Polycyclic compounds and their uses

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, and more specifically to polycyclic compounds used to modulate the Hippo pathway, methods for their preparation and use, and is primarily used for the treatment or prevention of proliferative disorders (e.g., cancer), in particular for the modulation and treatment of related diseases caused by 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 scaffold protein Salvador, and the large tumor inhibitor kinases LATS1-2, as well as the inhibitory transcription activators YAP (Yes1-related protein) and TAZ (a transcription activator with a PDZ-binding motif). YAP and TAZ are the main effectors of the Hippo signaling pathway, and together with the nuclear TEAD (transcription enhancement-related domain), they act as transcription factors, thereby increasing the expression of target genes such as CTGF (connective tissue growth factor) and CYR61. The Hippo pathway is a crucial regulator of cell growth, proliferation, and migration. The TEAD transcription factor is located at the core of the Hippo pathway and is critical to regulating organ growth and wound repair. Dysregulation of TEAD and its regulatory cofactor Yes-related protein (YAP) are associated with many human cancers and hyperproliferative pathological processes, and dysregulation of this pathway is frequently detected in human cancers. Similar to the TEAD protein, activation of YAP and TAZ has been identified in many human tumors and is important for tumor development, progression, and metastasis. For example, elevated YAP expression is associated with decreased survival in patients with breast, ovarian, colon, liver, and pancreatic cancers. Consistently, activation or overexpression of YAP or TAZ enhances TEAD-dependent gene expression (e.g., CCN1, CTGF, ITGB2, and Birc5 / sulbibin) and promotes cell proliferation and migration in many cell types. Conversely, blocking the signaling for YAP / TAZ-TEAD complex formation or intervening to inhibit the expression of many mitogenic TEAD target genes can significantly reduce cell proliferation and oncogenic transformation activity. Furthermore, the Hippo pathway crosstalks with other signaling pathways such as Wnt, Notch, Hedgehog, and MAPK, affecting various biological functions, and its dysfunction may be involved in many diseases in addition to cancer. Therefore, the YAP-TEAD complex is a promising therapeutic target point.

[0003] Furthermore, patent WO2009081259A1 discloses several compounds having structures similar to those of the present invention, the general formula of which is: [ka] Therefore, the inventors selected several compounds having representative structures and conducted activity tests. The results showed that all of these compounds lacked YAP / TEAD-related activity, and the detailed results are shown in Table 2. [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] The object of the present invention is to provide a compound represented by formula I, a method for preparing the same, and its use in the prevention or treatment of proliferative diseases. [Means for solving the problem]

[0005] A first aspect of the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [ka] Here, A is [ka] Selected from the group consisting of, B is [ka] Selected from the group consisting of, C is [ka] Selected from the group consisting of, L is selected from the group consisting of NR4, O, S, Se, sulfoxide, sulfone, and CR2R3. R1 is [Chemistry] selected from the group consisting of, which is linked to N on A, Each R2 is independently selected from the group consisting of H, halogen, CN, NH2, 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 cycloalkoxy group, aryl group, heteroaryl group, wherein the hydrogen in NH2, 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 cycloalkoxy group, aryl group, heteroaryl group may be optionally substituted, and the substituents are H, halogen, CN, NH2, 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 cycloalkoxy group, aryl group, 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, Each R3 is independently selected from the group consisting of H, halogen, CN, NH2, 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 cycloalkoxy group, aryl group, heteroaryl group, wherein the hydrogen in NH2, 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 cycloalkoxy group, aryl group, heteroaryl group may be optionally substituted, and the substituents are H, halogen, CN, NH2, hydroxyl group, ester group, urea group, urethane group, amide group, C1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Whether it is a cycloalkoxy group, aryl group, heteroaryl group, or different R3s, the linked B forms a 5-7 membered ring. R4 is H, ester group, -C(O)R5 is urea group, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Selected from the group consisting of cycloalkyl groups, aryl groups, and heteroaryl groups, where ester groups, urea groups, and C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 The hydrogen atoms in the cycloalkyl group, aryl group, and heteroaryl group may be optionally substituted, and the substituents may be H, halogen, CN, NH2, hydroxyl group, ester group, urea group, urethane group, amide group, or C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 These are cycloalkoxy groups, aryl groups, and heteroaryl groups. R5 is H, C 1-6 Alkyl alkyl group, C 3-6 Selected from the group consisting of cycloalkyl groups, aryl groups, and heteroaryl groups, m and n are 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 comprising 1, 2, or 3 heteroatoms selected from N, O, or S, preferably a 5- to 6-membered heteroaryl group comprising 1, 2, or 3 heteroatoms selected from N, O, or S, more preferably, [ka] It is selected from the group consisting of the following.

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

[0008] In another preferred example, 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 example, the urea group is -NH-(C=O)-NH2. In another preferred example, the urethane group is -NH-(C=O)-O-CH3.

[0009] In another preferred example, R2 can be independently H, halogen, CN, NH2, hydroxyl group, and C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Selected from the group consisting of cycloalkoxy groups, where NH2, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 The hydrogen atoms in the cycloalkoxy group may be optionally substituted, and the substituents may be H, halogen, CN, NH2, hydroxyl group, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 It is a cycloalkoxy group.

[0010] In another preferred example, R2 is independently H, halogen, and C. 1-6 Selected from the group consisting of alkyl groups, where C 1-6 The hydrogen atoms in the alkyl group may be optionally substituted, and the substituents are halogens.

[0011] In another preferred example, R3 can be independently H, halogen, CN, NH2, hydroxyl group, amide group, and C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Selected from the group consisting of cycloalkoxy groups, aryl groups, and heteroaryl groups, where NH2, amide groups, and C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 The hydrogen atoms in the cycloalkoxy group, aryl group, and heteroaryl group may be optionally substituted, and the substituents may be H, halogen, CN, NH2, hydroxyl group, amide group, or C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 These are cycloalkoxy groups, aryl groups, and heteroaryl groups.

[0012] In another preferred example, R3 can be independently H, halogen, CN, NH2, hydroxyl group, amide group, and C 1-6 Alkyl alkyl group, C 1-6 Selected from the group consisting of alkoxy groups, aryl groups, and heteroaryl groups, where NH2, amide groups, and C 1-6 Alkyl alkyl group, C 1-6 The hydrogen atoms in the alkoxy group, aryl group, and heteroaryl group may be optionally substituted, and the substituents may be H, halogen, CN, NH2, hydroxyl group, or C 1-6 Alkyl alkyl group, C 1-6 It is an alkoxy group.

[0013] In another preferred example, R4 is H, C 1-6 Selected from the group consisting of alkyl groups, where C 1-6 The hydrogen atoms in the alkyl group may be optionally substituted, and the substituents may be H, halogen, CN, NH2, hydroxyl group, C 1-6 Alkoxy group, C 3-6Cycloalkyl groups, C 3-6 It is a cycloalkoxy group. In another preferred example, m is selected from the group consisting of 0, 1, 2, and 3.

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

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

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

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

[0018] A second aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of a compound described in the first aspect of the present invention or a pharmaceutically 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 drug, the drug being used for the prevention and / or treatment of a proliferative disorder.

[0020] In another preferred example, the proliferative disorder is cancer. In another preferred example, the cancer is selected from the group consisting of glioma, prostate cancer, thoracic septal cancer, 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 the pharmaceutical composition described in the second aspect of the present invention for use in the preparation of a drug, the drug being 1) Prevention and / or treatment of related diseases caused by abnormal activity of YAP / TEAD, 2) Prevention and / or treatment of related diseases caused by dysregulation of the Hippo pathway, 3) It is used for purposes selected from the group consisting of prevention and / or treatment of related diseases caused by dysregulation of YAP or TAZ or YAP / TAZ or YAP / TEAD or YAP / TAZ / TEAD.

[0022] In another preferred example, the drug is used to prevent and / or treat related disorders caused by dysregulation of YAP / TEAD or YAP / TAZ / TEAD. In another preferred example, the associated disease caused by the aforementioned YAP / TEAD abnormal activity is cancer.

