Novel hetero-bicyclic compound for inhibiting YAP-TEAD interaction and pharmaceutical composition comprising same

Abstract

Provided are a compound selected from the group consisting of compounds of Formula 1, mirror isomers, non-mirror isomers, solvates and hydrates thereof, and pharmaceutically acceptable salts thereof, a method for producing the same, and uses thereof.

Description

Technical Field

[0001] The present disclosure relates to a pharmaceutical composition comprising a heterobicyclic compound that inhibits Yes-associated protein (YAP)-transcription enhancer associated region (TEAD) binding. The compounds of the present disclosure can directly inhibit YAP-TEAD binding in the Hippo pathway, which plays a key role in cancer development. Background Art

[0002] Hippo signaling is an important pathway for cancer biogenesis and tumor maintenance. YAP and 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 YAP / TAZ interact with transcription enhancer-associated region (TEAD) transcription factors, coactivate the expression of target genes and promote cell proliferation. TEAD regulates target genes closely related to tumor formation, such as connective tissue growth factor (CTGF) and Cyr61, AXL receptor tyrosine kinase and MYC. In addition, TEAD was found to be overexpressed in breast cancer stem cells and breast cancer, ovarian cancer, germ cell tumors, renal cell carcinoma, medulloblastoma and gastric cancer. Overactivation of YAP and TAZ and / or mutations in one or more members of the Hippo pathway network are associated with a variety of cancers. In addition, recent studies have reported that resistance to EGFR tyrosine kinase inhibitors, such as Tarceva (erlotinib), Iressa (gefitinib), or Tagrisso (osimertinib), as well as epithelial-mesenchymal transition (EMT) phenotypic changes are associated with YAP overexpression or YAP amplification.

[0003] The present inventors have developed a novel heterobicyclic compound for inhibiting YAP-TEAD interaction, thereby completing the present disclosure.

[0004] [Prior art documents]

[0005] [Patent document]

[0006] (Patent Document 1) International Publication No. WO2019040380

[0007] (Patent Document 2) International Publication No. WO2020243415

[0008] [Non-patent document]

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

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

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

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

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

[0014] (Non-patent document 6) Cells 2021, 10, 2715

[0015] (Non-patent document 7) Genes Cancer 2017, 8(3-4), 497 Summary of the invention

[0016] [Technical issues]

[0017] The object of the present disclosure 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 cancer development.

[0018] Another object of the present disclosure is to provide a pharmaceutical composition for treating or preventing diseases related to abnormal regulation of the Hippo signaling pathway, in particular, diseases related to TEAD activation, wherein the pharmaceutical composition comprises the compound as an active ingredient.

[0019] Other objectives and advantages of the present application will become apparent from the following detailed description and the appended claims. The contents not described in this specification are omitted because they can be fully recognized and inferred by technical personnel in this application or similar technical fields.

[0020] [Technical solution]

[0021] According to one embodiment of the present disclosure, a compound selected from the group consisting of the compound of Formula 1, its mirror image isomers, diastereomers, solvates and hydrates, and pharmaceutically acceptable salts thereof is provided.

[0022] Formula 1

[0023]

[0024] According to one embodiment of the present disclosure, a pharmaceutical composition is provided for treating or preventing diseases caused by abnormal regulation of the Hippo signaling pathway, specifically caused by TEAD activation, the pharmaceutical composition comprising a compound selected from the group consisting of a compound of Formula 1, its mirror image isomers, diastereomers, solvates and hydrates, and pharmaceutically acceptable salts thereof as an active ingredient.

[0025] [Beneficial effects]

[0026] The novel heterobicyclic compound having the structure of Formula 1 according to the present disclosure may have effects on diseases associated with the Hippo pathway, which plays a key role in the cancer development process, due to excellent inhibitory activity against YAP-TEAD binding, and thus may be effectively used as a therapeutic agent. DETAILED DESCRIPTION

[0027] Detailed description of preferred embodiments

[0028] Hereinafter, the present disclosure will be described in detail.

[0029] Unless otherwise defined, all technical terms used herein have the same meaning as those generally understood by those skilled in the art to which the present disclosure belongs. Although preferred methods or samples are described in the specification, their similar or equivalent ones may also be considered within the scope of the present disclosure.

[0030] According to one embodiment of the present disclosure, a compound selected from the group consisting of the compound of Formula 1, its mirror image isomers, diastereomers, solvates and hydrates, and pharmaceutically acceptable salts thereof is provided.

[0031] Formula 1

[0032]

[0033] In formula 1,

[0034] R 1 Can be hydrogen, halogen, C 1-6 Alkyl, halogen C 1-6 Alkyl, C 1-6 Alkoxy or cyano;

[0035] R 2 can be independently hydrogen, halogen, C 1-6 Alkyl, halogen C 1-6 alkyl, or substituted or unsubstituted -(CH 2 ) a -N(Q 1 )(Q 2 ),

[0036] Where Q 1 and Q2 can be independently hydrogen or C 1-4 alkyl;

[0037] It can be a carbocyclic group or a heterocyclic group;

[0038] Can be C 6-10 Aryl or C 4-10 heteroaryl;

[0039] L 1 Can be non-existent, a single bond, C 1-3 Alkyl or halogen C 1-3 alkyl;

[0040] R 3 and R 4 can be independently hydrogen, halogen, cyano, amine, C 1-6 Alkyl, halogen C 1-6 Alkyl, C 1-6 Alkoxy, halogen C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, substituted or unsubstituted C 3-6 Carbocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted C 2-6 Heterocyclic group, or substituted or unsubstituted C 4-10 heteroaryl;

[0041] R 5 Can be hydrogen, C 1-6 Alkyl or halogen C 1-6 alkyl;

[0042] R 6 can be independently hydrogen, halogen, C 1-6 Alkyl or halogen C 1-6 alkyl;

[0043] X and Y may each independently be -C- or -N-; and

[0044] a, m, n, q, r and p may each independently be an integer from 0 to 3.

[0045] As used herein, the term "halogen" may be F, Cl, Br or I.

[0046] Unless otherwise specified, as used herein, the term "alkyl" refers to a straight or branched hydrocarbon residue which may be substituted or unsubstituted. The alkyl group may be, for example, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl or tertiary butyl, but is not limited thereto.

[0047] Unless otherwise specified, as used herein, the term "alkenyl" refers to an alkyl group that may be substituted or unsubstituted and includes at least one double bond. The alkenyl group may be, for example, prop-1-ene, but-1-ene, but-2-ene, 3-methylbut-1-ene or pent-1-ene, but is not limited thereto.

[0048] Unless otherwise specified, as used herein, the term "cycloalkyl" refers to a saturated monocyclic and polycyclic hydrocarbon ring generally including the specified number of carbon atoms, which may be substituted or unsubstituted. The cycloalkyl group may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but is not limited thereto.

[0049] Unless otherwise specified, as used herein, the term "heterocycloalkyl" refers to a monocyclic alkyl group including at least one heteroatom selected from N, O and S, which may be substituted or unsubstituted. base, Phyllinyl, pyrrolidinyl, thio In some embodiments, the present invention comprises quinoline, imidazolidinyl, tetrahydrofuranyl or the like, but is not limited thereto.

