TEAD inhibitors and their use

Abstract

The present disclosure provides, in part, a compound of formula (I): [Formula 1] JPEG2025526321000103.jpg5456, wherein the variables are as defined herein, as well as pharmaceutical compositions comprising the compounds and methods of using the compounds.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 369,036, filed July 21, 2022, the contents of which are incorporated herein by reference in their entirety. Summary of the Invention

[0002]

[0013] In certain embodiments herein, disclosed are compounds of Formula (I), (I'), (I-1), or (I-1'), such as compounds of Formula (Ia), (Ia'), (Ib), (Ib'), (Ic), (Ic'), (Id), and / or (Ie), or pharmaceutically acceptable salts thereof. Additionally, in certain embodiments herein, disclosed are compositions comprising compounds of Formula (I), (I'), (I-1), or (I-1'), such as compounds of Formula (Ia), (Ia'), (Ib), (Ib'), (Ic), (Ic'), (Id), and / or (Ie), or pharmaceutically acceptable salts thereof. Additionally, in certain embodiments herein, methods are disclosed for inhibiting aberrant transcriptional enhanced associate (TEA) domain transcription factors (TEADs), thereby treating certain diseases or disorders, such as cancer, characterized by aberrant TEAD transcription complex activity (e.g., hyperactivation).

[0003] In certain embodiments herein, a compound of formula (I):

[0004] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0005] Also, in certain embodiments herein, a compound of formula (I'):

[0006] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0007] Also, in certain embodiments herein, a compound of formula (I-1):

[0008] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0009] Also, in certain embodiments herein, a compound of formula (I-1'):

[0010] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0011] Also provided herein in certain embodiments are compounds of formula (Ia):

[0012] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0013] Also provided herein in certain embodiments are compounds of formula (Ia'):

[0014] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0015] Also provided herein in certain embodiments are compounds of formula (Ib):

[0016] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0017] Also, in certain embodiments herein, a compound of formula (Ib'):

[0018] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0019] Also provided herein in certain embodiments are compounds of formula (Ic):

[0020] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0021] Also, in certain embodiments herein, a compound of formula (Ic'):

[0022] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0023] Also provided herein in certain embodiments are compounds of formula (Id):

[0024] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0025] Also provided herein in certain embodiments are compounds of formula (Ie):

[0026] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0027] In some embodiments, the compound of Formula (I), Formula (I'), Formula (I-1), Formula (I-1'), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ib'), Formula (Ic), Formula (Ic'), Formula (Id), or Formula (Ie) is selected from the compounds of Table 1 or a pharmaceutically acceptable salt thereof.

[0028] Also provided herein in certain embodiments is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0029] Further, in certain embodiments, disclosed herein are methods of treating a disease or condition (e.g., disregulation) mediated by TEAD activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the disease or condition is cancer characterized by aberrant TEAD transcriptional complex activity (e.g., hyperactivation). [Brief explanation of the drawings]

[0030] The present disclosure can be more fully understood with reference to the following drawings.

[0031] [Figure 1]Figure 1 shows the domain architecture of human TEAD1, TEAD2, TEAD3, and TEAD4. Percentage values represent the identity of the N-terminal DNA-binding domain (DNA-BD) and the C-terminal YAP / TAZ-binding domain (YAP / TAZ-BD) in TEAD2-4 compared to the respective binding domains in TEAD1. Post-translational modifications are also shown, including palmitoylation and phosphorylation of the DNA-BD as well as the p38-binding D domain. [Figure 2A] Diagram showing the upstream signaling and downstream transcriptional outputs of TEADs in cancer biology, which regulate key functions in tumorigenesis, stem cell maintenance, cancer immunology, and metabolism, as well as forming signaling feedback loops. Oncogenic signaling pathways include EGFR signaling, TGFβ signaling, WNt signaling, GPCR signaling, and oncogenes such as KRAS, BRAF, LKB1, APC, and GNAQ / 11 (indicated with *). [Figure 2B] FIG. 1 shows the role of TEADs in multiple stages of tumorigenesis. [Figure 3A] 1 is a graph showing tumor volumes before and after 7 days of treatment in individual mice bearing MSTO-211H tumors administered vehicle twice daily, 3 mg / kg of compound 1-1 twice daily, or 12.5 mg / kg of compound 5 twice daily. [Figure 3B] FIG. 3B is a graph showing the mean change in MSTO-211H tumor volume in the treatment groups described in FIG. 3A. DETAILED DESCRIPTION OF THE INVENTION

[0032] Certain embodiments provided herein include compounds and compositions, e.g., compounds of Formula (I), Formula (I'), Formula (I-1), or Formula (I-1'), e.g., compounds of Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ib'), Formula (Ic), Formula (Ic'), Formula (Id), and / or Formula (Ie), or pharmaceutically acceptable salts thereof. Certain embodiments provided herein also include compositions comprising compounds of Formula (I), Formula (I'), Formula (I-1), or Formula (I-1'), e.g., compounds of Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ib'), Formula (Ic), Formula (Ic'), Formula (Id), and / or Formula (Ie), or pharmaceutically acceptable salts thereof. Certain embodiments provided herein also include methods of using the compounds and compositions disclosed herein. Contemplated compounds and compositions disclosed herein are inhibitors of transcriptional enhancer element domain (TEAD) activity and are therefore useful in methods of treating certain diseases or disorders, such as cancer, characterized by aberrant TEAD transcriptional complex activity (e.g., hyperactivation).

[0033] Specific Terms Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the claimed subject matter belongs. Generally, the nomenclature used in and with the immunology, oncology, cell and tissue culture, molecular biology, and protein and oligonucleotide or polynucleotide chemistry and hybridization techniques described herein are well known and commonly used in the art. It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not intended to limit all claimed subject matter. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0034] The articles "a" and "an" are used herein to refer to one or to more than one (ie, to at least one) of the grammatical object of the article.

[0035] Chemical Substance Definition Definitions of specific functional groups and chemical terms are described in detail below.

[0036] In some embodiments, the compounds described herein contain one or more asymmetric centers and therefore exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, in some embodiments, the compounds described herein are in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In some embodiments, isomers are isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers are prepared by asymmetric synthesis. The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0037] In some embodiments, the compounds described herein also include one or more isotopic substitutions. For example, in some embodiments, H is 1 H, 2 H (D or deuterium), and 3 All isotopic forms including H (T or tritium), and C is 12 C. 13 C, and 14 All isotopic forms, including C, and O 16 O and 18 All isotopic forms including O, F 18 F and 19 All isotopic forms containing F, etc.

[0038] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6, C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 It is intended to include alkyl.

[0039] As used herein, "alkyl" refers to a straight- or branched-chain saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms ("C1-C 20 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C-C 10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C1-C9 alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C1-C7 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-C5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-C4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-C3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-C2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). Examples of C1-C6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0040] As used herein, "alkylene" refers to a divalent radical of an alkyl group. When a range or number of carbon atoms is given for a particular "alkylene" group, it is understood that the range or number refers to the range or number of carbon atoms in a linear carbon divalent chain. In some embodiments, an "alkylene" group is substituted or unsubstituted with one or more substituents described herein.

[0041] As used herein, "aryl" refers to an aromatic ring system ("C 6-14 "aryl" refers to a radical of a mono- or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., 6, 10, or 14 pi-electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms, as given in "aryl").

[0042] As used herein, "heteroaryl" refers to the radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., 6-10 electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where the heteroatoms are each independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, in heteroaryl groups containing one or more nitrogen atoms, the point of attachment is at a carbon atom or a nitrogen atom, if valence allows.

[0043] In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, a 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0044] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.

[0045] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon radical of 3 to 12, 3 to 10, 3 to 8, 4 to 8, or 4 to 6 carbons, such as "C-C" derived from a cycloalkane. 10Typical cycloalkyl groups include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and cyclopropane.

[0046] As used herein, "heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "3- to 10-membered heterocyclyl"). In some embodiments, in heterocyclyl groups containing one or more nitrogen atoms, the point of attachment is at a carbon atom or a nitrogen atom, where valence permits. In some embodiments, heterocyclyl groups are either monocyclic (a "monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems (a "bicyclic heterocyclyl"), and are saturated or partially unsaturated. In some embodiments, heterocyclyl bicyclic ring systems contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more cycloalkyl groups whose points of attachment are on the cycloalkyl or heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more phenyl or heteroaryl groups whose points of attachment are on the heterocyclyl ring; in such instances, the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably.

[0047] In some embodiments, heterocyclyl groups are 3- to 10-membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("3- to 10-membered heterocyclyl"). In some embodiments, heterocyclyl groups are 3- to 7-membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("3- to 7-membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5- to 10-membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5-5 membered heterocyclyl"). In some embodiments, a 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0048] "Hetero," when used to describe a compound or a group present thereon, means that one or more carbon atoms in the compound or group have been replaced with a nitrogen, oxygen, or sulfur heteroatom. In some embodiments, hetero applies to any of the aforementioned hydrocarbyl groups having 1 to 5, specifically 1 to 3, heteroatoms, such as alkyl, e.g., heteroalkyl; cycloalkyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; etc.

[0049] The terms "halo" and "halogen," as used herein, refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I). In certain embodiments, a halo group is either fluoro or chloro.

[0050] The term "haloalkyl" includes mono-, poly-, and perhaloalkyl groups substituted with one or more halogen atoms, the halogens being independently selected from fluorine, chlorine, bromine, and iodine.

[0051] The term "oxo" as used herein refers to =O.

[0052] As used herein, the term "hydroxyl" refers to --OH.

[0053] In general, the term "substituted," whether preceded by the term "optionally," refers to replacement with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are either the same or different at each position.

[0054] Nitrogen atoms are substituted or unsubstituted where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms.

[0055] These and other exemplary substituents are described in detail in the detailed description, examples, and claims. The present disclosure is not intended to be limited in any way by the above exemplary enumeration of substituents.

[0056] Other definitions As used herein, "pharmaceutically acceptable excipient" refers to any substance other than the active pharmaceutical ingredient present in a pharmaceutical formulation. Exemplary pharmaceutical excipients include those that aid in the manufacturing process, protect, support, or enhance stability, increase bioavailability, or improve patient tolerance. They may also aid in product specification or enhance the overall safety of the product during storage or use.

[0057] As used herein, "pharmaceutically acceptable salt" refers to a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, hypersensitivity, allergic reaction, or the like, and that is commensurate with a reasonable benefit-risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids, and with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and ammonium salts such as toluenesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-methyl-N ... + (C 1-4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additionally, pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0058] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., men and women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or the elderly)), and / or non-human animals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," "individual," and "subject" are used interchangeably herein. None of these terms require the supervision of a medical professional.

[0059] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0060] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions taken while a subject is suffering from a specified disease, disorder, or condition to lessen the severity of the disease, disorder, or condition or to delay or slow the progression of the disease, disorder, or condition.

[0061] As used herein, unless otherwise specified, a "therapeutically effective amount" or "effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount or effective amount of a compound means an amount of a therapeutic agent alone, or in combination with other therapeutic agents, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. In some embodiments, the term "therapeutically effective amount" or "effective amount" encompasses an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0062] compound In certain embodiments herein, a compound of formula (I):

[0063] [ka] or a pharmaceutically acceptable salt thereof, wherein X is NR a , O, and S; R 1 is a 5-10 membered heteroaryl having 1, 2, 3, or 4 heteroatoms, each independently selected from the group consisting of N, O, and S, wherein the 5-10 membered heteroaryl is optionally substituted; R 2 is a 3-10 membered heterocyclyl or -(C1-C4 alkylene)-(3-10 membered heterocycloalkyl), wherein the 3-10 membered heterocyclyl has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, and is optionally substituted; and the C1-C4 alkylene is optionally substituted; R 3a and R 3bOne of the following is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), C 3-10 is selected from the group consisting of cycloalkyl, phenyl, naphthyl, and 5- to 10-membered heteroaryl; 3-10 Cycloalkyl, phenyl, naphthyl, and 5- to 10-membered heteroaryl are optionally substituted and R 3a and R 3b the remainder being selected from the group consisting of hydrogen, halogen, and -C1-C6 alkyl; R 4 are each independently selected from halogen and -C1-C6 alkyl; R 5 are each independently selected from halogen and -C1-C6 alkyl; m is selected from the group consisting of 0, 1, 2, and 3; n is selected from the group consisting of 0, 1, 2, and 3; R a is selected from hydrogen and —C1-C6 alkyl; Disclosed are compounds, or pharmaceutically acceptable salts thereof.

[0064] Also, in certain embodiments herein, a compound of formula (I'):

[0065] [ka] or a pharmaceutically acceptable salt thereof, wherein X is NR a , O, and S; R 1 is a 5-10 membered heteroaryl having 1, 2, 3, or 4 heteroatoms, each independently selected from the group consisting of N, O, and S, wherein the 5-10 membered heteroaryl is optionally substituted; R 2is a 3-10 membered heterocyclyl or -(C1-C4 alkylene)-(3-10 membered heterocyclyl), wherein the 3-10 membered heterocyclyl contains at least 2 carbon atoms and 1, 2, 3, or 4 heteroatoms and is optionally substituted, wherein the heteroatom is nitrogen, and the C1-C4 alkylene is optionally substituted; R 3a and R 3b One of the following is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), C 3-10 is selected from the group consisting of cycloalkyl, phenyl, naphthyl, and 5- to 10-membered heteroaryl; 3-10 Cycloalkyl, phenyl, naphthyl, and 5- to 10-membered heteroaryl are optionally substituted and R 3a and R 3b the remainder being selected from the group consisting of hydrogen, halogen, and -C1-C6 alkyl; R 4 are each independently selected from halogen and -C1-C6 alkyl; R 5 are each independently selected from halogen and -C1-C6 alkyl; m is selected from the group consisting of 0, 1, 2, and 3; n is selected from the group consisting of 0, 1, 2, and 3; R a is selected from hydrogen and —C1-C6 alkyl; Disclosed are compounds, or pharmaceutically acceptable salts thereof.

[0066] Also, in certain embodiments herein, a compound of formula (I-1):

[0067] [ka] or a pharmaceutically acceptable salt thereof, wherein X is NR a , O, and S; R 1 is a 5-10 membered heteroaryl having 1, 2, 3, or 4 heteroatoms, each independently selected from the group consisting of N, O, and S, wherein the 5-10 membered heteroaryl is optionally substituted; R 2 is a 3-10 membered heterocyclyl or -(C1-C4 alkylene)-(3-10 membered heterocyclyl), wherein the 3-10 membered heterocyclyl contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, and is optionally substituted; and the C1-C4 alkylene is optionally substituted; R 3 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), C 3-10 is selected from the group consisting of cycloalkyl, phenyl, naphthyl, and 5- to 10-membered heteroaryl; 3-10 cycloalkyl, phenyl, naphthyl, and 5- to 10-membered heteroaryl are optionally substituted; R 4 are each independently selected from halogen and -C1-C6 alkyl; R 5 are each independently selected from halogen and -C1-C6 alkyl; m is selected from the group consisting of 0, 1, 2, 3, and 4; n is selected from the group consisting of 0, 1, 2, and 3; R a is selected from hydrogen and —C1-C6 alkyl; Disclosed are compounds, or pharmaceutically acceptable salts thereof.

[0068] Also, in certain embodiments herein, a compound of formula (I-1):

[0069] [ka] or a pharmaceutically acceptable salt thereof, wherein X is NRa , O, and S; R 1 is a 5-10 membered heteroaryl having 1, 2, 3, or 4 heteroatoms, each independently selected from the group consisting of N, O, and S, wherein the 5-10 membered heteroaryl is optionally substituted; R 2 is a 3-10 membered heterocyclyl or -(C1-C4 alkylene)-(3-10 membered heterocyclyl), wherein the 3-10 membered heterocyclyl contains at least 2 carbon atoms and 1, 2, 3, or 4 heteroatoms and is optionally substituted, wherein the heteroatom is nitrogen, and the C1-C4 alkylene is optionally substituted; R 3 is halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), C 3-10 is selected from the group consisting of cycloalkyl, phenyl, naphthyl, and 5- to 10-membered heteroaryl; 3-10 cycloalkyl, phenyl, naphthyl, and 5- to 10-membered heteroaryl are optionally substituted; R 4 are each independently selected from halogen and -C1-C6 alkyl; R 5 are each independently selected from halogen and -C1-C6 alkyl; m is selected from the group consisting of 0, 1, 2, 3, and 4; n is selected from the group consisting of 0, 1, 2, and 3; R a is selected from hydrogen and —C1-C6 alkyl; Disclosed are compounds, or pharmaceutically acceptable salts thereof.

[0070] In some embodiments, X is NR a is.

[0071] In some embodiments, the compound has formula (Ia):

[0072] [ka] or a pharmaceutically acceptable salt thereof, wherein R 3 is —C1-C6 alkyl or —C1-C6 haloalkyl; The remaining variables are as defined in formula (I).

[0073] In some embodiments, the compound has the formula (Ia'):

[0074] [ka] or a pharmaceutically acceptable salt thereof, wherein R 3 is —C1-C6 alkyl or —C1-C6 haloalkyl; The remaining variables are as defined in formula (I').

[0075] In some embodiments, R 1 is an optionally substituted 5-6 membered heteroaryl.

[0076] In some embodiments, R 1 are C1-C6 alkyl, halogen, C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), and -N(R b )2 is a 5- to 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: b are each independently selected from hydrogen and C1-C6 alkyl.

[0077] In some embodiments, R 1is a 5-6 membered heteroaryl selected from the group consisting of oxadiazole, imidazole, pyrazole, oxazole, triazole, tetrazole, pyridine, pyrazine, and pyridazine, and the 5-6 membered heteroaryl is selected from the group consisting of C-C alkyl, halogen, C-C haloalkyl, —O—(C-C alkyl), —O—(C-C haloalkyl), and —N(R b )2, optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: b are each independently selected from hydrogen and C1-C6 alkyl.

[0078] In some embodiments, R 1 is a 5-6 membered heteroaryl, each optionally substituted with 1, 2, 3, or 4 substituents selected from halogen and -C1-C6 alkyl.

[0079] In some embodiments, R 1 is a 5-6 membered heteroaryl selected from the group consisting of oxadiazole, imidazole, pyrazole, oxazole, triazole, tetrazole, pyridine, pyrazine, and pyridazine, wherein the 5-6 membered heteroaryl is optionally substituted with C1-C6 alkyl.

[0080] In some embodiments, R 1 is imidazole optionally substituted with methyl.

[0081] In some embodiments, R 1 is an oxazole.

[0082] In some embodiments, R 1 is tetrazole optionally substituted with methyl.

[0083] In some embodiments, R 1 is an oxadiazole optionally substituted with methyl, such as 1,3,4-oxadiazole.

[0084] In some embodiments, the compound has formula (Ib):

[0085] [ka] or a pharmaceutically acceptable salt thereof, wherein R d is selected from hydrogen and —C1-C6 alkyl; The remaining variables are as defined in formula (Ia).

[0086] In some embodiments, the compound has the formula (Ib'):

[0087] [ka] or a pharmaceutically acceptable salt thereof, wherein R d is selected from hydrogen and —C1-C6 alkyl; The remaining variables are as defined in formula (Ia').

[0088] In some embodiments, the compound has the formula (Ic):

[0089] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in formula (Ib).

[0090] In some embodiments, the compound has the formula (Ic'):

[0091] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in formula (Ib').

[0092] In some embodiments, R 2is a 3- to 7-membered monocyclic heterocyclyl or -(C1-C4 alkylene)-(3- to 7-membered monocyclic heterocyclyl), wherein the 3- to 7-membered monocyclic heterocyclyl has 1, 2, 3, or 4 heteroatoms, each independently selected from N, O, and S, and the 3- to 7-membered monocyclic heterocyclyl is optionally substituted, and the C1-C4 alkylene is optionally substituted (e.g., C 1-6 Alkyl, C 1-6 optionally substituted with haloalkyl, or C 1-4 Two geminal hydrogens on the alkylene carbon can be combined with the carbon atoms to which they are attached to form a 3- to 7-membered cycloalkyl ring.

[0093] In some embodiments, R 2 is a 3- to 7-membered monocyclic heterocyclyl or -(C1-C4 alkylene)-(3- to 7-membered monocyclic heterocyclyl), where the 3- to 7-membered monocyclic heterocyclyl contains at least 2 carbon atoms and 1, 2, 3, or 4 heteroatoms, and the heteroatom is nitrogen, and the 3- to 7-membered monocyclic heterocyclyl is optionally substituted, and the C1-C4 alkylene is optionally substituted (e.g., C 1-6 Alkyl, C 1-6 optionally substituted with haloalkyl, or C 1-4 Two geminal hydrogens on the alkylene carbon can be combined with the carbon atoms to which they are attached to form a 3- to 7-membered cycloalkyl ring.

[0094] In some embodiments, R 2 is a 3- to 7-membered monocyclic heterocyclyl or -(C-C alkylene)-(3- to 7-membered monocyclic heterocyclyl), each of which has 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, and each of which is C-C alkyl, oxo, hydroxyl, halogen, C-C haloalkyl, -O-(C-C alkyl), -O-(C-C haloalkyl), -N(R b )2, -C(O)OR g , -C(O)N(Rf )2, -S(O)2N(R f )2, -OC(O)N(R f )2, -NR f C(O)N(R f )2, -S(O) r -R f and R is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of b , R g , and R f each is independently selected from hydrogen and C1-C6 alkyl, each r is 1 or 2, and R f are each independently selected from C1-C6 alkyl and phenyl.

[0095] In some embodiments, R 2 is a 3- to 7-membered monocyclic heterocyclyl or -(C1-C4 alkylene)-(3- to 7-membered monocyclic heterocyclyl), wherein the 3- to 7-membered monocyclic heterocyclyl contains at least 2 carbon atoms and 1, 2, 3, or 4 heteroatoms, and the heteroatom is nitrogen; the 3- to 7-membered monocyclic heterocyclyl is, respectively, C1-C6 alkyl, oxo, hydroxyl, halogen, C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), -N(R b )2, -C(O)OR g , -C(O)N(R f )2, -S(O)2N(R f )2, -OC(O)N(R f )2, -NR f C(O)N(R f )2, and -S(O) r -R f and R is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of b , R g , and R f each is independently selected from hydrogen and C1-C6 alkyl, each r is 1 or 2, and R f are each independently selected from C1-C6 alkyl and phenyl.

[0096] In some embodiments, R 2 is a 3- to 7-membered monocyclic heterocyclyl, the 3- to 7-membered monocyclic heterocyclyl containing at least 2 carbon atoms and 1, 2, 3, or 4 heteroatoms, wherein the heteroatom is nitrogen, and the 3- to 7-membered monocyclic heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, —C1-C6 alkyl, oxo, and hydroxyl.

[0097] In some embodiments, R 2 is a 5-membered heterocyclyl having 1 or 2 nitrogen atoms, wherein the 5-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C6 alkyl and oxo.

[0098] In some embodiments, R 2 is a 5-membered heterocyclyl having 1 or 2 heteroatoms, wherein the heteroatoms are nitrogen atoms, and each 5-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from C-C alkyl, oxo, and hydroxyl.

[0099] In some embodiments, R 2 is -(C1-C4 alkylene)-(5-membered heterocyclyl having 1 or 2 nitrogen atoms), wherein the 5-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C6 alkyl and oxo.

