Novel compound, and pharmaceutical composition for prevention or treatment of cancer comprising same

Abstract

The compound represented by chemical formula 1 of the present specification can be usefully employed as a ubiquitin-specific-processing protease 1 (USP1) inhibitor for prevention or treatment of cancer.

Description

Novel compound and pharmaceutical composition containing the same for preventing or treating cancer

[0001] The present invention relates to a novel structural compound that can be usefully used in the prevention or treatment of cancer as an inhibitor of ubiquitin-specific-processing protease 1 (USP1).

[0002] Ubiquitin is a small (76 amino acid) protein that is attached to target proteins post-transcriptionally. The outcome of ubiquitination depends on the number and linkage topology of ubiquitin molecules conjugated to the target protein. For example, proteins displaying polyubiquitin chains linked via lysine 48 (K48) are typically targeted to the proteasome for degradation, whereas monoubiquitin or polyubiquitin chains linked via other lysines regulate non-protein-degrading functions such as cell cycle regulation, DNA damage repair, transcription, and endocytosis. Ubiquitination is a reversible process, and enzymes called deubiquitinases remove ubiquitin from target proteins.

[0003]

[0004] USP1 is a deubiquitinase that plays a role in DNA damage repair. USP1 interacts with USP1-associated factor 1 (UAF1) to form a complex required for deubiquitinase activity. The USP1 / UAF1 complex deubiquitinates monoubiquitinated PCNA (proliferating cell nuclear antigen) and monoubiquitinated FANCD2 (Fanconi anemia complementation group D2), proteins that play important roles in the translesion DNA synthesis (TLS) and Fanconi anemia (FA) pathways, respectively. The USP1 / UAF1 complex also deubiquitinates Fanconi anemia complementation group I (FANCI). These two pathways are essential for repairing DNA damage induced by DNA cross-linking agents such as cisplatin and mitomycin C (MMC).

[0005]

[0006] Safe and effective therapies targeting deubiquitinases are unknown, not yet commercially available, or not yet in clinical development.

[0007] The present invention provides a compound having a novel structure that can be usefully used for the prevention or treatment of cancer.

[0008] In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the compound.

[0009] To solve the above problem, the present invention provides a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof:

[0010] [Chemical Formula 1]

[0011]

[0012] In the above chemical formula 1,

[0013] R1 to R4 are each independently hydrogen, or C 1-4 It is alkyl,

[0014] L is C(R5)2, N(R5), or O,

[0015] R5 is each independently hydrogen, or C 1-4 It is alkyl,

[0016] A is C 5-6 Aryl; or C containing one or more heteroatoms selected from the group consisting of N, O and S 2-6 It is heteroaryl,

[0017] A is unsubstituted, or C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted with one or two substituents selected from the group consisting of cycloalkyl, halogen, -CO-NH2, and -SO2-NH2,

[0018] B is C 5-6 Aromatic ring; C containing one or more heteroatoms selected from the group consisting of N, O and S 2-12 Heteroaromatic ring; C 4-12 Cycloalkane; and C containing at least one heteroatom selected from the group consisting of N, O and S. 4-12 Any one of the divalent linkers selected from the group consisting of heterocycloalkanes,

[0019] B is unsubstituted, or C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted with one or two substituents selected from the group consisting of cycloalkyl and halogen,

[0020] C is C 5-6 Aryl; C containing one or more heteroatoms selected from the group consisting of N, O and S 2-12 Heteroaryl; C 4-12 Cycloalkyl; C containing one or more heteroatoms selected from the group consisting of N, O and S 4-12 Heterocycloalkyl, or -SO2-(C 1-4alkyl),

[0021] C is unsubstituted, or C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, halogen, -CO-(C 1-4 alkyl), and -SO2-(C 1-4 is substituted with one or two substituents selected from the group consisting of alkyl.

[0022]

[0023] Preferably, R1 to R4 are hydrogen.

[0024]

[0025] Preferably, L is CH2.

[0026]

[0027] Preferably, A is phenyl, or pyrimidinyl, wherein A is unsubstituted or substituted with one or two substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoro, chloro, bromo, -CO-NH2, and -SO2-NH2.

[0028]

[0029] Preferably, A is one selected from the group consisting of:

[0030]

[0031]

[0032] Preferably, B is one selected from the group consisting of:

[0033]

[0034]

[0035] Preferably, C is pyrazolyl, triazolyl, pyrimidinyl, imidazolyl, or pyridinyl, wherein C is unsubstituted or substituted with one or two substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tertbutyl, trifluoromethyl, methoxy, chloro, -CO-CH3, and -SO2-CH3.

[0036]

[0037] Preferably, C is one selected from the group consisting of:

[0038]

[0039]

[0040] Preferably, the above chemical formula 1 is represented by the following chemical formula 2:

[0041] [Chemical Formula 2]

[0042]

[0043] In the above chemical formula 2,

[0044] X1 and X2 are each independently CH or N,

[0045] R'1 and R'2 are each independently hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, or C 3-6 It is cycloalkyl,

[0046] R'3 and R'4 are each independently hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, or halogen.

[0047]

[0048] Preferably, both X1 and X2 are CH, or both are N.

[0049]

[0050] Preferably, R'1 and R'2 are each independently hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0051]

[0052] Preferably, R'3 and R'4 are each independently hydrogen, methyl, ethyl, propyl, isopropyl, or trifluoromethyl.

[0053]

[0054] Representative examples of compounds represented by the above chemical formula 1 are as follows:

[0055] 1) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0056] 2) 4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0057] 3) 2-(2-cyclopropylphenyl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0058] 4) 2-(2-cyclobutylphenyl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0059] 5) 2-(2-chlorophenyl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0060] 6) 2-(2-(difluoromethoxy)phenyl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0061] 7) 3-(4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacillin-2-yl)benzamide,

[0062] 8) 3-(4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacillin-2-yl)benzenesulfonamide,

[0063] 9) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0064] 10) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0065] 11) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0066] 12) 2-(2-isopropylphenyl)-6,6-dimethyl-4-(4-(pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0067] 13) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(6-methoxypyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0068] 14) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(6-(methylsulfonyl)pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0069] 15) 1-(6-(4-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-6,7-dihydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacillin-4(5H)-yl)methyl)phenyl)pyridin-2-yl)ethan-1-one,

[0070] 16) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(4-(trifluoromethyl)pyrimidin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0071] 17) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0072] 18) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-6,6-dimethyl-4-(4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0073] 19) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-((6-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0074] 20) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-((6'-(trifluoromethyl)-[2,2'-bipyridin]-5-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0075] 21) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophen-2-yl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0076] 22) 4-((5-(1-Isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophen-2-yl)methyl)-2-(2-isopropylphenyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0077] 23) 2-(2-isopropylphenyl)-6,6-dimethyl-4-(4-(methylsulfonyl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0078] 24) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(methylsulfonyl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0079] 25) 4-(4-(1H-pyrazol-1-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0080] 26) 4-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-cyclopropylphenyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0081] 27) 4-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-cyclobutylphenyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0082] 28) 4-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-chlorophenyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0083] 29) 4-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0084] 30) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0085] 31) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-6,6-dimethyl-4-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0086] 32) 2-(2-isopropylphenyl)-6,6-dimethyl-4-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0087] 33) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0088] 34) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0089] 35) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0090] 36) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0091] 37) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0092] 38) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-6,6-dimethyl-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0093] 39) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0094] 40) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0095] 41) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0096] 42) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0097] 43) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-((6-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0098] 44) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-((5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0099] 45) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-((5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin-2-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0100] 46) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(3-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0101] 47) 4-(4-(4-chloro-1-methyl-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0102] 48) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0103] 49) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-6,6-dimethyl-4-((1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0104] 50) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(2-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0105] 51) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(2-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline,

[0106] 52) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, and

[0107] 53) 2-(4-Cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(3-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline.

[0108]

[0109] In addition, the compound of the present invention may exist as a salt, enantiomer, stereoisomer, solvate, polymorph, or isotopic derivative, and in particular, may exist in the form of a pharmaceutically acceptable salt. As the salt, any salt commonly used in the art, such as an acid addition salt formed by a pharmaceutically acceptable free acid, may be used without limitation. The term "pharmaceutically acceptable salt" of the present invention means any and all organic or inorganic addition salts of the compound represented by Chemical Formula 1 at a concentration that is relatively non-toxic and harmless to the patient and has an effective effect, and the side effects caused by the salt do not reduce the beneficial effects of the compound represented by Chemical Formula 1.

[0110]

[0111] As the above-mentioned acid, organic acids and inorganic acids can be used. As the inorganic acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used. As the organic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. can be used, but are not limited thereto. Preferably, the salt may be hydrochloride.

[0112]

[0113] Additionally, a pharmaceutically acceptable metal salt can be obtained by a conventional method using a base. For example, the compound represented by the above chemical formula 1 is dissolved in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, the undissolved compound salt is filtered, and the filtrate is evaporated and dried to obtain a pharmaceutically acceptable metal salt. In this case, it is particularly preferable to prepare a sodium salt, a potassium salt, or a calcium salt as the metal salt.

[0114]

[0115] In addition, a salt or solvate of a compound represented by the chemical formula 1 that is not pharmaceutically acceptable can be used as an intermediate in the production of a compound represented by the chemical formula 1, a pharmaceutically acceptable salt, or a solvate thereof.

[0116]

[0117] Meanwhile, the compound represented by the above chemical formula 1 can be prepared by a method as shown in the following reaction scheme 1:

[0118] [Reaction Formula 1]

[0119]

[0120] In the above reaction formula 1, the remaining definitions except for X are as described above, and X is halogen, preferably bromo or chloro.

[0121]

[0122] The above reaction scheme 1 is a Suzuki coupling reaction, which is produced by reacting a palladium catalyst in the presence of a base. The reactor for the Suzuki coupling reaction can be modified according to what is known in the art. The above production method can be further detailed in the examples described below.

[0123]

[0124] Meanwhile, the compound represented by chemical formula 1' of the above reaction scheme 1 can be prepared by a method as in the following reaction scheme 2:

[0125] [Reaction Formula 2]

[0126]

[0127] In the above reaction formula 2, the remaining definitions except for X' are as described above, and X' is halogen, preferably bromo or chloro.

[0128]

[0129] The above reaction scheme 2 is an amine substitution reaction, which is produced by reacting in the presence of a base. The reactor for the amine substitution reaction can be modified according to what is known in the art. The above production method can be further detailed in the examples described below.

[0130]

[0131] In addition, the present invention provides a pharmaceutical composition comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0132]

[0133] The compounds of the present invention are USP1 inhibitors that reduce the level of USP1 protein or inhibit or reduce at least one biological activity of the USP1 protein. In some embodiments, the compounds of the present invention specifically bind to the USP1 protein. In some embodiments, the compounds of the present invention specifically bind to the USP1-UAF1 complex within the USP1 protein. In some embodiments, the compounds of the present invention specifically bind to USP1 mRNA. In some embodiments, the compounds of the present invention specifically bind to the USP1 protein (alone or in the USP1-UAF1 complex) or to the USP1 mRNA. In some embodiments, the compounds of the present invention specifically bind to UAF1 (alone or in the USP1-UAF1 complex).

[0134]

[0135] In some embodiments, the compounds of the present invention decrease the formation of the USP1-UAF1 complex. In some embodiments, the compounds of the present invention decrease the activity of the USP1-UAF1 complex. In some embodiments, the compounds of the present invention decrease the deubiquitinase activity of USP1. In some embodiments, the compounds of the present invention increase monoubiquitinated PCNA. In some embodiments, the compounds of the present invention increase monoubiquitinated FANCD2. In some embodiments, the compounds of the present invention increase monoubiquitinated FANCI.

[0136]

[0137] Specifically, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising a compound represented by the above chemical formula 1, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or isotope derivative thereof as an active ingredient.

[0138]

[0139] The term "prevention" of the present invention means any act of inhibiting or delaying the occurrence, spread, and recurrence of the disease by administering the composition of the present invention, and "treatment" means any act of improving or beneficially changing the symptoms of the disease by administering the composition of the present invention.

[0140]

[0141] The pharmaceutical composition of the present invention can be formulated into oral or parenteral dosage forms according to standard pharmaceutical practices. These dosage forms may contain, in addition to the active ingredient, pharmaceutically acceptable additives such as carriers, adjuvants, or diluents.

[0142]

[0143] Suitable carriers include, but are not limited to, saline, polyethylene glycol, ethanol, vegetable oils, and isopropyl myristate, and diluents include, but are not limited to, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine. In addition, the compounds of the present invention can be dissolved in oils, propylene glycol, or other solvents commonly used in the preparation of injectable solutions. In addition, the compounds of the present invention can be formulated as ointments or creams for topical action.

[0144]

[0145] The preferred dosage of the compound of the present invention varies depending on the patient's condition and body weight, the severity of the disease, the form of the drug, the route of administration, and the duration of administration, but can be appropriately selected by those skilled in the art. However, for desirable effects, the compound of the present invention is preferably administered at about 0.0001 to 100 mg / kg (body weight) per day, preferably about 0.001 to 100 mg / kg (body weight). Administration may be administered orally or parenterally once daily or in divided doses.

[0146]

[0147] Depending on the administration method, the pharmaceutical composition may contain about 0.001 to 99 wt%, preferably about 0.01 to 60 wt%, of the compound of the present invention.

[0148]

[0149] The pharmaceutical composition according to the present invention can be administered to mammals, including rats, mice, livestock, and humans, via various routes. Any route of administration is conceivable, including oral, rectal, intravenous, intramuscular, subcutaneous, intrauterine, or intracerebroventricular injection.

[0150] The compound represented by chemical formula 1 according to the present invention can be usefully used for the prevention or treatment of cancer as an inhibitor of ubiquitin-specific-processing protease 1 (USP1).

[0151] Hereinafter, preferred examples are presented to help understand the present invention, but the following examples are only to illustrate the present invention and the scope of the present invention is not limited to the following examples.

[0152]

[0153] Manufacturing Example 1: Preparation of 2-bromo-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0154]

[0155]

[0156] Step 1) Preparation of methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate

[0157] 3,3-Dibromo-1,1,1-trifluoropropane (19.70 g, 73.10 mmol) was added with distilled water (40 mL) and sodium acetate (5.99 g, 73.10 mmol), and the mixture was stirred at 100°C for 1 hour. After cooling to room temperature, methyl 4-formylbenzoate (I) (10.00 g, 60.92 mmol), methanol (280 mL), and aqueous ammonia (70 mL) were additionally added, and the mixture was stirred for 1 hour. The mixture was then stirred at 100°C for 2 hours. After completion of the reaction, distilled water (100 mL) was added, and the mixture was extracted with ethyl acetate (500 mL). The extracted organic layer was dried with MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (12 g, yield: 73%).

[0158] 1 H NMR (500 MHz, DMSO-d6) δ 13.57 (s, 1H), 8.12 (s, 1H), 7.51 (d, 2H, J = 3.6 Hz), 7.49 (d, 2H, J = 3.6 Hz) 3.86 (s, 3H).

[0159]

[0160] Step 2) Preparation of methyl 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate

[0161] Methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (12 g, 44.44 mmol) was dissolved in acetonitrile (440 mL), and 2-iodopropane (11.32 g, 66.66 mmol) and cesium carbonate (42 g, 133.32 mmol) were added, followed by stirring at 45°C for 24 h. After completion of the reaction, distilled water (120 mL) was added, and the mixture was extracted with ethyl acetate (600 mL). The extracted organic layer was dried with MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (7.5 g, yield: 54%).

[0162] 1 H NMR (500 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.50 (d, 2H, J = 3.6 Hz), 7.48 (d, 2H, J = 3.7 Hz) 4.48-4.47 (m, 1H), 3.88 (s, 3H), 1.40-1.38 (m, 6H).

[0163]

[0164] Step 3) Preparation of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol

[0165] Methyl 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (1 g, 3.20 mmol) was dissolved in tetrahydrofuran (32 mL) at 0°C, and lithium aluminum hydride solution (364 mg, 9.60 mmol) was slowly added. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was quenched with ethyl acetate while maintaining the temperature at 0°C. Distilled water (10 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The extracted organic layer was dried over MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure to obtain the target compound (720 mg, yield: 79%).

[0166] 1 H NMR (500 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.51 (d, 2H, J = 3.6 Hz), 7.47 (d, 2H, J = 3.7 Hz), 5.39-5.38 (m, 1H), 4.57 (s, 2H), 4.49-4.47 (m, 1H), 1.40 (d, 6H).

[0167]

[0168] Step 4) Preparation of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde

[0169] (4-(1-Isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (720 mg, 2.54 mmol) was dissolved in dichloromethane (25 mL), and pyridinium chlorochromate (1.09 g, 5.07 mmol) was added, followed by stirring at room temperature for 2 hours. After completion of the reaction, distilled water (10 mL) was added and extracted with ethyl acetate (50 mL). The extracted organic layer was dried over MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure to obtain the target compound (700 mg, yield: 98%).

[0170] 1 H NMR (500 MHz, DMSO-d6) δ 9.46 (s, 1H), 7.67 (s, 1H), 7.51 (d, 2H, J = 3.8 Hz), 7.47 (d, 2H, J = 3.6 Hz), 4.48-4.47 (m, 1H), 1.40 (d, 1H, J = 6.6 Hz).

[0171]

[0172] Step 5) Preparation of 3-bromo-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-1,2,4-triazol-5-amine

[0173] 3-Bromo-1H-1,2,4-triazol-5-amine (202 mg, 1.24 mmol), 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (350 mg, 1.24 mmol), methanol (12 mL), and acetic acid (149 mg, 2.48 mmol) were added and stirred at room temperature for 2 hours. Then, sodium cyanoborohydride (156 mg, 2.48 mmol) was slowly added. After completion of the reaction, distilled water (15 mL) was added and extracted with ethyl acetate (60 mL). The extracted organic layer was dried over MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (130 mg, yield: 24%).

[0174] 1 H NMR (500 MHz, DMSO-d6) δ 12.61 (s, 1H), 8.15 (s, 1H), 7.54-7.51 (m, 3H), 7.46 (d, 2H, J = 8.1 Hz), 4.48-4.46 (m, 1H), 4.41 (s, 2H), 1.40 (d, 6H, J = 6.7 Hz).

[0175]

[0176] Step 6) Preparation of 2-bromo-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0177] 3-Bromo-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-1,2,4-triazol-5-amine (100 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (2 mL), and bis(chloromethyl)dimethylsilane (41 mg, 0.26 mmol), potassium carbonate (128 mg, 0.93 mmol), and potassium iodide (4 mg, 0.023 mmol) were added. The reaction mixture was stirred at 40°C for 2 h. After completion of the reaction, distilled water (10 mL) was added and extracted with ethyl acetate (40 mL). The extracted organic layer was dried over MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (50 mg, yield: 42%).

[0178] 1 H NMR (500 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.54 (d, 2H, J = 8.1 Hz), 7.43 (d, 2H, J = 8.2 Hz), 4.68 (s, 2H), 4.49-4.44 (m, 1H), 2.68 (s, 2H), 1.39 (d, 6H, J = 6.7 Hz), 0.20 (s, 6H).

[0179]

[0180] Manufacturing Example 2: Preparation of 2-bromo-4-(2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0181]

[0182]

[0183] Step 1) Preparation of methyl 2-fluoro-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate

[0184] The target compound (8.32 g, yield: 53%) was obtained in the same manner as in step 1 of Preparation Example 1 using 3,3-dibromo-1,1,1-trifluoropropane (17.78 g, 65.88 mmol) and methyl 2-fluoro-4-formylbenzoate (I) (10.00 g, 54.90 mmol).

[0185] 1 H NMR (500 MHz, DMSO-d6) δ 13.33 (s, 1H), 7.84 (s, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 12.0 Hz, 1H) 3.67 (s, 3H).

