TEAD targeting compounds and methods thereof

Abstract

The present invention relates generally to TEAD targeting compounds and methods thereof.

Description

Technical Field

[0001] The present invention generally relates to TEAD targeting compounds and methods thereof. Background Art

[0002] The Hippo pathway plays a central role in regulating organ size and maintaining dynamic tissue homeostasis. The pathway involves TAOK1 / 2 / 3 phosphorylation or MST1 / 2 autophosphorylation, which initiates the Hippo kinase cascade. MST1 / 2 activation phosphorylates LATS1 / 2. Activated LATS1 / 2 phosphorylates YAP / TAZ under the action of SAV1, MOB1A / B, and NF2. This leads to 14-3-3-mediated cytoplasmic retention and SCF-mediated degradation of YAP / TAZ. YAP / TAZ are transcriptional coactivators that regulate gene transcription primarily by interacting with TEAD. Upregulation of TEAD target gene expression and partial loss of the kinase cascade or overexpression of YAP may lead to increased progenitor cell proliferation and tissue overgrowth.

[0003] Due to the unique ability of the Hippo pathway to promote regeneration, any abnormality in its core components may promote cancer cell migration, invasion, and malignancy. Aberrant overexpression of YAP / TAZ in tumors promotes tumorigenesis and is therefore considered an oncogene in a large number of solid cancers. Drug resistance is a major factor that undermines the efficacy of anticancer drugs. Due to the role of YAP / TAZ–TEAD in intrinsic and acquired resistance to various chemotherapeutic and targeted therapeutic agents, there is growing interest in combining TEAD inhibitors with various cancer therapies.

[0004] Accumulating evidence strongly suggests that elevated YAP / TAZ-TEAD activity is associated with multiple stages of cancer progression and cancer types. Drug treatment of the TEAD hydrophobic pocket, discovered in 2015, remains an attractive and proven strategy to modulate activity. Despite its importance, only three small molecule TEAD inhibitors are currently being tested in Phase I clinical trials: VT3989b NCT04665206 from Vivacare, IK-930b NCT05228015 from Ikena Oncology, and IAG933b NCT0485737 from Novartis Oncology. Therefore, there is a need to discover alternative TEAD inhibitors for cancer treatment.

[0005] It is hoped that it can overcome or improve at least one of the above problems. Summary of the invention

[0006] The present disclosure is based on the understanding that TEAD inhibitors could have tremendous therapeutic potential if administered to patients whose tumors express the YAP / TAZ-TEAD signature, as these patients are likely to respond to TEAD inhibitor therapy.

[0007] The present disclosure relates to covalent chemical scaffolds that may hijack the conserved cysteine ​​of TEAD. For example, CPD10 and CPD13 lead to downregulation of TEAD-regulated transcriptional target genes. Immunoprecipitation and immunoblotting data show that CPD10 and CPD13 lead to interruption of TEAD4 binding to YAP / TAZ and reduce the expression of target proteins in a dose-dependent manner. Cell proliferation and colony formation assays show that CPD10 and CPD13 lead to inhibition of cell growth and viability of osteosarcoma (U2OS) and lung cancer cells (A549).

[0008] The present disclosure relates to compounds of formula (I) or salts, solvates or prodrugs thereof:

[0009]

[0010] in,

[0011] n is an integer selected from 1 to 5; and

[0012] Ar is optionally substituted aryl or optionally substituted heteroaryl.

[0013] In some embodiments, Ar is optionally substituted heteroaryl.

[0014] In some embodiments, Ar is an optionally substituted heteroaryl, wherein the heteroatom is located at the 2' position relative to the N of the amide moiety.

[0015] In some embodiments, Ar is selected from optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted thiazolyl, optionally substituted pyrazolyl, or optionally substituted triazolyl.

[0016] In some embodiments, n is an integer selected from 1 to 4.

[0017] In some embodiments, the compound of formula (I) is a compound of formula (Ia):

[0018]

[0019] in,

[0020] n is an integer selected from 1 to 5;

[0021] X1 is a heteroatom selected from N, S or O;

[0022] X2, X3 and X4 are independently selected from C, N, O or S;

[0023] When X2 is N or C, R1 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

[0024] When X3 and X4 are independently N or C, R2 and R3 are independently selected from H, or optionally substituted alkyl.

[0025] In some embodiments, X1 is a heteroatom selected from N or S.

[0026] In some embodiments, at least one of X2, X3 and X4 is N, O or S.

[0027] In some embodiments, R1 is selected from optionally substituted cycloalkyl or optionally substituted aryl.

[0028] In some embodiments, at least one of R2 and R3 is optionally substituted alkyl.

[0029] In some embodiments, the compound of formula (I) is selected from:

[0030]

[0031] The present invention relates to a Hippo pathway regulator, wherein the regulator is a compound of formula (I). The compound of formula (I) is a YAP / TAZ-TEAD regulator.

[0032] The present disclosure also relates to a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier, excipient or diluent.

[0033] The present disclosure also relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0034] The present disclosure also relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof for use in treating cancer.

[0035] The present disclosure also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof in the manufacture of a medicament for treating cancer in a patient in need thereof.

[0036] In some embodiments, the cancer is characterized by elevated YAP / TAZ-TEAD activity and / or drug resistance.

[0037] In some embodiments, the cancer is selected from mesothelioma, liver cancer, gastric cancer, metastatic non-small cell lung cancer (NSCLC), and colorectal cancer.

[0038] BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Embodiments of the invention will now be described by way of non-limiting examples with reference to the accompanying drawings, in which:

[0040] Figure 1: A) Confirmation of palmitate and reported inhibitors employed in the TEAD pocket. B) Overlay of palmitate and reported inhibitors reveals similar physical and chemical properties (hydrogen donors and acceptors) that contribute to efficient and selective binding to the TEAD pocket. The position of the cysteine ​​is primed for exploitation. C) Examples of three different cysteine ​​warheads selected for screening.

