4-aminoquinazoline-linked acrylamide compound and preparation method and application thereof
阅读说明：本技术 一类4-氨基喹唑啉接丙烯酰胺类化合物及其制备方法和应用 (4-aminoquinazoline-linked acrylamide compound and preparation method and application thereof ) 是由 杨松 王培义 龙青素 吴志兵 于 2019-10-09 设计创作，主要内容包括：本发明涉及一类4-氨基喹唑啉接丙烯酰胺类化合物及其制备方法和应用。该化合物具有如通式(I)所示的结构：<Image he="427" wi="387" file="DSA0000191790910000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>本发明以喹唑啉类化合物为基础,将丙烯酰胺基引入到此体系中,合成一系列含丙烯酰胺基取代的4-氨基喹唑啉类化合物,该化合物对植物致病病原细菌具有良好的抑制作用,针对病原细菌如水稻白叶枯病菌、柑橘溃疡病菌等具有良好的抑制效果。(The invention relates to a 4-aminoquinazoline-linked acrylamide compound and a preparation method and application thereof. The compound has a structure shown as a general formula (I): according to the invention, based on quinazoline compounds, acrylamide groups are introduced into the system to synthesize a series of 4-aminoquinazoline compounds containing substituted acrylamide groups, and the compounds have good inhibition effects on plant pathogenic bacteria and have good inhibition effects on pathogenic bacteria such as rice bacterial blight, citrus canker pathogen and the like.)
1. A4-aminoquinazoline compound or a stereoisomer thereof, or a salt or solvate thereof, characterized in that: the compound has a structure shown as a general formula (I):
wherein
R1Independently selected from one or more of hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, hydroxyl, amino, halogen, mercapto, phosphino, nitro;
R2independently selected from hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkanoyl, optionally substituted or unsubstituted alkenylacyl, optionally substituted or unsubstituted alkynoyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl.
2. The 4-aminoquinazoline compound or a stereoisomer thereof, or a salt or solvate thereof according to claim 1, wherein: r1Independently selected from one or more of hydrogen, tritium, alkyl, alkoxy, hydroxyl, amino, nitro, halogen, sulfydryl and phosphino; preferably, R1Independently selected from hydrogen, deuterium, C1-C6Alkyl radical, C1-C6One or more of alkoxy, hydroxyl, amino, nitro, F, Cl, Br, mercapto, phosphino; more preferably, R1Independently selected from hydrogen, deuterium, C1-C3Alkyl radical, C1-C3Alkoxy, hydroxyl, amino, nitro, F, Cl, Br; most preferably, R1Independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, hydroxyl, amino, nitro, F, Cl, Br;
R2independently selected from hydrogen, deuterium, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, alkanoyl, alkenylacyl, alkynylacyl, aryl, heteroaryl; preferably, R2Independently selected from hydrogen, deuterium, C1-C8Alkyl radical, C1-C8Alkoxy radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C1-C8Alkyl acyl radical, C2-C8Alkenyl acyl, C2-C8Alkynoyl, C6-C15Aryl radical, C4-C10One or more of heteroaryl; more preferably, R2Independently selected from hydrogen, deuterium, C1-C5Alkyl radical, C1-C5Alkoxy radical, C2-C5Alkenyl radical, C2-C5Alkynyl, C1-C5Alkyl acyl radical, C2-C5Alkenyl acyl, C2-C5Alkynoyl, C6-C8Aryl radical, C4-C8One or more of heteroaryl; most preferably, R2Independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, vinyl, allyl, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, sec-butyryl, tert-butyryl, levulinyl, sec-butyryl, tert-butyryl, n-valeryl, isovaleryl, levyneopentanoyl, ethynyl, propargyl, phenylbenzyl, furyl, 2-furanmethylene, 3-furanmethylene, thienyl, 2-thiophenemethylene, 3-thiophenemethylene, pyrrolyl, 2-pyrrolemethylene, 3-pyrrolemethylene.
3. The 4-aminoquinazoline compound or a stereoisomer thereof, or a salt thereof or a solvate thereof according to claim 1, characterized by being selected from the following specific compounds:
4. a process for producing a compound according to claim 1 or a stereoisomer thereof, or a salt or solvate thereof, which comprises: compound (I)Anda step of reacting to produce a compound represented by the general formula (I) wherein R1And R2As claimed in claim 1.
