CN119100968A - A cyclopentane compound for inhibiting TEAD activity, preparation method and application thereof - Google Patents

Abstract

The present invention relates to a cyclopentadiene compound for inhibiting TEAD activity, a preparation method and application thereof. The present invention also relates to a pharmaceutical composition comprising the compound as an active ingredient and the use of the compound or pharmaceutical composition for treating and/or preventing diseases related to TEAD biological activity.

Description

Fused ring compound for inhibiting TEAD activity, preparation method and application thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to a fused ring compound for inhibiting TEAD activity, a preparation method and application thereof.

Background

YES-associated protein 1 (Yes Associated Protein 1, YAP 1), a transcriptional coactivator with a PDZ Binding sequence (Transcriptional Coactivator with PDZ-Binding Motif, TAZ) and a transcriptional enhancement association domain protein (Transcriptional enhanced associate domain, TEAD) are downstream effector molecules of the Hippo signaling pathway, which can regulate cell proliferation and stem cell function. Neurofibrin 2 (neurofibromin, NF2) is a key regulator of the Hippo signaling pathway, the core of which is a kinase cascade in which NF2 and FERM domain protein 6 (FERM domain containing protein, FRMD6) form a complex and form a complex with Mst1/2 (a homolog of Drosophila Hippo) kinase and SAV1 that phosphorylates and activates LATS 1/2. LATS1/2 kinase can then inhibit YAP1 and TAZ by phosphorylation modification. When the Hippo pathway, which is a cancer suppression signal, is abnormal in its components, YAP1 and TAZ are dephosphorylated and transported into the nucleus and interact with TEAD, thereby activating the expression of genes involved in cell proliferation and apoptosis inhibition.

Abnormalities in the Hippo signaling pathway are associated with the development of multiple tumors and are involved in driving multiple tumor resistance. The challenge of Hippo as a cancer inhibition pathway, targeting its upstream kinase, is the need to design as an agonist, whereas as a terminal effector of the Hippo pathway abnormalities, the transcription cofactors YAP1 and TAZ themselves have no DNA binding domain and need to exert their physiological and pathological effects by interacting with the transcription factor TEAD. Therefore, the targeting YAP1/TAZ-TEAD interaction can effectively aim at tumors with abnormal Hippo signal paths, and has wide application prospects in the aspects of enhancing chemotherapy, overcoming small molecule targeting drug resistance, resisting tumor immunity curative effects and the like.

There are currently five small molecule inhibitors currently on the market that target YAP1/TAZ-TEAD interactions, namely, ionis's antisense oligonucleotide inhibitor ION537 (NCT 04659096,2020/12/09), vivace's VT3989 (NCT 04665206,2020/12/11), novartis's IAG933 (NCT 04857372,2021/04/23), ikena's IK-930 (NCT 05228015,2022/02/08), and Beda's BPI-460372 (Notification No. 2023LP00011, 2023LP 00012) recently issued by the pharmaceutical industry as approval notices for clinical trials. In addition, many of these targeted drugs are in preclinical research, mainly including Peptide 17, small molecule inhibitor patent ex22, which is a pharmaceutical in France INVENTIVA, MCH-CP1, which is an inhibitor designed by the general institute of Boston hemp, U.S. and example 52, which is a combination of gene Tex and Minc, modified TED347, which is a natural product of the university of Indiana, and K-975, which is a pharmaceutical in Kirin, in Japan.

Disclosure of Invention

Problems to be solved by the invention:

In view of the extremely high application value and development prospect of TEAD inhibitors in tumor treatment, the application provides a novel compound capable of serving as the TEAD inhibitor.

Specifically, the invention relates to the following technical scheme:

The present invention provides a compound of formula (I), or a prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

wherein,

R ₁ is selected from C _1-8 alkyl;

Each R ₂ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, cyano, amino, carboxyl, C _3-12 cycloalkyl, C _5-10 aryl, 5-10 membered heterocycloalkyl, 5-10 membered heteroaryl, said heterocycloalkyl, heteroaryl containing 1-3 heteroatoms selected from N, O, S;

R ₃ is selected from carboxyl, -C (O) NHR, R is selected from C _1-6 alkyl, C _3-12 cycloalkyl, C _5-10 aryl, 5-10 membered heterocycloalkyl, 5-10 membered heteroaryl, R being optionally further substituted by R ^a, R ^a being selected from halogen, C _1-6 alkyl, C _3-12 cycloalkyl, 5-10 membered heterocycloalkyl, C _5-10 aryl, 5-10 membered heteroaryl, R ^a being optionally further substituted by R ^b, R ^b is selected from carboxyl, -C (O) NHR ^c、-C(O)R^c;R^c is selected from the group consisting of C _1-6 alkyl, C _3-12 cycloalkyl, C _5-10 aryl, 5-10 membered heterocycloalkyl, 5-10 membered heteroaryl, R ^c may be further substituted by R ^d, R ^d is selected from the group consisting of halogen, c _1-6 alkyl, cyano, amino, carboxyl, said heterocycloalkyl, heteroaryl containing 1-3 heteroatoms selected from N, O, S;

n is selected from 1, 2 and 3.

In one embodiment, the compound, or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, R ₁ is selected from the group consisting of C _1-6 alkyl, C _2-6 alkyl, C _7-8 alkyl, C _1-3 alkyl, C _4-6 alkyl, C _5-6 alkyl, and the alkyl group comprises a linear or branched alkyl group.

In a preferred embodiment, R ₁ is selected from C _1-3 alkyl.

In a more preferred embodiment, R ₁ is selected from methyl, ethyl, isopropyl.

