Animal models, screening methods, and treatment methods for intraocular diseases or disorders

Abstract

To provide screening methods and animal models related to intraocular diseases such as age-related macular degeneration (AMD), for example, for identifying candidate therapeutics for treating or preventing eye diseases, such as AMD.SOLUTION: Provided herein are compounds / compositions that are useful for killing or inhibiting the growth of a microorganism, such as Bacillus megaterium. Further provided are methods of using the compounds / compositions for treating infections with a microorganism, such as Bacillus megaterium, and for treating or preventing diseases or disorders associated with such infections, such as AMD.SELECTED DRAWING: Figure 1

Description

Technical field

[0001] [Cross reference to related applications] This application is filed with international application number PCT / CN2019 / 070 on January 7, 2019. 572, International Application No. PCT / CN2019 / 084 filed on April 25, 2019 369, and Chinese Patent Application No. 201811351 filed on November 14, 2018 660.9 and the disclosures of any of these patents are incorporated by reference in their entirety. Incorporated for all purposes by.

[0002] TECHNICAL FIELD The present invention relates generally to the technical field of diagnosis and treatment of eye diseases, and more specifically to the technical field of eye disease diagnosis and treatment. The present invention relates to methods for treating or preventing ocular diseases or disorders. Multiple implementations In embodiments, the present disclosure further relates to a subject, such as a human patient or a vertebrate, such as a dog, cat, horse or provides compounds, compositions, and compounds for treating and / or preventing age-related macular degeneration (AMD) in monkeys. and methods. [Background technology]

[0003] The eyes can be said to be a very important window into the soul. people use their eyes every day However, the eyes are extremely fragile. Various factors can cause eye discomfort and lesions. water. Common eye diseases include conjunctivitis and dry eye syndrome, as well as more serious intraocular diseases. or disorders include cataracts (Cat), age-related macular degeneration (AMD), glaucoma (GLA), Includes Chet disease (BD), Vogt-Koyanagi-Harada syndrome (VKH), uveitis, etc. Ru.

[0004] Among older adults, age-related macular degeneration (AMD) is the leading cause of irreversible vision loss worldwide. Ru. This is a confluent soft tissue deposited between the retinal pigment epithelium (RPE) and Bruch's membrane. characterized by sexual drusen and / or early stage macular retinal pigment changes (intermediate AMD) . In later stages, advanced AMD develops with macular geographic atrophy (dry AMD) and macular choroidal blood. It is characterized by two major subtypes: neovascular (wet AMD). Anti-VEGF treatment is Although it has been used to control wet AMD, there are currently no treatments approved for dry AMD. There was no therapy.

[0005] The pathogenesis of AMD includes both genetic and environmental factors. Currently, AMD In clinical pathology, environmental factors that cause local inflammation and lead to early soft drusen are clearly identified. It's not clear. Complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), HtrA serum Many alterations in genetic loci associated with AMD susceptibility, including lymphopeptidase 1 (HTRA1) were identified in a study, indicating that AMD may be an inflammatory disease.

[0006] Currently in the pathology of AMD, it causes local inflammation and leads to early soft drusen. Environmental factors are not clear. assessing an intraocular disease or disorder in a subject, e.g. a mammal or a human; Improved compositions and methods for treatment or prevention are needed. This disclosure addresses such needs. , and other related needs. [Summary of the invention] [Problem to be solved by the invention]

[0007] In embodiments, the invention provides screening methods for multiple types of eye diseases, such as human eye diseases. law, and animal models. These screening methods and animal models are partially The intraocular environment is not sterile, and some intraocular microbiota such as Bacillus megateri This study was based on the unexpected discovery that corn can be a cause of multiple eye diseases such as AMD. Ru. [Means to solve the problem]

[0008] In some embodiments, the invention provides candidate therapeutic agents for treating or preventing eye diseases such as AMD. Provides a screening method for identifying. The screening method includes, for example, In vitro screening methods or in vitro screening methods using, for example, the animal models described herein. It may also be a boss cleaning method.

[0009] In some embodiments, the invention provides methods for culturing a microorganism in a suitable medium in the presence of a test compound. step a) of determining the growth of said microorganism in said medium in the presence of said test compound. and, optionally, a candidate treatment that inhibits the growth of said microorganism compared to a control. step c) of identifying an agent. Some embodiments In some cases, microorganisms are more likely to be present in the intraocular space (e.g., Aqueous humor in the anterior chamber, suspensory ligament, ciliary body, ciliary body / ciliary muscle, vitreous humor in the posterior chamber, retina, choroid, vision Eye diseases include age-related macular degeneration (AMD), - Chet's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vo Selected from gt, Koyanagi-Harada syndrome (VKH), and combinations thereof. some fruit In embodiments, the subject is a human subject. In some embodiments, the method comprises treating a human eye disease. Treating diseases such as AMD, BD, Cat, EOS, GLA, VKH or a combination thereof or identify candidate therapeutic agents for prevention.

[0010] In some specific embodiments, the screening method includes screening for candidates for treating or preventing AMD. Identify therapeutic agents. In some embodiments, the microorganism is more susceptible to AMD than healthy subjects. Species that concentrate in the intraocular space (e.g., aqueous humor, vitreous humor, soft drusen) of affected subjects. including. In some embodiments, the microorganism is Staphylococcus epidermidis ( Staphylococcus epidermidis), Pseudomonas aerugino Pseudomonas aeruginosa, Staphylococcus aureus ylococcus aureus), Staphylococcus haemolyticus (Staph ylococcus haemolyticus), Pseudomonas putida (Pseu domonas putida), Stenotrophomonas maltophilia (Steno trophomonas maltophilia), Bacillus cereus (Bacil lus cereus), Bacillus megaterium ium), Lactobacillus reuteri , Gardnerella vaginalis, Ente Enterococcus faecium, Cytopha Cytophaga hutchinsonii, Bacillus li Bacillus licheniformis, and Xanthomona Contains one or more species selected from Xanthomonas oryzae . In some embodiments, the microorganism is Bacillus megaterium and / or Pseudomonas Including sp putida. In some embodiments, the microorganism is at least Bacillus megateri. Including um. In some embodiments, the microorganism comprises a mixture of microbial species, and the microbial species observed in the aqueous humor, vitreous humor and / or soft drusen of subjects suffering from AMD. Substantially similar to In some embodiments, the microorganism is partially or completely Derived from aqueous humor and / or vitreous humor of subjects suffering from age-related macular degeneration.

[0011] Candidate therapeutic agents to treat or prevent other eye diseases such as BD, Cat, EOS, GLA, VKH The screening method to identify AMD is similar to that described for AMD, but Different microorganisms are used as detailed in the application. For example, in the case of BD, the presence of the test compound The microorganism that is cultured in situ is usually Sphingomonas wich. wittichii), Klebsiella pneumoniae (Klebsiella pne) umoniae), Pseudomonas fluorescens (Pseudomonas fl uorescens), Ralstonia picketii (Ralstonia picket) tii), Lactobacillus crispa tus), Burkholderia multiv orans), Lactobacillus delbrichii (Lactobacillus del brueckii), and Meiothermus sylvanus (Meiothermus si) lvanus) (D). In the case of Cat, testing The microorganisms cultured in the presence of compounds are usually Pseudomonas mendocina (Pseudomonas mendocina). nas mendocina), Kytococcus sedentarius (Kytococcus sedentarius), Alicycliphilus denitrificans (Alicyc liphilus denitrificans), Achromobacter xyloxidans Achromobacter xylosoxidans, Sphingobium sii Sphingobium japonicum, Mycobacterium a Mycobacterium abscessus, Arthrobacter a Arthrobacter aurescens, Prevotella dental Squirrel (Prevotella dentalis), Sinorhizobium meliloti (Si norhizobium meliloti), and Acidovorax ebreus (A cidovorax ebreus). G.L.A. In this case, the microorganism cultured in the presence of the test compound is usually Acinetobacter baumannii (A cinetobacter baumannii), Acinetobacter calcoacetica Acinetobacter calcoaceticus, Comamonas test steroni (Comamonas testosteroni), Mycobacterium mosquito Mycobacterium kansasii, Bacillus thuringiensis Bacillus thuringiensis, Citrobacter koseri (C itrobacter koseri), Diadobacter fermentans (Dya dobacter fermentants), and Serratia marcescens (Ser. ratia marcescens). VKH In this case, the microorganism cultured in the presence of the test compound is usually Escherichia coli (Escherichia coli). coli), Micrococcus luteus , Bacillus subtilis, Corynebacterium aurimucosa Corynebacterium aurimucosum, and Finegoldii Even if it contains one or more species selected from A. magna (Finegoldia magna) good. In some embodiments, the microorganism used in the screening method is a mixture of microbial species. The microbial species may include BD, Cat, EOS, GLA or VKH, respectively. Substantially similar to that observed in the aqueous and / or vitreous humor of affected subjects . In some embodiments, the microorganism used in the screening method is aqueous humor and / or nitrate in subjects suffering from BD, Cat, EOS, GLA or VKH, respectively. It may also be derived from child body fluid.

[0012] The screening method of the present application does not require any specific test compound or any type of test compound. It is not limited to things either. In this application, some exemplary test compounds are described. There is. The screening method of the present application can be used for low throughput, medium throughput or high throughput. Alternatively, multiple types of test compounds may be tested in parallel, if necessary. vinegar Identification in cleaning methods is also not limited to any particular technique. For example, how many In some embodiments, identifying a candidate that prevents visible growth of the microorganism at or below the maximum test concentration. Including identification of therapeutic agents. In some embodiments, the identification is based on the visibility of the microorganism at or below the maximum test concentration. Includes identification of candidate therapeutic agents that prevent appreciable colonization.

[0013] The screening method of the present application is further applicable to subjects suffering from eye diseases rather than healthy subjects. determining, or further comprising the step of determining, one or more microbial species concentrated in the intraocular space of the Eye diseases include age-related macular degeneration (AMD), Behcet's disease (BD), and cataracts ( Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH) ) and combinations thereof. For example, in some embodiments, the invention provides: It is more concentrated in the intraocular space of subjects with age-related macular degeneration (AMD) than in healthy subjects. determining one or more microbial species present in step a), or determining one or more microbial species in the presence of the test compound; , a step of culturing microorganisms containing at least one of the microorganism species to be concentrated in a suitable medium. step b) and measuring the growth of said microorganism in said medium in the presence of said test compound. c) and optionally a candidate therapeutic agent that inhibits the growth of said microorganism compared to a control. and step d) of determining.

[0014] Some embodiments of the present invention relate to methods of producing the eye disease animal models of the present application. usually , animal models are used for human eye diseases. The animal model produced by the above method is also applicable to the present invention. This is an embodiment.

[0015] Usually, the method for creating an animal model involves using a microorganism and / or an inactivated protein derived from the microorganism. microorganisms that are more susceptible to eye disease than healthy subjects Eye diseases include cataracts (Cat), age-related macular Degenerative disease (AMD), glaucoma (GLA), Behcet's disease (BD), Vogt・Koyanagi・Harada syndrome (VKH), endophthalmitis (EOS), and combinations thereof. induce one or more symptoms of the disease.

[0016] In some specific embodiments, the invention provides methods for generating AMD animal models. go In some embodiments, the method comprises using a microorganism and / or an inactivated protein derived from said microorganism. involves introducing the microorganism into the intraocular space of the animal's eye, and the microorganism is more likely to be present in AMD than in healthy subjects. Contains species that concentrate in the intraocular space of affected subjects, and the introduction may induce one or more symptoms of AMD. Induce. The method typically introduces live microorganisms into the intraocular space of the animal. Some embodiments In this case, the microorganisms to be introduced include at least a living Bacillus megaterium. Like Alternatively, the animal is a non-human primate (eg, a monkey). In some embodiments, the motion The object is a rhesus monkey.

[0017] The AMD animal model created in this application can also be used to identify candidate therapeutic agents to treat or prevent AMD. can be used. For example, in some embodiments, the present invention also provides test compounds in the present application. step a) of administering to an AMD animal model as described and one or more ocular diseases following administration. step b) of determining the severity of the symptoms and, optionally, determining the severity of said symptoms compared to a control. step c) of identifying a candidate therapeutic agent that alleviates at least one provide law.

[0018] In some embodiments, the present invention also provides treatment or prevention of the eye diseases of the present application, such as AMD. Provide a way to prevent this. In some embodiments, the method provides instructions to a subject in need thereof. , for corresponding eye diseases such as AMD identified by any of the screening methods herein. administering an effective amount of any of the candidate therapeutic agents.

[0019] In some embodiments, the present disclosure relates to microorganisms associated with AMD, such as Bacillus megateri containing multiple types of compounds and / or said compounds that can kill or inhibit the growth of The present invention relates to a composition comprising: In some embodiments, the present disclosure provides formulas I, I, as defined herein. Compounds according to any one of I, III, IV-1, IV-2, V and any subformula thereof or a pharmaceutically acceptable salt or ester. In some embodiments, the present invention Indicates a compound of any of Compounds 1 to 8, or a pharmaceutically acceptable salt or ester. I will provide a. In some embodiments, compounds of the present disclosure may be derived from synthetic sources. In some embodiments, compounds of the present disclosure are isolated or substantially pure compounds. It may be a thing.

[0020] In certain embodiments, one or more compounds of the present disclosure are combined with any pharmaceutically acceptable excipient. A pharmaceutical composition comprising: For example, in some embodiments, the pharmaceutical composition comprises formulas I, II , III, IV-1, IV-2, V, any subformula of these, or compounds 1 to 8 or a pharmaceutically acceptable salt or ester, e.g. For example, the subject's eyes (e.g. intraocular space), blood and / or gastrointestinal tract, e.g. intestines. Effective in killing or inhibiting the growth of organisms such as Bacillus megaterium . The pharmaceutical compositions of the present application may be administered by any known delivery route, such as oral, topical, intravitreal, intramuscular. They may be prepared for delivery via intravenous, subcutaneous or intravenous administration. In some embodiments The pharmaceutical compositions of the present application may contain antibiotics and / or anti-VE, e.g. It may further include a GF drug.

[0021] In embodiments, the present disclosure provides methods of administering the present invention using a compound of the present disclosure or a pharmaceutical composition of the present application. Treating microorganisms such as Bacillus megaterium infections (e.g. ocular infections, e.g. in the intraocular space) and how to treat or prevent diseases or disorders associated with such infections (e.g. AMD). Provide more law.

[0022] In some embodiments, the present disclosure provides a method for administering the present microbial metaphor in a subject in need thereof. Provided are methods for killing or inhibiting the growth of Bacillus megaterium. go In some embodiments, the method comprises a compound of the present disclosure (e.g., formula I, II, III, IV-1 , IV-2, V, any subformula of these compounds, or any of compounds 1 to 8, or is a pharmaceutically acceptable salt or ester, or a pharmaceutical composition of the present application) to a subject in a therapeutically effective amount. the step of administering. In some embodiments, the subject has AMD. stomach In some embodiments, the subject does not have AMD. In some embodiments, the Examiners are at risk of developing AMD. In some embodiments, the subject's eye is exposed to microorganisms. For example, infected with Bacillus megaterium. In some embodiments, the method comprises For example, if the patient identifies that the intraocular space is infected with a microorganism such as Bacillus megaterium? , or further comprising the identified steps. In some embodiments, for example, as described herein As such, the subject is further administered an antibiotic and / or an anti-VEGF drug.

[0023] In some embodiments, the present disclosure provides a method for treating or preventing AMD in a subject in need thereof. provide law. In some embodiments, the method comprises a compound of the present disclosure (e.g., Formula I, II , III, IV-1, IV-2, V, any subformula of these, or compounds 1 to 8 or a pharmaceutically acceptable salt or ester) to the subject in a therapeutically effective amount. including steps to In some embodiments, the method includes, for example, as described herein. , further comprising administering to the subject an antibiotic and / or an anti-VEGF drug. some In embodiments, AMD is characterized by drusen symptoms (hard drusen, soft drusen, mixed drusen). Dry or wet age-related macular degeneration (including leusen and / or degraded drusen), e.g. It may be dry or wet age-related macular degeneration with soft drusen symptoms. Several In embodiments, the method comprises introducing a microorganism of the present application, e.g. The method further comprises the step of identifying or identifying a P. terinus as infected. Several In embodiments, the subject injects a microorganism of the present application, e.g., Bacillus megaterium, into the intraocular space. It's infected.

[0024] In some embodiments, the present disclosure provides methods for using traditional Chinese medicine (TCM) extracts with antibacterial activity. provide a method. In some embodiments, the method comprises: kills or inhibits the growth of the microorganisms of the present application, such as Bacillus megate (e.g. ocular infection, e.g. in the intraocular space) or to treat or prevent AMD. This is a method to prevent this. In some embodiments, the method provides the subject with licorice (e.g. For example, Glycyrrhiza uralensis), Juniperina (for example, Cyn anchum otophyllum), forsythia (e.g. Forsythia s uspense), Citrus aurantium (e.g. Citrus aurantium L.), Geo Cormorant (e.g. Rehmannia glutinosa Libosch), Chimpi (e.g. For example, Citrus reticulata Blanco), and Sansiti (e.g. Extract derived from one or more TCMs selected from Panax notoginseng) the step of administering. In some embodiments, the method includes a method in which the subject, e.g. during which the microorganism of the present application, such as Bacillus megaterium, is identified as infecting or identified. further steps. In some embodiments, the subject receives the present invention, e.g., into the intraocular space. infected with microorganisms such as Bacillus megaterium. Extract is a single TCM extract Or it may be an extract of one or more TCMs. Usually the extract is an aqueous extract. go In some embodiments, the extract is present in liquid, semi-solid or solid form or any other form. It's okay. In some embodiments, the subject is given antibiotics, e.g., as described herein. Anti-VEGF and / or anti-VEGF agents are also administered.

[0025] In some embodiments, the present disclosure provides treatment using antibiotics in a subject in need thereof. The microorganisms of the present application, e.g. Treat S. megaterium infections (e.g. eye infections, e.g. in the intraocular space) or treat AMD Provided are methods of treatment or prevention. In some embodiments, the method includes, e.g. and administering to the subject an effective amount of an antibiotic, as described. some implementations In this case, use any commercially available antibiotic, e.g. quality is available. In some embodiments, the method includes a method in which the subject, e.g. identified as infecting the desired microorganism, e.g. Bacillus megaterium, or Including more tep. In some embodiments, the subject receives the microorganisms of the present application, e.g., in the intraocular space. Those infected with eg Bacillus megaterium. In some embodiments, e.g. The subject is further administered an anti-VEGF drug as described in the application.

[0026] Administration herein is not limited to any particular route of administration. For example, some In embodiments, administration may be oral, topical, intravitreal, intramuscular, subcutaneous or intravenous. .

