Novel heterobicyclic compound for inhibiting yap-tead interaction and pharmaceutical composition comprising same

Abstract

The present invention relates to: a compound selected from a compound of chemical formula 1, and an optical isomer, diastereomer, solvate, and hydrate thereof, and a pharmaceutically acceptable salt of these; a preparation method thereof; and use thereof.

Description

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

[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, wherein the compound according to the present invention can directly inhibit YAP-TEAD binding in the Hippo pathway, which plays a key role in the process of cancer development.

[0002] The Hippo signaling cascade is a crucial 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 translocation to the nucleus, where they interact with the enhancer-associated domain (TEAD) transcription factor, 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 and in breast, ovarian, germ cell, renal cell, medullary, and gastric cancers. Overactivation of YAP and TAZ and / or mutations in one or more members of the Hippo pathway network have been associated with numerous cancers. Furthermore, recent studies have linked YAP overexpression or amplification with epithelial-mesenchymal transition (EMT) phenotype changes to resistance to the EGFR tyrosine kinase inhibitors Tarceva (erlotinib), Iressa (gefitinib), or Tagrisso (osimertinib).

[0003] The present inventors have completed the present invention by developing a novel heterobicyclic compound for inhibiting YAP-TEAD protein interaction.

[0004] [Prior Art Literature]

[0005] [Patent Document]

[0006] (Patent Document 1) International Patent Publication No. WO2019 / 040380

[0007] (Patent Document 2) International Patent Publication No. WO2020 / 243415

[0008] [Non-patent literature]

[0009] (Non-patent literature 1) Semin. Cancer Biol. 2022, 85, 33

[0010] (Non-patent literature 2) Nat. Rev. Drug Discov. 2014, 13(1), 63

[0011] (Non-patent literature 3) Cancer Res. 2011, 71(3), 873

[0012] (Non-patent literature 4) J. Cell Mol. Med. 2017, 21(11), 2663

[0013] (Non-patent document 5) Cancer Cell 2020, 37,104

[0014] (Non-patent document 6) Cells2021, 10,2715

[0015] (Non-patent literature 7) Genes Cancer 2017, 8(3-4), 497

[0016] One object of the present invention is to provide a novel heterobicyclic compound having excellent inhibitory activity against YAP-TEAD binding in the Hippo pathway, which plays a key role in the development of cancer.

[0017] Another object of the present invention is to provide a pharmaceutical composition for treating or preventing a related disease caused by a dysregulation of the Hippo signaling pathway, specifically TEAD activation, comprising the compound as an active ingredient.

[0018] Other purposes and advantages of this application will be further clarified by the detailed description below, along with the appended claims. Anything not described herein is readily apparent and inferable to those of ordinary skill in the technical field of this application or similar technical fields, and therefore, its description is omitted.

[0019] According to one embodiment of the present invention, a compound selected from the compounds of the following chemical formula 1, optical isomers, diastereomers, solvates, hydrates and pharmaceutically acceptable salts thereof is provided:

[0020] [Chemical Formula 1]

[0021]

[0022] According to one embodiment of the present invention, a pharmaceutical composition is provided for treating or preventing a disease related to a dysregulation of the Hippo signaling pathway, specifically, a disease caused by TEAD activation, comprising as an active ingredient a compound selected from the compound, an optical isomer, a diastereomer, a solvate, a hydrate, and a pharmaceutically acceptable salt thereof.

[0023] The novel heterobicyclic compound having the structure of chemical formula 1 in the present invention has excellent inhibitory activity against YAP-TEAD binding, and thus is effective against various 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.

[0024] Hereinafter, the present invention will be described in more detail.

[0025] Unless otherwise defined, all technical terms used in this invention have the same meaning as commonly understood by those skilled in the art in the relevant fields of the present invention. Furthermore, while preferred methods and samples are described herein, similar or equivalent methods are also included within the scope of the present invention.

[0026] definition

[0027] As used herein, the term “halogen” may be F, Cl, Br, or I.

[0028] As used herein, the term "alkyl" refers to a monovalent group derived from a saturated hydrocarbon by removing one hydrogen atom, unless otherwise stated. The alkyl includes a straight-chain, branched, or cyclic hydrocarbon residue which may be substituted or unsubstituted, and examples thereof include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, or t-butyl.

[0029] The term "alkenyl" as used herein, unless otherwise stated, refers to a monovalent group derived from a hydrocarbon by removing one hydrogen atom, which contains one or more unsaturated regions and at least one carbon-carbon double bond. The alkenyl includes an alkyl group containing one or more double bonds, which may be substituted or unsubstituted, and examples thereof include, but are not limited to, prop-1-ene, but-1-ene, but-2-ene, 3-methylbut-1-ene, or pent-1-ene.

[0030] The term "alkynyl" as used herein, unless otherwise stated, refers to a monovalent group derived from a hydrocarbon by the removal of one hydrogen atom, and which contains one or more regions of unsaturation, i.e., at least one carbon-carbon triple bond. The alkynyl may be, but is not limited to, -C≡CH, -CH2C≡CH, or -CH2CH2CH2C≡C-.

[0031] The term "alkylene" as used herein refers to a straight-chain, branched, or cyclic saturated divalent hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Alkylene is (-CH2-) p(where p is any integer) and may be, for example, but not limited to, methylene (-CH2-), 1,1-ethyl (-CH(CH3)-), 1,2-ethyl (-CH2CH2-), 1,1-propyl (-CH(CH2CH3)-), 1,2-propyl (-CH2CH(CH3)-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-).

[0032] The term "alkenylene" as used herein refers to a divalent group derived from an alkenyl by the removal of one hydrogen atom, i.e., a straight-chain, branched, or cyclic unsaturated divalent hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. For example, alkenylene may be, but is not limited to, methylene (-CH=), 1,2-ethylene (-CH=CH-), and the like.

[0033] The term "alkynylene" as used herein refers to a divalent group derived from an alkyne by the removal of one hydrogen atom, i.e., a straight-chain, branched, or cyclic unsaturated divalent hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. For example, alkynylene can be, but is not limited to, -C≡C-, -CH2C≡C-, or -CH2CH2CH2C≡C-.

[0034] As used herein, the term "cycloalkyl" means, unless otherwise stated, a saturated monocyclic or polycyclic hydrocarbon ring having a specified number of carbon atoms, which ring may be substituted or unsubstituted. The cycloalkyl group may be, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0035] As used herein, the term "heterocycloalkyl" means, unless otherwise stated, a monocyclic, optionally substituted, cyclic alkyl group containing one or more heteroatoms selected from N, O, and S. The heterocycloalkyl group may be, but is not limited to, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, thiomorpholinyl, imidazolidinyl, tetrahydrofuranyl, or similar groups.

[0036] As used herein, the term "haloalkyl" includes monohaloalkyl and polyhaloalkyl, which may be substituted or unsubstituted, unless otherwise stated. The terms halogen and alkyl are as defined above.

