RU2841260C2 - Benzamide derivative, method for preparation thereof and pharmaceutical composition for preventing or treating cancer, containing thereof as active ingredient - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a benzamide derivative of formula 1 or an optical isomer thereof. In formula 1, the values of the variables are as follows: X, Y and Z independently represent CH or N; R¹ is -H, halogen, C_1-10 alkyl, unsubstituted or substituted with one or more halogens, C_1-10 alkoxy, unsubstituted or substituted with one or more halogens, nitro, C_1-10 alkylsulfanyl, cyano or 5-membered heteroaryl containing 2 ring heteroatoms N; R² is a substituted phenyl or substituted 6-member heteroaryl containing 1–2 ring heteroatoms N, where said substituted phenyl is phenyl substituted with 1–2 substitutes selected from halogen, C_1-10 alkyl and amino-substituted piperidinyl, where said substituted 6-member heteroaryl is 6-member heteroaryl substituted with 1–2 substitutes selected from halogen, unsubstituted C_1-10 alkyl substituted C_1-10 alkyl, C_1-5 alkyl-substituted bicyclic 8-member heterocycloalkyl containing 2 ring heteroatoms N, and unsubstituted or substituted 4–8-membered fully or partially saturated heterocycloalkyl containing 1–2 heteroatoms N, where said substituted C_1-10 alkyl is substituted with 5–6 membered heterocycloalkyl containing 1 ring heteroatom N, which is substituted with 1 or 2 C_1-5 alkyl-substituted amino groups, where said substituted 4–8-membered fully or partially saturated heterocycloalkyl is 4–8-membered heterocycloalkyl substituted with one substituent selected from the group consisting of -OH, C_1-5 alkyl, C_1-5 alkyl substituted with 5–6-membered heterocycloalkyl containing 1–2 ring heteroatoms selected from N and O, amino, unsubstituted or substituted with 1 or 2 C_1-5 alkyl, 5–6-membered heterocycloalkyl containing 1 ring heteroatom N and unsubstituted or substituted C_1-5 alkyl, C_1-5 alkoxycarbonyl, 5–6 membered heteroaryl containing 1–3 ring heteroatoms N, phenylaminocarbonyl and C_1-5 alkoxy-C_1-5 alkoxy-phenyl; R³ is a halogen; R⁴ is -OH or C_1-15 alkoxy; R⁵ is -H; and R⁶ is -H or halogen. Also disclosed is the use of a compound of formula 1 or an optical isomer thereof for producing a drug for treating cancer with an EGFR mutation.

EFFECT: disclosed benzamide derivative can be used for preventing or treating cancer by suppressing the EGFR mutation and, when administered in combination with an EGFR antagonist, such as cetuximab, exhibits a significant synergistic anticancer effect.

8 cl, 2 tbl, 72 ex

Description

LEVEL OF TECHNOLOGY

1. Field of technology

The present invention relates to a benzamide derivative, a method for producing it, and a pharmaceutical composition for preventing or treating cancer containing it as an active ingredient.

2. Description of the prior art

Cancer incidence is associated with a variety of environmental factors, including chemicals, radiation, and viruses, as well as changes in oncogenes, tumor suppressor genes, and genes associated with apoptosis and DNA repair. Recent understanding of the molecular mechanisms of cancer has led to the development of targeted cancer therapy, a new treatment option.

Targeted agents are usually designed to target molecules that are specific to cancer cells to demonstrate their efficacy. The molecular targets include genes related to cancer cell signal transduction pathway, angiogenesis, matrix, cell cycle regulator, and apoptosis. Currently, “signal transduction pathway inhibitors,” including tyrosine kinase inhibitors and “angiogenesis inhibitors,” are used as important targeted agents in cancer treatment.

Protein tyrosine kinase is known to play an important role in many malignancies. 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 carcinoma (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, and EGFR tyrosine kinase activation has been known to cause continuous cell proliferation, invasion into surrounding tissues, distant metastasis, angiogenesis and increase cell survival.

In particular, EGFR is one of the ErbB family of tyrosine kinase receptors (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 ligand binds to the receptor, forming a homodimer or heterodimer, the intracellular tyrosine kinase is activated, and the signal stimulated by EGFR activates the phosphatidylinositol 3-kinase signaling pathway (PI3K/AKT/mT0R, RAS/RAF/MAPK, JAK/STAT) (Non-patent reference 1, Nat Rev Cancer 2007;7:169-81. Epidermal growth factor receptor mutations in lung cancer).

In particular, EGFR is overexpressed in more than half of non-small cell lung cancer (NSCLC) cases, and many studies have been conducted using EGFR as a treatment target. EGFR TKI (tyrosine kinase inhibitor) has been developed that inhibits EGFR tyrosine kinase activity, and typical drugs include gefitinib (IRESSA™), erlotinib (TARCEVA™), and lapatinib (TYKERB™, ΤYVERB™).

On the other hand, in 2004, it was reported that EGFR activation mutation correlated with the response to gefitinib therapy in non-small cell lung cancer (NSCLC). Specifically, EGFR mutation is largely classified into sensitizing mutation and resistance mutation, and exon 19 deletion and exon 21 L858R point mutation are the most important sensitizing mutations, accounting for about 85-90%, and exon 19 mutation is known to have the best sensitivity to TKIs. On the other hand, exon 20 T7 90M point mutation is the most important resistance mutation, and it is known to be found in more than 50% of patients with acquired resistance.

Somatic mutations identified to date include in-frame deletions in exon 19 or insertions in exon 20, as well as point mutations in which a single nucleic acid residue is modified in the expressed protein (e.g., L858R, G719S, G719C, G719A, and L861Q).

Despite the initial clinical effects of gefitinib/erlotinib in patients with EGFR-mutated NSCLC, most patients eventually develop progressive disease while receiving therapy with these agents. Early studies of relapsed specimens identified a secondary EGFR mutation, T790M, that renders zepitinib and erlotinib ineffective inhibitors of EGFR kinase activity. Subsequent studies showed that the EGFR T7 90M mutation was found in approximately 50% (24/48) of tumors from patients who acquired resistance to gefitinib or erlotinib. This secondary genetic modification occurs at a position similar to the gatekeeper residue and its associated secondary resistance allele in patients receiving kinase inhibitors (eg, T315Ι in ABL in imatinib-resistant CML).

It has long been known that the EGFR mutation, EGFR_de119 or EGFR_L858R, is the main cause of non-small cell lung cancer and head and neck cancer, and therapeutic drugs for them, Iressa and Taseba, have been developed and are currently used in clinical trials. However, acquired resistance resulting from secondary EGFR mutations due to the drug structure has been observed in patients with these drugs, and this has also been found to be the main cause of actual drug resistance. When using first-generation EGFR inhibitors, acquired resistance, the T790M mutation located in the gatekeeper of EGFR kinase, occurs within an average of 10 months, and first-generation EGFR inhibitors become ineffective. That is, a double mutation of EGFR_de119_T790M or EGFR_L858R_T790M occurs, and traditional therapeutic agents do not show efficacy.

Based on these facts, there is a need to develop 2nd and 3rd generation drugs with excellent drug efficacy and new structure.

Over the past 10 years, various new 3rd generation drug candidates that target the EGFR T790M double mutation have been discovered and are in ongoing clinical trials, and the most advanced of them is AZD9291 by the multinational pharmaceutical company AstraZeneca. However, resistance to AZD9291 has been reported to occur after about 10 months, resulting in the loss of efficacy of AZD9291, and in particular, resistance to triple mutations including C797S has been reported.

Accordingly, there is a need to develop inhibitors that exhibit relatively low inhibition of wild-type EGFR and higher inhibition of specific activated or resistant mutant forms of EGFR.

ESSENCE OF THE INVENTION

The aim of the present invention is to provide a benzamide derivative capable of preventing or treating cancer by inhibiting EGFR mutation.

Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cancer containing a benzamide derivative as an active ingredient.

Another object of the present invention is to provide a functional therapeutic food product intended for the prevention or alleviation of cancer, comprising a benzamide derivative as an active ingredient.

Another object of the present invention is to provide a combination composition for the prevention or treatment of cancer containing a benzamide derivative as an active ingredient.

In order to achieve the above objects, in one 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 pharmaceutically acceptable salt thereof.