[0050] Unless otherwise indicated, as used herein, the term "haloalkyl" is meant to include monohaloalkyl and polyhaloalkyl groups which may be substituted or unsubstituted. The terms "halogen" and "alkyl" are as described above.

[0051] Unless otherwise specified, as used herein, the term "alkoxy" refers to a straight or branched hydrocarbon residue connected via oxygen, which may be substituted or unsubstituted. Alkoxy may be, for example, methoxy, ethoxy, propoxy and butoxy, or isopropoxy, isobutoxy or tert-butoxy, but is not limited thereto.

[0052] As used herein, the term "alkoxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are substituted by one or more alkoxy groups. The alkoxyalkyl group may be, for example, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, ethoxypropyl and isopropoxymethyl, but is not limited thereto.

[0053] Unless otherwise indicated, as used herein, the term "aryl" refers to an aromatic group which may be substituted or unsubstituted and may include, for example, C 3 -C 10 Aryl, C 3 -C 8 Aryl, or C 3 -C 6 Aryl groups, in which double bonds are alternately (resonantly) located between adjacent carbon atoms or suitable heteroatoms. For example, aryl groups may be phenyl, biphenyl, naphthyl, toluoyl or naphthalenyl, but are not limited thereto.

[0054] Unless otherwise indicated, as used herein, the term "heteroaryl" refers to a substituted or unsubstituted monocyclic, bicyclic or polycyclic aromatic group, which includes at least one heteroatom selected from N, O and S. For example, a monocyclic heteroaryl group can be pyridyl, imidazolyl, thiazolyl, oxazolyl, thienyl, furanyl, pyrrolyl, isocyanate Azolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, Oxazolyl, phthalide pyrimidinyl or pyridinyl For example, the bicyclic heteroaryl group can be indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzo Azolyl, benzyl oxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolyl, isoquinolyl, furanyl or furopyridinyl, but are not limited thereto.

[0055] Unless otherwise indicated, as used herein, the term "carbocyclyl" refers to a substituent including carbon ring atoms, which has a saturated carbocyclyl (e.g., "cycloalkyl"), a partially saturated carbocyclyl (e.g., "cycloalkenyl"), or a completely unsaturated carbocyclyl (e.g., "aryl") structure. The carbocyclyl may have a monocyclic or polycyclic structure. As used herein, the carbocyclyl includes, for example, 3 to 14 carbon ring atoms, or, for example, 3 to 8 carbon ring atoms, and may be saturated, unsaturated, or aromatic. In this regard, ring atoms are atoms joined together to form one or more rings of the carbocyclyl substituent. For example, a saturated carbocyclyl may be cyclopropyl, cyclopentyl, or cyclohexyl, but is not limited thereto. For example, an unsaturated carbocyclyl may include 3 or fewer double bonds. For example, an aromatic carbocyclyl may be phenyl. Additionally, the term "carbocyclyl" may include fused carbocyclyl combinations such as naphthyl, phenanthrenyl, indanyl, and indenyl, but is not limited thereto.

[0056] Unless otherwise indicated, as used herein, the term "heterocyclyl" refers to a substituent including a carbocyclic ring having at least one heteroatom, which has a saturated heterocyclyl (e.g., "heterocyclylalkyl"), a partially saturated heterocyclyl (e.g., "heterocyclyl alkenyl"), or a fully unsaturated heterocyclyl (e.g., "heteroaryl") structure. The heterocyclyl may have a monocyclic or polycyclic structure. As used herein, the heterocyclyl includes, for example, 3 to 14 ring atoms in total, or, for example, 3 to 8 ring atoms in total, and may be saturated, unsaturated, or aromatic. In this regard, the ring atoms are atoms joined together to form one or more 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 carbon, nitrogen, oxygen, and sulfur. For example, the ring atoms of the heterocyclyl may include 4 or fewer heteroatoms, such as N, O, and S, for example, 3 to 14 ring atoms in total, or, for example, 5 to 7 ring atoms in total, and may be saturated, unsaturated, or aromatic. For example, the heterocyclic group can be furanyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isobutyl Azolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, diazolyl, Alkyl, N Phyl, dithianyl, N-thiomorpholinyl, pyrimidine, pyrimidine Piperidin Base, sulfolane base, tri Base, nitrogen bang base, In addition, the term "heterocyclic group" may include fused heterocyclic groups, such as benzimidazolinyl, benzoimidazole, benzophenone ... Azolyl, imidazopyridinyl, benzo Benzothia base, Azolopyridinyl, quinolinyl, quinazolinyl, quinoline The heterocyclic group may be a carbon-linked group or a heteroatom-linked group. For example, in the heteroatom-linked group, the N-linked heterocyclic group includes But it is not limited to this.

[0057] Unless otherwise indicated, as used herein, the term "fused heteroaryl" refers to a substituted or unsubstituted ring system in which a heteroaryl group is fused to another aryl group, heteroaryl group, or heterocycloalkyl group. For example, the fused heteroaryl group can form a 5+5-membered, 5+6-membered, 5+7-membered, 6+6-membered, or 6+7-membered fused ring system. In addition, the fused heteroaryl group can be, for example, But it is not limited to this.

[0059] The substituents used herein may be selected from, for example, cyano, amine, hydroxyl, C 1-6 Alkyl, halogen C 1-6 Alkyl, C 1-6 Alkoxy and halogen C 1-6 The substituents of the alkoxy group are, but not limited to,

[0060] For example, the substituted C 3-6 Cycloalkyl, C 6-10 Aryl or C 2-6 The heterocycloalkyl group may be an alkyl group in which one or more hydrogen atoms are substituted by a substituent selected from the group consisting of halogen, cyano, amine, hydroxyl, C 1-6 Alkyl, halogen C 1-6 Alkyl, C 1-6 Alkoxy and halogen C 1-6 Alkoxy, but not limited thereto.

[0061] As used herein, the term "stereoisomer" may refer to a compound of the present disclosure or a salt thereof, which has the same chemical formula or molecular formula but is optically or sterically different, and may include mirror image isomers or diastereomers.

[0062] As used herein, the term "enantiomers" refers to a pair of stereoisomers of a compound that are non-superimposable mirror images of one another.

[0063] As used herein, the term "diastereoisomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another.

[0064] The compounds of the present disclosure may include asymmetric or chiral centers and may therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present invention (such as diastereomers, enantiomers and racemic mixtures) form part of the present disclosure. An equimolar mixture (50:50) of two enantiomers is called a racemic mixture or a racemate.

[0065] As used herein, the term "solvate" refers to a compound of the present disclosure or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Suitable solvents may be volatile, non-toxic, and / or suitable for administration to humans. "Solvates" may include compounds and molecular complexes that include one or more pharmaceutically acceptable solvent molecules, such as ethanol.

[0066] As used herein, the term "hydrate" refers to a complex in which solvent molecules are complexed.

[0067] As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt and can be prepared by any suitable method available to those skilled in the art. For example, if the compound of the disclosure is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available to those skilled in the art, such as by treating the free base with an inorganic acid, an organic acid or the like.

