Novel heterocyclic compounds and pharmaceutical composition comprising the same as DNA polymerase theta inhibitors for the prevention or treatment of cancer

Abstract

The present disclosure relates to a novel heterocyclic compound represented by the Chemical Formula 1 and a pharmaceutical composition comprising the same, and the compound according to the present disclosure can be usefully used for the prevention or treatment of cancer.

Description

NOVEL HETEROCYCLIC COMPOUNDS AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME AS DNA POLYMERASE THETA INHIBITORS FOR THE PREVENTION OR TREATMENT OF CANCER

[0001] The present disclosure relates to a novel heterocyclic compound useful as Pol-theta (DNA Polymerase-theta, Polθ) inhibitor and a pharmaceutical composition comprising the same.

[0002] Targeting DNA repair deficiencies has become a proven and effective strategy in cancer treatment. However, DNA repair deficient cancers often become dependent on backup DNA repair pathways, which present an "Achilles heel" that can be targeted to eliminate cancer cells, and is the basis of synthetic lethality. Synthetic lethality is exemplified by the success of Poly ADP-ribose polymerase (PARP) inhibitors in treating BRCA-deficient breast and ovarian cancers.

[0003]

[0004] Robust repair of DNA double-strand breaks (DSBs) is essential for the maintenance of genome 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). Microhomology-mediated end-joining (MMEJ) is the most well characterized alt-NHEJ mechanism.

[0005]

[0006] Numerous genetic studies have highlighted a role for polymerase theta (Polθ) in stimulating MMEJ in higher organisms. It has been shown that cancer cells with deficiency in HR, NHEJ, or ATM (Ataxia-telangiectasia mutated; A-T mutated) are highly dependent on Polθ expression. The expression of Polθ is largely absent in normal cells but upregulated in breast, lung, and ovarian cancers. Additionally, the increase of Polθ expression correlates with poor prognosis in breast cancer. Importantly, Polθ is largely repressed in normal tissues but has been shown to be upregulated in matched cancer samples thus correlating elevated expression with disease. Its suppression or inhibition confers radio-sensitivity in tumor cells. Polθ inhibition could conceivably prevent the MMEJ-dependent functional reversion of BRCA2 mutations that underlies the emergence of cisplatin and PARPi (PARP inhibitor) resistance in tumors. Therefore, Polθ is an attractive target for novel synthetic lethal therapy in cancers containing DNA repair defects and there is a need to provide effective Polθ inhibitors for the treatment of cancer.

[0007]

[0008] In view of the above, as a result of studying novel compounds, the present inventors found that a compound having a chemical structure different from Polθ inhibitors reported so far has an excellent Polθ inhibitory effect, thereby completing the present disclosure. The compounds belonging to the present disclosure mainly have Polθ inhibitory activity on their own, but do not exclude a possibility of exhibiting a pharmacological action as an efficacious agent by a special body environment or by products of metabolic process, after absorption into the body.

[0009] It is one object of the present disclosure to provide a novel heterocyclic compound useful as a Pol-theta (Polθ) inhibitor, and a pharmaceutical composition comprising the same.

[0010] In order to achieve the above objects, there is provided a compound represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof:

[0011] [Chemical Formula 1]

[0012]

[0013] in Chemical Formula 1,

[0014] X is CH, or N,

[0015] R1is C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, halogen, or cyano,

[0016] R2is hydrogen, or halogen,

[0017] R3's are each independently, hydrogen, or halogen,

[0018] R4is C1-4haloalkyl, or C3-6cycloalkyl,

[0019] R5is C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, or halogen,

[0020] R6is hydrogen, C1-4alkyl, -CH2-C≡N, or -CH2-C≡C-L-R7,

[0021] L is a bond, -CH2-, -CH2CH2-, -CH2-O-, -CH2-NHCO-, -CH2-N(isopropyl)-CH(CH3)-, phenylene, or pyridinediyl,

[0022] R7is hydrogen, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, hydroxy, amino, (C1-4alkyl)amino, di(C1-4alkyl)amino, C6-10aryl, 3 to 8-membered heterocycloalkyl containing at least one nitrogen or oxygen members, or 3 to 8-membered heteroaryl containing at least one nitrogen, oxygen, or sulfur members, and

[0023] the C6-10aryl, 3 to 8-membered heterocycloalkyl, or 3 to 8-membered heteroaryl in R7is unsubstituted or substituted with C1-4alkyl, C1-4alkoxy, hydroxy, halogen, amino, (C1-4alkyl)amino, di(C1-4alkyl)amino, -NHCO(C1-4alkyl), -NHCO(C1-4haloalkyl), -NHSO2(C1-4alkyl), -N(SO2(C1-4alkyl))2, -SO2(C1-4alkyl), -SO2(NH2), -CH2SO2(C1-4alkyl), -CH2SO2(NH2), -CH(CH3)CO(NH2), -COOH, -CONH2, azetidine, morpholino, oxetanyl, piperazinyl, or piperidinyl.

[0024]

[0025] Further, in order to achieve the above objects, there is provided a pharmaceutical composition comprising the compound, or, a pharmaceutically acceptable salt thereof.

[0026]

[0027] Further, in order to achieve the above objects, there is provided a pharmaceutical composition for the prevention or treatment of cancer, comprising the compound, or a pharmaceutically acceptable salt thereof.

[0028] The compound represented by Chemical Formula 1 according to the present disclosure, or, a pharmaceutically acceptable salt thereof can be usefully used for the prevention or treatment of cancers.

[0029] Hereinafter, embodiments of the present disclosure will be described in more detail to facilitate understanding of the invention.

[0030]

[0031] Meanwhile, the present disclosure provides a compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt thereof.

[0032]

[0033] Preferably, R1is methyl, methoxy, cyclopropyl, fluoro, or cyano. Preferably, R2is hydrogen, fluoro, or chloro. Preferably, R1 is fluoro, and R2is hydrogen, or fluoro.

[0034]

[0035] Preferably, R3's are each independently, hydrogen, or fluoro. Preferably, R3's are hydrogen.

[0036]

[0037] Preferably, R4is trifluoromethyl, or cyclopropyl. Preferably, R5is methyl, trifluoromethyl, cyclopropyl, or chloro. Preferably, R4and R5are trifluoromethyl.

[0038]

[0039] Preferably, R6is hydrogen, methyl, or -CH2-C≡N.

[0040]

[0041] Preferably, R7is 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 in R7is 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, oxetanil, piperazinil, or piperidinyl.

[0042]

[0043] Preferably, the Chemical Formula 1 is represented by Chemical Formula 1-1:

[0044] [Chemical Formula 1-1]

[0045]

[0046] in Chemical Formula 1-1,

[0047] X is CH, or N,

[0048] R2is hydrogen, or fluoro,

[0049] R8is hydrogen, oxadiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 6-oxo-1,6-dihydropyridinyl, or pyrimidinyl, and

[0050] the oxadiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 6-oxo-1,6-dihydropyridinyl, or pyrimidinyl in R8is unsubstituted or substituted with methyl, methoxy, hydroxy, chloro, amino, -NHSO2(methyl), -N(SO2(methyl))2, -CH2SO2(methyl), -COOH, -CONH2, or morpholino.