[0100] In some embodiments, R 2 is -(C1-C4 alkylene)-(5-membered heterocyclyl having 1 or 2 heteroatoms), where the heteroatom is a nitrogen atom, and each 5-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C6 alkyl, oxo, and hydroxyl.

[0101] In some embodiments, R 2 teeth,

[0102] [ka] where t is selected from the group consisting of 0, 1, 2, and 3.

[0103] In some embodiments, R 2 teeth,

[0104] [ka] where t is selected from the group consisting of 0, 1, 2, and 3.

[0105] In some embodiments, t is 1.

[0106] In some embodiments, R 2 teeth,

[0107] [ka] wherein s is selected from the group consisting of 0, 1, 2, and 3; e is selected from hydrogen and C1-C6 alkyl.

[0108] In some embodiments, s is 0 and R e is methyl.

[0109] In some embodiments, R 2 teeth,

[0110] [ka] wherein u is selected from the group consisting of 0, 1, 2, and 3; e is selected from hydrogen and C1-C6 alkyl.

[0111] In some embodiments, R 2teeth,

[0112] [ka] wherein u is selected from the group consisting of 0, 1, 2, and 3; e is selected from hydrogen and C1-C6 alkyl.

[0113] In some embodiments, R 2 teeth,

[0114] [ka] wherein u is selected from the group consisting of 0, 1, 2, and 3; e is selected from hydrogen and C1-C6 alkyl.

[0115] In some embodiments, u is 0 and R e is methyl.

[0116] In some embodiments, the compound has the formula (Id):

[0117] [ka] or a pharmaceutically acceptable salt thereof, wherein R 3 is —C1-C6 alkyl or —C1-C6 haloalkyl; The remaining variables are as defined in formula (Ia).

[0118] In some embodiments, the compound has the formula (Ie):

[0119] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in formula (Id).

[0120] In some embodiments, R 3is C1-C6 alkyl or -C1-C6 haloalkyl.

[0121] In some embodiments, R 3 is a halogen.

[0122] In some embodiments, R 3 is trifluoromethyl.

[0123] In some embodiments, m and n are both 0.

[0124] In some embodiments, R a is hydrogen.

[0125] In some embodiments, the compound is a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0126] [Table 1-1]

[0127] [Table 1-2]

[0128] [Table 1-3]

[0129] [Table 1-4]

[0130] [Table 1-5]

[0131] Also disclosed herein in certain embodiments are compounds of Table 1a, or a pharmaceutically acceptable salt thereof.

[0132] [Table 2]

[0133] Pharmaceutical Compositions and Routes of Administration In certain embodiments, disclosed herein are pharmaceutical compositions comprising: (a) a compound disclosed herein (e.g., a compound of Formula (I), Formula (I'), Formula (I-1), Formula (I-1'), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ib'), Formula (Ic), Formula (Ic'), Formula (Id), or Formula (Ie)), or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient. In some embodiments, the excipient is selected from inert and solid diluents and diluents including fillers, sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. In some embodiments, the pharmaceutical compositions are administered alone or in combination with other therapeutic agents. Such compositions are prepared by any suitable method.

[0134] In some embodiments, the pharmaceutical compositions are administered in either single or multiple doses by any of the accepted pharmaceutical dosage forms having similar utility, including rectal, buccal, nasal, and transdermal routes, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, by local intraarterial injection, as an inhalant, or by an impregnated or coated device such as a stent, e.g., a cylindrical polymer inserted into an artery.

[0135] One form of administration is parenteral, particularly by injection. In some embodiments, forms in which the novel compositions of the present disclosure are incorporated for administration by injection include aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous solutions in saline are also used for injection. In some embodiments, ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils are also utilized. In some embodiments, proper fluidity is maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. In some embodiments, the prevention of microbial action is achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal.

[0136] Sterile injectable solution can be prepared by incorporating the compound of the present disclosure in a suitable solvent with various other ingredients as listed above, and then optionally performing filtered sterilization.Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains a basic dispersion medium and the other ingredients listed above that are required.For sterile powders to prepare sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying, which produces a powder of active ingredient and any additional desired ingredients from a previously sterile-filtered solution.

[0137] Oral administration is another route for administering the compounds disclosed herein. In some embodiments, administration is via capsules, enteric-coated tablets, or the like. In some embodiments, when preparing pharmaceutical compositions comprising at least one compound described herein, the active ingredient is typically diluted with an excipient and / or contained within a container in the form of a capsule, sachet, paper, or other container. In some embodiments, when the excipient serves as a diluent, it is in the form of a solid, semi-solid, or liquid material (as described above) that serves as a vehicle, carrier, or medium for the active ingredient. Thus, in some embodiments, the composition is in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), e.g., ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0138] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. In some embodiments, the formulation further comprises lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl- and propylhydroxy-benzoates, sweeteners, and flavoring agents.

[0139] In some embodiments, the compositions of the present disclosure are formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation used in the methods of the present disclosure utilizes transdermal delivery devices ("patches"). In some embodiments, such transdermal patches are used to provide continuous or discontinuous infusion of the compounds of the present disclosure in controlled amounts. The construction and use of transdermal patches to deliver pharmaceuticals is well known in the art. In some embodiments, such patches are constructed for continuous, pulsatile, or on-demand delivery of pharmaceuticals.

[0140] The compositions are preferably formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as single dosages for human subjects and other mammals, each containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect in combination with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. Preferably, for oral administration, dosage units each contain 1 mg to 2 g of a compound described herein, and for parenteral administration, 0.1 to 700 mg of a compound described herein. However, it will be understood that the amount of compound actually administered will typically be determined by a physician in light of relevant circumstances, including the disease being treated, the selected route of administration, the compound actually administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0141] When preparing solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulated composition containing a homogeneous mixture of the compounds of the present disclosure. In some embodiments, when these preformulated compositions are referred to as homogeneous, it is intended that the active ingredient is evenly dispersed throughout the composition so that the composition is easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0142] In some embodiments, tablets or pills of the present disclosure are coated or otherwise compounded to provide a dosage form offering the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, in some embodiments, the tablet or pill comprises an inner dosage component and an outer dosage component, the latter in the form of an envelope over the former. In some embodiments, the two components are separated by an enteric layer, which functions to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to delay its release. In some embodiments, a variety of materials are used for such enteric layers or coatings, including several polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0143] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof. In some embodiments, liquid or solid compositions contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, compositions are administered via the oral or nasal respiratory route for local or systemic effect. In some embodiments, compositions in pharmaceutically acceptable solvents are nebulized by use of inert gases. In some embodiments, nebulized solutions are inhaled directly from a nebulizing device, or the nebulizing device is attached to a face mask tent or intermittent positive pressure breathing machine. In some embodiments, solution, suspension, or powder compositions are administered orally or nasally from a device that delivers the formulation in an appropriate form.

[0144] Treatment method In certain embodiments herein, there is provided a method of treating a disease or disorder regulated by abnormal activity of a TEAD isoform (e.g., TEAD1 and / or TEAD4) (e.g., overactivation of a TEAD transcription complex) in an individual in need thereof, comprising administering to the individual a compound of Formula (I), Formula (I'), Formula (I-1), Formula (I-1'), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ib and administering a therapeutically effective amount of a compound of Formula (I), Formula (I'), Formula (I-1), Formula (I-1'), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ib'), Formula (Ic), Formula (Ic'), Formula (Id), or Formula (Ie), or a pharmaceutically acceptable salt thereof.

[0145] TEA domain transcription factors (TEADs) are downstream effectors of the Hippo signaling pathway. Four TEAD isoforms have been identified: TEAD1, TEAD2, TEAD3, and TEAD4. TEAD isoforms share a highly similar structure. The N-terminus of the four isoforms shares a highly conserved 68-amino acid TEA / ATTS DNA-binding domain, which binds to the MCAT element (50-CATTCCA / T-30). The C-terminus contains a transactivation domain that recruits the transcriptional coactivator YAP / TAZ.

[0146] TEAD protein expression is upregulated in many cancer types, including gastric, colorectal, breast, and prostate cancer. TEAD hyperactivation plays a role in tumor progression, metastasis, cancer metabolism, immunity, and drug resistance, and is correlated with poor patient survival.

[0147] Selective binding of TEAD1 and / or TEAD4 is beneficial for optimizing antitumor efficacy while minimizing undesired consequences. Inhibition of TEAD3 has been associated with off-target toxicity (e.g., nephrotoxicity), whereas inhibition of TEAD2 can be pro-proliferative.

[0148] The TEAD isoform selectivity demonstrated by the compounds disclosed herein is an advantage over TEAD inhibitors known in the art. For example, as demonstrated by Tang and Post using thermal shift assays, the TEAD inhibitor VT3989 interacts primarily with TEAD1-3. The reported thermal shift data is shown in Table 2 below (Tang and Post, "The TEAD autopalmitoylation inhibitor VT3989 improves efficacy and increases durability of efficacy of osimertinib in preclinical EGFR mutant tumor models," Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr. 8-13. Philadelphia, PA: AACR; Poster #5364). The data shown in Table 2 demonstrate that VT3989 provides minimal selectivity over TEAD2 and 3, TEAD isoforms whose inhibition is undesirable. Furthermore, VT3989 exhibits low levels of binding to TEAD4, a TEAD isoform whose inhibition is undesirable. Each change in ΔTm (°C) of 2.5°C can be associated with approximately a 10-fold difference in binding affinity (Bhayani et al., "Determination of dissociation constants of protein ligands by thermal shift assay," Biochemical and Biophysical Research Communications, 2022, 560:1-6).

[0149] [Table 3]

[0150] In some embodiments, the compounds disclosed herein selectively bind to one or more TEAD isoforms. In certain embodiments, the compounds disclosed herein selectively bind to TEAD1. In certain embodiments, the compounds presented herein selectively bind to TEAD4. In certain embodiments, the compounds disclosed herein selectively bind to TEAD1 and TEAD4. In some embodiments, the binding selectivity for TEAD1 is 10-fold, 100-fold, 1,000-fold, or 10,000-fold greater than TEAD2 and / or TEAD3. In some embodiments, the binding selectivity for TEAD4 is 10-fold, 100-fold, 1,000-fold, or 10,000-fold greater than TEAD2 and / or TEAD3. Evidence of the TEAD isoform selectivity demonstrated by the compounds disclosed herein is shown in Example 26 below.

[0151] In some embodiments, the compounds disclosed herein are useful as therapeutics for treating diseases or conditions mediated by overactivation of the YAP / TAZ-TEAD (e.g., TEAD1 and / or TEAD4) transcriptional coactivator complex. In some embodiments, the compounds disclosed herein are useful as therapeutics for treating diseases or conditions characterized by overactivation of TEAD (e.g., TEAD1, TEAD2, TEAD3, and TEAD4 isoforms). In some embodiments, the disease or condition is characterized by overexpression or genomic fusion or amplification of TEAD. TEAD1 and TEAD4 undergo recurrent onco-fusions, e.g., TEAD1-PARVA. These fusions can induce higher expression of TEADs and enhance transcription of TEAD target genes. TEAD4 amplification (genomic copy number gain) occurs in a variety of cancers, for example, ovarian and uterine cancers, as well as as part of the 12p13 locus in testicular germ cell tumors. These genomic amplifications of TEAD4 are associated with a large increase in its mRNA expression and can induce high TEAD-YAP / TAZ transcriptional activity.

[0152] In certain embodiments, the TEAD isoform is TEAD1. In certain embodiments, the TEAD isoform is TEAD4. In some embodiments, the disease, disorder, or condition is a cancer characterized by aberrant TEAD transcriptional complex activity (e.g., hyperactivation). Such cancers include, but are not limited to, breast cancer, lung cancer, gastric cancer, colorectal cancer, pancreatic cancer including pancreatic adenocarcinoma, mesothelioma including malignant mesothelioma, hepatocellular carcinoma, prostate cancer, head and neck cancer, renal cell carcinoma, and medulloblastomas. In some embodiments, the cancer is selected from pancreatic adenocarcinoma, hepatocellular carcinoma, breast cancer, and malignant mesothelioma. In certain embodiments, the pancreatic cancer is pancreatic adenocarcinoma. In certain embodiments, the cancer is malignant mesothelioma.

[0153] Also provided herein is a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in treating a disease or disorder mediated by overactivation of a TEAD isoform selected from TEAD1 and TEAD4 in a subject in need thereof.

[0154] In another aspect herein, there is provided use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for treating a disease or disorder mediated by overactivation of a TEAD isoform selected from TEAD1 and TEAD4 in a subject in need thereof.

[0155] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is renal cell carcinoma. In some embodiments, the cancer is medulloblastoma. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is metastatic cancer. In some embodiments, the cancer is metastatic breast cancer. In some embodiments, the cancer is metastatic lung cancer. In some embodiments, the cancer is metastatic gastric cancer. In some embodiments, the cancer is metastatic colorectal cancer. In some embodiments, the cancer is metastatic prostate cancer. In some embodiments, the cancer is metastatic head and neck cancer. In some embodiments, the cancer is metastatic renal cell carcinoma. In some embodiments, the cancer is metastatic mesothelioma. In some embodiments, the cancer is metastatic pancreatic cancer. In some embodiments, the cancer is metastatic hepatocellular carcinoma.

[0156] In some embodiments, the present disclosure provides a compound of Formula (I), Formula (I'), Formula (I-1), Formula (I-1'), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ib'), Formula (Ic), Formula (Ic'), Formula (Id), or Formula (Ie) for modulating TEAD activity. In some embodiments, the present disclosure provides a pharmaceutically acceptable salt of a compound of Formula (I), Formula (I'), Formula (I-1), Formula (I-1'), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ib'), Formula (Ic), Formula (Ic'), Formula (Id), or Formula (Ie) for modulating TEAD activity.

[0157] In some embodiments, the present disclosure provides a compound of Formula (I), Formula (I'), Formula (I-1), Formula (I-1'), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ib'), Formula (Ic), Formula (Ic'), Formula (Id), or Formula (Ie), or a pharmaceutically acceptable salt thereof, for use in medical therapy.

[0158] In some embodiments, the compound disclosed herein, or its pharmaceutically acceptable salt, or pharmaceutical composition, is administered alone or in combination with one or more other therapeutic agents.In some embodiments, the other therapeutic agent is any suitable chemotherapeutic agent.In some embodiments, the one or more other therapeutic agents are selected from modulators of other transcription factors.In some embodiments, the modulators of other transcription factors are selected from modulators of YAP, modulators of EGFR, or modulators of MEK.

[0159] In some embodiments, one or more other therapeutic agents are administered simultaneously with the compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. In some embodiments, one or more other therapeutic agents are administered sequentially with the compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. In some embodiments, one or more other therapeutic agents are administered before the compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. In some embodiments, one or more other therapeutic agents are administered after the compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. [Example]

[0160] The present disclosure is further illustrated in the following examples, which are given for illustrative purposes only and are not intended to limit the disclosure in any way. Abbreviation ACN Acetonitrile B2Pin2 Bis(pinacolato)diboron Boc tert-butyloxycarbonyl CAN Ammonium Cerium Nitrate DAST Diethylaminosulfur trifluoride DBU 1,8-diazabicyclo(5.4.0)undec-7-ene DCC dicyclohexylcarbodiimide DCE 1,1-dichloroethane DCM dichloromethane DEA Diethanolamine DEAD Diethyl azodicarboxylate DIAD Diisopropyl azodicarboxylate DIBAL Diisobutylaluminum hydride DIPEA N,N-Diisopropylethylamine, Hunig's base DMA N,N-dimethylacetamide DMAP 4-(dimethylamino)pyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc / EA ethyl acetate eq equivalent h time HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide HBTU (1H-benzotriazol-1-yloxy)(dimethylamino)-N,N-dimethylmethaniminium hexafluorophosphate hex hexane HOBT N-Hydroxybenzotriazole HPLC High Pressure Liquid Chromatography LAH Lithium aluminum hydride IPA Isopropyl Alcohol LCMS Liquid Chromatography Mass Spectrometry LDA Lithium diisopropylamide LiHMDS Lithium bis(trimethylsilyl)amide mCPBA meta-chloroperoxybenzoic acid MI molecular ion Min MgSO4 Anhydrous Magnesium Sulfate MS mass spectrometry MW Microwave NBS / NBRS N-Bromosuccinamide NCS N-chlorosuccinamide NFOBS / NFOBRS N-Fluoro-o-benzenedisulfonimide NFSI N-Fluorobenzenesulfonimide NHS N-hydroxysuccinimide NIS N-iodosuccinamide NMM N-methylmorpholine NMP 1-methyl-2-pyrrolidinone NMR nuclear magnetic resonance PdCl2(PPh3)2 Bis(triphenylphosphine)palladium chloride Pd(dppf)2Cl2[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)2Cl2.DCM [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (Pd(dba)2) Bis(dibenzylideneacetone)palladium (Pd2(dba)3) Tris(dibenzylideneacetone)palladium Rbf / RB round bottom flask RM reaction mixture RP reverse phase RT retention time SCX-2 Silica-based adsorbent with chemically bonded propylsulfonic acid functional groups SFC Supercritical Fluid Chromatography TBAF Tetra-n-butylammonium fluoride TBDMS tert-butyldimethylsilyl TEA Triethylamine TFAA Trifluoroacetic anhydride TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TMSCN Trimethylsilyl cyanide TPP Tripotassium Phosphate Ts / Tos Toluenesulfonyl Xantphos (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) XPhos-Pd-G1 2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) chloride XPhos-Pd-G2 Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0161] Analysis method Commercially available starting materials, reagents, and dry solvents were used as supplied. Flash column chromatography or glass column chromatography was performed using Merck silica gel 230–400 mesh size. Flash chromatography was also performed on a combi-flash RF Teledyne Isco machine. Preparative TLC was performed on Merck plates.

[0162] Liquid chromatography-mass spectrometry method Method A Method name: UC02_FAR1, Machine details: Water Acquity UPLC-H Class equipped with PDA and Acquity SQ detector, Column: Waters X-bridge C18, 50*2.1mm, 2.5 micron, Column temperature: 35℃, Autosampler temperature: 15℃, Mobile phase A: 0.1% formic acid in Milli-Q water (PH=2.70), Mobile phase B: 0.1% formic acid in Milli-Q water:acetonitrile (10:90), Mobile phase gradient details: T=0 min (97% A, 3% B), gradient to T=2.7 min (2% A, 98% B), Flow rate: 0.8mL / min, T=0 min (97% A, 3% B), Flow rate: 0.8mL / min, T=0 min (97% A, 3% B), Flow rate: 0.8mL / min, Gradient to T=3 min (0% A, 100% B), Flow rate: 1mL / min, T = 3.5 min (0% A, 100% B), Flow rate: 1 mL / min, Gradient (97% A, 3% B) until T = 3.51 min, Flow rate: 0.8 mL / min, Run end at T = 4 min (97% A, 3% B), Flow rate: 0.8 mL / min, Run time: 4 min, UV detection method: PDA, Wavelength: 200-500 nm, Mass parameters: Probe: ESI, Ionization mode: positive and negative, Cone voltage: 30 V and 10 V, Capillary voltage: 3.0 kV, Extractor voltage: 1 V, Rf lens: 0.1 V, Source temperature: 120 °C, Desolvation temperature: 400 °C. Cone gas flow rate: 100 L / h, Desolvation gas flow rate: 800 L / h.

[0163] Method B Method name: UC03_ABR2, Machine details: Waters Acquity Ultraperfomance LC connected to PDA and equipped with SQ detector, Column: Waters X-bridge C18, 50*4.6mm, 3.5 micron, Column temperature: 35℃, Autosampler temperature: 15℃, Mobile phase A: 5mM ammonium bicarbonate in Milli-Q water (pH=8.00), Mobile phase B: Acetonitrile, Mobile phase gradient details: T=0 min (97%A, 3%B) flow rate = 1.0ml / min, T=0.20 min (97%A, 3%B) flow rate = 1.0ml / min, Gradient to T=2.70 min (20%A, 80%B) flow rate = 1.0ml / min, Gradient to T=3.0 min (0%A, 100%B) flow rate = 1.2ml / min, T=3.50 min (0%A, 100%B) flow rate = Flow rate: 1.2 ml / min, T = 3.51 min (97% A, 3% B) = 1.0 ml / min, run ended at T = 4.0 min (97% A, 3% B) Flow rate: 1.0 ml / min, Run time: 4 min, UV detection method: PDA, Wavelength: 195 nm - 500 nm, Mass parameters: Probe: ESI, Ionization mode: positive and negative, Column voltage: 30 and 10 V, Capillary voltage: 3.0 kV, Extractor voltage: 2 V, Rf lens: 0.1 V, Source temperature: 120 °C, Probe temperature: 400 °C, Cone gas flow rate: 100 L / h, Desolvation gas flow rate: 800 L / h.

[0164] High-performance liquid chromatography Method A Method name: HP04_BR1, Machine details: Water alliance equipped with 2998 PDA detector e2695, column temperature: 25 °C, autosampler temperature: 25 °C, mobile phase A: 0.1% ammonium hydroxide solution in HPLC water, mobile phase B: 100% acetonitrile; mobile phase gradient details: T = 0 min (10% A, 90% B) flow rate: 1 mL / min, T = 7 min (90% A, 10% B) flow rate: 1 mL / min, gradient to T = 0 min (100% A, 0% B) flow rate: 1 mL / min, gradient to T = 14 min (100% A, 0% B) flow rate: 1 mL / min, T = 14.01 min (10% A, 90% B) flow rate: 1 mL / min, gradient to T = 17 min (10% A, 90% B) flow rate: 1 mL / min, run end at T = 17 min (10% A, 90% B), flow rate: 1 mL / min, run time: 17 min, UV detection method: PDA.

[0165] Method B Method name: HP05_TFAR1. Machine details: AGILENT TECHNOLOGY 1260 equipped with PDA detector. Infinity series, column temperature: 25 °C, autosampler temperature: 25 °C, mobile phase A: 0.05% trifluoroacetic acid in HPLC water, mobile phase B: 100% acetonitrile, mobile phase gradient details: T = 0 min (90% A, 10% B) flow rate: 1 mL / min, T = 7 min (10% A, 90% B) flow rate: 1 mL / min, gradient to T = 9 min (0% A, 100% B) flow rate: 1 mL / min, gradient to T = 14 min (0% A, 100% B) flow rate: 1 mL / min, T = 14.01 min (90% A, 10% B) flow rate: 1 mL / min, gradient to T = 17 min (90% A, 10% B) flow rate: 1 mL / min, run end at T = 17 min (90% A, 10% B) flow rate: 1 mL / min, run time: 17 min, UV detection method: PDA.

[0166] Method C Method name: HP06_TFAR1, Machine details: AGILENT TECHNOLOGY equipped with 2998 PDA detector 1100 series, column temperature: 25 °C, autosampler temperature: 25 °C, mobile phase A: 0.05% trifluoroacetic acid in HPLC water, mobile phase B: 100% acetonitrile, mobile phase gradient details: T = 0 min (90% A, 10% B) flow rate: 1 mL / min, T = 7 min (10% A, 90% B) flow rate: 1 mL / min, gradient to T = 9 min (0% A, 100% B) flow rate: 1 mL / min, gradient to T = 14 min (0% A, 100% B) flow rate: 1 mL / min, T = 14.01 min (90% A, 10% B) flow rate: 1 mL / min, gradient to T = 17 min (90% A, 10% B) flow rate: 1 mL / min, run end at T = 17 min (90% A, 10% B) flow rate: 1 mL / min, run time: 17 min, UV detection method: PDA.

