Novel compounds and pharmaceutical compositions containing them for the prevention or treatment of cancer or tumors.

Abstract

The present invention relates to a compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof, wherein the compound according to the present invention can be usefully used for the prevention or treatment of cancer or tumors. [Chemical formula 1] JPEG2026510431000063.jpg3346 In the above chemical formula 1, R1 to R4 are as defined in the specification.

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] The Hippo signaling system consists of 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). Mutations in higher-level signaling proteins, such as the tumor suppressor genes NF2, MST1 / 2, and LATS1 / 2, induce persistent binding between YAP / TAZ and TEAD. This promotes transcription by YAP / TAZ and TEAD, inducing the expression of genes related to cancer cell proliferation and tumorigenesis.

[0004] Activation of the tumor suppressor NF2 mediated phosphorylation of Lats1 / 2 by Mst1 / 2 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) and 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 to treat drug resistance. Therefore, the development of small molecule inhibitors to treat cancers caused by dysregulation of the Hippo signaling pathway is necessary.

[0006] 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 compound 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]

[0007] This invention provides a novel compound structure that can be usefully used for the treatment or prevention of cancer or tumors.

[0008] Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer or tumors, comprising the aforementioned compound. [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 a pharmaceutically acceptable salt thereof: [Chemical formula 1] JPEG2026510431000002.jpg3346 In the above chemical formula 1, R1 is C 6-10 An aryl; or a 5-membered or 6-membered heteroring containing 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S, The aforementioned R1 is unsubstituted; or a 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 2-4Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, amino, nitro, cyano, (C 1-4 Alkyl)amino, or di(C 1-4 Alkyl)amino; or is fused with a C 3-6 Cycloalkyl ring, R2 is C 6-10 Aryl; C 3-6 Cycloalkenyl; or a 5- or 6-membered heterocycle containing 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S, Said R2 is unsubstituted; or is substituted with 1 to 3 substituents each independently 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, and di(C 1-4 Alkyl)amino, R3 is hydrogen or halogen, R4 is -NHCO-R', -NHSO2-R', -COO-R', -CONH-R', or 1H-pyrrole-2,5-dione-1-yl, Said R' is hydrogen, C 1-4 Alkyl, C 2-4 Alkynyl, or a substituent represented by the following Chemical Formula 2: [Chemical Formula 2] JPEG2026510431000003.jpg2425In said Chemical Formula 2, R'1 is hydrogen, halogen, or cyano, R'2 are each independently hydrogen, C 6-10 Aryl, -CH2-NH2, -CH2-NH(C 1-4 Alkyl), or -CH2-N(C 1-4It is alkyl(2).

[0010] Preferably, R1 is phenyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, pyrrolidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl. The aforementioned R1 is 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 Substituted with alkyl)amino, or C 3-6 It fuses with a cycloalkyl ring.

[0011] Preferably, R1 is imidazolyl, imidazolyl fused with cyclopentane, pyrazolyl, or pyridinyl. The aforementioned R1 is either unsubstituted or substituted with methyl, ethyl, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0012] Preferably, R2 is phenyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, pyrrolidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl. The aforementioned R2 is 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.

[0013] Preferably, R2 is phenyl, pyridinyl, or cyclohexenyl. R2 is either unsubstituted or substituted with one to three substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, trifluoromethyl, and trifluoromethoxy.

[0014] Preferably, R3 is hydrogen or chloroform.

[0015] Preferably, R4 is -NHCO-R', -NHSO2-R', -COO-R', -CONH-R', or 1H-pyrrole-2,5-dione-1-yl. The aforementioned R' is hydrogen; C 1-4 Alkyl; unsubstituted or substituted with one or two substituents independently selected from the group consisting of phenyl, fluoro, and cyano. 2-4 Alkenil; or C 2-4 It is alkinyl.

[0016] Preferably, R4 is -NHCO-CH=CH2, -NHCO-CF=CH2, -NHCO-C(CN)=CH(phenyl), -NHCO-C≡C-CH3, -NHSO2-CH3, -NHSO2-CH=CH2, -COOH, -CONH-CH3, or 1H-pyrrole-2,5-dione-1-yl.

[0017] Preferably, the chemical formula 1 is represented by the following chemical formula 3: [Chemical formula 3] JPEG2026510431000004.jpg4467 In the above chemical formula 3, R'' represents hydrogen, halogen, and C, each independently. 1-4 Alkyl, or C 1-4 It is a haloalkyl, n is an integer between 1 and 3. R4 is either -NHCO-CH=CH2 or -COOH.

[0018] Typical examples of compounds represented by the aforementioned chemical formula 1 are as follows: 1) N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 2) N-(7-(1-methyl-1H-imidazole-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-indole-5-yl)acrylamide, 3) N-(2-(4-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 4) N-(7-(1-methyl-1H-imidazole-4-yl)-2-phenyl-1H-indole-5-yl)acrylamide, 5) N-(2-(2,4-difluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 6) N-(7-(1-methyl-1H-imidazole-4-yl)-2-(3,4,5-trifluorophenyl)-1H-indole-5-yl)acrylamide, 7) N-(7-(1-(difluoromethyl)-1H-imidazole-4-yl)-2-(4-fluorophenyl)-1H-indole-5-yl)acrylamide, 8) N-(2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 9) N-(2-(3,4-difluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 10) N-(2-(3-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 11) N-(2-(4-chlorophenyl)-7-(1-(difluoromethyl)-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 12) N-(2-(4-chloro-2-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 13) N-(2-cyclohexenyl-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 14) N-(2-(4-fluoro-3-methylphenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 15) N-(7-(1-methyl-1H-imidazole-4-yl)-2-p-tolyl-1H-indole-5-yl)acrylamide, 16) N-(7-(1-methyl-1H-imidazole-4-yl)-2-(3-(trifluoromethyl)phenyl)-1H-indole-5-yl)acrylamide, 19) N-(7-(1-methyl-1H-imidazole-4-yl)-2-(3-(trifluoromethyl)phenyl)-1H-indole-5-yl)methanesulfonamide, 20) N-(2-(4-chloro-3-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 21) N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)methanesulfonamide, 22) N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)-2-fluoroacrylamide, 23) N-(3-chloro-2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 24)(E)-N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)-2-cyano-3-phenylacrylamide, 25) N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)buto-2-inamide, 26) N-(2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)ethanesulfonamide, 27) 1-(2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)-1H-pyrrole-2,5-dione, 28) N-(2-(4-chlorophenyl)-7-(1-methyl-1H-pyrazole-3-yl)-1H-indole-5-yl)acrylamide, 29) N-(2-(3,4-dichlorophenyl)-7-(1-methyl-1H-pyrazole-3-yl)-1H-indole-5-yl)acrylamide, 30) N-(2-(3,4-dichlorophenyl)-7-(pyridine-2-yl)-1H-indole-5-yl)acrylamide, 31) N-(2-(4-fluorophenyl)-7-(pyridine-2-yl)-1H-indole-5-yl)acrylamide, 32) N-(2-(4-fluorophenyl)-7-(1-methyl-1H-pyrazol-3-yl)-1H-indole-5-yl)acrylamide, 33) N-(2-(2,4-difluorophenyl)-7-(1-methyl-1H-pyrazole-3-yl)-1H-indole-5-yl)acrylamide, 34) N-(2-(5-chloropyridine-2-yl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 35) 2-(4-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylic acid, 36) 7-(1-methyl-1H-imidazole-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-indole-5-carboxylic acid, 37) 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylic acid, 38) 2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylic acid, 39) 2-(4-chloro-3-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylic acid, 40) 2-(4-chlorophenyl)-N-methyl-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylamide, 41) N-(7-(1-methyl-1H-imidazole-4-yl)-2-(3,4,5-trichlorophenyl)-1H-indole-5-yl)acrylamide, 42) N-(2-(3-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 43) 2-(3,4-difluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylic acid, 44) N-(2-(3-chloro-4-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 45) N-(2-(2,4-dichlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 46) N-(2-(4-chloro-3,5-difluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 47) N-(2-(4-chloro-2,6-difluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 48) N-(7-(1-methyl-1H-imidazole-4-yl)-2-(4-(trifluoromethoxy)phenyl)-1H-indole-5-yl)acrylamide, 49) N-(2-(4-chlorophenyl)-7-(4-methylthiazole-2-yl)-1H-indole-5-yl)acrylamide, 50) N-(7-(1-ethyl-1H-imidazole-4-yl)-2-(3,4,5-trifluorophenyl)-1H-indole-5-yl)acrylamide, 51) N-(7-(1-ethyl-1H-imidazole-4-yl)-2-(4-fluorophenyl)-1H-indole-5-yl)acrylamide, and 52) N-(2-(4-bromophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide.

[0019] Furthermore, the compounds of the present invention may exist in the form of salts, particularly pharmaceutically acceptable salts. Any salt commonly used in the industry may be used without limitation, such as an acid addition salt formed by a pharmaceutically acceptable free acid. In this invention, "pharmaceutically acceptable salt" means any organic or inorganic addition salt of the compound at a concentration that is relatively non-toxic and harmless to the patient and whose side effects do not diminish the beneficial efficacy of the compound represented by chemical formula 1.

[0020] The free acid can be an organic acid or an inorganic acid. Inorganic acids can include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, stannic acid, etc. Organic acids can include, but are not limited to, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. Preferably, the salt may be a hydrochloride salt.

[0021] Furthermore, pharmaceutically acceptable metal salts can be obtained using a base in a conventional manner. For example, the compound represented by chemical formula 1 can be dissolved in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, the insoluble compound salt can be filtered out, and the filtrate can be evaporated and dried to obtain a pharmaceutically acceptable metal salt. In this case, it is particularly preferable to produce a sodium salt, a potassium salt, or a calcium salt as the metal salt.

[0022] Furthermore, a pharmaceutically acceptable salt or solvate of a compound represented by chemical formula 1 can be used as an intermediate in the manufacture of the compound represented by chemical formula 1, its pharmaceutically acceptable salt, or solvate.

[0023] On the other hand, the compound represented by chemical formula 1 can be produced by the following reaction formula 1 or 2.

[0024] [Reaction Equation 1] JPEG2026510431000005.jpg90140

[0025] [Reaction Equation 2] JPEG2026510431000006.jpg63140

[0026] In reaction equations 1 and 2, the definitions of the remaining elements, excluding Y, are as previously defined, and Y is C 1-4 It is alkyl, and more preferably, Y is methyl or ethyl.

[0027] Step 1 of each of reaction formulas 1 and 2 is a Still coupling reaction, and step 2 is a Sonogashira coupling reaction. The order of steps 1 and 2 can be changed depending on the reactivity of each reactant (see Example 28). In this case, X' is a substituent for the Still coupling reaction and may be, but is not limited to, -SnBu3 or -B(OH)2 for the Suzuki reaction.

[0028] Step 3 of each of the above reaction formulas 1 and 2 is a reaction that synthesizes indole by cyclization, and can be carried out under basic conditions, but is not limited to that.