In one embodiment, each R ₂ is independently selected from fluorine, chlorine, bromine, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, cyano, amino, carboxyl, C _5-12 cycloalkyl, C _5-8 aryl, 5-8 membered heterocycloalkyl, 5-8 membered heteroaryl, or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein said heterocycloalkyl, heteroaryl comprises 1-3 heteroatoms selected from N, O, S.

In a preferred embodiment, each R ₂ is independently selected from fluorine, chlorine, C _1-4 alkyl, C _1-4 haloalkyl, C _5-12 cycloalkyl.

In a more preferred embodiment, each R ₂ is independently selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, C _5-8 cycloalkyl, C _6-10 cycloalkyl, C _9-12 cycloalkyl, C _7-11 cycloalkyl.

In a still further preferred embodiment, each R ₂ is independently selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, -CF ₃、-CCl₃、-CHF₂、-CH₂ F, cyclopentane, cyclohexane, cycloheptane, cyclooctane, adamantane.

In a most preferred embodiment, each R ₂ is independently selected from fluorine, chlorine, methyl, -CF ₃、-CCl₃, adamantane.

In one embodiment, the compound, or a prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, R ₃ is selected from the group consisting of carboxy, -C (O) NHR, R is selected from the group consisting of C _1-4 alkyl, C _5-12 cycloalkyl, C _5-8 aryl, 5-8 heterocycloalkyl, 5-8 heteroaryl, R being optionally further substituted by R ^a, R ^a being selected from fluorine, chlorine, bromine, iodine, C _1-4 alkyl, c _5-12 cycloalkyl, 5-8 membered heterocycloalkyl, C _5-8 aryl, 5-8 membered heteroaryl, R ^a being optionally further substituted by R ^b, R ^b being selected from carboxyl, -C (O) NHR ^c、-C(O)R^c;R^c is selected from the group consisting of C _1-4 alkyl, C _5-12 cycloalkyl, C _5-8 aryl, 5-8 membered heterocycloalkyl, R ^c -8 membered heteroaryl, which may be further substituted with R ^d, R ^d is selected from fluorine, chlorine, bromine, iodine, C _1-4 alkyl, cyano, amino, carboxyl, said heterocycloalkyl, heteroaryl containing 1 to 3 heteroatoms selected from N, O, S.

In a preferred embodiment, R ₃ is selected from the group consisting of carboxy, -C (O) NHR, R is selected from the group consisting of C _1-3 alkyl, C _5-12 cycloalkyl, C _6-10 cycloalkyl, C _5-8 aryl, C _6-8 aryl, R may be further substituted with R ^a, R ^a is selected from fluorine, chlorine, C _5-8 aryl, C _6-8 aryl, 5-8 membered heteroaryl, 6-8 membered heterocycloalkyl, R ^a may be further substituted by R ^b; R ^b is selected from carboxyl group, -C (O) NHR ^c、-C(O)R^c;R^c is selected from the group consisting of C _1-3 alkyl, C _5-10 cycloalkyl, C _5-8 aryl, C _6-8 aryl, R ^c may be further substituted with R ^d, R ^d is selected from the group consisting of fluorine, Chlorine, C _1-3 alkyl, cyano, amino, carboxyl.

In a more preferred embodiment, R ₃ is selected from carboxyl, -C (O) NHR, R is selected from methyl, ethyl, propyl, isopropyl, cyclopentane, cyclohexane, cycloheptane, cyclooctane, adamantane, benzene ring, R may be further substituted with R ^a, R ^a is selected from fluorine, chlorine, benzene ring, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, R ^a may be further substituted with R ^b, R ^b is selected from carboxyl, -C (O) NHR ^c、-C(O)R^c;R^c is selected from methyl, ethyl, propyl, isopropyl, cyclopentane, cyclohexane, cycloheptane, cyclooctane, adamantane, benzene ring, R ^c may be further substituted with R ^d, R ^d is selected from fluorine, chlorine, methyl, ethyl, propyl, cyano, amino, carboxyl.

In a still further preferred embodiment R ₃ is selected from carboxyl, -C (O) NHR, R is selected from methyl, ethyl, benzene ring, adamantane, R may be further substituted with R ^a, R ^a is selected from fluorine, chlorine, benzene ring, 6 membered heteroaryl or heterocycloalkyl containing 1-3N atoms, R ^a may be further substituted with R ^b, R ^b is selected from carboxyl, -C (O) NHR ^c、-C(O)R^c;R^c is selected from methyl, ethyl, propyl, isopropyl, adamantane, benzene ring, R ^c may be further substituted with R ^d, R ^d is selected from fluorine, chlorine, methyl, ethyl, amino.

In a preferred embodiment, R ₃ is selected from carboxyl, -C (O) NHR, R is selected from phenyl- (CH ₂)_m -, pyridinyl- (CH ₂)_p -, adamantyl wherein m=0, 1 or 2, p=0, 1 or 2, wherein said phenyl or pyridinyl may be further substituted with R ^b, R ^b is selected from chloro, -piperazinyl-C (O) R ^c, carboxyl, -C (O) NHR ^c、-C(O)R^c;R^c is selected from methyl, ethyl, propyl, isopropyl, adamantane, benzene ring, R ^c may be further substituted with R ^d, R ^d is selected from fluorine, chlorine, methyl, ethyl, amino,

In a further preferred embodiment, R ₃ is selected from carboxyl, -C (O) NHR, R is selected from Wherein the phenyl or pyridyl group may be further substituted with R ^b, R ^b is selected from chloro, carboxy,

In a further preferred embodiment, R ₃ is selected from the group consisting of carboxyl,

Most preferably, R ₃ is selected from the group consisting of carboxyl,

In one embodiment, the compound, or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, has the structure described by formula (II):

wherein the definition of R ₁、R₂ and n refers to the aforementioned definition.

