CN113788846B - Tricyclic thiazolo [5,4-d ] pyrimidinone derivative and application thereof - Google Patents

Tricyclic thiazolo [5,4-d ] pyrimidinone derivative and application thereof Download PDF

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CN113788846B
CN113788846B CN202111253193.8A CN202111253193A CN113788846B CN 113788846 B CN113788846 B CN 113788846B CN 202111253193 A CN202111253193 A CN 202111253193A CN 113788846 B CN113788846 B CN 113788846B
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thiazolo
pyrimidin
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CN113788846A (en
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阿吉艾克拜尔·艾萨
曾艳
聂礼飞
胡尔西地·博扎罗夫
赵江瑜
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Xinjiang Technical Institute of Physics and Chemistry of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
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    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract

The invention relates to a tricyclic thiazolo [5,4 ]d]Pyrimidinone derivative and its use, the derivative uses ethyl cyanoacetate as initial raw material, under the action of sodium nitrite and phosphoric acid it produces hydroxylamine compound (A), then uses sodium hydrosulfite to reduce to obtain 2-amino ethyl cyanoacetate (B), and makes them respectively react with acetic anhydride and Lawsen reagent to obtain 5-amino-4-formate thiazole compound (D), then uses NBS to bromize, under the action of phosphorus oxychloride it can obtain 2-bromo-dihydropyrrole [1,2- ]a]Thiazolo [5,4 ]d]Pyrimidinone compounds (F) and 2-bromo-7, 8-dihydro-5HPyridine [1,2 ]a]Thiazolo [5,4 ]d]Pyrimidine-10 (6)H) The ketone derivative (G) is finally subjected to Suzuki coupling reaction to obtain 64 different substituted tricyclic thiazolo [5,4- ]d]Pyrimidinone compounds H1-H32 and I1-I32. And examined the inhibitory activity of these 64 compounds against ethyl (butyrylcholine esterase) and the antibacterial activity of candida albicans in alzheimer's disease, the results showed that: 46 compounds have strong inhibition activity to acetylcholinesterase; 27 compounds have inhibitory activity against Candida albicans.

Description

Tricyclic thiazolo [5,4-d ] pyrimidinone derivative and application thereof
Technical Field
The invention relates to a tricyclic thiazolo [5,4-d ] pyrimidinone derivative and application thereof.
Background
Alzheimer's Disease (AD) is a neurodegenerative disease produced by impaired memory, language and reasoning of the hemispheres of the brain, and was first discovered by the German neuropathologist Alois Alzheimer in 1906 and named by its name. In recent years, the prevalence of AD has increased year by year and has tended to be younger, and it is expected that more than 1.3 million people worldwide will have AD in 2050. Because of the lack of very effective control methods, it has become the fourth cause of death in humans following heart disease, cancer and stroke. Based on the fact that no effective drug is applied to clinically preventing the progress of the disease of the AD so as to treat the AD, the need of searching for a drug capable of effectively treating the AD is urgent.
In recent years, a plurality of traditional Chinese medicines are found to have remarkable curative effects on treating AD, such as icariin, sinapine, radix salviae miltiorrhizae, radix puerariae and the like, and have strong inhibition on AChE; although the drugs greatly improve the neurocognitive ability of patients and alleviate AD symptoms, the drugs have single clinical manifestation action target point, large toxic and side effects, short half-life (more times of taking drugs daily), easy occurrence of drug resistance, adverse reaction and the like,
Heterocyclic compounds are a class of compounds with good biological activity and occupy a very important place in pharmaceutical chemistry. Because nitrogen element and life have a very profound connection, most of nitrogen-containing heterocyclic compounds have the characteristics of high efficiency, low toxicity and good environmental compatibility, are an irreplaceable biogenic medicine, and become the main stream 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 a number of unique properties and biological activities. To date, thiazole-based drugs have been used clinically. Thiazole compounds are receiving increasing attention as bioisosteres of thiazole, imidazole, benzimidazole, triazole and tetrazole, and it is desired to find novel thiazole compounds having a broad spectrum, high efficiency, low toxicity and excellent pharmacokinetic properties.
The thiazole ring is an important five-membered aromatic heterocycle, contains nitrogen and sulfur heteroatoms, has rich electrons, is easy to form hydrogen bonds, coordinates with metal ions, has electrostatic and hydrophobic interactions and other non-covalent interactions, and the structure endows the thiazole compound with a plurality of special properties, has wide potential application in a plurality of fields, and causes great attention of a plurality of workers, and related research work including the synthesis method thereof is growing. Especially, as a series of thiazole compounds are successfully used for clinical and agricultural production, the development of thiazole compounds is one of the hot spot fields of research in recent years. In the medical field, thiazole compounds can be combined with various targets such as enzyme and receptor in organisms to show various biological activities, almost the whole medical field is covered, and a plurality of thiazole compounds are used in clinic, such as antibiotic medicine cefixime, anticancer medicine dasatinib, antiparasitic medicine nitazoxanide, anti-inflammatory medicine meloxicam and the like, which are first-line medicines of clinical preference.
Therefore, the activity of thiazole pyrimidine derivatives can be seen, and the research for searching and exploring the synthesis and the biological activity of the compounds has great theoretical significance and application value for searching lead compounds such as new medicines.
Reference is made to:
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[4]2Bai,Z.S.；Wang,D.X.Heterocyclic Compounds Genetic Engineering and Pesticides in21 Century.Pesticides 1998,37(6),2-6.
[5]Feng,K.S.；Chen,R.Y.；et al.Synthesis and Structure of3,4-Dipheny-3-diazaphos-pholid-In-2-thione-4-oxides Sulfides.Chem.J.Chin,Univ.1993,14(9),1244-1249.
[6]Zhang,C X.；Zhan,Z.B.；et al Synthesis of Cyclic Glycerophospho-lipid Conjugates of Adenosine.Chem.J.Chin.Univ.199,19(6),913-916.
[7]Zhou,J；et al.Synthesis and Herbicidal Activity ofl-Aryl-2-phenyl-3-methyl-3-isopropyl-1,4,2-diazaphosp-holidin-5-one-2-oxides.Chem,J.Chin,Univ,1999,20(7),1058-1062.
[8]Zhang,H.Z,Zhao,Z.L,Zhou,C.H.Recent advance in oxazolebased medicinal chemistry,[J].Eur J Med Chem，2018,144:444-492.
[9]Zhang,H.Z，Gan,L.L,Wang,H.et al.New progress in azole compounds as antimicrobial agents,[J].Mini-Rev Med Chem,2017,17(2)：122-166.
[10]Mayer,J.C.P.；Sauer,A.C.；Iglesias,B.A.；et al.Ferrocenylethenyl substituted 1,3,4-oxadiaz-olyl-1,2,4-oxadiazoles:Synthesis,characterization and DNA-binding assays[J].J Organomet Chem,2017,841:1-11.
[11]Revuelta,J,Machetti,F,Cicchi,S.Modern Heterocyclic Chemistry.Berlin:Wiley,2011.
[12]Hanusek,J.Study of formation and transformation of some five-and six-membered heterocyclic compounds containing nitrogen and sulfur.Chem Listy,2008,102(9):801-810.
[13]Abele,E.；Abele,R.；Lukevics,E.Chemistry of Heterocyclic Compounds.New York:Springer,2007.
[14] Zhou Runmin, ding Guohua, development of five-membered heterocyclic compound, chemical engineering and development, 2008,37 (3): 22-35.
[15]Kashyap,S.J.；Garg,V.K.；Sharma,P.K.；Kumar,N.；Dudhe,R.；Gupta,J.K.Thiazoles:Having diverse biological activities.Med Chem Res,2012,DOI10.1007/s00044-011-9685-2.
[16]Galm,U.；Wang,L.；Huang,S.X.；Unsin,C.；Comparative analysis of the biosynthetic gene clusters and pathways for three structurally related antitumor antibiotics:Bleomycin,tallysomycin,and zorbamycin.J Nat Prod,2011,74(3):526-536.
[17]Moghadam,M.S.；Maleki,S.；Darabpour,E.；Motamedi,H.；Antibacterial activity of eight Iranian plant extracts against methicillin and cefixime restistant staphylococcous aureus strains.Asian Pac J Trop Med,2010,3(4):262-265.
