CN112778333B - Tetrahydrooxazolopyridino-azoxanone derivative and application thereof - Google Patents

Abstract

The invention relates to a tetrahydro-oxazolo-pyrido-azoxy-hetero-ketone derivative and application thereof, in particular to a tetrahydro-oxazolo [5',4':4,5] derivative]Pyrido [1,2-a]Nitrogen oxa-11 (5)H) The keto derivatives are E1-E48. In the screening of antitumor activity, positive control of DOX is used; the derivatives are respectively considered to be the 48 tetrahydrooxazolo [5',4':4,5] of E1-E48]Pyrido [1,2-a]Azoxa-11 (5)H) The ketone derivatives have the inhibition effect on Hela human cervical carcinoma cells, MCF-7 breast cancer cells and A549 lung cancer cells, and the results show that: compounds E5, E8, E9, E20, E26, E28, E32, E34, E38, E41, E42, E44, E45, E46, E47 and E48 have inhibitory activity on Hela cervical cancer cells compared to the positive control; compounds E26, E38, E42, E45, E46 and E47 have inhibitory activity against MCF-7 breast cancer cells; compounds E8, E9, E26 and E47 had inhibitory activity against a549 lung cancer cells.

Description

Tetrahydrooxazolopyridinoazane derivative and application thereof

Technical Field

The invention relates to a tetrahydro-oxazolo-pyrido-azoxy-ketone derivative and application thereof, in particular to a tetrahydro-oxazolo [5',4':4,5] pyrido [1,2-a ] azoxy-11 (5H) -ketone derivative and application thereof, and cell activity screening results show that: 16 compounds have inhibitory activity on Hela cervical carcinoma cells; 6 compounds have inhibitory activity on MCF-7 breast cancer cells; there are 4 compounds with inhibitory activity against a549 lung cancer cells.

Background

According to the statistical data of the World Health Organization (WHO), about 1000 million people suffer from cancer every year and about 700 million people die worldwide, the number of people suffering from cancer in China is about 120 ten thousand, and the number of people dying from cancer every year is more than 90 ten thousand, so that the cancer-killing composition becomes the second killer of people only second to cardiovascular diseases. Although chemically synthesized anticancer drugs also have toxic side effects on normal cells of the human body in many cases. However, there are few reports on finding anticancer active ingredients with low toxicity and high therapeutic effect from natural animals and plants, so that chemically synthesized anticancer drugs are still one of the hot spots of research of domestic and foreign scientists in recent years.

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

Oxazoles containing nitrogen and oxygen atoms have many unique properties and biological activities. To date, oxazole-based drugs have been used clinically, such as linezolid, oxacillin, sulfisoxazole, raltegravir, furazolidone, toloxanone, and the like. Oxazole compounds are receiving increasing attention as bioisosteres of thiazoles, imidazoles, benzimidazoles, triazoles and tetrazoles, and it is expected that novel oxazoles having broad spectrum, high potency, low toxicity and excellent pharmacokinetic properties will be found.

The thiazole ring is an important five-membered aromatic heterocycle, contains nitrogen and sulfur heteroatoms, has abundant electrons, is easy to form hydrogen bonds, is coordinated with metal ions, has static electricity, hydrophobic interaction and other non-covalent bond interactions, has a plurality of special properties, has wide potential applications in a plurality of fields, draws great attention of a plurality of workers, and related research works including the synthesis method thereof are increased day by day. Especially, with the success of a series of thiazole compounds in clinical and agricultural production, the development of thiazole compounds has become one of the hot areas of research in recent years. In the field of medicine, thiazole compounds can be combined with targets such as various enzymes and receptors in organisms to show various biological activities, and almost coversThe whole field of medicine^[15]And a plurality of thiazole compounds are used clinically, such as antibiotic drug cefixime, anticancer drug dasatinib, antiparasitic drug nitazoxanide, anti-inflammatory drug meloxicam and the like are first-line drugs which are preferred clinically.

Therefore, from the biological activities of the oxazole pyrimidine derivatives and thiazole pyrimidine derivatives, the searching and exploring of the synthesis methods of the compounds have great theoretical and application values for searching lead compounds such as new medicines.

Reference documents:

[1] zhouyongyi, Guo Hua, ancient science New anticancer drug study dynamics brief introduction [ J ] chemical education, 2004,5:10-13.

[2] Phyllanthus urinaria, attempts to address the development situation of anticancer drugs [ J ]. strait pharmacology, 1995,3(7):63-64.

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

[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 of 3,4-Dipheny-3-diazaphos-pholidin-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] The synthesis research progress of five-membered heterocyclic compound, chemical technology 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,DOI 10.1007/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.

[18]Teoh,D.；Ayeni,T.A.；Rubatt,J.M.；Adams,D.J.；Grace,L.；Dasatinib has synergistic activity with paclitaxel and carboplatin in ovarian cancer cells.Gynecol Oncol,2011,121(1):187-192.

[19] Zhao Na, Zxi Chen, Nizoxanide clinical application research progress Chinese J.Opathology, 2010,5(2):146-152.

[20]Ah,Y.C.；Choi,J.K.；Choi,Y.K.；Ki,H.M.；Bae,J.H.；A novel transdermal patch incorporating meloxicam:In vitro and in vivo characterization.Int J Pharm,2010,385(2):12-19.

On the basis of comprehensive analysis of related patents and documents at home and abroad, the invention fully synthesizes tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -ketone compounds, carries out systematic modification and modification, introduces phenyl, fatty group and heterocycle containing different substituents into the tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -ketone compound molecules so as to improve the druggability of the tetrahydrooxazolo [5',4':4,5] pyridino [1,2-a ] azahetero-11 (5H) -ketone compounds, researches the inhibition activities of the compounds on Hela cervical cancer cells, MCF-7 breast cancer cells and A549 lung cancer cells, and the activity screening result shows that: 16 compounds have inhibitory activity on Hela cervical carcinoma cells; 6 compounds have inhibitory activity on MCF-7 breast cancer cells; there are 4 compounds with inhibitory activity against a549 lung cancer cells. The drug has obvious curative effect and definite target point and is a candidate drug with antitumor activity.

Disclosure of Invention

The invention aims to provide a tetrahydro-oxazolopyridino-azepinone derivative and application thereof, and particularly provides a tetrahydro-oxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one derivative which takes ethyl cyanoacetate as an initial raw material, generates a hydroxylamine compound (A) under the action of sodium nitrite and phosphoric acid, then is reduced to obtain ethyl 2-aminocyanoacetate (B), respectively reacts with different substituted acyl chlorides under the alkali condition, cyclizes under the action of trifluoroacetic acid to generate an oxazole compound (D1-D48) of different substituted 5-amino-4-formic ether, then reacts with cyclohexanamide under the action of phosphorus oxychloride to obtain tetrahydro-oxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -ones (E1-E48). And the obtained 48 compounds (E1-E48) have the inhibitory activity on Hela cervical carcinoma cells, MCF-7 breast cancer cells and A549 lung cancer cells, and 16 compounds, namely E5, E8, E9, E20, E26, E28, E32, E34, E38, E41, E42, E44, E45, E46, E47 and E48, have the inhibitory activity on Hela cervical carcinoma cells; 6 compounds E26, E38, E42, E45, E46 and E47 have inhibitory activity on MCF-7 breast cancer cells; there are 4 compounds E8, E9, E26 and E47 that have inhibitory activity against a549 lung cancer cells. Wherein E26 and E47 have inhibitory activity against all three tumor cells; e8 and E9 have inhibitory activity on Hela cervical cancer cells and A549 lung cancer cells; e26, E38, E42, E45, E46 and E47 have inhibitory activity against Hela cervical cancer cells and MCF-7 breast cancer cells.

The invention relates to a tetrahydro-oxazolo-pyrido-azepinone derivative, which is a tetrahydro-oxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -ketone derivative and has the structure as follows:

wherein:

compound E1 is 2-methyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E2 is 2-ethyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E3 is 2-propyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E4 is 2-butyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

the compound E5 is 2-dodecyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azaoxa-11 (5H) -one;

compound E6 is 2- (2-propenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E7 is 2-tert-butyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E8 is 2-adamantyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E9 is 2-benzyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E10 is 2-phenethyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E11 is 2-cyclopropyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E12 is 2-cyclobutyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E13 is 2-cyclopentyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

the compound E14 is 2-cyclohexyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E15 is 2- (furan-2-yl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E16 is 2- (thiophen-2-yl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E17 is 2- (tetrahydro-2H-pyran-4-yl) -6,7,8, 9-tetrahydro-oxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E18 is 2- (naphthalen-1-yl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E19 is 2- (naphthalen-2-yl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E20 is 2- (1,1' -biphenyl-4-yl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E21 is 2-phenyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E22 is 2- (2-methylphenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E23 is 2- (3-methylphenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E24 is 2- (4-methylphenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

the compound E25 is 2- (2-chlorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E26 is 2- (3-chlorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

the compound E27 is 2- (4-chlorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E28 is 2- (2-bromophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E29 is 2- (3-bromophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E30 is 2- (4-bromophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

the compound E31 is 2- (3, 5-xylyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E32 is 2- (3, 4-dichlorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E33 is 2- (3, 5-dichlorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E34 is 2- (2, 6-dichlorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E35 is 2- (2-fluorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E36 is 2- (3-fluorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

the compound E37 is 2- (4-fluorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azan-11 (5H) -one;

compound E38 is 2- (3, 5-difluorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

the compound E39 is 2- (3, 4-difluorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E40 is 2- (2, 6-difluorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E41 is 2- (2- (trifluoromethyl) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E42 is 2- (3- (trifluoromethyl) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E43 is 2- (4- (trifluoromethyl) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E44 is 2- (3, 5-bis (trifluoromethyl) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E45 is 2- (2- (trifluoromethoxy) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E46 is 2- (3- (trifluoromethoxy) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E47 is 2- (4- (trifluoromethoxy) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

the compound E48 is 2- (4- (tert-butyl) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azan-11 (5H) -one.