[0029] Step 4 of the above reaction equation 1 is a reaction that reduces a nitro group, and can be carried out using iron, but is not limited to iron.

[0030] Step 5 of the above reaction formula 1 is the reaction between the amine group and R4 with a carbonyl group or sulfonyl group, etc.

[0031] Step 4 of the above reaction formula 2 is a hydrolysis reaction, which can be carried out under basic conditions, but is not limited thereto.

[0032] Step 5 of the above reaction equation 2 may be, but is not limited to, a coupling reaction between the nucleophile and the carbonyl group by R4.

[0033] On the other hand, in chemical formula 1 of the present invention, R3 is hydrogen in reaction formulas 1 and 2. If R3 is not hydrogen, an indole derivative can be synthesized by a cyclization reaction after step 3 and before step 4, and then R3 can be substituted by an R3 substitution reaction.

[0034] The above manufacturing method will be further elaborated in the embodiments described later.

[0035] Furthermore, the present invention provides a pharmaceutical composition comprising a compound represented by the chemical formula 1 or a pharmaceutically acceptable salt thereof. Specifically, 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 a pharmaceutically acceptable salt thereof as an active ingredient.

[0036] The aforementioned terms “cancer” or “tumor” refer to the presence of cells that have typical characteristics of cancer-inducing cells, such as uncontrolled proliferation in an individual, indestructibility, potential for metastasis, rapid growth and proliferation rate, and reduced cell death / cell necrosis. Cancer cells sometimes include solid tumors, such as sarcomas or carcinomas. Sarcomas include alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastoma, angiosarcoma, chondrosarcoma, chordoma, clear cell sarcoma, dedifferentiated liposarcoma, desmoid, connective tissue round cell tumor, germ cell rhabdomyosarcoma, epithelial fibrosarcoma, epithelioid hemangioendothelioma, epithelioid sarcoma, olfactory neuroblastoma, Ewing's sarcoma, renal rhabdoid tumor, extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, giant cell tumor, pericytoma, infantile fibrosarcoma, inflammatory myofibroblastoma, and Kaposi's sarcoma. This includes tumors, osteosarcomas, liposarcomas, liposarcomas of bone, malignant fibrous histiocytoma, malignant fibrous histiocytoma of bone, malignant mesenchymal tumors, malignant peripheral nerve sheath tumors, mesenchymal chondrosarcomas, myxofibrosarcomas, myxoid liposarcomas, inflammatory myofibroblastic sarcomas, osteosarcomas, paraosteal osteosarcomas, periosteal osteosarcomas, pleomorphic liposarcomas, pleomorphic rhabdomyosarcomas, extraskeletal Ewing tumors, rhabdomyosarcomas, round cell liposarcomas, small cell osteosarcomas, solitary fibrous tumors, synovial sarcomas, and vascularized osteosarcomas. Carcinomas include adenocarcinoma, squamous cell carcinoma, adenosquamous cell carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal carcinoma, appendiceal carcinoma, bile duct carcinoma, bladder carcinoma, brain carcinoma, breast carcinoma, cervical carcinoma, colorectal carcinoma, carcinoma of unknown primary origin, esophageal carcinoma, eye carcinoma, primary fallopian tube carcinoma, gastrointestinal carcinoma, kidney carcinoma, liver carcinoma, lung carcinoma, medulloblastoma, malignant melanoma, oral carcinoma, ovarian carcinoma, pancreatic carcinoma, parathyroid carcinoma, penile carcinoma, pituitary carcinoma, prostate carcinoma, rectal carcinoma, skin carcinoma, gastric carcinoma, testicular carcinoma, throat carcinoma, thyroid carcinoma, uterine carcinoma, vaginal carcinoma, and vulvar carcinoma. In some cases, cancers used in this application include uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colorectal cancer, colon cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer, and meningioma.

[0037] Cancer also includes non-solid tumors, such as hematological cancers, in which the cancer cells originate from the bone marrow. Hematological cancers include leukemia, lymphoma, myeloma, non-Hodgkin lymphoma, Hodgkin lymphoma, T-cell malignancies, or B-cell malignancies. In particular, T-cell malignancies include mature T-cell lymphoma not otherwise classified, antiplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia, blastic natural killer cell lymphoma, platelet-gamma-delta T-cell lymphoma, and lymphoblastic lymphoma. B-cell malignancies include, but are not limited to, chronic lymphocytic leukemia, small lymphocytic lymphoma, vesicle lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, Waldenström macroglobulinemia, head and neck tumors, nodal marginal zone B-cell lymphoma, Burkitt lymphoma, primary mediastinal large B-cell lymphoma, immunoblastic large B-cell lymphoma, pro-lympholympic leukemia, lymphoplasmacytic lymphoma, nasal marginal zone lymphoma, plasmacytosis myeloma, plasmacytoma, intravascular large B-cell lymphoma, primary exudative lymphoma, or lymphomatoid granulomatosis.

[0038] In some cases, this includes recurrent or refractory cancers, which are solid tumors. Recurrent or refractory cancers include adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, antiplastic carcinoma, large cell carcinoma, small cell carcinoma, bile duct cancer, bladder cancer, brain tumors, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, eye tumors, primary fallopian tube cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, malignant melanoma, oral cancer, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumors, prostate cancer, rectal cancer, skin cancer, gastric cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.

[0039] 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.

[0040] The pharmaceutical compositions of the present invention can be formulated into oral or parenteral dosage forms by standard pharmaceutical practices. These dosage forms may contain, in addition to the active ingredient, pharmaceutically acceptable additives such as carriers, adjuvants, or diluents.

[0041] Suitable carriers include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oil, and isopropyl myristate. Diluents include, but are not limited to, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine. Furthermore, the compounds of the present invention can be dissolved in oils, propylene glycol, or other solvents commonly used in the manufacture of injectable solutions. In addition, for topical action, the compounds of the present invention can be formulated into ointments or creams.

[0042] The preferred dosage of the compound of the present invention varies depending on the patient's condition and weight, the severity of the disease, the form of the drug, the route of administration, and the duration, but can be appropriately selected by those skilled in the art. However, for the desired effect, it is preferable to administer the compound of the present invention at a dose of 0.0001 to 100 mg / kg (body weight), preferably 0.001 to 100 mg / kg (body weight) per day. The drug may be administered once a day or in divided doses, via oral or parenteral routes.

[0043] Depending on the administration method, the pharmaceutical composition may contain 0.001 to 99% by weight, preferably 0.01 to 60% by weight, of the compound of the present invention.

[0044] The pharmaceutical compositions according to the present invention can be administered to mammals, including mice, rats, livestock, and humans, via a variety of routes. While all methods of administration are conceivable, they may be administered, for example, orally, rectally or intravenously, intramuscularly, subcutaneously, intrauterine dura mater, or intracerebral (intracerebroventricular) injection. [Effects of the Invention]

[0045] The compound represented by chemical formula 1 according to the present invention or a pharmaceutically acceptable salt thereof can be usefully used for the prevention or treatment of cancer or tumors. [Brief explanation of the drawing]

[0046] [Figure 1] This shows the results of Experimental Example 3, demonstrating the expression regulatory properties of two TEAD target genes using real-time PCR in Example 1. [Modes for carrying out the invention]

[0047] The following are preferred embodiments for understanding the present invention, but these embodiments are merely illustrative and the scope of the present invention is not limited to these embodiments.

[0048] Example 1: Preparation of N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide JPEG2026510431000007.jpg90140

[0049] (Stage 1) In a sealed tube, 2,6-diiodo-4-nitroaniline (2.56 mmol, 1 g, 1.0 eq) was dissolved in 1,4-dioxane (10 mL). 1-methyl-4-(tributylstannyl)-1H-imidazole (2.56 mmol, 0.95 g, 1.0 eq) and Pd(PPh3)4 (0.25 mmol, 0.29 g, 0.1 eq) were added sequentially, and the mixture was reacted in a microwave reactor at 150°C for 1 hour. After the reaction was complete, the mixture was extracted with ethyl acetate and aqueous ammonium chloride, concentrated, and solidified with tertiary butyl methyl ether to obtain 2-iodo-6-(1-methyl-1H-imidazole-4-yl)-4-nitroaniline (0.57 g, yield: 64%).

[0050] (Stage 2) 2-iodo-6-(1-methyl-1H-imidazole-4-yl)-4-nitroaniline (0.58 mmol, 0.2 g, 1.0 eq), Pd(PPh3)4 (0.058 mmol, 0.067 g, 0.1 eq), copper iodide (0.03 mmol, 0.0057 g, 0.05 eq), triethylamine (1.7 mmol, 0.24 mL, 2.9 eq), and tetrahydrofuran (2 mL) were added sequentially, and sonic degassing was carried out under nitrogen atmosphere for 10 minutes. 1-chloro-4-ethynylbenzene (0.69 mmol, 0.094 g, 1.2 eq) was added, and the mixture was reacted at 50°C for 2 hours. After the reaction was complete, the product was extracted with ethyl acetate and aqueous ammonium chloride, concentrated, and solidified with tertiary butyl methyl ether to obtain 2-((4-chlorophenyl)ethynyl)-6-(1-methyl-1H-imidazole-4-yl)-4-nitroaniline (0.14 g, yield: 68%).

[0051] (Stage 3) 2-((4-chlorophenyl)ethynyl)-6-(1-methyl-1H-imidazole-4-yl)-4-nitroaniline (0.39 mmol, 0.14 g, 1.0 eq), sodium hydroxide (1.95 mmol, 0.078 g, 5.0 eq), and dimethylacetamide (10 mL) were sequentially added to a microwave vial and reacted at 150°C for 15 minutes. After the reaction was complete, the mixture was extracted with ethyl acetate and aqueous ammonium chloride, concentrated, and solidified with tertiary butyl methyl ether to obtain 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-5-nitro-1H-indole (0.079 g, yield: 57%).

[0052] (Stage 4) 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-5-nitro-1H-indole (0.22 mmol, 0.079 g, 1.0 eq), iron (1.0 mmol, 0.055 g, 4.54 eq), ammonium chloride (0.22 mmol, 0.012 g, 1.0 eq), and 10 mL of 70% ethanol (ethanol:distilled water = 7:3 (v:v)) were added sequentially. The reaction mixture was allowed to react overnight at 60°C. After the reaction was complete, iron and ethanol were removed, and the mixture was extracted with an aqueous solution of ammonium chloride, concentrated, and 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-amine was used in the next reaction without separation or purification.

