Novel aminobenzene derivatives having cancer cell growth inhibitory effects and pharmaceutical compositions for prevention or treatment containing the same as an active ingredient

Abstract

The compound represented by Chemical Formula 1 or 2 of the present invention, or a pharma- ceutically acceptable salt thereof, can be usefully used for the prevention or treatment of cancer or tumor.

Description

[Technical field]

[0001] The present invention relates to compounds having a novel structure that can be usefully used in the treatment or prevention of cancer or tumors. [Background technology]

[0002] The Hippo pathway influences organ development and cell proliferation by affecting the size and number of cells that compose organs, and inappropriate regulation of Hippo signaling has been implicated in the development of various cancers, including breast, head and neck, colon, ovarian, liver, brain, and prostate cancers, mesothelioma, and sarcoma.

[0003] The NF2, Mst1 / 2, and Lats1 / 2 genes that make up the Hippo signaling pathway are mutated in various cancers. Mutations in these tumor suppressors induce sustained binding of YAP / TAZ and TEAD, leading to gene expression related to cancer cell proliferation. The Hippo signaling pathway is composed of various elements, including NF2 (neurofibromatosis type 2), Mst1 / 2 (mammalian Ste20-like kinases 1 and 2), Lats1 / 2 (large tumor suppressor 1 / 2), YAP / TAZ (yes-associated protein / WW domain-containing transcription regulator protein), and TEADs (transcriptional enhanced associate domains).

[0004] Excessive activation of YAP and TAZ due to one or more mutations in the Hippo signaling pathway leads to tissue overgrowth and tumor formation, which is inversely correlated with the survival rate of cancer patients. Activation of YAP / TAZ is regulated by the response of a series of tumor suppressor genes that constitute the Hippo signaling pathway. Representative tumor suppressor genes include NF2, Mst1 / 2, and Lats1 / 2. When activation of the top molecule NF2 mediates phosphorylation of Lats1 / 2 by Mst1 / 2, phosphorylation of YAP and TAZ present in the cytoplasm is promoted. Phosphorylated YAP and TAZ are degraded by the proteasome after undergoing the ubiquitination process. Therefore, when the Hippo signaling system is activated (turned on), YAP and TAZ are inactivated. In contrast, under conditions that inactivate tumor suppressor genes, i.e., when Hippo signaling is turned off, YAP and TAZ are activated and translocated to the nucleus, where they bind to four proteins of the TEAD family (TEAD1 / 2 / 3 / 4) and induce the expression of target genes such as connective tissue growth factor (CTGF), cysteine-rich angiogenic inducer 61 (CYR61), GLI family zinc finger 2 (Gli2), Baculoviral IAP repeat containing 2 / 5 (Birc2 / 5), and fibroblast growth factor (FGF). Thus, genes activated by the YAP / TAZ-transcription factor complex regulate cell proliferation, cell migration, and cell death.

[0005] Abnormalities in the Hippo signaling system have been found in various cancers, and various research results have been reported to develop anticancer drugs that target YAP-TEAD. Going a step further, the relevance of the Hippo signaling system in the process of acquiring resistance after the application of existing approved anticancer drugs has been elucidated, and various studies are underway to prove the possibility of YAP-TEAD anticancer drugs as a combination therapeutic agent to treat drug resistance.

[0006] Therefore, there is a need to develop small molecule inhibitors to treat cancers caused by deregulation of the Hippo signaling pathway.

[0007] Therefore, the present inventors have studied drugs that can be usefully used to treat cancers in which Hippo signaling regulation is inactivated, and have confirmed that the YAP-TEAD inhibitor according to the present invention, which will be described later, binds to the palmitate binding site that mediates TEAD palmitoylation and inhibits the in vitro proliferation of a cell line with a mutation in the Hippo signaling pathway. As a result, the present inventors have confirmed that the YAP-TEAD inhibitor according to the present invention can be usefully used to treat cancers or tumors in which Hippo signaling is inactivated in cancer, and have completed the present invention. Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention provides compounds having novel structures that can be usefully used in the treatment or prevention of cancer or tumors. [Means for solving the problem]

[0009] In order to solve the above problems, the present invention provides a compound represented by the following chemical formula 1 or 2, or a pharma- ceutically acceptable salt thereof: [Chemical formula 1] JPEG2025503671000001.jpg2655[Chemical formula 2] JPEG2025503671000002.jpg3361 In the above Chemical Formulas 1 and 2, L1 is a single bond, C 1-6 Alkylene, C 2-4 Alkenylene, or C 2-4 is alkynylene, R1 is phenyl or a 5- or 6-ring heterocycle containing 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; The R1 is unsubstituted or is selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Thioalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Thioalkoxy, C 1-4 Haloalkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, amino, nitro, cyano, (C 1-4 alkyl)amino, or di(C 1-4 substituted with alkyl)amino; R2 is -N(R9)-L2-R5, JPEG2025503671000003.jpg2631, JPEG2025503671000004.jpg2831, or JPEG2025503671000005.jpg2933, L2 is a single bond, C 1-6 Alkylene, C 2-4 Alkenylene, or C 2-4 is alkynylene, R5 is C 3-7 cycloalkyl, phenyl, or a 5- or 6-ring heteroaryl containing 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; The R5 is unsubstituted or selected from the group consisting of hydroxy, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Thioalkyl, and C 3-6 cycloalkyl; R6 is independently hydrogen, halogen, or C 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, or C 3-7 is cycloalkyl, R9 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, or C 3-6 is cycloalkyl, R3 is independently hydrogen, halogen, or C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-4 is an alkoxy; R4 is independently hydrogen, C 1-4 a 5- or 6-ring heteroaliphatic ring containing 1 or 2 N substituted with alkyl, -CH2N(R7)2, or R7; R7 is independently hydrogen or C 1-4 is alkyl, X is CR8 or N; R8 is hydrogen or halogen; Y is CO, CS, or SO2.

[0010] Preferably, L1 is a single bond or -CH=CH-.

[0011] Preferably, R1 is phenyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, pyrrolidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl; The R1 is unsubstituted or is selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Thioalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, amino, nitro, cyano, (C 1-4 alkyl)amino, or di(C 1-4 substituted with alkyl)amino.

[0012] Preferably, L2 is a single bond, methylene (-CH2-), or ethylene (-CH2-CH2-).

[0013] Preferably, R5 is cyclopentyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, or thiazolyl; The R5 is unsubstituted or selected from the group consisting of hydroxy, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Thioalkyl, and C 3-6 cycloalkyl; and cycloalkyl.

[0014] Preferably, each R6 is independently hydrogen, fluoro, chloro, difluoromethyl, or trifluoromethyl.

[0015] Preferably, R9 is hydrogen.

[0016] Preferably, each R3 is independently hydrogen or methoxy.

[0017] Preferably, R4 are all hydrogen, or One of R4 is hydrogen and the other is -CH2N(R7)2 or a 5- or 6-ring heteroaliphatic ring containing 1 or 2 N substituted with R7.

[0018] Preferably, X is CH, CF or N.

[0019] Preferably, the compound represented by Chemical Formula 1 is a compound represented by Chemical Formula 3 below: [Chemical formula 3] JPEG2025503671000006.jpg5778In the above Chemical Formula 3, X is CH, CF, or N; A is benzene, pyridine, pyrimidine, imidazole, pyrazole, triazole, tetrazole, or oxadiazole; R' is hydrogen, halogen, C 1-4 Alkyl, or C 1-4 is an alkoxy; L1 is a single bond, C 1-6 Alkylene, or C 2-4 alkenylene, B is benzene, pyridine, pyrimidine, thiazolyl, cyclopentyl, or cyclohexyl; R" is independently hydrogen, hydroxy, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Thioalkoxy, C 1-4 haloalkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, or C 3-6 is cycloalkyl, n″ is an integer from 1 to 3, L2 is a single bond or C 1-6 is alkylene, R3 is hydrogen or C 1-4 is an alkoxy; R"' is hydrogen or -CH2-N(CH3)2; R3 is hydrogen or C 1-4 It is an alkoxy.

[0020] Preferably, the compound represented by Chemical Formula 1 is a compound represented by Chemical Formula 4: [Chemical formula 4] JPEG2025503671000007.jpg6269In the above Chemical Formula 4, X is CH, CF, or N; A is benzene, pyridine, pyrimidine, imidazole, pyrazole, triazole, tetrazole, or oxadiazole; R' is hydrogen, halogen, C 1-4 Alkyl, or C 1-4is an alkoxy; L1 is a single bond, C 1-6 Alkylene, or C 2-4 alkenylene, R6 is independently hydrogen, halogen, or C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, or C 3-7 is cycloalkyl, R3 is hydrogen or C 1-4 is an alkoxy; R"' is hydrogen or -CH2-N(CH3)2.

[0021] Representative examples of the compound represented by Formula 1 or Formula 2 are as follows: 1) N-(6-(cyclohexylamino)-[1,1'-biphenyl]-3-yl)acrylamide, 2) N-(4-(cyclohexylamino)-3-(pyridin-2-yl)phenyl)acrylamide, 3) N-(3-(pyridin-2-yl)-4-((cis-4-(trifluoromethyl)cyclohexyl)amino)phenyl)acrylamide, 4) N-(3-(pyridin-2-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide, 5) N-(2-methoxy-5-(pyridin-2-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide, 6) N-(3-(1-methyl-1H-imidazol-4-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide, 7) N-(4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(pyridin-2-yl)phenyl)acrylamide, 8) N-(4-((4,5-dichloropyridin-2-yl)amino)-3-(pyridin-2-yl)phenyl)acrylamide, 9) N-(4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 10) N-(4-((4,5-dichloropyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 11) N-(6-((4-fluorobenzyl)amino)-[1,1'-biphenyl]-3-yl)acrylamide, 12) N-(4-((4-fluorobenzyl)amino)-3-(pyridin-2-yl)phenyl)acrylamide, 13) N-(3-(5-chloropyridin-2-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide, 14) N-(4-(pyridin-2-yl)-3-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide, 15) N-(3-(pyrimidin-4-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide, 16) N-(4-((4,5-dichloropyridin-2-yl)amino)-3-(pyrimidin-4-yl)phenyl)acrylamide, 17) N-(3-(pyridin-4-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide, 18) N-(4-((4,5-dichloropyridin-2-yl)amino)-3-(pyridin-4-yl)phenyl)acrylamide, 19) N-(4-(5-chloro-4-fluoro-1H-indol-1-yl)-3-(pyridin-2-yl)phenyl)acrylamide, 20) N-(4-((5-cyclopropylpyridin-2-yl)amino)-3-(pyridin-2-yl)phenyl)acrylamide, 21) N-(4-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(pyridin-2-yl)phenyl)acrylamide, 22) N-(6-(((1r,4r)-4-hydroxycyclohexyl)amino)-5-phenylpyridin-3-yl)acrylamide, 23) (E)-N-(3-(4-fluorostyryl)-4-((2-(thiazol-2-yl)ethyl)amino)phenyl)acrylamide, 24) (E)-N-(3-(4-fluorostyryl)-4-((2-(thiazol-2-yl)ethyl)amino)phenyl)ethanesulfonamide, 25) N-(4-(cyclohexylamino)-3-(pyridin-3-yl)phenyl)acrylamide, 26) N-(4-(cyclopentylamino)-3-(pyridin-2-yl)phenyl)acrylamide, 27) (E)-N-(5-(4-fluorostyryl)-6-((2-(thiazol-2-yl)ethyl)amino)pyridin-3-yl)acrylamide, 28) (E)-N-(5-(4-fluorostyryl)-6-((2-(thiazol-2-yl)ethyl)amino)pyridin-3-yl)ethanesulfonamide, 29) N-(3-fluoro-5-(pyridin-2-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide, 30) N-(4-((5-chloro-4-cyclopropylpyridin-2-yl)amino)-3-(pyridin-2-yl)phenyl)acrylamide, 31) N-(3-(1-methyl-1H-imidazol-4-yl)-4-((4(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide, 32) ((E)-4-(dimethylamino)-N-(3-(1-methyl-1H-pyrazol-3-yl)-4-((4-(trifluoromethyl)pyridin-2-yl)amino)phenyl)-2-butenamide, 33) N-(4-((5-isopropylpyridin-2-yl)amino)-3-(pyridin-2-yl)phenyl)acrylamide, 34) N-(4-((5-ethynylpyridin-2-yl)amino)-3-(1-methyl-1H-pyrazol-3-yl)phenyl)acrylamide, 35) N-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide, 36) N-(4-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 37) N-(4-((4-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(1-methyl-1H-pyrazol-3-yl)phenyl)acrylamide, 38) N-(3-fluoro-5-(1-methyl-1H-imidazol-4-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide, 39) N-(2'-((5-(trifluoromethyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-5'-yl)acrylamide, 40) N-(4-((3-fluoro-4-(trifluoromethyl)phenyl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 41) N-(5-(1-methyl-1H-imidazol-4-yl)-6-((4-(trifluoromethyl)phenyl)amino)pyridin-3-yl)acrylamide, 42) N-(3-(1-methyl-1H-pyrazol-3-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide, 43) N-(4-((3-chloro-4-(trifluoromethyl)phenyl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 44) N-(4-((2,3-difluoro-4-(trifluoromethyl)phenyl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 45) N-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethoxy)phenyl)amino)phenyl)acrylamide, 46) N-(4-((3,5-difluoro-4-(trifluoromethyl)phenyl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 47) N-(4-((4-chlorophenyl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 48) N-(4-((5-bromo-6-methylpyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 49) N-(4-((5-chloro-6-methylpyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 50) N-(4-((5-chloropyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 51) N-(4-((5-bromo-4-chloropyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 52) N-(4-((5-bromopyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 53) N-(4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(1-methyl-1H-pyrazol-3-yl)phenyl)acrylamide, 54) N-(3-(1-methyl-1H-pyrazol-3-yl)-4-((4-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide, 55) N-(4-((4,5-dichloropyridin-2-yl)amino)-3-(1-methyl-1H-pyrazol-3-yl)phenyl)acrylamide, and 56) N-(4-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(1-methyl-1H-pyrazol-3-yl)phenyl)acrylamide.