[0186]

[0187] Step 2) Preparation of methyl 2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate

[0188] The target compound (3.30 g, yield: 35%) was obtained in the same manner as in step 2 of Preparation Example 1 using methyl 2-fluoro-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (8.32 g, 28.80 mmol) and acetonitrile (200 mL) and 2-iodopropane (7.34 g, 43.20 mmol).

[0189] 1 H NMR (500 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.03 (t, J = 7.8 Hz, 1H), 7.48 (t, J = 10.1 Hz, 2H), 4.58 - 4.53 (m, 1H), 3.90 (s, 3H), 1.43 (d, J) = 6.6 Hz, 6H).

[0190]

[0191] Step 3) Preparation of (2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol

[0192] The target compound (1.5 g, yield: 82%) was obtained in the same manner as in step 3 of Preparation Example 1 using methyl 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (2 g, 6.06 mmol) and lithium aluminum hydride solution (689 mg, 18.17 mmol).

[0193] 1 H NMR (500 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.02 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 11.1 Hz, 2H), 5.39 - 5.38 (m, 1H), 4.82 (s, 2H), 4.59 - 4.55 (m, 1H), 1.43 (d, J = 6.6 Hz, 6H).

[0194]

[0195] Step 4) Preparation of 2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde

[0196] The target compound (1.30 g, yield: 89%) was obtained in the same manner as in step 4 of Preparation Example 1 using (2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (1.50 g, 4.96 mmol) and pyridinium chlorochromate (2.14 g, 9.92 mmol).

[0197] 1 H NMR (500 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.01 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 11.0 Hz, 2H), 5.38 - 5.36 (m, 1H), 4.80 (s, 2H), 4.58 - 4.55 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H).

[0198]

[0199] Step 5) Preparation of 3-bromo-N-(2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-1,2,4-triazol-5-amine

[0200] The target compound (150 mg, yield: 18%) was obtained in the same manner as in step 5 of Preparation Example 1 using 3-bromo-1H-1,2,4-triazol-5-amine (300 mg, 1.84 mmol) and 2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (553 mg, 1.84 mmol).

[0201] 1 H NMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.19 (s, 1H), 7.51 - 7.47 (m, 2H), 7.40 (t, J = 9.7 Hz, 2H), 4.48 - 4.46 (m, 3H), 1.40 (d, J = 6.6 Hz, 6H).

[0202]

[0203] Step 6) Preparation of 2-bromo-4-(2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0204] The target compound (26 mg, yield: 41%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-(2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-1,2,4-triazol-5-amine (50 mg, 0.12 mmol) and bis(chloromethyl)dimethylsilane (19 mg, 0.13 mmol).

[0205] 1 H NMR (500 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.45 - 7.36 (m, 3H), 4.69 (s, 2H), 4.48 - 4.45 (m, 1H), 3.55 (s, 2H), 2.70 (s, 2H), 1.37 (d, J = 13.7 Hz, 6H), 0.17 (s, 6H).

[0206]

[0207] Manufacturing Example 3: Manufacturing of 2-bromo-6,6-dimethyl-4-(4-(pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0208]

[0209]

[0210] Step 1) Preparation of 3-bromo-N-(4-(pyridin-2-yl)benzyl)-1H-1,2,4-triazol-5-amine

[0211] The target compound (333.8 mg, yield: 55%) was obtained in the same manner as in step 5 of Preparation Example 1 using 3-bromo-1H-1,2,4-triazol-5-amine (300 mg, 1.84 mmol) and 4-(pyridin-2-yl)benzaldehyde (337.2 mg, 1.84 mmol).

[0212] 1H NMR (500 MHz, DMSO-d6) δ 12.59 (s, 1H), 8.69 (d, J = 4.7 Hz, 1H), 8.03 (m, 4H), 7.52 (s, 1H), 7.45 (d, J = 8.2 Hz, 3H), 4.39 (s, 2H).

[0213]

[0214] Step 2) Preparation of 2-bromo-6,6-dimethyl-4-(4-(pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0215] The target compound (109.2 mg, yield: 24%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-(4-(pyridin-2-yl)benzyl)-1H-1,2,4-triazol-5-amine (330 mg, 1.10 mmol) and bis(chloromethyl)dimethylsilane (191.3 mg, 1.21 mmol).

[0216] 1 H NMR (500 MHz, CDCl3) δ 8.72 (d, J = 4.8 Hz, 1H), 7.99 (d, J = 4.6 Hz, 2H), 7.81 - 7.75 (m, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.25 - 7.23 (m,1H), 4.77 (s, 2H), 3.55 (s, 2H), 2.56 (s, 2H).

[0217]

[0218] Manufacturing Example 4: Preparation of 2-bromo-4-(4-(6-methoxypyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0219]

[0220]

[0221] Step 1) Preparation of 4-(6-methoxypyridin-2-yl)benzaldehyde

[0222] 4-Bromobenzaldehyde (200 mg, 1.08 mmol) was dissolved in N,N-dimethylformamide (1 mL) and purified water (0.1 mL). (6-methoxypyridin-2-yl)boronic acid (247.9 mg, 1.62 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (88.2 mg, 0.10 mmol), and cesium carbonate (1.05 g, 3.24 mmol) were added. The reaction mixture was stirred in a microwave at 100°C for 2 h. After completion of the reaction, distilled water (3 mL) was added and extracted with ethyl acetate (12 mL). The extracted organic layer was dried over MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (72 mg, yield: 31.2%).

[0223] 1 H NMR (500 MHz, CDCl3) δ 10.08 (s, 1H), 8.24 - 8.20 (m, 2H), 7.99 - 7.95 (m, 2H), 7.68 (dd, J = 8.2, 7.4 Hz, 1H), 7.43 (dd, J = 7.3, 0.7 Hz, 1H), 6.77 (dd, J = 8.2, 0.6 Hz, 1H), 4.06 (s, 3H).

[0224]

[0225] Step 2) Preparation of 3-bromo-N-(4-(6-methoxypyridin-2-yl)benzyl)-1H-1,2,4-triazol-5-amine

[0226] The target compound (75.1 mg, yield: 21.2%) was obtained in the same manner as in step 5 of Preparation Example 1 using 3-bromo-1H-1,2,4-triazol-5-amine (160 mg, 0.98 mmol) and 4-(6-methoxypyridin-2-yl)benzaldehyde (209.3 mg, 0.98 mmol).

[0227] 1H NMR (500 MHz, DMSO-d6) δ 12.57 (s, 1H), 8.06 (d, J = 8.2 Hz, 2H), 7.77 (t, J = 7.8 Hz, 1H), 7.54 - 7.50 (m, 2H), 7.42 (d, J = 8.2 Hz, 2H), 6.77 (d, J = 8.2 Hz, 1H), 4.38 (d, J = 6.5 Hz, 2H), 3.95 (s, 3H).

[0228]

[0229] Step 3) Preparation of 2-bromo-4-(4-(6-methoxypyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0230] The target compound (35 mg, yield: 38%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-(4-(6-methoxypyridin-2-yl)benzyl)-1H-1,2,4-triazol-5-amine (75 mg, 0.20 mmol).

[0231] 1 H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 7.4 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 4.74 (s, 2H), 4.03 (s, 3H), 3.52 (s, 2H), 2.54 (s, 2H), 0.23 (s, 6H).

[0232]

[0233] Manufacturing Example 5: Preparation of 2-bromo-6,6-dimethyl-4-(4-(6-(methylsulfonyl)pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0234]

[0235]

[0236] Step 1) Preparation of 4-(6-(methylsulfonyl)pyridin-2-yl)benzaldehyde

[0237] 2-Bromo-6-(methylsulfonyl)pyridine (500 mg, 2.11 mmol) was dissolved in 1,4-dioxane (5 mL) and purified water (0.5 mL). (4-Formylphenyl)boronic acid (381.1 mg, 2.54 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (173 mg, 0.21 mmol), and cesium carbonate (2.1 g, 6.35 mmol) were added. The reaction mixture was stirred in a microwave at 80°C for 2 h. After completion of the reaction, distilled water (5 mL) was added and extracted with ethyl acetate (20 mL). The extracted organic layer was dried over MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (508.8 mg, yield: 91.9%).

[0238] 1 H NMR (500 MHz, CDCl3) δ 10.12 (s, 1H), 8.24 (d, J = 8.1 Hz, 2H), 8.12 - 8.01 (m, 5H), 3.35 (s, 3H).

[0239]

[0240] Step 2) Preparation of 3-bromo-N-(4-(6-(methylsulfonyl)pyridin-2-yl)benzyl)-1H-1,2,4-triazol-5-amine

[0241] The target compound (467.5 mg, yield: 58.9%) was obtained in the same manner as in step 5 of Preparation Example 1 using 4-(6-(methylsulfonyl)pyridin-2-yl)benzaldehyde (508 mg, 1.94 mmol) and 3-bromo-1H-1,2,4-triazol-5-amine (380.2 mg, 2.33 mmol).

[0242] 1H NMR (500 MHz, DMSO-d6) δ 12.60 (s, 1H), 8.30 (d, J = 7.9 Hz, 1H), 8.23 ​​(t, J = 7.9 Hz, 1H), 8.15 (d, J = 8.2 Hz, 2H), 7.98 (d, J = 7.6 Hz, 1H), 7.55 (t, J = 6.4 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 4.42 (d, J = 6.4 Hz, 2H), 3.39 (s, 3H).

[0243]

[0244] Step 3) Preparation of 2-bromo-6,6-dimethyl-4-(4-(6-(methylsulfonyl)pyridin-2-yl)benzyl)-4,5, 6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0245] The target compound (252 mg, yield: 44.7%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-(4-(6-(methylsulfonyl)pyridin-2-yl)benzyl)-1H-1,2,4-triazol-5-amine (467 mg, 1.14 mmol).

[0246] 1 H NMR (500 MHz, CDCl3) δ 8.04 - 8.00 (m, 5H), 7.44 (d, J = 8.0 Hz, 2H), 4.77 (s, 2H), 3.54 (s, 2H), 3.32 (s, 3H), 2.56 (s, 2H), 0.25 (s, 6H).

[0247]

[0248] Manufacturing Example 6: Preparation of 1-(6-(4-((2-bromo-6,6-dimethyl-6,7-dihydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacillin-4(5H)-yl)methyl)phenyl)pyridin-2-yl)ethan-1-one

[0249]

[0250]

[0251] Step 1) Preparation of 4-(6-acetylpyridin-2-yl)benzaldehyde

[0252] 1-(6-Bromopyridin-2-yl)ethan-1-one (500 mg, 3.33 mmol) was dissolved in 1,4-dioxane (60 mL) and purified water (6 mL). (4-Formylphenyl)boronic acid (1.33 g, 6.67 mmol), tetrakis(triphenylphosphine)palladium(0) (385 mg, 0.33 mmol), and tripotassium phosphate (2.12 g, 9.99 mmol) were added, and the reaction mixture was stirred in a microwave at 80°C for 2 h. After completion of the reaction, distilled water (200 mL) was added, and extracted with ethyl acetate (800 mL). The extracted organic layer was dried over MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (400 mg, yield: 53%).

[0253] 1 H NMR (500 MHz, CDCl3) δ 10.12 (s, 1H), 8.29 (d, J = 8.3 Hz, 2H), 8.06 - 8.02 (m, 4H), 8.00 - 7.95 (m, 1H), 2.84 (s, 3H).

[0254]

[0255] Step 2) Preparation of 1-(6-(4-(((3-bromo-1H-1,2,4-triazol-5-yl)amino)methyl)phenyl)pyridin-2-yl)ethan-1-one

[0256] The target compound (70 mg, yield: 30%) was obtained in the same manner as in step 5 of Preparation Example 1 using 3-bromo-1H-1,2,4-triazol-5-amine (101 mg, 0.62 mmol) and 4-(6-acetylpyridin-2-yl)benzaldehyde (140 mg, 0.62 mmol).

[0257] 1H NMR (500 MHz, DMSO-d6) δ 8.22 (d, J = 7.3 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 8.08 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 8.2 Hz, 2H), 4.41 (d, J = 6.4 Hz, 2H), 2.74 (s, 3H).

[0258]

[0259] Step 3) Preparation of 1-(6-(4-((2-bromo-6,6-dimethyl-6,7-dihydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacillin-4(5H)-yl)methyl)phenyl)pyridin-2-yl)ethan-1-one

[0260] The target compound (120 mg, yield: 49%) was obtained in the same manner as in step 6 of Preparation Example 1 using 1-(6-(4-(((3-bromo-1H-1,2,4-triazol-5-yl)amino)methyl)phenyl)pyridin-2-yl)ethan-1-one (200 mg, 0.54 mmol) and bis(chloromethyl)dimethylsilane (93 mg, 0.59 mmol).

[0261] 1 H NMR (500 MHz, CDCl3) δ 8.12 - 8.07 (m, 4H), 7.98 (d, J = 7.2 Hz, 2H), 7.93-7.88 (m, 4H), 7.52 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 17.2 Hz, 2H), 4.80 (d, J = 5.9 Hz, 2H), 4.77 (s, 2H), 3.54 (s, 2H), 2.83 (s, 3H), 2.57 (s, 2H), 0.25 (s, 6H).

[0262]

[0263] Manufacturing Example 7: Manufacturing of 2-bromo-6,6-dimethyl-4-(4-(4-(trifluoromethyl)pyrimidin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0264]

[0265]

[0266] Step 1) Preparation of 4-(4-(trifluoromethyl)pyrimidin-2-yl)benzaldehyde

[0267] 2-Bromo-4-(trifluoromethyl)pyrimidine (500 mg, 2.20 mmol) was dissolved in 1,4-dioxane (30 mL) and purified water (3 mL). (4-Formylphenyl)boronic acid (1.33 g, 4.41 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (190 mg, 0.22 mmol), and cesium carbonate (2.15 g, 6.61 mmol) were added, and the reaction mixture was stirred in a microwave at 80°C for 2 h. After completion of the reaction, distilled water (100 mL) was added, and extracted with ethyl acetate (400 mL). The extracted organic layer was dried over MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (400 mg, yield: 72%).

[0268] 1 H NMR (500 MHz, CDCl3) δ 10.13 (s, 1H), 9.11 (d, J = 5.0 Hz, 1H), 8.70 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 5.0 Hz, 1H).

[0269]

[0270] Step 2) Preparation of 3-bromo-N-(4-(4-(trifluoromethyl)pyrimidin-2-yl)benzyl)-1H-1,2,4-triazol-5-amine

[0271] 3-Bromo-1H-1,2,4-triazol-5-amine (258 mg, 1.59 mmol), 4-(4-(trifluoromethyl)pyrimidin-2-yl)benzaldehyde (400 mg, 1.59 mmol), methanol (12 mL), and acetic acid (191 mg, 3.18 mmol) were added and stirred at room temperature for 2 hours. Then, sodium cyanoborohydride (200 mg, 3.18 mmol) was slowly added. After completion of the reaction, distilled water (30 mL) was added and extracted with ethyl acetate (120 mL). The extracted organic layer was dried over MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (230 mg, yield: 36%).

[0272] 1 H NMR (500 MHz, DMSO-d6) δ 12.59 (s, 1H), 9.27 (s, 1H), 8.38 (d, J = 8.3 Hz, 2H), 7.95 (d, J = 5.0 Hz, 1H), 7.52 (d, J = 8.3 Hz, 3H), 4.44 (s, 2H).

[0273]

[0274] Step 3) Preparation of 2-bromo-6,6-dimethyl-4-(4-(4-(trifluoromethyl)pyrimidin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0275] 3-Bromo-N-(4-(4-(trifluoromethyl)pyrimidin-2-yl)benzyl)-1H-1,2,4-triazol-5-amine (230 mg, 0.58 mmol) was dissolved in N,N-dimethylformamide (5 mL), and bis(chloromethyl)dimethylsilane (99 mg, 0.63 mmol), potassium carbonate (321 mg, 2.32 mmol), and potassium iodide (10 mg, 0.058 mmol) were added. The reaction mixture was stirred at 40°C for 2 h. After completion of the reaction, distilled water (5 mL) was added and extracted with ethyl acetate (15 mL). The extracted organic layer was dried over MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (105 mg, yield: 37%).

[0276] 1 H NMR (500 MHz, CDCl3) δ 9.04 (d, J = 5.0 Hz, 1H), 8.48 (dd, J = 6.7, 1.6 Hz, 2H), 7.51 (d, J = 5.0 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 4.78 (s, 2H), 3.54 (s, 2H), 2.56 (s, 2H), 0.24 (s, 6H).

[0277]

[0278] Manufacturing Example 8: Preparation of 2-bromo-6,6-dimethyl-4-(4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0279]

[0280]

[0281] Step 1) Preparation of 4-(6-(trifluoromethyl)pyridin-2-yl)benzaldehyde

[0282] The target compound (527 mg, yield: 94.9%) was obtained in the same manner as in step 1 of Preparation Example 5 using 2-bromo-6-(trifluoromethyl)pyridine (500 mg, 2.21 mmol) and (4-formylphenyl)boronic acid (398 mg, 2.65 mmol).

[0283] 1 H NMR (500 MHz, CDCl3) δ 10.10 (s, 1H), 8.25 (d, J = 8.3 Hz, 2H), 8.02 - 7.99 (m, 4H), 7.70 - 7.68 (m, 1H).

[0284]

[0285] Step 2) Preparation of 3-bromo-N-(4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-1H-1,2,4-triazol-5-amine

[0286] The target compound (375 mg, yield: 44.9%) was obtained in the same manner as in step 5 of Preparation Example 1 using 4-(6-(trifluoromethyl)pyridin-2-yl)benzaldehyde (527 mg, 2.09 mmol) and 3-bromo-1H-1,2,4-triazol-5-amine (410.3 mg, 2.52 mmol).

[0287] 1 H NMR (500 MHz, DMSO-d6) δ 12.60 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.18 (t, J = 7.9 Hz, 1H), 8.12 - 8.07 (m, 2H), 7.85 (d, J = 7.7 Hz, 1H), 7.54 (t, J = 6.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 4.41 (d, J = 6.4 Hz, 2H).

[0288]

[0289] Step 3) Preparation of 2-bromo-6,6-dimethyl-4-(4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0290] The target compound (197.8 mg, yield: 43.5%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-(4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-1H-1,2,4-triazol-5-amine (375 mg, 0.94 mmol).

[0291] 1 H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 8.0 Hz, 2H), 7.92 (t, J = 7.2 Hz, 2H), 7.62 (t, J = 3.4 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 4.75 (s, 2H), 3.53 (s, 2H), 2.54 (s, 2H), 0.24 (s, 6H).

[0292]

[0293] Manufacturing Example 9: Preparation of 2-bromo-6,6-dimethyl-4-((6-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0294]

[0295]

[0296] Step 1) Preparation of 6-(trifluoromethyl)-[2,3'-bipyridine]-6'-carbaldehyde

[0297] The target compound (516 mg, yield: 92.5%) was obtained in the same manner as in step 1 of Preparation Example 5 using 2-bromo-6-(trifluoromethyl)pyridine (500 mg, 2.21 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinaldehyde (618.7 mg, 2.65 mmol).

[0298] 1H NMR (500 MHz, CDCl3) δ 10.17 (d, J = 0.8 Hz, 1H), 9.42 (dd, J = 2.3, 0.9 Hz, 1H), 8.61 (ddd, J = 8.1, 2.2, 0.8 Hz, 1H), 8.13 - 8.02 (m, 3H), 7.75 (dd, J = 4.9, 3.7 Hz, 1H).