[0068] In one embodiment, C 3-6 Cycloalkyl, C 6-10 Aryl, C 2-6 Heterocycloalkyl, C 1-10 Heteroaryl, or C 6-14 Fused heteroaryl,

[0069] Among them, C 2-6 Heterocycloalkyl, C 1-10 Heteroaryl or C 6-14 The fused heteroaryl groups may each independently include 1 to 4 heteroatoms selected from N, O and S.

[0070] In one embodiment, It can be phenyl, pyridyl, yl, pyrazolyl, imidazolyl, thienyl, furanyl, or Azolyl.

[0071] In one embodiment, C 6-10 Aryl.

[0072] In one embodiment, It can be phenyl or pyridyl.

[0073] In one embodiment, R 1 It may be hydrogen, halogen or cyano.

[0074] In one embodiment, R 2 can each independently be hydrogen, halogen or -CH 2 -NH 2 、-CH 2 -NHCH3 、-CH 2 -N(CH 3 ) 2 .

[0075] In one embodiment, R 2 may each independently be hydrogen or halogen.

[0076] In one embodiment, R 5 It may be hydrogen.

[0077] In one embodiment, R 6 may each independently be hydrogen or halogen.

[0078] In one embodiment, L 1 may be a single bond; and

[0079] R 3 and R 4 can be independently hydrogen, halogen, cyano, C 1-6 Alkyl, halogen C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 6-10 Aryl, or substituted or unsubstituted C 2-6 Heterocycloalkyl.

[0080] In one embodiment,

[0081] It can be phenyl, imidazolyl or furyl;

[0082] It may be phenyl;

[0083] L 1 Can be a single bond;

[0084] R 3 Can be halogen C 1-6 alkyl;

[0085] R 4 Can be hydrogen, halogen, C 1-6 Alkyl, halogen C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, or C 3-6 Cycloalkyl;

[0086] R 1 It can be hydrogen or halogen;

[0087] R 2 and R 5 May be hydrogen;

[0088] R 6 may each independently be hydrogen or halogen;

[0089] X and Y may each independently be -C- or -N-; and

[0090] m, n, q, r and p may each independently be an integer from 0 to 2.

[0091] In one embodiment,

[0092] Can

[0093] Can

[0094] L 1 Can be a single bond;

[0095] R 3 Can be halogen C 1-6 alkyl;

[0096] R 4 Can be hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, or C 3-6 Cycloalkyl;

[0097] R 1 It can be hydrogen or halogen;

[0098] R 2 and R 5 may each independently be hydrogen;

[0099] R 6 may each independently be hydrogen or halogen;

[0100] X can be carbon or nitrogen;

[0101] Y may be carbon; and

[0102] m, n, q, r and p may each independently be an integer from 0 to 2.

[0103] In one embodiment, the compound can be selected from the following compounds, their mirror image isomers, diastereomers, solvates and hydrates, and pharmaceutically acceptable salts thereof.

[0104] 1) N-(3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide;

[0105] 2) N-(3-(1-cyclopropyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide;

[0106] 3) N-(3-(Furan-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide;

[0107] 4) N-(3-(1-cyclobutyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide;

[0108] 5) N-(3-(2-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide;

[0109] 6) 2-Fluoro-N-(3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide;

[0110] 7) N-(3-(1-(2-methoxyethyl)-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide;

[0111] 8) N-(3-(1-cyclopropyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide

[0112] (trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide);

[0113] 9) N-(3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide; and

[0114] 10) N-(6-chloro-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide.

[0115] According to one embodiment of the present disclosure, a pharmaceutical composition is provided for treating or preventing diseases caused by abnormal regulation of the Hippo signaling pathway, specifically caused by TEAD activation, the pharmaceutical composition comprising a compound selected from the group consisting of a compound of Formula 1, its mirror image isomers, diastereomers, solvates and hydrates, and pharmaceutically acceptable salts thereof as an active ingredient.

[0116] In one embodiment, the composition can exhibit inhibitory activity against the binding of Yes-associated protein (YAP) to transcriptional enhancer-associated domain (TEAD).

[0117] In one embodiment, the composition can be used to treat cancer or tumor that can be cured by the inhibitory activity against YAP-TEAD binding.

[0118] In one embodiment, the pharmaceutical composition may include a therapeutically effective amount of a compound selected from the group consisting of the compound of Formula 1, its enantiomers, diastereomers, solvates and hydrates, and pharmaceutically acceptable salts thereof.

[0119] As used herein, the term "therapeutically effective amount" refers to the amount of a compound of the present disclosure required to treat or prevent a disease, condition or disorder, to alleviate, beneficially alter or remove one or more symptoms of a disease, condition or disorder, or to prevent or delay the onset of one or more symptoms of a disease, condition or disorder.

[0120] The effective dose of the pharmaceutical composition can be determined and prescribed by a physician skilled in the art. For example, the pharmaceutical composition can include the compound in an amount of 0.0001 mg to 10 g, but is not limited thereto.

[0121] In one embodiment, in addition to the active ingredient, the pharmaceutical composition may further include a pharmaceutically acceptable additive, such as a diluent, a disintegrant, a binder, a lubricant, a surfactant, a suspending agent or an emulsifier, but is not limited thereto.

[0122] The pharmaceutical compositions of the present disclosure may be formulated according to any known method and may be prepared into various dosage forms for oral administration, such as tablets, pills, powders, capsules, syrups, emulsions and microemulsions, or into various dosage forms for parenteral administration, such as intramuscular, intravenous or subcutaneous administration.

[0123] According to another embodiment of the present disclosure, a method of treating is provided in which a pharmaceutical composition is administered to an individual suffering from a disease caused by abnormal regulation of the Hippo signaling pathway, specifically caused by TEAD activation, wherein the pharmaceutical composition comprises a compound selected from the group consisting of a compound of Formula 1, its mirror image isomers, diastereomers, solvates and hydrates, and pharmaceutically acceptable salts thereof as an active ingredient.

[0124] As used herein, the terms "treating" or "treatment" refer to inhibiting the pathology or symptoms of a disease, condition or disorder in an individual who is experiencing or suffering from the pathology or symptoms of the disease, condition or disorder, such as inhibiting the disease, condition or disorder, such as preventing or reversing further development of the pathology and / or symptoms or ameliorating the disease, such as reducing the severity of the disease.

[0125] As used herein, the terms "preventing" or "prevention" refer to preventing a disease, e.g., preventing a disease, condition or disorder in an individual who may be susceptible to the disease, condition or disorder, but who does not yet experience or display the signs or symptoms of the disease.

[0126] As used herein, the term "subject" or "individual" may be a vertebrate, such as a mammal, fish, bird, reptile or amphibian. For example, the subject may be a human, a non-human primate, a horse, a pig, a rabbit, a dog, a sheep, a goat, a cow, a cat, a guinea pig or a rodent.

[0127] As used herein, the terms "administering" and "administering" refer to a method of providing a composition to a subject.

