CN114805353A - Synthesis of azatryptanthrin derivative and application of azatryptanthrin derivative in prevention and treatment of plant pathogenic bacteria, fungi bactericide and anti-plant virus preparation - Google Patents

Synthesis of azatryptanthrin derivative and application of azatryptanthrin derivative in prevention and treatment of plant pathogenic bacteria, fungi bactericide and anti-plant virus preparation Download PDF

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CN114805353A
CN114805353A CN202210027403.XA CN202210027403A CN114805353A CN 114805353 A CN114805353 A CN 114805353A CN 202210027403 A CN202210027403 A CN 202210027403A CN 114805353 A CN114805353 A CN 114805353A
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azatryptanthrin
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欧阳贵平
张广龙
王贞超
龙雪莎
汪从雨
谭画元
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Guizhou University
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Abstract

The invention discloses a series of substituted azatryptanthrin derivatives, the application of the invented compounds as preparations for preventing and treating plant pathogenic bacteria, fungi, bactericides and plant virus resistance, the general formula of the derivatives is shown as (I), wherein the definition of each substituent is detailed in the specification. The compound shown in the general formula has higher bactericidal activity and plant virus resistance activity on plant pathogenic bacteria such as rice bacterial blight and fungi such as rice blast, and can be used for preparing agricultural specific bactericides and tobacco mosaic virus resistant preparations;
Figure DDA0003464689460000011

Description

Synthesis of azatryptanthrin derivative and application of azatryptanthrin derivative in prevention and treatment of plant pathogenic bacteria, fungi bactericide and anti-plant virus preparation
Technical Field
The invention relates to the technical field of pharmaceutical chemistry and pesticide application, in particular to application of azatryptanthrin serving as a plant pathogenic bacteria bacterium, a fungus bactericide and an anti-plant virus.
Background
The main diseases affecting the growth of crops are bacterial diseases, fungal diseases and plant virus diseases, the harm seriously affects the quality and safety of agricultural products, constitutes a global food safety problem, and causes global social problems due to unfavorable control. For example, rice bacterial blight (Xanthomonas oryzae pv. oryzae) is a worldwide important bacterial disease, and the pathogenic bacterium is Xanthomonas oryzae, which has a large influence on yield, can reduce yield by 20-30%, can reach 50-60% by weight, and even can not be harvested in granules. Magnaporthe oryzae (Magnaporthe oryzae) is a fungal disease, and the pathogenic bacteria is Magnaporthe oryzae, which is one of the most destructive rice diseases in the world, and causes destructive diseases, and is called rice cancer. Tobacco Mosaic Virus (TMV), an RNA virus widely spread in commercial crops such as tobacco and vegetables, has strong infectious capacity, and greatly affects the economic benefit of farmers. When the traditional pesticide is used for a long time, the effect is obviously reduced due to the generation of resistance, the stress on the environment is forced, and the high-toxicity and low-efficiency pesticide is gradually forbidden and eliminated. Therefore, the natural source compound is taken as a lead, and the important value and significance are achieved in creating a novel, efficient, low-toxicity and environment-friendly green pesticide.
According to the reports of the literature, Tryptanthrin (Tryptanthrin), a natural alkaloid, is widely present in natural blue-producing plants, such as India tinctoria, isatis tinctoria, Polygonum tinctorium and the like, and is found in natural indigo, isatis roots, microbial fermentation liquor and marine microorganisms of traditional Chinese medicine finished products. The parent structure of tryptanthrin is an indoloquinazolinone fused heterocyclic compound, has wide biological activity and mainly has the activities in the aspects of antitumor, anti-inflammatory, antibacterial, antiallergic, leishmania resisting, immunotherapy and the like. The azatryptanthrin is a tryptanthrin derivative which carries out structural modification on tryptanthrin and has stronger biological activity.
The research on the biological activity and the application of tryptanthrin and azatryptanthrin progresses as follows:
in 2009, Hwang et al [ Hwang, j.m., Oh, t.kaneko, a.t., Franzblau, s.g., Ma, z.k., Cho, s.n., & Kim, p.design, Synthesis, and Structure-Activity Relationship Studies of tryptanthrin As Antitubercular Agents [ J ] j.nat. prod.2013,76,354-367] synthesized a series of tryptanthrin derivatives As Antitubercular candidates using the natural tryptanthrin Structure As Antitubercular compounds, found that C-11 deoxy and a-ring saturated hydrocarbon derivatives retain higher Activity against mycobacterium tuberculosis, have better solubility than tryptanthrin, their oral bioavailability in animals, maximizing the potential to combat this class of compounds.
In 2013, Yang et al [ Yang, S.S, Li, X.S., Fangfang Hu, F.F., Li, Y.L., Yang, Y.Y., Yan, J.K., Kuang, C.X, & Yang, Q.discovery of Tryptan thin Derivatives as potential Inhibitors of indole 2, 3-dioxygenic with synergistic Activity in Lewis Luminescence Cancer (LLC) Tumor-Bearing Mice [ J ] J.Med.Chem.2013,56, 8321. supplement 8331] designed and synthesized 3 series of 13 tryptamine Derivatives, and found that the 8 fluoro substituted compound had significant Indoleamine 2,3 Dioxygenase (IDO-1) inhibitory Activity to achieve nanomolar levels and enhanced T cell proliferation. When the compound is injected into Lewis Lung Cancer (LLC) tumor-bearing mice, the activity of IDO-1 can be obviously inhibited, and the tumor growth can be inhibited.
In 2019, Yang et al [ Yang, D, Zhang, S.N., Fang, X, Guo, L.L., Hu, N, Guo, Z.L., Li, X.S., Yang, S.S., He, J.C., Kuang, C.X., & Yang, Q.N-Benzyl/Aryl stabilized tryptanthin as Dual Inhibitors of indolymine 2,3-Dioxygenase and Trypophan 2,3-Dioxygenase [ J ] J.Med.Chem.2019,62, 9161-one 9174] synthesized N Benzyl or Aryl Substituted tryptamine derivatives as indolenine 2, 3-bis (IDO-1) and Tryptophan 2,3 bis (TDO) bis Inhibitors. These 8 fluoro 2 (N-benzyl or aryl) substituted tryptanthrin derivatives are able to interact directly with IDO1, TDO, IDO2, significantly enhance T cell proliferation in vitro, block the T cell kynurenine pathway, and inhibit tumor growth in LLC and H22 tumor-bearing mice.
In 2020, Catanzaro et al [ Catanzaro, E., Betari, N., Arenciba, J.M., Montanari, S., Sissi, C., Simone, A.D., Vassura, I., Santini, A., Andrisano, V., Tumiatti, V., Vivo, M.D., Krysko, D.V., Rocchi, M.B., Fimogari, C., Milelli, A.targeting topoisomere II with tryptanthrin derivatives: Discovery of7- ((2- (dimethyllano) ethyl) amino) indolo [2,1-b ] 2]quinazoline-6,12-dione as an antiproliferative agent and to treat cancer.[J]Eur.J.Med.Chem.2020,202,112504-112513.]The inhibitory activity of the N, N-dimethylethylamine substituted tryptanthrin derivative on the target human topoisomerase II (topoII) is researched, and the compound is found to have stronger inhibitory activity and IC 50 26.6 +/-4.7 mM, is more effective than a widely used clinical drug etoposide targeting topoII, has higher water solubility, has good antiproliferative activity on different tumor cell lines such as acute leukemia, colon cancer and breast cancer, and provides a promising lead for developing a new topoII inhibitor as an anticancer therapeutic drug.
In 2020, Hao et al, [ Hao, Y.N., Guo, J.C., Wang, Z.W., Liu, Y.X., Li, Y.Q., Ma, D.J., & Wang, Q.M.discovery of tryptanthins as Novel antibiotics and Anti-Phytopathogenic-fungi Agents. [ J ] J.Agric.food Chem.2020,68,5586-5595] were designed, synthesized and evaluated for Antiviral and fungicidal activity. The tryptanthrin has good antiviral activity on Tobacco Mosaic Virus (TMV) for the first time, the anti-TMV activity of most compounds is higher than that of ribavirin, and the further antiviral mechanism research on the C-11 deoxytryptanthrin compound shows that the tryptanthrin inhibits virus assembly by decomposing a 20S Coat Protein (CP) disc and has good antiviral activity as a novel antiviral lead compound.
