Aromatic ring compound for inhibiting lysyl tRNA synthetase

Abstract

The present application provides a kind of aromatic ring compound for inhibiting lysyl tRNA synthetase. Specifically, the present application provides a compound represented by formula A, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt, and its use as a lysyl tRNA synthetase inhibitor, for preparing the treatment of diseases or conditions related to the activity or expression amount of lysyl tRNA synthetase.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and more specifically, to aromatic cyclic drugs and their application in inhibiting lysyl-tRNA synthetase. Background Technology

[0002] Aminoacyl-tRNA synthases (aaRSs) catalyze the aminoacylation reaction of amino acids and their corresponding tRNAs to synthesize aminoacyl-tRNAs, a crucial raw material for protein translation. The specificity of this reaction directly determines the accuracy of genetic information translation. Each amino acid involved in protein biosynthesis requires a specific aaRS to catalyze its synthesis. Therefore, each aaRS is indispensable for the protein translation process. aaRSs have long been considered excellent platforms for researching novel antibiotics. They are not only found in the cytoplasm but also in some organelles capable of protein synthesis, such as mitochondria, chloroplasts, or acroplasts (found in protozoa such as those causing malaria). The aaRS family provides approximately 20 different targets for antibiotic development in bacteria, and more than twice that number in eukaryotic pathogens; for example, Plasmodium has 37 different aaRSs (including cytoplasmic, mitochondrial, and acroplastic aaRSs).

[0003] Malaria is an acute infectious disease caused by Plasmodium parasites, primarily transmitted through mosquito bites. While combination therapy with drugs such as artemisinin derivatives can effectively treat malaria, resistance to these treatments has been observed in recent years in regions such as western Cambodia and western Thailand. These regions have discovered multidrug-resistant Plasmodium parasites with reduced sensitivity to artemisinin, a condition known as "super malaria." If not effectively controlled, "super malaria" could spread further. Malaria remains one of the world's leading causes of death, and the development of artemisinin-based antimalarial drugs resistance in Plasmodium parasites is currently the greatest technical challenge facing global malaria control.

[0004] Meanwhile, despite the availability of various antibiotics, their overuse has accelerated the development of bacterial resistance. Drug-resistant bacteria, through continuous evolution and mutation, acquire resistance to different antimicrobial drugs. This resistance strengthens in the struggle, leading bacteria to progress from single-drug resistance to multidrug resistance and even pan-drug resistance, ultimately becoming drug-resistant superbugs. These bacteria exhibit strong resistance to antibiotics, escaping the risk of being eradicated. Currently, superbugs of particular concern include methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Streptococcus pneumoniae (MDRSP), and vancomycin-resistant enterococci (VRE), among others. Because most antibiotics are ineffective against them, superbugs have posed a significant threat to human health.

[0005] Therefore, there is an urgent need to develop new antibiotics with new targets. Summary of the Invention

[0006] The purpose of this invention is to provide a small molecule compound that can directly target lysyl-tRNA synthetase and has medicinal value as a novel antibiotic.

[0007] A first aspect of the present invention provides a compound, or an optical isomer thereof, or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, as shown in the following formula:

[0008]

[0009] In the formula,

[0010] Ar is selected from the following group: benzene ring, pyridine ring;

[0011] R1 is selected from the following group: substituted or unsubstituted C3-C8 saturated or unsaturated carbon rings, S(O)2Ra;

[0012] Ra is selected from the following group: H, substituted or unsubstituted C1-C6 alkyl groups;

[0013] R2 is selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, S(O)2Ra, C(O)Ra, C(O)ORa, C3-C8 carbon ring, 3-8 membered heterocycle; wherein the C3-C8 carbon ring or 3-8 membered heterocycle may optionally be substituted by one or more substituents selected from the group consisting of: halogen, C1-C6 alkyl, substituted or unsubstituted C3-C8 carbon ring, substituted or unsubstituted 3-8 membered heterocycle;

[0014] R3 is selected from the following group: H, halogen, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0015] R4 is selected from the following group: H, substituted or unsubstituted C1-C6 alkoxy groups, S(O)2Ra;

[0016] Furthermore, the substitution refers to the replacement of one or more H atoms on the group by a group selected from the group consisting of: halogen, C1-C6 alkyl, and C1-C6 alkoxy.

