Chiral secondary phosphine oxide compounds and chiral quinazolinone / pyrimidinone fused ring derivatives based thereon and applications

Abstract

The application belongs to the technical field of organic synthesis and chemical catalysis, and discloses a chiral large steric hindrance secondary phosphine oxide compound, a preparation method thereof and application thereof in catalytic reactions. The chiral large steric hindrance secondary phosphine oxide compound mainly takes a five-membered ring N-P-N heterocycle as a main ligand skeleton, can obtain a series of novel large steric hindrance ligands by adjusting substituent groups in raw materials, can be modified in space, can be applied to asymmetric bimetallic catalytic reactions as a ligand or a pro-ligand, can efficiently catalyze quinazolinone heterocyclic compound C-H cyclization addition reactions, and can obtain a target product with a yield of up to 95% and 99% ee, with less by-products and simple separation. The application further provides a chiral quinazolinone / pyrimidinone fused ring derivative and its racemate based on the catalytic reaction of the above compound, and the derivative and its racemate both have excellent effects of reversing liver injury cell activity, and can be used in the preparation of drugs or lead compounds for preventing or treating liver injury.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and chemical catalysis technology, and relates to a class of chiral, sterically hindered secondary phosphine oxide compounds, their preparation methods, and their applications in catalytic reactions, particularly as ligands or pre-ligands in asymmetric bimetallic catalysis, for highly efficient catalysis of the CH cyclization addition reaction of quinazolinone heterocyclic compounds. This invention also provides a class of chiral quinazolinone / pyrimidinone cyclic derivatives obtained based on the catalytic reactions of the above compounds, their racemates, and synthetic methods. Furthermore, it has been found that these compounds exhibit excellent activity reversing liver injury cell damage and can be used as drugs or lead compounds for the prevention or treatment of liver injury. Background Technology

[0002] Secondary phosphine oxides (SPOs) are phosphine oxides with one hydrogen atom. Compared to phosphine, they are more stable in air and moisture, and easier to prepare and store. In the presence of bases, Lewis acids, or transition metals, their phosphorus can undergo a pentavalent tautomerism to a trivalent form, creating an isomer similar to hypophosphoric acid. This isomer can then undergo coordination catalysis, and the stereochemical information surrounding the phosphorus center is preserved during the P(V)–P(III) tautomerism. Therefore, it is called a preligand or ligand and has broad application prospects.

[0003] Traditional chiral nitrogen-containing five-membered ring SPOs are typically synthesized from sterically hindered chiral amines. Literature reports that these sterically hindered chiral amines are obtained through the resolution of chiral small molecules such as malic acid or tartaric acid, but the yields are low and the variety is very limited, making large-scale production difficult and significantly restricting the types and applications of chiral nitrogen-containing five-membered ring SPOs. Therefore, developing SPOs with novel skeletal structures and their synthetic methods is of great value and will further enrich the exploration of SPO ligand systems and their applications.

[0004] Liver injury affects approximately 10% of the global population and is the fourth or fifth leading cause of death (World J. Emerg. Surg. 2020, 15, 24). Drug-induced and alcohol-dependent liver injury is the most common cause of liver injury (Clin. Med. 2016, 16, 104; Gastroenterology. 2011, 141(5), 1572). N-acetylcysteine ​​(NAC) is currently the only clinically approved effective protective agent against liver injury, but its high dosage and effectiveness only in treating early-stage liver injury limit its widespread clinical use. The safety and efficacy of other drugs for treating liver injury, such as glucocorticoids, magnesium isoglycyrrhizinate, and some traditional Chinese medicines, remain to be verified (Arch. Toxicol. 2020, 94, 3381). Therefore, there is an urgent need to develop new drugs to prevent or treat liver injury.

[0005] Quinazolinones / pyrimidinones are a class of nitrogen-containing heterocyclic compounds with great therapeutic potential and biological activity (Expert Opin. Ther. Pat. 2018, 28, 281.), exhibiting a wide range of pharmacological effects (Eur. J. Med. Chem. 2019, 170, 157; Eur. J. Med. Chem. 2020, 205, 112581; Clin. Exp. Pharmacol Physiol. 2020, 47, 143). Therefore, using quinazolinones / pyrimidinones as a parent compound, modifying and transforming their structures to synthesize various derivatives, and then screening them for biological activity, may be an important source for discovering drugs to treat liver injury. However, traditional synthetic methods are complex and difficult to obtain chiral compounds with high enantioselectivity. The novel, highly efficient chiral SPOs-involved transition metal-catalyzed CH cyclization reaction developed by the applicant of this invention makes it feasible to synthesize quinazolinone / pyrimidinone cyclic skeleton derivatives directly in one step or in a few simple steps using transition metal catalysis, thereby playing a positive role in promoting the synthesis, discovery of biological activities, and pharmaceutical applications of such compounds. Summary of the Invention

[0006] In order to overcome the shortcomings and deficiencies of the prior art, the primary objective of this invention is to provide a class of chiral, sterically hindered secondary phosphine oxides.

[0007] Another objective of this invention is to provide a method for preparing the above-mentioned chiral, sterically hindered secondary phosphine oxide.

[0008] Another objective of this invention is to provide the application of the aforementioned chiral, sterically hindered secondary phosphine oxides in catalytic reactions, particularly as ligands or pre-ligands in asymmetric bimetallic catalytic reactions, for the efficient catalytic addition of quinazolinone / pyrimidinone heterocyclic compounds to CH cyclization reactions.

[0009] This invention also provides a class of chiral quinazolinone / pyrimidinone cyclic derivatives or racemates thereof obtained based on the catalytic reaction of the above compounds. The chiral quinazolinone / pyrimidinone cyclic derivatives or racemates thereof of this invention exhibit excellent activity in reversing liver-damaged cell activity.

[0010] The present invention also provides a method for synthesizing the above-mentioned chiral quinazolinone / pyrimidinone cyclic derivatives or their racemic forms.

[0011] The present invention also provides the use of the above-mentioned chiral quinazolinone / pyrimidinone cyclic derivatives and their racemates or pharmaceutically acceptable salts thereof with the activity of reversing liver injury cells in the preparation of medicaments for the prevention or treatment of liver injury or lead compounds thereof.

[0012] The objective of this invention is achieved through the following solution:

[0013] A class of chiral, sterically hindered secondary phosphonooxides are compounds having one of the structures shown below, i.e., SPO1 and SPO2, or their enantiomers or racemates:

[0014]

[0015] Where: R 1 It may be at least one of hydrogen, substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C3-20 cycloalkyl, substituted or unsubstituted C4-20 heterocyclic, substituted or unsubstituted C6-20 aryl, substituted or unsubstituted C1-20 hydroxyl group, halogen, -Bn, -CF3, -NO2, or substituted amino; R 2 R 3 R 4 R represents one or more groups on a benzene ring in which hydrogen atoms have been substituted. 2 R 3 R 4 The same or different are at least one of the following: hydrogen, substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C3-20 cycloalkyl, substituted or unsubstituted C4-20 heterocyclic, substituted or unsubstituted C6-20 aryl, substituted or unsubstituted C1-20 hydroxyl group, substituted or unsubstituted C1-C20 acyl, substituted or unsubstituted C1-C20 amide, substituted or unsubstituted C2-C20 hydroxyoxycarbonyl, substituted or unsubstituted C2-C20 aminoacyl, halogen, -Bn, -CF3, -NO2, -OH, and substituted amino; or R 2 R 3 R 4 The same or different carbon atoms are connected to one or more carbon atoms on the benzene ring to form a ring, resulting in substituted or unsubstituted C10-C26 fused ring aromatic hydrocarbon structures.

[0016] Furthermore, the chiral, sterically hindered secondary phosphonooxide compound is a compound having one of the structures shown in SpO1 and SpO2, or its enantiomer or racemate, wherein R 1 It is at least one of hydrogen, methyl, ethyl, substituted or unsubstituted C3-20 alkyl, vinyl, substituted or unsubstituted C3-10 alkenyl, substituted or unsubstituted C3-20 cycloalkyl, substituted or unsubstituted C4-20 heterocyclic, substituted or unsubstituted benzene ring, substituted or unsubstituted C7-20 aryl, methoxy, ethoxy, substituted or unsubstituted C3-20 hydroxyl, -F, -Cl, -Br, -I, -CF3, -Bn, -NO2, and substituted amino;

[0017] R 2 R 3 R4 R represents one or more groups on a benzene ring in which hydrogen atoms have been substituted. 2 R 3 R 4 The same or different are hydrogen, methyl, ethyl, substituted or unsubstituted C3-20 alkyl, vinyl, substituted or unsubstituted C3-10 alkenyl, substituted or unsubstituted C3-20 cycloalkyl, substituted or unsubstituted C4-20 heterocyclic, substituted or unsubstituted benzene ring, substituted or unsubstituted C7-20 aryl, methoxy, ethoxy, substituted or unsubstituted C3-20 hydroxyl, substituted or unsubstituted formyl, substituted or unsubstituted acetyl, substituted Or at least one of the following: unsubstituted C3-C20 acyl group, substituted or unsubstituted formamid group, substituted or unsubstituted acetamido group, substituted or unsubstituted C3-C20 amide group, substituted or unsubstituted methoxycarbonyl group, substituted or unsubstituted ethoxycarbonyl group, substituted or unsubstituted C4-C20 hydroxycarbonyl group, substituted or unsubstituted C2-C20 aminoacyl group, -F, -Cl, -Br, -I, -CF3, -Bn, -NO2, -OH, substituted amino group; or R 2 R 3 R 4 The same or different groups are connected to one or more carbon atoms on the aromatic ring to form a ring, resulting in substituted or unsubstituted naphthyl, anthracene, or phenanthrene groups.

[0018] The above-mentioned substitutions of the same or different refer to the fact that one or more hydrogen atoms in the group can be substituted by halogen, C1-20 alkyl, C3-20 cycloalkyl, C4-20 heterocyclic, C6-20 aryl, C1-20 hydroxyl, -CF3, -NO2, -OH, C1-10 substituted amino groups, etc.

[0019] Furthermore, the aforementioned substitutions of the same or different refer to the fact that one or more hydrogen atoms in the group can be substituted by groups such as -F, -Cl, -Br, -I, methyl, ethyl, propyl, C4-20 alkyl, cyclopropane, C4-20 cycloalkyl, C4-20 heterocyclic, phenyl, C7-20 aryl, methoxy, ethoxy, C3-20 alkyloxy, -CF3, -NO2, -OH, dimethylamino, diethylamino, diisopropylamino, etc.

[0020] The chiral sterically hindered secondary phosphine oxide of the present invention uses a five-membered NPN heterocycle as the main ligand skeleton, and the nitrogen atom is further modified with a sterically hindered chiral group. The sterically hindered chiral group can effectively encapsulate the central phosphorus atom, which not only enhances the stability of the central phosphorus atom in the coordination process with the metal, but also plays a role in chirality regulation.

[0021] Furthermore, the chiral, sterically hindered secondary phosphonooxide compound SPO1 of the present invention introduces the substituent R into its structure. 1 R 2 It can be used to finely adjust the stereostructure and electronic properties of ligands and catalysts, thereby regulating the catalytic activity and enantioselectivity of the CH cyclization reaction of heterocyclic compounds, so as to achieve a catalytic effect of up to 95% yield and 98% ee.

[0022] The present invention also provides a method for preparing the above-mentioned chiral, sterically hindered secondary phosphine oxide, as follows:

[0023] When a chiral, sterically hindered secondary phosphine oxide has an SpO1 structure, it is prepared by condensing a chiral amine with glyoxal in reaction A to generate a diimine compound. The diimine compound is then reduced in reaction B to generate a diamine, which is then substituted with phosphorus trihalide in reaction C and hydrolyzed to obtain the chiral, sterically hindered secondary phosphine oxide.

[0024] The reaction process is a conventional and well-known process, and the amount of each material used in the reaction process is the conventional amount.

[0025] The specific route is shown below:

[0026]

[0027] The chiral amine is shown in the following structural formula or its enantiomer or racemate:

[0028]

[0029] The chiral amine can be prepared from chiral 2-amino-1,2-diphenylethanol or chiral amino acids.

