A triazole compound, a preparation method and application thereof

Abstract

This invention discloses a triazole compound, its preparation method, and its applications. The triazole compound is of formula I. The triazole compound provided by this invention exhibits strong binding activity to TEAD protein. After binding to TEAD protein, the compound significantly enhances the protein's thermal stability while inhibiting TEAD protein activity. It effectively disrupts the TEAD-YAP interaction and demonstrates strong anti-proliferative activity against the NCI-H226 cell line with abnormal Hippo pathway NF2 deficiency, thereby enabling the treatment of diseases related to abnormal TEAD protein regulation or Hippo pathway abnormalities.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, and in particular to a triazole compound, its preparation method, and its application. Background Technology

[0002] The Hippo signaling pathway is highly conserved in higher vertebrates and participates in regulating many biological processes, such as cell proliferation, survival, differentiation, and organ size regulation. Studies have shown that abnormal activity of the Hippo signaling pathway is often highly correlated with the occurrence of malignant tumors, such as lung cancer, liver cancer, and pancreatic cancer. Therefore, regulating the Hippo signaling pathway has great potential for cancer treatment. YAP / TAZ is the most important downstream effector of the Hippo signaling pathway, capable of regulating the expression of numerous Hippo-related genes. However, due to its disordered and open structural characteristics and lack of active catalytic sites, YAP / TAZ is not an ideal drug target. YAP / TAZ itself cannot interact directly with DNA; it needs to bind to the transcription factor TEAD to initiate downstream gene transcription. Therefore, blocking TEAD-YAP / TAZ binding is widely considered a more promising way to regulate Hippo transcriptional activity. Inhibiting the interactions between YAP, TAZ, TEAD, and YAP-TEAD or TAZ-TEAD proteins through drug intervention appears to be a strategy for the prevention and / or treatment of cancer and other hyperproliferative diseases. Currently, there are no approved drugs for the marketing of TEAD binding agents, YAP-TEAD, or TAZ-TEAD protein-protein interaction inhibitors.

[0003] Therefore, there is still a need to develop safe and effective inhibitors to inhibit the interaction between YAP-TEAD or TAZ-TEAD proteins. Summary of the Invention

[0004] The present invention aims to at least solve one of the aforementioned technical problems existing in the prior art. Therefore, the object of the present invention is to provide a triazole compound, its preparation method, and its application.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows: The first aspect of the invention provides compounds of formula I, or stereoisomers thereof, racemates thereof, deuterated compounds thereof, pharmaceutically acceptable salts thereof, crystalline compounds thereof, prodrugs thereof, and solvates thereof:

[0006] Where R1 is selected from -C(=O) R a -C(=O) OR a -S(=O)R a -SO2R a、; R a Selected from C1~C 10 Alkyl, C2~C 10 alkenyl, C2~C 10 Alkynyl; the alkyl, alkenyl, or alkynyl group is non-substituted, or is substituted by one or more R groups. a1 replace; R a1 Selected from deuterium, halogens, -OH, -CN, -NO2; R2 is selected from hydrogen, deuterium, and C1~C2. 10 Alkyl, 3-10 membered cycloalkyl, C1-C 10 The alkoxy group; the alkyl, cycloalkyl, or alkoxy group is unsubstituted, or is replaced by -NH-C(O)-R b -C(O)-NH-R b replace; R b Selected from 6-12 aryl groups, 5-10 heteroaryl groups, or R5 forming a 3-10 heterocyclic alkyl group with the atom attached to it; the aryl or heteroaryl group is non-substituted, or is formed by one or more R groups. a1 Substitution; the heterocyclic alkyl group is unsubstituted, or replaced by -C(O)-NH-R c replace; R c Selected from 6-12 aryl and 5-10 heteroaryl groups; R3 is selected from C1~C 10 Alkyl, 3-10 membered cycloalkyl, -C0-C4 alkylene-(3-10 membered cycloalkyl), C1-C 10 alkoxy groups, C6~C 18 Aryl; the alkyl, cycloalkyl, alkoxy, and aryl groups are non-substituted, or are substituted by one or more R groups. d replace; R d Selected from hydrogen, deuterium, halogens, -OH, -CN, Cl~C 10 Alkyl, C1~C 10 alkoxy, 6-12 aryl, -C(O)R e -S-C1~C4 alkyl, -S-C1~C4 haloalkyl, 5~10 heteroaryl-C0~C4 alkylene-NH-acrylate; R e Selected from C1~C 10 Alkyl, C1~C 10 alkoxy groups.

[0007] In some embodiments of the present invention, R1 is selected from... , , , .

[0008] In some embodiments of the present invention, R1 is selected from... , , , , , , , , ; where n is selected from natural numbers between 0 and 4, such as 1, 2, 3.

[0009] In some embodiments of the present invention, R1 is selected from... , , , , , .

[0010] In some embodiments of the present invention, R b Selected from , , , , , , , , , , , , , .

[0011] In some embodiments of the present invention, R c Selected from , , , .

[0012] In some embodiments of the present invention, in R2, the alkyl, cycloalkyl, or alkoxy group is selected from... , , replace.

[0013] In some embodiments of the present invention, R d Selected from hydrogen, deuterium, halogen, -OH, -CN, C1~C8 alkyl, phenyl, C1~C8 alkoxy, -C(O)-C1~C8 alkyl, -COO-C1~C8 alkyl, -S-C1~C4 alkyl, -S-C1~C4 haloalkyl, .

[0014] In some embodiments of the present invention, R3 is selected from... , , , , Where n is defined as described above, and m is selected from natural numbers between 0 and 4, such as 0, 1, 2, 3, and 4.

[0015] In some embodiments of the present invention, R3 is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , .

[0016] In some embodiments of the present invention, the compound of formula I is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0017] A second aspect of the present invention provides a method for preparing a compound of formula I, comprising the following steps: preparing a compound of formula II... The compound of formula I is prepared by reacting it with compound R3-N3 of formula III; wherein R1, R2, and R3 are defined as described above.

[0018] In some embodiments of the present invention, the reaction is an addition reaction; the catalyst is a copper salt, such as copper sulfate; the reaction is a copper-catalyzed azide-alkyne cycloaddition reaction.

[0019] In some embodiments of the invention, the reaction includes the use of the ligand THTTA.

[0020] A third aspect of the invention provides a pharmaceutical composition comprising the compound of formula I, or a stereoisomer thereof, a racemic mixture thereof, a deuterated compound thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, and optionally, a pharmaceutically acceptable carrier or excipient.

[0021] In some embodiments of the present invention, the pharmaceutical composition further includes at least one therapeutic agent.

[0022] In some embodiments of the present invention, the therapeutic agent is selected from anticancer agents, immunomodulators, anti-allergic agents, antiemetics, analgesics, cell protectants, and combinations thereof.

[0023] A fourth aspect of the invention provides the use of a compound of Formula I, or a stereoisomer thereof, a racemic mixture thereof, a deuterated compound thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating diseases mediated by TEADs.

[0024] In some embodiments of the present invention, the drug inhibits the activity of transcription factors TEAD (such as TEAD1, TEAD2, TEAD3, TEAD4) or inhibits the transcription of genes (e.g., genes controlled or regulated by transcription factors (such as TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4)) in subjects and / or biological samples (e.g., tissues, cells), treats or prevents diseases mediated by YAP / TAZ-TEAD interactions.

[0025] In some embodiments of the invention, the compounds described herein are provided in the pharmaceutical composition in an effective amount. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a preventatively effective amount.

[0026] In some embodiments of the present invention, the effective amount is an amount that effectively inhibits the activity of transcription factors (e.g., TEADs, such as TEAD1, TEAD2, TEAD3, TEAD4) by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98%.

[0027] In some embodiments of the present invention, the use of the compound of formula I, or its stereoisomer, racemate, deuterated compound, pharmaceutically acceptable salt, prodrug, solvate, or pharmaceutical composition in the preparation of a medicament having the activity of binding to TEAD and blocking the interaction between YAP / TAZ and TEAD.

[0028] In some embodiments of the present invention, the disease is associated with proteins that interact with TEAD.

[0029] In some embodiments of the present invention, the diseases or conditions associated with the proteins that interact with TEAD include, but are not limited to, cancer, metabolic diseases, inflammatory diseases, or neurodegenerative diseases.

[0030] In some embodiments of the present invention, the diseases or conditions mediated by TEAD are selected from colon cancer, diffuse large B-cell lymphoma, follicular lymphoma, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer; brain tumors, neuroblastoma, schwannoma, glioma, glioblastoma and astrocytoma; cervical cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, parathyroid tumors, uterine tumors and soft tissue sarcomas, cardiovascular diseases, neurodegenerative diseases, malaria, AIDS, gout, diabetes, renal failure, and chronic lung diseases.

[0031] In this invention, "YAP / TAZ and TEAD interaction-mediated diseases" refers to diseases in which the interaction between YAP / TAZ and TEAD is involved in the occurrence and / or development of the disease, and can be alleviated, treated and / or prevented by inhibiting the expression and / or activity of YAP and TEAD or by inhibiting or blocking the interaction between YAP and TEAD proteins.

[0032] In some embodiments of the present invention, the diseases mediated by the interaction between YAP / TAZ and TEAD are tumors, liver fibrosis, and kidney fibrosis.

[0033] In some embodiments of the present invention, the disease mediated by the interaction between YAP / TAZ and TEAD is a benign tumor.

[0034] In some embodiments of the invention, the disease mediated by the interaction between YAP / TAZ and TEAD is a malignant tumor, such as cancer or sarcoma.

[0035] In some embodiments of the present invention, the disease mediated by the interaction between YAP / TAZ and TEAD is a solid tumor or a hematologic malignancy.

[0036] In some embodiments of the present invention, the diseases mediated by the YAP / TAZ-TEAD interaction are mesotheliomas (e.g., pleural mesotheliomas (such as malignant pleural mesotheliomas), peritoneal mesotheliomas, pericardial mesotheliomas, or tunica vaginalis mesotheliomas), cervical squamous cell carcinomas, endometrial cancers, bladder urothelial carcinomas, skin squamous cell carcinomas, poroma (e.g., benign poroma), porocarcinomas, epithelioid angioendotheliomas, breast cancers (e.g., triple-negative breast cancer), lung cancers (e.g., non-small cell lung cancer), ovarian cancers, colorectal cancers, melanomas, pancreatic cancers, and prostate cancers. Adenocarcinoma, gastric cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), liver cancer (e.g., hepatocellular carcinoma or hepatoblastoma), bile duct cancer, schwannoma, renal cancer, sarcoma (e.g., rhabdomyosarcoma, embryonal rhabdomyosarcoma, osteosarcoma, undifferentiated pleomorphic sarcoma, Kaposi's sarcoma, and soft tissue sarcoma (e.g., rare soft tissue sarcoma)), bone cancer, brain cancer (e.g., ependymoma (e.g., supratentorial ependymoma, such as pediatric supratentorial ependymoma), neuroblastoma, medulloblastoma, glioma, or meningioma), or head and neck cancer (e.g., head and neck squamous cell carcinoma).

[0037] In some embodiments of the invention, the disease mediated by the YAP / TAZ-TEAD interaction is mesothelioma (e.g., pleural mesothelioma (such as malignant pleural mesothelioma), peritoneal mesothelioma, pericardial mesothelioma, or tunica vaginalis mesothelioma).

[0038] In some embodiments of the present invention, the disease mediated by the interaction between YAP / TAZ and TEAD is malignant pleural mesothelioma (MPM), a rare type of thoracic malignancy. Aberrant activation of the Hippo-YAP pathway is present in approximately 70% of MPM patients and is considered an important cancer driver gene. Reducing Hippo-YAP pathway activity through biological means and small chemical molecules has shown good inhibitory activity against tumor growth.

