Novel heterocyclic compounds and pharmaceutical compositions containing the same

Abstract

The present invention relates to compounds represented by formula I, their stereoisomers, their pharma- ceutically acceptable salts, their hydrates or solvates, and pharmaceutical compositions comprising same.

Description

[Technical field]

[0001] The present invention relates to novel heterocyclic compounds, their stereoisomers, their pharma- ceutically acceptable salts, their hydrates or solvates, and pharmaceutical compositions containing them. [Background technology]

[0002] The Hippo signaling pathway is a major signaling pathway that regulates normal cell proliferation in humans, as well as the growth and size of tissues and organs, such as skin, muscle, lung, and liver. The Hippo signaling pathway is known as a tumor suppressor in normal cells and tissues, but it has been reported to be involved in diseases such as tumors, and has been revealed to play an important role in the development and proliferation of cancer.

[0003] It has also been reported that the Hippo signaling pathway cross-talks with other signaling pathways that are traditionally involved in tumors, such as the Wnt, EGFR, or TGF-beta signaling pathways, and that the Hippo signaling pathway may be involved in various human cancers.

[0004] The Hippo signaling pathway begins with a kinase cascade consisting of MST-1 / 2 and LATS-1 / 2, and is activated by phosphorylating the transcriptional activator proteins YAP and TAZ.

[0005] If the Hippo signaling pathway is not activated, the YAP protein moves from the cytoplasm to the nucleus without being phosphorylated, binds to TEA domain (TEAD) proteins (TEAD1, 2, 3, 4) present in the nucleus, and acts as a transcription factor for genes involved in cell proliferation, such as CTGF, Cyr61, and FGF1, to induce their expression. Conversely, when the Hippo signaling pathway is activated, the YAP protein is phosphorylated, and the phosphorylated YAP protein is ubiquitinated in the cytoplasm and degraded by the proteasome, or binds to the tumor suppressor VGLL4 protein, preventing it from moving into the nucleus. As a result, it is no longer able to bind to TEAD proteins, and the expression of genes involved in cell proliferation is suppressed.

[0006] Recent reports have revealed that abnormal cell proliferation in various tumors is caused by abnormal expression of genes related to the Hippo signaling pathway, which is not normally regulated (Cell 2011 Nov 11;147(4):759-72,Folia Histochem Cytobiol.2015;53(2):105-19). In particular, it has been reported that in patients with mesothelioma, which has a poor prognosis, activation of the Hippo signaling pathway is inhibited by about 50% due to genetic mutations in the NF2 protein (Transl Lung Cancer Res.2014;3:75-83, Cancer Res.1995;55:1227-31).

[0007] The only known method to suppress the overexpression of genes involved in cell proliferation due to abnormal regulation of the Hippo signaling pathway is to inhibit the binding of YAP protein and TEAD protein in the cell nucleus. This is because MST-1 / 2 kinase and LATS-1 / 2 kinase, which are upstream proteins of the Hippo signaling pathway, phosphorylate YAP protein and inhibit its migration into the nucleus. Therefore, if the function of these kinases is inhibited, YAP protein is not phosphorylated and the YAP protein is not transported into the nucleus. This is because YAP binds to TEAD proteins after activation and can further promote overexpression of genes. In addition, since YAP protein is a protein with a very flexible structure that does not have a specific tertiary structure, it is difficult to target with therapeutic substances, and therefore TEAD proteins are currently the only targets that can suppress the Hippo signaling pathway. Furthermore, recent studies have revealed that S-palmitoylation of TEAD proteins itself is an essential factor for the stability and function of TEAD proteins (Cell Rep.2020 Jun 23;31(12):107809).

[0008] Therefore, various methods have been attempted to bind to the TEAD protein, thereby preventing the binding between the YAP protein and the TEAD protein, or to inhibit the function of the TEAD protein.

[0009] TEAD proteins, consisting of TEAD1, 2, 3, and 4, share a very high degree of similarity in amino acid composition with each other, at about 70%. All TEAD proteins undergo a post-translational protein modification process called palmitoylation, in which a fatty acid called palmitic acid is attached to a specific cysteine ​​group. This process is known to be necessary for improving the structural stability of TEAD proteins or for promoting binding with YAP or TAZ proteins to express genes (Chan, P. et al. Nat. Chem. Biol. (2016) 12: 282-289; Noland, CL et al. Structure (2016) 24: 179-186; Mesrouze, Y. et al. Protein Sci. (2017) 26: 2399-2409).

[0010] Recently, peptides that mimic some parts of the YAP protein that bind to TEAD proteins have been studied, but although these peptide substances showed strong binding to TEAD proteins in in vitro experiments (Furet, P. et al. Bioorg. Med Chem. Lett. (2019) 29: 2316-2319), they have not yet been developed as practical therapeutic drugs due to insufficient cell permeability and in vivo stability. To solve these peptide problems, there have been attempts to develop small molecule compounds that have excellent cell permeability and stability and bind to the interface where YAP proteins interact with TEAD proteins (Zhou, W. et al. Anal. Biochem. (2019) 586: 113413), but these small molecule compounds had low YAP-TEAD inhibitory effects and could not be developed as therapeutic substances that inhibit the Hippo signaling pathway.

[0011] From the results of previous research, it is known that it is very difficult to develop a therapeutic agent that inhibits the mechanism of the interface that directly binds to the YAP protein in TEAD proteins. To solve this problem, the importance of the palmitoylation process in TEAD proteins has recently emerged, and it is known that palmitic acid is a small molecule compound with 16 carbon atoms, and that the palmitoylation site is very similar in all TEAD proteins. A strategy has been reported to develop a small molecule compound that binds to the palmitoylation site of TEAD proteins.

[0012] It is known that various low molecular weight compounds, including flufenamic acid, can inhibit the palmitoylation of TEAD protein (Pobbati, AV et al. Structure (2015) 23: 2076-2086), and it has been reported that these low molecular weight compounds inhibit the palmitoylation of TEAD protein, thereby inhibiting the proliferation of cancer cells and potentially exhibiting stronger effects than the conventional substances mentioned above (Holden, JK et al. Cell Rep. (2020) 31: 107809; Kaneda, A. et al. Am. J. Cancer Res. (2020) 10: 4399-4415).

[0013] In conclusion, the Hippo signaling pathway is an important signaling pathway involved in diseases caused by excessive cell proliferation, such as cancer. To suppress the overexpression of genes induced by the Hippo signaling pathway, TEAD proteins, which are located at the bottom of the signaling pathway, have been presented as the only therapeutic target. Therefore, there has been a recent demand for the development of small molecule compounds that suppress palmitoylation of TEAD proteins and inhibit the overexpression of genes induced by the Hippo signaling pathway. [Prior art documents] [Non-patent literature]

[0014] [Non-Patent Document 1] Cell 2011 Nov 11;147(4):759-72 [Non-Patent Document 2] Folia Histochem Cytobiol.2015;53(2):105-119 [Non-Patent Document 3] Transl Lung Cancer Res.2014;3:75-83 [Non-Patent Document 4] Cancer Res.1995;55:1227-31 [Non-Patent Document 5] Cell Rep.2020 Jun 23;31(12):107809 [Non-Patent Document 6] Chan, P. et al. Nat. Chem. Biol. (2016) 12:282-289 [Non-Patent Document 7] Noland,C Let al.Structure(2016)24:179-186 [Non-Patent Document 8] Mesrouze, Y. et al. Protein Sci. (2017) 26:2399-2409 Summary of the Invention [Problem to be solved by the invention]

[0015] The present invention provides a compound represented by formula I, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or a solvate thereof.

