1,3-BENZODIOXOLE DERIVATIVE COMPOUND AND PHARMACEUTICAL COMPOSITION CONTAINING 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, their pharma- ceutically acceptable salts, their hydrates or solvates, 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 (e.g., acetylation, methylation, phosphorylation, ubiquitination) of their histones (histones H2A, H2B, H3, H4).

[0003] In general, trimethylation of the fourth lysine from the N-terminus of histone H3 (H3K4me3) functions to activate transcription, while trimethylation of the 27th lysine (H3K27me3) functions to repress 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 control embryonic development in Drosophila, and these genes are also conserved in vertebrates. In Drosophila, Enhancer of zeste protein is a catalytic subunit responsible for H3K27 methylation of PRC2. EZH1 (Enhancer of zeste homolog 1 (Drosophila)) and EZH2 (Enhancer of zeste homolog 2 (Drosophila)) are both mammalian homologs of Drosophila Enhancer of zeste. The enzymatic activity domains (SET domains) of EZH1 and EZH2 are highly homologous, and there are two types of PRC2 (PRC2-EZH1 and PRC2-EZH2) in humans and mice, which use EZH1 or EZH2 as the 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. It has also been reported that EZH1 and EZH2 act cooperatively in the formation and maintenance of hair follicles and the differentiation of Merkel cells, and play an important role in the maintenance of hematopoietic stem cells.

[0006] In follicular lymphoma or diffuse large B-cell lymphoma, somatic mutations (Y641F, Y641N, Y641S, Y641H, Y641C, A677G, A687V) have been found in EZH2 at tyrosine 641, alanine 677, and alanine 687, and it has been reported that these mutations enhance the function of EZH2 and significantly increase the amount of H3K27me3 modification in the cells. Compounds that inhibit the enzymatic activity of EZH2 suppress the proliferation of blood cancer cell lines with 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 hematological 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 to suppress the progression of acute myeloid leukemia caused by the MLL-AF9 fusion gene, which means 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 pharma- ceutically acceptable salt thereof, a hydrate or a 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 pharma-ceutically acceptable salt, or 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, its stereoisomer, a pharma-ceutically acceptable salt, or a hydrate or solvate thereof.

[0012] The present invention provides the use of a compound represented by chemical formula I, its stereoisomer, its pharma- ceutically 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 chemical formula I, its stereoisomer, its pharma- ceutically 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 belong to the scope of the present invention. In addition, the specific descriptions described below do not limit the scope of the present invention.

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

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

[0017] [ka]

[0018] In the above 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; N, O, and S; 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 having 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 having 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 by 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 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; 6- to 14-membered aryl; or 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; 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 by Rd; Rd is a C1-C6 alkoxy which may be 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 by 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 a C3-C8 cycloalkyl; or a 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms in the ring 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 by Rd; Rd is a C1-C6 alkoxy which may be 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 by 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 by 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, unless otherwise specified, "alkyl" means C 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 in the alkyl group described above.

[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 the alkyl group.

[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 following 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 above-mentioned cycloalkyl.

[0028] In the present invention, unless otherwise specified, "heterocycloalkyl" refers to a cyclic group in which at least one or more carbon atoms forming a ring in the cycloalkyl are independently replaced with a heteroatom or functional group selected from the group consisting of N, O, S, SO, and SO2. Examples of heterocycloalkyl include, but are not limited to, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiophenyl, oxepanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, azetidinyl, aziridinyl, and azepanyl.

[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 aromatic rings, fused or unfused. 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 1 to 3 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, and furopyridinyl.

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

[0033] (4) In any one of the above (1) to (3), the compound represented by the chemical formula I may be a compound described 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 compound, its stereoisomer, its pharma- ceutically acceptable salt, its hydrate or solvate: 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-(trans-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) 2-(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 43) 2-(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 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-trifluoro)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-trifluoro)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide 63) Stereoisomer A 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-trifluoro)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-trifluoro)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-trifluoro)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-trifluoro)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)pyridin-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)pyridin-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)pyridin-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) 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] Stereoisomer B of 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-trifluoro)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)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 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-trifluoroethyl)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) 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 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(phenethyl)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, "pharmaceutical 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 could mean not rubbing.

[0060] The pharma- ceutically 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. For example, 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.; sulfonic acid salts prepared with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc., but are not limited thereto. In one embodiment of the present invention, the pharmaceutically acceptable salt may be a hydrochloride salt.

[0062] In the present invention, the compound according to any of (1) to (5) above may have one or more asymmetric carbon centers and may thus 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 resolution by column chromatography or HPLC, or can be stereospecifically synthesized using optically pure starting materials and / or reagents of known sequence. In particular, the stereoisomers may be optical isomers.

[0063] In the present invention, the "hydrate" refers to a compound according to any one of (1) to (5) above or a pharma- ceutically 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 pharma- ceutically 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 compound according to any one of (1) to (5) of the present invention, its stereoisomer, its pharma- ceutically acceptable salt, or its hydrate or solvate inhibits 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, their pharma- ceutically acceptable salts, their hydrates or solvates 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 pharma- ceutically acceptable salt thereof.

[0068] The compound according to any one of the above (1) to (5) of the present invention, its stereoisomer or its pharma- ceutically acceptable salt 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 as defined in the compound represented by the chemical formula I.