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

[0024] A fifth aspect of the present invention provides a combination of a compound described in the first aspect of the present invention or a pharmaceutically acceptable salt, solvate, or prodrug thereof with a second drug for use in the prevention and / or treatment of cancer. The second drug is selected from the group consisting of ERK inhibitors, MEK inhibitors, KRAS inhibitors, BRAF inhibitors, EGFR inhibitors, Wnt inhibitors, and PD-1 inhibitors.

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

[0026] In another preferred example, 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 example, the BRAF inhibitor is selected from the group consisting of sorafenib, regorafenib, or a combination thereof.

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

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

[0029] It should be understood that, within the scope of the present invention, new or preferred technical solutions can be constructed by combining the above-described technical features of the present invention with the technical features specifically described below (e.g., in the examples). Due to space limitations, this will not be repeated here. [Modes for carrying out the invention]

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

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

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

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

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

[0035] In the present invention, "C 3-6 The term "cyclic hydrocarbon group" is C 3-6 Cycloalkyl groups, C 3-6 Cycloalkenyl group, C 3-6 It contains a group selected from the group consisting of cycloalkynyl groups.

[0036] In the present invention, "C 3-6 The term "cycloalkyl group" refers to a cyclic alkyl group having 3 to 6 carbon atoms on the ring, and non-limitingly includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0037] In the present invention, "C 5-8 The term "crosslinked cyclic group" refers to a cyclic alkyl group having crosslinks and 5 to 8 carbon atoms, and is not limited to, [ka] Includes, etc.

[0038] In the present invention, "C 1-6 The term "alkoxy group" refers, non-limitingly, to a linear or branched alkoxy group having 1 to 6 carbon atoms, including methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups. Preferably, it is a C1-4 alkoxy group.

[0039] In the present invention, the term "heterocyclic group" is defined as follows: [ka] This refers to a 4- to 8-membered heterocyclic group containing (but not limited to) 1, 2, or 3 heteroatoms selected from N, O, and S.

[0040] In the present invention, the terms "aromatic ring" and "aryl group" have the same meaning, and preferably "C 6-10 It is an "aryl group". 6-10 The term "aryl group" refers to aromatic ring groups such as phenyl groups and naphthyl groups, which have 6 to 10 carbon atoms on the ring and do not contain heteroatoms.

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

[0042] In this invention, the term "halogenation" refers to substitution with a halogen. In this invention, the term "deuterated" refers to substitution with deuterium.

[0043] In the present invention, the term “substitution” refers to the substitution of one or more hydrogen atoms on a particular group by a particular substituent. The particular substituent is one of the substituents described correspondingly in this specification or in each example. Unless otherwise specified, the particular substituent may have substituents selected from the particular group at any substitutable site of the group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the substituent combinations envisioned by the present invention are either stable combinations or chemically achievable combinations. The substituents include, but are not limited to, halogens, hydroxyl groups, carboxyl groups (-COOH), C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3-12 membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, etc.

[0044] In this invention, the terms 1-6 refer to 1, 2, 3, 4, 5, or 6. Other similar terms are independent and have the same meaning. The term "plural" refers to 2, 3, 4, 5, or 6 of 2-6.

[0045] It should be understood that when a particular group is present simultaneously at multiple different positions in a compound, its definition at each position is independent of each other and may be the same or different. In other words, the phrase "selected from the group consisting of..." has the same meaning as "selected independently from the group consisting of...".

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

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

[0048] As used herein, the term “pharmaceutically acceptable salt” refers to a salt that is suitable as a drug when formed with an acid or base of the compound of the present invention. pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is one formed with an acid of the compound of the present invention. Acids suitable for salt formation include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; 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, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0049] Other preferred salts are salts formed with the compound of the present invention and a base, 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 alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, t-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

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

[0051] Furthermore, the compounds of the present invention further include prodrugs of compounds represented by formula I. The term "prodrug" means that it may be biologically active or inactive in itself and, after being administered in an appropriate manner, is metabolized or chemically reacted in the human body to be converted into a compound of formula I, or a salt or solution composed of a compound of formula I. The prodrug includes (but is not limited to) forms of the compound such as carboxylates, carbonates, phosphates, nitrates, sulfates, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc.

[0052] The compounds of the present invention can also be prepared by any combination of various synthesis methods described herein or known in the art, and it should be understood that such combinations can be easily performed by those skilled in the art to which the present invention pertains.

[0053] Typically, the raw materials and reagents used in the preparation process of the compounds of the present invention can be purchased through commercial channels unless otherwise specified.

[0054] Pharmaceutical composition and administration method The present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0055] Because the compounds of the present invention possess excellent antitumor activity, the compounds of the present invention and their various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds 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 comprises the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier within a safe and effective amount range. Here, “safe and effective amount” means an amount of the compound sufficient to clearly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1 to 2000 mg of the compound / agent of the present invention, more preferably 10 to 1000 mg of the compound / agent of the present invention. Preferably, “one agent” is one capsule or tablet.

[0057] "Pharmacochemically acceptable carrier" refers to one or more compatible solid or liquid fillers or gels that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" means that each component of the composition can be blended with each other in relation to the compounds of the present invention and among them without significantly reducing the potency 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®), wetting agents (e.g., sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0058] The aforementioned pharmaceutical composition is in the form of an injection, capsule, tablet, pill, powder, or granule. The method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and typical methods 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 inactive excipient (or vector), such as 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, calcium carbonate, potato starch or tapioca starch, tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) retarders such as paraffin; (f) absorption enhancers such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricating components such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also include a buffering agent.

[0060] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared using coating and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compound from such compositions can be delayed in specific parts of the digestive tract. Examples of usable embedding components are polymers and waxes. If necessary, the active compound can form microcapsules with one or more of the above excipients.

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

[0062] In addition to these inert diluents, the composition may also include auxiliary agents such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances. In addition to the active compound, the suspension may include suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures thereof.

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

[0064] 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 as needed.

[0065] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., antitumor drugs). The therapeutic method of the present invention can be used alone or in combination with other therapeutic means or therapeutic agents.

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

[0067] Compared to the prior art, the present invention has the following main advantages. (1) The compound has excellent growth inhibitory activity. (2) The compound has excellent YAP-TEAD inhibitory activity. (3) The compound has excellent pharmacokinetic properties. (4) The compound has excellent properties for crossing 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 used solely for the purpose of illustrating the present invention and do not limit its scope. In the following examples, experimental methods that do not specify conditions typically follow conventional conditions, such as those described in Sambrook et al., Molecular Cloning: An Experimental Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or conditions proposed by the manufacturer. Unless otherwise specified, percentages and quantities are calculated by weight.

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

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

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

[0072] The experimental process is as follows: (1) Synthesis of compound T1-2 In a 500 mL three-necked flask, add 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), xanthophos (2.44 g, 4.22 mmol, 10% eqiv), and ultra-dried dioxane (200 mL). The flask is then evacuated, replaced with nitrogen gas, and the temperature is raised to 105 °C for 16 hours.

[0073] After the reaction is complete, the mixture is cooled to room temperature, 200 mL of water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. This crude product is then purified by column chromatography using 100% PE and a PE:EA ratio of 500:1 to obtain 5.4 g of product T1-2 (white solid).

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

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

[0076] (4) Synthesis of compounds T1-5 Compound T1-4 (1.45 g) is added to methanol (20 mL), then HCl / dioxane (40 mL, 4 M) is added, and the mixture is reacted overnight at room temperature. The mixture is concentrated, then saturated sodium bicarbonate is added, and the mixture is extracted with ethyl acetate. The mixture is then concentrated, and the solvent is removed with dichloromethane to obtain 1.14 g of 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), and DCM (2 mL) were added to a reaction tube. Then, at 0°C, a solution of acryloyl chloride (46.81 mg, 0.52 mmol, 1.2 eq) in DCM (1 mL) was added dropwise, and the mixture was stirred overnight at room temperature. The solution was washed with 0.1 N HCl, then EA was added for extraction, and the mixture was 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] Referencing the synthesis method of Example 1, the following compounds are synthesized. [ka] [ka] [ka]

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

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

[0082] The experimental process is as follows: (1) Synthesis of compound T2-2 In a 500 mL three-necked flask, add 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), xanthophos (2.44 g, 4.22 mmol, 10%), and ultra-dried dioxane (200 mL). The flask is then evacuated, purged with nitrogen gas, and heated to 105 °C for 16 hours.

