenzotriazole (7.3 mg, 0.054 mmol), synthesized in [Step 5] of [Synthesis Example 7], to N,N-dimethylformamide (0.5 ml), The mixture was stirred at room temperature for 18 hours. After adding ice water to the reaction mixture, the resulting solid was collected by filtration, and the obtained solid was purified by basic silica gel column chromatography to obtain the title compound (9 mg).

[0408]

[0409] [Synthetic Example 17] 2-((trans-4-aminocyclohexyl)methyl)-9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 20] and 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-((trans-4-(dimethylamino)cyclohexyl)methyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 21]

[0410] The same reaction as in [Synthetic Example 7] was carried out, except that t-butyl-(trans-4-(propin-2-yl)cyclohexyl)carbamate was used instead of t-butyl-(trans-4-ethynylcyclohexyl)carbamate in [Step 1] of [Synthetic Example 7], to obtain the title compounds (9 mg, [Compound 20], 5 mg, [Compound 21]), respectively.

[0411]

[0412] [Synthetic Example 18] 9-chloro-2-cyclohexyl-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 22]

[0413] The same reaction up to [Step 4] of [Synthesizing Example 7] was carried out, except that ethinylcyclohexane was used instead of t-butyl-(trans-4-ethynylcyclohexyl)carbamate in [Step 1] of [Synthesizing Example 7], and the title compound (36 mg) was obtained.

[0414]

[0415] [Synthetic Example 19] 9-chloro-2-cyclopentyl-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 23]

[0416] The same reaction up to [Step 4] of [Synthesizing Example 7] was carried out, except that ethinylcyclopentane was used instead of t-butyl-(trans-4-ethynylcyclohexyl)carbamate in [Step 1] of [Synthesizing Example 7], and the title compound (58 mg) was obtained.

[0417]

[0418] [Synthetic Example 20] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 24]

[0419] The same reaction up to [Step 4] of [Synthetic Example 7] was carried out, except that 4-ethynyltetrahydro-2H-pyran was used instead of t-butyl-(trans-4-ethynylcyclohexyl)carbamate in [Step 1] of [Synthetic Example 7], to obtain the title compound (23 mg).

[0420]

[0421] [Synthetic Example 21] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(4-(dimethylamino)phenyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 25]

[0422] The same reaction as in [Synthesizing Example 7] was carried out, except that 5-chloro-6,7-dihydroxy-8-methyl-3,4-dihydroisoquinoline-1(2H)-one [Intermediate 4] and 4-ethynyl-N,N-dimethylaniline were used instead of 6,7-dihydroxy-8-methyl-3,4-dihydroisoquinoline-1(2H)-one and t-butyl-(trans-4-ethynylcyclohexyl)carbamate in [Step 1] of [Synthesizing Example 7], to obtain the title compound (18 mg).

[0423]

[0424] [Synthetic Example 22] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(4-(dimethylamino)butyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 26]

[0425] The same reaction as in [Synthetic Example 21] was carried out, except that N,N-dimethylhex-5-in-1-amine was used instead of 4-ethynyl-N,N-dimethylaniline, and the title compound (5.9 mg) was obtained.

[0426]

[0427] [Synthetic Example 23] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(3,5-(dimethylisoxazole-4-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 27]

[0428] The same reaction as in [Synthetic Example 7] was carried out, except that 4-ethynyl-3,5-dimethylisoxazole was used instead of t-butyl-(trans-4-ethynylcyclohexyl)carbamate in [Step 1] of [Synthetic Example 7], and the title compound (40 mg) was obtained.

[0429]

[0430] [Synthetic Example 24] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-2-(piperidin-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 28] and 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-2-(1-methylpiperidin-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 29]

[0431] The same reaction as in [Synthetic Example 7] was carried out except that t-butyl-4-ethynylpiperidine-1-carboxylate was used instead of t-butyl-(trans-4-ethynylcyclohexyl)carbamate in [Step 1] of [Synthetic Example 7], and the title compounds (125 mg, [Compound 28], 30 mg, [Compound 29]) were obtained, respectively.

[0432]

[0433] [Synthetic Example 25] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(1-((R)-2-hydroxybutanoyl)piperidine-4-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 30]

[0434] The same reaction as in [Synthesizing Example 16] was carried out, except that 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 28] synthesized in [Synthesizing Example 24] was used instead of 2-(trans-4-aminocyclohexyl)-9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-2-(piperidin-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one in [Synthesizing Example 16], A title compound (21 mg) was obtained.

[0435]

[0436] [Synthetic Example 26] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-2-(1-(2,2,2-trifluoroethyl)piperidine-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 31]

[0437] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-2-(piperidin-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one (20 mg, 0.04 mmol, [Compound 28]), potassium carbonate (16 mg, 0.12 mmol), and 1,1,1-trifluoro-2-iodomethane (19.6 mg, 0.10 mmol) synthesized in [Synthesis Example 24] were sequentially added to N,N-dimethylformamide (1.0 ml). The reaction mixture was refluxed at 90°C for 18 hours. After cooling the reaction mixture to room temperature, 20% methanol-chloroform and water were added, and the organic layer was extracted. The extracted organic layer was dried using anhydrous sodium sulfate and subjected to vacuum distillation. The resulting residue was purified by basic silica gel column chromatography to obtain the title compound (2.5 mg).

[0438]

[0439] [Synthetic Example 27] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-2-(1-methyl-1H-indole-5-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 32]

[0440] The title compound (109 mg) was obtained by carrying out the same reaction as in [Synthetic Example 21], except that 5-ethynyl-1-methyl-1H-indole synthesized according to the method described in WO2016154434 was used instead of 4-ethynyl-N,N-dimethylaniline in [Synthetic Example 21].