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Based on comprehensive analysis of related patents and documents at home and abroad, the invention carries out total synthesis on tricyclic thiazolo [5,4-d ] pyrimidinone compounds, carries out systematic transformation and modification, introduces phenyl containing different substituents into molecules of the tricyclic thiazolo [5,4-d ] pyrimidinone compounds so as to improve the patentability of the tricyclic thiazolo [5,4-d ] pyrimidinone compounds, and researches the inhibition activity of the compounds on acetylcholinesterase, cancer cells (Hela cervical cancer cells and HT-29 human colon cancer cells) in Alzheimer's disease and the C.albicans, E.coli and S.aureus antibacterial activity of candida albicans so as to find candidate drugs with obvious curative effects, definite targets and anti-acetylcholinesterase and anti-tumor activity. The activity screening results show that: 46 compounds have strong inhibitory activity on acetylcholinesterase in Alzheimer disease; 9 compounds have inhibitory activity on butyrylcholinesterase in Alzheimer's disease; 2 compounds have inhibitory activity on Hela cervical cancer 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 against E.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 ] pyrimidinone derivative and application thereof. The derivative takes ethyl cyanoacetate as an initial raw material, hydroxylamine compound (A) is generated under the action of sodium nitrite and phosphoric acid, sodium hydrosulfite is reduced to obtain 2-amino ethyl cyanoacetate (B), then the 2-amino ethyl cyanoacetate (B) reacts with acetic anhydride and Lawson reagent to form a ring to obtain 5-amino-4-formate thiazole compound (D), then NBS is brominated, and then the 5-amino-4-formate thiazole compound (D) reacts with pyrrolidone and valerolactam to form a ring to obtain 2-bromo-dihydropyrrolo [1,2-a ] thiazolo [5,4-D ] pyrimidinone compound (F) and 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-D ] pyrimidine-10 (6H) ketone (G), and finally, suzuki reaction is carried out to obtain 64 different substituted tricyclic thiazolo [5,4-D ] pyrimidinone compounds H1-H32 and I1-I32. Meanwhile, the inhibition activity of the 64 compounds on ethyl (butyl) cholinesterase and the C.albicans antibacterial activity in Alzheimer disease are examined, and the results show that: 46 compounds have strong inhibitory activity on acetylcholinesterase in Alzheimer disease; compounds H7, H8, H10, H11, H20, H27, I11, I15, 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.albicans.
The invention relates to a tricyclic thiazolo [5,4-d ] pyrimidinone derivative, which has the structural formula:
Figure BDA0003323019370000041
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Figure BDA0003323019370000051
wherein:
the compound H1 is 2-phenyl-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidine-9 (5H) -ketone;
the compound H2 is 2- (2-methylphenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidine-9 (5H) -ketone;
compound H3 is 2- (3-methylphenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H4 is 2- (4-methylphenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H5 is 2- (4-tert-butylphenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H6 is 2- (2-chlorophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H7 is 2- (3-chlorophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H8 is 2- (4-chlorophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H9 is 2- (2-bromophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H10 is 2- (3-bromophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H11 is 2- (4-bromophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
Compound H12 is 2- (2-fluorophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H13 is 2- (4-fluorophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H14 is 2- (2-trifluoromethylphenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H15 is 2- (4-trifluoromethylphenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H16 is 2- (3-trimethoxyphenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H17 is 2- (4-trimethoxyphenyl) -6, 7-dihydropyrrol [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-tetrahydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzaldehyde;
compound H22 is 2- (3-acetylphenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
Compound H23 is 2- (3-nitrophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H24 is 2- (3, 5-dimethylphenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H25 is 2- (3, 5-dichlorophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H26 is 2- (3, 4-dichlorophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H27 is 2- (3, 5-dibromophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H28 is 2- (3, 5-difluorophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H29 is 2- (3, 5-dimethoxyphenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one
Compound H30 is 2- (3, 4-dimethoxyphenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one
Compound H31 is 2- (3-chloro-4-fluoro-phenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H32 is 3- (1, 1' -biphenyl-3-yl) -6, 7-dihydropyrrol [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-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I3 is 2- (3-methylphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I4 is 2- (4-methylphenyl) -7, 8-dihydro-5H-pyrido [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-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I7 is 2- (3-chlorophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I8 is 2- (4-chlorophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I9 is 2- (2-bromophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I10 is 2- (3-bromophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I11 is 2- (4-bromophenyl) -7, 8-dihydro-5H-pyrido [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-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I15 is 2- (4-trifluoromethylphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I16 is 2- (3-trimethoxyphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I17 is 2- (4-trimethoxyphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I18 is 2- (10-oxo-6,7,8,10-tetrahydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile;
compound I19 is 3- (10-oxo-6,7,8,10-tetrahydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile;
compound I20 is 4- (10-oxo-6,7,8,10-tetrahydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile;
compound I21 is 4- (10-oxo-6,7,8,10-tetrahydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzaldehyde;
compound I22 is 2- (3-acetylphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I23 is 2- (3-nitrophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
Compound I24 is 2- (3, 5-dimethylphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I25 is 2- (3, 5-dichlorophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I26 is 2- (3, 4-dichlorophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I27 is 2- (3, 5-dibromophenyl) -7, 8-dihydro-5H-pyrido [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 ] pyrimidinone derivatives have the application of 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 in preparing medicaments for treating Alzheimer's disease.
The application of the compounds H1, H6-H10, H15, H16, H19, H28-H31, I3, I8, I15, I16, I18-I22 and I27-I30 in preparing medicines for inhibiting candida albicans is provided.
The invention relates to a tricyclic thiazolo [5,4-d ] pyrimidinone derivative and application thereof, wherein the preparation method of the tricyclic thiazolo [5,4-d ] pyrimidinone derivative is carried out according to the following steps:
preparation of Compound A:
57.3g of sodium nitrite, 0.83mol and 100g of ethyl cyanoacetate, 0.83mol are dissolved in 700ml of pure water at the temperature of-10 ℃, 36.6ml of 85% concentrated phosphoric acid and 0.055mol are slowly added dropwise for 3 hours, then the mixture is heated to 45 ℃ and stirred for 1 hour, then 74ml of concentrated hydrochloric acid and 0.88mol are added, stirring is continued at the temperature of 0 ℃ for overnight, a large amount of white solid is separated out, and the white compound A is obtained by filtration without purification for the next reaction;
preparation of compound B:
under the condition of room temperature, 43g of the obtained white compound A, 0.3mol of which is dissolved in 500ml of pure water, 350ml of saturated sodium bicarbonate solution is slowly added dropwise under stirring, 156g of sodium dithionite and 0.9mol of which are added, the temperature is raised to 35 ℃ for reaction for 1 hour, then the reaction is carried out for 3 hours at room temperature, 500ml of dichloromethane is adopted for extraction for 3 times, the organic phases are combined, dried and concentrated, forward silica gel column chromatography gradient elution is adopted, and the eluent is petroleum ether and ethyl acetate with the volume ratio of 2:1, thus obtaining the compound B;
Preparation of compound C:
under the protection of argon, acetic anhydride 6.48g and 63.6mmol are slowly added into formic acid 2.22g and 53mmol solution in a dropwise manner, the mixture is heated to 50 ℃ for reaction for 5 hours, then, under the ice bath condition, compound B3.9 g and 25mmol are slowly added into the solution in a dropwise manner, the mixture reacts at room temperature until all raw materials disappear, dichloromethane is adopted for 500ml for extraction for 3 times, organic phases are combined, dried and concentrated, forward silica gel column chromatography gradient elution is adopted, the eluent is petroleum ether, ethyl acetate=5:1, and then, compound C is obtained;
preparation of compound D:
under the protection of argon, dissolving 1.56g of the obtained compound C10 mmol in 20ml of toluene, then adding 4.5g of Lawson reagent 11mmol, heating and refluxing for 24 hours until all raw materials disappear, filtering the reaction liquid, concentrating, and performing gradient elution by adopting a forward silica gel column chromatography, wherein the eluent is petroleum ether, and ethyl acetate=1:1 to obtain a compound D;
preparation of Compound E:
dissolving 1.72g of the obtained compound D10 mmol in 20mL of anhydrous tetrahydrofuran, adding 2.2g of NBS 12mmol a few times, reacting at room temperature for 3h until all raw materials disappear, quenching with water, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing gradient elution with forward silica gel column chromatography, wherein the eluent is petroleum ether, namely ethyl acetate=5:1, so as to obtain a compound E;
Preparation of compound F:
dissolving 2.5g of the obtained compound E10 mmol in 20mL of anhydrous dioxane, adding 1.3g of pyrrolidone 15mmol, slowly dropwise adding 2.4mL of phosphorus oxychloride, refluxing until all raw materials disappear, filtering the reaction solution, concentrating, and performing gradient elution by adopting a forward silica gel column chromatography, wherein the eluent is petroleum ether, namely ethyl acetate=1:2, thus obtaining a compound F;
preparation of compound G:
dissolving 2.5G of the obtained compound E10 mmol in 20mL of anhydrous dioxane, adding 1.3G of pyrrolidone 15mmol, slowly dropwise adding 2.4mL of phosphorus oxychloride, refluxing until all raw materials disappear, filtering the reaction solution, concentrating, and performing gradient elution by adopting a forward silica gel column chromatography, wherein the eluent is petroleum ether, namely ethyl acetate=1:2, thus obtaining a compound G;
preparation of Compounds H1-H32:
dissolving 0.27g of the obtained compound F1 mmol in 20mL of anhydrous toluene, respectively adding 0.98g of cesium carbonate, 1.2mmol of different substituted phenylboronic acid and 0.015g of tetraphenylphosphine palladium, carrying out reflux reaction under the protection of argon until all raw materials disappear, filtering the reaction solution, concentrating, adopting forward silica gel column chromatography for gradient elution, and obtaining the compounds H1-H32 respectively, wherein the eluent is pure ethyl acetate;
Preparation of Compounds I1-I32:
dissolving 0.284G of the obtained compound G in 1mmol in 20mL of anhydrous toluene, respectively adding 0.98G of cesium carbonate in 3mmol, 1.2mmol of different substituted phenylboronic acid and 0.015G of tetraphenylphosphine palladium in 0.01mmol, carrying out reflux reaction under the protection of argon until all raw materials disappear, filtering the reaction solution, concentrating, adopting forward silica gel column chromatography for gradient elution, and obtaining the compounds I1-I32 respectively, wherein the eluent is pure ethyl acetate;
the tricyclic thiazolo [5,4-D ] pyrimidinone derivative takes cyanoethyl acetate as an initial raw material, generates hydroxylamine compound (A) under the action of sodium nitrite and phosphoric acid, reduces with sodium hydrosulfite to obtain 2-amino cyanoethyl acetate (B), then respectively reacts with acetic anhydride and Lawson reagent to form a ring to obtain 5-amino-4-formate thiazoles compound (D), then respectively reacts with pyrrolidone and valerolactam under the action of phosphorus oxychloride after NBS bromination to form 2-bromo-dihydropyrrole [1,2-a ] thiazolo [5,4-D ] pyrimidinone compound (F) and 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-D ] pyrimidine-10 (6H) ketone (G), finally, 64 different substituted tricyclic thiazolo [5,4-D ] pyrimidinone compounds (H1-H32) and I1-I32) are obtained through Suzuki reaction,
The synthetic route is as follows:
Figure BDA0003323019370000101
Detailed Description
The present invention is further illustrated by examples, but the present invention is not limited to these examples;
reagent: all reagents were commercially available in analytical purity;
example 1
Preparation of Compound A:
57.3ml of sodium nitrite, 0.83mol and 100g of ethyl cyanoacetate, 0.83mol are dissolved in 700ml of pure water at the temperature of minus 10 ℃, 36.6ml of 85% concentrated phosphoric acid and 0.055mol are slowly added dropwise, the dropwise adding 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 are added, stirring is continued at the temperature of 0 ℃ for overnight, a large amount of white solid is separated out, and the white compound A is 2-cyano-2-ethyloxyiminoacetate which is obtained by filtration without purification and is used for the next reaction;
preparation of compound B:
under the condition of room temperature, 43g of the obtained white compound A is 2-cyano-2-hydroxy iminoacetic acid ethyl ester, 0.3mol is dissolved in 500ml of pure water, 350ml of saturated sodium bicarbonate solution is slowly added dropwise under stirring, 156g of sodium dithionite and 0.9mol are added, the temperature is raised to 35 ℃ for reaction for 1 hour, then the reaction is carried out for 3 hours at room temperature, 500ml of dichloromethane is adopted for extraction for 3 times, the organic phases are combined, drying and concentration are carried out, forward silica gel column chromatography gradient elution is adopted, the eluent is petroleum ether with the volume ratio of 2:1, namely, the compound B is 2-amino-2-cyano acetic acid ethyl ester, and purification is not needed for the next reaction;
1 H NMR(400MHz,CDCl 3 )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, acetic anhydride 6.48g and 63.6mmol are slowly dripped into a solution of formic acid 2.22g and 53mmol, heated to 50 ℃ for reaction for 5 hours, then compound B is slowly dripped into the solution of 2-amino-2-cyanoacetic acid ethyl ester 3.9g and 25mmol under the ice bath condition, the reaction is carried out at room temperature until all raw materials disappear, dichloromethane (500 ml) is adopted for extraction for 3 times, organic phases are combined, dried and concentrated, forward silica gel column chromatography gradient elution is adopted, and petroleum ether with the volume ratio of 5:1 is adopted as eluent, namely, ethyl acetate=, thus obtaining compound C is 2-formamido-2-cyanoacetic acid ethyl ester; yield: 76%, pale yellow solid, melting point: 128-130 ℃;
1 H NMR(400MHz,CDCl 3 )δ8.32(s,1H),6.46(s,1H),5.51(d,J＝5.1Hz,1H),4.34(q,J＝7.0Hz,2H),1.35(t,J＝7.1Hz,3H)；
preparation of compound D:
under the protection of argon, 1.56g 10mmol of the obtained compound C is 2-formamido-2-cyanoacetic acid ethyl ester is dissolved in 20ml of toluene, 4.5g 11mmol of Lawson reagent is added, heating reflux is carried out for 24 hours until all raw materials disappear, reaction liquid is filtered and concentrated, forward silica gel column chromatography gradient elution is adopted, eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1, namely the compound D is 5-amino-thiazole-4-ethyl formate, and the yield is: 73%, pale yellow solid, melting point: 135-136 ℃;
1 H NMR(400MHz,CDCl 3 )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 10mmol of the obtained compound D of 5-amino-thiazole-4-ethyl formate in 20mL of anhydrous tetrahydrofuran, adding 2.2g 12mmol of NBS for a few times, reacting at room temperature for 3h until all raw materials disappear, quenching with water, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and eluting with a forward silica gel column chromatography gradient, wherein the eluent is petroleum ether and ethyl acetate in a volume ratio of 5:1 to obtain the compound E of 2-bromo-5-amino-thiazole-4-ethyl formate, and the yield is: 73%, pale yellow solid, mp 151-152 ℃;
1 H NMR(400MHz,CDCl 3 )δ6.03(s,2H),4.38(q,J＝7.1Hz,2H),1.39(t,J＝7.1Hz,3H)；
preparation of compound F:
2.5g 10mmol of the obtained compound E is 2-bromo-5-amino-thiazole-4-ethyl formate and is dissolved in 20mL of anhydrous dioxane, 1.3g 15mmol of pyrrolidone is added, 2.4mL 25mmol of phosphorus oxychloride is slowly added dropwise, reflux reaction is carried out until all raw materials disappear, dichloromethane extraction is adopted, anhydrous sodium sulfate drying and decompression concentration are carried out, forward silica gel column chromatography gradient elution is adopted, the eluent is petroleum ether with the volume ratio of 1:2, namely ethyl acetate, the compound F is 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidine-9 (5H) -ketone, the yield is: 73%, pale yellow solid, melting point: 208-209 ℃;
1 H NMR(400MHz,CDCl 3 )δ4.25(t,J＝7.3Hz,2H),3.17(t,J＝8.0Hz,2H),2.66–2.16(m,2H)；
Preparation of compound G:
2.5G 10mmol of the obtained compound E is 2-bromo-5-amino-thiazole-4-ethyl formate and is dissolved in 20mL of anhydrous dioxane, 1.5G 15mmol of valerolactam is added, 2.4mL 25mmol of phosphorus oxychloride is slowly added dropwise, reflux reaction is carried out until all raw materials disappear, dichloromethane extraction is adopted, anhydrous sodium sulfate drying and decompression concentration are carried out, forward silica gel column chromatography gradient elution is adopted, the eluent is petroleum ether with the volume ratio of 10:1, namely ethyl acetate, the compound G is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone, and the yield is: 73% of light yellow solid with a melting point of 226-227 ℃;
1 H NMR(400MHz,CDCl 3 )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 of 1mmol of 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidine-9 (5H) -one obtained in example 1 is dissolved in 20mL of anhydrous toluene, 0.98g of cesium carbonate, 0.15g of 1.2mmol of phenylboronic acid and 0.015g of 0.01mmol of tetraphenylphosphine palladium are respectively added, reflux reaction is carried out under the protection of argon until all raw materials disappear, dichloromethane extraction and anhydrous sodium sulfate drying are adopted, reduced pressure concentration are carried out, forward silica gel column chromatography gradient elution is adopted, and the eluent is ethyl acetate methanol with the volume ratio of 10:1, so that the compound H1 is 2-phenyl-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidine-9 (5H) -one is obtained, and the yield is as follows: 68%, pale yellow solid, melting point: 276-277 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.27g of 1mmol of the compound F obtained in example 1, 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, which is obtained in the following steps, is dissolved in 20mL of anhydrous toluene, 0.98g of cesium carbonate, 0.16g of 1.2mmol of 2-methylphenylboronic acid, 0.015g of 0.01mmol of triphenylphosphine palladium, and the total disappearance of the raw materials are respectively added, reflux reaction is carried out under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate drying, decompression concentration and forward silica gel column chromatography gradient elution are adopted, the eluent is ethyl acetate methanol with the volume ratio of 10:1, and the compound H2 is 2- (2-methylphenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, the yield: 61%, pale yellow solid, melting point: 178-179 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.27g of 1mmol of the compound F obtained in example 1, 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, which is obtained in the following steps, is dissolved in 20mL of anhydrous toluene, 0.98g of cesium carbonate, 0.16g of 1.2mmol of 3-methylphenylboronic acid, 0.015g of 0.01mmol of triphenylphosphine palladium, and the total disappearance of the raw materials are respectively added, reflux reaction is carried out under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate drying, decompression concentration and forward silica gel column chromatography gradient elution are adopted, the eluent is ethyl acetate methanol with the volume ratio of 10:1, and the compound H3, 2- (3-methylphenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one is obtained, the yield: 72%, pale yellow solid, melting point: 213-214 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.27g of 1mmol of the compound F obtained in example 1, 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidine-9 (5H) -one, which is obtained in example 1, is dissolved in 20mL of anhydrous toluene, 0.98g of 3mmol of 4-methylphenylboronic acid, 0.16g of 1.2mmol of tetraphenylphosphine palladium, 0.015g of 0.01mmol of tetraphenylphosphine palladium, which is obtained in each case, are added, reflux-reacted until the raw materials completely disappear under the protection of argon, the mixture is extracted by methylene chloride, dried by anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by a forward silica gel column chromatography gradient, wherein the eluent is ethyl acetate methanol with the volume ratio of 10:1, so that the compound H4 is 2- (4-methylphenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidine-9 (5H) -one is obtained, the yield: 83%, pale yellow solid, melting point: 248-249 ℃;
