Tricyclic thiazolopyrimidone ether derivative and application thereof

Abstract

The invention relates to a tricyclic thiazolopyrimidine ketone ether derivative and application thereof.The derivative is prepared by the steps that ethyl cyanoacetate serves as an initial raw material, a hydroxylamine compound (A) is generated under the action of sodium nitrite and phosphoric acid, 2-amino ethyl cyanoacetate (B) is obtained through reduction, the 2-amino ethyl cyanoacetate (B) reacts with acetic anhydride and a Lawesson reagent to obtain a 5-amino-4-formate thiazole compound (D), and the 5-amino-4-formate thiazole compound (D) reacts with the sodium nitrite and the phosphoric acid to obtain the tricyclic thiazolopyrimidine ketone ether derivative. The preparation method comprises the following steps: taking 4-bromo-5, 7, 8, 9-tetrahydrothiazole [5 ', 4': 4, 5] pyrimidine [1, 2-a] azepine-11 (5H)-ketone as a raw material, performing NBS bromination to obtain a 2-bromo-dihydropyrrole [1, 2-a] thiazolo [5, 4-d] pyrimidine-9 (5H)-ketone compound (F) and a 2-bromo-6, 7, 8, 9-tetrahydrothiazole [5 ', 4': 4, 5] pyrimidine [1, 2-a] azepine-11 (5H)-ketone derivative (G) under the action of phosphorus oxychloride, and finally reacting with different substituted phenols (thiophenol) under the action of alkali to obtain 40 tricyclic thiazole pyrimidine ketone ether compounds H1-H20 and I1-I20. The invention also investigates the inhibitory activity of the 40 compounds on acetylcholin esterase and butyrylcholin esterase in Alzheimer's disease, and the result shows that 20 compounds have strong inhibitory activity on acetylcholin esterase, and 22 compounds have strong inhibitory activity on butyrylcholin esterase.

Description

Technical Field

[0001] The invention relates to a tricyclic thiazolopyrimidinone ether derivative and application thereof. Background Art

[0002] According to statistics from the World Health Organization, cancer affects about 10 million people and kills about 7 million people every year in the world. In China, the number of cancer cases is about 1.2 million, and the number of people who die from cancer each year is as high as more than 900,000, making it the second largest killer of humans after cardiovascular disease. Alzheimer's disease (AD) is a neurodegenerative disease caused by impaired memory, language, and reasoning in the cerebral hemisphere. It was first discovered by German neuropathologist Alois Alzheimer in 1906 and named after him. In recent years, the prevalence of Alzheimer's disease (AD) has increased year by year and is becoming younger. It is estimated that by 2050, more than 130 million people will suffer from Alzheimer's disease (AD) worldwide. Due to the lack of very effective prevention and treatment methods, it has become the fourth cause of death in humans after heart disease, cancer, and stroke. Since there is currently no effective drug used in clinical practice to prevent the onset of (AD) and then treat Alzheimer's disease (AD), it is urgent to find a drug that can effectively treat Alzheimer's disease (AD).

[0003] In recent years, it has been found that many traditional Chinese medicines have significant therapeutic effects in the treatment of Alzheimer's disease (AD). For example, icariin, sinapinic acid, salvia miltiorrhiza and kudzu root have strong inhibitory effects on AChE. Although these drugs have greatly improved the patient's neurocognitive ability and alleviated the symptoms of Alzheimer's disease (AD), they have a single target, large toxic side effects, short half-life (many times of daily medication), and are prone to drug resistance and adverse reactions.

[0004] Heterocyclic compounds are a class of compounds with good biological activity and occupy a very important position in medicinal chemistry. Since nitrogen has a very deep connection with life, most nitrogen-containing heterocyclic compounds have the characteristics of high efficiency, low toxicity, and good environmental compatibility. They are an irreplaceable class of biogenic medicines and have become the mainstream of drug research and development. Therefore, many drug molecules are designed and screened using nitrogen-containing heterocyclic rings as the parent.

[0005] Thiazole compounds containing nitrogen and sulfur atoms have many unique properties and biological activities. So far, thiazole-based drugs have been used in clinical practice. Thiazole compounds, as bioisosteres of thiazole, imidazole, benzimidazole, triazole and tetrazole, have received increasing attention. We hope to discover new thiazole compounds with broad spectrum, high efficiency, low toxicity and excellent pharmacokinetic properties.

[0006] Thiazole ring is an important five-membered aromatic heterocycle containing nitrogen and sulfur atoms. It is rich in electrons and is easy to form hydrogen bonds, coordination with metal ions, electrostatic and hydrophobic interactions and other non-covalent interactions. This structure gives thiazole compounds many special properties and has a wide range of potential applications in many fields. It has attracted great attention from many workers, and related research work including its synthesis methods is increasing. In particular, with the successful use of a series of thiazole compounds in clinical and agricultural production, the research and development of thiazole compounds has become one of the hot research areas in recent years. In the field of medicine, thiazole compounds can bind to various targets such as enzymes and receptors in organisms to show a variety of biological activities, covering almost the entire field of medicine, and many thiazole compounds have been used in clinical practice, such as the antibiotic drug cefixime, the anticancer drug dasatinib, the antiparasitic drug nitazoxanide, and the anti-inflammatory drug meloxicam, which are all the first-line drugs preferred in clinical practice.

[0007] Therefore, it can be seen from the activity of thiazolypyrimidine derivatives that the search and exploration of the synthesis and biological activity of these compounds has great theoretical significance and application value for finding lead compounds such as new medicines.

[0008] References:

[0009] [1] Zhou Yongyi, Guo Qihua, Gu Xuexin. Brief introduction to the research trends of anticancer drugs[J]. Chemical Education, 2004, 5:10-13.

[0010] [2] Ye Youzhu. On the development trend of anticancer drugs in my country [J]. Strait Pharmacy, 1995, 3(7): 63-64.

[0011] [3] Huang, JM; et al. Studies of a-Thiocarbonyl Phosphonic AcidDerivative Quinazolone Analogues Containing Phosphorus. Chem. J, Chin, Univ. 2000, 8 (21), 1216-1220.

[0012] [4] 2Bai, ZS; Wang, DX Heterocyclic Compounds Genetic Engineering and Pesticides in 21 Century. Pesticides 1998, 37(6), 2-6.

[0013] [5]Feng,K.S.;Chen,R.Y.;et al.Synthesis and Structure of 3,4-Dipheny-3-diazaphos-pholid-In-2-thione-4-oxides Sulfides.Chem.J.Chin,Univ.1993,14(9),1244-1249.

[0014] [6]Zhang,C X.;Zhan,Z.B.;et al Synthesis of Cyclic Glycerophospho-lipid Conjugates of Adenosine.Chem.J.Chin.Univ.199,19(6),913-916.

[0015] [7]Zhou,J;et al.Synthesis and Herbicidal Activity of l-Aryl-2-phenyl-3-methyl-3-isopropyl-1,4,2-diazaphosp-holidin-5-one-2-oxides.Chem,J.Chin,Univ,1999,20(7),1058-1062.

[0016] [8]Zhang,H.Z,Zhao,Z.L,Zhou,C.H.Recent advance in oxazolebasedmedicinal chemistry,[J].Eur J Med Chem,2018,144:444-492.

[0017] [9]Zhang,H.Z,Gan,L.L,Wang,H.et al.New progress in azole compounds asantimicrobial agents,[J].Mini-Rev Med Chem,2017,17(2):122-166.

[0018]

[10] Mayer, JCP; Sauer, AC; Iglesias, BA; et al. Ferrocenylethenylsubstituted 1,3,4-oxadiaz-olyl-1,2,4-oxadiazoles: Synthesis, characterization and DNA-binding assays[J]. J Organomet Chem, 2017, 841: 1-11.

[0019]

[11] Revuelta, J, Machetti, F, Cicchi, S. Modern Heterocyclic Chemistry. Berlin: Wiley, 2011.

[0020]

[12] Hanusek, J. Study of formation and transformation of some five-andsix-membered heterocyclic compounds containing nitrogen and sulfur. ChemListy, 2008, 102(9): 801-810.

[0021]

[13] Abele, E.; Abele, R.; Lukevics, E. Chemistry of Heterocyclic Compounds. New York: Springer, 2007.

[0022]

[14] Zhu Runmin, Ding Guohua. Research progress in the synthesis of five-membered heterocyclic compounds. Chemical Technology and Development, 2008, 37(3): 22-35.

[0023]

[15] Kashyap, SJ; Garg, VK; Sharma, PK; Kumar, N.; Dudhe, R.; Gupta, JK Thiazoles: Having diverse biological activities. Med Chem Res, 2012, DOI10.1007 / s00044-011-9685-2.

