Novel compound, and pharmaceutical composition for prevention or treatment of cancer or tumors comprising same

Abstract

The present invention relates to a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof. The compound according to the present invention can be effectively used for preventing or treating cancer or tumors.

Description

Novel compound and pharmaceutical composition containing the same for preventing or treating cancer or tumor

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

[0002] The Hippo signaling pathway influences organ development and cell proliferation by affecting the size and number of cells that compose an organ. Furthermore, inappropriate regulation of Hippo signaling has been linked to the development of various cancers (breast, head and neck, colon, ovarian, liver, brain, prostate, mesothelioma, sarcoma, etc.).

[0003]

[0004] The Hippo signaling pathway is composed of components such as neurofibromatosis type 2 (NF2), mammalian Ste20-like kinases 1 and 2 (Mst1 / 2), large tumor suppressor 1 / 2 (Lats1 / 2), yes-associated protein / WW domain-containing transcription regulator protein (YAP / TAZ), and transcriptional enhancing associate domains (TEADs). Mutations in upstream signaling proteins such as tumor suppressor genes NF2, MST1 / 2, and LATS1 / 2 induce persistent binding of YAP / TAZ and TEAD. This promotes transcription by YAP / TAZ and TEAD, inducing the expression of genes associated with cancer cell proliferation and tumorigenesis.

[0005]

[0006] Activation of the tumor suppressor NF2 mediates phosphorylation of Lats1 / 2 by Mst1 / 2, which promotes phosphorylation of cytoplasmic YAP and TAZ. Phosphorylated YAP and TAZ undergo ubiquitination and are subsequently degraded by the proteasome. Therefore, when the Hippo signaling pathway is activated (turned on), YAP and TAZ are inactivated. In contrast, when tumor suppressor genes are inactivated, i.e., when Hippo signaling is turned off, YAP and TAZ are activated and translocated to the nucleus, where they bind to four proteins of the TEAD family (TEAD1 / 2 / 3 / 4) to induce the expression of target genes such as connective tissue growth factor (CTGF), cysteine-rich angiogenic inducer 61 (CYR61), Gli2 (GLI family zinc finger 2), Birc2 / 5 (Baculoviral IAP repeat containing 2 / 5), and FGF (fibroblast growth factor). Thus, genes activated by the YAP / TAZ-transcription factor complex regulate cell proliferation, cell migration, and apoptosis.

[0007]

[0008] Abnormalities in the Hippo signaling pathway have been discovered in various cancers, and numerous studies have reported the development of anticancer agents targeting YAP-TEAD. Furthermore, the involvement of the Hippo signaling pathway in the acquisition of resistance to existing approved anticancer drugs has been discovered, and numerous studies are underway to demonstrate the potential of YAP-TEAD anticancer agents 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 essential.

[0009]

[0010] Accordingly, the present inventors studied a drug that can be usefully used in the treatment of cancer in which the Hippo signaling pathway is inactivated, and as a result, confirmed that the compound according to the present invention, which will be described later, binds to the palmitate binding site that mediates TEAD palmitoylation, and also inhibits the in vitro proliferation of a cell line with a mutation in the Hippo pathway. Through this, the present inventors confirmed that the YAP-TEAD inhibitor according to the present invention can be usefully used in the treatment of cancer or tumors in which the Hippo signaling pathway is inactivated, thereby completing the present invention.

[0011] The present invention provides a compound having a novel structure that can be usefully used in the treatment or prevention of cancer or tumors.

[0012] In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer or tumors comprising the compound.

[0013] To solve the above problem, the present invention provides a compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof:

[0014] [Chemical Formula 1]

[0015]

[0016] In the above chemical formula 1,

[0017] R1 is C 6-10 Aryl; or a 5- or 6-ring heterocycle containing 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S,

[0018] The above R1 is unsubstituted; or halogen, C 1-4 Alkyl, C 1-4 Thioalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C1-4 Thioalkoxy, C 1-4 Haloalkoxy, C 2-4 Alkenyl, C 2-4 alkynyl, C 3-6 Cycloalkyl, amino, nitro, cyano, (C 1-4 alkyl)amino, or di(C 1-4 substituted with alkyl)amino; or C 3-6 Fused with a cycloalkyl ring,

[0019] R2 is C 6-10 Aryl; C 3-6 Cycloalkenyl; or a 5- or 6-ring heterocycle containing 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S,

[0020] The above R2 is unsubstituted; or halogen, C 1-4 Alkyl, C 1-4 Thioalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Thioalkoxy, C 1-4 Haloalkoxy, C 2-4 Alkenyl, C 2-4 alkynyl, C 3-6 Cycloalkyl, amino, nitro, cyano, (C 1-4 alkyl)amino, and di(C 1-4 substituted with 1 to 3 substituents each independently selected from the group consisting of alkyl)amino,

[0021] R3 is hydrogen or halogen,

[0022] R4 is -NHCO-R', -NHSO2-R', -COO-R', -CONH-R', or 1H-pyrrole-2,5-dion-1-yl,

[0023] The above R' is hydrogen, C 1-4 Alkyl, C 2-4 Alkynyl, or a substituent represented by the following chemical formula 2:

[0024] [Chemical Formula 2]

[0025]

[0026] In the above chemical formula 2,

[0027] R'1 is hydrogen, halogen, or cyano,

[0028] R'2 are each independently hydrogen, C 6-10 Aryl, -CH2-NH2, -CH2-NH(C 1-4 alkyl), or -CH2-N(C 1-4 Alkyl)2.

[0029]

[0030] Preferably, R1 is phenyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, pyrrolidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl,

[0031] The above R1 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 is fused with a cycloalkyl ring.

[0032]

[0033] Preferably, R1 is imidazolyl, imidazolyl fused with cyclopentane, pyrazolyl, or pyridinyl,

[0034] The above R1 is unsubstituted or substituted with methyl, ethyl, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0035]

[0036] Preferably, R2 is phenyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, pyrrolidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl,

[0037] The above R2 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 alkyl) is substituted with amino.

[0038]

[0039] Preferably, R2 is phenyl, pyridinyl, or cyclohexenyl,

[0040] wherein R2 is unsubstituted or substituted with one to three substituents each independently selected from the group consisting of fluoro, chloro, bromo, methyl, trifluoromethyl, and trifluoromethoxy.

[0041]

[0042] Preferably, R3 is hydrogen or chloro.

[0043]

[0044] Preferably, R4 is -NHCO-R', -NHSO2-R', -COO-R', -CONH-R', or 1H-pyrrole-2,5-dion-1-yl,

[0045] The above R' is hydrogen; C 1-4 C, which is unsubstituted or substituted with one or two substituents each independently selected from the group consisting of phenyl, fluoro, and cyano; 2-4 alkenyl; or C 2-4 It's alkynyl.

