Ring-fused compound for inhibiting TEAD activity and preparation method and application thereof

Abstract

The invention relates to a ring-fused compound for inhibiting TEAD activity as well as a preparation method and application of the ring-fused compound. The invention further relates to a pharmaceutical composition containing the compound as an active ingredient and application of the compound or the pharmaceutical composition to treatment and / or prevention of diseases related to TEAD biological activity. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a cyclopentadiene compound for inhibiting TEAD activity, and a preparation method and application thereof. Background Art

[0002] Yes Associated Protein 1 (YAP1), Transcriptional Coactivator with PDZ-Binding Motif (TAZ), and Transcriptional enhanced associate domain (TEAD) are downstream effector molecules of the Hippo signaling pathway, which can regulate cell proliferation and stem cell function. Neurofibromin 2 (NF2) is a key regulator of the Hippo signaling pathway, and the core of the Hippo signaling pathway is a kinase cascade reaction, in which NF2 and FERM domain containing protein 6 (FRMD6) form a complex and form a complex with Mst1 / 2 (homolog of Drosophila Hippo) kinase and SAV1 that can phosphorylate and activate LATS1 / 2. LATS1 / 2 kinase can inhibit YAP1 and TAZ through phosphorylation modification. When the components of the Hippo pathway, which serves as a tumor suppressor signal, become abnormal, YAP1 and TAZ are dephosphorylated and transported into the cell nucleus, where they interact with TEAD, thereby activating the expression of genes related to cell proliferation and apoptosis inhibition.

[0003] Abnormalities in the Hippo signaling pathway are associated with the occurrence of many tumors and are involved in driving drug resistance in many tumors. As a cancer suppressor pathway, the challenge of targeting Hippo with its upstream kinase is that it needs to be designed into an agonist. As the terminal effectors of abnormal Hippo pathways, transcriptional cofactors YAP1 and TAZ themselves do not have DNA binding domains and need to interact with transcription factors TEAD to exert their physiological and pathological effects. Therefore, targeting the YAP1 / TAZ-TEAD interaction can effectively target tumors with abnormal Hippo signaling pathways and has broad application prospects in enhancing chemotherapy, overcoming small molecule targeted drug resistance, and anti-tumor immune efficacy.

[0004] There are no small molecule inhibitors targeting the YAP1 / TAZ-TEAD interaction on the market worldwide. Currently, there are five targeted drugs entering Phase I clinical trials, namely: Ionis' antisense oligonucleotide inhibitor ION537 (NCT04659096, 2020 / 12 / 09), Vivace's VT3989 (NCT04665206, 2020 / 12 / 11), Novartis' IAG933 (NCT04857372, 2021 / 04 / 23), Ikena's IK-930 (NCT05228015, 2022 / 02 / 08) and Beida Pharmaceutical's BPI-460372, which was recently issued the "Notice of Approval of Drug Clinical Trials" (Notice Number: 2023LP00011, 2023LP00012). There are also several other targeted drugs in the preclinical research stage, including Roche's peptide inhibitor Peptide 17, France's Inventiva Pharmaceuticals' small molecule inhibitor patent ex22, the inhibitor MCH-CP1 designed by Massachusetts General Hospital in Boston, USA, example 52 jointly developed by Genentech and WuXi AppTec, Indiana University's TED347 modified from the natural substance TED346, and Japan's Kirin Pharmaceutical's K-975. Summary of the invention

[0005] Problems to be solved by the invention:

[0006] In view of the extremely high application value and development prospects of TEAD inhibitors in tumor treatment, the present application provides a new compound that can serve as a TEAD inhibitor.

[0007] Specifically, the present invention relates to the following technical solutions:

[0008] The present invention provides a compound represented by formula (I), or a prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof:

[0009]

[0010] in,

[0011] R1 is selected from C 1-8 alkyl;

[0012] Each R2 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 5-10Aryl, 5-10 membered heterocycloalkyl, 5-10 membered heteroaryl; the heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, O and S;

[0013] R3 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 can be further R a Replacement; R a 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 Can be further R b Replacement; R b Selected from carboxyl, -C(O)NHR c 、-C(O)R c ; R c Selected from C 1-6 Alkyl, C 3-12 Cycloalkyl, C 5-10 Aryl, 5-10 membered heterocycloalkyl, 5-10 membered heteroaryl, R c Can be further R d Replacement; R d Selected from halogen, C 1-6 Alkyl, cyano, amino, carboxyl; the heterocycloalkyl and heteroaryl groups contain 1 to 3 heteroatoms selected from N, O, and S;

[0014] n is selected from 1, 2, and 3.

[0015] In one embodiment, in the above compound, or its prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer, R1 is selected from C 1-6 Alkyl, C 2-6 Alkyl, C 7-8 Alkyl, C 1-3 Alkyl, C 4-6 Alkyl, C 5-6 Alkyl group; the alkyl group includes a straight chain or a branched chain alkyl group.

[0016] In a preferred embodiment, R1 is selected from C 1-3 alkyl.