[Formula 1]

In formula 1

X, Y and Z independently represent carbon or nitrogen atoms;

R ¹ is -H, -OH, halogen, C _1-10 alkyl, unsubstituted or substituted by one or more halogens, C _1-10 alkoxy, unsubstituted or substituted by one or more halogens, nitro, C _1-10 alkylsulfanyl, cyano, amino, C _1-10 alkylamino, or 5-6-membered heteroaryl;

R ² is substituted C _6-10 aryl or substituted 5-10 membered heteroaryl,

wherein the substituted C _6-10 aryl or substituted 5-10 membered heteroaryl is independently substituted aryl or heteroaryl substituted with one or more substituents selected from the group consisting of halogen, unsubstituted or substituted C _1-10 alkyl, and unsubstituted or substituted 4-10 membered fully or partially saturated heterocycloalkyl,

wherein the substituted C _1-10 alkyl is substituted by a 5-6-membered heterocycloalkyl in which 1 or 2 C _1-5 alkyl are substituted by a substituted amino,

substituted 4-10 membered fully or partially saturated heterocycloalkyl is a 4-10 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of -OH, halogen, C _1-5 alkyl unsubstituted or substituted with one or more halogens, C _1-5 alkyl substituted with 5-6 membered heterocycloalkyl, C _1-5 alkoxy unsubstituted or substituted with one or more halogens, nitro, C _1-5 alkylsulfanyl, cyano, amino unsubstituted or substituted with 1 or 2 C _1-5 alkyls, 5-6 membered heterocycloalkyl unsubstituted or substituted with C _1-5 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 aryl;

R ³ is halogen;

R ⁴ is -OH, halogen or C _1-15 alkoxy;

R ⁵ is -H, -OH, halogen, C _1-4 alkyl or C _1-4 alkoxy; and

R ⁶ is -H, -OH, halogen, C _1-4 alkyl or C _1-4 alkoxy.

In another aspect of the present invention, the present invention provides a pharmaceutical composition containing a compound represented by formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of cancer.

In another aspect of the present invention, the present invention provides a functional therapeutic food composition containing a compound represented by formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient for preventing or alleviating cancer.

In another aspect of the present invention, the present invention provides a combination composition comprising a compound represented by formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient for preventing or alleviating cancer.

PREFERENTIAL EFFECT

The benzamide derivative provided in one aspect of the present invention can be used for the prevention or treatment of cancer by inhibiting EGFR mutation, and can be effectively used as an anticancer agent because it exhibits a significant synergistic effect when co-administered with an EGFR antagonist such as cetuximab.

DESCRIPTION OF PREFERRED IMPLEMENTATION OPTIONS

The present invention is now described in detail.

The embodiments of the present invention can be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. It is well understood by those skilled in the art who have an average level of knowledge in this field that the embodiments of the present invention are given to more accurately explain the present invention.

Furthermore, the "inclusion" of one element in a description does not exclude other elements, but may include other elements unless specifically stated otherwise.

The term "alkylene", "alkenyl" or "alkyl" includes straight or branched chain saturated hydrocarbon residues unless otherwise specified. For example, "C _1-6 alkyl" refers to an alkyl having a backbone of 1-6 carbon atoms. In particular, C _1-6 alkyl can include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, sec-pentyl, neopentyl, hexyl and the like.

The term "cycloalkyl", unless otherwise specified, includes carbocyclic groups containing carbon atoms. For example, "C _3-8 cycloalkyl" refers to a cycloalkyl with a backbone of 3-8 carbon atoms. In particular, C _3-8 cycloalkyl can include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "heterocycloalkyl", unless otherwise specified, includes a monovalent saturated moiety consisting of 1-3 rings containing 1, 2, 3, or 4 heteroatoms selected from N, O, or S. Two or three rings may include bridged, fused, or spiroheterocycloalkyl.

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

In one 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 pharmaceutically acceptable salt thereof.

[Formula 1]

In formula 1,

X, Y and Z independently represent carbon or nitrogen atoms;

R ¹ is -H, -OH, halogen, C _1-10 alkyl, unsubstituted or substituted by one or more halogens, C _1-10 alkoxy, unsubstituted or substituted by one or more halogens, nitro, C _1-10 alkylsulfanyl, cyano, amino, C _1-10 alkylamino, or 5-6-membered heteroaryl;

R ² is substituted C _6-10 aryl or substituted 5-10 membered heteroaryl,

wherein the substituted C _6-10 aryl or substituted 5-10 membered heteroaryl is independently substituted aryl or heteroaryl substituted with one or more substituents selected from the group consisting of halogen, unsubstituted or substituted C _1-10 alkyl, and unsubstituted or substituted 4-10 membered fully or partially saturated heterocycloalkyl,

wherein the substituted C _1-10 alkyl is substituted with a 5-6-membered heterocycloalkyl in which 1 or 2 C _1-5 alkyl are substituted with a substituted amino,

substituted 4-10 membered fully or partially saturated heterocycloalkyl is a 4-10 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of -OH, halogen, C _1-5 alkyl unsubstituted or substituted with one or more halogens, C _1-5 alkyl substituted with 5-6 membered heterocycloalkyl, C _1-5 alkoxy unsubstituted or substituted with one or more halogens, nitro, C _1-5 alkylsulfanyl, cyano, amino unsubstituted or substituted with 1 or 2 C _1-5 alkyls, 5-6 membered heterocycloalkyl unsubstituted or substituted with C _1-5 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 aryl;

R ³ is halogen;

R ⁴ is -OH, halogen or C _1-15 alkoxy;

R ⁵ is -H, -OH, halogen, C _1-4 alkyl or C _1-4 alkoxy; and

R ⁶ is -H, -OH, halogen, C _1-4 alkyl or C _1-4 alkoxy.

In another aspect,

X, Y and Z independently represent carbon or nitrogen atoms;

R ¹ is -H, -OH, halogen, C _1-5 alkyl, unsubstituted or substituted by one or more halogens, C _1-5 alkoxy, unsubstituted or substituted by one or more halogens, nitro, C _1-5 alkyl sulfanyl, cyano, amino, C _1-5 alkylamino, or 5-6-membered heteroaryl;

R ² is substituted C _6-10 aryl or substituted 5-6-membered heteroaryl,

wherein the substituted C _6-10 aryl or substituted 5-6-membered heteroaryl is independently aryl or heteroaryl substituted with one or more substituents selected from the group consisting of halogen, unsubstituted or substituted C _1-5 alkyl, and unsubstituted or substituted 4-8-membered fully or partially saturated heterocycloalkyl containing at least one N,

where the substituted C _1-5 alkyl is substituted by a 6-membered heterocycloalkyl in which 2 C _1-5 alkyl are substituted by a substituted amino,

substituted 4- to 8-membered fully or partially saturated heterocycloalkyl is a 4- to 8-membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of -OH, halogen, C _1-5 alkyl unsubstituted or substituted with one or more halogens, C _1-5 alkyl substituted by 5- to 6-membered heterocycloalkyl, C _1-5 alkoxy unsubstituted or substituted with one or more halogens, nitro, C _1-5 alkylsulfanyl, cyano, amino unsubstituted or substituted with 1 or 2 C _1-5 alkyls, 5- to 6-membered heterocycloalkyl unsubstituted or substituted with C _1-5 alkyl, 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 aryl;

R ³ is halogen;

R ⁴ is -OH, halogen or C _1-10 alkoxy;

R ⁵ is -H, -OH, or halogen; and

R ⁶ is -H, halogen, C _1-4 alkyl or C _1-4 alkoxy.

In another aspect,

X, Y and Z independently represent carbon or nitrogen atoms;

R ¹ is -H, -OH, halogen, C _1-5 alkyl unsubstituted or substituted by one or more halogens, C _1-5 alkoxy unsubstituted or substituted by one or more halogens, nitro, C _1-5 alkyl sulfanyl, cyano, amino, C _1-5 alkylamino, or 5-membered heteroaryl containing at least one N;

R ² is substituted phenyl or substituted 6-membered heteroaryl containing at least one N,

wherein the substituted phenyl or substituted 6-membered heteroaryl is independently phenyl or heteroaryl substituted with one or more substituents selected from the group consisting of halogen, unsubstituted or substituted C _1-3 alkyl, and unsubstituted or substituted 4-8-membered fully or partially saturated heterocycloalkyl containing at least one N,

where the substituted C _1-3 alkyl is substituted by a 6-membered heterocycloalkyl in which 2 C _1-3 alkyl are substituted by a substituted amino group,

substituted 4-8-membered heterocycloalkyl is a 4-8-membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of -OH, C _1-3 alkyl, unsubstituted or substituted by 5-6-membered heterocycloalkyl, amino, unsubstituted or substituted by 1 or 2 C _1-3 alkyls, 5-6-membered heterocycloalkyl, unsubstituted or substituted by C _1-3 alkyl, C _1-4 alkoxycarbonyl, 5-membered heteroaryl containing at least one N, phenylaminocarbonyl, and C _1-3 alkoxy-C _1-3 alkoxyphenyl;

R ³ is halogen;

R ⁴ is -OH, halogen or C _1-5 alkoxy;

R ⁵ is -H, -OH, or halogen; and

R ⁶ is -H, halogen, C _1-4 alkyl or C _1-4 alkoxy.