[0041] Figure 2: A) Schematic of activity-based protein profiling (ABPP). Covalent compounds that bind to conserved cysteines reduce the fluorescence signal. If the conserved cysteine ​​is unlabeled, the fluorescence will be more. B) Palmitoyl-CoA is used as a positive control to show that we have optimized ABPP for our assay. C) Screening campaign with an arbitrary cutoff of 0.25. Compounds with a normalized fluorescence less than 0.25 were considered hits (N=4 independent experiments). D) Typical gel readout of a screening campaign; palmitoyl-CoA as positive control; DMSO as negative control; compound activity was normalized by setting DMSO to 1 and palmitoyl-CoA to 0.

[0042] Figure 3: A) Intact mass spectra (MALDI) showing compound labeling with TEAD in vitro (right-shifted mass peak corresponding to one compound). Notably, only one of the four cysteine ​​residues reacted with the covalent compound. Not all compounds reacted with TEAD, reflecting that the cysteine ​​warhead does not label any cysteine ​​residue indiscriminately. B) SAR of the hits. C) LC-MS / MS analysis reveals that the more preferred cysteine ​​residue to be labeled is a conserved cysteine.

[0043] Figure 4 :A) CPD10 and CPD13 inhibit the expression of YAP / TAZ protein: A549 cells were treated with the indicated doses of CPD10 and immunoblotted for YAP, YAP / TAZ, and pan-TEAD. GAPDH and p53 signals were used as controls (A). Similarly, A549 cells treated with cpd13 reduced YAP protein signal at 10 μM (B). After treatment with 10 μM CPD10, the binding of YAP / TAZ to TEAD4 was significantly reduced (C).

[0044] Figure 5: CPD10 and CPD13 promote the cytoplasmic localization of TEAD4: CPD10 and CPD13 treatment produces TEAD4 cytoplasmic localization signals: Unlike DMSO-treated cells, CPD10 and CPD13 produce cytoplasmic signals, while the nuclear signals remain intact.

[0045] Figure 6 : CPD10 and CPD13 lead to downregulation of TEAD transcriptional targets: Relative expression of YAP and TAZ in A549 cells after low-dose CPD10 (A) and CPD13 (B) treatment. c-MYC is included as a non-transcriptional target of TEAD. NFKB1 is included because its expression is relative to YAP / TAZ. Downstream effectors of TEAD targets (CYR61, AXL, CTGF, and ANKRD1) were determined at 2.5, 5, and 10 μM CPD10 (C) and CPD13 (D), respectively.

[0046] Figure 7: CPD10 and CPD13 exhibit TEAD4-dependent cell proliferation and differential viability in U2OS and A549 cells: Cell proliferation assay data showed that CPD10 greatly enhanced the sensitivity of U2OS cells and A549 cells overexpressing TEAD4 (A and B). Depletion of TEAD4 in A549 cells resulted in a reduction in CPD10-induced cell proliferation (C). Colony formation assays showed that GFP-TEAD4 cells were more sensitive to 2.5 μM CPD10 than GFP overexpressing cells. Unlike control siRNA-treated cells, TEAD4-depleted cells were less sensitive to CPD13 (D).

[0047] Figure 8: TEAD modeling and CPD10 and CPD13 evaluation in the NCI-H226 mesothelioma cell line: In silico docking for TEAD-CPD10 / CPD13 modeling (A and B). TEAD-CPD10 modeling (C). TEAD4 immunoprecipitation in NCI-H226 mesothelioma cells treated with indicated concentrations of CPD10 and CPD13 to determine YAP-TEAD binding (D). Immunoblot gel quantification to determine the percentage of YAP-TEAD binding disruption (E). YAP-TEAD transcriptional target gene profile (F). Dose-dependent relative luminescence (ATP / ADP ratio) profile for NCI-H226 mesothelioma cells treated with CPD10 and CPD13 (G). Colony formation assay to determine CPD10 and CPD13-induced drug sensitivity and the ability to form colonies in NCI-H226 mesothelioma cells (H).

[0048] Fig. 9 CPD13 in different cells was compared with positive control.

[0049] Fig.10 Shown is a colony formation assay to determine cell viability after CPD2 treatment and recovery (5 days).

[0050] Fig.11 Shown is a colony formation assay to determine cell viability after CPD38 treatment and recovery (5 days). DETAILED DESCRIPTION

[0051] "Alkyl" refers to a monovalent alkyl group which may be linear or branched and preferably has 1 to 10 carbon atoms, or more preferably 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-hexyl, and the like.

[0052] "Alkenyl" refers to a monovalent alkenyl group, which may be straight or branched, preferably has 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and has at least 1 carbon-carbon double bond, preferably 1-2 carbon-carbon double bonds. Examples include ethenyl (-CH=CH2), n-propenyl (-CH2CH=CH2), isopropenyl (-C(CH3)=CH2), but-2-enyl (-CH2CH=CHCH3), etc.

[0053] "Halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0054] "Oxo / hydroxy" refers to the group =0, HO-.

[0055] "Aryl" refers to an unsaturated aromatic carbocyclic group having a single ring (eg, phenyl) or multiple condensed rings (eg, naphthyl or anthracenyl), preferably having 6 to 14 carbon atoms. Examples of aryl include phenyl, naphthyl, and the like.

[0056] "Heteroaryl" refers to a monovalent aromatic heterocyclic group that satisfies the Hückel aromaticity criterion (i.e., contains 4n+2 π electrons), and preferably contains 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, selenium and sulfur (including oxides of sulfur, selenium and nitrogen). Such heteroaryl groups may have a single ring (e.g., pyridyl, pyrrolyl or its N-oxide or furanyl) or multiple condensed rings (e.g., indolizinyl, benzimidazolyl, coumarinyl, quinolyl, isoquinolyl or benzothienyl).

[0057] Examples of heteroaryl groups include, but are not limited to, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, indole, indazole, purine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isothiazole, phenoxazine, phenothiazine, thiazole, thiadiazole, oxadiazole, oxatriazole, tetrazole, thiophene, benzo[b]thiophene, triazole, imidazopyridine, and the like.

