Ligustrazine derivatives, preparation methods and uses thereof

Abstract

The present invention provides a novel ligustrazine derivative and its composition, which has an obvious protective effect on neuronal cell damage in vitro and an obvious inhibitory effect on in vivo oxidative stress. At the same time, the compound provided by the present invention can significantly reduce the brain damage caused by persistent focal cerebral ischemia, significantly reduce the area of cerebral infarction, inhibit brain edema, and has no obvious teratogenic toxicity, and is suitable for development into a drug for protecting nerve cells, cardiovascular diseases and other diseases.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technology, and particularly to a ligustrazine derivative and its composition. Such compounds and their compositions can be developed for the use in treating diseases caused by oxidative stress and / or thrombosis induced by free radicals. Background Art

[0002] The mass of the human brain accounts for only about 2.0% of the body weight, but its oxygen consumption accounts for about one-fourth of the total body oxygen consumption, making it the organ with the largest oxygen consumption per unit mass of human tissue in the resting state. Therefore, the brain tissue generates more free radicals and peroxides and is more vulnerable to oxidative stress compared to other organs. Free radicals are the products of aerobic metabolism in cells, mainly including superoxide anion radicals, lipid oxygen radicals, nitric oxide radicals, hydroxyl radicals, etc. Free radicals have high reactivity and can affect the functions of biomolecules. When nerve cells are affected by free radicals, the functions of nerve cells can be affected, and in severe cases, it can lead to neurodegenerative diseases. Common neurodegenerative diseases such as Alzheimer's Disease (AD) and Parkinson's disease (PD) are all diseases caused by oxidative stress reactions. Oxidative stress also plays an important role in cerebrovascular diseases. When cerebrovascular endothelial cells are damaged, it can induce the formation of atherosclerotic plaques, which can further lead to the formation of acute cerebrovascular thrombosis, resulting in local cerebral blood supply insufficiency or blood supply interruption, causing irreversible damage to the brain. Oxidative stress is also closely related to cardiovascular diseases. For example, common atherosclerosis is the main cause of cardiovascular diseases. Oxidative stress plays an important role in the pathological processes of cardiovascular diseases such as myocardial ischemia, cardiac systolic dysfunction, and myocardial infarction.

[0003] Antioxidant drugs can effectively scavenge free radicals, protect nerve cells, prevent the occurrence of neurodegenerative diseases, and thus play a therapeutic role. Ligustrazine (TMP) is a natural product extracted from the traditional Chinese medicine Ligusticum wallichii, which has the effects of inhibiting platelet aggregation and anti-thrombosis. However, ligustrazine has poor lipid solubility and a short half-life, and it must be administered frequently clinically, which is likely to cause adverse events such as cumulative poisoning. Therefore, its clinical application is greatly limited. Edaravone is the first approved drug that can scavenge free radicals and can inhibit the damage of free radicals to brain cells, vascular endothelial cells, and nerve cells.

[0004] In view of the limitations of ligustrazine when used as a drug clinically, it is necessary to modify the structure of ligustrazine in order to obtain a more ideal clinical drug. Summary of the Invention

[0005] The present invention provides a ligustrazine derivative with a novel structure and its composition, which has an obvious protective effect on neuron cell damage in vitro and an obvious inhibitory effect on in vivo oxidative stress.

[0006] Another aspect of the present invention is that the compound provided by the present invention can significantly reduce the brain damage caused by persistent local cerebral ischemia, while significantly reducing the area of cerebral infarction and inhibiting brain edema, achieving unexpected technical effects.

[0007] Another aspect of the present invention is that the compound provided by the present invention has no obvious teratogenic toxicity and is suitable for developing drugs for protecting nerve cells, cardiovascular diseases and other diseases.

[0008] The present invention relates to compounds of formula I-1 and I-2:

[0009]

[0010] including their isomers, solvates, isotope derivatives, oxides, and their salts;

[0011] wherein:

[0012] Y1 and Y2 are each independently CH or N;

[0013] R0 is

[0014] n1 is 0 or 1;

[0015] R1, R2, and R3 are each independently hydrogen, deuterium, or C 1-6 alkyl;

[0016] R4 is hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy;

[0017] R5 is

[0018] R6 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, or

[0019] R6 is when, R5 is not

[0020] n2 is 1 or 2;

[0021] R7, R8, R9, R 10 、R 11 、R 12 are each independently hydrogen, deuterium, C 1-6 alkyl, or C in which one or more hydrogens are deuterated1-6 Alkyl;

[0022] L1 is hydrogen,

[0023] L2s are each independently hydrogen, and when L2 is hydrogen, R6 is only

[0024] R 13 is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 alkenyl, C 3-6 alkynyl, C 3-12 carbocyclic group, C 2-12 heterocyclic group; the above alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic group, heterocyclic group may be optionally substituted by one or more of hydrogen, deuterium, halogen, hydroxy, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto, mercaptomethyl, mercaptoethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl;

[0025] R 14 , R 15 s are each independently hydrogen, C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-12 carbocyclic group, C 2-12 heterocyclic group, C 6-12 aryl, C 3-10 heteroaryl, or R 14 , R 15 are linked to form a ring; the above alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group, aryl, heteroaryl may be optionally substituted by one or more of hydrogen, deuterium, halogen, hydroxy, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto, mercaptomethyl, mercaptomethyl, mercaptoethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl, -O(C=O)0R 16 substituted;

[0026] R 16 is C 1-6 alkyl, C 3-12 carbocyclic group, C 2-12 heterocyclic group, C 6-12 aryl, C 3-10Heteroaryl; the above-mentioned alkyl, carbocyclic group, heterocyclic group, aryl, heteroaryl may optionally be substituted by one or more of hydrogen, deuterium, halogen, hydroxyl, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto, mercaptomethyl, mercaptoethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl.

[0027] The compound has the structures of Formula II-1 and Formula II-2 as follows:

[0028]

[0029] The definitions of the substituents in Formula II-1 and Formula II-2 are as defined in Formula I-1 or Formula I-2.

[0030] The compound has the structures of Formula III-1 and Formula III-2 as follows:

[0031]

[0032] The definitions of the substituents in Formula III-1 and Formula III-2 are as defined in Formula I-1 or Formula I-2.

[0033] The compound has the structures of Formula IV-1 and Formula IV-2 as follows:

[0034]

[0035] The definitions of the substituents in Formula IV-1 and Formula IV-2 are as defined in Formula I-1 or Formula I-2.

[0036] The compound has the structures of Formula V-1 and V-2 as follows:

[0037]

[0038] The definitions of the substituents in Formula V-1 and Formula V-2 are as defined in Formula I-1 and Formula I-2.

[0039] The compound has the structures of Formula VI-1 and Formula VI-2 as follows:

[0040]

[0041] The definitions of the substituents in Formula VI-1 and Formula VI-2 are as defined in Formula I-1 and Formula I-2.

[0042] The compound has the structures of Formula VII-1 and Formula VII-2 as follows:

[0043]

[0044] The definitions of the substituents in Formula VII-1 and Formula VII-2 are as defined in Formula I-1 or Formula I-2.

[0045] The described compound has the structures of Formula VIII-1 and Formula VIII-2 as follows:

[0046]

[0047] The definitions of the substituents in Formula VIII-1 and Formula VIII-2 are as defined in Formula I-1 or Formula I-2.

[0048] The described compound has the following structure:

[0049]

[0050]

[0051]

[0052] The pharmaceutical composition is characterized in that it comprises a therapeutically effective amount of the described compound and its salts, together with a pharmaceutically acceptable carrier, adjuvant, vehicle and their combinations.

[0053] Use of the described compound and its salts, solvates, isomers, polymorphs in the preparation of a medicament for treating diseases related to free radicals.

[0054] The described use is characterized in that it can be used to treat diseases caused by oxidative stress and / or thrombosis induced by free radicals.

[0055] The described use is characterized in that the diseases caused by oxidative stress and / or thrombosis induced by free radicals include arteriosclerosis, Alzheimer's disease, Parkinson's disease, multiple sclerosis, or amyotrophic lateral sclerosis, heart failure, heart disease, stroke, myocardial ischemia and ischemia-reperfusion injury, myocardial infarction, coronary heart disease, or cardiac failure.

[0056] A method for treating a subject suffering from the described disease, characterized in that it comprises administering the described compound or the described pharmaceutical composition to the subject.

[0057] In the present invention, for a more detailed understanding of the present invention, the following definitions are given for each term.

[0058] The term "a", "an" or similar terms herein means including one and multiple numbers of objects, or a mixture thereof, not limited to one or a single one.

[0059] The term "independently" in this text means that if there are more than one variable, each instance of the substituent is selected from the available variable definitions independently of the other selections. Thus, each substituent can be the same as or different from the other substituents.

[0060] The term "or" or similar terms in this text means any one member or object within a specific range, as well as a combination of multiple members or objects.

[0061] The term "comprising" in this text means including but not limited to, and does not exclude other categories of species or compositions.

[0062] The term "heteroatom" in this text means an oxygen atom, a nitrogen atom, a sulfur atom, a phosphorus atom, a boron atom, a selenium atom, etc.

[0063] The term "amino" in this text means a functional group having one nitrogen atom and zero to two hydrogen atoms.

[0064] The term "halogen" in this text means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0065] The term "C 1-6 alkyl" in this text means a straight-chain, branched-chain, or unbranched saturated or unsaturated aliphatic hydrocarbon group containing at most 6 carbon atoms. Specific examples of alkyl groups are methyl, ethyl, isopropyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 2,2-dimethylpropyl, etc.

[0066] The term "C 1-6 alkoxy" in this text means a group in which an alkyl group containing at most 6 carbon atoms has an -O- or -OH group inserted at any reasonable position. This group can be straight-chain, branched-chain, or unbranched. Specific examples are methoxy, ethoxy, isopropoxy, tert-butoxy, isopentoxy, cyclopentoxy, 2-methoxybutyl, 2-ethoxypropyl, 2-hydroxybutyl, etc.

[0067] The term "C 1-6 alkylamino" in this text means a group in which an alkyl group containing at most 6 carbon atoms has an -N-, -NH-, or -NH2 group inserted at any reasonable position. This group can be straight-chain, branched-chain, or unbranched. Specific examples are methylamino, ethylamino, isopropylamino, tert-butylamino, cyclopentylamino, 2-methylaminobutyl, 2-ethylaminopropyl, 2-aminobutyl, etc.

[0068] The term "C 3-6 alkenyl" in this text means a straight-chain, branched-chain, or cyclic hydrocarbon group containing at least one carbon-carbon double bond in a molecule with 3 to 6 carbon atoms. For example, butenyl, cis-2-pentenyl, trans-2-hexenyl, 3,3-dimethyl-1-butenyl, etc.

[0069] The term "C3-6 "Alkynyl" refers to a straight-chain, branched-chain or cyclic hydrocarbon group containing at least one carbon-carbon triple bond in a molecule with 3 to 6 carbon atoms. For example, 2-propynyl, 3,3-dimethyl-1-butynyl, cyclopropylethynyl, 2-pentynyl, etc.

[0070] The term "C 3-12 "Carbocyclic group" means a saturated or unsaturated aliphatic cyclic hydrocarbon group containing 3 to 12 carbon atoms in a molecule. Specific examples are cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, cyclohexenyl, cyclopentenyl, 1,3-cyclohexadienyl, etc.

[0071] The term "C 2-12 "Heterocyclic group" means a saturated or unsaturated aliphatic ring group containing 2 to 12 carbon atoms and 1 to 6 heteroatoms in a molecule, which may contain one ring or multiple rings. Each ring of such polycyclic heterocyclic alkyl groups may have different connection modes, such as fused, bridged, spiro, etc. Specific examples are oxiranyl, pyrrolidinyl, furyl, piperidinyl, piperazinyl, pyrazinyl, pyranyl, tetrahydro-3-thienyl, thiacyclopentyl, etc.