[0051]

[0052] Representative examples of the compound represented by Chemical Formula 1 are as follows:

[0053] 1) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0054] 2) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0055] 3) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(pyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0056] 4) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-methyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0057] 5) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0058] 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]azepin-2(3H)-one,

[0059] 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]azepin-2(3H)-one,

[0060] 8) 1-(3-(2-aminopyrimidin-5-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0061] 9) 1-(3-(5-aminopyrazin-2-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0062] 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]azepin-2(3H)-one,

[0063] 11) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-morpholinopyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0064] 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]azepin-2(3H)-one,

[0065] 13) 2-(3-(2,4-bis(trifluoromethyl)phenyl)-7,8-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)acetonitrile,

[0066] 14) (R)-N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)prop-1-ynyl)pyridazin-3-yl)methanesulfonamide,

[0067] 15) (R)-N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)prop-1-ynyl)pyridazin-3-yl)-N-(methylsulfonyl)methanesulfonamide,

[0068] 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]azepin-2(3H)-one,

[0069] 17) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-methoxypyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0070] 18) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0071] 19) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-hydroxypyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0072] 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]azepin-2(3H)-one,

[0073] 21) 6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)prop-1-ynyl)pyridazine-3-carboxylic acid,

[0074] 22) 6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)prop-1-ynyl)pyridazine-3-carboxamide,

[0075] 23) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-(6-chloropyridazin-3-yl)prop-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0076] 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]azepin-2(3H)-one,

[0077] 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]azepin-2(3H)-one,

[0078] 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]azepin-2(3H)-one,

[0079] 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]azepin-2(3H)-one,

[0080] 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]azepin-2(3H)-one,

[0081] 29) 6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)prop-1-ynyl)pyridazine-3-sulfonamide,

[0082] 30) (6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)prop-1-ynyl)pyridazin-3-yl)methanesulfonamide,

[0083] 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]azepin-2(3H)-one,

[0084] 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]azepin-2(3H)-one,

[0085] 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,

[0086] 34) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(4-chloro-2-(trifluoromethyl)phenyl)-7-cyclopropyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0087] 35) N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)prop-1-ynyl)pyridazin-3-yl)methanesulfonamide,

[0088] 36) N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)prop-1-ynyl)pyridazin-3-yl)acetamide,

[0089] 37) N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)prop-1-ynyl)pyridazin-3-yl)-2,2,2-trifluoroacetamide,

[0090] 38) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-phenylprop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0091] 39) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(4-methoxyphenyl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0092] 40) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-methyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0093] 41) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-methoxy-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0094] 42) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-cyclopropyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0095] 43) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-7-cyclopropyl-3-(4-methyl-2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0096] 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]azepin-2(3H)-one,

[0097] 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]azepin-2(3H)-one,

[0098] 46) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-7-cyclopropyl-3-(4-cyclopropyl-2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0099] 47) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)but-2-ynyl)acetamide,

[0100] 48) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)but-2-ynyl)nicotinamide,

[0101] 49) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)but-2-ynyl)-5-methyl-1,3,4-oxadiazole-2-carboxamide,

[0102] 50) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)but-2-ynyl)benzamide,

[0103] 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]azepin-2(3H)-one,

[0104] 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]azepin-2(3H)-one,

[0105] 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]azepin-2(3H)-one,

[0106] 54) 2-(4-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)prop-1-ynyl)-1H-pyrazol-1-yl)propanamide,

[0107] 55) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4,4,4-trifluorobut-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0108] 56) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(but-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0109] 57) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-cyclohexylprop-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0110] 58) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-cyclopentylprop-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0111] 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]azepin-2(3H)-one,

[0112] 60) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(piperidin-4-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0113] 61) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(4-hydroxycyclohexyl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0114] 62) 1-(3-(4-aminocyclohexyl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0115] 63) 1-(4-aminobut-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0116] 64) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(4-(dimethylamino)but-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0117] 65) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-hydroxybut-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0118] 66) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-methoxybut-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0119] 67) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-(trifluoromethoxy)but-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0120] 68) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(pyridin-2-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0121] 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]azepin-2(3H)-one,

[0122] 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]azepin-2(3H)-one,

[0123] 71) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(oxetan-3-yl)pyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0124] 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]azepin-2(3H)-one,

[0125] 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]azepin-2(3H)-one,

[0126] 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]azepin-2(3H)-one,

[0127] 75) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-(pyridazin-3-yloxy)but-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0128] 76) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(5-(6-methylpyridazin-3-yl)pent-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,

[0129] 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]azepin-2(3H)-one,

[0130] 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]azepin-2(3H)-one,

[0131] 79) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)but-2-ynyl)-1,3,4-oxadiazole-2-carboxamide,

[0132] 80) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)but-2-ynyl)-1,3,4-thiadiazole-2-carboxamide, and

[0133] 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]azepin-2(3H)-one.

[0134]

[0135] In addition, the compounds of the present disclosure may exist in the form of salts, especially pharmaceutically acceptable salts. As salts, salts commonly used in the art, such as acid addition salts formed by pharmaceutically acceptable free acids can be used without limitation. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic addition salt of the compound represented by Chemical Formula 1, whose concentration is relatively non-toxic and harmless to a patient and activates effectively and whose side effects do not degrade the beneficial efficacy of the above compound.

[0136]

[0137] As the free acid, an organic acid and an inorganic acid can be used. Examples of the inorganic acids include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, and the like. Examples of the organic acids include 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, and the like, but are not limited thereto. Preferably, the salt may be a hydrochloride salt.

[0138]

[0139] Further, a pharmaceutically acceptable metal salt can be obtained by a conventional method using a base. For example, the compound represented by Chemical Formula 1 is dissolved in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, the non-soluble salt is filtered, and then the filtrate is evaporated and dried to obtain a pharmaceutically acceptable metal salt. At this time, it is particularly preferable to prepare a sodium salt, a potassium salt, or a calcium salt as the metal salt.

[0140]

[0141] In addition, a pharmaceutically unacceptable salt or solvate of the compound of Chemical Formula 1 may be used as an intermediate when preparing the compound of Chemical Formula 1, or the pharmaceutically acceptable salt or the solvate thereof.

[0142]

[0143] In one embodiment, the compound represented by Chemical Formula 1 may be prepared through Reaction Formula 1 below.

[0144] [Reaction Scheme 1]

[0145]

[0146]

[0147] In Reaction Scheme 1, X, and R1to R6are as defined above, and X' is halogen. Preferably, X' is bromo, or chloro.

[0148]

[0149] 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 palladium catalyst such as Pd2(dba)3.

[0150]

[0151] Step 2 is a step of preparing a compound represented by Chemical Formula 4' by reacting a compound represented by Chemical Formula 3' with hydroxyamine (NH2OH).

