Polycyclic compounds and uses thereof

Abstract

Methods for preparing polycyclic compounds and their use in the prevention and / or treatment of proliferative disorders, said compounds having the structure represented by Formula I. [Formula 1] JPEG2025515208000110.jpg3865

Description

[Technical field]

[0001] The present invention relates to the field of medical technology, in particular to polycyclic compounds used in regulating the Hippo pathway and their preparation methods and uses, mainly for the treatment or prevention of proliferative diseases (e.g., cancer), especially for the regulation and treatment of related diseases caused by the abnormal activity of YAP / TEAD. [Background technology]

[0002] The Hippo pathway is essentially composed of a core kinase cascade, which includes the Ste-20 family protein kinases MST1-2, the scaffolding proteins Salvador and the large tumor inhibitory kinase LATS1-2, as well as the inhibitory transcription activators YAP (Yes1-associated protein) and TAZ (transcription activator with PDZ-binding motifs). YAP and TAZ are the main effectors of the Hippo signaling pathway, which act as transcription factors together with TEAD (transcription enhancer associated domain) in the nucleus, thereby increasing the expression of target genes, such as CTGF (connective tissue growth factor), CYR61, etc. The Hippo pathway is a key regulator of cell growth, proliferation and migration. TEAD transcription factors are located at the core of the Hippo pathway and are crucial for regulating organ growth and wound repair. Dysregulation of TEAD and its regulatory cofactor Yes-associated protein (YAP) are implicated in many human cancers and hyperproliferative pathological processes, and dysregulation of the pathway is frequently detected in human cancers. Like TEAD proteins, activation of YAP and TAZ has been identified in many human tumors and is important for tumor initiation, progression and metastasis; for example, YAP expression is elevated in patients with breast, ovarian, colon, liver and pancreatic cancer, and is associated with reduced survival. Consistent with this, activation or overexpression of YAP or TAZ enhances TEAD-dependent gene expression (e.g., CCN1, CTGF, ITGB2 and Birc5 / survivin) and promotes cell proliferation and migration in many cell types. Conversely, blocking the signal of YAP / TAZ-TEAD complex formation or intervening to prevent the expression of many mitogenic TEAD target genes can greatly reduce cell proliferation and oncogenic transformation activity. In addition, the Hippo pathway also cross-talks with other signaling pathways, such as Wnt, Notch, Hedgehog and MAPK, thus affecting various biological functions, and its dysfunction may further be involved in many diseases in addition to cancer. Therefore, the YAP-TEAD complex is a promising therapeutic target point.

[0003] In addition, patent WO2009081259A1 discloses several compounds having a structure similar to that of the present invention, the general formula of which is: [ka] The inventors selected several compounds with representative structures and performed activity tests, and the results showed that all of these compounds had no YAP / TEAD-related activity. The detailed results are shown in Table 2. Summary of the Invention [Problem to be solved by the invention]

[0004] It is an object of the present invention to provide compounds of formula I as well as processes for their preparation and their use in the prevention or treatment of proliferative disorders. [Means for solving the problem]

[0005] A first aspect of the present invention provides a compound represented by formula I, or a pharma- ceutically acceptable salt, solvate or prodrug thereof: [ka] Where: A is, [ka] is selected from the group consisting of B is, [ka] is selected from the group consisting of C is [ka] is selected from the group consisting of L is selected from the group consisting of NR4, O, S, Se, sulfoxide, sulfone, and CR2R3; R1 is, [ka] which is linked to N on A; R2 is independently H, a halogen, CN, NH2, a hydroxyl group, an ester group, a urea group, a urethane group, an amide group, or C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 is selected from the group consisting of cycloalkoxy, aryl, and heteroaryl groups, where NH2, ester, urea, urethane, amide, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Hydrogen in the cycloalkoxy group, aryl group, and heteroaryl group may be optionally substituted, and the substituents include H, halogen, CN, NH2, a hydroxyl group, an ester group, a urea group, a urethane group, an amide group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 a cycloalkoxy group, an aryl group, or a heteroaryl group, or R2 forms a 3- to 7-membered ring with the structure to which it is linked, or forms a 3- to 7-membered ring between different R2s; R3 is independently H, a halogen, CN, NH2, a hydroxyl group, an ester group, a urea group, a urethane group, an amide group, or C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 is selected from the group consisting of cycloalkoxy, aryl, and heteroaryl groups, where NH2, ester, urea, urethane, amide, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Hydrogen in the cycloalkoxy group, aryl group, and heteroaryl group may be optionally substituted, and the substituents include H, halogen, CN, NH2, a hydroxyl group, an ester group, a urea group, a urethane group, an amide group, C1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 R3 is a cycloalkoxy group, an aryl group, or a heteroaryl group, or different R3s form a 5- to 7-membered ring with the linked B; R4 is H, an ester group, -C(O)R5, a urea group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 is selected from the group consisting of cycloalkyl groups, aryl groups, and heteroaryl groups, wherein an ester group, a urea group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Hydrogen in the cycloalkyl group, aryl group, and heteroaryl group may be optionally substituted, and the substituents include H, halogen, CN, NH2, a hydroxyl group, an ester group, a urea group, a urethane group, an amide group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 a cycloalkoxy group, an aryl group, or a heteroaryl group; R5 is H, C 1-6 Alkyl group, C 3-6 is selected from the group consisting of a cycloalkyl group, an aryl group, and a heteroaryl group; m and n are each independently selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6.

[0006] In another preferred example, the heteroaryl group is a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, preferably a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, more preferably [ka] is selected from the group consisting of:

[0007] In another preferred embodiment, the aryl group is a C6-C10 aryl group, preferably a phenyl group or a naphthyl group. In another preferred embodiment, the amide group is -(C=O)-NH2. In another preferred embodiment, the sulfone is -S(=O)2-. In another preferred embodiment, the sulfoxide is -S(=O)-.

[0008] In another preferred embodiment, the ester group is -(C=O)-OR or -O-(C=O)-R, where R is H or C. 1-6 It is an alkyl group. In another preferred embodiment, the urea group is -NH-(C=O)-NH2. In another preferred embodiment, the urethane group is -NH-(C=O)-O-CH3.

[0009] In another preferred embodiment, each R2 is independently H, a halogen, CN, NH2, a hydroxyl group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 cycloalkoxy groups, wherein NH, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 The hydrogen of the cycloalkoxy group may be optionally substituted, and the substituents may be H, halogen, CN, NH, hydroxyl, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 It is a cycloalkoxy group.

[0010] In another preferred embodiment, each R2 is independently H, halogen, C 1-6 alkyl groups, wherein C 1-6 The hydrogen of the alkyl group may be optionally substituted, said substituent being a halogen.

[0011] In another preferred embodiment, each R3 is independently H, a halogen, CN, NH2, a hydroxyl group, an amide group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 cycloalkoxy groups, aryl groups, and heteroaryl groups, wherein NH, amide groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Hydrogen in the cycloalkoxy group, aryl group, and heteroaryl group may be optionally substituted, and the substituents include H, halogen, CN, NH2, a hydroxyl group, an amide group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 The aryl group is a cycloalkoxy group, an aryl group, or a heteroaryl group.

[0012] In another preferred embodiment, each R3 is independently H, a halogen, CN, NH2, a hydroxyl group, an amide group, C 1-6 Alkyl group, C 1-6 alkoxy groups, aryl groups, and heteroaryl groups, wherein NH2, amide groups, C 1-6 Alkyl group, C 1-6 The hydrogen atoms in the alkoxy, aryl, and heteroaryl groups may be optionally substituted, and the substituents include H, halogen, CN, NH, hydroxyl, C 1-6 Alkyl group, C 1-6 It is an alkoxy group.

[0013] In another preferred embodiment, R4 is H, C 1-6 alkyl groups, wherein C 1-6 The hydrogen of the alkyl group may be optionally substituted, and the substituents include H, halogen, CN, NH, hydroxyl group, C 1-6 Alkoxy group, C 3-6Cycloalkyl groups, C 3-6 In another preferred embodiment, m is selected from the group consisting of 0, 1, 2, and 3.

[0014] In another preferred embodiment, n is selected from the group consisting of 0, 1, 2, and 3. In another preferred embodiment, m is 0. In another preferred embodiment, n is 0 or 1.

[0015] In another preferred embodiment, A is [ka] is selected from the group consisting of R2, m are as defined above. In another preferred embodiment, m is 0.

[0016] In another preferred embodiment, B is [ka] is selected from the group consisting of R3, n are as defined above. In another preferred embodiment, n is 0 or 1.

[0017] In another preferred embodiment, the compound is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka]

[0018] A second aspect of the present invention provides a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and a safe and effective amount of one or more compounds according to the first aspect of the invention or a pharma- ceutically acceptable salt, solvate or prodrug thereof.

[0019] A third aspect of the present invention provides the use of a pharmaceutical composition according to the second aspect of the present invention for use in the preparation of a medicament, said medicament being for use in the prevention and / or treatment of a proliferative disease.

[0020] In another preferred embodiment, the proliferative disease is cancer. In another preferred embodiment, the cancer is selected from the group consisting of glioma, prostate cancer, thoracic septum, breast cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer, and squamous cell carcinoma.

[0021] A fourth aspect of the present invention provides the use of a pharmaceutical composition according to the second aspect of the present invention for use in the preparation of a medicament, said medicament comprising 1) Prevention and / or treatment of diseases associated with abnormal activity of YAP / TEAD; 2) prevention and / or treatment of associated diseases caused by dysregulation of the Hippo pathway; and 3) prevention and / or treatment of associated diseases caused by dysregulation of YAP or TAZ or YAP / TAZ or YAP / TEAD or YAP / TAZ / TEAD.

[0022] In another preferred embodiment, the drug is used for the prevention and / or treatment of associated diseases caused by dysregulation of YAP / TEAD or YAP / TAZ / TEAD. In another preferred embodiment, the associated disease caused by the YAP / TEAD abnormal activity is cancer.

[0023] In another preferred embodiment, the Hippo pathway-related disease caused by dysregulation is cancer. In another preferred embodiment, the associated disease caused by dysregulation of said YAP or TAZ or YAP / TAZ or YAP / TEAD or YAP / TAZ / TEAD is cancer.

[0024] A fifth aspect of the invention provides a compound according to the first aspect of the invention, or a pharma- ceutically acceptable salt, solvate or prodrug thereof, in combination with a second drug for use in the prophylaxis and / or treatment of cancer, comprising The second drug is selected from the group consisting of an ERK inhibitor, a MEK inhibitor, a KRAS inhibitor, a BRAF inhibitor, an EGFR inhibitor, a Wnt inhibitor, and a PD-1 inhibitor.

[0025] In another preferred embodiment, the ERK inhibitor is selected from the group consisting of AZD0364, ulixertinib, or a combination thereof. In another preferred embodiment, the MEK inhibitor is selected from the group consisting of cobimetinib, binimetinib, or a combination thereof.

[0026] In another preferred embodiment, the KRAS inhibitor is selected from the group consisting of adagrasib (MRTX849), JNJ-74699157 (ARS-3248), JAB-3312, or a combination thereof. In another preferred embodiment, the BRAF inhibitor is selected from the group consisting of sorafenib, regorafenib, or a combination thereof.

[0027] In another preferred embodiment, the EGFR inhibitor is selected from the group consisting of osimertinib, dacomitinib, gefitinib, or a combination thereof. In another preferred embodiment, the Wnt inhibitor is selected from the group consisting of IWR-1, ETC-159, or a combination thereof.

[0028] In another preferred embodiment, the PD-1 inhibitor is selected from the group consisting of nivolumab, atezolizumab, pembrolizumab, or a combination thereof. In another preferred embodiment, the cancer is selected from the group consisting of glioma, prostate cancer, thoracic septum, breast cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer, and squamous cell carcinoma. Effect of the Invention

[0029] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be repeated here due to space limitations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] As a result of long-term thorough research, the present inventors have unexpectedly prepared a compound of formula I, which has a novel structure and has excellent proliferation inhibitory activity and excellent YAP-TEAD inhibitory activity.Preferably, the present invention obtains a compound with the above-mentioned excellent performance by optimizing R1.Based on this, the present inventors have completed the present invention.

[0031] term In the present invention, unless otherwise specified, the terms used have their ordinary meanings known to those skilled in the art. In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0032] In the present invention, "C 1-6 "Alkyl group" refers to straight or branched chain alkyl groups containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, neopentyl, t-pentyl, or the like.

[0033] In the present invention, "C 2-6The term "alkenyl group" refers to straight or branched chain alkenyl groups containing one double bond having 2 to 6 carbon atoms, including, but not limited to, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl groups.

[0034] In the present invention, "C 2-6 The term "alkynyl group" refers to straight or branched chain alkynyl groups containing one triple bond having 2 to 6 carbon atoms, including, but not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, and hexynyl groups.