[0072] The term "C 6-12 "Aryl" means a group containing 6 to 12 carbon atoms in a molecule and having at least one aromatic ring. Except for covalent groups, each ring of polycyclic aryl groups may have different connection modes, such as fused, bridged, etc., and the fused rings can be saturated or unsaturated. Specific examples are phenyl, naphthyl, diphenyl, α-tetrahydronaphthyl, indenyl, indanyl, benzodiazinyl, 3,4-dihydro-1H-benzopyranyl, etc.

[0073] The term "C 3-10 "Heteroaryl" means an aromatic heterocyclic group containing 3 to 10 carbon atoms and 1 to 6 heteroatoms in a molecule. Except for covalent groups, each ring of polycyclic aryl groups may have different connection modes, such as fused, bridged, etc., and the fused rings can be saturated or unsaturated. Specific examples are thienyl, imidazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, quinolinyl, isoquinolinyl, quinoxalinyl, thiazolyl, purinyl, 5,6,7,8-tetrahydroquinolinyl, etc.

[0074] When the compound of the present invention has one or more chiral centers, it includes the uses of all enantiomers and diastereoisomers, or mixtures thereof, and the use as an active ingredient in a pharmaceutical composition. When having a double bond, it includes the uses of all configurational isomers (such as cis and trans isomers), or mixtures thereof, and the use as an active ingredient in a pharmaceutical composition.

[0075] The compounds of the present invention include their tautomers, such as cationic tautomerism, anionic tautomerism, bimolecular proton transfer isomerism, ring internal tautomerism, ring-chain tautomerism, keto-enol tautomerism, amide-imino acid isomerism, lactam-lactim isomerism, etc.

[0076] The term "solvate" herein refers to a compound obtained by the penetration or incorporation of suitable solvent molecules into the crystal lattice of the compounds and salts of the present invention, and combined by coordination bonds (such as solvated metal ions) or covalent bonds. Suitable solvents include acetic acid, ethanol, water, acetone, etc. When the suitable solvent molecule is water, it can be simply referred to as "hydrate".

[0077] The term "isotope derivative" herein refers to a product obtained by replacing one or more atoms in a molecule with isotope atoms. The "isotope" herein refers to atoms with the same atomic number but different numbers of protons, such as 2 H, 3 H, 17 O, 18 O, 18 F, 13 C, 15 N, 36 Cl, 32 P, 11 B, etc. Isotope-substituted compounds can be used for drug metabolism and chemical reaction kinetics studies.

[0078] The compounds of the present invention contain basic nitrogen atoms (heterocyclic or aliphatic amino groups, etc.), and are easily oxidized by oxidants such as oxygen in the air and hydrogen peroxide to form N-oxides to generate other compounds of the present invention. Therefore, the converted N-oxide derivatives are part of the compounds of the present invention.

[0079] The term "salt" herein refers to a complex formed by a compound and a corresponding acid, and this property depends on the characteristics of the compound. The addition salts of the compound and an acid, such as inorganic acid salts such as hydrochloride, sulfate, hydrobromide, etc. Organic acid salts such as maleate, fumarate, acetate, propionate, malate, tartrate, malonate, succinate, citrate, cinnamate, mandelate, mesylate, p-toluenesulfonate, salicylate, etc.

[0080] The term "salt" herein also refers to the addition salts of the compound and a base, such as salts of inorganic bases such as sodium salt, potassium salt, ammonium salt, calcium salt, magnesium salt, etc. Salts of organic amines such as diethylamine salt, ethylenediamine salt, meglumine salt, tromethamine salt, arginine salt, lysine salt, histidine salt, piperidine salt, etc.

[0081] As used herein, the term "treatment" refers to the act of inhibiting the progression of, or reversing the symptoms of, an applicable disorder or one or more diseases, and also includes adjuvant treatment of diseases.

[0082] As used herein, the term "pharmaceutically acceptable carriers, adjuvants, vehicles and their compositions" refers to diluents, starches, dextrins, sugars, mannitol, microcrystalline cellulose, oils, binders, wetting agents, distilled water, ethanol, binders, starch paste, disintegrants, lubricants, glidants, etc.

[0083] As used herein, the term "therapeutically effective amount" means that the active ingredient is administered in the range of 0.01% - 75% (W / W%), at appropriate time intervals per day, and one or more dosage forms are administered to the individual in need, which can produce significant therapeutic results in the body. And the dosage can be adjusted according to factors such as the severity of the disease, the age and weight of the administered subject to achieve the desired therapeutic effect.

[0084] As used herein, the term "subject to be treated" refers to warm-blooded animals, such as humans, rats, guinea pigs, mice, gerbils, rabbits, dogs, pigs, sheep, monkeys, chickens, ducks, geese, cats, cows, horses, chimpanzees, etc.

[0085] The compounds and their compositions provided by the present invention can be prepared into pharmaceutical preparations and administered to individuals in need of treatment by various administration routes such as oral, intranasal, intraoral, skin surface, intravenous injection, etc. for prevention or treatment. Detailed implementation mode

[0086] The present invention will be further described below in conjunction with examples, but these examples do not limit the scope of the present invention. The experimental solvents or reagents used in the following examples are all purchased from the market without special instructions, and are used directly without further purification.

[0087] Example 1: Preparation and characteristics of compound CQ-01

[0088]

[0089] Compound S-2: Dissolve S-1 (5.3 g, 0.034 mol) in DCM, cool to 0 °C, and add m-CPBA (6.25 g, 0.041 mol) in batches. After adding, stir at room temperature for 16 hours. Detect the completion of the reaction by TLC, filter, pour the filtrate into saturated sodium carbonate aqueous solution, adjust the pH value to about 8.0, extract with DCM, and combine the organic phases until the aqueous phase has basically no fluorescence, then dry and concentrate to obtain 3.0 g of an oily substance, which is directly used for the next step.

[0090] Compound S-3: The concentrate S-2 (3.0 g) from the previous step was added to toluene. Hydrazine hydrate was added at room temperature, and then the temperature was raised to 110 °C and reacted for 6 hours. The reaction was completed as detected by TLC. The system was cooled, filtered, washed with water, concentrated and dried to obtain 2.8 g of a gray solid. MS: m / z = 169.1 (M+1). The overall yield of the two steps was 49.0%.

[0091] Compound S-4: Compound S-3 (2.8 g, 0.017 mol) was dissolved in toluene, and ethyl acetoacetate (5.42 g, 0.042 mol) was added. After addition, the temperature was raised to reflux for 6 hours. The reaction was completed as detected by TLC. After cooling, it was washed with water. After concentrating to remove the solvent, methyl tert-butyl ether was added for slurrying, and filtration gave an off-white solid: 1.0 g. MS: m / z = 235.2 (M+1). Yield: 25.0%.

[0092] Compound S-5: Compound S-4 (1.0 g, 4.27 mmol) was dissolved in DCM and cooled to 0 - 5 °C. Acetic anhydride (0.65 g, 6.41 mmol) was added dropwise. After addition, it was allowed to warm to room temperature naturally and stirred for 16 hours. The reaction was completed as detected by TLC. The system was poured into saturated sodium hydroxide aqueous solution, and the pH value was adjusted to about 8.0. Liquid separation was carried out. The aqueous phase was extracted with DCM until there was no fluorescence. The organic phases were combined, dried and concentrated. Column chromatography separation (DCM:MeOH = 10:1) gave 0.3 g of a white solid. MS: m / z = 235.1 (M+1). Yield: 30.27%.

[0093] Compound S-6: Compound S-5 (0.3 g, 1.29 mmol) was dissolved in DCM and cooled to 5 °C. Dess-Martin oxidant (0.66 g, 1.55 mmol) was slowly added. After addition, it was allowed to warm to room temperature naturally and reacted for 6 hours. The reaction was completed as detected by TLC. The system was added to an aqueous solution of sodium thiosulfate. Liquid separation was carried out. The aqueous phase was extracted with DCM and the organic phases were combined. After washing with saturated brine, it was dried and concentrated. Column chromatography gave 0.25 g of a white solid. MS: m / z = 233.1 (M+1). Yield: 83.5%. MS: m / z = 233 (M+1).

[0094] Compound S-7: Compound S-6 (0.25 g, 1.08 mmol) was dissolved in ethyl acetate. tert-Butylamine (0.24 g, 3.23 mmol) was added, 0.1 mL of acetic acid was added, and then it was heated to reflux and reacted for 8 hours. The reaction was completed as detected by TLC. After cooling, the solvent was removed by concentration. Column chromatography (DCM:MeOH = 10:1) gave 0.2 g of a white solid. MS: m / z = 288.0 (M+1). Yield: 64.5%.

[0095] Synthesis of Compound CQ-01: Dissolve compound S-7 (0.18 g, 0.63 mmol) in DCM, cool to 0 °C, slowly add m-CPBA (0.12 g, 0.69 mmol). After addition, let it warm to room temperature naturally and stir for 12 hours. TLC indicates that the reaction is complete. Pour the reaction system into an aqueous solution of sodium thiosulfate to remove the excess m-CPBA. Separate the layers, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 0.10 g of a white solid. MS: m / z = 304.3, yield: 52.4%. 1 1H NMR (CDCl3) δ 7.77 (s, 1H), 6.38 (d, J = 6.0 Hz, 1H), 2.67 (s, 3H), 2.55 (s, 3H), 2.42 (s, 3H), 0.99 (s, 9H).

[0096] Example 2: Preparation and Characterization of Compound CQ-04

[0097]

[0098] Synthesis of Compound CQ-04: Dissolve compound S-5 (0.23 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, and slowly add triphosgene (0.30 g, 1.00 mmol) and triethylamine (0.30 g, 3.00 mmol) under nitrogen protection. After addition, continue the reaction at room temperature for 16 hours. Cool to 0 °C, add dextrorotatory borneol (0.15 g, 1.00 mmol), heat to reflux and continue the reaction for 6 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 0.14 g of a white solid. MS: m / z = 415.1, yield: 33.7%. 1 1H NMR (CDCl3) δ 5.35 (s, 2H), 4.88 - 4.87 (m, 1H), 3.45 (s, 2H), 2.64 (s, 3H), 2.55 (s, 3H), 2.25 (s, 3H), 2.00 - 1.98 (m, 1H), 1.78 - 1.56 (m, 4H), 1.38 - 1.25 (m, 2H), 0.94 - 0.82 (m, 9H).

[0099] Example 3: Preparation and Characterization of Compound CQ-05

[0100]

[0101] Synthesis of Compound CQ-05: Dissolve Compound S-5 (0.23 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, and slowly add triphosgene (0.30 g, 1.00 mmol) and triethylamine (0.30 g, 3.00 mmol) under nitrogen protection. After the addition, continue the reaction at room temperature for 16 hours. Cool to 0 °C, add (+)-neomenthol (0.16 g, 1.00 mmol), heat to reflux and continue the reaction for 16 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 0.10 g of a white solid, MS: m / z = 417.2, yield: 25.0%. 1 H NMR (CDCl3) δ 5.39 (s, 2H), 4.86 - 4.85 (m, 1H), 3.47 (s, 2H), 2.63 (s, 3H), 2.52 (s, 3H), 2.23 (s, 3H), 2.02 - 1.99 (m, 1H), 1.75 - 1.53 (m, 6H), 1.35 - 1.26 (m, 3H), 0.91 - 0.85 (m, 9H).

[0102] Example 4: Preparation and Characterization of Compound CQ-10

[0103]

[0104] Synthesis of Compound CQ-10: Dissolve phosphorus dichloride 4-nitrobenzene (0.26 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, slowly add triethylamine (0.30 g, 3.00 mmol), and slowly add an anhydrous THF solution of Compound S-5 (0.23 g, 1.00 mmol) under nitrogen protection. After the addition, continue the reaction at room temperature for 16 hours. Cool to 0 °C, add dextrorotatory borneol (0.15 g, 1.00 mmol), heat to reflux and continue the reaction for 6 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. Add it to THF again, adjust the pH value to 3.0 - 4.0 with hydrochloric acid, stir at room temperature for 16 hours, cool, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 0.03 g of a white solid, MS: m / z = 451.2, yield: 6.6%. 1 H NMR (CDCl3) δ 5.33 (s, 2H), 4.85 - 4.83 (m, 1H), 3.41 (s, 2H), 2.61 (s, 3H), 2.50 (s, 3H), 2.22 (s, 3H), 1.97 - 1.93 (m, 1H), 1.72 - 1.51 (m, 4H), 1.36 - 1.27 (m, 2H), 0.92 - 0.85 (m, 9H).