[0058] "Heterocyclyl" refers to a monovalent saturated or unsaturated group having a monocyclic or polycyclic fused ring, preferably having 1 to 8 carbon atoms and 1 to 4 heteroatoms, the heteroatoms being selected from nitrogen, sulfur, oxygen, selenium or phosphorus in the ring. The most preferred heteroatom is nitrogen. For example, it should be understood that when R2 or R' is an optionally substituted heterocyclyl having one or more ring heteroatoms, the heterocyclyl can be connected to the core molecule of the compound of the invention via a C-C or C-heteroatom bond (particularly a C-N bond).

[0059] Examples of heterocyclic and heteroaryl groups include, but are not limited to, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isothiazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiadiazole, oxadiazole, oxatriazole, tetrazole, thiazolidine, thiophene, benzo[b]thiophene, morpholine, piperidinyl, pyrrolidine, tetrahydrofuranyl, triazole, and the like.

[0060] "Amino" refers to the radical -NR"R" wherein each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, and wherein each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.

[0061] In the present specification, "optionally substituted" refers to a group that may or may not be further substituted or fused (to form a fused polycyclic group) by one or more groups selected from the following groups: hydroxy, acyl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, thio, aralkyl, aralkyloxy, aryl, aryloxy, carboxyl, amido, cyano, halogen, nitro, phosphonyl, sulfo, phosphorylamino, phosphonyl, heteroaryl, heteroaralkyl, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, oxyacyl , oxime, oxime ether, hydrazone, oxygen acylamino, oxygen sulfonylamino, aminoacyloxy, trihalomethyl, trialkylsilyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylthio, trifluorovinyl, mono- and dialkylamino, mono- and di(substituted alkyl)amino, mono- and diarylamino, mono- and diheteroarylamino, mono- and diheterocyclylamino, and asymmetric disubstituted amines having different substituents selected from alkyl, aryl, heteroaryl and heterocyclyl, and may also include bonding to a solid support material (e.g., substituted onto a polymer resin). For example, an "optionally substituted amino" group may include amino acids and peptide residues.

[0062] Genetic alterations in Hippo pathway components are increasingly common in cancer. Therefore, small molecule covalent inhibitors with similar scaffolds that can access the TEAD pocket may have therapeutic effects in cancers associated with elevated YAP / TAZ-TEAD activity relative to normal levels.

[0063] Another strategy involves identifying scaffolds that tightly bind to the hydrophobic pocket. For example, covalent TEAD inhibitors can be developed to take advantage of the conserved cysteine. Without being bound by theory, it is believed that by combining these two strategies, the central hydrophobic pocket of TEAD can be more specifically targeted, thereby identifying scaffolds that simultaneously occupy the pocket and covalently bind to the conserved cysteine, achieving high potency and selectivity.

[0064] Palmitoylation of the conserved cysteine ​​of TEAD was found to be required for its stability and activity. Therefore, compounds with chemical scaffolds that preferentially and covalently bind to the conserved cysteine ​​in the palmitate binding pocket of TEAD were identified. A rational compound library selection approach was employed. Existing co-crystal structures of TEAD with palmitate and other non-covalent inhibitors were analyzed and physical and chemical similarities were identified to guide the rational selection of new compound classes for screening ( Figure 1A and B).

[0065] The pool of rationally selected compounds includes cysteine ​​warheads, preferably selected from chloroacetamide, acrylamide and vinyl sulfone ( Figure 1C ). Secondly, a fluorescent gel-based active protein profiling (ABPP) assay was designed ( Figure 2A and B) to screen our library for covalent compounds that bind to the conserved cysteine ​​of TEAD ( Figure 2C The best compounds were then back screened to validate binding activity using full mass spectrometry experiments (Figure 3A), while also obtaining useful information on structure-activity relationships (SAR) ( Figure 3B ). In addition, LC-MS / MS data showed that the preferred modification site was the conserved cysteine ​​residue ( Figure 3C ), where labeling prevents TEAD palmitoylation. Interestingly, the vinyl sulfone warhead was particularly effective. Our cell-based biochemical assay data strongly suggest its potential application in cancer therapy.

[0066] Therefore, the present disclosure provides a compound of formula (I) or a salt, solvate or prodrug thereof:

[0067]

[0068] in,

[0069] n is an integer selected from 1 to 5; and

[0070] Ar is optionally substituted aryl or optionally substituted heteroaryl.

[0071] These compounds are rationally selected from enamines, which were previously not known to have any biological properties. These compounds exhibit TEAD inhibitory properties and may be developed for cancer treatment.

[0072] These chemical scaffolds (e.g., CPD10 and CPD13) have cysteine ​​warheads (vinyl sulfone) that target the TEAD cysteine. Furthermore, in addition to targeting the hydrophobic pocket of TEAD, these compounds are optimized to interact with polar residues near the entrance of the pocket. The present invention is suitable for treating cancers with elevated YAP / TAZ-TEAD activity and drug resistance. Multiple studies have highlighted the importance of TEAD in human cancers. Overexpression of TEAD has been associated with multiple stages of cancer progression and cancer types. In addition, the Hippo pathway is known to be a key factor in the development of resistance to chemotherapy and targeted therapies, including inhibitors of the Ras, EGFR, RAF, and MEK pathways.

[0073] In some embodiments, Ar is an optionally substituted heteroaryl. In some embodiments, Ar is selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted thiazolyl, optionally substituted pyrazolyl or optionally substituted triazolyl.

[0074] In some embodiments, the optional substituent is selected from the group consisting of optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl. In some embodiments, the optional substituent is selected from the group consisting of optionally substituted phenyl and optionally substituted cyclohexyl. In some embodiments, the optional substituent is selected from the group consisting of phenyl and cyclohexyl.

[0075] In some embodiments, the optional substituent is selected from halogen, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl and optionally substituted amino. In some embodiments, the optional substituent is selected from optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkoxy and optionally substituted C2-C5 alkenyl. In some embodiments, the optional substituent is selected from C1-C5 alkyl, C1-C5 alkoxy and C2-C5 alkenyl.

[0076] In some embodiments, Ar is an optionally substituted heteroaryl, wherein the heteroatom is located at the 2' position relative to the N of the amide moiety.