The E5, E8, E9, E20, E26, E28, E32, E34, E38, E41, E42, E44, E45, E46, E47 and E48 in the tetrahydrooxazolopyridinoazane derivatives are used for preparing the medicines for treating Hela cervical cancer.

The E26, E38, E42, E45, E46 and E47 in the tetrahydro-oxazolopyridino-azepinone derivatives are used for preparing medicines for treating MCF-7 breast cancer.

The E8, E9, E26 and E47 in the tetrahydro-oxazolopyridino-azepinone derivatives are used for preparing a medicament for treating A549 lung cancer.

The applications of E26 and E47 in the tetrahydro-oxazolopyridino-azepinone derivatives in preparing medicaments for treating Hela cervical cancer, MCF-7 breast cancer and A549 lung cancer.

The E8 and E9 in the tetrahydro oxazolopyridine azoxanone derivatives are used for preparing medicaments for treating Hela cervical cancer and A549 lung cancer.

The E26, E38, E42, E45, E46 and E47 in the tetrahydro-oxazolopyridino-azoxanone derivatives are used for preparing medicaments for treating Hela cervical cancer and MCF-7 breast cancer.

The tetrahydro oxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -ketone derivative has a structure shown in a general formula (I):

the invention relates to a tetrahydro-oxazolo-pyrido-azepinone derivative and application thereof, in particular to a preparation method of a tetrahydro-oxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -ketone derivative, which comprises the following steps:

preparation of Compound A

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

Preparation of Compound B

Dissolving 43g of the white compound A obtained in the previous step in 0.3mol of pure water 500ml at room temperature, slowly dropwise adding 350ml of saturated sodium bicarbonate solution under stirring, then adding 156g of sodium hydrosulfite and 0.9mol, heating to 35 ℃, reacting for 1 hour, then reacting for 3 hours at room temperature, extracting for 3 times by using 500ml of dichloromethane, combining organic phases, drying and concentrating, and performing gradient elution by using forward silica gel column chromatography, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a compound B.

Preparation of Compounds C1-C48

Dissolving the obtained compound B1.28g and 10mmol in 50mL of anhydrous dichloromethane, adding 12mmol of different substituted formyl chlorides under the ice bath condition, then slowly dropwise adding 1.25g and 12mmol of triethylamine, reacting at room temperature until all raw materials disappear, filtering the reaction liquid, concentrating, and performing gradient elution by adopting forward silica gel column chromatography, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 10:1 to respectively obtain the compounds C1-C48.

Preparation of Compounds D1-D48

Dissolving the obtained compound C1-C4810 mmol in anhydrous dichloromethane, slowly dropwise adding 10mL trifluoroacetic acid, reacting at room temperature until the raw materials disappear, filtering the reaction solution, concentrating, and performing gradient elution by adopting forward silica gel column chromatography, wherein the eluent is petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain the compounds D1-D48 respectively.

Preparation of Compounds E1-E48

Dissolving the obtained compound D1-D4810 mmol in 20mL anhydrous dioxane, adding cyclohexanamide 15mmol, slowly dropwise adding phosphorus oxychloride 2.5mmol, refluxing to react until all raw materials disappear, filtering the reaction solution, concentrating, performing forward silica gel column chromatography gradient elution, and respectively obtaining compounds E1-E48 by using petroleum ether and ethyl acetate with the volume ratio of 1:1 as eluent.

The invention relates to a tetrahydro-oxazolo-pyrido-azepinone derivative, in particular to a tetrahydro-oxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -ketone derivative which takes ethyl cyanoacetate as a starting material, and is synthesized into different substituted oxazole derivatives by multiple steps in sequence, and then the oxazole derivatives react with cyclohexanamide under the action of phosphorus oxychloride to obtain the tetrahydro-oxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -ketone derivative, wherein the synthetic route is as follows:

Detailed Description

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

reagent: all reagents were commercially available analytical grade;

example 1

Preparation of compound a:

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

preparation of compound B:

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

preparation of Compounds C1-C48:

dissolving 1.28g of obtained compound B2-amino-2-cyanoethyl acetate in 10mmol of anhydrous dichloromethane 50mL, adding 12mmol of different substituted acyl chloride under an ice bath condition, slowly dropwise adding 1.25g of triethylamine and 12mmol of triethylamine, reacting at room temperature until all raw materials disappear, filtering the reaction solution, concentrating, performing gradient elution by adopting forward silica gel column chromatography, and respectively obtaining compounds C1-C48 by using an eluant of petroleum ether and ethyl acetate in a volume ratio of 10:1, wherein the eluant is used for the next reaction without purification; wherein each name of the compounds C1-C48 is

Compound C1 is N- (1-cyano-2-ethylperoxyethyl) acetamide;

compound C2 is N- (1-cyano-2-ethylperoxyethyl) propionamide;

compound C3 is N- (1-cyano-2-ethylperoxyethyl) butanamide;

compound C4 is N- (1-cyano-2-ethylperoxyethyl) pentanamide;

compound C5 is N- (1-cyano-2-ethylperoxyethyl) tridecamide;

compound C6 is N- (1-cyano-2-ethylperoxyethyl) methacrylamide;

compound C7 is N- (1-cyano-2-ethylperoxyethyl) adamantane-1-carboxamide;

compound C8 is N- (1-cyano-2-ethylperoxyethyl) neopentenamide;

compound C9 is N- (1-cyano-2-ethylperoxyethyl) -2-phenylacetamide;

compound C10 is N- (1-cyano-2-ethylperoxyethyl) -2-phenylacrylamide;

compound C11 is N- (1-cyano-2-ethylperoxyethyl) cyclopropylamide;

compound C12 is N- (1-cyano-2-ethylperoxyethyl) cyclobutanamide;

compound C13 is N- (1-cyano-2-ethylperoxyethyl) cyclopentamide;

compound C14 is N- (1-cyano-2-ethylperoxyethyl) cyclohexanamide;

compound C15 is N- (1-cyano-2-ethylperoxyethyl) furan-2-carboxamide;

compound C16 is N- (1-cyano-2-ethylperoxyethyl) thiophene-2-carboxamide;

compound C17 is N- (1-cyano-2-ethylperoxyethyl) tetrahydrofuran-4-carboxamide;

compound C18 is N- (1-cyano-2-ethylperoxyethyl) -1-naphthamide;

compound C19 is N- (1-cyano-2-ethylperoxyethyl) -2-naphthamide;

compound C20 is N- (1-cyano-2-ethylperoxyethyl) -biphenyl-4-carboxamide;

compound C21 is N- (1-cyano-2-ethylperoxyethyl) benzamide;

compound C22 is N- (1-cyano-2-ethylperoxyethyl) -2-methylbenzamide;

compound C23 is N- (1-cyano-2-ethylperoxyethyl) -3-methylbenzamide;

compound C24 is N- (1-cyano-2-ethylperoxyethyl) -4-methylbenzamide;

compound C25 is N- (1-cyano-2-ethylperoxyethyl) -2-chlorobenzamide;

compound C26 is N- (1-cyano-2-ethylperoxyethyl) -3-chlorobenzamide;

compound C27 is N- (1-cyano-2-ethylperoxyethyl) -4-chlorobenzamide;

compound C28 is N- (1-cyano-2-ethylperoxyethyl) -2-bromobenzamide;

compound C29 is N- (1-cyano-2-ethylperoxyethyl) -3-bromobenzamide;

compound C30 is N- (1-cyano-2-ethylperoxyethyl) -4-bromobenzamide;

compound C31 is N- (1-cyano-2-ethylperoxyethyl) -3, 5-dimethylbenzamide;

compound C32 is N- (1-cyano-2-ethylperoxyethyl) -3, 4-dichlorobenzamide;

compound C33 is N- (1-cyano-2-ethylperoxyethyl) -3, 5-dichlorobenzamide;

compound C34 is N- (1-cyano-2-ethylperoxyethyl) -2, 6-dichlorobenzamide;

compound C35 is N- (1-cyano-2-ethylperoxyethyl) -2-fluorobenzamide;

compound C36 is N- (1-cyano-2-ethylperoxyethyl) -3-fluorobenzamide;

compound C37 is N- (1-cyano-2-ethylperoxyethyl) -4-fluorobenzamide;

compound C38 is N- (1-cyano-2-ethylperoxyethyl) -3, 5-difluorobenzamide;

compound C39 is N- (1-cyano-2-ethylperoxyethyl) -3, 4-difluorobenzamide;

compound C40 is N- (1-cyano-2-ethylperoxyethyl) -2, 6-difluorobenzamide;

compound C40 is N- (1-cyano-2-ethylperoxyethyl) -2, 6-difluorobenzamide;

compound C41 is N- (1-cyano-2-ethylperoxyethyl) -2-trifluoromethylbenzamide;

compound C42 is N- (1-cyano-2-ethylperoxyethyl) -3-trifluoromethylbenzamide;

compound C43 is N- (1-cyano-2-ethylperoxyethyl) -4-trifluoromethylbenzamide;

compound C44 is N- (1-cyano-2-ethylperoxyethyl) -3, 5-bistrifluoromethylbenzamide;

compound C45 is N- (1-cyano-2-ethylperoxyethyl) -2-trifluoromethoxy benzamide;

compound C46 is N- (1-cyano-2-ethylperoxyethyl) -3-trifluoromethoxy benzamide;

compound C47 is N- (1-cyano-2-ethylperoxyethyl) -4-trifluoromethoxybenzamide;

compound C48 is N- (1-cyano-2-ethylperoxyethyl) -4-tert-butylbenzamide.