[0037] The term "alkoxy" as used herein, unless otherwise stated, refers to a straight-chain or branched hydrocarbon residue linked to oxygen, which may be substituted or unsubstituted. The alkoxy may be, but is not limited to, methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, or t-butoxy.

[0038] As used herein, the term "alkoxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced with alkoxy. Examples of the alkoxyalkyl group include, but are not limited to, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, ethoxypropyl, and isopropoxymethyl.

[0039] As used herein, the term "aryl", unless otherwise stated, refers to an aromatic group which may be substituted or unsubstituted, for example, C 3-10 Aryl, C 3-8 Aryl, or C 3-6 It may contain aryl, with double bonds alternating (resonating) between adjacent carbon atoms or suitable heteroatoms. Examples include, but are not limited to, phenyl, biphenyl, naphthyl, toluyl, or naphthalenyl.

[0040] As used herein, the term "heteroaryl" may mean a monocyclic or bicyclic or more, substituted or unsubstituted, aromatic group containing one or more heteroatoms selected from N, O, and S, unless otherwise stated. For example, a monocyclic heteroaryl may be, but is not limited to, pyridinyl, imidazolyl, thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridazinyl, pyrimidinyl, or pyrazinyl. For example, the bicyclic heteroaryl can be, but is not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, purinyl, or furopyridinyl.

[0041] As used herein, the term "carbocyclyl" means a substituent comprising a carbon ring atom, unless otherwise stated, having the structure of a saturated carbocyclyl (e.g., a "cycloalkane" or a "cycloalkyl"), a partially saturated carbocyclyl (e.g., a "cycloalkene" or a "cycloalkenyl"), or a fully unsaturated carbocyclyl (e.g., an "aryl"). The carbocyclyl may be a single ring (monocyclic) or a polycyclic ring structure. As used herein, a carbocyclyl comprises, for example, 3 to 14, or for example, 3 to 8, carbon ring atoms, which may be saturated, unsaturated, or aromatized. Herein, a ring atom is an atom that is bonded together to form a ring or rings of a carbocyclyl substituent. For example, a saturated carbocyclyl group can be, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. For example, an unsaturated carbocyclyl group can contain three or fewer double bonds. For example, an aromatic carbocyclyl group can be phenyl. Additionally, the carbocyclyl can include a fused combination of carbocyclyl groups, such as, but not limited to, naphthyl, phenanthryl, indanyl, and indenyl.

[0042] As used herein, the term "heterocyclyl" means, unless otherwise stated, a substituent having a ring structure of at least one heteroatom, which has the structure of a saturated heterocyclyl (e.g., "heterocycloalkyl"), a partially saturated heterocyclyl (e.g., "heterocycloalkenyl"), or a fully unsaturated heterocyclyl (e.g., "heteroaryl"). The heterocyclyl may be a single ring (monocyclic) or a polycyclic ring structure. As used herein, a heterocyclyl contains, for example, a total of 3 to 14, 6 to 14, or, for example, a total of 3 to 8 ring atoms, and may be saturated, unsaturated, or aromatized. Herein, a ring atom is an atom that is bonded together to form a ring or rings of a 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 the heterocyclyl may have up to four heteroatoms such as N, O, and S, may include, for example, a total of 3 to 14 ring atoms, or, for example, a total of 5 to 7 ring atoms, and may be saturated, unsaturated, or aromatized. For example, the heterocyclyl can be, but is not limited to, imidazolyl, imidazolinyl, imidazolidinyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, dioxolanyl, oxazolyl, thiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolaneyl, triazinyl, azepinyl, oxazepinyl, thiazepinyl, diazepinyl, or thiazolinyl.Additionally, the term heterocyclyl may include 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" may be a carbon-linked group or a heteroatom-linked group. For example, among the heteroatom-linked groups, N-linked heterocyclyl is. , , Including, but not limited to, the term "fused heteroaryl" as used herein, unless otherwise stated, refers to a substituted or unsubstituted ring system in which a heteroaryl group is linked in a fused manner to another aryl, heteroaryl, or heterocycloalkyl group. For example, a fused heteroaryl can form a 5+5 membered, 5+6 membered, 5+7 membered, 6+6 membered, or 6+7 membered fused ring system.

[0043] Any substituent herein may be, for example, halogen, cyano, amino, hydroxy, C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-6 Cycloalkyl, haloC 3-6 Cycloalkyl, C 1-6 Alkoxy, and haloC 1-6 Any one of the substituents selected from alkoxy, but is not limited thereto. For example, substituted alkyl, substituted carbocyclyl, substituted aryl, substituted heterocyclyl, or substituted heteroaryl may be substituted with one or more hydrogen atoms substituted with halogen, cyano, amino, hydroxy, C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-6 Cycloalkyl, haloC 3-6 Cycloalkyl, C 1-6 Alkoxy, and haloC 1-6It may be substituted with any one of the substituents selected from alkoxy, but is not limited thereto.

[0044] The term "stereoisomer" as used herein may mean a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but being optically or sterically different, and includes optical isomers or diastereoisomers.

[0045] As used herein, the term "optical isomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.

[0046] As used herein, the term "diastereoisomer" refers to a stereoisomer having two or more chiral centers, the molecules of which are not mirror images of each other.

[0047] The compounds of the present invention may 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, optical isomers, and racemic mixtures, are considered to form part of the present invention. A 50:50 mixture of optical isomers is called a racemic mixture or racemate.

[0048] The term "solvate" as used herein may refer to a compound of the present invention or a salt thereof comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents for the compound may be volatile, non-toxic, and / or suitable for human administration. The "solvate" may comprise a molecular complex comprising the compound and one or more pharmaceutically acceptable solvent molecules, such as ethanol.

[0049] As used herein, the term “hydrate” refers to a complex wherein the solvent molecule is water.

[0050] As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt, which can be prepared by any suitable method known to those skilled in the art. For example, if the compound of the present invention is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method known to those skilled in the art, for example, by treating the free base with an inorganic acid, organic acid, or the like.

[0051] The term "therapeutically effective amount" as used herein means an amount of a compound of the present invention that treats or prevents a specific disease, condition or disorder, attenuates, improves or eliminates one or more symptoms of a specific disease, condition or disorder, or prevents or delays the onset of one or more symptoms of a specific disease, condition or disorder.

[0052] As used herein, the term "treating" or "treatment" refers to inhibiting a disease, condition or disorder in a subject experiencing or exhibiting the pathology or signs of the disease, condition or disorder, such as preventing or reversing further development of the pathology and / or signs, or ameliorating the disease, such as reducing the severity of the disease.

[0053] The term "preventing" or "prevention" as used herein 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 does not yet experience or exhibit the pathology or signs of the disease.

[0054] As used herein, the term "subject" or "individual" may be a vertebrate animal 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.

[0055] The terms “administering” and “administration” as used herein refer to any method of providing the disclosed composition to a subject.

