Novel heterobicyclic compounds for inhibiting YAP-TEAD interaction and pharmaceutical compositions containing the same

Abstract

The present invention relates to a compound selected from the group consisting of compounds of Chemical Formula 1, their optical isomers, diastereomers, solvates, hydrates and pharmaceutically acceptable salts thereof, a method for preparing the same, and uses thereof.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition comprising a heterobicyclic compound that inhibits Yes-associated protein (YAP)-transcriptional enhancer associate domain (TEAD) binding. The compound according to the present invention can directly inhibit YAP-TEAD binding in the Hippo pathway, which plays a key role in the development of cancer. [Background technology]

[0002] The Hippo signaling cascade is an important pathway for cancer development and tumor maintenance. YAP and tafazzin (TAZ) are transcriptional coactivators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inactivation of the Hippo signaling pathway promotes YAP / TAZ entry into the nucleus, where they interact with transcriptional enhancer-associated domain (TEAD) transcription factors, coactivating target gene expression and promoting cell proliferation. TEAD regulates target genes such as connective tissue growth factor (CTGF), Cyr61, AXL receptor tyrosine kinase, and MYC, which are closely related to tumorigenesis. TEAD has also been shown to be overexpressed in breast cancer stem cells, breast cancer, ovarian cancer, phagocytic tumors, renal cell carcinoma, medulloblastoma, and gastric cancer. Hyperactivation of YAP and TAZ and / or mutations in one or more members of the Hippo pathway network are associated with many cancers.Recent studies have also reported that resistance to the EGFR tyrosine kinase inhibitors Tarceva (erlotinib), Iressa (gefitinib), or Tagrisso (osimertinib) is associated with YAP overexpression or amplification, along with epithelial-mesenchymal transition (EMT) phenotype changes.

[0003] The present inventors have completed the present invention by developing novel heterobicyclic compounds for inhibiting YAP-TEAD protein interaction. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Patent Publication No. WO2019 / 040380 [Patent Document 2] International Patent Publication No. WO2020 / 243415 [Non-patent literature]

[0005] [Non-Patent Document 1] Semin. Cancer Biol. 2022, 85, 33 [Non-patent document 2] Nat. Rev. Drug Discov. 2014, 13(1), 63 [Non-patent document 3] Cancer Res. 2011, 71(3), 873 [Non-patent document 4] J. Cell Mol. Med. 2017, 21(11), 2663 [Non-Patent Document 5] Cancer Cell 2020, 37, 104 [Non-patent document 6] Cells 2021, 10, 2715 [Non-Patent Document 7] GenesCancer 2017, 8(3-4), 497 Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide novel heterobicyclic compounds that have excellent inhibitory activity against YAP-TEAD binding in the Hippo pathway, which plays a key role in the development of cancer.

[0007] Another object of the present invention is to provide a pharmaceutical composition for treating or preventing disorders of the Hippo signaling pathway, specifically, disorders caused by TEAD activation, comprising the compound as an active ingredient.

[0008] Other objects and advantages of the present application will become more apparent from the following detailed description, taken in conjunction with the claims. Contents not described in this specification are fully understood and can be inferred by those skilled in the art in the present application or in a similar technical field, and therefore, the description thereof will be omitted. [Means for solving the problem]

[0009] According to one embodiment of the present invention, there is provided a compound selected from the group consisting of compounds of the following Chemical Formula 1, optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof: [Chemical formula 1] [ka]

[0010] According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating or preventing dysregulation of the Hippo signaling pathway, specifically, a related disease caused by TEAD activation, comprising a compound selected from the group consisting of the above compound, its optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof, as an active ingredient. [Effects of the Invention]

[0011] The novel heterobicyclic compound of the present invention having the structure of Chemical Formula 1 has excellent inhibitory activity against YAP-TEAD binding and is effective against multiple diseases related to the Hippo pathway, which plays a key role in the development of cancer, and can be usefully used as a therapeutic agent for these diseases.

[0012] The present invention will now be described in further detail.

[0013] Unless otherwise defined, all technical terms used herein have the meanings commonly understood by those of ordinary skill in the art in the field of the present invention. In addition, although preferred methods and samples are described in this specification, similar or equivalent methods and samples are also included within the scope of the present invention.

[0014] According to one embodiment of the present invention, there is provided a compound selected from the group consisting of compounds of the following Chemical Formula 1, optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof:

[0015] [Chemical formula 1] [ka]

[0016] In the above Chemical Formula 1, R1 and R2 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Carbocyclyl or haloC 1-6 is alkyl; R3 is hydrogen, halogen, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 alkoxy, or cyano; [ka] is carbocyclyl or heterocyclyl; [ka] is C 6-10 Aryl or C 4-10 is heteroaryl; L1 is absent, a bond, or C 1-3 Alkylene or halogen-substituted C 1-3 is alkylene; Each R4 and each R5 are independently hydrogen, halogen, cyano, amino, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, HaloC 1-6 Alkoxy, mono-(C 1-3 alkyl)-substituted carbamoyl (-(CO)-NH(C 1-3 alkyl), di-(C 1-3 Alkyl)-substituted carbamoyl (-(CO)-N(C1-3 Alkyl)2), C 1-3 Alkyl sulfinyl (-(SO)-(C 1-3 Alkyl)), C 1-3 Alkyl sulfonyl (-SO2-(C 1-3 alkyl), substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted C 2-6 Heterocyclyl, or substituted or unsubstituted C 4-10 is heteroaryl; X and Y are each independently -C- or -N-; m and n each independently represent an integer of 0 to 3.

[0017] The term "halogen" as used herein also refers to F, Cl, Br, or I.

[0018] The term "alkyl," as used herein, unless otherwise specified, refers to a substituted or unsubstituted straight-chain or branched hydrocarbon residue, such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, or t-butyl.

[0019] As used herein, the term "alkylene" refers to (-CH-) p The term "p" refers to a divalent linear or branched hydrocarbon group having the formula:

[0020] As used herein, unless otherwise specified, the term "alkenyl" refers to a substituted or unsubstituted alkyl group containing one or more double bonds, such as, but not limited to, prop-1-ene, but-1-ene, but-2-ene, 3-methylbut-1-ene, or pent-1-ene.

[0021] The term "cycloalkyl," as used herein, unless otherwise specified, refers to saturated monocyclic and polycyclic hydrocarbon rings, generally having the specified number of carbon atoms, including substituted and unsubstituted rings. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0022] As used herein, unless otherwise specified, the term "heterocycloalkyl" refers to a substituted or unsubstituted monocyclic cyclic alkyl containing one or more heteroatoms selected from N, O, and S. Examples of the heterocycloalkyl group include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, thiomorpholinyl, imidazolidinyl, tetrahydrofuranyl, or similar groups.

[0023] As used herein, the term "haloalkyl," unless otherwise specified, is meant to include substituted and unsubstituted monohaloalkyl and polyhaloalkyl. The terms "halogen and alkyl" are as defined above.

[0024] As used herein, unless otherwise specified, the term "alkoxy" refers to a substituted or unsubstituted straight or branched hydrocarbon residue linked through an oxygen atom, such as, but not limited to, methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, or t-butoxy.

[0025] As used herein, the term "alkoxyalkyl" refers to an alkyl in which one or more hydrogen atoms of the alkyl group are replaced with an alkoxy, such as, but not limited to, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, ethoxypropyl, and isopropoxymethyl.

[0026] As used herein, the term "aryl," unless otherwise specified, refers to a substituted or unsubstituted aromatic group, such as C3-10 Aryl, C 3-8 Aryl or C 3-6 It also includes aryl, where double bonds alternate (resonate) between adjacent carbon atoms or suitable heteroatoms, such as, but not limited to, phenyl, biphenyl, naphthyl, toluyl, or naphthalenyl.

[0027] The term "heteroaryl," as used herein, unless otherwise specified, refers to a monocyclic, bicyclic, or higher cyclic, substituted or unsubstituted, aromatic group containing one or more heteroatoms selected from N, O, and S. For example, monocyclic heteroaryls can be, but are not limited to, pyridinyl, imidazolyl, thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridazinyl, pyrimidinyl, or pyrazinyl. For example, bicyclic heteroaryls can be, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, purinyl, or furopyridinyl.

[0028] As used herein, the term "carbocyclyl," unless otherwise specified, refers to a substituent containing carbon ring atoms having a saturated carbocyclyl (e.g., "cycloalkyl"), partially saturated carbocyclyl (e.g., "cycloalkenyl"), or fully unsaturated carbocyclyl (e.g., "aryl") structure. The carbocyclyl may be a monocyclic or polycyclic ring structure. As used herein, a carbocyclyl may contain, for example, 3 to 14, or, for example, 3 to 8, carbon ring atoms and may be saturated, unsaturated, or aromatic. Here, the ring atoms are the atoms that are bonded together to form the ring or rings of the carbocyclyl substituent. For example, a saturated carbocyclyl group may be, but is not limited to, cyclopropyl, cyclopentyl, or cyclohexyl. For example, an unsaturated carbocyclyl may contain up to three double bonds. For example, an aromatic carbocyclyl group may be phenyl. The carbocyclyl also includes fused combinations of carbocyclyl groups, such as, but not limited to, naphthyl, phenanthryl, indanyl, and indenyl.

[0029] As used herein, unless otherwise specified, the term "heterocyclyl" refers to a substituent containing at least one heteroatom ring atom, having a saturated heterocyclyl (e.g., "heterocycloalkyl"), partially saturated heterocyclyl (e.g., "heterocycloalkenyl"), or fully unsaturated heterocyclyl (e.g., "heteroaryl") structure. The heterocyclyl may be a monocyclic or polycyclic ring structure. As used herein, heterocyclyl may contain, for example, a total of 3 to 14, 6 to 14, or 3 to 8 ring atoms, and may be saturated, unsaturated, or aromatic. Here, the ring atoms are atoms bonded together to form the ring or rings of the heterocyclyl substituent. For example, at least one of the ring atoms is nitrogen, oxygen, or sulfur, and the remaining ring atoms are independently selected from the group consisting of carbon, nitrogen, oxygen, and sulfur. For example, the ring atoms of said heterocyclyl may be, up to four of which may be heteroatoms such as N, O, and S, and may contain, for example, from 3 to 14 total ring atoms, or, for example, from 5 to 7 total ring atoms, and may be saturated, unsaturated, or aromatized. For example, the heterocyclyl can be, but is not limited to, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolanyl, triazinyl, azepinyl, oxazepinyl, thiazepinyl, diazepinyl, or thiazolinyl.The term "heterocyclyl" also includes fused heterocyclyl groups, such as, but not limited to, benzimidazolinyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, quinolinyl, quinazolinyl, quinoxazolinyl, dihydroquinazolinyl, benzothiazolyl, phthalimidyl, benzofuranyl, benzodiazepinyl, indolyl, or isoindolyl. "Heterocyclyl" can refer to a carbon-linked or heteroatom-linked group. For example, an N-linked heterocyclyl is a heteroatom-linked group. [ka] As used herein, unless otherwise specified, the term "fused heteroaryl" refers to a substituted or unsubstituted ring system in which a heteroaryl group is further connected in a fused manner to another aryl, heteroaryl, or heterocycloaryl group. For example, a fused heteroaryl can be a 5+5 membered, 5+6 membered, 5+7 membered, 6+6 membered, or 6+7 membered fused ring system. Fused heteroaryl also includes, for example, [ka] There are also, but are not limited to, these.

[0030] The optional substituents herein include, for example, cyano, amino, hydroxy, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy and HaloC 1-6 The substituent may be any one selected from the group consisting of alkoxy, but is not limited thereto.