Example 2

Preparation of Compounds D1-D48:

dissolving the compounds C1-C4810 mmol obtained in example 1 in anhydrous dichloromethane, slowly dropwise adding 10mL trifluoroacetic acid, reacting at room temperature until the raw materials disappear completely, concentrating the reaction solution, and performing forward silica gel column chromatography gradient elution by using petroleum ether and ethyl acetate according to the volume ratio of 2:1 to obtain compounds D1-D48, wherein the names of the compounds D1-D48 are as follows:

compound D1 is 2-methyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 84% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.31(s,2H),4.33(q,J＝7.2Hz,2H),2.34(s,3H),1.37(t,J＝7.1Hz,3H)；

compound D2 is 2-ethyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 80% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.58(s,2H),4.25(q,J＝7.1Hz,2H),2.58(q,J＝7.6Hz,2H),1.28(t,J＝7.1Hz,3H),1.20(t,J＝7.6Hz,3H)；

compound D3 is 2-propyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 76% of a light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.31(s,2H),4.31(q,J＝7.1Hz,2H),2.60(q,J＝7.5Hz,2H),1.71(t,J＝7.5Hz,2H),1.35(t,J＝7.1Hz,3H),0.95(t,J＝7.4Hz,3H)；

compound D4 is 2-butyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 86% light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.39(s,2H),4.29(q,J＝7.1Hz,2H),2.68(q,J＝7.5Hz,2H),1.64(t,J＝7.6Hz,2H),1.42–1.25(m,5H),0.88(t,J＝7.6Hz,3H)；

compound D5 was 2-dodecyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 81% of a light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.33(s,2H),4.31(q,J＝7.1Hz,2H),2.59(q,J＝7.6Hz,2H),1.67(t,J＝7.7Hz,2H),1.34(t,J＝7.1Hz,3H),1.30–1.12(m,18H),0.85(t,J＝6.8Hz,3H)；

compound D6 is 2- (2-propenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 78%, light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.69(s,1H),5.51(s,2H),5.27(s,1H),4.35(q,J＝7.1Hz,2H),2.10(d,J＝0.6Hz,3H),1.36(t,J＝7.1Hz,3H)；

compound D7 is 2-tert-butyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 71% of a light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.34(s,2H),4.32(q,J＝7.1Hz,2H),1.35(t,J＝7.1Hz,3H),1.32(s,9H)；

compound D8 was 2-adamantyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 79% of a light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.30(s,2H),4.32(q,J＝7.1Hz,2H),2.06-2.01(m,3H),1.98-1.92(m 6H),1.81–1.65(m,6H),1.35(t,J＝7.1Hz,3H)；

compound D9 was 2-benzyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 82% of a pale yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.30-7.20(m 5H),5.39(s,2H),4.30(q,J＝7.1Hz,2H),3.94(s,2H),1.34(t,J＝7.6Hz,3H)；

compound D10 is 2-phenethyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 86% light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.30-7.26(m,2H),7.22-7.17(m,3H),5.30(s,2H),4.29(q,J＝7.1Hz,2H),3.04-2.99(m,2H),2.97–2.87(m,2H),1.36(t,J＝7.1Hz,3H)；

compound D11 is 2-cyclopropyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 81% of a light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.30(s,2H),4.30(q,J＝7.1Hz,2H),1.90(tt,J＝8.4,5.2Hz,1H),1.34(t,J＝7.1Hz,3H),1.04–0.81(m,4H)；

compound D12 is 2-cyclobutyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 71% of a light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.51(s,2H),4.28(q,J＝7.1Hz,2H),3.44(p,J＝8.7Hz,1H),2.37-2.30(m,2H),2.29–2.15(m,2H),2.07–1.76(m,2H),1.31(t,J＝7.1Hz,3H)；

compound D13 is 2-cyclopentyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 74% light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.33(s,2H),4.31(q,J＝7.1Hz,2H),3.06(p,J＝8.2Hz,1H),2.03-1.94(m,2H),1.87–1.68(m,4H),1.64–1.55(m,2H),1.34(t,J＝7.1Hz,3H)；

compound D14 is 2-cyclohexyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 77% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.32(s,2H),4.31(q,J＝7.1Hz,2H),2.63(tt,J＝11.7,3.5Hz,1H),1.98(dd,J＝13.3,1.9Hz,2H),1.82–1.45(m,4H),1.34(t,J＝7.1Hz,3H),1.32–1.20(m,2H)；

compound D15 is 2- (furan-2-yl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 83% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.47(d,J＝1.4Hz,1H),6.90(dd,J＝3.5,0.8Hz,1H),6.52–6.41(m,1H),5.60(s,2H),4.35(q,J＝7.1Hz,2H),1.37(t,J＝7.1Hz,3H)；

compound D16 is 2- (thiophen-2-yl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 87% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.31(d,J＝1.4Hz,1H),6.64(dd,J＝3.5,0.8Hz,1H),6.31–6.25(m,1H),5.67(s,2H),4.28(q,J＝7.1Hz,2H),1.35(t,J＝7.1Hz,3H)；

compound D17 is 2- (tetrahydro-2H-pyran-4-yl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 85 percent;

a light-yellow solid, wherein the solid is,¹H NMR(400MHz,CDCl₃)δ5.41(s,2H),4.31(q,J＝7.1Hz,2H),3.98(dt,J＝11.6,3.4Hz,2H),3.51–3.37(m,2H),2.99–2.81(m,1H),1.93–1.74(m,3H),1.34(t,J＝7.1Hz,3H)；

compound D18 is 2- (naphthalen-1-yl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 78%, light yellow solid;

¹H NMR(400MHz,DMSO)δ8.27(d,J＝0.7Hz,1H),8.04–7.86(m,3H),7.56-7.51(m,3H),5.73(s,2H),4.20(q,J＝7.1Hz,2H),1.26(t,J＝7.1Hz,3H)；

compound D19 is 2- (naphthalen-2-yl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 74% light yellow solid;

¹H NMR(400MHz,DMSO)δ8.27(d,J＝0.7Hz,1H),8.04–7.84(m,3H),7.56-7.52(m,3H),5.73(s,2H),4.20(q,J＝7.1Hz,2H),1.26(t,J＝7.1Hz,3H)；

compound D20 is 2- (1,1' -biphenyl-4-yl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 81% of a light yellow solid;

¹H NMR(400MHz,DMSO)δ7.83(d,J＝8.5Hz,2H),7.77(d,J＝8.6Hz,2H),7.69(d,J＝7.3Hz,2H),7.48(m,2H),7.45(t,J＝7.6Hz,2H),7.36(t,J＝7.3Hz,1H),4.19(q,J＝7.1Hz,2H),1.25(t,J＝7.1Hz,3H)；

compound D21 is 2-phenyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 83% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.98–7.84(m,2H),7.48–7.32(m,3H),5.56(s,2H),4.38(q,J＝7.1Hz,2H),1.39(t,J＝7.1Hz,3H)；

compound D22 is 2- (2-methylphenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 74% light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.82(d,J＝7.7Hz,1H),7.36–7.11(m,3H),5.55(s,2H),4.37(q,J＝7.2Hz,2H),2.63(s,3H),1.39(t,J＝7.1Hz,3H)；

compound D23 is 2- (3-methylphenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 72% light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.79(s,1H),7.70(d,J＝7.8Hz,1H),7.28(t,J＝7.7Hz,1H),7.19(d,J＝7.9Hz,1H),5.52(s,2H),4.39(q,J＝7.1Hz,2H),2.36(s,3H),1.40(t,J＝7.1Hz,3H)；

compound D24 is 2- (4-methylphenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 83% of a pale yellow solid;

¹H NMR(400MHz,DMSO)δ7.64(d,J＝8.2Hz,2H),7.35(s,2H),7.26(d,J＝8.0Hz,2H),4.17(q,J＝7.1Hz,2H),2.31(s,3H),1.24(t,J＝7.1Hz,3H)；

compound D25 is 2- (2-chlorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 87% of a pale yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.94–7.83(m,1H),7.57–7.37(m,2H),7.37–7.21(m,1H),5.66(s,2H),4.36(q,J＝7.1Hz,2H),1.37(t,J＝5.5Hz,5H)；

compound D26 is 2- (3-chlorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 70% of light yellow solid;

