Compounds targeting TEAD and methods thereof

Abstract

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

Description

[Technical field]

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

[0002] The Hippo pathway plays a central role in controlling organ size and maintaining dynamic tissue balance. The pathway involves phosphorylation of TAOK1 / 2 / 3 or phosphorylation of MST1 / 2, which initiates the Hippo kinase cascade. Activated MST1 / 2 phosphorylates LATS1 / 2. Activated LATS1 / 2 phosphorylates YAP / TAZ under the activity of SAV1, MOB1A / B, and NF2. This results in 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 with partial deletion of the kinase cascade and overexpression of YAP can lead to increased progenitor cell proliferation and tissue hyperplasia.

[0003] The Hippo pathway has a unique ability to promote regeneration, and thus aberrations in its core components may promote cancer cell migration, invasion, and malignant transformation. Aberrant overexpression of YAP / TAZ in tumors promotes tumorigenesis and is therefore considered an oncogene in many solid cancers. Drug resistance is a major factor that impairs the efficacy of cancer therapeutics. YAP / TAZ-TEAD is involved in intrinsic and acquired resistance to various chemotherapeutic and targeted therapy drugs, which has led to increasing interest in combining TEAD inhibitors with various cancer treatments.

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

[0005] It would be desirable to overcome or ameliorate at least one of the above problems. Summary of the Invention

[0006] The present disclosure is based on the understanding that TEAD inhibitors, when administered to patients with tumors expressing the YAP / TAZ-TEAD signature, may have enormous therapeutic potential as they are highly likely to respond to TEAD inhibitor treatment.

[0007] The present disclosure relates to a covalent chemical scaffold that can hijack the conserved cysteine ​​of TEAD. For example, CPD10 and CPD13 led to downregulation of TEAD-regulated transcriptional target genes. Immunoprecipitation and immunoblotting data show that CPD10 and CPD13 disrupt 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 result in the inhibition of cell proliferation and viability in osteosarcoma (U2OS) and lung cancer cells (A549).

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

[0009] [ka]

[0010] (In the above formula, n is an integer selected from 1 to 5; Ar is an optionally substituted aryl or an optionally substituted heteroaryl.

[0011] In some embodiments, Ar is an optionally substituted heteroaryl.

[0012] In some embodiments, Ar is an optionally substituted heteroaryl where the heteroatom is at the 2' position relative to the nitrogen atom of the amide moiety.

[0013] In some embodiments, Ar is selected from optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted thiazolyl, optionally substituted pyrazolyl, or optionally substituted triazolyl.

[0014] In some embodiments, n is an integer selected from 1-4.

[0015] In some embodiments, the compound of formula (I) is of formula (Ia).

[0016] [ka]

[0017] (In the above formula, n is an integer selected from 1 to 5; X 1 is a heteroatom selected from N, S or O; X 2 , X 3 and X 4 is independently selected from C, N, O or S;

[0018] X 2 When is N or C, R 1 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; X 3 and X 4 When are independently N or O, R 2 and R 3 are independently selected from H, or optionally substituted alkyl.

[0019] In some embodiments, X 1 is a heteroatom selected from N or S

[0020] In some embodiments, X 2 , X 3 and X 4 At least one of is N, O or S.

[0021] In some embodiments, R 1 is selected from optionally substituted cycloalkyl or optionally substituted aryl.

[0022] In some embodiments, R 2 and R 3 At least one of is optionally substituted alkyl.

[0023] In some embodiments, the compound of formula (I) is selected from:

[0024] [ka]

[0025] The present disclosure relates to a modulator of the HIPPO pathway, the modulator being a compound of formula (I). The compound of formula (I) is a modulator of YAP / TAZ-TEAD.

[0026] The present disclosure also relates to pharmaceutical compositions comprising an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt, solvate or prodrug thereof, optionally in combination with a pharma- ceutically acceptable carrier, excipient or diluent.

[0027] 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 pharma- ceutically acceptable salt, solvate or prodrug thereof.

[0028] The present disclosure also relates to a compound of formula (I) or a pharma- ceutically acceptable salt, solvate or prodrug thereof for use in the treatment of cancer.

[0029] The present disclosure also relates to the use of a compound of formula (I) or a pharma- ceutically acceptable salt, solvate or prodrug thereof in the manufacture of a medicament for treating cancer in a patient in need thereof.

[0030] In some embodiments, the cancer is characterized by elevated YAP / TAZ-TEAD activity and / or drug resistance.

[0031] In some embodiments, the cancer is selected from mesothelioma, liver cancer, gastric cancer, metastatic non-small cell lung cancer (NSCLC), and colorectal cancer.

[0032] Embodiments of the invention will now be described, by way of non-limiting example, with reference to the drawings in which: [Brief description of the drawings]