1 H NMR(400MHz,CDCl 3 )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:
the compound F obtained in example 1 was 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one 0.27g,1mmol was dissolved in 20mL of anhydrous toluene, cesium carbonate 0.98g 3mmol, 4-tert-butylphenylboronic acid 0.22g1.2mmol, and triphenylphosphine palladium 0.015g 0.01mmol were added respectively, reflux reaction was carried out until all the starting materials disappeared under argon protection, extraction was carried out with methylene chloride, drying was carried out with anhydrous sodium sulfate, concentration was carried out under reduced pressure, gradient elution was carried out using a forward silica gel column, and the eluent was ethyl acetate: methanol in a volume ratio of 10:1, to obtain the compound H5 as 2- (4-tert-butylphenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, yield: 81%, pale yellow solid, melting point: 241-242 ℃;
1 H NMR(400MHz,CDCl 3 )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:
the compound F obtained in example 1 is 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one 0.27g 1mmol is dissolved in 20mL of anhydrous toluene, 0.98g 3mmol of cesium carbonate, 0.19g1.2mmol of 2-chlorobenzeneboronic acid, 0.015g 0.01mmol of triphenylphosphine palladium and the raw materials are completely disappeared under the protection of argon, dichloromethane extraction and anhydrous sodium sulfate drying are adopted, decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and the eluent is ethyl acetate methanol with the volume ratio of 10:1, so that the compound H6 is 2- (2-chlorophenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one is obtained, the yield: 68%, pale yellow solid, melting point: 197-198 ℃;
1 H NMR(400MHz,CDCl 3 )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:
the compound F obtained in example 1 is 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one 0.27g 1mmol is dissolved in 20mL of anhydrous toluene, 0.98g 3mmol of cesium carbonate, 0.19g1.2mmol of 3-chlorobenzeneboronic acid and 0.015g 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until the raw materials completely disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate drying, decompression concentration and forward silica gel column chromatography gradient elution are adopted, the eluent is ethyl acetate methanol with the volume ratio of 10:1, so that the compound H7 is 2- (3-chlorophenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, the yield: 63%, pale yellow solid, melting point: 218-219 ℃;
1 H NMR(400MHz,CDCl 3 )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:
the compound F obtained in example 1 is 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one 0.27g 1mmol is dissolved in 20mL of anhydrous toluene, 0.98g 3mmol of cesium carbonate, 0.19g1.2mmol of 4-chlorobenzeneboronic acid and 0.015g 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until the raw materials completely disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate drying, decompression concentration and forward silica gel column chromatography gradient elution are adopted, the eluent is ethyl acetate methanol with the volume ratio of 10:1, so that the compound H8 is 2- (4-chlorophenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, the yield: 79%, pale yellow solid, melting point: 238-239 ℃;
1 H NMR(400MHz,CDCl 3 )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:
the compound F obtained in example 1 is 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidine-9 (5H) -one 0.27g 1mmol is dissolved in 20mL of anhydrous toluene, 0.98g 3mmol of cesium carbonate, 0.24g1.2mmol of 2-bromophenylboric acid and 0.015g 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction and anhydrous sodium sulfate drying are adopted, decompression concentration is carried out, forward silica gel column chromatography gradient elution is adopted, and the eluent is ethyl acetate methanol with the volume ratio of 10:1, so that the compound H9 is 2- (2-bromophenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidine-9 (5H) -one is obtained, the yield: 58%, pale yellow solid, melting point: 187-188 ℃;
1 H NMR(400MHz,CDCl 3 )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:
the compound F obtained in example 1 is 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one 0.27g 1mmol is dissolved in 20mL of anhydrous toluene, 0.98g 3mmol of cesium carbonate, 0.24g1.2mmol of 3-bromophenylboronic acid, 0.015g 0.01mmol of triphenylphosphine palladium and the raw materials are completely disappeared under the protection of argon, dichloromethane extraction and anhydrous sodium sulfate drying are adopted, reduced pressure concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and the eluent is ethyl acetate methanol with the volume ratio of 10:1, so that the compound H10 is 2- (3-bromophenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, the yield: 73%, pale yellow solid, melting point: 211-212 ℃;
1 H NMR(400MHz,CDCl 3 )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:
the compound F obtained in example 1 is 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidine-9 (5H) -one 0.27g 1mmol is dissolved in 20mL of anhydrous toluene, 0.98g 3mmol of cesium carbonate, 0.24g1.2mmol of 4-bromophenylboric acid and 0.015g 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction and anhydrous sodium sulfate drying are adopted, decompression concentration is adopted, forward silica gel column chromatography gradient elution is adopted, and the eluent is ethyl acetate methanol with the volume ratio of 10:1, so that the compound H11 is 2- (4-bromophenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidine-9 (5H) -one is obtained, the yield: 77%, pale yellow solid, melting point: 234-235 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.27g of 1mmol of the compound F obtained in example 1, 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidine-9 (5H) -one, which is obtained in example 1, is dissolved in 20mL of anhydrous toluene, 0.98g of 3mmol of cesium carbonate, 0.17g of 1.2mmol of 2-fluorobenzeneboronic acid and 0.015g of 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction and anhydrous sodium sulfate drying are adopted, decompression concentration is carried out, forward silica gel column chromatography gradient elution is adopted, and the eluent is ethyl acetate methanol with the volume ratio of 10:1, so that the compound H12 is 2- (2-fluorophenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidine-9 (5H) -one, the yield: 59%, pale yellow solid, melting point: 261-262 ℃;
1 H NMR(400MHz,CDCl 3 )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 the example 1, 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidine-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 triphenylphosphine palladium, carrying out reflux reaction under the protection of argon until the raw materials completely disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, and carrying out gradient elution by using a forward silica gel column chromatography, wherein the volume ratio of the eluent is 10:1; ethyl acid ester methanol=10:1 to give compound H13 as 2- (4-fluorophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one in yield: 66%, pale yellow solid, melting point: 263-264 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.27g of 1mmol of the compound F obtained in example 1, 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one is dissolved in 20mL of anhydrous toluene, 0.98g of 3mmol of cesium carbonate, 0.23g of 1.2mmol of 2-trifluoromethylphenylboronic acid and 0.015g of 0.01mmol of tetraphenylphosphino palladium are respectively added, reflux reaction is carried out until all the raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate is adopted, reduced pressure concentration and forward silica gel column chromatography gradient elution is adopted, the eluent is ethyl acetate methanol with the volume ratio of 10:1, and the compound H14 is 2- (2-trifluoromethylphenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, the yield: 55%, pale yellow solid, melting point: 116-117 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.27g of 1mmol of the compound F obtained in example 1, 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one is dissolved in 20mL of anhydrous toluene, 0.98g of 3mmol of cesium carbonate, 0.23g of 1.2mmol of 4-trifluoromethylphenylboronic acid and 0.015g of 0.01mmol of tetraphenylphosphino palladium are respectively added, reflux reaction is carried out until all the raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate is adopted, reduced pressure concentration and forward silica gel column chromatography gradient elution is adopted, the eluent is ethyl acetate methanol with the volume ratio of 10:1, and the compound H15 is 2- (4-trifluoromethylphenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, the yield: 64%, pale yellow solid, melting point: 215-216 ℃;
1 H NMR(400MHz,CDCl 3 )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:
the compound F obtained in example 1 is 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one 0.27g 1mmol is dissolved in 20mL of anhydrous toluene, 0.98g 3mmol of cesium carbonate, 0.18g1.2mmol of 3-methoxyphenylboronic acid, 0.015g 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all the raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate drying, decompression concentration and forward silica gel column chromatography gradient elution are adopted, the eluent is ethyl acetate methanol with the volume ratio of 10:1, and the compound H16 is 2- (3-trimethoxyphenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, the yield: 67%, pale yellow solid, melting point: 192-194 ℃;
1 H NMR(400MHz,CDCl 3 )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:
the compound F obtained in example 1 is 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one 0.27g 1mmol is dissolved in 20mL of anhydrous toluene, 0.98g 3mmol of 4-methoxyphenylboronic acid 0.18g1.2mmol of tetraphenylphosphine palladium 0.015g of 0.01mmol are respectively added, reflux reaction is carried out until the raw materials completely disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate drying and reduced pressure concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and the eluent is ethyl acetate methanol with the volume ratio of 10:1, so that the compound H17 is 2- (4-trimethoxyphenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, the yield: 80%, pale yellow solid, melting point: 289-290 ℃;
1 H NMR(400MHz,CDCl 3 )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:
the compound F obtained in example 1 was 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one 0.27g 1mmol was dissolved in 20mL of anhydrous toluene, cesium carbonate 0.98g 3mmol, 2-cyanobenzylboronic acid 0.18g1.2mmol, triphenylphosphine palladium 0.015g 0.01mmol were added respectively, reflux reaction was carried out until the starting materials disappeared completely under the protection of argon, extraction was carried out with methylene chloride, drying was carried out with anhydrous sodium sulfate, concentration was reduced pressure, gradient elution was carried out with forward silica gel column chromatography, the eluent was ethyl acetate methanol in a volume ratio of 10:1, to give the compound H18 as 2- (9-oxo-5, 6,7, 9-tetrahydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile, yield: 67%, pale yellow solid, melting point: 201-202 ℃;
1 H NMR(400MHz,CDCl 3 )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:
the compound F obtained in example 1 was 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one 0.27g 1mmol was dissolved in 20mL of anhydrous toluene, cesium carbonate 0.98g 3mmol, 3-cyanobenzeneboronic acid 0.18g1.2mmol, triphenylphosphine palladium 0.015g 0.01mmol were added respectively, reflux reaction was carried out until the starting materials disappeared completely under the protection of argon, extraction was carried out with methylene chloride, drying was carried out with anhydrous sodium sulfate, concentration was reduced pressure, gradient elution was carried out with forward silica gel column chromatography, the eluent was ethyl acetate methanol in a volume ratio of 10:1, to give the compound H19 as 3- (9-oxo-5, 6,7, 9-tetrahydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile, yield: 73%, pale yellow solid, melting point: 276-277 ℃;
1 H NMR(400MHz,CDCl 3 )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:
the compound F obtained in example 1 was 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one 0.27g 1mmol was dissolved in 20mL of anhydrous toluene, cesium carbonate 0.98g 3mmol, 4-cyanobenzeneboronic acid 0.18g1.2mmol, triphenylphosphine palladium 0.015g 0.01mmol were added respectively, reflux reaction was carried out until the starting materials disappeared completely under the protection of argon, extraction was carried out with methylene chloride, drying was carried out with anhydrous sodium sulfate, concentration was reduced pressure, gradient elution was carried out with forward silica gel column chromatography, the eluent was ethyl acetate methanol in a volume ratio of 10:1, to give the compound H20 as 4- (9-oxo-5, 6,7, 9-tetrahydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile, yield: 62%, pale yellow solid, melting point: 171-172 ℃;
1 H NMR(400MHz,CDCl 3 )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:
the compound F obtained in example 1 was 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one 0.27g 1mmol was dissolved in 20mL of anhydrous toluene, cesium carbonate 0.98g 3mmol, 4-formylphenylboronic acid 0.18g1.2mmol, and triphenylphosphine palladium 0.015g 0.01mmol were added respectively, reflux reaction was carried out until all the starting materials disappeared under the protection of argon, extraction was carried out with methylene chloride, drying over anhydrous sodium sulfate, concentration under reduced pressure, gradient elution was carried out using a forward silica gel column chromatography, and the eluent was ethyl acetate methanol in a volume ratio of 10:1 to give the compound H21 as 4- (9-oxo-5, 6,7, 9-tetrahydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzaldehyde in the yield: 69%, pale yellow solid, melting point: 197-198 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.27g of 1mmol of the compound F obtained in example 1, 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, which is obtained in the following steps, is dissolved in 20mL of anhydrous toluene, 0.98g of cesium carbonate, 0.20g of 1.2mmol of 3-acetylphenylboronic acid, 0.015g of 0.01mmol of tetraphenylphosphine palladium, and the total disappearance of the raw materials are carried out under the protection of argon, the mixture is extracted by methylene chloride, dried by anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by a forward silica gel column chromatography gradient, and the eluent is ethyl acetate methanol with the volume ratio of 10:1, so that the compound H22 is 2- (3-acetylphenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, and the yield is obtained: 71%, pale yellow solid, melting point: 257-258 ℃;
1 H NMR(400MHz,CDCl 3 )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:
the compound F obtained in example 1 is 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one 0.27g 1mmol is dissolved in 20mL of anhydrous toluene, 0.98g 3mmol of cesium carbonate, 0.20g1.2mmol of 3-nitrobenzoic acid and 0.015g 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until the raw materials completely disappear under the protection of argon, dichloromethane extraction and anhydrous sodium sulfate drying are adopted, decompression concentration is carried out, forward silica gel column chromatography gradient elution is adopted, and the eluent is ethyl acetate methanol with the volume ratio of 10:1, so that the compound H23 is 2- (3-nitrophenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one is obtained, the yield: 61%, pale yellow solid, melting point: 294-295 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.27g of 1mmol of 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one obtained in example 1 is dissolved in 20mL of anhydrous toluene, 0.98g of cesium carbonate, 0.18g of 1.2mmol of 3, 5-dimethylboronic acid and 0.015g of 0.01mmol of tetraphenylphosphine palladium are respectively added, reflux reaction is carried out until all the raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate is used for drying, decompression concentration is adopted, forward silica gel column chromatography gradient elution is adopted, ethyl acetate methanol with the volume ratio of 10:1 is eluted, and the compound H24 is 2- (3, 5-dimethylphenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one is obtained, the yield: 84%, pale yellow solid, melting point: 276-277 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.27g of 1mmol of the compound F obtained in example 1, 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, which is obtained in the following steps, is dissolved in 20mL of anhydrous toluene, 0.98g of cesium carbonate, 0.23g of 1.2mmol of 3, 5-dichlorobenzoboric acid and 0.015g of 0.01mmol of tetraphenylphosphine palladium are respectively added, reflux reaction is carried out until all the raw materials disappear under the protection of argon, dichloromethane extraction is carried out, anhydrous sodium sulfate drying and reduced pressure concentration are carried out, forward silica gel column chromatography gradient elution is adopted, and the eluent is ethyl acetate methanol with the volume ratio of 10:1, so that the compound H25 is 2- (3, 5-dichlorophenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, and the yield: 77%, pale yellow solid, melting point: 288-289 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.27g of 1mmol of the compound F obtained in example 1, 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, which is obtained in the following steps, is dissolved in 20mL of anhydrous toluene, 0.98g of 3mmol of 3, 4-dichlorobenzoboric acid, 0.23g of 1.2mmol of tetraphenylphosphine palladium, 0.015g of 0.01mmol of tetraphenylphosphine palladium, and the mixture is refluxed under the protection of argon until all the raw materials disappear, the mixture is extracted by methylene chloride, dried by anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by a forward silica gel column chromatography gradient, wherein the eluent is ethyl acetate methanol with the volume ratio of 10:1, so that the compound H26 is 2- (3, 4-dichlorophenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one is obtained in the yield: 67%, pale yellow solid, melting point: 220-221 ℃;
1 H NMR(600MHz,CDCl 3 )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:
0.27g of 1mmol of the compound F obtained in example 1, 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, which is obtained in example 1, is dissolved in 20mL of anhydrous toluene, 0.98g of cesium carbonate, 0.33g of 1.2mmol of 3, 5-dibromophenylboronic acid, 0.015g of 0.01mmol of tetraphenylphosphine palladium, which is obtained in example 1, are added respectively, and the mixture is refluxed under the protection of argon until all the raw materials disappear, and the mixture is extracted by methylene chloride, dried by anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by a forward silica gel column chromatography gradient, wherein the eluent is ethyl acetate methanol with the volume ratio of 10:1, so that the compound H27 is 2- (3, 5-dibromophenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one is obtained in the yield: 74%, pale yellow solid, melting point: 265-266 ℃;
1 H NMR(600MHz,CDCl 3 )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:
0.27g of 1mmol of the compound F obtained in example 1, 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, which is obtained in example 1, is dissolved in 20mL of anhydrous toluene, 0.98g of cesium carbonate, 0.19g of 1.2mmol of 3, 5-difluorophenylboronic acid and 0.015g of 0.01mmol of tetraphenylphosphino palladium are respectively added, reflux reaction is carried out until all the raw materials disappear under the protection of argon, dichloromethane extraction, anhydrous sodium sulfate drying and reduced pressure concentration are carried out, forward silica gel column chromatography gradient elution is adopted, and the eluent is ethyl acetate with the volume ratio of 10:1, namely methanol=10:1, so that the compound H28, namely 2- (3, 5-difluorophenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one is obtained, and the yield: 64%, pale yellow solid, melting point: 271-272 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.27g of 1mmol of the compound F obtained in example 1, 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one is dissolved in 20mL of anhydrous toluene, 0.98g of 3mmol of cesium carbonate, 0.22g of 1.2mmol of 3, 5-dimethoxyphenylboronic acid and 0.015g of 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all the raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate is used for drying, decompression concentration is carried out, forward silica gel column chromatography gradient elution is adopted, and the eluent is ethyl acetate methanol with the volume ratio of 10:1, so that the compound H29 is 2- (3, 5-dimethoxyphenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, the yield: 61%, pale yellow solid, melting point: 255-256 ℃;
1 H NMR(600MHz,CDCl 3 )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:
0.27g of 1mmol of the compound F obtained in example 1, 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, which is obtained in example 1, is dissolved in 20mL of anhydrous toluene, 0.98g of cesium carbonate, 0.22g of 3, 4-dimethoxyphenylboronic acid, 1.2mmol, 0.015g of tetraphenylphosphine palladium, 0.01mmol, and under the protection of argon, are added respectively, reflux-reacted until all the raw materials disappear, the mixture is extracted by methylene chloride, dried by anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by a forward silica gel column chromatography gradient, wherein the eluent is ethyl acetate with the volume ratio of 10:1, namely methanol=10:1, to obtain the compound H30, namely 2- (3, 4-dimethoxyphenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, and the yield: 58%, pale yellow solid, melting point: 227-228 ℃;
