WO2020096416A1 - Compound inhibiting yap-tead binding, and pharmaceutical composition for preventing or treating cancer, comprising compound as active ingredient - Google Patents

Abstract

The present invention relates to a compound which inhibits the binding of Yes associated protein (YAP) and transcriptional enhancer associate domain (TEAD), a prodrug of same, a hydrate of same, a solvate of same or a pharmaceutically acceptable salt of same, and a composition comprising same as an active ingredient, the compound according to the present invention being able to be applied as an inhibitor which can directly inhibit YAP-TEAD binding in the Hippo pathway which plays a crucial role in the occurrence of cancer.

Description

A compound for inhibiting YAP-TEAD binding and a pharmaceutical composition for preventing or treating cancer containing it as an active ingredient

The present invention relates to a compound that inhibits YAP (Yes associated protein) -TEAD (transcriptional enhancer associate domain) binding, a prodrug thereof, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, and a cancer containing it as an active ingredient It relates to a pharmaceutical composition for the prevention or treatment of.

The latest anti-cancer drugs developed to date have been developed mainly as substances that selectively inhibit the function of proteins that are important in the development and growth of cancer cells. For example, among the many tyrosine kinase receptors (RTKs) that play a very important role in cancer cell growth, the development of inhibitors for epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VGFR) is a very encouraging clinical trial. Results were followed. Nevertheless, many signaling systems are still involved in the development and growth of cancer cells, of which many have yet to develop successful inhibitors. If a novel inhibitor capable of regulating such a cell signaling system that has not been developed is developed, it is expected that the therapeutic effect will be improved for patients who cannot be treated with anti-cancer drugs to date.

'Hippo signaling', known as a signaling system that is very important for the development and growth of cancer cells, is a signaling pathway that inhibits growth by regulating the cell cycle in cells (e.g., p53 pathway, APC (adenomatous polyposis coli) gene, It is one of the signaling pathways involving NF2 (neurofibromatosis type 2) gene, etc., and was first discovered in Drosophila in 1995, and research has been conducted so far (Genes Dev, Vol. 9; pp.534-546). The Hippo Pathway, also known as the 'Salvador-Warts-Hippo pathway', is an important signaling pathway and cell proliferation process that regulates cell proliferation and cell death and determines organ size.

The hippo pathway has recently emerged as a powerful tumor suppressor in mammalian cells since it was discovered 10 years ago as a signaling system that regulates tissue size in Drosophila and Mouse. Did. The hippo pathway consists of the Kinase Cascade of MST1 / 2-LATS1 / 2 and is inhibited by phosphorylation of the oncogene YAP / TAZ Transcriptional Coactivator. When the hippo pathway is inhibited, YAP / TAZ is activated and plays an important role in the development, metastasis, drug resistance and recurrence of various carcinomas, including cell cycle and growth, stem cell and regenerative medicine, by binding to TEAD transcriptional regulatory factors.

That is, when hypo-signal signaling is activated, the Mammalian Sterile 20-like (MST) kinase complexes with Salvador Family WW Domain Containing Protein 1 (SAV1) to phosphorylate large tumor suppressor (LATS) kinase, and the LATS kinase and MOB1 cofactor are subordinates. Phosphorylates the target YAP. Phosphorylated YAP binds to 14-3-3 protein and breaks down in the cytoplasm. As YAP breaks down, binding to the TEAD family in the nucleus is inhibited. In other words, when hypo-signaling is activated, YAP is suppressed, and gene expression binding to YAP is suppressed, thereby limiting the growth of cells and tissues. On the other hand, the inactivation of hypo-signaling, YAP enters the nucleus, forms a complex with the transcription factor TEAD, and causes gene expression to cause growth factors such as CTGF (connective tissue growth factor), Cry61 (cystein-rich 61), and FGF (fibroblast growth factor). It promotes the growth of cells and inhibits apoptosis through the secretion of (Genes Dev, Vol.26; pp.1300-1305). In the development and growth of cancer cells, YAP protein enters the nucleus and combines with the transcription factor TEAD protein to form a transcriptional supplement to produce various growth factors such as CTGF and FGF, which are reported to promote the growth and growth of cancer cells. Therefore, it can be seen that it is very important to prevent the function of the TEAD protein from being excessively activated (Cancer Res. 2007; 67: 9055-65). In prostate cancer, for example, high TEAD1 overexpression is associated with poor prognosis in patients (Br J Cancer 2008; 99: 1849-58), in addition, basal-like breast cancer, tubal cancer ( It has been reported to be involved in several human cancers, such as fallopian tube carcinoma, and germ cell tumor (PLoS One 2012; 7: e45498).

The hippo pathway can be involved in the proliferation of cancer cells and tumors, as well as the expression of resistance to chemotheraphy, the existing first-line treatment, and is considered a very important mechanism in cancer treatment. Recent studies have shown that transcription of YAP-TEAD plays a very important role in lung cancer develop and resistance to EGFR-TKI (epidermal growth factor receptor-tyrosine kinase inhibitor) (Biochem. Biophys. Res. Commun. Vol. 491 (2017), PP.493-499; Oncotarget Vol.9 (2018), pp.4637-4646).

In addition, there are important research reports that among the transcription targets by the YAP-TEAD protein, there is an important protein capable of regulating the immune environment in cancer tissue, PD-L1 (Programmed death-ligand 1) (Cancer Res. 2018 Mar 15; 78 (6): 1457-1470; Oncotarget. 2017 Dec 9; 8 (70): 114576-114587). According to the research results of these papers, it is reported that YAP-TEAD as well as TAZ-TEAD transcription complex plays a key role in over-expression of PD-L1, one of the most important proteins utilized by cancer cells in immune evasion by cancer cells. Became. In addition, there have been a number of reports on the immunomodulation of hippocampal signaling. As an example, it has recently been reported as an important signal pathway that modulates the function of CD8 + Dendritic cells (Nature 2018, Jun, 558 (7708)). CD8 + Dendritic cells are cells known to play an important role in anti-tumor immunity among dendritic cells, and it was experimentally confirmed that anti-tumor immunity is greatly reduced when hypotonic signaling is inactivated. In addition, when lactate increases due to increased glycolysis in human lung cancer cells, transcription of TAZ-TEAD is activated, thereby significantly increasing the expression of PD-L1 and G protein-coupled receptor 81 (GPR81). There are reports (Oncogene 2017 Oct 19; 36). It can be seen that metabolic changes in the majority of cancer tissues are an inevitable process, and the result of this study is an important result of close linkage of immune function, and TEAD protein transcription is very important in this process. Lastly, there is an important report that YAP-TEAD protein increases Treg cells (regulatory T cells), which are key elements of immune evasion mechanism in cancer tissues (Cancer discovry 2018, Jun 15).

According to various reports, it can be seen that the TEAD protein is a transcription factor that plays a very important role in the immune evasion mechanism in cancer tissue.

The important roles of the TEAD protein in the above mentioned cancer cell development, growth, and immune evasion mechanisms are also clinically proven. Clinically, it has been reported that YAP-TEAD and TAZ-TEAD transcription proteins are correlated with cancer prognosis and prognosis. As a result of clinical sample analysis of cancer patients, YAP (Yes associated protein), TAZ, which are major factors of the hippo pathway, have been reported. (transcriptional coactivator with PDZ-binding motif), TEAD (transcriptional enhancer associate domain), etc. are over-expressed, and it has been reported that their expression level and survival time in cancer patients show statistical significance (Sci. Rep. Vol. 8 ( 2018), 271 .; Oncotarget Vol. 9 (2018), pp.4637-4646).

Therefore, it is required to develop an inhibitor that can directly inhibit YAP-TEAD binding in the hippo pathway, which plays a key role in the process of cancer development, and through this, it is judged that it is possible to develop an anticancer agent with high therapeutic effect and low toxicity. (Trends in biochem. Sci. 2017, 42, 862-872 .; Int. J. of Mol. Sci. 2016, 17, 138).

Accordingly, the present inventors have discovered that the compound of a specific structure directly inhibits the TEAD protein, a transcription factor that is the core of hippo signaling, which is known as a signal system very important for the development and growth of cancer cells, and completed the present invention.

One object of the present invention is to provide a compound that inhibits YAP-TEAD binding, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is a pharmaceutical composition for preventing or treating cancer containing the compound that inhibits the YAP-TEAD binding, its prodrug, its hydrate, its solvate or its pharmaceutically acceptable salt as an active ingredient. Is to provide.

Another object of the present invention is to provide a YAP / TAZ-TEAD inhibitor composition containing the compound, its prodrug, its hydrate, its solvate or its salt as an active ingredient.

Another object of the present invention is to provide a health functional food composition for preventing or improving cancer containing the compound, its prodrug, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object, there is provided a compound represented by Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, which effectively inhibits YAP-TEAD binding:

[Formula 1]

(In the formula 1,

R ^a is hydrogen or -LR ₃ ;

R ₁ is hydrogen or-(CH ₂ ) _n -R;

R is C1-C10 alkoxy, C6-C20 aryloxy, hydroxy, C1-C10 alkylcarbonyloxy, C6-C20 arylcarbonyloxy, cyano, halogen, nitro, C1-C10 alkylsulfanyl, C6-C20 aryl Sulfanyl, sulfanyl, -NR ^a1 R ^a2 , C1-C10alkoxyC1-C10alkyl, C6-C20aryloxyC1-C10alkyl, C1-C10alkoxyC1-C10alkoxy, C1-C10alkoxyC1-C10alkoxyC1- C10 alkyl, C1-C10 alkylsulfonyl, C6-C20 arylsulfonyl, C1-C10 alkyl C6-C20 arylsulfonyl, C6-C20 aryl C1-C10 alkylsulfonyl, sulfo, C6-C20 aryl, C3-C20 cyclo Alkyl, carbamoyl, C1-C10 alkylaminocarbonyl, C6-C20 arylaminocarbonyl, sulfamoyl, C1-C10 alkylaminosulfonyl, C6-C20 arylaminosulfonyl, C1-C10 alkylcarbonyl, C6-C20 Arylcarbonyl, C1-C10 alkoxycarbonyl, C6-C20 aryloxycarbonyl, carboxyl, formyl, C2-C20 heteroaryl or C3-C20 heterocycloalkyl, wherein R aryl, heteroaryl and heterocycloalkyl is C1 -C10 alkyl, halogen, nitro, cyano, hydroxyl , C1-C10alkoxy, C6-C20aryloxy, C1-C10alkylsulfanyl, haloC1-C10alkylsulfanyl, C6-C20arylsulfanyl, diC1-C10alkylamino, C1-C10alkylsulfonyl, C6- C20 arylsulfonyl, C1-C10 alkyl C6-C20 arylsulfonyl, C6-C20 arylC1-C10 alkylsulfonyl, C3-C20 cycloalkyl, carboxyl, sulfo, formyl, carbamoyl, sulfamoyl, amino, C1-C10 Alkylcarbonyl, C6-C20 arylcarbonyl, C1-C10 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C1-C10 alkylcarbonyloxy, C6-C20 arylcarbonyloxy, C2-C20 heteroaryl and C3- May be further substituted with one or more substituents selected from the group consisting of C20 heterocycloalkyl;

R ^a1 and R ^a2 are each independently hydrogen, C1-C10 alkyl, C1-C10 alkylsulfonyl, C6-C20 arylsulfonyl, C1-C10 alkyl C6-C20 arylsulfonyl, C6-C20 arylC1-C10 alkylsulfur Phenyl, sulfo, C6-C20 aryl, C3-C20 cycloalkyl or sulfamoyl;

n is an integer from 1 to 10;

R ₂ is hydrogen, C1-C10 alkyl, C1-C10 alkoxy C1-C10 alkyl, C3-C20 cycloalkyl, C3-C20 cycloalkyloxyC1-C10 alkyl, C6-C20 aryl or C6-C20 aryloxyC1-C10 alkyl ego;

X is CH or N;

Z is -CH ₂ -or -CO-;

L is -SO _2- , -SO ₂ -L'-, -NHCO-, -CONH-, C1-C10alkylene or -CO-;

이고;L 'is -NH- or

ego;

L _a is C1-C10 alkylene;

n1 is an integer from 1 to 3;

m1 is an integer of 0 or 1;

However, when (i) X is CH, L is -SO ₂ -NH-,

(ii) when L is C1-C10 alkylene, R ₃ is C1-C10 alkyl, C1-C10 alkoxy or C6-C20 aryloxy is excluded;