[0033] [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 donor and acceptor) that promote strong and selective binding to the TEAD pocket. Cysteine ​​positions are primed to be exploited. C) Examples of three different cysteine ​​warheads selected for screening. [Diagram 2] A) Schematic of activity-based protein profiling (ABPP). Covalent compounds that bind to conserved cysteines reduce the fluorescent signal. If the conserved cysteines are not labeled, they generate more fluorescence. B) Palmitoyl-CoA was used as a positive control to show that ABPP was optimized for this assay. C) Screening campaign with an arbitrary cutoff value of 0.25. Compounds with normalized fluorescence below 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; palmitoyl-CoA to 0. [Diagram 3] A) Intact mass spectrometry (MALDI) showed labeling of TEAD with compounds in vitro (mass peaks shift to the right corresponding to one compound). Of note, only one of four cysteine ​​residues reacts with the covalent compound. Not all compounds react with TEAD, and not every cysteine ​​residue is indiscriminately labeled, reflecting the cysteine ​​warhead. B) SAR of the hits. C) LC-MS / MS analysis revealed that the more favored cysteine ​​residue labeled was the conserved cysteine. [Figure 4]A) CPD10 and CPD13 inhibit YAP / TAZ protein expression: 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, treatment of A549 cells with Cpd13 reduced YAP protein signals at 10 μM (B). YAP / TAZ binding of TEAD4 was significantly reduced in response to 10 μM CPD10 treatment (C). [Diagram 5] CPD10 and CPD13 promoted cytoplasmic localization of TEAD4: CPD10 and CPD13 treatment resulted in a cytoplasmic localization signal of TEAD4: Unlike DMSO-treated cells, CPD10 and CPD13 resulted in a cytoplasmic signal while the nuclear signal remained intact. [Figure 6] CPD10 and CPD13 led to downregulation of TEAD transcriptional targets: relative expression of YAP and TAZ in response to low dose CPD10 (A) and CPD13 (B) treatment in A549 cells. c-MYC was included as a non-transcriptional target of TEAD. NFKB1 was included as its expression is reciprocal with YAP / TAZ. Downstream effectors of TEAD targets (CYR61, AXL, CTGF and ANKRD1) were determined in response to 2.5, 5 and 10 μM CPD10 (C) and CPD13 (D), respectively. [Figure 7] In U2OS and A549 cells, CPD10 and CPD13 showed TEAD4-dependent cell proliferation and different viability: Data from cell proliferation assays showing that CPD10 strongly sensitizes U2OS and A549 cells overexpressing TEAD4 (A and B). Depletion of TEAD4 in A549 cells reduced CPD10-induced cell proliferation (C). Colony formation assay showing that GFP-TEAD4 cells are more sensitive to 2.5 μM CPD10 compared to GFP-overexpressing cells. Unlike control siRNA-treated cells, TEAD4-depleted cells are less sensitive to CPD13 (D). [Figure 8]Evaluation of TEAD modeling and CPD10 and CPD13 in NCI-H226 mesothelioma cell line: In silico docking for TEAD-CPD10 / CPD13 modeling (A and B). Modeling of TEAD-CPD10 (C). TEAD4 immunoprecipitation in NCI-H226 mesothelioma cells treated with the indicated concentrations of CPD10 and CPD13 to determine YAP-TEAD binding (D). Immunoblot gel quantification to determine % of YAP-TEAD binding disruption (E). YAP-TEAD transcriptional target gene profiling (F). Dose-dependent relative luminescence (ATP / ADP ratio) profiling in response to CPD10 and CPD13 treated NCI-H226 mesothelioma cells (G). Colony formation assay to determine CPD10 and CPD13 induced drug sensitivity and colony forming ability in NCI-H226 mesothelioma cells (H). [Figure 9] Comparison of CPD13 and positive control in different cells [Figure 10] 1 shows a colony formation assay to determine cell viability in response to CPD2 treatment and recovery (5 days). [Figure 11] 1 shows a colony formation assay to determine cell viability in response to CPD38 treatment and recovery (5 days). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] "Alkyl" refers to a monovalent alkyl group which may be linear or branched and preferably has 1 to 10 carbon atoms, 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.

[0035] "Alkenyl" refers to a monovalent alkenyl group which may be linear or branched, preferably has 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and has at least one, preferably 1 to 2 carbon-carbon double bonds. Examples include ethenyl (-CH=CH 2 ), n-propenyl (-CH2 CH=CH 2 ), isopropenyl (-C(CH 3 )=CH 2 ), but-2-enyl (-CH 2 CH=CHCH 3 ) etc.

[0036] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

[0037] "Oxo / hydroxy" refers to the group =O, HO-.

[0038] "Aryl" refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or an unsaturated aromatic carbocyclic group having multiple condensed rings (e.g., naphthyl or anthryl), preferably having 6 to 14 carbon atoms. Examples of aryl groups include phenyl and naphthyl groups.

[0039] "Heteroaryl" refers to a monovalent aromatic heterocyclic group that satisfies Hückel's rule for aromaticity (i.e., contains 4n+2 π electrons), preferably having 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, selenium, and sulfur (and including oxides of sulfur, selenium, and nitrogen) in the ring. Such heteroaryl groups can have a single ring (e.g., pyridyl, pyrrolyl or its N-oxide or furyl) or multiple condensed rings (e.g., indolizinyl, benzimidazolyl, coumarinyl, quinolinyl, isoquinolinyl, or benzothienyl).

[0040] Examples of heteroaryl groups include, but are not limited to, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, 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.

[0041] "Heterocyclyl" refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, preferably having from 1 to 8 carbon atoms and from 1 to 4 heteroatoms selected from nitrogen, sulfur, oxygen, selenium, or phosphorus in the ring. The most preferred heteroatom is nitrogen. For example, R 2 Or when R' is an optionally substituted heterocyclyl having one or more ring heteroatoms, it will be understood that the heterocyclyl group can be attached to the core molecule of the compounds of the invention via a C-C or a C-heteroatom bond, particularly a C-N bond.

[0042] Examples of heterocyclyl and heteroaryl groups include oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isothiazolidine, and phenylpyridine. These include, but are not limited to, phenyl, 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, morpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl, triazole, and the like.

[0043] "Amino" refers to the group -NR"R", where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, each of which is as described herein.