[0046]

[0047] 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-dion-1-yl.

[0048]

[0049] Preferably, the above chemical formula 1 is represented by the following chemical formula 3:

[0050] [Chemical Formula 3]

[0051]

[0052] In the above chemical formula 3,

[0053] R" are each independently hydrogen, halogen, C 1-4 Alkyl, or C 1-4 It is haloalkyl,

[0054] n is an integer from 1 to 3,

[0055] R4 is -NHCO-CH=CH2, or -COOH.

[0056]

[0057] Representative examples of compounds represented by the above chemical formula 1 are as follows:

[0058] 1) N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide,

[0059] 2) N-(7-(1-methyl-1H-imidazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide,

[0060] 3) N-(2-(4-fluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide,

[0061] 4) N-(7-(1-methyl-1H-imidazol-4-yl)-2-phenyl-1H-indol-5-yl)acrylamide,

[0062] 5) N-(2-(2,4-difluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide,

[0063] 6) N-(7-(1-methyl-1H-imidazol-4-yl)-2-(3,4,5-trifluorophenyl)-1H-indol-5-yl)acrylamide,

[0064] 7) N-(7-(1-(difluoromethyl)-1H-imidazol-4-yl)-2-(4-fluorophenyl)-1H-indol-5-yl)acrylamide,

[0065] 8) N-(2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide,

[0066] 9) N-(2-(3,4-difluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide,

[0067] 10) N-(2-(3-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide,

[0068] 11) N-(2-(4-chlorophenyl)-7-(1-(difluoromethyl)-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide,

[0069] 12) N-(2-(4-chloro-2-fluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide,

[0070] 13) N-(2-cyclohexenyl-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide,

[0071] 14) N-(2-(4-fluoro-3-methylphenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide,

[0072] 15) N-(7-(1-methyl-1H-imidazol-4-yl)-2-p-tolyl-1H-indol-5-yl)acrylamide,

[0073] 16) N-(7-(1-methyl-1H-imidazol-4-yl)-2-(3-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide,

[0074] 19) N-(7-(1-methyl-1H-imidazol-4-yl)-2-(3-(trifluoromethyl)phenyl)-1H-indol-5-yl)methanesulfonamide,

[0075] 20) N-(2-(4-chloro-3-fluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide,

[0076] 21) N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)methanesulfonamide,

[0077] 22) N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)-2-fluoroacrylamide,

[0078] 23) N-(3-chloro-2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide,

[0079] 24) (E)-N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)-2-cyano-3-phenylacrylamide,

[0080] 25) N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)but-2-ynamide,

[0081] 26) N-(2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)ethanesulfonamide,

[0082] 27) 1-(2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)-1H-pyrrole-2,5-dione,

[0083] 28) N-(2-(4-chlorophenyl)-7-(1-methyl-1H-pyrazol-3-yl)-1H-indol-5-yl)acrylamide,

[0084] 29) N-(2-(3,4-dichlorophenyl)-7-(1-methyl-1H-pyrazol-3-yl)-1H-indol-5-yl)acrylamide,

[0085] 30) N-(2-(3,4-dichlorophenyl)-7-(pyridin-2-yl)-1H-indol-5-yl)acrylamide,

[0086] 31) N-(2-(4-fluorophenyl)-7-(pyridin-2-yl)-1H-indol-5-yl)acrylamide,

[0087] 32) N-(2-(4-fluorophenyl)-7-(1-methyl-1H-pyrazol-3-yl)-1H-indol-5-yl)acrylamide,

[0088] 33) N-(2-(2,4-difluorophenyl)-7-(1-methyl-1H-pyrazol-3-yl)-1H-indol-5-yl)acrylamide,

[0089] 34) N-(2-(5-chloropyridin-2-yl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide,

[0090] 35) 2-(4-fluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-carboxylic acid,

[0091] 36) 7-(1-methyl-1H-imidazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-indole-5-carboxylic acid,

[0092] 37) 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-carboxylic acid,

[0093] 38) 2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-carboxylic acid,

[0094] 39) 2-(4-chloro-3-fluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-carboxylic acid,

[0095] 40) 2-(4-chlorophenyl)-N-methyl-7-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-carboxylamide,

[0096] 41) N-(7-(1-methyl-1H-imidazol-4-yl)-2-(3,4,5-trichlorophenyl)-1H-indol-5-yl)acrylamide,

[0097] 42) N-(2-(3-fluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide,

[0098] 43) 2-(3,4-difluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-carboxylic acid,

[0099] 44) N-(2-(3-chloro-4-fluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide,

[0100] 45) N-(2-(2,4-dichlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide,

[0101] 46) N-(2-(4-chloro-3,5-difluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide,

[0102] 47) N-(2-(4-chloro-2,6-difluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide,

[0103] 48) N-(7-(1-methyl-1H-imidazol-4-yl)-2-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)acrylamide,

[0104] 49) N-(2-(4-chlorophenyl)-7-(4-methylthiazol-2-yl)-1H-indol-5-yl)acrylamide,

[0105] 50) N-(7-(1-ethyl-1H-imidazol-4-yl)-2-(3,4,5-trifluorophenyl)-1H-indol-5-yl)acrylamide,

[0106] 51) N-(7-(1-ethyl-1H-imidazol-4-yl)-2-(4-fluorophenyl)-1H-indol-5-yl)acrylamide, and

[0107] 52) N-(2-(4-bromophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide.

[0108]

[0109] Furthermore, the compounds of the present invention may exist in the form of salts, particularly pharmaceutically acceptable salts. As salts, any salt commonly used in the art, such as acid addition salts formed with pharmaceutically acceptable free acids, may be used without limitation. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic addition salt of the compound represented by Chemical Formula 1, which has a concentration that is relatively non-toxic and harmless to the patient and has an effective effect, and wherein the side effects caused by the salt do not diminish the beneficial effects of the compound represented by Chemical Formula 1.

[0110]

[0111] As the above-mentioned acid, organic acids and inorganic acids can be used. As the inorganic acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used. As the organic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. can be used, but are not limited thereto. Preferably, the salt may be hydrochloride.

[0112]

[0113] Additionally, a pharmaceutically acceptable metal salt can be obtained by a conventional method using a base. For example, the compound represented by the above chemical formula 1 is dissolved in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, the undissolved compound salt is filtered, and the filtrate is evaporated and dried to obtain a pharmaceutically acceptable metal salt. In this case, it is particularly preferable to prepare a sodium salt, a potassium salt, or a calcium salt as the metal salt.

