Benzopyran COX-2 inhibitors and uses thereof

Abstract

The application belongs to the field of medicine, and specifically discloses a benzopyran COX-2 inhibitor and application thereof. The benzopyran COX-2 inhibitor is a compound shown in formula (I) or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, prodrug or isotopic variant thereof. The compound shown in formula (I) has good COX-2 selective inhibitory activity, and an optimal compound has an IC 50 as low as 28 nmol / L, can reduce gastrointestinal side effects and renal toxicity, has excellent inhibitory effect on PGE2, has almost no inhibitory effect on hERG channel current, has low cardiotoxicity, has high stability in human and rat liver microsomes, has a long half-life and a fast peak time when administered orally or by injection, and can be used for the treatment of anti-inflammatory analgesic diseases and tumor-related diseases through injection and oral absorption administration.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a benzopyran COX-2 inhibitor and an application thereof. Background Art

[0002] Inflammatory diseases are caused by an excessive or persistent inflammatory response to infection, injury, or other stimuli. These diseases involve multiple organs and systems, including the cardiovascular, digestive, and nervous systems. Although epoxide hydrolase 2 (COX-2) inhibitors are currently available for market, they still fall short of meeting the growing clinical needs of patients. Therefore, the development of anti-inflammatory and analgesic drugs remains a key area of ​​drug research and development.

[0003] Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of medications used to relieve pain, fever, and inflammation and are widely used in clinical practice. However, long-term use of NSAIDs can easily lead to gastrointestinal bleeding and cardiovascular toxicity. NSAIDs exert their effects by inhibiting the activity of epoxide hydrolases and are widely used to treat inflammation. However, most of these drugs are non-selective and tend to inhibit both epoxide hydrolase 1 (COX-1) and epoxide hydrolase 2 (COX-2). Most researchers believe that the pharmacological effects and adverse reactions of NSAIDs depend on the degree of inhibition of COX-1 and COX-2: stronger COX-1 inhibition leads to greater gastrointestinal and renal adverse reactions; stronger COX-2 inhibition leads to more pronounced anti-inflammatory and analgesic effects. Coxib class NSAIDs (selective COX-2 inhibitors) promptly arise at the historic moment under this theoretical background, and representative drugs are celecoxib (celecoxib), rofecoxib (rofecoxib), valdecoxib (valdecoxib), and its major advantage is that gastrointestinal adverse reaction is few.It is generally believed that selective COX-2 inhibitors, owing to not acting on COX-1, do not affect the synthesis of PGI2 that gastrointestinal tract and kidney are protected, and gastrointestinal side effect and nephrotoxicity are all less than general NSAIDs.Although existing selective COX-2 inhibitors can reduce gastrointestinal side effect and nephrotoxicity to a certain extent, can bring more benefits than traditional nonsteroidal anti-inflammatory drugs, but also may bring some new problems, for example celecoxib is suitable with NSAIDs to the therapeutic effect of chronic inflammation, but their acute analgesic effect is not as good as ibuprofen, and can produce larger cardiovascular side effect.Therefore, still need to develop the COX-2 selective inhibitor that safety and selectivity are better. Summary of the Invention

[0004] In order to overcome at least one technical problem existing in the above-mentioned prior art, one of the objects of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, prodrug, or isotopic variant thereof.

[0005]

[0006] A second object of the present invention is to provide a pharmaceutical composition.

[0007] The third object of the present invention is to provide the use of the above-mentioned compound in the preparation of anti-inflammatory and analgesic drugs or drugs for preventing or treating tumors.

[0008] In order to achieve the above object, the technical solution adopted by the present invention is:

[0009] The first aspect of the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, prodrug, or isotopic variant thereof.

[0010]

[0011] wherein R1 is selected from H, substituted or unsubstituted C 2～5 alkyl;

[0012] R2 is selected from H, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 2-6 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-6 Cycloalkyl, hydroxyalkyl, alkoxyalkyl;

[0013] R3 is selected from H, hydroxyl, alkoxy;

[0014] X is selected from fluorine, chlorine, bromine, iodine, and sulfur pentafluoride;

[0015] The substitution is substituted by at least one of F, Cl, bromine, I, and D, and the number of substitutions is from single substitution to the maximum number of substitutions;

[0016] When R2 is -CD3 or CH3, R1 and / or R3 are not H.

[0017] In some embodiments of the present invention, C 2～5The alkyl group is selected from -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH(CH3)CH2CH3, -CH2CH2CH2CH2 CH3, -C(CH3)2CH2CH3, -CH2C(CH3)2CH3, -CH2CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH2CH(CH3)CH2CH3, -CH2C(CH3)3.

[0018] In some embodiments of the present invention, C 1～4 Alkyl is selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3 or -CH(CH3)CH2CH3.

[0019] In some embodiments of the present invention, C 2-6 Unsaturated hydrocarbon group is selected from -CH=CH2, -CH=CHCH3,

[0020] -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=C(CH3)2, -C(CH3)=CH(CH3), -CH=CHCH2CH2CH3, -CH2CH2CH=CHCH3, -CH2CH2CH2CH=CH2, -CH=CHCH(CH3)2, -C H=C(CH3)CH2CH3, -C(CH3)=C(CH3)2, -CH=CHCH2CH2CH2CH3, -CH2CH2CH2CH=CHCH3, -CH2CH2CH2CH2CH=CH2, -CH=CHCH2CH(CH3)2, -CH=C(CH3)CH2CH2CH3, -C(CH3)=CHCH(CH3)2.

[0021] In some embodiments of the present invention, C 3-6 The cycloalkyl radical is selected from the group consisting of cyclopropyl, cyclobutyl, methylcyclopropyl, cyclopentyl, ethylcyclopropyl, methylcyclobutyl, methylcyclopentyl, cyclohexyl, propylcyclopropyl, ethylcyclobutyl.

[0022] In some embodiments of the present invention, the hydroxyalkyl group is selected from the group consisting of hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, and hydroxyheptyl.

[0023] In some embodiments of the invention, the alkoxyalkyl group is selected from methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, methoxyheptyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, ethoxyheptyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, propoxyhexyl, propoxyheptyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, butoxyhexyl, butoxyheptyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, pentoxyhexyl, and pentoxyheptyl.

[0024] In some embodiments of the present invention, R1 is selected from H, substituted or unsubstituted C 3～5 alkyl.

[0025] In some embodiments of the present invention, the R1 is selected from H, substituted or unsubstituted tert-butyl.

[0026] In some embodiments of the present invention, R2 is selected from H, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 2-4 Unsaturated hydrocarbon group, substituted or unsubstituted C 3-4 Cycloalkyl, hydroxy C 1～4 Alkyl, C 1～4 Alkoxy C 1～3 alkyl.

[0027] In some embodiments of the present invention, R2 is selected from -CH3, -CH2F, -CHF2, -CF3, -CF2D, -CFD2, -CH2D, -CHD2, -CD3, -CF=CH2, -CF=CHF, -CF=CF2, -CH=CF2, -CD=CD2, -CH=CD2, -CH=CHD, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH(CF3)2, -CH2CF3, -CHFCF3, -CF2CF3, -CH2CHF2, -CH2CH2F, -CH=CHCH3, -CF2CD3, -C(CH3)=CH2, -CH2CH2CH2CH3, cyclopropyl, cyclobutyl, vinyl, propenyl, butenyl, ethynyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, and propoxymethyl.

[0028] In some embodiments of the present invention, R1 and R3 are H, X is selected from fluorine, chlorine, bromine, sulfur pentafluoride; R2 is selected from fluorine and deuterium substituted C 1-4 Alkyl, substituted or unsubstituted C 2-4 Unsaturated hydrocarbon group.

[0029] In some embodiments of the present invention, R1 and R3 are H, X is selected from fluorine, chlorine, bromine, sulfur pentafluoride; R2 is selected from fluorine and deuterium substituted C 1-2 Alkyl, substituted or unsubstituted C 2-4 Unsaturated hydrocarbon group.

[0030] In some embodiments of the present invention, R1 and R3 are H, X is selected from fluorine, chlorine, bromine, sulfur pentafluoride; R2 is selected from -CF2D, -CFD2, vinyl, -C(CH3)=CH2, -CH=CHCH3, -CD=CD2.

[0031] In some embodiments of the present invention, R1 and R3 are H, X is selected from bromine, sulfur pentafluoride; R2 is selected from -CF2D, -CFD2, vinyl, -C(CH3)=CH2, -CH=CHCH3, -CD=CD2.

[0032] In some embodiments of the present invention, the number of substitutions is 1, 2, 3 or 4.

[0033] In some embodiments of the present invention, the compound is selected from

[0034]

[0035] In some embodiments of the present invention, the pharmaceutically acceptable salt comprises an alkali metal salt, an alkaline earth metal salt or an ammonium cation salt. In some embodiments of the present invention, the pharmaceutically acceptable salt comprises an aluminum salt, an ammonium salt, a calcium salt, a ferric salt, a ferrous salt, a lithium salt, a magnesium salt, a manganic salt, a manganous salt, a potassium salt, a sodium salt or a zinc salt.

[0036] The compound represented by formula (I) of the present invention or its pharmaceutically acceptable salt, ester, solvate, stereoisomer, prodrug, isotope variant has good COX-2 selective inhibition and can be used as a benzopyran COX-2 inhibitor.

[0037] The second aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound described in the first aspect of the present invention and a pharmaceutically acceptable excipient.

[0038] In some embodiments of the present invention, the dosage form of the pharmaceutical composition is selected from tablets, lozenges, lozenges, aqueous suspensions, oil suspensions, aqueous-oil suspensions, powders, granules, emulsions, hard capsules, soft capsules, syrups or elixirs.

[0039] The third aspect of the present invention provides the use of the compound described in the first aspect of the present invention in the preparation of anti-inflammatory and analgesic drugs or drugs for preventing or treating tumors.

[0040] In some embodiments of the present invention, the inflammation includes rheumatoid arthritis, gouty arthritis, osteoarthritis, spondylitis, systemic lupus erythematosus, psoriasis, eczema, subcutaneous inflammation, postpartum inflammation, intestinal disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, migraine, headache, periarteritis, thyroiditis, aplastic anemia, Hodgkin's disease, rheumatic fever, type I diabetes, neuromuscular disease, retinitis, conjunctivitis, retinal disease, uveitis, day blindness, acute injury to eye tissue, viral infection and cystic fibrosis pneumonia. , stroke, ischemia, mental trauma, allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, liver disease, postpartum pain, toothache, muscle pain, pain caused by cancer, Alzheimer's disease, multiple dementia, non-Alzheimer's disease, alcoholic dementia, senile dementia vascular disease, coronary heart disease, aneurysm, arteriosclerosis, atherosclerosis, myocardial infarction, embolism, stroke, thrombosis, angina pectoris, coronary artery plaque inflammation, bacterial inflammation, viral inflammation, surgical inflammation, ocular angiogenesis, retinal angiogenesis or gastric ulcer.

[0041] In some embodiments of the invention, the tumor is hemangioma, colon cancer, endometriosis, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, prostate cancer, nasopharyngeal carcinoma or leukemia.

[0042] Terms and descriptions:

[0043] As used herein, the term "deuterium" refers to a single deuterium atom, and a deuterium radical attached to a carbon atom or oxygen atom forms a deuterated compound. As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon group, including both branched and straight-chain groups, having a specific number of carbon atoms. For example, the definition of "C1-C5 alkyl" includes groups having 1, 2, 3, 4, or 5 carbon atoms in a straight or branched chain arrangement. For example, "C1-C5 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and the like.

[0044] The present invention includes free forms of compounds of formula (I), as well as pharmaceutically acceptable salts and stereoisomers thereof. The term "free form" refers to a compound in a non-salt form. The pharmaceutically acceptable salts include not only exemplary salts of the specific compounds described herein, but also typical pharmaceutically acceptable salts of all free forms of compounds of formula (I). The free forms of specific salts of the compounds can be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous base solution, such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, a dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate. The free form differs somewhat from its respective salt form in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention, such acid salts and base salts are equivalent to their respective free forms in other pharmaceutical aspects.

[0045] Pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing a basic or acidic moiety by conventional chemical methods. Typically, salts of basic compounds are prepared by ion exchange chromatography or by reacting a free base with a stoichiometric amount or an excess of an inorganic or organic acid in the desired salt form in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

[0046] Therefore, pharmaceutically acceptable salts of the compounds of this invention include conventional non-toxic salts of the compounds of this invention formed by reacting an alkaline compound of this invention with an inorganic or organic acid. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.

[0047] Base addition salts can be prepared in situ during the final separation and purification of the compounds of the invention by reacting the carboxylic acid-containing moiety with a suitable base, such as, but not limited to, hydroxides, carbonates, or bicarbonates of pharmaceutically acceptable metal cations, or with ammonia or organic primary, secondary, or tertiary amines. Pharmaceutically acceptable salts include, but are not limited to, alkali metal or alkaline earth metal cation salts such as, but not limited to, lithium, iron, sodium, manganese, potassium, zinc, calcium, magnesium, and aluminum, and non-toxic quaternary ammonium and amine cation salts, including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, and the like. Other representative organic amines that can be used to form base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0048] Since deprotonated acidic moieties such as carboxyl groups in the compounds may be anionic under physiological conditions, and this charge may then be balanced by internal cationic protonated or alkylated basic moieties such as tetravalent nitrogen atoms, it should be noted that the compounds of the present invention are potential inner salts or zwitterions.

[0049] The compound represented by formula (I) of the present invention can be prepared by reacting deuterated phenol as a starting material through three synthetic steps. For example, the following synthetic route can be used:

[0050]

[0051] The compound represented by formula (I) of the present invention or its pharmaceutically acceptable salts, esters, solvates, stereoisomers, prodrugs, and isotopic variants can be used in combination with other traditional anti-inflammatory drugs currently in use or in the development stage, such as steroids, non-steroidal drugs, iNOS inhibitors, LTB4 receptor agonists, LTA4 hydrolase inhibitors, etc., to enhance their clinical anti-inflammatory and analgesic effects. It can also be used in combination with antibiotics, alkylating drugs, antimetabolites, hormone drugs, immune drugs, interferon drugs, and other mixed drugs currently in use or in the development stage to enhance their clinical therapeutic or tumor inhibitory effects.

[0052] Dosage and dosage range

[0053] The compounds of the present invention may be administered to mammals, preferably humans, alone or in pharmaceutical compositions in combination with a pharmaceutically acceptable carrier, excipient, or diluent according to standard pharmaceutical techniques. The compounds / compositions may be administered orally or subcutaneously, intramuscularly, intraperitoneally, intravenously, rectally, topically, to the eyes, lungs, nasally, or parenterally.

[0054] When the compound of formula (I) is used for anti-inflammatory, analgesic, or cancer treatment, the oral dosage range is 0.1 to 500 mg / day / kg body weight. Suitable administration methods include single daily doses, multiple doses such as two, three, or four times daily, or administration using sustained-release technology. For many large mammals, the preferred dosage range is 0.1 to 1500 mg / day / kg body weight, preferably 0.5 to 100 mg / day / kg body weight. For patients with an average body weight of 70 kg, the daily dosage range is 1 to 500 mg. For some particularly active compounds, the daily dosage for adult patients can be as low as 0.1 mg / day.

[0055] The pharmaceutical composition containing the active ingredient can be prepared in a form suitable for oral administration, such as tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral administration can be prepared according to any method known in the art of manufacturing pharmaceutical compositions, and to provide pharmaceutically refined and palatable preparations, such compositions may contain one or more agents selected from sweeteners, flavorings, colorants, and preservatives. Tablets contain the active ingredient together with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binders such as starch, gelatin, polyvinyl pyrrolidone, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets can be uncoated or coated by known techniques to mask the unpleasant taste of the drug or to prolong disintegration and absorption in the gastrointestinal tract and thereby provide a longer-lasting drug effect. For example, water-soluble raw materials such as hydroxypropyl-methylcellulose or hydroxypropylcellulose can be used to mask the taste, or time-delay raw materials such as ethylcellulose and cellulose acetate butyrate can be used. Tablet dosage forms can be 0.1 mg / tablet, 0.2 mg / tablet, 0.25 mg / tablet, 0.5 mg / tablet, 1 mg / tablet, 2 mg / tablet, 5 mg / tablet, 10 mg / tablet, 25 mg / tablet, 50 mg / tablet, 100 mg / tablet and 250 mg / tablet. Other dosage forms such as capsules can be used as similar dosage references.

[0056] Preparations for oral use can also be prepared as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin; or as soft gelatin capsules in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oily medium such as peanut oil, liquid paraffin or olive oil.

[0057] Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic; dispersants or wetting agents which may be naturally occurring phosphatides such as lecithin, or condensation products of alkylene oxides with fatty acids such as polyoxyethylene stearate, or condensation products of alkylene oxides with long-chain fatty alcohols such as heptadecaethyleneoxycetanol, or condensation products of alkylene oxides with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of alkylene oxides with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.

[0058] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. Such oily suspensions can contain thickeners such as beeswax, paraffin wax or cetyl alcohol. Sweeteners and flavorings as described above can be added to provide preparations suitable for oral administration. These compositions can be stored by adding antioxidants such as butylated hydroxyanisol or alpha tocopherol.

[0059] Dispersible powders or granules are suitable for preparing an aqueous suspension by adding water to provide the active ingredient in admixture with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are described above in the examples mentioned. Other excipients such as sweeteners, flavorings, and coloring agents may also be present. These compositions may be stored by adding an antioxidant such as ascorbic acid.

[0060] The composition of the present invention can also be prepared in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids such as soybean lecithin, and esters or partial esters derived from a mixture of fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and alkylene oxides such as polyoxyethylene sorbitan monooleate. This emulsion can also contain sweeteners, flavorings, preservatives, and antioxidants.

[0061] Syrups and elixirs may be prepared using sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain a wetting agent, a preservative, flavoring and coloring agents and an antioxidant.

[0062] The pharmaceutical composition can be prepared as a sterile injectable aqueous solution. Among the acceptable carriers and solvents, water, Ringer's solution and isotonic sodium chloride solution can be used.

[0063] This sterile injectable preparation can also be prepared as a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is first dissolved in a mixture of soybean oil and lecithin, and the oil solution is then placed in a mixture of water and glycerol and processed to form a microemulsion.

[0064] Such injectable solutions or microemulsions can be introduced into the patient's bloodstream by local bolus injection. Alternatively, administering the solution or microemulsion in this manner can be advantageous in maintaining a constant circulating concentration of the compound. To maintain such a constant concentration, a continuous intravenous delivery device can be utilized. An example of such a device is the Deltec CADD-PLUS TM model 5400 intravenous pump.

[0065] Such pharmaceutical compositions can be prepared as sterile injectable solutions or oily suspensions for intramuscular or subcutaneous administration. Such suspensions can be prepared according to known techniques using the dispersants or wetting agents and suspending agents mentioned above. Sterile injectable formulations can also be prepared as sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. In addition, fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid have been found to be useful in injectable formulations.

[0066] Compound shown in formula (I) can also be administered in the form of a suppository for rectal administration. These compositions can be prepared by mixing drugs with suitable non-irritating adjuvants, which are solid at room temperature but liquid at rectal temperature and therefore melt in the rectum to release the drug. This raw material includes theobroma oil, glycerin gelatin, hydrogenated vegetable oil, mixtures of various molecular weight polyethylene glycols, and polyethylene glycol fatty acid esters.

[0067] For topical use, creams, ointments, gels, solutions or suspensions containing a compound of formula (I) are employed (for this purpose, topical applications include mouthwashes and gargles).

[0068] Compound shown in formula (I) of the present invention can be administered with intranasal form through the local use of suitable intranasal carrier and delivery device, or the form administration of skin patch well known to those of ordinary skill in the art is used through the skin.After administration with the form of transdermal delivery system, the dosage of whole dosage regimen is of course continuous than intermittent administration. The compounds of this invention can also be delivered as suppositories, the matrix such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oil, mixture of various molecular weight polyethylene glycols and polyethylene glycol fatty acid esters.

[0069] If the compounds of the present invention are administered to human subjects, the daily dosage will normally be determined by the prescribing physician, usually adjusting the dosage accordingly based on the age, weight, sex and response of each patient, and the severity of the patient's symptoms.

[0070] Drug metabolites and prodrugs:

[0071] Metabolites of the compounds of the present invention and pharmaceutically acceptable salts thereof, as well as prodrugs that can be converted into the structures of the compounds of the present invention and pharmaceutically acceptable salts thereof in vivo.

[0072] Combination medication:

[0073] The compound of formula (I) can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the original drug's mode of administration and dosage remain unchanged, and the compound of formula (I) is taken simultaneously or subsequently. When the compound of formula (I) is taken simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the compound of formula (I). Drug combination also includes taking the compound of formula (I) and one or more other known drugs during overlapping time periods. When the compound of formula (I) is used in combination with one or more other drugs, the dosage of the compound of formula (I) or the known drug may be lower than when they are taken alone.

[0074] Drugs or active ingredients that can be used in combination with the compound of formula (I) include but are not limited to:

[0075] 1) Traditional steroid anti-inflammatory analgesics, such as dexamethasone and diethylstilbestrol;

[0076] 2) Non-steroidal anti-inflammatory analgesics, such as diclofenac, clofenamic acid, metamizole, aminobivor, aspirin, phenylbutazone, piroxicam, indomethacin, naproxen, ibuprofen, piroxicam, cemethicone, nabumetone, ketoprofen, ketorolac, tetraclofenamic acid, sulindac, magnesium salicylate, sodium salicylate, choline magnesium salicylate, diflunisal, and disalsalate;

[0077] 3) LTB4 receptor antagonists, such as CGS-25019C, ETH-615, T-0757, LY-213024, LY-210073, LY223982, LY233469, ON0-LB457, ON0-4057, ON0-LB-448, SC-53228, SC-41930, SC-50605, SC-51146, SB-209247;

[0078] 4) 5-L0 inhibitors, such as A-76745, 78773, ABT761, CMI-392, E-3040, ML-3000, PF-5901, EF-40, F-1322, ML-3000, and R-840;

[0079] 5) iN0S inhibitors;

[0080] 6) LTA4 hydrolase inhibitors, such as RP-64966;

[0081] 7) Mu receptor antagonists;

[0082] 8) Kappa receptor antagonists;

[0083] 9) neurokinins receptor antagonists;

[0084] 10) Antibiotic anticancer drugs, such as Taiho4181A, Takeda TAN-868A, FujisawaFK-973, Bristol-Myers BL-6859, KM-5539, KT-5432;

[0085] 11) Alkylating anticancer drugs, such as Shionogi 254-S, Sanofi CY-233, Degussa D-19-384, NCINSC-164395, NCI NSC-342215, Proter PTT-119;

[0086] 12) Antimetabolite drugs, such as Lilly DATHF, Lilly LY-188011, Lilly LY-264618, NCINSC-127716, NCI NSC-164880, NCI NSC-39661, and NCI NSC-612567;

[0087] 13) Hormonal anticancer drugs;

[0088] 14) Immune anticancer drugs;

[0089] 15) Interferon anticancer drugs;

[0090] The combination of drugs includes the combination of the compound represented by formula (I) with one of the above drugs, and also includes the combination with two or more of the above drugs.

[0091] The beneficial effects of the present invention are: the compound represented by formula (I) of the present invention has good COX-2 inhibitory activity, and the preferred compound has an IC 50 As low as 28nmol / L, it has a high COX-2 selective inhibitory effect, which can reduce gastrointestinal side effects and nephrotoxicity; it has excellent inhibitory effect on PGE2 (whole blood experiment); it has almost no inhibitory effect on hERG channel current and low cardiac toxicity; at the same time, it has high stability in both human and rat liver microsomes, and when administered orally or by injection, it has a long half-life, a faster time to peak blood concentration, and a larger area under the blood concentration-time curve. It can be absorbed and administered by injection and oral administration for the treatment of anti-inflammatory and analgesic diseases and tumor-related diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0092] Figure 1 is a graph showing the tumor diameter-time relationship obtained when mouse tumors were treated with the compound in Example 2 and GIBH-1014;

[0093] Figure 2 This is a test graph of data when using the compound in Example 2, GIBH-1014, SC-75416 and indomethacin to treat paw swelling. DETAILED DESCRIPTION

[0094] The specific implementation of the present invention will be further described in detail below in conjunction with the accompanying drawings and examples, but the implementation and protection of the present invention are not limited thereto. It should be noted that if there are any processes that are not particularly described in detail below, they can be implemented or understood by those skilled in the art with reference to the prior art. The reagents or instruments used that do not indicate the manufacturer are all conventional products that can be purchased commercially.

[0095] Example 1

[0096] The chemical name of the compound in this example is: (S)-6-bromo-8-(fluoromethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0097]

[0098] (1) Synthesis of 5-bromo-2-hydroxy-1,3-benzenedicarboxaldehyde

[0099]

[0100] Dissolve 4-bromophenol (1 g, 5.81 mmol) in trifluoroacetic acid (10 mL). Add hexamethylenetetramine (3.26 g, 23.3 mmol) at 0°C. Replace the nitrogen atmosphere and allow to react at 120°C for 24 hours. Cool to room temperature, add hydrochloric acid (4 mol / L, 33 mL), and react at 80°C for 4 hours. Stir overnight at room temperature. Filter with suction, wash the filter cake with hydrochloric acid (1 mol / L, 10 mL), filter, and dry to obtain 500 mg of pure 5-bromo-2-hydroxy-1,3-benzenedicarboxaldehyde as a yellow solid in a 38% yield. 1 H NMR (400MHz, DMSO-d6) δ11.62(s,1H),10.20(s,2H),8.13(s,2H).

[0101] (2) Synthesis of ethyl 6-bromo-8-formaldehyde-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0102]

[0103] 5-Bromo-2-hydroxy-1,3-benzenedicarboxaldehyde (228 mg, 1 mmol) was added to a sealed tube, the atmosphere was replaced with nitrogen, and DMSO (1 mL), triethylamine (0.28 mL, 2 mmol), and ethyl trifluorocrotonate (252 mg, 1.5 mmol) were added. The reaction was allowed to proceed at 80°C for 8 h. TLC analysis indicated the formation of new spots and the complete consumption of the starting material. The product was cooled and diluted with ethyl acetate (5 mL), washed with saturated sodium bicarbonate (5 mL), 1 mol / L hydrochloric acid (5 mL), and saturated brine (5 mL), dried over anhydrous Na2SO4, and the solvent was evaporated. Column chromatography (eluent: petroleum ether (PE) to ethyl acetate (EA) in a 10:1 volume ratio) afforded 85 mg of the pure product as a white solid in a 23% yield. 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),8.12(d,J=2.5Hz,1H),8.01(s,1H),7.86( d, J=2.5Hz, 1H), 6.25 (q, J=7.0Hz, 1H), 4.44-4.00 (m, 2H), 1.29 (t, J=7.1Hz, 3H).