[0152]

[0153] Step 3 is a step of preparing a compound represented by Chemical Formula 5' through Beckmann rearrangement by using a compound represented by Chemical Formula 4'. The reaction is preferably carried out in the presence of polyphosphoric acid.

[0154]

[0155] Step 4 is a step of preparing a compound represented by Chemical Formula 1 by reacting a compound represented by Chemical Formula 5' with NaH and R6-X" (in which, R6is as defined in the above except hydrogen, and X" is halogen. Preferably, X" is bromo, or chloro).

[0156]

[0157] The above preparation method will be more specifically described in the Examples described hereinafter.

[0158]

[0159] According to a further embodiment of the present disclosure, there is provided a pharmaceutical composition comprising the compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt thereof.

[0160]

[0161] According to a further embodiment of the present disclosure, there is provided a pharmaceutical composition for the prevention or treatment of cancer diseases, which is effective for Polθ inhibitory actions, comprising the compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0162]

[0163] In this case, the cancer may be blood cancer, extranodal marginal zone B-cell lymphoma, glioblastoma, lymphoplasmacytic lymphoma, acute myelogenous 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, renal cancer, gastric cancer, transitional cell carcinoma, a carcinoid tumor, breast cancer, non-small cell lung cancer, or multiple myeloma.

[0164]

[0165] As used herein, the term "prevention" refers to any act to delay or inhibit occurrence, spread, or recurrence of the above-mentioned diseases by administration of the composition of the present disclosure, and "treatment" refers to any act to improve or change the symptoms of the above diseases for the better by administration of the composition of the present disclosure.

[0166]

[0167] The pharmaceutical composition according to the present disclosure can be formulated in types for oral or parenteral administrations according to a standard pharmaceutical practice. These formulations may contain additives such as a pharmaceutically acceptable carrier, an adjuvant, or a diluent in addition to the active ingredient.

[0168]

[0169] Suitable carriers include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oil, isopropyl myristate, and the like. Diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and the like, but are not limited thereto. Further, the compounds of the present disclosure can be dissolved in oils, propylene glycol, or other solvents commonly used in the preparation of injection solutions. Furthermore, the compounds of the present disclosure can be formulated in ointments or creams for topical application.

[0170]

[0171] A preferred dose of the compound of the present disclosure may be varied according to the condition and weight of a patient, the severity of a disease, the type of a drug, and the route and duration of administration, but it may be suitably selected by those skilled in the art. In order to achieve the desirable effects, however, the compound of the present disclosure may be administrated daily at a dose of 0.0001 to 100 mg / kg (body weight), and preferably 0.001 to 100 mg / kg (body weight). The administration may be performed once a day or in divided doses each day through an oral or parenteral route.

[0172]

[0173] Depending on the method of administration, the pharmaceutical composition may contain the compound of the present disclosure in an amount of 0.001 to 99 % by weight, preferably 0.01 to 60 % by weight.

[0174]

[0175] The pharmaceutical composition according to the present disclosure may be administered to mammals such as a rat, a mouse, a domestic animal, or a human, through various routes. The administration may be carried out through all possible methods, for example, oral, rectal, intravenous, intramuscular, subcutaneous, intra-endometrial, intracerebroventricular injection.

[0176]

[0177] Below, the present disclosure will be described in more detail by way of examples. However, these examples are provided for illustrative purposes only, and should not be construed as limiting the scope of the present disclosure to these examples.

[0178]

[0179] Example 1: Synthesis of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one

[0180]

[0181]

[0182] Step A: Synthesis of 2-[2,4-bis(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (2)

[0183] 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) were added Pd2(dba)3(250.99 mg, 0.27 mmol), tetrafluoro-λ5-boranuide tris(2-methylprop-2-yl)phosphane (316.99 mg, 1.10 mmol) and NaOH (146.18 mg, 3.65 mmol) at N2. The mixture was stirred at 100℃ under N2for 2 h to give a brown solution. Upon completion, the mixture was diluted with EtOAc (100 mL) and washed with H2O (50 mL * 2). The combined organic layers were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude product was purified by silica-gel column chromatography (Pet.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 white solid.

[0184] LCMS: m / z (M+H)+= 377.2.

[0185]

[0186] Step B: Synthesis of [(1Z)-2-[2,4-bis(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydro-1-naphthylidene]hydroxylamine (3)

[0187] To a solution of 2-[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) was added sodium acetate (161.33 mg, 1.97 mmol) at 25℃, the mixture was stirred at 60℃ for 2 h to give a yellow solution. Upon 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 Na2SO4and concentrated under reduced pressure to give [(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 yellow solid.

[0188] LCMS: m / z (M+H)+= 392.2.

[0189]

[0190] Step C: Synthesis of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one

[0191] [(1Z)-2-[2,4-bis(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydro-1-naphthylidene]hydroxylamine (350 mg, 0.89 mmol) and polyphosphoric acid (1.96 mL, 49.20 mmol) were stirred at 120℃ under N2for 1 h to give a brown solution. Upon completion, the mixture was quenched with H2O (100 mL) at 0℃ and extracted with EtOAc (100 mL * 3). The combined organic layers were dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (DCM: MeOH = 100:1 to 10:1) to give 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (50 mg, 0.13 mmol, 14.29%) as white solid.

[0192] 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).

[0193] LCMS: m / z (M+H)+= 392.2.

[0194]

[0195] Example 2: Synthesis of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one

[0196]

[0197] To a solution of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (30 mg, 0.08 mmol) in THF (5 mL) was added NaH (4.60 mg, 0.12 mmol, 60% purity) under N2in an ice bath. The mixture was stirred at 0℃ for 1 h, then 3-bromoprop-1-yne (0.01 mL, 0.09 mmol) was added at 0℃. The mixture was stirred at 0℃ for 2 h to give a yellow solution. Upon 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 Na2SO4and concentrated under reduced pressure. The residue was purified by HPLC (TFA condition) to give 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (11 mg, 0.03 mmol, 33.41%) as white solid.

[0198] 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, 7.7 Hz, 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).

[0199] LCMS: m / z (M+H)+= 430.2.

[0200]

[0201] Example 3: Synthesis of 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-benzazepin-2-one

[0202]

[0203] 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 (10 mg, 0.02 mmol) and 3-bromo-1,2-diazine (4.44 mg, 0.03 mmol) in DMF (3 mL) were added Pd(PPh3)4(1.35 mg), CuI (0.44 mg) and TEA (0.01 mL, 0.05 mmol) at 25℃ under N2. The mixture was stirred at 70℃ for 4 h to give a brown solution. Upon completion, the mixture was washed with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were dried over anhydrous Na2SO4and concentrated under vacuum. The residue was purified by HPLC (TFA condition) to give 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-benzazepin-2-one (4.72 mg, 0.01 mmol, 36.74%) as brown solid.

[0204] 1H 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).

[0205] LCMS: m / z (M+H)+= 508.1.