In 2020, Tsai et al [ Tsai, Y.C., Lee, C.L., Yen, H.R., Chang, Y.S., Lin, Y.P., Su-Hua Huang, S.H.,&Lin,C.W.Antiviral Action of Tryptanthrin Isolated from Strobilanthes cusia Leaf against Human Coronavirus NL63.[J]Biomolecules 2020,10,366-383]methanol extract of semen Cuscutae cotyledon and its main ingredient human coronavirus NL63 (HC)oV-NL63), it was found that out of the 6 identified components, tryptanthrin showed strong antiviral activity, reduced CPE and progeny virus production, IC for virus yield 50 The values were 1.52. mu.M each, and their effect on HCoV-NL63 was independent of cell type. The results indicate that tryptanthrin has the potential to be resistant to HCoV-NL63 infection.
Disclosure of Invention
The inventor surprisingly found that various substituted azatryptanthrin derivatives have remarkable inhibitory activity on the action of plant pathogenic bacteria, fungi and plant viruses.
The invention aims to provide application of various substituted azatryptanthrin derivatives as inhibitors of phytopathogen bacteria and fungi and anti-plant virus preparations.
The second purpose of the invention is to provide novel azatryptanthrin derivatives with five different positions.
The third purpose of the invention is to provide a one-pot method for preparing the novel azatryptanthrin derivatives with the five different positions.
The fourth purpose of the invention is to provide a method for controlling agricultural pests by using the composition.
A fifth object of the present invention is to provide a pharmaceutical composition comprising the above five different positions of the novel azatryptanthrin derivative.
In order to achieve the purpose, the invention adopts the following technical scheme:
the azatryptanthrin derivative has a structure shown as (I), and is used for preparing medicaments for preventing and treating plant pathogenic bacteria, fungi and plant viruses;
wherein A, B, C and D are respectively and independently selected from a pyridine unit ring formed by one N atom or two pyrimidine, pyrazine and pyridazine structural unit rings formed by combining N atoms;
R 1 ,R 2 ,R 3 ,R 4 each independently selected from hydrogen, nitro, C1-C4 alkoxy, C1-C4 alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, hydroxyl, cyano, carboxyl, methylsulfonyl, sulfoAn acid group, or a disubstituted, trisubstituted, tetrasubstituted derivative of any combination of the foregoing substituents;
Figure BDA0003464689440000031
wherein A is N and B-D is carbon.
Wherein B is N, A, C and D is carbon.
Wherein C is N, A, B and D is carbon.
Wherein D is N and A-C are carbon.
Wherein A and D are both N, and B and C are carbon.
Wherein B and D are both N, and A and C are carbon.
Wherein C and D are both N, and A and B are carbon.
The plant pathogenic bacteria comprise rice bacterial blight, citrus canker, kiwi canker, tobacco bacterial wilt, tomato canker, apple canker, grape canker, peach perforative pantoea and bacillus subtilis; the plant pathogenic fungi comprise rice sheath blight bacteria, cacao trichoderma of kiwifruit soft rot, grape seat cavity bacteria, pepper colletotrichum, rice blast bacteria, radix pseudostellariae root rot-fusarium oxysporum, colza bacteria, wheat gibberellic disease, eggplant verticillium wilt, pepper wilt and potato late blight; plant viruses include tobacco mosaic virus, cucumber mosaic virus and potato virus Y.
A pharmaceutical composition containing the derivative, and also comprises an auxiliary agent.
In the embodiment of the invention, the azatryptanthrin derivative provided by the invention is used as an inhibitor of phytopathogen bacteria and fungi and an anti-plant virus preparation, wherein the C1-C4 alkoxy refers to a compound selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or tert-butoxy; the C1-C4 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. The C1-C4 alkane refers to that hydrogen at any position on a carbon chain is replaced by halogen, hydroxyl and amino.
In one embodiment of the invention, the azatryptanthrin derivative provided by the invention is used as an inhibitor of phytopathogen bacteria and fungi and an anti-plant virus preparation, and is shown as a general formula (I), wherein halogen refers to fluorine, chlorine, bromine or iodine.
In one embodiment of the invention, the azatryptanthrin derivative provided by the invention is used as an inhibitor of phytopathogen bacteria and fungi and an anti-plant virus preparation, and is shown as a general formula (I), wherein A is N, and R is 1 ,R 2 ,R 3 ,R 4 Are respectively and independently selected from hydrogen, nitryl, C1-C4 alkoxy, C1-C4 alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, hydroxyl, cyano, carboxyl, methylsulfonyl, sulfonic group, or disubstituted, trisubstituted and tetrasubstituted derivatives of any combination of the substituent groups.
In one embodiment of the invention, the azatryptanthrin derivative provided by the invention is used as an inhibitor of phytopathogen bacteria and fungi and an anti-plant virus preparation, and is shown as a general formula (I), wherein B is N, and R is 1 ,R 2 ,R 3 ,R 4 Are respectively and independently selected from hydrogen, nitryl, C1-C4 alkoxy, C1-C4 alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, hydroxyl, cyano, carboxyl, methylsulfonyl and sulfonic acid, or a disubstituted, trisubstituted and tetrasubstituted derivative of any combination of the substituent groups.
In one embodiment of the invention, the azatryptanthrin derivative provided by the invention is used as an inhibitor of phytopathogen bacteria and fungi and an anti-plant virus preparation, and is shown as a general formula (I), wherein C is N, and R is 1 ,R 2 ,R 3 ,R 4 Are respectively and independently selected from hydrogen, nitryl, C1-C4 alkoxy, C1-C4 alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, hydroxyl, cyano, carboxyl, methylsulfonyl and sulfonic acid, or a disubstituted, trisubstituted and tetrasubstituted derivative of any combination of the substituent groups.
In one embodiment of the invention, the inventionThe azatryptanthrin derivative is used as an inhibitor of phytopathogen bacteria and fungi and an anti-plant virus preparation, and is shown as a general formula (I), wherein D is N, and R is 1 ,R 2 ,R 3 ,R 4 Are respectively and independently selected from hydrogen, nitryl, C1-C4 alkoxy, C1-C4 alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, hydroxyl, cyano, carboxyl, methylsulfonyl, sulfonic group, or disubstituted, trisubstituted and tetrasubstituted derivatives of any combination of the substituent groups.
In one embodiment of the invention, the azatryptanthrin derivative provided by the invention is used as an inhibitor of phytopathogen bacteria and fungi and an anti-plant virus preparation, and is shown as a general formula (I), wherein A and D are N, and R is 1 ,R 2 ,R 3 ,R 4 Are respectively and independently selected from hydrogen, nitryl, C1-C4 alkoxy, C1-C4 alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, hydroxyl, cyano, carboxyl, methylsulfonyl, sulfonic group, or disubstituted, trisubstituted and tetrasubstituted derivatives of any combination of the substituent groups.
In a particularly preferred embodiment of the invention, the invention provides the use of a compound of formula (I) as defined above, selected from the following compounds:
pyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
9-Fluoropyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
9-chloropyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
9-bromopyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
9-iodopyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
9-methylpyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one
9-methoxypyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
9-trifluoromethoxy-pyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
9-Nitropyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
10-chloropyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
10-bromopyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
7-chloropyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
7-fluoropyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
9, 10-Difluoropyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
8, 9-Difluoropyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
Pyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
9-Fluoropyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
9-chloropyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
9-bromopyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
9-methylpyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one
9-methoxypyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
9-trifluoromethoxy-pyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
9-Nitropyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
10-chloropyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
10-bromopyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
8-fluoropyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
9, 10-Difluoropyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
8, 9-Difluoropyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
Pyrido [4 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
8-fluoropyrido [4 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
8-chloropyrido [4 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
8-bromopyrido [4 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
8-methylpyrido [4 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one
Pyrido [3 ', 2': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
8-fluoropyrido [3 ', 2': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
8-Methoxypyrido [3 ', 2': 4,5] pyrimido [1,2-a ] indol-5 (11H) -ones
Indole [2,1-b ] pteridine-6, 12-ketone
8-fluoroindole [2,1-b ] pteridine-6, 12-one
8-chloroindole [2,1-b ] pteridine-6, 12-ketone
The invention provides a method for preparing an azatryptanthrin derivative shown as a general formula (I), which comprises the following steps:
the compound of formula (5), obtained by the conventional Sandmeyer process, is further reacted with the compound of formula (6) in one pot to give the compound of formula (I).
