TEAD inhibitors and methods of use

Abstract

The present disclosure provides, in part, a compound of formula (I): # imgabs0 #, wherein the variables are as defined herein; pharmaceutical compositions comprising the compounds, and methods of using the compounds in the treatment of physiological disorders mediated by TEA domain transcription factors, such as proliferative disorders.

Description

Cross-Related Applications

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 369,036, filed on July 21, 2022, the contents of which are hereby incorporated by reference in their entirety. Overview of public content

[0002] In certain embodiments, disclosed herein are compounds of Formula (I), Formula (I'), Formula (I-1), or Formula (I-1'), such as 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. In addition, disclosed herein are compositions comprising compounds of Formula (I), Formula (I'), Formula (I-1), or Formula (I-1'), such as 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, and pharmaceutically acceptable excipients. In certain embodiments, also disclosed herein are methods of inhibiting aberrant transcriptional enhanced associate (TEA) domain transcription factor (TEAD) transcription complex activity and thereby treating certain diseases or disorders characterized by aberrant TEAD transcription complex activity (e.g., hyperactivation), such as cancer.

[0003] In certain embodiments, disclosed herein are compounds of Formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0004] Furthermore, in certain embodiments, disclosed herein are compounds of formula (I'): (I'), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0005] Furthermore, in certain embodiments, disclosed herein are compounds of formula (I-1): (I-1), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0006] Furthermore, in certain embodiments, disclosed herein are compounds of formula (I-1'): (I-1'), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0007] Furthermore, in certain embodiments, disclosed herein are compounds of Formula (Ia): (Ia), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0008] Furthermore, in certain embodiments, disclosed herein are compounds of formula (Ia'): (Ia'), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0009] Furthermore, in certain embodiments, disclosed herein are compounds of Formula (Ib): (Ib), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0010] Furthermore, in certain embodiments, disclosed herein are compounds of formula (Ib'): (Ib'), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0011] Furthermore, in certain embodiments, disclosed herein are compounds of formula (Ic): (Ic), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0012] Furthermore, in certain embodiments, disclosed herein are compounds of formula (Ic'): (Ic'), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0013] Furthermore, in certain embodiments, disclosed herein are compounds of Formula (Id): (Id), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0014] Furthermore, in certain embodiments, disclosed herein are compounds of Formula (Ie): (Ie), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0015] 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 in Table 1 or pharmaceutically acceptable salts thereof.

[0016] In certain embodiments, also provided herein are pharmaceutical compositions comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0017] In certain embodiments, disclosed herein are methods of treating a disease or condition mediated by TEAD activity (e.g., dysregulation) 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 or a pharmaceutical composition disclosed herein. In some embodiments, the disease or condition is a cancer characterized by abnormal TEAD transcription complex activity (e.g., hyperactivation). BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The present disclosure may be more fully understood with reference to the following drawings.

[0019] Figure 1 is a diagram showing the domain architecture of human TEAD1, TEAD2, TEAD3, and TEAD4. The 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) of TEAD2-TEAD4 compared to the corresponding binding domain of TEAD1. Post-translational modifications, including palmitoylation and phosphorylation, and the p38 binding D domain of the DNA-BD are also shown.

[0020] Figure 2A Figure 1 is a diagram showing the upstream signaling output and downstream transcriptional output of TEAD in cancer biology, TEAD regulates key functions in tumorigenesis, stem cell maintenance, cancer immunology and metabolism, and the formation of signaling feedback loops. Oncogenic signaling pathways include EGFR signaling, TGFβ signaling, WNt signaling, GPCR signaling, and oncogenes (indicated with *), such as KRAS, BRAF, LKB1, APC, and GNAQ / 11.

[0021] Figure 2B is a diagram showing the role of TEAD in multiple stages of tumorigenesis.

[0022] Figure 3Ais a graph showing tumor volume before and 7 days after treatment in individual mice bearing MSTO-211H tumors treated with vehicle bid, 3 mg / kg Compound 1-1 bid, or 12.5 mg / kg Compound 5 bid.

[0023] Figure 3B It shows Figure 3A Graph of mean changes in MSTO-211H tumor volume among the treatment groups described in . Detailed Description

[0024] In certain embodiments, provided herein are compounds and compositions, such as compounds of Formula (I), Formula (I'), Formula (I-1), or Formula (I-1'), such as 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. In certain embodiments, provided herein are compositions comprising compounds of Formula (I), Formula (I'), Formula (I-1), or Formula (I-1'), such as 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, and pharmaceutically acceptable excipients. In certain embodiments, provided herein are methods of using the compounds and compositions disclosed herein. The contemplated compounds and compositions disclosed herein are inhibitors of transcription enhancer domain (TEAD) activity and are therefore useful in methods of treating certain diseases or disorders characterized by aberrant TEAD transcription complex activity (e.g., hyperactivation), such as cancer.

[0025] Certain terms Unless otherwise defined, all technical terms and scientific terms used herein have the same meanings as those generally understood by those skilled in the art of the subject matter to which protection is claimed. In general, the nomenclature used in conjunction with immunology, oncology, cell and tissue culture, molecular biology, and protein and oligonucleotide or polynucleotide chemistry and hybridization described herein, and the techniques of immunology, oncology, cell and tissue culture, molecular biology, and protein and oligonucleotide or polynucleotide chemistry and hybridization are those well known and commonly used in the art. It should be understood that the aforementioned general description and the following detailed description are only exemplary and illustrative, and do not limit any subject matter claimed. The section titles used herein are only for organizational purposes and are not to be construed as limiting the described subject matter.

[0026] 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.

[0027] Chemical Definition Definitions of specific functional groups and chemical terms are described in more detail below.

[0028] In some embodiments, the compounds described herein contain one or more asymmetric centers and therefore exist in various isomeric forms, for example, 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 a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In some embodiments, isomers are separated from the mixture 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 compounds described herein as individual isomers substantially free of other isomers and optionally as mixtures of various isomers.

[0029] In some embodiments, the compounds described herein further comprise one or more isotopic substitutions. For example, in some embodiments, H is in any isotopic form, including 1 H. 2 H (D or deuterium) and 3 H (T or tritium); C in any isotopic form, including 12 C. 13 C and 14 C; O in any isotopic form, including 16 O and 18 O; F in any isotopic form, including 18 F and 19 F; etc.

[0030] When a range of values ​​is listed, it is intended to include every value and sub-range within that range. For example, "C 1–6 "Alkyl" is intended to include 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 alkyl.

[0031] As used herein, "alkyl" refers to a group such as a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1– C 20 In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C 1– C 10 In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1– In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C 1– In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1– In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1– In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1– In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1– In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1– In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1- In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). 1– Examples of C6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0032] As used herein, "alkylene" refers to a divalent radical of an alkyl group. When a range or number of carbons is provided for a particular "alkylene" group, it is understood that the range or number refers to the range or number of carbons in a straight carbon divalent chain. In some embodiments, the "alkylene" group is substituted or unsubstituted with one or more substituents as described herein.

[0033] As used herein, "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic array) radical having 6-14 ring carbon atoms and zero heteroatoms ("C 6-14 "aryl").

[0034] As used herein, "heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in the cyclic array) having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is 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 a carbon atom or a nitrogen atom when valence permits.

[0035] In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0036] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. 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, pyridyl. 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.

[0037] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic or bridged cyclic (e.g., adamantyl) hydrocarbon group having 3-12, 3-10, 3-8, 4-8 or 4-6 carbon atoms derived from cycloalkanes, referred to herein as, for example, "C3-C 10 "Cycloalkyl". Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and cyclopropane.

[0038] As used herein, "heterocyclyl" or "heterocycle" refers to a group of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("3-10 membered heterocyclyl"). In some embodiments, in a heterocyclyl group comprising one or more nitrogen atoms, when valence permits, the point of attachment is a carbon atom or a nitrogen atom. In some embodiments, the heterocyclyl group is a monocyclic ("monocyclic heterocyclyl") or fused ring system, a bridged ring system or a spirocyclic system, such as a bicyclic system ("bicyclic heterocyclyl"), and is saturated or partially unsaturated. In some embodiments, the heterocyclyl bicyclic ring system comprises 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, wherein the point of attachment is on the cycloalkyl or heterocyclyl ring; or a heterocyclyl ring as defined above is fused to one or more phenyl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such cases, the number of ring members continues to represent 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.

[0039] In some embodiments, a heterocyclyl group is a 3-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 3-7 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-7 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 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, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“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, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 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 one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0040] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group have been replaced by nitrogen, oxygen or sulfur heteroatoms. In some embodiments, hetero applies to any of the hydrocarbyl groups described above, such as alkyl, e.g., heteroalkyl; cycloalkyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; and similar groups having 1 to 5, and particularly 1 to 3 heteroatoms.

[0041] As used herein, the terms "halo" and "halogen" refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodine, -I). In certain embodiments, the halogen group is fluorine or chlorine.

[0042] The term "haloalkyl" includes monohaloalkyl, polyhaloalkyl, and perhaloalkyl groups substituted with one or more halogen atoms, wherein the halogen is independently selected from fluorine, chlorine, bromine, and iodine.

[0043] The term "oxo" as used herein refers to =0.

[0044] As used herein, the term "hydroxy" refers to -OH.

[0045] In general, the term "substituted", whether or not preceded by the term "optionally", means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permitted substituent, such as a substituent that, when substituted, produces a stable compound, such as a substituent that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, 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 substituent at each position may be the same or different.

[0046] The nitrogen atoms may be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary and quaternary nitrogen atoms.

[0047] These and other exemplary substituents are described in greater detail in the Detailed Description, Examples, and Claims.This disclosure is not intended to be limited in any way by the above exemplary list of substituents.

[0048] Other definitions As used herein, "pharmaceutically acceptable excipient" refers to any substance other than the active pharmaceutical ingredient in a pharmaceutical formulation. Exemplary pharmaceutical excipients include those that aid in the manufacturing process; protect, support, or enhance stability; improve bioavailability; or increase patient acceptability. They may also aid in product identification or enhance the overall safety or function of a product during storage or use.

[0049] As used herein, "pharmaceutically acceptable salts" refer to those salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reaction, etc., and are commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. 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 acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or formed 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, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, 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 + (C 1–4 Representative alkali metal salts or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, etc. Where appropriate, additional pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

[0050] As used herein, a "subject" to which administration is intended includes, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, 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 medical personnel.

[0051] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0052] As used herein, and unless otherwise indicated, the terms "treat," "treating," and "treatment" contemplate actions that occur in a subject suffering from a particular disease, disorder, or condition to reduce the severity of the disease, disorder, or condition, or to slow or slow the progression of the disease, disorder, or condition.

[0053] As used herein, and unless otherwise indicated, 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 therapies, 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 therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0054] Compound In certain embodiments, disclosed herein are compounds of Formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: X is selected from NR a , O and S; R 1 is a 5-10 membered heteroaryl group having one, two, three or four heteroatoms each independently selected from the group consisting of N, O and S; wherein the 5-10 membered heteroaryl group is optionally substituted; R 2is a 3-10 membered heterocyclyl or -(C1-C4 alkylene)-(3-10 membered heterocyclyl), wherein the 3-10 membered heterocyclyl has one, two, three or four heteroatoms each independently selected from the group consisting of N, O and S and is optionally substituted, wherein the C1-C4 alkylene is optionally substituted; R 3a and R 3b One of the following is selected from the group consisting of halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), C 3-10 The group consisting of cycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl, wherein C 3-10 Cycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl are optionally substituted; and R 3a and R 3b The other one of which is selected from the group consisting of hydrogen, halogen and -C1-C6 alkyl; Each R 4 Independently selected from halogen and -C1-C6 alkyl; Each R 5 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; and R a is selected from hydrogen and -C1-C6 alkyl.

[0055] In certain embodiments, also disclosed herein are compounds of formula (I'): (I'), or a pharmaceutically acceptable salt thereof, wherein: X is selected from NR a , O and S; R 1 is a 5-10 membered heteroaryl group having one, two, three or four heteroatoms each independently selected from the group consisting of N, O and S; wherein the 5-10 membered heteroaryl group 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 one, two, three or four heteroatoms and is optionally substituted, wherein the heteroatom is nitrogen, and wherein the C1-C4 alkylene is optionally substituted; R 3a and R 3b One of the following is selected from the group consisting of halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), C3-10 The group consisting of cycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl, wherein C 3-10 Cycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl are optionally substituted; and R 3a and R 3b The other one of which is selected from the group consisting of hydrogen, halogen and -C1-C6 alkyl; Each R 4 Independently selected from halogen and -C1-C6 alkyl; Each R 5 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; and R a is selected from hydrogen and -C1-C6 alkyl.

[0056] In certain embodiments, the present invention also discloses a compound of formula (I-1): (I-1), or a pharmaceutically acceptable salt thereof, wherein: X is selected from NR a , O and S; R 1 is a 5-10 membered heteroaryl group having one, two, three or four heteroatoms each independently selected from the group consisting of N, O and S; wherein the 5-10 membered heteroaryl group 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 has one, two, three or four heteroatoms each independently selected from the group consisting of N, O and S and is optionally substituted, wherein the C1-C4 alkylene is optionally substituted; R 3 Selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), C 3-10 The group consisting of cycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl, wherein C 3-10 Cycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl are optionally substituted; Each R 4 Independently selected from halogen and -C1-C6 alkyl; Each R 5 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; and R a is selected from hydrogen and -C1-C6 alkyl.

[0057] In certain embodiments, the present invention also discloses a compound of formula (I-1'): (I-1'), or a pharmaceutically acceptable salt thereof, wherein: X is selected from NR a , O and S; R 1 is a 5-10 membered heteroaryl group having one, two, three or four heteroatoms each independently selected from the group consisting of N, O and S; wherein the 5-10 membered heteroaryl group 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 one, two, three or four heteroatoms and is optionally substituted, wherein the heteroatom is nitrogen, and wherein the C1-C4 alkylene is optionally substituted; R 3 Selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), C 3-10 The group consisting of cycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl, wherein C 3-10 Cycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl are optionally substituted; Each R 4 Independently selected from halogen and -C1-C6 alkyl; Each R 5 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; and R a is selected from hydrogen and -C1-C6 alkyl.

[0058] In some embodiments, X is NR a .

[0059] In some embodiments, the compound is of Formula (Ia): (Ia), or a pharmaceutically acceptable salt thereof, wherein: R 3 is -C1-C6 alkyl or -C1-C6 haloalkyl; and The remaining variables are defined as in formula (I).

[0060] In some embodiments, the compound is of Formula (Ia'): (Ia'), or a pharmaceutically acceptable salt thereof, wherein: R 3 is -C1-C6 alkyl or -C1-C6 haloalkyl; and The remaining variables are defined as in formula (I').

[0061] In some embodiments, R 1 is an optionally substituted 5-6 membered heteroaryl group.

[0062] In some embodiments, R 1 is a 5-6 membered heteroaryl group optionally substituted by 1, 2, 3 or 4 substituents each independently selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl) and -N(R b )2, where each R b Independently selected from hydrogen and C1-C6 alkyl.

[0063] In some embodiments, R 1 is a 5-6 membered heteroaryl group selected from the group consisting of oxadiazole, imidazole, pyrazole, oxazole, triazole, tetrazole, pyridine, pyrazine and pyridazine, wherein the 5-6 membered heteroaryl group is optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl) and -N(R b )2, where each R b Independently selected from hydrogen and C1-C6 alkyl.

[0064] In some embodiments, R 1 is a 5-6 membered heteroaryl group which is optionally substituted by 1, 2, 3 or 4 substituents each independently selected from halogen and -C1-C6 alkyl.

[0065] In some embodiments, R 1 is a 5-6 membered heteroaryl group selected from the group consisting of oxadiazole, imidazole, pyrazole, oxazole, triazole, tetrazole, pyridine, pyrazine and pyridazine, wherein the 5-6 membered heteroaryl group is optionally substituted with a C1-C6 alkyl group.

[0066] In some embodiments, R 1 is imidazole optionally substituted by methyl.

[0067] In some embodiments, R 1 It's oxazole.

[0068] In some embodiments, R 1 is a tetrazole optionally substituted with methyl.

[0069] In some embodiments, R 1 is an oxadiazole, such as 1,3,4-oxadiazole, which is optionally substituted with methyl.

[0070] In some embodiments, the compound is of Formula (Ib): (Ib), or a pharmaceutically acceptable salt thereof, wherein: R d is selected from hydrogen and -C1-C6 alkyl; and The remaining variables are defined as in formula (Ia).

[0071] In some embodiments, the compound is of Formula (Ib'): (Ib'), or a pharmaceutically acceptable salt thereof, wherein: R d is selected from hydrogen and -C1-C6 alkyl; and The remaining variables are defined as in formula (Ia').

[0072] In some embodiments, the compound is of Formula (Ic): (Ic), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in formula (Ib).

[0073] In some embodiments, the compound is of formula (Ic'): (Ic'), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in formula (Ib').

[0074] In some embodiments, R 2 is a 3-7 membered monocyclic heterocyclyl or -(C1-C4 alkylene)-(3-7 membered monocyclic heterocyclyl), wherein the 3-7 membered monocyclic heterocyclyl has one, two, three or four heteroatoms each independently selected from N, O and S, wherein the 3-7 membered monocyclic heterocyclyl is optionally substituted, and wherein the C1-C4 alkylene is optionally substituted (e.g., optionally with C 1-6 Alkyl, C 1-6 Alkyl halide substitution, or at C 1-4 The geminal hydrogens on the carbons of the alkylene group can be combined with the carbon atom to which they are attached to form a 3-7 membered cycloalkyl ring).

[0075] In some embodiments, R 2 is a 3-7 membered monocyclic heterocyclyl or -(C1-C4 alkylene)-(3-7 membered monocyclic heterocyclyl), wherein the 3-7 membered monocyclic heterocyclyl contains at least 2 carbon atoms and one, two, three or four heteroatoms, wherein the heteroatoms are nitrogen, and wherein the 3-7 membered monocyclic heterocyclyl is optionally substituted, and wherein the C1-C4 alkylene is optionally substituted (e.g., optionally with C 1-6 Alkyl, C 1-6 Alkyl halide substitution, or at C 1-4 The geminal dihydrogens on a carbon of an alkylene group can be combined with the carbon atom to which they are attached to form a 3-7 membered cycloalkyl ring).

[0076] In some embodiments, R 2 is a 3-7 membered monocyclic heterocyclic group or -(C1-C4 alkylene)-(3-7 membered monocyclic heterocyclic group), wherein the 3-7 membered monocyclic heterocyclic group has one, two, three or four heteroatoms each independently selected from N, O and S, and is optionally substituted by 1, 2, 3 or 4 substituents each independently selected from the group consisting of C1-C6 alkyl, oxo, 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. -S(O) r -R f , where R b , R g and R f Each of which is independently selected from hydrogen and C1-C6 alkyl, wherein each r is 1 or 2, and wherein each R f Independently selected from C 1-6 Alkyl and phenyl.

