Chiral or racemic pyrimidine-7-membered oxygen-nitrogen heterocyclic compounds, their preparation methods and applications

Abstract

This invention belongs to the field of organic synthesis and chemical catalysis technology, and discloses a class of chiral or racemic pyrimidine-7-membered oxonium heterocyclic compounds or their pharmaceutically acceptable salts, with the structural formula shown in Formula I; wherein, the carbon atoms marked with * are chiral carbon atoms with configurations of R, S, or R / S; the pyrimidine-7-membered oxonium heterocyclic compounds are levorotatory, dextrorotatory, or racemic; the chiral or racemic pyrimidine-7-membered oxonium heterocyclic compounds or their pharmaceutically acceptable salts of this invention are synthesized with high efficiency, high regioselectivity, and high enantioselectivity by using an iridium-phosphoramide ligand complex as a catalyst, from specially designed and synthesized allyl substrates via intramolecular allyl-catalyzed etherification reaction; they exhibit good in vitro and in vivo Alzheimer's disease inhibitory activity and can be used to prepare drugs or lead compounds for the prevention or treatment of Alzheimer's disease.

Description

Technical Field

[0001] This invention belongs to the field of chiral compound synthesis technology, and relates to a class of chiral or racemic pyrimidine-7-membered oxygen-nitrogen heterocyclic compounds, their preparation methods and applications. Background Technology

[0002] Compounds with good anti-Alzheimer's activity are of great value in the preparation of drugs for the prevention or treatment of Alzheimer's disease and its complications. The existing range of anti-Alzheimer's drugs is limited and cannot meet the needs of patients; therefore, there is an urgent need to develop more compounds with anti-Alzheimer's activity.

[0003] Carbon-heteroatom bonding reactions and their molecular skeleton construction strategies are among the main research areas in organic synthetic chemistry, playing a crucial role in the rapid and efficient synthesis of complex natural product molecules or the establishment of libraries of bioactive compounds. Among these, the study of asymmetric allylation reactions has seen rapid development in recent years, with various chiral monophosphine, bisphosphine, phosphine nitrogen, phosphine oxygen, dinitrogen, and nitrogen-sulfur ligands being applied to these reactions. Simultaneously, research has revealed that transition metal-catalyzed allylic substitution reactions possess unique properties; for example, allylic compounds containing terminal olefins can generate branched products with high regioselectivity. John F. Hartwig's group has conducted a relatively systematic study on the mechanism of asymmetric allylic substitution reactions, while You Shuli's group has focused on the study of metal complex-catalyzed allylic substitution reactions, achieving excellent results in expanding the types of nucleophiles, designing new ligands, and understanding reaction mechanisms. With further research, chemists have discovered that chiral phosphoramide ligands are relatively good ligands for asymmetric allylation reactions, forming catalysts with the central active metal Ir, effectively catalyzing these reactions. To date, transition metal-catalyzed allylation reactions, including amination, etherification, and dearomatization, can effectively construct CX (X = S, O, N, etc.) bonds, synthesizing many chiral polycyclic compounds widely found in natural products and pharmaceutical active molecules with high regioselectivity and enantioselectivity. Catalytic asymmetric allylation is an emerging environmentally friendly and atom-economical synthetic strategy for constructing new compounds. However, the types of effective chiral ligands and catalysts are still relatively limited, catalytic activity needs further improvement, and reported pathways and successful examples for constructing chiral heterocyclic compounds are very limited. The types of substrates and the synthesis of novel chiral compounds need further expansion. Therefore, in-depth research on the construction of chiral heterocyclic compounds based on this reaction has significant theoretical importance and broad application value.

[0004] Alzheimer's disease (AD) is a progressive, fatal, degenerative disease of the central nervous system, clinically characterized by a continuous decline in cognitive and memory function, a progressive decrease in daily living abilities, and various neuropsychiatric symptoms and behavioral disorders. Extracellular senile plaques composed of β-amyloid peptide (Aβ) and intracellular neurofibrillary tangles composed of abnormally phosphorylated tau protein are two typical pathological features of AD. Currently, the main drugs for treating AD include acetylcholinesterase (AChE) inhibitors and NMDA antagonists, but these can only alleviate cognitive impairment in early-stage patients, providing moderate symptom improvement, and cannot stop disease progression. Furthermore, the novel monoclonal antibody solanezumab, targeting Aβ, one of the main pathological features of AD, was declared ineffective in a phase III clinical trial in 2018. Therefore, there are currently no effective drugs for treating AD.

[0005] Pyrimidine-chiral heterocyclic compounds are important structural units in drug molecules and natural products, and also crucial pharmacophores in drug development. Drugs containing this type of structure exhibit diverse combinatorial biological activities and possess significant medicinal value in areas such as antihistamine, anti-inflammatory, anti-Alzheimer's disease, anti-schizophrenia, and anticancer activities. Given the unique structural characteristics, pharmacological activities, and wide-ranging applications of pyrimidine-chiral heterocyclic compounds, their synthesis and applications in chemistry and medicine have attracted increasing attention. However, to date, reports on the efficient synthesis of pyrimidine-chiral heterocyclic compounds remain very limited. Furthermore, reports on the synthesis of pyrimidine-chiral heterocyclic compounds using asymmetric catalysis are also scarce. There are no precedents for directly synthesizing pyrimidine-chiral seven-membered oxygen-nitrogen heterocyclic compounds and introducing chiral centers through asymmetric catalytic reactions. 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 or racemic pyrimidine and seven-membered oxygen-nitrogen heterocyclic compounds or pharmaceutically acceptable salts thereof.

[0007] The pyrimidine-7-membered oxygen-nitrogen heterocyclic compounds of the present invention can be levorotatory, dextrorotatory, or racemic. The levorotatory is a pure levorotatory product or a mixture of enantiomers in excess of levorotatory. The dextrorotatory is a pure dextrorotatory product or a mixture of enantiomers in excess of dextrorotatory. The racemic is an enantiomer mixture with an ee value of 0.

[0008] Another object of the present invention is to provide a method for preparing the above-mentioned chiral or racemic pyrimidine-7-membered oxygen-nitrogen heterocyclic compounds. The method of the present invention enables the efficient and highly enantioselective synthesis of optically active centrally chiral pyrimidine-7-membered oxygen-nitrogen heterocyclic compounds.

[0009] The present invention provides a method for preparing chiral pyrimidine-7-membered oxygen-nitrogen heterocyclic compounds and their enantiomers or racemates via intramolecular allyl-catalyzed etherification using allyl compounds as substrates. Specifically, the method utilizes iridium-phosphoramide ligand complexes as catalysts and specially designed allyl compounds as substrates to efficiently and with high enantioselectivity synthesize chiral pyrimidine-7-membered oxygen-nitrogen heterocyclic compounds via intramolecular allyl etherification. The enantiomers are obtained by preparing corresponding catalysts from ligands with opposite configurations and undergoing similar intramolecular allyl etherification catalytic reactions. The racemates are obtained by preparing corresponding catalysts from racemic ligands and undergoing similar intramolecular allyl etherification catalytic reactions.

[0010] Another object of the present invention is to provide the use of the above-mentioned pyrimidine-7-membered oxo-nitrogen heterocyclic compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments or lead compounds for the prevention or treatment of Alzheimer's disease.

[0011] The objective of this invention is achieved through the following solution:

[0012] A class of chiral or racemic pyrimidine-7-membered oxo-nitrogen heterocyclic compounds or pharmaceutically acceptable salts thereof, having the structural formula shown in Formula I; wherein, the carbon atom marked with * is a chiral carbon atom with a configuration of R, S or R / S; the pyrimidine-7-membered oxo-nitrogen heterocyclic compound is a levorotatory, dextrorotatory or racemic form;

[0013]

[0014] Among them, R 1 R 2 Individually selected from hydrogen, halogen atoms, hydroxyl, carboxyl, cyano, nitro, amino, mercapto, substituted or unsubstituted C1-C20 alkyl thiols, substituted or unsubstituted C1-C20 straight-chain or branched alkyl groups, C1-C20 fluoroalkyl groups, substituted or unsubstituted C1-C20 alkyloxy groups, substituted or unsubstituted benzyl groups, substituted or unsubstituted benzyloxy groups, substituted or unsubstituted C3-C20 cycloalkyl groups, substituted or unsubstituted C1-C20 N-alkyl-substituted amino groups, etc. The following are substituted or unsubstituted C1-C20 N,N-dialkyl-substituted amino groups, substituted or unsubstituted C1-C20 acyl groups, substituted or unsubstituted C1-C20 amide groups, substituted or unsubstituted C3-C20 ester groups, sulfonic acid groups, sulfonamide groups, substituted or unsubstituted C1-C20 sulfonyl groups, substituted or unsubstituted C3-C20 heterocyclic groups or heterocyclic aryl groups containing one or more of N, O and S, substituted or unsubstituted C1-C9 alkylsilyl groups, substituted or unsubstituted phenylsilyl groups, and substituted or unsubstituted aryl groups.

[0015] R 3The following are the possible meanings: hydrogen, substituted or unsubstituted C1-C20 straight-chain or branched alkyl, substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted C3-C20 cycloalkylmethylene, substituted or unsubstituted C3-C20 alkenyl, substituted or unsubstituted C3-C20 alkynyl, substituted or unsubstituted C3-C20 ester, substituted or unsubstituted benzyl, substituted or unsubstituted benzyloxy, substituted or unsubstituted C3-C20 heterocyclic methylene or heterocyclic aryl methylene containing one or more of N, O and S, substituted or unsubstituted C1-C20 acyl, sulfonic acid, sulfonamide, substituted or unsubstituted C1-C20 sulfonyl, substituted or unsubstituted C1-C20 alkyloxycarbonyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl methylene;

[0016] R 6 It can be vinyl or ethyl.

[0017] Wherein, the substituents mentioned above are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C1-C20 alkyl, C1-C20 fluoroalkyl, substituted or unsubstituted C3-C20 ester, C1-C20 alkenyl, C1-C20 alkynyl, C6-C20 aryl, C1-C20 hydroxyloxy, C1-C20 hydroxythio, C1-C20 N-alkyl-substituted amino, C1-C20

[0018] One or more of the N,N-dialkyl-substituted amino groups.

[0019] The aryl groups mentioned above are C6-C20 aryl groups.

[0020] Furthermore, R 1 R 2 R 3 R 6 One or more hydrogen atoms may be substituted by fluorine, chlorine, bromine, iodine, oxygen, sulfur, alkenyl, alkynyl, aryl, hydroxyl, amino, carbonyl, carboxyl, ester, cyano, methyl, ethyl, methoxy, methylthio, nitro or unsubstituted C3-C20 heterocyclic methylene or heterocyclic aryl methylene containing N, O and S.

