BENZAMIDE DERIVATIVES, PROCESS FOR THEIR PREPARATION, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AS ACTIVE INGREDIENTS FOR THE PREVENTION OR TREATMENT OF CANCER - Patent application

Abstract

The present invention relates to a benzamide derivative, a preparation method thereof, and a pharmaceutical composition for preventing or treating cancer, which contains the benzamide derivative as an active ingredient. The benzamide derivative provided in one embodiment of the present invention can be used for preventing or treating cancer by suppressing EGFR mutation, and when used in combination with an EGFR antagonist such as cetuximab, it shows a remarkable synergistic effect, and therefore can be effectively used as an anticancer drug.

Description

[Technical field]

[0001] The present invention relates to a benzamide derivative, a process for preparing the same, and a pharmaceutical composition containing the same as an active ingredient for preventing or treating cancer. [Background technology]

[0002] Cancer development involves various environmental factors, including chemicals, radiation, and viruses, as well as alterations in oncogenes, tumor suppressor genes, and genes related to apoptosis and DNA repair. In recent years, our understanding of the molecular mechanisms of cancer has enabled new therapeutic approaches, such as targeted anticancer therapy.

[0003] Targeted drugs are generally created to target molecules that cancer cells have characteristically in order to exert their effects. Molecular targets are genes related to signal transduction pathways, angiogenesis, matrix, cell cycle regulators, apoptosis, etc. in cancer cells. Currently, "signal transduction pathway inhibitors" including tyrosine kinase inhibitors and "angiogenesis inhibitors" are used as important molecular targeted drugs in cancer treatment.

[0004] Protein tyrosine kinases are known to play important roles in many malignant tumors. In particular, epidermal growth factor receptor (EGFR), a receptor tyrosine kinase of the erbB family, is abnormally activated in many epithelial cell tumors, including non-small cell lung cancer (NSCLC), breast cancer, glioma, squamous cell carcinoma of the head and neck, colon cancer, rectal cancer, head and neck cancer, gastric cancer, and prostate cancer. Activation of EGFR-tyrosine kinase is known to cause sustained cell proliferation, invasion into surrounding tissues, distant metastasis, and angiogenesis, and to increase cell survival.

[0005] In particular, EGFR is a member of the ErbB tyrosine kinase receptor family (EGFR, HER-2, ErbB-3, ErbB-4) and is a transmembrane tyrosine kinase having an intracellular domain including an extracellular ligand-binding domain and a tyrosine kinase domain. When a ligand binds to a receptor that forms a homodimer or heterodimer, an intracellular tyrosine kinase is activated, and the signal stimulated by EGFR activates the phosphatidylinositol 3 kinase (PI3K / ACT / mTOR, RAS / RAF / MAPK, JAK / STAT) signal transduction pathway (Non-Patent Document 1, Nat Rev Cancer 2007;7:169-81. Epidermal growth factor receptor mutations in lung cancer).

[0006] In particular, EGFR is overexpressed in more than half of non-small cell lung cancers (NSCLC), and many studies have been conducted targeting EGFR as a therapeutic target. EGFR TKIs (tyrosine kinase inhibitors) that inhibit EGFR tyrosine kinase activity have been developed, and a representative drug is gefitinib (IRESSA). TM ), erlotinib (TARCEVA TM ), lapatinib (TYKERB TM , TYVERB TM ) etc.

[0007] Meanwhile, in 2004, it was reported that EGFR activating mutations correlate with the efficacy of gefitinib therapy in non-small cell lung cancer (NSCLC). In particular, EGFR mutations are broadly classified into sensitive mutations and resistant mutations, with exon 19 deletion and L858R point mutation in exon 21 being the most important sensitive mutations, accounting for approximately 85-90%, and it is known that exon 19 mutations are more sensitive to TKIs. On the other hand, T790M point mutation in exon 20 is the most important resistant mutation, known to be found in more than 50% of acquired resistant patients.

[0008] Somatic mutations identified to date include in-frame deletions of exon 19 and insertions of exon 20, as well as point mutations that alter single nucleic acid residues in the expressed protein (e.g., L858R, G719S, G719C, G719A, L861Q).

[0009] Despite the initial clinical efficacy of gefitinib / erlotinib in patients with NSCLC harboring EGFR mutations, most patients eventually develop progressive disease during treatment with these agents. Early studies in recurrent specimens identified a secondary EGFR mutation, T790M, that renders zepithinib and erlotinib ineffective as inhibitors of EGFR kinase activity. Subsequent studies demonstrated that approximately 50% (24 / 48) of tumors from patients with acquired resistance to gefitinib or erlotinib harbor the EGFR T790M mutation. This secondary genetic modification occurs at a position similar to the "gatekeeper" residue and associated secondary resistance alleles in patients treated with kinase inhibitors (e.g., T315I of ABL in imatinib-resistant CML).

[0010] It has long been known that EGFR mutations, EGFR_del19 or EGFR_L858R, are the main cause of non-small cell lung cancer and head and neck cancer, and drugs such as Iressa and Taseba have been developed and are currently being used in clinical trials. However, when these drugs were administered to patients, acquired resistance was observed, which is caused by secondary EGFR mutations based on the structure of the drug, and it was also found that this is the main cause of actual drug resistance. After an average of 10 months of use of first-generation EGFR inhibitors, acquired resistance, the T790M mutation located in the gatekeeper of EGFR kinase, occurs, making the first-generation EGFR inhibitors ineffective. In other words, a double mutation, EGFR_del19_T790M or EGFR_L858R_T790M, occurs, and conventional treatments are ineffective.

[0011] In light of these facts, there is a growing demand for the development of second- and third-generation drugs with superior efficacy and new structures.

[0012] Over the past decade, various third-generation drug candidates effective against the EGFR T790M double mutation have been discovered and clinical research is underway, with the most cutting-edge being AZD9291 from global pharmaceutical company AstraZeneca. However, it has been reported that resistance to AZD9291 develops in about 10 months, causing the drug's efficacy to disappear, and resistance has been reported especially against the triple mutation including C797S.

[0013] Therefore, there is a need to develop inhibitors that exhibit relatively low inhibition of WT EGFR and high inhibition of specific active or resistant mutant forms of EGFR. Summary of the Invention

[0014] An object of the present invention is to provide benzamide derivatives capable of preventing or treating cancer by suppressing EGFR mutations.

[0015] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, comprising a benzamide derivative as an active ingredient.

[0016] Another object of the present invention is to provide a health food containing a benzamide derivative as an active ingredient for preventing or ameliorating cancer.

[0017] Another object of the present invention is to provide a combination preparation for preventing or treating cancer, which contains a benzamide derivative as an active ingredient.

[0018] To achieve the above object, one embodiment of the present invention provides a compound represented by formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof. [ka] In formula 1, X, Y and Z are independently carbon or nitrogen atoms; R 1is -H, -OH, halogen, unsubstituted or substituted with one or more halogens, 1-10 Alkyl, unsubstituted or substituted with one or more halogens 1-10 Alkoxy, Nitro, C 1-10 Alkyl sulfanyl, cyano, amino, C 1-10 alkylamino, or 5-6 membered heteroaryl; R 2 is replaced by C 6-10 aryl, or a substituted 5-10 membered heteroaryl; Here, the replaced C 6-10 The aryl or substituted 5-10 membered heteroaryl is independently selected from halogen, unsubstituted or substituted C 1-10 aryl or heteroaryl substituted with one or more substituents selected from the group consisting of alkyl, and unsubstituted or substituted 4-10 membered fully or partially saturated heterocycloalkyl; Here, the replaced C 1-10 Alkyl is one or two C 1-5 the alkyl is substituted with a 5-6 membered heterocycloalkyl which is substituted with a substituted amino; Substituted 4-10 membered fully or partially saturated heterocycloalkyl is -OH, halogen, unsubstituted or substituted with one or more halogens C 1-5 C substituted with alkyl, 5-6 membered heterocycloalkyl 1-5 Alkyl, unsubstituted or substituted with one or more halogens 1-5 Alkoxy, Nitro, C 1-5 Alkylsulfanyl, cyano, unsubstituted or one or two C 1-5 Alkyl-substituted amino, unsubstituted or C 1-5 5-6 membered heterocycloalkyl substituted with alkyl, C 1-5 Alkoxycarbonyl, 5-6 membered heteroaryl, C 6-10 Arylaminocarbonyl and C 1-5 Alkoxy-C 1-5 Alkoxy-C6-10 is a 4-10 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of aryl; R 3 is a halogen; R 4 is -OH, halogen or C 1-15 is alkoxy; R 5 -H, -OH, halogen, C 1-4 Alkyl or C 1-4 is alkoxy; and R 6 -H, -OH, halogen, C 1-4 Alkyl or C 1-4 It is an alkoxy.

[0019] In another aspect, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising a compound represented by formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0020] In another aspect of the present invention, the present invention provides a health functional food composition for preventing or ameliorating cancer, comprising a compound represented by formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0021] In another aspect, the present invention provides a combination preparation for preventing or ameliorating cancer, comprising a compound represented by formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof as an active ingredient. Effect of the Invention

[0022] In one embodiment of the present invention, the benzamide derivative can be used to prevent or treat cancer by suppressing EGFR mutations, and shows a remarkable synergistic effect when used in combination with an EGFR antagonist such as cetuximab, and therefore can be effectively used as an anticancer agent. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] The present invention will be described in detail below.

[0024] The embodiments of the present invention can be modified in various ways, and the scope of the present invention is not limited to the embodiments described below. It is understood by those skilled in the art that the embodiments of the present invention are shown in order to more specifically explain the present invention.

[0025] Furthermore, throughout this specification "inclusion" of an element does not exclude other elements and may include other elements unless specifically stated otherwise.

[0026] The terms "alkylene," "alkenyl," or "alkyl" include, unless otherwise specified, linear or branched saturated hydrocarbon residues. For example, "C 1-6 The term "alkyl" refers to an alkyl group having a skeleton of 1 to 6 carbon atoms. 1-6 Alkyl can be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, hexyl, and the like.

[0027] The term "heterocycloalkyl", unless otherwise specified, embraces monovalent saturated moieties consisting of one to three rings containing one, two, three or four heteroatoms selected from N, O or S.

[0028] The term "heteroaryl", unless otherwise specified, can include aromatic radicals having a single ring or two or three fused rings having one or more aromatic rings containing 1, 2, 3 or 4 ring heteroatoms selected from N, O or S.

[0029] In one embodiment of the present invention, the present invention provides a compound represented by formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof or a pharma- ceutically acceptable salt thereof.

[0030] [ka]

[0031] In formula 1, X, Y and Z are independently carbon or nitrogen atoms; R 1 is -H, -OH, halogen, unsubstituted or substituted with one or more halogens, 1-10 Alkyl, unsubstituted or substituted with one or more halogens 1-10 Alkoxy, Nitro, C 1-10 Alkyl sulfanyl, cyano, amino, C 1-10 alkylamino, or 5-6 membered heteroaryl; R 2 is replaced by C 6-10 aryl, or a substituted 5-10 membered heteroaryl; Here, the replaced C 6-10 The aryl or substituted 5-10 membered heteroaryl is independently selected from halogen, unsubstituted or substituted C 1-10 aryl or heteroaryl substituted with one or more substituents selected from the group consisting of alkyl, and unsubstituted or substituted 4-10 membered fully or partially saturated heterocycloalkyl; Here, the replaced C 1-10 Alkyl is one or two C 1-5 the alkyl is substituted with a 5-6 membered heterocycloalkyl which is substituted with a substituted amino; Substituted 4-10 membered fully or partially saturated heterocycloalkyl is -OH, halogen, unsubstituted or substituted with one or more halogens C 1-5 C substituted with alkyl, 5-6 membered heterocycloalkyl 1-5Alkyl, unsubstituted or substituted with one or more halogens 1-5 Alkoxy, Nitro, C 1-5 Alkylsulfanyl, cyano, unsubstituted or one or two C 1-5 Alkyl-substituted amino, unsubstituted or C 1-5 5-6 membered heterocycloalkyl substituted with alkyl, C 1-5 Alkoxycarbonyl, 5-6 membered heteroaryl, C 6-10 Arylaminocarbonyl and C 1-5 Alkoxy-C 1-5 Alkoxy-C 6-10 is a 4-10 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of aryl; R 3 is a halogen; R 4 is -OH, halogen or C 1-15 is alkoxy; R 5 -H, -OH, halogen, C 1-4 Alkyl or C 1-4 is alkoxy; and R 6 -H, -OH, halogen, C 1-4 Alkyl or C 1-4 It is an alkoxy.

[0032] In another aspect, X, Y and Z are independently carbon or nitrogen atoms; R 1 is -H, -OH, halogen, unsubstituted or substituted with one or more halogens, 1-5 Alkyl, unsubstituted or substituted with one or more halogens 1-5 Alkoxy, Nitro, C 1-5 Alkyl sulfanyl, cyano, amino, C 1-5 alkylamino, or 5-6 membered heteroaryl; R 2 is replaced by C 6-10 aryl, or substituted 5-6 membered heteroaryl; Here, the replaced C 6-10 The aryl or substituted 5-6 membered heteroaryl is independently selected from halogen, unsubstituted or substituted C 1-5 aryl or heteroaryl substituted with one or more substituents selected from the group consisting of alkyl, and unsubstituted or substituted 4-8 membered fully or partially saturated heterocycloalkyl containing at least one N; Here, the replaced C 1-5 Alkyl is a group consisting of two C 1-5 the alkyl is substituted with a 6-membered heterocycloalkyl which is substituted with a substituted amino; Substituted 4-8 membered fully or partially saturated heterocycloalkyl is -OH, halogen, unsubstituted or substituted with one or more halogens, 1-5 C substituted with alkyl, 5-6 membered heterocycloalkyl 1-5 Alkyl, unsubstituted or substituted with one or more halogens 1-5 Alkoxy, Nitro, C 1-5 Alkylsulfanyl, cyano, unsubstituted or one or two C 1-5 Alkyl-substituted amino, unsubstituted or C 1-5 5-6 membered heterocycloalkyl substituted with alkyl, C 1-5 Alkoxycarbonyl, 5-6 membered heteroaryl, C 6-10 Arylaminocarbonyl and C 1-5 Alkoxy-C 1-5 Alkoxy-C 6-10 is a 4-8 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of aryl; R3 is a halogen; R4 is -OH, halogen or C 1-10 is alkoxy; R5 is -H, -OH or halogen; and R6 is -H, halogen, C 1-4 Alkyl or C 1-4 It is an alkoxy.

[0033] In another aspect X, Y and Z are independently carbon or nitrogen atoms; R 1 is -H, -OH, halogen, unsubstituted or substituted with one or more halogens, 1-5 Alkyl, unsubstituted or substituted with one or more halogens 1-5 Alkoxy, Nitro, C 1-5 Alkyl sulfanyl, cyano, amino, C 1-5 alkylamino, or a 5-membered heteroaryl containing at least one N; R2 is a substituted phenyl or a substituted 6-membered heteroaryl containing at least one N; wherein the substituted phenyl or substituted 6-membered heteroaryl is independently selected from halogen, unsubstituted or substituted C 1-3 phenyl or heteroaryl substituted with one or more substituents selected from the group consisting of alkyl, and unsubstituted or substituted 4-8 membered fully or partially saturated heterocycloalkyl containing at least one N; Here, the replaced C 1-3 Alkyl is a group consisting of two C 1-3 the alkyl is substituted with a 6-membered heterocycloalkyl which is substituted with a substituted amino; Substituted 4-8 membered heterocycloalkyl is -OH, unsubstituted or substituted 5-6 membered heterocycloalkyl, 1-3 Alkyl, unsubstituted or with one or two C 1-3 Alkyl-substituted amino, unsubstituted or C 1-3 5-6 membered heterocycloalkyl substituted with alkyl, C 1-4 Alkoxycarbonyl, 5-membered heteroaryl containing at least one N, phenylaminocarbonyl and C 1-3 Alkoxy-C 1-3 is a 4-8 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of alkoxy-phenyl; R 3is a halogen; R 4 is -OH, halogen or C 1-5 is alkoxy; R 5 is -H, -OH or halogen; and R 6 -H, halogen, C 1-4 Alkyl or C 1-4 It is an alkoxy.

[0034] In another aspect, X, Y and Z are independently carbon or nitrogen atoms; R 1 is -H, -F, -Cl, -OH, -CH3, -CF3, -OCH3, -OCF3, isopropyl, tert-butyl, -SCH3, -NO2, -CN or imidazole; R2 is [ka] JPEG2024519054000004.jpg220170JPEG2024519054000005.jpg32170; R 3 is -F or -Cl; R 4 is -OH or -OCH3; R 5 is -H, -OH, -F, -Cl, straight or branched chain C 1-4 Alkyl, or straight or branched chain C 1-4 is alkoxy; and R 6 is -H, -OH, -F, -Cl, straight or branched chain C 1-4 Alkyl, or straight or branched chain C 1-4 It is an alkoxy.

[0035] Preferably, X is a carbon atom or a nitrogen atom; Y and Z are carbon atoms; R 1is -H, -F, -Cl, -OH, -CH3, -CF3, -OCH3, -OCF3, isopropyl, tert-butyl, -SCH3, -NO2, -CN or imidazole; R 2 teeth, [ka] JPEG2024519054000007.jpg223170JPEG2024519054000008.jpg31170; R 3 is -F; R 4 is -OH or -OCH3; R 5 is -H; and R 6 is -H, -F or -Cl.

[0036] Preferably, the compound represented by formula 1 may be a compound represented by formula 2 below. [ka]

[0037] In formula 2, X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently as defined in Formula 1 above.