[0077] In some embodiments, R 2is a 3-7 membered monocyclic heterocyclic group or -(C1-C4 alkylene)-(3-7 membered monocyclic heterocyclic group), wherein the 3-7 membered monocyclic heterocyclic group contains at least 2 carbon atoms and one, two, three or four heteroatoms, wherein the heteroatoms are nitrogen, and wherein the 3-7 membered monocyclic heterocyclic group is optionally substituted by 1, 2, 3 or 4 substituents each independently selected from the group consisting of C1-C6 alkyl, oxo, hydroxy, 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 , where R b , R g and R f Each of which is independently selected from hydrogen and C1-C6 alkyl, wherein each r is 1 or 2, and wherein each R f Independently selected from C 1-6 Alkyl and phenyl.

[0078] In some embodiments, R 2 is a 3-7 membered monocyclic heterocyclic group, wherein the 3-7 membered monocyclic heterocyclic group contains at least 2 carbon atoms and one, two, three or four heteroatoms, wherein the heteroatoms are nitrogen, and wherein the 3-7 membered monocyclic heterocyclic group is optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -C1-C6 alkyl, oxo and hydroxy.

[0079] In some embodiments, R 2 is a 5-membered heterocyclic group having one or two nitrogen atoms, wherein the 5-membered heterocyclic group is optionally substituted by 1, 2 or 3 substituents each independently selected from C1-C6 alkyl and oxo.

[0080] In some embodiments, R 2 is a 5-membered heterocyclic group having one or two heteroatoms, wherein the heteroatoms are nitrogen atoms, and wherein the 5-membered heterocyclic group is optionally substituted by 1, 2 or 3 substituents each independently selected from C1-C6 alkyl, oxo and hydroxy.

[0081] In some embodiments, R 2It is -(C1-C4 alkylene)-(5-membered heterocyclyl having one or two nitrogen atoms), wherein the 5-membered heterocyclyl is optionally substituted by 1, 2 or 3 substituents each independently selected from C1-C6 alkyl and oxo.

[0082] In some embodiments, R 2 It is -(C1-C4 alkylene)-(5-membered heterocyclyl having one or two heteroatoms), wherein the heteroatom is a nitrogen atom, and wherein the 5-membered heterocyclyl is optionally substituted by 1, 2 or 3 substituents each independently selected from C1-C6 alkyl, oxo and hydroxy.

[0083] In some embodiments, R 2 yes: , wherein t is selected from the group consisting of 0, 1, 2 and 3.

[0084] In some embodiments, R 2 yes: , wherein t is selected from the group consisting of 0, 1, 2 and 3.

[0085] In some embodiments, t is 1.

[0086] In some embodiments, R 2 yes: , where s is selected from the group consisting of 0, 1, 2, and 3, and R e Selected from hydrogen and C1-C6 alkyl.

[0087] In some embodiments, s is 0 and R e It's methyl.

[0088] In some embodiments, R 2 yes: , where u is selected from the group consisting of 0, 1, 2, and 3, and R e Selected from hydrogen and C1-C6 alkyl.

[0089] In some embodiments, R 2 yes: , where u is selected from the group consisting of 0, 1, 2, and 3, and R e Selected from hydrogen and C1-C6 alkyl.

[0090] In some embodiments, R 2 yes: , where u is selected from the group consisting of 0, 1, 2, and 3, and R eSelected from hydrogen and C1-C6 alkyl.

[0091] In some embodiments, u is 0 and R e It's methyl.

[0092] In some embodiments, the compound is of Formula (Id): (Id), or a pharmaceutically acceptable salt thereof, wherein R 3 is -C1-C6 alkyl or -C1-C6 haloalkyl; and The remaining variables are defined as in formula (Ia).

[0093] In some embodiments, the compound is of Formula (Ie): (Ie), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in formula (Id).

[0094] In some embodiments, R 3 It is a C1-C6 alkyl group or a C1-C6 haloalkyl group.

[0095] In some embodiments, R 3 It's a halogen.

[0096] In some embodiments, R 3 It is trifluoromethyl.

[0097] In some embodiments, m and n are both zero.

[0098] In some embodiments, R a It's hydrogen.

[0099] In some embodiments, the compound is a compound of Table 1 or a pharmaceutically acceptable salt thereof.

[0100] Table 1. List of compounds.

[0101]

[0102] In certain embodiments, also disclosed herein are compounds of Table 1a or pharmaceutically acceptable salts thereof.

[0103] Table 1a. List of compounds.

[0104]

[0105] 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), (I'), (I-1), (I-1'), (Ia), (Ia'), (Ib), (Ib'), (Ic), (Ic'), (Id), or (Ie)) or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable excipient. In some embodiments, the excipient is selected from: an inert solid diluent and an inert solid filler, a diluent including a sterile aqueous solution and various organic solvents, a penetration enhancer, a solubilizing agent, and an excipient. In some embodiments, the pharmaceutical composition is administered alone or in combination with other therapeutic agents. Such compositions are prepared in any suitable manner.

[0106] In some embodiments, the pharmaceutical composition is administered in single or multiple doses by any of the accepted modes of administration for agents with similar utility, including rectal, buccal, intranasal, and transdermal routes, by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as, for example, a stent or an arterial inserted cylindrical polymer.

[0107] A mode of administration is parenteral, particularly by injection. In some embodiments, the form of the novel composition of the present disclosure incorporated therein for administration by injection includes aqueous or oily suspensions or emulsions, with sesame oil, corn oil, cottonseed oil or peanut oil, and 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 glycols, etc. (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils are used. In some embodiments, suitable fluidity is maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of a dispersion, and by using a surfactant. In some embodiments, the effect of preventing microorganisms is achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0108] Sterile injectable solutions are prepared by incorporating the compounds according to the present disclosure into appropriate solvents with various other ingredients as enumerated above as needed, followed by filtration sterilization. Typically, dispersions are prepared by incorporating various sterilized active ingredients into sterile vehicles comprising a basic dispersion medium and other ingredients required from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation are vacuum drying and freeze drying techniques, which produce powders thereof from sterile filtered solutions of the active ingredient plus any additional required ingredients.

[0109] Oral administration is another route of administration of the compounds disclosed herein. In some embodiments, administration is via capsules or enteric-coated tablets, etc. In some embodiments, when preparing a pharmaceutical composition comprising at least one compound described herein, the active ingredient is usually diluted by an excipient and / or encapsulated in such a carrier in the form of a capsule, a pouch, paper or other container. In some embodiments, when an excipient is used as a diluent, it is in the form of a solid, semisolid or liquid material (as above), which is used as a vehicle, carrier or medium for the active ingredient. Therefore, in some embodiments, the composition is in the form of tablets, pills, powders, lozenges, pouches, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight of active compounds, soft gelatin capsules and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

[0110] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, sterile water, syrup and methylcellulose. In some embodiments, the formulations additionally comprise: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents.

[0111] In some embodiments, the compositions of the present disclosure are formulated to provide a quick, continuous or delayed release of active ingredients after being applied to a patient. Controlled release drug delivery systems for oral administration include osmotic pump systems and reservoirs containing polymer coatings or dissolution systems of drug-polymer matrix formulations. Another preparation used in the method of the present disclosure adopts a transdermal delivery device ("patch"). In some embodiments, such a transdermal patch is used to provide a continuous or discontinuous infusion of a controlled amount of a compound of the present disclosure. The construction and use of a transdermal patch for delivering medicaments is well known in the art. In some embodiments, such a patch is constructed for continuous, pulsed or on-demand delivery of medicaments.

[0112] The composition is preferably formulated into a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a single dose for human subjects and other mammals, each unit containing a predetermined amount of active material combined with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule) calculated to produce a desired therapeutic effect. The compound is usually administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains 1 mg to 2 g of the compound described herein, and for parenteral administration, preferably contains 0.1 mg to 700 mg of the compound described herein. However, it will be understood that the amount of the compound actually administered will usually be determined by the doctor according to the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered and its relative activity, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0113] For preparing solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure. In some embodiments, when referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition is easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0114] In some embodiments, the tablet or pill of the present disclosure is coated or otherwise compounded to provide a dosage form with the advantage of prolonged action, or to protect it from the acidic conditions of the stomach. For example, in some embodiments, tablet or pill comprises an inner dosage component and an outer dosage component, the latter being in the form of a film covering the former. In some embodiments, two components are separated by an enteric layer, which is used to resist the disintegration in the stomach and allows the inner component to enter the duodenum intact or delay release. In some embodiments, a variety of materials are used for such enteric layers or coatings, and such materials include a mixture of a variety of polymeric acids and polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

[0115] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. In some embodiments, liquid or solid compositions contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered by oral or nasal respiratory route to obtain local or systemic effects. In some embodiments, the composition in a pharmaceutically acceptable solvent is atomized by using an inert gas. In some embodiments, the atomized solution is inhaled directly from the atomizing device, or the atomizing device is attached to a face mask inhaler (facemask tent) or an intermittent positive pressure breathing machine. In some embodiments, the solution, suspension or powder composition is administered orally or nasally from a device for delivering the preparation in an appropriate manner.

[0116] Treatment In certain embodiments, disclosed herein are methods of treating a disease or disorder modulated by aberrant activity of a TEAD isoform (e.g., TEAD1 and / or TEAD4) (e.g., hyperactivation of a TEAD transcription complex) in an individual in need thereof, the method comprising administering to the individual a compound of Formula (I), (I'), (I-1), (I-1'), (Ia), (Ia'), (Ib), (Ib'), (Ic), (Ic'), (Id), or (Ie) or a pharmaceutically acceptable salt thereof (e.g., a therapeutically effective amount of a compound of Formula (I), (I'), (I-1), (I-1'), (Ia), (Ia'), (Ib), (Ib'), (Ic), (Ic'), (Id), or (Ie) or a pharmaceutically acceptable salt thereof).

[0117] TEA domain transcription factors (TEADs) are downstream effectors of the Hippo signaling pathway. Currently, four isoforms of TEAD have been identified—TEAD1, TEAD2, TEAD3, and TEAD4. TEAD isoforms share highly similar structures. The N-termini of the four isoforms share a highly conserved 68-amino acid TEA / ATTS DNA binding domain that binds to the MCAT element (50-CATTCCA / T-30). The C-terminus contains a transactivation domain that recruits the transcriptional coactivator YAP / TAZ.

[0118] The expression of TEAD proteins is upregulated in many cancer types, including gastric cancer, colorectal cancer, breast cancer, and prostate cancer. TEAD hyperactivation plays a role in tumor progression, metastasis, cancer metabolism, immunity, and drug resistance, and is associated with poor patient survival.

[0119] Selective binding of TEAD1 and / or TEAD4 is advantageous for optimizing antitumor efficacy while minimizing undesired effects. Inhibition of TEAD3 is associated with off-target toxicities (e.g., nephrotoxicity), while inhibition of TEAD2 may be pro-proliferative.

[0120] The TEAD isoform selectivity demonstrated by the compounds disclosed herein is superior to TEAD inhibitors known in the art. For example, as demonstrated by Tang and Post using thermal shift assays, TEAD inhibitor VT3989 mainly interacts with TEAD1-TEAD3. The reported thermal shift data are provided in Table 2 below (Tang and Post, "The TEAD autopalmitoylation inhibitor VT3989 improves efficacy and increases durability of efficacy ofosimertinib in preclinical EGFR mutant tumor models," Proceedings of theAmerican Association for Cancer Research Annual Meeting 2022; April 8-13, 2022.Philadelphia (PA): AACR; Poster #5364). The data provided in Table 2 show that VT3989 provides minimal selectivity for TEAD2 and TEAD3, which are TEAD isoforms that are not expected to be inhibited. In addition, VT3989 shows a lower level of binding to TEAD4, which is a TEAD isoform that is expected to be inhibited. 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.).

[0121] Table 2. Thermal shift assays of TEAD isoforms 1-4 treated with the TEAD inhibitor VT3989 compared to an inactive analog control.

[0122]

[0123] 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 disclosed herein selectively bind to TEAD4. In certain embodiments, the compounds disclosed herein selectively bind to TEAD1 and TEAD4. In some embodiments, the binding selectivity to TEAD1 is 10 times, 100 times, 1,000 times, or 10,000 times that of TEAD2 and / or TEAD3. In some embodiments, the binding selectivity to TEAD4 is 10 times, 100 times, 1,000 times, or 10,000 times that of TEAD2 and / or TEAD3. Evidence of TEAD isoform selectivity demonstrated by the compounds disclosed herein is provided in Example 26 below.

[0124] In some embodiments, the compounds disclosed herein can be used as medical therapies for treating diseases or conditions mediated by superactivation of YAP / TAZ-TEAD (e.g., TEAD1 and / or TEAD4) transcriptional coactivator complexes. In some embodiments, the compounds disclosed herein can be used as medical therapies for treating diseases or conditions characterized by superactivation 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 tumor fusion; for example, TEAD1-PARVA. These fusions drive higher expression of TEAD and can lead to enhanced transcription of TEAD target genes. Amplification (increase in genomic copy number) of TEAD4 occurs in a variety of cancers, as part of the 12p13 locus, for example, in ovarian and uterine cancers and testicular germ cell tumors. These genomic amplifications of TEAD4 are associated with a strong increase in its mRNA expression and can drive high TEAD-YAP / TAZ transcriptional activity.

[0125] 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 abnormal TEAD transcription 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 medulloblastoma. In some embodiments, the cancer is selected from pancreatic adenocarcinoma, hepatocellular carcinoma, breast cancer, and malignant mesothelioma. In certain embodiments, pancreatic cancer is pancreatic adenocarcinoma. In certain embodiments, the cancer is malignant mesothelioma.

[0126] Also provided herein is a compound or a pharmaceutically acceptable salt disclosed herein or a pharmaceutical composition disclosed herein for use in treating a disease or disorder mediated by hyperactivation of a TEAD isoform selected from TEAD1 and TEAD4 in a subject in need thereof.

[0127] In another aspect, provided herein is a use of a compound or pharmaceutically acceptable salt disclosed herein or a pharmaceutical composition disclosed herein in the preparation of a medicament for treating a disease or disorder mediated by hyperactivation of a TEAD isoform selected from TEAD1 and TEAD4 in a subject in need thereof.

[0128] 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.

[0129] In some embodiments, the present disclosure provides compounds of Formula (I), (I'), (I-1), (I-1'), (Ia), (Ia'), (Ib), (Ib'), (Ic), (Ic'), (Id), or (Ie) for modulating TEAD activity. In some embodiments, the present disclosure provides pharmaceutically acceptable salts of compounds of Formula (I), (I'), (I-1), (I-1'), (Ia), (Ia'), (Ib), (Ib'), (Ic), (Ic'), (Id), or (Ie) for modulating TEAD activity.

[0130] 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 use in medical therapy, or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments, the compounds disclosed herein and their pharmaceutically acceptable salts or pharmaceutical compositions are 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, one or more other therapeutic agents are selected from regulators of other transcription factors. In some embodiments, regulators of other transcription factors are selected from regulators of YAP, regulators of EGFR or regulators of MEK.

[0132] In some embodiments, one or more other therapeutic agents are administered simultaneously with a compound disclosed herein, or a pharmaceutical salt thereof, or a pharmaceutical composition. In some embodiments, one or more other therapeutic agents are administered sequentially with a compound disclosed herein, or a pharmaceutical salt thereof, or a pharmaceutical composition. In some embodiments, one or more other therapeutic agents are administered before a compound disclosed herein, or a pharmaceutical salt thereof, or a pharmaceutical composition. In some embodiments, one or more other therapeutic agents are administered after a compound disclosed herein, or a pharmaceutical salt thereof, or a pharmaceutical composition.

[0133] Example The present disclosure will be further illustrated in the following examples, which are provided for illustrative purposes only and are not intended to limit the present disclosure in any way.

[0134]

[0135]

[0136] Analytical methods 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 of 230-400 mesh size. Flash chromatography was also performed on a combi-flash RF Teledyne Isco machine. Preparative TLC was performed on Merck plates.

[0137] Liquid chromatography-mass spectrometry 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*2.1 mm, 2.5 micron, Column temperature: 35°C, Autosampler temperature: 15°C, 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) flow rate: 0.8 mL / min; T=0.75min (97% A, 3% B) flow rate: 0.8 mL / min; Gradient change to T=2.7 min (2% A, 98% B) flow rate: 0.8 mL / min; Gradient change to T=3 min (0% A, 100% B) flow rate: 1 mL / min; T=3.5 min (0% A, 100% B) flow rate: 1 mL / min; gradient change to T=3.51 min (97% A, 3% B) flow rate: 0.8 mL / min; end run at T=4 min (97% A, 3% B), flow rate: 0.8 mL / min, flow rate: -0.8 mL / min, run time: -4 min, UV detection method: -PDA, wavelength: -200-500 nm; quality parameters: probe: -ESI, ionization mode: -positive and negative, cone voltage: -30V and 10V, capillary voltage: -3.0 KV, extractor voltage: -1 V, Rf lens: -0.1 V, source temperature: -120℃, desolvation temperature: -400℃. Cone gas flow rate: -100 L / hour, desolvation gas flow rate: -800 L / hour.

[0138] 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*4.6 mm, 3.5 micron, Column temperature: 35°C, Autosampler temperature: 15°C, Mobile phase A: 5 mM ammonium bicarbonate (pH=8.00) in Milli Q water, Mobile phase B: Acetonitrile; Mobile phase gradient details: T=0 min (97% A, 3% B) flow=1.0 ml / min, T=0.20 min (97% A, 3% B) flow=1.0 ml / min; Gradient change to T=2.70 min (20% A, 80% B) flow=1.0 ml / min; Gradient change to T=3.0min (0% A, 100% B) flow=1.2 ml / min; T=3.50 min (0% A, 100% B) flow = 1.2 ml / min; T = 3.51 min (97% A, 3% B) flow = 1.0 ml / min; end run at T = 4.0 min (97% A, 3% B) flow = 1.0 ml / min, run time: -4 min, UV detection method: -PDA, wavelength: -195 nm-500 nm; Quality parameters: Probe: -ESI, Ionization mode: -positive and negative, Cone voltage: -30 V 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: -100 L / Hr, Desolvation gas flow: -800 L / Hr.

[0139] High performance liquid chromatography Method-A Method name: - HP04_BR1, Machine details: - Water alliancee2695 with 2998 PDA detector, 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: 1 mL / min; T=7 min (90%A, 10% B) flow: 1 mL / min; Gradient change to T=9 min (100% A, 0% B) flow: 1 mL / min; Gradient change to T=14 min (100% A, 0% B) flow: 1 mL / min; T=14.01 min (10% A, 90% B) flow: 1 mL / min; Gradient change to T=17 min (10% A, 90% B) flow: 1 mL / min; End run at T=17 min (10% A, 90% B), flow rate: 1 mL / min, run time: -17 min, UV detection method: -PDA.

[0140] Method-B Method name: -HP05_TFAR1, Machine details: AGILENT TECHNOLOGY 1260infinity series with PDA detector, 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: 1 mL / min; T=7 min (10% A, 90% B) flow: 1 mL / min; Gradient change to T=9 min (0% A, 100% B) flow: 1 mL / min; Gradient change to T=14 min (0% A, 100% B) flow: 1 mL / min; T=14.01 min (90% A, 10% B) flow: 1 mL / min; Gradient change to T=17 min (90% A, 10% B) flow: 1 mL / min; End run at T=17 min (90% A, 10% B), flow rate: 1 mL / min, run time: -17 min, UV detection method: -PDA.