[0104] (3) Synthesis of ethyl 6-bromo-8-carboxy-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0105]

[0106] 6-Bromo-8-formaldehyde-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid ethyl ester (37.8 mg, 0.1 mmol) was dissolved in a tert-butyl alcohol / 2-methyl-2-butene (2 mL / 0.5 mL) mixed solution. Sodium chlorite (83 mg, 0.92 mmol) and sodium dihydrogen phosphate (83 mg, 0.69 mmol) were dissolved in water (1 mL) at 0°C and slowly added dropwise to the above solution to obtain a pale yellow mixture, which was stirred at room temperature overnight. TLC monitored that the starting material was completely consumed, and the organic solvent was spin-dried. The residue was dissolved in water (2 mL), adjusted to pH 3 with HCl, extracted with EA (5 mL × 3), washed with cold water, dried and concentrated, and washed with petroleum ether (2 × 2 mL) to obtain 30 mg of pure product as a white solid in a yield of 76%. 1 H NMR (400MHz, DMSO-d6) δ13.49(s,1H),7.97(d,J=2.6Hz,1H),7.96(s,1H),7.86(d,J= 2.5Hz, 1H), 6.12 (q, J = 7.1Hz, 1H), 4.28 (dd, J = 7.1, 5.4Hz, 2H), 1.28 (t, J = 7.1Hz, 3H).

[0107] (4) Synthesis of ethyl 6-bromo-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0108]

[0109] Ethyl 6-bromo-8-carboxy-2-trifluoromethyl-2H-benzopyran-3-carboxylate (4.88 g, 12.34 mmol) was placed in a three-necked flask, the atmosphere was replaced with nitrogen, and tetrahydrofuran (40 mL) was added. A solution of deuterated borane in tetrahydrofuran (16 mL, 1 mol / L) was slowly added dropwise at 0°C. Stirring was continued at this temperature for 30 min, and the mixture was moved to 60°C and allowed to react overnight. TLC monitoring indicated complete consumption of the starting material and the formation of new spots. The reaction was quenched with heavy water (D2O) (2 mL), extracted with EA (40 mL × 2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and spin-dried. Column chromatography (eluent: PE and EA in a volume ratio of 10:1) afforded 3 g of the pure product as a white solid, with a yield of 64% and a deuteration rate of 96.5%. 1 H NMR (400MHz, DMSO-d6) δ7.94(s,1H),7.69(d,J=2.5Hz,1H),7.59(d,J=2.5Hz,1H),6. 05(q,J=7.2Hz,1H),5.35(s,1H),4.27(qd,J=7.1,5.3Hz,2H),1.28(t,J=7.1Hz,3H).

[0110] (5) Synthesis of (S)-6-bromo-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0111]

[0112] Ethyl 6-bromo-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylate (2.0 g, 5.24 mmol) was dissolved in methanol (32 mL). Aqueous NaOH (628 mg, 15.72 mmol, 16 mL) was added at 0°C and stirred at room temperature for 1 h. TLC analysis indicated the formation of new spots and the complete consumption of the starting material. The methanol was dried by spin-drying, washed with EA (20 mL), and the pH was adjusted to 1-2 with hydrochloric acid. The product was extracted with EA (30 mL x 2), washed with saturated sodium chloride (40 mL), dried over anhydrous Na2SO4, and the solvent was dried by spin-drying to obtain 1.8 g of pure 6-bromo-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid as a white solid. The yield was 97%, and the deuteration rate was 96.5%. 1 H NMR (400MHz, DMSO-d6) δ13.41(s,1H),7.86(s,1H),7.65(d,J=2.6Hz,1H),7.57(d,J=2.5Hz,1H),5.98(q,J=7.2Hz,1H),5.34(s,1H).

[0113] 6-Bromo-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid (1.8 g, 5.09 mmol) was subjected to chiral separation (column: DAICEL AD 250*30mm 10μm, 25°C, Waters SFC 150; mobile phase A:mobile phase B:supercritical CO2:IPA (containing 0.1% 7.0 mol / L ammonia in methanol) = 85:15; flow rate: 100 mL / min) to obtain (R)-6-bromo-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid (retention time RT = 3.692 min, 781.03 mg, white solid) and (S)-6-bromo-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid (RT = 5.045 min, 711.21 mg, light yellow solid). The NMR data of (R)-6-bromo-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid are: 1H NMR (400 MHz, DMSO-d6) δ7.75 (s, 1H), 7.61 (d, J = 2.5 Hz, 1H), 7.53 (d, J = 2.5 Hz, 1H), 5.96 (q, J = 7.2 Hz, 1H); the NMR data of (S)-6-bromo-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid are 1 H NMR (400MHz, DMSO-d6) δ7.81 (s, 1H), 7.63 (d, J = 2.5Hz, 1H), 7.55 (d, J = 2.5Hz, 1H), 5.97 (q, J = 7.2Hz, 1H).

[0114] (6) Synthesis of methyl (S)-6-bromo-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0115]

[0116] Under argon, a 100 mL single-necked flask was charged with the starting material (0.6 g, 1.69 mmol), potassium carbonate (0.467 g, 3.38 mmol), and 8 mL of DMF. Iodomethane (0.288 g, 2.03 mmol) was added at 0°C and allowed to react at room temperature for 1 h. TLC confirmed the complete reaction. After addition of 30 mL of methyl tert-butyl ether (MTBE), the reaction was quenched by 50 mL of ice water. The aqueous phase was washed with 20 mL of MTBE. The combined organic phases were washed with 20 mL of brine, dried over anhydrous sodium sulfate, and spun down to afford 0.7 g of a brownish-yellow oil. MS: 370.2 [M+H]+.

[0117] (7) Synthesis of (S)-6-bromo-8-(fluoromethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0118]

[0119] Under argon protection, (S)-6-bromo-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester (100 mg, 0.27 mmol) and 5 mL of dichloromethane (DCM) were added to a 100 mL single-necked bottle, cooled to -78 ° C, and diethylaminosulfur trifluoride (DAST, 131 mg, 0.813 mmol) was slowly added dropwise. The reaction was kept warm for 1.5 h. TLC showed that the reaction was complete, and 15 mL of pre-cooled saturated sodium bicarbonate solution was added dropwise to quench the reaction. The organic phase was washed with 20 mL*2 brine and dried over anhydrous sodium sulfate. The product was separated by Flash chromatography (eluent was PE and EA with a volume ratio of 10:1, R f =0.4), to give 30 mg of a white solid, with a yield of 30%.

[0120] (8) Synthesis of (S)-6-bromo-8-(fluoromethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0121]

[0122] In a 100 mL single-necked bottle, (S)-6-bromo-8-(fluoromethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester (30 mg, 0.081 mmol), 1.5 mL of methanol, 1 mL of purified water, and 1 mL of tetrahydrofuran were added. Lithium hydroxide (6 mg, 0.242 mmol) was added at 0° C., and the mixture was stirred at room temperature for 2 h. TLC monitoring indicated that the reaction was complete, the organic solvent was dried, and the mixture was extracted twice with 20 mL of methyl tert-butyl ether and water. The aqueous layer was adjusted to pH 3 with 1 mol / L hydrochloric acid, extracted with 20 mL of EA, and the organic phase was washed with 20 mL of brine, dried over anhydrous sodium sulfate, slurried with n-heptane, and centrifuged in a 1.5 mL EP tube. The mixture was dried to give 11 mg of a white powder in a 38% yield. 1 HNMR (500MHz, DMSO-d6) δ7.90 (s, 1H), 7.83 (d, J = 2.2Hz, 1H), 7.71 (d, J = 2.3Hz, 1H), 6.07 (q, J = 7.1Hz, 1H).

[0123] Example 2

[0124] The chemical name of the compound in this example is (S)-6-bromo-8-(difluoromethyl-d)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0125]

[0126] (1) Synthesis of methyl (S)-6-bromo-8-(formaldehyde-d)-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0127]

[0128] Under argon protection, (S)-6-bromo-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester (100 mg, 0.542 mmol) and 8 mL of DCM were added to a 100 mL single-necked flask, cooled to 0°C, and Dess-Martin periodinane (345 mg, 0.813 mmol) was added. The reaction was allowed to proceed at room temperature for 3 h. After the reaction of the raw materials was completed by TLC monitoring, 5 mL of saturated sodium thiosulfate aqueous solution was added dropwise at 0°C, and the DCM was dried by spin drying. 20 mL of MTBE and 15 mL of saturated sodium bicarbonate solution were added for washing. The organic phase was washed with brine and dried over anhydrous sodium sulfate. 267 mg of a white solid was obtained by spin drying, which was used directly in the next step without purification.

[0129] (2) Synthesis of (S)-6-bromo-8-(difluoromethyl-d)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0130]

[0131] Under argon protection, (S)-6-bromo-8-(formaldehyde-d)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester (267 mg, 0.429 mmol) and 10 mL of DCM were added to a 100 mL single-necked bottle, cooled to 0°C, and DAST (612 mg, 3.79 mmol) was slowly added dropwise. The reaction was carried out at 0°C for 0.5 h and stirred at room temperature for 1.5 h. TLC monitored the complete reaction of the raw material. 30 mL of saturated sodium bicarbonate solution was added dropwise at 0°C to quench the reaction. The organic phase was washed with 30 mL*2 brine and dried over anhydrous sodium sulfate. The product was separated by flash chromatography (eluent: PE:EA volume ratio = 20:1, R f =0.5), to give 130 mg of white oily semisolid, with a yield of 46%.

[0132] (3) Synthesis of (S)-6-bromo-8-(difluoromethyl-d)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0133]

[0134] In a 100 mL single-necked bottle, (S)-methyl 6-bromo-8-(difluoromethyl-d)-2-trifluoromethyl-2H-benzopyran-3-carboxylate (30 mg, 0.081 mmol), 1.5 mL of methanol, 1 mL of purified water, and 1 mL of tetrahydrofuran were added. Lithium hydroxide (6 mg, 0.242 mmol) was added at 0° C. and stirred at room temperature for 2 h. TLC monitored the complete reaction of the starting materials. The organic solvent was spin-dried, and the mixture was extracted twice with 20 mL of MTBE and water. The aqueous layer was adjusted to pH 3 with 1 mol / L hydrochloric acid, extracted with 20 mL of EA, and the organic phase was washed with 20 mL of brine, dried over anhydrous sodium sulfate, spin-dried, slurried with n-heptane, and centrifuged in a 1.5 mL EP tube. The mixture was spin-dried to obtain 11 mg of a white powder with a yield of 38%. 1 H NMR (500MHz, DMSO-d6) δ7.90 (s, 1H), 7.83 (d, J = 2.2Hz, 1H), 7.71 (d, J = 2.3Hz, 1H), 6.07 (q, J = 7.1Hz, 1H).

[0135] The preparation steps and synthetic route of the sodium salt of the compound in this example are as follows:

[0136]

[0137] To a 25 mL single-necked flask, add the starting material (1.0 g, 2.67 mmol) and ethanol (3 mL). Once the mixture becomes clear, slowly add dropwise NaOH (102.6 mg, 0.5 mol / L, 0.95 eq) dissolved in 5 mL of water. Stir at room temperature for 1.5 hours. Spin dry, add 8 mL of water, and the mixture becomes clear. Filter, wash once with 2 mL of water, and lyophilize the filtrate to obtain 1.06 g of a white solid.

[0138] The preparation steps and synthetic route of the potassium salt of the compound in this example are as follows:

[0139]

[0140] To a 50 mL single-necked flask, add the starting material (500 mg, 1.34 mmol) and ethanol (2 mL). Once the mixture becomes clear, slowly add 95% KOH (75 mg, 0.5 mol / L, 0.95 eq) dissolved in 5 mL of water dropwise. Stir at room temperature for 1.5 hours. Spin dry, add 5 mL of water, and the mixture becomes clear. Filter, wash once with 2 mL of water, and lyophilize the filtrate to yield 505 mg of a white solid.

[0141] Example 3

[0142] The chemical name of the compound in this example is: (S)-6-chloro-8-(fluoromethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0143]

[0144] (1) Synthesis of 5-chloro-2-hydroxy-1,3-benzenedicarboxaldehyde

[0145]

[0146] 4-Chlorophenol (10 g, 77.8 mmol) was dissolved in trifluoroacetic acid (TFA, 100 mL). Hexamethylenetetramine (44.2 g, 311.2 mmol) was added at 0°C, the atmosphere was replaced with nitrogen, and the mixture was allowed to react at 120°C for 24 hours. After cooling to room temperature, hydrochloric acid solution (5 mol / L, 300 mL) was added and the mixture was allowed to react at 80°C for 4 hours. The mixture was then stirred at room temperature overnight. The mixture was filtered, and the filter cake was washed with hydrochloric acid solution (1 mol / L, 50 mL), filtered, and dried to obtain 7 g of the pure product as a yellow solid in a 49% yield. 1 H NMR (400MHz, DMSO-d6) δ11.59 (s, 1H), 10.22 (d, J = 0.9 Hz, 2H), 8.02 (d, J = 0.9 Hz, 2H).

[0147] (2) Synthesis of ethyl 6-chloro-8-formaldehyde-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0148]

[0149] 5-Chloro-2-hydroxy-1,3-benzenedicarboxaldehyde (1.8 g, 10 mmol) was added to a sealed tube, the atmosphere was replaced with nitrogen, and dimethyl sulfoxide (DMSO, 11 mL), trifluoroacetic acid (TEA, 2.6 mL, 20 mmol), and ethyl trifluorocrotonate (2.24 mL, 15 mmol) were added. The reaction was allowed to proceed at 80°C for 24 h. TLC confirmed complete consumption of the starting material. The reaction was cooled, diluted with EA (40 mL), and washed with saturated sodium bicarbonate (50 mL), 1 mol / L hydrochloric acid (50 mL), and saturated brine (50 mL). The reaction was dried over anhydrous NaSO, and the solvent was evaporated. The product was purified by column chromatography (eluent: PE:EA, volume ratio = 10:1) to obtain 1.19 g of the pure product as a yellow solid in a 36% yield. 1 H NMR (400MHz, DMSO-d6) δ10.24 (s, 1H), 8.35–7.89 (m, 2H), 7.75 (d, J = 2.6Hz, 1H), 6.24 (t, J = 7.0Hz, 1H), 4.57–4.00 (m, 2H), 1.30 (t, J = 7.1Hz, 3H).

[0150] (3) Synthesis of ethyl 6-chloro-8-carboxy-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0151]

[0152] 6-Chloro-8-formaldehyde-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid ethyl ester (6.69g, 20mmol) is dissolved in tert-butyl alcohol / 2-methyl-2-butene (120mL / 30mL). Sodium chlorite (16.6g, 184mmol) and sodium dihydrogen phosphate (16.6g, 138mmol) are dissolved in water (60mL) at 0 ℃ and slowly added dropwise to the above solution. The yellow reaction mixture is stirred at room temperature overnight. TLC monitors that 6-chloro-8-formaldehyde-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid ethyl ester is completely consumed, and then the organic solvent is spin-dried, and the residue is dissolved in water (20mL), adjusted to pH=3 with HCl, extracted with EA (30mL×3), washed with cold water, dried and concentrated, and washed with petroleum ether (30×2mL) to obtain pure product 5.52g as a light yellow solid with a yield of 79%. 1 H NMR (400MHz, DMSO-d6) δ7.96 (s, 1H), 7.83 (d, J = 2.7Hz, 1H), 7.71 (d, J = 2.7Hz, 1H), 6.23–5.98 (m, 1H), 4.28 (m, 2H), 1.28 (t, J = 7.1Hz, 3H).

[0153] (4) Synthesis of ethyl 6-chloro-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0154]

[0155] Ethyl 6-chloro-8-carboxy-2-trifluoromethyl-2H-chromene-3-carboxylate (3.5 g, 10 mmol) was placed in a three-necked flask. The atmosphere was replaced with nitrogen, and 2-methyltetrahydrofuran (2-Me-THF, 50 mL) was added. A solution of deuterated borane in tetrahydrofuran (BD3·THF, 13 mL) was slowly added dropwise at 0°C. The mixture was stirred at 0°C for 30 min and then reacted at 60°C for 2 h. TLC indicated complete consumption of the starting material. The reaction was quenched with D2O (2 mL), extracted with EA (40 mL x 2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and spin-dried. The product was purified by column chromatography (eluent: PE:EA, volume ratio = 10:1) to afford 2.93 g of the pure product as a white solid, with a yield of 86% and a deuterated fraction of 96%. 1H NMR (400MHz, DMSO-d6) δ7.94(d,J=2.2Hz,1H),7.56(d,J=2.8Hz,1H),7.46(d ,J=2.7Hz,1H),6.04(m,1H),5.36(s,1H),4.27(m,2H),1.28(t,J=7.1Hz,3H).

[0156] (5) Synthesis of (S)-6-chloro-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0157]

[0158] Ethyl 6-chloro-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylate was dissolved in methanol (50 mL). Aqueous NaOH (1.05 g, 26.2 mmol, 25 mL) was added at 0°C and stirred at room temperature for 1 h. TLC monitored the complete consumption of ethyl 6-chloro-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylate. The methanol was dried by spin-drying, washed with EA (20 mL), and the pH was adjusted to 1-2 with hydrochloric acid. The product was extracted with EA (30 mL x 2), washed with saturated sodium chloride (40 mL), dried over anhydrous Na2SO4, and the solvent was dried by spin-drying to obtain 1.37 g of the pure product as a white solid in an 84% yield. LC-MS: tr = 1.436 min, 308.9 [MH]+.

[0159] 6-Chloro-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid (2.45 g, 7.89 mmol) was subjected to chiral separation (column: DAICEL AD 250*40mm 10μm, 25°C, Waters SFC 150; mobile phase A:mobile phase B:supercritical CO2:IPA (containing 0.2% 7.0 mol / L ammonia in methanol) volume ratio = 85:15; flow rate: 140 mL / min) to obtain (R)-6-chloro-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid (RT = 3.2 min, 1.14 g, pale yellow solid). 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.49 (d, J = 2.3 Hz, 1H), 7.41 (d, J = 2.8 Hz, 1H), 5.96 (q, J = 7.3 Hz, 1H). and (S)-6-chloro-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-chromene-3-carboxylic acid (RT = 4.567 min, 1.01 g, pale yellow solid), 1H NMR (400MHz, DMSO-d6) δ7.80 (s, 1H), 7.50 (s, 1H), 7.43 (s, 1H), 5.96 (q, J = 7.3Hz, 1H).

[0160] (6) Synthesis of methyl (S)-6-chloro-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0161]

[0162] Under argon, a 100 mL single-necked flask was charged with the starting material (500 mg, 1.61 mmol), potassium carbonate (445 mg, 3.22 mmol), and 8 mL of DMF. Iodomethane (0.12 mL, 1.93 mmol) was added at 0°C and allowed to react at room temperature for 2 h. After TLC monitoring, the reaction mixture was dehydrated by adding 30 mL of ethyl acetate and 50 mL of ice water to quench the reaction. The aqueous phase was extracted again with 20 mL of ethyl acetate. The combined organic phases were washed with 3 50 mL of semi-saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to obtain 480 mg of a brown oil (92% yield).

[0163] (7) Synthesis of methyl (S)-6-chloro-8-(fluoromethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0164]

[0165] Under argon, the starting material (260 mg, 0.8 mmol) and 10 mL of DCM were added to a 50 mL single-necked flask. The mixture was cooled to -78°C, and a solid precipitated. 15 mL of dichloromethane was added, followed by the slow dropwise addition of DAST (0.32 mL, 2.4 mmol) and the reaction was incubated for 1 h. TLC confirmed the complete reaction of the starting material. The reaction was quenched by the addition of 15 mL of pre-cooled saturated sodium bicarbonate solution. The product was extracted twice with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Flash chromatography was performed using an eluent of PE:EA (volume ratio) of 20:1 to yield 180 mg of an oil (69% yield).

[0166] (8) Synthesis of (S)-6-chloro-8-(fluoromethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0167]

[0168] To a 50 mL single-necked flask, add the starting material (180 mg, 0.551 mmol), 2.0 mL of methanol, and 2.0 mL of tetrahydrofuran. Add lithium hydroxide solution (40 mg of lithium hydroxide dissolved in 2.0 mL of water, 1.65 mmol) at 0°C and stir at room temperature for 2 h. TLC monitors the reaction until complete. Adjust the pH to 3-4 with 1 mol / L hydrochloric acid. Extract twice with EA. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and spin dry. Slurry with petroleum ether, centrifuge, and spin dry to obtain 140 mg of a white powder (81% yield). 1 H NMR (500MHz, DMSO-d6) δ13.49 (br s, 1H), 7.90 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 6.06 (q, J = 7.1Hz, 1H).

[0169] Example 4

[0170] The chemical name of the compound in this example is: (S)-6-chloro-8-(difluoromethyl-d)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0171]

[0172] (1) Synthesis of methyl (S)-6-chloro-8-(formaldehyde-d)-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0173]

[0174] Under argon, the starting material (220 mg, 0.677 g) and 15 mL of DCM were added to a 100 mL single-necked flask. The mixture was cooled in an ice-water bath and Dess-Martin periodinane (430 mg, 1.02 mmol) was added. The reaction was allowed to react at room temperature for 2 h. Completion of the reaction was monitored by TLC. Sodium thiosulfate aqueous solution and saturated sodium bicarbonate solution were added dropwise in an ice bath. Extraction was performed twice with dichloromethane. The organic phases were combined, washed with saturated sodium bicarbonate solution and saturated brine, and dried by spin drying. The sample was then dry-applied to a column using a 15:1 volume ratio of PE to EA to yield 200 mg of a white solid in a 92% yield.

[0175] (2) Synthesis of (S)-6-chloro-8-(difluoromethyl-d)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0176]

[0177] Under argon, a 100 mL single-necked flask was charged with the starting material (200 mg, 0.621 mmol) and 10 mL of DCM. The mixture was cooled to 0°C and slowly added dropwise with DAST (0.50 mL, 3.73 mmol). The mixture was allowed to react at 0°C for 0.5 h and then stirred at room temperature for 2 h. Completion of the reaction was monitored by TLC. The reaction was quenched by the addition of 30 mL of saturated sodium bicarbonate solution at 0°C. The mixture was extracted twice with dichloromethane, and the combined organic phases were washed with saturated brine, concentrated, and purified by column chromatography. Separation by flash chromatography using an eluent of PE:EA (volume ratio) of 25:1 afforded 195 mg of an oily product (91% yield).

[0178] (3) Synthesis of (S)-6-chloro-8-(difluoromethyl-d)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0179]

[0180] To a 500mL single-necked flask, add the starting material (195mg, 0.567mmol), 2.0mL of methanol, and 2.0mL of tetrahydrofuran. Add lithium hydroxide solution (41mg of lithium hydroxide dissolved in 2.0mL of water, 1.7mmol) at 0°C and stir at room temperature for 2h. TLC monitors the reaction until complete. Adjust the pH to 3-4 with 1mol / L hydrochloric acid. Extract twice with EA. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and spin dry. Slurry with petroleum ether, centrifuge, and spin dry to obtain 150mg of a white powder (80% yield). 1 H NMR (500MHz, DMSO-d6) δ13.57 (br s, 1H), 7.92 (s, 1H), 7.85 (d, J = 2.6Hz, 1H), 7.65 (d, J = 2.7Hz, 1H), 6.10 (q, J = 7.0Hz, 1H).

[0181] Example 5

[0182] The chemical name of the compound in this example is: (S)-6-fluoro-8-(fluoromethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0183]

[0184] (1) Synthesis of 5-fluoro-2-hydroxy-1,3-benzenedicarboxaldehyde

[0185]

[0186] 4-Fluorophenol (5 g, 44.64 mmol) was dissolved in TFA (80 mL). Hexamethylenetetramine (25 g, 178.56 mmol) was added at 0°C, the atmosphere was replaced with nitrogen, and the mixture was allowed to react at 120°C for 24 hours. After cooling to room temperature, hydrochloric acid solution (5 mol / L, 205 mL) was added and the mixture was allowed to react at 80°C for 4 hours. The mixture was then stirred at room temperature overnight. The mixture was filtered, and the filter cake was washed with hydrochloric acid solution (1 mol / L, 50 mL), filtered, and dried to obtain 2.4 g of the pure product as a yellow solid, with a yield of 32%. 1 H NMR (400 MHz, deuterated chloroform) δ 11.38 (s, 1H), 10.21 (s, 2H), 7.68 (d, J = 7.4 Hz, 2H).

[0187] (2) Synthesis of 6-fluoro-8-formaldehyde-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid ethyl ester

[0188]

[0189] 5-Fluoro-2-hydroxy-1,3-benzenedicarboxaldehyde (6.07 mg, 36.13 mmol) was added to a sealed tube, the atmosphere was replaced with nitrogen, and DMSO (40 mL), TEA (10 mL, 72.26 mmol), and ethyl trifluorocrotonate (8 mL, 54.20 mmol) were added. The reaction was allowed to react at 80°C for 24 h. TLC monitored the complete consumption of the starting material. The mixture was cooled, diluted with EA (40 mL), and washed with saturated sodium bicarbonate (50 mL), 1 mol / L hydrochloric acid (50 mL), and saturated brine (50 mL). The mixture was dried over anhydrous Na2SO4, and the solvent was evaporated. Column chromatography (eluent PE:EA, volume ratio = 10:1) afforded 8.03 g of the pure product as a white solid in a 23% yield. 1 H NMR (400MHz, DMSO-d6) δ10.27(d,J=2.8Hz,1H),8.01(s,1H),7.84(dd,J=8.1,3.2Hz,1H),7 .56(dd,J=8.4,3.2Hz,1H),6.22(q,J=7.1Hz,1H),4.38-4.22(m,2H),1.29(t,J=7.1Hz,3H).