[0039] In some embodiments of the present invention, the diseases mediated by the YAP / TAZ-TEAD interaction are breast cancer (e.g., triple-negative breast cancer), lung cancer (e.g., non-small cell lung cancer), colorectal cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), gastric cancer, liver cancer (e.g., hepatocellular carcinoma or hepatoblastoma), brain cancer (e.g., ependymoma (e.g., supratentorial ependymoma, such as pediatric supratentorial ependymoma), neuroblastoma, medulloblastoma, glioma, or meningioma), and head and neck cancer (e.g., head and neck squamous cell carcinoma).

[0040] The Hippo-YAP signaling pathway can induce resistance to various anticancer targeted drugs through mechanisms such as tumor cell dormancy and resistance to apoptosis. Therefore, inhibiting the Hippo-YAP signaling pathway can improve the sensitivity of tumor cells to targeted drugs. Furthermore, as a pathway that promotes tumor cell growth, Hippo-YAP is overactivated in multiple drug-resistant tumor models; inhibiting its activity can significantly improve the sensitivity of treated tumor cells to relevant inhibitors. Therefore, in some embodiments of the present invention, the compound of Formula I, or its stereoisomers, racemates, deuterated compounds, pharmaceutically acceptable salts, prodrugs, solvates, or pharmaceutical compositions thereof, can be used to improve the sensitivity of treated tumor cells to targeted drugs (such as EGFR inhibitors, BRAF inhibitors, MEK inhibitors, etc.), thereby enhancing the therapeutic efficacy of these targeted drugs.

[0041] Pharmaceutically acceptable excipients used in the manufacture of the provided pharmaceutical compositions include inert diluents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants and / or oils. The compositions may also contain excipients such as cocoa butter and suppository waxes, colorants, coating agents, sweeteners, flavoring agents, and aromatizers.

[0042] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0043] Exemplary granulating agents and / or dispersants include potato starch, corn starch, cassava starch, sodium starch glycolate, clay, alginate, guar gum, citrus pomace, agar, bentonite, cellulose and wood products, natural sponges, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinylpyrrolidone) (cross-linked polyvinylpyrrolidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (cross-linked carboxymethyl cellulose), methyl cellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0044] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., gum arabic, agar, alginic acid, sodium alginate, tragacanth gum, carrageenan, cholesterol, xanthan gum, pectin, gelatin, egg yolk, casein, lanolin, cholesterol, waxes, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, glyceryl triacetate monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxylated polymethylene, polyacrylic acid, acrylic polymers, and carboxyethylene polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethyl cellulose, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (20), poly... ethylene-oxygenated sorbitol (60), polyoxyethylene-oxygenated sorbitol monooleate (80), sorbitol monopalmitate (40), sorbitol monostearate (60), sorbitol tristearate (65), glyceryl monooleate, sorbitol monooleate (80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate), sucrose fatty acid esters, polyethylene glycol fatty acids Esters (e.g.), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether (30)), poly(ethylene-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, F-68, poloxamer P-188, cetrimonium bromide, cetylpyridine chloride, benzalkonium chloride, docusatesodium and / or mixtures thereof.

[0045] Exemplary binders include starch (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., gum arabic, sodium alginate, Irish moss extract, panwar gum, ghatti gum, mucilage of isapola husk, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate, and larch arabinogalactan), alginate, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethyl methacrylate, waxes, water, ethanol, and / or mixtures thereof.

[0046] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoal preservatives, alcohol preservatives, acid preservatives, and other preservatives. In some embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0047] Exemplary antioxidants include alpha-tocopherol, ascorbic acid, ascorbate palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0048] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridine chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethanol, glycerol, hexetidine, imidureurium, phenol, phenoxyethanol, phenethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0049] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0050] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethanol.

[0051] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0052] Other preservatives include tocopherol, tocopheryl acetate, deferric ammonium methanesulfonate, bromophthalium trimethylammonium, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Plus, methylparaben, 115, II, and... Exemplary buffers include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, calcium gluconate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propionic acid, calcium fructate, valeric acid, calcium hydrogen phosphate, phosphoric acid, trivalent calcium phosphate, calcium hydroxide, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginate, pyrogen-free raw water, isotonic saline, Ringer's solution, ethanol, and mixtures thereof.

[0053] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0054] Exemplary natural oils include bitter almond oil, almond oil, avocado oil, babassu coconut oil, bergamot oil, blackcurrant seed oil, borage oil, juniper oil, chamomile oil, canola oil, caraway oil, Brazilian wax palm oil, castor oil, cinnamon oil, cocoa butter, coconut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil, fish oil, flaxseed oil, geraniol oil, gourd oil, grapeseed oil, hazelnut oil, hyssop oil, isopropyl myristate, jojoba oil, kukui argan oil, and mixed lavender oil. Lavender oil, lemon oil, litsea cubeba oil, macadamia nut oil, mallow oil, mango seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, orange sea bream oil, palm oil, palm kernel oil, peach kernel oil, peanut oil, poppy seed oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, camellia oil, peppermint oil, sea buckthorn oil, sesame oil, shea butter, silicone oil, soybean oil, sunflower oil, tea tree oil, thistle oil, ailanthus oil, vetiver oil, walnut oil, and wheat germ oil. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, caprylic triglyceride, cyclomethicone, diethyl sebate, dimethicone 360, isopropyl myristate, mineral oil, octyl dodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0055] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may also contain inert diluents (such as water or other solvents), solubilizers, and emulsifiers commonly used in the art, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol, and mixtures thereof. In addition to inert diluents, oral compositions may include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers. In some embodiments for parenteral administration, the conjugates described herein are mixed with solubilizers (such as alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof).

[0056] Injectable formulations (e.g., sterile injectable aqueous or oily suspensions) can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable formulations can be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents that can be used are water, Ringer's solution (USP), and isotonic sodium chloride solution. Furthermore, sterile, fixed oils are routinely used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid are used in the preparation of injectables.

[0057] Injectable formulations may be sterilized, for example, by filtration through a bacterial trap or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media prior to use.

[0058] To prolong the effect of a drug, it is often necessary to slow down the absorption of drugs administered subcutaneously or intramuscularly. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. The absorption rate of the drug depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of parenteral drug formulations can be achieved by dissolving or suspending the drug in an oil-based medium.

[0059] Compositions for rectal or vaginal administration are typically suppositories, which can be prepared by mixing the conjugates described herein with a suitable non-irritating excipient or carrier (such as cocoa butter, polyethylene glycol, or suppository wax) that is solid at ambient temperature but liquid at body temperature and thus melts in the rectal or vaginal cavity and releases the active ingredient.

[0060] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier (such as sodium citrate or dicalcium phosphate) and / or the following substances: (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; (e) dissolution inhibitors, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) absorbents, such as kaolin and bentonite; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include buffers.

[0061] In soft-filled and hard-filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycol, similar types of solid compositions can be used as fillers. Solid dosage forms of tablets, sugar pills, capsules, pellets, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmacology. They may optionally contain opaque agents and may have compositions that release only one or more active ingredients or preferentially, optionally in a delayed manner, one or more active ingredients in a portion of the intestine. Examples of encapsulation compositions that can be used include polymeric substances and waxes. In soft-filled and hard-filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycol, similar types of solid compositions can be used as fillers.

[0062] The active ingredient may be microencapsulated together with one or more excipients as mentioned above. Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules may be prepared with coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings known in the field of pharmaceutical formulation. In such solid dosage forms, the active ingredient may be mixed with at least one inert diluent (such as sucrose, lactose, or starch). Such dosage forms may (as is generally the case) contain substances other than inert diluents, such as tablet lubricants and other tablet excipients, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pellets, the dosage form may contain a buffer. They may optionally contain an opaque agent and may have a composition that releases only one or more active ingredients or preferentially, optionally in a delayed manner, one or more active ingredients in a portion of the intestine. Examples of encapsulating agents that can be used include polymers and waxes.

[0063] Dosage forms for the topical and / or transdermal application of the compounds described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, and / or patches. Typically, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any desired preservative and / or buffer (where necessary). Additionally, this disclosure covers the use of transdermal patches, which often have the advantage of allowing for increased controlled delivery of the active ingredient into the body. Such dosage forms may be prepared, for example, by dissolving and / or dispensing the active ingredient in a suitable medium. Alternatively or additionally, the rate may be controlled by providing a rate-controlled membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0064] Suitable devices for delivering the intradermal pharmaceutical compositions described herein include short-needle devices. Intradermal compositions can be administered via devices that limit the effective penetration length of the needle into the skin. Alternatively or additionally, conventional syringes can be used in the classic mantoux method for intradermal administration. Jet injection devices that deliver liquid formulations to the dermis via liquid jet syringes and / or via needles that pierce the stratum corneum and generate a jet reaching the dermis are suitable. Ballistic powder / particle delivery devices that use compressed gas to accelerate compounds in powder form through the outer layer of skin to the dermis are suitable.

[0065] Formulations suitable for surface application include, but are not limited to, liquid and / or semi-liquid formulations, such as lotions, washes, oil-in-water and / or water-in-oil emulsions (such as creams, ointments, and / or pastes) and / or solutions and / or suspensions. Surface-applicable formulations may, for example, contain from about 1% to about 10% (w / w) of the active ingredient, although the concentration of the active ingredient may be up to the solubility limit of the active ingredient in the solvent. Formulations for surface application may also contain one or more of the other ingredients described herein.

[0066] The pharmaceutical compositions described herein are suitable for preparation, packaging, and / or sale in formulations for intrabuccional administration via the lungs. Such formulations may comprise dried particles containing an active ingredient and having a diameter in the range of about 0.5 to about 7 nanometers or about 1 to about 6 nanometers. Such compositions are suitably in the form of a dry powder for administration using a device comprising a dry powder reservoir (to which the flow of propellant can be directed to disperse the powder) and / or using an automatically propelled solvent / powder dispensing container (such as a device comprising an active ingredient dissolved and / or suspended in a sealed container with a low-boiling-point propellant). Such powders comprise particles in which at least 98% by weight have a diameter greater than 0.5 nanometers and at least 95% by number have a diameter less than 7 nanometers. Alternatively, at least 95% by weight have a diameter greater than 1 nanometer and at least 90% by number have a diameter less than 6 nanometers. The dry powder compositions may include a solid fine powder diluent, such as sugar, and are suitably provided in unit dosage forms.

[0067] Low-boiling-point propellants typically comprise liquid propellants having a boiling point below 65℉ at atmospheric pressure. Typically, the propellant constitutes 50 to 99.9% (w / w) of the composition, and the active ingredient constitutes 0.1 to 20% (w / w) of the composition. The propellant may also contain other components such as liquid nonionic and / or solid anionic surfactants and / or solid diluents (which may have a particle size on the same order of magnitude as the particles constituting the active ingredient).

[0068] The pharmaceutical compositions described herein, formulated for pulmonary delivery, can provide the active ingredient in the form of microdroplets in solution and / or suspension. Such formulations may be prepared, packaged, and / or sold as optional sterile aqueous and / or diluted alcoholic solutions and / or suspensions containing the active ingredient, and may be suitably administered using any spray and / or nebulizer. Such formulations may also contain one or more other ingredients, including but not limited to flavoring agents (such as sodium saccharin), volatile oils, buffers, surfactants, and / or preservatives (such as methylparabens). Microdroplets delivered via this route of administration may have an average diameter in the range of about 0.1 to about 200 nanometers.

[0069] Because it can be used for pulmonary delivery, the formulations described herein can be used for intranasal delivery of the pharmaceutical compositions described herein. Another formulation suitable for intranasal administration is a coarse powder containing the active ingredient and having an average particle size of about 0.2 to 500 micrometers. Such formulations are administered through the nasal passage by rapid inhalation from a container that keeps the powder close to the nostrils.