[0083] After the reaction is complete, the mixture is cooled to room temperature, 200 mL of water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. This crude product is then purified by column chromatography using 100% PE and a PE:EA ratio of 500:1 to obtain 5.4 g of product T2-2 (white solid).

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

[0085] (3) Synthesis of compound T2-4 Compound T2-3 (560 mg) was added to methanol (16 mL), followed by HCl / dioxane (40 mL, 4 M), and the mixture was reacted overnight at room temperature. After concentration, saturated sodium bicarbonate was added, the mixture was extracted with ethyl acetate, washed with saturated brine, then concentrated, and the solvent was 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), and DCM (10 mL) were added to a reaction tube, and then 1 mL of a DCM solution of acryloyl chloride (144.36 mg, 1.6 mmol, 1.2 eq) was added dropwise at 0°C and stirred overnight at room temperature. The solution was washed with 0.1 N HCl and then with saturated saline, and then EA was added for extraction, followed by separation and purification 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] Refer to the synthesis method of Example 2 to synthesize the following compound. [ka]

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

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

[0091] The experimental process is as follows: (1) Synthesis of T16-2 In a reaction flask, sequentially add T16-1 (3g, 12.77 mmol, 1.0eq), p-trifluoroaniline (2.06g, 12.77 mmol, 1eq), CS2CO3 (8.3g, 25.54 mmol, 2eq), xanthophos (740.6mg, 1.28 mmol, 10%eq), Pd(OAc)2 (143.66mg, 0.639 mmol, 5%eqiv), and 70mL of ultra-dried 1,4-dioxane. After purging with nitrogen gas three times, place the flask in an oil bath and heat to 105°C for 16 hours.

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

[0093] (2) Synthesis of T16-3 Add T16-2 (2g, 6.31 mmol, 1.0 eq), pinacol borate (2.33g, 7.57 mmol, 1.2 eqiv), potassium carbonate (1.74g, 12.62 mmol, 2.0 eqiv), water / 1,4-dioxane (1 / 10) (4mL / 40mL), and Pd(dppf)Cl2 (230.63mg, 0.316 mmol, 5% eq) sequentially to a 100mL neck flask. After purging with nitrogen gas once, the mixture is placed in an oil bath pot, heated to 105°C and reacted for 16 hours. After the reaction is complete, it is cooled to room temperature, diluted with diatomaceous earth, filtered, 80 mL of water is added, extracted with ethyl acetate (80 mL x 3), the organic layers are combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, the filtrate is filtered by suction, spin-dried, and passed through a column to obtain 2.6 g of T16-3 (pale yellow solid).

[0094] (3) Synthesis of T16-4 T16-3 (1 g) is dissolved in ethanol (15 mL), Pd / (OH)2 (100 mg, 10%) is added, and the mixture is reacted in a hydrogen gas environment for 16 hours until the starting material disappears. The mixture is then filtered directly and spin-dried 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), then HCl / dioxane (20 mL, 4 M) is added, and the mixture is reacted overnight at room temperature. Direct spin drying is performed to obtain 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), and DCM (3 mL) were added to a reaction tube, and then 1 mL of a DCM solution of acryloyl chloride (77 mg, 1.36 umol, 1.1 eq) was added dropwise at 0°C, and the mixture was stirred overnight at room temperature. The solution was washed with 0.1 N HCl, then EA was added for extraction, and then the mixture was 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] Refer to the synthesis method of Example 3 to synthesize the following compound. [ka] [ka]

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

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

[0101] The experimental process is as follows: (1) Synthesis of T22-2 In a reaction flask, sequentially add T22-1 (5g, 19.93 mmol, 1.0 eq), p-trifluoroaniline (3.21g, 19.93 mmol, 1 eq), CS2CO3 (12.98g, 39.85 mmol, 2 eq), xanthophos (1.15g, 1.99 mmol, 10% eq), Pd(OAc)2 (223.68mg, 0.996 mmol, 5% eqiv), and 70 mL of ultra-dried 1,4-dioxane. After purging with nitrogen gas three times, place the flask in an oil bath and raise the temperature to 105°C to react for 16 hours.

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

[0103] (2) Synthesis of T22-3 Add T22-2 (3g, 9.06 mmol, 1.0 eq), pinacol borate (3.36g, 10.87 mmol, 1.2 eqiv), potassium carbonate (2.5g, 18.12 mmol, 2.0 eqiv), water / 1,4-dioxane (1 / 10) (4mL / 40mL), and Pd(dppf)Cl2 (331.45mg, 453µmol, 5% eq) sequentially to a 100mL necked flask, repeating three times. After purging with nitrogen gas, the mixture is placed in an oil bath pot, heated to 105°C, and reacted for 16 hours. After the reaction is complete, it is cooled to room temperature, diluted with diatomaceous earth, filtered, 80 mL of water is added, extracted with ethyl acetate (80 mL x 3), the organic layers are combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, the filtrate is filtered by suction, spin-dried, and passed through a column to obtain 3.9 g of T22-3 (pale yellow solid).

[0104] (3) Synthesis of T22-4 T22-3 (3.9 g) is dissolved in ethanol (40 mL), Pd / (OH)2 (390 mg, 10%) is added, and the mixture is reacted in a hydrogen gas environment for 16 hours until the starting material disappears. The mixture is then filtered directly and spin-dried to obtain 3.7 g of crude product T22-4 (gray and viscous).

[0105] (4) Synthesis of compound T22-5 Compound T22-4 (1.4 g) was added to DCM (10 mL), followed by HCl / dioxane (25 mL, 4 M), and the mixture was allowed to react overnight at room temperature. Direct spin drying was then performed to obtain 1.2 g of gray 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), and DCM (2 mL) were added to a reaction tube. Then, a DCM solution (1 mL) of acryloyl chloride (77 mg, 0.85 mmol, 1.1 eq) was added dropwise at 0 °C, and the mixture was stirred overnight at room temperature. The solution was washed with 0.1 N HCl, then extracted with EA, and then separated and purified on a large plate to obtain 65 mg of T22 (white solid).

[0107] 1 H NMR (400 MHz, Methanol-d4) δ 7.91 (dd, J = 2.2, 0.9 Hz, 1H), 7.52 - 7.44 (m, 3H), 7.38 (d, J = 8.7 Hz, 2H), 6.81 (dd, J = 16.8, 10.7 Hz, 1H), 6.20 (dd, J = 16.8, 2.0 Hz, 1H), 5.74 (dd, J = 10.6, 2.0 Hz, 1H), 4.73 (d, J = 13.4 Hz, 1H), 4.25 (d, J = 13.5 Hz, 1H), 3.17 (td, J = 8.5, 4.3 Hz, 1H), 2.84 (dd, J = 13.6, 10.9 Hz, 1H), 2.27 (s, 3H), 1.92 (t, J = 9.7 Hz, 2H), 1.61 (d, J = 12.7 Hz, 2H).

[0108] Referring to the synthesis method of Example 4, the following compounds were synthesized.

Chemical Structure

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

Chemical Structure

[0110] The synthetic route is as follows.

Chemical Structure

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

[0112] (2) Synthesis of T27-3 In a 100 mL necked flask, sequentially 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). After purging with nitrogen gas three times, the mixture is placed in an oil bath pot, heated to 105°C, and reacted for 16 hours. After the reaction is complete, the mixture is cooled to room temperature, diluted with diatomaceous earth, filtered, 10 mL of water is added, and extracted with ethyl acetate (15 mL x 3). The organic layers are combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, the filtrate is filtered by suction, spin-dried, and passed through a column to obtain 1.2 g of T27-3 (pale yellow solid).

[0113] (3) Synthesis of T27-4 T27-3 (940 mg) was dissolved in ethanol (15 mL), triphenylphosphine rhodium chloride (160 mg, 10%) was added, and the mixture was reacted under high-pressure hydrogen gas conditions for 24 hours. The starting material did not react completely, so the mixture was 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), then HCl / dioxane (15 mL, 4 M) is added, and the mixture is reacted overnight at room temperature. Direct spin drying is performed to obtain 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), and DCM (3 mL) were added to a reaction tube. Then, at 0°C, a DCM solution of acryloyl chloride (84.1 mg, 0.93 umol, 1.1 eq) (1 mL) was added dropwise, and the mixture was stirred overnight at room temperature. The solution was washed with 0.1 N HCl, then EA was added for extraction, and the mixture was separated and purified on a large plate to obtain 180 mg of T27 (white solid).