[0021] Furthermore, the structural formula of the pyrimidine-7-membered oxygen-nitrogen heterocyclic compound is shown in Formula I, wherein R 1 R 2The groups are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, carboxyl, cyano, nitro, amino, mercapto, methylthio, substituted or unsubstituted C2-C20 alkylthio groups, methyl sulfone groups, substituted or unsubstituted C2-C20 alkyl sulfone groups, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, substituted or unsubstituted C5-C20 straight-chain or branched alkyl groups, trifluoromethyl, C2-C20 fluoroalkyl groups, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, substituted or unsubstituted C5-C20 alkyloxy groups, substituted or unsubstituted benzyl, substituted or unsubstituted benzyloxy, cyclopropoxy, etc. Alkyl, substituted or unsubstituted C4-C20 cycloalkyl, substituted or unsubstituted C1-C20 N-alkyl-substituted amino, substituted or unsubstituted C1-C20 N,N-dialkyl-substituted amino, substituted or unsubstituted C1-C20 acyl, substituted or unsubstituted C1-C20 amide, sulfonic acid, sulfonamide, substituted or unsubstituted C1-C20 sulfonyl, substituted or unsubstituted C3-C20 heterocyclic or heterocyclic aryl containing one or more of N, O and S, trimethylsilyl, triethylsilyl, substituted or unsubstituted C7-C9 alkylsilyl, triphenylsilyl, substituted or unsubstituted aryl;

[0022] R 3 The following groups are included: hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, substituted or unsubstituted C5-C20 straight-chain or branched alkyl, cyclopropane, substituted or unsubstituted C4-C20 cycloalkyl, substituted or unsubstituted C3-C20 cycloalkylmethylene, allyl, substituted or unsubstituted C4-C20 alkenyl, propargyl, substituted or unsubstituted C4-C20 alkynyl, formyl, acetyl, substituted or unsubstituted C3-C20 acyl, sulfonic acid, sulfonamide. The following are compounds: substituted or unsubstituted C1-C20 sulfonyl, benzoyl, substituted or unsubstituted aryl acyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, substituted or unsubstituted C5-C20 hydroxycarbonyl, substituted or unsubstituted C3-C20 heterocyclic methylene or heterocyclic aryl methylene containing one or more of N, O and S, substituted or unsubstituted benzyl, substituted or unsubstituted benzyloxy, substituted or unsubstituted aryl, substituted or unsubstituted aryl methylene;

[0023] R 6 It can be vinyl or ethyl.

[0024] Wherein, the substituents mentioned above are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C1-C20 alkyl, C1-C20 fluoroalkyl, C1-C20 alkenyl, C1-C20 alkynyl, C6-C20 aryl, C1-C20 alkyloxy, C1-C20 alkylthio, C1-C20 N-alkyl-substituted amino, and C1-C20 N,N-dialkyl-substituted amino.

[0025]

[0026] One or more of the following.

[0027] Furthermore, R 1 R 2 R 3 R 6 One or more hydrogen atoms may be substituted by fluorine, chlorine, bromine, iodine, oxygen, alkenyl, alkynyl, aryl, hydroxyl, amino, carbonyl, carboxyl, ester, cyano, methyl, ethyl, methoxy, methylthio, or nitro.

[0028] The aryl groups mentioned above are C6-C20 aryl groups.

[0029] Furthermore, the structural formula of the pyrimidine-7-membered oxygen-nitrogen heterocyclic compound is shown in Formula I, wherein R 1 R 2 Each group is independently selected from one or more heterocyclic groups or heterocyclic aryl groups selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, carboxyl, cyano, nitro, amino, mercapto, methylthio, methylsulfonyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, substituted or unsubstituted C5-C20 straight-chain or branched alkyl groups, trifluoromethyl, C2-C20 fluoroalkyl groups, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, substituted or unsubstituted C5-C20 alkyloxy groups, benzyl, benzyloxy, tert-butoxyamide, acetyl, acetamido, morpholino, piperidinyl, piperazine, pyrrole, tetrahydropyrrole, trimethylsilyl, triethylsilyl, triphenylsilyl, substituted or unsubstituted phenyl, substituted or unsubstituted aryl, substituted or unsubstituted C3-C20 containing N, O and S.

[0030] R 3 It can be hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropane, cyclohexane, formyl, acetyl, benzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-fluorobenzyl, benzoyl, p-toluenesulfonyl, tert-butoxycarbonyl, fluorenemethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-thiazolylmethylene, 2-thiophenemethylene, 2-furanmethylene, or 2-pyridinylmethylene;

[0031] R 6 It can be vinyl or ethyl.

[0032] Furthermore, R 1 R 2 R 3 R 6 One or more hydrogen atoms may be substituted by fluorine, chlorine, bromine, iodine, oxygen, alkenyl, alkynyl, aryl, hydroxyl, amino, carbonyl, carboxyl, ester, cyano, methyl, ethyl, methoxy, methylthio, or nitro.

[0033] The present invention also provides a method for preparing the above-mentioned chiral or racemic pyrimidine-7-membered oxygen-nitrogen heterocyclic compounds, specifically using an allyl compound intermediate as a raw material, an iridium complex generated by the reaction of an iridium compound with a phosphorus amide ligand as a catalyst, and reacting under the action of a co-catalyst to obtain the compound.

[0034] The reaction formula for the preparation method of this invention is shown below:

[0035]

[0036] Furthermore, the aforementioned R 6 The reaction product of vinyl groups can be reduced to give R. 6 It is a product of ethyl groups.

[0037] Where L is a chiral or achiral ligand, Boron agent is a combination of various co-catalysts and co-catalysts and additives, T is the reaction temperature, and Solvent is a variety of organic solvents.

[0038] In the preparation method of this invention, the molar ratio of the allyl compound intermediate, the iridium atom of the iridium compound, the ligand, and the co-catalyst is 1:(0.005-0.2):(0.005-0.4):(0.05-3).

[0039] In the method of this invention, the reaction can be carried out at 0-120°C. The reaction time can be 20 min-48 h.

[0040] In the method of the present invention, the iridium compound may be at least one of [Ir(COD)Cl]2, [Ir(dncot)Cl]2, [Ir(OMe)(COD)]2, [Ir(COD)2]BArF4, Ir(COD)2BF4, [Ir(OH)(COD)]2, Ir(ppy)3, [Ir(COD)2]SbF6, etc.

[0041] In the method of this invention, the ligand L refers to the phosphonamide ligand in CN109336887A, as detailed in paragraphs

[0076] -

[0085] of the specification.

[0042] In the method of this invention, the alkali can be an organic alkali or an inorganic alkali. Refer to the alkali in CN109336887A for details, see paragraph

[0086] of the specification.

[0043] In the method of this invention, the cocatalyst can be a boron cocatalyst, such as elemental boron or combined boron, including: various boranes such as trimethylboron, triethylboron, tri-n-propylboron, triisopropylboron, tri-n-butylboron, triisobutylboron, tri-tert-butylboron, triarylboron; various boric acids such as alkylboronic acid, arylboronic acid; and various borate esters such as trimethyl borate, triethyl borate, tri-n-propyl borate, triisopropyl borate, tri-n-butyl borate, triisobutyl borate, tri-tert-butyl borate, triaryl borate, etc.

[0044] In the method of this invention, the reaction is carried out in an organic solvent system. The organic solvent can be a polar solvent or a non-polar solvent. Preferably, the organic solvent can be one or a combination of more than one of the following: aromatic solvents or substituted aromatic solvents, halogenated hydrocarbon solvents, ether solvents, amide solvents, alkane solvents, cycloalkane solvents, nitrile solvents, dimethyl sulfoxide, alcohol solvents, and pyrrolidone solvents. Further, the aromatic solvents or substituted aromatic solvents preferably include at least one of toluene, xylene, ethylbenzene, cumene, chlorobenzene, and nitrobenzene; the halogenated hydrocarbon solvents preferably include at least one of dichloromethane, 1,2-dichloroethane, and trichloromethane; the ether solvents preferably include at least one of tetrahydrofuran, methyltetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1,4-dioxane, diphenyl ether, and dibenzyl ether; and the amide solvents preferably include N,N-dimethylformyl... The solvent comprises at least one of amine, N,N-dimethylacetamide, and N,N-dimethylpropionamide; the alkane solvent preferably comprises at least one of n-hexane, n-pentane, and n-heptane; the cycloalkane solvent preferably comprises at least one of cyclopentane, cyclohexane, and cycloheptane; the nitrile solvent preferably comprises acetonitrile; the pyrrolidone solvent preferably comprises at least one of α-pyrrolidone and N-methylpyrrolidone; and the alcohol solvent preferably comprises at least one of methanol, ethanol, isopropanol, n-propanol, and tert-butanol.

[0045] In the method of this invention, the allyl compound intermediate (S) a The structural formula is shown below:

[0046]

[0047] Wherein, LG is the leaving group, which can be hydroxyl, chlorine, bromine, etc. or Where M is NH or O;

[0048] R4 It is at least one of a halogen-substituted or unsubstituted C1-C20 alkyl group or a halogen-substituted or unsubstituted C1-C20 alkyl group;

[0049] R 5 It is a C1-C20 alkyl group, or a substituted or unsubstituted C6-C20 aryl group.

[0050] Preferred, formula (S) a ) of R 4 In this context, the halogen can be fluorine, chlorine, bromine, or iodine, each independently. Furthermore, the halogen-substituted C1-C20 alkyl group includes trichloromethyl.

[0051] Preferred, formula (S) a ) of R 5 In this context, the substituents can be one or more of C1-C20 alkyl groups, halogens, or C1-C20 hydroxyl groups. The aryl group is a C6-C20 aryl group.

[0052] Preferred, formula (S) a ) of R 4 and R 5 In this context, the alkyl groups of C1-C20 can be independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

[0053] Preferably, the hydroxyl groups of the C1-C20 groups are each independently selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, or benzyloxy. The aryl group is a C6-C20 aryl group, including phenyl and C7-C20 aryl groups.

[0054] The substituents can be one or more, and when there are multiple substituents, the substituents can be the same or different.

[0055] In the method of this invention, the allyl compound intermediate (S) a The compound can be prepared by a method comprising the following steps: 4-halo-2,6-disubstituted pyrimidine-5-carboxylic acid ethyl ester compound (compound 1) is reduced to 4-halo-2,6-disubstituted pyrimidine-5-methanol compound (compound 2), and then reacted with… The reaction yields compound S a .

