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

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] This invention relates to a novel compound structure that can be usefully used for 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 make up organs. Furthermore, improper regulation of Hippo signaling has been linked to the development of various cancers (including breast cancer, head and neck cancer, colon cancer, ovarian cancer, liver cancer, brain cancer, prostate cancer, mesothelioma, and sarcoma).

[0003] Mutations occur in the NF2, Mst1 / 2, and Lats1 / 2 genes, which constitute the Hippo signaling system, in various cancers. Such mutations in tumor suppressor factors induce persistent YAP / TAZ and TEAD binding, thereby inducing gene expression related to cancer cell proliferation. The Hippo signaling system is composed of various elements such as 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 tumorigenesis, which is inversely correlated with cancer patient survival. YAP / TAZ activation is regulated by the response of a series of tumor suppressor genes that make up the Hippo signaling pathway. Representative tumor suppressor genes include NF2, Mst1 / 2, and Lats1 / 2. Activation of the top-level molecule NF2 mediates phosphorylation of Lats1 / 2 by Mst1 / 2, which in turn promotes phosphorylation of YAP and TAZ in the cytoplasm. Phosphorylated YAP and TAZ are then degraded by the proteasome after undergoing ubiquitination. Therefore, when the Hippo signaling system is activated (turned on), YAP and TAZ are inactivated. In contrast, when tumor suppressor genes are inactivated, i.e., when Hippo signaling is inactivated (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) to induce the expression of target genes such as connective tissue growth factor (CTGF), CYR61 (cysteine-rich angiogenic inducer 61), Gli2 (GLI family zinc finger 2), Birc2 / 5 (Baculoviral IAP repeat containing 2 / 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 pathway have been discovered in various cancers, and various research results have been reported for the development of anticancer drugs targeting YAP-TEAD. Taking it a step further, the involvement of the Hippo signaling pathway in the process of acquiring resistance after the application of existing approved anticancer drugs has been elucidated, and various studies are underway to demonstrate the potential of YAP-TEAD anticancer drugs as combination therapies for treating drug resistance.

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

[0007] Therefore, the inventors of this invention studied pharmaceuticals that could be usefully used to treat cancers in which the regulation of Hippo signaling is inactivated. As a result, they confirmed that the YAP-TEAD inhibitor according to the present invention, described later, binds to the palmitate binding site that mediates TEAD palmitoylation, and also suppresses the in vitro proliferation of cell lines with mutations in the Hippo signaling system (Hippo pathway mutated cell line). Thus, they 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, and thus completed the present invention. [Overview of the project] [Problems that the invention aims to solve]

[0008] This invention provides a novel compound structure that can be usefully used for the treatment or prevention of cancer or tumors. [Means for solving the problem]

[0009] To solve the above problems, the present invention provides a compound represented by the following chemical formula 1 or 2, or a pharmaceutically acceptable salt thereof: [Chemical formula 1] JPEG0007869861000001.jpg2655[Chemical formula 2] JPEG0007869861000002.jpg3361 In the above chemical formulas 1 and 2, L1 is a single bond, C 1-6 Alkilen, C 2-4 Alkenylene, or C 2-4 It is alkynylene, R1 is phenyl or a 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S, wherein R1 is unsubstituted or substituted with 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 alkyl)amino, R2 is -N(R9)-L2-R5, JPEG0007869861000003.jpg2631, JPEG0007869861000004.jpg2831, or JPEG0007869861000005.jpg2933, L2 is a single bond, C 1-6 alkylene, C 2-4 alkenylene, or C 2-4 alkynylene, R5 is C 3-7 cycloalkyl, phenyl, or a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S, wherein R5 is unsubstituted or substituted with 1 to 3 substituents each independently 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 each independently hydrogen, halogen, C 1-6 alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, or C 3-7 It is a 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 It is a cycloalkyl, R3 is independent of hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-4 It is an alkoxy, R4 independently contains hydrogen and C 1-4 A 5-ring or 6-ring heteroaliphatic ring containing one or two alkyl, -CH2N(R7)2, or R7-substituted N atoms, R7 can each independently use hydrogen or C 1-4 It 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 aforementioned R1 is either unsubstituted or a 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 It is substituted with alkylamino.

[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 aforementioned R5 is either unsubstituted, or hydroxyl, halogen, or C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Thioalkyl, and C 3-6 Each molecule is substituted with one to three substituents independently selected from the group consisting of cycloalkyl groups.

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

[0015] Preferably, R9 is hydrogen.

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

[0017] Preferably, R4 is all hydrogen, or One of the R4 atoms is hydrogen, and the other is a five- or six-ring heteroaliphatic ring containing -CH2N(R7)2, or one or two nitrogen atoms substituted with R7.

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

[0019] Preferably, the compound represented by chemical formula 1 is the compound represented by the following chemical formula 3: [Chemical formula 3] JPEG0007869861000006.jpg5778 In the above chemical formula 3, X is CH, CF, or N. A is benzene, pyridine, pyrimidine, imidazole, pyrazole, triazole, tetrazole, or oxadiazole. R' represents hydrogen, halogen, and C 1-4 Alkyl, or C 1-4 It is an alkoxy, L1 is a single bond, C 1-6 Alkylene, or C 2-4 It is alkenylene, B is benzene, pyridine, pyrimidine, thiazolyl, cyclopentyl, or cyclohexyl. R'' independently represents hydrogen, hydroxyl, halogen, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Thioalkoxy, C 1-4 It is a haloalkoxy, C 2-4 Alkenil, C 2-4 Alkinyl, or C 3-6 It is a cycloalkyl, n'' is an integer between 1 and 3. L2 is a single bond, or C 1-6 Alkilen the law of nature, 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 the compound represented by the following chemical formula 4: [Chemical formula 4] JPEG0007869861000007.jpg6269 In the above chemical formula 4, X is CH, CF, or N. A is benzene, pyridine, pyrimidine, imidazole, pyrazole, triazole, tetrazole, or oxadiazole. R' represents hydrogen, halogen, and C 1-4 Alkyl, or C 1-4 It is an alkoxy, L1 is a single bond, C 1-6 Alkylene, or C 2-4 It is alkenylene, R6 is independent of hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, or C 3-7 It is a cycloalkyl, R3 is hydrogen, or C 1-4 It is an alkoxy, R''' is hydrogen or -CH2-N(CH3)2.

