Novel heterocyclic compound as pol theta inhibitor for treating and preventing cancer and pharmaceutical composition containing same

Abstract

The present invention relates to a novel heterocyclic compound represented by Chemical Formula 1 and a pharmaceutical composition containing the same, the compound according to the present invention being effective for preventing or treating cancer. [Chemical Formula 1] # imgabs0 # In 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 a Polθ (DNA Polymerase theta, Pol-theta) inhibitor and a pharmaceutical composition containing the compound. Background Art

[0002] Targeting DNA repair defects is a proven effective strategy for cancer treatment. However, cancers caused by DNA repair defects often rely on alternate DNA repair pathways that represent an "Achilles' heel" that can be targeted for cancer cell elimination and the basis for synthetic lethality. This 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] Robust repair of DNA double-strand breaks (DSBs) is essential for maintaining genome stability and cell viability. DSBs can be repaired by one of three major pathways: homologous recombination (HR), non-homologous end-joining (NHEJ), and alternative-NHEJ (alt-NHEJ). Microhomology-mediated end-joining (MMEJ) is the best characterized alternative-NHEJ mechanism.

[0004] On the other hand, many genetic studies have highlighted the role of Polθ in stimulating MMEJ in higher organisms. In particular, cancer cells lacking HR, NHEJ or ATM (Ataxia-telangiectasia mutated; A-Tmutated) were found to be highly dependent on Polθ expression. Polθ expression is almost absent in normal cells but is upregulated in breast, lung and ovarian cancers. In addition, increased Polθ expression is associated with poor prognosis in breast cancer. Importantly, Polθ is highly repressed in normal tissues but upregulated in relevant cancer samples, suggesting that high expression is associated with the disease. In addition, inhibition or suppression of Polθ confers radiation sensitivity in tumor cells. In addition, suppression of Polθ can prevent the MMEJ-dependent functional reversal of BRCA2 mutations, which is the basis for the emergence of cisplatin and PARPi resistance in tumors. Therefore, Polθ is an attractive target for novel synthetic lethal therapies in cancers with DNA repair defects, and it is necessary to provide effective Polθ inhibitors to treat cancer.

[0005] Therefore, the present inventors studied new compounds and found that compounds having a chemical structure different from the Polθ inhibitors reported so far have excellent Polθ inhibitory effects, thereby completing the present invention. Although the compounds belonging to the present invention themselves mainly have Polθ inhibitory activity, the possibility that they exhibit pharmacological effects as agonists due to special in vivo environments or products of metabolic processes after being absorbed in the body cannot be excluded. Summary of the invention

[0006] Technical issues

[0007] The present invention aims to provide a novel heterocyclic compound useful as a Polθ inhibitor and a pharmaceutical composition containing the compound.

[0008] Technical Solution

[0009] 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:

[0010] [Chemical formula 1]

[0011]

[0012] In the above chemical formula 1,

[0013] X is CH or N,

[0014] R1 is C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, halogen or cyano,

[0015] R2 is hydrogen or halogen,

[0016] R3 are each independently hydrogen or halogen,

[0017] R4 is C 1-4 Haloalkyl or C 3-6 Cycloalkyl,

[0018] R5 is C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl or halogen,

[0019] R6 is hydrogen, C 1-4 Alkyl, -CH2-C≡N or -CH2-C≡CL-R7,

[0020] L is a bond, -CH2-, -CH2CH2-, -CH2-O-, -CH2-NHCO-, -CH2-N(isopropyl)-CH(CH3), phenylene or pyridinediyl,

[0021] R7 is hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, hydroxyl, amino, (C 1-4 alkyl)amino, di(C 1-4 Alkyl)amino, C 6-10 aryl, a 3- to 8-membered heterocycloalkyl group containing at least one nitrogen or oxygen as a ring constituent element, or a 3- to 8-membered heteroaryl group containing at least one nitrogen, oxygen or sulfur as a ring constituent element,

[0022] The R7C 6-10 Aryl, 3- to 8-membered heterocycloalkyl or 3- to 8-membered heteroaryl is unsubstituted or replaced by 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), -NHSO2(C 1-4 Alkyl), -N(SO2(C 1-4 Alkyl))2, -SO2(C 1-4 alkyl), -SO2(NH2), -CH2SO2(C 1-4alkyl), -CH2SO2(NH2), -CH(CH3)CO(NH2), -COOH, -CONH2, azetidinyl, morpholinyl, oxetanyl, piperazinyl or piperidinyl.

[0023] In addition, in order to solve the above-mentioned problems, the present invention provides a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof.

[0024] In addition, in order to solve the above-mentioned problems, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising the compound or a pharmaceutically acceptable salt thereof.

[0025] Beneficial Effects

[0026] The compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention may be effectively used for preventing or treating cancer. DETAILED DESCRIPTION

[0027] Hereinafter, the present invention will be described in more detail to facilitate understanding of the present invention.

[0028] In another aspect, the present invention provides a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0029] Preferably, R1 is methyl, methoxy, cyclopropyl, fluorine or cyano. Preferably, R2 is hydrogen, fluorine or chlorine. Preferably, R1 is fluorine and R2 is hydrogen or fluorine.

[0030] Preferably, R3 is each independently hydrogen or fluorine. Preferably, R3 is hydrogen.

[0031] Preferably, R4 is trifluoromethyl or cyclopropyl. Preferably, R5 is methyl, trifluoromethyl, cyclopropyl or chloro. Preferably, R4 and R5 are trifluoromethyl.

[0032] Preferably, R6 is hydrogen, methyl or -CH2-C≡N.

[0033] Preferably, R7 is hydrogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyclopentyl, cyclohexyl, hydroxy, amino, methylamino, dimethylamino, phenyl, piperidinyl, tetrahydropyranyl, oxadiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 6-oxo-1,6-dihydropyridinyl, pyrimidinyl or thiadiazolyl. Preferably, the phenyl, piperidinyl, tetrahydropyranyl, oxadiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 6-oxo-1,6-dihydropyridinyl, pyrimidinyl or thiadiazolyl of R7 is unsubstituted or substituted by methyl, methoxy, hydroxyl, chlorine, 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, azetidinyl, morpholinyl, oxetanyl, piperazinyl or piperidinyl.

[0034] Preferably, the above chemical formula 1 is represented by the following chemical formula 1-1:

[0035] [Chemical formula 1-1]

[0036]

[0037] In the above chemical formula 1-1,

[0038] X is CH or N,

[0039] R2 is hydrogen or fluorine,

[0040] R8 is hydrogen, oxadiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 6-oxo-1,6-dihydropyridinyl or pyrimidinyl,

[0041] The oxadiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 6-oxo-1,6-dihydropyridinyl or pyrimidinyl in R8 is unsubstituted or substituted by methyl, methoxy, hydroxyl, chlorine, amino, -NHSO2(methyl), -N(SO2(methyl))2, -CH2SO2(methyl), -COOH, -CONH2 or morpholinyl.

[0042] Typical examples of the compound represented by Chemical Formula 1 are as follows:

[0043] 1) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0044] 2) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0045] 3) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(pyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0046] 4) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-methyl-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0047] 5) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0048] 6) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-oxo-1,6-dihydropyridin-2-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0049] 7) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(3,5-bis(trifluoromethyl)pyridin-2-yl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0050] 8) 1-(3-(2-aminopyrimidin-5-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0051] 9) 1-(3-(5-aminopyrazin-2-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0052] 10) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(1-(methylsulfonylmethyl)-1H-pyrazol-4-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0053] 11) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-morpholinopyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0054] 12) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7,8-difluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0055] 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,

[0056] 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-ynyl)pyridazin-3-yl)methanesulfonamide,

[0057] 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-ynyl)pyridazin-3-yl)-N-(methylsulfonyl)methanesulfonamide,

[0058] 16) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(5-methyl-1,3,4-oxadiazol-2-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0059] 17) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-methoxypyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0060] 18) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0061] 19) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-hydroxypyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0062] 20) 1-(3-(5-amino-1,3,4-oxadiazol-2-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0063] 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-ynyl)pyridazine-3-carboxylic acid,

[0064] 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-ynyl)pyridazine-3-carboxamide,

[0065] 23) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-(6-chloropyridazin-3-yl)prop-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0066] 24) 3-(2,4-bis(trifluoromethyl)phenyl)-7,8-difluoro-1-(3-(1-(methylsulfonylmethyl)-1H-pyrazol-4-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0067] 25) 1-(3-(6-(azetidin-3-yl)pyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0068] 26) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(piperidin-4-yl)pyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0069] 27) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(piperazin-1-yl)pyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0070] 28) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-8-chloro-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0071] 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-ynyl)pyridazine-3-sulfonamide,