[0027] Please note that the above summary and the detailed explanation below are merely examples and interpretations, and do not reflect the invention of the present application. It is not intended to limit. [Brief explanation of drawings]

[0028]

Figure 1

Figure 2

[0029] In embodiments, the present disclosure relates, in part, to the fact that the intraocular environment is not sterile, and that some ocular Based on the surprising discovery that the endoscopic microbiota can play a role in the pathogenesis of multiple eye diseases, such as AMD. It is. Submitted on October 26, 2018, with the name “METHODS AND COMPOSITIONS F OR ASSESSING AND TREATING INTRAOCULAR DISEASES AND DISORDERS” PCT application number No. PCT / CN2018 / 112022, the contents of which are incorporated by reference in their entirety. These initial discoveries, detailed in When B.megaterium is administered live, Discovered that drusenoid lesions can be induced by activating the complement system in vivo in rhesus macaques. did. Additionally, for example, by intravitreal administration of the antibiotic vancomycin. , killing or inhibiting the growth of such microorganisms increases the The size of drusenoid lesions in retinal tissue can be reduced. In addition, implementation of the present application See Example 9. From these data and results, it is clear that such microorganisms such as Bacillus mega Drugs that can kill terium or inhibit its growth may be useful in treating age-related macular degeneration. It is proven that

[0030] For example, as detailed in PCT Application No. PCT / CN2018 / 112022, 41 cases of cataract (Cat), 20 cases of AMD, 18 cases of glaucoma (GLA), Behcet's disease ( BD) in 9 cases, Vogt-Koyanagi-Harada syndrome (VKH) in 9 cases, and endophthalmitis (EOS) in 8 cases. Perform metagenomic sequencing analysis on aqueous humor (AH) specimens from patients. Interesting Notably, in these six patient types, the major intraocular human microbiome of all patients Regardless of the bacterial component, both the alpha diversity and homogeneity of the intraocular microbial community are clearly different. Become. Principal component analysis performed on the composition of the ocular microbiota (all microbial species used) (PCA) among patients with cataracts, EOS, and some glaucoma. There is a significant difference. However, in patients with AMD, VKH, BD, and some glaucoma , the intraocular human microbiome shares characteristics that are difficult to distinguish. Similarly, all meta As revealed by hierarchical cluster analysis of the abundance ratio of functional microbial genes from the genome. showed that each order has common features of microbial function, whereas each disease group has other There are outliers that can be classified into disease clusters. Individuals with remarkable intraocular human microbiome Characteristic bacterial species for each eye disease group tested, regardless of gender, can be identified. It takes In addition, it is clear from the results obtained that the composition and function of the intraocular microbiota may affect ocular diseases, e.g. For example, it can distinguish between AMD, cataract, glaucoma, BD, VKH and EOS.

[0031] Using metagenomic analysis to identify 14 bacterial species highly enriched in AH of AMD patients identify Propionibacterium acnes has the highest abundance in AH of AMD patients. Although highly microbial, among the 14 AMD-specific species, Bacillus licheniformi B. licheniformis, and B. megaterium (B. meg). aterium) is the most enriched species in AMD AH specimens. Next, the inventors stiff compared to non-drusen retinal tissue in six archival eye slides from AMD patients. 14 types of AMD-specific bacteria can be detected in sexual or soft drusen tissue. PCR analysis will be performed to examine whether it is possible. As a result, only 8 types of bacteria were detected. Among these, Propionibacterium acnes is the species with the highest abundance ratio, Bacillus megaterium is a species that concentrates in soft drusen. Propionibacterium ·Relative abundance ratio of acne among hard drusen, soft drusen and dry AMD lesion tissue. is comparable to that in non-drusen, non-lesional retinal tissue. For non-drusen / non-lesional tissue The relative abundance of Bacillus megaterium is approximately 18 times higher in soft drusen than However, this is not the case with AMD lesions. From these data, drusen formation and the possible role of Bacillus megaterium in AMD pathogenesis mechanism revealed .

[0032] Previous studies have shown that, in addition to many other proteins, drusen are a complex of multiple species. Contains complement components and polysaccharides. Furthermore, drusen components activate inflammasomes, Promotes the expression of IL-1β and IL-18. Therefore, the inventors first Bacillus megaterium, a Zen component, induces activation of the complement system in vitro and Promotes secretion of IL-1β and IL-18 by membrane pigment epitheliitis-19 (ARPE19) cells Find out if it is possible. The inventors discovered that Propionibacterium acnes but not wasps. We found that Rus megaterium significantly increases the pyroptosis of RPE cells in a time-dependent manner. I put it out. Activation of the complement system has been demonstrated by creating an active form of C5A protein. Ru. All two types of bacteria induce CFH protein secretion by ARPE19 cells, whereas , Bacillus megaterium is more susceptible to CFH than Propionibacterium acute. It's more obvious than Ness. Propionibacterium acnes as a result of pyroptosis In vitro infection with Bacillus megaterium but not Bacillus megaterium activates IL-1 by RPE cells. Causes secretion of β and IL-18. As is clear from these results, Bacillus medica Gatherium infection can cause inflammation, which is also found in soft drusen. There is sex.

[0033] Next, we tested whether Bacillus megaterium could induce inflammation in vivo. experiment. The non-human primate rhesus macaque (Macaca fascicu) laris)) takes into account the eye anatomy and intraocular environment shared by humans and rhesus macaques. considered as a model system. Propionibacterium acnes living in the eye infection or inoculation with its ultrasound-inactivated protein induces significant intraocular inflammation. Not yet. However, rather than proteins, living Bacillus megateriu in the eye infection causes significant intraocular inflammation. Attracting with live Bacillus megatherium Induced intraocular inflammation leads to increased expression of TNFA and IL6, but not IFNG and IL17A. Features. Importantly, only live Bacillus megaterium, C5A and CFH activates the complement system, including the pyroptotic cytokines IL-1β and IL- Unable to induce 18. Bacteria continue to live in the eye after the inflammation begins, and this causes This shows that intraocular inflammation can be sustained for a substantial period of time. In short, from these data , Bacillus megaterium infection chronically activates the complement system in vitro and in vivo. , which has been shown to be able to induce pyroptosis in eye cells.

[0034] Without wishing to be bound by theory, for example Bacillus megaterium bacteria The fact that the RPE and bloc activate local complement-mediated immune responses suggests that The formation of various drusen with Ruch's membrane can be interpreted. Lord Found in Drusen All essential proteins (including complement components e.g. C1Q and immunoglobulins) are first-line antibodies. It is a dye. Other drusen proteins such as vitronectin and apolipoprotein E , has recently been proven to be an anti-infective agent. Therefore, drusen formation is associated with aging. This is likely an important response when controlling bacterial pathogens that have invaded the retina. Thin Due to the diversity of bacteria, the shape and size of drusen can vary. For hard drusen , once the infection is cleared, the drusen disappear. However, some pathogens such as Bacillus S. megaterium induces long-term activation of immune responses in soft drusen and RPE Causes damage to cells and photoreceptors. Activation of macrophage inflammation and pyrolysis of RPE cells Tosis is a protective response that resists local infection, and it is a protective response mediated by NLRP3. Preventing retinal neovascularization by activating the flammasome and producing IL-18. This is consistent with previous findings.

[0035] Without wishing to be bound by theory, the infectious etiology of AMD also extends to all genetic studies. This is consistent with the conclusion of For example, defective CFH (induced by Bacillus megaterium infection) negative regulators of complement activation) lead to uncontrolled complement activation. Defective HTRA1( Local TGF-β (a protease that produces the active form of the immunosuppressive cytokine TGF-β) This leads to a decrease in β family proteins. These two types of genetic variation all occur in RPE cells and Causes dysregulation of local anti-infective responses that harm photoreceptors.

[0036] Furthermore, potential differences in pathogenic microbiota found in drusen may suggest different genetic risks. Can interpret associations between factors and different ethnicities (e.g., Caucasian or Asian). Therefore Therefore, the infectious etiology of AMD is a mechanism that causes early AMD pathology in the elderly. There is evidence to show that

[0037] In summary, in embodiments, we kill microorganisms and / or inhibit their growth. If inhibited, AMD, such as drusen symptoms (hard drusen, soft drusen, mixed drusen) Dry or wet age-related macular degeneration (including leusen and / or degraded drusen), e.g. For example, to treat and / or prevent dry or wet age-related macular degeneration with soft drusen symptoms. to clarify.

[0038] Screening method The discovery that multiple intraocular diseases are associated with specific microorganisms has also led to the identification of intraocular diseases such as AMD. support screening methods for candidate therapeutic agents. Therefore, some implementations of the present invention Embodiments relate to multiple screening methods. The screening method of this application is in vitro. methods (e.g. in culture dishes) or in vivo methods (e.g. using the animal models of the present application). ) may be used.

[0039] In some embodiments, the invention provides a screening method, the screening method comprising: comprises step a) of culturing the microorganism in a suitable medium in the presence of the test compound; step b) of measuring the growth of microorganisms in the medium in the presence of and, optionally, compared to a control. step c) of identifying a candidate therapeutic agent that inhibits the growth of the microorganism. Usually microorganisms The intraocular space (e.g., the aqueous humor in the anterior chamber) is lower in subjects with eye diseases than in healthy subjects. , suspensory ligament, ciliary body, ciliary body / ciliary muscle, vitreous humor in the posterior chamber, retina, choroid, optic nerve, crystalline lens eye diseases include age-related macular degeneration (AMD), Behcet's disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), V Selected from OGT, Koyanagi-Harada syndrome (VKH), and combinations thereof. Several In embodiments, the method provides access to the intraocular space of a subject suffering from an eye disease compared to a healthy subject. further comprising step d) of determining or having determined one or more microbial species to be concentrated; Diseases include age-related macular degeneration (AMD), Behcet's disease (BD), cataracts (Cat), and endophthalmitis. (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), and combinations thereof. Selected from a combination. In this method, the healthy subjects used for comparison are those without eye diseases. Refers to the subject. The term "control" referred to in the method refers to a placebo control without test compound. be. It will be obvious to those skilled in the art how to perform suitable experiments for comparison. In any of the foregoing embodiments of this application, to the extent that there is no direct contradiction, the subject may be a human subject. good. In any of the foregoing embodiments of the present application, to the extent that there is no direct contradiction, the screening method comprises: To identify candidate therapeutic agents for treating or preventing human diseases, such as the human eye diseases of the present application. Applicable.

[0040] In some embodiments, the invention provides compounds or combinations of compounds for the treatment or prevention of eye diseases. A method of screening for the effectiveness of combination therapy is provided, the method comprising: The subject, a family member or close genetic relationship of the subject who is affected by the eye disease, or a person who is affected by the eye disease. Samples taken from the aqueous humor or vitreous humor of subjects selected from deceased subjects known to have the disease. the step of obtaining the sample taken and the conditions selected from conditions that mimic the human intraocular space; Or culture one or more of the above samples in a cooked meat medium, and producing a culture; and adding said compound or combination of compounds to said one or more cultures. adding said compound or combination of compounds to said one or more cultures; determining whether to reduce the growth or population thereof. Some embodiments The method then comprises growing the one or more cultures in vitro based on the determined results. or identifying a compound or combination of compounds that reduces the population. You can.

[0041] In some embodiments, family members include members of the subject's immediate family, such as parents, children, or siblings. May include younger sister. In some embodiments, the family member has a long-standing eye disease. This may include people who occupy the same living space as the person being tested. In some embodiments, a close genetic The personal relationship may include a relationship with the subject who is suffering from the disease, and this relationship may include a relationship with the subject who is suffering from the disease. Within the three direct generations of genetic relationship, for example, the subject's great-grandparents, grandparents, parents, children, grandchildren / Granddaughter or great-granddaughter / great-great-granddaughter. In some embodiments, the close genetic relationship is the subject's older brother. May include younger siblings. In some embodiments, a close genetic relationship The relationship may include a relationship between the examinee and the examinee, which is a collateral relationship, such as an uncle, uncle, or father-in-law of the examinee. ·Includes mother-in-law, mother-in-law, cousin, sister, or niece or nephew.

[0042] In some embodiments, the invention provides compounds or combinations of compounds for the treatment or prevention of eye diseases. A method for screening the effectiveness of combinations is provided, the method comprising conditions that mimic the human intraocular space. One or more organisms are cultured under conditions selected from the following conditions or in a cooked meat medium. producing a culture, wherein the one or more organisms are Staphylococcus epi Dermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus Haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Drumstick Lus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella basalis, Enterococcus faecalis, Cytophaga hutchinsonii, Bacillus S. licheniformis, Xanthomonas oryzae, Sphingomonas wich, Kleb Sierra pneumoniae, Pseudomonas fluorescens, Ralstonia pickettii , Lactobacillus crispatus, Burkholderia multiborane, Lactobacillus Delbricki, Meiothermus sylvanus (D), Pseudomonas mendocina, Ki Tococcus sedentarius, Alicycliphilus denitrificans, Achromobac Ter xyloxidans, Sphingobium chaponicum, Mycobacterium ab Sesus, Arthrobacter aurescens, Prevotella dentalis, Sinorhizobium ·Meliloti, Acidovorax ebreus, Acinetobacter baumannii, Acineto Bacterium calcoaceticus, Comamonas testosteroni, Mycobacterium can Sashimi, Bacillus thuringiensis, Citrobacter coseri, Diadobacter f. amentans, Serratia marcescens, Escherichia coli, Micrococcus luteus, Grass fungi, Corynebacterium aurimucosum, Finegordia magna, and these a step selected from the group consisting of combinations; adding said compound or combination of compounds to said one or more cultures; determining whether to reduce the growth or population of more than one species of culture. stomach In some embodiments, the method comprises determining the one or more species in vitro based on the determination. Steps to identify compounds or combinations of compounds that reduce the growth or population of cultures on The method may further include steps.

[0043] In some embodiments, the invention provides compounds or combinations of compounds for the treatment or prevention of eye diseases. A method of screening for the effectiveness of combination therapy is provided, the method comprising: The subject, a family member or close genetic relationship of the subject who is affected by the eye disease, or a person who is affected by the eye disease. Samples taken from the aqueous humor or vitreous humor of subjects selected from deceased subjects known to have the disease. the step of obtaining the sample taken and the conditions selected from conditions that mimic the human intraocular space; Or culture one or more of the above samples in a cooked meat medium, and producing a culture and one or more inactivation tags derived from said one or more cultures; obtaining a solution of the protein and the compound or combination of compounds and the one or more compounds; mixing said compound or combination of compounds with said inactivated protein solution; determining whether the protein binds to the one or more inactivated proteins.

[0044] In some embodiments, the invention provides a compound or combination of compounds for the treatment of eye diseases. provides a method for screening the effectiveness of a subject suffering from said eye disease; A family member or close genetic relationship of the subject who is affected by the eye disease or who is affected by the eye disease. Collected from the aqueous humor or vitreous humor of subjects selected from deceased subjects known to have died. the step of obtaining the sample and the step of obtaining the sample under conditions selected from conditions that mimic the human intraocular space or in a cookie; Cultivate one or more organisms from the samples in Kudomite medium, and create one or more cultures. one or more inactivated proteins derived from said one or more cultures; and applying the one or more inactivated proteins to a mammalian inflammation model. introducing said compound or combination of compounds into said mammalian inflammation model. and the compound or combination of compounds inhibits inflammatory activity in the model. and determining whether or not to lower the amount.

[0045] In some embodiments, the invention provides compounds or combinations of compounds for the treatment or prevention of eye diseases. A method for screening the effectiveness of combinations is provided, the method comprising conditions that mimic the human intraocular space. One or more organisms are cultured under conditions selected from the following conditions or in a cooked meat medium. producing a culture, wherein the one or more organisms are Staphylococcus epi Dermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus Haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Drumstick Lus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella basalis, Enterococcus faecalis, Cytophaga hutchinsonii, Bacillus S. licheniformis, Xanthomonas oryzae, Sphingomonas wich, Kleb Sierra pneumoniae, Pseudomonas fluorescens, Ralstonia pickettii , Lactobacillus crispatus, Burkholderia multiborane, Lactobacillus Delbricki, Meiothermus sylvanus (D), Pseudomonas mendocina, Ki Tococcus sedentarius, Alicycliphilus denitrificans, Achromobac Ter xyloxidans, Sphingobium chaponicum, Mycobacterium ab Sesus, Arthrobacter aurescens, Prevotella dentalis, Sinorhizobium ·Meliloti, Acidovorax ebreus, Acinetobacter baumannii, Acineto Bacterium calcoaceticus, Comamonas testosteroni, Mycobacterium can Sashimi, Bacillus thuringiensis, Citrobacter coseri, Diadobacter f. amentans, Serratia marcescens, Escherichia coli, Micrococcus luteus, Grass fungi, Corynebacterium aurimucosum, Finegordia magna, and these a step selected from the group consisting of a combination; and 1 derived from said one or more cultures. obtaining a solution of more than one species of inactivated protein and said compound or combination of compounds; a solution of the one or more inactivated proteins; a step for determining whether the combination of compounds binds to the one or more inactivated proteins; Including top. In some embodiments, the method is based on the determination result. Identification of compounds or combinations of compounds that bind more than one inactivated protein in vitro The method may further include the step of:

[0046] In some embodiments, the invention provides compounds or combinations of compounds for the treatment or prevention of eye diseases. A method for screening the effectiveness of combinations is provided, the method comprising conditions that mimic the human intraocular space. One or more organisms are cultured under conditions selected from the following conditions or in a cooked meat medium. producing a culture, wherein the one or more organisms are Staphylococcus epi Dermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus Haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Drumstick Lus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella basalis, Enterococcus faecalis, Cytophaga hutchinsonii, Bacillus S. licheniformis, Xanthomonas oryzae, Sphingomonas wich, Kleb Sierra pneumoniae, Pseudomonas fluorescens, Ralstonia pickettii , Lactobacillus crispatus, Burkholderia multiborane, Lactobacillus Delbricki, Meiothermus sylvanus (D), Pseudomonas mendocina, Ki Tococcus sedentarius, Alicycliphilus denitrificans, Achromobac Ter xyloxidans, Sphingobium chaponicum, Mycobacterium ab Sesus, Arthrobacter aurescens, Prevotella dentalis, Sinorhizobium ·Meliloti, Acidovorax ebreus, Acinetobacter baumannii, Acineto Bacterium calcoaceticus, Comamonas testosteroni, Mycobacterium can Sashimi, Bacillus thuringiensis, Citrobacter coseri, Diadobacter f. amentans, Serratia marcescens, Escherichia coli, Micrococcus luteus, Grass fungi, Corynebacterium aurimucosum, Finegordia magna, and these a step selected from the group consisting of a combination; and 1 derived from said one or more cultures. obtaining a solution of one or more inactivated proteins; introducing said compound or combination of compounds into a mammalian inflammation model; introducing said compound or combination of compounds into said mammalian inflammation model; and determining whether the method reduces inflammatory activity in the model. some fruit In embodiments, the method comprises culturing the one or more cultures in vitro based on the determination. identifying a compound or combination of compounds that reduces the growth or population of It may also include. In some embodiments, the compound or combination of compounds includes one or more It may be an anti-inflammatory compound as above.