[0441]

[0442] [Synthetic Example 28] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-methoxycyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 33]

[0443] The title compound (50 mg) was obtained by carrying out the same reaction as in [Synthetic Example 21], except that trans-1-ethynyl-4-methoxycyclohexane was used instead of 4-ethynyl-N,N-dimethylaniline in [Synthetic Example 21].

[0444]

[0445] [Synthetic Example 29] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-2-(trans-4-(methylamino)cyclohexyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 34]

[0446] The same reaction up to [Step 5] of [Synthetic Example 7] was carried out to obtain the title compound (35 mg), except that t-butyl-(trans-ethynylcyclohexyl)(methyl)carbamate [intermediate 11] was used instead of t-butyl-(trans-4-ethynylcyclohexyl)carbamate in [Step 1] of [Synthetic Example 7].

[0447]

[0448] [Synthetic Example 30] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-3-(dimethylamino)cyclobutyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 35]

[0449] The same reaction was carried out except that t-butyl-(trans-3-ethynylcyclobutyl)carbamate was used instead of t-butyl-(trans-4-ethynylcyclohexyl)carbamate in [Step 1] of [Synthesizing Example 7] to obtain the title compound (3.5 mg).

[0450]

[0451] [Synthetic Example 31] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(cis-3-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 36]

[0452] The same reaction was carried out except that t-butyl-(cis-3-ethynylcyclohexyl)carbamate was used instead of t-butyl-(trans-4-ethynylcyclohexyl)carbamate in [Step 1] of [Synthetic Example 7] to obtain the title compound (19 mg).

[0453]

[0454] [Synthetic Example 32] 9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(cis-3-(dimethylamino)cyclopentyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 37]

[0455] The same reaction was carried out to obtain the title compound (8 mg), except that t-butyl-(cis-3-ethynylcyclopentyl)carbamate was used instead of t-butyl-(trans-4-ethynylcyclohexyl)carbamate in [Step 1] of [Synthesizing Example 7].

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487] [Synthetic Example 33] 2-(trans-4-aminocyclohexyl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 38] and 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 39]

[0488]

[0489] Step 1. Preparation of t-butyl-((trans-4-(2,4,9-trimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate

[0490]

[0491] The same reaction as in [Step 1] of [Synthetic Example 2] was carried out, except that 6,7-dihydroxy-5,8-dimethyl-3,4-dihydroxyisoquinoline-1(2H)-one [Intermediate 3] was used instead of 6,7-dihydroxy-3,4-dihydroxyisoquinoline-1(2H)-one in [Step 1] of [Synthetic Example 2], and the title compound (800g) was obtained.

[0492] Step 2. Preparation of t-butyl-((trans-4-(6-((2-(benzyloxy)-4,6-dimethylpyridine-3-yl)methyl)-2,4,9-trimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate

[0493]

[0494] Using the t-butyl-((trans-4-(2,4,9-trimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate (200 mg, 0.46 mmol) synthesized in [Step 1] above, the same reaction as [Step 2] of [Synthesis Example 2] was carried out to obtain the title compound (258 mg).

[0495] Step 3. Preparation of 2-(trans-4-aminocyclohexyl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 38]

[0496]

[0497] t-butyl-((trans-4-(6-((2-(benzyloxy)-4,6-dimethylpyridine-3-yl)methyl)-2,4,9-trimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate (258 mg, 0.41 mmol) synthesized in [Step 2] above and 4 M hydrochloric acid-1,4-dioxane solution (1.5 ml) were sequentially added to methanol, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, saturated sodium bicarbonate was added to neutralize the mixture, and extraction was performed using 20% ​​methanol-chloroform. The extracted organic layer was dried using anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was immersed in a 20% ethyl ester-diethyl ether mixture for 1 hour The solid produced by stirring was filtered and washed to obtain the title compound (137 mg).

[0498] Step 4. Preparation of 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 39]

[0499]

[0500] Using 2-(trans-4-aminocyclohexyl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one (130 mg, 0.27 mmol) synthesized in [Step 3] above, the same reaction as in [Step 5] of [Synthesis Example 2] was carried out to obtain the title compound (80 mg).

[0501]

[0502] [Synthetic Example 34] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one isomers A, B [Compound 40, Compound 41]

[0503] Each enantiomer was separated from the 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one synthesized in [Synthesis Example 33] under the following conditions. The absolute stereochemistry of each isomer was not measured.

[0504] Column: Daicel chiralcell OZ-H, 4.6X250mm, 5μM

[0505] Temperature: 35℃

[0506] Flow rate: 0.8 ml / min

[0507] Wavelength: 270 nM

[0508] Elution solvent: n-hexane:ethanol:diethylamine = 500:500:0.4(v / v%)

[0509] Peak 1: 15.8 min - Isomer A (99.9%ee)

[0510] Second peak: 23.1 min - Dimer B (99.9%ee)

[0511]

[0512] [Synthetic Example 35] 2-(trans-4-(dimethylamino)cyclohexyl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 42]

[0513] The same reaction as in [Synthetic Example 33] was carried out, except that 2-(benzyloxy)-3-(chloromethyl)-4-methoxy-6-methylpyridine was used instead of 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine in [Step 2] of [Synthetic Example 33], and the title compound (30 mg) was obtained.

[0514]

[0515] [Synthetic Example 36] 2-(trans-4-(dimethylamino)cyclohexyl)-2,4,9-trimethyl-6-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridine-3-yl)methyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 43]

[0516] The same reaction as in [Synthesizing Example 33] was carried out, except that 2-(benzyloxy)-3-(chloromethyl)-6-methyl-4-propylpyridine was used instead of 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine in [Step 2] of [Synthesizing Example 33], and the title compound (35 mg) was obtained.