[0053] (Stage 5) 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-amine (0.1 mmol, 0.032 g, 1.0 eq), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.3 mmol, 0.057 g, 3.0 eq), and 1 mL of dichloromethane were sequentially added to a flask. After adding 0.05 mL of triethylamine and acrylic acid (0.12 mmol, 0.0086 mL, 1.2 eq), the mixture was allowed to react overnight at room temperature. After the reaction was complete, the dichloromethane was removed, and the compound was purified by column chromatography to obtain the title compound (9.4 mg, yield: 25%). 1 H NMR (400 MHz, CDCl3) δ 11.14 s, 1H), 7.77 (s, 1H), 7.70-7.68 (m, 2H), 7.55-7.54 (m, 2H), 7.44-7.40 (m, 3H), 7.24-7.25 (m, 1H), 6.76 (d, J = 2.2 Hz, 1H), 6.46 (d, J = 16.0, 1H), 6.33-6.26 (m, 1H), 5.78 (d, J = 12.0, 1H), 3.79 (s, 3H)

[0054] Example 2: Preparation of N-(7-(1-methyl-1H-imidazole-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-indole-5-yl)acrylamide JPEG2026510431000008.jpg3360 The title compound (8.6 mg, yield: 21%) was obtained in the same manner as in Example 1, except that 1-trifluoromethyl-4-ethynylbenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1 H NMR (400 MHz, CDCl3) δ 11.28 (s, 1H), 7.87-7.85 (m, 2H), 7.80 (s, 1H), 7.70-7.68 (m, 2H), 7.60-7.58 (m, 2H), 7.41 (s, 1H), 7.25 (s, 1H), 6.88 (s, 1H), 6.46 (d, J = 12.0, 1H), 6.32-6.27 (m, 1H), 5.78 (d, J = 8.0, 1H), 3.80 (s, 3H).

[0055] Example 3: Preparation of N-(2-(4-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide JPEG2026510431000009.jpg3356 The title compound (8.6 mg, yield: 21%) was obtained in the same manner as in Example 1, except that 1-ethynyl-4-fluorobenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1H NMR (500 MHz, DMSO) δ 11.13 (s, 1H), 10.08 (s, 1H), 7.89-7.86 (m, 4H), 7.76 (s, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.35 (t, J = 8.8 Hz, 2H), 6.92 (d, J = 2.2 Hz, 1H), 6.49 (dd, J = 16.9, 10.1 Hz, 1H), 6.26 (dd, J = 17.0, 1.8 Hz, 1H), 5.74 (dd, J = 10.1, 1.8 Hz, 1H), 3.80 (s, 3H).

[0056] Example 4: Preparation of N-(7-(1-methyl-1H-imidazole-4-yl)-2-phenyl-1H-indole-5-yl)acrylamide JPEG2026510431000010.jpg3350 The title compound (11.9 mg, yield: 35%) was obtained in the same manner as in Example 1, except that ethynylbenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1 H NMR (500 MHz, DMSO) δ 11.13 (s, 1H), 10.08 (s, 1H), 7.89-7.86 (m, 4H), 7.76 (s, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.35 (t, J = 8.8 Hz, 2H), 6.92 (d, J = 2.2 Hz, 1H), 6.49 (dd, J = 16.9, 10.1 Hz, 1H), 6.26 (dd, J = 17.0, 1.8 Hz, 1H), 5.74 (dd, J = 10.1, 1.8 Hz, 1H), 3.80 (s, 3H).

[0057] Example 5: Preparation of N-(2-(2,4-difluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide JPEG2026510431000011.jpg3356 The title compound (6.0 mg, yield: 16%) was obtained in the same manner as in Example 1, except that 1-ethynyl-2,4-difluorobenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1 H NMR (500 MHz, DMSO) δ 11.48 (s, 1H), 10.08 (s, 1H), 8.04-7.99 (m, 1H), 7.88 (d, J = 10.0 Hz, 2H), 7.73-7.69 (m, 2H), 7.49-7.44 (m, 1H), 7.27 (td, J = 8.5, 2.0 Hz, 1H), 6.98 (d, J = 1.5 Hz, 1H), 6.50 (dd, J = 17.0, 10.0 Hz, 1H), 6.27 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (dd, J = 10.0, 2.0 Hz, 1H), 3.79 (s, 3H).

[0058] Example 6: Preparation of N-(7-(1-methyl-1H-imidazole-4-yl)-2-(3,4,5-trifluorophenyl)-1H-indole-5-yl)acrylamide JPEG2026510431000012.jpg3356 The title compound (17.8 mg, yield: 45%) was obtained in the same manner as in Example 1, except that 5-ethynyl-1,2,3-trifluorobenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1 H NMR (500 MHz, CDCl3) δ 11.21 (s, 1H), 7.82 (s, 1H), 7.61-7.60 (m, 2H), 7.42-7.29 (m, 3H), 7.31 (s, 1H), 6.76 (s, 1H), 6.32 (dd, J = 16.6, 10.4 Hz, 1H), 5.80 (d, J = 10.1 Hz, 1H), 3.82 (s, 3H).

[0059] Example 7: Preparation of N-(7-(1-(difluoromethyl)-1H-imidazole-4-yl)-2-(4-fluorophenyl)-1H-indole-5-yl)acrylamide The title compound (9.1 mg, yield: 23%) was obtained in the same manner as in Example 1, except that 1-(difluoromethyl)-4-(tributylstannyl)-1H-imidazole was used instead of 1-methyl-4-(tributylstannyl)-1H-imidazole in step 1 of Example 1, and 1-ethynyl-4-fluorobenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1 H NMR (500 MHz, DMSO) δ 10.85 (s, 1H), 10.05 (s, 1H), 8.42 (s, 1H), 8.26 (s, 1H), 7.97-7.88 (m, 3H), 7.94 (CHF2, t, J = 60 Hz, 1H), 7.83 (s, 1H), 7.34 (t, J = 8.7 Hz, 2H), 6.93 (s, 1H), 6.50 (dd, J = 16.9, 10.2 Hz, 1H), 6.27 (d, J = 15.6 Hz, 1H), 5.74 (d, J = 11.3 Hz, 1H).

[0060] Example 8: Preparation of N-(2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide JPEG2026510431000014.jpg3357 The title compound (3.5 mg, yield: 9%) was obtained in the same manner as in Example 1, except that 1,2-dichloro-4-ethynylbenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1H NMR (500 MHz, DMSO) δ 11.14 (s, 1H), 10.07 (s, 1H), 8.14 (s, 1H), 7.91 (s, 1H), 7.89 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.77 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.71 (s, 1H), 7.10 (s, 1H), 6.49 (dd, J = 17.0, 10.0 Hz, 1H), 6.26 (d, J = 17.0 Hz, 1H), 5.73 (d, J = 10.0 Hz, 1H), 3.80 (s, 3H).

[0061] Example 9: Preparation of N-(2-(3,4-difluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide JPEG2026510431000015.jpg3356 The title compound (2.0 mg, yield: 5%) was obtained in the same manner as in Example 1, except that 1,2-difluoro-4-ethynylbenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1 H NMR (500 MHz, CD3OD) δ 8.03 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 9.0, 2.0 Hz, 2H), 7.77 (dd, J = 8.5, 2.0 Hz, 1H), 7.67-7.62 (m, 4H), 6.92 (s, 1H), 6.50 (dd, J = 17.0, 10.0 Hz, 1H), 6.40 (dd, J = 17.0, 2.0 Hz, 1H), 5.79 (dd, J = 10.0, 1.5 Hz, 1H), 3.87 (s, 3H).

[0062] Example 10: Preparation of N-(2-(3-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide JPEG2026510431000016.jpg3352 The title compound (11.6 mg, yield: 31%) was obtained in the same manner as in Example 1, except that 1-chloro-3-ethynylbenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1 H NMR (500 MHz, DMSO) δ 11.16 (s, 1H), 10.07 (s, 1H), 7.91-7.90 (m, 3H), 7.80-7.77 (m, 2H), 7.70 (s, 1H), 7.55-7.52 (m, 1H), 7.42-7.41 (m, 1H) 7.06 (s, 1H) 6.49 (dd, J = 17.0, 10.4 Hz, 1H), 6.27 (d, J = 16.8 Hz, 1H), 5.74 (d, J = 11.0 Hz, 1H), 3.80 (s, 3H).

[0063] Example 11: Preparation of N-(2-(4-chlorophenyl)-7-(1-(difluoromethyl)-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide JPEG2026510431000017.jpg3857 The title compound (9.0 mg, yield: 22%) was obtained in the same manner as in Example 1, except that 1-(difluoromethyl)-4-(tributylstannyl)-1H-imidazole was used instead of 1-methyl-4-(tributylstannyl)-1H-imidazole in step 1 of Example 1. 1H NMR (500 MHz, DMSO) δ 10.90 (s, 1H), 10.11 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 7.98 (s, 1H), 7.94 (CHF2, t, J = 60.0 Hz, 1H) 7.91-7.89 (m, 2H), 7.83 (d, J = 1.5 Hz, 1H), 7.57-7.56 (m, 2H), 7.02 (d, J = 1.9 Hz, 1H), 6.50 (dd, J = 16.9, 10.2 Hz, 1H), 6.27 (dd, J = 17.0, 1.7 Hz, 1H), 5.83-5.67 (m, 1H).

[0064] Example 12: Preparation of N-(2-(4-chloro-2-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide JPEG2026510431000018.jpg3357 The title compound (4.5 mg, yield: 11%) was obtained in the same manner as in Example 1, except that 4-chloro-1-ethynyl-2-fluorobenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1 H NMR (500 MHz, DMSO) δ 11.52 (s, 1H), 10.09 (s, 1H), 8.00 (t, J = 8.5 Hz, 1H), 7.90-7.89 (m, 2H), 7.73-7.70 (m, 2H), 7.67 (dd, J = 11.5, 1.5 Hz, 1H), 7.44 (dd, J = 8.5, 1.5 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.50 (dd, J = 17.0, 10.0 Hz, 1H), 6.27 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (d, J = 10.0, 2.0 Hz, 1H), 3.79 (s, 3H).

[0065] Example 13: Preparation of N-(2-cyclohexenyl-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide JPEG2026510431000019.jpg3350 The title compound (11.0 mg, yield: 32%) was obtained in the same manner as in Example 1, except that 1-ethynylcyclohex-1-ene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1 H NMR (500 MHz, DMSO) δ 10.84 (s, 1H), 10.00 (s, 1H), 7.86 (s, 1H), 7.74 (s, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 6.53- 6.41 (m, 2H), 6.25 (d, J = 17.2 Hz, 2H), 5.72 (d, J = 10.1 Hz, 1H), 3.78 (s, 3H), 2.44-2.46 (m, 2H), 2.25-2.26 (m, 2H), 1.75-1.77 (m, 2H), 1.66-1.68 (m, 2H).

[0066] Example 14: Preparation of N-(2-(4-fluoro-3-methylphenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide JPEG2026510431000020.jpg3356 The title compound (6.0 mg, yield: 16%) was obtained in the same manner as in Example 1, except that 4-ethynyl-1-fluoro-2-methylbenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1H NMR (500 MHz, DMSO) δ 11.08 (s, 1H), 10.05 (s, 1H), 7.89 (s, 1H), 7.85 (s, 1H), 7.77-7.73 (m, 2H), 7.67-7.64 (m, 2H), 7.28 (t, J = 9.1 Hz, 1H), 6.88 (d, J = 2.2 Hz, 1H), 6.49 (dd, J = 16.9, 10.1 Hz, 1H), 6.26 (dd, J = 17.0, 1.8 Hz, 1H), 5.79-5.69 (m, 1H), 3.80 (s, 3H), 2.35 (s, 3H).