[0022] For example, the compound represented by Formula 1 according to the present invention can be prepared according to the following Reaction Scheme 1, and the compound represented by Formula 2 according to the present invention can be prepared according to the following Reaction Scheme 2: [Reaction Scheme 1] JPEG2025503671000008.jpg67141[Reaction scheme 2] In the above reaction schemes 1 and 2, the remaining definitions except for X′ and X″ are as defined above, and X′ and X″ are described below.

[0023] In the above reaction schemes 1 and 2, step 1 is an amine substitution reaction, and step 2 is a Suzuki coupling reaction, and the order of steps 1 and 2 can be changed depending on the reactivity of each reactant. In this case, X' is a substituent for the Suzuki coupling reaction, and may be, but is not limited to, -B(OH)2, tributylstannyl, etc.

[0024] Step 3 in each of the above reaction schemes 1 and 2 is a reaction for reducing a nitro group, which can be carried out using a palladium catalyst in the presence of hydrogen, but is not limited thereto.

[0025] Step 4 in each of Schemes 1 and 2 above is a reaction between an amine group and a carbonyl or sulfonyl group, where X″ can be, but is not limited to, hydroxy or halogen (e.g., chloro).

[0026] The above-mentioned production method can be more specifically embodied in the production examples described below.

[0027] The present invention also provides a pharmaceutical composition for preventing or treating cancer or tumor, comprising the compound represented by Formula 1 or 2, or a pharma- ceutically acceptable salt thereof, as an active ingredient.

[0028] The term "prevention" as used herein means any action that inhibits or delays the occurrence, spread and recurrence of said disease by administering the composition of the present invention, and "treatment" means any action that improves or favorably alters the symptoms of said disease by administering the composition of the present invention. Effect of the Invention

[0029] The compound represented by Chemical Formula 1 or 2 of the present invention, or a pharma- ceutically acceptable salt thereof, can be usefully used for the prevention or treatment of cancer or tumor. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] Hereinafter, preferred examples will be presented to aid in understanding the present invention. However, the following examples are merely illustrative of the present invention, and the scope of the present invention is not limited to the following examples.

[0031] Example 1: Preparation of N-(6-(cyclohexylamino)-[1,1'-biphenyl]-3-yl)acrylamide JPEG2025503671000010.jpg62141

[0032] (Stage 1) 2-Bromo-1-fluoro-4-nitrobenzene (5.0 mmol, 1.1 g, 1.0 eq) was dissolved in cyclohexanamine (1.5 mL) and reacted at 140° C. overnight. After completion of the reaction, the temperature was cooled to room temperature. Water (30 mL) was added and stirred for 1 hour, and the resulting solid was filtered to obtain 2-bromo-N-cyclohexyl-4-nitroaniline (1.3 g, yield: 86%).

[0033] (Stage 2) 2-Bromo-N-cyclohexyl-4-nitroaniline (1.0mmol, 0.29g, 1.0eq) was dissolved in a mixture (2.2mL) of 1,4-dioxane and water (1,4-dioxane:water = 10:1 (v:v)) in a sealed tube. Phenylboronic acid (1.2mmol, 0.15g, 1.2eq), sodium carbonate (2.0mmol, 0.21g, 2.0eq), (Ph3P)4Pd (0.05mmol, 0.057g, 0.05eq) were added in sequence, and the mixture was reacted at 100°C overnight. After completion of the reaction, the solvent was removed and the resulting material was separated and purified by column chromatography (ethyl acetate:hexane=1:10 (v:v)) to obtain N-cyclohexyl-5-nitro-[1,1'-biphenyl]-2-amine (0.24 g, yield: 81%).

[0034] (Stage 3) N-Cyclohexyl-5-nitro-[1,1'-biphenyl]-2-amine (0.8mmol, 0.24g, 1.0eq) was dissolved in methanol (10mL), Pd / C (24mg) was added, and the reaction was carried out at room temperature overnight under hydrogen (H2) atm. After the reaction was completed, the mixture was filtered through a celite pad, and the filtrate was concentrated and diluted with N 2 -Cyclohexyl-[1,1'-biphenyl]-2,5-diamine (0.24 g, yield: 100%) was obtained.

[0035] (Stage 4) N 2 -Cyclohexyl-[1,1'-biphenyl]-2,5-diamine (0.1mmol, 0.026g, 1.0eq), acrylic acid (0.12mmol, 0.0086g, 1.2eq), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.2g), and triethylamine (0.1mL) were dissolved in dichloromethane (1mL) and reacted at room temperature overnight. After completion of the reaction, dichloromethane was removed and the product was purified by column chromatography to obtain compound 1 (0.011g, yield: 35%).

[0036] 1H NMR (500 MHz, CDCl3) δ 7.50-7.30 (m, 8H), 7.27-7.22 (m, 1H), 6.66 (d, J = 8.8 Hz, 1H), 6.36 (d, J = 16.9 Hz, 1H), 6.23 (d, J = 10.2 Hz, 1H), 5.70-5.63 (m, 1H), 3.82 (brs, 1H), 3.30-3.20 (m, 1H), 2.02-1.91 (m, 2H), 1.68-1.64 (m, 3H), 1.36-1.30 (m, 2H), 1.17 (td, J = 11.7, 3.8 Hz, 1H), 1.10-1.02 (m, 2H).

[0037] Example 2: Preparation of N-(4-(cyclohexylamino)-3-(pyridin-2-yl)phenyl)acrylamide JPEG2025503671000011.jpg24141

[0038] (Stage 1) 2-Bromo-N-cyclohexyl-4-nitroaniline (0.5mmol, 0.15g, 1.0eq) was dissolved in 1,4-dioxane (1mL) in a sealed tube, and then 2-(tributylstannyl)pyridine (0.6mmol, 0.2mL, 1.2eq) and (Ph3P)4Pd (0.05mmol, 0.057g, 0.05eq) were added in sequence, and the mixture was reacted at 150°C overnight. After the reaction was completed, the solvent was removed, and the obtained material was separated and purified by column chromatography (ethyl acetate:hexane = 1:5 (v:v)) to obtain N-cyclohexyl-4-nitro-2-(pyridin-2-yl)aniline (0.1g, yield: 67%).

[0039] (Stage 2) N-Cyclohexyl-4-nitro-2-(pyridin-2-yl)aniline (1.0 mmol, 0.29 g, 1.0 eq) was dissolved in methanol (10 mL), Pd / C (30 mg) was added, and the mixture was reacted at room temperature overnight under hydrogen (H2) atm. After the reaction was completed, the mixture was filtered through a celite pad, and the filtrate was concentrated and diluted with N 1-Cyclohexyl-2-(pyridin-2-yl)benzene-1,4-diamine (0.27 g, yield: 100%) was obtained.

[0040] (Stage 3) N 1 -Cyclohexyl-2-(pyridin-2-yl)benzene-1,4-diamine (0.1mmol, 0.027g, 1.0eq), acrylic acid (0.12mmol, 0.0086g, 1.2eq), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.091g), N,N-diisopropylethylamine (0.1mL) were dissolved in dichloromethane (1mL) and reacted at room temperature overnight. After completion of the reaction, dichloromethane was removed and the product was purified by column chromatography to obtain compound 2 (13mg, yield: 42%).

[0041] 1 H NMR (500 MHz, CDCl3) δ 8.57 (d, J = 4.6 Hz, 1H), 7.94 (d, J = 2.3 Hz, 1H), 7.72-7.68 (m, 2H), 7.28 (d, J = 2.1 Hz, 1H), 7.16 (dd, J = 8.5, 3.1 Hz, 1H), 6.72 (d, J = 8.9 Hz, 1H), 6.40 (d, J = 16.8 Hz, 2H), 6.23 (dd, J = 16.8, 10.2 Hz, 1H), 5.71 (d, J = 10.2 Hz, 1H), 3.45-3.43 (m, 1H), 2.06-1.97 (m, 2H), 1.80-1.70 (m, 2H), 1.64-1.57 (m, 1H) 1.45-1.23 (m, 5H).

[0042] Example 3: Preparation of N-(3-(pyridin-2-yl)-4-((cis-4-(trifluoromethyl)cyclohexyl)amino)phenyl)acrylamide JPEG2025503671000012.jpg3052 The title compound (6 mg, yield: 15%) was obtained in the same manner as in Example 1, except that cis-4-(trifluoromethyl)-cyclohexane-1-amine was used instead of cyclohexylamine in Step 1 of Example 1, and 2-tributylstannylpyridine was used instead of phenylboronic acid in Step 2 of Example 1.

[0043] 1 H NMR (500 MHz, CDCl3) δ 8.52 (d, J = 4.3 Hz, 1H), 7.99 (d, J = 1.4 Hz, 1H), 7.77-7.62 (m, 4H), 7.29 (dd, J = 8.7, 1.6 Hz, 1H), 7.20-7.10 (m, 1H), 6.69 (s, 1H), 6.39 (dd, J = 17.2, 4.8 Hz, 1H), 6.27 (dd, J = 16.8, 10.1 Hz, 1H), 5.68 (d, J = 10.1 Hz, 1H), 3.35-3.20 (m, 1H), 2.27-2.23 (m, 2H), 2.15-1.98 (m, 2H), 1.50-1.38 (m, 2H), 1.25-1.20 (m, 2H).

[0044] Example 4: Preparation of N-(3-(pyridin-2-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide JPEG2025503671000013.jpg61141

[0045] (Stage 1) In a sealed tube, 2-bromo-1-fluoro-4-nitrobenzene (4.54 mmol, 1.0 g, 1.0 eq) was dissolved in 1,4-dioxane (20 mL), and then 2-(tributylstannyl)pyridine (5.0 mmol, 1.84 g, 1.1 eq) and (Ph3P)4Pd (0.45 mmol, 0.52 g, 0.1 eq) were added in sequence, and the mixture was reacted overnight at 150° C. After the reaction was completed, the solvent was removed, and the resulting material was separated and purified by column chromatography (ethyl acetate:hexane=1:3 (v:v)) to obtain 2-(2-fluoro-5-nitrophenyl)pyridine (0.68 g, yield: 68%).

[0046] (Stage 2) 2-(2-fluoro-5-nitrophenyl)pyridine (3.7mmol, 0.599g, 1.2eq) was dissolved in dimethylformamide (10mL), and then 55% NaH (10.0mmol, 0.43g) was added and stirred for 10 minutes. 5-(trifluoromethyl)pyridin-2-amine (3.1mmol, 0.68g, 1.0eq) was added and stirred at room temperature for 2 hours. When the reaction was completed, the reaction mixture was cooled to 0°C, and distilled water (30mL) was added. The resulting solid was filtered to obtain N-(4-nitro-2-(pyridin-2-yl)phenyl)-5-(trifluoromethyl)pyridin-2-amine (0.64g, yield: 57%).

