阅读说明：本技术 一种三环噻唑并[5,4-d]嘧啶酮类衍生物及其用途 (Tricyclic thiazolo [5,4-d ] pyrimidone derivative and application thereof ) 是由 阿吉艾克拜尔·艾萨 曾艳 聂礼飞 胡尔西地·博扎罗夫 赵江瑜 于 2021-10-27 设计创作，主要内容包括：本发明涉及一种三环噻唑并[5,4-d]嘧啶酮类衍生物及其用途,该衍生物以氰基乙酸乙酯为初始原料,在亚硝酸钠和磷酸作用下生成羟胺化合物(A),经保险粉还原得2-氨基氰基乙酸乙酯(B),分别和乙酸酐,劳森试剂反应得5-氨基-4-甲酸酯噻唑类化合物(D),再经NBS溴代后,在三氯氧磷作用下,得2-溴-二氢吡咯[1,2-a]噻唑并[5,4-d]嘧啶酮类化合物(F)和2-溴-7,8-二氢-5H-吡啶[1,2-a]噻唑并[5,4-d]嘧啶-10(6H)酮类衍生物(G),最后,经Suzuki偶联反应得到64个不同取代的三环噻唑并[5,4-d]嘧啶酮类化合物H1-H32和I1-I32。并考察了这64个化合物对阿尔兹海默症中的乙(丁)酰胆碱酯酶的抑制活性及白色念珠菌的抗菌活性,结果显示：有46个化合物对乙(丁)酰胆碱酯酶都有很强的抑制活性；27个化合物对白色念珠菌有抑制活性。(The invention relates to tricyclic thiazolo [5,4- d ]A pyrimidone derivative is prepared from ethyl cyanoacetate as initial raw material through generating hydroxylamine compound (A) under the action of sodium nitrite and phosphoric acid, reducing by sodium hydrosulfite to obtain 2-amino ethyl cyanoacetate (B), respectively reacting with acetic anhydride and Lawson reagent to obtain 5-amino-4-formate thiazole compound (D), bromizing by NBS, and reacting with phosphorus oxychloride to obtain 2-bromo-dihydropyrrole [1,2- a ]Thiazolo [5,4- d ]Pyrimidinone compounds (F) and 2-bromo-7, 8-dihydro-5 H -pyridine [1,2- a ]Thiazolo [5,4- d ]Pyrimidine-10 (6) H ) Ketone derivative (G) and finally obtaining 64 different substituted tricyclic thiazolo [5,4- d ]Pyrimidinone compounds H1-H32 and I1-I32. The 64 compounds are examined on the inhibitory activity of acetylcholinesterase in Alzheimer's disease and the antibacterial activity of Candida albicans, and the results show that: 46 compounds have strong inhibitory activity to acetyl cholinesterase; 27 compounds have inhibitory activity against Candida albicans.)

1. A tricyclic thiazolo [5,4-d ] pyrimidone derivative is characterized in that the structural formula of the derivative is as follows:

wherein:

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

compound H2 is 2- (2-methylphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

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

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

compound H5 is 2- (4-tert-butylphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

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

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

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

compound H9 is 2- (2-bromophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H10 is 2- (3-bromophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H11 is 2- (4-bromophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H12 is 2- (2-fluorophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H13 is 2- (4-fluorophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H14 is 2- (2-trifluoromethylphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H15 is 2- (4-trifluoromethylphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H16 is 2- (3-trimethoxyphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

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

compound H18 is 2- (9-oxo-5, 6,7, 9-tetrahydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile;

compound H19 is 3- (9-oxo-5, 6,7, 9-tetrahydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile;

compound H20 is 4- (9-oxo-5, 6,7, 9-tetrahydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile;

compound H21 is 4- (9-oxo-5, 6,7, 9-tetrahydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzaldehyde;

compound H22 is 2- (3-acetylphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H23 is 2- (3-nitrophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H24 is 2- (3, 5-dimethylphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H25 is 2- (3, 5-dichlorophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H26 is 2- (3, 4-dichlorophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H27 is 2- (3, 5-dibromophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H28 is 2- (3, 5-difluorophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H29 is 2- (3, 5-dimethoxyphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one

Compound H30 is 2- (3, 4-dimethoxyphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one

Compound H31 is 2- (3-chloro-4-fluoro-phenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H32 is 3- (1,1' -biphenyl-3-yl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound I1 is 2-phenyl-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I2 is 2- (2-methylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I3 is 2- (3-methylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I4 is 2- (4-methylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I5 is 2- (4-tert-butylphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I6 is 2- (2-chlorophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I7 is 2- (3-chlorophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I8 is 2- (4-chlorophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I9 is 2- (2-bromophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I10 is 2- (3-bromophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I11 is 2- (4-bromophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I12 is 2- (2-fluorophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I13 is 2- (4-fluorophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I14 is 2- (2-trifluoromethylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I15 is 2- (4-trifluoromethylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I16 is 2- (3-trimethoxyphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I17 is 2- (4-trimethoxyphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I18 is 2- (10-oxo-6, 7,8, 10-tetrahydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile;

compound I19 is 3- (10-oxo-6, 7,8, 10-tetrahydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile;

compound I20 is 4- (10-oxo-6, 7,8, 10-tetrahydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile;

compound I21 is 4- (10-oxo-6, 7,8, 10-tetrahydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzaldehyde;

compound I22 is 2- (3-acetylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I23 is 2- (3-nitrophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I24 is 2- (3, 5-dimethylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I25 is 2- (3, 5-dichlorophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I26 is 2- (3, 4-dichlorophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I27 is 2- (3, 5-dibromophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I28 is 2- (3, 5-difluorophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I29 is 2- (3, 5-dimethoxyphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I30 is 2- (3, 4-dimethoxyphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I31 is 2- (3-chloro-4-fluoro-phenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I32 is 2- (1,1' -biphenyl-3-yl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one.

2. Use of compounds H3-H5, H7-H8, H10-H12, H15-H16, H19-H25, H27-H28, H30-H31, I1, I3-I8, I10-I11, I13, I15-I17, I19-I23, I25-I31 in tricyclic thiazolo [5,4-d ] pyrimidinone derivatives according to claim 1 for the preparation of a medicament for the treatment of alzheimer's disease.

3. Use of compounds H1, H6-H10, H15-H16, H19, H28-H31, I3, I8, I15, I16, I18-I22, I27-I30 in tricyclic thiazolo [5,4-d ] pyrimidinone derivatives according to claim 1 in the preparation of a medicament for inhibiting candida albicans.

Technical Field

The invention relates to a tricyclic thiazolo [5,4-d ] pyrimidone derivative and application thereof.

Background

Alzheimer's Disease (AD) is a neurodegenerative disease produced by impaired memory, language and reasoning in the cerebral hemisphere, first discovered in 1906 by the german neuropathologist, Alois Alzheimer, and named after its name. The prevalence of AD has increased year by year in recent years and is a trend towards younger age, with more than 1.3 million people expected to suffer from AD worldwide by the year 2050. It has become the fourth cause of death in humans following heart disease, cancer and stroke due to the lack of a very effective method of prevention. Based on the fact that no effective medicine is applied to clinically preventing the progress of AD pathogenesis and further treating AD at present, a medicine capable of effectively treating AD is urgently needed to be found.

In recent years, a plurality of traditional Chinese medicines have remarkable curative effects on treating AD, such as icariin, sinapine, salvia miltiorrhiza, kudzu root and the like, which have strong inhibition on AChE; although the medicines greatly improve the neurocognitive ability of patients and alleviate AD symptoms, the medicines have single action target, great toxic and side effects, short half life (more times of daily medicine taking), easy occurrence of drug resistance, adverse reactions and the like in clinical manifestation,

heterocyclic compounds are a class of compounds with good biological activity and occupy a very important position in medicinal chemistry. Because nitrogen elements are deeply related to life, most of nitrogen-containing heterocyclic compounds have the characteristics of high efficiency, low toxicity and good environmental compatibility, are irreplaceable biological medicines and become the mainstream of medicine research and development. Thus, many drug molecules are designed and screened using nitrogen-containing heterocycles as precursors.

Thiazole compounds containing nitrogen and sulfur atoms have many unique properties and biological activities. To date, thiazole-based drugs have been used clinically. Thiazole compounds have received increasing attention as bioisosteres of thiazoles, imidazoles, benzimidazoles, triazoles and tetrazoles, and it is expected that novel thiazole compounds having a broad spectrum, high potency, low toxicity and excellent pharmacokinetic properties will be found.

The thiazole ring is an important five-membered aromatic heterocycle, contains nitrogen and sulfur heteroatoms, has abundant electrons, is easy to form hydrogen bonds, is coordinated with metal ions, has static electricity, hydrophobic interaction and other non-covalent bond interactions, has a plurality of special properties, has wide potential applications in a plurality of fields, draws great attention of a plurality of workers, and related research works including the synthesis method thereof are increased day by day. Especially, with the success of a series of thiazole compounds in clinical and agricultural production, the development of thiazole compounds has become one of the hot areas of research in recent years. In the field of medicine, thiazole compounds can be combined with targets such as various enzymes and receptors in organisms so as to show various biological activities, almost covers the whole field of medicine, and a plurality of thiazole compounds are used clinically, such as antibiotic drug cefixime, anticancer drug dasatinib, antiparasitic drug nitazoxanide, anti-inflammatory drug meloxicam and the like which are first-line drugs of clinical preference.

Therefore, the research on the synthesis and biological activity of the compounds can be found and explored from the activity of the thiazole pyrimidine derivatives, and the research has larger theoretical significance and application value for searching lead compounds such as new medicines and the like.

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The invention carries out total synthesis on tricyclic thiazolo [5,4-d ] pyrimidone compounds on the basis of comprehensive analysis of related patents and documents at home and abroad, carries out systematic transformation and modification, introduces phenyl containing different substituents into tricyclic thiazolo [5,4-d ] pyrimidone compound molecules so as to improve the drugability of the compounds, researches the inhibitory activity of the compounds on acetylcholinesterase in Alzheimer's disease, cancer cells (Hela cervical cancer cells and HT-29 human colon cancer cells) and the antibacterial activity of Candida albicans, Escherichia coli E.coli and Staphylococcus aureus S.aureus, and finds candidate drugs with obvious curative effect and definite target spot for resisting acetylcholinesterase and antitumor activity. The activity screening result shows that: 46 compounds have strong inhibitory activity on acetylcholinesterase in Alzheimer's disease; 9 compounds have inhibitory activity against butyrylcholinesterase in alzheimer's disease; 2 compounds have inhibitory activity on Hela cervical carcinoma cells; 4 compounds have inhibitory activity against HT-29 human colon cancer cells; 24 compounds have inhibitory activity against candida albicans; 3 compounds have inhibitory activity on escherichia coli; there are 3 compounds with inhibitory activity against staphylococcus aureus.