[0017] In a more preferred embodiment, R1 is selected from methyl, ethyl, isopropyl.

[0018] In one embodiment, in the above compounds, or their prodrugs, solvates, crystalline forms, pharmaceutically acceptable salts, stereoisomers or tautomers, each R2 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; the heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, O and S.

[0019] In a preferred embodiment, each R2 is independently selected from fluorine, chlorine, C 1-4 Alkyl, C 1-4 Haloalkyl, C 5-12 Cycloalkyl.

[0020] In a more preferred embodiment, each R2 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.

[0021] In a still more preferred embodiment, each R2 is independently selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, -CF3, -CCl3, -CHF2, -CH2F, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and adamantane.

[0022] In a most preferred embodiment, each R2 is independently selected from fluorine, chlorine, methyl, -CF3, -CCl3, adamantane.

[0023] In one embodiment, in the above compound, or its prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer, R3 is selected from carboxyl, -C(O)NHR; R is selected from C 1-4 Alkyl, C 5-12 Cycloalkyl, C 5-8 Aryl, 5-8 membered heterocycloalkyl, 5-8 membered heteroaryl, R can be further R a Replacement; R a 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 Can be further R b Replacement; R bSelected from carboxyl, -C(O)NHR c 、-C(O)R c ; R c Selected from C 1-4 Alkyl, C 5-12 Cycloalkyl, C 5-8 Aryl, 5-8 membered heterocycloalkyl, 5-8 membered heteroaryl, R c Can be further R d Replacement; R d Selected from fluorine, chlorine, bromine, iodine, C 1-4 Alkyl, cyano, amino, carboxyl; the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S.

[0024] In a preferred embodiment, R3 is selected from carboxyl, -C(O)NHR; R is selected from C 1-3 Alkyl, C 5-12 Cycloalkyl, C 6-10 Cycloalkyl, C 5-8 Aryl, C 6-8 Aryl, R can be further R a Replacement; R a Selected from fluorine, chlorine, C 5-8 Aryl, C 6-8 Aryl, 5-8 membered heteroaryl, 6-8 membered heteroaryl, 6-8 membered heterocycloalkyl, R a Can be further R b Replacement; R b Selected from carboxyl, -C(O)NHR c 、-C(O)R c ; R c Selected from C 1-3 Alkyl, C 5-10 Cycloalkyl, C 5-8 Aryl, C 6-8 Aryl, R c Can be further R d Replacement; R d Selected from fluorine, chlorine, C 1-3 Alkyl, cyano, amino, carboxyl.

[0025] In a more preferred embodiment, R3 is selected from carboxyl, -C(O)NHR; R is selected from methyl, ethyl, propyl, isopropyl, cyclopentane, cyclohexane, cycloheptane, cyclooctane, adamantane, benzene ring; R can be further R a Replacement; R a is selected from fluorine, chlorine, benzene ring, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, R a Can be further R b Replacement; R b Selected from carboxyl, -C(O)NHR c 、-C(O)Rc ; R c is selected from methyl, ethyl, propyl, isopropyl, cyclopentane, cyclohexane, cycloheptane, cyclooctane, adamantane, benzene ring, R c Can be further R d Replacement; R d Selected from fluorine, chlorine, methyl, ethyl, propyl, cyano, amino, carboxyl.

[0026] In a further preferred embodiment, R3 is selected from carboxyl, -C(O)NHR; R is selected from methyl, ethyl, benzene ring, adamantane, and R can be further R a Replacement; R a is selected from fluorine, chlorine, a benzene ring, a 6-membered heteroaryl or heterocycloalkyl containing 1 to 3 N atoms, R a Can be further R b Replacement; R b 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 Can be further R d Replacement; R d Selected from fluorine, chlorine, methyl, ethyl, amino.

[0027] In a preferred embodiment, R3 is selected from carboxyl, -C(O)NHR; R is selected from phenyl-(CH2) m -, pyridyl-(CH2) p -, adamantyl, wherein m = 0, 1 or 2, p = 0, 1 or 2; wherein the phenyl or pyridyl group may be further R b Replacement; R b 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 Can be further R d Replacement; R d is selected from fluorine, chlorine, methyl, ethyl, amino,

[0028] In a further preferred embodiment, R3 is selected from carboxyl, -C(O)NHR; R is selected from Wherein, the phenyl or pyridyl group may be further R b Replacement; R b Selected from chlorine, carboxyl,

[0029] In a further preferred embodiment, R3 is selected from carboxyl,

[0030] Most preferably, R3 is selected from carboxyl,

[0031] In one embodiment, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has a structure as described in formula (II):

[0032]

[0033] The definitions of R1, R2 and n refer to the above definitions.

[0034] In one embodiment, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has a structure as described in formula (III):

[0035]

[0036] The definitions of R1 and R3 refer to the above definitions.

[0037] In one embodiment, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, is selected from the following compounds:

[0038]

[0039]

[0040] The compounds of the present application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods known to those skilled in the art, and preferred embodiments include but are not limited to the examples of the present application. The chemical reactions of the specific embodiments of the present application are carried out in a suitable solvent, and the solvent must be suitable for the chemical changes of the present application and the reagents and materials required. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthetic steps or reaction processes based on the existing embodiments.