[0021] Typical examples of compounds represented by chemical formula 1 or chemical formula 2 are as follows: 1) N-(6-(cyclohexylamino)-[1,1'-biphenyl]-3-yl)acrylamide, 2) N-(4-(cyclohexylamino)-3-(pyridine-2-yl)phenyl)acrylamide, 3) N-(3-(pyridine-2-yl)-4-((cis-4-(trifluoromethyl)cyclohexyl)amino)phenyl)acrylamide, 4) N-(3-(pyridine-2-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide, 5) N-(2-methoxy-5-(pyridine-2-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide, 6) N-(3-(1-methyl-1H-imidazole-4-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide, 7) N-(4-((3-chloro-5-(trifluoromethyl)pyridine-2-yl)amino)-3-(pyridine-2-yl)phenyl)acrylamide, 8) N-(4-((4,5-dichloropyridine-2-yl)amino)-3-(pyridine-2-yl)phenyl)acrylamide, 9) N-(4-((3-chloro-5-(trifluoromethyl)pyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 10) N-(4-((4,5-dichloropyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 11) N-(6-((4-fluorobenzyl)amino)-[1,1'-biphenyl]-3-yl)acrylamide, 12) N-(4-((4-fluorobenzyl)amino)-3-(pyridine-2-yl)phenyl)acrylamide, 13) N-(3-(5-chloropyridine-2-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide, 14) N-(4-(pyridine-2-yl)-3-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide, 15) N-(3-(pyrimidine-4-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide, 16) N-(4-((4,5-dichloropyridine-2-yl)amino)-3-(pyrimidine-4-yl)phenyl)acrylamide, 17) N-(3-(pyridine-4-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide, 18) N-(4-((4,5-dichloropyridine-2-yl)amino)-3-(pyridine-4-yl)phenyl)acrylamide, 19) N-(4-(5-chloro-4-fluoro-1H-indole-1-yl)-3-(pyridine-2-yl)phenyl)acrylamide, 20) N-(4-((5-cyclopropylpyridine-2-yl)amino)-3-(pyridine-2-yl)phenyl)acrylamide, 21) N-(4-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)amino)-3-(pyridine-2-yl)phenyl)acrylamide, 22) N-(6-(((1r,4r)-4-hydroxycyclohexyl)amino)-5-phenylpyridine-3-yl)acrylamide, 23)(E)-N-(3-(4-fluorostyryl)-4-((2-(thiazole-2-yl)ethyl)amino)phenyl)acrylamide, 24)(E)-N-(3-(4-fluorostyryl)-4-((2-(thiazole-2-yl)ethyl)amino)phenyl)ethanesulfonamide, 25) N-(4-(cyclohexylamino)-3-(pyridine-3-yl)phenyl)acrylamide, 26) N-(4-(cyclopentylamino)-3-(pyridine-2-yl)phenyl)acrylamide, 27)(E)-N-(5-(4-fluorostyryl)-6-((2-(thiazole-2-yl)ethyl)amino)pyridine-3-yl)acrylamide, 28)(E)-N-(5-(4-fluorostyryl)-6-((2-(thiazole-2-yl)ethyl)amino)pyridine-3-yl)ethanesulfonamide, 29) N-(3-fluoro-5-(pyridine-2-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide, 30) N-(4-((5-chloro-4-cyclopropylpyridine-2-yl)amino)-3-(pyridine-2-yl)phenyl)acrylamide, 31) N-(3-(1-methyl-1H-imidazole-4-yl)-4-((4(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide, 32)((E)-4-(dimethylamino)-N-(3-(1-methyl-1H-pyrazole-3-yl)-4-((4-(trifluoromethyl)pyridine-2-yl)amino)phenyl)-2-butenamide, 33) N-(4-((5-isopropylpyridine-2-yl)amino)-3-(pyridine-2-yl)phenyl)acrylamide, 34) N-(4-((5-ethynylpyridine-2-yl)amino)-3-(1-methyl-1H-pyrazole-3-yl)phenyl)acrylamide, 35) N-(3-(1-methyl-1H-imidazole-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide, 36) N-(4-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 37) N-(4-((4-chloro-5-(trifluoromethyl)pyridine-2-yl)amino)-3-(1-methyl-1H-pyrazole-3-yl)phenyl)acrylamide, 38) N-(3-fluoro-5-(1-methyl-1H-imidazole-4-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide, 39) N-(2'-((5-(trifluoromethyl)pyridine-2-yl)amino)-[2,3'-bipyridine]-5'-yl)acrylamide, 40)N-(4-((3-fluoro-4-(trifluoromethyl)phenyl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 41) N-(5-(1-methyl-1H-imidazole-4-yl)-6-((4-(trifluoromethyl)phenyl)amino)pyridine-3-yl)acrylamide, 42) N-(3-(1-methyl-1H-pyrazole-3-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide, 43) N-(4-((3-chloro-4-(trifluoromethyl)phenyl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 44) N-(4-((2,3-difluoro-4-(trifluoromethyl)phenyl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 45) N-(3-(1-methyl-1H-imidazole-4-yl)-4-((4-(trifluoromethoxy)phenyl)amino)phenyl)acrylamide, 46) N-(4-((3,5-difluoro-4-(trifluoromethyl)phenyl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 47) N-(4-((4-chlorophenyl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 48) N-(4-((5-bromo-6-methylpyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 49) N-(4-((5-chloro-6-methylpyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 50)N-(4-((5-chloropyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 51) N-(4-((5-bromo-4-chloropyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 52) N-(4-((5-bromopyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 53) N-(4-((3-chloro-5-(trifluoromethyl)pyridine-2-yl)amino)-3-(1-methyl-1H-pyrazole-3-yl)phenyl)acrylamide, 54) N-(3-(1-methyl-1H-pyrazole-3-yl)-4-((4-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide, 55)N-(4-((4,5-dichloropyridine-2-yl)amino)-3-(1-methyl-1H-pyrazole-3-yl)phenyl)acrylamide, and 56) N-(4-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)amino)-3-(1-methyl-1H-pyrazole-3-yl)phenyl)acrylamide.