5. The method of claim 4, further comprising the steps of:
6. a composition characterized by comprising a compound of claim 1 or a stereoisomer thereof, or a salt or solvate thereof, and an agriculturally acceptable adjuvant or fungicide, insecticide or herbicide; preferably, the formulation of the composition is selected from Emulsifiable Concentrates (EC), Dusts (DP), Wettable Powders (WP), Granules (GR), Aqueous Solutions (AS), Suspension Concentrates (SC), ultra low volume sprays (ULV), Soluble Powders (SP), Microcapsules (MC), smoking agents (FU), aqueous Emulsions (EW), water dispersible granules (WG).
7. Use of a compound of claim 1 or a stereoisomer thereof, or a salt or solvate thereof, or a composition of claim 6, for controlling an agricultural pest, preferably a bacterial or fungal disease of a plant; more preferably, the agricultural pests are plant leaf blight and plant canker; most preferably, the agricultural pests are rice bacterial leaf blight, cucumber bacterial leaf blight, konjac bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber gray mold, pepper wilt, rape sclerotinia rot, wheat scab, potato late blight, and blueberry root rot.
8. A method for controlling agricultural pests is characterized in that: allowing the compound according to claim 1 or a stereoisomer thereof, or a salt or solvate thereof, or the composition according to claim 6 to act on harmful substances or their living environments; preferably, the agricultural pest is a bacterial or fungal disease of a plant; more preferably, the agricultural pests are rice bacterial leaf blight, tobacco bacterial wilt, cucumber bacterial leaf blight, konjak bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber gray mold, pepper wilt, rape sclerotinia rot, wheat scab, potato late blight and blueberry root rot.
9. A method for protecting a plant from an agricultural pest comprising a method step wherein the plant is contacted with a compound of claim 1 or a stereoisomer thereof, or a salt or solvate thereof, or a composition of claim 6.
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to an acrylamide-substituted quinazoline compound and a preparation method and application thereof.
Background
In recent years, plant bacterial diseases (such as bacterial leaf blight of rice, citrus canker and the like) occur and prevail in large scale in China, main economic crop diseases have the characteristics of high occurrence frequency, high harm degree, wide occurrence range, high prevention and control difficulty and the like, so that great loss is caused to national economy, particularly agricultural production in China, the activity of the existing commercial antibacterial agents (such as bismerthiazol, thiediazole copper, and the like) is not high enough, active compounds for efficiently resisting plant disease bacteria are urgently needed to be found, a green new pesticide with main intellectual property rights is created on the basis, and candidate medicines are provided for preventing and controlling the crop bacterial diseases.
Acrylamide is a reactive group and can selectively perform Michael addition or nucleophilic substitution reaction with sulfhydryl of cysteine in protein so as to inhibit enzyme activity, so that acrylamide group is successfully introduced into small molecular structure of antitumor drug in recent years due to the characteristic, and part of the drugs are commercialized. On the other hand, quinazoline compounds have a wide range of medical and agricultural biological activities, such as: anticancer, antibacterial, antiinflammatory, antioxidant, antispasmodic, antituberculosis, antimicrobial, antiviral, etc. In order to search for a high-efficiency antibacterial active compound, an acrylamide structure is introduced into a quinazoline matrix to synthesize a series of quinazoline compounds containing acrylamide groups, the biological activity of the quinazoline compounds is investigated, and an important scientific basis is provided for research and development and creation of new pesticides.
The study of the biological activity of acrylamide-containing compounds has progressed as follows:
in 2010, Honigberg et al [ Honigberg, l.a.; smith, a.m.; siriawad, m.; verner, e.; loury, D.; chang, b.; li, S.; pan, z.; thamm, d.h.; miller, r.a.; burgy, J.J.the Brutontrysine kinase inhibitor PCI-32765 blocks B-cell activation and isefficacions in models of autoimmune disease and B-cell malignacy [ J ]. Proc.Natl.Acad.Sci.USA, 2010, 107, 13075-13080] parent 4-aminopyrazolo [3, 4-d ] pyrimidine was introduced with an acrylamide group to develop a highly potent, irreversible Bruton's tyrosine kinase (Btk) inhibitor l-1 (Ibrutinib: IC50 < 0.5nM), which was found by clinical trials to be effective in the treatment of B-cell lymphoma and chronic lymphocytic leukemia and was approved by the Food and Drug Administration (FDA) in 2013.