[0056]

[0057] Furthermore, the reduction reaction can be carried out in the presence of diisobutylaluminum hydride at a concentration of 1-6 mol / L; the molar ratio of compound 1 to diisobutylaluminum hydride can be 1:1-1:5; the reaction temperature can be -78℃–25℃; and the reaction time can be 1-10 h.

[0058] Furthermore, in the presence of a base and a phase transfer catalyst, compound 2 and compound 3 undergo an intermolecular nucleophilic substitution reaction to give compound S. a The base can be an organic or inorganic base; the molar ratio of compound 2, compound 3 and the base can be 1:1:1 to 1:10:10; the reaction temperature can be 20℃–140℃; and the reaction time can be 30 min–2 h.

[0059] The substituent R in the 4-halo-2,6-disubstituted pyrimidine-5-carboxylic acid ethyl ester compound (compound 1) 1 R 2 It can be obtained directly from commercially available products or introduced from ethyl 2,4,6-trihalo-pyrimidine-5-carboxylate via conventional nucleophilic substitution reactions, Suzuki coupling reactions, or Grignard reactions.

[0060] Compound S a As a substrate, it is further catalyzed to obtain R. 6 The target compound I is vinyl.

[0061] Furthermore, the aforementioned R 6 The reaction product of vinyl groups can be reduced to give R. 6 The product is an ethyl group. The reduction reaction can be achieved through conventional reduction reactions such as catalytic hydrogenation reduction, negative hydrogen reduction of metal hydrides, and electron-proton reduction.

[0062] This invention uses an iridium complex formed by a metallic iridium compound and a phosphoramidite ligand as a catalyst to conduct an intramolecular allyl etherification reaction on an allyl substrate, thereby synthesizing pyrimidine and seven-membered oxygen-nitrogen heterocyclic compounds with high efficiency and high enantioselectivity. The enantiomers are obtained by preparing corresponding catalysts from ligands with opposite configurations and conducting similar intramolecular allyl etherification catalytic reactions. The racemic compounds are obtained by preparing corresponding catalysts from racemic ligands and conducting similar intramolecular allyl etherification catalytic reactions.

[0063] The method of this invention has the advantages of high catalytic activity, mild reaction conditions, good enantioselectivity, wide substrate applicability, and environmental friendliness. It can synthesize the target product with high efficiency, high regioselectivity and high enantioselectivity, and can be used to prepare a variety of pyrimidine chiral heterocyclic compounds.

[0064] The chiral or racemic pyrimidine-7-membered oxo-nitrogen heterocyclic compounds of the present invention, or their pharmaceutically acceptable salts, have good in vitro and in vivo Alzheimer's disease inhibitory activity and can be used to prepare drugs or lead compounds for the prevention or treatment of Alzheimer's disease.

[0065] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0066] This invention provides an efficient strategy and method for synthesizing novel pyrimidine chiral heterocyclic compounds using an iridium-phosphoramide ligand complex as a catalyst via intramolecular allyl-catalyzed etherification of specially designed allyl substrates. This method achieves high efficiency, high regioselectivity, and high enantioselectivity, and can be used to prepare a variety of pyrimidine chiral heterocyclic compounds.

[0067] Meanwhile, the present invention also conducted a preliminary in vitro and in vivo evaluation of the inhibitory activity of the constructed compound against Alzheimer's disease, and obtained good experimental results.

[0068] Compared with existing methods, the method of this invention is applicable to the catalytic reactions of various types of pyrimidine allyl compounds. It features milder reaction conditions, a wider range of applicable substrates, simpler operation, and better reaction yields (up to 99%) and high enantioselectivity (up to 99.5% ee). Furthermore, this is the first instance of using a metal iridium and phosphoramide ligand complex to catalyze the intramolecular asymmetric allylic etherification reaction of aromatic heterocyclic fatty alcohols, solving the traditional problem of insufficient nucleophilicity of fatty alcohols compared to phenols. This method for efficiently constructing pyrimidine-7-membered oxygen-nitrogen heterocyclic compounds using catalytic asymmetric intramolecular allylic etherification, and the resulting compounds, are currently unreported in domestic or international literature.

[0069] This invention not only enriches the application of bridged phosphoramidite ligands and other types of phosphoramidite ligands, but also broadens the applicable range of substrates for allylation reactions, providing novel heterocyclic structures and efficient methods for constructing chiral heterocyclic molecules for new drug development. Attached Figure Description

[0070] 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.

[0071] Figure 1 This is a bar graph showing the different configurations and concentrations of the compounds of this invention that exhibit anti-AD activity.

[0072] Figure 2 This is a bar graph showing how the compounds of this invention improve learning and memory function in AD mice.

[0073] Figure 3 This is a schematic diagram of the single-crystal structure of compound I-16 prepared in Example 10. Detailed Implementation

[0074] 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.

[0075] Example 1: Allyl compound intermediate (S) a Preparation of )

[0076]

[0077] Starting with compound 1, it was dissolved in a dry dichloromethane solution and the system was transferred to -78°C for later use. Then, diisobutylaluminum hydride (1.0 equiv, 1.5 mol / L in toluene) was slowly added using a syringe. After the addition was complete, the system was transferred to 0°C and stirred for 1 h. TLC was monitored until the reaction was complete, then water was added to quench the reaction, followed by dichloromethane extraction. The organic phase was concentrated under reduced pressure to obtain solid compound 2. Using N,N-diisopropylethylamine (2.0 equiv) as the base, acetonitrile as the solvent, and compound 2 (1.0 equiv) and the corresponding compound 3 (1.5 equiv) as reactants, the mixture was stirred at 110°C until the reaction was complete. Acetonitrile was then removed by rotary evaporation, followed by extraction with ethyl acetate. The organic phase was washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography to obtain the target compound S. a .

[0078]

[0079] S a -1a':(E)-4-(benzyl(5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)butyl-2-ene-1-methyl carbonate methyl carbonate

[0080] A pale yellow, viscous liquid; yield: 90%. 1 H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.37–7.31(m,3H),7.21(dd,J=6.9,1.7Hz,2H),5.94(dtt,J=15.5,5.2,1.3Hz,1H ),5.71(dtt,J=15.4,6.0,1.5Hz,1H),4.97(s,2H),4.64(dd,J=6.1,1.3Hz,2H),4.40–4.33(m,4H),3.80(s,3H),2.44(s,3H). 13C NMR(101MHz,Chloroform-d)δ170.26,161.34,158.89,155.52,137.97,130.76,128.79,12 7.23,126.51,125.93,111.73,67.52,61.19,54.88,51.96,50.39,13.99.HRMS(ESI)calcd for C 19 H 23 N3O4S[M+H] + :390.1482,Found:390.1481.

[0081] S a -1a: (E)-4-(benzyl(5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)but-2-en-1-yltert-butyl carbonate

[0082] A pale yellow, viscous liquid; yield: 90%. 1 H NMR(400MHz,Chloroform-d)δ7.88(s,1H),7.37–7.31(m,3H),7.24–7.19(m,2H),5.96–5.89(m,1H),5.71( dtt,J=15.4,6.0,1.6Hz,1H),4.97(s,2H),4.60–4.54(m,2H),4.39–4.31(m,4H),2.43(s,3H),1.50(s,9H). 13 C NMR(101MHz,Chloroform-d)δ170.56,161.34,159.38,153.24,138.11,130.45,128.76,127.1 7,126.53,126.31,111.62,82.34,66.62,61.29,51.83,50.29,27.77,14.01.HRMS(ESI)calcd for C 22 H 29 N3O4S[M+H] + :432.1952,Found:432.1953.

[0083] S a -1b: (E)-4-(benzyl(5-(hydroxymethyl)-6-methyl-2-(methylthio)pyrimidin-4-yl)amino)but-2-en-1-yl tert-butyl carbonate

[0084] Yellow, viscous liquid; yield: 92%. 1H NMR(600MHz,Chloroform-d)δ7.32–7.28(m,3H),7.23–7.20(m,2H),5.96–5.90(m,1H),5.74–5.67(m,1H),4. 84(s,2H),4.54(d,J=6.2Hz,2H),4.43(s,2H),4.20(d,J=5.5Hz,2H),2.39(s,3H),2.37(s,3H),1.48(s,9H). 13 C NMR(151MHz,Chloroform-d)δ168.65,167.77,163.77,153.27,138.27,128.59,128.45,128.22,127.12,1 26.98,126.81,126.63,110.17,82.26,66.72,56.99,52.69,51.08,27.76,21.48,13.91.HRMS(ESI)calcd for C 23 H 31 N3O4S[M+H] + :446.2108,Found:446.2106.

[0085] S a -1c: (E)-4-(benzyl(2-chloro-5-(hydroxymethyl)pyrimidin-4-yl)amino)but-2-en-1-yl tert-butyl carbonate

[0086] A pale yellow, viscous liquid; yield: 91%. 1 H NMR(400MHz,Chloroform-d)δ7.94(s,1H),7.38–7.33(m,2H),7.31–7.28(m,1H),7.25–7.20(m,2H),5.95–5.86 (m,1H),5.77–5.67(m,1H),4.96(s,2H),4.57(d,J=5.7Hz,2H),4.39(s,2H),4.32(d,J=5.3Hz,2H),1.50(s,9H). 13 CNMR(151MHz,Chloroform-d)δ162.93,160.59,159.46,153.22,137.43,129.58,128.89,1 27.48,126.92,126.74,114.65,82.42,66.52,60.72,51.87,50.40,27.76.HRMS(ESI)calcd for C 21 H 26 ClN3O4[M+H]+ :420.1685,Found:420.1682.

[0087] S a -1d: (E)-4-(benzyl(6-chloro-5-(hydroxymethyl)pyrimidin-4-yl)amino)but-2-en-1-yl tert-butyl carbonate

[0088] A pale yellow, viscous liquid; yield: 87%. 1 H NMR(400MHz,Chloroform-d)δ8.35(s,1H),7.36(dd,J=8.1,6.5Hz,2H),7.32–7.28(m,1H),7.26–7.22(m,2H ),5.98–5.90(m,1H),5.79–5.70(m,1H),4.91(s,2H),4.61–4.56(m,4H),4.26(d,J=5.3Hz,2H),1.51(s,9H). 13 C NMR(151MHz,Chloroform-d)δ164.79,162.49,155.95,153.24,137.28,129.94,128.82,12 7.39,127.27,126.85,113.81,82.38,66.57,58.32,52.60,51.05,27.77.HRMS(ESI)calcd for C 21 H 26 ClN3O4[M+H] + :420.1685,Found:420.1682.