[0105] Example 5: Preparation and Characterization of Compound CQ-11

[0106]

[0107] Synthesis of Compound CQ-11: Dissolve phosphorus dichloride 4-nitrobenzene (0.26 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, slowly add triethylamine (0.30 g, 3.00 mmol), and slowly add an anhydrous THF solution of compound S-5 (0.23 g, 1.00 mmol) under nitrogen protection. After addition, continue the reaction at room temperature for 15 hours. Cool to 0 °C, add (+)-neomenthol (0.16 g, 1.00 mmol), heat to reflux and continue the reaction for 8 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. Add it to THF again, adjust the pH value to 3.0 - 4.0 with hydrochloric acid, stir at room temperature for 15 hours, cool, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 0.04 g of white solid, MS: m / z = 453.1, yield: 8.7%. 1 H NMR (CDCl3) δ 5.33 (s, 2H), 4.81 - 4.78 (m, 1H), 3.41 (s, 2H), 2.61 (s, 3H), 2.48 (s, 3H), 2.20 (s, 3H), 2.01 - 1.96 (m, 1H), 1.71 - 1.52 (m, 6H), 1.33 - 1.25 (m, 3H), 0.90 - 0.85 (m, 9H).

[0108] Example 6: Preparation and Characterization of Compound CQ-14

[0109]

[0110] Synthesis of Compound CQ-14: Dissolve ethyl dichlorophosphate (0.16 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, slowly add triethylamine (0.30 g, 3.00 mmol), and slowly add an anhydrous THF solution of compound S-5 (0.23 g, 1.00 mmol) under nitrogen protection. After addition, continue the reaction at room temperature for 15 hours. Cool to 0 °C, add (+)-camphor alcohol (0.15 g, 1.00 mmol), heat to reflux and continue the reaction for 10 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 0.05 g of white solid, MS: m / z = 479.1, yield: 11.1%. 11H NMR (CDCl3) δ 5.35 (s, 2H), 4.89 - 4.87 (m, 1H), 4.11 - 4.09 (m, 2H), 3.44 (s, 2H), 2.65 (s, 3H), 2.53 (s, 3H), 2.24 (s, 3H), 2.01 - 1.96 (m, 1H), 1.75 - 1.58 (m, 4H), 1.37 - 1.26 (m, 5H), 0.96 - 0.89 (m, 9H).

[0111] Example 7: Preparation and Characterization of Compound CQ-15

[0112] Using the same method as for synthesizing compound CQ-14, 0.05 g of CQ-15 was synthesized. MS: m / z = 493.2, 1 1H NMR (CDCl3) δ 5.36 (s, 2H), 4.86 - 4.84 (m, 1H), 4.55 - 4.53 (m, 1H), 3.43 (s, 2H), 2.66 (s, 3H), 2.54 (s, 3H), 2.26 (s, 3H), 2.04 - 1.99 (m, 1H), 1.77 - 1.59 (m, 4H), 1.36 - 1.25 (m, 8H), 0.96 - 0.89 (m, 9H).

[0113] Example 8: Preparation and Characterization of Compound CQ-16

[0114]

[0115] Synthesis of Intermediate S-9: S-8 (14.2 g, 0.1 mol) was added to freshly distilled phosphorus oxychloride (286.6 g, 1.0 mol) under ice bath conditions, placed in a high-pressure reactor lined with a polytetrafluoroethylene sleeve, heated to an external temperature of 180 °C under sealed conditions for 96 hours, cooled to room temperature, and slowly added 1000 mL of ice water under ice bath conditions. The reaction solution was neutralized to a pH value between 7 and 8 with triethylamine, filtered, and the filtrate was extracted with dichloromethane (1000 mL × 3). The obtained organic phase was dried and concentrated, and the residue was separated by column chromatography to obtain 3.72 g of a white solid. MS: m / z = 265.4, yield: 11.0%.

[0116] Synthesis of Intermediate S-10: S-9 (3.6 g, 13.5 mmol) was added to acetic acid (50 mL) under ice bath conditions. Selenium dioxide (7.5 g, 67.5 mmol) was slowly added under ice bath conditions. The mixture was heated to reflux under open conditions and reacted for 24 hours. The temperature was lowered to room temperature, filtered, and the filtrate was concentrated. The obtained residue was added to ice water (100 mL), and neutralized with potassium carbonate to a pH value between 7 and 8. Then it was filtered, and the filtrate was extracted with dichloromethane (100 mL × 3). The obtained organic phase was dried and concentrated. The residue was separated by column chromatography to obtain 2.08 g of a white solid. MS: m / z = 279.3, yield: 55.1%.

[0117] Synthesis of Intermediate S-11: Compound S-10 (2.0 g, 7.1 mmol) was dissolved in DMF, 3-methyl-2-pyrazolin-5-one (0.7 g, 7.1 mmol) was added, and sodium hydride (0.6 g, 14.2 mmol) was added. The reaction was carried out at room temperature for 20 hours under nitrogen protection. Ice water was added, and it was filtered. The filtrate was extracted with dichloromethane. The obtained organic phase was dried and concentrated. The residue was separated by column chromatography to obtain 0.97 g of a white solid. MS: m / z = 297.0, yield: 46.4%.

[0118] Synthesis of Intermediate S-12: Compound S-11 (0.96 g, 3.2 mmol) was dissolved in acetic acid, ethanedithiol (0.30 g, 3.2 mmol) and p-toluenesulfonic acid (0.55 g, 3.2 mmol) were added. The reaction was carried out at room temperature for 15 hours under nitrogen protection. Ice water was added, and it was neutralized with potassium carbonate to a pH value between 7 and 8. Then it was extracted with dichloromethane. The obtained organic phase was dried and concentrated. The residue was separated by column chromatography to obtain 0.53 g of a white solid. MS: m / z = 387.2, yield: 43.3%.

[0119] Synthesis of Intermediate S-13: Compound S-12 (0.50 g, 1.3 mmol) was dissolved in anhydrous THF, and the temperature was lowered to -70 °C. 2.5 M n-butyllithium solution (0.68 mL, 4.2 mmol) was slowly added under nitrogen protection. After the addition, it was stirred for 1 hour, 0.5 mL of DMF was added, and the reaction was continued at -55 °C for 6 hours. It was cooled to room temperature, quenched with ice-cold ammonium chloride solution, and extracted with dichloromethane. The obtained organic phase was dried and concentrated. The residue was separated by column chromatography to obtain 0.26 g of a white solid. MS: m / z = 337.1, yield: 60.1%.

[0120] Synthesis of Intermediate S-14: Dissolve compound S-13 (0.25 g, 0.74 mmol) in methanol, cool the temperature to 0 °C, slowly add sodium borohydride (14.0 mg, 0.37 mmol), continue the reaction for 2 hours, concentrate, add ice water to the residue, extract with dichloromethane, dry and concentrate the obtained organic phase, and separate the residue by column chromatography to obtain 0.16 g of off-white solid, MS: m / z = 339.0, yield: 64.8%.

[0121] Synthesis of Intermediate S-15: Dissolve compound S-14 (0.15 g, 0.44 mmol) in acetone, cool the temperature to 0 °C, slowly add mercury(II) oxide (95.0 mg, 0.44 mmol) and mercury(II) chloride (119.0 mg, 0.44 mmol), react at room temperature for 21 hours, filter, concentrate, and separate the obtained residue by column chromatography to obtain 66.7 mg of off-white solid, MS: m / z = 249.1, yield: 61.2%.

[0122] Synthesis of Compound CQ-16: Dissolve compound S-15 (66.0 mg, 0.26 mmol) in ethyl acetate, add tert-butylamine (19.0 mg, 0.26 mmol), add 0.1 mL of acetic acid, then heat to reflux and react for 10 hours. After completion of TLC detection, cool down, concentrate to remove the solvent, and obtain an off-white solid by column chromatography (DCM:MeOH = 10:1). Dissolve the obtained solid in DCM, cool to 0 °C, slowly add m-CPBA (44.8 mg, 0.26 mmol), and naturally warm to room temperature after addition, then stir for 16 hours. After completion of TLC detection of the reaction, pour the system into an aqueous solution of sodium thiosulfate to remove the excess m-CPBA, separate the layers, extract the aqueous phase with DCM and combine the organic phases, dry and concentrate, and prepare the residue by preparative liquid phase to obtain 11.6 mg of off-white solid, MS: m / z = 320.1, yield: 13.9%. 1 H NMR (CDCl3) δ 7.69 (s, 1H), 4.69 - 4.68 (m, 2H), 3.07 (s, 3H), 2.51 (s, 3H), 2.40 (s, 3H), 1.00 - 0.97 (m, 9H).

[0123] Example 9: Preparation and Characterization of Compound CQ-19

[0124]

[0125] Compound S-16: Dissolve compound S-3 (2.8 g, 0.017 mol) in toluene, add ethyl acetoacetate-d (6.78 g, 0.051 mol). After addition, heat up to reflux for 10 hours. Detect the completion of the reaction by TLC, cool down, wash with water, concentrate to remove the solvent, then add methyl tert-butyl ether for pulping, filter to obtain an off-white solid. Separate by column chromatography to get an off-white solid: 0.79 g, MS: m / z = 222.4 (M+1), yield: 21.1%.

[0126] Compound S-17: Dissolve compound S-16 (0.75 g, 3.39 mmol) in DCM, cool to 0 - 5 °C, dropwise add acetic anhydride (0.65 g, 6.41 mmol). After addition, let it warm up to room temperature naturally and stir for 16 hours. Detect the completion of the reaction by TLC, pour the system into saturated sodium hydroxide aqueous solution, adjust the pH value to about 8.0, separate the layers, extract the aqueous phase with DCM until there is no fluorescence, combine the organic phases, dry and concentrate, separate by column chromatography (DCM:MeOH = 10:1) to obtain 0.26 g of white solid, MS: m / z = 235.1 (M+1), yield: 32.2%.

[0127] Compound S-18: Dissolve compound S-5 (0.25 g, 1.05 mmol) in DCM, cool to 5 °C, slowly add Dess-Martin oxidant (0.53 g, 1.24 mmol). After addition, let it warm up to room temperature naturally and react for 16 hours. Detect the completion of the reaction by TLC, add the system to aqueous sodium thiosulfate solution, separate the layers, extract the aqueous phase with DCM and then combine the organic phases, wash with saturated brine, dry and concentrate, obtain 37.1 mg of off-white solid by column chromatography, MS: m / z = 236.2 (M+1), yield: 15.2%.

[0128] Compound S-19: Dissolve compound S-18 (0.03 g, 0.13 mmol) in ethyl acetate, add tert-butylamine (24.0 mg, 0.32 mmol), add 0.1 mL of acetic acid, then heat to reflux and react for 20 hours. Detect the completion by TLC, cool down, concentrate to remove the solvent, column chromatography (DCM:MeOH = 10:1) to obtain 9.1 mg of off-white solid, MS: m / z = 291.1 (M+1), yield: 24.2%.

[0129] Synthesis of compound CQ-19: Dissolve compound S-19 (29.0 mg, 0.1 mmol) in DCM, cool to 0 °C, slowly add m-CPBA (34.3 mg, 0.2 mmol). After addition, let it warm to room temperature naturally and stir for 10 hours. TLC shows the reaction is complete. Pour the reaction system into an aqueous solution of sodium thiosulfate to remove the excess m-CPBA. Separate the layers, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 6.7 mg of a white solid. MS: m / z = 307.1, yield: 21.9%. 1 H NMR (CDCl3) δ 7.78 (s, 1H), 6.34 (d, J = 6.3 Hz, 1H), 2.66 (s, 3H), 2.46 (s, 3H), 0.97 (s, 9H).