[0128] The dosage, number of times or method of administration of a compound or pharmaceutical composition according to one embodiment may vary according to the severity of the individual to be treated, the disease or condition, the administration rate and the judgment of the prescribing physician. For example, the dosage for an individual weighing 70 kg may generally be 0.0001 mg to 10 g per day, such as 1 mg to 1 g. The number of administrations may be one to multiple times, such as one to four times, or according to the administration / withdrawal schedule, and the administration method may be performed via oral or parenteral routes. For example, a compound or pharmaceutical composition according to one embodiment may be administered via oral or parenteral routes, in an amount of 0.1 to 100 mg / kg (body weight).

[0129] A physician may start a subject at an initial dose of a compound or pharmaceutical composition of the disclosure at levels lower than required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0130] According to another embodiment of the present disclosure, a kit is provided, comprising a compound selected from the group consisting of the compound of Formula 1, its mirror isomers, diastereomers, solvates and hydrates, and pharmaceutically acceptable salts thereof as an active ingredient.

[0131] In one embodiment, the therapeutic agent may be a drug for treating a disease related to abnormal regulation of the Hippo signaling pathway (specifically, TEAD activation), such as a drug for treating cancer. For example, the therapeutic agent may be a chemotherapeutic drug for treating cancer.

[0132] In one embodiment, the compounds, compositions, and kits of the present disclosure may be administered alone or together with at least one other therapeutic agent simultaneously, separately, or sequentially.

[0133] In the context of the present disclosure, unless otherwise specified, a singular term may include a plural form and vice versa.

[0134] Throughout the specification, numerical values ​​are deemed to include the meaning of "about" even if not specified. As used herein, the term "about" means that the deviation of a value or range is within 5%, preferably within 1% to 2%.

[0135] As used herein, the term "to" refers to a range that includes the numerical values ​​provided before and after the term "to" as the lower limit and the upper limit thereof, respectively.

[0136] As used herein, the terms “having”, “may have”, “including” or “may include” indicate the presence of the corresponding feature (eg, a value or a component, such as an ingredient) and do not exclude the presence of other features.

[0137] The contents of all publications disclosed herein are incorporated by reference in their entirety.

[0138] Hereinafter, a method for producing the compound of Formula 1 will be described in detail.

[0139] The compound of formula 1 according to the present disclosure can be prepared by the synthetic method shown in reaction scheme 1.

[0140] [Reaction Scheme 1]

[0141]

[0142] [Process-1]

[0143] 5-Nitroindole (1 eq, standard equivalent 61.67 mmol) is dissolved in dimethylformamide, and a halogen-substituted B derivative (1.2 eq) and potassium carbonate (2 eq) are added thereto, and then copper (I) iodide (1 eq) is added thereto. The reaction solution is stirred at 120° C. overnight. After the reaction is completed, the reaction solution is cooled to room temperature, and water is added thereto, followed by extraction with ethyl acetate three times. The organic layer is dehydrated over anhydrous sodium sulfate and filtered under reduced pressure, and the filtered organic layer is concentrated under reduced pressure. The residue obtained therefrom is purified by MPLC to obtain the target compound A.

[0144] [Process-2]

[0145] Compound A (1 eq, standard equivalent) obtained in [Process-1] was dissolved in dichloromethane, and N-bromosuccinimide (1 eq) was slowly added thereto. The reaction solution was stirred at room temperature for 2 hours. After the reaction was confirmed to be complete, water was added thereto, followed by extraction with dichloromethane. The organic layer was dehydrated with anhydrous sodium sulfate and filtered under reduced pressure. After the filtered organic layer was concentrated under reduced pressure, the residue obtained therefrom was purified by MPLC to obtain the target compound B.

[0146] [Process-3]

[0147] Compound B (1 eq, standard equivalent) obtained in [Process-2] is subjected to Stille cross-coupling reaction or Suzuki coupling reaction with the corresponding A-stannane derivative and A-borane derivative (2 eq). After completion of the reaction, the organic layer is washed with water, dried over anhydrous sodium sulfate, and filtered under reduced pressure, and the filtered organic layer is then concentrated under reduced pressure. The residue obtained therefrom is purified by MPLC to obtain the target compound C.

[0148] [Process-4]

[0149] Compound C (1 eq, standard equivalent) obtained in [Process-3] was dissolved in ethanol and Pd / C (0.2 wt%) was added thereto. The reaction solution was stirred under hydrogen for 16 hours. After confirming the completion of the reaction, the reaction solution was filtered through celite and washed with methanol. The filtered organic layer was concentrated under reduced pressure to obtain the target compound D.

[0150] [Process-5]

[0151] Compound D (1 eq, standard equivalent) obtained in [Process-4] was dissolved in a tetrahydrofuran:water mixture (3:1 v / v), and sodium bicarbonate (1.5 eq) was added thereto. The reaction solution was cooled to a temperature of 0 to 5°C and acryloyl chloride (1.05 eq) was slowly added dropwise thereto while stirring. After the dropwise addition was completed, the reaction solution was stirred at 0 to 5°C for 1 hour. After the completion of the reaction was confirmed, water was added thereto, followed by extraction with ethyl acetate. The organic layer was dehydrated with anhydrous sodium sulfate and filtered under reduced pressure. After the filtered organic layer was concentrated under reduced pressure, the residue obtained therefrom was purified by MPLC to obtain the target compound E.

[0152] In reaction scheme 1, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 、 Y, n, m, q, r, p, L 1 , As defined in Formula 1, but not limited thereto, and may be varied within the scope understandable to those skilled in the art.

[0153] The compound of Formula 1 according to one embodiment of the present disclosure can be prepared according to, but not limited to, the method shown in the above reaction scheme 1 (but not limited thereto). Those skilled in the art of organic compounds can appropriately adjust the specific reaction pathway, reaction conditions, reaction amounts, and the like.

[0154] Hereinafter, the present disclosure will be described in more detail with reference to the following examples and experimental examples. However, the following examples and experimental examples are provided only to illustrate the present disclosure, and the scope of the present disclosure is not limited thereto.

[0155] Example 1: N-(3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0156] [Process-1] Preparation of 5-nitro-1-(4-(trifluoromethyl)phenyl)-1H-indole

[0157]

[0158] 5-Nitro-1H-indole (10.0 g, 61.67 mmol) was dissolved in 80 mL of dimethylformamide, and 4-bromotrifluorotoluene (10.6 mL, 74.00 mmol) and potassium carbonate (17.0 g, 123.34 mmol) were added thereto, and then copper (I) iodide (11.7 g, 61.67 mmol) was added thereto. The reaction solution was stirred overnight at 120 ° C. After the reaction was completed, the reaction solution was cooled to room temperature, and 200 mL of water was added thereto, followed by extraction with ethyl acetate three times. The organic layer was dehydrated with anhydrous sodium sulfate and filtered under reduced pressure, and the filtered organic layer was concentrated under reduced pressure. The residue obtained therefrom was purified by MPLC (ethyl acetate: hexane = 1: 3 (v / v)) to obtain 14 g of the title compound (yield: 74%).