[0030] Specifically, the preparation method may be as follows:

[0031] When chiral 2-amino-1,2-diphenylethanol (including (R,R), (R,S), (S,R), or (S,S)) is used as a starting material, it undergoes a Friedel-Crafts alkylation reaction with Lewis acid and benzene to generate chiral 1,2,2-triphenylethylamine.

[0032]

[0033] The chiral 2-amino-1,2-diphenylethanol includes (R,R), (R,S), (S,R), or (S,S).

[0034] When chiral amino acids are used as raw materials, their configuration can be (R), (S), or (R / S). R 2When the group is H, the chiral amine is prepared as follows: using chiral amino acids as raw materials, the amino group of the amino acid is protected with a Boc group, and the carboxyl group is amidated; then, the amidated amide group of the carboxyl group is reduced to an aldehyde group by a reduction reaction; the aldehyde group is added to the aldehyde group by a phenyl metal reagent to obtain the corresponding chiral Boc amino alcohol; finally, the target chiral amine molecule is obtained by Friedel-Crafts alkylation reaction.

[0035]

[0036] When chiral amino acids are used as raw materials, their configuration can be (R), (S), or (R / S). R 2 When the group is not H, the chiral amine is prepared as follows: using chiral amino acids as raw materials, the carboxyl group of the amino acid is subjected to two addition reactions with an aryl metal reagent to obtain a diaryl-substituted amino alcohol compound; then the amino group of the obtained amino alcohol compound is protected by a condensation reaction; then the hydroxyl group of the alcohol is reduced with a reducing agent to obtain an amino-protected chiral amine precursor; the protecting group of the chiral amine precursor is removed by a hydrolysis reaction to obtain the target chiral amine molecule.

[0037]

[0038] The reaction process is a conventional and well-known process, and the amount of each material used in the reaction process is the conventional amount.

[0039] The above method uses sterically hindered chiral amines as raw materials to prepare ligands through reaction. The sterically hindered chiral amines are synthesized from chiral 2-amino-1,2-diphenylethanol or chiral amino acids. The raw materials are simple and readily available, and the ligand structure can be controlled by changing the type of chiral amine (substituent group) and aryl (Ar) to obtain a series of novel sterically hindered ligands with a large modification space.

[0040] When a chiral, sterically hindered secondary phosphonooxide compound has an SpO2 structure, it is prepared by hydrolysis after a substitution reaction with a chiral 1,2-diphenylethylenediamine compound, followed by a disubstituted reaction with a diaryl halomethane and then hydrolysis.

[0041] The reaction route is shown below:

[0042]

[0043] The reaction process can be a conventional process, and the amount of each material used in the reaction process can be a conventional amount.

[0044] The above-described preparation method is simple to synthesize and can be modified by changing the substituents of the aryl group in the structure. Among them, chiral 1,2-diphenylethylenediamine is a relatively inexpensive chiral raw material that can be used to prepare the corresponding chiral target ligands in large quantities.

[0045] The chiral 1,2-diphenylethylenediamine compound has the following structural formula or its enantiomer or racemate:

[0046]

[0047] The present invention also provides the application of the above-mentioned chiral, sterically hindered secondary phosphine oxides in catalytic reactions, particularly as ligands or pre-ligands in asymmetric bimetallic catalytic reactions, for the efficient catalytic addition reaction of CH cyclization of quinazolinone heterocyclic compounds.

[0048] The present invention also provides a chiral quinazolinone / pyrimidinone cyclic derivative or its racemate obtained based on the catalytic reaction of the above-mentioned compounds.

[0049] The chiral quinazolinone / pyrimidinone cyclic derivatives are compounds having one of the following structures or their enantiomers:

[0050]

[0051] Where n is the number of carbons in the olefin chain, which can be 1-3;

[0052] R 5 This refers to one or more groups on an aromatic ring in which hydrogen atoms are substituted, selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C2-16 saturated heterocyclic, C1-16 alkyloxy, -CF3, nitro, -OH, C2-10 carbonyl, C2-10 amide, C2-10 alkyloxycarbonyl, C1-C10 dialkyl-substituted amino, C6-14 aryl, C4-15 substituents with a furan structure, C4-15 substituents with a thiophene structure, C4-15 substituents with a pyrrole structure, and C5-15 substituents with a pyridine structure; or R 5 The aromatic ring is linked to one or more carbon atoms to form a cyclic ring, resulting in a C6-15 fused-ring aromatic hydrocarbon structure; or R 5 The above-mentioned groups are formed by cyclically connecting one or more carbon atoms on an aromatic ring to obtain a C5-15 heterocyclic group or heterocyclic aryl group containing one or more of N, O and S; and the above-mentioned groups having one or more secondary substituents.

[0053] R 6 R 7 The same or different groups may be selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C3-10 cycloalkyl, C2-10 amide, -COR, etc. 8 -SO2R 9C7-14 aralkyl groups, C4-14 heteroaryl-substituted alkyl groups or saturated heterocyclic-substituted alkyl groups, and the above groups having one or more secondary substituents;

[0054] The secondary substituent, R 8 and R 9 They may be selected from halogens, C1-10 alkyl groups, C2-10 alkenyl groups, C2-10 alkynyl groups, C1-10 hydroxyl groups, -CF3, -OH, nitro groups, C6-14 aryl groups, and substituted amino groups, respectively.

[0055] Furthermore, R 5 A group on one or more aromatic rings in which hydrogen is substituted, selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, C4-10 alkyl, vinyl, propenyl, C4-10 alkenyl, ethynyl, propynyl, C4-10 alkynyl, cyclopropane, C4-10 cycloalkyl, C2-16 saturated heterocyclic groups, methoxy, ethoxy, C3-16 alkyloxy, -CF3, nitro, -OH, ethoxycarbonyl, propenyl, C4-10 carbonyl, acetamido, propamido, C4-10 amide, methoxycarbonyl, ethoxycarbonyl, C4-10 alkyloxycarbonyl, phenyl, C7-14 aryl, furanyl, thiophene, pyrrole, pyridinyl, morpholinyl, piperazine, piperidinyl, pyrrolealkyl, or R 5 The structures of fused-ring aromatic hydrocarbons such as naphthalene, anthracene, and phenanthrene are obtained by linking more than one carbon atom to an aromatic ring; or R 5 The above-mentioned groups are formed by cyclically connecting one or more carbon atoms on an aromatic ring to obtain a C5-15 heterocyclic group or heterocyclic aryl group containing one or more of N, O and S; and the above-mentioned groups having one or more secondary substituents.

[0056] R 6 R 7 The same or different groups may be selected from hydrogen, methyl, ethyl, propyl, C4-10 alkyl, vinyl, propenyl, C4-10 alkenyl, cyclopropane, C4-10 cycloalkyl, -COR 9 -SO2R 10 , benzyl, phenethyl, phenylpropyl, phenylbutyl, C11-14 phenylalkyl, C4-14 heteroaryl-substituted alkyl or saturated heterocyclic-substituted alkyl, and the above groups having one or more secondary substituents;

[0057] The secondary substituent, R 9 and R 10The same or different ones can be selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl, C4-10 alkyl, vinyl, propenyl, C4-10 alkenyl, ethynyl, propynyl, C4-10 alkynyl, methoxy, ethoxy, C3-10 alkyloxy, -CF3, -OH, nitro, phenyl, benzyl, C8-14 aryl, substituted amino.

[0058] The present invention also provides a method for preparing the above-mentioned chiral quinazolinone / pyrimidinone cyclic derivatives or their racemates, using N-3-olefin-substituted quinazolin-4-one or N-3-olefin-substituted pyrimidin-4-one as raw materials, and the compound of the present invention (SPO1 or SPO2 or its enantiomer or racemate) as a ligand, and catalyzing the reaction through a Ni-Al bimetallic catalytic system to obtain the chiral quinazolinone / pyrimidinone cyclic derivatives or their racemates.

[0059] Based on the SPO ligand of this invention, a series of chiral quinazolinone / pyrimidinone cyclic derivatives or their racemates can be prepared simply and conveniently, with product ee values ​​as high as 99%, few byproducts, and simple separation. The reaction equation is shown below:

[0060]

[0061] The structural formulas of the N-3-olefin chain-substituted quinazolin-4-one or N-3-olefin chain-substituted pyrimidin-4-one are as follows:

[0062]

[0063] Where n is the number of carbon atoms in the olefin chain, which can be 1-3.

[0064] Furthermore, the reaction time can be 0-72 h; the reaction temperature can be 0-120 °C.

[0065] Furthermore, the Ni-Al bimetallic catalytic system is a conventional catalytic system in the art and may include transition metal nickel complexes and Lewis acids.

[0066] Furthermore, the amount of the transition metal nickel complex is 1-20% of the amount of quinazolin-4-one or pyrimidin-4-one substituted with the N-3-olefin chain.

[0067] Furthermore, the molar ratio of the transition metal nickel complex to the SPOs compound of the present invention is 1:1 to 1:2.5; the molar ratio of the Lewis acid to the SPOs compound of the present invention is 1:1 to 5:1.

[0068] Furthermore, the transition metal nickel complex may include bis-(1,5-cyclooctadiene)nickel, nickel chloride, nickel chloride hexahydrate, nickel bromide, nickel iodide, nickel nitrate, nickel sulfate, nickel(II) glycol dimethyl ether chloride complex, nickel(II) glycol dimethyl ether bromide complex, nickel(II) chloride diethylene glycol dimethyl ether complex, nickel(II) bromide diethylene glycol dimethyl ether complex, tetra(triphenylphosphine)nickel, bis(triphenylphosphine) dibromide, bis(triphenylphosphine) dichloride, bis(tricyclohexylphosphine) nickel ... Nickel dibromide (butylphosphine), nickel(II) chloride dimer, bis(cyclopentadiene) nickel, 1,2-bis(diphenylphosphine)ethane nickel chloride, 1,3-bis(diphenylphosphine)propane nickel dichloride, nickel acetylacetone, bis(hexafluoroacetylacetone)nickel(II) hydrate, bis(2,2,6,6-tetramethyl-3,5-heptadecanoic acid) nickel, dichlorobis(tributylphosphine) nickel, [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine] nickel dichloride, nickel trifluoromethanesulfonate, etc.

[0069] Furthermore, the Lewis acid may include one or more of the following: trimethylaluminum, triethylaluminum, tripropylaluminum, tributylaluminum, triisobutylaluminum, dimethylaluminum chloride, methylaluminum dichloride, aluminum trichloride, triphenylaluminum, triphenoxyaluminum, triisopropoxyaluminum, diisobutylaluminum hydride, dimethylzinc, diethylzinc, diphenylzinc, trimethylboron, triethylboron, boron trifluoride ether, and tributylboron.

[0070] Furthermore, the reaction is preferably carried out in a solvent, which may include one or more of the following: 1,4-dioxane, dichloromethane, chloroform, trichloromethane, carbon tetrachloride, dichloroethane, tetrahydrofuran, diethyl ether, acetone, ethyl acetate, toluene, benzene, xylene, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, methyl tert-butyl ether, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, pyrrolidone, and N-methylpyrrolidone.

[0071] The present invention also provides the use of the above-mentioned chiral quinazolinone / pyrimidinone cyclic derivatives or their racemates or pharmaceutically acceptable salts in the preparation of medicaments for the prevention or treatment of liver injury or their lead compounds.

[0072] The chiral quinazolinone / pyrimidinone cyclic derivatives or their racemates obtained by the catalytic reaction of chiral sterically hindered secondary phosphooxides according to the present invention have excellent activity in reversing liver injury cells and can be applied to the preparation of drugs or lead compounds for the prevention or treatment of liver injury.

[0073] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0074] (1) The chiral sterically hindered secondary phosphine oxide of the present invention has a five-membered ring NPN heterocycle as the main ligand skeleton. Its preparation method is simple. A series of novel sterically hindered ligands can be obtained by adjusting the substituent groups in the raw materials. It has a large modification space.

[0075] (2) The chiral, sterically hindered secondary phosphonooxide of the present invention can be applied to the efficient catalysis of CH cyclization reaction of nickel and Lewis acid systems. In particular, it can efficiently catalyze the CH cyclization reaction of olefin chain-substituted quinazolinones / pyrimidinones at room temperature, and can obtain target products with a yield of up to 95% and an ee of 99%.