[0041] An important consideration in the planning of synthetic routes in this area is to select a suitable protecting group for a reactive functional group (such as an amino group in this application), for example, see Chem. Commun., 2019, 55, 7331--7334. All references cited in this application are incorporated herein as a whole, or synthetic methods known in the art and the methods described in the present invention are used in combination. The product obtained by each step of the reaction is obtained using separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for the synthesis can be conventionally synthesized according to the literature (such as provided by Scifinder) or purchased.

[0042] The present invention also provides a pharmaceutical composition, which comprises a compound represented by the above formula (I), (II) or (III), its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer and a pharmaceutically acceptable auxiliary ingredient, wherein the pharmaceutically acceptable auxiliary ingredient is preferably a pharmaceutically acceptable carrier, diluent, excipient or a combination thereof.

[0043] The present invention also provides the use of the compound described in the above formula (I), (II) or (III), its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer or the above pharmaceutical composition in the preparation of a drug for treating and / or preventing diseases related to the biological activity of TEAD.

[0044] In a preferred embodiment, the disease associated with TEAD biological activity is selected from cancer or hyperproliferative disease.

[0045] The present invention also provides a method for treating and / or preventing diseases associated with TEAD biological activity, comprising administering to a patient in need thereof a therapeutically and / or preventively effective amount of the compound of formula (I), (II) or (III), its prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer, or the above-mentioned pharmaceutical composition.

[0046] In a preferred embodiment, the disease associated with TEAD biological activity is selected from cancer or hyperproliferative disease.

[0047] The present invention also provides compounds described in the above formula (I), (II) or (III), their prodrugs, solvates, crystal forms, pharmaceutically acceptable salts, stereoisomers or tautomers or the above pharmaceutical compositions, which are used for treating and / or preventing diseases related to the biological activity of TEAD.

[0048] In a preferred embodiment, the disease associated with TEAD biological activity is selected from cancer or hyperproliferative disease.

[0049] Technical terms of the present invention:

[0050] 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 appreciated by those skilled in the art that the present invention may be implemented without these details. In other cases, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout the specification and claims, the words "comprise" and variations thereof, such as "comprises" and "comprising", should be interpreted as open-ended inclusive meanings, i.e., "including but not limited to". In addition, the titles provided herein are merely for convenience and are not intended to explain the scope or meaning of the claimed invention.

[0051] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described with respect to that embodiment is included in at least one embodiment. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing in different places throughout the specification do not necessarily all refer to the same embodiment. In addition, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Moreover, 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 used in a sense that includes "and / or", unless the context clearly dictates otherwise.

[0052] According to the practice in this field, The bonds used in the formulae herein to describe the points of attachment of the moiety or substituent to the parent core or structure.

[0053] In the present invention, the term "substituted" means that an atom or a group of atoms formally replaces hydrogen and is connected to another group as a "substituent". Unless otherwise noted, the term "substituted" refers to any degree of substitution in the case where such substitution is allowed, such as mono-, di-, tri-, tetra- or penta-substitutions. The substituents are selected independently, and the substitutions can be in any chemically accessible position. It should be understood that the substitution on the specified atom is limited by atomic valence. It should be understood that the substitution on the specified atom produces a chemically stable molecule.

[0054] In the present invention, the term "alkyl" used alone or in combination with other terms refers to a saturated hydrocarbon group which may be a straight chain or a branched chain. 1-8"Alkyl" refers to an alkyl group having 1 to 8 carbon atoms. Alkyl formally corresponds to an alkane with one CH bond replaced as the point of attachment of the alkyl group to the rest of the compound. In some embodiments, the alkyl group contains 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1-4 carbon atoms, 1-3 carbon atoms, or 1-2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-butyl, tert-butyl, isobutyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like.

[0055] 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.

[0056] In the present invention, the term "haloalkyl" used alone or in combination with other terms refers to an alkyl group substituted by one or more halogens, wherein the terms "halogen" and "alkyl" are as defined above.

[0057] In the present invention, the term "heteroatom" used alone or in combination with other terms includes S, O and N.

[0058] In the present invention, the term "alkoxy" used alone or in combination with other terms refers to a radical of the formula -OR a A group in which R a For alkyl groups as defined above. Unless specifically indicated in addition in this specification, alkoxy can be optionally substituted as described below, for example, replaced by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl etc. In some embodiments, alkoxy is optionally replaced by halogen,-CN,-OH,-OMe,-NH or-NO. In some embodiments, alkoxy is optionally replaced by halogen,-CN,-OH or-OMe. In some embodiments, alkoxy is optionally replaced by halogen.