[0067] Example 15: Preparation of N-(7-(1-methyl-1H-imidazole-4-yl)-2-p-tolyl-1H-indole-5-yl)acrylamide JPEG2026510431000021.jpg3354 The title compound (3.3 mg, yield: 9%) was obtained in the same manner as in Example 1, except that 1-ethynyl-4-methylbenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1 H NMR (500 MHz, DMSO) δ 11.13 (s, 1H), 10.05 (s, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 7.74-7.66 (m, 4H), 7.32 (d, J = 7.5 Hz, 2H), 6.88 (d, J = 2.0 Hz, 1H), 6.49 (d, J = 17.0, 10.0 Hz, 1H), 6.26 (dd, J = 17.0, 1.5 Hz, 1H), 5.73 (dd, J = 10.0, 1.5 Hz, 1H), 3.80 (s, 3H), 2.37 (s, 3H).

[0068] Example 16: Preparation of N-(7-(1-methyl-1H-imidazole-4-yl)-2-(3-(trifluoromethyl)phenyl)-1H-indole-5-yl)acrylamide JPEG2026510431000022.jpg3354 The title compound (3.2 mg, yield: 8%) was obtained in the same manner as in Example 1, except that 1-ethynyl-3-(trifluoromethyl)benzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1 H NMR (500 MHz, DMSO) δ 11.23 (s, 1H), 10.09 (s, 1H), 8.17 (s, 1H), 8.12 (d, J = 7.5 Hz, 1H), 7.91-7.90 (m, 2H), 7.77 (s, 1H), 7.76-7.70 (m, 3H), 7.14 (d, J = 2.0 Hz, 1H), 6.49 (dd, J = 17.0, 10.5 Hz, 1H), 6.27 (dd, J = 17.0, 1.5 Hz, 1H), 5.74 (dd, J =10.0, 1.5 Hz, 1H), 3.80 (s, 3H).

[0069] Example 17: Preparation of N-(7-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-yl)-2-(4-fluorophenyl)-1H-indole-5-yl)acrylamide The title compound (6.9 mg, yield: 18%) was obtained in the same manner as in Example 1, except that 1,2-(tributylstannyl)-6,7-dihydro-5H-pyrrole[1,2-a]imidazole was used instead of 1-methyl-4-(tributylstannyl)-1H-imidazole in step 1 of Example 1, and 1-ethynyl-4-fluorobenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1H NMR (500 MHz, DMSO) δ 11.14 (s, 1H), 10.03 (s, 1H), 7.92-7.79 (m, 3H), 7.70 (s, 1H), 7.62 (s, 1H), 7.43-7.29 (m, 2H), 6.90 (s, 1H), 6.49 (dd, J = 17.0, 10.2 Hz, 1H), 6.26 (d, J = 16.6 Hz, 1H), 5.73 (d, J = 11.4 Hz, 1H), 4.14-4.02 (m, 2H), 2.98-2.87 (m, 2H), two protons were missing due to overlapping.

[0070] Example 18: Preparation of N-(2-(4-chlorophenyl)-7-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-yl)-1H-indole-5-yl)acrylamide The title compound (6.8 mg, yield: 17%) was obtained in the same manner as in Example 1, except that in step 1 of Example 1, 2-(tributylstannyl)-6,7-dihydro-5H-pyrrole[1,2-a]imidazole was used instead of 1-methyl-4-(tributylstannyl)-1H-imidazole. 1 H NMR (500 MHz, DMSO) δ 11.17 (s, 1H), 10.04 (s, 1H), 7.89 (s, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.71 (s, 1H), 7.63 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 6.98 (s, 1H), 6.49 (dd, J = 16.9, 10.2 Hz, 1H), 6.26 (d, J = 15.2 Hz, 1H), 5.73 (d, J = 11.9 Hz, 1H), 4.14-4.05 (m, 2H), 2.97-2.88 (m, 2H), two protons were missing due to Icing.

[0071] Example 19: Preparation of N-(7-(1-methyl-1H-imidazole-4-yl)-2-(3-(trifluoromethyl)phenyl)-1H-indole-5-yl)methanesulfonamide JPEG2026510431000025.jpg331397-(1-methyl-1H-imidazole-4-yl)-2-(3-(trifluoromethyl)phenyl)-1H-indole-5-amine (0.1 mmol, 0.035 g, 1.0 eq) was dissolved in dichloromethane (1 mL) and cooled to 0°C. Triethylamine (0.15 mmol, 0.015 g, 1.5 eq) and methanesulfonyl chloride (0.11 mmol, 0.012 g, 1.1 eq) were added sequentially. The reaction mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, the dichloromethane was removed and the compound was purified by column chromatography to obtain the title compound (15.0 mg, yield: 35%). 1 H NMR (500 MHz, DMSO) δ 11.32 (s, 1H), 9.36 (s, 1H), 8.16 (s, 1H), 8.12 (d, J = 7.5 Hz, 1H), 7.90 (s, 1H), 7.81 (s, 1H), 7.75-7.21 (m, 2H), 7.40 (d, J = 1.5 Hz, 1H), 7.34 (d, J = 1.5 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 3.80 (s, 3H), 2.93 (s, 3H).

[0072] Example 20: Preparation of N-(2-(4-chloro-3-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide JPEG2026510431000026.jpg3357 The title compound (16.2 mg, yield: 39%) was obtained in the same manner as in Example 1, except that 1-chloro-4-ethynyl-2-fluorobenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1H NMR (500 MHz, DMSO) δ 11.13 (s, 1H), 10.20 (s, 1H), 8.03-7.99 (m, 2H), 7.96-7.94 (m, 1H), 7.83-7.77 (m, 2H), 7.73-7.70 (m, 2H), 7.15 (s, 1H), 6.50 (dd, J = 17.0, 10.5 Hz, 1H), 6.27 (dd, J = 17.0, 1.5 Hz, 1H), 5.76 (dd, J = 10.0, 1.5 Hz, 1H), 3.93 (s, 3H).

[0073] Example 21: Preparation of N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)methanesulfonamide JPEG2026510431000027.jpg321402-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-amine (0.1 mmol, 0.032 g, 1.0 eq) was dissolved in dichloromethane (1 mL) and cooled to 0°C. Triethylamine (0.15 mmol, 0.015 g, 1.5 eq) and methanesulfonyl chloride (0.11 mmol, 0.012 g, 1.1 eq) were added sequentially. The reaction mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, the dichloromethane was removed and the compound was purified by column chromatography to obtain the title compound (19.8 mg, yield: 49%). 1 H NMR (500 MHz, DMSO) δ 11.25(s, 1H), 9.34 (s, 1H), 7.89 (s, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.79 (s, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.37 (s, 1H), 7.32 (s, 1H), 6.99 (d, J = 1.5 Hz 1H), 3.80 (s, 3H), 2.92 (s, 3H).

[0074] Example 22: Preparation of N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)-2-fluoroacrylamide JPEG2026510431000028.jpg3557 The title compound (6.1 mg, yield: 15%) was obtained in the same manner as in Example 1, except that 2-fluoroacrylic acid was used instead of acrylic acid in step 5 of Example 1. 1 H NMR (500 MHz, DMSO) δ 11.23 (s, 1H), 10.19 (s, 1H), 7.90 (s, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.82 (s, 1H), 7.75 (m, 2H), 7.57 (d, J = 8.5 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 5.72 (dd, J = 48.0, 3.5 Hz, 1H), 5.41 (dd, J = 5.5, 3.5 Hz, 1H), 3.80 (s, 3H).

[0075] Example 23: Preparation of (N-(3-chloro-2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide JPEG2026510431000029.jpg60140

[0076] (Stage 1) 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-5-nitro-1H-indole (0.28 mmol, 0.1 g, 1.0 eq) was dissolved in dimethylformamide (1 mL). N-chlorosuccinimide (0.31 mmol, 0.041 g, 1.1 eq) was added, and the mixture was reacted overnight at room temperature. After the reaction was complete, distilled water was added, and the solid was filtered to obtain 3-chloro-2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-5-nitro-1H-indole (0.060 g, yield: 55%).

[0077] (Stage 2) 3-chloro-2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-5-nitro-1H-indole (0.15 mmol, 0.060 g, 1.0 eq), iron (1.5 mmol, 0.083 g, 1.0 eq), ammonium chloride (0.15 mmol, 0.008 g, 1.0 eq), and 70% ethanol (10 mL; ethanol:distilled water = 7:3 (v:v)) were added sequentially, and the reaction mixture was allowed to react at 80°C for 4 hours. After the reaction was complete, iron and ethanol were removed, and the mixture was extracted with an aqueous solution of ammonium chloride, concentrated, and 3-chloro-2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-amine was used in the next reaction without separation and purification.

[0078] (Stage 3) 3-Chloro-2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-amine (0.1 mmol, 0.035 g, 1.0 eq), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.2 mmol, 0.038 g, 2.0 eq), and dichloromethane (1 mL) were sequentially added to a flask. After adding triethylamine (0.2 mL) and acrylic acid (0.1 mmol, 0.0072 g, 1.0 eq), the mixture was allowed to react overnight at room temperature. After the reaction was complete, the dichloromethane was removed, and the mixture was purified by column chromatography to obtain the title compound (3.7 mg, yield: 9%). 1 H NMR (500 MHz, DMSO) δ 11.20 (s, 1H), 10.22 (s, 1H), 7.95 (s, 1H), 7.95-7.90 (m, 2H), 7.87 (s, 1H), 7.82-7.80 (m, 2H), 7.67-7.65 (m, 2H), 6.48 (d, J = 10.4 Hz, 1H), 6.28 (d, J = 17.3 Hz, 1H), 5.76 (d, J = 10.0 Hz, 1H), 3.79 (s, 3H).

[0079] Example 24: Preparation of (E)-N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)-2-cyano-3-phenylacrylamide JPEG2026510431000030.jpg3770 The title compound (19.8 mg, yield: 41%) was obtained in the same manner as in Example 1, except that (E)-2-cyano-3-phenylacrylic acid was used instead of acrylic acid in step 5 of Example 1. 1 H NMR (500 MHz, DMSO) δ 11.25 (s, 1H), 8.67 (s, 1H), 7.99-7.97(m, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.60 (s, 1H), 7.52-7.51 (m, 3H), 7.46-7.42 (m, 5H), 6.86 (d, J = 2.0 Hz, 1H), 3.81 (s, 3H).

[0080] Example 25: Preparation of N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)buto-2-inamide JPEG2026510431000031.jpg3361 The title compound (15.4 mg, yield: 39%) was obtained in the same manner as in Example 1, except that buto-2-inoic acid was used instead of acrylic acid in step 5 of Example 1. 1 H NMR (500 MHz, DMSO) δ 11.19 (s, 1H), 10.48 (s, 1H), 7.89 (s, 1H), 7.84 (d, J = 7.0 Hz, 2H), 7.73 (s, 1H), 7.71 (s, 1H), 7.66 (s, 1H), 7.57 (d, J = 7.0 Hz, 2H), 6.97 (s, 1H), 5.77 (s, 3H), 3.80 (s, 3H).