[0076] (3) Based on the present invention, the chiral quinazolinone / pyrimidinone cyclic derivatives or their racemates obtained by the catalytic reaction of chiral sterically hindered secondary phosphooxides have excellent effects in reversing the activity of liver-damaged cells and can be applied to the preparation of drugs or lead compounds for the prevention or treatment of liver injury. Attached Figure Description

[0077] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0078] Figure 1 The figure shows the cell experiment results of the chiral quinazolinone / pyrimidinone cyclic derivatives or their racemic forms of the present invention. Detailed Implementation

[0079] The present invention will be further described in detail below with reference to embodiments, but the implementation of the present invention is not limited thereto. Unless otherwise specified, the materials involved in the following embodiments are commercially available. Unless otherwise specified, the methods described are conventional methods. The amounts of each component are expressed in molar parts and volume parts, mol / L.

[0080] Example 1: Synthesis of chiral, sterically hindered secondary phosphonooxide compound SPO1a

[0081]

[0082] (1) Synthesis of chiral 1-phenyl-2,2-diphenyldiamine (compound 2)

[0083] 10 moles of (1R,2S)-2-amino-1,2-diphenylethanol (compound 1) were dissolved in 10 parts by volume of benzene, and 100 moles of trifluoromethanesulfonic acid were added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, 40% NaOH solution was added to adjust the pH to 10-12. After extraction, washing, and drying, a pale yellow solid product, compound 2, was obtained.

[0084] (2) Synthesis of SpO1a

[0085] 8 moles of compound 2 were dissolved in 40 parts by volume of dichloromethane, and 4 moles of 40% glyoxal aqueous solution and 40 moles of anhydrous sodium sulfate were added. One drop of formic acid was added as a catalyst, and the mixture was stirred at room temperature for 12 hours. After filtration and vacuum distillation, a grayish-brown foamy solid product, compound 3, was obtained. 3 moles of compound 3 were dissolved in 20 parts by volume of a mixed solution of tetrahydrofuran and methanol in a ratio of 2:1, and 15 moles of sodium borohydride were added. After reacting for 1 hour, another 15 moles of sodium borohydride were added, and the mixture was stirred at room temperature for 12 hours. The reaction was quenched with water, extracted with ethyl acetate, washed with water, dried, and vacuum distilled to obtain a pale yellow solid product, compound 4. Under N2 protection, 2 moles of compound 4 were dissolved in 10 volumes of dichloromethane, 16 moles of triethylamine and 2.5 moles of phosphorus trichloride were added, and the mixture was stirred at room temperature for 12 h. Then, 2 moles of water were added, and the mixture was stirred at room temperature for 2 h. The mixture was then distilled under reduced pressure and separated by silica gel column chromatography to obtain a white powdery solid product, SpO1a.

[0086] 1 H NMR (400MHz, CDCl3) δ7.39(t,J=7.0Hz,4H),7.33–7.27(m,2H),7.26–7.18(m,9H),7.17–7.04(m,10H),7.00–6.88(m,5H),5.57(d,J=648 .0Hz,1H),5.17(t,J=11.3Hz,1H),4.76(d,J=2.9Hz,1H),4.70–4.61(m,2H),2.85–2.95(m,1H),2.78(q,J=6.9Hz,2H),2.49–2.38(m,1H). 13C NMR (101MHz, CDCl3) δ143.10,142.19,141.48,141.36,139.81,138.02,12 9.06,128.61,128.50,128.48,128.46,128.44,128.31,128.22,128.13,12 8.03,128.00,127.05,127.03,126.79,126.60,126.17,126.02,64.37,64. 31,59.81,59.75,54.90,54.86,52.35,52.32,44.00,43.89,39.45,39.35. 31 P NMR (162MHz, CDCl3) δ 12.05.

[0087] Example 2: Synthesis of SpO1b, a sterically hindered secondary phosphonooxide compound

[0088] (1) Synthesis of sterically hindered amine compound 9b

[0089]

[0090] 10 moles of L-phenylglycine were added to 50 parts by volume of methanol solution, followed by 20 moles of thionyl chloride. The mixture was refluxed for 16 h, and the solvent was removed by rotary evaporation. The reaction was quantitatively analyzed to obtain L-phenylglycine methyl ester hydrochloride. Under N2 protection, L-phenylglycine methyl ester hydrochloride was dissolved in anhydrous diethyl ether, and 60 moles of 1 mol / L 3,5-dimethylphenyl magnesium bromide were added. The mixture was stirred at room temperature for 24 h, and the reaction was quenched with saturated ammonium chloride solution. The crude product was extracted with ethyl acetate, washed, dried, and distilled under reduced pressure to obtain the crude product. The crude product, compound 6b, was separated by column chromatography. 6 moles of compound 6b were dissolved in 10 parts by volume of pyridine, and 9 moles of acetic anhydride were added. The mixture was stirred at room temperature for 12 h, and water was added. The mixture was extracted with ethyl acetate, washed, dried, and distilled under reduced pressure. The crude product, compound 7b, was separated by column chromatography. 5 moles of compound 7b were dissolved in 10 volumes of acetic acid solution, and 0.5 moles of Pd / C and 100 moles of ammonium formate were added. The mixture was stirred at 120°C for 16 h, the reaction was quenched with water, extracted with ethyl acetate, washed, dried, and distilled under reduced pressure. The product was then separated by column chromatography to obtain a pale yellow solid, compound 8b. 3 moles of compound 8b were dissolved in 20 volumes of 10 mol / L hydrochloric acid aqueous solution, and 5 volumes of methanol were added. The mixture was refluxed for 72 h. After the reaction was complete, the pH was adjusted to 10-12 with 10% sodium hydroxide solution, extracted with ethyl acetate, washed, dried, and distilled under reduced pressure. The product was then separated by column chromatography to obtain a pale yellow solid, compound 9b.

[0091] (2) Synthesis of compound SpO1b

[0092] Two moles of compound 9b were dissolved in 10 volumes of dichloromethane. One mole of 40% glyoxal aqueous solution and 10 moles of anhydrous sodium sulfate were added, along with one drop of formic acid as a catalyst. The mixture was stirred at room temperature for 12 hours, filtered, and distilled under reduced pressure to obtain a grayish-brown, foamy solid product, compound 10b. 0.8 moles of compound 10b were dissolved in 5 volumes of a tetrahydrofuran:methanol mixture (2:1). 2.4 moles of sodium borohydride were added, and the mixture was reacted for 1 hour. Then, another 2.4 moles of sodium borohydride were added, and the mixture was stirred at room temperature for 12 hours. The reaction was quenched with water, extracted with ethyl acetate, washed, dried, and distilled under reduced pressure. The mixture was then separated by silica gel column chromatography to obtain a pale yellow solid product, compound 11b. Under N2 protection, 0.5 mol of compound 11b was dissolved in 5 vol parts of dichloromethane, 4 mol of triethylamine and 0.6 mol of phosphorus trichloride were added, and the mixture was stirred at room temperature for 12 h. Then, 0.5 mol of water was added, and the mixture was stirred at room temperature for 2 h. The crude product was obtained by vacuum distillation, and the product was separated by silica gel column chromatography to obtain a white powdery solid product, compound SpO1b.

[0093]

[0094] 1 H NMR (400MHz, CDCl3) δ7.44–7.38(m,2H),7.25–7.07(m,8H),7.02(d,J=1.6Hz,2H),6.88 –6.79(m,5H),6.67(s,2H),6.57(s,1H),6.53(d,J=1.6Hz,2H),5.65(d,J=644.0Hz,1H) ,5.20(t,J=12.0Hz,1H),4.73(t,J=12.2Hz,1H),4.51(d,J=11.8Hz,1H),4.42(d,J=12. 0Hz,1H),2.86–2.60(m,3H),2.40–2.32(m,1H),2.30(s,6H),2.17(s,12H),2.07(s,6H). 13C NMR (101MHz, CDCl3) δ143.24,142.09,141.44,141.26,140.24,138.42,137.65,1 37.59,137.45,137.14,129.07,128.13,128.10,127.92,127.86,127.77,127.59, 126.78,126.75,126.37,126.18,125.91,125.68,63.76,63.71,58.63,58.57,54.37,54.34,51.88,51.85,43.49,43.38,38.68,38.58,21.52,21.35,21.31,21.16. 31 P NMR (162MHz, CDCl3) δ 12.58.

[0095] Example 3: Synthesis of SpO1c, a sterically hindered secondary phosphine oxide

[0096] (1) Synthesis of sterically hindered amine compound 15c

[0097]

[0098] 10 moles of D-valine were added to a 1:4 mixture of tetrahydrofuran and water, along with 12 moles of Boc₂O and 20 moles of sodium carbonate. The mixture was stirred at room temperature for 12 h, acidified to pH 2 with 10% hydrochloric acid, extracted with ethyl acetate, washed, and distilled under reduced pressure to obtain a Boc-protected intermediate. This intermediate was dissolved in 50 moles of dichloromethane, and 15 moles of dimethylhydroxylamine hydrochloride, 40 moles of N-methylmorpholine, 20 moles of HOBT, and 20 moles of EDCI hydrochloride were added. The mixture was stirred at room temperature for 19 h, quenched with 1 mol / L hydrochloric acid, extracted with ethyl acetate, washed, dried, and distilled under reduced pressure to obtain a colorless oily product, compound 12c. 10 moles of compound 12c were dissolved in 50 moles of diethyl ether, and 10 moles of lithium aluminum hydride were added. The reaction was carried out for 2 h. The reaction was quenched by adding saturated sodium sulfate solution, followed by the addition of 60 parts by volume of 2 mol / L hydrochloric acid, extraction with ethyl acetate, washing, drying, and vacuum distillation to obtain a pale yellow oily product, compound 13c. Under nitrogen protection, 10 moles of compound 13c were dissolved in tetrahydrofuran, and 16 moles of phenylmagnesium bromide were added. The mixture was stirred at room temperature for 12 h, and the reaction was quenched by adding saturated ammonium chloride solution. The mixture was then extracted with ethyl acetate, washed, dried, and vacuum distilled, and separated by silica gel column chromatography to obtain a white powdery solid product, compound 14c. 10 moles of compound 14c were dissolved in 12 parts by volume of benzene, and 15 parts by volume of trifluoromethanesulfonic acid were added. The mixture was stirred at room temperature for 2 h, poured into ice water, and the pH was adjusted to 10-12 with 40% NaOH solution. The mixture was extracted, washed, dried, and vacuum distilled to obtain the crude product, which was then separated by column chromatography to obtain a pale yellow solid product, compound 15c.

[0099] (2) Synthesis of compound SpO1c

[0100] 8 moles of compound 15c were dissolved in 40 parts by volume of dichloromethane, 4 moles of 40% glyoxal aqueous solution were added, followed by 40 moles of anhydrous sodium sulfate. One drop of formic acid was added as a catalyst, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was filtered and distilled under reduced pressure to obtain a grayish-brown foamy solid product, compound 16c. 3 moles of compound 16c were dissolved in 20 parts by volume of a mixed solution of tetrahydrofuran and methanol in a ratio of 2:1, and 15 moles of sodium borohydride were added. After reacting for 1 hour, another 15 moles of sodium borohydride were added, and the mixture was stirred at room temperature for 12 hours. The reaction was quenched with water, extracted with ethyl acetate, washed, dried, and distilled under reduced pressure. The product was separated by silica gel column chromatography to obtain a pale yellow solid product, compound 17c. Under N2 protection, 2 moles of compound 17c were dissolved in 10 volumes of dichloromethane, 16 moles of triethylamine and 2.5 moles of phosphorus trichloride were added, and the mixture was stirred at room temperature for 12 h. Then, 2 moles of water were added, and the mixture was stirred at room temperature for 2 h. The mixture was then distilled under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain a white powdery solid product, compound SPO1c.