[0031] For example, the substituted C 3-6 Carbocyclyl, C 6-10 Aryl, C 2-6 Heterocyclyl, C 4-10Heteroaryl, C 3-6 Cycloalkyl or C 2-6 Heterocycloalkyl means that one or more of the hydrogen atoms in the alkyl group is replaced by halogen, cyano, amino, hydroxy, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy and HaloC 1-6 It may also be substituted with any one of the substituents selected from alkoxy, but is not limited thereto.

[0032] As used herein, the term "stereoisomer" means a compound of the present invention or a salt thereof that has the same chemical or molecular formula but is optically or sterically different, and includes optical isomers or diastereomers.

[0033] As used herein, the term "enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0034] As used herein, the term "diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another.

[0035] The compounds of the present invention contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, such as diastereomers, enantiomers, and racemic mixtures, are considered to be part of the present invention. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate.

[0036] As used herein, the term "solvate" refers to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are those that are volatile, non-toxic, and / or suitable for administration to humans. The "solvate" may include a molecular complex containing the compound and one or more pharmaceutically acceptable solvent molecules, such as ethanol.

[0037] The term "hydrate" as used herein refers to a complex where the solvent molecule is water.

[0038] As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt, which may be prepared by any suitable method available to those skilled in the art. For example, if the compound of the present invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available to those skilled in the art, such as by treating the free base with an inorganic or organic acid.

[0039] In one embodiment, [ka] is C 6-10 Aryl, C 1-10 Heteroaryl, C 6-14 fused heteroaryl, or C 2-6 is heterocyclyl, where C 1-10 Heteroaryl, C 6-14 fused heteroaryl, or C 2-6 The heterocyclyl may contain 1 to 4 heteroatoms independently selected from N, O, and S.

[0040] In one embodiment, [ka] is a phenyl group, a pyridinyl group, a pyrazinyl group, a pyrazolyl group, an imidazolyl group, a thiophenyl group, a furanyl group, an oxazole group, an azetidinyl group, or [ka] It is also.

[0041] [ka] means a single or double bond.

[0042] for example, [ka] teeth, [ka] It is also.

[0043] In one embodiment, [ka] is also a phenyl group or a pyridinyl group.

[0044] In one embodiment, R and R are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl or haloC 1-6 It is also alkyl.

[0045] In one embodiment, L1 is a bond; Each R4 and each R5 are independently hydrogen, halogen, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, HaloC 1-6 Alkoxy, mono-(C 1-3 alkyl)-substituted carbamoyl (-(CO)-NH(C 1-3 alkyl), di-(C 1-3 Alkyl)-substituted carbamoyl (-(CO)-N(C 1-3 Alkyl)2), C 1-3 Alkyl sulfonyl (-SO2-(C1-3 alkyl), substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 6-10 Aryl, or substituted or unsubstituted C 2-6 It is also heterocycloalkyl.

[0046] In one embodiment, L1 is C 1-3 is alkylene; Each R4 and each R5 are independently hydrogen, halogen, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, di-(C 1-3 Alkyl)-substituted carbamoyl (-(CO)-N(C 1-3 Alkyl)2), C 1-3 Alkyl sulfonyl (-SO2-(C 1-3 alkyl), substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 6-10 Aryl, or substituted or unsubstituted C 2-6 It is also heterocycloalkyl.

[0047] In one embodiment, R5 is independently hydrogen, halogen, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 3-6 cycloalkyl, or phenyl, or Halogen, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy and HaloC 1-6 C substituted with one or more substituents selected from alkoxy 3-6 It may also be cycloalkyl or phenyl.

[0048] In one embodiment, each R5 is hydrogen, halogen, cyano, methyl, ethyl, propyl, t-butyl, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl.

[0049] In one embodiment, the compound is also a compound selected from the following compounds: its optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof: 1) N-methyl-3-(3-methylpyrazin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 2) N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3) N-methyl-3-(1-methyl-1H-pyrazol-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 4) N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 5) N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-indole-5-sulfonamide; 6) 3-(1-isopropyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 7) N-ethyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 8) N-methyl-3-(pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 9) N-methyl-3-(5-methylthiophen-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 10) N-methyl-3-(5-methylfuran-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide;

[0050] 11) 3-(1-ethyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 12) N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-indole-5-sulfonamide; 13) 3-(2-fluorophenyl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 14) 1-(4-chlorophenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-sulfonamide; 15) N-methyl-3-(pyridin-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 16) 3-(1-cyclobutyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 17) N-methyl-3-phenyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 18) 1-(4-cyclohexylphenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-sulfonamide; 19) N,N-dimethyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 20) 3-(3-fluoropyridin-2-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide;

[0051] 21) N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(3-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 22) 1-(4-cyanophenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-sulfonamide; 23) 3-(furan-3-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 24) N-methyl-3-(5-methylfuran-2-yl)-1-phenyl-1H-indole-5-sulfonamide; 25) 3-(2,3-difluorophenyl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 26) N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-phenyl-1H-indole-5-sulfonamide; 27) 1-(3-chloro-4-(trifluoromethyl)phenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-sulfonamide; 28) 3-(1-cyclopropyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 29) 3-(1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 30) 3-(1-(2-fluorobenzyl)-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide;

[0052] 31) 3-(furan-2-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 32) N-methyl-3-(2-methyloxazol-5-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 33) N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamide; 34) N-methyl-3-(5-(trifluoromethyl)furan-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 35) N-methyl-3-(1-(oxetan-3-yl)-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 36) 3-(5-chlorofuran-2-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 37) N-methyl-3-(1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 38) 3-(1-(2-methoxyethyl)-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 39) N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(p-tolyl)-1H-indole-5-sulfonamide; 40) 1-(4-(t-butyl)phenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-sulfonamide;

[0053] 41) N-methyl-3-(oxazol-5-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 42) 3-(1-cyclopropyl-1H-imidazol-4-yl)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-methyl-1H-indole-5-sulfonamide; 43) 3-(1-cyclopropyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-sulfonamide; 44) 3-(1-cyclopropyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide; 45) 3-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 46) 3-(3-fluoroazetidin-1-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 47) N,N-dimethyl-2-(4-(5-(N-methylsulfamoyl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)-1H-imidazol-1-yl)acetamide; and 48) N-methyl-3-(1-(2-(methylsulfonyl)ethyl)-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide.

[0054] According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating or preventing dysregulation of the Hippo signaling pathway, specifically, a disease associated with TEAD activation, comprising, as an active ingredient, a compound selected from the group consisting of the compound, its optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof.

[0055] In one embodiment, the composition also exhibits activity in inhibiting Yes associated protein (YAP)-transcriptional enhancer associate domain (TEAD) binding.

[0056] In one embodiment, the composition exhibits inhibitory activity against YAP-TEAD binding, and is therefore also for treating treatable cancers or tumors.

[0057] In one embodiment, the pharmaceutical composition may comprise a therapeutically effective amount of a compound selected from the compound of Formula 1, its optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof.

[0058] As used herein, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that will treat or prevent a particular disease, condition or disorder, or that will attenuate, ameliorate or eliminate one or more symptoms of a particular disease, condition or disorder, or that will prevent or delay the onset of one or more symptoms of a particular disease, condition or disorder.

[0059] A physician skilled in the art can easily determine and prescribe the effective required dosage for the pharmaceutical composition. For example, the pharmaceutical composition may contain the compound in an amount of 0.0001 mg to 10 g, but is not limited thereto.

[0060] In one embodiment, the pharmaceutical composition may further contain pharmaceutically acceptable additives other than the active ingredient, such as, but not limited to, diluents, disintegrants, binders, lubricants, surfactants, suspending agents, or emulsifiers.

[0061] The pharmaceutical compositions of the present invention can be formulated by conventional methods and prepared into various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, etc., or parenteral dosage forms such as intramuscular, intravenous, or subcutaneous administration.

[0062] Another embodiment of the present invention provides a method for treating a subject suffering from a disorder of Hippo signaling pathway regulation, specifically, a related disease caused by TEAD activation, by administering a pharmaceutical composition containing, as an active ingredient, a compound selected from the group consisting of the compound of Formula 1, its optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof.

[0063] As used herein, the term "treating" or "treatment" refers to inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting pathology or symptoms of the disease, condition, or disorder, e.g., preventing or reversing further development of the pathology and / or symptoms, or ameliorating the disease, e.g., reducing disease severity.

[0064] As used herein, the term "preventing" or "prevention" refers to preventing a disease, for example, preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder, but who has not yet experienced or exhibited pathology or symptoms of the disease.

[0065] As used herein, the term "subject" or "individual" refers to a vertebrate, such as a mammal, fish, bird, reptile, or amphibian. For example, the subject may be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent.

[0066] As used herein, the terms "administer" and "administration" refer to any method of providing the disclosed compositions to a subject.

[0067] The dosage, frequency, or method of administration of a compound or pharmaceutical composition according to an embodiment may vary depending on the subject being treated, the severity of the disease or condition, the rate of administration, and the discretion of the prescribing physician. For example, a typical dosage for a 70 kg person may be 0.0001 mg to 10 g, e.g., 1 mg to 1 g, per day. The dosage may be one to several times, e.g., 1 to 4 times, or on an on / off schedule, and may be administered orally or parenterally. For example, a compound or pharmaceutical composition according to an embodiment may be administered orally or parenterally in an amount ranging from 0.1 to 100 mg / kg (body weight).

[0068] A physician may gradually increase the dose of a compound or pharmaceutical composition of the present invention administered to a subject, starting at a level lower than that required to produce the desired therapeutic effect, until the intended effect is achieved.

[0069] Another embodiment of the present invention provides a kit comprising, as an active ingredient, a compound selected from the group consisting of the compound of Formula 1, its pharmaceutically acceptable salts, optical isomers, diastereomers, hydrates, and solvates.

[0070] In one embodiment, the therapeutic agent is a drug for treating a disease caused by dysregulation of the Hippo signaling pathway, specifically, TEAD activation, such as a drug for treating cancer, e.g., a chemotherapy drug for treating cancer.

[0071] In one embodiment, the compounds, compositions, and kits of the present invention may be administered alone or simultaneously with at least one other therapeutic agent, either separately or sequentially.

[0072] In the context of the present invention, the singular forms of words include the plural and vice versa, unless the context clearly dictates otherwise.

[0073] Numerical values ​​described herein are considered to include the meaning of "about" even if not explicitly stated. As used herein, the term "about" means within 5%, preferably within 1% to 2%, of a given value or range.

[0074] In this specification, numerical ranges expressed using the term "to" refer to ranges that include the numerical values ​​stated before and after the term "to" as the lower and upper limits, respectively.

[0075] As used in this specification, the terms "have," "can have," "include," or "can include" indicate the presence of a given feature (e.g., a value or a component such as a component) and do not exclude the presence of additional features.

[0076] The contents of all publications referenced herein are hereby incorporated by reference in their entirety.

[0077] Hereinafter, the method for preparing the compound of Formula 1 will be described in detail.

[0078] The compound of formula 1 according to the present invention can be prepared by the synthesis method shown in reaction scheme 1. [Reaction Scheme 1] [ka]

[0079] [Stage-1] Under cooling conditions of 0-5°C, a starting material (e.g., PG-indoline; 1 equivalent, reference equivalent) is slowly added to chlorosulfonic acid (7.5 equivalents). The reaction mixture is warmed to room temperature, then heated to 70°C. After confirming the completion of the reaction, the reaction mixture is slowly added dropwise to water cooled to 0-5°C, and the formed solid is collected by filtration to obtain the target compound A.