[0047] (Stage 3) N-(4-nitro-2-(pyridin-2-yl)phenyl)-5-(trifluoromethyl)pyridin-2-amine (1.77 mmol, 0.64 g), Fe (17.7 mmol, 0.99 g), NH4Cl (1.77 mmol, 0.094 g) and 70% ethanol solution (10 mL) were added to the flask in sequence, and the reaction was allowed to proceed overnight at room temperature. After completion of the reaction, Fe and NH4Cl were removed to obtain 2-(pyridin-2-yl)-N 1 -(5-(trifluoromethyl)pyridin-2-yl)benzene-1,4-diamine (0.62 g, yield: 100%) was obtained.

[0048] (Stage 4) 2-(pyridin-2-yl)-N 1 -(5-(trifluoromethyl)pyridin-2-yl)benzene-1,4-diamine (0.1 mmol, 0.033 g, 1.0 eq), acrylic acid (0.12 mmol, 0.0086 g, 1.2 eq), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU; 0.12 mmol, 0.0046 g), N,N-diisopropylethylamine (0.3 mmol, 0.052 mL) were dissolved in dichloromethane (1 mL) and reacted at room temperature overnight. After completion of the reaction, dichloromethane was removed and the mixture was purified by column chromatography to give compound 4 (8 mg, 20%).

[0049] 1 H NMR (500 MHz, DMSO) δ 11.42 (s, 1H), 8.69 (d, J = 4.8 Hz, 1H), 8.44 (s, 1H), 8.31-8.26 (m, 2H), 7.85-7.75 (m, 2H), 7.62 (dd, J = 8.7, 2.1 Hz, 1H), 7.41-7.32 (m, 1H), 7.32-7.26 (m, 2H), 6.82 (d, J = 8.8 Hz, 1H), 6.47 (d, J = 16.6 Hz, 1H), 6.27 (dd, J = 16.8, 10.2 Hz, 1H), 5.80 (d, J = 10.3 Hz, 1H).

[0050] Example 5: Preparation of N-(2-methoxy-5-(pyridin-2-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide JPEG2025503671000014.jpg4039 The title compound (6 mg, yield: 15%) was obtained in the same manner as in Example 4, except that 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene was used instead of 2-bromo-1-fluoro-4-nitrobenzene in Step 1 of Example 4.

[0051] 1H NMR (500 MHz, CDCl3) δ 12.37 (s, 1H), 8.97 (s, 1H), 8.60 (d, J = 4.3 Hz, 1H), 8.45 (s, 1H), 8.36 (s, 1H), 7.93-7.70 (m, 3H), 7.62 (dd, J = 8.7, 2.3 Hz, 1H), 7.19 (dd, J = 6.6, 5.3 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1H), 6.44 (dd, J = 16.8, 1.0 Hz, 1H), 6.31 (dd, J = 16.8, 10.1 Hz, 1H), 5.76 (dd, J = 10.1, 0.9 Hz, 1H), 3.98 (s, 3H).

[0052] Example 6: Preparation of N-(3-(1-methyl-1H-imidazol-4-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide JPEG2025503671000015.jpg4338 The title compound (8 mg, yield: 20%) was obtained in the same manner as in Example 4, except that in Step 1 of Example 4, 1-methyl-4-(tributylstannyl)-1H-imidazole was used instead of 2-(tributylstannyl)pyridine.

[0053] 1 H NMR (500 MHz, MeOD) δ 8.34 (s, 1H), 8.07-7.92 (m, 2H), 7.72-7.66 (m, 2H), 7.73-7.65 (m, 1H), 7.37 (brs, 1H), 6.79 (d, J = 9.0 Hz, 1H), 6.50-6.32 (m, 2H), 5.77 (dd, J = 9.9, 1.9 Hz, 1H), 3.74 (s, 3H).

[0054] Example 7: Preparation of N-(4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(pyridin-2-yl)phenyl)acrylamide JPEG2025503671000016.jpg4042 The title compound (20 mg, yield: 47%) was obtained in the same manner as in Example 4, except that 3-chloro-5-(trifluoromethyl)pyridin-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine in Step 2 of Example 4.

[0055] 1 H NMR (500 MHz, MeOD) δ 8.67 (d, J = 4.0 Hz, 1H), 8.58 (d, J = 9.0 Hz, 1H), 8.31 (s, 1H), 8.18 (d, J = 2.4 Hz, 1H), 7.99-7.77 (m, 3H), 7.57 (dd, J = 9.0, 2.4 Hz, 1H), 7.36 (dd, J = 6.9, 5.0 Hz, 1H), 6.50-6.35 (m, 2H), 5.78 (dd, J = 9.8, 1.9 Hz, 1H).

[0056] Example 8: Preparation of N-(4-((4,5-dichloropyridin-2-yl)amino)-3-(pyridin-2-yl)phenyl)acrylamide JPEG2025503671000017.jpg3942 The title compound (14 mg, yield: 36%) was obtained in the same manner as in Example 4, except that in Step 2 of Example 4, 4,5-dichloro-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine.

[0057] 1 H NMR (500 MHz, MeOD) δ 8.64 (d, J = 4.3 Hz, 1H), 8.07-7.01 (m, 2H), 7.90-7.84 (m, 2H), 7.72 (d, J = 8.1 Hz, 1H), 7.61 (dd, J = 8.8, 2.4 Hz, 1H), 7.39-7.26 (m, 1H), 6.88 (s, 1H), 6.51-6.30 (m, 2H), 5.77 (dd, J = 9.8, 1.9 Hz, 1H).

[0058] Example 9: Preparation of N-(4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide JPEG2025503671000018.jpg4342 The title compound (15 mg, yield: 12%) was obtained in the same manner as in Example 4, except that in Step 1 of Example 4, 1-methyl-4-(tributylstannyl)-1H-imidazole was used instead of 2-(tributylstannyl)pyridine, and in Step 2 of Example 4, 3-chloro-4-(trifluoromethyl)pyridin-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine.

[0059] 1 H NMR (500 MHz, CDCl3) δ 11.83 (s, 1H), 8.65 (d, J = 8.9 Hz, 1H), 8.36 (s, 1H), 8.24 (s, 1H), 7.75 (s, 1H), 7.55 (s, 1H), 7.48 (s, 1H), 7.26 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.47 (d, J = 16.7 Hz, 1H), 6.30 (dd, J = 16.7, 10.2 Hz, 1H), 5.79 (d, J = 10.1 Hz, 1H), 3.75 (s, 3H).

[0060] Example 10: Preparation of N-(4-((4,5-dichloropyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide JPEG2025503671000019.jpg4242 The title compound (17 mg, yield: 45%) was obtained in the same manner as in Example 4, except that in Step 1 of Example 4, 1-methyl-4-(tributylstannyl)-1H-imidazole was used instead of 2-(tributylstannyl)pyridine, and in Step 2 of Example 4, 4,5-dichloro-(trifluoromethyl)pyridin-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine.

[0061] 1 H NMR (500 MHz, DMSO) δ 10.86 (s, 1H), 10.15 (s, 1H), 8.26 (s, 1H), 8.09 (d, J = 2.3 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.82 (s, 1H), 7.49-7.45 (m, 2H), 6.99 (s, 1H), 6.44 (dd, J = 16.9, 10.1 Hz, 1H), 6.25 (dd, J = 17.0, 1.8 Hz, 1H), 5.74 (dd, J = 10.3, 1.6 Hz, 1H), 3.72 (s, 3H).

[0062] Example 11: Preparation of N-(6-((4-fluorobenzyl)amino)-[1,1'-biphenyl]-3-yl)acrylamide JPEG2025503671000020.jpg3940 The title compound (16 mg, yield: 47%) was obtained in the same manner as in Example 1, except that 4-fluorobenzylamine was used instead of cyclohexanamine in Step 1 of Example 1.

[0063] 1 H NMR (500 MHz, CDCl3) δ 7.50-7.29 (m, 8H), 7.28-7.23 (m, 2H), 7.01-6.97 (m, 2H), 6.56 (d, J = 8.7 Hz, 1H), 6.37 (d, J = 16.5 Hz, 1H), 6.21 (dd, J = 16.8, 10.2 Hz, 1H), 5.68 (dd, J = 10.2, 0.9 Hz, 1H), 4.35-4.25 (m, 3H).

[0064] Example 12: Preparation of N-(4-((4-fluorobenzyl)amino)-3-(pyridin-2-yl)phenyl)acrylamide JPEG2025503671000021.jpg3940The title compound (18 mg, yield: 53%) was obtained in the same manner as in Example 1, except that 4-fluorobenzylamine was used instead of cyclohexaneamine in Step 1 of Example 1, and 2-tributylstannylpyridine was used instead of phenylboronic acid in Step 2 of Example 1.

[0065] 1 H NMR (500 MHz, CDCl3) δ 8.84 (brs, 1H) 8.53 (d, J = 4.7 Hz, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.72-7.71 (m, 2H), 7.54 (brs, 1H), 7.33-7.30 (m, 2H), 7.20 (dd, J = 8.8, 2.4 Hz, 1H), 7.15 (dd, J = 8.6, 4.5 Hz, 1H), 7.01-6.97 (m, 2H), 6.57 (d, J = 8.8 Hz, 1H), 6.40 (ddd, J = 16.8, 7.3, 1.0Hz, 1H), 6.24 (dd, J = 16.8, 10.2 Hz, 1H), 5.69 (dd, J = 10.3, 0.8 Hz, 1H), 4.41 (s, 2H).

[0066] Example 13: Preparation of N-(3-(5-chloropyridin-2-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide JPEG2025503671000022.jpg4146 The title compound (10 mg, yield: 25%) was obtained in the same manner as in Example 4, except that in Step 1 of Example 4, 5-chloro-2-(tributylstannyl)pyridine was used instead of 2-(tributylstannyl)pyridine.

[0067] 1H NMR (500 MHz, CDCl3) δ 10.93 (s, 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.42 (s, 1H), 8.24-8.19 (m, 2H), 7.80-7.56 (m, 4H), 7.31 (dd, J = 8.8, 2.2 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.46 (d, J = 16.4 Hz, 1H), 6.28 (dd, J = 16.8, 10.2 Hz, 1H), 5.78 (d, J = 10.9 Hz, 1H).

[0068] Example 14: Preparation of N-(4-(pyridin-2-yl)-3-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide JPEG2025503671000023.jpg50141

[0069] (Stage 1) 2-Bromo-5-nitroaniline (1.0mmol, 0.21g, 1.0eq) was dissolved in 1,4-dioxane (20mL) in a sealed tube, and then 2-(tributylstannyl)pyridine (1.2mmol, 0.44g, 1.2eq) and (Ph3P)4Pd (0.1mmol, 0.11g, 0.1eq) were added in sequence, and the mixture was reacted overnight at 150°C. After the reaction was completed, the solvent was removed, and the obtained material was separated and purified by column chromatography (ethyl acetate:hexane = 1:3 (v:v)) to obtain 5-nitro-2-(pyridin-2-yl)aniline (0.15g, yield: 70%).

[0070] (Stage 2) 5-nitro-2-(pyridin-2-yl)aniline (0.69mmol, 0.15g, 1.0eq), Cu(OAc)2 (1.72mmol, 0.31g, 2.5eq), (4-(trifluoromethyl)phenyl)boronic acid (1.4mmol, 0.27g, 2.0eq), and dichloromethane (10mL) were added to the flask in sequence and stirred. Pyridine (2.76mmol, 0.22g, 4.0eq) was added and stirred at room temperature for 48 hours. After the reaction was completed, Cu(OAc)2 was removed, and the mixture was separated and purified by column chromatography (ethyl acetate / hexane = 1:3 (v:v)) to obtain 5-nitro-2-(pyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline (0.22g, yield: 88%).

[0071] (Stage 3) A flask was charged with 5-nitro-2-(pyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline (0.61 mmol, 0.22 g, 1.0 eq), Fe (6 mmol, 0.33 g, 10 eq), NH4Cl (0.61 mmol, 0.032 g, 1.0 eq) and 70% ethanol solution (10 mL), and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, Fe and NH4Cl were removed to obtain 6-(pyridin-2-yl)-N 1 -(4-(trifluoromethyl)phenyl)benzene-1,3-diamine (0.2 g, yield: 99%) was obtained.

[0072] (Stage 4) 6-(Pyridin-2-yl)-N 1-(4-(trifluoromethyl)phenyl)benzene-1,3-diamine (0.1 mmol, 0.033 g, 1.0 eq), acrylic acid (0.1 mmol, 0.0072 g, 1.0 eq), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.12 mmol, 0.0046 g), N,N-diisopropylethylamine (0.1 mL) were dissolved in dichloromethane (1 mL) and reacted at room temperature overnight. After completion of the reaction, dichloromethane was removed and the mixture was purified by column chromatography to obtain compound 14 (13 mg, yield: 33%).