1 H NMR(600MHz,CDCl 3 )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:
0.27g of 1mmol of the compound F obtained in example 1, 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, which is obtained in example 1, is dissolved in 20mL of anhydrous toluene, 0.98g of cesium carbonate, 0.21g of 3mmol of 3-chloro-4-fluorobenzeneboronic acid, 0.01mmol of tetraphenylphosphine palladium, 0.015g of 0.01mmol, are added respectively, reflux reaction is carried out until all the raw materials disappear under the protection of argon, dichloromethane extraction, anhydrous sodium sulfate drying and decompression concentration are carried out, forward silica gel column chromatography gradient elution is adopted, and the eluent is ethyl acetate methanol with the volume ratio of 10:1, so that the compound H31, 2- (3-chloro-4-fluoro-phenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one is obtained, and the yield: 54%, pale yellow solid, melting point: 225-226 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.27g of 1mmol of the compound F obtained in example 1, 2-bromo-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, which is obtained in example 1, is dissolved in 20mL of anhydrous toluene, 0.98g of cesium carbonate, 0.24g of 1.2mmol of 1,1 '-biphenyl-2-yl phenylboronic acid, 0.015g of tetraphenylphosphine palladium, 0.01mmol of 0.015g of tetraphenylphosphine, and the mixture is refluxed under the protection of argon until all the raw materials disappear, and the mixture is extracted by methylene chloride, dried by anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by a forward silica gel column chromatography gradient, wherein an eluent is ethyl acetate/methanol with a volume ratio of 10:1, so as to obtain the compound H32, 2- (1, 1' -biphenyl-2-yl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one, and the yield: 71%, pale yellow solid, melting point: 233-234 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water with the volume ratio of 4:1, 0.98G 3mmol of phenylboronic acid is added into each solution, 0.15G 1.2mmol of triphenylphosphine palladium is added, 0.015G 0.01mmol of tetraphenylphosphine palladium is reacted under the protection of argon gas until all raw materials disappear, dichloromethane extraction is adopted, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and an eluent is petroleum ether ethyl acetate with the volume ratio of 1:2, so that the compound I1 is 2-phenyl-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is obtained, the yield is 83%, light yellow solid, and the melting point is 198-199 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.16G 1.2mmol of 2-methylbenzylboric acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and an eluent is petroleum ether of ethyl acetate in a volume ratio of 1:2, so that the compound I2 is 2- (2-methylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone, the yield is 69%, light yellow solid, and the melting point is 180-181 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.16G 1.2mmol of 3-methylphenylboronic acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and an eluent is petroleum ether of ethyl acetate in a volume ratio of 1:2, so that the compound I3 is 2- (3-methylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone, the yield is 74 percent, light yellow solid, and the melting point is 206-207 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.16G 1.2mmol of 4-methylphenylboronic acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out under the protection of argon until all raw materials disappear, dichloromethane extraction is adopted, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and an eluent is petroleum ether of ethyl acetate in a volume ratio of 1:2, so that the compound I4 is 2- (4-methylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone, the yield is 77%, light yellow solid, and the melting point is 256-257 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.22G 1.2mmol of 4-tert-butylphenylboronic acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate is used for drying, decompression concentration is adopted, forward silica gel column chromatography gradient elution is adopted, and petroleum ether with a volume ratio of 1:2 is adopted as eluent, so that the compound I5 is 2- (4-tert-butylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is obtained, the yield is 78%, light yellow solid with a melting point of-250 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.19G 1.2mmol of 2-chlorobenzeneboronic acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and an eluent is petroleum ether of ethyl acetate in a volume ratio of 1:2, so that the compound I6 is 2- (2-chlorophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone, the yield is 65%, light yellow solid, and the melting point is 179-180 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.19G 1.2mmol of 3-chlorobenzeneboronic acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and an eluent is petroleum ether of ethyl acetate in a volume ratio of 1:2, so that the compound I7 is 2- (3-chlorophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone, the yield is 74 percent, light yellow solid, and the melting point is 217-218 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.19G 1.2mmol of 4-chlorobenzeneboronic acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out under the protection of argon until all raw materials disappear, dichloromethane extraction is adopted, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and an eluent is petroleum ether ethyl acetate with a volume ratio of 1:2, so that the compound I8 is 2- (4-chlorophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone, the yield is 71%, light yellow solid, and the melting point is 230-231 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.24G 1.2mmol of 2-bromophenylboric acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out under the protection of argon until all raw materials disappear, dichloromethane extraction is adopted, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and an eluent is petroleum ether of which the volume ratio is 1:2, ethyl acetate, so that the compound I9 is 2- (2-bromophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone, the yield is 60 percent, light yellow solid, and the melting point is 167-168 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.24G 1.2mmol of 3-bromophenylboric acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out under the protection of argon until all raw materials disappear, dichloromethane extraction is adopted, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and an eluent is petroleum ether ethyl acetate in a volume ratio of 1:2, so that the compound I10 is 2- (3-bromophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone, the yield is 74%, light yellow solid, and the melting point is 234-235 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.24G 1.2mmol of 4-bromophenylboric acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out under the protection of argon until all raw materials disappear, dichloromethane extraction is adopted, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and an eluent is petroleum ether ethyl acetate with a volume ratio of 1:2, so that the compound I11 is 2- (4-bromophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone, the yield is 72%, light yellow solid, and the melting point is 226-227 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G of compound G2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone obtained in example 1 is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G of 3mmol of cesium carbonate, 0.17G of 2-fluorobenzeneboronic acid, 0.015G of 0.01mmol of tetraphenylphosphine palladium and the like are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and an eluent is petroleum ether ethyl acetate with a volume ratio of 1:2, so that the compound I12 is 2- (2-fluorophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone, the yield is 58%, light yellow solid with a melting point of 248-249 ℃ is obtained;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.17G 1.2mmol of 4-fluorobenzeneboronic acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and an eluent is petroleum ether of ethyl acetate in a volume ratio of 1:2, so that the compound I13 is 2- (4-fluorophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone, the yield is 69%, light yellow solid, and the melting point is 255-256 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.23G 1.2mmol of 2-trifluoromethylphenylboronic acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate is used for drying, decompression concentration is adopted, forward silica gel column chromatography gradient elution is adopted, the eluent is petroleum ether of ethyl acetate in a volume ratio of 1:2, and the compound I14 is 2- (2-trifluoromethyl phenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone, 59% is obtained, and a light yellow solid with a melting point of 108-109 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.23G 1.2mmol of 4-trifluoromethylphenylboronic acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate is used for drying, decompression concentration is adopted, forward silica gel column chromatography gradient elution is adopted, the eluent is petroleum ether of ethyl acetate in a volume ratio of 1:2, and the compound I15 is 2- (4-trifluoromethylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone, 57% of light yellow solid is obtained, and the melting point is 201-202 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.18G 1.2mmol of 3-methoxyphenylboric acid and 0.015G 0.01mmol of tetraphenylphosphine palladium are respectively added, reflux reaction is carried out under the protection of argon until all raw materials disappear, dichloromethane extraction is adopted, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and an eluent is petroleum ether of ethyl acetate in a volume ratio of 1:2, so that the compound I16 is 2- (3-trimethoxyphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone, the yield is 66%, light yellow solid, and the melting point is 202-203 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.18G 1.2mmol of 4-methoxyphenylboric acid and 0.015G 0.01mmol of tetraphenylphosphine palladium are respectively added, reflux reaction is carried out under the protection of argon until all raw materials disappear, dichloromethane extraction is adopted, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and an eluent is petroleum ether of ethyl acetate in a volume ratio of 1:2, so that the compound I17 is 2- (4-trimethoxyphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is obtained, the yield is 76%, light yellow solid, and the melting point is 196-197 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water with the volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.18G 1.2mmol of 2-cyanobenzylboronic acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and an eluent is petroleum ether with the volume ratio of 1:2, namely