[0016] The present invention provides a pharmaceutical composition comprising a compound represented by formula I, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or a solvate thereof as an active ingredient.

[0017] The present invention provides a pharmaceutical composition for preventing or treating cancer, comprising a compound represented by chemical formula I, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or a solvate thereof.

[0018] The present invention provides a pharmaceutical composition comprising a compound represented by chemical formula I, a stereoisomer thereof, a pharma- ceutical acceptable salt thereof, or a hydrate or solvate thereof for preventing or treating cancer, which is located at the lowest level of the Hippo signaling pathway, which is one of the signal pathways very important for cell development and proliferation, and acts as a switch regulating the expression of genes involved in cell development and proliferation, thereby inhibiting the function of the protein and suppressing the expression of the gene, leading to excessive cell proliferation.

[0019] The present invention provides the use of a compound represented by chemical formula I, its stereoisomer, its pharma- ceutically acceptable salt, its hydrate or solvate, or a pharmaceutical composition containing same, for the prevention or treatment of cancer.

[0020] The present invention relates to a compound of formula I, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or the like, for the manufacture of a medicament for the prophylaxis or treatment of cancer. provides uses for pharmaceutical compositions containing the same. [Means for solving the problem]

[0021] The present invention provides a novel TEAD inhibitor that inhibits palmitoylation of TEAD protein, which is structurally completely different from the palmitoylation inhibitors of TEAD protein reported so far, has excellent cell permeability and in vivo stability, and contributes to the development of therapeutic agents for diseases involving the Hippo signaling pathway, such as anticancer agents, using the novel substance.

[0022] The present invention will be described in more detail below. All combinations of the various elements disclosed in the present invention belong to the scope of the present invention. In addition, the specific descriptions described below should not be construed as limiting the scope of the present invention.

[0023] A compound represented by formula I, its stereoisomers, its pharma- ceutically acceptable salts, its hydrates or solvates The present invention provides a compound according to any one of the following (1) to (6), a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, or a hydrate or solvate thereof:

[0024] (1) A compound represented by the following chemical formula I, its stereoisomer, its pharma- ceutically acceptable salt, its hydrate or solvate: [ka] In the above formula I, L1 is a single bond, -(C1-C6 alkylene)- or -(C=O)-; R1 is H, C1-C3 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 6- to 14-membered aryl, or 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; One or more H of the R1 C1-C3 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 6- to 14-membered aryl, or 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring may be independently substituted or unsubstituted with C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, CF2H, CF3, -OCF3, -OH, -(C1-C3 alkylene)-OH, -(C=O)Rp, -COORq, -CN, -(C1-C3 alkylene)-CN, -NRxRy, -(C1-C3 alkylene)-NRsRt, or halogen, where Rp, Rq, Rs, Rt, Rx, and Ry are each independently H or C1-C6 alkyl; Z1 and Z2 are each independently N or CRa; Ra is H or C1-C6 alkoxy; Q1 and Q2 are each independently N, CH, or CRb, and at least one of Q1 and Q2 is CRb; Rb is [ka] and L2 is -(C=O)- or S(=O)2; R2, R3 and R5 are each independently H or C1-C6 alkyl; [ka] is XY or X=Y; [ka] is XY, then X and Y are each -CH-; [ka] when X=Y, X is -CH- or N and Y is -CR4 or N; R4 is H, C1-C6 alkyl or halogen; Z1, Z2, Q1 and Q2 are not all N, [ka] When X=Y, one or more of X and Y is N.

[0025] (2) In the above (1), in the above chemical formula I, L1 is a single bond, -(C1-C6 alkylene)- or -(C=O)-; R1 is H, C1-C3 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 6- to 14-membered aryl, or 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; One or more H of the R1 C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 6- to 14-membered aryl, or 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring may be independently substituted or unsubstituted with C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, CF2H, CF3, -OCF3, -OH, -CN, -NRxRy, or halogen, where Rx and Ry are independently H or C1-C6 alkyl; Z1 is N or CH; Z2 is N or CRa; Ra is H or C1-C6 alkoxy; Q1 and Q2 are each independently N, CH, or CRb, and at least one of Q1 and Q2 is CRb; Rb is [ka] and; R2 and R5 are each independently H or C1-C6 alkyl; R3 is C1-C6 alkyl; [ka] is XY or X=Y; [ka] is XY, then X and Y are -CH-; [ka] when X=Y, X is -CH- or N and Y is -CR4 or N; R4 is H, C1-C6 alkyl or halogen; Z1, Z2, Q1 and Q2 are not all N, [ka] When X=Y, one of X and Y is N.

[0026] (3) In the above (1) or (2), in the above chemical formula I, L1 is a single bond, -(C1-C6 alkylene)- or -(C=O)-; R1 is H, methoxy, cyclopentanyl, cyclohexanyl, cyclohexenyl, phenyl, pyridinyl, pyrazolyl, pyrimidinyl or thiophenyl; One or more H of methoxy, cyclohexanyl, cyclohexenyl, phenyl, pyridinyl, pyrazolyl, pyrimidinyl, or thiophenyl in R1 may each independently be substituted or unsubstituted with methyl, isopropyl, tert-butyl, sec-butyl, methoxy, isobutoxy, cyclohexyl, CF2H, CF3, -OCF3, -OH, -CN, NH2, or halogen; Z1 is N or CH; Z2 is N or CRa; Ra is H or methoxy; Q1 is N, CH or CRb1, Q2 is N, CH or CRb2, and at least one of Q1 and Q2 is CRb1 or CRb2; Rb1 is [ka] and Rb2 is [ka] and R2 is H or methyl; R3 is isopropyl; [ka] is XY or X=Y; [ka] is XY, then X and Y are -CH-; [ka] when X=Y, X is -CH- or N and Y is -CR4 or N; R4 is H, methyl or halogen; Z1, Z2, Q1 and Q2 are not all N, [ka] When X=Y, one of X and Y is N.

[0027] Specifically, in the above, Q1 is N, CH or CRb1, and Q2 is N, CH or CRb2, but when Q1 is N or CH, Q2 is CRb2; when Q2 is N or CH, Q1 is CRb1. The Rb1 and Rb2 are as described above.