[0159] 1 H-NMR (300MHz, CDCl 3 ): δ8.69-8.68(m,1H),8.20-8.16(m,1H),7.89-7.86(m,2H),7.68-7.65(m,2H),7.60-7.51(m,2H),6.94-6.93(m,1H).

[0160] [Process-2] Preparation of 3-bromo-5-nitro-1-(4-(trifluoromethyl)phenyl)-1H-indole

[0161]

[0162] 5-Nitro-1-(4-(trifluoromethyl)phenyl)-1H-indole (14.0 g, 45.71 mmol) obtained in [Process-1] was dissolved in 140 mL of dichloromethane, and N-bromosuccinimide (8.3 g, 45.71 mmol) was slowly added thereto. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, 50 mL of water was added thereto, followed by extraction three times with 50 mL of dichloromethane. The organic layer was dehydrated over anhydrous sodium sulfate and filtered under reduced pressure. After the filtered organic layer was concentrated under reduced pressure, the residue obtained therefrom was purified by MPLC (ethyl acetate: hexane = 1: 3 (v / v)) to obtain 16.2 g of the title compound (yield: 92%).

[0163] 1 H-NMR (300MHz, CDCl 3 ): δ8.62-8.61(m,1H),8.22-8.18(m,1H),7.88-7.85(m,2H),7.64-7.61(m,2H),7.57-7.54(m,2H).

[0164] [Process-3] Preparation of 3-(1-methyl-1H-imidazol-4-yl)-5-nitro-1-(4-(trifluoromethyl)phenyl)-1H-indole Indole

[0165]

[0166] 3-Bromo-5-nitro-1-(4-(trifluoromethyl)phenyl)-1H-indole (13.0 g, 33.75 mmol) obtained in [Process-2] was dissolved in 260 mL of dimethylacetamide, and copper (I) chloride (689 mg, 6.75 mmol), cesium fluoride (15.8 g, 101.26 mmol), [1,1'-bis(diphenylphosphino)bisferrocenyl]palladium dichloride ([Pd(dppf)Cl 2 ], (5.2 g, 6.75 mmol)] and tributyl-(1-methylimidazol-4-yl)stannane (24.0 g, 64.80 mmol). The reaction solution was stirred at 100 ° C overnight. After the reaction was completed, 100 mL of water was added thereto, followed by extraction with ethyl acetate three times. The organic layer was dehydrated over anhydrous sodium sulfate and filtered under reduced pressure. After the filtered organic layer was concentrated under reduced pressure, the residue obtained therefrom was purified by MPLC (dichloromethane: methanol = 20: 1 (v / v)) to obtain 6.8 g of the title compound (yield: 52%).

[0167] 1 H-NMR (300MHz, CDCl 3): δ8.92-8.91(m,1H),8.20-8.16(m,1H),7.92(s,1H),7.86-7.83(m,2H),7.69-7.56(m,4H),7.34(s,1H),3.83(s,3H).

[0168] [Process-4] Preparation of 3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-amine

[0169]

[0170] 3-(1-methyl-1H-imidazol-4-yl)-5-nitro-1-(4-(trifluoromethyl)phenyl)-1H-indole (6.8 g, 17.60 mmol) obtained in [Process-3] was dissolved in 140 mL of ethanol and Pd / C (1.9 g, 0.2 wt%) was added thereto. The reaction solution was stirred under hydrogen for 2 hours. After the reaction was completed, the reaction solution was filtered through celite and washed with methanol. After the filtered organic layer was concentrated under reduced pressure, the residue obtained therefrom was purified by MPLC (dichloromethane: methanol = 20: 1 (v / v)) to obtain 4.5 g of the title compound (yield: 72%).

[0171] 1 H-NMR (300MHz, CDCl 3 ): δ7.83-7.62(m,5H),7.58-7.43(m,2H),7.23-7.18(m,3H),6.75-6.67(m,1H),3.77(s,3H).

[0172] [Process-5] Preparation of N-(3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole- 5-Acrylamide

[0173]

[0174] 3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-amine (4.5 g, 12.62 mmol) obtained in [Process-4] was dissolved in 60 mL of tetrahydrofuran:water mixture (3:1, v / v), and sodium bicarbonate (1.6 g, 18.94 mmol) was added thereto. The reaction solution was cooled to a temperature of 0 to 5° C. and acryloyl chloride (1.2 mL, 13.25 mmol) was slowly added dropwise thereto while stirring. After the reaction was completed, 40 mL of water was added thereto, followed by extraction three times with 40 mL of ethyl acetate. The organic layer was dehydrated over anhydrous sodium sulfate and filtered under reduced pressure. After the filtered organic layer was concentrated under reduced pressure, the residue obtained therefrom was purified by MPLC (dichloromethane:methanol=30:1 (v / v)) to obtain 3.8 g of the title compound (yield: 74%).

[0175] 1 H-NMR (300 MHz, DMSO-d 6 ): δ10.19(s,1H),8.50(s,1H),7.96-7.88(m,5H),7.69-7.59(m,3H),7.42(s ,1H),6.54-6.45(m,1H),6.30-6.23(m,1H),5.76-5.72(m,1H),3.74(s,3H).

[0176] MS (ESI + ,m / z):411.2[M+H] +

[0177] Example 2: N-(3-(1-cyclopropyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0178]

[0179] 20 mg of the title compound (yield: 4%) was obtained by repeating the process of Example 1, except that tributyl-(1-cyclopropylimidazol-4-yl)stannane (621 mg, 1.56 mmol) was used instead of tributyl-(1-methylimidazol-4-yl)stannane in [Process-3] of Example 1.

[0180] 1 H-NMR (300MHz, CDCl 3 ): δ8.37(s,1H),7.81-7.76(m,3H),7.67-7.55(m,4H),7.49-7.34(m,3H),6.50-6.44(m ,1H),6.34-6.31(m,1H),5.80(d,J=10.0Hz,1H),3.43-3.40(m,1H),1.12-1.01(m,4H).

[0181] MS (ESI + ,m / z):437.4[M+H] +

[0182] Example 3: N-(3-(Furan-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0183] [Process-1] Preparation of 3-(furan-2-yl)-5-nitro-1-(4-(trifluoromethyl)phenyl)-1H-indole

[0184]

[0185] 3-Bromo-5-nitro-1-(4-(trifluoromethyl)phenyl)-1H-indole (300 mg, 0.77 mmol) obtained in [Process-2] of Example 1 was dissolved in 5 mL of 1,4-difluoromethane 2-(Furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (211 mg, 1.09 mmol), [1,1'-bis(diphenylphosphino)bisferrocenyl]palladium dichloride ([Pd(dppf)Cl 2 ]) (60 mg, 0.08 mmol) and sodium carbonate (165 mg, 1.55 mmol). The reaction solution was stirred at 100 ° C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and 20 mL of water was added thereto, followed by extraction with 20 mL of ethyl acetate three times. The organic layer was dehydrated over anhydrous sodium sulfate and filtered under reduced pressure, and the filtered organic layer was concentrated under reduced pressure. The residue obtained therefrom was purified by MPLC (ethyl acetate: hexane = 1: 2 (v / v)) to obtain 100 mg of the title compound (yield: 62%).