[0517]

[0518] [Synthetic Example 37] 2-cyclohexyl-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 44]

[0519] The same reaction up to [Step 4] of [Synthesizing Example 32] was carried out, except that ethinylcyclohexane was used instead of t-butyl-(trans-4-ethynylcyclohexyl)carbamate in [Step 1] of [Synthesizing Example 33], to obtain the title compound (123 mg).

[0520]

[0521] [Synthetic Example 38] 2-(trans-4-(ethylamino)cyclohexyl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 45] and 2-(trans-4-(diethylamino)cyclohexyl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 46]

[0522] In [Step 4] of [Synthesizing Example 33], instead of 2-(trans-4-aminocyclohexyl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one and 37% aqueous formaldehyde, 2-(trans-4-aminocyclohexyl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one (78 mg, 0.10 mmol) and Except for using acetaldehyde (9.3 mg, 0.21 mmol), the same reaction as [Step 4] of [Synthesizing Example 35] was carried out, and the resulting residue was purified by basic silica gel column chromatography to obtain the title compounds (45 mg, [Compound 45], 11 mg [Compound 46]), respectively.

[0523]

[0524] [Synthetic Example 39] 2-(trans-4-(ethyl(methyl)amino)cyclohexyl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 47]

[0525] Except for using 2-(trans-4-aminocyclohexyl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 45] synthesized in [Synthetic Example 38] instead of 2-(trans-4-(ethylamino)cyclohexyl)-6-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 45] from [Synthetic Example 33] in [Step 4] of [Synthetic Example 33] The same reaction as in [Step 4] was carried out to obtain the title compound (21 mg).

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537] [Synthetic Example 40] 9-bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 48]

[0538] t-butyl-((trans-4-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate (616 mg, 1.48 mmol) synthesized in [Step 1] of [Synthesis Example 7] was added to acetonitrile (7.5 ml), after which N-bromosuccinimide (316 mg, 1.77 mmol) was added. The reaction mixture was stirred at room temperature for 13 hours, then neutralized by adding saturated sodium bicarbonate water, and extracted using ethyl acetate. The extracted organic layer was dried using anhydrous sodium sulfate and subjected to vacuum distillation. The obtained residue was subjected to silica gel column chromatography t-butyl-((trans-4-(9-bromo-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate (550 mg) was obtained by purification.

[0539] Using the t-butyl-((trans-4-(9-bromo-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-2-yl)cyclohexyl)carbamate synthesized above, the same reaction from [Step 3] to [Step 5] of [Synthesis Example 7] was carried out to obtain the title compound (120 mg).

[0540]

[0541] [Synthetic Example 41] 9-bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one isomer [Compound 49, Compound 50]

[0542] Each enantiomer was separated from the 9-bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one synthesized in [Synthesis Example 40] under the following conditions. The absolute stereochemistry of each isomer was not measured.

[0543] Column: Daicel chiralcell OZ-H, 4.6X250mm, 5μM

[0544] Temperature: 35℃

[0545] Flow rate: 0.8 ml / min

[0546] Wavelength: 270 nM

[0547] Elution solvent: n-hexane:ethanol:diethylamine = 500:500:0.4(v / v%)

[0548] Peak 1: 14.0 min - Isomer A (99.9%ee)

[0549] Second peak: 20.6 min - Dimer B (99.9%ee)

[0550]

[0551] [Synthetic Example 42] 9-bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2,4-dimethyl-2-(trans-4-(methylamino)cyclohexyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 51]

[0552] The same reaction up to [Step 5] of [Synthetic Example 40] was carried out to obtain the title compound (70 mg), except that t-butyl (trans-4-ethynylcyclohexyl)(methyl)carbamate [Intermediate 11] was used instead of t-butyl-(trans-4-ethynylcyclohexyl)carbamate in [Synthetic Example 40].

[0553]

[0554] [Synthetic Example 43] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-vinyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 52]

[0555] 9-bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one (43 mg, 0.08 mmol, [Compound 48]) synthesized in [Synthesizing Example 40], 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (12 mg, 0.08 mmol), potassium phosphate (41 mg, 0.19 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (1:1) (8 mg, 0.01 mmol) was sequentially added to a 1,4-dioxane:water (8 ml, 4:1) mixture, and after argon gas evacuation, the mixture was refluxed at 90°C for 13 hours. After cooling the reaction mixture to room temperature, dichloromethane and water were added, and the organic layer was extracted. The extracted organic layer was dried using anhydrous sodium sulfate and subjected to vacuum distillation. The resulting residue was purified by basic silica gel column chromatography to obtain the title compound (37 mg).

[0556]

[0557] [Synthetic Example 44] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-ethynyl-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 53]

[0558] Step 1. Preparation of 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-9-carbaldehyde

[0559] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-vinyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one (33 mg, 0.07 mmol, [Compound 52]) synthesized in [Synthetic Example 43] was added to a mixture of tetrahydrofuran (0.6 ml) and water (0.3 ml), and 4% osmium tetraoxide (21 µl, 0.003 mmol) and sodium periodate (28 mg, 0.13 mmol) were added sequentially. After stirring the reaction mixture at room temperature for 13 hours, the insoluble matter was removed by filtration, saturated sodium nitrite was added to the filtrate, and the mixture was extracted with dichloromethane. The extracted organic layer was dried using anhydrous sodium sulfate and subjected to vacuum distillation to obtain the title compound (26.7 mg).