Disclosure of Invention

The invention aims to provide a tricyclic thiazolo [5,4-d ] pyrimidone derivative and application thereof. The derivative takes ethyl cyanoacetate 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 of sodium hydrosulfite, then the 2-amino ethyl cyanoacetate (B) reacts with acetic anhydride and Lawson reagent respectively to form a ring to obtain a 5-amino-4-formic ether thiazole compound (D), then the 5-amino-4-formic ether thiazole compound (D) reacts with pyrrolidone and valerolactam respectively to form a ring under the action of phosphorus oxychloride after being brominated, 2-bromine-dihydropyrrole [1,2-a ] thiazolo [5,4-D ] pyrimidone compound (F) and 2-bromine-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-D ] pyrimidine-10 (6H) ketone (G) are obtained through Suzuki reaction, 64 different substituted tricyclic thiazolo [5 ], 4-d ] pyrimidinones H1-H32 and I1-I32. Meanwhile, the 64 compounds were examined for inhibitory activity against acetylcholinesterase in alzheimer's disease and antibacterial activity against candida albicans c.albicans, and the results showed that: 46 compounds have strong inhibitory activity on acetylcholinesterase in Alzheimer's disease; the compounds H7, H8, H10, H11, H20, H27, I11, I15 and I19 have inhibitory activity on butyrylcholinesterase in Alzheimer's disease; the compounds H1, H6-H10, H15, H16, H19, H28-H31, I3, I8, I15, I16, I18-I22, I27-I30 have inhibitory activity against Candida albicans C.

The invention relates to a tricyclic thiazolo [5,4-d ] pyrimidone derivative, which has a structural formula as follows:

wherein:

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

compound H2 is 2- (2-methylphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

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

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

compound H5 is 2- (4-tert-butylphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

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

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

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

compound H9 is 2- (2-bromophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H10 is 2- (3-bromophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H11 is 2- (4-bromophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H12 is 2- (2-fluorophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H13 is 2- (4-fluorophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H14 is 2- (2-trifluoromethylphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H15 is 2- (4-trifluoromethylphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H16 is 2- (3-trimethoxyphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

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

compound H18 is 2- (9-oxo-5, 6,7, 9-tetrahydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile;

compound H19 is 3- (9-oxo-5, 6,7, 9-tetrahydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile;

compound H20 is 4- (9-oxo-5, 6,7, 9-tetrahydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile;

compound H21 is 4- (9-oxo-5, 6,7, 9-tetrahydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzaldehyde;

compound H22 is 2- (3-acetylphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H23 is 2- (3-nitrophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H24 is 2- (3, 5-dimethylphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H25 is 2- (3, 5-dichlorophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H26 is 2- (3, 4-dichlorophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H27 is 2- (3, 5-dibromophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H28 is 2- (3, 5-difluorophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H29 is 2- (3, 5-dimethoxyphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one

Compound H30 is 2- (3, 4-dimethoxyphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one

Compound H31 is 2- (3-chloro-4-fluoro-phenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound H32 is 3- (1,1' -biphenyl-3-yl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;

compound I1 is 2-phenyl-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I2 is 2- (2-methylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I3 is 2- (3-methylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I4 is 2- (4-methylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I5 is 2- (4-tert-butylphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I6 is 2- (2-chlorophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I7 is 2- (3-chlorophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I8 is 2- (4-chlorophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I9 is 2- (2-bromophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I10 is 2- (3-bromophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I11 is 2- (4-bromophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I12 is 2- (2-fluorophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I13 is 2- (4-fluorophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I14 is 2- (2-trifluoromethylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I15 is 2- (4-trifluoromethylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I16 is 2- (3-trimethoxyphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I17 is 2- (4-trimethoxyphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I18 is 2- (10-oxo-6, 7,8, 10-tetrahydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile;

compound I19 is 3- (10-oxo-6, 7,8, 10-tetrahydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile;

compound I20 is 4- (10-oxo-6, 7,8, 10-tetrahydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile;

compound I21 is 4- (10-oxo-6, 7,8, 10-tetrahydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzaldehyde;

compound I22 is 2- (3-acetylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I23 is 2- (3-nitrophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I24 is 2- (3, 5-dimethylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I25 is 2- (3, 5-dichlorophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I26 is 2- (3, 4-dichlorophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I27 is 2- (3, 5-dibromophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I28 is 2- (3, 5-difluorophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I29 is 2- (3, 5-dimethoxyphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I30 is 2- (3, 4-dimethoxyphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I31 is 2- (3-chloro-4-fluoro-phenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;

compound I32 is 2- (1,1' -biphenyl-3-yl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one.

The tricyclic thiazolo [5,4-d ] pyrimidone derivative is H3-H5, H7-H8, H10-H12, H15-H16, H19-H25, H27-H28, H30-H31, I1, I3-I8, I10-I11, I13, I15-I17, I19-I23 and I25-I31, and the application of the compound in preparation of medicines for treating Alzheimer's disease.

The tricyclic thiazolo [5,4-d ] pyrimidone derivative is prepared from compounds H1, H6-H10, H15, H16, H19, H28-H31, I3, I8, I15, I16, I18-I22 and I27-I30, and the application of the compounds in preparation of medicines for inhibiting candida albicans.

The invention relates to tricyclic thiazolo [5,4-d ] pyrimidone derivatives and application thereof, wherein the preparation method of the tricyclic thiazolo [5,4-d ] pyrimidone derivatives comprises the following steps:

preparation of compound a:

under the condition of the temperature of minus 10 ℃, 57.3g of sodium nitrite, 0.83mol of sodium nitrite and 100g of ethyl cyanoacetate, 0.83mol of ethyl cyanoacetate are dissolved in 700ml of pure water, then 36.6ml of 85 percent concentrated phosphoric acid and 0.055mol of 85 percent are slowly dripped, the dripping time lasts for 3 hours, then the temperature is raised to 45 ℃, the stirring is carried out for 1 hour, then 74ml of concentrated hydrochloric acid and 0.88mol of concentrated phosphoric acid are added, the stirring is continued overnight under the condition of the temperature of 0 ℃, a large amount of white solid is separated out, and the white compound A is obtained by filtering without purification and is used for the next reaction;

preparation of compound B:

dissolving 0.3mol of the obtained white compound A43g in 500ml of pure water at room temperature, slowly dropwise adding 350ml of saturated sodium bicarbonate solution under stirring, then adding 156g of sodium hydrosulfite and 0.9mol, heating to 35 ℃, reacting for 1 hour, then reacting for 3 hours at room temperature, extracting for 3 times by using 500ml of dichloromethane, combining organic phases, drying and concentrating, and performing gradient elution by using forward silica gel column chromatography, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a compound B;

preparation of compound C:

under the protection of argon, slowly dropping 6.48g and 63.6mmol of acetic anhydride into 2.22g and 53mmol of formic acid solution, heating to 50 ℃ for reaction for 5 hours, then, slowly dropping 3.9g and 25mmol of a compound B into the solution under the condition of ice bath, reacting at room temperature until all raw materials disappear, extracting for 3 times by using 500ml of dichloromethane, combining organic phases, drying, concentrating, performing gradient elution by using forward silica gel column chromatography, and eluting with petroleum ether, wherein ethyl acetate is 5:1 to obtain a compound C;

preparation of compound D:

under the protection of argon, dissolving 10mmol of the obtained compound C1.56g in 20ml of toluene, adding 4.5g 11mmol of Lawson reagent, heating and refluxing for 24 hours until all raw materials disappear, filtering the reaction solution, concentrating, performing gradient elution by adopting forward silica gel column chromatography, and obtaining a compound D, wherein the eluent is petroleum ether and ethyl acetate is 1: 1;

preparation of compound E:

dissolving 10mmol of the obtained compound D1.72g in 20mL of anhydrous tetrahydrofuran, adding 2.2g of NBS 12mmol in a small amount of times, reacting for 3 hours at room temperature until all raw materials disappear, quenching with water, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by adopting forward silica gel column chromatography, wherein an eluent is petroleum ether and ethyl acetate is 5:1, thus obtaining a compound E;

preparation of compound F:

dissolving 2.5g 10mmol of the obtained compound E in 20mL of anhydrous dioxane, adding 1.3g15mmol of pyrrolidone, slowly dropwise adding 2.4mL 25mmol of phosphorus oxychloride, carrying out reflux reaction until all raw materials disappear, filtering and concentrating the reaction solution, and carrying out gradient elution by adopting forward silica gel column chromatography, wherein an eluant is petroleum ether and ethyl acetate is 1:2, thus obtaining a compound F;

preparation of compound G:

dissolving 2.5G 10mmol of the obtained compound E in 20mL of anhydrous dioxane, adding 1.3G15mmol of pyrrolidone, slowly dropwise adding 2.4mL 25mmol of phosphorus oxychloride, refluxing to react until all raw materials disappear, filtering the reaction liquid, concentrating, and performing gradient elution by adopting forward silica gel column chromatography, wherein an eluant is petroleum ether and ethyl acetate is 1:2 to obtain a compound G;

preparation of Compounds H1-H32:

dissolving 0.27g 1mmol of the obtained compound F in 20mL of anhydrous toluene, respectively adding 0.98g 3mmol of cesium carbonate, 1.2mmol of different substituted phenylboronic acid and 0.015g 0.01mmol of palladium tetratriphenylphosphine, refluxing and reacting under the protection of argon until all raw materials disappear, filtering the reaction solution, concentrating, performing gradient elution by adopting forward silica gel column chromatography, and respectively obtaining compounds H1-H32, wherein the eluent is pure ethyl acetate;

preparation of Compounds I1-I32:

dissolving 0.285G 1mmol of the obtained compound G in 20mL of anhydrous toluene, adding 0.98G 3mmol of cesium carbonate, 1.2mmol of different substituted phenylboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine respectively, refluxing and reacting under the protection of argon until all raw materials disappear, filtering the reaction solution, concentrating, performing gradient elution by adopting forward silica gel column chromatography, and obtaining a compound I1-I32 by using pure ethyl acetate as an eluent;

the tricyclic thiazolo [5,4-D ] pyrimidone derivative is prepared by taking ethyl cyanoacetate as an initial raw material, generating a hydroxylamine compound (A) under the action of sodium nitrite and phosphoric acid, reducing the hydroxylamine compound with sodium hydrosulfite to obtain 2-aminocyanoacetic acid ethyl ester (B), then reacting with acetic anhydride and Lawson reagent respectively to form a ring to obtain a 5-amino-4-formate thiazolone compound (D), then reacting with pyrrolidone and valerolactam respectively to form a ring under the action of phosphorus oxychloride after NBS bromination to obtain a 2-bromo-dihydropyrrole [1,2-a ] thiazolo [5,4-D ] pyrimidone compound (F) and a 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-D ] pyrimidone-10 (6H) ketone (G), finally, 64 different substituted tricyclic thiazolo [5,4-d ] pyrimidone compounds (H1-H32 and I1-I32) are obtained through Suzuki reaction,

the synthetic route is as follows:

Detailed Description

The present invention is further illustrated by the following examples, but is not limited thereto;

reagent: all reagents were commercially available analytical grade;

example 1

Preparation of compound a:

under the condition of the temperature of minus 10 ℃, 57.3ml of sodium nitrite, 0.83mol of sodium nitrite and 100g of ethyl cyanoacetate and 0.83mol of sodium nitrite are dissolved in 700ml of pure water, then 36.6ml of 85 percent concentrated phosphoric acid and 0.055mol of 85 percent are slowly dripped, after the dripping time lasts for 3 hours, the temperature is raised to 45 ℃ and stirred for 1 hour, then 74ml of concentrated hydrochloric acid and 0.88mol of concentrated hydrochloric acid are added, the mixture is continuously stirred overnight at the temperature of 0 ℃, a large amount of white solid is separated out and filtered, and a white compound A which is ethyl 2-cyano-2-hydroxyiminoacetate is obtained and is used for the next reaction without purification;

preparation of compound B:

under the condition of room temperature, dissolving obtained white compound A which is 43g of 2-cyano-2-hydroxyiminoethyl acetate in 0.3mol in 500ml of pure water, slowly dropwise adding 350ml of saturated sodium bicarbonate solution under stirring, then adding 156g of sodium hydrosulfite and 0.9mol, heating to 35 ℃, reacting for 1 hour, then reacting for 3 hours at room temperature, extracting for 3 times by using 500ml of dichloromethane, combining organic phases, drying and concentrating, performing gradient elution by adopting forward silica gel column chromatography, wherein an eluant is petroleum ether and ethyl acetate in a volume ratio of 2:1, and obtaining compound B which is 2-amino-2-cyanoethyl acetate, and the compound B is used for the next reaction without purification;

¹H NMR(400MHz,CDCl₃)δ7.73(s,1H),4.81(s,2H),4.34(q,J＝7.0Hz,2H),1.36(t,J＝7.1Hz,3H)；

preparation of compound C:

under the protection of argon, slowly dropwise adding 6.48g and 63.6mmol of acetic anhydride into 2.22g and 53mmol of formic acid solution, heating to 50 ℃ for reaction for 5 hours, then, slowly dropwise adding 3.9g and 25mmol of compound B, namely ethyl 2-amino-2-cyanoacetate, into the solution under the condition of ice bath, reacting at room temperature until all raw materials disappear, extracting for 3 times by using dichloromethane (500ml), combining organic phases, drying, concentrating, performing forward silica gel column chromatography gradient elution, and obtaining a compound C, namely ethyl 2-formamido-2-cyanoacetate by using an eluent, namely petroleum ether and ethyl acetate in a volume ratio of 5: 1; yield: 76%, light yellow solid, melting point: 128 ℃ and 130 ℃;

¹H NMR(400MHz,CDCl₃)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)；

preparation of compound D:

under the protection of argon, dissolving 1.56g and 10mmol of the obtained compound C2-formamido-2-cyanoethyl acetate in 20ml of toluene, then adding 4.5g and 11mmol of Lawson reagent, heating and refluxing for 24 hours until all raw materials disappear, filtering and concentrating the reaction solution, performing gradient elution by adopting forward silica gel column chromatography, wherein an eluant is petroleum ether and ethyl acetate in a volume ratio of 1:1, and obtaining a compound D which is 5-amino-thiazole-4-ethyl formate, and the yield is as follows: 73%, light yellow solid, melting point: 135 ℃ and 136 ℃;

¹H NMR(400MHz,CDCl₃)δ7.88(s,1H),6.00(s,2H),4.39(q,J＝7.1Hz,2H),1.42(t,J＝7.1Hz,3H)；

preparation of compound E:

dissolving 1.72g and 10mmol of the obtained compound D, namely 5-amino-thiazole-4-ethyl formate, in 20mL of anhydrous tetrahydrofuran, adding 2.2g and 12mmol of NBS in a small amount of the anhydrous tetrahydrofuran for multiple times, reacting at room temperature for 3 hours until all raw materials disappear, quenching with water, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by adopting forward silica gel column chromatography, and obtaining a compound E, namely 2-bromo-5-amino-thiazole-4-ethyl formate, wherein an eluant is petroleum ether and ethyl acetate in a volume ratio of 5:1, and the yield is as follows: 73% of light yellow solid, mp 151-;

¹H NMR(400MHz,CDCl₃)δ6.03(s,2H),4.38(q,J＝7.1Hz,2H),1.39(t,J＝7.1Hz,3H)；

preparation of compound F:

dissolving 2.5g and 10mmol of the obtained compound E2-bromo-5-amino-thiazole-4-ethyl formate in 20mL anhydrous dioxane, adding 1.3g and 15mmol of pyrrolidone, slowly dropwise adding 2.4mL and 25mmol of phosphorus oxychloride, carrying out reflux reaction until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and carrying out forward silica gel column chromatography gradient elution, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:2, so as to obtain a compound F2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidine-9 (5H) -one, and the yield is as follows: 73%, light yellow solid, melting point: 208-209 ℃;

¹H NMR(400MHz,CDCl₃)δ4.25(t,J＝7.3Hz,2H),3.17(t,J＝8.0Hz,2H),2.66–2.16(m,2H)；

preparation of compound G:

dissolving 2.5G and 10mmol of the obtained compound E2-bromo-5-amino-thiazole-4-ethyl formate in 20mL of anhydrous dioxane, adding 1.5G and 15mmol of valerolactam, slowly dropwise adding 2.4mL and 25mmol of phosphorus oxychloride, carrying out reflux reaction until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, carrying out forward silica gel column chromatography gradient elution, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain a compound G2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone, and the yield is as follows: 73 percent of light yellow solid with the melting point of 226-;

¹H NMR(400MHz,CDCl₃)δ4.25(t,J＝7.3Hz,2H),3.17(t,J＝8.0Hz,2H),2.66–2.16(m,2H)。

example 2

Preparation of compound H1:

0.27g 1mmol of 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, was dissolved in 20mL of anhydrous toluene, adding cesium carbonate 0.98g and 3mmol, phenylboronic acid 0.15g and 1.2mmol, palladium tetratriphenylphosphine 0.015g and 0.01mmol respectively, under the protection of argon, carrying out reflux reaction until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, carrying out gradient elution by using forward silica gel column chromatography, wherein an eluant is ethyl acetate with the volume ratio of 10: 1: methanol to give compound H1 as 2-phenyl-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one in yield: 68%, light yellow solid, melting point: 276 ℃ and 277 ℃;

¹H NMR(400MHz,CDCl₃)δ8.06(dd,J＝6.8,2.8Hz,2H),7.47(d,J＝2.1Hz,2H),7.45(d,J＝0.9Hz,1H),4.27(t,J＝7.3Hz,2H),3.21(t,J＝8.0Hz,2H),2.57–2.18(m,2H)。

example 3

Preparation of compound H2:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.16g1.2mmol of 2-methylbenzeneboronic acid and 0.015g 0.01mmol of palladium tetratriphenylphosphine, refluxing under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution with forward silica gel by using ethyl acetate and methanol in a volume ratio of 10:1 to obtain the compound H2, namely 2- (2-methylphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 61%, light yellow solid, melting point: 178 ℃ and 179 ℃;

¹H NMR(400MHz,CDCl₃)δ7.74(d,J＝7.8Hz,1H),7.32(ddd,J＝22.2,14.9,8.4Hz,3H),4.44(t,J＝7.3Hz,2H),3.22(t,J＝8.0Hz,2H),2.65(s,3H),2.53–2.18(m,2H)。

example 4

Preparation of compound H3:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.16g1.2mmol of 3-methylbenzeneboronic acid and 0.015g 0.01mmol of palladium tetratriphenylphosphine, refluxing under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution with forward silica gel by using ethyl acetate and methanol in a volume ratio of 10:1 to obtain a compound H3, namely 2- (3-methylphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 72%, light yellow solid, melting point: 213-214 ℃;

¹H NMR(400MHz,CDCl₃)δ7.94(s,1H),7.81(d,J＝7.6Hz,1H),7.34(t,J＝7.6Hz,1H),7.28(d,J＝7.6Hz,1H),4.30(t,J＝7.3Hz,2H),3.22(t,J＝8.0Hz,2H),2.42(s,3H),2.41–2.30(m,2H)。

example 5

Preparation of compound H4:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.16g1.2mmol of 4-methylbenzeneboronic acid and 0.015g 0.01mmol of palladium tetratriphenylphosphine, refluxing under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution with forward silica gel by using ethyl acetate and methanol in a volume ratio of 10:1 to obtain the compound H4, namely 2- (4-methylphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 83%, light yellow solid, melting point: 248-249 deg.C;

¹H NMR(400MHz,CDCl₃)δ7.95(d,J＝8.2Hz,2H),7.26(d,J＝8.4Hz,2H),4.31(t,J＝7.3Hz,2H),3.21(t,J＝8.0Hz,2H),2.41(s,3H),2.41–2.30(m,2H)。

example 6

Preparation of compound H5:

dissolving 0.27g and 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g and 3mmol of cesium carbonate, 0.22g and 1.2mmol of 4-tert-butylboronic acid and 0.015g and 0.01mmol of palladium tetratriphenylphosphine respectively, carrying out reflux reaction under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, carrying out forward silica gel gradient elution, and carrying out eluent on ethyl acetate and methanol in a volume ratio of 10:1 to obtain the compound H5, namely 2- (4-tert-butylphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 81%, light yellow solid, melting point: 241-242 ℃;

¹H NMR(400MHz,CDCl₃)δ7.97(d,J＝8.6Hz,2H),7.45(d,J＝8.6Hz,2H),4.30(t,J＝7.3Hz,2H),3.19(t,J＝8.0Hz,2H),2.61–2.18(m,2H),1.33(s,9H)。

example 7

Preparation of compound H6:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.19g1.2mmol of 2-chlorobenzoboric acid and 0.015g 0.01mmol of tetratriphenylphosphine palladium respectively, carrying out reflux reaction under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, carrying out forward silica gel column chromatography gradient elution, and obtaining the compound H6, namely 2- (2-chlorophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one by using ethyl acetate and methanol in a volume ratio of 10:1, yield: 68%, light yellow solid, melting point: 197 ℃ and 198 ℃;