[0186] 1 H-NMR (300 MHz, DMSO-d 6 ): δ8.92(s,1H),8.43(s,1H),8.20-8.14(m,1H),8.04-7.95(m,4H),7.86-7.77(m,2H),6.95(d,J=2.9Hz,1H),6.68-6.66(m,1H).

[0187] [Process-2] Preparation of N-(3-(furan-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acryloyl amine

[0188]

[0189] 44 mg of the title compound was obtained by repeating the process of Example 1, except that 3-(2-furanyl)-5-nitro-1-(4-(trifluoromethyl)phenyl)indole (180 mg, 0.49 mmol) obtained in [Process-1] was used instead of 3-(1-methyl-1H-imidazol-4-yl)-5-nitro-1-(4-(trifluoromethyl)phenyl)-1H-indole in [Process-4] of Example 1.

[0190] 1 H-NMR (300 MHz, DMSO-d 6): δ10.2(s,1H),8.50(s,1H),8.13(s,1H),7.97-7.90(m,4H),7.76-7.74(m,1H),7.71-7.69(m,1H),7.59-7 .56(m,1H),6.72-6.71(m,1H),6.66-6.65(m,1H),6.64-6.47(m,1H),6.31-6.30(m,1H),5.78-5.74(m,1H).

[0191] MS (ESI + ,m / z):397.1[M+H] +

[0192] Example 4: N-(3-(1-cyclobutyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0193]

[0194] 17 mg of the title compound (yield: 10%) was obtained by repeating the process of Example 1, except that tributyl-(1-cyclobutylimidazol-4-yl)stannane (1.1 g, 2.59 mmol) was used instead of tributyl-(1-methylimidazol-4-yl)stannane in [Process-3] of Example 1.

[0195] 1 H-NMR (300MHz, CDCl 3 ): δ8.34(s,1H),7.81-7.67(m,3H),7.61-7.55(m,2H),7.45-7.35(m,5H),6.49-6.25(m,2H),5.8 0(d,J=10.0Hz,1H),4.72-4.61(m,1H),2.62-2.52(m,2H),2.50-2.39(m,2H),1.99-1.88(m,2H).

[0196] MS (ESI + ,m / z):451.5[M+H] +

[0197] Example 5: N-(3-(2-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0198]

[0199] The procedure of Example 3 was repeated except that (2-fluorophenyl)borate (27 mg, 0.13 mmol) was used instead of 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (yield: 24%).

[0200] 1 H-NMR (300 MHz, DMSO-d 6 ): δ10.19(s,1H),8.21(s,1H),8.01(s,1H),7.98-7.91(m,4H),7.75-7.73(m,2H),7.59- 7.56(m,1H),7.44-7.33(m,3H),6.50-6.41(m,1H),6.27-6.22(m,1H),5.75-5.71(m,1H).

[0201] MS (ESI + ,m / z):425.1[M+H] +

[0202] Example 6: 2-Fluoro-N-(3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0203]

[0204] After 3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-amine (55 mg, 0.15 mmol) obtained in [Process-4] of Example 1 was dissolved in 1.1 mL of tetrahydrofuran, 2-fluoroacrylate (15 mg, 0.17 mmol), diisopropylethylamine (0.1 mL, 18.94 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 88 mg, 0.23 mmol) were added thereto at 0°C. The reaction solution was heated to room temperature and stirred overnight. After the reaction was completed, 5 mL of water was added thereto, followed by extraction with ethyl acetate three times. The organic layer was dehydrated over anhydrous sodium sulfate and filtered under reduced pressure. After the filtered organic layer was concentrated under reduced pressure, the residue obtained therefrom was purified by MPLC (dichloromethane:methanol=15:1 (v / v)) to obtain 10 mg of the title compound (yield: 15%).

[0205] 1 H-NMR (300 MHz, DMSO-d 6): δ10.33(s,1H),8.49(s,1H),7.98(s,1H),7.95-7.87(m,4H),7.69-7.6 1(m,3H),7.45(s,1H),5.81-5.64(m,1H),5.45-5.38(m,1H),3.74(s,3H).

[0206] MS (ESI + ,m / z):429.2[M+H] +

[0207] Example 7: N-(3-(1-(2-methoxyethyl)-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0208]

[0209] 10 mg of the title compound (yield: 30%) was obtained by repeating the process of Example 1, except that tributyl-[1-(2-methoxyethyl)imidazol-4-yl)stannane (43 mg, 0.10 mmol) was used instead of tributyl-(1-methylimidazol-4-yl)stannane in [Process-3] of Example 1.

[0210] 1 H-NMR (300 MHz, DMSO-d 6 ): δ10.19(s,1H),8.50(s,1H),7.97(s,1H),7.94-7.87(m,4H),7.72(s,1H),7.68-7.66(m,2H),7.48(s,1H),6.5 4-6.48(m,1H),6.29-6.23(m,1H),5.76-5.72(m,1H),4.23(t,J=5.1Hz,2H),3.68(t,J=5.1Hz,2H),3.29(s,3H).

[0211] MS (ESI + ,m / z):455.2[M+H] +

[0212] Example 8: N-(3-(1-cyclopropyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide

[0213]

[0214] 7 mg of the title compound (yield: 10%) was obtained by repeating the process of Example 1, except that 5-bromo-1H-pyrrolo[2,3-b]pyridine (1.0 g, 5.07 mmol) was used instead of 5-nitro-1H-indole in [Process-1] of Example 1 and tributyl-(1-cyclopropylimidazol-4-yl)stannane (411 mg, 1.03 mmol) was used instead of tributyl-(1-methylimidazol-4-yl)stannane in [Process-3].

[0215] 1 H-NMR (300 MHz, DMSO-d 6 ): δ10.41(s,1H),8.94(d,J=2.3Hz,1H),8.66(d,J=2.3Hz,1H),8.34-8.30(m,3H),7.93-7.90(m,2H),7.83(d,J =1.2Hz,1H),7.60(d,J=1.2Hz,1H),6.51-6.45(m,1H),6.34-6.28(m,1H),5.82-5.75(m,2H),1.12-1.01(m,4H).

[0216] MS (ESI + ,m / z):438.4[M+H] +

[0217] Example 9: N-(3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide

[0218]

[0219] The procedure was repeated except that tributyl-(1-methylimidazol-4-yl)stannane (576 mg, 1.55 mmol) was used instead of tributyl-(1-cyclopropylimidazol-4-yl)stannane in Example 8 to obtain 30 mg of the title compound (yield: 26%).

[0220] 1 H-NMR (300MHz, CDCl 3 ): δ8.88(brs,1H),8.29(d,J=2.4Hz,1H),8.10-8.00(m,3H),7.77-7.75(m,2H),7.55-7.51(m,2H ),7.27-7.26(m,1H),6.54-6.48(m,1H),6.37-6.28(m,1H),5.85(d,J=10.8Hz,1H),3.77(s,3H).