[0081] Example 26: Preparation of N-(2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)ethenesulfonamide JPEG2026510431000032.jpg341402-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-amine (0.1 mmol, 0.036 g, 1.0 eq) was dissolved in dichloromethane (1 mL) and cooled to 0°C. Triethylamine (0.15 mmol, 0.015 g, 1.5 eq) and ethenesulfonyl chloride (0.11 mmol, 0.014 g, 1.1 eq) were added sequentially. The reaction mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, the dichloromethane was removed and the compound was purified by column chromatography to obtain the title compound (21.1 mg, yield: 51%). 1 H NMR (500 MHz, DMSO) δ 11.20 (s, 1H), 9.64 (s, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.82-7.74 (m, 3H), 7.34 (d, J = 1.5 Hz, 1H), 7.25 (s, 1H), 7.08 (d, J = 2.5 Hz, 1H), 6.75 (dd, J = 16.0, 9.5 Hz, 1H), 6.02-5.95 (m, 2H), 3.80 (s, 3H).

[0082] Example 27: Preparation of (1-(2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)-1H-pyrrole-2,5-dione JPEG2026510431000033.jpg30140 In a sealed tube, 2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-amine (0.1 mmol, 0.036 g, 1.0 eq), diethyl ether (0.3 mL), and maleic anhydride (0.1 mmol, 0.0098 g, 1.0 eq) were added sequentially, and the mixture was reacted at room temperature for 1 hour. After the reaction was complete, the diethyl ether was removed. Sodium acetate (0.05 mmol, 0.0041 g, 0.5 eq) and anhydride acetate (0.3 mL) were added to the concentrated residue, and the mixture was reacted at 90°C for 2 hours. After the reaction was complete, the mixture was extracted with aqueous potassium carbonate and ethyl acetate, concentrated, and purified by column chromatography to obtain the title compound (8.9 mg, yield: 20%). 1 H NMR (500 MHz, DMSO) δ 8.17 (d, J = 2.0 Hz, 1H), 7.91 (s, 1H), 7.86-7.84 (m, 2H), 7.78 (d, J = 8.5 Hz, 1H), 7.41-7.38 (m, 2H), 7.21 (s, 1H), 7.18 (d, J = 2.0 Hz, 1H), 3.79 (s, 3H).

[0083] Example 28: Preparation of N-(2-(4-chlorophenyl)-7-(1-methyl-1H-pyrazole-3-yl)-1H-indole-5-yl)acrylamide JPEG2026510431000034.jpg75140

[0084] (Stage 1) 2-iodo-4-nitroaniline (37.8 mmol, 10 g, 1.0 eq) was dissolved in dimethylformamide (74 mL) and cooled to 0°C. N-bromosuccinimide (41.6 mmol, 7.4 g, 1.1 eq) was added, and the mixture was reacted at room temperature for 5 hours. After the reaction was complete, distilled water (50 mL) was added and the mixture was stirred for 10 minutes. The yellow solid was filtered to obtain 2-bromo-6-iodo-4-nitroaniline (10 g, yield: 77%).

[0085] (Stage 2) 2-Bromo-6-iodo-4-nitroaniline (1.44 mmol, 0.5 g, 1.0 eq), Pd(PPh3)4 (0.072 mmol, 0.083 g, 0.05 eq), copper iodide (0.14 mmol, 0.026 g, 0.1 eq), triethylamine (4.32 mmol, 0.6 mL, 3.0 eq), and tetrahydrofuran (10 mL) were added sequentially, and sonic degassing was carried out under nitrogen atmosphere for 10 minutes. 1-Chloro-4-ethynylbenzene (1.59 mmol, 0.21 g, 1.1 eq) was added, and the mixture was reacted overnight at 40°C. After the reaction was complete, the product was extracted with ethyl acetate and aqueous ammonium chloride, concentrated, and solidified with tertiary butyl methyl ether to obtain 2-bromo-6-((4-chlorophenyl)ethynyl)-4-nitroaniline (0.3 g, yield: 59%).

[0086] (Stage 3) 2-bromo-6-((4-chlorophenyl)ethynyl)-4-nitroaniline (0.77 mmol, 0.3 g, 1.0 eq) was dissolved in 1,4-dioxane (10 mL) in a sealed tube. 1-methyl-3-(tributylstannyl)-1H-pyrazole (1.0 mmol, 0.37 g, 1.3 eq) and Pd(PPh3)4 (0.077 mmol, 0.088 g, 0.1 eq) were added sequentially, and the mixture was reacted in a microwave reactor at 150°C for 1 hour. After the reaction was complete, the mixture was extracted with ethyl acetate and aqueous ammonium chloride, concentrated, and solidified with tertiary butyl methyl ether to obtain 2-((4-chlorophenyl)ethynyl)-6-(1-methyl-1H-pyrazole-3-yl)-4-nitroaniline (0.14 g, yield: 51%).

[0087] (Stage 4) 2-((4-chlorophenyl)ethynyl)-6-(1-methyl-1H-pyrazole-3-yl)-4-nitroaniline (0.39 mmol, 0.14 g, 1.0 eq), sodium hydroxide (1.81 mmol, 0.072 g, 4.6 eq), and dimethylformamide (10 mL) were sequentially added to a microwave vial and reacted at 150°C for 20 minutes. After the reaction was complete, the mixture was extracted with ethyl acetate and aqueous ammonium chloride, concentrated, and solidified with tertiary butyl methyl ether to obtain 2-(4-chlorophenyl)-7-(1-methyl-1H-pyrazole-3-yl)-5-nitro-1H-indole (0.1 g, yield: 72%).

[0088] (Stage 5) 2-(4-chlorophenyl)-7-(1-methyl-1H-pyrazole-3-yl)-5-nitro-1H-indole (0.28 mmol, 0.1 g, 1.0 eq), iron (2.8 mmol, 0.15 g, 1.0 eq), ammonium chloride (0.28 mmol, 0.014 g, 1.0 eq), and 70% ethanol (5 mL; ethanol:distilled water = 7:3 (v:v)) were added sequentially. The reaction mixture was allowed to react at 70°C for 3 hours. After the reaction was complete, iron and ethanol were removed, and the mixture was extracted with an aqueous solution of ammonium chloride, concentrated, and 2-(4-chlorophenyl)-7-(1-methyl-1H-pyrazole-3-yl)-1H-indole-5-amine was used in the next reaction without separation or purification.

[0089] (Stage 6) 2-(4-chlorophenyl)-7-(1-methyl-1H-pyrazole-3-yl)-1H-indole-5-amine (0.1 mmol, 0.032 g, 1.0 eq), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.2 mmol, 0.038 g, 2.0 eq), and dichloromethane (1 mL) were sequentially added to a flask. After adding triethylamine (0.1 mL) and acrylic acid (0.11 mmol, 0.0079 g, 1.1 eq), the mixture was allowed to react overnight at room temperature. After the reaction was complete, the dichloromethane was removed, and the compound was purified by column chromatography to obtain the title compound (9.0 mg, yield: 25%). 1H NMR (500 MHz, DMSO) δ 10.77 (s, 1H), 10.10 (s, 1H), 8.00 (s, 1H), 7.92-7.88 (m, 3H), 7.71 (s, 1H), 7.57-7.55 (m, 2H), 7.03 (d, J = 2.1 Hz, 1H), 6.76 (d, J = 2.1 Hz, 1H), 6.49 (dd, J = 16.9, 10.1 Hz, 1H), 6.27 (d, J = 17.0 Hz, 1H), 5.75 (d, J = 10.1 Hz, 1H), 4.07 (s, 3H).

[0090] Example 29: Preparation of N-(2-(3,4-dichlorophenyl)-7-(1-methyl-1H-pyrazole-3-yl)-1H-indole-5-yl)acrylamide The title compound (14.8 mg, yield: 36%) was obtained in the same manner as in Example 28, except that 1,2-dichloro-4-ethynylbenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 28. 1 H NMR (500 MHz, DMSO) δ 10.82 (s, 1H), 10.11 (s, 1H), 8.20 (s, 1H), 8.02 (s, 1H), 7.89-7.88 (m, 2H), 7.78-7.67 (m, 2H), 7.14 (s, 1H), 6.76 (s, 1H), 6.48 (dd, J = 17.0, 10.2 Hz, 1H), 6.31-6.24 (m, 1H), 5.79-5.72 (m, 1H), 4.06 (s, 3H).

[0091] Example 30: Preparation of N-(2-(3,4-dichlorophenyl)-7-(pyridine-2-yl)-1H-indole-5-yl)acrylamide The title compound (11.4 mg, yield: 28%) was obtained in the same manner as in Example 28, except that 1,2-dichloro-4-ethynylbenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 28, and 2-(tributylstannyl)pyridine was used instead of 1-methyl-3-(tributylstannyl)-1H-pyrazole in step 3 of Example 28. 1 H NMR (500 MHz, DMSO) δ 11.57 (s, 1H), 10.19 (s, 1H), 8.88 (d, J = 4.5 Hz, 1H), 8.25 (br s, 1H), 8.12 (s, 1H), 8.05-8.00 (m, 3H), 7.94 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.47-7.43 (m, 1H), 7.18 (s, 1H), 6.50 (dd, J = 16.9, 10.1 Hz, 1H), 6.29 (d, J = 16.9 Hz, 1H), 5.77 (d, J = 10.1 Hz, 1H).

[0092] Example 31: Preparation of N-(2-(4-fluorophenyl)-7-(pyridine-2-yl)-1H-indole-5-yl)acrylamide The title compound (9.6 mg, yield: 27%) was obtained in the same manner as in Example 28, except that 1-ethynyl-4-fluorobenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 28, and 2-(tributylstannyl)pyridine was used instead of 1-methyl-3-(tributylstannyl)-1H-pyrazole in step 3 of Example 28. 1H NMR (500 MHz, DMSO) δ 11.56 (s, 1H), 10.18 (s, 1H), 8.88 (d, J = 4.6 Hz, 1H), 8.09 (s, 1H), 8.06 - 7.94 (m, 5H), 7.47 - 7.42 (m, 1H), 7.36 - 7.33 (m, 2H), 7.01 (d, J = 2.3 Hz, 1H), 6.50 (dd, J = 16.9, 10.1 Hz, 1H), 6.29 (d, J = 16.9 Hz, 1H), 5.77 (d, J = 11.9 Hz, 1H).

[0093] Example 32: Preparation of N-(2-(4-fluorophenyl)-7-(1-methyl-1H-pyrazol-3-yl)-1H-indole-5-yl)acrylamide The title compound (7.9 mg, yield: 22%) was obtained in the same manner as in Example 28, except that 1-ethynyl-4-fluorobenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 28. 1 H NMR (500 MHz, DMSO) δ 10.73 (s, 1H), 10.10 (s, 1H), 7.98 (s, 1H), 7.94-7.91 (m, 2H), 7.89 (d, J = 2.2 Hz, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.37-7.33 (m, 2H), 6.97 (d, J = 2.2 Hz, 1H), 6.76 (d, J = 2.2 Hz, 1H), 6.49 (dd, J = 16.9, 10.1 Hz, 1H), 6.27 (dd, J = 17.0, 1.8 Hz, 1H), 5.79-5.71 (m, 1H), 4.06 (s, 3H).