[0022] Furthermore, as an example, the compound represented by chemical formula 1 according to the present invention can be produced as shown in the following reaction formula 1, and the compound represented by chemical formula 2 according to the present invention can be produced as shown in the following reaction formula 2: [Reaction Equation 1] JPEG0007869861000008.jpg67141 [Reaction Equation 2] JPEG0007869861000009.jpg66141 In reaction equations 1 and 2, the definitions of the remaining terms, excluding X' and X'', are as previously defined, and X' and X'' are explained below.

[0023] In each of reaction formulas 1 and 2, step 1 is an amine substitution reaction, and step 2 is a Suzuki coupling reaction. 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 -B(OH)2, tributylstanyl, etc., but is not limited to these.

[0024] Each step 3 of reaction equations 1 and 2 is a reaction that reduces a nitro group, and can be carried out in the presence of hydrogen using a palladium catalyst, but is not limited to this.

[0025] Step 4 of each of the above reaction formulas 1 and 2 is a reaction between an amine group and a carbonyl group or a sulfonyl group, where X'' may be, but is not limited to, a hydroxyl group or a halogen (e.g., chloro).

[0026] The above manufacturing method can be further elaborated in the manufacturing examples described later.

[0027] Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer or tumors, comprising a compound represented by the chemical formula 1 or 2, or a pharmaceutically acceptable salt thereof, as an active ingredient.

[0028] In this invention, the term "prevention" means all actions that suppress or delay the onset, spread, and recurrence of the disease by administering the composition of the present invention, and "treatment" means all actions that improve or favorably alter the symptoms of the disease by administering the composition of the present invention. [Effects of the Invention]

[0029] The compounds represented by chemical formula 1 or 2 of the present invention, or their pharmaceutically acceptable salts, can be usefully used for the prevention or treatment of cancer or tumors. [Modes for carrying out the invention]

[0030] The following examples illustrate the present invention, but the scope of the present invention is not limited to these examples.

[0031] Example 1: Preparation of N-(6-(cyclohexylamino)-[1,1'-biphenyl]-3-yl)acrylamide JPEG0007869861000010.jpg62141

[0032] (Stage 1) 2-Bromo-1-fluoro-4-nitrobenzene (5.0 mmol, 1.1 g, 1.0 eq) was dissolved in cyclohexaneamine (1.5 mL) and reacted overnight at 140°C. After the reaction was complete, the temperature was cooled to room temperature. Water (30 mL) was added and the mixture was stirred for 1 hour. 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 (1.0 mmol, 0.29 g, 1.0 eq) was dissolved in a 2.2 mL mixture of 1,4-dioxane and water (1,4-dioxane:water = 10:1 (v:v)) in a sealed tube. Phenylboronic acid (1.2 mmol, 0.15 g, 1.2 eq), sodium carbonate (2.0 mmol, 0.21 g, 2.0 eq), and (Ph3P)4Pd (0.05 mmol, 0.057 g, 0.05 eq) were added sequentially, and the mixture was reacted overnight at 100°C. After the reaction was complete, the solvent was removed, and the resulting substance 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 (0.8 mmol, 0.24 g, 1.0 eq) was dissolved in methanol (10 mL), then Pd / C (24 mg) was added, and the mixture was reacted overnight at room temperature under conditions of 1 atm of hydrogen (H2). After the reaction was complete, the mixture was filtered through a celite pad, and the filtrate was concentrated to obtain 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 (0.1 mmol, 0.026 g, 1.0 eq), acrylic acid (0.12 mmol, 0.0086 g, 1.2 eq), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.2 g), and triethylamine (0.1 mL) were dissolved in dichloromethane (1 mL) and reacted overnight at room temperature. After the reaction was complete, the dichloromethane was removed and the mixture was purified by column chromatography to obtain compound 1 (0.011 g, 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-(pyridine-2-yl)phenyl)acrylamide JPEG0007869861000011.jpg24141

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

[0039] (Stage 2) N-cyclohexyl-4-nitro-2-(pyridine-2-yl)aniline (1.0 mmol, 0.29 g, 1.0 eq) was dissolved in methanol (10 mL), then Pd / C (30 mg) was added, and the mixture was reacted overnight at room temperature under conditions of 1 atm of hydrogen (H2). After the reaction was complete, the mixture was filtered through a celite pad, and the filtrate was concentrated and N 1-Cyclohexyl-2-(pyridine-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 (0.1 mmol, 0.027 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 (0.091 g), and N,N-diisopropylethylamine (0.1 mL) were dissolved in dichloromethane (1 mL) and reacted overnight at room temperature. After the reaction was complete, the dichloromethane was removed and the mixture was purified by column chromatography to obtain compound 2 (13 mg, 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-(pyridine-2-yl)-4-((cis-4-(trifluoromethyl)cyclohexyl)amino)phenyl)acrylamide 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-tributylstanylpyridine 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-(pyridine-2-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide JPEG0007869861000013.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). Then, 2-(tributylstanyl)pyridine (5.0 mmol, 1.84 g, 1.1 eq) and (Ph3P)4Pd (0.45 mmol, 0.52 g, 0.1 eq) were added sequentially, and the mixture was reacted overnight at 150°C. After the reaction was complete, the solvent was removed, and the resulting substance 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 (3.7 mmol, 0.599 g, 1.2 eq) was dissolved in dimethylformamide (10 mL), and then 55% NaH (10.0 mmol, 0.43 g) was added and the mixture was stirred for 10 minutes. 5-(trifluoromethyl)pyridine-2-amine (3.1 mmol, 0.68 g, 1.0 eq) was added and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was cooled to 0°C and then distilled water (30 mL) was added. The resulting solid was filtered to obtain N-(4-nitro-2-(pyridine-2-yl)phenyl)-5-(trifluoromethyl)pyridine-2-amine (0.64 g, yield: 57%).

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

[0048] (Stage 4) 2-(pyridine-2-yl)-N 1 -(5-(trifluoromethyl)pyridine-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), and N,N-diisopropylethylamine (0.3 mmol, 0.052 mL) were dissolved in dichloromethane (1 mL) and reacted overnight at room temperature. After the reaction was complete, the dichloromethane was removed and the mixture was purified by column chromatography to obtain 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-(pyridine-2-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide 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-imidazole-4-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide The title compound (8 mg, yield: 20%) was obtained in the same manner as in Example 4, except that 1-methyl-4-(tributylstanyl)-1H-imidazole was used instead of 2-(tributylstanyl)pyridine in step 1 of Example 4.