[0101]

[0102] 1 H NMR(400MHz, CDCl3) δ7.59(d,J=6.4Hz,2H),7.40–7.10(m,18H),6.78(d,J=620Hz,1H),4.14–4.05(m,3H),3.88(t,J=6.4Hz, 1H),2.81(m,1H),2.59(m,1H),2.31(m,1H),1.88(m,1H),1.77(m,1H),1.59(m,1H),0.98(d,J=8.0Hz,3H),0.80–0.62(m,9H). 13 CNMR(101MHz, CDCl3)δ143.59,143.02,142.15,142.08,128.90,128.82,128.77,128.38,128.32,128.25,127.99,127.88,126.67,126.60,12 6.45,126.10,60.81,60.74,59.69,59.64,53.61,53.58,53.50,53.47, 44.09,43.97,40.95,40.82,31.17,30.00,22.06,21.16,17.15,16.77. 31 P NMR (162MHz, CDCl3) δ 19.86.

[0103] Example 4: Synthesis of SpO1d, a sterically hindered secondary phosphonooxide compound

[0104] (1) Synthesis of sterically hindered amine compound 15d

[0105]

[0106] 10 moles of L-tert-leucine were added to a 1:4 mixture of tetrahydrofuran and water, along with 12 moles of Boc₂O and 20 moles of sodium carbonate. The mixture was stirred at room temperature for 12 h. After the reaction, the pH of the system was acidified to 2 with 10% hydrochloric acid solution. The mixture was extracted with ethyl acetate, washed, and the solvent was removed by vacuum distillation to obtain a Boc-protected intermediate. This intermediate was dissolved in 50 moles of dichloromethane, and 15 moles of dimethylhydroxylamine hydrochloride, 40 moles of N-methylmorpholine, 20 moles of HOBT, and 20 moles of EDCI hydrochloride were added. The mixture was stirred at room temperature for 19 h, and the reaction was quenched with 1 mol / L hydrochloric acid. The mixture was extracted with ethyl acetate, washed, dried, and then distilled under vacuum to obtain a colorless oily product, compound 12d. 10 moles of compound 12d were dissolved in 50 volumes of diethyl ether, and 10 moles of lithium aluminum hydride were added. The reaction was carried out for 2 hours, quenched with saturated sodium sulfate solution, and extracted with 60 volumes of 2 mol / L hydrochloric acid. The product was then extracted with ethyl acetate, washed, dried, and distilled under reduced pressure to obtain a pale yellow oily product, compound 13d. Under nitrogen protection, 10 moles of compound 13d were dissolved in tetrahydrofuran, and 16 moles of phenyl magnesium bromide were added. The mixture was stirred at room temperature for 12 hours, quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed, dried, and distilled under reduced pressure. The product was then separated by silica gel column chromatography to obtain a white powdery solid product, compound 14d. 10 moles of compound 14d were dissolved in 12 volumes of benzene, and 15 volumes of trifluoromethanesulfonic acid were added. The mixture was stirred at room temperature for 2 hours, and the reaction solution was poured into ice water. The pH was adjusted to 10-12 with 40% NaOH solution, extracted, washed, dried, and distilled under reduced pressure. The product was then separated by column chromatography to obtain a pale yellow solid product, compound 15d.

[0107] (2) Synthesis of compound SPO1d

[0108]

[0109] 8 moles of compound 15d were dissolved in 40 volumes of dichloromethane, and 4 moles of 40% glyoxal aqueous solution and 40 moles of anhydrous sodium sulfate were added. One drop of formic acid was added as a catalyst, and the mixture was stirred at room temperature for 12 hours. After filtration and vacuum distillation, a grayish-brown foamy solid product, compound 16d, was obtained. 3 moles of compound 16d were dissolved in 20 volumes of a mixed solution of tetrahydrofuran and methanol in a ratio of 2:1, and 15 moles of sodium borohydride were added. After reacting for 1 hour, another 15 moles of sodium borohydride were added, and the mixture was stirred at room temperature for 12 hours. The reaction was quenched with water, extracted with ethyl acetate, washed, dried, and then distilled under vacuum. The product was separated by silica gel column chromatography to obtain a pale yellow solid product, compound 17d. Under nitrogen protection, 2 moles of compound 17d were dissolved in 10 parts by volume of dichloromethane, followed by the addition of 16 moles of triethylamine and 2.5 moles of phosphorus trichloride. The mixture was stirred at room temperature for 12 hours, then 2 moles of water were added, and the mixture was stirred at room temperature for 2 hours. The mixture was then distilled under reduced pressure and separated by silica gel column chromatography to obtain a white powdery solid product, compound SpO1d. Product yield: 0.85 g, yield 74%.

[0110] 1 H NMR (400MHz, CDCl3) δ7.23 (d, J=620.0Hz, 1H), 7.74–6.95 (m, 20H), 4.35–3. 78(m,4H),2.58–2.20(m,2H),1.79–1.43(m,2H),0.82(s,9H),0.70(s,9H). 13 C NMR (101MHz, CDCl3) δ146.06,144.04,143.71,129.56,128.66,128.30,128.23,128.13,126.55, 126.23,126.11,125.64,63.20,62.83,54.30,54.12,44.21,40.80,38.77,37.41,29.64,28.98. 31 PNMR (162MHz, CDCl3) δ 21.18.

[0111] Referring to the preparation method of Example 2, this invention prepares different sterically hindered amines by reacting different halogenated aryl groups (replacing 3,5-dimethylphenyl magnesium bromide) with phenylglycine, thereby preparing different chiral sterically hindered secondary phosphine oxides SPO1e, SPO1f, SPO1g, SPO1h, SPO1i, and SPO1j, with the following structural formulas:

[0112]

[0113] Example 5: Synthesis of a sterically hindered secondary phosphine oxide, SpO2a

[0114] 10 mol of diphenylbromomethane and 5 mol of (1S,2S)-1,2-diphenylethylenediamine were dissolved in 20 volume parts of DMPU. 20 mol of sodium carbonate was added, and the mixture was stirred at 120°C for 2 h. 40 volume parts of water were added, and the mixture was extracted with ethyl acetate, washed, and distilled under reduced pressure. The resulting product was separated by column chromatography to obtain a white solid compound 19a. Under N2 protection, 2 mol of compound 19a was dissolved in 10 volume parts of dichloromethane. 16 mol of triethylamine and 2.5 mol of phosphorus trichloride were added, and the mixture was stirred at room temperature for 12 h. 2 mol of water was added, and the mixture was stirred at room temperature for 2 h. The mixture was then distilled under reduced pressure, and the resulting product was separated by silica gel column chromatography to obtain a white powdery solid compound SPO2a.

[0115]

[0116] 1 H NMR (400MHz, CDCl3) δ7.63–7.54(m,2H),7.54–7.39(m,5H),7.36–7.17(m,21H),7.30(d,J=640.0Hz,1H),7.13(dd, J=7.5,2.0Hz,2H),5.15(d,J=7.2Hz,1H),5.07(d,J=15.8Hz,1H),4.28(dd,J=13.3,3.6Hz,1H),4.24–4.19(m,1H). 13 C NMR (101MHz, CDCl3) δ141.34,141.31,139.77,139.72,139.67,138.96,13 8.77,138.75,138.18,138.15,130.32,129.57,129.07,128.71,128.64,1 28.49,128.42,128.39,128.04,127.97,127.93,127.81,127.54,127.40, 127.34,127.14,70.37,70.31,70.21,70.13,63.91,63.85,63.73,63.67. 31 P NMR (162MHz, CD3CN) δ 5.07.

[0117] Referring to the preparation method in Example 5, this invention obtains asymmetric, sterically hindered secondary phosphonooxide compounds SPO2b, SPO2c, SPO2d, SPO2e, SPO2f, and SPO2g by reacting different diaryl-substituted bromomethanes (instead of diphenylbromomethane) with (1S,2S)-1,2-diphenylethylenediamine. The structural formulas are shown below:

[0118]

[0119] Example 6: A class of chiral quinazolinone cyclic derivatives

[0120]

[0121] Using 3-(1-en-3-butyl)-quinazolin-4-one (compound 20b) as a starting material, compounds 20c and 20d were synthesized via a direct CH-activated cyclization reaction catalyzed by Ni-Al bimetallic catalysts with SPO as a ligand. Specifically, under nitrogen protection, 0.2 moles of compound 20b were dissolved in 2 volumes of dioxane, and a transition metal [Ni] and 40 mol% Lewis acid were added. The reaction was carried out under different SPO ligands to obtain products 20c and 20d, respectively.

[0122] Based on the preparation method of Example 6, the SPO ligand of the present invention was reacted with a previously disclosed SPO ligand, and the reaction conditions and catalytic effects are shown in Table 1. The structural formulas of the previously disclosed SPO ligands are shown below:

[0123]

[0124] Table 1

[0125]

[0126]

[0127] As shown in Table 1, the chiral, sterically hindered secondary phosphonium oxides SPO1a, SPO1b, SPO2a, and SPO2b of this invention can efficiently catalyze reactions at room temperature, achieving superior yields, ee values, and catalyst dosages compared to previously reported SPO compounds for selective formation of single products. SPO1a exhibits the best performance, directly yielding the five-membered cyclized product 20c with a yield as high as 95% and an ee value as high as 97%. Furthermore, the chiral, sterically hindered secondary phosphonium oxide SPO2b of this invention can efficiently catalyze the formation of the six-membered cyclized product 20d at 80°C with a yield as high as 87%.

[0128] Following the preparation method of Example 6, 1 mole of N-3-olefin-substituted quinazolin-4-one or N-3-olefin-substituted pyrimidin-4-one was used as the starting material. 5% Ni(cod)2, 40% AlMe3, and 10% SpO1 or SpO2 were added under a nitrogen atmosphere. Dioxane was used as the solvent, and the reaction was carried out at room temperature for 24 hours. After the reaction was completed, 10 volumes of 10% Na(EDTA)2 aqueous solution were added. The mixture was extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. A series of reaction products—chiral quinazolinone / pyrimidinone cyclic derivatives—were obtained by separation by silica gel column chromatography. The product structures, yields, and ee values ​​are shown in Examples 7-35.

[0129] Example 7: Chiral quinazolinone cyclic derivative 21c

[0130]

[0131] Using 5-methylquinazoline-4(1H)-one (21a) as a starting material, 1 mole of compound 21a was dissolved in 20 volumes of DMF, and 1 mole of potassium carbonate and 1 mole of 1-bromobutene were added. After stirring for 5 hours, 20 volumes of water were added, and the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Compound 21b was obtained by column chromatography using silica gel. Then, following the preparation method in Example 6, compound 21c was prepared from compound 21b, using SpO1a as the SpO. Yield: 94%, ee value: 86%.

[0132] 1 H NMR (400MHz, CDCl3) δ7.54(m,2H),7.18(d,J=4.0Hz,1H),4.23(m,1H),3.97(m, 1H),3.30(m,1H),2.89(s,3H),2.48(m,1H),1.87(m,1H),1.48(d,J=8.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ161.97,161.74,150.91,140.92,133.17,128.85,125.12,119.14,44.56,38.71,28.47,22.98,17.24.

[0133] Example 8: Chiral pyrimidinone cyclic derivative 22c

[0134]

[0135] Compound 22b was prepared from pyrrolo[2,3-D]pyrimidine-4(hydro)-one (22a) according to the method of Example 7. Then, compound 22c was prepared from compound 22b according to the method of Example 6, using SPO1a as the SPO source. Yield: 76%, ee value: 50%.

[0136] 1 H NMR (400MHz, CDCl3) δ8.95 (dd, J=8.0Hz, 4Hz, 1H), 8.61 (dd, J=8.0Hz, 4Hz, 1H), 7.41 (dd, J=8.0Hz, 4Hz,1H),4.31(m,1H),4.00(m,1H),3.40(m,1H),2.56(m,1H),1.93(m,1H),1.55(d,J=8.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ166.13,161.03,159.33,155.60,136.12,121.68,115.75,44.86,39.12,28.46,16.87.

[0137] Example 9: Chiral pyrimidinone cyclic derivative 23c

[0138]

[0139] Compound 23b was prepared from pyrimidin-4-one (23a) according to the method of Example 7. Then, compound 23c was prepared from compound 23b according to the method of Example 6, using SpO1b as the SPO. Yield: 86%, ee value: 80%.

