Novel heterocyclic compounds that are porcita inhibitors for the treatment and prevention of cancer, and pharmaceutical compositions containing the same.

Abstract

The present invention relates to a novel heterocyclic compound represented by chemical formula 1 and a pharmaceutical composition containing the same, wherein the compound according to the present invention can be usefully used for the prevention or treatment of cancer. [Formula 1] In the above chemical formula 1, X and R1 to R6 are as defined in the specification.

Description

Technical Field

[0001] The present invention relates to a novel heterocyclic compound useful as an inhibitor of porcine theta (DNA Polymerase theta, Pol-theta; Polθ) and a pharmaceutical composition containing the same.

Background Art

[0002] Targeting DNA repair defects is an effective strategy proven in cancer treatment. However, cancers with DNA repair defects sometimes depend on backup DNA repair pathways that can be targeted to remove cancer cells, which form the basis of synthetic lethality. Such synthetic lethality is exemplified by the success of poly ADP-ribose polymerase (PARP) inhibitors in the treatment of BRCA-deficient breast and ovarian cancers.

[0003] Powerful repair of DNA double-strand breaks (DSBs) is essential for maintaining genomic stability and cell viability. DSBs can be repaired by one of three main pathways: homologous recombination (HR), non-homologous end-joining (NHEJ), and alternative-NHEJ (alt-NHEJ). Here, microhomology-mediated end-joining (MMEJ) is the most specialized alternative-NHEJ mechanism.

[0004] Meanwhile, numerous genetic studies have highlighted the role of Polθ in stimulating MMEJ in higher organisms. In particular, cancer cells deficient in HR, NHEJ, or ATM (Ataxia-telangiectasia mutated; AT mutated) have been shown to be highly dependent on Polθ expression. Polθ expression is barely present in normal cells but increases in breast, lung, and ovarian cancers. Furthermore, increased Polθ expression is associated with a poor prognosis in breast cancer. Importantly, Polθ is significantly suppressed in normal tissues but increases in relevant cancer samples, suggesting a high correlation between disease and expression. Suppression or inhibition of Polθ also confers radiosensitivity to tumor cells. Moreover, inhibition of Polθ can prevent MMEJ-dependent functional reversion of BRCA2 mutations that underlie cisplatin and PARPi resistance induction in tumors. Therefore, Polθ is an attractive target for novel synthetic lethal therapies in cancers with DNA repair defects, and there is a need to provide effective Polθ inhibitors for cancer treatment.

[0005] Therefore, the inventors, after studying novel compounds, confirmed that compounds having a different chemical structure from Polθ inhibitors reported to date possess excellent Polθ inhibitory effects, thus completing the present invention. The compounds belonging to the present invention mainly possess Polθ inhibitory activity themselves, but the possibility that after being absorbed into the body, they may exhibit pharmacological effects as efficacy agents due to special internal environments or products of metabolic processes is not ruled out. [Overview of the project] [Problems that the invention aims to solve]

[0006] The present invention provides novel heterocyclic compounds useful as Polθ inhibitors and pharmaceutical compositions containing the same. [Means for solving the problem]

[0007] In order to solve the above problems, the present invention provides a compound represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof.

Chemical Formula

[0008] Furthermore, to solve the above problems, we provide a pharmaceutical composition containing a compound or a pharmaceutically acceptable salt thereof.

[0009] Furthermore, to solve the above problems, we provide a pharmaceutical composition for the prevention or treatment of cancer comprising a compound or a pharmaceutically acceptable salt thereof. [Effects of the Invention]

[0010] The compound represented by chemical formula 1 according to the present invention or a pharmaceutically acceptable salt thereof can be usefully used for the prevention or treatment of cancer. [Modes for carrying out the invention]

[0011] The present invention will be explained in more detail below to help you understand it better.

[0012] Herein, the present invention provides a compound represented by chemical formula 1, or a pharmaceutically acceptable salt thereof.

[0013] Preferably, R1 is methyl, methoxy, cyclopropyl, fluoro, or cyano. Preferably, R2 is hydrogen, fluoro, or chloro. Preferably, R1 is fluoro and R2 is hydrogen or fluoro.

[0014] Preferably, R3 is either hydrogen or fluorocarbon, independently of each other. Preferably, R3 is hydrogen.

[0015] Preferably, R4 is trifluoromethyl or cyclopropyl. Preferably, R5 is methyl, trifluoromethyl, cyclopropyl, or chloro. Preferably, R4 and R5 are trifluoromethyl.

[0016] Preferably, R6 is hydrogen, methyl, or -CH2-C≡N.

[0017] Preferably, R7 is hydrogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyclopentyl, cyclohexyl, hydroxy, amino, methylamino, dimethylamino, phenyl, piperidinyl, tetrahydropyranyl, oxadiazolyl, pyrazinyl, pyrazolyl, pyridadinyl, 6-oxo-1,6-dihydropyridinyl, pyrimidinyl, or thiadiazolyl. Preferably, R7 is phenyl, piperidinyl, tetrahydropyranyl, oxadiazolyl, pyrazinyl, pyrazolyl, pyridadinyl, 6-oxo-1,6-dihydropyridinyl, pyrimidinyl, or thiadiazolyl, which is either unsubstituted or substituted with methyl, methoxy, hydroxy, chloro, amino, methylamino, dimethylamino, -NHCO(methyl), -NHCO(trifluoromethyl), -NHSO2(methyl), -N(SO2(methyl))2, -SO2(methyl), -SO2(NH2), -CH2SO2(methyl), -CH2SO2(NH2), -CH(CH3)CO(NH2), -COOH, -CONH2, azetidine, morpholino, oxetanyl, piperazinyl, or piperazinyl.

[0018] Preferably, chemical formula 1 is represented by the following chemical formula 1-1. [ka] In chemical formula 1-1, X is CH or N, R2 is either hydrogen or fluorine. R8 is hydrogen, oxadiazolyl, pyrazinyl, pyrazolyl, pyridadinyl, 6-oxo-1,6-dihydropyridinyl, or pyrimidinyl. In R8, oxadiazolyl, pyrazinyl, pyrazolyl, pyridadinyl, 6-oxo-1,6-dihydropyridinyl, or pyrimidinyl is either unsubstituted or substituted with methyl, methoxy, hydroxy, chloro, amino, -NHSO2(methyl), -N(SO2(methyl))2, -CH2SO2(methyl), -COOH, -CONH2, or morpholino.

[0019] Typical examples of compounds represented by chemical formula 1 are as follows: 1) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 2) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 3) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(pyridazin-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 4) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-methyl-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 5) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 6)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-oxo-1,6-dihydropyridine-2-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 7) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(3,5-bis(trifluoromethyl)pyridine-2-yl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 8) 1-(3-(2-aminopyrimidine-5-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 9) 1-(3-(5-aminopyrazine-2-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 10)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(1-(methylsulfonylmethyl)-1H-pyrazole-4-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 11)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-morpholinopyridazine-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 12) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7,8-difluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 13) 2-(3-(2,4-bis(trifluoromethyl)phenyl)-7,8-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)acetonitrile, 14)(R)-N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-inyl)pyridazine-3-yl)methanesulfonamide, 15)(R)-N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-inyl)pyridazin-3-yl)-N-(methylsulfonyl)methanesulfonamide, 16)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(5-methyl-1,3,4-oxadiazole-2-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 17)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-methoxypyridazin-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 18) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 19)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-hydroxypyridazin-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 20)1-(3-(5-amino-1,3,4-oxadiazole-2-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 21)6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-inyl)pyridazine-3-carboxylic acid, 22)6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-inyl)pyridazine-3-carboxamide, 23)3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-(6-chloropyridazine-3-yl)prop-2-inyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 24)3-(2,4-bis(trifluoromethyl)phenyl)-7,8-difluoro-1-(3-(1-(methylsulfonylmethyl)-1H-pyrazole-4-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 25)1-(3-(6-(azetidine-3-yl)pyridazin-3-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 26)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(piperidine-4-yl)pyridazin-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 27)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(piperazin-1-yl)pyridazin-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 28) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-8-chloro-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 29)6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-inyl)pyridazine-3-sulfonamide, 30)(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-inyl)pyridazine-3-yl)methanesulfonamide, 31)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(methylsulfonylmethyl)pyridazin-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 32)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(methylsulfonyl)pyridazin-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 33) 1-(3-(6-aminopyridazin-3-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-carbonitrile, 34) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(4-chloro-2-(trifluoromethyl)phenyl)-7-cyclopropyl-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 35) N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-inyl)pyridazine-3-yl)methanesulfonamide, 36) N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-inyl)pyridazine-3-yl)acetamide, 37) N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-inyl)pyridazin-3-yl)-2,2,2-trifluoroacetamide, 38) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-phenylprop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 39) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(4-methoxyphenyl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 40) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-methyl-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 41) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-methoxy-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 42) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-cyclopropyl-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 43) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-7-cyclopropyl-3-(4-methyl-2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 44)3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-(6-(dimethylamino)pyridazin-3-yl)prop-2-inyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 45)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(methylamino)pyridazin-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 46) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-7-cyclopropyl-3-(4-cyclopropyl-2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 47) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)buto-2-inyl)acetamide, 48) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)buto-2-inyl)nicotinamide, 49) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)buto-2-inyl)-5-methyl-1,3,4-oxadiazole-2-carboxamide, 50)N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)buto-2-inyl)benzamide, 51) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-5,5,7-trifluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 52) 1-(3-(1-(azetidine-3-yl)-1H-pyrazole-4-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 53)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(1-methyl-1H-pyrazole-4-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 54) 2-(4-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-inyl)-1H-pyrazole-1-yl)propanamide, 55)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4,4,4-trifluorobuto-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 56)3-(2,4-bis(trifluoromethyl)phenyl)-1-(buto-2-inyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 57) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-cyclohexylprop-2-inyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 58) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-cyclopentylprop-2-inyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 59)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(tetrahydro-2H-pyran-4-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 60)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(piperidine-4-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 61)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(4-hydroxycyclohexyl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 62) 1-(3-(4-aminocyclohexyl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 63) 1-(4-aminobuto-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 64)3-(2,4-bis(trifluoromethyl)phenyl)-1-(4-(dimethylamino)buto-2-inyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 65)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-hydroxybuto-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 66)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-methoxybuto-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 67)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-(trifluoromethoxy)buto-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 68)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(pyridine-2-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 69) 1-(3-(1,3,4-thiadiazole-2-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 70)1-(3-(5-amino-1,3,4-thiadiazole-2-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 71)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(oxetan-3-yl)pyridazin-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 72) 1-(3-(1,3,4-oxadiazole-2-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 73) 1-(3-(5-amino-1,3,4-oxadiazole-2-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 74)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(1-(oxetan-3-yl)-1H-pyrazole-4-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 75)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-(pyridazine-3-yloxy)buto-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 76)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(5-(6-methylpyridazin-3-yl)pento-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 77)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(4-(6-methylpyridazin-3-yl)phenyl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 78)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-(isopropyl(1-(6-methylpyridazine-3-yl)ethyl)amino)buto-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 79) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)buto-2-inyl)-1,3,4-oxadiazole-2-carboxamide, 80)N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)buto-2-inyl)-1,3,4-thiadiazole-2-carboxamide, and 81)3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(6-methylpyridazin-3-yl)pyridine-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one.