[0141] Method-C Method name:- HP06_TFAR1, Machine details:- AGILENT TECHNOLOGY 1100 series with PDA detector, 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: 1 mL / min; T=7 min (10% A, 90% B) flow: 1 mL / min; Gradient change to T=9 min (0% A, 100% B) flow: 1 mL / min; Gradient change to T=14min (0% A, 100% B) flow: 1 mL / min; T=14.01 min (90% A, 10% B) flow: 1 mL / min; Gradient change to T=17 min (90% A, 10% B) flow: 1 mL / min; Run ends at T=17 min (90% A, 10% B), flow rate: 1 mL / min, run time: -17 min, UV detection method: -PDA.

[0142] NMR Unless otherwise stated, all analyses were performed using a Bruker Avance-400 instrument operating at 400 MHz and using the stated solvents at room temperature. 1 H nuclear magnetic resonance (NMR) spectroscopy. The samples were prepared as solutions in suitable deuterated solvents and referenced to suitable internal non-deuterated solvent peaks or tetramethylsilane. Chemical shifts were recorded in ppm (δ) downfield from tetramethylsilane. In all cases, the NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts per million, using conventional abbreviations for indicating major peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublet; dt, doublet of triplet; m, multiplet; br, broad peak; br s = broad singlet.

[0143] Purification methods Preparative purification by reverse phase HPLC Preparative HPLC Method-A Biotage-FC-01, with binary pump, with 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 change to t =25 min (55% A, 45% B); t =35 min (0%A, 100%B); gradient change to end of run t =45 min (100% A, 0% B); flow rate: 80 mL / min, analysis time 45 min.

[0144] synthesis Several chemical synthesis methods of the compounds of the present application are described herein. These methods and / or other well-known methods can be modified and / or adjusted in various ways to promote the synthesis of other compounds within the scope of the present application and claims. Such selectable methods and modifications should be understood to be within the spirit and scope of the present application and claims. Therefore, the methods set forth in the following description, schemes and examples are intended for illustrative purposes and should not be construed as limiting the scope of the present disclosure.

[0145] 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)

[0146] Step-1: A solution of CAS: 5445-26-1 (0.50 g, 2.390 mmol, 1.0 eq.) and Cs2CO3 (1.16 g, 3.585 mmol, 1.5 eq.) in DMF (5 mL) was stirred at room temperature for 15 min and cooled to 0 ° C. Methyl iodide (0.37 g, 2.629 mmol, 1.1 eq.) was added to the solution at 0 ° C. The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored on TLC (using EtOAc: hexane; 0.5: 9.5 as mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 16 h. The resulting reaction mixture was diluted with ice water (50 mL) and extracted with EtOAc (3x20 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide 0.720 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as stationary phase (0-9% EtOAc in hexanes) to afford ethyl 2-(4-nitrophenyl)propanoate (A1) (0.400 g, 1.791 mmol, yield: 74.97%).

[0147] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.21 (dd, J = 7.2, 2.0 Hz , 2H), 7.58(dd, J = 7.2, 2.0 Hz , 2H), 4.11-4.00 (m,3H), 1.43 (d, J = 7.2 Hz , 3H), 1.13 (t, J = 7.2 Hz, 3H).

[0148] LCMS (Method B): 2.90 min, 98.19%, 254.0 nm, MS: ES-222.19 (M-1) Step-2: At -78 ° C, to a stirred solution of ethyl 2-(4-nitrophenyl)propanoate (A1) (0.20 g, 0.896 mmol, 1.0 equiv) in THF (2 mL), LiHMDS (2.0 m in THF) (0.94 mL, 1.881 mmol, 2.1 equiv) was added. The mixture was stirred at -78 ° C for 1 h. CAS: 590-17-0 (0.12 g, 1.075 mmol, 1.2 equiv) was then added at -78 ° C. The resulting mixture was stirred at room temperature for 6 h. The reaction was monitored on TLC (using EtOAc: hexane; 2.0: 8.0 as mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 6 h. The resulting reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3x20 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide 0.32 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as stationary phase (0-2% EtOAc in hexanes) to afford ethyl 3-cyano-2-methyl-2-(4-nitrophenyl)propanoate (A2) (0.14 g, 0.533 mmol, yield: 59.58%).

[0149] 1 H NMR (CDCl3, 400 MHz): δ ppm, 8.28 (dd, J = 7.2, 2.0 Hz, 2H), 7.54 (dd, J = 7.2, 2.0 Hz, 2H), 4.27-4.20 (m, 2 H), 3.03 (q, J = 16.8 Hz , 2H), 1.88 (s,3H), 1.24 (t, J = 7.2 Hz , 3H).

[0150] Note: Impurity peaks were observed in 1H NMR.

[0151] LCMS (Method B): 2.75 min, 95.81 %, 254.0 nm, MS: ES-261.91 (M-1) Step-3: At room temperature, Raney Ni (0.80 g) is added to the solution of stirring in 7 N ammonia solution of 3-cyano-2-methyl-2-(4-nitrophenyl)ethyl propionate (A2) (0.80 g, 3.051 mmol, 1.0 equivalent) in methanol (8 mL). The mixture of gained is stirred at room temperature under H (g) atmosphere (200 psi) for 16 h. Monitoring reaction via TLC (using 100%EtOAc as mobile phase), it confirms that the reaction is completed after stirring at room temperature for 16 h. The reaction mixture of gained is directly filtered with diatomite. The filtrate is dried and concentrated under reduced pressure to provide 1.0 g crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as stationary phase (0-4% MeOH in dichloromethane) to afford 3-(4-aminophenyl)-3-methylpyrrolidin-2-one (A3) (0.6 g, 3.153 mmol, yield: 94.28%).

[0152] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 7.64 (br s, 1H), 7.03 (dd, J = 6.8 ,2.0 Hz, 2H), 6.51 (dd, J = 6.8 , 2.0 Hz, 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).

[0153] LCMS (Method A): 0.192 min, 88.83%, 220.0 nm, MS: ES+ 191.05 (M+1) Step-4: At 0 ° C, N-bromosuccinimide (0.17 g, 0.957 mmol, 0.7 equivalent) was added to the stirred solution of 3-(4-aminophenyl)-3-methylpyrrolidin-2-one (A3) (0.26 g, 1.368 mmol, 1.0 equivalent) in DMF (2 mL). The resulting mixture was stirred at room temperature for 4 h. The reaction was monitored on TLC (using 100% EtOAc as mobile phase), which confirmed that the reaction was completed after stirring at room temperature for 4 h. The resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3x20 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide 0.20 g crude product to obtain 3-(4-amino-3-bromophenyl)-3-methylpyrrolidin-2-one (A4) (0.20 g, 0.743 mmol, yield: 54.37%).

[0154] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 7.73 (br s, 1H), 7.32 (s, 1H), 7.09(d, J = 8.4 Hz , 1H), 6.75 (d , J = 8.4 Hz, 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).

[0155] LCMS (Method A): 1.467 min, 96.11%, 254.0 nm, MS: ES+ 191.05 (M, M+2:269.0,271.0) Step-5: At room temperature, to 3-(4-amino-3-bromophenyl)-3-methylpyrrolidin-2-one (A4) (0.50 g, 1.858 mmol, 1.0 equiv), CAS: 128796-39-4 (0.53 g, 2.787 mmol, 1.5 equiv) in DCM (10 mL) stirring solution, DIPEA (0.71 g, 5.574 mmol, 3.0 equiv) was added, then Cu (OAc) 2 (0.50 g, 2.787 mmol, 1.5 equiv) was added, and the resulting mixture was stirred at room temperature under O 2 atmosphere for 48 h. The reaction was monitored via TLC (using 100% EtOAc as mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 48 h. The resulting reaction mixture was diluted with water (20 mL) and extracted with DCM (3x20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to provide 0.6 g of crude product. The obtained crude material 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%).

[0156] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.26 (s, 1H), 7.87 (s,1H), 7.69 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 8.8 Hz , 2H), 7.43-7.34 (m,2H), 6.95 (d, J = 8.4 Hz ,2H), 3.28-3.22 (m, 1H), 3.17-3.11 (m, 1 H), 2.43 – 2.37 (m, 1 H), 2.19 – 2.13 (m, 1 H), 1.39 (s, 3 H).

[0157] LCMS (Method A): 2.490 min, 87.23 %, 254.0 nm, MS: ES+ 413.1 (M) 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) and then PdCl(dppf) (0.247 g, 0.338 mmol, 0.5 eq) under N2(g) atmosphere and the resulting mixture was stirred at 100°C under CO(g) at 40 bar pressure for 16 h. The reaction was monitored on TLC (using 100% EtOAc as mobile phase), which confirmed that the reaction was complete after stirring at 100°C for 16 h. The resulting reaction mixture was directly filtered over celite. The filtrate was dried over Na2SO4 and concentrated under reduced pressure to provide 0.42 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as stationary phase (0-0.5% MeOH in DCM) to afford methyl 5-(3-methyl-2-oxopyrrolidin-3-yl)-2-((4-(trifluoromethyl)phenyl)amino)benzoate (A6) (0.085 g, 0.216 mmol, yield: 31.97%).

[0158] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 9.28 (s, 1H), 7.93 (d, J = 2.4 Hz , 1 H), 7.86 (br s, 1H), 7.79-7.56 (m, 3H), 7.44 (d, J = 8.8 Hz , 1H), 7.33(d, J = 8.4 Hz , 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).

[0159] LCMS (Method A): 2.545 min, 91.89 %, 254.0 nm, MS: ES+ 393.0 (M+1) 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 equiv) in MeOH (2 mL) was added hydrazine hydrate (1.0 mL, 5.0) at room temperature, followed by stirring at 90 °C for 4 h. The reaction was monitored on TLC (using MeOH:DCM; 1:9 as mobile phase), which confirmed that the reaction was complete after stirring at 90 °C for 4 h. The resulting reaction mixture was concentrated under reduced pressure to provide 0.16 g of crude product. The crude material obtained was purified by trituration with pentane to obtain 5-(3-methyl-2-oxopyrrolidin-3-yl)-2-((4-(trifluoromethyl)phenyl)amino)benzohydrazide (A7) (0.16 g, 0.407 mmol, yield: quantitative).

[0160] LCMS (Method A): 1.989 min, 84.56 %, 254.0 nm, MS: ES+ 393.12 (M+1).

[0161] 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 equiv) in dichloromethane (1.5 mL) was added triethylamine (0.115 g, 1.146 mmol, 3.0 equiv) at 0 °C. Acetyl chloride (0.029 g, 0.382 mmol, 1.0 equiv) was then added at 0 °C and stirred at room temperature for 4 h. The reaction was monitored on TLC (using MeOH:DCM; 0.5:9.5 as mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 4 h. The resulting reaction mixture was diluted with H2O (5 mL) and extracted with DCM (3x10 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide 0.14 g of crude product. The crude material obtained was purified by trituration with pentane to afford N′-acetyl-5-(3-methyl-2-oxopyrrolidin-3-yl)-2-((4-(trifluoromethyl)phenyl)amino)benzohydrazide (A8) (0.14 g, 0.322 mmol, yield: quantitative).

[0162] LCMS (Method A): 1.994 min, 68.01%, 254.0 nm, MS: ES+ 435.3 (M+1).

[0163] 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 equiv) in dichloromethane (2 mL) was added triethylamine (0.097 g, 0.966 mmol, 3.0 equiv) at 0°C. TosCl (0.073 g, 0.386 mmol, 1.2 equiv) was then added at 0°C and stirred at room temperature for 3 h. The reaction was monitored on TLC (using MeOH: DCM; 1: 9 as mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 3 h. The resulting reaction mixture was diluted with H2O (5 mL) and extracted with DCM (3x10 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide 0.18 g of crude product. The obtained 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%).

[0164] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 9.20 (s, 1H), 7.89 (s, 2H), 7.62 (d, J = 8.4 Hz , 2H), 7.56 (s, 2H), 7.35 (d, J = 8.4 Hz , 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).

[0165] LCMS (Method A): 2.350 min, 99.70%, 254.0 nm, MS: ES+ 417.1 (M+1).

[0166] HPLC (Method B): 8.27 min, 99.87%, 254.0 nm 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)

[0167] 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) followed by potassium acetate (0.56 g, 5.807 mmol, 3.0 eq) at room temperature and purged with N2(g) for 30 min at room temperature. 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 on TLC (using EtOAc:hexane; 7:3 as mobile phase) which confirmed the completion of the reaction after stirring at 100 °C for 4 h. The reaction mixture of gained is H o (20 mL) dilutes and uses EtOAc (3x30 mL) to extract.The organic layer merged is through Na sO dry and under reduced pressure concentrate, to provide 1.4 g crude product.The crude material obtained is purified by flash column chromatography using silicon dioxide (230-400 mesh) as stationary phase (0-80%EtOAc in hexane) purifying, obtain 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, yield: 71.07%).

[0168] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.12 (s, 1H), 7.82 (s, 1H), 7.62 (d, J = 2.4 Hz , 1H), 7.52-7.47 (m, 3H), 7.29 (d, J = 8.4 Hz , 1H), 7.11 (d, J = 8.8 Hz ,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).

[0169] Step-2: To a stirred solution of 4-bromo-1-methyl-1H-imidazole (CAS: 25676-75-9) (0.25 g, 1.552 mmol, 1.0 equiv) in 1,4-dioxane:HO (7:3) (10 mL) at room temperature 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 equiv) followed by potassium carbonate (0.64 g, 4.658 mmol, 3.0 equiv) and purging with N2(g) was continued for 30 min at room temperature. Then PdCl2(dppf) (0.056 g, 0.077 mmol, 0.05 eq) was added and stirred at 100 °C for 6 h. The reaction was monitored on TLC (using MeOH:DCM; 0.5:9.5 as mobile phase), which confirmed that the reaction was complete after stirring at 100 °C for 6 h. The resulting reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3x30 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide 0.75 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as 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%).

[0170] 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 merged with the DMSO solvent peak LCMS (Method A): 1.851 min, 98.07%, 254.0 nm, MS: ES+ 415.17 (M+1).

[0171] HPLC (Method A): 8.15 min, 97.38%, 254.0 nm Example 3-Synthesis of 1-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzyl)imidazolidin-2-one (Compound 3)

[0172]

[0173] Step-1: To a solution of 4-amino-3-bromobenzoic acid methyl ester (CAS: 106896-49-5) (10.0 g, 43.478 mmol, 1.0 equiv), CAS: 455-13-0 (11.8 g, 43.478 mmol, 1.0 equiv) in toluene (100 mL), cesium carbonate (42 g, 130.43 mmol, 3.0 equiv) was added, and the reaction mixture was stirred at room temperature under N2 purge for 10 min. Then Pd(OAc)2 (0.97 g, 4.34 mmol, 0.1 equiv) and Xantphos (2.5 g, 4.347 mmol, 0.1 equiv) were added under a nitrogen atmosphere. The reaction mixture was heated at 100 °C under stirring for 16 h. The reaction was monitored on TLC (using EtOAc: hexane; 3: 7 as mobile phase). The reaction mixture of gained is quenched with ice-cold water (100 mL) and extracted with EtOAc (3 x 200 mL).The organic layer merged is through Na SO Drying and under reduced pressure concentration, to provide 13.0 g crude product.The crude material obtained is purified by manual column using silica (60-120 mesh) as stationary phase (eluent, 30% ethyl acetate in hexane) purifying, obtain 3-bromo-4-((4-(trifluoromethyl) phenyl) amino) methyl benzoate (A10) (8.7 g, 23.26 mmol, yield: 53%).

[0174] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.50 (s, 1H), 8.13 (d, J = 2.0 Hz ,1H), 7.84 (dd, J = 8.4 Hz , 2.0 Hz , 1H), 7.63 (d, J = 8.4 Hz , 2H), 7.41 (d, J = 8.4 Hz , 1H), 7.32 (d, J = 8.4 Hz , 2H), 3.83 (s, 3H) LCMS (Method A): 10.559 min, 99.69%, 210.0 nm, MS: ES+ 375 (M+1) 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 under N2 purge for 10 min. Pd(dppf)Cl2 (0.97 g, 4.347 mmol, 0.1 eq) was then added under nitrogen atmosphere, and the resulting mixture was heated at 95°C for 16 h. The reaction was monitored on TLC (using EtOAc:hexane; 1:9 as 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 layer was dried over Na2SO4 and concentrated under reduced pressure to provide 12.0 g crude product. The crude material obtained was directly used in the next step to obtain 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzoic acid methyl ester (A11) (12 g crude product, 28.503 mmol, yield: quantitative) LCMS (Method A): 3.219 min, 61.83%, 254.0 nm, MS: ES+ 422 (M+1) 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 under N2 purge for 10 min. Pd(dppf)Cl2 (2.0 g, 28.50 mmol, 0.1 eq) was then added under nitrogen atmosphere and the reaction mixture was heated to 90°C and maintained and stirred for 16 h. The reaction was monitored on TLC (using EtOAc: hexane; 7:3 as mobile phase). The resulting reaction mixture was quenched with ice-cold water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide 14.0 g of crude product. The crude material obtained was purified by manual column using silica (60-120 mesh) as stationary phase (eluent, 15% ethyl acetate in hexane) to obtain 3-(1-methyl-1H-imidazole-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzoic acid methyl esters (A12) (7.0 g, 18.66 mmol, yield: 65.49%).

[0175] 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, 1 H),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 small amount of aliphatic impurity was observed.

[0176] LCMS (Method A): 2.174 min, 98.88%, 254.0 nm, MS: ES+ 376 (M+1) Step-4: A solution of 3-(1-methyl-1H-imidazole-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzoic acid methyl ester (A12) (3.0 g, 8.0 mmol, 1.0 equiv), BocO (2.6 g, 12.0 mmol, 1.5 equiv) and DMAP (0.39 g, 3.20 mmol, 0.4 equiv) in DCM (20 mL) was stirred at room temperature for 16 h. The reaction was monitored on TLC (using EtOAc: hexane; 1: 1 as mobile phase), which confirmed that the reaction was complete after 16 h. The resulting reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3x50 mL). The combined organic layer was dried over NaSO and concentrated under reduced pressure to provide 4.0 g of crude product. The crude material obtained was purified by combi flash using silica (230-400 mesh) as the stationary phase (10% ethyl acetate in hexanes) to afford 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%).

[0177] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.65 (d, J = 2.0 Hz , 1H), 7.81 (dd, J = 8.8 Hz ,2.0 Hz , 1H), 7.72 (s,1H), 7.66 (d, J = 8.8 Hz , 2H), 7.39 (d, J = 8.8 Hz , 2H), 7.26 (d, J = 8.0 Hz , 1H), 7.20 (d, J = 1.2 Hz , 1H), 3.89 (s,3H), 3.63 (s,3H), 1.15 (s,9H).

[0178] LCMS (Method A): 2.234 min, 100%, 254.0 nm, MS: ES+ 476 (M+1) 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 equiv) in THF (14 mL) was added LiBH4 (2.9 mL, 2.947 mmol, 1.0 equiv) at room temperature. The reaction mixture was heated to 50 °C and kept stirring for 16 h. The reaction was monitored on TLC (using EtOAc:hexane; 9:1 as mobile phase), which confirmed that the reaction was complete 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 Na2SO4 and concentrated under reduced pressure to provide 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 hexanes) to afford 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%).