[0044] As used herein, the term "optionally substituted" means that the group is hydroxyl, acyl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, thio, arylalkyl, arylalkoxy, aryl, aryloxy, carboxyl, acylamino, cyano, halogen, nitro, phosphono, sulfo, phosphorylamino, phosphinyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, oxyacyl, oxime, oxime ether, hydrazone, oxyacylamino, oxysulfonylamino, aminoacyloxy, trihalomethyl ... They may or may not be further substituted or fused (to form a fused polycyclic group) with one or more groups selected from alkylsilyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, trifluoromethanethio, trifluoroethenyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclylamino, and unsymmetrical disubstituted amines having different substituents selected from alkyl, aryl, heteroaryl, and heterocyclyl, and the like, and may include bonds to a solid support material (e.g., substituted on a polymer resin). For example, "optionally substituted amino" groups may include amino acid and peptide residues.

[0045] Genetic alterations in Hippo pathway components are increasingly being detected in cancer. In this regard, small molecule covalent inhibitors of similar scaffolds that can enter the TEAD pocket may be therapeutically useful in cancers where YAP / TAZ-TEAD activity is elevated compared to baseline.

[0046] An alternative strategy involves identifying scaffolds that bind tightly to the hydrophobic pocket. For example, covalent TEAD inhibitors may be developed to exploit a conserved cysteine. Without being bound by the following theory, it is believed that the central hydrophobic pocket of TEAD may be more specifically targeted by combining these two strategies to identify scaffolds that simultaneously occupy the pocket and covalently bind to the conserved cysteine ​​in order to achieve high potency and selectivity.

[0047] We found that palmitoylation is required for the stability and activity of the conserved cysteine ​​of TEAD. Here, we identified compounds with chemical scaffolds that preferentially bind covalently to the conserved cysteine ​​in the palmitate-binding pocket of TEAD. We employed a rational approach for the selection of the compound library. We analyzed available cocrystal structures of TEAD with palmitate and other non-covalent inhibitors to identify physical and chemical similarities that guided the rational selection of new compound classes for screening (Figure 1A,B).

[0048] The rationally selected compound library pool contains cysteine ​​warheads, preferably selected from chloroacetamide, acrylamide and vinyl sulfone (Figure 1C). We then designed a fluorescent gel-based activity-based protein profiling (ABPP) assay (Figure 2A&B) to screen the library for covalent compounds that bind to the conserved cysteines of TEAD (Figure 2C). The best compounds were counter-screened and their binding activity was verified using an intact mass spectrometry assay (Figure 3A), while simultaneously obtaining useful information about the structure-activity relationship (SAR) (Figure 3B). Furthermore, LC-MS / MS data showed that the preferred site of modification was the conserved cysteine ​​residue (Figure 3C), and labeling prevented palmitoylation of TEAD. Interestingly, the vinyl sulfone warhead is particularly efficient. Our cell-based and biochemical assay data strongly suggest potential applications in cancer therapy.

[0049] Thus, the disclosure provides a compound of formula (I) or a salt, solvate or prodrug thereof:

[0050] [ka] (In the above formula, n is an integer selected from 1 to 5; Ar is an optionally substituted aryl or an optionally substituted heteroaryl.

[0051] These compounds were rationally selected from enamines not previously known to possess biological properties, and they exhibit TEAD inhibitory properties and may be developed for the treatment of cancer.

[0052] These chemical scaffolds (e.g., CPD10 and CPD13) have a cysteine ​​warhead (vinyl sulfone) that targets TEAD cysteines. Furthermore, in addition to targeting the hydrophobic pocket of TEAD, the compounds are optimized to interact with polar residues near the entrance of the pocket. The present invention is applicable to cancer therapy for cancers with elevated YAP / TAZ-TEAD activity and drug resistance. Multiple studies have highlighted the importance of TEAD in human cancer. Overexpression of TEAD has been implicated in multiple stages of cancer progression and cancer types. Furthermore, the Hippo pathway is known to be a key factor in developing resistance to chemotherapy and targeted therapies, including Ras, EGFR, RAF and MEK pathway inhibitors.

[0053] In some embodiments, Ar is an optionally substituted heteroaryl. In some embodiments, Ar is selected from an optionally substituted phenyl, an optionally substituted pyridinyl, an optionally substituted thiazolyl, an optionally substituted pyrazolyl, or an optionally substituted triazolyl.

[0054] In some embodiments, the optional substituents are selected from optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl. In some embodiments, the optional substituents are selected from optionally substituted phenyl and optionally substituted cyclohexyl. In some embodiments, the optional substituents are selected from phenyl and cyclohexyl.

[0055] In some embodiments, the optional substituents are selected from halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyenyl, and optionally substituted amino. In some embodiments, the optional substituents are optionally substituted C 1 ~C 5 Alkyl, optionally substituted C 1 ~C 5 Alkoxy and optionally substituted C 2 ~C 5 In some embodiments, the optional substituents are selected from C 1 ~C 5 Alkyl, C 1 ~C 5 Alkoxy and C 2 ~C 5 alkyenyl.

[0056] In some embodiments, Ar is an optionally substituted heteroaryl, where the heteroatom is at the 2' position relative to the N of the amide moiety.

[0057] 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.

[0058] 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).

[0059] [ka] (In the above formula, n is an integer selected from 1 to 5; X 1 is a heteroatom selected from N, S, or O; X 2 , X 3 , and X 4 is independently selected from C, N, O, or S;

[0060] R 1 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R 2 and R 3 are independently selected from H, or optionally substituted alkyl.

[0061] In some embodiments, the compound of formula (I) is a compound of formula (Ia).

[0062] [ka] (In the above formula, n is an integer selected from 1 to 5; X 1 is a heteroatom selected from N, S, or O; X 2 , X 3 , and X 4 is independently selected from C, N, O, or S;

[0063] X 2 When is N or C, R 1 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; X 3 and X 4 When are independently N or C, R 2 and R 3 are independently selected from H or optionally substituted alkyl.