[0017] In another preferred embodiment, Ar is selected from the group consisting of: benzene ring, pyridine ring;

[0018] R1 is selected from the following group: substituted or unsubstituted C3-C6 saturated or unsaturated carbon rings, S(O)2Ra;

[0019] Ra is selected from the following group: H, substituted or unsubstituted C1-C4 alkyl groups;

[0020] R2 is selected from the group consisting of: H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, S(O)2Ra, C(O)Ra, C(O)ORa, C3-C8 carbon ring, 3-8 membered heterocycle; wherein the C3-C6 carbon ring or 3-6 membered heterocycle may optionally be substituted by one or more substituents selected from the group consisting of: halogen, C1-C4 alkyl, substituted or unsubstituted C3-C6 carbon ring, substituted or unsubstituted 3-6 membered heterocycle;

[0021] R3 is selected from the following group: H, halogen, nitro, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy;

[0022] R4 is selected from the following group: H, substituted or unsubstituted C1-C4 alkoxy groups, S(O)2Ra;

[0023] Furthermore, the substitution refers to the replacement of one or more H atoms on the group by a group selected from the group consisting of: halogen, C1-C4 alkyl, and C1-C4 alkoxy.

[0024] In another preferred embodiment, Ar is selected from the group consisting of: benzene ring, pyridine ring;

[0025] R1 is selected from the following group: C3-C6 saturated or unsaturated carbon rings, S(O)2Ra;

[0026] Ra is selected from the following group: H, methyl;

[0027] R2 is selected from the group consisting of: H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, S(O)2Ra, C(O)Ra, C(O)ORa, C3-C8 carbon ring, 3-8 membered heterocycle; wherein the C3-C6 carbon ring or 3-6 membered heterocycle may optionally be substituted by one or more substituents selected from the group consisting of: halogen, C1-C4 alkyl, substituted or unsubstituted C3-C6 carbon ring, substituted or unsubstituted 3-6 membered heterocycle;

[0028] R3 is selected from the following group: H, halogen, nitro, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy;

[0029] R4 is selected from the following group: H, C1-C4 alkoxy, C(O)Ra, S(O)2Ra;

[0030] Furthermore, the substitution refers to the replacement of one or more H atoms on the group by a group selected from the group consisting of: halogen, C1-C4 alkyl, and C1-C4 alkoxy.

[0031] In another preferred embodiment, the compound of formula A has the structure shown in formula I:

[0032]

[0033] In this context, X and Y are each independently N or CH.

[0034] In another preferred embodiment, R1 is selected from the group consisting of isopropylsulfonyl, cyclohexyl, and 2,3-cyclohexenyl.

[0035] R2 independently represents a group selected from the group consisting of: hydrogen atom, methoxy group,

[0036] R3 independently represents a group selected from the group consisting of: hydrogen atom, fluorine atom, methoxy group, trifluoromethoxy group, acetyl group, trifluoromethyl group, methyl group, and nitro group.

[0037] Ar1 represents a benzene ring or a pyridine ring.

[0038] In another preferred embodiment, the compound is selected from the group consisting of:

[0039]

[0040]

[0041] A second aspect of the invention provides the use of a compound, an optical isomer thereof, a racemic mixture thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, as described in the first aspect of the invention, characterized in that it is used for purposes selected from the group consisting of:

[0042] (a) To prepare a pharmaceutical composition for the treatment or prevention of diseases or conditions related to the activity or expression level of lysyl tRNA synthetase;

[0043] (b) To prepare a pharmaceutical composition for the treatment or prevention of infectious diseases;

[0044] (c) Prepare agricultural and forestry products selected from the group consisting of herbicides, fungicides or insecticides.

[0045] In another preferred embodiment, the infectious disease is caused by a pathogen selected from the group consisting of viruses, bacteria, fungi, parasites, and malaria.

[0046] In another preferred embodiment, the infectious disease is inflammation.

[0047] In another preferred embodiment, the infectious disease is selected from the group consisting of fungal skin diseases and parasitic diseases caused by Plasmodium.

[0048] In another preferred embodiment, the malaria parasite is a erythrocytic stage malaria parasite.

[0049] A third aspect of the present invention provides a pharmaceutical composition or pesticide composition comprising: (a) a compound as described in the first aspect of the present invention, or an optical isomer thereof, or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier, or a pesticide-acceptable carrier.

[0050] In another preferred embodiment, the pharmaceutical composition contains 0.001-99 wt%, more preferably 0.1-90 wt%, and more preferably 1-80 wt% of a compound of formula A, or an optical isomer thereof or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, based on the total weight of the composition.

[0051] In another preferred embodiment, the pesticide composition is used to inhibit pathogenic microorganisms.

[0052] In another preferred embodiment, the pesticide composition is used to suppress agricultural weeds.

[0053] In another preferred embodiment, the pesticide composition is used to suppress agricultural pests.

[0054] In another preferred embodiment, the pesticide composition is selected from the group consisting of herbicides, fungicides, and insecticides.

[0055] In another preferred embodiment, the pesticide composition is in the form selected from the group consisting of gels, dispersants, emulsions, or solutions.