[0089] S a -1e: (E)-tert-butyl(4-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)(thiophen-2-ylmethyl)amino)but-2-en-1-yl)carbonate

[0090] A pale yellow, viscous liquid; yield: 89%. 1 H NMR(400MHz,Chloroform-d)δ7.90(s,1H),7.25–7.21(m,1H),7.03–6.92(m,2H),5.95–5.88(m,1H),5.79 –5.70(m,1H),5.01(s,2H),4.60–4.57(m,2H),4.44(s,2H),4.37–4.33(m,2H),2.53(s,3H),1.50(s,9H). 13C NMR(101MHz,Chloroform-d)δ170.42,161.08,159.23,153.24,140.62,130.76,126.45,126.3 8,126.09,125.63,112.13,82.40,66.58,61.08,49.59,47.30,27.76,14.12.HRMS(ESI)calcd forC 20 H 27 N3O4S2[M+H] + :438.1516,Found:438.1512.

[0091] S a -1f: (E)-tert-butyl(4-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)(naphth-1-ylmethyl)amino)but-2-en-1-yl)carbonate

[0092] Yellow, viscous liquid; yield: 89%. 1 H NMR(400MHz,Chloroform-d)δ7.99–7.95(m,1H),7.93–7.89(m,1H),7.82(s,1H),7.79(d ,J=8.2Hz,1H),7.58–7.53(m,2H),7.42(dd,J=8.2,7.0Hz,1H),7.24(dd,J=7.1,1.2Hz,1H ),5.98(dtt,J=15.5,5.2,1.3Hz,1H),5.73(dtt,J=15.4,6.0,1.5Hz,1H),5.45(s,2H),4 .57(dd,J=6.1,1.4Hz,2H),4.44(d,J=4.8Hz,2H),4.23(s,2H),2.39(s,3H),1.50(s,9H). 13 C NMR(151MHz,Chloroform-d)δ170.53,161.35,159.38,153.24,133.86,133.06,130.71,130.33,128.89,127.72,126.4 5,126.41,126.01,125.50,122.88,122.60,111.61,82.33,66.63,61.30,50.90,50.11,27.77,13.99.HRMS(ESI)calcd for C 26 H 31 N3O4S[M+H] + :482.2108,Found:482.2108.

[0093] S a -1g: (E)-4-(benzyl(2-cyclopropyl-5-(hydroxymethyl)pyrimidin-4-yl)amino)but-2-en-1-yl tert-butyl carbonate

[0094] A pale yellow, viscous liquid; yield: 80%. 1 H NMR(400MHz,Chloroform-d)δ7.80(s,1H),7.37–7.29(m,3H),7.24–7.19(m,2H),5.96–5.89(m,1H),5.70(dtt,J=15.4, 6.0,1.6Hz,1H),4.97(s,2H),4.60–4.54(m,2H),4.39–4.31(m,4H),2.24–2.20(m,1H),1.50(s,9H),1.30–0.90(m,4H).

[0095] S a -1h: (E)-4-(benzyl(5-(hydroxymethyl)-6-phenylpyrimidin-4-yl)amino)but-2-en-1-yl tert-butyl carbonate

[0096] A pale yellow, viscous liquid; yield: 91%. 1 H NMR(400MHz,Chloroform-d)δ7.83(s,1H),7.37–7.30(m,8H),7.24–7.09(m,2H),5.96–5.89(m,1H), 5.73(dtt,J=15.4,6.0,1.6Hz,1H),4.97(s,2H),4.60–4.54(m,2H),4.39–4.31(m,4H),1.51(s,9H).

[0097] Example 2

[0098] The phosphoramidite ligands L1-L25 refer to the phosphoramidite ligands in CN109336887A, and are detailed in the specific embodiments in paragraphs

[0117] -

[0133] of the specification.

[0099] Example 3

[0100] Allyl intermediate S a Study on ligands that undergo intramolecular allyl etherification reaction catalyzed by iridium-phosphoramide complexes using -1a' as a substrate.

[0101]

[0102] Table 1

[0103]

[0104] PhMe is toluene, and Bn is benzyl.

[0105] Example 4

[0106] Allyl intermediate S a Study on boron source and solvent for intramolecular allyl etherification reaction catalyzed by iridium-phosphoramide complex with -1a' as substrate.

[0107]

[0108] Table 2

[0109]

[0110] Wherein, THF is tetrahydrofuran, 1,4-dioxane is 1,4-dioxane, DCE is 1,2-dichloroethane, DME is ethylene glycol dimethyl ether, and PhMe is toluene.

[0111] Example 5

[0112] Allyl intermediate S a Study on catalyst dosage for intramolecular allyl etherification reaction catalyzed by iridium-phosphoramide complex using -1a' as substrate

[0113]

[0114] Table 5

[0115]

[0116] Example 6

[0117] Allyl intermediate S a Study on the leaving group of substrate -1a' as a substrate undergoing intramolecular allyl etherification reaction catalyzed by iridium-phosphoramide complex.

[0118]

[0119] Table 6

[0120]

[0121] Where LG refers to the leaving group, and Boc is tert-butyloxycarbonyl.

[0122] Example 7: Preparation of pyrimidine-7-membered oxygen-nitrogen heterocyclic compound (Compound I)

[0123] Under argon protection, iridium compound (0.08 mol), chiral phosphoramide ligand (0.16 mol), base (5 vol), and tetrahydrofuran (5 vol) were added. The reaction was carried out at 50°C for 30 minutes, then allowed to cool naturally to room temperature before the solvent was removed under reduced pressure. Substrate S was then added sequentially to the reaction tube. a The reaction mixture (1 molar), boron co-catalyst (0.25 molar), and organic solvent (20 parts by volume) was reacted at 20-80 °C. After the reaction was monitored by TLC, the solvent was removed under reduced pressure, and the crude product obtained after concentration was separated by column chromatography to obtain product I (petroleum ether:ethyl acetate = 5:1-10:1, v / v). The preparation methods and specific reaction conditions of compounds I-1 to I-6, I-58, and I-61 are shown in Table 7. The molar ratios in Table 7 refer to the substrate S. a The molar ratio of iridium:ligand:boron cocatalyst.

[0124]

[0125] Table 7

[0126]

[0127]

[0128] Wherein, Boc is tert-butyloxycarbonyl, iPr is isopropyl, PhMe is toluene, DCM is dichloromethane, DCE is 1,2-dichloroethane, DME is ethylene glycol dimethyl ether, and THF is tetrahydrofuran.

[0129]

[0130]

[0131] I-1: (R)-9-benzyl-2-(methylthio)-7-vinyl-5,7,8,9-tetrahydropyrimidino[4,5-e][1,4]oxazine

[0132] R f =0.50 (petroleum ether:ethyl acetate = 2:1, v / v); yellow oily liquid; 99% yield, 99% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min] -1 ,λ=254nm,t R (major) = 13.12 min, t R (minor) = 15.36 min]. [α] D 25 =577.2° (c=1.02, CH2Cl2).1 H NMR(400MHz,Chloroform-d)δ7.88(s,1H),7.37–7.27(m,5H),5.83–5.71(m,1H),5.35–5.27(m,1H),5.24–5.12(m,2H),4.82 (d,J=14.4Hz,1H),4.67(d,J=15.2Hz,1H),4.53(dd,J=14.4,0.7Hz,1H),4.45–4.37(m,1H),3.57–3.44(m,2H),2.45(s,3H). 13 CNMR(101MHz,Chloroform-d)δ170.34,163.12,154.91,137.69,135.48,128.65,12 7.96,127.47,116.97,112.52,79.59,65.52,53.49,53.32,14.07.HRMS(ESI)calcd forC 17 H 19 N3OS[M+H] + :314.1322,Found:314.1320.

[0133] I-2: (R)-9-benzyl-4-methyl-2-(methylthio)-7-vinyl-5,7,8,9-tetrahydropyrimidino[4,5-e][1,4]oxazine

[0134] R f =0.50 (petroleum ether:ethyl acetate = 2:1, v / v); yellow oily liquid; 98% yield, 96% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min] -1 ,λ=254nm,t R (major) = 6.31 min, t R (minor) = 6.96 min]. [α] D 25 =165.0° (c=0.98, CH2Cl2). 1H NMR(600MHz,Chloroform-d)δ7.36–7.32(m,2H),7.30–7.27(m,3H),5.81(dd d,J=16.5,10.7,5.2Hz,1H),5.35–5.30(m,1H),5.24–5.20(m,1H),5.15(d,J =15.3Hz,1H),4.92(d,J=14.8Hz,1H),4.68(d,J=15.3Hz,1H),4.64(d,J=14. 8Hz,1H),4.45–4.40(m,1H),3.51(d,J=5.6Hz,2H),2.41(s,3H),2.33(s,3H). 13 C NMR(151MHz,Chloroform-d)δ168.50,163.36,162.84,138.14,135.60,128.86,128.57,128.1 2,127.83,127.30,116.99,109.33,78.49,62.30,53.53,52.98,21.67,13.98.HRMS(ESI)calcd for C 18 H 21 N3OS[M+H] + :328.1478,Found:328.1477.

[0135] I-3: (R)-9-benzyl-2-chloro-7-vinyl-5,7,8,9-tetrahydropyrimidino[4,5-e][1,4]oxazine

[0136] R f =0.50 (petroleum ether:ethyl acetate = 2:1, v / v); pale yellow oily liquid; 58% yield, >99.9% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min] -1 ,λ=254nm,t R (major) = 10.43 min, t R (minor) = 12.74 min]. [α] D 25 =336.8° (c=0.73, CH2Cl2). 1H NMR(400MHz,Chloroform-d)δ7.88(s,1H),7.38–7.30(m,5H),5.76(ddd,J=17.2,10.6,5.1Hz,1H),5.32(dt,J=17.2,1.5Hz,1H),5.22(dt,J=10.6,1 .4Hz,1H),5.16(d,J=15.0Hz,1H),4.85(d,J=14.6Hz,1H),4.63(d,J=15.0 Hz,1H),4.56(d,J=14.6Hz,1H),4.48–4.42(m,1H),3.59(d,J=5.5Hz,2H). 13 C NMR(151MHz,Chloroform-d)δ164.70,159.05,155.60,136.63,134.97,128.78,128.29,127.85,117.29,115.59,79.41,64.47,53.57,52.76.HRMS(ESI)calcd for C 16 H 16 ClN3O[M+H] + :302.1055,Found:302.1053.