2013, Evans et al [ Evans, e.k.; tester, r.; aslanian, s.; karp, r.; sheets, m.; labenski, M.T.; witewski, s.r.; lounsbury, h.; chaturvedi, p.; mazdiyasni, h.; zhu, z.; nacht, m.; free, m.i.; petter, r.c.; dubrovskiy, a.; singh, j.; westlin, W.F., Inhibition of Btk with CC-292provides of activity in the microorganism and humans [ J ]. J.Pharmacol exp.Ther., 2013, 346, 219-228] compounds 1-2(Spebrutinib) were synthesized by substituting aniline at the 2-and 4-positions of the parent pyrimidine ring and then introducing an acrylamide group into the benzene ring. The experimental result of Btk enzyme activity inhibition shows that the Spebrutinib can efficiently and selectively inhibit Btk, and the IC50 of the Spebrutinib is less than 0.5 nM. It forms a strong covalent bond by the addition reaction of an acrylamide group with protein cysteine 481(Cys481) on Btk.
In 2014, Finlay et al [ Finlay, m.r.; anderton, m.; ashton, s.; ballard, p.; bethel, p.a.; box, m.r.; bradbury, r.h.; brown, s.j.; butterworth, s.; campbell, a.; chord, c.; colclough, n.; cross, d.a.; currie, g.s.; grist, m.; hassall, l.; hill, g.b.; james, d.; james, m.; kemmitt, p.; klinowska, T.; lamont, g.; lamont, s.g.; martin, n.; McFarland, h.l.; mellor, m.j.; orme, j.p.; perkins, d.; perkins, p.; richmond, g.; smith, p.; ward, r.a.; waring, m.j.; whittaker, d.; wells, s.; wrigley, G.L. discovery of a patent and electric EGFR inhibitor (AZD9291) of both sensing and T790M resistance and mutation of the same type of EGFR inhibitor 1-10a, which was studied according to its earlier work, was developed an irreversible inhibitor 1-10b (Osiminib, AZD9291) by structural optimization, the authors revealed an acrylamide group in the aniline region and introduced a 2-methylindole group on the pyrimidine ring, which selectively binds to Cys797, the ATP binding site in the EGFR tyrosine kinase domain. AZD9291 had an IC50 of 11.4nM against EGFR mutant L858R/T790M and was FDA approved for the treatment of non-small cell lung cancer (NSCLC) with a T790M site variation after EGFR kinase inhibitor resistance in 2015.
2016, Planken et al [ Planken, S.; behenna, d.c.; nair, s.k.; johnson, t.o.; nagata, a.; almaden, c.; bailey, s.; ballard, t.e.; bernier, l.; cheng, h.; Cho-Schultz, S.; dalvie, d.; deal, j.g.; dinh, d.m.; edwards, m.p.; ferre, r.a.; gajiwala, k.s.; hemkens, m.; kania, r.s.; kath, j.c.; matthews, j.; murray, b.w.; niessen, s.; luo, y.; xin, s.; zhang, c.; lafontaine, J.discovery of N- ((3R, 4R) -4-Fluoro-1- (6- ((3-methoxy-1-methyl-1H-pyrazol-4-yl) amino) -9-methyl-9H-purin-2-yl) pyrolidin-3-yl) acrylamide (PF-06747775) through Structure-Based Drug Design: a high affinity reversible inhibitory Inhibitor ligands with selective activity over wild-Type EGFR [ J ]. J.Med.chem., 2017, 60, 3002-3019] by adopting a method for designing a medicament by adopting a structure and further improving the drug resistance of EGFR mutants, compounds 1-12 are designed and synthesized, have high-efficiency inhibitory activity on four mutants of EGFR (exons 19Del EGFR, L858R, double mutants L858R/T790M and T790M/Del), and have selectivity exceeding that of wild-Type EGFR, and the IC50 is 3-12 nM.