[0190] (3) Synthesis of ethyl 6-fluoro-8-carboxy-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0191]

[0192] Ethyl 6-fluoro-8-formaldehyde-2-trifluoromethyl-2H-chromene-3-carboxylate (8.03 g, 25.25 mmol) was dissolved in tert-butanol / 2-methyl-2-butene (120 mL / 30 mL).℃ Sodium chlorite (21 g, 233.3 mmol) and sodium dihydrogen phosphate (20.9 g, 174.2 mmol) were dissolved in water (60 mL) and slowly added dropwise to the above solution. The pale yellow reaction mixture was stirred at room temperature overnight. TLC monitored the complete consumption of the starting material, then the organic solvent was spin-dried, and the residue was dissolved in water (20 mL), adjusted to pH 3 with HCl, extracted with EA (30 mL × 3), washed with cold water, dried and concentrated, and washed with petroleum ether (20 × 2 mL) to obtain 8.1 g of pure product as a white solid in a yield of 95%. 1 H NMR (400MHz, DMSO-d6) δ7.95(s,1H),7.67(dd,J=8.0,3.2Hz,1H),7.56(dd,J=8.8,3 .2Hz, 1H), 6.08 (q, J = 7.1Hz, 1H), 4.28 (qd, J = 7.1, 4.3Hz, 2H), 1.28 (t, J = 7.1Hz, 3H).

[0193] (4) Synthesis of ethyl 6-fluoro-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0194]

[0195] Ethyl 6-fluoro-8-carboxy-2-trifluoromethyl-2H-chromene-3-carboxylate (4.0 g, 11.98 mmol) was placed in a three-necked flask. The atmosphere was replaced with nitrogen, and 2-Me-THF (40 mL) was added. BD3·THF (17 mL) was slowly added dropwise at 0°C. The mixture was stirred at 0°C for 30 min and then reacted at 60°C for 2 h. TLC analysis indicated complete consumption of ethyl 6-fluoro-8-carboxy-2-trifluoromethyl-2H-chromene-3-carboxylate, with the formation of new spots. The reaction was quenched with D2O (2 mL), extracted with EA (40 mL x 2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and spin-dried. Column chromatography (eluent: PE:EA, volume ratio = 10:1) afforded 3.3 g of the pure product as a white solid, with a yield of 85% and a deuteration rate of 96%. 1 H NMR (400MHz, DMSO-d6) δ7.92(s,1H),7.34(dd,J=8.3,3.2Hz,1H),7.26(dd,J=9.4,3.2Hz,1 H), 6.00 (q, J = 7.2Hz, 1H), 5.36 (s, 1H), 4.27 (qd, J = 7.1, 4.9Hz, 2H), 1.28 (t, J = 7.1Hz, 3H).

[0196] (5) Synthesis of (S)-6-fluoro-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0197]

[0198] Ethyl 6-fluoro-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylate (2.58 g, 8.02 mmol) was dissolved in methanol (32 mL). Aqueous NaOH (962 mg, 24.06 mmol, 16 mL) was added at 0°C and stirred at room temperature for 1 h. TLC monitoring indicated the formation of new spots and the complete consumption of ethyl 6-fluoro-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylate. The methanol was dried by spin-drying, washed with EA (20 mL), and the pH was adjusted to 1-2 with hydrochloric acid. The product was extracted with EA (30 mL x 2), washed with saturated sodium chloride (40 mL), dried over anhydrous Na2SO4, and the solvent was dried by spin-drying to obtain 2.3 g of pure 6-fluoro-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid as a white solid in a yield of 97.5%.

[0199] LC-MS: tr=4.476min, 292.9[MH]+.

[0200] 6-Fluoro-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid (2.3 g, 7.8 mmol) was subjected to chiral separation (column: DAICEL AD 250*40mm 10μm, 25°C, Waters SFC 150; mobile phase A:mobile phase B:supercritical CO2:IPA (containing 0.2% 7.0 mol / L ammonia in methanol) volume ratio = 85:15; flow rate: 140 mL / min) to obtain (R)-6-fluoro-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid (RT = 2.794 min, 863.02 mg, light yellow solid) 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.28 (dd, J = 8.3, 3.3 Hz, 1H), 7.23 (dd, J = 9.4, 3.2 Hz, 1H), 5.93 (q, J = 7.3 Hz, 1H) and (S)-6-fluoro-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-chromene-3-carboxylic acid (RT = 4.562 min, 942.83 mg, light yellow solid). 1H NMR (400MHz, DMSO-d6) δ7.80 (s, 1H), 7.27 (dd, J = 8.3, 3.2Hz, 1H), 7.22 (dd, J = 9.4, 3.2Hz, 1H), 5.92 (q, J = 7.3Hz, 1H).

[0201] (6) Synthesis of methyl (S)-6-fluoro-8-(hydroxymethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0202]

[0203] Under argon, a 100 mL single-necked flask was charged with the starting material (500 mg, 1.7 mmol), potassium carbonate (470 mg, 3.4 mmol), and 8 mL of DMF. Iodomethane (0.13 mL, 2.04 mmol) was added at 0°C and allowed to react at room temperature for 2 h. TLC confirmed the complete reaction. 30 mL of ethyl acetate was added to the reaction solution, followed by 50 mL of ice water to quench the reaction. The aqueous phase was extracted again with 20 mL of ethyl acetate. The combined organic phases were washed with 3 50 mL of semi-saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to obtain 530 mg of a brownish-yellow oil (equivalent yield).

[0204] (7) Synthesis of (S)-6-fluoro-8-(fluoromethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0205]

[0206] Under argon, the starting material (293 mg, 0.95 mmol) and 20 mL of DCM were added to a 50 mL single-necked flask. The mixture was cooled to -78°C, and a solid precipitated. 15 mL of dichloromethane was added, followed by the slow dropwise addition of DAST (0.38 mL, 2.85 mmol), and the reaction was allowed to incubate for 1 h. TLC confirmed the complete reaction of the starting material, with the appearance of other impurities. The reaction was quenched by the dropwise addition of 15 mL of pre-cooled saturated sodium bicarbonate solution. The product was extracted twice with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Flash chromatography was performed using an eluent of PE:EA (volume ratio) of 20:1 to yield 160 mg of an oily substance, which cooled to white crystals, yielding 55%.

[0207] (8) Synthesis of (S)-6-fluoro-8-(fluoromethyl-d2)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0208]

[0209] To a 50 mL single-necked flask, add the starting material (160 mg, 0.515 eq), 2.0 mL of methanol, and 2.0 mL of tetrahydrofuran. Add lithium hydroxide solution (38 mg of lithium hydroxide dissolved in 2.0 mL of water, 1.55 mmol) at 0°C and stir at room temperature for 2 h. TLC monitors the reaction until complete. Adjust the pH to 3-4 with 1 mol / L hydrochloric acid. Extract twice with EA. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and spin dry. Slurry with petroleum ether, centrifuge, and spin dry to obtain 130 mg of a white solid (86% yield). 1 H NMR (500MHz, DMSO-d6) δ13.46 (br s, 1H), 7.89 (s, 1H), 7.51 (ddd, J = 8.4, 3.1, 1.7Hz, 1H), 7.41 (ddd, J = 8.9, 3.3, 1.7Hz, 1H), 6.02 (q, J = 7.2Hz, 1H).

[0210] Example 6

[0211] The chemical name of the compound in this example is (S)-6-fluoro-8-(difluoromethyl-d)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0212]

[0213] (1) Synthesis of methyl (S)-6-fluoro-8-(formaldehyde-d)-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0214]

[0215] Under argon, the starting material (240 mg, 0.778 mmol) and 15 mL of DCM were added to a 100 mL single-necked flask. The mixture was cooled in an ice-water bath and Dess-Martin periodinane (495 mg, 1.17 mmol) was added. The reaction was allowed to react at room temperature for 2 h. TLC monitored the reaction completion. Aqueous sodium thiosulfate solution and saturated sodium bicarbonate solution were added dropwise in an ice bath. The mixture was extracted twice with dichloromethane. The organic phases were combined, washed with saturated sodium bicarbonate solution and saturated brine, and then dried by spin drying. The sample was then dry-loaded using a 15:1 volume ratio of PE to EA eluent to yield 210 mg of a white solid (89%).

[0216] (2) Synthesis of (S)-6-fluoro-8-(difluoromethyl-d)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0217]

[0218] Under argon, the starting material (210 mg, 0.688 mmol) and 10 mL of DCM were added to a 100 mL single-necked flask. The mixture was cooled in an ice bath, and DAST (0.55 mL, 4.13 mmol) was slowly added dropwise. The temperature was slowly raised and stirred at room temperature for 2 h. TLC monitored the reaction for complete reaction. The reaction was quenched by adding 30 mL of saturated sodium bicarbonate solution dropwise in an ice bath. The mixture was extracted twice with dichloromethane, and the combined organic phases were added with saturated brine, concentrated, and purified by column chromatography. Separation by flash chromatography using a 20:1 volume ratio of PE to EA eluent gave 220 mg of an oily product (98% yield).

[0219] (3) Synthesis of (S)-6-fluoro-8-(difluoromethyl-d)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0220]

[0221] A 50 mL single-necked flask was charged with the starting material (220 mg, 0.672 mmol), 2.0 mL of methanol, and 2.0 mL of tetrahydrofuran. The mixture was placed in an ice bath and lithium hydroxide solution (48 mg of lithium hydroxide dissolved in 2.0 mL of water, 2.02 mmol) was added. The temperature was naturally raised and stirred at room temperature for 2 h. TLC monitored the reaction completion of the starting material. 1 mol / L hydrochloric acid was added to adjust the pH to 3-4. The mixture was extracted twice with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The mixture was slurried with petroleum ether and centrifuged. The mixture was dried to give 200 mg of a white solid (95% yield). 1 H NMR (500MHz, DMSO-d6) δ13.55(br,s,1H),7.92(s,1H),7.65(d,J=5.2Hz,1H),7.49(dd,J=8.7,3.1Hz,1H),6.06(d,J=7.1Hz,1H).

[0222] Example 7

[0223] The chemical name of the compound in this example is 6-chloro-7-tert-butyl-8-methyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0224]

[0225] (1) Synthesis of methyl 3-methoxy-2-methylbenzoate

[0226]

[0227] In a 250 mL single-necked flask, 3-methoxy-2-methylbenzoic acid (5.0 g, 30 mmol) and methanol (100 mL) were added. The mixture was protected by argon and cooled in an ice bath. Dichlorothionyl (4.0 mL, 60 mmol) was added dropwise. After the addition, the mixture was stirred at room temperature for 10 min, and the temperature was raised to 60 ° C for 3 hours. After the reaction was complete, the solvent was concentrated, ethyl acetate was added, and the mixture was washed with saturated sodium carbonate and saturated sodium chloride. The mixture was dried, concentrated, and directly proceeded to the next step.

[0228] (2) Synthesis of 2-(2-methyl-3-methoxyphenyl)propanol

[0229]

[0230] Methyl 3-methoxy-2-methylbenzoate (1.0 g, 5.55 mmol) was added to a 100 mL two-necked flask, purged with argon three times, tetrahydrofuran (20 mL) was added, cooled in an ice bath, stirred for 15 min, and methylmagnesium chloride (5.2 mL, 3.0 mol / L, dissolved in THF, 15.5 mmol) was slowly added dropwise. The mixture was stirred in an ice bath for 1 hour, and stirred at 10 ° C for 5 hours. After the reaction was complete, the mixture was quenched with saturated ammonium chloride and cooled in an ice bath. The mixture was extracted twice with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride, dried, concentrated, and subjected to column chromatography with an eluent of PE:EA volume ratio of 10:1 to give 790 mg of a white solid with a yield of 79%. 1 H NMR (500 MHz, deuterated chloroform) δ 7.13 (t, J = 7.9 Hz, 1H), 7.11–7.06 (m, 1H), 6.82–6.79 (m, 1H), 3.83 (s, 3H), 2.45 (s, 3H), 1.72 (s, 1H), 1.67 (s, 6H).

[0231] (3) Synthesis of 3-tert-butyl-2-methylanisole

[0232]

[0233] Under argon protection, 2-(2-methyl-3-methoxyphenyl)propanol (1.5 g, 8.32 mmol) and 10.0 mL of DCM were added to a 100 mL single-necked flask, cooled at 0°C, stirred for 5 min, and dichlorothionyl (1.51 mL) was slowly added dropwise. The mixture was stirred at 0°C for 3 hours (TLC showed that it was the raw material), and concentrated in an ice-water bath for 20 min; under argon protection, the mixture was cooled to -78°C, ultra-dry dichloromethane (20 mL) was added, and trimethylaluminum (10.4 mL, 1.6 mol / L, 16.64 mmol) was added dropwise after 20 min. The reaction was stirred at -78°C for 2 hours, the temperature was slowly raised naturally, and the mixture was stirred at room temperature overnight. After the reaction is complete, pour into ice water, add dichloromethane, stir for 30 minutes, separate, extract twice with DCM, combine the organic phases, wash with saturated sodium chloride, dry, pass through celite, concentrate, dilute with dichloromethane, add m-chloroperbenzoic acid (1.43 g, 8.32 mmol), stir at room temperature overnight; add silica gel and spin dry directly, eluent: PE: EA volume ratio = 100: 1, to obtain 1.0 g of colorless oil, yield: 68%. 1 H NMR (500 MHz, deuterated chloroform) δ 7.11 (t, J = 8.0 Hz, 1H), 7.05–6.98 (m, 1H), 6.76 (d, J = 8.0 Hz, 1H), 3.82 (s, 3H), 2.38 (s, 3H), 1.42 (s, 9H).

[0234] (4) Synthesis of 3-tert-butyl-2-methylphenol

[0235]

[0236] A 100 mL single-necked flask was charged with 3-tert-butyl-2-methylanisole (1.2 g, 6.73 mmol). A constant-pressure dropping funnel was installed and the atmosphere was replaced with argon. Extra-dry dichloromethane (20.0 mL) was added. Boron tribromide (13.5 mL, 13.46 mmol, 1.0 mol / L, dissolved in DCM) was then added to the constant-pressure dropping funnel. The mixture was cooled to -78°C and added dropwise. The temperature was slowly raised to room temperature over 2 hours. Stirring was continued at room temperature for one hour. TLC was used to monitor the reaction for completion. Water was added dropwise at low temperature to quench the reaction. The mixture was extracted twice with dichloromethane, the combined mixture was washed with saturated sodium chloride, concentrated, and subjected to column chromatography using a 20:1 volume ratio of PE to EA to afford 800 mg of a pale yellow oil (yield: 72%). 1 H NMR (500 MHz, deuterated chloroform) δ 7.01 (t, J = 7.8 Hz, 1H), 6.98 (dd, J = 8.1, 1.7 Hz, 1H), 6.67 (dd, J = 7.5, 1.6 Hz, 1H), 4.68 (s, 1H), 2.41 (s, 3H), 1.42 (s, 9H).

[0237] (5) Synthesis of 4-tert-butyl-3-methyl-2-hydroxybenzaldehyde

[0238]

[0239] Anhydrous magnesium chloride (927 mg, 9.74 mmol) and paraformaldehyde (585 mg, 19.48 mmol) were added to a 100 mL two-necked flask. The atmosphere was replaced with argon, and ultra-dry acetonitrile (10.0 mL) was added. The mixture was stirred at 30°C for 15 min, and triethylamine (1.36 mL) was added dropwise. The mixture was heated to 45°C and stirred for 15 min. A solution of 3-tert-butyl-2-methylphenol in acetonitrile (800 mg dissolved in 12 mL of acetonitrile) was added dropwise. The mixture was heated under reflux for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, ice-bathed, and quenched by the addition of dilute hydrochloric acid (1.0 mol / L). The mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, concentrated, and subjected to column chromatography using a 50:1 PE:EA eluent to afford 773 mg of an oily product (yield: 83%). 1 H NMR (500 MHz, deuterated chloroform) δ 11.37 (s, 1H), 9.83 (s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 2.42 (s, 3H), 1.44 (s, 9H).

[0240] (6) Synthesis of 5-chloro-4-tert-butyl-3-methyl-2-hydroxybenzaldehyde

[0241]

[0242] To a 50 mL single-necked flask, add 4-tert-butyl-3-methyl-2-hydroxybenzaldehyde (200 mg, 1.04 mmol) and ultra-dry acetonitrile (10.0 mL). Under argon, add N-chlorosuccinimide (NCS, 167 mg, 1.25 mmol) and p-toluenesulfonic acid monohydrate (238 mg, 1.25 mmol) in an ice bath. Stir and react at room temperature for 4 hours. After the reaction is complete, cool in an ice bath and quench with aqueous sodium bisulfite. Extract with ethyl acetate, wash with saturated sodium chloride, concentrate, and column chromatography (eluent: PE:EA, volume ratio = 50:1) to obtain 235 mg of a light yellow oil (yield: 100%). 1 H NMR (500 MHz, deuterated chloroform) δ 11.27 (s, 1H), 9.75 (s, 1H), 7.40 (s, 1H), 2.45 (s, 3H), 1.64 (s, 9H).

[0243] (7) Synthesis of ethyl 6-chloro-7-tert-butyl-8-methyl-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0244]

[0245] To a 15 mL sealed vial, 5-chloro-4-tert-butyl-3-methyl-2-hydroxybenzaldehyde (235 mg, 1.04), ethyl trifluorocrotonate (348 mg, 2.07 mmol), KF (120 mg, 2.07 mmol), and ultra-dry DMSO (2.5 mL) were added. Under argon, the mixture was heated to 130°C for 4 hours. The mixture was cooled to room temperature and the reaction was complete, as monitored by TLC. Water was added and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed three times with half-saturated sodium chloride, dried, concentrated, and subjected to column chromatography using a 50:1 volume ratio of PE to EA as the eluent to obtain 277 mg of a light yellow oil (yield: 71%). 1 H NMR (500 MHz, deuterated chloroform) δ 7.58 (s, 1H), 7.09 (s, 1H), 5.73 (q, J = 6.9 Hz, 1H), 4.40–4.25 (m, 2H), 2.43 (s, 3H), 1.61 (s, 9H), 1.35 (t, J = 7.2 Hz, 3H).

[0246] (8) 6-Chloro-7-tert-butyl-8-methyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0247]

[0248] To a 100 mL single-necked flask, add ethyl 6-chloro-7-tert-butyl-8-methyl-2-trifluoromethyl-2H-benzopyran-3-carboxylate (277 mg, 0.735 mmol), ethanol (5.0 mL), and tetrahydrofuran (5.0 mL). Stir at room temperature. Then, dropwise add aqueous sodium hydroxide solution (176 mg, 4.41 mmol of sodium hydroxide dissolved in 2 mL of water). Stir at room temperature for 2 hours. TLC monitors the complete reaction. Adjust the pH to 3-4 with dilute hydrochloric acid (1.0 mol / L). Extract twice with ethyl acetate. Combine the organic phases, wash with saturated sodium chloride, dry, filter, concentrate, slurry with petroleum ether, sonicate, centrifuge, and dry. A 200 mg light yellow solid is obtained (yield: 78%). 1 H NMR (500 MHz, deuterated chloroform) δ 7.73 (s, 1H), 7.13 (s, 1H), 5.71 (q, J = 6.8 Hz, 1H), 2.44 (s, 3H), 1.62 (s, 9H).

[0249] Example 8

[0250] The chemical name of the compound in this example is: 6-bromo-7-tert-butyl-8-methyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0251]

[0252] (1) Synthesis of 5-bromo-4-tert-butyl-3-methyl-2-hydroxybenzaldehyde

[0253]

[0254] In a 50 mL single-necked flask, the raw material (180 mg, 0.936 mmol), p-toluenesulfonic acid monohydrate (214 mg, 1.12 mmol), and ultra-dry acetonitrile (10.0 mL) were added. Under argon protection, N-bromosuccinimide (NBS, 200 mg, 1.12 mmol) was added in an ice bath, and the temperature was naturally raised to room temperature with stirring for 3 hours. Post-treatment: cooling in an ice bath, quenching the reaction with aqueous sodium bisulfite solution, extraction with ethyl acetate, washing with saturated sodium chloride, drying, concentration, and column chromatography with eluent: PE:EA volume ratio = 200:1 to obtain 190 mg of a light yellow oil with a crude yield of 75%. 1 H NMR (500 MHz, deuterated chloroform) δ 11.27 (d, J = 1.6 Hz, 1H), 9.74 (d, J = 1.7 Hz, 1H), 7.65 (s, 1H), 2.46 (d, J = 1.6 Hz, 3H), 1.66 (s, 9H).

[0255] (2) Synthesis of ethyl 6-bromo-7-tert-butyl-8-methyl-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0256]

[0257] To a 50 mL sealed vial, crude 5-bromo-4-tert-butyl-3-methyl-2-hydroxybenzaldehyde (370 mg, 1.36 mmol), ethyl trifluorocrotonate (459 mg, 2.73 mmol), KF (159 mg, 2.73 mmol), and ultra-dry DMSO (6 mL) were added. Under argon, the mixture was heated to 130°C for 5 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed three times with semi-saturated sodium chloride, dried, concentrated, and subjected to column chromatography using an 80 g column and an eluent ratio of PE:EA (volume ratio) of 100:0 to 100:1. The separation was good, yielding 190 mg of a light yellow oil (26% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 7.58 (s, 1H), 7.35 (s, 1H), 5.73 (q, J = 6.9 Hz, 1H), 4.44–4.18 (m, 2H), 2.43 (s, 3H), 1.64 (s, 9H), 1.35 (t, J = 7.1 Hz, 3H).

[0258] (3) Synthesis of 6-bromo-7-tert-butyl-8-methyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0259]

[0260] To a 100 mL single-necked flask, add ethyl 6-bromo-7-tert-butyl-8-methyl-2-trifluoromethyl-2H-benzopyran-3-carboxylate (190 mg, 0.45 mmol), ethanol (2.0 mL), and tetrahydrofuran (2.0 mL). Stir at room temperature. Then, dropwise add aqueous sodium hydroxide solution (54 mg, 1.35 mmol sodium hydroxide dissolved in 2 mL water). Stir at room temperature for 2 hours until the reaction is complete. Adjust the pH to 3-4 with dilute hydrochloric acid (1.0 mol / L). Extract twice with ethyl acetate. Combine the organic phases, wash with saturated sodium chloride, dry, filter, concentrate, slurry with petroleum ether, sonicate, centrifuge, and dry to obtain 145 mg of a light yellow solid (82% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 7.70 (s, 1H), 7.38 (s, 1H), 5.71 (q, J = 6.8 Hz, 1H), 2.44 (s, 3H), 1.64 (s, 9H).

[0261] Example 9

[0262] The chemical name of the compound in this example is: 6-chloro-7-tert-butyl-8-deuterated methyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0263]

[0264] (1) Synthesis of deuterated methylboronic acid

[0265]

[0266] To a 50 mL reaction tube, add raw material trimethyl borate (0.95 mL, 0.932 g / mL, 8.5 mmol) and anhydrous THF (10 mL), cool to -78 ° C, slowly add deuterated methylmagnesium iodide (4.7 mL, 4.7 mmol, 1 mol / L), keep stirring at -78 ° C for 3 hours, add 2.4 mL of dilute hydrochloric acid (1 mol / L) dropwise, move to room temperature and stir for 10 min, add 100 mL of methyl tert-butyl ether, wash twice with 25 mL of saturated brine, dry the organic phase with sodium sulfate, filter, and spin-dry the filtrate at room temperature (water bath temperature 25 ° C), and the obtained brown liquid is directly used in the next step.

[0267] (2) Synthesis of 3-methoxy-2-bromobenzaldehyde

[0268]

[0269] 3-hydroxy-2-bromobenzaldehyde (10.01 g, 50 mmol), potassium carbonate (8.26 g, 60 mmol) and DMF (60 mL) were added to a 250 mL single-necked bottle. Methyl iodide (3.3 mL, 2.28 g / mL, 52.5 mmol) was added dropwise under ice bath conditions and stirred at room temperature for 2 days. TLC showed that the raw material reaction was complete. 200 mL of water was added and the product was extracted three times with 200 mL of EA. The EA phases were combined and washed six times with 100 mL of saturated aqueous common salt water. The EA phases were dried over sodium sulfate, filtered, and the filtrate was spin-dried to give 10.71 g of a yellow solid.

[0270] (3) Synthesis of 1-(3-methoxy-2-bromophenyl)ethanol

[0271]

[0272] 3-Methoxy-2-bromobenzaldehyde (10.71 g, 50.0 mmol) and anhydrous THF (80 mL) were added to a 250 mL single-necked flask. The temperature was lowered to 0°C, and methylmagnesium bromide (20 mL, 3 mol / L, 60.0 mmol) was slowly added dropwise. The mixture was stirred at 0°C for 2 hours. TLC indicated that the reaction of the starting materials was complete. 300 mL of saturated ammonium chloride solution was slowly added dropwise, and the mixture was extracted three times with 200 mL of EA. The EA phases were combined and washed three times with 150 mL of saturated brine. The EA phases were dried over sodium sulfate, filtered, and the filtrate was spin-dried to dryness. The resulting yellow solid was directly used in the next step.

[0273] (4) Synthesis of 1-(3-methoxy-2-bromophenyl)ethanone

[0274]

[0275] To a 250 mL single-necked flask, 1-(3-methoxy-2-bromophenyl)ethanol (11.5 g, 50.0 mmol) and DCM (100 mL) were added portionwise. Under ice-cooling, Dess-Martin oxidation product (DMP, 25.41 g, 60.0 mmol) was added portionwise. Stirring was maintained under ice-cooling for half an hour, then brought to room temperature and stirred for 2 hours. TLC indicated completion of the reaction. Saturated sodium thiosulfate (200 mL) was slowly added dropwise under ice-cooling, resulting in a large amount of flocculent solids. Celite was added, stirred, and filtered through Celite. The filtrate was separated, and the aqueous phase was extracted once with 200 mL of DCM. The combined DCM phases were spun down to dryness. If a large amount of solids remained, 200 mL of EA / PE (1:20 by volume) was added, stirred, filtered, and the filtrate was spun down to dryness. Purification by flash silica gel column chromatography (EA:PE = 5:95 by volume) yielded 10.98 g of a colorless liquid.