[0064] Based on SAR studies, X 1 It has been found that it is preferable that X is a heteroatom. 1 It is believed that the heteroatoms of may interact beneficially with the TEAD hydrophobic pocket, possibly interacting with the peptide backbone or some proximal polar amino acids.

[0065] In some embodiments, X 1 is a heteroatom selected from N, or S. In some embodiments, X 1 is N. In some embodiments, X 1 is S.

[0066] In some embodiments, X 2 , X 3 , and X 4 At least one of X is N, O, or S. In some embodiments, 2 , X 3 , and X 4 At least one of is N or S.

[0067] In some embodiments, X 2 , X 3 , and X 4 At least two of X are N, O, or S. In some embodiments, 2 , X 3 , and X4 At least two of are N or S.

[0068] In some embodiments, R 1 is selected from optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl. In some embodiments, R 1 is selected from optionally substituted cycloalkyl, or optionally substituted aryl. In some embodiments, R 1 is selected from optionally substituted phenyl and optionally substituted cyclohexyl. In some embodiments, R 1 is selected from phenyl and cyclohexyl.

[0069] In some embodiments, R 2 and R 3 At least one of R is optionally substituted alkyl. 2 and R 3 At least one of the optionally substituted C 1 ~C 5 In some embodiments, R 2 and R 3 At least one of the following is C 1 ~C 5 In some embodiments, the alkyl is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, the alkyl is methyl.

[0070] The compound of formula (I) may be selected from:

[0071] [ka] TIFF2025517442000008.tif54168

[0072] In some embodiments, the compound of formula (I) is selected from the following:

[0073] [ka]

[0074] The present disclosure relates to modulators of the Hippo pathway, including compounds of formula (I).The compounds of formula (I) are modulators of YAP / TAZ-TEAD.

[0075] In some embodiments, the modulators are used in vitro. For example, the modulators can be used to treat cell lines, cells, or tumors excised from an organism. In other embodiments, the modulators are used in vivo.

[0076] 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.

[0077] The present disclosure also relates to pharmaceutical compositions comprising an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt, solvate or prodrug thereof, optionally in combination with a pharma- ceutically acceptable carrier, excipient or diluent.

[0078] In some embodiments, the composition further comprises palmitic acid or a pharma- ceutically acceptable salt, solvate, or prodrug thereof. For example, palmitate is the ionized form of palmitic acid, a fatty acid having a 16-carbon chain.

[0079] In some embodiments, the pharmaceutical composition further comprises another active ingredient, which may be an anti-cancer agent.

[0080] The compound of the present invention can be administered to the subject as its pharmaceutically acceptable salt.Suitable pharmaceutically acceptable salt includes but is not limited to the salt of pharmaceutically acceptable inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid and hydrobromic acid, or the salt of pharmaceutically acceptable organic acid 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, edetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid and valeric acid.

[0081] Base salts include, but are not limited to, those formed with pharma- ceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium. In particular, the invention includes within its scope cationic salts, e.g., sodium or potassium salts, or alkyl esters of the phosphate group (e.g., methyl, ethyl).

[0082] Basic nitrogen-containing groups can be quaternized with lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides, dialkyl sulfates, such as dimethyl sulfate, diethyl sulfate, and the like.

[0083] It will be understood that any compound that is a prodrug of a compound of formula (I) is also within the scope and spirit of the present invention. Thus, the compounds of the present invention can be administered to a subject in the form of a pharma- ceutically acceptable prodrug. The term "prodrug" is used in its broadest sense and includes derivatives that are converted to the compounds of the present invention in vivo. Such derivatives will be readily apparent to those skilled in the art. Other texts that generally describe prodrugs (and their preparation) include: Design of Prodrugs, 1985, H. Bundgaard (Elsevier); The Practice of Medicinal Chemistry, 1996, Camille G. Wermuth et al., Chapter 31 (Academic Press); and A Textbook of Drug Design and Development, 1991, Bundgaard et al., Chapter 5 (Harwood Academic Publishers).

[0084] The compounds of the present invention may be in crystalline form, either as free compounds or as solvates (e.g., hydrates), and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known in the art.

[0085] The compound of the present invention, or its pharmacologic acceptable salt, solvate or prodrug, is administered to a 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 onset or inhibiting the progression of macular degeneration, or stopping the onset or progression of macular degeneration, or completely reversing it.

[0086] As used herein, the term "effective amount" refers to an amount of a compound that provides a desired therapeutic activity when administered according to a desired dosing regimen. Administration can be at intervals of minutes, hours, days, weeks, months or years, or continuously over any one of these periods. A suitable dosage can be in the range of about 0.1 ng per kg body weight to 1 g per kg body weight, for example, in the range of 1 mg to 1 g per kg body weight per dosage. In one embodiment, the dosage can be in the range of 1 mg to 500 mg body weight per kg body weight per administration. In another embodiment, the dosage can be in the range of 1 mg to 250 mg body weight per kg body weight per administration. In yet another embodiment, the dosage can be in the range of 1 mg to 100 mg body weight per administration, such as up to 50 mg per kg body weight per administration.

[0087] Appropriate dosages and administration regimens can be determined by the attending physician and may depend on the severity of the condition, as well as the general age, health and weight of the patient being treated.