[0179] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.0 (d, J = 1.2 Hz, 1H), 7.66-7.62 (m,3H), 7.37 (d, J = 8.4 Hz , 2H), 7.20 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.08-7.05 (m,2H), 5.30 (t, J = 6.0 Hz , 1H), 4.55 (d, J = 6.0 Hz , 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) Step-6: To a stirred solution of tert-butyl (4-(hydroxymethyl)-2-(1-methyl-1H-imidazole-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A14) (0.6 g, 1.342 mmol, 1.0 equiv) in DCM (6 mL) was added DIPEA (0.074 g, 2.684 mmol, 2.0 equiv) and MeSO2Cl (0.183 g, 1.610 mmol, 1.2 equiv) at 0°C. The resulting mixture was allowed to warm to room temperature and kept stirring for 16 h. The reaction was monitored by TLC (using EtOAc:hexane; 7:3 as mobile phase), which confirmed that the reaction was complete. The resulting reaction mixture was diluted with water (10 mL) and extracted with DCM (3 x 20 mL), dried over Na2SO4 and concentrated under reduced pressure to provide 1.0 g of crude product. The crude material obtained was purified by CombiFlash® using silica (230-400 mesh) as the stationary phase (50% ethyl acetate in hexanes) to afford 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%).

[0180] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.11 (d, J = 2.4 Hz , 1H), 7.69-7.64(m, 3H), 7.38 (d, J = 8.8 Hz , 2H), 7.31 (dd, J = 8.0 Hz , 2.4 Hz , 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) Step-7: A solution of tert-butyl (4-(chloromethyl)-2-(1-methyl-1H-imidazole-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A15) (0.4 g, 0.860 mmol, 1.0 equiv) and CAS 107-15-3 (0.051 g, 0.86 mmol, 1.0 equiv) 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 mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 16 h. The resulting reaction mixture was diluted with water (10 mL) and extracted with DCM (3x20 mL), dried over NaSO and concentrated under reduced pressure to provide 0.4 g crude product. The obtained crude material was triturated by 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%).

[0181] 1 H NMR (DMSO-d6, 400 MHz): 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), 7.051-7.031(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).

[0182] LCMS (Method A): 1.50 min, 99.13%, 254.0 nm, MS: ES+ 489 (M+1) 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 equiv) in toluene (2.5 mL) was added DIPEA (0.074 g, 0.613 mmol, 2.0 equiv) and CDI (0.099 g, 0.613 mmol, 1.2 equiv) at room temperature. The resulting mixture was heated to 50 °C and kept stirring for 8 h. The reaction was monitored by TLC (using DCM:MeOH; 9:1 as mobile phase), which confirmed that the reaction was complete after stirring at 50 °C for 8 h. The resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3x20 mL), dried over Na2SO4 and concentrated under reduced pressure to provide 0.3 g of crude product. The crude material obtained was purified by combi flash using silica (200-400 mesh) as stationary phase (7% DCM in MeOH) to afford 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, yield: 34.94%).

[0183] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 7.92 (d, J = 1.6 Hz, 1H), 7.66-7.63 (m,3H), 7.38 (d, J = 8.4 Hz ,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).

[0184] LCMS (Method A): 1.908 min, 91.46%, 254.0 nm, MS: ES+ 516 (M+1) Step-9: To a stirred solution of tert-butyl (2-(1-methyl-1H-imidazole-4-yl)-4-((2-oxoimidazolidine-1-yl)methyl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A17) (0.15 g, 0.376 mmol, 1.0 equiv) 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 mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 2 h. The resulting reaction mixture was alkalized with saturated NaHCO (5 mL) and extracted with EtOAc (3x10 mL), dried over NaSO and concentrated under reduced pressure to provide 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 afford 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%).

[0185] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 9.87 (s, 1H), 7.77 (d, J = 0.8 Hz,1H), 7.64 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 1.2 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H),7.36 (d, J = 8.0 Hz, 1H), 7.10-7.07 (m, 3H), 6.41 (s,1H), 4.22 (s,2H), 3.69 (s,3H), 3.23 (s,4H).

[0186] LCMS (Method A): 1.690 min, 99.78%, 254.0 nm, MS: ES+ 415 (M+1) HPLC (Method A): 7.77 min, 96.04%, 254.0 nm Example 4-Synthesis of 1-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzyl)imidazolidine-2,4-dione (Compound 4)

[0187]

[0188] Step-1: At room temperature, NaH (0.086 g, 6.00 mmol, 2.0 equiv) was added to a stirred solution of imidazolidine-2,4-dione CAS 461-72-3 (0.3 g, 3.00 mmol, 1.0 equiv), CAS824-94-2 (0.46 g, 3.00 mmol, 1.0 equiv) in DMF (2 mL). The resulting mixture was heated to 80 ° C and kept stirring for 6 h. The reaction was monitored on TLC (using EtOAc: hexane; 7: 3 as mobile phase), which confirmed that the reaction was completed after 6 h. The resulting reaction mixture was quenched with water (5 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide 0.35 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as stationary phase (50% EA in hexanes) to afford 3-(4-methoxybenzyl)imidazolidine-2,4-dione (A18) (0.25 g, 1.136 mmol, yield: 37%).

[0189] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.10 (s, 1H), 7.23-7.19 (m, 2H), 6.88 (d, J = 8.8 Hz ,2H), 4.44-4.40 (m, 2H), 3.95 (s, 2H), 3.72 (s, 3H).

[0190] 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 kept stirring for 3 h. The reaction was monitored on TLC (using EA:HEX; 8:2 as mobile phase), which confirmed that the reaction was complete 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 Na2SO4 and concentrated under reduced pressure to provide 0.3 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as stationary phase (80% EA in HEX) to give tert-butyl (4-((3-(4-methoxybenzyl)-2,4-dioxoimidazolidine-1-yl)methyl)-2-(1-methyl-1H-imidazole-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A19) (0.18 g, 0.277 mmol, yield: 42%).

[0191] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 7.93 (d, J = 2.0 Hz , 1H), 7.67(s,1H), 7.64-7.62 (d, J = 8.8 Hz , 2H), 7.39 (d, J = 8.4 Hz , 2H), 7.24 (d, J = 8.8 Hz , 2H), 7.16 (dd, J=8.0 Hz, 2.4 Hz , 1H), 7.11-7.09 (m,2H), 6.88 (d, J = 8.4 Hz , 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).

[0192] LCMS (Method A): 2.259 min, 98.94 %, 254.0 nm, MS: ES+ 649 (M+1) Step-3: To a solution of tert-butyl (4-((3-(4-methoxybenzyl)-2,4-dioxoimidazolidin-1-yl)methyl)-2-(1-methyl-1H-imidazole-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A19) (0.18 g, 0.277 mmol, 1.0 equiv) in ACN:HO (1.8 mL) was added CAN (0.151 g, 0.277 mmol, 1.0 equiv). The resulting mixture was stirred at room temperature for 3 h. The reaction was monitored on TLC (using EA:HEX; 9:1 as mobile phase), which confirmed that the reaction was 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 provide 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 afford 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%).

[0193] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 10.95 (brs, 1H) 9.87 (s,1H), 7.87(d, J = 8.0 Hz , 1H), 7.67-7.65 (m, 3H), 7.44-7.26 (m,4H), 7.13 (d, J = 8.8 Hz ,1H), 4.53 (s, 2H), 3.91-3.87 (m, 2H), 3.78 (brs, 3H), 1.22 (s, 9H).

[0194] LCMS (Method A): 1.898 min, 62.16%, 254.0 nm, MS: ES+ 529 (M+1) 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 equiv) in DCM (1 mL) was added 4M 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 mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 2 h. The resulting reaction mixture was basified with saturated NaHCO (5 mL) and extracted with EtOAc (3 x 25 mL), dried over NaSO and concentrated under reduced pressure to provide 0.09 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase; the desired product was eluted in 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%).

[0195] 1 H NMR (DMSO-d6, 400 MHz): 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 = 8.4 Hz , 2H), 7.37 (d, J = 8.4 Hz ,1H), 7.12-7.10 (m, 3H), 4.42 (s, 2H), 3.87 (s, 2H), 3.70 (s, 3H).

[0196] LCMS (Method A): 1.710 min, 95.31%, 254.0 nm, MS: ES+ 429 (M+1) HPLC (Method A): 5.95 min, 97.18%, 210.0 nm Example 5-Chiral Separation of 3-methyl-3-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (Compound 5 and Compound 6)

[0197] The racemate of compound 2 (0.096 g) was subjected to chiral SFC purification on a (CHIRALPAK IA 250X50 mm 5µm) column, wherein two peaks were separated, namely 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 250X50 mm 5µm Mobile phase A: Liquid CO2 Mobile phase B: 0.1% M.NH3 in MEOH-ACN (50-50) Flow rate (ml / min): 160 Instrument ID: WATERS SFC 350 with 2489 UV detector Method: Time: Flow: %A: %B (0.01:160:60:40), (12.00:160:60:40) Compound 5 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 9.81 (s, 1H), 7.80 (s, 1H), 7.77-7.76 (m, 2H), 7.55 (s, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.4 Hz ,1H), 7.23(dd, J = 8.4, 2.0 Hz , 1H), 7.08 (d, J = 8.4 Hz , 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).

[0198] 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, 400 MHz): δ ppm, 9.82 (s, 1H), 7.81 (s, 1H), 7.77-7.76 (m, 2H), 7.55 (s, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.4 Hz,1H), 7.23(dd, J = 8.0,2.0 Hz, 1H), 7.08 (d, J = 8.4 Hz,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).

[0199] 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 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 (Compound 7 and Compound 8)

[0200] The racemate of compound 1 (0.2 g) was subjected to chiral SFC purification on a (CHIRALPAK IA 250X50 mm 5 µm) column, wherein two peaks were separated, namely 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 250X50 mm 5µm Mobile phase A: Liquid CO2 Mobile phase B: 0.1% M.NH3 in MEOH-ACN (50-50) Flow rate (ml / min): 160 Instrument ID: WATERS SFC 350 with 2489 UV detector Method: Time: Flow: %A: %B (0.01:160:55:45), (16.00:160:55:45) Input amount: 0.2 g Output: Compound 7 = 0.040 g (yield % = 38.52%) and Compound 8 = 0.045 g (yield % = 46.79%) Compound 7 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 9.20 (s, 1H), 7.90-7.89 (m, 2H), 7.62(d, J = 8.8 Hz , 2H), 7.56 (d, J = 2.4 Hz , 2H), 7.35 (d, J = 8.8 Hz , 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, 400 MHz): δ ppm), 7.99 (d, J = 2.0 Hz , 1H), 7.63-7.54 (m,4H),7.40 (d, J = 8.4 Hz , 2H), 3.47-3.42 (m, 2 H), 2.66 (s, 3H), 2.58-2.52 (m,1H), 2.36-2.30 (m, 1H), 1.63 (s, 3H), 1H combined with MeOD water, which is clearly visible in DMSO NMR LCMS (Method A): 2.344 min, 100.00 %, 254.0 nm, MS: ES+ 417.38 (M+1) HPLC (Method B): 8.33 min, 99.60%, 330.0 nm Chiral HPLC: 4.38 min, 100.00%, 300.0 nm Compound 8: 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 9.20 (s, 1H), 7.90-7.89 (m, 2H), 7.62(d, J = 8.4 Hz, 2H), 7.56 (s,2H), 7.35 (d, J = 8.4 Hz , 2H), 3.27-3.24 (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).

[0201] 1 H NMR (MeOD, 400 MHz): δ ppm), 7.96 (s, 1H), 7.60-7.54 (m, 4H), 7.37(d, J = 8.4 Hz , 2H), 2.60 (s, 3H), 2.55-2.49 (m, 1H), 2.34-2.27(m, 1H), 1.55(s, 3H).

[0202] 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 %, 235.0 nm Chiral HPLC: 3.65 min, 100 %, 300.0 nm 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)

[0203] Step-1: At 25 DEG C, to (A12) (1.5 g, 3.99 mmol, 1.0 equivalent) in methanol (15 mL) stirring solution, add NaOH solution (0.32 g, 7.99 mmol, 2.0 equivalent). Then RM is heated to 40 DEG C and keeps for 16h at 40 DEG C. The reaction is monitored by TLC (using 70%EtOAc in hexane as mobile phase), which confirms that the reaction is completed after stirring 16 h at 40 DEG C. The reaction mixture obtained is purified by grinding with DCM and pentane, to provide 3-(1-methyl isophthalic acid H-imidazoles-4-yl)-4-((4-(trifluoromethyl) phenyl) amino) benzoic acid (A21) (1.1 g, 3.04 mmol, yield: 76.18%).

[0204] 1H NMR (DMSO-d6, 400 MHz): 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 = 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.52-7.47 (m,1H), 7.31-7.21 (m, 2H) 3.78 (s, 3H).

[0205] LCMS (Method-A): 1.79, 79.92 %, 254 nm, MS: ES+ 362 (M), (M+1) Step-2: At 0 ° C, DIPEA (1.17 g, 9.14 mmol, 3.0 equivalents) and HATU (2.31 g, 6.09 mmol, 2.0 equivalents) were added to a solution of (A21) (1.1 g, 3.04 mmol, 1.0 equivalents) in DCM (10 mL) respectively. Then CAS No. 6638-79-5 (0.32 g, 3.35 mmol, 1.1 equivalents) was 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 mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 4 h. The resulting reaction mixture was extracted with DCM (3 x 100 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide 1.5 g of crude product. The crude material obtained was purified by manual column chromatography using silica (100-200 mesh) as the stationary phase (50% EtOAc in hexanes as the mobile phase) to afford 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%).

[0206] 1 H NMR (DMSO-d6, 400 MHz): δ ppm 10.72 (s,1H), 7.98 (s , 1H), 7.85 (s,1H), 7.72 (s,1H), 7.60 (d, J = 8.4 Hz , 2H), 7.49-7.36 (m , 2H), 7.29 (d,J = 8.4 Hz , 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).

[0207] Step-3: At room temperature, under nitrogen atmosphere, to a stirred solution of N-methoxy-N-methyl-3-(1-methyl-1H-imidazole-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzamide (A22) (1.0 g, 2.47 mmol, 1.0 equiv) in DCM, (BOC)2O (0.80 g, 3.70 mmol, 1.5 equiv) and DMAP (0.12 g, 0.98 mmol, 0.4 equiv) were added. The reaction mixture was stirred for 16 h. TLC showed that the reaction was complete (70% EtOAc in hexane as mobile phase). The resulting reaction mixture was extracted with DCM (3 x 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide 1.8 g of crude product. The crude material obtained was purified by manual column using silica (100-200 mesh) as stationary phase (using 50% EtOAc in hexanes as mobile phase) to afford 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%).

[0208] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.25 (d, J = 2.0 Hz , 1H), 7.72-7.65 (m,3H), 7.60 (d, J = 8.8 Hz, 1H), 7.47-7.41 (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) Step-4: To a solution of tert-butyl (4-(methoxy(methyl)carbamoyl)-2-(1-methyl-1H-imidazole-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A23) (0.45 g, 0.89 mmol, 1.0 equiv) in THF was added MeMgBr in THF (1.78 mL, 2.0 equiv) at 0°C. The reaction mixture was then allowed to warm to room temperature and stirred for 3 h. The reaction was monitored on TLC (using 50% EtOAc in hexanes as 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 provide 0.7 g of crude product. The crude material obtained was purified by manual column using silica (100-200 mesh) and the desired product was eluted (15%-20% EtOAc in hexanes as mobile phase) to afford 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%).

[0209] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.58 (d, J = 2.0 Hz , 1H), 7.83 (dd, J = 6.0 Hz, 1H), 7.72 (s, 1H), 7.66 (d, J = 8.8 Hz , 2H), 7.40 (d, J = 8.4 Hz , 2H),7.29-7.23 (m, 2H), 3.64 (s, 3H), 2.19 (s, 3H), 1.64 (s, 9H).

[0210] Note: 1 Impurity peaks observed in H NMR LCMS (Method A): 2.115, 100%, 254 nm, MS: ES+ 460 (M+1) Step-5: To a stirred solution of tert-butyl (4-acetyl-2-(1-methyl-1H-imidazole-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A24) (0.30 g, 0.653 mmol, 1.0 equiv) in ethanol (6 mL) was added ammonium carbonate (0.25 g, 2.61 mmol, 4.0 equiv) at room temperature, followed by TMSCN (3 mL) and ammonium hydroxide (6 mL) solution. The reaction mixture was then heated to 100 °C and stirred for 16 h. The reaction was monitored on TLC (using 70% EtOAc in hexanes as mobile phase). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide 0.7 g of crude product. The crude material obtained was purified by manual column using silica (100-200 mesh) as stationary phase (using 50% EtOAc in hexanes as mobile phase) to afford 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%).

[0211] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.71 (d, J = 6.0 Hz , 1H), 8.16 (d, J = 2.4Hz , 1H), 8.07 (s, 1H), 7.97 (dd, J = 12.0 Hz, 1H), 7.69 (s, 1H), 7.64 (d, J = 6.8 Hz , 2H), 7.36 (d, J = 6.8 Hz , 2H), 7.16-7.11 (m, 2H), 3.62 (s, 3H), 1.99 (s, 3H), 1.35 (s, 9H).

[0212] LCMS (Method A): 1.878 min, 85.79%, 243.0 nm, MS: ES+ 530 (M+1) Step-6: At room temperature, to a solution of tert-butyl (2-(1-methyl-1H-imidazole-4-yl)-4-(4-methyl-2,5-dioxoimidazolidine-4-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (A25) (0.25 g, 0.472 mmol, 1.0 eq.) in 2.5 ml DCM, HCl.dioxane (2.49 ml, 5.0 eq.) was added and stirred for 3 hours. The reaction was monitored on TLC (using 70% EtOAc in hexane as mobile phase). RM was concentrated under reduced pressure, and the crude material was basified with NaHCO solution, and extracted with EtOAc (3x50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to provide 0.35 g crude product. The crude material was purified by trituration with DCM and pentane solution to afford 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%).

[0213] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 10.76 (s, 1H), 9.92 (s, 1H), 8.55 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.79 (s, 1H), 7.58 (s, 1H), 7.51 (d, J = 8.8 Hz , 2H), 7.41 (d, J = 8.4 , 1H), 7.28 (dd, J = 6.0 Hz , 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 min, 98.94%, 210 nm.

[0214] Example 8 Synthesis of 8-(3-methyl-3-(3-(oxazol-2-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (Compound 10)

[0215] Step-1: At -78 ° C, a solution of oxazole (2.0 g, 28.9 mmol, 1.0 equivalent) in THF (20 mL) was prepared in 50 mL single-necked RB. n-BuLi (21.67 ml, 34.6 mmol, 1.2 equivalent) was added dropwise to the reaction solution, followed by ZnBr2. The resulting mixture was stirred for 1 h at -78 ° C, then a solution of iodine 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 mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 30 min. The resulting reaction mixture was quenched with NH4Cl solution (20 mL) and extracted with DCM (3x20 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide 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 hexanes) to afford 2-iodooxazole (A26) (2.0 g, 10.30 mmol, yield: 35%).

[0216] 1 H NMR (DMSO-d6, 400 MHz): δ ppm 8.25 (s, 1H), 7.23 (s, 1H).