2018, Wu et al [ Wu, k.d.; chen, g.s.; liu, j.r.; hsieh, c.e.; chern, J.W., acrylic functional group in amplification drugs-like properties: the anexample with EGFR inhibitors [ J ]. ACS Med. chem.Lett., 2019, 10, 22-26] synthesizes compounds 1-16 by taking EGFR inhibitor gefitinib as a lead compound and introducing an acrylamide group on 4-substituted NH of quinazoline, and biological research results show that the IC50 value of the compound on the EGFR is increased to 65.2nM from 0.5nM, but the solubility is increased. Experiments prove that the introduction of acrylamide groups improves the pharmaceutical performance of the compound.
The research on the biological activity of quinazoline compounds has progressed as follows:
2010, Mani et al [ Mani, c.p.; yakaiah, t.; gaytri, g.; pranay, k.k.; narsaiah, b.; murthy, U.S.; raghu, r.r.a.click chemistry: studies on the synthesis of novel fluorinated quinazoline derivatives and the biochemical evaluation of the same, which respectively introduce a phenyl group and a trifluoromethyl group at position 2 of quinazolinone, a terminal alkyne at position 3, and different lengths of fluoroalkanes to quinazoline precursors at position 4 by click chemistry, have been derived a series of compounds containing different lengths of alkanes. The biological activity test result shows that the compound has good biological activity on candida albicans, saccharomyces cerevisiae, aspergillus niger and the like.
2011, Desai et al [ Desai, n.c.; dodiya, Amit; bhatt, Nayan; kumar, Mukesh, digital 2- (2-chlorophenylyl) -quinazoline-4-ones as a potential antimicrobial biological agents [ J ]. Med. chem. Res., 2011, 21, 1127-1135] A series of derivatives containing a bis-quinazoline structure were designed by substituting 2-position and 3-position of quinazoline, and through in vitro biological activity studies, it was found that compounds 1-24a, 1-24b and 1-24c exhibited excellent antibacterial activity, and MIC values of 25, 25 and 12.5. mu.g/mL respectively against Streptococcus pyogenes (S.pyogenes) were superior to that of ampicillin (100. mu.g/mL) as a control medicament.
2013, Wang et al [ Wang, X.; li, P.; li, z.n.; yin, j.he, m.; xue, w.; chen, z.w.; song, B.A.Synthesis and biological-activity Evaluation of Novel Arylimines containment ga 3Aminoethyl-2- [ (p-trifluoromethyl) anilino ] -4(3H) quinazone Moiety [ J ]. J.Agric.food.chem., 2013, 61, 9575-9582 ] reports a series of quinazoline derivatives containing aromatic imine structures, and the results of biological activity tests show that the compounds show excellent water-resistant activity of rice bacterial blight.
In 2014, Van et al [ Van h.k.; burda, s.f., r.; shaw, l.n.; a series of N2, N4-quinazoline compounds are reported by Manetsch, R, Antibacterial activity of a series of N2, N4-disubstitated quinazoline-2, 4-diamines [ J ]. J.Med.chem., 2014, 57, 3075-mangnolia ] and biological activity test results show that the compounds have good Antibacterial activity, and structure-activity relationship (SAR) research shows that double substitution on N2 and N4 is favorable for improving the Antibacterial activity, wherein MIC values of the compounds 11a, 11b and 11c to staphylococcus aureus (S.aureus) are respectively 0.37, 0.67 and 0.73 mu M.
In 2014, Patel et al [ Patel, a.b.; chikhalia, k.h.; kumari, P.Synthesis and biological evaluation of novel quinazoline derivatives by Suzuki C-Cdoping [ J ]. Med.chem.Res., 2014, 23, 2338-2346 ] benzene was coupled to 2-position of quinazoline by Suzuki C-C coupling method, and a series of (thio) urea quinazoline derivatives were derived, and biological activity test results showed that the compounds showed good activity and that their antimycobacterial MIC values optimally reached 12.50. mu.g/mL (6.25. mu.g/mL for the control agent Pyrazinamide).