[0020] Furthermore, the compounds of the present invention can exist in the form of salts, particularly pharmaceutically acceptable salts. Any salt commonly used in the industry can be used without limitation, such as an acid addition salt formed by a pharmaceutically acceptable free acid. In this invention, "pharmaceutically acceptable salt" means any organic or inorganic addition salt of a compound in a concentration that has a relatively non-toxic and harmless effective effect on the patient, such that the side effects resulting from the salt do not diminish the beneficial efficacy of the compound represented by chemical formula 1.

[0021] As free acids, organic acids and inorganic acids can be used. As inorganic acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, stannic acid, etc., can be used. As organic acids, 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 to these. Preferably, the salt may be a hydrochloride salt.

[0022] Furthermore, pharmaceutically acceptable metal salts can be obtained using a base in a conventional manner. For example, a compound represented by chemical formula 1 can be dissolved in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, the insoluble compound salt can be filtered out, and the filtrate can be evaporated and dried to obtain a pharmaceutically acceptable metal salt. In this case, it is particularly preferable to produce a sodium salt, a potassium salt, or a calcium salt as the metal salt.

[0023] Furthermore, a pharmaceutically acceptable salt or solvate of the compound represented by chemical formula 1 can be used as an intermediate in the manufacture of the compound represented by chemical formula 1, its pharmaceutically acceptable salt, or solvate.

[0024] In one embodiment, the compound represented by chemical formula 1 can be produced by the following reaction formula 1.

[0025] [ka]

[0026] In reaction equation 1, X and R1 to R6 are as previously defined, and X' is a halogen. Preferably, X' is bromo or chloro.

[0027] Step 1 is a step in which a compound represented by chemical formula 1' and a compound represented by chemical formula 2' are reacted to produce a compound represented by chemical formula 3'. This reaction is preferably carried out in the presence of a palladium catalyst such as Pd2(dba)3.

[0028] Step 2 is a process in which the compound represented by chemical formula 3' is reacted with hydroxyamine (NH2OH) to produce the compound represented by chemical formula 4'.

[0029] Step 3 is a step in which the compound represented by chemical formula 5' is produced by a Beckmann rearrangement using the compound represented by chemical formula 4'. This reaction is preferably carried out in the presence of polyphosphate.

[0030] Step 4 is a step in which the compound represented by chemical formula 5' is reacted with NaH and R6-X'' (where R6 is as previously defined except for hydrogen, and X'' is a halogen; preferably X'' is bromo or chloro) to produce the compound represented by chemical formula 1.

[0031] The manufacturing method will be explained in more detail in the examples described later.

[0032] Another embodiment of the present invention provides a pharmaceutical composition comprising a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0033] Another embodiment of the present invention provides a pharmaceutical composition for the prevention or treatment of cancerous diseases, comprising a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the Polθ inhibitory effect is beneficial.

[0034] In this case, cancer may be hematological cancer, extranodal marginal zone B-cell lymphoma, glioblastoma, lymphoplasmacytic lymphoma, acute myeloid leukemia, macroglobulinemia, B-cell lymphoma, chronic lymphocytic leukemia, follicular lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, hairy cell leukemia, mantle cell lymphoma, glioblastoma, bladder cancer, pancreatic cancer, ovarian cancer, colorectal cancer, kidney cancer, gastric cancer, transitional cell carcinoma, carcinoid, breast cancer, non-small cell lung cancer, or multiple myeloma.

[0035] In this invention, the term "prevention" means all actions that suppress or delay the onset, spread, and recurrence of a disease by administering the composition of the present invention, and "treatment" means all actions that improve or favorably alter the symptoms of a disease by administering the composition of the present invention.

[0036] The pharmaceutical compositions of the present invention can be formulated into oral or parenteral dosage forms by standard pharmaceutical practices. These dosage forms may contain additives other than the active ingredient, such as pharmaceutically acceptable carriers, adjuvants, or diluents.

[0037] Suitable carriers include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oil, and isopropyl myristate. Suitable diluents include, but are not limited to, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine. The compounds of the present invention can also be dissolved in oils, propylene glycol, or other solvents commonly used in the manufacture of injectable solutions. Furthermore, for topical action, the compounds of the present invention can be formulated into ointments or creams.

[0038] The preferred dosage of the compound of the present invention varies depending on the patient's condition and weight, the severity of the disease, the form of the drug, the route of administration, and the duration, but can be appropriately selected by those skilled in the art. However, for the desired effect, it is preferable to administer the compound of the present invention at a dose of 0.0001 to 100 mg / kg (body weight), preferably 0.001 to 100 mg / kg (body weight) per day. The drug may be administered once daily or in divided doses, via oral or parenteral routes.

[0039] Depending on the administration method, the pharmaceutical composition may contain 0.001 to 99% by weight, preferably 0.01 to 60% by weight, of the compound of the present invention.

[0040] The pharmaceutical compositions according to the present invention can be administered to mammals, including mice, rats, livestock, and humans, via a variety of routes. While all methods of administration are conceivable, they may be administered, for example, orally, rectally or intravenously, intramuscularly, subcutaneously, intrauterine dura mater, or intracerebral (intracerebroventric μLar) injection.

[0041] The present invention will be described in more detail below with reference to the following examples. However, the following examples are merely illustrative of the present invention, and the scope of the present invention is not limited thereto. [Examples]

[0042] Example 1: Synthesis of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one [ka]

[0043] Step A: Synthesis of 2-[2,4-bis(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-one (2) To a solution of 6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (300 mg, 1.83 mmol) and 1-bromo-2,4-bis(trifluoromethyl)benzene (0.46 mL, 2.74 mmol) in dioxane (6 mL) and H2O (1.5 mL), Pd2(dba)3 (250.99 mg, 0.27 mmol), tetrafluoro-λ5-boranoidtris(2-methylprop-2-yl)phosphane (316.99 mg, 1.10 mmol), and NaOH (146.18 mg, 3.65 mmol) were added under N2. The mixture was stirred under N2 at 100°C for 2 hours to obtain a brown solution. Upon completion, the mixture was diluted with ELISA (100 mL) and washed with H2O (50 mL x 2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: siRNA = 100:1 to 10:1) to obtain 2-[2,4-bis(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (370 mg, 0.98 mmol, 53.82%) in white solid form. LCMS: m / z (M+H) + = 377.2.

[0044] Step B: Synthesis of [(1Z)-2-[2,4-bis(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydro-1-naphthylidene]hydroxylamine (3) A solution of [2,4-bis(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-one (370 mg, 0.98 mmol) and hydroxylamine hydrochloride (102.50 mg, 1.48 mmol) in MeOH (50 mL) was mixed with sodium acetate (161.33 mg, 1.97 mmol) at 25 °C and stirred at 60 °C for 2 hours to obtain a yellow solution. Upon completion, the mixture was quenched with H2O (100 mL) in an ice bath and extracted with  (200 mL x 2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain [(1Z)-2-[2,4-bis(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydro-1-naphthylidene]hydroxylamine (350 mg, 0.89 mmol, 90.96%) as a yellow solid. LCMS: m / z (M+H) + = 392.2.

[0045] Step C: Synthesis of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one [(1Z)-2-[2,4-bis(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydro-1-naphthylidene]hydroxylamine (350 mg, 0.89 mmol) and polyphosphate (1.96 mL, 49.20 mmol) were stirred under N2 at 120°C for 1 hour to obtain a brown solution. Upon completion, the mixture was quenched with H2O (100 mL) at 0°C and extracted with ELISA (100 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 10:1) to obtain 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (50 mg, 0.13 mmol, 14.29%) as a white solid.

[0046] 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.3 Hz, 1H), 7.89 - 7.81 (m, 2H), 7.33 (s, 1H), 7.04 (dd, J = 6.8, 4.2 Hz, 3H), 4.18 (dd, J = 12.3, 7.3 Hz, 1H), 3.15 (m, J = 7.7 Hz, 1H), 2.82 (m, J = 6.9 Hz, 1H), 2.64 - 2.52 (m, 1H), 2.36 (m, 1H). LCMS: m / z (M+H) + = 392.2.

[0047] Example 2: Synthesis of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one [ka]

[0048] 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (30 mg, 0.08 mmol) was added to a THF (5 mL) solution under N2 conditions in an ice bath with NaH (4.60 mg, 0.12 mmol, 60% purity). The mixture was stirred at 0°C for 1 hour, and then 3-bromoprop-1-in (0.01 mL, 0.09 mmol) was added at 0°C. The mixture was stirred at 0°C for 2 hours to obtain a yellow solution. Upon completion, the mixture was quenched with H2O (20 mL) in an ice bath and extracted with siRNA (20 mL x 2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by HPLC (TFA conditions) to obtain 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (11 mg, 0.03 mmol, 33.41%) as a white solid.