[0140] 1 H NMR(400MHz, CDCl3)δ7.90(d,J=8.0Hz,1H),6.29(t,J=8.0Hz,1H),4.26(m,1H ),3.96(m,1H),3.31(m,1H),2.49(m,1H),1.85(m,1H),1.43(d,J=8.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ167.59,161.28,154.16,112.81,45.15,39.06,28.10,16.96.

[0141] Example 10: Chiral quinazolinone cyclic derivative 24c

[0142]

[0143] Compound 24b was prepared from 6-methylquinazoline-4(1H)-one (24a) according to the method of Example 7. Then, compound 24c was prepared from compound 24b according to the method of Example 6, using SpO1a as the SPO source. Yield: 95%, ee value: 97%.

[0144] 1 H NMR (400MHz, CDCl3) δ8.08(s,1H),7.62(d,J=8.0Hz,1H),7.55(d,J=8.0Hz,1H),4.27(m,1H ),4.01(m,1H),3.32(m,1H),2.49(m,1H),2.48(s,3H),1.88(m,1H),1.49(d,J=8.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ161.53,161.00,147.25,136.25,135.51,126.71,125.75,120.35,44.52,38.65,28.65,21.21,17.21.

[0145] Example 11: Chiral quinazolinone cyclic derivative 25c

[0146]

[0147] Compound 25b was prepared from 5-fluoroquinazoline-4(1H)-one (25a) according to the method of Example 7. Then, compound 25c was prepared from compound 25b according to the preparation method of Example 6, using SpO1a as the SPO source. Yield: 55%, ee value: 97%.

[0148] 1 H NMR (400MHz, CDCl3) δ7.64(m,1H),7.48(d,J=8.0Hz,1H),7.08(dd,J=8.0Hz,4.0Hz,1H), 4.26(m,1H),4.00(m,1H),3.33(m,1H),2.50(m,1H),1.88(m,1H),1.49(d,J=8.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ163.39, 161.49 (d, J = 265Hz), 158.15 (d, J = 4Hz), 151.49, 134.36 (d, J = 1 1Hz), 122.80 (d, J = 4Hz), 112.79 (d, J = 21Hz), 110.49 (d, J = 6Hz), 44.68, 38.88, 28.33, 17.10.

[0149] Example 12: Chiral quinazolinone cyclic derivative 26c

[0150]

[0151] Compound 26b was prepared from 8-methoxyquinazoline-4(1H)-one (26a) according to the method of Example 7. Then, compound 26c was prepared from compound 26b according to the method of Example 6, using SpO1a as the SPO. Yield: 95%, ee value: 98%.

[0152] 1 H NMR (400MHz, CDCl3) δ7.88(d,J=8.0Hz,1H),7.38(t,J=8.0Hz,1H),7.20(d,J=8.0Hz,1H),4.28 (m,1H),4.07(m,1H),4.02(s,3H)3.43(m,1H),2.50(m,1H),1.90(m,1H),1.52(d,J=8.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ161.94,160.83,154.16,139.76,126.43,121.78,117.74,113.93,56.26,44.69,38.96,28.46,17.75.

[0153] Example 13: Chiral quinazolinone cyclic derivative 27c

[0154]

[0155] 10 moles of benzyl bromide and 10 moles of magnesium were dispersed in 50 volumes of tetrahydrofuran and heated to 60°C for 2 hours to prepare a benzyl magnesium bromide Grignard reagent. Then, 2,3-dihydrofuran was added to the system, and the mixture was stirred at room temperature for 8 hours. After the reaction was complete, saturated ammonium chloride was added to quench the reaction, and (Z)-5-phenyl-3-en-1-pentanol was obtained. 1 mole of (Z)-5-phenyl-3-en-1-pentanol was dissolved in dichloromethane, and 1 mole of methanesulfonyl chloride and 1 mole of triethylamine were added. The mixture was stirred at room temperature for 2 hours, and after the reaction was complete, water was added to quench the reaction, and the olefinic chain (Z)-5-phenyl-3-en-1-pentane-methanesulfonate was obtained.

[0156] Compound 27b was prepared by reacting (Z)-5-phenyl-3-ene-1-pentane-methanesulfonate with quinazolin-4(3H)-one (20a) as a starting material, following the method described in Example 7. Then, compound 27c was prepared from compound 27b using the method described in Example 6, with SpO1a as the SPO source. Yield: 90%, ee value: 92%.

[0157] 1 H NMR (400MHz, CDCl3) δ8.31(d,J=8.0Hz,1H),7.75(m,2H),7.48(m,1H),7.38-7.25(m,4H),7.23( t,J=8.0Hz,1H),4.30(m,1H),4.02(m,1H),3.29(m,1H),2.88(m,2H),2.53(m,2H),1.97(m,2H). 13 C NMR (101MHz, CDCl3) δ161.58,160.94,149.01,141.03,134.15,128.52,128.50 ,126.91,126.37,126.30,126.18,120.69,44.85,43.26,33.86,33.33,26.40.

[0158] Example 14: Chiral quinazolinone cyclic derivative 28c

[0159]

[0160] Compound 28b was prepared from 6-hydroxy-7-methoxy-3H-quinazolin-4-one (28a) according to the method of Example 7. Then, compound 28c was prepared from compound 28b according to the method of Example 6, using SpO1a as the SPO. Yield: 71%, ee value: 94.5%.

[0161] 1 H NMR (400MHz, CDCl3) δ7.61(s,1H),7.13(s,1H),5.95(m,1H),5.21(d,J=16Hz,1H),5.14(d,J=12Hz,1H),4.26(m,1H),4.19( t,J=8Hz,2H),4.02(m,1H),3.98(s,3H),3.32(m,1H),2.66(q,J=8Hz,2H),2.50(m,1H),1.88(m,1H),1.48(d,J=8.0Hz,3H). 13C NMR (101MHz, CDCl3) δ161.17,160.39,155.06,147.86,145.41,133.92,117.3 7,113.74,107.57,106.61,68.35,56.23,44.63,38.68,33.35,28.71,17.22.

[0162] Example 15: Chiral quinazolinone cyclic derivative 29c

[0163]

[0164] Compound 29b was prepared from 6,7-dimethoxy-3H-quinazolin-4-one (29a) according to the method of Example 7. Then, compound 29c was prepared from compound 29b according to the method of Example 6, using SpO1a as the SPO. Yield: 92%, ee value: 99%.

[0165] 1 H NMR (400MHz, CDCl3) δ7.61(s,1H),7.13(s,1H),4.28(m,1H),4.01(m,1H),4.00(s,6H)3.33(m,1H),2.49(m,1H),1.88(m,1H),1.49(d,J=8.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ161.20,160.36,154.70,148.55,145.42,113.81,107.42,105.35,56.28,56.25,44.65,38.68,28.71,17.21.

[0166] Example 16: Chiral quinazolinone cyclic derivative 30c

[0167] Compound 30b was prepared from 7-methoxy-3H-quinazolin-4-one (30a) according to the method of Example 7. Then, compound 30c was prepared from compound 30b according to the method of Example 6, using SpO1a as the SPO source. Yield: 93%, ee value: 97%.

[0168]

[0169] 1H NMR (400MHz, CDCl3) δ8.19(d,J=8.0Hz,1H),7.13(d,J=4.0Hz,1H),7.04(d,J=8.0Hz,1H),4.28( m,1H),4.01(m,1H),3.93(s,3H),3.34(m,1H),2.49(m,1H),1.90(m,1H),1.50(d,J=8.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ164.44,163.16,160.61,151.54,127.81,116.29,114.16,107.63,55.64,44.52,38.86,28.61,17.20.

[0170] Example 17: Chiral quinazolinone cyclic derivative 31c

[0171]

[0172] Compound 31b was prepared from 7-fluoro-3H-quinazolin-4-one (31a) according to the method of Example 7. Then, compound 31c was prepared from compound 31b according to the preparation method of Example 6, using SpO1a as the SPO. Yield: 64%, ee value: 93%.

[0173] 1 H NMR (400MHz, CDCl3) δ8.30 (dd, J=8.0Hz, 4.0Hz, 1H), 7.35 (dd, J=8.0Hz, 4.0Hz, 1H), 7.17 (t, J=8. 0Hz,1H),4.28(m,1H),4.01(m,1H),3.33(m,1H),2.51(m,1H),1.90(m,1H),1.49(d,J=8.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ166.36 (d, J = 252Hz), 163.75, 160.31, 151.58 (d, J = 7Hz), 128.94 (d, J = 1 1Hz), 117.42 (d, J = 3Hz), 114.88 (d, J = 23Hz), 112.35 (d, J = 22Hz), 44.62, 38.90, 28.57, 17.10. 19 F NMR (377MHz, CDCl3) δ -104.07.

[0174] Example 18: Chiral quinazolinone cyclic derivative 32c

[0175]

[0176] Compound 32b was prepared from 7-methyl-3H-quinazolin-4-one (32c) according to the method of Example 7. Then, compound 32c was prepared from compound 32b according to the method of Example 6, using SpO1a as the SPO. Yield: 85%, ee value: 96%.

[0177] 1 H NMR (400MHz, CDCl3) δ8.17(d,J=8.0Hz,1H),7.50(s,1H),7.26(d,J=4.0Hz,1H),4.26(m,1H ),4.01(m,1H),3.32(m,1H),2.49(m,1H),2.48(s,3H),1.88(m,1H),1.48(d,J=8.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ162.51,160.94,149.26,145.08,127.81,126.65,126.18,118.22,44.54,38.76,28.60,21.86,17.24.

[0178] Example 19: Chiral quinazolinone cyclic derivative 33c

[0179]

[0180] Compound 33b was prepared from 6-fluoro-3H-quinazolin-4-one (33a) according to the method of Example 7. Then, compound 33c was prepared from compound 33b according to the preparation method of Example 6, using SpO1a as the SPO. Yield: 76%, ee value: 93%.

[0181] 1 H NMR (400MHz, CDCl3) δ7.91 (dd, J = 8.0Hz, 4.0Hz, 1H), 7.69 (dd, J = 8.0Hz, 4.0Hz, 1H), 7.45 (t, J = 8. 0Hz,1H),4.28(m,1H),4.00(m,1H),3.32(m,1H),2.50(m,1H),1.88(m,1H),1.48(d,J=8.0Hz,3H). 13C NMR (101MHz, CDCl3) δ161.77 (d, J = 4.0Hz), 160.53 (d, J = 247.0Hz), 160.28 (d, J = 3.0Hz), 145.98 (d, J = 2.0Hz), 129 .25(d,J=8.0Hz),122.53(d,J=14.0Hz),121.89(d,J=8.0Hz),111.21(d,J=21.0Hz),44.63,38.65,28.66,17.13.

[0182] Example 20: Chiral quinazolinone cyclic derivative 34c

[0183]

[0184] Compound 34b was prepared from methyl 7-carboxylate-3H-quinazolin-4-one (34a) according to the method of Example 7. Then, compound 34c was prepared from compound 34b according to the method of Example 6, using SpO1a as the SPO. Yield: 74%, ee value: 96%.

[0185] 1 H NMR (400MHz, CDCl3) δ8.40(d,J=4Hz,1H),8.34(d,J=8Hz,1H),8.06(d,J=8Hz,1H),4.31(m,1 H),4.04(m,1H),3.99(s,3H),3.37(m,1H),2.54(m,1H),1.93(m,1H),1.52(d,J=8.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ166.17,163.25,160.42,149.08,135.15,128.85,126.65,126.21,123.63,52.55,44.74,38.81,28.59,17.06.

[0186] Example 21: Chiral quinazolinone cyclic derivative 35c

[0187]

[0188] Compound 35b was prepared from 7-trifluoromethyl-3H-quinazolin-4-one (35a) according to the method of Example 7. Then, compound 35c was prepared from compound 35b according to the method of Example 6, using SpO1a as the SPO. Yield: 90%, ee value: 94%.

[0189] 1H NMR(400MHz, CDCl3) δ8.40(d,J=4.0Hz,1H),8.00(s,1H),7.66(d,J=8.0Hz,1H),4.3 2(m,1H),4.05(m,1H),3.36(m,1H),2.53(m,1H),1.92(m,1H),1.52(d,J=8.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ163.85, 160.17, 149.30, 135.57 (q, J=32.0Hz), 127.50, 126.40 (q, J= 305.0Hz), 124.64 (q, J=4.0Hz), 123.00, 122.20 (q, J=3.0Hz), 44.82, 38.90, 28.57, 17.00. 19 F NMR (377MHz, CDCl3) δ -63.16.