¹H NMR(400MHz,CDCl₃)δ8.41(dd,J＝6.0,3.6Hz,1H),7.54–7.46(m,1H),7.44–7.35(m,2H),4.30(t,J＝7.3Hz,2H),3.23(t,J＝8.0Hz,2H),2.60–2.20(m,2H)。

example 8

Preparation of compound H7:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.19g1.2mmol of 3-chlorobenzoboric acid and 0.015g 0.01mmol of tetratriphenylphosphine palladium respectively, carrying out reflux reaction under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, carrying out forward silica gel column chromatography gradient elution, and obtaining the compound H7, namely 2- (3-chlorophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one by using ethyl acetate and methanol in a volume ratio of 10:1, yield: 63%, light yellow solid, melting point: 218-219 ℃;

¹H NMR(400MHz,CDCl₃)δ8.09(s,1H),7.88(d,J＝7.4Hz,1H),7.40(dt,J＝15.5,7.9Hz,2H),4.28(t,J＝7.3Hz,2H),3.21(t,J＝8.0Hz,2H),2.47–2.22(m,2H)。

example 9

Preparation of compound H8:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.19g1.2mmol of 4-chlorobenzoboric acid and 0.015g 0.01mmol of tetratriphenylphosphine palladium respectively, carrying out reflux reaction under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, carrying out forward silica gel column chromatography gradient elution, and obtaining the compound H8, namely 2- (4-chlorophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one by using ethyl acetate and methanol in a volume ratio of 10:1, yield: 79%, light yellow solid, melting point: 238 ℃ and 239 ℃;

¹H NMR(400MHz,CDCl₃)δ7.99(d,J＝8.5Hz,2H),7.43(d,J＝8.4Hz,2H),4.29(t,J＝7.3Hz,2H),3.22(t,J＝8.0Hz,2H),2.78–2.08(m,2H).

example 10

Preparation of compound H9:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.24g1.2mmol of 2-bromobenzeneboronic acid and 0.015g 0.01mmol of tetratriphenylphosphine palladium respectively, carrying out reflux reaction under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, carrying out forward silica gel gradient elution, and eluting with ethyl acetate and methanol in a volume ratio of 10:1 to obtain the compound H9, namely 2- (2-bromophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 58%, light yellow solid, melting point: 187-188 ℃;

¹H NMR(400MHz,CDCl₃)δ8.27(s,1H),7.94(d,J＝7.8Hz,1H),7.59(d,J＝7.7Hz,1H),7.33(t,J＝7.9Hz,1H),4.30(t,J＝7.3Hz,2H),3.23(t,J＝8.0Hz,2H),2.75–2.27(m,2H)。

example 11

Preparation of compound H10:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.24g1.2mmol of 3-bromobenzeneboronic acid and 0.015g 0.01mmol of tetratriphenylphosphine palladium respectively, carrying out reflux reaction under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, carrying out forward silica gel gradient elution, and carrying out eluent on ethyl acetate and methanol in a volume ratio of 10:1 to obtain the compound H10, namely 2- (3-bromophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 73%, light yellow solid, melting point: 211 ℃ and 212 ℃;

¹H NMR(400MHz,CDCl₃)δ8.26(s,1H),7.93(d,J＝7.8Hz,1H),7.59(d,J＝8.0Hz,1H),7.33(t,J＝7.9Hz,1H),4.32(t,J＝7.3Hz,2H),3.22(t,J＝8.0Hz,2H),2.52–2.22(m,2H)。

example 12

Preparation of compound H11:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.24g1.2mmol of 4-bromobenzeneboronic acid and 0.015g 0.01mmol of tetratriphenylphosphine palladium respectively, carrying out reflux reaction under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, carrying out forward silica gel gradient elution, and eluting with ethyl acetate and methanol in a volume ratio of 10:1 to obtain a compound H11, namely 2- (4-bromophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 77%, light yellow solid, melting point: 234 ℃ and 235 ℃;

¹H NMR(400MHz,CDCl₃)δ7.92(d,J＝8.4Hz,2H),7.59(d,J＝8.4Hz,2H),4.36(t,J＝7.3Hz,2H),3.21(t,J＝8.0Hz,2H),2.52–2.25(m,2H)。

example 13

Preparation of compound H12:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.17g1.2mmol of 2-fluorobenzeneboronic acid and 0.015g 0.01mmol of palladium tetratriphenylphosphine, carrying out reflux reaction under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, carrying out forward silica gel column chromatography gradient elution, and obtaining the compound H12, namely 2- (2-fluorophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one by using ethyl acetate and methanol in a volume ratio of 10:1, yield: 59%, pale yellow solid, melting point: 261-262 ℃;

¹H NMR(400MHz,CDCl₃)δ8.52(td,J＝7.8,1.5Hz,1H),7.51–7.40(m,1H),7.29(dd,J＝7.9,7.5Hz,1H),7.21(dd,J＝11.3,8.4Hz,1H),4.31(t,J＝7.3Hz,2H),3.23(t,J＝8.0Hz,2H),2.60–2.09(m,2H)。

example 14

Preparation of compound H13:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, respectively adding 0.98g 3mmol of cesium carbonate, 0.17g1.2mmol of 4-fluorobenzeneboronic acid and 0.015g 0.01mmol of palladium tetratriphenylphosphine, carrying out reflux reaction under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and carrying out gradient elution by adopting forward silica gel column chromatography with an eluent in a volume ratio of 10: 1; ethyl acetate methanol 10:1 to give compound H13 as 2- (4-fluorophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one in yield: 66%, light yellow solid, melting point: 263-264 ℃;

¹H NMR(400MHz,CDCl₃)δ8.05(dd,J＝8.5,5.3Hz,2H),7.15(t,J＝8.5Hz,2H),4.29(t,J＝7.3Hz,2H),3.22(t,J＝8.0Hz,2H),2.76–2.11(m,2H)。

example 15

Preparation of compound H14:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.23g1.2mmol of 2-trifluoromethylphenylboronic acid and 0.015g 0.01mmol of palladium tetratriphenylphosphine, refluxing under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing forward silica gel column chromatography gradient elution, and eluting with ethyl acetate and methanol in a volume ratio of 10:1 to obtain the compound H14, namely 2- (2-trifluoromethylphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 55%, light yellow solid, melting point: 116 ℃ and 117 ℃;

¹H NMR(400MHz,CDCl₃)δ7.77(d,J＝7.3Hz,1H),7.68(d,J＝7.2Hz,1H),7.60(dt,J＝14.5,7.3Hz,2H),4.26(t,J＝7.3Hz,2H),3.20(t,J＝7.9Hz,2H),2.75–2.07(m,2H)。

example 16

Preparation of compound H15:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.23g1.2mmol of 4-trifluoromethylphenylboronic acid and 0.015g 0.01mmol of palladium tetratriphenylphosphine, refluxing under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing forward silica gel column chromatography gradient elution, and eluting with ethyl acetate and methanol in a volume ratio of 10:1 to obtain the compound H15, namely 2- (4-trifluoromethylphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 64%, light yellow solid, melting point: 215 ℃ and 216 ℃;

¹H NMR(400MHz,CDCl₃)δ8.14(d,J＝8.2Hz,2H),7.69(d,J＝8.2Hz,2H),4.25(t,J＝7.3Hz,2H),3.20(t,J＝8.0Hz,2H),2.52–2.22(m,2H)。

example 17

Preparation of compound H16:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.18g1.2mmol of 3-methoxybenzeneboronic acid and 0.015g 0.01mmol of palladium tetratriphenylphosphine, refluxing under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing forward silica gel gradient elution, and using ethyl acetate and methanol in a volume ratio of 10:1 as eluent to obtain the compound H16, namely 2- (3-trimethoxyphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 67%, light yellow solid, melting point: 192 ℃ to 194 ℃;

¹H NMR(400MHz,CDCl₃)δ7.66(s,1H),7.56(d,J＝7.6Hz,1H),7.35(t,J＝8.0Hz,1H),7.02(d,J＝8.2Hz,1H),4.29(t,J＝7.3Hz,2H),3.90(m 3H),3.22(t,J＝7.9Hz,2H),2.57–2.18(m,2H)。

example 18

Preparation of compound H17:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.18g1.2mmol of 4-methoxybenzeneboronic acid and 0.015g 0.01mmol of palladium tetratriphenylphosphine, refluxing under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing forward silica gel gradient elution, and using ethyl acetate and methanol in a volume ratio of 10:1 as eluent to obtain the compound H17, namely 2- (4-trimethoxyphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 80%, light yellow solid, melting point: 289-290 ℃;

¹H NMR(400MHz,CDCl₃)δ8.00(d,J＝8.6Hz,2H),6.96(d,J＝8.6Hz,2H),4.29(t,J＝7.3Hz,2H),3.87(s,3H),3.21(t,J＝8.0Hz,2H),2.69–2.17(m,2H)。

example 19

Preparation of compound H18:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.18g1.2mmol of 2-cyanobenzoic acid and 0.015g 0.01mmol of tetratriphenylphosphine palladium respectively, carrying out reflux reaction under the protection of argon until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, carrying out reduced pressure concentration, carrying out gradient elution by using forward silica gel by using ethyl acetate and methanol in a volume ratio of 10:1 as eluent, obtaining the compound H18, namely 2- (9-oxo-5, 6,7, 9-tetrahydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile, yield: 67%, light yellow solid, melting point: 201-202 ℃;

¹H NMR(400MHz,CDCl₃)δ8.28(d,J＝8.0Hz,1H),7.81(d,J＝7.7Hz,1H),7.71(td,J＝7.8,0.9Hz,1H),7.61–7.52(m,1H),4.34(t,J＝7.3Hz,2H),3.24(t,J＝8.0Hz,2H),2.60–2.18(m,2H)。

example 20

Preparation of compound H19:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.18g1.2mmol of 3-cyanobenzoic acid and 0.015g 0.01mmol of tetratriphenylphosphine palladium respectively, carrying out reflux reaction under the protection of argon until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, carrying out reduced pressure concentration, carrying out gradient elution by using forward silica gel by using ethyl acetate and methanol in a volume ratio of 10:1 as eluent, obtaining the compound H19, namely 3- (9-oxo-5, 6,7, 9-tetrahydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile, yield: 73%, light yellow solid, melting point: 276 ℃ and 277 ℃;

¹H NMR(400MHz,CDCl₃)δ8.35(s,1H),8.27(d,J＝8.0Hz,1H),7.74(d,J＝7.7Hz,1H),7.59(t,J＝7.8Hz,1H),4.24(t,J＝7.3Hz,2H),3.23(t,J＝8.0Hz,2H),2.76–2.09(m,2H)。

example 21

Preparation of compound H20:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.18g1.2mmol of 4-cyanobenzoic acid and 0.015g 0.01mmol of tetratriphenylphosphine palladium respectively, carrying out reflux reaction under the protection of argon until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, carrying out reduced pressure concentration, carrying out gradient elution by using forward silica gel by using ethyl acetate and methanol in a volume ratio of 10:1 as eluent, obtaining the compound H20, namely 4- (9-oxo-5, 6,7, 9-tetrahydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile, yield: 62%, light yellow solid, melting point: 171 ℃ and 172 ℃;