¹H NMR(400MHz,DMSO)δ7.68(t,J＝3.4Hz,2H),7.50(s,2H),7.48(d,J＝7.0Hz,2H),4.18(q,J＝7.1Hz,2H),1.23(t,J＝7.1Hz,3H)；

compound D27 is 2- (4-chlorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 72% light yellow solid;

¹H NMR(400MHz,DMSO)δ7.73(d,J＝8.6Hz,2H),7.50(d,J＝8.6Hz,2H),7.45(s,2H),4.18(q,J＝7.1Hz,2H),1.23(t,J＝7.1Hz,3H)；

compound D28 is 2- (2-bromophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 76% of a light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.83(d,J＝7.5Hz,1H),7.68(dd,J＝7.8,1.7Hz,1H),7.49–7.28(m,2H),5.91(s,2H),4.28(q,J＝7.3Hz,2H),1.29(t,J＝7.1Hz,3H)；

compound D29 is 2- (3-bromophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 81% of a light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.97(t,J＝1.7Hz,1H),7.71(dd,J＝18.1,8.3Hz,2H),7.35(t,J＝7.9Hz,1H),5.58(s,2H),4.39(q,J＝7.3Hz,2H),1.39(t,J＝7.1Hz,3H)；

compound D30 is 2- (4-bromophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 83% of light yellow solid;

¹H NMR(400MHz,DMSO)δ7.66(s,2H),7.64(s,2H),7.49(s,2H),4.18(q,J＝7.1Hz,2H),1.24(t,J＝7.1Hz,3H)；

compound D31 is 2- (3, 5-xylyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 79% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.55(s,2H),7.00(s,1H),5.63(s,2H),4.38(q,J＝7.1Hz,2H),2.35(s,6H),1.38(t,J＝7.1Hz,3H)；

compound D32 was 2- (3, 4-dichlorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 77% of light yellow solid;

¹H NMR(400MHz,DMSO)δ7.84(d,J＝1.8Hz,1H),7.72(d,J＝8.5Hz,1H),7.68(dd,J＝8.5,1.9Hz,1H),7.56(s,2H),4.19(q,J＝7.1Hz,2H),1.24(t,J＝7.1Hz,3H)；

compound D33 was 2- (3, 5-dichlorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 76% of a light yellow solid;

¹H NMR(400MHz,DMSO)δ7.64(s,1H),7.63(s,2H),7.58(s,2H),4.19(q,J＝7.1Hz,2H),1.24(t,J＝7.1Hz,3H)；

compound D34 was 2- (2, 6-dichlorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 82% light yellow solid;

¹H NMR(400MHz,DMSO)δ7.34(s,1H),7.30(s,2H),7.21(s,2H),4.36(q,J＝7.1Hz,2H),1.35(t,J＝7.1Hz,3H)；

compound D35 was 2- (2-fluorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 85% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.96(td,J＝7.7,1.7Hz,1H),7.48–7.27(m,1H),7.16(ddd,J＝19.5,9.4,4.7Hz,2H),5.62(s,2H),4.38(q,J＝7.2Hz,2H),1.39(t,J＝7.1Hz,3H)；

compound D36 is 2- (3-fluorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 79% of light yellow solid;

¹H NMR(400MHz,DMSO)δ7.58(d,J＝7.9Hz,1H),7.48(s,2H),7.54–7.42(m,2H),7.25(td,J＝8.2,2.0Hz,1H),4.18(q,J＝7.1Hz,2H),1.24(t,J＝7.1Hz,3H)；

compound D37 was 2- (4-fluorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 76% of a light yellow solid;

¹H NMR(400MHz,DMSO)δ7.81–7.75(m,2H),7.44(s,2H),7.30(t,J＝8.9Hz,2H),4.18(q,J＝7.1Hz,2H),1.24(t,J＝7.1Hz,3H)；

compound D38 was 2- (3, 5-difluorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 82% light yellow solid;

¹H NMR(400MHz,DMSO)δ7.56(s,2H),7.34(s,1H),7.32(s,2H),4.19(q,J＝7.1Hz,2H),1.24(t,J＝7.1Hz,3H)；

compound D39 was 2- (3, 4-difluorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 81% of a light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.96(d,J＝7.6Hz,1H),7.71(d,J＝7.8Hz,1H),7.51(s,1H),5.73(s,2H),4.33(q,J＝7.1Hz,2H),1.35(t,J＝7.1Hz,3H)；

compound D40 was 2- (2, 6-difluorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 87% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ8.03(d,J＝2.0Hz,1H),7.75(dd,J＝8.4,2.0Hz,1H),7.47(d,J＝8.5Hz,1H),5.57(s,2H),4.39(q,J＝7.1Hz,2H),1.40(t,J＝7.1Hz,3H)；

compound D41 is 2- (2- (trifluoromethyl) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 78%, light yellow solid;

¹H NMR(400MHz,CDCl₃)δ8.18(s,1H),8.09(d,J＝8.1Hz,1H),7.62(d,J＝7.8Hz,1H),7.52(t,J＝7.8Hz,1H),5.63(s,2H),4.39(q,J＝7.1Hz,2H),1.40(t,J＝7.1Hz,3H)；

compound D42 is 2- (3- (trifluoromethyl) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 75% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ8.18(s,1H),8.10(d,J＝7.8Hz,1H),7.62(d,J＝7.8Hz,1H),7.52(t,J＝7.8Hz,1H),5.63(s,2H),4.39(q,J＝7.1Hz,2H),1.40(t,J＝7.1Hz,4H)；

compound D43 is 2- (4- (trifluoromethyl) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 88%, a pale yellow solid,¹H NMR(400MHz,CDCl₃)δ8.03(d,J＝8.1Hz,2H),7.65(d,J＝8.2Hz,2H),5.61(s,2H),4.40(q,J＝7.1Hz,2H),1.40(t,J＝7.1Hz,3H).

compound D44 is 2- (3, 5-bis (trifluoromethyl) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 81% of a light yellow solid;

¹H NMR(400MHz,CDCl₃)δ8.36(s,2H),7.85(s,1H),5.70(s,2H),4.41(q,J＝7.1Hz,2H),1.41(t,J＝7.1Hz,3H)；

compound D45 is 2- (2- (trifluoromethoxy) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 79% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ8.08(dd,J＝7.9,1.7Hz,1H),7.44–7.37(m,1H),7.32(ddd,J＝9.7,5.1,1.3Hz,2H),5.60(s,2H),4.37(q,J＝7.1Hz,2H),1.38(t,J＝7.1Hz,3H)；

compound D46 is 2- (3- (trifluoromethoxy) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 86% light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.87(d,J＝7.9Hz,1H),7.77(s,1H),7.43(t,J＝8.0Hz,1H),7.22(d,J＝0.8Hz,1H),5.58(s,2H),4.39(q,J＝7.1Hz,2H),1.40(t,J＝7.1Hz,3H)；

compound D47 is 2- (4- (trifluoromethoxy) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 80% of light yellow solid;

¹H NMR(400MHz,DMSO)δ7.85(d,J＝8.8Hz,2H),7.48(s,1H),7.45(d,J＝8.5Hz,2H),4.18(q,J＝7.1Hz,2H),1.24(t,J＝7.1Hz,3H)；

compound D48 is 2- (4- (tert-butyl) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 73% as a pale yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.85(d,J＝8.6Hz,2H),7.41(d,J＝8.6Hz,2H),5.53(s,2H),4.38(q,J＝7.1Hz,2H),1.39(t,J＝7.1Hz,3H),1.31(s,9H)。

example 3

Preparation of compound E1:

dissolving 0.17g and 10mmol of compound D1 obtained in example 2, namely 2-methyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain 1, namely compound E1, which is 2-methyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -one, wherein the yield is 75%, and the melting point is that: 73-75 ℃;

¹H NMR(400MHz,CDCl₃)δ4.42(t,J＝6.1Hz,2H),3.08(t,J＝6.6Hz,2H),2.57(s,3H),2.02–1.61(m,6H)。

example 4

Preparation of compound E2:

dissolving 0.18g and 10mmol of compound D2 obtained in example 2, namely 2-ethyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain 2, namely 2-ethyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -one, wherein the yield is 86%, and the melting point is that: 80-82 ℃;

¹H NMR(400MHz,CDCl₃)δ4.42(t,J＝6.1Hz,2H),3.08(t,J＝6.7Hz,2H),2.89(q,J＝7.6Hz,2H),1.89-1.78(m,2H),1.40(t,J＝7.6Hz,3H)。

example 5

Preparation of compound E3:

dissolving 0.20g and 10mmol of compound D3 obtained in example 2, namely 2-propyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain 3, namely 2-propyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -one, wherein the yield is 79%, and the melting point is that: 95-97 ℃;

1H NMR(400MHz,CDCl3)δ4.25(t,J＝8.1Hz,2H),3.20(t,J＝8.0Hz,2H),2.84(t,J＝7.4Hz,2H),2.34(p,J＝7.8Hz,2H),1.91-1.82(m,2H),1.01(t,J＝7.4Hz,3H).

example 6

Preparation of compound E4:

dissolving 0.21g and 10mmol of compound D4 obtained in example 2, namely 2-butyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain 4, namely 2-butyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -one, wherein the yield is 80%, and the melting point is that: 109-111 ℃;