[0299]

[0300] Step 2) Preparation of 3-bromo-N-((6-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)methyl)-1H-1,2,4-triazol-5-amine

[0301] The target compound (685 mg, yield: 82.1%) was obtained in the same manner as in step 5 of Preparation Example 1 using 6-(trifluoromethyl)-[2,3'-bipyridine]-6'-carbaldehyde (527 mg, 2.09 mmol) and 3-bromo-1H-1,2,4-triazol-5-amine (408.7 mg, 2.50 mmol).

[0302] 1 H NMR (500 MHz, DMSO-d6) δ 12.61 (s, 1H), 9.23 (d, J = 1.9 Hz, 1H), 8.46 (dd, J = 8.23, 2.3 Hz, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.23 ​​(d, J = 7.9 Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 6.3 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 4.53 (d, J = 6.3 Hz, 2H).

[0303]

[0304] Step 3) Preparation of 2-bromo-6,6-dimethyl-4-((6-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0305] The target compound (252 mg, yield: 30.4%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-((6-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)methyl)-1H-1,2,4-triazol-5-amine (685 mg, 1.71 mmol).

[0306] 1 H NMR (500 MHz, CDCl3) δ 9.17 (d, J = 2.1 Hz, 2H), 8.38 (dd, J = 8.2, 2.2 Hz, 1H), 8.00-7.93 (m, 2H), 7.68 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 4.90 (s, 2H), 3.55 (s, 2H), 2.74 (s, 2H), 0.27 (s, 6H).

[0307]

[0308] Manufacturing Example 10: Manufacturing of 2-bromo-6,6-dimethyl-4-((6'-(trifluoromethyl)-[2,2'-bipyridin]-5-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0309]

[0310]

[0311] Step 1) Preparation of 6'-(trifluoromethyl)-[2,2'-bipyridine]-5-carbaldehyde

[0312] The target compound (380 mg, yield: 93.4%) was obtained in the same manner as in step 1 of Preparation Example 5 using 2-bromo-6-(trifluoromethyl)pyridine (300 mg, 1.61 mmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (528.4 mg, 1.93 mmol).

[0313] 1H NMR (500 MHz, CDCl3) δ 10.09 (d, J = 1.9 Hz, 1H), 8.37 (t, J = 7.7 Hz, 1H), 8.15 - 8.10 (m, 1H), 8.02 (t, J = 7.9 Hz, 1H), 7.84 (dd, J = 8.0, 1.5 Hz, 1H), 7.76 - 7.71 (m, 2H).

[0314]

[0315] Step 2) Preparation of 3-bromo-N-((6'-(trifluoromethyl)-[2,2'-bipyridin]-5-yl)methyl)-1H-1,2,4-triazol-5-amine

[0316] The target compound (443.8 mg, yield: 73.8%) was obtained in the same manner as in step 5 of Preparation Example 1 using 6'-(trifluoromethyl)-[2,2'-bipyridine]-5-carbaldehyde (380 mg, 1.51 mmol) and 3-bromo-1H-1,2,4-triazol-5-amine (294.7 mg, 1.81 mmol).

[0317] 1 H NMR (500 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.69 (d, J = 1.7 Hz, 1H), 8.66 - 8.63 (m, 1H), 8.35 (dd, J = 7.9, 4.7 Hz, 1H), 8.25 (t, J = 7.9 Hz, 1H), 7.97 - 7.93 (m, 2H), 7.58 (t, J = 6.3 Hz, 1H), 4.45 (d, J = 6.3 Hz, 2H).

[0318]

[0319] Step 3) Preparation of 2-bromo-6,6-dimethyl-4-((6'-(trifluoromethyl)-[2,2'-bipyridin]-5-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0320] The target compound (252 mg, yield: 46.9%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-((6'-(trifluoromethyl)-[2,2'-bipyridin]-5-yl)methyl)-1H-1,2,4-triazol-5-amine (443 mg, 1.11 mmol).

[0321] 1 H NMR (500 MHz, CDCl3) δ 8.66 - 8.59 (m, 2H), 8.51 (dd, J = 10.0, 8.0 Hz, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.82 (dd, J = 8.1, 2.3 Hz, 1H), 7.69 (dd, J = 7.6, 1.0 Hz, 1H), 4.78 (s, 2H), 3.54 (s, 2H), 2.57 (s, 2H), 0.25 (s, 6H).

[0322]

[0323] Manufacturing Example 11: Preparation of 2-bromo-4-((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophen-2-yl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0324]

[0325]

[0326] Step 1) Preparation of methyl 5-(4-(trifluoromethyl)-1H-imidazol-2-yl)thiophene-2-carboxylate

[0327] The target compound (2.81 g, yield: 15%) was obtained in the same manner as in step 1 of Preparation Example 1 using 3,3-dibromo-1,1,1-trifluoropropane (19.03, 70.51 mmol) and methyl 5-formylthiophene-2-carboxylate (I) (10.00 g, 58.76 mmol).

[0328] 1H NMR (500 MHz, DMSO-d6) δ 13.45 (s, 1H), 8.32 (s, 1H), 8.12 (s, 1H), 7.69 (s, 1H), 3.88 (s, 3H).

[0329]

[0330] Step 2) Preparation of methyl 5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophene-2-carboxylate

[0331] The target compound (1.50 g, yield: 61%) was obtained in the same manner as in step 2 of Preparation Example 1 using methyl 5-(4-(trifluoromethyl)-1H-imidazol-2-yl)thiophene-2-carboxylate (2.70 g, 8.48 mmol) and 2-iodopropane (2.20 g, 12.72 mmol).

[0332] 1 H NMR (500 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.10 (s, 1H), 7.60 (S, 1H), 4.88 - 4.84 (m, 1H), 3.90 (s, 3H), 1.45 (d, J = 6.6 Hz, 6H).

[0333]

[0334] Step 3) Preparation of (5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophen-2-yl)methanol

[0335] The target compound (600 mg, yield: 86%) was obtained in the same manner as in step 3 of Preparation Example 1 using methyl 5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophene-2-carboxylate (700 mg, 2.41 mmol) and lithium aluminum hydride solution (229 mg, 6.03 mmol).

[0336] 1H NMR (500 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.10 (s, 1H), 7.56 (S, 1H), 4.80 (s, 2H), 4.59 - 4.55 (m, 1H), 1.45 (d, 6H, J = 6.6 Hz).

[0337]

[0338] Step 4) Preparation of 5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophene-2-carbaldehyde

[0339] The target compound (800 mg, yield: 94%) was obtained in the same manner as in step 4 of Preparation Example 1 using (5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophen-2-yl)methanol (800 mg, 2.76 mmol) and pyridinium chlorochromate (1.19 g, 5.51 mmol).

[0340] 1 H NMR (500 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.30 (s, 1H), 8.11 (s, 1H), 7.69 (S, 1H), 4.84 - 4.81 (m, 1H), 1.49 (d, J = 6.6 Hz, 1H).

[0341]

[0342] Step 5) Preparation of 3-bromo-N-((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophen-2-yl)methyl)-1H-1,2,4-triazol-5-amine

[0343] The target compound (260 mg, yield: 22%) was obtained in the same manner as in step 5 of Preparation Example 1 using 3-bromo-1H-1,2,4-triazol-5-amine (452 ​​mg, 2.77 mmol) and 5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophene-2-carbaldehyde (800 mg, 2.77 mmol).

[0344] 1H NMR (500 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.15 (s, 1H), 7.59 (s, 1H), 7.31 (S, 1H), 7.09 (s, 1H), 4.73 - 4.71 (m, 1H), 4.54 (d, J = 6.3 Hz, 2H), 1.44 (d, J = 6.6 Hz, 6H).

[0345]

[0346] Step 6) Preparation of 2-bromo-4-((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophen-2-yl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0347] The target compound (18 mg, yield: 52%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophen-2-yl)methyl)-1H-1,2,4-triazol-5-amine (30 mg, 0.069 mmol) and bis(chloromethyl)dimethylsilane (12 mg, 0.076 mmol).

[0348] 1 H NMR (500 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.33 (d, J = 6.5 Hz, 2H), 7.15 (d, J = 3.7 Hz, 2H), 4.76 (s, 2H), 4.73 - 4.70 (m, 1H), 3.48 (s, 2H), 2.70 (s, 2H), 1.43 (d, J = 6.6 Hz, 6H), 0.20 (s, 6H).

[0349]

[0350] Manufacturing Example 12: Preparation of 2-bromo-6,6-dimethyl-4-(4-(methylsulfonyl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0351]

[0352]

[0353] Step 1) Preparation of 3-bromo-N-(4-(methylsulfonyl)benzyl)-1H-1,2,4-triazol-5-amine

[0354] The target compound (206.8 mg, yield: 34%) was obtained in the same manner as in step 5 of Preparation Example 1 using 3-bromo-1H-1,2,4-triazol-5-amine (300 mg, 1.84 mmol) and 4-methylsulfonylbenzaldehyde (339.1 mg, 1.84 mmol).

[0355] 1 H NMR (500 MHz, DMSO-d6) δ 12.63 (s, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.62 - 7.54 (m, 3H), 4.45 (d, J = 6.4 Hz, 2H), 3.19 (s, 3H).

[0356]

[0357] Step 2) Preparation of 2-bromo-6,6-dimethyl-4-(4-(methylsulfonyl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0358] The target compound (101.2 mg, yield: 39.1%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-(4-(methylsulfonyl)benzyl)-1H-1,2,4-triazol-5-amine (206 mg, 0.62 mmol).

[0359] 1 H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 4.79 (s, 2H), 3.56 (s, 3H), 3.07 (s, 2H), 2.56 (s, 2H), 0.27 (s, 6H).

[0360]

[0361] Manufacturing Example 13: Manufacturing of 4-(4-(1H-pyrazol-1-yl)benzyl)-2-bromo-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0362]

[0363]

[0364] Step 1) Preparation of N-(4-(1H-pyrazol-1-yl)benzyl)-3-bromo-1H-1,2,4-triazol-5-amine

[0365] The target compound (615.2 mg, yield: 62.8%) was obtained in the same manner as in step 5 of Preparation Example 1 using 3-bromo-1H-1,2,4-triazol-5-amine (500 mg, 3.06 mmol) and 4-(1H-pyrazol-1-yl)benzaldehyde (528.3 mg, 3.06 mmol).

[0366] 1 H NMR (500 MHz, DMSO-d6) δ 12.57 (s, 1H), 8.46 (d, J = 2.5 Hz, 1H), 7.82 - 7.76 (m, 2H), 7.72 (d, J = 1.7 Hz, 1H), 7.49 (t, J = 6.4 Hz, 1H), 7.44 - 7.39 (m, 2H), 6.55 - 6.51 (m, 1H), 4.35 (d, J = 6.4 Hz, 2H).

[0367]

[0368] Step 2) Preparation of 4-(4-(1H-pyrazol-1-yl)benzyl)-2-bromo-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0369] The target compound (101.2 mg, yield: 40%) was obtained in the same manner as in step 6 of Preparation Example 1 using N-(4-(1H-pyrazol-1-yl)benzyl)-3-bromo-1H-1,2,4-triazol-5-amine (200 mg, 0.62 mmol).

[0370] 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 2.5 Hz, 1H), 7.73 (d, J = 1.4 Hz, 1H), 7.92 (d, J = 2.5 Hz, 1H), 7.73 (d, J = 1.4 Hz, 1H), 4.79 (s, 2H), 3.56 (s, 3H), 3.07 (s, 2H), 2.56 (s, 2H), 0.27 (s, 6H).

[0371]

[0372] Manufacturing Example 14: Preparation of 2-bromo-6,6-dimethyl-4-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0373]

[0374]

[0375] Step 1) Preparation of methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate

[0376] Methyl 4-hydrazinyl benzoate hydrochloride (1 g, 4.93 mmol) was added to 1,1,1,3,3,3-hexafluoroisopropanol (5 mL), and the temperature was lowered to 0℃. Difluoromethyl 3-oxobutanoyl fluoride (760.4 mg, 4.930 mmol) was added, and triethylamine (998 mg, 9.86 mmol) dissolved in 1,1,1,3,3,3-hexafluoroisopropanol (3 mL) was slowly added over 5 minutes, and the mixture was stirred at 25℃ for 2 hours. The reaction was quenched with purified water, and extracted with methylene chloride. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the target compound (1.23 g, yield 88.2%).

[0377] 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, J = 6.8, 1.9 Hz, 2H), 7.58 (d, J = 1.9 Hz, 2H), 6.49 (s, 1H), 3.96 (s, 3H), 2.41 (s, 3H).

[0378]

[0379] Step 2) Preparation of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol

[0380] The target compound (1.05 g, yield: 94%) was obtained in the same manner as in step 3 of Preparation Example 1 using methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate (1.24 g, 4.36 mmol) and lithium aluminum hydride solution (413 mg, 10.89 mmol).

[0381] 1 H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 9.0 Hz, 2H), 6.46 (s, 1H), 4.77 (s, 2H), 2.34 (s, 3H).

[0382]

[0383] Step 2) Preparation of 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzaldehyde

[0384] The target compound (950 mg, yield: 91%) was obtained in the same manner as in step 4 of Preparation Example 1 using (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (1.05 g, 4.10 mmol) and pyridinium chlorochromate (1.76 g, 8.19 mmol).

[0385] 1H NMR (500 MHz, CDCl3) δ 10.08 (s, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 10.0 Hz, 2H), 6.52 (s, 1H), 2.43 (s, 3H).

[0386]

[0387] Step 3) Preparation of 3-bromo-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-1,2,4-triazol-5-amine

[0388] The target compound (560 mg, yield: 37%) was obtained in the same manner as in step 5 of Preparation Example 1 using 3-bromo-1H-1,2,4-triazol-5-amine (609 mg, 3.74 mmol) and 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzaldehyde (950 mg, 3.74 mmol).

[0389] 1 H NMR (500 MHz, DMSO-d6) δ 12.63 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 6.75 (s, 1H), 4.43 (d, J = 6.4 Hz, 2H), 2.33 (s, 3H).

[0390]

[0391] Step 4) Preparation of 2-bromo-6,6-dimethyl-4-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0392] The target compound (80 mg, yield: 54%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-1,2,4-triazol-5-amine (150 mg, 0.37 mmol) and bis(chloromethyl)dimethylsilane (65 mg, 0.41 mmol).

[0393] 1 H NMR (500 MHz, DMSO-d6) δ 7.42 - 7.37 (m, 4H), 6.43 (s, 1H), 4.73 (s, 2H), 3.51 (s, 2H), 2.51 (s, 2H), 2.32 (s, 3H), 0.22 (s, 6H).

[0394]

[0395] Manufacturing Example 15: Preparation of 2-bromo-4-(2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0396]

[0397]

[0398] Step 1) Preparation of 2-fluoro-4-hydrazinylbenzoic acid

[0399] To a solution of 4-amino-2-fluorobenzoic acid (9 g, 58 mmol) in conc. HCl (54 mL) was added dropwise a solution of sodium nitrite (4 g, 58 mmol) in distilled water (31 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 h, and then a solution of tin(II) chloride (21.99 g, 116 mmol) in conc. HCl (27 mL) was added. The reaction mixture was stirred at 0°C for 1 h. The reaction mixture was filtered, and the solid was collected to obtain the target compound (11 g, yield 94%) as a yellow solid, which was used in the next step without further purification.

[0400] 1 H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 2H), 9.25 (s, 1H), 7.77 (t, J = 8.4 Hz, 1H), 6.83 - 6.81 (m, 2H), 3.99 (s, 3H).

[0401]

[0402] Step 2) Preparation of 2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoic acid

[0403] 2-Fluoro-4-hydrazinylbenzoic acid (10 g, 54.3 mmol) and difluoromethyl 3-oxobutanoyl fluoride (10.11 g, 65.1 mmol) were dissolved in ethanol (100 mL) and stirred at 25°C for 12 h. The mixture was concentrated in vacuo. The residue was purified by column chromatography to give the target compound (7 g, yield 38%) as a yellow solid.

[0404] 1 H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 8.05 (t, J = 8.4 Hz, 1H), 7.56 - 7.55 (m, 1H), 7.47 - 7.46 (m, 1H), 7.06 (s, 1H), 2.31 (s, 3H).

[0405]

[0406] Step 3) Preparation of (2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol

[0407] 2-Fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoic acid (5 g, 17.3 mmol) was dissolved in THF (50 mL), and LAH (1.31 g, 34.6 mmol) was slowly added at 0°C. The reaction mixture was stirred at 0°C for 2 h. The mixture was diluted with distilled water (1.3 mL), sodium hydroxide (1.3 mL, 15% in distilled water), and distilled water (3.9 mL), and the mixture was filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title compound (900 mg, yield 17%) as a yellow oil, which was used in the next step without further purification.

[0408] 1H NMR (400 MHz, DMSO-d6) δ 7.67 - 7.63 (m, 1H), 7.50 - 7.47 (m, 1H), 7.45 - 7.43 (m, 1H), 6.78 (s, 1H), 4.62 (d, J = 5.6 Hz, 2H), 2.37 (d, J = 0.4 Hz, 3H).

[0409]

[0410] Step 4) Preparation of 2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzaldehyde

[0411] (2-Fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (900 mg, 3.28 mmol) and manganese(IV) oxide (2.85 g, 32.8 mmol) were added to DCE (10 mL) and stirred at 65°C for 16 h, and then the mixture was filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography to give the target compound (600 mg, yield 63%) as a yellow oil.

[0412] 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.05 - 8.01 (m, 1H), 7.80 - 7.77 (m, 1H), 7.69 - 7.66 (m, 1H), 6.87 (s, 1H), 2.47 (d, J = 0.4 Hz, 3H).

[0413]

[0414] Step 5) Preparation of 3-bromo-N-(2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-1,2,4-triazol-5-amine

[0415] 2-Fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzaldehyde (600 mg, 2.2 mmol), 3-bromo-1H-1,2,4-triazol-5-amine (431 mg, 2.6 mmol), and acetic acid (132 mg, 2.2 mmol) were dissolved in toluene (10 mL) and stirred at 100°C for 8 h. Then, sodium cyanoborohydride (277 mg, 2.2 mmol) was added to the mixture at 0°C and stirred at 25°C for 3 h. The mixture was diluted with distilled water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to obtain the title compound (350 mg, yield 31%).

[0416] 1 H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 7.56 - 7.49 (m, 3H), 7.44 (d, J = 2.0 Hz, 1H), 6.78 (s, 1H), 4.47 (d, J = 6.4 Hz, 2H), 2.37 (s, 3H).

[0417]

[0418] Step 6) Preparation of 2-bromo-4-(2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0419] To a solution of 3-bromo-N-(2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-1,2,4-triazol-5-amine (350 mg, 0.83 mmol), potassium carbonate (461 mg, 3.34 mmol), and potassium iodide (13 mg, 0.08 mmol) was added N,N-dimethylformamide (4 mL), and bis(chloromethyl)dimethylsilane (157 mg, 1 mmol). The reaction mixture was stirred at 25°C for 16 h. The mixture was diluted with distilled water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (240 mg, yield 54%).

[0420] 1 H NMR (400 MHz, DMSO-d6) δ 7.58 - 7.55 (m, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.46 - 7.43 (m, 1H), 6.78 (s, 1H), 4.73 (s, 2H), 3.52 (s, 2H), 2.73 (s, 2H), 2.38 (s, 3H), 0.21 (s, 6H).

[0421]

[0422] Manufacturing Example 16: Preparation of 2-bromo-4-(3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0423]

[0424]

[0425] Step 1) Preparation of methyl 3-fluoro-4-hydrazinylbenzoate

[0426] The target compound (11 g, yield 95%) was obtained as a white solid using the same method as step 1 of Preparation Example 15 using methyl 4-amino-3-fluorobenzoate (10 g, 0.06 mol), and was used in the next step without further purification.

[0427] LCMS: Ms = 184.80 [M+H] + .