[0088] The compounds of the present invention can be administered in one dose or in a series of doses. Although it is possible to administer the active ingredient alone, it is preferable to provide it as a composition, preferably a pharmaceutical composition. The formulation of such compositions is well known to those skilled in the art. The composition can contain any suitable carrier, diluent or excipient. These include all conventional solvents, dispersion media, fillers, solid carriers, coating agents, antifungal and antibacterial agents, skin penetration agents, surfactants, isotonic and absorption agents, and the like. It will be understood that the composition of the present invention can also contain other auxiliary biologically active agents.

[0089] The carrier must be pharma- ceutically "acceptable" in the sense that it is compatible with the other components of the composition and is not harmful to the patient. The composition can be conveniently provided in unit dosage form and can be prepared by any method well known in the pharmaceutical art. Such a method includes the step of bringing the active ingredient into association with the carrier, which constitutes one or more accessory ingredients. In general, the composition is prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product.

[0090] Injectables for such use can be prepared in conventional forms, either as liquid solutions or suspensions, or in solid forms suitable for preparation as solutions or suspensions in liquid prior to injection, or as emulsions. Carriers can include, for example, water, saline (e.g., physiological saline (NS), phosphate buffered saline (PBS), balanced salt solution (BSS)), sodium lactate Ringer's solution, dextrose, glycerol, ethanol, and the like. Small amounts of auxiliary substances, such as wetting or emulsifying agents, buffers, and the like, can also be added as needed. Proper fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersion, and by using surfactants. For example, the compound, composition, or combination can be dissolved in a pharma- ceutically effective carrier and injected into the vitreous of the eye using a thin gauge hollow needle (e.g., a 30 gauge, 1 / 2 or 3 / 8 inch needle) using a temporal approach (e.g., about 3 to about 4 mm posterior to the limbus of the human eye to avoid damaging the lens).

[0091] Those skilled in the art will understand that other means for injecting and / or administering the compound, composition or combination into the vitreous of the eye can also be used.These other means can include, for example, intravitreal medical delivery devices.These devices and methods can include, for example, intravitreal medical delivery devices and biodegradable polymeric delivery members that are inserted into the eye for long-term delivery of drugs.These devices and methods can also include transscleral delivery devices.

[0092] Other methods of administration are possible, including topical or intravenous administration. For example, a solution or suspension of the compound, composition or combination of the present invention can be formulated as eye drops or as a membranous eye patch that is applied directly to the surface of the eye. Topical application typically involves administering the compound of the present invention in an amount of 0.1 ng to 10 mg.

[0093] The compounds, compositions or combinations of the present invention are also suitable for intravenous administration. For example, the compound of formula (I) or a pharma- ceutically acceptable salt, solvate or prodrug thereof may be administered intravenously at a dose of 16 mg / m 2 Doses of up to 100 mg / kg can be administered intravenously.

[0094] The compound, composition or combination of the present invention may also be suitable for oral administration, and can be provided as individual 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 an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.The active ingredient can also be provided as a bolus, lick or paste.In another embodiment, the compound of formula (I) or its pharma-ceutically acceptable salt, solvate or prodrug can be administered orally.

[0095] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form such as powder or granules in a suitable machine, optionally mixed with a binder (e.g., an inert diluent, a preservative disintegrant (e.g., sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose), a surfactant or a dispersing agent. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or scored, and can be formulated to provide slow or controlled release of the active ingredient therein, for example, using hydroxypropyl methylcellulose in various proportions to provide the desired release profile. Tablets can be optionally provided with an enteric coating to provide release in parts of the intestine other than the stomach.

[0096] The compounds, compositions or combinations of the present invention are suitable for topical administration in the mouth, including, for example, lozenges comprising the active ingredient in a flavored base such as sucrose and acacia or tragacanth gum, pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia gum, and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0097] The compounds, compositions or combinations of the present invention may be suitable for topical administration to the skin, and may include the compounds dissolved or suspended in any suitable carrier or base, and may be in the form of lotions, gels, creams, pastes, ointments, etc. Suitable carriers include mineral oil, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Transdermal patches may also be used to administer the compounds of the present invention.

[0098] The compound, composition or combination of the present invention may be suitable for parenteral administration, including aqueous and non-aqueous isotonic sterile injection solutions that may contain antioxidants, buffers, bactericides and solutes that make the compound, composition or combination isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents.The compound, composition or combination of the present invention may be provided in unit-dose or multi-dose sealed containers, such as ampoules and vials, and may be stored in a freeze-dried (lyophilized) state that only requires the addition of sterile liquid carriers, such as water for injection, immediately before use.Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the type previously described.

[0099] 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 an active ingredient.

[0100] In addition to the active ingredients specifically mentioned above, the compositions or combinations of the present invention may contain other agents conventionally used in the art considering the type of composition or combination, for example, those suitable for oral administration may contain additional agents such as binders, sweeteners, thickeners, flavorings, disintegrants, coatings, preservatives, lubricants and / or time delay agents, it will be understood. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin. Suitable disintegrants include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable flavors include peppermint oil, wintergreen, cherry, orange oil or raspberry flavor. Suitable coatings include polymers or copolymers of acrylic acid and / or methacrylic acid and / or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methylparaben, propylparaben 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.

[0101] 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 pharma- ceutically acceptable salt, solvate or prodrug thereof.

[0102] The present disclosure also relates to a compound of formula (I) or a pharma- ceutically acceptable salt, solvate or prodrug thereof for use in the treatment of cancer.

[0103] The present disclosure also relates to the use of a compound of formula (I) or a pharma- ceutically acceptable salt, solvate or prodrug thereof in the manufacture of a medicament for treating cancer in a patient in need thereof.

[0104] In some embodiments, the cancer is characterized by elevated YAP / TAZ-TEAD activity and / or drug resistance.