[0038] In another aspect, X is a carbon atom or a nitrogen atom; Y and Z are carbon atoms; R 1 is -H, -F, -Cl, -OH, -CH3, -CF3, -OCH3, -OCF3, isopropyl, tert-butyl, -SCH3, -NO2, -CN or imidazole; R 2 teeth, [ka] JPEG2024519054000011.jpg229170JPEG2024519054000012.jpg32170; R 3 is -F; R 4 is -OH or -OCH3; R 5 is -H; and R 6 is -H, -F or -Cl.

[0039] Most preferably, the compound represented by formula 1 may be any one compound selected from the group consisting of the following compounds: (1) (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide; (2) (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-isopropyl[1,1'-biphenyl]-3-carboxamide; (3) (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methoxy-[1,1'-biphenyl]-3-carboxamide; (4) (R)-4'-(4-aminopiperidin-1-yl)-5-(tert-butyl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-[1,1'-biphenyl]-3-carboxamide; (5) (R)-4'-(4-aminopiperidin-1-yl)-5-fluoro-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-[1,1'-biphenyl]-3-carboxamide; (6) (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamide; (7) (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-nitro-[1,1'-biphenyl]-3-carboxamide; (8) (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-(methylthio)-[1,1'-biphenyl]-3-carboxamide; (9) (R)-4'-(4-aminopiperidin-1-yl)-5-cyano-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-[1,1'-biphenyl]-3-carboxamide; (10) (R)-4'-(4-aminopiperidin-1-yl)-5-chloro-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-[1,1'-biphenyl]-3-carboxamide; (11) (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide; (12) (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methyl)-5-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide; (13) (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-(1H-imidazol-1-yl)-[1,1'-biphenyl]-3-carboxamide; (14) (R)-2-(4-(4-aminopiperidin-1-yl)phenyl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)isonicotinamide; (15) (R)-2-(4-(4-aminopiperidin-1-yl)phenyl)-N-((5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methyl)isonicotinamide; (16) (R)-3-(2-(4-aminopiperidin-1-yl)pyrimidin-5-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (17) (R)-3-(5-(4-aminopiperidin-1-yl)pyridin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (18) (R)-3-(5-(4-aminopiperidin-1-yl)pyrazin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (19) (R)-3-(6-(4-aminopiperidin-1-yl)pyridin-3-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (20) (R)-3-(6-(4-aminopiperidin-1-yl)pyridazin-3-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (21) (R)-3-(5-(4-aminopiperidin-1-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (22) (R)-4'-(4-aminopiperidin-1-yl)-3'-fluoro-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide; (23) (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-2',5-dimethyl-[1,1'-biphenyl]-3-carboxamide; (24) (R)-4'-(4-aminopiperidin-1-yl)-2'-fluoro-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide; (25) (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3',5-dimethyl-[1,1'-biphenyl]-3-carboxamide; (26) (R)-4'-(4-aminopiperidin-1-yl)-N-((6-fluoro-1H-indol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide; (27) (R)-4'-(4-aminopiperidin-1-yl)-N-((6-chloro-1H-indol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide; (28) (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-6-methyl-[1,1'-biphenyl]-3-carboxamide; (29) (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-4-methyl-[1,1'-biphenyl]-3-carboxamide; (30) (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-2-methyl-[1,1'-biphenyl]-3-carboxamide; (31) (S)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide; (32) 4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide; (33) (R)-3-(5-(4-aminopiperidin-1-yl)-4-methylpyridin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (34) (R)-3-(2-(4-aminopiperidin-1-yl)-4-methylpyrimidin-5-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (35) tert-butyl (R)-4-(2-(3-(((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)carbamoyl)-5-methylphenyl)pyrimidin-5-yl)piperazine-1-carboxylate; (36) (R)—N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(piperazin-1-yl)pyrimidin-2-yl)benzamide; (37) (R)—N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(4-methylpiperazin-1-yl)pyrimidin-2-yl)benzamide; (38) N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-3-methyl-5-[5-(4-propyl-1-piperidyl)pyrimidin-2-yl]benzamide; (39) 3-[5-[4-(dimethylamino)-1-piperidyl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-5-methyl-benzamide; (40) N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-3-methyl-5-[5-(1-piperidyl)pyrimidin-2-yl]benzamide; (41) N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-3-methyl-5-[5-[4-(1-methyl-4-piperidyl)piperazin-1-yl]pyrimidin-2-yl]benzamide; (42) (R)-3-(5-((4-(dimethylamino)piperidin-1-yl)methyl)pyridin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl))methyl)-5-methylbenzamide; (43) (R)-3-(6-((4-(dimethylamino)piperidin-1-yl)methyl)pyridin-3-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl))methyl)-5-methylbenzamide; (44) 3-[5-[(3R)-3-aminopyrrolidin-1-yl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-5-methylbenzamide; (45) (R)-3-(5-(4-(diethylamino)piperidin-1-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (46) N-((R)-(5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidin-2-yl)benzamide; (47) (R)-3-(5-(4-(1H-pyrrol-1-yl)piperidin-1-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (48) (R)-3-(5-(4-(1H-1,2,4-triazol-1-yl)piperidin-1-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (49) (R)—N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-(5-(4-hydroxypiperidin-1-yl)pyrimidin-2-yl)-5-methylbenzamide; (50) (R)-3-(5-([1,4'-bipiperidine]-1'-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (51) (R)—N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(4-(morpholinomethyl)piperidin-1-yl)pyrimidin-2-yl)benzamide; (52) (R)—N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)pyrimidin-2-yl)benzamide; (53) 3-[5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-5-methylbenzamide; (54) (R)—N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(4-(methylamino)piperidin-1-yl)pyrimidin-2-yl)benzamide; (55) (R)-1-(2-(3-(((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)carbamoyl)-5-methylphenyl)pyrimidin-5-yl)-N-phenylpiperidine-4-carboxamide; (56) (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-(5-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)pyrimidin-2-yl)-5-methylbenzamide; (57) (R)—N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-yl)benzamide; (58) (R)—N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(piperidin-4-yl)pyrimidin-2-yl)benzamide; (59) (R)-3-(5-(3-aminoazetidin-1-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (60) 3-(5-((S)-3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-2-yl)-N-((R)-(5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (61) 3-(5-((S)-3-aminopyrrolidin-1-yl)pyrimidin-2-yl)-N-((R)-(5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; and (62) (R)-3-(5-(azetidin-3-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide.

[0040] The compound represented by formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and the salt is preferably an acid addition salt formed with a pharmaceutically acceptable free acid.In this specification, the acid addition salt can be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid; non-toxic organic acids such as aliphatic mono / dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, alkanedioates, aromatic acids, and aliphatic / aromatic sulfonic acids; or organic acids such as trifluoroacetic acid, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, and fumaric acid. Pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, cabacate, fumarate, maleate, butyne-1,4-dicarboxylate, hexane-1,6-dicarboxylate, hexane-2,2 ... Examples of suitable salts include carboxylates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, benzenesulfonates, toluenesulfonates, chlorobenzenesulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, hydroxybutyrates, glycolates, malates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0041] The acid addition salt according to the present invention can be prepared by a conventional method known to those skilled in the art. For example, the derivative represented by formula 1 is dissolved in an organic solvent such as methanol, ethanol, acetone, methylene chloride, and acetonitrile, and an organic or inorganic acid is added thereto to induce a precipitate. The precipitate is then filtered and dried to obtain a salt. Alternatively, the solvent and excess acid are distilled under reduced pressure, and the salt is dried to obtain a salt. Alternatively, the precipitate is crystallized in an organic solvent to obtain a salt.

[0042] Pharmaceutically acceptable metal salts can be prepared using bases. Alkali metal salts or alkaline earth metal salts can be obtained by the following process: dissolving the compound in excess alkali metal hydroxide solution or alkaline earth metal hydroxide solution; filtering the insoluble compound salt; evaporating the remaining solution to dryness. At this time, the metal salt is preferably prepared in a pharma-ceutically suitable form of sodium salt, potassium salt, or calcium salt. Also, the corresponding silver salt can be prepared by reacting an alkali metal salt or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0043] Furthermore, the present invention includes not only the compounds represented by formula 1, but also pharma- ceutically acceptable salts thereof, and solvates, optical isomers, or hydrates that may be produced therefrom.

[0044] The term "hydrate" refers to the compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate of the compound of formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate may contain one or more equivalents of water, preferably 1 to 5 equivalents of water. The hydrate may be prepared by crystallizing the compound of formula 1, its isomer, or a pharma- ceutical acceptable salt thereof from water or a solvent containing water.

[0045] The term "solvate" refers to a compound of the invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents include solvents that are volatile, non-toxic, and / or suitable for administration to humans.

[0046] The term "isomer" refers to a compound of the present invention or a salt thereof that has the same chemical or molecular formula but is structurally or stereochemically different. Such isomers include structural isomers such as tautomers, stereoisomers such as R-isomers or S-isomers having asymmetric carbon centers, geometric isomers (trans, cis), and optical isomers (enantiomers). All of these isomers and mixtures thereof are included within the scope of the present invention.

[0047] The compound represented by formula 1 can be prepared through the following general formula, and general formula 1 and general formula 2 corresponding to the preparation process of the compound of Example 1 are shown below.

[0048] [ka]

[0049] Scheme 1. Reagents and Conditions: (a) (S)-2-methylpropane-2-sulfinamide, titanium(IV) ethoxide, THF, rt, 17 h; (b) 1-(phenylsulfonyl)-1H-indole, n-BuLi, THF, -78 °C to rt, 3 h; (c) 5 N NaOH, MeOH, reflux, overnight; (d) 4 N HCl in dioxane, MeOH, rt, 1 h.

[0050] [ka]

[0051] Scheme 2. Reagents and Conditions: (a) methyl 3-bromo-5-methylbenzoate, 4-hydroxyphenylboronic acid, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, potassium carbonate, dioxane, water, -78 °C, 1.5 h; (b) trifluoromethanesulfonic anhydride, pyridine, dichloromethane, rt, 3 h; (c) tert-butyl piperidin-4-ylcarbamate, Ruphos Pd G1, Cs2CO3, dioxane, 110 °C, overnight; (d) NaOH, dioxane, 110 °C, overnight; (e) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydroxybenzotriazole, triethylamine, CH2Cl2, rt, overnight; (f) 1M BBr3 in CH2Cl2, 0 °C to rt, 30 min.

[0052] In another aspect, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising a compound represented by formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0053] Here, the compound can suppress EGFR (epidermal growth factor receptor) mutation and prevent or treat cancer, where the EGFR mutation is at least one selected from the group consisting of EGFR L858R / T790M and EGFR L858R / T790M / C797S.

[0054] The compound represented by formula 1 of the present invention or a pharma- ceutically acceptable salt thereof can be administered orally or parenterally, and can be used in a common form of pharmaceutical preparation. That is, the compound of the present invention or a pharma- ceutically acceptable salt thereof can be prepared for oral or parenteral administration by mixing with a commonly used diluent or excipient such as an additive, a filler, a binder, a wetting agent, a disintegrant, a surfactant, etc. Solid preparations for oral administration are tablets, pills, powders, granules, and capsules. These solid preparations are prepared by mixing one or more compounds with one or more suitable excipients such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate, talc, etc. can be used. Liquid preparations for oral administration are suspensions, solutions, emulsions, and syrups, and the above preparations can contain various excipients such as wetting agents, sweeteners, flavors, and preservatives in addition to commonly used simple diluents such as water and liquid paraffin. Preparations for parenteral administration are sterile aqueous solutions, water-insoluble excipients, suspensions and emulsions.Water-insoluble excipients and suspensions can contain, in addition to the active compound or compounds, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injection esters such as ethylolate, etc.

[0055] A pharmaceutical composition containing the compound represented by formula 1 or a pharma- ceutical acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, or intrapleural injection.

[0056] In this case, in order to prepare the compound represented by formula 1 or a pharma- ceutically acceptable salt thereof for parenteral administration, the compound represented by formula 1 or a pharma- ceutically acceptable salt thereof is mixed with a stabilizer or buffer in water to form a solution or suspension, which is then formulated into an ampoule or vial, where the composition can be sterilized and further contains a preservative, a stabilizer, a wetting powder or emulsifier, a salt for osmotic pressure adjustment and / or a buffer, and other therapeutically useful substances, and the composition can be formulated by a conventional mixing, granulation or coating method.

[0057] Examples of preparations for oral administration include tablets, pills, hard / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, and troches. These preparations may contain diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine) and lubricants (e.g., silica, talc, stearic acid salts and their magnesium or calcium salts, and / or polyethylene glycol) in addition to the active ingredient. Tablets may contain binders such as magnesium aluminum silicate, gelatinized starch, gelatin, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone, and may additionally contain disintegrants and / or absorbents such as starch, agarose, alginic acid or its sodium salt or azeotropic mixture, colorants, flavors, and sweeteners, if necessary.

[0058] The pharmaceutical compositions of the invention are administered in pharma- ceutically effective doses.

[0059] The term "pharmaceutical effective dose" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment or improvement. The level of an effective dose depends on the type and severity of the subject, age, sex, drug activity, drug sensitivity, administration time, administration route and excretion rate, treatment duration, concomitant drugs, and other factors well known in the medical field. For example, an effective dose includes 0.001 mg / kg to 100 mg / kg, 0.01 mg / kg to 10 mg / kg, and 0.1 mg / kg to 1 mg / kg. The upper limit of the dose of the pharmaceutical composition of the present invention can be selected within an appropriate range by a person skilled in the art.

[0060] In another aspect of the present invention, the present invention provides a health functional food composition for preventing or ameliorating cancer, comprising a compound represented by formula 1, its optical isomer, a solvate thereof, a hydrate thereof or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0061] The compound represented by formula 1 of the present invention can be added as it is or mixed with other food ingredients according to a conventional method. The mixing ratio of the active ingredient can be adjusted according to the purpose of use (prevention or improvement). In general, the compound of the present invention is preferably added in an amount of 0.1 to 90 parts by weight based on the total weight of the food or beverage. However, when long-term administration is required for health hygiene or for adjusting health conditions, the amount may be less than the above amount, but since the compound of the present invention has been proven to be very safe, even a large amount may be acceptable.

[0062] Furthermore, the health drink composition of the present invention may further contain various flavors or natural carbohydrates, as with other drinks. The natural carbohydrates may be any of monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; polysaccharides such as dextrin and cyclodextrin; and sugar alcohols such as xylitol, sorbitol, and erythritol. In addition, natural sweeteners (thaumatin, stevia extract, e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic sweeteners (saccharin, aspartame, etc.) may also be contained as sweeteners. The content of natural carbohydrates is preferably 1 to 20 g, more preferably 5 to 12 g, in 100 g of the composition of the present invention.

[0063] In addition to the above ingredients, the compound of the present invention represented by formula 1 can contain various nutrients, vitamins, minerals (electrolytes), flavors such as natural flavors and synthetic flavors, colorants and extenders (cheese, chocolate, etc.), pectinic acid and its salts, alginic acid and its salts, organic acids, protective colloid viscosity agents, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonates used in addition to soda, etc. Furthermore, the compound of the present invention represented by formula 1 can contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks.

[0064] In another aspect, the present invention provides a combination preparation for preventing or treating cancer, comprising a compound represented by formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0065] In this case, the combined preparation is a preparation in which at least one selected from the group consisting of the components described below is administered in combination with the compound represented by formula 1.

[0066] Furthermore, the anti-cancer treatments described herein can be applied as monotherapy or can include, in addition to the compounds of the present invention, conventional surgery, radiation therapy, chemotherapy or immunotherapy. Such chemotherapy can be performed simultaneously, sequentially or separately from the treatment with the compounds of the present invention, and can include one or more of the following categories of anti-cancer drugs: (i) For example, alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolamide, and nitrosoureas); metabolic antagonists (e.g., gemcitabine, and fluoropyrimidines such as 5-fluorouracil and tegafur, folate antagonists such as raltitrexed, methotrexate, cytosine arabinoside, and hydrourea); antitumor antibiotics (e.g., adriamycin, bleomycin, anthracycline antibiotics such as doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin C, dactinomycin, mithramycin; mitotic inhibitors (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, taxoids such as taxol and taxotere, and polo kinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, and camptothecin); (ii) Cell proliferation inhibitors, for example antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or agonists (e.g., goserelin, leuprorelin and buserelin), progesterones (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, borazole and exemestane) and 5α-reductase inhibitors such as finasteride; (iii) Invasion inhibitors [e.g., 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline [AZD0530 (saracatinib); WO 01 / 94341], N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem, 2004, 47, 6658-6661) and c-Src kinase inhibitors such as bosutinib (SKI-606), as well as metalloprotease inhibitors such as marimastat, urokinase plasminogen activator receptor inhibitors, or antibodies against heparan]; (iv) Growth factor inhibitors (e.g., the anti-erbB2 antibody trastuzumab [Herceptin TM], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [Erbitux, C225], and other growth factor antibodies and growth factor receptor antibodies, as well as antibodies based on the literature [Stern et al., Critical reviews in oncology / haematology, 2005, Vol. 54, any of the growth factor antibodies and growth factor receptor antibodies disclosed in [pp 11-29]; tyrosine kinase inhibitors such as epidermal growth factor inhibitors (e.g., N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI EGFR tyrosine kinase inhibitors such as N-(2-[2-dimethylaminoethylmethylamino]-5-{[4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxyphenyl)prop-2-enamide (osimertinib, AZD9291), erbB2 tyrosine kinase inhibitors such as lapatinib; hepatocyte growth factor inhibitors; insulin growth factor inhibitors; platelet-derived growth factor inhibitors such as imatinib and / or nilotinib (AMN107); serine / threonine kinase inhibitors (e.g., sorafenib (BAY 43-9006), tipifarnib (R115777), farnesyltransferase inhibitors such as lonafarnib (SCH66336), Ras / Raf signaling inhibitors, MEK and / or AKT kinase mediated cell signaling inhibitors, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; cyclin-dependent kinase inhibitors such as Aurora kinase inhibitors (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and CDK2 and / or CDK4 inhibitors); (v) Angiogenesis inhibitors such as those that inhibit the action of vascular endothelial growth factor [e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin)] TM ), as well as VEGF receptor tyrosine kinase inhibitors such as 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 of WO 00 / 47212), such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and compounds disclosed in WO 97 / 22596, WO 97 / 30035, WO 97 / 32856 and WO 98 / 13354, and compounds acting by other mechanisms (e.g. linomide, integrin αvβ3 inhibitors and angiostatin)]; (vi) vascular disorder agents such as combretastatin A4 and compounds disclosed in WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213; (vii) endothelin receptor antagonists, such as zibotentan (ZD4054) and atrasentan; (viii) antisense therapy, such as ISIS2503 or anti-ras antisense, directed against the targets listed above; (ix) gene therapy approaches (e.g., approaches to replace abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) approaches such as approaches using cytosine deaminase, thymidine kinase or bacterial nitroreductase, approaches to increase a patient's resistance to chemotherapy or radiation therapy such as multidrug resistance gene therapy); and (x) Immunotherapeutic approaches (e.g., in vitro and in vivo approaches to increase the immunogenicity of a patient's tumor cells, such as those using transfection of cytokines such as interleukin-2, interleukin-4 or granulocyte-macrophage colony-stimulating factor, approaches to reduce T cell anergy, approaches using transfected immune cells such as dendritic cells transfected with cytokines, approaches using tumor cell lines transfected with cytokines, approaches using anti-idiotypic antibodies, approaches to reduce the action of immune suppressive cells such as regulatory T cells, myeloid-derived suppressor cells or IDO (indoleamine 2,3-deoxygenase)-expressing dendritic cells, and approaches using cancer vaccines consisting of proteins or peptides derived from tumor-associated antigens such as NY-ESO-1, MAGE-3, WT1, or Her2 / neu).