In another aspect,

X, Y and Z independently represent carbon or nitrogen atoms;

R ¹ is -H, -F, -Cl, -OH, -CH ₃ , -CF ₃ , -OCH ₃ , -OCF, isopropyl, tert-butyl, -SCH ₃ , -NO ₂ , -CN or imidazole,

R ² is

R ³ is -F or -Cl;

R ⁴ is -OH or -OCH ₃ ;

R ⁵ is -H, -OH, -F, -Cl, C _1-4 straight or branched alkyl, or C _1-4 straight or branched alkoxy; and

R ⁶ is -H, -OH, -F, -Cl, C _1-4 straight or branched alkyl, or C _1-4 straight or branched alkoxy.

Preferably,

X represents carbon or nitrogen atoms;

Y and Z represent carbon atoms;

R ¹ is -H, -F, -Cl, -OH, -CH ₃ , -CF ₃ , -OCH ₃ , -OCF ₃ , isopropyl, tert-butyl, -SCH ₃ , -NO, -CN or imidazole,

R ² is

R ³ is -F;

R ⁴ is -OH or -OCH ₃ ;

R ⁵ is -H; and

R ⁶ is -H, -F, or -Cl.

Preferably, the compound represented by formula 1 may be a compound represented by formula 2 below.

[Formula 2]

In formula 2, X, Y, Z, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ independently have the meanings defined in formula 1 above.

In another aspect,

X represents carbon or nitrogen atoms;

Y and Z represent carbon atoms;

R ¹ is -H, -F, -Cl, -OH, -CH ₃ , -CF ₃ , -OCH ₃ , -OCF ₃ , isopropyl, tert-butyl, -SCH ₃ , -NO ₂ , -CN or imidazole;

R ² is

R ³ is -F;

R ⁴ is -OH or -OCH ₃ ;

R ⁵ is -H; and

R ⁶ is -H, -F, or -Cl.

Most preferably, the compound represented by formula 1 may be any 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)-Ν-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methoxy-[1,1'-biphenyl]-3-carboxamide;

(4) (R)-4'-(4-amino piperidin-1-yl)-5-(tert-butyl)-Ν-((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)-Ν-((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)-Ν-((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)-Ν-((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)-Ν-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)isonicotinamide;

(15) (R)-2-(4-(4-aminopiperidin-1-yl)phenyl)-Ν-((5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methyl)isonicotinamide;

(16) (R)-3-(2-(4-aminopiperidin-1-yl)pyrimidin-5-yl)-Ν-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide;

(17) (R)-3-(5-(4-aminopiperidin-1-yl)pyridin-2-yl)-Ν-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide;

(18) (R)-3-(5-(4-aminopiperidin-1-yl)pyrazin-2-yl)-Ν-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide;

(19) (R)-3-(6-(4-aminopiperidin-1-yl)pyridin-3-yl)-Ν-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide;

(20) (R)-3-(6-(4-aminopiperidin-1-yl)pyridazin-3-yl)-Ν-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide;

(21) (R)-3-(5-(4-aminopiperidin-1-yl)pyrimidin-2-yl)-Ν-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide;

(22) (R)-4'-(4-aminopiperidin-1-yl)-3'-fluoro-Ν-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide;

(23) (R)-4'-(4-aminopiperidin-1-yl)-Ν-((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-Ν-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide;

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

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

(29) (R)-4'-(4-aminopiperidin-1-yl)-Ν-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-4-methyl-[1,1'-biphenyl]-3-carboxamide;

(30) (R)-4'-(4-aminopiperidin-1-yl)-Ν-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-2-methyl-[1,1'-biphenyl]-3-carboxamide;

(31) (S)-4'-(4-aminopiperidin-1-yl)-Ν-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methyl-[1,1'-biphenyl]-3-carboxamide;

(32) 4'-(4-aminopiperidin-1-yl)-Ν-((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)-Ν-((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-methylbenzamide;

(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-(lH-l,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'-bipiperidin]-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.

The compound represented by formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, wherein the salt is preferably an acid addition salt formed by pharmaceutically acceptable free acids. Herein, the acid addition salt can be derived 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, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid and fumaric acid. Examples of 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, isobutylate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, cabacate, fumarate, malate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutylate, citrate, lactate, hydroxybutylate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and mandelate.

The acid addition salt of the present invention can be produced by a conventional method known to those skilled in the art. For example, a derivative represented by formula 1 is dissolved in an organic solvent such as methanol, ethanol, acetone, methylene chloride and acetonitrile, to which an organic acid or an inorganic acid is added to induce precipitation. Then, the precipitate is filtered and dried to obtain a salt. Or, the solvent and excess acid are distilled under reduced pressure and dried to obtain a salt. Or, the precipitate is crystallized in an organic solvent to obtain the same.

A pharmaceutically acceptable metal salt can be obtained using a base. The alkali metal or alkaline earth metal salt is obtained by the following methods: dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution; filtering the insoluble salt of the compound; evaporating the remaining solution and drying it. In this case, the metal salt is preferably obtained in a pharmaceutically suitable form of sodium, potassium or calcium salt. And the corresponding silver salt is obtained by reacting the alkali metal or alkaline earth metal salt with the corresponding silver salt (e.g. silver nitrate).

In addition, the present invention includes not only the compound represented by formula 1, but also a pharmaceutically acceptable salt thereof and a solvate, optical isomer or hydrate possibly derived therefrom.

The term "hydrate" refers to a compound or a salt thereof of the present invention containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. A hydrate of the compound represented by 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 1 equivalent or more of water, preferably 1-5 equivalents of water. The hydrate can be obtained by crystallizing the compound represented by formula 1, its isomer or a pharmaceutically acceptable salt thereof from water or a solvent containing water.

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

The term "isomer" refers to a compound or a salt thereof according to the present invention having the same chemical formula or molecular formula, but structurally or spatially different. Such isomers include structural isomers such as tautomers, R or S isomers having an asymmetric carbon center, stereoisomers such as geometric isomers (trans, cis), and optical isomers (enantiomers). All these isomers and mixtures thereof are also included within the scope of the present invention.

The compound represented by formula 1 can be obtained by the following general formulas, and general formulas 1 and 2 corresponding to the method for obtaining the compound of Example 1 are shown below.

General Formula 1:

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 dissolved in dioxane, MeOH, rt, 1 h.

General Formula 2:

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-butylpiperidin-4-ylcarbamate, Ruphos Pd G1, Cs ₂ CO ₃ , dioxane, 110°C, overnight; (d) NaOH, dioxane, 110°C, overnight; (e) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydroxybenzotriazole, _{triethylamine} , _CH2Cl2 , rt, overnight; (f) 1 μM _BBr3 dissolved in _CH2Cl2 , ₀ °C to rt, 30 min.

In another aspect of the present invention, the present invention provides a pharmaceutical composition containing a compound represented by formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of cancer.

In this case, the compound can inhibit the EGFR (epidermal growth factor receptor) mutation for the prevention or treatment of cancer. At present, the EGFR mutation is at least one mutation selected from the group consisting of EGFR L858R/T790M and EGFR L858R/T790M/C797S.

The compound represented by formula 1 of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally and used in conventional pharmaceutical formulation forms. That is, the compound or a pharmaceutically acceptable salt thereof can be prepared for oral or parenteral administration by mixing with commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants and surfactants. Solid formulations for oral use are tablets, pills, powders, granules and capsules. These solid formulations are obtained by mixing one or more compounds with one or more suitable excipients such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. Except for simple excipients, lubricating agents such as magnesium stearate, talc, etc. can be used. Liquid formulations for oral administration are suspensions, solutions, emulsions and syrups, and the above-mentioned formulations may contain various excipients such as wetting agents, sweeteners, flavoring agents and preservatives, in addition to the commonly used simple diluents such as water and liquid paraffin. Formulations for parenteral administration are sterilized aqueous solutions, water-insoluble excipients, suspensions and emulsions.