[0190] Example 22: Chiral quinazolinone cyclic derivative 36c

[0191]

[0192] Using 6-bromo-3H-quinazolin-4-one as a starting material, 1 mole of 6-bromo-3H-quinazolin-4-one, 1 mole of 4-methoxyphenylboronic acid, 1 mole of potassium phosphate, and 0.04 mole of Pd(dba)2 were added under nitrogen protection. Toluene was used as the solvent, and the reaction was carried out at 100°C for 12 h to obtain 6-(4-methoxyphenyl)-3H-quinazolin-4-one (36a). Using compound 36a as a starting material, compound 36b was prepared according to the method of Example 7. Then, according to the preparation method of Example 6, compound 36c was prepared from compound 36b, using SpO1a as the SPO. Yield: 90%, ee value: 94%.

[0193] 1 H NMR (400MHz, CDCl3) δ8.48(d,J=2.0Hz,1H),7.97(d,J=8.0Hz,1H),7.77(d,J=8.0Hz,1H),7.66(d,J=8.0Hz,2H),7.02 (d,J=8.0Hz,2H)4.32(m,1H),4.05(m,1H),3.89(s,3H),3.37(m,1H),2.53(m,1H),1.92(m,1H),1.52(d,J=8.0Hz,3H). 13C NMR (101MHz, CDCl3) δ162.10,161.09,159.52,147.94,138.75,132.63,132.15 ,128.23,127.33,123.50,120.88,114.40,55.39,44.66,38.77,28.65,17.26.

[0194] Example 23: Chiral quinazolinone cyclic derivative 37c

[0195]

[0196] Compound 37b was prepared from 6-methoxy-3H-quinazolin-4-one (37a) according to the method of Example 7. Then, compound 37c was prepared from compound 37b according to the method of Example 6, using SpO1a as the SPO. Yield: 95%, ee value: 97%.

[0197] 1 H NMR (400MHz, CDCl3) δ7.67-7.59(m,2H),7.32(d,J=8.0Hz,1H),4.28(m,1H),4.01( m,1H),3.92(s,3H),3.32(m,1H),2.49(m,1H),1.88(m,1H),1.49(d,J=8.0Hz,3H). 13 CNMR(101MHz, CDCl3)δ160.82,160.25,157.99,143.78,128.39,124.27,121.35,105.86,55.82,44.62,38.52,28.74,17.27.

[0198] Example 24: Chiral quinazolinone cyclic derivative 38c

[0199]

[0200] Using 6-bromo-3H-quinazolin-4-one as a starting material, under nitrogen protection, 1 mole of 6-bromo-3H-quinazolin-4-one, 1 mole of 2-thiopheneboric acid, 1 mole of potassium phosphate, and 0.04 mole of Pd(dba)2 were added. Toluene was used as a solvent, and the reaction was carried out at 100°C for 12 h to obtain 6-(2-thiophene)-3H-quinazolin-4-one (38a). Using compound 38a as a starting material, compound 38b was prepared according to the method of Example 7. Then, according to the preparation method of Example 6, compound 38c was prepared from compound 38b, using SpO1a as the SPO. Yield: 92%, ee value: 94%.

[0201] 1 H NMR (400MHz, CDCl3) δ8.51(d,J=4.0Hz,1H),7.99(d,J=8.0Hz,1H),7.73(d,J=8.0Hz,1H),7.46(d,J=4.0Hz,1H),7.35(d,J= 4.0Hz,1H),7.13(t,J=4.0Hz,1H),4.32(m,1H),4.06(m,1H),3.37(m,1H),2.53(m,1H),1.92(m,1H),1.52(d,J=8.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ162.37,160.80,148.28,143.03,132.58,131.78,128 .28,127.50,125.60,123.94,122.69,121.01,44.73,38.80,28.61,17.21.

[0202] Example 25: Chiral quinazolinone cyclic derivative 39c

[0203]

[0204] Using 6-bromo-3H-quinazolin-4-one as a starting material, 1 mole of 6-bromo-3H-quinazolin-4-one, 1 mole of 2-furanboric acid, 1 mole of potassium phosphate, and 0.04 mole of Pd(dba)2 were added under nitrogen protection. Toluene was used as the solvent, and the reaction was carried out at 100°C for 12 h to obtain 6-(2-furan)-3H-quinazolin-4-one (39a). Using compound 39a as a starting material, compound 39b was prepared according to the method of Example 7. Then, according to the preparation method of Example 6, compound 39c was prepared from compound 39b, using SpO1a as the SPO. Yield: 95%, ee value: 92%.

[0205] Example 26: Chiral quinazolinone cyclic derivative 40c

[0206]

[0207] Compound 40b was prepared from benzo[g]quinazolin-4-one (40a) according to the method of Example 7. Then, compound 40c was prepared from compound 40b according to the method of Example 6, using SPO1a. Yield: 77%, ee value: 90%.

[0208] 1H NMR (400MHz, CDCl3) δ8.90(s,1H),8.20(s,1H),8.06(d,J=8.0Hz,1H),7.98(d,J=8.0Hz,1H),7.60(t,J=8.0Hz,1H ),7.53(t,J=8.0Hz,1H),4.31(m,1H),4.04(m,1H),3.37(m,1H),2.52(m,1H),1.92(m,1H),1.54(d,J=8.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ161.72,161.43,144.35,136.57,131.24,129.31,128 .32,127.92,127.78,126.08,124.43,119.62,44.40,38.71,28.68,17.18.

[0209] Example 27: Chiral quinazolinone cyclic derivative 41c

[0210]

[0211] 10 moles of bromobenzene and 10 moles of magnesium were dispersed in 50 volumes of tetrahydrofuran and heated to 60°C for 2 h to prepare a phenylmagnesium bromide Grignard reagent. Then, 2,3-dihydrofuran was added to the system, and the mixture was stirred at room temperature for 8 h. After the reaction was complete, saturated ammonium chloride was added to quench the reaction, and (Z)-4-phenyl-3-en-1-butanol was obtained. 1 mole of (Z)-4-phenyl-3-en-1-butanol was dissolved in dichloromethane, and 1 mole of methanesulfonyl chloride and 1 mole of triethylamine were added. The mixture was stirred at room temperature for 2 h, and after the reaction was complete, water was added to quench the reaction, and the olefinic chain (Z)-4-phenyl-3-en-1-but-methanesulfonate was obtained.

[0212] Compound 41b was prepared by reacting (Z)-4-phenyl-3-ene-1-butanesulfonate with 3H-quinazolin-4-one (20a) as a starting material, following the method of Example 7. Then, compound 41c was prepared from compound 41b using the method of Example 6, with SPO2a as the SPO source. Yield: 87%, ee value: 70%.

[0213] 1H NMR (400MHz, CDCl3) δ8.32(d,J=8.0Hz,1H),7.79(d,J=4.0Hz,2H),7.49(m,1H),7.32(m,2H) ,7.27(m,3H),4.08(m,1H),3.98(m,1H),3.58(m,2H),2.91(m,1H),2.29(m,1H),2.01(m,1H). 13 C NMR (101MHz, CDCl3) δ161.04,160.92,149.11,138.45,134.19,129.03,128 .69,126.98,126.77,126.43,126.36,120.78,45.51,44.73,38.06,25.57.

[0214] Example 28: Chiral quinazolinone cyclic derivative 42c

[0215]

[0216] Dissolve 1 mole of (Z)-3-en-1-hexanol in dichloromethane, add 1 mole of methanesulfonyl chloride and 1 mole of triethylamine, stir at room temperature for 2 h, quench with water after the reaction is complete, and separate to obtain the olefin chain (Z)-3-en-1-hex-methanesulfonate.

[0217] Compound 42b was prepared by reacting (Z)-3-ene-1-hexane-methanesulfonate with 3H-quinazolin-4-one (20a) as a starting material, following the method of Example 7. Then, compound 42c was prepared from compound 42b using the method of Example 6, with SPO1a as the SPO source. Yield: 66%, ee value: 94%;

[0218] 1 H NMR (400MHz, CDCl3) δ8.31(dd,J=8.1,1.4Hz,1H),7.78–7.67(m,2H),7.46(ddd,J=8.1,6.6,1.7Hz,1H),4.28(ddd,J=12.3,8.7,4.4Hz,1H),4 .05(dt,J=12.3,7.9Hz,1H),3.32–3.20(m,1H),2.53–2.42(m,1H),2.2 1–2.09(m,1H),1.94(m,1H),1.65–1.49(m,3H),1.03(t,J=7.2Hz,3H). 13C NMR (101MHz, CDCl3) δ162.03,160.98,149.14,134.08,126.93,126.38,126.19,120.76,44.88,43.85,34.40,26.20,20.46,13.98.

[0219] Example 29: Chiral pyrimidinone cyclic derivative 43c

[0220]

[0221] Compound 43b was prepared from 6-methyl-3H-pyrimidin-4-one (43a) according to the method of Example 7. Then, compound 43c was prepared from compound 43b according to the method of Example 6, using SPO2a. Yield: 84%, ee value: 50%;

[0222] 1 H NMR (400MHz, CDCl3) δ6.16(s,1H),4.18(m,1H),3.96(m,1H),3.27(m,1H),2.48(m,1H),2.32(s,3H),1.84(m,1H),1.43(d,J=8.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ166.43,165.03,161.57,110.06,44.83,38.99,28.12,23.76,17.27.

[0223] Example 30: Chiral quinazolinone cyclic derivative 44c

[0224]

[0225] Ten moles of 3-phenylbromopropane and ten moles of magnesium were dispersed in 50 volumes of tetrahydrofuran and heated to 60°C for 2 hours to prepare a phenylpropyl magnesium bromide Grignard reagent. Then, 2,3-dihydrofuran was added to the system, and the mixture was stirred at room temperature for 8 hours. After the reaction was complete, saturated ammonium chloride was added to quench the reaction, and (Z)-7-phenyl-3-en-1-heptanol was obtained. One mole of (Z)-7-phenyl-3-en-1-heptanol was dissolved in dichloromethane, and one mole of methanesulfonyl chloride and one mole of triethylamine were added. The mixture was stirred at room temperature for 2 hours, and after the reaction was complete, water was added to quench the reaction, and the olefinic chain (Z)-7-phenyl-3-en-1-heptan-methanesulfonate was obtained.

[0226] Compound 44b was prepared by reacting (Z)-7-phenyl-3-ene-1-heptane-methanesulfonate with compound 20a as a starting material, following the method of Example 7. Then, compound 44c was prepared from compound 44b as a starting material, following the preparation method of Example 6, using SpO1a as the SPO. Yield: 81%, ee value: 93%;

[0227] 1 H NMR (400MHz, CDCl3) δ8.30(d,J=8.0Hz,1H),7.74(m,2H),7.47(t,J=8.0Hz,1H),7.30(m,2H),7.22(m,3H),4.26(m,1H) ,4.04(m,1H),3.26(m,1H),2.69(m,2H),2.45(m,1H),2.22(m,1H),1.92(m,1H),1.75(m,2H),1.65(m,1H),1.55(m,2H). 13 C NMR (101MHz, CDCl3) δ161.78,161.02,149.21,142.30,134.10,128.39,128.32,126.9 7,126.37,126.21,125.76,120.72,44.85,43.96,35.71,32.12,31.23,26.78,26.22.

[0228] Example 31: Chiral quinazolinone cyclic derivative 45c

[0229]

[0230] Dissolve 1 mole of (Z)-3-en-1-pentanol in dichloromethane, add 1 mole of methanesulfonyl chloride and 1 mole of triethylamine, stir at room temperature for 2 h, quench with water after the reaction is complete, and separate to obtain the olefin chain (Z)-3-en-1-pentan-methanesulfonate.