[0167] NMR 1 H nuclear magnetic resonance (NMR) spectroscopy was performed using a Bruker Avance-400 operating at 400 MHz with the indicated solvents at room temperature unless otherwise noted. Samples were prepared as solutions in suitable deuterated solvents and referenced to the appropriate internal non-deuterated solvent peak or tetramethylsilane. Chemical shifts were recorded in ppm (δ) downfield with tetramethylsilane. In all cases, NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts per million using conventional abbreviations for major peak designations: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet; br, broad; br = broad singlet.

[0168] Purification method Preparative purification by reversed-phase HPLC Preparative HPLC method-A Biotage-FC-01 equipped with a binary pump with a UV / visible wavelength detector; Column: YMC, 120 g, 50 µm; Column temperature: room temperature; Mobile phase A: 0.1% formic acid in water; Mobile phase B: acetonitrile; Mobile phase gradient details: T = 0.01 min (100% A, 0% B), T = 3 min (85% A, 15% B), gradient until T = 25 min (55% A, 45% B), T = 35 min (0% A, 100% B), gradient until end of run at T = 45 min (100% A, 0% B); Flow rate: 80 mL / min; Analysis time: 45 min.

[0169] synthesis Several methods for the chemical synthesis of the compounds of the present application are described herein. These and / or other well-known methods may be modified and / or adapted in various ways to facilitate the synthesis of additional compounds within the scope of the present application and claims. It is understood that such alternative methods and modifications are within the spirit and scope of the present application and claims. Accordingly, the methods illustrated in the following description, schemes, and examples are intended for illustrative purposes, but should not be construed as limiting the scope of the present disclosure.

[0170] Example 1 - Synthesis of 3-methyl-3-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (Compound 1)

[0171] [ka]

[0172] Step 1: A solution of CAS:5445-26-1 (0.50 g, 2.390 mmol, 1.0 eq) and CsCO (1.16 g, 3.585 mmol, 1.5 eq) in DMF (5 mL) was stirred at room temperature for 15 minutes and cooled to 0 °C. To this solution, methyl iodide (0.37 g, 2.629 mmol, 1.1 eq) was added at 0 °C. The resulting mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC (using 0.5:9.5 EtOAc:hexane as the mobile phase) and found to be complete after stirring at room temperature for 16 hours. The resulting reaction mixture was diluted with ice water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.720 g of crude product. The obtained crude material was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (0-9% EtOAc in hexanes) to give ethyl 2-(4-nitrophenyl)propanoate (A1) (0.400 g, 1.791 mmol, yield: 74.97%). 1 H NMR (DMSO-d6,400MHz): δ ppm,8.21(dd,J=7.2,2.0Hz,2H),7.58(dd,J=7.2,2.0Hz,2H),4.11-4.00(m,3H),1.43(d,J=7.2Hz,3H),1.13(t,J=7.2Hz,3H). LCMS (Method B): 2.90 min, 98.19%, 254.0 nm, MS: ES-222.19 (M-1)

[0173] Step 2: To a stirred solution of ethyl 2-(4-nitrophenyl)propanoate (A1) (0.20 g, 0.896 mmol, 1.0 eq) in THF (2 mL) was added LiHMDS (2.0 M in THF) (0.94 mL, 1.881 mmol, 2.1 eq) at −78° C. The mixture was stirred at −78° C. for 1 h. Then, CAS:590-17-0 (0.12 g, 1.075 mmol, 1.2 eq) was added at −78° C. The resulting mixture was stirred at room temperature for 6 h. The reaction was monitored by TLC (using 2.0:8.0 EtOAc:Hexane as the mobile phase) and found to be complete after 6 h of stirring at room temperature. The resulting reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.32 g of crude product. The obtained crude material was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (0-2% EtOAc in hexanes) to give ethyl 3-cyano-2-methyl-2-(4-nitrophenyl)propanoate (A2) (0.14 g, 0.533 mmol, yield: 59.58%). 1 H NMR(CDCl3,400MHz):δ ppm,8.28(dd,J=7.2,2.0Hz,2H),7.54(dd,J=7.2,2.0Hz,2H),4.27-4.20(m,2H),3.03(q,J=16.8Hz,2H),1.88(s,3H),1.24(t,J=7.2Hz,3H). Note: Impurity peaks were observed in 1H NMR. LCMS (Method B): 2.75 min, 95.81%, 254.0 nm, MS: ES-261.91 (M-1)

[0174] Step 3: To a stirred solution of ethyl 3-cyano-2-methyl-2-(4-nitrophenyl)propanoate (A2) (0.80 g, 3.051 mmol, 1.0 eq) in 7N ammonia solution in methanol (8 mL) was added Raney Ni (0.80 g) at room temperature. The resulting mixture was stirred at room temperature for 16 h under an H2(g) atmosphere (200 psi). The reaction was monitored by TLC (using 100% EtOAc as the mobile phase) and found to be complete after stirring at room temperature for 16 h. The resulting reaction mixture was directly filtered through Celite. The filtrate was dried over Na2SO4 and concentrated under reduced pressure to give 1.0 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (0-4% MeOH in dichloromethane) to give 3-(4-aminophenyl)-3-methylpyrrolidin-2-one (A3) (0.6 g, 3.153 mmol, yield: 94.28%). 1 H NMR (DMSO-d6,400MHz):δ ppm,7.64(br s,1H),7.03(dd,J=6.8,2.0Hz,2H),6.51(dd,J=6.8,2.0Hz,2H),5.01(br s, 2H), 3.19-3.14 (m, 1H), 3.08-3.02 (m, 1H), 2.32-2.27 (m, 1H), 2.07-1.99 (m, 1H), 1.29 (s, 3H). LCMS (Method A): 0.192 min, 88.83%, 220.0 nm, MS: ES+191.05 (M+1)

[0175] Step 4: To a stirred solution of 3-(4-aminophenyl)-3-methylpyrrolidin-2-one (A3) (0.26 g, 1.368 mmol, 1.0 eq) in DMF (2 mL) was added N-bromosuccinimide (0.17 g, 0.957 mmol, 0.7 eq) at 0 °C. The resulting mixture was stirred at room temperature for 4 h. The reaction was monitored by TLC (using 100% EtOAc as the mobile phase) and found to be complete after 4 h of stirring at room temperature. The resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.20 g of crude 3-(4-amino-3-bromophenyl)-3-methylpyrrolidin-2-one (A4) (0.20 g, 0.743 mmol, 54.37% yield). 1 H NMR(DMSO-d6,400MHz):δ ppm,7.73(br s,1H),7.32(s,1H),7.09(d,J=8.4Hz,1H),6.75(d,J=8.4Hz,1H),5.19(s,2H),3.21 -3.15(m,1H),3.09-3.03(m,1H),2.33-2.27(m,1H),2.09-2.02(m,1H),1.29(s,3H). LCMS (Method A): 1.467 min, 96.11%, 254.0 nm, MS: ES+191.05 (M, M+2: 269.0, 271.0)

[0176] Step 5: To a stirred solution of 3-(4-amino-3-bromophenyl)-3-methylpyrrolidin-2-one (A4) (0.50 g, 1.858 mmol, 1.0 eq) and CAS: 128796-39-4 (0.53 g, 2.787 mmol, 1.5 eq) in DCM (10 mL), DIPEA (0.71 g, 5.574 mmol, 3.0 eq) was added at room temperature, followed by Cu(OAc) (0.50 g, 2.787 mmol, 1.5 eq). The resulting mixture was stirred at room temperature for 48 h under an O atmosphere. The reaction was monitored by TLC (using 100% EtOAc as the mobile phase), which confirmed completion after 48 h of stirring at room temperature. The resulting reaction mixture was diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.6 g of crude material, which was purified by RP column chromatography (0-85% ACN in water) to give 3-(3-bromo-4-((4-(trifluoromethyl)phenyl)amino)phenyl)-3-methylpyrrolidin-2-one (A5) (0.13 g, 0.314 mmol, yield: 16.93%). 1 H NMR(DMSO-d6,400MHz):δ ppm,8.26(s,1H),7.87(s,1H),7.69(d,J=2.0Hz,1H),7.48(d,J=8.8Hz,2H),7.43-7.34(m,2H),6.95(d, J=8.4Hz,2H),3.28-3.22(m,1H),3.17-3.11(m,1H),2.43-2.37(m,1H),2.19-2.13(m,1H),1.39(s,3H). LCMS (Method A): 2.490 min, 87.23%, 254.0 nm, MS: ES+413.1 (M)

[0177] Step 6: To a stirred solution of 3-(3-bromo-4-((4-(trifluoromethyl)phenyl)amino)phenyl)-3-methylpyrrolidin-2-one (A5) (0.28 g, 0.677 mmol, 1.0 eq) in MeOH (4 mL) was added KOAc (0.33 g, 3.389 mmol, 5.0 eq) under N2(g) atmosphere, followed by PdCl2(dppf) (0.247 g, 0.338 mmol, 0.5 eq), and the resulting mixture was stirred under CO(g) at 100 °C and 40 bar pressure for 16 h. The reaction was monitored by TLC (using 100% EtOAc as the mobile phase) and found to be complete after 16 h of stirring at 100 °C. The resulting reaction mixture was directly filtered through Celite. The filtrate was dried over Na2SO4 and concentrated under reduced pressure to give 0.42 g of crude product. The resulting crude material was purified by flash column chromatography using silica (230-400 mesh) as stationary phase (0-0.5% MeOH in DCM) to give methyl 5-(3-methyl-2-oxopyrrolidin-3-yl)-2-((4-(trifluoromethyl)phenyl)amino)benzoate (A6) (0.085 g, 0.216 mmol, yield: 31.97%). 1 H NMR(DMSO-d6,400MHz):δ ppm,9.28(s,1H),7.93(d,J=2.4Hz,1H),7.86(br s,1H),7.79-7.56(m,3H),7.44(d,J=8.8Hz,1H),7.33(d,J=8.4Hz,2H),3.84(s,3H),3. 03-3.22(m,1H),3.17-3.09(m,1H),2.42-2.34(m,1H),2.33-2.12(m,1H),1.34(s,3H). LCMS (Method A): 2.545 min, 91.89%, 254.0 nm, MS: ES+393.0 (M+1)

[0178] Step 7: To a stirred solution of methyl 5-(3-methyl-2-oxopyrrolidin-3-yl)-2-((4-(trifluoromethyl)phenyl)amino)benzoate (A6) (0.15 g, 0.382 mmol, 1.0 eq) in MeOH (2 mL) was added hydrazine hydrate (1.0 mL, 5.0) at room temperature and then stirred at 90° C. for 4 h. The reaction was monitored by TLC (using MeOH:DCM, 1:9 as the mobile phase) and found to be complete after stirring at 90° C. for 4 h. The resulting reaction mixture was concentrated under reduced pressure to give 0.16 g of crude product. The resulting crude material was purified by trituration with pentane to give 5-(3-methyl-2-oxopyrrolidin-3-yl)-2-((4-(trifluoromethyl)phenyl)amino)benzohydrazide (A7) (0.16 g, 0.407 mmol, quantitative yield). LCMS (Method A): 1.989 min, 84.56%, 254.0 nm, MS: ES+393.12 (M+1).

[0179] Step 8: To a stirred solution of 5-(3-methyl-2-oxopyrrolidin-3-yl)-2-((4-(trifluoromethyl)phenyl)amino)benzohydrazide (A7) (0.15 g, 0.382 mmol, 1.0 eq) in dichloromethane (1.5 mL) was added triethylamine (0.115 g, 1.146 mmol, 3.0 eq) at 0 °C. Then, acetyl chloride (0.029 g, 0.382 mmol, 1.0 eq) was added at 0 °C and stirred at room temperature for 4 h. The reaction was monitored by TLC (MeOH:DCM, 0.5:9.5, as the mobile phase) and found to be complete after 4 h of stirring at room temperature. The resulting reaction mixture was diluted with HO (5 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.14 g of crude product. The resulting crude material was purified by trituration with pentane to give N'-acetyl-5-(3-methyl-2-oxopyrrolidin-3-yl)-2-((4-(trifluoromethyl)phenyl)amino)benzohydrazide (A8) (0.14 g, 0.322 mmol, quantitative yield). LCMS (Method A): 1.994 min, 68.01%, 254.0 nm, MS: ES+435.3 (M+1).

[0180] Step 9: To a stirred solution of N'-acetyl-5-(3-methyl-2-oxopyrrolidin-3-yl)-2-((4-(trifluoromethyl)phenyl)amino)benzohydrazide (A8) (0.14 g, 0.322 mmol, 1.0 eq) in dichloromethane (2 mL) was added triethylamine (0.097 g, 0.966 mmol, 3.0 eq) at 0 °C. TosCl (0.073 g, 0.386 mmol, 1.2 eq) was then added at 0 °C and stirred at room temperature for 3 h. The reaction was monitored by TLC (MeOH:DCM, 1:9, as the mobile phase) and found to be complete after 3 h of stirring at room temperature. The resulting reaction mixture was diluted with HO (5 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.18 g of crude product. The resulting crude material was purified by preparative HPLC purification method A to give 3-methyl-3-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (compound 1) (0.025 g, 0.060 mmol, yield: 18.63%). 1 H NMR(DMSO-d6,400MHz):δ ppm,9.20(s,1H),7.89(s,2H),7.62(d,J=8.4Hz,2H),7.56(s,2H),7.35(d,J=8.4Hz,2H),3.30- 3.24(m,1H),3.17-3.13(m,1H),2.59(s,3H),2.45-2.38(m,1H),2.22-2.16(m,1H),1.42(s,3H). LCMS (Method A): 2.350 min, 99.70%, 254.0 nm, MS: ES+417.1 (M+1). HPLC (Method B): 8.27 min, 99.87%, 254.0nm

[0181] Example 2 - Synthesis of 3-methyl-3-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (Compound 2)

[0182] [ka]

[0183] Step 1: To a stirred solution of 3-(3-bromo-4-((4-(trifluoromethyl)phenyl)amino)phenyl)-3-methylpyrrolidin-2-one (A5) (1.2 g, 2.903 mmol, 1.0 eq) in 1,4-dioxane (12 mL) was added B2Pin2 (1.10 g, 4.355 mmol, 2.0 eq) at room temperature, followed by potassium acetate (0.56 g, 5.807 mmol, 3.0 eq) and purging with N2(g) at room temperature for 30 min. PdCl2(dppf) (0.10 g, 1.451 mmol, 0.05 eq) was then added and stirred at 100 °C for 4 h. The reaction was monitored by TLC (using 7:3 EtOAc:hexane as the mobile phase) and found to be complete after 4 h of stirring at 100 °C. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 1.4 g of crude product. The crude material was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (0-80% EtOAc in hexanes) to give 3-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (A9) (0.950 g, 2.065 mmol, 71.07% yield). 1H NMR(DMSO-d6,400MHz):δ ppm,8.12(s,1H),7.82(s,1H),7.62(d,J=2.4Hz,1H),7.52-7.47(m,3H),7.29(d,J=8.4Hz,1H),7.11(d,J=8.8H z,2H),3.26-3.212(m,1H),3.14-3.08(m,1H),2.38-2.31(m,1H),2.17-2.10(m,1H),1.38(s,3H),1.25(s,12H) LCMS (Method A): 2.173 min + 2.839 min, 58.16 + 41.84 = 100.00%, 254.0 nm, MS: ES + 461.20 (M + 1), 379.28 (M - 82).

[0184] Project 2: To a stirred solution of 4-bromo-1-methyl-1H-imidazole (CAS: 25676-75-9) (0.25 g, 1.552 mmol, 1.0 eq) in 1,4-dioxane:HO (7:3) (10 mL) was added 3-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (A9) (0.85 g, 1.863 mmol, 1.2 eq) at room temperature, followed by potassium carbonate (0.64 g, 4.658 mmol, 3.0 eq) and purging with N(g) at room temperature for 30 min. PdCl(dppf) (0.056 g, 0.077 mmol, 0.05 eq) was then added and stirred at 100 °C for 6 h. The reaction was monitored by TLC (using MeOH:DCM, 0.5:9.5 as the mobile phase) and found to be complete after stirring at 100 °C for 6 h. The resulting reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.75 g of crude product. The resulting crude material was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (0-3% MeOH in DCM) to give 3-methyl-3-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (compound 2) (0.10 g, 0.241 mmol, yield: 15.55%). 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 9.82 (s, 1H), 7.80-7.76 (m, 3H), 7.55 (s, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 1H), 7.23 (dd, J = 8.4, 1.6 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 3.69 (s, 3H), 3.25-3.22 (m, 1H), 3.17-3.14 (m, 1H), 2.44-2.41 (m, 1H), 2.18-2.14 (m, 1H), 1.42 (s, 3H). Note: One proton was integrated with the DMSO solvent peak. LCMS (Method A): 1.851 min, 98.07%, 254.0 nm, MS: ES+415.17 (M+1). HPLC (Method A): 8.15 minutes, 97.38%, 254.0nm

[0185] Example 3 - Synthesis of 1-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzyl)imidazolidin-2-one (Compound 3)

[0186] [ka]

[0187] Step 1: To a solution of methyl 4-amino-3-bromobenzoate (CAS: 106896-49-5) (10.0 g, 43.478 mmol, 1.0 eq), CAS: 455-13-0 (11.8 g, 43.478 mmol, 1.0 eq) in toluene (100 mL) was added cesium carbonate (42 g, 130.43 mmol, 3.0 eq), and the reaction mixture was stirred at room temperature with a 10-minute N2 purge. Pd(OAc)2 (0.97 g, 4.34 mmol, 0.1 eq) and Xantphos (2.5 g, 4.347 mmol, 0.1 eq) were then added under a nitrogen atmosphere. The reaction mixture was heated at 100 °C with stirring for 16 h. The reaction was monitored by TLC using 3:7 EtOAc:Hex as the mobile phase. The reaction mixture was quenched with ice-cold water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 13.0 g of crude product. The crude material was purified by manual column chromatography using silica (60-120 mesh) as the stationary phase (eluent 30% ethyl acetate in hexane) to give methyl 3-bromo-4-((4-(trifluoromethyl)phenyl)amino)benzoate (A10) (8.7 g, 23.26 mmol, yield: 53%). 1H NMR(DMSO-d6,400MHz):δ ppm,8.50(s,1H),8.13(d,J=2.0Hz,1H),7.84(dd,J=8.4Hz,2.0Hz,1H),7.6 3(d,J=8.4Hz,2H),7.41(d,J=8.4Hz,1H),7.32(d,J=8.4Hz,2H),3.83(s,3H) LCMS (Method A): 10.559 min, 99.69%, 210.0 nm, MS: ES+375 (M+1)

[0188] Step 2: To a solution of methyl 3-bromo-4-((4-(trifluoromethyl)phenyl)amino)benzoate (A10) (10.0 g, 43.47 mmol, 1.0 eq), CAS: 73183-34-3 (11.8 g, 43.47 mmol, 1.0 eq) in dioxane (100 mL) was added KOAc (42.0 g, 130.43 mmol, 3.0 eq), and the reaction mixture was stirred at room temperature with a 10-minute N purge. Pd(dppf)Cl (0.97 g, 4.347 mmol, 0.1 eq) was then added under a nitrogen atmosphere, and the resulting mixture was heated at 95 °C for 16 h. The reaction was monitored by TLC (using 1:9 EtOAc:Hex as the mobile phase). The resulting reaction mixture was quenched with ice-cold water (100 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 12.0 g of crude material, which was used directly in the next step to give methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzoate (A11) (12 g crude, 28.503 mmol, quantitative yield). LCMS (Method A): 3.219 min, 61.83%, 254.0 nm, MS: ES+422 (M+1)

[0189] Step 3: To a solution of methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzoate (A11) (12 g, 28.50 mmol, 1.0 eq), CAS: 25676-75-9 (5.04 g, 31.35 mmol, 1.1 eq) in dioxane:water (8:2) (120 mL) was added cesium carbonate (42.0 g, 57.07 mmol, 2.0 eq) and the reaction mixture was stirred at room temperature with a N2 purge for 10 minutes. Pd(dppf)Cl2 (2.0 g, 28.50 mmol, 0.1 eq) was then added under a nitrogen atmosphere and the reaction mixture was heated to 90 °C and maintained with stirring for 16 hours. The reaction was monitored by TLC using 7:3 EtOAc:Hex as the mobile phase. The reaction mixture was quenched with ice-cold water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 14.0 g of crude product. The crude material was purified by manual column chromatography using silica (60-120 mesh) as the stationary phase (eluent 15% ethyl acetate in hexane) to give methyl 3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzoate (A12) (7.0 g, 18.66 mmol, yield: 65.49%). 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 11.03 (s, 1H), 8.23 (d, J = 2.0 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J = 1.2 Hz, 1H), 7.74 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 3.84 (s, 3H), 3.74 (s, 3H). Note: A slight fatty impurity was observed. LCMS (Method A): 2.174 min, 98.88%, 254.0 nm, MS: ES+376 (M+1)

[0190] Step 4: A solution of methyl 3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzoate (A12) (3.0 g, 8.0 mmol, 1.0 eq), BocO (2.6 g, 12.0 mmol, 1.5 eq), and DMAP (0.39 g, 3.20 mmol, 0.4 eq) in DCM (20 mL) was stirred at room temperature for 16 h. The reaction was monitored by TLC (using 1:1 EtOAc:Hex as the mobile phase) and was found to be complete after 16 h. The resulting reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 4.0 g of crude product. The crude material obtained was purified by combi-flash using silica (230-400 mesh) as stationary phase (10% ethyl acetate in hexane) to give methyl 4-((tert-butoxycarbonyl)(4-(trifluoromethyl)phenyl)amino)-3-(1-methyl-1H-imidazol-4-yl)benzoate (A13) (1.4 g, 2.947 mmol, yield: 36.84%). 1 H NMR(DMSO-d6,400MHz):δ ppm,8.65(d,J=2.0Hz,1H),7.81(dd,J=8.8Hz,2.0Hz,1H),7.72(s,1H),7.66(d,J=8.8Hz,2H),7.39( d,J=8.8Hz,2H),7.26(d,J=8.0Hz,1H),7.20(d,J=1.2Hz,1H),3.89(s,3H),3.63(s,3H),1.15(s,9H). LCMS (Method A): 2.234 min, 100%, 254.0 nm, MS: ES+476 (M+1)

[0191] Step 5: To a solution of methyl 4-((tert-butoxycarbonyl)(4-(trifluoromethyl)phenyl)amino)-3-(1-methyl-1H-imidazol-4-yl)benzoate (A13) (1.4 g, 2.947 mmol, 1.0 eq) in THF (14 mL) was added LiBH (2.9 mL, 2.947 mmol, 1.0 eq) at room temperature. The reaction mixture was heated to 50 °C and stirring was maintained for 16 h. The reaction was monitored by TLC (using 9:1 EtOAc:Hex as the mobile phase), which confirmed completion of the reaction after 16 h. The resulting reaction mixture was quenched with water (30 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 1.6 g of crude product. The crude material obtained was purified by combi-flash using silica (230-400 mesh) as stationary phase (85% ethyl acetate in hexane) to give tert-butyl (4-(hydroxymethyl)-2-(1-methyl-1H-imidazol-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A14) (0.6 g, 1.342 mmol, yield: 45%). 1 H NMR(DMSO-d6,400MHz):δ ppm,8.0(d,J=1.2Hz,1H),7.66-7.62(m,3H),7.37(d,J=8.4Hz,2H),7.20(dd,J=8.4Hz,2.0Hz, 1H),7.08-7.05(m,2H),5.30(t,J=6.0Hz,1H),4.55(d,J=6.0Hz,2H),3.61(s,3H),1.17(s,9H) LCMS (Method A): 1.848 min, 99.83%, 254.0 nm, MS: ES+448 (M+1)