¹H NMR(400MHz,CDCl₃)δ8.14(d,J＝8.3Hz,2H),7.73(d,J＝8.3Hz,2H),4.32(t,J＝7.3Hz,2H),3.22(t,J＝8.0Hz,2H),2.60–2.18(m,2H)。

example 22

Preparation of compound H21:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.18g1.2mmol of 4-formaldehyde phenylboronic acid and 0.015g 0.01mmol of tetratriphenylphosphine palladium respectively, carrying out reflux reaction under the protection of argon until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, carrying out reduced pressure concentration, carrying out forward silica gel column chromatography gradient elution by using ethyl acetate and methanol in a volume ratio of 10:1 to obtain the compound H21, namely 4- (9-oxo-5, 6,7, 9-tetrahydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzaldehyde, yield: 69%, light yellow solid, melting point: 197 ℃ and 198 ℃;

¹H NMR(400MHz,CDCl₃)δ10.07(s,1H),8.23(d,J＝8.2Hz,2H),7.97(d,J＝8.3Hz,2H),4.26(t,J＝7.3Hz,2H),3.24(t,J＝8.0Hz,2H),2.75–2.27(m,2H)。

example 23

Preparation of compound H22:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.20g1.2mmol of 3-acetylphenylboronic acid and 0.015g 0.01mmol of tetratriphenylphosphine palladium respectively, refluxing under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution with forward silica gel by using ethyl acetate and methanol in a volume ratio of 10:1 to obtain a compound H22, namely 2- (3-acetylphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 71%, light yellow solid, melting point: 257 and 258 ℃;

¹H NMR(400MHz,CDCl₃)δ8.58(s,1H),8.27(d,J＝7.8Hz,1H),8.06(d,J＝7.8Hz,1H),7.58(t,J＝7.8Hz,1H),4.31(t,J＝7.3Hz,2H),3.24(t,J＝7.9Hz,2H),2.69(s,3H),2.60–2.22(m,2H)。

example 24

Preparation of compound H23:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.20g1.2mmol of 3-nitrobenzboronic acid and 0.015g 0.01mmol of palladium tetratriphenylphosphine, carrying out reflux reaction under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, carrying out reduced pressure concentration, carrying out forward silica gel gradient elution, and obtaining the compound H23, namely 2- (3-nitrophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one by using ethyl acetate and methanol in a volume ratio of 10:1, yield: 61%, light yellow solid, melting point: 294-295 ℃;

¹H NMR(400MHz,CDCl₃)δ8.83(s,1H),8.41(d,J＝7.8Hz,1H),8.31(d,J＝8.2Hz,1H),7.65(t,J＝8.0Hz,1H),4.25(t,J＝7.2Hz,2H),3.23(t,J＝8.0Hz,2H),2.74–2.24(m,2H)。

example 25

Preparation of compound H24:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g of 3mmol of cesium carbonate, 0.18g of 1.2mmol of 3, 5-dimethylbenzeneboronic acid and 0.015g of 0.01mmol of palladium tetratriphenylphosphine respectively, carrying out reflux reaction under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, carrying out forward silica gel column chromatography gradient elution according to the volume ratio of 10:1 of ethyl acetate to methanol to obtain the compound H24, namely 2- (3, 5-dimethylphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 84%, light yellow solid, melting point: 276 ℃ and 277 ℃;

¹H NMR(400MHz,CDCl₃)δ7.66(s,2H),7.08(s,1H),4.21(t,J＝7.3Hz,2H),3.18(t,J＝8.0Hz,2H),2.53–2.14(m,2H),2.35(s,6H)。

example 26

Preparation of compound H25:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.23g1.2mmol of 3, 5-dichlorophenylboronic acid and 0.015g 0.01mmol of tetratriphenylphosphine palladium respectively, carrying out reflux reaction under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, carrying out forward silica gel column chromatography gradient elution, and eluting with ethyl acetate and methanol in a volume ratio of 10:1 to obtain the compound H25, namely 2- (3, 5-dichlorophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 77%, light yellow solid, melting point: 288-289 ℃;

¹H NMR(400MHz,CDCl₃)δ7.95(d,J＝1.7Hz,2H),7.45(s,1H),4.30(t,J＝7.3Hz,2H),3.23(t,J＝8.0Hz,2H),2.52–2.24(m,2H)。

example 27

Preparation of compound H26:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.23g1.2mmol of 3, 4-dichlorophenylboronic acid and 0.015g 0.01mmol of tetratriphenylphosphine palladium respectively, carrying out reflux reaction under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, carrying out forward silica gel column chromatography gradient elution, and eluting with ethyl acetate and methanol in a volume ratio of 10:1 to obtain the compound H26, namely 2- (3, 4-dichlorophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 67%, light yellow solid, melting point: 220 ℃ and 221 ℃;

¹H NMR(600MHz,CDCl₃)δ8.20(s,1H),7.86(d,J＝8.4Hz,1H),7.54(d,J＝8.3Hz,1H),4.30(t,J＝7.2Hz,2H),3.23(t,J＝7.8Hz,2H),2.78–2.20(m,2H)。

example 28

Preparation of compound H27:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.33g1.2mmol of 3, 5-dibromophenylboronic acid and 0.015g 0.01mmol of palladium tetratriphenylphosphine respectively, carrying out reflux reaction under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, carrying out forward silica gel column chromatography gradient elution, and using ethyl acetate and methanol in a volume ratio of 10:1 as eluent to obtain the compound H27, namely 2- (3, 5-dibromophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 74%, light yellow solid, melting point: 265 ℃ and 266 ℃;

¹H NMR(600MHz,CDCl₃)δ8.14(s,2H),7.75(s,1H),4.30(t,J＝6.9Hz,2H),3.24(t,J＝7.5Hz,2H),2.59–2.27(m,2H)。

example 29

Preparation of compound H28:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.19g1.2mmol of 3, 5-difluorophenylboronic acid and 0.015g 0.01mmol of tetratriphenylphosphine palladium respectively, refluxing under the protection of argon until all the raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, eluting with a forward silica gel column chromatography gradient, wherein an eluent is ethyl acetate: methanol 10:1 in a volume ratio of 10:1, to obtain the compound H28, namely 2- (3, 5-difluorophenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 64%, light yellow solid, melting point: 271-272 ℃;

¹H NMR(400MHz,CDCl₃)δ7.60(d,J＝6.0Hz,2H),6.92(tt,J＝8.6,2.1Hz,1H),4.36(t,J＝7.3Hz,2H),3.23(t,J＝8.0Hz,2H),2.78–2.04(m,2H)。

example 30

Preparation of compound H29:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g of 3mmol of cesium carbonate, 0.22g of 1.2mmol of 3, 5-dimethoxyphenylboronic acid and 0.015g of 0.01mmol of palladium tetratriphenylphosphine respectively, refluxing and reacting under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by using forward silica gel column chromatography, and using ethyl acetate and methanol in a volume ratio of 10:1 as eluent to obtain the compound H29, namely 2- (3, 5-dimethoxyphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 61%, light yellow solid, melting point: 255-256 ℃;

¹H NMR(600MHz,CDCl₃)δ7.20(s,2H),6.57(s,1H),4.29(t,J＝7.2Hz,2H),3.87(s,6H),3.22(t,J＝7.8Hz,2H),2.37(p,J＝7.3Hz,2H)。

example 31

Preparation of compound H30:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.22g1.2mmol of 3, 4-dimethoxyphenylboronic acid and 0.015g 0.01mmol of palladium tetratriphenylphosphine under the protection of argon, refluxing until all the raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, eluting with a forward silica gel column chromatography gradient, wherein an eluent is ethyl acetate: methanol 10:1 in a volume ratio of 10:1, to obtain a compound H30, namely 2- (3, 4-dimethoxyphenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 58%, light yellow solid, melting point: 227 ℃ to 228 ℃;

¹H NMR(600MHz,CDCl₃)δ7.70(s,1H),7.51(d,J＝8.3Hz,1H),6.91(d,J＝8.3Hz,1H),4.29(t,J＝7.2Hz,2H),4.00(s,3H),3.95(s,3H),3.22(t,J＝7.8Hz,2H),2.39-2.34(m,2H)。

example 32

Preparation of compound H31:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.21g1.2mmol of 3-chloro-4-fluorobenzeneboronic acid and 0.015g 0.01mmol of palladium tetratriphenylphosphine respectively, refluxing and reacting under the protection of argon until all the raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, carrying out forward silica gel column chromatography gradient elution, and obtaining the compound H31, namely 2- (3-chloro-4-fluoro-phenyl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5 by using ethyl acetate and methanol in a volume ratio of 10:1 as eluent, 4-d ] pyrimidin-9 (5H) -one, yield: 54%, light yellow solid, melting point: 225-226 ℃;

¹H NMR(400MHz,CDCl₃)δ8.15(dd,J＝6.9,2.1Hz,1H),7.87(ddd,J＝8.5,4.4,2.2Hz,1H),7.21(t,J＝8.6Hz,1H),4.28(t,J＝7.3Hz,2H),3.20(t,J＝8.0Hz,2H),2.58–2.14(m,2H)。

example 33

Preparation of compound H32:

dissolving 0.27g 1mmol of the compound F obtained in example 1, namely 2-bromo-6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, in 20mL of anhydrous toluene, adding 0.98g 3mmol of cesium carbonate, 0.24g1.2mmol of 1,1 '-biphenyl-2-yl phenylboronic acid and 0.015g 0.01mmol of palladium tetratriphenylphosphine respectively, refluxing and reacting until all raw materials disappear under the protection of argon, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by adopting forward silica gel column chromatography, using ethyl acetate and methanol in a volume ratio of 10:1 as eluent to obtain a compound H32, namely 2- (1,1' -biphenyl-2-yl) -6, 7-dihydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 71%, light yellow solid, melting point: 233-234 ℃;

¹H NMR(400MHz,CDCl₃)δ8.21(dd,J＝7.2,1.9Hz,1H),7.57–7.44(m,2H),7.40–7.33(m,4H),7.34–7.28(m,2H),4.31(t,J＝7.3Hz,2H),3.13(t,J＝7.9Hz,2H),2.56–2.13(m,2H)。

example 34

Preparation of compound I1:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, adding 0.98G 3mmol of cesium carbonate, 0.15G 1.2mmol of phenylboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine under the protection of argon, carrying out reflux reaction until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, carrying out forward silica gel column chromatography gradient elution with an eluent of petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound I1, namely 2-phenyl-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, the yield is 83 percent, and the melting point is 198-199 ℃ and is light yellow solid;