[0206]

[0207] Example 4: Synthesis of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one

[0208]

[0209] To a solution of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (2.8 mg, 0.01 mmol) in THF (1 mL) was added NaH (0.43 mg, 0.01 mmol) in an ice bath. The mixture was stirred at 0℃ for 0.5 h, then MeI (0.01 mL, 0.01 mmol) was added at 0℃. The mixture was stirred at 25℃ for 1 h to give a yellow solution. Upon 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 Na2SO4and concentrated under reduced pressure. The residue was purified by HPLC (TFA condition) to give 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (2 mg, 0.01 mmol, 67.59%).

[0210] 1H 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).

[0211] LCMS: m / z (M+H)+= 406.2.

[0212]

[0213] Example 5: Synthesis of 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-benzazepin-2-one

[0214]

[0215] 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 (500 mg, 1.16 mmol) and 6-bromo-1,2-diazin-3-amine (243 mg, 1.40 mmol) in DMF (10 mL) were added Pd(PPh3)4(67.29 mg, 0.06 mmol), CuI (22.18 mg, 0.12 mmol) and TEA (0.32 mL, 2.33 mmol) at 25℃ under N2. The mixture was stirred at 70℃ for 4 h to give a brown solution. Upon completion, the mixture was diluted with water (300 mL), after filtration, the filtrate was extracted with EtOAc (200 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by HPLC (TFA condition) to give racemic compound 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-benzazepin-2-one (300 mg, 0.55 mmol, 47.03%) as a white solid.

[0216] 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).

[0217] LCMS: m / z (M+H)+= 523.2.

[0218]

[0219] Examples 5-1 and 5-2: Synthesis of (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]azepin-2-one & (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]azepin-2-one

[0220]

[0221] The racemic compound 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-benzazepin-2-one (300 mg, 0.55 mmol) was separated by prep-chiral HPLC with the following conditions: (Column: ChiralCel OX, 250×30 mm I.D., 10 μm; Mobile phase: A for CO2and 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) to afford the first peak (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]azepin-2-one (Example 5-1) (141.44mg, 0.26mmol, 47.15%) (100% ee, tR= 0.943) as a white solid and the second peak (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]azepin-2-one (Example 5-2) (148.74 mg, 0.27 mmol, 49.58%) (100% ee, tR= 1.898) as a white solid.

[0222]

[0223] Example 5-1

[0224] 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), 7.11 (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).

[0225] LCMS: m / z (M+H)+= 523.2.

[0226]

[0227] Example 5-2

[0228] 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).

[0229] LCMS: m / z (M+H)+= 523.2.

[0230]

[0231] Example 6: Synthesis of 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-benzazepin-2-one

[0232]

[0233] 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 (50 mg, 0.12 mmol) and 6-bromo-1,2-dihydropyridin-2-one (25.06 mg, 0.14 mmol) in DMF (5 mL) were 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) at 25℃ under N2. The mixture was stirred at 70℃ for 4 h to give a brown solution. Upon completion, the mixture was filtrated, the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (TFA condition) to give 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-benzazepin-2-one (5.43 mg, 0.01 mmol, 8.66%) as white solid.

[0234] 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).

[0235] LCMS: m / z (M+H)+= 523.1.

[0236]

[0237] Example 7: Synthesis of 1-[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-benzazepin-2-one

[0238]

[0239]

[0240] Step A: Synthesis of 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (2)

[0241] To a 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) in Toluene (30 mL) were added sodium 2-methylpropan-2-olate (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) at 20℃ under N2, the mixture was stirred at 70℃ under N2for 24 h to give a brown solution. Upon completion, the mixture was diluted with EtOAc (100 mL) and washed with H2O (50 mL * 2). The combined organic layers were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude product was purified by silica-gel column chromatography (Pet.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 white solid.

[0242] LCMS: m / z (M+H)+= 378.2.

[0243]

[0244] Step B: Synthesis of [(1Z)-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-6-fluoro-1,2,3,4-tetrahydro-1-naphthylidene]hydroxylamine (3)

[0245] To a 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) was added sodium acetate (26.09 mg, 0.32 mmol), the mixture was stirred at 80℃ for 18 h to give a yellow solution. Upon 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 Na2SO4and concentrated under reduced pressure to give [(1Z)-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-6-fluoro-1,2,3,4-tetrahydro-1-naphthylidene] hydroxylamine (40 mg, 0.10 mmol, 96.18%) as yellow solid.

[0246] LCMS: m / z (M+H)+= 393.2.

[0247]

[0248] Step C: Synthesis of 3-[3,5-bis(trifluoromethyl)pyridin-2-yl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (4)

[0249] [(1Z)-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-6-fluoro-1,2,3,4-tetrahydro-1-naphthylidene] hydroxylamine (40 mg, 0.10 mmol) in polyphosphoric acid (0.22 mL, 5.61 mmol) was stirred at 120℃ under N2for 20 minutes to give a brown solution. Upon completion, the mixture was quenched with H2O (50 mL) at 0℃ and extracted with EtOAc (50 mL * 3). The combined organic layers were dried over anhydrous Na2SO4and 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-benzazepin-2-one (10 mg, 0.03 mmol, 25.49%) as white solid.

[0250] LCMS: m / z (M+H)+= 393.2.

[0251]

[0252] Step D: Synthesis of 3-[3,5-bis(trifluoromethyl)pyridin-2-yl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (5)

[0253] To a solution of 3-[3,5-bis(trifluoromethyl)pyridin-2-yl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (10 mg, 0.03 mmol) in THF (5 mL) was added NaH (0.92 mg, 0.04 mmol, 30% in oil) under N2in an ice bath. The mixture was stirred at 0℃ for 1 h, then 3-bromoprop-1-yne (0.01 mL, 0.03 mmol) was added at 0℃. The mixture was stirred at 25℃ for 4 h to give a yellow solution. Upon 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 Na2SO4and concentrated under reduced pressure. The crude product was purified by TLC (Pet.ether: EtOAc = 5:1) to give 3-[3,5-bis(trifluoromethyl)pyridin-2-yl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (5 mg, 0.01 mmol, 50.00%) as white solid.

[0254] LCMS: m / z (M+H)+= 431.2.

[0255]

[0256] Step E: Synthesis of 1-[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-benzazepin-2-one

[0257] To a solution of 3-[3,5-bis(trifluoromethyl)pyridin-2-yl]-7-fluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (5 mg, 0.01 mmol) and 6-bromo-1,2-diazin-3-amine (2.43 mg, 0.01 mmol) in DMF (3 mL) were added Pd(PPh3)4(0.67 mg), CuI (0.22 mg) and TEA (0.01 mL, 0.02 mmol) at 20℃ under N2. The mixture was stirred at 70℃ under N2for 4 h to give a brown solution. Upon completion, the mixture was washed with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were dried over anhydrous Na2SO4and concentrated under vacuum. The crude product was purified by high performance liquid phase (trifluoroacetic acid / acetonitrile / water) to give 1-[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-benzazepin-2-one (0.8 mg, 4.54%) as white solid.