Water-insoluble excipients and suspensions may contain, in addition to the active compound or compounds, propylene glycol, polyethylene glycol, a vegetable oil such as olive oil, an injectable ester such as ethyl ester, etc.

A pharmaceutical composition containing a compound represented by formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.

At present, in order to obtain a compound represented by formula 1 or a pharmaceutically acceptable salt thereof as a parenteral formulation, the compound represented by formula 1 or a pharmaceutically acceptable salt thereof is mixed with a stabilizer or a buffering agent in water to obtain a solution or suspension, which is then formulated into ampoules or vials. The composition of the present invention can be sterilized and further contains preservatives, stabilizers, wettable powders or emulsifiers, salts and/or buffers for adjusting osmotic pressure and other therapeutically useful materials, and the composition can be formulated by a conventional mixing, granulating or coating method.

Examples of formulations for oral administration are tablets, pills, hard/soft capsules, solutions, suspensions, emulsions, syrups, granules, elixirs, lozenges, etc. These formulations may include diluents (e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine) and lubricating agents (e.g. silicon dioxide, talc, stearate and its magnesium or calcium salt and/or polyethylene glycol) in addition to the active ingredient. The tablets may include binding agents such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if necessary, disintegrating agents such as starch, agarose, alginic acid or its sodium salt or azeotropic mixtures and/or absorbents, colorants, flavors and sweeteners may be additionally included.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective dose.

The term "pharmaceutically effective dose" means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment or improvement. An effective dose level depends on factors such as the type and severity, age, sex of the subject, activity of the drug, sensitivity to the drug, time of administration, route of administration and rate of excretion, duration of treatment, concomitant drugs and other factors well known in the medical field. For example, an effective dose includes from 0.001 mg/kg to 100 mg/kg, from 0.01 mg/kg to 10 mg/kg or from 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 by those skilled in the art within a suitable range.

In another aspect of the present invention, the present invention provides a functional therapeutic food composition containing a compound represented by formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient for preventing or alleviating cancer.

The compound represented by formula 1 of the present invention can be added in pure form or mixed with other food components according to a conventional method. The mixing ratio of the active ingredients can be adjusted depending on the purpose of use (prevention or relief). In general, the compound of the present invention is preferably added to food or beverages in an amount of 0.1 to 90 parts by weight of the total weight of the food. However, if long-term administration is required for maintaining health and hygiene or regulating health conditions, the content may be lower than the above, but a higher content may be acceptable because the compound of the present invention has been proven to be very safe.

In addition, the health drink composition of the present invention may further include various flavors or natural carbohydrates, etc., like other drinks. The above-mentioned natural carbohydrates may be one 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 such as rebaudioside A, glycyrrhizin, etc.) and synthetic sweeteners (saccharin, aspartame, etc.) may be included as a sweetener. The content of the natural carbohydrate is preferably 1-20 g, and more preferably 5-12 g in 100 g of the composition of the present invention.

In addition to the ingredients mentioned above, the compound represented by formula 1 of the present invention may include various nutrients, vitamins, minerals (electrolytes), flavors including natural flavors and synthetic flavors, colorants and fillers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH regulators, stabilizers, antiseptics, glycerin, alcohols, carbonators that were previously added to carbonated drinks, etc. In addition, the compound represented by formula 1 of the present invention may contain natural fruit juice and fruit pulp for the production of fruit juice-containing drinks and vegetable drinks.

In another aspect of the present invention, the present invention provides a combination preparation containing a compound represented by formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of cancer.

At present, a combination preparation is a preparation in which at least one component selected from the group consisting of the components described below is administered in combination with a compound represented by formula 1.

In addition, the anticancer treatment described herein may be used as a monotherapy or may include conventional surgery, radiation therapy, chemotherapy or immunotherapy in addition to the compound of the present invention. Such chemotherapy may be administered simultaneously, sequentially or separately with the treatment using the compound of the present invention, and one or more of the following categories of anticancer agents may be used for the chemotherapy.

(i) Antiproliferative/antineoplastic drugs and combinations thereof used in medical oncology, such as alkylating agents (e.g. cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolamide and nitrosoureas); antimetabolites (e.g. gemcitabine and antifolates such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumor antibiotics (e.g. anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin C, dactinomycin and mithramycin); mitotic inhibitors (eg, vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, taxoids such as taxol and taxotere, and polokinase inhibitors); and topoisomerase inhibitors (eg, epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, and camptothecin);

(ii) Cell proliferation inhibitors, such as antiestrogens (e.g. tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxifene), antiandrogens (e.g. bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g. goserelin, leuprorelin and buserelin), progesterones (e.g. megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrozole, vorazole and eximestane) and 5α-reductase inhibitors such as finasteride;

(iii) Invasion inhibitors [e.g. c-Src kinase inhibitors such as 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 bosutinib (SKI-606), and metalloproteinase inhibitors such as marimastat, urokinase-type plasminogen activator receptor inhibitors or heparan antibodies];

(iv) Growth factor inhibitors (e.g., growth factor antibodies and growth factor receptor antibodies such as the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225], and any growth factor or growth factor receptor antibody described in the literature [Stern et al. Critical reviews in oncology/haematology, 2005, Vol. 54, pp11-299]; tyrosine kinase inhibitors such as epidermal growth factor inhibitors (e.g., EGFR tyrosine kinase inhibitors such as 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 1033), 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., Ras/Raf signaling inhibitors such as farnesyltransferase inhibitors such as sorafenib (BAY 43-9006), tipifarnib (R115777), and lonafarnib (SCH66336)), inhibitors of cell signaling through MEK and/or AKT kinase, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF (insulin-like growth factor) receptor kinase inhibitors; aurora kinase inhibitors (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin-dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors);

(v) Angiogenesis inhibitors, such as those that inhibit the effect of vascular endothelial growth factor [e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin™) and VEGF receptor tyrosine kinase inhibitors such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 of WO 00/47212], e.g., the compounds described in WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354, and compounds acting by other mechanisms (e.g. linomid, an integrin αvβ3 inhibitor and angiostatin)];

(vi) vascular damaging agents such as Combretastatin A4 and the compounds described in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) endothelial receptor antagonists such as zivotentan (ZD4054) or atrasentan;

(viii) antisense therapies, such as against the targets listed above, such as ISIS 2503 and anti-ras antisense;

(ix) Gene therapy approaches (e.g. approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) approaches such as cytosine deaminase, thymidine kinase or bacterial nitroreductase approaches, and approaches to enhance a patient's resistance to chemotherapy or radiotherapy such as multidrug resistance gene therapy); and

(x) Immunotherapy approaches (e.g., in vitro and in vivo approaches to enhance the immunogenicity of a patient's tumor cells, such as approaches using transfection with 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 cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines, approaches using anti-idiotypic antibodies, approaches to reduce the action of immunosuppressive cells such as regulatory T cells, myeloid-derived suppressor cells, or IDO (indoleamine 2,3-deoxygenase) expressing dendritic cells, and approaches using cancer vaccines composed of proteins or peptides derived from tumor-associated antigens such as NY-ESO-1, MAGE-3, WT1 or Her2/neu).

Thus, in a further aspect of the present invention, there is provided a pharmaceutical product for the combination treatment of cancer comprising a compound of formula (I) as defined above and an additional antitumor agent as defined above.

In this aspect of the present invention there is provided a pharmaceutical product for the combination treatment of cancer comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and an additional antitumor agent as defined above.

In this description, when the term "combination treatment" is used in relation to a combination therapy, it should be understood that it can mean simultaneous, separate or sequential administration. The meaning of "combined administration" should be interpreted similarly to "combination treatment". In one aspect of the present invention, "combination treatment" refers to simultaneous administration. In another aspect of the present invention, "combination treatment" refers to separate administration. In a further aspect of the present invention, "combination treatment" refers to sequential administration. If the administration is sequential or separate, the delay in administering 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, sequential treatment comprises administering each component of the combination for 11 days. In another embodiment, said period of time is 10 days. In another embodiment, said period of time is 9 days. In another embodiment, said period of time is 8 days. In another embodiment, said period of time is 7 days. In another embodiment, the said period of time is within 6 days. In another embodiment, the said period of time is within 5 days. In another embodiment, the said period of time is within 4 days. In another embodiment, the said period of time is within 3 days. In another embodiment, the said period of time is within 2 days. In another embodiment, the said period of time is within 24 hours. In another embodiment, the said period of time is within 12 days.