[0116] 1 1H 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] Refer to the synthesis method of Example 5 to synthesize the following compound. [ka] [ka] [ka]

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

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

[0120] The experimental process is as follows: (1) Synthesis of T33-2 Add T33-1 (5g, 18.8 mmol, 1.0 eq), p-trifluoroaniline (3.03g, 18.8 mmol, 1 eq), CS2CO3 (12.25mg, 37.6 mmol, 2 eq), xanthophos (1.09g, 1.88 mmol, 10% eq), Pd(OAc)2 (211.06mg, 0.94 mmol, 5% eqiv), and 100 mL of ultra-dried 1,4-dioxane sequentially to the reaction flask. After purging with nitrogen gas three times, the mixture is placed in an oil bath pot, heated to 105°C, and reacted for 16 hours. After the reaction is complete, it is cooled to room temperature, diluted with diatomaceous earth, filtered, 200 mL of water is added, extracted with ethyl acetate (100 mL x 3), the organic layers are combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, the filtrate is filtered by suction, spin-dried, and subjected to column chromatography to obtain 4 g of T33-2.

[0121] (2) Synthesis of T33-3 In a 100 mL necked flask, combine 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), and Pd(dppf)Cl2 (210 mg, 0.287 mmol, 5%). Add eq) sequentially, purge with nitrogen gas three times, then place in an oil bath pot, raise the temperature to 105°C and react for 16 hours. After the reaction is complete, cool to room temperature, dilute EA with diatomaceous earth, filter, add 50 mL of water, extract with ethyl acetate (50 mL x 3), combine the organic layers, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter the filtrate by suction, spin dry, and subject to column chromatography to obtain 1.8 g of T33-3.

[0122] (3) T33-4 synthesis T33-3 (1.8g, 4 mmol, 1.0eq) was dissolved in ethanol (20mL), and Pd(OH)2 (180mg, 10%) was added. The mixture was then reacted in a 50mL necked flask under a hydrogen gas environment at room temperature for 20 hours until the starting material was completely dissolved. The mixture was then filtered, concentrated, and subjected to column chromatography to obtain 1.5g of the 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 then react overnight at room temperature. Direct spin drying is performed to obtain 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), and DMF (5 mL) to a reaction tube. Then, under an ice bath at 0°C, add 2 mL of DMF solution of chloropropionyl chloride (146.6 mg, 1.62 mmol, 1.1 eq) dropwise, and stir overnight at room temperature. 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] Refer to the synthesis method of Example 6 to synthesize the following compound. [ka]

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

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

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

[0130] After the reaction is complete, the mixture is cooled to room temperature, 40 mL of water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. This crude product is then purified by column chromatography using 100% PE and a PE:EA ratio of 500:1 to obtain 1.3 g of T37-2.

[0131] (2) Synthesis of T37-3 Add the following to a 100 mL necked flask in order: 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). After purging with nitrogen gas three times, the mixture is placed in an oil bath pot, heated to 105°C, and reacted for 16 hours. After the reaction is complete, it is cooled to room temperature, diluted with diatomaceous earth, filtered, 10 mL of water is added, extracted with ethyl acetate (20 mL x 3), the organic layers are combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, the filtrate is filtered by suction, spin-dried, and passed through a column to obtain 1.4 g of T37-3 (pale yellow solid).

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

[0133] (4) Synthesis of compound T37-5 Compound T37-4 (350 mg) was added to dichloromethane (5 mL), followed by HCl / dioxane (20 mL, 4 M), and the mixture was allowed to react overnight at room temperature. The mixture was then directly spin-dried to obtain 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), and DCM (2 mL) were added to a reaction tube, and then 1 mL of DCM solution of acryloyl chloride (119.5 mg, 1.32 umol, 1.1 eq) was added dropwise at 0°C, and the mixture was stirred overnight at room temperature. Extraction with water and EA was 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 by the present invention: [ka]

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

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

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

[0140] (2) Synthesis of T40-3 T40-2 (1.3 mg, 3.72 ml, 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), and Pd(dppf)Cl2 (136 mg, 0.18 mmol, 5% eq) were sequentially added to a 50 mL neck flask. After purging with nitrogen gas three times, the temperature was raised to 105 °C and the mixture was reacted for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with diatomaceous earth, filtered, 15 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 brine (20 mL), dried over anhydrous sodium sulfate, the filtrate was filtered by suction, spin-dried, and passed through a column to obtain 1.1 g of T40-3 (pale yellow solid).

[0141] (3) Synthesis of T40-4 T40-3 (1.1 mg) is dissolved in ethanol (30 mL), triphenylphosphine rhodium chloride (200 mg, 20%) is added, and the mixture is reacted under high-pressure hydrogen gas conditions for 16 hours. After the reaction of the starting materials is complete, the mixture is passed 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), then HCl / dioxane (20 mL, 4 M) is added, and the mixture is reacted overnight at room temperature. Direct spin drying is performed to obtain 0.8 g of 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), and DCM (5 ml) were added to a reaction tube. Then, at 0°C, a DCM solution of acryloyl chloride (139.4 mg, 1.54 μmol, 1.1 eq) (2 mL) was added dropwise, and the mixture was stirred overnight at room temperature. The solution was washed with 0.1 N HCl, then EA was added for extraction, and the mixture was separated and purified on a large plate to obtain 210 mg of T40 (white solid).

[0144] 1 1H 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] Refer to the synthesis method of Example 8 to synthesize the following compound. [ka] [ka]

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

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

[0148] The experimental process is as follows: (1) Synthesis of compound T48-2 In a 500 mL three-necked flask, add compound T48-1 (10 g, 42.21 mmol, 1.0 equiv), p-trifluoroaniline (6.8 g, 42.21 mmol, 1.0 equiv), Cs2CO3 (11.49 g, 84.43 mmol, 2.0 equiv), Pd(OAc)2 (473.86 mg, 2.11 mmol, 5% equiv), Xantphos (2.44 g, 4.22 mmol, 10% equiv), and ultra-dry dioxane (200 mL). Evacuate the flask and replace the air with nitrogen gas. Heat the mixture to 105 °C and react for 16 hours.

[0149] After the reaction is complete, cool the mixture to room temperature, add 200 mL of water, extract with ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, concentrate to obtain a crude product, and purify by column chromatography using PE 100% and PE:EA = 500:1 to obtain 5.4 g of product T48-2 (white solid).

[0150] (2) Synthesis of compound T48-3 In a 100 mL single-necked flask, sequentially add compound T48-2 (1.2 g, 3.78 mmol, 1.0 eq), pinacol borate (1.4 g, 4.54 mmol, 1.2 equiv), potassium carbonate (1.05 g, 7.57 mmol, 2.0 equiv), water / 1,4-dioxane (1 / 10) (22 mL), and Pd(dppf)Cl2 (135.64 mg, 0.189 mmol, 5% eq). After replacing the air with nitrogen gas three times, place the flask in an oil bath, heat to 105 °C, and react for 16 hours. After the reaction is complete, cool to room temperature, add 20 mL of water, extract with ethyl acetate (25 mL × 3), combine the organic layers, wash with saturated brine (25 mL), dry over anhydrous sodium sulfate, filter the filtrate by suction filtration, spin dry, and pass through a column to obtain 1.5 g 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 in a hydrogen gas environment for 16 hours until the starting material disappears. The mixture is then filtered directly and spin-dried to obtain 1.45 g of crude product T48-4 (gray and viscous).

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

[0153] (7) Synthesis of compound T48 Compound α-methacrylic acid (96.55 mg, 0.78 mmol, 1 eq), DIEA (201.79 mg, 0.1.56 mmol, 2 eqs), and DCM (3 mL) were added to a reaction tube and stirred at room temperature for 10 minutes. Then compound T48-5 (300 mg, 0.935 mmol, 1.2 eqs) was added and stirred overnight at room temperature. The organic layer was extracted with water and DCM, washed once with brine, dried over anhydrous sodium sulfate, filtered, and the pure EA was transferred to a large plate to obtain 100 mg of a white solid.