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

[0071] Specifically, the 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 inactive in the reaction, but methanol, ethanol, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, water, N,N-dimethylformamide, dimethylsulfoxide, benzene, toluene, xylene, or a mixture thereof may be used. The palladium catalyst may be tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, tris(dibenzylideneacetone)dipalladium, palladium acetate, acetylacetonepalladium, or bis(triphenylphosphine)palladium dichloride. The nickel catalyst may be [1,1'-bis(diphenylphosphino)ferrocene]nickel dichloride, or 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 This is a step of producing the compound C2 by stirring the compound C3 in a solvent using an equivalent or excess amount of a basic aqueous solution under cooling or heating for 3 to 96 hours. Specifically, the 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 is a step of producing the compound C1 by stirring the compound C2 in a solvent inert to the reaction with an equivalent or excess amount of the corresponding amine and a condensing agent under cooling or heating for 1 to 24 hours. Specifically, the 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 the reaction, and 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 be further 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 same, and Its uses The present invention provides a pharmaceutical composition comprising, as an active ingredient, the compound according to any one of the above (1) to (5), a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0075] The present invention relates to an EZH1 (Enhancer of zeste homolog1) or EZH2 (Enhancer of zeste homolog1) compound, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, or a hydrate or solvate thereof, as an active ingredient. The present invention provides a pharmaceutical composition for preventing or treating a disease 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 pharma- ceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0077] In the present invention, "treatment" refers to any action of ameliorating or beneficially altering the symptoms of an individual suspected of or developing a disease by administering a compound according to any of (1) to (5) of the present invention, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, or a hydrate or solvate thereof.

[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, 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 relation to this, in a specific embodiment of the present invention, the inhibitory activity against EZH1 and / or EZH2 and the proliferation-suppressing activity of blood cancer cells of a compound according to any one of (1) to (5) of the present invention, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof were confirmed.

[0081] The pharmaceutical composition of the present invention is capable of inhibiting 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 pharma- ceutically acceptable carriers in addition to the compound according to any one of (1) to (5), its stereoisomer, its pharma- ceutically acceptable salt, its hydrate or solvate. The pharma- ceutically acceptable carriers are those commonly used in the art, and may be, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, glycine, starch, gum tragacanth, gum acacia, 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.

[0083] The pharmaceutical composition of the present invention may further contain, in addition to the above-mentioned components, a binder, an isotonicity agent, an adsorbent, a disintegrant, an antioxidant, a lubricant, a filler, a solubilizer, a solubilizer, a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, a dispersing agent, or a stabilizer. The pharmaceutical composition of the present invention may be formulated into oral preparations such as tablets, pills, powders, granules, capsules, suspensions, emulsions, internal liquids, emulsions, syrups, external preparations, suppositories, or sterile injection solutions using pharma- ceutical acceptable carriers and excipients, and manufactured in unit dose forms or in multi-volume containers. The formulations may be prepared by conventional methods used in the art for formulation, or by methods described in Remington's Pharmaceutical Science (1999). thThey may be prepared by the methods disclosed in "Therapeutic Agents for the Treatment of Acute Mycobacterial Inflammation" (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 be preferably 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, or emulsions. When the pharmaceutical composition of the present invention is an oral administration formulation, the pharma- ceutical acceptable carrier may be, but is 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 preparations include, but are not limited to, injections, etc. When the pharmaceutical composition of the present invention is a parenteral preparation, the pharma- ceutically acceptable carrier may be, but is not limited to, water, saline, glucose solution, analogous sugar 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 pharma- ceutically acceptable salt, 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. The dose varies depending on the patient's health condition, age, weight, sex, administration method, severity of disease, etc.

[0088] The pharma- ceutical effective amount and effective dosage of the pharmaceutical composition of the present invention can be varied depending on the formulation method, mode of administration, time of administration and / or route of administration of the pharmaceutical composition, and can be varied depending on various factors including the type and degree of reaction 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 used simultaneously or at different times together with the individual, other components of the composition, and similar factors well known in the medical field, and a person having 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 several 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 into consideration all of the above factors, the amount that can obtain the maximum effect with the minimum amount without side effects should be administered, which can be easily determined by a person skilled 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 in order to further improve the therapeutic efficiency.

[0091] 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 according to any one of (1) to (5), its stereoisomer, a pharma- ceutically acceptable salt, its hydrate or solvate, or a pharmaceutical composition containing same.

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

[0093] In the present invention, "individual" means any animal, such as a human, rat, mouse, livestock, etc., that has or may have 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 for preventing or treating a disease associated with EZH1 or EZH2 activity of the present invention may involve administering a therapeutically effective amount of a compound according to any of (1) to (5), its stereoisomer, or a pharma- ceutical acceptable salt thereof.

[0095] In the present invention, a "therapeutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and not to cause side effects, which may be determined by one skilled 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 period, co-administered or co-used drugs, and other factors well known in the medical art. It is desirable that a specific therapeutically effective amount for a particular patient be applied differently depending on various factors including the type and degree of response to be achieved, the specific composition, the patient's age, weight, general health condition, sex and dietary contents, administration time, administration route and excretion rate of the composition, treatment period, drugs used in combination with or co-administered with the specific composition, including whether other drugs are used, and similar factors well known in the medical art.

[0096] The method for preventing or treating a disease associated with EZH1 or EZH2 activity of the present invention includes not only treating the disease itself before the onset of symptoms, but also inhibiting or avoiding the symptoms by administering a compound according to any one of (1) to (5), its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate. In managing a disease, 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 frequency of dose vary depending on the age, weight and response of the individual patient. A suitable dose and method of administration can be easily selected by a person of ordinary skill in the art, who will naturally take such factors into consideration. In addition, 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 formulation useful for preventing or treating the disease together with a compound according to any one of (1) to (5), its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate. A synergistic or additive effect can be obtained by using a further active agent together with a compound according to any one of (1) to (5), its stereoisomer, its pharma- ceutically acceptable salt, its hydrate or solvate.