[0067] Thus, in a further aspect of the invention there is provided a pharmaceutical product for the combined treatment of cancer comprising a compound of formula (I) as defined above and a further anti-tumour agent as defined above.

[0068] In this aspect of the invention there is provided a pharmaceutical product for the combined treatment of cancer comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined above and a further antitumor agent as defined above.

[0069] It should be understood that when the term "combination treatment" is used herein in relation to a combination therapy, it may mean simultaneous, separate or sequential administration. The meaning of "combination administration" should be interpreted in the same way as "combination treatment". In one embodiment of the present invention, "combination treatment" means simultaneous administration. In another embodiment of the present invention, "combination treatment" means separate administration. In a further embodiment of the present invention, "combination treatment" refers to sequential administration. If the administration is sequential or separate, the delay in the administration of the second component should be such that the benefit of the effect resulting from the use of the combination is not lost. Thus, in one embodiment, the sequential treatment includes administering each component of the combination within a period of 11 days. In another embodiment, the period is 10 days. In another embodiment, the period is 9 days. In another embodiment, the period is 8 days. In another embodiment, the period is 7 days. In another embodiment, the period is 6 days or less. In another embodiment, the period is 5 days or less. In another embodiment, the period is 4 days or less. In another embodiment, the period is 3 days or less. In another embodiment, the period is 2 days or less. In another embodiment, the period of time is 24 hours or less, hi another embodiment, the period of time is 12 days or less.

[0070] In another aspect of the present invention, the present invention provides a method for treating cancer, comprising administering to a subject in need thereof a pharmaceutical composition or a health functional food composition comprising the compound represented by formula 1, its optical isomer, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0071] In another aspect of the present invention, the present invention provides a compound represented by formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof, for use in the prophylaxis or treatment of cancer.

[0072] In another aspect of the present invention, the present invention provides use of a compound represented by formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of cancer.

[0073] The benzamide derivatives provided in one aspect of the present invention can be used to prevent or treat cancer by suppressing EGFR mutations, and when administered in combination with an EGFR antagonist such as cetuximab, they exhibit a significant synergistic effect on anticancer activity and can be effectively used as anticancer agents. The above is supported by the examples and experimental examples described below.

[0074] In the method or use, the detailed description of the pharmaceutical composition given above is applicable. EXAMPLES

[0075] The present invention will be described in detail below with reference to the following examples and experimental examples. However, the following examples and experimental examples are intended to illustrate the present invention only, and the contents of the present invention are not limited thereto.

[0076] [ka]

[0077] Scheme 1. Reagents and Conditions: (a) (S)-2-methylpropane-2-sulfinamide, titanium(IV) ethoxide, THF, rt, 17 h; (b) 1-(phenylsulfonyl)-1H-indole, n-BuLi, THF, -78 °C to rt, 3 h; (c) 5 N NaOH, MeOH, reflux, overnight; (d) 4 N HCl in dioxane, MeOH, rt, 1 h.

[0078] [Preparation Example 1] (S,E)-N-(5-fluoro-2-methoxybenzylidene)-2-methylpropane-2-sulfinamide [ka]

[0079] A mixture of 5-fluoro-2-methoxybenzaldehyde (26.7 g, 173 mmol) and (S)-2-methylpropane-2-sulfinamide (20.0 g, 165 mmol) was dissolved in tetrahydrofuran (4 mL) along with titanium(IV) ethoxide (75.3 g, 330 mmol). The reaction flask was sealed with a septum and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was extracted with ethyl acetate and water. The ethyl acetate layer was collected, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (Hex / EtOAc, 10:1) on silica gel to give (S,E)-N-(5-fluoro-2-methoxybenzylidene)-2-methylpropane-2-sulfinamide (40.6 g).

[0080] Yield 95%: 1 H NMR (500 MHz, chloroform-d) δ 9.03 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 8.8, 3.2 Hz, 1H), 7.19 (ddd, J = 9.1, 7.7, 3.2 Hz, 1H), 6.94 (dd, J = 9.1, 4.1 Hz, 1H), 3.90 (s, 3H), 1.29 (s, 9H); LC-MS: 274.3 [M+H + ].

[0081] [Preparation Example 2] (S)-N-((R)-(5-fluoro-2-methoxyphenyl)(1-(phenylsulfonyl)-1H-indol-2-yl)methyl)-2-methylpropane-2-sulfinamide [ka]

[0082] At -78°C, n-butyllithium was added dropwise to a solution of 1-(phenylsulfonyl)-1H-indole (56.0 g, 218 mmol) dissolved in tetrahydrofuran (200 mL). After reacting at -78°C for 1 hour, a solution of (S,E)-N-(5-fluoro-2-methoxybenzylidene)-2-methylpropane-2-sulfinamide [Preparation Example 1] (40.0 g, 155 mmol) dissolved in THF (200 mL) was added and stirred at -78°C for 2 hours. The reaction was quenched by adding saturated aqueous NH4Cl solution and extracted with ethyl acetate. The ethyl acetate layer was collected, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed by evaporation under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH2Cl2 / EtOAc, 10:1) to give (S)-N-((R)-(5-fluoro-2-methoxyphenyl)(1-(phenylsulfonyl)-1H-indol-2-yl)methyl)-2-methylpropane-2-sulfinamide [Preparation 2] as a white solid (79.0 g, 98%).

[0083] 1 H NMR (300 MHz, chloroform-d) δ 8.15 (dd, J = 8.3, 1.1 Hz, 1H), 7.76 - 7.69 (m, 2H), 7.53 - 7.47 (m, 2H), 7.42 - 7.30 (m, 3H), 6.98 (ddd, J = 8.9, 7.7, 3.0 Hz, 1H), 6.90 (dd, J = 9.0, 4.5 Hz, 1H), 6.80 (d, J = 5.8 Hz, 1H), 6.76 (d, J = 0.9 Hz, 1H), 6.72 (dd, J = 9.1, 3.0 Hz, 1H), 3.92 (s, 3H), 1.26 (s, 9H); LC-MS: 531.6 [M+H + ].

[0084] [Preparation Example 3] (S)-N-((R)-(5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methyl)-2-methylpropane-2-sulfinamide [ka]

[0085] NaOH (8N, 69.6 g, 768 mmol, 96.0 mL) dissolved in water was added to a solution of (S)-N-((R)-(5-fluoro-2-methoxyphenyl)(1-(phenylsulfonyl)-1H-indol-2-yl)methyl)-2-methylpropane-2-sulfinamide (79.0 g, 154 mmol) dissolved in methanol (700 mL), and the mixture was refluxed overnight. The mixture was stirred at 80° C. for 24 hours and then cooled at room temperature. Aqueous solution was added thereto. The mixture was concentrated under reduced pressure. The residue was washed with water and MeOH and dried to give (S)-N-((R)-(5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methyl)-2-methylpropane-2-sulfinamide [Preparation Example 3] as a white solid (50.5 g, 87%).

[0086] 1 H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 2.50 Hz, 1H), 7.62 (dd, J = 3.31, 8.94 Hz, 1H), 7.45 (dt, J = 3.38, 8.63 Hz, 1H), 7.24 (dd, J = 4.25, 9.26 Hz, 1H), 3.91 (s, 3H), 1.17 (s, 9H).

[0087] [Preparation Example 4] (R)-(5-Fluoro-2-methoxyphenyl)(1H-indol-2-yl)methanamine [ka]

[0088] At room temperature, 4 N hydrochloric acid (0.16 mL, 0.32 mmol) dissolved in dioxane was added to a solution of (S)-N-((R)-(5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methyl)-2-methylpropane-2-sulfinamide [Preparation Example 3] (51.0 g, 135 mmol) dissolved in methanol (500 mL). The mixture was concentrated under reduced pressure. The residue was solidified with diethyl ether and filtered to give (R)-(5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methanamine [Preparation Example 4] (yellow solid) in 97% yield.

[0089] 1 H NMR (300 MHz, methanol-d4) δ 7.59 (dt, J = 7.8, 1.1 Hz, 1H), 7.40 - 7.35 (m, 1H), 7.26 - 7.13 (m, 3H), 7.07 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 6.99 (dd, J = 8.9, 2.7 Hz, 1H), 6.62 (t, J = 0.9 Hz, 1H), 6.01 (s, 1H), 3.97 (s, 3H), 3.68 (s, 3H);LC-MS: 391.4 [M+H + ].

[0090] [ka]

[0091] Scheme 2. Reagents and Conditions: (a) methyl 3-bromo-5-methylbenzoate, 4-hydroxyphenylboronic acid, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, potassium carbonate, dioxane, water, -78 °C, 1.5 h; (b) trifluoromethanesulfonic anhydride, pyridine, dichloromethane, rt, 3 h; (c) tert-butyl piperidin-4-ylcarbamate, Ruphos Pd G1, Cs2CO3, dioxane, 110 °C, overnight; (d) NaOH, dioxane, 110 °C, overnight; (e) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydroxybenzotriazole, triethylamine, CH2Cl2, rt, overnight; (f) 1M BBr3 in CH2Cl2, 0 °C to rt, 30 min.

[0092] [Preparation Example 5] Methyl 4'-hydroxy-5-methyl-[1,1'-biphenyl]-3-carboxylate [ka]

[0093] 4-Hydroxyphenylboronic acid (108 mg, 0.79 mmol), methyl 3-bromo-5-methylbenzoate (150 mg, 0.65 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (48 mg, 0.066 mmol) and potassium carbonate (181 mg, 1.3 mmol) were degassed in dioxane / HO (2.5 / 0.5 mL) for 10 min. The stirred suspension was heated to 100 °C for 1.5 h, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by MPLC to give 4'-hydroxy-5-methyl-[1,1'-biphenyl]-3-carboxylate [Preparation 5] as a yellow solid (120 mg, 75%).

[0094] 1H NMR (400 MHz, chloroform-d) δ 8.07 (s, 1H), 7.82 (s, 1H), 7.57 (s, 1H), 7.52 - 7.50 (m, 2H), 6.99 - 6.96 (m, 2H), 5.94 (br s, 1H), 3.98 (s, 3H), 2.47 (s, 3H); LC-MS: 243.2 [M+H + ].

[0095] [Preparation Example 6] Methyl 5-methyl-4'-(((trifluoromethyl)sulfonyl)oxy)-[1,1'-biphenyl]-3-carboxylate [ka]

[0096] Pyridine (0.052 ml, 0.64 mmol) was added to a solution of methyl 4'-hydroxy-5-methyl-[1,1'-biphenyl]-3-carboxylate (100 mg, 0.41 mmol) and trifluoromethanesulfonic anhydride (128 mg, 0.45 mmol) in anhydrous dichloromethane at room temperature. The mixture was stirred for 3 hours. The residue was extracted with water and sodium bicarbonate and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude compound was purified by MPLC to give methyl 5-methyl-4'-(((trifluoromethyl)sulfonyl)oxy)-[1,1'-biphenyl]-3-carboxylate [Preparation 6] as a yellow solid (102 mg, 66%).

[0097] 1 H NMR (400 MHz, chloroform-d) δ 8.06 (s, 1H), 7.90 (s, 1H), 7.69 - 7.67 (m, 2H), 7.57 (s, 1H), 7.38 - 7.36 (m, 2H), 3.96 (s, 3H), 2.49 (s, 3H); LC-MS: 375.3 [M+H + ].

[0098] [Preparation Example 7] Methyl 4'-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-5-methyl-[1,1'-biphenyl]-3-carboxylate [ka]

[0099] 4-(tert-Butoxycarbonylamino)piperidine (61.1 mg, 0.31mmol), methyl 5-methyl-4'-(((trifluoromethyl)sulfonyl)oxy)-[1,1'-biphenyl]-3-carboxylate [Preparation 6] (104 mg, 0. 28 mmol), Ruphos Pd G1 (22.7 mg, 0.028 mmol) and cesium carbonate (81.4 mg, 0.025 mmol) were degassed in anhydrous 1,4-dioxane (2.5 mL) for 10 min. The stirred suspension was heated at 110°C overnight, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated to give methyl 4'-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-5-methyl-[1,1'-biphenyl]-3-carboxylate [Preparation 7] (yellow solid), which was used in the next step without further purification. (65 mg, 55%)

[0100] 1 H NMR (400 MHz, chloroform-d) δ 8.06 (s, 1H), 7.90 (s, 1H), 7.58 (s, 1H), 7.56 - 7.53 (m, 2H), 7.03 - 7.00 (m, 2H), 4.57 - 4.47 (m, 1H), 3.95 (s, 3H), 3.77 - 3.67 (m, 2H), 2.96 - 2.89 (m, 2H), 2.47 (s, 3H), 2.11 - 2.07 (m, 2H), 1.63 - 1.53 (m, 2H), 1.49 (s, 9H); LC-MS: 425.5 [M+H + ].

[0101] [Preparation Example 8] 4'-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-5-methyl-[1,1'-biphenyl]-3-carboxylic acid [ka]

[0102] To a solution of methyl 4'-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-5-methyl-[1,1'-biphenyl]-3-carboxylate (58.9 mg, 0.14 mmol) in dioxane at room temperature was added NaOH (5.6 mg, 0.14 mmol). The mixture was heated at 110° C. and stirred for 12 hours. The resulting solid was filtered and dried to give 4'-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-5-methyl-[1,1'-biphenyl]-3-carboxylic acid [Preparation Example 8] as a yellow solid (45 mg, 79%).

[0103] [Preparation Example 9] tert-Butyl (R)-(1-(3'-(((5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methyl)carbamoyl)-5'-methyl-[1,1'-biphenyl]-4-yl)piperidin-4-yl)carbamate [ka]

[0104] Triethylamine (0.017 ml, 0.12 mmol) was added to a solution of (R)-(5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methanamine [Preparation Example 4] (30 mg, 0.11 mmol), 4'-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-5-methyl-[1,1'-biphenyl]-3-carboxylic acid [Preparation Example 8] (45 mg, 0.11 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (17 mg, 0.11 mmol), and hydroxybenzotriazole (15 mg, 0.11 mmol) in CHCl at room temperature. The mixture was stirred overnight. The residue was extracted with water and sodium bicarbonate and washed with brine. The organic layer was dried over magnesium sulfate and concentrated. The crude compound was purified by MPLC to give tert-butyl (R)-(1-(3'-((5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methyl)carbamoyl)-5'-methyl-[1,1'-biphenyl]-4-yl)piperidin-4-yl)carbamate [Preparation Example 9] as a yellow solid. (48 mg, 66%)

[0105] 1 H NMR (400 MHz, chloroform-d) δ 8.87 (s, 1H), 7.79 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.54 - 7.36 (m, 5H), 7.34 (d, J = 8.0 Hz, 1H), 7.20 - 6.99 (m, 7H), 6.72 (d, J = 8.0 Hz, 1H), 6.06 (s, 1H), 4.50 (m, 1H), 3.90 (s, 3H), 3.72 - 3.66 (m, 2H), 2.95 - 2.89 (m, 2H), 2.47 (s, 3H), 2.11 - 2.08 (m, 2H), 1.49 (s, 9H); LC-MS: 663.8 [M+H + ].

[0106] [Example 1] (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide [ka]

[0107] 1 M boron tribromide dissolved in dichloromethane (0.20 ml) was slowly added to tert-butyl (R)-(1-(3'-(((5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methyl)carbamoyl)-5'-methyl-[1,1'-biphenyl]-4-yl)piperidin-4-yl)carbamate [Preparation Example 9] (45 mg, 0.068 mmol) at 0°C. The reaction mixture was stirred at room temperature overnight and quenched with sodium bicarbonate at 0°C. Tetrahydrofuran was added thereto along with brine. The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by PTLC to obtain (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide [Example 1] (11 mg, 30%) as a white solid.

[0108] 1H NMR (400 MHz, DMSO-d6) δ 11.12 (br s, 1H), 9.27 (br d, J=8.38 Hz, 1H), 7.97 (s, 1H), 7.66 (s, 1H), 7.55-7.62 (m, 3H), 7.43 (d, J=7.88 Hz, 1H), 7.33 (d, J=8.00 Hz, 1H), 7.21 (dd, J=3.13, 9.76 Hz, 1H), 6.90-7.06 (m, 5H), 6.87-6.87 (m, 1H), 6.78-6.88 (m, 1H), 5.99 (s, 1H), 3.67-3.73 (m, LC-MS: 549.6 [M+H + ].