[0077] In some embodiments, n is an integer selected from 2 to 5, 3 to 5, or 4 to 5. In some embodiments, n is an integer selected from 1 to 4, 1 to 3, or 1 to 2. In some embodiments, n is 1.

[0078] In some embodiments, Ar is an optionally substituted heteroaryl. In some embodiments, Ar is an optionally substituted 5-membered heteroaryl. In some embodiments, the compound of formula (I) is a compound of formula (Ia):

[0079]

[0080] in,

[0081] n is an integer selected from 1 to 5;

[0082] X1 is a heteroatom selected from N, S or O;

[0083] X2, X3 and X4 are independently selected from C, N, O or S;

[0084] R1 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

[0085] R2 and R3 are independently selected from H or optionally substituted alkyl.

[0086] In some embodiments, the compound of formula (I) is a compound of formula (Ia):

[0087]

[0088] in,

[0089] n is an integer selected from 1 to 5;

[0090] X1 is a heteroatom selected from N, S or O;

[0091] X2, X3 and X4 are independently selected from C, N, O or S;

[0092] When X2 is N or C, R1 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

[0093] When X3 and X4 are independently N or C, R2 and R3 are independently selected from H, or optionally substituted alkyl.

[0094] Based on SAR studies, it was found that X1 is preferably a heteroatom. It is believed that the heteroatom at X1 may interact beneficially with the TEAD hydrophobic pocket (possibly with the peptide backbone or certain proximal polar amino acids).

[0095] In some embodiments, X1 is a heteroatom selected from N or S. In some embodiments, X1 is N. In some embodiments, X1 is S.

[0096] In some embodiments, at least one of X2, X3 and X4 is N, O or S. In some embodiments, at least one of X2, X3 and X4 is N or S.

[0097] In some embodiments, at least two of X2, X3, and X4 are N, O, or S. In some embodiments, at least two of X2, X3, and X4 are N or S.

[0098] In some embodiments, R1 is selected from optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl. In some embodiments, R1 is selected from optionally substituted cycloalkyl or optionally substituted aryl. In some embodiments, R1 is selected from optionally substituted phenyl and optionally substituted cyclohexyl. In some embodiments, R 1 Selected from phenyl and cyclohexyl.

[0099] In some embodiments, at least one of R2 and R3 is an optionally substituted alkyl. In some embodiments, at least one of R2 and R3 is an optionally substituted C1-C5 alkyl. In some embodiments, at least one of R2 and R3 is a C1-C5 alkyl. In some embodiments, the alkyl is methyl, ethyl, n-propyl or isopropyl. In some embodiments, the alkyl is methyl.

[0100] The compound of formula (I) may be selected from:

[0101]

[0102]

[0103] In some embodiments, the compound of formula (I) is selected from:

[0104]

[0105] The present invention relates to a Hippo pathway regulator comprising a compound of formula (I). The compound of formula (I) is a YAP / TAZ-TEAD regulator.

[0106] In some embodiments, the modulator is used in vitro. For example, the modulator can be used to treat a cell line cell or a tumor removed from an organism. In some embodiments, the modulator is used in vivo.

[0107] The present disclosure also relates to a composition comprising a compound of formula (I) or a salt, solvate or prodrug thereof, and palmitic acid or a salt, solvate or prodrug thereof.

[0108] The present disclosure also relates to a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier, excipient or diluent.

[0109] In some embodiments, the composition further comprises palmitic acid or a pharmaceutically acceptable salt, solvate or prodrug thereof. For example, palmitate is an ionized form of palmitic acid, which is a fatty acid with a 16-carbon chain.

[0110] In some embodiments, the pharmaceutical composition further comprises another active ingredient. The active ingredient may be an anticancer drug.

[0111] The compounds of the present invention can be administered to a subject in the form of a pharmaceutically acceptable salt thereof. Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid and hydrobromic acid or salts of pharmaceutically acceptable organic acids, such as acetic acid, propionic acid, butyric acid, tartaric acid, maleic acid, hydroxymaleic acid, fumaric acid, maleic acid, citric acid, lactic acid, mucic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, salicylic acid, sulfanilic acid, aspartic acid, glutamic acid, ethylenediaminetetraacetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid and valeric acid.

[0112] Alkaline salts include, but are not limited to, salts formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium. Specifically, the present invention includes cationic salts such as sodium or potassium salts, or alkyl esters (e.g., methyl, ethyl) of a phosphate group within its scope.

[0113] Basic nitrogen-containing groups may be quaternized with reagents such as lower alkyl halides (eg, methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates or esters (eg, dimethyl sulfate and diethyl sulfate).

[0114] It should be understood that any compound as a prodrug of the compound of formula (I) also belongs to the scope and spirit of the present invention. Therefore, the compound of the present invention can be administered to a subject in the form of a pharmaceutically acceptable prodrug. The term "prodrug" is used in its broadest sense, including those derivatives that are converted into the compounds of the present invention in vivo. Such derivatives are easily conceivable to those skilled in the art. Other texts that usually describe prodrugs (and their preparation) include: "Prodrug Design" (Design of Prodrugs), 1985, H.Bundgaard (Elsevier); "The Practice of Medicinal Chemistry" (The Practice of Medicinal Chemistry), 1996, Camille G.Wermuth et al., Chapter 31 (Academic Press); and "Drug Design and Development Textbook" (A Textbook of Drug Design and Development), 1991, Bundgaard et al., Chapter 5, (Harwood Academic Publishers).

[0115] The compounds of the present invention may be in the form of free compounds or solvates (eg hydrates) in crystal form, and both forms are within the scope of the present invention. Methods of solvation are well known in the art.

[0116] The compound of the present invention or its pharmaceutically acceptable salt, solvate or prodrug is administered to the patient in a therapeutically effective amount. As used herein, a therapeutically effective amount is intended to include at least partially achieving the desired effect, or delaying the occurrence of macular degeneration, or inhibiting its progression, or completely stopping or reversing its occurrence or progression.