Figure BDA0003464689440000051
Figure BDA0003464689440000061
Here, the substituents A, B, C, D and R referred to in the compounds of the formulae (6) and (5) 1 ，R 2 ，R 3 ，R 4 Are as defined above for the compounds of formula (I).
The invention provides a method for preparing an intermediate (5) and an azatryptanthrin derivative shown as a general formula (I), and the method specifically refers to the following method:
adding 220mL of distilled water into a 500mL round-bottom three-neck flask in advance, heating to 50 ℃, adding anhydrous sodium sulfate (0.1mol), stirring until the anhydrous sodium sulfate is completely dissolved, dropwise adding a corresponding aniline solution (0.1mol) which is completely dissolved in 5% dilute hydrochloric acid into a reaction system, then continuously dropwise adding hydroxylamine hydrochloride aqueous solution (0.3mol), refluxing for 5 hours, monitoring by TLC, cooling after the reaction is complete, carrying out vacuum filtration and drying to obtain the intermediate compound shown in the formula (5).
Adding azaanthranilic acid (0.01mol) shown in the formula (6) into dried dichloromethane, adding thionyl chloride (0.05ml) into the dichloromethane, refluxing for 3 hours, drying the solvent in a spinning mode, rapidly supplementing trichloromethane, adding an intermediate compound shown in the formula (5) (0.01mol) obtained by the reaction into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2 hours, monitoring by TLC (thin layer chromatography), drying the solvent in a spinning mode after the reaction is completed, and performing column chromatography separation (dichloromethane/methanol is 40:1 for elution) to obtain a pure compound.
The invention has the beneficial effects that: by adopting the technical scheme, the invention synthesizes five series of azatryptanthrin derivatives by introducing nitrogen heteroatom into a mother ring structure skeleton of tryptanthrin based on the main medicinal component tryptanthrin of Chinese traditional Chinese herbal medicine 'isatis root', and emphatically finds that the series of compounds have good inhibition effects on plant pathogenic bacteria, fungi and plant viruses [ for example, on Xanthomonas oryzae pv. oryzae, Xanthomonas citri, Actinidia kiwisi, Fusomomonas syzygium oryzae pv. actandiae, Psa), Magnaporthe oryzae and Tobacco Mosaic Virus (TMV) and the like ], thereby providing important theoretical basis and scientific basis for successfully creating a novel green and efficient pesticide for the alkaloid compounds.
Drawings
FIG. 1 shows the inhibitory activity of 4A-1 azatryptanthrin derivative against the blast disease of plant viruses.
Detailed Description
The following examples are provided to illustrate embodiments of the present invention, and modifications of the embodiments of the present invention by those skilled in the art in light of the present disclosure and reference to the accompanying drawings may be made without departing from the scope of the present invention.
Thionyl chloride, dichloromethane, methanol, aniline compounds, concentrated sulfuric acid and the like used in the experimental process are all commercially available analytical or chemical pure reagents, and part of the reagents are dried or steamed according to a literature method.
Melting Point measurement X-4 type digital display microscopy melting point apparatus (Shanghai micrometric photoelectric technology, Ltd.), Bruker Ascend-400spectrometer, JEOL ECX-500 Nuclear magnetic resonance (TMS is an internal standard, Germany), high resolution Mass spectrometer (HRMS, Sammer Feishell technology, Ltd.).
EXAMPLE 1 Compound 4A-1 (pyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 2-aminonicotinic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, carrying out spin-drying on the solvent, rapidly supplementing trichloromethane, adding isatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC, carrying out spin-drying on the solvent after the reaction is completed, and carrying out column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 4A-1.
Figure BDA0003464689440000071
Orange solid, yield 65%. M.P. >300 ℃,1H NMR (500MHz, DMSO-d6) δ 9.04(dd, J ═ 4.6,2.2Hz,1H),8.67(dd, J ═ 7.8,2.0Hz,1H),8.41(d, J ═ 8.0Hz,1H),7.88(d, J ═ 7.4Hz,2H),7.71(dd, J ═ 7.8,4.6Hz,1H),7.47(t, J ═ 7.4Hz,1H).
13C NMR(101MHz,DMSO)δ182.76,158.58,157.70,156.58,148.08,146.21,138.42,136.79,127.75,125.41,125.20,122.63,119.69,117.40..
C14H7N3O2[M+H]+,250.0611；found,250.0610.
EXAMPLE 2 Compound 4A-2 (9-Fluoropyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 2-aminonicotinic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, carrying out spin-drying on the solvent, quickly supplementing trichloromethane, adding 5-fluoroisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, carrying out TLC monitoring, carrying out spin-drying on the solvent after the reaction is completed, and carrying out column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 4A-2.
Figure BDA0003464689440000072
Yellow solid, yield 62%. M.P. >300 ℃,1H NMR (400MHz, DMSO) δ 9.09(dd, J ═ 4.6,2.0Hz,1H),8.72(dd, J ═ 7.9,2.0Hz,1H),8.47(dd, J ═ 8.8,4.2Hz,1H),7.86(dd, J ═ 7.1,2.7Hz,1H),7.76(ddd, J ═ 11.8,6.6,2.9, 2H).
13C NMR(101MHz,DMSO)δ181.95,159.70,158.42,157.59,156.75,148.38,142.51,136.85,125.34,124.68,124.44,119.60,119.23,112.51.C14H6FN3O2[M+H] + ,268.0517；found,268.0514.
EXAMPLE 3 Compound 4A-3 (10-bromopyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 2-aminonicotinic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, quickly supplementing trichloromethane, adding 4-bromoisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), drying the solvent in a spinning mode after the reaction is completed, and performing column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain a target compound 4A-3.
Figure BDA0003464689440000081
Yellow solid, yield 55%. M.P. >300 ℃,1H NMR (400MHz, DMSO) δ 9.10(dd, J ═ 4.6,2.0Hz,1H),8.73(dd, J ═ 7.9,2.0Hz,1H),8.50(dd, J ═ 7.8,0.9Hz,1H),7.78(ddd,6.3,4.7,3.2,2H),7.72(dd, J ═ 8.1,0.9Hz,1H).
13C NMR(101MHz,DMSO)δ180.39,158.48,157.61,156.84,147.79,147.67,138.99,136.96,132.01,125.29,121.12,120.31,119.48,116.48.
C14H6BrN3O2[M+H] + ,327.9716；found,327.9715
EXAMPLE 4 Compound 4A-4 (9-Nitropyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 2-aminonicotinic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, quickly supplementing trichloromethane, adding 5-nitroisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), drying the solvent in a spinning mode after the reaction is completed, and performing column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain a target compound 4A-4.
Figure BDA0003464689440000082
Yellow green solid, yield 41%. m.p.286-288 ℃,1H NMR (500MHz, DMSO) δ 9.07(dd, J ═ 4.6Hz,2.0Hz,1H),8.70(m,2H),8.61(d, J ═ 8.8Hz,1H),8.56(d, J ═ 2.4Hz,1H),7.75(dd, J ═ 8.0,4.6Hz,1H).
13C NMR NMR(126MHz,DMSO-D6)δ181.17,158.79,157.41,157.17,149.33,148.37,146.44,137.17,133.33,125.70,123.59,120.26,119.38,118.14
C14H6BrN3O2[M+H] + ,295.0462；found,295.0459
EXAMPLE 5 Compound 4A-5 (9-methylpyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 2-aminonicotinic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, carrying out spin-drying on the solvent, quickly supplementing trichloromethane, adding 5-methyl isatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, carrying out TLC monitoring, carrying out spin-drying on the solvent after the reaction is completed, and carrying out column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 4A-5.
Figure BDA0003464689440000083
Yellow solid, yield 57%. M.P. >300 ℃,1H NMR (400MHz, Chloroform-d) δ 9.11(s,1H),8.78(d, J ═ 7.9Hz,1H),8.48(d, J ═ 8.1Hz,1H),7.75(s,1H), 7.69-7.50 (m,2H),2.50(s,3H).