[0109] [Example 2] (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-isopropyl[1,1'-biphenyl]-3-carboxamide [ka]

[0110] (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-isopropyl[1,1'-biphenyl]-3-carboxamide [Example 2] (34%) was prepared in a similar manner to that described in [Example 1]; LC-MS: 577.7 [M+H + ].

[0111] [Example 3] (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methoxy-[1,1'-biphenyl]-3-carboxamide [ka]

[0112] (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methoxy-[1,1'-biphenyl]-3-carboxamide [Example 3] (53%) was prepared in a manner similar to that described in [Example 1].

[0113] 1 H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.28 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.0 Hz, 1H), 7.36-7.31 (m, 2H), 7.24 (s, 1H), 7.18-6.99 (m, 6H), 6.96 -6.92 (m, 1H), 6.85 (d, J = 8.4 Hz, 1H), 5.92 (s, 1H), 3.80 (s, 3H), 3.72-3.70 (m, 2H), 2.80-2.74 (m, 3H), 1.81-1.78 (m, 2H), 1.38-1.30 (m, 2H); LC-MS: 565.6 [M+H + ].

[0114] [Example 4] (R)-4'-(4-aminopiperidin-1-yl)-5-(tert-butyl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-[1,1'-biphenyl]-3-carboxamide [ka]

[0115] (R)-4'-(4-aminopiperidin-1-yl)-5-(tert-butyl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-[1,1'-biphenyl]-3-carboxamide [Example 4] (16%) was prepared in a similar manner to that described in [Example 1]; LC-MS: 591.7 [M+H + ].

[0116] [Example 5] (R)-4'-(4-aminopiperidin-1-yl)-5-fluoro-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-[1,1'-biphenyl]-3-carboxamide [ka]

[0117] (R)-4'-(4-aminopiperidin-1-yl)-5-fluoro-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-[1,1'-biphenyl]-3-carboxamide [Example 5] (22%) was prepared in a manner similar to that described in [Example 1].

[0118] 1 H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.41 (d, J = 8.0 Hz, 1H), 8.07 (s, 1H), 7.66-7.60 (m, 5H), 7.43 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 3.2, 9.6 Hz, 1H), 7.06-6.92 (m, 6H), 6.88-6.81 (m, 3H), 5.97 (s, 1H), 3.77-3.74 (m, 2H), 2.83-2.77 (m, 3H), 1.82-1.79 (m, 2H), 1.36-1.30 (m, 2H);LC-MS: 553.6 [M+H + ].

[0119] [Example 6] 4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamide [ka]

[0120] 4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamide [Example 6] (2%) was prepared in a manner similar to that described in [Example 1].

[0121] 1 H NMR (400 MHz, DMSO-d6) δ 11.07-11.21 (m, 1H), 9.51-9.62 (m, 1H), 8.33-8.45 (m, 1H), 8.10-8.15 (m, 1H), 8.00-8.06 (m, 1H), 7.64-7.70 (m, 2H), 7.40-7.44 (m, 1H), 7.30-7.34 (m, 2H), 7.12-7.16 (m, 1H), 7.04-7.08 (m, 1H), 7.05 (s, 2H), 6.94-6.97 (m, 1H), 6.83-6.88 (m, 1H), 6.78-6.82 (m, 1H), 6.62-6.69 (m, 1H), 5.96-6.00 (m, 1H), 5.29-5.32 (m, 2H), 1.99-2.04 (m, 1H), 1.93-1.98 (m, 2H), 1.82-1.91 (m, 2H), 1.42-1.46 (m, 4H), 0.83 (s, 2H); LC-MS: 603.6 [M+H + ].

[0122] [Example 7] 4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-nitro-[1,1'-biphenyl]-3-carboxamide [ka]

[0123] 4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-nitro-[1,1'-biphenyl]-3-carboxamide [Example 7] (3%) was prepared in a manner similar to that described in [Example 1].

[0124] 1 H NMR (400 MHz, DMSO-d6) δ 11.08-11.25 (m, 1H), 9.60-9.75 (m, 1H), 8.58-8.65 (m, 2H), 8.48-8.56 (m, 1H), 7.70-7.75 (m, 1H), 7.73 (d, J = 9.01 Hz, 1H), 7.41-7.46 (m, 1H), 7.30-7.37 (m, 1H), 7.15-7.22 (m, 1H), 6.92-7.10 (m, 5H), 6.82-6.90 (m, 2H), 5.91-6.01 (m, 1H), 3.75-3.82 (m, 2H), 2.76-2.91 (m, 3H), 2.41-2.47 (m, 1H), 1.75-1.88 (m, 2H), 1.32-1.43 (m, 2H), 1.24 (s, 2H); LC-MS: 580.6 [M+H + ].

[0125] [Example 8] 4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-(methylthio)-[1,1'-biphenyl]-3-carboxamide [ka]

[0126] 4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-(methylthio)-[1,1'-biphenyl]-3-carboxamide [Example 8] (2%) was prepared in a manner similar to that described in [Example 1].

[0127] 1 H NMR (400 MHz, DMSO-d6) δ 11.04-11.16 (m, 1H), 9.22-9.39 (m, 1H), 7.92 (t, J = 1.44 Hz, 1H), 7.69 (d, J = 1.50 Hz, 1H), 7.56-7.64 (m, 3H), 7.42 (d, J = 7.88 Hz, 1H), 7.33 (dd, J = 0.69, 8.07 Hz, 1H), 7.19 (dd, J = 3.13, 9.76 Hz, 1H), 7.00-7.08 (m, 3H), 6.91-6.99 (m, 2H), 6.79-6.88 (m, 2H), 5.96 (s, 1H), 3.74 (br d, J = 12.76 Hz, 2H), 3.70-3.71 (m, 1H), 2.75-2.86 (m, 3H), 2.75-2.76 (m, 1H), 2.57 (s, 3H), 2.44 (s, 1H), 1.74-1.86 (m, 2H), 1.33-1.40 (m, 2H), 1.24 (s, 2H);LC-MS: 581.7 [M+H + ].

[0128] [Example 9] 4'-(4-aminopiperidin-1-yl)-5-cyano-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-[1,1'-biphenyl]-3-carboxamide [ka]

[0129] 4'-(4-aminopiperidin-1-yl)-5-cyano-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-[1,1'-biphenyl]-3-carboxamide [Example 9] (2%) was prepared in a manner similar to that described in [Example 1].

[0130] 1 H NMR (400 MHz, DMSO-d6) δ 11.04-11.24 (m, 1H), 9.39-9.61 (m, 1H), 8.43-8.46 (m, 1H), 8.21-8.30 (m, 2H), 7.65-7.73 (m, 2H), 7.40-7.46 (m, 1H), 7.29-7.36 (m, 1H), 7.14-7.21 (m, 1H), 6.92-7.09 (m, 5H), 6.84-6.89 (m, 1H), 6.81 (d, J = 8.25 Hz, 1H), 5.98 (s, 1H), 3.80-3.85 (m, 2H), 2.96-3.07 (m, 1H), 2.79-2.89 (m, 2H), 1.96-2.03 (m, 1H), 1.81-1.89 (m, 2H), 1.41-1.51 (m, 2H), 0.81-0.90 (m, 2H); LC-MS: 660.6 [M+H + ].

[0131] [Example 10] (R)-4'-(4-aminopiperidin-1-yl)-5-chloro-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-[1,1'-biphenyl]-3-carboxamide [ka]

[0132] (R)-4'-(4-aminopiperidin-1-yl)-5-chloro-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-[1,1'-biphenyl]-3-carboxamide [Example 10] (15%) was prepared in a manner similar to that described in [Example 1].

[0133] 1 H NMR (400 MHz, DMSO-d6) δ 11.16 (br s, 1H), 9.46 (br d, J = 8.00 Hz, 1H), 8.13 (t, J = 1.50 Hz, 1H), 7.81-7.86 (m, 2H), 7.63 (d, J = 9.01 Hz, 2H), 7.40-7.47 (m, 1H), 7.33 (t, J = 1.00 Hz, 1H), 7.18 (dd, J = 3.19, 9.69 Hz, 1H), 7.00-7.06 (m, 3H), 6.92-6.99 (m, 2H), 6.83-6.88 (m, 1H), 6.80 (d, J = 1.00 Hz, 1H), 5.97 (s, 1H), 3.73 (br d, J = 12.76 Hz, 2H), 2.70-2.83 (m, 3H), 1.77 (br dd, J = 2.94, 12.57 Hz, 2H), 1.24-1.36 (m, 2H); LC-MS: 570.0 [M+H + ].

[0134] [Example 11] (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide [ka]

[0135] (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide [Example 11] (8%) was prepared in a manner similar to that described in [Example 1].

[0136] 1H NMR (400 MHz, DMSO-d6) δ 11.18 (br s, 1H), 9.53 (br d, J = 8.00 Hz, 1H), 8.26 (t, J = 1.00 Hz, 1H), 7.74 (d, J = 1.00 Hz, 2H), 7.66 (d, J = 8.88 Hz, 2H), 7.43 (d, J = 7.88 Hz, 1H), 7.32 (t, J = 7.74 Hz, 1H), 7.18 (dd, J = 3.19, 9.69 Hz, 1H), 7.00-7.07 (m, 3H), 6.92-6.99 (m, 2H), 6.80-6.89 (m, LC-MS: 619.6 [M+H + ].

[0137] [Example 12] (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methyl)-5-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide [ka]

[0138] After preparing the intermediate in a manner similar to that described in [Example 1], (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methyl)-5-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide [Example 12] (8%) was obtained as a by-product of [Example 11].

[0139] 1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.58 (d, J = 8.26 Hz, 1H), 8.26 (t, J = 1.44 Hz, 1H), 7.75 (s, 2H), 7.66 (d, J= 9.01 Hz, 2H), 7.43 (d, J = 7.75 Hz, 1H), 7.28-7.34 (m, 2H), 7.17 (q, J = 1.00 Hz, 1H), 7.08-7.12 (m, 1H), 7.02-7.08 (m, 3H), 6.92-6.97 (m, 1H), 6.86 (d, J = 8.13 Hz, 1H), 5.90-5.92 (m, 1H), 3.80 (s, 3H), 3.70-3.76 (m, J = 12.76 Hz, 2H), 2.75-2.84 (m, 3H), 1.74-1.81 (m, 2H), 1.27-1.35 (m, 2H); LC-MS: 633.6 [M+H + ].

[0140] [Example 13] (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-(1H-imidazol-1-yl)-[1,1'-biphenyl]-3-carboxamide [ka]

[0141] (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-(1H-imidazol-1-yl)-[1,1'-biphenyl]-3-carboxamide [Example 13] (44%) was prepared in a manner similar to that described in [Example 1].

[0142] 1H NMR (400 MHz, DMSO-d6) δ 11.17 (br s, 1H), 9.44 (br d, J = 7.38 Hz, 1H), 8.42 (t, J = 1.00 Hz, 1H), 8.14 (s, 1H), 8.02 (t, J = 1.38 Hz, 1H), 8.00 (t, J = 1.63 Hz, 1H), 7.91 (t, J=1.25 Hz, 1H), 7.72 (d, J = 8.88 Hz, 2H), 7.43 (d, J = 7.75 Hz, 1H), 7.33 (t, J = 1.00 Hz, 1H), 7.18 (dd, J = 3.13, 9.63 Hz, 1H), 7.14 (t, J = 1.00 Hz, 1H), 7.02-7.07 (m, 3H), 6.92-7.02 (m, 2H), 6.81-6.89 (m, 2H), 6.00 (s, 1H), 3.71-3.77 (m, 2H), 2.69-2.88 (m, 3H), 1.74-1.82 (m, 2H), 1.25-1.39 (m, 2H); LC-MS: 601.6 [M+H + ].

[0143] [Example 14] (R)-2-(4-(4-aminopiperidin-1-yl)phenyl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)isonicotinamide [ka]

[0144] (R)-2-(4-(4-aminopiperidin-1-yl)phenyl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)isonicotinamide [Example 14] (12%) was prepared in a manner similar to that described in [Example 1].

[0145] 1H NMR (400 MHz, DMSO-d6) δ 11.19 (br s, 1H), 9.60 (br d, J = 7.75 Hz, 1H), 8.71 (d, J = 5.00 Hz, 1H), 8.30 (s, 1H), 8.01 (d, J = 9.00 Hz, 2H), 7.65 (dd, J = 1.50, 5.13 Hz, 1H), 7.44 (d, J = 7.75 Hz, 1H), 7.38 (br d, J = 4.75 Hz, 1H), 7.30-7.36 (m, 1H), 7.19 (dd, J = 3.13, 9.63 Hz, 1H), 7.00-7.07 (m, 4H), 6.92-7.00 (m, 2H), 6.80-6.89 (m, 2H), 5.99 (s, 1H), 3.76 (br d, J = 12.76 Hz, 2H), 2.71-2.86 (m, 3H), 1.78 (br d, J = 10.26 Hz, 2H), 1.26-1.37 (m, 2H); LC-MS: 536.6 [M+H + ].

[0146] [Example 15] (R)-2-(4-(4-aminopiperidin-1-yl)phenyl)-N-((5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methyl)isonicotinamide [ka]

[0147] (R)-2-(4-(4-aminopiperidin-1-yl)phenyl)-N-((5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methyl)isonicotinamide [Example 15] (16%) was prepared in a manner similar to that described in [Example 1].

[0148] 1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.64 (d, J = 8.26 Hz, 1H), 8.71 (d, J = 5.12 Hz, 1H), 8.30 (s, 1H), 8.01 (d, J = 9.01 Hz, 2H), 7.62-7.68 (m, 1H), 7.43 (d, J = 7.88 Hz, 1H), 7.28-7.36 (m, 2H), 7.14-7.20 (m, 1H), 7.02-7.12 (m, 4H), 6.93-6.98 (m, 1H), 6.86 (d, J = 8.13 Hz, 1H), 5.92-5.95 (m, 1H), 3.81 (s, 3H), 3.76 (br d, J = 12.88 Hz, 2H), 2.70-2.86 (m, 3H), 1.74-1.82 (m, 2H), 1.27-1.36 (m, 2H); LC-MS: 550.6 [M+H + ].

[0149] [Example 16] (R)-3-(2-(4-aminopiperidin-1-yl)pyrimidin-5-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [ka]

[0150] (R)-3-(2-(4-aminopiperidin-1-yl)pyrimidin-5-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [Example 16] (31%) was prepared in a manner similar to that described in [Example 1].

[0151] 1H NMR (400 MHz, DMSO-d6) δ 11.13 (br s, 1H), 9.21 (br d, J = 8.50 Hz, 1H), 8.72-8.79 (m, 2H), 8.01 (s, 1H), 7.72 (s, 1H), 7.64 (s, 1H), 7.43 (d, J = 7.75 Hz, 1H), 7.33 (dd, J = 0.75, 8.00 Hz, 1H), 7.20 (dd, J = 3.19, 9.69 Hz, 1H), 7.03 (dt, J = 1.25, 7.57 Hz, 1H), 6.91-7.01 (m, 2H), 6.85 (dd, J = 4.88, 8.88 Hz, 1H), 6.81 (d, J = 8.13 Hz, 1H), 5.99 (s, 1H), 4.50-4.61 (m, 2H), 3.01-3.10 (m, 2H), 2.81-2.91 (m, 1H), 2.42 (s, 3H), 1.74-1.81 (m, 2H), 1.12-1.22 (m, 2H); LC-MS: 550.6 [M+H + ].

[0152] [Example 17] (R)-3-(5-(4-aminopiperidin-1-yl)pyridin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [ka]

[0153] (R)-3-(5-(4-aminopiperidin-1-yl)pyridin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [Example 17] (16%) was prepared in a manner similar to that described in [Example 1].

[0154] 1H NMR (400 MHz, DMSO-d6) δ 11.13 (br s, 1H), 9.27 (br d, J = 8.38 Hz, 1H), 8.38 (d, J = 2.75 Hz, 1H), 8.32 (s, 1H), 8.30 (br s, 1H), 7.99 (s, 1H), 7.84 (d, J = 8.88 Hz, 1H), 7.71 (s, 1H), 7.39-7.44 (m, 2H), 7.33 (dd, J = 0.69, 8.07 Hz, 1H), 7.23 (dd, J = 3.25, 9.76 Hz, 1H), 7.04 (dt, J = 1.19, 7.60 Hz, 1H), 6.91-7.00 (m, 2H), 6.80-6.87 (m, 2H), 6.00 (s, 1H), 3.76 (br d, J = 12.63 Hz, 2H), 2.80-2.87 (m, 2H), 2.71-2.79 (m, 1H), 2.43 (s, 3H), 1.76-1.83 (m, 2H), 1.30-1.38 (m, 2H); LC-MS: 550.6 [M+H + ].

[0155] [Example 18] (R)-3-(5-(4-aminopiperidin-1-yl)pyrazin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [ka]

[0156] (R)-3-(5-(4-aminopiperidin-1-yl)pyrazin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [Example 18] (46%) was prepared in a manner similar to that described in [Example 1].

