1,3-Benzodioxole derivative compounds and pharmaceutical compositions containing the same

Abstract

The present invention relates to compounds represented by formula I, their stereoisomers, their pharma- ceutically acceptable salts, their hydrates or solvates, and pharmaceutical compositions containing them. TIFF2025504821000198.tif44170

Description

[Technical Field]

[0001] The present invention relates to compounds represented by formula I, their stereoisomers, pharmaceutically acceptable salts thereof, hydrates or solvates thereof, and pharmaceutical compositions containing them. [Background technology]

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

[0003] In general, trimethylation of the fourth lysine from the N-terminus of histone H3 (H3K4me3) activates transcription, while trimethylation of the 27th lysine (H3K27me3) represses transcription. The former is modified by the trithorax complex, and the latter by Polycomb Repressive Complex 2 (PRC2).

[0004] Polycomb genes were identified as genes that regulate embryonic development in Drosophila, and these genes are conserved in vertebrates. In Drosophila, the Enhancer of zeste protein is the catalytic subunit of PRC2, responsible for H3K27 methylation. EZH1 (Enhancer of zeste homolog 1 (Drosophila)) and EZH2 (Enhancer of zeste homolog 2 (Drosophila)) are both mammalian homologs of the Drosophila Enhancer of zeste. The enzymatic activation domains (SET domains) of EZH1 and EZH2 share high homology, and two types of PRC2 exist in humans and mice: PRC2-EZH1 and PRC2-EZH2, each of which uses EZH1 or EZH2 as a catalytic subunit.

[0005] In embryonic stem cells (ES cells), EZH1 and EZH2 function cooperatively or complementary to each other and are involved in the maintenance of ES cells. EZH1 and EZH2 also act cooperatively in the formation and maintenance of hair follicles and Merkel cell differentiation, and have been reported to play an important role in the maintenance of hematopoietic stem cells.

[0006] In follicular lymphoma or diffuse large B-cell lymphoma, somatic mutations at tyrosine 641, alanine 677, and alanine 687 of EZH2 (Y641F, Y641N, Y641S, Y641H, Y641C, A677G, A687V) have been found, and it has been reported that these mutations increase EZH2 activity and significantly increase the amount of H3K27me3 modification in the cells. Compounds that inhibit the enzymatic activity of EZH2 suppress the growth of hematologic cancer cell lines harboring such somatic mutations in EZH2 both in vitro and in vivo (xenograft model).

[0007] This suggests that inhibition of EZH2 enzymatic activity may be useful in treating hematologic cancers with somatic mutations.

[0008] Recently, it has been shown that general inhibition of PRC2 suppresses the progression of acute myeloid leukemia caused by the MLL-AF9 fusion gene, but inhibition of EZH2 alone is not sufficient, suggesting that simultaneous inhibition of PRC2-EZH1 and PRC2-EZH2 is necessary to suppress acute myeloid leukemia caused by the MLL-AF9 fusion gene. Summary of the Invention [Problem to be solved by the invention]

[0009] The present invention provides a 1,3-benzodioxole derivative compound represented by formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof.

[0010] The present invention provides a pharmaceutical composition for the prevention or treatment of diseases associated with EZH1 or EZH2 activity, comprising a compound represented by chemical formula I, its stereoisomer, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof.

[0011] The present invention provides a method for preventing or treating a disease associated with EZH1 or EZH2 activity, comprising administering to an individual a compound represented by chemical formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof.

[0012] The present invention provides the use of a compound represented by chemical formula I, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate for the prevention or treatment of diseases associated with EZH1 or EZH2 activity.

[0013] The present invention provides the use of a compound represented by formula I, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate in the manufacture of a medicament for the prevention or treatment of a disease associated with EZH1 or EZH2 activity. [Means for solving the problem]

[0014] The present invention will be described in more detail below. All combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the specific descriptions described below should not be construed as limiting the scope of the present invention.

[0015] 1,3-benzodioxole derivative compounds, their stereoisomers, pharmaceutically acceptable salts thereof, hydrates or solvates thereof The present invention provides a compound according to any one of the following (1) to (5), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof:

[0016] (1) A compound represented by the following chemical formula I, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate:

[0017] [ka]

[0018] In the above chemical formula I, R1 is a 3- to 12-membered alkyl group containing 1 to 3 heteroatoms independently selected from the group consisting of H; C1-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; C3-C8 cycloalkyl; C3-C8 cycloalkenyl; C1-C6 alkoxy; -membered heterocycloalkyl or heterocycloalkenyl; 6- to 14-membered aryl; 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; -(C=O)-(C1-C6 alkyl); -CN; benzodioxolyl, or halogen; one or more H of the C1-C6 alkyl; C3-C8 cycloalkyl; 3- to 12-membered heterocycloalkyl or heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; 6- to 14-membered aryl; 5- to 12-membered heteroaryl or benzodioxolyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring in R1 may be substituted or unsubstituted by Ra; wherein Ra is C1-C6 alkyl; C1-C6 alkoxy; 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; -NRxRy; or halogen; one or more H of said Ra may be substituted or unsubstituted with Rb; Rb is C1-C6 alkyl; 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; or halogen; R2 is H; C1-C6 alkyl; C3-C8 cycloalkyl; 3- to 12-membered heterocycloalkyl or heterocycloalkenyl containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S; 6- to 14-membered aryl; or 5- to 12-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S; One or more H in R2 may be substituted or unsubstituted with Rc; Rc is C1-C6 alkyl; C3-C8 cycloalkyl; 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; -NRpRq; -(HC=O); -(C=O)-(C1-C6 alkyl); -S(=O)2-(C1-C6 alkyl); or halogen; One or more H in Rc may be substituted or unsubstituted with Rd; Rd is a C1-C6 alkoxy optionally substituted or unsubstituted with halogen; a 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; a 6- to 14-membered aryl; a halogen; or -OH; R3 is H; or C1-C6 alkyl; R4 is H; C1-C6 alkyl; or halogen; R5 and R6 are each independently H; or C1-C6 alkyl; Rx and Ry are each independently H; or C1-C6 alkyl; Rp and Rq are each independently H; C1-C6 alkyl, C3-C8 cycloalkyl, or -(C=O)-(C1-C6 alkyl); V is a single bond; or -(C1-C6 alkylene)-.

[0019] (2) In the above (1), in the above chemical formula I, R1 is a 6- to 14-membered aryl; a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, or a benzodioxolyl; One or more H in R1 may be substituted or unsubstituted with Ra; wherein Ra is C1-C6 alkyl; C1-C6 alkoxy; 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; -NRxRy; or halogen; one or more H of said Ra may be substituted or unsubstituted with Rb; Rb is independently selected from the group consisting of C1-C6 alkyl; N, O, and S. a 3- to 12-membered heterocycloalkyl containing up to 3 heteroatoms in the ring; or halogen; R2 is C3-C8 cycloalkyl; or 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; One or more H in R2 may be substituted or unsubstituted with Rc; Rc is C1-C6 alkyl; C3-C8 cycloalkyl; 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; -NRpRq, or -(C=O)-(C1-C6 alkyl); One or more H in Rc may be substituted or unsubstituted with Rd; Rd is a C1-C6 alkoxy optionally substituted or unsubstituted with halogen; a 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; a 6- to 14-membered aryl; a halogen; or -OH; R3 to R6 are each independently C1-C6 alkyl, Rx and Ry are each independently C1-C6 alkyl; Rp and Rq are each independently H; C1-C6 alkyl, C3-C8 cycloalkyl, or -(C=O)-(C1-C6 alkyl); V is a single bond.

[0020] (3) In the above (1) or (2), in the above chemical formula I, R1 is phenyl, pyridinyl, pyrimidinyl, indolyl, thiophenyl, isoxazolyl, furanyl, benzofuranyl or benzodioxolyl; One or more H in R1 may be substituted or unsubstituted with Ra; The Ra may be methyl, methoxy, -N(CH3)2, -N(CH3)(CH2CH3), -N(CH3)(CH2CH2CH2CH3), morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, [ka] or a halogen, one or more H of said Ra may be substituted or unsubstituted with Rb; Rb is methyl, ethyl, morpholinyl or halogen; R2 is cyclohexyl or piperidinyl; One or more H in R2 may be substituted or unsubstituted with Rc; Rc is methyl, ethyl, propyl, isopropyl, butyl, cyclohexyl, azetidinyl, -NH2, -N(CH3)2, -N(CH3)(CH2CH3), -N(CH3)(CH2CH2CH3), -N(CH3)(CH)(CH3)2, -N(CH3)(CH2CH2CH2CH3), -N(CH3)(CH6H 11 ), -N(CH3)(C=O)CH3 or -(C=O)CH3; One or more H in Rc may be substituted or unsubstituted with Rd; Rd is methoxy, ethoxy which may be substituted or unsubstituted with halogen, propoxy, butoxy which may be substituted or unsubstituted with halogen, isopropoxy, dioxolanyl, phenyl, halogen, or —OH; R3 to R6 are methyl.

[0021] In the present invention, "Cm-Cn" (wherein m and n are each independently an integer of 1 or more) means the number of carbon atoms, for example, "C1-C5 alkyl" means alkyl having 1 to 5 carbon atoms.

[0022] In the present invention, "alkyl" means C unless otherwise specified. n H 2n+1 Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, sec-pentyl, tert-pentyl, isopentyl, sec-isopentyl, neo-pentyl, and n-hexyl.

[0023] In the present invention, unless otherwise specified, "alkenyl" refers to an unsaturated hydrocarbon group containing at least one carbon-carbon double bond as defined above in the alkyl group.

[0024] In the present invention, unless otherwise specified, "alkynyl" refers to an unsaturated hydrocarbon group containing at least one carbon-carbon triple bond as defined above in alkyl.

[0025] In the present invention, "alkoxy" refers to OC unless otherwise specified. n H 2n+1 It means a monovalent group derived from a linear or branched saturated hydrocarbon moiety represented by the formula: Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, and hexoxy.

[0026] In the present invention, unless otherwise specified, "cycloalkyl" refers to a cyclic saturated hydrocarbon group having 3 or more carbon atoms, and the saturated hydrocarbon ring includes both monocyclic and polycyclic structures. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

[0027] In the present invention, unless otherwise specified, "cycloalkenyl" refers to a cyclic group containing at least one carbon-carbon double bond in the cycloalkyl defined above.

[0028] In the present invention, unless otherwise specified, "heterocycloalkyl" refers to a cyclic group in which at least one carbon atom forming the ring of the cycloalkyl is independently replaced with a heteroatom or functional group selected from the group consisting of N, O, S, SO, and SO. Examples of heterocycloalkyl include, but are not limited to, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiophenyl, oxepanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, azetidinyl, aziridinyl, azepanyl, and the like.

[0029] In the present invention, unless otherwise specified, "heterocycloalkenyl" refers to a cyclic group containing at least one carbon-carbon double bond in the heterocycloalkyl defined above.

[0030] In the present invention, unless otherwise specified, "aryl" refers to a monocyclic or polycyclic ring group having one or more fused or unfused aromatic rings. Examples of aryl include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indenyl, anthracenyl, etc.

[0031] In the present invention, unless otherwise specified, "heteroaryl" refers to a monocyclic or polycyclic ring group containing one to three heteroatoms selected from the group consisting of N, O, and S, and having one or more fused or unfused aromatic rings. Examples of heteroaryl include, but are not limited to, thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, purinyl, furopyridinyl, and the like.

[0032] In the present invention, "halogen" may be F, Cl, Br or I.

[0033] (4) In any of the above (1) to (3), the compound represented by the chemical formula I may be a compound listed in the following table.

[0034] [Table 1-1]

[0035] [Table 1-2]

[0036] [Table 1-3]

[0037] [Table 1-4]

[0038] [Table 1-5]

[0039] [Table 1-6]

[0040] [Table 1-7]

[0041] [Table 1-8]

[0042] [Table 1-9]

[0043] [Table 1-10]

[0044] [Table 1-11]

[0045] [Table 1-12]

[0046] (5) The following compounds, their stereoisomers, pharmaceutically acceptable salts thereof, hydrates or solvates thereof: 1) 2-(trans-4-(dimethylamino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 2) 2-(trans-4-(dimethylamino)cyclohexyl)-7-(2-((2S,6R)-2,6-dimethylaminomorpholino)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 3) 7-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 4) 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl- N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-(piperidin-1-yl)pyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide 5) 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-(pyrrolidin-1-yl)pyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide 6) 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(4-(morpholinomethyl)phenyl)benzo[d][1,3]dioxole-5-carboxamide 7) 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7-(1-methyl-1H-indol-5-yl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0047] 8) 7-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-5-yl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 9) 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(4-morpholinophenyl)benzo[d][1,3]dioxole-5-carboxamide 10) 2-(trans-4-(dimethylamino)cyclohexyl)-7-(4-fluorophenyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 11) 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(thiophen-3-yl)benzo[d][1,3]dioxole-5-carboxamide 12) 2-(trans-4-(dimethylamino)cyclohexyl)-7-(5-fluoro-2-methoxyphenyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 13) 2-(trans-4-(dimethylamino)cyclohexyl)-7-(3,5-dimethylisoxazol-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 14) 7-(2,6-Difluoropyridin-3-yl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 15) 7-(2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-5-yl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 16) 2-(trans-4-(dimethylamino)cyclohexyl)-7-(6-(3, 5-Dimethylpiperidin-1-yl)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 17) 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-thiomorpholinopyridin-3-yl)benzo[d][1,3]dioxole-5-carboxamide

[0048] 18) 2-(trans-4-(dimethylamino)cyclohexyl)-7-(furan-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 19) 7-(5-chlorothiophen-2-yl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 20) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-2-(trans-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 21) 2,4-Dimethyl-2-(trans-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-(piperidin-1-yl)pyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide 22) 7-(2-(dimethylamino)pyrimidin-5-yl)-2,4-dimethyl-2-(trans-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 23) 7-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-5-yl)-2,4-dimethyl-2-(trans-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 24) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(trans-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 25) 7-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-5-yl)-2-(trans-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 26) 7-(2-(dimethylamino)pyrimidin-5-yl)-2-(trans-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0049] 27) 7-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-2-(trans-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 28) 2-(trans-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-7-(6-methoxypyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 29) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-( (1st Set, 4th Round) -4-(((S)-2-hydroxypropyl)(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 30) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-2-(trans-4-(methyl(2-propoxyethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 31) 2-(trans-4-((2,2-dimethoxyethyl)(methyl)amino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 32) 2-(trans-4-(((1,3-dioxolan-2-yl)methyl)(methyl)amino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 33) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 34) 2,4-Dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-thiomorpholinopyridin-3-yl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 35) 7-(2-(dimethylamino)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide

[0050] 36) 7-(6-Methoxypyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 37) 7-(6-(3,5-dimethylpiperidin-1-yl)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 38) 7-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 39) 2,4-Dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-(piperidin-1-yl)pyrimidin-5-yl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 40) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(1-((S)-2-hydroxypropyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 41) 2-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 42) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl )-2,4-Dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2-propoxyethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 43) 2-(1-((1,3-dioxolan-2-yl)methyl)piperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 44) Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 45) Stereoisomer A of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide

[0051] 46) 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 47) Stereoisomer B of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 48) 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridinyl) Stereoisomer A of (benzo-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 49) Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 50) Stereoisomer A of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 51) Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(1-isopropylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 52) Stereoisomer A of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(1-isopropylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 53) Stereoisomer B of 2-(1-cyclohexylpiperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 54) Stereoisomer A of 2-(1-cyclohexylpiperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0052] 55) Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-phenethylpiperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 56) Stereoisomer A of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-phenethylpiperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 57) Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(4,4,4-trifluorobutyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 58) Stereoisomer A of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(4,4,4-trifluorobutyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 59) Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 60) Stereoisomer A of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 61) 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)-2-(1-(2,2,2-trifluoromethyl)-2-methylpropional ethyl )piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 62) 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)-2-(1-(2,2,2-trifluoromethyl)-2-methylpropional ethylStereoisomer B of )piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 63) 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)-2-(1-(2,2,2-trifluoromethyl)-2-methylpropional ethyl Stereoisomer A of )piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 64) Stereoisomer B of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)benzo[d][1,3]dioxole-5-carboxamide

[0053] 65) Stereoisomer A of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)benzo[d][1,3]dioxole-5-carboxamide 66) Stereoisomer B of 2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)benzo[d][1,3]dioxole-5-carboxamide 67) Stereoisomer A of 2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)benzo[d][1,3]dioxole-5-carboxamide 68) 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)-2-(1-(2,2,2-trifluoromethyl)-2-methylpropional) ethyl )piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 69) 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)-2-(1-(2,2,2-trifluoromethyl)-2-methylpropional ethyl Stereoisomer B of )piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 70) 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)-2-(1-(2,2,2-trifluoromethyl)-2-methylpropional ethyl Stereoisomer A of )piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 71) Stereoisomer B of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide 72) Stereoisomer A of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide 73) Stereoisomer B of 2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide 74) Stereoisomer A of 2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide

[0054] 75) 7-(2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 76) Stereoisomer B of 7-(2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 77) Stereoisomer A of 7-(2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 78) 7-(2-(ethyl(methyl)amino)pyridine M (6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 79) 7-(2-(ethyl(methyl)amino)pyridine MStereoisomer B of N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 80) 7-(2-(ethyl(methyl)amino)pyridine M Stereoisomer A of (6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 81) Stereoisomer B of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(2-(ethyl(methyl)amino)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 82) Stereoisomer A of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(2-(ethyl(methyl)amino)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 83) Stereoisomer B of 7-(2-(ethyl(methyl)amino)pyrimidin-5-yl)-2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 84) Stereoisomer A of 7-(2-(ethyl(methyl)amino)pyrimidin-5-yl)-2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0055] 85) 7-(6-(ethyl(methyl)amino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoromethyl)amino)-2-(2-methyl-4- ... ethyl )piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 86) Stereoisomer B of 7-(6-(ethyl(methyl)amino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 87) Stereoisomer A of 7-(6-(ethyl(methyl)amino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 88) Stereoisomer B of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(6-(ethyl(methyl)amino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 89) Stereoisomer B of 7-(6-(ethyl(methyl)amino)pyridin-3-yl)-2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 90) 2,4-Dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(4-(piperidin-1-yl)phenyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 91) 2,4-Dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-(piperidin-1-yl)pyridin-3-yl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 92) 2,4-Dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-thiomorpholinopyrimidin-5-yl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 93) 2',2'-Difluoro-2,7-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-[4,5'-bibenzo[d][1,3]dioxole]-6-carboxamide 94) 2,7-Dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-[4,5'-bibenzo[d][1,3]dioxole]-6-carboxamide

[0056] 95) 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-2,7-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-[4,5'-bibenzo[d][1,3]dioxole]-6-carboxamide 96) 7-(Benzofuran-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 97) 7-(Benzofuran-5-yl)-2-(1-(2,2-difluoroethyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 98) 7-(6-(butyl(methyl)amino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 99) 7-(6-(butyl(methyl)amino)pyridine M 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 100) 2-(trans-4-aminocyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride 101) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(trans-4-(3-hydroxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 102) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(3-(2,2,2-trifluoromethyl)propan-1-yl)methyl) Ethoxy )Azetidin-1-yl)cyclohexyl)benzo[d][1,3]dioxole-5-carboxamide 103) 2-(trans-4-(3-(2,2-difluoroethoxy)azetidin-1-yl)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0057] 104) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(3-(4,4,4-trifluorobutoxy)azetidin-1-yl)cyclohexyl)benzo[d][1,3]dioxole-5-carboxamide 105) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(trans-4-(3-isopropoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 106) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(trans-4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 107) Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-2-(trans-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 108) Stereoisomer A of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-2-(trans-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 109) 2-(trans-4-((2,2-difluoroethyl ) (Methyl)amino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 110) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(trans-4-(isopropyl(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 111) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(trans-4-(ethyl(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 112) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-2-(trans-4-(methyl(phenethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0058] 113) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-2-(trans-4-(methyl( 4,4,4-trifluorobutyl )amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 114) 2-(trans-4-(cyclohexyl(methyl)amino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 115) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(2,2,2-trifluoro-N-methylacetamido)cyclohexyl)benzo[d][1,3]dioxole-5-carboxamide

[0059] In the present invention, "pharmaceutically acceptable" means that the compound is physiologically acceptable and does not normally cause gastrointestinal disorders, allergic reactions such as dizziness, or similar reactions when administered to an individual. This can mean not rubbing.

[0060] The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods known to those of ordinary skill in the art.

[0061] The pharmaceutically acceptable salt of the present invention is not particularly limited as long as it is prepared using an acid that forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion. Examples include, but are not limited to, inorganic acid salts prepared with hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc.; organic acid salts prepared with tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc.; and sulfonates prepared with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc. In one embodiment of the present invention, the pharmaceutically acceptable salt may be a hydrochloride salt.

[0062] In the present invention, the compounds according to any of (1) to (5) above may have one or more asymmetric carbon centers and may therefore exist as enantiomeric mixtures, including racemic mixtures, single enantiomers (optical isomers), diastereomeric mixtures, and single diastereomers. These isomers can be separated by conventional techniques, such as column chromatography or HPLC, or can be stereospecifically synthesized using optically pure starting materials and / or reagents of known sequence. Specifically, the stereoisomers may be optical isomers.

[0063] In the present invention, the "hydrate" is a compound according to any one of (1) to (5) above or a pharmaceutically acceptable salt thereof bound to water by non-covalent intermolecular forces, and may contain a stoichiometric or non-stoichiometric amount of water.

[0064] In the present invention, the "solvate" is a compound according to any one of (1) to (5) above or a pharmaceutically acceptable salt thereof bound to a non-aqueous solvent by non-covalent intermolecular forces, and may contain the solvent in a stoichiometric or non-stoichiometric amount.

[0065] The compounds according to any one of (1) to (5) of the present invention, their stereoisomers, pharmaceutically acceptable salts thereof, hydrates or solvates thereof inhibit the activity of EZH1 and / or EZH2, thereby suppressing cell proliferation, and can be usefully used in the prevention or treatment of various diseases related thereto.

[0066] That is, the compounds according to any of (1) to (5) of the present invention, their stereoisomers, pharmaceutically acceptable salts thereof, hydrates or solvates thereof can be usefully used in the prevention or treatment of diseases associated with the activity of EZH1 and / or EZH2.

[0067] Method for producing 1,3-benzodioxole derivative compounds The present invention provides a method for producing a compound according to any one of the above (1) to (5), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0068] The compound according to any one of (1) to (5) of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof may be produced, for example, by the method of the following reaction scheme 1, but is not limited thereto. [ka]

[0069] In the reaction formula 1, R1 to R6 and V in C1 to C4 are each defined as in the compound represented by the chemical formula I.

[0070] [Step 1] Cross-coupling reaction In this step, compound C4 is stirred in a reaction-inert solvent in the presence of a base, using a palladium catalyst or a nickel catalyst; and an equivalent or excess amount of a boronic acid, a boronic acid pinacol ester (in the case of Suzuki-Miyaura coupling), an organotin reagent (in the case of Stille coupling), or an alkene compound (in the case of Heck reaction) under heating for 0.5 to 24 hours to produce compound C3.