In one embodiment, the compound, or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, has the structure of formula (III):

Wherein the definition of R ₁、R₃ refers to the aforementioned definition.

In one embodiment, the above compound, or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is selected from the group consisting of:

The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present application. The chemical reactions of the embodiments of the present application are accomplished in a suitable solvent that is compatible with the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the embodiments already present.

An important consideration in the art of synthetic route planning is the selection of suitable protecting groups for reactive functional groups (such as amino groups in the present application), for example, reference may be made to chem.Commun.,2019,55,7331-7334. All references cited herein are incorporated herein in their entirety or by reference to synthetic methods known in the art and methods described herein. The product from each step is obtained using separation techniques known in the art including, but not limited to, extraction, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials and chemical reagents required for the synthesis may be synthesized conventionally according to literature (as provided by SCIFINDER) or purchased.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I), (II) or (III) above, a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof, and a pharmaceutically acceptable auxiliary ingredient, preferably a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

The invention also provides the use of a compound of formula (I), (II) or (III), a prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof or a pharmaceutical composition thereof in the preparation of a medicament for treating and/or preventing a disease associated with TEAD biological activity.

In a preferred embodiment, the disease associated with TEAD biological activity is selected from cancer or hyperproliferative diseases.

The present invention also provides a method of treating and/or preventing a disease associated with TEAD biological activity, by administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of a compound of formula (I), (II) or (III) above, a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof, or a pharmaceutical composition of the above.

In a preferred embodiment, the disease associated with TEAD biological activity is selected from cancer or hyperproliferative diseases.

The invention also provides a compound shown in the formula (I), (II) or (III), a prodrug, a solvate, a crystal form, a pharmaceutically acceptable salt, a stereoisomer or a tautomer thereof or a pharmaceutical composition thereof, which is used for treating and/or preventing diseases related to the biological activity of TEAD.

In a preferred embodiment, the disease associated with TEAD biological activity is selected from cancer or hyperproliferative diseases.

Technical terms of the invention:

In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments. However, it will be understood by those skilled in the art that the present invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Throughout the specification and claims, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" will be interpreted in an open-ended fashion, i.e. "including but not limited to. Furthermore, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" appearing in various places throughout the specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Furthermore, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the context clearly dictates otherwise.

In accordance with the practice of the art,A bond as used in the formulae herein is described as the point of attachment of the moiety or substituent to the parent or host structure.

In the present invention, the term "substituted" means that an atom or group of atoms formally replaces hydrogen and is attached as a "substituent" to another group. The term "substituted" refers to any degree of substitution where such substitution is allowed, such as mono-, di-, tri-, tetra-, or penta-substitution, unless otherwise indicated. Substituents are independently selected and substitution can be at any chemically accessible position. It is understood that substitution on a given atom is limited by the valency. It is understood that substitution at a given atom results in a chemically stable molecule.

In the present invention, the term "alkyl" used alone or in combination with other terms refers to a saturated hydrocarbon group that may be straight or branched. The term "C _1-8 alkyl" refers to an alkyl group having 1 to 8 carbon atoms. Alkyl corresponds in form to an alkane in which one C-H bond is replaced with the point of attachment of the alkyl group to the rest of the compound. In some embodiments, the alkyl group contains 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, primary butyl, tertiary butyl, isobutyl, higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1, 2-trimethylpropyl, and the like.

In the present invention, the term "halo" or "halogen" used alone or in combination with other terms refers to F, cl, br and I. In some embodiments, the term "halo" refers to a halogen atom selected from F, cl or Br.

In the present invention, the term "haloalkyl" used alone or in combination with other terms refers to an alkyl group substituted with one or more halogens, wherein the terms "halogen", "alkyl" are as defined above.

In the present invention, the term "heteroatom" used alone or in combination with other terms includes S, O and N.

In the present invention, the term "alkoxy" used alone OR in combination with other terms refers to a group of formula-OR ^a, wherein R ^a is an alkyl group as defined above. Unless specifically indicated otherwise in the present specification, an alkoxy group may be optionally substituted as described below, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -OH, -OMe, -NH ₂, or-NO ₂. In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -OH, or-OMe. In some embodiments, the alkoxy group is optionally substituted with halogen.

In the present invention, the term "aryl" used alone or in combination with other terms refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2 fused rings). The term "C _6-10 aryl" refers to an aryl group having 6 to 10 ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, indanyl, indenyl, and the like. In some embodiments, the aryl group has 6 carbon atoms. In some embodiments, the aryl group has 10 carbon atoms. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group is naphthyl.

In the present invention, the term "heteroaryl", alone or in combination with other terms, refers to a mono-or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from S, O and N, which heteroatom may be in any ring thereof or in multiple (e.g., two or three) rings simultaneously. In some embodiments, the heteroaryl ring has 1,2, 3, or 4 heteroatom ring members independently selected from S, O and N. In some embodiments, any of the cyclic N in the heteroaryl moiety may be an N-oxide. In some embodiments, heteroaryl groups have 5 to 14 ring atoms, including carbon atoms and 1,2, 3, or 4 heteroatom ring members independently selected from S, O and N. In some embodiments, heteroaryl groups have 5 to 10 ring atoms, including carbon atoms, and 1,2, 3, or 4 heteroatom ring members independently selected from S, O and N. In some embodiments, heteroaryl groups have 5 to 6 ring atoms and 1 or 2 heteroatom ring members independently selected from S, O and N. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. In other embodiments, the heteroaryl is an eight-, nine-, or ten-membered fused bicyclic heteroaryl ring. Example heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thienyl, quinolinyl, isoquinolinyl, naphthyridinyl (including 1, 2-naphthyridin, 1, 3-naphthyridine, 1, 4-naphthyridine, 1, 5-naphthyridine, 1, 6-naphthyridine, 1, 7-naphthyridine, 1, 8-naphthyridine, 2, 3-naphthyridine, and 2, 6-naphthyridine), indolyl, benzothienyl, benzofuranyl, benzisoxazolyl, imidazo [1,2-b ] thiazolyl, purinyl, and the like.