[0560] Step 2. 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-ethynyl-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 53]

[0561] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-9-carbaldehyde (26.8 mg, 0.05 mmol) synthesized in [Step 1] above was added to methanol (0.6 ml), followed by the sequential addition of potassium carbonate (8.8 mg, 0.06 mmol) and dimethyl(1-diazo-2-oxopropyl)phosphonate (12.3 mg, 0.06 mmol). The reaction mixture was stirred at room temperature for 13 hours, and the organic layer was extracted by adding saturated saline solution and dichloromethane. The extracted organic layer was dried using anhydrous sodium sulfate and distilled under reduced pressure. The resulting residue was purified by basic silica gel column chromatography to obtain the title compound (10 mg).

[0562]

[0563] [Synthetic Example 45] 9-cyclopropyl-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 54]

[0564] The same reaction as in [Synthetic Example 43] was carried out, except that cyclopropylboronic acid was used instead of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane in [Synthetic Example 43], and the title compound (12 mg) was obtained.

[0565]

[0566] [Synthetic Example 46] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(4-(morpholinomethyl)phenyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 55]

[0567] The same reaction as in [Synthetic Example 43] was carried out, except that 4-(4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine was used instead of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolan in [Synthetic Example 43], and the title compound (14 mg) was obtained.

[0568]

[0569] [Synthetic Example 47] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-phenyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 56]

[0570] 9-bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one (70 mg, 0.13 mmol, [Compound 48]), phenylboronic acid (46 mg, 0.38 mmol), tripotassium phosphate (80 mg, 0.38 mmol), and Pd(dppf)Cl2·CH2Cl2 (1:1) (21 mg, 0.03 mmol) synthesized in [Synthesizing Example 40] were dissolved in 1,4-dioxane / water (4:1, 3.5 mL) and then replaced with argon gas. The reaction mixture was stirred at 80°C for 18 hours, then cooled to room temperature and filtered using Celite. The resulting product was extracted with dichloromethane, dried with anhydrous sodium sulfate, and then distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (50 mg).

[0571]

[0572] [Synthetic Example 48] 9-(cyclopent-1-en-1-yl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 57]

[0573] The same reaction as in [Synthetic Example 47] was carried out, except that 1-cyclopentenylboronic acid was used instead of phenylboronic acid in [Synthetic Example 47], and the title compound (100 mg) was obtained.

[0574]

[0575] [Synthetic Example 49] 9-cyclopentyl-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 58]

[0576] 9-(cyclopent-1-en-1-yl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one (75 mg, 0.14 mmol) synthesized in [Synthesis Example 48] and 10% palladium / carbon (75 mg) were dissolved in ethyl acetate / methanol (1:1, 5 mL) and a hydrogen balloon was installed. The reaction mixture was stirred at room temperature for 18 hours, filtered with Celite, and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (50 mg).

[0577]

[0578] [Synthetic Example 50] 9-(cyclohex-1-en-1-yl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 59]

[0579] The same reaction as in [Synthetic Example 47] was carried out, except that 1-cyclohexanylboronic acid was used instead of phenylboronic acid in [Synthetic Example 47], and the title compound (80 mg) was obtained.

[0580]

[0581] [Synthetic Example 51] 9-cyclohexyl-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 60]

[0582] In [Synthetic Example 49], instead of 9-(cyclopent-1-en-1-yl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one, 9-(cyclohex-1-en-1-yl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [compound Except for using

[59] , the same reaction as in [Synthetic Example 49] was carried out to obtain the title compound (25 mg).

[0583]

[0584] [Synthetic Example 52] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(prop-1-en-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 61]

[0585] The same reaction as in [Synthetic Example 47] was carried out, except that 2-isopropenboronic acid pinacol ester was used instead of phenylboronic acid in [Synthetic Example 47], and the title compound (80 mg) was obtained.

[0586]

[0587] [Synthetic Example 53] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-isopropyl-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 62]

[0588] In [Synthetic Example 49], instead of 9-(cyclopent-1-en-1-yl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one, 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(prop-1-en-2-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [compound Except for using

[61] , the same reaction as in [Synthetic Example 49] was carried out to obtain the title compound (27 mg).

[0589]

[0590] [Synthetic Example 54] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-ethyl-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 63]

[0591] Except for using 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 52] instead of 9-(cyclopent-1-en-1-yl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-vinyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 52] in [Synthetic Example 49] The same reaction as in

[49] was carried out to obtain the title compound (22 mg).

[0592]

[0593] [Synthetic Example 55] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-9-(furan-2-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 64]

[0594] The same reaction as in [Synthetic Example 47] was carried out, except that furan-2-boronic acid was used instead of phenylboronic acid in [Synthetic Example 47], and the title compound (27 mg) was obtained.

[0595]

[0596] [Synthetic Example 56] 9-(3,6-dihydro-2H-pyran-4-yl)-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 65]

[0597] The same reaction as in [Synthetic Example 47] was carried out, except that 3,6-dihydro-2H-pyran-4-borolane was used instead of phenylboronic acid in [Synthetic Example 47], and the title compound (37 mg) was obtained.

[0598]

[0599] [Synthetic Example 57] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(pyridine-3-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 66]

[0600] The same reaction as in [Synthetic Example 47] was carried out, except that pyridine-3-ylboronic acid was used instead of phenylboronic acid in [Synthetic Example 47], and the title compound (38 mg) was obtained.

[0601]

[0602] [Synthetic Example 58] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(thiazole-5-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 67]

[0603] The same reaction as in [Synthetic Example 47] was carried out, except that 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole was used instead of phenylboronic acid in [Synthetic Example 47], and the title compound (13 mg) was obtained.