[0025]

[16] Galm, U.; Wang, L.; Huang, SX; Unsin, C.; Comparative analysis of the biosynthetic gene clusters and pathways for three structurally related antitumor antibiotics: Bleomycin, tallysomycin, and zorbamycin. J Nat Prod, 2011, 74(3): 526-536.

[0026]

[17] Moghadam, MS; Maleki, S.; Darabpour, E.; Motamedi, H.; Antibacterial activity of eight Iranian plant extracts against methicillin and cefiximerestistant staphylococcous aureus strains. Asian Pac J TropMed, 2010, 3(4): 262-265.

[0027]

[18] Teoh, D.; Ayeni, TA; Rubatt, JM; Adams, DJ; Grace, L.; Dasatinib hassynergistic activity with paclitaxel and carboplatin in ovarian cancer cells. Gynecol Oncol, 2011, 121 (1): 187-192.

[0028] Based on the comprehensive analysis of relevant domestic and foreign patents and literature, the present invention fully synthesizes tricyclic thiazolylpyrimidinone ether compounds, and systematically transforms and modifies them, introduces phenyl groups containing different substituents into the molecules of tricyclic thiazolylpyrimidinone ether compounds, in order to improve their drugability, and studies the inhibitory activity of these compounds on acetylcholinesterase and butyrylcholinesterase, in order to find candidate drugs against acetylcholinesterase and butyrylcholinesterase with significant efficacy and clear targets. The activity screening results show that 20 compounds have strong inhibitory activity against acetylcholinesterase; 22 compounds have inhibitory activity against butyrylcholinesterase. Summary of the invention

[0029] The object of the present invention is to provide a tricyclic thiazolyl pyrimidine ketone ether derivative and its use. The derivative uses ethyl cyanoacetate as the initial raw material, generates a hydroxylamine compound (A) under the action of sodium nitrite and phosphoric acid, is reduced by hydrosulfite to obtain ethyl 2-aminocyanoacetate (B), reacts with acetic anhydride and Lawesson's reagent to obtain 5-amino-4-carboxylate thiazole compound (D), and then is brominated with NBS, and then under the action of phosphorus oxychloride, obtains 2-bromo-dihydropyrrole [1,2-a] thiazolyl [5,4-d] pyrimidine-9 (5H) -one compound (F) and 2-bromo-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one derivative (G), and finally, reacts with different substituted phenols (thiophenol) under the action of alkali to obtain 40 tricyclic thiazolyl pyrimidine ketone ether compounds H1-H20 and I1-I20. The inhibitory activity of these 40 compounds on acetylcholinesterase and butyrylcholinesterase in Alzheimer's disease was investigated. The results showed that 20 compounds had strong inhibitory activity on acetylcholinesterase, and 22 compounds had strong inhibitory activity on butyrylcholinesterase.

[0030] The tricyclic thiazolylpyrimidinone ether derivatives of the present invention have the structural formula:

[0031]

[0032] in:

[0033] Compound H1 is 2-(4-methylphenyloxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one;

[0034] Compound H2 is 2-(3-chlorophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one;

[0035] Compound H3 is 2-(3-bromophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one;

[0036] Compound H4 is 2-(4-bromophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one;

[0037] Compound H5 is 2-(3-fluorophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one;

[0038] Compound H6 is 2-(4-fluorophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one;

[0039] Compound H7 is 2-(3-trifluoromethylphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one;

[0040] Compound H8 is 2-(4-trifluoromethylphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one;

[0041] Compound H9 is 2-(3-methoxyphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one;

[0042] Compound H10 is 2-(4-trifluoromethoxyphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one;

[0043] Compound H11 is 2-(3-nitrophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one;

[0044] Compound H12 is 2-(3,4-dichlorophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one;

[0045] Compound H13 is 2-(3,5-difluorophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one;

[0046] Compound H14 is 2-(3,4-difluorophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one

[0047] Compound H15 is 2-(3,5-ditrifluoromethylphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one;

[0048] Compound H16 is 2-(1-naphthylphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one;

[0049] Compound H17 is 2-(4-phenylphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one;

[0050] Compound H18 is 2-(4-methylthio)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one;

[0051] Compound H19 is 2-(4-fluorophenylthio)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one;

[0052] Compound H20 is 2-(4-methoxyphenylthio)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one;

[0053] Compound I1 is 2-(4-methylphenyloxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one;

[0054] Compound I2 is 2-(3-chlorophenoxy)-6,7,8,9-tetrahydrothiazolidine[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one;

[0055] Compound I3 is 2-(3-bromophenoxy)-6,7,8,9-tetrahydrothiazolidine[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one;

[0056] Compound I4 is 2-(4-bromophenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one;

[0057] Compound I5 is 2-(3-fluorophenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one;

[0058] Compound I6 is 2-(4-fluorophenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one;

[0059] Compound I7 is 2-(3-trifluoromethylphenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one;

[0060] Compound I8 is 2-(4-trifluoromethylphenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one;

[0061] Compound I9 is ​​2-(3-methoxyphenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one;

[0062] Compound I10 is 2-(4-trifluoromethoxyphenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one;

[0063] Compound I11 is 2-(3-nitrophenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one;

[0064] Compound I12 is 2-(3,4-dichlorophenoxy)-6,7,8,9-tetrahydrothiazolidine[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one;

[0065] Compound I13 is 2-(3,5-difluorophenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one;

[0066] Compound I14 is 2-(3,4-difluorophenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one;

[0067] Compound I15 is 2-(3,5-ditrifluoromethylphenoxy)-6,7,8,9-tetrahydrothiazolidine[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one;

[0068] Compound I16 is 2-(1-naphthylphenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one;

[0069] Compound I17 is 2-(4-phenylphenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one;

[0070] Compound I18 is 2-(4-methylthio)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one;

[0071] Compound I19 is 2-(4-fluorophenylthio)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one;

[0072] Compound I20 is 2-(4-methoxyphenylthio)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one;

[0073] Use of compounds H2-H3, H5-H7, H9, H11, H13-H14, H16, H18-H20, I4, I7-I8, I11-I12, I16, and I19 among the tricyclic thiazolopyrimidine ether derivatives in the preparation of drugs for inhibiting acetylcholinesterase.

[0074] Use of compounds H1-H6, H13, H18-H20, I1, I5-I9, I11, I14, I16-I17, and I19-I20 among the tricyclic thiazolopyrimidinone ether derivatives in the preparation of drugs for inhibiting butyrylcholinesterase.

[0075] The tricyclic thiazolyl pyrimidinone ether derivatives and uses thereof of the present invention, wherein the preparation method of the tricyclic thiazolyl pyrimidinone ether derivatives is carried out according to the following steps:

[0076] Preparation of compound A:

[0077] At -10°C, 57.3 g, 0.83 mol of sodium nitrite and 100 g, 0.83 mol of ethyl cyanoacetate were dissolved in 700 ml of pure water, followed by slow dropwise addition of 36.6 ml, 0.055 mol of 85% concentrated phosphoric acid for 3 hours, followed by heating to 45°C and stirring for 1 hour, followed by addition of 74 ml, 0.88 mol of concentrated hydrochloric acid, and continued stirring at 0°C overnight, to which a large amount of white solid precipitated, which was filtered to obtain white compound A, which did not need to be purified for the next reaction;

[0078] Preparation of compound B:

[0079] Under room temperature, 43 g (0.3 mol) of the obtained white compound A was dissolved in 500 ml of pure water, 350 ml of a saturated sodium bicarbonate solution was slowly added dropwise under stirring, followed by the addition of 156 g (0.9 mol) of sodium dithionite, the temperature was raised to 35° C., the reaction was continued for 1 hour, and then the reaction was continued at room temperature for 3 hours, and the mixture was extracted 3 times with 500 ml of dichloromethane, the organic phases were combined, dried, concentrated, and gradient eluted by normal silica gel column chromatography, the eluent being petroleum ether:ethyl acetate in a volume ratio of 2:1, to obtain compound B;

[0080] Preparation of compound C:

[0081] Under argon protection, 6.48 g, 63.6 mmol of acetic anhydride was slowly added dropwise to 2.22 g, 53 mmol of formic acid solution, and the mixture was heated to 50°C for reaction for 5 h. Then, under ice bath conditions, 3.9 g, 25 mmol of compound B was slowly added dropwise to the above solution, and the mixture was reacted at room temperature until all the raw materials disappeared. The mixture was extracted with 500 ml of dichloromethane for 3 times, and the organic phases were combined, dried, concentrated, and gradient eluted by normal silica gel column chromatography with the eluent being petroleum ether:ethyl acetate = 5:1 to obtain compound C.