[0130] Example 10: Preparation and characterization of compound CQ-20

[0131]

[0132] Synthesis of compound CQ-20: Dissolve compound S-17 (0.24 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, and slowly add triphosgene (0.30 g, 1.00 mmol) and triethylamine (0.30 g, 3.00 mmol) under nitrogen protection. After addition, continue the reaction at room temperature for 15 hours. Cool to 0 °C, add dextrorotatory borneol (0.15 g, 1.00 mmol), heat to reflux and continue the reaction for 10 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 0.12 g of a white solid. MS: m / z = 418.2, yield: 29.0%. 1 H NMR (CDCl3) δ 5.37 (s, 2H), 4.89 - 4.87 (m, 1H), 3.48 (s, 2H), 2.63 (s, 3H), 2.29 (s, 3H), 2.00 - 1.97 (m, 1H), 1.76 - 1.54 (m, 4H), 1.36 - 1.24 (m, 2H), 0.95 - 0.87 (m, 9H).

[0133] Example 11: Preparation and characterization of compound CQ-22

[0134]

[0135] Synthesis of Compound CQ-22: Dissolve phosphorus dichloride 4-nitrobenzene (0.26 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, slowly add triethylamine (0.30 g, 3.00 mmol), and slowly add a solution of compound S-17 (0.24 g, 1.00 mmol) in anhydrous THF under nitrogen protection. After addition, continue the reaction at room temperature for 10 hours, cool to 0 °C, add (+)-borneol (0.15 g, 1.00 mmol), heat to reflux and continue the reaction for 8 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. Add it to THF again, adjust the pH value to 3.0 - 4.0 with hydrochloric acid, stir at room temperature for 16 hours, cool, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 25.4 mg of a white solid. MS: m / z = 454.1, yield: 5.6%. 1 H NMR (CDCl3) δ 5.35 (s, 2H), 4.81 - 4.78 (m, 1H), 3.43 (s, 2H), 2.64 (s, 3H), 2.25 (s, 3H), 1.99 - 1.95 (m, 1H), 1.71 - 1.52 (m, 4H), 1.35 - 1.28 (m, 2H), 0.93 - 0.85 (m, 9H).

[0136] Example 12: Preparation and Characterization of Compound CQ-23

[0137]

[0138] Synthesis of Compound CQ-23: Dissolve phosphorus dichloride 4-nitrobenzene (0.26 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, slowly add triethylamine (0.30 g, 3.00 mmol), and slowly add a solution of compound S-17 (0.24 g, 1.00 mmol) in anhydrous THF under nitrogen protection. After addition, continue the reaction at room temperature for 15 hours, cool to 0 °C, add (+)-neomenthol (0.16 g, 1.00 mmol), heat to reflux and continue the reaction for 10 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. Add it to THF again, adjust the pH value to 3.0 - 4.0 with hydrochloric acid, stir at room temperature for 15 hours, cool, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 0.04 g of a white solid. MS: m / z = 456.1, yield: 8.8%. 11H NMR (CDCl3) δ 5.38 (s, 2H), 4.83 - 4.80 (m, 1H), 3.46 (s, 2H), 2.62 (s, 3H), 2.22 (s, 3H), 2.03 - 1.98 (m, 1H), 1.73 - 1.56 (m, 6H), 1.32 - 1.24 (m, 3H), 0.91 - 0.85 (m, 9H).

[0139] Example 13: Preparation and Characterization of Compound CQ - 25

[0140]

[0141] Compound S - 21: Dissolve compound S - 20 (1.70 g, 10.0 mmol) in 50 mL of 1,4 - dioxane, add 5 mL of water, add [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (0.20 g, 0.1 eq) and N-[2 - bis(1 - adamantyl)phosphinophenyl]morpholine (0.10 g, 0.1 eq), then add potassium carbonate (2.76 g, 20.0 mmol), add 0.5 mL of hydrazine hydrate, reflux the reaction for 16 hours under nitrogen protection, cool to room temperature, adjust the pH value to 4.0 with 1.0 M hydrochloric acid, then adjust to alkaline with triethylamine, concentrate under reduced pressure, add 50 mL of water to the residue, extract with ethyl acetate, concentrate the organic phase to remove the solvent, and separate by column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow solid: 0.91 g, MS: m / z = 167.2 (M + 1), yield: 55.1%.

[0142] Compound S - 22: Dissolve compound S - 21 (1.66 g, 10.0 mmol) in 20 mL of ethanol, add 5 mL of acetic acid, add ethyl acetoacetate (2.60 g, 20.0 mmol), reflux the reaction for 16 hours under nitrogen protection, cool to room temperature, concentrate under reduced pressure, add 30 mL of water to the obtained residue, extract with ethyl acetate, concentrate the organic phase to remove the solvent, and separate by column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow solid: 1.2 g, MS: m / z = 233.3 (M + 1), yield: 51.8%.

[0143] Compound S - 23: Dissolve compound S - 22 (2.32 g, 10.0 mmol) in DCM, cool to 5 °C, slowly add Dess - Martin oxidant (4.24 g, 10.0 mmol), after adding, let it rise to room temperature naturally and react for 12 hours. Detect the completion of the reaction by TLC, add the system to an aqueous solution of sodium thiosulfate, separate the layers, extract the aqueous phase with DCM and combine the organic phases, wash with saturated brine and then dry and concentrate, and obtain 0.97 g of white solid by column chromatography, MS: m / z = 231.3 (M + 1), yield: 42.2%.

[0144] Compound S-24: Compound S-23 (0.23 g, 1.0 mmol) was dissolved in ethyl acetate, tert-butylamine (0.24 g, 3.23 mmol) was added, 0.1 mL of acetic acid was added, and then the mixture was heated to reflux for 8 hours. After completion of the reaction detected by TLC, the temperature was lowered, the solvent was removed by concentration, and column chromatography (DCM:MeOH = 10:1) was used to obtain a white solid: 0.09 g, MS: m / z = 286.4 (M+1), yield: 32.0%.

[0145] Synthesis of compound CQ-25: Compound S-24 (0.28 g, 1.0 mmol) was dissolved in DCM, cooled to 0 °C, m-CPBA (0.24 g, 1.4 mmol) was slowly added, and after addition, the mixture was allowed to warm to room temperature naturally and stirred for 12 hours. After the reaction was detected to be complete by TLC, the system was poured into an aqueous solution of sodium thiosulfate to remove the excess m-CPBA. After liquid separation, the aqueous phase was extracted with DCM and the organic phases were combined, dried and concentrated. The residue was prepared by preparative liquid chromatography to obtain 0.06 g of a white solid, MS: m / z = 302.2, yield: 20.1%. 1 H NMR (CDCl3) δ 8.11 (s, 1H), 7.88 (s, 1H), 7.34 (s, 1H), 3.53 (s, 2H), 2.61 (s, 3H), 2.47 (s, 3H), 2.03 (s, 3H), 1.14 - 1.12 (m, 9H).

[0146] Example 14: Preparation and Characterization of Compound CQ-26

[0147]

[0148] Compound S-25: Compound S-21 (1.66 g, 10.0 mmol) was dissolved in 20 mL of ethanol, 5 mL of acetic acid was added, ethyl acetoacetate-d (2.70 g, 20.0 mmol) was added, and the mixture was refluxed for 20 hours under nitrogen protection. After cooling to room temperature, the mixture was concentrated under reduced pressure. The resulting residue was added to 30 mL of water, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, and column chromatography (DCM:MeOH = 10:1) was used for separation to obtain 1.22 g of a pale yellow solid, MS: m / z = 236.2 (M+1), yield: 52.0%.

[0149] Compound S-26: Dissolve compound S-25 (2.35 g, 10.0 mmol) in DCM, cool to 5 °C, slowly add Dess-Martin oxidant (4.24 g, 10.0 mmol). After addition, let it warm to room temperature naturally and react for 12 hours. Detect the completion of the reaction by TLC. Add the reaction system to an aqueous solution of sodium thiosulfate, separate the layers. The aqueous phase is extracted with DCM and the organic phases are combined. After washing with saturated brine, it is dried and concentrated. Column chromatography gives 0.86 g of an off-white solid, MS: m / z = 234.1 (M+1), yield: 36.8%.

[0150] Compound S-27: Dissolve compound S-26 (0.23 g, 1.0 mmol) in ethyl acetate, add tert-butylamine (0.24 g, 3.23 mmol), add 0.1 mL of acetic acid, then heat to reflux and react for 8 hours. Detect the completion of the reaction by TLC. Cool down, concentrate to remove the solvent, and column chromatography (DCM:MeOH = 10:1) gives 0.08 g of a white solid, MS: m / z = 291.3 (M+1), yield: 28.8%.

[0151] Synthesis of compound CQ-26: Dissolve compound S-27 (0.29 g, 1.0 mmol) in DCM, cool to 0 °C, slowly add m-CPBA (0.24 g, 1.4 mmol). After addition, let it warm to room temperature naturally and stir for 20 hours. Detect the completion of the reaction by TLC. Pour the reaction system into an aqueous solution of sodium thiosulfate to remove the excess m-CPBA, separate the layers. The aqueous phase is extracted with DCM and the organic phases are combined. After drying and concentrating, the residue is prepared by preparative liquid chromatography to obtain 47.1 mg of an off-white solid, MS: m / z = 305.4, yield: 15.5%. 1 H NMR (CDCl3) δ 8.14 (s, 1H), 7.90 (s, 1H), 7.37 (s, 1H), 3.54 (s, 2H), 2.63 (s, 3H), 2.06 (s, 3H), 1.13 - 1.11 (m, 9H).

[0152] Example 15: Preparation and Characterization of Compound CQ-28

[0153]

[0154] Synthesis of compound CQ-28: Dissolve compound S-22 (0.23 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, and slowly add triphosgene (0.30 g, 1.00 mmol) and triethylamine (0.30 g, 3.00 mmol) under nitrogen protection. After the addition, continue the reaction at room temperature for 12 hours. Cool to 0 °C, add dextrorotatory borneol (0.15 g, 1.00 mmol), heat to reflux and continue the reaction for 10 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 0.06 g of a pale white solid, MS: m / z = 413.3, yield: 14.5%. 1 H NMR (CDCl3) δ 7.47 (s, 1H), 7.41 (s, 1H), 5.10 (s, 2H), 4.33 - 4.31 (m, 1H), 3.37 (s, 2H), 2.62 (s, 3H), 2.54 (s, 3H), 2.21 (s, 3H), 1.99 - 1.95 (m, 1H), 1.74 - 1.53 (m, 4H), 1.34 - 1.26 (m, 2H), 0.96 - 0.85 (m, 9H).

[0155] Example 16: Preparation and characterization of compound CQ-29

[0156]

[0157] Synthesis of compound CQ-29: Dissolve compound S-25 (0.24 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, and slowly add triphosgene (0.30 g, 1.00 mmol) and triethylamine (0.30 g, 3.00 mmol) under nitrogen protection. After the addition, continue the reaction at room temperature for 15 hours. Cool to 0 °C, add dextrorotatory borneol (0.15 g, 1.00 mmol), heat to reflux and continue the reaction for 20 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 0.07 g of a pale white solid, MS: m / z = 416.2, yield: 16.8%. 1 H NMR (CDCl3) δ 7.44 (s, 1H), 7.39 (s, 1H), 5.06 (s, 2H), 4.31 - 4.29 (m, 1H), 3.33 (s, 2H), 2.60 (s, 3H), 2.20 (s, 3H), 1.96 - 1.92 (m, 1H), 1.73 - 1.53 (m, 4H), 1.32 - 1.25 (m, 2H), 0.97 - 0.89 (m, 9H).