In another aspect of the present invention, the present invention provides a method for treating cancer, which comprises the step of administering a pharmaceutical composition or a functional therapeutic food composition containing a compound represented by formula 1, its optical isomer, its solvate, its hydrate or its pharmaceutically acceptable salt as an active ingredient, to a subject in need.

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 pharmaceutically acceptable salt thereof for use in the prevention or treatment of cancer.

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

The benzamide derivative provided in the aspect of the present invention can be used for the prevention or treatment of cancer by suppressing the mutation of EGFR, and exhibits a remarkable synergistic effect on anticancer activity when administered in combination with an EGFR antagonist such as Cetuximab, so that it can be effectively used as an anticancer agent. The above is supported by the examples and experimental examples described below.

The method or use may employ the detailed description of the pharmaceutical composition described above.

The present invention will now be described in detail using the following examples and experimental examples. However, the following examples and experimental examples are intended only to illustrate the present invention, and the content of the present invention is not limited to them.

General Formula 1:

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) δ N NaOH, MeOH, reflux overnight; (d) 4 N HCl dissolved in dioxane, MeOH, rt, 1 h.

Example of obtaining 1]

(S, E)-N-(5-fluoro-2-methoxybenzenlidene)-2-methylpropane-2-sulfinamide

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) 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 2-4 h. The reaction mixture was extracted with ethyl acetate and water. The ethyl acetate layer was collected, dried over anhydrous sodium sulfate and filtered, and the solvent was removed by evaporation under reduced pressure. The residue was purified by flash column chromatography (hexane/EtOAc, 10:1) packed with silica gel to give (S,E)-N-(5-fluoro-2-methoxybenzylidene)-2-methylpropane-2-sulfinamide (40.6 g).

95% yield: 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 ⁺ ].

[Example of receipt 2]

(S)-N-((R)-(5-fluoro-2-methoxyphenyl)(1-(phenylsulfonyl)-1H-indol-2-yl)methyl)-2-methylpropane-2-sulfinamide

At -78°C, n-butyl lithium 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 thereto, and the mixture was stirred at -78°C for 2 hours. The reaction was terminated by adding saturated aqueous NH ₄ Cl solution to the mixture, followed by extraction with vinyl acetate. The ethyl acetate layer was collected, dried over anhydrous sodium sulfate, and filtered. The solvent was removed by evaporation under reduced pressure. The residue was purified by flash column chromatography (CH ₂ Cl ₂ /EtOAc, 10:1) packed with silica gel to give (S)-N-((R)-(5-fluoro-2-methoxyphenyl)(1-(phenylsulfonyl)-1H-indol-2-yl)methyl)-2-methylpropane-2-sulfinamide [Preparation Example 2] as a white solid (79.0 g, 98%).

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 ⁺ ].

[Example of receipt 3]

(S)-N-((R)-(5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methyl)-2-methylpropane-2-sulfinamide

NaOH dissolved in water (8 N, 69.6 g, 768 mmol, 96.0 mL) 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. An 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%).

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).

[Example of receipt 4]

(R)-(5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methanamine

At room temperature, 4 N HCl dissolved in dioxane (0.16 ml, 0.32 mmol) 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 obtain (R)-(5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methanamine [Preparation Example 4] (yellow solid) in 97% yield.

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 ⁺ ].

General formula 2:

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-yl carbamate, Ruphos PdGl, _Cs2CO3 , _dioxane , 110°C, overnight; (d) NaOH, dioxane, 110°C, overnight; (e) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydroxybenzotriazole, _{triethylamine} , _CH2Cl2 , rt, overnight; (f) 1 M _BBr3 dissolved in _CH2Cl2 , ₀ °C to rt, 30 min.

[Example of receiving 5]

methyl 4'-hydroxy-5-methyl-[1,1'-biphenyl]-3-carboxylate

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/ _H2O (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 then concentrated. The residue was purified by MPLC to give 4'-hydroxy-5-methyl-[1,1'-biphenyl]-3-carboxylate [Preparation Example 5] as a yellow solid (120 mg, 75%).

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 (brs, 1H), 3.98 (s, 3H), 2.47 (s, 3H); LC-MS: 243.2 [M+H ⁺ ].

[Example of receipt 6]

methyl 5-methyl-4'-(((trifluoromethyl)sulfonyl)oxy)-[1,1'-biphenyl]-3-carboxylate

At room temperature, 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) dissolved in anhydrous dichloromethane. The mixture was stirred for 3 h. 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 Example 6] as a yellow solid (102 mg, 66%).

^1H 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 ⁺ ].

[Example of receiving 7]

methyl 4'-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-5-methyl-[1,1'-biphenyl]-3-carboxylate

4-(tert-Butoxycarbonylamino)piperidine (61.1 mg, 0.31 mmol), methyl 5-methyl-4'-(((trifluoromethyl)sulfonyl)oxy)-[1,1'-biphenyl]-3-carboxylate [Preparation Example 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 Example 7] (yellow solid), which was used in the next step without further purification. (65 mg, 55%)

^1H 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 ⁺ ].

[Example of receiving 8]

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

At room temperature, NaOH (5.6 mg, 0.14 mmol) was added 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) dissolved in dioxane. The mixture was heated at 110°C and stirred for 12 hours. 1 N hydrochloric acid was added until the mixture reached pH 2. 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, 19%).

[Example of receiving 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

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) dissolved in _CH2Cl2 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 then 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%).

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 ⁺ ].

[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

1 M boron tribromide dissolved in dichloromethane (0.20 ml) was slowly added to tert-butyl (R)-(1-(3'-(((5-fluoro-2-methoxyphenylhydroxyphenyl)(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 sodium bicarbonate was added thereto at 0°C to complete the reaction. Tetrahydrofuran was added thereto along with saturated brine. The collected organic layer was dried over MgSO ₄ , filtered and concentrated. The residue was purified by PTLC to give (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.

¹ H 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, 2H), 2.74-2.81 (m, 2H), 2.65-2.71 (m, 1H), 2.46 (shs, 1H), 2.41 (s, 3H), 1.71-1.83 (m, 2H), 1.23-1.37 (m, 2H); LC-MS: 549.6 [M+H ⁺ ].

[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

(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] (3.4%) was prepared in a manner similar to that described in [Example 1]; LC-MS: 577.7 [M+H ⁺ ].

[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

(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].

¹ H NMR (400 MHz, DMSO-d ₆ ) 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 ⁺ ].

[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

(R)-4'-(4-aminopiperdin-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 manner similar to that described in [Example 1]; LC-MS: 591.7 [M+H ⁺ ].

[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

(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 obtained in a manner similar to that described in [Example 1].

¹ H NMR (400 MHz, DMSO-d ₆ ) 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 ⁺ ].

[Example 6]

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

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 obtained in a manner similar to that described in [Example 1].

^1H 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 ⁺ ].

[Example 7]

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

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 obtained in a manner similar to that described in [Example 1].

^1H 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 ⁺ ].

[Example 8]

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

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 obtained in a manner similar to that described in [Example 1].

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 (shd, 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 ⁺ ].

[Example 9]

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

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 obtained in a manner similar to that described in [Example 1].

^1H 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 ⁺ ].

[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

(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 obtained in a manner similar to that described in [Example 1].

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 (bdd, J=12.76 Hz, 2H), 2.70-2.83 (m, 3H), 1.77 (bdd, J=2.94, 12.57 Hz, 2H), 1.24-1.36 (m, 2H); LC-MS: 570.0 [M+H ⁺ ].

[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

(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 obtained in a manner similar to that described in [Example 1].

¹ H 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, 2H), 5.96 (s, 1H), 3.73 (shkv, J=13.01 Hz, 1H), 2.72-2.84 (m, 3H), 1.77 (shd, J=9.88 Hz, 2H), 1.27-1.36 (m, 2H); LC-MS: 619.6 [M+H ⁺ ].

[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

After obtaining the intermediate compound 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%) is obtained as a by-product of [Example 11].

¹ H 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 ⁺ ].

[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

(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 obtained in a manner similar to that described in [Example 1].

¹ H 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 ⁺ ].