[0137] I-4:(R)-9-benzyl-4-chloro-7-vinyl-5,7,8,9-tetrahydropyrimidino[4,5-e][1,4]oxazine

[0138] R f =0.50 (petroleum ether:ethyl acetate = 2:1, v / v); pale yellow oily liquid; 93% yield, 94% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min] -1 ,λ=254nm,t R (major) = 7.48 min, t R (minor) = 8.92 min]. [α] D 25 =235.3° (c=0.51, CH2Cl2). 1H NMR(400MHz,Chloroform-d)δ8.31(s,1H),7.37–7.27(m,5H),5.84(ddd,J=17.2,10.7,5.0Hz,1H),5.36(dt,J=17.4,1.4Hz,1H),5.27(dt,J=10.7,1 .4Hz,1H),5.19(d,J=15.4Hz,1H),5.01(d,J=15.7Hz,1H),4.83(d,J=15.7 Hz,1H),4.70(d,J=15.3Hz,1H),4.54–4.46(m,1H),3.62(d,J=5.8Hz,2H). 13 C NMR(151MHz,Chloroform-d)δ164.38,157.45,155.66,137.06,134.96,128.74,127.80,127.64,117.38,113.26,78.00,62.24,53.61,51.90.HRMS(ESI)calcd for C 16 H 16 ClN3O[M+H] + :302.1055,Found:302.1052.

[0139] I-5: (R)-2-(methylthio)-9-(thiophene-2-ylmethyl)-7-vinyl-5,7,8,9-tetrahydropyrimidino[4,5-e][1,4]oxazine

[0140] R f =0.50 (petroleum ether:ethyl acetate = 2:1, v / v); yellow oily liquid; 83% yield, 96% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min] -1 ,λ=254nm,t R (major) = 16.02 min, t R (minor) = 20.36 min]. [α] D 25 =408.8° (c=1.21, CH2Cl2). 1H NMR(400MHz,Chloroform-d)δ7.90(s,1H),7.25(dd,J=5.1,1.2Hz,1H),7.03(dd,J=3.5,1.1Hz,1H),6.96(dd ,J=5.1,3.4Hz,1H),5.83(ddd,J=17.2,10.6,5.3Hz,1H),5.36(dt,J=17.3,1.5Hz,1H),5.24(dt,J=10.6,1.4 Hz,1H),5.11(d,J=15.2Hz,1H),4.89(d,J=15.2Hz,1H),4.77(d,J=14.4Hz,1H),4.50(d,J=14.4Hz,1H),4.41 (dddt,J=8.0,5.5,2.9,1.5Hz,1H),3.61(dd,J=15.2,2.8Hz,1H),3.39(dd,J=15.2,7.7Hz,1H),2.57(s,3H). 13 C NMR(101MHz,Chloroform-d)δ170.12,162.80,154.58,140.07,135.42,127.01,12 6.34,126.01,117.17,113.02,79.58,65.83,53.54,48.74,14.17.HRMS(ESI)calcd for C 15 H 17 N3OS2[M+H] + :320.0886,Found:320.0884.

[0141] I-6: (R)-2-(methylthio)-9-(naphth-1-ylmethyl)-7-vinyl-5,7,8,9-tetrahydropyrimidino[4,5-e][1,4]oxazine

[0142] R f =0.50 (petroleum ether:ethyl acetate = 2:1, v / v); yellow oily liquid; 94% yield, 98% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min] -1 ,λ=254nm,t R (major) = 15.07 min, t R (minor) = 17.76 min]. [α] D 25 =108.7° (c=1.0, CH2Cl2). 1H NMR(400MHz,Chloroform-d)δ8.03–7.97(m,1H),7.94–7.49(m,2H),7.84(d,J=8.4Hz,1H),7.56–7.51(m,2 H),7.45(dd,J=8.2,7.0Hz,1H),7.40–7.37(m,1H),5.67(d,J=15.2Hz,1H),5.57(ddd,J=17.2,10.6,5.2Hz ,1H),5.14(dt,J=17.3,1.5Hz,1H),5.06–5.04(m,1H),5.03–4.98(m,1H),4.80(d,J=14.4Hz,1H),4.50(d, J=14.4Hz,1H),4.18–4.10(m,1H),3.59(dd,J=15.3,3.0Hz,1H),3.48(dd,J=15.3,7.7Hz,1H),2.44(s,3H). 13 CNMR(151MHz,Chloroform-d)δ170.44,163.08,154.93,135.35,133.91,132.69,131.77,128.82,128.48,12 6.81,126.49,126.01,125.22,123.58,116.68,112.92,79.48,65.57,53.04,51.26,14.07.HRMS(ESI)calcd for C 21 H 21 N3OS[M+H] + :364.1478,Found:364.1474.

[0143] I-58:(R)-9-benzyl-4-phenyl-7-vinyl-5,7,8,9-tetrahydropyrimidino[4,5-e][1,4]oxazine

[0144] R f =0.10 (petroleum ether / ethyl acetate = 2:1, v / v); yellow oil, 35.0 mg, 90% yield; 93% ee [Daicel Chiralcel IF-3 (0.46 cm x 25 cm), n-hexane / 2-propanol = 97 / 3, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (minor) = 33.822min,t R (major) = 43.242 min];[α] D25 =34.5° (c=0.86, CH2Cl2). 1 HNMR(600MHz,Chloroform-d)δ8.64(s,1H),7.62–7.59(m,1H),7.49–7.46(m,3H),7.39–7.30(m,6H),5.83(ddd,J=17.5,10.7,5.3Hz,1H),5.33(dt, J=17.3,1.5Hz,1H),5.26–5.20(m,2H),4.94(d,J=14.8Hz,1H),4.78(d,J= 15.3Hz,1H),4.56(d,J=14.7Hz,1H),4.51–4.46(m,1H),3.70–3.57(m,2H). 13 C NMR(151MHz,Chloroform-d)δ164.62,164.36,156.25,138.15,137.79,135.54,129.47,129.46 ,128.67,128.38,127.90,127.43,117.15,113.29,78.49,64.10,53.65,53.21.HRMS(ESI)calcd for C 22 H 21 N3O[M+H] + :344.1457,Found:344.1456.

[0145] I-61:(R)-9-benzyl-2-(cyclopropyl)-7-vinyl-5,7,8,9-tetrahydropyrimidino[4,5-e][1,4]oxazine

[0146] R f =0.20 (petroleum ether / ethyl acetate = 2:1, v / v); yellow oil, 93% yield; 90% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 80 / 20, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (major) = 11.428 min, t R (minor) = 14.469 min];[α] D 25 =152.9° (c=0.75, CH2Cl2). 1H NMR(600MHz,Chloroform-d)δ7.93(s,1H),7.36–7.32(m,2H),7.31–7.27(m,3H), 5.78(ddd,J=17.0,10.6,5.2Hz,1H),5.33–5.28(m,1H),5.21–5.17(m,1H),5.10(d ,J=15.1Hz,1H),4.84(d,J=14.4Hz,1H),4.62(d,J=15.1Hz,1H),4.52(d,J=14.4Hz ,1H),4.41–4.35(m,1H),3.54–3.42(m,2H),2.10–2.05(m,1H),1.06–0.86(m,4H). 13 C NMR(151MHz,Chloroform-d)δ170.31,163.47,154.42,138.15,135.63,128.55,127.93,12 7.30,116.84,113.97,79.74,65.84,53.74,53.20,14.12,9.93,9.78.HRMS(ESI)calcdfor C 19 H 21 N3O[M+H] + :308.1757,Found:308.1754.

[0147] Compounds I-7 to I-24 were prepared according to the method described in Example 7 above, and the results are shown in Table 8.

[0148] Table 8

[0149] compound <![CDATA[R 1 ]]> <![CDATA[R 2 ]]> <![CDATA[R 3 ]]> Yield (%) ee value (%) I-7 <![CDATA[SCH3]]> H <![CDATA[4-MeOC6H4-CH2]]> 90 97 I-8 <![CDATA[SCH3]]> H Boc 98 99 I-9 <![CDATA[SCH3]]> H <![CDATA[2-MeC6H4-CH2]]> 90 99 I-10 <![CDATA[SCH3]]> H <![CDATA[CH2CH=CH2]]> 90 98 I-11 <![CDATA[SCH3]]> H <![CDATA[4-t-BuC6H4-CH2]]> 97 96 I-12 <![CDATA[SCH3]]> <![CDATA[CH3]]> <![CDATA[4-iPrC6H4-CH2]]> 80 99 I-13 <![CDATA[SCH3]]> <![CDATA[CH3]]> <![CDATA[4-CF3C6H4-CH2]]> 91 97 I-14 <![CDATA[SCH3]]> <![CDATA[CH3]]> <![CDATA[3-CF3C6H4-CH2]]> 96 95 I-15 <![CDATA[SCH3]]> <![CDATA[CH3]]> <![CDATA[3-ClC6H4-CH2]]> 98 98 I-16 <![CDATA[SCH3]]> <![CDATA[CH3]]> <![CDATA[2-BrC6H4-CH2]]> 98 96 I-17 H Cl Ts 98 98 I-18 H Cl <![CDATA[4-ClC6H4-CH2]]> 90 98 I-19 H Cl 3,4-dichlorobenzyl 95 96 I-20 H Cl Troc 98 96 I-21 Cl H <![CDATA[4-MeOC6H4-CH2]]> 95 97 I-22 Cl H <![CDATA[3-CF3C6H4-CH2]]> 96 95 I-23 Cl H Fmoc 91 97 I-24 Cl H <![CDATA[4-PhC6H4-CH2]]> 95 95

[0150] Example 8

[0151] Using 2-methylthiopyrimidine-7-membered oxygen-nitrogen heterocyclic compounds I-1, I-2, I-5–I-16 as substrates, 2-methylsulfonylpyrimidine-7-membered oxygen-nitrogen heterocyclic compounds I-25–I-38 were prepared by oxidation with m-chloroperoxybenzoic acid.

[0152]

[0153] 10 mol of 2-methylthiopyrimidine-7-membered oxo-nitrogen heterocyclic compound I-7 and 21 mol of m-chloroperoxybenzoic acid were added sequentially, followed by 200 parts by volume of organic solvent. The reaction was carried out at 0–80 °C. After the reaction was completed by TLC monitoring, the solvent was removed under reduced pressure, and the crude product obtained after concentration was separated by column chromatography to obtain product I-25 (petroleum ether:ethyl acetate = 1:1, v / v). The preparation of other compounds was carried out in the same manner, and the results are shown in Table 9.