[0073] 1 H NMR (500 MHz, CDCl3) δ 10.85 (s, 1H), 8.62 (d, J = 4.2 Hz, 1H), 7.83-7.75 (m, 2H), 7.70 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.45 (s, 1H), 7.31-7.24 (m, 3H), 7.22 (dd, J = 6.8, 5.2 Hz, 1H), 6.45 (dd, J = 16.8, 0.4 Hz, 1H), 6.25 (dd, J = 16.8, 10.3Hz, 1H), 5.78 (d, J = 10.8 Hz, 1H).

[0074] Example 15: Preparation of N-(3-(pyrimidin-4-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide JPEG2025503671000024.jpg4040 The title compound (5 mg, yield: 12%) was obtained in the same manner as in Example 4, except that in Step 1 of Example 4, 4-(tributylstannyl)pyrimidine was used instead of 2-(tributylstannyl)pyridine.

[0075] 1H NMR (500 MHz, CDCl3) δ 11.48 (s, 1H), 9.27 (s, 1H), 8.78 (d, J = 5.4 Hz, 1H), 8.53-8.29 (m, 3H), 7.84-7.61 (m, 3H), 7.35 (dd, J = 8.9, 2.4 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 6.47 (d, J = 17.2 Hz, 1H), 6.29 (dd, J = 16.8, 10.2 Hz, 1H), 5.80 (d, J = 10.3 Hz, 1H).

[0076] Example 16: Preparation of N-(4-((4,5-dichloropyridin-2-yl)amino)-3-(pyrimidin-4-yl)phenyl)acrylamide JPEG2025503671000025.jpg3942 The title compound (7 mg, yield: 19%) was obtained in the same manner as in Example 4, except that in Step 1 of Example 4, 4-(tributylstannyl)pyrimidine was used instead of 2-(tributylstannyl)pyridine, and in Step 2 of Example 4, 4,5-dichloro-(trifluoromethyl)pyridin-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine.

[0077] 1 H NMR (500 MHz, CDCl3) δ 11.33 (s, 1H), 9.27 (s, 1H), 8.78 (d, J = 5.5 Hz, 1H), 8.44 (d, J = 1.5 Hz, 1H), 8.27-8.14 (m, 2H), 7.77-7.72 (m, 2H), 7.33 (dd, J = 8.9, 2.3 Hz, 1H), 6.93 (s, 1H), 6.46 (d, J = 16.8 Hz, 1H), 6.29 (dd, J = 16.8, 10.2 Hz, 1H), 5.79 (d, J = 10.3 Hz, 1H).

[0078] Example 17: Preparation of N-(3-(pyridin-4-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide JPEG2025503671000026.jpg4040 The title compound (16 mg, yield: 42%) was obtained in the same manner as in Example 4, except that in Step 1 of Example 4, 4-(tributylstannyl)pyridine was used instead of 2-(tributylstannyl)pyridine.

[0079] 1 H NMR (500 MHz, CDCl3) δ 8.65-8.64 (m, 2H), 8.39 (s, 1H), 7.75 (s, 1H), 7.69-7.59 (m, 3H), 7.41-7.30 (m, 3H), 6.66 (d, J = 8.7 Hz, 1H), 6.52 - 6.39 (m, 2H), 6.26 (dd, J = 16.8, 10.3 Hz, 1H), 5.82 (d, J = 10.3 Hz, 1H).

[0080] Example 18: Preparation of N-(4-((4,5-dichloropyridin-2-yl)amino)-3-(pyridin-4-yl)phenyl)acrylamide JPEG2025503671000027.jpg3942 The title compound (14 mg, yield: 36%) was obtained in the same manner as in Example 4, except that in Step 1 of Example 4, 4-(tributylstannyl)pyridine was used instead of 2-(tributylstannyl)pyridine, and in Step 2 of Example 4, 4,5-dichloro-(trifluoromethyl)pyridine-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine.

[0081] 1H NMR (500 MHz, CDCl3) δ 8.63-8.62 (m, 2H), 8.11 (s, 1H), 7.74 (s, 1H), 7.65-7.55 (m, 3H), 7.32-7.31 (d, J = 5.9 Hz, 2H), 6.72 (s, 1H), 6.46 (dd, J = 16.8, 0.7 Hz, 1H), 6.34-6.22 (m, 2H), 5.80 (dd, J = 10.2, 0.8 Hz, 1H).

[0082] Example 19: Preparation of N-(4-(5-chloro-4-fluoro-1H-indol-1-yl)-3-(pyridin-2-yl)phenyl)acrylamide JPEG2025503671000028.jpg3843 The title compound (19 mg, yield: 48%) was obtained in the same manner as in Example 4, except that 5-chloro-4-fluoro-1H-indole was used instead of 5-(trifluoromethyl)pyridin-2-amine in Step 2 of Example 4.

[0083] 1 H NMR (500 MHz, CDCl3) δ 8.58 (d, J = 4.4 Hz, 1H), 8.16-8.06 (m, 2H), 7.90 (d, J = 2.4 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.30 (td, J = 7.8, 1.7 Hz, 1H), 7.10 (dd, J = 6.7, 5.0 Hz, 1H), 7.01 (dd, J = 8.6, 7.0 Hz, 1H), 6.95 (d, J = 3.2 Hz, 1H), 6.81 (d, J = 8.7 Hz, 1H), 6.60 (d, J = 3.1 Hz, 1H), 6.50 (dd, J = 14.8, 12.5 Hz, 1H), 6.29 (dd, J = 16.9, 10.3 Hz, 1H), 5.88-5.77 (m, 1H), 5.30 (s, 1H).

[0084] Example 20: Preparation of N-(4-((5-cyclopropylpyridin-2-yl)amino)-3-(pyridin-2-yl)phenyl)acrylamide JPEG2025503671000029.jpg4239 The title compound (3 mg, yield: 9%) was obtained in the same manner as in Example 4, except that in Step 2 of Example 4, 5-cyclopropylpyridin-1-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine.

[0085] 1 H NMR (500 MHz, CDCl3) δ 10.82 (s, 1H), 8.65 (d, J = 4.6 Hz, 1H), 8.23-8.00 (m, 3H), 7.81-7.65 (m, 2H), 7.46 (s, 1H), 7.31 (dd, J = 8.8, 2.0 Hz, 1H), 7.24-7.19 (m, 1H), 7.16 (dd, J = 8.5, 2.2 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), 6.44 (d, J = 17.1 Hz, 1H), 6.26 (dd, J = 16.8, 10.2 Hz, 1H), 5.75 (d, J = 10.2 Hz, 1H), 1.82-1.75 (m, 1H), 0.93-0.86 (m, 2H), 0.62-0.55 (m, 2H).

[0086] Example 21: Preparation of N-(4-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(pyridin-2-yl)phenyl)acrylamide JPEG2025503671000030.jpg4040 The title compound (9 mg, yield: 22%) was obtained in the same manner as in Example 4, except that 3-fluoro-5-(trifluoromethyl)pyridine-2-amine was used instead of 5-(trifluoromethyl)pyridine-2-amine in Step 2 of Example 4.

[0087] 1H NMR (500 MHz, CDCl3) δ 12.56 (s, 1H), 8.76 (d, J = 8.9 Hz, 1H), 8.68 (d, J = 4.7 Hz, 1H), 8.43 (s, 1H), 8.26 (s, 1H), 7.92-7.75 (m, 2H), 7.45-7.35 (m, 2H), 7.35- 7.26 (m, 2H), 6.47 (d, J = 16.8 Hz, 1H), 6.28 (dd, J = 16.8, 10.2 Hz, 1H), 5.80 (d, J = 10.2 Hz, 1H).

[0088] Example 22: Preparation of N-(6-(((1r,4r)-4-hydroxycyclohexyl)amino)-5-phenylpyridin-3-yl)acrylamide JPEG2025503671000031.jpg4431The title compound (11 mg, yield: 34%) was obtained in the same manner as in Example 1, except that in Step 1 of Example 1, trans-4-aminocyclohexan-1-ol and 3-bromo-2-chloro-5-nitropyridine were used instead of cyclohexanamine and 2-bromo-1-fluoro-4-nitrobenzene, respectively.

[0089] 1 H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 2.2 Hz, 1H), 7.84 (s, 1H), 7.76 (d, J = 2.2 Hz, 1H), 7.46-7.31 (m, 6H), 6.43-6.35 (m, 1H), 6.27 (dd, J = 16.9, 10.2 Hz, 1H), 5.73 (d, J = 12.2 Hz, 1H), 4.41-4.33 (m, 1H), 3.94-3.83 (m, 1H), 3.63-3.53 (m, 1H), 2.12-2.06 (m, 2H), 1.98-1.90 (m, 2H), 1.50-1.40 (m, 2H), 1.15-1.04 (m, 2H).

[0090] Example 23: Preparation of (E)-N-(3-(4-fluorostyryl)-4-((2-(thiazol-2-yl)ethyl)amino)phenyl)acrylamide JPEG2025503671000032.jpg2752 The title compound (14 mg, yield: 36%) was obtained in the same manner as in Example 1, except that 2-(thiazol-2-yl)ethan-1-amine was used instead of cyclohexaneamine in Step 1 of Example 1, and (E)-(4-fluorostyryl)boronic acid was used instead of phenylboronic acid in Step 2 of Example 1.

[0091] 1 H NMR (500 MHz, CDCl3) δ 7.72-7.59 (m, 3H), 7.43-7.40 (m, 2H), 7.35-7.30 (m, 1H), 7.21 (d, J = 3.3 Hz, 1H), 7.08-6.97 (m, 3H), 6.87 (d, J = 16.0 Hz, 1H), 6.64 (d, J = 8.7 Hz, 1H), 6.40 (d, J = 16.8 Hz, 1H), 6.25 (dd, J = 16.8, 10.2 Hz, 1H), 5.69 (d, J = 10.1 Hz, 1H), 4.53 (brs, 1H), 3.56 (t, J = 6.3 Hz, 2H), 3.33 (t, J = 6.3 Hz, 2H).

[0092] Example 24: Preparation of (E)-N-(3-(4-fluorostyryl)-4-((2-(thiazol-2-yl)ethyl)amino)phenyl)ethanesulfonamide JPEG2025503671000033.jpg2752 The title compound (8 mg, yield: 18%) was obtained in the same manner as in Example 1, except that in step 1 of Example 1, 2-(thiazol-2-yl)ethan-1-amine was used instead of cyclohexaneamine, in step 2 of Example 1, (E)-(4-fluorostyryl)boronic acid was used instead of phenylboronic acid, in step 4 of Example 1, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride was not used, and ethenesulfonyl chloride was used instead of acrylic acid.

[0093] 1 H NMR (500 MHz, CDCl3) δ 7.67 (d, J = 3.2 Hz, 1H), 7.48-7.45 (m, 2H), 7.25-7.21 (m, 2H), 7.08-7.05 (m, 3H), 6.98 (d, J = 15.9 Hz, 1H), 6.87 (d, J = 16.0 Hz, 1H), 6.63 (d, J = 8.6 Hz, 1H), 6.59-6.53 (m, 1H), 6.18 (d, J = 16.6 Hz, 1H), 6.51 (brs, 1H), 5.90 (d, J = 10.0 Hz, 1H), 4.71 (brs, 1H), 3.60-3.53 (m, 2H), 3.36 (t, J = 6.2 Hz, 2H).

[0094] Example 25: Preparation of N-(4-(cyclohexylamino)-3-(pyridin-3-yl)phenyl)acrylamide JPEG2025503671000034.jpg3439 The title compound (7 mg, yield: 22%) was obtained in the same manner as in Example 2, except that in Step 1 of Example 2, 3-(tributylstannyl)pyridine was used instead of 2-(tributylstannyl)pyridine.

[0095] 1H NMR (500 MHz, CDCl3) δ 8.62 (d, J = 1.2 Hz, 1H), 8.56 (d, J = 4.0 Hz, 1H), 8.26 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.48 (dd, J = 8.8, 2.1 Hz, 1H), 7.37-7.31 (m, 1H), 7.27 (d, J = 2.2 Hz, 1H), 6.68-6.64 (m, 2H), 6.36 (d, J = 16.1 Hz, 1H), 6.27 (dd, J = 16.9, 10.0 Hz, 1H), 5.68 - 5.57 (m, 1H), 3.25-3.21 (m, 1H), 1.95-1.88 (m, 2H), 1.70-1.50 (m, 2H), 1.40-0.95 (m, 6H).