[0117] As used herein, the term "effective amount" refers to the amount of a compound that provides the desired therapeutic activity when administered according to the desired dosage regimen. Administration can be performed every few minutes, hours, days, weeks, months, or years, or can be performed continuously in any of these time periods. A suitable dosage can be about 0.1 ng / kg body weight to 1 g / kg body weight per dose, for example, 1 mg / kg body weight to 1 g / kg body weight per dose. In one embodiment, the dosage can be 1 mg / kg body weight to 500 mg / kg body weight per dose. In another embodiment, the dosage can be 1 mg / kg body weight to 250 mg / kg body weight per dose. In another embodiment, the dosage can be 1 mg / kg body weight to 100 mg / kg body weight per dose, for example, up to 50 mg / kg body weight per dose.

[0118] The appropriate dosage and administration regimen can be determined by the attending physician and may depend on the severity of the condition and the general age, health, and weight of the patient to be treated.

[0119] The compounds of the present invention can be administered in a single dose or in a series of doses. Although it is possible to administer the active ingredient alone, it is best to use it as a composition, preferably as a pharmaceutical composition. The formulation of such compositions is well known to those skilled in the art. The composition may contain any suitable carrier, diluent or excipient. These include all conventional solvents, dispersion media, fillers, solid carriers, coatings, antifungal and antibacterial agents, skin penetrants, surfactants, isotonic agents and absorbents, etc. It should be understood that the compositions of the present invention may also include other supplementary physiologically active agents.

[0120] The carrier must be pharmaceutically "acceptable", i.e., compatible with the other ingredients in the composition and not harmful to the patient. The composition can be conveniently presented in unit dosage form and can be prepared by any method well known in the pharmaceutical art. Such methods include the step of combining the active ingredient with a carrier that constitutes one or more auxiliary ingredients. Generally, the composition is prepared by uniformly and intimately associating the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then shaping the product as desired.

[0121] Injections for this purpose can be prepared in conventional forms, as liquid solutions or suspensions or as solid forms suitable for preparation as solutions or suspensions in liquids prior to injection or as emulsions. For example, the carrier can include water, saline (e.g., normal saline (NS), phosphate buffered saline (PBS), balanced salt solution (BSS)), sodium lactate Ringer's solution, glucose, glycerol, ethanol, etc.; and if necessary, a small amount of auxiliary substances such as wetting agents or emulsifiers, buffers, etc. can be added. For example, the desired particle size can be maintained in the case of dispersion by using a coating such as lecithin and the appropriate fluidity can be maintained by using a surfactant. For example, the compound, composition or combination can be dissolved in a pharmaceutically effective carrier and injected into the vitreous body of the eye using a fine gauge hollow bore needle (e.g., 30 gauge, 1 / 2 or 3 / 8 inch needle) through a temporal approach (e.g., for human eyes, about 3 to about 4 mm behind the limbus to avoid damaging the lens).

[0122] Those skilled in the art will appreciate that other methods may also be used to inject and / or administer the compound, composition, or combination into the vitreous of the eye. For example, these other methods may include an intravitreal drug delivery device. For example, these devices and methods may include an intravitreal drug delivery device and a biodegradable polymer delivery member inserted into the eye for long-term delivery of the drug. These devices and methods may also include a transscleral delivery device.

[0123] Other modes of administration may also be used, including topical or intravenous administration. For example, a solution or suspension of the compound, composition or combination of the present invention may be formulated as eye drops, or as a film-like eye patch, which is applied directly to the surface of the eye. Topical administration generally involves administering 0.1 ng to 10 mg of the compound of the present invention.

[0124] The compounds, compositions or combinations of the present invention may also be suitable for intravenous administration. For example, a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof may be administered at up to 16 mg / m 2 The dose was administered intravenously.

[0125] The compounds, compositions or combinations of the present invention may also be suitable for oral administration and may be present as separate units, such as capsules, sachets or tablets, each containing a predetermined amount of active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as a water-in-oil liquid emulsion or an oil-in-water liquid emulsion. The active ingredient may also be present as a pill, ointment or paste. In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug is administered orally.

[0126] Tablets can be made by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form (e.g., powder or granules) in a suitable machine, optionally mixed with a binder (e.g., inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose) surfactant or dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Optionally, the tablets can be coated or scored and can be formulated to provide slow or controlled release of the active ingredient therein, for example, using hydroxypropylmethylcellulose in varying proportions to provide the desired release profile. Optionally, tablets with enteric coatings can be provided for release in parts of the intestinal tract other than the stomach.

[0127] The compounds, compositions or combinations of the present invention may be adapted for topical administration in the mouth, including lozenges containing the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles containing the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0128] The compound, composition or combination of the present invention may be suitable for topical administration to the skin, which may include a compound dissolved or suspended in any suitable carrier or matrix, and may be in the form of a lotion, gel, cream, paste, ointment, etc. Suitable carriers include mineral oil, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, sorbitol monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Transdermal patches may also be used to administer the compound of the present invention.

[0129] The compounds, compositions or combinations of the present invention may be suitable for parenteral administration, including aqueous and non-aqueous isotonic sterile injection solutions, which may contain antioxidants, buffers, bactericides and solutes to make the compounds, compositions or combinations isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. The compounds, compositions or combinations may be present in unit dose or multi-dose sealed containers, such as ampoules and vials, and may be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Extemporaneous injection solutions and suspensions may be prepared from the aforementioned sterile powders, granules and tablets.

[0130] Preferred unit dosage compositions or combinations are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[0131] It should be understood that, in addition to the above-mentioned active ingredients, the composition or combination of the present invention may also include other conventional agents in the art, which are related to the type of composition or combination in question, for example, compositions or combinations suitable for oral administration may include other agents, such as adhesives, sweeteners, thickeners, flavoring agents, disintegrants, coating agents, preservatives, lubricants and / or time delay agents. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin. Suitable disintegrants include corn starch, methylcellulose, polyvinyl pyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable flavoring agents include peppermint oil, wintergreen oil, cherry, orange or raspberry flavoring. Suitable coating agents include polymers or copolymers of acrylic acid and / or methacrylic acid and / or its esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, α-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulfite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.

[0132] The present disclosure also relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0133] The present disclosure also relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof for use in treating cancer.