[0158] Example 17: Preparation and characterization of compound CQ-30

[0159]

[0160] Synthesis of Compound CQ-30: Dissolve phosphorus dichloride 4-nitrobenzene (0.26 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, slowly add triethylamine (0.30 g, 3.00 mmol), and slowly add an anhydrous THF solution of compound S-22 (0.23 g, 1.00 mmol) under nitrogen protection. After the addition, continue the reaction at room temperature for 15 hours. Cool to 0 °C, add (+)-camphor alcohol (0.15 g, 1.00 mmol), heat to reflux and continue the reaction for 10 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. Add it to THF again, adjust the pH value to 3.0 - 4.0 with hydrochloric acid, stir at room temperature for 15 hours, cool, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 43.0 mg of a white solid. MS: m / z = 449.1, yield: 9.6%. 1 H NMR (CDCl3) δ 7.44 (s, 1H), 7.38 (s, 1H), 5.05 (s, 2H), 4.30 - 4.28 (m, 1H), 3.33 (s, 2H), 2.61 (s, 3H), 2.50 (s, 3H), 2.19 (s, 3H), 1.97 - 1.92 (m, 1H), 1.73 - 1.55 (m, 4H), 1.33 - 1.25 (m, 2H), 0.97 - 0.86 (m, 9H).

[0161] Example 18: Preparation and Characterization of Compound CQ-31

[0162]

[0163] Compound S-28: Dissolve compound S-23 (0.23 g, 1.0 mmol) in ethyl acetate, add tert-butylamine-d (0.08 g, 1.0 mmol), add 0.1 mL of acetic acid, and then heat to reflux for 10 hours. After completion of TLC detection, cool down, concentrate to remove the solvent, and perform column chromatography (DCM:MeOH = 10:1) to obtain 0.07 g of a white solid. MS: m / z = 297.3 (M+1), yield: 24.9%.

[0164] Synthesis of compound CQ-31: Dissolve compound S-28 (0.07 g, 0.24 mmol) in DCM, cool to 0 °C, slowly add m-CPBA (0.08 g, 0.5 mmol). After addition, let it warm to room temperature naturally and stir for 24 hours. TLC indicates that the reaction is complete. Pour the reaction system into an aqueous solution of sodium thiosulfate to remove the excess m-CPBA. Separate the layers, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is purified by preparative liquid chromatography to obtain 11.6 mg of a white solid. MS: m / z = 311.2, yield: 15.5%. 1 H NMR (CDCl3) δ 8.13 (s, 1H), 7.83 (s, 1H), 7.31 (s, 1H), 3.51 (s, 2H), 2.64 (s, 3H), 2.46 (s, 3H), 2.01 (s, 3H).

[0165] Example 19: Preparation and characterization of compound CQ-32

[0166]

[0167] Synthesis of compound M-2: Dissolve compound M-1 (70.31 g, 0.38 mol) in toluene (500 ml), add p-toluenesulfonic acid (3.27 g, 0.02 mol), ethylene glycol (70.75 g, 1.14 eq), heat to 130 °C and react for 10 hours. Add 500 ml of water to the system, extract with ethyl acetate (200 ml × 3). Wash the organic phase with saturated brine (200 ml), dry over anhydrous sodium sulfate, concentrate and purify by column chromatography to obtain 58.18 g of a white oily substance of M-2, with a yield of 66.84%.

[0168] Synthesis of compound M-3: Dissolve compound M-2 (10.18 g, 0.03 mol) in 50 ml of DMSO, add compound SM01 (3.33 g, 0.03 mol), potassium tert-butoxide (8.31 g, 0.07 mol), copper(I) iodide (0.77 g, 4 mmol), N,N-bis(furan-2-ylmethyl)oxalamide (1.01 g, 4 mmol), then displace with nitrogen three times, heat to 110 °C and react for 18 hours. After the reaction is complete, add 100 ml of water to the system, adjust the pH to 3 - 4 with 1N hydrochloric acid, then extract with ethyl acetate (50 ml × 3). Combine the organic phases, wash with water (50 ml) and saturated brine (50 ml), dry over anhydrous sodium sulfate, concentrate and purify by column chromatography to obtain 8.64 g of a solid. Then slurry with PE:EA = 10:1 (50 ml) and filter to obtain 5.72 g of a yellow solid M-3, MS: m / z = 247.1 (M + 1).

[0169] Synthesis of compound M-4:

[0170] Compound M-3 (1 g, 4.06 mmol) was added to a reaction flask. The system was dissolved in 15 ml of dichloromethane (DCM), and 5 ml of trifluoroacetic acid was added. The reaction was carried out at room temperature for 12 hours. The organic phase was concentrated to dryness, and 0.63 g of compound M-4 was obtained by column chromatography with a yield of 82%. MS: m / z = 203.1 (M+1).

[0171] Synthesis of compound M-5: Compound M-4 (0.6 g, 2.97 mmol) was dissolved in ethyl acetate, deuterated tert-butylamine (0.8 g, 9.79 mmol) was added, 0.1 mL of acetic acid was added, and then the mixture was heated to reflux for 8 hours. After completion of the reaction detected by TLC, the temperature was lowered, the solvent was removed by concentration, and column chromatography (DCM:MeOH = 10:1) gave 0.33 g of a white solid with a yield of 42.0%. MS: m / z = 267.2 (M+1).

[0172] Synthesis of compound CQ-32: Compound M-5 (0.26 g, 1.0 mmol) was dissolved in DCM, cooled to 0 °C, and m-CPBA (0.16 g, 1.0 mmol) was slowly added. After addition, the mixture was allowed to warm to room temperature naturally and stirred for 21 hours. After completion of the reaction detected by TLC, the system was poured into an aqueous solution of sodium thiosulfate to remove the excess m-CPBA. The layers were separated, the aqueous phase was extracted with DCM, and the organic phases were combined, dried, and concentrated. The residue was prepared by preparative liquid chromatography to obtain 60.0 mg of a white solid with MS: m / z = 283.2 and a yield of 21.2%. 1 H NMR (CDCl3) δ 8.14 (s, 1H), 7.88 - 7.86 (m, 2H), 7.51 - 7.49 (m, 2H), 3.11 (s, 2H), 2.03 (s, 3H).

[0173] Example 20: Preparation and characterization of compound CQ-33

[0174]

[0175] Synthesis of compound M-6: Compound M-4 (0.6 g, 2.97 mmol) was dissolved in ethyl acetate, tert-butylamine (0.7 g, 9.79 mmol) was added, 0.1 mL of acetic acid was added, and then the mixture was heated to reflux for 12 hours. After completion of the reaction detected by TLC, the temperature was lowered, the solvent was removed by concentration, and column chromatography separation gave 0.27 g of a white solid with a yield of 35.2%. MS: m / z = 258.0 (M+1).

[0176] Synthesis of Compound CQ-33: Dissolve Compound M-6 (0.26 g, 1.0 mmol) in DCM, cool to 0 °C, slowly add m-CPBA (0.16 g, 1.0 mmol). After addition, let it warm to room temperature naturally and stir for 25 hours. The reaction is detected to be complete by TLC. Pour the reaction system into an aqueous solution of sodium thiosulfate to remove the excess m-CPBA. Separate the layers, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 75.2 mg of a white solid. MS: m / z = 274.1, yield: 27.5%. 1 H NMR (CDCl3) δ 8.17 (s, 1H), 7.90 - 7.88 (m, 2H), 7.55 - 7.53 (m, 2H), 3.16 (s, 2H), 2.04 (s, 3H), 1.06 - 0.99 (m, 9H).

[0177] Example 21: Preparation and Characterization of Compound CQ-34

[0178]

[0179] Synthesis of Compound CQ-34: Under nitrogen protection, dissolve triphosgene (0.30 g, 1.0 mmol) in 20 ml of dry dichloromethane, add pyridine (0.25 g, 3.2 mmol), and slowly add a dichloromethane solution of Compound M-7 (0.15 g, 1.0 mmol) under an ice bath. After dropping, let it react at room temperature for 5 hours. Cool to 0 °C and slowly add a dichloromethane solution of CQ-33 (0.27 g, 1.0 mmol). After addition, continue to react at room temperature for 30 hours. Wash the reaction solution with water, concentrate the organic phase under reduced pressure. The obtained residue is separated by preparative liquid chromatography to obtain 52.1 mg of an off-white solid. MS: m / z = 454.3, yield: 11.5%. 1 H NMR (CDCl3) δ 8.09 (s, 1H), 7.60 - 7.59 (m, 2H), 7.41 - 7.39 (m, 2H), 6.56 (s, 1H), 4.33 - 4.30 (m, 1H), 2.41 (s, 3H), 1.90 - 1.57 (m, 5H), 1.31 - 1.27 (m, 2H), 0.97 - 0.89 (m, 9H).

[0180] Example 22: Preparation and Characterization of Compound CQ-35

[0181]

[0182] Synthesis of compound CQ-35: Under nitrogen protection, triphosgene (0.30 g, 1.0 mmol) was dissolved in 20 ml of dry dichloromethane, pyridine (0.25 g, 3.2 mmol) was added, and a dichloromethane solution of compound M-7 (0.15 g, 1.0 mmol) was slowly added under an ice bath. After the addition was complete, the reaction mixture was allowed to react at room temperature for 5 hours. The temperature was then lowered to 0 °C, and a dichloromethane solution of CQ-32 (0.28 g, 1.0 mmol) was slowly added. After the addition was complete, the reaction continued at room temperature for 36 hours. The reaction solution was washed with water, and the organic phase was concentrated under reduced pressure. The resulting residue was separated by preparative liquid chromatography to obtain 61.4 mg of a white solid. MS: m / z = 463.3, yield: 13.3%. 1 H NMR(CDCl3)δ8.17(s,1H),7.63-7.62(m,2H),7.42-7.41(m,2H),6.54(s,1H),4.32-4.30(m,1H),2.43(s,3H),1.91-1.59(m,5H),1.33-1.28(m,2H),0.87-0.85(m,9H).

[0183] Example 23: Preparation and characterization of compound CQ-37

[0184]

[0185] Synthesis of compound CQ-37: Under nitrogen protection, triphosgene (0.30 g, 1.0 mmol) was dissolved in 20 ml of dry dichloromethane, pyridine (0.25 g, 3.2 mmol) was added, and a dichloromethane solution of compound M-7 (0.15 g, 1.0 mmol) was slowly added under an ice bath. After the addition was complete, the reaction mixture was allowed to react at room temperature for 5 hours. The temperature was then lowered to 0 °C, and a dichloromethane solution of CQ-31 (0.31 g, 1.0 mmol) was slowly added. After the addition was complete, the reaction continued at room temperature for 30 hours. The reaction solution was washed with water, and the organic phase was concentrated under reduced pressure. The resulting residue was separated by preparative liquid chromatography to obtain 76.4 mg of a white solid. MS: m / z = 491.4, yield: 15.6%. 1 H NMR(CDCl3)δ8.15(s,1H),7.53(s,1H),7.12(s,1H),6.51(s,1H),4.35-4.33(m,1H),2.41(s,3H),2.30(s,3H),1.99(s,3H),1.94-1.55(m,5H),1.31-1.25(m,2H),0.88-0.85(m,9H).

[0186] Example 24: Preparation and characterization of compound CQ-38

[0187]

[0188] Synthesis of compound CQ-38: Under nitrogen protection, triphosgene (0.30 g, 1.0 mmol) was dissolved in 20 ml of dry dichloromethane, pyridine (0.25 g, 3.2 mmol) was added, and a dichloromethane solution of compound M-7 (0.15 g, 1.0 mmol) was slowly added under an ice bath. After the addition was complete, the reaction was carried out at room temperature for 5 hours. The temperature was cooled to 0 °C, and a dichloromethane solution of CQ-01 (0.30 g, 1.0 mmol) was slowly added. After the addition was complete, the reaction was continued at room temperature for 48 hours. The reaction solution was washed with water, and the organic phase was concentrated under reduced pressure. The obtained residue was separated by preparative liquid chromatography to obtain 51.3 mg of a pale white solid. MS: m / z = 484.3, yield: 10.6%. 1 H NMR (CDCl3) δ 8.11 (s, 1H), 6.40 (s, 1H), 4.32 - 4.30 (m, 1H), 2.61 (s, 3H), 2.44 (s, 3H), 2.02 (s, 3H), 1.97 - 1.54 (m, 5H), 1.36 - 1.26 (m, 2H), 1.01 - 0.92 (m, 9H), 0.90 - 0.84 (m, 9H).