[0035] In the present invention, "C 3-6 The term "cyclic hydrocarbon group" means 3-6 Cycloalkyl groups, C 3-6 Cycloalkenyl group, C 3-6 Cycloalkynyl groups include groups selected from the group consisting of cycloalkynyl groups.

[0036] In the present invention, "C 3-6 The term "cycloalkyl group" refers to cyclic alkyl groups having from 3 to 6 carbon atoms on the ring, and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0037] In the present invention, "C 5-8 The term "bridged cyclic group" refers to a cyclic alkyl group having a bridge and having 5 to 8 carbon atoms, including but not limited to: [ka] etc.

[0038] In the present invention, "C 1-6 The term "alkoxy group" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including, but not limited to, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group. A C1-4 alkoxy group is preferred.

[0039] In the present invention, the term "heterocyclic group" means [ka] " refers to a 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, including but not limited to:

[0040] In the present invention, the terms "aromatic ring" and "aryl group" have the same meaning, and preferably are 6-10 "Aryl group". 6-10 The term "aryl group" refers to an aromatic ring group having 6 to 10 carbon atoms and no heteroatoms in the ring, such as a phenyl group, a naphthyl group, and the like.

[0041] In the present invention, the terms "aromatic heterocycle" or "heteroaryl group" have the same meaning and refer to a heteroaromatic group containing one or more heteroatoms. For example, a "C3-C10 heteroaryl group" refers to an aromatic heterocycle containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen and 3-10 carbon atoms. Non-limiting examples include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl group, a heterocyclic group or a cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0042] In the present invention, the term "halogenated" refers to substitution with halogen. In the present invention, the term "deuterated" refers to substitution with deuterium.

[0043] In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is the substituent described correspondingly in the above specification or the substituent described in each example. Unless otherwise specified, a specific substituent can have a substituent selected from a specific group at any substitutable position of the group, and the substituent can be the same or different at each position. It should be understood by those skilled in the art that the combination of substituents contemplated by the present invention is a stable combination of those or a scientifically achievable combination. The substituents are, for example, halogen, hydroxyl group, carboxyl group (-COOH), C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C8 cycloalkyl group, 3-12 membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1-C10 sulfonyl group, etc. (not limited to these).

[0044] In the present invention, the term 1 to 6 refers to 1, 2, 3, 4, 5 or 6. Other similar terms each independently have the same meaning. The term "multiple" refers to 2 to 6, i.e. 2, 3, 4, 5 or 6.

[0045] It is to be understood that when a particular group is simultaneously present in several different positions on a compound, its definition at each position is independent of each other and may be the same or different, i.e., the term "selected from the group consisting of" has the same meaning as the term "each independently selected from the group consisting of."

[0046] Compounds and preparation methods The present invention provides a compound represented by formula I, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof: [ka] Here, each group is as defined above.

[0047] In another preferred embodiment, in the compound, any one of R1, R2, A, B, L, and C is each independently a corresponding group in the specific compound. In another preferred embodiment, the compound is a specific compound represented by the present invention.

[0048] As used herein, the term "pharmaceutical acceptable salt" refers to a medicament-compatible salt formed by the compound of the present invention and an acid or base. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is the salt formed by the compound of the present invention and an acid. Acids compatible with salt formation include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, etc., and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, etc.

[0049] Further preferred salts are salts formed by the compounds of the present invention with bases, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanol ammonium salts and other pharma- ceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, t-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0050] The term "solvate" refers to a complex formed when a compound of the present invention coordinates with solvent molecules in a specific ratio.

[0051] In addition, the compounds of the present invention further include prodrugs of the compounds represented by formula I. The term "prodrug" may be biologically active or inactive in itself, and after being administered in a suitable manner, it undergoes metabolism or chemical reaction in the human body to be converted into the compound of formula I, or into a salt or solution composed of the compound of formula I. The prodrugs include, but are not limited to, the carboxylate, carbonate, phosphate, nitrate, sulfate, sulfonate, sulfoxide ester, amino compound, carbamate, azo compound, phosphoramide, glucoside, ether, acetal, etc. forms of the compound.

[0052] It will be appreciated that the compounds of the present invention can also be prepared by any combination of the various synthetic methods described herein or known in the art, and that such combinations can be readily performed by one of ordinary skill in the art to which the present invention pertains.

[0053] Typically, the raw materials and reagents used in the processes for preparing the compounds of the present invention may be purchased through commercial channels, unless otherwise specified.

[0054] Pharmaceutical Compositions and Methods of Administration The present invention further provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier and a safe and effective amount of one or more of the above compounds or a pharma- ceutically acceptable salt, solvate or prodrug thereof.

[0055] Since the compound of the present invention has excellent antitumor activity, the compound of the present invention and its various crystal forms, pharma- ceutically acceptable inorganic or organic salts, hydrates or solvates, as well as pharmaceutical compositions containing the compound of the present invention as the main active ingredient, can be used to treat, prevent and alleviate tumor-related diseases.

[0056] The pharmaceutical composition of the present invention contains the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount range. Here, the "safe and effective amount" refers to an amount of the compound sufficient to clearly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound / agent of the present invention, more preferably 10-1000 mg of the compound / agent of the present invention. Preferably, the "one agent" is one capsule or tablet.

[0057] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances, which must be suitable for human use, have sufficient purity and sufficiently low toxicity. "Compatibility" refers to the ability of each component of the composition to be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween R), wetting agents (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0058] The pharmaceutical composition is in the form of an injection, capsule, tablet, pill, powder or granule. The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0059] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or vector), such as, for example, sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarders, such as paraffin; (f) absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricant components, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium dodecyl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0060] Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coating and shell materials, such as enteric coatings and other materials known in the art.They can contain opacifying agents, and the release of the active compound or compounds of such compositions can be delayed in a certain part of the digestive tract.Examples of embedding components that can be used are polymeric substances and waxes.If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients.

[0061] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage forms can contain inert diluents conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers, such as, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0062] Besides these inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. In addition to the active compounds, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar-agar, or mixtures of these substances.

[0063] Compositions for parenteral injection can include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous vehicles, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0064] The dosage forms of the compounds of the present invention used for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable vector and any preservatives, buffers or propellants that may be required.

[0065] The compounds of the present invention can be administered alone or in combination with other pharma- ceutically acceptable compounds (eg, anti-tumor drugs). The therapeutic methods of the present invention can be used alone or in combination with other therapeutic procedures or therapeutic agents.

[0066] When the pharmaceutical composition is used, a safe and popular amount of the compound of the present invention is applied to a mammal (e.g., human) in need of treatment, where the dosage at the time of administration is the effective dosage considered, and for a person weighing 60 kg, the daily dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, the specific dosage must also take into account factors such as the route of administration and the health condition of the patient, all of which are within the skill of a skilled physician.

[0067] Compared with the prior art, the present invention has the following main advantages: (1) The compound has excellent proliferation inhibitory activity. (2) The compound has excellent YAP-TEAD inhibitory activity. (3) The compounds have excellent pharmacokinetic properties. (4) The compound has excellent properties of penetrating the blood-brain barrier (BBB).

[0068] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, the experimental methods that do not show specific conditions usually follow conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or those suggested by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0069] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can all be applied to the method of the present invention. The preferred implementation methods and materials described herein are used for demonstration purposes only.

[0070] Example 1 Compounds synthesized according to the present invention: [ka]

[0071] The synthetic route is as follows: [ka]

[0072] The experimental process is as follows. (1) Synthesis of compound T1-2 Compound T1-1 (10 g, 42.21 mmol, 1.0 eqiv), p-trifluoroaniline (6.8 g, 42.21 mmol, 1.0 eqiv), CS2CO3 (11.49 g, 84.43 mmol, 2.0 eqiv), Pd(OAc)2 (473.86 mg, 2.11 mmol, 5% eqiv), Xantphos (2.44 g, 4.22 mmol, 10% eqiv), and ultra-dry dioxane (200 mL) were added to a 500 mL three-neck flask, and the mixture was evacuated and replaced with nitrogen gas. The mixture was then heated to 105°C and reacted for 16 hours.

[0073] After the reaction is completed, it is cooled to room temperature, 200mL of water is added, extracted with ethyl acetate, the organic layer is washed with saturated saline, dried with anhydrous sodium sulfate, concentrated to obtain the crude product, which is purified by column chromatography using PE100%, PE:EA=500:1 to obtain 5.4g of product T1-2 (white solid).

[0074] (2) Synthesis of compound T1-3 In a 100mL one-neck flask, compound T1-2 (1.2g, 3.78mol, 1.0eq), pinacol borate (1.4g, 4.54mmol, 1.2eqiv), potassium carbonate (1.05g, 7.57mmol, 2.0eqiv), water / 1,4-dioxane (1 / 10) (22mL), Pd(dppf)Cl2 (135.64mg, 0.189mmol, 5%eq) were added in sequence, and after three nitrogen gas replacements, the mixture was placed in an oil bath pot, heated to 105°C and reacted for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and then 20mL of water was added. Extraction was performed with ethyl acetate (25mL x 3), and the organic layers were combined, washed with saturated saline (25mL), dried over anhydrous sodium sulfate, and the filtrate was suction filtered, spin-dried, and passed through a column to obtain 1.5g of product T1-3 (light yellow viscous oil).

[0075] (3) Synthesis of compound T1-4 Compound T1-3 (1.5 g) is dissolved in ethanol (40 mL), Pd / (OH)2 (150 mg, 10%) is added, and the mixture is reacted for 16 hours under a hydrogen gas environment until the raw material disappears. The mixture is directly filtered and spin-dried to obtain 1.45 g of crude product T1-4 (gray viscous liquid).

[0076] (4) Synthesis of Compound T1-5 Compound T1-4 (1.45 g) is added to methanol (20 mL), HCl / dioxane (40 mL, 4 M) is added, and then reacted at room temperature overnight. Concentration is followed by addition of saturated sodium bicarbonate, extraction with ethyl acetate, followed by concentration and removal of the solvent with dichloromethane to give 1.14 g of a gray solid T1-5.

[0077] (7) Synthesis of Compound T1 Compound T1-5 (138.5 mg, 0.43 mmol, 1.0 eq), DIEA (111.41 mg, 0.86 mmol, 2. eq), DCM (2 mL) are added to the reaction tube, then acryloyl chloride (46.81 mg, 0.52 mmol, 1.2 eq) in DCM (1 mL) is added dropwise at 0 ° C. and stirred at room temperature overnight. The solution is washed with 0.1 N HCl, then EA is added to extract, then separated and purified on a large plate to obtain 42.6 mg of T1 (white solid).

[0078] 1 H NMR: CDCl38.6(s,1H),7.44-7.49(m,4H),7.37-7.49(d,1H),6.83-6.86(m,1H),6.52-6.59(s,1H),6.35(s,1H),6.23-6.27(d,1H), 5.56-5.67(d,1H),4.81-4.85(d,1H),4.10-4.13(d,1H),3.13-3.19(t,1H),2.67-2.77(d,2H),1.91-1.94(d,2H),1.15-1.18(m,2H) LC-MS[M+1]: 376.5.

[0079] The following compounds are synthesized with reference to the synthesis method of Example 1. [ka] [ka] [ka]

[0080] Example 2 Compounds synthesized according to the present invention: [ka]

[0081] The synthetic route is as follows: [ka]

[0082] The experimental process is as follows. (1) Synthesis of compound T2-2 Compound T2-1 (10 g, 42.21 mmol, 1.0 eqiv), p-trifluoroaniline (6.8 g, 42.21 mmol, 1.0 eqiv), CS2CO3 (11.49 g, 84.43 mmol, 2.0 eqiv), Pd(OAc)2 (473.86 mg, 2.11 mmol, 5% eqiv), Xantphos (2.44 g, 4.22 mmol, 10%), and ultra-dry dioxane (200 mL) were added to a 500 mL three-neck flask, and the mixture was evacuated and replaced with nitrogen gas. The mixture was then heated to 105°C and reacted for 16 hours.

[0083] After the reaction is completed, it is cooled to room temperature, 200mL of water is added, extracted with ethyl acetate, the organic layer is washed with saturated saline, dried with anhydrous sodium sulfate, concentrated to obtain the crude product, which is purified by column chromatography using PE100%, PE:EA=500:1 to obtain 5.4g of product T2-2 (white solid).

[0084] (2) Synthesis of compound T2-3 In a 100mL one-neck flask, compound T2-2 (1.2g, 3.78mol, 1.0eq), pinacol borate (1.4g, 4.54mmol, 1.2eqiv), potassium carbonate (1.05g, 7.57mmol, 2.0eqiv), water / 1,4-dioxane (1 / 10) (22mL), Pd(dppf)Cl2 (135.64mg, 0.189mmol, 5%eq) were added in sequence, and after three nitrogen gas replacements, the mixture was placed in an oil bath pot, heated to 105°C, and reacted for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and then 20mL of water was added, extracted with ethyl acetate (25mL x 3), the organic layers were combined, washed with saturated saline (25mL), dried over anhydrous sodium sulfate, and the filtrate was suction filtered, spin-dried, and passed through a column to obtain 1.5g of product T2-3 (light yellow viscous oil).