[0070] Formulations for nasal administration may, for example, contain as little as 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may contain one or more of the other ingredients described herein. The pharmaceutical compositions described herein may be prepared, packaged, and / or sold in the form of buccal administration formulations. Such formulations may be, for example, in the form of tablets and / or lozenges prepared using conventional methods, and may contain, for example, 0.1 to 20% (w / w) of the active ingredient, the balance comprising an orally soluble and / or degradable composition, and optionally one or more of the other ingredients described herein. Alternatively, formulations for buccal administration may comprise powders and / or aerosolized and / or nebulized solutions and / or suspensions containing the active ingredient. Such powders, aerosolized and / or aerosolized formulations may have an average particle size and / or droplet size in the range of about 0.1 to about 200 nanometers when dispersed, and may also contain one or more of the other ingredients described herein.

[0071] The pharmaceutical compositions described herein can be prepared, packaged, and / or sold in the form of formulations for ophthalmic application. Such formulations may be, for example, in the form of eye drops comprising, for example, 0.1-1.0% (w / w) of the active ingredient in a solution and / or suspension in an aqueous or oily liquid carrier or excipient. Such drops may also contain buffers, salts, and / or one or more other substances among the other ingredients described herein. Other ophthalmologically applicable formulations available include those containing the active ingredient in microcrystalline and / or liposomal formulations. Ear drops and / or eye drops are also covered within the scope of this disclosure.

[0072] The compounds and compositions provided herein may be administered via any route, including enterically (e.g., orally), parenterally, intravenously, intramuscularly, intra-arterially, intramedullaryly, intrathecally, subcutaneously, intravenously, dermally, rectically, vaginally, intraperitoneally, superficially (e.g., via powder, ointment, cream, and / or drops), via mucosa, via the nose, via the buccal, or sublingually; via endotracheal instillation, bronchial instillation, and / or inhalation; and / or as oral sprays, nasal sprays, and / or aerosols. Routes particularly covered include oral administration, intravenous administration (e.g., systemic intravenous injection), local administration via blood and / or lymphatic supply, and / or direct administration to the affected site. Generally, the most appropriate route of administration will depend on a number of factors, including the nature of the agent (e.g., its stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). In some embodiments, the compounds or pharmaceutical compositions described herein are suitable for superficial application to the subject's eyes.

[0073] The exact amount of compound required to achieve an effective dose will vary depending on the individual subject, such as the subject's species, age, and general condition; the severity of side effects or illness; the identity of the specific compound; the mode of administration, etc. An effective dose may be included in a single dose (e.g., a single oral dose) or multiple doses (e.g., multiple oral doses). In some embodiments, when multiple doses are administered to a subject or to a biological sample (e.g., tissue, cells), any two of the multiple doses comprise different or substantially the same amounts of the compound described herein. In some embodiments, when multiple doses are administered to a subject or to a biological sample (e.g., tissue, cells), the frequency of administering multiple doses to the subject or to the biological sample (e.g., tissue, cells) is three doses per day, two doses per day, one dose per day, one dose every other day, one dose every three days, one dose per week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In some embodiments, the frequency of administering multiple doses to a subject or to a biological sample (e.g., tissue, cells) is one dose per day. In some embodiments, the frequency of administering multiple doses to a subject or to a biological sample (e.g., tissue, cells) is two doses per day. In some embodiments, the frequency of administering multiple doses to a subject or to a biological sample (e.g., tissue, cells) is three doses per day. In some embodiments, when multiple doses are administered to a subject or to a biological sample (e.g., tissue, cells), the duration between the first and last doses of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifespan of the subject, tissue, or cells. In some embodiments, the duration between the first and last doses of the multiple doses is three months, six months, or one year. In some embodiments, the duration between the first and last doses of the multiple doses is the lifespan of the subject, tissue, or cells. In some embodiments, the dosage described herein (e.g., any dosage of a single dose or multiple doses) independently comprises the compound described herein in amounts between 0.1 μg and 1 μg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g (inclusive). In some embodiments, the dosage described herein independently comprises the compound described herein in amounts between 1 mg and 3 mg (inclusive).In some embodiments, the dosage described herein independently comprises a concentration of the compound described herein between 3 mg and 10 mg (inclusive). In some embodiments, the dosage described herein independently comprises a concentration of the compound described herein between 10 mg and 30 mg (inclusive). In some embodiments, the dosage described herein independently comprises a concentration of the compound described herein between 30 mg and 100 mg (inclusive).

[0074] The dosage ranges described herein provide guidance for the administration of the pharmaceutical compositions provided to adults. The dosage to be administered to, for example, children or adolescents, may be determined by a licensed physician or someone skilled in the art, and may be lower or the same as that administered to adults.

[0075] Terminology Definition "Substitution" refers to the replacement of hydrogen atoms in a molecule with other different atoms or groups.

[0076] "Multiple" refers to two or more groups. Therefore, the substitution by multiple groups described in this invention means substitution by two or more groups. The specific number of substituents is affected by the number of substituted sites and steric hindrance of the substituted group. It usually means substitution by two, three, four, five or six groups, and more preferably substitution by two or three groups.

[0077] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0078] The term "alkyl" refers to a fully saturated straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, linked by a single bond to the rest of the molecule, having, for example, 1 to 10 (preferably 1 to 8, more preferably 1 to 6) carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms, 1 to 9 carbon atoms, 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, etc. The alkyl groups in the embodiments of this disclosure are preferably C1-C4 alkyl groups. Unless otherwise specifically specified in this specification, alkyl groups may optionally be substituted.

[0079] In this invention, "alkylene" refers to a divalent saturated aliphatic hydrocarbon group having a specified number of carbon atoms. For example, "C a ~C b"Alkylene" refers to an alkylene group having a to b carbon atoms. Alkylene groups can be straight-chain or branched. For example, "C1-C6 alkylene" is intended to include methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene, etc. Therefore, the term "propylene" can be exemplified by the following structures: Similarly, the term "dimethylpropylene" can be exemplified, for example, by any of the following structures: or .

[0080] The term "alkoxy" refers to an oxygen atom substituted with an alkyl group as defined herein. For example, the term "C1-C..." 10 "Alkoxy" includes the group -O-C1-C 10 Alkyl groups, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, etc.

[0081] The term "cycloalkyl" refers to a cyclic alkyl group, including monocyclic, bicyclic, or polycyclic systems, that does not contain unsaturated bonds such as double bonds and does not contain any heteroatoms, such as C3-C8 cycloalkyl, C3-C7 cycloalkyl, or C3-C6 cycloalkyl. C3-C6 cycloalkyl refers to cycloalkyl groups including C3, C4, C5, and C6. "3-6 membered cycloalkyl" and "C3-C6 cycloalkyl" are used interchangeably. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0082] The term "alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, linked by single bonds to the rest of the molecule, and having one or more carbon-carbon double bonds (-C=C-). In some embodiments, the alkenyl group contains 2 to 10 carbon atoms. In some embodiments, the alkenyl group contains 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkenyl group contains 2 carbon atoms. Non-limiting examples of alkenyl groups include vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl. 6-Heptenyl, 1-Octenyl, 2-Octenyl, 3-Octenyl, 4-Octenyl, 5-Octenyl, 6-Octenyl, 7-Octenyl, 1-Nonenyl, 2-Nonenyl, 3-Nonenyl, 4-Nonenyl, 5-Nonenyl, 6-Nonenyl, 7-Nonenyl, 8-Nonenyl, 1-Decanyl, 2-Decanyl, 3-Decanyl, 4-Decanyl, 5-Decanyl, 6-Decanyl, 7-Decanyl, 8-Decanyl, 9-Decanyl. Unless otherwise specifically specified in this specification, the alkenyl group may optionally be substituted.

[0083] The term "alkynyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, linked by a single bond to the rest of the molecule, and having one or more carbon-carbon triple bonds (-C≡C-). In some embodiments, the alkynyl group contains 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkynyl group contains 2 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, propynyl, butynyl, pentyynyl, etc. Unless otherwise specifically specified in this specification, the alkynyl group may optionally be substituted.

[0084] The term "cycloalkyl" refers to a saturated, non-aromatic monocyclic or polycyclic hydrocarbon group or portion consisting only of carbon and hydrogen atoms, which may be linked to the remainder of the molecule via any suitable carbon atom. In some embodiments, the cycloalkyl group contains 3 to 10 ring carbon atoms, 3 to 9 ring carbon atoms, 3 to 8 ring carbon atoms, 3 to 7 ring carbon atoms, 3 to 6 ring carbon atoms, 3 to 5 ring carbon atoms, 4 to 10 ring carbon atoms, 4 to 9 ring carbon atoms, 4 to 8 ring carbon atoms, 4 to 7 ring carbon atoms, 4 to 6 ring carbon atoms, or 4 to 5 ring carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise specifically indicated in this specification, the carbon atoms in the cycloalkyl group may optionally be oxidized (thus forming an oxo (=O) group), and the cycloalkyl group may optionally be substituted.

[0085] The term "heterocyclic group" refers to a group having a 3- to 10-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the connecting point may be a carbon atom or a nitrogen atom, where the valence allows. Heterocyclic groups may be monocyclic ("monocyclic heterocyclic group") or fused ring, bridged ring, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group"), and may be saturated or partially unsaturated. A heterocyclic bicyclic system may include one or more heteroatoms in one or both rings. Unless otherwise stated, each instance of a heterocyclic group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclic group") or substituted with one or more substituents ("substituted heterocyclic group"). In some embodiments, the heterocyclic group is an unsubstituted 3- to 10-membered heterocyclic group. In some embodiments, the heterocyclic group is a substituted 3- to 10-membered heterocyclic group. In some embodiments, the heterocyclic group is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclic group, wherein one, two, or three atoms in the heterocyclic system are independently oxygen, nitrogen, or sulfur, where the valence allows. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxacyclopentyl, oxothiocyclopentyl, dithiocyclopentyl, and oxazolidinyl-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiocyclohexyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiohexyl, and dioxane. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazacyclohexyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxetaneheptyl, and thioheptanyl.

[0086] The term "aryl" refers to a group or portion of a conjugated hydrocarbon ring system having 6 to 18 carbon atoms (e.g., 6 to 14 carbon atoms or 6 to 10 carbon atoms, e.g., 6, 7, 8, 9, or 10 carbon atoms). The aryl group can be a monocyclic, bicyclic, tricyclic, or more ring system, and can be fused with a cyclic hydrocarbon group or a heterocyclic group. In the case of a polycyclic system, although all rings can be aromatic, only one ring needs to be aromatic. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthraceneyl, phenanthrene, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-one-7-yl, etc. Unless otherwise specifically specified in this specification, the aryl group may optionally be substituted.

[0087] The term "heteroaryl" refers to a conjugated cyclic group or portion having carbon atoms (e.g., 1 to 15 carbon atoms, 1 to 14 carbon atoms, 1 to 13 carbon atoms, 1 to 12 carbon atoms, 1 to 11 carbon atoms, 1 to 10 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms) and heteroatoms selected from nitrogen, oxygen, and sulfur (e.g., 1 to 6 heteroatoms, more preferably 1, 2, or 3 heteroatoms). In some embodiments, the heteroaryl may contain 5, 6, 7, 8, 9, or 10 cyclic atoms, e.g., 5 to 10 cyclic carbon atoms, 5 to 9 cyclic atoms, 5 to 8 cyclic atoms, 5 to 7 cyclic atoms, or 5 to 6 cyclic atoms. Unless otherwise specifically indicated in this specification, the heteroaryl may be a monocyclic, bicyclic, tricyclic, or more cyclic system and may be fused with a cyclic hydrocarbon group, aryl group, or heterocyclic group. The nitrogen, carbon, or sulfur atom in the heteroaryl group may optionally be oxidized, and the nitrogen atom may optionally be quaternized. For the purposes of this disclosure, the heteroaryl group is preferably a stable 5- to 10-membered aromatic group comprising 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered aromatic group comprising 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically specified in this specification, the heteroaryl group may optionally be substituted.