[0080] [Stage-2] Triethylamine (2 equivalents) is added to the reaction solution prepared by dissolving A (1 equivalent, reference equivalent) prepared in [Step-1] in dichloromethane. After adding the corresponding amine solution (2 equivalents) dropwise, the reaction solution is refluxed and stirred. After confirming the completion of the reaction, the reaction mixture is cooled to room temperature and the formed solid is collected by filtration to obtain the target compound B.

[0081] [Stage-3] B (1 equivalent, reference equivalent) obtained in [Step-2] above is dissolved in methanol, and then conc. HCl (4 equivalents) is added. The reaction mixture is stirred overnight at room temperature, then heated to 80°C and stirred for an additional 2 hours. After confirming the completion of the reaction, the internal temperature is cooled to room temperature, water is added, and aqueous sodium hydroxide solution is slowly added dropwise to adjust the pH to 3-4. The formed solid is collected by filtration to obtain the target compound C.

[0082] [Stage-4] C (1 equivalent, reference equivalent) obtained in [Step-3] was dissolved in dichloromethane, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 1 equivalent) was added. The reaction mixture was stirred overnight at room temperature. After confirming the completion of the reaction, the reaction mixture was filtered through CELITE and washed with dichloromethane. After concentrating under reduced pressure, the resulting residue was purified by MPLC to obtain the target compound D.

[0083] [Stage-5] D (1 equivalent, reference equivalent) obtained in [Step-4] above is dissolved in dimethylformamide, and the corresponding halogen-substituted B derivative (1.5 equivalents) and potassium carbonate (2.5 equivalents) are added, followed by cuprous iodide (0.2 equivalents). The reaction mixture is stirred overnight at room temperature. After confirming the completion of the reaction, the mixture is cooled to room temperature, water is added, and the mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtered organic layer is concentrated under reduced pressure. The resulting residue is purified by MPLC to obtain the target compound E.

[0084] [Stage-6] E (1 equivalent, reference equivalent) obtained in [Step-5] is dissolved in dimethylformamide, N-bromosuccinimide (1 equivalent) is slowly added dropwise, and the reaction mixture is stirred at room temperature. After confirming the completion of the reaction, water is added and the mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and then filtered under reduced pressure. The filtered organic layer is concentrated under reduced pressure. The resulting residue is purified by MPLC to obtain the target compound F.

[0085] [Stage-7] The F (1 equivalent, reference equivalent) obtained in [Step 6] is subjected to a Stille or Suzuki coupling reaction with the corresponding A-stannane derivative and A-borane derivative (2 equivalents). After the reaction is complete, the organic layer is washed with water, dried over anhydrous sodium sulfate, and then filtered under reduced pressure. The filtered organic layer is concentrated under reduced pressure. The resulting residue is purified by MPLC to obtain the target compound G.

[0086] In the above reaction formula 1, R1, R2, R3, R4, R5, X, Y, m, n, L1, [ka] are as defined in Chemical Formula 1, but are not limited thereto and may be changed within the scope of understanding of a person skilled in the art.

[0087] The compound of Formula 1 according to an embodiment of the present invention can be prepared by, but is not limited to, the method illustrated in Reaction Scheme 1. Those skilled in the art of organic compounds can appropriately adjust the specific reaction route, reaction conditions, reaction amounts, etc. [Example]

[0088] The present invention will be explained in more detail below with reference to the following examples and experimental examples, which are provided to aid in understanding the present invention and are not intended to limit the scope of the present invention in any way.

[0089] Example 1: N-methyl-3-(3-methylpyrazin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [Step-1] Preparation of 1-acetylindoline-5-sulfonyl chloride [ka]

[0090] 1-Indolin-1-ylethanone (30 g, 124.07 mmol) was added gradually in small portions over 15 minutes to chlorosulfonic acid (62 mL, 930.5 mmol) cooled to 0-5°C. The reaction mixture was warmed to room temperature and then heated to 70°C for 90 minutes. After confirming the completion of the reaction, the reaction solution was slowly added dropwise to water cooled to 0-5°C. The formed solid was collected by filtration, washed several times with water, and dried at 50°C to obtain 27 g of the title compound (55% yield). 1 H-NMR (300 MHz, DMSO-d6): δ 7.96-7.93 (m, 1H), 7.43-7.38 (m, 2H), 4.10 (t, J= 8.5 Hz, 2H), 3.13 (t, J= 8.5 Hz, 2H), 2.16 (s, 3H).

[0091] [Step-2] Preparation of 1-acetyl-N-methylindoline-5-sulfonamide [ka]

[0092] 1-acetylindoline-5-sulfonyl chloride (20 g, 77 mmol) obtained in [Step 1] was dissolved in 60 mL of dichloromethane, and triethylamine (21.5 mL, 154 mmol) was added. 2 M methylamine tetrahydrofuran solution (77 mL, 154 mmol) was added dropwise, and the reaction mixture was refluxed and stirred. After confirming the completion of the reaction, the mixture was cooled to room temperature. The formed solid was collected by filtration, washed several times with water, and dried at 50 °C to obtain 18.8 g of the title compound (96% yield). 1 H-NMR (300 MHz, DMSO-d6): δ 8.16-8.14 (m, 1H), 7.60-7.57 (m, 2H), 7.30 (s, 1H), 4.16 (t, J= 8.6 Hz, 2H), 3.21 (t, J= 8.5 Hz, 2H), 2.39 (s, 3H), 2.19 (s, 3H).

[0093] [Step-3] Preparation of N-methyl-1H-indoline-5-sulfonamide [ka]

[0094] 1-Acetyl-N-methylindoline-5-sulfonamide (6.2 g, 24.2 mmol) obtained in [Step 2] was dissolved in 72 mL of methanol, and then concentrated HCl (8.1 mL, 97.5 mmol) was added. The reaction mixture was stirred overnight at room temperature and then at 80°C for 2 hours. After confirming the completion of the reaction, the internal temperature was cooled to room temperature, 100 mL of water was added, and 1N aqueous sodium hydroxide solution was slowly added dropwise to adjust the pH to 3-4. The formed solid was collected by filtration, washed several times with water, and dried at 50°C to obtain 3.4 g of the title compound (66% yield). 1H-NMR (300 MHz, CDCl3): δ 7.56-7.53 (m, 2H), 6.66-6.61 (m, 1H), 4.17 (brs, 1H), 3.71 (t, J= 8.6 Hz, 2H), 3.11 (t, J= 8.5 Hz, 2H), 2.64 (d, J= 5.5 Hz, 3H), 1.59 (brs, 1H).

[0095] [Step-4] Preparation of N-methyl-1H-indole-5-sulfonamide [ka]

[0096] N-methyl-1H-indoline-5-sulfonamide (3.3 g, 15.5 mmol) prepared in [Step-3] was dissolved in 30 mL of dichloromethane, and then 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 3.5 g, 15.5 mmol) was added. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was filtered through CELITE and washed with dichloromethane. After concentration under reduced pressure, the resulting residue was purified by MPLC (ethyl acetate:hexane = 1:3 (v / v)) to obtain 1.9 g (58% yield) of the title compound. 1 H-NMR (300 MHz, CDCl3): δ 8.52 (s, 1H), 8.26-8.25 (m, 1H), 7.77-7.68 (m, 1H), 7.53-7.51 (m, 1H), 7.39-7.37 (m, 1H), 6.72-6.71 (m, 1H), 4.24 (brs, 1H), 2.67 (d, J= 5.5 Hz, 3H).

[0097] [Step-5] Preparation of N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0098] N-methyl-1H-indole-5-sulfonamide (1.9 g, 9.04 mmol) obtained in [Step 4] was dissolved in 20 mL of dimethylformamide, and 4-bromobenzotrifluoride (3.08 g, 13.6 mmol) and potassium carbonate (7.36 g, 22.6 mmol) were added, followed by cuprous iodide (344 mg, 1.8 mmol). The reaction mixture was stirred at 130 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, 100 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure. The resulting residue was purified by MPLC (ethyl acetate:hexane = 1:1 (v / v)) to obtain 1.2 g of the title compound (37% yield). 1 H-NMR (300 MHz, CDCl3): δ 8.31 (s, 1H), 7.87-7.84 (m, 2H), 7.76-7.73 (m, 1H), 7.67-7.51 (m, 3H), 7.49 (s, 1H), 6.88-6.87 (m, 1H), 4.35-4.11 (m, 1H), 2.70 (d, J= 5.5 Hz, 3H).

[0099] [Step-6] Preparation of 3-bromo-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0100] N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide (520 mg, 1.47 mmol) obtained in [Step-5] was dissolved in 30 mL of dimethylformamide, and N-bromosuccinimide (261 mg, 1.47 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, 100 mL of water was added and the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure. The resulting residue was purified by MPLC (ethyl acetate:hexane = 1:1 (v / v)) to obtain 420 mg of the title compound (66% yield). 1 H-NMR (300 MHz, CDCl3): δ 8.26-8.25 (m, 1H), 7.89-7.79 (m, 3H), 7.67-7.62 (m, 3H), 7.55 (s, 1H), 4.41-4.26 (m, 1H), 2.72 (s, 3H).

[0101] [Step-7] Preparation of N-methyl-3-(3-methylpyrazin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0102] The 3-bromo-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide (50 mg, 0.12 mmol) obtained in [Step 6] above was dissolved in 2 mL of N,N-dimethylacetamide, and the solution was added with cuprous chloride (3 mg, 0.02 mmol), cesium fluoride (53 mg, 0.35 mmol), [1,1'-bis(diphenylphosphino)bisferrocenyl]dichloride palladium ([Pd(dppf)Cl2], 16 mg, 0. To the reaction mixture were added 20 mL of water and three extractions with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated under reduced pressure. The residue was purified by MPLC (dichloromethane:methanol = 20:1 (v / v)) to give 18 mg (6% yield) of the title compound. 1 H-NMR (300 MHz, CDCl3): δ 8.77 (s, 1H), 8.59 (s, 1H), 8.45 (s, 1H), 7.83-7.80 (m, 2H), 7.68-7.65 (m, 3H), 4.88-4.87 (m, 1H), 2.80 (s, 3H), 2.67 (s, 3H). MS (ESI + , m / z): 447.1 [M+H] +

[0103] Example 2: N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0104] The process of Example 1 was repeated, except that tributyl-(1-methylimidazol-4-yl)stannane (171 mg, 0.46 mmol) was used instead of tributyl-(3-methylpyrazin-2-yl)stannane in [Step-7] of Example 1, to obtain 30 mg of the title compound (30% yield). 1 H-NMR (300 MHz, CDCl3): δ 8.56 (s, 1H), 7.94 (s, 1H), 7.77-7.76 (m, 6H), 7.54 (s, 1H), 7.37 (s, 1H), 4.83-4.81 (m, 1H), 3.81 (s, 3H), 2.69 (d, J= 5.4 Hz, 3H). MS (ESI + , m / z): 435.1 [M+H] +

[0105] Example 3: N-methyl-3-(1-methyl-1H-pyrazol-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0106] 3-Bromo-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide (50 mg, 0.11 mmol) obtained in [Step-6] of Example 1 was dissolved in 2.5 mL of 1,4-dioxane:water (1:4, v / v), and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (27 mg, 0.12 mmol), [1,1'-bis(diphenylphosphino)bisferrocenyl]dichloride palladium ([Pd(dppf)Cl]) (9 mg, 0.01 mmol), and sodium carbonate (24 mg, 0.23 mmol) were added. The reaction mixture was stirred at 100 °C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, added with 10 mL of water, and extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate:hexane = 1:1 (v / v)) to give 15 mg (30% yield) of the title compound. 1 H-NMR (300 MHz, CD3OD): δ 8.75 (s, 1H), 8.05 (s, 1H), 7.95-7.92 (m, 2H), 7.87-7.84 (m, 2H), 7.80-7.73 (m, 2H), 7.67-7.66 (m, 1H), 6.67 (s, 1H), 4.00 (s, 3H), 2.54 (s, 3H). MS (ESI + , m / z): 435.2 [M+H] +