[0085] (3) Synthesis of compound T2-4 Compound T2-3 (560 mg) is added to methanol (16 mL), HCl / dioxane (40 mL, 4 M) is added, and then reacted at room temperature overnight. After concentration, saturated sodium bicarbonate is added, extracted with ethyl acetate, washed with saturated saline, then concentrated, and the solvent is removed with dichloromethane to obtain 424 mg of white solid T2-4 (lcms: [M+1] 320.3).

[0086] (4) Synthesis of compound T2 Compound T2-4 (424 mg, 1.33 mmol, 1.0 eq), DIEA (343.75 mg, 2.66 mmol, 2.0 eq), DCM (10 mL) are added to the reaction tube, then acryloyl chloride (144.36 mg, 1.6 mmol, 1.2 eq) in DCM solution (1 mL) is added dropwise at 0 ° C., and stirred at room temperature overnight. The solution is washed with 0.1 N HCl and saturated saline, then EA is added for extraction, and then separated and purified by column to obtain 90.8 mg of T2 (white solid).

[0087] 1 H NMR: CDCl38.6(s,1H),7.91-7.93(m,1H),7.71-7.73(m,2H),7.60(s,1H),7.27(s,1H),6.77-6.84(m,2H),6.3 8-6.42(m,1H),6.18-6.22(d,2H),5.56-5.86(m,3H),3.94-4.15(m,2H),3.41-3.53(m,2H),1.92-2.43(m,2H) LC-MS[M+1]: 374.4.

[0088] The following compounds are synthesized with reference to the synthesis method of Example 2. [ka]

[0089] Example 3 Compounds synthesized according to the present invention: [ka]

[0090] The synthetic route is as follows: [ka]

[0091] The experimental process is as follows. (1) Synthesis of T16-2 Add T16-1 (3g, 12.77mmol, 1.0eq), p-trifluoroaniline (2.06g, 12.77mmol, 1eq), CS2CO3 (8.3g, 25.54mmol, 2eq), Xantphos (740.6mg, 1.28mmol, 10%eq), Pd(OAc)2 (143.66mg, 0.639mmol, 5%eqiv), and 70mL of ultra-dry 1,4 dioxane to the reaction flask in that order. After replacing with nitrogen gas three times, place in an oil bath and heat to 105℃ to react for 16 hours.

[0092] After the reaction is completed, it is cooled to room temperature, filtered through diatomaceous earth, 100mL of water is added, extracted with ethyl acetate, the organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated to obtain the crude product, which is purified by column chromatography using PE100%, PE:EA=500:1 to obtain 2.2g of T16-2 (white solid).

[0093] (2) Synthesis of T16-3 In a 100 mL one-neck flask, add T16-2 (2 g, 6.31 mmol, 1.0 eq), pinacol borate (2.33 g, 7.57 mmol, 1.2 eqiv), potassium carbonate (1.74 g, 12.62 mmol, 2.0 eqiv), water / 1,4-dioxane (1 / 10) (4 mL / 40 mL), and Pd(dppf)Cl2 (230.63 mg, 0.316 mmol, 5% eq) in that order. After nitrogen gas replacement, place in an oil bath, heat to 105 °C, and react for 16 hours. After the reaction is completed, cool to room temperature, dilute EA with diatomaceous earth, filter, add 80 mL of water, and extract with ethyl acetate (80 mL × 3). Combine the organic layers, wash with saturated saline (60 mL), dry over anhydrous sodium sulfate, suction filter the filtrate, spin dry, and pass through a column to obtain 2.6 g of T16-3 (light yellow solid).

[0094] (3) Synthesis of T16-4 Dissolve T16-3 (1 g) in ethanol (15 mL), add Pd / (OH)2 (100 mg, 10%), react for 16 h under hydrogen gas environment until the raw material disappears, filter directly, and spin-dry to obtain 800 mg of crude product T16-4 (white solid).

[0095] (4) Synthesis of compound T16-5 Compound T16-4 (700 mg) is added to DCM (10 mL), HCl / dioxane (20 mL, 4 M) is added, and then reacted overnight at room temperature. Directly spin-dried to give 600 mg of white solid T16-5.

[0096] (7) Synthesis of compound T-16 Compound T16-5 (400 mg, 1.24 umol, 1.0 eq), triethylamine (376.4 mg, 3.73 umol, 3.0 eq), DCM (3 mL) are added to the reaction tube, then acryloyl chloride (77 mg, 1.36 umol, 1.1 eq) in DCM solution (1 mL) is added dropwise at 0 ° C. and stirred at room temperature overnight. The solution is washed with 0.1 N HCl, then extracted with EA, then separated and purified on a large plate to obtain 110 mg of T16 (white solid).

[0097] 1 H NMR(400MHz,Chloroform-d)δ 8.07(s,2H),7.66-7.58(m,4H),6.63(dd,J=16.8,10.5Hz,1H),6.52(s,1H),6.30(d,J=16.7Hz,1H),5.72 (d,J=10.8Hz,1H),4.79(s,1H),4.20(d,J=13.7Hz,1H),3.29(s,1H),2.95(d,J=34.7Hz,2H),1.99(s,4H).

[0098] The following compounds are synthesized with reference to the synthesis method of Example 3. [ka] [ka]

[0099] Example 4 Compounds synthesized according to the present invention: [ka]

[0100] The synthetic route is as follows: [ka]

[0101] The experimental process is as follows. (1) Synthesis of T22-2 Add T22-1 (5g, 19.93mmol, 1.0eq), p-trifluoroaniline (3.21g, 19.93mmol, 1eq), CS2CO3 (12.98g, 39.85mmol, 2eq), Xantphos (1.15g, 1.99mmol, 10%eq), Pd(OAc)2 (223.68mg, 0.996mmol, 5%eqiv), and 70mL of ultra-dry 1,4-dioxane to the reaction flask in that order. After replacing with nitrogen gas three times, place in an oil bath and heat to 105℃ to react for 16 hours.

[0102] After the reaction is completed, it is cooled to room temperature, filtered through diatomaceous earth, 100mL of water is added, extracted with ethyl acetate, the organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated to obtain the crude product, which is purified by column chromatography using PE100%, PE:EA=500:1 to obtain 5.8g of T22-2 (white solid).

[0103] (2) Synthesis of T22-3 In a 100 mL one-neck flask, add T22-2 (3 g, 9.06 mmol, 1.0 eq), pinacol borate (3.36 g, 10.87 mmol, 1.2 eqiv), potassium carbonate (2.5 g, 18.12 mmol, 2.0 eqiv), water / 1,4-dioxane (1 / 10) (4 mL / 40 mL), and Pd(dppf)Cl2 (331.45 mg, 453 umol, 5% eq) in sequence, and repeat three times. After replacing with nitrogen gas, place in an oil bath, heat to 105°C, and react for 16 hours. After the reaction is completed, cool to room temperature, dilute EA with diatomaceous earth, filter, add 80 mL of water, and extract with ethyl acetate (80 mL x 3). Combine the organic layers, wash with saturated saline (60 mL), dry over anhydrous sodium sulfate, suction filter the filtrate, spin dry, and pass through a column to obtain 3.9 g of T22-3 (light yellow solid).

[0104] (3) Synthesis of T22-4 Dissolve T22-3 (3.9 g) in ethanol (40 mL), add Pd / (OH)2 (390 mg, 10%), react for 16 hours under hydrogen gas until the raw material disappears, filter directly, and spin-dry to obtain 3.7 g of crude product T22-4 (gray viscous).

[0105] (4) Synthesis of compound T22-5 Compound T22-4 (1.4 g) is added to DCM (10 mL), HCl / dioxane (25 mL, 4 M) is added, and then reacted at room temperature overnight. It is directly spun dry to give 1.2 g of a grey solid T22-5.

[0106] (7) Synthesis of compound T22 Compound T22-5 (300 mg, 0.773 mmol, 1.0 eq), triethylamine (234.3 mg, 2.32 mmol, 3.0 eq), DCM (2 mL) are added to the reaction tube, then acryloyl chloride (77 mg, 0.85 mmol, 1.1 eq) in DCM (1 mL) is added dropwise at 0 ° C. and stirred at room temperature overnight. The solution is washed with 0.1 N HCl, then extracted with EA, then separated and purified on a large plate to obtain 65 mg of T22 (white solid).

[0107] 1 H NMR(400MHz,Methanol-d4)δ 7.91(dd,J=2.2,0.9Hz,1H),7.52-7.44(m,3H),7.38(d,J=8.7Hz,2H),6.81(dd,J =16.8,10.7Hz,1H),6.20(dd,J=16.8,2.0Hz,1H),5.74(dd,J=10.6,2.0Hz,1H),4. 73(d,J=13.4Hz,1H),4.25(d,J=13.5Hz,1H),3.17(td,J=8.5,4.3Hz,1H),2.84(dd ,J=13.6,10.9Hz,1H),2.27(s,3H),1.92(t,J=9.7Hz,2H),1.61(d,J=12.7Hz,2H).

[0108] The following compounds are synthesized with reference to the synthesis method of Example 4. [ka]

[0109] Example 5 Compounds synthesized according to the present invention: [ka]

[0110] The synthetic route is as follows: [ka]

[0111] The experimental process is as follows. (1) Synthesis of T27-2 Add T27-1 (5 g, 18.42 mmol, 1.0 eq), p-trifluoroaniline (3.58 g, 22.11 mmol, 1.2 eq), CS2CO3 (14 g, 43.2 mmol, 2.5 eq), and 50 mL of DMF to the reaction flask in that order. After replacing with nitrogen gas three times, place in an oil bath, heat to 100°C, and react for 16 hours. After the reaction is completed, it is cooled to room temperature, filtered through diatomaceous earth, 100mL of water is added, extracted with ethyl acetate, the organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated to obtain the crude product, which is purified by column chromatography using pure PE to obtain 2.2gT27-2 (white solid).

[0112] (2) Synthesis of T27-3 In a 100 mL one-neck flask, add T27-2 (900 mg, 2.47 umol, 1.0 eq), pinacol borate (916.8 mg, 2.97 umol, 1.2 eqiv), potassium carbonate (682.4 mg, 4.95 umol, 2.0 eqiv), water / 1,4-dioxane (1 / 10) (1 mL / 10 mL), and Pd(dppf)Cl2 (181 mg, 0.247 mol, 10% eq) in that order. After three nitrogen gas replacements, the mixture was placed in an oil bath, heated to 105°C, and reacted for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and then diluted with diatomaceous earth, filtered, 10 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated saline (20 mL), and dried over anhydrous sodium sulfate. The filtrate was suction filtered, spin-dried, and passed through a column to obtain 1.2 g of T27-3 (light yellow solid).

[0113] (3) Synthesis of T27-4 T27-3 (940 mg) is dissolved in ethanol (15 mL), triphenylphosphine rhodium chloride (160 mg, 10%) is added, and the mixture is reacted under high pressure hydrogen gas conditions for 24 hours. The raw material does not completely react, and the mixture is passed through a column to obtain 370 mg of T27-4 (white solid).

[0114] (4) Synthesis of compound T27-5 Compound T27-4 (350 mg) is added to DCM (5 mL), HCl / dioxane (15 mL, 4 M) is added, and then reacted at room temperature overnight. Direct spin-drying gives 300 mg of white solid T27-5.

[0115] (5) Synthesis of compound T27 Compound T27-5 (300 mg, 0.85 umol, 1.0 eq), triethylamine (258 mg, 2.55 umol, 3.0 eq), DCM (3 mL) are added to the reaction tube, then a DCM solution (1 mL) of acryloyl chloride (84.1 mg, 0.93 umol, 1.1 eq) is added dropwise at 0 ° C. and stirred at room temperature overnight. The solution is washed with 0.1 N HCl, then extracted with EA, then separated and purified on a large plate to obtain 180 mg of T27 (white solid).

[0116] 1 H NMR (400MHz, Chloroform-d) δ 7.64-7.55(m,4H),7.38(d,J=7.9Hz,1H),6.90(d,J=8.0Hz,1H),6.62(dd,J= 16.8,10.5Hz,1H),6.46(s,1H),6.33(dd,J=16.8,2.0Hz,1H),5.74(dd,J=10 .6,1.9Hz,1H),4.91(d,J=13.3Hz,1H),4.20(d,J=13.7Hz,1H),3.22(d,J=13 .8Hz,1H),2.84-2.70(m,2H),1.98(d,J=13.3Hz,2H),1.63(d,J=13.1Hz,2H).