R ₃ is C1-C10 alkyl, C1-C10 alkoxy, C6-C20 aryloxy, C3-C20 heterocycloalkyl, C6-C20 aryl or C2-C20 heteroaryl, and heterocycloalkyl, aryl and heteroaryl of R ₃ Silver C1-C10 alkyl, halogen, halo C1-C10 alkyl, nitro, cyano, C1-C10 alkylcarbonylamino, C6-C20 arylcarbonylamino, amino, C1-C10alkoxy, haloC1-C10alkoxy, C1- C10alkoxyC1-C10alkoxy, C6-C20aryloxy, hydroxy, C1-C10alkylcarbonyl, haloC1-C10alkylcarbonyl, C6-C20arylcarbonyl, C1-C10alkoxycarbonyl, C6-C20aryloxy Carbonyl, carboxyl, formyl, sulfanyl, C1-C10 alkylsulfanyl, C6-C20 arylsulfanyl, diC1-C10 alkylamino C1-C10 alkoxy, dihydroxyaminosulfanyl, C1-C10 alkylsulfonyl, C6 -C20 arylsulfonyl, C1-C10 alkyl C6-C20 arylsulfonyl, C6-C20 arylC1-C10 alkylsulfonyl, sulfo, carbamoyl, C1-C10 alkylaminocarbonyl, C6-C20 arylaminocarbonyl, sulfa Moyl, C1-C10 alkylaminosulfonyl, At least one substituent selected from the group consisting of C6-C20 arylaminosulfonyl, C6-C20 aryl, C2-C20 heteroaryl, C1-C10 alkylcarbonyloxy, C6-C20 arylcarbonyloxy and C3-C20 heterocycloalkyl. Can be further substituted with;

R ₄ is halogen, halo C1-C10 alkyl, cyano, C1-C10 alkyl, C6-C20 aryl, C2-C20 heteroaryl, C1-C10 alkoxy, C6-C20 aryloxy, C2-C20 heteroaryloxy, halo C1 -C10 alkoxy, hydroxy, amino or aminoC1-C10 alkyl;

d is an integer from 0 to 5, and when d is an integer of 2 or more, R ₄ may be the same or different from each other;

a and b are each independently an integer of 0, 1 or 2, and a + b is an integer of 1, 2 or 3;

The heteroaryl and heterocycloalkyl include one or more heteroatoms selected from nitrogen, oxygen and sulfur.)

In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound of Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, a YAP / TAZ-TEAD inhibitor composition containing the compound of Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient is provided.

In addition, it provides a health functional food composition for preventing or improving cancer containing the compound of Formula 1, its prodrug, its hydrate, its solvate or a pharmaceutically acceptable salt thereof as an active ingredient.

The compound of Formula 1 according to the present invention can significantly inhibit the proliferation and growth of cancer cells by efficiently inhibiting YAP-TEAD binding in the hippo pathway, which is known as a signal system very important for the generation and growth of cancer cells, and can significantly inhibit the growth and growth of cancer cells. It has low toxicity against. Therefore, the compound of Formula 1 according to the present invention can be usefully used as an active ingredient in a pharmaceutical composition for treating or preventing cancer.

Figure 1-Size and number of colorectal cancers in each group in the AOM / DSS model (Number of experimental animals in each experimental group = 3) [initial point = number of colon cancers just before drug treatment]

Figure 2-Weight change during drug treatment period in AOM / DSS model

Figure 3-Results of measuring the degree of change in Treg cells through intestinal tissue FACS analysis in the AOM / DSS model

Hereinafter, the present invention will be described in more detail. Unless otherwise defined in the technical terms and scientific terms used at this time, those skilled in the art to which this invention belongs have meanings that are commonly understood, and the following description unnecessarily obscures the subject matter of the present invention. Descriptions of possible known functions and configurations are omitted.

The following terms used in the present specification are defined as follows, but they are merely exemplary and are not intended to limit the present invention, applications, or uses.

The terms "substituent", "radical", "group", "moiety", and "fragment" can be used interchangeably herein.

The term "C _A -C _B " in the present specification means "the carbon number is A or more and B or less".

The term "alkyl" as used herein refers to a monovalent straight chain or ground saturated hydrocarbon radical consisting only of carbon and hydrogen atoms. The alkyl may have 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Examples of the alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like.

The term "cycloalkyl" herein is a monovalent saturated or unsaturated carbocyclic radical consisting of one or more rings, and is not aromatic. The cycloalkyl can be monocyclic or a fused, spiro, or bridged bicyclic ring system. The cycloalkyl may have 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 7 carbon atoms. Specifically, the monocyclic cycloalkyl ring contains 3 to 10 carbon atoms in the ring, preferably 3 to 7 carbon atoms. The bicyclic cycloalkyl ring contains 7 to 17 carbon atoms in the ring, preferably 7 to 12 carbon atoms. Preferred bicyclic cycloalkyl rings include those in which a 4-, 5-, 6- or 7-membered ring is fused to a 5-, 6-, or 7-membered ring. Specific examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "aryl" as used herein is an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, single or fused ring containing suitably 4 to 7, preferably 5 or 6 ring atoms in each ring. It includes a system, and includes a form in which a plurality of aryls are connected by a single bond. Specific examples include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, and the like.

The term "heteroaryl" as used herein refers to an aryl group having 1 to 4 heteroatoms selected from N, O and S as aromatic ring skeleton atoms, and the remaining aromatic ring skeleton atoms being carbon, single or fused rings. System, and may be partially saturated. In addition, heteroaryl in the present specification includes a form in which one or more heteroaryls are connected by a single bond. Examples of the heteroaryl group include pyrrole, quinoline, isoquinoline, pyridine, pyrimidine, oxazole, thiazole, pyrazole, thiadiazole, triazole, imidazole, benzoimidazole, isooxazole, benzoisooxazole, Thiophene, benzothiophene, furan, benzofuran, imidazothiazole, benzothiadiazole, monovalent radicals of aromatic heterocycles such as benzoxadiazole, but is not limited thereto.

The term "heterocycloalkyl" as used herein is a monovalent radical of a non-aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S, wherein the non-aromatic heterocycle is a saturated or unsaturated monocycle, It includes both polycyclic or spirocyclic forms, can be bonded through a heteroatom or a carbon atom, and nitrogen, carbon, oxygen, or sulfur atoms in a non-aromatic heterocyclic radical can be oxidized in various oxidation states, depending on the case. Further, the nitrogen atom in the non-aromatic heterocyclic radical may be quaternized depending on the case. Examples of such heterocycloalkyl radicals are aziridine, pyrrolidine, pyrrolidinone, azetidine, piperidine, tetrahydropyridine, piperazine, morpholine, thiomorpholine, 4,5,6,7-tetrahydro Benzo [b] thiophene, 2,3-dihydrobenzofuran, benzo [d] [1,3] dioxole, 3,4-dihydro-2H-chromene, naphthalene-2 (1H) -one, 2H -Chromen-2-one, 2,3-dihydrobenzo [b] [1,4] dioxine, benzo [d] oxazole-2 (3H) -one, pyrimidine-2,4 (1H, 3H) -Dione, quinazolin-2,4 (1H, 3H) -dione, benzo [cd] indole-2 (1H) -one, 3-azabicyclo [3.1.0] hexane, octahydropyrrolo [3,4 a monovalent radical of a non-aromatic heterocycle such as -c] pyrrole, 2,7-diazaspiro [4.4] nonane, 2-azaspiro [4.4] nonane, and the like.

The term "alkoxy" as used herein is an -O-alkyl radical, and may have 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms. Here, 'alkyl' is as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, and the like.

The term "aryloxy" as used herein refers to the -O-aryl radical, where 'aryl' is as defined above. Examples of such aryloxy radicals include, but are not limited to, phenoxy and the like.

The term "halo" or "halogen" as used herein refers to a halogen group element, and includes, for example, fluoro, chloro, bromo and iodo.

The term "haloalkyl" or "haloalkoxy" as used herein refers to an alkyl or alkoxy group in which one or more hydrogen atoms are replaced by halogen atoms, where alkyl and halogen are as defined above. For example, haloalkyl includes fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, perfluoroethyl and the like, haloalkoxy is fluoromethoxy, difluorome And methoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, and perfluoroethoxy.

The term "hydroxy" as used herein means -OH, "amino" means -NH ₂ , "nitro" means -NO ₂ , "cyano" means -CN, and "carboxyl""Means-COOH," formyl "means -COH," sulfanyl (or mercapto) "means -SH," sulfo "means -SO ₃ H," sulfamoyl " Means -SO ₂ NH ₂ and "carbamoyl" means -CONH ₂ .

The term "alkylsulfanyl" as used herein refers to the -S-alkyl radical, where 'alkyl' is as defined above. Examples of such alkylsulfanyl radicals include, but are not limited to, methylsulfanyl, ethylsulfanyl, and the like.

The term "arylsulfanyl" used herein refers to the -S-aryl radical, where 'aryl' is as defined above. Examples of such arylsulfanyl radicals include, but are not limited to, phenylsulfanyl, naphthylsulfanyl, and the like.

The term "alkylsulfonyl" as used herein refers to a -SO ₂ -alkyl radical, where 'alkyl' is as defined above. Examples of such alkylsulfonyl radicals include, but are not limited to, methylsulfonyl, ethylsulfonyl, and the like.

The term "alkylamino" as used herein refers to an amino radical in which one or two alkyls are substituted, and specific examples include methylamino (-NHMe), dimethylamino (-NMe ₂ ), ethylamino (-NHEt), di Ethyl amino (-NEt ₂ ) and the like, but is not limited thereto.

The term "arylamino" used herein refers to an amino radical in which one or two aryls are substituted, and specific examples include, but are not limited to, phenylamino (-NHPh), diphenylamino (-NPh ₂ ), and the like. Does not.

The term "alkylcarbonyl" as used herein refers to a -C (= O) alkyl radical, where 'alkyl' is as defined above. Examples of such alkylcarbonyl radicals include, but are not limited to, methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, propylcarbonyl, butylcarbonyl, isobutylcarbonyl, t-butylcarbonyl, and the like.

The term "alkoxycarbonyl" used herein refers to a -C (= O) alkoxy radical, where 'alkoxy' is as defined above. Examples of such alkoxycarbonyl radicals include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, etc. It is not limited.

The term "alkylcarbonyloxy" as used herein refers to an -OC (= O) alkyl radical, where 'alkyl' is as defined above. Examples of such alkylcarbonyloxy radicals include methylcarbonyloxy, ethylcarbonyloxy, isopropylcarbonyloxy, propylcarbonyloxy, butylcarbonyloxy, isobutylcarbonyloxy, t-butylcarbonyloxy, etc. However, it is not limited thereto.

The term "alkoxycarbonyloxy" as used herein refers to an -OC (= O) alkoxy radical, where 'alkoxy' is as defined above. Examples of such alkoxycarbonyloxy radicals are methoxycarbonyloxy, ethoxycarbonyloxy, isopropoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy, t-butoxy Carbonyloxy and the like, but is not limited thereto.

The term "arylalkyl", "hydroxyalkyl", "alkoxyalkyl", "aminoalkyl" or "(alkylaryl) alkyl" as used herein refers to an alkyl radical substituted with at least one R, ie-(alkyl) -R By meaning, R is aryl, hydroxy, alkoxy, amino, or alkylaryl as defined above, wherein alkyl, aryl, hydroxy, alkoxy, amino or alkylaryl is as defined above.

The term "alkoxyalkoxy" or "hydroxyalkoxy" as used herein refers to an alkoxy radical substituted with at least one R, ie, -O- (alkyl) -R, wherein R is alkoxy or hydroxy as defined above. , Where alkyl, alkoxy or hydroxy are as defined above.

As used herein, the term "pharmaceutically acceptable" refers to a property that is not toxic to an individual such as a cell or a human exposed to the composition, and is meant to be suitable for use as a pharmaceutical agent. It is deemed to be safe and means that it has been officially approved by the state's governing body for this use or is on the Korean Pharmacopoeia or US Pharmacopeia list.

The term "pharmaceutically acceptable salt" in the present specification is a compound having a relatively non-toxic and harmless effect on a patient, and the side effects caused by this salt do not degrade the beneficial effects of the compound of the present invention itself. It means any organic or inorganic addition salt.

The term "cancer" herein is characterized by unregulated or dysregulated cell proliferation, reduced cellular differentiation, inadequate ability to invade surrounding tissue, and / or the ability to establish new growth at ectopic sites. Refers to a cellular disorder.