[0028] (4) In any one of (1) to (3), The compound represented by formula I may be a compound represented by formula II: [ka] In the above formula II, L1 is a single bond or -(C1-C6 alkylene)-; R1 is H, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 6- to 14-membered aryl, 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of N, O and S; One or more H of the R1 C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 6- to 14-membered aryl, or 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring may be independently substituted or unsubstituted with C1-C6 alkyl, C1-C6 alkoxy, CF2H, CF3, -OCF3, -OH, -CN, -NRxRy, or halogen, where Rx and Ry are independently H or C1-C6 alkyl; Z1 and Z2 are each independently N or CH; Q1 and Q2 are each independently N, CH, or CRb, and at least one of Q1 and Q2 is CRb; Rb is [ka] and; R4 is H, C1-C6 alkyl or halogen.

[0029] (5) In any one of the above (1) to (4), the compound represented by the chemical formula I may be a compound represented by the following chemical formula III: [ka] In the above formula III, L1 is a single bond, -(C1-C6 alkylene)- or -(C=O)-; R1 is H, C3-C8 cycloalkyl, 6- to 14-membered aryl, or 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of N, O, and S; One or more H of the C3-C8 cycloalkyl, 6- to 14-membered aryl, or 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring of R1 may be independently substituted or unsubstituted with C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, CF2H, CF3, -OCF3, or halogen; Z1 is N or CH; Z2 is N or CRa; Ra is H or C1-C6 alkoxy; Q1 is N or CH; Q2 is CRb; Rb is [ka] and R2 is H or C1-C6 alkyl; R3 is C1-C6 alkyl; R4 is H, C1-C6 alkyl or halogen; At least one of Z1, Z2, Q1 and Q2 is N.

[0030] In the present invention, the term "Cm-Cn" (wherein m and n are each independently an integer of 1 or more) means the number of carbon atoms, for example, "C1-C5 alkyl" means alkyl having 1 to 5 carbon atoms.

[0031] In the present invention, "substituted" or "substituted with" is defined to include the implicit proviso that such substitution, subject to the permitted valency of the substituted atom and substituent, leads to a stable compound, e.g., a compound that does not spontaneously change by rearrangement, cyclization, elimination, etc.

[0032] In the present invention, "single bond" means that adjacent atoms or atomic groups are directly bonded to each other. For example, in the compound represented by chemical formula I of the present invention, when L1 is a single bond, N and R1 are directly bonded, and in this case, the chemical formula may be represented as the following chemical formula Ia.

[0033] [ka] In the present invention, the [ka] means a single or double bond between two atoms. [ka] When is a single bond, the dotted line is null, [ka] is a double bond, the dotted line represents a solid line.

[0034] In the present invention, unless otherwise specified, "alkyl" refers to a linear (or straight-chain) saturated hydrocarbon group or a branched (or side-chain) saturated hydrocarbon group. Examples of alkyl include, but are not limited to, one or more selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and n-heptyl.

[0035] In the present invention, unless otherwise specified, "alkylene" refers to a divalent functional group derived from an alkyl as defined above.

[0036] In the present invention, unless otherwise specified, "alkenyl" refers to an unsaturated hydrocarbon group containing at least one carbon-carbon double bond in the alkyl group described above.

[0037] In the present invention, "alkoxy" refers to OC unless otherwise specified. n H 2n+1 Alkoxy refers to a monovalent group derived from a linear or branched saturated hydrocarbon group represented by the following formula: Examples of alkoxy include, but are not limited to, one or more selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, and hexoxy.

[0038] In the present invention, unless otherwise specified, "cycloalkyl" refers to a saturated hydrocarbon ring having 3 or more carbon atoms, and the saturated hydrocarbon ring includes both monocyclic and polycyclic structures. Cycloalkyl includes, for example, cyclopropyl, Examples include, but are not limited to, one or more selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0039] In the present invention, unless otherwise specified, "cycloalkenyl" refers to a cyclic group containing at least one carbon-carbon double bond in the cycloalkyl. Cycloalkenyl may be, for example, one or more selected from cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc., but is not limited thereto.

[0040] In the present invention, unless otherwise specified, "heterocycloalkyl" refers to a cyclic group in which at least one or more carbon atoms constituting the ring of the cycloalkyl are each independently substituted with a heteroatom or functional group selected from the group consisting of N, O, S, SO, and SO2. Examples of heterocycloalkyl include, but are not limited to, one or more selected from oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiophenyl, oxepanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, azetidinyl, aziridinyl, and azepanyl.

[0041] In the present invention, unless otherwise specified, "aryl" refers to a monocyclic or polycyclic ring group having one or more aromatic rings, fused or unfused. Aryl includes, but is not limited to, one or more selected from phenyl, biphenyl, naphthalenyl, tetrahydronaphthyl, indenyl, anthracenyl, and the like.

[0042] In the present invention, unless otherwise specified, "heteroaryl" refers to a monocyclic or polycyclic heterocycle containing at least one heteroatom selected from the group consisting of N, O, and S in the ring and having one or more fused or unfused aromatic rings. Examples of heteroaryl include, but are not limited to, one or more selected from thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzothiophenyl, benzofuranyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, purinyl, and furopyridinyl.

[0043] In the present invention, "halogen" may be F, Cl, Br or I, unless otherwise specified.

[0044] (6) In any one of (1) to (5) above, the compound represented by the chemical formula I may be one or more compounds selected from the group consisting of compounds listed in Table 1 below: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17]

[0045] In the present invention, "stereoisomer" includes diastereomers and optical isomers, and optical isomers include not only enantiomers but also mixtures of enantiomers and racemates.

[0046] In the present invention, "pharmaceutical acceptable" may mean physiologically tolerable and not usually causing allergic reactions such as gastrointestinal disorders, dizziness, or similar reactions when administered to an individual.

[0047] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt commonly used in the pharmaceutical industry, and examples of such salts include inorganic ion salts prepared from calcium, potassium, sodium, magnesium, etc.; inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, sulfuric acid, etc.; acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, asparagine, acetic acid ... Examples of suitable salts include organic acid salts prepared from carboxylic acid, ascorbic acid, vanillic acid, etc.; sulfonate salts prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.; amino acid salts prepared from glycine, arginine, lysine, etc.; and amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc., but the types of salts meant in the present invention are not limited to these listed salts.

[0048] The pharma- ceutically acceptable salts of the present invention can be prepared by conventional methods known to those of ordinary skill in the art.

[0049] The "hydrate" of the present invention is a compound according to any one of (1) to (6) or a pharma- ceutical acceptable salt thereof bound to water by non-covalent intermolecular forces, and may contain a stoichiometric or non-stoichiometric amount of water. Specifically, the hydrate may contain water in a molar ratio of about 0.25 to about 10 moles per mole of active ingredient, more specifically, about 0.5 moles, about 1 mole, about 1.5 moles, about 2 moles, about 2.5 moles, about 3 moles, about 5 moles, etc.