[0056] In the context of the present invention, the singular form of a word may include the plural, and vice versa, unless the context clearly indicates otherwise.

[0057] The numerical values ​​set forth herein are to be considered to include the meaning of "about" even if not explicitly stated. The term "about" as used herein means within 5% of a given value or range, preferably within 1% to 2%.

[0058] In this specification, the numerical range indicated using the term “to” refers to a range that includes the numerical values ​​described before and after the term “to” as the lower and upper limits, respectively.

[0059] The terms “have,” “may have,” “include,” or “may include” used in this specification indicate the presence of a feature (e.g., a numerical value, or a component such as an ingredient), and do not exclude the presence of additional features.

[0060] The contents of all publications cited as references in this specification are incorporated herein by reference in their entirety.

[0061]

[0062] One embodiment of the present invention provides a compound selected from the compounds of the following chemical formula 1, optical isomers, diastereomers, solvates, hydrates and pharmaceutically acceptable salts thereof:

[0063] [Chemical Formula 1]

[0064]

[0065] In the above chemical formula 1,

[0066] R1 is hydrogen, halogen, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6Alkoxy, cyano,

[0067] R2 and R3 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(C 1-3 Alkyl)2), C 1-3 Alkylsulfinyl (-(SO)-(C 1-3 alkyl)), C 1-3 Alkylsulfonyl (-SO2-(C 1-3 alkyl)), substituted or unsubstituted C 3-10 Carbocyclyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted C 1-10 Heterocyclyl, or substituted or unsubstituted C 4-10 is heteroaryl;

[0068] L1 and L2 is non-existent, combined, C 1-6 Alkylene, C 2-6 C substituted with alkenylene or halogen 1-3 It is alkylene;

[0069] L2 and The bond is a single or double bond;

[0070] W is -S(O)2-NR4R 5, -S(O)-NR4R 5, -C(O)-NR4R 5, , , , or and;

[0071] R4, R 5, R6 and R7 are independently hydrogen, halogen, cyano, C 1-6Alkyl, substituted or unsubstituted C 3-10 Carbocyclyl, substituted or unsubstituted C 6-10 Aryl or substituted or unsubstituted C 4-10 is heteroaryl;

[0072] is substituted or unsubstituted C 3-14 Carbocyclyl or substituted or unsubstituted C 1-14 It is heterocyclyl;

[0073] is substituted or unsubstituted, saturated or partially saturated, C 3-10 It is a carbocyclyl;

[0074] X and Y are each independently -C- or -N-;

[0075] l, m, n, o, p, and q are each independently integers from 0 to 3.

[0076] In one embodiment, the compound may be a compound selected from compounds of the following formula 1A, optical isomers, diastereomers, solvates, hydrates and pharmaceutically acceptable salts thereof:

[0077] [Chemical Formula 1A]

[0078]

[0079] In the above chemical formula 1A, R1, R2, R3, R4, R5, L1, L2, , , the definitions of X, Y, l, and m are the same as in Chemical Formula 1, respectively.

[0080] In one embodiment, the compound may be a compound selected from compounds of the following formula 1B, optical isomers, diastereomers, solvates, hydrates and pharmaceutically acceptable salts thereof:

[0081] [Chemical Formula 1B]

[0082]

[0083] In the above chemical formula 1B, R1, R2, R3, R4, R5, R6, R7, L1, L2, , , X, Y, l, m, n, o, p, and q are each defined as in Chemical Formula 1.

[0084] In one embodiment of the formula 1, formula 1A, or formula 1B, L2 is C 1-6 When alkyl, L2 and The bond may be a double bond.

[0085] In one embodiment, the compound is

[0086] is C 6-10 Aryl, C 1-10 Heteroaryl, C 6-14 Fused heteroaryl, or C 1-10 It is a heterocyclyl,

[0087] Here C 1-10 Heteroaryl, C 6-14 Fused heteroaryl, or C 1-10 The heterocyclyl may be a compound containing 1 to 4 heteroatoms each independently selected from N, O, and S.

[0088] In one embodiment, the compound is

[0089] is a phenyl group, pyridinyl group, pyrazinyl group, pyrazolyl group, imidazolyl group, thiophenyl group, furanyl group, oxazole group, azetidinyl group, or It may be a compound.

[0090] In one embodiment, the compound is

[0091] L1 is a bond;

[0092] Each R2 and each R3 are independently hydrogen, halogen, cyano, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, C1-6 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 (-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 may be a heterocycloalkyl compound.

[0093] In one embodiment, the compound is

[0094] is C 3-6 Cycloalkenyl, C 3-6 Cycloalkyl, C 4-6 Heterocycloalkyl, or C 4-6 It may be a heterocycloalkenyl compound.

[0095] In one embodiment, the compound is

[0096] Is and;

[0097] R8 is hydrogen, halogen, cyano, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, or haloC 1-6 It is alkoxy;

[0098] r and s may each independently be a compound that is an integer from 0 to 3.

[0099] In a compound according to an embodiment of the invention, W is -S(O)2-NH(C 1-3 alkyl) or -NH(C=0)(C 2-6 It may be alkenyl.

[0100] In one embodiment, the compound may be a compound selected from the following compounds, their optical isomers, diastereomers, solvates, hydrates and pharmaceutically acceptable salts thereof:

[0101] 1) 3-(1-Cyclopropyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-indole-5-sulfonamide;

[0102] 2) 3-(1-Cyclopropyl-1H-imidazol-4-yl)-1-(4,4-dimethylcyclohex-1-en-1-yl)-N-methyl-1H-indole-5-sulfonamide;

[0103] 3) 3-(1-cyclopropyl-1H-imidazol-4-yl)-1-(4,4-difluorocyclohex-1-en-1-yl)-N-methyl-1H-indole-5-sulfonamide; and

[0104] 4)N-(3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-indol-5-yl)acrylamide.

[0105] Another embodiment of the present invention provides a pharmaceutical composition for treating or preventing a disease associated with transcriptional enhancer associate domain (TEAD) activation, comprising as an active ingredient a compound selected from the above compound, optical isomers, diastereomers, solvates, hydrates and pharmaceutically acceptable salts thereof.

[0106] In one embodiment, the composition may be a pharmaceutical composition exhibiting activity that inhibits Yes associated protein (YAP)-transcriptional enhancer associate domain (TEAD) binding.

[0107] In one embodiment, the composition may be a pharmaceutical composition for treating a cancer or tumor that can be treated by exhibiting inhibitory activity against YAP-TEAD binding.

[0108] For example, the composition may comprise a therapeutically effective amount of a compound selected from the compound, its optical isomers, diastereomers, solvates, hydrates and pharmaceutically acceptable salts thereof.

[0109] For example, a physician skilled in the relevant art can readily determine and prescribe an effective required dosage for a pharmaceutical composition. For example, the pharmaceutical composition may contain, but is not limited to, 0.0001 mg to 10 g of the compound.