[0071] Specifically, Compound C3 can be produced by stirring at 60 to 120°C for 0.5 to 12 hours. The solvent is not particularly limited as long as it is inert to the reaction, but examples include methanol, ethanol, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, water, N,N-dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, and mixtures thereof. Examples of the palladium catalyst include tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, tris(dibenzylideneacetone)dipalladium, palladium acetate, palladium acetylacetone, and bis(triphenylphosphine)palladium dichloride. Examples of the nickel catalyst include [1,1'-bis(diphenylphosphino)ferrocene]nickel dichloride and bis(triphenylphosphine)nickel dichloride. The base may be an organic base such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) or 1,5-diazabicyclo[4.3.0]-5-nonene (DBN); or an inorganic base such as potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium phosphate or sodium phosphate.

[0072] [Step 2] Hydrolysis reaction In this step, compound C3 is stirred in a solvent with an equal or excess amount of a basic aqueous solution for 3 to 96 hours under cooling or heating to produce compound C2. Specifically, compound C2 can be produced by stirring at room temperature (10 to 25°C) to 60°C for 3 to 48 hours. The solvent is not particularly limited as long as it does not inhibit the reaction, and may be methanol, ethanol, tetrahydrofuran, dimethoxyethane, acetonitrile, or a mixture thereof. The base may be an inorganic base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide.

[0073] [Step 3] Amidation reaction This step produces compound C1 by stirring compound C2 in an inert solvent with an equivalent or excess amount of the corresponding amine and a condensing agent under cooling or heating for 1 to 24 hours. Specifically, compound C1 can be produced by stirring at room temperature to 120°C for 1 to 8 hours. The solvent is not particularly limited as long as it is inert to this reaction, but N,N-dimethylformamide, dimethylacetamide, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, or a mixture thereof may be used. The condensing agent may be pentafluorophenyl trifluoroacetate, dicyclocarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1,1'-carbonyldiimidazole, or the like. An additive or a base may also be used in the reaction. The additive may be N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), etc. The base may be an organic base such as triethylamine or diisopropylethylamine; or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide, or sodium hydroxide.

[0074] Compositions containing 1,3-benzodioxole derivative compounds, methods of treatment using the same, and Its uses The present invention provides a pharmaceutical composition comprising, as an active ingredient, the compound according to any one of (1) to (5) above, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof.

[0075] The present invention relates to a compound for enhancing zeste homolog 1 (EZH1) or enhancing zeste homolog 2 (EZH2), which comprises, as an active ingredient, a compound according to any one of (1) to (5), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof. The present invention provides a pharmaceutical composition for preventing or treating diseases associated with the activity of zeste homolog 2).

[0076] In the present invention, "prevention" means any action of suppressing or delaying the onset of a disease by administering a compound according to any of (1) to (5) of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof.

[0077] In the present invention, "treatment" means any action of administering a compound according to any of (1) to (5) of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof, to improve or beneficially change the symptoms of an individual suspected of or having a disease.

[0078] In the present invention, "diseases associated with EZH1 or EZH2 activity" refers to diseases that can be prevented or treated by inhibiting the activity of one or more enzymes selected from EZH1 and EZH2. "The activity of one or more enzymes selected from EZH1 and EZH2" refers to the enzyme activity of EZH1 and / or EZH2 that transfers a methyl group to lysine 27 of histone H3.

[0079] In the present invention, the disease associated with EZH1 or EZH2 activity may be a hematological cancer affecting the blood, bone marrow, or lymphatic system, and the hematological cancer may be one or more selected from lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, leukemia, and multiple myeloma.

[0080] In this regard, in a specific embodiment of the present invention, the inhibitory activity against EZH1 and / or EZH2 and the growth-suppressing activity of blood cancer cells of the compounds according to any of (1) to (5) of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof were confirmed.

[0081] The pharmaceutical composition of the present invention can inhibit the activity of one or more enzymes selected from EZH1 and EZH2, and can be usefully used in the prevention or treatment of various diseases associated therewith.

[0082] The pharmaceutical composition of the present invention may further contain one or more pharmaceutically acceptable carriers in addition to the compound according to any one of (1) to (5), its stereoisomer, its pharmaceutically acceptable salt, or its hydrate or solvate. The pharmaceutically acceptable carrier may be one commonly used in the art, specifically, lactose, dextrose, sucrose, sorbitol, mannitol, glycine, starch, tragacanth gum, acacia gum, calcium phosphate, calcium chloride, sodium chloride, alginic acid, sodium alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidine, polyethylene glycol, cellulose, water, ethanol, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, magnesium aluminum silicate, silica, orange essence, strawberry essence, vanilla essence, or mineral oil, but is not limited thereto.

[0083] In addition to the above ingredients, the pharmaceutical composition of the present invention may further contain binders, isotonicity agents, adsorbents, disintegrants, antioxidants, lubricants, fillers, solubilizers, solubilizers, lubricants, wetting agents, sweeteners, flavorings, emulsifiers, suspending agents, preservatives, dispersing agents, or stabilizers. The pharmaceutical composition of the present invention may be formulated into oral preparations such as tablets, pills, powders, granules, capsules, suspensions, emulsions, oral solutions, emulsions, syrups, external preparations, suppositories, or sterile injectable solutions using pharmaceutically acceptable carriers and excipients, and may be manufactured in unit dose forms or in multi-volume containers. The formulations may be prepared by conventional methods used in the art, or by methods described in Remington's Pharmaceutical Sciences (1999). th They may be prepared by the methods disclosed in "Therapeutic Agents for the Treatment of Diabetes" (ed., 1995), and may be formulated into various preparations depending on the disease or component.

[0084] The pharmaceutical composition of the present invention may be administered orally or parenterally depending on the intended method, and may preferably be administered orally, but is not limited thereto.

[0085] Non-limiting examples of oral administration formulations include, but are not limited to, tablets, pills, powders, capsules, syrups, emulsions, etc. When the pharmaceutical composition of the present invention is an oral administration formulation, pharmaceutically acceptable carriers that may be 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.

[0086] Non-limiting examples of parenteral administration preparations include, but are not limited to, injections, etc. When the pharmaceutical composition of the present invention is a parenteral administration preparation, pharmaceutically acceptable carriers may be, but are not limited to, water, saline, aqueous glucose solution, aqueous sugar analogue solution, alcohol, glycol, ether, oil, fatty acid, fatty acid ester, glyceride, etc.

[0087] The daily dose of the compound according to any one of (1) to (5) of the present invention, its stereoisomer, its pharmaceutically acceptable salt, or its hydrate or solvate may be about 0.1 to 2,000 mg / day for an adult weighing 70 kg, but is not limited thereto, and may be administered once or several times a day in divided doses. The dose varies depending on the patient's health condition, age, weight, sex, administration method, severity of the disease, etc.

[0088] The pharmaceutically effective amount and effective dosage of the pharmaceutical composition of the present invention can be varied depending on the formulation method, mode of administration, administration time and / or route of administration, etc., and can be varied depending on various factors including the type and degree of response to be achieved by administration of the pharmaceutical composition, the type, age, weight, general health condition, symptoms and degree of disease, sex, dietary content, excretion, drugs administered to the individual simultaneously or at different times, other components of the composition, etc., as well as similar factors well known in the medical field. A person of ordinary skill in the art can easily determine and prescribe an effective dosage for the intended treatment.

[0089] The pharmaceutical composition of the present invention may be administered once a day or in divided doses. The pharmaceutical composition of the present invention may be administered as a single therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. Taking all of the above factors into consideration, the amount that provides the maximum effect with the minimum amount without side effects should be administered, which can be easily determined by one of ordinary skill in the art to which the present invention pertains.

[0090] The pharmaceutical composition of the present invention can exhibit excellent effects even when used alone, but may also be used in combination with various other methods such as hormone therapy and drug therapy to further enhance therapeutic efficiency.

[0091] The present invention provides a method for preventing or treating a disease associated with EZH1 or EZH2 activity, which comprises administering to an individual a compound according to any one of (1) to (5), its stereoisomer, a pharmaceutically acceptable salt thereof, its hydrate or solvate, or a pharmaceutical composition containing the same.

[0092] In the present invention, "administration" means introducing a given substance into an individual by an appropriate method.

[0093] In the present invention, "individual" means any animal, such as a human, rat, mouse, or livestock, that has or may develop a disease associated with EZH1 or EZH2 activity, and specifically may be a mammal, including a human, but is not limited to this.

[0094] The method of the present invention for preventing or treating diseases associated with EZH1 or EZH2 activity may involve administering a therapeutically effective amount of a compound according to any one of (1) to (5), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0095] In the present invention, a "therapeutically effective amount" refers to an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to any medical treatment and that does not cause side effects, which may be determined by one of ordinary skill in the art depending on factors including the patient's sex, age, weight, health condition, type and severity of the disease, drug activity, drug sensitivity, administration method, administration time, administration route, excretion rate, treatment duration, co-administered or concomitant drugs, and other factors well known in the medical field. It is desirable that a specific therapeutically effective amount for a particular patient will vary depending on various factors, including the type and degree of response to be achieved, the specific composition, including whether or not other drugs are used, the patient's age, weight, general health condition, sex, and dietary content, administration time, administration route, and excretion rate of the composition, treatment duration, drugs used in combination with or concomitantly with the specific composition, and similar factors well known in the medical field.

[0096] The method for preventing or treating a disease associated with EZH1 or EZH2 activity of the present invention involves administering a compound according to any one of (1) to (5), its stereoisomer, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, not only to treat the disease itself before symptoms appear, but also to inhibit or prevent the symptoms. In disease management, the prophylactic or therapeutic dose of a particular active ingredient varies depending on the characteristics and severity of the disease or condition and the route by which the active ingredient is administered. The dose and dose frequency vary depending on the age, weight, and response of the individual patient. Appropriate doses and administration methods can be readily selected by those skilled in the art, taking such factors into consideration. The method for preventing or treating a disease associated with EZH1 or EZH2 activity of the present invention may further include administering a therapeutically effective amount of an active ingredient useful for preventing or treating the disease in addition to a compound according to any one of (1) to (5), its stereoisomer, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof. A synergistic or additive effect can be obtained by using a compound according to any one of (1) to (5), its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate together with an additional active agent.

[0097] The present invention provides use of a compound according to any one of (1) to (5), its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate, or a pharmaceutical composition containing the same, for the prevention or treatment of a disease associated with EZH1 or EZH2 activity.

[0098] The present invention provides use of a compound according to any one of (1) to (5), its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate, or a pharmaceutical composition containing the same, in the manufacture of a medicament for the prevention or treatment of a disease associated with EZH1 or EZH2 activity.

[0099] To produce a drug, a compound according to any one of (1) to (5) of the present invention, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate may be mixed with a pharmaceutically acceptable adjuvant, diluent, carrier, etc., and produced as a combined preparation together with other active ingredients, which can have a synergistic effect.

[0100] The items described in each section of the present invention, i.e., 1,3-benzodioxole derivative compounds, methods for producing the same, pharmaceutical compositions containing the same, therapeutic methods using the same, and uses thereof, are equally applicable unless they contradict each other. [Effects of the Invention]

[0101] The compound represented by chemical formula I of the present invention, its stereoisomers, pharmaceutically acceptable salts thereof, hydrates or solvates thereof, and pharmaceutical compositions containing them as active ingredients can be useful in the prevention or treatment of diseases associated with EZH1 or EZH2 activity. DETAILED DESCRIPTION OF THE INVENTION

[0102] The present invention will be described in more detail below with reference to examples. It will be obvious to those skilled in the art that these examples are merely illustrative of the present invention and should not be construed as limiting the scope of the present invention.

[0103] Preparation of Compounds of Formula I The compounds of formula I of the present invention can be prepared by the following methods. Unless otherwise specified, starting materials can be purchased or prepared by known methods. Any examples or use of exemplary terms provided in this application are merely illustrative of the present invention and are not intended to limit the scope of the present invention.

[0104] <Production example> In the following production examples, specific rotation was measured using a JASCO P-2000 Digital Polarimeter.

[0105] Production Example 1. Synthesis of 2-(trans-4-(dimethylamino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide and its hydrochloride salt (Compound 1 and its hydrochloride salt)

[0106] [ka]

[0107] [Step 1] Synthesis of methyl 2-(trans-4-aminocyclohexyl)-7-bromo-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate hydrochloride Methyl 7-bromo-2-(trans-4-((tert-butoxycarbonyl)amino) (cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate (20 g, 41.3 mmole) was added to 1 M aqueous hydrochloric acid (80 mL) and stirred at elevated temperature. After the reaction was complete, the internal temperature was cooled to room temperature, and isopropyl alcohol (80 mL) was added dropwise and stirred. The resulting crystals were filtered and dried at an internal temperature of 60°C to obtain the title compound (17.2 g).

[0108] [Step 2] Synthesis of methyl 7-bromo-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate Methanol (173 mL) was added to the compound (17 g, 41 mmole) obtained in [Step 1] above and stirred at room temperature. Dimethylamine (23 mL) was added and stirred. 35% aqueous formaldehyde solution (12 mL) was slowly added and stirred. After cooling, sodium triacetoxyborohydride (35 g) was slowly added and stirred at room temperature. After the reaction was complete, dichloromethane (173 mL) was added and aqueous sodium bicarbonate solution (173 mL) was added and washed. Magnesium sulfate was then added, filtered, and concentrated to obtain the title compound (16.8 g).

[0109] [Step 3] Synthesis of methyl 2-(trans-4-(dimethylamino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate Dioxane (160 mL) and purified water (80 mL) were added to the compound (16 g, 39 mmol) obtained in [Step 2]. Next, (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (16 g), tetrakis(triphenylphosphine)palladium (4.5 g), and sodium carbonate (12.3 g) were added, followed by heating and stirring. After the reaction was complete, hexane was added, and the precipitated solid was filtered through silica / Celite. The filtrate was washed with purified water (160 mL). Magnesium sulfate was added, filtered, and concentrated to give the title compound (20 g).

[0110] [Step 4] Synthesis of 2-(trans-4-(dimethylamino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylic acid Tetrahydrofuran (160 mL) and methanol (80 mL) were added to the compound (20 g, 38.2 mmole) obtained in Step 3 above. 2N aqueous sodium hydroxide solution (76 mL) was added, and the mixture was heated and stirred. After the reaction was complete, 2N aqueous hydrochloric acid solution (57 mL) was added and the mixture was concentrated. The resulting crystals were filtered, and ethyl acetate (400 mL) was added. Purified water (200 mL) was then added and the mixture was washed, magnesium sulfate was added, and the mixture was filtered. The mixture was then concentrated to obtain the title compound (19.2 g).

[0111] [Step 5] Synthesis of pentafluorophenyl 2-(trans-4-(dimethylamino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate Dimethylformamide (95 mL) was added to the compound (19 g, 37.3 mmol) obtained in Step 4 above, followed by triethylamine (21 mL). Pentafluorophenyl trifluoroacetate (10 mL) was then added dropwise, and the mixture was stirred at room temperature. After the reaction was completed, the next reaction was carried out.

[0112] [Step 6] 2-(trans-4-(dimethylamino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-di Synthesis of methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 1)

[0113] [ka] Triethylamine (16 mL) was added to the reaction mixture from Step 5. Then, 3-(aminomethyl)-6-methyl-4-(methylthio)pyridin-2(1H)-one hydrochloride (9.2 g) was added and stirred at an internal temperature of 50°C. After the reaction was completed, the reaction mixture was added dropwise to purified water (1,900 mL) and the resulting solid was filtered. The solid was dissolved in methylene chloride (380 mL), and the aqueous layer was separated. Magnesium sulfate was added, filtered, and concentrated to obtain the title compound (25 g).

[0114] 1 H NMR(Chloroform-d):8.53(d,1H),7.68(d,1H),7.20(t,1H),7.05(s,1H),6.53(d,1H),5.91(s,1H),4.58(d,2H),3.97(d,2 H),3.66(m,2H),2.47(t,2H),2.42(s,3H),2.25(d,9H),2.13(m,4H),1.95(m,4H),1.78(t,1H),1.54(s,3H),1.22(m,10H). LC-MS (ESI, m / z) = 676.4 (M+H+)

[0115] [Step 7] Synthesis of methyl 2-(trans-4-(dimethylamino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride (hydrochloride salt of Compound 1) The compound (25 g, 37 mmol) obtained in Step 6 was added to 1 M aqueous hydrochloric acid (130 mL), heated, and stirred. After the reaction was completed, the mixture was concentrated, dissolved in methanol (50 mL), and gradually added to ethyl acetate (200 mL) and stirred. The mixture was then filtered and dried at an internal temperature of 60°C to obtain the title compound (24 g).

[0116] Preparation Example 2. Synthesis of 2-(trans-4-(dimethylamino)cyclohexyl)-7-(2-((2S,6R)-2,6-dimethylaminomorpholino)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 2)

[0117] [ka]

[0118] The same reaction as in Preparation Example 1 was carried out except that (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 3] of Preparation Example 1, to obtain the title compound (30 mg).

[0119] 1H NMR(Chloroform-d):8.56(s,2H),7.10(s,1H),7.00(s,1H),5.92(s,1H),4.57(d,2H),4.56(d,2H),3. 58(s,2H),2.58(t,2H),2.41(s,3H),2.26(s,9H),1.94(s,4H),1.78(m,1H),1.54(s,3H),1.19(s,9H). LC-MS (ESI, m / z) = 677.4 (M+H + )

[0120] Preparation Example 3. Synthesis of 7-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 3)

[0121] [ka]

[0122] The same reaction as in Preparation Example 1 was carried out except that 2-(4,4-difluoropiperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 3] of Preparation Example 1, to obtain the title compound (25 mg).

[0123] 1 H NMR(D2O):8.23(s,1H),8.11(s,1H),7.29(d,1H),7.01(s,1H),6.25(s,1H),4.31(s,2H),3.76(m,4H),3.09(m ,1H),2.71(s,3H),2.38(s,3H),2.31(m,7H),2.12(m,8H),2.03(s,1H),1.65(s,3H),1.58(m,2H),1.42(m,2H). LC-MS (ESI, m / z) = 682.4 (M+H + )

[0124] Preparation Example 4. Synthesis of 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-(piperidin-1-yl)pyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 4)

[0125] [ka]

[0126] In Step 3 of Production Example 1, (2S,6R)-2,6-dimethyl-4-(5-(4,4 The same reaction as in Preparation Example 1 was carried out except that 2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine was used instead of 2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine, and the title compound (26 mg) was obtained.

[0127] 1 H NMR(Chloroform-d):8.55(s,2H),7.19(t,1H),7.00(s,1H),5.92(s,1H),4.58(d,2H),3.73(t,4H),2. 42(s,3H),2.26(d,9H),2.17(s,4H),1.95(d,4H),1.79(t,1H),1.64(d,2H),1.54(s,7H),1.21(m,4H). LC-MS (ESI, m / z) = 647.4 (M+H + )

[0128] Preparation Example 5. Synthesis of 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-(pyrrolidin-1-yl)pyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 5)

[0129] [ka]

[0130] The same reaction as in Preparation Example 1 was carried out except that 2-(pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 3] of Preparation Example 1, to obtain the title compound (70 mg).

[0131] 1 H NMR(Methanol-d3):8.85(s,1H),7.23(s,1H),6.36(m,1H),4.51(s,2H),3.70(s3H),3.20(s,1H),2.7 5(s,6H),2.54(m,4H),2.31(s,7H),2.10(m,8H),2.00(m,1H),1.65(s,3H),1.60(m,2H),1.56(m,2H). LC-MS (ESI, m / z) = 633.4 (M+H + )

[0132] Preparation Example 6. Synthesis of 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(4-(morpholinomethyl)phenyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 6)

[0133] [ka]

[0134] The same reaction as in Preparation Example 1 was carried out except that 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 3] of Preparation Example 1, to obtain the title compound (78 mg).

[0135] 1 H NMR(Chloroform-d):7.53(m,2H),7.27(m,2H),7.25(s,1H),5.90(s,1H),4.64(m2 H),3.80(6m 6H),3.04(s,1H),2.45(s,3H),2.36(s,3H),2.33(s,8H),2.00(m,7H),1.64(m,5H),1.55(m,5H). LC-MS (ESI, m / z) = 661.4 (M+H + )

[0136] Preparation Example 7. Synthesis of 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7-(1-methyl-1H-indol-5-yl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 7)

[0137] [ka]

[0138] The same reaction as in Preparation Example 1 was carried out except that 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 3] of Preparation Example 1, to obtain the title compound (67 mg).

[0139] 1 H NMR(Methanol-d3):7.85(s,1H),7.32(d,1H),7.18(d,1H),7.12(s,1H),7.11(d,1H),6.41(d,1H),6.20(s,1H) ),4.51(s,2H),3.75(s,3H),2.47(s,3H),2.24(m,12H),1.98(dd,4H),1.80(t,1H),1.58(s,3H),1.26(m,5H). LC-MS (ESI, m / z) = 615.4 (M+H + )

[0140] Preparation Example 8. Synthesis of 7-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-5-yl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 8)

[0141] [ka]

[0142] The same reaction as in Preparation Example 1 was carried out except that 2-(4,4-difluoropiperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 3] of Preparation Example 1, to obtain the title compound (99 mg).

[0143] 1 H NMR(Chloroform-d):8.59(s,2H),7.17(t,1H),7.04(s,1H),5.92(s,1H),4.57(d,2H),3.91(t, 4H),2.42(s,3H),2.28(m,9H),2.17(s,4H),1.92(m,8H),1.78(t,1H),1.55(s,3H),1.21(m,4H). LC-MS (ESI, m / z) = 683.3 (M+H + )

[0144] Preparation Example 9. Synthesis of 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(4-morpholinophenyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 9)

[0145] [ka]

[0146] The same reaction as in Preparation Example 1 was carried out except that 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 3] of Preparation Example 1, to obtain the title compound (56 mg).

[0147] 1 H NMR(Chloroform-d):7.55(m,2H),7.53(t,1H),7.25(s,1H),6.79(d,2H),5.93(s,3H),4.62(d,2H),3.82(m,4) H),3.08(m,4H),2.45(s,3H),2.32(m,10H),2.14(s,3H),2.00(m,4H),1.99(m,1H),1.57(s,3H),1.26(m,4H). LC-MS (ESI, m / z) = 647.4 (M+H + )

[0148] Preparation Example 10. Synthesis of 2-(trans-4-(dimethylamino)cyclohexyl)-7-(4-fluorophenyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 10)

[0149] [ka]

[0150] The same reaction as in Preparation Example 1 was carried out, except that 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 3] of Preparation Example 1, to obtain the title compound (78 mg).

[0151] 1 H NMR(Chloroform-d):7.58(m,2H),7.19(t,1H),7.08(s,1H),7.00(t,2H),5.92(s,1H),4.60(d,2H),2. 44(s,3H),2.31(s,3H),2.25(m,10H),2.09(m,4H),1.96(m,4H),1.80(t,1H),1.57(s,3H),1.23(m,4H). LC-MS (ESI, m / z) = 580.3 (M+H+ )

[0152] Preparation Example 11. Synthesis of 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(thiophen-3-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 11)

[0153] [ka]

[0154] The same reaction as in Preparation Example 1 was carried out except that 4,4,5,5-tetramethyl-2-(thiophen-3-yl)-1,3,2-dioxaborolane was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 3] of Preparation Example 1, to obtain the title compound (30 mg).