[0094] Example 33: Preparation of N-(2-(2,4-difluorophenyl)-7-(1-methyl-1H-pyrazole-3-yl)-1H-indole-5-yl)acrylamide The title compound (8.6 mg, yield: 23%) was obtained in the same manner as in Example 28, except that 1-ethynyl-2,4-difluorobenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 28. 1 H NMR (500 MHz, DMSO) δ 11.04 (s, 1H), 10.13 (s, 1H), 8.09-8.04 (m, 1H), 8.02 (s, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.52-7.47 (m, 1H), 7.27 (td, J = 8.5, 2.5 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 6.76 (d, J = 2.5 Hz, 1H), 6.49 (dd, J = 17.0, 10.0 Hz, 1H), 6.28 (dd, J = 17.0, 2.0 Hz, 1H), 5.75 (dd, J = 10.0, 2.0 Hz, 1H), 4.03 (s, 3H).

[0095] Example 34: Preparation of N-(2-(5-chloropyridine-2-yl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide JPEG2026510431000040.jpg58140

[0096] (Stage 1) In a sealed tube, 2-iodo-6-(1-methyl-1H-imidazole-4-yl)-4-nitroaniline (1.5 mmol, 0.52 g, 1.0 eq) was dissolved in THF (2.5 mL) and TEA (2.5 mL). Then, Pd(PPh3)4 (0.15 mmol, 173.3 mg, 0.1 eq) and CuI (0.15 mmol, 28.6 mg, 0.1 eq) were added, followed by 5-chloro-2-ethynylpyridine (3.0 mmol, 0.41 g, 2.0 eq). The mixture was reacted overnight at 55°C. After the reaction was complete, the temperature was cooled to room temperature. 5 mL of tertiary butyl methyl ether was added, and the solid was filtered to obtain 2-((5-chloropyridine-2-yl)ethynyl)-6-(1-methyl-1H-imidazole-4-yl)-4-nitroaniline (0.49 g, yield: 92%).

[0097] (Stage 2) In a sealed tube, 2-((5-chloropyridine-2-yl)ethynyl)-6-(1-methyl-1H-imidazole-4-yl)-4-nitroaniline (1.4 mmol, 0.48 g, 1.0 eq) was dissolved in DMF (7.0 mL), then CuI (0.14 mmol, 26.7 mg, 0.1 eq) was added, and the mixture was reacted at 150°C for 1 hour. After the reaction was complete, the temperature was cooled to room temperature. Extraction with saturated sodium chloride aqueous solution and ethyl acetate, followed by concentration, separation and purification by column chromatography, yielded 2-(5-chloropyridine-2-yl)-7-(1-methyl-1H-imidazole-4-yl)-5-nitro-1H-indole (0.22 g, yield: 44%). Steps 3 and 4 were performed in the same manner as in Example 1 to obtain the title compound (12.8 mg, yield: 31%). 1H NMR (500 MHz, DMSO) δ 9.93 (s, 1H), 8.66 (s, 1H), 8.02 (dd, J = 8.0, 2.5 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.79 (s, 1H), 7.76 (d, J = 2.5 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.40 (s 1H), 6.67 (s, 2H), 6.40 (dd, J = 16.0, 10.0 Hz, 1H), 6.23 (dd, J = 16.0, 1.5 Hz, 1H), 5.72 (dd, J = 10.0, 1.5 Hz, 1H), 3.75 (s, 3H).

[0098] Example 35: Preparation of 2-(4-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylic acid JPEG2026510431000041.jpg50140

[0099] (Stage 1) In a sealed tube, ethyl-4-amino-3,5-diiodobenzoate (2.0 mmol, 0.83 g, 1.0 eq) was dissolved in 1,4-dioxane (10 mL). Then, 1-methyl-4-(tributylstannyl)-1H-imidazole (2.1 mmol, 0.78 g, 1.05 eq) and Pd(PPh3)4 (0.4 mmol, 0.46 g, 0.2 eq) were added sequentially, and the mixture was reacted in a microwave reactor at 140°C for 1.5 hours. After the reaction was complete, the solvent was removed, and the resulting concentrated residue was separated and purified by column chromatography to obtain ethyl-4-amino-3-iodo-5-(1-methyl-1H-imidazole-4-yl)benzoate (0.32 g, yield: 44%).

[0100] (Stage 2) In a sealed tube, ethyl 4-amino-3-iodo-5-(1-methyl-1H-imidazole-4-yl)benzoate (0.5 mmol, 186 mg, 1.0 eq) was dissolved in tetrahydrofuran (0.8 mL). Then, 1-ethynyl-4-fluorobenzene (0.8 mmol, 96 mg, 1.6 eq), Pd(PPh3)4 (0.05 mmol, 58 mg, 0.1 eq), CuI (0.03 mmol, 4.8 mg, 0.05 eq), and triethylamine (0.8 mL) were added, and the mixture was reacted overnight at 55°C. After the reaction was complete, the temperature was cooled to room temperature. Water (10 mL) and ethyl acetate (5 mL) were added, and the target compound was extracted in the organic layer, dried, and concentrated to obtain ethyl 4-amino-3-((4-fluorophenyl)ethynyl)-5-(1-methyl-1H-imidazole-4-yl)benzoate (0.15 g, yield: 81%).

[0101] (Stage 3) In a sealed tube, ethyl 4-amino-3-((4-fluorophenyl)ethynyl)-5-(1-methyl-1H-imidazole-4-yl)benzoate (0.4 mmol, 0.15 g, 1.0 eq) was dissolved in dimethylacetamide (2 mL), and then sodium hydroxide (2.0 mmol, 80 mg, 5.0 eq) was added. The mixture was reacted in a microwave reactor at 140°C for 15 minutes. Extraction was performed using saturated sodium chloride aqueous solution (50 mL) and ethyl acetate (15 mL). The resulting organic layer was dried, and the solvent was removed. Separation and purification by column chromatography yielded ethyl 2-(4-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylate (70 mg, yield: 48%).

[0102] (Stage 4) Ethyl 2-(4-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylate (0.1 mmol, 0.036 g, 1.0 eq), 70% ethanol (0.5 mL; ethanol:distilled water = 7:3 (v:v)), and potassium hydroxide (0.2 mmol, 11.2 mg, 2.0 eq) were added sequentially to a sealed tube, and the mixture was refluxed for 2 hours. After the reaction was complete, the temperature was cooled to room temperature. Acetic acid (0.2 mL) and purified water (1 mL) were added to the reaction mixture, and the resulting solid was filtered to obtain the title compound (21.5 mg, yield: 19%). 1 H NMR (500 MHz, DMSO) δ 11.30 (s, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.84 (m, 2H), 7.79 (s, 1H), 7.35 (m, 2H), 6.94 (s, 1H), 3.79 (s, 3H).

[0103] Example 36: Preparation of 7-(1-methyl-1H-imidazole-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-indole-5-carboxylic acid The title compound (21.5 mg, yield: 56%) was obtained in the same manner as in Example 35, except that 1-ethynyl-4-(trifluoromethyl)benzene was used instead of 1-ethynyl-4-fluorobenzene in step 2 of Example 35. 1 H NMR (500 MHz, DMSO) δ 11.71 (s, 1H), 8.16 (s, 1H), 8.12-8.03 (m, 3H), 7.99 (s, 1H), 7.93 (s, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 1.7 Hz, 1H), 3.80 (s, 3H).

[0104] Example 37: Preparation of 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylic acid JPEG2026510431000043.jpg 3452 The title compound (8.6 mg, yield: 24%) was obtained in the same manner as in Example 35, except that 1-chloro-4-ethynylbenzene was used instead of 1-ethynyl-4-fluorobenzene in Step 2 of Example 35. 1 H NMR (500 MHz, DMSO) δ 12.50 (br, s, 1H), 11.60 (s, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 1.5 Hz, 1H), 3.80 (s, 3H).

[0105] Example 38: Preparation of 2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-carboxylic acid JPEG2026510431000044.jpg 3452 The title compound (6.7 mg, yield: 17%) was obtained in the same manner as in Example 35, except that 1,2-dichloro-4-ethynylbenzene was used instead of 1-ethynyl-4-fluorobenzene in Step 2 of Example 35. 1 H NMR (500 MHz, DMSO) δ 12.56 (br, s, 1H), 11.58 (s, 1H), 8.17 (d, J = 1.5 Hz, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.92 (s, 1H), 7.84 (dd, J = 8.5, 1.5 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 3.80 (s, 3H).

[0106] Example 39: Preparation of 2-(4-chloro-3-fluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-carboxylic acid The title compound (22.5 mg, yield: 60%) was obtained in the same manner as in Example 35, except that 1-chloro-4-ethynyl-2-fluorobenzene was used instead of 1-ethynyl-4-fluorobenzene in step 2 of Example 35. 1 H NMR (500 MHz, DMSO) δ 12.59 (br, s, 1H), 11.59 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.99-7.97 (m, 2H), 7.92 (s, 1H), 7.76-7.71 (m, 2H), 7.25 (s, 1H), 3.80 (s, 3H).

[0107] Example 40: Preparation of 2-(4-chlorophenyl)-N-methyl-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylamide JPEG2026510431000046.jpg89140

[0108] (Stage 1) In a sealed tube, ethyl-4-amino-3,5-diiodobenzoate (2.0 mmol, 0.83 g, 1.0 eq) was dissolved in 1,4-dioxane (10 mL). Then, 1-methyl-4-(tributylstannyl)-1H-imidazole (2.1 mmol, 0.78 g, 1.05 eq) and Pd(PPh3)4 (0.4 mmol, 0.46 g, 0.2 eq) were added sequentially, and the mixture was reacted in a microwave reactor at 140°C for 1.5 hours. After the reaction was complete, the solvent was removed, and the resulting concentrated residue was separated and purified by column chromatography to obtain ethyl-4-amino-3-iodo-5-(1-methyl-1H-imidazole-4-yl)benzoate (0.32 g, yield: 44%).

[0109] (Stage 2) In a sealed tube, ethyl 4-amino-3-iodo-5-(1-methyl-1H-imidazole-4-yl)benzoate (0.5 mmol, 186 mg, 1.0 eq) was dissolved in tetrahydrofuran (0.8 mL). Then, 1-ethynyl-4-chlorobenzene (0.8 mmol, 96 mg, 1.6 eq), Pd(PPh3)4 (0.05 mmol, 58 mg, 0.1 eq), CuI (0.03 mmol, 4.8 mg, 0.05 eq), and triethylamine (0.8 mL) were added, and the mixture was reacted overnight at 55°C. After the reaction was complete, the temperature was cooled to room temperature. Water (10 mL) and ethyl acetate (5 mL) were added, and the target compound was extracted in the organic layer, dried, and concentrated to obtain ethyl 4-amino-3-((4-chlorophenyl)ethynyl)-5-(1-methyl-1H-imidazole-4-yl)benzoate (0.16 g, yield: 84%).