[0110] For example, the pharmaceutical composition may further include pharmaceutically acceptable additives in addition to the active ingredient. The additives may include, but are not limited to, diluents, disintegrants, binders, lubricants, surfactants, suspending agents, or emulsifiers.

[0111] For example, the pharmaceutical composition can be formulated according to a conventional method and can be prepared in various oral administration forms such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, etc. or parenteral administration forms such as intramuscular, intravenous, or subcutaneous administration.

[0112] Another embodiment of the present invention provides a method of treatment for a subject suffering from a disease associated with a dysregulation of the Hippo signaling pathway, specifically, TEAD activation, by administering a compound selected from the compounds, optical isomers, diastereomers, solvates, hydrates and pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising the same as an active ingredient.

[0113] For example, the dosage, frequency, or method of administration of a compound or pharmaceutical composition may vary depending on the subject being treated, the severity of the disease or condition, the rate of administration, and the judgment of the prescribing physician. Furthermore, the physician may begin at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dose of the compound or pharmaceutical composition of the present invention administered to the subject until the intended effect is achieved.

[0114] Another embodiment of the present invention provides a compound selected from the above compound, its optical isomers, diastereomers, solvates, hydrates and pharmaceutically acceptable salts thereof, or a kit comprising the same as an active ingredient.

[0115] For example, the compounds, compositions, and kits may be administered alone or concurrently, separately, or sequentially with at least one other therapeutic agent.

[0116]

[0117] [Reaction formula]

[0118] Hereinafter, a method for producing the compound of the above chemical formula 1 will be described in detail using examples.

[0119] The compound of chemical formula 1 according to the present invention can be prepared according to the synthetic method shown in reaction scheme 1 or reaction scheme 2.

[0120] [Reaction Formula 1]

[0121]

[0122] In the above reaction formula 1, R1, R2, R3, R4, R5, L1, L2, , , X, Y, l, and m are defined as defined in the above chemical formula 1, but are not limited thereto and may be changed within a range understandable to those skilled in the art.

[0123]

[0124] [Step 1]

[0125] Under cooling conditions of 0-5℃, the 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 and reacted at 70℃. After confirming the completion of the reaction, the reaction solution is slowly added dropwise to water cooled to 0-5℃, and the formed solid is collected by filtration to obtain the target compound A.

[0126] [Step 2]

[0127] Triethylamine (1.5 equivalents) is added to the reaction solution prepared in [Step-1] above by dissolving A (1 equivalent, reference equivalent) in dichloromethane. The corresponding amine solution (1.5 equivalents) is added dropwise, and the reaction solution is stirred under reflux. After confirming the completion of the reaction, cool to room temperature, and collect the formed solid by filtration to obtain the target compound B.

[0128] [Step 3]

[0129] B (1 equivalent, standard equivalent) obtained in the above [Step-2] is dissolved in methanol, and then conc. HCl (4 equivalents) is added. The reaction solution is stirred at room temperature overnight, then heated to 80°C and stirred for an additional 2 hours. After confirming that the reaction is complete, the internal temperature is lowered to room temperature, water is added, and sodium hydroxide aqueous solution is slowly added dropwise to adjust the pH to 8. The formed solid is collected by filtration to obtain the target compound C.

[0130] [Step 4]

[0131] Dissolve C (1 equivalent, reference equivalent) obtained in the above [Step-3] in dichloromethane, add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 1 equivalent), and stir the reaction solution at room temperature overnight. After confirming the completion of the reaction, filter the reaction solution through CELITE and wash with dichloromethane. After concentrating under reduced pressure, the obtained residue is purified by MPLC to obtain the target compound D.

[0132] [Step 5]

[0133] Dissolve D (1 equivalent, reference equivalent) obtained in the above [Step-4] in dimethylformamide, slowly add N-bromosuccinimide (1 equivalent) dropwise, and stir the reaction solution at room temperature. After confirming the completion of the reaction, add water and extract with ethyl acetate. Dry the organic layer over anhydrous sodium sulfate, filter under reduced pressure, and concentrate the filtered organic layer under reduced pressure. Purify the obtained residue by MPLC to obtain the target compound E.

[0134] [Step 6]

[0135] E (1 equivalent, reference equivalent) obtained in the above [Step-5] is dissolved in tetrahydrofuran, and di-t-butyl dicarbonate (1.2 equivalents) and dimethylaminopyridine (0.1 equivalents) are added. The reaction solution is stirred at room temperature for 2 hours. After confirming that the reaction is complete, water is added and 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 obtained residue is purified by MPLC to obtain the target compound F.

[0136] [Step 7]

[0137] F (1 equivalent, reference equivalent) obtained in the above [Step-6] is subjected to Stille coupling reaction or Suzuki coupling reaction with the corresponding A-stanane derivative and A-borane derivative (2 equivalents). After completion of the reaction, the organic layer is washed with water, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtered organic layer is concentrated under reduced pressure. The obtained residue is purified by MPLC to obtain the target compound G.

[0138] [Step 8]

[0139] G (1 equivalent, reference equivalent) obtained in the above [Step-7] is dissolved in dimethylformamide, and the corresponding B derivative (1.2 equivalents), triethylamine (3 equivalents), and copper acetate (2 equivalents) are added, respectively, and the temperature is raised and stirred overnight. After completion of the reaction, the organic layer is washed with water, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtered organic layer is concentrated under reduced pressure. The obtained residue is purified by MPLC to obtain the target compound H.

[0140]

[0141] [Reaction Formula 2]

[0142]

[0143] In the above reaction formula 2, R1, R2, R3, R4, R5, R6, R7, L1, L2, , , X, Y, l, m, n, o, p, and q are defined as defined in the chemical formula 1 above, but are not limited thereto and may be changed within a range understandable to those skilled in the art.

[0144]

[0145] [Step 1]

[0146] Dissolve 5-nitroindole (1 equivalent, standard equivalent) in dimethylformamide, slowly add N-bromosuccinimide (1 equivalent) dropwise, and stir the reaction solution at room temperature. After confirming the completion of the reaction, add water and extract with ethyl acetate. Dry the organic layer over anhydrous sodium sulfate, filter under reduced pressure, and concentrate the filtered organic layer under reduced pressure. Purify the obtained residue by MPLC to obtain the target compound A.

[0147] [Step 2]

[0148] Dissolve A (1 equivalent, reference equivalent) obtained in the above [Step-1] in tetrahydrofuran and add di-t-butyl dicarbonate (1.2 equivalent) and dimethylaminopyridine (0.1 equivalent). Stir the reaction solution at room temperature for 2 hours. After confirming the completion of the reaction, add water and extract with ethyl acetate. Dry the organic layer over anhydrous sodium sulfate, filter under reduced pressure, concentrate the filtered organic layer under reduced pressure, and then purify the obtained residue by MPLC to obtain the target compound B.