[0056] A fourth aspect of the present invention provides a method for in vitro non-therapeutic inhibition of lysyl-tRNA synthetase protein translation, the method comprising: contacting lysyl-tRNA synthetase with a compound of formula A as described in the first aspect of the present invention, or an optical isomer thereof or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, thereby inhibiting the activity of lysyl-tRNA synthetase.

[0057] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0058] Figure 1 The binding curve of the compound of this invention with lysine tRNA synthetase of Plasmodium falciparum.

[0059] Figure 2 The effect of the compound of this invention on specifically inhibiting the activity of lysine tRNA synthetase in Plasmodium falciparum.

[0060] Figure 3Results of the inhibitory activity of some selected compounds on the growth of Plasmodium falciparum strains in the erythrocytic stage. Detailed Implementation

[0061] Through extensive and in-depth research, the inventors have discovered for the first time a class of aromatic compounds with structures as shown in Formula A that can efficiently inhibit lysine-tRNA synthetase from Plasmodium falciparum, significantly and directly inhibiting the growth of the parasite. Experiments show that the compound of Formula A has a good inhibitory effect on Plasmodium lysine-tRNA synthetase. It also exhibits low toxicity to mammalian cells. Because lysine-tRNA synthetase is ubiquitous in various pathogenic microorganisms, as well as agricultural weeds and pests, the compound of Formula A of this invention can also be used for human or veterinary applications in treating infectious diseases such as viruses, bacteria, fungi, parasites, malaria, and inflammation, as well as for use as a herbicide, fungicide, insecticide, and other agricultural and forestry pesticides.

[0062] the term

[0063] malaria

[0064] Malaria is widespread globally and is one of the most serious parasitic diseases threatening human health, posing a significant public health problem in vast areas of Asia, Africa, and Latin America. Statistics show that there are currently 120 million malaria patients and nearly 300 million carriers worldwide; millions of children in Africa die from malaria each year. While some individuals possess innate immunity to certain malaria parasites due to genetic factors, and infants in high-malaria areas may inherit some resistance from their mothers, most people are generally susceptible to malaria. In endemic areas, adults have a higher chance of repeated infection and may become carriers, while children are the primary susceptible population. Pregnant women, with their unique physiological functions and weakened immunity, are also more susceptible to malaria. Furthermore, individuals without immunity from non-malaria areas who enter malaria-endemic areas are also susceptible and can cause malaria outbreaks.

[0065] Lysyl tRNA synthase

[0066] Lysyl-tRNA synthetase (LysRS) catalyzes the synthesis of lysine and tRNA. Lys Production of lysyl-tRNA Lys Enzymes are ubiquitous in various pathogenic microorganisms, as well as agricultural weeds and pests. Existing research in this field has demonstrated their presence in the metabolic activities of many organisms and their potential as effective therapeutic targets for diseases or conditions such as viral infections.

[0067] Compound A

[0068] As used herein, "compound of the present invention" or "compound of formula A" are used interchangeably to refer to the compound represented by formula A, its racemic mixture, corresponding isomer, or pharmaceutically acceptable salt thereof. It should be understood that the term primarily includes mixtures of the foregoing components.

[0069]

[0070] In the formula,

[0071] R1 independently represents a group selected from the group consisting of isopropylsulfonyl, cyclohexyl, and 2,3-cyclohexenyl.

[0072] R2 independently represents a group selected from the group consisting of: hydrogen atom, methoxy group,

[0073] R3 independently represents a group selected from the group consisting of: hydrogen atom, fluorine atom, methoxy group, trifluoromethoxy group, acetyl group, trifluoromethyl group, methyl group, and nitro group.

[0074] Ar1 represents a benzene ring or a pyridine ring.

[0075] This invention also includes pharmaceutically acceptable salts of compounds of formula A. The term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of this invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are salts formed by the compounds of this invention with acids. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0076] The compound of formula A of the present invention can be prepared using methods well known to those skilled in the art, and there are no particular limitations on the reaction parameters of each step. Furthermore, the above compound is also commercially available.

[0077] Unless otherwise specified, all compounds mentioned in this invention are intended to include all possible optical isomers, such as compounds with a single chirality, or mixtures of various chiral compounds (i.e., racemates). In all compounds of this invention, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0078] use

[0079] The compound of formula A of the present invention can be used to inhibit pathogen lysine tRNA synthetase, thereby preventing or treating infectious diseases.

[0080] The present invention also provides a method for inhibiting lysyl-tRNA synthetase for use in agricultural herbicides, fungicides, and insecticides.