[0276] (5) Synthesis of 1-(3-methoxy-2-deuteromethylphenyl)ethanone

[0277]

[0278] A 30 mL microwave tube was charged with 1-(3-methoxy-2-bromophenyl)ethanone (1.8 g, 7.86 mmol), the brown liquid obtained in step (1) (1.84 g, 80%, 23.6 mmol), Pd(dppf)Cl2 (526.3 mg, 0.786 mmol), potassium phosphate (3.35 g, 15.7 mmol), and dioxane / water (10 mL / 1 mL). The tube was purged with argon, sealed, and microwaved at 120°C for 6 hours. TLC showed that the reaction of the raw materials was complete, with the product being the main product, but there was also a large amount of debrominated byproducts. This was probably because deuterated methylboronic acid was unstable at high temperatures and was quickly consumed, resulting in the debromination of the remaining raw materials. The mixture was spin-dried, and 100 mL of EA and 80 mL of water were added to the combined samples. The mixture was filtered through diatomaceous earth, and the filtrate was separated. The aqueous phase was extracted twice with 80 mL of EA. The EA phases were combined and washed three times with 60 mL of saturated brine. The EA phase was spin-dried and purified by flash silica gel column chromatography (eluent EA: PE volume ratio = 2.5:97.5) to obtain 1.08 g of light green liquid. 1 H NMR (500 MHz, deuterated chloroform) δ 7.22 (t, J = 7.9 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 3.84 (s, 3H), 2.55 (s, 3H).

[0279] (6) Synthesis of 3-tert-butyl-2-deuterated methylanisole

[0280]

[0281] DCM (40 mL) and titanium tetrachloride (1.6 mL, 1.73 g / m, 14.2 mmol) were added to a 250 mL single-necked bottle, cooled to -45 ° C, and a n-hexane solution of dimethylzinc (15 mL, 1 mol / L, 14.2 mmol) was added dropwise. The mixture was stirred at -45 ° C for 10 minutes (a lot of brown solids were precipitated). The raw material 1-(3-methoxy-2-deuterated methylphenyl) ethanone (1.08 g, 6.46 mmol) dissolved in DCM (20 mL) was added dropwise. The refrigeration and circulation were turned off, and the temperature was slowly raised to 0 ° C (4 hours). Stirring was maintained at 0 ° C for 3 hours. 4 mL of water was slowly added dropwise (degassing), and the mixture was moved to room temperature. Add 100mL of DCM and a large amount of diatomaceous earth, stir, filter the diatomaceous earth, wash three times with 50mL of DCM, spin-dry the filtrate, add 150mL of EA, wash twice with 60mL of saturated sodium bicarbonate solution, wash twice with 60mL of saturated brine, dry the EA phase with sodium sulfate, filter, spin-dry the filtrate, add DCM (25mL) to obtain a light yellow liquid, add m-chloroperbenzoic acid (mCPBA, 1.29g, 85%, 6.46mmol) under ice bath conditions, stir at room temperature overnight, and precipitate a lot of solid. Add 50mL of PE, filter, wash twice with 10mL of PE, spin-dry the filtrate, and purify by flash silica gel column chromatography (petroleum ether) to obtain 680mg of colorless liquid. 1 H NMR (500MHz, CDCl3) δ7.13 (t, J = 8.1 Hz, 1H), 7.04 (dd, J = 8.1, 1.2 Hz, 1H), 6.78 (dd, J = 8.1, 1.2 Hz, 1H), 3.84 (s, 3H), 1.44 (s, 9H).

[0282] (7) Synthesis of 3-tert-butyl-2-deuteromethylphenol

[0283]

[0284] In a 50mL single-necked bottle, add raw material 3-tert-butyl-2-deuterated methyl anisole (680mg, 3.75mmol) and DCM (8mL), cool to -78°C, add dropwise a dichloromethane solution of boron tribromide (5.6mL, 1mol / L, 5.63mmol), and slowly warm to 0°C (a lot of white solid appears at ultra-low temperature, and the system becomes clear after warming). TLC shows that there is still raw material remaining. Move to room temperature and stir for 1h. TLC shows that the raw material reaction is complete. Slowly add 20mL of water dropwise under ice bath conditions, extract three times with 30mL of DCM, combine the DCM phases and spin dry, and purify by flash silica gel column chromatography (eluent EA / PE volume ratio = 2.5 / 97.5) to obtain 625mg of colorless liquid.

[0285] (8) Synthesis of 4-tert-butyl-3-deuterated methyl-2-hydroxybenzaldehyde

[0286]

[0287] To a 50 mL single-necked flask, 3-tert-butyl-2-deuteromethylphenol (625 mg, 3.74 mmol), anhydrous acetonitrile (8 mL), triethylamine (1.1 mL, 0.728 g / mL, 7.48 mmol), paraformaldehyde (452.6 mg, 15.0 mmol), and anhydrous magnesium chloride (715.7 mg, 7.48 mmol) were added. Under argon, the temperature was slowly raised to reflux with stirring for 5 hours (a large amount of yellow solid precipitated). TLC showed that the reaction was complete, with the formation of a main spot with decreasing polarity. The mixture was spin-dried, and 60 mL of dilute hydrochloric acid (1 mol / L) was added. The mixture was extracted three times with 60 mL of EA. The combined EA phases were washed three times with 60 mL of saturated brine. The EA phases were spin-dried and purified by flash silica gel column chromatography (eluent: petroleum ether) to obtain 620 mg of a light yellow liquid.

[0288] (9) Synthesis of 5-chloro-4-tert-butyl-3-deuterated methyl-2-hydroxybenzaldehyde

[0289]

[0290] To a 25 mL single-necked flask, add 4-tert-butyl-3-deuteromethyl-2-hydroxybenzaldehyde (200.6 mg, 1.03 mmol), p-toluenesulfonic acid monohydrate (218.6 mg, 1.13 mmol), anhydrous acetonitrile (5 mL), and NCS (155.8 mg, 1.13 mmol). Stir at room temperature for 4 hours. TLC indicated complete reaction of the starting materials, forming a new, less polar spot. The product was then spin-dried and purified by flash silica gel column chromatography (eluent: EA / PE, volume ratio = 0 / 100) to yield 220 mg of a pale yellow liquid.

[0291] (10) Synthesis of ethyl 6-chloro-7-tert-butyl-8-deuterated methyl-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0292]

[0293] To a 10 mL sealed tube, add 5-chloro-4-tert-butyl-3-deuterated methyl-2-hydroxybenzaldehyde (220 mg, 0.96 mmol), ethyl trifluorocrotonate (324.2 mg, 1.92 mmol), anhydrous DMSO (2 mL), and potassium fluoride (113.2 mg, 1.92 mmol). The tube was sealed and heated to 130°C with stirring for 6 hours. TLC indicated the reaction was complete. 150 mL of EA was added, and the mixture was washed six times with 30 mL of saturated brine. The EA phase was then dried and purified by flash silica gel column chromatography (eluent EA:PE volume ratio = 0.3:99.7 to 1.8:98.2) to obtain 220 mg of a light yellow viscous liquid.

[0294] (11) Synthesis of 6-chloro-7-tert-butyl-8-deuterated methyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0295]

[0296] In the single-port bottle of 25mL, add 6-chloro-7-tert-butyl-8-deuteromethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid ethyl ester (220mg, 0.58mmol), NaOH (72.1mg, 1.74mmol), water (0.55mL), THF (1.5mL) and MeOH (1.5mL), stirring at room temperature 6 hours, TLC shows that the reaction is complete. Add 20mL water, adjust pH 3-4 with concentrated hydrochloric acid, there is a small amount of solid to separate out. Extract three times with 30mL EA, merge EA phase and use 30mL saturated common salt water washing three times, EA phase dried over sodium sulfate, filter, filtrate is spin-dried for, the light yellow solid obtained adds 5mL PE, stirring is warming up to slowly cool to room temperature after reflux, filter, 2mL PE washs twice, filtration cakes torrefaction, obtains off-white solid 155mg, 1 H NMR: 1 H NMR (500MHz, CDCl3) δ7.72 (s, 1H), 7.13 (s, 1H), 5.71 (q, J = 6.8Hz, 1H), 1.62 (s, 9H).

[0297] Example 10

[0298] The chemical name of the compound in this example is: 6-bromo-7-tert-butyl-8-deuterated methyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0299]

[0300] (1) Synthesis of 5-bromo-4-tert-butyl-3-deuteromethyl-2-hydroxybenzaldehyde

[0301]

[0302] To a 25 mL single-necked flask, 4-tert-butyl-3-duteromethyl-2-hydroxybenzaldehyde (420 mg, 2.15 mmol), p-toluenesulfonic acid monohydrate (486.5 mg, 2.58 mmol), anhydrous acetonitrile (5 mL), and N-bromosuccinimide (NBS, 464.8 mg, 2.58 mmol) were added. The mixture was stirred at room temperature overnight. TLC indicated that residual starting material remained. Additional N-bromosuccinimide (242.5 mg, 1.29 mmol) was added, and stirring was continued at room temperature for 4 hours. TLC indicated that the starting material had reacted completely. The product was then spin-dried and purified by flash silica gel column chromatography (eluent EA / PE volume ratio = 0 / 100) to obtain 330 mg of a light yellow liquid.

[0303] (2) Synthesis of ethyl 6-bromo-7-tert-butyl-8-deuterated methyl-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0304]

[0305] To a 10 mL sealed tube, add 5-bromo-4-tert-butyl-3-deuterated methyl-2-hydroxybenzaldehyde (330 mg, 1.20 mmol), ethyl trifluorocrotonate (402.8 mg, 2.4 mmol), anhydrous DMSO (2 mL), and potassium fluoride (102.6 mg, 1.8 mmol). The tube was sealed and heated to 130°C with stirring for 5 hours. TLC indicated complete reaction of the starting materials. 100 mL of EA was added, and the mixture was washed six times with 30 mL of saturated brine. The EA phase was then dried and purified by flash silica gel column chromatography (eluent: EA / PE, volume ratio = 0.3:99.7 to 1:99) to obtain 100 mg of a colorless viscous liquid.

[0306] (3) Synthesis of 6-bromo-7-tert-butyl-8-deuterated methyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0307]

[0308] In a 25mL single-necked bottle, 6-bromo-7-tert-butyl-8-deuterated methyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid ethyl ester (100mg, 0.236mmol), NaOH (32.4mg, 0.71mmol), water (0.25mL), MeOH (1mL) were added and stirred at room temperature for 6 hours. TLC showed that the reaction was complete. 20mL of water was added and the pH was adjusted to 3-4 with concentrated hydrochloric acid. A small amount of solid was precipitated and adhered to the magnetic son. 30mL of EA was extracted three times, the EA phase was combined and washed three times with 30mL of saturated brine, the EA phase was dried over sodium sulfate, filtered, and the filtrate was spin-dried. 2mL of PE was added to the obtained light yellow solid, stirred and heated to reflux, then slowly cooled to room temperature, filtered, washed twice with 1mL of PE, and the filter cake was dried to obtain 70mg of off-white solid. 1 H NMR (500MHz, CDCl3) δ7.71 (s, 1H), 7.39 (s, 1H), 5.72 (q, J = 6.8Hz, 1H), 1.64 (s, 9H).

[0309] Example 11

[0310] The chemical name of the compound in this example is 6-chloro-7-tert-butyl-8-ethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0311]

[0312] (1) Synthesis of 3-methoxy-2-ethylacetophenone

[0313]

[0314] In a 25 mL single-necked flask, 1-(3-methoxy-2-bromophenyl)ethanone (308.6 mg, 1.35 mmol), potassium ethyltrifluoroborate (553.4 mg, 4.04 mmol), palladium acetate (60.3 mg, 0.27 mmol), n-butyldi(1-adamantyl)phosphine (188.5 mg, 0.54 mmol), cesium carbonate (1.32 g, 4.04 mmol), toluene (5 mL) and water (2.5 mL) were added. Under argon protection, the mixture was heated to 80°C and stirred for 8 hours. TLC showed that the reaction of the raw materials was complete. 30 mL of water was added, and the mixture was extracted three times with 30 mL of EA. The EA phases were combined and washed three times with 30 mL of saturated brine. The EA phases were spin-dried and purified by flash silica gel column chromatography (eluent EA:PE volume ratio = 1.8:98.2) to obtain 80 mg of a light yellow solid. 1H NMR (500MHz, CDCl3) δ7.21 (t, J=7.9Hz, 1H), 7.11 (dd, J=7.7, 1.1Hz, 1H), 6.95 (dd, J=8 .2,1.1Hz,1H),3.84(s,3H),2.77(q,J=7.4Hz,2H),2.55(s,3H),1.15(t,J=7.4Hz,3H).

[0315] (2) Synthesis of 3-tert-butyl-2-ethylanisole

[0316]

[0317] DCM (10 mL) and titanium tetrachloride (0.7 mL, 1.73 g / mL, 6.31 mmol) were added to a 100 mL single-necked flask, cooled to -45 ° C, and a n-hexane solution of dimethylzinc (6.2 mL, 1 mol / L, 6.31 mmol) was added dropwise. The mixture was stirred at -45 ° C for 10 min (a lot of brown solid was precipitated). 3-Methoxy-2-ethylacetophenone (511.6 mg, 2.87 mmol) dissolved in DCM (8 mL) was added dropwise. The refrigeration and circulation were turned off, and the temperature was slowly raised to 0 ° C (5 hours). Stirring was maintained at 0 ° C for 3 hours. 1 mL of water was slowly added dropwise (degassing). TLC showed that the raw material reaction was complete. Move to room temperature, add 60mL of DCM and a large amount of diatomaceous earth, stir, filter the diatomaceous earth, wash three times with 50mL of DCM, spin dry the filtrate, add 150mL of EA, wash twice with 60mL of saturated sodium bicarbonate solution and twice with 60mL of saturated brine, dry the EA phase with sodium sulfate, filter, spin dry the filtrate, add DCM (5mL) to obtain a light yellow liquid, add mCPBA (546.8mg, 85%, 1eq) under ice bath conditions, stir at room temperature overnight, and a lot of solids precipitate. Spin dry, purify by flash silica gel column chromatography (eluent EA: PE volume ratio = 0: 100) to obtain 325mg of colorless liquid, 1 H NMR (500MHz, CDCl3) δ7.10 (t, J=8.1Hz, 1H), 7.00 (dd, J=8.2, 1.0Hz, 1H), 6.77 (d, J= 8.0Hz, 1H), 3.82 (s, 3H), 2.90 (q, J = 7.3Hz, 2H), 1.42 (s, 9H), 1.18 (t, J = 7.3Hz, 3H).

[0318] (3) Synthesis of 3-tert-butyl-2-ethylphenol

[0319]

[0320] 3-tert-Butyl-2-ethylanisole (325 mg, 1.69 mmol) and DCM (5 mL) were added to a 50 mL single-necked flask, cooled to -78°C, and a dichloromethane solution of boron tribromide (3.3 mL, 1 mol / L, 3.38 mmol) was added dropwise. The mixture was slowly warmed to room temperature and stirred for one hour. TLC showed that the reaction of the starting materials was complete. 20 mL of water was slowly added dropwise under ice bath conditions. The DCM was spin-dried and the mixture was extracted three times with 30 mL of EA. The EA phases were combined and washed three times with 30 mL of saturated brine. The EA phases were dried over sodium sulfate, filtered, and the filtrate was spin-dried to dryness. The resulting light yellow liquid was directly used in the next step.

[0321] (4) Synthesis of 4-tert-butyl-3-ethyl-2-hydroxybenzaldehyde

[0322]

[0323] In a 50 mL single-necked flask, 3-tert-butyl-2-ethylphenol (300 mg, 1.68 mmol), anhydrous acetonitrile (5 mL), triethylamine (0.48 mL, 0.728 g / mL, 3.36 mmol), paraformaldehyde (203.5 mg, 6.73 mmol), and anhydrous magnesium chloride (322.4 mg, 3.36 mmol) were added. Under argon protection, the temperature was slowly raised to reflux with stirring for 5 hours (a lot of yellow solid precipitated). TLC showed that a small amount of starting material remained. Reflux and stirring were continued for one hour. TLC showed that the reaction was complete. The mixture was spin-dried, 30 mL of dilute hydrochloric acid (1 mol / L) was added, and the mixture was extracted three times with 30 mL of EA. The combined EA phases were washed three times with 30 mL of saturated brine. The EA phases were dried over sodium sulfate, filtered, and the filtrate was spin-dried to dryness. The resulting yellow liquid was directly used in the next step.

[0324] (5) 5-Chloro-4-tert-butyl-3-ethyl-2-hydroxybenzaldehyde

[0325]

[0326] To a 25 mL single-necked flask, 4-tert-butyl-3-ethyl-2-hydroxybenzaldehyde (345 mg, 1.67 mmol), p-toluenesulfonic acid monohydrate (384.5 mg, 2.0 mmol), anhydrous acetonitrile (3 mL), and NCS (272.1 mg, 2.0 mmol) were added. The mixture was stirred at room temperature for 4 hours. TLC indicated complete reaction. The mixture was then dried and purified by flash silica gel column chromatography (eluent: EA:PE, volume ratio = 0:100) to obtain 240 mg of a light yellow liquid.

[0327] (6) 6-Chloro-7-tert-butyl-8-ethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid ethyl ester

[0328]

[0329] To a 10 mL sealed tube, add 5-chloro-4-tert-butyl-3-ethylmethyl-2-hydroxybenzaldehyde (240 mg, 1.0 mmol), ethyl trifluorocrotonate (342.4 mg, 2.0 mmol), anhydrous DMSO (2 mL), and potassium fluoride (117.2 mg, 2.0 mmol). The tube was sealed and heated to 130°C with stirring for 6 hours. TLC indicated the reaction was complete. 100 mL of EA was added, and the mixture was washed six times with 30 mL of saturated brine. The EA phase was then spin-dried and purified by flash silica gel column chromatography (eluent: EA:PE, volume ratio = 0.2:99.8 to 0.5:99.5) to obtain 305 mg of a colorless liquid.

[0330] (7) 6-Chloro-7-tert-butyl-8-ethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0331]

[0332] In a 25mL single-necked bottle, 6-chloro-7-tert-butyl-8-ethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid ethyl ester (305mg, 0.78mmol), NaOH (97.2mg, 2.34mmol), water (0.8mL) and MeOH (2.5mL) were added and stirred at room temperature for 5 hours. TLC showed that the reaction was complete. 20mL of water was added and the pH was adjusted to 3-4 with concentrated hydrochloric acid. A small amount of solid was precipitated and adhered to the magnetic son. 30mL of EA was extracted three times, the EA phase was combined and washed three times with 30mL of saturated brine, the EA phase was dried over sodium sulfate, filtered, and the filtrate was spin-dried. 5mL of PE was added to the obtained light yellow solid (which precipitated again after being dissolved), and the mixture was stirred and heated to reflux, then slowly cooled to room temperature, filtered, washed twice with 2mL of PE, and the filter cake was dried to obtain 230mg of an off-white solid. 1 H NMR (500MHz, CDCl3) δ7.72 (s, 1H), 7.15 (s, 1H), 5.74 (q, J = 6.8Hz, 1H), 3.03 (q, J = 7.3Hz, 2H), 1.65 (s, 9H), 1.18 (t, J = 7.3Hz, 3H).

[0333] Example 12

[0334] The chemical name of the compound in this example is: 6-chloro-7-tert-butyl-8-butyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0335]

[0336] (1) Synthesis of 3-methoxy-2-butylacetophenone

[0337]

[0338] In a 50 mL single-necked flask, 1-(3-methoxy-2-bromophenyl)ethanone (1.01 g, 4.4 mmol), potassium butyl trifluoroborate (3.62 g, 22.0 mmol), palladium acetate (106.5 mg, 0.44 mmol), n-butyldi(1-adamantyl)phosphine (321.3 mg, 0.88 mmol), cesium carbonate (7.19 g, 22.0 mmol), toluene (10 mL) and water (5 mL) were added. Under argon protection, the temperature was raised to 80°C and stirred for 8 hours. TLC showed that the raw materials reacted completely. Filtered, washed with 100 mL of EA, the filtrate was separated, and the EA phase was washed twice with 50 mL of saturated brine. The EA phase was spin-dried and purified by flash silica gel column chromatography (eluent EA:PE volume ratio = 2:98) to obtain 325 mg of a yellow solid-liquid mixture. 1 H NMR (500MHz, CDCl3) δ7.20 (t, J=8.0Hz, 1H), 7.10 (dd, J=7.7, 1.2Hz, 1H), 6.95 (d, J=8.1Hz, 1H), 3.84 (s,3H),2.78–2.72(m,2H),2.55(s,3H),1.52–1.45(m,2H),1.41–1.33(m,2H),0.92(t,J=7.3Hz,3H).

[0339] (2) Synthesis of 3-tert-butyl-2-butylanisole

[0340]

[0341] DCM (8 mL) and titanium tetrachloride (0.52 mL, 1.73 g / mL, 4.71 mmol) were added to a 100 mL single-necked flask, cooled to -45 ° C, and a n-hexane solution of dimethylzinc (4.7 mL, 1 mol / L, 4.71 mmol) was added dropwise. The mixture was stirred at -45 ° C for ten minutes (a lot of brown solid was precipitated). 3-Methoxy-2-butylacetophenone (325 mg, 1.57 mmol) dissolved in DCM (5 mL) was added dropwise. The temperature was slowly raised to 0 ° C (5 hours), stirred at 0 ° C for 3 hours, and 1 mL of water was slowly added dropwise (degassing). TLC showed that the raw material reaction was complete. The mixture was brought to room temperature, and 60 mL of DCM and a large amount of celite were added. The mixture was stirred, filtered through the celite, washed three times with 50 mL of DCM, and the filtrate was spin-dried. 60 mL of EA was added, and the mixture was washed twice with 30 mL of saturated sodium bicarbonate solution and twice with 30 mL of saturated brine. The EA phase was dried over sodium sulfate, filtered, and the filtrate was spin-dried. DCM (5 mL) was added to the resulting pale yellow liquid. Meta-chloroperbenzoic acid (325.1 mg, 85%, 1.57 mmol) was added under ice-cooling conditions. The mixture was stirred at room temperature overnight, and a large amount of solid precipitated. The mixture was spin-dried and purified by flash silica gel column chromatography (eluent: EA:PE volume ratio = 0:100) to obtain 200 mg of a colorless liquid.

[0342] (3) Synthesis of 3-tert-butyl-2-butylphenol

[0343]

[0344] 3-tert-Butyl-2-butylanisole (200 mg, 0.91 mmol) and DCM (6 mL) were added to a 50 mL single-necked bottle, cooled to -78 ° C, and a dichloromethane solution of boron tribromide (1.8 mL, 1 mol / L, 1.82 mmol) was added dropwise. The temperature was slowly raised to room temperature and stirred for one hour. TLC showed that the starting material was still residual, which may be due to the low reaction concentration. Stirring at room temperature for one hour was continued. TLC showed that the starting material was completely reacted. 20 mL of water was slowly added dropwise under ice bath conditions, the DCM was spin-dried, and extracted three times with 30 mL of EA. The EA phases were combined and washed three times with 30 mL of saturated brine. The EA phases were dried over sodium sulfate, filtered, and the filtrate was spin-dried. The resulting light yellow liquid was directly added to the next step.

[0345] (4) Synthesis of 4-tert-butyl-3-butyl-2-hydroxybenzaldehyde

[0346]

[0347] In a 25 mL single-necked flask, 3-tert-butyl-2-butylphenol (187 mg, 0.91 mmol), anhydrous acetonitrile (5 mL), triethylamine (0.25 mL, 0.728 g / mL, 1.82 mmol), paraformaldehyde (114.2 mg, 3.64 mmol), and anhydrous magnesium chloride (180.8 mg, 1.82 mmol) were added. Under argon protection, the temperature was slowly raised to reflux with stirring for 5 hours (a lot of yellow solid precipitated). TLC showed that the reaction was complete. The mixture was spin-dried, 30 mL of dilute hydrochloric acid (1 mol / L) was added, and the mixture was extracted three times with 30 mL of EA. The combined EA phases were washed three times with 30 mL of saturated brine. The EA phases were dried over sodium sulfate, filtered, and the filtrate was spin-dried. The resulting yellow liquid was directly used in the next step.

[0348] (5) Synthesis of 5-chloro-4-tert-butyl-3-butyl-2-hydroxybenzaldehyde

[0349]

[0350] To a 25 mL single-necked flask, add 4-tert-butyl-3-butyl-2-hydroxybenzaldehyde (210 mg, 0.90 mmol), p-toluenesulfonic acid monohydrate (208.1 mg, 1.08 mmol), anhydrous acetonitrile (3 mL), and NCS (150.6 mg, 1.08 mmol). Stir at room temperature for 5 hours. TLC indicated complete reaction. The mixture was then dried and purified by flash silica gel column chromatography (eluent: EA / PE, volume ratio = 0 / 100) to yield 170 mg of a yellow liquid.

[0351] (6) Synthesis of ethyl 6-chloro-7-tert-butyl-8-butyl-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0352]

[0353] To a 10 mL sealed tube, add 5-chloro-4-tert-butyl-3-butyl-2-hydroxybenzaldehyde (170 mg, 0.63 mmol), ethyl trifluorocrotonate (224.1 mg, 1.26 mmol), anhydrous DMSO (2 mL), and potassium fluoride (76.8 mg, 1.26 mmol). The tube was sealed and heated to 130°C with stirring for 6 hours. TLC indicated the reaction was complete. 100 mL of EA was added, and the mixture was washed six times with 30 mL of saturated brine. The EA phase was then spin-dried and purified by flash silica gel column chromatography (eluent: EA:PE, volume ratio = 0.2:99.8 to 0.5:99.5) to obtain 170 mg of a colorless liquid.

[0354] (7) Synthesis of 6-chloro-7-tert-butyl-8-butyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0355]

[0356] In a 25mL single-necked bottle, 6-chloro-7-tert-butyl-8-butyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid ethyl ester (170mg, 0.40mmol), NaOH (50.8mg, 1.20mmol), water (0.4mL) and MeOH (1.5mL) were added and stirred at room temperature for 5 hours. TLC showed that the reaction was complete. 20mL of water was added and the pH was adjusted to 3-4 with concentrated hydrochloric acid. A small amount of solid was precipitated and adhered to the magnetic son. 30mL of EA was extracted three times, the EA phase was combined and washed three times with 30mL of saturated brine, the EA phase was dried over sodium sulfate, filtered, and the filtrate was spin-dried. The obtained light yellow solid was added to PE, stirred and heated to reflux, then slowly cooled to room temperature, filtered, washed twice with PE, and the filter cake was dried to obtain 115mg of a white solid. 1 H NMR (500MHz, CDCl3) δ7.72(s,1H),7.14(s,1H),5.74(q,J=6.9Hz,1H),3.02–2.92(m,2H),1.64(s,9H),1.52–1.38(m,4H),0.96(t,J=7.1Hz,3H).