[0097] The present invention provides use of a compound according to any of (1) to (5), its stereoisomer, its pharma- ceutically 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 of (1) to (5), its stereoisomer, its pharma- ceutically 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] In order to manufacture a drug, a compound according to any one of the above (1) to (5) of the present invention, its stereoisomer, its pharma- ceutically acceptable salt, its hydrate or its solvate may be mixed with a pharma-ceutically acceptable adjuvant, diluent, carrier, etc., and produced as a composite preparation together with another active agent, which can have a synergistic effect.

[0100] The items described in each section of the present invention, i.e., the 1,3-benzodioxole derivative compound, the preparation method thereof, the pharmaceutical composition containing the same, the therapeutic method using the same and the use thereof, are equally applicable unless they are inconsistent with each other. Effect of the Invention

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

[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 thereto.

[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, the starting materials can be purchased or prepared by known methods. The use of all examples or exemplary terms provided in this application is merely illustrative of the present invention and does not limit the scope of the present invention.

[0104] <Production Example> In the following Production Examples, the 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 (Compound 1 and its hydrochloride)

[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) 1M-HCl aqueous solution (80mL) was added to 2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate (20g, 41.3mmole), and the mixture was heated and stirred. After the reaction was completed, the mixture was cooled to room temperature, and isopropyl alcohol (80mL) was added dropwise and stirred. The resulting crystals were filtered and dried at an internal temperature of 60°C to obtain the title compound (17.2g).

[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 the mixture was stirred at room temperature. Dimethylamine (23 mL) was added and the mixture was stirred. 35% aqueous formaldehyde solution (12 mL) was gradually added and the mixture was stirred. The mixture was cooled, and sodium triacetoxyborohydride (35 g) was gradually added, followed by stirring at room temperature. After the reaction was completed, dichloromethane (173 mL) was added, and an aqueous sodium bicarbonate solution (173 mL) was added to wash the mixture. Magnesium sulfate was then added, and the mixture was 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 mmole) obtained in the above [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) was added, tetrakis(triphenylphosphine)palladium (4.5 g) was added, sodium carbonate (12.3 g) was added, and the mixture was heated and stirred. After the reaction was completed, hexane was added, and the precipitated solid was filtered using silica / celite, and the filtrate was washed with purified water (160 mL). Magnesium sulfate was added, filtered, and concentrated to obtain 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 the above [Step 3]. 2N-sodium hydroxide aqueous solution (76 mL) was added, and the mixture was heated and stirred. After the reaction was completed, 2N-hydrochloric acid aqueous solution (57 mL) was added and concentrated. The generated crystals were filtered, and ethyl acetate (400 mL) was added. Then, purified water (200 mL) was added and washed, magnesium sulfate was added and filtered, and the mixture was 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 The compound (19 g, 37.3 mmole) obtained in [Step 4] was added to dimethylformamide (95 mL) and triethylamine (21 mL). Then, pentafluorophenyl trifluoroacetate (10 mL) was added dropwise and 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 solution from the reaction in [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 reactant was added dropwise to purified water (1,900 mL) and the resulting solid was filtered. The solid was dissolved in methylene chloride (380 mL) to separate the aqueous layer, 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 of compound 1) The compound (25 g, 37 mmole) obtained in the above [Step 6] was added to 1M hydrochloric acid aqueous solution (130 mL), heated and stirred. After the reaction was completed, the mixture was concentrated, dissolved in methanol (50 mL), 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 Production 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 Production Example 1, to obtain the title compound (30 mg).

[0119] 1 H 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 Production 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)pyridine in [Step 3] of Production 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 Except for using 2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine instead of 2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine, the same reaction as in Preparation Example 1 was carried out to obtain the title compound (26 mg).

[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 Production 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 Production Example 1, to obtain the title compound (70 mg).

[0131] 1H 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 Production 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 Production 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 Production 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 Production 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 Production 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 Production 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 Production 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 Production 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 Production 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 Production 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 Production 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 Production 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 Production 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 Production 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 Production 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 Production 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 Production 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 Production 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 Production 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 Production Example 1, to obtain the title compound (63 mg).

[0171] 1 H 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 Production 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)pyridine in [Step 3] of Production 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 Production 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 Production 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 1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 18)

[0180] [ka]

[0181] The same reaction as in Production 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 Production 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 Production 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 Production 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 (compound 20 and its hydrochloride)