[0117] The following compounds are synthesized with reference to the synthesis method of Example 5. [ka] [ka] [ka]

[0118] Example 6 Compounds synthesized according to the present invention: [ka]

[0119] The synthetic route is as follows: [ka]

[0120] The experimental process is as follows. (1) Synthesis of T33-2 Into a reaction flask, add T33-1 (5 g, 18.8 mmol, 1.0 eq), p-trifluoroaniline (3.03 g, 18.8 mmol, 1 eq), CS2CO3 (12.25 mg, 37.6 mmol, 2 eq), Xantphos (1.09 g, 1.88 mmol, 10% eq), Pd(OAc)2 (211.06 mg, 0.94 mmol, 5% eqiv), and 100 mL of ultra-dry 1,4 dioxane in that order. After three nitrogen gas replacements, the mixture was placed in an oil bath, heated to 105°C, and reacted for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and then the EA was diluted with diatomaceous earth, filtered, 200 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with saturated saline (200 mL), and dried over anhydrous sodium sulfate. The filtrate was suction filtered, spin-dried, and subjected to column chromatography to obtain 4 g of T33-2.

[0121] (2) Synthesis of T33-3 In a 100 mL one-neck flask, add T33-2 (2.0 g, 5.7 mmol, 1.0 eq), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (2.13 g, 6.91 mmol, 1.2 eq), potassium carbonate (1.59 g, 11.5 mmol, 2.0 eq), water / 1,4-dioxane (1 / 10) (2 mL / 20 mL), Pd(dppf)Cl2 (210 mg, 0.287 mmol, 5% eq) is added in sequence, and after three nitrogen gas replacements, the mixture is placed in an oil bath, heated to 105°C, and reacted for 16 hours. After the reaction is completed, the mixture is cooled to room temperature, and then the EA is diluted with diatomaceous earth, filtered, 50 mL of water is added, and the mixture is extracted with ethyl acetate (50 mL x 3). The organic layers are combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, and the filtrate is suction filtered, spin-dried, and subjected to column chromatography to obtain 1.8 g of T33-3.

[0122] (3) T33-4 synthesis Dissolve T33-3 (1.8 g, 4 mmol, 1.0 eq) in ethanol (20 mL), add Pd(OH)2 (180 mg, 10%), react in a 50 ml single-neck flask at room temperature under hydrogen gas environment for 20 h until the raw material is completely reacted, filtered, concentrated, and subjected to column chromatography to obtain 1.5 g of product compound T33-4.

[0123] (4)T33-5 synthesis Add T33-4 (1.5 mg) to DCM (20 mL), add HCl / dioxane (20 mL, 4 M), and react overnight at room temperature. Directly spin dry to give 1.8 g of T33-5.

[0124] (5) Synthesis of compound T33 Add T33-5 (520 mg, 1.48 mmol, 1.0 eq), triethylamine (448 mg, 4.44 mmol, 3.0 eq), DMF (5 mL) to a reaction tube, then add dropwise a DMF solution (2 ml) of chloropropionyl chloride (146.6 mg, 1.62 mmol, 1.1 eq) at 0 °C under ice bath, and stir at room temperature overnight. Extract with water and EA, then separate and purify by column chromatography to obtain 140 mg of T33 (white solid).

[0125] 1 H NMR(400MHz,Chloroform-d)δ 7.71-7.47(m,4H),7.36(d,J=8.3Hz,1H),6.62(dd,J=16.8,10.6Hz,1H),6.40-6.25(m,3H),5.72(dd,J=10.6,1.9Hz,1H),4. 88(d,J=13.4Hz,1H),4.17(d,J=13.7Hz,1H),3.88(s,3H),3.22(t,J=13.2Hz,1H),2.87-2.60(m,2H),1.95(d,J=13.4Hz,2H).

[0126] The following compounds are synthesized with reference to the synthesis method of Example 6. [ka]

[0127] Example 7 Compounds synthesized according to the present invention: [ka]

[0128] The synthetic route is as follows: [ka]

[0129] The experimental process is as follows. (1) Synthesis of T37-2 Add T37-1 (3.6 g, 12.54 mmol, 1.0 eq), p-trifluoroaniline (2.02 g, 12.54 mmol, 1 eq), CS2CO3 (8.17 g, 25.08 mmol, 2 eq), Xantphos (727.7 mg, 1.25 mmol, 10% eq), Pd(OAc)2 (140.77 mg, 0.627 mmol, 5% eqiv), and 50 mL of ultra-dry 1,4 dioxane in order to a microwave tube and react at 150 °C for 45 min.

[0130] After the reaction is completed, it is cooled to room temperature, 40mL of water is added, extracted with ethyl acetate, the organic layer is washed with saturated saline, dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which is purified by column chromatography using PE100%, PE:EA=500:1 to obtain 1.3g of T37-2.

[0131] (2) Synthesis of T37-3 In a 100 mL single-neck flask, add T37-2 (1.3 g, 3.55 mmol, 1.0 eq), pinacol borate (1.32 g, 4.26 mmol, 1.2 eqiv), potassium carbonate (981.2 mg, 7.1 mmol, 2.0 eqiv), water / 1,4-dioxane (1 / 10) (1.5 mL / 15 mL), and Pd(dppf)Cl2 (129.75 mg, 0.178 mmol, 5% eq) in sequence. After three nitrogen gas replacements, the mixture was placed in an oil bath, heated to 105°C, and reacted for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and then the EA was diluted with diatomaceous earth, filtered, 10 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with saturated saline (25 mL), and dried over anhydrous sodium sulfate. The filtrate was suction filtered, spin-dried, and passed through a column to obtain 1.4 g of T37-3 (light yellow solid).

[0132] (3) Synthesis of T37-4 Dissolve T37-3 (800 mg) in ethanol (10 mL), add Pd / C (80 mg, 10%), and react in a hydrogenation vessel at 60°C for 16 hours under a hydrogen gas atmosphere of 1.0 MPa until the raw material disappears. Finally, the product is precipitated in the hydrogenation vessel and filtered to obtain 350 mg of product T37-4 (white solid).

[0133] (4) Synthesis of compound T37-5 Compound T37-4 (350 mg) is added to dichloromethane (5 mL), HCl / dioxane (20 mL, 4 M) is added, and then reacted at room temperature overnight, followed by direct spin drying to give 300 mg of solid T37-5.

[0134] (7) Synthesis of compound T37 Compound T37-5 (300 mg, 1.2 umol, 1.0 eq), triethylamine (364.6 mg, 3.61 umol, 3.0 eq), DCM (2 mL) are added to the reaction tube, then a DCM solution (1 mL) of acryloyl chloride (119.5 mg, 1.32 umol, 1.1 eq) is added dropwise at 0 °C, and the mixture is stirred at room temperature overnight. Extraction with water and EA is then performed, followed by separation and purification on a large plate to obtain 60 mg of T37 (white solid).

[0135] 1 H NMR(400MHz,Chloroform-d)δ 7.61(d,J=8.1Hz,2H),7.36-7.29(m,2H),7.24-7.10(m,4H),6.51(d,J=13.6Hz,1H),6.22(d,J=16.7Hz,1H),5.66(d,J=10.6Hz,1H),4.76-4. 58(m,2H),4.43(s,1H),4.00(dd,J=37.0,13.4Hz,1H),3.69(s,1H),2.96(d,J=47.1Hz,2H),2.49(d,J=26.0Hz,2H),1.88(s,2H),1.56(s,2H).

[0136] Example 8 Compounds synthesized according to the present invention: [ka]

[0137] The synthetic route is as follows: [ka]

[0138] The experimental process is as follows. (1) Synthesis of T40-2 To a reaction flask, add T40-1 (2 g, 7.43 mmol, 1.0 eq), p-trifluorophenol (1.45 g, 8.92 mmol, 1.2 eq), CS2CO3 (4.83 g, 14.86 mmol, 2.0 eq), CuI (140 mg, 0.74 mmol, 0.1 eq), TMEDA (86 mg, 0.74 mmol, 0.1 eq), and DMSO (20 ml) in that order. Replace with nitrogen gas three times, and heat to 110°C and react for 16 hours.

[0139] After the reaction is completed, it is cooled to room temperature, filtered through diatomaceous earth, 40mL of water is added, extracted with ethyl acetate, the organic layer is washed with saturated saline, dried with anhydrous sodium sulfate, concentrated to obtain the crude product, which is purified by column chromatography using pure PE to obtain 1.3g of T40-2 (white solid).

[0140] (2) Synthesis of T40-3 T40-2 (1.3 mg, 3.72 umol, 1.0 eq), pinacol borate (1.38 mg, 4.46 mmol, 1.2 eqiv), potassium carbonate (1.03 mg, 7.44 mmol, 2.0 eqiv), water / 1,4-dioxane (1 / 10) (1.5 mL / 15 mL), Pd(dppf)Cl2 (136 mg, 0.18 mmol, 5% eq) were added in sequence to a 50 mL one-neck flask, and after three nitrogen gas replacements, the temperature was raised to 105 ° C. and reacted for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and then diluted with diatomaceous earth, filtered, 15 mL of water was added, and extracted with ethyl acetate (15 mL × 3). The organic layers were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and the filtrate was suction filtered, spin-dried, and passed through a column to obtain 1.1 g of T40-3 (light yellow solid).

[0141] (3) Synthesis of T40-4 Dissolve T40-3 (1.1 mg) in ethanol (30 mL), add triphenylphosphine rhodium chloride (200 mg, 20%), and react for 16 hours under high pressure hydrogen gas conditions. After the raw material reaction is completed, pass through a column to obtain 1 g of T40-4 (white solid).

[0142] (4) Synthesis of compound T40-5 Compound T40-4 (1 g) is added to DCM (10 mL), HCl / dioxane (20 mL, 4 M) is added, and then reacted at room temperature overnight. It is directly spun dry to give 0.8 g of a white solid T40-5.

[0143] (5) Synthesis of compound T40 Compound T40-5 (500 mg, 1.4 μmol, 1.0 eq), triethylamine (424.2 mg, 4.2 μmol, 3.0 eq), DCM (5 ml) are added to the reaction tube, then a DCM solution (2 mL) of acryloyl chloride (139.4 mg, 1.54 μmol, 1.1 eq) is added dropwise at 0 ° C. and stirred at room temperature overnight. The solution is washed with 0.1 N HCl, then extracted with EA, then separated and purified on a large plate to obtain 210 mg of T40 (white solid).

[0144] 1 H NMR (400MHz, Chloroform-d) δ 7.97(p,J=2.5Hz,1H),7.68(dt,J=8.3,3.3Hz,2H),7.57-7.50(m,1H),7.20(dd ,J=8.5,3.7Hz,2H),6.68-6.56(m,1H),6.37-6.26(m,1H),5.72(dp,J=10.5,2. 4Hz,1H),4.88(d,J=13.4Hz,1H),4.17(d,J=13.6Hz,1H),3.22(qd,J=9.7,8.9, 4.5Hz, 2H), 2.76 (t, J = 13.4Hz, 1H), 2.02 (d, J = 10.8Hz, 2H), 1.76-1.62 (m, 2H).

[0145] The following compounds are synthesized with reference to the synthesis method of Example 8. [ka] [ka]

[0146] Example 9 Compounds synthesized according to the present invention: [ka]

[0147] The synthetic route is as follows: [ka]

[0148] The experimental process is as follows. (1) Synthesis of compound T48-2 In a 500mL three-neck flask, compound T48-1 (10g, 42.21mmol, 1.0eqiv), p-trifluoroaniline (6.8g, 42.21mmol, 1.0eqiv), CS2CO3 (11.49g, 84.43mmol, 2.0eqiv), Pd(OAc)2 (473.86mg, 2.11mmol, 5%eqiv), Xantphos (2.44g, 4.22mmol, 10%eqiv), and ultra-dry dioxane (200mL) were added, and the mixture was evacuated and replaced with nitrogen gas. The mixture was heated to 105℃ and reacted for 16 hours.

[0149] After the reaction is completed, it is cooled to room temperature, 200mL of water is added, extracted with ethyl acetate, the organic layer is washed with saturated saline, dried with anhydrous sodium sulfate and concentrated to obtain the crude product, which is purified by column chromatography using PE100%, PE:EA=500:1 to obtain 5.4g of product T48-2 (white solid).

[0150] (2) Synthesis of compound T48-3 In a 100mL one-neck flask, compound T48-2 (1.2g, 3.78mol, 1.0eq), pinacol borate (1.4g, 4.54mmol, 1.2eqiv), potassium carbonate (1.05g, 7.57mmol, 2.0eqiv), water / 1,4-dioxane (1 / 10) (22mL), Pd(dppf)Cl2 (135.64mg, 0.189mmol, 5%eq) were added in sequence, and after three nitrogen gas replacements, the mixture was placed in an oil bath pot, heated to 105°C and reacted for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and then 20mL of water was added, extracted with ethyl acetate (25mL x 3), the organic layers were combined, washed with saturated saline (25mL), dried over anhydrous sodium sulfate, and the filtrate was suction filtered, spin-dried, and passed through a column to obtain 1.5g of product T48-3 (light yellow viscous oil).