The term "prophylaxis" as used herein means any action that inhibits or delays the development, spread, and recurrence of cancer diseases by administration of the composition of the present invention.

As used herein, the term "treatment" refers to all actions in which symptoms of cancer disease are improved or cured by administration of the composition of the present invention.

The term "improvement" as used herein means any action that at least reduces the severity of parameters associated with the condition being treated with administration, eg, the severity of symptoms, by administration of a composition of the invention.

The term "individual" herein refers to all animals, including humans, who are or are at risk of developing a cancer disease. The animals may be mammals such as cattle, horses, sheep, pigs, goats, camels, antelopes, dogs, cats, etc., which require treatment of similar symptoms as humans, but are not limited thereto. In addition, in the present invention, the individual may be excluded from humans, but is not limited thereto.

The term "administration" herein refers to introducing the composition of the present invention to an individual in any suitable way, and the route of administration of the composition of the present invention is administered through various routes, oral or parenteral, as long as it can reach the target tissue Can be.

The term "pharmaceutically effective amount" as used herein refers to an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and does not cause side effects.

As used herein, the term "food" refers to dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, beverages, tea, drinks, and alcoholic beverages. , Vitamin complexes, health functional foods and health foods, and includes all foods in the ordinary sense.

The term "health functional food" in this specification means a food manufactured and processed using raw materials or ingredients having functional properties useful for the human body according to Act 6727 on the Health Functional Food. It means to ingest for the purpose of obtaining useful effects for health purposes such as adjusting nutrients for structure and function or physiological action.

The present invention provides a compound represented by Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In the formula 1,

R ^a is hydrogen or -LR ₃ ;

R ₁ is hydrogen or-(CH ₂ ) _n -R;

R is C1-C10 alkoxy, C6-C20 aryloxy, hydroxy, C1-C10 alkylcarbonyloxy, C6-C20 arylcarbonyloxy, cyano, halogen, nitro, C1-C10 alkylsulfanyl, C6-C20 aryl Sulfanyl, sulfanyl, -NR ^a1 R ^a2 , C1-C10alkoxyC1-C10alkyl, C6-C20aryloxyC1-C10alkyl, C1-C10alkoxyC1-C10alkoxy, C1-C10alkoxyC1-C10alkoxyC1- C10 alkyl, C1-C10 alkylsulfonyl, C6-C20 arylsulfonyl, C1-C10 alkyl C6-C20 arylsulfonyl, C6-C20 aryl C1-C10 alkylsulfonyl, sulfo, C6-C20 aryl, C3-C20 cyclo Alkyl, carbamoyl, C1-C10 alkylaminocarbonyl, C6-C20 arylaminocarbonyl, sulfamoyl, C1-C10 alkylaminosulfonyl, C6-C20 arylaminosulfonyl, C1-C10 alkylcarbonyl, C6-C20 Arylcarbonyl, C1-C10 alkoxycarbonyl, C6-C20 aryloxycarbonyl, carboxyl, formyl, C2-C20 heteroaryl or C3-C20 heterocycloalkyl, wherein R aryl, heteroaryl and heterocycloalkyl is C1 -C10 alkyl, halogen, nitro, cyano, hydroxyl , C1-C10alkoxy, C6-C20aryloxy, C1-C10alkylsulfanyl, haloC1-C10alkylsulfanyl, C6-C20arylsulfanyl, diC1-C10alkylamino, C1-C10alkylsulfonyl, C6- C20 arylsulfonyl, C1-C10 alkyl C6-C20 arylsulfonyl, C6-C20 arylC1-C10 alkylsulfonyl, C3-C20 cycloalkyl, carboxyl, sulfo, formyl, carbamoyl, sulfamoyl, amino, C1-C10 Alkylcarbonyl, C6-C20 arylcarbonyl, C1-C10 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C1-C10 alkylcarbonyloxy, C6-C20 arylcarbonyloxy, C2-C20 heteroaryl and C3- May be further substituted with one or more substituents selected from the group consisting of C20 heterocycloalkyl;

R ^a1 and R ^a2 are each independently hydrogen, C1-C10 alkyl, C1-C10 alkylsulfonyl, C6-C20 arylsulfonyl, C1-C10 alkyl C6-C20 arylsulfonyl, C6-C20 arylC1-C10 alkylsulfur Phenyl, sulfo, C6-C20 aryl, C3-C20 cycloalkyl or sulfamoyl;

n is an integer from 1 to 10;

R ₂ is hydrogen, C1-C10 alkyl, C1-C10 alkoxy C1-C10 alkyl, C3-C20 cycloalkyl, C3-C20 cycloalkyloxyC1-C10 alkyl, C6-C20 aryl or C6-C20 aryloxyC1-C10 alkyl ego;

X is CH or N;

Z is -CH ₂ -or -CO-;

L is -SO _2- , -SO ₂ -L'-, -NHCO-, -CONH-, C1-C10alkylene or -CO-;

이고;L 'is -NH- or

ego;

L _a is C1-C10 alkylene;

n1 is an integer from 1 to 3;

m1 is an integer of 0 or 1;

However, when (i) X is CH, L is -SO ₂ -NH-,

(ii) when L is C1-C10 alkylene, R ₃ is C1-C10 alkyl, C1-C10 alkoxy or C6-C20 aryloxy is excluded;

R ₃ is C1-C10 alkyl, C1-C10 alkoxy, C6-C20 aryloxy, C3-C20 heterocycloalkyl, C6-C20 aryl or C2-C20 heteroaryl, and heterocycloalkyl, aryl and heteroaryl of R ₃ Silver C1-C10 alkyl, halogen, halo C1-C10 alkyl, nitro, cyano, C1-C10 alkylcarbonylamino, C6-C20 arylcarbonylamino, amino, C1-C10alkoxy, haloC1-C10alkoxy, C1- C10alkoxyC1-C10alkoxy, C6-C20aryloxy, hydroxy, C1-C10alkylcarbonyl, haloC1-C10alkylcarbonyl, C6-C20arylcarbonyl, C1-C10alkoxycarbonyl, C6-C20aryloxy Carbonyl, carboxyl, formyl, sulfanyl, C1-C10 alkylsulfanyl, C6-C20 arylsulfanyl, diC1-C10 alkylamino C1-C10 alkoxy, dihydroxyaminosulfanyl, C1-C10 alkylsulfonyl, C6 -C20 arylsulfonyl, C1-C10 alkyl C6-C20 arylsulfonyl, C6-C20 arylC1-C10 alkylsulfonyl, sulfo, carbamoyl, C1-C10 alkylaminocarbonyl, C6-C20 arylaminocarbonyl, sulfa Moyl, C1-C10 alkylaminosulfonyl, At least one substituent selected from the group consisting of C6-C20 arylaminosulfonyl, C6-C20 aryl, C2-C20 heteroaryl, C1-C10 alkylcarbonyloxy, C6-C20 arylcarbonyloxy and C3-C20 heterocycloalkyl. Can be further substituted with;

R ₄ is halogen, halo C1-C10 alkyl, cyano, C1-C10 alkyl, C6-C20 aryl, C2-C20 heteroaryl, C1-C10 alkoxy, C6-C20 aryloxy, C2-C20 heteroaryloxy, halo C1 -C10 alkoxy, hydroxy, amino or aminoC1-C10 alkyl;

d is an integer from 0 to 5, and when d is an integer of 2 or more, R ₄ may be the same or different from each other;

a and b are each independently an integer of 0, 1 or 2, and a + b is an integer of 1, 2 or 3;

The heteroaryl and heterocycloalkyl include one or more heteroatoms selected from nitrogen, oxygen and sulfur.)

In one embodiment, the compound of Formula 1 may be represented by Formula 2 below.

[Formula 2]

(In Formula 2, R ₁ , R ₂ , X, Z, L, R ₃ , R ₄ , a, b, and d are the same as defined in Formula 1.)

The compound of Formula 1 according to the present invention, particularly preferably the compound of Formula 2, directly inhibits the TEAD protein, a transcription factor that is the most important signal for hippo signaling, which is known as a signal system very important for the development and growth of cancer cells. That is, since the compound of Formula 1, particularly preferably, the compound of Formula 2 exhibits YAP-TEAD binding inhibitory activity in the hippo pathway, it is useful as a therapeutic and prophylactic agent for cancer, a disease mediated by TAP-TEAD binding. That is, the compound of Formula 1, particularly preferably the compound of Formula 2, can bind to TEAD competitively with YAP and inhibit YAP-TEAD interaction, thereby activating the hippo pathway to control the growth of cancer cells. In addition, the compound of Formula 1 according to the present invention shows low toxicity to normal cells.

In Chemical Formula 2 according to an embodiment, the a + b may be an integer of 1 or 2.

In Chemical Formula 2 according to an embodiment, X is N, a is an integer of 1 or 2, and b may be an integer of 0.

In Chemical Formula 2 according to an embodiment, X is N, a is an integer of 0, and b may be an integer of 1.

In Chemical Formula 2 according to an embodiment, X is N, a is an integer of 1, and b may be an integer of 1.

In Chemical Formula 2 according to an embodiment, X is N, a is an integer of 0, and b may be an integer of 2.

The compound of Chemical Formula 1 may be a compound represented by the following Chemical Formula 3, Chemical Formula 4, Chemical Formula 5, Chemical Formula 6 or Chemical Formula 7.

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

(In Chemical Formulas 3 to 7, R ₁ , R ₂ , Z, L, R ₃ , R ₄ and d are the same as defined in Chemical Formula 2.)

In Chemical Formula 2 according to an embodiment, X is CH, a is an integer of 0, b is an integer of 2, and L may be -SO ₂ -NH-.

In Chemical Formula 2 according to an embodiment, X is CH, a is an integer of 1, b is an integer of 1, and L may be -SO ₂ -NH-.

In Chemical Formula 2 according to an embodiment, X is CH, a is an integer of 2, b is an integer of 0, and L may be -SO ₂ -NH-.

The compound of Chemical Formula 2 may be a compound represented by the following Chemical Formula 8, Chemical Formula 9 or Chemical Formula 10.

[Formula 8]

[Formula 9]

[Formula 10]

(In Formulas 8 to 10, R ₁ , R ₂ , R ₃ , R ₄ and d are the same as defined in Formula 2)

In Chemical Formula 2 according to an embodiment, X is N, a is an integer of 1, b is an integer of 0, Z is -CH _2- , and L may be -SO _2- .

In Chemical Formula 2 according to an embodiment, X is N, a is an integer of 1, b is an integer of 0, Z is -CO-, and L is -SO ₂ -or C1-C5 alkyleneyl Can be.

In Chemical Formula 2 according to an embodiment, X is N, a is an integer of 0, b is an integer of 1, Z is -CH _2- , and L may be -SO _2- .

또는

이고, L _a는 C1-C5알킬렌일 수 있다.In Chemical Formula 2 according to an embodiment, X is N, a is an integer of 2, b is an integer of 0, L is -SO _2- , -CO-, -NHCO-,

or

, And L _a may be C1-C5 alkylene.

또는

이고, L _a는 C1-C5알킬렌일 수 있다.In Chemical Formula 2 according to an embodiment, X is N, a is an integer of 1, b is an integer of 1, and L is -SO _2- ,

or

, And L _a may be C1-C5 alkylene.

또는

이고, L _a는 C1-C5알킬렌일 수 있다.In Chemical Formula 2 according to an embodiment, X is N, a is an integer of 0, b is an integer of 2, and L is -SO _2- ,

or

, And L _a may be C1-C5 alkylene.

The compound of Chemical Formula 3 may be a compound represented by the following Chemical Formula 11, Chemical Formula 12, or Chemical Formula 13.

[Formula 11]

[Formula 12]

[Formula 13]

(In Formulas 11 to 13, R ₁ , R ₂ , R ₃ , R ₄ and d are the same as defined in Formula 2;

R _3a is C3-C20 heterocycloalkyl, C6-C20 aryl or C2-C20 heteroaryl, and heterocycloalkyl, aryl and heteroaryl of R _3a are C1-C10 alkyl, halogen, halo C1-C10 alkyl, nitro, Cyano, C1-C10 alkylcarbonylamino, C6-C20 arylcarbonylamino, amino, C1-C10alkoxy, haloC1-C10alkoxy, C1-C10alkoxyC1-C10alkoxy, C6-C20aryloxy, hydroxy, C1-C10 alkylcarbonyl, halo C1-C10 alkylcarbonyl, C6-C20 arylcarbonyl, carboxyl, formyl, sulfanyl, C1-C10 alkylsulfanyl, C6-C20 arylsulfanyl, diC1-C10 alkylaminoC1 -C10 alkoxy, dihydroxyaminosulfanyl, C1-C10 alkylsulfonyl, C6-C20 arylsulfonyl, sulfo, carbamoyl, C1-C10 alkylaminocarbonyl, C6-C20 arylaminocarbonyl, sulfamoyl, C1 One or more substitutions selected from the group consisting of -C10 alkylaminosulfonyl, C6-C20 arylaminosulfonyl, C6-C20 aryl, C2-C20 heteroaryl and C3-C20 heterocycloalkyl As it may be further substituted.)