[0155] 1 H NMR(Chloroform-d):7.59(d,1H),7.39(m,1H),7.25(m,1H),7.23(m,1H),7.19(s,1H),5.92(s,1H),4.60(d, 2H),2.43(s,3H),2.29(s,3H),2.24(s,6H),2.14(m,4H),1.97(t,4H),1.80(t,1H),1.58(s,3H),1.23(m,4H). LC-MS (ESI, m / z) = 568.3 (M+H + )

[0156] Preparation Example 12. Synthesis of 2-(trans-4-(dimethylamino)cyclohexyl)-7-(5-fluoro-2-methoxyphenyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 12)

[0157] [ka]

[0158] The same reaction as in Preparation Example 1 was carried out, except that 2-(5-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 3] of Preparation Example 1, to obtain the title compound (35 mg).

[0159] 1 H NMR(Chloroform-d):7.02(m,1H),6.98(m,2H),6.92(m,1H),6.79(m,1H),5.91(s,1H),4.58(d,2H),3.68(s, 3H),2.44(s,3H),2.32(s,2H),2.25(s,6H),2.13(s,4H),1.94(m,3H),1.79(t,1H),1.53(s,3H),1.20(m,4H). LC-MS (ESI, m / z) = 610.3 (M+H + )

[0160] Preparation Example 13. Synthesis of 2-(trans-4-(dimethylamino)cyclohexyl)-7-(3,5-dimethylisoxazol-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 13)

[0161] [ka]

[0162] The same reaction as in Preparation Example 1 was carried out except that 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 3] of Preparation Example 1, to obtain the title compound (80 mg).

[0163] 1 H NMR(Chloroform-d):7.01(m,1H),6.74(s,1H),5.97(s,1H),4.57(m,2H),2.45(s,3H),2.2 8(m,5H),2.25(s,6H),2.19(s,3H),2.16(s,2H),2.12(m,1H),1.92(d,4H),1.76(t,1H),1.51(s,2H),1.18(m,4H). LC-MS (ESI, m / z) = 581.4 (M+H + )

[0164] Preparation Example 14. Synthesis of 7-(2,6-difluoropyridin-3-yl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 14)

[0165] [ka]

[0166] The same reaction as in Preparation Example 1 was carried out except that 2,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 3] of Preparation Example 1, to obtain the title compound (63 mg).

[0167] 1 H NMR(Methanol-d3):8.15(s,1H),7.05(s,2H),6.42(s,1H),4.52(s,2H),2.82(s,1H),2.32(s,6) H),2.26(s,3H),2.13(m,5H),2.10(m,5H),1.61(s,6H),1.60(s,3H),1.55(m,2H),1.53(m,4H). LC-MS (ESI, m / z) = 599.0 (M+H + )

[0168] Preparation Example 15. Preparation of 7-(2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-5-yl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 15)

[0169] [ka]

[0170] The same reaction as in Preparation Example 1 was carried out except that 7-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)-2-oxa-7-azaspiro[3.5]nonane was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 3] of Preparation Example 1, to obtain the title compound (63 mg).

[0171] 1H NMR(Chloroform-d):8.58(s,1H),7.11(m,1H),7.04(d,1H),5.98(s,1H),4.61(dd,2H),4.47(s,2H),3.75(s,2H),2 .45(m,8H),2.36(s,3H),2.35(s,3H),2.29(m,5H),1.94(m,2H),1.90(m,2H),1.80(s,1H),1.56(m,3H),1.30(m,5H). LC-MS (ESI, m / z) = 689.4 (M+H + )

[0172] Preparation Example 16. Synthesis of 2-(trans-4-(dimethylamino)cyclohexyl)-7-(6-(3,5-dimethylpiperidin-1-yl)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 16)

[0173] [ka]

[0174] The same reaction as in Preparation Example 1 was carried out except that 2-(3,5-dimethylpiperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 3] of Preparation Example 1, to obtain the title compound (30 mg).

[0175] 1H NMR(Chloroform-d):8.52(s,1H),7.67(s,1H),7.25(m,1H),7.06(s,1H),6.62(m,1H),5.94(s,1H),4.62(d,2H),4.24(d,2H),2. 45(s,3H),2.39(s,6H),2.30(m,5H),2.30(s,3H),2.29(m,4H),2.17(m,2H),1.57(m,2H),1.56(m,3H),1.28(m,4H),0.94(m,6H). LC-MS (ESI, m / z) = 675.1 (M+H + )

[0176] Preparation Example 17. Synthesis of 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-thiomorpholinopyridin-3-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 17)

[0177] [ka] The same reaction as in Preparation Example 1 was carried out except that 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)thiomorpholine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 3] of Preparation Example 1, to obtain the title compound (20 mg).

[0178] 1H NMR(Chloroform-d):8.52(s,1H),7.70(d,1H),7.27(d,1H),6.52(d,1H),5.94(s,1H),4.61(m,2H),3.91(m,4H),2. 61(s,5H),2.45(s,3H),2.39(m,6H),2.31(s,3H),2.16(s,3H),2.15(m,4H),2.04(m,1H),2.01(s,3H),1.29(s,4H). LC-MS (ESI, m / z) = 665.0 (M+H + )

[0179] Preparation Example 18. 2-(trans-4-(dimethylamino)cyclohexyl)-7-(furan-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-o Synthesis of benzo[d][1,3]dioxole-5-carboxamide (18)

[0180] [ka]

[0181] The same reaction as in Preparation Example 1 was carried out, except that 2-(furan-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 3] of Preparation Example 1, to obtain the title compound (73 mg).

[0182] 1 H NMR(Chloroform-d):7.81(s,1H),7.36(t,1H),7.19(t,1H),7.06(s,1H),6.66(s,1H),5.95(s,1H),4. 59(m,2H),2.44(s,3H),2.24(m,9H),2.18(m,4H),1.95(m,4H),1.80(t,1H),1.58(s,3H),1.21(m,4H). LC-MS (ESI, m / z) = 552.3 (M+H + )

[0183] Preparation Example 19. Synthesis of 7-(5-chlorothiophen-2-yl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 19)

[0184] [ka]

[0185] The same reaction as in Preparation Example 1 was carried out except that 2-(5-chlorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 3] of Preparation Example 1, to obtain the title compound (93 mg).

[0186] 1 H NMR(Chloroform-d):7.25(m,1H),7.11(d,1H),7.04(s,1H),6.76(d,1H),5.95(s,1H),4.57(t,3H),2. 43(t,4H),2.35(s,1H),2.26(m,14H),2.19(m,7H),1.98(m,5H),1.79(t,1H),1.59(m,5H),1.21(m,6H) LC-MS (ESI, m / z) = 603.3 (M+H + )

[0187] Preparation Example 20. Synthesis of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-2-(trans-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide and its hydrochloride salt (Compound 20 and its hydrochloride salt)

[0188] [ka]

[0189] [Step 1] Synthesis of methyl 7-bromo-2-(trans-4-(tert-butoxycarbonyl)(methyl)amino)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate Methyl 7-bromo-2-(trans-4((tert-butoxycarbonyl)amino) Dimethylformamide (75 mL) was added to (cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate (15 g, 30.97 mmole), and methyl iodide (16 mL) was added. The internal temperature was then cooled to -5°C or below. Sodium hydride (3.372 g) was added, and the mixture was warmed to room temperature and stirred. After the reaction was complete, ethyl acetate (300 mL) was added, followed by purified water (300 mL) for washing. Magnesium sulfate was added, and the mixture was filtered and concentrated to give the title compound (16 g).

[0190] [Step 2] Synthesis of methyl-2-(trans-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethoxybenzo[d][1,3]dioxole-5-carboxylate Dioxane (150 mL) and purified water (75 mL) were added to the compound (15 g, 30.10 mmol) obtained in Step 1 above. Next, (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (12.8 g) and tetrakis(triphenylphosphine)palladium (3.58 g) were added, followed by sodium carbonate (13.1 g), and the mixture was heated and stirred. After the reaction was complete, hexane was added, and the precipitated solid was filtered through silica / Celite. The filtrate was washed with purified water (450 mL). Magnesium sulfate was added, filtered, and concentrated to give the title compound (18 g).

[0191] [Step 3] Synthesis of 2-(trans-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylic acid Tetrahydrofuran (150 mL) and methanol (75 mL) were added to the compound (18 g, 29.6 mmole) obtained in Step 2 above. 2N aqueous sodium hydroxide solution (74 mL) was added, and the mixture was heated and stirred. After the reaction was complete, 2N aqueous hydrochloric acid solution (74 mL) and ethyl acetate (350 mL) were added. Purified water (350 mL) was then added for washing, magnesium sulfate was added, and the mixture was filtered. The mixture was then concentrated to obtain the title compound (15.6 g).

[0192] [Step 4] Synthesis of pentafluorophenyl-2-(trans-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethylbenzo[1,3]dioxole-5-carboxylate The compound (15.6 g, 26.3 mmole) obtained in Step 3 was added to dimethylformamide (80 mL) and triethylamine (15 mL). Then, pentafluorophenyl trifluoroacetate (7.1 mL) was added dropwise and stirred at room temperature. After the reaction was completed, the next reaction was carried out.

[0193] [Step 5] Synthesis of tert-butyl (trans-4-(7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-5-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamyl)benzo[d][1,3]dioxol-2-yl)cyclohexyl)(methyl)carbamate Triethylamine (11 mL) was added to the reaction solution from step 4. Then, 3-(aminomethyl)-6-methyl-4-(methylthio)pyridin-2(1H)-one hydrochloride (7.6 g) was added and stirred at an internal temperature of 50°C. After the reaction was completed, the reaction mixture was added dropwise to purified water (936 mL) and the resulting solid was filtered. The solid was dissolved in methylene chloride (312 mL) and the aqueous layer was separated. Magnesium sulfate was added, filtered, and concentrated to give the title compound. The product (20 g) was obtained.

[0194] [Step 6] Synthesis of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl-methyl-2-(trans-4-(methylamino)cyclohexyl)benzo[d][1,3]dioxole-5-carboxylate hydrochloride The compound obtained in Step 5 (20 g, 26.2 mmol) was added to 1 M aqueous hydrochloric acid (100 mL), heated, and stirred. After the reaction was completed, the mixture was concentrated, dissolved in methanol (100 mL), and slowly added dropwise to ethyl acetate (400 mL). The mixture was then filtered and dried at an internal temperature of 60°C to obtain the title compound (21.6 g).

[0195] [Step 7] Synthesis of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-2-(trans-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 20)

[0196] [ka]

[0197] Acetonitrile (238 mL) was added to the compound obtained in [Step 6] (21.6 g, 29.4 mmole), followed by sodium bicarbonate (20 g). 2,2,2-trifluoroethyl trifluoromethanesulfonate (10.6 mL) was added dropwise, and the mixture was heated and stirred. After the reaction was complete, the mixture was concentrated, ethyl acetate (432 mL) was added, and purified water (432 mL) was added for washing. Magnesium sulfate was added, filtered, and then concentrated. The mixture was then dissolved in isopropyl alcohol (130 mL), hexane (151 mL) was added dropwise, and the resulting crystals were filtered and dried at an internal temperature of 60°C to obtain the title compound (21 g).

[0198] 1 H NMR(Chloroform-d):8.54(d,1H),7.70(d,1H),7.22(t,1H),7.07(s,1H),6.56(d,1H),5.91(s,1H),4.60(d,2H),4.01(d,2H),3.67(m,2) H),2.95(m,2H),2.51(m,2H),2.41(m.8H),2.30(s,3H),2.15(s,3H),1.99(m,2H),1.88(m,2H),1.78(m,1H),1.56(s,3H),1.25(m,12H). LC-MS (ESI, m / z) = 745.4 (M+H + )

[0199] [Step 8] 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-2-(trans-4-(methyl(2,2,2-trimethyl)phenyl)propan-1 ... Synthesis of (fluoroethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride (hydrochloride of compound 20) The compound obtained in Step 7 (21 g, 28.2 mmol) was added to 1 M aqueous hydrochloric acid (105 mL), and the mixture was heated and stirred. The internal temperature was cooled to room temperature, and isopropyl alcohol (105 mL) was added dropwise and stirred. The resulting crystals were filtered and dried at an internal temperature of 60°C to obtain the title compound (20 g).

[0200] Preparation Example 21. Synthesis of 2,4-dimethyl-2-(trans-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-(piperidin-1-yl)pyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 21)

[0201] [ka]

[0202] The same reaction as in Preparation Example 20 was carried out, except that 2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 2] of Preparation Example 20, to obtain the title compound (78 mg).

[0203] 1H NMR(DMSO-d6):11.50(s,1H),8.62(d,2H),7.91(m,1H),7.05(s,1H),6.05(s,1H),4.27(m,2H),3.74(m,4H),3.06(m,2H) ),2.47(m,4H),2.29(s,3H),2.17(m,6H),1.85(m.3H),1.80(s,2H),1.60(s,2H),1.55(s,3H),1.48(m,4H),1.17(m,4H). LC-MS (ESI, m / z) = 716.3 (M+H + )

[0204] Preparation Example 22. Synthesis of 7-(2-(dimethylamino)pyrimidin-5-yl)-2,4-dimethyl-2-(trans-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 22)

[0205] [ka]

[0206] The same reaction as in Preparation Example 20 was carried out, except that N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 2] of Preparation Example 20, to obtain the title compound (66 mg).

[0207] 1H NMR(DMSO-d6):11.50(s,1H),8.65(d,2H),7.91(m,1H),7.05(s,1H),6.05(s,1H),3.08(s,6H),3.06(m,2H) ),2.46(m,4H),2.28(s,2H),2.17(s,3H),2.13(s,3H),1.85(m.3H),1.80(s,2H),1.55(s,3H),1.18(m,4H). LC-MS (ESI, m / z) = 625.3 (M+H + )

[0208] Preparation Example 23. Synthesis of 7-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-5-yl)-2,4-dimethyl-2-(trans-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 23)

[0209] [ka]

[0210] In Step 2 of Preparation Example 20, (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine was replaced with (2S,6R)-2,6-dimethyl-4-(5-(4,4, The same reaction as in Preparation Example 20 was carried out except that 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholine was used, to give the title compound (50 mg).

[0211] 1H NMR(Chloroform-d):8.60(s,2H),8.41(s,1H),7.08(s,1H),7.03(s,1H),5.95(s,1H),4.60(m,2H),4.54(m,3H),3.63(m, 3H),2.92(m,2H),2.62(m,3H),2.44(m,3H),2.43(m,7H),2.29(s,3H),2.21(m,4H),1.80(m,1H),1.55(s,3H),1.20(m,7H). LC-MS (ESI, m / z) = 745.4 (M+H + )

[0212] Preparation Example 24. Synthesis of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(trans-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 24)

[0213] [ka]

[0214] The same reaction as in Production Example 20 was carried out except that 1-bromo-2-methoxyethane was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 7] of Production Example 20, to give the title compound (48 mg).

[0215] 1H NMR(Chloroform-d):8.50(s,1H),7.72(d,1H),7.15(m,1H),7.07(s,1H),6.59(d,1H),5.96(s,1H),4.62(d,2H),4.04(d,2H),3.70(m,2H),3. 68(t,2H),3.49(s,3H),2.53(s,2H),2.51(s,3H),2.45(s,3H),2.37(s, 3H),2.30(s,3H),2.23(m,4H),2.19(m,1H),1.58(s,3H),1.26(m,10H). LC-MS (ESI, m / z) = 720.5 (M+H + )

[0216] Preparation Example 25. 7-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-5-yl)-2-(trans-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxo Synthesis of benzoyl-5-carboxamide (compound 25)

[0217] [ka]

[0218] The same reaction as in Preparation Example 20 was carried out except that (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 2] of Preparation Example 20, and 1-bromo-2-methoxyethane was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 7], to obtain the title compound (27 mg).

[0219] 1H NMR(DMSO-d6):11.49(s,1H),8.65(s,2H),7.91(t,1H),7.05(s,1H),6.05(s,1H),4.51(d,1H),4.27(d,2H),3.52(m,2H),3.30 (s,2H),3.29(s,3H),2.47(m,6H),2.46(s,1H),2.45(s,6H),2.40(m,2H),2.17(m,2H),2.13(s,3H),1.13(m,4H),1.11(m,6H). LC-MS (ESI, m / z) = 721.4 (M+H + )

[0220] Preparation Example 26. Synthesis of 7-(2-(dimethylamino)pyrimidin-5-yl)-2-(trans-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 26)

[0221] [ka]

[0222] The same reaction as in Preparation Example 20 was carried out, except that N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 2] of Preparation Example 20, and 1-bromo-2-methoxyethane was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 7], to obtain the title compound (19 mg).

[0223] 1H NMR(DMSO-d6):11.49(s,1H),8.63(s,2H),7.91(s,1H),7.05(s,1H),6.05(s,1H),4.27(m,2H),3.29(s,3H),3.12 (s,6H),2.48(s,3H),2.47(s,1H),2.46(s,3H),2.45(s,6H),2.41(m,2H),2.16(m,2H),2.13(m,2H),1.55(m,3H). LC-MS (ESI, m / z) = 651.4 (M+H + )

[0224] Preparation Example 27. Synthesis of 7-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-2-(trans-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 27)

[0225] [ka]

[0226] The same reaction as in Preparation Example 20 was carried out, except that 2-(4,4-difluoropiperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 2] of Preparation Example 20, and 1-bromo-2-methoxyethane was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 7], to obtain the title compound (30 mg).

[0227] 1H NMR(Chloroform-d):8.50(s,1H),7.67(d,1H),7.29(m,1H),6.57(d,1H),5.89(s,1H),4.58(d,2H),3.65(t,3H),3.39(t,2H),3.28(s, 3H),2.57(t,2H),2.40(s,3H),2.38(s,1H),2.28(s,3H),2.24(s,3H),2.11(s,3H),1.95(m,2H),1.93(s,1H),1.54(s,3H),1.21(t,3H). LC-MS (ESI, m / z) = 727.0 (M+H + )

[0228] Preparation Example 28. Synthesis of 2-(trans-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-7-(6-methoxypyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 28)

[0229] [ka]

[0230] The same reaction as in Preparation Example 20 was carried out, except that 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 2] of Preparation Example 20, and 1-bromo-2-methoxyethane was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 7], to obtain the title compound (56 mg).

[0231] 1H NMR(Chloroform-d):4.60(d,2H),3.89(s,3H),3.42(t,2H),3.31(s,3H),2.61(t,2H),2.43(s,3H),2. 30(s,1H),2.27(s,3H),2.12(s,3H),1.96(m,2H),1.88(m,2H),1.76(m,1H),1.55(s,3H),1.22(t,3H). LC-MS (ESI, m / z) = 637.4 (M+H + )

[0232] Preparation Example 29. 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-( (1st Set, 4th Round) Synthesis of 4-(((S)-2-hydroxypropyl)(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 29)

[0233] [ka]

[0234] The same reaction as in Production Example 20 was carried out except that (S)-1-chloro-2-propanol was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 7] of Production Example 20, to give the title compound (34 mg).

[0235] 1H NMR(Chloroform-d):8.50(d,1H),7.69(d,1H),7.13(m,1H),7.05(s,1H), 6.58(d,1H),5.94(s,1H),4.57(s,2H),4.18(s,1H),4.01(dd,2H),3.69(m, 2H),2.65(m,4H),2.50(t,2H),2.44(s,3H),2.26(s,3H),2.19(s,5H),2.0 4(m,2H),1.83(t,1H),1.55(s,3H),1.40(m,4H),1.24(d,8H),1.16(d,3H). LC-MS (ESI, m / z) = 720.5 (M+H + )

[0236] Preparation Example 30. Synthesis of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-2-(trans-4-(methyl(2-propoxyethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 30)

[0237] [ka]

[0238] The same reaction as in Production Example 20 was carried out except that 2-chloroethyl propyl ether was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 7] of Production Example 20, to give the title compound (28 mg).

[0239] 1H NMR(Chloroform-d):8.50(s,1H),7.70(dd,1H),7.19(t,1H),7.06(s,1H),6. 54(d,1H),5.92(s,1H),4.59(d,2H),3.98(d,2H),3.79(m,2H),3.51(t,2H),3. 35(t,2H),2.69(t,2H),2.50(t,3H),2.43(s,3H),2.33(s,3H),2.28(s,3H),2 .14(s,3H),1.92(m,4H),1.79(m,1H),1.54(m,5H),1.24(d,11H),0.86(t,3H). LC-MS (ESI, m / z) = 749.3 (M+H + )

[0240] Preparation Example 31. Synthesis of 2-(trans-4-((2,2-dimethoxyethyl)(methyl)amino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 31)

[0241] [ka]

[0242] The same reaction as in Production Example 20 was carried out except that bromoacetaldehyde dimethyl acetal was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 7] of Production Example 20, to give the title compound (53 mg).

[0243] 1H NMR(Chloroform-d):8.53(s,1H),7.69(d,1H),7.19(m,1H),7.06(d,1H), 6.56(m,1H),5.92(s,1H),4.59(s,2H),4.48(s,1H),3.98(d,2H),3.67(m,2 H),3.33(d,6H),2.58(s,2H),2.48(t,3H),2.42(s,3H),2.35(s,3H),2.28 (d,3H),2.14(s,3H),1.91(d,4H),1.78(s,1H),1.54(d,3H),1.23(m,12H). LC-MS (ESI, m / z) = 750.5 (M+H + )

[0244] Preparation Example 32. Synthesis of 2-(trans-4-(((1,3-dioxolan-2-yl)methyl)(methyl)amino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 32)

[0245] [ka]

[0246] The same reaction as in Production Example 20 was carried out except that 2-bromomethyl-1,3-dioxolane was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 7] of Production Example 20, to give the title compound (40 mg).

[0247] 1H NMR(Chloroform-d):8.52(d,1H),7.69(m,1H),7.18(t,1H),7.06(s,1H),6.55(d,1H),5.93(s,1H),5.00(t,1H),4.59(d,2H),3.99(m,3H),3. 82(m,1H),3.68(m,2H),2.71(d,1H),2.50(m,2H),2.43(s,5H),2.28(s, 3H),2.15(s,3H),1.97(m,4H),1.79(d,1H),1.54(s,3H),1.25(m,11H). LC-MS (ESI, m / z) = 748.5 (M+H + )

[0248] Preparation Example 33. 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridine Synthesis of (3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide and its hydrochloride salt (Compound 33 and its hydrochloride salt)

[0249] [ka]

[0250] [Step 1] Synthesis of tert-butyl 4-(7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)pyridine-1-carboxylate tert-Butyl 4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate (20 g, 44.2 mmole) was added to dioxane (200 mL) and purified water (100 mL). Next, (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (18.3 g), tetrakis(triphenylphosphine)palladium (5.11 g), and sodium carbonate (14 g) were added, followed by heating and stirring. After the reaction was complete, hexane (200 mL) and purified water (100 mL) were added. The precipitated solid was filtered using silica / Celite, and the filtrate was washed with purified water (200 mL). Magnesium sulfate was added, and the mixture was filtered and concentrated to give the title compound (16 g).

[0251] [Step 2] Synthesis of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylic acid Tetrahydrofuran (128 mL) and purified water (64 mL) were added to the compound (16 g, 27.5 mmole) obtained in Step 1 above. 2N aqueous sodium hydroxide solution (69 mL) was added, and the mixture was heated and stirred. After the reaction was complete, 2N aqueous hydrochloric acid solution (69 mL) and ethyl acetate (128 mL) were added. The mixture was then washed with 300 mL of purified water twice, magnesium sulfate was added, and the mixture was filtered. The mixture was then concentrated to give the title compound (14.2 g).