In the present invention, the term "cycloalkyl" used alone or in combination with other terms refers to non-aromatic hydrocarbon ring systems (monocyclic, bicyclic or polycyclic), polycyclic (e.g., bicyclic or tricyclic) including fused, spiro, bridged rings, including cyclized alkyl groups. The term "C _3-8 cycloalkyl" or "C _3-14 cycloalkyl" refers to cycloalkyl groups having 3 to 8 or 3 to 14 ring member carbon atoms, respectively. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2,3, or 4 fused rings) groups and spiro rings. Cycloalkyl groups may have 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13 or 14 ring carbons (C _3-14). In some embodiments, cycloalkyl has 3-12 ring members, 3-10 ring members, 3-8 ring members, 3-6 ring members, 3-5 ring members, or 3-4 ring members. In some embodiments, cycloalkyl is a single ring. In some embodiments, cycloalkyl is monocyclic or bicyclic. In some embodiments, the cycloalkyl is a C _3-8 monocyclic cycloalkyl. The ring-forming carbon atoms of cycloalkyl groups may optionally be oxidized to form oxo or thioionic groups. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In the present invention, unless specifically stated otherwise, the term "heterocycloalkyl" used alone or in combination with other terms refers to a non-aromatic ring system (monocyclic, bicyclic or polycyclic), polycyclic (e.g., bicyclic or tricyclic) including fused, spiro, bridged rings having at least one heteroatom ring member independently selected from N, S and O, and having 4-14 ring members, 4-10 ring members, or 4-8 ring members, the heteroatoms may be on any of their rings, or on multiple (e.g., two or three) rings simultaneously. The term "heterocycloalkyl" includes monocyclic 4-, 5-, 6-and 7-membered heterocycloalkyl groups. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1,2, or 3 heteroatoms independently selected from N, S and O. In some embodiments, the heterocycloalkyl is a spiro ring having 1,2, or 3 heteroatoms independently selected from N, S and O. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can optionally be oxidized to form oxo or thioxo groups or other oxidized bonds (e.g., C (O), S (O), C (S) or S (O) ₂, N-oxide, etc.), or the nitrogen atom can be quaternized. Heterocycloalkyl groups may be attached via a ring-forming carbon atom or a ring-forming heteroatom.

In the present invention, the term "therapeutically effective amount" used alone or in combination with other terms refers to an amount of a compound administered to a mammal and/or subject as a single dose or as part of a series of doses that is effective to produce the desired therapeutic effect.

The invention has the beneficial effects that:

The compound and the pharmaceutical composition provided by the invention have good effect of inhibiting the biological activity of TEAD, and can be used as medicines related to the prevention and/or improvement and/or treatment of diseases related to the effect. In addition, it has significant advantages over controls in terms of pharmacokinetic characteristics (e.g., plasma exposure AUC, peak concentration C _max, in vivo half-life T _1/2, and mean residence time MRT), which suggests that the compounds of the invention can achieve higher levels of drug exposure in vivo following oral administration, have a sustained therapeutic substance basis, and have the potential to bring about unexpected antitumor activity.

Detailed description of the preferred embodiments

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Modifications, substitutions, and alterations are also possible in many other forms without departing from the basic technical spirit of the present invention, according to the general knowledge and conventional means of the present art.

The present invention is described in detail below by way of examples, but is not meant to be limiting in any way. The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the embodiments of the invention without departing from the spirit and scope of the invention, which is also intended to be covered by the appended claims.

EXAMPLE 1 preparation of 3-methyl-1- [4- (trifluoromethyl) phenyl ] indole-5-carboxylic acid

Step 1 preparation of 3-methyl-1H-indole-5-carboxylic acid methyl ester (int-1 b)

Methyl 4-hydrazinobenzoate hydrochloride (4052 mg,20 mmol), propionaldehyde (1162 mg,20 mmol) and 1, 4-dioxane (60 mL) were added to a 150mL flask at room temperature, and triethylamine (2424 mg,24 mmol) was added under stirring at room temperature, and the reaction was completed at room temperature for 2 hours, monitored by TLC, and the starting material was reacted completely to give intermediate hydrazone. To the reaction system was added 3mol/L hydrochloric acid aqueous solution (10 mL), and the reaction was continued at 100℃for 15 hours, followed by TLC monitoring (EA/PE=1:3) to complete the reaction of the intermediate starting material.

The solvent was distilled off under reduced pressure, 30ml of ethyl acetate and 30ml of 1mol/L aqueous sodium hydroxide solution were added, stirred, extracted, the organic phase was washed with 30ml of diluted brine again, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (EA/pe=1:5) to give the target product methyl 3-methyl-1H-indole-5-carboxylate (int-1 b) (1380 mg,7.3mmol,36.5% yield). LC-MS (M/z): 190.1 (M+1).