[0154] I-25:(R)-9-(4-methoxybenzyl)-2-(methylsulfonyl)-7-vinyl-5,7,8,9-tetrahydropyrimidino[4,5-e][1,4]oxazine

[0155]

[0156] R f =0.10 (petroleum ether / ethyl acetate = 1:1, v / v); yellow oily liquid, 92% yield; 97% ee [Daicel Chiralcel IF-3 (0.46cm x 25cm), n-hexane / 2-propanol = 75 / 25, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (minor) = 44.257min,t R (major) = 47.147 min; [α] D 25 = -7.6° (c = 0.89, CH2Cl2). 1 HNMR(600MHz,Chloroform-d)δ8.07(s,1H),7.26(d,J=8.3Hz,2H),6.88(d,J=8.4 Hz,2H),5.78(ddd,J=17.5,10.6,5.0Hz,1H),5.34(dt,J=17.2,1.4Hz,1H),5.25(d t,J=10.7,1.3Hz,1H),5.09(d,J=14.8Hz,1H),4.89(d,J=15.0Hz,1H),4.61(dd,J= 14.9,8.9Hz,2H),4.50–4.46(m,1H),3.81(s,3H),3.70–3.59(m,2H),3.22(s,3H). 13C NMR(151MHz,Chloroform-d)δ164.18,163.75,159.31,154.66,134.80,129.60,128.2 5,119.56,117.47,114.20,79.36,64.54,55.31,53.39,52.58,38.99.HRMS(ESI)calcd for C 18 H 21 N3O4S[M+H] + :376.1326,Found:376.1324.

[0157] Table 9

[0158] compound <![CDATA[R 1 ]]> <![CDATA[R 2 ]]> <![CDATA[R 3 ]]> Yield (%) ee value (%) I-26 methylsulfonyl H Bn 93 98 I-27 methylsulfonyl <![CDATA[CH3]]> Bn 93 98 I-28 methylsulfonyl H thiophen-2-ylmethyl 92 97 I-29 methylsulfonyl H naphthalen-1-ylmethyl 96 94 I-30 methylsulfonyl H Boc 93 94 I-31 methylsulfonyl H <![CDATA[2-MeC6H4-CH2]]> 98 95 I-32 methylsulfonyl H <![CDATA[CH2CH=CH2]]> 95 98 I-33 methylsulfonyl H <![CDATA[4-t-BuC6H4-CH2]]> 92 98 I-34 methylsulfonyl <![CDATA[CH3]]> <![CDATA[4-iPrC6H4-CH2]]> 90 94 I-35 methylsulfonyl <![CDATA[CH3]]> <![CDATA[4-t-BuC6H4-CH2]]> 95 98 I-36 methylsulfonyl <![CDATA[CH3]]> <![CDATA[3-FC6H4-CH2]]> 93 97 I-37 methylsulfonyl <![CDATA[CH3]]> 3,5-difluorobenzyl 95 90 I-38 methylsulfonyl <![CDATA[CH3]]> <![CDATA[2-ClC6H4-CH2]]> 95 98

[0159] Example 9

[0160] When the R of the pyrimidine-7-membered oxygen-nitrogen heterocyclic compound of the present invention 1 Or R 2 When the halogen is present, R can be prepared by nucleophilic substitution reaction with amine compounds or alkoxides. 1 Or R 2 Pyrimidine-7-membered oxygen-nitrogen heterocyclic compounds with different substituents.

[0161] For example, using 4-chloropyrimidine-7-membered oxygen-nitrogen heterocyclic compounds I-4, I-17–I-20 or 2-chloropyrimidine-7-membered oxygen-nitrogen heterocyclic compounds I-3, I-21–I-24 as substrates, pyrimidine-7-membered oxygen-nitrogen heterocyclic compounds I-39–I-57 can be prepared by intermolecular nucleophilic substitution reactions with amine compounds or alkoxides under alkaline conditions.

[0162]

[0163] 2-Chloroprene-7-membered oxonium heterocyclic compound I-3 or I-21 (10 mol) or 4-chloropyrimidine-7-membered oxonium heterocyclic compound I-4 (10 mol) and amine compound RR'NH (21 mol) or alkoxide compound R”OM (21 mol) were added sequentially. Then, 20 mol of base and 200 parts by volume of organic solvent were added sequentially to the reaction tube, and the reaction was carried out at 0-180 °C. After the reaction was completed by TLC monitoring, the solvent was removed under reduced pressure, and the crude product obtained after concentration was separated by column chromatography to obtain the product. (Petroleum ether:ethyl acetate = 5:1, v / v). The preparation of other compounds was carried out in the same manner, and the results are shown in Table 10.

[0164]

[0165] I-39:(R)-9-(4-methoxybenzyl)-2-(pyrrolidone-1-yl)-7-vinyl-5,7,8,9-tetrahydropyrimidino[4,5-e][1,4]oxazine

[0166] R f =0.10 (petroleum ether / ethyl acetate = 1:1, v / v); yellow oily liquid, 96% yield; 97% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 80 / 20, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (minor) = 20.541 min,t R (major) = 26.271 min];[α] D 25 =137.2° (c=0.73, CH2Cl2). 1 HNMR(600MHz,Chloroform-d)δ7.79(s,1H),7.32–7.29(m,2H),6.88(d,J=8.2Hz,2H) ,5.81–5.73(m,1H),5.31–5.26(m,1H),5.16(d,J=10.7Hz,1H),5.04(d,J=14.8Hz,1H) ,4.75(d,J=14.0Hz,1H),4.55(d,J=14.8Hz,1H),4.44(d,J=14.0Hz,1H),4.35–4.29(m ,1H),3.82(s,3H),3.61–3.48(m,4H),3.44–3.32(m,2H),2.00–1.88(d,J=6.2Hz,4H). 13 C NMR(151MHz,Chloroform-d)δ164.23,158.79,155.88,147.08,136.15,130.73,129.39,1 16.47,113.85,105.97,79.67,66.33,55.28,53.81,52.46,46.50,25.51.HRMS(ESI)calcd for C 21 H 26 N4O2[M+H] + :367.2129,Found:367.2124.

[0167] I-40:(R)-9-(4-methoxybenzyl)-2-(morpholinyl)-7-vinyl-5,7,8,9-tetrahydropyrimidino[4,5-e][1,4]oxazine

[0168] R f =0.10 (petroleum ether / ethyl acetate = 1:1, v / v); yellow oily liquid, 95% yield; 97% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (minor) = 22.667min,t R [(major) = 25.672 min]; [α] D 25 =185.2° (c=0.68, CH2Cl2). 1 HNMR(600MHz,Chloroform-d)δ7.80(s,1H),7.25(d,J=8.3Hz,2H),6.88(d,J=8 .3Hz,2H),5.81–5.72(m,1H),5.29(d,J=17.3Hz,1H),5.17(d,J=10.6Hz,1H),5 .00(d,J=14.9Hz,1H),4.77(d,J=14.1Hz,1H),4.52(d,J=14.9Hz,1H),4.45(d, J=14.0Hz,1H),4.36–4.30(m,1H),3.83(s,3H),3.74(s,8H),3.47–3.35(m,2H). 13 CNMR(151MHz,Chloroform-d)δ164.28,161.11,158.89,155.95,135.97,130.31,129.22,11 6.60,113.94,107.35,79.68,66.87,66.04,55.29,53.68,52.57,44.46.HRMS(ESI)calcdfor C 21 H 26 N4O3[M+H] + :383.2078,Found:383.2073.

[0169] I-41:(R)-9-(benzyl)-2-(4-(benzo[d][1,3]dioxo-5-ylmethyl)piperazin-1-yl)-7-vinyl-5,7,8,9-tetrahydropyrimidino[4,5-e][1,4]oxazine

[0170] R f =0.10 (petroleum ether / ethyl acetate = 1:2, v / v); yellow oily liquid, 98% yield; 96% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 65 / 35, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (minor) = 13.861 min,t R (major) = 17.518 min];[α] D 25 =167.3° (c=0.83, CH2Cl2). 1 HNMR(600MHz,Chloroform-d)δ7.79(s,1H),7.34–7.29(m,5H),6.88(s,1H),6.76(d,J=0.9Hz,2H),5 .96(s,2H),5.77(ddd,J=17.2,10.6,5.4Hz,1H),5.29(dt,J=17.2,1.5Hz,1H),5.16(dt,J=10.7,1.5H z,1H),5.06(d,J=15.2Hz,1H),4.76(d,J=14.1Hz,1H),4.57(d,J=15.2Hz,1H),4.45(d,J=14.0Hz,1H ),4.35(td,J=5.9,4.3Hz,1H),3.77–3.73(m,4H),3.44(s,2H),3.43–3.39(m,2H),2.45–2.42(m,4H). 13 C NMR(151MHz,Chloroform-d)δ164.27,160.98,156.04,147.63,146.63,138.48,136.00,131.82,128.50,127.92,127.1 7,122.30,116.59,109.56,107.85,106.84,100.88,79.72,66.17,62.88,54.16,53.34,52.82,43.90.HRMS(ESI)calcd for C 28 H 31 N5O3[M+H] + :486.2500,Found:486.2497.

[0171] Table 10

[0172]

[0173]

[0174] Example 10

[0175] When the R of the pyrimidine-7-membered oxygen-nitrogen heterocyclic compound of the present invention 1 Or R 2 When the halogen is present, R can be prepared by coupling reaction with boric acid compounds. 1 Or R 2 Pyrimidine-7-membered oxygen-nitrogen heterocyclic compounds with different substituents.

[0176] For example, using 4-chloropyrimidine-7-membered oxygen-nitrogen heterocyclic compounds I-4, I-17–I-20 or 2-chloropyrimidine-7-membered oxygen-nitrogen heterocyclic compounds I-3, I-21–I-24 as substrates, pyrimidine-7-membered oxygen-nitrogen heterocyclic compounds were coupled with various borate compounds under palladium catalyst catalysis to prepare pyrimidine-7-membered oxygen-nitrogen heterocyclic compounds I-58–I-74.