[0252] [Step 3] Synthesis of tert-butyl 4-(7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-5-((pentafluorophenoxy)carbonyl)benzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate The compound (14.2 g, 25.1 mmole) obtained in Step 2 was added to dimethylformamide (70 mL) and triethylamine (14 mL). Then, pentafluorophenyl trifluoroacetate (6.8 mL) was added dropwise and stirred at room temperature. After the reaction was completed, the next reaction was carried out.

[0253] [Step 4] Synthesis of tert-butyl 4-(7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-5-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)benzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate Triethylamine (10 mL) was added to the reaction mixture from Step 3. Then, 3-(aminomethyl)-6-methyl-4-(methylthio)pyridin-2(1H)-one hydrochloride (7.2 g) was added and stirred at an internal temperature of 50°C. After the reaction was completed, the reaction mixture was added dropwise to purified water (710 mL) and the resulting solid was filtered. The solid was dissolved in methylene chloride (284 mL), and the aqueous layer was separated. Magnesium sulfate was added, filtered, and concentrated to obtain the title compound (16.9 g).

[0254] [Step 5] Synthesis of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)2-(piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride The compound obtained in Step 4 (16.9 g, 23 mmol) was added to 1 M hydrochloric acid (ethanol aqueous solution) (85 mL), and the mixture was heated and stirred. After the reaction was completed, the reaction mixture was added dropwise to ethyl acetate (338 mL), and the resulting solid was filtered and dried at an internal temperature of 60°C to obtain the title compound (15.4 g).

[0255] [Step 6] Synthesis of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 33)

[0256] [ka]

[0257] Acetonitrile (308 mL) was added to the compound (15.4 g, 22 mmole) obtained in [Step 5] above, followed by sodium bicarbonate (15.5 g). Trifluoroethyl trifluoromethanesulfonate (8.2 mL) was added dropwise, and the mixture was heated and stirred. After the reaction was complete, the mixture was concentrated, ethyl acetate (308 mL) was added, and purified water (462 mL) was added and washed. Magnesium sulfate was added, filtered, and then concentrated. Isopropyl alcohol (92 mL) was then added, and the mixture was heated to dissolve. Hexane (100 mL) was added dropwise, and the resulting crystals were filtered and dried at an internal temperature of 60°C to obtain the title compound (11 g).

[0258] 1 H NMR(Chloroform-d):8.42(s,1H),7.60(d,1H),7.33(s,1H),6.98(s,1H),6.46(d,1H),5.82(s,1H),4.47(s,2H),3. 89(d,2H),3.57(s,2H),2.85(m,4H),2.32(m,5H),2.20(s,5H),2.02(s,3H),1.72(d,3H),1.49(s,5H),1.13(d,6H). LC-MS (ESI, m / z) = 716.4 (M+H + )

[0259] [Step 7] Synthesis of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride (hydrochloride salt of Compound 33) The compound obtained in Step 6 (11 g, 14.8 mmol) was added to 1 M aqueous hydrochloric acid (100 mL), and the mixture was heated and stirred. The internal temperature was cooled to room temperature, and ethyl acetate (230 mL) was added dropwise and stirred. The resulting crystals were filtered and dried at an internal temperature of 60°C to obtain the title compound (11 g).

[0260] Preparation Example 34. Synthesis of 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-thiomorpholinopyridin-3-yl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 34)

[0261] [ka]

[0262] The same reaction as in Preparation Example 33 was carried out, except that 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)thiomorpholine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 1] of Preparation Example 33, to obtain the title compound (88 mg).

[0263] 1H NMR(Chloroform-d):8.55(s,1H),7.76(s,1H),7.13(s,1H),6.56(s,1H),5.94(s,1H),4.61(d,2H),3.95(m, 4H),3.01(d,2H),2.96(m,2H),2.65(m,4H),2.46(s,3H),2.33(m,5H),2.18(s,3H),1.82(m,3H),1.59(m,5H). LC-MS (ESI, m / z) = 704.3 (M+H + )

[0264] Preparation Example 35. Synthesis of 7-(2-(dimethylamino)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 35)

[0265] [ka]

[0266] The same reaction as in Preparation Example 33 was carried out, except that N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 1] of Preparation Example 33, to obtain the title compound (21 mg).

[0267] 1 H NMR(Chloroform-d):8.64(s,1H),7.28(s,1H),7.07(S,1H),5.94(s,1H),4.61(d,2H),3.19(s, 6H),2.96(m,2H),2.94(m,2H),2.45(s,3H),2.31(m,5H),2.29(s,3H),1.81(m,2H),1.79(s,6H). LC-MS (ESI, m / z) = 647.3 (M+H + )

[0268] Preparation Example 36. Synthesis of 7-(6-methoxypyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 36)

[0269] [ka]

[0270] The same reaction as in Preparation Example 33 was carried out, except that 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 1] of Preparation Example 33, to obtain the title compound (20 mg).

[0271] 1 H NMR(Chloroform-d):8.45(s,1H),7.78(d,1H),7.22(s,1H),7.07(s,1H),6.69(d,1H),5.92(s,1H),4.58(d, 2H),3.89(d,3H),3.00(d,2H),2.93(m,2H),2.43(s,3H),2.29(m,5H),2.12(s,3H),1.80(m,3H),1.57(m,5H). LC-MS (ESI, m / z) = 633.4 (M+H + )

[0272] Preparation Example 37. Synthesis of 7-(6-(3,5-dimethylpiperidin-1-yl)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 37)

[0273] [ka]

[0274] The same reaction as in Preparation Example 33 was carried out, except that 2-(3,5-dimethylpiperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 1] of Preparation Example 33, to obtain the title compound (47 mg).

[0275] 1 H NMR(Chloroform-d):8.51(s,1H),7.68(m,1H),7.25(m,1H),7.08(s,1H),6.60(m,1H),5.92(d,1H),4.60(s,2H),4.20(d,2H),2. 99(m,2H),2.93(m,2H),2.43(d,3H),2.29(d,7H),2.15(d,3H),1.80(s,4H),1.56(m,7H),1.24(s,1H),0.93(m,7H),0.79(m,1H). LC-MS (ESI, m / z) = 714.5 (M+H + )

[0276] Preparation Example 38. Synthesis of 7-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 38)

[0277] [ka]

[0278] In Step 1 of Production Example 33, (2S,6R)-2,6-dimethyl-4-(5-(4, The same reaction as in Preparation Example 33 was carried out except that (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholine was used instead of 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine, to obtain the title compound (37 mg).

[0279] 1 H NMR(Chloroform-d):8.59(s,2H),7.11(t,1H),7.03(s,1H),5.96(s,1H),4.59(d,2H),4.50(dd,2H),3.61(m,2H),3 .00(d,2H),2.95(m,2H),2.59(t,2H),2.44(s,3H),2.28(m,5H),2.21(s,3H),1.79(m,3H),1.56(s,5H),1.23(d,9H). LC-MS (ESI, m / z) = 717.4 (M+H + )

[0280] Preparation Example 39. Synthesis of 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-(piperidin-1-yl)pyrimidin-5-yl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 39)

[0281] [ka]

[0282] The same reaction as in Preparation Example 33 was carried out, except that 2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in [Step 1] of Preparation Example 33, to obtain the title compound (55 mg).

[0283] 1 H NMR(Chloroform-d):8.57(s,2H),7.23(m,1H),7.03(s,1H),5.94(s,1H),4.58(d,2H),3.75(t,4H),2. 99(d,2H),2.93(m,2H),2.43(s,3H),2.29(m,5H),2.19(s,3H),1.80(m,3H),1.65(m,2H),1.57(s,9H). LC-MS (ESI, m / z) = 687.3 (M+H + )

[0284] Preparation Example 40. 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(1-((S)-2-hydroxypropyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carbohydrate Synthesis of oxamide (compound 40)

[0285] [ka]

[0286] The same reaction as in Production Example 33 was carried out except that (S)-1-chloro-2-propanol was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 6] of Production Example 33, to give the title compound (66 mg).

[0287] 1 H NMR(Chloroform-d):8.49(t,1H),7.74(d,1H),7.21(s,1H),7.06(s,1H),6.59(d,1H),5.95(s,1H),4.58(s,2H),4.01(dd, 3H),3.68(m,2H),2.50(t,4H),2.44(s,4H),2.28(s,3H),2.18(s,3H),1.88(m,4H),1.58(s,3H),1.24(d,9H),1.13(d,3H). LC-MS (ESI, m / z) = 692.4 (M+H + )

[0288] Preparation Example 41. Synthesis of 2-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 41)

[0289] [ka]

[0290] In Step 6 of Preparation 33, 2,2,2-trifluoromethanesulfonic acid The same reaction as in Preparation Example 33 was carried out except that bromoacetaldehyde dimethyl acetal was used instead of bromoethyl, to give the title compound (201 mg).

[0291] 1 H NMR(Chloroform-d):8.50(s,1H),7.67(dd,1H),7.20(t,1H),7.05(s,1H),6.53( d,1H),5.92(s,1H),4.59(d,2H),4.51(t,1H),3.98-4.00(m,2H),3.66-3.67(m,2H ),3.31(s,6H),3.06(d,2H),2.48-2.53(m,4H),2.42(s,3H),2.27(s,3H),2.13(s, 3H),2.05(t,2H),1.76-1.80(m,3H),1.64-1.66(m,2H),1.55(s,3H),1.24(d,8H). LC-MS (ESI, m / z) = 722.4 (M+H + )

[0292] Production Example 42. 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridine-3 -yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2-propoxyethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide Synthesis of (Compound 42)

[0293] [ka]

[0294] The same reaction as in Production Example 33 was carried out except that 2-chloroethyl propyl ether was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 6] of Production Example 33, to give the title compound (220 mg).

[0295] 1 H NMR(Chloroform-d):7.59(d,1H),7.39(m,1H),7.25(m,1H),7.23(m,1H),7.19(s,1H),5.92(s,1H),4.60(d, 2H),2.43(s,3H),2.29(s,3H),2.24(s,6H),2.14(m,4H),1.97(t,4H),1.80(t,1H),1.58(s,3H),1.23(m,4H). LC-MS (ESI, m / z) = 568.3 (M+H + )

[0296] Production Example 43. 2-(1-((1,3-dioxolan-2-yl)methyl)piperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide Synthesis of (Compound 43)

[0297] [ka]

[0298] The same reaction as in Production Example 33 was carried out except that 2-bromomethyl-1,3-dioxolane was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 6] of Production Example 33, to obtain the title compound (124 mg).

[0299] 1 H NMR(Chloroform-d):7.02(m,1H),6.98(m,2H),6.92(m,1H),6.79(m,1H),5.91(s,1H),4.58(d,2H),3.68(s, 3H),2.44(s,3H),2.32(s,2H),2.25(s,6H),2.13(s,4H),1.94(m,3H),1.79(t,1H),1.53(s,3H),1.20(m,4H). LC-MS (ESI, m / z) = 610.3 (M+H + )

[0300] Preparation Example 44. Synthesis of Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 44)

[0301] [ka] Stereoisomer B of [ka]

[0302] The processes of [Steps 1 to 6] of the above Preparation Example 33 were carried out in the same manner, except that in [Step 1], stereospecific tert-butyl (R)-4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate (3 g, 6.38 mmole) was used instead of tert-butyl 4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate as the starting material, to obtain the title compound (3.3 g, 4.60 mmole).

[0303] tert-butyl (R)-4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate [ka] When the purity of the isomer was measured by liquid chromatography under the following conditions, the RT was measured at 6.01 min, the chiral purity was 99.3%, and the specific rotation [α] D 25 = +4.0 (c = 1, chloroform) was used.

[0304] -Detector: UV spectrophotometer (measurement wavelength 270 nm) -Column: Chiralpak OX-3 or equivalent (e.g., Chiralpak OX-3, particle size 3 μm, 4.6 mm x 15 cm) -Column temperature: 25℃ Mobile phase: a mixture of hexane / ethanol (98:2, v / v). -Flow rate: 1.0mL / min -Analysis time: 15 minutes

[0305] 1 H NMR(DMSO-d6):11.5(s,1H),8.43(s,1H),7.95(t,1H),7.80(s,1H),7.02(s,1H),6.90(d,1H),6.05(s,1H),4.27(d,2H),4.13(d,2H),3.53 -3.59(m,2H),3.06-3.10(m,2H),2.92(d,2H),2.39-2.43(m,5H),2.38-2.39(m,1H),2.24-2.30(m,2H),2.17(s,3 H),2.13(s,3H),1.81-1.88(m,1H),1.67-1.73(m,2H),1.56(s,3H),1.32-1.40(m,2H),1.13(s,3H),1.12(s,3H). LC-MS (ESI, m / z) = 716.8 (M+H + ) Specific rotation [α] D 25 =-55.0000(c=0.1, methanol)

[0306] Preparation Example 45. Synthesis of Stereoisomer A of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 45)

[0307] [ka] Stereoisomer A of [ka]

[0308] The processes of [Steps 1 to 6] of Preparation 33 were carried out in the same manner, except that in [Step 1], stereospecific tert-butyl (S)-4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate (3 g, 6.38 mmole) was used instead of tert-butyl 4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate as the starting material, to obtain the title compound (3.2 g, 4.47 mmole).

[0309] tert-butyl (S)-4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate [ka] When the purity of the isomer was measured by liquid chromatography under the following conditions, the RT was measured at 5.24 min, the chiral purity was 98.8%, and the specific rotation [α] D 25 =-3.6 (c=1, chloroform) was used.

[0310] -Detector: UV spectrophotometer (measurement wavelength 270 nm) -Column: Chiralpak OX-3 or equivalent (e.g., Chiralpak OX-3, particle size 3 μm, 4.6 mm x 15 cm) -Column temperature: 25℃ Mobile phase: a mixture of hexane / ethanol (98:2, v / v). -Flow rate: 1.0mL / min -Analysis time: 15 minutes

[0311] 1H NMR(DMSO-d6):11.5(s,1H),8.43(s,1H),7.95(t,1H),7.80(s,1H),7.02(s,1H),6.90(d,1 H),6.05(s,1H),4.27(d,2H),4.13(d,2H),3.53-3.59(m,2H),3.06-3.10(m,2H),2.92(d,2 H),2.36-2.40(m,5H),2.34-2.36(m,1H),2.22-2.30(m,2H),2.17(s,3H),2.13(s,3H),1.8 1-1.88(m,1H),1.67-1.73(m,2H),1.56(s,3H),1.32-1.40(m,2H),1.13(s,3H),1.12(s,3H) LC-MS (ESI, m / z) = 716.8 (M+H + ) Specific rotation [α] D 25 =+55.7000(c=0.1, methanol)

[0312] Preparation Example 46. Synthesis of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 46)

[0313] [ka]

[0314] The processes of [Steps 1 to 5] of Production Example 33 were carried out in the same manner, and 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)2-(piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride was obtained in [Step 5].

[0315] The resulting hydrochloride (0.5 g, 0.70 mmol) was added to acetonitrile (10 mL), sodium carbonate (0.43 g), and 2-iodo-1,1-difluoroethane (0.12 mL) and stirred at an internal temperature of 100 °C for 24 hours. After cooling, dichloromethane (5 mL) was added, filtered, and concentrated. The mixture was then separated with dichloromethane (10 mL) and purified water (10 mL). The oil layer was dried over magnesium sulfate (MgSO4) and concentrated. The resulting crystals were filtered and dried at an internal temperature of 60 °C to yield the title compound (0.3 g).

[0316] 1 H NMR(DMSO-d6):11.5(s,1H),8.36(s,1H),8.19(t,1H),8.00(s,1H),7.23(s,1H),7 .09(s,1H),6.61(t,1H),6.06(s,1H),4.26-4.28(m,4H),3.62-3.64(m,4H),3.52-3 .62(m,2H),3.06-3.07(m,2H),2.61-2.65(m,2H),2.41(s,3H),2.22(s,3H),2.14(s ,3H),1.91-1.93(m,2H),1.88-1.91(m,3H),1.60(s,3H),1.14(s,3H),1.13(s,3H). LC-MS (ESI, m / z) = 698.4 (M+H + )

[0317] Preparation Example 47. Synthesis of Stereoisomer B of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 47)

[0318] [ka] Stereoisomer B of [ka]

[0319] The reaction was carried out in the same manner as in Preparation Example 46, except that stereospecific tert-butyl (R)-4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate (3 g, 6.38 mmole) was used instead of tert-butyl 4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate in [Step 1], to obtain the title compound (0.2 g).

[0320] 1 H NMR(DMSO-d6):11.5(s,1H),8.44(s,1H),7.94(t,1H),7.79(s,1H),7.02(s,1H),6.90(d,1H) ),6.04-6.05(m,2H),4.26(d,2H),4.13(d,2H),3.55-3.56(m,2H),2.89-2.92(m,2H),2.60-2 .69(m,2H),2.39(s,3H),2.36-2.38(m,2H),2.16(s,3H),2.13(s,3H),2.07-2.12(m,2H),1.8 0-1.86(m,1H),1.65-1.72(m,2H),1.56(s,3H),1.35-1.40(m,2H),1.13(s,3H),1.12(s,3H). LC-MS (ESI, m / z) = 698.6 (M+H + ) Specific rotation [α] D 25 =-58.1500(c=0.1, methanol)

[0321] Preparation Example 48. Synthesis of Stereoisomer A of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 48)

[0322] [ka] Stereoisomer A of [ka]

[0323] The reaction was carried out in the same manner as in Preparation Example 46, except that in [Step 1], stereospecific tert-butyl (S)-4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate (3 g, 6.38 mmole) was used instead of tert-butyl 4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate, to obtain the title compound (0.2 g).

[0324] 1 H NMR(DMSO-d6):11.5(s,1H),8.44(s,1H),7.94(t,1H),7.79(s,1H),7.02(s,1H),6.90(d,1H) ),6.04-6.05(m,2H),4.26(d,2H),4.13(d,2H),3.57-3.58(m,2H),2.89-2.92(m,2H),2.60-2 .69(m,2H),2.40(s,3H),2.36-2.38(m,2H),2.16(s,3H),2.13(s,3H),2.07-2.12(m,2H),1.8 0-1.86(m,1H),1.65-1.72(m,2H),1.56(s,3H),1.35-1.40(m,2H),1.13(s,3H),1.12(s,3H). LC-MS (ESI, m / z) = 698.6 (M+H + ) Specific rotation [α] D 25 =+65.5667(c=0.1, methanol)

[0325] Preparation Example 49. Synthesis of Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 49)

[0326] [ka] Stereoisomer B of [ka]

[0327] The reaction was carried out in the same manner as in Preparation Example 47, except that iodoethane (0.11 mL) was used instead of 2-iodo-1,1-difluoroethane in [Step 6], to give the title compound (0.1 g).

[0328] 1 H NMR(DMSO-d6):11.5(s,1H),8.48(s,1H),7.96(t,1H),7.82(d,1H),7.05(s,1H),6.9 0(d,1H),6.05(s,1H),4.27(d,2H),4.14(d,2H),3.55-3.59(m,2H),3.40-3.47(m,2H ),3.00-3.05(m,2H),2.80-2.86(m,2H),2.47(s,3H),2.41-2.44(m,2H),2.18(s,3H) ,2.12(s,3H),1.87-1.99(m,3H),1.56-1.66(m,5H),1.12-1.13(m,6H),1.12(s,3H). LC-MS (ESI, m / z) = 662.6 (M+H + ) Specific rotation [α] D 25 =-55.4000(c=0.1, methanol)

[0329] Preparation Example 50. Synthesis of Stereoisomer A of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 50)

[0330] [ka] Stereoisomer A of [ka]

[0331] The reaction was carried out in the same manner as in Preparation Example 48, except that iodoethane (0.11 mL) was used instead of 2-iodo-1,1-difluoroethane in [Step 6], to give the title compound (0.1 g).

[0332] 1 H NMR(DMSO-d6):11.5(s,1H),8.49(s,1H),7.96(t,1H),7.82(d,1H),7.05(s,1H),6.9 0(d,1H),6.05(s,1H),4.27(d,2H),4.14(d,2H),3.55-3.57(m,2H),3.40-3.49(m,2H ),3.00-3.06(m,2H),2.80-2.86(m,2H),2.47(s,3H),2.41-2.43(m,2H),2.18(s,3H) ,2.13(s,3H),1.90-1.99(m,3H),1.55-1.65(m,5H),1.12-1.13(m,6H),1.12(s,3H). LC-MS (ESI, m / z) = 662.6 (M+H+ ) Specific rotation [α] D 25 =+67.8834(c=0.1, methanol)

[0333] Preparation Example 51. Synthesis of Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(1-isopropylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 51)

[0334] [ka] Stereoisomer B of [ka]

[0335] The reaction was carried out in the same manner as in Preparation Example 47, except that 2-iodopropane (0.13 mL) was used instead of 2-iodo-1,1-difluoroethane in [Step 6], to give the title compound (0.2 g).

[0336] 1 H NMR(DMSO-d6):11.5(s,1H),8.46(s,1H),7.95(t,1H),7.81(d,1H),7.03(s,1H),6.89(d, 1H),6.05(s,1H),4.27(d,2H),4.13(d,2H),3.56-3.58(m,2H),3.02-3.10(m,2H),2.41(s ,3H),2.38-2.40(m,2H),2.36-2.37(m,2H),2.17(s,3H),2.13(s,3H),2.00-2.10(m,2H), 1.80-1.84(m,2H),1.58(s,3H),1.45-1.48(m,2H),1.13(s,3H),1.12(s,3H),1.02(s,6H). LC-MS (ESI, m / z) = 676.6 (M+H+ ) Specific rotation [α] D 25 =-61.1000(c=0.1, methanol)

[0337] Preparation Example 52. Synthesis of Stereoisomer A of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(1-isopropylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 52)

[0338] [ka] Stereoisomer A of [ka]

[0339] The reaction was carried out in the same manner as in Preparation Example 48, except that 2-iodopropane (0.13 mL) was used instead of 2-iodo-1,1-difluoroethane in [Step 6], to give the title compound (0.2 g).

[0340] 1 H NMR(DMSO-d6):11.5(s,1H),8.46(s,1H),7.95(t,1H),7.80(d,1H),7.02(s,1H),6.90(d, 1H),6.05(s,1H),4.27(d,2H),4.14(d,2H),3.56-3.58(m,2H),2.83-2.88(m,2H),2.41(s ,3H),2.38-2.40(m,2H),2.36-2.37(m,2H),2.17(s,3H),2.13(s,3H),2.00-2.10(m,2H), 1.72-1.81(m,2H),1.57(s,3H),1.38-1.43(m,2H),1.13(s,3H),1.12(s,3H),0.95(s,6H). LC-MS (ESI, m / z) = 676.6 (M+H+ ) Specific rotation [α] D 25 =+67.5167(c=0.1, methanol)

[0341] Preparation Example 53. Synthesis of Stereoisomer B of 2-(1-cyclohexylpiperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 53)

[0342] [ka] Stereoisomer B of [ka]

[0343] The reaction was carried out in the same manner as in Preparation Example 47, except that iodocyclohexane (0.17 mL) was used instead of 2-iodo-1,1-difluoroethane in [Step 6], to give the title compound (0.2 g).