[0107] Example 4: N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0108] The process of Example 3 was repeated, except that 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (27 mg, 0.13 mmol) was used instead of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, to obtain 11 mg (21% yield) of the title compound. 1 H-NMR (300 MHz, CDCl3): δ 8.35 (s, 1H), 7.86-7.83 (m, 2H), 7.78-7.74 (m, 3H), 7.67-7.60 (m, 3H), 7.55 (s, 1H), 4.03 (s, 3H), 2.67 (d, J= 5.5 Hz, 3H). MS (ESI + , m / z): 435.2 [M+H] +

[0109] Example 5: N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-indole-5-sulfonamide [ka]

[0110] The procedure of Example 1 was repeated, except that 1-bromo-4-(trifluoromethoxy)benzene (443 mg, 1.78 mmol) was used instead of 4-bromobenzotrifluoride in [Step-5] of Example 1, and tributyl-(1-methylimidazol-4-yl)stannane (223 mg, 0.60 mmol) was used instead of tributyl-(3-methylpyrazin-2-yl)stannane in [Step-7], and ethyl acetate:hexane = 2:1 (v / v) was used instead of dichloromethane:methanol = 20:1 (v / v) during purification, to obtain 20 mg (14% yield) of the title compound. 1H-NMR (300 MHz, CDCl3): δ 8.50 (d, J= 1.6 Hz, 1H), 7.86 (s, 1H), 7.74-7.70 (m, 1H), 7.61-7.53 (m, 4H), 7.43-7.40 (m, 2H), 7.31 (s, 1H), 4.31-4.29 (m, 1H), 3.80 (s, 3H), 2.66 (d, J= 5.5 Hz, 3H). MS (ESI + , m / z): 451.2 [M+H] +

[0111] Example 6: 3-(1-Isopropyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0112] The process of Example 1 was repeated, except that tributyl-(1-isopropylimidazol-4-yl)stannane (95 mg, 0.23 mmol) was used instead of tributyl-(3-methylpyrazin-2-yl)stannane in [Step-7] of Example 1, and ethyl acetate:hexane = 2:1 (v / v) was used instead of dichloromethane:methanol = 20:1 (v / v) during purification, to obtain 39 mg (71% yield) of the title compound. 1 H-NMR (300 MHz, CDCl3): δ 8.14 (d, J= 1.1 Hz, 1H), 7.89-7.78 (m, 4H), 7.70-7.67 (m, 3H), 7.50 (s, 1H), 7.18 (s, 1H), 4.39-4.29 (m, 2H), 2.66 (d, J= 5.4 Hz, 3H), 1.48 (d, J= 6.8 Hz, 6H). MS (ESI + , m / z): 463.2 [M+H] +

[0113] Example 7: N-ethyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0114] The process of Example 1 was repeated, except that 2M ethylamine tetrahydrofuran solution (27 mL) was used instead of 2M methylamine tetrahydrofuran solution in [Step-2] of Example 1, and tributyl-(1-methylimidazol-4-yl)stannane (171 mg, 0.46 mmol) was used instead of tributyl-(3-methylpyrazin-2-yl)stannane in [Step-7], to obtain 17 mg (17% yield) of the title compound. 1 H-NMR (300 MHz, DMSO-d6): δ 8.74 (s, 1H), 8.16 (s, 1H), 8.01-7.94 (m, 4H), 7.84-7.81 (m, 1H), 7.74 (s, 1H), 7.70-7.67 (m, 1H), 7.56 (s, 1H), 7.48-7.44 (m, 1H), 3.76 (s, 3H), 2.80-2.76 (m, 2H), 0.98 (t, J= 7.3 Hz, 3H). MS (ESI + , m / z): 449.1 [M+H] +

[0115] Example 8: N-methyl-3-(pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0116] The procedure of Example 1 was repeated, except that tributyl-(2-pyridinyl)stannane (85 mg, 0.23 mmol) was used instead of tributyl-(3-methylpyrazin-2-yl)stannane in [Step-7] of Example 1, and ethyl acetate:hexane = 1:1 (v / v) was used instead of dichloromethane:methanol = 20:1 (v / v) during purification, to obtain 7 mg (14% yield) of the title compound. 1 H-NMR (300 MHz, DMSO-d6): δ 9.15 (s, 1H), 8.73-8.71 (m, 2H), 8.04-8.01 (m, 5H), 7.98-7.83 (m, 2H), 7.72-7.68 (m, 1H), 7.40-7.39 (m, 1H), 7.30-7.26 (m, 1H), 2.42 (d, J= 4.8 Hz, 3H). MS (ESI + , m / z): 432.2 [M+H] +

[0117] Example 9: N-methyl-3-(5-methylthiophen-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0118] The process of Example 3 was repeated, except that 4,4,5,5-tetramethyl-2-(5-methyl-2-thienyl)-1,3,2-dioxaborane (29 mg, 0.12 mmol) was used instead of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyrazole, to afford 26 mg (52% yield) of the title compound. 1H-NMR (300 MHz, CDCl3): δ 8.54 (s, 1H), 7.86-7.84 (m, 2H), 7.78-7.75 (m, 1H), 7.67-7.62 (m, 3H), 7.59 (s, 1H), 7.15-7.14 (m, 1H), 6.82-6.81 (m, 1H), 4.30-4.25 (m, 1H), 2.69-2.67 (m, 3H), 2.56-2.55 (m, 3H). MS (ESI + , m / z): 451.2 [M+H] +

[0119] Example 10: N-methyl-3-(5-methylfuran-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0120] The procedure of Example 3 was repeated, except that 4,4,5,5-tetramethyl-2-(5-methyl-2-furyl)-1,3,2-dioxaborane (27 mg, 0.12 mmol) was used instead of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyrazole, to afford 29 mg (50% yield) of the title compound. 1 H-NMR (300 MHz, CDCl3): δ 8.54-8.53 (m, 1H), 7.86-7.83 (m, 2H), 7.78-7.62 (m, 5H), 6.60-6.59 (m, 1H), 6.14-6.12 (m, 1H), 4.31-4.26 (m, 1H), 2.70-2.68 (m, 3H), 2.41 (s, 3H). MS (ESI + , m / z): 435.20 [M+H] +

[0121] Example 11: 3-(1-ethyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0122] The process of Example 1 was repeated, except that tributyl-(1-ethylimidazol-4-yl)stannane (73 mg, 0.18 mmol) was used instead of tributyl-(3-methylpyrazin-2-yl)stannane in [Step-7] of Example 1, to obtain 9 mg (17% yield) of the title compound. 1 H-NMR (300 MHz, CDCl3): δ 8.52 (s, 1H), 7.92 (s, 1H), 7.84 (d, J= 8.9 Hz, 2H), 7.73-7.66 (m, 4H), 7.60-7.59 (m, 2H), 7.35 (s, 1H), 4.12-4.09 (m, 2H), 2.67 (d, J= 5.4 Hz, 3H), 1.25 (s, 3H). MS (ESI + , m / z): 449.2 [M+H] +

[0123] Example 12: N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-indole-5-sulfonamide [ka]

[0124] The procedure of Example 5 was repeated, except that 2-bromo-5-(trifluoromethyl)pyridine (427 mg, 1.85 mmol) was used instead of 1-bromo-4-(trifluoromethoxy)benzene, to afford 21 mg (34% yield) of the title compound. 1H-NMR (300 MHz, CD3OD): δ 8.90 (s, 1H), 8.78-8.75 (m, 1H), 8.44 (s, 1H), 8.34 (s, 1H), 8.29-8.25 (m, 1H), 7.91-7.88 (m, 1H), 7.83-7.79 (m, 2H), 7.58 (s, 1H) 3.85 (s, 3H), 2.55 (s, 3H). MS (ESI + , m / z): 436.2 [M+H] +

[0125] Example 13: 3-(2-fluorophenyl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0126] The process of Example 3 was repeated, except that (2-fluorophenyl)boronic acid (21 mg, 0.15 mmol) was used instead of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, to afford 5.5 mg (10% yield) of the title compound. 1 H-NMR (300 MHz, CDCl3): δ 8.40 (s, 1H), 7.87 (d, J= 8.4 Hz, 2H), 7.99 (d, J= 1.8 Hz, 1H), 7.77-7.66 (m, 5H), 7.36-7.28 (m, 3H), 4.26-4.24 (m, 1H), 2.67 (d, J= 5.5 Hz, 3H). MS (ESI + , m / z): 449.2 [M+H] +

[0127] Example 14: 1-(4-chlorophenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-sulfonamide [ka]

[0128] The procedure of Example 5 was repeated, except that 1-bromo-4-chloro-benzene (344 mg, 1.78 mmol) was used instead of 1-bromo-4-(trifluoromethoxy)benzene, to obtain 10 mg (15% yield) of the title compound. 1 H-NMR (300 MHz, CDCl3): δ 8.52 (d, J= 1.5 Hz, 1H), 7.87 (s, 1H), 7.75-7.72 (m, 1H), 7.61-7.47 (m, 6H), 7.33 (d, J= 7.0 Hz, 1H), 4.44-4.39 (m, 1H), 3.82 (s, 3H), 2.69 (d,J= 5.4 Hz, 3H). MS (ESI + , m / z): 401.1 [M+H] +

[0129] Example 15: N-methyl-3-(pyridin-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0130] The procedure of Example 1 was repeated, except that tributyl-(4-pyridyl)stannane (73 mg, 0.19 mmol) was used instead of tributyl-(3-methylpyrazin-2-yl)stannane in [Step-7] of Example 1, to obtain 5 mg (9% yield) of the title compound. 1 H-NMR (300 MHz, CDCl3): δ 8.54 (s, 1H), 8.32 (s, 1H), 7.99-7.89 (m, 8H), 7.87-7.83 (m, 2H), 2.54 (s, 3H). MS (ESI+ , m / z): 432.2 [M+H] +

[0131] Example 16: 3-(1-cyclobutyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0132] The process of Example 1 was repeated, except that tributyl-(1-cyclobutylimidazol-4-yl)stannane (95 mg, 0.23 mmol) was used instead of tributyl-(3-methylpyrazin-2-yl)stannane in [Step-7] of Example 1, and ethyl acetate:hexane = 2:1 (v / v) was used instead of dichloromethane:methanol = 20:1 (v / v) during purification, to obtain 5 mg (9% yield) of the title compound. 1 H-NMR (300 MHz, CDCl3): δ 8.53 (d, J= 1.2 Hz, 1H), 7.91 (s, 1H), 7.84 (d, J= 8.4 Hz, 2H), 7.76-7.60 (m, 5H), 7.38 (d, J= 1.1 Hz, 1H), 4.72-4.66 (m, 1H), 4.33-4.29 (m, 1H), 2.67 (d, J= 5.4 Hz, 3H), 2.61-2.55 (m, 2H), 2.51-2.45 (m, 2H), 2.09-1.95 (m, 2H). MS (ESI + , m / z): 475.2 [M+H] +