[0149] [Step 3]

[0150] B (1 equivalent, reference equivalent) obtained in the above [Step-2] is dissolved in dimethylacetamide, and cuprous chloride (0.2 equivalent), cesium fluoride (3 equivalents), [1,1'-bis(diphenylphosphino)bisferrocenyl]palladium dichloride (0.2 equivalents), and A-stannane derivative (2 equivalents) are added, and the reaction solution is stirred while warming overnight. After confirming that the reaction is complete, water is added and 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 obtained residue is purified by MPLC to obtain the target compound C.

[0151] [Step 4]

[0152] C (1 equivalent, reference equivalent) obtained in the above [Step-3] is dissolved in pyridine, copper acetate (2 equivalents) and a dioxaborolane derivative (1.1 equivalents) are added, and the reaction solution is stirred and heated overnight. After confirming that the reaction is complete, water is added and 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 obtained residue is purified by MPLC to obtain the target compound D.

[0153] [Step 5]

[0154] The obtained D (1 equivalent, reference equivalent) obtained in the above [Step-4] is dissolved in methanol:water = 2:1 (v / v) and iron (2.5 equivalents) and ammonium chloride (2.5 equivalents) are added. The reaction solution is stirred at 80°C for 3 hours. After confirming the completion of the reaction, the reaction solution is filtered through CELITE, washed with dichloromethane, water is added, and extracted with dichloromethane. The organic layer is dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtered organic layer is concentrated under reduced pressure. The obtained residue is purified by MPLC to obtain the target compound E.

[0155] [Step 6]

[0156] E (1 equivalent, reference equivalent) obtained in the above [Step-5] is dissolved in tetrahydrofuran:water 3:1 (v / v), and then sodium bicarbonate (1.5 equivalents) is added. The reaction solution is cooled to 0-5°C, and then acryloyl chloride (1.05 equivalents) is slowly added dropwise and stirred. After the addition is complete, the mixture is stirred at 0-5°C for 1 hour. After confirming that the reaction is complete, 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 obtained residue is purified by MPLC to obtain the target compound F.

[0157]

[0158] The compound of chemical formula 1 according to one embodiment of the present invention can be prepared according to the method illustrated in Scheme 1 or Scheme 2, but is not limited thereto. A person having ordinary knowledge in the field of organic compounds can appropriately adjust the specific reaction route, reaction conditions, reaction amount, etc.

[0159] Hereinafter, the present invention will be described in more detail with the following examples and experimental examples. However, these examples and experimental examples are intended only to aid understanding of the present invention and are not intended to limit the scope of the present invention in any way.

[0160]

[0161] [Example]

[0162]

[0163] Example 1: 3-(1-Cyclopropyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-indole-5-sulfonamide

[0164]

[0165] [Step-1] Preparation of 1-acetylindoline-5-sulfonyl chloride

[0166]

[0167] 1-Indoline-1-ylethanolamine (30 g, 124.1 mmol) was slowly added to chlorosulfonic acid (62 mL, 930.5 mmol) in small portions over 15 minutes under conditions 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 (55% yield) of the title compound.

[0168] 1 H-NMR (300 MHz, DMSO-d6): δ7.96-7.93 (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).

[0169] [Step 2] Preparation of 1-acetyl-N-methylindoline-5-sulfonamide

[0170]

[0171] 1-Acetylindoline-5-sulfonyl chloride (20 g, 77 mmol) obtained in the above [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 solution was stirred under reflux. After confirming the completion of the reaction, it 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 (96% yield) of the title compound.

[0172] 1 H-NMR (300 MHz, DMSO-d6): δ8.16-8.14 (m, 1H), 7.60-7.57 (m, 2H), 7.28-7.23 (m, 1H), 4.16 (t,J=8.6 Hz, 2H), 3.21 (t,J=8.5 Hz, 2H), 2.39 (d,J=5.1 Hz, 3H), 2.19 (s, 3H).

[0173] [Step 3] Preparation of N-methyl-1H-indoline-5-sulfonamide

[0174]

[0175] 1-Acetyl-N-methylindoline-5-sulfonamide (6.2 g, 24.2 mmol) obtained in the above [Step-2] was dissolved in 72 mL of methanol, and conc. HCl (8.1 mL, 97.5 mmol) was added. The reaction solution was stirred at room temperature overnight and then at 80°C for 2 hours. After confirming the completion of the reaction, the internal temperature was lowered to room temperature, 100 mL of water was added, and 1 N sodium hydroxide aqueous solution was slowly added dropwise to adjust the pH to 7-8. The formed solid was collected by filtration, washed several times with water, and dried at 50°C to obtain 3.4 g (66% yield) of the title compound.

[0176] 1H-NMR (300 MHz, CDCl3): δ7.56-7.53 (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).

[0177] [Step 4] Preparation of N-methyl-1H-indole-5-sulfonamide

[0178]

[0179] N-Methyl-1H-indoline-5-sulfonamide (3.3 g, 15.5 mmol) prepared in the above [Step-3] was dissolved in 30 mL of dichloromethane, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 3.5 g, 15.5 mmol) was added, and the reaction solution was stirred at room temperature overnight. After completion of the reaction, the reaction solution was filtered through CELITE and washed with dichloromethane. After concentration under reduced pressure, the obtained residue was purified by MPLC (ethyl acetate:hexane = 1:3 (v / v)) to obtain 1.9 g (58% yield) of the title compound.

[0180] 1 H-NMR (300 MHz, CDCl3): δ8.52 (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).

[0181] [Step 5] Preparation of 3-bromo-N-methyl-1H-indole-5-sulfonamide

[0182]

[0183] N-Methyl-1H-indole-5-sulfonamide (9.6 g, 45.66 mmol) obtained in the above [Step-4] was dissolved in 190 mL of dimethylformamide, N-bromosuccinimide (8.29 g, 46.12 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 3 hours. After confirming the completion of the reaction, water was added and extraction was performed 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 obtained residue was purified by MPLC (ethyl acetate: hexane = 1:4 (v / v)) to obtain 11 g (83% yield) of the title compound.

[0184] 1 H-NMR (300 MHz, CDCl3): δ9.51 (brs, 1H), 8.14 (d,J= 0.9 Hz, 1H), 7.69 (dd,J= 8.6, 0.9 Hz, 1H), 7.48 (d,J= 8.6 Hz, 1H), 7.36 (d,J= 2.6 Hz, 1H), 4.60 (brs, 1H), 2.65 (d,J= 5.5 Hz, 3H).

[0185] [Step-6] Preparation of t-butoxy 3-bromo-5-(N-(t-butoxycarbonyl)-N-methylsulfonyl)-1H-indole-1-carboxylate

[0186]

[0187] 3-Bromo-N-methyl-1H-indole-5-sulfonamide (3.0 g, 10.4 mmol) obtained in the above [Step-5] was dissolved in 30 mL of tetrahydrofuran, and di-t-butyl dicarbonate (4.9 g, 22.8 mmol) and 4-dimethylaminopyridine (0.13 mg, 1.0 mmol) were added. The reaction solution was stirred at room temperature for 3 hours, and after the reaction was completed, 100 mL of water was added and 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 obtained residue was purified by MPLC (ethyl acetate: hexane = 1:3 (v / v)) to obtain 1.7 g (92% yield) of the title compound.