[0258] LCMS: m / z (M+H)+= 524.2.

[0259]

[0260] Example 8: Synthesis of 1-[3-(2-aminopyrimidin-5-yl)prop-2-ynyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one

[0261]

[0262] 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 (40 mg, 0.09 mmol) and 5-bromopyrimidin-2-amine (16.21 mg, 0.09 mmol) in DMF (3 mL) were added Pd(PPh3)4(5.38 mg), CuI (1.77 mg, 0.01 mmol) and TEA (0.03 mL, 0.19 mmol) at 25℃ under N2. The mixture was stirred at 70℃ for 4 h to give a brown solution. Upon completion, the mixture was filtrated, the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (TFA condition) to give 1-[3-(2-aminopyrimidin-5-yl)prop-2-ynyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (8.97 mg, 0.02 mmol, 17.08%) as white solid.

[0263] 1H 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).

[0264] LCMS: m / z (M+H)+= 523.2.

[0265]

[0266] Example 9: Synthesis of 1-[3-(5-aminopyrazin-2-yl)prop-2-ynyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one

[0267]

[0268] 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 (50 mg, 0.12 mmol) in DMF (2 mL) were 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) at 25℃. The reaction was degassed N2three times at 20℃ and stirred at 70℃ for 16 h. Upon completion, the mixture was filtrated, the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (TFA condition) to give 1-[3-(5-aminopyrazin-2-yl)prop-2-ynyl]-3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (2.2 mg, 3.28%) as a white solid.

[0269] 1H 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).

[0270] LCMS: m / z (M+H)+= 523.2.

[0271]

[0272] Example 10: Synthesis of 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]azepin-2-one

[0273]

[0274] 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 (200 mg, 0.47 mmol) and 4-bromo-1-((methylsulfonyl)methyl)-1H-pyrazole (122.51 mg, 0.51 mmol) in DMF (3 mL) were 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) at 25℃ under N2. The mixture was stirred at 100℃ for 18 h to give a brown solution. Upon completion, the mixture was washed with saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous Na2SO4and concentrated under vacuum. The crude product was purified by high performance liquid phase (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]azepin-2-one (7.11 mg, 0.01 mmol, 2.54%) as white solid.

[0275] 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).

[0276] LCMS: m / z (M+H)+= 588.2.

[0277]

[0278] Example 11: Synthesis of 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-{3-[6-(1,4-oxazinan-4-yl)-1,2-diazin-3-yl]prop-2-ynyl}-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one

[0279]

[0280] 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 (50 mg, 0.12 mmol) and 3-bromo-6-(1,4-oxazinan-4-yl)-1,2-diazine (28.43 mg, 0.12 mmol) in DMF (5 mL) were 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) at 25℃ under N2. The mixture was stirred at 70℃ for 4 h to give a brown solution. Upon completion, the mixture was filtrated, the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (TFA condition) to give 3-[2,4-bis(trifluoromethyl)phenyl]-7-fluoro-1-{3-[6-(1,4-oxazinan-4-yl)-1,2-diazin-3-yl]prop-2-ynyl}-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (38.36 mg, 0.06 mmol, 52.80%) as white solid.

[0281] 1H 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).

[0282] LCMS: m / z (M+H)+= 593.2.

[0283]

[0284] Example 12: Synthesis of 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]azepin-2-one

[0285]

[0286]

[0287] Step A: Synthesis of 2-[2,4-bis(trifluoromethyl)phenyl]-6,7-difluoro-1,2,3,4-tetrahydronaphthalen-1-one (2)

[0288] 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) were added Pd2(dba)3(678.62 mg, 0.74 mmol), tetrafluoro-λ5-boranuide tris(2-methylprop-2-yl)phosphane (857.06 mg, 2.96 mmol) and NaOH (395.24 mg, 9.88 mmol) at 20℃. The mixture was stirred at 100℃ under N2for 2 h to give a brown solution. Upon completion, the mixture was diluted with EtOAc (100 mL) and washed with H2O (50 mL * 2). The organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude product was purified by silica-gel column chromatography (Pet.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 white solid.

[0289] LCMS: m / z (M+H)+= 395.2.

[0290]

[0291] Step B: Synthesis of [(1Z)-2-[2,4-bis(trifluoromethyl)phenyl]-6,7-difluoro-1,2,3,4-tetrahydro-1-naphthylidene]hydroxylamine (3)

[0292] To a 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) was added NaOAc (1.25 g, 15.22 mmol) at 20℃, the mixture was stirred at 80℃ for 18 h to give a yellow solution. Upon 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 Na2SO4and concentrated under reduced pressure to give [(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 yellow solid.

[0293] LCMS: m / z (M+H)+= 410.2.

[0294]

[0295] Step C: Synthesis of 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (4)

[0296] [(1Z)-2-[2,4-bis(trifluoromethyl)phenyl]-6,7-difluoro-1,2,3,4-tetrahydro-1-naphthylidene]hydroxylamine (1.8 g, 4.40 mmol) in polyphosphoric acid (9.63 mL, 241.89 mmol) was stirred at 120℃ under N2for 20 minutes to give a brown solution. Upon completion, the mixture was quenched with H2O (200 mL) at 0℃ and extracted with EtOAc (100 mL * 3). The combined organic layers were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude product was purified by silica-gel column chromatography (Pet.ether: EtOAc = 0 to 30 %) to give 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (450 mg, 1.10 mmol, 25.00%) as white solid.

[0297] LCMS: m / z (M+H)+= 410.2.

[0298]

[0299] Step D: Synthesis of 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (5)

[0300] To a solution of 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (200 mg, 0.49 mmol) in THF (5 mL) was added NaH (11.73 mg, 0.49 mmol, 30% in oil) under N2in an ice bath. The mixture was stirred at 0℃ for 1 h, then 3-bromoprop-1-yne (0.05 mL, 0.59 mmol) was added at 0℃. The mixture was stirred at 25℃ for 4 h to give a yellow solution. Upon 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 Na2SO4and concentrated under reduced pressure. The crude product was purified by silica-gel column chromatography (Pet.ether: EtOAc= 0 to 30%) to give 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (180 mg, 0.40 mmol, 82.35%) as white solid.

[0301] LCMS: m / z (M+H)+= 448.2.

[0302]

[0303] Step E: Synthesis of 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]azepin-2-one

[0304] To a solution of 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-1-(prop-2-ynyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (40 mg, 0.09 mmol) and 6-bromo-1,2-diazin-3-amine (18.67 mg, 0.11 mmol) in DMF (3 mL) were added Pd(PPh3)4(5.17 mg), CuI (1.70 mg, 0.01 mmol) and TEA (0.02 mL, 0.18 mmol) at 20℃. The mixture was stirred at 70℃ for 4 h to give a brown solution. Upon completion, the mixture was washed with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (50 mL * 3). The combined organic layers were dried over anhydrous Na2SO4and concentrated under vacuum. The crude product was purified by high performance liquid phase (trifluoroacetic acid / acetonitrile / water) to give 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]azepin-2-one (17.82 mg, 0.03 mmol, 36.88%) as white solid.