[0151] (3) Synthesis of compound T48-4 Compound T48-3 (1.5 g) is dissolved in ethanol (40 mL), Pd / (OH)2 (150 mg, 10%) is added, and the mixture is reacted for 16 hours under hydrogen gas until the raw material disappears. The mixture is directly filtered and spin-dried to obtain 1.45 g of crude product T48-4 (gray viscous).

[0152] (4) Synthesis of compound T48-5 Compound T48-4 (1.45 g) is added to methanol (20 mL), HCl / dioxane (40 mL, 4 M) is added, and then reacted at room temperature overnight. Concentrate, then add saturated sodium bicarbonate, extract with ethyl acetate, then concentrate, and remove the solvent with dichloromethane to obtain 1.14 g of a gray solid T48-5.

[0153] (7) Synthesis of compound T48 Add compound α-methacrylic acid (96.55 mg, 0.78 mmol, 1 eq), DIEA (201.79 mg, 0.1.56 mmol, 2 eq), DCM (3 mL) to the reaction tube and stir at room temperature for 10 min, then add compound T48-5 (300 mg, 0.935 mmol, 1.2 eq) and stir at room temperature overnight. Extract the organic layer with water and DCM, wash once with brine, dry with anhydrous sodium sulfate, and after filtration, climb onto a large plate to obtain pure DIEA, 100 mg of white solid.

[0154] 1 H NMR (400MHz, DMSO-d6) δ 8.45(s,1H),8.05(dd,J=4.8,1.8Hz,1H),7.71(d,J=8.6Hz,2H),7.59(dd,J=7. 6,1.8Hz,1H),7.53(d,J=8.6Hz,2H),6.89(dd,J=7.5,4.8Hz,1H),5.06(dt,J=53 .9,1.5Hz,2H),4.48(s,1H),3.97(s,1H),3.22(td,J=10.3,8.7,6.0Hz,2H),2.7 4(s,1H),1.85(d,J=1.4Hz,3H),1.79(d,J=12.3Hz,2H),1.45(d,J=13.5Hz,2H).

[0155] The following compounds are synthesized with reference to the synthesis method of Example 9. [ka] [ka]

[0156] Example 10 Compounds synthesized according to the present invention: [ka]

[0157] The synthetic route is as follows: [ka]

[0158] The experimental process is as follows. (1) Synthesis of T54-2 Add T54-1 (3.6 g, 12.54 mmol, 1.0 eq), p-trifluoroaniline (2.02 g, 12.54 mmol, 1 eq), CS2CO3 (8.17 g, 25.08 mmol, 2 eq), Xantphos (727.7 mg, 1.25 mmol, 10% eq), Pd(OAc)2 (140.77 mg, 0.627 mmol, 5% eqiv), and 50 mL of ultra-dry 1,4 dioxane in order to a microwave tube and react at 150 °C for 45 min.

[0159] After the reaction is completed, it is cooled to room temperature, 40mL of water is added, extracted with ethyl acetate, the organic layer is washed with saturated saline, dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which is purified by column chromatography using PE100%, PE:EA=500:1 to obtain 1.3g of T54-2.

[0160] (2) Synthesis of T54-3 In a 100 mL single-neck flask, add T54-2 (1.3 g, 3.55 mmol, 1.0 eq), pinacol borate (1.32 g, 4.26 mmol, 1.2 eqiv), potassium carbonate (981.2 mg, 7.1 mmol, 2.0 eqiv), water / 1,4-dioxane (1 / 10) (1.5 mL / 15 mL), and Pd(dppf)Cl2 (129.75 mg, 0.178 mmol, 5% eq) in sequence. After three nitrogen gas replacements, the mixture was placed in an oil bath, heated to 105°C, and reacted for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and then the EA was diluted with diatomaceous earth, filtered, 10 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with saturated saline (25 mL), and dried over anhydrous sodium sulfate. The filtrate was suction filtered, spin-dried, and passed through a column to obtain 1.4 g of T54-3 (light yellow solid).

[0161] (3) Synthesis of T54-4 Dissolve T54-3 (1.4 g) in ethanol (15 mL), add triphenylphosphine rhodium chloride (210 mg, 20%), and react under high pressure hydrogen gas conditions for 24 hours. The raw material does not completely react, and pass through a column to obtain 1.4 g of T54-4 (white solid).

[0162] (4) Synthesis of T54-5 Add T54-4 (1.5g, 3.29mmol, 1.0eq), S2 (1.72g, 8.23mmol, 2.5eq), NaHCO3 (1.24g, 14.81mmol, 4.5eq), Pd(OAC)2 (73.7mg, 0.33mmol, 0.1eq) and Pcy3 (184.53mg, 0.66mmol, 0.2eq) to the reaction flask, add 1,4 dioxane / EtOH / water (7:2:1) (11.9ml / 3.4ml / 1.7ml) to the solvent, replace with nitrogen gas three times, place in oil bath, heat to 105℃ and react for 12 hours. After the reaction is completed, the mixture is cooled to room temperature, and then 20 mL of water is added. The mixture is extracted with ethyl acetate (25 mL x 3). The organic layers are combined, washed with saturated saline (25 mL), dried over anhydrous sodium sulfate, and the filtrate is suction filtered, spin-dried, and passed through a column to obtain 1.53 g of product T54-5.

[0163] (5) Synthesis of compound T54-6 Compound T54-5 (1.53 g) is added to DCM (10 mL), HCl / dioxane (25 mL, 4 M) is added, and then reacted at room temperature overnight. It is directly spun dry to give 1.6 g of a white solid T54-6.

[0164] (6) Synthesis of compound T54 Compound T54-6 (1.6 mg, 4 mmol, 1.0 eq), triethylamine (1.2 g, 12 mmol, 3.0 eq), DCM (12 mL) are added to a reaction flask, then a solution of acryloyl chloride (397.3 mg, 4.4 mmol, 1.1 eq) in DCM (6 mL) is added dropwise at 0 °C, and stirred at room temperature overnight. The solution is washed with 0.1 N HCl, then extracted with EA, and then purified by column chromatography using petroleum ether and EA to obtain 452 mg of T54 (white solid).

[0165] 1 H NMR(400MHz,Chloroform-d)δ 8.32(d,J=2.2Hz,1H),7.72(s,1H),7.62-7.48(m,6H),6.63(dd,J=16.8,10.6Hz,1H),6.46-6.26(m,2H),5.74(dd,J=10.5,1.9Hz,1H ),4.92(d,J=13.4Hz,1H),4.24-4.16(m,1H),3.96(s,3H),3.24(t,J=12.8Hz,1H),2.95-2.73(m,2H),2.07-1.98(m,2H),1.73(s,2H).

[0166] The following compounds are synthesized with reference to the synthesis methods of Examples 10 and 14. [ka] [ka] [ka] [ka] [ka] [ka]

[0167] Example 11 Compounds synthesized according to the present invention: [ka]

[0168] The synthetic route is as follows: [ka]

[0169] The experimental process is as follows. (1) Synthesis of compound T57-2 Compound T57-1 (5 g, 21.01 mmol, 1.0 eqiv), p-trifluoroaniline (4.73 g, 21.01 mmol, 1.0 eqiv), CS2CO3 (13.66 g, 42.02 mmol, 2.0 eqiv), Pd(OAc)2 (235.85 mg, 1.05 mmol, 5% eqiv), Xantphos (1.22 g, 2.11 mmol, 10% eqiv), and ultra-dry dioxane (50 mL) were added to a 100 mL three-neck flask, and the mixture was evacuated and replaced with nitrogen gas. The mixture was then heated to 105 °C and reacted for 16 hours.

[0170] After the reaction is completed, it is cooled to room temperature, 200mL of water is added, extracted with ethyl acetate, the organic layer is washed with saturated saline, dried with anhydrous sodium sulfate, concentrated to obtain the crude product, which is purified by column chromatography using PE100%, PE:EA=500:1 to obtain 910mg of product T57-2 (white solid).

[0171] (2) Synthesis of compound T57-3 Compound T57-2 (800 g, 2.52 mmol, 1.0 eqiv), S2 (499 mg, 2.52 mmol, 1.0 eqiv), CS2CO3 (1.6 g, 5.04 mmol, 2.0 eqiv), Pd(OAc)2 (28.3 mg, 0.126 mmol, 5% eqiv), Xantphos (146 mg, 0.252 mmol, 10% eqiv), and ultra-dry dioxane (10 mL) were added to a 100 mL three-neck flask, and the mixture was evacuated and replaced with nitrogen gas. The mixture was then heated to 105°C and reacted for 16 hours. After three nitrogen gas replacements, place in an oil bath, heat to 105°C, and react for 16 hours. After the reaction is completed, cool to room temperature, add 20mL of water, extract with ethyl acetate (25mL x 3), combine the organic layers, wash with saturated saline (25mL), dry with anhydrous sodium sulfate, suction filter the filtrate, spin dry, and pass through a column to obtain 721mg of product T57-3 (white solid).

[0172] (3) Synthesis of compound T57-4 Compound T57-3 (500 mg) is added to MeOH (5 mL), fluoroboric acid (5 mL, 50%) is added, and then reacted at room temperature for 3 h. Extract with aqueous sodium bicarbonate and EA three times, wash with saturated NaCl once, dry with anhydrous Na2SO4, filter, and spin dry to obtain 457 mg of product T57-4.

[0173] (4) Synthesis of compound T57 Compound T57-4 (450 mg, 1.34 mmol, 1.0 eq), triethylamine (406.02 mg, 4.02 mmol, 3.0 eq), DCM (4 mL) are added to the reaction flask, then a solution of acryloyl chloride (133.7 mg, 1.47 mmol, 1.1 eq) in DCM (2 mL) is added dropwise at 0 °C, and stirred at room temperature overnight. The solution is washed with 0.1 N HCl, then extracted with EA, and then purified by column chromatography using petroleum ether and EA to obtain 135 mg of T57 (yellow solid).

[0174] 1H NMR(400MHz,DMSO-d6)δ 8.53(s,1H),7.77-7.69(m,3H),7.66(d,J=2.9Hz,1H),7.58(d,J=8.6Hz,2H),6.30(dd,J=17.0,10.3Hz, 1H),6.09(dd,J=17.0,2.3Hz,1H),5.67(dd,J=10.3,2.3Hz,1H),4.39(s,2H),4.23(s,4H),4.11(s,2H).

[0175] Example 12 Compounds synthesized according to the present invention: [ka]

[0176] The synthetic route is as follows: [ka]

[0177] The experimental process is as follows. (1) Synthesis of T58-2 Add T58-1 (5g, 21.01mmol, 1.0eq), p-trifluorophenol (3.4g, 21.01mmol, 1eq), CS2CO3 (10.24g, 42.02mmol, 2eq), xantphos (1.22mg, 2.1mmol, 10%eq), Pd3(dba)2 (962.3mg, 1.05mmol, 5%eqiv), and 50mL of ultra-dry 1,4 dioxane to the reaction flask in that order. After replacing with nitrogen gas three times, place in an oil bath, heat to 105℃, and react for 16 hours.

[0178] After the reaction is completed, it is cooled to room temperature, filtered through diatomaceous earth, 100mL of water is added, extracted with ethyl acetate, the organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated to obtain the crude product, which is purified by column chromatography using PE100%, PE:EA=500:1 to obtain 4g of T58-2 (white solid).

[0179] (2) Synthesis of T58-3 In a 100 mL one-neck flask, add T58-2 (2 g, 6.27 mmol, 1.0 eq), pinacol borate (2.91 g, 9.41 mmol, 1.5 eqiv), potassium carbonate (1.73 g, 12.54 mmol, 2.0 eqiv), water / 1,4-dioxane (1 / 10) (2 mL / 20 mL), and Pd(dppf)Cl2 (229.2 mg, 0.31 mmol, 5% eq) in sequence, and nitrogenate three times. After nitrogen gas replacement, place in an oil bath, heat to 105°C, and react for 16 hours. After the reaction is completed, cool to room temperature, dilute EA with diatomaceous earth, filter, add 300 mL of water, and extract with ethyl acetate (30 mL x 3). Combine the organic layers, wash with saturated saline (30 mL), and dry over anhydrous sodium sulfate. Suction filter the filtrate, spin-dry, and pass through a column to obtain 2.01 g of T58-3 (light yellow solid).

[0180] (3) Synthesis of T58-4 Dissolve T58-3 (500 mg) in ethanol (8 mL), add Pd / (OH)2 (50 mg, 10%), react for 5 hours under hydrogen gas environment until the raw material disappears, filter directly, and spin-dry to obtain 490 mg of crude product T58-4 (white solid).

[0181] (4) Synthesis of compound T58-5 Compound T58-4 (490 mg) is added to DCM (6 mL), HCl / dioxane (6 mL, 4 M) is added, and then reacted at room temperature overnight. It is directly spun dry to give 470 mg of a grey solid T58-5.