[0072] 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-ynyl)pyridazin-3-yl)methanesulfonamide,

[0073] 31) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(methylsulfonylmethyl)pyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0074] 32) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(methylsulfonyl)pyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0075] 33) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine -7-carbonitrile,

[0076] 34) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(4-chloro-2-(trifluoromethyl)phenyl)-7-cyclopropyl-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0077] 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-ynyl)pyridazin-3-yl)methanesulfonamide,

[0078] 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-ynyl)pyridazin-3-yl)acetamide,

[0079] 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-ynyl)pyridazin-3-yl)-2,2,2-trifluoroacetamide,

[0080] 38) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-phenylprop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0081] 39) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(4-methoxyphenyl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0082] 40) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-methyl-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0083] 41) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-methoxy-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0084] 42) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-cyclopropyl-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0085] 43) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-7-cyclopropyl-3-(4-methyl-2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0086] 44) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-(6-(dimethylamino)pyridazin-3-yl)prop-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0087] 45) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(methylamino)pyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0088] 46) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-7-cyclopropyl-3-(4-cyclopropyl-2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0089] 47) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine -1-yl)but-2-ynyl)acetamide,

[0090] 48) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine -1-yl)but-2-ynyl)nicotinamide,

[0091] 49) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine -1-yl)but-2-ynyl)-5-methyl-1,3,4-oxadiazole-2-carboxamide,

[0092] 50) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine -1-yl)but-2-ynyl)benzamide,

[0093] 51) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-5,5,7-trifluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0094] 52) 1-(3-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0095] 53) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(1-methyl-1H-pyrazol-4-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0096] 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-ynyl)-1H-pyrazol-1-yl)propanamide,

[0097] 55) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4,4,4-trifluorobut-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0098] 56) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(but-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0099] 57) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-cyclohexylprop-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0100] 58) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-cyclopentylprop-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0101] 59) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(tetrahydro-2H-pyran-4-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0102] 60) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(piperidin-4-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0103] 61) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(4-hydroxycyclohexyl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0104] 62) 1-(3-(4-aminocyclohexyl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0105] 63) 1-(4-aminobut-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0106] 64) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(4-(dimethylamino)but-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0107] 65) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-hydroxybut-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0108] 66) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-methoxybut-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0109] 67) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-(trifluoromethoxy)but-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0110] 68) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(pyridin-2-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0111] 69) 1-(3-(1,3,4-thiadiazol-2-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0112] 70) 1-(3-(5-amino-1,3,4-thiadiazol-2-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0113] 71) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(oxetane-3-yl)pyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0114] 72) 1-(3-(1,3,4-oxadiazol-2-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0115] 73) 1-(3-(5-amino-1,3,4-oxadiazol-2-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0116] 74) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0117] 75) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-(pyridazin-3-yloxy)but-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0118] 76) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(5-(6-methylpyridazin-3-yl)pent-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0119] 77) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(4-(6-methylpyridazin-3-yl)phenyl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0120] 78) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-(isopropyl(1-(6-methylpyridazin-3-yl)ethyl)amino)but-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone,

[0121] 79) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine -1-yl)but-2-ynyl)-1,3,4-oxadiazole-2-carboxamide,

[0122] 80) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine -1-yl)but-2-ynyl)-1,3,4-thiadiazole-2-carboxamide, and

[0123] 81) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(6-methylpyridazin-3-yl)pyridin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone.

[0124] In addition, the compounds of the present invention may exist in the form of salts, particularly in the form of pharmaceutically acceptable salts. As salts, salts commonly used in the art, such as acid addition salts formed by pharmaceutically acceptable free acids (free acids) may be used without restriction. The term "pharmaceutically acceptable salt" of the present invention refers to any organic or inorganic addition salt of the compound whose side effects caused by the salt at a concentration having a relatively nontoxic and harmless effective effect on the patient will not reduce the beneficial effects of the compound represented by Chemical Formula 1.

[0125] As the free acid, organic acid and inorganic acid can be used, as inorganic acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used, as 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 not limited thereto. Preferably, the salt can be a hydrochloride.

[0126] In addition, pharmaceutically acceptable metal salts can be obtained by conventional methods using a base. For example, the compound represented by Chemical Formula 1 is dissolved in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, undissolved compound salts are filtered, and the filtrate is evaporated and dried to obtain a pharmaceutically acceptable metal salt. At this time, as the metal salt, it is particularly preferred to prepare a sodium salt, a potassium salt or a calcium salt.

[0127] In addition, a non-pharmaceutically acceptable salt or solvate of the compound represented by Chemical Formula 1 may be used as an intermediate for preparing the compound represented by Chemical Formula 1, a pharmaceutically acceptable salt or solvate thereof.

[0128] In one embodiment, the compound represented by Chemical Formula 1 can be prepared by Reaction Formula 1 below.

[0129] [Reaction 1]

[0130]

[0131] In the above reaction formula 1, X, and R1 to R6 are as defined above, and X' is a halogen. Preferably, X' is bromine or chlorine.

[0132] The step 1 is a step of preparing a compound represented by Chemical Formula 3' by reacting a compound represented by Chemical Formula 1' with a compound represented by Chemical Formula 2'. The reaction is preferably carried out in the presence of a palladium catalyst such as Pd2(dba)3.

[0133] The step 2 is a step of preparing a compound represented by Chemical Formula 4' by reacting the compound represented by Chemical Formula 3' with hydroxylamine (NH2OH).

[0134] The step 3 is a step of preparing the compound represented by the chemical formula 5' by using the compound represented by the chemical formula 4' through Beckmann rearrangement reaction. The reaction is preferably carried out in the presence of polyphosphoric acid.

[0135] The step 4 is a step of preparing the compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 5' with NaH and R6-X" (wherein R6 is as defined above except for hydrogen and X" is a halogen. Preferably, X" is bromine or chlorine).

[0136] The preparation method can be further specifically implemented in the following examples.

[0137] According to another embodiment of the present invention, a pharmaceutical composition is provided, which includes the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0138] According to another embodiment of the present invention, there is provided a pharmaceutical composition for preventing or treating cancer diseases which facilitates Pol θ inhibition, comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0139] In this case, the cancer can be a blood cancer, extranodal marginal zone B-cell lymphoma, glioblastoma, lymphoplasmacytic lymphoma, acute myeloid leukemia, macroglobulinemia, B-cell lymphoma, chronic lymphocytic leukemia, follicular lymphoma, non-Hodgkin's 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 epithelial carcinoma, carcinoid tumor, breast cancer, non-small cell lung cancer or multiple myeloma.

[0140] The term "prevention" of the present invention refers to any action of inhibiting or delaying the occurrence, spread or recurrence of the disease by administering the composition of the present invention, and "treatment" refers to any action of improving or beneficially changing the symptoms of the disease by administering the composition of the present invention.

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

[0142] Suitable carriers include physiological saline, polyethylene glycol, ethanol, vegetable oil and isopropyl myristate, etc., and diluents include lactose, glucose, sucrose, mannitol, sorbitol, cellulose and / or glycine, etc., but are not limited thereto. In addition, the compound of the present invention can be dissolved in oil, propylene glycol or other solvents that are generally used to prepare injection solutions. In addition, the compound of the present invention can be formulated into ointments or creams for local action.

[0143] The preferred dosage of the compounds of this invention depends on the patient's condition and body weight, the degree of the disease, the form of the medicine, the route of administration and the duration, but can be appropriately selected by those skilled in the art. However, for the desired effect, the compounds of this invention are preferably administered in an amount of 0.0001 to 100 mg / kg (body weight) per day, preferably in an amount of 0.001 to 100 mg / kg (body weight) per day. Can be administered by oral or parenteral route, once a day or in divided doses.

[0144] 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, depending on the administration method.

[0145] The pharmaceutical composition according to the present invention can be administered to mammals including rats, mice, livestock and humans by various routes. Any mode of administration can be envisioned, such as oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine or intracerebroventricular administration.

[0146] Hereinafter, the present invention will be described in more detail by the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited to the following examples.

[0147] Example 1: 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone

[0148]

[0149] Step A: Synthesis of 2-[2,4-bis(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (2)

[0150] Under N2, Pd2(dba)3 (250.99 mg, 0.27 mmol), tetrafluoro-λ5-boranuide tri(2-methylprop-2-yl)phosphine (316.99 mg, 1.10 mmol) and NaOH (146.18 mg, 3.65 mmol) were added 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) under N2. The mixture was stirred at 100°C for 2 hours under N2 to obtain a brown solution. After completion, the mixture was diluted with EtOAc (100 mL) and washed with H2O (50 mL*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: EtOAc = 100: 1 to 10: 1) to give 2-[2,4-bis(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (370 mg, 0.98 mmol, 53.82%) as a white solid.