[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, and the internal temperature was cooled to -5°C or lower. Sodium hydride (3.372 g) was added, and the temperature was raised to room temperature and stirred. After the reaction was completed, ethyl acetate (300 mL) was added, and purified water (300 mL) was added and washed. Magnesium sulfate was added, filtered, and concentrated to obtain 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 mmole) obtained in the above [Step 1]. 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) was added, followed by tetrakis(triphenylphosphine)palladium (3.58 g), sodium carbonate (13.1 g), and the mixture was heated and stirred. After the reaction was completed, hexane was added, and the precipitated solid was filtered using silica / celite, and the filtrate was washed with purified water (450 mL). Magnesium sulfate was added, filtered, and concentrated to obtain 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-sodium hydroxide aqueous solution (74 mL) was added, and the mixture was heated and stirred. After the reaction was completed, 2N-hydrochloric acid aqueous solution (74 mL) and ethyl acetate (350 mL) were added. Purified water (350 mL) was then added for washing, magnesium sulfate was added, filtered, and 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 the reaction in [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 reactant was added dropwise to purified water (936 mL) and the resulting solid was filtered. The solid was dissolved in methylene chloride (312 mL) to separate the aqueous layer, magnesium sulfate was added, filtered, and concentrated to obtain 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 (20 g, 26.2 mmole) obtained in the above [Step 5] was added to 1M hydrochloric acid aqueous solution (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 (21.6 g, 29.4 mmole) obtained in [Step 6] above, and sodium hydrogen carbonate (20 g) was added. 2,2,2-trifluoroethyl trifluoromethanesulfonate (10.6 mL) was added dropwise, and the mixture was heated and stirred. After the reaction was completed, 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-triphenylphosphine)phenyl)phenyl)-2,4-dimethyl Synthesis of (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 (21 g, 28.2 mmole) obtained in [Step 7] above was added to 1M hydrochloric acid aqueous solution (105 mL), heated and stirred. The internal temperature was cooled to room temperature, and isopropyl alcohol (105 mL) was added dropwise and stirred. The generated 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 is replaced with (2S,6R)-2,6-dimethyl-4-(5-(4,4, The same reaction as in Production 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 obtain 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 ru-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 in [Step 2] of Preparation Example 20, 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 was used, and in [Step 7], 1-bromo-2-methoxyethane was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate, 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)pyridine in [Step 2] of Preparation Example 20, and 1-bromo-2-methoxyethane was used in place 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. Synthesis of 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-(trans-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 obtain the title compound (34 mg).

[0235] 1 H 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 obtain the title compound (28 mg).

[0239] 1 H 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 obtain the title compound (53 mg).

[0243] 1 H 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 obtain the title compound (40 mg).

[0247] 1 H 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 (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 (compound 33 and its hydrochloride)

[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 Dioxane (200 mL) was added to tert-butyl 4-(7-bromo-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate (20 g, 44.2 mmole), and purified water (100 mL) was added. 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) was added, tetrakis(triphenylphosphine)palladium (5.11 g) was added, and sodium carbonate (14 g) was added, and the mixture was heated and stirred. After the reaction was completed, hexane (200 mL) and purified water (100 mL) were added, and the precipitated solid was filtered using silica / celite, and the filtrate was washed with purified water (200 mL). After addition of magnesium sulfate and filtration, the mixture was 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 the above [Step 1]. 2N-sodium hydroxide aqueous solution (69 mL) was added, and the mixture was heated and stirred. After the reaction was completed, 2N-hydrochloric acid aqueous solution (69 mL) was added, and ethyl acetate (128 mL) was added. Then, purified water was added twice in 300 mL portions for washing, magnesium sulfate was added, filtered, and concentrated to obtain 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 solution from the reaction in [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 reactant was added dropwise to purified water (710 mL) and the resulting solid was filtered. The solid was dissolved in methylene chloride (284 mL) to separate the aqueous layer, 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 the above [Step 4] (16.9 g, 23 mmole) was added with 1 M hydrochloric acid (ethanol aqueous solution) (85 mL), and the mixture was heated and stirred. After the reaction was completed, the reaction solution 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 the above [Step 5], and sodium hydrogen carbonate (15.5 g) was added. Trifluoroethyl trifluoromethanesulfonate (8.2 mL) was added dropwise, and the mixture was heated and stirred. After the reaction was completed, 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] 1H 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 of compound 33) The compound (11 g, 14.8 mmole) obtained in step 6 was added to 1M aqueous hydrochloric acid (100 mL), 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 Production 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 Production Example 33, to obtain the title compound (88 mg).

[0263] 1 H 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] 1H 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 Production 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)pyridine in [Step 1] of Production Example 33, to obtain the title compound (47 mg).

[0275] 1H 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, Except for using (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholine instead of 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine, the same reaction as in Production Example 33 was carried out to obtain the title compound (37 mg).

[0279] 1H 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-carbo 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 obtain 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 Production Example 33, 2,2,2-trifluoromethanesulfonic acid The same reaction as in Production 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] Preparation Example 42. Synthesis of 2-(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 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 obtain 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] Preparation Example 43. Synthesis of 2-(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 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] 1H 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 steps of [Steps 1-6] 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 isomers 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, 3μm particle size, 4.6mm x 15cm) -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 steps of [Steps 1-6] of the above Preparation Example 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 isomers 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, 3μm particle size, 4.6mm x 15cm) -Column temperature: 25℃ -Mobile phase: A mixture of hexane / ethanol (98:2, v / v). -Flow rate: 1.0mL / min -Analysis time: 15 minutes

[0311] 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,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] Acetonitrile (10 mL), sodium carbonate (0.43 g) and 2-iodo-1,1-difluoroethane (0.12 mL) were added to the obtained hydrochloride (0.5 g, 0.70 mmole) and stirred at an internal temperature of 100° C. for 24 hours. After cooling, dichloromethane (5 mL) was added, filtered, and concentrated, the layers were separated with dichloromethane (10 mL) and purified water (10 mL), and the oil layer was dried over magnesium sulfate (MgSO4) and then concentrated. The crystals formed using ethanol (2 mL) and hexane (20 mL) were filtered and dried at an internal temperature of 60° C. to obtain the title compound (0.3 g).

[0316] 1H 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 Production 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 Production 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 in [Step 6], iodoethane (0.11 mL) was used instead of 2-iodo-1,1-difluoroethane, 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 obtain 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 in [Step 6], 2-iodopropane (0.13 mL) was used instead of 2-iodo-1,1-difluoroethane, 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 in [Step 6], 2-iodopropane (0.13 mL) was used instead of 2-iodo-1,1-difluoroethane, 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 in [Step 6], iodocyclohexane (0.17 mL) was used instead of 2-iodo-1,1-difluoroethane, 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 in [Step 6], iodocyclohexane (0.17 mL) was used instead of 2-iodo-1,1-difluoroethane, to give the title compound (0.2 g).