[0114]

[0115] In addition, a pharmaceutically unacceptable salt or solvate of the compound represented by the chemical formula 1 can be used as an intermediate in the production of the compound represented by the chemical formula 1, a pharmaceutically acceptable salt, or a solvate thereof.

[0116]

[0117] Meanwhile, the compound represented by the above chemical formula 1 can be prepared through the following reaction formula 1 or 2.

[0118] [Reaction Formula 1]

[0119]

[0120] [Reaction Formula 2]

[0121]

[0122]

[0123] In the above reaction formulas 1 and 2, the remaining definitions except Y are as defined above, and Y is C 1-4 is alkyl, and more preferably Y is methyl or ethyl.

[0124]

[0125] Step 1 of each of the above reaction formulas 1 and 2 is a Stille coupling reaction, and step 2 is a Sonogashira coupling reaction. The order of steps 1 and 2 may be changed depending on the reactivity of each reactant (see Example 28). At this time, X' is a substituent for the Stille coupling reaction, and may be -SnBu3 or -B(OH)2 for the Suzuki reaction, but is not limited thereto.

[0126]

[0127] Each step 3 of the above reaction schemes 1 and 2 is a reaction for synthesizing indole through a cyclization reaction, and can be carried out under basic conditions, but is not limited thereto.

[0128]

[0129] Step 4 of the above reaction scheme 1 is a reaction for reducing a nitro group, and can be carried out using iron, but is not limited thereto.

[0130]

[0131] Step 5 of the above reaction scheme 1 is a reaction between an amine group and a carbonyl group or sulfonyl group according to R4.

[0132]

[0133] Step 4 of the above reaction scheme 2 is a hydrolysis reaction that can be carried out under basic conditions, but is not limited thereto.

[0134]

[0135] Step 5 of the above reaction scheme 2 may be, but is not limited to, a nucleophile-carbonyl group coupling reaction according to R4.

[0136]

[0137] Meanwhile, the above reaction formulas 1 and 2 are for the case where R3 in the chemical formula 1 of the present invention is hydrogen, and when R3 is not hydrogen, an indole derivative can be synthesized through a cyclization reaction after step 3 and before step 4, and then R3 can be substituted through an R3 substitution reaction.

[0138]

[0139] The above manufacturing method is further specified in the examples described below.

[0140]

[0141] In addition, the present invention provides a pharmaceutical composition comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof. Specifically, the present invention provides a pharmaceutical composition for preventing or treating cancer or a tumor, comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0142]

[0143] The term "cancer" or "tumor" refers to the presence in an organism of cells with typical characteristics of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation, and decreased cell death / apoptosis. Cancer cells often include solid tumors, such as sarcomas or carcinomas. Sarcomas include: cystic rhabdomyosarcoma, cystic soft part sarcoma, ameloblastoma, hemangiosarcoma, chondrosarcoma, chordoma, clear cell sarcoma, dedifferentiated liposarcoma, desmoid, desmoids, small desmoblastoma, embryonal rhabdomyosarcoma, epithelioid fibrosarcoma, epithelioid hemangioendothelioma, epithelioid sarcoma, sensory neuroblastoma, Ewing sarcoma, renal rhabdomyosarcoma, extraosseous myxoid chondrosarcoma, extraosseous osteosarcoma, fibrosarcoma, giant cell tumor, perithecium, infantile fibrosarcoma, inflammatory myofibroblastoma, Kaposi sarcoma, osteosarcoma, liposarcoma, bone liposarcoma, malignant fibrous histiocytoma, malignant fibrous histiocytoma of bone, malignant mesenchymal tumor, malignant peripheral nerve sheath tumor, mesenchymal chondrosarcoma, myxofibrosarcoma, myxoid liposarcoma, myoinflammatory fibrosarcoma, osteosarcoma, periprosthetic Includes osteosarcoma, periosteal osteosarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, extraskeletal Ewing's tumor, rhabdomyosarcoma, round cell liposarcoma, small cell osteosarcoma, solitary fibrous tumor, synovial sarcoma, and angioectatic osteosarcoma. Cancers include adenocarcinoma, squamous cell carcinoma, adenosquamous cell carcinoma, metaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer, bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of unknown primary site, esophageal cancer, eye tumor, primary fallopian tube cancer, digestive cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, malignant melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, penile tumor, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer. In some cases, cancers used herein may include uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colon cancer, stomach cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer, and meningioma.

[0144]

[0145] Cancer also includes non-solid tumors, such as blood cancers, wherein the cancer cells originate from the bone marrow. Blood cancers include leukemia, lymphoma, myeloma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, T-cell malignancies, or B-cell malignancies. In particular, T-cell malignancies include mature T-cell lymphoma not otherwise classified, anaplastic 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, follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, Waldenström macroglobulinemia, head and neck tumors, lymphoid marginal zone B-cell lymphoma, Burkitt's lymphoma, primary mediastinal B-cell lymphoma, immunoglobulin lymphoma, precursor B-lymphoblastic lymphoma, prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, intravascular large B-cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.

[0146]

[0147] In some cases, it includes recurrent or refractory cancer, and the cancer is a solid tumor. Recurrent or refractory cancer includes adenocarcinoma, squamous cell carcinoma, adenosquamous cell carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, biliary tract cancer, bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, esophageal cancer, eye tumor, primary fallopian tube cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, malignant melanoma, oral cancer, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.

[0148]

[0149] The term "prevention" of the present invention means any act of inhibiting or delaying the occurrence, spread, and recurrence of the disease by administering the composition of the present invention, and "treatment" means any act of improving or beneficially changing the symptoms of the disease by administering the composition of the present invention.

[0150]

[0151] The pharmaceutical composition of the present invention can be formulated into oral or parenteral dosage forms according to standard pharmaceutical practices. These dosage forms may contain, in addition to the active ingredient, pharmaceutically acceptable additives such as carriers, adjuvants, or diluents.

[0152]

[0153] Suitable carriers include, but are not limited to, saline, polyethylene glycol, ethanol, vegetable oils, and isopropyl myristate, and diluents include, but are not limited to, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine. In addition, the compounds of the present invention can be dissolved in oils, propylene glycol, or other solvents commonly used in the preparation of injectable solutions. In addition, the compounds of the present invention can be formulated as ointments or creams for topical action.