[0105] In some embodiments, the cancer is selected from mesothelioma, liver cancer, gastric cancer, metastatic non-small cell lung cancer (NSCLC), and colon cancer.

[0106] In some embodiments, the method, compound or use thereof further comprises another active ingredient, which may be an anti-cancer agent.

[0107] In some embodiments, the methods comprise administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt, solvate or prodrug thereof in combination with an effective amount of an anti-cancer active ingredient.

[0108] In some embodiments, the compounds of formula (I) or pharma- ceutically acceptable salts, solvates or prodrugs thereof are used in combination with anti-cancer active ingredients for use in the treatment of cancer.

[0109] In one embodiment, the disclosure provides the use of a compound of formula (I) or a salt, solvate or prodrug thereof in the manufacture of a medicament for treating cancer in combination with an anti-cancer active ingredient.

[0110] In one embodiment, the disclosure provides the use of an anti-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.

[0111] In some embodiments, the compound of formula (I) or a salt, solvate or prodrug thereof and the anti-cancer active ingredient are added simultaneously or sequentially in any order.

[0112] The term "combination" as used herein refers to the co-administration of combination partners to a single patient and is intended to include therapeutic regimens in which the drugs are not necessarily administered by the same route of administration or at the same time.The therapeutic compounds or treatments used in such combination therapy can be administered together with the compound of formula (I) or its pharmacologic acceptable salt, solvate or prodrug in one combined unit dosage separately or sequentially in separate unit dosage forms. EXAMPLES

[0113] Figure 3C shows the MS / MS results of the compound reaction with TEAD, revealing that the conserved cysteine ​​is modified in vitro. The following is observed: Four cysteine ​​residues per TEAD-YBD 4 peptides, each containing one cysteine % modified peptides = number of modified peptides / total peptides detected Cysteines known to be palmitoylated were preferentially modified by the compounds Contains a known conserved cysteine

[0114] [ka] Peptides are the primary target Contains other cysteines known to be palmitoylated

[0115] [ka] peptides were identified.

[0116] FIG. 4 shows that CPD10 and CPD13 inhibit YAP / TAZ protein expression.

[0117] Methods: A549 cells (60% confluent) were mock treated or treated with the indicated doses of CPD10 and CPD13 for 24 hours. Cells were washed with ice-cold 1x PBS and lysed in protein lysis buffer. Total cell lysates were quantified with Pierce™ BCA Protein assay kit (catalog no: 23225) and denatured in 4x LDS buffer (Thermo catalog no: NP0007) with competing amounts of DTT, followed by boiling for 3 minutes. Samples were resolved on 8% SDS-PAGE, transferred to nitrocellulose membranes and immunoblotted with the indicated antibodies.

[0118] 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, a competing amount of DTT was added, and the samples were boiled for 3 min. The supernatant was collected and used for immunoblotting.

[0119] Results: To determine CPD10- and CPD13-mediated expression of Hippo signaling target proteins in A549 cells, whole-cell lysates from mock- and compound-treated cells were immunoblotted to determine the levels of TEAD4, Pan-TEAD, YAP, and TAZ proteins. Interestingly, in response to CPD10 treatment, YAP expression was downregulated in a dose-dependent manner. TAZ expression was significantly decreased at 10 Um. At the highest concentration, TEAD4 and Pan-TEAD expression was also decreased (A). Similar to CPD10, CPD13 downregulated YAP expression at 10 Um (B). To determine the levels of other transcriptional targets, p53 protein was tested in the same set of protein samples. Compounds 10 and 13 did not alter wild-type p53 expression, suggesting that the compounds act specifically on the Hippo signaling pathway. GAPDH was used as a loading control.

[0120] To determine whether CPD10 or 13 lead to downregulation of TEAD4 binding to its transcriptional targets YAP and TAZ, U2OS cells stably expressing GFP alone and GFP-fused TEAD4 were mock treated or treated with the indicated doses of CPD10. GFP-TRAP assay was performed to pull down 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 decreased in response to 10uM CPD10 treatment. GFP blot showing GFP and GFP-fused TEAD4 signals in whole cell lysates and purified protein samples (C).

[0121] FIG. 5 shows that CPD10 and CPD13 treatment led to cytoplasmic localization of TEAD4.

[0122] Methods: U2OS cells stably expressing GFP-TEAD4 were seeded at a density of 50,000 cells on glass coverslips in 6-well plates. The next day, cells were treated with DMSO or with the indicated compounds at 10 μM concentration. After 18 h of treatment, cells were washed and fixed with 4% formaldehyde for 20 min. Blocking was performed with 3% BSA in PBST for 1 h. Cells were incubated with the indicated antibodies overnight in a cold room. The next day, after washing three times with PBST, samples were incubated with the respective 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 mounting medium. After drying, cells were imaged with a 63× objective and processed with ZEN×64 Blue software.

[0123] Results: In DMSO-treated control samples, a strong DAPI signal was observed, with a very nuclear-localized TEAD4 (green) signal. Nuclear and cytoplasmic YAP and TAZ were observed in DMSO- or compound-treated cells. Interestingly, in response to CPD10 and 13 treatment, GFP signals were detected outside the nucleus. Although CPD10 or CD13 treatment did not reduce the presence of TEAD4 throughout the nucleus, these two inhibitors induce a cytoplasmic localization of the TEAD4 protein.

[0124] FIG. 6 shows CPD10- and CPD13-dependent transcriptional target gene regulation.