¹H NMR(400MHz,CDCl₃)δ8.21–7.90(m,2H),7.56–7.35(m,3H),4.13(t,J＝6.1Hz,2H),3.00(dd,J＝9.1,4.2Hz,2H),2.20–1.68(m,4H)。

example 35

Preparation of compound I2:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, respectively adding 0.98G 3mmol of cesium carbonate, 0.16G1.2mmol of 2-methylbenzeneboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine into the mixed solution, refluxing the mixed solution under the protection of argon until all raw materials disappear, extracting the mixed solution by using dichloromethane, drying the dried raw materials by using anhydrous sodium sulfate, concentrating the dried raw materials under reduced pressure, eluting the dried raw materials by using forward silica gel column chromatography gradient elution, and obtaining a compound I2, namely 2- (2-methylphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 69% yield as a pale yellow solid with a melting point of 180-181 ℃;

¹H NMR(400MHz,CDCl₃)δ7.74(d,J＝7.7Hz,1H),7.38-7.26(m,3H),4.16(t,J＝6.2Hz,2H),3.03(t,J＝6.7Hz,2H),2.65(s,3H),2.10–1.91(m,4H)。

example 36

Preparation of compound I3:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, respectively adding 0.98G 3mmol of cesium carbonate, 0.16G1.2mmol of 3-methylbenzeneboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine into the mixed solution, refluxing the mixed solution under the protection of argon until all raw materials disappear, extracting the mixed solution by using dichloromethane, drying the dried raw materials by using anhydrous sodium sulfate, concentrating the dried raw materials under reduced pressure, eluting the dried raw materials by using forward silica gel column chromatography gradient elution, and obtaining a compound I3, namely 2- (3-methylphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 74% yield as a pale yellow solid with melting point 206-207 ℃;

¹H NMR(400MHz,CDCl₃)δ7.94(s,1H),7.81(d,J＝7.7Hz,1H),7.34(t,J＝7.6Hz,1H),7.27(d,J＝8.6Hz,1H),4.15(t,J＝6.2Hz,2H),3.02(t,J＝6.7Hz,2H),2.42(s,3H),2.09–1.87(m,4H)。

example 37

Preparation of compound I4:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, respectively adding 0.98G 3mmol of cesium carbonate, 0.16G1.2mmol of 4-methylbenzeneboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine into the mixed solution, refluxing the mixed solution under the protection of argon until all raw materials disappear, extracting the mixed solution by using dichloromethane, drying the dried raw materials by using anhydrous sodium sulfate, concentrating the dried raw materials under reduced pressure, eluting the dried raw materials by using forward silica gel column chromatography gradient elution, and obtaining a compound I4, namely 2- (4-methylphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 77% yield as a pale yellow solid with a melting point of 256-257 ℃;

¹H NMR(400MHz,CDCl₃)δ7.95(d,J＝8.2Hz,2H),7.25(d,J＝7.9Hz,2H),4.14(t,J＝6.2Hz,2H),3.01(t,J＝6.7Hz,2H),2.40(s,3H),2.18–1.82(m,4H)。

example 38

Preparation of compound I5:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, respectively adding 0.98G 3mmol of cesium carbonate, 0.22G1.2mmol of 4-tert-butylbenzoic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine, refluxing and reacting until all raw materials disappear under the protection of argon, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, eluting by forward silica gel gradient column chromatography, eluting with petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound I5, namely 2- (4-tert-butylphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 78% yield as a pale yellow solid with a melting point of 249-250 ℃;

¹H NMR(400MHz,CDCl₃)δ8.00(d,J＝8.2Hz,2H),7.47(d,J＝8.3Hz,2H),4.15(t,J＝6.0Hz,2H),3.02(t,J＝6.5Hz,2H),2.18–1.70(m,4H),1.35(s,9H)。

example 39

Preparation of compound I6:

dissolving 0.28G 1mmol of the compound G obtained in example 1, 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, adding 0.98G 3mmol of cesium carbonate, 0.19G1.2mmol of 2-chlorobenzeneboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine under the protection of argon, refluxing until all the raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, eluting with forward silica gel gradient column chromatography to obtain a compound I6 of 2- (2-chlorophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 65% yield as a pale yellow solid with a melting point of 179-180 ℃;

¹H NMR(400MHz,CDCl₃)δ8.42–8.37(m,1H),7.49(d,J＝2.6Hz,1H),7.42–7.35(m,2H),4.16(t,J＝5.3Hz,2H),3.04(t,J＝6.4Hz,2H),2.18–1.86(m,4H)。

example 40

Preparation of compound I7:

dissolving 0.28G 1mmol of the compound G obtained in example 1, 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, adding 0.98G 3mmol of cesium carbonate, 0.19G1.2mmol of 3-chlorobenzeneboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine under the protection of argon, refluxing until all the raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, eluting with forward silica gel gradient column chromatography to obtain a compound I7 of 2- (3-chlorophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 74% yield as a pale yellow solid with melting point 217 ℃ at 218 ℃;

¹H NMR(400MHz,CDCl₃)δ8.11(t,J＝1.7Hz,1H),7.91(dt,J＝7.4,1.5Hz,1H),7.45-7.37(m,2H),4.15(t,J＝6.2Hz,2H),3.03(t,J＝6.7Hz,2H),2.28–1.76(m,4H)。

EXAMPLE 41

Preparation of compound I8:

dissolving 0.28G 1mmol of the compound G obtained in example 1, 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, adding 0.98G 3mmol of cesium carbonate, 0.19G1.2mmol of 4-chlorobenzeneboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine under the protection of argon, refluxing until all the raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, eluting with forward silica gel gradient column chromatography to obtain a compound I8 of 2- (4-chlorophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 71% yield as a pale yellow solid with a melting point of 230-231 ℃;

¹H NMR(400MHz,CDCl₃)δ8.00(d,J＝8.6Hz,2H),7.44(d,J＝8.6Hz,2H),4.15(t,J＝6.2Hz,2H),3.03(t,J＝6.7Hz,2H),2.30–1.78(m,4H)。

example 42

Preparation of compound I9:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, adding 0.98G 3mmol of cesium carbonate, 0.24G1.2mmol of 2-bromobenzeneboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine under the protection of argon into the mixed solution, carrying out reflux reaction until all raw materials disappear, extracting the mixed solution by using dichloromethane, drying the dried raw materials by using anhydrous sodium sulfate, carrying out reduced pressure concentration, carrying out elution by using forward silica gel column chromatography gradient elution, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound I9, namely 2- (2-bromophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 60% yield as a pale yellow solid with a melting point of 167-;

¹H NMR(400MHz,CDCl₃)δ8.18(dd,J＝7.9,1.7Hz,1H),7.68(dd,J＝8.0,1.0Hz,1H),7.41(td,J＝7.7,1.2Hz,1H),7.29(td,J＝7.7,1.7Hz,1H),4.15(t,J＝6.2Hz,2H),3.03(t,J＝6.7Hz,2H),2.28–1.82(m,4H)。

example 43

Preparation of compound I10:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, respectively adding 0.98G 3mmol of cesium carbonate, 0.24G1.2mmol of 3-bromobenzeneboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine into the mixed solution under the protection of argon, carrying out reflux reaction until all raw materials disappear, extracting the mixture by using dichloromethane, drying the mixture by using anhydrous sodium sulfate, carrying out reduced pressure concentration, carrying out elution by using forward silica gel column chromatography gradient, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:2, and obtaining a compound I10, namely 2- (3-bromophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 74% yield as a pale yellow solid with melting point of 234-235 ℃;

¹H NMR(400MHz,CDCl₃)δ8.26(t,J＝1.8Hz,1H),8.03–7.84(m,1H),7.58(ddd,J＝7.9,1.8,0.9Hz,1H),7.32(t,J＝7.9Hz,1H),4.14(t,J＝6.2Hz,2H),3.02(t,J＝6.7Hz,2H),2.41–1.78(m,4H)。

example 44

Preparation of compound I11:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, adding 0.98G 3mmol of cesium carbonate, 0.24G1.2mmol of 4-bromobenzeneboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine under the protection of argon into the mixed solution, carrying out reflux reaction until all raw materials disappear, extracting the mixture by using dichloromethane, drying the mixture by using anhydrous sodium sulfate, carrying out reduced pressure concentration, carrying out elution by using forward silica gel column chromatography gradient elution, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound I11, namely 2- (4-bromophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 72% yield as a pale yellow solid with a melting point of 226-;

¹H NMR(400MHz,CDCl₃)δ7.91(d,J＝8.6Hz,2H),7.58(d,J＝8.7Hz,2H),4.13(t,J＝6.2Hz,2H),3.01(t,J＝6.7Hz,2H),2.17–1.85(m,4H)。

example 45

Preparation of compound I12:

dissolving 0.28G 1mmol of the compound G2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone obtained in example 1 in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, adding 0.98G 3mmol of cesium carbonate, 0.17G1.2mmol of 2-fluorobenzeneboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine under the protection of argon, refluxing until all the raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing forward silica gel column chromatography gradient elution with a petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound I12 of 2- (2-fluorophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 58% yield as a pale yellow solid with a melting point of 248-249 ℃;

¹H NMR(400MHz,CDCl₃)δ8.52(t,J＝7.6Hz,1H),7.45(dd,J＝13.1,6.3Hz,1H),7.31(dd,J＝11.6,7.5Hz,1H),7.21(dd,J＝11.2,8.6Hz,1H),4.17(t,J＝6.1Hz,2H),3.05(t,J＝6.6Hz,2H),2.30–1.80(m,4H)。

example 46

Preparation of compound I13:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, adding 0.98G 3mmol of cesium carbonate, 0.17G1.2mmol of 4-fluorobenzeneboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine under the protection of argon into the mixed solution, performing reflux reaction until all raw materials disappear, extracting the mixture by using dichloromethane, drying the mixture by using anhydrous sodium sulfate, concentrating the dried mixture under reduced pressure, performing forward silica gel gradient column chromatography, and eluting by using petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound I13, namely 2- (4-fluorophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 69% yield as a pale yellow solid with a melting point of 255-;

¹H NMR(400MHz,CDCl₃)δ8.06(dd,J＝8.6,5.3Hz,2H),7.15(t,J＝8.6Hz,2H),4.15(t,J＝6.2Hz,2H),3.03(t,J＝6.6Hz,2H),2.15–1.79(m,4H)。

example 47

Preparation of compound I14:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, respectively adding 0.98G 3mmol of cesium carbonate, 0.23G1.2mmol of 2-trifluoromethylphenylboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine, refluxing and reacting until all raw materials disappear under the protection of argon, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, carrying out gradient elution by using forward silica gel column chromatography, using petroleum ether and ethyl acetate in a volume ratio of 1:2 as eluent, obtaining a compound I14, namely 2- (2-trifluoromethylphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 59% yield as a pale yellow solid with melting point of 108-109 ℃;