[0151] LCMS: m / z(M+H) + =377.2

[0152] Step B: Synthesis of [(1Z)-2-[2,4-bis(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydro-1-naphthylene]hydroxylamine (3)

[0153] At 25°C, sodium acetate (161.33 mg, 1.97 mmol) was added to a solution of [2,4-bis(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (370 mg, 0.98 mmol) and hydroxylamine hydrochloride (102.50 mg, 1.48 mmol) in MeOH (50 mL), and stirred at 60°C for 2 hours to obtain a yellow solution. After completion, the mixture was quenched with H2O (100 mL) in an ice bath and extracted with EtOAc (200 mL*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-fluoro-1,2,3,4-tetrahydro-1-naphthylene]hydroxylamine (350 mg, 0.89 mmol, 90.96%) as a yellow solid.

[0154] LCMS: m / z(M+H) + =392.2

[0155] Step C: 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone

[0156] [(1Z)-2-[2,4-bis(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydro-1-naphthylene]hydroxylamine (350 mg, 0.89 mmol) and polyphosphoric acid (1.96 mL, 49.20 mmol) were stirred at 120 ° C under N2 for 1 hour to obtain a brown solution. After completion, the mixture was quenched with H2O (100 mL) at 0 ° C and extracted with EtOAc (100 mLx3). 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-ketone (50 mg, 0.13 mmol, 14.29%) as a white solid.

[0157] 1 H NMR(400MHz, CDCl3) δ7.93(d,J=8.3Hz,1H),7.89-7.81(m,2H),7.33(s,1H),7.04(dd,J=6.8,4.2Hz,3H),4 .18(dd,J=12.3,7.3Hz,1H),3.15(m,J=7.7Hz,1H),2.82(m,J=6.9Hz,1H),2.64-2.52(m,1H),2.36(m,1H).

[0158] LCMS: m / z(M+H) + =392.2

[0159] Example 2: 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone

[0160]

[0161] In an ice bath under N2, 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine was added. NaH (4.60 mg, 0.12 mmol, purity 60%) was added to a solution of -2-ketone (30 mg, 0.08 mmol) in THF (5 mL). After the mixture was stirred at 0°C for 1 hour, 3-bromoprop-1-yne (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. After completion, the mixture was quenched with H2O (20 mL) in an ice bath and extracted with EtOAc (20 mL*2). The combined organic layers were 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-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine -2-ketone (11 mg, 0.03 mmol, 33.41%) as a white solid.

[0162] 1 H NMR(400MHz, CDCl3)δ7.99(d,J=8.2Hz,1H),7.89-7.79(m,2H),7.40(dd,J=8.8,4.9 Hz,1H),7.10(td,J=8.4,2.9Hz,1H),7.01(dd,J=8.5,2.9Hz,1H),4.75(dd,J=17.3,2 .5Hz,1H),4.39(dd,J=17.3,2.4Hz,1H),4.17(m,J=12.3,7.0Hz,1H),3.13(m,J=13.4 ,7.7Hz,1H),2.75(dd,J=13.7,6.7Hz,1H),2.62(m,J=7.6Hz,1H),2.32-2.17(m,2H).

[0163] LCMS: m / z(M+H) + =430.2

[0164] Example 3: 3-[2,4-bis(trifluoromethyl)phenyl]-1-[3-(1,2-diazin-3-yl)prop-2-ynyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone

[0165]

[0166] At 25°C under N2, 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine was added. Pd(PPh3)4(1.35mg), CuI(0.44mg) and TEA(0.01mL, 0.05mmol) were added to a DMF(3mL) solution of -2-ketone(10mg, 0.02mmol) and 3-bromo-1,2-diazine(4.44mg, 0.03mmol). The mixture was stirred at 70°C for 4 hours to obtain a brown solution. After completion, the mixture was washed with saturated aqueous NH4Cl(10mL) and extracted with EtOAc(10mL*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-ynyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine -2-one (4.72 mg, 0.01 mmol, 36.74%) as a brown solid.

[0167] 1 H NMR (400MHz, CDCl3) δ7.98(d,J=8.3Hz,1H),7.90-7.81(m,2H),7.58(d,J=77.9Hz,4H),7.12(s,1H),7.03(d,J=8.6Hz,1H),4.99(d,J=17.6Hz,1H ),4.76(d,J=17.5Hz,1H),4.21(m,J=12.2,7.0Hz,1H),3.19(m,J=16.0Hz ,1H),2.79(m,J=12.9,6.5Hz,1H),2.71-2.61(m,1H),2.31-2.18(m,1H).

[0168] LCMS: m / z(M+H) + =508.1

[0169] Example 4: 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone

[0170]

[0171] In an ice bath, 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine NaH (0.43 mg, 0.01 mmol) was added to a solution of -2-ketone (2.8 mg, 0.01 mmol) in THF (1 mL). After the mixture was stirred at 0°C for 0.5 hours, 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. After completion, the mixture was quenched with H2O (20 mL) in an ice bath and extracted with EtOAc (20 mL*2). The combined organic layers were 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%).

[0172] 1 H NMR(400MHz, CDCl3) δ7.96(d,J=8.3Hz,1H),7.88-7.79(m,2H),7.27-7.20(m,1H),7.08(td,J=8.4,2.9Hz,1H),6.98(dd,J=8.5,2 .9Hz,1H),4.16(m,1H),3.36(s,3H),3.01(dt,J=13.3,6.7Hz,1H),2.75(m,1H),2.66-2.53(m,1H),2.23(dt,J=12.9,6.3Hz,1H).

[0173] LCMS: m / z(M+H) + =406.2

[0174] Example 5: 1-[3-[3-(6-amino-1,2-diazin-3-yl)prop-2-ynyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone

[0175]

[0176] At 25°C under N2, 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine was added. Pd(PPh3)4(67.29mg, 0.06mmol), CuI(22.18mg, 0.12mmol) and TEA(0.32mL, 2.33mmol) were added to a DMF(10mL) solution of -2-ketone(500mg, 1.16mmol) and 6-bromo-1,2-diazine-3-amine(243mg, 1.40mmol). The mixture was stirred at 70°C for 4 hours to obtain a brown solution. After completion, the mixture was diluted with water (300mL), filtered, and the filtrate was extracted with EtOAc(200mL). The organic layer was washed with brine (100mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by HPLC (TFA conditions) to give the racemic compound 1-[3-[3-(6-amino-1,2-diazin-3-yl)prop-2-ynyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine -2-ketone (300 mg, 0.55 mmol, 47.03%) as a white solid.

[0177] 1 H NMR(400MHz, CDCl3)δ7.98(d,J=8.3Hz,1H),7.89-7.80(m,2H),7.47(dd,J=8.8,4.9Hz,1H),7 .20-7.10(m,2H),7.01(dd,J=8.5,2.9Hz,1H),6.73(d,J=9.2Hz,1H),5.34(s,2H),4.95(d,J= 17.5Hz,1H),4.69(d,J=17.5Hz,1H),4.20(dd,J=12.3,7.0Hz,1H),3.19(td,J=13.3,7.6Hz,1 H), 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).

[0178] LCMS: m / z(M+H) + =523.2

[0179] Examples 5-1 and 5-2: (R)-1-(3-(6-aminopyridazin-3-yl)prop-2-yn-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-yn-1-yl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine Synthesis of -2-ketone

[0180]

[0181] The racemic compound 1-[3-[3-(6-amino-1,2-diazin-3-yl)prop-2-ynyl]-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 preparative chiral HPLC under the following conditions: (chromatographic column: ChiralCel OX, 250×30 mm ID, 10 μm; mobile phase: A is CO2, B is ethanol (0.1% NH3H2O); gradient: B 30%; wavelength: 220 nm; sample preparation: the compound was dissolved in about 40 ml of MeOH / DCM; injection: 8 ml per injection; flow rate: 150 mL / min; back pressure: 100 bar) The first peak gave (R)-1-(3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine -2-ketone (Example 5-1) (141.44 mg, 0.26 mmol, 47.15%) (100% ee, t R =0.943), a white solid, and the second peak was (S)-1-(3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine -2-ketone (Example 5-2) (148.74 mg, 0.27 mmol, 49.58%) (100% ee, t R =1.898), a white solid.

[0182] Example 5-1

[0183] 1H NMR (400MHz, CDCl3) δ7.98 (d, J=8.3Hz, 1H), 7.89-7.79 (m, 2H), 7.47 (dd, J=8.8, 4. 9Hz,1H),7.11(ddd,J=10.6,7.0,4.2Hz,2H),7.00(dd,J=8.5,2.9Hz,1H),6.69(d,J =9.1Hz,1H),5.69(s,2H),4.94(d,J=17.4Hz,1H),4.68(d,J=17.5Hz,1H),4.19(dd ,J=12.3,6.9Hz,1H),3.19(td,J=13.4,7.7Hz,1H),2.81-2.59(m,2H),2.24(m,1H).