In 2017, Jiang et al [ Jiang, z.y.hong, w.d.; cui, x.p.; gao, h.g.; wu, p.p.; a series of quinazoline diamine substituted compounds were synthesized by Chen, Y.S., Synthesis and structure-activity correlation of N4-benzylamine-N2-isoproyl-quinazoline-2, 4-diamines derivative as a potential antimicrobial agents [ J.RSC.Advances ], 2017, 52227-52237 ], 8 compounds with better antibacterial activity were screened by structural studies, and the results of biological activity showed that the MIC of compound 12 to Escherichia coli (E.coli), Staphylococcus aureus (S.aureus) and Staphylococcus epidermidis (S.epidermidis) was 3.9. mu.g/mL and the MIC to methicillin-resistant Staphylococcus aureus (MRSA) was 7.8. mu.g/mL. Is superior to the control medicament vancomycin (31.2 mu g/mL).
In 2018, Yang et al [ Yang, L.; ge, S.; huang, j.; bao, X.P.Synthesis of novel (E) -2- (4- (1H-1, 2, 4-triazol-1-yl) styryl) -4- (alkyl/arylmethyl) quinazolinedivatives as antimicrobial agents [ J ]. mol.Divers, 2018, 22, 71-82] reported a series of quinazoline derivatives containing triazole, which were further tested for inhibitory activity against 3 plant pathogenic bacteria, rice bacterial blight (Xoo), citrus canker (Xac) and tobacco bacterial wilt (R.solanacearum). The activity results showed that compounds 1-33a, 1-33b, 1-33c had EC50 against Citrus canker (Xac) of 53.2, 67.7 and 70.7. mu.g/mL, respectively, slightly higher than the control drug bismerthiazol (87.7. mu.g/mL).
Disclosure of Invention
The invention provides a 4-aminoquinazoline compound or a stereoisomer thereof, or a salt or a solvate thereof.
Another object of the present invention is to provide an intermediate compound for preparing the above compound or a stereoisomer thereof, or a salt or solvate thereof, and a preparation method thereof.
It is still another object of the present invention to provide a composition comprising the above compound or a stereoisomer thereof, or a salt or solvate thereof.
It is a further object of the present invention to provide the above compounds or stereoisomers thereof, or salts or solvates thereof, or the use of said compositions.
Another object of the present invention is to provide a method for controlling agricultural pests using the above compound or a stereoisomer thereof, or a salt or solvate thereof, or the composition.
In order to realize the purpose, the invention adopts the following technical scheme:
a4-aminoquinazoline compound or a stereoisomer thereof, or a salt or solvate thereof, wherein the compound has a structure shown as a general formula (I):
wherein
Independently selected from one or more of hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, hydroxyl, amino, halogen, mercapto, phosphino, nitro;
R2independently selected from hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkanoyl, optionally substituted or unsubstituted alkenylacyl, optionally substituted or unsubstituted alkynoyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl.
R1Independently selected from hydrogen, deuteriumOne or more of alkyl, alkoxy, hydroxyl, amino, nitro, halogen, mercapto, phosphino;
preferably, R1Independently selected from hydrogen, deuterium, C1-C6Alkyl radical, C1-C6One or more of alkoxy, hydroxyl, amino, nitro, F, Cl, Br, mercapto, phosphino;
more preferably, R1Independently selected from hydrogen, deuterium, C1-C3Alkyl radical, C1-C3Alkoxy, hydroxyl, amino, nitro, F, Cl, Br;
most preferably, R1Independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, hydroxyl, amino, nitro, F, Cl, Br;
R2independently selected from hydrogen, deuterium, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, alkanoyl, alkenylacyl, alkynylacyl, aryl, heteroaryl;
preferably, R2Independently selected from hydrogen, deuterium, C1-C8Alkyl radical, C1-C8Alkoxy radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C1-C8Alkyl acyl radical, C2-C8Alkenyl acyl, C2-C8Alkynoyl, C6-C15Aryl radical, C4-C10One or more of heteroaryl;
more preferably, R2Independently selected from hydrogen, deuterium, C1-C5Alkyl radical, C1-C5Alkoxy radical, C2-C5Alkenyl radical, C2-C5Alkynyl, C1-C5Alkyl acyl radical, C2-C5Alkenyl acyl, C2-C5Alkynoyl, C6-C8Aryl radical, C4-C8One or more of heteroaryl;
most preferably, R2Independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentylVinyl, allyl, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, sec-butyryl, tert-butyryl, levulinyl, sec-butyryl, tert-butyryl, n-valeryl, isovaleryl, neopentanoyl, ethynyl, propargyl, phenyl, benzyl, furyl, 2-furanmethylene, 3-furanmethylene, thienyl, 2-thiophenemethylene, 3-thiophenemethylene, pyrrolyl, 2-pyrrolemethylene, 3-pyrrolemethylene.