[0047] In some embodiments, the invention provides compounds or combinations of compounds for the treatment or prevention of eye diseases. provides a method for screening the efficacy of a compound or combination of compounds; administering the compound or combination of compounds to said mammalian model of the present application. the step of determining whether the combination effectively reduces or prevents one or more symptoms of said eye disease; Including. In some embodiments, the drusenoid lesions are present in the mammalian model. Once formed, the compound or combination of compounds is administered. In some embodiments , a compound or a combination of compounds, according to the in vitro screening method of the present application. One or more compounds or combinations of compounds that are identified. In some embodiments, Injection may include intraocular injection. In some embodiments, the one or more symptoms development of senoid lesions, growth or loading of microorganisms, production of inflammatory molecules or markers; selected from the group consisting of a combination of

[0048] The microorganism used in the method may be a substantially biologically pure species or a plurality of different species. You can. In some embodiments, the microorganism is at least one species that is an etiologic agent of an eye disease. Contains seeds. In some embodiments, the microorganism comprises at least one species, and the at least one species Killing or inhibiting the growth of both species is beneficial in treating or preventing eye diseases. That's true. Any technique known in the art may be used to culture the microorganisms and select the medium. Also, some illustrative details are provided in the Examples section. In some embodiments microorganisms may be cultured in liquid cooked meat medium. Measuring or determining microbial growth There are no particular limitations on the methods used, and they are generally known in the field, and are described in the Examples section of this application. Several exemplary methods have been described. For the avoidance of doubt, in this application No quantitative measurements are required in the measurement or determination. In some embodiments, for example, The test compound prevents visible growth of microorganisms below the maximum test concentration and / or If the compound prevents visible colonization of microorganisms below the maximum test concentration, visually Just observing is enough.

[0049] Candidate therapeutic agents may be identified by any suitable technique known in the art. some fruit In embodiments, the test compound inhibits microbial growth relative to a control at or below the maximum test concentration. for example, can be identified as a candidate therapeutic agent for treating or preventing the corresponding eye disease. stomach In some embodiments, the test compound prevents visible growth of microorganisms at or below the maximum test concentration. If the drug stops, it can be identified as a candidate therapeutic agent. In some embodiments, the test compound is As a candidate therapeutic agent if it prevents visible colonization of microorganisms at or below the maximum test concentration. can be identified.

[0050] Test compounds can be tested at a single concentration or at multiple concentrations. stomach In some embodiments, a minimum inhibitory concentration (MIC) of the corresponding test compound may be established. , the concentration allows for comparisons between different test compounds and for further comparison of candidate therapeutic agents. It is advantageous for determination / selection.

[0051] Screening methods for AMD In some specific embodiments, the screening method includes candidate treatments for treating or preventing AMD. It can be used to identify therapeutic agents. In any of the foregoing embodiments of the present application, no contradiction is apparent in the context. AMD is characterized by drusen symptoms (hard drusen, soft drusen, mixed drusen). dry or wet age-related macular degeneration (including deteriorating drusen), e.g. It may be dry or wet age-related macular degeneration with Leusen symptoms. Some embodiments The method then comprises step a) of culturing the microorganism in a suitable medium in the presence of the test compound. , step b) of measuring the growth of the microorganism in the medium in the presence of the test compound. usually, Microorganisms are more likely to be present in the intraocular space (e.g., in the anterior chamber) in subjects with AMD than in healthy subjects. aqueous humor, suspensory ligament, ciliary body, ciliary body / ciliary muscle, vitreous humor in the posterior chamber, retina, choroid, optic nerve, Contains species concentrated in the lens or iris). For example, in some embodiments, the microorganism Aqueous humor, vitreous humor and / or soft drusen in subjects with AMD compared to healthy controls Contains species that are highly concentrated. In some embodiments, the microorganism is Staphylococcus epi Dermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus Haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Drumstick Lus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella basalis, Enterococcus faecalis, Cytophaga hutchinsonii, Bacillus containing one or more species selected from S. licheniformis and Xanthomonas oryzae. Good too. In some embodiments, the microorganism is Bacillus megaterium and / or Pseudo May contain Monas putida. In some embodiments, the microorganism is at least Bacillus. ·Contains Megatherium. In some embodiments, the microorganism is substantially biologically pure. May be a Bacillus megaterium population.

[0052] Various initial concentrations of microorganisms can be used in the screening methods of the present application. for example , in some embodiments, for the screening methods of the present application. concentration of about 1*10 5 ~1*10 9 ( For example about 1*10 6 , about 1*10 8 or about 1*10 8 ) pieces / mL Bacillus megaterium The suspension is placed in a culture dish containing approximately 10-15 mL of culture medium and incubated at appropriate temperature and conditions, e.g. May be incubated for 24 hours at 37°C. For example, in some embodiments, the present application Regarding the screening method, approximately 1*10 5 ~1*10 9 (For example, about 1*10 5 or 1*10 7 ) Bacillus megaterium may be used.

[0053] In some embodiments, the microbial species may include a mixture of microbial species, and the microbial species include: Observation of aqueous humor, vitreous humor and / or soft drusen in subjects suffering from age-related macular degeneration is substantially similar to that given. For example, in some embodiments, the person suffering from AMD Pathogenic species identified in the aqueous humor, vitreous humor, and / or soft drusen of subjects with It may be included in the microorganisms used in the leaning method. The term "substantially similar" means that the microorganism is microorganisms found in the aqueous humor, vitreous humor and / or soft drusen of subjects suffering from MD. It is not required to have the same composition of microbial species as the biological species. Microorganisms account for most of the identified , concentrated in the aqueous humor, vitreous humor, and / or soft drusen of subjects suffering from AMD ( It is sufficient to include a microbial species (preferably pathogenic), eg as described herein. The term "substantially similar" when used in conjunction with other eye diseases should be understood similarly. stomach In some embodiments, the microorganism is present in a subject suffering from age-related macular degeneration, in part or in whole. It may be derived from the aqueous humor and / or vitreous humor. For example, some embodiments , microorganisms are isolated from the aqueous humor and / or vitreous humor of subjects suffering from age-related macular degeneration. It can be obtained by culturing the obtained sample. In some embodiments, the test compound If a substance inhibits the growth of microorganisms (e.g. Bacillus megaterium) compared to a control, It can be identified as a candidate therapeutic agent for treating or preventing AMD.

[0054] In some embodiments, a screen for identifying candidate therapeutic agents to treat or prevent AMD is provided. This method is more effective in subjects suffering from age-related macular degeneration (AMD) than in healthy subjects. Determining or having determined one or more microbial species concentrated in the intraocular space and testing Microorganisms, including at least one of the microorganism species that concentrate in a suitable medium in the presence of a compound. step b) of culturing said microorganism in said medium in the presence of said test compound; step c) of measuring, and optionally inhibiting the growth of said microorganism compared to a control. step d) of identifying a candidate therapeutic agent.

[0055] In some embodiments, the determination is made in a subject suffering from AMD rather than a healthy subject. It may be necessary to obtain information that one or more microbial species are concentrated in the intraocular space of the eye. stomach. In some embodiments, the determination is made from the intraocular space of a subject suffering from AMD. assessing the presence, absence and / or amount of microorganisms in a sample of The presence, absence and / or amount of said microorganisms may be compared to healthy controls. Microorganism The method of assessing the presence, absence and / or quantity of a substance is described in PCT Application No. PCT / CN2018 / 1 Including those listed in 12022. In some embodiments, the microorganism comprises a mixture of microbial species. The microbial species may be present in the aqueous humor or vitreous humor of a subject suffering from age-related macular degeneration. and / or substantially similar to those observed in soft drusen. some implementations In some cases, microorganisms are present in the aqueous humor and / or may be derived from the vitreous humor. For example, in some embodiments, the microorganism is , a sample obtained from the aqueous humor and / or vitreous humor of a subject suffering from age-related macular degeneration. can be obtained by culturing the cells. In some embodiments, the test compound is a control compound. If it inhibits the growth of microorganisms compared to can be identified as

[0056] In some embodiments, a screen for identifying candidate therapeutic agents to treat or prevent AMD is provided. The sampling method uses a sample from the intraocular space of a subject suffering from AMD, e.g. aqueous humor, Step a) of obtaining vitreous humor and / or soft drusen and culturing in the presence of a test compound. step b) of incubating said sample in the presence of said test compound; step c) of measuring the growth of microorganisms in said medium and, optionally, said d) identifying a candidate therapeutic agent that inhibits the growth of the microorganism. stomach In some embodiments, the sample is obtained from the aqueous humor of a subject suffering from AMD. In some embodiments, the sample is obtained from the vitreous humor of a subject suffering from AMD. be done. In some embodiments, the sample is a soft drink from a subject suffering from AMD. Retrieved from Zen. As shown in the Examples section of this application, sample incubation is A sterile environment (e.g. in a sterile medium in a closed environment). In some embodiments, a negative control is used You may. In some embodiments, the test compound increases the amount of microorganisms in the culture medium compared to a control. If it inhibits growth, it can be identified as a candidate therapeutic agent for treating or preventing AMD.

[0057] In some embodiments, the invention provides compounds or compounds for the treatment or prevention of AMD. Provided is a method for screening the effectiveness of a combination, said method comprising: The test subject, a family member or close genetic relationship of the test subject with AMD, or a close genetic relationship with AMD. Samples collected from the aqueous humor or vitreous humor of subjects selected from deceased subjects known to have Steps to obtain a sample of the human eye and conditions that mimic the human intraocular space. Cultivate one or more organisms from the above samples under conditions or cooked meat medium, and producing a culture of more than one species; and adding said compound or combination of compounds to said one or more species. adding said compound or combination of compounds to said one or more cultures; determining whether to reduce the growth of the culture or its population. Several In embodiments, the method comprises culturing the one or more species in vitro based on the determined result. identifying a compound or combination of compounds that reduces the growth of a substance or its population; It may further include.

[0058] In some embodiments, the invention provides a compound or combination of compounds for the treatment of eye diseases. Provided is a method for screening the effectiveness of Cultivate one or more organisms under controlled conditions or in cooked meat medium to produce one or more cultures. the step of producing, wherein the one or more organisms are Staphylococcus epidermide; Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyti Kas, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus ceae Reus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis Enterococcus faecalis, Cytophaga hutchinsoniii, Bacillus ricke Niformis, Xanthomonas oryzae, Sphingomonas wich, Klebsiella Pneumoniae, Pseudomonas fluorescens, Ralstonia pickettii, Lacto Bacillus crispatus, Burkholderia multiborane, Lactobacillus delbri Ki, Meiothermus sylvanus (D), Pseudomonas mendocina, Chitococca S sedentarius, Alicycliphilus denitrificans, Achromobacter ki Syloxydans, Sphingobium chaponicum, Mycobacterium abscessus, Arthrobacter aurescens, Prevotella dentalis, Sinorhizobium melilo Tee, Acidovorax ebreus, Acinetobacter baumannii, Acinetobacter ·Calcoaceticus, Comamonas testosteroni, Mycobacterium kansasii, Ba Chillus thuringiensis, Citrobacter koseri, Diadobacter fermentensis tans, Serratia marcescens, E. coli, Micrococcus luteus, Bacillus subtilis, Co. Lineobacterium aurimucosum, Finegordia magna, and combinations thereof a step selected from the group consisting of adding said compound or combination of compounds to said one or more cultures; determining whether to reduce the growth of the culture or its population. Several In embodiments, the method comprises culturing the one or more species in vitro based on the determined result. identifying a compound or combination of compounds that reduces the growth of a substance or its population; It may further include.

[0059] In some embodiments, the invention provides compounds or compounds for the treatment or prevention of AMD. Provided is a method for screening the effectiveness of a combination, said method comprising: The test subject, a family member or close genetic relationship of the test subject with AMD, or a close genetic relationship with AMD. Samples collected from the aqueous humor or vitreous humor of subjects selected from deceased subjects known to have obtaining a sample under conditions that mimic the human intraocular space or cooked meat; A process for culturing one or more organisms from the samples in a medium to produce one or more cultures. step and a solution of one or more inactivated proteins derived from said one or more cultures. said compound or combination of compounds and said one or more inactivated proteins; and mixing the compound or combination of compounds with a solution of the one or more compounds. and determining whether the method binds to the inactivated protein.

[0060] In some embodiments, the invention provides compounds or compounds for the treatment or prevention of AMD. Provided is a method for screening the effectiveness of a combination, said method comprising: The test subject, a family member or close genetic relationship of the test subject with AMD, or a close genetic relationship with AMD. Samples collected from the aqueous humor or vitreous humor of subjects selected from deceased subjects known to have obtaining a sample under conditions selected from conditions that mimic the human intraocular space; Cultivate one or more organisms from the samples in a cooked meat medium; and one or more inactivated proteins derived from said one or more cultures. obtaining a solution of protein and inactivating the one or more inactivated proteins in a mammalian inflammation model. introducing said compound or combination of compounds into said mammalian inflammation model. and the compound or combination of compounds exhibits inflammatory activity in the model. and determining whether or not the quality is to be reduced.

[0061] In some embodiments, the invention provides compounds or combinations of compounds for the treatment or prevention of eye diseases. A method for screening the effectiveness of combinations is provided, the method comprising conditions that mimic the human intraocular space. One or more organisms are cultured under conditions selected from the following conditions or in a cooked meat medium. producing a culture, wherein the one or more organisms are Staphylococcus epi Dermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus Haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Drumstick Lus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella basalis, Enterococcus faecalis, Cytophaga hutchinsonii, Bacillus S. licheniformis, Xanthomonas oryzae, Sphingomonas wich, Kleb Sierra pneumoniae, Pseudomonas fluorescens, Ralstonia pickettii , Lactobacillus crispatus, Burkholderia multiborane, Lactobacillus Delbricki, Meiothermus sylvanus (D), Pseudomonas mendocina, Ki Tococcus sedentarius, Alicycliphilus denitrificans, Achromobac Ter xyloxidans, Sphingobium chaponicum, Mycobacterium ab Sesus, Arthrobacter aurescens, Prevotella dentalis, Sinorhizobium ·Meliloti, Acidovorax ebreus, Acinetobacter baumannii, Acineto Bacterium calcoaceticus, Comamonas testosteroni, Mycobacterium can Sashimi, Bacillus thuringiensis, Citrobacter coseri, Diadobacter f. amentans, Serratia marcescens, Escherichia coli, Micrococcus luteus, Grass fungi, Corynebacterium aurimucosum, Finegordia magna, and these a step selected from the group consisting of a combination; and 1 derived from said one or more cultures. obtaining a solution of more than one species of inactivated protein and said compound or combination of compounds; a solution of the one or more inactivated proteins; a step for determining whether the combination of compounds binds to the one or more inactivated proteins; Including top. In some embodiments, the method is based on the determination result. Identification of compounds or combinations of compounds that bind more than one inactivated protein in vitro The method may further include the step of:

[0062] In some embodiments, the invention provides a compound or combination of compounds for the treatment of eye diseases. Provided is a method for screening the effectiveness of Cultivate one or more organisms under controlled conditions or in cooked meat medium to produce one or more cultures. the step of producing, wherein the one or more organisms are Staphylococcus epidermide; Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyti Kas, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus ceae Reus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis Enterococcus faecalis, Cytophaga hutchinsoniii, Bacillus ricke Niformis, Xanthomonas oryzae, Sphingomonas wich, Klebsiella Pneumoniae, Pseudomonas fluorescens, Ralstonia pickettii, Lacto Bacillus crispatus, Burkholderia multiborane, Lactobacillus delbri Ki, Meiothermus sylvanus (D), Pseudomonas mendocina, Chitococca S sedentarius, Alicycliphilus denitrificans, Achromobacter ki Syloxydans, Sphingobium chaponicum, Mycobacterium abscessus, Arthrobacter aurescens, Prevotella dentalis, Sinorhizobium melilo Tee, Acidovorax ebreus, Acinetobacter baumannii, Acinetobacter ·Calcoaceticus, Comamonas testosteroni, Mycobacterium kansasii, Ba Chillus thuringiensis, Citrobacter koseri, Diadobacter fermentensis tans, Serratia marcescens, E. coli, Micrococcus luteus, Bacillus subtilis, Co. Lineobacterium aurimucosum, Finegordia magna, and combinations thereof one or more cultures derived from said one or more cultures. obtaining a solution of inactivated proteins; and sucking the one or more inactivated proteins. introducing the compound or combination of compounds into an animal inflammation model; introducing the compound or combination of compounds into the model of inflammation; and determining whether the method reduces inflammatory activity in the patient. In some embodiments The method further comprises growing or growing the one or more cultures in vitro based on the determined results. further comprising identifying a compound or combination of compounds that reduces the population. But that's fine. In some embodiments, the compound or combination of compounds has one or more anti-inflammatory properties. It may also be a disease compound.

[0063] In some embodiments, the invention provides a compound or combination of compounds for the treatment of eye diseases. Provided is a method for screening the efficacy of a compound or combination of compounds. administering a compound or combination of compounds to said mammalian model of the present application. determining whether the treatment effectively reduces or prevents one or more symptoms of AMD; include. In some embodiments, after a drusenoid lesion is formed in said mammalian model. , administering said compound or combination of compounds. In some embodiments, the compound or The combination of compounds identified by the in vitro screening method of the present application is 1 It is more than one type of compound or a combination of compounds. In some embodiments, administration is by intraocular injection. It may also include radiation. In some embodiments, the one or more symptoms are drusenoid lesions. occurrence, microbial growth or loading, production of inflammatory molecules or markers, and combinations thereof. selected from the group consisting of.

[0064] Screening methods for other diseases In some embodiments, the screening method includes screening for candidate therapeutic agents that treat or prevent BD. Can be used for identification. In some embodiments, the method includes administering a suitable step a) of cultivating microorganisms in a medium; and culturing microorganisms in said medium in the presence of said test compound. step b) of measuring the growth of a microorganism, said microorganism being more susceptible to BD than in a healthy subject. The intraocular space of the affected subject (e.g. aqueous humor in the anterior chamber, suspensory ligament, ciliary body, ciliary body / ciliary muscle) , the vitreous humor in the posterior chamber, the retina, the choroid, the optic nerve, the lens, or the iris). example For example, in some embodiments, the microorganism is present in a subject suffering from BD compared to a healthy control. Contains species that concentrate in the aqueous humor and / or vitreous humor of humans. In some embodiments, the microorganism is Sphingomonas witch, Klebsiella pneumoniae, Pseudomonas fluorore sens, Ralstonia picketii, Lactobacillus crispatus, Burkholdereri A. multiborane, Lactobacillus delbricii, and Meiothermus sylvanus It may contain one or more species selected from (D). In some embodiments, the microorganism is The microbial species, which may include a mixture of biological species, are present in the aqueous humor and in the subject suffering from BD. / or substantially similar to that observed in the vitreous humor. In some embodiments, the micro The organism is derived, in part or in whole, from the aqueous humor and / or vitreous humor of a subject suffering from BD. It may be something. For example, in some embodiments, the microorganism is afflicted with BD. Obtained by culturing samples obtained from the subject's aqueous humor and / or vitreous humor. It can be done. In some embodiments, the test compound inhibits microbial growth relative to a control. If so, it can be identified as a candidate therapeutic agent for treating or preventing BD.