[0184] LCMS: m / z(M+H) + =523.2

[0185] Example 5-2

[0186] 1 H NMR (400MHz, CDCl3) δ7.98 (d, J=8.3Hz, 1H), 7.89-7.79 (m, 2H), 7.47 (dd, J= 8.8,4.9Hz,1H),7.16-7.06(m,2H),7.00(dd,J=8.5,2.9Hz,1H),6.69(d,J=9 .1Hz,1H),5.63(s,2H),4.94(d,J=17.5Hz,1H),4.69(d,J=17.5Hz,1H),4.1 9(dd,J=12.3,7.0Hz,1H),3.19(m,1H),2.76(dd,J=13.7,6.7Hz,1H),2.65(m 1H),2.24(m,1H).

[0187] LCMS: m / z(M+H) + =523.2

[0188] Example 6: 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-[3-(6-oxo-1H-pyridin-2-yl)prop-2-ynyl]-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone

[0189]

[0190] At 25°C under N2, 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine was added. 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 to a DMF (5 mL) solution of -2-one (50 mg, 0.12 mmol) and 6-bromo-1,2-dihydropyridin-2-one (25.06 mg, 0.14 mmol). The mixture was stirred at 70 ° C for 4 hours to obtain a brown solution. After 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-pyridin-2-yl)prop-2-ynyl]-2,3,4,5-tetrahydro-1H-1-benzazepine -2-ketone (5.43 mg, 0.01 mmol, 8.66%) as a white solid.

[0191] 1 H NMR (400MHz, CDCl3) δ7.97 (d, J = 8.3Hz, 1H), 7.89-7.80 (m, 2H), 7.47 (m, 1H), 7.34 ( m,1H),7.13(m,1H),7.03(dd,J=8.5,2.9Hz,1H),6.55(d,J=9.3Hz,1H),6.30(d,J= 6.9Hz,1H),4.90(d,J=17.7Hz,1H),4.70(d,J=17.6Hz,1H),4.19(m,1H),3.12(dt, J=13.4,6.8Hz,1H),2.78(m,1H),2.71-2.57(m,1H),2.26(dt,J=13.2,6.4Hz,1H).

[0192] LCMS: m / z(M+H) + =523.1

[0193] Example 7: 1-[3-[3-(6-amino-1,2-diazin-3-yl)prop-2-ynyl]-3-[3,5-bis(trifluoromethyl)pyridin-2-yl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone

[0194]

[0195] Step A: Synthesis of 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (2)

[0196] At 20°C under N2, sodium 2-methylpropan-2-ol (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 to a toluene (30 mL) solution of 6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (250 mg, 1.52 mmol) and 2-chloro-3,5-bis(trifluoromethyl)pyridine (759.96 mg, 3.05 mmol) and the mixture was stirred at 70°C under N2 for 24 hours to obtain a brown solution. After completion, the mixture was diluted with EtOAc (100 mL) and washed with H2O (50 mL*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: EtOAc = 0 to 10%) to give 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (40 mg, 0.11 mmol, 6.96%) as a white solid.

[0197] LCMS: m / z(M+H) + =378.2

[0198] Step B: Synthesis of [(1Z)-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-6-fluoro-1,2,3,4-tetrahydro-1-naphthylene]hydroxylamine (3)

[0199] Sodium acetate (26.09 mg, 0.32 mmol) was added to a solution of 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (40 mg, 0.11 mmol) and hydroxylamine hydrochloride (22.10 mg, 0.32 mmol) in MeOH (5 mL), and the mixture was stirred at 80°C for 18 hours to obtain a yellow solution. After completion, the mixture was quenched with H2O (10 mL) in an ice bath and extracted with EtOAc (20 mL*2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain [(1Z)-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-6-fluoro-1,2,3,4-tetrahydro-1-naphthylene]hydroxylamine (40 mg, 0.10 mmol, 96.18%) as a yellow solid.

[0200] LCMS: m / z(M+H) + =393.2

[0201] Step C: 3-[3,5-bis(trifluoromethyl)pyridin-2-yl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone (4)

[0202] [(1Z)-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-6-fluoro-1,2,3,4-tetrahydro-1-naphthylene]hydroxylamine (40 mg, 0.10 mmol) in polyphosphoric acid (0.22 mL, 5.61 mmol) was stirred at 120°C under N2 for 20 minutes to give a brown solution. After completion, the mixture was quenched with H2O (50 mL) at 0°C and extracted with EtOAc (50 mL*3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by TLC (Pet.ether:EtOAc=30%) to give 3-[3,5-bis(trifluoromethyl)pyridin-2-yl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine -2-ketone (10 mg, 0.03 mmol, 25.49%) as a white solid.

[0203] LCMS: m / z(M+H) + =393.2

[0204] Step D: 3-[3,5-bis(trifluoromethyl)pyridin-2-yl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone (5)

[0205] In an ice bath under N2, 3-[3,5-bis(trifluoromethyl)pyridin-2-yl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine was added. NaH (0.92 mg, 0.04 mmol, 30% in oil) was added to a solution of -2-one (10 mg, 0.03 mmol) in THF (5 mL). After the mixture was stirred at 0°C for 1 hour, 3-bromoprop-1-yne (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. After completion, the mixture was quenched with H2O (20 mL) in an ice bath and extracted with EtOAc (20 mL*2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by TLC (Pet.ether:EtOAc=5:1) to obtain 3-[3,5-bis(trifluoromethyl)pyridin-2-yl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine -2-ketone (5 mg, 0.01 mmol, 50.00%) as a white solid.

[0206] LCMS: m / z(M+H) + =431.2

[0207] Step E: 1-[3-[3-(6-amino-1,2-diazin-3-yl)prop-2-ynyl]-3-[3,5-bis(trifluoromethyl)pyridin-2-yl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone

[0208] At 20°C under N2, 3-[3,5-bis(trifluoromethyl)pyridin-2-yl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine was added. Pd(PPh3)4(0.67mg), CuI(0.22mg) and TEA(0.01mL, 0.02mmol) were added to a DMF(3mL) solution of -2-ketone(5mg, 0.01mmol) and 6-bromo-1,2-diazine-3-amine(2.43mg, 0.01mmol). The mixture was stirred at 70°C for 4 hours under N2 to obtain a brown solution. After completion, the mixture was washed with saturated aqueous NH4Cl(10mL) and extracted with EtOAc(10mL*3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by high performance liquid chromatography (trifluoroacetic acid / acetonitrile / ) to obtain 1-[3-[3-(6-amino-1,2-diazine-3-yl)prop-2-ynyl]-3-[3,5-bis(trifluoromethyl)pyridin-2-yl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine -2-one (0.8 mg, 4.54%) as a white solid.

[0209] LCMS: m / z(M+H) + =524.2

[0210] Example 8: 1-[3-(2-aminopyrimidin-5-yl)prop-2-ynyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone

[0211]

[0212] At 25°C under N2, 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine was added. Pd(PPh3)4(5.38mg), CuI(1.77mg, 0.01mmol) and TEA(0.03mL, 0.19mmol) were added to a solution of -2-one(40mg, 0.09mmol) and 5-bromopyrimidin-2-amine(16.21mg, 0.09mmol) in DMF(3mL). The mixture was stirred at 70°C for 4 hours to obtain a brown solution. After 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-aminopyrimidin-5-yl)prop-2-ynyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine -2-ketone (8.97 mg, 0.02 mmol, 17.08%) as a white solid.

[0213] 1 H NMR (400MHz, CDCl3) δ8.34 (s, 2H), 7.98 (d, J = 8.3Hz, 1H), 7.90-7.80 (m, 2H), 7.44(dd,J=8.8,4.9Hz,1H),7.13(td,J=8.4,2.9Hz,1H),7.03(dd,J=8.4,2. 9Hz,1H),5.33(s,2H),4.94(d,J=17.4Hz,1H),4.63(d,J=17.4Hz,1H),4.19( dd,J=12.3,7.0Hz,1H),3.15(m,1H),2.76(m,1H),2.65(m,1H),2.26(m,1H).

[0214] LCMS: m / z(M+H) + =523.2

[0215] Example 9: 1-[3-(5-aminopyrazin-2-yl)prop-2-ynyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone

[0216]

[0217] At 25°C, 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine was added. 5-Bromopyrazin-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 to a solution of -2-ketone (50 mg, 0.12 mmol) in DMF (2 mL). The reactants were degassed with N2 three times at 20°C. After stirring at 70°C for 16 hours, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (TFA conditions) to give 1-[3-[3-(5-aminopyrazin-2-yl)prop-2-ynyl]-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.