[0059] In the present invention, the term "aryl" used alone or in combination with other terms refers to an aromatic hydrocarbon group, which may be a monocyclic or polycyclic (eg, having two fused rings). 6-10 "Aryl" refers to an aromatic radical having 6 to 10 ring carbon atoms. Aryl radicals include, for example, phenyl, naphthyl, indanyl, indenyl, and the like. In some embodiments, an aryl radical has 6 carbon atoms. In some embodiments, an aryl radical has 10 carbon atoms. In some embodiments, an aryl radical is phenyl. In some embodiments, an aryl radical is naphthyl.

[0060] In the present invention, the term "heteroaryl" used alone or in combination with other terms refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from S, O and N, wherein the heteroatom can be on any ring or on multiple (e.g., two or three) rings at the same time. 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 ring-forming N in the heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 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, the heteroaryl has 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, the heteroaryl has 5 to 6 ring atoms and 1 or 2 heteroatom ring members independently selected from S, O and N. In some embodiments, heteroaryl is a five-membered or six-membered heteroaryl ring. In other embodiments, heteroaryl is an eight-membered, nine-membered or ten-membered fused bicyclic heteroaryl ring. Example heteroaryl includes, but is not limited to, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, oxazolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thienyl, quinolyl, isoquinolyl, naphthyridinyl (including 1,2-naphthyridine, 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, etc.

[0061] In the present invention, the term "cycloalkyl" used alone or in combination with other terms refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), polycyclic (such as bicyclic or tricyclic) including fused rings, spiro rings, bridged rings, including cyclized alkyl. 3-8 Cycloalkyl" or "C 3-14 "Cycloalkyl" refers to a cycloalkyl group having 3-8 or 3-14 ring member carbon atoms, respectively. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocyclic groups. Cycloalkyl groups may have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring member carbon atoms (C 3-14 ). In some embodiments, the 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, the cycloalkyl is a monocyclic ring. In some embodiments, the cycloalkyl is a monocyclic ring or a bicyclic ring. In some embodiments, the cycloalkyl is C 3-8Monocyclic cycloalkyl. The ring-forming carbon atoms of the cycloalkyl can be optionally oxidized to form oxo or sulfide groups. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0062] In the present invention, unless otherwise specified, 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) includes fused ring, spirocyclic, bridged ring, which has at least one heteroatom ring member independently selected from N, S and O, and it has 4-14 ring members, 4-10 ring members or 4-8 ring members, and the heteroatom can be on any ring thereof, or on multiple (e.g., two or three) rings at the same time. The term "heterocycloalkyl" includes monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyls. In some embodiments, heterocycloalkyl is a monocyclic group with 1, 2 or 3 heteroatoms independently selected from N, S and O. In some embodiments, heterocycloalkyl is a spirocyclic ring with 1, 2 or 3 heteroatoms independently selected from N, S and O. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may be optionally oxidized to form oxo or sulfide groups or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O) 2, N-oxides, etc.), or the nitrogen atom may be quaternized. The heterocycloalkyl group may be connected via a ring-forming carbon atom or a ring-forming heteroatom.

[0063] 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.

[0064] Beneficial effects of the present invention:

[0065] The compounds and pharmaceutical compositions provided by the present invention show good effects of inhibiting the biological activity of TEAD, and can be used as drugs for the prevention and / or improvement and / or treatment of diseases related to the effects. In addition, the pharmacokinetic characteristics (e.g., plasma exposure AUC, peak concentration C max , half-life in vivo T 1 / 2 This indicates that after oral administration, the compound of the present invention can achieve a higher drug exposure level in the body, has a material basis for sustained therapeutic effects, and has the potential to bring unexpected anti-tumor activity. Specific implementation plan

[0066] Unless otherwise defined, all technical and scientific terms in the present invention have the same meaning as those commonly understood by those skilled in the art. Other various forms of modification, substitution or change may be made according to common technical knowledge and customary means in the art without departing from the above basic technical concept of the present invention.

[0067] The present invention is described in detail below by examples, but it is not intended to limit the present invention in any adverse way. The compounds of the present invention can be prepared by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination thereof with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art, and preferred embodiments include but are not limited to the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and improvements are made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention, and they should also be regarded as the protection scope of the present invention.

[0068] Example 1: Preparation of 3-methyl-1-[4-(trifluoromethyl)phenyl]indole-5-carboxylic acid

[0069]

[0070] Step 1: Preparation of 3-methyl-1H-indole-5-carboxylic acid methyl ester (int-1b)

[0071] At room temperature, methyl 4-hydrazinobenzoate hydrochloride (4052 mg, 20 mmol), propionaldehyde (1162 mg, 20 mmol) and 1,4-dioxane (60 mL) were added to a 150 ml flask. Under stirring at room temperature, triethylamine (2424 mg, 24 mmol) was added. After the addition was completed, the reaction was carried out at room temperature for 2 hours. TLC monitoring showed that the raw materials reacted completely to generate the intermediate hydrazone. 3 mol / L hydrochloric acid aqueous solution (10 mL) was added to the reaction system, and the temperature was raised to 100 ° C for 15 hours. TLC monitoring (EA / PE = 1:3) showed that the intermediate raw materials reacted completely.