[0049] 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.2 Hz, 1H), 7.89 - 7.79 (m, 2H), 7.40 (dd, J = 8.8, 4.9 Hz, 1H), 7.10 (td, J = 8.4, 2.9 Hz, 1H), 7.01 (dd, J = 8.5, 2.9 Hz, 1H), 4.75 (dd, J = 17.3, 2.5 Hz, 1H), 4.39 (dd, J = 17.3, 2.4 Hz, 1H), 4.17 (m, J = 12.3, 7.0 Hz, 1H), 3.13 (m, J = 13.4, 7.7Hz, 1H), 2.75 (dd, J = 13.7, 6.7 Hz, 1H), 2.62 (m, J = 7.6 Hz, 1H), 2.32 - 2.17 (m, 2H). LCMS: m / z (M+H) + = 430.2.

[0050] Example 3: Synthesis of 3-[2,4-bis(trifluoromethyl)phenyl]-1-[3-(1,2-diazine-3-yl)prop-2-inyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one [ka]

[0051] To a solution of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (10 mg, 0.02 mmol) and 3-bromo-1,2-diazine (4.44 mg, 0.03 mmol) in DMF (3 mL), Pd(PPh3)4 (1.35 mg), CuI (0.44 mg), and TEA (0.01 mL, 0.05 mmol) were added under N2 conditions at 25 °C. The mixture was stirred at 70 °C for 4 hours to obtain a brown solution. Upon completion, the mixture was washed with saturated aqueous solution NH4Cl (10 mL) and extracted with Â(10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by HPLC (TFA conditions) to obtain 3-[2,4-bis(trifluoromethyl)phenyl]-1-[3-(1,2-diazine-3-yl)prop-2-inyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (4.72 mg, 0.01 mmol, 36.74%) as a brown solid.

[0052] 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.3 Hz, 1H), 7.90 - 7.81 (m, 2H), 7.58 (d, J = 77.9 Hz, 4H), 7.12 (s, 1H), 7.03 (d, J = 8.6 Hz, 1H), 4.99 (d, J = 17.6 Hz, 1H), 4.76 (d, J = 17.5 Hz, 1H), 4.21 (m, J = 12.2, 7.0 Hz, 1H), 3.19 (m, J = 16.0 Hz, 1H), 2.79 (m, J = 12.9, 6.5 Hz, 1H), 2.71 - 2.61 (m, 1H), 2.31 - 2.18 (m, 1H). LCMS: m / z (M+H) + = 508.1.

[0053] Example 4: Synthesis of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one [ka]

[0054] 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (2.8 mg, 0.01 mmol) was dissolved in THF (1 mL) and NaH (0.43 mg, 0.01 mmol) was added in an ice bath. The mixture was stirred at 0°C for 0.5 hours, and then MeI (0.01 mL, 0.01 mmol) was added at 0°C. The mixture was stirred at 25°C for 1 hour to obtain a yellow solution. Upon completion, the mixture was quenched with H2O (20 mL) in an ice bath and extracted with Âxa (20 mL x 2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by HPLC (TFA conditions) to obtain 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (2 mg, 0.01 mmol, 67.59%).

[0055] 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.3 Hz, 1H), 7.88 - 7.79 (m, 2H), 7.27 - 7.20 (m, 1H), 7.08 (td, J = 8.4, 2.9 Hz, 1H), 6.98 (dd, J = 8.5, 2.9 Hz, 1H), 4.16 (m, 1H), 3.36 (s, 3H), 3.01 (dt, J = 13.3, 6.7 Hz, 1H), 2.75 (m, 1H), 2.66 - 2.53 (m, 1H), 2.23 (dt, J = 12.9, 6.3 Hz, 1H). LCMS: m / z (M+H) + = 406.2.

[0056] Example 5: Synthesis of 1-[3-[3-(6-amino-1,2-diazine-3-yl)prop-2-inyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one [ka]

[0057] To a solution of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (500 mg, 1.16 mmol) and 6-bromo-1,2-diazine-3-amine (243 mg, 1.40 mmol) in DMF (10 mL), Pd(PPh3)4 (67.29 mg, 0.06 mmol), CuI (22.18 mg, 0.12 mmol), and TEA (0.32 mL, 2.33 mmol) were added under N2 conditions at 25 °C. The mixture was stirred at 70 °C for 4 hours to obtain a brown solution. Upon completion, the mixture was diluted with water (300 mL), filtered, and the filtrate was extracted with ELISA (200 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by HPLC (TFA conditions) to obtain the racemic compound 1-[3-[3-(6-amino-1,2-diazine-3-yl)prop-2-inyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (300 mg, 0.55 mmol, 47.03%) as a white solid.

[0058] 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.3 Hz, 1H), 7.89 - 7.80 (m, 2H), 7.47 (dd, J = 8.8, 4.9 Hz, 1H), 7.20 - 7.10 (m, 2H), 7.01 (dd, J = 8.5, 2.9 Hz, 1H), 6.73 (d, J = 9.2 Hz, 1H), 5.34 (s, 2H), 4.95 (d, J = 17.5 Hz, 1H), 4.69 (d, J = 17.5 Hz, 1H), 4.20 (dd, J = 12.3, 7.0 Hz, 1H), 3.19 (td, J = 13.3, 7.6 Hz, 1H), 2.77 (dd, J = 13.7, 6.7 Hz, 1H), 2.65 (td, J = 12.5, 7.6 Hz, 1H), 2.25 (tt, J = 13.0, 6.8 Hz, 1H). LCMS: m / z (M+H) + = 523.2.

[0059] Examples 5-1 and 5-2: Synthesis of (R)-1-(3-(6-aminopyridazin-3-yl)prop-2-in-1-yl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one and (S)-1-(3-(6-aminopyridazin-3-yl)prop-2-in-1-yl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one [ka]

[0060] The racemic compound 1-[3-[3-(6-amino-1,2-diazine-3-yl)prop-2-inyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (300 mg, 0.55 mmol) was separated by prep-chiral HPLC under the following conditions: (Column: ChiralCel OX, 250 × 30 mm ID, 10 μm; Mobile phase: A for CO2 and B for Ethanol (0.1% NH3H2O); Gradient: B 30%; Wavelength: 220 nm; Sample preparation: Compound was dissolved in ~40 ml MeOH / DCM; Injection: 8 ml per injection; Flow rate: 150 mL / min; Back pressure: 100 bar). The first peak is (R)-1-(3-(6-aminopyridazine-3-yl)prop-2-in-1-yl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one (Example 5-1) (141.44 mg, 0.26 mmol, 47.15%) (100% ee, t R =0.943) is observed as a white solid, and the second peak is (S)-1-(3-(6-aminopyridazin-3-yl)prop-2-in-1-yl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one (Example 5-2) (148.74 mg, 0.27 mmol, 49.58%) (100% ee, t R (=1.898) was obtained as a white solid.

[0061] Example 5-1 11H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.3 Hz, 1H), 7.89 - 7.79 (m, 2H), 7.47 (dd, J = 8.8, 4.9 Hz, 1H), 7.11 (ddd, J = 10.6, 7.0, 4.2 Hz, 2H), 7.00 (dd, J = 8.5, 2.9 Hz, 1H), 6.69 (d, J = 9.1 Hz, 1H), 5.69 (s, 2H), 4.94 (d, J = 17.4 Hz, 1H), 4.68 (d, J = 17.5 Hz, 1H), 4.19 (dd, J = 12.3, 6.9 Hz, 1H), 3.19 (td, J = 13.4, 7.7 Hz, 1H), 2.81 - 2.59 (m, 2H), 2.24 (m, 1H). LCMS: m / z (M+H) + =523.2。

[0062] Example 5-2 1 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.3 Hz, 1H), 7.89 - 7.79 (m, 2H), 7.47 (dd, J = 8.8, 4.9 Hz, 1H), 7.16 - 7.06 (m, 2H), 7.00 (dd, J = 8.5, 2.9 Hz, 1H), 6.69 (d, J = 9.1 Hz, 1H), 5.63 (s, 2H), 4.94 (d, J = 17.5 Hz, 1H), 4.69 (d, J = 17.5 Hz, 1H), 4.19 (dd, J = 12.3, 7.0 Hz, 1H), 3.19 (m, 1H), 2.76 (dd, J = 13.7, 6.7 Hz, 1H), 2.65 (m 1H), 2.24 (m, 1H). LCMS: m / z (M+H) + =523.2。

[0063] Example 6: Synthesis of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-[3-(6-oxo-1H-pyridine-2-yl)prop-2-inyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one [ka]

[0064] To a 5 mL solution of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (50 mg, 0.12 mmol) and 6-bromo-1,2-dihydropyridine-2-one (25.06 mg, 0.14 mmol) in DMF, Pd(PPh3)4 (6.73 mg, 0.01 mmol), CuI (2.22 mg, 0.01 mmol), and TEA (0.03 mL, 0.23 mmol) were added at 25°C under N2. The mixture was stirred at 70°C for 4 hours to obtain a brown solution. Upon completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (TFA conditions) to obtain 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-[3-(6-oxo-1H-pyridine-2-yl)prop-2-inyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (5.43 mg, 0.01 mmol, 8.66%) as a white solid.

[0065] 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.3 Hz, 1H), 7.89 - 7.80 (m, 2H), 7.47 (m, 1H), 7.34 (m, 1H), 7.13 (m, 1H), 7.03 (dd, J = 8.5, 2.9 Hz, 1H), 6.55 (d, J = 9.3 Hz, 1H), 6.30 (d, J = 6.9 Hz, 1H), 4.90 (d, J = 17.7 Hz, 1H), 4.70 (d, J = 17.6 Hz, 1H), 4.19 (m, 1H), 3.12 (dt, J = 13.4, 6.8 Hz, 1H), 2.78 (m, 1H), 2.71 - 2.57 (m, 1H), 2.26 (dt, J = 13.2, 6.4 Hz, 1H). LCMS: m / z (M+H) + = 523.1.