[0177]

[0178] Under argon protection, 10 mol of 2-chloropyrimidine-7-membered oxonium heterocyclic compound I-3 or 10 mol of 4-chloropyrimidine-7-membered oxonium heterocyclic compound I-4 and boric acids such as alkylboronic acid, arylboronic acid, various borate esters such as trimethyl borate, triethyl borate, tri-n-propyl borate, triisopropyl borate, tri-n-butyl borate, triisobutyl borate, tri-tert-butyl borate, triaryl borate, or various potassium borates such as alkylpotassium borate, arylpotassium borate (20 mol) were added sequentially. Then, 0.5 mol of palladium compound, 1 mol of ligand, 20 mol of base, and 200 parts by volume of organic solvent were added sequentially, and the reaction was carried out at 0-180 °C. After the reaction was monitored by TLC, the solvent was removed under reduced pressure, and the crude product obtained after concentration was separated by column chromatography to obtain the product (petroleum ether: ethyl acetate = 5:1, v / v). The preparation of other compounds was carried out in the same manner, and the results are shown in Tables 11-12.

[0179]

[0180] I-59:(R)-9-benzyl-4-(thiophen-2-yl)-7-vinyl-5,7,8,9-tetrahydropyrimidino[4,5-e][1,4]oxazine

[0181] R f=0.10 (petroleum ether / ethyl acetate = 2:1, v / v); yellow oil, 91% yield; 91% ee [Daicel Chiralcel IF-3 (0.46cm x 25cm), n-hexane / 2-propanol = 95 / 5, v = 1.0 mL·min -1 T = 25℃, λ = 254nm, t R (minor) = 27.536min,t R [(major) = 32.282 min]; [α] D 25 =89.7° (c=0.75, CH2Cl2). 1 H NMR(600MHz,Chloroform-d)δ8.53(s,1H),7.56–7.50(m,1H),7.40–7.29(m,6H) ),7.18–7.14(m,1H),5.92–5.80(m,1H),5.36(d,J=17.1Hz,1H),5.27(d,J=10. 8Hz,1H),5.22(d,J=15.6Hz,1H),5.11(d,J=14.9Hz,1H),4.88–4.81(m,1H),4. 78(d,J=15.4Hz,1H),4.56–4.50(m,1H),3.73–3.66(m,1H),3.66–3.59(m,1H). 13 C NMR(151MHz,Chloroform-d)δ164.44,156.60,156.08,141.81,137.70,135.48,129.78,129.27 ,128.66,127.80,127.66,127.42,117.20,111.60,78.19,63.80,53.46,52.66.HRMS(ESI)calcd forC 20 H 19 N3OS[M+H] + :350.1322,Found:350.1317.

[0182] I-60:(R)-9-benzyl-2-(6-methoxypyridin-3-yl)-7-vinyl-5,7,8,9-tetrahydropyrimidino[4,5-e][1,4]oxazine

[0183] R f=0.10 (petroleum ether / ethyl acetate = 2:1, v / v); yellow oil, 93% yield; 94% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 95 / 5, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (major) = 23.363 min, t R (minor) = 26.420min];[α] D 25 =107.2° (c=0.63, CH2Cl2). 1 H NMR (600MHz, Chloroform-d) δ9.16 (s, 1H), 8.50 (d, J = 7.3Hz, 1H), 8.13 (s, 1H), 7. 37–7.29(m,5H),6.79(d,J=7.8Hz,1H),5.85–5.77(m,1H),5.34–5.30(m,1H),5.2 9–5.24(m,1H),5.24–5.19(m,1H),4.94–4.88(m,1H),4.82–4.76(m,1H),4.64–4. 59(m,1H),4.49–4.43(m,1H),4.00(s,3H),3.62–3.56(m,1H),3.56–3.50(m,1H). 13 C NMR(151MHz,Chloroform-d)δ165.42,163.54,161.35,155.13,147.77,138.24,137.87,135.56,128.68,128.33 ,127.93,127.84,127.43,127.28,116.94,114.99,110.27,79.74,65.75,53.67,53.57,53.36.HRMS(ESI)calcd for C 20 H 19 N3OS[M+H] + :375.1816,Found:375.1814.

[0184] I-62:(R)-9-benzyl-2-(benzofuran-2-yl)-7-vinyl-5,7,8,9-tetrahydropyrimidino[4,5-e][1,4]oxazine

[0185] R f=0.40 (petroleum ether / ethyl acetate = 2:1, v / v); yellow oil, 93% yield; 95% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 95 / 5, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (major) = 51.429 min, t R (minor) = 54.393min];[α] D 25 =13.6° (c=0.75, CH2Cl2). 1 H NMR(600MHz,Chloroform-d)δ8.19(s,1H),7.66–7.62(m,2H),7.55(s,1H),7.42(d ,J=7.5Hz,2H),7.38(t,J=7.2Hz,4H),7.33(d,J=7.2Hz,1H),5.82(ddd,J=16.5,10. 7,5.3Hz,1H),5.37–5.30(m,2H),5.23(d,J=10.6Hz,1H),4.92(d,J=14.6Hz,1H),4. 79(d,J=15.0Hz,1H),4.63(d,J=14.6Hz,1H),4.48–4.43(m,1H),3.64–3.52(m,2H). 13 C NMR(151MHz,Chloroform-d)δ163.56,156.38,155.72,155.06,154.01,137.81,135.43,128.71,128.27,127 .57,125.75,123.17,121.83,117.05,115.91,112.08,108.56,79.67,65.67,53.44,53.39.HRMS(ESI)calcd for C 24 H 21 N3O2[M+H] + :384.1707,Found:384.1702.

[0186] Table 11

[0187]

[0188] Table 12

[0189] compound <![CDATA[R 1 ]]> R”’ <![CDATA[R 3 ]]> Yield (%) ee value (%) I-69 H 4-isopropylpheny <![CDATA[4-PhC6H4-CH2]]> 96 98 I-70 H furan-2-yl <![CDATA[4-PhC6H4-CH2]]> 90 97 I-71 H isopropyl 3,5-difluorobenzyl 95 97 I-72 H quinolin-3-yl 3,5-difluorobenzyl 97 98 I-73 H cyclopropyl Ts 93 98 I-74 H thiazol-4-yl Ts 98 97

[0190] Example 11

[0191] Using pyrimidine-7-membered oxygen-nitrogen heterocyclic compound I-7 as a substrate, pyrimidine-7-membered oxygen-nitrogen heterocyclic compound I-75 was prepared by reduction reaction with hydrogen in the presence of palladium on carbon.

[0192]

[0193] A pyrimidine-7-membered oxo-nitrogen heterocyclic compound I-7 (10 mol) and palladium reagent on carbon (0.1 mol) were added sequentially. Then, 200 parts by volume of organic solvent were added to the reaction tube. The system was purged with a hydrogen balloon to create a hydrogen atmosphere, and the reaction was carried out at 0-80°C until the reactants were completely reacted. After the reaction was complete, the solvent was removed under reduced pressure, and the crude product obtained after concentration was separated by column chromatography to yield product I-75 (petroleum ether:ethyl acetate = 5:1, v / v).

[0194] I-75:(R)-7-ethyl-9-(4-methoxybenzyl)-2-(methylthio)-5,7,8,9-tetrahydropyrimidino[4,5-e][1,4]oxazine

[0195]

[0196] R f =0.30 (petroleum ether:ethyl acetate = 5:1, v / v); yellow oily liquid; 91% yield, 95% ee [Daicel Chiralcel IC-3 (0.46cm x 25cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min] -1 ,λ=250nm,t R (major) = 50.68 min, t R (minor) = 43.47 min]. [α] D 25 =183.2° (c=0.75, CH2Cl2). 1 H NMR(600MHz,Chloroform-d)δ7.88(s,1H),7.27–7.19(m,2H),6.94–6.87(m,2H),5.14–5.08(m,1H),4.79–4.72(m,1H),4.58–4.53(m,1H),4 .48–4.42(m,1H),3.83(s,3H),3.71–3.65(m,1H),3.48–3.40(m,1H), 3.35–3.27(m,1H),2.48(s,3H),1.60–1.52(m,2H),0.92–0.88(m,3H). 13C NMR(151MHz,Chloroform-d)δ170.21,163.40,159.01,154.84,129.78,129.39,114. 01,112.75,80.71,66.13,55.29,53.27,52.71,26.37,14.07,10.00.HRMS(ESI)calcd for C 18 H 23 N3O2S[M+H] + :346.1584,Found:346.1575.

[0197] Example 12: Anti-Alzheimer's disease (AD) activity of pyrimidine-7-membered oxygen-nitrogen heterocyclic compounds

[0198] (1) Cell culture and establishment of AD model

[0199] BV-2 cells were purchased from DSMZ (German collection of microorganisms and cell cultures), Germany. All cell culture reagents were purchased from Life Technologies (Grand Island, Nebraska, USA). Cells were cultured in Dulbecco modified Eagle's medium (Gibco, USA) containing 10% fetal bovine serum (Gibco, USA) at 37°C in a 5% CO2 incubator. An in vitro AD model was established by co-inducing BV-2 cells with 1 μg / mL lipopolysaccharide (LPS) and 1 mM adenosine triphosphate disodium (ATP). 5xFAD mice were used as the AD model mice, with wild-type (WT) mice serving as normal controls. 5xFAD mice are transgenic AD mice carrying five familial gene mutations in the APP / PS1 gene. These mice exhibit clinical manifestations and pathological characteristics similar to AD patients and are a recognized model for studying the pathogenesis, therapeutic targets, and drug discovery of AD. Six-month-old female mice were used in this experiment.

[0200] (2) Cell Viability Assay

[0201] Cell viability was determined using CCK-8 [2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfonic acid benzene)-2H-tetrazole monosodium salt]. Specific steps: 1×10⁻⁶ cells were added to the solution... 4Cells were seeded into each well of a 96-well plate and allowed to adhere for 24 hours in an incubator. Then, 1 μg / mL LPS and 1 mM ATP were added for 6 hours of co-treatment. Next, culture medium containing different concentrations of the drug (compound of this invention / curcumin / donepezil) was added to each well for 24 hours. Finally, CCK-8 was added and the plate was incubated at 37°C for 1 hour. The absorbance at 450 nm was measured using a microplate reader (BIO-RAD, USA). Results are shown below. Figure 1 .

[0202] (3) Water Maze Test

[0203] The Morris water maze experiment was used to study learning and memory functions in mice. The tests included spatial location and spatial orientation. In the spatial location phase, each mouse was randomly placed in four different quadrants with its head facing the wall for five consecutive days. The distance the mice swam, the time required to reach the underwater platform (escape delay), and the average swimming speed were recorded, using a video tracking system to record information for each test. On day 6, the spatial orientation test was conducted. The underwater platform was removed, and the time spent by the mice in the target quadrant (i.e., the target intersection) of the hidden platform was calculated over 60 seconds. The mice were divided into four groups: AD model mice (5xFAD), wild-type mice (WT), AD mice treated with 1-1+5xFAD, and normal mice treated with 1-1+WT. The 5xFAD group received 10 mg / kg intraperitoneally once daily; the WT group received the same dose of saline once daily.