[0221] MS (ESI + ,m / z):412.4[M+H] +

[0222] Example 10: N-(6-chloro-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0223] [Process-1] Preparation of 5-bromo-6-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indole

[0224]

[0225] 5-Bromo-6-chloro-1H-indole (5.0 g, 21.69 mmol) was dissolved in 50 mL of dimethyl sulfoxide, and 4-bromobenzotrifluoride (7.4 g, 32.54 mmol), potassium carbonate (6.0 g, 43.39 mmol) and N,N'-dimethylethylenediamine (0.2 g, 2.17 mmol) were added thereto, and then copper (I) iodide (4.9 g, 26.03 mmol) was added thereto. The reaction solution was stirred at 110 ° C overnight. After the reaction was completed, the reaction solution was cooled to room temperature, and 100 mL of water was added thereto, followed by extraction with ethyl acetate three times. The organic layer was dehydrated with anhydrous sodium sulfate and filtered under reduced pressure. After the filtered organic layer was concentrated under reduced pressure, the residue obtained therefrom was purified by MPLC (ethyl acetate: hexane = 1: 20 (v / v)) to obtain 5.34 g of the title compound (yield: 66%).

[0226] 1 H-NMR (300MHz, CDCl 3 ): δ7.94(s,1H),7.82(d,J=8.5Hz,2H),7.66(s,1H),7.59(d,J=8.3Hz,2H),7.35(d,J=3.3Hz,1H),6.65(d,J=3.0Hz,1H).

[0227] [Process-2] Preparation of tertiary butyl (6-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)carbamate

[0228]

[0229] 5-Bromo-6-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indole (5.3 g, 14.25 mmol) obtained in [Process-1] was dissolved in 80 mL of toluene, and tris(dibenzylideneacetone)dipalladium ([Pd 2 (dba) 3])(1.3 g, 1.43 mmol), sodium tert-butoxide (2.7 g, 28.49 mmol), tert-butyl carbamate (2.0 g, 17.09 mmol) and (2-biphenyl) di-tert-butylphosphine (JohnPhos, 0.4 g, 1.43 mmol). The reaction solution was stirred at 90°C for 4 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and 100 mL of water was added thereto, followed by extraction with ethyl acetate three times. The organic layer was dehydrated over anhydrous sodium sulfate and filtered under reduced pressure. After the filtered organic layer was concentrated under reduced pressure, the residue obtained therefrom was purified by MPLC (ethyl acetate: hexane = 1: 20 (v / v)) to obtain 2.7 g of the title compound (yield: 46%).

[0230] 1 H-NMR (300MHz, CDCl 3 ): δ8.39(s,1H),7.79(d,J=8.3Hz,2H),7.60-7.58(m,3H),7.32(d,J=3.3Hz,1H),6.96(brs,1H),6.67-6.65(m,1H),1.56(s,9H).

[0231] [Process-3] Preparation of 6-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-amine hydrochloride

[0232]

[0233] 4N hydrochloric acid The 1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)carbamic acid tert-butyl ester (2.5 g, 6.14 mmol) was slowly added dropwise at 0°C to the 1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)carbamate obtained in [Process-2]. The reaction solution was stirred at 0°C for 4 hours. After the reaction was completed, the formed solid was collected by filtration, washed several times with hexane, and dried to obtain 1.96 g of the target compound (yield: 92%).

[0234] 1 H-NMR (300 MHz, DMSO-d 6 ): δ7.94(d,J=8.5Hz,2H),7.84(d,J=8.6Hz,2H),7.79(d,J=3.5Hz,1H),7.72(s,1H),7.41(s,1H),6.72(d,J=3.2Hz,1H),3.85(brs,3H).

[0235] [Process-4] Preparation of N-(6-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0236]

[0237] The 6-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-amine hydrochloride (0.6 g, 1.73 mmol) obtained in [Process-3] was dissolved in 12 mL of tetrahydrofuran, and triethylamine (0.9 mL, 6.91 mmol) was added dropwise thereto. The reaction solution was cooled to a temperature of 0 to 5° C., and acryloyl chloride (0.2 mL, 2.25 mmol) was slowly added dropwise thereto, followed by stirring at room temperature for 2.5 hours. After the reaction was completed, 25 mL of water was added thereto, followed by extraction with ethyl acetate three times. The organic layer was dehydrated over anhydrous sodium sulfate and filtered under reduced pressure. After the filtered organic layer was concentrated under reduced pressure, the residue obtained therefrom was purified by MPLC (ethyl acetate: hexane = 1: 5 (v / v)) to obtain 0.5 g of the title compound (yield: 79%).

[0238] 1 H-NMR (300MHz, CDCl 3 ): δ8.76(brs,1H),7.82-7.76(m,3H),7.61-7.59(m,3H),7.35(d,J=3.3Hz ,1H),6.72-6.71(m,1H),6.51-6.29(m,2H),5.82(dd,J=1.4,10.0Hz,1H).

[0239] [Process-5] Preparation of N-(3-bromo-6-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0240]

[0241] 0.4 g of the title compound (yield: 66%) was obtained by repeating the process of Example 1, except that N-(6-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide (0.5 g, 1.34 mmol) was used instead of 5-nitro-1-(4-(trifluoromethyl)phenyl)-1H-indole in [Process-2] of Example 1 and the reaction solution was stirred at 0°C for 2 hours.

[0242] 1 H-NMR (300MHz, CDCl 3 ): δ8.72(brs,1H),7.82(d,J=8.4Hz,2H),7.77(s,1H),7.59-7.56(m,3H),7.4 0(s,1H),6.54-6.48(m,1H),6.39-6.30(m,1H),5.84(dd,J=1.2,10.1Hz,1H).

[0243] [Process-6] Preparation of N-(6-chloro-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H- Indol-5-yl) acrylamide

[0244]

[0245] 9 mg of the title compound was obtained by repeating the process of Example 1 (yield: 2%), except that N-(3-bromo-6-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide (0.4 g, 0.88 mmol) was used instead of 3-bromo-5-nitro-1-(4-(trifluoromethyl)phenyl)-1H-indole in [Process-3] of Example 1 and the reaction solution was stirred at 100°C for 2 hours.

[0246] 1 H-NMR (300 MHz, DMSO-d 6 ): δ9.81(s,1H),8.41(s,1H),8.05(s,1H),7.98-7.90(m,4H),7.80(s,1H),7.69(s,1H),7.55 (s,1H),6.66-6.56(m,1H),6.26(dd,J=2.0,17.0Hz,1H),5.80(d,J=10.0Hz,1H),3.74(s,3H).