The compound of Formula 4 may be specifically a compound represented by Formula 14 below.

[Formula 14]

(In Formula 14, R ₁ , R ₂ , R ₃ , R ₄ and d are the same as defined in Formula 2.)

The compound of Formula 5 may be a compound represented by the following Formula 15, Formula 16, Formula 17, Formula 18, or Formula 19.

[Formula 15]

[Formula 16]

[Formula 17]

[Formula 18]

[Formula 19]

(In the formulas 15 to 19, R ₁ , R ₂ , R ₃ , R ₄ and d are the same as defined in Formula 2;

L _a is C1-C5 alkylene.)

The compound of Chemical Formula 6 may be a compound represented by Chemical Formula 20, Chemical Formula 21, or Chemical Formula 22.

[Formula 20]

[Formula 21]

[Formula 22]

(In Chemical Formulas 20 to 22, R ₁ , R ₂ , R ₃ , R ₄ and d are the same as defined in Chemical Formula 2;

L _a is C1-C5 alkylene.)

The compound of Formula 7 may be a compound represented by Formula 23, Formula 24, or Formula 25 below.

[Formula 23]

[Formula 24]

[Formula 25]

(In Formulas 23 to 25, R ₁ , R ₂ , R ₃ , R ₄ and d are the same as defined in Formula 2;

L _a is C1-C5 alkylene.)

In the compounds of Formulas 8 to 25 according to one embodiment,

R ₁ is hydrogen or-(CH ₂ ) _n -R;

R is C1-C6 alkoxy, C6-C12 aryloxy, hydroxy, cyano, halogen, nitro, C1-C6 alkylsulfanyl, C6-C12 arylsulfanyl, sulfanyl, -NR ^a1 R ^a2 , C1-C6alkoxy C1-C6 alkyl, C6-C12 aryloxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkylsulfonyl, C6-C12 arylsulfonyl , C1-C6alkylC6-C12arylsulfonyl, C6-C12arylC1-C6alkylsulfonyl, sulfo, C6-C12aryl, C1-C6alkoxycarbonyl, C6-C12aryloxycarbonyl, carboxyl, formyl, C2 -C12 heteroaryl or C3-C12 heterocycloalkyl, wherein the aryl, heteroaryl and heterocycloalkyl of R is C1-C6 alkyl, halogen, nitro, cyano, hydroxy, C1-C6 alkoxy, C6-C12 aryloxy , C1-C6 alkylsulfonyl, C6-C12 arylsulfonyl, C1-C6 alkyl C6-C12 arylsulfonyl, C6-C12 arylC1-C6 alkylsulfonyl, carboxyl, sulfo, formyl, carbamoyl, sulfamoyl and amino Further one or more substituents selected from the group consisting of It may be;

R ^a1 and R ^a2 are each independently hydrogen, C1-C6 alkyl, C1-C6 alkylsulfonyl, C6-C12 arylsulfonyl, C1-C6 alkyl C6-C12 arylsulfonyl, C6-C12 arylC1-C6 alkylsulfur Phonyl, sulfo or sulfamoyl;

n is an integer from 1 to 5;

R ₂ is hydrogen, C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl or C6-C12 aryloxyC1-C6 alkyl;

R ₃ is C1-C6 alkyl, C1-C6 alkoxy, C6-C12 aryloxy, C3-C12 heterocycloalkyl, C6-C12 aryl or C2-C12 heteroaryl;

R _3a is C3-C12 heterocycloalkyl, C6-C12 aryl or C2-C12 heteroaryl;

The heterocycloalkyl, aryl and heteroaryl of R ₃ and R _3a are C1-C6 alkyl, halogen, halo C1-C6 alkyl, nitro, cyano, C1-C6 alkylcarbonylamino, C6-C12 arylcarbonylamino, Amino, C1-C6 alkoxy, halo C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, C6-C12 aryloxy, hydroxy, C1-C6 alkylcarbonyl, halo C1-C6 alkylcarbonyl, C6-C12 aryl Carbonyl, carboxyl, formyl, sulfanyl, C1-C6 alkylsulfanyl, C6-C12 arylsulfanyl, diC1-C6 alkylamino C1-C6 alkoxy, dihydroxyaminosulfanyl, C1-C6 alkylsulfonyl, C6 -C12 arylsulfonyl, sulfo, carbamoyl, C1-C6 alkylaminocarbonyl, C6-C12 arylaminocarbonyl, sulfamoyl, C1-C6 alkylaminosulfonyl, C6-C12 arylaminosulfonyl, C6-C12 aryl , C2-C12 heteroaryl and C3-C12 heterocycloalkyl may be further substituted with one or more substituents selected from the group consisting of;

L _a is C1-C5 alkylene;

R ₄ is halogen, halo C1-C6 alkyl, cyano, C1-C6 alkyl, C6-C12 aryl, C2-C12 heteroaryl, C1-C6 alkoxy, C6-C12 aryloxy, C2-C12 heteroaryloxy, halo C1 -C6 alkoxy, hydroxy, amino or aminoC1-C6 alkyl;

d is an integer from 0 to 5, and when d is an integer of 2 or more, R ₄ may be the same or different from each other.

In one embodiment, the compound of Formula 2 may be a compound selected from Formulas 8 to 25.

In the compound according to an embodiment, R ₁ is hydrogen or-(CH ₂ ) _n -R;

R is C1-C6 alkoxy, hydroxy, cyano, halogen, C1-C6 alkylsulfanyl, -NR ^a1 R ^a2 , C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkoxy, C1-C6 alkoxy C1-C6alkoxy C1-C6 alkyl, C1-C6 alkylsulfonyl, C6-C12 arylsulfonyl, C6-C12 aryl, C1-C6 alkoxycarbonyl, C6-C12 aryloxycarbonyl, C2-C12 heteroaryl or C3 -C12 heterocycloalkyl, wherein the aryl, heteroaryl and heterocycloalkyl of R is C1-C6 alkyl, halogen, nitro, cyano, hydroxy, C1-C6 alkoxy, C6-C12 aryloxy, C1-C6 alkylsulfur Can be further substituted with one or more substituents selected from the group consisting of phenyl, C6-C12 arylsulfonyl, C1-C6 alkyl C6-C12 arylsulfonyl, C6-C12 arylC1-C6 alkylsulfonyl, carboxyl, sulfo and formyl. There is;

R ^a1 and R ^a2 are each independently C1-C6 alkyl, C1-C6 alkylsulfonyl or C6-C12 arylsulfonyl;

n is an integer from 1 to 3;

R ₂ is hydrogen or C1-C6alkoxyC1-C6alkyl;

R ₃ is C1-C6 alkyl, C1-C6 alkoxy, C3-C12 heterocycloalkyl, C6-C12 aryl or C2-C12 heteroaryl;

R _3a is C3-C12 heterocycloalkyl, C6-C12 aryl or C2-C12 heteroaryl;

The heterocycloalkyl, aryl and heteroaryl of R ₃ and R _3a are C1-C6 alkyl, halogen, halo C1-C6 alkyl, nitro, cyano, C1-C6 alkylcarbonylamino, C6-C12 arylcarbonylamino, Amino, C1-C6 alkoxy, halo C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, hydroxy, C1-C6 alkylcarbonyl, halo C1-C6 alkylcarbonyl, C6-C12 arylcarbonyl, carboxyl, formyl , Sulfanyl, C1-C6 alkylsulfanyl, C6-C12 arylsulfanyl, diC1-C6 alkylamino C1-C6 alkoxy, dihydroxyaminosulfanyl, C1-C6 alkylsulfonyl, C6-C12 arylsulfonyl, May be further substituted with one or more substituents selected from the group consisting of sulfo, carbamoyl, sulfamoyl, C6-C12 aryl, C2-C12 heteroaryl and C3-C12 heterocycloalkyl;

R ₄ is halogen, halo C1-C6 alkyl, cyano, C1-C6 alkyl, C6-C12 aryl, C2-C12 heteroaryl, C1-C6 alkoxy, C6-C12 aryloxy, C2-C12 heteroaryloxy, halo C1 -C6 alkoxy, hydroxy, amino or aminoC1-C6 alkyl;

d is an integer from 0 to 5, and when d is an integer of 2 or more, R ₄ may be the same or different from each other.

In the compound according to an embodiment, R ₁ may be hydrogen.

In the compound according to an embodiment, preferably, R ₁ is-(CH ₂ ) _n -OR ₁₁ ,-(CH ₂ ) _n -OH,-(CH ₂ ) _n -CN,-(CH ₂ ) _n -X ₁ ,-(CH ₂ ) _n -SR ₁₂ ,-(CH ₂ ) _n -NR ₁₃ R ₁₄ ,-(CH ₂ ) _n -NR ₁₃ -SO ₂ R ₁₅ ,-(CH ₂ ) _n -L ₁ -OR ₁₁ ,-(CH ₂ ) _n -SO ₂ R ₁₆ or-(CH ₂ ) _n -C (= O) OR _17, or may be selected from the following structures.

(R ₁₁ is C 1 -C 4 alkyl or C 1 -C 4 alkoxy C 1 -C 4 alkyl;

X ₁ is halogen;

R ₁₂ to R ₁₄ are each independently C1-C4 alkyl;

R ₁₅ , R ₁₆ , R ₁₇ and R ₂₀ are each independently C 1 -C 4 alkyl or C 6 -C 12 aryl;

L ₁ is C1-C4 alkylene;

R ₁₈ and R ₁₉ are, independently of each other, C 1 -C 4 alkyl, halogen, nitro, cyano, hydroxy, C 1 -C 4 alkoxy, C 6 -C 12 aryloxy, carboxyl, sulfo or formyl;

R 'is hydrogen or C1-C4 alkyl;

Q is CH ₂ , NH, O or S;

n is an integer from 1 to 3;

p is an integer from 0 to 5, and when p is an integer of 2 or more, R ₁₈ may be identical to or different from each other;

q is an integer from 0 to 4, and when q is an integer of 2 or more, R ₁₉ may be the same or different from each other.)

More preferably, R ₁ may be selected from the following structures.

In the compound according to an embodiment, R ₃ is C1-C6 alkyl, C1-C6 alkoxy, C3-C12 heterocycloalkyl, C6-C12 aryl or C2-C12 heteroaryl, and heterocycloalkyl of R ₃ , Aryl and heteroaryl are C1-C6 alkyl, halogen, halo C1-C6 alkyl, nitro, C1-C6 alkylcarbonylamino, amino, C1-C6 alkoxy, halo C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy , Hydroxy, halo C1-C6 alkylcarbonyl, carboxyl, diC1-C6 alkylamino C1-C6 alkoxy, dihydroxyaminosulfanyl, C1-C6 alkylsulfonyl, C6-C12 aryl and C2-C12 heteroaryl It may be further substituted with one or more substituents selected from the group consisting of.