[0082] Preparation of compound D:

[0083] Under argon protection, 1.56 g (10 mmol) of the obtained compound C was dissolved in 20 ml of toluene, and then 4.5 g (11 mmol) of Lawesson's reagent was added, and the mixture was heated under reflux for 24 hours until all the raw materials disappeared. The reaction solution was filtered, concentrated, and eluted by normal silica gel column chromatography with a gradient elution ratio of petroleum ether:ethyl acetate = 1:1 to obtain compound D;

[0084] Preparation of compound E:

[0085] The obtained compound D (1.72 g, 10 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, and NBS (2.2 g, 12 mmol) was added in small amounts several times, and the mixture was reacted at room temperature for 3 h until all the raw materials disappeared, quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution, and the eluent was petroleum ether: ethyl acetate = 5:1, to obtain compound E;

[0086] Preparation of compound F:

[0087] The obtained compound E 2.5g 10mmol was dissolved in 20mL of anhydrous dioxane, and pyrrolidone 1.3g 15mmol was added, and then phosphorus oxychloride 2.4ml 25mmol was slowly added dropwise, and refluxed to react until all the raw materials disappeared. The reaction solution was filtered and concentrated, and the mixture was eluted by normal silica gel column gradient elution, and the eluent was petroleum ether: ethyl acetate = 1:2, to obtain compound F;

[0088] Preparation of compound G:

[0089] The obtained compound E 2.5g 10mmol was dissolved in 20mL of anhydrous dioxane, and caprolactam 1.7g 15mmol was added, and then phosphorus oxychloride 2.4ml 25mmol was slowly added dropwise, and refluxed to react until all the raw materials disappeared. The reaction solution was filtered and concentrated, and the mixture was eluted by normal silica gel column gradient elution, and the eluent was petroleum ether: ethyl acetate = 1:2, to obtain compound G;

[0090] Preparation of compounds H1-H20:

[0091] The obtained compound F (0.27 g 1 mmol) was dissolved in 10 mL of anhydrous acetonitrile, and 0.98 g 3 mmol of cesium carbonate and 1.2 mmol of differently substituted phenols (thiophenols) were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared. The reaction solution was filtered and concentrated, and the mixture was eluted by normal silica gel column chromatography with gradient elution using pure ethyl acetate as the eluent to obtain compounds H1-H20 respectively.

[0092] Preparation of compounds I1-I20:

[0093] The obtained compound G (0.29 g 1 mmol) was dissolved in 10 mL of anhydrous acetonitrile, and 0.98 g 3 mmol of cesium carbonate and 1.2 mmol of differently substituted phenols (thiophenols) were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared. The reaction solution was filtered and concentrated, and the mixture was eluted by normal silica gel column chromatography with gradient elution using pure ethyl acetate as the eluent to obtain compounds I1-I20 respectively.

[0094] The tricyclic thiazolyl pyrimidine ketone ether derivative of the present invention uses ethyl cyanoacetate as an initial raw material, generates a hydroxylamine compound (A) under the action of sodium nitrite and phosphoric acid, reduces ethyl 2-aminocyanoacetate (B) through hydrosulfite reduction, reacts with acetic anhydride and Lawesson's reagent to obtain a 5-amino-4-carboxylate thiazole compound (D), and then brominates with NBS, and under the action of phosphorus oxychloride, obtains a 2-bromo-dihydropyrrole [1,2-a] thiazolyl [5,4-d] pyrimidine-9 (5H) -one compound (F) and a 2-bromo-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one derivative (G), and finally reacts with different substituted phenols (thiophenol) under the action of a base to obtain 40 tricyclic thiazolyl pyrimidine ketone ether compounds H1-H20 and I1-I20.

[0095] Its synthetic route is as follows:

[0096] DETAILED DESCRIPTION

[0097] The present invention is further described based on examples, but the present invention is not limited to these examples;

[0098] Reagents: All reagents were commercially available of analytical grade;

[0099] Example 1

[0100] Preparation of Compound A:

[0101] At -10°C, 57.3ml, 0.83mol of sodium nitrite and 100g, 0.83mol of ethyl cyanoacetate were dissolved in 700ml of pure water, followed by slow dropwise addition of 36.6ml, 0.055mol of 85% concentrated phosphoric acid for 3 hours, followed by heating to 45°C and stirring for 1 hour, followed by addition of 74ml, 0.88mol of concentrated hydrochloric acid, followed by continued stirring at 0°C overnight, a large amount of white solid precipitated, filtered, and obtained white compound A as ethyl 2-cyano-2-hydroxyiminoacetate, which did not require purification for the next step;

[0102] Preparation of compound B:

[0103] Under room temperature, the obtained white compound A is ethyl 2-cyano-2-hydroxyiminoacetate 43g, 0.3mol is dissolved in 500ml of pure water, 350ml of saturated sodium bicarbonate solution is slowly added dropwise under stirring, and then 156g of sodium dithionite, 0.9mol is added, the temperature is raised to 35°C, the reaction is carried out for 1 hour, and then the reaction is carried out at room temperature for 3 hours, and 500ml of dichloromethane is used for extraction 3 times, the organic phases are combined, dried, concentrated, and gradient eluted by normal silica gel column chromatography, and the eluent is petroleum ether: ethyl acetate in a volume ratio of 2:1, that is, compound B is ethyl 2-amino-2-cyanoacetate, which does not need to be purified for the next step reaction;

[0104] 1 H NMR (400 MHz, CDCl 3 )δ7.73(s,1H),4.81(s,2H),4.34(q,J=7.0Hz,2H),1.36(t,J=7.1Hz,3H);

[0105] Preparation of compound C:

[0106] Under argon protection, 6.48 g, 63.6 mmol of acetic anhydride was slowly added dropwise to 2.22 g, 53 mmol of formic acid solution, heated to 50°C for reaction for 5 h, then, under ice bath conditions, 3.9 g, 25 mmol of compound B, ethyl 2-amino-2-cyanoacetate, was slowly added dropwise to the above solution, reacted at room temperature until all the raw materials disappeared, extracted 3 times with 500 ml of dichloromethane, combined the organic phases, dried, concentrated, and eluted with normal silica gel column chromatography gradient elution, the eluent was petroleum ether: ethyl acetate in a volume ratio of 5:1, that is, compound C, ethyl 2-formamido-2-cyanoacetate, was obtained; yield: 76%, light yellow solid, melting point: 128-130°C;

[0107] 1 H NMR (400 MHz, CDCl 3)δ8.32(s,1H),6.46(s,1H),5.51(d,J=5.1Hz,1H),4.34(q,J=7.0Hz,2H),1.35(t,J=7.1Hz,3H);

[0108] Preparation of compound D:

[0109] Under argon protection, the obtained compound C, ethyl 2-formamido-2-cyanoacetate 1.56 g 10 mmol, was dissolved in 20 ml of toluene, and then 4.5 g 11 mmol of Lawesson's reagent was added, and the mixture was heated and refluxed for 24 hours until all the raw materials disappeared. The reaction solution was filtered and concentrated, and the mixture was eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether:ethyl acetate in a volume ratio of 1:1, and the compound D, ethyl 5-amino-thiazole-4-carboxylate, was obtained with a yield of 73%, a light yellow solid, and a melting point of 135-136°C.