[0110] (Stage 3) In a sealed tube, ethyl 4-amino-3-((4-chlorophenyl)ethynyl)-5-(1-methyl-1H-imidazole-4-yl)benzoate (0.4 mmol, 0.15 g, 1.0 eq) was dissolved in dimethylacetamide (2 mL), and then sodium hydroxide (2.0 mmol, 80 mg, 5.0 eq) was added. The mixture was reacted in a microwave reactor at 140°C for 15 minutes. After extraction with saturated sodium chloride aqueous solution (50 mL) and ethyl acetate (15 mL), the resulting organic layer was dried and the solvent was removed. Separation and purification by column chromatography yielded ethyl 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylate (81 mg, yield: 53%).

[0111] (Stage 4) In a sealed tube, ethyl 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylate (0.2 mmol, 0.080 g, 1.0 eq), 70% ethanol (0.5 mL; ethanol:distilled water = 7:3 (v:v)), and potassium hydroxide (0.2 mmol, 22.4 mg, 2.0 eq) were added sequentially, and the mixture was refluxed for 2 hours. After the reaction was complete, the temperature was cooled to room temperature. Acetic acid (0.2 mL) and purified water (1 mL) were added to the reaction mixture, and the resulting solid was filtered to obtain 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylic acid (36 mg, yield: 51%).

[0112] (Stage 5) 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylic acid (0.1 mmol, 0.035 g, 1.0 eq), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.2 mmol, 0.038 g, 2.0 eq), and dichloromethane (1 mL) were sequentially added to a flask. After adding triethylamine (0.1 mL) and acrylic acid (0.11 mmol, 0.0079 g, 1.1 eq), the mixture was reacted overnight at room temperature. After the reaction was complete, the dichloromethane was removed, and the compound was purified by column chromatography to obtain the title compound (10.3 mg, yield: 28%). 1 H NMR (500 MHz, DMSO) δ 11.47 (s, 1H), 8.38-8.35 (m, 1H), 8.00-7.99 (m, 1H), 7.92 (s, 1H), 7.89-7.87 (m, 3H), 7.60-7.58 (m, 2H), 7.11 (s, 1H), 3.81 (s, 3H), 2.83 (s, 3H).

[0113] Example 41: Preparation of N-(7-(1-methyl-1H-imidazole-4-yl)-2-(3,4,5-trichlorophenyl)-1H-indole-5-yl)acrylamide JPEG2026510431000047.jpg3356 The title compound (16.8 mg, yield: 19%) was obtained in the same manner as in Example 1, except that 1,2,3-trichloro-5-ethynylbenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1 H NMR (500 MHz, DMSO) δ 11.10 (s, 1H), 10.10 (s, 1H), 8.16 (s, 2H), 7.94 (s, 1H), 7.89 (s, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 7.20 (d, J = 1.5 Hz, 1H), 6.49 (dd, J = 17.0, 10.0 Hz, 1H), 6.26 (d, J = 17.0 Hz, 1H), 5.74 (d, J = 10.0 Hz, 1H), 3.8 (s, 3H).

[0114] Example 42: Preparation of N-(2-(3-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide JPEG2026510431000048.jpg3251 The title compound (13.5 mg, yield: 36%) was obtained in the same manner as in Example 1, except that 1-ethynyl-3-fluorobenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1 H NMR (500 MHz, DMSO) δ 11.16 (s, 1H), 10.08 (s, 1H), 7.89 (s, 2H), 7.77 (s, 1H), 7.70-7.65 (m, 3H), 7.55 (dd, J = 8.0 Hz 1H), 7.21-7.17 (m, 1H), 7.04 (d, J =2.5 Hz, 1H), 6.49 (dd, J = 17.0, 10.0 Hz, 1H), 6.27 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (dd, J = 10.0, 2.0 Hz, 1H), 3.80 (s, 3H).

[0115] Example 43: Preparation of 2-(3,4-difluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylic acid JPEG2026510431000049.jpg3451 The title compound (23.4 mg, yield: 74%) was obtained in the same manner as in Example 35, except that 4-ethynyl-1,2-difluorobenzene was used instead of 1-ethynyl-4-fluorobenzene in step 2 of Example 35. 1 H NMR (500 MHz, DMSO) δ 11.52 (s, 1H), 8.11 (s, 1H), 8.08 (s, 1H), 8.01-7.96 (m, 2H), 7.91 (s, 1H), 7.70-7.69 (m, 1H), 7.61 (dd, J = 9.0 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 3.80 (s, 3H).

[0116] Example 44: Preparation of N-(2-(3-chloro-4-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide The title compound (10.8 mg, yield: 27%) was obtained in the same manner as in Example 1, except that 2-chloro-4-ethynyl-1-fluorobenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1 H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 10.06 (s, 1H), 8.08 (d, J = 5.0 Hz, 1H), 7.88 (d, J = 7.0 Hz, 2H), 7.83 (s, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.56-7.52 (m, 1H),7.01 (s, 1H), 7.01 (s, 1H), 6.49 (dd, J = 17.0, 10.0 Hz, 1H), 6.26 (d, J = 10.0 Hz, 1H), 3.80 (s, 3H).

[0117] Example 45: Preparation of N-(2-(2,4-dichlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide JPEG2026510431000051.jpg3256 The title compound (12.0 mg, yield: 27%) was obtained in the same manner as in Example 1, except that 2,4-dichloro-1-ethynylbenzene was used instead of 1-chloro-4-ethynylbenzene in Step 2 of Example 1. 1 H NMR (500 MHz, DMSO) δ 1.50 (s, 1H), 10.09 (s, 1H), 7.91 (s, 1H), 7.89 - 7.84 (m, 2H), 7.80 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 1.5 Hz, 1H), 7.59 - 7.57 (m, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.50 (dd, J = 17.0, 10.0 Hz, 1H), 6.27 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (dd, J = 10.0, 2.0 Hz, 1H), 3.78 (s, 3H).

[0118] Example 46: Preparation of N-(2-(4-chloro-3,5-difluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide JPEG2026510431000052.jpg3356 The title compound (36.2 mg, yield: 18%) was obtained in the same manner as in Example 1, except that 2-chloro-5-ethynyl-1,3-difluorobenzene was used instead of 1-chloro-4-ethynylbenzene in Step 2 of Example 1. 1H NMR (500 MHz, DMSO) δ 11.10 (s, 1H), 10.11 (s, 1H), 7.94 (s, 1H), 7.89-7.88 (m, 3H), 7.79 (s, 1H), 7.72 (s, 1H), 7.18 (s, 1H), 6.49 (dd, J = 17.0, 10.0 Hz, 1H), 6.26 (d, J = 17.0 Hz, 1H), 5.74 (dd, J = 10.0 Hz, 1H), 3.81 (s, 3H).

[0119] Example 47: Preparation of N-(2-(4-chloro-2,6-difluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide JPEG2026510431000053.jpg3357 The title compound (34.7 mg, yield: 10%) was obtained in the same manner as in Example 1, except that 5-chloro-2-ethynyl-1,3-difluorobenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1 H NMR (500 MHz, DMSO) δ 11.65 (s, 1H), 10.11 (s, 1H), 7.90 (s, 2H), 7.74 (dd, J = 7.0, 1.5 Hz, 1H), 7.60 (d, J = 9.5 Hz, 1H), 7.00 (s, 1H), 6.50 (d, J = 17.0, 10.0 Hz, 1H), 6.27 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (dd, J = 10.0, 2.0 Hz, 1H), 3.79 (s, 3H).

[0120] Example 48: N-(7-(1-methyl-1H-imidazole-4-yl)-2-(4-(trifluoromethoxy)phenyl)-1H-indole-5-yl)acrylamide JPEG2026510431000054.jpg3262 The title compound (38.0 mg, yield: 89%) was obtained in the same manner as in Example 1, except that 1-ethynyl-4-(trifluoromethoxy)benzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1 H NMR (500 MHz, DMSO) δ 11.17 (s, 1H), 10.06 (s, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.88 (s, 2H), 7.76 (s, 1H), 7.70 9s, 1H), 7.49 (d, J = 8.5 Hz, 1H), 6.98 (s, 1H), 6.49 (dd, J = 17.0, 10.0 Hz, 1H), 6.26 (d, J = 17.0 Hz, 1H), 5.73 (d, J = 10.0 Hz, 1H), 3.80 (s, 3H).

[0121] Example 49: Preparation of N-(2-(4-chlorophenyl)-7-(4-methylthiazole-2-yl)-1H-indole-5-yl)acrylamide The title compound (15.1 mg, yield: 38%) was obtained in the same manner as in Example 28, except that 4-methyl-2-(tributylstannyl)thiazole was used instead of 1-methyl-3-(tributylstannyl)-1H-pyrazole in step 3 of Example 28. 1 H NMR (500 MHz, DMSO) δ 11.08 (s, 1H), 10.23 (s, 1H), 8.12 (d, J = 1.7 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.40 (s, 1H), 7.10 (d, J = 2.3 Hz, 1H), 6.47 (dd, J = 17.0, 10.1 Hz, 1H), 6.36 - 6.23 (m, 1H), 5.81 - 5.71 (m, 1H), 2.60 (s, 3H).

[0122] Example 50: Preparation of N-(7-(1-ethyl-1H-imidazole-4-yl)-2-(3,4,5-trifluorophenyl)-1H-indole-5-yl)acrylamide The title compound (15.0 mg, yield: 36%) was obtained in the same manner as in Example 28, except that 5-ethynyl-1,2,3-trifluorobenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 28, and 1-ethyl-4-(tributylstannyl)-1H-imidazole was used instead of 1-methyl-3-(tributylstannyl)-1H-pyrazole in step 3 of Example 28. 1 H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 1.9 Hz, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 7.42 - 7.33 (m, 4H), 6.74 (d, J = 2.6 Hz, 1H), 6.49 (d, J = 16.8 Hz, 1H), 6.32 (dd, J = 16.8, 10.2 Hz, 1H), 5.80 (d, J = 10.1 Hz, 1H), 4.10 (q, J = 7.3 Hz, 2H), 1.56 (t, J = 7.3 Hz, 3H).

[0123] Example 51: Preparation of N-(7-(1-ethyl-1H-imidazole-4-yl)-2-(4-fluorophenyl)-1H-indole-5-yl)acrylamide The title compound (25.2 mg, yield: 66%) was obtained in the same manner as in Example 28, except that 1-ethynyl-4-fluorobenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 28, and 1-ethyl-4-(tributylstannyl)-1H-imidazole was used instead of 1-methyl-3-(tributylstannyl)-1H-pyrazole in step 3 of Example 28. 1H NMR (500 MHz, DMSO) δ 11.14 (s, 1H), 10.05 (s, 1H), 7.96 (s, 1H), 7.94 - 7.81 (m, 4H), 7.71 (d, J = 1.8 Hz, 1H), 7.35 (t, J = 8.7 Hz, 2H), 6.91 (d, J = 2.3 Hz, 1H), 6.49 (dd, J = 17.0, 10.1 Hz, 1H), 6.26 (dd, J = 17.0, 2.1 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H), 4.13 (q, J = 7.3 Hz, 2H), 1.46 (t, J = 7.3 Hz (3H).