[0066] Example 7: Synthesis of 1-[3-[3-(6-amino-1,2-diazine-3-yl)prop-2-inyl]-3-[3,5-bis(trifluoromethyl)pyridine-2-yl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one [ka]

[0067] Step A: Synthesis of 2-[3,5-bis(trifluoromethyl)pyridine-2-yl]-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-one (2) To a toluene (30 mL) solution of 6-fluoro-1,2,3,4-tetrahydronaphthalene-1-one (250 mg, 1.52 mmol) and 2-chloro-3,5-bis(trifluoromethyl)pyridine (759.96 mg, 3.05 mmol), sodium 2-methylpropane-2-oleate (292.67 mg, 3.05 mmol), (3R)-4-(2,6-dimethoxyphenyl)-3-(1,1-dimethylethyl)-2,3-dihydro-1,3-benzoxaphosphole (20.12 mg, 0.06 mmol) and Pd(OAc)2 (6.84 mg, 0.03 mmol) were added at 20°C under N2, and the mixture was stirred under N2 at 70°C for 24 hours to obtain a brown solution. Upon completion, the mixture was diluted with ELISA (100 mL) and washed with H2O (50 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: siRNA = 0-10%) to obtain 2-[3,5-bis(trifluoromethyl)pyridine-2-yl]-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (40 mg, 0.11 mmol, 6.96%) as a white solid. LCMS: m / z (M+H) + = 378.2.

[0068] Step B: Synthesis of [(1Z)-2-[3,5-bis(trifluoromethyl)pyridine-2-yl]-6-fluoro-1,2,3,4-tetrahydro-1-naphthylidene]hydroxylamine (3) To a solution of 2-[3,5-bis(trifluoromethyl)pyridine-2-yl]-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-one (40 mg, 0.11 mmol) and hydroxylamine hydrochloride (22.10 mg, 0.32 mmol) in MeOH (5 mL), sodium acetate (26.09 mg, 0.32 mmol) was added and stirred at 80°C for 18 hours to obtain a yellow solution. Upon completion, the mixture was quenched with H2O (10 mL) in an ice bath and extracted with  (20 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain [(1Z)-2-[3,5-bis(trifluoromethyl)pyridine-2-yl]-6-fluoro-1,2,3,4-tetrahydro-1-naphthylidene]hydroxylamine (40 mg, 0.10 mmol, 96.18%) as a yellow solid. LCMS: m / z (M+H) + = 393.2.

[0069] Step C: Synthesis of 3-[3,5-bis(trifluoromethyl)pyridine-2-yl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (4) [(1Z)-2-[3,5-bis(trifluoromethyl)pyridine-2-yl]-6-fluoro-1,2,3,4-tetrahydro-1-naphthylidene]hydroxylamine (40 mg, 0.10 mmol) in polyphosphate (0.22 mL, 5.61 mmol) was stirred under N2 at 120°C for 20 minutes to obtain a brown solution. Upon completion, the mixture was quenched with H2O (50 mL) at 0°C and extracted with ELISA (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by TLC (petroleum ether: Â1=30%) to obtain 3-[3,5-bis(trifluoromethyl)pyridine-2-yl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (10 mg, 0.03 mmol, 25.49%) as a white solid. LCMS: m / z (M+H) + = 393.2.

[0070] Step D: Synthesis of 3-[3,5-bis(trifluoromethyl)pyridine-2-yl]-7-fluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (5) 3-[3,5-bis(trifluoromethyl)pyridine-2-yl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (10 mg, 0.03 mmol) was dissolved in THF (5 mL) and NaH (0.92 mg, 0.04 mmol, 30% in oil) was added under N2 conditions in an ice bath. The mixture was stirred at 0°C for 1 hour, and then 3-bromoprop-1-yin (0.01 mL, 0.03 mmol) was added at 0°C. The mixture was stirred at 25°C for 4 hours to obtain a yellow solution. Upon completion, the mixture was quenched with H2O (20 mL) in an ice bath and extracted with Â(20 mL x 2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by TLC (petroleum ether: Â=5:1) to obtain 3-[3,5-bis(trifluoromethyl)pyridine-2-yl]-7-fluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (5 mg, 0.01 mmol, 50.00%) as a white solid. LCMS: m / z (M+H) + = 431.2.

[0071] Step E: Synthesis of 1-[3-[3-(6-amino-1,2-diazine-3-yl)prop-2-inyl]-3-[3,5-bis(trifluoromethyl)pyridine-2-yl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one To a solution of 3-[3,5-bis(trifluoromethyl)pyridine-2-yl]-7-fluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (5 mg, 0.01 mmol) and 6-bromo-1,2-diazine-3-amine (2.43 mg, 0.01 mmol) in DMF (3 mL), Pd(PPh3)4 (0.67 mg), CuI (0.22 mg), and TEA (0.01 mL, 0.02 mmol) were added at 20 °C under N2. The mixture was stirred under N2 at 70 °C for 4 hours to obtain a brown solution. Upon completion, the mixture was washed with saturated aqueous solution NH4Cl (10 mL) and extracted with Â(10 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified using a high-performance liquid phase (trifluoroacetic acid / acetonitrile / water) to obtain 1-[3-[3-(6-amino-1,2-diazine-3-yl)prop-2-inyl]-3-[3,5-bis(trifluoromethyl)pyridine-2-yl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (0.8 mg, 4.54%) as a white solid. LCMS: m / z (M+H) + = 524.2.

[0072] Example 8: Synthesis of 1-[3-(2-aminopyrimidine-5-yl)prop-2-inyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one [ka]

[0073] To a solution of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (40 mg, 0.09 mmol) and 5-bromopyrimidine-2-amine (16.21 mg, 0.09 mmol) in DMF (3 mL), Pd(PPh3)4 (5.38 mg), CuI (1.77 mg, 0.01 mmol), and TEA (0.03 mL, 0.19 mmol) were added at 25 °C under N2. The mixture was stirred at 70 °C for 4 hours to obtain a brown solution. Upon completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (TFA conditions) to obtain 1-[3-[3-(2-aminopyrimidine-5-yl)prop-2-inyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (8.97 mg, 0.02 mmol, 17.08%) as a white solid.

[0074] 1 H NMR (400 MHz, CDCl3) δ 8.34 (s, 2H), 7.98 (d, J = 8.3 Hz, 1H), 7.90 - 7.80 (m, 2H), 7.44 (dd, J = 8.8, 4.9 Hz, 1H), 7.13 (td, J = 8.4, 2.9 Hz, 1H), 7.03 (dd, J = 8.4, 2.9 Hz, 1H), 5.33 (s, 2H), 4.94 (d, J = 17.4 Hz, 1H), 4.63 (d, J = 17.4 Hz, 1H), 4.19 (dd, J = 12.3, 7.0 Hz, 1H), 3.15 (m, 1H), 2.76 (m, 1H), 2.65 (m, 1H), 2.26 (m, 1H). LCMS: m / z (M+H) + = 523.2.

[0075] Example 9: Synthesis of 1-[3-(5-aminopyrazine-2-yl)prop-2-inyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one [ka]

[0076] To a solution of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (50 mg, 0.12 mmol) in DMF (2 mL), 5-bromopyrazine-2-amine (30.40 mg, 0.17 mmol), Pd(PPh3)4 (6.73 mg, 0.01 mmol), CuI (2.22 mg, 0.01 mmol), and TEA (0.05 mL, 0.35 mmol) were added at 25°C. The reaction mixture was degassed three times with N2 at 20°C, stirred at 70°C for 16 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (TFA conditions) to obtain 1-[3-[3-(5-aminopyrazine-2-yl)prop-2-inyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (2.2 mg, 3.28%) as a white solid.

[0077] 1 H NMR (400 MHz, CDCl3) δ 8.09 - 7.85 (m, 3H), 7.83 (s, 1H), 7.52 - 7.39 (m, 1H), 7.27 - 7.26 (m, 1H), 7.12(m, J = 0.6 Hz, 1H), 7.06 - 6.99 (m, 1H), 5.08 - 4.95 (m, 1H), 4.74 - 4.58 (m, 1H), 4.27 - 4.13 (m, 1H), 3.30 - 3.11 (m, 1H), 2.63 (s, 2H), 2.34 - 2.17 (m, 1H). LCMS: m / z (M+H) + = 523.2.

[0078] Example 10: Synthesis of 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(1-((methylsulfonyl)methyl)-1H-pyrazole-4-yl)prop-2-in-1-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one [ka]

[0079] To a solution of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (200 mg, 0.47 mmol) and 4-bromo-1-((methylsulfonyl)methyl)-1H-pyrazole (122.51 mg, 0.51 mmol) in DMF (3 mL), XPhos Pd G3 (39.43 mg, 0.05 mmol), CuI (8.87 mg, 0.05 mmol), and TEA (0.19 mL, 1.40 mmol) were added under N2 conditions at 25 °C. The mixture was stirred at 100 °C for 18 hours to obtain a brown solution. Upon completion, the mixture was washed with saturated aqueous solution NH4Cl (30 mL) and extracted with  (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified using a high-performance liquid phase (trifluoroacetic acid / acetonitrile / water) to obtain 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(1-((methylsulfonyl)methyl)-1H-pyrazole-4-yl)prop-2-in-1-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one (7.11 mg, 0.01 mmol, 2.54%) as a white solid.

[0080] 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.3 Hz, 1H), 7.91 - 7.82 (m, 2H), 7.72 (s, 1H), 7.61 (s, 1H), 7.46 (dd, J = 8.8, 5.0 Hz, 1H), 7.14 (m, 1H), 7.04 (dd, J = 8.5, 3.0 Hz, 1H), 5.24 (s, 2H), 4.90 (d, J = 17.4 Hz, 1H), 4.64 (d, J = 17.4 Hz, 1H), 4.20 (dd, J = 12.3, 7.0 Hz, 1H), 3.17 (m, 1H), 2.89 (s, 3H), 2.78 (dd, J = 13.7, 6.6 Hz, 1H), 2.73 - 2.60 (m, 1H), 2.27 (m, 1H). LCMS: m / z (M+H) + = 588.2.