[Example 14]

(R)-2-(4-(4-aminopiperidin-1-yl)phenyl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)isonicotinamide

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

¹ H NMR (400 MHz, DMSO-d6) δ 11.19 (br s, 1H), 9.60 (bd, 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 (bd, 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 (shd, J=12.76 Hz, 2H), 2.71-2.86 (m, 3H), 1.78 (shd, J=10.26 Hz, 2H), 1.26-1.37 (m, 2H); LC-MS: 536.6 [M+H ⁺ ].

[Example 15]

(R)-2-(4-(4-aminopiperidin-1-yl)phenyl)-N-((5-fluoro-2-methoxyphenyl)(1H-indol-2-yl)methyl)isonicotinamide

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

¹ H 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 (bd, 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 ⁺ ].

[Example 16]

(R)-3-(2-(4-aminopiperidin-1-yl)pyrimidin-5-yl)-N-((5-fluoro-2-pydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide

(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 obtained in a manner similar to that described in [Example 1].

¹ H 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 ⁺ ].

[Example 17]

(R)-3-(5-(4-aminopiperidin-1-yl)pyridin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide

(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 obtained in a manner similar to that described in [Example 1].

¹ H 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 (bd, 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 ⁺ ].

[Example 18]

(R)-3-(5-(4-aminopiperidin-1-yl)pyrazin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide

(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 obtained in a manner similar to that described in [Example 1].

¹ H 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 ⁺ ].

[Example 19]

(R)-3-(6-(4-aminopiperidin-1-yl)pyridin-3-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide

(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 obtained in a manner similar to that described in [Example 1].

¹ H 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 (bd, J=12.76 Hz, 2H), 2.88-2.98 (m, 2H), 2.75-2.85 (m, 1H), 2.41 (s, 3H), 1.75 (bd, J=12.38 Hz, 2H), 1.15-1.24 (m, 2H); LC-MS: 550.6 [M+H ⁺ ].

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

^1H NMR (400 MHz, DMSO-d6) δ ppm 11.08-11.21 (m, 1H), 9.25-9.45 (m, 1H) 8.00-8.11 (m, 1H), 8.37 (s, 1H), 7.96 (d, J=9.76 Hz, 1H), 7.80 (s, 1 N), 7.30-7.45 (m, 3 N), 7.18-7.26 (m, 1 N), 6.95 (shd, J=6.88 Hz, 3 N), 6.83 (s, 2 N), 6.00 (s, 1 N), 5.97-5.97 (m, 1 N), 4.24-4.40 (m, 2 N), 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 ⁺ ].

[Example 21]

(R)-3-(5-(4-aminopiperidin-1-yl)pyrimidin-2-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 [Example 21] (24%) was obtained in a manner similar to that described in [Example 1].

¹ H NMR (40 0 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 (bd, 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 ⁺ ].

[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

(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 obtained in a manner similar to that described in [Example 1].

¹ H 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 ⁺ ].

[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

(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 obtained in a manner similar to that described in [Example 1].

¹ H 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 (bd, 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 ⁺ ].

[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

(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 obtained in a manner similar to that described in [Example 1].

¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (br s, 1H), 9.22 (bd, 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, J=12, 8 Hz, 2H), 2.77-2.86 (m, 2H), 2.71-2.77 (m, 1H), 2.41 (s, 3H), 1.76 (bd, J=13.13 Hz, 2H), 1.23-1.33 (m, 2H); LC-MS: 567.6 [M+H ⁺ ].

[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

(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 obtained in a manner similar to that described in [Example 1].

¹ H 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 (bd, 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 ⁺ ].

[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

(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 obtained in a manner similar to that described in [Example 1].

¹ H 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 (s, 1H), 3.70 (shd, J=12.76 Hz, 2H), 2.67-2.81 (m, 3H), 2.41 (s, 3H), 1.74-1.82 (m, 2H), 1.23-1.37 (m, 2H); LC-MS: 5 67.6 [M+H ⁺ ].

[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

(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 obtained in a manner similar to that described in [Example 1].

¹ H 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 ⁺ ].

[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

(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 obtained in a manner similar to that described in [Example 1].

^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 ⁺ ].

[Example 29]

(R)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-55-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 [Example 29] (4%) was obtained in a manner similar to that described in [Example 1].

¹ H 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 (bd, 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 ⁺ ].

[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

(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 obtained in a manner similar to that described in [Example 1].

^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 (shd, 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 ⁺ ].

[Example 31]

(S)-4'-(4-aminopiperidin-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-56-methyl-[1,1'-biphenyl]-3-carboxamide

(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 obtained in a manner similar to that described in [Example 1].

¹ H 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 ⁺ ].

[Example 32]

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

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 obtained in a manner similar to that described in [Example 1].

¹ H 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 ⁺ ].

[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;

(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 obtained in a manner similar to that described in [Example 1].

¹ H 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 (bd, J=12.01 Hz, 2H), 2.69-2.79 (m, 3H), 2.44 (s, 3H), 2.32 (s, 3H), 1.83 (bd, J=10.88 Hz, 2H), 1.35-1.48 (m, 2H); LC-MS: 564.6 [M+H ⁺ ].

[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

(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 obtained in a manner similar to that described in [Example 1].

¹ H 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 (bd, J=0.75 Hz, 1H), 7.18 (dd, J=3.13, 9.76 Hz, 1H), 7.03 (bd, J=1.00 Hz, 1H), 6.91-6.99 (m, 2H), 6.85 (bd, 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 ⁺ ].

[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

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 obtained in a manner similar to that described in [Preparation Example 9].

¹ H 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=11.13, 7.57 Hz, 1H), 6.92-7.01 (m, 2H), 6.80-6.88 (m, 2H), 6.00 (t, J=1.00 Hz, 1H), 3.46-3.53 (m, 4H), 3.28-3.32 (m, 4H), 2.44 (s, 3H), 1.43 (s, 9H); LC-MS: 637.7 [M+H ⁺ ].

[Example 36]

(R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(piperazin-1-yl)pyrimidin-2-yl)benzamide

(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 obtained in a manner similar to that described in [Example 1].

¹ H 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 ⁺ ].

[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

(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 obtained in a manner similar to that described in [Example 1].

^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 (shd, J=12.26 Hz, 2H), 2.78-2.94 (m, 5H), 2.44 (s, 3H), 1.92 (shs, 2H), 1.64 (shd, J=10.13 Hz, 2H), 1.05-1.16 (m, 6H); LC-MS: 551.6 [M+H ⁺ ].

[Example 38]

N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-3-methyl-5-[5-(4-propyl-1-piperidyl)pyrimidin-2-yl]benzamide

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

^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 (shs, 2H), 1.23 (piece, J=7.44 Hz, 4H), 0.91-0.92 (m, 1H), 0.89 (t, J=7.13 Hz, 3H)); LC-MS: 557.7 [M+H ⁺ ].

[Example 39]

3-[5-[4-(dimethylamino)-1-piperidyl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-5-methylbenzamide

3-[5-[4-(Dimethylamino)-1-piperidyl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-5-methylbenzamide [Example 39] (7%) was obtained in a manner similar to that described in [Preparation Example 9].

¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.38 (br s, 1H), 8.61 (bd, 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 (bd, J=7.13 Hz, 1H), 6.34 (s, 1H), 3.62 (sd, 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 (shd, J=12, 13 Hz, 1H), 1.78 (shd, J=12.63 Hz, 1H), 1.52-1.65 (m, 1H), 1.39-1.50 (m, 1H), 1.28 (shs, 1H); LC-MS: 578.7 [M+H ⁺ ].

[Example 40]

N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-3-methyl-5-[5-(1-piperidyl)pyrimidin-2-yl]benzamide

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

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 ⁺ ].

[Example 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

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 [Example 41] (10%) was obtained in a manner similar to that described in [Preparation Example 9].

¹ H 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 (shs, 2H), 3.08 (s, 2H), 2.79 (shd, J=11.51 Hz, 2H), 2.67 (shdd, 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 (bd, J=11.51 Hz, 2H), 1.37-1.50 (m, 2H); LC-MS: 634.76 [M+H ⁺ ].

[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

(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 obtained in a manner similar to that described in [Preparation Example 9].