[0081] In one embodiment, the present invention provides an in vitro non-therapeutic method for inhibiting Plasmodium falciparum lysyl-tRNA synthetase, comprising, for example, contacting Plasmodium falciparum lysyl-tRNA synthetase with a compound of formula A (or its optical isomer or racemic mixture, or its solvate or pharmaceutically acceptable salt) in an in vitro culture system to inhibit the activity of Plasmodium falciparum lysyl-tRNA synthetase.

[0082] The present invention also provides a method for inhibiting lysyl-tRNA synthetase from Plasmodium falciparum, which may be therapeutic or non-therapeutic. Typically, the method includes the step of administering the compound of formula A of the present invention to a desired object. Preferably, the object includes humans and non-human animals (rodents, rabbits, monkeys, livestock, poultry, dogs, cats, pigeons, etc.).

[0083] Composition and method of application

[0084] Because the compounds of the present invention have excellent inhibitory activity against lysyl-tRNA synthetase, the compounds of the present invention, or their optical isomers or racemates, or their solvates or pharmaceutically acceptable salts, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient, can be used for (a) inhibiting the activity of lysyl-tRNA synthetase; (b) for human or veterinary use in treating infectious diseases such as viruses, bacteria, fungi, parasites, malaria, and inflammation by inhibiting the activity of lysyl-tRNA synthetase, and for use as herbicides, fungicides, insecticides, and other agricultural and forestry drugs.

[0085] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects.

[0086] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0087] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0088] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin wax; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0089] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and in such compositions, the release of the active compound or compound can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0090] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0091] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0092] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0093] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0094] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0095] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0096] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) in need of treatment. The dosage at the time of administration is the pharmaceutically considered effective dosage, and the specific dosage should take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0097] pesticide compositions

[0098] Suitable pesticide compositions are bioactive compounds used to control agricultural pests, including but not limited to herbicides, plant growth regulators, crop desiccants, fungicides, bactericides, bacteriostatic agents, insecticides, and repellents, together with their water-soluble salts and esters.

[0099] The pesticide compositions of the present invention may be in the form of gels, dispersants, emulsions, or solutions, wherein various wetting agents, dispersants, emulsifiers, or gelling agents are optionally incorporated. Dispersants and emulsifiers include sulfosalicylate esters, quaternary ammonium derivatives or products based on condensates of ethylene oxide and nonanol and octanol, or carboxylic acid esters of dehydrated sorbitol that are soluble by etherifying free hydroxyl groups through condensation with ethylene oxide, and mixtures of these types of agents. These gels, emulsions, suspensions, dispersions, and / or solutions may be prepared using aqueous, organic, or aqueous-organic diluents, such as acetophenone, isophorone, toluene, xylene, mineral oil, animal oil, or vegetable oil, and water-soluble polymers (and mixtures of these diluents), which may contain ionic or nonionic wetting agents, dispersants, or emulsifiers, or mixtures thereof, such as those types described above.

[0100] In a preferred experimental design, the composition of the present invention is in the form of an aqueous solution, i.e., the carrier is water.

[0101] The main advantages of this invention include:

[0102] (a) The compound of formula A of the present invention has a significant inhibitory effect on lysyl-tRNA synthetase, and its inhibitory effect on the IC50 of Plasmodium falciparum lysyl-tRNA synthetase is significant. 50 The value reached 578.8 nM.

[0103] (b) The typical compound A of the present invention targets the lysine tRNA synthetase of Plasmodium falciparum with a well-defined mechanism of action.

[0104] (c) The compound of formula A of the present invention has good prospects for development and application in the treatment of a variety of diseases related to the target of lysyl tRNA synthetase.

[0105] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0106] Synthesis Examples

[0107] The general synthesis method of this invention is as follows:

[0108] Step 1

[0109]

[0110] Under argon protection, 2,4-dichloro-1,3,5-triazine (1.5 equivalents) was added to aniline compound (300 mg). Anhydrous tetrahydrofuran (10 mL) was added to the reaction system in the dark, followed by stirring with N,N-diisopropylethylamine (1 mL). The mixture was stirred at room temperature for 48 hours under argon protection in the dark. After the reaction was completed, the mixture was quenched with water, and the aqueous phase was extracted with ethyl acetate (3 × 5 mL). The organic phases were combined and dried over Na₂SO₄. After removing the solvent by rotary evaporation, the crude product was purified by rapid column chromatography (petroleum ether: ethyl acetate 3:1) to give a white solid product (400 mg, yield 85%).