[0344] 1 H NMR(DMSO-d6):11.5(s,1H),8.49(s,1H),7.96(t,1H),7.82(d,1H),7.05(s,1H),6.90(d,1H),6.05( s,1H),4.27(d,2H),4.14(d,2H),3.55-3.59(m,2H),3.38-3.41(m,2H),3.10-3.12(m,2H),2.89-2.91 (m,2H),2.41(s,3H),2.36-2.40(m,4H),2.18(s,3H),2.13(s,3H),1.87-1.95(m,4H),1.74-1.79(m, 2H),1.60(s,3H),1.54-1.58(m,2H),1.28-1.34(m,2H),1.20-1.26(m,2H),1.13(s,3H),1.12(s,3H). LC-MS (ESI, m / z) = 716.6 (M+H + ) Specific rotation [α] D 25 =-62.5333(c=0.1, methanol)

[0345] Preparation Example 54. Synthesis of Stereoisomer A of 2-(1-cyclohexylpiperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 54)

[0346] [ka] Stereoisomer A of [ka]

[0347] The reaction was carried out in the same manner as in Preparation Example 48, except that iodocyclohexane (0.17 mL) was used instead of 2-iodo-1,1-difluoroethane in [Step 6], to give the title compound (0.2 g).

[0348] 1H NMR(DMSO-d6):11.5(s,1H),8.49(s,1H),7.96(t,1H),7.82(d,1H),7.05(s,1H),6.90(d,1H),6.05( s,1H),4.27(d,2H),4.15(d,2H),3.54-3.58(m,2H),3.38-3.41(m,2H),3.10-3.12(m,2H),2.93-3.60 (m,2H),2.41(s,3H),2.38-2.40(m,4H),2.19(s,3H),2.13(s,3H),1.87-1.95(m,4H),1.74-1.79(m, 2H),1.60(s,3H),1.56-1.58(m,2H),1.28-1.34(m,2H),1.20-1.26(m,2H),1.13(s,3H),1.12(s,3H). LC-MS (ESI, m / z) = 716.6 (M+H + ) Specific rotation [α] D 25 =+67.3834(c=0.1, methanol)

[0349] Preparation Example 55. Synthesis of Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-phenethylpiperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 55)

[0350] [ka] Stereoisomer B of [ka]

[0351] The reaction was carried out in the same manner as in Preparation Example 47, except that iodocyclohexane (0.17 mL) was used instead of 2-iodo-1,1-difluoroethane in [Step 6], to give the title compound (0.2 g).

[0352] 1 H NMR(DMSO-d6):11.5(s,1H),8.46(s,1H),7.95(t,1H),7.81(d,1H),7.20-7.30(m,2H),7.10-7.20(m,3H) ,7.03(s,1H),6.90(d,1H),6.05(s,1H),4.27(d,2H),4.14(d,2H),3.53-3.58(m,2H),3.01-3.10(m,2H),2 .70-2.97(m,2H),2.41(s,3H),2.38-2.40(m,2H),2.17(s,3H),2.13(s,3H),1.93-1.95(m,2H),1.87-1.9 1(m,2H),1.81-1.85(m,2H),1.70-1.81(m,2H),1.58(s,3H),1.38-1.48(m,2H),1.13(s,3H),1.12(s,3H). LC-MS (ESI, m / z) = 738.6 (M+H + ) Specific rotation [α] D 25 =-82.3667(c=0.1, methanol)

[0353] Preparation Example 56. Synthesis of Stereoisomer A of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-phenethylpiperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 56)

[0354] [ka] Stereoisomer A of [ka]

[0355] The reaction was carried out in the same manner as in Preparation Example 48, except that iodocyclohexane (0.17 mL) was used instead of 2-iodo-1,1-difluoroethane in [Step 6], to give the title compound (0.2 g).

[0356] 1 H NMR(DMSO-d6):11.5(s,1H),8.45(s,1H),7.95(t,1H),7.81(d,1H),7.21-7.22(m,2H),7.03-7.18(m,3H) ,7.02(s,1H),6.91(d,1H),6.05(s,1H),4.27(d,2H),4.14(d,2H),3.56-3.57(m,2H),2.92-2.99(m,2H),2 .66-2.69(m,2H),2.41(s,3H),2.38-2.40(m,2H),2.17(s,3H),2.13(s,3H),1.87-1.91(m,2H),1.85-1.8 7(m,2H),1.81-1.85(m,2H),1.70-1.81(m,2H),1.58(s,3H),1.38-1.48(m,2H),1.13(s,3H),1.12(s,3H). LC-MS (ESI, m / z) = 738.6 (M+H + ) Specific rotation [α] D 25 =+78.3167(c=0.1, methanol)

[0357] Preparation Example 57. Synthesis of Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(4,4,4-trifluorobutyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 57)

[0358] [ka] Stereoisomer B of [ka]

[0359] The reaction was carried out in the same manner as in Preparation Example 47, except that 1,1,1-trifluoro-4-iodobutane (0.17 mL) was used instead of 2-iodo-1,1-difluoroethane in [Step 6], to give the title compound (0.2 g).

[0360] 1 H NMR(DMSO-d6):11.5(s,1H),8.44(s,1H),7.95(t,1H),7.80(d,1H),7.03(s,1H),6.89(d,1H),6 .05(s,1H),4.27(d,2H),4.14(d,2H),3.55-3.58(m,2H),2.82-2.89(m,2H),2.41(s,3H),2.34-2 .41(m,3H),2.28-3.34(m,2H),2.18-2.28(m,2H),2.17(s,3H),2.13(s,3H),1.80-1.90(m,2H), 1.68-1.74(m,2H),1.58-1.63(m,2H),1.57(s,3H),1.30-1.41(m,2H),1.13(s,3H),1.12(s,3H). LC-MS (ESI, m / z) = 744.7 (M+H + ) Specific rotation [α] D 25 =-57.7500(c=0.1, methanol)

[0361] Preparation Example 58. Synthesis of Stereoisomer A of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(4,4,4-trifluorobutyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 58)

[0362] [ka] Stereoisomer A of [ka]

[0363] The reaction was carried out in the same manner as in Preparation Example 48, except that 1,1,1-trifluoro-4-iodobutane (0.17 mL) was used instead of 2-iodo-1,1-difluoroethane in [Step 6], to give the title compound (0.2 g).

[0364] 1 H NMR(DMSO-d6):11.5(s,1H),8.44(s,1H),7.95(t,1H),7.80(d,1H),7.03(s,1H),6.89(d,1H),6 .05(s,1H),4.27(d,2H),4.13(d,2H),3.56-3.57(m,2H),2.82-2.89(m,2H),2.41(s,3H),2.35-2 .41(m,3H),2.28-3.34(m,2H),2.17-2.28(m,2H),2.17(s,3H),2.13(s,3H),1.80-1.90(m,2H), 1.68-1.74(m,2H),1.57-1.63(m,2H),1.56(s,3H),1.30-1.41(m,2H),1.13(s,3H),1.12(s,3H). LC-MS (ESI, m / z) = 744.6 (M+H + ) Specific rotation [α] D 25 =+76.4834(c=0.1, methanol)

[0365] Preparation Example 59. Synthesis of Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 59)

[0366] [ka] Stereoisomer B of [ka]

[0367] The reaction was carried out in the same manner as in Preparation Example 47, except that phenyl trifluoroacetate (0.15 mL) was used instead of 2-iodo-1,1-difluoroethane in [Step 6], to give the title compound (0.2 g).

[0368] 1 H NMR(DMSO-d6):11.5(s,1H),8.44(s,1H),7.95(t,1H),7.80(d,1H),7.04(s,1H),6.88(d, 1H),6.05(s,1H),4.36(d,1H),4.27(d,2H),4.13(d,2H),3.88(d,1H),3.55-3.57(m,2H), 3.21(t,1H),2.83(t,1H),2.41(s,3H),2.32-2.38(m,2H),2.21-2.30(m,1H),2.17(s,3H) ,2.13(s,3H),1.88-1.95(m,2H).1.57(s,3H),1.27-1.34(m,2H)1.13(s,3H).1.12(s,3H). LC-MS (ESI, m / z) = 730.5 (M+H + ) Specific rotation [α] D 25 =-91.4000(c=0.1, methanol)

[0369] Preparation Example 60. Synthesis of Stereoisomer A of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 60)

[0370] [ka] Stereoisomer A of [ka]

[0371] The reaction was carried out in the same manner as in Preparation Example 48, except that phenyl trifluoroacetate (0.15 mL) was used instead of 2-iodo-1,1-difluoroethane in [Step 6], to give the title compound (0.2 g).

[0372] 1 H NMR(DMSO-d6):11.5(s,1H),8.44(s,1H),7.95(t,1H),7.81(d,1H),7.04(s,1H),6.89(d, 1H),6.05(s,1H),4.35(d,1H),4.27(d,2H),4.14(d,2H),3.89(d,1H),3.55-3.58(m,2H), 3.21(t,1H),2.83(t,1H),2.41(s,3H),2.32-2.38(m,2H),2.21-2.30(m,1H),2.17(s,3H) ,2.13(s,3H),1.88-1.95(m,2H).1.57(s,3H),1.27-1.35(m,2H)1.13(s,3H).1.12(s,3H). LC-MS (ESI, m / z) = 730.5 (M+H + ) Specific rotation [α] D 25 =+66.5167(c=0.1, methanol)

[0373] Preparation 61. 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)-2-(1-(2,2,2-trifluoromethyl)-2-methyl)- ethyl Synthesis of )piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 61)

[0374] [ka]

[0375] [Steps 1 to 5] were carried out in the same manner as above, except that 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (Intermediate 1) in [Step 1] of Production Example 33, to obtain 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)-2-(piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride.

[0376] Acetonitrile (10 mL), sodium carbonate (0.43 g), and trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride salt (0.5 g, 0.70 mmole), and the mixture was stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, the mixture was filtered, and concentrated. Then, ethanol (2 mL) and hexane (20 mL) were added, and the resulting crystals were filtered and dried at an internal temperature of 60° C. to obtain the title compound (0.3 g).

[0377] 1 H NMR(DMSO-d6):11.5(s,1H),8.44(d,1H),7.95(t,1H),7.82(d,1H),7.04(s,1H), 6.89(d,1H),6.04(s,1H),4.26(d,2H),3.62-3.64(m,4H),3.43-3.45(m,4H),3.0 2-3.12(m,2H),2.91-2.98(m,2H),2.41(s,3H),2.20-2.28(m,2H),2.26(s,3H),2 .22(s,3H),1.81-1.88(m,1H),1.68-1.72(m,2H),1.56(s,3H),1.35-1.40(m,2H). LC-MS (ESI, m / z) = 688.4 (M+H+ )

[0378] Preparation 62. 2,4-Dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)-2-(1-(2,2,2-trifluoromethyl)-2- ...2-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)-2-(1-(2,2,2-trifluoromethyl)-2-methyl)-2-methyl-4-(methylthio)-2-methyl-4-(methylthio)-2-methyl-4-(methylthio)-2-methyl-4-(methylthio)-2-methyl-4-(methylthio)- ethyl Synthesis of Stereoisomer B of )piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 62)

[0379] [ka] Stereoisomer B of [ka]

[0380] The reaction was carried out in the same manner as in Preparation Example 61, except that in [Step 1], stereospecific tert-butyl (R)-4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate (3 g, 6.38 mmole) was used instead of tert-butyl 4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate as the starting material, to obtain the title compound (0.3 g).

[0381] 1H NMR(DMSO-d6):11.5(s,1H),8.45(d,1H),7.95(t,1H),7.81(d,1H),7.03(s,1H), 6.89(d,1H),6.04(s,1H),4.26(d,2H),3.65-3.66(m,4H),3.44-3.45(m,4H),3.0 6-3.12(m,2H),2.90-2.98(m,2H),2.40(s,3H),2.20-2.28(m,2H),2.26(s,3H),2 .22(s,3H),1.81-1.88(m,1H),1.68-1.72(m,2H),1.56(s,3H),1.35-1.40(m,2H) LC-MS (ESI, m / z) = 688.5 (M+H + ) Specific rotation [α] D 25 =-52.9667(c=0.1, methanol)

[0382] Preparation 63. 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)-2-(1-(2,2,2-trifluoromethyl)-2-methyl) ... ethyl Synthesis of Stereoisomer A of )piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 63)

[0383] [ka] Stereoisomer A of [ka]

[0384] The reaction was carried out in the same manner as in Preparation Example 61, except that in [Step 1], stereospecific tert-butyl (S)-4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate (3 g, 6.38 mmole) was used instead of tert-butyl 4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate as the starting material, to obtain the title compound (0.3 g).

[0385] 1 H NMR(DMSO-d6):11.5(s,1H),8.45(d,1H),7.95(t,1H),7.81(d,1H),7.03(s,1H), 6.89(d,1H),6.04(s,1H),4.26(d,2H),3.65-3.67(m,4H),3.44-3.46(m,4H),3.1 0-3.12(m,2H),2.91-2.94(m,2H),2.42(s,3H),2.39-2.40(m,2H),2.26(s,3H),2 .22(s,3H),1.81-1.88(m,1H),1.68-1.72(m,2H),1.56(s,3H),1.35-1.40(m,2H). LC-MS (ESI, m / z) = 688.5 (M+H + ) Specific rotation [α] D 25 =+73.2333(c=0.1, methanol)

[0386] Preparation Example 64. Synthesis of Stereoisomer B of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 64)

[0387] [ka] Stereoisomer B of [ka]

[0388] The reaction was carried out in the same manner as in Preparation Example 62, except that 2-iodo-1,1-difluoroethane (0.12 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 6], to give the title compound (0.2 g).

[0389] 1 H NMR(DMSO-d6):11.5(s,1H),8.45(d,1H),7.95(t,1H),7.81(d,1H),7.03(s,1H),6 .89(d,1H),6.04-6.05(m,2H),4.26(d,2H),3.57-3.66(m,4H),3.45-3.46(m,4H),2 .88-2.89(m,2H),2.64-2.65(m,2H),2.40(s,3H),2.17(s,3H),2.13(s,3H),2.06- 2.09(m,2H),1.82-1.84(m,1H),1.60-1.62(m,2H),1.57(s,3H),1.32-1.40(m,2H). LC-MS (ESI, m / z) = 670.5 (M+H + ) Specific rotation [α] D 25 =-61.8334(c=0.1, methanol)

[0390] Preparation Example 65. Synthesis of Stereoisomer A of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 65)

[0391] [ka] Stereoisomer A of [ka]

[0392] The reaction was carried out in the same manner as in Preparation Example 63, except that 2-iodo-1,1-difluoroethane (0.12 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 6], to give the title compound (0.2 g).

[0393] 1 H NMR(DMSO-d6):11.5(s,1H),8.46(d,1H),7.95(t,1H),7.81(d,1H),7.03(s,1H),6 .89(d,1H),6.04-6.05(m,2H),4.26(d,2H),3.66-3.68(m,4H),3.44-3.46(m,4H),2 .89-2.92(m,2H),2.61-2.65(m,2H),2.40(s,3H),2.17(s,3H),2.13(s,3H),2.05- 2.09(m,2H),1.80-1.85(m,1H),1.68-1.70(m,2H),1.57(s,3H),1.30-1.38(m,2H). LC-MS (ESI, m / z) = 670.5 (M+H + ) Specific rotation [α] D 25 =+57.7334(c=0.1, methanol)

[0394] Preparation Example 66. Synthesis of Stereoisomer B of 2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 66)

[0395] [ka] Stereoisomer B of [ka]

[0396] The reaction was carried out in the same manner as in Preparation Example 62, except that iodoethane (0.11 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 6], to give the title compound (0.1 g).

[0397] 1 H NMR(DMSO-d6):11.5(s,1H),8.45(s,1H),7.95(t,1H),7.82(d,1H),7.03(s,1H) ,6.89(d,1H),6.04(s,1H),4.26(d,2H),3.66-3.68(m,4H),3.44-3.46(m,4H),2 .88-2.89(m,2H),2.40(s,3H),2.22-2.28(m,2H),2.17(s,3H),2.13(s,3H),1.7 4-1.90(m,3H),1.69-1.71(m,2H),1.56(s,3H),1.32-1.37(m,2H),0.93(t,3H). LC-MS (ESI, m / z) = 634.6 (M+H + )

[0398] Preparation Example 67. Synthesis of Stereoisomer A of 2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 67)

[0399] [ka] Stereoisomer A of [ka]

[0400] The reaction was carried out in the same manner as in Preparation Example 63, except that iodoethane (0.11 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 6], to give the title compound (0.1 g).

[0401] 1 H NMR(DMSO-d6):11.5(s,1H),8.46(s,1H),7.95(t,1H),7.82(d,1H),7.03(s,1H) ),6.89(d,1H),6.05(s,1H)4.26(d,2H),3.66-3.67(m,4H),3.45-3.46(m,4H),2 .95-2.98(m,2H),2.44(s,3H),2.32-2.40(m,2H),2.17(s,3H),2.13(s,3H),1.8 3-1.89(m,3H),1.71-1.79(m,2H),1.57(s,3H),1.37-1.41(m,2H),0.97(t,3H). LC-MS (ESI, m / z) = 634.6 (M+H + )

[0402] Preparation 68. 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)-2-(1-(2,2,2-trifluoromethyl)-2-methyl)-4 ... ethyl Synthesis of )piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 68)

[0403] [ka]

[0404] Steps 1 to 5 were carried out in the same manner as in Step 1 of Production Example 33, except that 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (Intermediate 1). In Step 5, 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyridin-5-yl)-2-(piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride was obtained.

[0405] Acetonitrile (10 mL), sodium carbonate (0.43 g), and trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride salt (0.5 g, 0.70 mmole), and the mixture was stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, the mixture was filtered, and concentrated. Then, ethanol (2 mL) and hexane (20 mL) were added, and the resulting crystals were filtered and dried at an internal temperature of 60° C. to obtain the title compound (0.3 g).

[0406] 1 H NMR(DMSO-d6):11.5(s,1H),8.66(s,2H),7.90(t,1H),7.06(s,1H),6.04( s,1H),4.26(d,2H),3.65-3.69(m,4H),3.62-3.64(m,4H),3.07-3.10(m,2H ),2.90-2.92(m,2H),2.40(s,3H),2.22-2.28(m,2H),2.19(s,3H),2.12(s, 3H),1.81-1.87(m,1H),1.68-1.72(m,2H),1.56(s,3H),1.35-1.38(m,2H). LC-MS (ESI, m / z) = 689.5 (M+H + )

[0407] Preparation 69. 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)-2-(1-(2,2,2-trifluoromethyl)-2-methyl)-4 ... ethyl Synthesis of Stereoisomer B of )piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 69)

[0408] [ka] Stereoisomer B of [ka]

[0409] The reaction was carried out in the same manner as in Preparation Example 68, except that in [Step 1], stereospecific tert-butyl (R)-4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate (3 g, 6.38 mmole) was used instead of tert-butyl 4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate as the starting material, to obtain the title compound (0.3 g).

[0410] 1 H NMR(DMSO-d6):11.5(s,1H),8.67(s,2H),7.90(t,1H),7.07(s,1H),6.04( s,1H),4.26(d,2H),3.68-3.70(m,4H),3.63-3.64(m,4H),3.08-3.10(m,2H ),2.91-2.92(m,2H),2.40(s,3H),2.22-2.28(m,2H),2.19(s,3H),2.12(s, 3H),1.81-1.88(m,1H),1.68-1.71(m,2H),1.56(s,3H),1.35-1.38(m,2H). LC-MS (ESI, m / z) = 689.5 (M+H + ) Specific rotation [α] D 25 =-50.8167(c=0.1, methanol)

[0411] Preparation 70. 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)-2-(1-(2,2,2-trifluoromethyl)-2-methyl)-4 ... ethyl Synthesis of Stereoisomer A of )piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 70)

[0412] [ka] Stereoisomer A of [ka]

[0413] The reaction was carried out in the same manner as in Preparation Example 68, except that in [Step 1], stereospecific tert-butyl (S)-4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate (3 g, 6.38 mmole) was used instead of tert-butyl 4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate as the starting material, to obtain the title compound (0.3 g).

[0414] 1H NMR(DMSO-d6):11.5(s,1H),8.67(s,2H),7.90(t,1H),7.06(s,1H),6.04( s,1H),4.26(d,2H),3.68-3.70(m,4H),3.63-3.64(m,4H),3.08-3.12(m,2H ),2.92-2.98(m,2H),2.40(s,3H),2.20-2.30(m,2H),2.16(s,3H),2.12(s, 3H),1.80-1.86(m,1H),1.64-1.72(m,2H),1.56(s,3H),1.34-1.36(m,2H). LC-MS (ESI, m / z) = 689.5 (M+H + ) Specific rotation [α] D 25 =+62.5000(c=0.1, methanol)

[0415] Preparation Example 71. Synthesis of Stereoisomer B of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 71) )

[0416] [ka] Stereoisomer B of [ka]

[0417] The reaction was carried out in the same manner as in Preparation Example 69, except that 2-iodo-1,1-difluoroethane (0.12 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 6], to give the title compound (0.2 g).

[0418] 1H NMR(DMSO-d6):11.5(s,1H),8.67(s,2H),7.91(t,1H),7.06(s,1H),6.04-6. 05(m,2H),4.27(d,2H),3.68-3.70(m,4H),3.63-3.64(m,4H),2.89-2.91(m, 2H),2.62-2.65(m,2H),2.40(s,3H),2.17(s,3H),2.13(s,3H),2.07-2.09(m ,2H),1.81-1.86(m,1H),1.68-1.73(m,2H),1.57(s,3H),1.32-1.40(m,2H). LC-MS (ESI, m / z) = 671.5 (M+H + ) Specific rotation [α] D 25 =-66.4167(c=0.1, methanol)

[0419] Preparation Example 72. Synthesis of Stereoisomer A of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 72)

[0420] [ka] Stereoisomer A of [ka]

[0421] The reaction was carried out in the same manner as in Preparation Example 70, except that 2-iodo-1,1-difluoroethane (0.12 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 6], to give the title compound (0.2 g).

[0422] 1H NMR(DMSO-d6):11.5(s,1H),8.67(s,2H),7.91(t,1H),7.06(s,1H),6.0 5-6.06(m,2H),4.27(d,2H),3.68-3.70(m,4H),3.63-3.64(m,4H),2.87 -2.90(m,2H),2.62-2.65(m,1H),2.40(s,3H),2.17(s,3H),2.13(s,3H) ,2.07-2.09(m,1H),1.68-1.73(m,2H),1.57(s,3H),1.32-1.40(m,2H). LC-MS (ESI, m / z) = 671.5 (M+H + ) Specific rotation [α] D 25 =+55.1000(c=0.1, methanol)

[0423] Preparation Example 73. Synthesis of Stereoisomer B of 2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 73)

[0424] [ka] Stereoisomer B of [ka]

[0425] The reaction was carried out in the same manner as in Preparation Example 69, except that iodoethane (0.11 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 6], to give the title compound (0.1 g).