13C NMR(101MHz,CDCl3)δ181.80,156.41,151.52,147.60,147.14,140.57,139.00,138.15,136.60,125.84,124.64,117.61,21.14.
C15H9N3O2[M+H] + ,267.0768；found,267.0766
EXAMPLE 6 Compound 4A-6 (9-methoxypyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 2-aminonicotinic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, quickly supplementing trichloromethane, adding 5-methoxyisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), drying the solvent in a spinning mode after the reaction is completed, and performing column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 4A-6.
Figure BDA0003464689440000091
Red solid, yield 52%. m.p.289-290 ℃,1H NMR (400MHz, Chloroform-d) δ 9.10(dd, J ═ 4.6,2.0Hz,1H),8.76(dd, J ═ 8.0,2.0Hz,1H),8.50(d, J ═ 8.8Hz,1H),7.62(dd, J ═ 7.9,4.6Hz,1H),7.41(d, J ═ 2.7Hz,1H),7.33(dd, J ═ 8.8,2.8Hz,1H),3.93(s,3H).
13C NMR(101MHz,CDCl3)δ181.72,159.13,157.81,157.47,156.33,147.26,139.85,136.53,124.98,124.67,122.95,119.83,119.05,108.78,56.07
C15H9N3O3[M+H] + ,280.0717；found,280.0713
EXAMPLE 7 Compound 4A-7(9, 10-difluoropyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 2-aminonicotinic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, quickly supplementing trichloromethane, adding 4, 5-difluoroisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), and performing column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) until the reaction is complete to obtain a target compound 4A-7.
Figure BDA0003464689440000092
Yellow solid, yield 37%. m.p.236-238 ℃,1H NMR (500MHz, DMSO-d6) δ 9.06(dd, J ═ 4.6,1.7Hz,1H),8.68(dd, J ═ 7.8,2.0Hz,1H),8.38(dd, J ═ 10.3,6.3Hz,1H),8.16(t, J ═ 8.3Hz,1H),7.74(dd, J ═ 8.0,4.6Hz,1H).
13C NMR(126MHz,DMSO-D6)δ180.79,158.39,157.60,156.95,148.00,143.09,142.98,136.96,125.54,125.54,119.46,115.18,115.01,107.70,107.51.
C14H5F2N3O2[M+H] + ,286.0423；found,286.0420
EXAMPLE 8 Compound 4A-8(8, 9-difluoropyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 2-aminonicotinic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, quickly supplementing trichloromethane, adding 5, 6-difluoroisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), and performing column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) until the reaction is complete to obtain a target compound 4A-8.
Figure BDA0003464689440000101
Orange solid, yield 55%. m.p.236-238 ℃,1H NMR (500MHz, DMSO-d6) δ 9.06(dd, J ═ 4.6,2.0Hz,1H),8.68(dd, J ═ 7.9,2.0Hz,1H),8.38(dd, J ═ 10.3,6.4Hz,1H),8.16(dd, J ═ 8.8,7.8Hz,1H),7.74(dd, J ═ 7.9,4.6Hz,1H).
13C NMR(126MHz,DMSO-D6)δ180.79,158.39,157.59,156.96,148.00,142.98,136.95,125.55,119.66,119.46,115.18,115.02,107.70,107.51.
C14H5F2N3O2[M+H]+,286.0423；found,286.0419
EXAMPLE 9 Compound 4A-9 (9-Chloropyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 2-aminonicotinic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, quickly supplementing trichloromethane, adding 5-chloroisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), drying the solvent in a spinning mode after the reaction is completed, and performing column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 4A-9.
Figure BDA0003464689440000102
Yellow solid, yield 63%. M.P. >300 ℃,1H NMR (500MHz, DMSO-d6) δ 9.05(dd, J ═ 4.6Hz,2.0Hz,1H),8.68(dd, J ═ 7.9,2.0Hz,1H),8.41(d, J ═ 8.6Hz,1H),7.98(s,1H),7.91(dd, J ═ 8.6,2.3Hz,1H),7.73(dd, J ═ 7.9,4.6Hz,1H).
13C NMR(101MHz,DMSO)δ181.61,158.46,157.61,156.75,147.98,144.63,137.49,136.85,132.08,125.36,124.99,124.37,119.55,118.98.
C14H6ClN3O2[M+H]+,284.0221；found,284.0219
EXAMPLE 10 Compound 4A-10 (9-bromopyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 2-aminonicotinic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a rotary manner, rapidly supplementing trichloromethane, adding 5-bromoisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), drying the solvent in a rotary manner after the reaction is completed, and performing column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 4A-10.
Figure BDA0003464689440000111
Yellow solid, yield 57%. M.P. >300 ℃,1H NMR (500MHz, DMSO-d6) δ 9.05(dd, J ═ 4.6,2.0Hz,1H),8.68(dd, J ═ 7.9,2.0Hz,1H),8.34(d, J ═ 8.5Hz,1H),8.08(d, J ═ 2.1Hz,1H),8.03(dd, J ═ 8.5,2.1Hz,1H),7.72(dd, J ═ 7.9,4.6Hz,1H).
13C NMR(126MHz,DMSO-D6)δ181.60,158.55,156.86,149.08,145.05,140.43,136.95,135.35,127.89,125.44,124.72,119.58,119.35,112.32.
C14H6BrN3O2[M+H]+,327.9716；found,327.9714
EXAMPLE 11 Compound 4A-11 (10-chloropyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 2-aminonicotinic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, quickly supplementing trichloromethane, adding 4-chloroisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), drying the solvent in a spinning mode after the reaction is completed, and performing column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 4A-11.
Figure BDA0003464689440000112
Yellow solid, yield 68%. M.P. >300 ℃,1H NMR (400MHz, DMSO-d6) δ 9.10(dd, J ═ 4.6,2.0Hz,1H),8.73(dd, J ═ 7.9,2.0Hz,1H),8.46(dd, J ═ 8.1,0.7Hz,1H),7.88(t, J ═ 8.1Hz,1H),7.77(dd, J ═ 7.9,4.6Hz,1H),7.56(dd, J ═ 8.2,0.8Hz,1H).
13C NMR(101MHz,DMSO)δ179.86,158.54,157.59,156.84,147.65,147.36,139.10,136.95,132.06,128.85,125.31,119.60,119.44,116.08.
C14H6ClN3O2[M+H]+,284.0221；found,284.0219
EXAMPLE 12 Compound 4A-12 (7-Fluoropyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 2-aminonicotinic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, carrying out spin-drying on the solvent, quickly supplementing trichloromethane, adding 7-fluoroisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, carrying out TLC monitoring, carrying out spin-drying on the solvent after the reaction is completed, and carrying out column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 4A-12.
Figure BDA0003464689440000121
Yellow solid, yield 34%. M.P. >300 ℃,1H NMR (500MHz, DMSO-d6) δ 9.03(dd, J ═ 4.6,1.8Hz,1H),8.66(dd, J ═ 7.8,1.9Hz,1H),7.75(m,2H),7.71(dd, J ═ 8.0,4.6Hz,1H),7.52(ddt, J ═ 11.8,7.5,3.7Hz,1H).
13C NMR(101MHz,DMSO)δ182.22,157.41,156.64,150.90,148.18,137.24,129.87,129.81,127.35,127.12,126.44,125.34,121.65,119.74
C14H6FN3O2[M+H]+,268.0517；found,268.0514
EXAMPLE 13 Compound 4A-13 (9-trifluoromethoxy-pyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 2-aminonicotinic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, quickly supplementing trichloromethane, adding 5-trifluoromethoxy isatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), and performing column chromatography separation (dichloromethane/methanol is 40:1 for elution) until the reaction is complete to obtain a target compound 4A-13.
Figure BDA0003464689440000122
Yellow solid, yield 34%. m.p.232-234 ℃,1H NMR (400MHz, DMSO-d6) δ 9.10(dd, J ═ 4.6,2.0Hz,1H),8.73(dd, J ═ 7.9,2.0Hz,1H),8.55(d, J ═ 8.7Hz,1H),7.99(d, J ═ 2.6Hz,1H),7.93(dd, J ═ 8.9,2.6Hz,1H),7.78(dd, J ═ 7.9,4.6Hz,1H).