[0111] Step 2

[0112]

[0113] Under argon protection, 1.5 equivalents of o-methoxyaniline substrate were added to the product (50 mg) from step 1. Anhydrous N,N-dimethylformamide (DMF, 3 mL) was added to the reaction mixture in the dark, followed by stirring with N,N-diisopropylethylamine (DIPEA, 0.75 mL). The mixture was stirred at room temperature for 12 hours under argon protection in the dark. After the reaction was complete, the mixture was quenched with water, and the aqueous phase was extracted with ethyl acetate (3 × 5 mL). The organic phases were combined and dried over Na₂SO₄. After removing the solvent by rotary evaporation, the crude product was purified by rapid column chromatography (petroleum ether:ethyl acetate 2:1) to obtain the final product.

[0114] By using different o-methoxyaniline substrates, the following compounds were obtained:

[0115] JZ031

[0116]

[0117] 1 H NMR(500MHz,cdcl3)δ8.29(s,1H),8.08(s,1H),7.81(d,J=8.4Hz,1H), 7.47(s,1H),7.28(dd,J=8.5,1.7Hz,1H),7.25(d,J=2.9Hz,1H),7.16(dd,J= 17.0,9.8Hz,1H),6.51(d,J=2.0Hz,1H),6.02(d,J=7.6Hz,1H),5.71(d,J=9.7 Hz,1H),3.85(s,3H),3.66(d,J=11.8Hz,2H),3.61(d,J=5.3Hz,1H),2.68(dd, J=26.4,14.2Hz,6H),2.63(s,2H),2.36(s,3H),2.13(d,J=9.3Hz,2H),2.02–1.90 (m,5H),1.70(ddd,J=26.9,19.0,10.0Hz,6H),1.66–1.54(m,2H).

[0118] JZ032

[0119]

[0120] 1H NMR(500MHz,cdcl3)δ8.27(s,1H),8.05(d,J=30.8Hz,1H),7.65(s, 1H),7.47(s,1H),7.35–7.28(m,1H),7.25–7.20(m,2H),6.50(s,1H),3.83(s,3H), 3.64(d,J=11.4Hz,2H),2.78–2.59(m,7H),2.51(s,3H),2.38(t,J=11.4Hz,1H),2.31(s,3H),2.17(d,J=2.6Hz,2H),1.94(d,J=12.1Hz,2H),1.81(d,J=10.9Hz, 4H),1.69(ddd,J=18.3,15.5,8.0Hz,3H),1.50–1.31(m,4H),1.31–1.19(m,2H).

[0121] JZ033

[0122]

[0123] 1 H NMR(500MHz,cdcl 3 )δ9.45(s,1H),8.71(s,1H),8.46(s,2H),7.91(dd, J=7.9,1.3Hz,2H),7.66(t,J=7.4Hz,1H),7.33(d,J=8.4Hz,1H),7.28(d,J= 7.7Hz,1H),6.97(d,J=8.5Hz,1H),3.98(s,3H),3.31–3.20(m,1H),1.32(t,J= 6.0Hz,6H).

[0124] JZ034

[0125]

[0126] 1H NMR(500MHz,cdcl3)δ9.51(s,1H),9.03(s,1H),8.59(d,J=8.4Hz,1H), 8.46(s,1H),7.89(t,J=7.1Hz,1H),7.81(dd,J=8.5,1.5Hz,1H),7.73(s,1H), 7.63(t,J=7.8Hz,1H),7.22(t,J=7.6Hz,1H),6.95(d,J=8.6Hz,1H),3.97(s,3H),3.88(s,3H),3.31–3.20(m,1H),1.31(t,J=6.7Hz,6H).

[0127] JZ035

[0128]

[0129] 1 H NMR(500MHz,cdcl3)δ9.31(s,1H),8.43(d,J=66.0Hz,2H),8.10(d,J =8.8Hz,1H),7.87(d,J=7.9Hz,1H),7.61(s,2H),7.22(t,J=7.4Hz,1H),6.51 (t,J=7.0Hz,2H),3.87(s,3H),3.81(s,3H),3.24(dq,J=14.2,7.1Hz,1H),1.30 (d,J=6.8Hz,6H).

[0130] JZ036

[0131]

[0132] 1 H NMR(400MHz,cdcl3)δ9.38(s,1H),8.51(d,J=8.4Hz,1H),8.37(s,1H), 8.10(s,1H),7.81(dd,J=7.9,1.2Hz,2H),7.63–7.54(m,1H),7.17(dd,J=13.5,5.9Hz,1H),6.74(t,J=8.6Hz,1H),6.58–6.47(m,1H),3.78(d,J=9.7Hz,3H), 3.77–3.63(m,3H),3.18(m,J=6.8Hz,1H),1.24(d,J=6.8Hz,6H).

[0133] JZ037

[0134]

[0135] 1 H NMR(500MHz,acetone)δ9.77(s,1H),9.30(s,1H),8.59(d,J=8.3Hz, 2H),8.43–8.32(m,1H),7.94–7.83(m,2H),7.73(t,J=7.8Hz,2H),7.36(dtd,J =15.3,8.5,1.0Hz,2H),3.53–3.40(m,2H),1.35–1.21(m,12H).