[0096] Example 26: Preparation of N-(4-(cyclopentylamino)-3-(pyridin-2-yl)phenyl)acrylamide JPEG2025503671000035.jpg3139 The title compound (4 mg, yield: 14%) was obtained in the same manner as in Example 1, except that cyclopentanamine was used instead of cyclohexaneamine in Step 1 of Example 1, and 2-tributylstannylpyridine was used instead of phenylboronic acid in Step 2 of Example 1.

[0097] 1H NMR (500 MHz, CDCl3) δ 8.07 (s, 1H), 8.02 (s, 1H), 7.48-7.41 (m, 2H), 7.10-7.02 (m, 3H), 6.96 (d, J = 15.9 Hz, 1H), 6.77 (d, J = 15.9 Hz, 1H), 6.43 (d, J = 16.9 Hz, 1H), 6.26 (dd, J = 16.8, 10.3 Hz, 1H), 5.77 (d, J = 10.2 Hz, 1H), 3.63-3.62 (m, 1H), 2.25-2.12 (m, 2H), 2.05-1.96 (m, 2H), 1.52 - 1.46 (m, 2H), 1.25-1.20 (m, 2H).

[0098] Example 27: Preparation of (E)-N-(5-(4-fluorostyryl)-6-((2-(thiazol-2-yl)ethyl)amino)pyridin-3-yl)acrylamide JPEG2025503671000036.jpg2752 The title compound (19 mg, yield: 45%) was obtained in the same manner as in Example 1, except that in Step 1 of Example 1, 2-(thiazol-2-yl)ethan-1-amine and 3-bromo-2-chloro-5-nitropyridine were used instead of cyclohexanamine and 2-bromo-1-fluoro-4-nitrobenzene, respectively, and in Step 2 of Example 1, (E)-(4-fluorostyryl)boronic acid was used instead of phenylboronic acid.

[0099] 1H NMR (500 MHz, CDCl3) δ 8.07 (s, 1H), 8.02 (s, 1H), 7.67 (d, J = 3.1 Hz, 1H), 7.46-7.39 (m, 2H), 7.21 (d, J = 3.1 Hz, 1H), 7.05-7.02 (m, 2H), 6.92 (d, J = 16.1 Hz, 1H), 6.83 (d, J = 16.0 Hz, 1H), 6.42 (d, J = 16.9 Hz, 1H), 6.27 (dd, J = 16.8, 10.2 Hz, 1H), 5.74 (d, J = 10.0 Hz, 1H), 5.39 (s, 1H), 4.56 (s, 1H), 3.85 (d, J = 5.7 Hz, 2H), 3.35 (t, J = 6.2 Hz, 2H).

[0100] Example 28: Preparation of (E)-N-(5-(4-fluorostyryl)-6-((2-(thiazol-2-yl)ethyl)amino)pyridin-3-yl)ethanesulfonamide JPEG2025503671000037.jpg2752 The title compound (4 mg, yield: 11%) was obtained in the same manner as in Example 1, except that in step 1 of Example 1, cyclohexaneamine and 2-bromo-1-fluoro-4-nitrobenzene were replaced with 2-(thiazol-2-yl)ethane-1-amine and 3-bromo-2-chloro-5-nitropyridine, respectively, in step 2 of Example 1, phenylboronic acid was replaced with (E)-(4-fluorostyryl)boronic acid, and in step 4 of Example 1, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride was not used, and ethenesulfonyl chloride was used instead of acrylic acid.

[0101] 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 2.2 Hz, 1H), 7.67 (d, J = 3.3 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.48-7.45 (m, 2H), 7.22 (d, J = 3.2 Hz, 1H), 7.08-7.06 (m, 2H), 6.92 (d, J = 16.1 Hz, 1H), 6.82 (d, J = 16.0 Hz, 1H), 6.57 (dd, J = 16.5, 9.9 Hz, 1H), 6.18 (d, J = 16.6 Hz, 1H), 5.94 (d, J = 9.9 Hz, 1H), 5.59 (t, J = 5.2 Hz, 1H), 3.89-3.86 (m, 2H), 3.40-3.29 (m, 3H).

[0102] Example 29: Preparation of N-(3-fluoro-5-(pyridin-2-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide JPEG2025503671000038.jpg4039 The title compound (10 mg, yield: 25%) was obtained in the same manner as in Example 4, except that 1-bromo-2,3-difluoro-5-nitrobenzene was used instead of 2-bromo-1-fluoro-4-nitrobenzene in Step 1 of Example 4.

[0103] 1 H NMR (500 MHz, CDCl3) δ 9.51 (s, 1H), 8.72 (d, J = 4.4 Hz, 1H), 8.40 (s, 1H), 7.87-7.74 (m, 2H), 7.69 (d, J = 8.0 Hz, 1H), 7.65-7.56 (m, 2H), 7.38-7.30 (m, 2H), 6.60 - 6.48 (m, 2H), 6.29 (dd, J = 16.8, 10.2 Hz, 1H), 5.87 (d, J = 10.6 Hz, 1H).

[0104] Example 30: Preparation of N-(4-((5-chloro-4-cyclopropylpyridin-2-yl)amino)-3-(pyridin-2-yl)phenyl)acrylamide JPEG2025503671000039.jpg3944 The title compound (12 mg, yield: 30%) was obtained in the same manner as in Example 4, except that in Step 2 of Example 4, 5-chloro-4-cyclopropylpyridin-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine.

[0105] 1 H NMR (500 MHz, CDCl3) δ 10.90 (s, 1H), 8.67 (d, J = 4.4 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 8.09 (s, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.77 (dd, J = 11.9, 4.5 Hz, 2H), 7.73 (d, J = 7.9 Hz, 1H), 7.34 (dd, J = 8.8, 2.2 Hz, 1H), 7.27-7.21 (m, 1H), 6.45 (d, J = 16.7 Hz, 1H), 6.35-6.23 (m, 2H), 5.80-5.71 (m, 1H), 2.19-2.13 (m, 1H), 1.16-1.02 (m, 2H), 0.81-0.66 (m, 2H).

[0106] Example 31: Preparation of N-(3-(1-methyl-1H-imidazol-4-yl)-4-((4(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide JPEG2025503671000040.jpg3844 The title compound (3 mg, yield: 9%) was obtained in the same manner as in Example 4, except that 1-methyl-4-(tributylstannyl)-1H-imidazole was used instead of 2-(tributylstannyl)pyridine in Step 1 of Example 4, and 4-(trifluoromethyl)pyridin-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine in Step 2 of Example 4.

[0107] 1 H NMR (500 MHz, CDCl3) δ 11.34 (s, 1H), 8.44 (d, J = 8.8 Hz, 1H), 8.35 (d, J = 5.1 Hz, 1H), 8.22 (s, 1H), 7.54 (s, 1H), 7.48 (s, 1H), 7.26 (s, 1H), 7.19 (d, J = 7.2 Hz, 1H), 7.01 (s, 1H), 6.86 (d, J = 4.9 Hz, 1H), 6.47 (d, J = 16.8 Hz, 1H), 6.29 (dd, J = 16.8, 10.2 Hz, 1H), 5.78 (d, J = 10.2 Hz, 1H), 3.74 (s, 3H).

[0108] Example 32: Preparation of (E)-4-(dimethylamino)-N-(3-(1-methyl-1H-pyrazol-3-yl)-4-((4-(trifluoromethyl)pyridin-2-yl)amino)phenyl)-2-butenamide JPEG2025503671000041.jpg3356 The title compound (23 mg, yield: 52%) was obtained in the same manner as in Example 4, except that in step 1 of Example 4, 1-methyl-4-(tributylstannyl)-1H-pyrazole was used instead of 2-(tributylstannyl)pyridine, in step 2 of Example 4, 4-(trifluoromethyl)pyridin-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine, in step 4 of Example 4, (E)-4-(dimethylamino)2-butenoyl chloride HCl salt was used instead of acrylic acid, and HATU was not used.

[0109] 1H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 10.31 (brs, 1H), 10.18 (s, 1H), 8.35 (d, J = 5.2 Hz, 1H), 8.15 (d, J = 8.9 Hz, 1H), 8.09 (d, J = 2.3 Hz, 1H), 7.82 (d, J = 2.2 Hz, 1H), 7.63 (dd, J = 8.9, 2.3 Hz, 1H), 7.06 (s, 1H), 7.00 (d, J = 5.2 Hz, 1H), 6.81-6.74 (m, 1H), 6.55 (d, J = 2.2 Hz, 1H), 6.46 (d, J = 15.3 Hz, 1H), 3.97 (s, 3H), 3.89 (brs, 2H), 2.74 (s, 6H).

[0110] Example 33: Preparation of N-(4-((5-isopropylpyridin-2-yl)amino)-3-(pyridin-2-yl)phenyl)acrylamide JPEG2025503671000042.jpg4039 The title compound (3 mg, yield: 8%) was obtained in the same manner as in Example 4, except that in Step 2 of Example 4, 5-isopropylpyridin-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine.

[0111] 1 H NMR (500 MHz, CDCl3) δ 10.82 (brs, 1H), 8.66 (d, J = 4.3 Hz, 1H), 8.17 (s, 1H), 8.12-8.04 (m, 2H), 7.79-7.72 (m, 2H), 7.43-7.32 (m, 3H), 7.23 (t, J = 5.6 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 6.45 (d, J = 16.8 Hz, 1H), 6.26 (dd, J = 16.8, 10.2 Hz, 1H), 5.76 (d, J = 10.2 Hz, 1H), 2.83 (dt, J = 13.8, 6.8 Hz, 1H), 1.22 (d, J = 6.9 Hz, 1H).

[0112] Example 34: Preparation of N-(4-((5-ethynylpyridin-2-yl)amino)-3-(1-methyl-1H-pyrazol-3-yl)phenyl)acrylamide JPEG2025503671000043.jpg4143 The title compound (22 mg, yield: 58%) was obtained in the same manner as in Example 4, except that 1-methyl-4-(tributylstannyl)-1H-pyrazole was used instead of 2-(tributylstannyl)pyridine in Step 1 of Example 4, and 5-ethynylpyridin-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine in Step 2 of Example 4.

[0113] 1 H NMR (500 MHz, CDCl3) δ 10.48 (s, 1H), 8.38 (dd, J = 5.2, 3.3 Hz, 2H), 8.13 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 8.6, 1.9 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.32 (dd, J = 8.8, 1.9 Hz, 1H), 7.22 (s, 1H), 6.77 (d, J = 8.6 Hz, 1H), 6.64 (d, J = 1.8 Hz, 1H), 6.45 (d, J = 16.8 Hz, 1H), 6.26 (dd, J = 16.8, 10.2 Hz, 1H), 5.78 (d, J = 10.2 Hz, 1H), 4.00 (s, 3H), 3.10 (s, 1H).

[0114] Example 35: Preparation of N-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide JPEG2025503671000044.jpg60141

[0115] (Stage 1) 2-Bromo-4-nitroaniline (4.6mmol, 1.0g, 1.0eq) was dissolved in 1,4-dioxane (9mL) in a sealed tube, and then 1-methyl-4-(tributylstannyl)-1H-imidazole (5.5mmol, 2.1g, 1.2eq) and (Ph3P)4Pd (0.46mmol, 0.53g, 0.1eq) were added in sequence, and the mixture was reacted at 150°C for 2 hours. After the reaction was completed, the solvent was removed, and the resulting material was separated and purified by column chromatography (ethyl acetate:hexane = 1:1 (v:v)) to obtain 2-(1-methyl-1H-imidazol-4-yl)-4-nitroaniline (0.64g, yield: 64%).

[0116] (Stage 2) 2-(1-methyl-1H-imidazol-4-yl)-4-nitroaniline (5.1mmol, 1.1g, 1.0eq), Cu(OAc)2 (6.1mmol, 1.1g, 1.2eq), (4-(trifluoromethyl)phenyl)boronic acid (6.1mmol, 1.2g, 1.2eq), and dichloromethane (25mL) were added to the flask in sequence and stirred. Triethylamine (10mmol, 1.0g, 2.0eq) was added and stirred at room temperature for 2 hours. After the reaction was completed, Cu(OAc)2 was removed, and the mixture was separated and purified by column chromatography (ethyl acetate / hexane = 1:3 (v:v)) to obtain 2-(1-methyl-1H-imidazol-4-yl)-4-nitro-N-(4-(trifluoromethyl)phenyl)aniline (1.2g, yield: 67%).