[0428]

[0429] Step 2) Preparation of methyl 3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate

[0430] The target compound (4 g, yield 21%) was obtained in the same manner as in step 2 of Preparation Example 15 using methyl 3-fluoro-4-hydrazinylbenzoate (11 g, 0.06 mol) and 1,1,1-trifluoropentane-2,4-dione (11.11 g, 0.07 mol).

[0431] 1 H NMR (400 MHz, DMSO-d6) δ 8.04 - 7.96 (m, 2H), 7.84 (d, J = 7.6 Hz, 1H), 6.85 (s, 1H), 3.92 (s, 3H), 2.25 (s, 3H).

[0432]

[0433] Step 3) Preparation of (3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol

[0434] The target compound (3.5 g, yield 91%) was obtained in the same manner as in step 3 of Preparation Example 15 using methyl 3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate (4 g, 13.2 mmol), and was used in the next step without further purification.

[0435] 1H NMR (400 MHz, DMSO-d6) δ 7.60 - 7.56 (m, 1H), 7.45 - 7.40 (m, 1H), 7.36 - 7.34 (m, 1H), 6.78 (s, 1H), 5.52 - 5.49 (m, 1H), 4.61 (d, J = 6.0 Hz, 2H), 2.20 (s, 3H).

[0436]

[0437] Step 4) Preparation of 3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzaldehyde

[0438] The target compound (3.5 g, yield 95%) was obtained in the same manner as in step 4 of Preparation Example 15 using (3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (3.5 g, 12.8 mmol).

[0439] 1 H NMR (400 MHz, DMSO-d6) δ 10.10 (d, J = 1.6 Hz, 1H), 8.05 - 8.02 (m, 1H), 7.99 - 7.97 (m, 1H), 7.94 - 7.90 (m, 1H), 6.86 (s, 1H), 2.26 (s, 3H).

[0440]

[0441] Step 5) Preparation of 3-bromo-N-(3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-1,2,4-triazol-5-amine

[0442] The target compound (1.2 g, yield 35%) was obtained in the same manner as in step 5 of Preparation Example 15 using 3-fluoro-4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]benzaldehyde (2 g, 7.3 mmol) and 5-bromo-2H-1,2,4-triazol-3-amine (1.43 g, 8.7 mmol).

[0443] 1H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 7.66 - 7.56 (m, 2H), 7.44 (d, J = 11.2 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 6.78 (s, 1H), 4.45 (d, J = 6.4 Hz, 2H), 2.20 (s, 3H).

[0444]

[0445] Step 6) Preparation of 2-bromo-4-(3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0446] The target compound (600 mg, yield 39%) was obtained in the same manner as in step 6 of Preparation Example 15 using 5-bromo-N-({3-fluoro-4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl}methyl)-2H-1,2,4-triazol-3-amine (1.16 g, 2.8 mmol).

[0447] 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 1H), 7.43 (d, J = 11.2 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.79 (s, 1H), 4.72 (s, 2H), 3.52 (s, 2H), 2.72 (s, 2H), 2.21 (s, 3H), 0.22 (s, 6H).

[0448]

[0449] Manufacturing Example 17: Preparation of 2-bromo-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0450]

[0451]

[0452] Step 1) Preparation of methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate

[0453] Methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (2.95 g, 10.95 mmol) was dissolved in N,N-dimethylformamide (30 mL) at 0°C, and sodium hydride (315 mg, 13.13 mmol) was added, followed by stirring for 30 minutes. Iodomethane (1.86 g, 13.13 mmol) was slowly added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, distilled water (30 mL) was added, and the mixture was extracted with ethyl acetate (120 mL). The extracted organic layer was dried over MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (1.64 g, yield: 53%).

[0454] 1 H NMR (500 MHz, DMSO-d6) δ 8.09 (d, J = 8.4 Hz, 2H), 8.02 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H) 3.90 (s, 3H), 3.85 (s, 3H).

[0455]

[0456] Step 2) Preparation of (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol

[0457] The target compound (1.54 g, yield: 100%) was obtained in the same manner as in step 3 of Preparation Example 1 using methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (1.64 g, 5.77 mmol) and lithium aluminum hydride solution (657 mg, 17.31 mmol).

[0458] 1H NMR (500 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 5.32 (t, J = 5.7 Hz, 1H), 4.58 (s, J = 5.6 Hz, 2H), 3.78 (s, 3H).

[0459]

[0460] Step 3) Preparation of 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde

[0461] The target compound (1.45 g, yield: 95%) was obtained in the same manner as in step 4 of Preparation Example 1 using (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (1.54 g, 6.01 mmol) and pyridinium chlorochromate (2.59 g, 12.02 mmol).

[0462] 1 H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.15 - 7.76 (m, 4H), 7.37 (s, 1H), 3.98 (s, 3H).

[0463]

[0464] Step 4) Preparation of 3-bromo-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-1,2,4-triazol-5-amine

[0465] The target compound (155 mg, yield: 25%) was obtained in the same manner as in step 5 of Preparation Example 1 using 3-bromo-1H-1,2,4-triazol-5-amine (256 mg, 1.57 mmol) and 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (400 mg, 1.57 mmol).

[0466] 1H NMR (500 MHz, DMSO-d6) δ 12.63 (s, 1H), 7.93 (s, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.52 (s, 1H), 7.45 (d, J = 8.2 Hz, 2H), 4.41 (d, J = 6.5) Hz, 2H), 3.77 (s, 3H).

[0467]

[0468] Step 5) Preparation of 2-bromo-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0469] The target compound (75 mg, yield: 40%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-1,2,4-triazol-5-amine (155 mg, 0.39 mmol) and bis(chloromethyl)dimethylsilane (67 mg, 0.42 mmol).

[0470] 1 H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.31 (s, 1H), 4.73 (s, 2H), 3.76 (s, 3H), 3.52 (s, 2H), 2.52 (s, 2H), 0.23 (s, 6H).

[0471]

[0472] Manufacturing Example 18: Preparation of 2-bromo-4-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0473]

[0474]

[0475] Step 1) Preparation of methyl 2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate

[0476] The target compound (0.94 g, yield: 89.8%) was obtained in the same manner as in step 1 of Preparation Example 17 using methyl 2-fluoro-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (1 g, 3.45 mmol) and iodomethane (0.54 g, 3.81 mmol).

[0477] 1 H NMR (500 MHz, CDCl3) δ 8.06 (t, J = 7.7 Hz, 1H), 7.54 - 7.49 (m, 2H), 7.36 (s, 1H), 3.96 (s, 3H), 3.84 (s, 3H).

[0478]

[0479] Step 2) Preparation of (2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol

[0480] The target compound (852 mg, yield: 99%) was obtained in the same manner as in step 3 of Preparation Example 1 using methyl 2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (940 mg, 3.11 mmol).

[0481] 1 H NMR (500 MHz, CDCl3) δ 7.55 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 7.8Hz, 1H), 7.35 (d, J = 10.5Hz, 1H), 7.32 (s, 1H), 4.82 (s, 2H), 3.78 (s, 3H), 2.19 (s, 1H).

[0482]

[0483] Step 3) Preparation of 2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde

[0484] The target compound (689.6 mg, yield: 83.7%) was obtained in the same manner as in step 4 of Preparation Example 1 using (2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (830 mg, 3.02 mmol).

[0485] 1 H NMR (500 MHz, CDCl3) δ 10.41 (s, 1H), 7.99 (t, J = 7.6 Hz, 1H), 7.59 - 7.56 (m,2H), 7.38 (s, 1H), 3.86 (s, 3H).

[0486]

[0487] Step 4) Preparation of 3-bromo-N-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-1,2,4-triazol-5-amine

[0488] The target compound (601.9 mg, yield: 56.7%) was obtained in the same manner as in step 5 of Preparation Example 1 using 2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (689 mg, 2.53 mmol) and 3-bromo-1H-1,2,4-triazol-5-amine (453.8 mg, 2.78 mmol).

[0489] 1 H NMR (500 MHz, DMSO-d6) δ 12.63 (s, 1H), 7.96 (s, 1H), 7.57 - 7.45 (m, 4H), 4.46 (d, J = 5.8 Hz, 2H), 3.80 (s, 3H).

[0490]

[0491] Step 5) Preparation of 2-bromo-4-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0492] The target compound (265.3 mg, yield: 36.8%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-1,2,4-triazol-5-amine (600 mg, 1.43 mmol).

[0493] 1 H NMR (500 MHz, CDCl3) δ 7.50 (t, J = 7.5 Hz, 1H), 7.42 - 7.38 (m,2H), 7.32 (s, 1H), 4.81 (s, 2H), 3.79 (s, 3H), 3.52 (s, 2H), 2.61 (s, 2H), 0.25 (s, 6H).

[0494]

[0495] Manufacturing Example 19: Preparation of 2-bromo-4-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0496]

[0497]

[0498] Step 1) Preparation of 3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde

[0499] The target compound (236.5 mg, yield: 66.3%) was obtained in the same manner as in step 1 of Preparation Example 5 using 2-bromo-1-methyl-4-(trifluoromethyl)-1H-imidazole (300 mg, 1.31 mmol) and 3-fluoro-4-formylphenylboronic acid (264 mg, 1.57 mmol).

[0500] 1 H NMR (500 MHz, CDCl3) δ10.08 (s, 1H), 7.90 - 7.73 (m,3H), 7.43 (s, 1H), 3.07 (s, 3H).

[0501]

[0502] Step 2) Preparation of 3-bromo-N-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-1,2,4-triazol-5-amine

[0503] The target compound (321 mg, yield: 88.3%) was obtained in the same manner as in step 5 of Preparation Example 1 using 3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (236 mg, 0.86 mmol) and 3-bromo-1H-1,2,4-triazol-5-amine (155.4 mg, 0.95 mmol).

[0504] LCMS: Ms = 420.10 [M+H] + .

[0505]

[0506] Step 3) Preparation of 2-bromo-4-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0507] The target compound (151.7 mg, yield: 78.9%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-1,2,4-triazol-5-amine (160 mg, 0.38 mmol).

[0508] 1 H NMR (500 MHz, CDCl3) δ7.59 (t, J = 7.5 Hz, 1H),7.36 (s, 1H), 7.59 (t, J = 7.5 Hz, 1H),7.21 - 7.12 (m, 2H), 4.75 (s, 2H), 3.65 (s, 3H), 3.55 (s, 2H), 2.54 (s, 2H), 0.26 (s, 6H).

[0509]

[0510] Manufacturing Example 20: Preparation of 2-bromo-6,6-dimethyl-4-((6-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0511]

[0512]

[0513] Step 1) Preparation of methyl 6-(4-(trifluoromethyl)-1H-imidazol-2-yl)nicotinate

[0514] The target compound (2.5 g, yield: 30%) was obtained in the same manner as in step 1 of Preparation Example 1 using 3,3-dibromo-1,1,1-trifluoropropane (8.07 g, 29.9 mmol) and methyl 6-formylpyridine-3-carboxylate (4.5 g, 27.2 mmol).

[0515] 1 H NMR (400 MHz, DMSO-d6) δ 13.83 (s, 1H), 9.13 (d, J = 1.6 Hz, 1H), 8.43 - 8.40 (m, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 3.92 (s, 3H).

[0516]

[0517] Step 2) Preparation of methyl 6-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)nicotinate

[0518] The target compound (330 mg, yield: 56%) was obtained in the same manner as in step 1 of Preparation Example 17 using methyl 6-(4-(trifluoromethyl)-1H-imidazol-2-yl)nicotinate (500 mg, 1.84 mmol).

[0519] 1H NMR (400 MHz, DMSO-d6) δ 9.14 (d, J = 2.0 Hz, 1H), 8.41 - 8.39 (m, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.09 (s, 1H), 4.14 (s, 3H), 3.92 (s, 3H).

[0520]

[0521] Step 3) Preparation of (6-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methanol

[0522] The target compound (700 mg, yield: 97%) was obtained in the same manner as in step 3 of manufacturing example 1 using methyl 6-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)nicotinate (800 mg, 2.80 mmol).

[0523] 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.89 - 7.86 (m, 1H), 5.43 (s, 1H), 4.60 (d, J = 5.6 Hz, 2H), 4.08 (s, 3H).

[0524]

[0525] Step 4) Preparation of 6-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)nicotinaldehyde

[0526] The target compound (770 mg, yield: 65%) was obtained in the same manner as in step 4 of Preparation Example 15 using (6-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methanol (1.06 g, 4.1 mmol).

[0527] 1 H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 9.18 - 9.15 (m, 1H), 8.38 - 8.29 (m, 2H), 8.13 (s, 1H), 4.15 (s, 3H).

[0528]

[0529] Step 5) Preparation of 3-bromo-N-((6-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)-1H-1,2,4-triazol-5-amine

[0530] The target compound (370 mg, yield: 31%) was obtained in the same manner as in step 5 of Preparation Example 1 using 6-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)nicotinaldehyde (670 mg, 2.62 mmol) and 3-bromo-1H-1,2,4-triazol-5-amine (471 mg, 2.88 mmol).

[0531] 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 1.6 Hz, 1H), 8.05 (s, 1H), 7.99 (d, J = 1.2 Hz, 1H), 7.87 - 7.84 (m, 1H), 7.55 (t, J = 6.0 Hz, 1H), 6.30 (s, 1H), 4.42 (d, J = 6.4 Hz, 2H), 4.08 (s, 3H).

[0532]

[0533] Step 6) Preparation of 2-bromo-6,6-dimethyl-4-((6-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0534] The target compound (260 mg, yield: 60%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-((6-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)-1H-1,2,4-triazol-5-amine (320 mg, 0.79 mmol).

[0535] LCMS: Ms = 486.10 [M+H] + .

[0536]

[0537] Manufacturing Example 21: Preparation of 2-bromo-6,6-dimethyl-4-((5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0538]

[0539]

[0540] Step 1) Preparation of methyl 5-(4-(trifluoromethyl)-1H-imidazol-2-yl)picolinate

[0541] The target compound (1.8 g, yield: 17%) was obtained in the same manner as in step 1 of Preparation Example 1 using 3,3-dibromo-1,1,1-trifluoropropane (8.99 g, 33.3 mmol) and methyl 5-formylpicolinate (5 g, 27.5 mmol).

[0542] LCMS: Ms = 272.05 [M+H] + .

[0543]

[0544] Step 2) Preparation of methyl 5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)picolinate

[0545] The target compound (530 mg, yield: 44%) was obtained in the same manner as in step 1 of Preparation Example 17 using methyl 5-(4-(trifluoromethyl)-1H-imidazol-2-yl)picolinate (1.06 g, 3.9 mmol).

[0546] LCMS: Ms = 286.00 [M+H] + .

[0547]

[0548] Step 3) Preparation of (5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)methanol

[0549] The target compound (165 mg, yield: 61%) was obtained in the same manner as in step 3 of Preparation Example 1 using methyl 5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)picolinate (270 mg, 0.95 mmol).

[0550] 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.89 - 7.86 (m, 1H), 5.43 (s, 1H), 4.60 (d, J = 5.6 Hz, 2H), 4.08 (s, 3H).

[0551] LCMS: Ms = 258.00 [M+H] + .

[0552]

[0553] Step 4) Preparation of 5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)picolinaldehyde

[0554] The target compound (330 mg, yield: 53%) was obtained in the same manner as in step 4 of Preparation Example 15 using (5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)methanol (560 mg, 2.17 mmol).

[0555] 1 H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.19 (d, J = 1.2 Hz, 1H), 8.43 - 8.41 (m, 1H), 8.10 - 8.04 (m, 2H), 3.90 (s, 3H).

[0556]

[0557] Step 5) Preparation of 3-bromo-N-((5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,4-triazol-5-amine

[0558] The target compound (165 mg, yield: 30%) was obtained in the same manner as in step 5 of Preparation Example 1 using 5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)picolinaldehyde (300 mg, 1.17 mmol) and 3-bromo-1H-1,2,4-triazol-5-amine (230 mg, 1.41 mmol).

[0559] 1 H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 8.86 (s, 1H), 8.14 - 8.11 (m, 1H), 7.99 (s, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 4.52 (d, J = 6.4 Hz, 2H), 3.81 (s, 3H).

[0560]

[0561] Step 6) Preparation of 2-bromo-6,6-dimethyl-4-((5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0562] The target compound (165 mg, yield: 55%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-((5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,4-triazol-5-amine (210 mg, 0.52 mmol).

[0563] LCMS: Ms = 486.10 [M+H] + .

[0564]

[0565] Manufacturing Example 22: Preparation of 2-bromo-6,6-dimethyl-4-((5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin-2-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0566]

[0567]

[0568] Step 1) Preparation of 5-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazine-2-carboxamide

[0569] The target compound (740 mg, yield: 43%) was obtained in the same manner as in step 1 of Preparation Example 1 using 3,3-dibromo-1,1,1-trifluoropropane (1.94 g, 7.2 mmol) and methyl 5-formylpyrazine-2-carboxylate (1 g, 6 mmol).

[0570] LCMS: Ms = 258.10 [M+H] + .

[0571]

[0572] Step 2) Preparation of methyl 5-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazine-2-carboxylate

[0573] The target compound (320 mg, yield: 35%) was obtained using 5-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazine-2-carboxamide (760 mg, 2.95 mmol) in the same manner as in step 1 of Preparation Example 17.

[0574] 1 H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.23 (s, 1H), 8.09 (s, 1H), 3.96 (s, 3H).

[0575]

[0576] Step 3) Preparation of (5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin-2-yl)methanol

[0577] Methyl 5-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]pyrazine-2-carboxylate (2.2 g, 7.7 mmol) was dissolved in ethanol (22 mL), sodium borohydride (440 mg, 11.5 mmol) and calcium chloride (1.28 g, 11.5 mmol) were added, and the mixture was stirred at 0°C for 0.5 h. Distilled water (100 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with brine (40 mL) and dried over sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the title compound (1.9 g, yield 85%), which was used in the next step without further purification.

[0578] 1 H NMR (400 MHz, DMSO-d6) δ 9.16 (d, J = 1.6 Hz, 1H), 8.83 - 8.69 (m, 1H), 8.08 (d, J = 0.8 Hz, 1H), 5.79 - 5.60 (m, 1H), 4.70 (d, J = 6.0 Hz, 2H), 4.07 (s, 3H).

[0579]

[0580] Step 4) Preparation of 5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazine-2-carbaldehyde

[0581] Dimethyl phthalate (1.82 g, 4.2 mmol) was added to (5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin-2-yl)methanol (1 g, 3.9 mmol) dissolved in methylene chloride (20 mL), and the mixture was stirred at 0°C for 1 h. Aqueous sodium bicarbonate solution (50 mL) was added to the mixture, and then extracted with methylene chloride (3 x 50 mL). The combined extracts were washed with brine (40 mL) and dried over sodium sulfate. The organic phase was concentrated under reduced pressure and purified by column chromatography to give the title compound (650 mg, yield 59%) as a white solid.

[0582] 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 9.47 (d, J = 1.2 Hz, 1H), 9.16 (d, J = 1.2 Hz, 1H), 8.21 (s, 1H), 4.13 (s, 3H).

[0583]

[0584] Step 5) Preparation of 3-bromo-N-((5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin-2-yl)methyl)-1H-1,2,4-triazol-5-amine

[0585] The target compound (220 mg, yield: 25%) was obtained in the same manner as in step 5 of Preparation Example 1 using 5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazine-2-carbaldehyde (500 mg, 1.95 mmol) and 3-bromo-1H-1,2,4-triazol-5-amine (381 mg, 2.34 mmol).

[0586] 1 H NMR (400 MHz, DMSO-d6) δ 12.65 (s, H), 9.18 (d, J = 1.2 Hz, 1H), 8.66 (d, J = 1.2 Hz, 1H), 8.09 (s, 1H), 7.59 (s, 1H), 4.58 (d, J = 6.4 Hz, 2H), 4.05 (s, 3H).