[0154]

[0155] The preferred dosage of the compound of the present invention varies depending on the patient's condition and body weight, the severity of the disease, the form of the drug, the route of administration, and the duration of administration, but can be appropriately selected by those skilled in the art. However, for desirable effects, the compound of the present invention is preferably administered at a daily dose of 0.0001 to 100 mg / kg (body weight), preferably 0.001 to 100 mg / kg (body weight). Administration may be administered orally or parenterally once daily or in divided doses.

[0156]

[0157] Depending on the administration method, the pharmaceutical composition may contain 0.001 to 99 wt%, preferably 0.01 to 60 wt%, of the compound of the present invention.

[0158]

[0159] The pharmaceutical composition according to the present invention can be administered to mammals, including rats, mice, livestock, and humans, via various routes. Any route of administration is conceivable, including oral, rectal, intravenous, intramuscular, subcutaneous, intrauterine, or intracerebroventricular injection.

[0160] 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.

[0161] Figure 1 shows the results of Experimental Example 3, showing the expression regulation properties of two TEAD target genes of Example 1 using real-time PCR.

[0162] Hereinafter, preferred examples are presented to help understand the present invention, but the following examples are only to illustrate the present invention and the scope of the present invention is not limited to the following examples.

[0163]

[0164] Example 1: Preparation of N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide

[0165]

[0166]

[0167] (Step 1)

[0168] 2,6-Diiodo-4-nitroaniline (2.56 mmol, 1 g, 1.0 eq) was dissolved in 1,4-dioxane (10 mL) in a sealed tube. 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 sequentially added, and the mixture was reacted in a microwave reactor at 150°C for 1 hour. After completion of the reaction, the mixture was extracted with ethyl acetate and ammonium chloride aqueous solution, concentrated, and solidified with tert-butyl methyl ether to obtain 2-iodo-6-(1-methyl-1H-imidazol-4-yl)-4-nitroaniline (0.57 g, yield: 64%).

[0169]

[0170] (Step 2)

[0171] 2-Iodo-6-(1-methyl-1H-imidazol-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 sequentially added, and ultrasonic degassing was performed for 10 minutes under a nitrogen atmosphere. 1-Chloro-4-ethynylbenzene (0.69 mmol, 0.094 g, 1.2 eq) was added and reacted at 50°C for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and ammonium chloride aqueous solution, concentrated, and solidified with tert-butyl methyl ether to obtain 2-((4-chlorophenyl)ethynyl)-6-(1-methyl-1H-imidazol-4-yl)-4-nitroaniline (0.14 g, yield: 68%).

[0172]

[0173] (Step 3)

[0174] 2-((4-chlorophenyl)ethynyl)-6-(1-methyl-1H-imidazol-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 min. After completion of the reaction, the mixture was extracted with ethyl acetate and ammonium chloride aqueous solution, concentrated, and solidified with tert-butyl methyl ether to obtain 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-5-nitro-1H-indole (0.079 g, yield: 57%).

[0175]

[0176] (Step 4)

[0177] 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-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 reacted at 60°C overnight. After completion of the reaction, iron and ethanol were removed, extracted with aqueous ammonium chloride solution, concentrated, and 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-amine was used in the next reaction without separation or purification.

[0178]

[0179] (Step 5)

[0180] 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-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. 0.05 mL of triethylamine and acrylic acid (0.12 mmol, 0.0086 mL, 1.2 eq) were added, and the mixture was reacted at room temperature overnight. After completion of the reaction, dichloromethane was removed, and the mixture was purified by column chromatography to obtain the title compound (9.4 mg, yield: 25%).

[0181] 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)

[0182]

[0183] Example 2: Preparation of N-(7-(1-methyl-1H-imidazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0184]

[0185] 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.

[0186] 1H 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).

[0187]

[0188] Example 3: Preparation of N-(2-(4-fluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide

[0189]

[0190] 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.

[0191] 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).

[0192]

[0193] Example 4: Preparation of N-(7-(1-methyl-1H-imidazol-4-yl)-2-phenyl-1H-indol-5-yl)acrylamide

[0194]

[0195] 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.

[0196] 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).

[0197]

[0198] Example 5: Preparation of N-(2-(2,4-difluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide

[0199]

[0200] 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.

[0201] 1H 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).

[0202] Example 6: Preparation of N-(7-(1-methyl-1H-imidazol-4-yl)-2-(3,4,5-trifluorophenyl)-1H-indol-5-yl)acrylamide

[0203]

[0204] 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.

[0205] 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).

[0206]

[0207] Example 7: Preparation of N-(7-(1-(difluoromethyl)-1H-imidazol-4-yl)-2-(4-fluorophenyl)-1H-indol-5-yl)acrylamide

[0208]

[0209] 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.

[0210] 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).

[0211]

[0212] Example 8: Preparation of N-(2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide

[0213]

[0214] 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.

[0215] 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).

[0216]

[0217] Example 9: Preparation of N-(2-(3,4-difluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide

[0218]

[0219] 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.

[0220] 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).

[0221]

[0222] Example 10: Preparation of N-(2-(3-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide

[0223]

[0224] 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.

[0225] 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).

[0226]

[0227] Example 11: Preparation of N-(2-(4-chlorophenyl)-7-(1-(difluoromethyl)-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide

[0228]

[0229] 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.

[0230] 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).

[0231]

[0232] Example 12: Preparation of N-(2-(4-chloro-2-fluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide

[0233]

[0234] 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.

[0235] 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).

[0236]

[0237] Example 13: Preparation of N-(2-cyclohexenyl-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide

[0238]

[0239] 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.

[0240] 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).

[0241]

[0242] Example 14: Preparation of N-(2-(4-fluoro-3-methylphenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide

[0243]

[0244] 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.

[0245] 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).

[0246]

[0247] Example 15: Preparation of N-(7-(1-methyl-1H-imidazol-4-yl)-2-(p-tolyl)-1H-indol-5-yl)acrylamide

[0248]

[0249] 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.

[0250] 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).

[0251]

[0252] Example 16: Preparation of N-(7-(1-methyl-1H-imidazol-4-yl)-2-(3-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0253]

[0254] 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.

[0255] 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).

[0256]

[0257] Example 17: Preparation of N-(7-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2-(4-fluorophenyl)-1H-indol-5-yl)acrylamide

[0258]

[0259] The title compound (6.9 mg, yield: 18%) was obtained in the same manner as in Example 1, except that 1,2-(tribunylstannyl)-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.

[0260] 1 H 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.

[0261]

[0262] Example 18: Preparation of N-(2-(4-chlorophenyl)-7-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-1H-indol-5-yl)acrylamide

[0263]

[0264] The title compound (6.8 mg, yield: 17%) was obtained in the same manner as in Example 1, except that 2-(tribunylstannyl)-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.