[0110] 1 H NMR (400 MHz, CDCl 3 )δ7.88(s,1H),6.00(s,2H),4.39(q,J=7.1Hz,2H),1.42(t,J=7.1Hz,3H);

[0111] Preparation of compound E:

[0112] The obtained compound D, 5-amino-thiazole-4-carboxylic acid ethyl ester 1.72 g 10 mmol, was dissolved in anhydrous tetrahydrofuran 20 mL, and NBS 2.2 g 12 mmol was added in small amounts several times, and the reaction was carried out at room temperature for 3 h until the raw material disappeared completely, and the reaction was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 5:1, so as to obtain compound E, 2-bromo-5-amino-thiazole-4-carboxylic acid ethyl ester, with a yield of 73%, light yellow solid, mp 151-152°C;

[0113] 1 H NMR (400 MHz, CDCl 3 )δ6.03(s,2H),4.38(q,J=7.1Hz,2H),1.39(t,J=7.1Hz,3H);

[0114] Preparation of compound F:

[0115] The obtained compound E, 2.5 g 10 mmol of ethyl 2-bromo-5-amino-thiazole-4-carboxylate, was dissolved in 20 mL of anhydrous dioxane, and 1.3 g 15 mmol of pyrrolidone was added, and then 2.4 ml 25 mmol of phosphorus oxychloride was slowly added dropwise, and refluxed until the raw materials disappeared completely, extracted with dichloromethane, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and eluted with normal silica gel column chromatography gradient, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 1:2, so as to obtain compound F, 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, with a yield of 73%, a light yellow solid, and a melting point of 208-209°C;

[0116] 1 H NMR (400 MHz, CDCl 3 )δ4.25(t,J=7.3Hz,2H),3.17(t,J=8.0Hz,2H),2.66–2.16(m,2H);

[0117] Preparation of compound G:

[0118] The obtained compound E, 2.5 g 10 mmol of ethyl 2-bromo-5-amino-thiazole-4-carboxylate, was dissolved in 20 mL of anhydrous dioxane, and 1.7 g 15 mmol of caprolactam was added, and then 2.4 ml 25 mmol of phosphorus oxychloride was slowly added dropwise, and refluxed until the raw materials disappeared completely, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted with normal silica gel column chromatography gradient, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 5:1, so as to obtain compound G, 2-bromo-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one, with a yield of 71%, a light yellow solid, and a melting point of 212-213 ° C;

[0119] 1 H NMR (400 MHz, CDCl 3 )δ4.25(t,J=7.3Hz,2H),3.17(t,J=8.0Hz,2H),2.66–2.16(m,6H);

[0120] The obtained compound F (0.27 g 1 mmol) was dissolved in 10 mL of anhydrous acetonitrile, and 0.98 g 3 mmol of cesium carbonate and 1.2 mmol of differently substituted phenols (thiophenols) were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared. The reaction solution was filtered and concentrated, and the mixture was eluted by normal silica gel column chromatography with gradient elution using pure ethyl acetate as the eluent to obtain compounds H1-H20 respectively.

[0121] Example 2

[0122] Preparation of compound H1:

[0123] The compound F obtained in Example 1, which is 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one 0.27 g 1 mmol, was dissolved in 10 mL of anhydrous acetonitrile, and cesium carbonate 0.98 g 3 mmol and 4-methylphenol 0.13 g 1.2 mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution, and the eluent was petroleum ether:ethyl acetate in a volume ratio of 1:2, to obtain compound H1, which is 2-(4-methylphenyloxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, with a yield of 89%, as a light yellow solid, with a melting point of 142-143°C;

[0124] 1 H NMR (400 MHz, CDCl 3 )δ7.18(s,4H),4.62–3.60(m,2H),3.14(t,J=8.0Hz,2H),2.34(s,3H),2.33–2.19(m,2H).

[0125] Example 3

[0126] Preparation of compound H2:

[0127] The compound F obtained in Example 1, which is 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one 0.27 g 1 mmol, was dissolved in 10 mL of anhydrous acetonitrile, and cesium carbonate 0.98 g 3 mmol and 3-chlorophenol 0.15 g 1.2 mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution, and the eluent was petroleum ether:ethyl acetate in a volume ratio of 1:2, to obtain compound H2, which is 2-(3-chlorophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, with a yield of 85%, as a light yellow solid, with a melting point of 97-98°C;

[0128] 1 H NMR (400 MHz, CDCl 3 )δ7.32(dd,J=9.2,6.9Hz,2H),7.28–7.23(m,2H),4.67–3.82(m,2H),3.16(t,J=8.0Hz,2H),2.84–1.85(m,2H).

[0129] Example 4

[0130] Preparation of compound H3:

[0131] The compound F obtained in Example 1, which is 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one 0.27 g 1 mmol, was dissolved in 10 mL of anhydrous acetonitrile, and cesium carbonate 0.98 g 3 mmol and 3-bromophenol 0.21 g 1.2 mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether:ethyl acetate in a volume ratio of 1:2, to obtain compound H3, which is 2-(3-bromophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, with a yield of 80%, as a light yellow solid, with a melting point of 112-113°C;

[0132] 1 H NMR (400 MHz, CDCl 3 )δ7.47(t,J=2.0Hz,1H),7.37(dt,J=7.6,1.5Hz,1H),7.34–7.28(m,1H),7.2 8–7.24(m,1H),4.24–4.17(m,2H),3.15(t,J=8.0Hz,2H),2.38–2.19(m,2H).

[0133] Example 5

[0134] Preparation of compound H4

[0135] The compound F obtained in Example 1, which is 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one 0.27 g 1 mmol, was dissolved in 10 mL of anhydrous acetonitrile, and cesium carbonate 0.98 g 3 mmol and 4-bromophenol 0.21 g 1.2 mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether:ethyl acetate in a volume ratio of 1:2, to obtain compound H4, which is 2-(4-bromophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, with a yield of 84%, as a light yellow solid, with a melting point of 161-162°C;

[0136] 1 H NMR (400 MHz, CDCl 3)δ7.49(d,J=8.9Hz,2H),7.36–7.01(m,2H),4.38–4.00(m,2H),3.14(t,J=8.0Hz,2H),2.54–2.15(m,2H).

[0137] Example 6

[0138] Preparation of compound H5:

[0139] The compound F obtained in Example 1, which is 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one 0.27 g 1 mmol, was dissolved in 10 mL of anhydrous acetonitrile, and cesium carbonate 0.98 g 3 mmol and 3-fluorophenol 0.14 g 1.2 mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether:ethyl acetate in a volume ratio of 1:2, to obtain compound H5, which is 2-(3-fluorophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, with a yield of 78%, as a light yellow solid, with a melting point of 153-154°C;

[0140] 1 H NMR (400 MHz, CDCl 3 )δ7.35(td,J=8.3,6.5Hz,1H),7.18–7.05(m,2H),6.95(td,J=8.3,2.4Hz,1H),4.45–3.89(m,2H),3.16(t,J=8.0Hz,2H),2.63–2.06(m,2H).

[0141] Example 7

[0142] Preparation of compound H6

[0143] The compound F obtained in Example 1, which is 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one 0.27 g 1 mmol, was dissolved in 10 mL of anhydrous acetonitrile, and cesium carbonate 0.98 g 3 mmol and 4-fluorophenol 0.14 g 1.2 mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether:ethyl acetate in a volume ratio of 1:2, to obtain compound H6, which is 2-(4-fluorophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, with a yield of 81%, as a light yellow solid, with a melting point of 175-176°C;

[0144] 1 H NMR (400 MHz, CDCl 3 )δ7.56–7.20(m,2H),7.07(dd,J=9.0,8.1Hz,2H),4.41–3.87(m,2H),3.14(t,J=8.0Hz,2H),2.54–2.15(m,2H).

[0145] Example 8

[0146] Preparation of compound H7:

[0147] The compound F obtained in Example 1, which is 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one 0.27 g 1 mmol, was dissolved in 10 mL of anhydrous acetonitrile, and cesium carbonate 0.98 g 3 mmol and 3-trifluoromethylphenol 0.19 g 1.2 mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether:ethyl acetate in a volume ratio of 1:2, to obtain compound H7, which is 2-(3-trifluoromethylphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, with a yield of 73%, as a light yellow solid, with a melting point of 104-105°C;

[0148] 1 H NMR (400 MHz, CDCl 3 )δ7.63–7.56(m,1H),7.54(s,1H),7.51–7.45(m,2H),4.27–4.13(m,2H),3.15(t,J=8.0Hz,2H),2.45–2.18(m,2H).

[0149] Example 9

[0150] Preparation of compound H8:

[0151] The compound F obtained in Example 1, which is 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one 0.27 g 1 mmol, was dissolved in 10 mL of anhydrous acetonitrile, and cesium carbonate 0.98 g 3 mmol and 4-trifluoromethylphenol 0.19 g 1.2 mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether:ethyl acetate in a volume ratio of 1:2, to obtain compound H8, which is 2-(4-trifluoromethylphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, with a yield of 75%, as a light yellow solid, with a melting point of 136-137°C;

[0152] 1 H NMR (400 MHz, CDCl 3 )δ7.66(d,J=8.6Hz,2H),7.48(d,J=8.6Hz,2H),4.58–3.91(m,2H),3.17(t,J=8.0Hz,2H),2.87–1.87(m,2H).