[0065] In some embodiments, a screen for identifying candidate therapeutic agents to treat or prevent BD One type of bleaching method concentrates in the intraocular space of subjects with BD more than in healthy subjects. Determine or determine the microbial species in step a) and the appropriate Step b of cultivating microorganisms containing at least one of the microorganism species to be concentrated in a medium; ) and c) measuring the growth of said microorganism in said medium in the presence of said test compound. and, optionally, a step to identify a candidate therapeutic agent that inhibits the growth of said microorganism compared to a control. The method may further include step d). In some embodiments, the determination is made in a healthy subject. This suggests that one or more microbial species are concentrated in the intraocular space of subjects with BD. It may also be to obtain information about In some embodiments, the determining determines whether the person is suffering from BD. Presence, absence and / or amount of microorganisms in samples from the intraocular space of affected subjects and optionally comparing the presence, absence and / or quantity of said microorganisms with healthy controls. It may be that. Methods for assessing the presence, absence and / or quantity of microorganisms are described in PCT application no. Including those listed in No. PCT / CN2018 / 112022. In some embodiments, The microorganism may include a mixture of microbial species, said microbial species being present in a subject suffering from BD. Substantially similar to that observed in aqueous and / or vitreous humor. Some embodiments In this case, microorganisms are present in the aqueous humor and / or vitreous humor of subjects who are partially or completely affected by BD. It may be derived from For example, in some embodiments, the microorganism is by culturing samples obtained from the aqueous humor and / or vitreous humor of subjects with It can be obtained by In some embodiments, the test compound inhibits microbial growth relative to a control. can be identified as a candidate therapeutic agent for treating or preventing BD.

[0066] In some embodiments, a screen for identifying candidate therapeutic agents to treat or prevent BD The method uses a sample from the intraocular space of a subject suffering from BD, such as aqueous humor and / or Step a) of obtaining the vitreous humor and incubating said sample in culture medium in the presence of the test compound. incubating step b) and growth of microorganisms in said medium in the presence of said test compound. step c) of measuring, and optionally inhibiting the growth of said microorganism compared to a control. step d) of identifying a candidate therapeutic agent. In some embodiments, The sample is obtained from the aqueous humor of a subject suffering from BD. In some embodiments , the sample is obtained from the vitreous humor of a subject suffering from BD. Example section of this application Incubate the sample as shown in Figure 3.2.1. Usually in a sterile medium in a sterile environment (e.g. a closed environment) to avoid contamination with microbial species. It will be done. In some embodiments, a negative control may be used. Some embodiments A test compound treats BD if it inhibits the growth of microorganisms in the medium compared to the control. or can be identified as a candidate therapeutic agent for prevention.

[0067] In some embodiments, the screening method includes screening for candidate therapeutic agents that treat or prevent cataracts. can be used for identification. In some embodiments, the method includes a suitable test compound in the presence of a test compound. step a) of cultivating the microorganism in a suitable medium; and culturing the microorganism in the medium in the presence of the test compound. step b) of measuring the growth of the organism, wherein the microorganism is more susceptible to cataracts than in healthy subjects. Intraocular space (e.g., aqueous humor in the anterior chamber, suspensory ligament, ciliary body, ciliary body / hair) in subjects suffering from Contains species concentrated in the vitreous humor in the posterior chamber, retina, choroid, optic nerve, lens or iris) . For example, in some embodiments, the microorganism is afflicted with cataracts compared to healthy controls. Contains species that concentrate in the aqueous humor and / or vitreous humor of subjects. In some embodiments, microorganisms Things include Pseudomonas mendocina, Cytococcus sedentarius, Alicycliphyll S. denitrificans, Achromobacter xyloxidans, Sphingobium s. japonicum, Mycobacterium abscessus, Arthrobacter aurescens, Pre Botella dentalis, Sinorhizobium meliloti, and Acidovorax ebreu It may contain one or more species selected from the following. In some embodiments, the microorganism is a microorganism The microbial species may contain a mixture of species, said microbial species being present in the aqueous humor and / or the subject suffering from cataracts. or substantially similar to that observed in the vitreous humor. In some embodiments, microorganisms The substance is derived, in part or in whole, from the aqueous humor and / or vitreous humor of a subject suffering from cataracts. It may be something. For example, in some embodiments, the microorganism is afflicted with cataracts. obtained by culturing samples obtained from the aqueous humor and / or vitreous humor of a subject can be done. In some embodiments, the test compound inhibits microbial growth relative to a control. If so, it can be identified as a candidate therapeutic agent for treating or preventing cataract.

[0068] In some embodiments, a screen for identifying candidate therapeutic agents for treating or preventing cataracts is provided. This method concentrates more in the intraocular space of subjects suffering from cataracts than in healthy subjects. Determining one or more microbial species, or step a) determining one or more microbial species and a step of culturing microorganisms containing at least one of the microbial species to be enriched in a suitable medium; b) and measuring the growth of said microorganism in said medium in the presence of said test compound. c) and, optionally, identifying a candidate therapeutic agent that inhibits the growth of said microorganism compared to a control. d) may further be included. In some embodiments, the determination is made in a healthy subject. One or more microbial species are concentrated in the intraocular space of subjects with cataracts than in subjects with cataracts. It may also be to obtain information that. In some embodiments, the determination is The presence, absence and / or absence of microorganisms in samples from the intraocular space of subjects suffering from the disorder. or assessing the amount and optionally the presence, absence and / or amount of said microorganisms relative to healthy controls. It may be to compare. The method for assessing the presence, absence and / or quantity of microorganisms is PCT Including those listed in application number PCT / CN2018 / 112022. Some embodiments , the microorganism may include a mixture of microbial species, said microbial species being affected by cataracts. substantially similar to that observed in the aqueous humor and / or vitreous humor of human subjects. some In embodiments of the invention, the microorganism is present in the aqueous humor and / or may be derived from the vitreous humor. For example, in some embodiments, the microorganism is , culturing samples obtained from the aqueous humor and / or vitreous humor of subjects suffering from cataracts. It can be obtained by In some embodiments, the test compound has a , identified as a candidate therapeutic agent for treating or preventing cataracts if it inhibits the growth of microorganisms can be done.

[0069] In some embodiments, a screen for identifying candidate therapeutic agents for treating or preventing cataracts is provided. The cleaning method uses samples from the intraocular space of subjects suffering from cataracts, such as aqueous humor and step a) of obtaining vitreous humor and / or vitreous humor; step b) of incubating a microorganism in said medium in the presence of said test compound; step c) of measuring the growth of said microorganism and optionally inhibiting the growth of said microorganism compared to a control. step d) of identifying a candidate therapeutic agent that is harmful. Some embodiments In this case, a sample is obtained from the aqueous humor of a subject suffering from cataract. some implementation In this format, the sample is obtained from the vitreous humor of a subject suffering from cataracts. of the main application As shown in the Examples section, incubating the sample involves first incubating the sample from the subject. Typically, sterilization is performed in a sterile environment (e.g., a closed environment) to avoid contaminating non-existing microbial species. It is carried out in a bacterial culture medium. In some embodiments, a negative control may be used. some in embodiments, if the test compound inhibits the growth of microorganisms in the culture medium as compared to the control; Can be identified as candidate therapeutic agents for treating or preventing cataracts.

[0070] In some embodiments, the screening method includes screening for candidate therapeutic agents that treat or prevent GLA. can be used for identification. In some embodiments, the method includes a suitable test compound in the presence of a test compound. step a) of cultivating the microorganism in a suitable medium; and culturing the microorganism in the medium in the presence of the test compound. step b) of measuring the growth of an organism, wherein said microorganism has a higher GLA than a healthy subject. Intraocular space (e.g., aqueous humor in the anterior chamber, suspensory ligament, ciliary body, ciliary body / hair) in subjects suffering from Contains species concentrated in the vitreous humor in the posterior chamber, retina, choroid, optic nerve, lens or iris) . For example, in some embodiments, the microorganism is diseased in GLA compared to healthy controls. Contains species that concentrate in the aqueous humor and / or vitreous humor of subjects. In some embodiments, microorganisms The items are Acinetobacter baumannii, Acinetobacter calcoaceticus, and Comamonas. Testosterone, Mycobacterium kansasii, Bacillus thuringiensis, Trobacter coseri, Diadobacter fermentans, and Serratia marceae It may contain one or more species selected from the senses. In some embodiments, the microorganism is The microbial species may contain a mixture of biological species, said microbial species being present in the aqueous humor and in a subject suffering from GLA. and / or substantially similar to that observed in the vitreous humor. In some embodiments, The microorganisms originate from the aqueous humor and / or vitreous humor of subjects suffering from GLA, in part or in whole. It may be something that does. For example, in some embodiments, the microorganism is infected with GLA. by culturing samples obtained from the aqueous humor and / or vitreous humor of subjects with can be obtained. In some embodiments, the test compound inhibits microbial growth relative to a control. If inhibited, it can be identified as a candidate therapeutic agent for treating or preventing GLA.

[0071] In some embodiments, a screen for identifying candidate therapeutic agents for treating or preventing GLA is provided. This method concentrates more in the intraocular space of subjects with GLA than in healthy subjects. Determining one or more microbial species, or step a) determining one or more microbial species and a step of culturing microorganisms containing at least one of the microbial species to be enriched in a suitable medium; b) and measuring the growth of said microorganism in said medium in the presence of said test compound. c) and, optionally, identifying a candidate therapeutic agent that inhibits the growth of said microorganism compared to a control. The method may further include step d). In some embodiments, the determination is based on a healthy subject. One or more microbial species are more concentrated in the intraocular space of subjects with GLA than in the examiner. It may also be to obtain information that the In some embodiments, the determination includes G Presence, absence and presence of microorganisms in samples from the intraocular space of subjects suffering from LA and / or assessing the amount and optionally the presence, absence and / or amount of said microorganisms in healthy controls. It may also be a comparison. Methods for assessing the presence, absence and / or quantity of microorganisms are Including those listed in T application number PCT / CN2018 / 112022. some implementations In embodiments, the microorganism may include a mixture of microbial species, said microbial species being affected by GLA. substantially similar to that observed in the aqueous humor and / or vitreous humor of human subjects. how many In such embodiments, the microorganism is present in the aqueous humor and / or in a subject suffering from GLA, in part or in whole. Alternatively, it may be derived from the vitreous humor. For example, in some embodiments, microorganisms culture samples obtained from the aqueous humor and / or vitreous humor of subjects suffering from GLA. It can be obtained by cultivating. In some embodiments, the test compound is If it inhibits the growth of microorganisms, it may be considered as a candidate therapeutic agent for treating or preventing GLA. can be determined.

[0072] In some embodiments, a screen for identifying candidate therapeutic agents for treating or preventing GLA is provided. The sampling method uses samples from the intraocular space of subjects suffering from GLA, such as aqueous humor and step a) of obtaining vitreous humor and / or vitreous humor; step b) of incubating a microorganism in said medium in the presence of said test compound; step c) of measuring the growth of said microorganism and optionally inhibiting the growth of said microorganism compared to a control. step d) of identifying a candidate therapeutic agent that is harmful. Some embodiments In this case, a sample is obtained from the aqueous humor of a subject suffering from GLA. some implementation In this format, the sample is obtained from the vitreous humor of a subject suffering from GLA. of the main application As shown in the Examples section, incubating the sample involves first incubating the sample from the subject. Typically, sterilization is performed in a sterile environment (e.g., a closed environment) to avoid contaminating non-existing microbial species. It is carried out in a bacterial culture medium. In some embodiments, a negative control may be used. some in embodiments, if the test compound inhibits the growth of microorganisms in the culture medium as compared to the control; Can be identified as candidate therapeutic agents for treating or preventing GLA.

[0073] In some embodiments, the screening method includes screening for candidate therapeutic agents that treat or prevent VKH. can be used for identification. In some embodiments, the method includes a suitable test compound in the presence of a test compound. step a) of cultivating the microorganism in a suitable medium; and culturing the microorganism in the medium in the presence of the test compound. step b) of measuring the growth of the organism, wherein the microorganism Intraocular space (e.g., aqueous humor in the anterior chamber, suspensory ligament, ciliary body, ciliary body / hair) in subjects suffering from Contains species concentrated in the vitreous humor in the posterior chamber, retina, choroid, optic nerve, lens or iris) . For example, in some embodiments, the microorganism is susceptible to VKH compared to healthy controls. Contains species that concentrate in the aqueous humor and / or vitreous humor of subjects. In some embodiments, microorganisms These include Escherichia coli, Micrococcus luteus, Bacillus subtilis, and Corynebacterium aurimco. Sam, and one or more species selected from Finegordia magna. some implementation In the form, the microorganism may include a mixture of microbial species, said microbial species being susceptible to VKH. substantially similar to that observed in the aqueous humor and / or vitreous humor of subjects with go In some embodiments, the microorganism is present in the aqueous humor of a subject suffering from VKH, in part or in whole. / or may be derived from the vitreous humor. For example, in some embodiments, microorganisms samples obtained from the aqueous humor and / or vitreous humor of subjects suffering from VKH. It can be obtained by culturing. In some embodiments, the test compound is If it inhibits the growth of microorganisms, it can be used as a candidate therapeutic agent to treat or prevent VKH. can be identified.

[0074] In some embodiments, a screen for identifying candidate therapeutic agents for treating or preventing VKH is provided. This method concentrates more in the intraocular space of subjects with VKH than in healthy subjects. Determining one or more microbial species, or step a) determining one or more microbial species and a step of culturing microorganisms containing at least one of the microbial species to be enriched in a suitable medium; b) and measuring the growth of said microorganism in said medium in the presence of said test compound. c) and, optionally, identifying a candidate therapeutic agent that inhibits the growth of said microorganism compared to a control. The method may further include step d). In some embodiments, the determination is based on a healthy subject. One or more microbial species are more concentrated in the intraocular space of the examinee with VKH than the examiner. It may also be to obtain information that the In some embodiments, the determination is that V Presence, absence and presence of microorganisms in samples from the intraocular space of subjects suffering from KH and / or assessing the amount and optionally the presence, absence and / or amount of said microorganisms in healthy controls. It may also be a comparison. Methods for assessing the presence, absence and / or quantity of microorganisms are Including those listed in T application number PCT / CN2018 / 112022. some implementations In embodiments, the microorganism may include a mixture of microbial species, said microbial species being affected by VKH. substantially similar to that observed in the aqueous humor and / or vitreous humor of human subjects. how many In such embodiments, the microorganism is present in the aqueous humor and / or in a subject suffering from VKH, in part or in whole. Alternatively, it may be derived from the vitreous humor. For example, in some embodiments, microorganisms culture samples obtained from the aqueous humor and / or vitreous humor of subjects suffering from VKH. It can be obtained by cultivating. In some embodiments, the test compound is If it inhibits the growth of microorganisms, it may be considered as a candidate therapeutic agent for treating or preventing VKH. can be determined.

[0075] In some embodiments, a screen for identifying candidate therapeutic agents for treating or preventing VKH is provided. The sampling method uses samples from the intraocular space of subjects suffering from VKH, such as aqueous humor and step a) of obtaining vitreous humor and / or vitreous humor; step b) of incubating a microorganism in said medium in the presence of said test compound; step c) of measuring the growth of said microorganism and optionally inhibiting the growth of said microorganism compared to a control. step d) of identifying a candidate therapeutic agent that is harmful. Some embodiments In this case, a sample is obtained from the aqueous humor of a subject suffering from VKH. some implementation In this format, the sample is obtained from the vitreous humor of a subject suffering from VKH. of the main application As shown in the Examples section, incubating the sample involves first incubating the sample from the subject. Typically, sterilization is performed in a sterile environment (e.g., a closed environment) to avoid contaminating non-existing microbial species. It is carried out in a bacterial culture medium. In some embodiments, a negative control may be used. some in embodiments, if the test compound inhibits the growth of microorganisms in the culture medium as compared to the control; Can be identified as candidate therapeutic agents for treating or preventing VKH.

[0076] test compound Test compounds used in the screening methods of the present application (e.g., candidates for treating or preventing AMD) (used to identify therapeutic agents) is not particularly limited. For example, the test compound is children, biological products (including polypeptides and polynucleotides), or combinations of small molecules and biological products. It may also be a conjugate, such as a conjugate of an antibody drug. Other suitable types of test compounds may also be included in this book. The proposed method may be used for screening. The test compound is not necessarily a single compound. is not limited. In some cases, mixtures of compounds may be used for screening. for example , in some embodiments, the extract or fraction thereof, such as a traditional Chinese medicine (TCM) extract, is Can be used as a test compound for cleaning.

[0077] For example, the test compound may be a small molecule drug, a chemical drug, a large molecule drug, a biological drug, or a natural drug. It may also be a drug (herbal medicine or herbal medicine extract). In some embodiments, the test compound are β-lactam antibiotics, aminoglycoside antibiotics, and tetracycline antibiotics. quality, chloramphenicol antibiotics, macrolide antibiotics, glycopeptide antibiotics substances, quinolone antibiotics, nitroimidazole antibiotics, rifamycin antibiotics , echinocandin antibiotics, polyene antibiotics, pyrimidine antibiotics, allylamide or azole antibiotics or combinations thereof.

[0078] In some embodiments, the test compound is a beta-lactam antibiotic, such as penicillins. , cephalosporins, thienamycins, monobactams, β-lactamase inhibitors, Methoxypenicillins, etc.; aminoglycoside antibiotics, such as streptomycin, gelatin, etc.; tammycin, kanamycin, tobramycin, amikacin, neomycin, ribomycin antibiotics, micronomycin, azithromycin, etc.; tetracycline antibiotics, e.g. Lacycline, oxytetracycline, chlortetracycline, and doxycycline Chloramphenicol antibiotics, such as chloramphenicol, thiamphenicol, etc. macrolide antibiotics, such as erythromycin, leucomycin, odorless erythromycin, etc. Thromycin, acetylspiramycin, medimycin, josamycin, azithroma Glycopeptide antibiotics, such as vancomycin, norvancomycin, Icoplanin, etc.; quinolone antibiotics, such as norfloxacin, ofloxacin, cip Rofloxacin, pefloxacin, gatifloxacin; nitroimidazole antibiotics, For example, metronidazole, tinidazole, ornidazole, etc.; rifamycin antibiotics , such as rifampicin; echinocandin antibiotics; polyene antibiotics; pyrimidine antibiotics; allylamine antibiotics; azole antibiotics; other antibiotics: fosfomy Syn, capreomycin, cycloserine, lincomycin, clindamycin, mito Mycin, actinomycin D, bleomycin, doxorubicin, isoniazid, pira It may also contain one or more of dinamide, cyclosporin, etc.