¹H NMR(400MHz,CDCl₃)δ7.80(d,J＝7.2Hz,1H),7.70(d,J＝7.4Hz,1H),7.68–7.58(m,2H),4.16(t,J＝6.1Hz,2H),3.04(t,J＝6.6Hz,2H),2.38–1.83(m,4H)。

example 48

Preparation of compound I15:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, respectively adding 0.98G 3mmol of cesium carbonate, 0.23G1.2mmol of 4-trifluoromethylphenylboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine, refluxing and reacting until all raw materials disappear under the protection of argon, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, carrying out gradient elution by using forward silica gel column chromatography, using petroleum ether and ethyl acetate in a volume ratio of 1:2 as eluents, and obtaining a compound I15, namely 2- (4-trifluoromethylphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in a yield of 57% as a pale yellow solid with a melting point of 201-202 ℃;

¹H NMR(400MHz,CDCl₃)δ8.18(d,J＝8.2Hz,2H),7.72(d,J＝8.2Hz,2H),4.16(t,J＝6.1Hz,2H),3.04(t,J＝6.6Hz,2H),2.21–1.84(m,4H)。

example 49

Preparation of compound I16:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, respectively adding 0.98G 3mmol of cesium carbonate, 0.18G1.2mmol of 3-methoxyphenylboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine into the mixed solution, refluxing the mixed solution under the protection of argon until all raw materials disappear, extracting the mixed solution by using dichloromethane, drying the dried raw materials by using anhydrous sodium sulfate, concentrating the dried raw materials under reduced pressure, eluting the dried raw materials by using forward silica gel column chromatography gradient elution, and obtaining a compound I16, namely 2- (3-trimethoxyphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 66% yield as a pale yellow solid with melting point of 202-203 ℃;

¹H NMR(400MHz,CDCl₃)δ7.67(s,1H),7.56(d,J＝7.7Hz,1H),7.35(t,J＝8.0Hz,1H),7.01(dd,J＝8.2,2.1Hz,1H),4.14(t,J＝6.1Hz,2H),3.89(s,3H),3.02(t,J＝6.6Hz,2H),2.39–1.80(m,4H)。

example 50

Preparation of compound I17:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, respectively adding 0.98G 3mmol of cesium carbonate, 0.18G1.2mmol of 4-methoxyphenylboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine into the mixed solution, refluxing the mixed solution under the protection of argon until all raw materials disappear, extracting the mixed solution by using dichloromethane, drying the dried raw materials by using anhydrous sodium sulfate, concentrating the dried raw materials under reduced pressure, eluting the dried raw materials by using forward silica gel column chromatography gradient elution, and obtaining a compound I17, namely 2- (4-trimethoxyphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 76% yield as a pale yellow solid with a melting point of 196-197 ℃;

¹H NMR(400MHz,CDCl₃)δ8.01(d,J＝8.8Hz,2H),6.97(d,J＝8.8Hz,2H),4.46–4.04(m,2H),3.87(s,3H),3.02(t,J＝6.6Hz,2H),2.06-1.93(m,4H)。

example 51

Preparation of compound I18:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, respectively adding 0.98G 3mmol of cesium carbonate, 0.18G1.2mmol of 2-cyanobenzoic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine, refluxing and reacting until all raw materials disappear under the protection of argon, extracting by using dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, eluting by using forward silica gel column chromatography gradient elution, using petroleum ether and ethyl acetate in a volume ratio of 1:2 as eluents to obtain a compound I18, namely 2- (10-oxo-6, 7,8, 10-tetrahydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile in 55% yield, a pale yellow solid, a melting point of 179-180 ℃;

¹H NMR(400MHz,CDCl₃)δ8.28(d,J＝8.0Hz,1H),7.82(d,J＝7.9Hz,1H),7.72(t,J＝7.8Hz,1H),7.57(t,J＝7.6Hz,1H),4.17(t,J＝6.1Hz,2H),3.05(t,J＝6.6Hz,2H),1.96-2.06(m,4H)。

example 52

Preparation of compound I19:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, respectively adding 0.98G 3mmol of cesium carbonate, 0.18G1.2mmol of 3-cyanobenzoic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine into the mixed solution, refluxing the mixed solution under the protection of argon until all raw materials disappear, extracting the mixed solution by using dichloromethane, drying the dried raw materials by using anhydrous sodium sulfate, concentrating the dried raw materials under reduced pressure, eluting the mixed solution by using forward silica gel column chromatography with a gradient eluent of petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound I19, namely 3- (10-oxo-6, 7,8, 10-tetrahydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile in a yield of 67% as a pale yellow solid with a melting point of 231-;

¹H NMR(400MHz,CDCl₃)δ8.35(s,1H),8.27(d,J＝7.9Hz,1H),7.73(d,J＝7.5Hz,1H),7.59(t,J＝7.8Hz,1H),4.15(t,J＝5.6Hz,2H),3.03(t,J＝6.5Hz,2H),2.05-1.96(m 4H)。

example 53

Preparation of compound I20:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, respectively adding 0.98G 3mmol of cesium carbonate, 0.18G1.2mmol of 4-cyanobenzoic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine into the mixed solution, refluxing the mixed solution under the protection of argon until all raw materials disappear, extracting the mixed solution by using dichloromethane, drying the dried raw materials by using anhydrous sodium sulfate, concentrating the dried raw materials under reduced pressure, eluting the dried raw materials by using forward silica gel column chromatography gradient elution, and obtaining a compound I20, namely 4- (10-oxo-6, 7,8, 10-tetrahydro-5H-pyridine [1], 2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile in a yield of 68% as a pale yellow solid with a melting point of 169-170 ℃;

¹H NMR(400MHz,CDCl₃)δ8.17(d,J＝7.6Hz,2H),7.76(d,J＝7.6Hz,2H),4.16(t,J＝5.4Hz,2H),3.05(t,J＝6.4Hz,2H),2.25–1.88(m,4H)。

example 54

Preparation of compound I21:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, respectively adding 0.98G 3mmol of cesium carbonate, 0.18G1.2mmol of 4-formaldehyde phenylboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine, refluxing and reacting until all raw materials disappear under the protection of argon, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, carrying out gradient elution by using forward silica gel column chromatography, using petroleum ether and ethyl acetate in a volume ratio of 1:2 as eluent, obtaining a compound I21, namely 4- (10-oxo-6, 7,8, 10-tetrahydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzaldehyde in 73% yield, a pale yellow solid with a melting point of 171-172 ℃;

¹H NMR(400MHz,CDCl₃)δ10.07(s,1H),8.24(d,J＝8.2Hz,2H),7.98(d,J＝8.2Hz,2H),4.16(t,J＝6.1Hz,2H),3.05(t,J＝6.6Hz,2H),2.32–1.81(m,4H)。

example 55

Preparation of compound I22:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, respectively adding 0.98G 3mmol of cesium carbonate, 0.20G1.2mmol of 3-acetylphenylboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine into the mixed solution, refluxing the mixed solution under the protection of argon until all raw materials disappear, extracting the mixed solution by using dichloromethane, drying the dried raw materials by using anhydrous sodium sulfate, concentrating the dried raw materials under reduced pressure, eluting the dried raw materials by using forward silica gel column chromatography gradient, and eluting petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound I22, 2- (3-acetylphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 80% yield as a pale yellow solid with a melting point of 195-196 ℃;

¹H NMR(400MHz,CDCl₃)δ8.52(s,1H),8.20(dd,J＝7.8,0.8Hz,1H),8.00(d,J＝7.8Hz,1H),7.53(t,J＝7.8Hz,1H),4.10(t,J＝6.2Hz,2H),2.99(t,J＝6.6Hz,2H),2.65(s,3H),2.08–1.88(m,4H)。

example 56

Preparation of compound I23:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, respectively adding 0.98G 3mmol of cesium carbonate, 0.20G1.2mmol of 3-nitrobenzeneboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine into the mixed solution, refluxing the mixed solution under the protection of argon until all raw materials disappear, extracting the mixed solution by using dichloromethane, drying the dried raw materials by using anhydrous sodium sulfate, concentrating the dried raw materials under reduced pressure, eluting the dried raw materials by using forward silica gel column chromatography gradient elution, and obtaining a compound I23, namely 2- (3-nitrophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 63% yield as a pale yellow solid with a melting point of 261-262 ℃;

¹H NMR(400MHz,CDCl₃)δ8.85(s,1H),8.43(d,J＝7.8Hz,1H),8.32(dd,J＝8.2,1.1Hz,1H),7.67(t,J＝8.0Hz,1H),4.16(t,J＝6.1Hz,2H),3.05(t,J＝6.6Hz,2H),2.49–1.75(m,4H)。

example 57

Preparation of compound I24:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, adding 0.98G 3mmol of cesium carbonate, 0.18G1.2mmol of 3, 5-dimethylbenzeneboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine under the protection of argon, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, eluting with petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound I24, namely 2- (3, 5-dimethylphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in a yield of 70% as a pale yellow solid with a melting point of 258-;

¹H NMR(400MHz,CDCl₃)δ7.70(s,2H),7.10(s,1H),4.15(t,J＝6.1Hz,2H),3.03(t,J＝6.6Hz,2H),2.38(s,6H),2.24–1.80(m,4H)。

example 58

Preparation of compound I25:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, adding 0.98G 3mmol of cesium carbonate, 0.23G1.2mmol of 3, 5-dichlorophenylboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine into the mixed solution respectively, refluxing the mixed solution under the protection of argon until all raw materials disappear, extracting the mixed solution by using dichloromethane, drying the dried solution by using anhydrous sodium sulfate, concentrating the dried solution under reduced pressure, eluting the mixed solution by using forward silica gel column chromatography gradient, and using petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound I25, namely 2- (3, 5-dichlorophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in a yield of 72% as a pale yellow solid with a melting point of 271-272 ℃;

¹H NMR(400MHz,CDCl₃)δ7.94(d,J＝1.5Hz,1H),7.24(s,2H),4.14(t,J＝6.1Hz,2H),3.02(t,J＝6.6Hz,2H),2.32–1.74(m,4H)。

example 59

Preparation of compound I26:

dissolving 0.28G 1mmol of the compound G2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one obtained in example 1 in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, adding 0.98G 3mmol of cesium carbonate, 0.23G1.2mmol of 3, 4-dichlorophenylboronic acid and 0.015G 0.01mmol of tetratriphenylphosphine palladium respectively, refluxing under the protection of argon until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, eluting with forward silica gel gradient column chromatography, eluting with petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound I26 of 2- (3, 4-dichlorophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 77% yield as a pale yellow solid with a melting point of 218-220 ℃;