¹ H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.66 (br s, 1H), 9.29 (d, J=B,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 (bd, J=11.38 Hz, 2H), 2.43-2.48 (m, 3H), 2.16 (s, 6H), 2.00-2.10 (m, 1H), 1.96 (pcs, J=10.82 Hz, 2H), 1.71 (shd, J=12.01 Hz, 2H), 1.30-1.47 (m, 2H); LC-MS: 592.7 [M+H ⁺ ].

[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

(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 obtained in a manner similar to that described in [Preparation Example 9].

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 (bd, J=11.38 Hz, 2H), 2.43-2.48 (m, 3H), 2.16 (s, 6H), 2.00-2.10 (m, 1H), 1.96 (pcs, J=10.82 Hz, 2H), 1.71 (shd, J=12.01 Hz, 2H), 1.30-1.47 (m, 2H); LC-MS: 592.7 [M+H ⁺ ].

[Example 44]

3-[5-[(3R)-3-aminopyrrolidin-1-yl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-5-methylbenzamide

3-[5-[(3R)-3-aminopyrrolidin-1-yl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-5-methylbenzamide [Example 44] (86%) was obtained in a manner similar to that described in [Example 1].

¹ H 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 (shdd, J=4.25, 9, 63 Hz, 1H), 2.43 (s, 3H), 2.03-2.13 (m, 1H), 1.74 (kvd, J=6, 05, 12.12 Hz, 1H); LC-MS: 537.6 [M+H+].

[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

(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 obtained in a manner similar to that described in [Preparation Example 9].

^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 (shd, J=12, 26 Hz, 2H), 2.78-2.94 (m, 5H), 2.44 (s, 3H), 1.92 (shs, 2H), 1.64 (shd, J=10.13 Hz, 2H), 1.05-1.16 (m, 6H); LC-MS: 607.7 [M+H+].

[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

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 obtained in a manner similar to that described in [Preparation Example 9].

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 (shs, 2H), 2.53 (shs, 6H), 2.44 (s, 3H), 2.09 (shs, 1H), 1.90 (shd, J=11.63 Hz, 1H), 1.75-1.86 (m, 1H), 1.72 (shd, J=11.51 Hz, 1H); LC-MS: 577.6 [M+H+].

[Example 47]

(R)-3-(5-(4-(1H-pyrrol-1-yl)piperidin-1-yl)pyrimidin-2-yl)-N-((5-fluoro-2-pydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide

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

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 (shs, 2H), 2.53 (shs, 6H), 2.44 (s, 3H), 2.09 (shs, 1H), 1.90 (shd, J=11.63 Hz, 1H), 1.75-1.86 (m, 1H), 1.72 (shd, J=11.51 Hz, 1H); LC-MS: 601.6 [M+H+].

[Example 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

(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 obtained in a manner similar to that described in [Preparation Example 9].

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 (shs, 2H), 2.53 (shs, 6H), 2.44 (s, 3H), 2.09 (shs, 1H), 1.90 (shd, J=11.63 Hz, 1H), 1.75-1.86 (m, 1H), 1.72 (shd, J=11.51 Hz, 1H); LC-MS: 603.6 [M+H+].

[Example 49]

(R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-(5-(4-hydroxypiperidin-1-yl)pyrimidin-2-yl)-5-methylbenzamide

(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 obtained in a manner similar to that described in [Preparation Example 9].

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 (shs, 2H), 2.53 (shs, bN), 2.44 (s, 3H), 2.09 (shs, 1H), 1.90 (shd, J=11.63 Hz, 1H), 1.75-1.86 (m, 1H), 1.72 (shd, J=11.51 Hz, 1H); LC-MS: 552.6 [M+H+].

[Example 50]

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

¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (br s, 1H), 9.66 (br s, 1H), 9.29 (bd, 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 (dc, 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 (bd, J=12.76 Hz, 2H), 2.74-2.85 (m, 2H), 2.47 (bd, J=2.75 Hz, 4H), 2.44 (s, 3H), 2.37-2.42 (m, 1H), 1.82 (bd, J=11.38 Hz, 2H), 1.51-1.60 (m, 2H), 1.48 (bd, J=4, 88 Hz, 4H), 1.38 (bd, J=5, 13 Hz, 2H); LC-MS: 619.7 [M+H+].

[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

(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 obtained in a manner similar to that described in [Preparation Example 9].

¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (br s, 1H), 9.66 (br s, 1H), 9.29 (bd, 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 (bd, J=12.76 Hz, 2H), 2.74-2.85 (m, 2H), 2.47 (bd, J=2.75 Hz, 4H), 2.44 (s, 3H), 2.37-2.42 (m, 1H), 1.82 (bd, J=11.38 Hz, 2H), 1.51-1.60 (m, 2H), 1.48 (bd, J=4, 88 Hz, 4H), 1.38 (bd, J=5.13 Hz, 2H); LC-MS: 635.7 [M+H+].

[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

(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 obtained in a manner similar to that described in [Preparation Example 9].

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 (bd, J=12.76 Hz, 2H), 2.74-2.85 (m, 2H), 2.47 (bd, J=2, 75 Hz, 4H), 2.44 (s, 3H), 2.37-2.42 (m, 1H), 1.82 (bd, J=11.38 Hz, 2H), 1.51-1.60 (m, 2H), 1.48 (bd, J=4.88 Hz, 4H), 1.38 (bd, J=5, 13 Hz, 2H); LC-MS: 619.7 [M+H+].

[Example 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

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

¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.67 (bd, 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, 8.07 Hz, 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, 1H), 3.08 (s, 1H), 2.78-2.88 (m, 1H), 2.44 (s, 3H), 2.22 (s, 6H), 2.14-2.20 (m, 1H), 1.83 (kvd, J=9.32, 12.07 Hz, 1H); LC-MS: 565.65 [M+H+].

[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

(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 obtained in a manner similar to that described in [Example 1].

^1H 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, 1N), 4.01 (shd, J=12.88 Hz, 1H), 3.98-4.05 (m, 1H), 3.17 (d, J=5, 25 Hz, 1H), 2.90 (shs, 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+].

[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

(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 obtained in a manner similar to that described in [Preparation Example 9].

^1H 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 (shs, 2H), 1.71-1.83 (m, 2H); LC-MS: 656.7 [M+H+].

[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

(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 obtained in a manner similar to that described in [Preparation Example 9].

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 (kV, J=7.05 Hz, 5H), 3.60-3.66 (m, 2H), 3.45-3.51 (m, 4H), 3.30 (s, 3H), 3.19 (shd, 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+].

[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)benzamide

(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 obtained in a manner similar to that described in [Example 1].

^1H 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 (shs, 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+].

[Example 58]

(R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-3-methyl-5-(5-(piperidin-4-yl)pyrimidin-2-yl)benzamide

(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 hydrogen at room temperature for 24 hours. The reaction solution was filtered through celite, and then the filtrate was concentrated. The residue was purified by MPLC to give (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.

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+].

[Example 59]

3-[5-(3-aminoazetidin-1-yl)pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-5-methylbenzamide

3-[5-(3-Aminoazetidin-1-yl)pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-5-methylbenzamide [Example 59] (54%) was obtained in a manner similar to that described in [Example 1].

^1H 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+].

[Example 60]

3-[5-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-5-methylbenzamide

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

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+].

[Example 61]

3-[5-[(3S)-3-aminopyrrolidin-1-yl]pyrimidin-2-yl]-N-[(R)-(5-fluoro-2-hydroxyphenyl)-(1H-indol-2-yl)methyl]-5-methylbenzamide

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

¹ H NMR (400 MHz, DMSO-d6) δ 11.10 (d, J=1.25 Hz, 1H), 9.26 (d, J=B, 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 (shd, J=5.25 Hz, 1H), 3.47-3.56 (m, 3H), 3.07 (shdd, J=4, 25, 9.88 Hz, 1H), 2.53 (shs, 1H), 2.44 (s, 3H), 2.08-2.15 (m, 1H), 1.75-1.84 (m, 1H); LC-MS: 537.61 [M+H+].

[Example 62]

(R)-3-(5-(azetidin-3-yl)pyrimidin-2-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indol-2-yl)methyl)-5-methylbenzamide

(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 obtained in a manner similar to that described in [Example 1].

^1H NMR (400 MHz, Methanol-d4) δ 10.53 (bs, 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=8.0 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.09-7.06 (m, 1H), 7.00-6.85 (m, 4H), 6.21 (s, 1H), 4.47-4.38 (m, 5H), 2.53 (s, 3H); LC-MS: 508.35 [M+H+]

The structures of the compounds obtained in Examples 1-62 are summarized and shown in Table 1 below.