[0133] Example 17: N-methyl-3-phenyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0134] The procedure of Example 3 was repeated, except that phenylboronic acid (20 mg, 0.16 mmol) was used instead of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, to afford 14 mg (28% yield) of the title compound. 1 H-NMR (300 MHz, CDCl3): δ 8.51 (s, 1H), 7.86 (d, J= 8.6 Hz, 2H), 7.99 (d, J= 1.8 Hz, 1H), 7.77-7.61 (m, 5H), 7.54 (s, 1H), 7.51-7.49 (m, 2H), 7.42-7.39 (m, 1H), 4.28-4.23 (m, 1H), 2.66 (d, J= 1.8 Hz, 3H). MS (ESI + , m / z): 431.2 [M+H] +

[0135] Example 18: 1-(4-cyclohexylphenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-sulfonamide [ka]

[0136] The procedure of Example 5 was repeated, except that 1-bromo-4-cyclohexylbenzene (439 mg, 1.78 mmol) was used instead of 1-bromo-4-(trifluoromethoxy)benzene, to obtain 18 mg (29% yield) of the title compound. 1H-NMR (300 MHz, CDCl3): δ 8.41 (s, 1H), 7.84-7.79 (m, 2H), 7.68-7.61 (m, 2H), 7.58 (s, 1H), 7.52-7.36 (m, 4H), 4.58-4.54 (m, 1H), 3.83 (s, 3H), 2.65-2.59 (m, 1H), 2.51 (s, 3H), 1.94-1.88 (m, 4H), 1.81-1.77 (m, 1H), 1.58-1.31 (m, 5H). MS (ESI + , m / z): 449.2 [M+H] +

[0137] Example 19: N,N-dimethyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0138] The process of Example 1 was repeated except that in [Step-2] of Example 1, 2M methylamine tetrahydrofuran solution was replaced with 2M dimethylamine tetrahydrofuran solution (17.3 mL, 34.7 mmol) and tributyl-(1-methylimidazol-4-yl)stannane (112 mg, 0.3 mmol) was used instead of tributyl-(3-methylpyrazin-2-yl)stannane, to obtain 19 mg (19% yield) of the title compound. 1 H-NMR (300 MHz, DMSO-d6): δ 8.68 (s, 1H), 8.18 (s, 1H), 8.00-7.92 (m, 4H), 7.87-7.84 (m, 1H), 7.74 (s, 1H), 7.63-7.59 (m, 1H), 7.58 (s, 1H), 3.74 (s, 3H), 2.62 (s, 6H). MS (ESI + , m / z): 449.2 [M+H] +

[0139] Example 20: 3-(3-fluoropyridin-2-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0140] The process of Example 1 was repeated, except that tributyl-(3-fluoro-2-pyridinyl)stannane (89 mg, 0.23 mmol) was used instead of tributyl-(3-methylpyrazin-2-yl)stannane in [Step-7] of Example 1, and ethyl acetate:hexane = 1:1 (v / v) was used instead of dichloromethane:methanol = 20:1 (v / v) during purification, to obtain 19 mg (35% yield) of the title compound. 1 H-NMR (300 MHz, DMSO-d6): δ 8.75 (s, 1H), 8.59 (d, J= 4.8 Hz, 1H), 8.45 (s, 1H), 8.25 (s, 1H), 8.05-7.97 (m, 4H), 7.91-7.83 (m, 2H), 7.76-7.72 (m, 1H), 7.43-7.41 (m, 1H), 2.40 (d, J= 4.8 Hz, 3H). MS (ESI + , m / z): 450.3 [M+H] +

[0141] Example 21: N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(3-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0142] The procedure of Example 5 was repeated, except that 3-bromobenzotrifluoride (490 mg, 2.14 mmol) was used instead of 1-bromo-4-(trifluoromethoxy)benzene, to give 20 mg (22% yield) of the title compound. 1 H-NMR (300 MHz, DMSO-d6): δ 8.73 (s, 1H), 8.16 (s, 1H), 8.04-8.02 (m, 2H), 7.88-7.86 (m, 2H), 7.66-7.65 (m, 2H), 7.64-7.63 (m, 1H), 7.55-7.54 (m, 1H), 7.35-7.34 (m, 1H), 3.74 (s, 3H), 2.40 (d, J= 4.9 Hz, 3H). MS (ESI + , m / z): 435.2 [M+H] +

[0143] Example 22: 1-(4-cyanophenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-sulfonamide [ka]

[0144] The procedure of Example 5 was repeated, except that 4-iodobenzonitrile (500 mg, 2.14 mmol) was used instead of 1-bromo-4-(trifluoromethoxy)benzene, to give 25 mg (50% yield) of the title compound. 1 H-NMR (300 MHz, DMSO-d6): δ 8.73-8.72 (m, 1H), 8.16 (s, 1H), 8.10-8.07 (m, 2H), 7.93-7.83 (m, 3H), 7.74 (s, 1H), 7.68-7.64 (m, 1H), 7.56 (s, 1H), 7.39-7.34 (m, 1H), 3.75 (s, 3H), 2.40 (d, J= 4.9 Hz, 3H). MS (ESI+ , m / z): 392.2 [M+H] +

[0145] Example 23: 3-(furan-3-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0146] The procedure of Example 3 was repeated, except that 3-furylboronic acid (21 mg, 0.18 mmol) was used instead of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyrazole, to afford 13 mg (19% yield) of the title compound. 1 H-NMR (300 MHz, DMSO-d6): δ 8.28-8.23 (m, 3H), 8.01-7.92 (m, 4H), 7.87-7.83 (m, 2H), 7.71-7.68 (m, 1H), 7.50-7.30 (m, 1H), 7.02 (s, 1H), 2.40 (d, J= 4.8 Hz, 3H). MS (ESI + , m / z): 421.2 [M+H] +

[0147] Example 24: N-methyl-3-(5-methylfuran-2-yl)-1-phenyl-1H-indole-5-sulfonamide [ka]

[0148] The procedure of Example 10 was repeated, except that bromobenzene (339 mg, 2.14 mmol) was used instead of 4-bromobenzotrifluoride, to give 5 mg (9% yield) of the title compound. 1H-NMR (300 MHz, DMSO-d6): δ 8.40 (s, 1H), 8.12 (s, 1H), 7.74-7.60 (m, 6H), 7.52-7.46 (m, 1H), 7.47-7.42 (m, 1H), 6.69-6.68 (m, 1H), 6.26-6.25 (m, 1H), 2.42 (s, 3H), 2.40 (d, J= 4.8 Hz, 3H). MS (ESI + , m / z): 367.2 [M+H] +

[0149] Example 25: 3-(2,3-difluorophenyl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0150] The process of Example 3 was repeated, except that 2,3-difluorophenylboronic acid (32 mg, 0.21 mmol) was used instead of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, to obtain 10 mg (14% yield) of the title compound. 1 H-NMR (300 MHz, CDCl3): δ 8.39 (s, 1H), 7.88 (d, J= 8.6 Hz, 2H), 7.81-7.67 (m, 5H), 7.49-7.44 (m, 1H), 7.24-7.18 (m, 2H), 4.29-4.25 (m, 1H), 2.68 (d, J= 5.5 Hz, 3H). MS (ESI + , m / z): 467.2 [M+H] +

[0151] Example 26: N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-phenyl-1H-indole-5-sulfonamide [ka]

[0152] The procedure of Example 5 was repeated, except that bromobenzene (339 mg, 2.14 mmol) was used instead of 1-bromo-4-(trifluoromethoxy)benzene, to give 22 mg (35% yield) of the title compound. 1 H-NMR (300 MHz, DMSO-d6): δ 8.69 (s, 1H), 8.03 (s, 1H), 7.71-7.60 (m, 7H), 7.53 (s, 1H), 7.53-7.52 (m, 1H), 7.49-7.46 (m, 1H), 3.74 (s, 3H), 2.40 (d, J= 4.8 Hz, 3H). MS (ESI + , m / z): 367.2 [M+H] +

[0153] Example 27: 1-(3-chloro-4-(trifluoromethyl)phenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-sulfonamide [ka]

[0154] The procedure of Example 5 was repeated, except that 4-bromo-2-chloro-1-(trifluoromethyl)benzene (566 mg, 2.14 mmol) was used instead of 1-bromo-4-(trifluoromethoxy)benzene, to afford 2.5 mg (3% yield) of the title compound. 1H-NMR (300 MHz, CDCl3): δ 8.51-8.50 (m, 1H), 7.91-7.87 (m, 2H), 7.80-7.66 (m, 3H), 7.58-7.56 (m, 2H), 7.33 (s, 1H), 4.63-4.61 (m, 1H), 3.80 (s, 3H), 2.66 (d, J= 4.9 Hz, 3H). MS (ESI + , m / z): 469.2 [M+H] +

[0155] Example 28: 3-(1-cyclopropyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0156] The process of Example 1 was repeated, except that tributyl-(1-cyclopropylimidazol-4-yl)stannane (73 mg, 0.18 mmol) was used instead of tributyl-(3-methylpyrazin-2-yl)stannane in [Step-7] of Example 1, and ethyl acetate:hexane = 2:1 (v / v) was used instead of dichloromethane:methanol = 20:1 (v / v) during purification, to obtain 3 mg (5% yield) of the title compound. 1 H-NMR (300 MHz, DMSO-d6): δ 8.75 (d, J=1.6 Hz, 1H), 8.16 (s, 1H), 8.00-7.90 (m, 4H), 7.85-7.81 (m, 2H), 7.67-7.62 (m, 2H), 7.37-7.35 (m, 1H), 3.62-3.55 (m, 1H), 2.41 (d, J= 4.8 Hz, 3H), 1.03-0.99 (m, 4H). MS (ESI + , m / z): 461.1 [M+H] +

[0157] Example 29: 3-(1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0158] The procedure of Example 1 was repeated, except that t-butyl 4-(tributylstannyl)-1H-imidazole-1-carboxylate (150 mg, 0.33 mmol) was used instead of tributyl-(3-methylpyrazin-2-yl)stannane in [Step-7] of Example 1, and ethyl acetate:hexane = 4:1 (v / v) was used instead of dichloromethane:methanol = 20:1 (v / v) during purification, to obtain 14 mg (20% yield) of the title compound. 1 H-NMR (300 MHz, DMSO-d6): δ 12.2 (brs, 1H), 8.73 (s, 1H), 8.16 (s, 1H), 7.99-7.90 (m, 4H), 7.84-7.82 (m, 2H), 7.67-7.65 (m, 1H), 7.57 (s, 1H), 7.36-7.34 (m, 1H), 2.41 (d, J= 4.8 Hz, 3H). MS (ESI + , m / z): 421.2 [M+H] +

[0159] Example 30: 3-(1-(2-fluorobenzyl)-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0160] The process of Example 1 was repeated, except that tributyl-[1-[(2-fluorophenyl)methyl]imidazol-4-yl]stannane (86 mg, 0.18 mmol) was used instead of tributyl-(3-methylpyrazin-2-yl)stannane in [Step-7] of Example 1, and ethyl acetate:hexane = 1:1 (v / v) was used instead of dichloromethane:methanol = 20:1 (v / v) during purification, to obtain 9 mg (13% yield) of the title compound. 1 H-NMR (300 MHz, CDCl3): δ 8.53 (d, J= 1.4 Hz, 1H), 7.89 (s, 1H), 7.83 (d, J= 8.4 Hz, 2H), 7.76-7.72 (m, 1H), 7.67-7.64 (m, 4H), 7.36-7.35 (m, 2H), 7.20-7.11 (m, 3H), 5.27 (s, 2H), 4.32-4.30 (m, 1H), 2.66 (d, J= 5.5 Hz, 3H). MS (ESI + , m / z): 529.3 [M+H] +