¹H NMR(400MHz,CDCl₃)δ8.19(s,1H),7.85(d,J＝8.4Hz,1H),7.52(d,J＝8.4Hz,1H),4.14(t,J＝6.1Hz,2H),3.03(t,J＝6.6Hz,2H),2.11–1.88(m,4H)。

example 60

Preparation of compound I27:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, respectively adding 0.98G 3mmol of cesium carbonate, 0.33G1.2mmol of 3, 5-dibromophenylboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine, refluxing and reacting until all raw materials disappear under the protection of argon, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, carrying out gradient elution by using forward silica gel column chromatography, using petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound I27, namely 2- (3, 5-dibromophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 79% yield as a pale yellow solid with a melting point of 261-262 ℃;

¹H NMR(400MHz,CDCl₃)δ8.12(s,2H),7.24(s,1H),4.13(t,J＝6.1Hz,2H),3.02(t,J＝6.6Hz,2H),2.33–1.76(m,4H)。

example 61

Preparation of compound I28:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, respectively adding 0.98G 3mmol of cesium carbonate, 0.19G1.2mmol of 3, 5-difluorophenylboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine, refluxing and reacting until all raw materials disappear under the protection of argon, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, carrying out gradient elution by using forward silica gel column chromatography, using petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound I28, namely 2- (3, 5-difluorophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 71% yield as a pale yellow solid with a melting point of 248-249 ℃;

¹H NMR(400MHz,CDCl₃)δ7.57(d,J＝6.4Hz,2H),6.89(td,J＝8.6,2.2Hz,1H),4.12(t,J＝6.1Hz,2H),3.01(t,J＝6.6Hz,2H),2.30–1.76(m,4H)。

example 62

Preparation of compound I29:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, adding 0.98G 3mmol of cesium carbonate, 0.22G1.2mmol of 3, 5-dimethoxyphenylboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine under the protection of argon, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, eluting with petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound I29, namely 2- (3, 5-dimethoxyphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 58% yield as a pale yellow solid with a melting point of 223-224 ℃;

¹H NMR(400MHz,CDCl₃)δ7.20(d,J＝1.8Hz,2H),6.56(s,1H),4.15(t,J＝6.1Hz,2H),3.87(s,6H),3.03(t,J＝6.6Hz,2H),2.30–1.83(m,4H)。

example 63

Preparation of compound I30:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, adding 0.98G 3mmol of cesium carbonate, 0.22G1.2mmol of 3, 4-dimethoxyphenylboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine under the protection of argon, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, eluting with petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound I30, namely 2- (3, 4-dimethoxyphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in 63% yield as a pale yellow solid with a melting point of 216-217 ℃;

¹H NMR(400MHz,CDCl₃)δ7.70(d,J＝1.3Hz,1H),7.49(dd,J＝8.4,1.4Hz,1H),6.90(d,J＝8.4Hz,1H),4.14(t,J＝6.1Hz,2H),3.99(s,3H),3.93(s,3H),3.01(t,J＝6.6Hz,2H),2.12–1.88(m,4H)。

example 64

Preparation of compound I31:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) ketone, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, respectively adding 0.98G 3mmol of cesium carbonate, 0.21G1.2mmol of 3-chloro-4-fluorobenzeneboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine, refluxing and reacting until all raw materials disappear under the protection of argon, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, carrying out gradient elution by using forward column chromatography on silica gel, using petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound I31, namely 2- (3-chloro-4-fluoro-phenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one in a yield of 57% as a pale yellow solid with a melting point of 257-258 ℃;

¹H NMR(400MHz,CDCl₃)δ8.17(dd,J＝6.9,2.0Hz,1H),8.05–7.63(m,1H),7.22(t,J＝8.6Hz,1H),4.15(t,J＝6.1Hz,2H),3.03(t,J＝6.6Hz,2H),2.53–1.73(m,4H)。

example 65

Preparation of compound I32:

dissolving 0.28G 1mmol of the compound G obtained in example 1, namely 2-bromo-7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one, in 5mL of a mixed solution of toluene and water in a volume ratio of 4:1, respectively adding 0.98G 3mmol of cesium carbonate, 0.24G1.2mmol of 1,1 '-biphenyl-2-yl phenylboronic acid and 0.015G 0.01mmol of palladium tetratriphenylphosphine, refluxing and reacting until all raw materials disappear under the protection of argon, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, carrying out gradient elution by using forward silica gel column chromatography, using petroleum ether and ethyl acetate in a volume ratio of 1:2 as eluent, and obtaining a compound I32, namely 2- (1,1' -biphenyl-3-yl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone, the yield is 74 percent, and the melting point is 197-198 ℃;

¹H NMR(400MHz,CDCl₃)δ8.22(d,J＝7.3Hz,1H),7.47(dd,J＝15.1,7.3Hz,2H),7.38-7.29(m,6H),4.11(t,J＝6.2Hz,2H),2.93(t,J＝6.5Hz,2H),2.21–1.87(m,4H)。

example 66

The screening of the anti-tumor activity of the tricyclic thiazolo [5,4-d ] pyrimidone compound comprises the following steps:

cell survival rate by thiazole blue method:

the experimental process comprises the following steps:

cells grown in logarithmic growth phase were aspirated off medium, washed once with phosphate buffer, trypsinized, terminated by adding medium, gently pipetting, counted, seeded in 96-well plates (100. mu.l/well) at the corresponding cell density, cultured overnight, added with compounds (20. mu.l/well) with a concentration gradient of 3 wells for each compound, CO was added to each concentration, and₂culturing at 37 deg.C for 48 hr, removing old culture medium, adding thiazole blue 100 μ l, culturing for 2 hr, incubating at 37 deg.C for 2 hr, and measuring light absorption value (OD) at 570nm with MB microplate reader;

calculating the formula:

percent cell viability ═ 100% of (compound OD-blank OD/control OD-blank OD);

cytostatic rate ═ 1% (% cell viability ═ 1- (compound OD-blank OD/control OD-blank OD)]X 100%, fitting with Graphpad Prism 7 to obtain IC₅₀；

Sample treatment: dissolving a sample by using thionyl chloride, storing at low temperature, and controlling the concentration of the thionyl chloride in a final system within a range not influencing the detection activity;

data processing and results description: the activity of the samples was tested by primary screening under a single concentration condition, e.g., 50. mu.M monomer compound concentration, with% inhibition greater than 50%, and further tested for the dose-dependent relationship of activity, i.e., IC₅₀Values, obtained by nonlinear fitting of sample concentrations to sample activity, were calculated as Graphpad Prism 7, and in general, each sample was set with duplicate wells (n.gtoreq.3) in the test, and expressed as Standard Deviation (SD) in the results in tables 1 and 2:

example 67

The invention relates to a screening method for the antibacterial activity of tricyclic thiazolo [5,4-d ] pyrimidone compounds, which comprises the following steps:

melting agar culture medium, cooling to 46 + -0.5 deg.C, adding cultured bacteria liquid, mixing well to make testThe concentration of the bacterial suspension is 5 multiplied by 10⁵cfu/mL-5×10⁶cfu/mL, poured into a petri dish, 15-20 mL/dish, and left for 20min to solidify. Punching with agar puncher, with diameter of 5-6mm and 4-5 holes/dish, uniformly distributing, and the distance between the centers of the holes is more than 25mm and the distance between the centers of the holes and the periphery of the culture dish is more than 15 mm. 20. mu.L of the test solution was added to each well. Covering the culture dish, placing in an incubator at 37 ℃ for 30-60min to completely absorb the solution, performing inverted culture for 16-18 h, observing the result, measuring the diameter of the antibacterial ring by using a vernier caliper, recording, repeating the step for 3 times, and taking an average value, wherein the result is shown in tables 1 and 2.

Example 68

The invention relates to a screening method of acetylcholinesterase in the anti-Alzheimer disease of tricyclic thiazolo [5,4-d ] pyrimidone compounds, which comprises the following steps:

the total reaction volume was 200. mu.L: mu.L of sample, 158 mu.L of Tris-HCl buffer solution containing acetyl (butyryl) cholinesterase (final concentration is 0.02U/mL), and enzyme activity control group of enzyme-free Tris-HCl buffer solution, incubating at room temperature for 10min, adding 20 mu.L of iodinated thioacetyl (butyryl) choline, reacting at 37 ℃ for 10min, adding 20 mu.L of DTNB into each hole, shaking and mixing uniformly, and measuring the absorption value at 405 nm; taking huperzine A as positive control; the inhibition rate (%) [ (enzyme active group-enzyme activity control group) - (drug group-drug control group)/(enzyme active group-enzyme activity control group) ] × 100%; the results are shown in tables 1 and 2:

example 67

The screening of the tricyclic thiazolo [5,4-d ] pyrimidone compound for resisting acetyl (butyryl) cholinesterase comprises the following steps:

the total reaction volume was 200. mu.L: mu.L of sample, 138 mu.L of Tris-HCl buffer solution containing acetylcholinesterase (final concentration is 0.03U/mL), and enzyme activity control group of Tris-HCl buffer solution without enzyme, incubating at room temperature for 10min, adding 20 mu.L of thioacetylcholine iodide, reacting at 37 ℃ for 10min, adding 20 mu.L of 1% SDS and 20 mu.L of DTNB into each well, oscillating and mixing uniformly, and measuring the absorption value at 405 nm; taking huperzine A as positive control; the inhibition rate (%) (enzyme active group-enzyme activity control group) - (drug group-drug control group)/(enzyme active group-enzyme activity control group) x 100%, the results are shown in tables 1 and 2:

TABLE 1 bioactive results of H1-H32 derivatives

TABLE 2 biological Activity results of derivatives of I1-I32

As can be seen from the table: the 64 tricyclic thiazolo [5,4-d ] pyrimidone derivatives have inhibitory activity on acetyl (butyryl) cholinesterase in Alzheimer's disease, cancer cells (Hela cervical cancer cells and HT-29 human colon cancer cells) and antibacterial activity on Candida albicans C.albicans, Escherichia coli E.coli and Staphylococcus aureus S.aureus, and the results show that: the compounds H3-H5, H7-H8, H10-H12, H15-H16, H19-H25, H27-H28, H30-H31, I1, I3-I8, I10-I11, I13, I15-I17, I19-I23 and I25-I31 all have strong inhibitory activity on acetylcholinesterase in Alzheimer's disease; the compounds H7, H8, H10, H11, H20, H27, I11, I15 and I19 have inhibitory activity on butyrylcholinesterase in Alzheimer's disease; the compound I26 and I27 have inhibitory activity on Hela cervical carcinoma cells; the compounds I5, I11, I15 and I26 have inhibitory activity on HT-29 human colon cancer cells; compounds H1, H6-H10, H15, H16, H19, H28-H31, I3, I8, I15, I16, I18-I22, I27-I30 have inhibitory activity against candida albicans c.albicans; compounds I8, I15, I21 all have inhibitory activity against e.coli and s.aureus.