[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)pyridine-2-yl)amino)-3-(pyridine-2-yl)phenyl)acrylamide JPEG0007869861000016.jpg4042 The title compound (20 mg, yield: 47%) was obtained in the same manner as in Example 4, except that 3-chloro-5-(trifluoromethyl)pyridine-2-amine was used instead of 5-(trifluoromethyl)pyridine-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-dichloropyridine-2-yl)amino)-3-(pyridine-2-yl)phenyl)acrylamide JPEG0007869861000017.jpg3942 The title compound (14 mg, yield: 36%) was obtained in the same manner as in Example 4, except that 4,5-dichloro-2-amine was used instead of 5-(trifluoromethyl)pyridine-2-amine in step 2 of Example 4.

[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)pyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide The title compound (15 mg, yield: 12%) was obtained in the same manner as in Example 4, except that 1-methyl-4-(tributylstanyl)-1H-imidazole was used instead of 2-(tributylstanyl)pyridine in step 1 of Example 4, and 3-chloro-4-(trifluoromethyl)pyridine-2-amine was used instead of 5-(trifluoromethyl)pyridine-2-amine in step 2 of Example 4.

[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-dichloropyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide The title compound (17 mg, yield: 45%) was obtained in the same manner as in Example 4, except that 1-methyl-4-(tributylstanyl)-1H-imidazole was used instead of 2-(tributylstanyl)pyridine in step 1 of Example 4, and 4,5-dichloro-(trifluoromethyl)pyridine-2-amine was used instead of 5-(trifluoromethyl)pyridine-2-amine in step 2 of Example 4.

[0061] 1 1H 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 JPEG0JPEG0007869861000020.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 cyclohexylamine in Step 1 of Example 1.

[0063] 1 1H 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 The 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-tributylstanylpyridine 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-chloropyridine-2-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide JPEG0007869861000022.jpg4146 The title compound (10 mg, yield: 25%) was obtained in the same manner as in Example 4, except that 5-chloro-2-(tributylstanyl)pyridine was used instead of 2-(tributylstanyl)pyridine in step 1 of Example 4.

[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-(pyridine-2-yl)-3-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide JPEG0007869861000023.jpg50141

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

[0070] (Stage 2) In a flask, 5-nitro-2-(pyridine-2-yl)aniline (0.69 mmol, 0.15 g, 1.0 eq), Cu(OAc)2 (1.72 mmol, 0.31 g, 2.5 eq), (4-(trifluoromethyl)phenyl)boronic acid (1.4 mmol, 0.27 g, 2.0 eq), and dichloromethane (10 mL) were added sequentially, and the mixture was stirred. After adding pyridine (2.76 mmol, 0.22 g, 4.0 eq), the mixture was stirred at room temperature for 48 hours. After the reaction was complete, 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-(pyridine-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline (0.22 g, yield: 88%).

[0071] (Stage 3) In a flask, 5-nitro-2-(pyridine-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 10 mL of 70% ethanol solution were added, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, Fe and NH4Cl were removed, and 6-(pyridine-2-yl)-N 1 -(4-(trifluoromethyl)phenyl)benzene-1,3-diamine (0.2 g, yield: 99%) was obtained.

[0072] (Stage 4) 6-(pyridine-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), and N,N-diisopropylethylamine (0.1 mL) were dissolved in dichloromethane (1 mL) and reacted overnight at room temperature. After completion of the reaction, dichloromethane was removed and the residue 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, 10.3 Hz, 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 The title compound (5 mg, yield: 12%) was obtained in the same manner as in Example 4, except that 4-(tributylstannyl)pyrimidine was used instead of 2-(tributylstannyl)pyridine in Step 1 of Example 4.

[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-dichloropyridine-2-yl)amino)-3-(pyrimidine-4-yl)phenyl)acrylamide The title compound (7 mg, yield: 19%) was obtained in the same manner as in Example 4, except that 4-(tributylstanyl)pyrimidine was used instead of 2-(tributylstanyl)pyridine in step 1 of Example 4, and 4,5-dichloro-(trifluoromethyl)pyridine-2-amine was used instead of 5-(trifluoromethyl)pyridine-2-amine in step 2 of Example 4.

[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-(pyridine-4-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide JPEG0007869861000026.jpg4040 The title compound (16 mg, yield: 42%) was obtained in the same manner as in Example 4, except that 4-(tributylstanyl)pyridine was used instead of 2-(tributylstanyl)pyridine in step 1 of Example 4.

[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-dichloropyridine-2-yl)amino)-3-(pyridine-4-yl)phenyl)acrylamide The title compound (14 mg, yield: 36%) was obtained in the same manner as in Example 4, except that 4-(tributylstanyl)pyridine was used instead of 2-(tributylstanyl)pyridine in step 1 of Example 4, and 4,5-dichloro-(trifluoromethyl)pyridine-2-amine was used instead of 5-(trifluoromethyl)pyridine-2-amine in step 2 of Example 4.

[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-indole-1-yl)-3-(pyridine-2-yl)phenyl)acrylamide JPEG0007869861000028.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)pyridine-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-cyclopropylpyridine-2-yl)amino)-3-(pyridine-2-yl)phenyl)acrylamide The title compound (3 mg, yield: 9%) was obtained in the same manner as in Example 4, except that 5-cyclopropylpyridine-1-amine was used instead of 5-(trifluoromethyl)pyridine-2-amine in step 2 of Example 4.

[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)pyridine-2-yl)amino)-3-(pyridine-2-yl)phenyl)acrylamide JPEG0007869861000030.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-phenylpyridine-3-yl)acrylamide JPEG0007869861000031.jpg4431 The 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-aminocyclohexane-1-ol and 3-bromo-2-chloro-5-nitropyridine were used instead of cyclohexaneamine 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-(thiazole-2-yl)ethyl)amino)phenyl)acrylamide The title compound (14 mg, yield: 36%) was obtained in the same manner as in Example 1, except that 2-(thiazole-2-yl)ethane-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-(thiazole-2-yl)ethyl)amino)phenyl)ethanesulfonamide JPEG0007869861000033.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-(thiazole-2-yl)ethane-1-amine was used instead of cyclohexaneamine; in step 2 of Example 1, (E)-(4-fluorostyryl)boronic acid was used instead of phenylboronic acid; and in step 4 of Example 1, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride was omitted 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-(pyridine-3-yl)phenyl)acrylamide JPEG0007869861000034.jpg3439 The title compound (7 mg, yield: 22%) was obtained in the same manner as in Example 2, except that 3-(tributylstanyl)pyridine was used instead of 2-(tributylstanyl)pyridine in step 1 of Example 2.