[0154] 1 1H 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] Refer to the synthesis method of Example 9 to synthesize the following compound. [ka] [ka]

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

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

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

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

[0160] (2) Synthesis of T54-3 In a 100 mL single-neck flask, T54-2 (1.3 g, 3.55 mmol, 1.0 eq), pinacol borate (1.32 g, 4.26 mmol, 1.2 equiv), potassium carbonate (981.2 mg, 7.1 mmol, 2.0 equiv), water / 1,4-dioxane (1 / 10) (1.5 mL / 15 mL), and Pd(dppf)Cl2 (129.75 mg, 0.178 mmol, 5% eq) were added sequentially. After three nitrogen gas replacements, it was placed in an oil bath and heated to 105 °C for 16 hours of reaction. After the reaction, it was cooled to room temperature, then EA was diluted with diatomaceous earth, filtered, 10 mL of water was added, and it was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated brine (25 mL), 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 materials did not react completely, and it was passed through a column to obtain 1.4 g of T54-4 (white solid).

[0162] (4) Synthesis of T54-5 Add T54-4 (1.5 g, 3.29 mmol, 1.0 eq), S2 (1.72 g, 8.23 mmol, 2.5 eq), NaHCO3 (1.24 g, 14.81 mmol, 4.5 eq), Pd(OAC)2 (73.7 mg, 0.33 mmol, 0.1 eq), and Pcy3 (184.53 mg, 0.66 mmol, 0.2 eq) to the reaction flask, add 1,4-dioxane / EtOH / water (7:2:1) (11.9 ml / 3.4 ml / 1.7 ml) as the solvent, place it in an oil bath after three nitrogen gas replacements, heat to 105 °C and react for 12 hours. After the reaction, cool to room temperature, then add 20 mL of water, extract with ethyl acetate (25 mL × 3), combine the organic layers, wash with saturated brine (25 mL), dry over anhydrous sodium sulfate, suction filter the filtrate, spin dry, and pass through a column to obtain 1.53 g of the product T54-5.

[0163] (5) Synthesis of compound T54-6 Compound T54-5 (1.53 g) was added to DCM (10 mL), followed by HCl / dioxane (25 mL, 4 M), and the mixture was reacted overnight at room temperature. Direct spin drying was performed to obtain 1.6 g of the 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), and DCM (12 mL) were added to a reaction flask. Then, at 0°C, a solution of acryloyl chloride (397.3 mg, 4.4 mmol, 1.1 eq) in DCM (6 mL) was added dropwise, and the mixture was stirred overnight at room temperature. The solution was washed with 0.1 N HCl, then extracted with EA, and subsequently 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] Referencing the synthesis methods of Examples 10 and 14, the following compounds are synthesized. [ka] [ka] [ka] [ka] [ka] [ka]

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

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

[0169] The experimental process is as follows: (1) Synthesis of compound T57-2 In a 100 mL three-necked flask, add 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), xanthophos (1.22 g, 2.11 mmol, 10% eqiv), and ultra-dried dioxane (50 mL). The flask is then evacuated, replaced with nitrogen gas, and the temperature is raised to 105 °C for 16 hours.

[0170] After the reaction is complete, the mixture is cooled to room temperature, 200 mL of water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. This crude product is then purified by column chromatography using PE 100% and PE:EA = 500:1 to obtain 910 mg of product T57-2 (white solid).

[0171] (2) Synthesis of compound T57-3 Into a 100 mL three-necked flask, add compound T57-2 (800 g, 2.52 mmol, 1.0 equiv), S2 (499 mg, 2.52 mmol, 1.0 equiv), CS2CO3 (1.6 g, 5.04 mmol, 2.0 equiv), Pd(OAc)2 (28.3 mg, 0.126 mmol, 5% equiv), xantphos (146 mg, 0.252 mmol, 10% equiv), and ultra-dry dioxane (10 mL). Evacuate the flask and replace the air with nitrogen gas. Heat the mixture to 105 °C and react for 16 hours. After three nitrogen gas replacements, place the flask in an oil bath and heat to 105 °C for 16 hours of reaction. After the reaction is complete, cool to room temperature, add 20 mL of water, extract with ethyl acetate (25 mL × 3), combine the organic layers, wash with saturated brine (25 mL), dry over anhydrous sodium sulfate, filter the filtrate by suction filtration, spin dry, and pass through a column to obtain 721 mg of product T57-3 (white solid).

[0172] (3) Synthesis of compound T57-4 Add compound T57-3 (500 mg) to MeOH (5 mL), add boric acid fluoride (5 mL, 50%), and then react at room temperature for 3 hours. Extract three times with aqueous sodium bicarbonate solution and EA, wash once with saturated NaCl, dry over anhydrous Na2SO4, filter, and spin dry to obtain 457 mg of product T57-4.

[0173] (4) Synthesis of compound T57 Add compound T57-4 (4 50 mg, 1.34 mmol, 1.0 eq), triethylamine (406.02 mg, 4.02 mmol, 3.0 eq), and DCM (4 mL) to a reaction flask. Then, at 0 °C, slowly add a DCM solution (2 mL) of acryloyl chloride (133.7 mg, 1.47 mmol, 1.1 eq) dropwise and stir overnight at room temperature. Wash the solution with 0.1 N HCl, then add EA for extraction, and then purify 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 by the present invention: [ka]

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

[0177] The experimental process is as follows: (1) Synthesis of T58-2 In a reaction flask, sequentially add T58-1 (5g, 21.01 mmol, 1.0 eq), p-trifluorophenol (3.4g, 21.01 mmol, 1 eq), CS2CO3 (10.24g, 42.02 mmol, 2 eq), xanthophos (1.22mg, 2.1 mmol, 10% eq), Pd3(dba)2 (962.3mg, 1.05 mmol, 5% eqiv), and 50 mL of ultra-dried 1,4-dioxane. After purging with nitrogen gas three times, place the flask in an oil bath and heat to 105°C for 16 hours.

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

[0179] (2) Synthesis of T58-3 In a 100 mL necked flask, sequentially 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), and nitrate three times. After gas substitution, the mixture is placed in an oil bath pan, heated to 105°C, and reacted for 16 hours. After the reaction is complete, it is cooled to room temperature, diluted with diatomaceous earth, filtered, 300 mL of water is added, extracted with ethyl acetate (30 mL x 3), the organic layers are combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, the filtrate is filtered by suction, spin-dried, and passed through a column to obtain 2.01 g of T58-3 (pale yellow solid).

[0180] (3) Synthesis of T58-4 T58-3 (500 mg) is dissolved in ethanol (8 mL), Pd / (OH)2 (50 mg, 10%) is added, and the mixture is reacted in a hydrogen gas environment for 5 hours until the starting material disappears. The mixture is then filtered directly and spin-dried to obtain 490 mg of crude product T58-4 (white solid).

[0181] (4) Synthesis of compound T58-5 Compound T58-4 (490 mg) was added to DCM (6 mL), followed by HCl / dioxane (6 mL, 4 M), and the mixture was reacted overnight at room temperature. Direct spin drying was performed to obtain 470 mg of gray 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 mmol, 3.0 eq), and DCM (5 mL) were added to a reaction tube, and then 2 mL of a DCM solution of acryloyl chloride (144.4 mg, 1.6 mmol, 1.1 eq) was added dropwise at 0°C, and the mixture was stirred overnight at room temperature. The solution was washed with 0.1 N HCl, then EA was added for extraction, and then the mixture was separated and purified on a large plate to obtain 210 mg of T58 (white solid).