[0134] The present disclosure also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof in the manufacture of a medicament for treating cancer in a patient in need thereof.

[0135] In some embodiments, the cancer is characterized by elevated YAP / TAZ-TEAD activity and / or drug resistance.

[0136] In some embodiments, the cancer is selected from mesothelioma, liver cancer, gastric cancer, metastatic non-small cell lung cancer (NSCLC), and colorectal cancer.

[0137] In some embodiments, the method, compound or use further comprises another active ingredient. The active ingredient may be an anticancer drug.

[0138] In some embodiments, the method comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, in combination with an effective amount of a cancer active ingredient.

[0139] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is used in combination with a cancer active ingredient for treating cancer.

[0140] In one embodiment, the present disclosure provides use of a compound of formula (I) or a salt, solvate or prodrug thereof in combination with a cancer active ingredient in the preparation of a medicament for treating cancer.

[0141] In one embodiment, the present disclosure provides the use of a cancer active ingredient in combination with a compound of formula (I) or a salt, solvate or prodrug thereof in the manufacture of a medicament for treating cancer.

[0142] In some embodiments, the compound of formula (I) or its salt, solvate or prodrug and the cancer active ingredient are added simultaneously or sequentially in any order.

[0143] The term "combination" as used herein refers to the co-administration of a combination drug to a single patient, and is intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The therapeutic compound or treatment method used in such a combination therapy can be administered together with a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug, administered sequentially, administered separately in a combined unit dose or a separate unit dose.

[0144] Example

[0145] Figure 3CShown are the MS / MS results of the compounds reacting with TEAD, revealing in vitro modification of the conserved cysteine.

[0146] We observed that:

[0147] Four cysteine ​​residues / TEAD-YBD;

[0148] Tetrapeptides, each containing one cysteine;

[0149] ·% modified peptides = number of modified peptides / total number of peptides detected;

[0150] Palmitoylated cysteine ​​is known to be preferentially modified by the compound;

[0151] The SPLCEYMINFIHK peptide containing a known conserved cysteine ​​is the primary target;

[0152] • A VCSFGK peptide containing another cysteine ​​known to be palmitoylated was revealed.

[0154] Figure 4 It was shown that CPD10 and CPD13 inhibited the expression of YAP / TAZ proteins.

[0155] Methods: A549 cells (60% confluency) were treated with the indicated doses of CPD10 and CPD13 for 24 h or mock treated. Cells were washed with ice-cold 1X PBS and lysed in protein lysis buffer. Whole cell lysates were purified by Pierce TM BCA protein assay kit (Cat. No. 23225) was used for quantification, denatured in 4XLDS buffer (Thermo Cat. No. NP0007), added with a competing amount of DTT, and then boiled for 3 minutes. Samples were resolved in 8% SDS-PAGE, transferred to nitrocellulose membranes, and immunoblotted with the indicated antibodies.

[0156] GFP-TRAP assay: To purify TEAD4 binders, GFP-Trap magnetic agarose (gtma-100) was used and the assay was performed strictly according to the manufacturer's instructions. At the end of the assay, the agarose beads were resuspended in 2X LDS lysis buffer, to which a competing amount of DTT was added, and the samples were boiled for 3 minutes. The supernatant was collected and used for immunoblotting.

[0157] Results: To determine the expression of CPD10 and CPD13-mediated hippo signaling target proteins in A549 cells, whole cell lysates of mock-treated and compound-treated cells were immunoblotted to determine the levels of TEAD4, pan-TEAD, YAP, and TAZ proteins. Interestingly, YAP expression was downregulated in a dose-dependent manner after CPD10 treatment. TAZ expression was significantly reduced at 10 U m. At the highest concentration, TEAD4 and pan-TEAD expression were also reduced (A). Similar to CPD10, CPD13 also downregulated YAP expression at 10 U m (B). To determine the levels of other transcriptional targets, we tested p53 protein in the same protein sample set. Compounds 10 and 13 did not alter the expression of wild-type p53, indicating that the compounds act specifically on the hippo signaling pathway. GAPDH was used as a loading control.

[0158] To determine whether CPD10 or 13 leads to downregulation of TEAD4 binding to its transcriptional targets YAP and TAZ, U2OS cells stably expressing GFP and GFP-fused TEAD4 were mock treated or treated with the indicated doses of CPD10. GFP-TRAP assay was performed to isolate TEAD4 binders and immunoblotted. As one of the strong binders of TEAD4, YAP / TAZ protein signal was detected in the purified complex. Interestingly, this binding was significantly reduced after 10uM CPD10 treatment. GFP blot indicates GFP and GFP-fused TEAD4 signals in whole cell lysates and purified protein samples (C).

[0159] Figure 5 It is shown that CPD10 and CPD13 treatment results in TEAD4 cytoplasmic localization.

[0160] Methods: U2OS cells stably expressing GFP-TEAD4 were seeded at a density of 50,000 cells onto glass coverslips in six-well plates. The next day, cells were treated with DMSO or with the indicated compounds at a concentration of 10 μM. After 18 h of treatment, cells were washed with 4% formaldehyde and fixed for 20 min. Blocking was performed in 3% BSA in PBST for 1 h. Cells were incubated with the indicated antibodies overnight in a cold room. The next day, after washing 3 times in PBST, samples were incubated with the corresponding secondary antibodies for 45 min at room temperature. After washing, nuclear staining was performed with DAPI for 10 min. Coverslips were added to glass slides with the help of mounting media. After drying, cells were imaged under a 63x objective and processed with ZEN x64 blue software.

[0161] Results: In DMSO-treated control samples, we observed that the TEAD4 (green) signal was very localized in the nucleus and strongly overlapped with the DAPI signal. Nuclear and cytoplasmic YAP and TAZ were observed in cells treated with DMSO or compounds. Interestingly, we detected GFP signals from outside the nucleus after CPD10 and 13 treatment. Although the presence of overall nuclear TEAD4 was not reduced by CPD10 or CD13 treatment, both inhibitors induced cytoplasmic localization of TEAD4 protein.