13C NMR(101MHz,DMSO)δ181.59,158.50,156.86,154.45,148.26,144.64,140.12,136.92,130.71,125.41,124.42,119.48,119.07,118.41.
EXAMPLE 14 Compound 4A-14 (9-iodopyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 2-aminonicotinic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, carrying out spin-drying on the solvent, quickly supplementing trichloromethane, adding 5-iodoisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, carrying out TLC monitoring, carrying out spin-drying on the solvent after the reaction is completed, and carrying out column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 4A-14.
Figure BDA0003464689440000131
Yellow solid, yield 44%. M.P. >300 ℃,1H NMR (400MHz, Chloroform-d) δ 9.13(dd, J ═ 4.6,2.0Hz,1H),8.78(dd, J ═ 7.9,2.0Hz,1H),8.40(d, J ═ 8.4Hz,1H),8.26(d, J ═ 1.8Hz,1H),8.13(dd, J ═ 8.4,1.9Hz,1H),7.65(dd, J ═ 7.9,4.5Hz,1H).
13C NMR(101MHz,CDCl3)δ180.18,158.02,156.59,146.60,145.98,145.06,136.66,134.27,132.51,130.83,128.80,124.87,123.45,119.57.
EXAMPLE 15 Compound 4A-15(8, 10-Chloropyrido [2 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 2-aminonicotinic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, quickly supplementing trichloromethane, adding 4, 6-dichloroisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), and performing column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) until the reaction is complete to obtain the target compound 4A-15.
Figure BDA0003464689440000132
Yellow solid, yield 67%. M.P. >300 ℃,1H NMR (400MHz, Chloroform-d) δ 9.15(dd, J ═ 4.8,1.9Hz,1H),8.79(dd, J ═ 7.9,2.0Hz,1H), 8.31-8.14 (m,1H),7.67(dd, J ═ 7.9,4.6Hz,1H),6.88(td, J ═ 8.8,2.0Hz,1H).
EXAMPLE 16 Compound 3A-1 (pyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 3-amino-4-pyridine carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, rapidly supplementing trichloromethane, adding isatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC, performing column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) until the reaction is complete, and obtaining the target compound 3A-1.
Figure BDA0003464689440000133
Yellow solid, yield 47%. M.P. >300 ℃,1H NMR (400MHz, DMSO-d6) δ 9.31(d, J ═ 0.8Hz,1H),8.89(d, J ═ 5.1Hz,1H),8.49(d, J ═ 8.0Hz,1H),8.19(dd, J ═ 5.1,0.8Hz,1H), 7.96-7.89 (m,2H),7.53(td, J ═ 7.5,0.9Hz,1H).
13C NMR(101MHz,DMSO)δ182.39,157.31,152.76,149.87,147.08,146.16,141.69,138.47,129.38,127.90,125.44,122.74,119.72,117.67
C14H7N3O2[M+H]+,250.0611；found,250.0609
EXAMPLE 17 Compound 3A-2 (9-Fluoropyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 3-amino-4-pyridine carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, quickly supplementing trichloromethane, adding 5-fluoroisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), and separating by column chromatography (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 3A-1.
Figure BDA0003464689440000141
Yellow solid, yield 45%. M.P. >300 ℃,1H NMR (500MHz, DMSO-d6) δ 9.27(s,1H),8.86(d, J ═ 5.1Hz,1H),8.46(dd, J ═ 8.8,4.3Hz,1H),8.16(d, J ═ 5.1Hz,1H),7.82(dd, J ═ 7.2,2.8Hz,1H),7.73(td, J ═ 8.9,2.7, 1H).
13C NMR(101MHz,DMSO)δ181.50,157.12,152.78,150.00,147.27,142.47,141.56,129.27,124.78,124.54,119.71,119.55,112.48,112.24.
C14H6FN3O2[M+H]+,268.0517；found,268.0514
EXAMPLE 18 Compound 3A-3 (9-Chloropyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 3-amino-4-pyridine carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, quickly supplementing trichloromethane, adding 5-chloroisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), and separating by column chromatography (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 3A-3.
Figure BDA0003464689440000142
Yellow solid, yield 42%. M.P. >300 ℃,1H NMR (400MHz, DMSO-d6) δ 9.50(s,1H),9.03(d, J ═ 5.6Hz,1H),8.46(d, J ═ 8.6Hz,1H),8.03(s,1H), 8.01-7.86 (m,2H).
13C NMR(101MHz,DMSO)δ181.20,157.19,152.79,150.07,146.93,144.55,141.54,137.55,132.25,129.17,125.03,124.45,119.74,119.24.
C14H6ClN3O2[M+H]+,284.0221；found,284.0219
EXAMPLE 19 Compound 3A-4 (9-bromopyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 3-amino-4-pyridine carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, quickly supplementing trichloromethane, adding 5-bromoisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), and separating by column chromatography (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 3A-4.
Figure BDA0003464689440000151
Yellow solid, yield 34%. M.P. >300 ℃,1H NMR (500MHz, DMSO-d6) δ 9.28(s,1H),8.86(d, J ═ 5.1Hz,1H),8.37(d, J ═ 8.5Hz,1H),8.16(d, J ═ 5.2Hz,1H),8.10(d, J ═ 2.2Hz,1H),8.05(dd, J ═ 8.4,1.9Hz,1H).
13C NMR(101MHz,DMSO)δ181.13,157.18,152.78,150.08,146.96,144.93,141.81,140.43,129.17,127.84,124.71,120.19,119.75,119.54.
C14H6BrN3O2[M+H]+,327.9716；found,327.9715
EXAMPLE 20 Compound 3A-5 (10-chloropyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 3-amino-4-pyridine carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, quickly supplementing trichloromethane, adding 4-chloroisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), and separating by column chromatography (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 3A-5.
Figure BDA0003464689440000152
Yellow solid, yield 35%. M.P. > 270-.
13C NMR(101MHz,DMSO)δ179.42,157.24,152.72,149.95,147.31,146.51,141.51,139.12,132.13,129.12,128.98,119.74,119.63,116.34.
C14H6ClN3O2[M+H]+,284.0221；found,284.0220
EXAMPLE 21 Compound 3A-6 (10-bromopyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 3-amino-4-pyridine carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, quickly supplementing trichloromethane, adding 4-bromoisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), and separating by column chromatography (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 3A-6.
Figure BDA0003464689440000161
Yellow solid, yield 40%. M.P. >269-271 ℃,1H NMR (400MHz, DMSO-d6) δ 9.33(d, J ═ 0.8Hz,1H),8.90(d, J ═ 5.1Hz,1H),8.53(dd, J ═ 7.8,1.0Hz,1H),8.20(dd, J ═ 5.1,0.8Hz,1H), 7.84-7.72 (m,2H).
13C NMR(101MHz,DMSO)δ179.96,157.18,152.75,149.93,147.73,141.53,139.01,132.14,129.13,121.15,120.33,119.76,116.74.
C14H6BrN3O2[M+H]+,327.9716；found,327.9716
EXAMPLE 22 Compound 3A-7 (9-Nitropyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 3-amino-4-pyridine carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, rapidly supplementing trichloromethane, adding 5-nitroisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), and separating by column chromatography (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 3A-7.
Figure BDA0003464689440000162
Yellow solid, yield 33%. m.p.295-296 ℃,1H NMR (500MHz, DMSO-d6) δ 9.32(s,1H),8.90(d, J ═ 5.3Hz,1H),8.72(dd, J ═ 8.7,2.4Hz,1H),8.65(d, J ═ 8.9Hz,1H),8.57(d, J ═ 2.4Hz,1H),8.20(d, J ═ 5.2Hz,1H).
13C NMR(101MHz,DMSO)δ180.70,157.53,152.83,150.43,149.21,147.17,146.50,141.20,133.26,128.98,123.59,120.21,119.89,118.38.
C14H6N4O4[M+H]+,295.0462；found,295.0460
EXAMPLE 23 Compound 3A-8 (7-Fluoropyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 3-amino-4-pyridine carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, quickly supplementing trichloromethane, adding 7-fluoroisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), and performing column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 3A-8.
Figure BDA0003464689440000171
Yellow solid, yield 23%. M.P. >300 ℃,1H NMR (500MHz, DMSO-d6) δ 9.25(s,1H),8.85(d, J ═ 5.1Hz,1H),8.14(d, J ═ 5.1Hz,1H),7.77(dd, J ═ 11.8,7.9Hz,2H),7.53(td, J ═ 7.7,3.6Hz,1H).