[0247] MS (ESI + ,m / z):445.1[M+H] +

[0248] Experimental Example 1: TEAD reporter activity inhibition test

[0249] The ability of synthetic compounds to inhibit TEAD transcription of target genes was measured. This evaluation method is a method for measuring TEAD transcriptional activity as follows: by using the MCF7 cell line (BPS Bioscienc, Inc., USA), the luminescence intensity of luciferase expressed when TEAD binds to the target gene and activates its transcription is measured. The cell line is constructed by introducing the firefly luciferase reporter gene into GTIIC (5'-ACATTCCA-3'), which is a specific binding structure for TEAD. The cell line was cultured in MEM medium supplemented with 10% FBS, 1% penicillin / streptomycin, 1% non-essential amino acids, 10μg / ml insulin and 400μg / ml geneticin. In the test for inhibiting TEAD reporter activity, geneticin was excluded. The cells were cultured at 4×10 4Cells were aliquoted into white 96-well plates at a density of 10 cells / 100 μl and cultured for 6 hours. 50 μl of the test compound diluted to 3X concentration was mixed into each well. After 24 hours of cell culture, the luciferase signal was measured based on luminescence using the ONE-Glo Luciferase Assay System (Promega, E6120) according to the manufacturer's protocol. The 50% inhibitory concentration (IC) for TEAD transcriptional activity was calculated using GraphPad Prism 9. 50 ).

[0250] IC less than 100nM 50 The value is expressed as A, IC not less than 100nM but less than 500nM 50 The value is expressed as B and is not less than 500nM IC 50 The value is denoted as C.

[0251] [Table 1]

[0252] Synthetic compounds <![CDATA[IC 50 ,nM]]> 1 A 2 A 3 A 4 A 5 A 6 B 7 A 8 A 9 A 10 B

[0253] Experimental Example 2: Cell Growth Inhibition Test

[0254] Identify the ability of synthetic compounds to inhibit the growth of NCI-H226 cells. NCI-H226 mesothelioma cancer cell line lacking NF2 gene was cultured in RPMI 1640 medium supplemented with 10% FBS and 1% penicillin / streptomycin. The cultured cells were cultured at 0.7×10 3 The cells were aliquoted into 96-well plates at a density of 10 cells / 100 μl and cultured for 24 hours, and then 100 μl of the test compound diluted to 2X concentration was mixed into each well and cultured for 6 days. Cell growth inhibition was measured using the SRB assay method, and the 50% inhibitory concentration (GI) of the compound on cell growth was calculated using GraphPad Prism9. 50 ).

[0255] GI less than 100nM 50 GI values ​​are expressed as A and are not less than 100 nM 50 The value is denoted as B.

[0256] [Table 2]

[0257] Synthetic compounds <![CDATA[GI 50 ,nM]]> 1 A 2 A 3 A 4 A 5 A 7 A 8 A 9 A

[0258] Although the present disclosure has been specifically shown and described with reference to its exemplary embodiments. However, it should be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the present disclosure as defined by the following claims. The preferred embodiments should be regarded as merely descriptive and not for limiting purposes. Therefore, the scope of the present disclosure is not limited by the embodiments of the present invention, but by the appended claims, and all differences within the scope should be construed as included in the present disclosure.

Claims

1. A compound selected from the group consisting of a compound of the following formula 1, its mirror image isomers, diastereomers, solvates and hydrates, and pharmaceutically acceptable salts thereof: Formula 1 In formula 1, R1 is hydrogen, halogen, C 1-6 Alkyl, halogen C 1-6 Alkyl, C 1-6 Alkoxy or cyano; R2 is each independently hydrogen, halogen, C 1-6 Alkyl, halogen C 1-6 Alkyl, or substituted or unsubstituted -(CH2) a -N(Q1)(Q2), Where Q1 and Q2 are each independently hydrogen or C 1-4 alkyl; is a carbocyclic group or a heterocyclic group; C 6-10 Aryl or C 4-10 heteroaryl; L1 is non-existent, a single bond, C 1-3 Alkyl or halogen C 1-3 alkyl; R3 and R4 are each independently hydrogen, halogen, cyano, amine, C 1-6 Alkyl, halogen C 1-6 Alkyl, C 1-6 Alkoxy, halogen C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, substituted or unsubstituted C 3-6 Carbocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted C 2-6 Heterocyclic group, or substituted or unsubstituted C 4-10 heteroaryl; R5 is hydrogen, C 1-6 Alkyl or halogen C 1-6 alkyl; R6 are each independently hydrogen, halogen, C 1-6 Alkyl or halogen C 1-6 alkyl; X and Y are each independently -C- or -N-; and a, m, n, q, r and p are each independently an integer from 0 to 3.

2. The compound according to claim 1, wherein C 3-6 Cycloalkyl, C 6-10 Aryl, C 2-6 Heterocycloalkyl, C 1-10 Heteroaryl, or C 6-14 Fused heteroaryl, Wherein C 2-6 Heterocycloalkyl, the C 1-10 Heteroaryl or the C 6-14 The fused heteroaryl groups each independently contain 1 to 4 heteroatoms selected from N, O and S.

3. The compound according to claim 1, wherein Phenyl, pyridyl, pyridinyl yl, pyrazolyl, imidazolyl, thienyl, furanyl, or Azolyl.

4. The compound according to claim 1, wherein It is phenyl or pyridyl.

5. The compound according to claim 1, wherein R1 is hydrogen, halogen or cyano.

6. The compound according to claim 1, wherein each R2 is independently hydrogen or halogen.

7. The compound according to claim 1, wherein R5 is hydrogen.

8. The compound according to claim 1, wherein each R6 is independently hydrogen or halogen.

9. The compound according to claim 1, wherein L1 is a single bond; and R3 and R4 are each independently hydrogen, halogen, cyano, C 1-6 Alkyl, halogen C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 6-10 Aryl, or substituted or unsubstituted C 2-6 Heterocycloalkyl.

10. The compound according to claim 1, wherein is phenyl, imidazolyl or furyl; is phenyl; L 1 is a single bond; R3 is a halogen C 1-6 alkyl; R4 is hydrogen, halogen, C 1-6 Alkyl, halogen C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, or C 3-6 Cycloalkyl; R1 is hydrogen or halogen; R2 and R5 are each hydrogen; R6 are each independently hydrogen or halogen; X and Y are each independently -C- or -N-; and m, n, q, r and p are each independently an integer from 0 to 2.

11. The compound according to claim 1, wherein the compound is selected from the compounds shown below, their mirror image isomers, diastereomers, solvates and hydrates, and pharmaceutically acceptable salts thereof: 1) N-(3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide; 2) N-(3-(1-cyclopropyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide; 3) N-(3-(Furan-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide; 4) N-(3-(1-cyclobutyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide; 5) N-(3-(2-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide; 6) 2-Fluoro-N-(3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide; 7) N-(3-(1-(2-methoxyethyl)-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide; 8) N-(3-(1-cyclopropyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide; 9) N-(3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide; and 10) N-(6-chloro-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide.

12. A pharmaceutical composition for treating or preventing diseases caused by transcription enhancer associated domain (TEAD) activation, comprising a compound according to any one of claims 1 to 11 as an active ingredient, wherein the compound is selected from a compound, a mirror image isomer, a diastereomer, a solvate and a hydrate thereof, and a pharmaceutically acceptable salt thereof. 13 . The pharmaceutical composition according to claim 12 , wherein the composition has an activity of inhibiting Yes-associated protein (YAP)-transcriptional enhancer associated domain (TEAD) binding.

14. The pharmaceutical composition according to claim 12, wherein the composition is used to treat cancer or tumor that can be cured by the inhibitory activity of the composition against YAP-TEAD binding.

Images