[0604]

[0605] [Synthetic Example 59] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(1-methyl-1H-pyrazole-4-yl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one [Compound 68]

[0606] The same reaction as in [Synthetic Example 47] was carried out, except that 1-methylpyrazole-4-borolane was used instead of phenylboronic acid in [Synthetic Example 47], and the title compound (36 mg) was obtained.

[0607]

[0608] [Synthetic Example 60] 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-9-carbonitrile [Compound 69]

[0609] 9-bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one (50 mg, 0.09 mmol, [Compound 48]) synthesized in [Synthesizing Example 40], tris(dibenzylideneacetone)dipalladium(0) (33 mg, 0.036 mmol), 1,1'-bis(diphenylphosphino)ferrocene (40 mg, 0.072 mmol), zinc cyanide (32 mg, 0.27 mmol), and zinc (5 mg, 0.072 mmol) Dimethylacetamide (2 ml) was added sequentially, and after argon gas exchange, the mixture was refluxed at 80°C for 16 hours. After cooling the reaction mixture to room temperature, dichloromethane and water were added, and the organic layer was extracted. The extracted organic layer was dried using anhydrous sodium sulfate and distilled under reduced pressure. The resulting residue was purified by basic silica gel column chromatography to obtain the title compound (26 mg).

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633] Experimental Example 1: Evaluation of Inhibitory Activity of EZH1 / EZH2 Methyltransferases

[0634] The inhibitory activity of the above synthetic compounds against EZH1 or EZH2 methyltransferase was measured. The experiment was commissioned to Reaction Biology, and the activity against EZH1 or EZH2 was measured using the radiometric scintillation proximity assay. The IC50 of the above synthetic compounds against EZH1 or EZH2 was 50 To measure, 2.3 nmol / L EZH1 or EZH2, 1 νmol / L histone H3 (21-44)-lys(biotin), 1.5 νmol / LS-adenylmethionine (SAM), 500 nmol / L in the compound or DMSO 3H-SAM was mixed into the reaction buffer and reacted at room temperature for 90 minutes. The reaction buffer 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 after adding SPA beads coated with PVT streptavidin, the reaction was carried out again at room temperature for 1 hour. The methylation values ​​of the substrate peptides were measured using a TopCount NXT plate reader. The measurements were converted to percentage activities by setting the mean value of the DMSO-treated wells to 100% and the background mean value to 0%, and then the IC50 values ​​were analyzed using the “log(inhibitor) vs. normalized response - variable slope” method in the GraphPad PRISM v6 program. 50 The value was derived.

[0635]

[0636] Experimental Example 2: Cell Growth Inhibition Test

[0637] To confirm the inhibition of cell growth of blood cancer cell lines by the above synthetic compound, evaluations were conducted on KARPAS 422, RPMI 8226, KMS-11, JeKo-1, MV-4-11, Mino, Pfeiffer, SU-DHL-4, and RS4;11 cell lines. Pfeiffer and SU-DHL-4 cell lines were tested by outsourcing to KYinno, and RS4;11 cell lines were tested by outsourcing to Shanghai Chempartner. The remaining Kasumi-1, MV-4-11, MM.1S, KMS-11, JeKo-1, Mino (ATCC), RPMI 8226 (KCLB), and KARPAS 422 (ECACC) cell lines were tested after purchase.

[0638] DMSO was added to the medium at a final concentration of 0.1% or less, or a DMSO solution of the above-mentioned synthetic compound, at the concentrations and treatment times listed in [Table 5] below, and cultured at 37°C under 5% CO2. Each cultured cell was seeded into a 6-well plate or a 48-96-well plate, and subculture or medium exchange was performed at intervals of 3 to 4 days. After a total of 7 to 14 days of subculture, the cells were seeded into a 96-well plate. After seeding into the 96-well plate 3 to 5 days prior to the effect measurement date, the luminescence (Tz) was measured on the day of seeding. Using the Cell Titer-Glo Cell Viability Assay (Promega, G7573) according to the attached manual, the luminescence was measured using a plate reader device, Synergy NeoAlpha (Biotek). The cell proliferation inhibition rate was calculated based on the following formula from the luminescence amount (Tz) measured on the sowing day and the luminescence amounts of the DMSO-treated group (C) and the sample-added group (Ti) measured on the effect evaluation day.

[0639] [ceremony]

[0640] [(Ti-Tz) / (C-Tz)]

[0641] [(Ti-Tz) / C] x 100 for concentrations for which Ti <Tz.

[0642]

[0643] Cell Line Source Culture Medium Culture Time Treatment Concentration KARPAS 42 2ECACC 20% RPMI 16 40 7 days 0.001 ~ 1,000 nM (1 / 10 dilution) RPMI 8 22 6KCLB 10% RPMI 16 40 7 days 0.06 ~ 1,000 nM (1 / 5 dilution) KMS-11ATCC 10% RPMI 16 40 10 days 0.1 ~ 10,000 nM (1 / 10 dilution) JeKo-1ATCC 20% RPMI 16 40 10 days 0.1 ~ 10,000 nM (1 / 10 dilution) MV4;11ATCC 10% IMDM 10 days 0.32 ~ 1,000 nM (1 / 5 dilution) Kasumi-1ATCC 20% RPMI 16 40 10 days 0.32 ~ 1,000 nM (1 / 5 dilution) MM. 1SATCC 10% RPMI 1640 11 il 0.01 ~ 1,000 nM (1 / 10 dilution) MinoATCC 15% RPMI 1640 14 il 0.1 ~ 10,000 nM (1 / 10 dilution)

[0644] The results of Experimental Example 1 and Experimental Example 2 are shown in [Table 6] and [Table 7] below.