[0217] Step-2: In a 30 mL reactor, under N2 atmosphere, to a stirred solution of 2-iodooxazole (A26) (0.25 g, 0.54 mmol, 1.0 equiv) in dioxane (2 mL) was added (A9) (0.126 g, 0.65 mmol, 1.2 equiv), followed by K2CO3 (0.22 g, 1.62 mmol, 3 equiv) and water. PdCl2(dppf) (0.019 g, 0.02 mmol, 0.05 equiv) was added. The reactor was sealed and the reaction was stirred at 90 ° C for 2 h. The reaction was monitored by TLC (using EA: hexane; 7.0: 3.0 as mobile phase), which confirmed that the reaction was complete. The resulting reaction mixture was quenched with water (10 mL) and extracted with EA (3 x 10 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide 0.3 g of crude product. The obtained 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%).

[0218] 1 H NMR (DMSO-d6, 400 MHz): δ ppm 9.92 (s, 1H), 8.28 (s, 1H), 8.01 (d, J = 2.0Hz , 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 is merged with the DMSO solvent peak, which is clearly visible in the MeOD NMR 1 H NMR (MeOD, 400 MHz): δ ppm 10.17 (s, 1H), 8.09 (d, J = 1.6 Hz, 1H),7.99 (s, 1H), 7.61-7.56 (m, 3H), 7.48 (d, J = 8.8 Hz , 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).

[0219] LCMS: 2.63 min, 100%, 241.0 nm, MS: ES+ 402.2 (M+1) HPLC: 9.26 min, 100%, 210 nm 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)

[0220] Step-1a: A stirred solution of CAS: 6154-04-7 (0.1 g, 1.009 mmol, 1.0 eq.) in ACN (2.5 mL) was prepared in a 10 mL glass vial at room temperature. To this reaction solution was added iodine (0.256 g, 1.009 mmol, 1.0 eq.) at the same temperature. The resulting reaction mixture was then stirred at 45 °C and tIn 4-iodo-2-methyl-2H-tetrazole (A27) (0.145 g, 0.690 mmol, yield: 68.72%), 5-iodo-2-methyl-2H-tetrazole (A27) (0.145 g, 0.690 mmol, yield: 68.72%) was added in the mixture of 4-nitro-1-nitropropene (Bu nitrite), and then the reaction was stirred for 3 h at 45 ° C. Monitoring reaction by TLC (50% ethyl acetate in hexane as mobile phase), it confirms that the reaction is completed after stirring 3 h at 45 ° C. The reaction mixture of gained is cooled at room temperature, then diluted with ethyl acetate (100 mL) for reaction mixture, and washed with sodium sulfite solution (100 mL) and NaCl solution, then through Na2SO4 is dried and concentrated under reduced pressure to obtain crude material, and this crude material is used hexane and ethyl acetate purification by column chromatography. Product is eluted with 10% ethyl acetate in hexane, to provide 5-iodo-2-methyl-2H-tetrazole (A27) (0.145 g, 0.690 mmol, yield: 68.72%).

[0221] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 4.39 (s, 3H) LCMS (Method A): 1.178 min, 100%, 254.0 nm, MS: ES+ 211.05 (M+1) Step-1: At room temperature, in a 10 mL glass vial, NaCO (0.035 g, 0.325 mmol, 3.0 equivalents) was added to a stirred solution of A9 (0.05 g, 0.108 mmol, 1.0 equivalents) and A27 (0.023 g, 0.108 mmol, 1.0 equivalents) in dioxane: water (1.0 mL: 0.3 mL). The resulting reaction mixture was stirred for 15 min at room temperature under a nitrogen purge. PdCl (dppf) (0.0038 g, 0.050 mmol, 0.05 equivalents) was added at room temperature, and then the vial was sealed and heated to 110 ° C, where stirring was maintained for 2 h. The reaction was monitored by TLC (100% ethyl acetate in hexane as mobile phase), which confirmed that the reaction was complete after stirring at 110 ° C for 2 h. The reaction mixture of gained is cooled at room temperature, then poured into cold water (50 mL) and extracted with ethyl acetate (30 mL x 2), the organic layer is through Na2SO4 drying and concentrated under reduced pressure to obtain crude material, the crude material is purified by column chromatography using hexane and ethyl acetate. The product is eluted with 70% ethyl acetate in hexane, and further purified by preparative HPLC purification method-A, to provide 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%).

[0222] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.72 (s, 1H), 8.02 (s, 1H), 7.89 (s,1H), 7.55-7.52 (m, 4H), 7.20 (d, J = 8.4 Hz , 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).

[0223] LCMS (Method A): 2.439 min, 100%, 254.0 nm, MS: ES+ 417.3 (M+1) HPLC (Method B): 8.506 min, 99.48%, 210.0 nm Example 10-Synthesis of 3-methyl-3-(3-(pyridazin-3-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (Compound 12)

[0224] Step-1: At room temperature, POBr (0.032 g, 0.80 mmol, 2.0 equiv) was added to a solution of pyridazine-3 (2H) -one (CAS 504-30-3) (0.15, 0.40 mmol, 1.0 equiv) in ACN (3 mL), and the resulting mixture was heated to 80 ° C and kept stirring for 3 h. The reaction was monitored on TLC (using EtOAc: Hex; 1: 1 as mobile phase), which confirmed that the reaction was 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 provide 0.35 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) and the desired product was eluted with 40% EA in hexanes to afford 3-bromopyridazine (A28) (0.15 g, 0.943 mmol, yield: 30.19%).

[0225] 1 H NMR (DMSO-d6, 400 MHz): 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).

[0226] LCMS (Method A): 0.856 min, 100%, 254.0 nm, MS: ES+ 160.9 (M+2) 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:H2O (1 mL) was added cesium carbonate (0.211 g, 0.651 mmol, 3.0 eq) and the resulting mixture was purged with N2 for 10 min followed by the addition of PdCl2(dppf) (0.0078 g, 0.010 mmol, 0.05 eq). The reaction mixture was heated at 90°C with stirring for 2 h. In TLC (using DCM: MeOH; 9: 1 as mobile phase), the reaction is monitored. The reaction mixture gained is quenched with ice-cold water (5 mL) and extracted with EtOAc (3 x 5 mL). The organic layer merged is dried over Na2SO4 and concentrated under reduced pressure to provide 0.15 g crude product. The crude material obtained is purified by manual flash chromatography using silica (200-400 mesh) as stationary phase (7%DCM in MeOH), to obtain 3-methyl-3-(3-(pyridazine-3-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (compound 12) (0.013 g, 0.0315 mmol, yield: 14.51%).

[0227] 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 merged with the MeOD solvent peak, which is clearly visible in the DMSO NMR 1 H NMR (MeOD, 400 MHz): 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 = 8.4 Hz , 2H), 2.64-2.58 (m, 1H), 2.38-2.31 (m, 1H), 1.61 (s, 3H), 1.21 (s, 1H).

[0228] LCMS (Method A): 2.175 min, 99%, 254.0 nm, MS: ES+ 412 (M+1) HPLC (Method A): 7.58 min, 99.24%, 254.0 nm Chiral HPLC (Method A): 4.31 min, 51.14%, 240.0 nm; 4.80 min, 48.85%, 240.0 nm Example 11-Synthesis of 3-methyl-3-(3-(pyrazin-2-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (Compound 13)

[0229] Step-1: A stirred solution of (A9) (0.15 g, 0.325 mmol, 1.0 eq.) in dioxane:H2O (7:3) was prepared in a 10 mL glass vial at room temperature. To the reaction solution, CAS: 56423-63-3 (0.05 g, 0.314 mmol, 1.0 eq.), Na2CO3 (0.10 g, 1.02 mmol, 3.0 eq.) were added at the same temperature under N2 atmosphere. PdCl2(dppf) (0.01 g, 0.01 mmol, 0.05 eq.) was then added, stirred, and heated at 110°C for 1 h. The reaction was monitored by TLC (MeOH:DCM, 1:9), which confirmed that the reaction was complete after stirring at 110°C for 1 h. The resulting reaction mixture was extracted with EA (20 ml) and H2O (20 ml). The organic layer was dried over Na2SO4, the solvent was removed on a rotary evaporator and purified by glass column chromatography using 230-400 mesh silica. The product (Compound 13) was eluted in 10% MeOH:DCM (0.040 g, 0.096 mmol Yield: 29.76%).

[0230] 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 = 2.4Hz, 1H ), 7.86 (s , 1H), 7.72 (d , J = 1.6 Hz , 1H), 7.54-7.51 (m , 1H),7.42 (d, J = 8.4Hz, 3H).), 6.93 (d, J = 8.4Hz, 2H), 3.27-3.24 (m , 1H), 3.20-3.16 (m,1H ), 2.22-2.15 (m, 1H), 1.44 (s, 3H), 1H merged with the DMSO solvent peak, which is clearly visible in MeOD NMR 1 H NMR (MeOD, 400 MHz): δ ppm, 8.97 (s, 1H), 8.69 (s, 1H), 8.50 (d, J = 2.4Hz, 1H), 7.79 (d, J = 1.6 Hz ,1H), 7.56-7.49 (m , 2H), 7.42 (d , J = 8.4Hz, 2H), 7.03(d, J = 8.4 Hz, 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 (Compound 14 and Compound 15)

[0232] program: Compound 9 (0.109 g) racemate was subjected to chiral SFC purification on a (CHIRALPAK IA 250X4.6 mm 5 µm) column, wherein two peaks were separated, namely 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%).

[0233] Column ID: CHIRALPAK IA, 250*4.6mm, 5 microns Mobile phase A: Liquid CO2 Mobile phase B: 0.1% M.NH3 in MEOH-ACN (50-50) Flow rate (ml / min): 4 Instrument ID: Waters SFC Survey System with 2998 PDA detector.

[0234] Method: 70:30 isocratic method; where flow rate = 4 ml / min; column oven temperature = 40°C; back pressure = 100 bar, and analysis time 9 min.

[0235] Input amount: 0.109 g Output: Compound 14 = 0.027 g (yield % = 24.77%) and Compound 15 = 0.037 g (yield % = 33.94%) Compound 14 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 10.76(brs, 1H), 9.92 (s, 1H), 8.60(s, 1H),7.83 (d, J =2.0 Hz ,1H), 7.79 (s,1H), 7.58 (s,1H), 7.51(d, J=8.4Hz , 2H),7.41(d, J=8.8Hz ,1H), 7.28 (dd, J=8.4 Hz, 2.0Hz ,1H), 7.11(d, J=8.4Hz , 2H), 3.71(s,3H), 1.68(s, 3H).

[0236] 1 H NMR (MeOD, 400 MHz): δ ppm), 7.81(d, J = 2.4 Hz , 1H), 7.70 (s, 1H),7.47-7.44 (m, 3H), 7.41-7.39 (m, 2H), 7.09 (d, J = 8.4 Hz , 2H), 3.76 (s, 3H), 1.82 (s, 3H).

[0237] 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 Chiral HPLC: 3.25 min, 100.00%, 240.0 nm Compound 15 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 10.77 (s,1H), 9.92 (s,1H), 8.60 (s,1H), 7.81 (dd, J=16.8 Hz, 2.4 Hz , 2H), 7.58 (s,1H), 7.51 (d, J=8.8 Hz , 2H), 7.41(d, J=8.4 Hz,1H), 7.28 (dd, J=8.8 Hz,2.4 Hz ,1H), 7.11(d, J=8.4 Hz , 2H), 3.71 (s,3H), 1.68 (s, 3H).

[0238] 1 H NMR (MeOD, 400 MHz): δ ppm), 7.81(d, J = 2.4 Hz , 1H), 7.71 (s, 1H),7.46-7.44 (m, 3H), 7.41-7.37 (m, 2H), 7.08(d, J = 8.4 Hz , 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%, 210.0 nm Chiral HPLC: 3.73 min, 93.63%, 240.0 nm 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)

[0239]

[0240] Step 1a A solution of glycine methyl ester hydrochloride (CAS: 5680-79-5) (275 g, 2190.3 mmol, 1.0 equiv) in methanol (100 mL) was cooled to 0 ° C, and TEA (332.4 g, 3285 mmol, 1.5 equiv) was then added. The mixture was stirred for 30 min, and then 4-methoxybenzaldehyde CAS: 123-11-5 (298.2 g, 2190.3 mmol 1.0 equiv) was added, and the mixture was stirred at room temperature for 4 h. The solution was cooled to 0 ° C, and then NaBH4 (165.5 g, 4380.7 mmol, 2.0 equiv) was added to the reaction mixture in batches. After stirring at room temperature for 16 h, the reaction was monitored on TLC (using EtOAc: hexane; 4:6 as mobile phase). The resulting reaction mixture was filtered, and the filtrate was distilled off, and water (500 mL) was added. The mixture was extracted with EtOAc (4 x 500 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide 202 g of crude product. The crude material obtained was directly used in the next step without any further purification. The reaction gave (4-methoxybenzyl)glycine methyl ester (A29) (202 crude products, 965.9 mmol, yield: quantitative).

[0241] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 7.21 (d, J = 8.8 Hz, 2H), 6.86 (dd, J = 6.8 Hz , 2.0 Hz , 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) Step-1: At 0 ° C, to a solution of ethyl 2-(4-nitrophenyl)acetate (400 g, 1912.04 mmol, 1.0 equivalent) in THF, add H The NaOH solution (229 g, 5736 mmol, 3.0 equivalent) in O (800 mL) was then stirred at room temperature for 16 h. The reaction mixture was monitored on TLC (using MeOH:DCM 1:9 as mobile phase). The resulting reaction mixture was distilled out, and water (100 mL) was then added. The mixture was acidified with 1N HCl and extracted with EtOAc (3 x 500 mL). The combined organic layer was dried over Na SO and concentrated under reduced pressure to provide a crude product. The obtained crude material was purified by manual column using silica (100-200 mesh) as stationary phase (eluent 7% MeOH:MDC) to afford 2-(4-nitrophenyl)acetic acid (A30) (200 g, 1104.0 mmol, yield: 57.63%).

[0242] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 12.59 (s, 1H), 8.193 (d, J = 8.8 Hz ,2H), 7.56 (d, J = 8.8 Hz , 2H), 3.79 (s,2H).

[0243] Step-2: To a solution of 2-(4-nitrophenyl)acetic acid (A30) (144 g, 794.92 mmol, 1.0 eq.) in DMF was added (4-methoxybenzyl)glycine methyl ester (A29) (216.0 g, 1033 mmol, 1.3 eq.) and DIPEA (112.7 g, 874 mmol, 1.1 eq.), and the reaction mixture was stirred at room temperature, followed by the addition of HATU (453.3 g, 1192.3 mmol, 1.5 eq.), and the mixture was stirred for 16 h. The reaction was monitored on TLC (using EtOAc: hexane; 5:5 as mobile phase). The resulting reaction mixture was poured into ice-cold water (1000 mL) to give a brown solid precipitate, and the mixture was stirred for 30 min, then filtered and dried. The crude material was used directly in the next step. The reaction afforded N-(4-methoxybenzyl)-N-(2-(4-nitrophenyl)acetyl)glycine methyl ester (A31) (100 g crude product, 268.5 mmol, yield: 33.78%).

[0244] 1H NMR (DMSO-d6, 400 MHz): 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), 4.64 (s, 1H), 4.45 (s, 1H), 4.25 (s,1H), 4.00 (s, 2H) 3.87 (s, 1H), 3.74(s, 3 H) 3.61 (s,3H), LCMS (Method A): 2.139 min, 97.36%, 254.0 nm, MS: ES+ 373.2 (M+1) Step-3: To a solution of N-(4-methoxybenzyl)-N-(2-(4-nitrophenyl)acetyl)glycine methyl ester (A31) (70.0 g, 187.98 mmol, 1.0 eq.) in DMF (700 mL) was added KO in portions at room temperature. t To 4- (4- methoxybenzyl) -3- (4- nitrophenyl) pyrrolidine -2,4- dione (A32) (75g, 220.37mmol, yield: quantitative).

[0245] 1 H NMR (DMSO-d6, 400 MHz): 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 = 8.8 Hz , 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) Step-4: A solution of 1-(4-methoxybenzyl)-3-(4-nitrophenyl)pyrrolidine-2,4-dione (A32) (65.0 g, 190.99 mmol, 1.0 equivalent) in DMF (650 mL) was cooled to 0 ° C, and K2CO3 (28.9 g, 210.09 mmol, 1.1 equivalent) was then added. The resulting mixture was stirred for 15 min, and then MeI (40.3 g, 286.48 mmol, 1.5 equivalent) was added dropwise at 0 ° C. The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored on TLC (using EtOAc: hexane; 4:6 as mobile phase), which confirmed that the reaction was completed 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 Na2SO4 and concentrated under reduced pressure to provide 53 g of crude product. The obtained crude material was purified by column chromatography using silica (100-200 mesh) as the stationary phase (24% ethyl acetate in hexanes) to provide 1-(4-methoxybenzyl)-3-methyl-3-(4-nitrophenyl)pyrrolidine-2,4-dione (A33) (33 g, 93.22 mmol, yield: 48.80%).

[0246] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.26-8.22(m, 2H), 7.64-7.60 (m,2H),7.25 (d, J = 8.4 Hz , 2H), 6.95-6.92(m, 2H), 4.65 (d, J = 14.8 Hz, 1H), 4.55 (d, J = 14.8 Hz 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) Step-5: At room temperature, NH4Cl (41.9 g, 790.9 mmol, 10.0 equiv) and Fe (22.06 g, 395.48 mmol, 5.0 equiv) were added 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 equiv) in water (280 mL). 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 mobile phase), which confirmed that the reaction was completed after 5 h. The resulting reaction mixture was filtered, then washed with 10% MeOH (400 mL) in DCM, and then the aqueous layer was extracted with 10% MeOH (400 mL) in DCM. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide 24 g of crude product. The crude material obtained was purified by trituration with methanol / ether to afford 3-(4-aminophenyl)-1-(4-methoxybenzyl)-3-methylpyrrolidine-2,4-dione (A34) (20 g, 61.65 mmol, yield: 77.97%).

[0247] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 7.23 (d, J = 8.4 Hz , 2H), 6.92 (d, J = 8.4 Hz , 2H), 6.90 (d, J = 8.4 Hz , 2H), 6.50 (d, J = 8.8 Hz , 2H), 5.16 (s, 2H),4.69 (d, J = 14.8 Hz , 1H), 4.43 (d, J = 14.8 Hz, 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) 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 equiv) in toluene was added MSA (CAS: 75-75-2) (55.2 ml, 2.4 v) at room temperature, and the reaction was then stirred at 80°C. The reaction was monitored by TLC (using DCM:MeOH; 9:1 as mobile phase), which confirmed that the reaction was complete after stirring at 80°C for 24 h. The resulting reaction mixture was stirred and then settled. Toluene was decanted, and water (200 mL) was then added, and the resulting mixture was washed with ethyl acetate (4 x 300 mL). The aqueous layer was basified with NaHCO3 and then extracted with ethyl acetate (4 x 300 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to provide 3-(4-aminophenyl)-3-methylpyrrolidine-2,4-dione (A35) (7.0 g, 34.29 mmol, yield: 48.37%).