[0050] The "solvate" of the present invention is a compound according to any one of (1) to (6), a stereoisomer thereof or a pharma- ceutical acceptable salt thereof, and a non-aqueous solvent bound by non-covalent intermolecular forces, and may contain a stoichiometric or non-stoichiometric amount of solvent. Specifically, the solvate may contain about 0.25 to about 10 moles of solvent molecules based on 1 mole of active ingredient, more specifically, about 0.5 moles, about 1 mole, about 1.5 moles, about 2 moles, about 2.5 moles, about 3 moles, about 5 moles, etc.

[0051] The compound according to any one of (1) to (6) of the present invention is located at the lowest level of the Hippo signaling pathway, which is one of the signaling pathways that is very important for cell development and proliferation, and binds to the TEAD protein, which acts as a switch that regulates the expression of genes involved in cell development and proliferation, thereby inhibiting the function of the protein and suppressing the expression of the gene, and can be effectively used for the prevention or treatment of cancer that leads to excessive cell proliferation.

[0052] Pharmaceutical compositions containing compounds of formula I, methods of treatment therewith and uses thereof The present invention provides a pharmaceutical composition comprising, as an active ingredient, the compound according to any one of the above (1) to (6), a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0053] The present invention provides a pharmaceutical composition for preventing or treating cancer, comprising, as an active ingredient, the compound according to any one of (1) to (6) above, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0054] The cancer may be one or more selected from, but is not limited to, lung cancer, stomach cancer, ovarian cancer, prostate cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, testicular cancer, bladder cancer, breast cancer, uterine cancer, cervical cancer, head and neck cancer, blood cancer, bone cancer, liver cancer, thyroid cancer, parathyroid cancer, skin cancer, lymphoma, mesothelioma, leukemia, myeloma, sarcoma, and virus-related cancer. The virus-related cancer may be one or more selected from, but is not limited to, nasopharyngeal cancer, vaginal cancer, vulvar cancer, penile cancer, Kaposi's sarcoma, Burkitt's lymphoma, T-cell lymphoma, and Merkel cell carcinoma.

[0055] In the present invention, "prevention" means any action of suppressing or delaying the onset of a TEAD protein-related disease, for example, cancer, by administering a compound according to any of (1) to (6) of the present invention, its stereoisomer, its pharma- ceutically acceptable salt, or its hydrate or solvate.

[0056] In the present invention, "treatment" means any action of improving or beneficially changing the symptoms of a TEAD protein-related disease, for example, cancer, by administering a compound according to any of (1) to (6) of the present invention, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0057] The pharmaceutical composition of the present invention may further contain one or more pharma- ceutically acceptable carriers in addition to the compound according to any one of (1) to (6) above, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

[0058] Here, the pharma- ceutically acceptable carrier is one commonly used in the art for formulation, and may be one or more selected from lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginic acid, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, etc., but is not limited thereto.

[0059] Furthermore, the pharmaceutical composition of the present invention may further contain, in addition to the above-mentioned components, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, and the like.

[0060] The pharmaceutical composition of the present invention also contains an intracellular signaling inhibitor. The pharmaceutical composition of the present invention may further comprise one or more drugs selected from the group consisting of transduction inhibitors, mitosis inhibitors, alkylating agents, antimetabolites, antibiotics, growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, biological reaction modifiers, antihormonal agents, antiandrogens, cell differentiation / proliferation / survival inhibitors, and apoptosis inducers. When the pharmaceutical composition of the present invention is formulated, the pharmaceutical composition may be used in combination with the above-mentioned further drugs or may be formulated as a composite formulation.

[0061] The pharmaceutical composition of the present invention may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dosage will vary depending on the condition and physical condition of the patient. The dosage may vary depending on the severity of the disease, the drug form, the route of administration and the time of administration, but may be appropriately selected by those skilled in the art.

[0062] The pharmaceutical composition of the present invention may further contain, in addition to the compound according to any one of (1) to (6) above, a pharma- ceutically acceptable salt thereof, a stereoisomer thereof, a hydrate thereof, or a solvate thereof, one or more components that exhibit the same or similar effects, or that bring about a synergistic effect on the efficacy of the drug when used in combination.

[0063] The present invention provides a method for preventing or treating cancer, comprising administering to an individual a compound according to any one of the above (1) to (6), a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a pharmaceutical composition containing same.

[0064] The method for preventing or treating cancer of the present invention may comprise administering a therapeutically effective amount of a compound according to any one of (1) to (6) above, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a pharmaceutical composition containing the same.

[0065] In the present invention, a "therapeutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and not to cause side effects, which may be determined by a person skilled in the art depending on factors including the patient's sex, age, weight, health condition, type of disease, severity, drug activity, drug sensitivity, administration method, administration time, administration route, excretion rate, treatment period, co-administered or co-used drugs, and other factors well known in the medical field. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, or may be administered singly or multiple times. Taking all of these factors into consideration, it is important to administer an amount that provides maximum effect at a minimum amount without side effects, which can be easily determined by a person skilled in the art.

[0066] Specifically, the effective amount of the pharmaceutical composition of the present invention varies depending on the age, sex, condition, weight, absorption rate, inactivation rate and excretion rate of the active ingredient in the body, type of disease, and concomitant drugs of the patient, and is generally 0.01 to 300 mg per kg of body weight, more specifically, about 0.1 to 100 mg, which may be administered daily or every other day, or may be administered in 1 to 3 divided doses per day. However, since the amount may be increased or decreased depending on the administration route, severity of obesity, sex, weight, age, etc., the above-mentioned dosage does not limit the scope of the present invention in any way.

[0067] In the present invention, the term "individual" refers to a subject in which a disease is to be prevented or treated, and more specifically, may refer to mammals such as humans, monkeys, mice, dogs, cats, horses, and cows, but is not limited thereto.

[0068] The present invention provides use of a compound according to any one of the above (1) to (6), a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a pharmaceutical composition containing the same, for the prevention or treatment of cancer.

[0069] The present invention provides use of a compound according to any one of (1) to (6), a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a pharmaceutical composition containing the same, for the manufacture of a medicament for the prophylaxis or treatment of cancer.

[0070] The items mentioned in each item of the present invention, i.e., the compound, the pharmaceutical composition containing it, the treatment method using it and its use, are similarly applied unless they are mutually contradictory. The other terms and abbreviations used in the present invention have their original meanings unless otherwise defined. Effect of the Invention

[0071] The present invention provides a compound represented by chemical formula I, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, which is a compound having a novel structure and has excellent cell permeability and in vivo stability.

[0072] The compound represented by chemical formula I of the present invention, its stereoisomer, its pharma- ceutically acceptable salt, its hydrate or solvate inhibits the activity of TEAD protein, and therefore can be useful in the prevention or treatment of cancer. [Brief description of the drawings]

[0073] [Figure 1] 1 and 2 show the results of evaluating the tumor growth inhibitory effect of the compound of the present invention using a xenograft mouse model in Experimental Example 4, and FIG. 2 shows the results on day 24 of FIG. [Diagram 2] 1 and 2 show the results of evaluating the tumor growth inhibitory effect of the compound of the present invention using a xenograft mouse model in Experimental Example 4, and FIG. 2 shows the results on day 24 of FIG. [Diagram 3] FIG. 3 shows the results of evaluation of changes in mouse body weight caused by administration of the compound of the present invention in Experimental Example 4. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0074] The present invention will be described in more detail below with reference to Preparations and Examples. However, it will be obvious to those skilled in the art that the following Preparations and Examples are merely illustrative of the present invention and should not be construed as limiting the scope of the present invention thereto.