[0357] Example 13

[0358] The chemical name of the compound in this example is 6-chloro-7-(1,1,1-trifluoro-2-methylpropane-2-yl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0359]

[0360] (1) Synthesis of trimethyl((1,1,1-trifluoro-2-(3-methoxyphenyl)prop-2-yl)oxy)silane

[0361]

[0362] To a 100 mL single-necked flask, add 3-methoxyacetophenone (3.0 g, 20.0 mmol), DME (25.0 mL), and cesium fluoride (607 mg, 4.0 mmol). The atmosphere was replaced with argon, cooled in an ice bath, and (trifluoromethyl)trimethylsilane (4.5 mL, 30.0 mmol) was added dropwise. The mixture was stirred in an ice-water bath for 4 hours. After the reaction was complete, the sample was directly loaded onto silica gel for dry-cleaning. The eluent was PE:EA (volume ratio = 100:1). 4.95 g of a colorless oil was obtained, with a yield of 85%.

[0363] (2) Synthesis of 1,1,1-trifluoro-2-(3-methoxyphenyl)propanol

[0364]

[0365] To a 200 mL single-necked flask, add trimethyl((1,1,1-trifluoro-2-(3-methoxyphenyl)propan-2-yl)oxy)silane (4.95 g, 118.5 mmol) and acetonitrile (20.0 mL). Stir at room temperature. Add concentrated hydrochloric acid (10 mL, 7.0 eq) dropwise and allow to react at room temperature for 30 min until the reaction is complete. Dilute with 50 mL of ice water and extract twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride, dried, filtered, concentrated, and subjected to column chromatography using wet loading with an eluent ratio of PE:EA of 50:1 to 15:1 by volume to obtain 3.66 g of a colorless oil (98% yield).

[0366] (3) Synthesis of 1,1,1-trifluoro-2-(3-methoxyphenyl)propyl methanesulfonate

[0367]

[0368] NaH (0.73 g, 18.2 mmol) was added to a 100 mL single-necked flask. The atmosphere was replaced with argon, and the mixture was cooled in an ice bath. Anhydrous tetrahydrofuran (10 mL) was added and the mixture was stirred in an ice-water bath for 10 min. 1,1,1-trifluoro-2-(3-methoxyphenyl)propanol (2.0 g, 9.08 mmol, dissolved in 10 mL THF) was added dropwise. The mixture was stirred in an ice bath for 30 min. Methanesulfonyl chloride (1.41 mL, 18.2 mmol) was added dropwise. The mixture was stirred in an ice bath for 1 hour. The mixture was then warmed to room temperature and stirred overnight. The mixture was cooled in an ice bath, quenched by dripping with water, and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, concentrated, and subjected to column chromatography using a 5:1 PE:EA (volume ratio) eluent to afford 2.55 g of a colorless oil (yield: 94%). 1 HNMR (500 MHz, deuterated chloroform) δ7.40–7.32 (m, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 6.97 (d, J = 8.3 Hz, 1H), 3.83 (s, 3H), 3.12 (s, 3H), 2.28 (s, 3H).

[0369] (4) Synthesis of 1-methoxy-3-(1,1,1-trifluoro-2-methylprop-2-yl)benzene

[0370]

[0371] A 100 mL single-necked flask was charged with 1,1,1-trifluoro-2-(3-methoxyphenyl)propyl methanesulfonate (2.55 g, 8.55 mmol). The atmosphere was replaced with argon, and the mixture was cooled in an ice bath. Anhydrous dichloromethane (30 mL) was added and the reaction was stirred in an ice-water bath for 10 min. Trimethylaluminum (5.9 mL, 9.4 mmol, 1.6 mol / L, dissolved in toluene) was added dropwise. The reaction was stirred in an ice bath for 1 hour. The mixture was warmed to room temperature and stirred overnight. The mixture was cooled in an ice bath and quenched by the dropwise addition of saturated sodium chloride (8 mL). Saturated aqueous sodium carbonate (30 mL) was added, and the mixture was passed through celite and extracted twice with dichloromethane. The combined organic phases were washed with saturated sodium chloride, concentrated, and subjected to column chromatography using a PE:EA volume ratio of 200:1 to 50:1 as the eluent to obtain 1.36 g of a colorless oil (yield: 72%).

[0372] (5) Synthesis of 3-(1,1,1-trifluoro-2-methylprop-2-yl)phenol

[0373]

[0374] A 100 mL single-necked flask was charged with 1-methoxy-3-(1,1,1-trifluoro-2-methylprop-2-yl)benzene (1.36 g, 6.23 mmol). A constant-pressure dropping funnel was installed and the atmosphere was replaced with argon. Extra-dry dichloromethane (20.0 mL) was added. Boron tribromide (12.5 mL, 12.46 mmol, 1.0 mol / L, dissolved in DCM) was then added to the constant-pressure dropping funnel. The mixture was cooled to -78°C and added dropwise. The temperature was slowly raised to room temperature over 2 hours and stirred at room temperature overnight. TLC indicated completion of the reaction. Water was added dropwise at low temperature to quench the reaction. The mixture was extracted twice with dichloromethane, the combined solution was washed with saturated sodium chloride, concentrated, and subjected to column chromatography using a 15:1 PE:EA (volume ratio) eluent to afford 1.26 g of a colorless oil (yield: 100%). 1 H NMR (500 MHz, deuterated chloroform) δ 7.23 (t, J = 7.9, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.98 (s, 1H), 6.78 (d, J = 7.8 Hz, 1H), 4.88 (s, 1H), 1.55 (s, 6H).

[0375] (6) Synthesis of 2-hydroxy-(1,1,1-trifluoro-2-methylprop-4-yl)benzaldehyde

[0376]

[0377] MgCl2 (1.18 g, 12.44 mmol) and paraformaldehyde (747 mg, 24.88 mmol) were added to a 100 mL two-necked flask, the atmosphere was replaced with argon, ultra-dry acetonitrile (10.0 mL) was added, and the mixture was stirred at 30 °C for 15 min. Triethylamine (1.73 mL, 12.44 mmol) was added dropwise, and the mixture was heated to 45 °C and stirred for 15 min. An acetonitrile solution of 3-(1,1,1-trifluoro-2-methylprop-2-yl)phenol (1.27 g, 6.22 mmol, dissolved in 12 mL of acetonitrile solution) was added dropwise. The mixture was heated under reflux for 3 hours until the reaction was complete. The mixture was cooled to room temperature, placed in an ice bath, and diluted hydrochloric acid (1.0 mol / L) was added dropwise to quench the reaction. The mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, concentrated, and subjected to column chromatography. The sample was loaded by dry method. The eluent was PE:EA in a volume ratio of 50:1 to obtain 1.08 g of an oily product. The yield was 75%. 1 H NMR (500 MHz, deuterated chloroform) δ 10.96 (s, 1H), 9.91 (s, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.13 (s, 1H), 1.58 (s, 6H).

[0378] (7) Synthesis of 5-chloro-2-hydroxy-(1,1,1-trifluoro-2-methylprop-4-yl)benzaldehyde

[0379]

[0380] To a 50 mL single-necked flask, 3-hydroxy-(1,1,1-trifluoro-2-methylprop-4-yl)benzaldehyde (220 mg, 0.95 mmol), p-toluenesulfonic acid monohydrate (198 mg, 1.04 mmol), and ultra-dry acetonitrile (10.0 mL) were added. Under argon, NCS (140 mg, 1.04 mmol) was added in an ice bath. The temperature was naturally raised and the reaction was stirred at room temperature for 1 hour. TLC indicated that the starting material had not reacted completely. The reaction was continued at room temperature with stirring for 3 hours. p-toluenesulfonic acid monohydrate (108 mg, 0.57 mmol) and NCS (76 mg, 0.57 mmol) were added and the reaction was continued with stirring at room temperature overnight. The reaction was cooled in an ice bath and quenched with aqueous sodium bisulfite solution. The product was extracted with ethyl acetate and washed with saturated sodium chloride. The product was concentrated and purified by column chromatography using a 200:1 PE:EA v / v ratio as eluent to afford 200 mg of a colorless oil. 1 HNMR (500 MHz, deuterated chloroform) δ 10.67 (s, 1H), 9.85 (s, 1H), 7.60 (s, 1H), 7.22 (s, 1H), 1.77 (s, 6H).

[0381] (8) Synthesis of ethyl 6-chloro-7-(1,1,1-trifluoro-2-methylpropane-2-yl)-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0382]

[0383] To a 15 mL sealed vial, 5-chloro-2-hydroxy-(1,1,1-trifluoro-2-methylprop-4-yl)benzaldehyde (160 mg, 0.6 mmol), ethyl trifluorocrotonate (202 mg, 1.2 mmol), KF (70 mg, 1.2 mmol), and ultra-dry DMSO (2.5 mL) were added. Under argon, the mixture was heated to 130°C for 5 hours, cooled to room temperature, and the reaction was complete after TLC monitoring. Water was added and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed three times with half-saturated sodium chloride, dried, concentrated, and subjected to column chromatography. Dry loading and filtration were performed using an elution solvent (PE:EA, volume ratio = 100:1) to obtain 160 mg of a light yellow oil (yield: 64%). 1 H NMR (500 MHz, deuterated chloroform) δ 7.62 (s, 1H), 7.27 (s, 1H), 7.17 (s, 1H), 5.71 (q, J = 6.8 Hz, 1H), 4.33 (qq, J = 10.8, 7.2 Hz, 2H), 1.75 (d, J = 4.1 Hz, 6H), 1.36 (t, J = 7.1 Hz, 3H).

[0384] (9) Synthesis of 6-chloro-7-(1,1,1-trifluoro-2-methylpropane-2-yl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0385]

[0386] To a 100 mL single-necked flask, ethyl 6-chloro-7-(1,1,1-trifluoro-2-methylpropane-2-yl)-2-trifluoromethyl-2H-chromene-3-carboxylate (160 mg, 0.384 mmol), ethanol (3.0 mL), and tetrahydrofuran (3.0 mL) were added, stirred at room temperature, and an aqueous sodium hydroxide solution (92 mg, 2.30 mmol, dissolved in 3 mL of water) was added dropwise. The mixture was stirred at room temperature for 2 hours. TLC monitored the complete reaction of the starting material. The pH was adjusted to 3-4 with dilute hydrochloric acid (1.0 mol / L), and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried, filtered, concentrated, slurried with petroleum ether, sonicated, centrifuged, and dried to afford 123 mg of a white solid in a yield of 83%. 1H NMR (500MHz, DMSO-d6) δ13.52(br s,1H),7.88(s,1H),7.71(s,1H),7.23(s,1H),6.01(q,J=7.2Hz,1H),1.74(s,6H).

[0387] Example 14

[0388] The chemical name of the compound in this example is: 6-chloro-7-(1,1,1-trifluoro-2-methylpropane-2-yl)-8-methyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0389]

[0390] (1) Synthesis of trimethyl((1,1,1-trifluoro-2-(2-methyl-3-methoxyphenyl)prop-2-yl)oxy)silane

[0391]

[0392] To a 100 mL single-necked flask, add 3-methoxy-2-methylacetophenone (1.38 g, 8.4 mmol), DME (15.0 mL), and cesium fluoride (255 mg, 1.68 mmol). Replace the atmosphere with argon and cool in an ice bath. Add (trifluoromethyl)trimethylsilane (1.9 mL, 112.61 mmol) dropwise. Stir in an ice-water bath for 4.5 hours. TLC indicates complete reaction. Add water and extract twice with ethyl acetate. Combine the organic phases, wash with saturated sodium chloride, dry, filter, concentrate, and proceed directly to the next step.

[0393] (2) Synthesis of 1,1,1-trifluoro-2-(3-methoxy-2-methylphenyl)propanol

[0394]

[0395] To a 200 mL single-necked flask, add trimethyl((1,1,1-trifluoro-2-(2-methyl-3-methoxyphenyl)propan-2-yl)oxy)silane (2.58 g, 8.42 mmol) and acetonitrile (10.0 mL). Stir in an ice bath, then dropwise add concentrated hydrochloric acid (5.0 mL, 59 mmol). Allow to react with stirring and natural warming for 30 min. TLC monitors the complete reaction. Dilute with 50 mL of ice water, extract twice with ethyl acetate, combine the organic phases, wash with saturated sodium chloride, dry, filter, concentrate, and dry-load by column chromatography using a 30:1 volume ratio of PE to EA as the eluent to obtain 1.9 g of a light yellow oil (99% yield).

[0396] (3) Synthesis of 1,1,1-trifluoro-2-(3-methoxy-2-methylphenyl)propyl methanesulfonate

[0397]

[0398] NaH (0.65 g, 16.22 mmol) was added to a 100 mL two-necked flask. The atmosphere was replaced with argon and the mixture was cooled in an ice bath. Anhydrous tetrahydrofuran (10 mL) was added and the mixture was stirred in an ice-water bath for 10 min. 1,1,1-Trifluoro-2-(3-methoxy-2-methylphenyl)propanol (1.9 g, 8.11 mmol, dissolved in 10 mL THF) was added dropwise and the mixture was stirred in an ice-water bath for 30 min. Methanesulfonyl chloride (1.26 mL, 16.22 mmol) was added dropwise and the mixture was stirred in an ice-water bath for 1 hour. The mixture was then warmed to room temperature and stirred at room temperature for 3 hours. TLC monitored the complete reaction of the starting material. The mixture was cooled in an ice bath and quenched with water. The mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, concentrated, and subjected to column chromatography using a PE:EA ratio (volume ratio) of 20:1 to 5:1 to obtain 1.95 g of a colorless oil. The total yield for the two steps was 77%. 1 H NMR (500 MHz, deuterated chloroform) δ 7.21 (t, J = 8.2 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 3.84 (s, 3H), 3.13 (s, 3H), 2.44 (d, J = 1.6 Hz, 3H), 2.37 (d, J = 1.4 Hz, 3H).

[0399] (4) Synthesis of 1-methoxy-2-methyl-3-(1,1,1-trifluoro-2-methylprop-2-yl)benzene

[0400]

[0401] A 200 mL single-necked flask was charged with 1,1,1-trifluoro-2-(3-methoxy-2-methylphenyl)propyl methanesulfonate (2.0 g, 6.4 mmol). The atmosphere was replaced with argon, and the mixture was cooled in an ice bath. Anhydrous dichloromethane (30 mL) was added and the reaction was stirred in an ice-water bath for 10 min. Trimethylaluminum (4.4 mL, 7.04 mmol, 1.6 mol / L, dissolved in toluene) was added dropwise. The reaction was stirred in an ice bath for 1 hour, then naturally warmed to room temperature and stirred overnight. The mixture was cooled in an ice bath and quenched by the addition of saturated sodium chloride (8 mL). Saturated aqueous sodium carbonate (30 mL) was added, and the mixture was passed through celite and extracted twice with dichloromethane. The combined organic phases were washed with saturated sodium chloride, concentrated, and subjected to column chromatography using a PE:EA ratio of 200:1 to 50:1 by volume as the eluent to afford 1.35 g of a colorless oil (91% yield). 1H NMR (500 MHz, deuterated chloroform) δ 7.15 (t, J = 8.0 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.85 (dd, J = 7.8, 1.4 Hz, 1H), 3.83 (s, 3H), 2.39 (s, 3H), 1.71 (s, 6H).

[0402] (5) Synthesis of 2-methyl-3-(1,1,1-trifluoro-2-methylprop-2-yl)phenol

[0403]

[0404] A 100 mL single-necked flask was charged with the starting material (1.35 g, 5.81 mmol), fitted with a constant pressure dropping funnel, and the atmosphere was replaced with argon. Ultra-dry dichloromethane (20.0 mL) was added, and boron tribromide (11.65 mL, 11.63 mmol, 1.0 mol / L, dissolved in DCM) was placed in the constant pressure dropping funnel. The mixture was cooled to -78°C, and boron tribromide was added dropwise. The temperature was slowly raised to room temperature over 2 hours. The reaction was stirred at room temperature for one hour. TLC monitored the reaction for complete reaction. Water was added dropwise at low temperature to quench the reaction. The mixture was extracted twice with dichloromethane, combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, passed through silica gel, washed with ethyl acetate, and concentrated to give 1.6 g of a crude colorless oil (100% yield). The crude oil was used directly in the next step.

[0405] (6) Synthesis of 2-hydroxy-3-methyl-(1,1,1-trifluoro-2-methylprop-4-yl)benzaldehyde

[0406]

[0407] A 100 mL single-necked flask was charged with the starting material (1.25 g, 5.73 mmol), MgCl2 (1.18 g, 11.46 mmol), and paraformaldehyde (747 mg, 22.91 mmol). Ultra-dry acetonitrile (10.0 mL) was added, and triethylamine (1.6 mL, 11.46 mmol) was added dropwise. The atmosphere was replaced with argon and the reaction was heated under reflux for 2 hours. The reaction of the starting material was monitored by TLC. Post-treatment: cooled to room temperature, ice bathed, and dilute hydrochloric acid (1.0 mol / L) was added dropwise to quench the reaction. The reaction was extracted twice with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride, concentrated, and subjected to column chromatography. Dry loading was performed with an eluent of PE:EA in a volume ratio of 50:1 to obtain 1.3 g of an oily product with a yield of 92%. 1 H NMR (500 MHz, deuterated chloroform) δ 11.46 (s, 1H), 9.87 (s, 1H), 7.38 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 2.44 (s, 3H), 1.72 (s, 6H).

[0408] (7) Synthesis of 2-hydroxy-3-methyl-5-chloro-(1,1,1-trifluoro-2-methylprop-4-yl)benzaldehyde

[0409]

[0410] To a 50 mL single-necked flask, the starting material (250 mg, 1.02 mmol), p-toluenesulfonic acid monohydrate (212 mg, 1.12 mmol), and ultra-dry acetonitrile (15.0 mL) were added. Under argon, NCS (149 mg, 1.12 mmol) was added in an ice bath. The temperature was naturally raised and stirred at room temperature for 1.5 hours. A plate was observed, indicating that most of the starting material had not reacted completely, with a new, less polar spot appearing. The temperature was raised to 45°C and stirred for 5 hours. A plate was observed, indicating that approximately 60% of the starting material had not reacted completely. Additional p-toluenesulfonic acid monohydrate (190 mg, 1.02 mmol) and NCS (135 mg, 1.02 mmol) were added, and the reaction was continued at 45°C for 1 hour. The temperature was then naturally lowered and stirred at room temperature overnight. The reaction was cooled in an ice bath and quenched with aqueous sodium bisulfite solution. The reaction was extracted with ethyl acetate, washed with saturated sodium chloride, concentrated, and purified by column chromatography using petroleum ether as the eluent to afford 205 mg of a light yellow solid (72% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 11.24 (s, 1H), 9.82 (s, 1H), 7.50 (s, 1H), 2.49 (s, 3H), 1.94 (d, J = 0.8 Hz, 6H).

[0411] (8) 6-Chloro-7-(1,1,1-trifluoro-2-methylpropane-2-yl)-8-methyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid ethyl ester

[0412]

[0413] To a 15 mL sealed vial, add the starting material (200 mg, 0.71 mmol), ethyl trifluorocrotonate (240 mg, 1.42 mmol), KF (83 mg, 1.42 mmol), and ultra-dry DMSO (2.5 mL). Under argon, heat to 130°C for 4.5 hours, cool to room temperature, and monitor the complete reaction of the starting material by TLC. Add water and extract twice with ethyl acetate. The organic phases are combined, washed three times with half-saturated sodium chloride, dried, concentrated, and subjected to column chromatography using an eluent: PE:EA (volume ratio) of 100:0 to 98.5:1.5 to obtain 200 mg of a light yellow oil (yield: 65%).

[0414] (9) 6-Chloro-7-(1,1,1-trifluoro-2-methylpropane-2-yl)-8-methyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0415]

[0416] To a 100 mL single-necked flask, add the starting material (200 mg, 0.464 mmol), ethanol (3.0 mL), and tetrahydrofuran (3.0 mL). Stir at room temperature. Then, dropwise add aqueous sodium hydroxide solution (111 mg, dissolved in 3 mL of water, 2.79 mmol). Stir at room temperature for 2 hours. Samples were taken for TLC monitoring to confirm complete reaction. Adjust the pH to 3-4 with dilute hydrochloric acid (1.0 mol / L). Extract twice with ethyl acetate. Combine the organic phases, wash with saturated sodium chloride, dry, filter, concentrate, slurry with petroleum ether, sonicate, centrifuge, and dry to obtain 170 mg of a white solid (yield: 91%). 1 H NMR (500MHz, DMSO-d6) δ 13.49 (br s, 1H), 7.84 (s, 1H), 7.59 (s, 1H), 6.05 (q, J = 7.2Hz, 1H), 2.41 (s, 3H), 1.91 (d, J = 3.2Hz, 6H).

[0417] Example 15

[0418] The chemical name of the compound in this example is: 6-bromo-8-(1,1-difluorodeuterated ethyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0419]

[0420] (1) Synthesis of ethyl 6-bromo-8-(1-hydroxydeuterated ethyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0421]

[0422] Feeding: Ethyl 6-bromo-8-formaldehyde-2-trifluoromethyl-2H-chromene-3-carboxylate (150 mg, 0.395 mmol) was added to a 50 mL single-necked flask. The atmosphere was replaced with argon three times, and tetrahydrofuran (35 mL) was added. The mixture was cooled to -20°C and stirred for 15 min. Deuterated methylmagnesium chloride (0.42 mL, 1.0 mol / L dissolved in Et2O, 0.415 mmol) was slowly added dropwise. The mixture was stirred at -20°C for 1 hour. Workup: The mixture was quenched with saturated ammonium chloride at -20°C and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated ammonium chloride and saturated sodium chloride, dried, concentrated, and subjected to column chromatography. Dry loading was performed using an eluent of PE:EA (volume ratio) = 15:1 to obtain 80 mg of a light yellow oil (yield 51%). 1H NMR (500 MHz, deuterated chloroform) δ 7.64 (s, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 5.76 (q, J = 6.8 Hz, 1H), 5.12 (s, 1H), 4.32 (qq, J = 10.8, 7.1 Hz, 2H), 2.13 (br s, 1H), 1.35 (t, J = 7.2 Hz, 3H).

[0423] (2) Synthesis of ethyl 6-bromo-8-(deuterated acetyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0424]

[0425] To a 50 mL single-necked flask, ethyl 6-bromo-8-(1-hydroxydeuterated ethyl)-2-trifluoromethyl-2H-chromene-3-carboxylate (80 mg, 0.2 mmol) was added, followed by ultra-dry dichloromethane (5 mL). The mixture was cooled in an ice-water bath under argon and stirred for 10 min. Dess-Martin periodinane (128 mg, 0.3 mmol) was added, and the mixture was stirred in an ice-water bath for 1 hour. The mixture was then warmed to room temperature and stirred for 1 hour. The reaction was complete. Workup: The mixture was cooled in an ice-water bath, quenched by the addition of aqueous sodium bisulfite solution, diluted with dichloromethane, and adjusted to pH 8-9 by the addition of saturated sodium carbonate. The mixture was extracted twice with dichloromethane. The combined organic phases were washed with saturated sodium chloride, concentrated, and subjected to column chromatography. Dry-loading was performed using a 20:1 PE:EA (volume ratio) eluent to afford 80 mg of a colorless oil (90% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 7.92 (d, J = 2.5 Hz, 1H), 7.67 (s, 1H), 7.50 (d, J = 2.5 Hz, 1H), 5.87 (q, J = 6.7 Hz, 1H), 4.40–4.31 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H).

[0426] (3) Synthesis of ethyl 6-bromo-8-(1,1-difluorodeuterated ethyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0427]

[0428] Under argon protection, ethyl 6-bromo-8-(deuterated acetyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylate (100 mg, 0.252 mmol) and 3.0 mL of DCM were added to a 50 mL single-necked bottle, cooled in an ice bath, and diethylaminosulfur trifluoride (0.20 mL, 1.51 mmol) was added dropwise. The temperature was slowly raised naturally and the reaction was carried out at room temperature for 1 h. TLC monitoring showed that most of the raw materials had not reacted completely. The mixture was stirred at room temperature overnight. Most of the raw materials had not reacted completely. Diethylaminosulfur trifluoride (0.80 mL, 6 mmol) was added, and the temperature was raised to reflux (53 ° C) for 8 hours. The raw materials had not reacted completely. The mixture was stirred at room temperature overnight. Diethylaminosulfur trifluoride (1.0 mL) was added and stirred at room temperature for 3 days. The raw materials were completely reacted.

[0429] Post-treatment: Water was added dropwise in an ice bath to quench the reaction, extracted twice with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Flash chromatography was performed using an eluent of PE:EA (volume ratio = 100:1) to obtain 40 mg of a white solid (yield 41%). 1 H NMR (500 MHz, deuterated chloroform) δ 7.65 (m, 2H), 7.43 (s, 1H), 5.82 (q, J = 6.8 Hz, 1H), 4.34 (p, J = 7.3 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H).

[0430] (6) Synthesis of 6-bromo-8-(1,1-difluorodeuterated ethyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0431]

[0432] To a 50 mL single-necked flask, add ethyl 6-bromo-8-(1,1-difluorodeuterated ethyl)-2-trifluoromethyl-2H-chromene-3-carboxylate (40 mg, 0.096 mmol), 1.0 mL of methanol, and 1.0 mL of tetrahydrofuran. Add lithium hydroxide solution (12 mg of lithium hydroxide dissolved in 1.0 mL of water, 0.478 mmol) in an ice bath and stir at room temperature for 2 h. TLC monitored the reaction for complete reaction. Post-treatment: Adjust the pH to 3-4 with 1 mol / L hydrochloric acid. Extract twice with EA. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and spin dry. Pulp with petroleum ether, centrifuge, and spin dry to obtain 30 mg of a white solid (88% yield). 1 H NMR (500MHz, DMSO-d6) δ 13.53 (br s, 1H), 7.93 (s, 1H), 7.91 (s, 1H), 7.63 (s, 1H), 6.12 (q, J = 7.2Hz, 1H).