[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-(pyridine-2-yl)phenyl)acrylamide 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-tributylstanylpyridine 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-(thiazole-2-yl)ethyl)amino)pyridine-3-yl)acrylamide Except for using 2-(thiazole-2-yl)ethane-1-amine and 3-bromo-2-chloro-5-nitropyridine instead of cyclohexaneamine and 2-bromo-1-fluoro-4-nitrobenzene in step 1 of Example 1, and using (E)-(4-fluorostyryl)boronic acid instead of phenylboronic acid in step 2 of Example 1, the title compound (19 mg, yield: 45%) was obtained in the same manner as in Example 1.

[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-(thiazole-2-yl)ethyl)amino)pyridine-3-yl)ethanesulfonamide Except for using 2-(thiazole-2-yl)ethane-1-amine and 3-bromo-2-chloro-5-nitropyridine instead of cyclohexaneamine and 2-bromo-1-fluoro-4-nitrobenzene in step 1 of Example 1, (E)-(4-fluorostyryl)boronic acid instead of phenylboronic acid in step 2 of Example 1, and not using N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and using ethenesulfonyl chloride instead of acrylic acid in step 4 of Example 1, the title compound (4 mg, yield: 11%) was obtained in the same manner as in Example 1.

[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-(pyridine-2-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide JPEG0007869861000038.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-cyclopropylpyridine-2-yl)amino)-3-(pyridine-2-yl)phenyl)acrylamide JPEG0007869861000039.jpg3944 The title compound (12 mg, yield: 30%) was obtained in the same manner as in Example 4, except that 5-chloro-4-cyclopropylpyridine-2-amine was used instead of 5-(trifluoromethyl)pyridine-2-amine in step 2 of Example 4.

[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-imidazole-4-yl)-4-((4(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide The title compound (3 mg, yield: 9%) was obtained in the same manner as in Example 4, except that 1-methyl-4-(tributylstanyl)-1H-imidazole was used instead of 2-(tributylstanyl)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.

[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-pyrazole-3-yl)-4-((4-(trifluoromethyl)pyridine-2-yl)amino)phenyl)-2-butenamide Except for using 1-methyl-4-(tributylstanyl)-1H-pyrazole instead of 2-(tributylstanyl)pyridine in step 1 of Example 4, using 4-(trifluoromethyl)pyridine-2-amine instead of 5-(trifluoromethyl)pyridine-2-amine in step 2 of Example 4, using (E)-4-(dimethylamino)2-butenoyl chloride HCl salt instead of acrylic acid in step 4 of Example 4, and not using HATU, the title compound (23 mg, yield: 52%) was obtained in the same manner as in Example 4.

[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-isopropylpyridine-2-yl)amino)-3-(pyridine-2-yl)phenyl)acrylamide JPEG0007869861000042.jpg4039 The title compound (3 mg, yield: 8%) was obtained in the same manner as in Example 4, except that 5-isopropylpyridine-2-amine was used instead of 5-(trifluoromethyl)pyridine-2-amine in step 2 of Example 4.

[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-ethynylpyridine-2-yl)amino)-3-(1-methyl-1H-pyrazole-3-yl)phenyl)acrylamide JPEG0007869861000043.jpg4143 The title compound (22 mg, yield: 58%) was obtained in the same manner as in Example 4, except that 1-methyl-4-(tributylstanyl)-1H-pyrazole was used instead of 2-(tributylstanyl)pyridine in step 1 of Example 4, and 5-ethynylpyridine-2-amine was used instead of 5-(trifluoromethyl)pyridine-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-imidazole-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide JPEG0007869861000044.jpg60141

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

[0116] (Stage 2) In a flask, 2-(1-methyl-1H-imidazole-4-yl)-4-nitroaniline (5.1 mmol, 1.1 g, 1.0 eq), Cu(OAc)2 (6.1 mmol, 1.1 g, 1.2 eq), (4-(trifluoromethyl)phenyl)boronic acid (6.1 mmol, 1.2 g, 1.2 eq), and dichloromethane (25 mL) were added sequentially, and the mixture was stirred. After adding triethylamine (10 mmol, 1.0 g, 2.0 eq), the mixture was stirred at room temperature for 2 hours. After the reaction was complete, 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-imidazole-4-yl)-4-nitro-N-(4-(trifluoromethyl)phenyl)aniline (1.2 g, yield: 67%).

[0117] (Stage 3) In a flask, 2-(1-methyl-1H-imidazole-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 15 mL of 70% ethanol solution were added, and the mixture was stirred at 40°C for 4 hours. After the reaction was complete, Fe and NH4Cl were removed, and the mixture was separated and purified by column chromatography (ethyl acetate) to obtain 2-(1-methyl-1H-imidazole-4-yl)-N1 -(4-(trifluoromethyl)phenyl)benzene-1,4-diamine (0.60 g, yield: 59%) was obtained.

[0118] (Stage 4) 2-(1-methyl-1H-imidazole-4-yl)-N 1 -(4-(trifluoromethyl)phenyl)benzene-1,4-diamine (1.8 mmol, 0.60 g, 1.0 eq), acrylic acid (2.2 mmol, 0.16 g, 1.2 eq), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (2.7 mmol, 0.52 g, 1.5 eq), and triethylamine (0.76 mL) were dissolved in dichloromethane (9 mL) and reacted at room temperature for 3 hours. After the reaction was complete, the dichloromethane was removed, and the compound was separated and purified by column chromatography (ethyl acetate) to obtain the title compound (0.35 g, 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)pyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide The title compound (5 mg, yield: 12%) was obtained in the same manner as in Example 4, except that 1-methyl-4-(tributylstanyl)-1H-imidazole was used instead of 2-(tributylstanyl)pyridine in step 1 of Example 4, and 3-fluoro-5-(trifluoromethyl)pyridine-2-amine was used instead of 5-(trifluoromethyl)pyridine-2-amine in step 2 of Example 4.