[0348] 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),4.15(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] D25 =+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 in [Step 6], iodocyclohexane (0.17 mL) was used instead of 2-iodo-1,1-difluoroethane, 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 in [Step 6], iodocyclohexane (0.17 mL) was used instead of 2-iodo-1,1-difluoroethane, to give the title compound (0.2 g).

[0356] 1H 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 in [Step 6], 1,1,1-trifluoro-4-iodobutane (0.17 mL) was used instead of 2-iodo-1,1-difluoroethane, 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 obtain 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 in [Step 6], phenyl trifluoroacetate (0.15 mL) was used instead of 2-iodo-1,1-difluoroethane, 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 in [Step 6], phenyl trifluoroacetate (0.15 mL) was used instead of 2-iodo-1,1-difluoroethane, 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 Example 61. Synthesis 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-trifluoro)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 61)

[0374] [ka]

[0375] In [Step 1] of the above-mentioned Production Example 33, (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine was used instead of 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (intermediate 1), and the steps of [Steps 1 to 5] were carried out in the same manner 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 (0.5 g, 0.70 mmole) and stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, filtered and concentrated, ethanol (2 mL) and hexane (20 mL) were used to generate crystals, which were then 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 Example 62. Synthesis of 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-trifluoro)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 Production 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 a starting material, to obtain the title compound (0.3 g).

[0381] 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),3.65-3.66(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 Example 63. Synthesis of Stereoisomer A 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-trifluoro)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 Production 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 a starting material, to obtain the title compound (0.3 g).

[0385] 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),3.65-3.67(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 in [Step 6], 2-iodo-1,1-difluoroethane (0.12 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate, to give the title compound (0.2 g).

[0389] 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),6.04-6.05(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 in [Step 6], 2-iodo-1,1-difluoroethane (0.12 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate, to give the title compound (0.2 g).

[0393] 1H 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 in [Step 6], iodoethane (0.11 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate, to give the title compound (0.1 g).

[0397] 1H 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 in [Step 6], iodoethane (0.11 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate, to give the title compound (0.1 g).

[0401] 1H 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 Example 68. Synthesis 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-trifluoro)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 68)

[0403] [ka]

[0404] In [Step 1] of the above-mentioned Production Example 33, (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (Intermediate 1) was used instead of 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholine. Except for this, the processes of [Steps 1 to 5] were carried out in the same manner, and 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 in [Step 5].

[0405] Acetonitrile (10 mL), sodium carbonate (0.43 g) and trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride (0.5 g, 0.70 mmole) and stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, filtered and concentrated, ethanol (2 mL) and hexane (20 mL) were used to generate crystals, which were then 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 Example 69. Synthesis of 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-trifluoro)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 Production 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 a 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 Example 70. Synthesis of 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-trifluoro)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 Production 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 a starting material, to obtain the title compound (0.3 g).

[0414] 1 H 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 in [Step 6], 2-iodo-1,1-difluoroethane (0.12 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate, to give the title compound (0.2 g).

[0418] 1 H 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 in [Step 6], 2-iodo-1,1-difluoroethane (0.12 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate, to give the title compound (0.2 g).

[0422] 1 H 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 in [Step 6], iodoethane (0.11 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate, to give the title compound (0.1 g).

[0426] 1 H 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 in [Step 6], iodoethane (0.11 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate, to give the title compound (0.1 g).

[0430] 1 H 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] In [Step 1] of the above-mentioned Production Example 33, (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (intermediate 1) was replaced with 2-(4-ethylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine, and the steps of [Steps 1 to 5] were carried out in the same manner, and 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 was obtained in [Step 5].

[0434] Acetonitrile (10 mL), sodium carbonate (0.43 g) and trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride (0.5 g, 0.70 mmole) and stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, filtered and concentrated, and the crystals formed using ethanol (2 mL) and hexane (20 mL) 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 a 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 a 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. Synthesis of 7-(2-(ethyl(methyl)amino)pyridin-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 78)

[0445] [ka]

[0446] In [Step 1] of the above-mentioned Production Example 33, (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (Intermediate 1) was replaced with N-ethyl-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine. Except for this, [Steps 1 to 5] were carried out in the same manner, and 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 in [Step 5].

[0447] Acetonitrile (10 mL), sodium carbonate (0.43 g) and trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride (0.5 g, 0.73 mmole) and stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, filtered and concentrated, and the crystals formed using ethanol (2 mL) and hexane (20 mL) 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. Synthesis of stereoisomer B of 7-(2-(ethyl(methyl)amino)pyridin-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 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 a 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. Synthesis of stereoisomer A of 7-(2-(ethyl(methyl)amino)pyridin-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 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 a starting material, to obtain the title compound (0.3 g).

[0456] 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),3.06-3.12(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 in [Step 6], 2-iodo-1,1-difluoroethane (0.13 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate, to give the title compound (0.2 g).

[0460] 1 H 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 in [Step 6], 2-iodo-1,1-difluoroethane (0.13 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate, to give the title compound (0.2 g).

[0464] 1 H 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 in [Step 6], iodoethane (0.12 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate, to give the title compound (0.1 g).

[0468] 1 H 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 in [Step 6], iodoethane (0.12 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate, to give the title compound (0.1 g).