[0183] 1 1H 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 by the present invention: [ka]

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

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

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

[0188] (2) Synthesis of T59-3 Add T59-2 (1.34g, 4.21 mmol, 1.0 eq), pinacol borate (1.56g, 5.05 mmol, 1.2 eqiv), potassium carbonate (1.16g, 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) sequentially to a 100 mL necked flask, and 3 After purging with nitrogen gas once, the mixture is placed in an oil bath pot, heated to 105°C and reacted for 16 hours. After the reaction is complete, it is cooled to room temperature, diluted with diatomaceous earth, filtered, 10 mL of water is added, extracted with ethyl acetate (15 mL x 3), the organic layers are combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, the filtrate is filtered by suction, spin-dried, and passed through a column to obtain 1.73 g of T59-3 (pale yellow solid).

[0189] (3) Synthesis of T59-4 Dissolve T59-3 (1.73 g) in ethanol (20 mL), add palladium hydroxide (173 mg, 10%), and react under atmospheric pressure, room temperature, and hydrogen gas conditions for 12 hours until the starting materials are completely dissolved. The mixture is then passed 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) was added to DCM (5 mL), followed by HCl / dioxane (15 mL, 4 M), and the mixture was reacted overnight at room temperature. Direct spin drying was performed to obtain 358 mg of the 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), and DCM (3 mL) were added to a reaction tube. Then, at 0°C, a DCM solution (1 mL) of acryloyl chloride (92.8 mg, 1.03 mol, 1.1 eq) was added dropwise, and the mixture was stirred overnight at room temperature. The solution was washed with 0.1 N HCl, then EA was added for extraction, and the mixture was 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] Refer to the synthesis method of Example 13 to synthesize the following compound. [ka]

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

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

[0196] The experimental process is as follows: (1) Synthesis of T60-2 In a microwave tube, 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), xanthophos (5.39 g, 9.328 mmol, 10% eq), Pd(OAc)2 (1.044 g, 4.66 mmol, 5% eqiv), and 250 mL of ultra-dried 1,4-dioxane were added sequentially. The mixture was reacted under microwave at 150°C for 1 hour until the reaction was complete. After cooling to room temperature, 40 mL of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain 17.76 g of T60-2.

[0197] (2) Synthesis of T60-3 In a 500 mL necked flask, sequentially 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 g / 178 mL), and Pd(dppf)Cl2 (3.3 g, 4.508 mmol, 10% eq). The mixture is then purged with nitrogen gas three times and reacted in an oil bath at 105 °C for 16 hours. After the reaction is complete, the reaction mixture is cooled to room temperature, EA is diluted with diatomaceous earth, filtered, water is added, and the mixture is extracted with ethyl acetate. The organic layers are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. This product is then purified by column chromatography to obtain 15.5 g of T60-3.

[0198] (3) Synthesis of T60-4 T60-3 (15.5 g, 32.97 mmol, 1.0 eq) was dissolved in ethanol (250 mL), triphenylphosphine rhodium oxide (2.3 g, 15%) was added, and the mixture was reacted in a hydrogenation vessel under a 1.0 MPa hydrogen gas environment at 60°C for 48 hours until the starting materials were completely dissolved. The mixture was then filtered, concentrated, and subjected to column chromatography to obtain 12.37 g of the product compound T60-4.

[0199] (4) Synthesis of compound T60-5 Compound T60-4 (3.7g, 8.17 mmol, 1 eq), pinacol diborate (5.2g, 20.47 mmol, 2.5 eq), tricyclohexylphosphine (457mg, 1.634 mmol, 0.2 eq), palladium acetate (183mg, 0.817 mmol, 0.1 eq), and cesium fluoride (5.59g, 36.77 mmol, 4.5 eq) were added to ultra-dried 1,4-dioxane (37 mL) and reacted at 105°C for 3.5 hours. An lcms test indicated that the reaction was complete and that almost all of the product was present. The mixture was filtered through diatomaceous earth, concentrated to dryness, and yielded 5.5 g of the crude product, a yellowish-brown 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), and palladium acetate (4.9 mg, 0.0217 mmol, 0.1 eq) were added to 1,4-dioxane / ethanol / water = 7:2:1 (2 mL), heated to 105°C and reacted for 16 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, extracted with EA, the organic phase was 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), followed by HCl / dioxane (2 mL, 4 M), and the mixture was allowed to react overnight at room temperature. The mixture was then directly spin-dried to obtain 76 mg of the 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), and DCM (1 mL) were added to a reaction tube, and then 1 mL of a DCM solution of acryloyl chloride (25 mg, 0.275 mmol, 1.1 eq) was added dropwise at 0°C, and the mixture was stirred overnight at room temperature. Extraction with water and EA was 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] Refer to the synthesis method of Example 14 to synthesize the following compound. [ka]

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

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

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

[0208] (2) Synthesis of T63-3 In a 100 mL necked flask, combine 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), and Pd(dppf)Cl2 (110 mg, 0.15 mmol, 5%). Add eq) sequentially, purge with nitrogen gas three times, then place in an oil bath pot, raise the temperature to 105°C and react for 16 hours. After the reaction is complete, cool to room temperature, dilute EA with diatomaceous earth, filter, add 10 mL of water, extract with ethyl acetate (20 mL x 3), combine the organic layers, wash with saturated brine (25 mL), dry over anhydrous sodium sulfate, filter the filtrate by suction, spin dry, and subject to column chromatography to obtain 1.2 g of T63-3 (oil).

[0209] (3) Synthesis of T63-4 T63-3 (650 mg, 1.50 mmol, 1.0 eq) is dissolved in ethanol (10 mL), Pd(OH)2 (65 mg, 10%) is added, and the mixture is reacted in a 50 mL necked flask under a hydrogen gas environment at room temperature for 20 hours until the starting materials are completely dissolved. The mixture is then filtered and concentrated to obtain 620 g of the product compound T63-4.

[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 overnight at room temperature. Direct spin drying is performed to obtain 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), and DCM (5 mL) to a reaction tube. Then, under an ice bath at 0°C, add a DCM solution (5 mL) of acryloyl chloride (148 mg, 1.36 mmol, 1.05 eq) dropwise, and stir overnight at room temperature. 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 by the present invention: [ka]

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

[0215] The experimental process is as follows: (1) Synthesis of T64-2 In a 100 mL necked flask, combine 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) The %eq) were added sequentially, and after purging with nitrogen gas three times, the mixture was placed in an oil bath pot, heated to 105°C, and reacted for 16 hours. After the reaction was complete, the mixture cooled to room temperature, diluted with diatomaceous earth, filtered, 10 mL of water was added, extracted with ethyl acetate (20 mL x 3), the organic layers were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, the filtrate was filtered by suction, spin-dried, and subjected to column chromatography to obtain 744 g of T64-2.

[0216] (2) T64-3 synthesis T64-2 (400 mg, 0.95 mmol, 1.0 eq) is dissolved in ethanol (10 mL), Pd(OH)2 (40 mg, 10%) is added, and the mixture is reacted in a 50 mL neck flask under a hydrogen gas environment at room temperature for 20 hours until the starting materials are completely dissolved. The mixture is then filtered and concentrated to obtain 410 mg of the 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 then react overnight at room temperature. Direct spin drying is performed to obtain 320 mg of T64-4.

[0218] (4) Synthesis of compound T64 T64-4 (130 mg, 0.402 mmol, 1.0 eq), triethylamine (123 mg, 1.2 mmol, 3.0 eq), and DCM (1 mL) were added to a reaction tube. Then, under an ice bath at 0°C, a DCM solution (1 mL) of chloropropionyl chloride (51 mg, 0.40 mmol, 1.0 eq) was added dropwise, and the mixture was stirred overnight at room temperature. The mixture was extracted with water and DCM, and then separated and purified by column chromatography to obtain 50 mg of T64 (white solid).

[0219] 1 1H 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 by the present invention: [ka]

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

[0222] The experimental process is as follows: (1) Synthesis of T65-2 In a reaction flask, T65-1 (1.5g, 5.2 mmol, 1.0eq), p-trifluoroaniline (855g, 5.2 mmol, 1eq), CS2CO3 (720mg, 10.4 mmol, 2eq), xanthophos (300g, 0.52 mmol, 10%eq), Pd(OAc)2 (60g, 0.26 mmol, 5%eqiv), and 15mL of ultra-dried 1,4-dioxane were added sequentially. After purging with nitrogen gas three times, the flask was placed in an oil bath pot and the temperature was raised to 105°C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with diatomaceous earth, filtered, 20mL of water was added, and the mixture was extracted with ethyl acetate (30mL x 3). The organic layers were combined, washed with saturated brine (25mL), dried over anhydrous sodium sulfate, the filtrate was filtered by suction, spin-dried, and subjected to column chromatography to obtain 1.6g of T65-2.