[0157] 1H NMR (400 MHz, DMSO-d6) δ 11.12 (br s, 1H), 9.24 (br d, J = 8.38 Hz, 1H), 8.70-8.75 (m, 1H), 8.41 (t, J = 1.00 Hz, 1H), 8.27-8.34 (m, 1H), 7.92-7.97 (m, 1H), 7.73 (s, 1H), 7.43 (d, J = 7.75 Hz, 1H), 7.33 (t, J = 8.13 Hz, 1H), 7.23 (dd, J = 3.25, 9.76 Hz, 1H), 7.04 (dt, J = 1.25, 7.57 Hz, 1H), 6.91-7.00 (m, 2H), 6.85 (dd, J = 4.82, 8.82 Hz, 1H), 6.81 (d, J = 8.38 Hz, 1H), 6.00 (s, 1H), 4.20-4.35 (m, 2H), 2.95-3.09 (m, 2H), 2.79-2.88 (m, 1H), 2.43 (s, 3H), 1.62-1.85 (m, 2H), 1.17-1.33 (m, 2H); LC-MS: 551.6 [M+H + ].

[0158] [Example 19] (R)-3-(6-(4-aminopiperidin-1-yl)pyridin-3-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [ka]

[0159] (R)-3-(6-(4-aminopiperidin-1-yl)pyridin-3-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [Example 19] (83%) was prepared in a manner similar to that described in [Example 1].

[0160] 1H NMR (400 MHz, DMSO-d6) δ 11.14 (br s, 1H), 9.25 (br s, 1H), 8.50 (d, J = 2.50 Hz, 1H), 7.98 (s, 1H), 7.88 (dd, J = 2.56, 8.94 Hz, 1H), 7.68 (s, 1H), 7.61 (s, 1H), 7.42 (d, J = 7.75 Hz, 1H), 7.33 (t, J = 8.00 Hz, 1H), 7.20 (dd, J = 3.06, 9.69 Hz, 1H), 7.00-7.06 (m, 1H), 6.90-7.00 (m, 3H), 6.78-6.87 (m, 2H), 5.99 (s, 1H), 4.23 (br d, J = 12.76 Hz, 2H), 2.88-2.98 (m, 2H), 2.75-2.85 (m, 1H), 2.41 (s, 3H), 1.75 (br d, J = 12.38 Hz, 2H), 1.15-1.24 (m, 2H); LC-MS: 550.6 [M+H + ].

[0161] [Example 20] (R)-3-(6-(4-aminopiperidin-1-yl)pyridazin-3-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [ka]

[0162] (R)-3-(6-(4-aminopiperidin-1-yl)pyridazin-3-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [Example 20] (72%) was prepared in a manner similar to that described in [Example 1].

[0163] 1H NMR (400 MHz, DMSO-d6) δ ppm 11.08 - 11.21 (m, 1 H),, 9.25 - 9.45 (m, 1 H) 8.00 - 8.11 (m, 1 H), 8.37 (s, 1 H), 7.96 (d, J = 9.76 Hz, 1H), 7.80 (s, 1 H), 7.30 - 7.45 (m, 3 H), 7.18 - 7.26 (m, 1 H), 6.95 (br d, J = 6.88 Hz, 3 H), 6.83 (s, 2 H), 6.00 (s, 1 H), 5.97 - 5.97 (m, 1 H), 4.24 - 4.40 (m, 2 H), 3.00 - 3.13 (m, 2 H),, 2.80 - 2.89 (m, 1 H), 2.42 - 2.46 (m, 3 H), 1.74 - 1.84 (m, 2 H), 1.20 - 1.29 (m, 2 H); LC-MS: 551.6 [M+H + ].

[0164] [Example 21] (R)-3-(5-(4-aminopiperidin-1-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [ka]

[0165] (R)-3-(5-(4-aminopiperidin-1-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [Example 21] (24%) was prepared in a manner similar to that described in [Example 1].

[0166] 1H NMR (400 MHz, DMSO-d6) δ 11.11 (br s, 1H), 9.29 (br d, J = 8.63 Hz, 1H), 8.57-8.61 (m, 3H), 8.24 (s, 1H), 7.80 (s, 1H), 7.43 (d, J = 7.88 Hz, 1H), 7.33 (d, J = 7.96 Hz, 1H), 7.25 (dd, J = 3.19, 9.82 Hz, 1H), 7.04 (dt, J = 1.25, 7.57 Hz, 1H), 6.92-7.00 (m, 2H), 6.79-6.87 (m, 2H), 6.00 (s, 1H), 3.82 (brd, J = 13.01 Hz, 2H), 2.86-2.92 (m, 2H), 2.75-2.81 (m, 1H), 2.44 (s, 3H), 1.76-1.85 (m, 2H), 1.28-1.36 (m, 2H); LC-MS: 551.6 [M+H + ].

[0167] [Example 22] (R)-4'-(4-aminopiperidin-1-yl)-3'-fluoro-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide [ka]

[0168] (R)-4'-(4-aminopiperidin-1-yl)-3'-fluoro-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide [Example 22] (59%) was prepared in a manner similar to that described in [Example 1].

[0169] 1H NMR (400 MHz, DMSO-d6) δ 11.13 (br s, 1H), 9.27 (br d, J = 8.50 Hz, 1H), 8.00 (s, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.47-7.58 (m, 2H), 7.43 (d, J = 7.75 Hz, 1H), 7.32 (t, J=7.72 Hz, 1H), 7.19 (dd, J = 3.13, 9.63 Hz, 1H), 7.11 (t, J = 8.94 Hz, 1H), 7.04 (dt, J = 1.13, 7.57 Hz, 1H), 6.91-7.01 (m, 2H), 6.79-6.89 (m, 2H), 5.98 (s, 1H), 3.37-3.41 (m, 2H), 2.79-2.90 (m, 1H), 2.69-2.76 (m, 2H), 2.42 (s, 3H), 1.77-1.84 (m, 2H), 1.34-1.49 (m, 2H); LC-MS: 567.6 [M+H + ].

[0170] [Example 23] (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-2',5-dimethyl-[1,1'-biphenyl]-3-carboxamide [ka]

[0171] (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-2',5-dimethyl-[1,1'-biphenyl]-3-carboxamide [Example 23] (56%) was prepared in a manner similar to that described in [Example 1].

[0172] 1H NMR (400 MHz, DMSO-d6) δ 11.09 (br s, 1H), 9.18 (br d, J = 8.50 Hz, 1H), 7.71 (s, 1H), 7.68 (s, 1H), 7.41 (d, J = 7.63 Hz, 1H), 7.31 (dd, J = 0.75, 8.13 Hz, 1H), 7.28 (s, 1H), 7.20 (dd, J = 3.25, 9.76 Hz, 1H), 7.07 (d, J = 8.38 Hz, 1H), 7.02 (dt, J = 1.19, 7.54 Hz, 1H), 6.91-6.99 (m, 2H), 6.78-6.87 (m, 4H), 5.97 (s, 1H), 3.66 (br d, J = 12.76 Hz, 2H), 2.72-2.77 (m, 2H), 2.67-2.71 (m, 1H), 2.40 (s, 3H), 2.20 (s, 3H), 1.72-1.80 (m, 2H), 1.26-1.36 (m, 1H); LC-MS: 563.6 [M+H + ].

[0173] [Example 24] (R)-4'-(4-aminopiperidin-1-yl)-2'-fluoro-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide [ka]

[0174] (R)-4'-(4-aminopiperidin-1-yl)-2'-fluoro-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide [Example 24] (55%) was prepared in a manner similar to that described in [Example 1].

[0175] 1H NMR (400 MHz, DMSO-d6) δ 11.11 (br s, 1H), 9.22 (br d, J = 8.00 Hz, 1H), 7.85 (s, 1H), 7.71 (s, 1H), 7.47 (s, 1H), 7.37-7.44 (m, 2H), 7.32 (t, J = 8.01 Hz, 1H), 7.20 (dd, J = 3.19, 9.69 Hz, 1H), 7.03 (dt, J = 1.13, 7.57 Hz, 1H), 6.91-7.00 (m, 2H), 6.78-6.87 (m, 4H), 5.98 (s, 1H), 3.73 (br d, LC-MS: 567.6 [M+H + ].

[0176] [Example 25] (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3',5-dimethyl-[1,1'-biphenyl]-3-carboxamide [ka]

[0177] (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3',5-dimethyl-[1,1'-biphenyl]-3-carboxamide [Example 25] (50%) was prepared in a manner similar to that described in [Example 1].

[0178] 1H NMR (400 MHz, DMSO-d6) δ 11.12 (br s, 1H), 9.25 (br d, J = 8.13 Hz, 1H), 7.96 (s, 1H), 7.70 (s, 1H), 7.60 (s, 1H), 7.40-7.53 (m, 3H), 7.32 (t, J = 7.73 Hz, 1H), 7.21 (dd, J = 3.19, 9.69 Hz, 1H), 7.09 (d, J = 8.25 Hz, 1H), 7.03 (dt, J = 1.13, 7.57 Hz, 1H), 6.91-7.00 (m, 2H), 6.79-6.88 (m, 2H), 5.98 (s, 1H), 3.05 (br d, J = 12.13 Hz, 2H), 2.59-2.69 (m, 3H), 2.42 (s, 3H), 2.30 (s, 3H), 1.77-1.84 (m, 2H), 1.36-1.48 (m, 2H); LC-MS: 563.6 [M+H + ].

[0179] [Example 26] (R)-4'-(4-aminopiperidin-1-yl)-N-((6-fluoro-1H-indol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide [ka]

[0180] (R)-4'-(4-aminopiperidin-1-yl)-N-((6-fluoro-1H-indol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide [Example 26] (47%) was prepared in a manner similar to that described in [Example 1].

[0181] 1H NMR (400 MHz, DMSO-d6) δ 11.21 (br s, 1H), 9.27 (br d, J = 8.38 Hz, 1H), 7.96 (s, 1H), 7.65 (s, 1H), 7.56-7.60 (m, 3H), 7.42 (dd, J = 5.50, 8.63 Hz, 1H), 7.22 (dd, J = 3.13, 9.76 Hz, 1H), 7.08 (dd, J = 2.31, 10.07 Hz, 1H), 7.01 (d, J = 9.01 Hz, 2H), 6.93-6.98 (m, 1H), 6.77-6.88 (m, 3H), 5.98 LC-MS: 567.6 [M+H + ].

[0182] [Example 27] (R)-4'-(4-aminopiperidin-1-yl)-N-((6-chloro-1H-indol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide [ka]

[0183] (R)-4'-(4-aminopiperidin-1-yl)-N-((6-chloro-1H-indol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide [Example 27] (45%) was prepared in a manner similar to that described in [Example 1].

[0184] 1H NMR (400 MHz, DMSO-d6) δ 11.31 (br s, 1H), 9.29 (br d, J = 8.63 Hz, 1H), 7.96 (s, 1H), 7.66 (s, 1H), 7.59 (br d, J = 8.50 Hz, 3H), 7.44 (d, J = 8.38 Hz, 1H), 7.32-7.37 (m, 1H), 7.22 (br dd, J = 3.13, 9.76 Hz, 1H), 6.92-7.07 (m, 5H), 6.78-6.92 (m, 2H), 6.01 (s, 1H), 3.78-3.80 (m, 2H), 2.78-2.81 (m, 2H), 2.41 (s, 3H), 1.85-1.91 (m, 2H), 1.44-1.51 (m, 2H); LC-MS: 584.0 [M+H + ].

[0185] [Example 28] (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-6-methyl-[1,1'-biphenyl]-3-carboxamide [ka]

[0186] (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-6-methyl-[1,1'-biphenyl]-3-carboxamide [Example 28] (3%) was prepared by a method similar to that described in [Example 1].

[0187] 1H NMR (400 MHz, DMSO-d6) δ 10.50-11.24 (m, 1H), 8.93-9.33 (m, 1H), 7.42 (d, J = 7.75 Hz, 1H), 7.24-7.35 (m, 3H), 7.19-7.24 (m, 1H), 7.09-7.16 (m, 3H), 7.00-7.06 (m, 1H), 6.91-7.00 (m, 4H), 6.78-6.86 (m, 1H), 6.68-6.76 (m, 1H), 5.96-6.14 (m, 1H), 3.93-4.08 (m, 2H), 3.40 (s, 1H), 2.62-2.77 (m, 3H), 2.15 (s, 3H), 1.72-1.86 (m, 2H), 1.25-1.43 (m, 2H); LC-MS: 549.6 [M+H + ].

[0188] [Example 29] (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-4-methyl-[1,1'-biphenyl]-3-carboxamide [ka]

[0189] (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-4-methyl-[1,1'-biphenyl]-3-carboxamide [Example 29] (4%) was prepared by a method similar to that described in [Example 1].

[0190] 1H NMR (400 MHz, DMSO-d6) δ 10.77-11.21 (m, 1H), 9.07-9.28 (m, 1H), 7.61 (d, J=1.88 Hz, 1H), 7.51 (d, J=8.75 Hz, 3H), 7.39-7.45 (m, 1H), 7.32-7.37 (m, 1H), 7.27 (s, 1H), 7.10-7.18 (m, 1H), 7.04 (s, 1H), 7.00 (d, J=9.01 Hz, 2H), 6.95 (br d, J=8.00 Hz, 2H), 6.79-6.88 (m, 1H), 6.67-6.77 (m, 1H), 6.03 (s, 1H), 3.87-4.06 (m, 2H), 3.38-3.41 (m, 1H), 2.65-2.75 (m, 3H), 2.30 (s, 3H), 1.69-1.85 (m, 2H), 1.22-1.39 (m, 2H); LC-MS: 549.6 [M+H + ].

[0191] [Example 30] (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-2-methyl-[1,1'-biphenyl]-3-carboxamide [ka]

[0192] (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-2-methyl-[1,1'-biphenyl]-3-carboxamide [Example 30] (9%) was prepared by a method similar to that described in [Example 1].

[0193] 1H NMR (400 MHz, DMSO-d6) δ 10.83-11.27 (m, 1H), 9.04-9.32 (m, 1H), 7.76-7.83 (m, 2H), 7.29-7.43 (m, 3H), 7.23 (d, J = 8.63 Hz, 3H), 7.01 (s, 5H), 6.76-6.87 (m, 2H), 5.97 (s, 1H), 5.76 (s, 1H), 3.68 (br d, J = 12.63 Hz, 2H), 3.37-3.42 (m, 1H), 2.64-2.81 (m, 3H), 2.30 (s, 3H), 1.73-1.81 (m, 2H), 1.26-1.39 (m, 2H); LC-MS: 549.6 [M+H + ].

[0194] [Example 31] (S)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide [ka]

[0195] (S)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide [Example 31] (53%) was prepared in a manner similar to that described in [Example 1].

[0196] 1H NMR (400 MHz, DMSO-d6) δ 11.11 (br s, 1H), 9.25 (br d, J = 8.51 Hz, 1H), 7.97 (s, 1H), 7.66 (s, 1H), 7.54-7.62 (m, 3H), 7.42 (d, J = 7.75 Hz, 1H), 7.33 (dd, J = 0.81, 8.07 Hz, 1H), 7.21 (dd, J = 3.13, 9.76 Hz, 1H), 6.91-7.06 (m, 6H), 6.79-6.87 (m, 2H), 5.98 (s, 1H), 3.65-3.74 (m, 2H), 2.69-2.81 (m, 3H), 2.41 (s, 3H), 1.73-1.83 (m, 2H), 1.25-1.37 (m, 2H); LC-MS: 549.6 [M+H + ].

[0197] [Example 32] 4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide [ka]

[0198] 4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide [Example 32] (31%) was prepared in a manner similar to that described in [Example 1].

[0199] 1H NMR (400 MHz, DMSO-d6) δ 11.12 (br s, 1H), 9.26 (br d, J = 8.50 Hz, 1H), 7.96 (s, 1H), 7.65 (s, 1H), 7.54-7.63 (m, 3H), 7.42 (d, J = 7.88 Hz, 1H), 7.32 (d, J = 8.76 Hz, 1H), 7.21 (dd, J = 3.19, 9.69 Hz, 1H), 6.91-7.05 (m, 5H), 6.79-6.87 (m, 2H), 5.98 (s, 1H), 3.69 (br d, J = 12.63 Hz, 2H), 2.70-2.80 (m, 3H), 2.41 (s, 3H), 1.74-1.82 (m, 2H), 1.24-1.37 (m, 2H); LC-MS: 549.6 [M+H + ].

[0200] [Example 33] (R)-3-(5-(4-aminopiperidin-1-yl)-4-methylpyridin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; [ka]

[0201] (R)-3-(5-(4-aminopiperidin-1-yl)-4-methylpyridin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [Example 33] (23%) was prepared in a manner similar to that described in [Example 1].

[0202] 1H NMR (400 MHz, DMSO-d6) δ 11.12 (br s, 1H), 9.26 (br d, J = 8.38 Hz, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.77 (s, 1H), 7 .43 (d, J = 7.75 Hz, 1H), 7.33 (d, J=8.13 Hz, 1H), 7.23 (dd, J = 3.13, 9.76 Hz, 1H), 7.01-7.08 (m, 1H), 6.90-6.99 (m, 2H), 6.80-6.88 (m, 2H), 6.00 (s, 1H), 3.14 (br d, J = 12.01 Hz, 2H), 2.69-2.79 (m, 3H), 2.44 (s, 3H), 2.32 (s, 3H), 1.83 (br d, J = 10.88 Hz, 2H), 1.35-1.48 (m, 2H); LC-MS: 564.6 [M+H + ].

[0203] [Example 34] (R)-3-(2-(4-aminopiperidin-1-yl)-4-methylpyrimidin-5-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [ka]

[0204] (R)-3-(2-(4-aminopiperidin-1-yl)-4-methylpyrimidin-5-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [Example 34] (13%) was prepared in a manner similar to that described in [Example 1].