[0231]

[0232] Compound 45b was prepared by reacting compound 20a with (Z)-3-ene-1-hexyl-methanesulfonate according to the method of Example 7. Then, compound 45c was prepared from compound 45b using the method of Example 6, with SpO1a as the SPO source. Yield: 90%, ee value: 89%;

[0233] 1H NMR(400MHz, CDCl3)δ8.31(d,J=8.0Hz,1H),7.80-7.66(m,2H),7.46(t,J=8.0Hz,1H),4.26(m,1H),4 .04(m,1H),3.20(m,1H),2.47(m,1H),2.17(m,1H),1.95(m,1H),1.68(m,1H),1.11(t,J=8.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ161.67,161.08,149.35,134.06,127.02,126.34,126.15,120.73,45.33,44.83,25.66,25.35,11.47.

[0234] Example 32: Chiral quinazolinone cyclic derivative 46c

[0235]

[0236] Using 6-bromo-3H-quinazolin-4-one as a starting material, under nitrogen protection, 1 mole of 6-bromo-3H-quinazolin-4-one, 1 mole of morpholine, 1 mole of potassium phosphate, 0.04 mole of Pd(dba)2, and 0.04 mole of BINAP were added, with toluene as the solvent. The reaction was carried out at 100°C for 12 h, and 6-morpholin-3H-quinazolin-4-one (46a) was obtained by separation. Using compound 46a as a starting material, compound 46b was prepared according to the method of Example 7. Then, according to the preparation method of Example 6, compound 46c was prepared from compound 46b, using SpO1a as the SPO. Yield: 93%, ee value: 93%.

[0237] Example 33: Chiral quinazolinone cyclic derivative 47c

[0238]

[0239] Using 6-bromo-3H-quinazolin-4-one as a starting material, under nitrogen protection, 1 mole of 6-bromo-3H-quinazolin-4-one, 1 mole of pyridine-3-boric acid, 1 mole of potassium phosphate, 0.04 mole of Pd(dba)2, and 0.04 mole of S-Phos were added. Toluene was used as a solvent, and the reaction was carried out at 100°C for 12 h, yielding 6-(3-pyridine)-3H-quinazolin-4-one (47a). Using compound 47a as a starting material, compound 47b was prepared according to the method of Example 7. Then, following the preparation method of Example 6, compound 47c was prepared from compound 47b, using SpO1a as the SPO. Yield: 73%, ee value: 90%.

[0240] Example 34: Chiral quinazolinone cyclic derivative 48c

[0241]

[0242] Using 6-bromo-3H-quinazolin-4-one as a starting material, under nitrogen protection, 1 mole of 6-bromo-3H-quinazolin-4-one, 1 mole of N-methylpyrrole-2-boric acid, 1 mole of potassium phosphate, 0.04 mole of Pd(dba)2, and 0.04 mole of S-Phos were added. Toluene was used as a solvent, and the reaction was carried out at 100°C for 12 h. 6-(N-methylpyrrole-2)-3H-quinazolin-4-one (48a) was obtained by separation. Using compound 48a as a starting material, compound 48b was prepared according to the method of Example 7. Then, following the preparation method of Example 6, compound 48c was prepared from compound 48b, using SpO1a as the SPO. Yield: 83%, ee value: 87%.

[0243] Example 35: Chiral quinazolinone cyclic derivative 49c

[0244]

[0245] One mole of (Z)-5-(3,5-difluorophenyl)pent-3-en-1-ol was dissolved in dichloromethane, and one mole of methanesulfonyl chloride and one mole of triethylamine were added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added to quench the reaction, and the olefin chain (Z)-5-(3,5-difluorophenyl)pent-3-en-1-methanesulfonate was obtained. Using compound 20a as a starting material, compound 49b was prepared by reacting it with (Z)-5-(3,5-difluorophenyl)pent-3-en-1-methanesulfonate according to the method of Example 7. Then, compound 49c was prepared from compound 49b according to the preparation method of Example 6, using SpO1a as the SPO. Yield: 90%, ee value: 87%.

[0246] 1 H NMR (400MHz, CDCl3) δ8.31(dd,J=8.0,1.5Hz,1H),7.80–7.67(m,2H),7.51–7.44(m,1H),6.90–6.77(m,2H),6.68(td,J=6.7,3.4Hz,1H),4.32(ddd, J=12.5,8.8,3.8Hz,1H),4.05(ddd,J=12.4,7.5,4.3Hz,1H),3.27(td,J= 8.7,5.2Hz,1H),2.96–2.81(m,2H),2.57–2.43(m,2H),2.09–1.83(m,2H). 13C NMR (151MHz, CDCl3) δ163.97,163.88,162.32,162.24,161.07,160.91,148.96,146.52,145.08,145.02,144.96,134.23,12 6.96,126.43,126.42,120.72,111.40,111.36,111.27,111.24,101.88,101.71,101.54,44.77,42.99,33.33,33.06,26.48. 19 F NMR (377MHz, CDCl3) δ-110.22.

[0247] Example 36: Activity test of quinazolinone cyclic derivatives

[0248] This invention relates to a cell viability assay for reversing acetaminophen (APAP) and alcohol-induced liver injury using chiral quinazolinone cyclic derivatives and their racemic mixtures. APAP is a common antipyretic and analgesic drug, and also a common cause of liver failure, making it a frequently used model for reversing liver injury. Improper alcohol consumption is also one of the most common causes of liver injury, and the hepatocellular alcohol injury model is the most common in vitro model for investigating alcohol-induced liver injury (AILI). The assay was performed using the CCK-8 assay. CCK-8 is short for Cell Counting Kit-8, a kit based on WST-8 (chemical name: 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfonylbenzene)-2H-tetrazole monosodium salt) widely used for rapid and highly sensitive detection of cell proliferation and cytotoxicity. WST-8 is an upgraded product of MTT. Its working principle is as follows: in the presence of an electron coupling reagent, it can be reduced by mitochondrial dehydrogenases to generate a highly water-soluble, orange-yellow formazan product. The intensity of the color is directly proportional to cell proliferation and inversely proportional to cytotoxicity. The OD value is measured at 450 nm using a microplate reader, indirectly reflecting the number of viable cells. N-acetyl-L-cysteine ​​(NAC) is a commonly used drug in clinical practice to reverse APAP and alcoholic liver injury. The commonly used dose for treating liver injury is 5 mM; therefore, the concentration of NAC in the control group of the following tests is 5 mM.

[0249] Specific test content: For the APAP-induced liver injury model, human hepatocytes L02 (Shanghai Cell Bank, Chinese Academy of Sciences) were seeded into 96-well plates. 4First, cells were cultured at 37℃ and 5% CO2 for 24 hours. Then, either the target compound at a given concentration or 5 mM of the positive control NAC was added for 6 hours, followed by culture in medium containing 10 mM APAP for another 24 hours. Finally, CCK-8 reagent was added, and the cells were cultured for another 1 hour. After treatment, the OD value was measured at 450 nm using a microplate reader to determine the final cell viability. Cell viability was calculated as the ratio of the OD value of the treated group to that of the normal group (with the normal cell group as the Control group and cell viability set at 100%). The results are shown below. Figure 1 A- Figure 1 D. For the in vitro model of alcohol-dependent liver injury induced by L02, the method was the same as that for the APAP-induced liver injury model. The alcohol concentration was 400 mM, and the concentrations of the tested compounds and NAC were the same as those used in drug-induced liver injury. The results are shown in [Figure number missing]. Figure 1 E- Figure 1 F.

[0250] Depend on Figure 1 As can be seen from A, compared to the blank control group (APAP group), the chiral quinazolinone / pyrimidinone cyclic derivative (S configuration) of the present invention exhibited a protective effect similar to that of 5 mM NAC at a concentration of 20 μM in the activity test. For most of the tested structural compounds, the cell survival rate after administration was higher than that of NAC, indicating higher activity. This shows that compared to the positive control drug NAC, the chiral quinazolinone / pyrimidinone cyclic derivative or its racemic form of the present invention can have a better protective and reversal effect against APAP-induced liver injury at lower administered concentrations. Figure 1 As shown in Figure B, even at concentrations lower than 20 μM (10 μM), the chiral quinazolinone / pyrimidinone cyclic compounds (S configuration) at 25c, 28c, 31c, 33c, and 40c still provided high cell viability, indicating that these compounds remained effective at 10 μM. Figure 1 As can be seen from C, further reducing the concentration, at 5 μM, the 25c, 28c, 31c, 33c, and 40c (all S conformations) still showed high cell viability, although the activity of 25c decreased slightly at the low concentration of 5 μM. Comparison with the corresponding racemic mixtures revealed that the racemic mixtures also exhibited good protective and reversal activities, but the S conformation showed superior activity. Furthermore, from... Figure 1 As can be seen from D, the S configurations of 25c, 28c, 31c, 33c, and 40c are the most active configurations, while their racemic forms are intermediate. The R configuration has lower activity than the S configuration and the racemic form, but still exhibits good protective and reversal effects against liver injury. In the anti-alcohol-dependent liver injury activity test, [the following text appears to be incomplete and requires further context: "by..."] Figure 1As shown in Figure E, compared to the blank control group AILI, the chiral quinazolinone / pyrimidinone cyclic derivative (S configuration) of this invention, at a concentration of 20 μM, exhibited a protective effect similar to that of 5 mM NAC. Most of the compounds in the figure showed higher cell viability after administration than NAC, indicating better activity. Figure 1 As can be seen from F, similar to the APAP model, the S configuration of 25c, 28c, 31c, 33c, and 40c is the configuration with the best activity, the racemic version is in the middle, and the R configuration has lower activity than the S configuration and the racemic version, but still has good protective and reversal activity against liver injury.

[0251] The above results indicate that both the chiral and racemic products of this invention exhibit significant protective and reversal effects against APAP- and alcohol-induced hepatocyte damage.

[0252] The above embodiments of the present invention demonstrate that, using the sterically hindered SPO ligand of the present invention for Ni-Al bimetallic catalytic alkylation of olefins (CH cyclization), a series of chiral quinazolinone / pyrimidinone cyclic compounds can be synthesized simply and efficiently. Based on known principles, corresponding racemic compounds can be obtained using appropriate racemic ligands. Furthermore, the preparation method of the present invention has advantages such as low cost, simple operation, mild conditions, high reactivity, high yield, and high enantioselectivity of asymmetric catalysis. In vitro cell model experiments show that the chiral quinazolinone / pyrimidinone cyclic compounds of the present invention and their racemates exhibit excellent biological activity in protecting against and reversing hepatocyte injury.

[0253] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A class of chiral, sterically hindered, secondary phosphonooxides, characterized in that... Compounds having one of the structures shown in SPO1 and SPO2, or their enantiomers or racemates: ； SPO1 SPO2 Where: R 1 It is at least one of hydrogen, substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C3-20 cycloalkyl, substituted or unsubstituted C4-20 heterocyclic, substituted or unsubstituted C6-20 aryl, substituted or unsubstituted C1-20 hydroxyl group, halogen, -Bn, -CF3, -NO2, or substituted amino; R 2 R 3 R 4 R represents one or more groups on a benzene ring in which hydrogen atoms have been substituted. 2 R 3 R 4 The same or different are at least one of the following: hydrogen, substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C3-20 cycloalkyl, substituted or unsubstituted C4-20 heterocyclic, substituted or unsubstituted C6-20 aryl, substituted or unsubstituted C1-20 hydroxyl group, substituted or unsubstituted C1-C20 acyl, substituted or unsubstituted C1-C20 amide, substituted or unsubstituted C2-C20 hydroxyoxycarbonyl, substituted or unsubstituted C2-C20 aminoacyl, halogen, -Bn, -CF3, -NO2, -OH, and substituted amino; or R 2 R 3 R 4 The same or different carbon atoms are connected to one or more carbon atoms on the benzene ring to form a ring, resulting in substituted or unsubstituted C10-C26 fused ring aromatic hydrocarbon structures; The substitution of the same or different refers to the substitution of one or more hydrogen atoms in a group by a halogen, a C1-20 alkyl, a C3-20 cycloalkyl, a C4-20 heterocyclic group, a C6-20 aryl, a C1-20 hydroxyl group, -CF3, -NO2, -OH, or a C1-10 substituted amino group.