Most preferably, the compound is selected from the following specific compounds:
an intermediate compound for preparing the compound of claim 1 or a stereoisomer thereof, or a salt or solvate thereof, as shown below:
wherein R is1And R2As described above.
Preferably, the method for preparing the compound or the stereoisomer thereof, or the salt or the solvate thereof, further comprises: compound (I)A step of producing a compound represented by the general formula (I) in the presence of a halogen compound.
Preferably, the preparation method further comprises:in the presence of substituted aminesWherein R is1And R2As described in the preceding paragraph.
More preferably, the preparation method further comprises the following specific steps:
wherein R is1And R2As described above.
A composition comprising said compound or a stereoisomer thereof, or a salt or solvate thereof, and an agriculturally acceptable adjuvant or fungicide, insecticide or herbicide;
preferably, the formulation of the composition is selected from Emulsifiable Concentrates (EC), Dusts (DP), Wettable Powders (WP), Granules (GR), Aqueous Solutions (AS), Suspension Concentrates (SC), ultra low volume sprays (ULV), Soluble Powders (SP), Microcapsules (MC), smoking agents (FU), aqueous Emulsions (EW), water dispersible granules (WG).
The compound or the stereoisomer thereof, or the salt or the solvate thereof, or the composition can be used for controlling agricultural pests, preferably bacterial or fungal diseases of plants; more preferably, the agricultural pests are plant leaf blight and plant canker; most preferably, the agricultural pests are rice bacterial leaf blight, cucumber bacterial leaf blight, tobacco bacterial wilt, konjac bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber gray mold, pepper wilt, rape sclerotinia rot, wheat scab, potato late blight and blueberry root rot.
A method for controlling agricultural pests, which comprises allowing the compound or a stereoisomer thereof, or a salt or solvate thereof, or the composition to act on the pests or their living environments; preferably, the agricultural pest is a bacterial or fungal disease of a plant; more preferably, the agricultural pests are rice bacterial leaf blight, cucumber bacterial leaf blight, konjac bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber gray mold, pepper wilt, rape sclerotinia rot, wheat scab, potato late blight and blueberry root rot.
A method for protecting a plant from an agricultural pest comprising the method step wherein a plant is contacted with the compound or stereoisomer thereof, or salt or solvate thereof, or the composition.
The term "alkyl" as used herein is intended to include both branched and straight chain saturated hydrocarbon radicals having the specified number of carbon atoms. E.g. "C1-10Alkyl "(or alkylene) groups are intended to be C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl groups. In addition, for example "C1-6Alkyl "denotes an alkyl group having 1 to 6 carbon atoms. Alkyl groups may be unsubstituted or substituted such that one or more of its hydrogen atoms are replaced with another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
"alkenyl" is a hydrocarbon group that includes both straight and branched chain structures and has one or more carbon-carbon double bonds that occur at any stable point in the chain. E.g. "C2-6Alkenyl "(or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.
"alkynyl" is intended to include both straight and branched chain hydrocarbons having one or more carbon-carbon triple bonds at any stable point in the chain. E.g. "C2-6Alkynyl "(or alkynylene) is intended to include C2, C3, C4, C5, and C6 alkynyl; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
The term "substituted" as used herein means that any one or more hydrogen atoms on the designated atom or group is replaced with the designated group of choice, provided that the general valence of the designated atom is not exceeded. If not otherwise stated, substituents are named to the central structure. For example, it is understood that when (cycloalkyl) alkyl is a possible substituent, the point of attachment of the substituent to the central structure is in the alkyl moiety. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C ═ C, C ═ N or N ═ N).