[0072] The solvent was evaporated under reduced pressure, 30 ml of ethyl acetate and 30 ml of 1 mol / L sodium hydroxide aqueous solution were added, stirred, and extracted; the organic phase was washed and extracted with 30 ml of dilute brine; the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (EA / PE=1:5) to obtain the target product 3-methyl-1H-indole-5-carboxylic acid methyl ester (int-1b) (1380 mg, 7.3 mmol, 36.5% yield). LC-MS (m / z): 190.1 (M+1).

[0073] Step 2: Preparation of methyl 3-methyl-1-[4-(trifluoromethyl)phenyl]indole-5-carboxylate (int-1c)

[0074] At room temperature, int-1b (50 mg, 0.26 mmol) and 1,4-dioxane (10 mL) were added to a 50 ml flask, followed by 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). After the addition was completed, nitrogen was replaced for protection, the temperature was raised to 110 ° C for reaction for 15 hours, and TLC detection (EA / PE=1:3) showed that the raw materials were completely reacted.

[0075] The reaction solution was directly concentrated under reduced pressure and the solvent was evaporated. Column chromatography (EA / PE=1:6) was used to obtain the target product, 3-methyl-1-[4-(trifluoromethyl)phenyl]indole-5-carboxylic acid methyl ester (int-1c) (65 mg, 0.195 mmol, 75.0% yield). LC-MS (m / z): 334.1 (M+1).

[0076] Step 3: Preparation of 3-methyl-1-[4-(trifluoromethyl)phenyl]indole-5-carboxylic acid (Compound 1)

[0077] At room temperature, int-1c (65 mg, 0.19 mmol) and methanol (5 mL) were added to a 50 mL flask. Under stirring, 3 mol / L sodium hydroxide aqueous solution (1 mL) was added dropwise to the reaction system, and the temperature was raised to 70°C and the reaction was continued for 2 hours. TLC detection (EA / PE=1:3) showed that the raw material was completely reacted.

[0078] The methanol solvent was evaporated under reduced pressure, 10 ml of water was added, the pH was adjusted to 5 with dilute hydrochloric acid, and then 10 ml of ethyl acetate was added for extraction, and the aqueous layer was back-extracted with 5 ml of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and n-hexane was added for pulping, filtered, and dried to obtain the target product 3-methyl-1-[4-(trifluoromethyl)phenyl]indole-5-carboxylic acid (Compound 1) (41 mg, 0.13 mmol, 65.9% yield) as a white solid. LC-MS (m / z): 320.1 (M+1). HPLC: 98.1%.

[0079] 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).

[0080] Example 2: Preparation of 3-ethyl-1-[4-(trifluoromethyl)phenyl]indole-5-carboxylic acid

[0081]

[0082] Step 1: Preparation of 3-ethyl-1H-indole-5-carboxylic acid methyl ester (int-2b)

[0083] The synthesis of int-2b is the same as int-1b. Butyraldehyde is used as the reaction reagent instead of propionaldehyde, and the operation is the same. Column chromatography separation (EA / PE=1:5) gave the target product 3-ethyl-1H-indole-5-carboxylic acid methyl ester (int-2b) (260 mg, 1.28 mmol, 32.0% yield). LC-MS (m / z): 204.1 (M+1).

[0084] Step 2: Preparation of methyl 3-ethyl-1-[4-(trifluoromethyl)phenyl]indole-5-carboxylate (int-2c)

[0085] The synthesis of int-2c is the same as int-1c. Int-2b is used as the raw material instead of int-1b, and the operation method is the same. Column chromatography (EA / PE=1:8) is used to obtain the target product 3-ethyl-1-[4-(trifluoromethyl)phenyl]indole-5-carboxylic acid methyl ester (int-2c) (295mg, 0.85mmol, 66.4% yield). LC-MS (m / z): 348.1 (M+1).

[0086] Step 3: Preparation of 3-ethyl-1-[4-(trifluoromethyl)phenyl]indole-5-carboxylic acid (Compound 2)

[0087] The synthesis of compound 2 is the same as compound 1. Int-2c is used as the raw material instead of int-1c, and the operation method is the same. After drying, the target product 3-ethyl-1-[4-(trifluoromethyl)phenyl]indole-5-carboxylic acid (compound 2) (205 mg, 0.59 mmol, 69.8% yield) is obtained as a white solid. LC-MS (m / z): 334.1 (M+1). HPLC: 96.44%.

[0088] 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).

[0089] Example 3: Preparation of 3-isopropyl-1-[4-(trifluoromethyl)phenyl]indole-5-carboxylic acid

[0090]

[0091] Step 1: Preparation of methyl 3-isopropyl-1H-indole-5-carboxylate (int-3b)

[0092] The synthesis of int-3b is the same as int-1b. The reaction reagent uses isovaleraldehyde instead of propionaldehyde, and the operation method is the same. Column chromatography separation (EA / PE=1:6) gave the target product 3-isopropyl-1H-indole-5-carboxylic acid methyl ester (int-3b) (310 mg, 1.43 mmol, 35.7% yield). LC-MS (m / z): 218.1 (M+1).