[0079] In some embodiments, the test compound is an insect antimicrobial peptide, such as a lepidopteran antimicrobial peptide. Tide, Diptera antimicrobial peptide, Coleoptera antimicrobial peptide, Odonata antimicrobial peptide, Hymenoptera Antibacterial peptides, silkworm antibacterial peptides, etc.; mammalian antibacterial peptides, such as porcine antibacterial peptides; antibacterial peptide, sheep antibacterial peptide, bovine antibacterial peptide, human antibacterial peptide, etc.; amphibian antibacterial peptide Tid: Xenopus, etc.; Antibacterial peptides derived from fish, molluscs, and crustaceans: Minami Pardachirus pavoninus antibacterial peptide, catfish ( parasilurus asotus) antibacterial peptide, mussel antibacterial peptide, shrimp Antibacterial peptides, etc.; Plant antibacterial peptides: Thionin, etc.; Bacterial antibacterial peptides; Petido: one or more of bacitracin, gramicidin, polymyxin, and nisin May include.

[0080] In some embodiments, the test compound is Calcined ancie nt ink), Salvia Miltiorrhiza (Salvia Miltiorrhiza), Salvia Miltiorrhiza ( Arnebia euchroma), Banrangcon (Radix Isatidis) , Houttuynia, Honeysuckle, Uren (Rhizoma Coptis), Scutellaria (Scutellaria), Hoko Dandelion, Purslane, Hawtho rn), Forsythia (Isatidis Folium), Forsythia (Fructu) s Forsythiae), Inchin (Herba Artemisiae Capi) llaris), Andrographis paniculata N ees), Radix Bupleuri, Rhubarb, Shi Euphorbia Humifusa, Stemonae Garlic, Cortex Phellodendri, Horse chestnut Eucommia, Cortex Fraxini, Jashoushi ( Fructus Cnidii), Galla Chinensis, Deer Viola yedoensis makino, Ubay (Fructus) Mume), daylily (Radix Glycyrrhizae), red lily (P ericarpium Granati), Schisandra chine nsis), Spina Gleditsiae, and Termina lia Chebula), Sophora flavescens, Sophora flavescens Cortex Pseudolaricis, Epimedium ), one or more of the following: Artemisia apiacea Hance It may also include extracts or fractions thereof.

[0081] The screening method described above may be a low, medium or high throughput screening method. Generally, multiple test compounds can be screened. For example, some In embodiments, the screening method comprises screening one or more test compounds in parallel. (including tests conducted substantially simultaneously), for example, 10 or more types, 100 or more types , more than 1000 compounds may be screened in parallel. The test compound is a single A concentration or concentrations may be tested. In some embodiments, multiple test compounds When screening for or at least one that is not a known antibiotic with efficacy against one or more species of said microorganisms. may also contain one test compound. In some embodiments, the plurality of test compounds is ampicillin, vancomycin, neomycin, metronidazole or tetracyc It may also include at least one test compound that is not phosphorus. In some embodiments, the trial The test compound is a known broad-spectrum antibiotic or active against one or more species of said microorganisms. It is not a known antibiotic. For example, in some embodiments, the test compound is Ampicillin, vancomycin, neomycin, metronidazole or tetracycline isn't it.

[0082] In some embodiments, test compounds may include anti-inflammatory compounds. Appropriate anti-inflammatory compounds The product may include ophthalmic compounds known in the art. In some embodiments, an anti-inflammatory compound The substance is a steroid or non-steroidal anti-inflammatory compound, a plant extract or a fraction of an extract, or It may also include a combination of these.

[0083] animal models In embodiments, the invention provides animal models for eye diseases and methods of making the animal models. and more.

[0084] In some embodiments, the invention provides a method of producing an animal model, the method comprising: and / or introducing the inactivated protein derived from the microorganism into the intraocular space of the animal's eye. include. Microorganisms are usually more prevalent in the intraocular space (e.g. For example, the aqueous humor in the anterior chamber, the suspensory ligament, the ciliary body, the ciliary body / ciliary muscle, the vitreous humor in the posterior chamber, the retina, and the choroid. Eye diseases include cataracts, aging Macular degeneration (AMD), glaucoma (GLA), Behcet's disease (BD), Vogt・Koyanagi・ Selected from Harada syndrome (VKH), endophthalmitis (EOS) and combinations thereof, the introduction is Inducing one or more symptoms of eye disease. In some embodiments, the method comprises Determining one or more microbial species concentrated in the intraocular space of subjects suffering from eye disease , or further comprising the step of determining that the eye disease is age-related macular degeneration (AMD), Cat disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt· Selected from Koyanagi-Harada syndrome (VKH) and combinations thereof.

[0085] In some embodiments, the method may introduce live microorganisms into the intraocular space of an animal's eye. In some embodiments, the method comprises inactivating a microbial protein, e.g. Sonically inactivated proteins may be introduced into the intraocular space of the animal's eye. mentioned in the method of the present application The subject and animal may be the same or different. For example, in some embodiments If the eye disease is a disease of a pet animal, the subject and animal may be the same. how many In such embodiments, the eye disease may be a human disease, i.e., the subject is a human subject. , and the animal is preferably a non-human mammal, more preferably a non-human primate (e.g. monkey). In some embodiments, the animal has eye anatomy and structure similar to humans. / or have an intraocular environment. Preferably, microorganisms and / or inactivated proteins derived from said microorganisms are used. Animals should be free of eye disease prior to introduction of the bark.

[0086] AMD animal model In some specific embodiments, the invention provides methods for generating AMD animal models. go In some embodiments, the method comprises using a microorganism and / or an inactivated protein derived from said microorganism. the intraocular space of the animal's eye. Normally, microorganisms are more abundant in A than in healthy subjects. Intraocular spaces of subjects suffering from MD (e.g., aqueous humor in the anterior chamber, suspensory ligament, ciliary body, Species concentrated in the ciliary muscle, vitreous humor in the posterior chamber, retina, choroid, optic nerve, lens or iris) including, said introduction induces one or more symptoms of AMD. unless the context says otherwise , the microorganisms introduced into the intraocular space of the animal are living microorganisms. some implementations In the microorganisms, Staphylococcus epidermidis, Pseudomonas aeruginos Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium , Lactobacillus reuteri, Gardnerella basalis, Enterococcus fecker Squirrel, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomona Contains one or more species selected from S. oryzae. In some embodiments, the microorganism is Containing Bacillus megaterium and / or Pseudomonas putida. Some embodiments The microorganisms include, at least, Bacillus megaterium. In some embodiments , the microorganism is a virtually biologically pure Bacillus megaterium population. Several In embodiments, the microorganism comprises a mixture of microbial species, and the microbial species is a species affected by age-related macular degeneration. Substantially similar to that observed in the aqueous humor, vitreous humor and / or soft drusen of affected subjects. is similar to. In some embodiments, the microorganism, in part or in whole, is associated with age-related macular degeneration. It is derived from the aqueous humor and / or vitreous humor of an affected subject. For example, some In embodiments, the microorganism is present in the aqueous humor and / or vitreous of a subject suffering from age-related macular degeneration. It can be obtained by culturing samples obtained from body fluids. Preferably the animal A non-human mammal, more preferably a non-human primate (eg, a monkey). some In embodiments, the animal has an ocular anatomy and / or intraocular environment similar to humans. do. In some embodiments, the animal is a rhesus macaque, such as a cynomolgus macaque. how many In such embodiments, the animal is not a rhesus macaque. In some embodiments, the animal is a crab. Not Izar.

[0087] Introducing the microorganism and / or inactivated protein derived from said microorganism into any suitable intraocular space of the animal. You may enter. In some embodiments, the microorganism and / or the inactivated protein derived from the microorganism The protein is injected into the subretinal space of the animal. Usually, microorganisms and / or inactivation derived from said microorganisms. Although the protein is injected into the animal's eye, other methods of delivery are also suitable.

[0088] Typically, microorganisms and / or inactivated proteins derived from said microorganisms are used to treat one or more symptoms of AMD. introduced in an amount and concentration sufficient to induce For example, as shown in the Examples section, approximately 2 20 CFU of bacteria in 0 μL PBS solution can cause one or more symptoms of AMD, e.g. May induce noid lesions. In some embodiments, the microorganism and / or the microorganism-derived The inactivated protein is introduced in a fixed amount and concentration that induces is sufficient. 1) drusenoid lesions e.g. in the retinal tissue of animals; 2) e.g. Drusen-like nodules below the retinal pigment epithelial layer; 3) case e.g. pyroptosis of retinal pigment epithelial cells in animal eyes; 4) pyroptosis of the complement system in animal eyes; activation and / or inflammation, e.g. C5A, CFH, caspase 1, and NLRP3 proteins. 5) For example, increased expression of active IL-1β and and / or secretion of IL-18; or any combination of 6) 1)-5).

[0089] The animal used in the method for producing an animal model of the present application is preferably a healthy animal, for example, The animal has no eye disease before the inactivated protein and / or the microorganism-derived inactivated protein is introduced. do not have. Preferably, before and after the introduction of the microorganism and / or the protein derived from said microorganism. If the animal is given any antibiotics during the period, e.g., before one or more symptoms of AMD appear, do not have.

[0090] In some embodiments, the method for producing an AMD animal model comprises into the intraocular space of the animal's eye, the sample comprising: obtained from the intraocular space of a subject, the introduction of which induces one or more symptoms of AMD. some In this embodiment, prior to introduction into the animal, the sample is incubated in culture medium and optionally It is purified and / or prepared for injection. In some embodiments, the method comprises Steps to obtain samples, e.g. aqueous humor, vitreous humor and / or soft drusen, from the intraocular space of The method further comprises step 1) and step 2) of incubating the sample in a medium. stomach In some embodiments, the sample is obtained from the aqueous humor of a subject suffering from AMD. In some embodiments, the sample is obtained from the vitreous humor of a subject suffering from AMD. It will be done. In some embodiments, the sample is a soft drink from a subject suffering from AMD. Retrieved from Zen. As shown in the Examples section of this application, sample incubation is A sterile environment ( eg in a sterile medium in a closed environment).

[0091] Typically, methods for generating AMD animal models involve producing one or more AMD symptoms that persist for a defined period of time in the animal. can occur. For example, in the absence of interference, animal models produced by the methods of the present application typically , exhibiting one or more AMD symptoms within a period of time greater than 1 week, 1 month or over the life of the animal. vinegar. Animal models produced by the methods of the present application are also a novel feature of embodiments of the present invention.

[0092] The AMD animal model created in this application can also be used to identify candidate therapeutic agents to treat or prevent AMD. used. For example, in some embodiments, the invention further provides screening methods. and the screening method involves administering a comprehensive test compound to the AMD animal model of the present application. and step b) of determining the severity of the one or more symptoms of the eye disease after administration. , optionally, a candidate therapeutic agent that reduces at least one of said symptoms compared to a control. identifying step c). In some embodiments, when compared to a control, the test compound 1) reduce drusenoid lesions in the retinal tissue of animals, e.g. and 2) reduce drusen-like nodules below the retinal pigment epithelial layer in animal eyes. 3) reducing pyroptosis of retinal pigment epithelial cells in animal eyes; 4) reduce complement system activation and / or inflammation in the animal's eye, e.g. C5A, CFH, reducing the expression of caspase 1 and NLRP3 proteins; 5) in the eyes of animals; reducing the secretion of active IL-1β and / or IL-18 by retinal pigment epithelial cells , or any combination of 6)1)-5) is possible. and test compounds such as can be identified as candidate therapeutic agents for treating or preventing AMD. some implementations In a state of , the intraocular space or cavity), the blood and / or the gastrointestinal tract, e.g. the intestines; and such test compounds are also candidates for treating or preventing AMD. It can be identified as a co-therapeutic agent. In some embodiments, the "control" related information is It may also be information observed in the animal prior to administering the compound. In some embodiments, " The relevant information for the 'control' may be what was observed in the animals receiving the placebo treatment, e.g. A placebo formulation containing no test compound is administered.

[0093] Test compounds used in screening methods using AMD animal models (described above in this application) are Preferably, but not exclusively, the test compound is administered to subjects suffering from AMD compared to healthy controls. Effectively kills microorganisms (e.g. Bacillus megaterium) that concentrate in the human intraocular space. or as capable of inhibiting its growth (e.g., any of the screens described above in this application) method) is pre-screened. The test compound can be administered via any suitable route. These may be administered in any study dosing protocol and any appropriate study dose. The selection may be made by one skilled in the art based on factors such as, for example, the potency of the test compound (if known). stomach. For example, the test compound may be administered orally, topically, intravitreally, intramuscularly, subcutaneously or intravenously. Good too.

[0094] Screening methods using AMD animal models (described herein) typically have low to moderate throughput. This is a cut screening method. In some embodiments, multiple test compounds are screened. and the plurality of test compounds are known broad-spectrum antibiotics or the microorganisms. testing of at least one non-known antibiotic with efficacy against one or more species of It is a compound. In some embodiments, the plurality of test compounds include ampicillin, vanacin, At least not comycin, neomycin, metronidazole or tetracycline Contains one test compound. In some embodiments, the test compound has a known broad spectrum is not an antibiotic or a known antibiotic with efficacy against one or more species of said microorganisms. stomach. For example, in some embodiments, the test compound is ampicillin, vancomycin, Not neomycin, metronidazole or tetracycline.

[0095] In some embodiments, the invention provides a method of producing a mammalian model of an eye disease, the method comprising: contains one or more microorganisms and / or one or more inactivated proteins of said one or more microorganisms. The method includes the step of introducing the method into a mammalian eye to create a mammalian model. some implementations In embodiments, the method further comprises the step of monitoring the onset and progression of one or more markers of eye disease. May include. Markers for eye diseases are derived from these biological agents known in the art for a given disease. and / or chemical markers, including, but not limited to, symptoms of eye disease. go In some embodiments, monitoring the onset and progression of one or more markers of eye disease comprises The method may also include monitoring an inflammatory response in the mammal's eye. In some embodiments, one of the eye diseases The step of monitoring the onset and progression of more than one species marker is the step of monitoring the onset or progression of drusenoid lesions. may include monitoring. In some embodiments, the method includes the method in which the mammal of said one or more microorganisms and / or of said one or more microorganisms in order to develop a noid lesion. further comprising allowing a sufficient amount of time to elapse after introducing the one or more inactivated proteins. . In some embodiments, the one or more microorganisms and / or one of the one or more microorganisms The step of introducing the one or more species of inactivated protein may include the step of introducing the one or more species of inactivated protein. It may also include intraocular injection of inactivated proteins of one or more of the above microorganisms. some In embodiments, intraocular injection may include injection into the vitreous humor or aqueous humor of the mammal.

[0096] Method of treatment In some embodiments, the invention further provides methods of treating or preventing AMD. In some embodiments, the method provides a subject in need thereof with any of the screens of the present application. The step of administering an effective amount of any candidate treatment for AMD identified in the leaning method. Including. In some embodiments, the method includes the subject placing a staphylococcus in the intraocular space, e.g. Coccus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staph Gyrococcus haemolyticus, Pseudomonas putida, Stenotrophomonas malto Philia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella basalis, Enterococcus faecalis, Cytophaga hatchin one or more selected from B. sonii, Bacillus licheniformis, and Xanthomonas oryzae. Identifying or identifying the above species as infected and any of the screenings in this application. The process of administering to a subject an effective amount of any candidate therapeutic agent for AMD identified by the Including step. In some embodiments, the method globally identifies or For example, if a person injects Bacillus megaterium and / or Pseudomonas putida into the intraocular space, preferably at least identified as being infected with Bacillus megaterium, or step and any candidate for AMD identified by any of the screening methods herein. administering an effective amount of the therapeutic agent to the subject. In some embodiments, the method For example, in the intraocular space, Staphylococcus epidermidis, Pseudomonas L. Gynosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas petit Da, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megateri Lactobacillus reuteri, Gardnerella basalis, Enterococcus fae carlis, Cytophaga hutchinsonii, Bacillus licheniformis, and Xantho selecting a subject infected with one or more species selected from Monas oryzae; Subject to any candidate therapeutic agent for AMD identified by any of the screening methods of this application. administering the method to the examiner in an effective amount. In some embodiments, the method includes, for example: Bacillus megaterium and / or Pseudomonas putida, preferably a small amount, in the intraocular space. At least the step of selecting a subject infected with Bacillus megaterium; If the subject has any candidate treatment for AMD identified by any of the screening methods. and administering the effective amount. In some embodiments, the subject is disease (BD), cataract (Cat), endophthalmitis (EOS), glaucoma (GLA), Vogt・Koyanagi · Not suffering from Harada syndrome (VKH) or any combination thereof. some fruit In embodiments, the subject has AMD. In some embodiments, the subject has AMD have not been diagnosed with the disease. In some embodiments, the subject develops AMD. There is a risk of Administration is not restricted to any particular route, e.g. oral, topical, vitreous. It may be intracorporeal, intramuscular, subcutaneous and / or intravenous.

[0097] In some embodiments, the method of treating or preventing AMD includes a method for treating or preventing AMD in which the subject, e.g. , Staphylococcus epidermidis, Pseudomonas aeruginosa, yellow grape Cocci, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomo Solanum maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus ·Reuteri, Gardnerella basalis, Enterococcus faecalis, Cytopha selected from Bacillus licheniformis, Bacillus licheniformis, and Xanthomonas oryzae. The step of identifying or having identified one or more species as infected and pre-administering antibiotics. and administering to the subject an effective amount. The antibiotics used in this application are common refers to compounds with antibacterial activity, which may be naturally occurring or synthetic. . In this application, several antibiotics are mentioned. In some embodiments, the method includes For example, if the examiner finds Bacillus megaterium and / or Pseudomonas putida in the intraocular space, preferably at least identified as being infected with Bacillus megaterium, or and administering an effective amount of the antibiotic to the subject. Some embodiments In this method, for example, the intraocular space contains Staphylococcus epidermidis, Pseudococcus Monas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudo Monas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus S. megatherium, Lactobacillus reuteri, Gardnerella basalis, Enterococcus Cass faecalis, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae. and administering an effective amount of an antibiotic to the subject. some implementations In some embodiments, the method includes, for example, injecting Bacillus megaterium and / or Pseudomonas into the intraocular space. Select subjects infected with B. putida, preferably at least Bacillus megaterium. and administering an effective amount of the antibiotic to the subject. some implementation In one form, the method involves treating a subject infected with Bacillus megaterium in the intraocular space, e.g. and administering an effective amount of the antibiotic to the subject. some In embodiments, the subject has Behcet's disease (BD), cataracts (Cat), endophthalmitis (E). OS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), or any of these Not affected by the combination. In some embodiments, the subject has AMD . In some embodiments, the subject has not been diagnosed with AMD. how many In such embodiments, the subject is at risk of developing AMD. Administration by any specific route For example, without limitation, oral, topical, intravitreal, intramuscular, subcutaneous and / or intravenous administration. You can. In any embodiment of this application, an "effective amount" of an antibiotic is in an amount that effectively kills or inhibits the growth of one or more microbial species in the eye. The one or more microbial species may be enriched in AMD patients compared to healthy controls, e.g. , said one or more microbial species is Bacillus megaterium and / or Pseudomonas petit and preferably at least Bacillus megaterium.