[0075] Preparation of Compounds of Formula I The compounds of formula I of the present invention can be prepared by the following methods. Unless otherwise specified, the starting materials can be purchased or prepared by known methods. Any examples or use of exemplary terms provided in this application are merely illustrative of the present invention and are not intended to limit the scope of the present invention.

[0076] <Production Example> The compounds according to the present invention are synthesized by the methods described below, and can be derived by combining the following specific synthesis methods, which are common to those skilled in the art. Each compound used in the synthesis was purchased from an external vendor or synthesized using an organic synthesis method obvious to those skilled in the art, and was used without a separate purification step. The compounds in each example were synthesized using a 400 MHz 1 The results were confirmed by H-NMR (Agilent, 400-MR) and LC-Mass (Waters, SQD2) analyses.

[0077] In this specification, Cs2CO3 means cesium carbonate, CuI means copper(I) iodide, Cu2O means copper(I) oxide, DMSO means dimethylsulfoxide, NH4Cl means ammonium chloride, NMP means N-methyl-2-pyrrolidone, and Zn means zinc.

[0078] Production Example 1. Synthesis of N-(3-methyl-1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide (Compound 3)

[0079] [Step a-1] Synthesis of 3-methyl-5-nitro-1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridine: Alkylation of amines with alkyl halides 4-(trifluoromethyl)benzyl bromide (8.26 g, 34.54 mmol) was slowly added dropwise to a mixture of 3-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (5.10 g, 28.79 mmol), Cs2CO3 (14.07 g, 43.18 mmol) and dimethylformamide (144 mL), and the mixture was stirred at 70 °C for 4 hours. The temperature of the reaction mixture was then lowered to room temperature (15-25 °C), distilled water (300 mL) was added to terminate the reaction, and the obtained solid was filtered. The filtered solid was washed four times with distilled water (50 mL) and twice with diethyl ether (50 mL), and then dried in a vacuum oven at 60 °C for 2 hours. Then, without further purification, the target compound 3-methyl-5-nitro-1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridine (8.34 g, 86.43%) was obtained as a white solid.

[0080] [Step b-1] Synthesis of 3-methyl-1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-5-amine: Synthesis of primary amines by selective amination of nitro compounds NH4Cl (9.98 g, 186.56 mmol) and zinc dust (12.20 g, 186.56 mmol) were added dropwise to a mixture of 1,4-dioxane / distilled water (3:1 v / v, 120 mL) and 3-methyl-5-nitro-1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridine (8.34 g, 24.87 mmol) synthesized in the above [Step a-1] at 0°C, and the mixture was stirred at room temperature for 3 hours. Next, distilled water (100 mL) was gradually added while the container containing the reaction mixture was immersed in cooling water (0-5°C) to terminate the reaction. Next, the reaction mixture was cooled by immersing the container in the cooling water (0-5°C) and then cooled by immersing the container in the cooling water (0-5°C) and then cooled by immersing the container in the cooling water (0-5°C). Then ... TMThe reaction mixture was washed with distilled water (200 mL) and ethyl acetate (200 mL) while the filtrate was washed three times with brine (50 mL), then the organic layer was separated, dried over magnesium sulfate (MgSO4), and concentrated by drying under reduced pressure. The concentrated mixture was recrystallized using hexane and diethyl ether and filtered. The obtained solid compound was washed three times with hexane (20 mL), then dried in a vacuum oven at 60 °C for 2 h to obtain the target compound 3-methyl-1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-5-amine (4.81 g, 63.34%) as a pale yellowish white solid without further purification.

[0081] [Step c-1] Synthesis of N-(3-methyl-1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide (Compound 3): Synthesis of amide by reaction of acyl chloride and amine [ka] 3-Methyl-1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-5-amine (4.81 g, 15.75 mmol) and dichloromethane (80 mL) were stirred at 0°C under nitrogen (N2), and triethylamine (2.64 mL, 18.91 mmol) and acryloyl chloride (1.34 mL, 16.54 mmol) were added dropwise in that order, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then concentrated by drying under reduced pressure, and the concentrated mixture was separated by column chromatography (hexane:ethyl acetate=3:1) and purified by recrystallization (solvent: dichloromethane:hexane=1:1, v / v) to obtain the target compound. The product, N-(3-methyl-1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide (compound 3) (4.97 g, 87.79%) was obtained as a white solid.

[0082] The target compounds in Table 2 below were synthesized by substantially the same reaction as in Preparation Example 1, except that the starting compounds in Table 2 below corresponding to each target compound were used instead of 3-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine used in [Step a-1] of Preparation Example 1.

[0083] However, in Compound 21 and Compound 25, but-2-enoyl chloride was used in place of acryloyl chloride in Compound 21, and isobutyryl chloride was used in place of acryloyl chloride in Compound 25.

[0084] [Table 2-1] [Table 2-2]

[0085] In the above Preparation Example 1, instead of 3-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine and 4-(trifluoromethyl)benzyl bromide, the starting compounds and R A The target compounds in Table 3 below were synthesized by substantially the same reaction as in Production Example 1 above, except that -X was used.

[0086] However, in compound 23, but-2-enoyl chloride was used instead of acryloyl chloride.

[0087] [Table 3-1] [Table 3-2] [Table 3-3]

[0088] Preparation Example 2. Synthesis of N-(3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide (Compound 27)

[0089] [Step a-2] Synthesis of 3-methyl-5-nitro-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine: Suzuki coupling Alkylation reaction by coupling A mixture of 3-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (5.03 g, 28.40 mmol), 4-(trifluoromethyl)phenylboronic acid (13.18 g, 69.38 mmol), copper(II) acetate (Cu(OAc)2) (7.74 g, 42.60 mmol), triethylamine (11.88 mL, 85.21 mmol) and dichloromethane (120 mL) was refluxed at 110 °C for 2 h under nitrogen (N2). Then, the mixture was separated by filtration using Celite. TM The reaction mixture was filtered while being washed with methanol (50 mL), dichloromethane (100 mL) and ethyl acetate (100 mL). The filtrate was concentrated in vacuum, dissolved again in ethyl acetate (100 mL) and washed twice with distilled water (50 mL). The organic layer was separated, dried over magnesium sulfate (MgSO4), concentrated under reduced pressure, and then purified by column chromatography (hexane:ethyl acetate=2:1, v / v) to obtain the target compound, 3-methyl-5-nitro-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine (2.95 g, 32.34%), as a white solid.