[0223] (2) Synthesis of T65-3 In a 100 mL necked flask, combine 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), and Pd(dppf)Cl2 (146 mg, 0.2 mmol, 5 The %eq) were added sequentially, and after purging with nitrogen gas three times, the mixture was placed in an oil bath pot, heated to 105°C and reacted for 16 hours. After the reaction was complete, the mixture cooled to room temperature, diluted with diatomaceous earth, filtered, 10 mL of water was added, extracted with ethyl acetate (20 mL x 3), the organic layers were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, the filtrate was filtered by suction, spin-dried, and subjected to column chromatography to obtain 1.3 g of T65-3.

[0224] (3)T65-4 synthesis T65-3 (1.2g, 2.55 mmol, 1.0eq) is dissolved in ethanol (10mL), Pd(OH)2 (120mg, 10%) is added, and the mixture is reacted in a 50mL necked flask under a hydrogen gas environment at room temperature for 20 hours until the starting materials are completely mixed. The mixture is then filtered and concentrated to obtain 1.03g of the product compound T65-4.

[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 overnight at room temperature. Direct spin drying is performed to obtain 800 mg of T65-5.

[0226] (5) Synthesis of compound T65 T65-5 (200 mg, 0.539 mmol, 1.0 eq), triethylamine (163 mg, 1.617 mmol, 3.0 eq), and DCM (1 mL) were added to a reaction tube. Then, under an ice bath at 0°C, a DCM solution of chloropropionyl chloride (72 mg, 0.566 mmol, 1.05 eq) (1 mL) was added dropwise, and the mixture was stirred overnight at room temperature. The mixture was extracted with water and DCM, and then separated and purified 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 by the present invention: [ka]

[0229] Synthesis pathway: [ka]

[0230] The experimental process is as follows: Synthesis of T83-3 Compounds T83-1 (4g, 1.0eq), T83-2 (8.28g, 1.5eq), CS2CO3 (16g, 2.0eq), and Xantphos (1.4g, 0.10eq) were dissolved in dioxane (40mL), substituted with N2, and heated to 80°C. Pd(OAc)2 (275.3mg, 0.05eq) was added, and the temperature was raised to 105°C. The mixture was stirred overnight while heating, and the next day the sample was fed. LCMS was accurate, and TLC: OK. Workup: Water and EA were added for extraction, spin-dried, and the sample was mixed and subjected to column chromatography to obtain T83-3 (3.98g).

[0231] T83-4 synthesis Compound T83-3 (3.98 g, 1.0 eq) and NBS (4.6 g, 2.0 eq) were dissolved in CH3CN (40 mL), replaced with N2, and the mixture was heated to 90°C, stirred overnight while heating, and the next day the sample was fed. LC-MS was accurate, and TLC: OK. Workup: Water and EA were added for extraction, spin-dried, and the sample was mixed and subjected to column chromatography to obtain T83-4 (972 mg). LC-MS 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), and Pd(dppf)Cl2 (196 mg, 0.1 eq) were dissolved in dioxane (10 mL) and H2O (1 mL), N2 was substituted, and the mixture was heated to 105 °C and reacted overnight. LC-MS showed that most of the product was present. Workup: EA was diluted, filtered through diatomaceous earth, the filtrate was concentrated to dryness, spin-dried, and after mixing with the sample, it was subjected to column chromatography to obtain T83-5 (1.05 g).

[0233] Synthesis of T83-6 T83-5 (1.15 g) was dissolved in ethanol (19 mL), Pd(OH)2 (115 mg, 0.1 eq) was added, H2 was substituted, and the mixture was heated to 60°C under atmospheric pressure of approximately 1 MPa and reacted overnight. LC-MS showed that almost all of the product was present, and TLC: OK. Workup: Filtered through diatomaceous earth, the filtrate was concentrated to dryness, spin-dried, and after mixing with the sample, column chromatography was performed to obtain product T83-6 (1.2 g).

[0234] Synthesis of T83-7 T83-6 (1.2g) was dissolved in dichloromethane (6mL) and 1,4-dioxane hydrochloride (12mL), N2 was substituted, and the mixture was reacted at room temperature for about 2 hours. LC-MS showed that almost all of the product was present, and TLC: OK. Workup: Spin-dried, ethanol was added and then spin-dried again. This was repeated three times to obtain the crude product T83-7 (1.2g), and LC-MS was accurate.

[0235] T83 synthesis T83-7 (300 mg, 1.0 eq) was dissolved in dichloromethane solution (2 mL), TEA (258 mg, 3.0 eq) was added under ice bath conditions, and a mixed solution containing acryloyl chloride (84.4 mg, 1.1 eq) and dichloromethane (1 mL) was slowly added dropwise under N2 protection. The mixture was then allowed to react at room temperature for approximately 4 hours, and LC-MS showed that most of the product was present. Workup: The mixture was spin-dried, and after mixing, it was subjected to 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 testing experiment Experimental Example 1: Cell Proliferation Inhibition Experiment Measurement of YAP-TEAD inhibitor compound proliferation inhibition against human pleural mesothelioma cells NCI-H226. Experimental materials and equipment: Human pleural mesothelioma cells NCI-H226 were 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 digestate), 1x PBS (phosphate buffer, pH 7.2), 96-well plate (Corning), fetal bovine serum (FBS), 10000 U / mL penicillin-G / streptomycin, high-speed refrigerated centrifuge (EPPENDORF 5810R), enzyme-linked immunosorbent detector (Tecan Spark).

[0238] Preparation for the experiment: 1. Cell Plating A) Culture tumor cells to 80-90% density in RPMI-1640 (containing 10% FBS and 100 U / mL penicillin-G / streptomycin) under conditions of 37°C, 5% CO2, and saturated humidity. B) Remove the culture medium from the 10cm culture dish. C) Rinse the cells once with 10 mL of 1x PBS. D) Add 4 mL of 0.25% EDTA-trypsin, incubate in a 37°C, 5% CO2 incubator for 5 minutes to digest the trypsin, transfer to a 15 mL centrifuge tube, centrifuge at 200 g for 5 minutes, discard the supernatant to obtain cell precipitate. E) Resuspend in 4 mL of DMEM medium, count, and adjust to 10,000 cells / ml. F) Add the cell suspension to a 96-well plate, 100 μL per well, and incubate overnight in a 37°C, 5% CO2 incubator.

[0239] 2. Compound treatment Dilution of the compound A) Preparation of gradient dilution solutions of the test compound: The test compound is prepared as a 1 mM stock solution. Then, 1.5 μl of the stock solution is dissolved in 1.5 ml of DMSO-free culture medium, and a 3-fold gradient dilution is performed 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 to ensure uniformity, take 100 μL of each culture compound solution, replace the culture medium in the cell culture plate, and prepare four duplicate wells for each concentration. C) Transfer the cells to an incubator and incubate for 3 days.

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

[0241] 4. Data Analysis Use the following formula to calculate cell viability (%Cell Viability). Cell viability (%) = [A (drug added) - A (blank)] / [A (zero drug added) - A (blank)] × 100 A (drug addition): Absorbance of wells containing cells, CCK8 solution, and drug solution. A (blank): Absorbance of a well containing culture medium and CCK8 solution, but without cells. A (0 drug addition): Absorbance of wells containing cells and CCK8 solution but without drug solution. Cell viability: Cell proliferation viability or cytotoxic viability is curve-fitted using GraphPad Prism 8 software, IC 50 Obtain a numerical value.

[0242] Experimental Example 2. Nanoluciferase method for detecting YAP-TEAD inhibitor activity (1) Experimental materials and equipment: 293T cells were 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 digestate), 1x PBS (phosphate buffer, pH 7.2), 96-well leukocyte culture plate (PerkinElmer), fetal bovine serum (FBS), 10000 U / 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 20 μM - Add before use.