[0189] Example 25: Preparation and characterization of compound CQ-39

[0190]

[0191] Synthesis of compound CQ-39: Under nitrogen protection, triphosgene (0.30 g, 1.0 mmol) was dissolved in 20 ml of dry dichloromethane, pyridine (0.25 g, 3.2 mmol) was added, and a dichloromethane solution of compound M-7 (0.15 g, 1.0 mmol) was slowly added under an ice bath. After the addition was complete, the reaction was carried out at room temperature for 5 hours. The temperature was cooled to 0 °C, and a dichloromethane solution of S-28 (0.30 g, 1.0 mmol) was slowly added. After the addition was complete, the reaction was continued at room temperature for 40 hours. The reaction solution was washed with water, and the organic phase was concentrated under reduced pressure. The obtained residue was separated by preparative liquid chromatography to obtain 47.7 mg of a pale white solid. MS: m / z = 493.3, yield: 9.7%. 1 H NMR (CDCl3) δ 8.08 (s, 1H), 6.36 (s, 1H), 4.29 - 4.28 (m, 1H), 2.62 (s, 3H), 2.43 (s, 3H), 2.01 (s, 3H), 1.94 - 1.54 (m, 5H), 1.33 - 1.25 (m, 2H), 0.89 - 0.85 (m, 9H).

[0192] Example 26: Preparation and characterization of compounds CQ-40 and CQ-41

[0193]

[0194] Synthesis of Compound CQ-40: Dissolve Compound S-5 (0.23 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, and slowly add triphosgene (0.30 g, 1.00 mmol) and triethylamine (0.30 g, 3.00 mmol) under nitrogen protection. After the addition, continue the reaction at room temperature for 16 hours. Cool to 0 °C, add (-)-borneol (0.15 g, 1.00 mmol), heat to reflux and continue the reaction for 8 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 91.3 mg of a white solid. MS: m / z = 415.3, yield: 22.0%. 1 H NMR (CDCl3) δ 5.37 (s, 2H), 4.87 - 4.85 (m, 1H), 3.42 (s, 2H), 2.66 (s, 3H), 2.53 (s, 3H), 2.24 (s, 3H), 2.01 - 1.98 (m, 1H), 1.76 - 1.55 (m, 4H), 1.37 - 1.26 (m, 2H), 0.95 - 0.84 (m, 9H).

[0195] Synthesis of Compound CQ-41: Dissolve Compound S-5 (0.23 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, and slowly add triphosgene (0.30 g, 1.00 mmol) and triethylamine (0.30 g, 3.00 mmol) under nitrogen protection. After the addition, continue the reaction at room temperature for 16 hours. Cool to 0 °C, add (R)-(+)-norbornanamine (0.15 g, 1.00 mmol), heat to reflux and continue the reaction for 5 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 100.1 mg of a white solid. MS: m / z = 414.0, yield: 24.1%. 1 H NMR (CDCl3) δ 5.30 (s, 2H), 3.41 - 3.39 (m, 1H), 3.23 (s, 2H), 2.60 (s, 3H), 2.47 (s, 3H), 2.19 (s, 3H), 1.71 - 1.54 (m, 4H), 1.35 - 1.25 (m, 2H), 0.92 - 0.83 (m, 9H).

[0196] Example 27: Preparation and Characterization of Compounds CQ-42 and CQ-43

[0197]

[0198] Synthesis of compound CQ-42: Dissolve phosphorus dichloride 4-nitrobenzene (0.26 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, slowly add triethylamine (0.30 g, 3.00 mmol), and slowly add a solution of compound S-5 (0.23 g, 1.00 mmol) in anhydrous THF under nitrogen protection. After the addition, continue the reaction at room temperature for 16 hours. Cool to 0 °C, add borneol (0.15 g, 1.00 mmol), heat to reflux and continue the reaction for 15 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. Add it to THF again, adjust the pH value to 3.0 - 4.0 with hydrochloric acid, stir at room temperature for 20 hours, cool, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 39.6 mg of white solid, MS: m / z = 451.4, yield: 8.8%. 1 H NMR(CDCl3)δ5.31(s,2H),4.83-4.81(m,1H),3.38(s,2H),2.60(s,3H),2.51(s,3H),2.23(s,3H),1.94-1.91(m,1H),1.73-1.54(m,4H),1.33-1.26(m,2H),0.91-0.86(m,9H).

[0199] Synthesis of compound CQ-43: Dissolve phosphorus dichloride 4-nitrobenzene (0.26 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, slowly add triethylamine (0.30 g, 3.00 mmol), and slowly add a solution of compound S-5 (0.23 g, 1.00 mmol) in anhydrous THF under nitrogen protection. After the addition, continue the reaction at room temperature for 16 hours. Cool to 0 °C, add (R)-(+)-norbornanamine (0.15 g, 1.00 mmol), heat to reflux and continue the reaction for 5 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. Add it to THF again, adjust the pH value to 3.0 - 4.0 with hydrochloric acid, stir at room temperature for 20 hours, cool, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 33.2 mg of white solid, MS: m / z = 450.1, yield: 7.4%. 1 H NMR(CDCl3)δ5.26(s,2H),3.16(s,2H),2.61(s,3H),2.52(s,3H),2.32-2.28(m,1H),2.16(s,3H),1.72-1.53(m,4H),1.32-1.25(m,2H),0.90-0.85(m,9H).

[0200] Example 28: Preparation and Characterization of Compounds CQ-44 and CQ-45

[0201]

[0202] Synthesis of Compound CQ-44: Dissolve Compound S-17 (0.23 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, and slowly add triphosgene (0.30 g, 1.00 mmol) and triethylamine (0.30 g, 3.00 mmol) under nitrogen protection. After the addition, continue the reaction at room temperature for 16 hours. Cool to 0 °C, add (R)-(+)-norbornanamine (0.15 g, 1.00 mmol), heat to reflux and continue the reaction for 6 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid phase to obtain 51.2 mg of a white solid. MS: m / z = 417.2, yield: 12.3%. 1 1H NMR (CDCl3) δ 5.27 (s, 2H), 3.40 - 3.38 (m, 1H), 3.21 (s, 2H), 2.64 (s, 3H), 2.45 (s, 3H), 1.73 - 1.57 (m, 4H), 1.32 - 1.25 (m, 2H), 0.89 - 0.84 (m, 9H).

[0203] Synthesis of Compound CQ-45: Dissolve phosphorus dichloride 4-nitrobenzene (0.26 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, slowly add triethylamine (0.30 g, 3.00 mmol), and slowly add an anhydrous THF solution of Compound S-17 (0.23 g, 1.00 mmol) under nitrogen protection. After the addition, continue the reaction at room temperature for 16 hours. Cool to 0 °C, add (R)-(+)-norbornanamine (0.15 g, 1.00 mmol), heat to reflux and continue the reaction for 5 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. Add it to THF again, adjust the pH value to 3.0 - 4.0 with hydrochloric acid, stir at room temperature for 24 hours, cool, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid phase to obtain 33.2 mg of a white solid. MS: m / z = 453.3, yield: 7.4%. 1 1H NMR (CDCl3) δ 5.25 (s, 2H), 3.14 (s, 2H), 2.63 (s, 3H), 2.50 (s, 3H), 2.30 - 2.27 (m, 1H), 1.73 - 1.56 (m, 4H), 1.31 - 1.25 (m, 2H), 0.91 - 0.86 (m, 9H).

[0204] Example 29: Preparation and Characterization of Compounds CQ-46 and CQ-47

[0205]

[0206] Synthesis of Compound CQ-46: Dissolve Compound S-22 (0.23 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, and slowly add triphosgene (0.30 g, 1.00 mmol) and triethylamine (0.30 g, 3.00 mmol) under nitrogen protection. After addition, continue the reaction at room temperature for 12 hours. Cool to 0 °C, add (-)-borneol (0.15 g, 1.00 mmol), heat to reflux and continue the reaction for 12 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 68.0 mg of a white solid. MS: m / z = 413.0, yield: 16.5%. 1 H NMR (CDCl3) δ 7.45 (s, 1H), 7.37 (s, 1H), 5.08 (s, 2H), 4.32 - 4.31 (m, 1H), 3.34 (s, 2H), 2.61 (s, 3H), 2.56 (s, 3H), 2.19 (s, 3H), 1.97 - 1.94 (m, 1H), 1.73 - 1.54 (m, 4H), 1.32 - 1.25 (m, 2H), 0.93 - 0.86 (m, 9H).

[0207] Synthesis of Compound CQ-47: Dissolve Compound S-22 (0.23 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, and slowly add triphosgene (0.30 g, 1.00 mmol) and triethylamine (0.30 g, 3.00 mmol) under nitrogen protection. After addition, continue the reaction at room temperature for 12 hours. Cool to 0 °C, add (R)-(+)-norbornanamine (0.15 g, 1.00 mmol), heat to reflux and continue the reaction for 8 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 72.7 mg of a white solid. MS: m / z = 412.2, yield: 17.7%. 1 HNMR (CDCl3) 7.61 - 7.60 (m, 1H), δ 7.47 (s, 1H), 7.39 (s, 1H), 5.08 (s, 2H), 4.83 (s, 2H), 3.28 - 3.26 (m, 1H), 3.13 (s, 2H), 2.64 (s, 3H), 2.53 (s, 3H), 2.22 (s, 3H), 1.74 - 1.57 (m, 4H), 1.31 - 1.24 (m, 2H), 0.90 - 0.85 (m, 9H).

[0208] Example 30: Preparation and Characterization of Compounds CQ-48 and CQ-49

[0209]

[0210] Synthesis of Compound CQ-48: Phosphorus dichloride 4-nitrobenzene (0.26 g, 1.00 mmol) was dissolved in anhydrous THF, cooled to 0 °C, and triethylamine (0.30 g, 3.00 mmol) was slowly added. Under nitrogen protection, a solution of compound S-22 (0.23 g, 1.00 mmol) in anhydrous THF was slowly added. After the addition, the reaction was continued at room temperature for 15 hours, cooled to 0 °C, bornyl alcohol (0.15 g, 1.00 mmol) was added, and the mixture was heated to reflux and reacted for another 10 hours. The temperature was lowered to room temperature, concentrated, ice water was added, and the aqueous phase was extracted with DCM. The organic phases were combined, dried and concentrated. It was added to THF again, and the pH value was adjusted to 3.0 - 4.0 with hydrochloric acid, and stirred at room temperature for 20 hours, cooled, and the aqueous phase was extracted with DCM. The organic phases were combined, dried and concentrated. The residue was prepared by preparative liquid chromatography to obtain 42.6 mg of a white solid, MS: m / z = 449.1, yield: 9.5%. 1 1H NMR (CDCl3) δ 7.46 (s, 1H), 7.38 (s, 1H), 5.29 (s, 2H), 3.22 - 3.20 (m, 1H), 3.10 (s, 2H), 2.62 (s, 3H), 2.53 (s, 3H), 2.21 (s, 3H), 1.92 - 1.90 (m, 1H), 1.75 - 1.53 (m, 4H), 1.34 - 1.25 (m, 2H), 0.92 - 0.85 (m, 9H).