[0192] Step 6: To a solution of tert-butyl (4-(hydroxymethyl)-2-(1-methyl-1H-imidazol-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A14) (0.6 g, 1.342 mmol, 1.0 eq) in DCM (6 mL) stirred at 0 °C, DIPEA (0.074 g, 2.684 mmol, 2.0 eq) and MeSO2Cl (0.183 g, 1.610 mmol, 1.2 eq) were added. The resulting mixture was warmed to room temperature and stirring was maintained for 16 h. The reaction was monitored by TLC (using 7:3 EtOAc:Hex as the mobile phase) to confirm completion. The resulting reaction mixture was diluted with water (10 mL), extracted with DCM (3 x 20 mL), dried over Na2SO4, and concentrated under reduced pressure to give 1.0 g of crude product. The crude material obtained was purified by CombiFlash® using silica (230-400 mesh) as stationary phase (50% ethyl acetate in hexane) to give tert-butyl (4-(chloromethyl)-2-(1-methyl-1H-imidazol-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A15) (0.40 g, 0.860 mmol, yield: 64%). 1 H NMR(DMSO-d6,400MHz):δ ppm,8.11(d,J=2.4Hz,1H),7.69-7.64(m,3H),7.38(d,J=8.8Hz,2H),7.31(dd, J=8.0Hz,2.4Hz,1H),7.14-7.12(m,2H),4.84(s,2H),3.62(s,3H),1.17(s,9H) LCMS (Method A): 2.266 min, 100%, 254.0 nm, MS: ES+466 (M+1)

[0193] Step 7: A solution of tert-butyl (4-(chloromethyl)-2-(1-methyl-1H-imidazol-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A15) (0.4 g, 0.860 mmol, 1.0 eq) and CAS 107-15-3 (0.051 g, 0.86 mmol, 1.0 eq) in DCM (4.0 mL) was stirred at room temperature for 16 h. The reaction was monitored by TLC (using DCM:MeOH, 9:1, as the mobile phase) and found to be complete after 16 h of stirring at room temperature. The resulting reaction mixture was diluted with water (10 mL) and extracted with DCM (3 x 20 mL). Drying over NaSO and concentration under reduced pressure gave 0.4 g of crude product. The crude material obtained was triturated with n-pentane to give tert-butyl (4-(((2-aminoethyl)amino)methyl)-2-(1-methyl-1H-imidazol-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A16) (0.25 g, 0.511 mmol, yield: 59%). 1 H NMR(DMSO-d6,400MHz):δ ppm,7.98(s,1H),7.65-7.64(m,3H),7.62(s,1H),7.39-7.37(m,2H),7.23-7.21(m,1H),7.09(s,1H),7.051-7.0 31(m,1H),3.74(s,2H),3.64-3.54(m,4H),3.35-3.30(m,1H),2.65-2.62(m,2H),2.55-2.50(m,2H),1.17(s,9H). LCMS (Method A): 1.50 min, 99.13%, 254.0 nm, MS: ES+489 (M+1)

[0194] Step 8: To a stirred solution of tert-butyl (4-(((2-aminoethyl)amino)methyl)-2-(1-methyl-1H-imidazol-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A16) (0.25 g, 0.511 mmol, 1.0 eq) in toluene (2.5 mL) was added DIPEA (0.074 g, 0.613 mmol, 2.0 eq) and CDI (0.099 g, 0.613 mmol, 1.2 eq) at room temperature. The resulting mixture was heated to 50° C. and stirring was maintained for 8 hours. The reaction was monitored by TLC (using DCM:MeOH, 9:1, as the mobile phase), which confirmed completion of the reaction after 8 hours of stirring at 50° C. The reaction mixture was diluted with water (10 mL), extracted with EtOAc (3 x 20 mL), dried over NaSO, and concentrated under reduced pressure to give 0.3 g of crude material, which was purified by combi-flash using silica (200-400 mesh) as the stationary phase (7% DCM in MeOH) to give tert-butyl (2-(1-methyl-1H-imidazol-4-yl)-4-((2-oxoimidazolidin-1-yl)methyl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A17) (0.092 g, 0.178 mmol, 34.94% yield). 1 H NMR(DMSO-d6,400MHz):δ ppm,7.92(d,J=1.6Hz,1H),7.66-7.63(m,3H),7.38(d,J=8.4Hz,2H),7.14-7 .08(m,3H),6.47(s,1H),4.30(s,2H),3.61(s,3H),3.17(s,3H),1.17(s,9H). LCMS (Method A): 1.908 min, 91.46%, 254.0 nm, MS: ES+516 (M+1)

[0195] Step 9: To a stirred solution of tert-butyl (2-(1-methyl-1H-imidazol-4-yl)-4-((2-oxoimidazolidin-1-yl)methyl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A17) (0.15 g, 0.376 mmol, 1.0 eq) in DCM (1 mL) was added 4 M HCl in dioxane (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC (using DCM:MeOH, 9:1 as the mobile phase) and found to be complete after stirring at room temperature for 2 h. The resulting reaction mixture was basified with saturated NaHCO3 (5 mL), extracted with EtOAc (3 x 10 mL), dried over Na2SO4, and concentrated under reduced pressure to give 0.09 g of crude product. The crude material obtained was purified by combi-flash using silica (200-400 mesh) as stationary phase (5% DCM in MeOH) to give 1-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzyl)imidazolidin-2-one (compound 3) (0.026 g, 0.062 mmol, yield: 35%). 1 H NMR(DMSO-d6,400MHz):δ ppm,9.87(s,1H),7.77(d,J=0.8Hz,1H),7.64(d,J=2.0Hz,1H),7.50(d,J=1.2Hz,1H),7.51(d,J=8.8H z,2H),7.36(d,J=8.0Hz,1H),7.10-7.07(m,3H),6.41(s,1H),4.22(s,2H),3.69(s,3H),3.23(s,4H). LCMS (Method A): 1.690 min, 99.78%, 254.0 nm, MS: ES+415 (M+1) HPLC (Method A): 7.77 min, 96.04%, 254.0nm

[0196] Example 4 - Synthesis of 1-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzyl)imidazolidine-2,4-dione (Compound 4)

[0197] [ka]

[0198] Step 1: To a stirred solution of imidazolidine-2,4-dione CAS 461-72-3 (0.3, 3.00 mmol, 1.0 eq) and CAS 824-94-2 (0.46 g, 3.00 mmol, 1.0 eq) in DMF (2 mL) was added NaH (0.086 g, 6.00 mmol, 2.0 eq) at room temperature. The resulting mixture was heated to 80 °C and stirring was maintained for 6 h. The reaction was monitored by TLC (using 7:3 EtOAc:Hex as the mobile phase), which confirmed completion after 6 h. The resulting reaction mixture was quenched with water (5 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.35 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (50% EA in Hex) to give 3-(4-methoxybenzyl)imidazolidine-2,4-dione (A18) (0.25 g, 1.136 mmol, 37% yield). 1 H NMR (DMSO-d6,400MHz): δ ppm,8.10(s,1H),7.23-7.19(m,2H),6.88(d,J=8.8Hz,2H),4.44-4.40(m,2H),3.95(s,2H),3.72(s,3H).

[0199] Step 2: To a solution of tert-butyl (4-(chloromethyl)-2-(1-methyl-1H-imidazol-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A15) (0.3 g, 0.645 mmol, 1.0 eq) and 3-(4-methoxybenzyl)imidazolidine-2,4-dione (A18) (0.212 g, 0.967 mmol, 1.5 eq) in ACN (3 mL) was added CsCO (0.524 g, 1.612 mmol, 2.5 eq). The reaction mixture was heated to 80 °C and stirring was maintained for 3 h. The reaction was monitored by TLC (using EA:HEX, 8:2 as the mobile phase), which confirmed completion after 3 h. The resulting reaction mixture was quenched with ice-cold water (5 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.3 g of crude material, which was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (80% EA in HEX) to give tert-butyl (4-((3-(4-methoxybenzyl)-2,4-dioxoimidazolidin-1-yl)methyl)-2-(1-methyl-1H-imidazol-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A19) (0.18 g, 0.277 mmol, 42% yield). 1 H NMR(DMSO-d6,400MHz):δ ppm,7.93(d,J=2.0Hz,1H),7.67(s,1H),7.64-7.62(d,J=8.8Hz,2H),7.39(d,J=8.4Hz,2H),7.24(d,J=8.8Hz,2H),7.16(dd,J=8.0Hz ,2.4Hz,1H),7.11-7.09(m,2H),6.88(d,J=8.4Hz,2H),4.58(s,2H),4.52(s,2H),3.96(s,2H),3.73(s,3H),3.62(s,3H),1.24(s,9H). LCMS (Method A): 2.259 min, 98.94%, 254.0 nm, MS: ES+649 (M+1)

[0200] Step 3: To a solution of tert-butyl (4-((3-(4-methoxybenzyl)-2,4-dioxoimidazolidin-1-yl)methyl)-2-(1-methyl-1H-imidazol-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A19) (0.18 g, 0.277 mmol, 1.0 eq) in ACN:HO (1.8 mL) was added CAN (0.151 g, 0.277 mmol, 1.0 eq). The resulting mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC (EA:HEX, 9:1, as the mobile phase) and found to be complete after 3 h. The resulting reaction mixture was quenched with ice-cold water (5 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.2 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as stationary phase (5% DCM in MeOH) to give tert-butyl (4-((2,4-dioxoimidazolidin-1-yl)methyl)-2-(1-methyl-1H-imidazol-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A20) (0.09 g, 0.170 mmol, yield: 61%). 1 H NMR(DMSO-d6,400MHz):δ ppm,10.95(brs,1H)9.87(s,1H),7.87(d,J=8.0Hz,1H),7.67-7.65(m,3H),7.44-7.26(m ,4H),7.13(d,J=8.8Hz,1H),4.53(s,2H),3.91-3.87(m,2H),3.78(brs,3H),1.22(s,9H). LCMS (Method A): 1.898 min, 62.16%, 254.0 nm, MS: ES+529 (M+1)

[0201] Step 4: To a stirred solution of tert-butyl (4-((2,4-dioxoimidazolidin-1-yl)methyl)-2-(1-methyl-1H-imidazol-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A20) (0.09 g, 0.170 mmol, 1.0 eq) in DCM (1 mL) was added 4 M HCl in dioxane (10 mL) at room temperature, and the reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC (using DCM:MeOH, 9:1 as the mobile phase), which confirmed completion after 2 h of stirring at room temperature. The resulting reaction mixture was basified with saturated NaHCO3 (5 mL), extracted with EtOAc (3 x 25 mL), dried over Na2SO4, and concentrated under reduced pressure to give 0.09 g. The resulting crude material was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (desired product eluted with 7% DCM in MeOH) to give 1-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzyl)imidazolidine-2,4-dione (compound 4) (0.0091 g, 0.0212 mmol, yield: 12.33%). 1 H NMR(DMSO-d6,400MHz):δ ppm,10.73(s,1H),9.98(s,1H),7.78(s,1H),7.64(s,1H),7.59(s,1H),7.51(d,J=8.4H z,2H),7.37(d,J=8.4Hz,1H),7.12-7.10(m,3H),4.42(s,2H),3.87(s,2H),3.70(s,3H). LCMS (Method A): 1.710 min, 95.31%, 254.0 nm, MS: ES+429 (M+1) HPLC (Method A): 5.95 minutes, 97.18%, 210.0nm

[0202] Example 5 - Chiral Separation of 3-methyl-3-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (Compounds 5 and 6)

[0203] [ka]

[0204] The racemate of compound 2 (0.096 g) was subjected to chiral SFC separation on a (CHIRALPAK IA 250 × 50 mm 5 μm) column, and two peaks were separated into compound 2 peak 1 (compound 5) (0.036 g, yield = 37.89%) and compound 2 peak 2 (compound 6) (0.034 g, yield = 35.79%). Column ID: CHIRALPAK IA 250 x 50 mm 5 μm Mobile phase A: LIQ.CO2 Mobile phase B: 0.1% M NH3 in MEOH-ACN (50-50) Flow rate (ML / min): 160 Instrument ID: 2489 WATERS SFC 350 with UV detector Method: Time: Flow rate:%A:%B(0.01:160:60:40),(12.00:160:60:40) compound 5 1 H NMR(DMSO-d6,400MHz):δ ppm,9.81(s,1H),7.80(s,1H),7.77-7.76(m,2H),7.55(s,1H),7.49(d,J=8.8Hz,2H),7.34(d,J=8.4Hz,1H),7.23(dd,J=8 .4,2.0Hz,1H),7.08(d,J=8.4Hz,2H),3.69(s,3H),3.26-3.17(m,2H),2.42-2.41(m,1H),2.18-2.08(m,1H),1.42(s,3H). LCMS (Method A): 1.807 min, 100.0%, 254.0 nm, MS: ES+415.17 (M+1) HPLC (Method A): 8.03 min, 99.48%, 254.0 nm Chiral HPLC: 3.19 min, 100.00%, 310.0 nm compound 6 1H NMR(DMSO-d6,400MHz):δ ppm,9.82(s,1H),7.81(s,1H),7.77-7.76(m,2H),7.55(s,1H),7.49(d,J=8.8Hz,2H),7.34(d,J=8.4Hz,1H),7.23(dd,J=8 .0,2.0Hz,1H),7.08(d,J=8.4Hz,2H),3.69(s,3H),3.26-3.14(m,2H),2.41-2.33(m,1H),2.18-2.12(m,1H),1.42(s,3H). LCMS (Method A): 1.812 min, 97.93%, 254.0 nm, MS: ES+415.17 (M+1) HPLC (Method A): 8.03 min, 97.26%, 254.0 nm Chiral HPLC: 3.68 min, 100.00%, 310.0 nm

[0205] Example 6 - Synthesis of 3-methyl-3-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (Compounds 7 and 8)

[0206] [ka]

[0207] The racemate of compound 1 (0.2 g) was subjected to chiral SFC purification on a (CHIRALPAK IA 250 × 50 mm 5 μm) column, and two peaks were separated into compound 1 peak 1 (compound 7) (0.040 g, yield = 38.52%) and compound 1 peak 2 (compound 8) (0.045 g, yield = 46.79%). Column ID: CHIRALPAK IA 250 x 50 mm 5 μm Mobile phase A: LIQ. CO2 Mobile phase B: 0.1% M NH3 in MEOH-ACN (50-50) Flow rate (ML / min): 160 Instrument ID: 2489 WATERS SFC 350 with UV detector Method: Time: Flow rate: %A: %B (0.01:160:55:45), (16.00:160:55:45) Input strength: 0.2g. Yield: Compound 7 = 0.040 g (% yield = 38.52%) and Compound 8 = 0.045 g (% yield = 46.79%) Compound 7: 1 H NMR(DMSO-d6,400MHz):δ ppm,9.20(s,1H),7.90-7.89(m,2H),7.62(d,J=8.8Hz,2H),7.56(d,J=2.4Hz,2H),7.35(d,J=8.8Hz,2H ),3.26-3.24(m,1H),3.17-3.12(m,1H),2.59(s,3H),2.44-2.38(m,1H),2.22-2.16(m,1H),1.42(s,3H) 1 H NMR(MeOD,400MHz):δ ppm),7.99(d,J=2.0Hz,1H),7.63-7.54(m,4H),7.40(d,J=8.4Hz,2H),3.47-3.42 (m,2H),2.66(s,3H),2.58-2.52(m,1H),2.36-2.30(m,1H),1.63(s,3H),1Hを、DMSO In NMR, visual recognition can be achieved and MeOD moisture content can be integrated. LCMS (Method A): 2.344 min, 100.00%, 254.0 nm, MS: ES+417.38 (M+1) HPLC (Method B): 8.33 minutes, 99.60%, 330.0 nm KIRAL HPLC: 4.38 minutes, 100.00%, 300.0nm Compound 8: 1 H NMR(DMSO-d6,400MHz):δ ppm,9.20(s,1H),7.90-7.89(m,2H),7.62(d,J=8.4Hz,2H),7.56(s,2H),7.35(d,J=8.4Hz,2H),3.2 7-3.24(m,1H),3.17-3.11(m,1H),2.59(s,3H),2.44-2.38(m,1H),2.22-2.16(m,1H),1.42(s,3H). 1H NMR (MeOD, 400MHz): δ ppm), 7.96 (s, 1H), 7.60-7.54 (m, 4H), 7.37 (d, J = 8.4Hz, 2H), 2.60 (s, 3H), 2.55-2.49 (m, 1H), 2.34-2.27 (m, 1H), 1.55 (s, 3H). LCMS (Method A): 2.329 min, 98.58%, 254.0 nm, MS: ES+417.43 (M+1) HPLC (Method B): 8.32 min, 99.74%, 235.0nm Chiral HPLC: 3.65 min, 100%, 300.0 nm

[0208] Example 7 - Synthesis of 5-methyl-5-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)imidazolidine-2,4-dione (Compound 9)

[0209] [ka]

[0210] Step 1: To a stirred solution of (A12) (1.5 g, 3.99 mmol, 1.0 eq) in methanol (15 mL) was added NaOH solution (0.32 g, 7.99 mmol, 2.0 eq) at 25 °C. The RM was then heated to 40 °C and maintained at 40 °C for 16 h. The reaction was monitored by TLC (using 70% EtOAc in hexane as the mobile phase) and found to be complete after 16 h of stirring at 40 °C. The resulting reaction mixture was purified by trituration with DCM and pentane to give 3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzoic acid (A21) (1.1 g, 3.04 mmol, yield: 76.18%). 1H NMR(DMSO-d6,400MHz):δ ppm,12.70(brs,1H),10.22(brs,1H),8.31(brs,1H),8.17(s,1H),7.86(s,1H),7.80(d ,J=8.4Hz,1H),7.62(d,J=8.4Hz,2H),7.52-7.47(m,1H),7.31-7.21(m,2H)3.78(s,3H). LCMS (Method A): 1.79,79.92%,254nm,MS:ES+362(M),(M+1)

[0211] Step 2: To a solution of (A21) (1.1 g, 3.04 mmol, 1.0 eq) in DCM (10 mL) were added DIPEA (1.17 g, 9.14 mmol, 3.0 eq) and HATU (2.31 g, 6.09 mmol, 2.0 eq), respectively, at 0 °C. CAS No. 6638-79-5 (0.32 g, 3.35 mmol, 1.1 eq) was then added to the reaction mixture at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The reaction was monitored by TLC (using 70% EtOAc in hexane as the mobile phase), which confirmed completion of the reaction after 4 h of stirring at room temperature. The resulting reaction mixture was extracted with DCM (3 x 100 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 1.5 g of crude product. The obtained crude material was purified by manual column chromatography using silica (100-200 mesh) as the stationary phase (50% EtOAc in hexane as the mobile phase) to give N-methoxy-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzamide (A22) (1.0 g, 2.47 mmol, yield: 81.23%). 1 H NMR(DMSO-d6,400MHz):δ ppm 10.72(s,1H),7.98(s,1H),7.85(s,1H),7.72(s,1H),7.60(d,J=8.4Hz,2H),7 .49-7.36(m,2H),7.29(d,J=8.4Hz,2H),3.73(s,3H),3.61(s,3H),3.27(s,3H) LCMS (Method A): 1.816, 92.00%, 254.0 nm, MS: ES+405 (M+1).

[0212] Step 3: To a stirred solution of N-methoxy-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzamide (A22) (1.0 g, 2.47 mmol, 1.0 eq) in DCM was added (BOC)O (0.80 g, 3.70 mmol, 1.5 eq) and DMAP (0.12 g, 0.98 mmol, 0.4 eq) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 16 h. The reaction was complete by TLC (70% EtOAc in hexanes as mobile phase). The resulting reaction mixture was extracted with DCM (3 x 100 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 1.8 g of crude product. The obtained crude material was purified by manual column chromatography using silica (100-200 mesh) as the stationary phase (50% EtOAc in hexanes as the mobile phase) to give tert-butyl (4-(methoxy(methyl)carbamoyl)-2-(1-methyl-1H-imidazol-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A23) (0.45 g, 0.89 mmol, yield: 36.07%). 1 H NMR(DMSO-d6,400MHz):δ ppm,8.25(d,J=2.0Hz,1H),7.72-7.65(m,3H),7.60(d,J=8.8Hz,1H),7.47-7.4 1(m,2H),7.18-7.17(m,2H),3.66(s,3H),3.62(s,3H),3.28(s,3H),1.16(s,9H) LCMS (Method A): 2.032 min, 85.41%, 254.0 nm, MS: ES+505 (M+1)

[0213] Step 4: To a solution of tert-butyl (4-(methoxy(methyl)carbamoyl)-2-(1-methyl-1H-imidazol-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A23) (0.45 g, 0.89 mmol, 1.0 eq) in THF was added MeMgBr (1.78 mL, 2.0 eq) in THF at 0 °C. The reaction mixture was then warmed to room temperature and stirred for 3 h. The reaction was monitored by TLC (using 50% EtOAc in hexane as the mobile phase). It was then extracted with EA (3 x 100 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.7 g of crude product. The resulting crude material was purified by manual column chromatography using silica (100-200 mesh) as the eluted desired product (15-20% EtOAc in hexanes as mobile phase) to give tert-butyl (4-acetyl-2-(1-methyl-1H-imidazol-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A24) (0.30 g, 0.653 mmol, yield: 73.20%). 1 H NMR(DMSO-d6,400MHz):δ ppm,8.58(d,J=2.0Hz,1H),7.83(dd,J=6.0Hz,1H),7.72(s,1H),7.66(d,J=8.8Hz,2 H),7.40(d,J=8.4Hz,2H),7.29-7.23(m,2H),3.64(s,3H),2.19(s,3H),1.64(s,9H). Note: Impurity peaks 1 H NMR was used to observe the LCMS (Method A):2.115,100%,254nm,MS:ES+460(M+1)

[0214] Step 5: To a stirred solution of tert-butyl (4-acetyl-2-(1-methyl-1H-imidazol-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A24) (0.30 g, 0.653 mmol, 1.0 eq) in ethanol (6 mL) was added ammonium carbonate (0.25 g, 2.61 mmol, 4.0 eq), followed by TMSCN (3 mL) and ammonium hydroxide (6 mL) solution at room temperature. The reaction mixture was then heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC (using 70% EtOAc in hexane as the mobile phase). The resulting reaction mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.7 g of crude product. The obtained crude material was purified by manual column chromatography using silica (100-200 mesh) as the stationary phase (50% EtOAc in hexanes as the mobile phase) to give tert-butyl (2-(1-methyl-1H-imidazol-4-yl)-4-(4-methyl-2,5-dioxoimidazolidin-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A25) 0.25 g, 0.472 mmol, yield: 73.21%. 1 H NMR(DMSO-d6,400MHz):δ ppm,8.71(d,J=6.0Hz,1H),8.16(d,J=2.4Hz,1H),8.07(s,1H),7.97(dd,J=12.0Hz,1H),7.69(s,1H),7 .64(d,J=6.8Hz,2H),7.36(d,J=6.8Hz,2H),7.16-7.11(m,2H),3.62(s,3H),1.99(s,3H),1.35(s,9H). LCMS (Method A): 1.878 min, 85.79%, 243.0 nm, MS: ES+530 (M+1)

[0215] Step 6: To a solution of tert-butyl (2-(1-methyl-1H-imidazol-4-yl)-4-(4-methyl-2,5-dioxoimidazolidin-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A25) (0.25 g, 0.472 mmol, 1.0 eq) in 2.5 ml DCM was added HCl. Dioxane (2.49 mL, 5.0 eq) was added at room temperature and stirred for 3 h. The reaction was monitored by TLC (using 70% EtOAc in hexane as the mobile phase). The RM was concentrated under reduced pressure and the crude material was basified with NaHCO3 solution and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 0.35 g of crude product. The crude material was purified by trituration with DCM and pentane solution to give 5-methyl-5-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)imidazolidine-2,4-dione (compound 9) (0.127 g, 0.295 mmol, yield: 62.64%). 1 H NMR(DMSO-d6,400MHz):δ ppm,10.76(s,1H),9.92(s,1H),8.55(s,1H),7.83(d,J=2.0Hz,1H),7.79(s,1H),7.58(s,1H),7.51(d,J =8.8Hz,2H),7.41(d,J=8.4,1H),7.28(dd,J=6.0Hz,1H),7.11(d,J=8.4,2H),3.71(s,3H),1.68(s,3H); LCMS (Method A): 1.64 min, 98.82%, 296.0 nm, MS: ES+430 (M+1) HPLC (Method A): 5.15 minutes, 98.94%, 210nm,

[0216] Example 8 - Synthesis of (3-methyl-3-(3-(oxazol-2-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (Compound 10)

[0217] [ka]

[0218] Step 1: A stirred solution of oxazole (2.0 g, 28.9 mmol, 1.0 eq) in THF (20 mL) was prepared in a 50 mL single-neck RB at -78 °C. n-BuLi (21.67 mL, 34.6 mmol, 1.2 eq) was added dropwise to the reaction solution, followed by the addition of ZnBr. The resulting mixture was stirred at -78 °C for 1 h, and then an iodine solution in THF was added to the reaction mixture and stirred at room temperature for 30 min. The reaction was monitored by TLC (using EA:Hexane, 2.0:8.0 as the mobile phase) and found to be complete after 30 min of stirring at room temperature. The resulting reaction mixture was quenched with NH4Cl solution (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 2.5 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (5% ethyl acetate in hexane) to give 2-iodooxazole (A26) (2.0 g, 10.30 mmol, yield: 35%). 1 H NMR (DMSO-d6, 400MHz): δ ppm 8.25 (s, 1H), 7.23 (s, 1H).