[0433] Example 16

[0434] The chemical name of the compound in this example is: (S)-6-bromo-8-(cyclopropyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0435]

[0436] (1) Synthesis of 3-cyclopropylsalicylaldehyde

[0437]

[0438] 3-Bromosalicylaldehyde (1.0 g, 4.97 mmol), 10 mL of toluene, 2.5 mL of water, cyclopropylboronic acid (1.28 g, 14.92 mmol), tricyclohexylphosphine (558 mg, 1.99 mmol), potassium phosphate (3.7 g, 17.41 mmol), palladium acetate (223 mg, 0.995 mmol) were added to a 50 mL sealed tube. The mixture was reacted at 110 ° C for 8 hours under argon protection, cooled to room temperature, and post-processed: the pH value was adjusted to 6 with dilute hydrochloric acid, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride, dried, and column chromatography was performed. Dry loading, column chromatography, eluent: PE: EA volume ratio = 100: 1, to give 400 mg of yellow oil, with a yield of 50%. 1 H NMR (500 MHz, deuterated chloroform) δ 11.38 (s, 1H), 9.89 (s, 1H), 7.40–7.34 (m, 1H), 7.15–7.06 (m, 1H), 6.93 (t, J = 7.6 Hz, 1H), 2.20 (td, J = 8.5, 4.3 Hz, 1H), 1.06–0.92 (m, 2H), 0.74–0.62 (m, 2H).

[0439] (2) Synthesis of 5-bromo-3-cyclopropylsalicylaldehyde

[0440]

[0441] To a 100 mL single-necked flask, 3-cyclopropylsalicylaldehyde (400 mg, 2.47 mmol) and anhydrous acetonitrile (10.0 mL) were added. The mixture was cooled to -10°C under argon and N-bromosuccinimide (527 mg, 2.96 mmol) was added. The reaction was stirred at -10°C for 1.5 hours. TLC indicated that the starting material had not reacted completely. Additional N-bromosuccinimide (150 mg, 0.3 eq) was added and the reaction was stirred at -10°C for 2 hours. The reaction was quenched by water and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried, concentrated, and subjected to column chromatography using a dry-run method with an eluent of PE:EA (volume ratio) of 200:1 to afford 313 mg of a yellow solid (53% yield). 1H NMR (500 MHz, deuterated chloroform) δ 11.30 (s, 1H), 9.82 (s, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 2.18 (tt, J = 8.5, 5.3 Hz, 1H), 1.08–0.96 (m, 2H), 0.75–0.63 (m, 2H).

[0442] (3) Synthesis of (S)-6-bromo-8-(cyclopropyl)-2-trifluoromethyl-2H-benzopyran-3-carbaldehyde

[0443]

[0444] To a 100 mL single-necked flask, 5-bromo-3-cyclopropylsalicylaldehyde (330 mg, 1.29 mmol) was added. Under argon, (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]pyrrolidine (89 mg, 0.257 mmol), o-nitrobenzoic acid (48 mg, 0.257 mmol), trifluorocrotonaldehyde (339 mg, 2.57 mmol), and magnesium sulfate (2.0 g) were added. The mixture was stirred overnight at room temperature. Filtered, concentrated, and column chromatography was performed using a dry-phase loading method using an eluent of PE:EA (volume ratio) = 30:1 to obtain 290 mg of a light yellow oil (yield: 65%).

[0445] (4) (S)-6-Bromo-8-(cyclopropyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0446]

[0447] To a 100 mL single-necked flask, (S)-6-bromo-8-(cyclopropyl)-2-trifluoromethyl-2H-chromen-3-carbaldehyde (290 mg, 0.835 mmol) and anhydrous DMF (10.0 mL) were added. Potassium persulfate (OXONE, 1.23 g, 2.0 mmol) was added in an ice bath and stirred overnight at room temperature. The reaction was quenched by the addition of saturated sodium bisulfite, and the pH was adjusted to 3-4 with dilute hydrochloric acid. The product was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried, concentrated, and purified by column chromatography using a 20:1 (volume ratio) of PE:EA and a 20:1 (volume ratio) of DCM:MeOH. The product was then slurried with petroleum ether to yield 50 mg of a pale yellow solid. 1 H NMR (500 MHz, deuterated chloroform) δ 7.75 (s, 1H), 7.19 (d, J = 2.3 Hz, 1H), 7.04 (d, J = 2.3 Hz, 1H), 5.75 (q, J = 6.8 Hz, 1H), 2.09 (tt, J = 8.6, 5.3 Hz, 1H), 1.01–0.95 (m, 2H), 0.75–0.60 (m, 2H).

[0448] Example 17

[0449] The chemical name of the compound in this example is (S)-6-bromo-8-(trifluoromethyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0450]

[0451] (1) Synthesis of (S)-6-bromo-8-(trifluoromethyl)-2-trifluoromethyl-2H-benzopyran-3-carbaldehyde

[0452]

[0453] To a 50 mL single-necked flask, 5-bromo-3-trifluoromethylsalicylaldehyde (125 mg, 0.465 mmol) was added. Under argon, (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine (31 mg, 0.093 mmol), o-nitrobenzoic acid (54 mg, 0.093 mmol), trifluorocrotonaldehyde (29 mL, 0.93 mmol), and magnesium sulfate (2.6 g) were added. The mixture was stirred overnight at room temperature. Filtered, concentrated, and column chromatography was performed using a dry-phase loading method with an eluent of PE:EA (volume ratio) of 10:1 to obtain 160 mg of an oil (92% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 9.70 (s, 1H), 7.76 (s, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.49 (s, 1H), 5.82 (q, J = 6.5 Hz, 1H).

[0454] (2) Synthesis of (S)-6-bromo-8-(trifluoromethyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0455]

[0456] To a 50 mL single-necked flask, (S)-6-bromo-8-(trifluoromethyl)-2-trifluoromethyl-2H-chromen-3-carbaldehyde (160 mg, 0.426 mmol) and anhydrous DMF (5.0 mL) were added. OXONE (630 mg, 1.02 mmol) was added in an ice bath and stirred overnight at room temperature. The reaction was quenched by the addition of saturated sodium bisulfite. The pH was adjusted to 3-4 with dilute hydrochloric acid. The mixture was extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride, dried, concentrated, and subjected to column chromatography using an eluent of PE:EA (volume ratio) = 20 / 1 and DCM:MeOH (volume ratio) = 20:1. The mixture was recrystallized from petroleum ether and cooled in the refrigerator to yield 32 mg of an off-white solid. 1H NMR (500 MHz, deuterated chloroform) δ 7.77 (s, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 2.4 Hz, 1H), 5.81 (q, J = 6.5 Hz, 1H).

[0457] Example 18

[0458] The chemical name of the compound in this example is: (S)-6-bromo-8-(difluoromethyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0459]

[0460] (1) Synthesis of (S)-6-bromo-8-(difluoromethyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0461]

[0462] Under argon, (S)-methyl 6-bromo-8-(formyl)-2-trifluoromethyl-2H-chromene-3-carboxylate (140 mg, 0.383 mmol) and 10 mL of DCM were added to a 50 mL single-necked flask. The mixture was cooled in an ice bath, and diethylaminosulfur trifluoride (0.12 mL, 2.3 mmol) was slowly added dropwise. The mixture was allowed to warm to room temperature and react for 1 h. TLC monitored the complete reaction of the starting material. The reaction was quenched by the dropwise addition of saturated sodium bicarbonate solution in an ice bath. The mixture was extracted twice with dichloromethane. The combined organic phases were added to saturated brine, concentrated, and purified by column chromatography using a 50:1 volume ratio of PE to EA to afford 110 mg of an oily product (75% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 7.70 (s, 1H), 7.67 (s, 1H), 7.47 (s, 1H), 6.87 (t, J = 55.0 Hz, 1H), 5.78 (q, J = 6.2 Hz, 1H), 3.88 (s, 3H).

[0463] (2) Synthesis of (S)-6-bromo-8-(difluoromethyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0464]

[0465] To a 50 mL single-necked flask, add (S)-methyl 6-bromo-8-(difluoromethyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylate (110 mg, 0.284 mmol), 1.5 mL of methanol, and 1.5 mL of tetrahydrofuran. Add lithium hydroxide (1.5 mL, 1.0 mol / L, 0.852 mmol) in an ice bath, and naturally warm to room temperature with stirring for 2 h. TLC monitors the complete reaction of the starting materials. Adjust the pH to 3-4 with 1 mol / L hydrochloric acid in an ice bath, extract twice with EA, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, spin dry, slurry with petroleum ether, centrifuge, and spin dry to obtain 97 mg of a white solid (92% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 7.77 (s, 1H), 7.73 (s, 1H), 7.51 (t, J = 1.6 Hz, 1H), 6.87 (t, J = 54.8 Hz, 1H), 5.77 (q, J = 6.6 Hz, 1H).

[0466] Example 19

[0467] The chemical name of the compound in this example is: (S)-6-sulfur pentafluoride-8-(vinyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0468]

[0469] (1) Synthesis of 5-sulfur pentafluoride-3-bromosalicylaldehyde

[0470]

[0471] To a 100 mL single-necked flask, 5-pentafluorosulfosalicylaldehyde (500 mg, 2.01 mmol) and anhydrous acetic acid (10.0 mL) were added under argon. Pyridinium tribromide (967 mg, 3.02 mmol) was added and the mixture was heated to 80°C and stirred for 4 hours. The mixture was then cooled to room temperature and stirred for 2 days. TLC indicated that the reaction was incomplete. Additional pyridinium tribromide (450 mg) was added and the mixture was heated to 80°C and stirred for 8 hours. The mixture was then cooled to room temperature and stirred overnight. The reaction was quenched by the addition of saturated sodium bisulfite and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated sodium bicarbonate until alkaline, washed with dilute hydrochloric acid, and washed with saturated sodium chloride. The mixture was then dried, concentrated, and subjected to column chromatography using a dry-run method with an eluent of PE:EA (volume ratio = 100:1) to yield 170 mg of a pale yellow oil (yield = 26%). 1 H NMR (500 MHz, deuterated chloroform) δ 11.91 (s, 1H), 9.90 (s, 1H), 8.17 (d, J = 2.6 Hz, 1H), 7.97 (d, J = 2.6 Hz, 1H).

[0472] (2) Synthesis of (S)-6-sulfur pentafluoride-8-bromo-2-trifluoromethyl-2H-benzopyran-3-carbaldehyde

[0473]

[0474] To a 50 mL single-necked flask, add 5-sulfur pentafluoride-3-bromosalicylaldehyde (1.2 g, 3.67 mmol). Under argon, add (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine (239 mg, 0.734 mmol), o-nitrobenzoic acid (123 mg, 0.734 mmol), trifluorocrotonaldehyde (60 mL, 9.17 mmol), and magnesium sulfate (6.0 g). Stir overnight at room temperature. Filter, concentrate, and dry-load the mixture by column chromatography using a 50:1 volume ratio of PE to EA to obtain 1.0 g of an oily product (yield: 63%). 1 H NMR (500 MHz, deuterated chloroform) δ 9.73 (s, 1H), 8.00 (d, J = 2.5 Hz, 1H), 7.68 (d, J = 2.5 Hz, 1H), 7.53 (s, 1H), 5.89 (q, J = 6.5 Hz, 1H).

[0475] (3) Synthesis of (S)-6-sulfur pentafluoride-8-bromo-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0476]

[0477] In a 50 mL single-necked flask, add the starting material (113 mg, 2.31 mmol) and anhydrous DMF (5.0 mL). Add OXONE (385 mg) in portions and stir at room temperature overnight. Add saturated sodium bisulfite to quench the reaction, extract twice with ethyl acetate, combine the organic phases, wash with saturated sodium chloride, dry, and concentrate. The product is used directly in the next step.

[0478] (4) Synthesis of (S)-6-sulfur pentafluoride-8-bromo-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0479]

[0480] Under argon, a 100 mL single-necked flask was charged with (S)-6-sulfur pentafluoride-8-bromo-2-trifluoromethyl-2H-chromene-3-carboxylic acid (1.0 g, 2.23 mmol), potassium carbonate (615 mg, 4.45 mmol), and 10 mL of DMF. Iodomethane (0.21 mL, 3.34 mmol) was added in an ice bath and allowed to react overnight at room temperature. Ethyl acetate was added to the reaction solution, followed by ice water to quench the reaction. The aqueous phase was extracted again with ethyl acetate. The combined organic phases were washed with semi-saturated brine, concentrated, and subjected to column chromatography. Dry-loading was performed using an eluent of PE:EA (volume ratio) of 25:1 to afford 980 mg of a white semisolid, semi-oil product, with a two-step yield of 90%. 1 H NMR (500 MHz, deuterated chloroform) δ 7.93 (d, J = 2.5 Hz, 1H), 7.70 (s, 1H), 7.59 (d, J = 2.5 Hz, 1H), 5.89 (q, J = 6.4 Hz, 1H), 3.90 (s, 3H).

[0481] (5) Synthesis of (S)-6-sulfur pentafluoride-8-vinyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0482]

[0483] Under argon, a 25 mL sealed tube was charged with (S)-6-sulfur pentafluoride-8-bromo-2-trifluoromethyl-2H-chromene-3-carboxylic acid methyl ester (100 mg, 0.215 mmol), palladium chloride (4 mg, 0.022 mmol), triphenylphosphine (17 mg, 0.065 mmol), cesium carbonate (211 mg, 0.648 mmol), potassium ethylene trifluoroborate (58 mg, 0.432 mmol), tetrahydrofuran (1.8 mL), and water (0.2 mL). The mixture was heated to 85°C for 8 hours. Ethyl acetate was added to the reaction solution, followed by water to quench the reaction. The aqueous phase was extracted again with ethyl acetate, and the combined organic phases were washed with half-saturated brine, concentrated, and subjected to column chromatography using a dry-run method with an eluent of PE:EA (volume ratio) of 25:1 to afford 80 mg of a colorless oil (91% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 7.85 (d, J = 2.6 Hz, 1H), 7.71 (s, 1H), 7.53 (d, J = 2.6 Hz, 1H), 6.94 (dd, J = 17.7, 11.2 Hz, 1H), 5.87 (d, J = 17.7 Hz, 1H), 5.83 (q, J = 6.6 Hz, 1H), 5.50 (d, J = 11.2 Hz, 1H), 3.89 (s, 3H).

[0484] (6) Synthesis of (S)-6-sulfur pentafluoride-8-vinyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0485]

[0486] To a 50 mL single-necked flask, add the starting material (50 mg, 0.122 mmol), 1.0 mL of methanol, and 1.0 mL of tetrahydrofuran. Add lithium hydroxide solution (1.0 mL, 1.0 mol / L lithium hydroxide aqueous solution, 0.365 mmol) at 0°C and stir at room temperature for 2 h. TLC monitoring of the reaction indicates that the starting material is completely reacted. Adjust the pH to 3-4 with 1 mol / L hydrochloric acid. Extract twice with EA. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and spin dry. Slurry with petroleum ether, centrifuge, and spin dry to obtain 26 mg of a white powder (54% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 7.88 (d, J = 2.6 Hz, 1H), 7.85 (s, 1H), 7.57 (d, J = 2.6 Hz, 1H), 6.95 (dd, J = 17.7, 11.2 Hz, 1H), 5.89 (d, J = 17.7 Hz, 1H), 5.82 (q, J = 6.6 Hz, 1H), 5.52 (d, J = 11.2 Hz, 1H).

[0487] Example 20

[0488] The chemical name of the compound in this example is (S)-6-sulfur pentafluoride-8-trifluoromethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0489]

[0490] (1) Synthesis of (S)-6-sulfur pentafluoride-8-trifluoromethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0491]

[0492] Under argon protection, the raw material (the product synthesized in step (4) of Example 19) (100 mg, 0.216 mmol), cuprous iodide (163 mg, 0.864 mmol) and 2.0 mL of DMF were added to a 25 mL sealed tube, and methyl fluorosulfonyldifluoroacetate (0.40 mL, 2.16 mmol) was added. The mixture was heated to 80°C for 20 hours and cooled to room temperature. Ethyl acetate was added to the reaction solution, and water was added to quench the reaction. The mixture was passed through celite, the layers were separated, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed three times with half-saturated brine, concentrated, and subjected to column chromatography. The sample was loaded by dry method, and the eluent: PE:EA volume ratio = 30:1 was used to obtain 18 mg of solid, with a yield of 19%.1 H NMR (500 MHz, deuterated chloroform) δ 7.97 (d, J = 2.6 Hz, 1H), 7.81 (d, J = 2.6 Hz, 1H), 7.75 (s, 1H), 5.90 (q, J = 6.4 Hz, 1H), 3.91 (s, 3H).

[0493] (2) Synthesis of (S)-6-sulfur pentafluoride-8-trifluoromethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0494]

[0495] To a 50 mL single-necked flask, add the starting material (19 mg, 0.042 mmol), 1.0 mL of methanol, and 1.0 mL of tetrahydrofuran. Add lithium hydroxide solution (1.0 mL, 1.0 mol / L lithium hydroxide aqueous solution) at 0°C and stir at room temperature for 2 h. TLC monitored the reaction for completeness. Post-treatment: Adjust the pH to 3-4 with 1 mol / L hydrochloric acid. Extract twice with EA. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and spin dry. Slurry with petroleum ether, centrifuge, and spin dry to obtain 6 mg of a white powder (34% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 7.99 (d, J = 1.9 Hz, 1H), 7.85 (s, 1H), 7.84 (s, 1H), 5.89 (q, J = 6.5 Hz, 1H).

[0496] Example 21

[0497] The chemical name of the compound in this example is (S)-6-sulfur pentafluoride-8-ethynyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0498]

[0499] (1) Synthesis of (S)-6-sulfur pentafluoride-8-trimethylsilyl acetylene-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0500]

[0501] To a 50 mL sealed bottle, the starting material (400 mg, 0.864 mmol), cuprous iodide (50 mg, 0.259 mmol), PdCl2(PPh3)2 (61 mg, 0.086 mmol), triphenylphosphine (68 mg, 0.259 mmol), triethylamine (0.48 mL, 3.45 mmol), trimethylsilylacetylene (0.25 mL, 1.73 mmol), and anhydrous acetonitrile (3.0 mL) were added. The atmosphere was replaced with argon and heated to 60°C for 8 hours. TLC monitored the complete reaction. The reaction was quenched with water and extracted twice with ethyl acetate. The product was washed with saturated sodium chloride, dried, and passed through celite. The mother liquor was then spin-dried and subjected to column chromatography using a 100:1 PE:EA (volume ratio) eluent to afford 380 mg of a yellow oil (92% yield). 1 HNMR (500 MHz, deuterated chloroform) δ 7.80 (s, 1H), 7.68 (s, 1H), 7.55 (s, 1H), 5.87 (q, J = 6.5 Hz, 1H), 3.88 (s, 3H), 0.27 (s, 9H).

[0502] (2) Synthesis of (S)-6-sulfur pentafluoride-8-ethynyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0503]

[0504] To a 50 mL single-necked flask at room temperature, add the starting material (100 mg, 0.208 mmol) and anhydrous methanol (5.0 mL). Add potassium carbonate (58 mg, 0.416 mmol) in an ice bath. Stir the mixture in an ice bath for 5 min. TLC monitors the complete reaction. Water is added dropwise to quench the reaction in an ice bath. Extract twice with ethyl acetate, combine the organic phases, wash with saturated sodium chloride, concentrate, and column chromatography (eluent: PE:EA, volume ratio = 100:1) to obtain 78 mg of a colorless oil, with a yield of 92%. 1 H NMR (500 MHz, deuterated chloroform) δ 7.85 (s, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 5.88 (q, J = 6.5 Hz, 1H), 3.89 (s, 3H), 3.41 (s, 1H).

[0505] (3) Synthesis of (S)-6-sulfur pentafluoride-8-ethynyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0506]

[0507] To a 50 mL single-necked flask, add (S)-6-sulfur pentafluoride-8-ethynyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester (78 mg, 0.191 mmol), 1.0 mL of methanol, and 1.0 mL of tetrahydrofuran. Add lithium hydroxide (1.0 mL, 1.0 mol / L aqueous solution) at 0°C, and stir at 0°C for 4 h. TLC monitoring indicates that the reaction is not complete. Warm up to room temperature and stir for 30 min, and the reaction is complete. Add 1 mol / L hydrochloric acid to adjust the pH to 3-4 in an ice bath. Extract twice with EA, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, spin dry, slurry with petroleum ether, centrifuge, and spin dry to obtain 44 mg of a white solid (60% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 7.88 (s, 1H), 7.82 (s, 1H), 7.65 (s, 1H), 5.86 (q, J = 6.6 Hz, 1H), 3.43 (t, J = 2.3 Hz, 1H).

[0508] Example 22

[0509] The chemical name of the compound in this example is: (S)-6-sulfur pentafluoride-8-hydroxymethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid.

[0510]

[0511] (1) Synthesis of (S)-6-sulfur pentafluoride-8-formyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0512]

[0513] To a 100 mL single-necked bottle was added the raw material (the product synthesized in Example 19, step (5)) (630 mg, 1.54 mmol), tetrahydrofuran (9.0 mL), tert-butanol (9.0 mL), water (3.0 mL), potassium osmate dihydrate (19 mg, 0.0614 mmol), and N-methylmorpholine N-oxide (NMO) aqueous solution (360 mg, 3.0 mL of water, 3.07 mmol) was added dropwise. The mixture was stirred at room temperature for 5 hours, and the raw material reaction was complete. Ethyl acetate was added to the reaction solution, and then water was added to quench the reaction. The aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, concentrated, and dioxane (16.0 mL) and water (4.0 mL) were added. Sodium periodate (985 mg, 4.61 mmol) was added in an ice bath, and the temperature was naturally raised with stirring to react for 30 min. TLC monitored the complete reaction of the raw material. Water was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, and subjected to column chromatography. Dry loading was performed with an eluent of PE:EA in a volume ratio of 15:1 to obtain 530 mg of a colorless oil with a yield of 84%.1 H NMR (500 MHz, deuterated chloroform) δ 10.43 (s, 1H), 8.24 (d, J = 2.7 Hz, 1H), 7.84 (d, J = 2.7 Hz, 1H), 7.77 (s, 1H), 5.94 (q, J = 6.5 Hz, 1H), 3.92 (s, 3H).

[0514] (2) Synthesis of (S)-6-sulfur pentafluoride-8-hydroxymethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0515]

[0516] To a 50 mL single-necked flask at -30°C, add the starting material (100 mg, 0.242 mmol), anhydrous tetrahydrofuran (5.0 mL), and sodium borohydride (5 mg, 0.121 mmol). Stir the reaction at -30°C for 2 hours. Complete conversion of the starting material was monitored by TLC. Water was added dropwise at -30°C to quench the reaction. The mixture was extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride, dried, concentrated, and subjected to column chromatography using wet loading with an eluent of PE:EA (volume ratio) of 6:1 to afford 80 mg of a colorless oil (80% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 7.88 (d, J = 2.6 Hz, 1H), 7.73 (s, 1H), 7.58 (d, J = 2.7 Hz, 1H), 5.82 (q, J = 6.6 Hz, 1H), 4.78 (d, J = 5.2 Hz, 2H), 3.89 (s, 3H), 2.01 (t, J = 6.1 Hz, 1H).

[0517] (3) Synthesis of (S)-6-sulfur pentafluoride-8-hydroxymethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0518]

[0519] To a 50 mL single-necked flask, add the starting material (40 mg, 0.096 mmol), 1.0 mL of methanol, and 1.0 mL of tetrahydrofuran. Add lithium hydroxide solution (1.0 mL, 1.0 mol / L lithium hydroxide aqueous solution) in an ice bath, and stir and react for 2 h. TLC monitoring of the reaction indicates that the starting material has reacted completely. Adjust the pH to 3-4 with 1 mol / L hydrochloric acid. Extract twice with EA. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and spin dry. Wash with petroleum ether and spin dry to obtain 38 mg of a white oil (98% yield). 1H NMR (500 MHz, deuterated chloroform) δ 7.91 (d, J = 2.6 Hz, 1H), 7.85 (s, 1H), 7.62 (d, J = 2.6 Hz, 1H), 5.81 (q, J = 6.6 Hz, 1H), 4.80 (s, 2H).

[0520] Example 23

[0521] The chemical name of the compound in this example is (S)-6-sulfur pentafluoride-8-methoxymethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0522]

[0523] (1) Synthesis of (S)-6-sulfur pentafluoride-8-methoxymethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0524]

[0525] In a 50 mL single-necked flask, the raw material (the product synthesized in Example 22, step (2)) (40 mg, 0.101 mmol) and anhydrous tetrahydrofuran (3.0 mL) were added. Under argon protection, the mixture was cooled in an ice bath. NaH (36 mg, 0.203 mmol) was added and stirred in an ice bath for 10 min. Methyl iodide (0.1 mL, 0.606 mmol) was added dropwise. The temperature was naturally raised and the reaction was stirred at room temperature for 2 hours. Water was added to quench the reaction in an ice bath. The pH was adjusted to 3-4 with dilute hydrochloric acid. The mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried, concentrated, and subjected to column chromatography. Dry loading was performed using an eluent of PE:EA in a volume ratio of 20:1 to obtain 32 mg of a colorless oil with a yield of 74%.

[0526] (2) Synthesis of (S)-6-sulfur pentafluoride-8-methoxymethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0527]

[0528] To a 50 mL single-necked flask, add (S)-6-sulfur pentafluoride-8-methoxymethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester (32 mg, 0.075 mmol), 1.0 mL of methanol, and 1.0 mL of tetrahydrofuran. Add lithium hydroxide solution (1.0 mL, 1.0 mol / L lithium hydroxide aqueous solution) in an ice bath, and stir and react for 2 h. TLC monitoring indicates that the reaction is complete. Add 1 mol / L hydrochloric acid to adjust the pH to 3-4. Extract twice with EA. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and spin dry. Wash with petroleum ether and spin dry to obtain 22 mg of a white solid (73% yield). 1H NMR (500 MHz, deuterated chloroform) δ 7.88 (d, J = 2.6 Hz, 1H), 7.83 (s, 1H), 7.60 (d, J = 2.6 Hz, 1H), 5.80 (q, J = 6.6 Hz, 1H), 4.57–4.49 (m, 2H), 3.48 (s, 3H).