[0248] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.55 (s, 1H), 6.91 (d, J = 8.8 Hz ,2H), 6.52 (d, J = 8.8 Hz,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) Step-7a: The stirring solution of 3-(4-aminophenyl)-3-methylpyrrolidine-2,4-dione (A35) (4.0 g, 19.59 mmol, 1.0 equivalent) in DMF is cooled to 0 ° C. NBS (2.44 g, 13.61 mmol, 0.7 equivalent) is added in batches, and the resulting mixture is stirred for 10 min. The reaction is monitored by TLC (using DCM: MeOH; 7: 3 as mobile phase), which confirms that the reaction is complete. The reaction mixture is diluted with ice-cold water (100 mL) and extracted with EtOAc (3 x 250 mL). The organic layer is separated, and washed with ice-cold water and brine, then dried over Na2SO4 and concentrated under reduced pressure to provide 3.2 g crude product. The crude material obtained was purified by column chromatography using silica (100-200 mesh) as the stationary phase (1.4% DCM in MeOH) to afford 3-(4-amino-3-bromophenyl)-3-methylpyrrolidine-2,4-dione (A36) (2.57 g, 9.11 mmol, yield: 47.68%).

[0249] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.63 (s, 1 H), 7.20 (d, J = 2 Hz, 1H), 6.99-6.97(d, d, J = 2 Hz, J = 2 Hz,1 H), 6.75(d, J = 8.4 Hz 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) 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 equiv) in DMF (15 mL) was added 1-methyl-4-(tributyltinyl)-1H-imidazole (11.7 g, 31.78 mmol, 2.0 equiv). The resulting mixture was stirred at room temperature and purged with N2(g) for 15 min, followed by the addition of PdCl2(dppf)2 (2.324 g, 3.18 mmol, 0.2 equiv). The resulting mixture was stirred at room temperature and purged with N2(g) for 15 min, and the reaction was then heated to 130 °C in a microwave for 30 min. The reaction was monitored by TLC (using DCM:MeOH; 9:1 as mobile phase), which confirmed that the reaction was complete after 30 min. The reaction mixture was extracted with EtOAc (2 x 200 mL). The organic layer was separated and washed with brine (200 mL), then dried over Na2SO4 and concentrated under reduced pressure to provide 2.0 g of crude product. The obtained crude material was purified by column chromatography using silica (100-200 mesh) as the stationary phase (2% MeOH in DCM) to provide 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%).

[0250] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.56 (s, 1H), 7.69 (s, 1H), 7.57-7.45 (m, 3H), 7.23 (d, J = 2.4 Hz, 1H), 6.83-6.80 (m,1H), 6.62 (d, J = 8.4 Hz,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) 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) at room temperature was added (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)2 (1.14 g, 6.33 mmol, 31.5 eq). The resulting mixture was stirred at room temperature in an open atmosphere for 3 h. The reaction was monitored by TLC (using DCM:MeOH; 9:1 as mobile phase), which confirmed that the reaction was complete after 3 h. The reaction mixture was quenched with water (6 mL) and extracted with DCM (3 x 100 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide 0.850 g of crude product. The crude material obtained was purified by column chromatography using silica (230-400 mesh) as stationary phase (10% MeOH in DCM) to provide 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%).

[0251] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 9.92 (s, 1H), 8.68 (s, 1H), 7.78 (s, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 1.2 Hz , 1H), 7.50 (d, J = 8.4 Hz ,2H), 7.38 (d, J = 8.4 Hz , 1H), 7.11 (d, J = 8.8 Hz ,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%, 254.0 nm Chiral HPLC: 9.118 min, 44.84%, 320.0 nm; 9.607 min, 55.159%, 320.0 nm 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)

[0252] Chiral separation of compound 17 and compound 18: Compound 16 (0.1 g) racemate was subjected to chiral SFC purification on a YMC CELLULOSE SC (250 X 20 mm 5 µm) column, wherein two peaks, Compound 17 and Compound 18, were separated.

[0253] Column ID: YMC CELLULOSE SC (250 X 20 mm 5 µm) Mobile phase A: Liquid CO2 Mobile phase B: M.NH3-HEP-IPA (70-30) Flow rate (ml / min): 24 Instrument ID: PHP-04-AGEILENT 1260 Series INFINITY-2 with UV Detector Method: Time: Flow: %A: %B (0:24:0:100), (32:24:0:100) Input amount: 0.1 g.

[0254] 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, 400 MHz): δ ppm, 9.91 (s, 1H), 8.69 (s, 1H), 7.79 (s, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.57 (s,1H), 7.50 (d, J = 8.8 Hz , 2H), 7.38 (d, J = 8.4 Hz , 1H), 7.10 (d, J = 8.4 Hz,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%, 254.0 nm Chiral HPLC (Method A): 14.99 min, 100%, 262 nm Compound 18 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 9.92 (s, 1H), 8.69 (s, 1H), 7.78 (s, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 1.2 Hz, 1H), 7.50 (d, J = 8.8 Hz, 2H),7.38 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 8.4 Hz,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%, 254.0 nm Chiral HPLC (Method A): 16.90 min, 98.02%, 262 nm 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)

[0255] 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 equiv) in MeOH (1.0 ml) and DCM (1.0 ml) at 0°C was added NaBH4 (0.013 g, 0.350 mmol, 1.5 equiv) and the resulting mixture was stirred at room temperature for 30 min. The reaction was monitored by TLC (using DCM:MeOH; 9:1 as mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 30 min. The reaction mixture was diluted with CHCl3, and then a solution of NH4Cl in water (5 mL) was added. The mixture was extracted with DCM (3 x 20 mL), and the organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide 0.06 g of crude product. The crude material obtained was purified by reverse phase column chromatography as the stationary phase (C18), mobile phase (100% water: ACN) to afford 4-hydroxy-3-methyl-3-(3-(1-methyl-1 H -imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (Compound 19) (0.032 g, 0.0743 mmol, yield: 32%).

[0256] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 9.76 (s, 1H), 7.88 (s, 1H), 7.76 (s, 1H), (s, 1H), 7.69 (s, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.51 (d, J = 10 Hz,1H), 7.44 (s, 1H), 7.31 (d, J = 8.4 Hz , 1H), 7.08 (d, J= 8.4 Hz,3H), 5.17 (s,1H),4.12 (t, J = 5.8 Hz , 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%, 254.0 nm Chiral HPLC: (peak-1) 6.42 min, 47.61%, 305.0 nm; (peak-2) 6.76 min, 45.58%, 305.0 nm 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)

[0257] Chiral separation of compound 20 and compound 21: Compound 11 (18.2 mg) racemate was subjected to chiral SFC purification on a CHIRALPAK IG, 250 x 10 mm, 5 µm column, wherein 2 peaks, Compound 20 and Compound 21, were separated.

[0258] Column ID: CHIRALPAK IG, 250 x 10 mm, 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: %A: %B (Initial: 38:6:6), (80:20) Input amount: 18.2 mg.

[0259] Output: Compound 20 = 0.0677 g (yield % = 37.2%) and Compound 21 = 0.061 g (yield % = 33.52%) Compound 20: 1 H NMR (400 MHz, MeOD): δ ppm, 8.24 (d, J = 2.4 Hz , 1H), 7.58-7.50 (m,4 H), 7.31 (d, J = 8.4 Hz , 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 %, 254.0 nm Chiral HPLC (Method A): 5.08 min, 100.0%, 304 nm Compound 21: 1 H NMR (400 MHz, MeOD): δ ppm, 8.24 (d, J = 2.4 Hz , 1H), 7.58-7.50 (m,4 H), 7.31 (d, J = 8.4 Hz , 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).

[0260] LCMS (Method A): 2.37 min, 98.96 %, 254.0 nm, MS: ES+ 417 (M+1) HPLC (method A): 8.52 min, 100 %, 254.0 nm Chiral HPLC (Method A): 5.33 min, 98.87 %, 304 nm 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)

[0261] Step-1: To a solution of 3-(4-amino-3-bromophenyl)-3-methylpyrrolidin-2-one (A4) (0.6 g, 2.230 mmol, 1.0 equiv) in DCM (6 mL) was added CAS: 1423-26-3 (0.632 g, 3.345 mmol, 1.5 equiv), DIPEA (1.1 ml, 6.69 mmol, 3.0 equiv) and Cu (OAc) (0.605 g, 3.345 mmol, 1.5 equiv), and the reaction mixture was then stirred at room temperature for 48 h, with the vial open to air (i.e., without diaphragm). The reaction was monitored on TLC (using 90% EtOAc in hexane as mobile phase). Water (10 mL) was added to the reaction mixture, and the mixture was extracted with DCM (3x 25 mL). The combined organic layer was dried over NaSO and concentrated under reduced pressure to provide 0.8 g crude product. The crude material obtained was purified by manual column chromatography using silica (100-200 mesh) as the stationary phase (the desired product was eluted in 50%-55% EtOAc in hexanes as the mobile phase) to afford 3-(3-bromo-4-((3-(trifluoromethyl)phenyl)amino)phenyl)-3-methylpyrrolidin-2-one (A38) (0.2 g, 0.484 mmol, yield: 21.71%).

[0262] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.07 (s, 1H), 7.87 (bs, 1H), 7.66(d, J = 2.0 Hz , 1H), 7.42-7.29 (m, 3 H), 7.20 (s, 1 H), 7.15 -7.0 (m, 2H), 3.17-3.13 (m, 2 H), 2.41-2.13 (m, 2H), 1.38 (s, 3H).

[0263] LCMS (Method A): 2.352 min, 100%, 254.0 nm, MS: ES+ 413 (M+1) 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) at room temperature was added 1-methyl-4-(tributylstannyl)-1H-imidazole (0.323 g, 0.871 mmol, 2.0 eq) and the resulting mixture was purged with N2(g) at room temperature for 10 min. PdCl2(dppf) (0.063 g, 0.087 mmol, 0.2 eq) was then added and the mixture was stirred at 140°C in a microwave for 30 min. The reaction was monitored on TLC (using EA:HEX; 9.0:1.0 as mobile phase), which confirmed the completion of the reaction after stirring at 140°C for 30 min. The resulting reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide 0.3 g of crude product. The obtained crude material was purified by flash column chromatography using silica (230-400 mesh) as stationary phase (75% EA in HEX) to give 3-methyl-3-(3-(1-methyl-1H-imidazole-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrrolidin-2-one (Compound 22) (0.055 g, 0.132 mmol, yield: 30.48%).

[0264] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 9.78 (s, 1H), 7.79-7.72 (m, 3H),7.58-7.57 (m, 1H), 7.39 (d, J = 87.6 Hz , 1 H), 7.30-7.20 (m, 4H), 7.08 (d, J = 7.6 Hz , 1H), 3.72 (s, 3H), 3.36- 3.15 (m, 2H), 2.46-2.13 (m, 2H), 1.42 (s, 3H).

[0265] LCMS (Method A): 1.67 min, 100%, 254.0 nm, MS: ES+ 415.17 (M+1). HPLC (method A): 4.68 min, 100 %, 254.0 nm Chiral HPLC (Method A): (Peak-1) 6.03 min, 50.52 %, 300 nm; (Peak-2) 6.21 min, 49.47 %, 300 nm Example 18-Synthesis of 1-(3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)ethan-1-one (Compound 23)

[0266] Step-1: At room temperature, a solution of 1-(4-amino-3-bromophenyl) ethyl-1-ketone (CAS number: 56759-32-1) (0.5 g, 2.33 mmol, 1.0 equivalent) in DMF 5 mL was prepared in a 30 mL glass microwave vial. At room temperature under a nitrogen gas atmosphere, 1-methyl-4-(tributyltin alkyl)-1H-imidazole (1.73 g, 4.672 mmol, 2.0 equivalent) was added to the solution. PdCl2(dppf) (0.17 g, 0.233 mmol, 0.1 equivalent) 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 mobile phase), which confirmed that the reaction was complete after stirring at 130 ° C for 30 min. The resulting reaction mixture was extracted with EA (3x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to provide a crude product (0.60 g). The crude material obtained was purified by Combi-Flash chromatography using silica gel (300-400 mesh) (the desired product was eluted in 50%-55% EA in hexane) to provide 1-(4-amino-3-(1-methyl-1H-imidazole-4-yl)phenyl)ethan-1-one (A39) (0.35 g, 1.627 mmol, yield: 69.61%).

[0267] 1 H NMR (DMSO-d6, 400 MHz): δ ppm 8.00 (d, J = 2.0 Hz 1H), 7.73 (s,1H),7.69 (s,1H), 7.56 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H), 7.22 (bs,2H), 6.69 (d, J= 8.4 Hz 1H), 3.72 (s,3H), 2.44 (s, 3 H) LCMS (Method A): 1.01 min, 98.61%, 254 nm, MS: ES+ 216 (M+1) 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)boric acid (CAS: 128796-39-4) (3.29 g, 17.44 mmol, 1.0 eq.) and K3PO4 (7.39 g, 34.88 mmol, 2.0 eq.) were added at room temperature under nitrogen gas atmosphere. Cu(OAc)2 (3.78 g, 20.92 mmol, 1.2 eq.) was added to the resulting reaction mixture, and the mixture was purged with N2 gas. 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), which confirmed that the reaction was complete after stirring for 2 h at 110 ℃. The reaction mixture was extracted with EA (3 x 150 mL). The organic layer combined was dried over Na2SO4, filtered and concentrated under reduced pressure to provide a crude product (5.5 g). The crude material obtained was purified by Combi-Flash chromatography using silica gel (300-400 mesh) (eluted with the required product in 45%-50%EA in hexane), to provide 1-(3-(1-methyl-1H-imidazole-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)second-1-ketone (compound 23) (4.0 g, 11.14 mmol, yield: 31.95%).

[0268] 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 11.15 (s,1H), 8.23 ​​(d, J = 2.0 Hz 1H),7.87 (s,2H), 7.76 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H), 7.64 (d, J = 8.4 Hz 2H), 7.48(d, J = 8.4 Hz 1H), 7.37 (d, J = 8.4 Hz 2H), 3.75 (s,3H), 2.50 (s, 3 H) LCMS (Method A): 2.01 min, 99.01%, 254 nm, MS: ES+ 360 (M+1) Biological Examples Prior art TEAD inhibitors 1-1, 1-2, 1-3, and 1-4 (structures provided in Table 3) were used as reference compounds throughout Biological Examples 19-29.

[0269] Table 3. Prior art TEAD inhibitors

[0270] Example 19 - NCI-H226, H23 and H28 proliferation and cell viability assays Cell proliferation of the TEAD-dependent NF2-expressing mesothelioma cell line NCI-H226 was determined using two different protocols. The results were confirmed in two different TEAD-independent lung cancer cell lines, H23 and H28, which were used as non-reactive controls, as indicated: a) CellTiter-Glo® 2.0 (Promega #G9243). The effects of TEAD inhibitors disclosed herein on cell proliferation were determined in the TEAD1 genetically dependent cell line NCI-H226 (responder cell line) and TEAD-independent cell lines (NCI-H23, HEK293T) (as non-responder negative controls). Cells were seeded in 96-well plates (ThermoScientific #167008) in a humidified incubator at 37°C, 5% CO2 with 800 (NCI-H226 and HEK-293T) cells or 2000 (NCI-H23) cells / well in growth medium (RPMI-1640, Gibco #61870-010) or DMEM (Gibco #31966-021, HEK293T) for NCI-H226 and NCI-H23; 24 hours later, fresh growth medium containing test compounds or DMSO vehicles was added and incubated with cells for 144 hours. TEAD inhibitor stock solutions were prepared in DMSO at 1000-fold excess, and the dose response test compound dose range was used from 10,000 nM to 0.1 nM. Each treatment was performed in triplicate. After processing 144 hours, determine the relative cell survival number using CellTiter-Glo 2.0 determination according to the manufacturer's instructions.Allow the test plate and CellTiter-Glo 2.0 reagent to balance to room temperature.CellTiter-Glo 2.0 reagent is added to 96-well cell plates with a ratio of 1:1 reagent to culture medium, the plate is placed on a plate shaker for 2 minutes, and then incubated at room temperature for another 10 minutes to allow complete cell lysis to occur.Then the mixture is transferred to a white 96-well photometer assay plate (Greiner Bio One #655075).CLARIOStar Plus multi-mode plate reader (BMG Labtech) is used to quantify luminescence in luminescence detection mode with recommended settings (ultra-Glo preset: emission 545 nm-50 nm, open automatic focusing and enhanced dynamic range).Relative cell density is expressed as a function of inhibitor concentration relative to the control wells of DMSO only.IC using GraphPad Prism and biological effects 50 Values ​​plotted using EC 50 The nonlinear fit function is calculated using an unconstrained sigmoid 4-parameter logistic least squares fit.

[0271] b) Cell Titer One (Promega, # G3582). Promega Substrate CellTiter Aqueous One Solution Reagent was also used to determine the effect of TEAD inhibitors disclosed herein on cell proliferation. The effect of TEAD inhibitors on cell proliferation responders (H226) and non-responder negative control cancer cell lines (CAMA1, H28) and untransformed normal human cells (HUVEC, NHDF) was evaluated. The dissociated cells were resuspended in culture medium (depending on the cell line, resuspended in DMEM, RPMI or EMEM, all with 10% FBS, with gentamicin as an antibiotic). The cells were seeded in 96-well plates at 750 cells / well at 100 μL / well, and allowed to settle and attach. After incubation for 24 hours (37°C, 5% CO2, humidified incubator), 100 μL of culture medium containing the test compound was added. Dilution series of 2000-fold concentrated stock solutions of test compounds were prepared in DMSO with final concentrations ranging from 0.1 nM to 10,000 nM. After addition of the medium containing the test compounds, the cells were incubated at 37°C, 5% CO2, in a humidified incubator for 6 days. To measure cell density, 20 μL of Promega Substrate Cell Titer 96 Aqueous OneSolution Reagent (Promega, # G3582) was added to each well according to the manufacturer's instructions. The plates were incubated at 37°C for typically 3-8 hours to reach an OD of 1.5 at 490 nm in control cells (no compound). The OD was measured using a Vmax [Molecular Devices] spectrophotometer plate reader. Wells with medium only were used as background controls, and cell density was normalized to the DMSO vehicle control. EC 50 The concentration that achieved 50% of the maximum growth inhibition was used.

[0272] For IC 50 and EC 50 Data, "A" represents a value less than 0.2 µM; the symbol "B" represents a value in the range of 0.2 µM to 1 µM; and the symbol "C" represents a value greater than 1 µM. ND: No data.