[0093] Step 2: Preparation of 3-isopropyl-1-[4-(trifluoromethyl)phenyl]indole-5-carboxylic acid methyl ester (int-3c) The synthesis of int-3c is the same as int-1c. The reaction raw material uses int-3b instead of int-1b, and the operation method is the same. Column chromatography separation (EA / PE=1:8) gave the target product 3-isopropyl-1-[4-(trifluoromethyl)phenyl]indole-5-carboxylic acid methyl ester (int-3c) (325mg, 0.90mmol, 63.0% yield). LC-MS (m / z): 362.1 (M+1).

[0094] Step 3: Preparation of 3-isopropyl-1-[4-(trifluoromethyl)phenyl]indole-5-carboxylic acid (Compound 3)

[0095] The synthesis of compound 3 is the same as compound 1. Int-3c is used as the raw material instead of int-1c, and the operation method is the same. After drying, the target product 3-isopropyl-1-[4-(trifluoromethyl)phenyl]indole-5-carboxylic acid (compound 3) (235 mg, 0.67 mmol, 75.9% yield) is obtained as a white solid. LC-MS (m / z): 348.3 (M+1). HPLC: 99.3%.

[0096] 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).

[0097] Example 4: Testing of the Inhibitory Activity of the Compounds of the Invention on TEAD

[0098] 1. Experimental Materials

[0099] 1.1640 basal medium (purchased from Gibco, product number: C11875500BT)

[0100] 2.1640 complete medium: add 10% (v / v) FBS and 1% (v / v) to 1640 basal medium

[0101] Penicillin-streptomycin mixture (double antibody)

[0102] 3. Fetal bovine serum (FBS) (purchased from Gibco, catalog number: 10099-141)

[0103] 4. Penicillin-streptomycin mixed solution (double antibody) (purchased from Gibco, catalog number: 15140122)

[0104] 5.1X PBS (purchased from Bio-Tech, catalog number: A610100-0001)

[0105] 6. Trypsin (purchased from Gibco, catalog number: 15140122)

[0106] 7. Transfection reagent: X-tremeGENE HP DNA Transfection Reagent (purchased from Roche, catalog number: 06366546001)

[0108] 8. Luciferase Assay System (purchased from Promega, catalog number: E151A) 9. Cell Culture Lysis Reagent: Cell Culture Lysis 5X reagent (purchased from Promega, catalog number:

[0109] E153A)

[0110] 10.TECAN Spark Multi-function Microplate Reader

[0111] 11. Plasmid: GFP (purchased from Addgene, catalog number: 11153)

[0112] 12. Reporter gene plasmid pGL3b-8XGTIIC-luciferase (purchased from Fenghui, catalog number: FH2289)

[0113] 13. Reporter gene plasmid PGL4.10[LUC2] (purchased from Ubest Biotech, catalog number: VT1558)

[0114] 14. Cell line: L-02 (purchased from ATCC)

[0115] 15.96-well flat-bottom cell culture plate, 96-well white-bottom cell culture plate (purchased from Costar)

[0116] 16. Cell culture incubator (purchased from Thermo, model: 371 Steri-Cycle)

[0117] 17. Sample loading tank (purchased from BKMAN, item number: 110420001)

[0118] 18. Pipette (ranges: 1mL, 200μL, 100μL, 20μL, 10μL)

[0119] 2. Experimental steps

[0120] L-02 cell line was collected by trypsin digestion, seeded into 96-well flat-bottom cell culture plates at 50% bottom area, 80 μL per well, and cultured overnight in a 37° C., 5% CO 2 incubator.

[0121] After cells were seeded overnight, they were transfected with background plasmid group (PGL4.10[LUC2](50ng / well)+GFP(10ng / well)) and reporter plasmid group (8XGTIIC-luciferase(50ng / well)+GFP(10ng / well)), with the transfection ratio of plasmid μg: transfection reagent = 1:3.

[0122] Take out the transfection reagent X-tremeGENE HP DNA Transfection Reagent and 1640 basal medium from the refrigerator in advance and equilibrate to room temperature. Add 10 ng / well of GFP plasmid to 1640 basal medium (5 μL / well), gently pipette to mix, and then divide into two tubes, add PGL4.10[LUC2] (50 ng / well) and 8XGTIIC-luciferase (50 ng / well) respectively; then add 0.18 μL / well of liposomes to 1640 basal medium (5 μL / well), gently pipette to mix, and stand at room temperature for 5 minutes; mix the plasmid mixture and transfection reagent mixture in equal volumes, gently pipette to mix, and stand at room temperature for 15 minutes; according to the transfection complex 10 μL / well, 1640 complete medium 90 μL / well gently pipette to mix, remove the cell supernatant, and add 100 μL / well to a 96-well flat-bottom cell culture plate, and culture overnight at 37°C, 5% CO2 incubator.

[0123] Before drug addition, 90 μL / well was supplemented with 1640 complete medium, DMSO was added to the background group, and DMSO (well without drug addition) and concentration gradient compounds (0.01-10000 nM) were added to the reporter plasmid group, and cultured in a 37°C, 5% CO2 incubator for 24 hours.