In the compound according to an embodiment, R ₂ is hydrogen or C 1 -C 4 alkoxy C 1 -C 4 alkyl;

R ₃ is selected from C1-C4 alkyl, C1-C4 alkoxy or the following structure;

R ₂₁ to R ₂₆ are each independently C1-C4 alkyl, halogen, halo C1-C4 alkyl, nitro, cyano, C1-C4 alkylcarbonylamino, C6-C12 arylcarbonylamino, amino, C1-C4alkoxy, HaloC1-C4alkoxy, C1-C4alkoxyC1-C4alkoxy, hydroxy, C1-C4alkylcarbonyl, haloC1-C4alkylcarbonyl, C6-C12arylcarbonyl, carboxyl, formyl, sulfanyl, C1-C4 Alkylsulfanyl, C6-C12 arylsulfanyl, diC1-C4alkylaminoC1-C4alkoxy, dihydroxyaminosulfanyl, C1-C4alkylsulfonyl, C6-C12arylsulfonyl, sulfo, carbamoyl, sulfamoyl , C6-C12 aryl, C2-C12 heteroaryl or C3-C12 heterocycloalkyl;

Y ₁ and Y ₂ are each independently NR ″, O or S;

Z is-(CR ₂₇ R ₂₈ ) _x- ;

R ₂₇ and R ₂₈ are each independently hydrogen, C1-C4 alkyl or halogen;

x is an integer from 1 to 3;

T is CH ₂ or O;

R '' is hydrogen or C1-C4 alkyl;

r is an integer from 0 to 3, and when r is an integer of 2 or more, R ₂₁ may be the same or different from each other; s is an integer from 0 to 2, and when s is an integer from 2, R ₂₂ may be the same or different from each other; t is an integer from 0 to 4, and when t is an integer of 2 or more, R ₂₃ may be the same or different from each other; u is an integer from 0 to 5, and when u is an integer of 2 or more, R ₂₄ may be the same or different from each other; v is an integer from 0 to 6, and when v is an integer of 2 or more, R ₂₅ may be the same or different from each other; w is an integer from 0 to 7, and when w is an integer of 2 or more, R ₂₆ may be the same or different from each other;

R ₄ is halogen, haloC1-C4alkyl, cyano, C1-C4alkyl, Ar ₁ , HET ₁ , C1-C4alkoxy, -O-Ar ₁ , -O-HET ₁ , haloC1-C4alkoxy, hydroxy , Amino or aminoC1-C4alkyl;

Ar ₁ is phenyl, biphenyl or naphthyl;

HET ₁ is pyrrolyl, furyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, Pyrimidyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzothienyl, isoindoleyl, indazolyl, benzoisoxazolyl, benzoisothiazolyl, benzoimidazolyl Benzooxazolyl, benzothiazolyl or benzotriazolyl;

d is an integer of 0 to 3, and when d is an integer of 2 or more, R ₄ may be the same or different from each other.

In the compound according to an embodiment, preferably, R ₄ may be halogen, halo C1-C4 alkyl or C1-C4 alkoxy.

In the compound according to an embodiment, R ₃ may be selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or the following structure.

(In the above, R ₂₁ to R ₂₆ are each independently C1-C4 alkyl, halogen, halo C1-C4 alkyl, nitro, C1-C4 alkylcarbonylamino, amino, C1-C4alkoxy, haloC1-C4alkoxy, C1 -C4alkoxyC1-C4alkoxy, hydroxy, haloC1-C4alkylcarbonyl, carboxyl, diC1-C4alkylaminoC1-C4alkoxy, dihydroxyaminosulfanyl, C1-C4alkylsulfonyl, C6-C12aryl Or C2-C12 heteroaryl;

Z is-(CR ₂₇ R ₂₈ ) _x- ;

R ₂₇ and R ₂₈ are each independently hydrogen, C1-C4 alkyl or halogen;

x is an integer from 1 to 3;

R '' is hydrogen or C1-C4 alkyl;

r is an integer from 0 to 3, and when r is an integer of 2 or more, R ₂₁ may be the same or different from each other; s is an integer from 0 to 2, and when s is an integer from 2, R ₂₂ may be the same or different from each other; t is an integer from 0 to 4, and when t is an integer of 2 or more, R ₂₃ may be the same or different from each other; u is an integer from 0 to 5, and when u is an integer of 2 or more, R ₂₄ may be the same or different from each other; v is an integer from 0 to 6, and when v is an integer of 2 or more, R ₂₅ may be the same or different from each other; w is an integer from 0 to 7, and when w is an integer of 2 or more, R ₂₆ may be the same or different from each other.)

More specifically, R ₃ is methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy or butoxy, or may be selected from the following structures.

More specifically, R ₄ is bromo, fluoro, chloro, trifluoromethyl, cyano, methyl, ethyl, propyl, butyl, Ar ₁ , HET ₁ , C1-C4 alkoxy, -O-Ar ₁ , -O -HET ₁ , trifluoromethoxy, hydroxy, amino, aminomethyl, aminoethyl or aminopropyl; Ar ₁ is phenyl, biphenyl or naphthyl; HET ₁ is pyrrolyl, furyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, Pyrimidyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzothienyl, isoindoleyl, indazolyl, benzoisoxazolyl, benzoisothiazolyl, benzoimidazolyl Benzooxazolyl, benzothiazolyl or benzotriazolyl; d is an integer of 0 to 3, and when d is an integer of 2 or more, R ₄ may be the same or different from each other.

In one embodiment, the compound of Formula 1 may be represented by Formula 26 below.

[Formula 26]

(In Formula 26, R ₁ , R ₂ , X, Z, R ₄ , a, b, and d are the same as defined in Formula 1.)

In the compound of Formula 26 according to an embodiment, X may be N, a may be an integer of 2, and b may be an integer of 0.

In the compound of Formula 26 according to an embodiment, X is N, a is an integer of 1, and b can be an integer of 1.

In the compound of Formula 26 according to an embodiment, X is N, a is an integer of 0, and b may be an integer of 2.

The compound of Chemical Formula 26 may be a compound represented by the following Chemical Formula 27, Chemical Formula 28, or Chemical Formula 29.

[Formula 27]

[Formula 28]

[Formula 29]

(In Chemical Formulas 27 to 29, R ₁ , R ₂ , R ₄ and d are the same as defined in Chemical Formula 1.)

The compound according to an embodiment may be more preferably selected from the following group of compounds, but is not limited thereto.

The compound of Formula 1 may be prepared by various methods known according to the type of the substituent, it will be apparent to those skilled in the art that it may be performed by using a method known in the art or by appropriate modification.

The compounds of the present invention can be used in the form of prodrugs, hydrates, solvates and pharmaceutically acceptable salts to enhance absorption in vivo or to increase solubility. Also included are prodrugs, hydrates, solvates, or salts thereof.

The compounds of the present invention can be used in the form of pharmaceutically acceptable salts, and pharmaceutically acceptable salts are salts prepared according to conventional methods in the art, and methods for preparing the salts are known to those skilled in the art. Specifically, the pharmaceutically acceptable salts include, but are not limited to, pharmacologically or physiologically acceptable salts derived from the following free acids and bases.

The pharmaceutically acceptable salt of the compound of the present invention means a salt prepared according to a conventional method in the art, and such a manufacturing method is known to those skilled in the art. Specifically, the pharmaceutically acceptable salts include, but are not limited to, pharmacologically or physiologically acceptable salts derived from the following inorganic and organic acids and bases.

Acid addition salts are prepared by dissolving the compound of the present invention in a conventional method, for example, in an excess aqueous acid solution, and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The molar amount of the compound and the acid or alcohol in water (eg, glycol monomethyl ether) can be heated and then the mixture is evaporated to dryness or the precipitated salt can be suction filtered. At this time, organic and inorganic acids can be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, and tartaric acid can be used as the inorganic acid, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, and maleic acid can be used as the organic acid. (maleic acid), succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, etc. can be used. , Not limited to these.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound of the present invention in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the compound salt of the present invention at cost, and then evaporating and drying the filtrate. At this time, as the metal salt, it is particularly suitable to manufacture sodium, potassium, or calcium salts, but is not limited thereto. Further, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

Pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in the compounds of Formula 1, unless indicated otherwise. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of hydroxy groups, and other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, and hydrogen phosphate. , Dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, etc., and preparation of salts known in the art It can be prepared through a method.

The hydrate of the compound of the present invention is a compound of the present invention containing a stoichiometric or non-stoichiometric amount of water bound by a non-covalent intermolecular force, or It means salt.

Solvates of the compounds of the present invention refer to the compounds of the present invention or salts thereof comprising a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvents for this are volatile and non-toxic solvents.

The compound of the present invention can be administered in the form of a prodrug that degrades in the human or animal body and provides the compound of the present invention as an active ingredient. Prodrugs can be used to alter and / or improve the physical and / or pharmacokinetic profile of the parent compound and can be formed if the parent compound contains suitable groups or substituents that can be derived to form a prodrug.

If any compound (prodrug) is separated in the body to form a compound of the present invention or a salt thereof, such a compound is also included in the scope of the present invention. As used herein and unless otherwise indicated, the term “prodrug” is hydrolyzed, oxidized, and subjected to other reactions under biological conditions (ex vivo or in vivo) to supply the active compound, particularly the compound of the present invention. It means the compound of this invention which can be made. Examples of prodrugs are biohydrolyzable amides, biodegradable esters, biodegradable carbamates, biodegradable carbonates, biodegradable Ureides, and biodegradable moieties, including biodegradable phosphate analogs, to compounds that produce biodegradable compounds of the present invention. It is not limited. Preferably, the prodrug of a compound having a carboxyl group functional group is a lower alkyl ester of a carboxylic acid. Carboxylic esters are usually formed by esterifying a portion of the carboxylic acid present in the molecule. The prodrug is Burger's Medicinal Chemistry and Drug Discovery 6thed. (Donald J. Abrahamed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).

In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound of Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Here, the compound of Formula 1, preferably Formula 2, its prodrug, its hydrate, its solvate or its pharmaceutically acceptable salt can prevent or treat cancer through YAP-TEAD binding inhibitory activity in the hippo pathway. have. That is, the compound of Chemical Formula 1, preferably Chemical Formula 2, can bind to TEAD competitively with YAP and inhibit YAP-TEAD interaction, thereby activating the hippo pathway to effectively control cancer growth.

In the pharmaceutical composition according to an embodiment, the cancer is lung cancer, colon cancer, colon cancer, rectal cancer, breast cancer, prostate cancer, bladder cancer, blood cancer, leukemia, myelogenous leukemia, lymphoma, cervical carcinoma, osteosarcoma ), Glioblastoma, melanoma, pancreatic cancer, stomach cancer, liver cancer, kidney cancer, gallbladder cancer, biliary cancer, esophageal cancer, ovarian cancer or neuroblastoma, preferably colon cancer, colon cancer or It may be rectal cancer.

In one embodiment, the pharmaceutical composition further comprises a conventional non-toxic pharmaceutically acceptable carrier, excipient, or diluent in addition to the active ingredient, conventional formulations in the pharmaceutical field, i.e., oral administration or parenteral administration It can be formulated as a solvent formulation.

Examples of the pharmaceutically acceptable carrier, excipient or diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, and cellulose. , Methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.

The pharmaceutical composition of the present invention is formulated in various forms such as oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, and injections of sterile injection solutions according to a conventional method according to the purpose of use. It can be used orally or by various routes including intravenous, intraperitoneal, subcutaneous, rectal and topical administration.

In addition, the pharmaceutical composition of the present invention may further include a filler, an anti-coagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, a preservative, and the like.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient in the composition, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. Is formulated by mixing. In addition, lubricants such as magnesium stearate and talc may be used in addition to simple excipients.

Oral liquid preparations may include suspending agents, intravenous solutions, emulsions, syrups, etc. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, are included. Can be.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a base for suppositories, Witepsol, Macrogol, Tween 61, cacao butter, laurin butter, and glycerogelatin may be used. On the other hand, injections may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives, and the like.

The pharmaceutical composition of the present invention may be sterilized, or may further contain an auxiliary agent such as a preservative, stabilizer, thickener, hydration or emulsifying accelerator, salt and / or buffer for osmotic pressure control, and other therapeutically useful substances. It may also contain, and may be formulated according to conventional methods such as dissolution, dispersion, and gelation.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount, the pharmaceutical composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, can be administered sequentially or simultaneously with a conventional therapeutic agent, , Single or multiple doses. Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect in a minimal amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the compound in the composition of the present invention may vary depending on the patient's age, sex, and body weight, and generally, 1 to 100 mg / kg, preferably 5 to 60 mg / kg body weight is administered daily or every other day, or 1 It can be administered by dividing 1 to 3 times a day. However, the dosage may be increased or decreased depending on the route of administration, the severity of the disease, sex, weight, age, etc., so that the dosage does not limit the scope of the present invention in any way.

In addition, the present invention provides a method for preventing or treating cancer diseases, comprising administering the pharmaceutical composition to an individual who has or is at risk of developing cancer diseases.

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

The effective dose level is the patient's gender, age, weight, health status, type of disease, severity, drug activity, sensitivity to the drug, administration method, administration time, route of administration, and rate of discharge, duration of treatment, combination or concurrent use It can be easily determined by those skilled in the art according to factors including the drug to be used and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered single or multiple. Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect in a minimal amount without side effects, which can be easily determined by those skilled in the art.

The administration route and mode of administration for administering the pharmaceutical composition of the present invention are not particularly limited, and any route and mode of administration can be followed as long as the composition containing the composition can reach the desired site. Specifically, the composition may be administered through various routes, oral or parenteral, and non-limiting examples of the route of administration include oral, rectal, topical, intravenous, intraperitoneal, intramuscular, intraarterial, transdermal, and non- And those administered via intraoral or inhalation.