[0081] Example 11: Synthesis of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-{3-[6-(1,4-oxazinan-4-yl)-1,2-diazine-3-yl]prop-2-inyl}-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one [ka]

[0082] 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (50 mg, 0.12 mmol) and 3-bromo-6-(1,4-oxazinan-4-yl)-1,2-diazine (28.43 mg, 0.12 mmol) were placed in DMF (5 mL) and heated under N2 at 25 °C. Pd(PPh3)4 (6.73 mg, 0.01 mmol), CuI (2.22 mg, 0.01 mmol), and TEA (0.03 mL, 0.23 mmol) were added. The mixture was stirred at 70 °C for 4 hours to obtain a brown solution. Upon completion, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (TFA conditions) to obtain 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-{3-[6-(1,4-oxazinan-4-yl)-1,2-diazine-3-yl]prop-2-inyl}-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (38.36 mg, 0.06 mmol, 52.80%) as a white solid.

[0083] 1 H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.3 Hz, 1H), 7.90 - 7.79 (m, 2H), 7.50 (dd, J = 8.8, 4.9 Hz, 1H), 7.19 (d, J = 9.4 Hz, 1H), 7.11 (m, 1H), 7.00 (dd, J = 8.5, 2.9 Hz, 1H), 6.78 (d, J = 9.5 Hz, 1H), 4.96 (d, J = 17.5 Hz, 1H), 4.70 (d, J = 17.5 Hz, 1H), 4.20 (dd, J = 12.3, 7.0 Hz, 1H), 3.83 (dd, J = 5.8, 3.9 Hz, 4H), 3.68 - 3.62 (m, 4H), 3.21 (m, 1H), 2.77 (dd, J = 13.8, 6.6 Hz, 1H), 2.64 (m, 1H), 2.25 (m, 1H). LCMS: m / z (M+H) + = 593.2.

[0084] Example 12: Synthesis of 1-(3-(6-aminopyridazin-3-yl)prop-2-in-1-yl)-3-(2,4-bis(trifluoromethyl)phenyl)-7,8-difluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one [ka]

[0085] Step A: Synthesis of 2-[2,4-bis(trifluoromethyl)phenyl]-6,7-difluoro-1,2,3,4-tetrahydronaphthalene-1-one (2) To a solution of 6,7-difluoro-1,2,3,4-tetrahydronaphthalen-1-one (900 mg, 4.94 mmol) and 1-bromo-2,4-bis(trifluoromethyl)benzene (1.00 mL, 5.93 mmol) in dioxane (20 mL) and H2O (5 mL), Pd2(dba)3 (678.62 mg, 0.74 mmol), tetrafluoro-λ5-boranoidtris(2-methylprop-2-yl)phosphane (857.06 mg, 2.96 mmol), and NaOH (395.24 mg, 9.88 mmol) were added at 20°C. The mixture was stirred under N2 at 100°C for 2 hours to obtain a brown solution. Upon completion, the mixture was diluted with ELISA (100 mL) and washed with H2O (50 mL x 2). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: SiO₂ = 0-10%) to obtain 2-[2,4-bis(trifluoromethyl)phenyl]-6,7-difluoro-1,2,3,4-tetrahydronaphthalen-1-one (1.8 g, 4.57 mmol, 92.31%) as a white solid. LCMS: m / z (M+H) + = 395.2.

[0086] Step B: Synthesis of [(1Z)-2-[2,4-bis(trifluoromethyl)phenyl]-6,7-difluoro-1,2,3,4-tetrahydro-1-naphthylidene]hydroxylamine (3) To a solution of 2-[2,4-bis(trifluoromethyl)phenyl]-6,7-difluoro-1,2,3,4-tetrahydronaphthalen-1-one (1.8 g, 4.57 mmol) and hydroxylamine hydrochloride (1.06 g, 15.22 mmol) in MeOH (50 mL), NaOAc (1.25 g, 15.22 mmol) was added at 20 °C, and the mixture was stirred at 80 °C for 18 hours to obtain a yellow solution. Upon completion, the mixture was quenched with H2O (100 mL) in an ice bath and extracted with siRNA (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain [(1Z)-2-[2,4-bis(trifluoromethyl)phenyl]-6,7-difluoro-1,2,3,4-tetrahydro-1-naphthylidene]hydroxylamine (1.8 g, 4.40 mmol, 86.54%) as a yellow solid. LCMS: m / z (M+H) + = 410.2.

[0087] Step C: Synthesis of 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (4) [(1Z)-2-[2,4-bis(trifluoromethyl)phenyl]-6,7-difluoro-1,2,3,4-tetrahydro-1-naphthylidene]hydroxylamine (1.8 g, 4.40 mmol) was mixed with polyphosphate (9.63 mL, 241.89 mmol) and stirred under N2 at 120°C for 20 minutes to obtain a brown solution. Upon completion, the mixture was quenched with H2O (200 mL) at 0°C and extracted with ELISA (100 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: siRNA = 0-30%) to obtain 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (450 mg, 1.10 mmol, 25.00%) as a white solid. LCMS: m / z (M+H) + = 410.2.

[0088] Step D: Synthesis of 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (5) 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (200 mg, 0.49 mmol) was dissolved in THF (5 mL) and NaH (11.73 mg, 0.49 mmol, 30% in oil) was added under N2 conditions in an ice bath. The mixture was stirred at 0°C for 1 hour, and then 3-bromoprop-1-in (0.05 mL, 0.59 mmol) was added at 0°C. The mixture was stirred at 25°C for 4 hours to obtain a yellow solution. Upon completion, the mixture was quenched with H2O (50 mL) in an ice bath and extracted with RINKAN (50 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: HCl = 0-30%) to obtain 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (180 mg, 0.40 mmol, 82.35%) as a white solid. LCMS: m / z (M+H) + = 448.2.

[0089] Step E: Synthesis of 1-(3-(6-aminopyridazin-3-yl)prop-2-in-1-yl)-3-(2,4-bis(trifluoromethyl)phenyl)-7,8-difluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one To a solution of 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (40 mg, 0.09 mmol) and 6-bromo-1,2-diazine-3-amine (18.67 mg, 0.11 mmol) in DMF (3 mL), Pd(PPh3)4 (5.17 mg), CuI (1.70 mg, 0.01 mmol), and TEA (0.02 mL, 0.18 mmol) were added at 20 °C. The mixture was stirred at 70 °C for 4 hours to obtain a brown solution. Upon completion, the mixture was washed with saturated aqueous solution NH4Cl (50 mL) and extracted with Â(50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified using a high-performance liquid phase (trifluoroacetic acid / acetonitrile / water) to obtain 1-(3-(6-aminopyridazin-3-yl)prop-2-in-1-yl)-3-(2,4-bis(trifluoromethyl)phenyl)-7,8-difluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one (17.82 mg, 0.03 mmol, 36.88%) as a white solid.

[0090] 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.9 Hz, 1H), 7.92 - 7.77 (m, 2H), 7.38 (d, J = 11.1 Hz, 1H), 7.28 - 7.11 (m, 2H), 6.88 (s, 1H), 5.73 (s, 2H), 4.94 (d, J = 17.7 Hz, 1H), 4.70 (d, J = 17.8 Hz, 1H), 4.19 (d, J = 10.4 Hz, 1H), 3.17 (s, 1H), 2.87 - 2.58 (m, 2H), 2.27 (s, 1H). LCMS: m / z (M+H) + = 541.2.

[0091] Example 13: Synthesis of {3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl}acetonitrile [ka]

[0092] 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (30 mg, 0.07 mmol) was dissolved in THF (5 mL) and NaH (2.64 mg, 0.11 mmol, 30% in oil) was added under N2 conditions in an ice bath. The mixture was stirred at 0°C for 1 hour, and then bromoacetonitrile (0.01 mL, 0.09 mmol) was added at 0°C. The mixture was stirred at 25°C for 4 hours to obtain a yellow solution. Upon completion, the mixture was quenched with H2O (50 mL) in an ice bath and extracted with  (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified using a high-performance liquid phase (ammonium bicarbonate / acetonitrile / water) to obtain {3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl}acetonitrile (10.63 mg, 0.04 mmol, 60.86%) as a white solid.

[0093] 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.3 Hz, 1H), 7.93 - 7.85 (m, 2H), 7.25 - 7.17 (m, 2H), 4.95 (d, J = 17.3 Hz, 1H), 4.41 (d, J = 17.3 Hz, 1H), 4.21 (m, 1H), 3.09 (m, 1H), 2.84 (m, 1H), 2.67 (m, 1H), 2.30 (m, 1H). LCMS: m / z (M+H) + = 449.2.

[0094] Examples 14 and 15: Synthesis of (R)-N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-in-1-yl)pyridazin-3-yl)methanesulfonamide (Example 14) and (R)-N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-in-1-yl)pyridazin-3-yl)-N-(methylsulfonyl)methanesulfonamide (Example 15) [ka]

[0095] To a solution of 1-[3-[6-amino-1,2-diazine-3-yl]prop-2-inyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (15 mg, 0.03 mmol) in pyridine (1.5 mL), MsCl (0.04 mmol) was added at 0°C, and the mixture was stirred at 20°C for 18 hours to obtain a brown solution. Upon completion, the mixture was diluted with ELISA (15 mL) and washed with HCl (20 mL, 1 N). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified using a high-performance liquid phase (trifluoroacetic acid / acetonitrile / water) to obtain (R)-N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-in-1-yl)pyridazin-3-yl)methanesulfonamide (4.52 mg, 0.01 mmol, 22.67%) (Example 14) (R)-N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-in-1-yl)pyridazin-3-yl)-N-(methylsulfonyl)methanesulfonamide (4.71 mg, 0.01 mmol, 22.12%) (Example 15) was obtained as a white solid.