[0265] 1H 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 overlapping.

[0266]

[0267] Example 19: Preparation of N-(7-(1-methyl-1H-imidazol-4-yl)-2-(3-(trifluoromethyl)phenyl)-1H-indol-5-yl)methanesulfonamide

[0268]

[0269] 7-(1-Methyl-1H-imidazol-4-yl)-2-(3-(trifluoromethyl)phenyl)-1H-indol-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 reacted at room temperature for 2 hours. After completion of the reaction, dichloromethane was removed, and the title compound (15.0 mg, yield: 35%) was obtained through column chromatography.

[0270] 1H 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).

[0271]

[0272] Example 20: Preparation of N-(2-(4-chloro-3-fluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide

[0273]

[0274] 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.

[0275] 1 H 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).

[0276]

[0277] Example 21: Preparation of N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)methanesulfonamide

[0278]

[0279] 2-(4-Chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-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 reacted at room temperature for 2 hours. After completion of the reaction, dichloromethane was removed, and the title compound (19.8 mg, yield: 49%) was obtained through column chromatography.

[0280] 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).

[0281]

[0282] Example 22: Preparation of N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)-2-fluoroacrylamide

[0283]

[0284] 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.

[0285] 1H 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).

[0286]

[0287] Example 23: Preparation of (N-(3-chloro-2-(4-chlorophenylyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide

[0288]

[0289]

[0290] (Step 1)

[0291] 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-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 at room temperature overnight. After completion of the reaction, distilled water was added, and the solid was filtered to obtain 3-chloro-2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-5-nitro-1H-indole (0.060 g, yield: 55%).

[0292]

[0293] (Step 2)

[0294] 3-Chloro-2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-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 reacted at 80°C for 4 hours. After completion of the reaction, iron and ethanol were removed, and then extracted with an aqueous ammonium chloride solution, concentrated, and 3-chloro-2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-amine was used in the next reaction without separation or purification.

[0295]

[0296] (Step 3)

[0297] 3-Chloro-2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-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. Triethylamine (0.2 mL) and acrylic acid (0.1 mmol, 0.0072, 1.0 eq) were added, and the mixture was reacted at room temperature overnight. After completion of the reaction, dichloromethane was removed, and the title compound (3.7 mg, yield: 9%) was obtained through column chromatography.

[0298] 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).

[0299]

[0300] Example 24: Preparation of (E)-N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)-2-cyano-3-phenylacrylamide

[0301]

[0302] 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.

[0303] 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).

[0304]

[0305] Example 25: Preparation of N-(2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)but-2-ynamide

[0306]

[0307] The title compound (15.4 mg, yield: 39%) was obtained in the same manner as in Example 1, except that but-2-inoic acid was used instead of acrylic acid in step 5 of Example 1.

[0308] 1H 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).

[0309]

[0310] Example 26: Preparation of N-(2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)ethenesulfonamide

[0311]

[0312] 2-(3,4-Dichlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-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 reacted at room temperature for 2 hours. After completion of the reaction, dichloromethane was removed, and the title compound (21.1 mg, yield: 51%) was obtained through column chromatography.

[0313] 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).

[0314]

[0315] Example 27: Preparation of (1-(2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)-1H-pyrrole-2,5-dione

[0316]

[0317] 2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-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 sequentially added to a sealed tube, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, diethyl ether was removed. To the concentrated residue, sodium acetate (0.05 mmol, 0.0041 g, 0.5 eq) and acetic anhydride (0.3 mL) were added, and the mixture was reacted at 90°C for 2 hours. After completion of the reaction, the mixture was extracted with aqueous potassium carbonate solution and ethyl acetate, concentrated, and purified by column chromatography to obtain the title compound (8.9 mg, yield: 20%).

[0318] 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).

[0319]

[0320] Example 28: Preparation of N-(2-(4-chlorophenyl)-7-(1-methyl-1H-pyrazol-3-yl)-1H-indol-5-yl)acrylamide

[0321]

[0322]

[0323] (Step 1)

[0324] 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 reacted at room temperature for 5 hours. After completion of the reaction, distilled water (50 mL) was added and stirred for 10 minutes. The yellow solid was filtered to obtain 2-bromo-6-iodo-4-nitroaniline (10 g, yield: 77%).

[0325]

[0326] (Step 2)

[0327] 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 sequentially added, and ultrasonic degassing was performed for 10 minutes under a nitrogen atmosphere. 1-Chloro-4-ethynylbenzene (1.59 mmol, 0.21 g, 1.1 eq) was added and reacted at 40°C overnight. After completion of the reaction, the mixture was extracted with ethyl acetate and ammonium chloride aqueous solution, concentrated, and solidified with tert-butyl methyl ether to obtain 2-bromo-6-((4-chlorophenyl)ethynyl)-4-nitroaniline (0.3 g, yield: 59%).

[0328]

[0329] (Step 3)

[0330] 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 sequentially added, and the mixture was reacted in a microwave reactor at 150°C for 1 hour. After completion of the reaction, the mixture was extracted with ethyl acetate and ammonium chloride aqueous solution, concentrated, and solidified with tert-butyl methyl ether to obtain 2-((4-chlorophenyl)ethynyl)-6-(1-methyl-1H-pyrazol-3-yl)-4-nitroaniline (0.14 g, yield: 51%).

[0331]

[0332] (Step 4)

[0333] 2-((4-chlorophenyl)ethynyl)-6-(1-methyl-1H-pyrazol-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 min. After completion of the reaction, the mixture was extracted with ethyl acetate and aqueous ammonium chloride solution, concentrated, and solidified with tert-butyl methyl ether to obtain 2-(4-chlorophenyl)-7-(1-methyl-1H-pyrazol-3-yl)-5-nitro-1H-indole (0.1 g, yield: 72%).

[0334]

[0335] (Step 5)

[0336] 2-(4-chlorophenyl)-7-(1-methyl-1H-pyrazol-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 reacted at 70°C for 3 hours. After completion of the reaction, iron and ethanol were removed, extracted with aqueous ammonium chloride solution, concentrated, and 2-(4-chlorophenyl)-7-(1-methyl-1H-pyrazol-3-yl)-1H-indol-5-amine was used in the next reaction without separation or purification.

[0337]

[0338] (Step 6)

[0339] 2-(4-chlorophenyl)-7-(1-methyl-1H-pyrazol-3-yl)-1H-indol-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. Triethylamine (0.1 mL) and acrylic acid (0.11 mmol, 0.0079 g, 1.1 eq) were added, and the mixture was reacted at room temperature overnight. After completion of the reaction, dichloromethane was removed, and the title compound (9.0 mg, yield: 25%) was obtained through column chromatography.