[0188] 1 H-NMR (300 MHz, CDCl3): δ8.32 (d,J= 8.9 Hz, 1H), 8.17 (s, 1H), 7.89 (d,J= 7.9 Hz, 1H), 7.79 (s, 1H), 3.41 (s, 3H), 1.70 (s, 9H), 1.38 (s, 9H).

[0189] [Step-7] Preparation of 3-(1-cyclopropyl-1H-imidazol-4-yl)-N-methyl-1H-indole-5-sulfonamide

[0190]

[0191] t-Butoxy 3-bromo-5-(N-(t-butoxycarbonyl)-N-methylsulfonyl)-1H-indole-1-carboxylate (3.0 g, 6.13 mmol) obtained in the above [Step-6] was dissolved in 30 mL of dimethylacetamide, and cuprous chloride (121 mg, 1.23 mmol), cesium fluoride (2.79 g, 18.39 mmol), [1,1'-bis(diphenylphosphino)bisferrocenyl]palladium dichloride (897 mg, 1.23 mmol), tributyl-(1-cyclopropylimidazol-4-yl)stannane (4.87 g, 12.26 mmol), potassium carbonate (2.11 g, 15.33 mmol) were added, and the reaction solution was stirred at 110°C for 2 hours. After the reaction was completed, 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 = 30:1 (v / v)) to obtain 850 mg (43% yield) of the title compound.

[0192] 1 H-NMR (300 MHz, CDCl3): δ9.26 (brs, 1H), 8.46 (d,J= 1.7 Hz, 1H), 7.74 (d,J= 2.4 Hz, 1H), 7.68-7.63 (m, 2H), 7.47-7.44 (m, 1H), 7.35 (s, 1H), 4.62-4.57 (m, 1H), 3.43-3.40 (m, 1H), 2.64 (d,J= 5.5 Hz, 3H), 1.07-1.05 (m, 4H).

[0193] [Step-8] 3-(1-Cyclopropyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-indole-5-sulfonamide

[0194]

[0195] 3-(1-Cyclopropyl-1H-imidazol-4-yl)-N-methyl-1H-indole-5-sulfonamide (100 mg, 0.32 mmol) obtained in the above [Step-7] was dissolved in 2 mL of dimethylformamide, and 4,4,5,5-tetramethyl-2-[4-(trifluoromethyl)cyclohexen-1-yl]-1,3,2-dioxaborolane) (131 mg, 0.47 mmol), triethylamine (0.13 mL, 0.95 mmol), and copper acetate (115 mg, 0.63 mmol) were added, respectively. The reaction solution was stirred at 100°C overnight, and after the reaction was completed, the reaction solution was cooled to room temperature, 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, filtered under reduced pressure, and the filtered organic layer was concentrated under reduced pressure. The obtained residue was purified by MPLC (ethyl acetate:hexane = 2:1 (v / v)) to obtain 3 mg (2% yield) of the title compound.

[0196] 1 H-NMR (300 MHz, CDCl3): δ8.41 (d,J= 1.5 Hz, 1H), 7.70-7.66 (m, 2H), 7.59 (d,J= 0.8 Hz, 1H), 7.53 (d,J= 8.7 Hz, 1H), 7.33 (d,J= 1.1 Hz, 1H), 5.97-5.95 (m, 1H), 4.73-4.68 (m, 1H), 3.42-3.35 (m, 1H), 2.63 (d,J= 5.3 Hz, 3H), 2.60-2.40 (m, 2H), 2.26-2.20 (m, 1H), 1.96-1.81 (m, 2H), 1.96-1.81 (m, 2H), 1.04-1.02 (m, 4H).

[0197] MS (ESI + , m / z): 465.1 [M+H] +

[0198]

[0199] Example 2: 3-(1-Cyclopropyl-1H-imidazol-4-yl)-1-(4,4-dimethylcyclohex-1-en-1-yl)-N-methyl-1H-indole-5-sulfonamide

[0200]

[0201] The procedure of Example 1 was repeated except that 2-(4,4-dimethylcyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (152 mg, 0.65 mmol) was used instead of 4,4,5,5-tetramethyl-2-[4-(trifluoromethyl)cyclohexen-1-yl]-1,3,2-dioxaborolane in [Step-8] of the above Example 1, to obtain 11 mg (5% yield) of the title compound.

[0202] 1 H-NMR (300 MHz, CDCl3): δ8.40 (d,J= 1.3 Hz, 1H), 7.70-7.64 (m, 2H), 7.60 (s, 1H), 7.55 (d,J= 8.8 Hz, 1H), 7.33 (d,J= 1.2 Hz, 1H), 5.91-5.90 (m, 1H), 4.24-4.22 (m, 1H), 3.43-3.39 (m, 1H), 2.66 (d,J= 5.5 Hz, 3H), 2.50-2.40 (m, 2H), 2.11-2.09 (m, 2H), 1.63-1.62 (m, 2H), 1.07-1.05 (m, 10H).

[0203] MS (ESI + , m / z): 425.1 [M+H] +

[0204]

[0205] Example 3: 3-(1-Cyclopropyl-1H-imidazol-4-yl)-1-(4,4-difluorocyclohex-1-en-1-yl)-N-methyl-1H-indole-5-sulfonamide

[0206]

[0207] The procedure of Example 1 was repeated except that 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (622 mg, 1.96 mmol) was used instead of 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1,3,2-dioxaborolane in [Step-8] of the above Example 1, to obtain 11 mg (2% yield) of the title compound.

[0208] 1 H-NMR (300 MHz, CDCl3): δ8.46 (s, 1H), 7.74-7.71 (m, 2H), 7.63 (d,J=1.3 Hz, 1H), 7.57 (d,J=8.8 Hz, 1H), 7.37 (s, 1H), 5.89-5.88 (m, 1H), 4.46-4.41 (m, 1H), 2.97-2.78 (m, 4H), 2.67 (d,J=5.7 Hz, 3H), 2.41-2.27 (m, 2H), 1.27-1.09 (m, 4H).

[0209] MS (ESI + , m / z): 433.1 [M+H] +

[0210]

[0211] Example 4: N-(3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-indol-5-yl)acrylamide

[0212]

[0213] [Step 1] Preparation of 3-bromo-5-nitro-1H-indole

[0214]

[0215] 5-Nitro-1H-indole (5.0 g, 30.83 mmol) was dissolved in 50 mL of dimethylformamide under conditions cooled to 0-5°C, and N-bromosuccinimide (6.2 g, 33.91 mmol) was slowly added. The reaction solution was stirred at 0-5°C for 1 hour. After the reaction was completed, 200 mL of cold water was added, and the formed solid was collected by filtration, washed several times with hexane, and dried at room temperature to obtain 6.8 g (91% yield) of the title compound.