¹H NMR(400MHz,CDCl₃)δ4.39(t,J＝6.1Hz,2H),3.05(t,J＝6.5Hz,2H),2.83(t,J＝7.5Hz,2H),1.83-1.71(m,4H),1.43-1.33(m,2H),0.90(t,J＝7.4Hz,3H)。

example 7

Preparation of compound E5:

dissolving 0.32g and 10mmol of compound D5 obtained in example 2, namely 2-dodecyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain compound E5, namely 2-dodecyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -one, wherein the yield is 85%, and a light yellow solid, and the melting point: 79 to 81 ℃;

¹H NMR(400MHz,CDCl₃)δ4.40(t,J＝6.1Hz,2H),3.06(t,J＝6.7Hz,2H),2.83(t,J＝7.5Hz,2H),2.03–1.68(m,8H),1.48–1.13(m,18H),0.85(t,J＝6.8Hz,3H)。

example 8

Preparation of compound E6:

0.19g, 10mmol of the compound D6 obtained in example 2, which is 2- (2-propenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, was dissolved in 20mL of anhydrous dioxane, and 0.17g, 15mmol of piracetamide was added, then slowly dropwise adding 0.38g and 2.5mmol of phosphorus oxychloride, carrying out reflux reaction until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, carrying out gradient elution by using forward silica gel column chromatography, wherein an eluant is petroleum ether with a volume ratio of 1: ethyl acetate to give compound E6 as a 2- (2-propenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one, 85% yield, light yellow solid, melting point: 89-91 ℃;

¹H NMR(400MHz,CDCl₃)δ6.13(m,1H),5.55(s,1H),4.43(t,J＝6.1Hz,2H),3.09(t,J＝6.6Hz,2H),2.22(s,3H),1.91–1.74(m,6H)。

example 9

Preparation of compound E7:

dissolving 0.21g and 10mmol of compound D7 obtained in example 2, namely 2-tert-butyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing gradient elution by forward silica gel column chromatography, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E7, namely 2-tert-butyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -one, the yield is 82%, and a light yellow solid has a melting point: 99-101 ℃;

¹H NMR(400MHz,CDCl₃)δ4.41(t,J＝6.1Hz,2H),3.08(t,J＝6.7Hz,2H),1.93–1.71(m,6H),1.44(s,9H)。

example 10

Preparation of compound E8:

dissolving 0.29g and 10mmol of compound D8 obtained in example 2, namely 2-adamantyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and eluting by petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain 8, namely 2- ((3r,5r,7r) adamantyl-1-yl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one, wherein the yield is 76% of light yellow solid, melting point: 109-111 ℃;

¹H NMR(400MHz,CDCl₃)δ4.40(t,J＝6.1Hz,2H),3.06(t,J＝6.1Hz,2H),2.08(s,9H),1.88–1.67(m,12H)。

example 11

Preparation of compound E9:

dissolving 0.25g and 10mmol of compound D9 obtained in example 2, namely 2-benzyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain 9, namely 2-benzyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -one, wherein the yield is 89%, and the melting point is that: 151 ℃ and 153 ℃;

¹H NMR(400MHz,CDCl₃)δ7.41–7.19(m,5H),4.38(t,J＝6.1Hz,2H),4.17(s,2H),3.03(t,J＝6.7Hz,2H),1.78(m,6H)。

example 12

Preparation of compound E10:

dissolving 0.26g and 10mmol of compound D10 obtained in example 2, namely 2-phenethyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain compound E10, namely 2-phenethyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -one, wherein the yield is 72%, and a light yellow solid has a melting point: 139-141 ℃;

¹H NMR(400MHz,CDCl₃)δ7.19-7.31(m,5H),4.45(t,J＝6.1Hz,2H),3.07(t,J＝6.7Hz,2H)3.18(s,2H),1.94–1.70(m,6H)。

example 13

Preparation of compound E11:

dissolving 0.20g and 10mmol of compound D11 obtained in example 2, namely 2-cyclopropyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E11, namely 2-cyclopropyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -one, wherein the yield is 73%, and a light yellow solid, and the melting point: 86-88 ℃;

¹H NMR(400MHz,CDCl₃)δ4.39(t,J＝6.1Hz,2H),3.05(t,J＝6.7Hz,2H),2.12(tt,J＝8.4,4.9Hz,1H),1.95–1.68(m,6H),1.24-1.20(m,2H),1.15–1.07(m,2H)。

example 14

Preparation of compound E12:

dissolving 0.21g and 10mmol of compound D12 obtained in example 2, namely 2-cyclobutyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E12, namely 2-cyclobutyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -one, wherein the yield is 78%, and a light yellow solid, and the melting point: 91-93 ℃;

¹H NMR(400MHz,CDCl₃)δ4.42(t,J＝6.1Hz,2H),3.70(p,J＝8.5Hz,1H),3.08(t,J＝6.6Hz,2H),2.61–2.46(m,2H),2.46–2.33(m,2H),2.17–1.96(m,2H),1.90–1.71(m,6H)。

example 15

Preparation of compound E13:

dissolving 0.22g and 10mmol of compound D13 obtained in example 2, namely 2-cyclopentyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E13, namely 2-cyclopentyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -one, with the yield of 81%, a light yellow solid, the melting point: 113 ℃ and 115 ℃;

¹H NMR(400MHz,CDCl₃)δ4.41(t,J＝6.1Hz,2H),3.29(p,J＝8.0Hz,1H),3.07(t,J＝6.7Hz,2H),2.18–1.93(m,4H),1.91–1.61(m,10H)。

example 16

Preparation of compound E14:

dissolving 0.24g and 10mmol of compound D14 obtained in example 2, namely 2-cyclohexyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing gradient elution by forward silica gel column chromatography, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain 14, namely 2-cyclohexyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -one, the yield is 79%, and a light yellow solid, the melting point: 127-129 ℃;

¹H NMR(400MHz,CDCl₃)δ4.52–4.37(t,J＝6.1Hz,2H),3.21–3.02(t,J＝6.5Hz,2H),2.88(tt,J＝11.3,3.6Hz,1H),2.12-2.08(m,2H),1.96–1.58(m,10H),1.51–1.20(m,4H)。

example 17

Preparation of compound E15:

dissolving 0.22g and 10mmol of compound D15 obtained in example 2, namely 2- (furan-2-yl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing forward silica gel column chromatography gradient elution, eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E15, namely 2- (furan-2-yl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -one, with the yield of 81 percent and light yellow solid, melting point: 121-123 ℃;

¹H NMR(400MHz,CDCl₃)δ7.62(dd,J＝1.7,0.7Hz,1H),7.22(dd,J＝3.5,0.7Hz,1H),6.57(dd,J＝3.5,1.8Hz,1H),4.44(t,J＝6.1Hz,2H),3.10(t,J＝6.6Hz,2H),1.93–1.68(m,6H)。

example 18

Preparation of compound E16:

dissolving 0.24g and 10mmol of compound D16 obtained in example 2 which is 2- (thiophene-2-yl) -5-amino-4-ethyl formate oxazole in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain compound E16 which is 2- (thiophene-2-yl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azaza-11 (5H) -one, and the yield is 84% of light yellow solid, melting point: 135 ℃ and 137 ℃;

¹H NMR(400MHz,CDCl₃)δ7.84(dd,J＝3.7,1.2Hz,1H),7.53(dd,J＝5.0,1.2Hz,1H),7.15(dd,J＝5.0,3.7Hz,1H),4.52–4.35(t,J＝6.1Hz,2H),3.21–3.01(t,J＝6.7Hz,2H),1.97–1.75(m,6H)。

example 19

Preparation of compound E17:

dissolving 0.24g and 10mmol of compound D17 obtained in example 2, namely 2- (tetrahydro-2H-pyran-4-yl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly dropwise adding 0.38g and 2.5mmol of phosphorus oxychloride, refluxing to react until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, performing forward silica gel column chromatography gradient elution, and using petroleum ether and ethyl acetate with the volume ratio of 1:1 as eluent to obtain a compound E17, namely 2- (tetrahydro-2H-pyran-4-yl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azaza-11 (5H) -one, yield 75%, light yellow solid, melting point: 139-141 ℃;

¹H NMR(400MHz,CDCl₃)δ4.42(t,J＝6.1Hz,2H),4.02(dt,J＝11.9,3.7Hz,2H),3.54(td,J＝11.0,3.3Hz,2H),3.15(dt,J＝10.0,4.9Hz,1H),3.08(t,J＝6.7Hz,2H),2.08-1.96(m,4H),1.89–1.61(m,6H)。

example 20

Preparation of compound E18:

dissolving 0.28g and 10mmol of compound D18 obtained in example 2, namely 2- (naphthalene-1-yl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding phosphorus oxychloride (0.38g and 2.5mmol) dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing forward silica gel column chromatography gradient elution, eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain compound E18, namely 2- (naphthalene-1-yl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azaza-11 (5H) -ketone, with the yield of 76 percent and light yellow solid, melting point: 169 ℃ and 171 ℃;

¹H NMR(400MHz,CDCl₃)δ8.71(s,1H),8.26(dd,J＝8.7,1.7Hz,1H),7.99–7.93(m,2H),7.92–7.84(m,1H),7.59-7.53(m,2H),4.55–4.42(t,J＝6.1Hz,2H),3.25–3.04(t,J＝6.7Hz,2H),1.91–1.78(m,6H)。

example 21

Preparation of compound E19:

dissolving the compound D19 obtained in example 2, namely 2- (naphthalene-2-yl) -5-amino-4-ethyl formate oxazole (0.28g and 10mmol) in 20mL of anhydrous dioxane, adding cyclohexanamide (0.17g and 15mmol), slowly adding phosphorus oxychloride (0.38g and 2.5mmol) dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and performing gradient elution by forward silica gel column chromatography, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain the compound E19.