[0529] Example 24

[0530] The chemical name of the compound in this example is: (S)-6-sulfur pentafluoride-8-(monofluoromethyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0531]

[0532] (1) Synthesis of (S)-6-sulfur pentafluoride-8-fluoro-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0533]

[0534] Under argon protection, the raw material (the product synthesized in Example 22, step (2)) (76 mg, 0.183 mmol) and 10 mL of DCM were added to a 50 mL single-necked bottle, cooled to -78 ° C, and diethylaminosulfur trifluoride (0.08 mL, 0.55 mmol) was slowly added dropwise. The reaction was kept warm for 1 h. TLC monitoring showed that the raw material reaction was complete. Saturated sodium bicarbonate solution was added dropwise to quench the reaction. The mixture was extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, concentrated, and column chromatography was performed with an eluent of PE:EA in a volume ratio of 25:1 to obtain 49 mg of an oily substance with a yield of 64%. 1 H NMR (500 MHz, deuterated chloroform) δ 7.83 (d, J = 2.6 Hz, 1H), 7.74 (s, 1H), 7.64 (d, J = 2.6 Hz, 1H), 5.82 (q, J = 6.6 Hz, 1H), 5.60–5.26 (m, 2H), 3.89 (d, J = 1.0 Hz, 3H).

[0535] (2) Synthesis of (S)-6-sulfur pentafluoride-8-fluoro-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0536]

[0537] To a 50 mL single-necked flask, add the starting material (49 mg, 0.117 mmol), 1.0 mL of methanol, and 1.0 mL of tetrahydrofuran. Add lithium hydroxide solution (1.0 mL, 1.0 mol / L lithium hydroxide aqueous solution) in an ice bath, and stir and heat naturally for 2 h. TLC monitoring of the reaction indicates that the starting material has reacted completely. Adjust the pH to 3-4 with 1 mol / L hydrochloric acid. Extract twice with EA. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and spin dry. Slurry with petroleum ether, centrifuge, and spin dry to obtain 25 mg of a white solid (53% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 7.86 (s, 2H), 7.68 (d, J = 2.6 Hz, 1H), 5.82 (q, J = 6.5 Hz, 1H), 5.50 (dd, J = 47.0, 2.5 Hz, 2H).

[0538] Example 25

[0539] The chemical name of the compound in this example is: (S)-6-sulfur pentafluoride-8-difluoromethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0540]

[0541] (1) Synthesis of (S)-6-sulfur pentafluoride-8-difluoromethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0542]

[0543] Under argon, the starting material (the product synthesized in Example 22, step (1)) (60 mg, 0.145 mmol) and 5 mL of DCM were added to a 50 mL single-necked flask. The mixture was cooled to 0°C and diethylaminosulfur trifluoride (0.12 mL, 0.873 mmol) was slowly added dropwise. The mixture was reacted at 0°C for 0.5 h and stirred at room temperature for 2 h. The reaction was quenched by the addition of 30 mL of saturated sodium bicarbonate solution at 0°C. The mixture was extracted twice with dichloromethane, and the organic phases were combined, saturated with brine, concentrated, and purified by column chromatography. Separation was performed by flash chromatography using an eluent of PE:EA in a volume ratio of 15:1 to obtain 60 mg of an oily product with a yield of 95%. 1 HNMR (500 MHz, deuterated chloroform) δ 8.00–7.94 (m, 1H), 7.75 (s, 2H), 6.91 (t, J = 54.6 Hz, 1H), 5.86 (q, J = 6.5 Hz, 1H), 3.90 (d, J = 1.1 Hz, 3H).

[0544] (2) Synthesis of (S)-6-sulfur pentafluoride-8-difluoromethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0545]

[0546] To a 50 mL single-necked flask, add the starting material (60 mg, 0.146 mmol), 1.0 mL of methanol, and 1.0 mL of tetrahydrofuran. Add lithium hydroxide solution (1.0 mL, 1.0 mol / L, dissolved in aqueous solution) in an ice bath, and allow to react with stirring for 2 h. TLC monitoring of the reaction indicates that the starting material has reacted completely. Adjust the pH to 3-4 with 1 mol / L hydrochloric acid. Extract twice with EA. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and spin dry. Pulp with petroleum ether, centrifuge, and spin dry to obtain 40 mg of a white powder (69% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 8.01 (d, J = 2.6 Hz, 1H), 7.86 (s, 1H), 7.79 (d, J = 2.6 Hz, 1H), 6.92 (t, J = 54.6 Hz, 1H), 5.85 (q, J = 6.4 Hz, 1H).

[0547] Example 26

[0548] The chemical name of the compound in this example is: 6-bromo-8-deuterated methyl-2-trifluoromethyl-2-hydroxy-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0549]

[0550] (1) Synthesis of ethyl 6-bromo-8-deuterated methyl-2-trifluoromethyl-2-hydroxy-2H-benzopyran-3-carboxylate

[0551]

[0552] To a 50 mL round-bottom, single-necked flask were added 5-bromo-3-deuterated methyl salicylaldehyde (300 mg, 1.38 mmol), ethyl trifluorocrotonate (278 mg, 1.51 mmol), piperidine (35 mg, 0.412 mmol), and ethanol (10 mL). A reflux condenser was installed and the atmosphere was replaced with argon three times. The mixture was heated to reflux (85°C) and reacted for 4 h. The solvent was concentrated, and the sample was dry-applied and subjected to column chromatography using an eluent (PE:EA, volume ratio = 30:1) to afford 402 mg of a pale yellow solid, yielding 76%. 1 H NMR(500MHz,DMSO-d6)δ9.13(s,1H),7.91(s,1H),7.64(d,J=2.5Hz,1H),7.51(d , J=2.4Hz, 1H), 4.23 (dddd, J=18.0, 10.9, 7.1, 3.8Hz, 2H), 1.27 (t, J=7.1Hz, 3H).

[0553] (2) Synthesis of 6-bromo-8-deuterated 2-trifluoromethyl-2-hydroxy-2H-benzopyran-3-carboxylic acid

[0554]

[0555] To a 50 mL round-bottom, single-necked flask was added ethyl 6-bromo-8-deuterated methyl-2-trifluoromethyl-2-hydroxy-2H-benzopyran-3-carboxylate (100 mg, 0.26 mmol), methanol (2.0 mL), and water (2.0 mL). The temperature was lowered to 0°C, and lithium hydroxide (18.7 mg) was added. The temperature was raised to room temperature and stirred for 3 h. TLC indicated complete reaction. The pH was adjusted to 3-4 with aqueous citric acid. The product was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, concentrated, and dry-applied for column chromatography using eluents: PE:EA (volume ratio) = 10:1, DCM:MeOH (volume ratio) = 12:1. The mixture was slurried in n-heptane and centrifuged to yield 26 mg of a white solid. 1 H NMR (500MHz, DMSO-d6) δ7.41(s,1H),7.37(s,1H),7.33(s,1H).

[0556] Example 27

[0557] The chemical name of the compound in this example is: 6-bromo-8-deuterated methyl-2-trifluoromethyl-2-methoxy-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0558]

[0559] (1) Synthesis of ethyl 6-bromo-8-deuterated methyl-2-trifluoromethyl-2-methoxy-2H-benzopyran-3-carboxylate

[0560]

[0561] To a 50 mL round-bottom single-necked flask, the starting material (the product synthesized in step (2) of Example 26) (100 mg, 0.26 mmol) was added. Under argon, potassium carbonate (72 mg, 0.52 mmol) and ultra-dry acetonitrile (5.0 mL) were added. The mixture was cooled to 0°C and iodomethane (0.39 mmol) was added dropwise. The reaction was allowed to proceed at 0°C for 4 hours. TLC indicated that the starting material had not reacted completely. The mixture was stirred at room temperature overnight. Saturated sodium bicarbonate was slowly added dropwise at 0°C to quench the reaction. The mixture was extracted twice with dichloromethane. The organic phases were combined, washed with saturated sodium chloride, concentrated, and subjected to column chromatography using an eluent (PE:EA volume ratio = 25:1). The yield was 96%.

[0562] (2) Synthesis of 6-bromo-8-deuterated 2-trifluoromethyl-2-fluoro-2H-benzopyran-3-carboxylic acid

[0563]

[0564] To a 50 mL single-necked flask, ethyl 6-bromo-8-deuterated methyl-2-trifluoromethyl-2-methoxy-2H-chromene-3-carboxylate (75 mg, 0.188 mmol), methanol (2.0 mL), and tetrahydrofuran (2.0 mL) were added. Under argon, the temperature was lowered to 0°C, and an aqueous solution of lithium hydroxide (1.0 mol / L, 1.0 mL) was added dropwise. The reaction was continued at 0°C for 2 h. TLC observation showed complete conversion of the starting material. The pH was adjusted to 5-6 with saturated aqueous citric acid solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, washed with n-heptane, sonicated, and centrifuged to obtain 47 mg of a white solid. 1 H NMR (500MHz, DMSO-d6) δ 13.20 (s, 1H), 8.11 (s, 1H), 7.67 (d, J = 2.6Hz, 1H), 7.55 (d, J = 2.5Hz, 1H), 3.34 (s, 3H).

[0565] Example 28

[0566] The chemical name of the compound in this example is: (S)-6-sulfur pentafluoride-8-(difluoromethyl-d)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0567]

[0568] (1) Synthesis of methyl (S)-6-sulfur pentafluoride-8-(difluoromethyl-d)-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0569]

[0570] Under argon, methyl 6-sulfur pentafluoride-8-deuteraldehyde-2-trifluoromethyl-2H-chromene-3-carboxylate (150 mg, 0.363 mmol) and 5 mL of DCM were added to a 50 mL single-necked flask. The mixture was cooled to 0°C, and diethylaminosulfur trifluoride (0.29 mL, 2.18 mmol) was slowly added dropwise. The mixture was allowed to react at 0°C for 0.5 h and then stirred at room temperature for 2 h. The reaction was quenched by dropwise addition of saturated sodium bicarbonate solution at 0°C. The mixture was extracted twice with dichloromethane, and the combined organic phases were washed with saturated brine, concentrated, and purified by column chromatography. Separation by flash chromatography using an eluent of PE:EA (volume ratio) of 25:1 afforded 130 mg of an oil (83% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 8.01–7.92 (m, 1H), 7.75 (s, 2H), 5.86 (q, J = 6.5 Hz, 1H), 3.90 (s, 3H).

[0571] (2) Synthesis of (S)-6-sulfur pentafluoride-8-(difluoromethyl-d)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0572]

[0573] Add (S)-6-sulfur pentafluoride-8-(difluoromethyl-d)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester (125 mg, 0.304 mmol), 1.0 mL of methanol, and 1.0 mL of tetrahydrofuran to a 50 mL single-necked flask. Add lithium hydroxide (1.0 mL, 1.0 mol / L, dissolved in aqueous solution, 0.914 mmol) in an ice bath, and stir and heat naturally for 2 h. TLC monitoring of the reaction of the raw materials revealed that the reaction was complete. 1 mol / L hydrochloric acid was added to adjust the pH to 3-4, and the mixture was extracted twice with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was slurried with petroleum ether, centrifuged, and dried by spin drying to obtain 95 mg of a white powder (80% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 8.04–7.95 (m, 1H), 7.87 (s, 1H), 7.79 (d, J = 2.7 Hz, 1H), 5.86 (q, J = 6.5 Hz, 1H).

[0574] Example 29

[0575] The chemical name of the compound in this example is: (S)-6-sulfur pentafluoride-8-isopropenyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0576]

[0577] (1) Synthesis of (S)-6-sulfur pentafluoride-8-isopropenyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0578]

[0579] Under argon, to a 25 mL sealed tube was added (S)-methyl 6-sulfur pentafluoride-8-bromo-2-trifluoromethyl-2H-chromene-3-carboxylate (100 mg, 0.216 mmol), palladium chloride (4.0 mg, 0.0216), triphenylphosphine (17 mg, 0.065 mmol), cesium carbonate (211 mg, 0.648 mmol), potassium isopropenyltrifluoroborate (64 mg, 0.432 mmol), tetrahydrofuran (1.8 mL), and water (0.2 mL). The mixture was heated to 85°C for 8 hours. Ethyl acetate was added to the reaction solution, followed by water to quench the reaction. The aqueous phase was extracted again with ethyl acetate, and the combined organic phases were washed with half-saturated brine, concentrated, and subjected to column chromatography using a dry-run method with an eluent of PE:EA in a volume ratio of 30:1 to afford 90 mg of a white solid in a 98% yield. 1 H NMR (500 MHz, deuterated chloroform) δ 7.71 (s, 1H), 7.61 (d, J = 2.5 Hz, 1H), 7.54 (d, J = 2.6 Hz, 1H), 5.81 (q, J = 6.6 Hz, 1H), 5.28 (s, 1H), 5.13 (s, 1H), 3.88 (s, 3H), 2.13 (d, J = 1.4 Hz, 3H).

[0580] (2) Synthesis of (S)-6-sulfur pentafluoride-8-isopropenyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0581]

[0582] To a 50 mL single-necked flask, add (S)-6-sulfur pentafluoride-8-isopropenyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester (90 mg, 0.212 mmol), 1.0 mL of methanol, and 1.0 mL of tetrahydrofuran. Add lithium hydroxide (1.0 mL, 1.0 mol / L, dissolved in aqueous solution, 0.636 mmol) in an ice bath, and stir and react naturally for 2 h. TLC monitoring of the reaction of the raw materials shows that the reaction is complete. Add 1 mol / L hydrochloric acid to adjust the pH to 3-4, extract twice with EA, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, spin dry, slurry with n-heptane, centrifuge, and spin dry to obtain 50 mg of a white powder in a 60% yield. 1 H NMR (500 MHz, deuterated chloroform) δ 7.83 (s, 1H), 7.66–7.61 (m, 1H), 7.58 (d, J = 2.7 Hz, 1H), 5.80 (q, J = 6.6 Hz, 1H), 5.30 (d, J = 1.6 Hz, 1H), 5.14 (s, 1H), 2.13 (s, 3H).

[0583] Example 30

[0584] The chemical name of the compound in this example is: (S)-6-sulfur pentafluoride-8-n-propenyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0585]

[0586] (1) Synthesis of (S)-6-sulfur pentafluoride-8-n-propenyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0587]

[0588] Under argon, a 25 mL sealed tube was charged with (S)-6-sulfur pentafluoride-8-bromo-2-trifluoromethyl-2H-chromene-3-carboxylic acid methyl ester (100 mg, 0.216 mmol), bistriphenylphosphine palladium dichloride (16 mg, 0.0216 mmol), cesium fluoride (98 mg, 0.645 mmol), trans-1-propen-1-yl boronic acid (38 mg, 0.432 mmol), dioxane (1.2 mL), and water (0.6 mL). The mixture was heated to 85°C for 8 hours. Ethyl acetate was added to the reaction solution, followed by water to quench the reaction. The aqueous phase was extracted again with ethyl acetate, and the combined organic phases were washed with half-saturated brine, concentrated, and subjected to column chromatography. Dry-loading was performed using an eluent of PE:EA in a volume ratio of 30:1 to obtain 80 mg of a colorless oil (87%). 1 H NMR (500 MHz, deuterated chloroform) δ 7.78 (s, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.46 (d, J = 2.4 Hz, 1H), 6.61 (d, J = 15.9 Hz, 1H), 6.38 (ddd, J = 15.6, 6.7, 1.8 Hz, 1H), 5.87–5.74 (m, 1H), 3.89 (d, J = 1.8 Hz, 3H), 1.95 (d, J = 6.4 Hz, 3H).

[0589] (2) Synthesis of (S)-6-sulfur pentafluoride-8-n-propenyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0590]

[0591] To a 50 mL single-necked flask, add (S)-6-sulfur pentafluoride-8-n-propenyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester (60 mg, 0.187 mmol), 1.0 mL of methanol, and 1.0 mL of tetrahydrofuran. Add lithium hydroxide (1.0 mL, 1.0 mol / L, dissolved in aqueous solution, 0.56 mmol) in an ice bath, and stir and react naturally for 2 h. TLC monitoring of the reaction of the raw materials shows that the reaction is complete. Add 1 mol / L hydrochloric acid to adjust the pH to 3-4, extract twice with EA, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, spin dry, slurry with n-heptane, centrifuge, and spin dry to obtain 70 mg of a white solid powder in a 90% yield. 1 H NMR (500 MHz, deuterated chloroform) δ 7.83 (s, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.50 (d, J = 2.5 Hz, 1H), 6.62 (d, J = 15.8 Hz, 1H), 6.39 (dq, J = 15.7, 6.6 Hz, 1H), 5.80 (q, J = 6.6 Hz, 1H), 1.96 (d, J = 6.6 Hz, 3H).

[0592] Example 31

[0593] The chemical name of the compound in this example is: (S)-6-sulfur pentafluoride-8-(1-fluorovinyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0594]

[0595] (1) Synthesis of (S)-6-sulfur pentafluoride-8-(1-fluoro-2-bromoethyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0596]

[0597] Under argon protection, the raw material (the product synthesized in Example 19, step (5)) (100 mg, 0.244 mmol), NBS (66 mg, 0.366 mmol), and dichloromethane (3.0 mL) were added to a 50 mL single-necked bottle. The mixture was cooled in an ice bath and triethylamine trihydrofluoride (59 mg, 0.366 mmol) was added. The temperature was naturally raised and stirred at room temperature overnight. Sodium bicarbonate was added in an ice bath to quench the reaction. The aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with dilute hydrochloric acid, washed with saturated brine once, dried, concentrated, and subjected to column chromatography. Dry loading was performed using an eluent: PE:EA volume ratio = 50:1. 98 mg of oil was obtained, with a yield of 82%. 1H NMR (500 MHz, deuterated chloroform) δ 7.78 (dd, J = 4.2, 2.3 Hz, 1H), 7.74 (s, 1H), 7.66–7.63 (m, 1H), 5.91 (p, J = 6.2 Hz, 1H), 5.50 (ddd, J = 16.8, 11.1, 5.4 Hz, 1H), 4.14–4.07 (m, 1H), 4.06–4.01 (m, 1H), 3.90 (d, J = 1.5 Hz, 3H).

[0598] (2) Synthesis of (S)-6-sulfur pentafluoride-8-(1-fluorovinyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0599]

[0600] Under argon, a 50 mL single-necked vial was charged with (S)-6-sulfur pentafluoride-8-(1-fluoro-2-bromoethyl)-2-trifluoromethyl-2H-chromene-3-carboxylic acid methyl ester (98 mg, 0.192 mmol), dichloromethane (5.0 mL), and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU, 36 mg, 0.231 mmol). The mixture was heated under reflux for 4 hours. After cooling, the reaction mixture was added with dilute hydrochloric acid and extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, concentrated, and subjected to column chromatography using a dry-phase loading method using an eluent of PE:EA (volume ratio) of 50:1 to obtain 64 mg of a colorless oil (78% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 7.82 (d, J = 2.6 Hz, 1H), 7.72 (s, 1H), 7.60 (d, J = 2.5 Hz, 1H), 6.09 (dd, J = 13.5, 2.1 Hz, 2H), 5.90–5.82 (m, 1H), 3.89 (s, 3H).

[0601] (3) (S)-6-Sulfur pentafluoride-8-(1-fluorovinyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0602]

[0603] To a 50 mL single-necked flask, add (S)-6-sulfur pentafluoride-8-(1-fluorovinyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester (60 mg, 0.14 mmol), 1.0 mL of methanol, and 1.0 mL of tetrahydrofuran. Add lithium hydroxide (1.0 mL, 1.0 mol / L, dissolved in aqueous solution, 0.42 mmol) in an ice bath, and stir and react naturally for 2 h. TLC monitoring of the reaction of the raw materials indicates complete reaction. 1 mol / L hydrochloric acid is added to adjust the pH to 3-4. Extract twice with EA, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, spin dry, slurry with n-heptane, centrifuge, and spin dry to obtain 20 mg of a white solid powder (40% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 7.84 (s, 2H), 7.64 (t, J = 2.2 Hz, 1H), 6.10 (dd, J = 11.4, 2.1 Hz, 2H), 5.85 (q, J = 6.4 Hz, 1H).

[0604] Example 32

[0605] The chemical name of the compound in this example is: (S)-6-sulfur pentafluoride-8-(2,2-difluorovinyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0606]

[0607] (1) Synthesis of tert-butyl (S)-6-sulfur pentafluoride-8-vinyl-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0608]

[0609] Under argon, to a 25 mL sealed tube was added tert-butyl (S)-6-sulfur pentafluoride-8-bromo-2-trifluoromethyl-2H-chromene-3-carboxylate (200 mg, 0.396 mmol), palladium chloride (7 mg, 0.04 mmol), triphenylphosphine (32 mg, 0.119 mmol), cesium carbonate (387 mg, 0.387 mmol), potassium ethylene trifluoroborate (107 mg, 0.792 mmol), tetrahydrofuran (1.8 mL), and water (0.2 mL). The mixture was heated to 85°C for 8 hours. Ethyl acetate was added to the reaction solution, followed by water to quench the reaction. The aqueous phase was extracted again with ethyl acetate, and the combined organic phases were washed with half-saturated brine, concentrated, and subjected to column chromatography using a dry-run method with an eluent ratio of PE:EA (70:1) to afford 175 mg of a white solid in a 98% yield. 1H NMR (500 MHz, deuterated chloroform) δ 7.82 (d, J = 2.6 Hz, 1H), 7.60 (s, 1H), 7.52 (d, J = 2.6 Hz, 1H), 6.94 (dd, J = 17.7, 11.2 Hz, 1H), 5.87 (d, J = 17.7 Hz, 1H), 5.79 (q, J = 6.7 Hz, 1H), 5.49 (d, J = 11.2 Hz, 1H), 1.55 (s, 9H).

[0610] (2) Synthesis of tert-butyl (S)-6-sulfur pentafluoride-8-formyl-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0611]

[0612] To a 50 mL single-necked bottle was added tert-butyl (S)-6-sulfur pentafluoride-8-vinyl-2-trifluoromethyl-2H-chromene-3-carboxylate (185 mg, 0.409 mmol), tetrahydrofuran (3.0 mL), tert-butanol (3.0 mL), water (1.0 mL), and potassium osmate dihydrate (5.1 mg, 0.0164 mmol). An aqueous solution of NMO (96 mg, 1.0 mL of water, 0.818 mmol) was added dropwise. The mixture was stirred at room temperature overnight and the reaction was complete after monitoring by TLC. Ethyl acetate was added to the reaction solution, and then water was added to quench the reaction. The aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, concentrated, and dioxane (8.0 mL) and water (2.0 mL) were added. Sodium periodate (263 mg, 1.23 mmol) was added in an ice bath, and the temperature was naturally raised with stirring to react for 30 min. TLC monitored the complete reaction of the raw material. Water was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, and subjected to column chromatography. Dry loading was performed with an eluent of PE:EA in a volume ratio of 30:1 to obtain 66 mg of a white solid with a yield of 36%.

[0613] (3) Synthesis of tert-butyl (S)-6-sulfur pentafluoride-8-(2,2-difluorovinyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylate

[0614]

[0615] Under argon, a 25 mL single-necked vial was charged with tert-butyl (S)-6-sulfur pentafluoride-8-formyl-2-trifluoromethyl-2H-chromene-3-carboxylate (66 mg, 1.0 eq), triphenylphosphine (58 mg, 0.145 mmol), DMF (2.5 mL), and sodium difluorochloroacetate (27 mg, 0.174 mmol). The mixture was heated to 110°C for 2.5 hours. TLC monitored the complete reaction. After cooling, ethyl acetate was added to the reaction solution, followed by water to quench the reaction. The aqueous phase was extracted again with ethyl acetate, and the combined organic phases were washed with semi-saturated brine, concentrated, and subjected to column chromatography. Dry-loading was performed using an eluent of PE:EA (volume ratio = 200:1) to afford 46 mg of a semisolid product (66% yield). 1 HNMR (500 MHz, deuterated chloroform) δ7.85 (d, J=2.5 Hz, 1H), 7.59 (s, 1H), 7.52 (d, J=2.5 Hz, 1H), 5.78 (q, J=6.7 Hz, 1H), 5.61 (dd, J=25.3, 3.6 Hz, 1H), 1.55 (s, 9H).

[0616] (4) (S)-6-Sulfur pentafluoride-8-(2,2-difluorovinyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0617]

[0618] To a 25 mL single-necked flask, add (S)-6-sulfur pentafluoride-8-(2,2-difluorovinyl)-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid tert-butyl ester (46 mg, 0.094 mmol) and 2.0 mL of dichloromethane. Add trifluoroacetic acid (0.5 mL) in an ice bath and stir to react for 5 h. TLC monitoring of the reaction indicated complete reaction. Concentrate, add trifluoroacetic acid several times with dichloromethane, and spin-dry to a solid. Add n-heptane, centrifuge, and spin-dry to obtain 25 mg of a white powder (65% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 7.91 (d, J = 1.7 Hz, 1H), 7.84 (s, 1H), 7.57 (s, 1H), 5.81 (q, J = 6.6 Hz, 1H), 5.63 (dd, J = 25.0, 3.0 Hz, 1H).

[0619] Example 33

[0620] The chemical name of the compound in this example is: (S)-6-sulfur pentafluoride-8-perdeuterated vinyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0621]

[0622] (1) Synthesis of deuterated methyltriphenylphosphine iodide

[0623]

[0624] Add triphenylphosphine (2.17 g, 8.28 mmol) and anhydrous toluene (15 mL) to a 50 mL single-necked flask. Cool in an ice bath, then add deuterated iodomethane (0.43 mL, 0.429 mmol). Heat naturally and stir overnight. Filter, wash with toluene, and spin dry to obtain 2.6 g of a white solid, which is used directly in the next step.

[0625] (2) Synthesis of (S)-6-sulfur pentafluoride-8-perdeuterated vinyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0626]

[0627] Under argon protection, methyl-D3-triphenylphosphine iodide (520 mg, 1.27 mmol) and ultra-dry tetrahydrofuran (5.0 mL) were added to a 50 mL two-necked flask, cooled at -10 ° C, n-butyl lithium (0.41 mL, 1.02 mmol) was added dropwise, and the mixture was stirred and reacted naturally for 2 hours. The mixture was cooled to 0 ° C, and the raw material (100 mg of the raw material was dissolved in 2.0 mL of THF, 0.508 mmol) was added dropwise. The mixture was naturally warmed to room temperature for 1.5 h, stirred and reacted at room temperature for 0.5 hour, cooled in an ice bath, and the raw material (210 mg of the raw material was dissolved in 3.0 mL of THF, 1.0 eq) was added dropwise. The mixture was naturally warmed and stirred and reacted for 2 hours. The mixture was cooled in an ice bath, and dilute hydrochloric acid was added dropwise to quench the reaction. The pH was adjusted to 6-7. Ethyl acetate was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, and concentrated. Potassium carbonate and DMF were added, and iodomethane was added dropwise in an ice bath. The mixture was stirred at room temperature for 1.5 hours, and water was added to quench the reaction. The mixture was extracted twice with ethyl acetate, and the organic phases were combined and washed with half-saturated brine three times. The mixture was concentrated and subjected to column chromatography. The sample was loaded by dry method. The eluent was PE:EA in a volume ratio of 50:1 to obtain 40 mg of an oily substance with a yield of 20%. 1 H NMR (500 MHz, deuterated chloroform) δ 7.85 (d, J = 2.4 Hz, 1H), 7.71 (s, 1H), 7.53 (d, J = 2.5 Hz, 1H), 5.83 (q, J = 6.7 Hz, 1H), 3.89 (s, 3H).