[0125] Methods: A549 cells (60% confluent) were mock treated or treated with the indicated doses of CPD10 and CPD13 for 24 hours. Cells were washed with ice-cold 1x PBS. RNA extraction was performed using Quick-RNA™ Miniprep Kit (Zymo Research, Cat. No. R1055) following the product's instructions exactly. 2μg RNA samples quantified by Nanodrop were subjected to cDNA synthesis using cDNA Reverse Transcription Kit (Thermo Cat. No. 4368814) following the product's instructions exactly. For RT PCR experiments, comparative target gene expression was performed using SYBR™ Green (Thermo Cat. No. 4309155) Master mix. Relative target gene expression was compared and plotted on the Y-axis.

[0126] Results: Relative expression of YAP and TAZ in response to low dose CPD10 (A) and CPD13 (B) treatment in A549 cells. c-MYC was included as a non-transcriptional target of TEAD. NFKB1 was included because its expression is reciprocal with YAP / TAZ. Downstream effectors of TEAD targets (CYR61, AXL, CTGF and ANKRD1) were determined in response to 2.5, 5 and 10 μM CPD10 (C) and CPD13 (D).

[0127] CPD10 and CPD13 downregulate transcriptional target genes of TEAD:

[0128] To determine the relative expression of CPD10- and CPD13-induced TEAD target genes, A549 cells were treated with the indicated doses for 24 h. Transcriptional profiling was performed with the respective primer pairs. In response to 2.5 μM CPD10, YAP / TAZ expression was downregulated. A slight increase in NFKB1 was detected. Furthermore, the expression of one of the potent non-Hippo transcription factors, C-Myc, was examined. As expected, c-MYC expression was not affected by CPD10 treatment (A). CPD13 treatment significantly reduced YAP / TAZ expression. C-Myc expression was not affected. Previous findings suggest that YAP attenuates the NF-κB pathway. The increased expression of NFKB1 is consistent with the significant downregulation of YAP expression by 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, in response to CPD10, most targets (CYR61, AXL and CTGF) were suppressed at 2.5μM and then downregulated in a dose-dependent manner. ANKRD1 expression was significantly decreased at 10μM (C). A549 cells treated with the indicated doses of CPD13 showed a significant decrease in all four tested targets (CYR61, AXL, CTGF and ANKRD1) at 2.5um and were downregulated in a dose-dependent manner (D). Overall, these data suggest that TEAD4 inhibition by CPD10 and CPD13 results in the downregulation of Hippo signaling target genes.

[0129] FIG. 7 shows cell proliferation and colony formation assays.

[0130] Methods: Indicated cells were plated at 3000 cells / 80μl per well. TEAD4 depletion was performed by reverse transfection of Dharmacon smart pool NTsiRNA and TEAD4 siRNA in 0.25ul Lipofectamine mixed with 25% OPTIMEM. 18 hours post-transfection, cells were harvested in fresh DMEM medium for 24 hours. Cells were treated with indicated compounds at different doses. 48 hours post-treatment, cells were harvested in fresh medium for 3 days. Cell Titre Glow (CTG) assay was used.

[0131] For colony formation assays, the indicated cells were plated at a density of 5,000 cells in 2 ml of DMEM medium. TEAD4 depletion was performed by reverse transfection with Dharmacon smart pool NTsiRNA and TEAD4 siRNA in 2.5 ul of Lipofectamine mixed with 25% OPTIMEM. 18 hours after transfection, cells were treated with DMSO or with the indicated compounds at different doses. After 48 hours of treatment, cells were harvested with fresh medium for 4 days. At the end of the experiment, cells were fixed with glutaraldehyde and stained with crystal violet solution for 2 hours. After washing, plates were scanned and imaged.

[0132] Results: In U2OS and A549 cells, the levels of CPD10 and CPD13 showed TEAD4-dependent cell proliferation and differential sensitivity. U2OS cells stably expressing GFP-fused TEAD4 and GFP alone were treated with different doses of CPD10 and cell proliferation was analyzed. U2OS cells expressing GFP alone were not sensitive to low doses of CPD10 treatment (A), whereas U2OS cells overexpressing GFP-TEAD4 showed high sensitivity to CPD10 treatment at 5uM or less (B). Furthermore, depletion experiments and subsequent comparative sensitivity analysis were performed using cell lines expressing higher levels of TEAD4. Interestingly, unlike NTsi-treated cells, TEAD4-depleted A549 cells showed low sensitivity, indicating that CPD10 activity is TEAD4-dependent (C).

[0133] In line 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 the assay. Unlike TEAD4-depleted cells, U2OS cells treated with control siRNA showed extremely high sensitivity to 2.5 μM CPD treatment. Similarly, U2OS cells overexpressing GFP-fused TEAD4 showed extremely high sensitivity compared to cells expressing GFP alone. We also tested our CPD13 in siRNA depletion experiments and observed that, similar to CPD10, CPD13-dependent cell sensitivity was TEAD4-dependent (C, lower panel). Taken together, these data suggest that CPD10- and CPD13-mediated cell proliferation and sensitivity are TEAD4-dependent.

[0134] Figure 8 shows TEAD modeling and evaluation of CPD10 and CPD13 in NCI-H226 mesothelioma cell line. Methods: Modeling of TEAD-CPD10 / CPD13 using in silico docking. Evaluation of CPD10 and CPD13 in NCI-H226 mesothelioma cell line:

[0135] Actively proliferating cells were treated with DMSO or with the indicated concentrations of CPD10 and CPD13 for 24 hours. Cells were harvested in ice-cold PBS and pellets were lysed in IP lysis buffer (25mM Tris-HCl pH 7.4, 150mM NaCl, 1mM EDTA, 1% NP-40 and 5% glycerol and competing amounts of protease inhibitors). Samples were lysed by sonication, BCA assay was performed and equal concentrations of protein were added with TEAD4 antibody (3ul). After overnight incubation in the cold room, anti-rabbit magnetic beads were added to the samples and TEAD and binding complexes were trapped for 2 hours. Samples were washed three times and the bound fraction was collected using a magnetic stand. Samples were added with 4x LDS, competing amounts of DTT and boiled for 3 minutes. Total cell lysates (Input) and IP samples were resolved on 8% SDS-PAGE gels and immunoblotted with the indicated antibodies.