2- (naphthalen-2-yl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5]Pyrido [1,2-a ]]Oxa-11 (5H) -one, 80% yield, light yellow solid, melting point: 167-169 deg.C;¹H NMR(400MHz,CDCl₃)δ8.69(s,1H),8.25(dd,J＝8.6,1.7Hz,1H),7.94(d,J＝8.6Hz,2H),7.89–7.81(m,1H),7.61–7.49(m,2H),4.67–4.22(t,J＝6.0Hz,2H),3.13(t,J＝5.2Hz,2H),1.95–1.76(m,6H).

example 22

Preparation of compound E20:

dissolving 0.31g and 10mmol of compound D20 obtained in example 2, namely 2- (1,1 '-biphenyl-4-yl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly dropwise adding 0.38g and 2.5mmol of phosphorus oxychloride, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, performing forward silica gel column chromatography gradient elution, and obtaining a compound E20, namely 2- (1,1' -biphenyl-4-yl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -one, by using petroleum ether and ethyl acetate in a volume ratio of 1:1, yield 83%, light yellow solid, melting point: 164-166 ℃;

¹H NMR(400MHz,CDCl₃)δ8.26(d,J＝8.5Hz,2H),7.81–7.70(m,2H),7.67–7.62(m,2H),7.48(t,J＝7.4Hz,2H),7.43–7.36(m,1H),4.48((t,J＝6.0Hz,2H),3.14(t,J＝5.0Hz,2H),2.08–1.72(m,6H)。

example 23

Preparation of compound E21:

dissolving 0.23g and 10mmol of compound D21 obtained in example 2, namely 2-phenyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain 21, namely 2-phenyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -one, wherein the yield is 81%, and the melting point is that: 163 ℃ and 165 ℃;

¹H NMR(400MHz,CDCl₃)δ8.18(dd,J＝7.6,1.9Hz,1H),7.49(d,J＝7.2Hz,1H),4.61–4.34(m,1H),3.28–3.01(m,1H),1.99–1.65(m,4H)。

example 24

Preparation of compound E22:

compound D22 obtained in example 2, which is 2- (2-methylphenyl) -5-amino-4-carboxylic acid ethyl ester oxazole 0.25g, 10mmol, was dissolved in 20mL of anhydrous dioxane, and cyclohexylamide 0.17g, 15mmol was added, then slowly dropwise adding 0.38g and 2.5mmol of phosphorus oxychloride, carrying out reflux reaction until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, carrying out gradient elution by using forward silica gel column chromatography, wherein an eluant is petroleum ether with a volume ratio of 1: ethyl acetate to give compound E22 as a 2- (2-methylphenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one, 77% yield, light yellow solid, melting point: 126 ℃ and 128 ℃;

¹H NMR(400MHz,CDCl₃)δ8.29–8.05(m,1H),7.72–7.35(m,1H),7.36–7.28(m,2H),4.46(t,J＝6.1Hz,2H),3.12(t,J＝6.5Hz,2H),2.78(s,3H),1.93-1.75(m,6H)。

example 25

Preparation of compound E23:

compound D23 obtained in example 2, which is 2- (3-methylphenyl) -5-amino-4-carboxylic acid ethyl ester oxazole 0.25g, 10mmol, was dissolved in 20mL of anhydrous dioxane, and cyclohexylamide 0.17g, 15mmol was added, then slowly dropwise adding 0.38g and 2.5mmol of phosphorus oxychloride, carrying out reflux reaction until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, carrying out gradient elution by using forward silica gel column chromatography, wherein an eluant is petroleum ether with a volume ratio of 1: ethyl acetate to give compound E23 as a 2- (3-methylphenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one, 81% yield, light yellow solid, melting point: 152 ℃ and 154 ℃;

¹H NMR(400MHz,CDCl₃)δ8.04(s,1H),7.97(d,J＝7.6Hz,1H),7.37(t,J＝7.6Hz,1H),7.32(d,J＝7.7Hz,1H),4.46(t,J＝6.1Hz,2H),3.12(t,J＝6.7Hz,2H),2.42(s,3H),2.10–1.77(m,6H)。

example 26

Preparation of compound E24:

compound D24 obtained in example 2, which is 2- (4-methylphenyl) -5-amino-4-carboxylic acid ethyl ester oxazole 0.25g, 10mmol, was dissolved in 20mL of anhydrous dioxane, and cyclohexylamide 0.17g, 15mmol was added, and then slowly dropwise adding 0.38g and 2.5mmol of phosphorus oxychloride, performing reflux reaction until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by using forward silica gel column chromatography, wherein an eluent is petroleum ether with the volume ratio of 1: ethyl acetate to give compound E24 as a 2- (4-methylphenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one, yield 86% as a pale yellow solid, melting point: 196 ℃ and 198 ℃;

¹H NMR(400MHz,CDCl₃)δ8.06(d,J＝8.2Hz,2H),7.28(d,J＝8.0Hz,2H),4.44(t,J＝6.1Hz,2H),3.10(t,J＝6.7Hz,2H),2.40(s,3H),1.97–1.73(m,6H)。

example 27

Preparation of compound E25:

dissolving 0.27g and 10mmol of compound D25 obtained in example 2, namely 2- (2-chlorophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, eluting with a forward silica gel column chromatography gradient, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain compound E25, namely 2- (2-chlorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -one, with the yield of 78%, a light yellow solid, the melting point: 157 ℃ and 159 ℃;

¹H NMR(400MHz,CDCl₃)δ8.13(dd,J＝7.7,1.8Hz,1H),7.51(dd,J＝7.8,1.5Hz,1H),7.42(td,J＝7.6,1.9Hz,1H),7.37(td,J＝7.6,1.5Hz,1H),4.45(t,J＝6.1Hz,2H),3.12(t,J＝6.7Hz,2H),1.93–1.72(m,6H)。

example 28

Preparation of compound E26:

dissolving 0.27g and 10mmol of compound D26 obtained in example 2, namely 2- (3-chlorophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, eluting with a forward silica gel column chromatography gradient, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain compound E26, namely 2- (3-chlorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -one, wherein the yield is 88%, and a light yellow solid, and the melting point: 191-193 ℃;

¹H NMR(400MHz,CDCl₃)δ8.20(s,1H),8.07(d,J＝7.6Hz,1H),7.45(dt,J＝15.6,8.0Hz,2H),4.46(t,J＝6.1Hz,2H),3.13(t,J＝6.7Hz,2H),2.56–1.68(m,6H)。

example 29

Preparation of compound E27:

dissolving 0.27g and 10mmol of compound D27 obtained in example 2, namely 2- (4-chlorophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all the raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, eluting with a forward silica gel column chromatography gradient, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain compound E27, namely 2- (4-chlorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azaxo-11 (5H) -one, wherein the yield is 89%, and a light yellow solid is as follows, and the melting point: 237-239 ℃;

¹H NMR(400MHz,CDCl₃)δ8.11(d,J＝8.5Hz,2H),7.46(d,J＝8.5Hz,2H),4.45(t,J＝6.1Hz,2H),3.12(t,J＝6.6Hz,2H),1.92–1.75(m,6H)。

example 30

Preparation of compound E28:

dissolving 0.31g and 10mmol of compound D28 obtained in example 2, namely 2- (2-bromophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and eluting with a forward silica gel column chromatography gradient, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E28, namely 2- (2-bromophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -one, the yield is 77%, and the light yellow solid has a melting point: 157 ℃ and 159 ℃;

¹H NMR(400MHz,CDCl₃)δ8.07(dd,J＝7.8,1.7Hz,1H),7.71(dd,J＝8.0,0.9Hz,1H),7.42(td,J＝7.7,1.2Hz,1H),7.33(td,J＝7.7,1.8Hz,1H),4.44(t,J＝6.1Hz,2H),3.12(t,J＝6.5Hz,2H),1.93–1.60(m,6H)。

example 31

Preparation of compound E29:

dissolving 0.31g and 10mmol of compound D29 obtained in example 2, namely 2- (3-bromophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and eluting with a forward silica gel column chromatography gradient, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E29, namely 2- (3-bromophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one, with the yield of 79 percent and a light yellow solid, the melting point: 210 ℃ and 212 ℃;

¹H NMR(400MHz,CDCl₃)δ8.35(t,J＝1.8Hz,1H),8.10(d,J＝7.9Hz,1H),7.63(dd,J＝8.0,1.8Hz,1H),7.36(t,J＝7.9Hz,1H),4.45(t,J＝6.1Hz,2H),3.12(t,J＝6.6Hz,2H),2.02–1.69(m,6H)。

example 32

Preparation of compound E30:

compound D30 obtained in example 2 as 2- (4-bromophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole 0.31g, 10mmol was dissolved in 20mL of anhydrous dioxane, and 0.17g, 15mmol of cyclohexanamide was added, then 0.38g, 2.5mmol of phosphorus oxychloride was slowly added dropwise, the reaction was refluxed until all the starting material disappeared, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, eluted with a forward silica gel column chromatography gradient with petroleum ether ethyl acetate in a volume ratio of 1:1 to give compound E30 as 2- (4-bromophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one in 84% yield as a pale yellow solid, melting point: 237-239 ℃;