[0426] 1H NMR(DMSO-d6):11.5(s,1H),8.70(s,2H),7.92(t,1H),7.10(s,1H),6.05(s,1H) ),4,27(d,2H),3.70-3.72(m,4H),3.63-3.65(m,4H),3.40-3.51(m,2H),3.25-3 .27(m,2H),3.01-3.05(m,2H),2.82-2.88(m,2H),2.41(s,3H),2.20(s,3H),2.1 3(s,3H),1.92-2.00(m,2H),1.61(s,3H),1.54-1.57(m,1H),1.14-1.16(t,3H). LC-MS (ESI, m / z) = 635.6 (M+H + ) Specific rotation [α] D 25 =-48.7834(c=0.1, methanol)

[0427] Preparation Example 74. Synthesis of Stereoisomer A of 2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 74)

[0428] [ka] Stereoisomer A of [ka]

[0429] The reaction was carried out in the same manner as in Preparation Example 70, except that iodoethane (0.11 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 6], to give the title compound (0.1 g).

[0430] 1H NMR(DMSO-d6):11.5(s,1H),8.71(s,2H),7.92(t,1H),7.10(s,1H),6.06(s,1H) ),4,27(d,2H),3.70-3.72(m,4H),3.63-3.65(m,4H),3.40-3.51(m,2H),3.25-3 .29(m,2H),3.01-3.05(m,2H),2.82-2.88(m,2H),2.41(s,3H),2.19(s,3H),2.1 3(s,3H),1.90-1.98(m,2H),1.60(s,3H),1.53-1.59(m,1H),1.15-1.20(t,3H). LC-MS (ESI, m / z) = 635.6 (M+H + ) Specific rotation [α] D 25 =+56.6834(c=0.1, methanol)

[0431] Preparation Example 75. Synthesis of 7-(2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 75)

[0432] [ka]

[0433] Steps 1 to 5 were carried out in the same manner as in Step 1 of Production Example 33, except that 2-(4-ethylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (Intermediate 1) to give 7-(2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(pyridin-4-yl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride in Step 5.

[0434] Acetonitrile (10 mL), sodium carbonate (0.43 g), and trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride salt (0.5 g, 0.70 mmole), and the mixture was stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, the mixture was filtered, and concentrated. Then, ethanol (2 mL) and hexane (20 mL) were added, and the resulting crystals were filtered and dried at an internal temperature of 60° C. to obtain the title compound (0.2 g).

[0435] 1 H NMR(DMSO-d6):11.5(s,1H),8.65(s,2H),7.91(t,1H),7.05(s,1H),6.05(s,1H),4 .27(d,2H),3.66-3.70(m,4H),3.06-3.12(m,2H),2.91-2.93(m,2H),2.40(s,3H),2 .36-2.40(m,4H),2.30-2.34(m,2H),2.22-2.28(m,2H),2.17(s,3H),2.13(s,3H), 1.82-1.87(m,1H),1.68-1.70(m,2H),1.56(s,3H),1.34-1.38(m,2H),1.00(t,3H). LC-MS (ESI, m / z) = 716.4 (M+H + )

[0436] Preparation Example 76. Synthesis of Stereoisomer B of 7-(2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 76)

[0437] [ka] Stereoisomer B of [ka]

[0438] The reaction was carried out in the same manner as in Preparation Example 75, except that in [Step 1], stereospecific tert-butyl (R)-4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate (3 g, 6.38 mmole) was used instead of tert-butyl 4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate as the starting material, to obtain the title compound (0.2 g).

[0439] 1 H NMR(DMSO-d6):11.5(s,1H),8.64(s,2H),7.92(s,1H),7.05(s,1H),6.05(s,1H),4 .27(d,2H),3.75-3.70(m,4H),3.06-3.10(m,2H),2.91-2.93(m,2H),2.41(s,3H),2 .36-2.40(m,4H),2.30-2.34(m,2H),2.21-2.28(m,2H),2.17(s,3H),2.13(s,3H), 1.82-1.87(m,1H),1.68-1.70(m,2H),1.56(s,3H),1.35-1.38(m,2H),1.00(t,3H). LC-MS (ESI, m / z) = 716.6 (M+H + )

[0440] Preparation 77. 7-(2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl) Synthesis of Stereoisomer A of )piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 77)

[0441] [ka] Stereoisomer A of [ka]

[0442] The reaction was carried out in the same manner as in Preparation Example 75, except that in [Step 1], stereospecific tert-butyl (S)-4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate (3 g, 6.38 mmole) was used instead of tert-butyl 4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate as the starting material, to obtain the title compound (0.2 g).

[0443] 1H NMR(DMSO-d6):11.5(s,1H),8.64(s,2H),7.92(s,1H),7.06(s,1H),6.05(s,1H),4 .27(d,2H),3.73-3.74(m,4H),3.06-3.12(m,2H),2.91-2.93(m,2H),2.41(s,3H),2 .34-2.43(m,4H),2.26-2.34(m,2H),2.20-2.26(m,2H),2.17(s,3H),2.13(s,3H), 1.82-1.87(m,1H),1.68-1.70(m,2H),1.56(s,3H),1.35-1.39(m,2H),1.01(t,3H). LC-MS (ESI, m / z) = 716.6 (M+H + )

[0444] Preparation Example 78. 7-(2-(ethyl(methyl)amino)pyridine) M Synthesis of (6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 78)

[0445] [ka]

[0446] Steps 1 to 5 were carried out in the same manner as in Preparation Example 33, except that N-ethyl-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (Intermediate 1) in Step 1. In Step 5, 7-(2-(ethyl(methyl)amino)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride was obtained.

[0447] Acetonitrile (10 mL), sodium carbonate (0.43 g), and trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride salt (0.5 g, 0.73 mmole), and the mixture was stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, the mixture was filtered, and concentrated. Then, ethanol (2 mL) and hexane (20 mL) were added, and the resulting crystals were filtered and dried at an internal temperature of 60° C. to obtain the title compound (0.3 g).

[0448] 1 H NMR(DMSO-d6):11.5(s,1H),8.62(s,2H),7.90(d,1H),7.05(s,1H),6.05 (s,1H),4.26(d,2H),3.62-3.63(m,2H),3.06-3.10(m,5H),2.91-2.92(m, 2H),2.40(s,3H),2.24-2.28(m,2H),2.17(s,3H),2.13(s,3H),1.83-1.8 8(m,1H),1.69-1.72(m,2H),1.56(s,3H),1.36-1.38(m,2H),1.07(t,3H). LC-MS (ESI, m / z) = 661.5 (M+H + )

[0449] Preparation Example 79. 7-(2-(ethyl(methyl)amino)pyridine) MSynthesis of Stereoisomer B of N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 79)

[0450] [ka] Stereoisomer B of [ka]

[0451] The reaction was carried out in the same manner as in Preparation Example 78, except that in [Step 1], stereospecific tert-butyl (R)-4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate (3 g, 6.38 mmole) was used instead of tert-butyl 4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate as the starting material, to obtain the title compound (0.3 g).

[0452] 1 H NMR(DMSO-d6):11.5(s,1H),8.62(s,2H),7.90(t,1H),7.05(s,1H),6.05 (s,1H),4.26(d,2H),3.62-3.65(m,2H),3.06-3.10(m,5H),2.91-2.92(m, 2H),2.40(s,3H),2.24-2.28(m,2H),2.17(s,3H),2.13(s,3H),1.82-1.8 4(m,1H),1.69-1.70(m,2H),1.56(s,3H),1.36-1.40(m,2H),1.07(t,3H). LC-MS (ESI, m / z) = 661.5 (M+H + ) Specific rotation [α] D 25 =-49.3500(c=0.1, methanol)

[0453] Preparation Example 80. 7-(2-(ethyl(methyl)amino)pyridine) M Synthesis of Stereoisomer A of N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 80)

[0454] [ka] Stereoisomer A of [ka]

[0455] The reaction was carried out in the same manner as in Preparation Example 78, except that in [Step 1], stereospecific tert-butyl (S)-4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate (3 g, 6.38 mmole) was used instead of tert-butyl 4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate as the starting material, to obtain the title compound (0.3 g).

[0456] 1H NMR(DMSO-d6):11.5(s,1H),8.62(s,2H),7.90(t,1H),7.05(s,1H),6.05 (s,1H),4.26(d,2H),3.62-3.65(m,2H),3.06-3.12(m,5H),2.91-2.92(m, 2H),2.41(s,3H),2.24-2.28(m,2H),2.17(s,3H),2.13(s,3H),1.83-1.8 8(m,1H),1.69-1.72(m,2H),1.56(s,3H),1.36-1.38(m,2H),1.07(t,3H). LC-MS (ESI, m / z) = 661.5 (M+H + ) Specific rotation [α] D 25 =+63.2167(c=0.1, methanol)

[0457] Preparation Example 81. Synthesis of Stereoisomer B of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(2-(ethyl(methyl)amino)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 81)

[0458] [ka] Stereoisomer B of [ka]

[0459] The reaction was carried out in the same manner as in Preparation Example 79, except that 2-iodo-1,1-difluoroethane (0.13 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 6], to give the title compound (0.2 g).

[0460] 1H NMR(DMSO-d6):11.5(s,1H),8.63(s,2H),7.90(t,1H),7.04(s,1H),6.04-6. 05(m,2H),4.26(d,2H),3.61-3.64(m,2H),3.07(s,3H),2.91-2.92(m,2H),2 .62-2.65(m,2H),2.40(s,3H),2.17(s,3H),2.13(s,3H),2.06(t,2H),1.80- 1.81(m,1H),1.68-1.69(m,2H),1.56(s,3H),1.35-1.36(m,2H),1.08(t,3H). LC-MS (ESI, m / z) = 643.5 (M+H + ) Specific rotation [α] D 25 =-52.7667(c=0.1, methanol)

[0461] Preparation Example 82. Synthesis of Stereoisomer A of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(2-(ethyl(methyl)amino)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 82)

[0462] [ka] Stereoisomer A of [ka]

[0463] The reaction was carried out in the same manner as in Preparation Example 80, except that 2-iodo-1,1-difluoroethane (0.13 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 6], to give the title compound (0.2 g).

[0464] 1H NMR(DMSO-d6):11.5(s,1H),8.62(s,2H),7.91(t,1H),7.05(s,1H),6.04-6. 05(m,2H),4.26(d,2H),3.62-3.65(m,2H),3.08(s,3H),2.89-2.92(m,2H),2 .62-2.78(m,2H),2.41(s,3H),2.17(s,3H),2.13(s,3H),2.06(t,2H),1.81- 1.86(m,1H),1.68-1.69(m,2H),1.57(s,3H),1.35-1.39(m,2H),1.07(t,3H). LC-MS (ESI, m / z) = 643.5 (M+H + ) Specific rotation [α] D 25 =+62.1000(c=0.1, methanol)

[0465] Preparation Example 83. Synthesis of Stereoisomer B of 7-(2-(ethyl(methyl)amino)pyrimidin-5-yl)-2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 83)

[0466] [ka] Stereoisomer B of [ka]

[0467] The reaction was carried out in the same manner as in Preparation Example 79, except that iodoethane (0.12 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 6], to give the title compound (0.1 g).

[0468] 1H NMR(DMSO-d6):11.5(s,1H),8.63(s,2H),7.92(t,1H),7.08(s,1H),6.06(s ,1H),4.28(d,2H),3.61-3.64(m,2H),3.40-3.47(m,2H),3.08(s,3H),2.96 -3.05(m,2H),2.61-2.90(m,2H),2.41(s,3H),2.19(s,3H),2.13(s,3H),1. 91-1.96(m,3H),1.60(s,3H),1.55-1.57(m,2H),1.14(t,3H),1.07(t,3H). LC-MS (ESI, m / z) = 607.5 (M+H + )

[0469] Preparation Example 84. Synthesis of Stereoisomer A of 7-(2-(ethyl(methyl)amino)pyrimidin-5-yl)-2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 84)

[0470] [ka] Stereoisomer A of [ka]

[0471] The reaction was carried out in the same manner as in Preparation Example 80, except that iodoethane (0.12 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 6], to give the title compound (0.1 g).

[0472] 1H NMR(DMSO-d6):11.5(s,1H),8.63(s,2H),7.92(t,1H),7.08(s,1H),6.06(s, 1H),4.27(d,2H),3.63-3.66(m,2H),3.43-3.55(m,2H),3.08(s,3H),3.03-3 .06(m,2H),2.80-2.96(m,2H),2.41(s,3H),2.21(s,3H),2.13(s,3H),1.93- 2.00(m,3H),1.60(s,3H),1.28-1.32(m,2H),1.11-1.28(m,3H),1.07(t,3H). LC-MS (ESI, m / z) = 607.5 (M+H + )

[0473] Preparation 85. 7-(6-(ethyl(methyl)amino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoromethyl)amino)-2-(2-methyl-4- ... ethyl Synthesis of )piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 85)

[0474] [ka]

[0475] [Steps 1 to 5] were carried out in the same manner as above, except that N-ethyl-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (Intermediate 1) in [Step 1] of Production Example 33, and 7-(6-(ethyl(methyl)amino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride was obtained in [Step 5].

[0476] Acetonitrile (10 mL), sodium carbonate (0.43 g), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride salt (0.5 g, 0.73 mmole), and the mixture was stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, the mixture was filtered, and concentrated. After ethanol (2 mL) and hexane (20 mL) were added, the resulting crystals were filtered and dried at an internal temperature of 60° C. to obtain the title compound (0.3 g).

[0477] 1 H NMR(DMSO-d6):11.6(s,1H),8.41(s,1H),7.92(t,1H),7.76(d,1H),7.01(s,1H),6 .65(d,1H),6.03(s,1H),4.25(d,2H),3.51-3.53(m,2H),3.05-3.11(m,2H),2.96(s ,3H),2.91-2.93(m,2H),2.41(s,3H),2.26-2.28(m,2H),2.16(s,3H),2.13(s,3H), 1.82-1.86(m,1H),1.69-1.71(m,2H),1.56(s,3H),1.36-1.41(m,2H),1.04(t,3H). LC-MS (ESI, m / z) = 660.5 (M+H + )

[0478] Preparation Example 86. Synthesis of Stereoisomer B of 7-(6-(ethyl(methyl)amino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 86)

[0479] [ka] Stereoisomer B of [ka]

[0480] The reaction was carried out in the same manner as in Preparation Example 85, except that in [Step 1], stereospecific tert-butyl (R)-4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate (3 g, 6.38 mmole) was used instead of tert-butyl 4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate as the starting material, to obtain the title compound (0.3 g).

[0481] 1 H NMR(DMSO-d6):11.5(s,1H),8.41(s,1H),7.93(t,1H),7.76(d,1H),7.01(s,1H),6 .65(d,1H),6.04(s,1H),4.26(d,2H),3.52-3.55(m,2H),3.06-3.12(m,2H),2.96(s ,3H),2.91-2.93(m,2H),2.41(s,3H),2.27-2.29(m,2H),2.16(s,3H),2.13(s,3H), 1.82-1.86(m,1H),1.69-1.71(m,2H),1.56(s,3H),1.36-1.41(m,2H),1.04(t,3H). LC-MS (ESI, m / z) = 660.5 (M+H + ) Specific rotation [α] D 25 =-61.9834(c=0.1, methanol)

[0482] Preparation Example 87. Synthesis of Stereoisomer A of 7-(6-(ethyl(methyl)amino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 87)

[0483] [ka] Stereoisomer A of [ka]

[0484] The reaction was carried out in the same manner as in Preparation Example 85, except that in [Step 1], stereospecific tert-butyl (S)-4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate (3 g, 6.38 mmole) was used instead of tert-butyl 4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate as the starting material, to obtain the title compound (0.3 g).

[0485] 1H NMR(DMSO-d6):11.5(s,1H),8.41(s,1H),7.93(t,1H),7.76(d,1H),7.01(s,1H),6 .65(d,1H),6.05(s,1H),4.26(d,2H),3.51-3.56(m,2H),3.08-3.12(m,2H),2.97(s ,3H),2.91-2.94(m,2H),2.41(s,3H),2.26-2.28(m,2H),2.16(s,3H),2.13(s,3H), 1.82-1.87(m,1H),1.69-1.73(m,2H),1.56(s,3H),1.36-1.41(m,2H),1.03(t,3H). LC-MS (ESI, m / z) = 660.5 (M+H + )

[0486] Preparation Example 88. Synthesis of Stereoisomer B of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(6-(ethyl(methyl)amino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 88)

[0487] [ka] Stereoisomer B of [ka]

[0488] The reaction was carried out in the same manner as in Preparation Example 86, except that 2-iodo-1,1-difluoroethane (0.13 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 6], to give the title compound (0.2 g).

[0489] 1H NMR(DMSO-d6):11.5(s,1H),8.40(s,1H),7.94(t,1H),7.74(d,1H),7.01(s,1H),6. 66(d,1H),5.95-6.07(m,3H),4.26(d,2H),3.52-3.55(m,2H)2.97(s,3H),2.90-2.92 (m,2H),2.62-2.67(m,2H),2.41(s,3H),2.16(s,3H),2.13(s,3H),2.07-2.10(m,2H) .1.80-1.84(m,1H),1.68-1.71(m,2H),1.56(s,3H),1.35-1.42(m,2H),1.04(t,3H). LC-MS (ESI, m / z) = 642.5 (M+H + )

[0490] Preparation Example 89. Synthesis of Stereoisomer B of 7-(6-(ethyl(methyl)amino)pyridin-3-yl)-2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 89)

[0491] [ka] Stereoisomer B of [ka]

[0492] The reaction was carried out in the same manner as in the above Preparation Example 86, except that iodoethane (0.12 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in [Step 6], to give the title compound (0.1 g).

[0493] 1H NMR(DMSO-d6):11.5(s,1H),8.46(s,1H),7.95(t,1H),7.77(d,1H),7.03(s,1H),6 .65(d,1H),6.05(s,1H),4.26(d,2H),3.54-3.56(m,2H),3.47-3.49(m,2H),3.01-3 .04(m,2H),2.97(s,3H),2.84-2.90(m,2H),2.41(s,3H),2.19-2.20(m,1H),2.18(s ,3H),2.13(s,3H),1.94-2.01(m,2H),1.60-1.65(m,5H),1.16(t,3H),1.04(t,3H). LC-MS (ESI, m / z) = 606.5 (M+H + )

[0494] Preparation Example 90. Synthesis of 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(4-(piperidin-1-yl)phenyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 90)

[0495] [ka]

[0496] Steps 1 to 5 were carried out in the same manner as in Step 1 of Production Example 33, except that 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (Intermediate 1) in Step 1. In Step 5, 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(4-(piperidin-1-yl)phenyl)-2-(piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride was obtained.

[0497] Acetonitrile (10 mL), sodium carbonate (0.43 g), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride salt (0.5 g, 0.73 mmole), and the mixture was stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, the mixture was filtered, and concentrated. After ethanol (2 mL) and hexane (20 mL) were added, the resulting crystals were filtered and dried at an internal temperature of 60° C. to obtain the title compound (0.3 g).

[0498] 1 H NMR(DMSO-d6):11.5(s,1H),7.95(t,1H),7.50(d,2H),7.01(s,1H),6.91(d,2H),6 .04(s,1H),4.26(d,2H),3.14-3.16(m,4H),3.04-3.14(m,2H),2.91-2.96(m,2H),2 .41(s,3H),2.20-2.28(m,2H),2.16(s,3H),2.13(s,3H),1.82-1.86(m,1H),1.66- 1.73(m,2H),1.55-1.58(m,4H),1.55(s,3H),1.49-1.54(m,2H),1.35-1.40(m,2H). LC-MS (ESI, m / z) = 685.5 (M+H + )

[0499] Preparation Example 91. Synthesis of 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-(piperidin-1-yl)pyridin-3-yl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 91)

[0500] [ka]

[0501] Steps 1 to 5 were carried out in the same manner as in Step 1 of Production Example 33, except that 2-(piperidin-1-yl)-5-(4,4,5,5-tetraamyl-1,3,2-dioxaborolan-2-yl)pyridine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (Intermediate 1). In Step 1, 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-(piperidin-1-yl)pyridin-3-yl)-2-(piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride was obtained in Step 5.

[0502] Acetonitrile (10 mL), sodium carbonate (0.43 g), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride salt (0.5 g, 0.73 mmole), and the mixture was stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, the mixture was filtered, and concentrated. After ethanol (2 mL) and hexane (20 mL) were added, the resulting crystals were filtered and dried at an internal temperature of 60° C. to obtain the title compound (0.3 g).

[0503] 1 H NMR(DMSO-d6):11.5(s,1H),8.40(s,1H),7.94(t,1H),7.81(d,1H),7.02(s,1H),6 .89(d,1H),6.05(d,1H),4.26(d,2H),3.51-3.54(m,4H),3.09(d,2H),2.93(d,2H), 2.41(s,3H),2.22-2.30(m,2H),2.16(s,3H),2.13(s,3H),1.80-1.90(m,1H),1.69- 1.71(d,2H),1.56-1.57(m,2H),1.56(s,3H),1.51-1.52(m,4H),1.34-1.40(m,2H). LC-MS (ESI, m / z) = 686.4 (M+H + )

[0504] Preparation Example 92. Synthesis of 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-thiomorpholinopyrimidin-5-yl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 92)

[0505] [ka]

[0506] Steps 1 to 5 were carried out in the same manner as in Step 1 of Production Example 33, except that 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)thiomorpholine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (Intermediate 1). In Step 5, 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(piperidin-4-yl)-7-(6-thiomorpholinopyridin-3-yl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride was obtained.

[0507] Acetonitrile (10 mL), sodium carbonate (0.43 g), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride salt (0.5 g, 0.73 mmole), and the mixture was stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, the mixture was filtered, and concentrated. After ethanol (2 mL) and hexane (20 mL) were added, the resulting crystals were filtered and dried at an internal temperature of 60° C. to obtain the title compound (0.3 g).

[0508] 1H NMR(DMSO-d6):11.5(s.1H),8.70(s,2H),7.91(t,1H),7.06(s,1H),6.04(s ,1H),4.24-4.28(m,2H),4.06-4.08(m,4H),3.08-3.10(m,2H),2.88-2.95(m ,2H),2.58-2.60(m,4H)2.41(s.3H),2.21-2.30(m,2H),2.17(s,3H),2.13(s ,3H),1.78-1.88(m,1H),1.65-1.71(m,2H),1.56(s,3H),1.34-1.38(m,2H). LC-MS (ESI, m / z) = 705.8 (M+H + )

[0509] Preparation Example 93. Synthesis of 2',2'-difluoro-2,7-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-[4,5'-bibenzo[d][1,3]dioxole]-6-carboxamide (Compound 93)

[0510] [ka]

[0511] In Step 1 of Production Example 33, 2',2'-difluoro-2,7-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(piperidin-4-yl)-[4,5'-bibenzo[d][1,3]dioxole-6-carboxamide hydrochloride was obtained in Step 5.

[0512] Acetonitrile (10 mL), sodium carbonate (0.43 g), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride salt (0.5 g, 0.73 mmole), and the mixture was stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, the mixture was filtered, and concentrated. After ethanol (2 mL) and hexane (20 mL) were added, the resulting crystals were filtered and dried at an internal temperature of 60° C. to obtain the title compound (0.3 g).