[0117] (Stage 3) 2-(1-methyl-1H-imidazol-4-yl)-4-nitro-N-(4-(trifluoromethyl)phenyl)aniline (3.1 mmol, 1.1 g, 1.0 eq), Fe (31 mmol, 1.7 g, 10 eq), NH4Cl (3.1 mmol, 0.17 g, 1.0 eq) and 70% ethanol solution (15 mL) were added to the flask, and the mixture was stirred at 40°C for 4 hours. After the reaction was completed, Fe and NH4Cl were removed, and the mixture was separated and purified by column chromatography (ethyl acetate) to obtain 2-(1-methyl-1H-imidazol-4-yl)-N1 -(4-(trifluoromethyl)phenyl)benzene-1,4-diamine (0.60 g, yield: 59%) was obtained.

[0118] (Stage 4) 2-(1-Methyl-1H-imidazol-4-yl)-N 1 -(4-(trifluoromethyl)phenyl)benzene-1,4-diamine (1.8mmol, 0.60g, 1.0eq), acrylic acid (2.2mmol, 0.16g, 1.2eq), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (2.7mmol, 0.52g, 1.5eq), and triethylamine (0.76mL) were dissolved in dichloromethane (9mL) and reacted at room temperature for 3 hours. After completion of the reaction, dichloromethane was removed, and the product was separated and purified by column chromatography (ethyl acetate) to obtain the title compound (0.35g, yield: 51%).

[0119] 1 H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.38 (s, 1H), 8.15 (d, J = 2.3 Hz, 1H), 7.75 (s, 1H), 7.57 (dd, J = 8.7, 2.3 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.42 (s, 1H), 7.31 (d, J = 8.7 Hz, 1H), 6.98 (d, J = 8.5 Hz, 2H), 6.45 (dd, J = 17.0, 10.1 Hz, 1H), 6.26 (dd, J = 17.0, 1.8 Hz, 1H), 5.75 (dd, J = 10.2, 1.8 Hz, 1H), 3.67 (s, 3H).

[0120] Example 36: Preparation of N-(4-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide JPEG2025503671000045.jpg4340 The title compound (5 mg, yield: 12%) was obtained in the same manner as in Example 4, except that in Step 1 of Example 4, 1-methyl-4-(tributylstannyl)-1H-imidazole was used instead of 2-(tributylstannyl)pyridine, and in Step 2 of Example 4, 3-fluoro-5-(trifluoromethyl)pyridin-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine.

[0121] 1 H NMR (500 MHz, CDCl3) δ 12.09 (s, 1H), 8.82 (d, J = 9.0 Hz, 1H), 8.28 (s, 2H), 7.55 (s, 1H), 7.48 (s, 1H), 7.42 (d, J = 9.8 Hz, 1H), 7.28 (s, 1H), 7.15 (dd, J = 8.9, 2.2 Hz, 1H), 6.47 (d, J = 16.7 Hz, 1H), 6.30 (dd, J = 16.7, 10.2 Hz, 1H), 5.79 (d, J = 10.2 Hz, 1H), 3.75 (s, 3H).

[0122] Example 37: Preparation of N-(4-((4-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(1-methyl-1H-pyrazol-3-yl)phenyl)acrylamide JPEG2025503671000046.jpg3843 The title compound (10 mg, yield: 24%) was obtained in the same manner as in Example 4, except that in Step 1 of Example 4, 1-methyl-4-(tributylstannyl)-1H-pyrazole was used instead of 2-(tributylstannyl)pyridine, and in Step 2 of Example 4, 4-chloro-5-(trifluoromethyl)pyridin-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine.

[0123] 1H NMR (500 MHz, CDCl3) δ 10.71 (s, 1H), 8.47 (s, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.18 (s, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 6.88 (s, 1H), 6.68 (d, J = 1.8 Hz, 1H), 6.48 (d, J = 16.8 Hz, 1H), 6.29 (dd, J = 16.8, 10.2 Hz, 1H), 5.82 (d, J = 10.2 Hz, 1H), 4.04 (s, 3H) one proton is missing due to overlapping.

[0124] Example 38: Preparation of N-(3-fluoro-5-(1-methyl-1H-imidazol-4-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide JPEG2025503671000047.jpg4338 The title compound (8 mg, yield: 20%) was obtained in the same manner as in Example 4, except that in Step 1 of Example 4, 1-bromo-2,3-difluoro-5-nitrobenzene and 1-methyl-4-(tributylstannyl)-1H-imidazole were used instead of 2-bromo-1-fluoro-4-nitrobenzene and 2-(tributylstannyl)pyridine, respectively.

[0125] 1 H NMR (500 MHz, CDCl3) δ 9.00 (s, 1H), 8.88 (s, 1H), 8.40 (s, 1H), 8.08 (s, 1H), 7.95 (s, 1H), 7.81 (d, J = 9.5 Hz, 1H), 7.59 - 7.51 (m, one proton is missing due to overlapping.

[0126] Example 39: Preparation of N-(2'-((5-(trifluoromethyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-5'-yl)acrylamide JPEG2025503671000048.jpg4039 The title compound (7 mg, yield: 18%) was obtained in the same manner as in Example 1, except that in Step 1 of Example 1, 5-(trifluoromethyl)pyridine-2-amine and 3-bromo-2-chloro-5-nitropyridine were used instead of cyclohexanamine and 2-bromo-1-fluoro-4-nitrobenzene, respectively, and in Step 2 of Example 1, 1-methyl-4-(tributylstannyl)-1H-imidazole was used instead of phenylboronic acid.

[0127] 1 H NMR (500 MHz, CDCl3) δ 12.42 (s, 1H), 8.80 (d, J = 4.7 Hz, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.53 (d, J = 7.2 Hz, 2H), 8.30 (d, J = 2.4 Hz, 1H), 7.91 (s, 1H), 7.82 (t, J = 7.9 Hz, 3H), 7.32 (d, J = 4.0 Hz, 1H), 6.51 (d, J = 16.8 Hz, 1H), 6.35 (dd, J = 16.8, 10.2 Hz, 1H), 5.84 (d, J = 10.3 Hz, 1H) one proton is missing due to overlapping

[0128] Example 40: Preparation of N-(4-((3-fluoro-4-(trifluoromethyl)phenyl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide JPEG2025503671000049.jpg4340 The title compound (6 mg, yield: 15%) was obtained in the same manner as in Example 35, except that (3-fluoro-4-(trifluoromethyl)phenyl)boronic acid was used instead of (4-(trifluoromethyl)phenyl)boronic acid in Step 2 of Example 35.

[0129] 1H NMR (500 MHz, CDCl3) δ 10.17 (s, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.51 (s, 1H), 7.46 - 7.34 (m, 2H), 7.25 (s, 1H), 7.20 (dd, J = 8.6, one proton is missing due to overlapping.

[0130] Example 41: Preparation of N-(5-(1-methyl-1H-imidazol-4-yl)-6-((4-(trifluoromethyl)phenyl)amino)pyridin-3-yl)acrylamide JPEG2025503671000050.jpg3843 The title compound (6 mg, yield: 15%) was obtained in the same manner as in Example 35, except that 3-bromo-5-nitropyridin-2-amine was used instead of 2-bromo-4-nitroaniline in Step 2 of Example 35.

[0131] 1 H NMR (500 MHz, MeOD) δ 8.29 (dd, J = 15.9, 2.5 Hz, 2H), 7.88 (d, J = 8.6 Hz, 2H), 7.76 (s, 1H), 7.59 - 7.49 (m, 3H), 6.43 (dd, J = 15.0, 5.9 Hz, 2H), 5.82 (dd, J = 9.6, 2.1 Hz, 1H), 3.83 (s, 3H).

[0132] Example 42: Preparation of N-(3-(1-methyl-1H-pyrazol-3-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide JPEG2025503671000051.jpg3843 The title compound (7 mg, yield: 18%) was obtained in the same manner as in Example 35, except that 1-methyl-4-(tributylstannyl)-1H-pyrazole was used instead of 1-methyl-4-(tributylstannyl)-1H-imidazole in Step 1 of Example 35.

[0133] 1 H NMR (500 MHz, DMSO) δ 10.21 (s, 1H), 9.03 (s, 1H), 8.11 (d, J = 2.3 Hz, 1H), 7.76 (d, J = 2.2 Hz, 1H), 7.68 (dd, J = 8.7, 2.3 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.7 Hz, 1H), 7.01 (d, J = 8.5 Hz, 2H), 6.53 (d, J = 2.2 Hz, 1H), 6.45 (dd, J = 17.0, 10.1 Hz, 1H), 6.27 (dd, J = 17.0, 1.8 Hz, 1H), 5.76 (dd, J = 10.1, 1.8 Hz, 1H), 3.92 (s, 3H).

[0134] Example 43: Preparation of N-(4-((3-chloro-4-(trifluoromethyl)phenyl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide JPEG2025503671000052.jpg3843 The title compound (10 mg, yield: 24%) was obtained in the same manner as in Example 35, except that (3-chloro-4-(trifluoromethyl)phenyl)boronic acid was used instead of 4-(trifluoromethyl)phenyl)boronic acid in Step 2 of Example 35.

[0135] 1H NMR (500 MHz, CDCl3) δ 10.14 (s, 1H), 8.11 (s, 1H), 7.58 - 7.34 (m, 4H), 7.23 (d, J = 19.3 Hz, 3H), 7.04 - 6.99 (m, 1H), 6.47 (d, J = 16.8 Hz, 1H), 6.29 (dd, J = 16.8, 10.2 Hz, 1H), 5.80 (d, J = 10.2 Hz, 1H), 3.75 (s, 3H).

[0136] Example 44: Preparation of N-(4-((2,3-difluoro-4-(trifluoromethyl)phenyl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide JPEG2025503671000053.jpg3843 The title compound (8 mg, yield: 19%) was obtained in the same manner as in Example 35, except that (2,3-difluoro-4-(trifluoromethyl)phenyl)boronic acid was used instead of (4-(trifluoromethyl)phenyl)boronic acid in Step 2 of Example 35.

[0137] 1 H NMR (500 MHz, CDCl3) δ 10.18 (s, 1H), 8.06 (d, J = 1.2 Hz, 1H), 7.63 (s, 1H), 7.51 (s, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.22 (s, 1H), 7.12 (t, J = 4.9 Hz, 2H), 6.47 (d, J = 16.7 Hz, 1H), 6.30 (dd, J = 16.8, 10.2 Hz, 1H), 5.79 (d, J = 10.3 Hz, 1H), 3.73 (s, 3H).

[0138] Example 45: Preparation of N-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethoxy)phenyl)amino)phenyl)acrylamide JPEG2025503671000054.jpg3843 The title compound (8 mg, yield: 20%) was obtained in the same manner as in Example 35, except that (4-(trifluoromethoxy)phenyl)boronic acid was used instead of (4-(trifluoromethyl)phenyl)boronic acid in Step 2 of Example 35.

[0139] 1 H NMR (500 MHz, CDCl3) δ 10.18 (s, 1H), 8.06 (d, J = 1.2 Hz, 1H), 7.63 (s, 1H), 7.51 (s, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.22 (s, 1H), 7.12 (t, J = 4.9 Hz, 2H), 6.47 (d, J = 16.7 Hz, 1H), 6.30 (dd, J = 16.8, 10.2 Hz, 1H), 5.79 (d, J = 10.3 Hz, 1H), 3.73 (s, 3H).

[0140] 1 H NMR (500 MHz, CDCl3) δ 9.78 (s, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.87 (s, 1H), 7.72 - 7.66 (m, 2H), 7.57 (td, J = 7.4, 1.2 Hz, 1H), 7.51 - 7.45 (m, 2H), 7.29 (d, J = 4.9 Hz, 1H), 7.17 - 7.13 (m, 2H), , 6.43 (d, J = 16.6 Hz, 1H), 6.35 - 6.25 (m, 1H), 5.73 (dd, J = 10.1, 1.1 Hz, 1H), 3.69 (s, 3H).

[0141] Example 46: Preparation of N-(4-((3,5-difluoro-4-(trifluoromethyl)phenyl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide JPEG2025503671000055.jpg4340 The title compound (5 mg, yield: 12%) was obtained in the same manner as in Example 35, except that (3,5-difluoro-4-(trifluoromethyl)phenyl)boronic acid was used instead of (4-(trifluoromethyl)phenyl)boronic acid in Step 2 of Example 35.