[0090] [Step b-1] and [Step c-1] Synthesis of N-(3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide (Compound 27) [ka] The target compound, N-(3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide (compound 27), was synthesized by substantially the same reactions as in [step b-1] and [step c-1] of Preparation Example 1, except that 3-methyl-5-nitro-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine, an intermediate compound synthesized by an alkylation reaction using Suzuki coupling in [step a-2] of Preparation Example 2, was used instead of the alkylation reaction in [step a-1] of Preparation Example 1.

[0091] In [Step a-2] of the above-mentioned Production Example 2, instead of 3-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine and 4-(trifluoromethyl)phenylboronic acid, the starting compounds and R A The target compounds in Table 4 below were synthesized by substantially the same reaction as in Production Example 2 above, except that -B(OH)2 was used.

[0092] However, in compound 85, ethenesulfonyl chloride was used instead of acryloyl chloride, and in compound 88, but-2-enoyl chloride was used instead of acryloyl chloride.

[0093] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8]

[0094] Preparation Example 3: Synthesis of N-methyl-N-(3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)acrylamide (Compound 86) Compound 42 (N-(3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)acrylamide) (122.2 mg, 350 μmol) synthesized by [Step c-1] of Preparation Example 2 and N,N-dimethylformamide (1 mL) were stirred at room temperature, and cesium carbonate (172.7 mg, 530 μmol) and methyl iodide (32.9 μmL, 530 μmol) were added in sequence. The reaction mixture was stirred at room temperature for 3 hours, and then distilled water (10 mL) was added to terminate the reaction. The mixture was extracted twice with ethyl acetate (20 mL) and washed with distilled water (10 mL) and saturated brine (10 mL). The organic layer was separated, dried over magnesium sulfate, concentrated by drying under reduced pressure, and then purified by column chromatography (hexane:ethyl acetate=2:1, v / v) to obtain the target compound, N-methyl-N-(3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)acrylamide (91.3 mg, 72.4%) as a white solid.

[0095] The target compounds 90 to 92 in Table 5 were synthesized by substantially the same reaction as in Production Example 3, except that in Production Example 3, compound 66, compound 65 and compound 77 were used instead of compound 42 (N-(3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)acrylamide), respectively.

[0096] [Table 5]

[0097] Preparation Example 4. Synthesis of N-(3-methyl-1-(4-(trifluoromethyl)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide (Compound 24)

[0098] [Step a-3] Synthesis of (3-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-1-yl)(4-(trifluoromethyl)phenyl)methanone: Synthesis of amide by acylation reaction A mixture of 3-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (50 mg, 282.23 μmol), 4-(trifluoromethyl)benzoyl chloride (125.82 μL, 846.68 μmol), triethylamine (51.14 μL, 366.89 μmol) and dichloromethane (2 mL) was stirred under nitrogen (N2) at room temperature for 2 h, then treated with distilled water (5 mL), extracted twice with ethyl acetate (5 mL), washed with distilled water (5 mL) and saturated brine (5 mL). The organic layer was separated, dried over magnesium sulfate (MgSO4), concentrated by drying under reduced pressure, and then purified by column chromatography (hexane:ethyl acetate = 2:1, v / v) to obtain the target compound, (3-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-1-yl)(4-(trifluoromethyl)phenyl)methanone (61 mg, 61.88%) as a white solid.

[0099] [Step b-1] and [Step c-1] Synthesis of N-(3-methyl-1-(4-(trifluoromethyl)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide (Compound 24) [ka] The target compound, N-(3-methyl-1-(4-(trifluoromethyl)benzoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)acrylamide (compound 24), was synthesized by substantially the same reactions as those in [step b-1] and [step c-1] of Production Example 1, except that the compound (3-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-1-yl)(4-(trifluoromethyl)phenyl)methanone obtained in [step a-3] of Production Example 4 was used.

[0100] Preparation Example 5. Synthesis of N-(1-cyclohexyl-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide (Compound 57)

[0101] [Step a-4] Synthesis of 1-cyclohexyl-3-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine: using microwave The starting materials of [Step a-1] of Preparation Example 1, 3-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (200 mg, 112 μmol), potassium carbonate (K2CO3) (460 mg, 338 μmol), LiCl (47 mg, 112 μmol), and CuI (21 mg, 11 μmol) were mixed in a microwave synthesis vial. Dimethylformamide (2 mL) was added while argon (Ar) gas was purged into the vial, and cyclohexane bromide (170 μL, 1.35 mmol) was added dropwise. The reaction mixture was reacted in a microwave reactor (Biotage initiator+, Biotage's microwave synthesis device "initiator+") at 150 °C for 30 minutes. The reaction mixture was then treated with 1N NaOH aqueous solution and extracted twice with ethyl acetate (10 mL). The organic layer was dried over magnesium sulfate (MgSO4), and the mixture concentrated by drying under reduced pressure was purified by column chromatography (hexane:ethyl acetate=3:1, v / v) to obtain the target compound, 1-cyclohexyl-3-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (20 mg, 6.9%) as a white solid.

[0102] [Step b-1] and [Step c-1] Synthesis of N-(1-cyclohexyl-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide (Compound 57) [ka] The target compound, N-(1-cyclohexyl-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide (compound 57) (yield 34.4%) was synthesized by substantially the same reactions as those in [step b-1] and [step c-1] of Production Example 1, except that the compound 1-cyclohexyl-3-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine obtained in [step a-4] of Production Example 5 was used.

[0103] Preparation Example 6. Synthesis of N-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)acrylamide (Compound 19)

[0104] [Step e-1] 1-(4-(trifluoromethyl)benzyl)-1H-pyrazolo[ Synthesis of 3,4-d]pyrimidin-6-amines: Copper-catalyzed amination of halides In the above-mentioned [Step a-1] of Preparation Example 1, except that 6-chloro-1H-pyrazolo[3,4-d]pyrimidine was used instead of 3-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine, a compound 6-chloro-1-(4-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (31 mg, 99.14 μmol), Cu2O (70.93 mg, 495.71 μmol) and a reaction solvent (1 mL, NH4OH:NMP=1:1, v / v) were placed in a pressure vessel under nitrogen (N2) and reacted at 180° C. for 4 hours. Then, the mixture was cooled to 100° C. and cooled to 100° C. for 4 hours. TM The reaction mixture was filtered while being washed three times with distilled water (3 mL) and ethyl acetate (3 mL). The organic layer of the filtrate was separated and dried over magnesium sulfate (MgSO4), and the mixture concentrated by drying under reduced pressure was purified by column chromatography (ethyl acetate:hexane = 1:1, v / v) to obtain the target compound, 1-(4-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (27 mg, 92.87%) as a white solid.

[0105] [Step c-1] Synthesis of N-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)acrylamide [ka] The target compound, N-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)acrylamide, was synthesized by substantially the same reaction as in [Step c-1] of Production Example 1, except that the compound 1-(4-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine obtained in [Step e-1] of Production Example 6 was used.

[0106] Instead of 6-chloro-1H-pyrazolo[3,4-d]pyrimidine and 4-(trifluoromethyl)benzyl bromide in Preparation Example 6, the starting compounds and R A -X or R A The target compounds in Table 6 below were synthesized by substantially the same reaction as in Preparation Example 6 above, except that -B(OH)2 was used.