[0513] 1 H NMR(DMSO-d6):11.5(s,1H),7.95(t,1H),7.67(s,1H),7.49-7.51(m,1H), 7.46-7.47(m,1H),7.07(s,1H),6.05(s,1H),4.27(d,2H),3.06-3.12(m,2H ),2.89-2.95(m,2H),2.41(s,3H),2.25-2.31(m,2H),2.19(s,3H),2.13(s, 3H),1.83-1.88(m,1H),1.69-1.71(m,2H),1.58(s,3H),1.35-1.40(m,2H). LC-MS (ESI, m / z) = 682.7 (M+H + )

[0514] Preparation Example 94. Synthesis of 2,7-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-[4,5'-bibenzo[d][1,3]dioxole]-6-carboxamide (Compound 94)

[0515] [ka]

[0516] Steps 1 to 5 were carried out in the same manner as in Preparation Example 33, except that 2-(benzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (Intermediate 1) in Step 1. Thus, 2,7-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(piperidin-4-yl)-[4,5′-bibenzo[d][1,3]dioxole]-6-carboxamide hydrochloride was obtained in Step 5.

[0517] Acetonitrile (10 mL), sodium carbonate (0.43 g), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride salt (0.5 g, 0.73 mmole), and the mixture was stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, the mixture was filtered, and concentrated. After ethanol (2 mL) and hexane (20 mL) were added, the resulting crystals were filtered and dried at an internal temperature of 60° C. to obtain the title compound (0.3 g).

[0518] 1 H NMR(DMSO-d6):11.5(s,1H),7.96(t,1H),7.21(s,1H),7.19-7.20(m,1H),7.0 1(s,1H),6.97-6.98(m,1H),6.04(s,1H),6.01(s,2H),4.26(d,2H),3.06-3.13 (m,2H),2.91-2.94(m,2H),2.41(s,3H),2.21-2.30(m,2H),2.17(s,3H),2.13 (s,3H),1.82-1.87(m,1H),1.68-1.72(m,2H),1.56(s,3H),1.32-1.38(m,2H). LC-MS (ESI, m / z) = 646.7 (M+H + )

[0519] Preparation Example 95. Synthesis of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-2,7-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-[4,5'-bibenzo[d][1,3]dioxole]-6-carboxamide (Compound 95)

[0520] [ka]

[0521] 2,7-Dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(piperidin-4-yl)-[4,5'-bibenzo[d][1,3]dioxole]-6-carboxamide hydrochloride (0.5 g, 0.73 mmole), obtained by a method similar to that of [Steps 1 to 5] of Preparation Example 94, was added to acetonitrile (10 mL), sodium carbonate (0.43 g), and 2-iodo-1,1-difluoroethane (0.09 mL), and the mixture was stirred at an internal temperature of 100 ° C. for 24 hours. After cooling, dichloromethane (5 mL) was added, the mixture was filtered, and the mixture was concentrated. After ethanol (2 mL) and hexane (20 mL) were added, the resulting crystals were filtered and dried at an internal temperature of 60 ° C. to obtain the title compound (0.3 g).

[0522] 1 H NMR(DMSO-d6):11.5(s,1H),7.96(t,1H),7.21(s,1H),7.19-7.20(m,1H),7.0 1(s,1H),6.97-6.98(m,1H),6.04(s,1H),6.01(t,1H),4.26(d,2H),2.89-2.92 (m,2H),2.61-2.68(m,2H),2.46(s,3H),2.17(s,3H),2.13(s,3H),2.05-2.10 (m,2H),1.83-1.84(m,1H),1.67-1.70(m,2H),1.57(s,3H),1.34-1.39(m,2H). LC-MS (ESI, m / z) = 628.5 (M+H + )

[0523] Preparation Example 96. Synthesis of 7-(benzofuran-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 96)

[0524] [ka]

[0525] In Step 1 of Production Example 33, (2S,6R)-2,6-dimethyl-4-(5-( Steps 1 to 5 were carried out in the same manner, except that 2-(benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridin-2-yl)morpholine (Intermediate 1). Step 5: 7-(benzofuran-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride was obtained.

[0526] Acetonitrile (10 mL), sodium carbonate (0.43 g), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride salt (0.5 g, 0.73 mmole), and the mixture was stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, the mixture was filtered, and concentrated. After ethanol (2 mL) and hexane (20 mL) were added, the resulting crystals were filtered and dried at an internal temperature of 60° C. to obtain the title compound (0.3 g).

[0527] 1 H NMR (DMSO-d6): 1H NMR(DMSO-d6):11.5(s,1H),7.99(s,2H),7.91(s,1H),7.61-7.63(m,1H),7.6 0-7.61(m,1H),7.09(s,1H),6.99(s,1H),6.04(s,1H),4.27(d,2H),3.06-3.10 (m,2H),2.92-2.94(m,2H),2.41(s,3H),2.26-2.30(m,2H),2.19(s,3H),2.13 (s,3H),1.84-1.89(m,2H),1.71-1.74(m,2H),1.58(s,3H),1.38-1.41(m,2H). LC-MS (ESI, m / z) = 642.6 (M+H + )

[0528] Preparation Example 97. Synthesis of 7-(benzofuran-5-yl)-2-(1-(2,2-difluoroethyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 97)

[0529] [ka]

[0530] Acetonitrile (10 mL), sodium carbonate (0.43 g), and 2-iodo-1,1-difluoroethane (0.09 mL) were added to 7-(benzofuran-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride (0.5 g, 0.73 mmole), obtained by a method similar to that of [Steps 1 to 5] of Preparation Example 96, and the mixture was stirred at an internal temperature of 100°C for 24 hours. After cooling, dichloromethane (5 mL) was added, filtered, and concentrated. After ethanol (2 mL) was added, the mixture was concentrated. The resulting crystals were filtered and dried at an internal temperature of 60° C. to give the title compound (0.3 g).

[0531] 1 H NMR(DMSO-d6):11.5(s,1H),7.99(s,2H),7.90(s,1H),7.62-7.63(m,1H),7.6 0-7.61(m,1H),7.08(s,1H),6.99(s,1H),5.94-6.06(m,2H),4.27(d,2H),2.91 (d,2H),2.60-2.67(m,2H),2.41(s,3H),2.19(s,3H),2.13(s,3H),2.06-2.10 (m,2H),1.83-1.87(m,1H),1.69-1.72(m,2H),1.58(s,3H),1.33-1.41(m,2H). LC-MS (ESI, m / z) = 624.6 (M+H + )

[0532] Preparation Example 98. Synthesis of 7-(6-(butyl(methyl)amino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 98)

[0533] [ka]

[0534] [Steps 1 to 5] were carried out in the same manner as above, except that N-butyl-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (Intermediate 1) in [Step 1] of Production Example 33, and 7-(6-(butyl(methyl)amino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride was obtained in [Step 5].

[0535] Acetonitrile (10 mL), sodium carbonate (0.43 g), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride salt (0.5 g, 0.73 mmole), and the mixture was stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, the mixture was filtered, and concentrated. Then, ethanol (2 mL) and hexane (20 mL) were added, and the resulting crystals were filtered and dried at an internal temperature of 60° C. to obtain the title compound (0.3 g).

[0536] 1 H NMR(DMSO-d6):11.5(s,1H),8.40(s,1H),7.93(t,1H),7.74(d,1H),7.01(s,1H),6.64(d,1 H),6.05(s,1H),4.26(d,2H),3.48(t,2H),3.06-3.12(m,2H),2.97(s,3H),2.94(d,2H),2.41(s,3H),2.27(t,2H),2.17(s,3H) ),2.13(s,3H),1.84(t,1H),1.70(d,2H),1.56(s,3H),1.46-1.50(m,2H),1.32-1.43(m,2H),1.24-1.28(m,2H),0.88(t,3H). LC-MS (ESI, m / z) = 688.8 (M+H + )

[0537] Preparation Example 99. 7-(6-(butyl(methyl)amino)pyridine M Synthesis of (6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 99)

[0538] [ka]

[0539] Steps 1 to 5 were carried out in the same manner as in Preparation Example 33, except that N-butyl-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine was used instead of (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (Intermediate 1) in Step 1. In Step 5, 7-(2-(butyl(methyl)amino)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride was obtained.

[0540] Acetonitrile (10 mL), sodium carbonate (0.43 g), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride salt (0.5 g, 0.73 mmole), and the mixture was stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, the mixture was filtered, and concentrated. After ethanol (2 mL) and hexane (20 mL) were added, the resulting crystals were filtered and dried at an internal temperature of 60° C. to obtain the title compound (0.3 g).

[0541] 1H NMR(DMSO-d6):11.5(s,1H),8.62(s,2H),7.90(t,1H),7.05(s,1H),6.05(s ,1H),4.26(d,2H),3.58(t,2H),3.06-3.10(m,5H),2.92(d,2H),2.41(s,3H ),2.27(t,2H),2.18(s,3H),2.13(s,3H),1.85(t,1H),1.70(d,2H),1.57(s ,3H),1.49-1.53(m,2H),1.30-1.41(m,2H),1.24-1.29(m,2H),0.88(t,3H). LC-MS (ESI, m / z) = 689.8 (M+H + )

[0542] Preparation Example 100. Synthesis of 2-(trans-4-aminocyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride (Compound 100)

[0543] [ka]

[0544] [Step 1] Synthesis of 2-((trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethoxymorpholino)pyridin-3-yl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylic acid Methyl 7-bromo-2-((trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate (10 g, 20.64 mmole) was added to dioxane (50 mL) and purified water (25 mL). Next, (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (8.54 g) was added, followed by tetrakis(triphenylphosphine)palladium (0.48 g) and sodium carbonate (4.37 g), and the mixture was stirred at 90°C for 4 hours. After the reaction was completed, ethyl acetate was added. The reaction mixture was filtered and washed with ethyl acetate (25 mL). After concentration under reduced pressure, ethyl acetate (80 mL) and purified water (80 mL) were added and stirred for 30 minutes. The reaction mixture was allowed to stand and separated into layers. Anhydrous sodium sulfate and activated carbon were added to the organic layer and stirred for 1 hour. The reaction mixture was filtered and concentrated. The resulting methyl 2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethoxymorpholino)pyridin-3-yl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate intermediate was used for the next reaction without further purification.

[0545] The resulting intermediate was dissolved in tetrahydrofuran (72 mL) and methanol (36 mL), and then 2N aqueous sodium hydroxide solution (46.5 mL) was added and the mixture was refluxed and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (70 mL) and purified water (30 mL) were added to the residue, and the pH was adjusted to 4.0 with 20% aqueous hydrochloric acid solution (13 mL). The reaction mixture was allowed to stand, and then the layers were separated. Anhydrous sodium sulfate and activated carbon were added to the organic layer, and the mixture was stirred for 1 hour. The reaction mixture was filtered and washed with dichloromethane (20 mL). The filtered organic matter was concentrated under reduced pressure, and acetonitrile (90 mL) was added to the residue. The mixture was refluxed and stirred for 2 hours, and then cooled. The resulting solid was filtered, washed with acetonitrile (30 mL), and then dried under reduced pressure to obtain the title compound 2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethoxymorpholino)pyridin-3-yl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylic acid (9.9 g, 17.01 mmol).

[0546] [Step 2] Synthesis of tert-butyl (trans-4-(7-(6-((2S,6R)-2,6-dimethoxymorpholino)pyridin-3-yl)-2,4-dimethyl-5-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)benzo[d][1,3]dioxol-2-yl)cyclohexyl)carbamate Dimethylformamide (18 mL) and triethylamine (9.5 mL) were added to the compound obtained in [Step 1] (9.9 g, 17.01 mmole). Pentafluorophenyl trifluoroacetate (3.04 mL) was then added dropwise, and the mixture was stirred at room temperature for 3 hours. Triethylamine (4.73 mL) was then added to the reaction mixture, followed by 3-(aminomethyl)-6-methyl-4-(methylthio)pyridin-2(1H)-one hydrochloride (4.5 g), and the mixture was stirred at an internal temperature of 50°C. After the reaction was completed, the mixture was concentrated under reduced pressure. The concentrated residue was dissolved in dichloromethane (40 mL) and purified water (40 mL), and the aqueous layer was separated. Purified water (30 mL) was added to the organic layer, and the pH was adjusted to 3.5 with 20% aqueous hydrochloric acid. The layers were then separated to separate the organic layer. Anhydrous sodium sulfate and activated carbon were added to the separated organic layer, and the mixture was stirred for 1 hour. The reaction mixture was filtered, washed with dichloromethane (15 mL), concentrated, and used in Step 3 without further purification.

[0547] [Step 3] Synthesis of 2-(trans-4-aminocyclohexyl)-7-(6-((2S,6R)-2,6-dimethoxymorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride

[0548] [ka]

[0549] To the compound obtained in Step 2, 1M hydrochloric acid (aqueous ethanol solution) (100 mL) was added, and the mixture was heated to 70°C and stirred. After the reaction was completed, the reaction mixture was added dropwise to ethyl acetate (338 mL), and the resulting solid was filtered and dried at an internal temperature of 60°C to obtain the title compound (11.0 g, 16.98 mmol).

[0550] 1H NMR(DMSO-d6):11.5(s,1H),8.44(s,1H),8.16(br.s,2H),7.95(t,1H),7.81(d,1H),7.03( s,1H),6.89(d,1H),6.05(s,1H),4.26(d,2H),4.14(d,2H),3.55-3.57(m,2H),2.89-2.93( m,1H),2.41(s,3H),2.34-2.39(m,2H),2.17(s,3H),2.13(s,3H),1.95-2.01(m,2H),1.81- 1.90(m,3H),1.55(s,3H),1.28-1.39(m,2H),1.18-1.28(m,2H),1.13(s,3H),1.11(s,3H). LC-MS (ESI, m / z) = 648.6 (M+H + )

[0551] Preparation Example 101. Synthesis of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(trans-4-(3-hydroxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 101)

[0552] [ka]

[0553] Dichloromethane and purified water were added to the compound obtained in [Step 3] of Preparation Example 100 (8 g, 12.3 mmole). 2N aqueous sodium hydroxide solution was added to adjust the pH to 7-8, followed by layer separation. The oil layer was dried over sodium sulfate. After filtration and concentration, ethanol was added, followed by (R)-epichlorohydrin and heating. After the reaction was complete, the mixture was cooled, calcium carbonate was added, the mixture was heated, and the reaction was continued. After cooling and filtration, the mixture was separated into layers using dichloromethane and purified water. The oil layer was dried over sodium sulfate, filtered, concentrated, purified using a column, and recrystallized from dichloromethane and ethyl acetate to obtain the title compound (5.4 g, 7.7 mmole).

[0554] 1 H NMR(DMSO-d6):11.5(s,1H),8.43(s,1H),7.94(t,1H),7.79(d,1H),7.02(s,1H),6.89(d,1H),6.05( s,1H),5.25(br.s,1H),4.27(d,2H),4.14(d,2H),4.09-4.13(m,1H),3.51-3.60(m,2H),3.40-3.51( m,2H),2.68-2.74(m,3H),2.41(s,3H),2.36-2.40(m,2H),2.15(s,3H),2.13(s,3H),1.78-1.87(m,3 H),1.73-1.75(m,2H),1.54(s,3H),1.28-1.21(m,2H),1.13(s,3H),1.12(s,3H),0.87-0.81(m,2H). LC-MS (ESI, m / z) = 704.6 (M+H + )

[0555] Preparation Example 102. 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(3-(2,2,2-trifluoromethyl)propan-1-yl)methyl) Ethoxy Synthesis of )azetidin-1-yl)cyclohexyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 102)

[0556] [ka]

[0557] Dimethylformamide (20 mL) was added to the compound obtained in Preparation Example 101 (300 mg, 0.42 mmole). Cesium carbonate (347 mg) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (99 mg) were added, and the mixture was stirred at 90°C for 15 hours and distilled. The mixture was separated into layers using dichloromethane and purified water, dried over anhydrous sodium sulfate, filtered, washed, and then distilled under reduced pressure. The mixture was purified by column chromatography to obtain the title compound (135 mg).

[0558] 1 H NMR(DMSO-d6):11.5(s,1H),8.42(s,1H),8.09(t,1H),7.76(d,1H),7.01(s,1H),6.90(d,1 H),6.89(s,1H),4.88-4.92(m,2H),4.38-4.39(m,2H),4.30-4.31(m,1H),4.20-4.30(m,2H) ),4.13-4.15(m,2H),3.55-3.57(m,3H),2.60-2.66(m,2H),2.36-2.43(m,2H),2.35(s,3H) ,2.16(s,3H),1.79-1.81(m,7H),1.55(s,3H),1.13(s,3H),1.12(s,6H),1.01-1.08(m,2H). LC-MS (ESI, m / z) = 786.6 (M+H + )

[0559] Preparation Example 103. Synthesis of 2-(trans-4-(3-(2,2-difluoroethoxy)azetidin-1-yl)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 103)

[0560] [ka]

[0561] The compound obtained in Preparation Example 101 (300 mg, 0.43 mmole) was used in the same manner as in Preparation Example 102, except that 2-iodo-1,1-difluoroethane (0.04 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in Preparation Example 102, to give the title compound (71 mg, 0.09 mmole).

[0562] 1 H NMR(DMSO-d6):11.5(s,1H),8.42(s,1H),8.06(t,1H),7.77-7.79(m,1H),7.01(s,1H),6.90(d,1H),6.85(s,1H), 6.33(t,1H),6.05(s,1H),4.50-4.51(m,2H),4.30-4.38(m,3H),4.13-4.15(m,2H),4.06-4.07(m,1H),3.55-3.57 (m,2H),3.43-3.45(m,2H),2.60-2.66(m,2H),2.45-2.47(m,2H),2.36-2.43(m,2H),2.35(s,3H),2.15(s,3H),1. 79-1.81(m,1H),1.75-1.78(m,4H),1.72-1.75(m,2H),1.54(s,3H),1.13(s,3H),1.12(s,6H),0.83-0.86(m,2H). LC-MS (ESI, m / z) = 768.7 (M+H + )

[0563] Manufacturing Example 104. 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(3-(4,4,4-trifluorobutoxy)azetidin-1-yl)cyclohexyl)benzo[d][1,3]dioxole-5-carboxamide Synthesis of (Compound 104)

[0564] [ka]

[0565] The compound obtained in Preparation Example 101 (300 mg, 0.43 mmole) was used in the same manner as in Preparation Example 102, except that 1,1,1-trifluoro-4-iodobutane (0.06 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in Preparation Example 102, to give the title compound (71 mg, 0.09 mmole).

[0566] 1 H NMR(DMSO-d6):11.6(s,1H),8.44(s,1H),7.93(t,1H),7.78-7.81(m,1H),7.01(d,1H),6.89(d,1H),6 .78(s,1H),4.36-4.39(m,2H),4.29-4.30(m,2H),4.26-4.29(m,2H),4.13-4.15(m,2H),3.95-3.97(m, 2H),3.55-3.57(m,3H),2.60-2.66(m,4H),2.43-2.46(m,3H),2.35-2.38(m,2H),2.43(s,3H),2.15(s ,3H),1.78-1.87(m,4H),1.76-1.77(m,1H),1.55(s,3H),1.13(s,3H),1.12(s,6H),1.01-1.08(m,2H). LC-MS (ESI, m / z) = 814.7 (M+H + )

[0567] Preparation Example 105. Synthesis of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(trans-4-(3-isopropoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 105)

[0568] [ka]

[0569] The compound obtained in Preparation Example 101 (300 mg, 0.43 mmole) was used in the same manner as in Preparation Example 102, except that 2-iodopropane (0.04 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in Preparation Example 102, to give the title compound (56 mg, 0.08 mmole).

[0570] 1 H NMR(DMSO-d6):11.5(s,1H),8.42(s,1H),8.00(t,1H),7.77(d,1H),7.00(s,1H),6.90(d,1H),6.72(s,1 H),5.20-5.23(m,2H),4.34(d,2H),4.30-4.31(m,1H),4.14(d,2H),4.06-4.08(m,1H),3.56-3.57(m,2H) ),2.43-2.46(m,3H),2.34-2.42(m,2H),2.30(s,3H),2.16(s,3H),1.79-1.87(m,1H),1.78-1.87(m,4H) ,1.72-1.74(m,2H),1.54(s,3H),1.23(s,3H),1.22(s,3H),1.13(s,3H),1.12(s,6H),0.83-0.86(m,2H). LC-MS (ESI, m / z) = 746.7 (M+H + )

[0571] Preparation Example 106. Synthesis of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(trans-4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 106)

[0572] [ka]

[0573] The compound obtained in Preparation Example 101 (300 mg, 0.43 mmole) was used in the same manner as in Preparation Example 102, except that iodomethane (0.03 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in Preparation Example 102, to give the title compound (10 mg, 0.02 mmole).

[0574] 1 H NMR(DMSO-d6):11.5(s.1H),8.43(s,1H),7.94(t,1H),7.80(d,1H),7.02(s,1H),6.89(d,1H),6.05(s,1H) ),4.24-4.27(d,2H),4.14(d,2H),3.45-3.60(m,2H),3.36-3.37(m,1H),2.86-2.90(m,2H),2.61-2.64(m, 2H),2.58-2.59(m,1H),2.41(s,3H),2.34-2.39(m,2H),2.28-2.33(m,2H),2.18(s,3H),2.16(s,3H),2.1 3(s,3H),1.84-1.89(m,2H),1.72-1.82(m,3H),1.55(s,3H),1.14-1.20(m,2H),1.13(s,3H),1.12(s,3H). LC-MS (ESI, m / z) = 718.5 (M+H + )

[0575] Preparation Example 107. Synthesis of Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-2-(trans-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 107)

[0576] [ka] Stereoisomer B of [ka]

[0577] The same reaction as in [Step 1] to [Step 7] of Preparation Example 20 was carried out, except that stereospecific methyl-(R)-7-bromo-2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate (0.5 g, 1.03 mmole) was used instead of methyl-7-bromo-2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate as the starting material in [Step 1] of Preparation Example 20, to obtain the title compound (0.2 g, 0.27 mmole).

[0578] 1 H NMR(DMSO-d6):11.5(s,1H),8.29(d,2H),8.09(s,1H),7.51(d,1H),7.15(s,1H),6.12 (s,1H),4.36(d,2H),4.29(s,2H),4.12-4.13(m,1H),3.63-3.64(m,2H),3.23-3.24(m, 1H),2.76-2.78(m,6H),2.75(s,3H),2.42(s,3H),2.22(s,3H),2.17-2.21(m,2H),1.9 8(s,3H),1.59(s,3H),1.56-1.58(m,2H),1.21-1.41(m,2H),1.14(s,3H),1.13(s,3H). LC-MS (ESI, m / z) = 744.8 (M+H + )

[0579] Preparation Example 108. 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-2-(trans-4-(methyl(2,2,2-triphenylphosphine)-2-yl)-2,4-dimethyl ... Synthesis of Stereoisomer A of (6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 108)

[0580] [ka] Stereoisomer A of [ka]

[0581] The same reaction as in [Step 1] to [Step 7] of Preparation Example 20 was carried out, except that stereospecific methyl-(S)-7-bromo-2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate (0.5 g, 1.03 mmole) was used instead of methyl-7-bromo-2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate as the starting material in [Step 1] of Preparation Example 20, to obtain the title compound (0.2 g, 0.27 mmole).