[0161] Example 31: 3-(furan-2-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0162] The procedure of Example 3 was repeated, except that 2-(2-furyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (31 mg, 0.16 mmol) was used instead of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, to afford 16 mg of the title compound (32% yield). 1H-NMR (300 MHz, DMSO-d6): δ 8.47 (d, J= 1.4 Hz, 1H), 8.35 (s, 1H), 8.02-7.94 (m, 4H), 7.87-7.83 (m, 2H), 7.71 (dd, J= 8.8, 1.7 Hz, 1H), 7.50-7.41 (m, 1H), 6.86 (d, J= 3.9 Hz, 1H), 6.67 (d, J= 1.9 Hz, 1H), 2.41 (s, 3H). MS (ESI + , m / z): 421.2 [M+H] +

[0163] Example 32: N-methyl-3-(2-methyloxazol-5-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0164] The process of Example 3 was repeated, except that 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (27 mg, 0.13 mmol) was used instead of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, to afford 4 mg of the title compound (8% yield). 1 H-NMR (300 MHz, DMSO-d6): δ 8.37-8.36 (m, 2H), 8.02-7.95 (m, 4H), 7.89-7.86 (m, 1H), 7.75-7.72 (m, 1H), 7.46 (s, 2H), 2.53 (s, 3H), 2.42 (d, J= 3.1 Hz, 3H). MS (ESI + , m / z): 436.3 [M+H] +

[0165] Example 33: N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamide [ka]

[0166] [Step-1] Preparation of indoline-6-sulfonic acid [ka]

[0167] Indoline (10 g, 83.9 mmol) was added dropwise to 46 mL of sulfuric acid at 0-5° C. and stirred at 135° C. for 1 hour. After confirming the completion of the reaction, the mixture was cooled to room temperature and the formed solid was filtered to synthesize 6.7 g of indoline-6-sulfonic acid (40% yield). 1 H-NMR (300 MHz, DMSO-d6): δ 7.63-7.61 (m, 2H), 7.43-7.41 (m, 1H), 3.77-3.72 (m, 2H), 3.22-3.17 (m, 2H).

[0168] [Step-2] Preparation of 1-acetylindoline-6-sulfonic acid [ka]

[0169] Indoline-6-sulfonic acid (4.6 g, 23.1 mmol) was added to acetic anhydride (3.3 mL, 34.6 mmol) and pyridine (11.2 mL, 138.5 mmol) and stirred overnight at 100 °C. After the reaction was completed, the mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate and then filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure to synthesize 4.1 g of 1-acetylindoline-6-sulfonic acid (74% yield). 1H-NMR (300 MHz, DMSO-d6): δ 8.33 (s, 1H), 7.28-7.25 (m, 1H), 7.16-7.14 (m, 1H), 4.12-4.08 (m, 2H), 3.13-3.08 (m, 2H), 2.16 (s, 3H).

[0170] [Step-3] Preparation of N-methylindoline-6-sulfonamide [ka]

[0171] 1-acetylindoline-6-sulfonic acid (4 g, 16.6 mmol) was dissolved in 50 mL of acetonitrile, and a catalytic amount of dimethylformamide and POCl3 (8 mL, 85 mmol) were added. The mixture was refluxed for 1 hour, concentrated, and then poured onto ice. The solid formed was filtered to obtain 1-acetylindoline-6-sulfonyl chloride as a brown solid, which was used in the next step without further purification. This was dissolved in dichloromethane, 2 M methylamine (23 mL, 69.3 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After confirming the completion of the reaction, the solvent was removed under reduced pressure. The mixture was then added to 40 mL of methanol, and concentrated HCl (3 mL, 92.4 mmol) was added and stirred at 80 °C. After confirming the completion of the reaction, ethyl acetate was added and washed with water. The organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure and purified with dichloromethane:methanol = 10:1 (v / v) to obtain 2.6 g of the title compound (53% yield). 1 H-NMR (300 MHz, CDCl3): δ 7.19-7.18 (m, 2H), 7.04 (s, 1H), 3.66 (t, J= 8.5 Hz, 2H), 3.01 (t, J= 8.5 Hz, 2H), 2.66 (d, J= 3.3 Hz, 3H).

[0172] [Step-4] Preparation of N-methyl-1H-indole-6-sulfonamide [ka]

[0173] N-methylindoline-6-sulfonamide (1.8 g, 8.5 mmol) prepared in [Step-3] was dissolved in 20 mL of dichloromethane, and then 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 1.9 g, 8.5 mmol) was added. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was filtered through Celite and washed with dichloromethane. After concentration under reduced pressure, the resulting residue was purified by MPLC (ethyl acetate:hexane = 1:10 (v / v)) to obtain 1.9 g (58% yield) of the title compound. 1 H-NMR (300 MHz, CDCl3): δ 8.10 (s, 1H), 7.70-7.56 (m, 1H), 7.55-7.52 (m, 1H), 7.40-7.38 (m, 1H), 6.57-6.56 (m, 1H), 4.99-4.97 (m, 1H), 2.55 (d, J= 5.3 Hz, 3H).

[0174] [Step-5] Preparation of N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamide [ka]

[0175] The procedure of Example 2 was repeated, except that N-methyl-1H-indole-6-sulfonamide (1 g, 4.75 mmol) was used instead of N-methyl-1H-indole-5-sulfonamide, to give 18 mg (16% yield) of the title compound. 1H-NMR (300 MHz, DMSO-d6): δ 8.39-8.28 (m, 1H), 8.37 (s, 1H), 8.04-8.02 (m, 3H), 7.93-7.90 (m, 2H), 7.72 (s, 1H), 7.65-7.62 (m, 2H), 7.38-7.36 (m, 1H), 3.73 (s, 3H), 2.40 (d, J= 6.0 Hz, 3H). MS (ESI + , m / z): 435.1 [M+H] +

[0176] Example 34: N-methyl-3-(5-(trifluoromethyl)furan-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0177] The process of Example 3 was repeated, except that 4,4,5,5-tetramethyl-2-(5-(trifluoromethyl)furan-2-yl)-1,3,2-dioxaborolane (68 mg, 0.25 mmol) was used instead of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, to afford 30 mg of the title compound (25% yield). 1 H-NMR (300 MHz, DMSO-d6): δ 8.55 (s, 1H), 8.45 (d, J= 1.3 Hz, 1H), 8.03-7.97 (m, 4H), 7.90-7.87 (m, 1H), 7.77-7.73 (m, 1H), 7.48-7.42 (m, 2H), 7.07 (d, J= 3.6 Hz, 1H), 2.43 (d, J= 2.9 Hz, 3H). MS (ESI + , m / z): 489.4 [M+H] +

[0178] Example 35: N-methyl-3-(1-(oxetan-3-yl)-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0179] The process of Example 1 was repeated, except that 1-(oxetan-3-yl)-4-(tributylstannyl)-1H-imidazole (209 mg, 0.51 mmol) was used instead of tributyl-(3-methylpyrazin-2-yl)stannane in [Step-7] of Example 1, to obtain 5 mg of the title compound (4% yield). 1 H-NMR (300 MHz, CDCl3): δ 8.56 (s, 1H), 7.92 (s, 1H), 7.86-7.84 (m, 2H), 7.78-7.75 (m, 2H), 7.70-7.69 (m, 2H), 7.67-7.66 (m, 1H), 7.61-7.60 (m, 1H), 5.40-5.39 (m, 1H), 5.19 (t, J= 7.1 Hz, 2H), 5.00-4.96 (m, 2H), 4.35-4.33 (m, 1H), 2.69 (d, J= 5.5 Hz, 3H). MS (ESI + , m / z): 477.2 [M+H] +

[0180] Example 36: 3-(5-chlorofuran-2-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0181] The procedure of Example 3 was repeated, except that 2-(5-chloro-2-furyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (74 mg, 0.32 mmol) was used instead of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, to afford 4 mg of the title compound (3% yield). 1 H-NMR (300 MHz, DMSO-d6): δ 8.39 (s, 1H), 8.02-7.84 (m, 6H), 7.74 (d, J= 1.6 Hz, 1H), 7.47-7.45 (m, 1H), 6.94 (d, J= 3.4 Hz, 1H), 6.69 (d, J= 3.4 Hz, 1H), 2.42 (d, J= 4.4 Hz, 3H). MS (ESI + , m / z): 455.0 [M+H] +

[0182] Example 37: N-methyl-3-(1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0183] The process of Example 1 was repeated, except that tributyl-[1-[(2-fluoroethyl)imidazol-4-yl]stannane (158 mg, 0.36 mmol) was used instead of tributyl-(3-methylpyrazin-2-yl)stannane in [Step-7] of Example 1, and ethyl acetate:hexane = 2:1 (v / v) was used instead of dichloromethane:methanol = 20:1 (v / v) during purification, to obtain 30 mg (26% yield) of the title compound. 1H-NMR (300 MHz, DMSO-d6): δ 8.73 (d, J= 1.4 Hz, 1H), 8.26 (s, 1H), 8.00-7.92 (m, 5H), 7.86 (d, J= 8.8 Hz, 1H), 7.69-7.65 (m, 2H), 7.36-7.35 (m, 1H), 5.18-5.11 (m, 2H), 2.41 (d, J= 5.1 Hz, 3H). MS (ESI + , m / z): 503.4 [M+H] +

[0184] Example 38: 3-(1-(2-methoxyethyl)-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0185] The process of Example 1 was repeated, except that tributyl-[1-(2-methoxyethyl)imidazol-4-yl]stannane (316 mg, 0.76 mmol) was used instead of tributyl-(3-methylpyrazin-2-yl)stannane in [Step-7] of Example 1, to obtain 30 mg (24% yield) of the title compound. 1 H-NMR (300 MHz, DMSO-d6): δ 8.74 (s, 1H), 8.16 (s, 1H), 7.99-7.91 (m, 4H), 7.85-7.82 (m, 1H), 7.77 (s, 1H), 7.68-7.64 (m, 1H), 7.60 (s, 1H), 7.36-7.34 (m, 1H), 4.22 (t, J= 5.0 Hz, 2H), 3.67 (t, J= 5.2 Hz, 2H), 3.29 (s, 3H), 2.41 (d, J= 5.0 Hz, 3H). MS (ESI + , m / z): 479.2 [M+H] +

[0186] Example 39: N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(p-tolyl)-1H-indole-5-sulfonamide [ka]

[0187] The procedure of Example 1 was repeated except that 1-bromo-4-methyl-benzene (747 mg, 4.28 mmol) was used instead of 4-bromobenzotrifluoride in [Step-5] of Example 1, and tributyl-(1-methylimidazol-4-yl)stannane (132 mg, 0.35 mmol) was used instead of tributyl-(3-methylpyrazin-2-yl)stannane in [Step-7], and ethyl acetate:hexane = 2:1 (v / v) was used instead of dichloromethane:methanol = 20:1 (v / v) during purification, to obtain 16 mg (23% yield) of the title compound. 1 H-NMR (300 MHz, DMSO-d6): δ 8.69 (d, J= 1.2 Hz, 1H), 7.98 (s, 1H), 7.71-7.70 (m, 1H), 7.66-7.52 (m, 5H), 7.43-7.40 (m, 2H), 7.30-7.28 (m, 1H), 3.74 (s, 3H), 2.41-2.39 (m, 6H). MS (ESI + , m / z): 381.2 [M+H] +

[0188] Example 40: 1-(4-(t-butyl)phenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-sulfonamide [ka]