[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)pyridine-2-yl)amino)-3-(1-methyl-1H-pyrazole-3-yl)phenyl)acrylamide The title compound (10 mg, yield: 24%) was obtained in the same manner as in Example 4, except that 1-methyl-4-(tributylstanyl)-1H-pyrazole was used instead of 2-(tributylstanyl)pyridine in step 1 of Example 4, and 4-chloro-5-(trifluoromethyl)pyridine-2-amine was used instead of 5-(trifluoromethyl)pyridine-2-amine in step 2 of Example 4.

[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-imidazole-4-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide 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-(tributylstanyl)-1H-imidazole were used instead of 2-bromo-1-fluoro-4-nitrobenzene and 2-(tributylstanyl)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, 2H), 6.51 (d, J = 16.8 Hz, 1H), 6.36 (d, J = 10.2 Hz, 1H), 5.84 (d, J = 10.1 Hz, 1H), 3.85 (s, 3H) one proton is missing due to overlapping.

[0126] Example 39: Preparation of N-(2'-((5-(trifluoromethyl)pyridine-2-yl)amino)-[2,3'-bipyridine]-5'-yl)acrylamide 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 cyclohexaneamine and 2-bromo-1-fluoro-4-nitrobenzene, respectively, and in step 2 of Example 1, 1-methyl-4-(tributylstanyl)-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 tilping

[0128] Example 40: Preparation of N-(4-((3-fluoro-4-(trifluoromethyl)phenyl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide 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-imidazole-4-yl)-6-((4-(trifluoromethyl)phenyl)amino)pyridine-3-yl)acrylamide The title compound (6 mg, yield: 15%) was obtained in the same manner as in Example 35, except that 3-bromo-5-nitropyridine-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-pyrazole-3-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide JPEG0007869861000051.jpg3843 The title compound (7 mg, yield: 18%) was obtained in the same manner as in Example 35, except that 1-methyl-4-(tributylstanyl)-1H-pyrazole was used instead of 1-methyl-4-(tributylstanyl)-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-imidazole-4-yl)phenyl)acrylamide 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-imidazole-4-yl)phenyl)acrylamide 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-imidazole-4-yl)-4-((4-(trifluoromethoxy)phenyl)amino)phenyl)acrylamide JPEG0007869861000054.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-imidazole-4-yl)phenyl)acrylamide JPEG0007869861000055.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-imidazole-4-yl)phenyl)acrylamide JPEG0007869861000056.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-methylpyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide The title compound (7 mg, yield: 17%) was obtained in the same manner as in Example 4, except that 1-methyl-4-(tributylstanyl)-1H-imidazole was used instead of 2-(tributylstanyl)pyridine in step 1 of Example 4, and 5-bromo-6-methylpyridine-2-amine was used instead of 5-(trifluoromethyl)pyridine-2-amine in step 2 of Example 4.

[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-methylpyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide The title compound (10 mg, yield: 27%) was obtained in the same manner as in Example 4, except that 1-methyl-4-(tributylstanyl)-1H-imidazole was used instead of 2-(tributylstanyl)pyridine in step 1 of Example 4, and 5-chloro-6-methylpyridine-2-amine was used instead of 5-(trifluoromethyl)pyridine-2-amine in step 2 of Example 4.

[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-chloropyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide The title compound (12 mg, yield: 28%) was obtained in the same manner as in Example 4, except that 1-methyl-4-(tributylstanyl)-1H-imidazole was used instead of 2-(tributylstanyl)pyridine in step 1 of Example 4, and 4-chloropyridine-2-amine was used instead of 5-(trifluoromethyl)pyridine-2-amine in step 2 of Example 4.

[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-chloropyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide The title compound (10 mg, yield: 23%) was obtained in the same manner as in Example 4, except that 1-methyl-4-(tributylstanyl)-1H-imidazole was used instead of 2-(tributylstanyl)pyridine in step 1 of Example 4, and 5-bromo-4-chloropyridine-2-amine was used instead of 5-(trifluoromethyl)pyridine-2-amine in step 2 of Example 4.

[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-bromopyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide The title compound (5 mg, yield: 13%) was obtained in the same manner as in Example 4, except that 1-methyl-4-(tributylstanyl)-1H-imidazole was used instead of 2-(tributylstanyl)pyridine in step 1 of Example 4, and 5-bromopyridine-2-amine was used instead of 5-(trifluoromethyl)pyridine-2-amine in step 2 of Example 4.

[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)pyridine-2-yl)amino)-3-(1-methyl-1H-pyrazole-3-yl)phenyl)acrylamide The title compound (3 mg, yield: 7%) was obtained in the same manner as in Example 4, except that 1-methyl-4-(tributylstanyl)-1H-imidazole was used instead of 2-(tributylstanyl)pyridine in step 1 of Example 4, and 3-chloro-5-(trifluoromethyl)pyridine-2-amine was used instead of 5-(trifluoromethyl)pyridine-2-amine in step 2 of Example 4.

[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-pyrazole-3-yl)-4-((4-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide The title compound (15 mg, yield: 39%) was obtained in the same manner as in Example 4, except that 1-methyl-4-(tributylstanyl)-1H-pyrazole was used instead of 2-(tributylstanyl)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-dichloropyridine-2-yl)amino)-3-(1-methyl-1H-pyrazole-3-yl)phenyl)acrylamide The title compound (15 mg, yield: 39%) was obtained in the same manner as in Example 4, except that 1-methyl-4-(tributylstanyl)-1H-pyrazole was used instead of 2-(tributylstanyl)pyridine in step 1 of Example 4, and 3,4-dichloropyridine-2-amine was used instead of 5-(trifluoromethyl)pyridine-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)pyridine-2-yl)amino)-3-(1-methyl-1H-pyrazole-3-yl)phenyl)acrylamide The title compound (14 mg, yield: 35%) was obtained in the same manner as in Example 4, except that 1-methyl-4-(tributylstanyl)-1H-pyrazole was used instead of 2-(tributylstanyl)pyridine in step 1 of Example 4, and 2-fluoro-4-(trifluoromethyl)pyridine-2-amine was used instead of 5-(trifluoromethyl)pyridine-2-amine in step 2 of Example 4.