[0219] Step 2: In a 30 mL reactor, a stirred solution of 2-iodooxazole (A26) (0.25 g, 0.54 mmol, 1.0 eq) in dioxane (2 mL) was added (A9) (0.126 g, 0.65 mmol, 1.2 eq), followed by K2CO3 (0.22 g, 1.62 mmol, 3 eq) and water under N2 atm. PdCl2(dppf) (0.019 g, 0.02 mmol, 0.05 eq) was added. The reactor was sealed, and the reaction was stirred at 90 °C for 2 h. The reaction was monitored by TLC (EA:hexane, 7.0:3.0, as the mobile phase) to confirm completion. The resulting reaction mixture was quenched with water (10 mL) and extracted with EA (3 x 10 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 0.3 g of crude product. The resulting crude material was purified by preparative HPLC purification method A to give (3-methyl-3-(3-(oxazol-2-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (compound 10) (0.03 g, 0.017 mmol, yield: 27%). 1 H NMR (DMSO-d6, 400 MHz): δ ppm 9.92 (s, 1H), 8.28 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.87 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.55-7.49 (m, 3H), 7.37 (d, J = 8.4 Hz, 2H), 3.29-3.14 (m, 2H), 2.22-2.15 (m, 1H), 1.42 (s, 3H). Note: 1H was integrated with the DMSO solvent peak clearly visible in MeOD NMR. 1 H NMR(MeOD,400MHz):δ ppm 10.17(s,1H),8.09(d,J=1.6Hz,1H),7.99(s,1H),7.61-7.56(m,3H),7.48(d,J=8.8Hz,1H) ,7.40-7.38(m,3H),3.44-3.32(m,1H),2.58-2.52(m,1H),2.36-2.31(m,1H),1.58(s,3H). LCMS:2.63min,100%,241.0nm,MS:ES+402.2(M+1) HPLC: 9.26 minutes, 100%, 210nm

[0220] Example 9 - Synthesis of 3-methyl-3-(3-(2-methyl-2H-tetrazol-5-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (Compound 11)

[0221] [ka]

[0222] Step 1a: In a 10 mL glass vial, a stirred solution of CAS: 6154-04-7 (0.1 g, 1.009 mmol, 1.0 eq) in ACN (2.5 mL) was prepared at room temperature. To this reaction solution, iodine (0.256 g, 1.009 mmol, 1.0 eq) was added at the same temperature. The resulting reaction mixture was then stirred at 45°C. t Bu nitrite was added, and the reaction was then stirred at 45°C for 3 hours. The reaction was monitored by TLC (50% ethyl acetate in hexane as the mobile phase), which confirmed completion after 3 hours of stirring at 45°C. The resulting reaction mixture was cooled to room temperature, and then the reaction mixture was diluted with ethyl acetate (100 mL), washed with sodium sulfite (100) solution and NaCl solution, and the organics were then dried over NaSO and concentrated under reduced pressure to give the crude material, which was purified by column chromatography using hexane and ethyl acetate. The product was eluted with 10% ethyl acetate in hexane to give 5-iodo-2-methyl-2H-tetrazole (A27) (0.145 g, 0.690 mmol, yield: 68.72%). 1 H NMR(DMSO-d6,400MHz):δ ppm,4.39(s,3H) LCMS (Method A): 1.178 min, 100%, 254.0 nm, MS: ES+211.05 (M+1)

[0223] Step 1: To a stirred solution of A9 (0.05 g, 0.108 mmol, 1.0 eq) and A27 (0.023 g, 0.108 mmol, 1.0 eq) in dioxane:water (1.0:0.3 mL) in a 10 mL glass vial, Na2CO3 (0.035 g, 0.325 mmol, 3.0 eq) was added at room temperature. The resulting reaction mixture was stirred at room temperature while purging with nitrogen for 15 minutes. PdCl2(dppf) (0.0038 g, 0.050 mmol, 0.05 eq) was added at room temperature, and the vial was then sealed and heated to 110 °C while maintaining stirring for 2 hours. The reaction was monitored by TLC (100% ethyl acetate in hexane as the mobile phase), which confirmed completion of the reaction after 2 hours of stirring at 110 °C. The resulting reaction mixture was cooled at room temperature and then poured into ice water (50 mL), extracted with ethyl acetate (30 twice), and the organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude material, which was purified by column chromatography using hexane and ethyl acetate. The product was eluted with 70% ethyl acetate in hexane and further purified by preparative HPLC purification method A to give 3-methyl-3-(3-(2-methyl-2H-tetrazol-5-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (Compound 11) (0.031 g, 0.0744 mmol, yield: 34.44%). 1 H NMR(DMSO-d6,400MHz):δ ppm,8.72(s,1H),8.02(s,1H),7.89(s,1H),7.55-7.52(m,4H),7.20(d,J=8.4Hz,2H),4.44(s, 3H),3.30-3.24(m,1H),3.18-3.12(m,1H),2.45-2.38(m,1H),2.22-2.17(m,1H),1.43(s,3H). LCMS (Method A): 2.439 min, 100%, 254.0 nm, MS: ES+417.3 (M+1) HPLC (Method B): 8.506 min, 99.48%, 210.0nm

[0224] Example 10 - Synthesis of 3-methyl-3-(3-(pyridazin-3-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (Compound 12)

[0225] [ka]

[0226] Step 1: To a solution of pyridazin-3(2H)-one (CAS 504-30-3) (0.15, 0.40 mmol, 1.0 eq) in ACN (3 mL) was added POBr (0.032 g, 0.80 mmol, 2.0 eq) at room temperature, and the resulting mixture was heated to 80 °C and stirred for 3 h. The reaction was monitored by TLC (using 1:1 EtOAc:Hex as the mobile phase) and found to be complete after 3 h. The resulting reaction mixture was quenched with saturated NaHCO (5 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.35 g of crude product. The obtained crude material was purified by flash column chromatography using silica (230-400 mesh) as the desired product eluted with 40% EA in hexane to give 3-bromopyridazine (A28) (0.15 g, 0.943 mmol, yield: 30.19%). 1 H NMR (DMSO-d6, 400MHz): δ ppm, 9.27 (dd, J = 4.8 Hz, 1.2 Hz 1H), 8.06 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.72-7.69 (m, 1H). LCMS (Method A): 0.856 min, 100%, 254.0 nm, MS: ES+160.9 (M+2)

[0227] Step 2: To a solution of 3-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (A9) (0.1 g, 0.217 mmol, 1.0 eq), 3-bromopyridazine (A28) (0.051 g, 0.329 mmol, 1.5 eq) in dioxane:HO (1 mL) was added cesium carbonate (0.211 g, 0.651 mmol, 3.0 eq), and the resulting mixture was purged with N for 10 min, after which PdCl(dppf) (0.0078 g, 0.010 mmol, 0.05 eq) was added. The reaction mixture was heated at 90 °C with stirring for 2 h. The reaction was monitored by TLC (using DCM:MeOH, 9:1, as the mobile phase). The resulting reaction mixture was quenched with ice-cold water (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.15 g of crude product. The resulting crude material was purified by manual flash chromatography using silica (200-400 mesh) as the stationary phase (7% DCM in MeOH) to give 3-methyl-3-(3-(pyridazin-3-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (compound 12) (0.013 g, 0.0315 mmol, yield: 14.51%). 1 H NMR (DMSO-d6, 400 MHz): δ ppm 9.17-9.16 (d, J = 4.8 Hz, 1H), 8.93 (s, 1H), 7.88-7.86 (m, 2H), 7.73-7.68 (m, 2H), 7.55-7.53 (m, 1H), 7.46-7.41 (m, 3H), 6.93 (d, J = 8.4 Hz, 2H), 3.30-3.26 (m, 1H), 3.20-3.17 (m, 1H), 2.23-2.18 (m, 1H), 1.45 (s, 3H); 1H integrated with MeOD solvent peak clearly visible in DMSO NMR. 1H NMR(MeOD,400MHz):δ ppm,9.11-9.10(m,1H),8.07-8.05(m,1H),7.78-7.72(m,2H),7.59-7.52(m,2H),7.41(d,J=8.4 Hz,2H),7.03(d,J=8.4Hz,2H),2.64-2.58(m,1H),2.38-2.31(m,1H),1.61(s,3H),1.21(s,1H). LCMS (Method A): 2.175 min, 99%, 254.0 nm, MS: ES+412 (M+1) HPLC (Method A): 7.58 min, 99.24%, 254.0nm Chiral HPLC (Method A): 4.31 min, 51.14%, 240.0 nm; 4.80 min, 48.85%, 240.0 nm

[0228] Example 11 - Synthesis of 3-methyl-3-(3-(pyrazin-2-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (Compound 13)

[0229] [ka]

[0230] Step 1: A stirred solution of (A9) (0.15 g, 0.325 mmol, 1.0 eq) in dioxane:HO (7:3) was prepared in a 10 ml glass vial at room temperature. To this reaction solution (CAS: 56423-63-3 (0.05 g, 0.314 mmol, 1.0 eq) was added NaCO (0.10 g, 1.02 mmol, 3.0 eq) under N atmosphere at the same temperature. PdCl(dppf) (0.01 g, 0.01 mmol, 0.05 eq) was then added and stirred at 110 °C for 1 h. The reaction was monitored by TLC (MeOH:DCM, 1:9) and stirred at 110 °C for 1 h. After stirring, the reaction was confirmed to be complete. The resulting reaction mixture was extracted with EA (20 mL) and HO (20 mL). The organic layer was dried over NaSO, the solvent was removed on a rotary evaporator, and the mixture was purified by glass column chromatography using 230-400 mesh silica. The product (compound 13) was eluted with 10% MeOH:DCM (0.040 g, 0.096 mmol, yield: 29.76%). 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.85 (d, J = 11.6 Hz, 2H), 8.72 (s, 1H), 8.55 (d, J = 2.4 Hz, 1H), 7.86 (s, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.54-7.51 (m, 1H), 7.42 (d, J = 8.4 Hz, 3H), 6.93 (d, J = 8.4 Hz, 2H), 3.27-3.24 (m, 1H), 3.20-3.16 (m, 1H), 2.22-2.15 (m, 1H), 1.44 (s, 3H), 1H integrated with the clearly visible DMSO solvent peaks in MeOD NMR. 1 H NMR(MeOD,400MHz):δ ppm,8.97(s,1H),8.69(s,1H),8.50(d,J=2.4Hz,1H),7.79(d,J=1.6Hz,1H),7.56-7.49(m,2H),7.42(d,J =8.4Hz,2H),7.03(d,J=8.4Hz,2H),3.44-3.38(m,1H),2.62-2.58(m,1H),2.38-2.33(m,1H),1.61(s,3H) LCMS (Method A): 2.30 min, 100%, 254.0 nm, MS: ES+413.2 (M+1) HPLC (Method B): 8.19 min, 100%, 254 nm.

[0231] Example 12 - Chiral Separation of 5-methyl-5-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)imidazolidine-2,4-dione (Compounds 14 and 15)

[0232] [ka]

[0233] procedure: The racemate of compound 9 (0.109 g) was subjected to chiral SFC purification on a (CHIRALPAK IA 250 × 4.6 mm 5 μm) column, and two peaks were separated into compound 9 peak 1 (compound 14) (0.027 g, yield = 24.77%) and compound 9 peak 2 (compound 15) (0.037 g, yield = 33.94%). Column ID: CHIRALPAK IA, 250*4.6mm, 5 microns Mobile phase A: LIQ.CO2 Mobile phase B: 0.1% M NH3 in MEOH-ACN (50-50) Flow rate (ML / min): 4mL Equipment ID: 2998 WATERS SFC Investigator system with PDA detector. Method: 70:30 isocratic; flow rate = 4 ml / min; column oven temperature = 40°C; back pressure = 100 bar, analysis time 9 minutes. Input amount: 0.109g. Output: Compound 14 = 0.027 g (% yield = 24.77%) and Compound 15 = 0.037 g (% yield = 33.94%) compound 14 1H NMR(DMSO-d6,400MHz):δ ppm,10.76(brs,1H),9.92(s,1H),8.60(s,1H),7.83(d,J=2.0Hz,1H),7.79(s,1H),7.58(s,1H),7.51(d,J=8.4 Hz,2H),7.41(d,J=8.8Hz,1H),7.28(dd,J=8.4Hz,2.0Hz,1H),7.11(d,J=8.4Hz,2H),3.71(s,3H),1.68(s,3H). 1 H NMR(MeOD,400MHz):δ ppm),7.81(d,J=2.4Hz,1H),7.70(s,1H),7.47-7.44(m,3H),7.41-7.39(m,2H),7.09(d,J=8.4Hz,2H),3.76(s,3H),1.82(s,3H). LCMS (Method A): 1.70 min, 100.00%, 298.0 nm, MS: ES+430.3 (M+1) HPLC (Method B): 5.24 min, 100%, 254.0 nm KIRAL HPLC: 3.25 minutes, 100.00%, 240.0nm Compound 15 1 H NMR(DMSO-d6,400MHz):δ ppm,10.77(s,1H),9.92(s,1H),8.60(s,1H),7.81(dd,J=16.8Hz,2.4Hz,2H),7.58(s,1H),7.51(d,J=8.8Hz ,2H),7.41(d,J=8.4Hz,1H),7.28(dd,J=8.8Hz,2.4Hz,1H),7.11(d,J=8.4Hz,2H),3.71(s,3H),1.68(s,3H). 1 H NMR(MeOD,400MHz):δ ppm),7.81(d,J=2.4Hz,1H),7.71(s,1H),7.46-7.44(m,3H),7.41-7.37(m,2H),7.08(d,J=8.4Hz,2H),3.76(s,3H),1.82(s,3H) LCMS (Method A): 1.69 min, 97.02%, 254.0 nm, MS: ES+430.4 (M+1) HPLC (Method B): 5.01 min, 96.44%, 210.0nm Chiral HPLC: 3.73 min, 93.63%, 240.0 nm

[0234] Example 13 - Synthesis of 3-methyl-3-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidine-2,4-dione (Compound 16)

[0235] [ka]

[0236] Process 1a A solution of glycine methyl ester hydrochloride (CAS: 5680-79-5) (275 g, 2190.3 mmol, 1.0 eq) in methanol (100 mL) was cooled to 0 °C, and then TEA (332.4 g, 3285 mmol, 1.5 eq) was added. The mixture was stirred for 30 minutes, and then 4-methoxybenzaldehyde CAS: 123-11-5 (298.2 g, 2190.3 mmol, 1.0 eq) was added, and the mixture was stirred at room temperature for 4 hours. The solution was cooled to 0 °C, and then NaBH (165.5 g, 4380.7 mmol, 2.0 eq) was added dropwise to the reaction mixture. After stirring at room temperature for 16 hours, the reaction was monitored by TLC (using 4:6 EtOAc:Hex as the mobile phase). The resulting reaction mixture was filtered, the filtrate was evaporated, and water (500 mL) was added. The mixture was extracted with EtOAc (4 x 500 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 202 g of crude product. The crude material obtained was used directly in the next step without any purification. The reaction gave methyl (4-methoxybenzyl)glycinate (A29) (202 crude, 965.9 mmol, quantitative yield). 1 H NMR (DMSO-d6,400MHz):δ ppm,7.21(d,J=8.8Hz,2H),6.86(dd,J=6.8Hz,2.0Hz,2H),3.73(s,3H),3.62(br s,2H),3.61(s,3H)3.28(s,2H) LCMS (Method A): 0.951 min, 81.11%, 220.0 nm, MS: ES+210 (M+1)

[0237] Step 1: To a solution of ethyl 2-(4-nitrophenyl)acetate (400 g, 1912.04 mmol, 1.0 eq) in THF was added a solution of NaOH (229 g, 5736 mmol, 3.0 eq) in HO (800 mL) at 0 °C, and the reaction mixture was then stirred at room temperature for 16 h. The reaction was monitored by TLC (using MeOH:DCM 1:9 as the mobile phase). The resulting reaction mixture was distilled, and then water (100 mL) was added. The mixture was acidified with 1 N HCl and extracted with EtOAc (3 x 500 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product. The resulting crude material was purified by manual column chromatography using silica (100-200 mesh) as the stationary phase (eluent 7% MeOH:MDC) to give 2-(4-nitrophenyl)acetic acid (A30) (200 g, 1104.0 mmol, yield: 57.63%). 1 H NMR (DMSO-d6,400MHz): δ ppm,12.59(s,1H),8.193(d,J=8.8Hz,2H),7.56(d,J=8.8Hz,2H),3.79(s,2H).

[0238] Step 2: To a solution of 2-(4-nitrophenyl)acetic acid (A30) (144 g, 794.92 mmol, 1.0 eq) in DMF, methyl (4-methoxybenzyl)glycinate (A29) (216.0 g, 1033 mmol, 1.3 eq) and DIPEA (112.7 g, 874 mmol, 1.1 eq) were added, and the reaction mixture was stirred at room temperature. HATU (453.3 g, 1192.3 mmol, 1.5 eq) was then added, and the mixture was stirred for 16 h. The reaction was monitored by TLC (using 5:5 EtOAc:Hex as the mobile phase). The resulting reaction mixture was poured into ice-cold water (1000 mL), resulting in a brown solid precipitate. The mixture was stirred for 30 min, then filtered and dried. The crude material was used directly in the next step. The reaction gave methyl N-(4-methoxybenzyl)-N-(2-(4-nitrophenyl)acetyl)glycinate (A31) (100 g crude, 268.5 mmol, yield: 33.78%). 1 H NMR(DMSO-d6,400MHz):δ ppm,8.20-8.16(m,2H),7.51-7.49(m,2H),7.22-7.17(m,2H),6.93-6.86(m,2H),4.6 4(s,1H),4.45(s,1H),4.25(s,1H),4.00(s,2H)3.87(s,1H),3.74(s,3H)3.61(s,3H), LCMS (Method A): 2.139 min, 97.36%, 254.0 nm, MS: ES+373.2 (M+1)

[0239] Step 3: To a solution of N-(4-methoxybenzyl)-N-(2-(4-nitrophenyl)acetyl)glycinate (A31) (70.0 g, 187.98 mmol, 1.0 eq) in DMF (700 mL) was added Ko tBu (22.14 g, 197.37 mmol, 1.05 eq) was added portionwise at room temperature, and the reaction mixture was then stirred at room temperature for 16 hours. The reaction was monitored by TLC (MeOH:DCM, 5:5, as the mobile phase) and confirmed to be complete after 16 hours. The resulting reaction mixture was quenched with water (1000 mL) and then acidified with dilute HCl, resulting in a yellow solid precipitate. The mixture was stirred for 30 minutes, then filtered and dried to give 1-(4-methoxybenzyl)-3-(4-nitrophenyl)pyrrolidine-2,4-dione (A32) (75 g, 220.37 mmol, quantitative yield). 1 H NMR (DMSO-d6,400MHz): δ ppm,12.71(br s,1H),8.40-8.37(m,2H),8.24-8.20(m,2H),7.19(d,J=8.8 Hz. 2H),6.93(d,J=8.8Hz,2H),4.50(s,2H),3.89(s,2H),3.73(s,3H), LCMS (Method A): 2.092 min, 99.16%, 230.0 nm, MS: ES+341.2 (M+1)

[0240] Step 4: A solution of 1-(4-methoxybenzyl)-3-(4-nitrophenyl)pyrrolidine-2,4-dione (A32) (65.0 g, 190.99 mmol, 1.0 eq) in DMF (650 mL) was cooled to 0 °C, and then K2CO3 (28.9 g, 210.09 mmol, 1.1 eq) was added. The resulting mixture was stirred for 15 min, and then MeI (40.3 g, 286.48 mmol, 1.5 eq) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC (using 4:6 EtOAc:Hex as the mobile phase), which confirmed completion after 16 h. The resulting reaction mixture was quenched with ice-cold water (200 mL) and extracted with EtOAc (4 x 500 mL). The organic layer was washed with cold brine solution. The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 53 g of crude material, which was purified by column chromatography using silica (100-200 mesh) as the stationary phase (24% ethyl acetate in hexanes) to give 1-(4-methoxybenzyl)-3-methyl-3-(4-nitrophenyl)pyrrolidine-2,4-dione (A33) (33 g, 93.22 mmol, yield: 48.80%). 1 H NMR(DMSO-d6,400MHz):δ ppm,8.26-8.22(m,2H),7.64-7.60(m,2H),7.25(d,J=8.4Hz,2H),6.95-6.92(m,2H),4.65(d,J=14.8Hz,1H),4.55(d,J=14.8Hz 1H),4.03(s,2H),3.74(s,3H),3.61(s,3H), LCMS (Method A): 2.336 min, 99.24%, 254.0 nm, MS: ES+355 (M+1)