ethyl acetate, so that the compound I18 is 2- (10-oxo-6,7,8,10-tetrahydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-2-yl) benzonitrile with the yield of 55 percent, light yellow solid with the melting point of 179-180 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water with the volume ratio of 4:1, 0.98G 3mmol of 3-cyanobenzylboronic acid, 0.18G 1.2mmol of triphenylphosphine palladium and 0.015G 0.01mmol are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and petroleum ether with the volume ratio of 1:2 is adopted as eluent, so that the compound I19 is 3- (10-oxo-6,7,8,10-tetrahydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-2-yl) benzonitrile with the yield of 67 percent, light yellow solid with the melting point of 231-232 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.18G 1.2mmol of 4-cyanobenzylboronic acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and an eluent is petroleum ether of ethyl acetate in a volume ratio of 1:2, so that the compound I20 is 4- (10-oxo-6,7,8,10-tetrahydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-2-yl) benzonitrile with a yield of 68 percent, light yellow solid with a melting point of 169-170 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water with the volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.18G 1.2mmol of 4-formylphenylboronic acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and petroleum ether with the volume ratio of 1:2 is adopted as eluent, so that the compound I21 is 4- (10-oxo-6,7,8,10-tetrahydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-2-yl) benzaldehyde with the yield of 73 percent, light yellow solid with the melting point of 171-172 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.20G 1.2mmol of 3-acetylphenylboronic acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and an eluent is petroleum ether in a volume ratio of 1:2, ethyl acetate is adopted, so that the compound I22,2- (3-acetylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is obtained, the yield is 80%, light yellow solid with a melting point of 195-196 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.20G 1.2mmol of 3-nitrobenzeneboronic acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, and an eluent is petroleum ether ethyl acetate with a volume ratio of 1:2, so that the compound I23 is 2- (3-nitrophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone, the yield is 63%, light yellow solid, and the melting point is 261-262 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.18G 1.2mmol of 3, 5-dimethylbenzeneboronic acid, 0.015G 0.01mmol of triphenylphosphine palladium and argon are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate is used for drying, decompression concentration is adopted, forward silica gel column chromatography gradient elution is adopted, the eluent is petroleum ether of ethyl acetate in a volume ratio of 1:2, and the compound I24 is 2- (3, 5-dimethylphenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is obtained, the yield is 70%, light yellow solid with a melting point of 258-259 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.23G 1.2mmol of 3, 5-dichlorobenzoboric acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate is adopted for drying, decompression concentration is adopted, forward silica gel column chromatography gradient elution is adopted, the eluent is petroleum ether ethyl acetate in a volume ratio of 1:2, and the compound I25 is 2- (3, 5-dichlorophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is obtained, the yield is 72%, light yellow solid, and the melting point is 271-272 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G of compound G2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone obtained in example 1 is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G of 3mmol, 0.23G of 3, 4-dichlorobenzoboric acid and 0.015G of 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate is used for drying, decompression concentration is adopted, forward silica gel column chromatography gradient elution is adopted, the eluent is petroleum ether in a volume ratio of 1:2, ethyl acetate, and the compound I26 is obtained, wherein the yield is 77% of 2- (3, 4-dichlorophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone, and the melting point is 218-220 ℃ and the light yellow solid is obtained;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.33G 1.2mmol of 3, 5-dibromophenylboronic acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate is adopted, decompression concentration is adopted, forward silica gel column chromatography gradient elution is adopted, the eluent is petroleum ether ethyl acetate with a volume ratio of 1:2, and the compound I27 is 2- (3, 5-dibromophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is obtained, the yield is 79%, light yellow solid, and the melting point is 261-262 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G of cesium carbonate, 0.19G of 3mmol,3, 5-difluorophenylboronic acid, 0.2 mmol of tetraphenylphosphine palladium, 0.015G of 0.01mmol are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate is adopted for drying, decompression concentration is adopted, forward silica gel column chromatography gradient elution is adopted, the eluent is petroleum ether ethyl acetate with a volume ratio of 1:2, and the compound I28 is 2- (3, 5-difluorophenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is obtained, the yield is 71%, light yellow solid, and the melting point is 248-249 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.22G 1.2mmol of 3, 5-dimethoxyphenylboronic acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate is adopted, decompression concentration is adopted, forward silica gel column chromatography gradient elution is adopted, the eluent is petroleum ether ethyl acetate with a volume ratio of 1:2, and the compound I29 is 2- (3, 5-dimethoxy phenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is obtained, the yield is 58%, light yellow solid with a melting point of 223 ℃ to 224 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.22G 1.2mmol of 3, 4-dimethoxyphenylboronic acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate is adopted, decompression concentration is adopted, forward silica gel column chromatography gradient elution is adopted, the eluent is petroleum ether ethyl acetate with a volume ratio of 1:2, and the compound I30 is 2- (3, 4-dimethoxy phenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is obtained, the yield is 63%, light yellow solid, and the melting point is 216-217 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.21G 1.2mmol of 3-chloro-4-fluorobenzeneboronic acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, the mixture is refluxed under the protection of argon until all raw materials disappear, dichloromethane extraction is adopted, anhydrous sodium sulfate is adopted for drying, decompression concentration is adopted, forward silica gel column chromatography gradient elution is adopted, the eluent is petroleum ether of ethyl acetate in a volume ratio of 1:2, and the compound I31 is 2- (3-chloro-4-fluoro-phenyl) -7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone, the yield is 57%, the light yellow solid is obtained, and the melting point is 257 ℃ to 258 ℃;
1 H NMR(400MHz,CDCl 3 )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:
0.28G 1mmol of compound G obtained in example 1 is 2-bromo-7, 8-dihydro-5H-pyridine [1,2-a ] thiazolo [5,4-d ] pyrimidine-10 (6H) ketone is dissolved in a mixed solution of 5mL of toluene and water in a volume ratio of 4:1, 0.98G 3mmol of cesium carbonate, 0.24G 1.2mmol of 1,1 '-biphenyl-2-yl phenylboronic acid and 0.015G 0.01mmol of triphenylphosphine palladium are respectively added, reflux reaction is carried out until all raw materials disappear under the protection of argon, dichloromethane extraction is adopted, anhydrous sodium sulfate drying and decompression concentration are adopted, forward silica gel column chromatography gradient elution is adopted, the eluent is petroleum ether in a volume ratio of 1:2, ethyl acetate is adopted, and the compound I32 is 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%, the light yellow solid with a melting point of 197 ℃ to 197 ℃ is obtained;
1 H NMR(400MHz,CDCl 3 )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 invention discloses antitumor activity screening of tricyclic thiazolo [5,4-d ] pyrimidinone compounds:
cell viability was measured by thiazole blue method:
the experimental process comprises the following steps:
cells grown in logarithmic growth phase were aspirated, washed once with phosphate buffer, digested with pancreatin, stopped with medium, gently blown, counted, seeded in 96-well plates (100 μl/well) at the corresponding cell density, cultured overnight, added with compounds (20 μl/well), each compound set at a concentration gradient, 3 wells per concentration, CO 2 Culturing in an incubator at 37 ℃ for 48 hours, sucking old culture medium, adding 100 μl of thiazole blue, culturing for 2 hours, incubating at 37 ℃ for 2 hours, and measuring light absorption value (OD) at 570nm by using an MB enzyme-labeled instrument;
the calculation formula is as follows:
percent cell viability = (compound OD-blank OD/control OD-blank OD) ×100%;
cell inhibition ratio% = 1-percent cell viability% = [1- (compound OD-blank OD/control OD-blank OD)]X 100%, using Graphpad Prism 7, according to the formulaFitting to obtain IC 50 ；
Sample treatment: dissolving a sample by using thionyl chloride, preserving at low temperature, and controlling the concentration of the thionyl chloride in a final system within a range which does not influence the detection activity;
data processing and result description: the activity of the sample is tested under the condition of single concentration of the primary screening, such as the concentration of the monomer compound is 50 mu M, the inhibition rate is more than 50 percent, and the dependence of the activity dose is further tested, namely IC 50 Values obtained by nonlinear fitting of sample concentrations by sample activity, calculated using the software Graphpad Prism 7, and typically, multiple wells (n.gtoreq.3) were set for each sample in the test, and the results were expressed in standard deviation (Standard Deviation, SD) as shown in tables 1 and 2:
Example 67
The invention discloses an antibacterial activity screening method of tricyclic thiazolo [5,4-d ] pyrimidinone compounds:
melting agar medium, cooling to 46+ -0.5deg.C, adding cultured bacterial liquid, and mixing thoroughly to give test bacterial suspension with concentration of 5×10 5 cfu/mL-5×10 6 cfu/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, and uniformly distributing, wherein 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 dish is more than 15 mm. mu.L of the test solution was added to each well. The dishes were covered, placed in a 37℃incubator for 30-60min to allow the solution to be completely absorbed, incubated for 16-18 h with inversion, the results observed, the diameter of the inhibition ring was measured with vernier calipers and recorded, each set was repeated 3 times, and the average was taken, and the results are shown in tables 1 and 2.