[0204] (4) Results Analysis

[0205] In the cell viability assay, this invention used the CCK-8 assay to determine the cell viability after 24 hours of culture at different drug concentrations. The results are shown in [Figure number missing]. Figure 1 The concentrations of the compounds in this invention are 10 μM and 2.5 μM, respectively; the concentration of the positive control curcumin is 20 μM (the conventional effective concentration for activation); and the concentration of donepezil is 50 μM (the conventional effective concentration for activation). Figure 1 As shown in Figures AB, compared to the blank control group and the AD group, the pyrimidine-7-membered oxo-nitrogen heterocyclic compound (R configuration) of the present invention, at a concentration of 10 μM, exhibited a protective effect similar to that of 50 μM donepezil and 20 μM curcumin in the activity test. Furthermore, the cell survival rate after administration was significantly higher than that of donepezil and curcumin, indicating that the compound of the present invention has better pharmaceutical activity. These results demonstrate that, compared to the positive control drugs donepezil and curcumin, the pyrimidine-7-membered oxo-nitrogen heterocyclic compound derivative or its racemic form of the present invention can reverse the LPS and ATP co-induced BV-2 cell damage. Figure 1As can be seen from C, further reducing the concentration, at a concentration of 2.5 μM, I-1, I-9, I-15, and I-16 (all R conformations) still showed good cell viability. Furthermore, from Figure 1 D revealed that the racemates corresponding to I-1, I-9, I-15, and I-16 also exhibited good protective and reversal activities. However, overall, the R configuration was the most active configuration, with its racemate in the middle range. The S configuration had lower activity than the R configuration and the racemate, but still had good protective and reversal effects on AD.

[0206] Compound I-1 of the present invention was administered to 5xFAD mice and wild-type control mice (WT) for one month. Their learning and memory functions were then tested using a water maze spatial location test. Figure 2 As shown, Figure 2 A represents the comparison of the latency periods for various mouse species to reach the target platform in the experiment; Figure 2 B represents a comparison of the path lengths required for various mouse species to reach the target platform in the experiment; Figure 2 C represents the comparison of the number of times each type of mouse crossed the target platform within 60 seconds in the experiment; Figure 2 D represents the movement trajectory of various mouse species in each quadrant during the experiment. Figure 2 A, Figure 2 As can be seen from B, compared with wild-type mice, 5xFAD mice exhibited lower learning ability in locating underwater platforms, showing increased latency and path length in spatial positioning training tests. Treatment with compound I-1 significantly shortened the latency and distance traveled by AD mice to reach the target platform. These results indicate that AD mice have impaired spatial memory, and that treatment with compound I-1 can reverse this impairment. Figure 2 C Figure 2 As can be seen from D, AD mice spent less time in the target quadrant and crossed the target platform fewer times than control mice; treatment with compound I-1 significantly reversed these two indicators in AD mice; these results indicate that treatment with the compounds of this invention can improve cognitive deficits in AD mice. Figure 2 It is evident that treatment with compound I-1 did not have a significant effect on memory and cognitive deficits in wild-type mice.

[0207] The above results demonstrate that the chiral or racemic pyrimidine-7-membered oxo-nitrogen heterocyclic compounds of this invention exhibit significant protective and reversal effects against Alzheimer's disease in both in vitro and in vivo models. They can be applied in the preparation of drugs or lead compounds for the prevention or treatment of Alzheimer's disease.

[0208] 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 or racemic pyrimidine-7-membered oxo-nitrogen heterocyclic compounds or pharmaceutically acceptable salts thereof, characterized in that... The structural formula is shown in Formula I; where the carbon atoms marked with * are chiral carbon atoms with the following configuration. R , S or R / S The pyrimidine-7-membered oxygen-nitrogen heterocyclic compound is a levorotatory, dextrorotatory, or racemic form. ， Among them, R 1 R 2 Individually selected from hydrogen, halogen atoms, hydroxyl, carboxyl, cyano, nitro, amino, mercapto, substituted or unsubstituted C1-C20 alkyl thiols, substituted or unsubstituted C1-C20 alkyl sulfones, substituted or unsubstituted C1-C20 straight-chain or branched-chain alkyl groups, substituted or unsubstituted C1-C20 alkyloxy groups, substituted or unsubstituted C3-C20 cycloalkyl groups, and substituted or unsubstituted C1-C20... N - Hydrocarbon-substituted amino group, substituted or unsubstituted C1-C20 N , N - Dialkyl substituted amino group, C1-C20 acyl group, C1-C20 amide group, sulfonic acid group, sulfonamide group, substituted or unsubstituted C1-C20 sulfonyl group, substituted or unsubstituted C3-C20 heterocyclic group or heterocyclic aryl group containing one or more of N, O and S, substituted or unsubstituted aryl group. R 3 The following are the possible meanings: hydrogen, substituted or unsubstituted C1-C20 straight-chain or branched alkyl, substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted C3-C20 cycloalkylmethylene, allyl, propargyl, substituted or unsubstituted C3-C20 heterocyclic methylene or heterocyclic aryl methylene containing one or more of N, O and S, C1-C20 acyl, aryl acyl, sulfonic acid, sulfonamide, substituted or unsubstituted C1-C20 sulfonyl, p-toluenesulfonyl, substituted or unsubstituted C1-C20 alkyloxycarbonyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl methylene; R 6 It is vinyl or ethyl; The substituents are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C1-C20 alkyl, C1-C20 fluoroalkyl, C1-C20 alkenyl, C1-C20 alkynyl, aryl, C1-C20 alkyloxy, and C1-C20 alkylthio. One or more of the following; The aryl group is a C6-C20 aryl group.

2. The chiral or racemic pyrimidine-7-membered oxo-nitrogen heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that... The structural formula of the pyrimidine-7-membered oxygen-nitrogen heterocyclic compound is shown in Formula I, wherein R 1 R 2 Individually selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, carboxyl, cyano, nitro, amino, mercapto, methylthio, substituted or unsubstituted C2-C20 alkyl sulfonyl, substituted or unsubstituted C2-C10 alkyl sulfonyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, substituted or unsubstituted C5-C20 straight-chain or branched alkyl, trifluoromethyl, C2-C20 fluoroalkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, substituted or unsubstituted C5-C20 alkyloxy, cyclopropane, substituted or unsubstituted C4-C20 cycloalkyl, substituted or unsubstituted C1-C20 N - Hydrocarbon-substituted amino group, substituted or unsubstituted C1-C20 N , N - Dialkyl substituted amino group, C1-C20 acyl group, C1-C20 amide group, sulfonic acid group, sulfonamide group, substituted or unsubstituted C1-C20 sulfonyl group, substituted or unsubstituted C3-C20 heterocyclic group or heterocyclic aryl group containing one or more of N, O and S, substituted or unsubstituted aryl group. R 3 The following are compounds: hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, substituted or unsubstituted C5-C20 straight-chain or branched alkyl, cyclopropane, substituted or unsubstituted C4-C20 cycloalkyl, substituted or unsubstituted C3-C20 cycloalkylmethylene, allyl, propargyl, formyl, acetyl, C3-C20 acyl, sulfonic acid, sulfonamide, substituted or unsubstituted C1-C20 sulfonyl, benzoyl, tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, substituted or unsubstituted C5-C20 hydroxyoxycarbonyl, substituted or unsubstituted C3-C20 heterocyclic methylene or heterocyclic aryl methylene containing one or more of N, O and S, substituted or unsubstituted benzyl, substituted or unsubstituted aryl; R 6 It can be vinyl or ethyl.

3. The chiral or racemic pyrimidine-7-membered oxo-nitrogen heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that... The structural formula of the pyrimidine-7-membered oxygen-nitrogen heterocyclic compound is shown in Formula I, wherein R 1 R 2 Each group is independently selected from one or more heterocyclic groups or heterocyclic aryl groups selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, carboxyl, cyano, nitro, amino, mercapto, methylthio, methylsulfonyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, substituted or unsubstituted C5-C20 straight-chain or branched alkyl groups, trifluoromethyl, C2-C20 fluoroalkyl groups, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, substituted or unsubstituted C5-C20 alkyloxy groups, benzyl, tert-butoxyamido, acetyl, acetamido, morpholino, piperidinyl, piperazine, pyrrole, tetrahydropyrrole, substituted or unsubstituted phenyl, substituted or unsubstituted C3-C20 containing N, O and S. R 3 It can be hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropane, cyclohexane, formyl, acetyl, benzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-fluorobenzyl, benzoyl, p-toluenesulfonyl, tert-butoxycarbonyl, fluorenemethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-thiazolylmethylene, 2-thiophenemethylene, 2-furanmethylene, or 2-pyridinylmethylene; R 6 It can be vinyl or ethyl.

4. A method for preparing a chiral or racemic pyrimidine-7-membered oxygen-nitrogen heterocyclic compound according to any one of claims 1-3, characterized in that... Specifically, the reaction is carried out using allyl compound intermediates as raw materials and iridium complexes generated by the interaction of iridium compounds and phosphoramidite ligands as catalysts, with the reaction proceeding under the action of a co-catalyst. The structural formula of the allyl compound intermediate is shown below: ， Wherein, LG is the leaving group, which can be hydroxyl, chlorine, bromine, etc. or Where M is NH or O; R 4 It is at least one of a halogen-substituted or unsubstituted C1-C20 alkyl group or a halogen-substituted or unsubstituted C1-C20 alkyl group; R 5 It is a C1-C20 alkyl group or a C6-C20 aryl group; The cocatalyst is a boron cocatalyst, selected from at least one of the following: trimethylboron, triethylboron, tri-n-propylboron, triisopropylboron, tri-n-butylboron, triisobutylboron, tri-tert-butylboron, triarylboron, alkylboronic acid, arylboronic acid, and borate ester.

5. The preparation method according to claim 4, characterized in that... The allyl compound intermediate is prepared by the following steps: a 4-halo-2,6-disubstituted pyrimidine-5-carboxylic acid ethyl ester compound is reduced to a 4-halo-2,6-disubstituted pyrimidine-5-methanol compound, which is then reacted with... The reaction is obtained.

6. The use of the chiral or racemic pyrimidine-7-membered oxo-nitrogen heterocyclic compound according to any one of claims 1-3 in the preparation of a medicament for the prevention or treatment of Alzheimer's disease.

Images