[0153] Example 10

[0154] Preparation of compound H9:

[0155] The compound F obtained in Example 1, which is 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one 0.27 g 1 mmol, was dissolved in 10 mL of anhydrous acetonitrile, and cesium carbonate 0.98 g 3 mmol and 3-methoxyphenol 0.15 g 1.2 mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether:ethyl acetate in a volume ratio of 1:2, to obtain compound H9, which is 2-(3-methoxyphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, with a yield of 73%, as a light yellow solid, with a melting point of 118-119°C;

[0156] 1 H NMR (400 MHz, CDCl 3)δ7.27(t,J=8.2Hz,1H),6.92–6.85(m,1H),6.83(t,J=2.3Hz,1H),6.78(dd,J=8.3,2 .4Hz,1H),4.56–4.04(m,2H),3.77(s,3H),3.12(t,J=8.0Hz,2H),2.54–2.08(m,2H).

[0157] Embodiment 11

[0158] Preparation of compound H10:

[0159] The compound F obtained in Example 1, which is 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one 0.27 g 1 mmol, was dissolved in 10 mL of anhydrous acetonitrile, and cesium carbonate 0.98 g 3 mmol and 4-trifluoromethoxyphenol 0.22 g 1.2 mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether:ethyl acetate in a volume ratio of 1:2, to obtain compound H10, which is 2-(4-trifluoromethoxyphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, with a yield of 76%, as a light yellow solid, with a melting point of 189-190°C;

[0160] 1 H NMR (400 MHz, CDCl 3 )δ7.51–7.32(m,2H),7.29–6.93(m,2H),4.49–3.95(m,2H),3.15(t,J=8.0Hz,2H),2.76–1.95(m,2H).

[0161] Example 12

[0162] Preparation of compound H11:

[0163] The compound F obtained in Example 1, which is 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one 0.27 g 1 mmol, was dissolved in 10 mL of anhydrous acetonitrile, and cesium carbonate 0.98 g 3 mmol and 3-nitrophenol 0.17 g 1.2 mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether:ethyl acetate in a volume ratio of 1:2, to obtain compound H11, which is 2-(3-nitrophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, with a yield of 68%, as a light yellow solid, with a melting point of 181-182°C;

[0164] 1 H NMR (400 MHz, CDCl 3 )δ8.16(t,J=2.2Hz,1H),8.11(dd,J=8.2,1.2Hz,1H),7.88–7.74(m,1H),7.58 (t,J=8.2Hz,1H),4.54–4.00(m,2H),3.17(t,J=8.0Hz,2H),2.78–2.19(m,2H).

[0165] Embodiment 13

[0166] Preparation of compound H12:

[0167] The compound F obtained in Example 1, which is 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one 0.27 g 1 mmol, was dissolved in 10 mL of anhydrous acetonitrile, and cesium carbonate 0.98 g 3 mmol and 3,4-dichlorophenol 0.20 g 1.2 mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether:ethyl acetate in a volume ratio of 1:2, to obtain compound H12, which is 2-(3,4-dichlorophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, with a yield of 80%, as a light yellow solid, with a melting point of 175-176°C;

[0168] 1 H NMR (400 MHz, CDCl 3 )δ7.53–7.39(m,2H),7.37–7.23(m,1H),4.21(m,2H),3.16(t,J=8.0Hz,2H),2.69–1.96(m,2H).

[0169] Embodiment 14

[0170] Preparation of compound H13:

[0171] The compound F obtained in Example 1, which is 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one 0.27 g 1 mmol, was dissolved in 10 mL of anhydrous acetonitrile, and cesium carbonate 0.98 g 3 mmol and 3,5-difluorophenol 0.16 g 1.2 mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether:ethyl acetate in a volume ratio of 1:2, to obtain compound H13, which is 2-(3,5-difluorophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, with a yield of 77%, as a light yellow solid, with a melting point of 184-185°C;

[0172] 1 H NMR (400 MHz, CDCl 3 )δ7.08–6.84(m,2H),6.69(tt,J=8.8,2.3Hz,1H),4.84–3.73(m,2H),3.16(t,J=8.0Hz,2H),2.63–1.87(m,2H).

[0173] Embodiment 15

[0174] Preparation of compound H14

[0175] The compound F obtained in Example 1, which is 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one 0.27 g 1 mmol, was dissolved in 10 mL of anhydrous acetonitrile, and cesium carbonate 0.98 g 3 mmol and 3,4-difluorophenol 0.16 g 1.2 mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether:ethyl acetate in a volume ratio of 1:2, to obtain compound H14, which is 2-(3,4-difluorophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, with a yield of 71%, as a light yellow solid, with a melting point of 191-192°C;

[0176] 1 H NMR (400 MHz, CDCl 3)δ7.27–7.20(m,1H),7.20–7.14(m,1H),7.14–7.08(m,1H),4.32–4.02(m,2H),3.15(t,J=8.0Hz,2H),2.43–1.96(m,2H).

[0177] Example 16

[0178] Preparation of compound H15:

[0179] The compound F obtained in Example 1, which is 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one 0.27 g 1 mmol, was dissolved in 10 mL of anhydrous acetonitrile, and cesium carbonate 0.98 g 3 mmol and 3,5-ditrifluoromethylphenol 0.28 g 1.2 mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether:ethyl acetate in a volume ratio of 1:2, to obtain compound H15, which is 2-(3,5-ditrifluoromethylphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, with a yield of 74%, as a light yellow solid, with a melting point of 210-211°C;

[0180] 1 H NMR (400 MHz, CDCl 3 )δ7.81(s,2H),7.75(s,1H),4.91–3.89(m,2H),3.17(t,J=8.0Hz,2H),2.76–2.13(m,2H).

[0181] Embodiment 17

[0182] Preparation of compound H16:

[0183] The compound F obtained in Example 1, which is 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one (0.27 g 1 mmol), was dissolved in 10 mL of anhydrous acetonitrile, and cesium carbonate (0.98 g 3 mmol) and 1-naphthol (0.17 g 1.2 mmol) were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether:ethyl acetate in a volume ratio of 1:2, to obtain compound H16, which is 2-(1-naphthylphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one. The yield was 86%, and the mixture was a light yellow solid with a melting point of 165-166°C.

[0184] 1 H NMR (400MHz, cdcl 3 )δ8.07(dd,J=6.5,2.4Hz,1H),7.88(dd,J=6.5,2.8Hz,1H),7.78(d,J=8.0Hz,1H) ,7.65–7.40(m,4H),4.99–3.78(m,2H),3.13(t,J=8.0Hz,2H),2.85–2.13(m,2H).

[0185] Embodiment 18

[0186] Preparation of compound H17:

[0187] The compound F obtained in Example 1, which is 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one 0.27 g 1 mmol, was dissolved in 10 mL of anhydrous acetonitrile, and cesium carbonate 0.98 g 3 mmol and 4-phenylphenol 0.20 g 1.2 mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution, and the eluent was petroleum ether:ethyl acetate in a volume ratio of 1:2, to obtain compound H17, which is 2-(4-phenylphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, with a yield of 81%, as a light yellow solid, with a melting point of 163-164°C;

[0188] 1 H NMR (400MHz, cdcl 3 )δ7.62–7.58(m,2H),7.55(dt,J=3.0,1.8Hz,2H),7.47–7.37(m,4H),7.37 –7.30(m,1H),4.78–3.71(m,2H),3.16(t,J=8.0Hz,2H),2.78–1.80(m,2H).

[0189] Embodiment 19

[0190] Preparation of compound H18:

[0191] The compound F obtained in Example 1, which is 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one 0.27 g 1 mmol, was dissolved in 10 mL of anhydrous acetonitrile, and cesium carbonate 0.98 g 3 mmol and 4-methylthiophenol 0.15 g 1.2 mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether:ethyl acetate in a volume ratio of 1:2, to obtain compound H8, which is 2-(4-methylthio)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, with a yield of 73%, as a light yellow solid, with a melting point of 160-161°C;

[0192] 1 H NMR (400MHz, cdcl 3 )δ7.56(d,J=8.1Hz,2H),7.25(d,J=9.3Hz,2H),4.69–3.76(m,2H),3.11(t,J=8.0Hz,2H),2.40(s,3H),2.36–2.22(m,2H).

[0193] Embodiment 20

[0194] Preparation of compound H19:

[0195] The compound F obtained in Example 1, which is 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one 0.27 g 1 mmol, was dissolved in 10 mL of anhydrous acetonitrile, and cesium carbonate 0.98 g 3 mmol and 4-fluorobenzenethiol 0.15 g 1.2 mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution, and the eluent was petroleum ether:ethyl acetate in a volume ratio of 1:2, to obtain compound H19, which is 2-(4-fluorophenylthio)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, with a yield of 70%, as a light yellow solid, with a melting point of 168-169°C;

[0196] 1 H NMR (400MHz, cdcl 3 )δ8.01–7.47(m,2H),7.23–6.63(m,2H),4.52–3.58(m,2H),3.12(t,J=8.0Hz,2H),2.76–1.89(m,2H).