[0218] 1 H NMR (400MHz, CDCl3) δ8.09-7.85(m,3H),7.83(s,1H),7.52-7.39(m,1H),7.27-7.26(m,1H),7.12(m,J=0.6Hz,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).

[0219] LCMS: m / z(M+H) + =523.2

[0220] Example 10: 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(1-((methylsulfonyl)methyl)-1H-pyrazol-4-yl)prop-2-yn-1-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine Synthesis of -2-ketone

[0221]

[0222] At 25°C under N2, 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine was added. 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 to a solution of -2-ketone (200 mg, 0.47 mmol) and 4-bromo-1-((methylsulfonyl)methyl)-1H-pyrazole (122.51 mg, 0.51 mmol) in DMF (3 mL). The mixture was stirred at 100 ° C for 18 hours to obtain a brown solution. After completion, the mixture was washed with saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by high performance liquid chromatography (trifluoroacetic acid / acetonitrile / water) to give 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(1-((methylsulfonyl)methyl)-1H-pyrazol-4-yl)prop-2-yn-1-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine -2-ketone (7.11 mg, 0.01 mmol, 2.54%) as a white solid.

[0223] 1 H NMR (400MHz, CDCl3) δ8.01 (d, J = 8.3Hz, 1H), 7.91-7.82 (m, 2H), 7.72 (s, 1H), 7.61 (s, 1H),7.46(dd,J=8.8,5.0Hz,1H),7.14(m,1H),7.04(dd,J=8.5,3.0Hz,1H),5.24(s,2 H),4.90(d,J=17.4Hz,1H),4.64(d,J=17.4Hz,1H),4.20(dd,J=12.3,7.0Hz,1H),3.1 7(m,1H),2.89(s,3H),2.78(dd,J=13.7,6.6Hz,1H),2.73-2.60(m,1H),2.27(m,1H).

[0224] LCMS: m / z(M+H) + =588.2

[0225] Example 11: 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-{3-[6-(1,4-oxazinane-4-yl)-1,2-diazin-3-yl]prop-2-ynyl}-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone

[0226]

[0227] 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine -2-ketone (50 mg, 0.12 mmol) and 3-bromo-6-(1,4-oxazinane-4-yl)-1,2-diazine (28.43 mg, 0.12 mmol) were added to DMF (5 mL), and 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. After completion, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (TFA conditions) to give 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-{3-[6-(1,4-oxazinane-4-yl)-1,2-diazin-3-yl]prop-2-ynyl}-2,3,4,5-tetrahydro-1H-1-benzazepine -2-one (38.36 mg, 0.06 mmol, 52.80%) as a white solid.

[0228] 1 H NMR(400MHz, CDCl3)δ7.99(d,J=8.3Hz,1H),7.90-7.79(m,2H),7.50(dd,J=8.8,4.9Hz,1H),7 .19(d,J=9.4Hz,1H),7.11(m,1H),7.00(dd,J=8.5,2.9Hz,1H),6.78(d,J=9.5Hz,1H),4.96(d ,J=17.5Hz,1H),4.70(d,J=17.5Hz,1H),4.20(dd,J=12.3,7.0Hz,1H),3.83(dd,J=5.8,3.9Hz ,4H),3.68-3.62(m,4H),3.21(m,1H),2.77(dd,J=13.8,6.6Hz,1H),2.64(m,1H),2.25(m,1H).

[0229] LCMS: m / z(M+H) + =593.2

[0230] Example 12: 1-(3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl)-3-(2,4-bis(trifluoromethyl)phenyl)-7,8-difluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine Synthesis of -2-ketone

[0231]

[0232] Step A: Synthesis of 2-[2,4-bis(trifluoromethyl)phenyl]-6,7-difluoro-1,2,3,4-tetrahydronaphthalen-1-one (2)

[0233] At 20°C, Pd2(dba)3 (678.62 mg, 0.74 mmol), tetrafluoro-λ5-boranetri(2-methylprop-2-yl)phosphine (857.06 mg, 2.96 mmol) and NaOH (395.24 mg, 9.88 mmol) were added 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). The mixture was stirred at 100°C under N2 for 2 hours to obtain a brown solution. After completion, the mixture was diluted with EtOAc (100 mL) and washed with H2O (50 mL*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:EtOAc=0 to 10%) to give 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.

[0234] LCMS: m / z(M+H) + =395.2

[0235] Step B: Synthesis of [(1Z)-2-[2,4-bis(trifluoromethyl)phenyl]-6,7-difluoro-1,2,3,4-tetrahydro-1-naphthylene]hydroxylamine (3)

[0236] At 20°C, NaOAc (1.25 g, 15.22 mmol) was added 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), and stirred at 80°C for 18 hours to obtain a yellow solution. After completion, the mixture was quenched with H2O (100 mL) in an ice bath and extracted with EtOAc (100 mL*2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give [(1Z)-2-[2,4-bis(trifluoromethyl)phenyl]-6,7-difluoro-1,2,3,4-tetrahydro-1-naphthylene]hydroxylamine (1.8 g, 4.40 mmol, 86.54%) as a yellow solid.

[0237] LCMS: m / z(M+H) +=410.2

[0238] Step C: 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone (4)

[0239] A solution of [(1Z)-2-[2,4-bis(trifluoromethyl)phenyl]-6,7-difluoro-1,2,3,4-tetrahydro-1-naphthylene]hydroxylamine (1.8 g, 4.40 mmol) in polyphosphoric acid (9.63 mL, 241.89 mmol) was stirred at 120°C under N2 for 20 minutes to obtain a brown solution. After completion, the mixture was quenched with H2O (200 mL) at 0°C and extracted with EtOAc (100 mLx3). 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: EtOAc = 0 to 30%) to obtain 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepine -2-ketone (450 mg, 1.10 mmol, 25.00%) as a white solid.

[0240] LCMS: m / z(M+H) + =410.2

[0241] Step D: 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone (5)

[0242] In an ice bath under N2, 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepine was added. NaH (11.73 mg, 0.49 mmol, 30% in oil) was added to a solution of -2-ketone (200 mg, 0.49 mmol) in THF (5 mL). After the mixture was stirred at 0°C for 1 hour, 3-bromoprop-1-yne (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. After completion, the mixture was quenched with H2O (50 mL) in an ice bath and extracted with EtOAc (50 mL*3). 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: EtOAc = 0 to 30%) to obtain 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine -2-ketone (180 mg, 0.40 mmol, 82.35%) as a white solid.

[0243] LCMS: m / z(M+H) + =448.2

[0244] Step E: 1-(3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl)-3-(2,4-bis(trifluoromethyl)phenyl)-7,8-difluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine Synthesis of -2-ketone

[0245] At 20°C, 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine was added. Pd(PPh3)4(5.17mg), CuI(1.70mg, 0.01mmol) and TEA(0.02mL, 0.18mmol) were added to a DMF(3mL) solution of -2-ketone(40mg, 0.09mmol) and 6-bromo-1,2-diazine-3-amine(18.67mg, 0.11mmol). The mixture was stirred at 70°C for 4 hours to obtain a brown solution. After completion, the mixture was washed with saturated aqueous NH4Cl(50mL) and extracted with EtOAc(50mL*3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by high performance liquid chromatography (trifluoroacetic acid / acetonitrile / water) to obtain 1-(3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl)-3-(2,4-bis(trifluoromethyl)phenyl)-7,8-difluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine -2-ketone (17.82 mg, 0.03 mmol, 36.88%) as a white solid.

[0246] 1 H NMR (400MHz, CDCl3) δ7.98(d,J=7.9Hz,1H),7.92-7.77(m,2H),7.38(d,J=11.1Hz,1H),7.28-7.11(m,2H),6.88(s,1H),5.73 (s,2H),4.94(d,J=17.7Hz,1H),4.70(d,J=17.8Hz,1H),4.19(d,J=10.4Hz,1H),3.17(s,1H),2.87-2.58(m,2H),2.27(s,1H).

[0247] LCMS: m / z(M+H) + =541.2

[0248] Example 13: {3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of acetonitrile

[0249]

[0250] In an ice bath under N2, 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepine was added. NaH (2.64 mg, 0.11 mmol, 30% in oil) was added to a solution of -2-ketone (30 mg, 0.07 mmol) in THF (5 mL). After the mixture was stirred at 0°C for 1 hour, 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. After completion, the mixture was quenched with H2O (50 mL) in an ice bath and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (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.

[0251] 1 H NMR (400MHz, CDCl3) δ7.98(d,J=8.3Hz,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=17.3Hz,1H),4.21(m,1H),3.09(m,1H),2.84(m,1H),2.67(m,1H),2.30(m,1H).