[0273] Table 4. Cytotoxic potency of H226 responder and H23 non-responder cell lines measured by CTG assay Compound No. <![CDATA[NCI-H226 EC 50 ]]> <![CDATA[NCI-H23 IC 50 ]]> 1 A C 2 A C 3 A ND 4 A ND 5 A ND 6 A ND 7 B ND 8 A ND 9 A ND 10 A ND 11 A ND 12 A ND 13 A ND 14 A ND 15 A ND 16 A ND 17 A ND 18 A ND 19 B ND 20 A ND 21 A ND 22 A ND 23 A ND 24 A ND Table 5. Cytotoxic potency of H226 and H28 cell lines measured by Cell Titer One assay Compound No. <![CDATA[NCI-H226 IC 50 ]]> <![CDATA[NCI-H28 IC 50 ]]> 1 A ND 2 A ND 3 A ND 4 A ND 5 A C 6 B ND 7 A ND 8 B ND 9 A ND 10 A ND 11 A ND 12 C ND 13 C ND 14 C ND 15 A ND Example 20 - Mero14 proliferation and cell viability assay Mero14 cells are trypsinized, counted and plated with 400 cells / well in 200 μl of growth medium in 96-well flat-bottom tissue culture treated plates. The cells plated are incubated overnight at 37 ° C, 5% CO2, and then processed in triplicate for each assay point with compound. The serially diluted compound of 50 μl is added to each well to obtain a final DMSO concentration of 0.5% / well and a total volume of 250 μl / well. The cells processed are incubated at 37 ° C, 5% CO2 for 144 hours (6 days). After compound treatment, Promega CellTiter-Glo 2.0 is used to determine the remaining viable cells as follows: 150 μl of culture medium is taken out from each well to be determined, and 100 μl of room temperature CellTiter-Glo 2.0 reagent is added. Plate is placed on an orbital shaker at room temperature with 500 rpm for 2 minutes, and then incubated at room temperature without shaking for another 10 minutes. 150 μl of cell lysate was removed from each well and dispensed into individual wells of a white opaque 96-well plate. Luminescence was read at 545 nm using a BMG CLARIOstar plate reader. The luminescence signal is proportional to the number of viable cells, and the percentage of viable cells relative to the DMSO control was then calculated for each assay point. The percentage of viability relative to the DMSO control was plotted against compound concentration and a curve was fitted using nonlinear regression in GraphPad Prism software. EC was calculated using GraphPad Prism software as follows 50 Value and absolute IC 50 Value: For EC 50 Values ​​were obtained using an unconstrained four-parameter logistic curve fit (sigmoidal, 4PL, X is concentration). 50 values, the baseline is constrained to Y=0 and the top is at 100 (absolute IC 50 , X is concentration). Area under the curve (AUC): Prism calculates the area under the curve by the trapezoidal method. This analysis treats the fitted curve simply as a series of connected XY points. Prism only calculates the area under the "curve" defined by connecting the points with straight lines. The units of AUC are the units of the Y axis times the units of the X axis.

[0274] For EC 50 For the data, the symbol "A" represents a value less than 0.2 µM; the symbol "B" represents a value in the range of 0.2 µM to 1 µM; and the symbol "C" represents a value greater than 1 µM.

[0275] Table 6. Cytotoxic potency of the Mero14 cell line measured by the CTG assay Compound No. EC50 1-2 B 1-3 A 5 A 15 A 20 A Example 21 - Mero82 proliferation and cell viability assay Mero 82 cells are trypsinized, counted and plated in 200 μl of growth medium in 96-well flat-bottom tissue culture treated plates at 400 cells / well. The plated cells are incubated overnight at 37 ° C, 5% CO2, and then treated in triplicate with compounds for each assay point. 50 μl of serially diluted compounds are added to each well to obtain a final DMSO concentration of 0.5% / well and a total volume of 250 μl / well. The cells treated are incubated at 37 ° C, 5% CO2 for 144 hours (6 days). After compound treatment, Promega CellTiter-Glo 2.0 is used to determine the remaining viable cells as follows: 150 μl of culture medium is taken out from each well to be determined, and 100 μl of room temperature CellTiter-Glo 2.0 reagent is added. The plate is placed on an orbital shaker at room temperature for 2 minutes at 500 rpm, and then incubated at room temperature without shaking for another 10 minutes. 150 μl of cell lysate was removed from each well and dispensed into individual wells of a white opaque 96-well plate. Luminescence was read at 545 nm using a BMG CLARIOstar plate reader. The luminescence signal is proportional to the number of viable cells, and the percentage of viable cells relative to the DMSO control was then calculated for each assay point. The percentage of viability relative to the DMSO control was plotted against compound concentration and a curve was fitted using nonlinear regression in GraphPad Prism software. EC was calculated using GraphPad Prism software as follows 50 Value and absolute IC 50 Value: For EC 50 Values ​​were obtained using an unconstrained four-parameter logistic curve fit (sigmoidal, 4PL, X is concentration). 50 values, the baseline is constrained to Y=0 and the top to 100 (absolute IC 50 , X is concentration). Area under the curve (AUC): Prism calculates the area under the curve by the trapezoidal method. This analysis treats the fitted curve simply as a series of connected XY points. Prism only calculates the area under the "curve" defined by connecting the points with straight lines. The units of AUC are the units of the Y axis times the units of the X axis.

[0276] For EC 50 For the data, the symbol "A" represents a value less than 0.2 µM; the symbol "B" represents a value in the range of 0.2 µM to 1 µM; and the symbol "C" represents a value greater than 1 µM.

[0277] Table 7. Cytotoxic potency of the Mero82 cell line measured by the CTG assay Compound No. EC50 1-2 C 1-3 A 5 A 15 A 20 A Example 22 - BHY Proliferation and Cell Viability Assay BHY cells are trypsinized, counted and plated with 2500 cells / well in 200 μl of growth medium of 96-well flat-bottom tissue culture treated plates. The plated cells are incubated overnight at 37 ° C, 5% CO2, and then processed in triplicate for each assay point with compounds. The serially diluted compounds of 50 μl are added to each well to obtain a final DMSO concentration of 0.5% / well and a total volume of 250 μl / well. The cells treated are incubated at 37 ° C, 5% CO2 for 144 hours (6 days). After compound treatment, Promega CellTiter-Glo 2.0 is used to determine the remaining viable cells as follows: 150 μl of culture medium is taken out from each well to be determined, and 100 μl of room temperature CellTiter-Glo 2.0 reagent is added. The plate is placed on an orbital shaker at room temperature for 2 minutes at 500 rpm, and then incubated at room temperature without shaking for another 10 minutes. 150 μl of cell lysate was removed from each well and dispensed into individual wells of a white opaque 96-well plate. Luminescence was read at 545 nm using a BMG CLARIOstar plate reader. The luminescence signal is proportional to the number of viable cells and the percentage of viable cells relative to the DMSO control was then calculated for each assay point. The percentage of viability relative to the DMSO control was plotted against compound concentration and a curve was fitted using nonlinear regression in GraphPad Prism software. EC 50 Value and absolute IC 50 The values ​​were calculated using GraphPad Prism software as follows: For EC 50 Values ​​were obtained using an unconstrained four-parameter logistic curve fit (sigmoidal, 4PL, X is concentration). 50 values, the baseline is constrained to Y=0 and the top is at 100 (absolute IC 50 , X is concentration). Area under the curve (AUC): Prism calculates the area under the curve by the trapezoidal method. This analysis treats the fitted curve simply as a series of connected XY points. Prism only calculates the area under the "curve" defined by connecting the points with straight lines. The units of AUC are the units of the Y axis times the units of the X axis.

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

[0279] Table 8. Cytotoxic potency of BHY cell lines measured by CTG assay Compound No. EC50 1-2 C 1-3 A 5 B Example 23 - LOU-NH91 proliferation and cell viability assay LOU-NH91 cells are trypsinized, counted and plated with 1000 cells / well in 200 μl of growth medium of 96-well flat-bottom tissue culture treated plates. The cells plated are incubated overnight at 37 ° C, 5% CO2, and then processed in triplicate for each assay point with compound. The serially diluted compound of 50 μl is added to each well to obtain the final DMSO concentration of 0.5% / well and the total volume of 250 μl / well. The cells processed are incubated at 37 ° C, 5% CO2 for 216 hours (9 days). After compound treatment, Promega CellTiter-Glo 2.0 is used to determine the remaining viable cells as follows: take out 150 μl of culture medium from each well to be determined, and add 100 μl of room temperature CellTiter-Glo 2.0 reagent. Plate is placed on an orbital shaker at room temperature for 2 minutes at 500 rpm, and then incubated at room temperature without shaking for another 10 minutes. 150 μl of cell lysate was removed from each well and dispensed into individual wells of a white opaque 96-well plate. Luminescence was read at 545 nm using a BMG CLARIOstar plate reader. The luminescence signal is proportional to the number of viable cells and the percentage of viable cells relative to the DMSO control was then calculated for each assay point. The percentage of viability relative to the DMSO control was plotted against compound concentration and a curve was fitted using nonlinear regression in GraphPad Prism software. EC 50 Value and absolute IC 50 The values ​​were calculated using GraphPad Prism software as follows: For EC 50 Values ​​were obtained using an unconstrained four-parameter logistic curve fit (sigmoidal, 4PL, X is concentration). 50 values, the baseline is constrained to Y=0 and the top is at 100 (absolute IC 50 , X is concentration). Area under the curve (AUC): Prism calculates the area under the curve by the trapezoidal method. This analysis treats the fitted curve simply as a series of connected XY points. Prism only calculates the area under the "curve" defined by connecting the points with straight lines. The units of AUC are the units of the Y axis times the units of the X axis.

[0280] For EC 50 For the data, the symbol "A" represents a value less than 0.2 µM; the symbol "B" represents a value in the range of 0.2 µM to 1 µM; and the symbol "C" represents a value greater than 1 µM.

[0281] Table 9. Cytotoxic potency of LOU-NH91 cell line measured by CTG assay Compound No. EC50 1-2 A 1-3 A 5 A Example 24 - MSTO-211H proliferation and cell viability assay MSTO-211H cells are trypsinized, counted and plated with 1500 cells / well in 200 μl of growth medium of 96-well flat-bottom tissue culture treated plates. The cells plated are incubated overnight at 37 ° C, 5% CO2, and then processed in triplicate for each assay point with compounds. The serially diluted compounds of 50 μl are added to each well to obtain a final DMSO concentration of 0.5% / well and a total volume of 250 μl / wells. The cells treated are incubated at 37 ° C, 5% CO2 for 144 hours (6 days). After compound treatment, Promega CellTiter-Glo 2.0 is used to determine the remaining viable cells as follows: 150 μl of culture medium is taken out from each well to be determined, and 100 μl of room temperature CellTiter-Glo 2.0 reagents are added. The plate is placed on an orbital shaker at room temperature for 2 minutes at 500 rpm, and then incubated at room temperature without shaking for another 10 minutes. 150 μl of cell lysate was removed from each well and dispensed into individual wells of a white opaque 96-well plate. Luminescence was read at 545 nm using a BMG CLARIOstar plate reader. The luminescence signal is proportional to the number of viable cells, and the percentage of viable cells relative to the DMSO control was then calculated for each assay point. The percentage of viability relative to the DMSO control was plotted against compound concentration and a curve was fitted using nonlinear regression in GraphPad Prism software. EC was calculated using GraphPad Prism software as follows 50 Value and absolute IC 50 Value: For EC 50 Values ​​were obtained using an unconstrained four-parameter logistic curve fit (sigmoidal, 4PL, X is concentration). 50 values, the baseline is constrained to Y=0 and the top is at 100 (absolute IC 50, X is concentration). Area under the curve (AUC): Prism calculates the area under the curve by the trapezoidal method. This analysis treats the fitted curve simply as a series of connected XY points. Prism only calculates the area under the "curve" defined by connecting the points with straight lines. The units of AUC are the units of the Y axis times the units of the X axis.

[0282] For EC 50 For the data, the symbol "A" represents a value less than 0.2 µM; the symbol "B" represents a value in the range of 0.2 µM to 1 µM; and the symbol "C" represents a value greater than 1 µM.

[0283] Table 10. Cytotoxic potency of MSTO-211H cell line measured by CTG assay Compound No. EC50 1-2 A 1-3 A 5 A 15 A 20 A Example 25 - SDM103T2 proliferation and cell viability assay SDM103T2 cells are trypsinized, counted and plated with 800 cells / well in the growth medium of 200 μl of 96-well flat-bottom tissue culture treated plates. The cells plated are incubated overnight at 37 ° C, 5% CO2, and then processed in triplicate for each assay point with compound. The serially diluted compound of 50 μl is added to each well, and the final DMSO concentration of 0.5% / well and the total volume of 250 μl / wells are obtained. The cells processed are incubated at 37 ° C, 5% CO2 for 144 hours (6 days). After compound treatment, Promega CellTiter-Glo 2.0 is used to determine the remaining viable cells as follows: take out the culture medium of 150 μl from each well to be measured, and add the room temperature CellTiter-Glo 2.0 reagent of 100 μl. Plate is placed on an orbital shaker at room temperature for 2 minutes with 500 rpm, and then incubated in room temperature without shaking for another 10 minutes. 150 μl of cell lysate was removed from each well and dispensed into individual wells of a white opaque 96-well plate. Luminescence was read at 545 nm using a BMG CLARIOstar plate reader. The luminescence signal is proportional to the number of viable cells and the percentage of viable cells relative to the DMSO control was then calculated for each assay point. The percentage of viability relative to the DMSO control was plotted against compound concentration and a curve was fitted using nonlinear regression in GraphPad Prism software. EC 50 Value and absolute IC 50 The values ​​were calculated using GraphPad Prism software as follows: For EC 50 Values ​​were obtained using an unconstrained four-parameter logistic curve fit (sigmoidal, 4PL, X is concentration). 50values, the baseline is constrained to Y=0 and the top is at 100 (absolute IC 50 , X is concentration). Area under the curve (AUC): Prism calculates the area under the curve by the trapezoidal method. This analysis treats the fitted curve simply as a series of connected XY points. Prism only calculates the area under the "curve" defined by connecting the points with straight lines. The units of AUC are the units of the Y axis times the units of the X axis.

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

[0285] Table 11. Cytotoxic potency of SDM103T2 cell line measured by CTG assay Compound No. EC50 1-1 A 1-2 C 1-3 A 5 A 15 A 20 A Example 26 - TEAD Thermal Shift Assay (TSA) Thermal shift assay (TSA) is a biophysical method to evaluate the stability of proteins as a function of temperature. The assay measures the thermal denaturation temperature under different conditions such as different drug concentrations. For this example, a fluorescent dye bound to an unfolded protein was used. SYPRO Orange binds non-specifically to hydrophobic surfaces, and water strongly quenches its fluorescence. When the protein is unfolded, the exposed hydrophobic surface binds the dye, resulting in an increase in fluorescence by excluding water. Detergent micelles also bind the dye and significantly increase background noise. The binding of small molecules to proteins results in stabilization against thermal denaturation, where the degree of thermal stability is proportional to the strength of binding.

[0286] The study described in this example investigated the changes in melting temperatures (ΔTm) of TEAD isoforms 1-4 when treated with TEAD inhibitors. Compound 1-1-known strong TEAD1 inhibitor and weak TEAD2 inhibitor; and compound 1-4-pan-TEAD inhibitor were used as controls. As expected, compound 1-1 showed a significant thermal shift only for TEAD1, while compound 1-4 showed thermal shifts for all four TEAD isoforms. As shown in Table 12, compound 5 showed strong TEAD1 and TEAD4 binding.

[0287] Experimental parameters / conditions

[0288] Assay buffer preparation

[0289] Dissolve Tris-HCL in 5 mL of cell culture grade water and allow to dissolve completely. Adjust pH to 8 using NaOH. Add additional assay buffer components in the order listed above. Mix the buffer slowly.

[0290] Measuring 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 to a 5-fold concentration, followed by the addition of test compound stock solution to a concentration of 10 μM or 30 μM in the assay buffer.

[0291] Melt cycles were performed in a Bio-RAD PCR instrument from 20°C to 95°C at a ramp rate of 1°C / min.

[0292] Thermal displacement data are provided in Table 12.

[0293] Table 12. Thermal displacement measurement data

[0294] Example 27 - TEAD inhibitors inhibit MSTO-211H tumors in mouse xenografts This study evaluated the in vivo antitumor efficacy of the test compounds in the treatment of MSTO-211H xenografts of lung cancer in BALB / c nude mice.

[0295]

[0296] Animals and housing conditions Species: House mouse ( Mus Musculus ) Strain: BALB / c nude Age: 6-8 weeks Gender: Female Weight: 18-22 g Number of animals inoculated with tumors: 80 mice Number of animals included in the treatment: 36 mice Number of animals not included: 44 mice Animal provider: Beijing Vital River Biotechnology Experimental Animal Co. Ltd Certification number: 20170011010591 Study Design Part 1 Group <![CDATA[N a ]]> Compound Dosage (mg / kg) <![CDATA[Administration volume b (µl / g)]]> Route of administration <![CDATA[Frequency of administration c > <![CDATA[Drug administration schedule c > 1 4 vehicle -- 10 PO BID 31 2 4 5 12.5 10 PO BID 31 4 4 20 12.5 10 PO BID 31 6 4 15 12.5 10 PO BID 31 Notice: a. N, number of animals in each group.

[0297] b. Dosing volume: Adjust the dosing volume to 10 μL / g based on body weight.

[0298] c. If weight loss is >15%, adjust treatment.

[0299] Part 2

[0300] Part 3

[0301] 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 a week by trypsin-EDTA. Cells growing in the exponential growth phase with a cell viability of 95% or more were harvested and tumor inoculations were counted.

[0302] Tumor cell information Cell lines Cancer Type Species supplier Catalog Number MSTO-211H Lung cancer Human ATCC CRL-2081 Tumor inoculation Each mouse was inoculated subcutaneously in the right abdomen with MSTO-211H tumor cells (5×10 6 +50% Matrigel / 0.2 mL) for tumor development. Animals were tagged with unique 6-digit earrings for identification. Treatment for Part 1 began on day 5 after cell inoculation, when the average tumor volume reached 181 mm 3 Treatment in part 2 began on day 16 after cell inoculation, when the mean tumor volume reached 254 mm 3 Treatment in part 3 began on day 33 after cell inoculation, when the mean tumor volume reached 969 mm 3 .

[0303] Tumor measurement The primary endpoint was to determine whether tumor growth could be delayed. Tumor volume was measured in two dimensions twice weekly using calipers, and volume was expressed in mm using the following formula: 3 Meaning: V = 0.5 axb 2, where a and b are the long and short diameters of the tumor, respectively. The tumor size is then used to calculate the T / C value. The TGI value (in percentage) or T / C value (in percentage) is an indication of antitumor effectiveness; T and C are the average tumor volume or tumor weight of the treatment group and the control group, respectively, on a given day.

[0304] The TGI of each group was calculated 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, T0 is the mean tumor volume of the treatment group on the day treatment started, V i Is with T i The mean tumor volume of the vehicle control group on the same day, and V0 is the mean tumor volume of the vehicle group on the day treatment started.

[0305] 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 V0 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.

[0306] When the media group reaches 681 mm 3 The antitumor efficacy of Part 1 of the study was analyzed for PG-D31.

[0307] When the media group reaches 738 mm 3 The antitumor efficacy of Part 2 of the study was analyzed for PG-D30.

[0308] When the media group reaches 1791 mm 3 The antitumor efficacy of Part 3 of the study was analyzed for PG-D13.

[0309] Statistical analysis Summary statistics of tumor volume for each group at each time point are provided, including the mean and standard error of the mean (SEM).

[0310] Data obtained at the end of the study were subjected to statistical analysis of differences in tumor volume between groups.

[0311] One-tailed T-test was performed to compare tumor volumes between the two groups. All data were analyzed using GraphPad Prism 6.0. p<0.05was considered statistically significant.

[0312] Tumor volume trace Changes in tumor volume during the study are provided in Tables 13-15.

[0313] Table 13. Tumor sizes during the Part 1 study.

[0314]

[0315] Notice: a. Mean ± SEM Table 14. Tumor sizes during the Part 2 study.

[0316]

[0317] Table 15. Tumor sizes during the Part 3 study.

[0318]

[0319] Tumor growth inhibition assay The TGI for Part 1 was calculated based on tumor volume measurements for PG-D31 after the start of treatment (Table 16).