[0340] 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).

[0341]

[0342] Example 29: Preparation of N-(2-(3,4-dichlorophenyl)-7-(1-methyl-1H-pyrazol-3-yl)-1H-indol-5-yl)acrylamide

[0343]

[0344] In step 2 of Example 28, 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.

[0345] 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).

[0346]

[0347] Example 30: Preparation of N-(2-(3,4-dichlorophenyl)-7-(pyridin-2-yl)-1H-indol-5-yl)acrylamide

[0348]

[0349] 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.

[0350] 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).

[0351]

[0352] Example 31: Preparation of N-(2-(4-fluorophenyl)-7-(pyridin-2-yl)-1H-indol-5-yl)acrylamide

[0353]

[0354] 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.

[0355] 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).

[0356]

[0357] Example 32: Preparation of N-(2-(4-fluorophenyl)-7-(1-methyl-1H-pyrazol-3-yl)-1H-indol-5-yl)acrylamide

[0358]

[0359] 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.

[0360] 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).

[0361]

[0362] Example 33: Preparation of N-(2-(2,4-difluorophenyl)-7-(1-methyl-1H-pyrazol-3-yl)-1H-indol-5-yl)acrylamide

[0363]

[0364] 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.

[0365] 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).

[0366]

[0367] Example 34: Preparation of N-(2-(5-chloropyridin-2-yl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide

[0368]

[0369]

[0370] (Step 1)

[0371] 2-Iodo-6-(1-methyl-1H-imidazol-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) in a sealed tube, and 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) and reacted overnight at 55°C. After completion of the reaction, the temperature was cooled to room temperature. Tert-butyl methyl ether (5 mL) was added and the solid was filtered to obtain 2-((5-chloropyridin-2-yl)ethynyl)-6-(1-methyl-1H-imidazol-4-yl)-4-nitroaniline (0.49 g, yield: 92%).

[0372]

[0373] (Step 2)

[0374] 2-((5-chloropyridin-2-yl)ethynyl)-6-(1-methyl-1H-imidazol-4-yl)-4-nitroaniline (1.4 mmol, 0.48 g, 1.0 eq) was dissolved in DMF (7.0 mL) in a sealed tube, and CuI (0.14 mmol, 26.7 mg, 0.1 eq) was added and reacted at 150°C for 1 h. After completion of the reaction, the temperature was cooled to room temperature. The residue was extracted with saturated aqueous sodium chloride solution and ethyl acetate, concentrated, and purified by column chromatography to obtain 2-(5-chloropyridin-2-yl)-7-(1-methyl-1H-imidazol-4-yl)-5-nitro-1H-indole (0.22 g, yield: 44%). Steps 3 and 4 were performed using the same method as in Example 1 to obtain the title compound (12.8 mg, yield: 31%).

[0375] 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).

[0376]

[0377] Example 35: Preparation of 2-(4-fluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-carboxylic acid

[0378]

[0379]

[0380] (Step 1)

[0381] Ethyl-4-amino-3,5-diiodobenzoate (2.0 mmol, 0.83 g, 1.0 eq) was dissolved in 1,4-dioxane (10 mL) in a sealed tube, and 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 sequentially added. The mixture was reacted in a microwave reactor at 140°C for 1.5 h. After completion of the reaction, the solvent was removed, and the obtained concentrated residue was purified by column chromatography to obtain ethyl 4-amino-3-iodo-5-(1-methyl-1H-imidazol-4-yl)benzoate (0.32 g, yield: 44%).

[0382]

[0383] (Step 2)

[0384] In a sealed tube, ethyl 4-amino-3-iodo-5-(1-methyl-1H-imidazol-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 reacted at 55°C overnight. After completion of the reaction, the temperature was cooled to room temperature. Water (10 mL) and ethyl acetate (5 mL) were added, and the target compound was extracted from the organic layer, dried, and concentrated to obtain ethyl 4-amino-3-((4-fluorophenyl)ethynyl)-5-(1-methyl-1H-imidazol-4-yl)benzoate (0.15 g, yield: 81%).

[0385]

[0386] (Step 3)

[0387] In a sealed tube, ethyl 4-amino-3-((4-fluorophenyl)ethynyl)-5-(1-methyl-1H-imidazol-4-yl)benzoate (0.4 mmol, 0.15 g, 1.0 eq) was dissolved in dimethylacetamide (2 mL), sodium hydroxide (2.0 mmol, 80 mg, 5.0 eq) was added, and the mixture was reacted in a microwave reactor at 140°C for 15 min. Saturated sodium chloride aqueous solution (50 mL) and ethyl acetate (15 mL) were added, and the resulting organic layer was dried and the solvent was removed. Column chromatography separation and purification yielded ethyl 2-(4-fluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-carboxylate (70 mg, yield: 48%).

[0388]

[0389] (Step 4)

[0390] In a sealed tube, ethyl 2-(4-fluorophenyl)-7-(1-methyl-1H-imidazol-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 sequentially added, and the mixture was refluxed for 2 hours. After completion of the reaction, 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%).

[0391] 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).

[0392]

[0393] Example 36: Preparation of 7-(1-methyl-1H-imidazol-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-indole-5-carboxylic acid

[0394]

[0395] 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.

[0396] 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).

[0397]

[0398] Example 37: Preparation of 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-carboxylic acid

[0399]

[0400] 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.

[0401] 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).

[0402]

[0403] Example 38: Preparation of 2-(3,4-dichlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-carboxylic acid

[0404]

[0405] 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.

[0406] 1H 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).

[0407]

[0408] Example 39: Preparation of 2-(4-chloro-3-fluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-carboxylic acid

[0409]

[0410] 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.

[0411] 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).

[0412]

[0413] Example 40: Preparation of 2-(4-chlorophenyl)-N-methyl-7-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-carboxylamide

[0414]

[0415]

[0416] (Step 1)

[0417] Ethyl-4-amino-3,5-diiodobenzoate (2.0 mmol, 0.83 g, 1.0 eq) was dissolved in 1,4-dioxane (10 mL) in a sealed tube, and 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 sequentially added. The mixture was reacted in a microwave reactor at 140°C for 1.5 h. After completion of the reaction, the solvent was removed, and the obtained concentrated residue was purified by column chromatography to obtain ethyl 4-amino-3-iodo-5-(1-methyl-1H-imidazol-4-yl)benzoate (0.32 g, yield: 44%).