[0472] 1 H 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 Example 85. Synthesis 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-trifluoro)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide (Compound 85)

[0474] [ka]

[0475] In [Step 1] of the above-mentioned Production Example 33, (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (intermediate 1) was replaced with N-ethyl-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine. Except for this, the steps of [Steps 1 to 5] were carried out in the same manner, 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 (0.5 g, 0.73 mmole) and stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, filtered and concentrated, ethanol (2 mL) and hexane (20 mL) were used to generate crystals, which were then 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 a 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 Production 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 a 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 in [Step 6], 2-iodo-1,1-difluoroethane (0.13 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate, 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 Preparation Example 86, except that in [Step 6], iodoethane (0.12 mL) was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate, 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] In [Step 1] of the above-mentioned Production Example 33, (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (intermediate 1) was replaced with 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine, and the steps of [Steps 1 to 5] were carried out in the same manner, and 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 in [Step 5].

[0497] Acetonitrile (10 mL), sodium carbonate (0.43 g) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride (0.5 g, 0.73 mmole) and stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, filtered and concentrated, ethanol (2 mL) and hexane (20 mL) were used to generate crystals, which were then 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] In [Step 1] of the above-mentioned Production Example 33, (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (Intermediate 1) was replaced with 2-(piperidin-1-yl)-5-(4,4,5,5-tetraamyl-1,3,2-dioxaborolan-2-yl)pyridine. Except for this, the steps of [Steps 1 to 5] were carried out in the same manner, and 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 (0.5 g, 0.73 mmole) and stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, filtered and concentrated, ethanol (2 mL) and hexane (20 mL) were used to generate crystals, which were then 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] In [Step 1] of the above-mentioned Production Example 33, (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (intermediate 1) was replaced with 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)thiomorpholine. Except for this, the processes of [Steps 1 to 5] were carried out in the same manner, and 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 in [Step 5].

[0507] Acetonitrile (10 mL), sodium carbonate (0.43 g) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride (0.5 g, 0.73 mmole) and stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, filtered and concentrated, ethanol (2 mL) and hexane (20 mL) were used to generate crystals, which were then 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 the above-mentioned Production Example 33, (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (intermediate 1) was used instead of 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Except for this, [Steps 1 to 5] were carried out in the same manner, and 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 (0.5 g, 0.73 mmole) and stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, filtered and concentrated, ethanol (2 mL) and hexane (20 mL) were used to generate crystals, which were then 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] In [Step 1] of the above-mentioned Production Example 33, (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (intermediate 1) was replaced with 2-(benzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Except for this, [Steps 1 to 5] were carried out in the same manner to obtain [Step 5] 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.

[0517] Acetonitrile (10 mL), sodium carbonate (0.43 g) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride (0.5 g, 0.73 mmole) and stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, filtered and concentrated, ethanol (2 mL) and hexane (20 mL) were used to generate crystals, which were then 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 the same method as in [Steps 1-5] of the above-mentioned Preparation Example 94 was added with acetonitrile (10 mL), sodium carbonate (0.43 g) and 2-iodo-1,1-difluoroethane (0.09 mL), and stirred at an internal temperature of 100 ° C. for 24 hours. After cooling, dichloromethane (5 mL) was added, filtered, and concentrated, the crystals generated using ethanol (2 mL) and hexane (20 mL) 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-( Except for using 2-(benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 1), the steps of [Steps 1 to 5] were carried out in the same manner as above, and 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 in [Step 5].

[0526] Acetonitrile (10 mL), sodium carbonate (0.43 g) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride (0.5 g, 0.73 mmole) and stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, filtered and concentrated, ethanol (2 mL) and hexane (20 mL) were used to generate crystals, which were then 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 the same method as in [Steps 1 to 5] of Preparation Example 96, and the mixture was stirred at an internal temperature of 100° C. for 24 hours. The mixture was cooled, dichloromethane (5 mL) was added, filtered, and concentrated, followed by addition of ethanol (2 mL). The resulting crystals were filtered off using hexane (20 mL) and hexane (20 mL) 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] In [Step 1] of the above-mentioned Production Example 33, (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (intermediate 1) was replaced with N-butyl-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine. Except for this, the steps of [Steps 1 to 5] were carried out in the same manner as above, 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 (0.5 g, 0.73 mmole) and stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, filtered and concentrated, ethanol (2 mL) and hexane (20 mL) were used to generate crystals, which were then 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. 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 99)

[0538] [ka]

[0539] In [Step 1] of the above-mentioned Production Example 33, (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (intermediate 1) was replaced with N-butyl-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine. Except for this, the steps of [Steps 1 to 5] were carried out in the same manner, and 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 in [Step 5].

[0540] Acetonitrile (10 mL), sodium carbonate (0.43 g) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.20 mL) were added to the obtained hydrochloride (0.5 g, 0.73 mmole) and stirred for 24 hours at an internal temperature of 100° C. After cooling, dichloromethane (5 mL) was added, filtered and concentrated, ethanol (2 mL) and hexane (20 mL) were used to generate crystals, which were then 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 with ethyl acetate (50 mL), and the precipitated solid was filtered using Celite 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 left to stand and separated into layers, and anhydrous sodium sulfate and activated carbon were added to the organic layer and stirred for 1 hour. The reaction mixture was filtered and concentrated, and 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 subjected to the next reaction without further purification.