[0096] Example 14 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.3 Hz, 1H), 7.92 - 7.83 (m, 2H), 7.44 (m, 1H), 7.25 (d, J = 9.3 Hz, 1H), 7.20 - 7.11 (m, 2H), 7.06 (m, 1H), 4.93 (d, J = 17.6 Hz, 1H), 4.72 (d, J = 17.7 Hz, 1H), 4.22 (m, 1H), 3.17 (m, 1H), 3.12 (s, 3H), 2.82 (dd, J = 13.6, 6.6 Hz, 1H), 2.68 (m, 1H), 2.30 (m, 1H) LCMS: m / z (M+H) + = 601.2.

[0097] Example 15 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.3 Hz, 1H), 7.92 - 7.83 (m, 2H), 7.60 (d, J = 8.7 Hz, 1H), 7.52 - 7.41 (m, 2H), 7.15 (m, 1H), 7.06 (dd, J = 8.4, 2.9 Hz, 1H), 5.05 (d, J = 17.7 Hz, 1H), 4.77 (d, J = 17.7 Hz, 1H), 4.23 (dd, J = 12.3, 7.0 Hz, 1H), 3.66 (s, 6H), 3.22 (m, 1H), 2.83 (dd, J = 13.8, 6.7 Hz, 1H), 2.69 (m, 1H), 2.29 (m, 1H). LCMS: m / z (M+H) + = 679.2.

[0098] Example 16: Synthesis of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-[3-(5-methyl-1,3,4-oxadiazole-2-yl)prop-2-inyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one [ka]

[0099] To a solution of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (30 mg, 0.07 mmol) and 5-bromo-2-methyl-1,3,4-oxadiazole (13.66 mg, 0.08 mmol) in DMF (3 mL), Pd(PPh3)4 (4.04 mg), CuI (1.33 mg, 0.01 mmol), and TEA (0.02 mL, 0.14 mmol) were added at 20 °C under N2. The mixture was stirred under N2 at 70 °C for 4 hours to obtain a brown solution. Upon completion, the mixture was diluted with H2O (50 mL) and extracted with  (50 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified using a high-performance liquid phase (trifluoroacetic acid / acetonitrile / water) to obtain 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-[3-(5-methyl-1,3,4-oxadiazole-2-yl)prop-2-inyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (7.07 mg, 0.01 mmol, 19.75%) as a white solid.

[0100] 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.3 Hz, 1H), 7.92 - 7.83 (m, 2H), 7.41 (m, 1H), 7.15 (dd, J = 8.4, 2.9 Hz, 1H), 7.06 (dd, J = 8.4, 2.9 Hz, 1H), 5.06 (d, J = 17.8 Hz, 1H), 4.68 (d, J = 17.8 Hz, 1H), 4.21 (m, 1H), 3.16 (m, 1H), 2.82 (m, 1H), 2.67 (m, 1H), 2.56 (s, 3H), 2.28 (m, 1H). LCMS: m / z (M+H) + = 512.2.

[0101] Example 17: Synthesis of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-[3-(6-methoxy-1,2-diazine-3-yl)prop-2-inyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one [ka]

[0102] To a solution of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (30 mg, 0.07 mmol) and 3-bromo-6-methoxy-1,2-diazine (15.88 mg, 0.08 mmol) in DMF (3 mL), Pd(PPh3)4 (4.04 mg), CuI (1.33 mg, 0.01 mmol), and TEA (0.02 mL, 0.14 mmol) were added at 20 °C under N2. The mixture was stirred under N2 at 70 °C for 4 hours to obtain a brown solution. Upon completion, the mixture was diluted with H2O (50 mL) and extracted with  (50 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified using a high-performance liquid phase (trifluoroacetic acid / acetonitrile / water) to obtain 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-[3-(6-methoxy-1,2-diazine-3-yl)prop-2-inyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (5.28 mg, 0.01 mmol, 13.56%) as a white solid.

[0103] 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.3 Hz, 1H), 7.92 - 7.82 (m, 2H), 7.50 (m, 1H), 7.33 (d, J = 9.1 Hz, 1H), 7.14 (m, 1H), 7.04 (d, J = 7.2 Hz, 1H), 6.91 (d, J = 9.1 Hz, 1H), 5.01 (d, J = 17.4 Hz, 1H), 4.71 (d, J = 17.6 Hz, 1H), 4.24 - 4.18 (m, 1H), 4.16 (s, 3H), 3.31 - 3.18 (m, 1H), 2.80 (m, 1H), 2.67 (d, J = 9.2 Hz, 1H), 2.28 (d, J = 8.0 Hz, 1H). LCMS: m / z (M+H) + = 538.2.

[0104] Example 18: Synthesis of 1-(3-(6-aminopyridazine-3-yl)prop-2-in-1-yl)-3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one [ka]

[0105] Step A: Synthesis of 1-bromo-2-cyclopropyl-4-(trifluoromethyl)benzene (2) A solution of PdCl2(dppf)-CH2Cl2 (0.40 g, 0.48 mmol), cyclopropylboronic acid (1.00 g, 11.63 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (3.4 g, 9.69 mmol), and potassium phosphate (6.17 g, 29.07 mmol) in dioxane (20 mL) and water (10 mL) was stirred at 100 °C for 16 hours. After completion, the reaction mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by column chromatography with hexane elution to obtain 1-bromo-2-cyclopropyl-4-(trifluoromethyl)benzene (2.1 g, 6.73 mmol, 69.50%) as a colorless oil.

[0106] Step B: Synthesis of 2-[2-cyclopropyl-4-(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-one (3) In a N2 atmosphere, tetrafluoro-λ5-boranoidtris(2-methylprop-2-yl)phosphane (65.45 mg, 0.23 mmol), Pd2(dba)3 (34.55 mg, 0.04 mmol), and sodium hydroxide (301.81 mg, 7.55 mmol) were added to a 100 mL three-necked flask equipped with a magnetic stirring rod at 25°C. Then, a solution of 6-fluoro-1,2,3,4-tetrahydronaphthalene-1-one (743.26 mg, 4.53 mmol) in dioxane (8 mL) and a solution of 1-bromo-2-cyclopropyl-4-(trifluoromethyl)benzene (1000.00 mg, 3.77 mmol) in H2O (2 mL) were added, respectively. The mixture was stirred at 100°C for 2 hours. Upon completion, the mixture was diluted with siRNA (20 mL), washed with saturated aqueous solution NH4Cl (20 mL), and dried over anhydrous sodium 2SO4. The filtrate was concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether:siRNA = 20:1) to obtain 2-[2-cyclopropyl-4-(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-one (800 mg, 2.30 mmol, 60.88%). LCMS: m / z (M+H) + = 349.2.

[0107] Step C: Synthesis of (E)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-6-fluoro-3,4-dihydronaphthalene-1(2H)-oneoxime(4) A solution of 2-[2-cyclopropyl-4-(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-one (800 mg, 2.30 mmol), hydroxylamine hydrochloride (478.77 mg, 6.89 mmol), and sodium acetate (565.17 mg, 6.89 mmol) in methanol (10 mL) and water (4 mL) was stirred at 70°C for 4 hours. Upon completion, the reaction mixture was evaporated to about half of its initial volume and then diluted with water (15 mL). The resulting crystals were collected, washed with water, and dried to obtain (E)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-6-fluoro-3,4-dihydronaphthalene-1(2H)-one oxime (600 mg, 1.40 mmol, 61.11%) as a white solid. LCMS: m / z (M+H) + = 364.2.

[0108] Step D: Synthesis of 3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one (5) (E)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-6-fluoro-3,4-dihydronaphthalene-1(2H)-one oxime (200 mg, 0.55 mmol) was added to polyphosphate (5 mL) and stirred at 120°C for 15 minutes. Upon completion, the mixture was quenched with H2O (50 mL) at 0°C and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium 2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0-30%) to obtain 3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one (50 mg, 0.03 mmol, 5.00%) as a colorless oil. LCMS: m / z (M+H) + = 364.2.

[0109] Step E: Synthesis of 3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1-(prop-2-in-1-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one (6) 3-(2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one (50 mg, 0.14 mmol) was dissolved in THF (5 mL) and NaH (6.61 mg, 0.28 mmol) was added at 0 °C. After 30 minutes, 3-bromoprop-1-in (0.02 mL, 0.21 mmol) was added at 0 °C, and the mixture was stirred at 25 °C for 3 hours. Upon completion, the mixture was quenched with H₂O (15 mL) in an ice bath. The mixture was then extracted with ethyl acetate (15 mL x 3). The combined organic layers were dried over anhydrous sodium 2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0-30%) to obtain 3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1-(prop-2-in-1-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one (39 mg, 0.10 mmol, 70.61%) as a yellow oil. LCMS: m / z (M+H) + = 402.2.

[0110] Step F: Synthesis of 1-(3-(6-aminopyridazin-3-yl)prop-2-in-1-yl)-3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one To a solution of 3-(2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1-(prop-2-yn-1-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one (40 mg, 0.10 mmol) in DMF (5 mL), 6-bromo-1,2-diazine-3-amine (20.81 mg, 0.12 mmol), TEA (20.17 mg, 0.20 mmol), CuI (1.90 mg, 0.01 mmol), and Pd(PPh3)4 (5.76 mg) were added under N2 conditions at 25°C, and the mixture was stirred at 70°C for 4 hours. The mixture was then washed with saturated aqueous solution NH4Cl (50 mL) and extracted with Âxy (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified in high-performance liquid phase (trifluoroacetic acid / acetonitrile / water) to obtain 1-(3-(6-aminopyridazin-3-yl)prop-2-in-1-yl)-3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one (3 mg, 0.01 mmol, 5.48%) as a white solid.

[0111] 1H NMR (400 MHz, DMSO) δ 8.09 - 8.04 (m, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.32 (s, 1H), 7.22 (d, J = 9.0 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.0 Hz, 1H), 6.77 (s, 2H), 6.70 (d, J = 9.0 Hz, 1H), 5.13 (m, 1H), 4.89 (s, 2H), 2.71 - 2.63 (m, 2H), 2.22 - 2.15 (m, 2H), 1.91 - 1.85 (m, 1H), 1.07 - 1.00 (m, 2H), 0.85 - 0.81 (m, 2H). LCMS: m / z (M+H) + = 495.2.