[0107] However, in compound 1, ethenesulfonyl chloride was used instead of acryloyl chloride.

[0108] [Table 6-1] [Table 6-2]

[0109] The analytical results of the compounds of the examples of the present application are as shown in Table 7 below:

[0110] [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8] [Table 7-9] [Table 7-10] [Table 7-11] [Table 7-12] [Table 7-13] [Table 7-14]

[0111] <Experimental Example> Experimental example 1. TEAD-responsive element (TRE) reporter assay Activation of the TEAD response element (TRE) induces stable expression of the TEAD reporter gene, which expresses firefly luciferase. The MCF-7 cell line injected as described above was obtained from BPS biosciences (#60618). The cell line was cultured at 37°C and 5% CO2 in a cell-specific culture medium (BPS biosciences) supplemented with 10 μg / mL insulin (Sigma).

[0112] The cells were dispensed into a 96-well plate, and 24 hours later, the compound of the embodiment or the vehicle (final 1% DMSO) was diluted in serum-free culture medium to a final concentration of 0.2 μM and treated. 24 hours after the treatment, 100 μL of luciferase assay working solution (ONE-Step Luciferase assay reagent; BPS bioscience) containing a luciferase substrate was added to each well, and the wells were placed on a shaker for 15 minutes to mix well. The luminescence level of luciferase expressed by TEAD activation was then measured using a microplate reader (TECAN). The luminescence level of the vehicle group (solvent-treated control group) was set as 100%, and the relative luciferase activity (%) was calculated, and the results are shown in Table 8 below.

[0113] [Table 8-1] [Table 8-2]

[0114] From Table 8, it was confirmed that the compound according to the present invention can effectively suppress the transcription of luciferase by TEAD, and thus can effectively inhibit the expression of genes dependent on TEAD activity. That is, it was confirmed that the compound according to the present invention can be effectively used for the prevention or treatment of cancer by inhibiting the expression of these genes.

[0115] Experimental Example 2. Evaluation of palmitoylation of TEAD proteins Recombinant GST-TEAD1 protein (209-426a.a.) was added with each compound at a concentration of 5μM and incubated for 15 minutes. After incubation, 3μM alkyne palmitoyl-CoA (Cayman Chemical) and 50mM MES buffer (pH6.4) were added for autopalmitoylation of the protein, and the mixture was incubated for 30 minutes, after which 1% SDS (sodium dodecyle sulfate) was added to terminate the reaction. Next, biotinylation was performed using the CLICK (Click chemistry tools) reaction, and the protein solution was concentrated to prepare samples.

[0116] Sample analysis was performed using SDS-PAGE and streptavidin HRP (Thermo Scientific). Results were quantified using Image J (NIH), and the band intensity obtained in the streptavidin blot was analyzed for palmitoylation inhibition ability based on the control group (DMSO). Normalization of each sample was performed using anti-GST (91G1) (Cell signaling) antibody.

[0117] [Table 9-1] [Table 9-2]

[0118] As can be seen from Table 9, the compounds according to the present invention inhibit the autopalmitoylation of TEAD protein and inhibit the interaction between YAP / TAZ and TEAD, and therefore are useful for the prevention or treatment of cancer.

[0119] Experimental Example 3. Evaluation of inhibition of cancer cell proliferation NF2-deficient mesothelioma cell line NCI-H226 was purchased from ATCC (#CRL-5826). NCI-H226 cells were cultured in RRPMI medium (ATCC) containing penicillin (100 units / mL), streptomycin (100 μg / mL) and 10% fetal bovine serum (FBS) at 37°C and 5% CO2.

[0120] The NCI-H226 cells were dispensed into a 96-well plate, and after 24 hours, all the cell culture medium was removed. Each compound or vehicle (fenil 1% DMSO) corresponding to a certain concentration range (0.01, 0.05, 0.1, 0.5, 1, 5, 10 μM) was diluted with culture medium containing 2% FBS, and 100 μL was applied to each well and cultured under 37 ° C and 5% CO2 conditions. Five days after the treatment, the cells were treated with CellTiter-Glo (registered trademark) 2.0 Reagent (Promega) in the same amount as the culture medium to measure cell proliferation, placed on a shaker for 2 minutes to mix well, and cultured at room temperature for 10 minutes to stabilize the luminescence signal. Then, the luminescence signal was measured using a microplate reader (TECAN) to measure ATP by intracellular luciferase reaction. The maximum concentration (GI 50 ) values ​​were derived using the SoftMax Pro5.4.1 program, and the results are shown in Table 10 below.

[0121] [Table 10]

[0122] As can be seen from Table 10, the compound of the present invention reduced the proliferation of cancer cells by 50% at a very low concentration. In other words, it was confirmed that the compound of the present invention significantly inhibits the proliferation of cancer cells and can be effectively used for the prevention or treatment of cancer.

[0123] Experimental Example 4. Evaluation of anti-cancer effect using NF2-deficient mesothelioma xenograft mouse model (in vivo efficacy) To confirm the anticancer effect of the compound of the present application in animals, the tumor growth inhibitory ability was evaluated using an NF2-deficient mesothelioma xenograft mouse model. NCI-H226 cells for inoculation were cultured in RRPMI medium (ATCC) containing penicillin (100 units / mL), streptomycin (100 μg / mL) and 10% FBS at 37°C and 5% CO2. The cultured cells were inoculated into 5-week-old BALB / c nude (Charles River Japan) mice at 10 cells / mouse using PBS (Gibco) buffer before inoculation. 7 The cells were prepared and transplanted by subcutaneous inoculation.

[0124] The size of the engrafted tumor is 60-80 mm 3 When the tumor growth rate reached 100%, the experimental groups were divided into a vehicle group (7 mice) and each drug-administered group (7 mice). The drug-administered groups were orally administered a certain dose (5 or 15 mpk (mg per kg)) of each compound (compounds 42, 86, and 90) once a day for 24 days. During administration, tumor size was measured to evaluate the anticancer effect, and body weight was also measured to confirm the toxic reaction caused by the drug. Statistical processing for evaluating tumor growth inhibition ability was performed using Graphpad. The analysis was performed using the Prism9 program, and the results are shown in Figures 1 to 3.

[0125] As can be seen from Figures 1 to 3, the compound of the present application not only exhibits excellent tumor-suppressing activity, but also does not induce weight loss or death in test animals, and is a safe compound with no drug toxicity, and therefore can be usefully used in the prevention or treatment of cancer.