13C NMR(101MHz,DMSO)δ181.80,155.28,152.38,150.11,147.13,141.30,130.03,129.96,127.36,127.13,126.52,121.64,121.61,120.09.
C14H6FN3O2[M+H]+,268.0517；found,268.0514
EXAMPLE 24 Compound 3A-9 (9-methoxypyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 3-amino-4-pyridine carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, quickly supplementing trichloromethane, adding 5-methoxyisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), and separating by column chromatography (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 3A-9.
Figure BDA0003464689440000172
Red solid, yield 27%. m.p.269-271 ℃,1H NMR (400MHz, DMSO-d6) δ 9.29(s,1H),8.87(d, J ═ 5.1Hz,1H),8.38(d, J ═ 9.6Hz,1H),8.17(d, J ═ 5.1Hz,1H),7.46(dd, J ═ 6.4,2.8Hz,2H),3.89(s,3H).
13C NMR(101MHz,DMSO-d6)δ182.29,158.81,156.84,152.74,149.80,147.50,141.70,140.05,129.45,124.39,123.95,119.63,118.92,109.19,55.40.
C15H9N3O3[M+H]+,280.0717；found,280.0715
EXAMPLE 25 Compound 3A-10 (9-methylpyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 3-amino-4-pyridine carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, quickly supplementing trichloromethane, adding 5-methyl isatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), and separating by column chromatography (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 3A-10.
Figure BDA0003464689440000173
Yellow solid, yield 39%. m.p.292-294 ℃,1H NMR (500MHz, Chloroform-d) δ 9.38(s,1H),8.87(d, J ═ 5.1Hz,1H),8.45(d, J ═ 8.2Hz,1H),8.19(d, J ═ 5.1Hz,1H),7.72(s,1H),7.60(m,1H),2.46(s,3H).
13C NMR(126MHz,CHLOROFORM-D)δ181.86,156.73,153.45,150.00,146.03,143.92,141.32,139.25,138.41,129.27,125.97,122.10,119.50,117.94,21.24..
C15H9N3O2[M+H]+,267.0768；found,267.0766
EXAMPLE 26 Compound 3A-11(8, 9-difluoropyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 3-amino-4-pyridine carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, rapidly supplementing trichloromethane, adding 5, 6-difluoroisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), drying the solvent in a spinning mode after the reaction is completed, and performing column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 3A-11.
Figure BDA0003464689440000181
Yellow solid, yield 25%. m.p.292-294 ℃,1H NMR (400MHz, DMSO-d6) δ 9.32(s,1H),8.92(d, J ═ 5.1Hz,1H),8.45(dd, J ═ 10.3,6.5Hz,1H),8.21(t, J ═ 6.1Hz,2H).
C14H5F2N3O2[M+H]+,286.0423；found,286.0421
EXAMPLE 27 Compound 3A-12(9, 10-difluoropyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 3-amino-4-pyridine carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, rapidly supplementing trichloromethane, adding 4, 5-difluoroisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), drying the solvent in a spinning mode after the reaction is completed, and performing column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 3A-12.
Figure BDA0003464689440000182
Yellow solid, yield 23%. m.p.242-244 ℃, 11H NMR (500MHz, DMSO-d6) δ 9.28(s,1H),8.88(d, J ═ 5.1Hz,1H),8.41(dd, J ═ 10.3,6.3Hz,1H),8.17(m,2H).
C14H5F2N3O2[M+H]+,286.0423；found,286.0424
EXAMPLE 28 Compound 3A-13 (9-trifluoromethoxy-pyrido [3 ', 4': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 3-amino-4-pyridine carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, quickly supplementing trichloromethane, adding 5-trifluoromethoxy isatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), drying the solvent in a spinning mode after the reaction is completed, and performing column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 3A-13.
Figure BDA0003464689440000191
Yellow solid, yield 26%. M.P. >300 ℃,1H NMR (400MHz, Chloroform-d) δ 9.44(s,1H),8.94(d, J ═ 5.1Hz,1H),8.72(d, J ═ 8.8Hz,1H),8.25(dd, J ═ 5.2,0.9Hz,1H),7.82(d, J ═ 1.3Hz,1H),7.68(dd, J ═ 9.2,2.2Hz,1H).
13C NMR(101MHz,CDCl3)δ180.44,156.66,153.53,150.42,148.23,145.42,143.78,140.97,130.65,128.99,123.19,119.66,119.47,117.87.
EXAMPLE 29 Compound 2A-1 (pyrido [4 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 4-aminopyridine-3-carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, rapidly supplementing trichloromethane, adding isatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC, performing column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) until the reaction is complete, and obtaining the target compound 2A-1.
Figure BDA0003464689440000192
Yellow solid, yield 39%. m.p.252-254 ℃,1H NMR (500MHz, DMSO-d6) δ 9.44(s,1H),8.96(d, J ═ 5.5Hz,1H),8.42(d, J ═ 8.1Hz,1H),7.87(dd, J ═ 10.3,6.1Hz,3H),7.47(t, J ═ 7.5Hz,1H).
13C NMR NMR(126MHz,DMSO-D6)δ182.58,157.75,155.21,152.60,150.36,148.98,146.33,138.56,127.86,125.52,123.16,122.42,118.92,117.60.
C14H7N3O2[M+H]+,250.0611；found,250.0608
EXAMPLE 30 Compound 2A-2 (8-Fluoropyrido [4 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 4-aminopyridine-3-carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, rapidly supplementing trichloromethane, adding 5-fluoroisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), and separating by column chromatography (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain a target compound 2A-2.
Figure BDA0003464689440000201
Yellow solid, yield 39%. m.p.286-288 ℃,1H NMR (500MHz, DMSO-d6) δ 9.45(s,1H),8.98(d, J ═ 5.6Hz,1H),8.44(dd, J ═ 8.8,4.3Hz,1H),7.87(d, J ═ 5.6Hz,1H),7.81(dd, J ═ 7.3,2.7Hz,1H),7.72(t, J ═ 9.0Hz,1H).
13C NMR(101MHz,DMSO)δ181.58,157.51,155.23,152.45,150.29,142.59,124.75,124.51,124.22,123.09,119.33,118.76,112.45,112.21.
C14H6FN3O2[M+H]+,268.0517；found,268.0515
EXAMPLE 31 Compound 2A-3 (8-chloropyrido [4 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 4-aminopyridine-3-carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, rapidly supplementing trichloromethane, adding 5-chloroisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), and separating by column chromatography (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain a target compound 2A-3.
Figure BDA0003464689440000202
Yellow solid, yield 39%. M.P. >300 ℃,1H NMR (400MHz, DMSO-d6) δ 9.50(s,1H),9.03(d, J ═ 5.6Hz,1H),8.46(d, J ═ 8.6Hz,1H),8.03(s,1H),7.94(m,2H).
13C NMR(101MHz,DMSO)δ181.29,157.56,155.34,152.47,150.33,148.76,144.70,137.55,132.13,125.01,124.11,123.11,119.12,118.66.
C14H6ClN3O2[M+H]+,284.0221；found,284.0220
EXAMPLE 32 the compound 2A-4 (8-bromopyrido [4 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 4-aminopyridine-3-carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, rapidly supplementing trichloromethane, adding 5-bromoisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), and separating by column chromatography (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain a target compound 2A-4.
Figure BDA0003464689440000203
Yellow solid, yield 39%. m.p.296-298 ℃,1H NMR (500MHz, DMSO-d6) δ 9.45(s,1H),8.98(d, J ═ 5.7Hz,1H),8.35(d, J ═ 8.4Hz,1H),8.08(s,1H),8.04(d, J ═ 8.5Hz,1H),7.87(d, J ═ 5.5Hz,1H).
13C NMR(126MHz,DMSO-D6)δ181.28,157.64,155.43,152.55,150.41,148.69,145.11,140.49,127.90,124.44,123.19,120.13,119.48,118.69.