[0197] Embodiment 21

[0198] Preparation of compound H20:

[0199] The compound F obtained in Example 1, which is 2-bromo-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one 0.27 g 1 mmol, was dissolved in 10 mL of anhydrous acetonitrile, and cesium carbonate 0.98 g 3 mmol and 4-methoxythiophenol 0.17 g 1.2 mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution, and the eluent was petroleum ether:ethyl acetate in a volume ratio of 1:2, to obtain compound H20, which is 2-(4-methoxyphenylthio)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, with a yield of 67%, as a light yellow solid, with a melting point of 145-146°C;

[0200] 1 H NMR (400MHz, cdcl 3 )δ7.60(d,J=8.8Hz,2H),6.96(d,J=8.8Hz,2H),4.58–4.02(m,2H),3.84(s,3H),3.10(t,J=8.0Hz,2H),2.48–1.89(m,2H).

[0201] Embodiment 22

[0202] Preparation of compound I1:

[0203] The compound G obtained in Example 1, which is 2-bromo-6,7,8,9-thiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one 0.3g 1mmol, was dissolved in 10mL of anhydrous acetonitrile, and cesium carbonate 0.98g 3mmol and 4-methylphenol 0.13g 1.2mmol were added respectively. Under argon protection, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 1:1, to obtain compound I1, which is 2-(4-methylphenyloxy)-6,7,8,9-thiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one, with a yield of 83%, a light yellow solid, and a melting point of 138-139°C;

[0204] 1 H NMR (400 MHz, CDCl 3)δ7.20(s,4H),4.42–4.37(m,2H),3.23–2.82(m,2H),2.36(s,3H),2.04–1.48(m,6H).

[0205] Embodiment 23

[0206] Preparation of compound I2:

[0207] The compound G obtained in Example 1, which is 2-bromo-6,7,8,9-thiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one 0.3g 1mmol, was dissolved in 10mL of anhydrous acetonitrile, and cesium carbonate 0.98g 3mmol and 3-chlorophenol 0.15g 1.2mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether: ethyl acetate in a volume ratio of 1:1, to obtain compound I2, which is 2-(3-chlorophenoxy)-6,7,8,9-thiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one, with a yield of 87%, a light yellow solid, and a melting point of 92-93°C;

[0208] 1 H NMR (400 MHz, CDCl 3 )δ7.35–7.26(m,1H),7.26–7.13(m,2H),6.89–6.61(m,1H),4.60–3.84(m,2H),3.63–2.89(m,2H),1.91–1.69(m,6H).

[0209] Embodiment 24

[0210] Preparation of compound I3:

[0211] The compound G obtained in Example 1, which is 2-bromo-6,7,8,9-thiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one 0.3g 1mmol, was dissolved in 10mL of anhydrous acetonitrile, and cesium carbonate 0.98g 3mmol and 3-bromophenol 0.21g 1.2mmol were added respectively. Under argon protection, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether: ethyl acetate in a volume ratio of 1:1, to obtain compound I3, which is 2-(3-bromophenoxy)-6,7,8,9-thiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one, with a yield of 89%, a light yellow solid, and a melting point of 125-126°C;

[0212] 1 H NMR (400 MHz, CDCl 3 )δ7.45(t,J=2.0Hz,1H),7.40–7.32(m,1H),7.32–7.27(m,1H),7.26–7.18(m,1H),4.73–3.99(m,2H),3.23–2.72(m,2H),2.24–1.25(m,6H).

[0213] Embodiment 25

[0214] Preparation of compound I4:

[0215] The compound G obtained in Example 1, which is 2-bromo-6,7,8,9-thiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one 0.3g 1mmol, was dissolved in 10mL of anhydrous acetonitrile, and cesium carbonate 0.98g 3mmol and 4-bromophenol 0.21g 1.2mmol were added respectively. Under argon protection, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 1:1, to obtain compound I4, which is 2-(4-bromophenoxy)-6,7,8,9-thiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one, with a yield of 78%, a light yellow solid, and a melting point of 154-155°C;

[0216] 1 H NMR (400 MHz, CDCl 3 )δ7.76–7.34(m,2H),7.34–6.96(m,2H),4.58–4.05(m,2H),3.65–2.57(m,12H),2.39–1.38(m,6H).

[0217] Embodiment 26

[0218] Preparation of compound I5:

[0219] The compound G obtained in Example 1, which is 2-bromo-6,7,8,9-thiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one 0.3g 1mmol, was dissolved in 10mL of anhydrous acetonitrile, and cesium carbonate 0.98g 3mmol and 3-fluorophenol 0.14g 1.2mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether: ethyl acetate in a volume ratio of 1:1, to obtain compound I5, which is 2-(3-fluorophenoxy)-6,7,8,9-thiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one, with a yield of 80%, as a light yellow solid, with a melting point of 153-154°C;

[0220] 1 H NMR (400 MHz, CDCl 3 )δ7.36(td,J=8.3,6.5Hz,1H),7.20–7.06(m,1H),6.97(td,J=8.3,2.3Hz,1H),4.61–4.18(m,1H),3.88–2.89(m,1H),1.97–1.38(m,3H).

[0221] Embodiment 27

[0222] Preparation of compound I6:

[0223] The compound G obtained in Example 1, which is 2-bromo-6,7,8,9-thiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one 0.3g 1mmol, was dissolved in 10mL of anhydrous acetonitrile, and cesium carbonate 0.98g 3mmol and 4-fluorophenol 0.14g 1.2mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 1:1, to obtain compound I6, which is 2-(4-fluorophenoxy)-6,7,8,9-thiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one, with a yield of 84%, a light yellow solid, and a melting point of 143-44°C;

[0224] 1 H NMR (400 MHz, CDCl 3 )δ7.45–7.24(m,2H),7.15–6.64(m,2H),4.69–4.02(m,2H),3.30–2.70(m,2H),2.34–1.45(m,6H).

[0225] Embodiment 28

[0226] Preparation of compound I7:

[0227] The compound G obtained in Example 1, 0.3 g 1 mmol of 2-bromo-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidin [1,2-a] azapine-11 (5H) -one, was dissolved in 10 mL of anhydrous acetonitrile, and 0.98 g 3 mmol of cesium carbonate and 0.19 g 3-trifluoromethylphenol were added respectively. 1.2mmol, under argon protection, reflux reaction until all the raw materials disappear, extract with dichloromethane, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and use normal silica gel column chromatography gradient elution, the eluent is petroleum ether: ethyl acetate with a volume ratio of 1:1, to obtain compound I7 as 2-(3-trifluoromethylphenoxy)-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidin [1,2-a] azapine-11 (5H) -one, yield: 75%, light yellow solid, melting point: 112-113 ° C;

[0228] 1 H NMR (400 MHz, CDCl 3 )δ7.69–7.57(m,1H),7.57–7.39(m,3H),4.59–4.22(m,2H),3.35–2.86(m,2H),2.13–1.46(m,6H).

[0229] Embodiment 29

[0230] Preparation of compound I8:

[0231] The compound G obtained in Example 1, 0.3 g 1 mmol of 2-bromo-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidin [1,2-a] azapine-11 (5H) -one, was dissolved in 10 mL of anhydrous acetonitrile, and 0.98 g 3 mmol of cesium carbonate and 0.19 g 4-trifluoromethylphenol were added respectively. 1.2mmol, under the protection of argon, reflux reaction until all the raw materials disappear, extract with dichloromethane, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and use normal silica gel column chromatography gradient elution, the eluent is petroleum ether: ethyl acetate with a volume ratio of 1:1, to obtain compound I8 as 2-(4-trifluoromethylphenoxy)-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidin [1,2-a] azapine-11 (5H) -one, yield: 79%, light yellow solid, melting point: 173-174 ° C;

[0232] 1 H NMR (400 MHz, CDCl 3)δ7.68(d,J=8.7Hz,2H),7.50(d,J=8.6Hz,2H),4.62–4.18(m,2H),3.77–2.75(m,2H),2.27–1.48(m,6H).