[0136] JZ038

[0137]

[0138] 1 H NMR(400MHz,cdcl3)δ9.27(s,1H),8.45(d,J=8.1Hz,1H),8.37(s,1H), 8.27(d,J=5.6Hz,1H),7.78(dt,J=79.5,39.7Hz,2H),7.57(t,J=7.8Hz,1H), 7.24–7.13(m,1H),7.07–6.96(m,1H),6.91(t,J=7.7Hz,1H),6.84(dd,J=10.6, 9.4Hz,1H),3.90–3.79(m,3H),3.26–3.11(m,1H),1.24(d,J=6.9Hz,6H).

[0139] JZ039

[0140]

[0141] 1 H NMR(400MHz,cdcl3)δ9.35(s,1H),8.61–8.48(m,1H),8.43(s,1H), 8.13(d,J=29.0Hz,1H),7.88(dd,J=16.9,10.1Hz,1H),7.76(d,J=47.8Hz,1H), 7.65(t,J=7.8Hz,1H),7.27–7.19(m,1H),6.84(dt,J=21.4,4.9Hz,2H),3.95– 3.78(m,3H),3.35–3.17(m,1H),2.37–2.19(m,3H),1.29(dd,J=19.4,7.0Hz, 6H).

[0142] JZ040

[0143]

[0144] 1 H NMR(500MHz,cdcl3)δ8.35(s,1H),7.76(d,J=61.3Hz,2H),7.26(dd, J=17.5,12.7Hz,2H),7.18(t,J=7.3Hz,1H),6.77(d,J=8.6Hz,1H),6.51(d,J =7.2Hz,1H),6.00(s,1H),5.70(s,1H),3.80(d,J=25.4Hz,3H),3.73–3.53(m, 3H),3.22(dd,J=89.3,73.3Hz,2H),2.17(d,J=0.7Hz,1H),2.07(d,J=27.5Hz, 2H),2.01–1.94(m,1H),1.74(s,1H),1.58(d,J=18.6Hz,2H).

[0145] JZ041

[0146]

[0147] 1 H NMR(500MHz,cdcl 3 )δ9.48(s,1H),8.75–8.64(m,1H),8.61–8.53(m, 1H),8.49–8.44(m,1H),8.05–7.99(m,1H),7.95–7.90(m,1H),7.82–7.77(m, 1H),7.68(ddd,J=20.8,12.1,4.9Hz,1H),4.04(dd,J=7.8,4.3Hz,3H),4.03– 3.99(m,2H),3.28–3.22(m,1H),1.32(dt,J=4.9,2.6Hz,6H).

[0148] JZ042

[0149]

[0150] 1H NMR(500MHz,cdcl3)δ9.37(s,1H),8.56(dd,J=23.0,14.4Hz,1H),8.48 (d,J=11.0Hz,1H),7.88(dd,J=21.4,6.4Hz,2H),7.66(t,J=8.0Hz,1H),6.99– 6.87(m,1H),4.08–4.00(s,3H),3.25(dt,J=13.9,6.9Hz,1H),3.19(d,J=14.3 Hz,2H),1.31(t,J=6.5Hz,6H).

[0151] JZ043

[0152]

[0153] 1 H NMR(500MHz,cdcl 3 )δ9.28(s,1H),8.52(d,J=8.4Hz,1H),8.34(s,1H), 7.86(d,J=7.9Hz,1H),7.68–7.63(m,1H),7.20(d,J=7.8Hz,1H),6.90(d,J=7.8Hz,1H),6.61(dd,J=7.8,5.1Hz,1H),5.60(s,1H),4.74(s,1H),3.83(s,3H), 3.31–3.18(m,1H),1.30(d,J=6.8Hz,6H).

[0154] JZ044

[0155]

[0156] 1 HNMR(400MHz,CDCl3)δ9.49(s,1H),8.55–8.49(m,1H),8.38(s,1H), 8.14(dd,J=10.6,3.0Hz,1H),7.95–7.86(m,1H),7.67(dd,J=17.3,8.5Hz,2H), 7.31(dd,J=14.1,6.3Hz,1H),6.83(dd,J=9.0,4.9Hz,1H),6.79–6.71(m,1H), 3.92(d,J=12.8Hz,3H),3.23(m,J=13.7,6.8Hz,1H),1.32(t,J=7.3Hz,6H).