[0305] 1H 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).

[0306] LCMS: m / z (M+H)+= 541.2.

[0307]

[0308] Example 13: Synthesis of {3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl}acetonitrile

[0309]

[0310] To a solution of 3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (30 mg, 0.07 mmol) in THF (5 mL) was added NaH (2.64 mg, 0.11 mmol, 30% in oil) under N2in an ice bath. The mixture was stirred at 0℃ for 1 h, then bromoacetonitrile (0.01 mL, 0.09 mmol) was added at 0℃. The mixture was stirred at 25℃ for 4 h to give a yellow solution. Upon 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 Na2SO4and concentrated under reduced pressure. The crude product was purified by high performance liquid phase (ammonium bicarbonate / acetonitrile / water) to give {3-[2,4-bis(trifluoromethyl)phenyl]-7,8-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl}acetonitrile (10.63 mg, 0.04 mmol, 60.86%) as white solid.

[0311] 1H 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).

[0312] LCMS: m / z (M+H)+= 449.2.

[0313]

[0314] 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]azepin-1-yl)prop-1-yn-1-yl)pyridazin-3-yl)methanesulfonamide (Example 14) & (R)-N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)prop-1-yn-1-yl)pyridazin-3-yl)-N-(methylsulfonyl)methanesulfonamide (Example 15)

[0315]

[0316] To a solution of 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-benzazepin-2-one (15 mg, 0.03 mmol) in pyridine (1.5 mL) was added MsCl (0.04 mmol) at 0℃, the mixture was stirred at 20℃ for 18 h to give a brown solution. Upon completion, the mixture was diluted with EtOAc (15 mL) and washed with HCl (20 mL, 1 N). The organic layer was dried over anhydrous Na2SO4and concentrated under vacuum. The crude product was purified by high performance liquid phase (trifluoroacetic acid / acetonitrile / water) to give (R)-N-(6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)prop-1-yn-1-yl)pyridazin-3-yl)methanesulfonamide (4.52 mg, 0.01 mmol, 22.67%) (Example 14) as 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]azepin-1-yl)prop-1-yn-1-yl)pyridazin-3-yl)-N-(methylsulfonyl)methanesulfonamide (4.71 mg, 0.01 mmol, 22.12%) (Example 15) as white solid.

[0317]

[0318] Example 14

[0319] 1H 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)

[0320] LCMS: m / z (M+H)+= 601.2.

[0321]

[0322] Example 15

[0323] 1H 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).

[0324] LCMS: m / z (M+H)+= 679.2.

[0325]

[0326] Example 16: Synthesis of 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-benzazepin-2-one

[0327]

[0328] 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) and 5-bromo-2-methyl-1,3,4-oxadiazole (13.66 mg, 0.08 mmol) in DMF (3 mL) were added Pd(PPh3)4(4.04 mg), CuI (1.33 mg, 0.01 mmol) and TEA (0.02 mL, 0.14 mmol) at 20℃ under N2. The mixture was stirred at 70℃ under N2for 4 h to give a brown solution. Upon completion, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL). The combined organic layer was dried over anhydrous Na2SO4and concentrated under vacuum. The crude product was purified by high performance liquid phase (trifluoroacetic acid / acetonitrile / water) to give 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-benzazepin-2-one (7.07 mg, 0.01 mmol, 19.75%) as white solid.

[0329] 1H 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).

[0330] LCMS: m / z (M+H)+= 512.2.

[0331]

[0332] Example 17: Synthesis of 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-benzazepin-2-one

[0333]

[0334] 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) and 3-bromo-6-methoxy-1,2-diazine (15.88 mg, 0.08 mmol) in DMF (3 mL) were added Pd(PPh3)4(4.04 mg), CuI (1.33 mg, 0.01 mmol) and TEA (0.02 mL, 0.14 mmol) at 20℃ under N2. The mixture was stirred at 70℃ under N2for 4 h to give a brown solution. Upon completion, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL). The combined organic layer was dried over anhydrous Na2SO4and concentrated under vacuum. The crude product was purified by high performance liquid phase (trifluoroacetic acid / acetonitrile / water) to give 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-benzazepin-2-one (5.28 mg, 0.01 mmol, 13.56%) as white solid.

[0335] 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).

[0336] LCMS: m / z (M+H)+= 538.2.

[0337]

[0338] Example 18: Synthesis of 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]azepin-2-one

[0339]

[0340]

[0341] Step A: Synthesis of 1-bromo-2-cyclopropyl-4-(trifluoromethyl)benzene (2)

[0342] 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℃ for 16 h. Upon completion, the reaction mixture was allowed to cool to room temperature, filtered and concentrated. The residue was purified via column chromatography eluting with hexane to give 1-bromo-2-cyclopropyl-4-(trifluoromethyl)benzene (2.1 g, 6.73 mmol, 69.50%) as colorless oil.

[0343]

[0344] Step B: Synthesis of 2-[2-cyclopropyl-4-(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (3)

[0345] Under a N2atmosphere, to a 100 mL of three-necked flask equipped with a magnetic stir bar were added tetrafluoro-λ5-boranuide tris(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) at 25℃, then 6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (743.26 mg, 4.53 mmol), 1-bromo-2-cyclopropyl-4-(trifluoromethyl)benzene (1000.00 mg, 3.77 mmol) in dioxane (8 mL) and H2O (2 mL) were added respectively. The mixture was stirred at 100℃ for 2 h. Upon 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 in vacuo and the residue was purified by a silica gel column chromatography (Pet.ether: EtOAc = 20:1) to give 2-[2-cyclopropyl-4-(trifluoromethyl)phenyl]-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-one (800 mg, 2.30 mmol, 60.88%).

[0346] LCMS: m / z (M+H)+= 349.2.

[0347]

[0348] Step C: Synthesis of (E)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-6-fluoro-3,4-dihydronaphthalen-1(2H)-one oxime (4)

[0349] A mixture 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 70℃ for 4 h. Upon completion, the reaction mixture was evaporated to about half its initial volume and 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 white solid.

[0350] LCMS: m / z (M+H)+= 364.2.

[0351]

[0352] Step D: Synthesis of 3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (5)

[0353] (E)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-6-fluoro-3,4-dihydronaphthalen-1(2H)-one oxime (200 mg, 0.55 mmol) in polyphosphoric acid (5 mL) was stirred at 120℃ for 15 min. Upon completion, the mixture was quenched with H2O (50 mL) at 0℃ and extracted with EtOAc (50 mL * 3). The combined organic layers were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude product was purified by silica-gel column chromatography (Pet.ether: EtOAc = 0 to 30 %) to give 3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (50 mg, 0.03 mmol, 5.00%) as colorless oil.

[0354] LCMS: m / z (M+H)+= 364.2.