[0244] (2) Transient transfection of 293T cells Recovered 293T cells are inoculated into a 10 cm culture dish, placed in a 5% CO2 incubator, and cultured 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, log-phase cells are digested with trypsin-EDTA, the reaction is stopped by adding culture medium, and the mixture is homogenized with a pipette to prepare a cell suspension. Using Vi-cell, measure the cell concentration and dilute to a suspension of 5 × 10^5 cells per 1 mL. After preparing the cell suspension, gently mix it uniformly 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 × 10^6. Culture 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 antibiotic- and serum-free opti-MEM Medium to each tube. Then, add 15 μg of plasmid (pGL3B-8xGTiiC-nLuc-CMV-fLuc) to one tube and gently pipette to mix uniformly. Add the Lipo6000 transfection reagent to the other tube and gently pipette to mix uniformly. After standing at room temperature for 5 minutes, gently add the DNA-containing culture medium to the Lipo6000 transfection reagent-containing culture medium, gently invert the centrifuge tubes to mix uniformly, and stand at room temperature for 5 minutes. The above mixture is uniformly dropped into a 10 cm culture dish and incubated for 6 hours, after which it is replaced with fresh complete culture medium.

[0247] (3) Plating of 96-well plates One day after transfection, the cells are digested with trypsin-EDTA, the reaction is stopped by adding culture medium, and the mixture is uniformly mixed by pipetting to prepare a cell suspension. Cell concentration was measured using Vi-cell and diluted to a suspension of 20,000 cells per 1 ml. After preparing the cell suspension, gently mix it uniformly. For a 96-well plate, add 100 μL per well, resulting in a cell density of 2000 cells per well.

[0248] (4) Addition of compound The inoculated cell culture plates are placed in an incubator and cultured, and after approximately 24 hours, the compound in a concentration gradient is added. Dilute a 10 mM compound stock solution to 50 μM with culture medium. Add the 50 μM compound solution sequentially to the third row of a deep well plate, and then add 216 μL of 0.5% DMSO-containing medium to rows 4 through 11.

[0249] Gradient dilution: Aspirate 100 μL of solution from the 3rd row and add it to the 4th row. Mix thoroughly, then aspirate 100 μL of solution from the 4th row and add it to the 5th row. Repeat this process up to the 11th row. Using a multichannel pipette, aspirate 25 μL of compound solution from a deep-well plate and add it to a 96-well culture plate, repeating this process four times for each compound on the 96-well plate. Ultimately, a maximum concentration of 10,000 nM and a concentration gradient of 1:3.16 are formed on the 96-well plate.

[0250] (5) Addition and reading of nanoluciferase detection reagent After culturing the 96-well plate in a 5% CO2 incubator at a constant temperature of 37°C for 48 hours, remove it and allow it to equilibrate at room temperature for 10 minutes. Add 100 μL of detection reagent to each well and shake slowly on a horizontal shaker for 10 minutes to completely lyse the cells. Detect the fluorescence value of each well using a PerkinElmer Envision microplate reader.

[0251] (6) Calculation of the result Using 0nM as a control, the values ​​in each well were converted to percentages, and nonlinear fitting was performed using the Inhibitor vs. Response (three parameters) setting in GrapPad prism software to determine IC. 50 Calculate.

[0252] As shown in Table 1, here 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 Studies of Drugs Oral administration solvent: 5% DMSO + 10% Solutol HS15 + 85% physiological saline Preparation process for oral formulations: Weigh the appropriate powder, add the appropriate amount of DMSO, vortex, add the appropriate amount of Solutol solution, vortex, add the appropriate amount of physiological saline, vortex, and sonicate to form a uniform and clear formulation solution. Store two samples of the clear solution formulation in 100 μL / part portions, and keep them at an environment of 2-8°C.

[0255] The animal room is equipped with an air conditioning system and good ventilation, maintaining the room temperature within the range of 20-26°C and the humidity within the range of 40-70%. Artificial lighting is used in the animal room, with 12 hours of light and 12 hours of dark (except when it is necessary to turn on the work lights for experimental procedures and cleaning), and experimental animals are allowed to eat and drink freely. Rats that have been properly cared for after purchase, passed a veterinarian's inspection, and possess the necessary physical conditions will be registered for this experiment, and each rat will be assigned a tail number. Animals in the oral administration group will be fasted overnight starting the day before administration, and will resume feeding 4 hours after administration, with free access to water.

[0256] Animal grouping and administration [Table A]

[0257] Before administration, inspect the condition of the formulation, ensure its uniformity by vortexing, stirring, or shaking, and calculate the theoretical dose for each group of SD rats according to the following formula.

number

[0258] Sample collection information [Table B]

[0259] [Table 3]

[0260] All documents referenced in this invention are cited as references in this application, as if each document were cited individually. Furthermore, after reading the above teachings of this invention, persons skilled in the art can make various changes or modifications to the invention, and these equivalent forms are also included within the scope defined by the claims appended to this application.

Claims

1. A compound represented by formula I, or a pharmaceutically acceptable salt or solvate thereof, 【Chemistry 1】 Here, A is, 【Chemistry 2】 Selected from the group consisting of, B is, 【Transformation 3】 Selected from the group consisting of, C is, 【Chemistry 4】 Selected from the group consisting of, L stands for NR ４ Selected from the group consisting of , O, and S, R １ teeth, 【Transformation 5】 A group consisting of is selected, and it is connected to N on A, R ２ These are H, halogen, and C, respectively, independently. １－６ Selected from the group consisting of alkyl groups, R ３ is, independently of each other, H, halogen, CN, NH ２ , hydroxyl group, ester group, amide group, C １－６ alkyl group, C １－６ alkoxy group, aryl group, and heteroaryl group, where the hydrogen in NH ２ , ester group, amide group, C １－６ alkyl group, C １－６ alkoxy group, aryl group, and heteroaryl group may be optionally substituted, and the substituents are H, halogen, CN, NH ２ , hydroxyl group, and C １－６ alkyl group, R ４ H and C １－６ Selected from the group consisting of alkyl groups, m and n are each independently selected from the group consisting of 0, 1, 2, 3, and 4. Here, The ester group is -(C=O)-O-R or -O-(C=O)-R, where R is H or C1-6 alkyl. The amide group is -(C=O)-NH₂, Here, the compound is 【Transformation 6】 It is not a compound selected from the group consisting of, The compound represented by formula I, or a pharmaceutically acceptable salt or solvate thereof.

2. m is selected from the group consisting of 0, 1, 2, and 3. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

3. n is selected from the group consisting of 0, 1, 2, and 3. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

4. A is, 【Transformation 7】 Selected from the group consisting of, R ２ , m is as defined in claim 1. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

5. B is, 【Transformation 8】 Selected from the group consisting of, R ３ , n is as defined in claim 1. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

6. The aforementioned compound is as follows: 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 Characterized by being selected from the group consisting of The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

7. A pharmaceutical composition, Pharmacologically acceptable carriers, and One or more safe effective amounts of the compound described in claim 1, or a pharmaceutically acceptable salt or solvate thereof. The pharmaceutical composition characterized by containing the following:

8. Use of the pharmaceutical composition according to claim 7, A drug used in the preparation of a drug, the drug being used for the prevention and / or treatment of proliferative disorders, Use of the pharmaceutical composition according to claim 7.

9. Use of the pharmaceutical composition according to claim 7, Used in the preparation of drugs, the drug is 1) Prevention and / or treatment of related diseases caused by abnormal activity of YAP / TEAD, 2) Prevention and / or treatment of related diseases caused by dysregulation of the Hippo pathway, 3) Prevention and / or treatment of related diseases caused by dysregulation of YAP or TAZ or YAP / TAZ or YAP / TEAD or YAP / TAZ / TEAD Characterized to be used for applications selected from the group consisting of, Use of the pharmaceutical composition according to claim 7.

10. The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, in combination with a second drug, The aforementioned combination is used in the preparation of a drug, which is used for the prevention and / or treatment of cancer. The second drug is characterized by being selected from the group consisting of ERK inhibitors, MEK inhibitors, KRAS inhibitors, BRAF inhibitors, EGFR inhibitors, Wnt inhibitors, and PD-1 inhibitors. The use of a combination of the compound described in claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, and a second drug.

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