[0545] The intermediate obtained was dissolved in tetrahydrofuran (72 mL) and methanol (36 mL), and then 2N aqueous sodium hydroxide solution (46.5 mL) was added and stirred under reflux for 4 hours. The reaction product 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 product 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 product 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, and the mixture was stirred under reflux 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 (9.9 g, 17.01 mmole) obtained in the above [Step 1]. Then, pentafluorophenyl trifluoroacetate (3.04 mL) was added dropwise and stirred at room temperature for 3 hours. Triethylamine (4.73 mL) was added to the reaction solution, followed by 3-(aminomethyl)-6-methyl-4-(methylthio)pyridin-2(1H)-one hydrochloride (4.5 g) and stirring at an internal temperature of 50°C. After the reaction was completed, the solution was concentrated under reduced pressure, and the concentrated residue was dissolved in dichloromethane (40 mL) and purified water (40 mL) to separate the aqueous layer, and purified water (30 mL) was added to the organic layer, adjusted to pH 3.5 with 20% aqueous hydrochloric acid, and the layers were separated to separate the organic layer. Anhydrous sodium sulfate and activated carbon were added to the separated organic layer and stirred for 1 hour. The reaction mixture was filtered, washed with dichloromethane (15 mL), concentrated, and carried on to the reaction 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] 1M hydrochloric acid (aqueous ethanol solution) (100 mL) was added to the compound obtained in the above [Step 2], and the mixture was heated to 70° C. and stirred. After the reaction was completed, the reaction solution 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 (8 g, 12.3 mmole) obtained in [Step 3] of Preparation Example 100. The pH was adjusted to 7-8 by adding 2N-sodium hydroxide aqueous solution, the layers were separated, and the oil layer was dried with sodium sulfate. After filtration and concentration, ethanol was added, (R) epichlorohydrin was added, and the temperature was raised. After the reaction was completed, the mixture was cooled, calcium carbonate was added, the temperature was raised, the reaction was carried out, cooled, filtered, and then the layers were separated with dichloromethane and purified water. The oil layer was dried with sodium sulfate, filtered, concentrated, purified by column, and recrystallized with 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. 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-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)cyclohexyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 102)

[0556] [ka]

[0557] Dimethylformamide (20 mL) was added to the compound (300 mg, 0.42 mmole) obtained in Preparation Example 101. 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 with dichloromethane and purified water, dried over anhydrous sodium sulfate, filtered and washed, and then distilled under reduced pressure. The product 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] Except for using 2-iodo-1,1-difluoroethane (0.04 mL) instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in Example 102, the compound obtained in Example 101 (300 mg, 0.43 mmole) was used in a reaction similar to that in Example 102 to obtain 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] Preparation Example 104. 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 104)

[0564] [ka]

[0565] Except for using 1,1,1-trifluoro-4-iodobutane (0.06 mL) instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in Example 102, the compound obtained in Example 101 (300 mg, 0.43 mmole) was used in a reaction similar to that in Example 102 to obtain 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] Except for using 2-iodopropane (0.04 mL) instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in Example 102, the compound obtained in Example 101 (300 mg, 0.43 mmole) was used in a reaction similar to that in 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] Except for using iodomethane (0.03 mL) instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in Preparation Example 102, the compound obtained in Preparation Example 101 (300 mg, 0.43 mmole) was used in a reaction similar to that in Preparation Example 102 to obtain 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 was carried out from [Step 1] to [Step 7] of Preparation Example 20, 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)) 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 was carried out from [Step 1] to [Step 7] of Preparation Example 20, 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. Synthesis of 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 (Compound 109)

[0584] [ka]

[0585] The reaction in [Step 7] was carried out using the compound (0.5 g, 0.68 mmole) obtained by the same reaction as in [Steps 1 to 6] of the above Preparation Example 20, 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 reaction in [Step 7] was carried out using the compound (0.5 g, 0.68 mmole) obtained by the same reaction as in [Steps 1 to 6] of the above Preparation Example 20, except that in [Step 7], the reaction was carried out using 2-iodopropane (0.14 ml) instead 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]. However, 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 reaction in [Step 7] was carried out using the compound (0.5 g, 0.68 mmole) obtained by the same reaction as in [Steps 1 to 6] of the above Preparation Example 20, 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. 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 113)

[0600] [ka]

[0601] The reaction in [Step 7] was carried out using the compound (0.5 g, 0.68 mmole) obtained by the same reaction as in [Steps 1 to 6] of the above Preparation Example 20, 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 reaction in [Step 7] was carried out using the compound (0.5 g, 0.68 mmole) obtained by the same reaction as in [Steps 1 to 6] of the above Preparation Example 20, except that in [Step 7], the reaction was carried out using cyclohexyl iodide (0.18 mL) instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate, to obtain 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 reaction in [Step 7] was carried out using the compound (0.5 g, 0.68 mmole) obtained by the same reaction as in [Steps 1 to 6] of Preparation Example 20, except that in [Step 7], the reaction was carried out using phenyl trifluoroacetate (0.20 mL) instead 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 In order 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 the AlphaLISA method.

[0613] The test substance dissolved in dimethyl sulfoxide (DMSO) was diluted in a test solution (20 mM Tris pH 8.0, 0.1% BSA, 0.01% Triton X-100, 0.5 mM DTT) according to the final treatment concentration (5 nM or 10 nM), and mixed with EZH1 and EZH2, respectively, and then histone H3 peptide and S-adenosylmethionine (SAM) were added to start the enzyme reaction. After reacting for 2 hours, acceptor beads were added, and after reacting for another hour, donor beads were added. After reacting for another 30 minutes, the reaction was terminated. Activity was measured using the Magellan program with Spark10M equipment. DMSO was used as a control group, and the inhibition rate of enzyme activity was calculated according to 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 against 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 the chemical formula I of the present invention against Pfeiffer cells, which are lymphoma cells having EZH2 mutation (A677G), was evaluated.