[0252] LCMS: m / z(M+H) + =449.2

[0253] Examples 14 and 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-yn-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 Synthesis of N-(methylsulfonyl)methanesulfonamide (Example 15)

[0254]

[0255] At 0°C, 1-[3-[6-amino-1,2-diazin-3-yl]prop-2-ynyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine was added. MsCl (0.04 mmol) was added to a solution of -2-ketone (15 mg, 0.03 mmol) in pyridine (1.5 mL), and the mixture was stirred at 20°C for 18 hours to obtain a brown solution. After completion, the mixture was diluted with EtOAc (15 mL) and washed with HCl (20 mL, 1N). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by high performance liquid chromatography (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-yn-1-yl)pyridazin-3-yl)methanesulfonamide (4.52 mg, 0.01 mmol, 22.67%) (Example 14) as a white solid, 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-yn-1-yl)pyridazin-3-yl)-N-(methylsulfonyl)methanesulfonamide (4.71 mg, 0.01 mmol, 22.12%) (Example 15) as a white solid.

[0256] Embodiment 14

[0257] 1H NMR (400MHz, CDCl3) δ7.98(d,J=8.3Hz,1H),7.92-7.83(m,2H),7.44(m,1H),7.25(d,J=9.3Hz,1H),7.20-7.11(m,2H),7.06(m,1H),4.93( d,J=17.6Hz,1H),4.72(d,J=17.7Hz,1H),4.22(m,1H),3.17(m,1H),3.12(s,3H),2.82(dd,J=13.6,6.6Hz,1H),2.68(m,1H),2.30(m,1H).

[0258] LCMS: m / z(M+H) + =601.2

[0259] Embodiment 15

[0260] 1 H NMR (400MHz, CDCl3) δ8.00 (d, J = 8.3Hz, 1H), 7.92-7.83 (m, 2H), 7.60 (d, J = 8. 7Hz,1H),7.52-7.41(m,2H),7.15(m,1H),7.06(dd,J=8.4,2.9Hz,1H),5.05( d,J=17.7Hz,1H),4.77(d,J=17.7Hz,1H),4.23(dd,J=12.3,7.0Hz,1H),3.66 (s, 6H), 3.22 (m, 1H), 2.83 (dd, J = 13.8, 6.7Hz, 1H), 2.69 (m, 1H), 2.29 (m, 1H).

[0261] LCMS: m / z(M+H) + =679.2

[0262] Example 16: 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-[3-(5-methyl-1,3,4-oxadiazol-2-yl)prop-2-ynyl]-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone

[0263]

[0264] At 20°C under N2, 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine was added. Pd(PPh3)4(4.04mg), CuI(1.33mg, 0.01mmol) and TEA(0.02mL, 0.14mmol) were added to a solution of -2-ketone(30mg, 0.07mmol) and 5-bromo-2-methyl-1,3,4-oxadiazole(13.66mg, 0.08mmol) in DMF(3mL). The mixture was stirred at 70°C for 4 hours under N2 to obtain a brown solution. After completion, the mixture was diluted with H2O(50mL) and extracted with EtOAc(50mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by high performance liquid chromatography (trifluoroacetic acid / acetonitrile / water) to obtain 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-[3-(5-methyl-1,3,4-oxadiazol-2-yl)prop-2-ynyl]-2,3,4,5-tetrahydro-1H-1-benzazepine -2-ketone (7.07 mg, 0.01 mmol, 19.75%) as a white solid.

[0265] 1 H NMR (400MHz, CDCl3) δ8.00(d,J=8.3Hz,1H),7.92-7.83(m,2H),7.41(m,1H),7.15(dd,J=8.4,2.9Hz,1H),7.06(dd,J=8.4,2.9Hz,1 H), 5.06 (d, J = 17.8Hz, 1H), 4.68 (d, J = 17.8Hz, 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).

[0266] LCMS: m / z(M+H) + =512.2

[0267] Example 17: 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-[3-(6-methoxy-1,2-diazin-3-yl)prop-2-ynyl]-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone

[0268]

[0269] At 20°C under N2, 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine was added. Pd(PPh3)4(4.04mg), CuI(1.33mg, 0.01mmol) and TEA(0.02mL, 0.14mmol) were added to a DMF(3mL) solution of -2-ketone(30mg, 0.07mmol) and 3-bromo-6-methoxy-1,2-diazine(15.88mg, 0.08mmol). The mixture was stirred at 70°C for 4 hours under N2 to obtain a brown solution. After completion, the mixture was diluted with H2O(50mL) and extracted with EtOAc(50mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by high performance liquid chromatography (trifluoroacetic acid / acetonitrile / water) to obtain 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-[3-(6-methoxy-1,2-diazin-3-yl)prop-2-ynyl]-2,3,4,5-tetrahydro-1H-1-benzazepine -2-one (5.28 mg, 0.01 mmol, 13.56%) as a white solid.

[0270] 1 H NMR (400MHz, CDCl3) δ8.00 (d, J = 8.3Hz, 1H), 7.92-7.82 (m, 2H), 7.50 (m, 1H), 7. 33(d,J=9.1Hz,1H),7.14(m,1H),7.04(d,J=7.2Hz,1H),6.91(d,J=9.1Hz,1H), 5.01(d,J=17.4Hz,1H),4.71(d,J=17.6Hz,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=9.2Hz,1H),2.28(d,J=8.0Hz,1H).

[0271] LCMS: m / z(M+H) + =538.2

[0272] Example 18: 1-(3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl)-3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine Synthesis of -2-ketone

[0273]

[0274] Step A: Synthesis of 1-bromo-2-cyclopropyl-4-(trifluoromethyl)benzene (2)

[0275] 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 eluting with hexane to give 1-bromo-2-cyclopropyl-4-(trifluoromethyl)benzene (2.1 g, 6.73 mmol, 69.50%) as a colorless oil.

[0276] Step B: Synthesis of 2-[2-cyclopropyl-4-(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (3)

[0277] Under N2 environment at 25°C, tetrafluoro-λ5-boranetri(2-methylpropan-2-yl)phosphine (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 3-necked flask (100 mL) equipped with a magnetic stirring bar, and a solution of 6-fluoro-1,2,3,4-tetrahydronaphthalen-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. After completion, the mixture was diluted with EtOAc (20 mL), washed with saturated aqueous NH4Cl (20 mL), and dried over anhydrous Na2SO4. The filtrate was concentrated under vacuum, and the residue was purified by silica gel column chromatography (Pet.ether:EtOAc=20:1) to obtain 2-[2-cyclopropyl-4-(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (800 mg, 2.30 mmol, 60.88%).

[0278] LCMS: m / z(M+H) + =349.2

[0279] Step C: Synthesis of (E)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-6-fluoro-3,4-dihydronaphthalen-1(2H)-one oxime (4)

[0280] A solution of 2-[2-cyclopropyl-4-(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (800 mg, 2.30 mmol), hydroxylamine hydrochloride (478.77 mg, 6.89 mmol), sodium acetate (565.17 mg, 6.89 mmol) in methanol (10 mL) and water (4 mL) was stirred at 70°C for 4 hours. After completion, the reaction mixture was evaporated to about half of the initial volume and then diluted with water (15 mL). The resulting crystals were collected, washed with water and dried to give (E)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-6-fluoro-3,4-dihydronaphthalen-1(2H)-one oxime (600 mg, 1.40 mmol, 61.11%) as a white solid.

[0281] LCMS: m / z(M+H) + =364.2

[0282] Step D: 3-(2-Cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine Synthesis of -2-ketone (5)

[0283] (E)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-6-fluoro-3,4-dihydronaphthalene-1(2H)-one oxime (200 mg, 0.55 mmol) was added to polyphosphoric acid (5 mL) and stirred at 120°C for 15 minutes. After completion, the mixture was quenched with H2O (50 mL) at 0°C and extracted with EtOAc (50 mL*3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (Pet.ether:EtOAc=0 to 30%) to obtain 3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine -2-ketone (50 mg, 0.03 mmol, 5.00%) as a colorless oil.

[0284] LCMS: m / z(M+H) + =364.2

[0285] Step E: 3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1-(prop-2-yn-1-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine Synthesis of -2-ketone (6)

[0286] At 0°C, 3-(2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine was added. To a solution of -2-one (50 mg, 0.14 mmol) in THF (5 mL) was added NaH (6.61 mg, 0.28 mmol). After 30 minutes, 3-bromoprop-1-yne (0.02 mL, 0.21 mmol) was added at 0°C, and the mixture was stirred at 25°C for 3 hours. After completion, the mixture was quenched with H2O (15 mL) in an ice bath and extracted with EtOAc (15 mL*3). 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: EtOAc = 0 to 30%) to give 3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1-(prop-2-yn-1-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine -2-ketone (39 mg, 0.10 mmol, 70.61%) as a yellow oil.