[0211] Synthesis of Compound CQ-49: Phosphorus dichloride 4-nitrobenzene (0.26 g, 1.00 mmol) was dissolved in anhydrous THF, cooled to 0 °C, and triethylamine (0.30 g, 3.00 mmol) was slowly added. Under nitrogen protection, a solution of compound S-22 (0.23 g, 1.00 mmol) in anhydrous THF was slowly added. After the addition, the reaction was continued at room temperature for 15 hours, cooled to 0 °C, (R)-(+)-norbornanamine (0.15 g, 1.00 mmol) was added, and the mixture was heated to reflux and reacted for 5 hours. The temperature was lowered to room temperature, concentrated, ice water was added, and the aqueous phase was extracted with DCM. The organic phases were combined, dried and concentrated. It was added to THF again, and the pH value was adjusted to 3.0 - 4.0 with hydrochloric acid, and stirred at room temperature for 21 hours, cooled, and the aqueous phase was extracted with DCM. The organic phases were combined, dried and concentrated. The residue was prepared by preparative liquid chromatography to obtain 38.0 mg of a white solid, MS: m / z = 448.3, yield: 8.5%. 11H NMR (CDCl3) δ 7.43 (s, 1H), 7.35 (s, 1H), 5.12 (s, 2H), 3.14 (s, 2H), 2.65 (s, 3H), 2.55 (s, 3H), 2.24 (s, 3H), 2.13 - 2.11 (m, 1H), 1.74 - 1.57 (m, 4H), 1.32 - 1.25 (m, 2H), 0.91 - 0.83 (m, 9H).

[0212] Example 31: Preparation and Characterization of Compounds CQ - 48 and CQ - 49

[0213]

[0214] Synthesis of Compound CQ - 50: Dissolve Compound S - 25 (0.24 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, and slowly add triphosgene (0.30 g, 1.00 mmol) and triethylamine (0.30 g, 3.00 mmol) under nitrogen protection. After addition, continue the reaction at room temperature for 15 hours. Cool to 0 °C, add (R)-(+)-norbornanamine (0.15 g, 1.00 mmol), heat to reflux and continue the reaction for 6 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 0.07 g of an off - white solid. MS: m / z = 414.4, Yield: 16.8%. 1 1H NMR (CDCl3) δ 7.46 (s, 1H), 7.35 (s, 1H), 5.04 (s, 2H), 4.29 (s, 2H), 3.23 - 3.21 (m, 1H), 2.30 (s, 3H), 2.17 (s, 3H), 1.77 - 1.54 (m, 4H), 1.33 - 1.24 (m, 2H), 0.96 - 0.87 (m, 9H).

[0215] Synthesis of Compound CQ-51: Dissolve phosphorus dichloride 4-nitrobenzene (0.26 g, 1.00 mmol) in anhydrous THF, cool to 0 °C, slowly add triethylamine (0.30 g, 3.00 mmol), and slowly add a solution of compound S-22 (0.23 g, 1.00 mmol) in anhydrous THF under nitrogen protection. After the addition, continue the reaction at room temperature for 15 hours. Cool to 0 °C, add (R)-(+)-norbornanamine (0.15 g, 1.00 mmol), heat to reflux and continue the reaction for 4 hours. Cool to room temperature, concentrate, add ice water, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. Add it to THF again, adjust the pH value to 3.0 - 4.0 with hydrochloric acid, stir at room temperature for 22 hours, cool, extract the aqueous phase with DCM, combine the organic phases, dry and concentrate. The residue is prepared by preparative liquid chromatography to obtain 36.9 mg of white solid, MS: m / z = 451.0, yield: 8.2%. 1 H NMR(CDCl3)δ7.42(s,1H),7.31(s,1H),5.10(s,2H),3.11(s,2H),2.62(s,3H),2.53(s,3H),2.11 - 2.10(m,1H),1.75 - 1.56(m,4H),1.33 - 1.24(m,2H),0.92 - 0.84(m,9H).

[0216] Example 32: Preparation and Characterization of Compounds CQ-52 and CQ-53

[0217]

[0218] Synthesis of Compound S-29: Dissolve compound S-5 (0.23 g, 1.00 mmol) in dichloromethane, cool to 0 °C, add 2-((tert-butoxycarbonyl)amino)ethane-1-sulfonic acid (0.22 g, 1.00 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.19 g, 1.00 mmol) under nitrogen protection, then add triethylamine (0.30 g, 3.00 mmol), stir at room temperature for 20 hours, wash with water, dry the organic phase and concentrate, and obtain 123.5 mg of off-white solid by column chromatography, MS: m / z = 442.2, yield: 28.0%.

[0219] Synthesis of Compound CQ-52: Dissolve compound S-29 (0.10 g, 0.23 mmol) in dichloromethane (10 ml), cool to 0 °C, add trifluoroacetic acid (1.0 ml) under nitrogen protection, stir at room temperature for 15 hours, add triethylamine (3.0 ml), concentrate and separate by column chromatography to obtain 11.0 mg of off-white solid, MS: m / z = 342.2, yield: 14.3%. 11H NMR (CDCl3) δ 4.65 (s, 2H), 3.22 - 3.20 (m, 2H), 3.04 - 3.00 (m, 4H), 2.59 (s, 3H), 2.49 (s, 3H), 1.98 (s, 3H).

[0220] Synthesis of Compound S-30: Dissolve Compound S-5 (0.23 g, 1.00 mmol) in dichloromethane, cool to 0 °C, add 2-(tert-butoxycarbonyl)amino)propane-1-sulfonic acid (0.24 g, 1.00 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.19 g, 1.00 mmol) under nitrogen protection, then add triethylamine (0.30 g, 3.00 mmol), stir at room temperature for 21 hours, wash with water, concentrate the organic phase after drying, and obtain 121.9 mg of a white solid by column chromatography. MS: m / z = 456.1, yield: 26.8%.

[0221] Synthesis of Compound CQ-53: Dissolve Compound S-30 (0.10 g, 0.22 mmol) in dichloromethane (10 ml), cool to 0 °C, add trifluoroacetic acid (1.0 ml) under nitrogen protection, stir at room temperature for 15 hours, add triethylamine (3.0 ml), concentrate and separate by column chromatography to obtain 13.0 mg of a white solid. MS: m / z = 356.0, yield: 16.7%. 1 1H NMR (CDCl3) δ 4.62 (s, 2H), 3.03 - 3.01 (m, 4H), 2.62 - 2.60 (m, 2H), 2.58 (s, 3H), 2.46 (s, 3H), 2.01 (s, 3H), 1.95 - 1.93 (m, 2H).

[0222] Example 33: Preparation and Characterization of Compound CQ-54

[0223]

[0224] Synthesis of compound CQ-54: Under nitrogen protection, triphosgene (0.30 g, 1.0 mmol) was dissolved in 20 ml of dry dichloromethane, pyridine (0.25 g, 3.2 mmol) was added, and a dichloromethane solution of compound (+)-borneol (0.15 g, 1.0 mmol) was slowly added under an ice bath. After the addition was complete, the reaction mixture was allowed to react at room temperature for 5 hours. The temperature was then lowered to 0 °C, and a dichloromethane solution of S-29 (0.44 g, 1.0 mmol) was slowly added. After the addition was complete, the reaction was continued at room temperature for 20 hours. The reaction mixture was washed with water, and the organic phase was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (10 ml), trifluoroacetic acid (1.0 ml) was added under nitrogen protection, and the mixture was stirred at room temperature for 15 hours. Triethylamine (3.0 ml) was added, and after concentration, preparative liquid chromatography was used for separation to obtain 34.9 mg of a white solid. MS: m / z = 522.1, yield: 6.7%. 1 H NMR(CDCl3)δ4.63(s,2H),4.32-4.30(m,1H),3.20-3.18(m,2H),3.02-2.99(m,4H),2.62(s,3H),2.51(s,3H),1.99(s,3H),1.92-1.90(m,1H),1.73-1.52(m,4H),1.33-1.29(m,2H),0.91-0.85(m,9H).

[0225] Example 34: Preparation and characterization of compound CQ-55

[0226] Using the method for synthesizing CQ-54 and S-30 to synthesize CQ-55, 30.2 mg of a white solid was obtained. MS: m / z = 536.3, yield: 5.8%. 1 H NMR(CDCl3)δ4.61(s,2H),4.34-4.33(m,1H),3.04-2.99(m,4H),2.64-2.63(m,2H),2.61(s,3H),2.54(s,3H),1.98(s,3H),1.91-1.88(m,2H),1.74-1.54(m,4H),1.35-1.31(m,2H),0.92-0.86(m,9H).

[0227] Example 35: Preparation and characterization of compounds CQ-56 and CQ-57

[0228] Synthesized by the method for synthesizing compound CQ-52:

[0229] CQ-56: 16.5 mg, MS: m / z = 312.0, yield: 5.3%. 1 H NMR(CDCl3)δ7.51-7.48

[0230] (m, 4H), 4.63 (s, 2H), 3.21 - 2.19 (m, 2H), 3.05 - 3.03 (m, 2H), 3.01 (s, 2H), 1.94 (s, 3H).

[0231] CQ-57: 24.4 mg, MS: m / z = 326.1, Yield: 7.5%. 1 H NMR(CDCl3) δ 7.54 - 7.50

[0232] (m, 4H), 4.60 (s, 2H), 3.03 - 3.01 (m, 4H), 2.61 - 2.58 (m, 2H), 2.01 - 1.99 (m, 2H), 1.93 (s, 3H).

[0233] Example 36: Preparation and Characterization of Compounds CQ-58 and CQ-59

[0234] Prepared by the method for synthesizing compound CQ-54:

[0235] CQ-58: 31.4 mg, MS: m / z = 492.3, Yield: 6.4%. 1 H NMR(CDCl3) δ 7.63 - 7.61

[0236] (m, 2H), 7.31 - 7.29 (m, 2H), 6.68 (s, 1H), 4.69 (s, 2H), 4.31 - 4.30 (m, 1H), 3.22 - 3.20 (m, 2H), 3.03 - 3.01 (m, 2H), 1.93 - 1.91 (m, 1H), 1.71 - 1.55 (m, 4H), 1.32 - 1.27 (m, 2H), 2.24 (s, 3H), 0.89 - 0.85 (m, 9H).

[0237] CQ-59: 18.7 mg, MS: m / z = 506.1, Yield: 3.4%. 1 H NMR(CDCl3) δ 7.64 - 7.62 (m, 2H), 7.34 - 7.31 (m, 2H), 6.66 (s, 1H), 4.63 (s, 2H), 4.32 - 4.30 (m, 1H), 3.02 - 3.00 (m, 2H), 2.59 - 2.56 (m, 2H), 1.95 - 1.92 (m, 3H), 1.74 - 1.56 (m, 4H), 1.30 - 1.26 (m, 2H), 2.23 (s, 3H), 0.90 - 0.85 (m, 9H).