Step 2 preparation of methyl 3-methyl-1- [4- (trifluoromethyl) phenyl ] indole-5-carboxylate (int-1 c)

To a 50mL flask at room temperature were added int-1b (50 mg,0.26 mmol) and 1, 4-dioxane (10 mL), cesium carbonate (212 mg,0.65 mmol), 4-bromo-1- (trifluoromethyl) benzene (71 mg,0.32 mmol) and XPhos Palladacycle gen.4 (22 mg,0.03 mmol) and then added, the addition was completed, nitrogen blanket was taken, the temperature was raised to 110℃and the reaction was allowed to proceed for 15 hours, and the reaction was complete by TLC (EA/PE=1:3).

The reaction solution was concentrated under reduced pressure, and the solvent was distilled off. Column chromatography (EA/pe=1:6) afforded the target product methyl 3-methyl-1- [4- (trifluoromethyl) phenyl ] indole-5-carboxylate (int-1 c) (65 mg,0.195mmol,75.0% yield). LC-MS (M/z): 334.1 (M+1).

Step 3 preparation of 3-methyl-1- [4- (trifluoromethyl) phenyl ] indole-5-carboxylic acid (Compound 1)

To a 50mL flask, int-1C (65 mg,0.19 mmol) and methanol (5 mL) were added at room temperature, and 3mol/L aqueous sodium hydroxide (1 mL) was added dropwise to the reaction system with stirring, and the reaction was continued at 70℃for 2 hours. TLC detection (EA/pe=1:3), starting material was complete.

The methanol solvent was distilled off under reduced pressure, 10ml of water was added, the pH was adjusted to 5 with diluted hydrochloric acid, then 10ml of ethyl acetate was added for extraction, the aqueous layer was back extracted with 5ml of ethyl acetate, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated, slurried with n-hexane, filtered, and dried to give the target product 3-methyl-1- [4- (trifluoromethyl) phenyl ] indole-5-carboxylic acid (compound 1) (41 mg,0.13mmol,65.9% yieldd) as a white solid. LC-MS (M/z): 320.1 (M+1): HPLC:98.1%.

¹H NMR(400MHz,DMSO)δ12.64(s,1H),8.26(d,J＝1.3Hz,1H),7.94(d,J＝8.6Hz,2H),7.84(d,J＝8.7Hz,3H),7.69(dd,J＝9.8,4.7Hz,2H),2.37(d,J＝0.6Hz,3H).

EXAMPLE 2 preparation of 3-ethyl-1- [4- (trifluoromethyl) phenyl ] indole-5-carboxylic acid

Step 1 preparation of 3-ethyl-1H-indole-5-carboxylic acid methyl ester (int-2 b)

The synthesis of int-2b is identical to that of int-1 b. The reactant uses butyraldehyde instead of propionaldehyde, the operation is the same. Column chromatography (EA/pe=1:5) afforded the target product, 3-ethyl-1H-indole-5-carboxylic acid methyl ester (int-2 b) (260 mg,1.28mmol,32.0% yield). LC-MS (M/z): 204.1 (M+1).

Step 2 preparation of 3-ethyl-1- [4- (trifluoromethyl) phenyl ] indole-5-carboxylic acid methyl ester (int-2 c)

The synthesis of int-2c is identical to that of int-1 c. The reaction raw material uses int-2b to replace int-1b, and the operation method is the same. Column chromatography (EA/pe=1:8) afforded the target product 3-ethyl-1- [4- (trifluoromethyl) phenyl ] indole-5-carboxylic acid methyl ester (int-2 c) (295 mg,0.85mmol,66.4% yield). LC-MS (M/z): 348.1 (M+1).

Step 3 preparation of 3-ethyl-1- [4- (trifluoromethyl) phenyl ] indole-5-carboxylic acid (Compound 2)

The synthesis of compound 2 is the same as compound 1. The reaction raw material uses int-2c to replace int-1c, and the operation method is the same. After drying, the desired product 3-ethyl-1- [4- (trifluoromethyl) phenyl ] indole-5-carboxylic acid (compound 2) (205 mg,0.59mmol,69.8% yield) was obtained as a white solid. LC-MS (M/z): 334.1 (M+1): HPLC:96.44%.

¹H NMR(400MHz,DMSO)δ12.68(s,1H),8.28(d,J＝1.3Hz,1H),7.94(d,J＝8.6Hz,2H),7.90-7.79(m,3H),7.76-7.62(m,2H),3.09-2.67(m,2H),1.34(t,J＝7.5Hz,3H).

EXAMPLE 3 preparation of 3-isopropyl-1- [4- (trifluoromethyl) phenyl ] indole-5-carboxylic acid

Step 1 preparation of 3-isopropyl-1H-indole-5-carboxylic acid methyl ester (int-3 b)

The synthesis of int-3b is identical to that of int-1 b. The reaction reagent uses isovaleraldehyde to replace propionaldehyde, and the operation method is the same. Column chromatography (EA/pe=1:6) afforded the target product, 3-isopropyl-1H-indole-5-carboxylic acid methyl ester (int-3 b) (310 mg,1.43mmol,35.7% yield). LC-MS (M/z): 218.1 (M+1).

Step 2 preparation of methyl 3-isopropyl-1- [4- (trifluoromethyl) phenyl ] indole-5-carboxylate (int-3 c) the synthesis of int-3c is identical to int-1 c. The reaction raw material uses int-3b to replace int-1b, and the operation method is the same. Column chromatography (EA/pe=1:8) afforded the target product 3-isopropyl-1- [4- (trifluoromethyl) phenyl ] indole-5-carboxylic acid methyl ester (int-3 c) (325 mg,0.90mmol,63.0% yield). LC-MS (M/z): 362.1 (M+1).