[0287] LCMS: m / z(M+H) + =402.2

[0288] Step F: 1-(3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl)-3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine Synthesis of -2-ketone

[0289] To 3-(2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1-(prop-2-yn-1-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine was added at 25° C. under N 2 . 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 to a solution of -2-ketone (40 mg, 0.10 mmol) in DMF (5 mL), and the mixture was stirred at 70 ° C for 4 hours. After completion, the mixture was washed with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (50 mL*3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by high performance liquid chromatography (trifluoroacetic acid / acetonitrile / water) to give 1-(3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl)-3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine -2-ketone (3 mg, 0.01 mmol, 5.48%) as a white solid.

[0290] 1H NMR (400MHz, DMSO) δ8.09-8.04 (m, 1H), 7.37 (d, J = 7.9Hz, 1H), 7.32 (s, 1H), 7.22(d,J=9.0Hz,1H),7.17(d,J=8.8Hz,2H),6.90(d,J=8.0Hz,1H),6.77(s ,2H),6.70(d,J=9.0Hz,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).

[0291] LCMS: m / z(M+H) + =495.2

[0292] Example 19: 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-[3-(6-hydroxy-1,2-diazin-3-yl)prop-2-ynyl]-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone

[0293]

[0294] At 20°C under N2, 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine was added. Pd(PPh3)4(4.04mg), CuI(1.33mg, 0.01mmol) and TEA(0.02mL, 0.14mmol) were added to a DMF(3mL) solution of 6-bromo-3H,2H-1,2-diazine-3-one(30mg, 0.07mmol) and 6-bromo-3H,2H-1,2-diazine-3-one(14.70mg, 0.08mmol). The mixture was stirred at 70°C for 4 hours under N2 to obtain a brown solution. After completion, the mixture was diluted with H2O(50mL) and extracted with EtOAc(50mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by high performance liquid chromatography (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-ynyl]-2,3,4,5-tetrahydro-1H-1-benzazepine -2-ketone (23.68 mg, 0.05 mmol, 64.63%) as a white solid.

[0295] 1H NMR (400MHz, CDCl3) δ10.81(s,1H),7.99(d,J=8.3Hz,1H),7.92-7.83(m,2H),7.45(dd,J=8.8,4.9Hz,1H),7.21-7.10(m,2H),7.05(dd,J=8.4,2. 9Hz,1H),6.90(d,J=9.8Hz,1H),4.93(d,J=17.6Hz,1H),4.69(d,J=17.6H z,1H),4.21(m,1H),3.16(m,1H),2.81(m,1H),2.67(m,1H),2.28(m,1H).

[0296] LCMS: m / z(M+H) + =524.2

[0297] Example 20: 1-[3-(5-amino-1,3,4-oxadiazol-2-yl)prop-2-ynyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine Preparation of -2-ketone

[0298]

[0299] Step A: Synthesis of 5-bromo-1,3,4-oxadiazol-2-amine (2)

[0300] At -78 ° C, n-BuLi (4.94 mL, 12.35 mmol) was added to a solution of 1,3,4-oxadiazole-2-amine (300 mg, 3.53 mmol) in tetrahydrofuran (10 mL), and then bromine (565 mg, 3.53 mmol) was added, and the mixture was stirred at 25 ° C under N2 for 16 hours. After completion, the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine (brine; 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by silica gel chromatography (solvent: petroleum ether: EtOAc = 5:1 to 10:1) to obtain 5-bromo-1,3,4-oxadiazole-2-amine (120 mg, 0.74 mmol, 20.96%) as a white solid.

[0301] LCMS: m / z(M+H) + =164.4

[0302] Step B: 1-[3-(5-amino-1,3,4-oxadiazol-2-yl)prop-2-ynyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone

[0303] At 20°C, 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine was added. 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 to a solution of -2-ketone (418 mg, 0.97 mmol) in DMF (8 mL), and stirred at 70 ° C under N2 for 4 hours. After completion, the mixture was poured into water (15 mL) and extracted with EtOAc (30 mLx3). The combined organic layer was washed with brine (brine; 50 mLx2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC (ACN: water (1‰ NH4OH)) to give 1-[3-(5-amino-1,3,4-oxadiazol-2-yl)prop-2-ynyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine -2-ketone (1.34 mg, 0.002 mmol, 0.32%) as a white solid.

[0304] LCMS: m / z(M+H) + =513.1

[0305] Example 21: 6-(3-{3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of 1,2-dioxadiazine-3-carboxylic acid

[0306]

[0307] At 20°C, 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine was added. 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 to a solution of -2-ketone (20 mg, 0.05 mmol) in DMF (1 mL). The mixture was degassed with N2 three times and stirred at 70°C under N2 for 4 hours. After the reaction was completed, it was filtered and the filtrate was purified by high performance liquid chromatography (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-ynyl)-1,2-diazine-3-carboxylic acid (5.1 mg, 0.01 mmol, 18.20%) as a yellow solid.

[0308] 1 H NMR (400MHz, MeOD) δ8.14-8.05(m,1H),7.98(d,J=9.2Hz,2H),7.91(s,1H),7.25(d,J=9.3Hz,4H),7.07-6.9 1(m,1H),6.71(d,J=4.6Hz,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).

[0309] LCMS: m / z(M+H) + =552.2

[0310] Example 22: 6-(3-{3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of 1,2-dioxadiazine-3-carboxamide

[0311]

[0312] At 20°C, 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine was 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) were added to a solution of -2-one in DMF (1 mL) (30 mg, 0.07 mmol). The reactants were degassed with N2 three times and stirred at 70 °C under N2 for 4 hours. After completion, the mixture was filtered and the filtrate was purified by pre-HPLC (FA conditions) to give 6-(3-{3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine) -1-yl}prop-1-ynyl)-1,2-diazine-3-carboxamide (4.75 mg, 0.01 mmol, 12.35%) as a white solid.

[0313] 1 H NMR(400MHz, CDCl3)δ8.25(d,J=8.6Hz,1H),7.98(m,2H),7.91-7.81(m,2H), 7.62(d,J=8.6Hz,1H),7.48(dd,J=4.9,8.8Hz,1H),7.14(m,1H),7.05(dd,J= 2.9,8.4Hz,1H),5.86(s,1H),5.04(d,J=17.7Hz,1H),4.77(d,J=17.7Hz,1H) ,4.23(dd,J=7.0,12.3Hz,1H),3.22(m,1H),2.87-2.60(m,2H),2.28(m,1H).

[0314] LCMS: m / z(M+H) + =551.2

[0315] Example 23: 3-[2,4-bis(trifluoromethyl)phenyl]-1-[3-(6-chloro-1,2-diazin-3-yl)prop-2-ynyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis of -2-ketone

[0316]

[0317] At 25°C under N2, 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepine was added. 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 to a solution of -2-ketone (40 mg, 0.09 mmol) in DMF (2 mL), and the mixture was stirred at 70 ° C for 4 hours. After completion, the mixture was concentrated under reduced pressure. The crude product was purified by p-TLC (Pet.ether:EtOAc=1:2) to obtain 3-[2,4-bis(trifluoromethyl)phenyl]-1-[3-(6-chloro-1,2-diazin-3-yl)prop-2-ynyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepine -2-ketone (50 mg, 0.08 mmol, 89.14%) as a white solid.

[0318] 1 H NMR (400MHz, DMSO) δ8.14(s,1H),7.96(d,J=9.1Hz,2H),7.81(d,J=8.9Hz,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).

[0319] LCMS: m / z(M+H) + =542.2

[0320] Experimental example: Inhibitory activity against Polθ

[0321] The inhibitory activity of the compounds prepared in the examples was tested for Polθ as follows.