[0088] Examples of heteroaryl groups include, but are not limited to, thiophene, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzimorpholinyl, benziisodiazolyl, benzotriazolyl, benzopyrazolyl, imidazopyridyl, pyridomorpholinyl, pyrazolopyridyl, indole, furanyl, pyrroleyl, triazolyl, tetrazolyl, triazinyl, pyridinoneyl, pyrimidinoneyl, pyridazinoneyl, inazinyl, isoindoleyl, indazoleyl, isoindazoleyl, purine, quinolinyl, isoquinolinyl, diazonyl, naphthidyl, quinoxolinyl, pteridinyl, carbazoleyl, carbolinyl, phenanthridine, phenanthridine Phenolic, acridine, phenazinyl, isothiazolyl, benzothiazolyl, benzothiophene, oxatriazolyl, cyclolinyl, quinazolinyl, indene, o-diazaphenanthyl, phenoxazinyl, phenthiazolyl, 4,5,6,7-tetrahydrobenzo[b]thiophene, naphthopyridyl, [1,2,4]triazolo[4,3-b]pyrazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-c]pyrimidinyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-b]pyrazinyl, and imidazo[1,2-a]pyrazinyl, etc.

[0089] In this document, "stereoisomer" refers to a compound composed of identical atoms bonded by the same bonds, but with different three-dimensional structures. This disclosure will cover various stereoisomers and mixtures thereof.

[0090] When the compounds of this disclosure contain an alkene double bond, unless otherwise stated, the compounds of this disclosure are intended to contain E- and Z-geometric isomers.

[0091] "Tautomer" refers to an isomer formed when a proton is transferred from one atom of a molecule to another atom of the same molecule. All tautomer forms of the compounds disclosed herein are also included within the scope of this disclosure.

[0092] The compounds disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may produce enantiomers, diastereomers, and other stereoisomers. Each chiral carbon atom may be defined as (R)- or (S)- based on stereochemistry. This disclosure is intended to include all possible isomers, as well as their racemic and optically pure forms. The preparation of the compounds disclosed herein may use racemic, diastereomer, or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography. Conventional techniques for the preparation / separation of individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography.

[0093] In this invention, "deuterated compound" refers to a compound in which any hydrogen atom is deuterated.

[0094] The term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0095] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionates, hexanoates, octanoates, decanoates, undecenoates, glycolates, gluconates, lactates, sebates, adipates, glutarate, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbic acid salts, salicylates, 4-aminosalicylic acid salts, and naphthalene disulfonates. These salts can be prepared using methods known in this field.

[0096] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

[0097] As used herein, the terms “crystal form,” “crystalline form,” and “polymorph” are used interchangeably and refer to the crystal structure in which a compound (or its salts, solvates, or other derivatives such as prodrugs or metabolites) can crystallize in different crystalline packings (all having the same elemental composition). Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, or other factors can cause one crystalline form to dominate. Polymorphs of a compound can be prepared by crystallization under different conditions.

[0098] The term "solvent" refers to a compound that typically associates with a solvent via a solvent decomposition reaction. This physical association can include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. Compounds of Formula I can be prepared, for example, in crystalline form and can be solvates. Suitable solvates include pharmaceutically acceptable solvates and also include both stoichiometric and non-stoichiometric solvates. In some cases, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid, the solvate can be separated. "Solvent" encompasses both solution phases and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0099] The term "hydrate" refers to a compound that associates with water. Typically, the number of water molecules in a hydrate of a compound is in a definite ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R·xH₂O, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), low-hydrates (x is a number greater than 0 and less than 1, such as hemihydrates (R·0.5H₂O)), and polyhydrates (x is a number greater than 1, such as dihydrates (R·2H₂O) and hexahydrates (R·6H₂O)).

[0100] The term "prodrug" refers to those compounds that, after administration, will be metabolized (i.e., converted in the body) into pharmacologically active compounds of this disclosure. When the compounds of this disclosure are poorly absorbed from the gastrointestinal tract on their own, their bioavailability can be improved by formulating them as prodrugs. Examples of prodrugs of the compounds of this disclosure may include simple esters of compounds containing a carboxyl group (e.g., by reacting with C according to methods known in the art). 1-4 Esters obtained by alcohol condensation; esters of compounds containing hydroxyl groups (e.g., obtained by reacting with C according to methods known in the art). 1-4 Monocarboxylic acids, C 3-6Esters obtained by condensation of dicarboxylic acids or their anhydrides, such as succinic anhydride or fumaric anhydride; imines of compounds containing amino groups (e.g., obtained by condensation with C according to methods known in the art). 1-4 Imines obtained by condensation of aldehydes or ketones; urethanes of compounds containing amino groups, such as those esters described by Leu et al. (J. Med. Chem., 42: 3623-3628 (1999)) and Greenwald et al. (J. Med. Chem., 42: 3657-3667 (1999)); aldol acetals or ketal acetals of compounds containing hydroxyl groups (e.g., those acetals obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

[0101] The beneficial effects of this invention are: The triazole compound provided by this invention exhibits strong binding activity to TEAD protein. After binding to TEAD protein, the compound significantly enhances the protein's thermal stability while inhibiting TEAD protein activity. It effectively disrupts the TEAD-YAP interaction and demonstrates strong anti-proliferative activity against the NCI-H226 cell line with NF2 deficiency and Hippo pathway abnormalities. Therefore, it can be used to treat diseases related to TEAD protein regulation abnormalities or Hippo pathway abnormalities. This invention's compound is similar to related anti-tumor compounds targeting TEAD, such as MYF-01-037 (…). Cancer Cell. 2020, 37(1), 104-122. J. Med. Chem. Compared to 2022 65(13):9206-9229.), its in vitro activity and antitumor activity at both the cellular and animal levels are significantly improved, making it an effective in vivo targeted TEAD inhibitor. It is expected to be developed into an original Class I antitumor drug. Attached Figure Description

[0102] Figure 1 The compound in Example 36 exhibits antiproliferative activity against cell lines NCI-H226 and NCI-H2452. Detailed Implementation

[0103] The present invention will be further described in detail below through specific embodiments. Unless otherwise specified, the raw materials, reagents, or apparatus used in the embodiments and comparative examples are all available from conventional commercial sources or can be obtained by existing technical methods. Unless otherwise specified, the test or experimental methods are conventional methods in the art.

[0104] Example 1 In this embodiment, compound 1 was prepared, and the specific process is as follows:

[0105] S1. Propyleneamine (1.684 mL, 26.30 mol, 1.0 equivalent) was added to 30 mL of ultra-dry dichloromethane solution. Triethylamine (3.99 g, 39.45 mmol, 1.5 equivalent) was added to the reaction solution at 0 °C. After reacting for 5 minutes, acryloyl chloride (2.158 mL, 26.65 mol, 1.01 equivalent) diluted in 20 mL of ultra-dry dichloromethane was slowly added dropwise. The reaction was carried out at room temperature for 12 hours. TLC was used to confirm the reaction was complete. The reaction was quenched with water, extracted three times with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under vacuum, and purified by Flash column chromatography (gradient: methanol / dichloromethane = 0% ~ methanol / dichloromethane = 10%) to obtain the intermediate. N -Propylene propionamide int-1-1.

[0106] S2. Add 1,3-diaminopentane (51 mg, 0.50 mmol, 1.0 eq), potassium bicarbonate (670 μL, 2.00 mmol, 4.0 eq, 3 M in water), FSO2N3 (1.5 mL, 0.50 mmol, 1.0 eq, 350 M in MTBE / DMSO) and DMSO (2 mL) to a 10 mL round-bottom flask. Stir at room temperature for 2 hours to generate the azide intermediate int-1-2. Then add buffer salt (0.5 mL) to the reaction solution and stir for 15 minutes. Then add the following in sequence: N - Propylene propionamide (36.0 mg, 0.50 mmol, 1.0 equivalent, in 1 mL DMSO) and CuSO4 / THPTA (0.5 mL, 5 mM in water). The reaction mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LC-MS, the reaction mixture was purified by Biotage column chromatography (gradient: 0.1 FA in water / acetonitrile = 100% ~ 0.1 FA in water / acetonitrile = 0%) to give 23 mg of white solid 1, yield 16.9%. 1 H NMR (500 MHz, DMSO- d 6) δ 8.67-8.50 (m, 2H), 8.05(s, 1H), 7.91 (s, 1H), 6.34-5.99 (m, 4H), 5.65-5.55 (m, 2H), 4.47-4.33 (m,5H), 4.22-4.08 (m, 2H), 2.42 (q, J= 7.2 Hz, 2H), 1.90-1.79 (m, 2H), 0.66 (t, J = 7.2 Hz, 3H). LC-MS (ESI): m / z 373.2 [M + H] + . Note: Buffe preparation: Sodium ascorbate (2.48 g, 12.5 mmol), Na2HPO4 (7.00 g, 49.3 mmol), citric acid (4.87 g, 25.4 mmol) and water, bring to a final volume of 100 mL.

[0107] Example 2 In this embodiment, compound 2 was prepared, and the specific process is as follows:

[0108] S1. Propyleneamine (1.684 mL, 26.30 mol, 1.0 equivalent) was added to 30 mL of ultra-dry dichloromethane solution. The reaction was initiated at 0 °C with the addition of triethylamine (3.99 g, 39.45 mmol, 1.5 equivalent). After 5 minutes of reaction, chloroacetyl chloride (2.114 mL, 26.65 mol, 1.01 equivalent) diluted in 20 mL of ultra-dry dichloromethane was slowly added dropwise. The reaction was continued at room temperature for 12 hours. TLC was used to confirm the reaction was complete. The reaction was quenched with water, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting product was purified by Flash column chromatography (gradient: methanol / dichloromethane = 0% ~ methanol / dichloromethane = 10%) to obtain the intermediate 2-chloro- N -2-Propyne-1-ylacetamide int-2-1.