Combinations of substituents and or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure implies that the compound is sufficiently stable to be isolated in useful purity from the reaction mixture and subsequently formulated to form an effective therapeutic agent. Preferably, the compounds described so far do not contain N-halogen, S (O)2H or S (O) H group.
The term "cycloalkyl" refers to cycloalkyl groups, including mono-, bi-or polycyclic ring systems. C3-7Cycloalkyl groups are intended to include C3, C4, C5, C6 and C7 cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. As used herein, "carbocycle" or "carbocycle residue" refers to any stable 3, 4, 5, 6 or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12 or 13-membered bi-or tricyclic ring which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, pentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadiene, [3.3.0]Bicyclo-octane, [4.3.0]Bicyclo nonane, [4.4.0]Bicyclo decane, [2.2.2]Bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl and tetrahydronaphthyl (tetralin). As mentioned above, bridged rings are also included in carbocyclic rings (e.g. [2.2.2 ]]Bicyclooctane). Preferred carbocycles, if not otherwise stated, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl. When the term "carbocycle" is used, it is intended to include "aryl". A bridged ring occurs when one or more carbon atoms connects two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is pointed out that the bridge always converts a single ring into a double ring. When the rings are bridged, substituents of the rings are also present on the bridge.
The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which may be substituted.
The term "halogen" or "halogen atom" refers to chlorine, bromine, fluorine and iodine.
The term "heteroaryl" refers to substituted and unsubstituted aromatic 5 or 6 membered monocyclic groups, 9-or 10-membered bicyclic groups, and 11 to 14 membered tricyclic groups having at least one heteroatom (O, S or N) in at least one ring, said heteroatom containing ring preferably having 1, 2 or 3 heteroatoms selected from O, S and N. The heteroatom-containing heteroaryl groups can contain one or two oxygen or sulfur atoms per ring and/or from 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one fully aromatic ring, and the other fused rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. If the other ring is cycloalkyl or heterocyclic, it is additionally optionally substituted with ═ O (oxygen), as valency permits.
Exemplary monocyclic heteroaryls include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.
Exemplary bicyclic heteroaryls include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzofuranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, fluoropyridinyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.
The compounds of the invention are understood to include both the free form and salts thereof, unless otherwise indicated. The term "salt" means an acid and/or base salt formed from an inorganic and/or organic acid and a base. In addition, the term "salt" may include zwitterions (internal salts), such as when the compound of formula I contains a basic moiety, such as an amine or pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as acceptable metal and amine salts, wherein the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, such as separation or purification steps in the preparation process, and are therefore included within the scope of the present invention. Salts of the compounds of formula I may be formed, for example, by combining a compound of formula I with an amount of acid or base, for example, in equal amounts, in a vehicle, for example, in which the salt precipitates or in which it is present in an aqueous vehicle, and then lyophilizing.
When reference is made to substituents being alkenyl, alkynyl, alkyl, halo, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxy, amino, mercapto, phosphino, or when these substituents are specifically alkenyl, alkynyl, alkyl, halo, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxy, amino, mercapto, phosphino as specified, one to three of the above substituents are meant. Such as methylphenyl refers to phenyl substituted with one to three methyl groups.
By adopting the technical scheme, the quinazoline compound is taken as a base, alkyl, alkynyl and acrylamide groups capable of improving the biological activity of a target compound are introduced into the system to synthesize a series of quinazoline compounds containing alkyl, alkynyl and acrylamide groups, and the quinazoline compounds are found to have good inhibition effect on pathogenic bacteria, have good inhibition effect on pathogenic bacteria [ such as Xanthomonas oryzae pv. oryzae, Xoo, Xanthomonas anopodis pv. citri, Xac) and the like ], and provide an important scientific basis for research and development of new pesticides.
Examples
The invention is further illustrated by the following examples. It should be understood that the method described in the examples is only for illustrating the present invention and not for limiting the present invention, and that simple modifications of the preparation method of the present invention based on the concept of the present invention are within the scope of the claimed invention. All the starting materials and solvents used in the examples are commercially available products.