[0098] In some embodiments, the invention enables a subject in need thereof to: Further provided are methods for 1) reducing drusenoid lesions in, e.g., retinal tissue; 2) reducing drusen-like nodules, e.g. below the retinal pigment epithelial layer in the eye; 3) 4) reducing the pyroptosis of retinal pigment epithelial cells in the eye; 4) reducing the complement system in the eye; Decrease activation and / or inflammation, e.g. C5A, CFH, Caspase 1, and NLR reducing the expression of P3 protein, 5) activity by retinal pigment epithelial cells in the eye I Decrease the secretion of L-1β and / or IL-18, or any combination of 6)1)-5) Matching. The method is directed against AMD identified by any of the screening methods of the present application. administering to the subject an effective amount of any candidate therapeutic agent. In some embodiments , the present invention can reduce drusen symptoms (e.g., soft drusen symptoms) in subjects who need it. ), wherein the method comprises any of the screening methods of the present application. administering to the subject an effective amount of any candidate therapeutic agent for AMD that has been determined. Drusen symptoms (e.g., soft drusen) are caused by microbial infections, such as the pathogenic bacteria of the present application. may be induced by. Drusen symptoms (e.g. soft drusen) are common in people with AMD. may be related to the subject being tested.

[0099] In some embodiments, the invention enables a subject in need thereof to: provide further ways to do so. 1) Reducing drusenoid lesions, e.g. in retinal tissue , 2) reducing drusen-like nodules below the retinal pigment epithelial layer in the eye, 3 ) reducing pyroptosis of retinal pigment epithelial cells in the eye, 4) the complement system in the eye decrease activation and / or inflammation of, e.g., C5A, CFH, caspase 1, and NL Decrease expression of RP3 protein, 5) activity by retinal pigment epithelial cells in the eye reducing the secretion of IL-1β and / or IL-18, or any of 6)1)-5) combination. The method includes administering an effective amount of an antibiotic to the subject. for example, In some embodiments, the method reduces drusenoid lesions in the subject. some In an embodiment, the method reduces drusen-like nodules in the subject. some implementations In embodiments, the method reduces pyroptosis of retinal pigment epithelial cells in the subject's eye. In some embodiments, the method includes activation of the complement system and / or inflammation in the subject's eye. decrease. In some embodiments, the method includes retinal pigment epithelial cells in the subject's eye. decrease secretion of active IL-1β and / or IL-18 by cells. bound by theory For example, antibiotics can be used to treat bacteria (e.g. pathogenic bacteria) in the intraocular space of the patient. or inhibit the growth of a subject suffering from e.g. AMD. can reduce drusen formation, drusenoid lesions and / or drusen-like nodules in As is clear from this application, AMD is caused by one or more pathogenic microorganisms (e.g. Bacillus S. megaterium and / or Pseudomonas putida) infections. Also, illness microorganisms, such as those mentioned in the present application, such as Bacillus megaterium and / or It is thought that Domonas putida may induce eye inflammation. Therefore, the disease being administered Antibiotics that can kill or inhibit the growth of pathogenic microorganisms should not be used in subjects (e.g. AMD). It can also reduce ocular inflammation in affected subjects. In some embodiments, the book The invention alleviates drusen symptoms (e.g., soft drusen) in a subject in need thereof. Further provided is a method of treating the subject, the method comprising the step of administering to the subject an effective amount of an antibiotic. including. Drusen symptoms (e.g., soft drusen) can be caused by microbial infections, such as the aforementioned diseases of the present application. It may also be induced by progenic bacteria. Drusen symptoms (e.g. soft drusen) are associated with AMD. may be related to a subject who is In some embodiments, the method includes forming a drusenoid lesion. and / or reduce nodules.

[0100] In some embodiments, the invention enables a subject in need thereof to: provide further ways to do so. 1) Reducing drusenoid lesions, e.g. in retinal tissue , 2) reducing drusen-like nodules below the retinal pigment epithelial layer in the eye, 3 ) reducing pyroptosis of retinal pigment epithelial cells in the eye, 4) the complement system in the eye decrease activation and / or inflammation of, e.g., C5A, CFH, caspase 1, and NL Decrease expression of RP3 protein, 5) activity by retinal pigment epithelial cells in the eye reducing the secretion of IL-1β and / or IL-18, or any of 6)1)-5) combination. The method comprises a compound of the present disclosure (e.g., Formula I (e.g., Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5), Formula II (e.g., Formula II-1, Formula II-2, Formula II- 3, Formula II-4, Formula II-5, Formula II-6, Formula II-7, Formula II-8, Formula II-9, Formula I I-10), Formula III (e.g., Formula III-1, Formula III-2, Formula III-3), Formula IV -1 or IV-2 (e.g., formula IV-3, formula IV-4, formula IV-5, formula IV-6) compound, glycoside (e.g., formula V), compound selected from compounds 1 to 8, or pharmaceutically acceptable possible salts or esters, or pharmaceutically acceptable salts or esters of said compounds or pharmaceutically acceptable salts or esters. Pharmaceutical composition, where the aglycones of glycosides are phenolic compounds, flavonoids, coumarin sterol, benzoic acid, or sterol) to the subject in an effective amount. example For example, in some embodiments, the method includes a method for reducing drusenoid lesions in a subject. It is something. In some embodiments, the method reduces drusen-like nodules in the subject. . In some embodiments, the method involves pyroptosis of retinal pigment epithelial cells in the subject's eye. reduce the amount of In some embodiments, the method comprises determining the activity of the complement system in the subject's eye. decrease inflammation and / or inflammation. In some embodiments, the method comprises: decreases the secretion of active IL-1β and / or IL-18 by retinal pigment epithelial cells. Reason Without wishing to be bound by theory, the compounds of the present disclosure may be used, for example, in the intraocular space of a subject. kills or inhibits the growth of bacteria (e.g. pathogenic bacteria), thereby preventing e.g. Drusen formation, drusenoid lesions and / or drusen-like tubercles in subjects suffering from D. It is believed that AMD can reduce the number of pathogenic Regarding infections with microorganisms (e.g. Bacillus megaterium and / or Pseudomonas putida) It's connected. Also, pathogenic microorganisms, such as those mentioned in this application, such as Bacillus megateri It is believed that Pseudomonas putida and / or Pseudomonas putida may induce ocular inflammation. did Thus, compounds of the present disclosure that kill or inhibit the growth of pathogenic microorganisms to which they are administered can also reduce ocular inflammation in a subject (eg, a subject suffering from AMD). stomach In some embodiments, the invention alleviates drusen symptoms (e.g. For example, a method of treating soft drusen) is further provided, the method comprising a compound of the present disclosure. administering an effective amount to the examiner. Drusen symptoms (e.g. soft drusen) Microbial infection may be induced, for example with the pathogenic bacteria of the present application. drusen symptoms (e.g. soft drusen) may be associated with subjects suffering from AMD. In some embodiments , the method reduces drusenoid lesions and / or nodules.

[0101] There are no particular restrictions on subjects suitable for treatment by the method of the present application. Some preferred embodiments In this case, the subject has AMD. In some embodiments, AMD is associated with drusen syndrome (including hard drusen, soft drusen, mixed drusen and / or degraded drusen) ) with dry or wet age-related macular degeneration, such as dry or wet age-related macular degeneration with soft drusen symptoms. It may be age-related macular degeneration. In some embodiments, the subject has AMD. not present. In some embodiments, the subject is at risk of developing AMD. Several In embodiments, the subject has soft drusen between the retinal pigment epithelium (RPE) and Bruch's membrane. is deposited. In some embodiments, the subject has retinal pigment changes in the macula. go In some embodiments, the subject has dry AMD. In some embodiments, the The examiner has wet AMD. In some embodiments, the subject is a human subject . In some embodiments, the subject has more AMD patient eyes in the intraocular space than healthy subjects. infected with one or more species concentrated in the internal space, eg, as described above in this application. stomach In some embodiments, the subject has Staphylococcus epidermidis in the intraocular space. , Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus , Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereu Bacillus megaterium, Lactobacillus reuteri, Gardnerella basalis, Enterococcus faecalis, Cytophaga hutchinsonii, Bacillus lichenifi infected with one or more species selected from Xanthomonas oryzae and Xanthomonas oryzae. go In some embodiments, the subject has Bacillus megaterium and / or Phus in the intraocular space. Infected with Domonas putida, preferably at least Bacillus megaterium. go In some embodiments, the subject has Behcet's disease (BD), cataract (Cat), endophthalmitis. (EOS), glaucoma (GLA), Vogt-Koyanagi-Harada syndrome (VKH), or any of these conditions. Not affected by any combination of symptoms. In some embodiments, the method includes a method in which the subject During the course of the infection, one or more species are more concentrated in the intraocular space of AMD patients than in healthy subjects. It may further include the step of identifying or having identified, e.g., as described above in this application. be. In some embodiments, the method comprises providing the subject with Staphylococcus in the intraocular space. Epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococca S. haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnere La vaginalis, Enterococcus faecalis, Cytophaga hutchinsonii, Ba one or more species selected from Chirus licheniformis and Xanthomonas oryzae. The method may further include the step of identifying or identifying as being contaminated. some implementations in the intraocular space, the method comprises: Bacillus putida, preferably at least Bacillus megaterium. Alternatively, the method may further include the identified step.

[0102] Administration of antibiotics is not restricted to any particular route of administration. For example, administration can be oral, topical, Administration may be intravitreal, intramuscular, subcutaneous and / or intravenous. For example, some In embodiments, the antibiotic is administered by intravitreal injection, such as intravitreal depot injection or intravitreal implantation. quality is administered. In some embodiments, more than one route of administration (e.g., oral or intravitreal) may be used. combinations of routes) are available. For example, in some embodiments, the antibiotic is They may be administered orally or intravitreally simultaneously or sequentially in any order. For example, some In embodiments, the antibiotics are administered orally, intravenously, simultaneously or sequentially according to any order. You can. In the case of the same active ingredient or two different active ingredients, in combination with other routes of administration. It may also be used together. Antibiotics can be used as solids, liquids, semi-solids, solutions, suspensions, implants or other forms. It may be prepared in any suitable form. For example, oral antibiotics are usually in solid or liquid form. It may be. In some embodiments, antibiotics may be prepared into the implant. vitreous body In the case of internal injection, there are no particular restrictions on the injection site. For example, in some embodiments, the injection It may also be a suprachoroidal injection. Other suitable sites are known in the art. The effective amount is Multiple factors such as time of administration, route of administration, duration of treatment, efficacy of the antibiotic (e.g. health Kills or inhibits the growth of one or more microorganisms that are concentrated in the intraocular space compared to healthy controls. harm), can vary depending on its clearance and whether another drug is co-administered . multiple antibiotics, such as any one of these antibiotics described herein, and Antibiotics listed in PCT / CN2019 / 070572 submitted on January 7, 2019 Any one of the patents may be used in the method of the present application, the contents of which are incorporated herein by reference. Incorporated into this application by.

[0103] In some embodiments, the antibiotic is a beta-lactam antibiotic, an aminoglycoside antibiotic, Biological substances, tetracycline antibiotics, chloramphenicol antibiotics, macrolides antibiotics, glycopeptide antibiotics, quinolone antibiotics, nitroimidazole antibiotics Biological substances, rifamycin antibiotics, echinocandin antibiotics, polyene antibiotics, Pyrimidine antibiotics, allylamine antibiotics, or azole antibiotics, or It may be a combination.

[0104] In some embodiments, the antibiotic is a beta-lactam antibiotic, such as penicillins ( For example, penicillin V), amoxicillin, ampicillin, bacampicillin, carbenicillin cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafsiri Oxacillin, Penicillin G, Piperacillin, Pivampicillin, Pivmecillinum, Thi Calcilin, cephalosporins such as cephastril, cefadroxil, cephalex Syn, cephaloglycine, cephalonium, cephaloridine, cephalothin, cefapiri cefatridine, cefazafurur, cefazedone, cefazolin, cephalazine, Floxazine, Ceftesol, Cefaclor, Cefamandole, Cefmetazole, Cef fonicid, cefotetan, cefoxitin, cefprozil, cefuroxime, cefzonam, Cefcapene, Cefdaroxime, Cefdinir, Cefditoren, Cefetamet, Cefixi cefmenoxime, cefodizime, cefotaxime, cefpimizole, cefpodoxime , cefteram, ceftibuten, ceftiofur, ceftaroline, ceftizoxime, ceftri Axone, cefoperazone, ceftazidime, cefclizine, cefepime, cefluprenam , cefoselis, cefozopran, cefpirome, cefquinome, ceftobiprole, cefta Lorin, cefaclomedine, cephalolam, cefaparol, cefcanel, cefedrol , cefenpidone, ceftrizole, cefibitril, cefmatilene (cefmati) len), cefmepidium, cefovecin, cefoxazole le, cefrotil, cefsumide, cefratime, ceftioxide, thienamycins, mono Bactams, β-lactamase inhibitors, methoxypenicillins; aminoglycoside antibiotics Substances such as streptomycin, gentamicin, kanamycin (e.g. A), tobramycin, amikacin, neomycin (e.g. neomycin B, neomycin icin C, neomycin E), ribomycin, micronomycin, azithromycin, di Bekacin, sisomicin, netilmicin, paromomycin, bramycin, etc.; Tetrasa Icrine antibiotics, such as tetracycline, oxytetracycline, chlortetra cyclin, and doxycycline, etc.; chloramphenicol antibiotics, e.g. Mufenicol, thiamphenicol, etc.; macrolide antibiotics, e.g. erythromycin Syn, leucomycin, odorless erythromycin, acetylspiramycin, medimycin N, josamycin, azithromycin, clarithromycin, dirithromycin, loki Cithromycin, telithromycin, etc.; glycopeptide antibiotics, e.g. vancomycin quinolone antibiotics, such as norfloxa, norvancomycin, teicoplanin, etc. Syn, ofloxacin, ciprofloxacin, pefloxacin, gatifloxacin, eno Xacin, lomefloxacin, nalidixic acid, levofloxacin, moxifloxacin, besifloxacin; nitroimidazole antibiotics, e.g. metronidazole, tinidazo Rifamycin antibiotics, such as rifampicin; ginsin antibiotics; polyene antibiotics; pyrimidine antibiotics; allylamine antibiotics quality; azole antibiotics; other antibiotics: fosfomycin, capreomycin, cyclo Serine, lincomycin, clindamycin, mitomycin, actinomycin D, blu Reomycin, doxorubicin, isoniazid, pyrazinamide, cyclosporine, polymium Xin B combinations such as polymyxin B / trimethoprim, polymyxin B / bacitra It may contain one or more of cin, polymyxin B / neomycin / gramicidin, etc.

[0105] In some embodiments, the antibiotic is amikacin, amoxicillin, ampicillin, Luvalsan, Azithromycin, Azlocillin, Aztreonam, Bacitracin, Capre Omycin, carbenicillin, cefaclor, cefadroxil, cephalexin, cef Farotin, cefamandole, cefazolin, cefdinir, cefditoren, cefixime , cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime, Chloro Ramphenicol, Cilastatin, Clarithromycin, Clavulanic acid, Clindamycin clofazimine, cloxacillin, colistin, cycloserine, dalfopristi dapsone, daptomycin, dicloxacillin, dirithromycin, doripenem, doripenem, Xycycline, erythromycin, ethambutol, ethionamide, flucloxacili Fosfomycin, furazolidone, fusidic acid, gentamicin, imipenem, isoni Azide, kanamycin, lincomycin, linezolid, loracarbef, mafenide, melo Penem, methoxypenicillin, metronidazole, mezlocillin, minocycline, mupi Rosin, Nafcillin, Neomycin, Netilmicin, Nitrofurantoin, Oxaciri Oxytetracycline, Paromomycin, Penicillin G, Penicillin V, Piperacy Phosphorus, platensimycin, polymyxin B, pyrazinamide, quinupristin, rapamycin Syn, rifabutin, rifampicin, rifamycin (Ri fampin), rifapentine, rifaximin, roxithromycin, sulfazia silver, spectinomycin, streptomycin, sulbactam, sulfacetamide, Sulfadiazine, Sulfamethizole, Sulfamethoxazole, Sulfanilamide , sulfasalazine, sulfisoxazole, tazobactam, teicoplanin, telaban Telavancin, telithromycin, temocillin, tetracycline, thi Amphenicol, ticarcillin, tigecycline, tinidazole, tobramycin, Rimethoprim, Troleandomycin, Vancomycin, Enoxacin, Lomefloxa Syn, nalidixic acid, ciprofloxacin, levofloxacin, gatifloxacin, moki Cifloxacin, ofloxacin, norfloxacin, cefotetan, cefonicide, Farazine, Cephapirin, Cephalothin, Cefmetazole, Cefotaxime, Moxara ctam, cefepime, ceftaroline fosamil, ceftobiprole, dalbavancin, Meclocycline, methacycline, ertapenem, fidaxomicin, geldanamycin Syn, Herbimycin, Posizolid, Rade zolid), Torezolid, oritavancin (Oritava ncin), spiramycin, sulfadimethoxine, sulfonamide chrysoidine (Su lfonamidochrysoidine), gemifloxacin, nadifloxacin, Trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin, te Ixobactin, Malacidins and It may be selected from a combination of these.

[0106] In some embodiments, the present invention provides any of the methods herein for treating or preventing AMD. A candidate therapeutic agent identified by the screening method, or a pharmaceutical composition containing the candidate therapeutic agent, Provide more.

[0107] Compound In some embodiments, the present disclosure relates to microorganisms associated with AMD, such as Bacillus megateri. containing multiple types of compounds and / or said compounds that can kill or inhibit the growth of The present invention relates to a composition comprising:

[0108] The compounds of the present application typically have antimicrobial activity by themselves or in combination with another agent. Application of the present application The compound may be bactericidal or bacteriostatic. Known to have antibacterial activity Multiple types of compounds may be used in embodiments of the present invention. For example, in some embodiments , the compounds of the present application may contain any alcohol, phenol, etc. known to have antibacterial activity. compounds, amines, sulfonamides, quinolones, anthraquinones and / or rests It may also contain compounds related to aromatic acid. Limited examples of useful compounds include benzoic acid, benzyl acetate, alcohol, coumarins, catechols, polyphenols, chalconoids (licocalco stilbenes such as resveratrol, isoresveratrol, etc. Nolic acids such as p-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, protocate Citric acid, gallic acid, vanillic acid, syringic acid, cinnamic acid, coumaric acids, caffeic acids, fer lacic acids, chlorogenic acids, sinapic acids, etc., flavonoids such as catechin, naringenin, Quercetin, rutin, chrysin, etc., tannins such as ellagic acid, and these esthetics. and their glycosides.