¹H NMR(400MHz,CDCl₃)δ8.06(d,J＝8.6Hz,2H),7.64(d,J＝8.5Hz,2H),4.47(t,J＝6.1Hz,2H),3.13(t,J＝6.7Hz,2H),1.99–1.72(m,6H)。

example 33

Preparation of compound E31:

dissolving 0.26g and 10mmol of compound D31 obtained in example 2, which is 2- (3, 5-xylyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing forward silica gel column chromatography gradient elution, eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain compound E31, which is 2- (3, 5-dimethylphenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azaza-11 (5H) -one, with a yield of 73% of a light yellow solid, melting point: 235-237 ℃;

¹H NMR(400MHz,CDCl₃)δ7.83(s,2H),7.14(s,1H),4.46(t,J＝6.1Hz,2H),3.12(t,J＝6.7Hz,2H),2.38(s,6H),1.99–1.70(m,6H)。

example 34

Preparation of compound E32:

dissolving 0.3g and 10mmol of compound D32 obtained in example 2, namely 2- (3, 4-dichlorophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, performing forward silica gel column chromatography gradient elution, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E32, namely 2- (3, 4-dichlorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -ketone, the yield is 76 percent, and a pale yellow solid, melting point: 196 ℃ and 198 ℃;

¹H NMR(400MHz,CDCl₃)δ8.27(d,J＝2.0Hz,1H),7.98(dd,J＝8.4,2.0Hz,1H),7.56(d,J＝8.4Hz,1H),4.45(t,J＝6.1Hz,2H),3.12(t,J＝6.7Hz,2H),1.97–1.77(m,6H)。

example 35

Preparation of compound E33:

dissolving 0.3g and 10mmol of compound D33 obtained in example 2, namely 2- (3, 5-dichlorophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, performing forward silica gel column chromatography gradient elution, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E33, namely 2- (3, 5-dichlorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -ketone, the yield is 83 percent, and a pale yellow solid, melting point: 250 ℃ and 252 ℃;

¹H NMR(400MHz,CDCl₃)δ7.46–7.38(m,3H),4.46(t,J＝6.1Hz,2H),3.13(t,J＝6.6Hz,2H),1.99–1.68(m,6H)。

example 36

Preparation of compound E34:

dissolving 0.3g and 10mmol of compound D34 obtained in example 2, namely 2- (2, 6-dichlorophenyl) -5-amino-4-ethyl formate oxazole in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, carrying out forward silica gel column chromatography gradient elution, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E34, namely 2- (2, 6-dichlorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -ketone, the yield is 75 percent, and a pale yellow solid, melting point: 191-193 ℃;

¹H NMR(400MHz,CDCl₃)δ8.08(d,J＝1.9Hz,2H),7.49(t,J＝1.9Hz,1H),4.46(t,J＝6.1Hz,2H),3.13(t,J＝6.6Hz,2H),2.01–1.77(m,6H)。

example 37

Preparation of compound E35:

dissolving 0.25g and 10mmol of compound D35 obtained in example 2, namely 2- (2-fluorophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and eluting with a forward silica gel column chromatography gradient, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E35, namely 2- (2-fluorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azaxo-11 (5H) -one, the yield is 70%, and a light yellow solid is obtained, and the melting point is as follows: 198-200 ℃;

¹H NMR(400MHz,CDCl₃)δ8.19(td,J＝7.5,1.7Hz,1H),7.75–7.40(m,1H),7.34–7.14(m,2H),4.45(t,J＝6.0Hz,2H),3.12(t,J＝6.7Hz,2H),1.87-1.77(m,6H)。

example 38

Preparation of compound E36:

dissolving 0.25g and 10mmol of compound D36 obtained in example 2, namely 2- (3-fluorophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and eluting with a forward silica gel column chromatography gradient, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E36, namely 2- (3-fluorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azaxo-11 (5H) -one, the yield is 78%, and a light yellow solid is obtained, and the melting point is as follows: 174 ℃ and 176 ℃;

¹H NMR(400MHz,CDCl₃)δ7.93(d,J＝7.8Hz,1H),7.83(dt,J＝9.2,2.3Hz,1H),7.44(td,J＝8.1,5.7Hz,1H),7.18(td,J＝8.4,2.6Hz,1H),4.43(t,J＝6.1Hz,2H),3.10(t,J＝6.7Hz,2H),1.91-1.77(m,6H)。

example 39

Preparation of compound E37:

dissolving 0.25g and 10mmol of compound D37 obtained in example 2, namely 2- (4-fluorophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and eluting with a forward silica gel column chromatography gradient, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E37, namely 2- (4-fluorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azaxo-11 (5H) -one, the yield is 80%, and a light yellow solid is obtained, and the melting point is as follows: 185-187 deg.C;

¹H NMR(400MHz,CDCl₃)δ8.17(dd,J＝8.9,5.3Hz,2H),7.16(t,J＝8.7Hz,2H),4.44(t,J＝6.1Hz,2H),3.10(t,J＝6.7Hz,2H),1.93–1.72(m,6H)。

example 40

Preparation of compound E38:

dissolving 0.27g and 10mmol of compound D38 obtained in example 2, namely 2- (3, 5-difluorophenyl) -5-amino-4-ethyl formate oxazole in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, eluting by a forward silica gel column chromatography gradient, eluting by petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E38, namely 2- (3, 5-difluorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azahetero-11 (5H) -one, wherein the yield is 74 percent and the yellow solid is obtained, melting point: 165-167 ℃;

¹H NMR(400MHz,CDCl₃)δ7.71(d,J＝5.5Hz,2H),6.96(tt,J＝8.7,2.9Hz,1H),4.47(t,J＝6.1Hz,2H),3.13(t,J＝6.7Hz,2H),1.96–1.71(m,6H)。

EXAMPLE 41

Preparation of compound E39:

dissolving 0.27g and 10mmol of compound D39 obtained in example 2, namely 2- (3, 4-difluorophenyl) -5-amino-4-ethyl formate oxazole in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, carrying out forward silica gel column chromatography gradient elution, eluting by petroleum ether and ethyl acetate in a volume ratio of 1:1, and removing to obtain a compound E39, namely 2- (3, 4-difluorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azaza-11 (5H) -ketone, wherein the yield is 76 percent, and a pale yellow solid, melting point: 154-156 ℃;

¹H NMR(400MHz,CDCl₃)δ8.01(ddd,J＝10.5,7.5,2.1Hz,1H),7.95(ddd,J＝8.7,4.0,1.8Hz,1H),7.35–7.28(m,1H),4.51–4.43(t,J＝6.1Hz,2H),3.22–3.06(t,J＝6.7Hz,2H),1.95–1.76(m,6H)。

example 42

Preparation of compound E40:

dissolving the compound D40 obtained in example 2, namely 2- (2, 6-difluorophenyl) -5-amino-4-ethyl formate oxazole (0.27g, 10mmol) in 20mL of anhydrous dioxane, adding cyclohexanamide (0.17g, 15mmol), then slowly adding phosphorus oxychloride (0.38g, 2.5mmol) dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, eluting with a forward silica gel column chromatography gradient, eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E40, namely 2- (2, 6-difluorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one, with a yield of 67%, pale yellow solid, melting point: 156 ℃ and 158 ℃;

¹H NMR(400MHz,CDCl₃)δ7.48(tt,J＝8.5,6.1Hz,1H),7.06(t,J＝8.4Hz,2H),4.45(t,J＝6.1Hz,2H),3.12(t,J＝6.5Hz,2H),1.96–1.64(m,6H)。

example 43

Preparation of compound E41:

dissolving 0.3g and 10mmol of compound D41 obtained in example 2, namely 2- (2- (trifluoromethyl) phenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, carrying out forward silica gel column chromatography gradient elution, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E41, namely 2- (2- (trifluoromethyl) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azaza-11 (5H) -ketone, the yield is 69%, and the product is a light yellow solid, melting point: 129-131 ℃;

¹H NMR(400MHz,CDCl₃)δ8.19(d,J＝7.4Hz,1H),7.88-7.84(m,1H),7.76–7.60(m,2H),4.47(t,J＝6.1Hz,2H),3.14(t,J＝6.6Hz,2H),2.02–1.78(m,6H)。

example 44:

preparation of compound E42:

dissolving 0.3g and 10mmol of compound D42 obtained in example 2, namely 2- (3- (trifluoromethyl) phenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, carrying out forward silica gel column chromatography gradient elution, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E42, namely 2- (3- (trifluoromethyl) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azaza-11 (5H) -ketone, the yield is 73 percent, and the product is a pale yellow solid, melting point: 145-147 ℃;