[0189] The procedure of Example 1 was repeated except that 1-bromo-4-t-butyl-benzene (979 mg, 4.41 mmol) was used instead of 4-bromobenzotrifluoride in [Step-5] of Example 1, and tributyl-(1-methylimidazol-4-yl)stannane (176 mg, 0.47 mmol) was used instead of tributyl-(3-methylpyrazin-2-yl)stannane in [Step-7], and ethyl acetate:hexane = 2:1 (v / v) was used instead of dichloromethane:methanol = 20:1 (v / v) during purification, to obtain 50 mg (48% yield) of the title compound. 1 H-NMR (300 MHz, DMSO-d6): δ 8.70 (d, J= 1.4 Hz, 1H), 8.01 (s, 1H), 7.73-7.57 (m, 7H), 7.52 (d, J= 1.2 Hz, 1H), 7.31 (s, 1H), 3.75 (s, 3H), 2.41 (d, J= 4.6 Hz, 3H), 1.38 (s, 9H). MS (ESI + , m / z): 423.2 [M+H] +

[0190] Example 41: N-methyl-3-(oxazol-5-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0191] The procedure of Example 3 was repeated, except that 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (189 mg, 0.97 mmol) was used instead of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, and ethyl acetate:hexane = 2:1 (v / v) was used instead of ethyl acetate:hexane = 1:1 (v / v) during purification, to obtain 16 mg (5% yield) of the title compound. 1H-NMR (300 MHz, CDCl3): δ 8.52 (s, 1H), 7.99 (s, 1H), 7.90-7.80 (m, 4H), 7.69-7.65 (m, 3H), 7.42 (s, 1H), 4.34 (brs, 1H), 2.71 (d, J=5.5 Hz, 3H). MS (ESI + , m / z): 422.1 [M+H] +

[0192] Example 42: 3-(1-cyclopropyl-1H-imidazol-4-yl)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-methyl-1H-indole-5-sulfonamide [ka]

[0193] The procedure of Example 28 was repeated, except that 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (367 mg, 1.42 mmol) was used instead of 4-bromobenzotrifluoride, to give 11 mg (6% yield) of the title compound. 1 H-NMR (300 MHz, CDCl3): δ 8.55 (s, 1H), 7.84 (s, 1H), 7.83-7.77 (m, 4H), 7.63-7.40 (m, 2H), 4.46-4.44 (m, 1H), 3.49-3.44 (m, 1H), 2.71 (t, J = 5.4 Hz, 1H), 2.70 (d, J= 5.4 Hz, 3H), 0.87-0.85 (m, 4H). MS (ESI + , m / z): 479.1 [M+H] +

[0194] Example 43: 3-(1-cyclopropyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-sulfonamide [ka]

[0195] [Step-1] Preparation of 5-bromo-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine [ka]

[0196] 5-Bromo-1H-pyrrolo[2,3-b]pyridine (1 g, 5.07 mmol) was dissolved in 5 mL of 1,4-dioxane, followed by the addition of racemic trans-1,2-diaminocyclohexane (0.013 mL, 0.10 mmol), cuprous iodide (1.9 mg, 0.01 mmol), potassium triphosphate (538 mg, 2.54 mmol), and 1-iodo-4-(trifluoromethyl)benzene (1.42 g, 5.07 mmol), and the reaction mixture was refluxed overnight under nitrogen. After completion of the reaction, the mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate. After concentration under reduced pressure, the resulting residue was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure. The resulting residue was purified by MPLC (ethyl acetate:hexane=1:9 (v / v)) to give 800 mg (46% yield) of the title compound. 1 H-NMR (300 MHz, CDCl3): δ 8.39 (d, J= 2.2 Hz, 1H), 8.09 (d, J= 2.2 Hz, 1H), 7.93-7.90 (m, 2H), 7.78-7.75 (m, 2H), 7.55 (d, J= 3.7 Hz, 1H), 6.62 (d, J= 3.7 Hz, 1H).

[0197] [Step-2] Preparation of 5-(benzylthio)-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine [ka]

[0198] 5-Bromo-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine (800 mg, 2.34 mmol) obtained in [Step 1] was dissolved in 10 mL of toluene. Benzyl mercaptan (0.27 mL, 2.34 mmol), [tris(dibenzylideneacetone)dipalladium(0)] (214 mg, 0.23 mmol), Xantphos (271 mg, 0.47 mmol), and N,N-diisopropylethylamine (1.22 mL, 7.03 mmol) were added, and the reaction mixture was refluxed overnight. After confirming completion of the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure. The resulting residue was purified by MPLC (ethyl acetate:hexane = 1:9 (v / v)) to obtain 900 mg of the title compound (98% yield). 1 H-NMR (300 MHz, CDCl3): δ 8.36 (s, 1H), 7.98-7.92 (m, 3H), 7.81-7.78 (m, 2H), 7.56 (d, J= 3.7 Hz, 1H), 7.29-7.19 (m, 5H), 6.62 (d, J=3.7 Hz, 1H), 4.07 (s, 2H).

[0199] [Step-3] Preparation of 1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-sulfonyl chloride [ka]

[0200] 5-(benzylthio)-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine (900 mg, 2.34 mmol) obtained in [Step-2] was dissolved in 19.8 mL of acetic acid:water = 10:1 (v / v), and N-chlorosuccinimide (937 mg, 7.02 mmol) was slowly added under cooled conditions at 0-5 °C. The reaction mixture was stirred at 0-5 °C for 15 minutes, then warmed to room temperature and stirred overnight. After confirming the completion of the reaction, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure. The resulting residue was purified by MPLC (ethyl acetate:hexane = 1:9 (v / v)) to obtain 380 mg (45% yield) of the title compound. 1 H-NMR (300 MHz, CDCl3): δ 9.01 (d, J= 2.3 Hz, 1H), 8.66 (d, J= 2.3 Hz, 1H), 7.95-7.92 (m, 2H), 7.86-7.83 (m, 2H), 7.77 (d, J= 3.7 Hz, 1H), 6.92 (d, J= 3.7 Hz, 1H).

[0201] [Step-4] Preparation of N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-sulfonamide [ka]

[0202] 1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-sulfonyl chloride (380 mg, 1.05 mmol) obtained in [Step-3] was dissolved in 7.6 mL of dichloromethane, and then 2 M methylamine tetrahydrofuran solution (4.2 mL, 2.10 mmol) was added dropwise and stirred at room temperature overnight. After the reaction was completed, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure. The resulting residue was purified by MPLC (ethyl acetate:hexane = 1:2 (v / v)) to obtain 370 mg (44% yield) of the title compound. 1 H-NMR (300 MHz, CDCl3): δ 8.85 (d, J= 2.1 Hz, 1H), 8.50 (d, J= 2.1 Hz, 1H), 7.96-7.93 (m, 2H), 7.84-7.81 (m, 2H), 7.70 (d, J= 3.7 Hz, 1H), 6.83 (d, J= 3.7 Hz, 1H), 4.41-4.35 (m, 1H), 2.73 (d, J= 5.4 Hz, 3H).

[0203] [Step-5] Preparation of 3-bromo-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-sulfonamide [ka]

[0204] N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-sulfonamide (370 mg, 1.04 mmol) obtained in [Step-4] was dissolved in 7.4 mL of dimethylformamide, and N-bromosuccinimide (198 mg, 1.09 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 1.5 hours. Upon completion of the reaction, 100 mL of water was added and the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure. The resulting residue was purified by MPLC (ethyl acetate:hexane = 1:3 (v / v)) to obtain 190 mg of the title compound (42% yield). 1 H-NMR (300 MHz, CDCl3): δ 8.87 (s, 1H), 8.46 (d, J= 2.1 Hz, 1H), 7.92-7.89 (m, 2H), 7.84-7.81 (m, 2H), 7.74 (s, 1H), 4.50-4.48 (m, 1H), 2.74 (d, J= 5.4 Hz, 3H).

[0205] [Step-6] 3-(1-cyclo-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-sulfonamide [ka]

[0206] 3-Bromo-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-sulfonamide (70 mg, 0.16 mmol) obtained in [Step-5] was dissolved in 1.4 mL of dimethylacetamide, and cuprous chloride (3.2 mg, 0.03 mmol), cesium fluoride (74 mg, 0.48 mmol), [1,1'-bis(diphenylphosphino)bisferrocenyl]dichloride palladium (23 mg, 0.03 mmol), and tributyl-(1-cyclopropylimidazol-4-yl)stannane (103 mg, 0.25 mmol) were added, and the reaction mixture was stirred overnight at 100°C. After completion of the reaction, water was added and the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtered organic layer was concentrated under reduced pressure. The resulting residue was purified by MPLC (dichloromethane:methanol=20:1 (v / v)) to give 4 mg (5% yield) of the title compound. 1 H-NMR (300 MHz, DMSO-d6): δ 9.01 (d, J= 2.2 Hz, 1H), 8.74 (d, J= 2.2 Hz, 1H), 8.54 (s, 1H), 8.26-8.25 (m, 2H), 8.12 (s, 1H), 8.00-7.97 (m, 2H), 7.90-7.83 (m, 1H), 7.63-7.61 (m, 1H), 3.69-3.61 (m, 1H), 2.45 (s, 3H), 1.08-1.02 (m, 4H). MS (ESI + , m / z): 462.2 [M+H] +

[0207] Example 44: 3-(1-cyclopropyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide [ka]

[0208] The procedure of Example 43 was repeated, except that 5-bromo-1H-indazole (5 g, 25.4 mmol) was used instead of 5-bromo-1H-pyrrolo[2,3-b]pyridine in [Step-1] of Example 43, to obtain 11 mg (9% yield) of the title compound. 1 H-NMR (300 MHz, DMSO-d6): δ 9.01 (s, 1H), 8.34-8.21 (m, 3H), 8.12-8.01 (m, 3H), 7.91-7.64 (m, 2H), 7.52 (s, 1H), 3.69-3.61 (m, 1H), 2.28-2.27 (m, 3H), 1.10-0.98 (m, 4H). MS (ESI + , m / z): 462.1 [M+H] +

[0209] Example 45: 3-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0210] The process of Example 3 was repeated, except that 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (43 mg, 0.17 mmol) was used instead of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, to obtain 26 mg (34% yield) of the title compound. 1 H-NMR (300 MHz, DMSO-d6): δ 8.69 (d, J= 1.4 Hz, 1H), 8.13 (s, 1H), 7.99-7.91 (m, 4H), 7.83 (d, J= 8.9 Hz, 1H), 7.67-7.64 (m, 1H), 7.52 (s, 1H), 7.37-7.35 (m, 1H), 4.04 (t, J= 6.8 Hz, 2H), 2.84 (t, J= 7.3 Hz, 2H), 2.59-2.56 (m, 2H), 2.40 (d, J= 4.4 Hz, 3H). MS (ESI + , m / z): 461.1 [M+H] +

[0211] Example 46: 3-(3-fluoroazetidin-1-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0212] 3-Bromo-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide (200 mg, 0.46 mmol) obtained in Step 6 of Example 1 was dissolved in 4 mL of 1,4-dioxane, and the solution was added with 3-fluoroazetidine hydrochloride (63 mg, 0.55 mmol), tris(dibenzylideneacetone)dipalladium(0) ([Pd(dba)] (21 mg, 0.02 mmol), xantphos To the reaction mixture, 10 mL of water was added and the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate:hexane = 1:3 (v / v)) to give 10 mg of the title compound (5% yield). 1 H-NMR (300 MHz, DMSO-d6): δ 7.94-7.93 (m, 3H), 7.91-7.79 (m, 3H), 7.63-7.59 (m, 1H), 7.36 (s, 1H), 5.64-5.40 (m, 1H), 4.37-4.25 (m, 2H), 4.06-3.93 (m, 2H), 2.40-2.38 (m, 3H). MS (ESI + , m / z): 428.1 [M+H] +