[0157] JZ045

[0158]

[0159] 1 H NMR (400MHz, CDCl3) δ9.33 (s, 1H), 8.45 (s, 2H), 7.91 (d, J = 7.7Hz, 1H), 7.86 (d, J = 7.5Hz, 1H), 7.68 (dd, J = 15.3, 7.8Hz, 1H), 7.35–7.23 (m, 2H), 6.95–6.83(m,2H),3.96–3.89(m,3H),3.28–3.20(m,1H),1.30(d,J=6.8Hz, 6H).

[0160] Biological Example 1

[0161] Experiment on the binding of compounds to lysine-tRNA synthetase of Plasmodium falciparum

[0162] First, the *Plasmodium falciparum* lysine-tRNA synthetase protein was diluted to 10 μM in a buffer containing 20 mM tris(hydroxymethyl)aminomethane (pH adjusted to 8.0 with hydrochloric acid), 200 mM sodium chloride, 500 μM lysine, and 200 μM of different compounds, and incubated at room temperature for 10 minutes. Then, the protein was further diluted in an assay buffer containing 20 mM tris(hydroxymethyl)aminomethane (pH 8.0) and 200 mM sodium chloride. Orange dye (Sigma) was diluted to a 40-fold concentration, and then 10 μl of the 40-fold dye solution was added to the reaction system, resulting in a final concentration of 4-fold. After vortexing and mixing, the sample was aliquoted into 96-well PCR plates to achieve a final assay volume of 20 μl. After complete mixing, the final solution was heated from 25°C to 90°C at a rate of 0.015°C / s, and the fluorescence signal was monitored using a QuantStudio 3 instrument (Applied Biosystems, Thermo Fisher Scientific).

[0163] Test results as follows Figure 1 As shown in the figure, the binding curve of the compound of the present invention to Plasmodium falciparum lysine tRNA synthetase is as follows. Figure 1 As shown, the results indicate that the compounds of this invention have a good binding effect with Plasmodium falciparum lysine tRNA synthetase, and the compounds have a certain influence on the thermal denaturation temperature of Plasmodium falciparum lysine tRNA synthetase. Specifically, compounds JZ034, JZ038, and JZ042, ​​after binding with Plasmodium falciparum lysine tRNA synthetase, increased its thermal denaturation temperature by 10.31℃, 10.06℃, and 8.82℃, respectively.

[0164] Biological Example 2

[0165] Compounds JZ034, JZ036, and JZ038 effectively and specifically inhibit the activity of lysine tRNA synthetase from Plasmodium falciparum.

[0166] Phosphate ions produced by the enzymatic aminoacylation of Plasmodium falciparum lysyl-tRNA synthetase were determined using a malachite green phosphate assay system (Sigma-Aldrich) on BIOFIL 96-well tissue culture plates. The assay was performed in an 80 μL system containing 40 mM 4-hydroxyethylpiperazine ethanesulfonic acid (pH 7.5), 100 nM Plasmodium falciparum lysyl-tRNA synthetase protein, 1 mM dithiothreitol, 8 mM magnesium chloride, 500 μM L-lysine, 0.32 nM-125 μM of the compound, and 100 μM adenine triphosphate. The reagent mixture was shaken at 1000 rpm for one minute and then incubated at 30 °C for 6 hours. Enzyme activity was terminated by adding 20 μL of malachite green working reagent for color development. The mixture was shaken at 1000 rpm for one minute and then incubated at room temperature for 30 minutes. Finally, the OD at 612 nm was measured using a Magellan Tecan plate reader, and the half-maximal inhibitory concentration (IC50) of the compound was calculated using Prism (GraphPad) to perform nonlinear regression fitting curves. 50 The result is as follows Figure 2 As shown, Figure 2 The inhibition curves of lysyl-tRNA synthetase activity of Plasmodium falciparum are shown, along with the IC50 values ​​of compounds JZ034, JZ036, and JZ038. 50 The values ​​were 9.682 μM, 578.8 nM, and 4.545 μM, respectively.

[0167] Biological Example 3

[0168] Compounds JZ034, JZ036, and JZ038 effectively inhibit the growth of Plasmodium parasites.

[0169] According to standard procedures in human O +Parasites were cultured in erythrocytes. To prepare >80% circular parasites, asynchronous cultures of the parasites were pretreated with 5% sorbitol to synchronize their growth cycle to the intermediate circular phase (6–10 hours post-invasion). Antimalarial activity was tested in 96-well plates using Plasmodium falciparum strains. The parasites were incubated in 96-well plates with a compound containing 1% parasitic disease and 2% hematocrit, for a total of 200 μL. The maximum concentration of the compound was 10 μM. The parasites were grown at 37°C, 5% CO2, 5% O2, and 90% N2 for 72 hours. After 72 hours, 100 μL of lysis buffer (0.12 mg / ml saponin, 0.12% Triton X-100, 30 mM 4-hydroxyethylpiperazine ethanesulfonic acid, 7.5 mM ethylenediaminetetraacetic acid) containing 5X SYBR Green I (Invitrogen; provided at 10000× concentration) was added to each well of the plate. The plates were then incubated in the dark for 2 hours, and fluorescence signals were read by excitation at 485 nm and emission at 535 nm on an instrument. The inhibitory activity of compounds JZ034, JZ036, and JZ038 against *Plasmodium falciparum* strains in the erythrocytic stage is shown in the following results. Figure 3 As shown, the half-maximum effective concentrations (C5) of compounds JZ034, JZ036, and JZ038 were measured. 50 The effective concentrations were 453 nM, 250 nM, and 2.17 μM, respectively. It can be seen that the preferred compound also significantly inhibited the growth of Plasmodium falciparum in its erythrocytic stage.