[0587]

[0588] Step 6) Preparation of 2-bromo-6,6-dimethyl-4-((5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin-2-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0589] The target compound (160 mg, yield: 48%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-((5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin-2-yl)methyl)-1H-1,2,4-triazol-5-amine (220 mg, 0.54 mmol).

[0590] LCMS: Ms = 489.00 [M+H] + .

[0591]

[0592] Manufacturing Example 23: Preparation of 2-bromo-4-(3-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0593]

[0594]

[0595] Step 1) Preparation of 3-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde

[0596] The target compound (407.6 mg, yield: 76.4%) was obtained in the same manner as in step 1 of Preparation Example 5 using 2-bromo-1-methyl-4-(trifluoromethyl)-1H-imidazole (430 mg, 1.87 mmol) and 2-methoxy-5-formylphenylboronic acid (346.8 mg, 2.06 mmol).

[0597] 1 H NMR (500 MHz, CDCl3) δ 9.93 (s, 1H), 8.04 (t, J = 5.2 Hz, 2H), 7.35 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H), 3.57 (s, 3H).

[0598]

[0599] Step 2) Preparation of 3-bromo-N-(3-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-1,2,4-triazol-5-amine

[0600] The target compound (142.5 mg, yield: 23.1%) was obtained in the same manner as in step 5 of Preparation Example 1 using 3-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (407 mg, 1.43 mmol) and 3-bromo-1H-1,2,4-triazol-5-amine (280 mg, 1.71 mmol).

[0601] 1 H NMR (500 MHz, DMSO-d6) δ 12.55 (s, 1H), 7.91 (s, 1H), 7.48 - 7.46 (m, 2H), 7.35 (s, 1H), 7.16 (d, J = 8.6 Hz, 1H), 4.30 (d, J = 6.4 Hz, 2H), 3.80 (s, 3H), 3.48 (s, 3H).

[0602]

[0603] Step 3) Preparation of 2-bromo-4-(3-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0604] The target compound (46.4 mg, yield: 27.3%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-(3-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-1,2,4-triazol-5-amine (142.3 mg, 0.33 mmol).

[0605] 1 H NMR (500 MHz, CDCl3) δ 7.46 - 7.44 (m, 1H), 7.38 (s, 1H), 6.97 (d, J = 8.6 Hz, 1H), 4.68 (s, 2H), 3.82 (s, 3H), 3.56 (s, 3H), .3.51 (s, 2H), 2.60 (s, 2H), 0.24 (s, 6H).

[0606]

[0607] Manufacturing Example 24: Preparation of 2-bromo-4-(4-(4-chloro-1-methyl-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0608]

[0609]

[0610] Step 1) Preparation of 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

[0611] 4-Chloro-1H-imidazole (10 g, 97.5 mmol) was dissolved in THF (100 mL), and sodium hydride (4.29 g, 107.2 mmol, 60%) was added portionwise at 0°C. The resulting mixture was stirred at 0°C for 0.5 h, then 2-(trimethylsilyl)ethoxymethyl chloride (17.88 g, 107.2 mmol) was added dropwise at 0°C, and the resulting mixture was stirred at 25°C for 2 h. The reaction was quenched with distilled water (100 mL), extracted with ethyl acetate (3 x 200 mL), and the combined organic matter was washed with brine, dried over anhydrous Na2SO4, and filtered under reduced pressure. The residue was purified by column chromatography to obtain the target compound (14 g, yield 61%).

[0612] 1 H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 6.94 (s, 1H), 5.20 (s, 2H), 3.48 (t, J = 8.4 Hz, 2H), 0.90 (t, J = 8.0 Hz, 2H), -0.02 (s, 9H).

[0613]

[0614] Step 2) Preparation of 2-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

[0615] To a solution of 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (12 g, 51.3 mmol) in CCl4 (120 mL) were added N-bromosuccinimide (9.13 g, 51.3 mmol) and 2,2'-azobis(2-methylpropionitrile) (0.84 g, 5.13 mmol). The resulting mixture was stirred at 80°C for 6 hours. The resulting mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the target compound (7.7 g, yield 47%).

[0616] 1 H NMR (400 MHz, DMSO-d6) δ 7.66 (s, 1H), 5.25 (s, 2H), 3.54 (t, J = 8.0 Hz, 2H), 0.86 (t, J = 8.0 Hz, 2H), -0.04 (s, 9H).

[0617]

[0618] Step 3) Preparation of methyl 4-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)benzoate

[0619] 2-Bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (7.7 g, 24.6 mmol) was dissolved in dioxane (42 mL) and purified water (10.5 mL), and methyl 4-(dihydroxyboranyl)benzoate (4.65 g, 25.8 mmol), Pd(dppf)Cl2 (0.9 g, 1.23 mmol), and potassium phosphate tribasic (10.44 g, 49.2 mmol) were added. The resulting solution was stirred at 100 °C for 12 h, and then the mixture was concentrated under vacuum. The residue was purified by column chromatography to obtain the target compound (6.5 g, yield 71.95%) as a white solid.

[0620] 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 7.05 (s, 1H), 5.24 (s, 2H), 3.93 (s, 2H), 3.62 (t, J = 8.0 Hz, 2H), 0.95 (t, J = 8.4 Hz, 2H), 0.01 (s, 9H).

[0621]

[0622] Step 4) Preparation of methyl 4-(4-chloro-1H-imidazol-2-yl)benzoate

[0623] Methyl 4-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)benzoate (6.5 g, 17.7 mmol) was added to 2 M HCl / ethyl acetate (15 mL) and stirred at 40°C for 6 h. After completion, the mixture was adjusted to pH ~8 with aqueous sodium carbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to obtain the target compound (5 g, yield 90%) as a white solid, which was used in the next step without further purification.

[0624] 1 H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.03 (s, 4H), 7.45 (s, 1H), 3.87 (s, 3H).

[0625]

[0626] Step 5) Preparation of methyl 4-(4-chloro-1H-imidazol-2-yl)benzoate

[0627] The target compound (190 mg, yield: 42%) was obtained in the same manner as in step 1 of Preparation Example 17 using methyl 4-(4-chloro-1H-imidazol-2-yl)benzoate (426 mg, 1.80 mmol) and iodomethane (307 mg, 2.16 mmol).

[0628] 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.3 Hz, 2H), 6.91 (s, 1H), 3.94 (s, 3H), 3.76 (s, 3H).

[0629]

[0630] Step 6) Preparation of (4-(4-chloro-1-methyl-1H-imidazol-2-yl)phenyl)methanol

[0631] The target compound (213 mg, yield: 100%) was obtained in the same manner as in step 3 of Preparation Example 1 using methyl 4-(4-chloro-1-methyl-1H-imidazol-2-yl)benzoate (240 mg, 0.96 mmol) and lithium aluminum hydride solution (107 mg, 2.87 mmol).

[0632] 1 H NMR (500 MHz, DMSO-d6) δ 8.11 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 6.85 (s, 1H), 5.54 (s, 1H), 4.85 - 4.80 (m, 2H), 3.77 (s, 3H).

[0633]

[0634] Step 7) Preparation of 4-(4-chloro-1-methyl-1H-imidazol-2-yl)benzaldehyde

[0635] The target compound (200 mg, yield: 97%) was obtained in the same manner as in step 4 of Preparation Example 15 using (4-(4-chloro-1-methyl-1H-imidazol-2-yl)phenyl)methanol (210 g, 0.94 mmol) and pyridinium chlorochromate (406 g, 1.88 mmol).

[0636] 1 H NMR (500 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.10 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 6.87 (s, 1H), 3.78 (s, 3H).

[0637]

[0638] Step 8) Preparation of 3-bromo-N-(4-(4-chloro-1-methyl-1H-imidazol-2-yl)benzyl)-1H-1,2,4-triazol-5-amine

[0639] The target compound (80 mg, yield: 24%) was obtained in the same manner as in step 5 of Preparation Example 1 using 3-bromo-1H-1,2,4-triazol-5-amine (148 mg, 0.91 mmol) and 4-(4-chloro-1-methyl-1H-imidazol-2-yl)benzaldehyde (200 mg, 0.91 mmol).

[0640] 1 H NMR (500 MHz, DMSO-d6) δ 12.62 (s, 1H), 7.90 (s, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.54 (s, 1H), 7.45 (d, J = 8.2 Hz, 2H), 4.41 (m, 2H), 3.75 (s, 3H).

[0641]

[0642] Step 9) Preparation of 2-bromo-4-(4-(4-chloro-1-methyl-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0643] The target compound (30 mg, yield: 30%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-(4-(4-chloro-1-methyl-1H-imidazol-2-yl)benzyl)-1H-1,2,4-triazol-5-amine (80 mg, 0.22 mmol) and bis(chloromethyl)dimethylsilane (38 mg, 0.24 mmol).

[0644] 1H NMR (500 MHz, DMSO-d6) δ 7.46 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 6.89 (s, 1H), 4.75 (s, 2H), 3.74 (s, 3H), 3.52 (s, 2H), 2.51 (s, 2H), 0.20 (s, 6H)

[0645]

[0646] Manufacturing Example 25: Preparation of 2-bromo-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0647]

[0648]

[0649] Step 1) Preparation of methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octane-1-carboxylate

[0650] 3,3-Dibromo-1,1,1-trifluoropropane (3.30 g, 12.23 mmol) was added with distilled water (7 mL) and sodium acetate (1.00 g, 12.23 mmol), and the mixture was stirred at 100°C for 1 hour. After cooling to room temperature, methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate(I) (2.00 g, 10.19 mmol), methanol (49 mL), and aqueous ammonia (12 mL) were additionally added, and the mixture was stirred for 1 hour. The mixture was then stirred at 100°C for 2 hours. After completion of the reaction, distilled water (20 mL) was added, and extraction was performed with ethyl acetate (100 mL). The extracted organic layer was dried with MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column to obtain the target compound (2.31 g, yield: 75%).

[0651] 1H NMR (500 MHz, DMSO-d6) δ 12.29 (s, 1H), 7.63 (s, 1H), 1.84 - 4.76 (m, 12H).

[0652]

[0653] Step 2) Preparation of methyl 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octane-1-carboxylate

[0654] Methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octane-1-carboxylate (2.31 g, 7.64 mmol) was dissolved in acetonitrile (70 mL), and 2-iodopropane (1.95 g, 11.46 mmol) and cesium carbonate (7.47 g, 22.90 mmol) were added, followed by stirring at 70°C for 24 h. After completion of the reaction, distilled water (30 mL) was added, and the mixture was extracted with ethyl acetate (150 mL). The extracted organic layer was dried over MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (130 mg, yield: 5%).

[0655] 1 H NMR (500 MHz, DMSO-d6) δ 7.94 (s, 1H), 4.87 - 4.84 (m, 1H), 1.99 - 1.92 (m, 6H), 1.82 - 1.78 (m, 6H), 1.38 - 1.35 (m, 6H).

[0656]

[0657] Step 3) Preparation of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methanol

[0658] The target compound (787.1 mg, yield: 97.4%) was obtained in the same manner as in step 3 of Preparation Example 1 using methyl 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octane-1-carboxylate (880 mg, 2.55 mmol).

[0659] 1 H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 1.1 Hz, 1H), 4.81 - 4.76 (m, 1H), 3.33 (d, J = 4.5 Hz, 2H), 2.04 - 2.04 (m, 6H), 1.55 - 1.53 (m, 6H), 1.44 (d, J = 6.7 Hz, 6H).

[0660]

[0661] Step 4) Preparation of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octane-1-carbaldehyde

[0662] The target compound (641.3 mg, yield: 82.7%) was obtained in the same manner as in step 4 of Preparation Example 1 using (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methanol (780 mg, 2.46 mmol).

[0663] 1 H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 7.24 (s, 1H), 4.78 - 4.72 (m, 1H), 2.08 (t, J = 7.8 Hz, 6H), 1.78 (t, J = 7.8 Hz, 6H), 1.45 (d, J = 6.7 Hz, 6H).

[0664]

[0665] Step 5) Preparation of 3-bromo-N-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-1H-1,2,4-triazol-5-amine

[0666] The target compound (254 mg, yield: 64.7%) was obtained in the same manner as in step 5 of Preparation Example 1 using 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octane-1-carbaldehyde (267 mg, 0.85 mmol) and 3-bromo-1H-1,2,4-triazol-5-amine (152.5 mg, 0.94 mmol).

[0667] 1 H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 7.92 (s, 1H), 6.87 (t, J = 6.3 Hz, 1H), 4.85 - 4.82 (m, 1H), 2.91 (d, J = 6.4 Hz, 2H), 1.49 - 1.46 (m, 6H), 1.37 (d, J = 6.4 Hz, 6H).

[0668]

[0669] Step 6) Preparation of 2-bromo-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0670] The target compound (25.6 mg, yield: 21.6%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-1H-1,2,4-triazol-5-amine (100 mg, 0.22 mmol).

[0671] 1H NMR (500 MHz, CDCl3) δ 7.22 (s, 1H), 4.81 - 4.73 (m, 1H), 3.51 (s, 2), 3.34 (s, 2H), 2.81 (s, 2H), 2.05 - 2.02 (m, 6H), 1.61-1.53 (m, 6H), 1.45 - 1.41 (m, 6H), 0.31 (s, 6H).

[0672]

[0673] Manufacturing Example 26: Preparation of 2-bromo-6,6-dimethyl-4-((1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0674]

[0675]

[0676] Step 1) Preparation of ethyl 1-(6-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxylate

[0677] Ethylpiperidine-4-carboxylate (417 mg, 2.65 mmol) was dissolved in dimethyl sulfoxide (20 mL), and 2-bromo-6-(trifluoromethyl)pyridine (200 mg, 0.88 mmol) and N,N-diisopropylethylamine (569 mg, 4.41 mmol) were added, and the mixture was stirred at 120°C for 4 hours. After completion of the reaction, distilled water (20 mL) was added, and the mixture was extracted with ethyl acetate (60 mL). The extracted organic layer was dried over MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (260 mg, yield: 98%).

[0678] 1 H NMR (500 MHz, CDCl3) δ 7.47 (s, 1H), 6.88 (s, 1H), 6.75 (s, 1H), 3.84 (s, 2H), 3.17-3.10 (m, 4H), 1.45 (s, 3H), 1.75-1.56 (m, 4H).

[0679]

[0680] Step 2) Preparation of (1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol

[0681] Ethyl 1-(6-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxylate (260 mg, 0.85 mmol) was dissolved in tetrahydrofuran (10 mL) at 0°C, and lithium aluminum hydride solution (95 mg, 2.55 mmol) was slowly added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was quenched with ethyl acetate while maintaining the temperature at 0°C. Distilled water (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The extracted organic layer was dried with MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure to obtain the target compound (210 mg, yield: 95%).

[0682] 1 H NMR (500 MHz, CDCl3) δ 7.45 (s, 1H), 6.88 (s, 1H), 6.75 (s, 1H), 5.39-5.38 (m, 1H), 3.85 (s, 2H), 3.18-3.08 (m, 4H), 1.80-1.70 (m, 4H).

[0683]

[0684] Step 3) Preparation of 1-(6-(trifluoromethyl)pyridin-2-yl)piperidine-4-carbaldehyde

[0685] (1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol (240 mg, 0.92 mmol) was dissolved in methylene chloride (10 mL), and pyridinium chlorochromate (397 mg, 1.84 mmol) was added, followed by stirring at room temperature for 2 hours. After completion of the reaction, distilled water (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The extracted organic layer was dried with MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure to obtain the target compound (240 mg, yield: 100%).

[0686] 1 H NMR (500 MHz, DMSO-d6) δ 9.46 (s, 1H), 7.47 (s, 1H), 6.88 (s, 1H), 6.77 (s, 1H), 3.18-3.08 (m, 4H), 1.80-1.70 (m, 4H).

[0687]

[0688] Step 4) Preparation of 3-bromo-N-((1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)-1H-1,2,4-triazol-5-amine

[0689] 3-Bromo-1H-1,2,4-triazol-5-amine (166 mg, 1.02 mmol), 1-(6-(trifluoromethyl)pyridin-2-yl)piperidine-4-carbaldehyde (240 mg, 0.92 mmol), methanol (10 mL), and acetic acid (117 mg, 1.86 mmol) were added and stirred at room temperature for 2 hours. Then, sodium cyanoborohydride (112 mg, 1.86 mmol) was slowly added. After completion of the reaction, distilled water (10 mL) was added and extracted with ethyl acetate (40 mL). The extracted organic layer was dried over MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (160 mg, yield: 43%).

[0690] 1 H NMR (500 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.47 (s, 1H), 7.10 (s, 1H), 6.88 (s, 1H), 6.77 (s, 1H), 4.40 (s, 2H), 3.18-3.08 (m, 4H), 1.80-1.70 (m, 4H).

[0691]

[0692] Step 5) Preparation of 2-bromo-6,6-dimethyl-4-((1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0693] 3-Bromo-N-((1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)-1H-1,2,4-triazol-5-amine (160 mg, 0.39 mmol) was dissolved in N,N-dimethylformamide (3 mL), and bis(chloromethyl)dimethylsilane (68 mg, 0.43 mmol), potassium carbonate (216 mg, 1.56 mmol), and potassium iodide (6 mg, 0.039 mmol) were added. The reaction mixture was stirred at 40°C for 2 h. After completion of the reaction, distilled water (3 mL) was added and extracted with ethyl acetate (15 mL). The extracted organic layer was dried over MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (45 mg, yield: 24%).

[0694] 1 H NMR (500 MHz, DMSO-d6) δ 7.55 (s, 1H), 6.89 (s, 1H), 6.77 (s, 1H), 4.38 (s, 2H), 3.18-3.08 (m, 4H), 1.80-1.70 (m, 4H).

[0695]

[0696] Manufacturing Example 27: Preparation of 2-bromo-4-(2-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0697]

[0698]

[0699] Step 1) Preparation of 2-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzaldehyde

[0700] The target compound (743.4 mg, yield: 97.5%) was obtained in the same manner as in step 1 of Preparation Example 5 using 2-bromo-6-(trifluoromethyl)pyridine (640 mg, 2.83 mmol) and (3-fluoro-4-formylphenyl)boronic acid (571 mg, 3.39 mmol).

[0701] 1 H NMR (500 MHz, CDCl3) δ 10.45 (s, 1H), 8.04-7.96 (m, 5H), 7.75-7.73 (m, 1H).

[0702]

[0703] Step 2) Preparation of 3-bromo-N-(2-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-1H-1,2,4-triazol-5-amine

[0704] The target compound (1.07 g, yield: 77.4%) was obtained in the same manner as in step 5 of Preparation Example 1 using 2-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzaldehyde (743 mg, 2.76 mmol) and 3-bromo-1H-1,2,4-triazol-5-amine (674.7 mg, 4.14 mmol).

[0705] 1 H NMR (500 MHz, DMSO-d6) δ 12.61 (s, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.19 (t, J = 7.9 Hz, 1H), 7.96 - 7.87 (m, 3H), 7.51 - 7.47 (m, 2H), 4.45 (d, J = 6.1 Hz, 2H).

[0706]

[0707] Step 3) Preparation of 2-bromo-4-(2-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0708] The target compound (105 mg, yield: 17%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-(2-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-1H-1,2,4-triazol-5-amine (500 mg, 1.20 mmol).

[0709] 1 H NMR (500 MHz, CDCl3) δ 7.95 (t, J = 7.8 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.85 - 7.82 (m, 1H), 7.79 - 7.77 (m, 2H), 7.64 (d, J = 7.2 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 4.83 (s, 2H), 3.51 (s, 2H), 2.63 (s, 2H), 0.24 (s, 6H).