[0205] 1H NMR (400 MHz, DMSO-d6) δ 10.91-11.23 (m, 1H), 9.05-9.28 (m, 1H), 8.20 (s, 1H), 7.65-7.89 (m, 2H), 7.39-7.45 (m, 1H), 7.36 (s, 1H), 7.31 (br d, J = 0.75 Hz, 1H), 7.18 (dd, J = 3.13, 9.76 Hz, 1H), 7.03 (br d, J = 1.00 Hz, 1H), 6.91-6.99 (m, 2H), 6.85 (br d, J = 4.88 Hz, 1H), 6.80 (s, 1H), 5.95-6.04 (m, 1H), 4.51-4.60 (m, 2H), 2.96-3.03 (m, 2H), 2.78-2.88 (m, 1H), 2.37-2.43 (m, 3H), 2.29 (s, 3H), 1.70-1.80 (m, 2H), 1.10-1.20 (m, 2H); LC-MS: 565.6 [M+H + ].

[0206] [Example 35] tert-Butyl (R)-4-(2-(3-(((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)carbamoyl)-5-methylphenyl)pyrimidin-5-yl)piperazine-1-carboxylate [ka]

[0207] tert-Butyl (R)-4-(2-(3-(((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)carbamoyl)-5-methylphenyl)pyrimidin-5-yl)piperazine-1-carboxylate [Example 35] (82%) was prepared in a manner similar to that described in [Preparation Example 9].

[0208] 1H NMR (400 MHz, DMSO-d6) δ 11.08-11.13 (m, 1H), 9.65 (s, 1H), 9.29 (d, J=8.63 Hz, 1H), 8.62 (s, 3H), 8.25 (s, 1H), 7.82 (s, 1H), 7.43 (d, J=8.00 Hz, 1H), 7.33 (d, J=7.67 Hz, 1H), 7.25 (dd, J=3.19, 9.82 Hz, 1H), 7.04 (dt, J=1.13, 7.57 Hz, 1H), 6.92-7.01 (m, 2H), 6.80-6.88 (m, 2H), 6.00 (t, LC-MS: 637.7 [M+H + ].

[0209] [Example 36] (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(piperazin-1-yl)pyrimidin-2-yl)benzamide [ka]

[0210] (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(piperazin-1-yl)pyrimidin-2-yl)benzamide [Example 36] (11%) was prepared in a manner similar to that described in [Example 1].

[0211] 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.65 (br s, 1H), 9.28 (d, J=8.63 Hz, 1H), 8.55-8.63 (m, 3H), 8.23-8.26 (m, 1H), 7.80 (s, 1H), 7.43 (d, J=7.88 Hz, 1H), 7.33 (dd, J=0.75, 8.13 Hz, 1H), 7.25 (dd, J=3.13, 9.76 Hz, 1H), 7.04 (dt, J=1.19, 7.60 Hz, 1H), 6.91-7.01 (m, 2H), 6.79-6.88 (m, 2H), 6.00 (t, J=1.00 Hz, 1H), 3.19-3.25 (m, 4H), 2.81-2.89 (m, 4H), 2.43-2.46 (m, 3H); LC-MS: 537.7 [M+H + ].

[0212] [Example 37] (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(4-methylpiperazin-1-yl)pyrimidin-2-yl)benzamide [ka]

[0213] (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(4-methylpiperazin-1-yl)pyrimidin-2-yl)benzamide [Example 37] (54%) was prepared in a manner similar to that described in [Example 1].

[0214] 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.67 (s, 1H), 9.28 (d, J=8.63 Hz, 1H), 8.58-8.66 (m, 3H), 8.22-8.26 (m, 1H), 7.82 (s, 1H), 7.43 (d, J=7.88 Hz, 1H), 7.31-7.36 (m, 1H), 7.26 (dd, J=3.13, 9.76 Hz, 1H), 7.02-7.08 (m, 1H), 6.92-7.01 (m, 2H), 6.80-6.89 (m, 2H), 5.99-6.02 (m, 1H), 4.02 (br d, J=12.26 Hz, 2H), 2.78-2.94 (m, 5H), 2.44 (s, 3H), 1.92 (br s, 2H), 1.64 (br d, J=10.13 Hz, 2H), 1.05-1.16 (m, 6H); LC-MS: 551.6 [M+H + ].

[0215] [Example 38] N-[(R)-(5-fluoro-2-hydroxy-phenyl)-(1H-indol-2-yl)methyl]-3-methyl-5-[5-(4-propyl-1-piperidyl)pyrimidin-2-yl]benzamide [ka]

[0216] N-[(R)-(5-fluoro-2-hydroxy-phenyl)-(1H-indol-2-yl)methyl]-3-methyl-5-[5-(4-propyl-1-piperidyl)pyrimidin-2-yl]benzamide [Example 38] (18%) was prepared in a manner similar to that described in [Preparation Example 9].

[0217] 1H NMR (400 MHz, DMSO-d6) δ 11.07-11.15 (m, 1H), 9.59-9.76 (m, 1H), 9.22-9.31 (m, 1H), 8.60 (s, 1H),8.58 (s, 2H), 8.24 (s, 1H), 7.96 (s, 1H), 7.80 (s, 1H), 7.43 (d, J=7.75 Hz, 1H), 7.32 (s, 1H), 7.25 (dd, J=3.13, 9.76 Hz, 1H), 6.91-7.07 (m, 4H), 6.84-6.88 (m, 1H), 6.83 (s, 1H), 5.98-6.03 (m, 1H), 2.75-2.83 (m,4H), 2.42-2.45 (m, 3H), 1.72-1.80 (m, 2H), 1.39-1.47 (m, 1H), 1.33 (br s, 2H), 1.23 (br t, LC-MS: 557.7 [M+H + ].

[0218] [Example 39] 3-[5-[4-(dimethylamino)-1-piperidyl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxy-phenyl)-(1H-indol-2-yl)methyl]-5-methyl-benzamide [ka]

[0219] 3-[5-[4-(dimethylamino)-1-piperidyl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxy-phenyl)-(1H-indol-2-yl)methyl]-5-methyl-benzamide [Example 39] (7%) was prepared by a method similar to that described in [Preparation Example 9].

[0220] 1H NMR (400 MHz, chloroform-d) δ 9.38 (br s, 1H), 8.61 (br d, J=8.00 Hz, 1H), 8.44 (s, 1H),8.12-8.19 (m, 3H), 7.66 (s, 1H), 7.52 (d, J=7.75 Hz, 1H), 7.26-7.31 (m, 2H), 7.12 (t, J=7.16 Hz, 1H),7.04-7.10 (m, 1H), 6.97 (dd, J=2.81, 8.82 Hz, 1H), 6.81-6.92 (m, 2H), 6.70 (br d, J=7.13Hz, 1H), 6.34 (s,1H), 3.62 (br d, J=12.63 Hz, 1H), 3.45-3.54 (m, 2H), 2.60-2.74 (m, 2H), 2.35 (s, 3H), 2.33 (s, 6H), 2.26(ddd, J=4.00, 7.72, 14.66 Hz, 1H), 1.88 (br d, J=12.13 Hz, 1H), 1.78 (br d, J=12.63 Hz, 1H), 1.52-1.65 (m,1H), 1.39-1.50 (m, 1H), 1.28 (br s, 1H); LC-MS: 578.7 [M+H + ].

[0221] [Example 40] N-[(R)-(5-fluoro-2-hydroxy-phenyl)-(1H-indol-2-yl)methyl]-3-methyl-5-[5-(1-piperidyl)pyrimidin-2-yl]benzamide [ka]

[0222] N-[(R)-(5-fluoro-2-hydroxy-phenyl)-(1H-indol-2-yl)methyl]-3-methyl-5-[5-(1-piperidyl)pyrimidin-2-yl]benzamide [Example 40] (24%) was prepared in a manner similar to that described in [Preparation Example 9].

[0223] 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.65 (s, 1H), 9.28 (d, J=8.63 Hz, 1H), 8.56-8.63 (m, 3H), 8.24 (s, 1H), 7.80 (s, 1H), 7.43 (d, J=7.75 Hz, 1H), 7.34 (d, J=8.00 Hz, 1H), 7.26 (dd, J=2.94, 9.69 Hz, 1H), 7.01-7.08 (m, 1H), 6.90-7.00 (m, 2H), 6.80-6.89 (m, 2H), 6.00 (s, 1H), 2.44 (s, 3H), 1.40-1.81 (m, 7H); LC-MS: 536.61 [M+H + ].

[0224] [Example 41] N-[(R)-(5-fluoro-2-hydroxy-phenyl)-(1H-indol-2-yl)methyl]-3-methyl-5-[5-[4-(1-methyl-4-piperidyl)piperazin-1-yl]pyrimidin-2-yl]benzamide [ka]

[0225] N-[(R)-(5-fluoro-2-hydroxy-phenyl)-(1H-indol-2-yl)methyl]-3-methyl-5-[5-[4-(1-methyl-4-piperidyl)piperazin-1-yl]pyrimidin-2-yl]benzamide [Example 41] (10%) was prepared in a manner similar to that described in [Preparation Example 9].

[0226] 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.68 (br s, 1H), 9.28 (d, J=8.51 Hz, 1H), 8.56-8.64 (m, 3H), 8.24 (s, 1H), 7.81 (s, 1H), 7.43 (d, J=7.75 Hz, 1H), 7.33 (d, J=8.13 Hz, 1H), 7.25 (dd, J=3.13, 9.76 Hz, 1H), 7.01-7.07 (m, 1H), 6.91-7.00 (m, 2H), 6.79-6.88 (m, 2H), 6.00 (s, 1H), 3.29 (br s, 2H), 3.08 (s, 2H), 2.79 (br d, J=11.51 Hz, 2H), 2.67 (br dd, J=1.88, 3.63 Hz, 1H), 2.62-2.66 (m, 3H), 2.44 (s, 3H), 2.17-2.23 (m, 1H), 2.14 (s, 3H), 1.80-1.90 (m, 2H), 1.74 (br d, J=11.51 Hz, 2H), 1.37-1.50 (m, 2H); LC-MS: 634.76 [M+H + ].

[0227] [Example 42] (R)-3-(5-((4-(dimethylamino)piperidin-1-yl)methyl)pyridin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl))methyl)-5-methylbenzamide [ka]

[0228] (R)-3-(5-((4-(dimethylamino)piperidin-1-yl)methyl)pyridin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl))methyl)-5-methylbenzamide [Example 42] (84%) was prepared in a manner similar to that described in [Preparation Example 9].

[0229] 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.66 (br s, 1H), 9.29 (d, J=8.51 Hz, 1H), 8.54-8.60 (m, 1H), 8.42 (s, 1H), 8.07 (s, 1H), 7.94-8.05 (m, 1H), 7.78-7.86 (m, 2H), 7.43 (d, J=7.75 Hz, 1H), 7.33 (d, J=8.00 Hz, 1H), 7.23 (dd, J=3.13, 9.63 Hz, 1H), 7.01-7.08 (m, 1H), 6.91-7.01 (m, 2H), 6.81-6.91 (m,2H), 6.00 (s, 1H), 3.47-3.54 (m, 2H), 2.83 (br d, J=11.38 Hz, 2H), 2.43-2.48 (m, 3H), 2.16 (s, 6H), 2.00-2.10 (m, 1H), 1.96 (br t, J=10.82 Hz, 2H), 1.71 (br d, J=12.01 Hz, 2H), 1.30-1.47 (m, 2H); LC-MS: 592.7 [M+H+].

[0230] [Example 43] (R)-3-(6-((4-(dimethylamino)piperidin-1-yl)methyl)pyridin-3-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl))methyl)-5-methylbenzamide [ka]

[0231] (R)-3-(6-((4-(dimethylamino)piperidin-1-yl)methyl)pyridin-3-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl))methyl)-5-methylbenzamide [Example 43] (90%) was prepared in a manner similar to that described in [Preparation Example 9].

[0232] 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.66 (br s, 1H), 9.29 (d, J=8.51 Hz, 1H), 8.54-8.60 (m, 1H), 8.42 (s, 1H), 8.07 (s, 1H), 7.94-8.05 (m, 1H), 7.78-7.86 (m, 2H), 7.43 (d, J=7.75 Hz, 1H), 7.33 (d, J=8.00 Hz, 1H), 7.23 (dd, J=3.13, 9.63 Hz, 1H), 7.01-7.08 (m, 1H), 6.91-7.01 (m, 2H), 6.81-6.91 (m,2H), 6.00 (s, 1H), 3.47-3.54 (m, 2H), 2.83 (br d, J=11.38 Hz, 2H), 2.43-2.48 (m, 3H), 2.16 (s, 6H), 2.00-2.10 (m, 1H), 1.96 (br t, J=10.82 Hz, 2H), 1.71 (br d, J=12.01 Hz, 2H), 1.30-1.47 (m, 2H); LC-MS: 592.7 [M+H+].

[0233] [Example 44] 3-[5-[(3R)-3-aminopyrrolidin-1-yl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxy-phenyl)-(1H-indol-2-yl)methyl]-5-methyl-benzamide [ka]

[0234] 3-[5-[(3R)-3-aminopyrrolidin-1-yl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxy-phenyl)-(1H-indol-2-yl)methyl]-5-methyl-benzamide [Example 44] (86%) was prepared in a similar manner to that described in [Example 1].

[0235] 1H NMR (400 MHz, DMSO-d6) δ 11.14 (br s, 1H), 9.31 (br d, J=8.13 Hz, 1H), 8.58 (s, 1H), 8.17-8.24 (m, 3H), 7.76 (s, 1H), 7.43 (d, J=7.75 Hz, 1H), 7.34 (d, J=8.00 Hz, 1H), 7.25 (dd, J=2.69, 9.69 Hz, 1H), 7.01-7.08 (m, 1H), 6.91-7.00 (m, 2H), 6.78-6.87 (m, 2H), 6.02 (s, 1H), 3.58-3.64 (m, 1H), 3.45-3.53 (m, 3H), 3.00 (br dd, J=4.25, 9.63 Hz, 1H), 2.43 (s, 3H), 2.03-2.13 (m, 1H), 1.74 (qd, J=6.05, 12.12 Hz, 1H); LC-MS: 537.6 [M+H+].

[0236] [Example 45] (R)-3-(5-(4-(diethylamino)piperidin-1-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [ka]

[0237] (R)-3-(5-(4-(diethylamino)piperidin-1-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [Example 45] (96%) was prepared in a manner similar to that described in [Preparation Example 9].

[0238] 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.67 (s, 1H), 9.28 (d, J=8.63 Hz, 1H), 8.58-8.66 (m, 3H), 8.22-8.26 (m, 1H), 7.82 (s, 1H), 7.43 (d, J=7.88 Hz, 1H), 7.31-7.36 (m, 1H), 7.26 (dd, J=3.13, 9.76 Hz, 1H), 7.02-7.08 (m, 1H), 6.92-7.01 (m, 2H), 6.80-6.89 (m, 2H), 5.99-6.02 (m, 1H), 4.02 (br d, J=12.26 Hz, 2H), 2.78-2.94 (m, 5H), 2.44 (s, 3H), 1.92 (br s, 2H), 1.64 (br d, J=10.13 Hz, 2H), 1.05-1.16 (m, 6H); LC-MS: 607.7 [M+H+].

[0239] [Example 46] N-((R)-(5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidin-2-yl)benzamide [ka]

[0240] N-((R)-(5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidin-2-yl)benzamide [Example 46] (91%) was prepared in a manner similar to that described in [Preparation Example 9].

[0241] 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.65 (s, 1H), 9.26 (d, J=8.63 Hz, 1H), 8.66-8.67 (m, 1H), 8.65-8.66 (m, 1H), 8.58 (s, 1H), 8.44-8.45 (m, 1H), 8.42-8.43 (m, 1H), 8.38 (s, 2H), 8.19-8.24 (m, 1H), 7.78 (s, 1H), 7.41-7.45 (m, 1H), 7.33 (dd, J=0.75, 8.00 Hz, 1H), 7.26 (dd, J=3.19, 9.82 Hz, 1H), 7.04 (dt, J=1.13, 7.57 Hz, 1H), 6.92-7.01 (m, 2H), 6.79-6.88 (m, 2H), 5.99-6.02 (m, 1H), 3.35-3.43 (m, 3H), 3.07 (br s, 2H), 2.53 (br s, 6H), 2.44 (s, 3H), 2.09 (br s, 1H), 1.90 (br d, J=11.63 Hz, 1H), 1.75-1.86 (m, 1H), 1.72 (br d, J=11.51 Hz, 1H); LC-MS: 577.6 [M+H+].

[0242] [Example 47] (R)-3-(5-(4-(1H-pyrrol-1-yl)piperidin-1-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [ka]

[0243] (R)-3-(5-(4-(1H-pyrrol-1-yl)piperidin-1-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [Example 47] (86%) was prepared in a manner similar to that described in [Preparation Example 9].

[0244] 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.65 (s, 1H), 9.26 (d, J=8.63 Hz, 1H), 8.66-8.67 (m, 1H), 8.65-8.66 (m, 1H), 8.58 (s, 1H), 8.44-8.45 (m, 1H), 8.42-8.43 (m, 1H), 8.38 (s, 2H), 8.19-8.24 (m, 1H), 7.78 (s, 1H), 7.41-7.45 (m, 1H), 7.33 (dd, J=0.75, 8.00 Hz, 1H), 7.26 (dd, J=3.19, 9.82 Hz, 1H), 7.04 (dt, J=1.13, 7.57 Hz, 1H), 6.92-7.01 (m, 2H), 6.79-6.88 (m, 2H), 5.99-6.02 (m, 1H), 3.35-3.43 (m, 3H), 3.07 (br s, 2H), 2.53 (br s, 6H), 2.44 (s, 3H), 2.09 (br s, 1H), 1.90 (br d, J=11.63 Hz, 1H), 1.75-1.86 (m, 1H), 1.72 (br d, J=11.51 Hz, 1H); LC-MS: 601.6 [M+H+].

[0245] [Example 48] (R)-3-(5-(4-(1H-1,2,4-triazol-1-yl)piperidine-1-methyl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [ka]

[0246] (R)-3-(5-(4-(1H-1,2,4-triazol-1-yl)piperidin-1-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [Example 48] (78%) was prepared in a manner similar to that described in [Preparation Example 9].