[0170] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound, or an optical isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, as shown in the following formula: (A) In the formula, Ar is selected from the following group: benzene ring; R1 is selected from the following group: S(O)2Ra; Ra is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl groups; R2 is selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, C(O)ORa; R3 is selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; R4 is selected from the following group: H, substituted or unsubstituted C1-C6 alkoxy groups; Furthermore, R2, R3, and R4 are not all H at the same time; Furthermore, the substitution refers to the replacement of one or more H atoms on the group by a group selected from the group consisting of C1-C6 alkyl and C1-C6 alkoxy groups.

2. The compound of claim 1, or its optical isomer or racemate, or its pharmaceutically acceptable salt, characterized in that, Ar is selected from the following group: benzene ring; R1 is selected from the following group: S(O)2Ra; Ra is selected from the group consisting of substituted or unsubstituted C1-C4 alkyl groups; R2 is selected from the following group: H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, C(O)ORa; R3 is selected from the following group: H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy; R4 is selected from the following group: H, substituted or unsubstituted C1-C4 alkoxy groups; Furthermore, the substitution refers to the replacement of one or more H atoms on the group by a group selected from the group consisting of C1-C4 alkyl and C1-C4 alkoxy groups.

3. The compound of claim 1, or its optical isomer or racemate, or its pharmaceutically acceptable salt, characterized in that, Ar is selected from the following group: benzene ring; R1 is selected from the following group: S(O)2Ra; Ra is selected from the following group: methyl; R2 is selected from the following group: H, C1-C4 alkyl, C1-C4 alkoxy, C(O)ORa; R3 is selected from the following group: H, C1-C4 alkyl, C1-C4 alkoxy; R4 is selected from the following group: H, C1-C4 alkoxy.

4. The compound according to any one of claims 1-3, or its optical isomer or racemate, or its pharmaceutically acceptable salt, characterized in that, The compound of formula A has the structure shown in formula I: I In this context, X and Y are each independently represented by CH.

5. The compound of claim 1, or its optical isomer or racemate, or its pharmaceutically acceptable salt, characterized in that, R1 is selected from the group consisting of isopropylsulfonyl; R2 independently represents a group selected from the group consisting of: hydrogen atom, methoxy group; R3 independently represents a group selected from the group consisting of: hydrogen atom, methoxy group, and methyl group.

6. The compound of claim 1, or its optical isomer or racemate, or its pharmaceutically acceptable salt, characterized in that, R2 independently represents a group selected from the group consisting of: hydrogen atom, methoxy group; R3 independently represents a group selected from the group consisting of: hydrogen atom, methoxy group, and methyl group.

7. The compound of claim 1, or its optical isomer or racemate, or its pharmaceutically acceptable salt, characterized in that, The compounds are selected from the following group:

8. Use of the compound as claimed in claim 1, or an optical isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that, For use in the group selected below: (a) To prepare compositions for the treatment or prevention of diseases or conditions related to the activity or expression level of lysyl tRNA synthetase.

9. The use as described in claim 8, characterized in that, Used to prepare pharmaceutical compositions for the treatment or prevention of infectious diseases.

10. The use as described in claim 8, characterized in that, Used to prepare pesticide compositions selected from the group consisting of herbicides, fungicides, or insecticides.

11. The use as described in claim 9, characterized in that, The infectious diseases described are caused by pathogens selected from the group consisting of: viruses, bacteria, fungi, parasites, and malaria.

12. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: (a) the compound of claim 1, or an optical isomer thereof or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier.

13. A pesticide composition, characterized in that, The pesticide composition comprises: (a) the compound of claim 1, or an optical isomer thereof or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, and (b) a pesticidely acceptable carrier.

14. A method for non-therapeutic inhibition of protein translation by lysyl-tRNA synthetase in vitro, characterized in that, The activity of lysyl tRNA synthase is inhibited by contacting it with a compound of formula A as described in claim 1, or an optical isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof.

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