[0233] Embodiment 30

[0234] Preparation of compound I9:

[0235] The compound G obtained in Example 1, which is 2-bromo-6,7,8,9-thiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one 0.3g 1mmol, was dissolved in 10mL of anhydrous acetonitrile, and cesium carbonate 0.98g 3mmol and 3-methoxyphenol 0.15g 1.2mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 1:1, to obtain compound I9, which is 2-(3-methoxyphenoxy)-6,7,8,9-thiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one, with a yield of 75%, a light yellow solid, and a melting point of 94-95°C;

[0236] 1 H NMR (400 MHz, CDCl 3 )δ7.30(t,J=8.2Hz,1H),6.92(dd,J=8.1,2.3Hz,1H),6.85(t,J=2.3Hz,1H),6.81(dd,J =8.3,2.4Hz,1H),4.59–4.22(m,2H),3.80(s,3H),3.21–2.94(m,2H),2.15–1.59(m,6H).

[0237] Embodiment 31

[0238] Preparation of compound I10:

[0239] The compound G obtained in Example 1, 0.3 g 1 mmol of 2-bromo-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one, was dissolved in 10 mL of anhydrous acetonitrile, and 0.98 g 3 mmol of cesium carbonate and 0.22 g 4-trifluoromethoxyphenol were added respectively. 1.2mmol, under argon protection, reflux reaction until all the raw materials disappear, extract with dichloromethane, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and use normal silica gel column chromatography gradient elution, the eluent is petroleum ether: ethyl acetate with a volume ratio of 1:1, to obtain compound I10 as 2-(4-trifluoromethoxyphenoxy)-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidin [1,2-a] azapine-11 (5H) -one, yield: 80%, light yellow solid, melting point: 158-159 ° C;

[0240] 1 H NMR (400 MHz, CDCl 3 )δ7.40(d,J=9.1Hz,2H),7.26(d,J=9.0Hz,2H),4.92–4.11(m,2H),3.77–2.73(m,2H),2.32–1.39(m,6H).

[0241] Embodiment 32

[0242] Preparation of compound I11:

[0243] The compound G obtained in Example 1, 0.3 g 1 mmol of 2-bromo-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidin [1,2-a] azapine-11 (5H) -one, was dissolved in 10 mL of anhydrous acetonitrile, and 0.98 g 3 mmol of cesium carbonate and 0.17 g 3-nitrophenol were added respectively. 1.2mmol, under argon protection, reflux reaction until all the raw materials disappear, extract with dichloromethane, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and use normal silica gel column chromatography gradient elution, the eluent is petroleum ether: ethyl acetate with a volume ratio of 1:1, to obtain compound I11, which is 2-(3-nitrophenoxy)-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidin [1,2-a] azapine-11 (5H) -one, yield: 64%, light yellow solid, melting point: 148-149 ° C;

[0244] 1 H NMR (400 MHz, CDCl 3)δ8.17(t,J=2.2Hz,1H),8.10(dd,J=8.2,2.0Hz,1H),7.77(dd,J=8.3,2.4Hz,1H) ,7.57(t,J=8.2Hz,1H),4.62–4.04(m,2H),3.24–2.78(m,2H),2.06–1.37(m,6H).

[0245] Embodiment 33

[0246] Preparation of compound I12:

[0247] The compound G obtained in Example 1, 0.3 g 1 mmol of 2-bromo-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidin [1,2-a] azapine-11 (5H) -one, was dissolved in 10 mL of anhydrous acetonitrile, and 0.98 g 3 mmol of cesium carbonate and 0.20 g 3,4-dichlorophenol were added respectively. 1.2mmol, under the protection of argon, reflux reaction until all the raw materials disappear, extract with dichloromethane, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and use normal silica gel column chromatography gradient elution, the eluent is petroleum ether: ethyl acetate with a volume ratio of 1:1, to obtain compound I12 as 2-(3,4-dichlorophenoxy)-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidin [1,2-a] azapine-11 (5H) -one, yield: 82%, light yellow solid, melting point: 158-159 ° C;

[0248] 1 H NMR (400 MHz, CDCl 3 )δ7.47(dd,J=5.8,2.8Hz,2H),7.27(dd,J=8.9,2.8Hz,1H),4.64–3.90(m,2H),3.67–2.66(m,2H),2.42–1.13(m,6H).

[0249] Embodiment 34

[0250] Preparation of compound I13:

[0251] The compound G obtained in Example 1, 0.3 g 1 mmol of 2-bromo-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidin [1,2-a] azapine-11 (5H) -one, was dissolved in 10 mL of anhydrous acetonitrile, and 0.98 g 3 mmol of cesium carbonate and 0.16 g 3,5-difluorophenol were added respectively. 1.2mmol, under argon protection, reflux reaction until all the raw materials disappear, extract with dichloromethane, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and use normal silica gel column chromatography gradient elution, the eluent is petroleum ether: ethyl acetate with a volume ratio of 1:1, to obtain compound I13 as 2-(3,5-difluorophenoxy)-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidin [1,2-a] azapine-11 (5H) -one, yield: 77%, light yellow solid, melting point: 205-206 ° C;

[0252] 1 H NMR (400 MHz, CDCl 3 )δ6.96(dd,J=7.5,2.3Hz,2H),6.72(tt,J=8.8,2.3Hz,1H),4.62–3.77(m,2H),3.37–2.75(m,2H),2.32–1.34(m,6H).

[0253] Embodiment 35

[0254] Preparation of compound I14:

[0255] The compound G obtained in Example 1, 0.3 g 1 mmol of 2-bromo-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidin [1,2-a] azapine-11 (5H) -one, was dissolved in 10 mL of anhydrous acetonitrile, and 0.98 g 3 mmol of cesium carbonate and 0.16 g 3,4-difluorophenol were added respectively. 1.2mmol, under argon protection, reflux reaction until all the raw materials disappear, extract with dichloromethane, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and use normal silica gel column chromatography gradient elution, the eluent is petroleum ether: ethyl acetate with a volume ratio of 1:1, to obtain compound I14 as 2-(3,4-difluorophenoxy)-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidin [1,2-a] azapine-11 (5H) -one, yield: 76%, light yellow solid, melting point: 140-141 ° C;

[0256] 1 H NMR (400 MHz, CDCl 3)δ7.29–7.23(m,1H),7.20(dd,J=18.0,9.3Hz,1H),7.13(ddd,J=9.0,5.2,2.6Hz,1H),4.92–3.79(m,2H),3.41–2.57(m,2H),2.38–1.43(m,6H).

[0257] Embodiment 36

[0258] Preparation of compound I15:

[0259] The compound G obtained in Example 1, 0.3 g 1 mmol of 2-bromo-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidin [1,2-a] azapine-11 (5H) -one, was dissolved in 10 mL of anhydrous acetonitrile, and 0.98 g 3 mmol of cesium carbonate and 0.28 g 3,5-ditrifluoromethylphenol were added respectively. 1.2mmol, under the protection of argon, reflux reaction until all the raw materials disappear, extract with dichloromethane, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and use normal silica gel column chromatography gradient elution, the eluent is petroleum ether: ethyl acetate with a volume ratio of 1:1, to obtain compound I15 as 2-(3,5-ditrifluoromethylphenoxy)-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidin [1,2-a] azapine-11 (5H) -one, yield: 71%, light yellow solid, melting point: 130-131 ° C;

[0260] 1 H NMR (400 MHz, CDCl 3 )δ7.80(s,2H),7.72(s,1H),4.76–4.23(m,2H),3.58–2.69(m,2H),2.29–1.40(m,6H).

[0261] Embodiment 37

[0262] Preparation of compound I16:

[0263] The compound G obtained in Example 1, which is 2-bromo-6,7,8,9-thiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one 0.3g 1mmol, was dissolved in 10mL of anhydrous acetonitrile, and cesium carbonate 0.98g 3mmol and 1-naphthol 0.17g 1.2mmol were added respectively. Under argon protection, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether: ethyl acetate in a volume ratio of 1:1, to obtain compound I16, which is 2-(1-naphthylphenoxy)-6,7,8,9-thiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one, with a yield of 80%, as a light yellow solid, with a melting point of 149-150°C;

[0264] 1 H NMR (400 MHz, CDCl 3 )δ8.07(dd,J=6.4,2.6Hz,1H),7.96–7.82(m,1H),7.78(d,J=8.0Hz,1H),7 .62–7.40(m,4H),4.62–4.03(m,2H),3.72–2.50(m,2H),2.30–1.40(m,6H).