[0182] (7) Synthesis of compound T58 Compound T58-5 (470 mg, 1.45 mmol, 1.0 eq), triethylamine (439.4 mg, 4.35 umol, 3.0 eq), DCM (5 mL) are added to the reaction tube, then acryloyl chloride (144.4 mg, 1.6 mmol, 1.1 eq) in DCM solution (2 mL) is added dropwise at 0 ° C. and stirred at room temperature overnight. The solution is washed with 0.1 N HCl, then extracted with EA, then separated and purified on a large plate to obtain 210 mg of T58 (white solid).

[0183] 1 H NMR (400MHz, Chloroform-d) δ 8.24(d,J=2.6Hz,1H),7.94(d,J=2.6Hz,1H),7.70(d,J=8.6Hz,2H),7.24(s,2H ),6.63(dd,J=16.9,10.6Hz,1H),6.29(dd,J=16.9,1.9Hz,1H),5.70(dd,J=10. 6,1.9Hz,1H),4.82(d,J=13.4Hz,1H),4.18(d,J=13.8Hz,1H),3.45(td,J=10.7 ,5.4Hz,1H),3.26(t,J=12.7Hz,1H),2.85(t,J=12.9Hz,1H),2.11-1.83(m,4H).

[0184] Example 13 Compounds synthesized according to the present invention: [ka]

[0185] The synthetic route is as follows: [ka]

[0186] The experimental process is as follows. (1) Synthesis of T59-2 Add T59-1 (2 g, 8.51 mmol, 1.0 eq), p-trifluorophenol (2.06 g, 12.77 mmol, 1.5 eq), CS2CO3 (6.9 g, 21.28 mmol, 2.5 eq), and 20 mL of DMF to the reaction flask in that order. After replacing with nitrogen gas three times, place in an oil bath, heat to 80°C, and react for 16 hours.

[0187] After the reaction is completed, it is cooled to room temperature, filtered through diatomaceous earth, 100mL of water is added, extracted with ethyl acetate, the organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which is purified by column chromatography using pure PE to obtain 1.34g of T59-2 (white solid).

[0188] (2) Synthesis of T59-3 In a 100 mL one-neck flask, add T59-2 (1.34 g, 4.21 mmol, 1.0 eq), pinacol borate (1.56 g, 5.05 mmol, 1.2 eqiv), potassium carbonate (1.16 g, 8.42 mol, 2.0 eqiv), water / 1,4-dioxane (1 / 10) (1.5 mL / 15 mL), and Pd(dppf)Cl2 (153.88 mg, 0.21 mol, 5% eq) in that order. After nitrogen gas replacement, place in an oil bath, heat to 105°C, and react for 16 hours. After the reaction is completed, cool to room temperature, dilute EA with diatomaceous earth, filter, add 10 mL of water, and extract with ethyl acetate (15 mL x 3). Combine the organic layers, wash with saturated saline (20 mL), and dry over anhydrous sodium sulfate. Suction filter the filtrate, spin-dry, and pass through a column to obtain 1.73 g of T59-3 (light yellow solid).

[0189] (3) Synthesis of T59-4 Dissolve T59-3 (1.73 g) in ethanol (20 mL), add palladium hydroxide (173 mg, 10%), react for 12 hours under normal pressure and room temperature hydrogen gas conditions until the raw material is completely dissolved, and pass through a column to obtain 1.3 mg of T59-4 (white solid).

[0190] (4) Synthesis of compound T59-5 Compound T59-4 (400 mg) is added to DCM (5 mL), HCl / dioxane (15 mL, 4 M) is added, and then reacted at room temperature overnight. It is directly spun dry to give 358 mg of a white solid T59-5.

[0191] (5) Synthesis of compound T59 Compound T59-5 (300 mg, 0.932 mmol, 1.0 eq), triethylamine (282.3 mg, 2.795 mol, 3.0 eq), DCM (3 mL) are added to the reaction tube, then a DCM solution (1 mL) of acryloyl chloride (92.8 mg, 1.03 mol, 1.1 eq) is added dropwise at 0 ° C. and stirred at room temperature overnight. The solution is washed with 0.1 N HCl, then extracted with EA, then separated and purified on a large plate to obtain 110 mg of T59 (white solid).

[0192] 1 H NMR(400MHz,Chloroform-d)δ 8.04(dd,J=4.8,1.8Hz,1H),7.66(d,J=8.6Hz,2H),7.57(dd,J=7.5,1.9Hz,1H),7.20(d,J=8 .4Hz,2H),7.05(dd,J=7.5,4.9Hz,1H),6.63(dd,J=16.8,10.6Hz,1H),6.31(dd,J=16.8,1.9H z,1H),5.71(dd,J=10.6,1.9Hz,1H),4.88(d,J=13.4Hz,1H),4.15(d,J=13.7Hz,1H),3.24(tt ,J=12.2,3.8Hz,2H),2.76(t,J=12.8Hz,1H),2.02(t,J=12.3Hz,2H),1.72(d,J=12.1Hz,2H).

[0193] The following compounds are synthesized by referring to the synthesis method of Example 13. [ka]

[0194] Example 14 Compounds synthesized according to the present invention: [ka]

[0195] The synthetic route is as follows: [ka]

[0196] The experimental process is as follows. (1) Synthesis of T60-2 In a microwave tube, add T60-1 (25 g, 93.28 mmol, 1.0 eq), p-trifluoroaniline (15.02 g, 93.28 mmol, 1 eq), CS2CO3 (60.6 g, 186.56 mmol, 2 eq), Xantphos (5.39 g, 9.328 mmol, 10% eq), Pd(OAc)2 (1.044 g, 4.66 mmol, 5% eqiv), and 250 mL of ultra-dry 1,4 dioxane in sequence, react at 150 °C for 1 h under microwave until the reaction is complete, cool to room temperature, add 40 mL of water, extract with ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, concentrate to obtain the crude product, and purify by column chromatography to obtain 17.76 g of T60-2.

[0197] (2) Synthesis of T60-3 In a 500 mL one-neck flask, add T60-2 (17.76 g, 45.08 mmol, 1.0 eq), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (22.6 g, 67.62 mmol, 1.5 eq), potassium carbonate (13.5 g, 90.16 mmol, 2.0 eq), water / 1,4-dioxane (1 / 10) (17.8 / 178 mL), and Pd(dppf)Cl2 (3.3 g, 4.508 mmol, 10% eq) in that order, replace with nitrogen gas three times, and react in an oil bath at 105 °C for 16 hours. After the reaction is completed, the reaction solution is cooled to room temperature, EA is diluted with diatomaceous earth, filtered, water is added, and extracted with ethyl acetate. The organic layers are combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which is purified by column chromatography to obtain 15.5 g of T60-3.

[0198] (3) Synthesis of T60-4 Dissolve T60-3 (15.5g, 32.97mmol, 1.0eq) in ethanol (250mL), add triphenylphosphine rhodium oxide (2.3g, 15%), react in a hydrogenation vessel under 1.0mpa hydrogen gas environment at 60℃ for 48 hours until the raw material is completely reacted, filtered, concentrated, and subjected to column chromatography to obtain 12.37g of product compound T60-4.

[0199] (4) Synthesis of compound T60-5 Compound T60-4 (3.7 g, 8.17 mmol, 1 eq), pinacol diborate (5.2 g, 20.47 mmol, 2.5 eq), tricyclohexylphosphine (457 mg, 1.634 mmol, 0.2 eq), palladium acetate (183 mg, 0.817 mmol, 0.1 eq), and cesium fluoride (5.59 g, 36.77 mmol, 4.5 eq) are added to ultra-dry 1,4 dioxane (37 mL) and reacted at 105 °C for 3.5 h, shown by LCMS to be mostly product and reaction complete, filtered through diatomaceous earth, and concentrated to dryness to give 5.5 g of crude product, a tan solid, T60-5.

[0200] (5) Synthesis of compound T60-6 Compound T60-5 (253 mg, 0.543 mol, 2.5 eq), 5-bromo-1-methylpyrazole (32 mg, 0.217 mmol, 1.0 eq), sodium bicarbonate (82.1 mg, 0.977 mmol, 4.5 eq), tricyclohexylphosphine (12.2 mg, 0.0434 mmol, 0.2 eq), palladium acetate (4.9 mg, 0.0217 mmol, 0.1 eq) are added to 1,4 dioxane / ethanol / water = 7:2:1 (2 mL), heated to 105 ° C. and reacted for 16 hours, after the reaction is completed, filtered through diatomaceous earth, extracted with EA, the organic phase is concentrated, and subjected to column chromatography to obtain 70 mg of T60-6.

[0201] (6) Synthesis of compound T60-7 Compound T60-6 (70 mg) was added to dichloromethane (1 mL), HCl / dioxane (2 mL, 4 M) was added, and then reacted at room temperature overnight, followed by direct spin drying to obtain 76 mg of crude solid T60-7.

[0202] (7) Synthesis of compound T60 Compound T60-7 (76 mg, 0.25 mmol, 1.0 eq), triethylamine (76 mg, 0.75 mmol, 3.0 eq), DCM (1 mL) are added to the reaction tube, then a DCM solution (1 mL) of acryloyl chloride (25 mg, 0.275 mmol, 1.1 eq) is added dropwise at 0 °C, and the mixture is stirred at room temperature overnight. Extraction with water and EA is performed, followed by separation and purification on a large plate to obtain 5 mg of T60 (white solid).

[0203] 1 H NMR(400MHz,Chloroform-d)δ 8.24(s,1H),7.61(d,J=14.6Hz,3H),7.53(s,1H),7.46(s,1H),6.69-6.48(m,2H),6.32(d,J=19.7Hz,2H),5.74(d,J=10 .6Hz,1H),4.93(s,1H),4.22(s,1H),3.89(s,3H),3.27(s,1H),2.83(s,2H),2.06(d,J=13.2Hz,2H),1.77-1.66(m,2H). LC-MS[M+1]: 456.5

[0204] The following compounds are synthesized with reference to the synthesis method of Example 14. [ka]

[0205] Example 15 Compounds synthesized according to the present invention: [ka]

[0206] The synthetic route is as follows: [ka]

[0207] The experimental process is as follows. (1) Synthesis of T63-2 Add T63-1 (1.0 g, 3.154 mmol, 1.0 eq), CS2CO3 (2.56 g, 7.87 mmol, 2.5 eq), CH3I (660 mg, 4.68 mmol, 1.5 eq), and 50 mL of DMF in order to a microwave tube and react at room temperature for 4 hours. After the reaction is completed, 10 mL of water is added, and the mixture is extracted with 50 ml of ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain 1.38 g of crude oily product T63-2 with a content of about 70%.

[0208] (2) Synthesis of T63-3 In a 100 mL one-neck flask, add T63-2 (1.38 g, 2.91 mmol, 1.0 eq), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (1.12 g, 3.62 mmol, 1.2 eq), potassium carbonate (820 mg, 5.8 mmol, 2.0 eqiv), water / 1,4-dioxane (1 / 10) (1.0 mL / 10 mL), Pd(dppf)Cl2 (110 mg, 0.15 mmol, 5% eq) was added in sequence, and the mixture was purged with nitrogen gas three times before being placed in an oil bath, heated to 105°C, and reacted for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and then diluted with EA from diatomaceous earth, filtered, 10 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with saturated saline (25 mL), dried over anhydrous sodium sulfate, and the filtrate was suction filtered, spin-dried, and subjected to column chromatography to obtain 1.2 g of T63-3 (oil).

[0209] (3) Synthesis of T63-4 Dissolve T63-3 (650 mg, 1.50 mmol, 1.0 eq) in ethanol (10 mL), add Pd(OH)2 (65 mg, 10%), react in a 50 mL one-neck flask under hydrogen gas environment at room temperature for 20 h until the raw material is completely completed, filter and concentrate to obtain product compound T63-4, 620 g.

[0210] (5)Synthesis of T63-5 Add T63-4 (620 mg) to DCM (20 mL), add HCl / dioxane (20 mL, 4 M), and then react at room temperature overnight. Directly spin dry to give 520 g of white solid T63-5.

[0211] (6) Synthesis of compound T63 Add T63-5 (520 mg, 1.55 mmol, 1.0 eq), triethylamine (471 mg, 4.66 mmol, 3.0 eq), DCM (5 mL) to the reaction tube, then add dropwise acryloyl chloride (148 mg, 1.36 mmol, 1.05 eq) in DCM (5 mL) at 0 °C under ice bath, and stir at room temperature overnight. Extract with water and EA, then separate and purify by column chromatography to obtain 100 mg of T63 (white solid).