[0126] Although the present invention has been described with reference to an embodiment, it will be understood by those skilled in the art that various modifications and variations of the present invention may be made without departing from the spirit and scope of the present invention as defined by the following claims. The practical scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A compound represented by the following chemical formula I, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or a solvate thereof: 【Chemistry 1】 In the above formula I, L １ is a single bond, -(C1-C6 alkylene)- or -(C=O)-; R １ is H, C1-C3 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 6- to 14-membered aryl, or 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; The R １ One or more H of C1-C3 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 6- to 14-membered aryl, or 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring are each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, CF ２ H, C.F. ３ , -OCF ３ , -OH, -(C1-C3 alkylene)-OH, -(C=O)Rp, -COORq, -CN, -(C1-C3 alkylene)-CN, -NRxRy, -(C1-C3 alkylene)-NRsRt, or halogen, where Rp, Rq, Rs, Rt, Rx, and Ry are each independently H or C1-C6 alkyl; Z １ and Z ２ are each independently N or CRa; Ra is H or C1-C6 alkoxy; Q １ and Q. ２ are each independently N, CH or CRb; Q １ and Q. ２ At least one of is CRb; Rb is 【Chemistry 2】 and L ２ is -(C=O)- or S(=O) ２ and R ２ , R ３ and R ５ are each independently H or C1-C6 alkyl; 【Chemistry 3】 is X−Y or X═Y; 【Chemistry 4】 is X-Y, X and Y are each -CH ２ - and 【Chemistry 5】 When X=Y, X is -CH- or N and Y is -CR ４ or N; R ４ is H, C1-C6 alkyl or halogen; Z １ , Z ２ , Q １ and Q. ２ But neither of them is N, 【Chemistry 6】 When X=Y, one or more of X and Y is N.

2. In the above formula I, L １ is a single bond, -(C1-C6 alkylene)- or -(C=O)-; R １ is H, C1-C3 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 6- to 14-membered aryl, or 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; The R １ One or more H of C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 6- to 14-membered aryl, or 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring are each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, CF ２ H, C.F. ３ , -OCF ３ , -OH, -CN, -NRxRy or halogen, where Rx and Ry are each independently H or C1-C6 alkyl; Z １ is N or CH; Z ２ is N or CRa; Ra is H or C1-C6 alkoxy; Q １ and Q. ２ are each independently N, CH or CRb; Q １ and Q. ２ At least one of is CRb; Rb is 【Chemistry 7】 and R ２ and R ５ are each independently H or C1-C6 alkyl; R ３ is C1-C6 alkyl; 【Chemistry 8】 is X−Y or X═Y; 【Chemistry 9】 is X-Y, X and Y are -CH ２ - and 【Chemistry 10】 When X=Y, X is -CH- or N and Y is -CR ４ or N; R ４ is H, C1-C6 alkyl or halogen; Z １ , Z ２ , Q １ and Q. ２ But neither of them is N, 【Chemistry 11】 When X=Y, one of X and Y is N; A compound of formula I according to claim 1, its stereoisomer, its pharma- ceutically acceptable salt, its hydrate or solvate.

3. In the above formula I, L １ is a single bond, -(C1-C6 alkylene)- or -(C=O)-; R １ is H, methoxy, cyclopentanyl, cyclohexanyl, cyclohexenyl, phenyl, pyridinyl, pyrazolyl, pyrimidinyl or thiophenyl, The R １ One or more H in methoxy, cyclohexanyl, cyclohexenyl, phenyl, pyridinyl, pyrazolyl, pyrimidinyl, or thiophenyl is each independently methyl, isopropyl, tert-butyl, sec-butyl, methoxy, isobutoxy, cyclohexyl, CF ２ H, C.F. ３ , -OCF ３ , -OH, -CN, NH ２ or halogen substituted or unsubstituted; Z １ is N or CH; Z ２ is N or CRa; Ra is H or methoxy; Q １ is N, CH or CRb １ And Q ２ is N, CH or CRb ２ And Q １ and Q. ２ At least one of the following is CRb １ or CRb ２ and Rb １ teeth, 【Chemistry 12】 and Rb ２ teeth, 【Chemistry 13】 and R ２ is H or methyl; R ３ is isopropyl; 【Chemistry 14】 is X−Y or X═Y; 【Chemistry 15】 is X-Y, X and Y are -CH ２ - and 【Chemistry 16】 When X=Y, X is -CH- or N and Y is -CR ４ or N; R ４ is H, methyl or halogen; Z １ , Z ２ , Q １ and Q. ２ But neither of them is N, 【Chemistry 17】 When X=Y, one of X and Y is N; A compound of formula I according to claim 1, its stereoisomer, its pharma- ceutically acceptable salt, its hydrate or solvate.

4. The compound represented by formula I is represented by formula II: A compound of formula I according to claim 1, its stereoisomer, its pharma- ceutically acceptable salt, its hydrate or solvate: 【Chemistry 18】 In the above formula II, L １ is a single bond or -(C1-C6 alkylene)-; R １ is H, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 6- to 14-membered aryl, 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of N, O and S; The R １ One or more H of C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 6- to 14-membered aryl, or 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring are Each independently is C1-C6 alkyl, C1-C6 alkoxy, CF ２ H, C.F. ３ , -OCF ３ , -OH, -CN, -NRxRy or halogen, where Rx and Ry are each independently H or C1-C6 alkyl; Z １ and Z ２ are each independently N or CH; Q １ and Q. ２ are each independently N, CH or CRb; Q １ and Q. ２ At least one of is CRb; Rb is 【Chemistry 19】 and R ４ is H, C1-C6 alkyl or halogen.

5. The compound represented by formula I is represented by formula III: A compound of formula I according to claim 1, its stereoisomer, its pharma- ceutically acceptable salt, its hydrate or solvate: 【Chemistry 20】 In the above formula III, L １ is a single bond, -(C1-C6 alkylene)- or -(C=O)-; R １ is H, C3-C8 cycloalkyl, 6- to 14-membered aryl, or 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of N, O, and S; The R １ one or more H in the C3-C8 cycloalkyl, 6- to 14-membered aryl, or 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring are each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, CF ２ H, C.F. ３ , -OCF ３ or halogen substituted or unsubstituted, Z １ is N or CH; Z ２ is N or CRa; Ra is H or C1-C6 alkoxy; Q １ is N or CH; Q ２ is CRb; Rb is 【Chemistry 21】 and R ２ is H or C1-C6 alkyl; R ３ is C1-C6 alkyl; R ４ is H, C1-C6 alkyl or halogen; Z １ , Z ２ , Q １ and Q. ２ At least one of is N.

6. The compound represented by formula I is at least one selected from the group consisting of the compounds shown in the following table: A compound of formula I according to claim 1, its stereoisomer, its pharma- ceutically acceptable salt, its hydrate or solvate: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or a solvate thereof as an active ingredient.

8. The pharmaceutical composition of claim 7 , wherein the pharmaceutical composition is for the prevention or treatment of cancer.

9. A method for preventing or treating cancer, comprising administering to an individual a compound according to any one of claims 1 to 6, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or a solvate thereof.

10. Use of a compound according to any one of claims 1 to 6, its stereoisomer, its pharma- ceutically acceptable salt, its hydrate or solvate for the prevention or treatment of cancer.

11. Use of a compound according to any one of claims 1 to 6, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or a solvate thereof for the manufacture of a medicament for the prevention or treatment of cancer.

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