[0213] Example 47: N,N-dimethyl-2-(4-(5-(N-methylsulfamoyl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)-1H-imidazol-1-yl)acetamide [ka]

[0214] The process of Example 1 was repeated, except that N,N-dimethyl-2-(4-(tributylstannyl)-1H-imidazol-1-yl)acetamide (326 mg, 0.74 mmol) was used instead of tributyl-(3-methylpyrazin-2-yl)stannane in [Step-7] of Example 1, to obtain 50 mg (27% yield) of the title compound. 1 H-NMR (300 MHz, DMSO-d6): δ 8.70 (d, J= 1.5 Hz, 1H), 8.16 (s, 1H), 8.00-7.92 (m, 4H), 7.85-7.82 (m, 1H), 7.68 (s, 1H), 7.68-7.64 (m, 1H), 7.49 (s, 1H), 7.36-7.35 (m, 1H), 5.09 (s, 2H), 3.06 (s, 3H), 2.89 (s, 3H), 2.41 (d, J= 5.0 Hz, 3H). MS (ESI + , m / z): 506.1 [M+H] +

[0215] Example 48: N-methyl-3-(1-(2-(methylsulfonyl)ethyl)-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide [ka]

[0216] The process of Example 1 was repeated, except that 1-(2-(methylsulfonyl)ethyl)-4-(tributylstannyl)-1H-imidazole (510 mg, 1.10 mmol) was used instead of tributyl-(3-methylpyrazin-2-yl)stannane in [Step-7] of Example 1, to obtain 65 mg (21% yield) of the title compound. 1H-NMR (300 MHz, DMSO-d6): δ 8.70 (d, J= 1.4 Hz, 1H), 8.22 (s, 1H), 8.19-7.95 (m, 4H), 7.92-7.82 (m, 2H), 7.75-7.65 (m, 2H), 7.38-7.33 (m, 1H), 4.52 (t, J= 7.0 Hz, 2H), 3.77 (t, J= 7.4 Hz, 2H), 2.96 (s, 3H), 2.41 (d, J= 5.0 Hz, 3H). MS (ESI + , m / z): 527.1 [M+H] +

[0217] Experimental Example 1: Inhibition test of TEAD reporter activity The ability of the synthetic compounds to inhibit TEAD target gene transcription was measured. This assay uses MCF7 cells (BPS Bioscience, Inc., USA) transfected with a firefly luciferase reporter gene at the specific TEAD binding site, GTIIC (5'-ACATTCCA-3'). The luciferase luminescence expressed upon TEAD binding to target genes and activating transcription was measured to determine the transcriptional activity of TEAD. The cell lines were cultured in MEM medium supplemented with 10% FBS, 1% penicillin / streptomycin, 1% non-essential amino acids, 10 μg / ml insulin, and 400 μg / ml geneticin. Geneticin was omitted during the TEAD reporter activity inhibition test. 4x10 4 The cells were dispensed into a white 96-well plate at 100 μl / well and cultured for 6 hours. 50 μl of experimental compounds diluted to 3X concentration were added to each well. After 24 hours of culture, luciferase signals were measured by luminescence using the ONE-Glo luciferase assay system (Promega, E6120) according to the manufacturer's protocol. The 50% inhibition value (IC) of TEAD transcriptional activity was calculated. 50) was calculated using GraphPad Prism 9.

[0218] I C 50 Values ​​below 100 nM were designated as A, values ​​between 100 nM and 500 nM as B, and values ​​above 500 nM as C.

[0219] [Table 1]

[0220] Experimental Example 2: Cell growth inhibition test The synthetic compounds were confirmed to inhibit cell growth of NCI-H226 cells. NCI-H226 is a mesothelioma cancer cell line lacking the NF2 gene. The cells were cultured in RPMI 1640 medium supplemented with 10% FBS and 1% penicillin / streptomycin. 0.7x10 cells were cultured. 3 The cells were then cultured for 24 hours, and 100 μl of the experimental compound diluted to 2X concentration was added to each well, followed by culturing for 6 days. The SRB test method was used to measure cell growth inhibition, and the 50% inhibition value (GI) of the compound on cell growth was calculated. 50 ) was calculated using GraphPad Prism9.

[0221] GI 50 Values ​​below 100 nM were designated A, and values ​​above 100 nM were designated B.

[0222] [Table 2]

[0223] The present invention has been described above with reference to specific embodiments. Those skilled in the art will recognize that the present invention can be embodied in various modified forms without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the claims, not the foregoing description, and all variations within the scope of the claims should be construed as being within the scope of the present invention.

Claims

1. A compound selected from the group consisting of compounds of the following formula 1, their optical isomers, diastereomers, solvates, hydrates and pharmaceutically acceptable salts thereof: 【Chemical 1】 In the above Chemical Formula 1, R １ and R ２ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ３－６ Carbocyclyl or halo C １－６ is alkyl; R ３ is hydrogen, halogen, C １－６ Alkyl, haloC １－６ Alkyl, C １－６ alkoxy, or cyano; 【Chemistry 2】 is carbocyclyl or heterocyclyl; 【Chemistry 3】 is C ６－１０ Aryl or C ４－１０ is heteroaryl; L １ is absent, a bond, or C １－３ Alkylene or halogen-substituted C １－３ alkylene; Each R ４ and each R ５ are each independently hydrogen, halogen, cyano, amino, C １－６ Alkyl, haloC １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkoxyalkyl, haloC １－６ Alkoxy, mono-(C １－３ alkyl)-substituted carbamoyl (-(CO)-NH(C １－３ alkyl)), di-(C １－３ alkyl)-substituted carbamoyl (—(CO)—N(C １－３ alkyl) ２ ), C １－３ Alkyl sulfinyl (-(SO)-(C １－３ alkyl), C １－３ Alkylsulfonyl (-SO ２ -(C １－３ alkyl), substituted or unsubstituted C ３－６ Carbocyclyl, substituted or unsubstituted C ６－１０ Aryl, substituted or unsubstituted C ２－６ heterocyclyl, or substituted or unsubstituted C ４－１０ is heteroaryl; X and Y are each independently —C— or —N—; m and n each independently represent an integer of 0 to 3; 【Request 2】 【Chemical 4】 is C ６－１０ Aryl, C １－１０ Heteroaryl, C ６－１４ fused heteroaryl, or C ２－６ heterocyclyl, wherein C １－１０ Heteroaryl, C ６－１４ fused heteroaryl, or C ２－６ 2. The compound of claim 1, wherein the heterocyclyl contains 1 to 4 heteroatoms independently selected from N, O, and S. 【Request 3】 【Chemical 5】 is a phenyl group, a pyridinyl group, a pyrazinyl group, a pyrazolyl group, an imidazolyl group, a thiophenyl group, a furanyl group, an oxazole group, an azetidinyl group, or 【Chemistry 6】 2. The compound of claim 1, wherein: 【Request 4】 【Chemical 7】 is a phenyl group or a pyridinyl group.

5. R １ and R ２ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ３－６ Cycloalkyl or haloC １－６ The compound of claim 1 , wherein the aryl group is alkyl.

6. L １ is a bond; Each R ４ and each R ５ are each independently hydrogen, halogen, cyano, C １－６ Alkyl, haloC １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkoxyalkyl, haloC １－６ Alkoxy, mono-(C １－３ alkyl)-substituted carbamoyl (-(CO)-NH(C １－３ alkyl)), di-(C １－３ alkyl)-substituted carbamoyl (—(CO)—N(C １－３ alkyl) ２ ), C １－３ Alkylsulfonyl (-SO ２ -(C １－３ alkyl), substituted or unsubstituted C ３－６ Cycloalkyl, substituted or unsubstituted C ６－１０ Aryl, or substituted or unsubstituted C ２－６ The compound of claim 1 which is a heterocycloalkyl.

7. L １ is C １－３ alkylene; Each R ４ and each R ５ are each independently hydrogen, halogen, cyano, C １－６ Alkyl, haloC １－６ Alkyl, C １－６ Alkoxy, HaloC １－６ Alkoxy, di-(C １－３ alkyl)-substituted carbamoyl (—(CO)—N(C １－３ alkyl) ２ ), C １－３ Alkylsulfonyl (-SO ２ -(C １－３ alkyl), substituted or unsubstituted C ３－６ Cycloalkyl, substituted or unsubstituted C ６－１０ Aryl, or substituted or unsubstituted C ２－６ The compound of claim 1 which is a heterocycloalkyl.

8. R ５ are hydrogen, halogen, cyano, and C, respectively. １－６ Alkyl, haloC １－６ Alkyl, C １－６ Alkoxy, HaloC １－６ Alkoxy, C ３－６ cycloalkyl, or phenyl, or Halogen, cyano, C １－６ Alkyl, haloC １－６ Alkyl, C １－６ Alkoxy and haloC １－６ C substituted with one or more substituents selected from alkoxy ３－６ The compound of claim 1 , which is cycloalkyl or phenyl.

9. R ５ is independently hydrogen, halogen, cyano, methyl, ethyl, propyl, t-butyl, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl.

10. The compound according to claim 1, wherein the compound is selected from the following compounds, their optical isomers, diastereomers, solvates, hydrates and pharmaceutically acceptable salts thereof: N-methyl-3-(3-methylpyrazin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-methyl-1H-pyrazol-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-indole-5-sulfonamide; 3-(1-isopropyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-ethyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(5-methylthiophen-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(5-methylfuran-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3-(1-ethyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-indole-5-sulfonamide; 3-(2-fluorophenyl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 1-(4-chlorophenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-sulfonamide; N-methyl-3-(pyridin-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3-(1-cyclobutyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-phenyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 1-(4-cyclohexylphenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-sulfonamide; N,N-dimethyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3-(3-fluoropyridin-2-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(3-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 1-(4-cyanophenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-sulfonamide; 3-(furan-3-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(5-methylfuran-2-yl)-1-phenyl-1H-indole-5-sulfonamide; 3-(2,3-difluorophenyl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-phenyl-1H-indole-5-sulfonamide; 1-(3-chloro-4-(trifluoromethyl)phenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-sulfonamide; 3-(1-cyclopropyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3-(1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3-(1-(2-fluorobenzyl)-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3-(furan-2-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(2-methyloxazol-5-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamide; N-methyl-3-(5-(trifluoromethyl)furan-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-(oxetan-3-yl)-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3-(5-chlorofuran-2-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3-(1-(2-methoxyethyl)-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(p-tolyl)-1H-indole-5-sulfonamide; 1-(4-(t-butyl)phenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-sulfonamide; N-methyl-3-(oxazol-5-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3-(1-cyclopropyl-1H-imidazol-4-yl)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-methyl-1H-indole-5-sulfonamide; 3-(1-cyclopropyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-sulfonamide; 3-(1-cyclopropyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide; 3-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3-(3-fluoroazetidin-1-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N,N-dimethyl-2-(4-(5-(N-methylsulfamoyl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)-1H-imidazol-1-yl)acetamide; and N-methyl-3-(1-(2-(methylsulfonyl)ethyl)-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide.

11. A pharmaceutical composition for treating or preventing a disease caused by transcriptional enhancer associate domain (TEAD) activation, comprising as an active ingredient a compound selected from the group consisting of the compound according to any one of claims 1 to 10, its optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof.

12. The pharmaceutical composition according to claim 11, wherein the composition exhibits activity of inhibiting Yes associated protein (YAP)-transcriptional enhancer associate domain (TEAD) binding.

13. The pharmaceutical composition of claim 11, for treating a treatable cancer or tumor by exhibiting inhibitory activity against YAP-TEAD binding.

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