[0142] 1 H NMR (500 MHz, CDCl3) δ 10.32 (s, 1H), 8.14 (s, 1H), 7.49 (d, J = 11.9 Hz, 2H), 7.39 (d, J = 8.7 Hz, 1H), 7.24 (s, 1H), 7.21 (s, 1H), 6.65 (d, J = 12.0 Hz, 2H), 6.47 (d, J = 16.7 Hz, 1H), 6.30 (s, 1H), 5.80 (d, J = 10.4 Hz, 1H), 3.75 (s, 3H).

[0143] Example 47: Preparation of N-(4-((4-chlorophenyl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide JPEG2025503671000056.jpg3743 The title compound (15 mg, yield: 42%) was obtained in the same manner as in Example 35, except that (4-chlorophenyl)boronic acid was used instead of (4-trifluoromethyl)phenyl)boronic acid in Step 2 of Example 35.

[0144] 1H NMR (500 MHz, CDCl3) δ 9.69 (s, 1H), 8.03 (dd, J = 9.6, 2.0 Hz, 1H), 7.54 (s, 1H), 7.47 (s, 1H), 7.29 (d, J = 8.9 Hz, 1H), 7.23 - 7.16 (m, 3H), 7.16 - 7.12 (m, 1H), 7.10 (d, J = 8.6 Hz, 2H), 6.44 (d, J = 16.8 Hz, 1H), 6.28 (dd, J = 16.8, 10.2 Hz, 1H), 5.76 (t, J = 8.1 Hz, 1H), 3.71 (s, 3H).

[0145] Example 48: Preparation of N-(4-((5-bromo-6-methylpyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide JPEG2025503671000057.jpg4139 The title compound (7 mg, yield: 17%) was obtained in the same manner as in Example 4, except that in Step 1 of Example 4, 1-methyl-4-(tributylstannyl)-1H-imidazole was used instead of 2-(tributylstannyl)pyridine, and in Step 2 of Example 4, 5-bromo-6-methylpyridin-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine.

[0146] 1 H NMR (500 MHz, CDCl3) δ 10.76 (s, 1H), 8.38 (d, J = 8.9 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.63 - 7.39 (m, 3H), 7.25 - 7.17 (m, 2H), 6.57 (d, J = 8.7 Hz, 1H), 6.45 (d, J = 16.7 Hz, 1H), 6.31 (d, J = 10.2 Hz, 1H), 5.77 (d, J = 10.2 Hz, 1H), 3.71 (s, 3H), 2.58 (s, 3H).

[0147] Example 49: Preparation of N-(4-((5-chloro-6-methylpyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide JPEG2025503671000058.jpg4139 The title compound (10 mg, yield: 27%) was obtained in the same manner as in Example 4, except that in Step 1 of Example 4, 1-methyl-4-(tributylstannyl)-1H-imidazole was used instead of 2-(tributylstannyl)pyridine, and in Step 2 of Example 4, 5-chloro-6-methylpyridin-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine.

[0148] 1 H NMR (500 MHz, CDCl3) δ 10.71 (s, 1H), 8.38 (d, J = 8.9 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 15.4 Hz, 2H), 7.37 (d, J = 8.7 Hz, 1H), 7.28 - 7.15 (m, 2H), 6.64 (d, J = 8.7 Hz, 1H), 6.45 (d, J = 16.6 Hz, 1H), 6.29 (dd, J = 16.8, 10.2 Hz, 1H), 5.77 (d, J = 10.2 Hz, 1H), 3.73 (s, 3H), 2.54 (s, 3H).

[0149] Example 50: Preparation of N-(4-((5-chloropyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide JPEG2025503671000059.jpg4435 The title compound (12 mg, yield: 28%) was obtained in the same manner as in Example 4, except that in Step 1 of Example 4, 1-methyl-4-(tributylstannyl)-1H-imidazole was used instead of 2-(tributylstannyl)pyridine, and in Step 2 of Example 4, 4-chloropyridin-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine.

[0150] 1 H NMR (500 MHz, CDCl3) δ 10.94 (s, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.17 (dd, J = 6.9, 2.2 Hz, 2H), 7.51 (s, 1H), 7.42 (dd, J = 9.0, 2.4 Hz, 2H), 7.26 (s, 1H), 7.18 (dd, J = 8.8, 2.1 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.46 (d, J = 16.8 Hz, 1H), 6.28 (dd, J = 16.8, 10.2 Hz, 1H), 5.78 (d, J = 10.2 Hz, 1H), 3.74 (s, 3H).

[0151] Example 51: Preparation of N-(4-((5-bromo-4-chloropyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide JPEG2025503671000060.jpg4433 The title compound (10 mg, yield: 23%) was obtained in the same manner as in Example 4, except that in Step 1 of Example 4, 1-methyl-4-(tributylstannyl)-1H-imidazole was used instead of 2-(tributylstannyl)pyridine, and in Step 2 of Example 4, 5-bromo-4-chloropyridin-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine.

[0152] 1 H NMR (500 MHz, CDCl3) δ 11.08 (s, 1H), 8.29 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.73 (s, 1H), 7.49 (s, 1H), 7.25 - 7.14 (m, 2H), 6.95 (s, 1H), 6.45 (d, J = 16.7 Hz, 1H), 6.30 (dd, J = 16.8, 10.2 Hz, 1H), 5.77 (d, J = 10.3 Hz, 1H), 3.71 (s, 3H).

[0153] Example 52: Preparation of N-(4-((5-bromopyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide JPEG2025503671000061.jpg4430 The title compound (5 mg, yield: 13%) was obtained in the same manner as in Example 4, except that in Step 1 of Example 4, 1-methyl-4-(tributylstannyl)-1H-imidazole was used instead of 2-(tributylstannyl)pyridine, and in Step 2 of Example 4, 5-bromopyridin-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine.

[0154] 1 H NMR (500 MHz, CDCl3) δ 10.91 (s, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 10.2, 3.6 Hz, 2H), 7.38 (s, 1H), 7.27 (s, 1H), 7.17 (dd, J = 8.8, 2.1 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.46 (d, J = 16.7 Hz, 1H), 6.28 (dd, J = 16.8, 10.2 Hz, 1H), 5.78 (d, J = 10.2 Hz, 1H), 3.75 (s, 3H).

[0155] Example 53: Preparation of N-(4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(1-methyl-1H-pyrazol-3-yl)phenyl)acrylamide JPEG2025503671000062.jpg3743 The title compound (3 mg, yield: 7%) was obtained in the same manner as in Example 4, except that in Step 1 of Example 4, 1-methyl-4-(tributylstannyl)-1H-imidazole was used instead of 2-(tributylstannyl)pyridine, and in Step 2 of Example 4, 3-chloro-5-(trifluoromethyl)pyridin-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine.

[0156] 1 H NMR (500 MHz, DMSO) δ 11.36 (s, 1H), 10.19 (s, 1H), 8.63 (d, J = 9.0 Hz, 1H), 8.50 (s, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 7.59 (d, J = 9.1 Hz, 1H), 6.62 (d, J = 2.2 Hz, 1H), 6.48-6.38 (m, 1H), 6.26 (d, J = 17.0 Hz, 1H), 5.75 (d, J = 10.2 Hz, 1H), 3.96 (s, 3H).

[0157] Example 54: Preparation of N-(3-(1-methyl-1H-pyrazol-3-yl)-4-((4-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide JPEG2025503671000063.jpg3344 The title compound (15 mg, yield: 39%) was obtained in the same manner as in Example 4, except that 1-methyl-4-(tributylstannyl)-1H-pyrazole was used instead of 2-(tributylstannyl)pyridine in Step 1 of Example 4, and 4-(trifluoromethyl)pyridine-2-amine was used instead of 5-(trifluoromethyl)pyridine-2-amine in Step 2 of Example 4.

[0158] 1H NMR (500 MHz, DMSO) δ 10.19 (s, 1H), 10.17 (s, 1H), 8.35 (d, J = 5.2 Hz, 1H), 8.13 (d, J = 8.9 Hz, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.81 (d, J = 2.1 Hz, 1H), 7.60 (dd, J = 8.9, 2.2 Hz, 1H), 7.04 (s, 1H), 7.00 (d, J = 5.2 Hz, 1H) 6.55 (d, J = 2.1 Hz, 1H), 6.44 (dd, J = 16.9, 10.1 Hz, 1H), 6.26 (dd, J = 17.0, 1.7 Hz, 1H), 5.77-5.74 (m, 1H), 3.96 (s, 3H).

[0159] Example 55: Preparation of N-(4-((4,5-dichloropyridin-2-yl)amino)-3-(1-methyl-1H-pyrazol-3-yl)phenyl)acrylamide JPEG2025503671000064.jpg3743 The title compound (15 mg, yield: 39%) was obtained in the same manner as in Example 4, except that 1-methyl-4-(tributylstannyl)-1H-pyrazole was used instead of 2-(tributylstannyl)pyridine in Step 1 of Example 4, and 3,4-dichloropyridin-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine in Step 2 of Example 4.

[0160] 1H NMR (500 MHz, DMSO) δ 10.15 (s, 1H), 10.11 (s, 1H), 8.26 (s, 1H), 8.06-8.04 (m, 2H), 7.80 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 8.9, 2.3 Hz, 1H), 7.07 (s, 1H), 6.54 (d, J = 2.2 Hz, 1H), 6.42 (dd, J = 16.9, 10.1 Hz, 1H), 6.24 (dd, J = 17.0, 1.8 Hz, 1H), 5.73 (dd, J = 10.1, 1.8Hz, 1H), 3.96 (s, 3H)

[0161] Example 56: Preparation of N-(4-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(1-methyl-1H-pyrazol-3-yl)phenyl)acrylamide JPEG2025503671000065.jpg3743 The title compound (14 mg, yield: 35%) was obtained in the same manner as in Example 4, except that in Step 1 of Example 4, 1-methyl-4-(tributylstannyl)-1H-pyrazole was used instead of 2-(tributylstannyl)pyridine, and in Step 2 of Example 4, 2-fluoro-4-(trifluoromethyl)pyridin-2-amine was used instead of 5-(trifluoromethyl)pyridin-2-amine.

[0162] 1 H NMR (500 MHz, CDCl3) δ 11.59 (s, 1H), 8.93 (d, J = 8.9 Hz, 1H), 8.33 (s, 1H), 8.26 (s, 1H), 7.46 (t, J = 6.4 Hz, 2H), 7.35 (d, J = 7.2 Hz, one proton is missing due to overlapping.

[0163] Experimental Example 1: Activity inhibition test of transcription factor TEAD The compounds prepared in the above examples were analyzed using Hippo Pathway TEAD reporter-MCF7 recombinant cell line (BPS Bioscience, Catalog #60618) by ONE-Glo. TM The transcription factor TEAD activity was measured using the Luciferase assay (Promega, Catalog #E6110).

[0164] Specifically, the TEAD Reporter-MCF7 cell line contains the firefly luciferase gene, whose expression is regulated under the control of the TEAD response element in the human breast cancer cell line MCF7. Under unstressed conditions, the cell line has unphosphorylated YAP / TAZ in the nucleus, which induces the persistent expression of the luciferase reporter.

[0165] TEAD Reporter-MCF7 cells were prepared in 100 μL of cell culture medium (MEM medium, 10% FBS, 1% P / S, 400 μg / mL Geneticin, 1% N-ethyl acetate A, 1 mM NA pyruvate, 10 μg / mL Insulin) in a white clear-bottom 96-well microplate. The prepared plate was cultured in a 37°C, 5% CO2 incubator for 24 hours, and then treated with the previously prepared compound of the example so that the final concentration was 0.001, 0.01, 0.1, 1, and 10 μM, and all treatment solutions were repeated three times. The plate treated with the compound of the example was cultured in a 37°C, 5% CO2 incubator for 24 hours, and the enzymatic reaction was started by adding 100 μL / well of a substrate solution containing luciferin to the white clear-bottom 96-well microplate. The plate was incubated at room temperature for 5 minutes, and luminescence (integration time 1000 ms) was measured using a Flexstation3 multi-mode microplate reader.TM Luciferase enzyme activity, which represents the activity of the transcription factor TEAD, was measured by chemiluminescence according to the luciferase assay instructions, and the inhibitory activity of the compounds according to the present invention was calculated. The results of each compound were analyzed using Microsoft Excel, and the IC 50 The values ​​were calculated by GraphPad Prism software and the results are shown in Table 1 below.