<Experimental Example 1> Evaluation of cell growth inhibitory ability in BaF3 cells overexpressing wild type (WT) and mutant EGFR

In order to confirm that the compound represented by formula 1, provided in one aspect of the present invention, acts as an allosteric inhibitor against WT and mutant EGFR, the cell growth inhibitory effect was evaluated on BaF3 cells overexpressing WT and mutant EGFR.

More specifically, the ability of the compound of the present invention to inhibit cell growth in the Ba/F3 cell line overexpressing the EGFR mutant HT1 was assessed using the CellTiter 9 6 aqueous non-radioactive cell proliferation assay system from Promega as follows. The aqueous non-radioactive cell proliferation assay is a method for confirming the ability to inhibit cell growth by measuring the degree of color development due to the reduction of MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) to Formazan by a reductase secreted by mitochondria present in living cells in a cell culture state. The mutated cell lines 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/C7 91S (LTC) used in the present invention were purchased from the laboratory of Professor Byung-cheol Cho, Yonsei University. All cell lines were cultured in RPMI medium supplemented with 10% FBS, 1% penicillin-streptomycin and 1 μg/ml puromycin in a 5% _CO2 incubator at 37°C.

The inhibitory effect of the compound on cell survival according to each EGFR mutation was analyzed using the following assay method.

BaF3 cells were distributed in a 9 6-well cell culture plate at a density of 2000~10000 cells/100 μl/well and cultured for 24 hours. Thereafter, the concentration of the compound represented by formula 1 provided in one aspect of the present invention was prepared to double the final concentrations of 0.1 nM, 1 nM, 10 nM, 100 nM, 1000 nM and 10000 nM, and the compound was treated in the plate (100 μl/well). The plate was reacted in an incubator at 37°C for 72 hours. Then, the plate was treated with MTS (20 μl/well), and the plate was incubated at 37°C for 2-4 hours. Finally, after measuring the absorbance at 490 nm using a microplate reader, the relative value compared to 0 nM (% control) was obtained to confirm the cell growth inhibiting ability of the compound. The measured values were analyzed using Prism software (version 8.0, Graphpad Software, Inc.) and the IC ₅₀ (50 of inhibitory concentration) value, an indicator of the cell growth inhibiting ability of the compound, was calculated.

The results are shown in Table 2 below.

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.

As mentioned above, the present invention has been described in detail by means of preferred production examples, examples and experimental examples, but the scope of the present invention is not limited to the specific examples and should be interpreted by the appended claims. In addition, those skilled in the art should understand that many modifications and variations are possible without departing from the scope of the present invention.

Claims (120)

1. The compound represented by formula 1 below or its optical isomer: , where in formula 1 X, Y and Z independently represent CH or N; R ¹ is -H, halogen, C _1-10 alkyl, unsubstituted or substituted by one or more halogens, C _1-10 alkoxy, unsubstituted or substituted by one or more halogens, nitro, C _1-10 alkylsulfanyl, cyano, or 5-membered heteroaryl containing 2 ring heteroatoms N; R ² is substituted phenyl or substituted 6-membered heteroaryl containing 1-2 ring heteroatoms N, wherein said substituted phenyl is phenyl substituted with 1-2 substituents selected from halogen, C _1-10 alkyl and amino-substituted piperidinyl, wherein said substituted 6-membered heteroaryl is a 6-membered heteroaryl substituted with 1-2 substituents selected from halogen, unsubstituted C _1-10 alkyl, substituted C _1-10 alkyl, C _1-5 alkyl substituted bicyclic 8-membered heterocycloalkyl containing 2 ring heteroatoms N, and unsubstituted or substituted 4-8-membered fully or partially saturated heterocycloalkyl containing 1-2 ring heteroatoms N, wherein said substituted C _1-10 alkyl is substituted with a 5-6 membered heterocycloalkyl containing 1 ring heteroatom N which is substituted with 1 or 2 C _1-5 alkyl substituted amino groups, wherein said substituted 4-8-membered fully or partially saturated heterocycloalkyl is a 4-8-membered heterocycloalkyl substituted with one substituent selected from the group consisting of -OH, C _1-5 alkyl, C _1-5 alkyl substituted with a 5-6-membered heterocycloalkyl containing 1-2 ring heteroatoms selected from N and O, amino unsubstituted or substituted with 1 or 2 C _1-5 alkyls, 5-6-membered heterocycloalkyl containing 1 ring heteroatom N and unsubstituted or substituted with C _1-5 alkyl, C _1-5 alkoxycarbonyl, 5-6-membered heteroaryl containing 1-3 ring heteroatoms N, phenylaminocarbonyl and C _1-5 alkoxy-C _1-5 alkoxy-phenyl; R ³ is halogen; R ⁴ is -OH or C _1-15 alkoxy; R ⁵ is -H; and R ⁶ is -H or halogen. 2. A compound or its optical isomer according to claim 1, characterized in that: X, Y and Z independently represent CH or N; R ¹ is -H, halogen, C _1-5 alkyl, unsubstituted or substituted by one or more halogens, C _1-5 alkoxy, unsubstituted or substituted by one or more halogens, nitro, C _1-5 alkylsulfanyl, cyano, or 5-membered heteroaryl containing 2 ring heteroatoms N; R ² is substituted phenyl or substituted 6-membered heteroaryl containing 1-2 ring heteroatoms N, wherein said substituted phenyl is phenyl substituted with 1-2 substituents selected from halogen, C _1-5 alkyl and amino-substituted piperidinyl, wherein the substituted 6-membered heteroaryl is a 6-membered heteroaryl substituted with 1-2 substituents selected from the group consisting of halogen, unsubstituted or substituted C _1-5 alkyl, C _1-5 alkyl-substituted bicyclic 8-membered heterocycloalkyl containing 2 ring heteroatoms N, and unsubstituted or substituted 4-6-membered fully or partially saturated heterocycloalkyl containing 1-2 ring heteroatoms N, wherein said substituted C _1-5 alkyl is substituted by piperidinyl which is substituted by 2 C _1-5 alkyl substituted amino groups, wherein the substituted 4-6-membered fully or partially saturated heterocycloalkyl is a 4-6-membered heterocycloalkyl substituted with one substituent selected from the group consisting of -OH, C _1-5 alkyl, C _1-5 alkyl substituted with a 5-6-membered heterocycloalkyl containing 1-2 ring heteroatoms selected from N and O, amino unsubstituted or substituted with 1 or 2 C _1-5 alkyls, piperidinyl unsubstituted or substituted with C _1-5 alkyl, C _1-5 alkoxycarbonyl, 5-membered heteroaryl containing 1 or 3 N ring heteroatoms, phenylaminocarbonyl and C _1-5 alkoxy-C _1-5 alkoxy-phenyl; R ³ is halogen; R ⁴ is -OH or C _1-10 alkoxy; R ⁵ is -H; and R ⁶ is -H or halogen. 3. A compound or its optical isomer according to claim 2, characterized in that R ⁴ is -OH or C _1-5 alkoxy. 4. A compound or its optical isomer according to claim 1, characterized in that: X, Y and Z independently represent CH or N; R ¹ is -H, -F, -Cl, -CH ₃ , -CF ₃ , -OCH ₃ , -OCF ₃ , isopropyl, tert-butyl, -SCH ₃ , -NO ₂ , -CN or imidazolyl; R ² is: 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. 5. The compound or its optical isomer according to claim 1, characterized in that the compound represented by formula 1 is a compound represented by formula 2 below: , where in formula 2 X, Y, Z, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ independently have the meanings defined in formula 1 according to clause 1. 6. A compound or its optical isomer according to claim 1, characterized in that: X represents CH or N; Y and Z represent CH; R ¹ is -H, -F, -Cl, -CH ₃ , -CF ₃ , -OCH ₃ , -OCF ₃ , isopropyl, tert-butyl, -SCH ₃ , -NO ₂ , -CN or imidazolyl; R ² is: R ³ is -F; R ⁴ is -OH or -OCH ₃ ; R ⁵ is -H; and R ⁶ is -H, -F, or -Cl. 7. A compound or its optical isomer according to claim 1, characterized in that the compound represented by formula 1 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; (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-methylbenzamide; (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-l,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'-bipiperidin]-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. 8. Use of a compound represented by formula 1 according to claim 1 or an optical isomer thereof for the production of a medicinal product for the treatment of cancer with an EGFR mutation.