[0241] Step 5: To a stirred solution of 1-(4-methoxybenzyl)-3-methyl-3-(4-nitrophenyl)pyrrolidine-2,4-dione (A33) (28.0 g, 79.09 mmol, 1.0 eq) in water (280 mL) was added NH4Cl (41.9 g, 790.9 mmol, 10.0 eq) and Fe (22.06 g, 395.48 mmol, 5.0 eq) at room temperature. The reaction mixture was heated to 100 °C and then stirred for 5 h. The reaction was monitored by TLC (using MeOH:DCM 1:9 as the mobile phase), which confirmed completion after 5 h. The resulting reaction mixture was filtered and washed with 10% MeOH in DCM (400 mL), and the aqueous layer was then extracted with 10% MeOH in DCM (400 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 24 g of crude product. The crude material obtained was purified by trituration with methanol / ether to give 3-(4-aminophenyl)-1-(4-methoxybenzyl)-3-methylpyrrolidine-2,4-dione (A34) (20 g, 61.65 mmol, yield: 77.97%). 1 H NMR(DMSO-d6,400MHz):δ ppm,7.23(d,J=8.4Hz,2H),6.92(d,J=8.4Hz,2H),6.90(d,J=8.4Hz,2H),6.50(d,J=8.8Hz,2H),5.16 (s,2H),4.69(d,J=14.8Hz,1H),4.43(d,J=14.8Hz,2H),3.92-3.74(m,2H),3.72(s,3H),1.39(s,3H) LCMS (Method A): 1.684 min, 100%, 254.0 nm, MS: ES+325 (M+1)

[0242] Step 6a: To a stirred solution of 3-(4-aminophenyl)-1-(4-methoxybenzyl)-3-methylpyrrolidine-2,4-dione (A34) (23.0 g, 70.90 mmol, 1.0 eq) in toluene, MSA (CAS: 75-75-2) (55.2 mL, 2.4 v) was added at room temperature, and the reaction was then stirred at 80 °C. The reaction was monitored by TLC (using DCM:MeOH, 9:1, as the mobile phase) and found to be complete after 24 h of stirring at 80 °C. The resulting reaction mixture was stirred and allowed to settle. The toluene was decanted, then water (200 mL) was added, and the resulting mixture was washed with ethyl acetate (4 x 300 mL). The aqueous layer was basified with NaHCO and then extracted with ethyl acetate (4 x 300 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 3-(4-aminophenyl)-3-methylpyrrolidine-2,4-dione (A35) (7.0 g, 34.29 mmol, yield: 48.37%). 1 H NMR (DMSO-d6,400MHz):δ ppm,8.55(s,1H),6.91(d,J=8.8Hz,2H),6.52(d,J=8.8Hz,2H),5.16(s,2H),4.0-3.90(m,2H),1.34(s,3H), LCMS (Method A): 0.368 min, 100%, 210.0 nm, MS: ES+205 (M+1)

[0243] Step 7a: A stirred solution of 3-(4-aminophenyl)-3-methylpyrrolidine-2,4-dione (A35) (4.0 g, 19.59 mmol, 1.0 eq) in DMF was cooled to 0 °C. NBS (2.44 g, 13.61 mmol, 0.7 eq) was added dropwise, and the resulting mixture was stirred for 10 min. The reaction was monitored by TLC (using DCM:MeOH; 7:3 as the mobile phase) to confirm completion. The reaction mixture was diluted with ice-cold water (100 mL) and extracted with EtOAc (3 x 250 mL). The organic layer was separated, washed with ice-cold water and brine, then dried over NaSO and concentrated under reduced pressure to give 3.2 g of crude product. The obtained crude material was purified by column chromatography using silica (100-200 mesh) as stationary phase (1.4% DCM in MeOH) to give 3-(4-amino-3-bromophenyl)-3-methylpyrrolidine-2,4-dione (A36) (2.57 g, 9.11 mmol, yield: 47.68%). 1 H NMR (DMSO-d6,400MHz):δ ppm,8.63(s,1H),7.20(d,J=2Hz,1H),6.99-6.97(d,d,J=2Hz,J=2Hz,1H),6.75(d,J=8.4Hz 1H),4.09-3.90(m,2H),1.36(s,3H) LCMS (Method A): 1.491 min, 100%, 254.0 nm, MS: ES+283 (M+1)

[0244] Step 8a: To a stirred solution of 3-(4-amino-3-bromophenyl)-3-methylpyrrolidine-2,4-dione (A36) (4.5 g, 15.8 mmol, 1.0 eq) in DMF (15 mL) was added 1-methyl-4-(tributylstannyl)-1H-imidazole (11.7 g, 31.78 mmol, 2.0 eq). The resulting mixture was stirred at room temperature and purged with N(g) for 15 minutes, followed by the addition of PdCl(dppf) (2.324 g, 3.18 mmol, 0.2 eq). The resulting mixture was stirred at room temperature and purged with N(g) for 15 minutes, and the reaction was then heated in a microwave oven at 130 °C for 30 minutes. The reaction was monitored by TLC (using DCM:MeOH, 9:1, as the mobile phase), which indicated completion after 30 minutes. The reaction mixture was extracted with EtOAc (200 mL x 2). The organic layer was separated and washed with brine (200 mL), then dried over NaSO and concentrated under reduced pressure to give 2.0 g of crude product. The crude material was purified by column chromatography using silica (100-200 mesh) as the stationary phase (2% MeOH in DCM) to give 3-(4-amino-3-(1-methyl-1H-imidazol-4-yl)phenyl)-3-methylpyrrolidine-2,4-dione (A37) (1.7 g, 5.97 mmol, yield: 37.69%). 1 H NMR(DMSO-d6,400MHz):δ ppm,8.56(s,1H),7.69(s,1H),7.57-7.45(m,3H),7.23(d,J=2.4Hz,1H),6.83-6.80(m ,1H),6.62(d,J=8.4Hz,1H),6.23(s,2H),4.09-3.98(m,2H),3.71(s,3H),1.39(s,3H), LCMS (Method A): 0.940 min, 80.71%, 254.0 nm, MS: ES+285.1 (M+1)

[0245] Step 9a: To a stirred solution of 3-(4-amino-3-(1-methyl-1H-imidazol-4-yl)phenyl)-3-methylpyrrolidine-2,4-dione (A37) (1.2 g, 4.22 mmol, 1.0 eq) in DCM (12 mL), (4-(trifluoromethyl)phenyl)boronic acid (CAS: 128796-39-4) (0.80 g, 4.22 mmol, 1.0 eq), DIPEA (1.6 g, 12.6 mmol, 3.0 eq), and Cu(OAC) (1.14 g, 6.33 mmol, 31.5 eq) were added at room temperature. The resulting mixture was stirred at room temperature under open atmosphere for 3 hours. The reaction was monitored by TLC (using DCM:MeOH, 9:1, as the mobile phase) and was found to be complete after 3 hours. The reaction mixture was quenched with water (200 mL) and extracted with DCM (3 x 100 mL). The organic layer was dried over NaSO and concentrated under reduced pressure to give 0.850 g of crude product. The crude material was purified by column chromatography using silica (230-400 mesh) as the stationary phase (10% MeOH in DCM) to give 3-methyl-3-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidine-2,4-dione (compound 16) (0.574 g, 1.33 mmol, yield: 31.8%). 1 H NMR(DMSO-d6,400MHz):δ ppm,9.92(s,1H),8.68(s,1H),7.78(s,1H),7.64(d,J=2.0Hz,1H),7.57(d,J=1.2Hz,1H),7.50(d,J=8 .4Hz,2H),7.38(d,J=8.4Hz,1H),7.11(d,J=8.8Hz,3H),4.09-3.98(m,2H),3.70(s,3H),1.49(s,3H), LCMS (Method A): 1.851 min, 97.00%, 254.0 nm, MS: ES+429.2 (M+1) HPLC (Method A): 7.71 min, 98.83%, 254.0nm Chiral HPLC: 9.118 min, 44.84%, 320.0 nm; 9.607 min, 55.159%, 320.0 nm

[0246] Example 14 - Chiral Separation of 3-methyl-3-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidine-2,4-dione (Compound 17 and Compound 18)

[0247] [ka]

[0248] Chiral separation of compound 17 & compound 18: The racemate of compound 16 (0.1 g) was subjected to chiral SFC purification on a YMC CELLULOSE SC (250 x 20 mm 5 um) column, and two peaks were separated into compound 17 and compound 18. Column ID: YMC CELLULOSE SC (250 x 20 mm 5 μm) Mobile phase A: Liq.CO2 Mobile phase B: M.NH3-HEP-IPA(70-30) Flow rate (ML / min): 24 Instrument ID: PHP-04-AGEILENT 1260 SERISE INFINITY-2 with UV detector Method: Time: Flow rate: %A:%B(0:24:0:100),(32:24:0:100) Input amount: 0.1g. Output: Compound 17 = 0.026 g (% yield = 26.0%) and Compound 18 = 0.030 g (% yield = 30.0%) Compound 17: 1 H NMR(DMSO-d6,400MHz):δ ppm,9.91(s,1H),8.69(s,1H),7.79(s,1H),7.62(d,J=2.0Hz,1H),7.57(s,1H),7.50(d,J=8.8H z,2H),7.38(d,J=8.4Hz,1H),7.10(d,J=8.4Hz,3H),4.09-3.98(m,2H),3.70(s,3H),1.49(s,3H) LCMS (Method A): 1.797 min, 99.91%, 254.0 nm, MS: ES+429.3 (M+1) HPLC (Method A): 5.508 min, 99.88%, 254.0nm Chiral HPLC (Method A): 14.99 min, 100%, 262 nm Compound 18: 1 H NMR(DMSO-d6,400MHz):δ ppm,9.92(s,1H),8.69(s,1H),7.78(s,1H),7.62(d,J=2.0Hz,1H),7.57(d,J=1.2Hz,1H),7.50(d,J= 8.8Hz,2H),7.38(d,J=8.8Hz,1H),7.11(d,J=8.4Hz,3H),4.09-3.98(m,2H),3.70(s,3H),1.49(s,3H) LCMS (Method A): 1.792 min, 100%, 254.0 nm, MS: ES+429.3 (M+1) HPLC (Method A): 5.497 min, 100%, 254.0nm Chiral HPLC (Method A): 16.90 min, 98.02%, 262 nm

[0249] Example 15 - Synthesis of 4-hydroxy-3-methyl-3-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (Compound 19)

[0250] [ka]

[0251] To a stirred solution of 3-methyl-3-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidine-2,4-dione (compound 16) (0.100 g, 0.233 mmol, 1.0 eq) in MeOH (1.0 mL) and DCM (1.0 mL) was added NaBH (0.013 g, 0.350 mmol, 1.5 eq) at 0 °C, and the resulting mixture was stirred at room temperature for 30 min. The reaction was monitored by TLC (using DCM:MeOH, 9:1, as the mobile phase), which confirmed completion after 30 min of stirring at room temperature. The reaction mixture was diluted with CHCl, and then a solution of NHCl in water (5 mL) was added. The mixture was extracted with DCM (3 x 20 mL), and the organic layer was dried over NaSO and concentrated under reduced pressure to give 0.06 g of crude product. The resulting crude material was purified by reverse-phase column chromatography using C18 as the stationary phase and 100% water:ACN as the mobile phase to give 4-hydroxy-3-methyl-3-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (compound 19) (0.032 g, 0.0743 mmol, 32% yield). 1 H NMR(DMSO-d6,400MHz):δ ppm,9.76(s,1H),7.88(s,1H),7.76(s,1H),(s,1H),7.69(s,1H),7.65(d,J=2.0Hz,1H),7.51(d,J=10Hz,1H),7.44(s,1H) ),7.31(d,J=8.4Hz,1H),7.08(d,J=8.4Hz,3H),5.17(s,1H),4.12(t,J=5.8Hz,1H),3.70(s,3H),2.84(s,1H),1.42(s,3H) LCMS (Method A): 1.595 min, 100.0%, 254.0 nm, MS: ES+431 (M+1) HPLC (Method A): 4.350 min, 100.0%, 254.0nm Chiral HPLC: (Peak 1) 6.42 min, 47.61%, 305.0 nm; (Peak 2) 6.76 min, 45.58%, 305.0 nm

[0252] Example 16 - Chiral Separation of 3-methyl-3-(3-(2-methyl-2H-tetrazol-5-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (Compound 20 and Compound 21)

[0253] [ka]

[0254] Chiral separation of compound 20 and compound 21: The racemate of compound 11 (18.2 mg) was subjected to chiral SFC purification on a CHIRALPAK IG, 250×10 mm, 5 μm column, and two peaks were separated into compound 20 and compound 21. Column ID: CHIRALPAK IG, 250×10mm, 5μm Mobile phase A: 0.1% NH3 in heptane Mobile phase B: 0.1% NH3 in IPA:MEOH (50:50) Flow rate (ML / min):6 Instrument ID: PHP-04-AGILENT 1260 SERIES INFINITY-II with UV detector Method: Time: Flow rate: %A:%B(IITIAL:38:6:6),(80:20) Input amount: 18.2 mg. Output: Compound 20 = 0.0677 g (% yield = 37.2%) and Compound 21 = 0.061 g (% yield = 33.52%) Compound 20: 1 H NMR(400MHz,MeOD):δ ppm,8.24(d,J=2.4Hz,1H),7.58-7.50(m,4H),7.31(d,J=8.4Hz,2H),4.47( s,3H),3.47-3.37(m,1H),2.59-2.53(m,1H),2.37-3.30(m,1H),1.60(s,3H) LCMS (Method A): 2.41 min, 100%, 254.0 nm, MS: ES+417 (M+1) HPLC (Method A): 8.51 min, 100%, 254.0nm Chiral HPLC (Method A): 5.08 min, 100.0%, 304 nm Compound 21: 1 H NMR(400MHz,MeOD):δ ppm,8.24(d,J=2.4Hz,1H),7.58-7.50(m,4H),7.31(d,J=8.4Hz,2H),4.47(s,3H),3. 47-3.44(m,1H),3.43-3.37(m,1H),2.59-2.53(m,1H),2.37-2.30(m,1H),1.60(s,3H LCMS (Method A): 2.37 min, 98.96%, 254.0 nm, MS: ES+417 (M+1) HPLC (Method A): 8.52 min, 100%, 254.0nm Chiral HPLC (Method A): 5.33 min, 98.87%, 304 nm

[0255] Example 17 - Synthesis of 3-methyl-3-(3-(1-methyl-1H-imidazol-4-yl)-4-((3-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (Compound 22)

[0256] [ka]

[0257] Step 1: To a solution of 3-(4-amino-3-bromophenyl)-3-methylpyrrolidin-2-one (A4) (0.6 g, 2.230 mmol, 1.0 eq) in DCM (6 mL) were added CAS:1423-26-3 (0.632 g, 3.345 mmol, 1.5 eq), DIPEA (1.1 mL, 6.69 mmol, 3.0 eq), and Cu(OAc) (0.605 g, 3.345 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 48 h with the vial open and exposed to air (i.e., without a septum). The reaction was monitored by TLC (using 90% EtOAc in hexane as the mobile phase). Water (10 mL) was added to the reaction mixture, and the mixture was extracted with DCM (3 x 25 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.8 g of crude product. The obtained crude material was purified by manual column chromatography using silica (100-200 mesh) as the stationary phase (desired product eluted with 50-55% EtOAc in hexanes as the mobile phase) to give 3-(3-bromo-4-((3-(trifluoromethyl)phenyl)amino)phenyl)-3-methylpyrrolidin-2-one (A38) (0.2 g, 0.484 mmol, yield: 21.71%). 1 H NMR(DMSO-d6,400MHz):δ ppm,8.07(s,1H),7.87(bs,1H),7.66(d,J=2.0Hz,1H),7.42-7.29(m,3H),7.2 0(s,1H),7.15-7.0(m,2H),3.17-3.13(m,2H),2.41-2.13(m,2H),1.38(s,3H). LCMS (Method A): 2.352 min, 100%, 254.0 nm, MS: ES+413 (M+1)

[0258] Step 2: To a stirred solution of 3-(3-bromo-4-((3-(trifluoromethyl)phenyl)amino)phenyl)-3-methylpyrrolidin-2-one (A38) (0.18 g, 0.435 mmol, 1.0 eq) in DMF (2 mL) was added 1-methyl-4-(tributylstannyl)-1H-imidazole (0.323 g, 0.871 mmol, 2.0 eq) at room temperature, and the resulting mixture was purged with N2(g) at room temperature for 10 minutes. PdCl2(dppf) (0.063 g, 0.087 mmol, 0.2 eq) was then added, and the mixture was stirred in a microwave at 140 °C for 30 minutes. The reaction was monitored by TLC (using EA:HEX, 9.0:1.0 as the mobile phase), which showed completion after 30 minutes of stirring at 140 °C. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.3 g of crude product. The crude material was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (75% EA in HEX) to give 3-methyl-3-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (compound 22) (0.055 g, 0.132 mmol, yield: 30.48%). 1 H NMR(DMSO-d6,400MHz):δ ppm,9.78(s,1H),7.79-7.72(m,3H),7.58-7.57(m,1H),7.39(d,J=87.6Hz,1H),7.30-7.20(m ,4H),7.08(d,J=7.6Hz,1H),3.72(s,3H),3.36-3.15(m,2H),2.46-2.13(m,2H),1.42(s,3H). LCMS (Method A): 1.67 min, 100%, 254.0 nm, MS: ES+415.17 (M+1). HPLC (Method A): 4.68 minutes, 100%, 254.0nm Chiral HPLC (Method A): (Peak 1) 6.03 min, 50.52%, 300 nm; (Peak 2) 6.21 min, 49.47%, 300 nm

[0259] Example 18 - Synthesis of 1-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)ethan-1-one (Compound 23)

[0260] [ka]

[0261] Step 1: A solution of 1-(4-amino-3-bromophenyl)ethan-1-one (CAS No. 56759-32-1) (0.5 g, 2.33 mmol, 1.0 eq) in 5 mL of DMF was prepared in a 30 mL glass microwave vial at room temperature. To this solution, 1-methyl-4-(tributylstannyl)-1H-imidazole (1.73 g, 4.672 mmol, 2.0 eq) was added at room temperature under a nitrogen atmosphere. PdCl(dppf) (0.17 g, 0.233 mmol, 0.1 eq) was added to the resulting reaction mixture, and the mixture was purged with N2 gas. The reaction mixture was heated to 130 °C and stirred for 30 min. The reaction was monitored by TLC (70% EtOAc in hexane as the mobile phase), which confirmed completion after 30 min at 130 °C. The resulting reaction mixture was extracted with EA (100 mL x 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product (0.60 g). The crude material was purified by Combi-flash chromatography using silica gel (300-400 mesh) (desired product eluted with 50-55% EA in hexanes) to give 1-(4-amino-3-(1-methyl-1H-imidazol-4-yl)phenyl)ethan-1-one (A39) (0.35 g, 1.627 mmol, yield: 69.61%). 1H NMR (DMSO-d6,400MHz):δ ppm 8.00(d,J=2.0Hz 1H),7.73(s,1H),7.69(s,1H),7.56(dd,J=8.8Hz,J=2.0Hz,1H),7.22(bs,2H),6.69(d,J=8.4Hz 1H),3.72(s,3H),2.44(s,3H) LCMS (Method A): 1.01 min, 98.61%, 254 nm, MS: ES+216 (M+1)

[0262] Step 2: A stirred solution of 1-(4-amino-3-(1-methyl-1H-imidazol-4-yl)phenyl)ethan-1-one (A39) (3.5 g, 17.44 mmol, 1.0 eq) in DMSO (37.5 mL) was prepared in a 100 mL RBF at room temperature. To this solution, (4-(trifluoromethyl)phenyl)boronic acid (CAS: 128796-39-4) (3.29 g, 17.44 mmol, 1.0 eq) and KPO (7.39 g, 34.88 mmol, 2.0 eq) were added under a nitrogen atmosphere at room temperature. To the resulting reaction mixture, Cu(OAc) (3.78 g, 20.92 mmol, 1.2 eq) was added, and the mixture was purged with N. The reaction mixture was heated to 110 °C and stirred for 2 h. The reaction was monitored by TLC (80% EtOAc in hexane as mobile phase) and was found to be complete after 2 h at 110 °C. The reaction mixture was extracted with EA (3 x 150 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product (5.5 g). The crude material was purified by Combi-Flash chromatography using silica gel (300-400 mesh) (desired product eluted with 45-50% EA in hexane) to give 1-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)ethan-1-one (compound 23) (4.0 g, 11.14 mmol, yield: 31.95%). 1H NMR (DMSO-d6,400MHz):δ ppm,11.15(s,1H),8.23(d,J=2.0Hz 1H),7.87(s,2H),7.76(dd,J=8.8Hz,J=2.0Hz,1H),7.64(d,J=8.4Hz 2H),7.48(d,J=8.4Hz 1H),7.37(d,J=8.4Hz 2H),3.75(s,3H),2.50(s,3H) LCMS (Method A): 2.01 min, 99.01%, 254 nm, MS: ES+360 (M+1)

[0263] Biological Examples Prior art TEAD inhibitors 1-1, 1-2, 1-3, and 1-4 (structures shown in Table 3) are used as reference compounds throughout Biological Examples 19-29.

[0264] [Table 4]

[0265] Example 19 – Proliferation and cell viability assays of NCI-H226, H23, and H28 Cell proliferation of the TEAD-dependent NF2-null mesothelioma cell line, NCI-H226, was assayed using two different protocols. As shown, the results were confirmed in two different TEAD-independent lung cancer cell lines, H23 and H28, used as unresponsive controls.

[0266] a) CellTiter-Glo® 2.0 (Promega #G9243). The effects of the TEAD inhibitors disclosed herein on cell proliferation were determined on the TEAD1 genetically dependent cell line NCI-H226 (responder cell line) and a TEAD-independent cell line (NCI-H23, HEK293T) as a non-responder negative control. Cells were seeded at 800 (NCI-H226 and HEK-293T) or 2,000 (NCI-H23) cells per well in growth medium (RPMI-1640, Gibco #61870-010) for NCI-H226 and NCI-H23, or DMEM containing 10% heat-inactivated fetal bovine serum (Gibco #31966-021, HEK293T) in a 96-well plate (Thermo Scientific #167008) at 37°C, 5% CO2, in a humidified incubator. After 24 h, fresh growth medium containing test compound or DMSO vehicle was added and incubated with the cells for 144 h. TEAD inhibitor stocks were made at a 1,000-fold overdose in DMSO, and a dose-response test compound was used over a dose range of 10,000 to 0.1 nM. Each treatment was performed in triplicate. After 144 hours of treatment, relative cell viability was determined using the CellTiter-Glo 2.0 assay according to the manufacturer's instructions. The test plate and CellTiter-Glo 2.0 reagent were equilibrated at room temperature. The CellTiter-Glo 2.0 reagent was added to the 96-well cell plate at a 1:1 reagent-to-media ratio, and the plate was placed on a plate shaker for 2 minutes, then incubated at room temperature for an additional 10 minutes to allow for complete cell lysis. The mixture was then transferred to a white 96-well luminometer assay plate (Greiner Bio One #655075). Luminescence was quantified using a CLARIOStar Plus multimode plate reader (BMG Labtech) in luminescence detection mode with the recommended settings (ultra-Glo preset: emission 545-50 nm, with autofocus and enhanced dynamic range on). Relative cell density was expressed as a function of inhibitor concentration relative to DMSO-only control wells. Plot the data using GraphPad Prism and calculate the IC for biological effect.50 Values were calculated as EC using a sigmoidal, 4-parameter logistic least-squares fit. 50 Calculated using a nonlinear fitting function.