[0265] Embodiment 38

[0266] Preparation of compound I17:

[0267] The compound G obtained in Example 1, which is 2-bromo-6,7,8,9-thiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one 0.3g 1mmol, was dissolved in 10mL of anhydrous acetonitrile, and cesium carbonate 0.98g 3mmol and 4-phenylphenol 0.20g 1.2mmol were added respectively. Under the protection of argon, the mixture was refluxed until all the raw materials disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution. The eluent was petroleum ether: ethyl acetate in a volume ratio of 1:1, to obtain compound I17, which is 2-(4-phenylphenoxy)-6,7,8,9-thiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one, with a yield of 73%, as a light yellow solid, with a melting point of 165-166°C;

[0268] 1 H NMR (400 MHz, CDCl 3)δ7.59(dd,J=17.5,7.9Hz,4H),7.44(dd,J=17.4,8.0Hz,4H),7.37(q,J=7.7Hz,1H),4.64–4.25(m,2H),3.17–2.78(m,2H),2.31–1.53(m,6H).

[0269] Embodiment 39

[0270] Preparation of compound I18:

[0271] The compound G obtained in Example 1, which is 2-bromo-6,7,8,9-thiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one 0.3g 1mmol, was dissolved in 10mL of anhydrous acetonitrile, and cesium carbonate 0.98g 3mmol and 4-toluene thiophenol 0.15g 1.2mmol were added respectively. Under argon protection, the mixture was refluxed until the raw materials disappeared completely, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by normal silica gel column chromatography with gradient elution, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 1:1, to obtain compound I18, which is 2-(4-tolylthio)-6,7,8,9-thiazolidine [5',4':4,5] pyrimidine [1,2-a] azapine-11 (5H) -one, with a yield of 81%, as a light yellow solid, with a melting point of 162-163°C;

[0272] 1 H NMR (400 MHz, CDCl 3 )δ7.56(d,J=8.1Hz,2H),7.25(d,J=7.4Hz,2H),4.96–4.16(m,2H),3.98–2.89(m,2H),2.40(s,3H),2.20–1.62(m,6H).

[0273] Embodiment 40

[0274] Preparation of compound I19:

[0275] The compound G obtained in Example 1, 0.3 g 1 mmol of 2-bromo-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidin [1,2-a] azapine-11 (5H) -one, was dissolved in 10 mL of anhydrous acetonitrile, and 0.98 g 3 mmol of cesium carbonate and 0.15 g 4-fluorothiophenol were added. 1.2mmol, under argon protection, reflux reaction until all the raw materials disappear, extract with dichloromethane, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and use normal silica gel column chromatography gradient elution, the eluent is petroleum ether: ethyl acetate with a volume ratio of 1:1, to obtain compound I19 as 2-(4-fluorophenylthio)-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidin [1,2-a] azapine-11 (5H) -one, yield: 76%, light yellow solid, melting point: 148-149 ° C;

[0276] 1 H NMR (400 MHz, CDCl 3 )δ7.75–7.59(m,2H),7.22–7.08(m,2H),4.61–3.69(m,2H),3.30–2.29(m,2H),2.39–1.28(m,6H).

[0277] Embodiment 41

[0278] Preparation of compound I20:

[0279] The compound G obtained in Example 1, 0.3 g 1 mmol of 2-bromo-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidin [1,2-a] azapine-11 (5H) -one, was dissolved in 10 mL of anhydrous acetonitrile, and 0.98 g 3 mmol of cesium carbonate and 0.17 g 4-methoxythiophenol were added. 1.2mmol, under argon protection, reflux reaction until all the raw materials disappear, extract with dichloromethane, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and use normal silica gel column chromatography gradient elution, the eluent is petroleum ether: ethyl acetate with a volume ratio of 1:1, to obtain compound I20 as 2-(4-methoxyphenylthio)-6,7,8,9-tetrahydrothiazolidine [5',4':4,5] pyrimidin [1,2-a] azapine-11 (5H) -one, yield: 72%, light yellow solid, melting point: 188-189 ° C;

[0280] 1 H NMR (400 MHz, CDCl 3 )δ7.82–7.36(m,2H),7.30–6.56(m,2H),4.58–4.18(m,2H),3.83(s,2H),3.33–2.76(m,2H),2.08–1.58(m,6H).

[0281] Embodiment 42

[0282] Screening of the tricyclic thiazolylpyrimidinone ether compounds of the present invention for their resistance to acetylcholinesterase:

[0283] The total reaction volume was 200 μL: 2 μL sample, 158 μL Tris-HCl buffer solution containing acetylcholinesterase (final concentration 0.02 U / mL), the enzyme activity control group was a Tris-HCl buffer solution without enzyme, incubated at room temperature for 10 min, then 20 μL of iodinated acetylcholine (butyryl) choline was added, and the temperature was 37°C for 10 min. After that, 20 μL DTNB was added to each well, oscillated and mixed, and the absorbance at 405 nm was measured; Huperzine A was used as a positive control; inhibition rate (%) = [(enzyme activity group-enzyme activity control group)-(drug group-drug control group) / (enzyme activity group-enzyme activity control group)] × 100%; the results are shown in Table 1:

[0284] Table 1 Biological activity results of compounds H1-H20 and I1-I20

[0285]

[0286]

[0287] It can be seen from the table that the 40 tricyclic thiazolylpyrimidine ether derivatives of the present invention have inhibitory activity on acetylcholinesterase. The results show that compounds H2-H3, H5-H7, H9, H11, H13-H14, H16, H18-H20, I4, I7-I8, I11-I12, I16, and I19 have strong inhibitory activity on acetylcholinesterase; compounds H1-H6, H13, H18-H20, I1, I5-I9, I11, I14, I16-I17, and I19-I20 have inhibitory activity on butyrylcholinesterase.

Claims

1. A tricyclic thiazolopyrimidinone ether derivative, characterized in that The structural formula of this type of derivative is: in: Compound H1 is 2-(4-methylphenyloxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one; Compound H2 is 2-(3-chlorophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one; Compound H3 is 2-(3-bromophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one; Compound H4 is 2-(4-bromophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one; Compound H5 is 2-(3-fluorophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one; Compound H6 is 2-(4-fluorophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one; Compound H7 is 2-(3-trifluoromethylphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one; Compound H8 is 2-(4-trifluoromethylphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one; Compound H9 is 2-(3-methoxyphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one; Compound H10 is 2-(4-trifluoromethoxyphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one; Compound H11 is 2-(3-nitrophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one; Compound H12 is 2-(3,4-dichlorophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one Compound H13 is 2-(3,5-difluorophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one Compound H14 is 2-(3,4-difluorophenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one; Compound H15 is 2-(3,5-ditrifluoromethylphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one; Compound H16 is 2-(1-naphthylphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one; Compound H17 is 2-(4-phenylphenoxy)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one; Compound H18 is 2-(4-methylthio)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one; Compound H19 is 2-(4-fluorophenylthio)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one; Compound H20 is 2-(4-methoxyphenylthio)-6,7-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one; Compound I1 is 2-(4-methylphenyloxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one; Compound I2 is 2-(3-chlorophenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one; Compound I3 is 2-(3-bromophenoxy)-6,7,8,9-tetrahydrothiazolidine[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one; Compound I4 is 2-(4-bromophenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one; Compound I5 is 2-(3-fluorophenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one; Compound I6 is 2-(4-fluorophenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one; Compound I7 is 2-(3-trifluoromethylphenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one; Compound I8 is 2-(4-trifluoromethylphenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one; Compound I9 is ​​2-(3-methoxyphenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one; Compound I10 is 2-(4-trifluoromethoxyphenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one; Compound I11 is 2-(3-nitrophenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one; Compound I12 is 2-(3,4-dichlorophenoxy)-6,7,8,9-tetrahydrothiazolidine[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one; Compound I13 is 2-(3,5-difluorophenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one; Compound I14 is 2-(3,4-difluorophenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one; Compound I15 is 2-(3,5-ditrifluoromethylphenoxy)-6,7,8,9-tetrahydrothiazolidine[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one; Compound I16 is 2-(1-naphthylphenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one; Compound I17 is 2-(4-phenylphenoxy)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one; Compound I18 is 2-(4-methylthio)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one; Compound I19 is 2-(4-fluorophenylthio)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one; Compound I20 is 2-(4-methoxyphenylthio)-6,7,8,9-tetrahydrothiazol[5',4':4,5]pyrimidin[1,2-a]azepine-11(5H)-one.

2. A use of compounds H2-H3, H5-H7, H9, H11, H13-H14, H16, H18-H20, I4, I7-I8, I11-I12, I16, and I19 of the tricyclic thiazolopyrimidinone ether derivatives as claimed in claim 1 in the preparation of drugs for inhibiting acetylcholinesterase.

3. Use of compounds H1-H6, H13, H18-H20, I1, I5-I9, I11, I14, I16-I17, I19-I20 of the tricyclic thiazolopyrimidinone ether derivatives as claimed in claim 1 in the preparation of a drug for inhibiting butyrylcholinesterase.

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