[0162] Figure 6 CPD10- and CPD13-dependent transcriptional target gene regulation is shown.

[0163] Methods: A549 cells (60% confluence) were treated with the indicated doses of CPD10 and CPD13 for 24 h or mock treated. Cells were washed with ice-cold 1X PBS. RNA was extracted using the Quick-RNATM miniprep kit (Zymo Research, Cat. No. R1055) strictly following the manufacturer's instructions. cDNA synthesis was performed using a cDNA reverse transcription kit (Thermo Cat. No. 4368814) from 2 μg of RNA sample quantified by Nanodrop strictly following the manufacturer's instructions. In RT PCR experiments, SYBR TM Comparative analysis of target gene expression was performed using the HER2 Green (Thermo Product No. 4309155) Master Mix. Relative target gene expression was compared and plotted on the Y-axis.

[0164] Results: Relative expression of YAP and TAZ in A549 cells after low-dose CPD10 (A) and CPD13 (B) treatment. c-MYC was included as a non-transcriptional target of TEAD. NFKB1 was included because its expression is relative to YAP / TAZ. Downstream effectors of TEAD targets (CYR61, AXL, CTGF, and ANKRD1) were determined at 2.5, 5, and 10 μM CPD10 (C) and CPD13 (D).

[0165] CPD10 and CPD13 downregulate TEAD transcriptional target genes:

[0166] To determine the relative expression of TEAD target genes induced by CPD10 and CPD13, A549 cells were treated with the indicated doses for 24 h. Transcriptional analysis was performed using the corresponding primer pairs. After treatment with 2.5 μM CPD10, YAP / TAZ expression was downregulated. A slight increase in NFKB1 was observed. In addition, we tested the expression of a potent non-hippo transcription factor, C-Myc. As expected, c-MYC expression was not affected by CPD10 treatment (A). After CPD13 treatment, a significant decrease in YAP / TAZ expression was detected. C-Myc expression was not affected. Earlier results have shown that YAP attenuates the NF-κB pathway. The increase in NFKB1 expression is consistent with the significant downregulation of YAP expression after CPD13 treatment (B). To determine the status of TEAD transcriptional target genes at higher concentrations, A549 cells were treated with the indicated doses of compounds and the expression of CYR61, AXL, CTGF, and ANKRD1 was analyzed. Interestingly, after CPD10 treatment, most targets (CYR61, AXL, and CTGF) were inhibited at 2.5 μM and subsequently downregulated in a dose-dependent manner. The expression of ANKRD1 was significantly reduced at 10 μM (C). A549 cells treated with the indicated doses of CPD13 resulted in a significant reduction in all four tested targets (CYR61, AXL, CTGF, and ANKRD1) at 2.5 μM and further downregulated in a dose-dependent manner (D). Together, these data indicate that inhibition of TEAD4 by CPD10 and CPD13 leads to downregulation of Hippo signaling target genes.

[0167] Figure 7 shows the cell proliferation and colony formation assay.

[0168] Methods: Indicator cells were seeded into each well at a density of 3000 cells / 80μl. TEAD4 depletion was performed by reverse transfection using 20nM Dharmaconsmart pool NTsiRNA and TEAD4 siRNA in 0.25ul liposomes mixed with 25% OPTIMEM. After 18 hours of transfection, cells were recovered in fresh DMEM medium for 24 hours. Cells were treated with different doses of the indicated compounds. After 48 hours of dosing, cells were recovered in fresh medium for 3 days. Cell Titre Glow (CTG) was used for determination.

[0169] In the colony formation assay, indicator cells were seeded at a density of 5,000 cells in 2 ml of DMEM medium. TEAD4 depletion was performed by reverse transfection using 20 nM of Dharmacon smart pool NTsiRNA and TEAD4 siRNA in 2.5 ul liposomes mixed with 25% OPTIMEM. After 18 hours of transfection, cells were treated with DMSO or with different doses of indicator compounds. After 48 hours of treatment, cells were recovered in fresh medium for 4 days. At the end of the experiment, cells were fixed with glutaraldehyde and stained in crystal violet solution for 2 hours. After washing, the scanning plate was used for image processing.

[0170] Results: CPD10 and CPD13 levels showed TEAD4-dependent cell proliferation and differential sensitivity in U2OS and A549 cells. U2OS cells stably expressing GFP-fused TEAD4 and GFP alone were treated with different doses of CPD10 and analyzed for cell proliferation. U2OS cells expressing GFP alone showed no sensitivity to low-dose CPD10 treatment (A), while U2OS cells overexpressing GFP-TEAD4 showed higher sensitivity to CPD10 treatment below 5uM (B). In addition, we used cell lines expressing higher levels of TEAD4 and performed depletion experiments followed by comparative sensitivity analysis. Interestingly, unlike NTsi-treated cells, TEAD4-depleted A549 cells showed lower sensitivity, suggesting that CPD10 activity is dependent on TEAD4 (C).

[0171] Consistent with the proliferation assay, we performed colony formation assays in U2OS cells depleted or overexpressing TEAD4. Cells stably expressing GFP and GFP-fused TEAD4 were also included in this assay. Unlike TEAD4-depleted cells, U2OS cells treated with control siRNA showed very high sensitivity to 2.5 μM CPD10 treatment. Similarly, U2OS cells overexpressing GFP-fused TEAD4 showed very high sensitivity compared to cells expressing GFP alone. We also tested our CPD13 in siRNA depletion experiments, and we observed that similar to CPD10, CPD13-dependent cell sensitivity was dependent on TEAD4 (C, lower panel). Taken together, these data indicate that CPD10- and CPD13-mediated cell proliferation and sensitivity are dependent on TEAD4.

[0172] FIG8 shows TEAD modeling and CPD10 and CPD13 assessment in the NCI-H226 mesothelioma cell line.

[0173] Methods: TEAD–CPD10 / CPD13 was modeled using computer simulation docking.