[0710]

[0711] Manufacturing Example 28: Preparation of 2-bromo-4-(3-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0712]

[0713]

[0714] Step 1) Preparation of 3-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzaldehyde

[0715] The target compound (430 mg, yield: 72.2%) was obtained in the same manner as in step 1 of Preparation Example 5 using 2-bromo-6-(trifluoromethyl)pyridine (500 mg, 2.21 mmol) and (2-fluoro-4-formylphenyl)boronic acid (446 mg, 2.65 mmol).

[0716] 1H NMR (500 MHz, CDCl3) δ 10.08 (s, 1H), 8.37 (t, J = 7.7 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 8.02 (t, J = 7.9 Hz, 1H), 7.85-7.83 (m, 1H), 7.74-7.71 (m, 1H).

[0717] Step 2) Preparation of 3-bromo-N-(3-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-1H-1,2,4-triazol-5-amine

[0718] The target compound (382.1 mg, yield: 57.5%) was obtained in the same manner as in step 5 of Preparation Example 1 using 3-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzaldehyde (430 mg, 1.59 mmol) and 3-bromo-1H-1,2,4-triazol-5-amine (390.5 mg, 2.39 mmol).

[0719] 1 H NMR (500 MHz, DMSO-d6) δ 12.61 (s, 1H), 8.17 (t, J = 7.9 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.89 - 7.84 (m, 2H), 7.54 (t, J = 6.5 Hz, 1H), 7.31-7.26 (m, 2H), 4.39 (d, J = 6.5 Hz, 2H).

[0720]

[0721] Step 3) Preparation of 2-bromo-4-(3-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0722] The target compound (182.5 mg, yield: 39.7%) was obtained in the same manner as in step 6 of Preparation Example 1 using 3-bromo-N-(3-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-1H-1,2,4-triazol-5-amine (382 mg, 0.92 mmol).

[0723] 1 H NMR (500 MHz, CDCl3) δ 8.09 (t, J = 8.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.94 (t, J = 7.8 Hz, 1H), 7.65-7.63 (m, 1H), 7.22 (dd, J = 8.0 Hz, 1.3 Hz, 1H), 7.14 (dd, J = 12.0 Hz, 1.2 Hz, 1H), 4.77 (s, 2H), 3.55 (s, 2H), 2.58 (s, 2H), 0.27 (s, 6H).

[0724]

[0725] Example 1: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0726]

[0727] 2-Bromo-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (50 mg, 0.097 mmol) was dissolved in 1,4-dioxane (1 mL) and purified water (0.1 mL). (1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (8 mg, 0.0097 mmol) and cesium carbonate (95 mg, 0.29 mmol) were added, and the reaction mixture was stirred in a microwave at 80°C for 23 h. After completion of the reaction, distilled water (5 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The extracted organic layer was dried with MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (19 mg, yield: 34%).

[0728] 1 H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.18 (s, 1H), 7.54-7.50 (m, 4H), 4.74 (s, 2H), 4.48-4.45 (m, 1H), 3.88 (s, 3H), 3.61 (s, 2H), 2.73 (s, 2H), 2.06 (m, 1H), 1.26 (d, 6H) 1.02-1.00 (m, 2H), 0.94-0.93 (m, 2H), 0.26 (s, 6H).

[0729]

[0730] Example 2: Preparation of 4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0731]

[0732] 2-Bromo-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (30 mg, 0.058 mmol) was dissolved in 1,4-dioxane (1 mL) and purified water (0.1 mL). (2-Isopropylphenyl)boronic acid (19 mg, 0.12 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (5 mg, 0.0058 mmol), and cesium carbonate (57 mg, 0.17 mmol) were added, and the reaction mixture was stirred in a microwave at 80°C for 2 h. After the reaction was completed, distilled water (3 mL) was added and extracted with ethyl acetate (12 mL). The extracted organic layer was dried with MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (18 mg, yield: 56%).

[0733] 1H NMR (500 MHz, CDCl3) δ 7.67 (d, 1H, J = 7.7 Hz), 7.52-7.47 (m, 4H), 7.42 (s, 1H), 7.37 (d, 1H, J = 7.2 Hz), 7.32 (t, 1H, J = 4.1 Hz), 7.18 (t, 1H, J = 7.9 Hz), 4.83 (s, 2H), 4.57-4.53 (m, 1H), 3.85-3.82 (m, 1H), 3.63 (s, 2H), 2.58 (s, 2H), 1.44 (d, 6H, J = 6.7 Hz) 1.23 (d, 6H, J = 6.9 Hz), 0.28 (s, 6H).

[0734]

[0735] Example 3: Preparation of 2-(2-cyclopropylphenyl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0736]

[0737] 2-Bromo-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (20 mg, 0.040 mmol) was dissolved in 1,4-dioxane (0.5 mL) and purified water (0.05 mL). (2-Cyclopropylphenyl)boronic acid (13 mg, 0.080 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (4 mg, 0.0040 mmol), and cesium carbonate (39 mg, 0.12 mmol) were added, and the reaction mixture was stirred in a microwave at 80°C for 2 h. After the reaction was completed, distilled water (2 mL) was added and extracted with ethyl acetate (8 mL). The extracted organic layer was dried with MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (4 mg, yield: 18%).

[0738] 1 H NMR (500 MHz, CDCl3) δ 7.75 (d, 1H, J = 7.6 Hz), 7.52-7.46 (m, 4H), 7.42 (s, 1H), 7.25 (d, 1H, J = 7.5 Hz), 7.17 (t, 1H, J = 7.4 Hz), 6.88 (d, 1H, J = 7.8 Hz), 4.85 (s, 2H), 4.58-4.55 (m, 1H), 3.65 (s, 2H), 2.87-2.84 (m, 1H), 2.83 (s, 2H), 1.29 (d, 6H, J = 6.9 Hz), 0.93 (d, 2H, J = 1.7 Hz), 0.87 (d, 2H, J = 7.0 Hz), 0.28 (s, 6H).

[0739]

[0740] Example 4: Preparation of 2-(2-cyclobutylphenyl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0741]

[0742] 2-Bromo-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (20 mg, 0.040 mmol) was dissolved in 1,4-dioxane (0.5 mL) and purified water (0.05 mL), and (2-cyclobutylphenyl)boronic acid (14 mg, 0.080 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (4 mg, 0.0040 mmol), and cesium carbonate (39 mg, 0.12 mmol) were added. The reaction mixture was stirred in a microwave at 80°C for 2 h. After the reaction was completed, distilled water (2 mL) was added and extracted with ethyl acetate (8 mL). The extracted organic layer was dried with MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (3 mg, yield: 13%).

[0743] 1H NMR (500 MHz, CDCl3) δ 7.66 (d, 1H, J = 7.6 Hz), 7.53-7.47 (m, 4H), 7.41 (d, 2H, J = 6.5 Hz), 7.34 (t, 1H, J = 7.5 Hz), 7.20 (t, 1H, J = 7.4 Hz), 4.85 (s, 2H), 4.58-4.55 (m, 1H), 4.29-4.26 (m, 1H), 3.64 (s, 2H), 2.58 (s, 2H), 2.25-2.21 (m, 2H), 2.12-2.08 (m, 2H), 1.94-1.76 (m, 2H), 1.45 (d, 6H, J = 6.7 Hz), 0.27 (s, 6H).

[0744]

[0745] Example 5: Preparation of 2-(2-chlorophenyl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0746]

[0747] The target compound (8 mg, yield: 38%) was obtained in the same manner as in Example 1 using 2-bromo-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (20 mg, 0.039 mmol) and (2-chlorophenyl)boronic acid (12 mg, 0.078 mmol).

[0748] 1H NMR (500 MHz, CDCl3) δ 7.87 - 7.85 (m, 1H), 7.53 - 7.46 (m, 4H), 7.45 - 7.42 (m, 2H), 7.30 - 7.27 (m, 2H), 4.85 (s, 2H), 4.58 - 4.56 (m, 1H), 3.67 (s, 2H), 2.58 (s, 2H), 1.46 (d, J = 6.7 Hz, 6H), 0.26 (s, 6H).

[0749]

[0750] Example 6: Preparation of 2-(2-(difluoromethoxy)phenyl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0751]

[0752] The target compound (29.7 mg, yield: 61.6%) was obtained in the same manner as in Example 1 using 2-bromo-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (40 mg, 0.078 mmol) and (4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)boronic acid (21.5 mg, 0.093 mmol).

[0753] 1H NMR (500 MHz, CDCl3) δ 8.59 (s, 1H), 7.64 (s, 0.25H), 7.53 (s, 0.5H), 7.51 - 7.50 (m, 4H), 7.42 (s, 1H), 7.35 (s, 0.25H), 4.79 (s, 2H), 4.59 - 4.54 (m, 1H), 3.66 (s, 2H), 2.62 (s, 2H), 2.31 - 2.27 (m, 1H), 1.46 (d, J = 6. Hz, 6H), 1.25 (t, J = 3.2 Hz, 2H), 1.06 - 1.04 (m, 2H), 0.30 (s, 6H).

[0754]

[0755] Example 7: Preparation of 3-(4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacillin-2-yl)benzamide

[0756]

[0757] The target compound (17.7 mg, yield: 65.7%) was obtained in the same manner as in Example 1 using 2-bromo-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (25 mg, 0.049 mmol) and (3-carbamoylphenyl)boronic acid (9.6 mg, 0.058 mmol).

[0758] 1H NMR (500 MHz, CDCl3) δ 8.39 (s, 1H), 8.16 (s, 1H), 8.06 (s, 1H), 8.02, (d, J = 7.7 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.56-7.45 (m, 5H), 7.38 (s, 1H), 4.85 (s, 2H), 4.49 - 4.46 (m, 1H), 3.62 (s, 2H), 2.69 (s, 2H), 1.39 (d, J = 6.6 Hz, 6H), 0.23 (s, 6H).

[0759]

[0760] Example 8: Preparation of 3-(4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacillin-2-yl)benzenesulfonamide

[0761]

[0762] The target compound (14.1 mg, yield: 49.1%) was obtained in the same manner as in Example 1 using 2-bromo-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (25 mg, 0.049 mmol) and 3-(aminosulfonyl)benzeneboronic acid (11.74 mg, 0.058 mmol).

[0763] 1H NMR (500 MHz, CDCl3) δ 8.35 (s, 1H), 8.16 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.56 - 7.50 (m, 4H), 7.41 (s, 1H), 4.85 (s, 2H), 4.50 - 4.45 (m, 1H), 3.63 (s, 2H), 2.70 (s, 2H), 1.40 (d, J = 6.6 Hz, 6H), 0.23 (s, 6H).

[0764]

[0765] Example 9: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0766]

[0767] The target compound (18 mg, yield: 45%) was obtained in the same manner as in Example 1 using 2-bromo-4-(2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (35 mg, 0.066 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (26 mg, 0.132 mmol).

[0768] 1H NMR (500 MHz, CDCl3) δ 8.58 (s, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.43 (s, 1H), 7.28 (t, J = 9.8 Hz, 2H), 4.88 (s, 2H), 4.57 - 4.54 (m, 1H), 3.96 (s, 3H), 3.66 (s, 2H), 2.68 (s, 2H), 2.14 - 2.12 (m, 1H), 1.47 (d, J = 6.7 Hz, 6H), 1.20 - 1.19 (m, 2H), 0.97 - 0.95 (m, 2H), 0.30 (s, 6H).

[0769]

[0770] Example 10: Preparation of 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0771]

[0772] The target compound (15 mg, yield: 43%) was obtained in the same manner as in Example 1 using 2-bromo-4-(2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (30 mg, 0.056 mmol) and (4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)boronic acid (26 mg, 0.11 mmol).

[0773] 1H NMR (500 MHz, CDCl3) δ 8.60 (s, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.66 (s, 0.2H), 7.51 (s, 0.6H), 7.43 (s, 1H), 7.35 (dd, J = 15.0, 4.8 Hz, 1.2H), 7.27 (s, 1H), 4.87 (s, 2H), 4.61 - 4.55 (m, 1H), 3.65 (s, 2H), 2.72 (s, 2H), 2.33 - 2.28 (m, 1H), 1.47 (d, J = 6.7 Hz, 6H), 1.30 - 1.23 (m, 2H), 1.07 - 1.04 (m, 2H), 0.32 (s, 6H).

[0774]

[0775] Example 11: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0776]

[0777] 2-Bromo-6,6-dimethyl-4-(4-(pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (30 mg, 0.072 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (21.0 mg, 0.1086 mmol) were dissolved in 1,4-dioxane (1 mL) and purified water (0.1 mL). (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (5.9 mg, 0.0072 mmol) and cesium carbonate (70.7 mg, 0.21 mmol) were added, and the reaction mixture was stirred in a microwave at 80°C for 2 h. After the reaction was completed, distilled water (3 mL) was added and extracted with ethyl acetate (6 mL). The extracted organic layer was dried with MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (26.3 mg, yield: 75.1%).

[0778] 1 H NMR (500 MHz, DMSO-d6) δ 8.66-8.64 (m, 1H), 8.60 (s, 1H), 8.05 (d, J = 8.3 Hz, 2H), 7.96 (d, J = 8.0 Hz, 1H), 7.87 (td, J = 7.7, 1.8 Hz, 1H,), 7.48 (d, J = 8.3 Hz, 2H), 7.35-7.32 (m, 1H), 4.70 (s, 2H), 3.88 (s, 3H), 3.59 (s, 2H), 2.69 (s, 2H), 2.08-2.02 (m, 1H), 1.23 (s, 3H), 1.03-1.00 (m, 2H), 0.94-0.91 (m, 2H), 0.23 (s, 6H).

[0779]

[0780] Example 12: Preparation of 2-(2-isopropylphenyl)-6,6-dimethyl-4-(4-(pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0781]

[0782] 2-Bromo-6,6-dimethyl-4-(4-(pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (30 mg, 0.072 mmol) and (2-isopropylphenyl)boronic acid (17.8 mg, 0.1086 mmol) were dissolved in 1,4-dioxane (1 mL) and purified water (0.1 mL). (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (5.9 mg, 0.0072 mmol) and cesium carbonate (70.7 mg, 0.21 mmol) were added, and the reaction mixture was stirred in a microwave at 80°C for 3 h. After the reaction was completed, distilled water (3 mL) was added and extracted with ethyl acetate (6 mL). The extracted organic layer was dried with MgSO4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (22.8 mg, yield: 69.4%).

[0783] 1 H NMR (500 MHz, DMSO-d6) δ 8.64-8.63 (m, 1H), 8.05 (d, J = 8.3 Hz, 2H), 7.94 (d, J = 8.0 Hz, 1H), 7.85 (td, J = 7.7, 1.8 Hz, 1H,), 7.64 (dd, J = 7.8, 1.2 Hz, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 7.7 Hz, 1H), 7.33-7.29 (m, 2H), 7.19-7.15 (m, 1H), 4.73 (s, 2H), 3.96-3.91 (m, 1H), 3.57 (s, 2H), 2.68 (s, 2H), 1.15 (d, J = 6.9 Hz, 6H), 0.21 (s, 6H).

[0784]

[0785] Example 13: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(6-methoxypyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0786]

[0787] The target compound (30.1 mg, yield: 73.9%) was obtained using 2-bromo-4-(4-(6-methoxypyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (35 mg, 0.079 mmol) and 4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (23.1 mg, 0.12 mmol).

[0788] 1 H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.06 (d, J = 8.1 Hz, 2H), 7.78 (t, J = 7.8 Hz, 1H), 7.56 (d, J = 7.4 Hz, 1H,), 7.47 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 6.77 (d, J = 8.2 Hz, 1H), 4.70 (s, 2H), 3.95 (s, 3H)), 3.89 (s, 3H), 3.59 (s, 2H), 2.70 (s, 2H), 2.08 - 2.03 (m, 1H), 1.02 - 0.94 (m, 2H), 0.94 - 0.92 (m, 2H), 0.25 (s, 6H).

[0789]

[0790] Example 14: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(6-(methylsulfonyl)pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0791]

[0792] The target compound (9.3 mg, yield: 20.4%) was obtained using 2-bromo-6,6-dimethyl-4-(4-(6-(methylsulfonyl)pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (40 mg, 0.081 mmol) and 4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (23.6 mg, 0.12 mmol).

[0793] 1 H NMR (500 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.03 - 7.96 (m,5H), 7.50 (d, J = 8.2 Hz, 2H), 4.83 (s, 2H), 3.97 (s, 3H)), 3.68 (s, 2H), 3.32 (s, 3H), 2.64 (s, 2H), 2.14 (t, J = 4.4 Hz, 1H), 0.97 - 0.94 (m, 2H), 0.89 - 0.86 (m, 2H), 0.31 (s, 6H).

[0794]

[0795] Example 15: Preparation of 1-(6-(4-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-6,7-dihydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacillin-4(5H)-yl)methyl)phenyl)pyridin-2-yl)ethan-1-one

[0796]

[0797] The target compound (46 mg, yield: 42%) was obtained in the same manner as in Example 1 using 1-(6-(4-((2-bromo-6,6-dimethyl-6,7-dihydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacillin-4(5H)-yl)methyl)phenyl)pyridin-2-yl)ethan-1-one (95 mg, 0.21 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (82 mg, 0.42 mmol).

[0798] 1H NMR (500 MHz, CDCl3) δ 8.59 (s, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.98 (dd, J = 7.1, 1.4 Hz, 2H), 7.93-7.87 (m, 2H), 7.51 (d, J = 8.2 Hz, 2H), 4.83 (s, 2H), 3.98 (s, 3H), 3.67 (s, 2H), 2.82 (s, 3H), 2.66 (s, 2H), 2.17 - 2.13 (m, 1H), 1.21 - 1.19 (m, 2H), 0.98 - 0.96 (m, 2H), 0.31 (s, 6H).

[0799]

[0800] Example 16: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(4-(trifluoromethyl)pyrimidin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0801]

[0802] The target compound (12 mg, yield: 11%) was obtained in the same manner as in Example 1 using 2-bromo-6,6-dimethyl-4-(4-(4-(trifluoromethyl)pyrimidin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (100 mg, 0.21 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (80 mg, 0.42 mmol).

[0803] 1H NMR (500 MHz, CDCl3) δ 9.04 (d, J = 5.0 Hz, 1H), 8.58 (s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 7.51-7.49 (m, 3H), 4.84 (s, 2H), 3.98 (s, 3H), 3.67 (s, 2H), 2.82 (s, 3H), 2.63 (s, 2H), 2.17 - 2.11 (m, 1H), 1.25 - 1.18 (m, 2H), 0.99 - 0.94 (m, 2H), 0.31 (s, 6H).

[0804]

[0805] Example 17: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0806]

[0807] The target compound (24.9 mg, yield: 72.6%) was obtained in the same manner as in Example 1 using 2-bromo-6,6-dimethyl-4-(4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (30 mg, 0.062 mmol) and 4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (18.1 mg, 0.093 mmol).

[0808] 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 8.18 (t, J = 7.9 Hz, 1H), 8.10 (d, J = 8.1 Hz, 2H), 7.86 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H),4.73 (s, 2H), 3.88 (s, 3H)), 3.60 (s, 2H), 2.70 (s, 2H), 2.07 - 2.02 (m, 1H), 1.02 - 1.01 (m, 2H), 0.94 - 0.92 (m, 2H), 0.25 (s, 6H).

[0809]

[0810] Example 18: Preparation of 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-6,6-dimethyl-4-(4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0811]

[0812] The target compound (21.3 mg, yield: 43.7%) was obtained in the same manner as in Example 1 using 2-bromo-6,6-dimethyl-4-(4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (40 mg, 0.083 mmol) and (4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)boronic acid (28.6 mg, 0.124 mmol).