[0124] The 96-well flat-bottom cell culture plate with cells cultured was taken out of the incubator, the cell supernatant was removed, 60 μL 1X Cell Culture Lysis was added for lysis, and the cells were fully lysed by pipetting. 50 μL of the lysate was transferred to a 96-well half-well white-bottom plate, and the GFP value (Ex485 / Em520) was detected using a TECAN multifunctional microplate reader. Then 30 μL luciferase substrate was added to each well, and the Luci value was immediately detected on the instrument.

[0125] Calculation: First calculate the ratio Ratio = LUC / GFP, then calculate the relative activity of each well using the Ratio value of each well. The formula is as follows:

[0126] Relative Activity(%)=(Ratio (化合物孔) -Ratio (背景孔) ) / (Ratio (DMSO孔) -Ratio (背景

[0127] 孔) )×100%

[0128] In GraphPad Prism 8.0.1 software, create a new "XY" data table, fill in the compound concentration in the X column, and fill in the corresponding relative activity of each well in the Y column; click "Analyze", select "Transform", check "Transform X values ​​using X = log (X)", and convert the X-axis data to the corresponding log value; click "Analyze" again, select "Nonlinear regression (curve fit)", select "log (inhibitor) vs. normalized response Least squares fit" in "Dose-response-Stimulation", and the IC value of each compound in this experiment can be obtained in the nonlinear fitting table of data transformation. 50 .

[0129] Table 1 Inhibitory activity of the compounds of the present invention on TEAD

[0130] Example <![CDATA[TEAD IC 50 (nM)]]> 1 96.87 2 11.26 3 83.79

[0131] From the results in the table, it can be seen that the IC50 values ​​of the compounds of the present invention are all less than 100 nM, and they have excellent inhibitory effects on the activity of TEAD.

[0132] Example 5 Pharmacokinetic Test

[0133] Eighteen female BALB / c mice of about 8 weeks old (purchased from Guangdong Medical Experimental Animal Center) were randomly divided into three groups, 6 mice in each group. The test compound was formulated in a solvent containing 5% DMSO, 70% PEG400 and 25% purified water, and the compound was administered by gavage at 5 mg / kg, a single dose, and blood was collected alternately through the fundus venous plexus. The blood collection time points were 15min, 30min, 1h, 2h, 4h, 8h and 24h before and after administration. About 0.06mL of blood was collected in a centrifuge tube (heparin sodium anticoagulation), centrifuged at 4°C, 3200g for 10 minutes, and the supernatant plasma was separated and frozen at -20°C for testing. Several plasma samples were accurately taken, extracted with acetonitrile, and the concentration of the compound in plasma was determined by liquid chromatography-mass spectrometry (LC-MS / MS). The pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0 based on the average blood drug concentration data at different time points. The data are summarized in Table 1:

[0134] Table 1 Pharmacokinetic parameters of the test compounds in mice after oral administration

[0135]

[0136] Among them, the control compound A is Yangshen molecule VT-103, a commercially available TEAD inhibitor, whose structure is

[0137] The control compound B is the most active TEAD inhibitor disclosed in the patent CN115925688A of Insilicon, and its structure is

[0138] From the above results, it can be seen that after oral administration, the representative compound 2 of the present invention has a high plasma exposure (AUC) and peak concentration (C max ) were significantly higher than the two control compounds, especially the control compound B which was structurally similar to it; and the half-life of compound 2 in vivo (T 1 / 2 ) and mean residence time (MRT) are both relatively long, comparable to the control compound A, and significantly longer than the control compound B with a similar structure. The above pharmacokinetic characteristics indicate that the compounds of the present invention can achieve a higher drug exposure level in vivo after oral administration, have a material basis for sustained therapeutic effects, and have the potential to bring unexpected anti-tumor activity.

[0139] Industrial Applicability

[0140] The compounds of the present invention have excellent effects of inhibiting the biological activity of TEAD and can be used as drugs for treating or preventing diseases related to the effects.

[0141] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A compound represented by formula (I), or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof: in, R1 is selected from C 1-8 alkyl; Each R2 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; the heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, O and S; R3 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 can be further R a Replacement; R a 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 Can be further R b Replacement; R b Selected from carboxyl, -C(O)NHR c 、-C(O)R c ; R c Selected from C 1-6 Alkyl, C 3-12 Cycloalkyl, C 5-10 Aryl, 5-10 membered heterocycloalkyl, 5-10 membered heteroaryl, R c Can be further R d Replacement; R d Selected from halogen, C 1-6 Alkyl, cyano, amino, carboxyl; the heterocycloalkyl and heteroaryl groups contain 1 to 3 heteroatoms selected from N, O, and S; n is selected from 1, 2, and 3.