[0628] (3) (S)-6-Sulfur pentafluoride-8-perdeuterated vinyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0629]

[0630] To a 50 mL single-necked flask, add (S)-6-sulfur pentafluoride-8-perdeuterovinyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester (27 mg, 0.065 mmol), 1.0 mL of methanol, and 1.0 mL of tetrahydrofuran. Add lithium hydroxide (1.0 mL, 1.0 mol / L aqueous solution, 0.196 mmol) in an ice bath, and stir and react naturally for 2 h. TLC monitoring of the reaction of the raw materials shows that the reaction is complete. Add 1 mol / L hydrochloric acid to adjust the pH to 3-4, extract twice with EA, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, spin dry, slurry with n-heptane, centrifuge, and spin dry to obtain 18 mg of a white solid powder (90% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 7.88 (s, 1H), 7.83 (s, 1H), 7.56 (d, J = 2.5 Hz, 1H), 5.82 (q, J = 6.6 Hz, 1H).

[0631] Example 34

[0632] The chemical name of the compound in this example is (S)-6-bromo-8-trifluoroethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid, and its synthesis route and steps are as follows:

[0633]

[0634] (1) Synthesis of (S)-6-bromo-8-trifluoroethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester

[0635]

[0636] Under argon protection, to a 25 mL sealed tube were added (S)-6-bromo-8-iodo-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid methyl ester (150 mg, 0.324 mmol), Mn (63 mg, 1.13 mmol), nickel iodide (10.2 mg, 0.0324 mmol), dppf palladium dichloride (18 mg, 0.0324 mmol), 4,4-di-tert-butylbipyridyl (dtbpy, 8.7 mg, 0.0324 mmol), 2-iodo-1,1,1-trifluoroethane (88 mg, 0.421 mmol) and N,N-dimethylacetamide (DMAc, 1.5 mL). Under argon protection, the temperature was raised to 70 ° C and stirred for 6 hours, and then stirred at room temperature for one day. Ethyl acetate was added to the reaction solution, and then water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate again. The organic phases were combined, washed three times with half-saturated brine, dried, concentrated, and subjected to column chromatography. Dry loading was performed using an eluent of PE:EA (volume ratio = 100:1) to obtain 45 mg of a colorless oil with a yield of 33%. 1H NMR (500 MHz, deuterated chloroform) δ 7.65 (d, J = 2.3 Hz, 1H), 7.43 (s, 1H), 7.35 (s, 1H), 5.77 (tt, J = 6.9, 3.9 Hz, 1H), 3.87 (d, J = 2.4 Hz, 3H), 3.47–3.39 (m, 2H).

[0637] (2) Synthesis of (S)-6-bromo-8-trifluoroethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid

[0638]

[0639] To a 50 mL single-necked flask, add (S)-methyl 6-bromo-8-trifluoroethyl-2-trifluoromethyl-2H-benzopyran-3-carboxylate (45 mg, 0.109 mmol), 1.0 mL of methanol, and 1.0 mL of tetrahydrofuran. Add lithium hydroxide (1.0 mL, 1.0 mol / L aqueous solution, 0.327 mmol) in an ice bath, and stir and react for 2 h. TLC monitoring of the reaction showed that the starting material had reacted completely. 1 mol / L hydrochloric acid was added to adjust the pH to 3-4. Extract twice with EA, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, spin dry, slurry with n-heptane, centrifuge, and spin dry to obtain 35 mg of a white solid powder (81% yield). 1 H NMR (500 MHz, deuterated chloroform) δ 7.77 (s, 1H), 7.46 (s, 1H), 7.40 (s, 1H), 5.76 (q, J = 6.8 Hz, 1H), 3.45 (q, J = 10.6 Hz, 2H).

[0640] Drug activity testing:

[0641] (1) COX-2 activity test

[0642] The compounds in Examples 1 to 34, the sodium / potassium salt of Example 2, GIBH-1014, celecoxib, and SC-75416 were tested for inhibition of COX-2 enzyme activity using the FI method. SC-75416 is a small molecule COX-2 inhibitor developed by Pfizer. GIBH-1014 is a small molecule COX-2 inhibitor developed by the Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences. Its chemical name is 6,8-deuterated dimethyl-2-(trifluoromethyl)-2H-benzopyran-3-carboxylic acid. The structural formulas of SC-75416 and GIBH-1014 are as follows: The FI method utilizes the peroxidase component of COXs, 1,2,3,4,6-O-pentagalloylglucose (PGG) reacting with 10-acetyl-3,7-dihydroxyphenazine (ADHP) to produce the highly fluorescent compound resorufin. Resorufin has an excitation wavelength of 530-540 nm and an emission wavelength of 585-595 nm, making it easy to analyze fluorescence. The test compound was dissolved and diluted with DMSO (Sigma, D4540) to 100× the detection concentration. A nanoliter pipetting system ( 100 nL of compound was transferred to a 384 assay plate (Corning, 4514) using a 655 SYSTEM. Hemin, 10-acetyl-3,7-dihydroxyphenazine (ADHP), arachidonic acid, and potassium hydroxide were prepared in 1x COX Buffer (100 mmol / L, Tris-HCl, pH 8.0). Transfer 2.5 μL of 4x COX2 enzyme (Cayman, 700100) solution to a 384 assay plate and centrifuge at 1000 rpm for 1 minute; transfer 2.5 μL of 4x Hemin solution to a 384 assay plate and centrifuge at 1000 rpm for 1 minute, incubate at 25°C for 10 minutes; transfer 2.5 μL of 4x ADHP solution to a 384 assay plate and centrifuge at 1000 rpm for 1 minute; transfer 2.5 μL of 4x Arachidonic Acid and Potassium Hydroxide mixed solution to a 384 assay plate and centrifuge at 1000 rpm for 1 minute; finally, read the FI signal (ex528 / em587) using a multifunctional microplate reader (BMG, CLARIOstar Plus). The negative control reading was set to 0% inhibition, and the positive control reading was set to 100% inhibition. The inhibition rate of each test solution was calculated, and the data were analyzed using GraphPad 8 software. The IC value of the compound was obtained using a nonlinear fitting formula. 50 (half inhibitory concentration), the inhibitory IC of the compounds in Examples 1 to 34 measured according to the above test method 50 The data are shown in Table 1 below.

[0643] Table 1 IC values ​​of each compound for COX-2 inhibition 50

[0644]

[0645]

[0646] As shown in Table 1, the inhibitory activity of a series of compounds of the present invention on human recombinant COX-2 enzyme is IC 50 The values ​​reached nanomolar level, among which the compounds in Examples 1-2, the sodium salt and potassium salt of Example 2, Example 19, Examples 29-30, and Example 33 had better COX-2 inhibitory activity than GIBH-1014, celecoxib, and SC-75416.

[0647] (2) COX-1 activity test

[0648] The inhibition experiment of COX-1 enzyme activity by the compounds of Examples 1 to 2, Examples 18 to 19, Examples 29 to 30 and Example 33 and GIBH-1014 was tested using the FI method. This method utilizes the properties of COX-1 peroxidase to convert arachidonic acid (AA) into PGG2. PGG2 reacts with ADHP under the action of peroxidase to generate a highly fluorescent compound, Resorufin. The excitation wavelength of Resorufin is 530-540 nm and the emission wavelength is 585-595 nm, thereby analyzing the generated fluorescence intensity. After the test compound is dissolved, it is diluted with DMSO (Sigma, D4540) to 100× the detection concentration. A nanoliter pipetting system ( 100 nL of compound was transferred to a 384 assay plate (Corning, 4514) using a 655 SYSTEM. Hemin, 10-acetyl-3,7-dihydroxyphenazine (ADHP), arachidonic acid, and potassium hydroxide were prepared in 1x COX Buffer (100 mmol / L Tris-HCl, pH 8.0). Transfer 2.5 μL of 4x COX1 enzyme (Cayman, 700100) solution to a 384 assay plate and centrifuge at 1000 rpm for 1 minute; transfer 2.5 μL of 4x Hemin solution to a 384 assay plate and centrifuge at 1000 rpm for 1 minute, incubate at 25°C for 10 minutes; transfer 2.5 μL of 4x ADHP solution to a 384 assay plate and centrifuge at 1000 rpm for 1 minute; transfer 2.5 μL of 4x Arachidonic Acid and Potassium Hydroxide mixed solution to a 384 assay plate and centrifuge at 1000 rpm for 1 minute; finally, read the FI signal (ex528 / em587) using a multifunctional microplate reader (BMG, CLARIOstar Plus). The reading value of the negative control was set as 0% inhibition rate, and the reading value of the positive control was set as 100% inhibition rate. The inhibition rate of each test solution was calculated, and then the data were analyzed by GraphPad 8 software. The IC50 (half maximal inhibition concentration) of the compound was obtained using a nonlinear fitting formula. The inhibition IC50 of the compounds of Examples 1 to 2, Examples 18 to 19, Examples 29 to 30 and Example 33 and GIBH-1014 on COX-1 measured according to the above test method was 50 The data is shown in Table 2 below.

[0649] Table 2 IC values ​​of each compound for COX-1 inhibition 50 and COX-2 to COX-1 selectivity ratio

[0650]

[0651] As can be seen from Table 2, Examples 1 to 2, Examples 18 to 19, Examples 29 to 30 and Example 33 of the present invention have poor inhibitory activity against COX-1 enzyme, and the selectivity ratio of COX-2 to COX-1 of Examples 1 to 2, Examples 18 to 19, Examples 29 to 30 and Example 33 is significantly better than that of GIBH-1014, that is, they have better COX-2 selective inhibition than GIBH-1014.

[0652] (3) TXB2 / PGE2 test experiment

[0653] In the whole blood experiment, venous blood from healthy donors was collected using tubes without anticoagulants and heparin tubes, and different concentrations of the compounds of Examples 1 to 2, Examples 18 to 19, Examples 29 to 30, and Example 33 and GIBH-1014 (1×10 -8 ~1×10 -4 ) was mixed with the blood in the tube without anticoagulant and the blood was coagulated. The supernatant was then collected and the amount of TXB2 produced was determined by ELISA. Different concentrations of the compounds of Examples 1 to 2, Examples 18 to 19, Examples 29 to 30, and Example 33 and GIBH-1014 (1×10 -8 ~1×10 -4 ) was mixed with blood in a heparin tube, and lipopolysaccharide was added to a final concentration of 100 μg / ml. The mixture was then incubated at 37°C overnight and centrifuged. The supernatant was then used to measure the amount of PGE2 produced by ELISA. Based on the inhibitory effect of deuterated benzopyran compounds on the two isomerases and their inhibitory effect on the production of TXB2 / PGE2 in the whole blood experiment, the half inhibitory concentration (IC 50 ) values, as shown in Table 3.

[0654] Table 3 Inhibitory IC values ​​of each compound on TXB2 and PGE2 50 value

[0655]

[0656] As can be seen from Table 3, Examples 1 to 2, Examples 18 to 19, Examples 29 to 30 and Example 33 of the present invention have poor inhibitory activity against TXB2 and have good selectivity, and Examples 1 to 2, Examples 18 to 19, Examples 29 to 30 and Example 33 are all better than GIBH-1014 in terms of PGE2 inhibitory activity.

[0657] (4) hERG potassium channel inhibitory activity experiment

[0658] The cells used in this experiment were CHO cells transfected with HergC DNA and stably expressing the hERG channel. The cells were cultured in a medium containing the following components: Ham's F12 medium, 10% (v / v) inactivated fetal bovine serum, 100 μg / mL hygromycin B, and 100 μg / mL geneticin. 2.1.2 CHO hERG cells were grown in culture dishes containing the above-mentioned medium in an incubator at 37°C and 5% CO2. 24 to 48 hours prior to electrophysiological experiments, CHO hERG cells were transferred to circular glass slides placed in culture dishes and grown in the same medium and conditions as described above. The density of CHO hERG cells per circular slide was such that the majority of cells were independent and single. Electrophysiological recording system and data analysis: Whole-cell currents were recorded using a manual patch clamp system (HEKA EPC-10 signal amplifier and digitizer, purchased from HEKA Electronics, Germany). A circular slide with CHO hERG cells growing on its surface was placed in an electrophysiological recording chamber under an inverted microscope. Extracellular solution was continuously perfused into the recording chamber (approximately 1 ml per minute). Conventional whole-cell patch clamp current recording techniques were used. Unless otherwise specified, experiments were performed at room temperature (25°C). The cells were clamped at -80 mV. The clamping voltage was depolarized to +20 mV to activate the HERG potassium channel, and then re-clamped to -50 mV after 5 seconds to eliminate inactivation and generate a tail current. The peak tail current was used as the magnitude of the HERG current. Once the hERG potassium current recorded in the above steps stabilizes under continuous perfusion of extracellular solution into the recording chamber, the drug to be tested can be superimposed until the inhibitory effect on the hERG current reaches a steady state. Stability is generally determined by the coincidence of the three most recent consecutive current recording lines. After achieving stability, the cells are flushed with extracellular solution until the hERG current returns to its pre-drug level. One or more drugs, or multiple concentrations of the same drug, can be tested on a single cell, but extracellular fluid flushing is required between drug administrations. Cisapride (purchased from Sigma) was used as a positive control to ensure the quality of the cells used. The experimental data were analyzed using HEKAPatchmaster, Microsoft Excel, and Graphpad Prism. The specific test results are shown in Table 4. The higher the inhibition rate of hERG channel current in Table 4, the greater the risk of hERG cardiotoxicity.

[0659] Table 4 Inhibition rate of hERG channel current by compounds (%)

[0660] serial number Inhibition rate (10 μmol / L) Inhibition rate (30 μmol / L) Example 1 40.3 － Example 2 3.38 5.53 Example 18 7.82 14.36 Example 19 4.35 8.42 Example 29 11.3 18.6 Example 30 5.43 9.53 Example 33 8.42 17.5 GIBH-1014 44.82 －

[0661] As can be seen from Table 4, the inhibition rates of the compounds of Examples 1-2, Examples 18-19, Examples 29-30 and Example 33 on hERG channel current at a concentration of 10 μmol / L are all lower than that of GIBH-1014, that is, the relevant examples have a lower hERG cardiotoxicity risk than GIBH-1014, and the compounds of Example 2, Examples 18-19, Examples 29-30 and Example 33 have almost no inhibitory effect on the hERG channel at a concentration of 30 μmol / L.

[0662] (5) Compound liver microsome stability test

[0663] 1) Preparation of buffer solution:

[0664] Buffer A: 1.0 L of 0.1 mol / L potassium dihydrogen phosphate buffer (containing 1.0 mmol / L EDTA);

[0665] Buffer B: 1.0 L of 0.1 mol / L potassium hydrogen phosphate buffer (containing 1.0 mmol / L EDTA);

[0666] Buffer C: Add buffer A to 700 mL of buffer B and stop when the pH reaches 7.4.

[0667] 2) Preparation of 10mmol / L stock solution:

[0668] The test compound and the control substance were dissolved in DMSO to prepare 10 mmol / L stock solution.

[0669] 3) Preparation of dosing solution:

[0670] 500 μmol / L solution: add 10 μL of 10 mmol / L stock solution to 190 μL ACN;

[0671] 1.5 μmol / L dosing solution (dissolved in human liver microsomes or rat liver microsomes):

[0672] Add 18.75 μL of 20 mg / mL human liver microsomes or rat liver microsomes to 479.75 μL of buffer C, then add 1.5 μL of 500 μmol / L solution and vortex gently to mix.

[0673] 4) Preparation of 6mmol / L NADPH solution:

[0674] Weigh reduced coenzyme II (NADPH), then add an appropriate amount of buffer C to prepare a 6 mmol / L NADPH solution.

[0675] 5) 30 μL of 1.5 μmol / L dosing solution was added to the wells of a 96-well plate set at different time points (0 min, 5 min, 15 min, 30 min, 45 min), with a replicate of 2.

[0676] 6) Prepare the 0-minute sample: first add 135 μL of ACN (including internal standard) to the 0-minute well, and then add 15 μL of 6 mmol / L NADPH solution.

[0677] 7) Preheat the 96-well plate containing 1.5 μmol / L dosing solution and NADPH solution in a 37°C water bath for 5 minutes.

[0678] 8) Add 15 μL of preheated 6 mmol / L NADPH solution to the wells set at 5 min, 15 min, 30 min, and 45 min to initiate the reaction and start timing.

[0679] 9) At 5, 15, 30, and 45 minutes, add 135 μL of ACN (containing internal standard) to terminate the reaction. Vortex for 10 minutes and centrifuge the sample at 5594 × g for 15 minutes in a Thermo Multifuge × 3R centrifuge.

[0680] 10) Take 50 μL of supernatant from the centrifuged sample and transfer it to a 96-well sample plate to which 50 μL of water has been added. Mix the wells and then send the sample to LC-MS / MS for analysis.

[0681] 11) Calculate using the following formula:

[0682] Half-life T 1 / 2 =0.693 / K (K is the rate constant, K=ln[concentration] / incubation time)

[0683] Clearance Cl int =(0.693 / T1 / 2)×(1 / (liver microsome concentration (0.5 mg / mL)))×scaling factor.

[0684] The liver microsome stability data of Examples 1-2, Examples 18-19, Examples 29-30, Example 33 and GIBH-1014 measured according to the above test method are shown in Table 5 below.

[0685] Table 5 Liver microsomal stability data of compounds

[0686]

[0687]

[0688] As can be seen from Table 5, the compounds in Examples 1-2, 18-19, 29-30, and 33 of the present invention have good stability in human and rat liver microsomes. Among them, the stability of Example 2, 18-19, 29-30, and 33 in human liver microsomes is significantly better than that of GIBH-1014.

[0689] (6) Pharmacokinetic test of compound in SD rats

[0690] Male SD rats (purchased from SBEF (Beijing) Biotechnology Co., Ltd.). Each test compound was administered to SD rats by injection (1 mg / kg, 3 rats per group) and oral administration (5 mg / kg, 3 rats per group) for pharmacokinetic studies. The test compounds (GIBH-1014, SC-75416, compounds in Examples 1-2, 18-19, 29-30, and 33) were prepared on the day of administration. The test compounds were dissolved in 5% DMSO + 10% polyethylene glycol-15 hydroxystearate + 85% saline, vortexed for 2 minutes, and sonicated for 5 minutes to prepare the dosing solution. Animals receiving injections did not need to be fasted. Animals were fasted for 12 hours before oral administration and resumed eating 4 hours after administration. Following oral and intravenous administration of the drug by gavage, pharmacokinetic samples were collected from SD rats via the jugular vein. For intravenous administration, samples were collected at 5, 15, 30, 1, 2, 4, 7, and 24 hours after administration; for oral administration, samples were collected at 15, 30, 1, 2, 4, 7, and 24 hours after administration. Three whole blood samples (approximately 0.2 mL) were collected at each time point and anticoagulated with sodium heparin. Blood samples were immediately placed on ice and centrifuged within 1 hour to separate plasma (centrifugation conditions: 4000 rpm, 5 minutes, 2-8°C). Collected plasma was stored at -75°C ± 15°C prior to analysis. After pretreatment, LC-MS / MS analysis was performed, and the resulting data were used to calculate pharmacokinetic parameters using WinNonlin software. The results are shown in Tables 6 and 7 below.

[0691] Table 6 Summary of main pharmacokinetic parameters after injection in SD rats

[0692]

[0693]

[0694] Table 7 Summary of main pharmacokinetic parameters after oral administration in SD rats

[0695]

[0696] As shown in Table 6, when administered by injection, Example 2 and Example 19 have a longer half-life (T 1 / 2 ), a larger area under the plasma concentration-time curve (AUC), a lower clearance (CL), and a good peak concentration (C max ).

[0697] As shown in Table 7, when orally administered, Examples 2 and 19 have longer half-lives (T 1 / 2 ), faster time to peak blood concentration (T max ), higher peak drug concentration (C max ) and a larger area under the plasma concentration-time curve (AUC), and have similar bioavailability (F). Therefore, the compounds of the present invention can be used for the treatment of diseases by injection and oral absorption administration.

[0698] (7) Compound testing in CT26 mouse colon cancer model

[0699] Murine CT26.WT colorectal cancer cells were obtained from ATCC. The cancer cell line was cultured under standard conditions (RPMI, 10% FBS, 1% penicillin-streptomycin, 1% L-glutamine (cRPMI)) and confirmed to be mycoplasma-free. Tumor cells were harvested after trypsinization (Sigma), washed three times with PBS (Gibco), filtered through a 70 μm cell strainer, and counted. 10 5 Cells (in 100 μL of endotoxin-free PBS) were subcutaneously injected into the right flank of recipient C57BL / 6 mice. The viable tumor cells at the time of injection were >98% as determined by trypan blue (Life Technologies) staining. One week before the start of the experiment, the animals were housed in an environmentally controlled room (23°C ± 1°C, relative humidity 30% to 70%, at least 10 room ventilations per hour, 12-h light / dark cycle), and standard animal feed and water were provided to the animals for ad libitum food and drink. The mice were randomly divided into 5 experimental groups (vehicle group, control group, high, medium and low dose groups of Example 2), with 6 mice in each group. Starting on day 0, mice received oral administration of GIBH-1014 (10 mg / kg) and Example 2 (1 mg / kg, 3 mg / kg, 10 mg / kg) for 21 days, and tumor size was measured starting on the third day. Tumor size was quantified as the average of the longest diameter and its perpendicular direction. During the experiment, the weight of the mice was monitored at least once a week. The administration of Example 2 and GIBH-1014 had no effect on the weight change of the mice. The curve of the treated tumor diameter-time of the mice measured according to the above test method is shown in FIG. Figure 1 As shown. Figure 1It can be seen that at the same oral dose of 10 mg / kg, the tumor diameter reduction in the Example 2 group was significantly better than that in the GIBH-1014 group, indicating that the compound in Example 2 is significantly more effective than GIBH-1014 in treating colon cancer, and a lower dose is required to achieve the same therapeutic effect.

[0700] (8) Effects of compounds on carrageenan-induced rat foot swelling model

[0701] SD rats, male, 180-220 g, were housed individually (n=5 / group). One week prior to the experiment, the animals were housed in an environmentally controlled room (23°C ± 1°C, relative humidity 30%-70%, at least 10 air changes per hour, 12-h light / dark cycle) and provided with standard animal feed and water ad libitum. The compound of Example 2, GIBH-1014, SC-75416, and indomethacin were dissolved in a solution containing 0.5% methylcellulose, 0.025% Tween 20, and normal saline (NS), respectively. The solvent was 0.5% sodium carboxymethylcellulose, 0.5% CMC-Na. 600 mg of carrageenan (Sigma) was dissolved in 20 mL of saline. Half an hour after the injection (blank group, Example 2 dose group: 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg and 30 mg / kg, GIBH-1014 group: 10 mg / kg and 30 mg / kg, SC-75416 group: 10 mg / kg and 30 mg / kg, indomethacin group: 10 mg / kg and 30 mg / kg), 300 μL of 3% carrageenan was injected into the right hind paw. At 0h and 3h after the carrageenan injection, the volume of the right hind paw was measured using a volume meter. Calculate the inhibition percentage (%) = (1-A / B) × 100%; wherein A is the paw volume increment of the compound group, and B is the paw volume increment of the vehicle group. The paw swelling data measured according to the above test method are as follows: Figure 2 As shown. Figure 2 As shown, the compound in Example 2 reduced paw swelling in SD rats in a dose-dependent manner within the 0.3-30 mg / kg dose range. At doses of 10 mg / kg and 30 mg / kg, the Example 2 group exhibited superior paw swelling inhibition compared to the GIBH-1014, SC-75416, and indomethacin groups, demonstrating that at the same dose, the compound in Example 2 of the present invention exhibited superior paw swelling inhibition effects compared to GIBH-1014, SC-75416, and indomethacin.

[0702] In summary, the compounds represented by formula (I) of the present invention have good COX-2 inhibitory activity, and the preferred compounds have an IC 50As low as 28nmol / L, it has a high COX-2 selective inhibitory effect, which can reduce gastrointestinal side effects and nephrotoxicity; it has excellent inhibitory effect on PGE2 (whole blood experiment); it has almost no inhibitory effect on hERG channel current and low cardiac toxicity; at the same time, it has high stability in both human and rat liver microsomes, and when administered orally or by injection, it has a long half-life, a faster time to peak blood concentration, and a larger area under the blood concentration-time curve. It can be absorbed and administered by injection and oral administration for the treatment of anti-inflammatory and analgesic diseases and tumor-related diseases.

[0703] While the embodiments of the present invention have been described in detail above, the present invention is not limited to the embodiments described above. Various modifications may be made within the scope of knowledge possessed by a person skilled in the art without departing from the spirit of the present invention. Furthermore, the embodiments of the present invention and the features thereof may be combined with one another unless there is a conflict.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, R1 is selected from H; R2 is selected from -CHF2, -CF2D, -CFD2, -CD=CD2, -C(CH3)=CH2, vinyl, propenyl; R3 is selected from H; X is selected from bromine and sulfur pentafluoride.

2. The compound according to claim 1, characterized in that: The compound is selected from 3. The compound according to claim 1, characterized in that: The pharmaceutically acceptable salts include alkali metal salts, alkaline earth metal salts or ammonium cation salts.

4. The compound according to claim 1, characterized in that: The pharmaceutically acceptable salts include aluminum salts, ammonium salts, calcium salts, ferric salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts or zinc salts.

5. A pharmaceutical composition, characterized in that: The invention comprises the compound according to any one of claims 1 to 4, and pharmaceutically acceptable excipients.

6. The pharmaceutical composition according to claim 5, characterized in that: The dosage form of the pharmaceutical composition is selected from tablets, lozenges, aqueous suspensions, oil suspensions, aqueous-oil suspensions, powders, granules, emulsions, hard capsules, soft capsules, syrups or elixirs.

7. Use of the compound according to any one of claims 1 to 4 in the preparation of anti-inflammatory and analgesic drugs or drugs for preventing or treating tumors.

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