Step 3 preparation of 3-isopropyl-1- [4- (trifluoromethyl) phenyl ] indole-5-carboxylic acid (Compound 3)

The synthesis of compound 3 is the same as compound 1. The reaction raw material uses int-3c to replace int-1c, and the operation method is the same. Drying gave the target product 3-isopropyl-1- [4- (trifluoromethyl) phenyl ] indole-5-carboxylic acid (compound 3) (235 mg,0.67mmol,75.9% yield) as a white solid. LC-MS (M/z): 348.3 (M+1): HPLC:99.3%.

¹H NMR(400MHz,DMSO)δ12.70(s,1H),8.32(d,J＝1.2Hz,1H),7.93(d,J＝8.6Hz,2H),7.90-7.81(m,3H),7.70(d,J＝8.7Hz,1H),7.63(s,1H),3.67-2.89(m,1H),1.37(d,J＝6.9Hz,6H).

EXAMPLE 4 testing of TEAD inhibitory Activity of the Compounds of the invention

1. Experimental materials

1.1640 Basal Medium (purchased from Gibco, cat# C11875500 BT)

2.1640 Complete Medium 1640 basal Medium 10% (v/v) FBS and 1% (v/v) were added

Green streptomycin mixed liquor (double antibody)

3. Fetal Bovine Serum (FBS) (available from Gibco, cat# 10099-141)

4. Green streptomycin mixed liquor (double antibody) (purchased from Gibco, cat# 15140122)

5.1 XPBS (available from Producer, cat# A610100-0001)

6. Trypsin (Trypsin) (available from Gibco under the trade name 15140122)

7. Transfection reagent X-TREMEGENE HP DNA Transfection Reagent (available from Roche, cat:

06366546001)

8. Luciferase assay System-luciferases ASSAY SYSTEM (available from Promega, cat# E151A) 9-cell culture lysis reagent: cell Culture Lysis X reagent (available from Promega, cat#:

E153A)

TECAN Spark multifunctional enzyme-labeled instrument

11. Plasmid GFP (available from Addgene, cat# 11153)

12. Reporter gene plasmid pGL3b-8XGTIIC-luciferase (purchased from Feng Hui, cat# FH 2289)

13. Reporter gene plasmid PGL4.10[ LUC2] (purchased from Youbao organism, cat# VT 1558)

14. Cell line L-02 (purchased from ATCC)

15.96 Well flat bottom cell culture plate, 96 well white bottom cell culture plate (available from Costar)

16. Cell incubator (purchased from Thermo, model 371: 371 Steri-Cycle)

17. Sample addition groove (purchased from BKMAN, goods number: 110420001)

18. Pipetting gun (measuring ranges are 1mL, 200 mu L, 100 mu L, 20 mu L, 10 mu L respectively)

2. Experimental procedure

L-02 cell lines were harvested by Trypsin (Trypsin) digestion and seeded at 50% bottom area into 96-well flat bottom cell culture plates and cultured overnight in 80. Mu.L per well, 37℃in a 5% CO ₂ incubator.

Cells were transfected overnight following the background plasmid group (PGL 4.10[ LUC2] (50 ng/well) +GFP (10 ng/well)) and the reporter plasmid group (8 XGTIIC-luciferase (50 ng/well) +GFP (10 ng/well)) at a transfection ratio of plasmid μg: transfection reagent=1:3.

The transfection reagents X-TREMEGENE HP DNA Transfection Reagent and 1640 basal medium were removed from the refrigerator in advance and equilibrated to room temperature. Adding 10ng/well of GFP plasmid into 1640 basal medium (5 mu L/well), gently blowing and mixing, split charging into two tubes, adding PGL4.10[ LUC2] (50 ng/well) and 8XGTIIC-luciferase (50 ng/well) respectively, adding 0.18 mu L/well liposome into 1640 basal medium (5 mu L/well), gently blowing and mixing, standing at room temperature for 5min, mixing plasmid mixture and transfection reagent mixture in equal volume, gently blowing and mixing, standing at room temperature for 15min, gently blowing and mixing according to 10 mu L/well and 1640 complete medium 90 mu L/well of transfection complex, removing cell supernatant, adding 100 mu L/well into 96-well flat bottom cell culture plate, culturing at 37 ℃ in 5% CO ₂ incubator overnight.

The complete culture medium 1640 is supplemented with 90 mu L/well before dosing, DMSO is added to the background group, DMSO (no drug adding holes) and a concentration gradient compound (0.01-10000 nM) are respectively added to the reporter group, and the culture is carried out in a culture box with 5% CO ₂ at 37 ℃ for 24 hours.

The 96-well flat bottom cell culture plate with the cells cultured is taken out from an incubator, cell supernatant is subtracted, 60 mu L of 1X Cell Culture Lysis is added for lysis, the full lysis is performed by a pipette, 50 mu L of the lysate is transferred to a 96 Kong Bankong white bottom plate, GFP value (Ex 485/Em 520) is detected by using a TECAN multifunctional enzyme-labeled instrument, 30 mu L of luciferase substrate is added to each well, and the Luci value is immediately detected by a machine.