Example 68
Screening of ethyl (butyryl) cholinesterase in anti-Alzheimer's disease of tricyclic thiazolo [5,4-d ] pyrimidinone compounds:
the total reaction volume was 200. Mu.L: 2. Mu.L of sample, 158. Mu.L of Tris-HCl buffer solution containing ethyl (butyl) cholinesterase (final concentration is 0.02U/mL), enzyme activity control group is Tris-HCl buffer solution without enzyme, incubation is carried out for 10min at room temperature, then 20. Mu.L of thioethyl (butyl) choline iodide is added, after reaction is carried out for 10min at 37 ℃, 20. Mu.L of DTNB is added to each hole, shaking and mixing are carried out, and the absorption value at 405nm is measured; huperzine A is used as a positive control; inhibition ratio (%) = [ (enzyme activity group-enzyme activity control group) - (drug group-drug control group)/(enzyme activity group-enzyme activity control group) ]x100%; the results are shown in tables 1 and 2:
Example 67
Screening of anti-ethyl (butyl) cholinesterase of tricyclic thiazolo [5,4-d ] pyrimidinone compounds:
the total reaction volume was 200. Mu.L: 2. Mu.L of sample, 138. Mu.L of Tris-HCl buffer solution containing acetylcholinesterase (final concentration is 0.03U/mL), enzyme activity control group is Tris-HCl buffer solution without enzyme, incubation is carried out for 10min at room temperature, then 20. Mu.L of thioacetylcholine iodide is added, after reaction is carried out for 10min at 37 ℃, 20. Mu.L of 1% SDS and 20. Mu.L of DTNB are added to each hole, shaking and mixing are carried out, and the absorption value at 405nm is measured; huperzine A is used as a positive control; inhibition ratio (%) = [ (enzyme activity group-enzyme activity control group) - (drug group-drug control group)/(enzyme activity group-enzyme activity control group) ] ×100%, and the results are shown in tables 1 and 2:
TABLE 1 biological Activity results of H1-H32 derivatives
Figure BDA0003323019370000321
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Figure BDA0003323019370000331
Table 2 biological Activity results of I1-I32 derivatives
Figure BDA0003323019370000332
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Figure BDA0003323019370000341
From the table it can be seen that: the 64 tricyclic thiazolo [5,4-d ] pyrimidinone derivatives have inhibitory activity on ethyl (butyrylcholine esterase) enzyme, cancer cells (Hela cervical cancer cells and HT-29 human colon cancer cells) in Alzheimer's disease, and the antibacterial activity of 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 have strong inhibitory activity on acetylcholinesterase in Alzheimer's disease; compounds H7, H8, H10, H11, H20, H27, I11, I15, I19 have inhibitory activity on butyrylcholinesterase in alzheimer's disease; compound I26, I27 has inhibitory activity against Hela cervical cancer cells; compounds I5, I11, I15, I26 have inhibitory activity against HT-29 human colon cancer cells; the compounds H1, H6-H10, H15, H16, H19, H28-H31, I3, I8, I15, I16, I18-I22, I27-I30 have inhibitory activity on Candida albicans C.albicans; compounds I8, I15, I21 have inhibitory activity against E.coli and S.aureus.

Claims (3)

1. A tricyclic thiazolo [5,4-d ] pyrimidinone derivative is characterized in that the structural formula of the derivative is as follows:
Figure QLYQS_1
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Figure QLYQS_2
wherein:
the compound H1 is 2-phenyl-6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidine-9 (5H) -ketone;
compound H3 is 2- (3-methylphenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H4 is 2- (4-methylphenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H5 is 2- (4-tert-butylphenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H6 is 2- (2-chlorophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H7 is 2- (3-chlorophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H8 is 2- (4-chlorophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H9 is 2- (2-bromophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H10 is 2- (3-bromophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H11 is 2- (4-bromophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H12 is 2- (2-fluorophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
Compound H15 is 2- (4-trifluoromethylphenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H16 is 2- (3-trimethoxyphenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
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-tetrahydropyrrolo [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzaldehyde;
compound H22 is 2- (3-acetylphenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H23 is 2- (3-nitrophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H24 is 2- (3, 5-dimethylphenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H25 is 2- (3, 5-dichlorophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one; compound H27 is 2- (3, 5-dibromophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
compound H28 is 2- (3, 5-difluorophenyl) -6, 7-dihydropyrrol [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one;
Compound H29 is 2- (3, 5-dimethoxyphenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one compound H30 is 2- (3, 4-dimethoxyphenyl) -6, 7-dihydropyrrole [1,2-a ] thiazolo [5,4-d ] pyrimidin-9 (5H) -one compound H31 is 2- (3-chloro-4-fluoro-phenyl) -6, 7-dihydropyrrole [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 I3 is 2- (3-methylphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I4 is 2- (4-methylphenyl) -7, 8-dihydro-5H-pyrido [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-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I7 is 2- (3-chlorophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I8 is 2- (4-chlorophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I10 is 2- (3-bromophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
Compound I11 is 2- (4-bromophenyl) -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 I15 is 2- (4-trifluoromethylphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one; compound I16 is 2- (3-trimethoxyphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one; compound I17 is 2- (4-trimethoxyphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one; compound I18 is 2- (10-oxo-6,7,8,10-tetrahydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile;
compound I19 is 3- (10-oxo-6,7,8,10-tetrahydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile;
compound I20 is 4- (10-oxo-6,7,8,10-tetrahydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzonitrile;
compound I21 is 4- (10-oxo-6,7,8,10-tetrahydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-2-yl) benzaldehyde;
compound I22 is 2- (3-acetylphenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I23 is 2- (3-nitrophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
Compound I25 is 2- (3, 5-dichlorophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I26 is 2- (3, 4-dichlorophenyl) -7, 8-dihydro-5H-pyrido [1,2-a ] thiazolo [5,4-d ] pyrimidin-10 (6H) one;
compound I27 is 2- (3, 5-dibromophenyl) -7, 8-dihydro-5H-pyrido [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.
2. A tricyclic thiazolo [5,4-d ] pyrimidinone derivative according to claim 1, wherein H3-H5 is a compound,
use of 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 the manufacture of a medicament for the treatment of Alzheimer's disease.
3. Use of a compound H1, H6-H10, H15-H16, H19, H28-H31, I3, I8, I15, I16, I18-I22, I27-I30 in a tricyclic thiazolo [5,4-d ] pyrimidinone derivative according to claim 1 for the preparation of a medicament for inhibiting candida albicans.
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