[0267] b) Cell Titer One (Promega, #G3582). The effects of the TEAD inhibitors disclosed herein on cell proliferation were further determined using Promega Substrate Cell Titer Aqueous One Solution Reagent. TEAD inhibitors were evaluated for their effects on responding cancer cell lines (H226) and non-responding negative control cancer cell lines (CAMA1, H28) on cell proliferation, as well as non-transformed normal human cells (HUVEC, NHDF). Dissociated cells were resuspended in culture medium (DMEM, RPMI, or EMEM, depending on the cell line, all containing 10% FBS and gentamicin as an antibiotic). Cells were plated at 100 μL / well in 96-well plates at 750 cells per well and allowed to attach. After 24 hours of incubation (37°C, 5% CO2, humidified incubator), 100 μL of test compound-containing culture medium was added. A dilution series of 2000x concentrated stocks of test compounds was prepared in DMSO, with final concentrations ranging from 0.1 to 10,000 nM. After the addition of test compound-containing medium, cells were incubated at 37°C, 5% CO2, in a humidified incubator for 6 days. To measure cell density, Promega Substrate Cell Titer 96 Aqueous One Solution Reagent (Promega, #G3582) was added to each well according to the manufacturer's instructions. After incubation of the plate at 37°C for typically 3–8 hours, control wells (containing no compound) reached an OD of 1.5 at 490 nm. OD was measured using a Vmax [Molecular Devices] spectrophotometer plate reader. Medium-only wells served as background controls, and cell densities were normalized to the DMSO vehicle control. EC 50 was taken as the concentration achieving 50% of optimal growth inhibition.

[0268] I C50 and EC 50 In the data, "A" indicates a value less than 0.2 μM, the symbol "B" indicates a value in the range of 0.2 μM to 1 μM, and the symbol "C" indicates a value greater than 1 μM. ND: No data available.

[0269] [Table 5]

[0270] [Table 6]

[0271] Example 20 – Mero14 proliferation and cell viability assay Mero14 cells were trypsinized, counted, and seeded at 400 cells per well in 200 μl of growth medium in 96-well flat-bottom tissue culture-treated plates. Seeded cells were incubated overnight at 37°C and 5% CO2 before compound treatment in triplicate for each assay time point. 50 μl of serially diluted compound was added to each well, resulting in a final DMSO concentration of 0.5% per well and a total volume of 250 μl per well. Treated cells were incubated at 37°C and 5% CO2 for 144 hours (6 days). After compound treatment, remaining viable cells were detected using the Promega CellTiter-Glo 2.0 assay as follows: 150 μl of medium was removed from each well and assayed, and 100 μl of room-temperature CellTiter-Glo 2.0 reagent was added. Plates were placed on an orbital shaker at 500 rpm for 2 minutes at room temperature, then incubated at room temperature for an additional 10 minutes without shaking. 150 μl of cell lysate was removed from each well and dispensed into one well of a white, opaque 96-well plate. Emission was read at 545 nm using a BMG CLARIOstar plate reader. The luminescence signal was directly proportional to the number of viable cells, and the percent viable cells relative to the DMSO control were calculated for each assay time point. Viability relative to the DMSO control was plotted against compound concentration, and the curves were fitted to a nonlinear regression using GraphPad Prism software. EC50 and absolute IC 50 Values were calculated using GraphPad Prism software as follows: EC 50 For values, an unrestricted 4-parameter logistic curve fit was used (sigmoidal, 4PL, X is the concentration). Absolute IC 50 For values, the baseline was constrained to Y=0 and the top to 100 (absolute IC 50 , where X is the concentration). Area Under the Curve (AUC): Prism calculated the area under the curve by the trapezoidal method. In this analysis, the fitted curve is considered as a simple series of connected XY points. Prism calculates the area under the "curve" defined by simply connecting the points with straight lines. The units of AUC are the units of the Y axis multiplied by the units of the X axis.

[0272] EC 50 In the data, the symbol "A" indicates a value less than 0.2 μM, the symbol "B" indicates a value in the range of 0.2 μM to 1 μM, and the symbol "C" indicates a value greater than 1 μM.

[0273] [Table 7]

[0274] Example 21 –Mero82 proliferation and cell viability assay Mero82 cells were trypsinized, counted, and seeded at 400 cells per well in 200 μl of growth medium in 96-well flat-bottom tissue culture-treated plates. Seeded cells were incubated overnight at 37°C and 5% CO2 before compound treatment in triplicate for each assay time point. 50 μl of serially diluted compound was added to each well, resulting in a final DMSO concentration of 0.5% per well and a total volume of 250 μl per well. Treated cells were incubated at 37°C and 5% CO2 for 144 hours (6 days). After compound treatment, remaining viable cells were detected using the Promega CellTiter-Glo 2.0 assay as follows: 150 μl of medium was removed from each well and assayed, and 100 μl of room-temperature CellTiter-Glo 2.0 reagent was added. Plates were placed on an orbital shaker at 500 rpm at room temperature for 2 minutes, then incubated at room temperature for an additional 10 minutes without shaking. 150 μl of cell lysate was removed from each well and dispensed into one well of a white, opaque 96-well plate. Emission was read at 545 nm using a BMG CLARIOstar plate reader. The luminescence signal was directly proportional to the number of viable cells, and the percent viable cells relative to the DMSO control were calculated for each assay time point. Viability relative to the DMSO control was plotted against compound concentration, and the curves were fitted to a nonlinear regression using GraphPad Prism software. EC 50 and absolute IC 50 Values were calculated using GraphPad Prism software as follows: EC 50 For values, an unrestricted 4-parameter logistic curve fit was used (sigmoidal, 4PL, X is the concentration). Absolute IC 50 For values, the baseline was constrained to Y=0 and the top to 100 (absolute IC 50 , where X is the concentration). Area Under the Curve (AUC): Prism calculates the area under the curve by the trapezoidal method. In this analysis, the fitted curve is considered as a simple series of connected XY points. Prism calculates the area under the "curve" defined by simply connecting the points with straight lines. The units of AUC are the units of the Y axis multiplied by the units of the X axis.

[0275] EC 50 In the data, the symbol "A" indicates a value less than 0.2 μM, the symbol "B" indicates a value in the range of 0.2 μM to 1 μM, and the symbol "C" indicates a value greater than 1 μM.

[0276] [Table 8]

[0277] Example 22 – BHY proliferation and cell viability assay BHY cells were trypsinized, counted, and seeded at 2500 cells per well in 200 μl of growth medium in 96-well flat-bottom tissue culture-treated plates. Seeded cells were incubated overnight at 37°C and 5% CO2 before compound treatment in triplicate for each assay time point. 50 μl of serially diluted compound was added to each well, resulting in a final DMSO concentration of 0.5% per well and a total volume of 250 μl per well. Treated cells were incubated at 37°C and 5% CO2 for 144 hours (6 days). After compound treatment, remaining viable cells were detected using the Promega CellTiter-Glo 2.0 assay as follows: 150 μl of medium was removed from each well and assayed, and 100 μl of room-temperature CellTiter-Glo 2.0 reagent was added. Plates were placed on an orbital shaker at 500 rpm and room temperature for 2 minutes, then incubated at room temperature without shaking for an additional 10 minutes. 150 μl of cell lysate was removed from each well and dispensed into one well of a white, opaque 96-well plate. Emission was read at 545 nm using a BMG CLARIOstar plate reader. The luminescence signal was directly proportional to the number of viable cells, and the percent viable cells relative to the DMSO control were calculated for each assay time point. Viability relative to the DMSO control was plotted against compound concentration, and the curves were fitted to a nonlinear regression using GraphPad Prism software. EC 50 and absolute IC 50 Values are calculated using GraphPad Prism software as follows: EC 50For values, an unrestricted 4-parameter logistic curve fit was used (sigmoidal, 4PL, X is the concentration). Absolute IC 50 For values, the baseline was constrained to Y=0 and the top to 100 (absolute IC 50 , where X is the concentration). Area Under the Curve (AUC): Prism calculates the area under the curve by the trapezoidal method. In this analysis, the fitted curve is considered as a simple series of connected XY points. Prism calculates the area under the "curve" defined by simply connecting the points with straight lines. The units of AUC are the units of the Y axis multiplied by the units of the X axis.

[0278] EC 50 In the data, the symbol "A" indicates a value less than 0.2 μM, the symbol "B" indicates a value in the range of 0.2 μM to 1 μM, and the symbol "C" indicates a value greater than 1 μM.

[0279] [Table 9]

[0280] Example 23 – Proliferation and cell viability assay of LOU-NH91 LOU-NH91 cells were trypsinized and counted, and 1,000 cells were seeded per well in 200 μl of growth medium in a 96-well, flat-bottom, tissue-culture-treated plate. Seeded cells were incubated overnight at 37°C and 5% CO2 before compound treatment in triplicate for each assay time point. 50 μl of serially diluted compound was added to each well, resulting in a final DMSO concentration of 0.5% per well and a total volume of 250 μl per well. Treated cells were incubated at 37°C and 5% CO2 for 216 hours (9 days). After compound treatment, remaining viable cells were detected using the Promega CellTiter-Glo 2.0 assay as follows: 150 μl of medium was removed from each well and assayed, and 100 μl of room-temperature CellTiter-Glo 2.0 reagent was added. The plate was placed on an orbital shaker at 500 rpm for 2 minutes at room temperature, then incubated at room temperature for an additional 10 minutes without shaking. 150 μl of cell lysate was removed from each well and dispensed into one well of a white, opaque 96-well plate. Emission was read at 545 nm using a BMG CLARIOstar plate reader. The luminescence signal was directly proportional to the number of viable cells, and the percent viable cells relative to the DMSO control were calculated for each assay time point. Viability relative to the DMSO control was plotted against compound concentration, and the curves were fitted to a nonlinear regression using GraphPad Prism software. EC 50 and absolute IC 50 Values were calculated using GraphPad Prism software as follows: EC 50 For values, an unrestricted 4-parameter logistic curve fit was used (sigmoidal, 4PL, X is the concentration). Absolute IC 50 For values, the baseline was constrained to Y=0 and the top to 100 (absolute IC 50 , where X is the concentration). Area Under the Curve (AUC): Prism calculates the area under the curve by the trapezoidal method. In this analysis, the fitted curve is considered as a simple series of connected XY points. Prism calculates the area under the "curve" defined by simply connecting the points with straight lines. The units of AUC are the units of the Y axis multiplied by the units of the X axis.

[0281] EC 50 In the data, the symbol "A" indicates a value less than 0.2 μM, the symbol "B" indicates a value in the range of 0.2 μM to 1 μM, and the symbol "C" indicates a value greater than 1 μM.

[0282] [Table 10]

[0283] Example 24 – Proliferation and cell viability assays of MSTO-211H MSTO-211H cells were trypsinized and counted, then seeded at 1500 cells per well in 200 μl of growth medium in 96-well flat-bottom tissue culture-treated plates. Seeded cells were incubated overnight at 37°C and 5% CO2 before compound treatment in triplicate for each assay time point. 50 μl of serially diluted compound was added to each well, resulting in a final DMSO concentration of 0.5% per well and a total volume of 250 μl per well. Treated cells were incubated at 37°C and 5% CO2 for 144 hours (6 days). After compound treatment, remaining viable cells were detected using the Promega CellTiter-Glo 2.0 assay as follows: 150 μl of medium was removed from each well and assayed, and 100 μl of room-temperature CellTiter-Glo 2.0 reagent was added. Plates were placed on an orbital shaker at 500 rpm for 2 minutes at room temperature, then incubated at room temperature for an additional 10 minutes without shaking. 150 μl of cell lysate was removed from each well and dispensed into one well of a white, opaque 96-well plate. Emission was read at 545 nm using a BMG CLARIOstar plate reader. The luminescence signal was directly proportional to the number of viable cells, and the percent viable cells relative to the DMSO control were calculated for each assay time point. Viability relative to the DMSO control was plotted against compound concentration, and the curves were fitted to a nonlinear regression using GraphPad Prism software. EC 50 and absolute IC 50 Values were calculated using GraphPad Prism software as follows: EC 50For values, an unrestricted 4-parameter logistic curve fit was used (sigmoidal, 4PL, X is the concentration). Absolute IC 50 For values, the baseline was constrained to Y=0 and the top to 100 (absolute IC 50 , where X is the concentration). Area Under the Curve (AUC): Prism calculates the area under the curve by the trapezoidal method. In this analysis, the fitted curve is considered as a simple series of connected XY points. Prism calculates the area under the "curve" defined by simply connecting the points with straight lines. The units of AUC are the units of the Y axis multiplied by the units of the X axis.

[0284] EC 50 In the data, the symbol "A" indicates a value less than 0.2 μM, the symbol "B" indicates a value in the range of 0.2 μM to 1 μM, and the symbol "C" indicates a value greater than 1 μM.

[0285] [Table 11]

[0286] Example 25 – SDM103T2 proliferation and cell viability assays SDM103T2 cells were trypsinized and counted, and 800 cells were seeded per well in 200 μl of growth medium in 96-well flat-bottom tissue culture-treated plates. Seeded cells were incubated overnight at 37°C and 5% CO2 before compound treatment in triplicate for each assay time point. 50 μl of serially diluted compound was added to each well, resulting in a final DMSO concentration of 0.5% per well and a total volume of 250 μl per well. Treated cells were incubated at 37°C and 5% CO2 for 144 hours (6 days). After compound treatment, remaining viable cells were detected using the Promega CellTiter-Glo 2.0 assay as follows: 150 μl of medium was removed from each well and assayed, and 100 μl of room-temperature CellTiter-Glo 2.0 reagent was added. Plates were placed on an orbital shaker at 500 rpm at room temperature for 2 minutes, then incubated at room temperature without shaking for an additional 10 minutes. 150 μl of cell lysate was removed from each well and dispensed into one well of a white, opaque 96-well plate. Emission was read at 545 nm using a BMG CLARIOstar plate reader. The luminescence signal was directly proportional to the number of viable cells, and the percent viable cells relative to the DMSO control were calculated for each assay time point. Viability relative to the DMSO control was plotted against compound concentration, and the curves were fitted to a nonlinear regression using GraphPad Prism software. EC 50 and absolute IC 50 Values were calculated using GraphPad Prism software as follows: EC 50 For values, an unrestricted 4-parameter logistic curve fit was used (sigmoidal, 4PL, X is the concentration). Absolute IC 50 For values, the baseline was constrained to Y=0 and the top to 100 (absolute IC 50 , where X is the concentration). Area Under the Curve (AUC): Prism calculates the area under the curve by the trapezoidal method. In this analysis, the fitted curve is considered as a simple series of connected XY points. Prism calculates the area under the "curve" defined by simply connecting the points with straight lines. The units of AUC are the units of the Y axis multiplied by the units of the X axis.

[0287] EC 50 In the data, the symbol "A" indicates a value less than 0.2 μM, the symbol "B" indicates a value in the range of 0.2 μM to 1 μM, and the symbol "C" indicates a value greater than 1 μM.

[0288] [Table 12]

[0289] Example 26 – Thermal shift assay (TSA) of TEAD The thermal shift assay (TSA) is a biophysical method for assessing protein stability by temperature change. This assay measures the thermal denaturation temperature under various conditions, such as different drug concentrations. In this example, a fluorescent dye that binds to unfolded proteins was used. SYPRO Orange binds nonspecifically to hydrophobic surfaces, and water strongly quenches its fluorescence. When a protein is unfolded, exposed hydrophobic surfaces bind to the dye, resulting in increased fluorescence by excluding water. Detergent micelles also bind to the dye, dramatically increasing background noise. Small molecule binding to proteins stabilizes them against thermal denaturation, and the degree of thermal stability is proportional to the binding strength.

[0290] In the study described in this example, we investigated the change in melting temperature (ΔTm) of TEAD isoforms 1 to 4 upon treatment with TEAD inhibitors. Compound 1-1, a known potent TEAD1 and weak TEAD2 inhibitor, as well as compound 1-4, a pan-TEAD inhibitor, were used as controls. As expected, compound 1-1 showed a significant thermal shift only for TEAD1, whereas compound 1-4 showed thermal shifts for all four TEAD isoforms. As shown in Table 12, compound 5 exhibited strong TEAD1 and TEAD4 binding.

[0291] [Table 13]

[0292] [Table 14]

[0293] Tris-HCl was dissolved in 5 mL of cell culture grade water until completely dissolved. The pH was adjusted to 8 using NaOH. Additional assay buffer components were added in the order listed above. The buffer was mixed gently.

[0294] Assay flow Assay buffer was prepared according to the procedure outlined above and dispensed into the test wells. Spyro orange was added to the assay buffer at a 5x concentration, followed by the addition of a stock solution of the test compound to the assay buffer at a concentration of 10 μM or 30 μM.

[0295] Lysis cycles were performed in a Bio-RAD PCR instrument from 20 to 95°C with a ramp rate of 1°C / min.

[0296] The thermal shift data are shown in Table 12.

[0297] [Table 15]

[0298] Example 27 –Inhibition of mouse xenograft MSTO-211H tumors by TEAD inhibitors This study evaluated the in vivo antitumor efficacy of the test compounds in BALB / c nude mice in the treatment of MSTO-211H xenografts of lung cancer. Abbreviation AAALAC (Association for Assessment and Accreditation of Laboratory Animal Care International) BW Body Weight g grams IACUC Institutional Animal Care and Use Committee kg kilogram mg milligram mL milliliter mm millimeters PO Oral administration (Per Os) R&D Research and Development RT room temperature RTV relative tumor volume SEM standard error TGI tumor growth inhibition TV tumor volume TW tumor weight μL microliter dd H2O (double distilled water) T / C relative tumor growth rate AA Antibiotic-Antifungal CMC-Na Carbonyl Methylcellulose-Na BID twice a day (Bis in Die) Tween80 Animals and housing conditions Species: House mouse (Mus Musculus) Strain: BALB / c nude Age: 6-8 weeks Gender: Female Weight: 18-22g Number of animals inoculated with tumor: 80 mice Number of animals enrolled in treatment: 36 mice Number of unregistered animals: 44 mice Animal supplier: Beijing Vital River Biotechnology Experimental Animal Co. Ltd Registration number: 20170011010591

[0299] [Table 16]

[0300] [Table 17]

[0301] [Table 18] cell culture MSTO-211H tumor cells were maintained in RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% antibiotic-antimycotic at 37°C in an atmosphere of 5% CO2 in air. Tumor cells were routinely subcultured twice weekly with trypsin-EDTA. Cells growing in exponential growth phase with cell viability of 95% or higher were harvested and counted for tumor inoculation.

[0302] [Table 19]

[0303] Tumor inoculation Each mouse received an injection of MSTO-211H tumor cells (5 × 10 6 + 50% Matrigel / 0.2 mL) was subcutaneously inoculated and tumors were allowed to develop. For identification, animals were given earrings with unique six significant digits. The mean tumor volume was 181 mm 3 Part 1 treatment was initiated 5 days after cell inoculation when the mean tumor volume reached 254 mm 3 The second part of treatment was initiated 16 days after cell inoculation when the mean tumor volume reached 969 mm 3 When the IL-14 expression level reached 1.0, part 3 of treatment was initiated 33 days after cell inoculation.

[0304] Tumor measurements The primary endpoint was to determine whether tumor growth could be slowed. Tumor volume was measured twice weekly in two dimensions using calipers, and volume was calculated in mm using the following formula: 3 Expressed as: V = 0.5a × b 2, where a and b are the long and short diameters of the tumor, respectively. The tumor size was then used to calculate the T / C value. The TGI value (in percent) or T / C value (in percent) is an index of antitumor efficacy, and T and C are the tumor volume or tumor weight, respectively, of the treatment group and the control group on a given day.

[0305] TGI was calculated for each group using the following formula: TGI (%) = [1-(T i -T0) / (V i -V0)] × 100; Ti is the mean tumor volume of the treatment group on a given day, T0 is the mean tumor volume of the treatment group on the day treatment began, and V i is T i V is the mean tumor volume of the vehicle control group on the same day, and V is the mean tumor volume of the vehicle group on the day treatment began.

[0306] Relative T / C(%)=T RTV / C RTV ×100(RTV(%)=V t / V0×100, V t is the mean tumor volume on a given day, and V is the mean tumor volume on the first day of treatment. RTV is the RTV of the treatment group, and C RTV is the RTV of the vehicle control group).

[0307] Vehicle group: 681mm 3 If the antitumor efficacy of the Part 1 study was reached, the antitumor efficacy of PG-D31 was analyzed.

[0308] Vehicle group: 738mm 3 If the antitumor efficacy of the second part of the study was reached, it was analyzed against PG-D30.

[0309] Vehicle group: 1791mm 3 If the antitumor efficacy of the Part 3 study was reached, the antitumor efficacy was analyzed for PG-D13.

[0310] statistical analysis Summary statistics including the mean and standard error (SEM) were provided for tumor volume in each group at each time point.

[0311] Statistical analysis of tumor volume differences between groups was performed on data obtained at the end of the study.

[0312] A one-tailed T-test was performed to compare tumor volumes between the two groups. All data were analyzed using GraphPad Prism 6.0. p<0.05 was considered statistically significant.

[0313] Tumor volume tracking The changes in tumor volume over the study period are shown in Tables 13-15.

[0314] [Table 20]

[0315] [Table 21]

[0316] [Table 22]

[0317] Analysis of tumor growth inhibition TGI in Part 1 was calculated based on tumor volume measurements for PG-D31 after treatment initiation (Table 16).

[0318] TGI in Part 2 was calculated based on tumor volume measurements for PG-D30 after treatment initiation (Table 17).

[0319] The TGI for Part 3 was calculated based on tumor volume measurements for PG-D13 after treatment initiation (Table 18).

[0320] [Table 23]

[0321] [Table 24]

[0322] [Table 25]

[0323] Example 28 – Inhibition of mouse xenograft MSTO-211H tumors by TEAD inhibitors compared to prior art TEAD inhibitors This study evaluated the in vivo antitumor efficacy of the test compounds in BALB / c nude mice in the treatment of MSTO-211H xenografts of lung cancer.

[0324] [Table 26]

[0325] Based on the long half-life of compound 1-1 reported by Tang et al. ("Small Molecule Inhibitors of TEAD Auto-palmitoylation Selectively Inhibit Proliferation and Tumor Growth of NF2-deficient Mesothelioma" by Tang et al., Mol. Cancer Ther., 2021, 20(6):986-998), a dose of compound 1-1 was utilized at 3 mg / kg.

[0326] cell culture MSTO-211H tumor cells were maintained in vitro in RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% antibiotic-antimycotic at 37°C in an atmosphere of 5% CO2 in air. Tumor cells were routinely subcultured twice weekly with trypsin-EDTA. Cells growing in exponential growth phase were harvested and counted for tumor inoculation.

[0327] Tumor inoculation Each mouse was inoculated with MSTO-211H tumor cells (10 × 10 6 + 50% Matrigel / 0.2 mL) was subcutaneously inoculated and tumors were allowed to develop. Starting on day 7 after cell inoculation, test subjects were administered vehicle (e.g., 0.5% CMC-Na + 1% Tween 80). When tumor volume reached 500 mm 3 ~1200mm 3 When the cell count reached 100, treatment was initiated 28 days after cell inoculation.