[0645] Example Number Enzyme inhibitory activity (IC 50 , nM)Cell growth inhibitory activity (GI) 50 , nM)EZH1EZH2KARPAS-422(EZH2 Y641N Mutation)Pfeiffer(EZH2 A677GMutation) 197.614.3--23717.9--3--39-4202.61.9 ~ 2.6-5161.32.4-6--310-7543.84.8-8573.213-916 ~ 431.5 ~ 5.02.0 ~ 150.971010 ~ 210.8 ~ 1.42.5 ~ 130.8411>1,000116 ~ 473563 ~ >1,000-1223 ~ 503.24.9 ~ 150.661323 ~ 351.8 ~ 2.31.8 ~ 9.60.2714273.250-15653.618-16891168-17745.652-18474.316-19454.4440-20483.718-211377.275-<2218016>1,000-23684.4>1,000-24343.062-2516611--26856.299-273103.9--28553.214-291365.051-301903.4307-31513.8231-32-->1,000-33--187-349.71.43.21.4835--57-36--87-37--22-38544.4--399.7 ~ 301.2 ~ 6.23.2 ~ 8.40.76 ~ 0.9940281.81.80.7141>1,0006969-4231 ~ 343.4 ~ 6.02.6 ~ 8.80.97 ~ 1.41438.11.4586.7644340.4--45186.2--46169.7--47207.0--482.6 ~ 400.4 ~ 2.63.7 ~ 12.40.77497.0 ~ 160.35 ~ 1.41.2 ~ 9.70.2150>1,000205419-51411.64.4-5232 ~ 553.4 ~ 3.74.4 ~ 9.7-5327 ~ 1394.5 ~ 9.15.1 ~ 14-54416.419-55265.6--56--11-57--13-58--13-59--28-60--28-61--4.8-62--6.2-63--4.4-64--5.0-65--8.8-66--6.4-67--4.3-68--5.1-69652.710-Control Group A83 ~ 1972.0 ~ 2.919 ~ 771.93Control Group B17 ~ 461.0 ~ 2.01.3 ~ 150.57

[0646] Cell lineCell growth inhibitory activity (GI 50 , nM)Control Group A Control Group BEx. 49SU-DHL-42812111RS4;119326224MV4-112206.13.9Kasumi-1>1,00032451MM.1S2042.31.4RPMI82263157.86.4KMS-11554258.1Mino2252.52.0JeKo-13,5827142

[0647]

[0648]

[0649] Experimental Example 3: Metabolic Stability Test in Liver Microsomes

[0650] To confirm the hepatic metabolic stability of the above-mentioned synthetic compound, 5 μM of the test substance and 1 mg / mL of human, dog, rat, and mouse liver microsomes are reacted for 1 hour in the presence of a NADPH regenerating system while maintaining the temperature at 37°C. After 1 hour, the reaction is terminated, and the supernatant obtained by centrifugation is analyzed by HPLC. Using the peak values ​​obtained from the analysis results, the residual amount (%) is calculated using the following formula based on the value of the test substance reacted for 1 hour compared to the test substance at 0 minutes.

[0651] (Peak value of test substance reacted for 1 hour / Peak value of test substance at 0 min) X 100 = Residual amount (%)

[0652] The results of Experiment Example 3 are shown in [Table 8] below.

[0653] Example No. 1 Residual amount of test substance after reaction (%) Human Dog Rat Mouse 484NTNT 79589NTNT 78957NTNT 561079NTNT 551137NTNT 701257NTNT 611382NTNT 793466NTNT 1003962NTNT 804082NTNT 844153NTNT 634274NTNT 884352NTNT 614854NTNT 5249677484525035NTNT 545170NTNT 645262NTNT 615367NTNT 85 Control Group ANA 14NANA Control Group B 65838150

[0654] NT: not tested; NA: not applicable

[0655] Experimental Example 4: Mouse Pharmacokinetics

[0656] As an EZH2 inhibitor, pharmacokinetic studies were performed on mice (ICR, 8 weeks old, male) of the above-mentioned synthetic compound.

[0657] The oral administration group maintains a fasting state from the day before the test until 4 hours after the administration of the substance. On the day of test substance administration, the animals are weighed, and the synthetic compound is prepared using a selected solvent based on a concentration of 30 mg / kg (10 mL / kg). The test substances are administered orally as a single dose; a fixed amount is taken from the blood at a set time, separated into plasma, and concentration analysis is performed using LC-MS / MS (Waters UPLC H-Class / Xevo TQ; Waters, USA). Pharmacokinetic coefficients are calculated using the linear-log trapezoidal summation formula via non-compartment analysis of the Phoenix WinNonlin (Certara, USA) program, based on the plasma concentration curves at each time point. The results of Experimental Example 4 are shown in [Table 9] below.

[0658]

[0659] Example No. Area under the oral gully curve AUC (ng·hr / mL) Half-life T1 / 2 (hr) 4770 NC 914,942 ~ 16,449 2.4 ~ 2.313 1,036 NC 393,649 NC 4817,296 ~ 18,676 2.8 ~ 3.2499,963 2.950 12,239 2.55 11,523 NC Control A 4,884 0.6 Control B 3,425 ~ 5,003 NC ~ 1.0

[0660] NC: not calculated

[0661] Comparison Example

[0662] Control A is N-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide (tasemetostat), the synthesis of which is described in Example No. 44 on page 220 of International Patent Application WO2012 / 142504, and has the following structure;

[0663]

[0664]

[0665] Control B is (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxol-5-carboxamide (valemethostat), the synthesis of which is described in Example No. 35 on page 137 of International Patent Application WO2015 / 141616, and has the following structure;

[0666]

[0667]

[0668] Example of Comparative Experiment: Inhibitory activity of EZH1 / EZH2 methyltransferase and cell growth inhibition experiment using blood cancer cell lines

[0669] Control A [N-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-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-dihydropyridine-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxol-5-carboxamide (valemethostat)] synthesized by the method described in the Comparative Example showed inhibitory activity against EZH1 / EZH2 methyltransferase according to the same method described in Experimental Examples 1 and 2. and cell growth inhibition experiments were conducted using blood cancer cell lines.