[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: Inhibition Test of Transcription Factor TEAD Activity The compounds prepared in the above examples were subjected to ONE-Glo using the Hippo Pathway TEAD reporter-MCF7 recombinant cell line (BPS Bioscience, Catalog#60618). TM The activity of the transcription factor TEAD 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 TEAD reaction elements, within the human breast cancer cell line MCF7. In this cell line, unphosphorylated YAP / TAZ is present in the nucleus under stress-free conditions, which sustainably induces luciferase reporter expression.

[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 incubated at 37°C in a 5% CO2 incubator for 24 hours, after which the previously prepared compound from the example was treated to final concentrations of 0.001, 0.01, 0.1, 1, and 10 μM, and this process was repeated three times for each treatment solution. The plate treated with the compound from the example was incubated at 37°C in a 5% CO2 incubator for 24 hours, and the enzymatic reaction was initiated by adding 100 μL / well of a substrate aqueous solution containing luciferin to a white clear-bottom 96-well microplate. The reaction was allowed to proceed at room temperature for 5 minutes, and luminescence (integration time 1000ms) was measured using a Flexstation3 multi-mode microplate reader. ONE-GloTM Following the instructions for the luciferase assay, the luciferase enzyme activity representing the activity of the transcription factor TEAD was measured by chemiluminescence, and the inhibitory activity of the compounds according to the present invention was calculated. The results for each compound were analyzed using Microsoft Excel, and IC was performed. 50 The values ​​were calculated using GraphPad Prism software, and the results are shown in Table 1 below.

[0166] Experimental Example 2: Cell Proliferation Inhibition Test Cell proliferation was measured using the CellTiter-Glo® Luminescedent Cell Viability (Promega, Catalog#G7571) method with respect to the compounds produced in the above examples, using NCI-H226 (addexbio), NCI-H28 (Korea Cell Line Bank), and MSTO-211H (elabscience) human mesothelioma cell lines. This evaluation method confirms cell viability by measuring the enzyme activity when the luciferase enzyme is activated by ATP leached from living cells and reacts with the luciferin substrate.

[0167] Specifically, NCI-H226, NCI-H28, and MSTO-211H cells were prepared in 100 μL of cell culture medium (RPMI medium, 10% FBS, 1% P / S, 4.5 g / L D-Glucose, 2.383 g / L HEPES Buffer, L-Glutamine, 1.5 g / L Sodium Bicarbonate, 110 mg / L Sodium Pyravate) in a white clear-bottom 96-well microplate. The prepared plate was incubated at 37°C in a 5% CO2 incubator for 24 hours, after which the previously prepared compounds from the examples were treated to final concentrations of 0.001, 0.01, 0.1, 1, and 10 μM, and this process was repeated three times for all treatment solutions. Plates treated with the compounds of the examples were cultured at 37°C in a 5% CO2 incubator. The enzymatic reaction was initiated by adding 100 μL / well of a substrate aqueous solution containing luciferin to a white clear-bottom 96-well microplate. The reaction was allowed to proceed for 10 minutes at room temperature in the dark, and luminescence was measured using a Flexstation3 multi-mode microplate reader. Following the CellTiter-Glo® Luminescedent Cell Viability documentation, the luciferase enzyme activity representing ATP levels was measured by chemiluminescence, and the inhibitory activity of the compounds according to the present invention was calculated. The results for each compound were analyzed using Microsoft Excel, and IC50 was used. 50 The values ​​were calculated using GraphPad Prism software, and the results are shown in Tables 1 and 2 below.

[0168] [Table 1]

[0169] [Table 2]

Claims

1. The compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 In the aforementioned chemical formula 1, L １ is a single bond, or C ２－４ It is alkenylene, R １ This is a five- or six-ring heterocycle containing phenyl, or one to four heteroatoms independently selected from the group consisting of N, O, and S. The aforementioned R １ is either unsubstituted, or halogen, or C １－４ Substituted with alkyl, R ２ is -N(R ９ )-L ２ -R ５ or 【Chemistry 2】 And, L ２ is a single bond, or C １－６ It is alkylene, R ５ This is a five-ring or six-ring heteroaryl compound containing one to four heteroatoms independently selected from the group consisting of N, O, and S. The aforementioned R ５ is either unsubstituted or halogen, C １－４ Alkyl, C １－４ Haloalkyl and C ３－６ Substituting with one to three substituents independently selected from the group composed of cycloalkyl groups, R ６ These are hydrogen atoms, R ９ It is hydrogen, R ３ These are, independently, hydrogen or C １－４ It is an alkoxy, R ４ These are, independently, hydrogen or -CH₂ ２ N(R) ７ ) ２ And, R ７ Each of them is independent of C １－４ It is alkyl, X is CR ８ , or N, R ８ is hydrogen or halogen, Y is CO, or SO ２ And, However, the following compounds are excluded from the compounds represented by chemical formula 1 above: 【Transformation 3】 。

2. L １ This is a single bond, or -CH=CH-. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. R １ These are phenyl, pyridinyl, pyrimidinyl, imidazolyl, or pyrazolyl, The aforementioned R １ is either unsubstituted, or halogen, or C １－４ Substituted with alkyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. L ２ It is a single bond, or ethylene. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. R ５ These are pyridinyl or thiazolyl, The aforementioned R ５ is either unsubstituted or halogen, C １－４ Alkyl, C １－４ Haloalkyl and C ３－６ Substituting with one to three substituents independently selected from the group composed of cycloalkyl groups, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

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

7. R ４ is all hydrogen, or R ４ One of them is hydrogen, and the other is -CH ２ N(R) ７ ) ２ That is, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. X is CH, CF, or N. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, represented by the following chemical formula 3: 【Chemistry 4】 In the aforementioned chemical formula 3, X is CH, CF, or N. A is benzene, pyridine, pyrimidine, imidazole, or pyrazole. R' is hydrogen, halogen, or C １－４ It is alkyl, L １ is a single bond, or C ２－４ It is alkenylene, B is pyridine or thiazolyl, R' represents hydrogen, halogen, and C, each independently. １－４ Alkyl, C １－４ Haloalkyl, or C ３－６ It is a cycloalkyl, n'' is an integer between 1 and 3. L ２ is a single bond, or C １－６ It is alkylene, R''' represents hydrogen, or -CH ２ -N(CH ３ ) ２ And, R ３ is hydrogen, or C １－４ It is an alkoxy.