[0216] 1 H-NMR (300 MHz, DMSO-d6): δ12.20 (s, 1H), 8.31 (d,J=2.2 Hz, 1H), 8.09-8.05 (m, 1H), 7.87 (d,J=2.6 Hz, 1H), 7.65 (d,J=9.0 Hz, 1H).

[0217] [Step 2] Preparation of t-butyl 3-bromo-5-nitro-1H-indole-1-carboxylate

[0218]

[0219] 3-Bromo-5-nitro-1H-indole (3.4 g, 14.11 mmol) obtained in the above [Step-1] was dissolved in 34 mL of tetrahydrofuran, and then di-t-butyl-dicarbonate (6.5 mL, 28.21 mmol) and 4-dimethylaminopyridine (172 mg, 1.41 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, 200 mL of cold water was added and stirred at room temperature for 30 minutes. The formed solid was collected by filtration, washed several times with hexane, and dried at room temperature to obtain 4.8 g (99% yield) of the title compound.

[0220] 1 H-NMR (300 MHz, CDCl3): δ8.46-8.45 (m, 1H), 8.28-8.26 (m, 2H), 7.78 (s, 1H), 1.69 (s, 9H).

[0221] [Step-3] Preparation of 3-(1-methyl-1H-imidazol-4-yl)-5-nitro-1H-indole

[0222]

[0223] t-Butyl 3-bromo-5-nitro-1H-indole-1-carboxylate (4.8 g, 14.07 mmol) obtained in the above [Step-2] was dissolved in 96 mL of dimethylacetamide, and cuprous chloride (287 mg, 2.81 mmol), cesium fluoride (6.6 g, 42.21 mmol), [1,1'-bis(diphenylphosphino)bisferrocenyl]palladium dichloride (2.16 g, 2.81 mmol), and tributyl-(1-methylimidazol-4-yl)stannane (10.4 g, 28.14 mmol) were added, and the reaction solution was stirred at 110°C overnight. After the reaction was completed, 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 = 30:1 (v / v)) to obtain 350 mg (10% yield) of the title compound.

[0224] 1 H-NMR (300 MHz, DMSO-d6): δ11.8 (s, 1H), 9.07 (d,J= 2.1 Hz, 1H), 8.02-7.98 (m, 1H), 7.81 (s, 1H), 7.67 (d,J= 0.8 Hz, 1H), 7.56-7.51 (m, 2H), 3.72 (s, 3H).

[0225] [Step-4] Preparation of 3-(1-methyl-1H-imidazol-4-yl)-5-nitro-1-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-indole

[0226]

[0227] 3-(1-Methyl-1H-imidazol-4-yl)-5-nitro-1H-indole (500 mg, 2.06 mmol) obtained in the above [Step-3] was dissolved in 5 mL of pyridine, then copper acetate (750 mg, 4.12 mmol) and 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1,3,2-dioxaborolane (627 mg, 2.27 mmol) were added, and the reaction solution was stirred at 100°C overnight. After the reaction was completed, it was cooled to room temperature, and 100 mL of water and 50 mL of 10% hydrochloric acid aqueous solution were added, followed by extraction 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 obtained residue was purified by MPLC (ethyl acetate:dichloromethane = 1:1 (v / v)) to obtain 60 mg (7% yield) of the title compound.

[0228] 1 H-NMR (300 MHz, CDCl3): δ8.82 (s, 1H), 8.14 (d,J= 8.9 Hz, 1H), 7.73-7.60 (m, 2H), 7.49 (d,J= 9.1 Hz, 1H), 7.36-7.35 (m, 1H), 6.02 (s, 1H), 3.80 (s, 3H), 2.63-2.51 (m, 5H), 2.28-2.24 (m, 1H), 1.89-1.83 (m, 1H).

[0229] [Step-5] Preparation of 3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-indol-5-amine

[0230]

[0231] 3-(1-Methyl-1H-imidazol-4-yl)-5-nitro-1-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-indole (60 mg, 0.15 mmol) obtained in the above [Step-4] was dissolved in 3 mL of methanol:water = 2:1 (v / v), and iron (21 mg, 0.38 mmol) and ammonium chloride (21 mg, 0.38 mmol) were added. The reaction solution was stirred at 80°C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through CELITE, and washed with dichloromethane. After concentration under reduced pressure, the obtained residue was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtered organic layer was concentrated under reduced pressure to obtain 25 mg (45% yield) of the title compound.

[0232] 1 H-NMR (300 MHz, CDCl3): δ7.53 (s, 1H), 7.48 (s, 1H), 7.32-7.29 (m, 1H), 7.18 (d, J= 2.0 Hz, 1H), 7.11 (s, 1H), 6.70-6.66 (m, 1H), 5.90 (s, 1H), 3.75 (s, 3H), 2.62-2.42 (m, 5H), 2.22-2.19 (m, 1H), 1.89-1.83 (m, 1H).

[0233] [Step-6] Preparation of N-(3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-indol-5-yl)acrylamide

[0234]

[0235] 3-(1-Methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-indol-5-amine (25 mg, 0.07 mmol) obtained in the above [Step-5] was dissolved in 2 mL of tetrahydrofuran:water = 3:1 (v / v), and then sodium bicarbonate (8.9 mg, 0.10 mmol) was added. After the reaction solution was cooled to 0-5°C, acryloyl chloride (5.9 μL, 0.07 mmol) was slowly added dropwise and stirred for 30 minutes. After the reaction was completed, 5 mL of 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 (ethyl acetate:dichloromethane:methanol = 7:7:1 (v / v)) to obtain 6 mg (20% yield) of the title compound.

[0236] 1 H-NMR (300 MHz, CDCl3): δ8.33 (s, 1H), 7.61 (d, J= 3.0 Hz, 1H), 7.47-7.41 (m, 4H), 7.34 (s, 1H), 6.48-6.42 (m, 1H), 6.32-6.23 (m, 1H), 5.95 (s, 1H), 5.79 (d,J= 10.0 Hz, 1H), 3.75 (s, 3H), 2.63-2.32 (m, 6H), 1.89-1.81 (m, 1H).

[0237] MS (ESI + , m / z): 415.1 [M+H] +

[0238]

[0239] [Experimental Example]

[0240]

[0241] Experimental Example 1: TEAD Reporter Activity Inhibition Test

[0242] The target gene transcription inhibition ability of TEAD was measured for the above synthetic compounds. This evaluation method is a method of measuring the transcriptional activity of TEAD by measuring the luciferase luminescence expressed when TEAD binds to the target gene and activates transcription using MCF7 cell line (BPS Bioscience, Inc., USA) in which a firefly luciferase reporter gene was introduced into the specific binding structure of TEAD, GTIIC (5'-ACATTCCA-3'). The cell line was 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, and Geneticin was excluded during the TEAD reporter activity inhibition test. 4 x 10 4 The cells were dispensed into a white 96-well plate at 100 μl / well and incubated for 6 hours. 50 μl of the test compound diluted to 3X concentration was mixed into each well. After 24 hours of incubation, the luciferase signal was measured by luminescence using the ONE-Glo luciferase assay system (Promega, E6120) according to the manufacturer's protocol. The 50% inhibition value (IC) for TEAD transcriptional activity 50 ) was calculated using GraphPad Prism 9.