[0670] The results are shown in [Table 6] and [Table 7] above.

[0671] As shown in [Table 6] and [Table 7] above, it can be seen that the compound according to the present invention has excellent enzyme inhibitory activity against EZH1 and / or EZH2 and growth inhibitory activity against blood cancer cell lines resulting therefrom, compared with the comparative control group.

[0672] The present invention relates to novel heterotriclic derivative compounds and their uses, and more specifically, to novel heterotriclic derivative compounds having inhibitory activity of EZH1 (Enhancer of zeste homolog 1) and / or EZH2 (Enhancer of zeste homolog 2), pharmacologically acceptable salts thereof, or pharmaceutical compositions comprising such compounds.

Claims

1. A compound selected from the heterotricyclic derivative compound of the following chemical formula 1, pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof: [Chemical Formula 1] R 1 C containing H, halogen, cyano, 0 to 3 halogen atoms 1-6 Alkyl, C containing 0 to 3 halogen atoms 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Alkylcarbonyl C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 A 5 to 6 membered aromatic heterocyclyl containing 1 to 3 heteroatoms independently selected from the group consisting of cycloalkenyl, aryl, N, O, and S in the ring, or a 5 to 6 membered aliphatic heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S in the ring, which may or may not contain an unsaturated bond in a portion of the ring; C above 3-6 A 5 to 6 membered aromatic heterocyclyl containing 1 to 3 heteroatoms independently selected from the group consisting of cycloalkyl, aryl, N, O, and S in the ring, or a 5 to 6 membered aliphatic heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S in the ring, which may or may not contain an unsaturated bond in a portion of the ring, is unsubstituted or substituted with 1 to 3 independently selected from the following group A; L is bond, C 1-6 Alkylene, or oxyC 1-6 It is alkylene; R 2 Silver H, C 1-6 Alkyl, C 3-6 5 to 6 membered aliphatic heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of cycloalkyl, N, O, and S within the ring, aryl, 5 to 6 membered aromatic heterocyclyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S within the ring, or 5 to 12 membered bicyclic heteroaryl; C above 1-6 Alkyl, C 3-6 Cycloalkyl, 5 to 6 membered aliphatic heterocyclyl, aryl, 5 to 6 membered aromatic heterocyclyl, or 5 to 12 membered bicyclic heteroaryl is unsubstituted or substituted with 1 to 3 independently selected from the following C group; R 3 is C 1-6 It is alkyl; R 4 is H, halogen, or C containing 0 to 3 halogen atoms 1-6 It is alkyl; R 5 is C 1-6 Alkyl, or C 1-6 It is alkoxy; R 6 is C 1-6 It is alkyl; Group A is halogen, C 1-6 Alkyl, C 1-6 A 5 to 6 membered aliphatic heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of alkoxy, N, O, and S in the ring, wherein said C 1-6 Alkyl, C 1-6 Alkoxy and 5 to 6 membered aliphatic heterocyclyl are unsubstituted or substituted with 1 to 3 independently selected from the following group B; Group B is halogen, C 1-6 A 5 to 6 membered aliphatic heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of alkyl, N, O, and S within the ring; Group C contains hydroxy, formyl, and C containing 0 to 3 halogen atoms. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Alkylsulfonyl, -NR 20 R 21 , C 1-6 Alkoxy C 1-6 Alkyl, diC 1-6 Alkylamino C 1-6 A 4 to 6 membered aliphatic heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of alkyl, N, O, and S in the ring, wherein R 20 and R 21 are each independently H, formyl, and C 1-6 Alkyl, substituted or unsubstituted C 1-6 It is an alkylcarbonyl.

2. In paragraph 1, R 1 This H, halogen, C containing 0 to 3 halogen atoms 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 A compound which is a 5 to 6 membered aromatic heterocyclyl containing 1 to 3 heteroatoms independently selected from the group consisting of cycloalkenyl, aryl, N, O, and S in the ring, or an aliphatic heterocyclyl containing or not containing an unsaturated bond in a portion of a 5 to 6 membered ring containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S in the ring.

3. In paragraph 2, R 1 A compound which is H, halogen, methyl, ethyl, nitrile, methoxy, ethoxy, cyclopropyl, vinyl, acetylenyl, phenyl, isopropenyl, isopropyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, furanyl, pyridine, pyrazolyl, dihydropyranyl, or thiazolyl.

4. In paragraph 1, R 2 Go C 1-6 Alkyl, C 3-6 5 to 6 membered aliphatic heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of cycloalkyl, N, O, and S in the ring, 5 to 6 membered aromatic heterocyclyl containing 1 to 3 heteroatoms independently selected from the group consisting of aryl, N, O, and S in the ring, or 5 to 12 membered bicyclic heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, and 5 to 6 membered aliphatic heterocyclyl, aryl, 5 to 6 membered aromatic heterocyclyl, or 5 to 12 membered bicyclic heteroaryl, C 1-6 Alkyl, C 1-6 Alkylsulfonyl, hydroxy, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, diC 1-6 A compound unsubstituted or substituted with 1 to 3 independently selected from the group consisting of alkylamino, 3 to 6 membered aliphatic heterocyclyl or alkylamide containing 1 to 2 heteroatoms in the ring.