In addition, the method for preventing or treating cancer of the present invention can be used in combination with surgery, radiation therapy, hormone therapy, chemotherapy, and methods using biological response modifiers.

In addition, the present invention is a YAP / TAZ-TEAD inhibitor composition containing, as an active ingredient, an effective amount of a compound represented by Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.

In addition, the present invention, as an active ingredient, an effective amount of a compound represented by Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient for preventing or improving cancer health function Provide a food composition.

The health functional food composition may be provided in the form of a powder, granule, tablet, capsule, syrup, or beverage, and the health functional food is used in combination with other foods or food additives other than the compound of Formula 1, which is an active ingredient. Depending on the method, it can be suitably used. The mixing amount of the active ingredient may be appropriately determined according to its purpose of use, for example, prevention, health or therapeutic treatment.

The compound of Formula 1 contained in the dietary supplement composition may be used according to the effective dose of the pharmaceutical composition, but in the case of long-term intake for health and hygiene purposes or for health control purposes, the above range It may be the following, since the active ingredient has no problem in terms of safety, it can be used even in an amount of the above range.

The health functional food composition includes meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, dairy products including gums, ice cream, various soups, beverages, teas, drinks, alcoholic beverages, and vitamin complexes It can be formulated in a variety of formulations, such as.

Hereinafter, the present invention will be described in more detail through preferred embodiments. However, this is presented as an example of the present invention, and the scope of the present invention is not limited by this in any sense, and the scope of the present invention is only defined according to the following claims.

Preparation Example A

Intermediate a-1 was obtained by Nitration reaction using Benzo [cd] indol-2 (1H) -one commercially available from a reagent company as a starting material, and after obtaining N-alkylation, alkylated intermediate b-1-1 was obtained, and Nitro The amine intermediate c-1-1 was obtained through the reduction reaction of the group, and the intermediate e-1-1 was obtained by amide coupling with the piperidine carboxylic acid compound d-1-1 protected with Boc. Subsequently, amine f-1-1 obtained after Boc-deprotection was subjected to a sulfonylation reaction with a sulfonyl chloride compound to obtain a final compound g-1-1. The general method of each reaction is specified below.

Step 1: Synthesis of Compound a-1

Benzo [cd] indol-2 (1H) -one (10 g, 59.1 mmol) was dissolved in acetic acid (45 mL) and stirred at 10 ° C. Nitric acid (60%, 5.88 mL, 76.8 mmol) was added slowly, followed by stirring at 50 ° C for 24 hours. After the reaction mixture was cooled to room temperature, water was added and filtered, followed by washing with water to obtain compound a-1 as an ocher solid (12.6 g, 100%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.41 (s, 1H), 8.89 (d, J = 8.4 Hz, 1H), 8.63 (d, J = 8.1 Hz, 1H), 8.18 (d, J = 6.9 Hz, 1H), 8.07 (dd, J = 8.5, 7.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H)

Step 2: Synthesis of Compound b-1-1

Compound a-1 (5.24 g, 24.5 mmol) prepared in step 1 was dissolved in DMF (20 mL) and stirred at 0 ° C. K ₂ CO ₃ (6.76 g, 48.9 mmol) and 1-Bromo-3-methoxypropane (3.01 mL, 26.9 mmol) were added, heated to 50 ° C. and stirred for 24 hours. After the reaction mixture was cooled to room temperature, water was added and filtered, and then washed with water to obtain compound b-1-1 as an ocher solid (6.99 g, 100%).

Step 3: Synthesis of Compound c-1-1

After dissolving compound b-1-1 (3.63 g, 12.7 mmol) prepared in step 2 in methanol / ethyl acetate (1/1 v / v, 40 mL), Palladium 10% on Carbon (363 mg) was added and Stirred under hydrogen gas for 24 hours. The reaction mixture was filtered using celite and concentrated under reduced pressure to obtain compound c-1-1 as a red solid (90% to 100%).

Step 4: Synthesis of compound d-1-1

Piperidine carboxylic acid (803 mg, 6.22 mmol) was dissolved in dioxane / water (2/1 v / v, 15 mL) with stirring, NaOH (274 mg, 6.84 mmol) was added, followed by stirring at 0 ° C. Boc anhydride (1.57 mL, 6.84 mmol) was added, and the mixture was stirred at room temperature for 24 hours, concentrated under reduced pressure, and left a little solvent to cool to 0 ° C. Acidify with 1M HCl, adjust the pH to 2, and extract with ethyl acetate (10 mL × 3). The obtained organic layer was dried over MgSO ₄ and concentrated under reduced pressure to obtain compound d-1-1 as a white solid (1.42 g, 100%).

Step 5: Synthesis of Compound e-1-1

Compound d-1-1 (111 mg, 0.482 mmol) prepared in step 4 was dissolved in DMF (4 mL) and stirred at 0 ° C. DIEA (252 μL, 1.45 mmol), HATU (367 mg, 0.965 mmol) was added and stirred for 1 hour. The compound c-1-1 (124 mg, 0.482 mmol) prepared in step 3 was dissolved in DMF (2 mL), slowly added to the reaction mixture, heated to 60 ° C. and stirred for 24 hours. After completion of the reaction by adding water, extraction was performed with ethyl acetate (5 mL × 3), dried over anhydrous Na ₂ SO ₄ , and purified by flash chromatography to obtain compound e-1-1 as a yellow solid (40% ~). 77%).

Step 6: Synthesis of Compound f-1-1

The compound e-1-1 prepared in step 5 (170 mg, 0.364 mmol) was dissolved in CH ₂ Cl ₂ (5 mL) and stirred at 0 ° C. After adding trifluoroacetic acid (278 μL, 3.64 mmol), the mixture was stirred at room temperature. Sat. After basifying to pH 8 with NaHCO ₃ , extracted with CHCl ₃ (10 mL × 3), dried over anhydrous Na ₂ SO ₄ , and purified by flash chromatography to obtain compound f-1-1 as a yellow solid (78% ~). 97%).

Step 7: Synthesis of Compound g-1-1

Compound f-1-1 prepared in Step 6 (17.8 mg, 0.0484 mmol) was dissolved in CHCl ₃ (2 mL), and then stirred at 0 ° C. Triethylamine (10 μL, 0.0727 mmol) and compound Ar-sulfonyl-Cl (1.2 eq) were added and stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by flash chromatography to obtain compound g-1-1 as a yellow solid (20% to 99%).

Preparation Example B

Unlike Preparation A, piperidine acid was first sulfonylated to obtain intermediate d-1-2, followed by amide coupling with amine intermediate C-1-2 to synthesize the final compound, g-1-2.

Step 1: Synthesis of Compound d-1-2

Piperidine carboxylic acid (1 g, 7.74 mmol) was dissolved in THF / H ₂ O = 1/1 (v / v) (100 mL) and Na ₂ CO ₃ (17 mL, 17.0 mmol) was added while stirring at 0 ° C. and 30 After stirring for a minute, the compound Ar-sulfonyl-Cl (1.2 eq) was added and stirred for 12 hours. The reaction mixture was extracted with ether (150 mL × 2), KHSO ₄ solid was added to the resulting water layer, the pH was adjusted to 3, and then extracted with ethyl acetate (15 mL × 3). The obtained organic layer was dried over anhydrous Na ₂ SO _4, and then concentrated under reduced pressure to obtain compound d-1-2 (100%).

Step 2: Synthesis of Compound g-1-2

After dissolving the compound d-1-2 (1 eq) prepared in step 1 in MeCN, 3-picoline (2.2 eq) and Methanesulfonyl chloride (1.2 eq) were added while stirring at 0 ° C. and stirred for 1 hour. Compound c-1-2 (1.2 eq) was dissolved in MeCN and added slowly, followed by stirring at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by flash chromatography to obtain compound g-1-2 as a yellow solid (20% to 70%).

Preparation Example C

Step 1: Synthesis of Compound c-1-5

The compound c-1-5 was obtained by reacting in the same manner as in Step 3 of Preparation Example A, except that Compound a-1 was used instead of Compound b-1-1 of Step 3 of Preparation Example A.

Step 2: Synthesis of Compound g-1-4

Preparation Example B except that Compound c-1-5 was used instead of Compound c-1-2 of Step 2 of Preparation Example B, and Compound d-1-3 was used instead of Compound d-1-2. The reaction was carried out in the same manner as in Step 2 to obtain compound g-1-4.

Step 3: Synthesis of Compound g-1-5

3-(( tert -Butyldimethylsilyl) oxy) -propanol (39 mg, 0.204 mmol), PPh ₃ (54 mg, 0.204 mmol) was dissolved in THF (1 mL) and stirred at 0 ° C. Compound g-1-4 (30 mg, 0.0679 mmol) was dissolved in THF (1 mL) and added, followed by stirring at the same temperature for 15 minutes. After adding DIAD (40 μL, 0.204 mmol), the mixture was heated to 70 ° C. and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by flash chromatography to obtain compound g-1-5 as a yellow liquid.

Step 4: Synthesis of Compound 45

Compound g-1-5 (67 mg, 0.109 mmol) was dissolved in THF (2 mL) and TBAF (1.0 M, 328 μL, 0.328 mmol) was added while stirring at 0 ° C., followed by stirring at room temperature. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by flash chromatography to obtain compound 45 as a yellow solid (5.7 mg, 17%).

[Examples 1 to 169]

According to the methods of Preparation Examples A to C, compounds 1 to 169 of Table 1 were prepared, and identification data of the prepared compounds 1 to 169 are shown in Table 2 below.

[Table 1]

[Table 2]

<Experiment 1> YAP-TEAD binding inhibitory effect measurement

The in vitro binding inhibition rate of YAP-TEAD was measured using a luciferase assay capable of measuring the degree of inhibition of YAP-TEAD previously reported in Cancers 2018, 10 (5), 140.

HEK293T cells were purchased from the American Type Culture Collection and cultured in DMEM media containing 10% FBS, L-glutamine and peniciline / streptomycin. The HEK293T cell was seeded in a 24 well plate at a density of 1 × 10 ⁵ and then coated with polyethyleneamine (10 μg / mL). These cells were transfected using TEAD luciferase reporter plasmind 8XGTIIC-Luciferase (Addgene reference 34615) and control β-galactosidase plasmid CMV-β-Gal using lipofectamine 2000 reagent (Life Technologies, Inc.) according to the manufacturer's manual. Thereafter, the compound of the present invention was treated for 24 hours at a concentration of 10 μM, and cells were lysed using Reporter lysis buffer (Promega, France), and then luciferase activity was read with a Mithras LB940 plate reader and normalized with β-galactosidase. Table 3 shows the results.

 [Table 3]

From the results of Table 3 above, it can be seen that the compounds of the present invention exhibit an inhibition rate of 50% or more at a concentration of 10 μM, and TEAD-dependent transcription by inhibition of the binding of YAP-TEAD due to the structural characteristics of the compounds of the present invention. It was confirmed that it can effectively inhibit. Therefore, the compounds of the present invention can exhibit anti-cancer activity by inhibiting the expression of cyr61, CTGF, and PD-L1, which play an important role in the carcinogenesis process, among the main target genes of TEAD-dependent transcription.

<Experimental Example 2> Measurement of anticancer activity through MTT assay

HT-29, a commercially available colon cancer cell line, was cultured by trypsin-EDTA treatment, and then seeded in a 96 well plate. After incubation for 24 hours, each cell was treated with a candidate compound (compound of the invention) to a final concentration of 0-2 μM. The treated cells were cultured for an additional 72 hours, and cell viability was measured by an ATP detection method (CellTiter-Glo® Luminescent Cell Viability Assay, Promega).

In order to confirm the anticancer effect of the compounds according to the present invention, a proliferation assay was performed on HT29 cell, a colorectal cancer cell line, by the above method, and the resulting IC ₅₀ values are shown in Table 4 below.

[Table 4]

From the results of Table 4 above, the compounds of the present invention showed an IC ₅₀ value of 45.4 μM or less, specifically 2.2 to 45.4 μM, and the compounds of the present invention were used to inhibit the binding of YAP-TEAD to the colon cancer cell line HT29 cell. It was confirmed that cell proliferation was inhibited.

<Experimental Example 3> Anti-cancer activity evaluation experiment using AOM / DSS orthotopic syngenic mouse model

In order to measure the anti-cancer effect in the immune-living state in the large intestine, anti-cancer activity was measured using a known AOM / DSS model ( J. Vis. Exp. (67), e4100 10.3791 / 4100, Cell Death & Dis. 2018, 9, 153.).