[0619] Pfeiffer cultured cells in RPMI 1640 containing 10% bovine serum. 10,000 cells were inoculated 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 the 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 50 The values ​​were obtained by performing 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 compound of the present invention effectively inhibits the proliferation of blood cancer cells and is useful for the prevention or treatment of blood cancer.

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

Claims

1. A compound represented by the following chemical formula I, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or a solvate thereof: 【Chemistry 1】 In the above formula I, R １ is H;C １ -C ６ Alkyl; C ２ -C ６ Alkenyl; C ２ -C ６ Alkynyl; C ３ -C ８ Cycloalkyl; C ３ -C ８ Cycloalkenyl; C １ -C ６ Alkoxy; 3- to 12-membered heterocycloalkyl or heterocycloalkenyl containing in the ring from 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; 6- to 14-membered aryl; 5- to 12-membered heteroaryl containing in the ring from 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; -(C=O)-(C １ -C ６ alkyl); -CN; benzodioxolyl or halogen; The R １ C １ -C ６ Alkyl; C ３ -C ８ 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 containing 1 to 3 heteroatoms independently selected from the group consisting of N, O and S in the ring or benzodioxolyl, 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 in the ring independently selected from the group consisting of N, O and S; -NRxRy; or halogen; One or more H of Ra may be substituted or unsubstituted by Rb; The Rb is C １ -C ６ alkyl; 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of N, O and S; or halogen; R ２ is H;C １ -C ６ Alkyl; C ３ -C ８ cycloalkyl; a 3- to 12-membered heterocycloalkyl or heterocycloalkenyl containing in the ring from 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; a 6- to 14-membered aryl; or a 5- to 12-membered heteroaryl containing in the ring from 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; 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 in the ring independently selected from the group consisting of N, O and S; -NRpRq; -(HC=O); -(C=O)-(C １ -C ６ -alkyl); -S(=O) ２ - (C １ -C ６ alkyl); or halogen; One or more H of 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 in the ring independently selected from the group consisting of N, O, and S; a 6- to 14-membered aryl; halogen; or -OH; R ３ is H; or C １ -C ６ is alkyl, R ４ is H;C １ -C ６ alkyl; or halogen; R ５ and R ６ are each independently H; or C １ -C ６ is alkyl, Rx and Ry are each independently H; or C １ -C ６ is alkyl, Rp and Rq are each independently H; １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl or -(C=O)-(C １ -C ６ alkyl), V is a single bond; or -(C １ -C ６ alkylene)-.

2. In the above formula I, R １ is a 6- to 14-membered aryl; a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of N, O and S, or a benzodioxolyl; The R １ 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 in the ring independently selected from the group consisting of N, O and S; -NRxRy; or halogen; One or more H of Ra may be substituted or unsubstituted by Rb; The Rb is C １ -C ６ alkyl; 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms in the ring 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 in the ring independently selected from the group consisting of N, O and S; -NRpRq or -(C=O)-(C １ -C ６ alkyl), One or more H of 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 in the ring independently selected from the group consisting of N, O, and S; a 6- to 14-membered aryl; halogen; or -OH; R ３ ~R ６ are each independently １ -C ６ is alkyl, Rx and Ry are each independently C １ -C ６ is alkyl, Rp and Rq are each independently H; １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl or -(C=O)-(C １ -C ６ alkyl), 2. The compound of formula I according to claim 1, wherein V is a single bond, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or a solvate thereof.

3. In the above formula I, R １ is phenyl, pyridinyl, pyrimidinyl, indolyl, thiophenyl, isoxazolyl, furanyl, benzofuranyl or benzodioxolyl; The R １ 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 Ra may be substituted or unsubstituted by 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 of 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 The compound of formula I according to claim 2, wherein R is methyl, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or a solvate thereof.

4. The compound represented by formula I according to claim 1, its stereoisomer, its pharma- ceutically acceptable salt, its hydrate or solvate, is a compound as set forth in the following table: 【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】

5. The following compound, its stereoisomer, its pharma- ceutically acceptable salt, its hydrate or solvate: 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-(trans-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]diox Sole-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-carboxamide D 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) 2-(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 43) 2-(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 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) 7-(6-((2S,6R)-2,6-dimethylmorpholino)pyridine-3-yl Stereoisomer A of 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-trifluoro)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-trifluoro)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-trifluoro)piperidin-4-yl)benzo[d][ 1,3]dioxole-5-carboxamide stereoisomer A 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-trifluoro)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-trifluoro)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-trifluoro)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) 7-(2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)-2, Stereoisomer B of 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)pyridin-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)pyridin-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)pyridin-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-trifluoro)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) 2-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(6- Stereoisomer B of (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)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 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) ethyl)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-trifluoroethyl)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) 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 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 113) 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 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

6. A compound according to any one of claims 1 to 5, a stereoisomer thereof, a pharma- ceutically 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.

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

8. The pharmaceutical composition according to claim 7, 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.

9. A method for preventing or treating a disease associated with EZH1 or EZH2 activity, comprising administering to an individual a compound according to any one of claims 1 to 5, its stereoisomer, its pharma- ceutically acceptable salt, its hydrate or solvate.

10. Use of a compound according to any one of claims 1 to 5, its stereoisomer, its pharma- ceutically acceptable salt, its hydrate or solvate for the prevention or treatment of a disease associated with EZH1 or EZH2 activity.

11. A compound according to any one of claims 1 to 5, its stereoisomers or its pharma- ceutically acceptable derivatives in the manufacture of a medicament for the prevention or treatment of a disease associated with EZH1 or EZH2 activity. Use of a salt thereof, a hydrate or a solvate thereof.

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