Calculation the Ratio ratio=luc/GFP is calculated first and then the relative activity of each well is calculated from the Ratio values of each well. The formula is as follows:

Relative Activity(%)=(Ratio_{( Compound pore )}-Ratio_{( Background hole )})/(Ratio_{(DMSO Hole(s) )}-Ratio_{( Background}

_{Hole(s) )})×100%

In GRAPHPAD PRISM.0.1 software, a "XY" data table is created, X columns are filled with compound concentrations, Y columns are filled with corresponding relative activities of each well, clicking "analysis" and selecting "transformation" to pick up "Transform X values using X =log (X)", converting X-axis data into corresponding log values, clicking "analysis" and selecting "Nonlinear regression (cut fit)" again, and selecting "log (inhibitor) vs. normalized response Least squares fit" in "Dose-response-Stimulation", and obtaining IC ₅₀ of each compound in the test in the nonlinear fitting table of data transformation.

TABLE 1 TEAD inhibitory Activity of the inventive Compounds

Examples	TEAD IC50(nM)
		1	96.87
2	11.26
		3	83.79

As can be seen from the results in the table, the compounds of the present invention have IC50 values of less than 100nM and excellent inhibitory effect on TEAD activity.

EXAMPLE 5 drug substitution test

Female BALB/c mice (purchased from the medical laboratory animal center, guangdong province) of about 8 weeks old were randomly divided into three groups of 6. Test compounds were formulated in vehicles containing 5% DMSO, 70% PEG400 and 25% purified water, 5mg/kg of the compound was administered by gavage, and blood was alternately collected through the ocular fundus venous plexus in a single administration at blood collection time points of 15min,30min,1h,2h,4h,8h and 24h before and after administration. About 0.06mL of blood is collected in a centrifuge tube (anticoagulation of heparin sodium), centrifuged for 10 minutes at 4 ℃ and 3200g, and the supernatant plasma is separated and frozen at-20 ℃ for testing. A plurality of plasma samples are accurately taken, acetonitrile is added for extraction, and a liquid chromatography-mass spectrometry (LC-MS/MS) is used for measuring the concentration of the compound in the plasma. Pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0 from the mean plasma concentration data at different time points. The data are summarized in Table 1:

table 1 pharmacokinetic parameters of test compounds in mice following oral administration

Wherein the control compound A is yang reference molecule VT-103, a commercially available TEAD inhibitor, which has the structure of

The control compound B is the most active TEAD inhibitor disclosed in the English patent CN115925688A, and has the structure as follows

From the above results, it can be seen that the representative compound 2 according to the present invention has significantly higher plasma exposure (AUC) and peak concentration (C _max) in mice than 2 control compounds, especially control compound B having a structure similar to that of the compound, and that compound 2 has a longer in vivo half-life (T _1/2) and average residence time (MRT) compared to control compound a and significantly longer than control compound B having a structure similar to that of the compound. The pharmacokinetic characteristics show that the compound can reach higher drug exposure level in vivo after oral administration, has a substance basis for continuously exerting curative effect, and has the potential of bringing unexpected anti-tumor activity.

Industrial applicability

The compound of the present invention has excellent effect of inhibiting the biological activity of TEAD, and can be used as a medicament for treating or preventing diseases associated with the effect.

The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.

Claims (9)

1. A compound of formula (I), or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

wherein,

R ₁ is selected from C _1-8 alkyl;

Each R ₂ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, cyano, amino, carboxyl, C _3-12 cycloalkyl, C _5-10 aryl, 5-10 membered heterocycloalkyl, 5-10 membered heteroaryl, said heterocycloalkyl, heteroaryl containing 1-3 heteroatoms selected from N, O, S;

R ₃ is selected from carboxyl, -C (O) NHR, R is selected from C _1-6 alkyl, C _3-12 cycloalkyl, C _5-10 aryl, 5-10 membered heterocycloalkyl, 5-10 membered heteroaryl, R being optionally further substituted by R ^a, R ^a being selected from halogen, C _1-6 alkyl, C _3-12 cycloalkyl, 5-10 membered heterocycloalkyl, C _5-10 aryl, 5-10 membered heteroaryl, R ^a being optionally further substituted by R ^b, R ^b is selected from carboxyl, -C (O) NHR ^c、-C(O)R^c;R^c is selected from the group consisting of C _1-6 alkyl, C _3-12 cycloalkyl, C _5-10 aryl, 5-10 membered heterocycloalkyl, 5-10 membered heteroaryl, R ^c may be further substituted by R ^d, R ^d is selected from the group consisting of halogen, c _1-6 alkyl, cyano, amino, carboxyl, said heterocycloalkyl, heteroaryl containing 1-3 heteroatoms selected from N, O, S;

n is selected from 1, 2 and 3.

2. The compound of claim 1, or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R ₁ is selected from the group consisting of C _1-6 alkyl, C _2-6 alkyl, C _7-8 alkyl, C _1-3 alkyl, C _4-6 alkyl, C _5-6 alkyl;

Preferably, R ₁ is selected from C _1-3 alkyl;

More preferably, R ₁ is selected from methyl, ethyl, propyl, isopropyl.

3. The compound of claim 1, or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each R ₂ is independently selected from the group consisting of fluoro, chloro, bromo, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, cyano, amino, carboxyl, C _5-12 cycloalkyl, C _5-8 aryl, 5-8 membered heterocycloalkyl, 5-8 membered heteroaryl, wherein said heterocycloalkyl, heteroaryl contains 1-3 heteroatoms selected from N, O, S;

Preferably, each R ₂ is independently selected from fluorine, chlorine, C _1-4 alkyl, C _1-4 haloalkyl, C _5-12 cycloalkyl;

More preferably, each R ₂ is independently selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, C _5-8 cycloalkyl, C _6-10 cycloalkyl, C _9-12 cycloalkyl, C _7-11 cycloalkyl;

Still more preferably, each R ₂ is independently selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, -CF ₃、-CCl₃、-CHF₂、-CH₂ F, cyclopentane, cyclohexane, cycloheptane, cyclooctane, adamantane;

Most preferably, each R ₂ is independently selected from fluorine, chlorine, methyl, -CF ₃、-CCl₃, adamantane.