[0243] IC 50 If the value is less than 100 nM, it is indicated as A, if it is 100 nM or more but less than 500 nM, it is indicated as B, and if it is 500 nM or more, it is indicated as C.

[0244] Synthetic compound IC 50, nM1A2A3A4A

[0245]

[0246] Experimental Example 2: Cell Growth Inhibition Test

[0247] The above synthetic compound was confirmed to inhibit cell growth in NCI-H226 cells. NCI-H226 is a mesothelioma cancer cell line with NF2 gene deficiency, and was cultured in a medium containing RPMI 1640 supplemented with 10% FBS and 1% Penicillin / Streptomycin. The cultured cells were cultured at a density of 0.7 x 10 3 100 μl / well was dispensed into a 96-well plate and cultured for 24 hours. Then, 100 μl of the test compound diluted to 2X concentration was mixed into each well and cultured for 6 days. The SRB test method was used to measure cell growth inhibition, and the 50% inhibition value (GI) for cell growth by the compound 50 ) was calculated using GraphPad Prism 9.

[0248] GI 50 If the value is less than 100 nM, it is indicated as A, and if it is 100 nM or more, it is indicated as B.

[0249] Synthetic compound GI 50, nM1A2A3B4A

[0250]

[0251] The present invention has been described above, focusing on specific examples thereof. Those skilled in the art will appreciate that the present invention can be implemented in modified forms without departing from its essential characteristics. Therefore, the disclosed specific examples should be considered illustrative rather than limiting. The scope of the present invention is set forth in the claims, not the foregoing description, and all differences within the scope equivalent thereto should be construed as being encompassed by the present invention.

[0252] The novel heterobicyclic compound having the structure of chemical formula 1 in the present invention has excellent inhibitory activity against YAP-TEAD binding, and thus is effective against various 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.

Claims

1. A compound selected from the compounds of the following chemical formula 1, optical isomers, diastereomers, solvates, hydrates and pharmaceutically acceptable salts thereof: [Chemical Formula 1] In the above chemical formula 1, R1 is hydrogen, halogen, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 alkoxy, or cyano; R2 and R3 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(C 1-3 Alkyl)2), C 1-3 Alkylsulfinyl (-(SO)-(C 1-3 Alkyl)), C 1-3 Alkylsulfonyl (-SO2-(C 1-3 alkyl)), substituted or unsubstituted C 3-10 Carbocyclyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted C 1-10 Heterocyclyl, or substituted or unsubstituted C 4-10 is heteroaryl; L1 and L2 is nonexistent, combined, C 1-6 Alkylene, C 2-6 C substituted with alkenylene or halogen 1-6 is alkylene; L2 and The bond is a single or double bond; W is -S(O)2-NR4R 5, -S(O)-NR4R 5, -C(O)-NR4R 5, , , ,or and; R4, R 5, R6, and R7 are independently hydrogen, halogen, cyano, C 1-6 Alkyl, substituted or unsubstituted C 3-10 Carbocyclyl, substituted or unsubstituted C 6-10 Aryl or substituted or unsubstituted C 4-10 is heteroaryl; is substituted or unsubstituted C 3-14 Carbocyclyl or substituted or unsubstituted or C 1-10 is heterocyclyl; is substituted or unsubstituted, saturated or partially saturated, C 3-10 It is carbocyclyl; X and Y are each independently -C- or -N-; l, m, n, o, p, and q are each independently an integer from 0 to 3.

2. In claim 1, a compound selected from the compounds of the following chemical formula 1A, optical isomers, diastereomers, solvates, hydrates and pharmaceutically acceptable salts thereof: [Chemical Formula 1A] In the above chemical formula 1A, R1, R2, R3, R4, R5, L1, L2, , , X, Y, l, and m are defined as in Chemical Formula 1, respectively.

3. In claim 1, a compound selected from the compounds of the following chemical formula 1B, optical isomers, diastereomers, solvates, hydrates and pharmaceutically acceptable salts thereof: [Chemical Formula 1B] In the above chemical formula 1B, R1, R2, R3, R4, R5, R6, R7, L1, L2, , , X, Y, l, m, n, o, p, and q are defined as in Chemical Formula 1, respectively.

4. In claim 1, is C 6-10 Aryl, C 1-10 Heteroaryl, C 6-14 Fused heteroaryl, or C 1-10 It is a heterocyclyl, C here 1-10 Heteroaryl, C 6-14 Fused heteroaryl, or C 1-10 Heterocyclyl is a compound containing 1 to 4 heteroatoms each independently selected from N, O, and S.

5. In claim 1, 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 A compound of phosphorus.

6. In claim 1, L1 is a bond; Each R2 and each R3 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 Alkylsulfonyl (-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 A heterocycloalkyl compound.

7. In claim 1, is C 3-6 Cycloalkenyl, C 3-6 Cycloalkyl, C 4-6 Heterocycloalkyl, or C 4-6 A compound which is a heterocycloalkenyl.

8. In claim 7, Is and; R8 is hydrogen, halogen, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, or haloC 1-6 It is alkoxy; A compound wherein r and s are each independently an integer from 0 to 3.

9. In claim 1, the compound is a compound selected from the following compounds, optical isomers, diastereomers, solvates, hydrates and pharmaceutically acceptable salts thereof: 1) 3-(1-Cyclopropyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-indole-5-sulfonamide; 2) 3-(1-Cyclopropyl-1H-imidazol-4-yl)-1-(4,4-dimethylcyclohex-1-en-1-yl)-N-methyl-1H-indole-5-sulfonamide; 3) 3-(1-Cyclopropyl-1H-imidazol-4-yl)-1-(4,4-difluorocyclohex-1-en-1-yl)-N-methyl-1H-indole-5-sulfonamide; and 4)N-(3-(1-Methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1H-indol-5-yl)acrylamide.

10. A pharmaceutical composition for treating or preventing a related disease caused by transcriptional enhancer associate domain (TEAD) activation, comprising as an active ingredient a compound selected from the group consisting of a compound according to any one of claims 1 to 9, an optical isomer, a diastereomer, a solvate, a hydrate, and a pharmaceutically acceptable salt thereof.

11. In claim 10, the composition is a pharmaceutical composition exhibiting activity of inhibiting Yes associated protein (YAP)-transcriptional enhancer associate domain (TEAD) binding.

12. A pharmaceutical composition for treating cancer or tumor, wherein the composition according to claim 11 exhibits inhibitory activity against YAP-TEAD binding.

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