[0813] 1H NMR (500 MHz, CDCl3) δ 8.73 (s, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.18 (t, J = 7.9 Hz, 1H), 8.08 (d, J = 8.3 Hz, 2H), 7.96 (s, 0.25H), 7.86 (d, J = 7.6 Hz, 1H), 7.81 (s, 0.5H), 7.67 (s, 0.25H), 7.55 (d, J = 8.3 Hz, 2H), 4.74 (s, 2H), 3.63 (s, 2H), 2.73 (s, 2H), 2.27 - 2.22 (m, 1H), 1.10 - 1.06 (m, 2H), 1.04 - 1.02 (m, 2H), 0.25 (s, 6H).

[0814]

[0815] Example 19: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-((6-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0816]

[0817] The target compound (19.6 mg, yield: 42.9%) was obtained in the same manner as in Example 1 using 2-bromo-6,6-dimethyl-4-((6-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (40 mg, 0.083 mmol) and 4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (24.1 mg, 0.124 mmol).

[0818] 1H NMR (500 MHz, CDCl3) δ 9.16 (s, 1H), 8.57 (s, 1H), 8.36 (dd, J = 8.1 Hz, 2.1 Hz, 1H), 8.00 - 7.96 (m, 1H), 7.94 - 7.92 (m, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.56 (d, J = 8.2 Hz, 2H),4.96 (s, 2H), 3.96 (s, 3H)), 3.69 (s, 2H), 2.81 (s, 2H), 2.10 - 2.06 (m, 1H), 1.17 - 1.16 (m, 2H), 0.93 - 0.92 (m, 2H), 0.32 (s, 6H).

[0819]

[0820] Example 20: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-((6 '-(trifluoromethyl)-[2,2'-bipyridin]-5-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0821]

[0822] The target compound (26 mg, yield: 56.9%) was obtained in the same manner as in Example 1 using 2-bromo-6,6-dimethyl-4-((6'-(trifluoromethyl)-[2,2'-bipyridin]-5-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (40 mg, 0.083 mmol) and 4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (24.1 mg, 0.124 mmol).

[0823] 1H NMR (500 MHz, CDCl3) δ 8.72 (s, 1H), 8.61 (s, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.48 (d, J = 8.1 Hz, 1H), 7.99 (t, J = 7.8 Hz, 1H), 7.89 (dd, J = 8.1 Hz, 2.2 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H),4.83 (s, 2H), 3.99 (s, 3H)), 3.66 (s, 2H), 2.65 (s, 2H), 2.14 - 2.09 (m, 1H), 1.22 - 1.19 (m, 2H), 1.01 - 0.98 (m, 2H), 0.31 (s, 6H).

[0824]

[0825] Example 21: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophen-2-yl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0826]

[0827] The target compound (6 mg, yield: 28%) was obtained in the same manner as in Example 1 using 2-bromo-4-((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophen-2-yl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (18 mg, 0.036 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (14 mg, 0.071 mmol).

[0828] 1H NMR (500 MHz, CDCl3) δ 8.62 (s, 1H), 8.13 (s, 1H), 7.33 (d, J = 3.5 Hz, 1H), 7.19 (d, J = 3.5 Hz, 1H), 4.79 (s, 2H), 4.76 - 4.73 (m, 1H), 3.88 (s, 3H), 3.57 (s, 2H), 2.68 (s, 2H), 2.11 - 2.09 (m, 1H), 1.44 (d, J = 6.6 Hz, 1H), 1.01 - 0.97 (m, 4H), 0.25 (s, 6H).

[0829]

[0830] Example 22: Preparation of 4-((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophen-2-yl)methyl)-2-(2-isopropylphenyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0831]

[0832] The target compound (7 mg, yield: 29%) was obtained in the same manner as in Example 1 using 2-bromo-4-((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophen-2-yl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (20 mg, 0.040 mmol) and (2-isopropylphenyl)boronic acid (13 mg, 0.079 mmol).

[0833] 1H NMR (500 MHz, CDCl3) δ 7.68 (dd, J = 7.7, 1.1 Hz, 1H), 7.38 - 7.37 (m, 2H), 7.33 (t, J = 3.5 Hz, 1H), 7.21 - 7.17 (m, 2H), 7.08 (d, J = 3.6) Hz, 1H), 4.91 (s, 2H), 4.75 - 4.73 (m, 1H), 3.90 - 3.87 (m, 1H), 3.61 (s, 2H), 3.57 (s, 2H), 2.67 (s, 2H), 1.47 (d, J = 6.7 Hz, 1H), 1.27 (d, J = 13.8 Hz, 1H), 0.31 (s, 6H).

[0834]

[0835] Example 23: Preparation of 2-(2-isopropylphenyl)-6,6-dimethyl-4-(4-(methylsulfonyl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0836]

[0837] The target compound (11 mg, yield: 50%) was obtained in the same manner as in Example 1 using 2-bromo-6,6-dimethyl-4-(4-(methylsulfonyl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (20 mg, 0.048 mmol) and (2-isopropylphenyl)boronic acid (16 mg, 0.096 mmol).

[0838] 1H NMR (500 MHz, CDCl3) δ 7.68 (dd, J = 7.7, 1.1 Hz, 1H), 7.38 - 7.37 (m, 2H), 7.33 (t, J = 3.5 Hz, 1H), 7.21 - 7.17 (m, 2H), 7.08 (d, J = 3.6) Hz, 1H), 4.91 (s, 2H), 4.75 - 4.73 (m, 1H), 3.90 - 3.87 (m, 1H), 3.61 (s, 2H), 3.57 (s, 2H), 2.67 (s, 2H), 1.47 (d, J = 6.7 Hz, 1H), 1.27 (d, J = 13.8 Hz, 1H), 0.31 (s, 6H).

[0839]

[0840] Example 24: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(methylsulfonyl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0841]

[0842] The target compound (8 mg, yield: 35%) was obtained in the same manner as in Example 1 using 2-bromo-6,6-dimethyl-4-(4-(methylsulfonyl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (20 mg, 0.048 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (19 mg, 0.048 mmol).

[0843] 1H NMR (500 MHz, CDCl3) δ 8.58 (s, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.1 Hz, 1H), 4.85 (s, 2H), 3.96 (s, 3H), 3.68 (s, 2H), 3.06 (s, 3H), 2.62 (s, 2H), 2.11 - 2.07 (m, 1H), 1.20 - 1.18 (m, 2H), 0.96 - 0.93 (m, 2H), 0.33 (s, 6H).

[0844]

[0845] Example 25: Preparation of 4-(4-(1H-pyrazol-1-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0846]

[0847] The target compound (39 mg, yield: 42%) was obtained in the same manner as in Example 1 using 4-(4-(1H-pyrazol-1-yl)benzyl)-2-bromo-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (80 mg, 0.20 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (77 mg, 0.40 mmol).

[0848] 1H NMR (500 MHz, CDCl3) δ 8.59 (s, 1H), 7.92 (d, J = 2.5 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 6.47 (t, J = 2.1 Hz, 1H), 4.78 (s, 2H), 3.97 (s, 3H), 3.66 (s, 2H), 2.60 (s, 2H), 2.15 - 2.12 (m, 1H), 1.21 - 1.19 (m, 2H), 0.99 - 0.95 (m, 2H), 0.29 (s, 6H).

[0849]

[0850] Example 26: Preparation of 4-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-cyclopropylphenyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0851]

[0852] The target compound (5 mg, yield: 23%) was obtained in the same manner as in Example 1 using 4-(4-(1H-pyrazol-1-yl)benzyl)-2-bromo-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (20 mg, 0.050 mmol) and (2-cyclopropylphenyl)boronic acid (16 mg, 0.10 mmol).

[0853] 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 2.3 Hz, 1H), 7.76 - 7.72 (m, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.24 (t, J = 3.8 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H), 6.47 (t, J = 2.0 Hz, 1H), 4.81 (s, 2H), 3.64 (s, 2H), 2.88 - 2.84 (m, 1H), 2.59 (s, 2H), 0.95 - 0.89 (m, 2H), 0.71 - 0.68 (m, 2H), 0.27 (s, 6H).

[0854]

[0855] Example 27: Preparation of 4-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-cyclobutylphenyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0856]

[0857] The target compound (9 mg, yield: 40%) was obtained in the same manner as in Example 1 using 4-(4-(1H-pyrazol-1-yl)benzyl)-2-bromo-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (20 mg, 0.050 mmol) and (2-cyclobutylphenyl)boronic acid (18 mg, 0.10 mmol).

[0858] 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 2.3 Hz, 1H), 7.72 (s, 1H), 7.68 - 7.65 (m, 3H), 7.48 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 7.7 Hz, 1H), 7.35 (t, J = 5.7 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 6.47 (t, J = 2.1 Hz, 1H), 4.81 (s, 2H), 4.30 - 4.27 (m, 1H), 3.62 (s, 2H), 2.59 (s, 1H), 2.27 - 2.22 (m, 2H), 2.12 - 2.08 (m, 2H), 1.96 - 1.89 (m, 1H), 1.78 - 1.66 (m, 1H), 0.28 (s, 6H).

[0859]

[0860] Example 28: Preparation of 4-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-chlorophenyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0861]

[0862] The target compound (12 mg, yield: 55%) was obtained in the same manner as in Example 1 using 4-(4-(1H-pyrazol-1-yl)benzyl)-2-bromo-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (20 mg, 0.050 mmol) and (2-chlorophenyl)boronic acid (16 mg, 0.10 mmol).

[0863] 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 2.8 Hz, 1H), 7.88 - 7.86 (m, 1H), 7.72 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 7.0 Hz, 1H), 7.29 - 7.27 (m, 2H), 6.47 (t, J = 1.9 Hz, 1H), 4.81 (s, 2H), 3.65 (s, 2H), 2.58 (s, 2H), 0.26 (s, 6H).

[0864]

[0865] Example 29: Preparation of 4-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0866]

[0867] The target compound (13 mg, yield: 59%) was obtained in the same manner as in Example 1 using 4-(4-(1H-pyrazol-1-yl)benzyl)-2-bromo-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (20 mg, 0.050 mmol) and (2-isopropylphenyl)boronic acid (16 mg, 0.10 mmol).

[0868] 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 2.3 Hz, 1H), 7.72 (s, 1H), 7.68 - 7.65 (m, 3H), 7.47 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 7.7 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 6.46 (s, 1H), 4.79 (s, 2H), 3.87 - 3.84 (m, 1H), 3.62 (s, 2H), 2.58 (s, 2H), 1.25 (d, 6H, J = 6.8 Hz), 0.26 (s, 6H).

[0869]

[0870] Example 30: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0871]

[0872] The target compound (17 mg, yield: 43%) was obtained in the same manner as in Example 1 using 2-bromo-6,6-dimethyl-4-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (35 mg, 0.072 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (28 mg, 0.14 mmol).

[0873] 1H NMR (500 MHz, CDCl3) δ 8.58 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 6.46 (s, 1H), 4.82 (s, 2H), 3.96 (s, 3H), 3.67 (s, 2H), 2.60 (s, 2H), 2.34 (s, 3H), 2.14 - 2.11 (m, 1H), 1.20 - 1.18 (m, 2H), 0.98 - 0.95 (m, 2H), 0.30 (s, 6H).

[0874]

[0875] Example 31: Preparation of 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-6,6-dimethyl-4-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0876]

[0877] The target compound (17 mg, yield: 35%) was obtained in the same manner as in Example 1 using 2-bromo-6,6-dimethyl-4-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (40 mg, 0.082 mmol) and (4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)boronic acid (38 mg, 0.16 mmol).

[0878] 1H NMR (500 MHz, CDCl3) δ 8.59 (s, 1H), 7.64 (s, 0.2H), 7.53 (d, J = 7.8 Hz, 2H), 7.50 (s, 0.5H), 7.42 (d, J = 7.8 Hz, 2H), 7.35 (s, 0.2H), 6.46 (s, 1H), 4.80 (s, 2H), 3.66 (s, 2H), 2.62 (s, 2H), 2.34 (s, 3H), 2.30 - 2.28 (m, 1H), 1.26 - 1.23 (m, 2H), 1.06 - 1.04 (m, 2H), 0.31 (s, 6H).

[0879]

[0880] Example 32: Preparation of 2-(2-isopropylphenyl)-6,6-dimethyl-4-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0881]

[0882] The target compound (13 mg, yield: 34%) was obtained in the same manner as in Example 1 using 2-bromo-6,6-dimethyl-4-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (35 mg, 0.072 mmol) and (2-isopropylphenyl)boronic acid (24 mg, 0.14 mmol).

[0883] 1H NMR (500 MHz, CDCl3) δ 7.67 (d, J = 6.5 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.42 - 7.40 (m, 2H), 7.38 (d, 1H, J = 7.0 Hz), 7.33 (t, J = 6.9 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 6.46 (s, 1H), 4.83 (s, 2H), 3.85 - 3.81 (m, 1H), 3.64 (s, 2H), 2.59 (s, 2H), 2.35 (s, 3H), 1.26 (d, J = 9.8 Hz, 6H), 0.28 (s, 6H).

[0884]

[0885] Example 33: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0886]

[0887] 2-Bromo-4-(2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (100 mg, 0.20 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (46 mg, 0.24 mmol), potassium phosphate tribasic (126 mg, 0.60 mmol) and XPhos-Pd-G3 (17 mg, 0.02 mmol) were dissolved in dioxane / distilled water = 4 / 1 (5 mL) and stirred at 70°C for 1 h under N2. The mixture was diluted with distilled water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give the target compound (40.73 mg, yield 34%) as a white solid.

[0888] LCMS: Ms = 573.25 [M+H] + .

[0889] 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.62 - 7.53 (m, 2H), 7.43 - 7.40 (m, 1H), 6.78 (s, 1H), 4.77 (s, 2H), 3.87 - 3.85 (m, 3H), 3.61 (s, 2H), 2.78 (s, 2H), 2.37 (s, 3H), 2.06 - 2.00 (m, 1H), 1.02 - 0.98 (m, 2H), 0.94 - 0.88 (m, 2H), 0.26 (s, 6H).

[0890]

[0891] Example 34: Preparation of 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0892]

[0893] The target compound (61.6 mg, yield: 34%) was obtained in the same manner as in Example 33 using 2-bromo-4-(2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (130 mg, 0.26 mmol) and (4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)boronic acid (72 mg, 0.31 mmol).

[0894] LCMS: Ms = 609.30 [M+H] + .

[0895] 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.97 - 7.62 (m, 1H), 7.63 - 7.60 (m, 1H), 7.58 - 7.55 (m, 1H), 7.38 - 7.35 (m, 1H), 6.78 (s, 1H), 4.79 (s, 2H), 3.64 (s, 2H), 2.81 (s, 2H), 2.37 (s, 3H), 2.26 - 2.18 (m, 1H), 1.10 - 1.06 (m, 2H), 1.03 - 1.00 (m, 2H), 0.26 (s, 6H).

[0896]

[0897] Example 35: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0898]

[0899] The target compound (31.5 mg, yield: 12%) was obtained in the same manner as in Example 33 using 2-bromo-4-(3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (200 mg, 0.39 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (93 mg, 0.47 mmol).

[0900] LCMS: Ms = 573.30 [M+H] + .

[0901] 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.52 (d, J = 10.4 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 6.78 (s, 1H), 4.75 (s, 2H), 3.87 (s, 3H), 3.61 (s, 2H), 2.76 (s, 2H), 2.20 (s, 3H), 2.09 - 1.99 (m, 1H), 1.03 - 1.01 (m, 2H), 0.92 - 0.90 (m, 2H), 0.26 (s, 6H).

[0902]

[0903] Example 36: Preparation of 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0904]

[0905] The target compound (35.9 mg, yield: 14%) was obtained in the same manner as in Example 33 using 2-bromo-4-(3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (200 mg, 0.39 mmol) and (4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)boronic acid (110 mg, 0.47 mmol).

[0906] LCMS: Ms = 609.30 [M+H] + .

[0907] 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.99 - 7.55 (m, 2H), 7.50 (d, J = 10.8 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 6.78 (s, 1H), 4.77 (s, 2H), 3.65 (s, 2H), 2.79 (s, 2H), 2.25 - 2.21 (m, 1H), 2.20 (s, 3H), 1.13 - 1.07 (m, 2H), 1.04 - 1.02 (m, 2H), 0.26 (s, 6H).

[0908]

[0909] Example 37: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0910]

[0911] The target compound (14 mg, yield: 41%) was obtained in the same manner as in Example 1 using 2-bromo-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (30 mg, 0.062 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (24 mg, 0.12 mmol).

[0912] 1H NMR (500 MHz, CDCl3) δ 8.58 (s, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.32 (s, 1H), 4.81 (s, 2H), 3.96 (s, 3H), 3.77 (s, 3H), 3.66 (s, 2H), 2.59 (s, 2H), 2.15 - 2.10 (m, 1H), 1.21 - 1.18 (m, 2H), 0.98 - 0.94 (m, 2H), 0.29 (s, 6H).

[0913]

[0914] Example 38: Preparation of 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-6,6-dimethyl-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0915]

[0916] The target compound (15 mg, yield: 45%) was obtained in the same manner as in Example 1 using 2-bromo-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (27 mg, 0.056 mmol) and (4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)boronic acid (26 mg, 0.11 mmol).

[0917] 1H NMR (500 MHz, CDCl3) δ 8.59 (s, 1H), 7.63 (s, 0.2H), 7.60 (d, J = 8.0 Hz, 2H), 7.50 - 7.48 (m, 2.5H), 7.34 (s, 0.2H), 7.30 (s, 1H), 4.78 (s, 2H), 3.75 (s, 3H), 3.64 (s, 2H), 2.60 (s, 2H), 2.30 - 2.27 (m, 1H), 1.25 - 1.21 (m, 2H), 1.05 - 1.02 (m, 2H), 0.29 (s, 6H).

[0918]

[0919] Example 39: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0920]

[0921] The target compound (20.1 mg, yield: 58.9%) was obtained in the same manner as in Example 1 using 2-bromo-4-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (30 mg, 0.06 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (12.1 mg, 0.06 mmol).

[0922] 1H NMR (500 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.97 (s, 1H), 7.59 - 7.52 (m, 3H), 4.77 (s, 2H), 3.86 (s, 2H), 3.80 (s, 2H), 3.61 (s, 2H), 2.77 (s, 2H), 2.03 (t, J = 6.3 Hz, 1H), 1.00 - 0.99 (m, 2H), 0.92 - 0.90 (m, 2H), 0.25 (s, 6H).

[0923]

[0924] Example 40: Preparation of 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0925]

[0926] The target compound (6.6 mg, yield: 18.2%) was obtained in the same manner as in Example 1 using 2-bromo-4-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (30 mg, 0.06 mmol) and (4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)boronic acid (12.1 mg, 0.06 mmol).

[0927] 1H NMR (500 MHz, CDCl3) δ 8.64 (s, 1H), 7.62 (t, J = 7.3 Hz, 1H), 7.47 (s, 0.5H), 7.43 (d, J = 10.1 Hz, 1H), 7.38 - 7.32 (m, 1.5H), 7.27 (s, 1H), 4.90 (s, 2H), 3.78 (s, 3H), 3.68 (s, 2H), 2.79 (s, 2H), 2.23 - 2.21 (m, 1H), 1.29 - 1.27 (m, 2H), 1.09 - 1.08 (m, 2H), 0.33 (s, 6H).

[0928]

[0929] Example 41: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0930]

[0931] The target compound (26.7 mg, yield: 67.1%) was obtained in the same manner as in Example 1 using 2-bromo-4-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (35 mg, 0.069 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (14.8 mg, 0.076 mmol).

[0932] 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.01 (s, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.43 (d, J = 11.2 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 4.74 (s, 2H), 3.87 (s, 2H), 3.61 (s, 2H), 3.60 (s, 3H), 2.74 (s, 2H), 2.07 - 2.04 (m, 1H), 1.03 - 1.01 (m, 2H), 0.94 - 0.92 (m, 2H), 0.26 (s, 6H).