[0212] 1 H NMR(400MHz,Chloroform-d)δ 8.45(dd,J=4.7,1.9Hz,1H),7.66(dd,J=7.8,1.9Hz,1H),7.43(dd,J=7.9,1.4Hz, 2H),7.31-7.23(m,2H),6.68-6.50(m,3H),6.29(dd,J=16.8,1.9Hz,1H),5.69(dd ,J=10.5,1.9Hz,1H),4.79(d,J=13.4Hz,1H),4.06(d,J=13.7Hz,1H),3.35(s,3H) ,3.06-2.85(m,2H),2.55(t,J=12.9Hz,1H),1.82-1.71(m,2H),1.69-1.50(m,2H).

[0213] Example 16 Compounds synthesized according to the present invention: [ka]

[0214] The synthetic route is as follows: [ka]

[0215] The experimental process is as follows. (1) Synthesis of T64-2 In a 100 mL one-neck flask, add T64-1 (1.0 g, 3.17 mmol, 1.0 eq), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (1.17 g, 3.84 mmol, 1.2 eq), potassium carbonate (876 mg, 6.34 mmol, 2.0 eq), water / 1,4-dioxane (1 / 10) (1.0 mL / 10 mL), Pd(dppf)Cl2 (110 mg, 0.15 mmol, 5 %eq) was added in sequence, and the mixture was purged with nitrogen gas three times before being placed in an oil bath, heated to 105°C, and reacted for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and then diluted with EA from diatomaceous earth, filtered, 10 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with saturated saline (25 mL), dried over anhydrous sodium sulfate, and the filtrate was suction filtered, spin-dried, and subjected to column chromatography to obtain 744 g of T64-2.

[0216] (2) T64-3 synthesis Dissolve T64-2 (400 mg, 0.95 mmol, 1.0 eq) in ethanol (10 mL), add Pd(OH)2 (40 mg, 10%), react in a 50 mL one-neck flask under hydrogen gas environment at room temperature for 20 h until the raw material is completely completed, filter, and concentrate to obtain 410 mg of product compound T64-3.

[0217] (3)T64-4 synthesis Add T64-3 (410 mg) to DCM (20 mL), add HCl / dioxane (20 mL, 4 M), and react overnight at room temperature. Directly spin dry to give 320 mg of T64-4.

[0218] (4) Synthesis of compound T64 Add T64-4 (130, 0.402 mmol, 1.0 eq), triethylamine (123 mg, 1.2 mmol, 3.0 eq), DCM (1 mL) to the reaction tube, then add dropwise chloropropionyl chloride (51 mg, 0.40 mmol, 1.0 eq) in DCM (1 mL) at 0 °C under ice bath, and stir at room temperature overnight. Extract with water and DCM, then separate and purify by column chromatography to obtain 50 mg of T64 (white solid).

[0219] 1 H NMR (400MHz, Chloroform-d) δ 7.35(d,J=8.4Hz,2H),7.23-7.20(m,1H),7.19-7.14(m,3H),6.68(d,J=8.4Hz, 2H),6.53(dd,J=16.8,10.6Hz,1H),6.22(dd,J=16.9,1.9Hz,1H),5.62(dd,J=10 .6,2.0Hz,1H),5.54(s,1H),4.79-4.70(m,1H),4.02(d,J=13.7Hz,1H),3.10-2 .92(m,2H),2.63-2.52(m,1H),1.75(dd,J=13.3,3.4Hz,2H),1.57-1.51(m,1H).

[0220] Example 17 Compounds synthesized according to the present invention: [ka]

[0221] The synthetic route is as follows: [ka]

[0222] The experimental process is as follows. (1) Synthesis of T65-2 In a reaction flask, add T65-1 (1.5g, 5.2mmol, 1.0eq), p-trifluoroaniline (855g, 5.2mmol, 1eq), CS2CO3 (720mg, 10.4mmol, 2eq), xantphos (300g, 0.52mmol, 10%eq), Pd(OAc)2 (60g, 0.26mmol, 5%eqiv), and ultra-dried 1,4 dioxane 15mL in sequence, and after three times of nitrogen gas replacement, place in an oil bath pot, heat to 105 ° C and react for 16 hours. After the reaction is completed, cool to room temperature, dilute EA with diatomaceous earth, filter, add 20mL of water, extract with ethyl acetate (30mL × 3), combine the organic layers, wash with saturated saline (25mL), dry with anhydrous sodium sulfate, suction filter the filtrate, spin dry, and subject to column chromatography to obtain 1.6g of T65-2.

[0223] (2) Synthesis of T65-3 In a 100 mL one-neck flask, add T65-2 (1.46 g, 3.97 mmol, 1.0 eq), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (1.47 g, 3.97 mmol, 1.2 eq), potassium carbonate (1.1 g, 7.94 mmol, 2.0 eq), water / 1,4-dioxane (1 / 10) (1.4 mL / 14 mL), Pd(dppf)Cl2 (146 mg, 0.2 mmol, 5 %eq) was added in sequence, and the mixture was replaced with nitrogen gas three times before being placed in an oil bath, heated to 105°C, and reacted for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and then diluted with EA from diatomaceous earth, filtered, 10 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with saturated saline (25 mL), dried over anhydrous sodium sulfate, and the filtrate was suction filtered, spin-dried, and subjected to column chromatography to obtain 1.3 g of T65-3.

[0224] (3)T65-4 synthesis Dissolve T65-3 (1.2 g, 2.55 mmol, 1.0 eq) in ethanol (10 mL), add Pd(OH)2 (120 mg, 10%), react in a 50 mL one-neck flask under hydrogen gas environment at room temperature for 20 h until the raw material is completely reacted, filtered, concentrated to obtain product compound T65-4, 1.03 g.

[0225] (4)T65-5 synthesis Add T65-4 (1.03 mg) to DCM (20 mL), add HCl / dioxane (20 mL, 4 M), and then react at room temperature overnight. Directly spin dry to give 800 mg of T65-5.

[0226] (5) Synthesis of compound T65 Add T65-5 (200 mg, 0.539 mmol, 1.0 eq), triethylamine (163 mg, 1.617 mmol, 3.0 eq), DCM (1 mL) to the reaction tube, then add chloropropionyl chloride (72 mg, 0.566 mmol, 1.05 eq) in DCM (1 mL) dropwise at 0 °C under ice bath, and stir at room temperature overnight. Extract with water and DCM, then separate and purify by column chromatography to obtain 40 mg of T65 (white solid).

[0227] 1 H NMR(400MHz,Chloroform-d)δ 7.90-7.69(m,4H),7.56(td,J=12.3,10.4,7.5Hz,4H),7.29(t,J=7.5Hz,1H),6.74-6.50(m,2H),6.27(dd,J=16.8,2.0Hz,1H),5.68( dd,J=10.5,2.0Hz,1H),4.89(d,J=13.0Hz,1H),4.18(d,J=13.3Hz,1H),3.24(s,1H),2.85(d,J=13.4Hz,2H),2.06(d,J=13.4Hz,2H).

[0228] Example 18 Compounds synthesized according to the present invention: [ka]

[0229] Synthesis Route: [ka]

[0230] The experimental process is as follows. Synthesis of T83-3 Compound T83-1 (4g, 1.0eq), T83-2 (8.28g, 1.5eq), CS2CO3 (16g, 2.0eq), Xantphos (1.4g, 0.10eq) are dissolved in dioxane (40mL), and after N2 replacement, the temperature is raised to 80 ° C., Pd (OAc)2 (275.3mg, 0.05eq) is added, the temperature is raised to 105 ° C., and the mixture is stirred overnight while heating, and the next day, sample feeding is performed, LCMS is accurate, TLC: OK. Work-up: Extract with water and EA, spin dry, mix the sample, and then perform column chromatography to obtain T83-3 (3.98g).

[0231] Synthesis of T83-4 Compound T83-3 (3.98 g, 1.0 eq) and NBS (4.6 g, 2.0 eq) were dissolved in CH3CN (40 mL), and after N2 replacement, the temperature was raised to 90 ° C., and the mixture was stirred overnight while heating. The next day, the sample was fed, and the LCMS was accurate, and TLC: OK. Work-up: Extracted by adding water and EA, spin-dried, and the sample was mixed and then subjected to column chromatography to obtain T83-4 (972 mg), and the LCMS was accurate.

[0232] Synthesis of T83-5 T83-4 (1 g, 1.0 eq), pinacol diborate (1.24 g, 1.5 eq), K2CO3 (737 mg, 2.0 eq), Pd(dppf)Cl2 (196 mg, 0.1 eq) are dissolved in dioxane (10 mL) and H2O (1 mL), purged with N2, heated to 105 °C and reacted overnight, showing mostly product by LCMS. Workup: Dilute with EA, filter through diatomaceous earth, concentrate the filtrate to dryness, spin dry, mix the samples and then subject to column chromatography to give T83-5 (1.05 g).

[0233] Synthesis of T83-6 Dissolve T83-5 (1.15 g) in ethanol (19 mL), add Pd(OH)2 (115 mg, 0.1 eq), replace H2, heat to 60 °C under atmospheric pressure of about 1 MPa, react overnight, show mostly product by LCMS, TLC: OK. Work-up: filter through diatomaceous earth, concentrate the filtrate to dryness, spin-dry, mix the sample and then perform column chromatography to obtain product T83-6 (1.2 g).

[0234] Synthesis of T83-7 Dissolve T83-6 (1.2g) in dichloromethane (6mL) and 1,4-dioxane hydrochloride (12ml), replace N2, react at room temperature for about 2 hours, LCMS shows mostly product, TLC: OK. Workup: spin dry, add ethanol and spin dry, repeat 3 times to obtain product crude T83-7 (1.2g), LCMS is accurate.

[0235] Synthesis of T83 Dissolve T83-7 (300 mg, 1.0 eq) in dichloromethane solution (2 mL), add TEA (258 mg, 3.0 eq) under ice bath condition, slowly add a mixed solution containing acryloyl chloride (84.4 mg, 1.1 eq) and dichloromethane (1 mL) under N2 protection, then return to room temperature and react for about 4 hours, showing that most of the product is the product by LCMS. Workup: Spin dry, mix the sample, then run it through column chromatography to obtain T83 (144 mg).

[0236] 1 H NMR(400MHz,Chloroform-d)δ 8.47-8.42(m,1H),8.14(d,J=1.4Hz,1H),7.62-7.52(m,3H),6.77(s,1H),6.60(dd, J=16.8,10.5Hz,1H),6.31(dd,J=16.8,1.9Hz,1H),5.72(dd,J=10.6,1.9Hz,1H),4.8 6(d,J=13.5Hz,1H),4.15(d,J=14.0Hz,1H),3.15(t,J=13.0Hz,1H),3.06(tt,J=12.0 ,3.6Hz,1H),2.69(t,J=12.7Hz,1H),1.88(d,J=13.1Hz,2H),1.72(t,J=12.2Hz,2H).

[0237] Bioactivity Test Experiment Experimental example 1. Cell proliferation inhibition experiment Growth inhibition assay of YAP-TEAD inhibitor compounds against human pleural mesothelioma cells NCI-H226 Experimental materials and equipment: Human pleural mesothelioma cells NCI-H226 are purchased from Nanjing COBIOER BIOSCIENCES CO.,LTD. RPMI-1640 medium (Biochannel), DMSO (dimethyl sulfoxide), CCK8 (WST-8) cell analysis kit (Beyotime), 0.25% EDTA-trypsin (Tripsin digestion solution), 1xPBS (phosphate buffer, PH7.2), 96-well plate (Corning), fetal bovine serum (FBS), 10000U / mL penicillin-G / streptomycin, high-speed refrigerated centrifuge (EPPENDORF 5810R), enzyme-linked immunosorbent assay detector (Tecan Spark).

[0238] Experimental preparation: 1. Cell Plating A) Tumor cells are cultured in RPMI-1640 (containing 10% FBS and 100 U / mL penicillin-G / streptomycin) under 37 °C, 5% CO2 and saturated humidity conditions to 80-90% confluency. B) Remove the medium from the 10 cm culture dish. C) Rinse the cells once with 10 mL of 1xPBS. D) Add 4 mL of 0.25% EDTA-trypsin, place in a 37°C, 5% CO2 incubator for trypsin digestion for 5 minutes, transfer to a 15 mL centrifuge tube, and centrifuge at 200 g for 5 minutes. Discard the supernatant to obtain a cell pellet. E) Resuspend in 4 mL of DMEM medium, count and adjust to 10,000 cells / ml. F) The cell suspension is added to a 96-well plate at a volume of 100 μL per well and incubated overnight in a 37° C., 5% CO2 incubator.

[0239] 2. Compound Treatment Compound dilution A) Preparation of gradient dilution solutions of test compounds: Test compounds are prepared to 1 mM stock solutions. Then, 1.5 μl of the stock solution is dissolved in 1.5 ml of DMSO-free culture medium, and diluted 3-fold with 0.1% DMSO culture medium, resulting in a total of nine concentrations. The compound concentrations after dilution are as follows: 333.33nM, 111.11nM, 37.03nM, 12.35nM, 4.15nM, 1.37nM, 0.46nM, 0.15nM B) After thoroughly mixing, 100 μL of each compound solution was taken and used to replace the culture medium in the cell culture plate. Four duplicate wells were prepared for each concentration. C) The cells are transferred to an incubator and incubated for 3 days.