[0328] [Table 27]

[0329] Tumor measurements The primary endpoint was to determine whether tumor growth could be slowed. Tumor size was measured twice weekly in two dimensions using calipers, and volume was calculated in mm using the following formula: 3 Expressed as: V = 0.5a × b 2 , where a and b are the long and short diameters of the tumor, respectively. The tumor size was then used to calculate the T / C and TGI values.

[0330] The T / C value (in percent) is an index of antitumor efficacy, where T and C are the mean volumes on a given day for the treatment and control groups, respectively.

[0331] statistical analysis Summary statistics, including the mean and standard error of the mean (SEM), were calculated for tumor volume in each group at each time point.

[0332] Statistical analysis of tumor volume differences between groups was performed on data obtained at the end of the study.

[0333] A one-tailed t-test was performed to compare tumor volumes between the two groups. All data were analyzed using GraphPad Prism 6.0. p<0.05 was considered statistically significant.

[0334] Tumor volume tracking Changes in tumor volume were recorded over the study period. The changes in tumor volume 7 days after treatment compared to pre-treatment for each of groups 1 to 3 are shown in Figures 3A and 3B. Figure 3A shows the tumor volume changes for individual test subjects, and Figure 3B shows the average tumor volume changes for each treatment group. Tumor growth was observed in the vehicle and compound 1-1 treatment groups, while tumor reduction was observed in the compound 5 treatment group.

[0335] Example 29 –Inhibition of mouse xenograft NCI-H226 tumors by TEAD inhibitors This study evaluated the in vivo antitumor efficacy of test compounds in NOD SCID mice in the treatment of the NCI-H226 lung tumor model. Abbreviation AAALAC (Association for Accreditation of Laboratory Animal Care International) BW Body Weight g grams IACUC Animal Care and Use Committee kg kilogram mg milligram mL milliliter mm millimeters PO Oral administration R&D Research and Development RT room temperature RTV relative tumor volume SEM standard error TGI tumor growth inhibition TV tumor volume TW tumor weight μL microliter dd H2O double distilled water T / C relative tumor growth rate AA Antibiotic-Antifungal CMC-Na Carbonyl Methylcellulose-Na QD Once a day (Quaque Die) BID twice a day Tween80 Animals and housing conditions Species: House mouse Strain: NOD SCID Age: 6-8 weeks Gender: Female Weight: 18-22g Number of animals inoculated with tumor: 69 mice Number of animals enrolled in treatment: 40 mice Number of unregistered animals: 29 mice Animal supplier: Beijing Vital River Biotechnology Experimental Animal Co. Ltd Registration number: 20221110Abzz0619000681

[0336] [Table 28]

[0337] cell culture NCI-H226 tumor cells were maintained in vitro in RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% antibiotic-antimycotic at 37°C in an atmosphere of 5% CO2 in air. Tumor cells were routinely subcultured twice weekly with trypsin-EDTA. Cells growing in exponential growth phase were harvested and counted for tumor inoculation.

[0338] [Table 29]

[0339] Tumor inoculation Each mouse received an injection of NCI-H226 tumor cells (10 × 10 6 + 50% Matrigel / 0.2 mL) was subcutaneously inoculated and tumors were allowed to develop. For identification, animals were given earrings with unique six significant digits. The mean tumor volume was 154 mm 3 Treatment was initiated when the average size of

[0340] Tumor measurements The primary endpoint was to determine whether tumor growth could be slowed or whether mice could be cured. Tumor volume was measured twice weekly in two dimensions using calipers, and volume was calculated in mm using the following formula: 3 Expressed as: V = 0.5a × b 2 , where a and b are the long and short diameters of the tumor, respectively. The tumor size was then used to calculate the T / C value. The TGI value (in percent) or T / C value (in percent) is an index of antitumor efficacy, and T and C are the tumor volume or tumor weight, respectively, of the treatment group and the control group on a given day.

[0341] TGI was calculated for each group using the following formula: TGI (%) = [1-(T i -T0) / (V i -V0)]×100;T i is the mean tumor volume of the treatment group on a given day, T is the mean tumor volume of the treatment group on the day treatment began, and V i is T i V is the mean tumor volume of the vehicle control group on the same day, and V is the mean tumor volume of the vehicle group on the day treatment began.

[0342] Relative T / C(%)=T RTV / C RTV ×100(RTV(%)=V t / V0×100, V t is the mean tumor volume on a given day, and V is the mean tumor volume on the first day of treatment. RTV is the RTV of the treatment group, and C RTV is the RTV of the vehicle control group).

[0343] Tumor weights were measured at the end of the study. weight / C weight The value (in percent) is calculated using the formula: T weight / C weight (%)=TW treatment / TW vehicle ×100, where T and C are the mean tumor weights of the treated and control groups, respectively.

[0344] statistical analysis Summary statistics including the mean and standard error (SEM) were provided for tumor volume in each group at each time point.

[0345] Statistical analysis of tumor volume differences between groups was performed on data obtained at the end of the study.

[0346] A one-tailed T-test was performed to compare tumor volumes between the two groups. All data were analyzed using GraphPad Prism 6.0. p<0.05 was considered statistically significant.

[0347] Vehicle group: 472mm 3 If the antitumor efficacy of the study was reached, the study was analyzed against PG-D28.

[0348] Tumor volume tracking The change in tumor volume over the study period is shown in Table 19.

[0349] [Table 30]

[0350] Analysis of tumor growth inhibition The rate of tumor growth inhibition of the test compound was calculated based on tumor volume measurements 28 days after the start of treatment. The T / C values calculated by tumor volume were close to each other, and the trends are shown in Table 20.

[0351] [Table 31]

Claims

1. Chemical formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein X is NR ａ , O, and S; R １ is a 5-10 membered heteroaryl having 1, 2, 3, or 4 heteroatoms, each independently selected from the group consisting of N, O, and S, wherein said 5-10 membered heteroaryl is optionally substituted; R ２ is a 3- to 10-membered heterocyclyl or -(C １ -C ４ alkylene)-(3- to 10-membered heterocycloalkyl), each of which has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, and is optionally substituted; １ -C ４ The alkylene is optionally substituted; R ３ａ and R ３ｂ One of them is halogen, -C １ -C ６ Alkyl, —C １ -C ６ haloalkyl, —O—(C １ -C ６ alkyl), —O—(C １ -C ６ haloalkyl), C ３－１０ is selected from the group consisting of cycloalkyl, phenyl, naphthyl, and 5- to 10-membered heteroaryl; ３－１０ Cycloalkyl, said phenyl, said naphthyl, and said 5- to 10-membered heteroaryl are optionally substituted, and R ３ａ and R ３ｂ The remainder are hydrogen, halogen, and -C １ -C ６ is selected from the group consisting of alkyl, R ４ are each independently a halogen and —C １ -C ６ alkyl, R ５ are each independently a halogen and —C １ -C ６ alkyl, m is selected from the group consisting of 0, 1, 2, and 3; n is selected from the group consisting of 0, 1, 2, and 3; R ａ is hydrogen and -C １ -C ６ selected from alkyl, The compound, or a pharmaceutically acceptable salt thereof.

2. Chemical formula (I'): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, wherein X is NR ａ , O, and S; R １ is a 5-10 membered heteroaryl having 1, 2, 3, or 4 heteroatoms, each independently selected from the group consisting of N, O, and S, wherein said 5-10 membered heteroaryl is optionally substituted; R ２ is a 3- to 10-membered heterocyclyl or -(C １ -C ４ alkylene)-(3- to 10-membered heterocyclyl), wherein said 3- to 10-membered heterocyclyl contains at least two carbon atoms and 1, 2, 3, or 4 heteroatoms and is optionally substituted, wherein said heteroatom is nitrogen; C １ -C ４ The alkylene is optionally substituted; R ３ａ and R ３ｂ One of them is halogen, -C １ -C ６ Alkyl, —C １ -C ６ haloalkyl, —O—(C １ -C ６ alkyl), —O—(C １ -C ６ haloalkyl), C ３－１０ is selected from the group consisting of cycloalkyl, phenyl, naphthyl, and 5- to 10-membered heteroaryl; ３－１０ Cycloalkyl, said phenyl, said naphthyl, and said 5- to 10-membered heteroaryl are optionally substituted, and R ３ａ and R ３ｂ The remainder are hydrogen, halogen, and -C １ -C ６ is selected from the group consisting of alkyl, R ４ are each independently a halogen and —C １ -C ６ alkyl, R ５ are each independently a halogen and —C １ -C ６ alkyl, m is selected from the group consisting of 0, 1, 2, and 3; n is selected from the group consisting of 0, 1, 2, and 3; R ａ is hydrogen and -C １ -C ６ selected from alkyl, The compound, or a pharmaceutically acceptable salt thereof.

3. Chemical formula (I-1): 【Chemistry 3】 or a pharmaceutically acceptable salt thereof, wherein X is NR ａ , O, and S; R １ is a 5-10 membered heteroaryl having 1, 2, 3, or 4 heteroatoms, each independently selected from the group consisting of N, O, and S, wherein said 5-10 membered heteroaryl is optionally substituted; R ２ is a 3- to 10-membered heterocyclyl or -(C １ -C ４ alkylene)-(3- to 10-membered heterocyclyl), each of which contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, and is optionally substituted; １ -C ４ The alkylene is optionally substituted; R ３ is a halogen, -C １ -C ６ Alkyl, —C １ -C ６ haloalkyl, —O—(C １ -C ６ alkyl), —O—(C １ -C ６ haloalkyl), C ３－１０ is selected from the group consisting of cycloalkyl, phenyl, naphthyl, and 5- to 10-membered heteroaryl; ３－１０ cycloalkyl, said phenyl, said naphthyl, and said 5- to 10-membered heteroaryl are optionally substituted; R ４ are each independently a halogen and —C １ -C ６ alkyl, R ５ are each independently a halogen and —C １ -C ６ alkyl, m is selected from the group consisting of 0, 1, 2, 3, and 4; n is selected from the group consisting of 0, 1, 2, and 3; R ａ is hydrogen and -C １ -C ６ selected from alkyl, The compound, or a pharmaceutically acceptable salt thereof.

4. Chemical formula (I-1'): 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, wherein X is NR ａ , O, and S; R １ is a 5-10 membered heteroaryl having 1, 2, 3, or 4 heteroatoms, each independently selected from the group consisting of N, O, and S, wherein said 5-10 membered heteroaryl is optionally substituted; R ２ is a 3- to 10-membered heterocyclyl or -(C １ -C ４ alkylene)-(3- to 10-membered heterocyclyl), wherein said 3- to 10-membered heterocyclyl contains at least two carbon atoms and 1, 2, 3, or 4 heteroatoms and is optionally substituted, wherein said heteroatom is nitrogen; C １ -C ４ The alkylene is optionally substituted; R ３ is a halogen, -C １ -C ６ Alkyl, —C １ -C ６ haloalkyl, —O—(C １ -C ６ alkyl), —O—(C １ -C ６ haloalkyl), C ３－１０ is selected from the group consisting of cycloalkyl, phenyl, naphthyl, and 5- to 10-membered heteroaryl; ３－１０ cycloalkyl, said phenyl, said naphthyl, and said 5- to 10-membered heteroaryl are optionally substituted; R ４ are each independently a halogen and —C １ -C ６ alkyl, R ５ are each independently a halogen and —C １ -C ６ alkyl, m is selected from the group consisting of 0, 1, 2, 3, and 4; n is selected from the group consisting of 0, 1, 2, and 3; R ａ is hydrogen and -C １ -C ６ selected from alkyl, The compound, or a pharmaceutically acceptable salt thereof.

5. X is NR ａ 5. The compound according to any one of claims 1 to 4, wherein:

6. The compound has the formula (Ia): 【Chemistry 5】 or a pharmaceutically acceptable salt thereof, wherein R ３ is -C １ -C ６ Alkyl or -C １ -C ６ is haloalkyl, The remaining variables are as defined in claim 1.

4. A compound according to claim 1 or 3, or a pharmaceutically acceptable salt thereof.

7. The compound has the formula (Ia'): 【Chemistry 6】 or a pharmaceutically acceptable salt thereof, wherein R ３ is -C １ -C ６ Alkyl or -C １ -C ６ is haloalkyl, The remaining variables are as defined in claim 2.

5. A compound according to claim 2 or 4, or a pharmaceutically acceptable salt thereof.

8. R １ 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein is optionally substituted 5-6 membered heteroaryl.

9. R １ However, each １ -C ６ Alkyl, halogen, C １ -C ６ haloalkyl, —O—(C １ -C ６ alkyl), —O—(C １ -C ６ haloalkyl), and —N(R ｂ ) ２ and R is a 5- to 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of ｂ are each independently hydrogen and C １ -C ６ 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein:

10. R １ are halogen and -C, respectively. １ -C ６ 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, which is a 5-6 membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents selected from alkyl.

11. R １ is a 5- to 6-membered heteroaryl selected from the group consisting of oxadiazole, imidazole, pyrazole, oxazole, triazole, tetrazole, pyridine, pyrazine, and pyridazine, and each of said 5- to 6-membered heteroaryls is selected from the group consisting of C １ -C ６ Alkyl, halogen, C １ -C ６ haloalkyl, —O—(C １ -C ６ alkyl), —O—(C １ -C ６ haloalkyl), and —N(R ｂ ) ２ and R is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of ｂ are each independently hydrogen and C １ -C ６ 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein:

12. R １ is a 5- to 6-membered heteroaryl selected from the group consisting of oxadiazole, imidazole, pyrazole, oxazole, triazole, tetrazole, pyridine, pyrazine, and pyridazine, and said 5- to 6-membered heteroaryl is １ -C ６ 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, optionally substituted with alkyl.

13. R １ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein is imidazole optionally substituted with methyl.

14. R １ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein is oxazole.

15. R １ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein is tetrazole optionally substituted with methyl.

16. R １ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein is an oxadiazole optionally substituted with methyl, such as 1,3,4-oxadiazole.

17. The compound has the formula (Ib): 【Chemistry 7】 or a pharmaceutically acceptable salt thereof, wherein R ｄ is hydrogen and -C １ -C ６ alkyl, The remaining variables are as defined in claim 6.

10. A compound according to any one of claims 1, 3, and 6, or a pharmaceutically acceptable salt thereof.

18. The compound has the formula (Ib'): 【Chemistry 8】 or a pharmaceutically acceptable salt thereof, wherein R ｄ is hydrogen and -C １ -C ６ alkyl, The remaining variables are as defined in claim 7.

8. A compound according to any one of claims 2, 4, and 7, or a pharmaceutically acceptable salt thereof.

19. The compound has formula (Ic): 【Chemistry 9】 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 17, or a pharmaceutically acceptable salt thereof.

20. The compound has the formula (Ic'): 【Chemistry 10】 19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 18, or a pharmaceutically acceptable salt thereof.

21. R ２ is a 3- to 7-membered monocyclic heterocyclyl or -(C １ -C ４ alkylene)-(3- to 7-membered monocyclic heterocyclyl), wherein said 3- to 7-membered monocyclic heterocyclyl contains at least 2 carbon atoms and 1, 2, 3, or 4 heteroatoms, wherein said heteroatom is nitrogen, and said 3- to 7-membered monocyclic heterocyclyl is optionally substituted; C １ -C ４ The alkylene is optionally substituted (e.g., C １－６ Alkyl, C １－６ optionally substituted with haloalkyl, or １－４ 21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein two geminal hydrogens on the alkylene carbon can, together with the carbon atoms to which they are attached, form a 3- to 7-membered cycloalkyl ring.

22. R ２ is a 3- to 7-membered monocyclic heterocyclyl or -(C １ -C ４ alkylene)-(3- to 7-membered monocyclic heterocyclyl), wherein said 3- to 7-membered monocyclic heterocyclyl contains at least 2 carbon atoms and 1, 2, 3, or 4 heteroatoms, said heteroatoms being nitrogen, and said 3- to 7-membered monocyclic heterocyclyl is each C １ -C ６ Alkyl, oxo, hydroxyl, halogen, C １ -C ６ haloalkyl, —O—(C １ -C ６ alkyl), —O—(C １ -C ６ haloalkyl), -N(R ｂ ) ２ , -C(O)OR ｇ , -C(O)N(R ｆ ) ２ , -S(O) ２ N (R ｆ ) ２ , -OC(O)N(R ｆ ) ２ , -NR ｆ C(O)N(R ｆ ) ２ , and -S(O) ｒ -R ｆ and R is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of ｂ , R ｇ , and R ｆ each independently selected from hydrogen and C １ -C ６ alkyl, each r is 1 or 2, and R ｆ However, each independently, C １ -C ６ 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein said alkyl is selected from alkyl and phenyl.

23. R ２ is a 3- to 7-membered monocyclic heterocyclyl, said 3- to 7-membered monocyclic heterocyclyl containing at least 2 carbon atoms and 1, 2, 3, or 4 heteroatoms, said heteroatoms being nitrogen, and said 3- to 7-membered monocyclic heterocyclyl is independently selected from halogen, —C １ -C ６ 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of alkyl, oxo, and hydroxyl.

24. R ２ is a 5-membered heterocyclyl having 1 or 2 heteroatoms, wherein the heteroatom is a nitrogen atom, and the 5-membered heterocyclyl is each １ -C ６ 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, oxo, and hydroxyl.

25. R ２ But -(C １ -C ４ alkylene)-(5-membered heterocyclyl having 1 or 2 heteroatoms), wherein the heteroatom is a nitrogen atom, and the 5-membered heterocyclyl is each C １ -C ６ 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, oxo, and hydroxyl.

26. R ２ but, 【Chemistry 11】 23. The compound of any one of claims 1 to 22, wherein t is selected from the group consisting of 0, 1, 2, and 3, or a pharmaceutically acceptable salt thereof.

27. R ２ but, 【Chemistry 12】 23. The compound of any one of claims 1 to 22, wherein t is selected from the group consisting of 0, 1, 2, and 3, or a pharmaceutically acceptable salt thereof.

28. 28. The compound of claim 26 or 27, or a pharmaceutically acceptable salt thereof, wherein t is 1.

29. R ２ but, 【Chemistry 13】 wherein s is selected from the group consisting of 0, 1, 2, and 3; ｅ is hydrogen and C １ -C ６ 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, selected from alkyl.

30. s is 0 and R ｅ 30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein is methyl.

31. R ２ but, 【Chemistry 14】 wherein u is selected from the group consisting of 0, 1, 2, and 3; ｅ is hydrogen and C １ -C ６ 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, selected from alkyl.

32. R ２ but, 【Chemistry 15】 wherein u is selected from the group consisting of 0, 1, 2, and 3; ｅ is hydrogen and C １ -C ６ 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, selected from alkyl.

33. R ２ but, 【Chemistry 16】 wherein u is selected from the group consisting of 0, 1, 2, and 3; ｅ is hydrogen and C １ -C ６ 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, selected from alkyl.

34. u is 0 and R ｅ 34. The compound of any one of claims 31 to 33, or a pharmaceutically acceptable salt thereof, wherein is methyl.

35. The compound has the formula (Id): 【Chemistry 17】 or a pharmaceutically acceptable salt thereof, wherein R ３ is -C １ -C ６ Alkyl or -C １ -C ６ is haloalkyl, The remaining variables are as defined in claim 6.

32. A compound according to any one of claims 1 to 24 and 31, or a pharmaceutically acceptable salt thereof.

36. The compound has the formula (Ie): 【Chemistry 18】 36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 35.

37. R １ 37. The compound of any one of claims 1 to 10 and 21 to 36, or a pharmaceutically acceptable salt thereof, wherein contains at least one ring carbon atom and contains only carbon and nitrogen atoms.

38. R ３ But C １ -C ６ Alkyl or -C １ -C ６ 38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

39. R ３ 39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein is halogen.

40. R ３ 40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein is trifluoromethyl.

41. 41. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein m and n are both 0.

42. R ａ 42. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

43. 43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Table 1 or a pharmaceutically acceptable salt thereof.

44. 44. A pharmaceutical composition comprising: (a) a compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient.

45. 45. A method for treating a disease or disorder mediated by overactivation of a TEAD isoform selected from TEAD1 and TEAD4 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 44.

46. 46. The method of claim 45, wherein the disease or condition is cancer characterized by hyperactivation of a TEAD isoform selected from TEAD1 and TEAD4.

47. 47. The method of claim 46, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, gastric cancer, colorectal cancer, pancreatic cancer including pancreatic adenocarcinoma, mesothelioma including malignant mesothelioma, hepatocellular carcinoma, prostate cancer, head and neck cancer, renal cell carcinoma, and medulloblastoma.

48. 48. The method of claim 47, wherein the pancreatic cancer is pancreatic adenocarcinoma.

49. 48. The method of claim 47, wherein the mesothelioma is malignant mesothelioma.

50. 48. The method of claim 46 or 47, wherein the cancer is selected from the group consisting of hepatocellular carcinoma, breast cancer, pancreatic adenocarcinoma, and mesothelioma.

51. 51. The method of any one of claims 46, 47, and 50, wherein the cancer is mesothelioma.

52. The method of any one of claims 46 to 51, wherein the cancer is a metastatic cancer.

53. 53. The method of claim 52, wherein the cancer is metastatic breast cancer.

54. 53. The method of claim 52, wherein the cancer is metastatic lung cancer.

55. 53. The method of claim 52, wherein the cancer is metastatic gastric cancer.

56. 53. The method of claim 52, wherein the cancer is metastatic colorectal cancer.

57. 53. The method of claim 52, wherein the cancer is metastatic prostate cancer.

58. 53. The method of claim 52, wherein the cancer is metastatic head and neck cancer.

59. 53. The method of claim 52, wherein the cancer is metastatic renal cell carcinoma.

60. 53. The method of claim 52, wherein the cancer is metastatic mesothelioma.

61. 53. The method of claim 52, wherein the cancer is metastatic pancreatic cancer.

62. 53. The method of claim 52, wherein the cancer is metastatic hepatocellular carcinoma.

63. 63. The method of any one of claims 45 to 62, wherein the therapeutically effective amount of the compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 44, is administered in combination with one or more other therapeutic agents.

64. 45. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 44, for use in treating a disease or disorder mediated by overactivation of a TEAD isoform selected from TEAD1 and TEAD4 in a subject in need thereof.

65. 65. The compound of claim 64, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, wherein the disease or condition is cancer characterized by overactivation of a TEAD isoform selected from TEAD1 and TEAD4.

66. 66. The compound of claim 65, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, gastric cancer, colorectal cancer, pancreatic cancer including pancreatic adenocarcinoma, mesothelioma including malignant mesothelioma, hepatocellular carcinoma, prostate cancer, head and neck cancer, renal cell carcinoma, and medulloblastoma.

67. Use of a compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 44, in the manufacture of a medicament for treating a disease or disorder mediated by overactivation of a TEAD isoform selected from TEAD1 and TEAD4 in a subject in need thereof.

68. 68. The use of claim 67, wherein the disease or condition is cancer characterized by hyperactivation of a TEAD isoform selected from TEAD1 and TEAD4.

69. 69. The use of claim 68, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, gastric cancer, colorectal cancer, pancreatic cancer including pancreatic adenocarcinoma, mesothelioma including malignant mesothelioma, hepatocellular carcinoma, prostate cancer, head and neck cancer, renal cell carcinoma, and medulloblastoma.

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