C14H6BrN3O2[M+H]+,327.9716；found,327.9729
EXAMPLE 33 Compound 2A-5 (8-methylpyrido [4 ', 3': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 4-aminopyridine-3-carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, rapidly supplementing trichloromethane, adding 5-methylindole (0.01mol) into a reaction system, dropwise adding catalytic equivalent triethylamine (0.001mol), refluxing for 2h, monitoring by TLC (thin layer chromatography), and separating by column chromatography (eluting with dichloromethane/methanol at a ratio of 40: 1) to obtain a target compound 2A-5.
Figure BDA0003464689440000211
Yellow solid, yield 39%. M.P. >300 ℃,1H NMR (500MHz, Chloroform-d) δ 9.64(s,1H),8.98(d, J ═ 5.4Hz,1H),8.45(d, J ═ 8.2Hz,1H),7.83(d, J ═ 5.5Hz,1H),7.71(s,1H),7.61(dd, J ═ 8.2,1.1Hz,1H),2.46(s,3H).
13C NMR(126MHz,CHLOROFORM-D)δ182.09,157.12,154.96,152.28,150.95,147.83,144.20,139.50,138.31,126.01,123.12,121.57,118.63,117.91,21.21.
C15H9N3O2[M+H]+,264.0768；found,264.0767
EXAMPLE 34 Compound 1A-1 (pyrido [3 ', 2': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 3-aminopyridine-2-carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, rapidly supplementing trichloromethane, adding isatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC, performing column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) until the reaction is complete, and obtaining the target compound 1A-1.
Figure BDA0003464689440000212
Yellow solid, yield 39%. M.P. >300 ℃,1H NMR (500MHz, DMSO-d6) δ 8.91(dd, J ═ 4.4,1.7Hz,1H),8.48(d, J ═ 8.2Hz,1H),8.34(dd, J ═ 8.3,1.4Hz,1H),7.90(dd, J ═ 8.2,4.3Hz,1H),7.86(ddd, J ═ 9.3,7.5,1.7, 2H),7.47(td, J ═ 7.5,1.0Hz,1H).
13C NMR(126MHz,DMSO-D6)δ182.54,156.87,151.91,146.46,145.84,144.05,140.67,138.47,138.39,129.82,127.75,125.42,122.83,117.75
EXAMPLE 35 Compound 1A-2 (8-Fluoropyrido [3 ', 2': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 3-aminopyridine-2-carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, rapidly supplementing trichloromethane, adding 5-fluoroisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), and separating by column chromatography (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 1A-2.
Figure BDA0003464689440000221
Yellow solid, yield 39%. M.P. >300 ℃,1H NMR (500MHz, DMSO-d6) δ 8.91(dd, J ═ 4.3,1.5Hz,1H),8.49(dd, J ═ 8.8,4.2Hz,1H),8.35(dd, J ═ 8.2,1.5Hz,1H),7.91(dd, J ═ 8.2,4.3Hz,1H),7.79(dd, J ═ 7.0,2.7, 1H),7.71(td, J ═ 9.0,2.8Hz,1H).
13C NMR(126MHz,DMSO-D6)δ181.65,156.71,152.06,146.04,143.98,142.78,140.58,138.45,129.91,124.69,124.50,119.61,112.44,112.24
EXAMPLE 36 Compound 1A-3 (8-methoxypyrido [3 ', 2': 4,5] pyrimido [1,2-a ] indol-5 (11H) -one)
Adding 3-aminopyridine-2-carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, rapidly supplementing trichloromethane, adding 5-methoxyisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), and separating by column chromatography (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 1A-3.
Figure BDA0003464689440000222
Yellow solid, yield 33%. M.P. >300 ℃,1H NMR (400MHz, DMSO-d6) δ 8.94(dd, J ═ 4.4,1.6Hz,1H),8.42(dd, J ═ 8.2,1.0Hz,1H),8.37(dd, J ═ 8.2,1.6Hz,1H),7.93(dd, J ═ 8.3,4.4Hz,1H), 7.48-7.41 (m,2H),3.88(s,3H).
EXAMPLE 37 Compound 14-1 (indole [2,1-b ] pteridine-6, 12-one)
Adding 3-aminopyrazine-2-carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, drying the solvent in a spinning mode, rapidly supplementing trichloromethane, adding isatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, monitoring by TLC (thin layer chromatography), performing column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) after the reaction is completed, and obtaining the target compound 14A-1.
Figure BDA0003464689440000231
Yellow solid, yield 40%. M.P. >300 ℃,1H NMR (500MHz, DMSO-d6) δ 9.10(d, J ═ 2.2Hz,1H),8.99(d, J ═ 2.1Hz,1H),8.46(d, J ═ 8.0Hz,1H),7.91(d, J ═ 7.4Hz,1H),7.88(t, J ═ 7.8Hz,1H),7.51(t, J ═ 7.6Hz,1H).
C13H6N4O2[M+H]+,251.0564；found,251.0562
EXAMPLE 38 Compound 14-2 (8-fluoroindole [2,1-b ] pteridine-6, 12-one)
Adding 3-aminopyrazine-2-carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, carrying out spin-drying on the solvent, rapidly supplementing trichloromethane, adding 5-fluoroisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, carrying out TLC monitoring, carrying out full reaction, spin-drying the solvent, and carrying out column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 14A-2.
Figure BDA0003464689440000232
Yellow solid, yield 32%. M.P. >300 ℃,1H NMR (500MHz, DMSO-d6) δ 9.11(d, J ═ 2.3Hz,1H),9.00(d, J ═ 2.2Hz,1H),8.47(dd, J ═ 8.7,4.1Hz,1H),7.85(dd, J ═ 6.9,2.8Hz,1H),7.74(td, J ═ 8.9,2.8Hz,1H).
13C NMR(126MHz,DMSO-D6)δ181.34,157.10,154.10,151.06,148.40,146.98,142.42,136.16,124.91,124.72,119.52,119.45,112.79,112.59.
C13H5FN4O2[M+H]+,267.0768；found,267.0766
EXAMPLE 39 Compound 14-3 (8-Chloroindolo [2,1-b ] pteridine-6, 12-one)
Adding 3-aminopyrazine-2-carboxylic acid (0.01mol) into 25mL of dried dichloromethane, adding thionyl chloride (0.05mL) for refluxing for 3h, carrying out spin-drying on the solvent, rapidly supplementing trichloromethane, adding 5-chloroisatin (0.01mol) into a reaction system, dropwise adding triethylamine (0.001mol) with catalytic equivalent, refluxing for 2h, carrying out TLC monitoring, carrying out full reaction, spin-drying the solvent, and carrying out column chromatography separation (dichloromethane/methanol is eluted at a ratio of 40: 1) to obtain the target compound 14A-3.
Figure BDA0003464689440000233
Yellow solid, yield 29%. M.P. >300 ℃,1H NMR (500MHz, DMSO-d6) δ 9.11(d, J ═ 2.1Hz,1H),9.00(d, J ═ 2.2Hz,1H),8.45(d, J ═ 8.5Hz,1H),8.02(d, J ═ 2.2Hz,1H),7.93(dd, J ═ 8.6,2.4Hz,1H)
.13C NMR(101MHz,DMSO)δ180.98,157.06,154.08,150.98,147.95,147.56,146.92,144.49,137.69,136.06,132.43,125.20,124.36,119.17.
C13H5ClN4O2[M+H]+,285.0174；found,285.0174
Examples of biological Activity
Testing of the inhibitory activity of phytopathogen bacteria:
the inhibition rate of the azatryptanthrin derivative on plant pathogenic bacteria is tested by a turbidity method, and the pathogenic bacteria are rice bacterial blight (Xoo), citrus canker (Xac) and kiwi canker (Psa). Blank control is DMSO, and bismerthiazol and benziothiazolinone are positive control drugs. Inoculating Xoo, Xac and Psa pathogenic bacteria into M210 solid medium (NA) under constant temperature shaking table conditions of 28 deg.C and 180rpm, and shaking culturing at 28 deg.C and 180rpm until logarithmic phase for use. 5mL of toxic NB-containing liquid culture medium with different concentrations (example 100, 50 mu g/mL) corresponding to the tested compound and the positive control drug is added into a test tube, 40 mu L of NB culture medium liquid containing plant pathogenic bacteria growing to logarithmic phase is respectively added, the NB culture medium liquid is oscillated in a constant temperature shaking table at 28 ℃ and 180rpm, the rice bacterial blight is cultured for about 36 hours, the kiwifruit canker and the citrus canker are cultured for about 48 hours, when the OD value of the control group in the shaking table is between 0.6 and 0.8, the OD values of the blank control group, the positive control drug and the compound are respectively measured at 595nm by a microplate reader.