10. The compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof: 【Transformation 5】 In the aforementioned chemical formula 1, L １ It is a single bond, R １ It is phenyl, The aforementioned R １ It is a non-substitution, R ２ is -N(R ９ )-L ２ -R ５ And, L ２ It is a single bond, R ５ C ３－７ It is a cycloalkyl, The aforementioned R ５ It is either unsubstituted or substituted with one substituent independently selected from the group consisting of hydroxyl or halogen. R ９ It is hydrogen, R ３ Each of them is independently hydrogen, R ４ Each of them is independently hydrogen, X is CR ８ , or N, R ８ It is hydrogen, Y is CO.

11. The compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof: 【Transformation 6】 In the aforementioned chemical formula 1, L １ It is a single bond, R １ This is a five- or six-ring heterocycle containing phenyl, or one to four heteroatoms independently selected from the group consisting of N, O, and S. The aforementioned R １ It is a non-substitution, R ２ is -N(R ９ )-L ２ -R ５ And, L ２ C １－６ It is alkylene, R ５ It is phenyl, The aforementioned R ５ It is replaced by one halogen, R ９ It is hydrogen, R ３ Each of them is independently hydrogen, R ４ Each of them is independently hydrogen, X is CR ８ And, R ８ is hydrogen, and Y is CO.

12. A compound, or a pharmaceutically acceptable salt thereof, 1) N-(6-(cyclohexylamino)-[1,1'-biphenyl]-3-yl)acrylamide, 4) N-(3-(pyridine-2-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide, 5) N-(2-methoxy-5-(pyridine-2-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide, 7) N-(4-((3-chloro-5-(trifluoromethyl)pyridine-2-yl)amino)-3-(pyridine-2-yl)phenyl)acrylamide, 8) N-(4-((4,5-dichloropyridine-2-yl)amino)-3-(pyridine-2-yl)phenyl)acrylamide, 9) N-(4-((3-chloro-5-(trifluoromethyl)pyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 10) N-(4-((4,5-dichloropyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 11) N-(6-((4-fluorobenzyl)amino)-[1,1'-biphenyl]-3-yl)acrylamide, 12) N-(4-((4-fluorobenzyl)amino)-3-(pyridine-2-yl)phenyl)acrylamide, 13) N-(3-(5-chloropyridine-2-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide, 15) N-(3-(pyrimidine-4-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide, 16) N-(4-((4,5-dichloropyridine-2-yl)amino)-3-(pyrimidine-4-yl)phenyl)acrylamide, 17) N-(3-(pyridine-4-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide, 18) N-(4-((4,5-dichloropyridine-2-yl)amino)-3-(pyridine-4-yl)phenyl)acrylamide, 19) N-(4-(5-chloro-4-fluoro-1H-indole-1-yl)-3-(pyridine-2-yl)phenyl)acrylamide, 20) N-(4-((5-cyclopropylpyridine-2-yl)amino)-3-(pyridine-2-yl)phenyl)acrylamide, 21) N-(4-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)amino)-3-(pyridine-2-yl)phenyl)acrylamide, 22) N-(6-(((1r,4r)-4-hydroxycyclohexyl)amino)-5-phenylpyridine-3-yl)acrylamide, 23) (E)-N-(3-(4-fluorostyryl)-4-((2-(thiazole-2-yl)ethyl)amino)phenyl)acrylamide, 24) (E)-N-(3-(4-fluorostyryl)-4-((2-(thiazole-2-yl)ethyl)amino)phenyl)ethanesulfonamide, 27) (E)-N-(5-(4-fluorostyryl)-6-((2-(thiazole-2-yl)ethyl)amino)pyridine-3-yl)acrylamide, 28) (E)-N-(5-(4-fluorostyryl)-6-((2-(thiazole-2-yl)ethyl)amino)pyridine-3-yl)ethanesulfonamide, 29) N-(3-fluoro-5-(pyridine-2-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide, 30) N-(4-((5-chloro-4-cyclopropylpyridine-2-yl)amino)-3-(pyridine-2-yl)phenyl)acrylamide, 31) N-(3-(1-methyl-1H-imidazole-4-yl)-4-((4(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide, 32) (E)-4-(dimethylamino)-N-(3-(1-methyl-1H-pyrazole-3-yl)-4-((4-(trifluoromethyl)pyridine-2-yl)amino)phenyl)-2-butenamide, 33) N-(4-((5-isopropylpyridine-2-yl)amino)-3-(pyridine-2-yl)phenyl)acrylamide, 34) N-(4-((5-ethynylpyridine-2-yl)amino)-3-(1-methyl-1H-pyrazole-3-yl)phenyl)acrylamide, 36) N-(4-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 37) N-(4-((4-chloro-5-(trifluoromethyl)pyridine-2-yl)amino)-3-(1-methyl-1H-pyrazole-3-yl)phenyl)acrylamide, 38) N-(3-fluoro-5-(1-methyl-1H-imidazole-4-yl)-4-((5-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide, 39) N-(2'-((5-(trifluoromethyl)pyridine-2-yl)amino)-[2,3'-bipyridine]-5'-yl)acrylamide, 48) N-(4-((5-bromo-6-methylpyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 49) N-(4-((5-chloro-6-methylpyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 50) N-(4-((5-chloropyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 51) N-(4-((5-bromo-4-chloropyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 52) N-(4-((5-bromopyridine-2-yl)amino)-3-(1-methyl-1H-imidazole-4-yl)phenyl)acrylamide, 53) N-(4-((3-chloro-5-(trifluoromethyl)pyridine-2-yl)amino)-3-(1-methyl-1H-pyrazole-3-yl)phenyl)acrylamide, 54) N-(3-(1-methyl-1H-pyrazole-3-yl)-4-((4-(trifluoromethyl)pyridine-2-yl)amino)phenyl)acrylamide, 55) N-(4-((4,5-dichloropyridine-2-yl)amino)-3-(1-methyl-1H-pyrazole-3-yl)phenyl)acrylamide, and 56) N-(4-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)amino)-3-(1-methyl-1H-pyrazole-3-yl)phenyl)acrylamide A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

13. A pharmaceutical composition for the prevention or treatment of cancer or tumor, comprising as an active ingredient a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

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