[0124] Example 52: Preparation of N-(2-(4-bromophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide JPEG2026510431000058.jpg3257 The title compound (38.0 mg, yield: 89%) was obtained in the same manner as in Example 1, except that 1-bromo-4-ethynylbenzene was used instead of 1-chloro-4-ethynylbenzene in step 2 of Example 1. 1 H NMR (500 MHz, DMSO) δ 11.16 (s, 1H), 10.07 (s, 1H), 7.92 - 7.86 (m, 2H), 7.83 - 7.75 (m, 3H), 7.73 - 7.67 (m, 3H), 6.99 (d, J = 2.4 Hz, 1H), 6.49 (dd, J = 16.9, 10.1 Hz, 1H), 6.35 - 6.12 (m, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H), 3.80 (s, 3H).

[0125] 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).

[0126] 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.

[0127] 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 0.0005, 0.005, 0.05, 0.5, and 5 μM, repeating this process 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-Glo TMFollowing the instructions for the luciferase assay, the enzymatic activity of luciferase 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.

[0128] 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) and NCI-H28 (Korea Cell Line Bank) 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.

[0129] Specifically, NCI-H226 and NCI-H28 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 compound from the example was treated to final concentrations of 0.0005, 0.005, 0.05, 0.5, and 5 μM, and this process was repeated three times for all treatment solutions. The plate treated with the compound from the example was incubated at 37°C in a 5% CO2 incubator, 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 in the dark at room temperature for 10 minutes, and luminescence was measured using a Flexstation3 multi-mode microplate reader. Following the CellTiter-Glo® Luminescedent Cell Viability documentation, the enzyme activity of luciferase 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 Table 1 below.

[0130] [Table 1]

[0131] Experimental Example 3: CTGF and CYR61 Analysis Test Place 5 × 10⁶ NCI-H226 (AddexBio) human mesothelioma cells per well in a 6-well cell culture plate. 5The cells were cultured in the specified number. After a 24-hour stabilization process, the cells treated with Example 1 at a concentration of 500 nM were used as the control group, and cells treated with the same amount of DMSO were used as the control group. 24 hours after treatment, the cells were collected to obtain RNA for target gene expression analysis.

[0132] RNA was extracted from cells using TRIzol solution (Ambion). After cell lysis and digestion were complete, chloroform was added to each sample, and the homogeneous solution was separated into aqueous and organic phases by centrifugation.

[0133] The expression of YAP-TEAD-regulated genes ctgf (connective tissue growth factor) and cyr61 (Cysteine-rich angiogenic inducer 61), and the housekeeping gene gapdh (Glyceraldehyde 3-phosphate dehydrogenase), was quantified by qRT-PCR analysis using Maxima SYBR Green / Fluorescein qPCR Master Mix and primers for each gene. The period threshold (Ct) values ​​of ctgf, cyr61, and gapdh for cell cDNA samples were measured, and the expression of ctgf and cyr61 was normalized relative to gapdh.

[0134] The expression of each gene in the experimental group treated with Example 1 was normalized relative to the control group treated with DMSO. Figure 1 shows the expression regulatory properties of two TEAD target genes in Example 1 using real-time PCR.

Claims

1. The compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof: [Chemical formula 1] In the aforementioned chemical formula 1, R １ C ６－１０ A 5-membered or 6-membered heteroring containing aryls; or one to four heteroatoms independently selected from the group consisting of N, O, and S, The foregoing R １ 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; or fused with a C ３－６ cycloalkyl ring, R ２ C ６－１０ Ariel; C ３－６ A cycloalkenyl; or a five-membered or six-membered heteroring containing one to four heteroatoms independently selected from the group consisting of N, O, and S, The aforementioned R ２ 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 Alkenil, C ２－４ Alkinyl, C ３－６ Cycloalkyl, amino, nitro, cyano, (C １－４ Alkyl)amino and di(C) １－４ Substituting with one to three substituents independently selected from the group consisting of alkyl)amino compounds, R ３ is hydrogen or halogen, R ４ is -NHCO-R', -NHSO ２ -R', -COO-R', -CONH-R', or 1H-pyrrole-2,5-dione-1-yl, The aforementioned R' is hydrogen, C １－４ Alkyl, C ２－４ It is an alkynyl substituent, or a substituent represented by the following chemical formula 2: [Chemical formula 2] In the aforementioned chemical formula 2, R' １ These are hydrogen, halogen, or cyano, R' ２ These are, independently, hydrogen and C ６－１０ Ariel, -CH ２ -NH ２ ien-CH ２ -NH(C) １－４ Alkyl), or -CH ２ -N(C) １－４ Alkyl) ２ That is the case.

2. R １ These are phenyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, pyrrolidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl. The aforementioned 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, or C ３－６ It fuses with a cycloalkyl ring. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. R １ These are imidazolyl, imidazolyl fused with cyclopentane, pyrazolyl, or pyridinyl. The aforementioned R １ is either unsubstituted or substituted with methyl, ethyl, fluoromethyl, difluoromethyl, or trifluoromethyl. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. R ２ These are phenyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, pyrrolidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl. The aforementioned R ２ 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) The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. R ２ These are phenyl, pyridinyl, or cyclohexenyl, The aforementioned R ２ It is either unsubstituted or substituted with one to three substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, trifluoromethyl, and trifluoromethoxy. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. R ３ is hydrogen, or chloroform. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. R ４ is -NHCO-R', -NHSO ２ -R', -COO-R', -CONH-R', or 1H-pyrrole-2,5-dione-1-yl, The aforementioned R' is hydrogen; C １－４ Alkyl; unsubstituted or substituted with one or two substituents independently selected from the group consisting of phenyl, fluoro, and cyano. ２－４ Alkenyl; or C ２－４ Alkinyl is The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. R ４ is -NHCO-CH=CH ２ , -NHCO-CF=CH ２ -NHCO-C(CN)=CH(phenyl), -NHCO-C≡C-CH ３ , - NHSO ２ -CH ３ , - NHSO ２ -CH=CH ２ , -COOH, -CONH-CH ３ , or 1H-pyrrole-2,5-dione-1-yl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. The aforementioned chemical formula 1 is represented by the following chemical formula 3: The compound according to claim 1, or a pharmaceutically acceptable salt thereof: [Chemical formula 3] In the aforementioned chemical formula 3, R' represents hydrogen, halogen, and C, each independently. １－４ Alkyl, or C １－４ It is a haloalkyl, n is an integer between 1 and 3. R ４ is -NHCO-CH=CH ２ , or -COOH.

10. The compound represented by the aforementioned chemical formula 1 is 1) N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 2) N-(7-(1-methyl-1H-imidazole-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-indole-5-yl)acrylamide, 3) N-(2-(4-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 4) N-(7-(1-methyl-1H-imidazole-4-yl)-2-phenyl-1H-indole-5-yl)acrylamide, 5) N-(2-(2,4-difluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 6) N-(7-(1-methyl-1H-imidazole-4-yl)-2-(3,4,5-trifluorophenyl)-1H-indole-5-yl)acrylamide, 7) N-(7-(1-(difluoromethyl)-1H-imidazole-4-yl)-2-(4-fluorophenyl)-1H-indole-5-yl)acrylamide, 8) N-(2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 9) N-(2-(3,4-difluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 10) N-(2-(3-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 11) N-(2-(4-chlorophenyl)-7-(1-(difluoromethyl)-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 12) N-(2-(4-chloro-2-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 13) N-(2-cyclohexenyl-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 14) N-(2-(4-fluoro-3-methylphenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 15) N-(7-(1-methyl-1H-imidazole-4-yl)-2-p-tolyl-1H-indole-5-yl)acrylamide, 16) N-(7-(1-methyl-1H-imidazole-4-yl)-2-(3-(trifluoromethyl)phenyl)-1H-indole-5-yl)acrylamide, 19) N-(7-(1-methyl-1H-imidazole-4-yl)-2-(3-(trifluoromethyl)phenyl)-1H-indole-5-yl)methanesulfonamide, 20) N-(2-(4-chloro-3-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 21) N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)methanesulfonamide, 22) N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)-2-fluoroacrylamide, 23) N-(3-chloro-2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 24) (E)-N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)-2-cyano-3-phenylacrylamide, 25) N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)buto-2-inamide, 26) N-(2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)ethanesulfonamide, 27) 1-(2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)-1H-pyrrole-2,5-dione, 28) N-(2-(4-chlorophenyl)-7-(1-methyl-1H-pyrazole-3-yl)-1H-indole-5-yl)acrylamide, 29) N-(2-(3,4-dichlorophenyl)-7-(1-methyl-1H-pyrazole-3-yl)-1H-indole-5-yl)acrylamide, 30) N-(2-(3,4-dichlorophenyl)-7-(pyridine-2-yl)-1H-indole-5-yl)acrylamide, 31) N-(2-(4-fluorophenyl)-7-(pyridine-2-yl)-1H-indole-5-yl)acrylamide, 32) N-(2-(4-fluorophenyl)-7-(1-methyl-1H-pyrazol-3-yl)-1H-indole-5-yl)acrylamide, 33) N-(2-(2,4-difluorophenyl)-7-(1-methyl-1H-pyrazole-3-yl)-1H-indole-5-yl)acrylamide, 34) N-(2-(5-chloropyridine-2-yl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 35) 2-(4-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylic acid, 36) 7-(1-methyl-1H-imidazole-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-indole-5-carboxylic acid, 37) 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylic acid, 38) 2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylic acid, 39) 2-(4-chloro-3-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylic acid, 40) 2-(4-chlorophenyl)-N-methyl-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylamide, 41) N-(7-(1-methyl-1H-imidazole-4-yl)-2-(3,4,5-trichlorophenyl)-1H-indole-5-yl)acrylamide, 42) N-(2-(3-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 43) 2-(3,4-difluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-carboxylic acid, 44) N-(2-(3-chloro-4-fluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 45) N-(2-(2,4-dichlorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 46) N-(2-(4-chloro-3,5-difluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 47) N-(2-(4-chloro-2,6-difluorophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide, 48) N-(7-(1-methyl-1H-imidazole-4-yl)-2-(4-(trifluoromethoxy)phenyl)-1H-indole-5-yl)acrylamide, 49) N-(2-(4-chlorophenyl)-7-(4-methylthiazole-2-yl)-1H-indole-5-yl)acrylamide, 50) N-(7-(1-ethyl-1H-imidazole-4-yl)-2-(3,4,5-trifluorophenyl)-1H-indole-5-yl)acrylamide, 51) N-(7-(1-ethyl-1H-imidazole-4-yl)-2-(4-fluorophenyl)-1H-indole-5-yl)acrylamide, and 52) N-(2-(4-bromophenyl)-7-(1-methyl-1H-imidazole-4-yl)-1H-indole-5-yl)acrylamide It is one of the groups selected from the group consisting of The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition for the prevention or treatment of cancer or tumor, comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, as an active ingredient.

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