[0238] The following example compounds were prepared using a similar synthetic method:

[0239]

[0240]

[0241]

[0242]

[0243]

[0244] Example 37: Test on the Protective Effect of Compounds against Glutamate-Induced Neuronal Cell Damage

[0245] Newborn suckling mice were taken. After disinfecting the skin with 75% ethanol solution, the cerebral cortex was surgically removed and placed in D-Hank's solution. After the tissue was disrupted, 0.1% trypsin solution was added, and after mixing evenly, it was placed in an incubator at 37 °C for digestion for 15 minutes. Then, DMEM solution containing 10% FBS was added to terminate the digestion, and digestion was continued in an incubator at 37 °C for 10 minutes. It was placed in a centrifuge tube and centrifuged at 2000 r / p for 10 minutes. The supernatant was discarded, 2.5 mL of neuronal medium (Neurobasal Medium) was added, and the suspension was filtered through a 400-mesh sieve, and the supernatant was subjected to cell counting. Then, it was inoculated into a 96-well plate at a density of 1×10 4 cells / well and incubated in an incubator at 37 °C for 72 hours. During this period, every 24 hours, the culture medium was discarded and fresh culture medium was re-added. After 72 hours, each well was made up to a volume of 300 μL, and the corresponding compound was added to each well to keep the final concentration at 1.0 μM. Edaravone was used as a positive control drug, and 3 parallel wells were set for each drug concentration. After 30 minutes, Glu (5 μL) and Gly (5 μL) were added to each well. During this period, the cell state was observed. After 30 minutes, the medium was completely changed, and after being placed in the incubator for 8 h, the culture medium (extracellular) was collected. After washing twice with PBS solution, 300 μL of double-distilled water was added, and then it was repeatedly frozen and thawed 3 times at -78 °C, and then the culture solution (intracellular) was collected, and the LDH leakage rate was measured according to the standard operation method. The absorbance of each well at 440 nm was measured on an enzyme-linked immunosorbent assay (ELISA) reader, and the leakage rate was calculated according to the following formula 1:

[0246] Formula 1: Leakage rate = extracellular measured value / (extracellular measured value + intracellular measured value) × 100%

[0247] Then, the inhibition rate was calculated according to the following formula 2:

[0248] Formula 2: Inhibition rate (%) = (leakage rate of glutamate group - leakage rate of compound group) / (leakage rate of glutamate group - leakage rate of blank control group) × 100%

[0249] The calculation results are shown in Table 1:

[0250] Table 1: Inhibition rate of compounds on nerve cell damage at a concentration of 1.0 μM

[0251]

[0252]

[0253] The results show that the compounds CQ-01, CQ-04, CQ-17, CQ-26, CQ-32, and CQ-58 of the present invention have obvious protective effects on glutamate-induced neuronal cell damage. The inhibition rates of nerve cell damage are all above 50%, higher than the inhibition rate of the positive control edaravone. Moreover, the inhibition rates of the compounds CQ-01, CQ-04, CQ-17, CQ-26, CQ-32, and CQ-58 on glutamate-induced neuronal cell damage protection are more than 1.5 times the inhibition rate of edaravone, showing a good effect of protecting neuronal cell damage in vitro.

[0254] Example 38: Effect of compounds on the LPS-induced zebrafish oxidation model

[0255] Randomly select normally developed zebrafish embryos and place them in a 12-well plate at a density of 25 per well. The blank control group only adds an equal volume of buffer solution (5.0 mM NaCl, 0.17 mM KCl, 0.33 mM CaCl2, 0.33 mM MgSO4), and is set as: blank control group, model group, CQ-01 group, CQ-04 group, CQ-17 group, CQ-26 group, CQ-32 group, CQ-58 group, edaravone group, with three replicates in each group. After sucking dry the water in each well, add an equal amount of buffer solution to each well. Then add the corresponding compound solution (containing 2.0% DMSO as a co-solvent) to each well. The final concentration of the compound is 1.0 μM. The blank control group and the model group only add an equal volume of buffer solution. After 1 hour, add 0.5 mL of LPS solution (final concentration of 10.0 μg / mL) to each group, and then place it in an incubator at 27 °C and continue to incubate for 24 hours. Transfer the experimental solution in each well to a new well plate, discard the original buffer solution, add a fresh equal volume of buffer solution, and continue to incubate in a 37 °C incubator until 3 dpf. Then remove the egg membrane from each well, add 5.0 ml of fluorescent probe (DCHF-DA) to each well to detect the ROS content, and incubate in the dark for 1 hour. Then wash the embryos three times with buffer solution, add tricaine for anesthesia, and use ImageJ to analyze the fluorescence intensity. Calculate the ROS inhibition rate according to the following formula 3:

[0256] Formula 3: Inhibition rate (%) = [1 - (relative fluorescence intensity of the drug-administered group / relative fluorescence intensity of the model group)] × 100%

[0257] The calculation results are shown in Table 2:

[0258] Compound Inhibition rate (%) Compound Inhibition rate (%) Compound Inhibition rate (%) Model group 0.0 CQ-17 group 71.2 CQ-58 group 70.5 CQ-01 group 77.7 CQ-26 group 69.8 Edaravone group 51.2 CQ-04 group 78.4 CQ-32 group 69.3

[0259] The data indicate that the compounds CQ-01, CQ-04, CQ-17, CQ-26, CQ-32, and CQ-58 provided by the present invention all have obvious inhibitory effects on LPS-induced oxidative stress in zebrafish, and are stronger than the inhibitory effect of edaravone. In particular, the inhibitory rates of compounds CQ-01 and CQ-04 on LPS-induced oxidative stress in zebrafish are more than 50% higher, achieving unexpected technical effects.

[0260] Example 39: Effects of Compounds CQ-01 and CQ-04 on the Model of Persistent Focal Cerebral Ischemia Induced by Middle Cerebral Artery Occlusion in Infarcted Rats

[0261] Fifty male SD rats with a body weight of 280 ± 20 g were randomly selected and randomly divided into 5 groups, with 10 rats in each group, namely: sham operation group, model group, CQ-01 group, CQ-04 group, and edaravone group. The rats were anesthetized and fixed supine, and an incision of 2.0 cm was made in the middle of the neck. The right artery was separated and a suture was threaded through for standby. Then the external carotid artery was separated and ligated. One branch of the internal carotid artery and its adjacent branches were separated below the external artery and threaded. It was ligated near the bifurcation. The proximal end of the separated common carotid artery was blocked with an artery clip, and the distal end was gently pulled up with a suture. A small incision was made on the common carotid artery, and a nylon wire rod with one end heated into a spherical shape (0.28 mm) was inserted into the small opening and slowly pushed into the anterior cerebral artery (20 mm), and then pulled back about 2 mm to reach the middle cerebral artery opening of the brain, about 17 mm long. The nylon wire rod was ligated and fixed with a suture. The proximal end was ligated with another suture, the artery clip was removed, and the rats were normally fed after the operation, with free access to water and food. The rats in the sham operation group only received corresponding treatments without ligation. After 2 hours, drugs were administered by tail vein injection, and the dose was: 2.0 mg / kg. The sham operation group and the model group only received an equal volume of normal saline. The behavioral indicators of the rats were observed 24 hours after drug administration, and scored according to the Longa method. The scoring criteria are shown in Table 3:

[0262] Table 3: Scoring Criteria of Longa Method

[0263] Behavioral index Score No neurological deficit 0 points The front paw on the paralyzed side cannot be fully extended 1 point Circle towards the paralyzed side when walking 2 points Fall towards the paralyzed side when walking 3 points Unable to walk automatically, with loss of consciousness 4 points

[0264] The arithmetic mean of the scores of each group of rats was used as the final score of this group. The calculation results are shown in Table 4:

[0265] Table 4: Effects of Compounds on the Behavioral Ability of Focal Cerebral Ischemia Rats

[0266] Group Dose (mg / kg) Score Sham operation group -- 0.0±0.0 Model group -- 2.49±0.78 CQ-01 group 2.0 0.23±0.11 CQ-04 group 2.0 0.24±0.10 Edaravone group 2.0 0.70±0.21

[0267] Data showed that rats in the model group had obvious locomotor disorders, indicating successful modeling. Compared with the model group, the behavioral ability of rats with persistent local cerebral ischemia in the drug administration group was extremely significantly improved; compared with edaravone, the compound CQ-01 group and CQ-04 group showed more obvious improvement in the behavioral ability of rats with persistent local cerebral ischemia after administration.

[0268] After behavioral assessment, the animals were euthanized, the right brain was separated, the olfactory bulb, cerebellum and lower brainstem were removed, and cut into 5 slices with uniform thickness. Stained with 2.0% triphenyltetrazolium chloride (2.0%), normal tissue was red and the infarcted area was white, and then the percentage of infarcted tissue weight in the total brain was calculated. The stained brain tissue was dried and weighed, and the water content of the rat brain was calculated by dry weight and wet weight methods. The calculation results are shown in Table 5:

[0269] Table 5: Effects of compounds on the persistent cerebral ischemia model in rats

[0270] Group Dose (mg / kg) Cerebral infarction area (%) Brain water content (%) Sham operation group -- 0 77.6±0.9 Model group -- 23.5±5.4 80.2±1.5 CQ-01 group 2.0 14.8±1.8 76.3±3.7 CQ-04 group 2.0 11.4±1.0 76.2±4.5 Edaravone group 2.0 11.1±1.4 78.0±3.9

[0271] Data showed that rats in the model group had a larger cerebral infarction area and higher water content, indicating successful modeling. After administration, the cerebral infarction area of rats in the drug administration group was significantly reduced, and the water content decreased. At the same time, the compounds CQ-01 and CQ-04 of the present invention could more significantly improve the degree of ischemia in rats, reduce the range of cerebral infarction, and inhibit the occurrence of brain edema, achieving unexpected beneficial technical effects.

[0272] Example 40: Safety evaluation of compounds CQ-01 and CQ-04

[0273] Randomly selected 9hpf wild-type zebrafish embryos with normal development and placed them in 96-well plates, with 1 zebrafish embryo in each well, 20 embryos in a group. 100 μL of sample solution was added to each well, maintaining a concentration of 1.0 μM. The blank control group was only added with an equal volume of clear water. Then incubated in an incubator at 28 °C until 96hpf, and the survival rate and malformation rate of fish embryos were observed and counted under a stereomicroscope. The results are shown in Table 6 below:

[0274] Table 6: Effects of compounds on zebrafish embryos

[0275] Group Concentration (μM) Survival rate (%) Malformation rate (%) Blank control group -- 0.0 0.0 CQ-01 group 1.0 0.0 0.0 CQ-04 group 1.0 0.0 0.0

[0276] Data showed that at a concentration of 1.0 μM, the mortality rate of compounds CQ-01 and CQ-04 on zebrafish embryos until 96hpf was 0, and the malformation rate was 0, indicating that compounds CQ-01 and CQ-04 had low toxicity and had the prospect of being developed into suitable drugs.

[0277] Through the above specific description of this patent, those skilled in the art can thoroughly understand the features of this invention. At the same time, the improved results of this invention also fall within the scope of the appended claims of this application.

Claims

1. A compound of formula I-1 and its salts: Wherein: Y1 and Y2 are each independently CH or N; R1, R2, and R3 are each independently hydrogen, deuterium, or a C 1-6 alkyl group; R4 is hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy; R5 is R6 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, or When R6 is R5 is not n2 is 1 or 2; R7, R8, R9, R 10 , R 11 , R 12 each independently represents hydrogen, deuterium, C 1-6 alkyl, or C 1-6 alkyl in which one or more hydrogens are deuterated; L2 is independently hydrogen, and when L2 is hydrogen, R6 is only R 13 is C 1-6 alkyl, C 1-6 alkylamino, C 3-12 carbocyclic group; R 14 and R 15 each independently represents hydrogen, C 1-6 alkyl, or C 3-12 carbocyclic group.

2. The compound according to claim 1, having the following structure of formula II-1: The definitions of the substituents in formula II-1 are as defined in formula I-1.

3. The compound according to claim 1, having the following formula III-1: The definitions of the substituents in formula III-1 are as defined in formula I-1.

4. The compound according to claim 1, having the following formula IV-1: The definitions of the substituents in formula IV-1 are as defined in formula I-1.

5. The compound according to claim 1, having the following structure of formula V-1: The definitions of the substituents in formula V-1 are as defined in formula I-1.

6. The compound according to claim 1, having the following structure of formula VII-1: The definitions of the substituents in formula VII-1 are as defined in formula I-1.

7. The compound according to claim 1, having the following structure of formula VIII-1: The definitions of the substituents in formula VIII-1 are as defined in formula I-1.

8. A compound or its salt, the compound having the following structure:

9. A pharmaceutical composition, characterized in that, It comprises the compound or its salt according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier, adjuvant, vehicle and their combinations.

10. Use of the compound or its salt according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating diseases related to free radicals.

11. The use according to claim 10, characterized in that, It can be used for treating diseases caused by oxidative stress and / or thrombosis induced by free radicals.

12. The use according to claims 10 to 11, characterized in that, The diseases caused by oxidative stress and / or thrombosis induced by free radicals are arteriosclerosis, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, heart failure, stroke, myocardial ischemia and ischemia-reperfusion injury, myocardial infarction, coronary heart disease.

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