[0112] Example 19: Synthesis of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-[3-(6-hydroxy-1,2-diazine-3-yl)prop-2-inyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one [ka]

[0113] To a solution of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (30 mg, 0.07 mmol) and 6-bromo-3H,2H-1,2-diazine-3-one (14.70 mg, 0.08 mmol) in DMF (3 mL), Pd(PPh3)4 (4.04 mg), CuI (1.33 mg, 0.01 mmol), and TEA (0.02 mL, 0.14 mmol) were added at 20 °C under N2. The mixture was stirred under N2 at 70 °C for 4 hours to obtain a brown solution. Upon completion, the mixture was diluted with H2O (50 mL) and extracted with ELISA (50 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified using a high-performance liquid phase (trifluoroacetic acid / acetonitrile / water) to obtain 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-[3-(6-hydroxy-1,2-diazine-3-yl)prop-2-inyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (23.68 mg, 0.05 mmol, 64.63%) as a white solid.

[0114] 1 H NMR (400 MHz, CDCl3) δ 10.81 (s, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.92 - 7.83 (m, 2H), 7.45 (dd, J = 8.8, 4.9 Hz, 1H), 7.21 - 7.10 (m, 2H), 7.05 (dd, J = 8.4, 2.9 Hz, 1H), 6.90 (d, J = 9.8 Hz, 1H), 4.93 (d, J = 17.6 Hz, 1H), 4.69 (d, J = 17.6 Hz, 1H), 4.21 (m, 1H), 3.16 (m, 1H), 2.81 (m, 1H), 2.67 (m, 1H), 2.28 (m, 1H). LCMS: m / z (M+H) + = 524.2.

[0115] Example 20: Preparation of 1-[3-(5-amino-1,3,4-oxadiazole-2-yl)prop-2-inyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one [ka]

[0116] Step A: Synthesis of 5-bromo-1,3,4-oxadiazole-2-amine (2) To a solution of 1,3,4-oxadiazole-2-amine (300 mg, 3.53 mmol) in tetrahydrofuran (10 mL), n-BμLi (4.94 mL, 12.35 mmol) was added at -78 °C, followed by the addition of bromine (565 mg, 3.53 mmol). The mixture was stirred under N2 at 25 °C for 16 hours. Upon completion, the mixture was poured into water (50 mL) and extracted with  (50 mL x 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (solvent:petroleum ether: = 5:1~10:1) to obtain 5-bromo-1,3,4-oxadiazole-2-amine (120 mg, 0.74 mmol, 20.96%) as a white solid. LCMS: m / z (M+H) + = 164.4.

[0117] Step B: Synthesis of 1-[3-(5-amino-1,3,4-oxadiazole-2-yl)prop-2-inyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one To a solution of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (418 mg, 0.97 mmol) in DMF (8 mL), 5-bromo-1,3,4-oxadiazole-2-amine (80 mg, 0.49 mmol), CuI (18 mg, 0.09 mmol), Pd(PPh3)4 (56 mg, 0.05 mmol), and TEA (49 mg, 0.48 mmol) were added at 20°C and stirred under N2 at 70°C for 4 hours. Upon completion, the mixture was poured into water (15 mL) and extracted with ELISA (30 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-HPLC ((ACN:water (1‰NH4OH)) to obtain 1-[3-(5-amino-1,3,4-oxadiazole-2-yl)prop-2-inyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (1.34 mg, 0.002 mmol, 0.32%) as a white solid. LCMS: m / z (M+H) + = 513.1.

[0118] Example 21: Synthesis of 6-(3-{3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl}prop-1-inyl)-1,2-diazine-3-carboxylic acid [ka]

[0119] To a solution of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (20 mg, 0.05 mmol) in DMF (1 mL), 6-bromo-1,2-diazine-3-carboxylic acid (15.22 mg, 0.08 mmol), CuI (1.90 mg, 0.01 mmol), TEA (0.02 mL, 0.15 mmol), and Pd(Ph3)4 (5.78 mg, 0.01 mmol) were added at 20°C. The mixture was degassed three times with N2 and stirred under N2 at 70°C for 4 hours. After the reaction was complete, the filtrate was filtered and purified with a high-performance liquid phase (trifluoroacetic acid / acetonitrile / water) to obtain 6-(3-{3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl}prop-1-inyl)-1,2-diazine-3-carboxylic acid (5.1 mg, 0.01 mmol, 18.20%) as a yellow solid.

[0120] 1 H NMR (400 MHz, MeOD) δ 8.14 - 8.05 (m, 1H), 7.98 (d, J = 9.2 Hz, 2H), 7.91 (s, 1H), 7.25 (d, J = 9.3 Hz, 4H), 7.07 - 6.91 (m, 1H), 6.71 (d, J = 4.6 Hz, 1H), 4.60 - 4.46 (m, 1H), 3.05 - 2.85 (m, 2H), 2.50 - 2.31 (m, 1H), 2.28 - 2.01 (m, 1H). LCMS: m / z (M+H) + = 552.2.

[0121] Example 22: Synthesis of 6-(3-{3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl}prop-1-inyl)-1,2-diazine-3-carboxamide [ka]

[0122] To a solution of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (30 mg, 0.07 mmol) in DMF (1 mL) were added 6-chloro-1,2-diazine-3-carboxamide (13 mg, 0.08 mmol), Pd(PPh3)4 (8.07 mg, 0.01 mmol), TEA (0.03 mL, 0.21 mmol), and CuI (2.66 mg, 0.01 mmol) at 20 °C. The reaction mixture was degassed three times with N2 and stirred at 70 °C for 4 h under N2. Upon completion, the mixture was filtered and the filtrate was purified by pre-HPLC (FA conditions) to afford 6-(3-{3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl}prop-1-ynyl)-1,2-diazine-3-carboxamide (4.75 mg, 0.01 mmol, 12.35%) as a white solid.

[0123] 1 H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.6 Hz, 1H), 7.98 (m, 2H), 7.91 - 7.81 (m, 2H), 7.62 (d, J = 8.6 Hz, 1H), 7.48 (dd, J = 4.9, 8.8 Hz, 1H), 7.14 (m, 1H), 7.05 (dd, J = 2.9, 8.4 Hz, 1H), 5.86 (s, 1H), 5.04 (d, J = 17.7 Hz, 1H), 4.77 (d, J = 17.7 Hz, 1H), 4.23 (dd, J = 7.0, 12.3 Hz, 1H), 3.22 (m, 1H), 2.87 - 2.60 (m, 2H), 2.28 (m, 1H). LCMS: m / z (M+H) + =551.2.

[0124] Example 23: Synthesis of 3-[2,4-bis(trifluoromethyl)phenyl]-1-[3-(6-chloro-1,2-diazine-3-yl)prop-2-inyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one [ka]

[0125] To a solution of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-inyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (40 mg, 0.09 mmol) in DMF (2 mL), 3-bromo-6-chloropyridazine (21.63 mg, 0.11 mmol), triethylamine (0.03 mL, 0.19 mmol), copper(I) iodide (1.77 mg, 0.01 mmol), and Pd(PPh3)4 (5.38 mg) were added under N2 conditions at 25°C, and the mixture was stirred at 70°C for 4 hours. Upon completion, the mixture was concentrated under reduced pressure. The crude product was purified by p-TLC (petroleum ether: siRNA = 1:2) to obtain 3-[2,4-bis(trifluoromethyl)phenyl]-1-[3-(6-chloro-1,2-diazine-3-yl)prop-2-inyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (50 mg, 0.08 mmol, 89.14%) as a white solid.

[0126] 1 H NMR (400 MHz, DMSO) δ 8.14 (s, 1H), 7.96 (d, J = 9.1 Hz, 2H), 7.81 (d, J = 8.9 Hz, 1H), 7.68 (m, 1H), 7.44 - 7.39 (m, 1H), 7.33 (m, 2H), 5.09 (m, 1H), 4.83 (m, 1H), 4.05 (m), 3.05 (m, 1H), 2.95 - 2.76 (m, 2H), 2.27 - 2.12 (m, 1H). LCMS: m / z (M+H) + = 542.2.

[0127] Experimental example: Inhibitory activity against Polθ The inhibitory activity of the compounds prepared in the examples against Polθ was measured as follows.

[0128] The inhibitory activity of the compound against Polθ was measured in vitro using the PicoGreen assay. Recombinant Polθ-polymerase domains (aa1819-2590) were manufactured by ChemPartner and stored in preparative quantities at -80°C. Test measurements were performed using a 1X buffer containing 25 mM Tris HCl pH 7.5, 12.5 mM NaCl, 0.5 mM MgCl2, 5% glycerol, 0.01% Triton X-100, 0.01% BGG, and 1 mM DTT. The test compound was diluted with 100% DMSO to have the correct volume range and appropriate volume (20 nL) for the concentration reaction at the 10p point, and then dispensed into a 384-well microassay plate (Greiner small volume black plate product code 784076) using a Labcyte Echo 655 acoustic dispenser. At this time, the DMSO concentration was maintained at 0.2% by back-filling with DMSO solution. 5 μL of purified recombinant Polθ was diluted to 2X working concentration (6 nM Polθ) in analytical buffer. This was divided into each well of a compound plate using a VIAFLO 16-channel manual pipette (Integra) and pre-cultured at room temperature (RT) for 15 minutes. 5 μL of 2X working concentration dNTPs (40 μM) (Thermo#R1121) and primer (60 nM PTD) (5'-GCG GCT GTC ATA AG-3' (SEQ5 ID NO:1)):template (5'-GCT ACA TTG ACA ATG GCA TCA AAT CTC AGA TTG CGT CTT ATG ACA GCC GCG-3' (SEQ ID NO:2)) duplex (1:1.1) was diluted in test buffer, and the reaction mixture was cultured at room temperature for 60 minutes. The reaction was interrupted by adding a 1:80 diluted solution of 10 mM EDTA, 25 mM Tris pH 7.5, and PicoGreen dye (Invitrogen P7581).After 90 minutes in the dark at room temperature, fluorescence values ​​were read using a 2105-0020 Envision Microwave Ltilabel Reader with a 485 / 535 nm module, and the raw data was analyzed using log(inhibitor) vs. response-variable gradient (4 parameters) for IC. 50 The values ​​were calculated. The results are shown in Table 1 below.