[0418]

[0419] (Step 2)

[0420] In a sealed tube, ethyl 4-amino-3-iodo-5-(1-methyl-1H-imidazol-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 reacted at 55°C overnight. After completion of the reaction, the temperature was cooled to room temperature. Water (10 mL) and ethyl acetate (5 mL) were added, and the target compound was extracted from the organic layer, dried, and concentrated to obtain ethyl 4-amino-3-((4-chlorophenyl)ethynyl)-5-(1-methyl-1H-imidazol-4-yl)benzoate (0.16 g, yield: 84%).

[0421]

[0422] (Step 3)

[0423] In a sealed tube, ethyl 4-amino-3-((4-chlorophenyl)ethynyl)-5-(1-methyl-1H-imidazol-4-yl)benzoate (0.4 mmol, 0.15 g, 1.0 eq) was dissolved in dimethylacetamide (2 mL), and 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 min. Saturated sodium chloride aqueous solution (50 mL) and ethyl acetate (15 mL) were added, and the resulting organic layer was dried and the solvent was removed. The residue was separated and purified by column chromatography to obtain ethyl 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-carboxylate (81 mg, yield: 53%).

[0424]

[0425] (Step 4)

[0426] In a sealed tube, ethyl 2-(4-chlorophenyl)-7-(1-methyl-1H-imidazol-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 sequentially added, and the mixture was refluxed for 2 hours. After completion of the reaction, 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-imidazol-4-yl)-1H-indole-5-carboxylic acid (36 mg, yield: 51%).

[0427]

[0428] (Step 5)

[0429] 2-(4-Chlorophenyl)-7-(1-methyl-1H-imidazol-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. Triethylamine (0.1 mL) and acrylic acid (0.11 mmol, 0.0079 g, 1.1 eq) were added, and the mixture was reacted at room temperature overnight. After completion of the reaction, dichloromethane was removed, and the title compound (10.3 mg, yield: 28%) was obtained through column chromatography.

[0430] 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).

[0431]

[0432] Example 41: Preparation of N-(7-(1-methyl-1H-imidazol-4-yl)-2-(3,4,5-trichlorophenyl)-1H-indol-5-yl)acrylamide

[0433]

[0434] 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.

[0435] 1H 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).

[0436]

[0437] Example 42: Preparation of N-(2-(3-fluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide

[0438]

[0439] 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.

[0440] 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).

[0441]

[0442] Example 43: Preparation of 2-(3,4-difluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-carboxylic acid

[0443]

[0444] 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.

[0445] 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).

[0446]

[0447] Example 44: Preparation of N-(2-(3-chloro-4-fluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide

[0448]

[0449] 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.

[0450] 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).

[0451]

[0452] Example 45: Preparation of N-(2-(2,4-dichlorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide

[0453]

[0454] 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.

[0455] 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).

[0456]

[0457] Example 46: Preparation of N-(2-(4-chloro-3,5-difluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide

[0458]

[0459] 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.

[0460] 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).

[0461]

[0462] Example 47: Preparation of N-(2-(4-chloro-2,6-difluorophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide

[0463]

[0464] 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.

[0465] 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).

[0466]

[0467] Example 48: N-(7-(1-methyl-1H-imidazol-4-yl)-2-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)acrylamide

[0468]

[0469] 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.

[0470] 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).

[0471]

[0472] Example 49: Preparation of N-(2-(4-chlorophenyl)-7-(4-methylthiazol-2-yl)-1H-indol-5-yl)acrylamide

[0473]

[0474] 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.

[0475] 1H 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).

[0476]

[0477] Example 50: Preparation of N-(7-(1-ethyl-1H-imidazol-4-yl)-2-(3,4,5-trifluorophenyl)-1H-indol-5-yl)acrylamide

[0478]

[0479] 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.

[0480] 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).

[0481]

[0482] Example 51: Preparation of N-(7-(1-ethyl-1H-imidazol-4-yl)-2-(4-fluorophenyl)-1H-indol-5-yl)acrylamide

[0483]

[0484] 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.

[0485] 1 H 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).

[0486]

[0487] Example 52: Preparation of N-(2-(4-bromophenyl)-7-(1-methyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylamide

[0488]

[0489] 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.

[0490] 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).

[0491]

[0492] Experimental Example 1: Inhibition test of transcription factor TEAD activity

[0493] For the compounds prepared in the above examples, ONE-Glo was used using the Hippo Pathway TEAD reporter-MCF7 recombinant cell line (BPS Bioscience, Catalog #60618). TM Transcription factor TEAD activity was measured using the Luciferase assay (Promega, Catalog #E6110).

[0494]

[0495] Specifically, the TEAD Reporter-MCF7 cell line contains the firefly luciferase gene, whose expression is regulated under the control of a TEAD response element in the human breast cancer cell line MCF7. This cell line consistently induces expression of the luciferase reporter by maintaining unphosphorylated YAP / TAZ in the nucleus under unstressed conditions.

[0496]

[0497] TEAD Reporter-MCF7 cells were prepared in 100 μL of cell culture medium (MEM medium, 10% FBS, 1% P / S, 400 μg / mL Geneticin, 1% N-ethyl acetate A, 1 mM NA pyruvate, 10 μg / mL Insulin) in a white clear-bottom 96-well microplate. The prepared plate was cultured in a 5% CO2 incubator at 37°C for 24 hours, and then treated with the compounds of the previously prepared examples to a final concentration of 0.0005, 0.005, 0.05, 0.5, and 5 μM, and all treatments were repeated three times. The plate treated with the example compound was cultured in a 37°C, 5% CO2 incubator for 24 hours, and the enzymatic reaction was initiated by adding 100 μL / well of a substrate 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 1000 ms) was measured using a Flexstation3 multi-mode microplate reader. ONE-Glo TM Luciferase enzyme activity, which represents the activity of transcription factor TEAD, was measured by chemiluminescence according to the luciferase assay manual, and the inhibitory activity of the compounds according to the present invention was calculated. The results of each compound were analyzed using Microsoft Excel, and IC 50 The values ​​were calculated by GraphPad Prism software, and the results are shown in Table 1 below.

[0498]

[0499] Experimental Example 2: Cell Proliferation Inhibition Test

[0500] For the compounds prepared in the above examples, CellTiter-Glo was used with NCI-H226 (addexbio) and NCI-H28 (Korea Cell Line Bank) cell lines. ® Cell proliferation was measured using the Luminescent Cell Viability (Promega, Catalog #G7571) method. This assay measures cell viability by measuring the enzyme activity of luciferase, which is activated by ATP released from living cells, reacts with a luciferin substrate, and then reacts with the luciferin substrate.