[0136] Relative quantification of immunoblot signals was performed using IMAGE J software.

[0137] Actively proliferating cells were treated with the indicated concentrations of CPD10 and CPD13 and harvested 24 hours later. RNA was extracted and cDNA was synthesized. The indicated primer pairs were used for RT-PCR. Relative gene expression was determined using GAPDH amplification. The colony formation assay was carried out essentially as described in the previous section.

[0138] result: The vinyl sulfone warhead forms a covalent bond with Cys359. The sulfone forms hydrogen-bonding interactions with the lysine side chain (Lys336) and the cysteine ​​backbone (Cys359). The remainder of the molecule occupies a hydrophobic pocket.

[0139] Endogenous TEAD4 IP showed strong YAP-TEAD binding, which was largely disrupted in CPD10- and CPD13-treated samples. Signal intensity quantification data show a significant decrease in YAP-TEAD binding. Transcriptional profiling data show that CPD10 and CPD13 repress TEAD transcriptional target genes. Colony formation assay data show that CPD10 and CPD13 strongly sensitize NCI-H226 mesothelioma cells, indicating their therapeutic potential.

[0140] Figure 9 shows downregulation of Hippo-dependent gene transcripts. RT-qPCR showed a dose-dependent decrease in CTGF and CYR61 transcripts. MGH-CP1 (positive control) and Cpd13 were tested in MCF10 and A549.

[0141] The colony formation assay data for compounds 2 and 38 are shown in Figures 10 and 11, respectively. The results suggest that CPD2- and CPD38-induced cell sensitivity is independent of TEAD.

[0142] The above indicates that TEAD is an attractive target for cancer therapy.

[0143] It will be understood that many further modifications and permutations of various aspects of the described embodiments are possible, and accordingly, the described aspects are intended to embrace all such alterations, modifications and variations that are within the spirit and scope of the appended claims.

[0144] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" are understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of other integers or steps or groups of integers or steps.

[0145] Throughout this specification and the claims which follow, unless the context requires otherwise, the phrase "consisting essentially of" and variations such as "consists essentially of" are understood to indicate that the recited elements are essential, i.e., required elements of the invention. This phrase permits 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.

[0146] Reference in this specification to any prior publication (or information derived therefrom) or known matter is not, and should not be construed as, an acknowledgement, admission or any sort of suggestion that the prior publication (or information derived therefrom) or known matter forms part of the common general knowledge in the field of endeavor to which this specification pertains.

Claims

1. A compound of formula (I) or its salt, solvate, or prodrug. 【Chemistry 1】 (In the above formula, n is an integer selected from 1 to 5; Ar is an aryl or heteroaryl compound that may be substituted as needed.

2. The compound according to claim 1, wherein Ar is a heteroaryl which may be substituted in some cases.

3. The compound according to claim 1, wherein Ar is a heteroaryl which may be substituted in some cases, and the heteroatom is located at the 2' position relative to the N of the amide moiety.

4. The compound according to claim 1, wherein Ar is selected from optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted thiazolyl, optionally substituted pyrazolyl, or optionally substituted triazolyl.

5. The compound according to claim 1, wherein n is an integer selected from 1 to 4.

6. The compound according to claim 1, wherein the compound of formula (I) is the compound of formula (Ia). 【Chemistry 2】 (In the above formula, n is an integer selected from 1 to 5; X １ is a heteroatom selected from N, S, or O; X ２ , X ３ and X ４ is selected independently from C, N, O, or S; X ２ When R is N or C, １ is selected from optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; X ３ and X ４ When each of X and X is independently N or C, R ２ and R ３ is independently selected from H or optionally substituted alkyl.)

7. X １ The compound according to claim 6, wherein is a heteroatom selected from N or S.

8. X ２ , X ３ and X ４ The compound according to claim 6, wherein at least one of is N, O, or S.

9. R １ The compound according to claim 6, wherein the is selected from an optionally substituted cycloalkyl or optionally substituted aryl.

10. R ２ and R ３ The compound according to claim 6, wherein at least one of the alkyl groups may optionally be substituted.

11. The compound according to claim 1, wherein the compound of formula (I) is selected from the following. 【Transformation 3】

12. A HIPPO pathway modulator, which is a compound of formula (I) as described in Claim 1.

13. A pharmaceutical composition comprising the compound of formula (I) described in Claim 1 or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

14. The pharmaceutical composition according to claim 13, further comprising an active ingredient.

15. A pharmaceutical composition for use in the treatment of cancer, comprising a compound of formula (I) as described in Claim 1 or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

16. Use of the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug according to claim 1 in the manufacture of a pharmaceutical product for treating cancer in patients who require it.

17. Use of the pharmaceutical composition according to claim 15 or the compound according to claim 16, wherein the cancer is characterized by elevated YAP / TAZ-TEAD activity and / or drug resistance.

18. Use of the pharmaceutical composition according to claim 15 or the compound according to claim 16, wherein the cancer is selected from mesothelioma, liver cancer, gastric cancer, metastatic non-small cell lung cancer (NSCLC), and colorectal cancer.

19. The use of the pharmaceutical composition according to claim 15 or the compound according to claim 16, wherein the compound of formula (I) is used in combination with an active ingredient.

Images