4. The compound of claim 1, wherein R ₃ is selected from the group consisting of carboxy, -C (O) NHR, R is selected from the group consisting of C _1-4 alkyl, C _5-12 cycloalkyl, C _5-8 aryl, 5-8 heterocycloalkyl, 5-8 heteroaryl, R being optionally further substituted by R ^a, R ^a being selected from fluorine, chlorine, bromine, iodine, C _1-4 alkyl, c _5-12 cycloalkyl, 5-8 membered heterocycloalkyl, C _5-8 aryl, 5-8 membered heteroaryl, R ^a being optionally further substituted by R ^b, R ^b being selected from carboxyl, -C (O) NHR ^c、-C(O)R^c;R^c is selected from the group consisting of C _1-4 alkyl, C _5-12 cycloalkyl, C _5-8 aryl, 5-8 membered heterocycloalkyl, R ^c -8 membered heteroaryl, which may be further substituted with R ^d, R ^d is selected from fluorine, chlorine, bromine, iodine, C _1-4 alkyl, cyano, amino, carboxyl, said heterocycloalkyl, heteroaryl comprising 1 to 3 heteroatoms selected from N, O, S;

preferably, R ₃ is selected from the group consisting of carboxy, -C (O) NHR, R is selected from the group consisting of C _1-3 alkyl, C _5-12 cycloalkyl, C _6-10 cycloalkyl, C _5-8 aryl, C _6-8 aryl, R may be further substituted with R ^a, R ^a is selected from fluorine, chlorine, C _5-8 aryl, C _6-8 aryl, 5-8 membered heteroaryl, 6-8 membered heterocycloalkyl, R ^a being optionally further substituted by R ^b, R ^b being selected from carboxyl, -C (O) NHR ^c、-C(O)R^c;R^c is selected from the group consisting of C _1-3 alkyl, C _5-10 cycloalkyl, C _5-8 aryl, C _6-8 aryl, R ^c may be further substituted with R ^d, R ^d is selected from the group consisting of fluorine, Chlorine, C _1-3 alkyl, cyano, amino, carboxyl;

More preferably, R ₃ is selected from carboxyl, -C (O) NHR, R is selected from methyl, ethyl, propyl, isopropyl, cyclopentane, cyclohexane, cycloheptane, cyclooctane, adamantane, benzene ring, R may be further substituted with R ^a, R ^a is selected from fluorine, chlorine, benzene ring, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, R ^a may be further substituted with R ^b, R ^b is selected from carboxyl, -C (O) NHR ^c、-C(O)R^c;R^c is selected from methyl, ethyl, propyl, isopropyl, cyclopentane, cyclohexane, cycloheptane, cyclooctane, adamantane, benzene ring, R ^c may be further substituted with R ^d, R ^d is selected from fluorine, chlorine, methyl, ethyl, propyl, cyano, amino, carboxyl;

Also preferably, R ₃ is selected from carboxyl, -C (O) NHR, R is selected from methyl, ethyl, benzene ring, adamantane, R may be further substituted with R ^a, R ^a is selected from fluorine, chlorine, benzene ring, 6 membered heteroaryl or heterocycloalkyl containing 1-3N atoms, R ^a may be further substituted with R ^b, R ^b is selected from carboxyl, -C (O) NHR ^c、-C(O)R^c;R^c is selected from methyl, ethyl, propyl, isopropyl, adamantane, benzene ring, R ^c may be further substituted with R ^d, R ^d is selected from fluorine, chlorine, methyl, ethyl, amino;

Or preferably, R ₃ is selected from carboxyl, -C (O) NHR, R is selected from phenyl- (CH ₂)_m -, pyridinyl- (CH ₂)_p -, adamantyl wherein m = 0,1 or 2, p = 0,1 or 2, wherein the phenyl or pyridinyl may be further substituted with R ^b, R ^b is selected from chlorine, -piperazinyl-C (O) R ^c, carboxyl, -C (O) NHR ^c、-C(O)R^c;R^c is selected from methyl, ethyl, propyl, isopropyl, adamantane, benzene ring, R ^c may be further substituted with R ^d, R ^d is selected from fluorine, chlorine, methyl, ethyl, amino;

Further preferably, R ₃ is selected from the group consisting of carboxyl, -C (O) NHR, R is selected from Wherein the phenyl or pyridyl group may be further substituted with R ^b, R ^b is selected from chloro, carboxy,

Also preferably, R ₃ is selected from the group consisting of carboxyl,

Most preferably, R ₃ is selected from the group consisting of carboxyl,

5. The compound of any one of claims 1 to 3, or a prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound has the structure of formula (II):

wherein R ₁、R₂ and n are as defined in claims 1 to 3.

6. The compound of any one of claims 1-2 or 4, or a prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound has the structure of formula (III):

Wherein R ₁ and R ₃ are as defined in claims 1-2 or 4.

7. The compound according to any one of claims 1 to 6, or a prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein the compound is selected from the group consisting of:

8. A pharmaceutical composition comprising a compound of any one of claims 1-7, a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof, and a pharmaceutically acceptable auxiliary ingredient.

9. Use of a compound according to any one of claims 1-7, a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof or a pharmaceutical composition according to claim 8 for the manufacture of a medicament for the treatment and/or prophylaxis of a disease associated with TEAD biological activity;

preferably, the disease associated with TEAD biological activity is selected from cancer or hyperproliferative diseases.