[0247] 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.65 (s, 1H), 9.26 (d, J=8.63 Hz, 1H), 8.66-8.67 (m, 1H), 8.65-8.66 (m, 1H), 8.58 (s, 1H), 8.44-8.45 (m, 1H), 8.42-8.43 (m, 1H), 8.38 (s, 2H), 8.19-8.24 (m, 1H), 7.78 (s, 1H), 7.41-7.45 (m, 1H), 7.33 (dd, J=0.75, 8.00 Hz, 1H), 7.26 (dd, J=3.19, 9.82 Hz, 1H), 7.04 (dt, J=1.13, 7.57 Hz, 1H), 6.92-7.01 (m, 2H), 6.79-6.88 (m, 2H), 5.99-6.02 (m, 1H), 3.35-3.43 (m, 3H), 3.07 (br s, 2H), 2.53 (br s, 6H), 2.44 (s, 3H), 2.09 (br s, 1H), 1.90 (br d, J=11.63 Hz, 1H), 1.75-1.86 (m, 1H), 1.72 (br d, J=11.51 Hz, 1H); LC-MS: 603.6 [M+H+].

[0248] [Example 49] (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-(5-(4-hydroxypiperidin-1-yl)pyrimidin-2-yl)-5-methylbenzamide [ka]

[0249] (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-(5-(4-hydroxypiperidin-1-yl)pyrimidin-2-yl)-5-methylbenzamide [Example 49] (15%) was prepared in a manner similar to that described in [Preparation Example 9].

[0250] 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.65 (s, 1H), 9.26 (d, J=8.63 Hz, 1H), 8.66-8.67 (m, 1H), 8.65-8.66 (m, 1H), 8.58 (s, 1H), 8.44-8.45 (m, 1H), 8.42-8.43 (m, 1H), 8.38 (s, 2H), 8.19-8.24 (m, 1H), 7.78 (s, 1H), 7.41-7.45 (m, 1H), 7.33 (dd, J=0.75, 8.00 Hz, 1H), 7.26 (dd, J=3.19, 9.82 Hz, 1H), 7.04 (dt, J=1.13, 7.57 Hz, 1H), 6.92-7.01 (m, 2H), 6.79-6.88 (m, 2H), 5.99-6.02 (m, 1H), 3.35-3.43 (m, 3H), 3.07 (br s, 2H), 2.53 (br s, 6H), 2.44 (s, 3H), 2.09 (br s, 1H), 1.90 (br d, J=11.63 Hz, 1H), 1.75-1.86 (m, 1H), 1.72 (br d, J=11.51 Hz, 1H); LC-MS: 552.6 [M+H+].

[0251] [Example 50] (R)-3-(5-([1,4'-bipiperidine]-1'-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [ka]

[0252] (R)-3-(5-([1,4'-bipiperidine]-1'-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [Example 50] (26%) was prepared in a manner similar to that described in [Preparation Example 9].

[0253] 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (br s, 1H), 9.66 (br s, 1H), 9.29 (br d, J=8.38 Hz, 1H), 8.56-8.63 (m, 3H), 8.23-8.25 (m, 1H), 7.80 (s, 1H), 7.43 (d, J=7.75 Hz, 1H), 7.33 (dd, J=0.69, 8.07 Hz, 1H), 7.25 (dd, J=3.19, 9.82 Hz, 1H), 7.04 (dt, J=1.13, 7.57 Hz, 1H), 6.92-7.01 (m, 2H), 6.79-6.87 (m, 2H), 6.00 (s, 1H), 3.94 (br d, J=12.76 Hz, 2H), 2.74-2.85 (m, 2H), 2.47 (br d, J=2.75 Hz, 4H), 2.44 (s, 3H), 2.37-2.42 (m, 1H), 1.82 (br d, J=11.38 Hz, 2H), 1.51-1.60 (m, 2H), 1.48 (br d, J=4.88 Hz, 4H), 1.38 (br d, J=5.13 Hz, 2H); LC-MS: 619.7 [M+H+].

[0254] [Example 51] (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(4-(morpholinomethyl)piperidin-1-yl)pyrimidin-2-yl)benzamide [ka]

[0255] (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(4-(morpholinomethyl)piperidin-1-yl)pyrimidin-2-yl)benzamide [Example 51] (100%) was prepared in a manner similar to that described in [Preparation Example 9].

[0256] 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (br s, 1H), 9.66 (br s, 1H), 9.29 (br d, J=8.38 Hz, 1H), 8.56-8.63 (m, 3H), 8.23-8.25 (m, 1H), 7.80 (s, 1H), 7.43 (d, J=7.75 Hz, 1H), 7.33 (dd, J=0.69, 8.07 Hz, 1H), 7.25 (dd, J=3.19, 9.82 Hz, 1H), 7.04 (dt, J=1.13, 7.57 Hz, 1H), 6.92-7.01 (m, 2H), 6.79-6.87 (m, 2H), 6.00 (s, 1H), 3.94 (br d, J=12.76 Hz, 2H), 2.74-2.85 (m, 2H), 2.47 (br d, J=2.75 Hz, 4H), 2.44 (s, 3H), 2.37-2.42 (m, 1H), 1.82 (br d, J=11.38 Hz, 2H), 1.51-1.60 (m, 2H), 1.48 (br d, J=4.88 Hz, 4H), 1.38 (br d, J=5.13 Hz, 2H); LC-MS: 635.7 [M+H+].

[0257] [Example 52] (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)pyrimidin-2-yl)benzamide [ka]

[0258] (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)pyrimidin-2-yl)benzamide [Example 52] (11%) was prepared in a manner similar to that described in [Preparation Example 9].

[0259] 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (br s, 1H), 9.66 (br s, 1H), 9.29 (br d, J=8.38 Hz, 1H), 8.56-8.63 (m, 3H), 8.23-8.25 (m, 1H), 7.80 (s, 1H), 7.43 (d, J=7.75 Hz, 1H), 7.33 (dd, J=0.69, 8.07 Hz, 1H), 7.25 (dd, J=3.19, 9.82 Hz, 1H), 7.04 (dt, J=1.13, 7.57 Hz, 1H), 6.92-7.01 (m, 2H), 6.79-6.87 (m, 2H), 6.00 (s,1H), 3.94 (br d, J=12.76 Hz, 2H), 2.74-2.85 (m, 2H), 2.47 (br d, J=2.75 Hz, 4H), 2.44 (s, 3H), 2.37-2.42 (m, 1H), 1.82 (br d, J=11.38 Hz, 2H), 1.51-1.60 (m,2H), 1.48 (br d, J=4.88 Hz, 4H), 1.38 (br d, J=5.13 Hz, 2H); LC-MS: 619.7 [M+H+].

[0260] [Example 53] 3-[5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxy-hydroxy)-(1H-indol-2-yl)methyl]-5-methyl-benzamide [ka]

[0261] 3-[5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxy-phenyl)-(1H-indol-2-yl)methyl]-5-methyl-benzamide [Example 53] (33%) was prepared in a manner similar to that described in [Preparation Example 9].

[0262] 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.67 (br d, J=0.75 Hz, 1H), 9.28 (d, J=8.63 Hz, 1H), 8.58 (s, 1H), 8.21-8.26 (m, 3H), 7.76 (d, J=0.63 Hz, 1H), 7.43 (d, J=7.88 Hz, 1H), 7.34 (dd, J=0.75, 8.13 Hz, 1H), 7.26 (dd, J=3.19, 9.82 Hz, 1H), 7.04 (ddd, J=1.19, 7.00, 8.07Hz, 1H), 6.89-6.99 (m, 2H), 6.78-6.89 (m, 2H), 6.01 (s, 1H), 3.58 (dd, J=7.19, 9.57 Hz, 1H), 3.48-3.55 (m, 1H), 3.34-3.39 (m, 1H), 3.10-3.17 (m, LC-MS: 565.65 [M+H+].

[0263] [Example 54] (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(4-(methylamino)piperidin-1-yl)pyrimidin-2-yl)benzamide [ka]

[0264] (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(4-(methylamino)piperidin-1-yl)pyrimidin-2-yl)benzamide [Example 54] (10%) was prepared in a manner similar to that described in [Example 1].

[0265] 1 H NMR (400 MHz, DMSO-d6)δ 11.10 (s, 1H), 9.61-9.73 (m, 1H), 9.21-9.39 (m, 1H), 8.64 (s, 3H), 8.23-8.26 (m, 1H), 7.83 (s, 1H), 7.41-7.45 (m, 1H), 7.31-7.35 (m, 1H), 7.22-7.28 (m, 1H), 7.02-7.07 (m, 1H), 6.92-7.00 (m, 2H), 6.80-6.88 (m, 2H), 5.98-6.03 (m, 1H), 4.01 (br d, J=12.88 Hz, 1H), 3.98-4.05 (m, 1H), 3.17 (d, J=5.25 Hz, 1H), 2.90 (br s, 2H), 2.58-2.59 (m, 2H), 2.45 (s, 4H), 2.32-2.35 (m, 2H), 2.03-2.10 (m, 3H), 1.53-1.62 (m, 2H); LC-MS: 565.6 [M+H+].

[0266] [Example 55] (R)-1-(2-(3-(((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)carbamoyl)-5-methylphenyl)pyrimidin-5-yl)-N-phenylpiperidine-4-carboxamide [ka]

[0267] (R)-1-(2-(3-(((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)carbamoyl)-5-methylphenyl)pyrimidin-5-yl)-N-phenylpiperidine-4-carboxamide [Example 55] (10%) was prepared in a manner similar to that described in [Preparation Example 9].

[0268] 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (d, J=1.63 Hz, 1H), 9.95 (s, 1H), 9.67 (s, 1H), 9.29 (d, J=8.63 Hz, 1H), 8.58-8.66 (m, 3H), 8.26 (d, J=0.63 Hz, 1H), 7.96 (s, 1H), 7.81 (s, 1H), 7.58-7.65 (m, 2H), 7.43 (d, J=7.88 Hz, 1H), 7.23-7.37 (m, 4H), 6.91-7.08 (m, 4H), 6.77-6.89 (m, 2H), 5.96-6.04 (m, 1H), 3.96-4.04 (m, 2H), 3.18 (d, J=5.00 Hz, 1H), 2.89 (s, 2H), 2.45 (s, 3H), 1.92 (br s, 2H), 1.71-1.83 (m, 2H); LC-MS: 656.7 [M+H+].

[0269] [Example 56] (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-(5-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)pyrimidin-2-yl)-5-methylbenzamide [ka]

[0270] (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-(5-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)pyrimidin-2-yl)-5-methylbenzamide [Example 56] (10%) was prepared in a manner similar to that described in [Preparation Example 9].

[0271] 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (d, J=1.63 Hz, 1H), 9.67 (s, 1H), 9.30 (d, J=8.50 Hz, 1H), 8.62-8.68 (m, 3H), 8.27 (d, J=0.63 Hz, 1H), 7.83 (s, 1H), 7.44 (d, J=7.88 Hz, 1H), 7.34 (dd, J=0.81, 8.07 Hz, 1H), 7.27 (dd, J=3.19, 9.82 Hz, 1H), 7.04 (ddd, J=1.19, 7.10, 8.10 Hz, 1H), 6.95-6.99 (m, 3H), 6.94-6.95 (m, 1H), 6.81-6.89 (m, 4H), 5.99-6.03 (m, 1H), 4.00-4.07 (m, 1H), 4.03 (q, J=7.05 Hz, 5H), 3.60-3.66 (m, 2H), 3.45-3.51 (m, 4H), 3.30 (s, 3H), 3.19 (br d, J=4.88 Hz, 4H), 2.87-2.91 (m, 1H), 2.45 (s, 3H), 1.99 (s, 6H), 1.18 (t, J=7.13 Hz, 6H); LC-MS: 687.7 [M+H+].

[0272] [Example 57] (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-yl)methylbenzamide [ka]

[0273] (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-yl)benzamide [Example 57] (81%) was prepared in a manner similar to that described in [Example 1].

[0274] 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.35 (d, J=8.51 Hz, 1H), 8.94-9.07 (m, 2H), 8.74 (s, 1H), 8.37 (s, 1H), 7.92 (s, 1H), 7.43 (d, J=7.88 Hz, 1H), 7.34 (d, J=8.00 Hz, 1H), 7.25 (dd, J=3.13, 9.76 Hz, 1H), 6.92-7.07 (m, 3H), 6.80-6.88 (m, 2H), 6.53 (br s, 1H), 6.01 (s, 1H), 3.40-3.44 (m, 2H), 2.95 (t, J=5.50 Hz, 2H), 2.46-2.48 (m, 3H), 2.38-2.44 (m, 2H); LC-MS: 534.6 [M+H+].

[0275] [Example 58] (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(piperidin-4-yl)pyrimidin-2-yl)benzamide [ka]

[0276] (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-yl)benzamide [Example 57] (150 mg, 0.28 mmol) and 10% palladium / carbon (15 mg, 0.14 mmol) were stirred in methanol and dichloromethane (1:1) under a hydrogen atmosphere at room temperature for 24 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated. The residue was purified by MPLC to obtain (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(piperidin-4-yl)pyrimidin-2-yl)benzamide [Example 58] (70 mg, 46%) as a white solid.

[0277] 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.35 (d, J=8.51 Hz, 1H), 8.94-9.07 (m, 2H), 8.74 (s, 1H), 8.37 (s, 1H), 7.92 (s, 1H), 7.43 (d, J=7.88 Hz, 1H), 7.34 (d, J=8.00 Hz, 1H), 7.25 (dd, J=3.13, 9.76 Hz, 1H), 6.92-7.07 (m, 3H), 6.80-6.88 (m, 2H), 6.53 (br s, 1H), 6.01 (s, 1H), 3.40-3.44 (m, 2H), 2.95 (t, J=5.50 Hz, 2H), 2.46-2.48 (m, 3H), 2.38-2.44 (m, 2H); LC-MS: 536.6 [M+H+].

[0278] [Example 59] 3-[5-(3-aminoazetidin-1-yl)pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxy-phenyl)-(1H-indol-2-yl)methyl]-5-methyl-benzamide [ka]

[0279] 3-[5-(3-aminoazetidin-1-yl)pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxy-phenyl)-(1H-indol-2-yl)methyl]-5-methyl-benzamide [Example 59] (54%) was prepared in a similar manner to that described in [Example 1].

[0280] 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.58 (s, 1H), 8.17-8.25 (m, 1H), 8.13 (s, 2H), 7.79 (s, 1H), 7.43 (d, J=7.88 Hz, 1H), 7.33 (dd, J=0.75, 8.13 Hz, 1H), 7.25 (dd, J=3.13, 9.76 Hz, 1H), 6.91-7.07 (m, 3H), 6.79-6.88 (m, 2H), 5.99-6.02 (m, 1H), 4.20 (t, J=7.44 Hz, 2H), 3.89 (quin, J=6.50 Hz, 1H), 3.54-3.61 (m, 2H), 2.43 (s, 3H)); LC-MS: 523.58 [M+H+].

[0281] [Example 60] 3-[5-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxy-phenyl)-(1H-indol-2-yl)methyl]-5-methyl-benzamide [ka]

[0282] 3-[5-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxy-phenyl)-(1H-indol-2-yl)methyl]-5-methyl-benzamide [Example 60] (28%) was prepared in a manner similar to that described in [Preparation Example 9].

[0283] 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (br s, 1H), 9.31 (br d, J=8.76 Hz, 1H), 8.58 (s, 1H), 8.17-8.29 (m, 3H), 7.76 (s, 1H), 7.43 (d, J=7.75 Hz, 1H), 7.33 (dd, J=0.81, 8.07 Hz, 1H), 7.25 (dd, J=3.25, 9.76 Hz, 1H), 7.04 (ddd, J=1.13, 7.04, 8.10 Hz, 1H), 6.91-7.00 (m, 2H), 6.78-6.87 (m, 2H), 6.01 (s, 1H), 3.50-3.62 (m, 2H), 3.10-3.17 (m, 1H), 3.08 (s, 3H), 2.43 (s, 3H), 2.22 (s, 6H), 2.14-2.20 (m, 1H), 1.78-1.89 (m, 1H); LC-MS: 565.65 [M+H+].

[0284] [Example 61] 3-[5-[(3S)-3-aminopyrrolidin-1-yl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxy-phenyl)-(1H-indol-2-yl)methyl]-5-methyl-benzamide [ka]

[0285] 3-[5-[(3S)-3-aminopyrrolidin-1-yl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxy-phenyl)-(1H-indol-2-yl)methyl]-5-methyl-benzamide [Example 61] (21%) was prepared in a manner similar to that described in [Example 1].

[0286] 1H NMR (400 MHz, DMSO-d6) δ 11.10 (d, J=1.25 Hz, 1H), 9.26 (d, J=8.63 Hz, 1H), 8.58 (s, 1H), 8.17-8.26 (m, 3H), 7.76 (s, 1H), 7.43 (d, J=7.75 Hz, 1H), 7.30-7.38 (m, 1H), 7.26 (dd, J=3.13, 9.76 Hz, 1H), 7.04 (dt, J=1.13, 7.57 Hz, 1H), 6.91-7.01 (m, 2H), 6.79-6.88 (m, 2H), 6.01 (s, 1H), 3.66 (br d, J=5.25 Hz, 1H), 3.47-3.56 (m, 3H), 3.07 (br dd, J=4.25, 9.88 Hz, 1H), 2.53 (br s, 1H), 2.44 (s, 3H), 2.08-2.15 (m, 1H), 1.75-1.84 (m, 1H); LC-MS: 537.61 [M+H+].

[0287] [Example 62] (R)-3-(5-(azetidin-3-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [ka]

[0288] (R)-3-(5-(azetidin-3-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide [Example 62] (5%) was prepared in a manner similar to that described in [Example 1].