[0240] 3. Analysis and detection of CCK8 (WST-8) cells A) Take out the cell culture plate and add 10 μl of CCK-8 (WST-8) solution to each well in a biosafety cabinet. B) Place the cell culture plate back into the incubator and continue to incubate for 3 hours. C) To measure absorbance values ​​with a TECAN enzyme-linked immunosorbent assay detector, select a wavelength of 450 nm.

[0241] 4. Data Analysis Calculate % Cell Viability using the following formula: Cell viability (%) = [A (drug addition) - A (blank)] / [A (0 drug addition) - A (blank)] x 100 A (drug addition): absorbance of wells with cells, CCK8 solution and drug solution A (blank): absorbance of wells with medium and CCK8 solution but no cells A (0 addition of drug): Absorbance of wells with cells and CCK8 solution but no drug solution Cell viability: Cell proliferation viability or cytotoxicity viability was calculated by curve fitting using GraphPad Prism 8 software to obtain IC 50 Get a numerical value.

[0242] Experimental Example 2. Nanoluciferase method to detect YAP-TEAD inhibitor activity (1) Experimental materials and equipment: 293T cells are purchased from Nanjing COBIOER BIOSCIENCES CO., LTD. DMEM medium (high sugar, no phenol red, Bio-Channel), DMSO (dimethyl sulfoxide), Lipo6000™ transfection reagent (Beyotime), pGL3B-8xGTiiC-nLuc-CMV-fLuc plasmid, 0.25% EDTA-trypsin (Tripsin digestion solution), 1xPBS (phosphate buffer, PH7.2), 96-well leukocyte culture plate (PerkinElmer), fetal bovine serum (FBS), 10000U / mL penicillin-G / streptomycin, high-speed refrigerated centrifuge (EPPENDORF 5810R), 37°C, CO2 incubator, Vi-Cell R cell counter, Envision microplate reader (PerkinElmer).

[0243] reagent Reagent Catalog Number Concentration Nano Luciferase Detection Reagent MES pH6.0 69892-25G 100mM CDTA CAS:125572-95-4 1mM Tergitol NP10-100ML 0.5% (v / v) Mazu DF 204 A8311-50ML 0.05%(v / v) KCl CAS:7447-40-7 150mM DTT Roche 10197777001 1mM Thiourea T8656-50G 35mM Furimazine 1374040-24-0 20μM added before use

[0244] (2) Transient transfection of 293T cells Seed the recovered 293T cells into a 10 cm culture dish and place it in a 5% CO incubator at a constant temperature of 37 °C. To ensure transfection efficiency, it is necessary to use cells in the logarithmic phase (cell density is approximately 50% to 70%).

[0245] The day before transfection, digest log-phase cells with trypsin-EDTA, add medium to stop the reaction, and mix evenly with a pipette to prepare a cell suspension. Measure the cell concentration using Vi-cell and dilute to a suspension of 5 x 10^5 cells per mL. After preparing the cell suspension, mix gently to homogenize and add 10 mL of the liquid to a 10 cm culture dish. Thus, the number of cells per 10 cm culture dish is 5 x 10^6. Incubate at a constant temperature of 37°C in a 5% CO2 incubator for 1 day.

[0246] Prepare two clean sterile centrifuge tubes, add 750 μL of opti-MEM Medium without antibiotics and serum to each, then add 15 μg of plasmid (pGL3B-8xGTiiC-nLuc-CMV-fLuc) to one of the tubes and mix evenly by gently pipetting with a pipette, add Lipo6000 transfection reagent to the other tube and mix evenly by gently pipetting with a pipette. After leaving it at room temperature for 5 minutes, gently add the DNA-containing culture solution to the Lipo6000 transfection reagent-containing culture solution, gently invert the centrifuge tube to mix evenly, and leave it at room temperature for 5 minutes. The above mixture was evenly dropped onto a 10 cm culture dish, and after culturing for 6 hours, the medium was replaced with fresh complete medium.

[0247] (3) Plating on 96-well plates One day after transfection, digest the cells with trypsin-EDTA, add medium to stop the reaction, and mix evenly by pipetting to prepare a cell suspension. Measure cell concentration using Vi-cell and dilute to a suspension of 20,000 cells per ml. After preparing the cell suspension, mix it gently to make it uniform. For a 96-well plate, add 100 μL per well, and the density of the cells to be tested is 2000 / well.

[0248] (4) Addition of compounds The seeded cell culture plates are placed in an incubator for incubation and after approximately 24 hours, a gradient of compound concentrations is added. A 10 mM compound stock solution is diluted to 50 μM with medium, and the 50 μM compound solution is added sequentially to the third column of a deep well plate, followed by addition of 216 μL of 0.5% DMSO-containing medium to columns 4 to 11.

[0249] Gradient dilution: Aspirate 100 μL of solution from column 3 and add it to column 4, mix evenly, then aspirate 100 μL of solution from column 4 and add it to column 5, and repeat the process up to column 11. Using a multichannel pipette, aspirate 25 µL of compound solution from the deep well plate and add it to the 96-well culture plate, repeating each compound four times on the 96-well plate, ultimately forming a concentration gradient of 1:3.16 with a maximum concentration of 10,000 nM on the 96-well plate.

[0250] (5) Addition of nanoluciferase detection reagent and reading The 96-well plates are incubated at a constant temperature of 37° C. in a 5% CO 2 incubator for 48 hours and then removed and allowed to equilibrate at room temperature for 10 minutes. Add 100 μL of detection reagent to each well and shake at low speed on a horizontal shaker for 10 min to completely lyse the cells. Detect the fluorescence value of each well using a PerkinElmer Envision microplate reader.

[0251] (6) Calculation of results Using 0 nM as a control, values ​​for each well were converted to percentages and nonlinear fitting was performed using [Inhibitor] vs. response (three parameters) in GrahpPad prism software to obtain IC 50 Calculate.

[0252] As shown in Table 1, where A≦100 nM, 100 nM <B<1μM、5μM≧C≧1μM [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16]

[0253] [Table 2]

[0254] Experimental Example 3. Pharmacokinetic study of drugs Oral administration solvent: 5% DMSO + 10% Solutol HS15 + 85% saline Preparation process of oral dosage formulation: weigh out appropriate powder, add appropriate amount of DMSO, vortex, add appropriate amount of Solutol solution, vortex, add appropriate amount of saline, vortex and sonicate to form a homogeneous and transparent formulation solution. Prepare two samples of the clear solution, 100 μL each, and store at 2-8°C.

[0255] The animal room should be equipped with an air conditioning system and well ventilated, with the temperature kept between 20 and 26°C and the humidity kept between 40 and 70%. Artificial lighting should be used in the animal room, with 12 hours of light and 12 hours of darkness (except for experimental operations and cleaning, when task lighting must be turned on), and experimental animals should be allowed to eat and drink freely. After purchasing the animals, rats that were at least normally maintained, passed the veterinarian's examination, and had eligible physical conditions were enrolled in this experiment, and each rat was given a tail number. The animals in the oral administration group were fasted overnight from the day before administration, and resumed eating 4 hours after administration, with free access to water.

[0256] Animal grouping and dosing [Table A]

[0257] Before administration, inspect the condition of the dosage formulation and ensure the homogeneity of the formulation by vortexing, stirring or shaking, and calculate the theoretical dosage for SD rats in each group according to the following formula:

number

[0258] Sample collection information [Table B]

[0259] [Table 3]

[0260] All documents mentioned in the present invention are incorporated by reference in this application as if each document was incorporated by reference individually. Furthermore, after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalents are also included in the scope defined by the appended claims of this application.

Claims

1. A compound of formula I, or a pharma- ceutically acceptable salt, solvate or prodrug thereof, 【Chemistry 1】 Where: A is, 【Chemistry 2】 is selected from the group consisting of B is, 【Chemistry 3】 is selected from the group consisting of C is, 【Chemistry 4】 is selected from the group consisting of L is NR ４ , O, S, Se, sulfoxide, sulfone, CR ２ R ３ is selected from the group consisting of R １ teeth, 【Chemistry 5】 which is linked to N on A; R ２ are each independently H, a halogen, CN, or NH ２ , hydroxyl group, ester group, urea group, urethane group, amide group, C １－６ Alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl group, C ３－６ is selected from the group consisting of a cycloalkoxy group, an aryl group, and a heteroaryl group, ２ , ester group, urea group, urethane group, amide group, C １－６ Alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl group, C ３－６ Hydrogen in the cycloalkoxy group, aryl group, and heteroaryl group may be optionally substituted, and the substituents are H, halogen, CN, NH ２ , hydroxyl group, ester group, urea group, urethane group, amide group, C １－６ Alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl group, C ３－６ a cycloalkoxy group, an aryl group, a heteroaryl group, or R ２ R forms a 3- to 7-membered ring with the structure to which it is linked, or ２ A 3- to 7-membered ring is formed between them. R ３ are each independently H, a halogen, CN, or NH ２ , hydroxyl group, ester group, urea group, urethane group, amide group, C １－６ Alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl group, C ３－６ is selected from the group consisting of a cycloalkoxy group, an aryl group, and a heteroaryl group, ２ , ester group, urea group, urethane group, amide group, C １－６ Alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl group, C ３－６ Hydrogen in the cycloalkoxy group, aryl group, and heteroaryl group may be optionally substituted, and the substituents are H, halogen, CN, NH ２ , hydroxyl group, ester group, urea group, urethane group, amide group, C １－６ Alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl group, C ３－６ R is a cycloalkoxy group, an aryl group, a heteroaryl group, or a different ３ Between them, together with the linked B, they form a 5- to 7-membered ring; R ４ is H, an ester group, -C(O)R ５ , urea group, C １－６ Alkyl group, C １－６ Alkoxy group, C ３－６ is selected from the group consisting of a cycloalkyl group, an aryl group, and a heteroaryl group, wherein an ester group, a urea group, C １－６ Alkyl group, C ３－６ Hydrogen in the cycloalkyl group, aryl group, and heteroaryl group may be optionally substituted, and the substituents are H, halogen, CN, NH ２ , hydroxyl group, ester group, urea group, urethane group, amide group, C １－６ Alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl group, C ３－６ a cycloalkoxy group, an aryl group, or a heteroaryl group; R ５ is H, C １－６ Alkyl group, C ３－６ is selected from the group consisting of a cycloalkyl group, an aryl group, and a heteroaryl group; The compound represented by formula I, or a pharma- ceutically acceptable salt, solvate or prodrug thereof, wherein m and n are each independently selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6.

2. m is selected from the group consisting of 0, 1, 2, and 3.

2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate or prodrug thereof.

3. n is selected from the group consisting of 0, 1, 2, and 3.

2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate or prodrug thereof.

4. A is, 【Chemistry 6】 is selected from the group consisting of R ２ , m are as defined in claim 1 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate or prodrug thereof.

5. B is, 【Chemistry 7】 is selected from the group consisting of R ３ , n is as defined in claim 1.

2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate or prodrug thereof.

6. The compound is as follows: 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 The compound is selected from the group consisting of 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate or prodrug thereof.

7. 1. A pharmaceutical composition comprising: a pharma- ceutically acceptable carrier, and A safe and effective amount of one or more compounds according to claim 1, or a pharma- ceutically acceptable salt, solvate or prodrug thereof. The pharmaceutical composition comprising:

8. Use of the pharmaceutical composition according to claim 7, Use of the pharmaceutical composition according to claim 7 for the preparation of a medicament, said medicament being used for the prevention and / or treatment of a proliferative disease.

9. Use of the pharmaceutical composition according to claim 7, for use in the preparation of a drug, said drug comprising: 1) Prevention and / or treatment of associated diseases caused by abnormal activity of YAP / TEAD; 2) Prevention and / or treatment of associated diseases caused by dysregulation of the Hippo pathway; 3) Use of the pharmaceutical composition according to claim 7 for a purpose selected from the group consisting of prevention and / or treatment of associated diseases caused by dysregulation of YAP or TAZ or YAP / TAZ or YAP / TEAD or YAP / TAZ / TEAD.

10. 13. A combination of a compound of claim 1, or a pharma- ceutically acceptable salt, solvate or prodrug thereof, with a second drug, comprising: For use in the prevention and / or treatment of cancer, 2. The combination of the compound of claim 1, or a pharma- ceutically acceptable salt, solvate or prodrug thereof, with a second drug, wherein the second drug is selected from the group consisting of an ERK inhibitor, a MEK inhibitor, a KRAS inhibitor, a BRAF inhibitor, an EGFR inhibitor, a Wnt inhibitor and a PD-1 inhibitor.

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