The calculation formula for correcting the OD value and the inhibition rate is as follows:
corrected OD value-bacteria-containing medium OD value-sterile medium OD value
Percent inhibition is [ (OD value of control medium liquid OD value after correction-OD value of medium containing toxin corrected)/OD value of control medium liquid OD value after correction ] × 100
The examples of the present invention are given to illustrate the technical solution of the present invention, but the contents of the examples are not limited thereto, and some experimental results of the target compounds are shown in Table 1
TABLE 1 inhibitory Activity of Aza tryptanthrin derivatives against three plant pathogens
Figure BDA0003464689440000241
Figure BDA0003464689440000251
Figure BDA0003464689440000261
"NT means not tested" and the test results are the average of three determinations.
The experimental data show that the tested azatryptanthrin derivatives have good inhibitory activity on plant pathogenic bacteria, the inhibition rate of most compounds under the test concentration is greater than that of positive control compounds, namely bismerthiazol and benziothiazolinone, the azatryptanthrin derivatives can be used as potential drugs for inhibiting plant disease bacteria, and the azatryptanthrin derivatives have good application prospects.
Testing of fungal inhibitory Activity of plant pathogenic fungi:
making the filter paper into a circular filter paper sheet with the diameter of 6mm by using a puncher, and sterilizing the circular filter paper sheet at the temperature of 121 ℃ for 30 minutes for later use. On a clean bench, a cake of test bacteria (diameter: 6mm) was inoculated onto a PDA plate (diameter: 9cm) 2cm from the edge. And a sterile filter paper sheet was placed at equal distances on the other edge of the plate, and the filter paper sheet was then impregnated with 10 μ L of the test compound. DMSO served as a negative control. The 25% wettable powder carbendazim is used as a positive control, and the concentration is 20mg/mL (DMSO is used as a solvent). The concentration of azatryptanthrin derivative was 200. mu.g/mL (DMSO is solvent). All plates were incubated at 28 ℃ for 2-7 days, and the negative control plate hypha radial growth radius R1 and the experimental plate hypha radial growth radius containing metabolites (R2) were measured for inhibition (%) (R1-R2)/R1 × 100%. If the inhibition rate is close to 0, no bacteriostatic effect is shown, namely the minimum bacteriostatic concentration is obtained, and the steps are repeated for three times.
TABLE 2 inhibitory Activity of partial azatryptanthrin derivatives against Pyricularia oryzae
Figure BDA0003464689440000262
The experimental data show that the tested azatryptanthrin derivative has better inhibitory activity on the blast disease of fungal plants, the inhibitory activity under the test concentration is better than that of a positive control carbendazim, and the azatryptanthrin derivative can be used as a potential medicament for inhibiting the fungi of the fungal diseases of the plants and has better application prospect.
Testing of antiviral Activity of plants:
the tobacco mosaic virus model plant heart-leaf tobacco is used as a test carrier, the activity test of the azatryptanthrin derivative against the Tobacco Mosaic Virus (TMV) is carried out by adopting a half-leaf cumic spot method, and a positive control drug is ningnanmycin.
Testing for TMV therapeutic activity: selecting heart leaf tobacco (with 5-6 leaves) with consistent growth vigor, removing small leaves at the top end, spreading carborundum on the leaves, dipping virus juice with a writing brush, rubbing the whole leaves to inoculate the leaves, naturally drying the leaves, washing the leaves with clear water, coating a compound to be tested and a positive control drug at the concentration of 500 mu g/mL on the half leaves by using the writing brush, and recording the number of dead spots after 6-7 days.
Testing for TMV protective activity: selecting heart-leaf tobacco (with 5-6 leaves), removing small leaves at the top end, coating a corresponding medicament on the left half leaf and a reagent of a corresponding solvent on the right half leaf by using a writing brush as a reference, spreading carborundum uniformly on the whole leaf after 24 hours, dipping virus juice by using the writing brush to inoculate the virus on the whole leaf, washing by using clear water, and recording the number of dead spots after 6-7 days.
Testing for TMV passivation activity: selecting heart leaf tobacco (with 5-6 leaves) with consistent growth vigor, removing small leaves at the top, taking a corresponding dosage of medicament and virus juice, mixing for 30min, uniformly stirring, inoculating the mixture to the left leaf blade on which carborundum is scattered, inoculating the virus juice to the right leaf blade, after 30min, washing the leaves clean with clear water, and recording the number of dead spots after 6-7 days.
The inhibition rate was calculated by the following formula:
Figure BDA0003464689440000263
wherein, the average number of half-leaf withered spots without medicament and the average number of half-leaf withered spots with medicament are the average value of three groups of repetition.
TABLE 3 inhibitory Activity of partial azatryptanthrin derivatives against Tobacco Mosaic Virus (TMV)
Serial number Compound numbering Protective Activity (%) Therapeutic Activity (%) Passivation Activity (%)
1 4A-1 55.9±5.65 48.3±9.35 60.7±7.40
2 4A-2 61.1±9.16 54.8±7.94 75.2±5.36
3 Ningnanmycin 78.6±3.72 71.3±5.48 90.9±2.67
The experimental data show that the tested azatryptanthrin derivative has a certain inhibiting effect on plant virus diseases, can be used as a potential plant virus resisting medicine, and has a good application prospect.
The above description is only exemplary embodiments of the present invention, and is not intended to limit the present invention in any way, and any simple modification, equivalent change and modification made to the above embodiments according to the technical spirit of the present invention are within the scope of the present invention without departing from the technical spirit of the present invention.

Claims (11)

1. The azatryptanthrin derivative has a structure shown as (I), and is used for preparing medicaments for preventing and treating plant pathogenic bacteria, fungi and plant viruses;
wherein A, B, C and D are respectively and independently selected from a pyridine unit ring formed by one N atom or two pyrimidine, pyrazine and pyridazine structural unit rings formed by combining N atoms;
R 1 ,R 2 ,R 3 ,R 4 are respectively and independently selected from hydrogen, nitryl, C1-C4 alkoxy, C1-C4 alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, hydroxyl, cyano, carboxyl, methylsulfonyl, sulfonic acid group, or disubstituted, trisubstituted and tetrasubstituted derivatives of any combination of the above substituent groupsAn organism;
Figure RE-FDA0003626969260000011
2. the derivative of claim 1, wherein a is N and B-D is carbon.
3. The derivative of claim 1 wherein B is N, A, C and D is carbon.
4. The derivative of claim 1 wherein C is N, A, B and D is carbon.
5. The derivative of claim 1, wherein D is N and A-C are carbon.
6. The derivative of claim 1 wherein A, D are both N, B and C are carbon.
7. The derivative of claim 1 wherein B, D are both N, A and C are carbon.
8. The derivative of claim 1 wherein C, D are both N, A and B are carbon.
9. A process for preparing an azatryptanthrin derivative according to claim 1, wherein: the method comprises the following steps:
synthesizing different substituted isatin derivatives by adopting Sandmeyer method, and reacting with the compound of formula (6) to obtain the compound of formula (I):
Figure RE-FDA0003626969260000012
10. the method of claim 9, wherein: the preparation method of the intermediate compound shown in the formula (5) comprises the following steps:
Figure RE-FDA0003626969260000021
11. a pharmaceutical composition comprising a derivative according to any one of claims 1 to 10.
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CN115197227A (en) * 2022-08-09 2022-10-18 贵州大学 Tryptanthrin 1-position or 3-position substituted aromatic thioether derivative, and preparation method and application thereof
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CN115710276A (en) * 2022-11-21 2023-02-24 贵州大学 7-fatty amine substituted tryptanthrin derivative, preparation method and application thereof
CN115850284A (en) * 2022-11-21 2023-03-28 贵州大学 8-fluoro-9-fatty amine substituted tryptanthrin derivative, and preparation method and application thereof
CN115710276B (en) * 2022-11-21 2024-04-05 贵州大学 7-fatty amine substituted tryptamine ketone derivative, preparation method and application thereof

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