2. The chiral, sterically hindered, second-order phosphonooxide compound according to claim 1, characterized in that... The chiral, sterically hindered secondary phosphonooxide compound is a compound having one of the structures shown in SpO1 and SpO2, or its enantiomer or racemate, wherein R 1 It is at least one of hydrogen, methyl, ethyl, substituted or unsubstituted C3-20 alkyl, vinyl, substituted or unsubstituted C3-10 alkenyl, substituted or unsubstituted C3-20 cycloalkyl, substituted or unsubstituted C4-20 heterocyclic, substituted or unsubstituted benzene ring, substituted or unsubstituted C7-20 aryl, methoxy, ethoxy, substituted or unsubstituted C3-20 hydroxyl, -F, -Cl, -Br, -I, -CF3, -Bn, -NO2, and substituted amino; R 2 R 3 R 4 R represents one or more groups on a benzene ring in which hydrogen atoms have been substituted. 2 R 3 R 4 The same or different are hydrogen, methyl, ethyl, substituted or unsubstituted C3-20 alkyl, vinyl, substituted or unsubstituted C3-10 alkenyl, substituted or unsubstituted C3-20 cycloalkyl, substituted or unsubstituted C4-20 heterocyclic, substituted or unsubstituted benzene ring, substituted or unsubstituted C7-20 aryl, methoxy, ethoxy, substituted or unsubstituted C3-20 hydroxyl, substituted or unsubstituted formyl, substituted or unsubstituted acetyl, substituted Or at least one of the following: unsubstituted C3-C20 acyl group, substituted or unsubstituted formamid group, substituted or unsubstituted acetamido group, substituted or unsubstituted C3-C20 amide group, substituted or unsubstituted methoxycarbonyl group, substituted or unsubstituted ethoxycarbonyl group, substituted or unsubstituted C4-C20 hydroxycarbonyl group, substituted or unsubstituted C2-C20 aminoacyl group, -F, -Cl, -Br, -I, -CF3, -Bn, -NO2, -OH, substituted amino group; or R 2 R 3 R 4 The same or different groups are respectively connected to one or more carbon atoms on the aromatic ring to form a ring, resulting in substituted or unsubstituted naphthyl, anthracene, or phenanthrene groups; The substitution of the same or different refers to the substitution of one or more hydrogen atoms in a group by a halogen, a C1-20 alkyl, a C3-20 cycloalkyl, a C4-20 heterocyclic group, a C6-20 aryl, a C1-20 hydroxyl group, -CF3, -NO2, -OH, or a C1-10 substituted amino group.

3. The chiral, sterically hindered, secondary phosphine oxide compound according to any one of claims 1-2, characterized in that: The substitution of the same or different refers to the substitution of one or more hydrogen atoms in a group by a group of -F, -Cl, -Br, -I, methyl, ethyl, propyl, C4-20 alkyl, cyclopropane, C4-20 cycloalkyl, C4-20 heterocyclic, phenyl, C7-20 aryl, methoxy, ethoxy, C3-20 alkyloxy, -CF3, -NO2, -OH, dimethylamino, diethylamino, or diisopropylamino.

4. The method for preparing the chiral, sterically hindered secondary phosphine oxide compound according to any one of claims 1-3, characterized in that: When a chiral sterically hindered secondary phosphine oxide has an SpO1 structure, it is prepared by condensing a chiral amine with glyoxal in reaction A to generate a diimine compound. The diimine compound is then reduced in reaction B to generate a diamine, which is then subjected to a substitution reaction C with phosphorus trihalide and hydrolyzed to obtain the chiral sterically hindered secondary phosphine oxide. The chiral amine is shown in the following structural formula or its enantiomer or racemate: ； When a chiral, sterically hindered secondary phosphonooxide has an SpO2 structure, it is prepared by hydrolysis after a substitution reaction with a chiral 1,2-diphenylethylenediamine compound, followed by a substitution reaction with a diaryl halomethane, and then a disubstituted reaction with a phosphorus trihalide. The chiral 1,2-diphenylethylenediamine compound has the following structural formula or its enantiomer or racemate: 。 5. The application of the chiral, sterically hindered secondary phosphine oxide compound according to any one of claims 1-3 in the catalytic CH alkylation reaction.

6. A chiral quinazolinone / pyrimidinone cyclic derivative obtained by catalytic reaction of a chiral, sterically hindered secondary phosphine oxide according to any one of claims 1-3, characterized in that: The chiral quinazolinone / pyrimidinone cyclic derivative is a compound or its enantiomer having the structure shown below: ； Where n is the number of carbons in the olefin chain, which is 1; R 5 This refers to one or more groups on an aromatic ring in which hydrogen atoms are substituted, selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C2-16 saturated heterocyclic, C1-16 alkyloxy, -CF3, nitro, -OH, C2-10 carbonyl, C2-10 amide, C2-10 alkyloxycarbonyl, C1-C10 dialkyl-substituted amino, C6-14 aryl, C4-15 substituents with a furan structure, C4-15 substituents with a thiophene structure, C4-15 substituents with a pyrrole structure, and C5-15 substituents with a pyridine structure; or R 5 The aromatic ring is linked to one or more carbon atoms to form a cyclic ring, resulting in a C6-15 fused-ring aromatic hydrocarbon structure; or R 5 The above-mentioned groups are formed by cyclically connecting one or more carbon atoms on an aromatic ring to obtain a C5-15 heterocyclic group or heterocyclic aryl group containing one or more of N, O and S; and the above-mentioned groups having one or more secondary substituents. R 6 R 7 The same or different groups are selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C3-10 cycloalkyl, C2-10 amide, and -COR, respectively. 8 -SO2R 9 C7-14 aralkyl groups, C4-14 heteroaryl-substituted alkyl groups or saturated heterocyclic-substituted alkyl groups, and the above groups having one or more secondary substituents; The secondary substituent, R 8 and R 9 The same or different ones are selected from halogens, C1-10 alkyl groups, C2-10 alkenyl groups, C2-10 alkynyl groups, C1-10 hydroxyl groups, -CF3, -OH, nitro groups, C6-14 aryl groups, and substituted amino groups.

7. The chiral quinazolinone / pyrimidinone cyclic derivative of claim 6, characterized in that: R 5 A group on one or more aromatic rings in which hydrogen is substituted, selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, C4-10 alkyl, vinyl, propenyl, C4-10 alkenyl, ethynyl, propynyl, C4-10 alkynyl, cyclopropane, C4-10 cycloalkyl, C2-16 saturated heterocyclic groups, methoxy, ethoxy, C3-16 alkyloxy, -CF3, nitro, -OH, ethoxycarbonyl, propenyl, C4-10 carbonyl, acetamido, propamido, C4-10 amide, methoxycarbonyl, ethoxycarbonyl, C4-10 alkyloxycarbonyl, phenyl, C7-14 aryl, furanyl, thiophene, pyrrole, pyridinyl, morpholinyl, piperazine, piperidinyl, pyrrolealkyl, or R 5 Fused ring aromatic hydrocarbon structures of naphthalene, anthracene, or phenanthrene obtained by linking more than one carbon atom to an aromatic ring; or R 5 The above-mentioned groups are formed by linking one or more carbon atoms on an aromatic ring to obtain a C5-15 heterocyclic group or heterocyclic aryl group containing one or more of N, O and S; and the above-mentioned groups having one or more secondary substituents. R 6 R 7 The same or different are selected from hydrogen, methyl, ethyl, propyl, C4-10 alkyl, vinyl, propenyl, C4-10 alkenyl, cyclopropane, C4-10 cycloalkyl, -COR 9 -SO2R 10 , benzyl, phenethyl, phenylpropyl, phenylbutyl, C11-14 phenylalkyl, C4-14 heteroaryl-substituted alkyl or saturated heterocyclic-substituted alkyl, and the above groups having one or more secondary substituents; The secondary substituent, R 9 and R 10 The same or different ones are selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl, C4-10 alkyl, vinyl, propenyl, C4-10 alkenyl, ethynyl, propynyl, C4-10 alkynyl, methoxy, ethoxy, C3-10 alkyloxy, -CF3, -OH, nitro, phenyl, benzyl, C8-14 aryl, substituted amino.

8. A method for preparing a chiral quinazolinone / pyrimidinone cyclic derivative or its racemic form, characterized in that: Using quinazoline-4-one or pyrimidin-4-one with N-3-olefin chain substituted as raw material, and the chiral sterically hindered secondary phosphine oxide compound as described in any one of claims 1-3 as ligand, a Ni-Al bimetallic catalytic system is used to catalyze the reaction to obtain chiral quinazoline / pyrimidinone cyclic derivatives or their racemates. The structural formulas of the N-3-olefin chain-substituted quinazolin-4-one or N-3-olefin chain-substituted pyrimidin-4-one are as follows: ； Where n is 1; The chiral quinazolinone / pyrimidinone cyclic derivative is a compound having one of the following structures or an enantiomer thereof: ； R 5 This refers to one or more groups on an aromatic ring in which hydrogen atoms are substituted, selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C2-16 saturated heterocyclic, C1-16 alkyloxy, -CF3, nitro, -OH, C2-10 carbonyl, C2-10 amide, C2-10 alkyloxycarbonyl, C1-C10 dialkyl-substituted amino, C6-14 aryl, C4-15 substituents with a furan structure, C4-15 substituents with a thiophene structure, C4-15 substituents with a pyrrole structure, and C5-15 substituents with a pyridine structure; or R 5 The aromatic ring is linked to one or more carbon atoms to form a cyclic ring, resulting in a C6-15 fused-ring aromatic hydrocarbon structure; or R 5 The above-mentioned groups are formed by cyclically connecting one or more carbon atoms on an aromatic ring to obtain a C5-15 heterocyclic group or heterocyclic aryl group containing one or more of N, O and S; and the above-mentioned groups having one or more secondary substituents. R 6 R 7 The same or different groups are selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C3-10 cycloalkyl, C2-10 amide, and -COR, respectively. 8 -SO2R 9 C7-14 aralkyl groups, C4-14 heteroaryl-substituted alkyl groups or saturated heterocyclic-substituted alkyl groups, and the above groups having one or more secondary substituents; The secondary substituents, R 8 and R 9 The same or different ones are selected from halogens, C1-10 alkyl groups, C2-10 alkenyl groups, C2-10 alkynyl groups, C1-10 hydroxyl groups, -CF3, -OH, nitro groups, C6-14 aryl groups, and substituted amino groups.

9. Use of chiral quinazolinone / pyrimidinone cyclic derivatives or their racemates or pharmaceutically acceptable salts in the preparation of medicaments for the prevention or treatment of liver injury; The chiral quinazolinone / pyrimidinone cyclic derivative is a compound having one of the following structures or an enantiomer thereof: ； in, n is 1; R 5 This refers to one or more groups on an aromatic ring in which hydrogen atoms are substituted, selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C2-16 saturated heterocyclic, C1-16 alkyloxy, -CF3, nitro, -OH, C2-10 carbonyl, C2-10 amide, C2-10 alkyloxycarbonyl, C1-C10 dialkyl-substituted amino, C6-14 aryl, C4-15 substituents with a furan structure, C4-15 substituents with a thiophene structure, C4-15 substituents with a pyrrole structure, and C5-15 substituents with a pyridine structure; or R 5 The aromatic ring is linked to one or more carbon atoms to form a cyclic ring, resulting in a C6-15 fused-ring aromatic hydrocarbon structure; or R 5 The above-mentioned groups are formed by cyclically connecting one or more carbon atoms on an aromatic ring to obtain a C5-15 heterocyclic group or heterocyclic aryl group containing one or more of N, O and S; and the above-mentioned groups having one or more secondary substituents. R 6 R 7 The same or different groups are selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C3-10 cycloalkyl, C2-10 amide, and -COR, respectively. 8 -SO2R 9 C7-14 aralkyl groups, C4-14 heteroaryl-substituted alkyl groups or saturated heterocyclic-substituted alkyl groups, and the above groups having one or more secondary substituents; The secondary substituents, R 8 and R 9 The same or different ones are selected from halogens, C1-10 alkyl groups, C2-10 alkenyl groups, C2-10 alkynyl groups, C1-10 hydroxyl groups, -CF3, -OH, nitro groups, C6-14 aryl groups, and substituted amino groups.

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