5. In paragraph 4, L is a bond, or methylene; R 2 is butyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, piperidyl, phenyl, pyridine, indole or isoxazole; R 3 A compound wherein said butyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, piperidyl, phenyl, pyridine, indole or isoxazole is substituted or unsubstituted with one independently selected from the group consisting of methyl, ethyl, ethylsulfonyl, hydroxy, methoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, ethylmethylamino, piperidyl, pyrrolidyl, trifluoroethyl or (R)-2-hydroxybutanamide.

6. In paragraph 1, L is a bond; R 1 and R 4 are each independently H, halogen or methyl; R 2 Go C 3-6 Cycloalkyl or NR 20 R 21 C replaced by 3-6 It is cycloalkyl; R 3 , R 5 Wow R 6 This is methyl; At this time, the above NR 20 R 21 Silver amino, C 1-6 Alkylamino and diC 1-6 A compound selected from the group consisting of alkylamino.

7. In paragraph 1, The compound of the above chemical formula 1 is a compound characterized in that it is selected from the group consisting of the following compounds: 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; 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2-methyl-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)-2,9-dimethyl-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-(trans-4-(dimethylamino)cyclohexyl)-2,9-dimethyl-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-(trans-4-(dimethylamino)cyclohexyl)-2,9-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer A; 4-Chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,9-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer B; 4,9-Dichloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 2-(trans-4-aminocyclohexyl)-9-chloro-6-((4,6-dimethyl-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-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; 9-Chloro-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 isomer A; 9-Chloro-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 Isomer B; 9-Chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(cis-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 9-Chloro-2-(trans-4-(dimethylamino)cyclohexyl)-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-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-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; 9-Chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(ethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 9-Chloro-2-(trans-4-(diethylamino)cyclohexyl)-6-((4,6-dimethyl-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-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,4-dimethyl-2-(trans-4-(piperidin-1-yl)cyclohexyl)-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-dimethyl-2-(trans-4-(pyrrolidin-1-yl)cyclohexyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; (2S)-N-(trans-4-(9-chloro-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-2-yl)cyclohexyl)-2-hydroxybutanamide; 2-((trans-4-aminocyclohexyl)methyl)-9-chloro-6-((4,6-dimethyl-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-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-((trans-4-(dimethylamino)cyclohexyl)methyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 9-Chloro-2-cyclohexyl-6-((4,6-dimethyl-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-cyclopentyl-6-((4,6-dimethyl-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-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,4-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-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)phenyl)-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)butyl)-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-(3,5-(dimethylisoxazol-4-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-dimethyl-2-(piperidin-4-yl)-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-dimethyl-2-(1-methylpiperidin-4-yl)-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-(1-((R)-2-hydroxybutanoyl)piperidin-4-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-dimethyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-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-dimethyl-2-(1-methyl-1H-indol-5-yl)-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-(trans-4-methoxycyclohexyl)-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-dimethyl-2-(trans-4-(methylamino)cyclohexyl)-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-(trans-3-(dimethylamino)cyclobutyl)-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-(cis-3-(dimethylamino)cyclohexyl)-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-(cis-3-(dimethylamino)cyclopentyl)-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)-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-(trans-4-(dimethylamino)cyclohexyl)-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-(trans-4-(dimethylamino)cyclohexyl)-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-(trans-4-(dimethylamino)cyclohexyl)-2,4,9-trimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one isomer B; 2-(trans-4-(dimethylamino)cyclohexyl)-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-(trans-4-(dimethylamino)cyclohexyl)-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; 2-Cyclohexyl-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; 2-(trans-4-(ethylamino)cyclohexyl)-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-(trans-4-(diethylamino)cyclohexyl)-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-(trans-4-(ethyl(methyl)amino)cyclohexyl)-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; 9-Bromo-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; 9-Bromo-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 isomer A; 9-Bromo-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 Isomer B; 9-Bromo-6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,4-dimethyl-2-(trans-4-(methylamino)cyclohexyl)-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-vinyl-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-ethynyl-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 9-Cyclopropyl-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; 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-9-(4-(morpholinomethyl)phenyl)-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-phenyl-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-(trans-4-(dimethylamino)cyclohexyl)-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-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 9-(Cyclohex-1-en-1-yl)-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; 9-Cyclohexyl-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; 6-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-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-(trans-4-(dimethylamino)cyclohexyl)-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-(trans-4-(dimethylamino)cyclohexyl)-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-(trans-4-(dimethylamino)cyclohexyl)-9-(furan-2-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one; 9-(3,6-dihydro-2H-pyran-4-yl)-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; 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; 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; 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; and 6-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-9-carbonitrile; 8. A pharmaceutical composition comprising a compound described in any one of claims 1 to 7 or a pharmacologically acceptable salt thereof as an active ingredient.

9. In paragraph 8, The pharmaceutical composition is for use in treating cancer or tumors that can be treated by inhibiting EZH1 (Enhancer of zeste homolog 1) and / or EZH2 (Enhancer of zeste homolog 2) enzyme activity.

10. A pharmaceutical preparation comprising the pharmaceutical composition of paragraph 8.

11. In paragraph 10, A pharmaceutical preparation characterized in that the pharmaceutical preparation is in the form of a tablet, pill, powder, capsule, syrup or emulsion.

12. In paragraph 10, A pharmaceutical preparation characterized in that the above pharmaceutical preparation additionally comprises at least one selected from the group consisting of pharmaceutically acceptable carriers, adjuvants and excipients.

13. Use of a compound or a pharmacologically acceptable salt thereof as described in any one of claims 1 to 7 for the treatment of cancer or tumor.