¹H NMR(400MHz,CDCl₃)δ8.49(s,1H),8.36(d,J＝7.8Hz,1H),7.77(d,J＝7.8Hz,1H),7.64(t,J＝7.9Hz,1H),4.47(t,J＝6.1Hz,2H),3.15(t,J＝6.6Hz,2H),1.93–1.76(m,6H)。

example 45

Preparation of compound E43:

dissolving 0.3g and 10mmol of compound D43 obtained in example 2, namely 2- (4- (trifluoromethyl) phenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, carrying out forward silica gel column chromatography gradient elution, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E43, namely 2- (4- (trifluoromethyl) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azaza-11 (5H) -ketone, the yield is 79 percent, and a light yellow solid, melting point: 199-;

¹H NMR(400MHz,CDCl₃)δ8.27(d,J＝8.2Hz,2H),7.74(d,J＝8.4Hz,2H),4.45(t,J＝6.1Hz,2H),3.12(t,J＝6.6Hz,2H),1.96–1.66(m,6H)。

example 46

Preparation of compound E44:

dissolving 0.37g and 10mmol of compound D44 obtained in example 2, namely 2- (3, 5-bis (trifluoromethyl) phenyl) -5-amino-4-ethyl formate oxazole in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly dropwise adding 0.38g and 2.5mmol of phosphorus oxychloride, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, performing forward silica gel column chromatography gradient elution, and obtaining a compound E44, namely 2- (3, 5-bis (trifluoromethyl) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4, 5] pyrido [1,2-a ] azaza-11 (5H) -ketone by using a petroleum ether and ethyl acetate in a volume ratio of 1:1, yield 73%, light yellow solid, melting point: 221-223 ℃;

¹H NMR(400MHz,CDCl₃)δ8.64(s,2H),7.99(s,1H),4.47(t,J＝6.1Hz,2H),3.15(t,J＝6.7Hz,2H)2.01–1.68(m,6H)。

example 47

Preparation of compound E45:

dissolving 0.32g and 10mmol of compound D45 obtained in example 2, namely 2- (2- (trifluoromethoxy) phenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, eluting by forward silica gel column chromatography gradient, wherein the eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain compound E45, namely 2- (2- (trifluoromethoxy) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4, 5-tetrahydrooxazolo]Pyrido [1,2-a ]]Oxa-11 (5H) -one, yield 72%, light yellow solid, melting point: 175-177 ℃;¹H NMR(400MHz,CDCl₃)δ8.32(dd,J＝7.8,1.7Hz,1H),7.57(td,J＝7.9,1.7Hz,1H),7.49–7.35(m,2H),4.47(t,J＝6.1Hz,2H),3.14(t,J＝6.7Hz,2H),1.97–1.76(m,6H)。

example 48

Preparation of compound E46:

dissolving 0.32g and 10mmol of compound D46 obtained in example 2, namely 2- (3- (trifluoromethoxy) phenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, eluting with a forward silica gel column chromatography gradient, wherein the eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E46, namely 2- (3- (trifluoromethoxy) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azaza-11 (5H) -one, the yield is 77%, pale yellow solid, melting point: 147 ℃ and 149 ℃;

¹H NMR(400MHz,CDCl₃)δ8.13(d,J＝7.9Hz,1H),8.06(s,1H),7.54(t,J＝8.1Hz,1H),7.37(dd,J＝8.9,1.6Hz,1H),4.47(t,J＝6.1Hz,2H),3.14(t,J＝6.6Hz,2H),2.35–1.74(m,6H)。

example 49

Preparation of compound E47:

dissolving 0.32g and 10mmol of compound D47 obtained in example 2, namely 2- (4- (trifluoromethoxy) phenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, eluting with a forward silica gel column chromatography gradient, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E47, namely 2- (4- (trifluoromethoxy) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azaza-11 (5H) -one, the yield is 84%, pale yellow solid, melting point: 212-214 ℃;

¹H NMR(400MHz,CDCl₃)δ8.23(d,J＝8.8Hz,2H),7.34(d,J＝8.4Hz,2H),4.68–4.27(t,J＝6.1Hz,2H),3.51–2.76(t,J＝6.5Hz,2H),2.02–1.73(m,6H)。

example 50

Preparation of compound E48:

dissolving 0.29g and 10mmol of compound D48 obtained in example 2, namely 2- (4- (tert-butyl) phenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.17g and 15mmol of cyclohexanamide, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing forward silica gel column chromatography gradient elution, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a compound E48, namely 2- (4- (tert-butyl) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azaza-11 (5H) -ketone, the yield is 82 percent, and a pale yellow solid, melting point: 214-216 ℃;

¹H NMR(400MHz,CDCl₃)δ8.12(d,J＝8.6Hz,2H),7.51(d,J＝8.6Hz,2H),4.46(t,J＝6.1Hz,2H),3.12(t,J＝6.5Hz,2H),1.89-1.79(m,6H),1.35(s,9H)。

example 51

The invention relates to a screening method for the anti-tumor activity of tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] aza-11 (5H) -ketone, which comprises the following steps:

cell survival rate by thiazole blue assay:

the experimental process comprises the following steps:

sucking the cells growing in the logarithmic growth phase, removing the culture medium, washing once with phosphate buffer solution, digesting with pancreatin, adding the culture medium, stopping, gently blowing, counting, inoculating in a 96-well plate (100 mu l/well) at a corresponding cell density, culturing overnight, adding compounds (20 mu l/well), setting a concentration gradient for each compound, setting 3 wells for each concentration, culturing for 48 hours in an incubator at 37 ℃, removing the old culture medium, adding 100 mu l of thiazole blue, continuing to culture for 2 hours, incubating at 37 ℃ for 2 hours, and measuring the light absorption value (OD) at 570nm by using an MB microplate reader;

calculating the formula:

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

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

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

data processing and results description: primary screening under single concentration conditions, e.g., 50 μ M monomer compound concentration; the extract 50 μ g/μ L, the activity of the sample was tested, the inhibition% was greater than 50%, and the dose dependence of the activity, i.e. IC, was further tested₅₀Values obtained by nonlinear fitting of sample activity to sample concentration, calculated as Graphpad Prism 4, typically, multiple wells (n.gtoreq.3) were set for each sample in the test, and expressed as Standard Deviation (SD) in the results, see Table 1:

TABLE 1 results of antitumor biological Activity of derivatives of E1-E48

As can be seen from the table: the results of the inhibition effect of 48 compounds in the tetrahydro-oxazolopyridine-nitrogen-oxygen hetero-ketone derivative on Hela human cervical cancer cells, MCF-7 breast cancer cells and A549 lung cancer cells show that: compounds E5, E8, E9, E20, E26, E28, E32, E34, E38, E41, E42, E44, E45, E46, E47 and E48 have inhibitory activity on Hela cervical cancer cells compared to the positive control; compounds E26, E38, E42, E45, E46 and E47 have inhibitory activity against MCF-7 breast cancer cells; compounds E8, E9, E26 and E47 had inhibitory activity against a549 lung cancer cells.

Claims (7)

1. A tetrahydro oxazolo pyrido azepinone derivative is characterized in that the derivative is a tetrahydro oxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one derivative, and the structure of the derivative is as follows:

wherein:

compound E5 is 2-dodecyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E8 is 2-adamantyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E9 is 2-benzyl-6, 7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E20 is 2- (1,1' -biphenyl-4-yl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E26 is 2- (3-chlorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E28 is 2- (2-bromophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E32 is 2- (3, 4-dichlorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E34 is 2- (2, 6-dichlorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E38 is 2- (3, 5-difluorophenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E41 is 2- (2- (trifluoromethyl) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E42 is 2- (3- (trifluoromethyl) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E44 is 2- (3, 5-bis (trifluoromethyl) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E45 is 2- (2- (trifluoromethoxy) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E46 is 2- (3- (trifluoromethoxy) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

compound E47 is 2- (4- (trifluoromethoxy) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azepin-11 (5H) -one;

the compound E48 is 2- (4- (tert-butyl) phenyl) -6,7,8, 9-tetrahydrooxazolo [5',4':4,5] pyrido [1,2-a ] azan-11 (5H) -one.

2. Use of E5, E8, E9, E20, E26, E28, E32, E34, E38, E41, E42, E44, E45, E46, E47 and E48 in the tetrahydro-oxazolopyridinoazalone derivative according to claim 1 for the preparation of a medicament for the treatment of Hela cervical cancer.

3. Use of E26, E38, E42, E45, E46 and E47 in the tetrahydrooxazolopyridinoazepinone derivative according to claim 1 in the preparation of a medicament for treating MCF-7 breast cancer.

4. Use of E8, E9, E26 and E47 in the tetrahydro-oxazolopyridino-azedone derivative as claimed in claim 1 in preparation of a medicament for treating A549 lung cancer.

5. Use of E26 and E47 in the tetrahydrooxazolopyridino azepinone derivative as claimed in claim 1 in preparation of medicaments for treating Hela cervical cancer, MCF-7 breast cancer and A549 lung cancer.

6. Use of E8 and E9 in the tetrahydro-oxazolopyridino-azepinone derivative as defined in claim 1 in preparing medicaments for treating Hela cervical cancer and A549 lung cancer.

7. Use of E26, E38, E42, E45, E46 and E47 in the tetrahydro-oxazolopyridino-azoazedone derivative as claimed in claim 1 in the preparation of a medicament for treating Hela cervical cancer and MCF-7 breast cancer.