[0174] CPD10 and CPD13 evaluation in NCI-H226 mesothelioma cell line:

[0175] DMSO was added to actively growing cells, or cells were treated with the indicated concentrations of CPD10 and CPD13 for 24 hours. Cells were collected in ice-cold PBS and the precipitate was lysed in IP lysis buffer (25mM Tris-HCl pH 7.4, 150mM NaCl, 1mM EDTA, 1% NP-40 and 5% glycerol and competitive amounts of protease inhibitors). Samples were lysed by ultrasound, BCA assays were performed, and equal concentrations of protein and TEAD4 antibodies (3ul) were added. After incubation overnight in a cold room, anti-rabbit magnetic beads were added to the samples to capture TEAD and binding complexes for 2 hours. The samples were washed 3 times and the binding fractions were collected with the aid of a magnetic stand. 4XLDS, competitive amounts of DTT were added to the samples and boiled for 3 minutes. Whole cell lysates (input) and IP samples were dissolved in 8% SDS-PAGE gels and immunoblotted with indicated antibodies.

[0176] Relative quantification of immunoblot signals was quantified using Image J software.

[0177] The indicated concentrations of CPD10 and CPD13 were added to actively growing cells and cells were harvested 24 hours later. RNA was extracted and cDNA was synthesized. RT-PCR was performed using the indicated primer pairs. Relative gene expression was determined using GAPDH amplification.

[0178] Colony formation assays were performed essentially as described in the previous section.

[0179] Results: The vinyl sulfone warhead forms a covalent bond with Cys359. The sulfone forms hydrogen bonding interactions with the lysine (Lys336) side chain and the cystine (Cys359) backbone. The rest of the molecule occupies a hydrophobic pocket.

[0180] Endogenous TEAD4 IP showed strong YAP-TEAD binding, which was severely disrupted in CPD10- and CPD13-treated samples. Signal intensity quantification data showed a significant reduction in YAP-TEAD binding. Transcriptional analysis data showed that CPD10 and CPD13 led to the repression of TEAD transcriptional target genes. Colony formation assay data showed that CPD10 and CPD13 greatly enhanced the sensitivity of NCI-H226 mesothelioma cells, demonstrating their therapeutic potential.

[0181] Fig. 9Downregulation of Hippo-dependent gene transcripts was shown. RT-qPCR revealed a dose-dependent decrease in CTGF and CYR61 transcripts. MGH-CP1 (positive control) and Cpd13 were tested in MCF10 and A549.

[0182] The colony formation test data of compounds 2 and 38 are shown in Fig.10 and 11 The results indicate that the cell sensitivity induced by CPD2 and CPD38 is independent of TEAD.

[0183] The above indicates that TEAD is an attractive target for cancer therapy.

[0184] It will be appreciated that various aspects of the described embodiments are susceptible to numerous further modifications and permutations. Accordingly, the described aspects are intended to embrace all such changes, modifications and variations that fall within the spirit and scope of the appended claims.

[0185] Throughout the specification and in the claims that follow, unless the context requires otherwise, the word "comprise" or variations such as "comprising" and "containing" will be understood to imply the inclusion of a stated integer or step or groups of integers or steps but not the exclusion of any other integer or step or groups of integers or steps.

[0186] Throughout the specification and the claims that follow, unless the context requires otherwise, the phrase "consisting essentially of" and variations such as "consisting essentially of" will be understood to indicate that the recited element(s) are essential, i.e., essential elements of the invention. The term allows for the presence of other unrecited elements that do not materially affect the characteristics of the invention, but excludes additional unspecified elements that affect the basic and novel characteristics of the defined method.

[0187] Reference in this specification to any previous publication (or information obtained therefrom) or any known matter is not and should not be taken as an admission or any form of suggestion that the previous publication (or information obtained therefrom) or known matter forms part of the common general knowledge in the field to which this specification relates.

Claims

1. A compound of formula (I) or a salt, solvate or prodrug thereof: in, n is an integer selected from 1 to 5; and Ar is optionally substituted aryl or optionally substituted heteroaryl.

2. The compound according to claim 1, wherein Ar is optionally substituted heteroaryl.

3. The compound according to claim 1 or 2, wherein Ar is an optionally substituted heteroaryl wherein the heteroatom is located at the 2' position relative to the N of the amide moiety.

4. The compound according to any one of claims 1 to 3, wherein Ar is selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted thiazolyl, optionally substituted pyrazolyl or optionally substituted triazolyl.

5. The compound according to any one of claims 1 to 4, wherein n is an integer selected from 1-4.

6. The compound according to any one of claims 1 to 5, wherein The compound of formula (I) is a compound of formula (Ia): in, n is an integer selected from 1 to 5; X1 is a heteroatom selected from N, S or O; X2, X3 and X4 are independently selected from C, N, O or S; When X2 is N or C, R1 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; When X3 and X4 are independently N or C, R2 and R3 are independently selected from H, or optionally substituted alkyl.

7. The compound according to claim 6, wherein X1 is a heteroatom selected from N or S.

8. The compound of claim 6 or 7, wherein at least one of X2, X3 and X4 is N, O or S.

9. The compound according to any one of claims 6 to 8, wherein R1 is selected from optionally substituted cycloalkyl or optionally substituted aryl.

10. The compound according to any one of claims 6 to 9, wherein At least one of R2 and R3 is an optionally substituted alkyl group.

11. The compound according to any one of claims 1 to 10, wherein The compound of formula (I) is selected from:

12. A Hippo pathway regulator, wherein: The modulator is a compound of formula (I).

13. A pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier, excipient or diluent.

14. The pharmaceutical composition according to claim 13, wherein The pharmaceutical composition also comprises an active ingredient.

15. A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof.

16. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof for use in treating cancer.

17. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of a medicament for treating cancer in a patient in need thereof.

18. The method of claim 15, the compound of claim 16, or the use of claim 17, wherein the cancer is characterized by drug resistance and / or elevated YAP / TAZ-TEAD activity.

19. The method, compound or use according to any one of claims 15 to 18, wherein The cancer is selected from the group consisting of mesothelioma, liver cancer, gastric cancer, metastatic non-small cell lung cancer (NSCLC), and colorectal cancer.

20. The method, compound or use according to any one of claims 15 to 19, wherein the compound of formula (I) is used in combination with an active ingredient.

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