[0355]

[0356] Step E: Synthesis of 3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1-(prop-2-yn-1-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (6)

[0357] To a solution of 3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (50 mg, 0.14 mmol) in THF (5 mL) was added NaH (6.61 mg, 0.28 mmol) at 0℃. After 30 min later 3-bromoprop-1-yne (0.02 mL, 0.21 mmol) was added at 0℃ and the mixture was stirred at 25℃ for 3 h. Upon 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 Na2SO4and concentrated under reduced pressure. The crude product was purified by silica-gel column chromatography (Pet.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]azepin-2-one (39 mg, 0.10 mmol, 70.61%) as yellow oil.

[0358] LCMS: m / z (M+H)+= 402.2.

[0359]

[0360] Step F: Synthesis of 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]azepin-2-one

[0361] To a solution of 3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-1-(prop-2-yn-1-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (40 mg, 0.10 mmol) in DMF (5 mL) was added 6-bromo-1,2-diazin-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) at 25℃ under N2, and the mixture was stirred at 70℃ for 4 hr. Upon completion, the mixture was washed with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (50 mL * 3). The combined organic layers were dried over anhydrous Na2SO4and concentrated under vacuum. The crude product was purified by high performance liquid phase (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]azepin-2-one (3 mg, 0.01 mmol, 5.48%) as white solid.

[0362] 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).

[0363] LCMS: m / z (M+H)+= 495.2.

[0364]

[0365] Example 19: Synthesis of 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-benzazepin-2-one

[0366]

[0367] 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) and 6-bromo-3H,2H-1,2-diazin-3-one (14.70 mg, 0.08 mmol) in DMF (3 mL) were added Pd(PPh3)4(4.04 mg), CuI (1.33 mg, 0.01 mmol) and TEA (0.02 mL, 0.14 mmol) at 20℃ under N2. The mixture was stirred at 70℃ under N2for 4 h to give a brown solution. Upon completion, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL). The combined organic layer was dried over anhydrous Na2SO4and concentrated under vacuum. The crude product was purified by high performance liquid phase (trifluoroacetic acid / acetonitrile / water) to give 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-benzazepin-2-one (23.68 mg, 0.05 mmol, 64.63%) as white solid.

[0368] 1H 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).

[0369] LCMS: m / z (M+H)+= 524.2.

[0370]

[0371] Example 20: Synthesis of 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-benzazepin-2-one

[0372]

[0373]

[0374] Step A: Synthesis of 5-bromo-1,3,4-oxadiazol-2-amine (2)

[0375] To a solution of 1,3,4-oxadiazol-2-amine (300 mg, 3.53 mmol) in tetrahydrofuran (10 mL) was added n-BuLi (4.94 mL, 12.35 mmol) under -78℃, then bromine (565 mg, 3.53 mmol) was added to the mixture and stirred at 25℃ under N2for 16 hours. Upon completion, the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel chromatography (eluent: petroleum ether: EtOAc = 5: 1 to 10: 1) to afford 5-bromo-1,3,4-oxadiazol-2-amine (120 mg, 0.74 mmol, 20.96%) as white solid.

[0376] LCMS: m / z (M+H)+= 164.4.

[0377]

[0378] Step B: Synthesis of 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-benzazepin-2-one

[0379] 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 (418 mg, 0.97 mmol) in DMF (8 mL) were added 5-bromo-1,3,4-oxadiazol-2-amine (80 mg, 0.49 mmol), CuI (18 mg, 0.09 mmol), Pd(PPh3)4(56 mg, 0.05 mmol), TEA (49 mg, 0.48 mmol) at 20℃ and stirred at 70℃ for 4 hours under N2. Upon completion, the mixture was poured into water (15 mL) and extracted with EtOAc (30 mL * 3). The combined organic layers were washed with brine (50 mL * 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude produce was purified by Prep-HPLC ((ACN : water (1‰ NH4OH)) to afford 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-benzazepin-2-one (1.34 mg, 0.002 mmol, 0.32%) as a white solid.

[0380] LCMS: m / z (M+H)+= 513.1.

[0381]

[0382] Example 21: Synthesis of 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-carboxylic acid

[0383]

[0384] 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 (20 mg, 0.05 mmol) in DMF (1 mL) were 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) at 20℃. The mixture was degassed N2three times and stirred at 70℃ under N2for 4 h. Upon completion, the reaction was filtered, the filtrate was purified by high performance liquid phase (trifluoroacetic acid / acetonitrile / water) to give 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-carboxylic acid (5.1 mg, 0.01 mmol, 18.20%) as a yellow solid.

[0385] 1H 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).

[0386] LCMS: m / z (M+H)+= 552.2.

[0387]

[0388] Example 22: Synthesis of 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

[0389]

[0390] 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℃. The reaction was degassed N2three times and stirred at 70℃ under N2for 4h. Upon completion, the mixture was filtered, the filtrate was purified by pre-HPLC (FA condition) to give 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.

[0391] 1H 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).

[0392] LCMS: m / z (M+H)+= 551.2.

[0393]

[0394] Example 23: Synthesis of 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-benzazepin-2-one

[0395]

[0396] 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 (40 mg, 0.09 mmol) in DMF (2 mL) was added 3-bromo-6-chloropyridazine (21.63 mg, 0.11mmol), Triethylamine (0.03 mL, 0.19 mmol), iodocopper(I) (1.77 mg, 0.01 mmol) and Pd(PPh3)4(5.38 mg) at 25℃ under N2and the mixture was stirred at 70℃ for 4 hr. Upon completion, the mixture was concentrated under reduced pressure. The crude product was purified by p-TLC (Pet.ether: EtOAc = 1:2) to give 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-benzazepin-2-one (50 mg, 0.08 mmol, 89.14%) as white solid.

[0397] 1H 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).

[0398] LCMS: m / z (M+H)+= 542.2.

[0399]

[0400] Experimental example: Inhibitory activity against Polθ

[0401] Inhibitory activities against Polθ were measured for the compounds prepared in the above examples as follows.

[0402]

[0403] A PicoGreen assay was used to measure the ability of compounds to inhibit the activity of Ροlθ in vitro. A Recombinant Polθ-polymerase domain (aa1819-2590) was produced by ChemPartner and stored at -80℃ in aliquots. Assay measurements were performed with a 1X buffer including 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. Test compounds were prepared by dilution in 100 % DMSO to give the correct dose range for 10 point concentration response and appropriate volume (20 nL) dispensed into 384 well microassay plates (Greiner small volume black plate product code 784076) using a Labcyte Echo 655 acoustic dispenser. The DMSO concentration was maintained at 0.2 % by back filling with DMSO solution. 5 μL purified recombinant Polθ was diluted in assay buffer to a 2X working concentration (6 nM Polθ). This was dispensed into each well of the compound plate using a VIAFLO 16 channel manual pipette (Integra) and preincubated at RT for 15 min. 5 μL of 2X working solution of 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' (SEQ5 ID NO: 2)) duplex (1:1.1) diluted in assay buffer was then added and the reaction incubated for 60 min at RT. The reaction was stopped by addition of 10 mM EDTA, 25 mM tris pH 7.5 and 1:80 dilution of PicoGreen dye (Invitrogen P7581). After 90 minutes at RT in the dark, fluorescence was read on a 2105-0020 EnVision Multilabel Reader using a 485 / 535 nm module and raw data analyzed using log(inhibitor) vs. response - variable slope (four parameters) to generate IC50values. The results are shown in Table 1 below.