[0166] Experimental Example 2: Cell proliferation inhibition test For the compounds prepared in the above examples, cell proliferation was measured using human mesothelioma cell lines NCI-H226 (addexbio), NCI-H28 (Korea Cell Line Bank) and MSTO-211H (eLabscience) by CellTiter-Glo® Luminescent Cell Viability (Promega, Catalog #G7571). This evaluation method is a method in which when luciferase enzyme is activated by ATP released from living cells, it reacts with luciferin substrate, and the enzyme activity at this time is measured to confirm cell viability.

[0167] Specifically, NCI-H226, NCI-H28 and MSTO-211H cells were prepared in 100μL of cell culture medium (RPMI medium, 10% FBS, 1% P / S, 4.5g / L D-Glucose, 2.383g / L HEPES Buffer, L-Glutamine, 1.5g / L Sodium Bicarbonate, 110mg / L Sodium Pyruvate) in a white clear-bottom 96-well microplate. The prepared plate was cultured in a 37℃, 5% CO2 incubator for 24 hours, and then treated with the previously prepared compound of the Example to a final concentration of 0.001, 0.01, 0.1, 1 and 10μM, and all treatment solutions were repeated three times. The plate treated with the compound of the Example was incubated at 37°C in a 5% CO2 incubator, and 100 μL / well of an aqueous substrate solution containing luciferin was added to a white clear-bottom 96-well microplate to initiate the enzymatic reaction. The reaction was allowed to proceed in the dark at room temperature for 10 minutes, and luminescence was measured using a Flexstation3 multi-mode microplate reader. Luciferase enzyme activity, which represents the amount of ATP, was measured by chemiluminescence according to the CellTiter-Glo (registered trademark) Luminescent Cell Viability manual, and the inhibitory activity of the compound according to the present invention was calculated. The results of each compound were analyzed using Microsoft Excel, and IC 50 The values ​​were calculated by GraphPad Prism software, and the results are shown in Tables 1 and 2 below.

[0168] [Table 1]

[0169] [Table 2]

Claims

1. A compound represented by the following formula 1 or 2, or a pharma- ceutically acceptable salt thereof: [Chemical formula 1] [Chemical formula 2] In the above Chemical Formulas 1 and 2, L １ is a single bond, C １－６ Alkylene, C ２－４ Alkenylene, or C ２－４ is alkynylene, R １ is phenyl or a 5- or 6-ring heterocycle containing 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; The R １ is unsubstituted or halogen, C １－４ Alkyl, C １－４ Thioalkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ Thioalkoxy, C １－４ Haloalkoxy, C ２－４ Alkenyl, C ２－４ Alkynyl, C ３－６ Cycloalkyl, amino, nitro, cyano, (C １－４ alkyl)amino, or di(C １－４ substituted with alkyl)amino; R ２ is -N(R ９ ) -L ２ -R ５ , 、 ,or and L ２ is a single bond, C １－６ Alkylene, C ２－４ Alkenylene, or C ２－４ is alkynylene, R ５ is C ３－７ cycloalkyl, phenyl, or a 5- or 6-ring heteroaryl containing 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; The R ５ is unsubstituted or is selected from hydroxy, halogen, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl, C １－４ Haloalkoxy, C １－４ Thioalkyl, and C ３－６ cycloalkyl; R ６ are each independently hydrogen, halogen, or C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, or C ３－７ is cycloalkyl, R ９ is hydrogen, halogen, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl, C １－４ Haloalkoxy, or C ３－６ is cycloalkyl, R ３ are each independently hydrogen, halogen, or C １－６ Alkyl, C １－６ Haloalkyl, or C １－４ is an alkoxy; R ４ are each independently hydrogen, C １－４ Alkyl, -CH ２ N (R ７ ) ２ , or R ７ a 5- or 6-ring heteroaliphatic ring containing 1 or 2 N substituted with R ７ are each independently hydrogen or C １－４ is alkyl, X is CR ８ or N, R ８ is hydrogen or a halogen, Y is CO, CS, or SO ２ It is.

2. L １ is a single bond or -CH=CH-; 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

3. R １ is phenyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, pyrrolidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl; The R １ is unsubstituted or halogen, C １－４ Alkyl, C １－４ Thioalkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, amino, nitro, cyano, (C １－４ alkyl)amino, or di(C １－４ substituted with (alkyl)amino; 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

4. L ２ is a single bond, methylene, or ethylene; 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

5. R ５ is cyclopentyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, or thiazolyl; The R ５ is unsubstituted or is selected from hydroxy, halogen, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl, C １－４ Haloalkoxy, C １－４ Thioalkyl, and C ３－６ cycloalkyl; 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

6. R ６ are each independently hydrogen, fluoro, chloro, difluoromethyl, or trifluoromethyl; 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

7. R ９ is hydrogen, 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

8. R ３ are each independently hydrogen or methoxy; 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

9. R ４ are all hydrogen, or R ４ One of the groups is hydrogen and the other is —CH ２ N (R ７ ) ２ , or R ７ is a 5- or 6-ring heteroaliphatic ring containing 1 or 2 N substituted with 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

10. X is CH, CF or N; 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

11. The compound according to claim 1, represented by the following chemical formula 3: [Chemical formula 3] In the above Chemical Formula 3, X is CH, CF, or N; A is benzene, pyridine, pyrimidine, imidazole, pyrazole, triazole, tetrazole, or oxadiazole; R' is hydrogen, halogen, C １－４ Alkyl, or C １－４ is an alkoxy; L １ is a single bond, C １－６ Alkylene, or C ２－４ alkenylene, B is benzene, pyridine, pyrimidine, thiazolyl, cyclopentyl, or cyclohexyl; R" is independently hydrogen, hydroxy, halogen, cyano, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ Thioalkoxy, C １－４ haloalkoxy, C ２－４ Alkenyl, C ２－４ Alkynyl, or C ３－６ is cycloalkyl, n″ is an integer from 1 to 3; L ２ is a single bond, or C １－６ is alkylene, R ３ is hydrogen or C １－４ is an alkoxy; R"' is hydrogen or -CH ２ -N(CH ３ ) ２ and R ３ is hydrogen or C １－４ It is an alkoxy.

12. The compound according to claim 1, represented by the following chemical formula 4: [Chemical formula 4] In the above Chemical Formula 4, X is CH, CF, or N; A is benzene, pyridine, pyrimidine, imidazole, pyrazole, triazole, tetrazole, or oxadiazole; R' is hydrogen, halogen, C １－４ Alkyl, or C １－４ is an alkoxy; L １ is a single bond, C １－６ Alkylene, or C ２－４ alkenylene, R ６ are each independently hydrogen, halogen, or C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, or C ３－７ is cycloalkyl, R ３ is hydrogen or C １－４ is an alkoxy; R"' is hydrogen or -CH ２ -N(CH ３ ) ２ It is.

13. The compound is 1) N-(6-(cyclohexylamino)-[1,1'-biphenyl]-3-yl)acrylamide, 2) N-(4-(cyclohexylamino)-3-(pyridin-2-yl)phenyl)acrylamide, 3) N-(3-(pyridin-2-yl)-4-((cis-4-(trifluoromethyl)cyclohexyl)amino)phenyl)acrylamide, 4) N-(3-(pyridin-2-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide, 5) N-(2-methoxy-5-(pyridin-2-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide, 6) N-(3-(1-methyl-1H-imidazol-4-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide, 7) N-(4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(pyridin-2-yl)phenyl)acrylamide, 8) N-(4-((4,5-dichloropyridin-2-yl)amino)-3-(pyridin-2-yl)phenyl)acrylamide, 9) N-(4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 10) N-(4-((4,5-dichloropyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 11) N-(6-((4-fluorobenzyl)amino)-[1,1′-biphenyl]-3-yl)acrylamide, 12) N-(4-((4-fluorobenzyl)amino)-3-(pyridin-2-yl)phenyl)acrylamide, 13) N-(3-(5-chloropyridin-2-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide, 14) N-(4-(pyridin-2-yl)-3-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide, 15) N-(3-(pyrimidin-4-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide, 16) N-(4-((4,5-dichloropyridin-2-yl)amino)-3-(pyrimidin-4-yl)phenyl)acrylamide, 17) N-(3-(pyridin-4-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide, 18) N-(4-((4,5-dichloropyridin-2-yl)amino)-3-(pyridin-4-yl)phenyl)acrylamide, 19) N-(4-(5-chloro-4-fluoro-1H-indol-1-yl)-3-(pyridin-2-yl)phenyl)acrylamide, 20) N-(4-((5-cyclopropylpyridin-2-yl)amino)-3-(pyridin-2-yl)phenyl)acrylamide, 21) N-(4-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(pyridin-2-yl)phenyl)acrylamide, 22) N-(6-(((1r,4r)-4-hydroxycyclohexyl)amino)-5-phenylpyridin-3-yl)acrylamide, 23) (E)-N-(3-(4-fluorostyryl)-4-((2-(thiazol-2-yl)ethyl)amino)phenyl)acrylamide, 24) (E)-N-(3-(4-fluorostyryl)-4-((2-(thiazol-2-yl)ethyl)amino)phenyl)ethanesulfonamide, 25) N-(4-(cyclohexylamino)-3-(pyridin-3-yl)phenyl)acrylamide, 26) N-(4-(cyclopentylamino)-3-(pyridin-2-yl)phenyl)acrylamide, 27) (E)-N-(5-(4-fluorostyryl)-6-((2-(thiazol-2-yl)ethyl)amino)pyridin-3-yl)acrylamide, 28) (E)-N-(5-(4-fluorostyryl)-6-((2-(thiazol-2-yl)ethyl)amino)pyridin-3-yl)ethanesulfonamide, 29) N-(3-fluoro-5-(pyridin-2-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide, 30) N-(4-((5-chloro-4-cyclopropylpyridin-2-yl)amino)-3-(pyridin-2-yl)phenyl)acrylamide, 31) N-(3-(1-methyl-1H-imidazol-4-yl)-4-((4(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide, 32) (E)-4-(dimethylamino)-N-(3-(1-methyl-1H-pyrazol-3-yl)-4-((4-(trifluoromethyl)pyridin-2-yl)amino)phenyl)-2-butenamide, 33) N-(4-((5-isopropylpyridin-2-yl)amino)-3-(pyridin-2-yl)phenyl)acrylamide, 34) N-(4-((5-ethynylpyridin-2-yl)amino)-3-(1-methyl-1H-pyrazol-3-yl)phenyl)acrylamide, 35) N-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide, 36) N-(4-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 37) N-(4-((4-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(1-methyl-1H-pyrazol-3-yl)phenyl)acrylamide, 38) N-(3-fluoro-5-(1-methyl-1H-imidazol-4-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide, 39) N-(2'-((5-(trifluoromethyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-5'-yl)acrylamide, 40) N-(4-((3-fluoro-4-(trifluoromethyl)phenyl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 41) N-(5-(1-methyl-1H-imidazol-4-yl)-6-((4-(trifluoromethyl)phenyl)amino)pyridin-3-yl)acrylamide, 42) N-(3-(1-methyl-1H-pyrazol-3-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide, 43) N-(4-((3-chloro-4-(trifluoromethyl)phenyl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 44) N-(4-((2,3-difluoro-4-(trifluoromethyl)phenyl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 45) N-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethoxy)phenyl)amino)phenyl)acrylamide, 46) N-(4-((3,5-difluoro-4-(trifluoromethyl)phenyl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 47) N-(4-((4-chlorophenyl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 48) N-(4-((5-bromo-6-methylpyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 49) N-(4-((5-chloro-6-methylpyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 50) N-(4-((5-chloropyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 51) N-(4-((5-bromo-4-chloropyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 52) N-(4-((5-bromopyridin-2-yl)amino)-3-(1-methyl-1H-imidazol-4-yl)phenyl)acrylamide, 53) N-(4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(1-methyl-1H-pyrazol-3-yl)phenyl)acrylamide, 54) N-(3-(1-methyl-1H-pyrazol-3-yl)-4-((4-(trifluoromethyl)pyridin-2-yl)amino)phenyl)acrylamide, 55) N-(4-((4,5-dichloropyridin-2-yl)amino)-3-(1-methyl-1H-pyrazol-3-yl)phenyl)acrylamide, and 56) N-(4-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(1-methyl-1H-pyrazol-3-yl)phenyl)acrylamide Any one selected from the group consisting of:

2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

14. A pharmaceutical composition for preventing or treating cancer or tumor, comprising as an active ingredient the compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof.

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