[0109] S2. 2-(4-chlorophenoxy)aniline (109 mg, 0.50 mmol, 1.0 equivalent) was added to 2 mL of acetonitrile solution, and the mixture was cooled to 0 °C. Tert-butyl nitrite (119 μL, 0.75 mol, 1.5 equivalent) and azidotrimethylsilane (106 μL, 0.60 mol, 1.2 equivalent) were slowly added dropwise. After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 20 minutes. The reaction was monitored by TLC until complete. The mixture was quenched with ice water, extracted three times with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under vacuum to obtain the crude azide intermediate int-2-2. No purification was required; it was used directly in the next reaction. The azide intermediate (0.50 mmol, 1.0 equivalent) was added to 2 mL of DMSO solution, and buffer salt (0.5 mL) was added. After stirring for 15 minutes, 2-chloro- N2-Propyne-1-ylacetamide (65 mg, 0.50 mmol, 1.0 equivalent, in 1 mL DMSO) and CuSO4 / THPTA (0.5 mL, 5 mM in water) were reacted. The reaction mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LC-MS, the reaction was quenched with water. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed twice with water and twice with saturated brine, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by Flash column chromatography (gradient: ethyl acetate / petroleum ether = 0% ~ ethyl acetate / petroleum ether = 10%) to give 148 mg of white solid, yield 78.5%. 1 H NMR (500 MHz, DMSO- d 6) δ 8.77 (t, J = 5.7 Hz, 1H), 8.36 (s, 1H), 7.77 (dd, J = 8.0, 1.7 Hz, 1H), 7.58-7.52 (m, 1H), 7.47-7.33 (m, 3H), 7.15 (dd, J = 8.3, 1.3 Hz, 1H), 7.11-7.01 (m,2H), 4.40 (d, J = 5.7 Hz, 2H), 4.08 (s, 2H). LC-MS (ESI): m / z 377.1 [M + H] + . Examples 3-8 Examples 3-8 show the preparation of compounds 3-8, and the specific process is as follows: S1, 2-chloro- N The preparation method of 2-propyn-1-ylacetamide is described in Example 2; S2. Add 0.50 mmol (1.0 equivalent) of aromatic primary amine compounds with different corresponding substitutions to 2 mL of acetonitrile solution. Cool to 0 °C, and slowly add tert-butyl nitrite (119 μL, 0.75 mol, 1.5 equivalent) and azidotrimethylsilane (106 μL, 0.60 mol, 1.2 equivalent). After the addition is complete, remove the ice bath and stir at room temperature for 30 minutes to 2 hours. Monitor the reaction for completion by TLC. Quench with ice water, extract three times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain crude azide intermediate. No purification is required; it can be used directly in the next reaction. Add the azide intermediate (0.50 mmol, 1.0 equivalent) to 2 mL of DMSO solution, add buffer salt (0.5 mL), stir for 15 minutes, and then add 2-chloro- N 2-Propyno-1-ylacetamide (65 mg, 0.50 mmol, 1.0 equivalent, in 1 mL DMSO) and CuSO4 / THPTA (0.5 mL, 5 mM in water). The reaction solution was stirred overnight at room temperature. After the reaction was complete as monitored by LC-MS, the reaction was quenched with water, extracted three times with ethyl acetate, and the combined organic phases were washed twice with water and saturated brine, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by Flash column chromatography (gradient: ethyl acetate / petroleum ether = 0% ~ ethyl acetate / petroleum ether = 50%) to obtain the product. The specific compound structures and characterization data are shown in Table 1 below. Table 1

[0110] Example 9 In this embodiment, compound 9 was prepared, and the specific process is as follows:

[0111] S1, 2-chloro- N The preparation method of 2-propyn-1-ylacetamide is described in Example 2; S2. Add 3-cyclohexyl- to a 10 mL round-bottom flask. D1,2-alanine methyl ester hydrochloride (111 mg, 0.50 mmol, 1.0 eq), potassium bicarbonate (670 μL, 2.00 mmol, 4.0 eq, 3 M in water), FSO₂N₃ (1.5 mL, 0.50 mmol, 1.0 eq, 350 M in MTBE / DMSO) and DMSO (2 mL) were stirred at room temperature for 2 hours to generate the azide intermediate int-9-1. Then, buffer salt (0.5 mL) was added to the reaction solution, and after stirring for 15 minutes, 2-chloro- N 2-Propyne-1-ylacetamide (65 mg, 0.50 mmol, 1.0 equivalent, in 1 mL DMSO) and CuSO4 / THPTA (0.5 mL, 5 mM in water) were reacted. The reaction mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LC-MS, the reaction mixture was purified by Biotage column chromatography (gradient: 0.1 FA in water / acetonitrile = 100% ~ 0.1 FA in water / acetonitrile = 0%) to give 115 mg of white solid, yield 67.1%. 1 H NMR (500 MHz, DMSO- d 6) δ 8.74 (t, J = 5.8 Hz, 1H), 8.09 (s, 1H), 5.58 (dd, J = 10.9, 4.7 Hz, 1H), 4.37 (d, J = 5.7 Hz, 2H), 4.10 (s, 2H), 3.67 (s, 3H), 2.19-2.10 (m, 1H), 2.02-1.97 (m, 1H), 1.76 (d, J = 8.4 Hz, 1H), 1.65-1.49 (m, 4H), 1.11-0.85 (m, 6H).LC-MS (ESI): m / z 343.1 [M + H] + . Example 10 In this embodiment, compound 10 was prepared, and the specific process is as follows:

[0112] S1. Propyleneamine (1.10 g, 20.00 mmol, 1.0 equivalent) was added to 20 mL of ultra-dry dichloromethane solution. The reaction was carried out at 0 °C with the addition of triethylamine (3.04 g, 30.00 mmol, 1.5 equivalent). After 5 minutes of reaction, 2-chloroethanesulfonyl chloride (3.26 g, 20.00 mmol, 1.0 equivalent) diluted in 8 mL of ultra-dry dichloromethane was slowly added dropwise. The reaction was carried out at room temperature for 16 hours. TLC was used to confirm the completion of the reaction. The reaction was quenched with water, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting product was purified by Flash column chromatography (gradient: methanol / dichloromethane = 0% ~ methanol / dichloromethane = 10%) to obtain 1.548 g of a pale yellow oily intermediate, 2-vinyl- N -2-Propyne-1-ylsulfonamide int-10-1, yield 53.3%. 1 H NMR (500 MHz, DMSO- d 6) δ 7.81 (t, J = 5.9 Hz, 1H), 6.72 (dd, J =16.6, 10.0 Hz, 1H), 6.07 (d, J = 16.5 Hz, 1H), 5.99 (d, J = 10.0 Hz, 1H), 3.72(dd, J = 5.9, 2.5 Hz, 2H), 3.25 (t, J = 2.5 Hz, 1H); LC-MS (ESI): m / z 146.0 [M+H] + . S2. Add 4-aminobiphenyl (85 mg, 0.50 mmol, 2.0 equivalence), potassium bicarbonate (225 μL, 1.00 mmol, 4.0 equivalence, 3 M in water), FSO2N3 (750 μL, 0.50 mmol, 2.0 eq, 350 M in MTBE / DMSO), and DMSO (2 mL) to a 10 mL round-bottom flask. Stir at room temperature for 2 hours to generate the azide intermediate int-10-2. Then add buffer salt (0.2 mL) to the reaction solution and stir for 15 minutes. Afterward, add 2-vinyl- N2-Propyne-1-ylsulfonamide (36 mg, 0.25 mmol, 1.0 equivalent, in 1 mL DMSO) and CuSO4 / THPTA (0.2 mL, 5 mMin water). The reaction mixture was stirred overnight at room temperature. After the reaction was complete as monitored by LC-MS, water was added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed twice with water and saturated brine, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by Flash column chromatography (gradient: ethyl acetate / petroleum ether = 0% ~ ethyl acetate / petroleum ether = 50%) to give 21 mg of white solid, yield 24.7%. 1 H NMR (500 MHz, DMSO- d 6) δ 8.76 (s,1H), 8.02-7.98 (m, 2H), 7.93-7.87 (m, 3H), 7.75 (d, J = 7.4 Hz, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 6.76 (dd, J = 16.6, 10.0 Hz, 1H), 6.08(d, J = 16.5 Hz, 1H), 5.99 (d, J = 9.9 Hz, 1H), 4.23 (d, J = 5.9 Hz, 2H). LC-MS (ESI): m / z 341.1 [M + H] + . Examples 11-31 Examples 11-31 show the preparation of compounds 11-31, and the specific process is as follows: S1,2-vinyl- N The preparation method of 2-propyn-1-ylsulfonamide is described in Example 10; S2. Add different substituted primary amine compounds (0.50 mmol, 2.0 eq), potassium bicarbonate (335 μL, 1.00 mmol, 4.0 eq, 3 M in water), FSO2N3 (750 μL, 0.50 mmol, 2.0 eq, 350 M in MTBE / DMSO) and DMSO (2 mL) to a 10 mL round-bottom flask. Stir at room temperature for 2 hours to generate an azide intermediate. Then add buffer salt (0.2 mL) to the reaction solution and stir for 15 minutes. Then add (36 mg, 0.25 mmol, 1.0 eq, in 1 mL DMSO) and CuSO4 / THPTA (0.2 mL, 5 mM in water) in sequence. The reaction mixture was stirred overnight at room temperature. After the reaction was complete as monitored by LC-MS, water was added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed twice with water and twice with saturated brine, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by Flash column chromatography (gradient: ethyl acetate / petroleum ether = 0% ~ ethyl acetate / petroleum ether = 50%) to obtain the final product. The specific compound structures and characterization data are shown in Table 2 below. Table 2

[0113] Example 32 In this embodiment, compound 32 was prepared, and the specific process is as follows:

[0114] S1: 218 mg of p-aminophenol (2.00 mmol, 1.0 equivalent) was dissolved in acetone (10 mL), followed by the addition of 2-cyclohexylbromoethane (382 mg, 2.00 mmol, 1.0 equivalent) and potassium carbonate (828 mg, 6.00 mmol, 3.0 equivalent). The reaction mixture was incubated at 70 °C for 4 hours. After TLC detection, the reaction mixture was cooled to room temperature, quenched with water, and extracted three times with ethyl acetate. The combined organic phases were washed twice with water and twice with saturated brine, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by Flash column chromatography (gradient: ethyl acetate / petroleum ether = 0% ~ ethyl acetate / petroleum ether = 20%) to obtain 72 mg of a pale yellow solid intermediate, int-32-1, in yield 16.4%. 1H NMR (500 MHz, DMSO-d6) δ 6.64-6.60 (m, 2H), 6.51-6.46 (m, 2H), 4.56 (s, 2H), 3.83 (t, J =6.6 Hz, 2H), 1.73-1.58 (m, 5H), 1.53 (q, J = 6.6 Hz, 2H), 1.47-1.37(m, 1H),1.25-1.10 (m, 3H), 0.96-0.88 (m, 2H). LC-MS (ESI): m / z 220.1 [M + H] + . S2, 2-vinyl- N The preparation method of 2-propyn-1-ylsulfonamide is as described in Example 10. Intermediate int-32-1 (65 mg, 0.3 mmol, 1.0 eq) was dissolved in DMSO (2 mL), followed by the sequential addition of potassium bicarbonate (400 μL, 1.20 mmol, 4.0 eq, 3 M in water) and FSO2N3 (857 μL, 0.3 mmol, 1.0 eq, 350 M in MTBE / DMSO). The reaction mixture was stirred at room temperature for 2 hours to generate an azide intermediate. Then, buffer salt (0.2 mL) was added to the reaction mixture, and after stirring for 15 minutes, 2-vinyl- N 2-Propyne-1-ylsulfonamide (32 mg, 0.25 mmol, 0.8 equivalence, in 1 mL DMSO) and CuSO4 / THPTA (0.2 mL, 5 mM in water) were reacted. The reaction mixture was stirred overnight at room temperature. After the reaction was completed by LC-MS, water was added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed twice with water and twice with saturated brine, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by Flash column chromatography (gradient: ethyl acetate / petroleum ether = 0% ~ ethyl acetate / petroleum ether = 50%) to give 85 mg of white solid product 32, yield: 75.3%. 1 H NMR (500 MHz, DMSO- d 6) δ 8.57 (s, 1H), 7.87 (t, J = 5.3Hz, 1H), 7.78-7.74 (m, 2H), 7.13-7.08 (m, 2H), 6.74 (dd, J = 16.6, 10.0 Hz, 1H), 6.07 (d, J= 16.6 Hz, 1H), 5.98 (d, J = 10.0 Hz, 1H), 4.20 (d, J = 4.1 Hz, 2H), 4.06 (t, J LC-MS (ESI): m / z 377.2 [M + H] + . Example 33 In this embodiment, compound 33 was prepared, and the specific process is as follows:

[0115] S1: Dissolve 4-iodotrifluorotoluene (816 mg, 3.00 mmol, 1.0 equivalent) in ultra-dry toluene (20 mL), then add tert-butyl (4-aminophenyl)aminocarbamate (750 mg, 3.60 mmol, 1.2 equivalent) and cesium carbonate (1368 mg, 4.20 mmol, 1.4 equivalent) sequentially. After purging with argon three times, quickly add palladium acetate (13 mg, 0.06 mmol, 0.02 equivalent) and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (186 mg, 0.3 mmol, 0.1 equivalent). After purging with argon three more times, reflux the reaction solution at 100 °C for 5 hours. After the reaction was detected by TLC, the reaction solution was cooled to room temperature, the reaction was quenched with water, filtered through diatomaceous earth, extracted three times with ethyl acetate, and the combined organic phases were washed twice with water and saturated brine, respectively. The organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by Flash column chromatography (gradient: ethyl acetate / petroleum ether = 0% ~ ethyl acetate / petroleum ether = 20%) to obtain 561 mg of pale pink solid intermediate int-33-1, with a yield of 53.1%. 1 HNMR (500 MHz, DMSO- d 6) δ 9.24 (s, 1H), 8.48 (s, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.09-7.05 m, 2H), 7.00 (d, J= 8.5 Hz, 2H), 1.47 (s,9H). LC-MS (ESI): m / z 352.07 [M + H] + . S2, 2-vinyl- N The preparation method of 2-propyn-1-ylsulfonamide follows the procedure described in Example 10. The intermediate (140 mg, 0.40 mmol, 1.0 eq) was dissolved in ethyl acetate (2 mL), and ethyl chloride-ethyl acetate (1 mL) was slowly added under ice bath conditions. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction was monitored by TLC until complete, and the solvent was evaporated to dryness. After dissolving in DMSO (2 mL), potassium bicarbonate (533 μL, 1.60 mmol, 4.0 eq, 3 M in water) and FSO₂N₃ (1142 μL, 0.4 mmol, 1.0 eq, 350 M in MTBE / DMSO) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours to generate the azide intermediate int-33-2. Then, buffer salt (0.2 mL) was added to the reaction mixture, and after stirring for 15 minutes, 2-vinyl- N 2-Propyne-1-ylsulfonamide (32 mg, 0.25 mmol, 0.8 equivalence, in 1 mL DMSO) and CuSO4 / THPTA (0.2 mL, 5 mM in water) were reacted. The reaction mixture was stirred overnight at room temperature. After the reaction was completed by LC-MS, water was added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed twice with water and saturated brine, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by Flash column chromatography (gradient: ethyl acetate / petroleum ether = 0% ~ ethyl acetate / petroleum ether = 50%) to give 58 mg of gray solid product, yield: 34.2%. 1 H NMR (500 MHz, DMSO- d 6) δ 8.98 (s, 1H), 8.57 (s, 1H), 7.89 (t, J = 5.6 Hz, 1H), 7.81-7.77 (m,2H), 7.58 (d, J = 8.5 Hz, 2H), 7.35-7.31 (m, 2H), 7.24 (d, J = 8.5 Hz, 2H), 6.75 (dd, J = 16.6, 10.0 Hz, 1H), 6.08 (d, J= 16.6 Hz, 1H), 5.99 (d, J = 10.0Hz, 1H), 4.21 (d, J = 4.6 Hz, 2H). LC-MS (ESI): m / z 423.1 [M + H] + . Example 34

[0116] S1: Compound 22 (200.0 mg, 0.6 mmol, 1.0 equivalent) from Example 22 was dissolved in 5 mL of ultra-dry N,N-dimethylformamide. Sodium hydride (30 mg, 0.8 mmol, 1.2 equivalent) was slowly added under ice bath conditions. After stirring for 30 minutes, 2-(Boc-amino)ethyl bromide (152 mg, 0.6 mmol, 1.0 equivalent) was added, and the mixture was heated to 55°C and stirred for 1 hour. After thin-layer chromatography showed that the reaction was complete, the reaction was quenched with ice water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution and water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The solution was then purified by Flash column chromatography (gradient: ethyl acetate / petroleum ether = 0% ~ ethyl acetate / petroleum ether = 30%) to obtain 32 mg of colorless liquid compound int-34-1, with a yield of 11.1%. 1 H NMR(500 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.81-7.77 (m, 2H), 7.17-7.05 (m, 2H), 6.88(d, J = 5.5 Hz, 1H), 6.77 (dd, J = 16.5, 10.0 Hz, 1H), 6.08 (d, J = 16.5 Hz, 1H), 6.02 (d, J = 10.0, 1H), 4.50 (s, 2H), 4.00 (t, J = 6.5, 2H), 3.14-3.11 (m,2H), 1.75 (h, J = 7.1 Hz, 2H), 1.35 (s, 9H), 1.25-1.2 (m, 2H), 0.99 (t, J = 7.4Hz, 3H). LC-MS (ESI): m / z 466.2 [M+H] + . S2: 7-Clonimidozop[1,2-A]pyridine-3-carboxylic acid (100.0 mg, 0.6 mmol, 1.0 equivalent), N-hydroxysuccinimide (128.0 mg, 1.1 mmol, 2.0 equivalent), and EDCI (210.0 mg, 1.1 mmol, 2.0 equivalent) were dissolved in 3 mL of N,N-dimethylformamide and stirred overnight at room temperature. After thin-layer chromatography showed complete reaction, the reaction was quenched with ice water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The solution was purified by Biotage column chromatography (gradient: 0.1% formic acid in water / acetonitrile = 100% ~ 0.1% formic acid in water / acetonitrile = 0%) to give 90 mg of white solid compound int-34-2, yield 58.0%. 1 H NMR (500 MHz, DMSO-d6) δ9.10 (dd, J = 7.6, 5.9 Hz, 1H), 8.67 (s, 1H), 7.91 (dd, J = 9.4, 2.7 Hz, 1H),7.45-7.40 (m, 1H), 2.91 (s, 4H). S3: Intermediate int-34-1 (28.0 mg, 0.06 mmol, 1.0 equivalent) was dissolved in 2 mL of ethyl acetate. 2 mL of hydrogen chloride-ethyl acetate was added under ice bath conditions. The mixture was slowly heated to room temperature and stirred for 2 hours. After monitoring the complete reaction of reactant a by HPLC-MS, the mixture was concentrated under vacuum to remove ethyl acetate, and the mixture was evacuated for 30 minutes using an oil pump. The reaction residue was dissolved in 3 mL of N,N-dimethylformamide, followed by the addition of intermediate I-2 (18.0 mg, 0.07 mmol, 1.1 equivalent). The pH of the solution was then adjusted to alkaline with triethylamine, and the reaction was carried out at room temperature for 30 minutes. After the reaction was monitored to be complete by HPLC-MS, the reaction was quenched with aqueous solution and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride aqueous solution and water, dried with anhydrous sodium sulfate, and concentrated under vacuum. The mixture was then separated and purified by Biotage column chromatography (gradient: 0.1% formic acid in water / acetonitrile = 100% ~ 0.1% formic acid in water / acetonitrile = 0%) to give 25 mg of white solid compound 34, yield 79.0%. 1 H NMR (500 MHz, DMSO-d6) δ 9.40(t, J = 6.9 Hz, 1H), 8.65 (s, 1H), 8.58 (t, J = 5.8 Hz, 1H), 8.24 (s, 1H), 7.71(d, J= 8.6 Hz, 2H), 7.55 (dd, J = 9.8, 2.7 Hz, 1H), 7.16-7.10 (m, 1H), 7.07(d, J = 8.6 Hz, 2H), 6.82 (dd, J = 16.5, 9.9 Hz, 1H), 6.10 (d, J = 16.5 Hz, 1H), 6.02 (d, J = 9.9 Hz, 1H), 4.55 (s, 2H), 3.99 (t, J = 6.5 Hz, 2H), 3.50-3.47 (m,2H), 3.23-3.15 (m, 2H), 1.76 (h, J = 7.1 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H).LC-MS (ESI): m / z 528.07 [M+H] + . Example 35

[0117] S1: Compound 22 (100.0 mg, 0.3 mmol, 1.0 equivalent) was dissolved in 5 mL of ultradry N,N-dimethylformamide. Sodium hydride (15.0 mg, 0.4 mmol, 1.2 equivalent) was slowly added under ice bath conditions. After stirring for 30 minutes, 3-(Boc-amino)propyl bromide (81.0 mg, 0.3 mmol, 1.0 equivalent) was added, and the mixture was heated to 55 °C and stirred for 15 minutes. After thin-layer chromatography showed that the reaction was complete, the reaction was quenched with ice water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution and water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The solution was then purified by Flash column chromatography (gradient: ethyl acetate / petroleum ether = 0% ~ ethyl acetate / petroleum ether = 30%) to give 45.0 mg of white solid compound int-35-1, with a yield of 30.3%. 1 H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.83-7.75 (m, 2H), 7.16-7.08(m, 2H), 6.82-6.73 (m, 2H), 6.08 (d, J = 16.5 Hz, 1H), 6.02 (d, J= 9.9 Hz,1H), 4.48 (s, 2H), 4.00 (t, J = 6.5 Hz, 2H), 3.09 (t, J = 7.4 Hz, 2H), 2.94-2.89 (m, 2H), 1.79-1.72 (m, 2H), 1.72-1.65 (m, 2H), 1.34 (s, 9H), 0.99 (t, J =7.4 Hz, 3H). LC-MS (ESI): m / z 480.2 [M+H] + . S2: Dissolve intermediate int-35-1 (53.0 mg, 0.11 mmol, 1.0 equivalent) in 2 mL of ethyl acetate. Add 2 mL of hydrogen chloride-ethyl acetate under ice bath conditions. Slowly heat to room temperature and stir for 2 hours. After the reaction of int-35-1 is complete, monitor the reaction by HPLC-MS. Concentrate under vacuum to remove ethyl acetate, and evacuate under oil pump for 30 minutes. Dissolve the reaction residue in 3 mL of N,N-dimethylformamide, then add intermediate int-34-2 (34.0 mg, 0.12 mmol, 1.1 equivalent). Adjust the pH of the solution to alkaline with triethylamine and react at room temperature for 30 minutes. After the reaction was monitored to be complete by HPLC-MS, the reaction was quenched with aqueous solution and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride aqueous solution and water, dried with anhydrous sodium sulfate, and concentrated under vacuum. The mixture was then separated and purified by Biotage column chromatography (gradient: 0.1% formic acid in water / acetonitrile = 100% ~ 0.1% formic acid in water / acetonitrile = 0%) to give 43 mg of light brown solid compound 35, with a yield of 72.2%. 1 H NMR (500 MHz, DMSO-d6) δ 9.41 (dd, J = 7.7, 6.0 Hz, 1H), 8.64 (s, 1H), 8.45 (t, J = 5.7 Hz,1H), 8.25 (s, 1H), 7.75-7.68 (m, 2H), 7.57 (dd, J = 9.8, 2.7 Hz, 1H), 7.12(td, J = 7.7, 2.7 Hz, 1H), 7.09-7.03 (m, 2H), 6.82 (dd, J = 16.5, 9.9 Hz, 1H), 6.10 (d, J = 16.5 Hz, 1H), 6.04 (d,J = 9.9 Hz, 1H), 4.51 (s, 2H), 3.98 (t, J =6.6 Hz, 2H), 3.27 (t, J = 6.5 Hz, 2H), 3.19 (t, J = 7.3 Hz, 2H), 1.84 (p, J =7.2 Hz, 2H), 1.75 (h, J = 7.1 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). LC-MS (ESI): m / z 542.13 [M+H] + . Example 36