[0322] The inhibitory activity of the compounds on Polθ was tested in the test tube using PicoGreen assay. Recombinant Polθ-polymerase domain (aa1819-2590) was prepared by ChemPartner and stored in aliquots at -80°C. The test was performed using 1X buffer containing 25mMTris HCL pH 7.5, 12.5mM NaCl, 0.5mM MgCl2, 5% glycerol, 0.01% Triton X-100, 0.01% BGG and 1mM DTT. The test compounds were diluted with 100% DMSO to have the correct dose range and appropriate volume (20nL) for the 10-point concentration response and then dispensed into 384-well microassay plates (Greiner small volume black plates product code 784076) using a Labcyte Echo 655 acoustic dispenser. At this time, the concentration of DMSO was maintained at 0.2% by backfilling the DMSO solution. 5uL of purified recombinant Polθ was diluted to 2X working concentration (6nM Polθ) in assay buffer. Then, it was dispensed into each well of the compound plate using a VIAFLO 16-channel manual pipette (Integra) and pre-incubated for 15 minutes at room temperature (RT). 5uL of 2X working concentration of dNTPs (40uM) (Thermo #R1121) and primer (60nM PTD) (5'-GCG GCT GTC ATA AG-3' (SEQ5 ID NO: 1)): template (5'-GCTACA 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 with assay buffer and the reaction was incubated at room temperature for 60 minutes. The reaction was terminated by adding 10 mM EDTA, 25 mM Tris pH 7.5 and a 1:80 dilution of PicoGreen dye (Invitrogen P7581). After 90 min at room temperature in the dark, fluorescence was read using a 2105-0020 Envision multi-label plate reader with a 485 / 535 nm module and raw data were analyzed using log (inhibitor) vs. response - variable slope (4 parameters) to calculate IC 50 The results are shown in Table 1 below.

[0323]

Table 1

[0324] Example No. <![CDATA[PolθIC 50 (nM)]]> Example No. <![CDATA[PolθIC 50 (nM)]]> Example 2 100.4 Example 12 112.1 Example 3 72.86 Embodiment 14 20.88 Example 5 77.81 Embodiment 15 189.6 Example 5-1 14.65 Example 16 90.31 Example 6 113.1 Embodiment 17 45.42 Example 8 48.41 Embodiment 19 34.67 Example 9 100.4 Embodiment 22 131 Example 10 90.04 Embodiment 23 696.3 Embodiment 11 33.57

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following chemical formula 1: [Chemical formula 1] In the above chemical formula 1, X is CH or N, R1 is C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, halogen or cyano, R2 is hydrogen or halogen, R3 are each independently hydrogen or halogen, R4 is C 1-4 Haloalkyl or C 3-6 Cycloalkyl, R5 is C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl or halogen, R6 is hydrogen, C 1-4 Alkyl, -CH2-C≡N or -CH2-C≡CL-R7, L is a bond, -CH2-, -CH2CH2-, -CH2-O-, -CH2-NHCO-, -CH2-N(isopropyl)-CH(CH3), phenylene or pyridinediyl, R7 is hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, hydroxyl, amino, (C 1-4 alkyl)amino, di(C 1-4 Alkyl)amino, C 6-10 aryl, a 3- to 8-membered heterocycloalkyl group containing at least one nitrogen or oxygen as a ring constituent element, or a 3- to 8-membered heteroaryl group containing at least one nitrogen, oxygen or sulfur as a ring constituent element, The R7C 6-10 Aryl, 3- to 8-membered heterocycloalkyl or 3- to 8-membered heteroaryl is unsubstituted or replaced by 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), -NHSO2(C 1-4 Alkyl), -N(SO2(C 1-4 Alkyl))2, -SO2(C 1-4 alkyl), -SO2(NH2), -CH2SO2(C 1-4 alkyl), -CH2SO2(NH2), -CH(CH3)CO(NH2), -COOH, -CONH2, azetidinyl, morpholinyl, oxetanyl, piperazinyl or piperidinyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is methyl, methoxy, cyclopropyl, fluoro or cyano.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen, fluorine or chlorine.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is each independently hydrogen or fluorine.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 is trifluoromethyl or cyclopropyl.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R5 is methyl, trifluoromethyl, cyclopropyl or chloro.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R6 is hydrogen, methyl or -CH2-C≡N.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R7 is hydrogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyclopentyl, cyclohexyl, hydroxy, amino, methylamino, dimethylamino, phenyl, piperidinyl, tetrahydropyranyl, oxadiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 6-oxo-1,6-dihydropyridinyl, pyrimidinyl or thiadiazolyl.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein The phenyl, piperidinyl, tetrahydropyranyl, oxadiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 6-oxo-1,6-dihydropyridinyl, pyrimidinyl or thiadiazolyl of R7 is unsubstituted or substituted by methyl, methoxy, hydroxyl, chlorine, 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, azetidinyl, morpholinyl, oxetanyl, piperazinyl or piperidinyl.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The above chemical formula 1 is represented by the following chemical formula 1-1: [Chemical formula 1-1] In the above chemical formula 1-1, X is CH or N, R2 is hydrogen or fluorine, R8 is hydrogen, oxadiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 6-oxo-1,6-dihydropyridinyl or pyrimidinyl, The oxadiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 6-oxo-1,6-dihydropyridinyl or pyrimidinyl in R8 is unsubstituted or substituted by methyl, methoxy, hydroxyl, chlorine, amino, -NHSO2(methyl), -N(SO2(methyl))2, -CH2SO2(methyl), -COOH, -CONH2 or morpholinyl.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound represented by Chemical Formula 1 is any one compound selected from the group consisting of the following compounds, 1) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 2) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 3) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(pyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 4) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-methyl-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 5) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 6) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-oxo-1,6-dihydropyridin-2-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 7) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(3,5-bis(trifluoromethyl)pyridin-2-yl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 8) 1-(3-(2-aminopyrimidin-5-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 9) 1-(3-(5-aminopyrazin-2-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 10) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(1-(methylsulfonylmethyl)-1H-pyrazol-4-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 11) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-morpholinopyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 12) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7,8-difluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 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-ynyl)pyridazin-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-ynyl)pyridazin-3-yl)-N-(methylsulfonyl)methanesulfonamide, 16) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(5-methyl-1,3,4-oxadiazol-2-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 17) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-methoxypyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 18) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 19) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-hydroxypyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 20) 1-(3-(5-amino-1,3,4-oxadiazol-2-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 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-ynyl)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-ynyl)pyridazine-3-carboxamide, 23) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-(6-chloropyridazin-3-yl)prop-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 24) 3-(2,4-bis(trifluoromethyl)phenyl)-7,8-difluoro-1-(3-(1-(methylsulfonylmethyl)-1H-pyrazol-4-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 25) 1-(3-(6-(azetidin-3-yl)pyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 26) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(piperidin-4-yl)pyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 27) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(piperazin-1-yl)pyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 28) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-8-chloro-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 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-ynyl)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-ynyl)pyridazin-3-yl)methanesulfonamide, 31) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(methylsulfonylmethyl)pyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 32) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(methylsulfonyl)pyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 33) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine -7-carbonitrile, 34) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(4-chloro-2-(trifluoromethyl)phenyl)-7-cyclopropyl-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 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-ynyl)pyridazin-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-ynyl)pyridazin-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-ynyl)pyridazin-3-yl)-2,2,2-trifluoroacetamide, 38) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-phenylprop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 39) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(4-methoxyphenyl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 40) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-methyl-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 41) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-methoxy-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 42) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-cyclopropyl-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 43) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-7-cyclopropyl-3-(4-methyl-2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 44) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-(6-(dimethylamino)pyridazin-3-yl)prop-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 45) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(methylamino)pyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 46) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-7-cyclopropyl-3-(4-cyclopropyl-2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 47) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine -1-yl)but-2-ynyl)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)but-2-ynyl)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)but-2-ynyl)-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)but-2-ynyl)benzamide, 51) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-5,5,7-trifluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 52) 1-(3-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 53) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(1-methyl-1H-pyrazol-4-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 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-ynyl)-1H-pyrazol-1-yl)propanamide, 55) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4,4,4-trifluorobut-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 56) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(but-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 57) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-cyclohexylprop-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 58) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-cyclopentylprop-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 59) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(tetrahydro-2H-pyran-4-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 60) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(piperidin-4-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 61) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(4-hydroxycyclohexyl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 62) 1-(3-(4-aminocyclohexyl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 63) 1-(4-aminobut-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 64) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(4-(dimethylamino)but-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 65) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-hydroxybut-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 66) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-methoxybut-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 67) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-(trifluoromethoxy)but-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 68) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(pyridin-2-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 69) 1-(3-(1,3,4-thiadiazol-2-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 70) 1-(3-(5-amino-1,3,4-thiadiazol-2-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 71) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(oxetane-3-yl)pyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 72) 1-(3-(1,3,4-oxadiazol-2-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 73) 1-(3-(5-amino-1,3,4-oxadiazol-2-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 74) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 75) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-(pyridazin-3-yloxy)but-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 76) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(5-(6-methylpyridazin-3-yl)pent-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 77) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(4-(6-methylpyridazin-3-yl)phenyl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 78) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-(isopropyl(1-(6-methylpyridazin-3-yl)ethyl)amino)but-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone, 79) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine -1-yl)but-2-ynyl)-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)but-2-ynyl)-1,3,4-thiadiazole-2-carboxamide, and 81) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(6-methylpyridazin-3-yl)pyridin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepine -2(3H)-ketone.

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

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