[0933]

[0934] Example 42: Preparation of 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0935]

[0936] The target compound (20.6 mg, yield: 48.7%) was obtained in the same manner as in Example 1 using 2-bromo-4-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (35 mg, 0.069 mmol) and (4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)boronic acid (19.2 mg, 0.083 mmol).

[0937] 1H NMR (500 MHz, CDCl3) δ 8.73 (s, 1H), 7.99 (s, 1H), 7.93 (s, 0.25H), 7.79 (s, 0.5H), 7.64 (s, 0.5H), 7.53 (t, J = 8.3 Hz, 1H), 7.39 - 7.36 (m, 2H), 4.75 (s, 2H), 3.63 (s, 2H), 3.58 (s, 3H), 2.76 (s, 2H), 2.25 - 2.20 (m, 1H), 1.09 - 1.07 (m, 2H), 1.04 - 1.02 (m, 2H), 0.25 (s, 6H).

[0938]

[0939] Example 43: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-((6-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0940]

[0941] The target compound (56.4 mg, yield: 18%) was obtained in the same manner as in Example 33 using 2-bromo-6,6-dimethyl-4-((6-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (240 mg, 0.49 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (115 mg, 0.59 mmol).

[0942] LCMS: Ms = 556.30 [M+H] + .

[0943] 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 1.6 Hz, 1H), 8.61 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.99 (s, 1H), 7.94 - 7.91 (m, 1H), 4.72 (s, 2H), 4.08 (s, 3H), 3.89 (s, 3H), 3.59 (s, 2H), 2.74 (s, 2H), 2.10 - 2.02 (m, 1H), 1.03 - 1.01 (m, 2H), 0.95 - 093 (m, 2H), 0.25 (s, 6H).

[0944]

[0945] Example 44: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-((5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0946]

[0947] The target compound (36.47 mg, yield: 19%) was obtained in the same manner as in Example 33 using 2-bromo-6,6-dimethyl-4-((5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (145 mg, 0.29 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (70 mg, 0.35 mmol).

[0948] LCMS: Ms = 556.30 [M+H] + .

[0949] 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J = 2.0 Hz, 1H), 8.58 (s, 1H), 8.12 - 8.09 (m, 1H), 8.00 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 4.82 (s, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.64 (s, 2H), 2.88 (s, 2H), 2.08 - 1.90 (m, 1H), 1.01 - 0.95 (m, 2H), 0.87 - 0.84 (m, 2H), 0.28 (s, 6H).

[0950]

[0951] Example 45: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-((5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin-2-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0952]

[0953] The target compound (48.84 mg, yield: 25%) was obtained in the same manner as in Example 33 using 2-bromo-6,6-dimethyl-4-((5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin-2-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (150 mg, 0.31 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (59 mg, 0.31 mmol).

[0954] LCMS: Ms = 557.20 [M+H] + .

[0955] 1H NMR (400 MHz, DMSO-d6) δ 9.18 (d, J = 1.6 Hz, 1H), 8.74 (d, J = 1.6 Hz, 1H), 8.59 (s, 1H), 8.09 (d, J = 0.8 Hz, 1H), 4.84 (s, 2H), 4.05 (s, 3H), 3.86 (s, 3H), 3.62 (s, 2H), 2.92 (s, 2H), 2.03 - 1.92 (m, 1H), 0.98 - 0.95 (m, 2H), 0.87 - 0.84 (m, 2H), 0.27 (s, 6H).

[0956]

[0957] Example 46: Preparation of 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(3-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0958]

[0959] The target compound (30 mg, yield: 59%) was obtained in the same manner as in Example 1 using 2-bromo-4-(3-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (43 mg, 0.083 mmol) and (4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)boronic acid (38 mg, 0.17 mmol).

[0960] 1H NMR (500 MHz, CDCl3) δ 8.59 (s, 1H), 7.62 (s, 0.2H), 7.58 (d, J = 8.5 Hz, 2H), 7.48 (s, 0.5H), 7.42 (s, 1H), 7.37 - 7.32 (m, 1.3H), 6.96 (d, J = 8.6 Hz, 1H), 4.71 (s, 2H), 3.82 (s, 3H), 3.64 (s, 2H), 3.54 (s, 3H), 2.64 (s, 2H), 2.30 - 2.26 (m, 1H), 1.24 - 1.21 (m, 2H), 1.03 - 1.00 (m, 2H), 0.30 (s, 6H).

[0961]

[0962] Example 47: Preparation of 4-(4-(4-chloro-1-methyl-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0963]

[0964] The target compound (3 mg, yield: 9%) was obtained in the same manner as in Example 1 using 2-bromo-4-(4-(4-chloro-1-methyl-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (30 mg, 0.066 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (26 mg, 0.13 mmol).

[0965] 1H NMR (500 MHz, CDCl3) δ 8.58 (s, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 6.87 (s, 1H), 4.80 (s, 2H), 3.96 (s, 3H), 3.71 (s, 3H), 3.66 (s, 2H), 2.59 (s, 2H), 2.14 - 2.11 (m, 1H), 1.21 - 1.18 (m, 2H), 0.97 - 0.94 (m, 2H), 0.29 (s, 6H).

[0966]

[0967] Example 48: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0968]

[0969] The target compound (4.1 mg, yield: 16.5%) was obtained in the same manner as in Example 1 using 2-bromo-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (22 mg, 0.040 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (11.7 mg, 0.060 mmol).

[0970] 1H NMR (500 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.22 (s, 1H), 4.77 - 4.72 (m, 1H), 3.93 (s, 3), 3.65 (s, 2H), 3.40 (s, 2H), 2.87 (s, 2H), 2.11 - 2.09 (m, 1H), 2.01 - 1.98 (m, 6H), 1.64 - 1.61 (m, 6H), 1.19 - 1.17 (m, 6H), 0.94 - 0.93 (m, 2H), 0.92 - 0.91 (m, 2H), 0.36 (s, 6H).

[0971]

[0972] Example 49: Preparation of 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-6,6-dimethyl-4-((1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0973]

[0974] The target compound (13 mg, yield: 24%) was obtained in the same manner as in Example 1 using 2-bromo-6,6-dimethyl-4-((1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (45 mg, 0.092 mmol) and (4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)boronic acid (42 mg, 0.18 mmol).

[0975] 1H NMR (500 MHz, CDCl3) δ 8.57 (s, 1H), 7.60 (s, 0.2H), 7.54 - 7.50 (m, 1.3H), 7.45 (s, 0.5H), 7.30 (s, 0.3H), 6.87 (d, J = 7.3 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 4.37 (d, J = 12.9 Hz, 2H), 3.65 (s, 1H), 3.46 (d, J = 7.1 Hz, 2H), 2.88 (t, J = 12.6 Hz, 2H), 2.82 (s, 2H), 2.29 - 2.26 (m, 1H), 2.17 - 2.13 (m, 1H), 1.77 (d, J = 13.0 Hz, 1H), 1.37 - 1.27 (m, 6H), 1.02 - 1.01 (m, 2H), 0.35 (s, 6H).

[0976]

[0977] Example 50: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(2-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0978]

[0979] The target compound (16 mg, yield: 35.1%) was obtained using 2-bromo-4-(2-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (40 mg, 0.079 mmol) and 4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (23.2 mg, 0.119 mmol).

[0980] 1H NMR (500 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.35 (d, J = 8.1 Hz, 1H), 8.21 (t, J = 7.9 Hz, 1H), 7.96 - 7.93 (m, 2H), 7.90 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 4.77 (s, 2H), 3.87 (s, 3H)), 3.61 (s, 2H), 2.77 (s, 2H), 2.04 - 1.99 (m, 1H), 1.01 - 0.98 (m, 2H), 0.90 - 0.89 (m, 2H), 0.25 (s, 6H).

[0981]

[0982] Example 51: Preparation of 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(2-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0983]

[0984] The target compound (34.6 mg, yield: 47.6%) was obtained in the same manner as in Example 1 using 2-bromo-4-(2-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (60 mg, 0.119 mmol) and (4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)boronic acid (55.1 mg, 0.239 mmol).

[0985] 1H NMR (500 MHz, CDCl3) δ 8.72 (s, 1H), 8.33 (d, J = 8.1 Hz, 1H), 8.21 (t, J = 8.0 Hz, 1H), 7.96 - 7.88 (m, 3.25H), 7.79 (s, 0.5H), 7.65 (s, 0.25H), 7.61 (t, J = 7.8 Hz, 1H), 4.78 (s, 2H), 3.64 (s, 2H), 2.80 (s, 2H), 2.24-2.19 (m, 1H), 1.08 - 1.05 (m, 2H), 1.00 - 0.97 (m, 2H), 0.25 (s, 6H).

[0986]

[0987] Example 52: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0988]

[0989] The target compound (17.4 mg, yield: 25.5%) was obtained in the same manner as in Example 1 using 2-bromo-4-(3-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (60 mg, 0.119 mmol) and (4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)boronic acid (58.1 mg, 0.299 mmol).

[0990] 1H NMR (500 MHz, CDCl3) δ 8.59 (s, 1H), 8.08 (t, J = 8.2 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.93 (t, J = 7.8 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.29 - 7.27 (m, 2H), 4.81 (s, 2H), 3.98 (s, 3H), 3.67 (s, 2H), 2.65 (s, 2H), 2.14-2.10 (m, 1H), 1.23 - 1.21 (m, 2H), 1.00 - 0.97 (m, 2H), 0.32 (s, 6H).

[0991]

[0992] Example 53: Preparation of 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(3-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline

[0993]

[0994] The target compound (23.5 mg, yield: 32.4%) was obtained in the same manner as in Example 1 using 2-bromo-4-(3-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline (60 mg, 0.119 mmol) and (4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)boronic acid (55.1 mg, 0.239 mmol).

[0995] 1H NMR (500 MHz, CDCl3) δ 8.59 (s, 1H), 8.08 (t, J = 8.1 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.93 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 6.9 Hz, 1.3H), 7.48 (s, 0.5H), 7.34 (s, 0.2H), 7.30 - 7.28 (m, 1H), 7.25 - 7.22 (m, 1H), 4.79 (s, 2H), 3.67 (s, 2H), 2.66 (s, 2H), 2.28-2.24 (m, 1H), 1.43 - 1.41 (m, 2H), 1.07 - 1.04 (m, 2H), 0.33 (s, 6H).

[0996]

[0997] Experimental Example: Deubiquitination Assay for USP1 / UAF1 Activity and Inhibitor Testing

[0998] The USP1 / UAF1 activity of the compound of the present invention was evaluated by the following method.

[0999]

[1000] Recombinant Human His6 USP1 / UAF1 Complex (R&D SYSTEMS, E-568) was used for the USP-1 deubiquitinase activity assay. During the experiment, DTT was added to DUB Assay Buffer (abcam, ab241002) to a final concentration of 1 mM (hereinafter referred to as Assay Buffer). Recombinant Human His6 USP1 / UAF1 Complex was diluted with Assay Buffer to prepare a 2 nM USP-1 Enzyme solution. Test compounds, which are USP-1 deubiquitinase inhibitors, were tested at final concentrations ranging from 0.008 to 1 μM. Test compounds were first diluted in DMSO to 100x the final experimental concentration. The assay solution was prepared by diluting the 100x test compound (DMSO 100%) diluted 100x in Assay Buffer to 10x the final experimental concentration (DMSO 10%). Recombinant human ubiqutin rhodamine 110 C-terminal derivative (R&D SYSTEMS, U-555) used as a substrate was diluted with Assay Buffer to prepare a substrate solution at a concentration of 0.2125 μM (final concentration: 0.17 μM). All experiments were performed at room temperature.

[1001]

[1002] First, 5 μl of 2 nM USP-1 Enzyme solution and 5 μl of the assay solution of the test compound were reacted for 15 minutes. At this time, 5 μL of Assay buffer was added instead of the Enzyme solution as an untreated (background) control, and 5 μL of the assay solution with a concentration of 0 μM was added as a solvent control. To this, 40 μL of 0.2125 μM Substrate solution was added, and the reaction was performed for 15 minutes under the conditions of a final volume of 50 μL, 0.2 nM Enzyme, and 0.17 μM substrate. The above contents are summarized in Table 1 below.

[1003] Assay conditionReagent additionsPurposeTest compound1) 5 mL 10X test compound2) 5 mL Enzyme solution3) 40 mL Substrate solutionTest compound USP-1 inhibition confirmationPositive control1) 5 mL 10X control2) 5 mL Enzyme solution3) 40 mL Substrate solutionControl inhibition(%) confirmationVehicle control (No inhibitor)1) 5 mL Assay buffer(10% DMSO)2) 5 mL Enzyme solution3) 40 mL Substrate solution100% activity(0% inhibition)Background1) 5 mL Assay buffer(10% DMSO)2) 5 mL Assay buffer3) 40 mL Substrate solutionAbsolute minimum activity, non-specific reaction

[1004]

[1005] Fluorescence of the final reaction product was measured using a microplate reader under 480 nm excitation / 540 nm emission conditions. The percentage inhibition activity (% inhibition) of the test compound against USP-1 deubiquitinase was calculated using the following formula.

[1006] % inhibition = ((Vehicle control RLU) - (Test compound RLU)) / ((Vehicle control RLU) - (background RLU)) x 100

[1007]

[1008] IC of the compound 50 The inhibitory activity percentage was calculated using GraphPad Prism5 software based on the values, and the results are shown in Table 2 below. In Table 2 below, each symbol means the following.

[1009] "+": IC 50 This represents more than 10 μM

[1010] "++": IC 50 This indicates 300 nM or more but less than 10 μM

[1011] "+++": IC 50 This indicates 100 nM or more and less than 300 nM

[1012] "++++": IC 50 This represents less than 100 nM

[1013]

[1014] Example number USP1 IC 50 Example number USP1 IC 50 Example number USP1 IC 50Example 1++++Example 19++Example 37++++Example 2+++Example 20++Example 38++++Example 3+++Example 21++Example 39++++Example 4++Example 22++Example 40++++Example 5++Example 23++Example 41++++Example 6++++Example 24++Example 42++++Example 7++Example 25++Example 43++Example 8++Example 26++Example 44++Example 9++++Example 27++Example 45++Example 10++++Example 28++Example 46++Example 11+++Example 29++Example 47+++Example 12++Example 30++++Example 48+++Example 13++Example 31++++Example 49++Example 14++Example 32++Example 50+++Example 15++Example 33++++Example 51++++Example 16++Example 34++++Example 52++++Example 17++++Example 35++++Example 53++++Example 18+++Example 36++++

Claims

1. A compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof [Chemical Formula 1] In the above chemical formula 1, R1 to R4 are each independently hydrogen, or C 1-4 It is alkyl, L is C(R5)2, N(R5), or O, R5 is each independently hydrogen, or C 1-4 It is alkyl, A is C 5-6 Aryl; or C containing one or more heteroatoms selected from the group consisting of N, O and S 2-6 It is heteroaryl, A is unsubstituted, or C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted with one or two substituents selected from the group consisting of cycloalkyl, halogen, -CO-NH2, and -SO2-NH2, B is C 5-6 Aromatic ring; C containing one or more heteroatoms selected from the group consisting of N, O and S 2-12 Heteroaromatic ring; C 4-12 Cycloalkane; and C containing at least one heteroatom selected from the group consisting of N, O and S. 4-12 Any one of the divalent linkers selected from the group consisting of heterocycloalkanes, B is unsubstituted, or C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted with one or two substituents selected from the group consisting of cycloalkyl and halogen, C is C 5-6 Aryl; C containing one or more heteroatoms selected from the group consisting of N, O and S 2-12 Heteroaryl; C 4-12 Cycloalkyl; C containing one or more heteroatoms selected from the group consisting of N, O and S 4-12 Heterocycloalkyl, or -SO2-(C 1-4 alkyl), C is unsubstituted, or C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, halogen, -CO-(C 1-4 alkyl), and -SO2-(C 1-4 is substituted with one or two substituents selected from the group consisting of alkyl.

2. In paragraph 1, R1 to R4 are hydrogen, A compound or a pharmaceutically acceptable salt thereof.

3. In paragraph 1, L is CH2, A compound or a pharmaceutically acceptable salt thereof.

4. In paragraph 1, A is phenyl or pyrimidinyl, A is unsubstituted or substituted with one or two substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoro, chloro, bromo, -CO-NH2, and -SO2-NH2. A compound or a pharmaceutically acceptable salt thereof.

5. In paragraph 1, A is one selected from the group consisting of: A compound or a pharmaceutically acceptable salt thereof.

6. In paragraph 1, B is one selected from the group consisting of: A compound or a pharmaceutically acceptable salt thereof.

7. In paragraph 1, C is pyrazolyl, triazolyl, pyrimidinyl, imidazolyl, or pyridinyl, C is unsubstituted or substituted with one or two substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, methoxy, chloro, -CO-CH3, and -SO2-CH3, A compound or a pharmaceutically acceptable salt thereof.

8. In paragraph 1, C is one selected from the group consisting of: A compound or a pharmaceutically acceptable salt thereof.

9. In paragraph 1, The above chemical formula 1 is represented by the following chemical formula 2, Compound or pharmaceutically acceptable salt thereof: [Chemical Formula 2] In the above chemical formula 2, X1 and X2 are each independently CH or N, R'1 and R'2 are each independently hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, or C 3-6 It is cycloalkyl, R'3 and R'4 are each independently hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, or halogen.

10. In paragraph 1, The compound represented by the above chemical formula 1 is 1) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 2) 4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 3) 2-(2-cyclopropylphenyl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 4) 2-(2-cyclobutylphenyl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 5) 2-(2-chlorophenyl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 6) 2-(2-(difluoromethoxy)phenyl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 7) 3-(4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacillin-2-yl)benzamide, 8) 3-(4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacillin-2-yl)benzenesulfonamide, 9) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 10) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 11) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 12) 2-(2-isopropylphenyl)-6,6-dimethyl-4-(4-(pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 13) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(6-methoxypyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 14) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(6-(methylsulfonyl)pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 15) 1-(6-(4-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-6,7-dihydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacillin-4(5H)-yl)methyl)phenyl)pyridin-2-yl)ethan-1-one, 16) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(4-(trifluoromethyl)pyrimidin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 17) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 18) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-6,6-dimethyl-4-(4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 19) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-((6-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 20) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-((6'-(trifluoromethyl)-[2,2'-bipyridin]-5-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 21) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophen-2-yl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 22) 4-((5-(1-Isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophen-2-yl)methyl)-2-(2-isopropylphenyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 23) 2-(2-isopropylphenyl)-6,6-dimethyl-4-(4-(methylsulfonyl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 24) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(methylsulfonyl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 25) 4-(4-(1H-pyrazol-1-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 26) 4-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-cyclopropylphenyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 27) 4-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-cyclobutylphenyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 28) 4-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-chlorophenyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 29) 4-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 30) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 31) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-6,6-dimethyl-4-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 32) 2-(2-isopropylphenyl)-6,6-dimethyl-4-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 33) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 34) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 35) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 36) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 37) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 38) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-6,6-dimethyl-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 39) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 40) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 41) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 42) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 43) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-((6-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 44) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-((5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 45) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4-((5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin-2-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 46) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(3-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 47) 4-(4-(4-chloro-1-methyl-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 48) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 49) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-6,6-dimethyl-4-((1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 50) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(2-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 51) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(2-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, 52) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline, and 53) 2-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-4-(3-fluoro-4-(6-(trifluoromethyl)pyridin-2-yl)benzyl)-6,6-dimethyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a][1,3,5]diazacilline Any one compound selected from the group consisting of, A compound or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition for preventing or treating cancer, comprising a compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

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