[0118] S1: Compound 22 (150.0 mg, 0.48 mmol, 1.0 equivalent) was dissolved in 5 mL of ultradry N,N-dimethylformamide. Sodium hydride (21.0 mg, 0.57 mmol, 1.2 equivalent) was slowly added under ice bath conditions. After stirring for 30 minutes, tert-butyl bromoacetate (99.0 mg, 0.51 mmol, 1.1 equivalent) was added, and the mixture was slowly heated to room temperature and stirred for 30 minutes. After thin-layer chromatography showed that the reaction was complete, the reaction was quenched with ice water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution and water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The solution was then purified by Flash column chromatography (gradient: ethyl acetate / petroleum ether = 0% ~ ethyl acetate / petroleum ether = 30%) to give 105.0 mg of white solid compound int-36-1, yield 51.6%. 1 H NMR (500 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.82-7.74 (m, 2H), 7.17-7.08(m, 2H), 6.83 (dd, J = 16.5, 10.0 Hz, 1H), 6.14 (d, J = 16.5 Hz, 1H), 6.07 (d, J = 10.0 Hz, 1H), 4.52 (s, 2H), 4.00 (t, J = 6.5 Hz, 2H), 3.92 (s, 2H), 1.75 (h, J = 7.1 Hz, 2H), 1.38 (s, 9H), 0.99 (t,J = 7.4 Hz, 3H). LC-MS (ESI): m / z437.14 [M+H] + . S2: Dissolve intermediate int-36-1 (85.0 mg, 0.19 mmol, 1.0 equivalent) in 2 mL of ethyl acetate, add 2 mL of hydrogen chloride-ethyl acetate under ice bath, slowly heat to room temperature and stir for 2 hours, monitor the complete reaction of reactant a by HPLC-MS, concentrate under vacuum to remove ethyl acetate, and evacuate under oil pump for 30 minutes. The reaction residue was dissolved in 3 mL of N,N-dimethylformamide, followed by the addition of 2-methylaminopyrimidine (31.0 mg, 0.29 mmol, 1.1 equivalents). The pH of the solution was then adjusted to alkaline with N,N-diisopropylethylamine. Finally, HATU (2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate) (108.0 mg, 0.28 mmol, 1.5 equivalents) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was monitored by HPLC-MS until complete, the reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution and water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The solution was then purified by Biotage column chromatography (gradient: 0.1% formic acid in water / acetonitrile = 100% ~ 0.1% formic acid in water / acetonitrile = 0%) to give 32 mg of white solid compound 36, with a yield of 35.7%. 1 H NMR(500 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.74 (s, 1H), 8.68 (s, 1H), 8.60 (t, J =5.8 Hz, 1H), 7.79-7.73 (m, 2H), 7.38 (t, J = 4.9 Hz, 1H), 7.14-7.08 (m, 2H), 6.87 (dd, J = 16.5, 9.9 Hz, 1H), 6.14 (d, J = 16.6 Hz, 1H), 6.05 (d, J = 9.9 Hz,1H), 4.52 (s, 2H), 4.50 (d, J = 5.8 Hz, 2H), 4.00 (t, J = 6.5 Hz, 2H), 3.93 (s,2H), 1.80-1.71 (m, 2H), 0.99 (t, J= 7.4 Hz, 3H). LC-MS (ESI): m / z 472.08 [M+H] + . Example 37:

[0119] S1: Compound 22 (100.0 mg, 0.31 mmol, 1.0 equivalent) was dissolved in 5 mL of ultradry N,N-dimethylformamide. Sodium hydride (15.0 mg, 0.37 mmol, 1.2 equivalent) was slowly added under ice bath conditions. After stirring for 30 minutes, 4-bromobutyl tert-butyl ester (76.0 mg, 0.34 mmol, 1.1 equivalent) was added, and the mixture was slowly heated to room temperature and stirred for 30 minutes. After thin-layer chromatography showed that the reaction was complete, the reaction was quenched with ice water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution and water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The solution was then purified by Flash column chromatography (gradient: ethyl acetate / petroleum ether = 0% ~ ethyl acetate / petroleum ether = 30%) to give 120.0 mg of white solid compound int-37-1, with a yield of 83.3%. 1 H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.82-7.75 (m, 2H), 7.14-7.08(m, 2H), 6.77 (dd, J = 16.5, 10.0 Hz, 1H), 6.07 (d, J = 16.7 Hz, 1H), 6.01 (d, J = 10.0 Hz, 1H), 4.48 (s, 2H), 4.00 (t, J = 6.5 Hz, 2H), 3.10 (t, J = 7.2 Hz, 2H), 2.20 (t, J = 7.2 Hz, 2H), 1.83-1.70 (m, 4H), 1.36 (s, 9H), 0.99 (t, J =7.4 Hz, 3H).LC-MS (ESI): m / z 465.2 [M+H] + . S2: Dissolve intermediate int-37-1 (77.0 mg, 0.16 mmol, 1.0 equivalent) in 2 mL of ethyl acetate, add 2 mL of hydrogen chloride-ethyl acetate under ice bath, slowly heat to room temperature and stir for 2 hours, monitor the complete reaction of reactant a by HPLC-MS, concentrate under vacuum to remove ethyl acetate, and evacuate under oil pump for 30 minutes. The reaction residue was dissolved in 3 mL of N,N-dimethylformamide, followed by the addition of 2-methylaminopyrimidine (27.0 mg, 0.25 mmol, 1.5 equivalents). The pH of the solution was then adjusted to alkaline with N,N-diisopropylethylamine. Finally, HATU (2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate) (95.0 mg, 0.25 mmol, 1.5 equivalents) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was monitored by HPLC-MS to be complete, the reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution and water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The mixture was then purified by Biotage column chromatography (gradient: 0.1% formic acid in water / acetonitrile = 100% ~ 0.1% formic acid in water / acetonitrile = 0%) to give 50 mg of yellow oily compound 37, with a yield of 62.6%. 1 H NMR (500 MHz, DMSO-d6) δ 8.70 (d, J = 4.9 Hz, 2H), 8.64 (s, 1H), 8.39 (t, J = 5.9Hz, 1H), 7.80-7.74 (m, 2H), 7.34 (t, J = 4.9 Hz, 1H), 7.13-7.06 (m, 2H), 6.78(dd, J = 16.5, 10.0 Hz, 1H), 6.08 (d, J = 16.5 Hz, 1H), 6.02 (d, J = 10.0 Hz,1H), 4.51 (s, 2H), 4.44 (d, J = 5.8 Hz, 2H), 3.99 (t, J = 6.5 Hz, 2H), 3.13 (t, J = 7.4 Hz, 2H), 2.21 (t, J = 7.4 Hz, 2H), 1.84 (p, J = 7.4 Hz, 2H), 1.75 (h, J = 7.1 Hz, 2H), 0.99 (t,J = 7.4 Hz, 3H). LC-MS (ESI): m / z 500.09 [M+H] + . Example 38:

[0120] S1: Aniline (9.3 g, 100.0 mmol, 1.0 equivalent) was dissolved in 100 mL of pyridine, and phenyl chloroformate (14.0 mL, 100.0 mmol, 1.0 equivalent) was slowly added dropwise while stirring overnight at room temperature. After thin-layer chromatography showed that the reaction was complete, the reaction was quenched with 100 mL of 10% citric acid aqueous solution, and then extracted three times with 180 mL of ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution, and water, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain 17.1 g of crude intermediate compound int-38-1, which can be used directly in the next reaction without purification.

[0121] S2: Intermediate compound int-38-1 (17.1 g, 80.0 mmol, 1.0 equivalent) was dissolved in 100 mL of dimethyl sulfoxide, followed by the addition of tert-butylpiperazine carboxylate (15.0 g, 80.0 mmol, 1.0 equivalent) and aqueous sodium hydroxide solution (8.0 mL, 80.0 mmol, 10 N, 1.0 equivalent). The mixture was stirred at room temperature for 2 hours. After the reaction was monitored by HPLC-MS until complete, the reaction was quenched with 100 mL of aqueous solution and extracted three times with 180 mL of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, and water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The purified intermediate was then separated and purified by a Flash column chromatography (gradient: ethyl acetate / petroleum ether = 5% ~ ethyl acetate / petroleum = 30%) to give 19.5 g of white solid intermediate int-38-2, yield 80%. 1 H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 7.4 Hz, 2H), 7.32 –7.28 (m, 2H), 7.06 (t, J = 7.4 Hz, 1H), 6.51 (s, 1H), 3.49 (s, 8H), 1.50 (s, 9H). MS (ESI) m / z: 306.3 (M + H + ). S3: The intermediate int-38-2 (150.0 mg, 0.50 mmol, 1.0 equivalent) was dissolved in 2 mL of ethyl acetate. 2 mL of hydrogen chloride-ethyl acetate was added under ice bath conditions. The mixture was slowly heated to room temperature and stirred for 2 hours. After monitoring the complete reaction of the reactant int-38-2 by HPLC-MS, the mixture was concentrated under vacuum to remove ethyl acetate. The mixture was then evacuated under oil pump for 30 minutes to obtain the white solid compound int-38-3.

[0122] S4: Compound 22 (50.0 mg, 0.16 mmol, 1.0 equivalent) was dissolved in 5 mL of ultradry N,N-dimethylformamide. Sodium hydride (7.0 mg, 0.19 mmol, 1.2 equivalent) was slowly added under ice bath conditions. After stirring for 30 minutes, tert-butyl bromoacetate (33.0 mg, 0.17 mmol, 1.1 equivalent) was added, and the mixture was slowly heated to room temperature and stirred for 30 minutes. After thin-layer chromatography showed that the reaction was complete, the reaction was quenched with ice water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution and water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The mixture was then purified by Flash column chromatography (gradient: ethyl acetate / petroleum ether = 0% ~ ethyl acetate / petroleum ether = 30%) to give 35 mg of white solid intermediate int-38-4, in yield 51.6%. 1 H NMR (500 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.82-7.74 (m, 2H), 7.17-7.08(m, 2H), 6.83 (dd, J = 16.5, 10.0 Hz, 1H), 6.14 (d, J = 16.5 Hz, 1H), 6.07 (d, J = 10.0 Hz, 1H), 4.52 (s, 2H), 4.00 (t, J = 6.5 Hz, 2H), 3.92 (s, 2H), 1.75 (h, J = 7.1 Hz, 2H), 1.38 (s, 9H), 0.99 (t, J = 7.4 Hz, 3H). LC-MS (ESI): m / z437.14 [M+H] + . S5: Dissolve intermediate int-38-4 (100.0 mg, 0.23 mmol, 1.0 equivalent) in 2 mL of ethyl acetate, add 2 mL of hydrogen chloride-ethyl acetate under ice bath, slowly heat to room temperature and stir for 2 hours, monitor the complete reaction of reactant a by HPLC-MS, concentrate under vacuum to remove ethyl acetate, and evacuate under oil pump for 30 minutes. The reaction residue was dissolved in 3 mL of N,N-dimethylformamide, followed by the addition of intermediate int-38-3 (71.0 mg, 0.34 mmol, 1.5 equivalents). The pH of the solution was then adjusted to alkaline with N,N-diisopropylethylamine. Finally, HATU (2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate) (131.0 mg, 0.34 mmol, 1.5 equivalents) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was monitored by HPLC-MS until complete, the reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution and water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The mixture was then purified by Biotage column chromatography (gradient: 0.1% formic acid in water / acetonitrile = 100% ~ 0.1% formic acid in water / acetonitrile = 0%) to give 45 mg of a pale yellow solid, compound 38, in 34.5% yield. 1 HNMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.57 (s, 1H), 7.83-7.73 (m, 2H), 7.47-7.41 (m, 2H), 7.27-7.19 (m, 2H), 7.15-7.07 (m, 2H), 6.94-6.91 (m, 1H), 6.86(dd, J = 16.6, 9.9 Hz, 1H), 6.14 (d, J = 16.6 Hz, 1H), 6.05 (d, J = 9.9 Hz, 1H), 4.49 (s, 2H), 4.18 (s, 2H), 3.99 (t, J = 6.5 Hz, 2H), 3.52-3.41 (m, 8H), 1.75(h, J = 7.1 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H).LC-MS (ESI): m / z 568.20 [M+H] + . Example 39:

[0123] S1: Compound 22 (100.0 mg, 0.31 mmol, 1.0 equivalent) was dissolved in 5 mL of ultradry N,N-dimethylformamide. Sodium hydride (15.0 mg, 0.37 mmol, 1.2 equivalent) was slowly added under ice bath conditions. After stirring for 30 minutes, 4-bromobutyl tert-butyl ester (76.0 mg, 0.34 mmol, 1.1 equivalent) was added, and the mixture was slowly heated to room temperature and stirred for 30 minutes. After thin-layer chromatography showed that the reaction was complete, the reaction was quenched with ice water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution and water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The solution was then purified by Flash column chromatography (gradient: ethyl acetate / petroleum ether = 0% ~ ethyl acetate / petroleum ether = 30%) to give 120 mg of white solid compound int-39-1, with a yield of 83.3%. 1 H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.82-7.75 (m, 2H), 7.14-7.08(m, 2H), 6.77 (dd, J = 16.5, 10.0 Hz, 1H), 6.07 (d, J = 16.7 Hz, 1H), 6.01 (d, J = 10.0 Hz, 1H), 4.48 (s, 2H), 4.00 (t, J = 6.5 Hz, 2H), 3.10 (t, J = 7.2 Hz, 2H), 2.20 (t, J = 7.2 Hz, 2H), 1.83-1.70 (m, 4H), 1.36 (s, 9H), 0.99 (t, J =7.4 Hz, 3H).LC-MS (ESI): m / z 465.2 [M+H] + . S2: Dissolve intermediate a (100.0 mg, 0.22 mmol, 1.0 equivalent) in 2 mL of ethyl acetate, add 2 mL of hydrogen chloride-ethyl acetate under ice bath, slowly heat to room temperature and stir for 2 hours. After monitoring the complete reaction of the reaction raw material a by HPLC-MS, concentrate under vacuum to remove ethyl acetate, and evacuate under oil pump for 30 minutes. The reaction residue was dissolved in 3 mL of N,N-dimethylformamide, followed by the addition of intermediate I-3 (70.0 mg, 0.33 mmol, 1.5 equivalents). The pH of the solution was then adjusted to alkaline with N,N-diisopropylethylamine. Finally, HATU (2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate) (125.0 mg, 0.33 mmol, 1.5 equivalents) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was monitored by HPLC-MS until complete, the reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution and water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The solution was then purified by Biotage column chromatography (gradient: 0.1% formic acid in water / acetonitrile = 100% ~ 0.1% formic acid in water / acetonitrile = 0%) to give 83 mg of yellow solid compound 39, with a yield of 63.3%. 1 H NMR (500 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.56 (s, 1H), 7.85-7.73 (m, 2H), 7.50-7.38 (m, 2H), 7.30-7.20 (m, 2H), 7.15-7.06 (m, 2H), 6.96-6.90 (m, 1H), 6.79 (dd, J = 16.4, 10.0 Hz, 1H), 6.08 (d, J = 16.5 Hz, 1H), 6.03 (d, J = 10.0 Hz, 1H), 4.50 (s,2H), 3.98 (t, J = 6.6 Hz, 2H), 3.50-3.38 (m, 8H), 3.15-3.10 (m, 2H), 2.34 (t, J = 7.2 Hz, 2H), 1.81 (p, J = 6.9 Hz, 2H), 1.74 (q, J = 7.0 Hz, 2H), 0.99 (t, J =7.4 Hz, 3H). LC-MS (ESI): m / z 596.3 [M+H] + . Example 40 Protein thermal migration experiment This embodiment employs differential scanning fluorometry to detect the thermal stability of proteins under different conditions, investigating the effect of the heterocyclic compound prepared in this embodiment on the thermal stability of the three isoforms TEAD1 / 2 / 4. A 20 μL mixture of 2.5 μM TEAD protein, 5×SYPRO Orange dye (Invitrogen), and 2.5 μM of the heterocyclic compound was added to a 96-well plate (DN Biotech). The wells were sealed with a heat-sealing film (Thermo Scientific). Subsequently, on a QuantStudio™ 6 Flex real-time PCR system (Applied Biosystems), the reaction system was linearly heated from 25 °C to 95 °C within 25 min according to standard procedures, with real-time monitoring of fluorescence signal intensity. Next, the temperature-fluorescence intensity curve, i.e., the protein melting curve, was fitted using Protein Themal Shift™ Software Version 1.2 Life (Technologies), and the protein melting temperature (Tm) was determined. In this experiment, DMSO was used as a negative control, and the change (ΔTm) of the compound on the Tm value of TEAD protein was calculated. The results are shown in Table 3. The compounds in the embodiments of this invention can significantly improve the thermal stability of TEAD1 / 2 / 3 / 4 proteins.

[0124] Table 3. Thermal migration test results of TEADs family proteins prepared in this invention.

[0125] Example 41: Time-Resolved Fluorescence Resonance Energy Transfer (TR-FERT) Activity Assay TR-FRET experiments were performed in experimental buffer (50 mM HEPES pH 7.5, 200 mM NaCl, and 0.1% Pluronic F-68 solution). The synthesis method of the TR-FRET tracer WZJ10 is described in the reference (…). J Med Chem.2023, 66(7), 4617-4632). In the experiment, 100 nM His-TEAD-YBD recombinant protein was added to a 384-well plate, pretreated with the compound prepared in the TEAD inhibitor example for 5 h, then 800 nM WZJ-10 was added, and finally MAb Anti-6HISTb cryptate Gold htf (PerkinElmer, #61HI2TLA) was added to a final concentration of 50 ng / mL. TR-FRET signals (490 / 520 nm) were collected using a PHERAstarFSX plate reader (BMG Labtech). Compound IC 50 The values ​​were obtained using GraphpadPrism 8.0 software. The test results are shown in Table 4.

[0126] Table 4. IC50 values ​​of the FRET inhibitory activity of the TEADs family of small molecule compounds prepared in this invention.

[0127] Example 42: Cell line proliferation toxicity test NCI-H226 and NCI-H2452 cells were cultured in RPMI 1640 complete medium. Normally growing cells were digested with trypsin-based cell digestion solution, centrifuged, counted, and seeded into 96-well plates at a density of 1000 cells per well. After 24 h of cell seeding, the cells were treated with 10 μL of an inhibitor at different concentration gradients per well, with three replicates for each concentration. The starting concentration was 20 μM, and the cells were diluted 4-fold each time. A corresponding 0.1% DMSO negative control group was also included. After 72 h of drug treatment, the cell culture plates were removed from the incubator, the culture medium in the 96-well plates was aspirated, and 190 μL of RPMI 1640 complete medium was added again. The cells were then cultured again for 72 h. The 96-well plates were then removed and allowed to equilibrate at room temperature for 10 min. The culture medium in the 96-well plates was aspirated, and 200 μL of CellTiter-Lumi was added. TM Chemiluminescence cell viability assay solution (mixed 1:1 with culture medium) was shaken for two minutes and then reacted at room temperature for 10 minutes. 150 μL of the solution was transferred from a clear 96-well plate to a 96-well white plate for chemiluminescence readings. Cell viability was calculated by subtracting the background value from the reading in each well. Viability (%) = (Sample / Vehicle-1)*100. Sample represents the chemiluminescence of the drug-treated group, and Vehicle represents the absorbance of the DMSO control group. Using GraphPad Prism 7.0 software, an S-shaped dose-viability curve was plotted using a nonlinear regression model, and the IC50 was calculated. 50 or GI 50Values. Test results are shown in Table 5 and Figure 1 As shown.

[0128] Table 5. Cell line proliferation toxicity test results of the small molecule compounds prepared in this invention.

[0129] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A compound of formula I, or its stereoisomers, racemates, deuterated compounds, pharmaceutically acceptable salts, crystalline forms, prodrugs, or solvates: in, R1select-C(=O) R a , -C(=O) OR a -S(=O)R a , -SO2R a ,; R a Selected from C1~C 10 Alkyl, C2~C 10 alkenyl, C2~C 10 Alkynyl; the alkyl, alkenyl, or alkynyl group is non-substituted, or is substituted by one or more R groups. a1 replace; R a1 Selected from deuterium, halogens, -OH, -CN, -NO2; R2 is selected from hydrogen, deuterium, and C1~C2. 10 Alkyl, 3-10 membered cycloalkyl, C1-C 10 The alkoxy group; the alkyl, cycloalkyl, or alkoxy group is unsubstituted, or is replaced by -NH-C(O)-R b -C(O)-NH-R b replace; R b Selected from 6-12 aryl groups, 5-10 heteroaryl groups, or R5 forming a 3-10 heterocyclic alkyl group with the atom attached to it; the aryl or heteroaryl group is non-substituted, or is formed by one or more R groups. a1 Substitution; the heterocyclic alkyl group is unsubstituted, or replaced by -C(O)-NH-R c replace; R c Selected from 6-12 aryl and 5-10 heteroaryl groups; R3 is selected from C1~C 10 Alkyl, 3-10 membered cycloalkyl, -C0-C4 alkylene-(3-10 membered cycloalkyl), C1-C 10 alkoxy groups, C6~C 18 Aryl; the alkyl, cycloalkyl, alkoxy, and aryl groups are non-substituted, or are substituted by one or more R groups. d replace; R d Selected from hydrogen, deuterium, halogens, -OH, -CN, Cl~C 10 Alkyl, C1~C 10 alkoxy, 6-12 aryl, -C(O)R e -S-C1~C4 alkyl, -S-C1~C4 haloalkyl, 5~10 heteroaryl-C0~C4 alkylene-NH-acrylate; R e Selected from C1~C 10 Alkyl, C1~C 10 alkoxy groups.

2. The compound of formula I according to claim 1, characterized in that: R1 is selected from , , , , , , , , ; where n is selected from natural numbers between 0 and 4.

3. The compound of formula I according to claim 1, characterized in that: R3 is selected from , , , , Wherein, n is defined as in claim 2, and m is selected from natural numbers between 0 and 4.

4. The compound of formula I according to claim 1, characterized in that: R3 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , .

5. The compound of formula I according to claim 1, characterized in that: Compounds of Formula I are selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 6. A method for preparing a compound of formula I according to any one of claims 1 to 5, characterized in that: Includes the following steps: Compound of Formula II The compound of formula I was prepared by reacting it with compound R3-N3 of formula III. The definitions of R1, R2, and R3 are as described in any one of claims 1 to 5.

7. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 5, or a stereoisomer thereof, a racemic mixture thereof, a deuterated compound thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, and optionally, a pharmaceutically acceptable carrier or excipient.

8. The use of a compound of formula I according to any one of claims 1 to 5, or a stereoisomer thereof, a racemic mixture thereof, a deuterated compound thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, or the pharmaceutical composition of claim 7 in the preparation of a medicament for treating diseases mediated by TEADs.

9. The use of a compound of formula I according to any one of claims 1 to 5, or a stereoisomer thereof, a racemic mixture thereof, a deuterated compound thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, or the pharmaceutical composition of claim 7 in the preparation of a medicament having the activity of binding to TEAD and blocking the interaction between YAP / TAZ and TEAD.

10. The application according to claim 8, characterized in that: The diseases or conditions mediated by TEAD are selected from: colon cancer, diffuse large B-cell lymphoma, follicular lymphoma, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer; brain tumors, neuroblastoma, schwannoma, glioma, glioblastoma and astrocytoma; cervical cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, parathyroid tumors, uterine tumors and soft tissue sarcomas, cardiovascular diseases, neurodegenerative diseases, malaria, AIDS, gout, diabetes, renal failure, and chronic lung diseases.

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