[0109] A feature of the compounds of the present application is usually some functional group present in their molecular structure. For example, In some embodiments, the compounds of the present application are characterized by an alcoholic hydroxyl group, a phenolic hydroxyl group, and a phenolic hydroxyl group. groups and / or carboxylic acid groups or derivatives thereof, such as esters, amides, carbonate esters esters, carbamates, sulfonic acid esters, glycosides, etc. go In some embodiments, amino groups, sulfonamide groups, thiol groups and / or sulfoxide groups. Compounds having groups or sulfone groups may also be used in the compositions and methods of the present application.

[0110] The compound of the present application may have a polycyclic core structure, a bicyclic core structure, or a monocyclic core structure; Any of these may be substituted with multiple groups described above in this application.

[0111] In some embodiments, the compound of the present application has Formula I or a pharmaceutically acceptable salt or ester. It may be characterized by having. JPEG2023157021000002.jpg4159. For the avoidance of doubt, in formula I, the cyclic structure Cy 1 and another cyclic structure Cy 2 There are two Ringer L & L ’ These two cyclic structures may be the same, or may be different, the two ringers are Cy 1 and Cy 2 forms another ring structure with do. In addition, Cy 1 and Cy 2 are L and L respectively ’ It is a ring structure independent from . In formula I, Cy 1 and Cy 2 are each independently an optionally substituted cycloalkyl ring ( For example, C 3-7 cycloalkyl ring), optionally substituted heterocycle e.g. 4-7 membered heterocycle (e.g. one or two cycloheterocycles independently selected from N, O, and S) having a telo atom), an optionally substituted aromatic ring (e.g. C 6-10 Aromatic rings (e.g. phenyl group)) or an optionally substituted heteroaromatic ring, such as an optionally substituted 5- to 10-membered heteroaromatic ring aromatic ring (e.g., a 5- or 6-membered heteroaromatic ring independently selected from N, O, and S) a heteroaromatic ring having one or two cycloheteroatoms), L and L ’ are each independently empty or ringer (e.g., supra in this application); The term "ringer" when used in isn't it. For example, in some embodiments, the ringer has one part to which it is connected May form a ring structure, for example, L and Cy 1 is Cy 2 forming a ring structure independently from Good too, L 2 is empty, may be replaced with C 1-6 Alkylene group, optionally substituted C 1-6 hetero Alkylene group, optionally substituted C 2-6 Alkenylene group, optionally substituted C 2-6 a Lukynylene group, optionally substituted C 3-6 Cycloalkylene group, optionally substituted aryl group Ren group, optionally substituted heteroarylene group, or optionally substituted 4-7 membered heterosyl group It may be a rylene group, W is -OR 1 ;-COR 2 ;-COOR 1a ;-OCOOR 1a ;-NR 3 R 4 ;-CO NR 3a R 4a ;-OCONR 3b R 4b ;-SO 2 NR 3c R 4c ;-OSO 2 NR 3 d R 4d ;-SR 5 ;-SO 2 R 5a ;-OCOR 2a ;-OSO 2 R 5a or JPEG2023157021000003.jpg1818, here, R 1 and R 1a each independently represents hydrogen, an optionally substituted alkyl group, a substituted optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted heteroaryl group It is a good heterocyclic group, R 3 and R 4 are independently hydrogen, -COR 2b ,-SO 2 R 5b , replaced with Moyoi C 1-6 Alkyl group, optionally substituted C 2-6 alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted phenyl group, optionally substituted 5- or 6-membered heteroaryl group, or optionally substituted 4- is a 7-membered heterocyclic group, or R 3 and R 4 are substituted along with the atoms to which they bond. form a 4-7 membered heterocyclic group which may be R 2 ,R 2a ,R 2b ,R 5 ,R 5a and R 5b are each independently hydrogen, -OH, -NR 3e R 4e , C may be replaced 1-6 Alkyl group, optionally substituted C 2-6 a alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 1-6 Arco xy group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted C 3-6 cyclo Alkoxy group, optionally substituted phenyl group; optionally substituted 5- or 6-membered heteroaryl a 4- to 7-membered heterocyclic group that may be substituted, and R 3a ,R 3b ,R 3c ,R 3d ,R 3e ,R 4a ,R 4b ,R 4c ,R 4d and R 4e are each independently hydrogen, optionally substituted C 1-6 Alkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 1 -6 Alkoxy group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted C 3 -6 Cycloalkoxy group, optionally substituted phenyl group; optionally substituted 5- or 6-membered group a teroaryl group; or an optionally substituted 4-7 membered heterocyclic group, or R 3a and R 4a ,R 3b and R 4b ,R 3c and R 4c ,R 3d and R 4d or R 3e and R4e teeth , together with the atoms to which they are bonded, form an optionally substituted 4- to 7-membered heterocyclic group. Cy in formula I 1 and Cy 2 may be an aromatic or non-aromatic ring system, and in some cases, May contain heteroatoms. In a preferred embodiment, Cy in formula I 1 and Cy 2 out of At least one of them is an aryl group or a heteroaromatic ring, e.g. an optionally substituted C 6-10 aroma ring, or a 5-10 membered heteroaromatic ring which may be substituted. For example, some embodiments So, Cy 1 and Cy 2 does not indicate any substituents that are the core structure of formula I The structure of JPEG2023157021000004.jpg1822 may be one of the following. JPEG2023157021000005.jpg78122, where L 2 -W may be connected to the left or right ring, where L and L ’ is the main application It may be any one of the above, and this application describes suitable substituents for the ring. Ru.

[0112] In some embodiments, Cy in Formula I 1 and Cy 2 are all aryl groups or heteroaromatics. It may be an incense ring. For example, in some embodiments, the compound of Formula I has Formula I-1. It's okay. JPEG2023157021000006.jpg4558.

[0113] In some embodiments, Ar in Formula I-1 1 and Ar 2 are each independently replaced. C 6-10 It is an aromatic ring or a 5-10 membered heteroaromatic ring which may be substituted. stomach In some embodiments, Ar in Formula I-1 1 and Ar 2 are each independently replaced. It is optionally a benzene ring or a 5- or 6-membered heteroaromatic ring. For example, some implementations In the formula I-1, Ar 1 and Ar 2 are each independently an optionally substituted benzene ring, optionally substituted thiophene ring, optionally substituted furan ring, optionally substituted pin ring, optionally substituted thiophene ring, optionally substituted furan ring, It is a lysine ring or an optionally substituted pyrimidine ring. Formula I-1 typically has a polycyclic core structure. For example, in some embodiments, Ar 1 Reach Ar 2 does not indicate any substituents that are the core structure of formula I-1 Allow JPEG2023157021000007.jpg1822 to be one of the following. JPEG2023157021000008.jpg92170, where L 2 -W may be connected to the left or right ring, where L and L ’ is in principle and this application describes suitable substituents for use in rings.

[0114] In some embodiments, compounds of Formula I may have Formula I-2. JPEG2023157021000009.jpg3058, During the ceremony, m is 0, 1, 2 or 3; R 10 each time it appears, independently halogen, L 2’ -W ’ , C may be replaced 1-6 Alkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Archi Nyl group, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-6 cycloal Kyl group, optionally substituted C 3-6 Cycloalkoxy group, optionally substituted phenyl group; Optionally substituted 5- or 6-membered heteroaryl group; or optionally substituted 4-7 membered heterocyclic group or two adjacent R 10 , or one R 10 and L or L ’ are these cycloalkyl group, heterocyclic group, aryl group, or forming a heteroaromatic ring, Here, -L 2’ -W ’ are chosen independently each time they appear, and L 2’ may be independently empty or replaced each time C 1-6 alkylene group, substituted C may be 1-6 heteroalkylene group, optionally substituted C 2-6 alkenylene group, C that may be replaced 2-6 Alkynylene group, optionally substituted C 3-6 cycloalkylene group, an optionally substituted arylene group, an optionally substituted heteroarylene group, or a substituted is an optional 4-7 membered heterocyclylene group, and W ’ Each time it appears, independently, -OR 1 ;-COR 2 ;-COOR 1a ;-OCOOR 1a ;-NR 3 R 4 ;-CONR 3a R 4a ;-OCONR 3b R 4b ;-SO 2 NR 3c R 4c ;-OSO 2 NR 3d R 4d ;-SR 5 ;-SO 2 R 5a ;-OCOR 2a ;-OSO 2 R 5a or JPEG2023157021000010.jpg1818, where R 1 ,R 1a ,R 2 ,R 2a ,R 2b ,R 3 ,R 4 ,R 3a ,R 3b , R 3c ,R 3d ,R 3e ,R 4a ,R 4b ,R 4c ,R 4d ,R 4e ,R 5 ,R 5a as well as R 5b are defined in this application, see for example Formula I. In addition, the structural unit -L 2’ -W ’ and-L 2 -Each instance of W is independently chosen and They may be the same or different.

[0115] In some embodiments, Cy in formula I-2 1 is an optionally substituted benzene ring, an optionally substituted thiophene ring, an optionally substituted furan ring, an optionally substituted pyridine ring, or It is an optionally substituted pyrimidine ring. In some embodiments, Cy in formula I-2 1 teeth , C may be replaced 3-6 cycloalkyl ring or optionally substituted 4-7 heterocycle , the heterocycle has 1 or 2 cycloheteroatoms independently selected from N, O, and S. do.

[0116] In some embodiments, Cy 1 , the core structure of formula I-2 is one of the following: Make it as good as possible. JPEG2023157021000011.jpg32116 where -L 2 -W is connected to the right benzene ring, L and L ’ is defined in this application, This application describes suitable substituents for rings.

[0117] In a more preferred embodiment, Cy in formula I 1 and Cy 2 Both are benzene rings. example For example, in some embodiments, a compound of formula I-2 may have formula I-3. JPEG2023157021000012.jpg2676, During the ceremony, L, L ’ ,L2 ,W,R 10 and m are defined in this application, see e.g. formula I-2, n is 0, 1, 2 or 3; R 11 each time it appears, independently, halogen, -L 2’ -W ’ , C may be replaced 1 -6 Alkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 a Rukynyl group, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-6 cyclo Alkyl group, optionally substituted C 3-6 Cycloalkoxy group, optionally substituted phenyl group; optionally substituted 5- or 6-membered heteroaryl group; or optionally substituted 4-7 membered heteroaryl group May be a cyclic group, or two adjacent R 11 , or one R 11 and L or L ’ is an optionally substituted cycloalkyl group, a heterocyclic group, or an atom to which these are bonded. forming a aryl group or a heteroaromatic ring, where L 2’ and W ’ is defined in this application, See for example the definition of formula I-2, and -L 2’ -W ’ is chosen independently each time it appears. It will be done. L and L in formula I (for example, any one of formulas I-1 to I-3) ’ is independently, May be empty or ringer. In some embodiments, L and L in Formula I ’ That's it Each independently, empty, -C(O)-, optionally substituted C 1-4 alkylene group, substituted Moyoi C 2-4 Alkenylene group, -O-, -S-, -NR 100 -, -S(O)-, -S O 2 -, -X 1 -G 1 -, -X 2 -G 2 -X 2a -or-CR 101 R 102 - and here, X 1 ,X 2 and X 2a may be independently replaced with C 1-4 alkylene group, substituted may be C 2-4 Alkenylene group, -O-, -C(O)-, -S-, -NR 100a -, -S(O)-, -SO 2 -or-CR 101a R 102a - and G 1 and G 2 may be independently replaced with C 1-4 Alkylene group, optionally substituted C 2-4 Alkenylene group, -C(O)-, -NR 100a -, -S(O)-, -SO 2 - or -CR 101a R 102a - and Preferably, in some embodiments -X 1 -G 1 -or-X 2 -G 2 -X 2a -teeth, O-N, S-S, S-N(SO 2 -N) or -C(O)-S bonds, R 100 and R 100a are each independently the lone pair (if applicable), hydrogen, C OR 2c ,-SO 2 R 5c , C may be replaced 1-6 Alkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 3- 6 Cycloalkyl group, optionally substituted phenyl group, optionally substituted 5- or 6-membered hetero is an aryl group, or an optionally substituted 4-7 membered heterocyclic group, or R 100 or R 1 00a is R 10 or R 11 forming a heterocycle or heteroaromatic ring which may be substituted with a group, R 101 ,R 101a ,R 102 and R 102a are each independently, if present, Hydrogen, -OH, halogen, optionally substituted C 1-6 Alkyl group, optionally substituted C 2 -6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-6 Cycloalkoxy group, optionally substituted amino group, optionally substituted phenyl group, substituted a 5- or 6-membered heteroaryl group that may be substituted, or a 4-7 membered heterocyclic group that may be substituted. , or R 101 and R 102 , or R 101a and R 102a These combine Forms an optionally substituted 3-7 membered cycloalkyl group or heterocyclyl ring with the atom or R 101 and R 102 or R 101a and R 102a One side is R 10 or R 11 Along with the group, optionally substituted cycloalkyl group or heterocyclyl ring form, and R 2c and R 5c are each independently hydrogen, optionally substituted C 1-6 alkyl group, C that may be replaced 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, substituted C may be 1-6 Alkoxy group, optionally substituted C 3-6 Cycloalkyl group, substituted C may be 3-6 Cycloalkoxy group, optionally substituted phenyl group; even if substituted a 5- or 6-membered heteroaryl group; or an optionally substituted 4- to 7-membered heterocyclic group. Ringer L or L ’ If R forms a double bond with one of the ring carbons, this means that R 101 and R 102 CR where both exist 101 R 102 This means that the valence of carbon exceeds 4. This is for the purpose of In such a case, R 101 and R 102 one of them does not exist, and L or L ’ is the CR defined in this application 101 or CR 102 It is. L or L ’ is the ring carbon If it forms a double bond with one, this is NR 100 may be, where R 100 teeth, Usually a lone pair of electrons. Other similar situations in this disclosure should be understood as well. .

[0118] In some embodiments, L and L in Formula I ’ are, independently, empty, -O-, -C (O)-, -S-, -NR 100 -, -S(O)-, -SO 2 -or-CR 101 R 10 2 -is. In some embodiments, the compound of formula I is any of I-4 to I-5. It has a formula according to one of the following. JPEG2023157021000013.jpg5295 and JPEG2023157021000014.jpg5198In formula, X 3 ,X 4 and X 5 are independently empty, -O-, -C(O)-, -S-, -NR 100a -, -S(O)-, -SO 2 -or-CR 101a R 102a - and R 10 ,R 11 ,R 100a ,R 101a ,R102a ,W,L 2 , m and n are defined in this application. is justified.

[0119] In some embodiments, the compound has formula I-4, where X 3 and X 4 are respectively independently -O-, -C(O)-, -S-, -NR 100a -or-SO 2 -is. stomach In some embodiments, the compound has formula I-5, where X 5 -O-, -C(O)-, -S-, -NR 100a -or-SO 2 -is. In some embodiments, R 100a is hydrogen or optionally substituted C 1-4 It is an alkyl group. L in formula I (e.g., any of the above subformulas of the present application, e.g. formulas I-1 to I-5) 2 Is a connoisseur Usually empty, i.e. the W group is Cy 2 connected directly to. In some embodiments, in formula I L of 2 is C 1-4 alkylene group, C 2-4 alkenylene group, C 2-4 alkynylene group is C 1-4 It may also be a heteroalkylene group. For example, the W group is a methylene group or an ethenyl group. Cy via group 2 may be connected to. The plurality of W groups may be of formula I (e.g., any of the subformulas listed above in this application, e.g., formulas I-1 to I-5). Suitable for compounds of In a preferred embodiment, each occurrence of the W group is independently -O H, -NH 2 ,-SO 2 N.H. 2 ,-SO 2 NH(C 1-4 alkyl), -SO 2 NH(C 1-4 alkanoyl), -COOH, JPEG2023157021000015.jpg1818, -C(O)(O-C 1-10 alkyl), -C(O)(O-C 2-10 alkenyl), -OC(O)NH 2 , -OC(O)NH(C 1-4 alkyl)-, -O-(CO)-(C 1-4 alkyl), -O-(C 1-4 alkyl), where each C 1-4 Alkyl group is independently C 1-4 Alkyl group, C 1-4 Alkoxy group, -OH, -NH 2 , and f It may be substituted with 1-3 substituents independently selected from fluorine. some implementation In the form, W in formula I is -OH, -NH 2 ,-SO 2 N.H. 2 ,-SO 2 NH (acetyl) ,-COOH, JPEG2023157021000016.jpg1818 or -O-C(O)-CH 3 It is. As stated in this application, L 2’ -W ’ In some embodiments, Cy 1 Or Cy 2 example Ar 1 Or Ar 2 may be selected as a substituent for use in When applicable, Formula I (this application L in any of the above subformulas of (including formulas I-1 to I-5) 2’ every time it appears , for example Ar 1 Or Ar 2 (if applicable) may be independently empty and immediately T-W ’ The base is Cy 1 Or Cy 2 directly connected to or C 1-4 alkylene group, C 2-4 a Lukenylene group, C 2-4 Alkynylene group or C 1-4 It is a heteroalkylene group. for example ,W ’ The group is, for example, Ar 1 Or Ar 2 As for C via methylene group or ethenyl group y 1 Or Cy 2 may be connected to. Where applicable, formula I (any of the above subformulas of the present application) , for example, W in formulas I-1 to I-5) ’ each time it appears, -OH, -N H 2 ,-SO 2 N.H. 2 ,-SO 2 NH(C 1-4 alkyl), -SO 2 NH(C 1-4 a lucanoyl), -COOH, JPEG2023157021000017.jpg1818, -C(O)(O-C 1-10 alkyl), -C(O)(O-C 2-10 alkenyl), -OC(O)NH 2 , -OC(O)NH(C 1-4 alkyl)-, -O-(CO)-(C 1-4 alkyl), -O-(C 1-4 alkyl), where each C 1-4 a The lkyl group is independently C 1-4 Alkyl group, C 1-4 Alkoxy group, -OH, -NH 2 , and 1-3 substituents independently selected from fluorine. how many In such embodiments, when applicable, W in formula I ’ Each instance of -OH, -NH 2 ,-SO 2 N.H. 2 ,-SO 2 NH (acetyl), -COOH, JPEG2023157021000018.jpg1818 or -O-C(O)-CH 3 It may be. The plurality of groups may be of any applicable formula I (e.g., any subformula of any of the foregoing in this application, e.g. an applicable , R in formulas I-2 to I-5) 10 and R 11 Applicable to Some embodiments So, R 10 and R 11 each time it appears, independently, F;Cl;-O H;-NH 2 ;-SO 2 N.H. 2 ;-SO 2 NH(C 1-4 alkyl);-SO 2 NH(C 1-4 alkanoyl);-COOH; JPEG2023157021000019.jpg1818;-C(O)(O-C 1-10 alkyl), -C(O)(O-C 2-10 alkenyl), -OC(O)NH 2 ;-OC(O)NH(C 1-4 alkyl)-;-O-(CO)-(C 1-4 alkyl), C 1-4 Alkyl group, C 1-4 Alkoxy group, -OH, -NH 2 , and C optionally substituted with 1-3 substituents independently selected from 1-4 Alkyl group ;C 1-4 Alkyl group, C 1-4 Alkoxy group, -OH, -NH 2 , and independent from fluorine C optionally substituted with 1-3 substituents selected from 2-6 Alkenyl group;C 1-4 Al kill group, C 1-4 Alkoxy group, -OH, -NH 2 , and 1 independently selected from fluorine -C optionally substituted with 3 substituents 2-6 Alkynyl group;C 1-4 Alkyl groups and C optionally substituted with 1-3 substituents independently selected from fluorine 3-6 cycloalkyl Base;C 1-4 Substituted with 1-3 substituents independently selected from alkyl groups and fluorine may be C 3-6 Cycloalkoxy group; or C 1-4 Alkyl group, C 1-4 alkoxy group , -OH, -NH 2 , and 1 to 3 substituents independently selected from fluorine. good C 1-4 It may also be an alkoxy group. In some embodiments, R 10 and R 11 each time it appears, -OH;-NH 2 ;-SO 2 N.H. 2 ;- S.O. 2 NH(C 1-4 alkyl);-SO 2 NH(C 1-4 alkanoyl);-COOH ; JPEG2023157021000020.jpg1818;-C(O)(O-C 1-10 alkyl), -C(O)(O-C 2-10 alkenyl), -OC(O)NH 2 ;-OC(O)NH(C 1-4 alkyl)-;-O-(CO)-(C 1-4 alkyl);C 1-4 Alkyl group; or C 1-4 It may also be an alkoxy group. stomach In some embodiments, R 10 one or more instances of and / or R 11 one or more There are multiple instances of L as independently described in this application. 2’ -W ’ selected from There may be. Usually m, if applicable, is 0, 1 or 2, preferably 1. Usually n is 0, 1, 2 or 3, preferably 1 or 2, if applicable.