[0582] 1 H NMR(DMSO-d6):11.5(s,1H),8.29(d,2H),8.09(s,1H),7.50(d,1H),7.15(s,1H),6.12 (s,1H),4.36(d,2H),4.29(s,2H),4.12-4.13(m,1H),3.64-3.67(m,2H),3.21-3.23(m, 1H),2.76-2.75(m,6H),2.43(s,3H),2.20(s,3H),2.19(s,3H),2.16-2.18(m,2H),1.9 7(s,3H),1.59(s,3H),1.42-1.58(m,2H),1.21-1.32(m,2H),1.14(s,3H),1.13(s,3H). LC-MS (ESI, m / z) = 744.8 (M+H + )

[0583] Preparation Example 109. 2-(trans-4-((2,2-difluoroethyl )Synthesis of (methyl)amino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 109)

[0584] [ka]

[0585] The compound (0.5 g, 0.68 mmole) obtained by the same reaction as in [Steps 1 to 6] of Preparation Example 20 was used to carry out the reaction in [Step 7], except that in [Step 7], the reaction was carried out using 2-iodo-1,1-difluoroethane (0.12 ml) instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate, to obtain the title compound (0.2 g).

[0586] 1 H NMR(DMSO-d6):11.5(s,1H),8.44(s,1H),7.94(t,1H),7.80(d,1H),7.02(s,1H),6.89(d,1H),6.0 4(s,1H),5.91(t,1H),4.27(d,2H),4.13(d,2H),3.52-3.57(m,2H),2.66-2.73(m,2H),2.41(s,3H) ),2.36-2.40(m,2H),2.30-2.36(m,1H),2.22(s,3H),2.16(s,3H),2.13(s,3H),1.85-1.88(m,2H) ,1.76-1.85(m,1H),1.68-1.72(m,2H),1.54(s,3H),1.14-1.18(m,4H),1.13(s,3H),1.12(s,3H). LC-MS (ESI, m / z) = 726.6 (M+H + )

[0587] Preparation Example 110. Synthesis of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(trans-4-(isopropyl(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 110)

[0588] [ka]

[0589] The compound (0.5 g, 0.68 mmole) obtained by the same reaction as in [Steps 1 to 6] of Preparation Example 20 was used to carry out the reaction in [Step 7], except that in [Step 7], 2-iodopropane (0.14 ml) was used in place of 2,2,2-trifluoroethyl trifluoromethanesulfonate to obtain the title compound (0.1 g).

[0590] 1 H NMR(DMSO-d6):11.5(s,1H),8.44(s,1H),7.94(t,1H),7.81(d,1H),7.02(s,1H),6.89(d,1H),6. 05(s,1H),4.27(d,2H),4.14(d,2H),3.54-3.59(m,2H),2.86-2.90(m,1H),2.41(s,3H),2.28-2. 40(m,2H),2.32-2.40(m,1H4),2.16(s,3H),2.13(s,3H),2.05(s,3H),1.84-1.88(m,2H),1.72-1 .84(m,3H),1.54(s,3H),1.14-1.23(m,4H),1.13(s,3H),1.12(s,3H),0.90(s,3H),0.89(s,3H). LC-MS (ESI, m / z) = 704.7 (M+H + )

[0591] Preparation Example 111. Synthesis of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(trans-4-(ethyl(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 111)

[0592] [ka]

[0593] The compound (0.5 g, 0.68 mmole) obtained by the same reaction as in [Steps 1 to 6] of Preparation Example 20 was used to carry out the reaction in [Step 7], except that in [Step 7], the reaction was carried out using 2-iodoethane (0.11 mL) instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate, to obtain the title compound (0.1 g).

[0594] 1 H NMR(DMSO-d6):11.5(s,1H),8.46(s,1H),7.94(t,1H),7.81(d,1H),7.04(s,1H),6.89(d,1H) ,6.05(s,1H),4.26(d,2H),4.14(d,2H),3.53-4.57(m,2H),2.62(d,3H),2.41(s,3H),2.36-2. 40(m,2H),2.34-2.36(m,1H),2.17(s,3H),2.13(s,3H),1.87-1.1.97(m,3H),1.57(s,3H),1. 43-1.52(m,2H),1.20-1.25(m,2H),1.16-1.20(m,4H),1.13(s,3H),1.12(s,3H),0.83(t,3H). LC-MS (ESI, m / z) = 690.6 (M+H + )

[0595] Preparation Example 112. Synthesis of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-2-(trans-4-(methyl(phenethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 112)

[0596] [ka]

[0597] The compound (0.5 g, 0.68 mmole) obtained by the same reaction as in [Steps 1 to 6] of Preparation Example 20 was used to carry out the reaction in [Step 7], except that in [Step 7], the reaction was carried out using 2-iodoethylbenzene (0.20 mL) instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate, to obtain the title compound (0.2 g).

[0598] 1 H NMR(DMSO-d6):11.5(s,1H),8.43(s,1H),7.94(t,1H),7.80(d,1H),7.18-7.22(m,2H),7.15-7.18(m,3H ),7.01(s,1H),6.90(d,1H),6.05(s,1H),4.27(d,2H),4.14(d,2H),3.54-2.59(m,2H),2.51-2.63(m,2H) ),2.45(s,3H),2.41(s,3H),2.36-2.40(m,2H),2.34-2.36(m,1H),2.18-2.22(m,2H),2.16(s,3H),2.13 (s,3H),1.81-1.88(m,2H),1.70-1.78(m,3H),1.54(s,3H),1.16-1.29(m,4H),1.13(s,3H),1.12(s,3H). LC-MS (ESI, m / z) = 766.7 (M+H + )

[0599] Preparation Example 113. 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-2-(trans-4-(methyl( 4,4,4-trifluorobutyl Synthesis of)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 113)

[0600] [ka]

[0601] The compound (0.5 g, 0.68 mmole) obtained by the same reaction as in [Steps 1 to 6] of Preparation Example 20 was used to carry out the reaction in [Step 7], except that in [Step 7], the reaction was carried out using 1,1,1-trifluoro-4-iodobutane (0.17 mL) instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate, to obtain the title compound (0.2 g).

[0602] 1 H NMR(DMSO-d6):11.5(s,1H),8.45(s,1H),7.94(t,1H),7.81(d,1H),7.03(s,1H),6.89(d,1H),6 .05(s,1H),4.27(d,2H),4.14(d,2H),3.53-3.57(m,2H),2.41(s,3H),2.34-2.41(m,4H),2.31-2 .34(m,1H),2.17(s,3H),2.13(s,3H),1.89-1.95(m,3H),1.67-1.80(m,4H),1.66-1.68(m,1H), 1.61-1.65(m,2H),1.57(s,3H),1.42-1.48(m,2H),1.20-1.34(m,4H),1.13(s,3H),1.12(s,3H). LC-MS (ESI, m / z) = 772.7 (M+H + )

[0603] Preparation Example 114. Synthesis of 2-(trans-4-(cyclohexyl(methyl)amino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 114)

[0604] [ka]

[0605] The compound (0.5 g, 0.68 mmole) obtained by the same reaction as in [Steps 1 to 6] of Preparation Example 20 was used to carry out the reaction in [Step 7], except that in [Step 7], cyclohexyl iodide (0.18 mL) was used in place of 2,2,2-trifluoroethyl trifluoromethanesulfonate to give the title compound (0.05 g).

[0606] 1 H NMR(DMSO-d6):11.5(s,1H),8.45(s,1H),7.95(t,1H),7.82(d,1H),7.01(s,1H),6.90(d,1H),6.05(s,1H),4.27(d ,2H),4.14(d,2H),3.54-3.58(m,2H),3.38-3.41(m,2H),3.10-3.12(m,2H),2.93-3.60(m,2H),2.41(s,3H),2.34-2 .41(m,2H),2.31-2.34(m,1H),2.17(s,3H),2.13(s,3H),1.89-1.95(s,3H),1.67-1.80(m,4H),1.66-1.68(m,1H), 1.61-1.65(m,2H),1.57(s,3H),1.55-1.56(m,2H),1.42-1.48(m,2H),1.28-1.34(m,2H),1.13(s,3H),1.12(s,3H). LC-MS (ESI, m / z) = 744.7 (M+H + )

[0607] Preparation Example 115. Synthesis of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(2,2,2-trifluoro-N-methylacetamido)cyclohexyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 115)

[0608] [ka]

[0609] The compound (0.5 g, 0.68 mmole) obtained by the same reaction as in [Steps 1 to 6] of Preparation Example 20 was used to carry out the reaction in [Step 7], except that in [Step 7], phenyl trifluoroacetate (0.20 mL) was used in place of 2,2,2-trifluoroethyl trifluoromethanesulfonate to obtain the title compound (0.2 g).

[0610] 1 H NMR(DMSO-d6):11.5(s,1H),8.45(s,1H),7.95(t,1H),7.82(d,1H),7.04(s,1H),6.90 (d,1H),6.05(s,1H),4.27(d,2H),4.14(d,2H),3.53-3.57(m,2H),2.89-2.91(m,2H),2 .41(s,3H),2.34-2.41(m,3H),2.17(s,3H),2.13(s,3H),1.89-1.95(m,3H),1.66-1.6 8(m,1H),1.61-1.65(m,2H),1.57(s,3H),1.20-1.34(m,4H),1.13(s,3H),1.12(s,3H). LC-MS (ESI, m / z) = 758.6 (M+H + )

[0611] <Experimental Example> The cell lines used in the experiments were purchased from the American Type Culture Collection (ATCC).

[0612] Experimental Example 1: Evaluation of inhibitory activity against EZH1 and EZH2 To confirm the inhibitory effect of the 1,3-benzodioxole derivative compound represented by chemical formula I of the present invention on EZH1 and / or EZH2 activity, the activity was measured using AlphaLISA method.

[0613] Test substances dissolved in dimethyl sulfoxide (DMSO) were diluted to the final treatment concentration (5 nM or 10 nM) in a test solution (20 mM Tris pH 8.0, 0.1% BSA, 0.01% Triton X-100, 0.5 mM DTT) and mixed with EZH1 and EZH2, respectively. The enzyme reaction was initiated by adding histone H3 peptide and S-adenosylmethionine (SAM). After 2 hours of reaction, acceptor beads were added, followed by an additional hour of reaction, followed by donor beads. The reaction was then terminated after an additional 30 minutes. Activity was measured using the Magellan program on a Spark10M instrument. DMSO was used as a control. The enzyme activity inhibition rate was calculated using the following formula, and the results are shown in the table below.

[0614] <Calculation formula> Activity inhibition rate (%) = (1 - (test substance treatment group / control group)) x 100

[0615] [Table 1] [Table 2-1]

[0616] [Table 2-2]

[0617] As can be seen from the above table, it was confirmed that the compounds of the present invention exhibit excellent inhibitory effects on EZH1 and / or EZH2 enzyme activity.

[0618] Experimental example 2: Evaluation of inhibition of blood cancer cell proliferation The growth inhibitory activity of the 1,3-benzodioxole derivative compound represented by chemical formula I of the present invention against Pfeiffer cells, which are lymphoma cells having EZH2 mutation (A677G), was evaluated.

[0619] Pfeiffer cells were cultured in RPMI 1640 containing 10% bovine serum. 10,000 cells were seeded into each well of a 96-well culture dish, treated with the test substance at different concentrations, and then cultured for 11 days. During the 11 days, the test substance was replaced every 3 to 4 days. After culture, the cells were treated with CCK-8 (Cell Counting Kit-8) reagent in each well, and the absorbance was measured at 450 nm to determine the IC for cell proliferation. 50 The values ​​were obtained by nonlinear regression curve fitting using the GraphPad program (GraphPad Prism 5.0 software), and the results are shown in the table below.

[0620] [Table 2] [Table 3-1]

[0621] [Table 3-2]

[0622] As can be seen from the above table, it was confirmed that the compounds of the present invention effectively inhibit the proliferation of blood cancer cells and are useful for the prevention or treatment of blood cancer.

[0623] Although certain parts of the present invention have been described in detail above, it will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments and are not intended to limit the scope of the present invention. Accordingly, the true scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A compound represented by chemical formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, 【Chemistry 1】 In the above formula I, R １ is a 6- to 14-membered aryl; a 6- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, or benzodioxolyl; The R １ one or more H may be substituted or unsubstituted by Ra; The Ra is C １ -C ６ Alkyl; C １ -C ６ alkoxy; 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; -NRxRy; or halogen; One or more H of said Ra may be substituted or unsubstituted with Rb; The Rb is C １ -C ６ alkyl; 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; or halogen; R ２ is C ３ -C ８ cycloalkyl; or a 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S, in the ring; The R ２ one or more H may be substituted or unsubstituted with Rc; The Rc is C １ -C ６ Alkyl; C ３ -C ８ Cycloalkyl; 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O and S in the ring; -NRpRq or -(C=O)-(C １ -C ６ alkyl), One or more H in Rc may be substituted or unsubstituted with Rd; The Rd is a C group which may be substituted or unsubstituted with halogen. １ -C ６ alkoxy; a 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; a 6- to 14-membered aryl; halogen; or —OH; R ３ ~R ６ are each independently C １ -C ６ is alkyl, Rx and Ry are each independently C １ -C ６ is alkyl, Rp and Rq are each independently H; C １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl or -(C=O)-(C １ -C ６ alkyl), A compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof, wherein V is a single bond.

2. In the above formula I, R １ is phenyl, pyridinyl, pyrimidinyl, indolyl, benzofuranyl or benzodioxolyl, The R １ one or more H may be substituted or unsubstituted by Ra; The Ra is methyl, methoxy, —N(CH ３ ) ２ , -N(CH ３ ) (CH ２ CH ３ ), -N(CH ３ ) (CH ２ CH ２ CH ２ CH ３ ), morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, 【Chemistry 2】 or a halogen, One or more H of said Ra may be substituted or unsubstituted with Rb; Rb is methyl, ethyl, morpholinyl or halogen; R ２ is cyclohexyl or piperidinyl, The R ２ one or more H may be substituted or unsubstituted with Rc; The Rc is methyl, ethyl, propyl, isopropyl, butyl, cyclohexyl, azetidinyl, -NH ２ , -N(CH ３ ) ２ , -N(CH ３ ) (CH ２ CH ３ ), -N(CH ３ ) (CH ２ CH ２ CH ３ ), -N(CH ３ ) (CH) (CH ３ ) ２ , -N(CH ３ ) (CH ２ CH ２ CH ２ CH ３ ), -N(CH ３ ) (C ６ H １１ ), -N(CH ３ )(C=O)CH ３ or -(C=O)CH ３ and One or more H in Rc may be substituted or unsubstituted with Rd; Rd is methoxy, ethoxy which may be substituted or unsubstituted with halogen, propoxy, butoxy which may be substituted or unsubstituted with halogen, isopropoxy, dioxolanyl, phenyl, halogen, or —OH; R ３ ~R ６ 2. The compound of formula I according to claim 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof, wherein: is methyl.

3. A compound represented by chemical formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, 【Transformation 3】 The compound represented by formula I is a compound as set forth in the following table, including a compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12

4. The following compounds, their stereoisomers, pharmaceutically acceptable salts thereof, hydrates or solvates thereof: 1) 2-(trans-4-(dimethylamino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 2) 2-(trans-4-(dimethylamino)cyclohexyl)-7-(2-((2S,6R)-2,6-dimethylaminomorpholino)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 3) 7-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 4) 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-(piperidin-1-yl)pyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide 5) 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-(pyrrolidin-1-yl)pyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide 6) 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(4-(morpholinomethyl)phenyl)benzo[d][1,3] Dioxole-5-carboxamide 7) 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-7-(1-methyl-1H-indol-5-yl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 8) 7-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-5-yl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 9) 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(4-morpholinophenyl)benzo[d][1,3]dioxole-5-carboxamide 10) 2-(trans-4-(dimethylamino)cyclohexyl)-7-(4-fluorophenyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 11) 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(thiophen-3-yl)benzo[d][1,3]dioxole-5-carboxamide 12) 2-(trans-4-(dimethylamino)cyclohexyl)-7-(5-fluoro-2-methoxyphenyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 13) 2-(trans-4-(dimethylamino)cyclohexyl)-7-(3,5-dimethylisoxazol-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 14) 7-(2,6-difluoropyridin-3-yl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 15) 7-(2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-5-yl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 16) 2-(trans-4-(dimethylamino)cyclohexyl)-7-(6-(3,5-dimethylpiperidin-1-yl)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 17) 2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-thiomorpholinopyridin-3-yl)benzo[d][1,3]dioxole-5-carboxamide 18) 2-(trans-4-(dimethylamino)cyclohexyl)-7-(furan-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 19) 7-(5-chlorothiophen-2-yl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 20) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-2-(trans-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 21) 2,4-dimethyl-2-(trans-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-(piperidin-1-yl)pyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide 22) 7-(2-(dimethylamino)pyrimidin-5-yl)-2,4-dimethyl-2-(trans-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 23) 7-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-5-yl)-2,4-dimethyl-2-(trans-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 24) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(trans-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 25) 7-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-5-yl)-2-(trans-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 26) 7-(2-(dimethylamino)pyrimidin-5-yl)-2-(trans-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 27) 7-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-2-(trans-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 28) 2-(trans-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-7-(6-methoxypyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 29) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-((1S,4R)-4-(((S)-2-hydroxypropyl)(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3] Dioxole-5-carboxamide 30) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-2-(trans-4-(methyl(2-propoxyethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 31) 2-(trans-4-((2,2-dimethoxyethyl)(methyl)amino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 32) 2-(trans-4-(((1,3-dioxolan-2-yl)methyl)(methyl)amino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 33) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 34) 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-thiomorpholinopyridin-3-yl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 35) 7-(2-(dimethylamino)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 36) 7-(6-Methoxypyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 37) 7-(6-(3,5-dimethylpiperidin-1-yl)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 38) 7-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 39) 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-(piperidin-1-yl)pyrimidin-5-yl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 40) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(1-((S)-2-hydroxypropyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamine Do 41) 2-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 42) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl )-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2-propoxyethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 43) 2-(1-((1,3-dioxolan-2-yl)methyl)piperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 44) Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 45) Stereoisomer A of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 46) 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 47) Stereoisomer B of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 48) Stereoisomer A of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 49) Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 50) Stereoisomer A of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 51) Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(1-isopropylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 52) Stereoisomer A of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(1-isopropylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 53) Stereoisomer B of 2-(1-cyclohexylpiperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 54) Stereoisomer A of 2-(1-cyclohexylpiperidin-4-yl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 55) Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-phenethylpiperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 56) Stereoisomer A of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-phenethylpiperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 57) Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(4,4,4-trifluorobutyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 58) Stereoisomer A of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(4,4,4-trifluorobutyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 59) Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 60) Stereoisomer A of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 61) 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 62) Stereoisomer B of 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 63) 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)methyl Stereoisomer A of 1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 64) Stereoisomer B of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)benzo[d][1,3]dioxole-5-carboxamide 65) Stereoisomer A of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)benzo[d][1,3]dioxole-5-carboxamide 66) Stereoisomer B of 2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)benzo[d][1,3]dioxole-5-carboxamide 67) Stereoisomer A of 2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-morpholinopyridin-3-yl)benzo[d][1,3]dioxole-5-carboxamide 68) 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 69) Stereoisomer B of 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 70) Stereoisomer A of 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 71) Stereoisomer B of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide 72) Stereoisomer A of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide 73) Stereoisomer B of 2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide 74) Stereoisomer A of 2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-morpholinopyrimidin-5-yl)benzo[d][1,3]dioxole-5-carboxamide 75) 7-(2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 76) Stereoisomer B of 7-(2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 77) Stereoisomer A of 7-(2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 78) 7-(2-(ethyl(methyl)amino)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 79) Stereoisomer B of 7-(2-(ethyl(methyl)amino)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 80) Stereoisomer A of 7-(2-(ethyl(methyl)amino)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 81) Stereoisomer B of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(2-(ethyl(methyl)amino)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 82) Stereoisomer A of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(2-(ethyl(methyl)amino)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 83) Stereoisomer B of 7-(2-(ethyl(methyl)amino)pyrimidin-5-yl)-2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 84) Stereoisomer A of 7-(2-(ethyl(methyl)amino)pyrimidin-5-yl)-2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 85) 7-(6-(ethyl(methyl)amino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 86) Stereoisomer B of 7-(6-(ethyl(methyl)amino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 87) Stereoisomer A of 7-(6-(ethyl(methyl)amino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 88) Stereoisomer B of 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(6-(ethyl(methyl)amino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 89) Stereoisomer B of 7-(6-(ethyl(methyl)amino)pyridin-3-yl)-2-(1-ethylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 90) 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(4-(piperidin-1-yl)phenyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 91) 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(6-(piperidin-1-yl)pyridin-3-yl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 92) 2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7-(2-thiomorpholinopyrimidin-5-yl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 93) 2',2'-Difluoro-2,7-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-[4,5'-bibenzo[d][1,3]dioxole]-6-carboxamide 94) 2,7-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-[4,5'-bibenzo[d][1,3]dioxole]-6-carboxamide 95) 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-2,7-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-[4,5'-bibenzo[d][1,3]dioxole]-6-carboxamide 96) 7-(benzofuran-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 97) 7-(benzofuran-5-yl)-2-(1-(2,2-difluoroethyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 98) 7-(6-(butyl(methyl)amino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 99) 7-(6-(butyl(methyl)amino)pyrimidin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 100) 2-(trans-4-aminocyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6 -methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride 101) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(trans-4-(3-hydroxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 102) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(3-(2,2,2-trifluoroethoxy)azetidin-1-yl)cyclohexyl)benzo[d][1,3]dioxole-5-carboxamide 103) 2-(trans-4-(3-(2,2-difluoroethoxy)azetidin-1-yl)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 104) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(3-(4,4,4-trifluorobutoxy)azetidin-1-yl)cyclohexyl)benzo[d][1,3]dioxole-5-carboxamide 105) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(trans-4-(3-isopropoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 106) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(trans-4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 107) Stereoisomer B of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-2-(trans-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 108) Stereoisomer A of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-2-(trans-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 109) 2-(trans-4-((2,2-difluoroethyl)(methyl)amino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 110) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(trans-4-(isopropyl(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydro- (Dropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 111) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(trans-4-(ethyl(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 112) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-2-(trans-4-(methyl(phenethyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 113) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-2-(trans-4-(methyl(4,4,4-trifluorobutyl)amino)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 114) 2-(trans-4-(cyclohexyl(methyl)amino)cyclohexyl)-7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide 115) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(trans-4-(2,2,2-trifluoro-N-methylacetamido)cyclohexyl)benzo[d][1,3]dioxole-5-carboxamide

5. A compound according to any one of claims 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof, as an active ingredient. A pharmaceutical composition for preventing or treating a disease associated with EZH1 (Enhancer of zeste homolog 1) or EZH2 (Enhancer of zeste homolog 2) activity.

6. The pharmaceutical composition of claim 5 , wherein the disease associated with EZH1 or EZH2 activity is a blood cancer.

7. 7. The pharmaceutical composition according to claim 6, wherein the blood cancer is one or more selected from lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, leukemia, and multiple myeloma.

8. Use of a compound according to any one of claims 1 to 4, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate in the manufacture of a medicament for the prevention or treatment of a disease associated with EZH1 or EZH2 activity.

Images