[0320] The TGI for Part 2 was calculated based on tumor volume measurements for PG-D30 after the start of treatment (Table 17).

[0321] The TGI for Part 3 was calculated based on tumor volume measurements for PG-D13 after the start of treatment (Table 18).

[0322] Table 16. Tumor sizes on Day 31 of the Part 1 study.

[0323]

[0324] a. Mean ± SEM.

[0325] bT / C(%) = T RTV / C RTV × 100, TGI = [1-(T i -T0) / (V i -V0)] ×100.

[0326] c. One-tailed T-test analysis was performed to compare the tumor volumes between the two groups.

[0327] Table 17. Tumor sizes on Day 30 of the Part 2 study.

[0328]

[0329] Table 18. Tumor sizes on Day 13 of the Part 3 study.

[0330]

[0331] Example 28 - Inhibition of MSTO-211H Tumors Xenografted in Mice by TEAD Inhibitors of the Present Disclosure Compared with Prior Art TEAD Inhibitors This study evaluated the in vivo antitumor efficacy of the test compounds in BALB / c nude mice bearing MSTO-211H xenografts of lung cancer.

[0332] Study Design

[0333] Based on the long half-life of Compound 1-1, a 3 mg / kg dose of Compound 1-1 was used, as reported by Tang et al. (Tang et al. "Small Molecule Inhibitors of TEAD Auto-palmitoylation Selectively Inhibit Proliferation and Tumor Growth of NF2-deficient Mesothelioma," Mol. Cancer Ther. , 2021, 20(6): 986-998).

[0334] Cell culture MSTO-211H tumor cells were maintained in vitro in RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% antibiotic-antimycotic in an atmosphere of 5% CO2 in air at 37°C. Tumor cells were routinely subcultured twice a week by trypsin-EDTA. Cells growing in the exponential growth phase were harvested and counted for tumor inoculation.

[0335] Tumor inoculation Each mouse was inoculated subcutaneously in the right abdomen with MSTO-211H tumor cells (10×10 6 + 50% Matrigel / 0.2 mL) for tumor development. Test subjects began receiving vehicle (e.g., 0.5% CMC Na + 1% Tween 80) on day 7 after cell inoculation. When tumor volume reached 500 mm 3 Up to 1200 mm 3 When the cells were inoculated, treatment was started on day 28.

[0336] Compound preparation

[0337] Tumor measurement The primary endpoint was to determine whether tumor growth could be delayed. Tumor dimensions were measured twice weekly in two dimensions using calipers, and volumes were expressed in mm using the following formula: 3 Meaning: V = 0.5 axb 2 , where a and b are the long and short diameters of the tumor, respectively. The tumor size is then used to calculate the T / C value and TGI value.

[0338] The T / C value (in percentage) is an indication of antitumor effectiveness; T and C are the mean volumes of the treated and control groups, respectively, on a given day.

[0339] Statistical analysis Summary statistics including mean and standard error of the mean (SEM) were calculated for tumor volume for each group at each time point.

[0340] Data obtained at the end of the study were subjected to statistical analysis of differences in tumor volume between groups.

[0341] 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.

[0342] Tumor volume trace Changes in tumor volume were recorded during the study. For each of Groups 1-3, the changes in tumor volume after 7 days of treatment compared to before treatment are provided in Figure 3A and Figure 3B middle. Figure 3A The change in tumor volume for an individual test subject is provided, and Figure 3B Mean tumor volume changes for each treatment group are provided. Tumor growth was observed in the vehicle-treated group and the compound 1-1-treated group, while tumor reduction was observed in the compound 5-treated group.

[0343] Example 29 - Inhibition of NCI-H226 Tumors by TEAD Inhibitors in Mice This study evaluated the in vivo antitumor efficacy of the test compounds for the treatment of the NCI-H226 lung tumor model in NOD SCID mice.

[0344]

[0345] Animals and housing conditions Species: House mouse Strain: NOD SCID Age: 6-8 weeks Gender: Female Weight: 18-22 g Number of animals inoculated with tumors: 69 mice Number of animals included in the treatment: 40 mice Number of animals not included: 29 mice Animal supplier: Beijing Vital River Biotechnology Experimental Animal Co. Ltd Certification number: 20221110Abzz0619000681 Study Design Group <![CDATA[N a ]]> Compound Dosage (mg / kg) <![CDATA[Dosing volume b (µL / g)]]> Route of administration <![CDATA[Frequency of administration c > <![CDATA[Medication schedule c > 1 5 Untreated -- 2 5 vehicle -- 10 PO BID 28 6 5 5 5 10 PO BID 28 7 5 5 15 10 PO BID 28 8 5 5 15 10 PO QD 28 Notice: a. N, number of animals in each group.

[0346] b. Dosing volume: Adjust the dosing volume to 10 μL / g based on body weight.

[0347] c. If weight loss >15%, adjust treatment schedule.

[0348] 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 a week by trypsin-EDTA. Cells growing in the exponential growth phase were harvested and counted for tumor inoculation.

[0349] Tumor cell information

[0350] Tumor inoculation Each mouse was inoculated subcutaneously in the right abdomen with NCI-H226 tumor cells (10×10 6 + 50% Matrigel l / 0.2mL) for tumor development. Animals were tagged with unique 6-digit earrings for identification. When the average tumor volume reached 154 mm 3 Start treatment when the average size of

[0351] Tumor measurement The primary endpoint was to determine whether tumor growth could be delayed or whether the mice could be cured. Tumor volume was measured in two dimensions twice weekly using calipers, and volume was expressed in mm using the following formula: 3 Meaning: V = 0.5 a × b 2 , where a and b are the long and short diameters of the tumor, respectively. The tumor size is then used to calculate the T / C value. The TGI value (in percentage) or T / C value (in percentage) is an indicator of antitumor effectiveness; T and C are the average tumor volume or tumor weight of the treatment group and the control group, respectively, on a given day.

[0352] The TGI of each group was calculated 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, T0 is the mean tumor volume of the treatment group on the day treatment started, V i is with T i The mean tumor volume of the vehicle control group on the same day, and V0 is the mean tumor volume of the vehicle group on the day treatment started.

[0353] Relative T / C(%)=T RTV / C RTV ×100 (RTV(%) = V t / V0×100,V t is the average tumor volume on a given day, and V0 is the average 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.

[0354] Tumor weights were measured at the end of the study. 重量 / C 重量 The value (in percentage) is calculated according to the following formula: 重量 / C 重量 (%)=TW 治疗 / TW 媒介物 ×100, where T and C are the average tumor weights of the treatment group and the control group, respectively.

[0355] Statistical analysis Summary statistics of tumor volume for each group at each time point are provided, including the mean and standard error of the mean (SEM).

[0356] Data obtained at the end of the study were subjected to statistical analysis of differences in tumor volume between groups.

[0357] 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.

[0358] When the media group reaches 472 mm 3 The anti-tumor effectiveness of PG-D28 was analyzed.

[0359] Tumor volume trace Changes in tumor volume during the study are provided in Table 19.

[0360] Table 19. Tumor sizes over the course of the study.

[0361]

[0362] Notice: a. Mean ± SEM Tumor growth inhibition assay The tumor growth inhibition rate of the test compound was calculated based on the tumor volume measurement results on day 28 after the start of treatment. The T / C values ​​calculated based on the tumor volume were close to each other, and the trend is shown in Table 20.

[0363] Table 20. Tumor size on day 28.

[0364]

[0365] a. Mean ± SEM.

[0366] b. T / C(%) = T RTV / C RTV × 100, TGI = [1-(T i -T0) / (V i -V0)] ×100.

[0367] c. One-tailed T-test analysis was performed to compare tumor volumes between the two groups.

Claims

1. A compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: X is selected from NR a , O and S; R 1 is a 5-10 membered heteroaryl group having one, two, three or four heteroatoms each independently selected from the group consisting of N, O and S; wherein the 5-10 membered heteroaryl group 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 has one, two, three or four heteroatoms each independently selected from the group consisting of N, O and S and is optionally substituted, wherein the C1-C4 alkylene is optionally substituted; R 3a and R 3b One of the following is selected from the group consisting of halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), C 3-10 The group consisting of cycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl, wherein the C 3-10 Cycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl are optionally substituted; and R 3a and R 3b The other one of which is selected from the group consisting of hydrogen, halogen and -C1-C6 alkyl; Each R 4 Independently selected from halogen and -C1-C6 alkyl; Each R 5 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; and R a is selected from hydrogen and -C1-C6 alkyl.

2. A compound of formula (I'): (I'), or a pharmaceutically acceptable salt thereof, wherein: X is selected from NR a , O and S; R 1 is a 5-10 membered heteroaryl group having one, two, three or four heteroatoms each independently selected from the group consisting of N, O and S; wherein the 5-10 membered heteroaryl group 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 one, two, three or four heteroatoms and is optionally substituted, wherein the heteroatom is nitrogen, and wherein the C1-C4 alkylene is optionally substituted; R 3a and R 3b One of the following is selected from the group consisting of halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), C 3-10 The group consisting of cycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl, wherein the C 3-10 Cycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl are optionally substituted; and R 3a and R 3b The other one of which is selected from the group consisting of hydrogen, halogen and -C1-C6 alkyl; Each R 4 Independently selected from halogen and -C1-C6 alkyl; Each R 5 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; and R a is selected from hydrogen and -C1-C6 alkyl.

3. A compound having the chemical formula (I-1): (I-1), or a pharmaceutically acceptable salt thereof, wherein: X is selected from NR a , O and S; R 1 is a 5-10 membered heteroaryl group having one, two, three or four heteroatoms each independently selected from the group consisting of N, O and S; wherein the 5-10 membered heteroaryl group 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 has one, two, three or four heteroatoms each independently selected from the group consisting of N, O and S and is optionally substituted, wherein the C1-C4 alkylene is optionally substituted; R 3 Selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), C 3-10 The group consisting of cycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl, wherein the C 3-10 Cycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl are optionally substituted; Each R 4 Independently selected from halogen and -C1-C6 alkyl; Each R 5 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; and R a is selected from hydrogen and -C1-C6 alkyl.

4. A compound having the chemical formula (I-1'): (I-1'), or a pharmaceutically acceptable salt thereof, wherein: X is selected from NR a , O and S; R 1 is a 5-10 membered heteroaryl group having one, two, three or four heteroatoms each independently selected from the group consisting of N, O and S; wherein the 5-10 membered heteroaryl group 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 one, two, three or four heteroatoms and is optionally substituted, wherein the heteroatom is nitrogen, and wherein the C1-C4 alkylene is optionally substituted; R 3 Selected from halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), C 3-10 The group consisting of cycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl, wherein the C 3-10 Cycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl are optionally substituted; Each R 4 Independently selected from halogen and -C1-C6 alkyl; Each R 5 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; and R a is selected from hydrogen and -C1-C6 alkyl.

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

6. The compound according to claim 1 or 3, wherein the compound is a compound of formula (Ia): (Ia), or a pharmaceutically acceptable salt thereof, wherein: R 3 is -C1-C6 alkyl or -C1-C6 haloalkyl; and The remaining variables are as defined in claim 1.

7. The compound according to claim 2 or 4, wherein the compound is a compound of formula (Ia'): (Ia'), or a pharmaceutically acceptable salt thereof, wherein: R 3 is -C1-C6 alkyl or -C1-C6 haloalkyl; and The remaining variables are as defined in claim 2.

8. A compound according to any one of claims 1 to 7, wherein R 1 is an optionally substituted 5-6 membered heteroaryl group.

9. A compound according to any one of claims 1 to 8, wherein R 1 is a 5-6 membered heteroaryl group optionally substituted by 1, 2, 3 or 4 substituents each independently selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl) and -N(R b )2, where each R b Independently selected from hydrogen and C1-C6 alkyl.

10. A compound according to any one of claims 1 to 9, wherein R 1 is a 5-6 membered heteroaryl group which is optionally substituted by 1, 2, 3 or 4 substituents each independently selected from halogen and -C1-C6 alkyl.

11. A compound according to any one of claims 1 to 10, wherein 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 1, 2, 3 or 4 substituents each independently selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl) and -N(R b )2, where each R b Independently selected from hydrogen and C1-C6 alkyl.

12. A compound according to any one of claims 1 to 11, wherein R 1 is a 5-6 membered heteroaryl group selected from the group consisting of oxadiazole, imidazole, pyrazole, oxazole, triazole, tetrazole, pyridine, pyrazine and pyridazine, wherein the 5-6 membered heteroaryl group is optionally substituted with a C1-C6 alkyl group.

13. A compound according to any one of claims 1 to 12, wherein R 1 is imidazole optionally substituted by methyl.

14. A compound according to any one of claims 1 to 12, wherein R 1 It's oxazole.

15. A compound according to any one of claims 1 to 12, wherein R 1 is a tetrazole optionally substituted with methyl.

16. A compound according to any one of claims 1 to 12, wherein R 1 is an oxadiazole, such as 1,3,4-oxadiazole, which is optionally substituted with methyl.

17. The compound according to any one of claims 1, 3 and 6, wherein the compound is a compound of formula (Ib): (Ib), or a pharmaceutically acceptable salt thereof, wherein: R d is selected from hydrogen and -C1-C6 alkyl; and The remaining variables are as defined in claim 6.

18. The compound according to any one of claims 2, 4 and 7, wherein the compound is a compound of formula (Ib'): (Ib'), or a pharmaceutically acceptable salt thereof, wherein: R d is selected from hydrogen and -C1-C6 alkyl; and The remaining variables are as defined in claim 7.

19. The compound according to claim 17, wherein the compound is a compound of formula (Ic): (Ic), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 17.

20. The compound according to claim 18, wherein the compound is a compound of formula (Ic'): (Ic'), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 18.

21. A compound according to any one of claims 1 to 20, wherein R 2 is a 3-7 membered monocyclic heterocyclyl or -(C1-C4 alkylene)-(3-7 membered monocyclic heterocyclyl), wherein the 3-7 membered monocyclic heterocyclyl contains at least 2 carbon atoms and one, two, three or four heteroatoms, wherein the heteroatoms are nitrogen, and wherein the 3-7 membered monocyclic heterocyclyl is optionally substituted, and wherein the C1-C4 alkylene is optionally substituted (e.g., optionally with C 1-6 Alkyl, C 1-6 or substituted with a haloalkyl group, or 1-4 The geminal dihydrogens on a carbon of an alkylene group can combine together with the carbon atom to which they are attached to form a 3-7 membered cycloalkyl ring).

22. A compound according to any one of claims 1 to 21, wherein R 2 is a 3-7 membered monocyclic heterocyclic group or -(C1-C4 alkylene)-(3-7 membered monocyclic heterocyclic group), wherein the 3-7 membered monocyclic heterocyclic group contains at least 2 carbon atoms and one, two, three or four heteroatoms, wherein the heteroatoms are nitrogen, and wherein the 3-7 membered monocyclic heterocyclic group is optionally substituted by 1, 2, 3 or 4 substituents each independently selected from the group consisting of C1-C6 alkyl, oxo, hydroxy, 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 , where R b , R g and R f Each of which is independently selected from hydrogen and C1-C6 alkyl, wherein each r is 1 or 2, and wherein each R f Independently selected from C 1-6 Alkyl and phenyl.

23. A compound according to any one of claims 1 to 22, wherein R 2 is a 3-7 membered monocyclic heterocyclic group, wherein the 3-7 membered monocyclic heterocyclic group contains at least 2 carbon atoms and one, two, three or four heteroatoms, wherein the heteroatoms are nitrogen, and wherein the 3-7 membered monocyclic heterocyclic group is optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -C1-C6 alkyl, oxo and hydroxy.

24. A compound according to any one of claims 1 to 22, wherein R 2 is a 5-membered heterocyclic group having one or two heteroatoms, wherein the heteroatoms are nitrogen atoms, and wherein the 5-membered heterocyclic group is optionally substituted by 1, 2 or 3 substituents each independently selected from C1-C6 alkyl, oxo and hydroxy.

25. A compound according to any one of claims 1 to 22, wherein R 2 It is -(C1-C4 alkylene)-(5-membered heterocyclyl having one or two heteroatoms), wherein the heteroatom is a nitrogen atom, and wherein the 5-membered heterocyclyl is optionally substituted by 1, 2 or 3 substituents each independently selected from C1-C6 alkyl, oxo and hydroxy.

26. A compound according to any one of claims 1 to 22, wherein R 2 yes: , wherein t is selected from the group consisting of 0, 1, 2 and 3.

27. A compound according to any one of claims 1 to 22, wherein R 2 yes: , wherein t is selected from the group consisting of 0, 1, 2 and 3.

28. The compound according to claim 26 or 27, wherein t is 1.

29. A compound according to any one of claims 1 to 22, wherein R 2 yes: , where s is selected from the group consisting of 0, 1, 2, and 3, and R e Selected from hydrogen and C1-C6 alkyl.

30. The compound according to claim 29, wherein s is 0 and R e It's methyl.

31. A compound according to any one of claims 1-22, wherein R 2 yes: , where u is selected from the group consisting of 0, 1, 2, and 3, and R e Selected from hydrogen and C1-C6 alkyl.

32. A compound according to any one of claims 1-22, wherein R 2 yes: , where u is selected from the group consisting of 0, 1, 2, and 3, and R e Selected from hydrogen and C1-C6 alkyl.

33. A compound according to any one of claims 1-22, wherein R 2 yes: , where u is selected from the group consisting of 0, 1, 2, and 3, and R e Selected from hydrogen and C1-C6 alkyl.

34. according to the compound described in any one of claims 31-33, wherein u is 0 and R e It's methyl.

35. A compound according to any one of claims 1-24 and 31, wherein the compound is a compound of formula (Id): (Id), or a pharmaceutically acceptable salt thereof, Where R 3 is -C1-C6 alkyl or -C1-C6 haloalkyl; and The remaining variables are as defined in claim 6.

36. The compound according to claim 35, wherein the compound is a compound of formula (Ie): (Ie), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 35.

37. A compound according to any one of claims 1-10 and 21-36, wherein R 1 Contains at least one ring carbon atom and contains only carbon atoms and nitrogen atoms.

38. A compound according to any one of claims 1 to 37, wherein R 3 It is C1-C6 alkyl or -C1-C6 haloalkyl.

39. A compound according to any one of claims 1 to 38, wherein R 3 It's a halogen.

40. A compound according to any one of claims 1-39, wherein R 3 It is trifluoromethyl.

41. The compound of any one of claims 1-40, wherein m and n are both 0.

42. A compound according to any one of claims 1 to 41, wherein R a It's hydrogen.

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

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

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

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

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

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

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 46-51, wherein the cancer is a metastatic cancer.

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

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

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

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

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

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

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

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

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

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

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

64. A compound or pharmaceutically acceptable salt according to any one of claims 1-43, or a pharmaceutical composition according to claim 44, for use in treating a disease or condition mediated by hyperactivation of a TEAD isoform selected from TEAD1 and TEAD4 in a subject in need thereof.

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

66. The compound or pharmaceutically acceptable salt or pharmaceutical composition for use according to claim 65, 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 or pharmaceutically acceptable salt according to any one of claims 1-43 or a pharmaceutical composition according to claim 44 in the preparation of a medicament for treating a disease or condition mediated by hyperactivation of a TEAD isoform selected from TEAD1 and TEAD4 in a subject in need thereof.

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

69. The use according to 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.

Images