[0501]

[0502] 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 pyruvate) in a white clear-bottom 96-well microplate. The prepared plate was cultured in a 37°C, 5% CO2 incubator for 24 hours, and then treated with the compounds of the previously prepared examples to a final concentration of 0.0005, 0.005, 0.05, 0.5, and 5 μM, and all treatments were repeated three times. The plate treated with the example compound was cultured in a 37°C, 5% CO2 incubator, and the enzymatic reaction was initiated by adding 100 μL / well of a substrate solution containing luciferin to a white, clear-bottom 96-well microplate. The reaction was performed in the dark at room temperature for 10 minutes, and luminescence was measured using a Flexstation3 multi-mode microplate reader. CellTiter-Glo ®Luciferase enzyme activity, which represents the amount of ATP, was measured by chemiluminescence according to the Luminescednt Cell Viability manual, and the inhibitory activity of the compounds according to the present invention was calculated. The results of each compound were analyzed using Microsoft Excel, and IC 50 The values ​​were calculated by GraphPad Prism software, and the results are shown in Table 1 below.

[0503] Example number TEAD IC 50 (nM)growth IC 50 (μM)H226growth IC 50 (μM)H28Example numberTEAD IC 50 (nM)growth IC 50 (μM)H226growth IC 50 (μM)H2810.00940.0210>5300.12600.33860.55320.03900.06504.140310.03 000.0121.76730.00350.00251.530320.02300.00761.35740.03000.01004.40 0330.05100.02434.91450.00640.0042>5350.10000.1367>560.00590.00444.000370.02600.13450.75980.11000.05700.950390.03600.0219>590.02000.0 0532.950420.09700.00452.080100.06000.02002.469430.05400.0078>5120.07900.02252.800440.03700.02171.900130.04600.02233.500460.09000.079 01.360140.04900.02512.300500.02700.0154>5190.19000.20990.438510.04800.00762.540210.2360>52.221520.34600.05800.868280.01500.00842.300

[0504]

[0505] Experimental Example 3: CTGF and CYR61 Analysis Test

[0506] NCI-H226 (AddexBio) human mesothelioma cells were seeded at 5 x 10 per well in 6-well cell culture plates. 5 The cells were cultured in a 500 nM concentration. After stabilization for 24 hours, Example 1 was treated at a concentration of 500 nM, and cells treated with the same amount of DMSO were set as a control group. 24 hours after treatment, cells were collected to obtain RNA for target gene expression analysis.

[0507]

[0508] RNA was extracted from cells using TRIzol solution (Ambion). After cell lysis and digestion, chloroform was added to each sample, and the homogenate was separated into aqueous and organic phases by centrifugation.

[0509]

[0510] 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 cycle threshold (Ct) values ​​of ctgf, cyr61, and gapdh were measured for cell cDNA samples, and ctgf and cyr61 expression was normalized to gapdh.

[0511]

[0512] The expression of each gene in the experimental group treated with Example 1 was normalized to that of the control group treated with DMSO. Figure 1 illustrates the expression regulation properties of two TEAD target genes of Example 1 using real-time PCR.

Claims

1. A compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, R1 is C 6-10 Aryl; or a 5- or 6-ring heterocycle containing 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, The above R1 is unsubstituted; or halogen, C 1-4 Alkyl, C 1-4 Thioalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Thioalkoxy, C 1-4 Haloalkoxy, C 2-4 Alkenyl, C 2-4 alkynyl, C 3-6 Cycloalkyl, amino, nitro, cyano, (C 1-4 alkyl)amino, or di(C 1-4 substituted with alkyl)amino; or C 3-6 Fused with a cycloalkyl ring, R2 is C 6-10 Aryl; C 3-6 Cycloalkenyl; or a 5- or 6-ring heterocycle containing 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, The above R2 is unsubstituted; or halogen, C 1-4 Alkyl, C 1-4 Thioalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Thioalkoxy, C 1-4 Haloalkoxy, C 2-4 Alkenyl, C 2-4 alkynyl, C 3-6 Cycloalkyl, amino, nitro, cyano, (C 1-4 alkyl)amino, and di(C 1-4 substituted with 1 to 3 substituents each independently selected from the group consisting of alkyl)amino, R3 is hydrogen or halogen, R4 is -NHCO-R', -NHSO2-R', -COO-R', -CONH-R', or 1H-pyrrole-2,5-dion-1-yl, The above R' is hydrogen, C 1-4 Alkyl, C 2-4 Alkynyl, or a substituent represented by the following chemical formula 2: [Chemical Formula 2] In the above 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 1-4 Alkyl)2.

2. In paragraph 1, R1 is phenyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, pyrrolidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl, The above R1 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 Fused with a cycloalkyl ring, A compound, or a pharmaceutically acceptable salt thereof.

3. In paragraph 1, R1 is imidazolyl, imidazolyl fused with cyclopentane, pyrazolyl, or pyridinyl, wherein R1 is unsubstituted or substituted with methyl, ethyl, fluoromethyl, difluoromethyl, or trifluoromethyl; A compound, or a pharmaceutically acceptable salt thereof.

4. In paragraph 1, R2 is phenyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, pyrrolidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl, The above R2 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, A compound, or a pharmaceutically acceptable salt thereof.

5. In paragraph 1, R2 is phenyl, pyridinyl, or cyclohexenyl, wherein R2 is unsubstituted or substituted with 1 to 3 substituents each independently selected from the group consisting of fluoro, chloro, bromo, methyl, trifluoromethyl, and trifluoromethoxy; A compound, or a pharmaceutically acceptable salt thereof.

6. In paragraph 1, R3 is hydrogen, or chloro, A compound, or a pharmaceutically acceptable salt thereof.

7. In paragraph 1, R4 is -NHCO-R', -NHSO2-R', -COO-R', -CONH-R', or 1H-pyrrole-2,5-dion-1-yl, The above R' is hydrogen; C 1-4 C, which is unsubstituted or substituted with one or two substituents each independently selected from the group consisting of phenyl, fluoro, and cyano; 2-4 alkenyl; or C 2-4 alkynyl, A compound, or a pharmaceutically acceptable salt thereof.

8. In paragraph 1, 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-dion-1-yl, A compound, or a pharmaceutically acceptable salt thereof.

9. In paragraph 1, The above chemical formula 1 is represented by the following chemical formula 3, A compound, or a pharmaceutically acceptable salt thereof: [Chemical Formula 3] In the above chemical formula 3, R" are each independently hydrogen, halogen, C 1-4 Alkyl, or C 1-4 It is haloalkyl, n is an integer from 1 to 3, R4 is -NHCO-CH=CH2, or -COOH.

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

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

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