[0289] 1H NMR (400 MHz, Methanol-d4) δ 10.53 (br s, 1H), 9.18 (d, J = 8.4 Hz, 1H), 8.94 (s, 1H), 8.76 (s, 1H), 8.46 (s, 1H), 7.89 (s, 1H), 7.46 (d, J LC-MS: 508.35 [M+H+]

[0290] The structures of the compounds prepared in Examples 1 to 62 are summarized in Table 1 below. [Table 1] JPEG2024519054000089.jpg234170JPEG2024519054000090.jpg220170JPEG2024519054000091.jpg234170JPEG2024519054000092.jpg73170

[0291] <Test Example 1> Evaluation of cell proliferation inhibition ability in wild-type (WT) and mutant EGFR-overexpressing BaF3 cells In order to confirm that the compound represented by formula 1 provided in one embodiment of the present invention acts as an allosteric inhibitor against WT and mutant EGFR, the cell proliferation inhibitory effect was evaluated using BaF3 cells overexpressing WT and mutant EGFR.

[0292] More specifically, the cell proliferation inhibitory ability of the compound of the present invention against Ba / F3 cell lines overexpressing WT and mutant EGFR was evaluated using Promega's CellTiter 96 AQueous Non-Radioactive Cell Proliferation Assay system as follows. The AQueous Non-Radioactive Cell Proliferation Assay is a method for confirming the cell proliferation inhibitory ability by reducing MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) to formazan by a reductase secreted from mitochondria present in living cells in a cell culture state and measuring the degree of color development. The Ba / F3 EGFR WT and Ba / F3 EGFR del19 / T790M / C797S (DTC), Ba / F3 EGFR L858R (L), Ba / F3 EGFR L858R / T790M (LT), and Ba / F3 EGFR L858R / T790M / C797S (LTC) mutant cell lines used in the present invention were purchased from Professor Byung-cheol Cho's laboratory at Yonsei University. All cell lines were cultured in RPMI supplemented with 10% FBS, 1% penicillin-streptomycin, and 1 μg / ml puromycin at 37°C in a 5% CO2 incubator.

[0293] The cell survival inhibitory effect of the compounds depending on each EGFR mutation was analyzed by the following analytical method.

[0294] BaF3 cells were seeded in a 96-well cell culture plate at a density of 2000 to 10000 cells / 100 μL / well and cultured for 24 hours. Then, the compound represented by formula 1 provided in one embodiment of the present invention was prepared at twice the final concentration of 0.1 nM, 1 nM, 10 nM, 100 nM, 1000 nM, and 10000 nM, and applied to the plate (100 μL / well). The plate was reacted in an incubator at 37°C for 72 hours. Next, MTS was applied to the plate (20 μL / well) and incubated at 37°C for 2 to 4 hours. Finally, the absorbance at 490 nm was measured using a microplate reader, and the relative value (% control) compared to 0 nM was obtained to confirm the cell proliferation inhibitory ability of the compound. The measured values ​​were analyzed using the Prism program (version 8.0, Graphpad Software, Inc.), and IC, an index of the cell proliferation inhibitory ability of the compound, was calculated. 50 The values ​​(half maximal inhibitory concentrations) were calculated.

[0295] The results are shown in Table 2 below. [Table 2] JPEG2024519054000094.jpg122170

[0296] As shown in Table 2, the compounds of the present invention were found to exhibit excellent activity against EGFR L858R / T790M and L858R / T790M / C797S mutations.

[0297] As described above, the present invention has been described in detail through preferred preparations, examples and test examples, but the scope of the present invention is not limited to specific examples, but should be interpreted by the appended claims. Furthermore, it should be understood that a person skilled in the art can make many modifications and variations without departing from the scope of the present invention.

Claims

Claim 1. A compound, its optical isomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein the compound is a compound represented by the following formula 1 (14) (R)-2-(4-(4-aminopiperidin-1-yl)phenyl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)isonicotinamide; or (15) (R)-2-(4-(4-aminopiperidin-1-yl)phenyl)-N-((5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methyl)isonicotinamide A compound, its optical isomer, solvate, hydrate, or pharmaceutically acceptable salt thereof. 【Chemical 1】 In formula 1, X, Y, and Z are CH; R 1 is halogen, unsubstituted or C substituted with one or more halogens 1-10 alkyl, unsubstituted or C substituted with one or more halogens 1-10 alkoxy, nitro, C 1-10 alkylsulfanyl, cyano, or 5-6 membered heteroaryl; R 2 is a substituted C 6-10 aryl, or a substituted 5- to 10-membered heteroaryl, and Here, the substituted C 6-10 aryl is substituted with a 5-6 membered heterocycloalkyl substituted with an amino group, optionally substituted with halogen or C 1 alkyl, and may also be substituted Here, the substituted 5- to 10-membered heteroaryl is substituted with one substituent selected from the group consisting of substituted C 1-10 alkyl, and unsubstituted or substituted 4- to 10-membered fully saturated or partially saturated heterocycloalkyl. Here, the replaced C 1-10 alkyl is substituted with a 5-6 membered heterocycloalkyl substituted with an amino substituted with two C 1-5 alkyls, The replaced 4- to 10-membered fully saturated or partially saturated heterocycloalkyl consists of a single ring or two bridged rings and is substituted with -OH, C substituted with unsubstituted or 5- to 6-membered heterocycloalkyl 1-5 alkyl, amino substituted with unsubstituted or one or two C 1-5 alkyl, 5- to 6-membered heterocycloalkyl, C 1-5 alkoxycarbonyl, 5- to 6-membered heteroaryl, C 6-10 arylcarbonylamino and C 1-5 alkoxy-C 1-5 alkoxy-C 6-10 and is substituted with one substituent selected from the group consisting of aryl; R 3 is a halogen; R 4 is -OH or C1-5 alkoxy; R 5 is -H; and R 6 is -H or halogen.

2. R 1 is halogen, unsubstituted or substituted with one or more halogens C 1-5 alkyl, unsubstituted or substituted with one or more halogens C 1-5 alkoxy, nitro, C 1-5 alkylsulfanyl, cyano, or 5- to 6-membered heteroaryl; R 2 is a substituted C 6-10 aryl, or a substituted 5- or 6-membered heteroaryl, and Here, the substituted C 6-10 aryl is substituted with a 5- to 6-membered heterocycloalkyl containing at least one N substituted with an amino group, Here, the substituted 5- or 6-membered heteroaryl is substituted with one substituent selected from the group consisting of substituted C 1-5 alkyl, and unsubstituted or substituted 4- to 8-membered fully saturated or partially saturated heterocycloalkyl containing at least one N Here, the substituted C 1-5 alkyl is substituted with a 6-membered heterocycloalkyl substituted with an amino substituted with two C 1-5 alkyls, The replaced 4- to 8-membered fully saturated or partially saturated heterocycloalkyl is -OH, C substituted with unsubstituted or 5- to 6-membered heterocycloalkyl 1-5 alkyl, unsubstituted or amino substituted with one or two C 1-5 alkyl, 5- to 6-membered heterocycloalkyl, C 1-5 alkoxycarbonyl, 5- to 6-membered heteroaryl, C 6-10 arylaminocarbonyl and C 1-5 alkoxy-C 1-5 alkoxy-C 6-10 substituted with one substituent selected from the group consisting of aryl The compound according to claim 1, its optical isomer, solvate, hydrate, or pharmaceutically acceptable salt thereof.

3. R 1 is -OH, halogen, C alkyl which may or may not be substituted with one or more halogens 1-5 alkoxy, nitro, C 1-5 alkylsulfanyl, cyano, amino, C 1-5 alkylamino, or a 5-membered heteroaryl containing at least one N; 1-5 ​ R 2 is phenyl which is substituted or substituted 6-membered heteroaryl containing at least one N, Here, the substituted phenyl is substituted with one amino and is substituted with one or more substituents selected from the group consisting of a substituted 6-membered heterocycloalkyl containing at least one N, a halogen, and a C 1-3 alkyl, Here, the substituted 6-membered heteroaryl is halogen, unsubstituted or substituted C 1-3 alkyl, and one or more substituents selected from the group consisting of unsubstituted or substituted 4-8 membered fully saturated or partially saturated heterocycloalkyl containing at least one N, and is substituted with Here, the substituted C 1-3 alkyl is substituted with a 6-membered heterocycloalkyl substituted with an amino substituted with two C 1-3 alkyls, The replaced 4- to 8-membered heterocycloalkyl is -OH, C 1-3 alkyl, unsubstituted or substituted with one or two C 1-3 alkylamino, unsubstituted or C 1-3 5- to 6-membered heterocycloalkyl substituted with alkyl, C 1-4 alkoxycarbonyl, 5-membered heteroaryl containing at least one N, phenylaminocarbonyl and C 1-3 alkoxy-C 1-3 a monocyclic or bridged two-ring substituted with one or more substituents selected from the group consisting of alkoxy-phenyl The compound according to claim 1, its optical isomer, solvate, hydrate, or pharmaceutically acceptable salt thereof.

4. R 1 is -F, -Cl, -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , isopropyl, tert-butyl, -SCH 3 , -NO 2 , -CN or imidazolyl, and R 2 is 【Chemical 2】 【Chem.】 【Chem.】 and; R 3 is -F or -Cl; R 4 is -OH or -OCH 3 ; R 5 is -H; and R 6 is -H, -F, or -Cl, The compound according to claim 1, its optical isomer, solvate, hydrate, or pharmaceutically acceptable salt thereof.

5. The compound is a compound represented by the following formula 2 (14) (R)-2-(4-(4-aminopiperidin-1-yl)phenyl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)isonicotinamide, or (15) (R)-2-(4-(4-aminopiperidin-1-yl)phenyl)-N-((5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methyl)isonicotinamide The compound according to claim 1, its optical isomer, solvate, hydrate, or pharmaceutically acceptable salt thereof. [Chemical 3] In Formula 2, X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are, independently, as defined in Formula 1 of Claim 1.

6. The compound according to claim 1, its optical isomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the following compounds: (1) (R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide; (2) (R)-4'-(4-Aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-isopropyl[1,1'-biphenyl]-3-carboxamide; (3) (R)-4'-(4-Aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methoxy-[1,1'-biphenyl]-3-carboxamide; (4) (R)-4'-(4-Aminopiperidin-1-yl)-5-(tert-butyl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-[1,1'-biphenyl]-3-carboxamide; (5) (R)-4'-(4-Aminopiperidin-1-yl)-5-fluoro-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-[1,1'-biphenyl]-3-carboxamide; (6) (R)-4'-(4-Aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamide; (7) (R)-4'-(4-Aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-nitro-[1,1'-biphenyl]-3-carboxamide; (8) (R)-4'-(4-Aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-(methylthio)-[1,1'-biphenyl]-3-carboxamide; (9) (R)-4'-(4-Aminopiperidin-1-yl)-5-cyano-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-[1,1'-biphenyl]-3-carboxamide; (10) (R)-4'-(4-Aminopiperidin-1-yl)-5-chloro-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-[1,1'-biphenyl]-3-carboxamide; (11) (R)-4'-(4-Aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide; (12) (R)-4'-(4-Aminopiperidin-1-yl)-N-((5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methyl)-5-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide; (13) (R)-4'-(4-Aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-(1H-imidazol-1-yl)-[1,1'-biphenyl]-3-carboxamide; (14) (R)-2-(4-(4-Aminopiperidin-1-yl)phenyl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)isonicotinamide; (15) (R)-2-(4-(4-Aminopiperidin-1-yl)phenyl)-N-((5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methyl)isonicotinamide; (16) (R)-3-(2-(4-Aminopiperidin-1-yl)pyrimidin-5-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (17) (R)-3-(5-(4-Aminopiperidin-1-yl)pyridin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (18) (R)-3-(5-(4-Aminopiperidin-1-yl)pyrazin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (19) (R)-3-(6-(4-Aminopiperidin-1-yl)pyridin-3-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (20) (R)-3-(6-(4-Aminopiperidin-1-yl)pyridazin-3-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (R)-3-(5-(4-Aminopiperidin-1-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (R)-4'-(4-Aminopiperidin-1-yl)-3'-fluoro-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide; (R)-4'-(4-Aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-2',5-dimethyl-[1,1'-biphenyl]-3-carboxamide; (R)-4'-(4-Aminopiperidin-1-yl)-2'-fluoro-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide; (R)-4'-(4-Aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3',5-dimethyl-[1,1'-biphenyl]-3-carboxamide; (R)-4'-(4-Aminopiperidin-1-yl)-N-((6-fluoro-1H-indol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide; (R)-4'-(4-Aminopiperidin-1-yl)-N-((6-chloro-1H-indol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide; (R)-4'-(4-Aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-6-methyl-[1,1'-biphenyl]-3-carboxamide; (R)-4'-(4-Aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-4-methyl-[1,1'-biphenyl]-3-carboxamide; (30) (R)-4'-(4-Aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-2-methyl-[1,1'-biphenyl]-3-carboxamide; (31) (S)-4'-(4-Aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide; (32) 4'-(4-Aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide; (33) (R)-3-(5-(4-Aminopiperidin-1-yl)-4-methylpyridin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (34) (R)-3-(2-(4-Aminopiperidin-1-yl)-4-methylpyrimidin-5-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (35) tert-Butyl (R)-4-(2-(3-(((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)carbamoyl)-5-methylphenyl)pyrimidin-5-yl)piperazine-1-carboxylate; (36) (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(piperazin-1-yl)pyrimidin-2-yl)benzamide; (37) (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(4-methylpiperazin-1-yl)pyrimidin-2-yl)benzamide; (38) N-[(R)-(5-Fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-3-methyl-5-[5-(4-propyl-1-piperidyl)pyrimidin-2-yl]benzamide; (39)3-[5-[4-(Dimethylamino)-1-piperidyl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-5-methyl-benzamide; (40)N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-3-methyl-5-[5-(1-piperidyl)pyrimidin-2-yl]benzamide; (41)N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-3-methyl-5-[5-[4-(1-methyl-4-piperidyl)piperazin-1-yl]pyrimidin-2-yl]benzamide; (42)(R)-3-(5-((4-(Dimethylamino)piperidin-1-yl)methyl)pyridin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl))methyl)-5-methylbenzamide; (43)(R)-3-(6-((4-(Dimethylamino)piperidin-1-yl)methyl)pyridin-3-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl))methyl)-5-methylbenzamide; (44)3-[5-[(3R)-3-aminopyrrolidin-1-yl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-5-methylbenzamide; (45)(R)-3-(5-(4-(diethylamino)piperidin-1-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (46)N-((R)-(5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidin-2-yl)benzamide; (47)(R)-3-(5-(4-(1H-pyrrol-1-yl)piperidin-1-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (R)-3-(5-(4-(1H-1,2,4-Triazol-1-yl)piperidin-1-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-(5-(4-hydroxypiperidin-1-yl)pyrimidin-2-yl)-5-methylbenzamide; (R)-3-(5-([1,4'-Bipiperidin]-1'-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(4-(morpholinomethyl)piperidin-1-yl)pyrimidin-2-yl)benzamide; (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)pyrimidin-2-yl)benzamide; 3-[5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-5-methylbenzamide; (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(4-(methylamino)piperidin-1-yl)pyrimidin-2-yl)benzamide; (R)-1-(2-(3-(((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)carbamoyl)-5-methylphenyl)pyrimidin-5-yl)-N-phenylpiperidine-4-carboxamide; (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-(5-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)pyrimidin-2-yl)-5-methylbenzamide; (R)-N-((5-Fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-yl)benzamide; (R)-N-((5-Fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(piperidin-4-yl)pyrimidin-2-yl)benzamide; (R)-3-(5-(3-Aminoazetidin-1-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; 3-(5-((S)-3-(Dimethylamino)pyrrolidin-1-yl)pyrimidin-2-yl)-N-((R)-(5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; 3-(5-((S)-3-Aminopyrrolidin-1-yl)pyrimidin-2-yl)-N-((R)-(5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide; and (R)-3-(5-(Azetidin-3-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide.

7. A pharmaceutical composition for the prevention or treatment of cancer, comprising as an active ingredient the compound according to claim 1, an optical isomer thereof, a solvate thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition according to claim 7, wherein the compound suppresses EGFR (epidermal growth factor receptor) mutation and prevents or treats cancer.

9. The pharmaceutical composition according to claim 8, wherein the EGFR mutation is at least one selected from the group consisting of EGFR L858R / T790M and EGFR L858R / T790M / C797S.

10. A health functional food composition for the prevention or improvement of cancer, comprising as an active ingredient the compound according to claim 1, an optical isomer thereof, a solvate thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof.

11. A combination preparation for the prevention or treatment of cancer, comprising as an active ingredient the compound according to claim 1, its optical isomers, their solvates, their hydrates or their pharmaceutically acceptable salts.

12. The combination preparation according to claim 11, wherein the combination preparation is administered in combination with at least one selected from the group consisting of the following components: cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, nitrosourea, gemcitabine, hydroxyurea, adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin C, dactinomycin, mitramycin, vincristine, vinblastine, vindesine, vinorelbine, taxol, taxotere, etoposide, teniposide, amsacrine, topotecan, camptothecin, tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, iodoxyfene, bicalutamide, flutamide, nilutamide, cyproterone acetate, goserelin, leuprorelin, buserelin, megestrol acetate, anastrozole, letrozole, vorazole, exemestane, finasteride, saracatinib, dasatinib, bosutinib, marimastat, cetuximab, gefitinib, erlotinib, panitumumab, osimertinib, lapatinib, imatinib, nilotinib, sorafenib, tipifarnib, lonafarnib, bevacizumab, vandetanib, batatinib, sunitinib, axitinib, pazopanib, 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline, combretastatin A4, dibotetan and atrasentan.

13. Use of the compound according to claim 1, its optical isomers, their solvates, their hydrates or their pharmaceutically acceptable salts for the manufacture of a medicament for the prevention or treatment of cancer.

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