2. The compound according to claim 1, or its prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer, characterized in that: R1 is selected from C 1-6 Alkyl, C 2-6 Alkyl, C 7-8 Alkyl, C 1-3 Alkyl, C 4-6 Alkyl, C 5-6 Alkyl; the alkyl group includes a straight chain or a branched chain alkyl group; Preferably, R1 is selected from C 1-3 alkyl; More preferably, R1 is selected from methyl, ethyl, propyl, isopropyl.

3. The compound according to claim 1, or its prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer, characterized in that: Each R2 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; the heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, O and S; Preferably, each R2 is independently selected from fluorine, chlorine, C 1-4 Alkyl, C 1-4 Haloalkyl, C 5-12 Cycloalkyl; More preferably, each R2 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; Also preferably, each R2 is independently selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, -CF3, -CCl3, -CHF2, -CH2F, cyclopentane, cyclohexane, cycloheptane, cyclooctane, adamantane; Most preferably, each R2 is independently selected from fluorine, chlorine, methyl, -CF3, -CCl3, adamantane.

4. The compound according to claim 1, or its prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer, characterized in that: R3 is selected from carboxyl, -C(O)NHR; R is selected from C 1-4 Alkyl, C 5-12 Cycloalkyl, C 5-8 Aryl, 5-8 membered heterocycloalkyl, 5-8 membered heteroaryl, R can be further R a Replacement; R a 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 Can be further R b Replacement; R b Selected from carboxyl, -C(O)NHR c 、-C(O)R c ; R c Selected from C 1-4 Alkyl, C 5-12 Cycloalkyl, C 5-8 Aryl, 5-8 membered heterocycloalkyl, 5-8 membered heteroaryl, R c Can be further R d Replacement; R d Selected from fluorine, chlorine, bromine, iodine, C 1-4 Alkyl, cyano, amino, carboxyl; the heterocycloalkyl and heteroaryl groups contain 1 to 3 heteroatoms selected from N, O, and S; Preferably, R3 is selected from carboxyl, -C(O)NHR; R is selected from C 1-3 Alkyl, C 5-12 Cycloalkyl, C 6-10 Cycloalkyl, C 5-8 Aryl, C 6-8 Aryl, R can be further R a Replacement; R a Selected from fluorine, chlorine, C 5-8 Aryl, C 6-8 Aryl, 5-8 membered heteroaryl, 6-8 membered heteroaryl, 6-8 membered heterocycloalkyl, R a Can be further R b Replacement; R b Selected from carboxyl, -C(O)NHR c 、-C(O)R c ; R c Selected from C 1-3 Alkyl, C 5-10 Cycloalkyl, C 5-8 Aryl, C 6-8 Aryl, R c Can be further R d Replacement; R d Selected from fluorine, chlorine, C 1-3 Alkyl, cyano, amino, carboxyl; More preferably, R3 is selected from carboxyl, -C(O)NHR; R is selected from methyl, ethyl, propyl, isopropyl, cyclopentane, cyclohexane, cycloheptane, cyclooctane, adamantane, benzene ring; R can be further R a Replacement; R a is selected from fluorine, chlorine, benzene ring, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, R a Can be further R b Replacement; R b 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 Can be further R d Replacement; R d Selected from fluorine, chlorine, methyl, ethyl, propyl, cyano, amino, carboxyl; Still more preferably, R3 is selected from carboxyl, -C(O)NHR; R is selected from methyl, ethyl, benzene ring, adamantane, and R can be further R a Replacement; R a is selected from fluorine, chlorine, a benzene ring, a 6-membered heteroaryl or heterocycloalkyl containing 1 to 3 N atoms, R a Can be further R b Replacement; R b 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 Can be further R d Replacement; R d Selected from fluorine, chlorine, methyl, ethyl, amino; Or preferably, R3 is selected from carboxyl, -C(O)NHR; R is selected from phenyl-(CH2) m -, pyridyl-(CH2) p -, adamantyl, wherein m = 0, 1 or 2, p = 0, 1 or 2; wherein the phenyl or pyridyl group may be further R b Replacement; R b 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 Can be further R d Replacement; R d Selected from fluorine, chlorine, methyl, ethyl, amino; More preferably, R3 is selected from carboxyl, -C(O)NHR; R is selected from Wherein, the phenyl or pyridyl group may be further R b Replacement; R b Selected from chlorine, carboxyl, Still more preferably, R3 is selected from carboxyl, Most preferably, R3 is selected from carboxyl, 5. The compound according to any one of claims 1 to 3, or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof, characterized in that: The compound has the structure of formula (II): wherein R1, R2 and n are as defined in claims 1-3.

6. The compound according to any one of claims 1 to 2 or 4, or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof, characterized in that: The compound has the structure of formula (III): Wherein, R1 and R3 are as defined in claim 1-2 or 4.

7. The compound according to any one of claims 1 to 6, or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof, characterized in that: The compound is selected from the following compounds:

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer and a pharmaceutically acceptable auxiliary ingredient.

9. Use of the compound according to any one of claims 1 to 7, its prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing a disease associated with TEAD biological activity; Preferably, the disease associated with TEAD biological activity is selected from cancer or hyperproliferative disease.

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