[0404] Example No.PolθIC50(nM)Example No.PolθIC50(nM)Ex.2100.4Ex.12112.1Ex.372.86Ex.1420.88Ex.577.81Ex.15189.6Ex.5-114.65Ex.1690.31Ex.6113.1Ex.1745.42Ex.848.41Ex.1934.67Ex.9100.4Ex.22131Ex.1090.04Ex.23696.3Ex.1133.57

Claims

1.A compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt thereof:[Chemical Formula 1]in Chemical Formula 1,X is CH, or N,R1is C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, halogen, or cyano,R2is hydrogen, or halogen,R3's are each independently, hydrogen, or halogen,R4is C1-4haloalkyl, or C3-6cycloalkyl,R5is C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, or halogen,R6is hydrogen, C1-4alkyl, -CH2-C≡N, or -CH2-C≡C-L-R7,L is a bond, -CH2-, -CH2CH2-, -CH2-O-, -CH2-NHCO-, -CH2-N(isopropyl)-CH(CH3)-, phenylene, or pyridinediyl,R7is hydrogen, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, hydroxy, amino, (C1-4alkyl)amino, di(C1-4alkyl)amino, C6-10aryl, 3 to 8-membered heterocycloalkyl containing at least one nitrogen or oxygen members, or 3 to 8-membered heteroaryl containing at least one nitrogen, oxygen, or sulfur members, andthe C6-10aryl, 3 to 8-membered heterocycloalkyl, or 3 to 8-membered heteroaryl in R7is unsubstituted or substituted with C1-4alkyl, C1-4alkoxy, hydroxy, halogen, amino, (C1-4alkyl)amino, di(C1-4alkyl)amino, -NHCO(C1-4alkyl), -NHCO(C1-4haloalkyl), -NHSO2(C1-4alkyl), -N(SO2(C1-4alkyl))2, -SO2(C1-4alkyl), -SO2(NH2), -CH2SO2(C1-4alkyl), -CH2SO2(NH2), -CH(CH3)CO(NH2), -COOH, -CONH2, azetidine, morpholino, oxetanyl, piperazinyl, or piperidinyl.2.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinR1is methyl, methoxy, cyclopropyl, fluoro, or cyano.3.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinR2is hydrogen, fluoro, or chloro.4.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinR3's are each independently, hydrogen, or fluoro.5.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinR4is trifluoromethyl, or cyclopropyl.6.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinR5is methyl, trifluoromethyl, cyclopropyl, or chloro.7.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinR6is hydrogen, methyl, or -CH2-C≡N.8.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinR7is 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 or a pharmaceutically acceptable salt thereof according to claim 8, whereinthe phenyl, piperidinyl, tetrahydropyranyl, oxadiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 6-oxo-1,6-dihydropyridinyl, pyrimidinyl, or thiadiazolyl in R7is 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, oxetanil, piperazinil, or piperidinyl.10.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinthe Chemical Formula 1 is represented by Chemical Formula 1-1:[Chemical Formula 1-1]in Chemical Formula 1-1,X is CH, or N,R2is hydrogen, or fluoro,R8is hydrogen, oxadiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 6-oxo-1,6-dihydropyridinyl, or pyrimidinyl, andthe oxadiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, 6-oxo-1,6-dihydropyridinyl, or pyrimidinyl in R8is unsubstituted or substituted with methyl, methoxy, hydroxy, chloro, amino, -NHSO2(methyl), -N(SO2(methyl))2, -CH2SO2(methyl), -COOH, -CONH2, or morpholino.11.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinthe compound represented by the Chemical Formula 1 is any one selected from the group consisting of:1) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,2) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,3) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(pyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,4) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-methyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,5) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,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]azepin-2(3H)-one,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]azepin-2(3H)-one,8) 1-(3-(2-aminopyrimidin-5-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,9) 1-(3-(5-aminopyrazin-2-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,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]azepin-2(3H)-one,11) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-morpholinopyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,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]azepin-2(3H)-one,13) 2-(3-(2,4-bis(trifluoromethyl)phenyl)-7,8-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-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]azepin-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]azepin-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]azepin-2(3H)-one,17) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-methoxypyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,18) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,19) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-hydroxypyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,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]azepin-2(3H)-one,21) 6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-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]azepin-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]azepin-2(3H)-one,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]azepin-2(3H)-one,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]azepin-2(3H)-one,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]azepin-2(3H)-one,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]azepin-2(3H)-one,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]azepin-2(3H)-one,29) 6-(3-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-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]azepin-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]azepin-2(3H)-one,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]azepin-2(3H)-one,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]azepin-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]azepin-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]azepin-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]azepin-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]azepin-2(3H)-one,39) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(4-methoxyphenyl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,40) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-methyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,41) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-methoxy-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,42) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-cyclopropyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,43) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-7-cyclopropyl-3-(4-methyl-2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,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]azepin-2(3H)-one,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]azepin-2(3H)-one,46) 1-(3-(6-aminopyridazin-3-yl)prop-2-ynyl)-7-cyclopropyl-3-(4-cyclopropyl-2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,47) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-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]azepin-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]azepin-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]azepin-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]azepin-2(3H)-one,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]azepin-2(3H)-one,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]azepin-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]azepin-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]azepin-2(3H)-one,56) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(but-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,57) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-cyclohexylprop-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,58) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(3-cyclopentylprop-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,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]azepin-2(3H)-one,60) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(piperidin-4-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,61) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(4-hydroxycyclohexyl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,62) 1-(3-(4-aminocyclohexyl)prop-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,63) 1-(4-aminobut-2-ynyl)-3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,64) 3-(2,4-bis(trifluoromethyl)phenyl)-1-(4-(dimethylamino)but-2-ynyl)-7-fluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,65) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-hydroxybut-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,66) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-methoxybut-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,67) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-(trifluoromethoxy)but-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,68) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(pyridin-2-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,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]azepin-2(3H)-one,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]azepin-2(3H)-one,71) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(3-(6-(oxetan-3-yl)pyridazin-3-yl)prop-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,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]azepin-2(3H)-one,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]azepin-2(3H)-one,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]azepin-2(3H)-one,75) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(4-(pyridazin-3-yloxy)but-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,76) 3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-1-(5-(6-methylpyridazin-3-yl)pent-2-ynyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one,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]azepin-2(3H)-one,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]azepin-2(3H)-one,79) N-(4-(3-(2,4-bis(trifluoromethyl)phenyl)-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-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]azepin-1-yl)but-2-ynyl)-1,3,4-thiadiazole-2-carboxamide, and81) 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]azepin-2(3H)-one.12.A pharmaceutical composition for the prevention or treatment of cancer, comprising the compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

Images