After adapting the B6 mouse in the animal room for 1 week, AOM (azoxymethane) injection was injected intraperitoneally based on 10 mg per Kg. After 1 week, 2.5% DSS (dextran sulfate sodium) aqueous solution was watered for 1 week, followed by 3 times of alternative water supply with fresh water to induce colon cancer. After induction of colorectal cancer, YAP-TEAD inhibitory compound 17 of the present invention was injected intraperitoneally for 3 weeks, 5 times a week, based on 50 mg per Kg. After the end of the dosing period, the intestinal tissue was surgically extracted, and the number and size of cancer tissues in the intestinal tissue were measured, and the results were shown in FIGS. 1 to 3.

The results of observing the tumor size and number according to the administration of the compound of the present invention are shown in FIG. 1, from which the increase in the tumor size is significantly reduced compared to the case where the increase in tumor size is not administered when administering the compound of the present invention Was confirmed. In addition, normal weight gain was observed in all subjects during the experiment, and no specificity was observed in each tissue and organ after autopsy.

In addition, in order to confirm the potential toxicity of the compound of the present invention, the whole weight of the drug-treated whole body was measured and the results are shown in FIG. 2, compared with the group not treated with DSS, the weight of the group treated with DSS only decreased, but the present invention No particular additional weight loss was observed by administration of the compounds of the invention.

In addition, FACS analysis was performed to confirm the proportion of Treg cells that play an important role in immunosuppression in cancer tissues. As a method, after incision of cancer tissue in the intestinal tissue, collagenase was used to make a single cell, and antibody staining for CD4 and Fop3 markers was performed, followed by FACS analysis, and the results are shown in FIG. 3.

Treg cells, which are known to play an important role in immunosuppression in tumor microenvironment, are significantly increased in AOM / DSS-induced colorectal cancer tissue. However, in the group in which the compound 17 of the present invention was administered intraperitoneally for 3 weeks, it was confirmed that Treg cells decreased. Accordingly, it has been found that the compounds of the present invention increase the immune anti-cancer activity by reducing immunosuppression by overexpression of Treg in the process of carcinogenesis of colorectal cancer.

Claims (17)

A compound represented by Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof: [Formula 1]

(In the formula 1, R ^a is hydrogen or -LR ₃ ; R ₁ is hydrogen or-(CH ₂ ) _n -R; R is C1-C10 alkoxy, C6-C20 aryloxy, hydroxy, C1-C10 alkylcarbonyloxy, C6-C20 arylcarbonyloxy, cyano, halogen, nitro, C1-C10 alkylsulfanyl, C6-C20 aryl Sulfanyl, sulfanyl, -NR ^a1 R ^a2 , C1-C10alkoxyC1-C10alkyl, C6-C20aryloxyC1-C10alkyl, C1-C10alkoxyC1-C10alkoxy, C1-C10alkoxyC1-C10alkoxyC1- C10 alkyl, C1-C10 alkylsulfonyl, C6-C20 arylsulfonyl, C1-C10 alkyl C6-C20 arylsulfonyl, C6-C20 aryl C1-C10 alkylsulfonyl, sulfo, C6-C20 aryl, C3-C20 cyclo Alkyl, carbamoyl, C1-C10 alkylaminocarbonyl, C6-C20 arylaminocarbonyl, sulfamoyl, C1-C10 alkylaminosulfonyl, C6-C20 arylaminosulfonyl, C1-C10 alkylcarbonyl, C6-C20 Arylcarbonyl, C1-C10 alkoxycarbonyl, C6-C20 aryloxycarbonyl, carboxyl, formyl, C2-C20 heteroaryl or C3-C20 heterocycloalkyl, wherein R aryl, heteroaryl and heterocycloalkyl is C1 -C10 alkyl, halogen, nitro, cyano, hydroxyl , C1-C10alkoxy, C6-C20aryloxy, C1-C10alkylsulfanyl, haloC1-C10alkylsulfanyl, C6-C20arylsulfanyl, diC1-C10alkylamino, C1-C10alkylsulfonyl, C6- C20 arylsulfonyl, C1-C10 alkyl C6-C20 arylsulfonyl, C6-C20 arylC1-C10 alkylsulfonyl, C3-C20 cycloalkyl, carboxyl, sulfo, formyl, carbamoyl, sulfamoyl, amino, C1-C10 Alkylcarbonyl, C6-C20 arylcarbonyl, C1-C10 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C1-C10 alkylcarbonyloxy, C6-C20 arylcarbonyloxy, C2-C20 heteroaryl and C3- May be further substituted with one or more substituents selected from the group consisting of C20 heterocycloalkyl; R ^a1 and R ^a2 are each independently hydrogen, C1-C10 alkyl, C1-C10 alkylsulfonyl, C6-C20 arylsulfonyl, C1-C10 alkyl C6-C20 arylsulfonyl, C6-C20 arylC1-C10 alkylsulfur Phenyl, sulfo, C6-C20 aryl, C3-C20 cycloalkyl or sulfamoyl; n is an integer from 1 to 10; R ₂ is hydrogen, C1-C10 alkyl, C1-C10 alkoxy C1-C10 alkyl, C3-C20 cycloalkyl, C3-C20 cycloalkyloxyC1-C10 alkyl, C6-C20 aryl or C6-C20 aryloxyC1-C10 alkyl ego; X is CH or N; Z is -CH ₂ -or -CO-; L is -SO _2- , -SO ₂ -L'-, -NHCO-, -CONH-, C1-C10alkylene or -CO-; L 'is -NH- or

ego; L _a is C1-C10 alkylene; n1 is an integer from 1 to 3; m1 is an integer of 0 or 1; However, when (i) X is CH, L must be -SO ₂ -NH-, (ii) when L is C1-C10 alkylene, R ₃ is C1-C10 alkyl, C1-C10 alkoxy or C6-C20 aryloxy is excluded; R ₃ is C1-C10 alkyl, C1-C10 alkoxy, C6-C20 aryloxy, C3-C20 heterocycloalkyl, C6-C20 aryl or C2-C20 heteroaryl, and heterocycloalkyl, aryl and heteroaryl of R ₃ Silver C1-C10 alkyl, halogen, halo C1-C10 alkyl, nitro, cyano, C1-C10 alkylcarbonylamino, C6-C20 arylcarbonylamino, amino, C1-C10alkoxy, haloC1-C10alkoxy, C1- C10alkoxyC1-C10alkoxy, C6-C20aryloxy, hydroxy, C1-C10alkylcarbonyl, haloC1-C10alkylcarbonyl, C6-C20arylcarbonyl, C1-C10alkoxycarbonyl, C6-C20aryloxy Carbonyl, carboxyl, formyl, sulfanyl, C1-C10 alkylsulfanyl, C6-C20 arylsulfanyl, diC1-C10 alkylamino C1-C10 alkoxy, dihydroxyaminosulfanyl, C1-C10 alkylsulfonyl, C6 -C20 arylsulfonyl, C1-C10 alkyl C6-C20 arylsulfonyl, C6-C20 arylC1-C10 alkylsulfonyl, sulfo, carbamoyl, C1-C10 alkylaminocarbonyl, C6-C20 arylaminocarbonyl, sulfa Moyl, C1-C10 alkylaminosulfonyl, At least one substituent selected from the group consisting of C6-C20 arylaminosulfonyl, C6-C20 aryl, C2-C20 heteroaryl, C1-C10 alkylcarbonyloxy, C6-C20 arylcarbonyloxy and C3-C20 heterocycloalkyl. Can be further substituted with; R ₄ is halogen, halo C1-C10 alkyl, cyano, C1-C10 alkyl, C6-C20 aryl, C2-C20 heteroaryl, C1-C10 alkoxy, C6-C20 aryloxy, C2-C20 heteroaryloxy, halo C1 -C10 alkoxy, hydroxy, amino or aminoC1-C10 alkyl; d is an integer from 0 to 5, and when d is an integer of 2 or more, R ₄ may be the same or different from each other; a and b are each independently an integer of 0, 1 or 2, and a + b is an integer of 1, 2 or 3; The heteroaryl and heterocycloalkyl include one or more heteroatoms selected from nitrogen, oxygen and sulfur.) According to claim 1, A compound represented by Formula 2, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof: [Formula 2]

(In Formula 2, R ₁ , R ₂ , X, Z, L, R ₃ , R ₄ , a, b, and d are the same as defined in Formula 1 of Claim 1) According to claim 2, A compound represented by the following Chemical Formula 3, Chemical Formula 4, Chemical Formula 6, Chemical Formula 6 or Chemical Formula 7, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof: [Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

(In the above formulas 3 to 7, R ₁ , R ₂ , Z, L, R ₃ , R ₄ and d are the same as defined in formula 2 in claim 2) According to claim 1, A compound represented by the following Chemical Formula 8, Chemical Formula 9 or Chemical Formula 10, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof: [Formula 8]

[Formula 9]

[Formula 10]

(In the formulas 8 to 10, R ₁ , R ₂ , R ₃ , R ₄ and d are the same as defined in Formula 2 in claim 2) According to claim 3, A compound represented by any one selected from the following Formulas 11 to 25, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof: [Formula 11]

[Formula 12]

[Formula 13]

[Formula 14]

[Formula 15]

[Formula 16]

[Formula 17]

[Formula 18]

[Formula 19]

[Formula 20]

[Formula 21]

[Formula 22]

[Formula 23]

[Formula 24]

[Formula 25]