[0129] [Table 1]

Claims

1. A compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 In chemical formula 1, X is CH or N, R １ C １－４ Alkyl, C １－４ Alkoxy, C ３－６ It is a cycloalkyl, halogen, or cyano, R ２ is hydrogen or halogen, R ３ These are, independently, hydrogen or halogen, R ４ is C １－４ haloalkyl, or C ３－６ cycloalkyl, and R ５ C １－４ Alkyl, C １－４ Haloalkyl, C ３－６ It is a cycloalkyl or halogen, R ６ is hydrogen, C １－４ Alkyl, -CH ２ -C≡N, or -CH ２ -C≡C-L-R ７ And, L is a bond, -CH ２ -ien-CH ２ CH ２ -ien-CH ２ -O-, -CH ２ -NHCO-, -CH ２ -N(isopropyl)-CH(CH ３ ) - Phenylene or pyridinediyl, R ７ is hydrogen, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl, C １－４ Haloalkoxy, C ３－６ Cycloalkyl, hydroxy, amino, (C １－４ Alkyl)amino, di(C) １－４ Alkyl)amino, C ６－１０ An aryl, a 3- to 8-membered heterocycloalkyl containing at least one nitrogen or oxygen as a ring element, or a 3- to 8-membered heteroaryl containing at least one nitrogen, oxygen or sulfur as a ring element, The aforementioned R ７ In C ６－１０ Aryl, 3- to 8-membered heterocycloalkyl, or 3- to 8-membered heteroaryl is unsubstituted or C １－４ Alkyl, C １－４ Alkoxy, hydroxy, halogen, amino, (C １－４ Alkyl)amino, di(C) １－４ Alkyl)amino, -NHCO(C １－４ Alkyl), -NHCO(C １－４ Haloalkyl), -NHSO ２ (C １－４ Alkyl), -N (SO ２ (C １－４ Alkyl)) ２ , -SO ２ (C １－４ Alkyl), -SO ２ (NH ２ ), -CH ２ SO ２ (C １－４ Alkyl), -CH ２ SO ２ (NH ２ ), -CH(CH ３ )CO(NH ２ ), -COOH, -CONH ２ It is substituted with azetidine, morpholino, oxetanil, piperazinil, or piperidinil.

2. R １ These are methyl, methoxy, cyclopropyl, fluoro, or cyano compounds. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. R ２ is hydrogen, fluoro, or chloro. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. R ３ These are, independently, hydrogen or fluoro. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. R ４ It is trifluoromethyl or cyclopropyl. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. R ５ These are methyl, trifluoromethyl, cyclopropyl, or chloro. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. R ６ is hydrogen, methyl, or -CH ２ -C ≡ N, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. R ７ These are hydrogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyclopentyl, cyclohexyl, hydroxy, amino, methylamino, dimethylamino, phenyl, piperidinyl, tetrahydropyranyl, oxadiazolyl, pyrazinyl, pyrazolyl, pyridadinyl, 6-oxo-1,6-dihydropyridinyl, pyrimidinyl, or thiadiazolyl. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. The aforementioned R ７ Phenyl, piperidinyl, tetrahydropyranyl, oxadiazolyl, pyrazinyl, pyrazolyl, pyridadinyl, 6-oxo-1,6-dihydropyridinyl, pyrimidinyl, or thiadiazolyl may be unsubstituted or methyl, methoxy, hydroxy, chloro, amino, methylamino, dimethylamino, -NHCO(methyl), -NHCO(trifluoromethyl), -NHSO ２ (methyl), -N(SO ２ (methyl) ２ , -SO ２ (methyl), -SO ２ (NH ２ ), -CH ２ SO ２ (methyl), -CH ２ SO ２ (NH ２ ), -CH(CH ３ )CO(NH ２ ), -COOH, -CONH ２ Substituted with azetidine, morpholino, oxetanil, piperazinil, or piperazinil. The compound according to claim 8, or a pharmaceutically acceptable salt thereof.

10. The aforementioned chemical formula 1 is represented by the following chemical formula 1-1: The compound according to claim 1, or a pharmaceutically acceptable salt thereof. 【Chemistry 2】 In chemical formula 1-1, X is CH or N, R ２ is hydrogen or fluorine, R ８ These are hydrogen, oxadiazolyl, pyrazinyl, pyrazolyl, pyridadinyl, 6-oxo-1,6-dihydropyridinyl, or pyrimidinyl. said R ８ wherein oxadiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 6 - oxo - 1,6 - dihydropyridinyl, or pyrimidinyl is unsubstituted or substituted with methyl, methoxy, hydroxy, chloro, amino, - NHS ２ (methyl), - N(SO ２ (methyl)) ２ , - CH ２ SO ２ (methyl), - COOH, - CONH ２ , or morpholino.

11. The compound represented by the aforementioned chemical formula 1 is 1) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 2) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 3) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(pyridazin-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 4) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-methyl-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 5) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 6) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-oxo-1,6-dihydropyridine-2-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 7) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(3,5-bis(trifluoromethyl)pyridine-2-yl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 8) 1-(3-(2-aminopyrimidine-5-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 9) 1-(3-(5-aminopyrazine-2-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 10) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(1-(methylsulfonylmethyl)-1H-pyrazole-4-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 11) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-morpholinopyridazine-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 12) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7,8-difluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 13) 2-(3-(2,4-bis(trifluoromethyl)phenyl)-7,8-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)acetonitrile, 14) (R)-N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-inyl)pyridazine-3-yl)methanesulfonamide, 15) (R)-N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-inyl)pyridazin-3-yl)-N-(methylsulfonyl)methanesulfonamide, 16) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(5-methyl-1,3,4-oxadiazole-2-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 17) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-methoxypyridazin-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 18) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 19) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-hydroxypyridazin-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 20) 1-(3-(5-amino-1,3,4-oxadiazole-2-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 21) 6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-inyl)pyridazine-3-carboxylic acid, 22) 6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-inyl)pyridazine-3-carboxamide, 23) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-(6-chloropyridazine-3-yl)prop-2-inyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 24) 3-(2,4-bis(trifluoromethyl)phenyl)-7,8-difluoro-1-(3-(1-(methylsulfonylmethyl)-1H-pyrazole-4-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 25) 1-(3-(6-(azetidine-3-yl)pyridazin-3-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 26) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(piperidine-4-yl)pyridazin-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 27) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(piperazine-1-yl)pyridazin-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 28) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-8-chloro-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 29) 6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-inyl)pyridazine-3-sulfonamide, 30) (6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-inyl)pyridazine-3-yl)methanesulfonamide, 31) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(methylsulfonylmethyl)pyridazin-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 32) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(methylsulfonyl)pyridazin-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 33) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-carbonitrile, 34) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(4-chloro-2-(trifluoromethyl)phenyl)-7-cyclopropyl-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 35) N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-inyl)pyridazine-3-yl)methanesulfonamide, 36) N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-inyl)pyridazine-3-yl)acetamide, 37) N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-inyl)pyridazine-3-yl)-2,2,2-trifluoroacetamide, 38) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-phenylprop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 39) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(4-methoxyphenyl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 40) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-methyl-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 41) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-methoxy-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 42) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-cyclopropyl-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 43) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-7-cyclopropyl-3-(4-methyl-2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 44) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-(6-(dimethylamino)pyridazin-3-yl)prop-2-inyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 45) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(methylamino)pyridazin-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 46) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-7-cyclopropyl-3-(4-cyclopropyl-2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 47) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)buto-2-inyl)acetamide, 48) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)buto-2-inyl)nicotinamide, 49) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)buto-2-inyl)-5-methyl-1,3,4-oxadiazole-2-carboxamide, 50) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)buto-2-inyl)benzamide, 51) 1-(3-(6-aminopyridazine-3-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-5,5,7-trifluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 52) 1-(3-(1-(azetidine-3-yl)-1H-pyrazole-4-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 53) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(1-methyl-1H-pyrazole-4-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 54) 2-(4-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)prop-1-inyl)-1H-pyrazole-1-yl)propanamide, 55) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4,4,4-trifluorobuto-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 56) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(buto-2-inyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 57) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-cyclohexylprop-2-inyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 58) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-cyclopentylprop-2-inyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 59) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(tetrahydro-2H-pyran-4-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 60) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(piperidine-4-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 61) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(4-hydroxycyclohexyl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 62) 1-(3-(4-aminocyclohexyl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 63) 1-(4-aminobuto-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 64) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(4-(dimethylamino)buto-2-inyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 65) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-hydroxybuto-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 66) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-methoxybuto-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 67) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-(trifluoromethoxy)buto-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 68) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(pyridine-2-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 69) 1-(3-(1,3,4-thiadiazole-2-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 70) 1-(3-(5-amino-1,3,4-thiadiazole-2-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 71) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(oxetan-3-yl)pyridazin-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 72) 1-(3-(1,3,4-oxadiazole-2-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 73) 1-(3-(5-amino-1,3,4-oxadiazole-2-yl)prop-2-inyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 74) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(1-(oxetan-3-yl)-1H-pyrazole-4-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 75) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-(pyridazine-3-yloxy)buto-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 76) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(5-(6-methylpyridazin-3-yl)pento-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 77) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(4-(6-methylpyridazin-3-yl)phenyl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 78) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-(isopropyl(1-(6-methylpyridazine-3-yl)ethyl)amino)buto-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one, 79) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)buto-2-inyl)-1,3,4-oxadiazole-2-carboxamide, 80) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)buto-2-inyl)-1,3,4-thiadiazole-2-carboxamide, and 81) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(6-methylpyridazin-3-yl)pyridine-3-yl)prop-2-inyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one It is one of the groups selected from the group consisting of The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition for the prevention or treatment of cancer, comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

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