(In the formulas 11 to 25, R ₁ , R ₂ , R ₃ , R ₄ and d are the same as defined in Formula 2 in claim 2; R _3a is C3-C20 heterocycloalkyl, C6-C20 aryl or C2-C20 heteroaryl, and heterocycloalkyl, aryl and heteroaryl of R _3a are C1-C10 alkyl, halogen, halo C1-C10 alkyl, nitro, Cyano, C1-C10 alkylcarbonylamino, C6-C20 arylcarbonylamino, amino, C1-C10alkoxy, haloC1-C10alkoxy, C1-C10alkoxyC1-C10alkoxy, C6-C20aryloxy, hydroxy, C1-C10 alkylcarbonyl, halo C1-C10 alkylcarbonyl, C6-C20 arylcarbonyl, carboxyl, formyl, sulfanyl, C1-C10 alkylsulfanyl, C6-C20 arylsulfanyl, diC1-C10 alkylaminoC1 -C10 alkoxy, dihydroxyaminosulfanyl, C1-C10 alkylsulfonyl, C6-C20 arylsulfonyl, sulfo, carbamoyl, C1-C10 alkylaminocarbonyl, C6-C20 arylaminocarbonyl, sulfamoyl, C1 One or more substitutions selected from the group consisting of -C10 alkylaminosulfonyl, C6-C20 arylaminosulfonyl, C6-C20 aryl, C2-C20 heteroaryl and C3-C20 heterocycloalkyl It may further be substituted, and a; L _a is C1-C5 alkylene.) The method of claim 4 or 5, R ₁ is hydrogen or-(CH ₂ ) _n -R; R is C1-C6 alkoxy, C6-C12 aryloxy, hydroxy, cyano, halogen, nitro, C1-C6 alkylsulfanyl, C6-C12 arylsulfanyl, sulfanyl, -NR ^a1 R ^a2 , C1-C6alkoxy C1-C6 alkyl, C6-C12 aryloxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkylsulfonyl, C6-C12 arylsulfonyl , C1-C6alkylC6-C12arylsulfonyl, C6-C12arylC1-C6alkylsulfonyl, sulfo, C6-C12aryl, C1-C6alkoxycarbonyl, C6-C12aryloxycarbonyl, carboxyl, formyl, C2 -C12 heteroaryl or C3-C12 heterocycloalkyl, wherein the aryl, heteroaryl and heterocycloalkyl of R is C1-C6 alkyl, halogen, nitro, cyano, hydroxy, C1-C6 alkoxy, C6-C12 aryloxy , C1-C6 alkylsulfonyl, C6-C12 arylsulfonyl, C1-C6 alkyl C6-C12 arylsulfonyl, C6-C12 arylC1-C6 alkylsulfonyl, carboxyl, sulfo, formyl, carbamoyl, sulfamoyl and amino Further one or more substituents selected from the group consisting of It may be; R ^a1 and R ^a2 are each independently hydrogen, C1-C6 alkyl, C1-C6 alkylsulfonyl, C6-C12 arylsulfonyl, C1-C6 alkyl C6-C12 arylsulfonyl, C6-C12 arylC1-C6 alkylsulfur Phonyl, sulfo or sulfamoyl; n is an integer from 1 to 5; R ₂ is hydrogen, C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl or C6-C12 aryloxyC1-C6 alkyl; R ₃ is C1-C6 alkyl, C1-C6 alkoxy, C6-C12 aryloxy, C3-C12 heterocycloalkyl, C6-C12 aryl or C2-C12 heteroaryl; R _3a is C3-C12 heterocycloalkyl, C6-C12 aryl or C2-C12 heteroaryl; The heterocycloalkyl, aryl and heteroaryl of R ₃ and R _3a are C1-C6 alkyl, halogen, halo C1-C6 alkyl, nitro, cyano, C1-C6 alkylcarbonylamino, C6-C12 arylcarbonylamino, Amino, C1-C6 alkoxy, halo C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, C6-C12 aryloxy, hydroxy, C1-C6 alkylcarbonyl, halo C1-C6 alkylcarbonyl, C6-C12 aryl Carbonyl, carboxyl, formyl, sulfanyl, C1-C6 alkylsulfanyl, C6-C12 arylsulfanyl, diC1-C6 alkylamino C1-C6 alkoxy, dihydroxyaminosulfanyl, C1-C6 alkylsulfonyl, C6 -C12 arylsulfonyl, sulfo, carbamoyl, C1-C6 alkylaminocarbonyl, C6-C12 arylaminocarbonyl, sulfamoyl, C1-C6 alkylaminosulfonyl, C6-C12 arylaminosulfonyl, C6-C12 aryl , C2-C12 heteroaryl and C3-C12 heterocycloalkyl may be further substituted with one or more substituents selected from the group consisting of; L _a is C1-C5 alkylene; R ₄ is halogen, halo C1-C6 alkyl, cyano, C1-C6 alkyl, C6-C12 aryl, C2-C12 heteroaryl, C1-C6 alkoxy, C6-C12 aryloxy, C2-C12 heteroaryloxy, halo C1 -C6 alkoxy, hydroxy, amino or aminoC1-C6 alkyl; d is an integer from 0 to 5, and when d is an integer of 2 or more, R ₄ may be the same or different from each other, a compound, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. The method of claim 6, R ₁ is hydrogen or — (CH ₂ ) _n -R; R is C1-C6 alkoxy, hydroxy, cyano, halogen, C1-C6 alkylsulfanyl, -NR ^a1 R ^a2 , C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkoxy, C1-C6 alkoxy C1-C6alkoxy C1-C6 alkyl, C1-C6 alkylsulfonyl, C6-C12 arylsulfonyl, C6-C12 aryl, C1-C6 alkoxycarbonyl, C6-C12 aryloxycarbonyl, C2-C12 heteroaryl or C3 -C12 heterocycloalkyl, wherein the aryl, heteroaryl and heterocycloalkyl of R is C1-C6 alkyl, halogen, nitro, cyano, hydroxy, C1-C6 alkoxy, C6-C12 aryloxy, C1-C6 alkylsulfur Can be further substituted with one or more substituents selected from the group consisting of phenyl, C6-C12 arylsulfonyl, C1-C6 alkyl C6-C12 arylsulfonyl, C6-C12 arylC1-C6 alkylsulfonyl, carboxyl, sulfo and formyl. There is; R ^a1 and R ^a2 are each independently C1-C6 alkyl, C1-C6 alkylsulfonyl or C6-C12 arylsulfonyl; n is an integer from 1 to 3; R ₂ is hydrogen or C1-C6alkoxyC1-C6alkyl; R ₃ is C1-C6 alkyl, C1-C6 alkoxy, C3-C12 heterocycloalkyl, C6-C12 aryl or C2-C12 heteroaryl; R _3a is C3-C12 heterocycloalkyl, C6-C12 aryl or C2-C12 heteroaryl; The heterocycloalkyl, aryl and heteroaryl of R ₃ and R _3a are C1-C6 alkyl, halogen, halo C1-C6 alkyl, nitro, cyano, C1-C6 alkylcarbonylamino, C6-C12 arylcarbonylamino, Amino, C1-C6 alkoxy, halo C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, hydroxy, C1-C6 alkylcarbonyl, halo C1-C6 alkylcarbonyl, C6-C12 arylcarbonyl, carboxyl, formyl , Sulfanyl, C1-C6 alkylsulfanyl, C6-C12 arylsulfanyl, diC1-C6 alkylamino C1-C6 alkoxy, dihydroxyaminosulfanyl, C1-C6 alkylsulfonyl, C6-C12 arylsulfonyl, May be further substituted with one or more substituents selected from the group consisting of sulfo, carbamoyl, sulfamoyl, C6-C12 aryl, C2-C12 heteroaryl and C3-C12 heterocycloalkyl; R ₄ is halogen, halo C1-C6 alkyl, cyano, C1-C6 alkyl, C6-C12 aryl, C2-C12 heteroaryl, C1-C6 alkoxy, C6-C12 aryloxy, C2-C12 heteroaryloxy, halo C1 -C6 alkoxy, hydroxy, amino or aminoC1-C6 alkyl; d is an integer from 0 to 5, and when d is an integer of 2 or more, R ₄ may be the same or different from each other, a compound, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. The method of claim 7, R ₁ is hydrogen, a compound, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. The method of claim 7, R ₁ is-(CH ₂ ) _n -OR ₁₁ ,-(CH ₂ ) _n -OH,-(CH ₂ ) _n -CN,-(CH ₂ ) _n -X ₁ ,-(CH ₂ ) _n -SR ₁₂ ,-(CH ₂ ) _n -NR ₁₃ R ₁₄ ,-(CH ₂ ) _n -NR ₁₃ -SO ₂ R ₁₅ ,-(CH ₂ ) _n -L ₁ -OR ₁₁ ,-(CH ₂ ) _n -SO ₂ R ₁₆ or-(CH ₂ ) _n -C (= O) OR _17, or a compound selected from the following structure, a prodrug thereof, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof.

(R ₁₁ is C 1 -C 4 alkyl or C 1 -C 4 alkoxy C 1 -C 4 alkyl; X ₁ is halogen; R ₁₂ to R ₁₄ are each independently C1-C4 alkyl; R ₁₅ , R ₁₆ , R ₁₇ and R ₂₀ are each independently C 1 -C 4 alkyl or C 6 -C 12 aryl; L ₁ is C1-C4 alkylene; R ₁₈ and R ₁₉ are, independently of each other, C 1 -C 4 alkyl, halogen, nitro, cyano, hydroxy, C 1 -C 4 alkoxy, C 6 -C 12 aryloxy, carboxyl, sulfo or formyl; R 'is hydrogen or C1-C4 alkyl; Q is CH ₂ , NH, O or S; n is an integer from 1 to 3; p is an integer from 0 to 5, and when p is an integer of 2 or more, R ₁₈ may be identical to or different from each other; q is an integer from 0 to 4, and when q is an integer of 2 or more, R ₁₉ may be the same or different from each other.) The method of claim 7, R ₂ is hydrogen or C 1 -C 4 alkoxy C 1 -C 4 alkyl; R ₃ is selected from C1-C4 alkyl, C1-C4 alkoxy or the following structure;

R ₂₁ to R ₂₆ are each independently C1-C4 alkyl, halogen, halo C1-C4 alkyl, nitro, cyano, C1-C4 alkylcarbonylamino, C6-C12 arylcarbonylamino, amino, C1-C4alkoxy, HaloC1-C4alkoxy, C1-C4alkoxyC1-C4alkoxy, hydroxy, C1-C4alkylcarbonyl, haloC1-C4alkylcarbonyl, C6-C12arylcarbonyl, carboxyl, formyl, sulfanyl, C1-C4 Alkylsulfanyl, C6-C12 arylsulfanyl, diC1-C4alkylaminoC1-C4alkoxy, dihydroxyaminosulfanyl, C1-C4alkylsulfonyl, C6-C12arylsulfonyl, sulfo, carbamoyl, sulfamoyl , C6-C12 aryl, C2-C12 heteroaryl or C3-C12 heterocycloalkyl; Y ₁ and Y ₂ are each independently NR ″, O or S; Z is-(CR ₂₇ R ₂₈ ) _x- ; R ₂₇ and R ₂₈ are each independently hydrogen, C1-C4 alkyl or halogen; x is an integer from 1 to 3; T is CH ₂ or O; R '' is hydrogen or C1-C4 alkyl; r is an integer from 0 to 3, and when r is an integer of 2 or more, R ₂₁ may be the same or different from each other; s is an integer from 0 to 2, and when s is an integer from 2, R ₂₂ may be the same or different from each other; t is an integer from 0 to 4, and when t is an integer of 2 or more, R ₂₃ may be the same or different from each other; u is an integer from 0 to 5, and when u is an integer of 2 or more, R ₂₄ may be the same or different from each other; v is an integer from 0 to 6, and when v is an integer of 2 or more, R ₂₅ may be the same or different from each other; w is an integer from 0 to 7, and when w is an integer of 2 or more, R ₂₆ may be the same or different from each other; R ₄ is halogen, haloC1-C4alkyl, cyano, C1-C4alkyl, Ar ₁ , HET ₁ , C1-C4alkoxy, -O-Ar ₁ , -O-HET ₁ , haloC1-C4alkoxy, hydroxy , Amino or aminoC1-C4alkyl; Ar ₁ is phenyl, biphenyl or naphthyl; HET ₁ is pyrrolyl, furyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, Pyrimidyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzothienyl, isoindoleyl, indazolyl, benzoisoxazolyl, benzoisothiazolyl, benzoimidazolyl Benzooxazolyl, benzothiazolyl or benzotriazolyl; d is an integer from 0 to 3, and when d is an integer of 2 or more, R ₄ may be the same or different from each other, a compound, a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. The method of claim 10, R ₃ is C 1 -C 4 alkyl, C 1 -C 4 alkoxy or a compound selected from the following structure, a prodrug thereof, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof.

(In the above, R ₂₁ to R ₂₆ are each independently C1-C4 alkyl, halogen, halo C1-C4 alkyl, nitro, C1-C4 alkylcarbonylamino, amino, C1-C4alkoxy, haloC1-C4alkoxy, C1 -C4alkoxyC1-C4alkoxy, hydroxy, haloC1-C4alkylcarbonyl, carboxyl, diC1-C4alkylaminoC1-C4alkoxy, dihydroxyaminosulfanyl, C1-C4alkylsulfonyl, C6-C12aryl Or C2-C12 heteroaryl; Z is-(CR ₂₇ R ₂₈ ) _x- ; R ₂₇ and R ₂₈ are each independently hydrogen, C1-C4 alkyl or halogen; x is an integer from 1 to 3; R '' is hydrogen or C1-C4 alkyl; r is an integer from 0 to 3, and when r is an integer of 2 or more, R ₂₁ may be the same or different from each other; s is an integer from 0 to 2, and when s is an integer from 2, R ₂₂ may be the same or different from each other; t is an integer from 0 to 4, and when t is an integer of 2 or more, R ₂₃ may be the same or different from each other; u is an integer from 0 to 5, and when u is an integer of 2 or more, R ₂₄ may be the same or different from each other; v is an integer from 0 to 6, and when v is an integer of 2 or more, R ₂₅ may be the same or different from each other; w is an integer from 0 to 7, and when w is an integer of 2 or more, R ₂₆ may be the same or different from each other.) According to claim 1, The compound is any one selected from the following, a compound, a prodrug thereof, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition for the prevention or treatment of cancer, comprising the compound according to claim 1, a prodrug thereof, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient. The method of claim 13, The cancer may include lung cancer, colon cancer, colon cancer, rectal cancer, breast cancer, prostate cancer, bladder cancer, blood cancer, leukemia, myeloid leukemia, lymphoma, cervical carcinoma, osteosarcoma, glioblastoma, melanoma ( melanoma), pancreatic cancer, stomach cancer, liver cancer, kidney cancer, gallbladder cancer, biliary cancer, esophageal cancer, ovarian cancer, thyroid cancer, skin cancer or neuroblastoma, pharmaceutical composition. The method of claim 13, A pharmaceutical composition, which further comprises a pharmaceutically acceptable carrier, diluent or excipient. A YAP / TAZ-TEAD inhibitor composition comprising the compound according to claim 1, its prodrug, its hydrate, its solvate or its pharmaceutically acceptable salt as an active ingredient. A composition for preventing or improving cancer, comprising the compound according to claim 1, a prodrug thereof, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

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