[0120] In some embodiments, the compound of the present application has Formula II or a pharmaceutically acceptable salt or may feature an ester. JPEG2023157021000021.jpg2184, During the ceremony, Cy 10 and Cy 11 are each independently an optionally substituted cycloalkyl ring (e.g. B,C 3-7 cycloalkyl ring), optionally substituted heterocycle (e.g. 4-7 membered heterocycle) , an optionally substituted aromatic ring (e.g., C 6-10 aromatic ring), optionally substituted heteroaromatic rings (e.g., 5-10 membered heteroaromatic rings), or cycloalkyl rings or heterocycles and aryl groups. or a heteroaromatic ring, and the ring structure is a fused ring or other ring structure. They may be connected in a L 10 is empty or ringer; L 11 is empty, may be replaced with C 1-6 Alkylene group, optionally substituted C 1-6 Hetae loalkylene group, optionally substituted C 2-6 Alkenylene group, optionally substituted C 2-6 Alkynylene group, optionally substituted C 3-6 Cycloalkylene group, optionally substituted ali -lene group, optionally substituted heteroarylene group, or optionally substituted 4- to 7-membered heterocycle It is a krylene group, W 10 is -OR 1 ;-COOR 1a ;-OCOOR 1a ;-COR 2 ;-NR 3 R 4 ; -CONR 3a R 4a ;-OCONR 3b R 4b ;-SO 2 NR 3c R 4c ;-OSO 2 NR 3d R 4d ;-SR 5 ;-SO 2 R 5a ;-OCOR 2a ;-OSO 2 R 5a ; or JPEG2023157021000022.jpg1818, During the ceremony, R 1 and R 1a each independently represents hydrogen, an optionally substituted alkyl group, a substituted optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted heteroaryl group It is a good heterocyclic group, R 3 and R 4 are independently hydrogen, -COR 2b ,-SO 2 R 5b , replaced with Moyoi C 1-6 Alkyl group, optionally substituted C 2-6 alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted phenyl group, optionally substituted 5- or 6-membered heteroaryl group, or optionally substituted 4- is a 7-membered heterocyclic group, or R 3 and R 4 are substituted along with the atoms to which they bond. form a 4-7 membered heterocyclic group which may be R 2 ,R 2a ,R 2b ,R 5 ,R 5a and R 5b are each independently hydrogen, -OH, -NR 3e R 4e , C may be replaced 1-6 Alkyl group, optionally substituted C 2-6 a alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 1-6 Arco xy group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted C 3-6 cyclo Alkoxy group, optionally substituted phenyl group; optionally substituted 5- or 6-membered heteroaryl a 4- to 7-membered heterocyclic group that may be substituted, and R 3a ,R 3b ,R 3c ,R 3d ,R 3e ,R 4a ,R 4b ,R 4c ,R 4d and R 4e are each independently hydrogen, optionally substituted C 1-6 Alkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 1 -6 Alkoxy group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted C 3 -6 Cycloalkoxy group, optionally substituted phenyl group; optionally substituted 5- or 6-membered group a teroaryl group; or an optionally substituted 4-7 membered heterocyclic group, or R 3a and R 4a ,R 3b and R 4b ,R 3c and R 4c ,R 3d and R 4d or R 3e and R 4e teeth , together with the atoms to which they are bonded, form an optionally substituted 4- to 7-membered heterocyclic group.

[0121] In some embodiments, in Formula II, Cy 10 and Cy 11 At least one of the C that may be replaced 6-10 An aromatic ring or an optionally substituted 5-10 membered heteroaromatic ring . In some embodiments, Cy 11 may be replaced with C 6-10 aromatic ring or substituted It is a 5- to 10-membered heteroaromatic ring. Cy 11 is a bicyclic or polycyclic aryl group or B If it is an aromatic ring, L 10 -Cy 10 and L 11 -W 10 independently and via any ring. Cy 11 may be connected to In some embodiments, Cy 11 is an aryl group or may have a fused ring structure containing a heteroaromatic ring and a cycloalkyl group or a heterocyclic structure. In such embodiments, Cy 11 is an aryl group or a heteroaromatic ring and a cycloalkyl group L via any one of the groups or heterocyclic structures 10 -Cy 10 and L11 -W 10 to may be concatenated, or alternatively, L 10 -Cy 10 and L 11 -W 10 one side is , Cy via an aryl group or a heteroaromatic ring 11 connected to L 10 -Cy 10 and L 1 1 -W 10 The other is Cy via a cycloalkyl group or a heterocyclic structure. 11 connected to.

[0122] In some embodiments, the compound of Formula II has at least one benzene ring and Cy 10 -L 10 -Cy 11 It may have the following core structure as: JPEG2023157021000023.jpg66170 where Cy 10 may be the left ring or the right ring in the above figure, i.e. the figure is oriented in a particular direction. without being limited to, where L 11 -W 10 is connected to either the left ring or the right ring or both rings may be fully substituted.

[0123] In some embodiments, the compound of formula II is Cy 10 -L 10 -Cy 11 as below It may have a core structure. JPEG2023157021000024.jpg68170 where Cy 10 may be the left ring or the right ring in the above figure, i.e. the figure is oriented in a particular direction. unrestricted, where L 11 -W 10 is connected to either the left ring or the right ring Often all two rings may be substituted.

[0124] In some embodiments, Cy in Formula II 10 and Cy 11 are all aryl groups or hetero groups. (b) It is an aromatic ring. In some embodiments, the compound of Formula II has Formula II-1. JPEG2023157021000025.jpg2381, During the ceremony, Ar 10 and Ar 11 are each independently replaced with C 6-10 aromatic ring or It is a 5-10 membered heteroaromatic ring which may be substituted. In some embodiments, in formula II-1 Ar 10 and Ar 11 each independently represents an optionally substituted benzene ring or a substituted It is a 5- or 6-membered heteroaromatic ring that may be In some embodiments, A in Formula II-1 r 10 and Ar 11 each independently represents an optionally substituted benzene ring, an optionally substituted benzene ring, and an optionally substituted benzene ring. a thiophene ring, an optionally substituted furan ring, an optionally substituted pyridine ring, or a substituted It is a pyrimidine ring that may be In some embodiments, Ar in Formula II-1 10 as well as Ar 11 One of them is a bicyclic aryl group or a bicyclic heteroaromatic ring, even if each is substituted. Well, for example, in some embodiments, Ar 11 is an optionally substituted bicyclic aryl group Alternatively, it may be a bicyclic heteroaromatic ring.

[0125] In some embodiments, Cy in Formula II 11 is a benzene ring. Some embodiments , the compound of formula II has formula II-2. JPEG2023157021000026.jpg4160, During the ceremony, Ar 10 ,L 10 ,L 11 and W 10 is defined in this application, see e.g. formula II-1 death, m is 0, 1, 2 or 3; R 20 each time it appears, independently, halogen, -L 11’ -W 10’ , may be replaced C 1-6 Alkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2 -6 Alkynyl group, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted C 3-6 Cycloalkoxy group, optionally substituted group phenyl group; optionally substituted 5- or 6-membered heteroaryl group; or optionally substituted 4-7 is a membered heterocyclic group, or two adjacent R 20 , or one R 20 and L 10 Or L 11 is an optionally substituted cycloalkyl group or heterocyclic group, together with the atoms to which these are bonded. , forming an aryl group or a heteroaromatic ring, Here, -L 11’ -W 10’ is chosen independently each time it appears, Here L 11’ may be independently empty or replaced each time C 1-6 alkylene group, optionally substituted C 1-6 heteroalkylene group, optionally substituted C 2-6 Arkeni Ren group, optionally substituted C 2-6 Alkynylene group, optionally substituted C 3-6 cycloa alkylene group, optionally substituted arylene group, optionally substituted heteroarylene group, or is an optionally substituted 4-7 membered heterocyclylene group, and W 10’ every time it appears , independently, -OR 1 ;-COR 2 ;-COOR 1a ;-OCOOR 1a ;-NR 3 R 4 ;-CONR 3a R 4a ;-OCONR 3b R 4b ;-SO 2 NR 3c R 4c ;-OSO 2 NR 3d R 4d ;-SR 5 ;-SO 2 R 5a ;-OCOR 2a ;-OSO 2 R 5a or JPEG2023157021000027.jpg1818, where R 1 ,R 1a ,R 2 ,R 2a ,R 2b ,R 3 ,R 4 ,R 3a ,R 3b ,R 3c ,R 3d ,R 3e ,R 4a ,R 4b ,R 4c ,R 4d ,R 4e ,R 5 ,R 5a and R 5b are defined in this application, see for example Formula II. In addition, the structural unit -L 11’ -W 10’ and-L 11 -W 10 Each instance of is independently chosen and identical. may be different.

[0126] In some embodiments, Cy in Formula II 11 is a benzo-fused ring. some implementations In embodiments, the compound of formula II has formula II-3. JPEG2023157021000028.jpg3460, During the ceremony, Ar 10 ,L 10 ,L 11 and W 10 is defined in this application, see e.g. formula II-1 death, m is 0, 1, 2 or 3; R 20 each time it appears, independently, halogen, -L 11’ -W 10’ , may be replaced C 1-6 Alkyl group, optionally substituted C2-6 Alkenyl group, optionally substituted C 2 -6 Alkynyl group, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted C 3-6 Cycloalkoxy group, optionally substituted group phenyl group; optionally substituted 5- or 6-membered heteroaryl group; or optionally substituted 4-7 is a membered heterocyclic group, or two adjacent R 20 , or one R 20 and L 10 Or L 11 is an optionally substituted cycloalkyl group or heterocyclic group, together with the atoms to which these are bonded. , forming an aryl group or a heteroaromatic ring, Here L 11’ and W 10’ are defined in this application, see e.g. formula II-2, and ,-L 11’ -W 10’ are chosen independently each time they appear, and Ring B is a 4- to 7-membered cycloalkyl ring, a 4- to 7-membered heterocycle, a benzene ring, a 5- or 6-membered heteroaromatic ring rings, each of which may be substituted.

[0127] In some embodiments, Cy in Formula II 11 is a benzo-fused bicyclic aryl group or a heteroaromatic group. It is a fragrant ring. For example, in some embodiments, Cy in Formula II 11 has the following core structure May have. JPEG2023157021000029.jpg64147, During the ceremony, L 10 -Cy 10 and L 11 -W 10 independently through any one of the two rings. Cy 11 and the benzene ring has 1-3 R as defined herein. 20 based on Therefore, it may be replaced. For example, with respect to a benzothiophene ring, some embodiments So, L 10 -Cy 10 may be connected to the thiophene ring, L 11 -W 10 is benzene may be connected to a ring and vice versa; in some cases, L 10 -Cy 10 as well as L 11 -W 10 may all be connected to the same ring, for example a benzene ring.

[0128] In some embodiments, the compound of Formula II may have any of the following structures. JPEG2023157021000030.jpg84170In formula, Cy 10 ,L 10 ,R 20 , m, R 21 ,n,R 100a ,L 11 and W 10 is defined in this application. See, for example, Formula II and subformulas of the present application, such as Formula II-3. Several In embodiments, Cy 10 is Ar defined for formula II-3 10 It is.

[0129] In some embodiments, the compound of Formula II-3 may have Formula II-4. JPEG2023157021000031.jpg3570, During the ceremony, Ar 10 ,L 10 ,R 20 , m, L 11 and W 10 are defined in this application, e.g. formula I See I-3, n is 0 or 1, R 21 each time it appears, independently, halogen, oxo, -L 11’ -W 10’ , replaced C 1-6 Alkyl group, optionally substituted C 2-6 Alkenyl group, even if substituted good C 2-6 Alkynyl group, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted C 3-6 cycloalkoxy group, substituted an optional phenyl group; an optionally substituted 5- or 6-membered heteroaryl group; or an optionally substituted 5- or 6-membered heteroaryl group; is a 4-7 membered heterocyclic group, where L 11’ and W 10’ is defined in this application, e.g. See for example formula II-2, and -L 11’ -W 10’ is chosen independently each time it appears. Re, X if valence allows 10 and X 11 are independently empty, -O-, -C(O )-, -S-, -NR 100a -, -S(O)-, -SO 2 -or-CR 101a R 10 2a - and Here, R 100a is the lone pair of electrons (if applicable), hydrogen, COR 2c ,-SO 2 R 5 c , C may be replaced 1-6 Alkyl group, optionally substituted C 2-6 alkenyl group, C may be replaced 2-6 Alkynyl group, optionally substituted C 3-6 Cycloalkyl group, an optionally substituted phenyl group, an optionally substituted 5- or 6-membered heteroaryl group, or a substituted is a 4- to 7-membered heterocyclic group which may be 100a is R 20 or R 21 groups and substitutions forming a heterocycle or heteroaromatic ring which may be R 101a and R 102a are independently hydrogen, -OH, halogen, if present. C that may be replaced 1-6 Alkyl group, optionally substituted C 2-6 alkenyl group, C may be replaced 2-6 Alkynyl group, optionally substituted C 3-6 Cycloalkyl group, C may be replaced 1-6 Alkoxy group, optionally substituted C 3-6 cycloalkoxy group, An optionally substituted amino group, an optionally substituted phenyl group, an optionally substituted 5- or 6-membered is a heteroaryl group, or an optionally substituted 4-7 membered heterocyclic group, or R 101a and R 102a together with the atoms to which they are bonded, are optionally substituted 3- to 7-membered cycloa forming a alkyl group or a heterocyclyl ring, or R 101a and R 102a One side is R 20 or R 21 Along with the group, an optionally substituted cycloalkyl group or heterocyclyl ring form, and R 2c and R 5c are each independently hydrogen, optionally substituted C 1-6 alkyl group, C that may be replaced 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, substituted C may be 1-6 Alkoxy group, optionally substituted C 3-6 Cycloalkyl group, substituted C may be 3-6 Cycloalkoxy group, optionally substituted phenyl group; even if substituted a 5- or 6-membered heteroaryl group; or an optionally substituted 4-7 membered heterocyclic group; or R 20 or R 21 and L 10 ,X 10 or X 11 are the atoms to which they bond. In the form of an optionally substituted cycloalkyl group, heterocyclic group, aryl group or heteroaromatic ring, to be accomplished. X 10 or X 11 If R forms a double bond with one of the ring carbons, this means that R 101a and R 102a CR in which all exist 101a R 102a This means that the valence of carbon is 4. This is to exceed. In such a case, R101a and R 102a one of them exists Z, and X 10 or X 11 is the CR defined in this application 101a or CR 102a It is. X 10 or X 11 If forms a double bond with one of the ring carbons, then this is NR 100a Deah OK, here R 100a is usually a lone pair of electrons.

[0130] In some embodiments, the compound of Formula II has Formula II-5. JPEG2023157021000032.jpg3767, During the ceremony, Ar 10 ,L 10 ,R 20 , m, R 21 ,n,L 11 and W 10 is defined in this application , see for example formula II-4. Cy in formula II (e.g., any of the above subformulas of the present application, e.g. formulas II-1 to II-4) 10 and Cy 11 may be linked directly or via multiple groups. For example, some In embodiments, L in formula II (e.g., formulas II-1 to II-5) 10 is empty, -C(O )-, C which may be replaced 1-4 Alkylene group, optionally substituted C 2-4 alkenylene group, optionally substituted C 3-6 Cycloalkylene group, optionally substituted 4- to 7-membered heterocycle Krylene group, optionally substituted phenylene group, optionally substituted 5- or 6-membered heteroaryl Ren group, -O-, -S-, -NR 100 -, -S(O)-, -SO 2 -, -X 1 -G 1 - ,-X 2 -G 2 -X 2a -, -X 12 -G 10 -, -X 13 -G 11 -X 13a -or- CR 101 R 102 - and here, X 1 ,X 2 and X 2a may be independently replaced with C 1-4 alkylene group, substituted may be C 2-4 Alkenylene group, optionally substituted C 3-6 Cycloalkylene group, substituted an optionally substituted 4- to 7-membered heterocyclylene group, an optionally substituted phenylene group, a substituted 5- or 6-membered heteroarylene group, -O-, -C(O)-, -S-, -NR 100a -, -S(O)-, -SO 2 -or-CR 101a R 102a - and G 1 and G 2 may be independently replaced with C 1-4 Alkylene group, optionally substituted C 2-4 Alkenylene group, optionally substituted C 3-6 Cycloalkylene group, even if substituted Good 4-7 membered heterocyclylene group, optionally substituted phenylene group, optionally substituted 5 or 6-membered heteroarylene group, -C(O)-, -NR 100a -, -S(O)-, -SO 2 -or-CR 101a R 102a - and Preferably, in some embodiments -X 1 -G 1 -or-X 2 -G 2 -X 2a - is O -N, S-S, S-N(SO 2 (excluding -N bond) or -C(O)-S bond, X 12 ,X 13 and X 13a may be independently replaced with C 1-4 alkylene group, C may be replaced 2-4 Alkenylene group, optionally substituted C 3-6 cycloalkylene group , optionally substituted 4-7 membered heterocyclylene group, optionally substituted phenylene group, substituted optionally 5- or 6-membered heteroarylene group, -O-, -C(O)-, -S-, -NR 1 00a -, -S(O)-, -SO 2 -or-CR 101a R 102a - and and G 10 and G 11 is independently -X 1 -G 1 -or-X 2 -G 2 -X 2a -And , In some embodiments, -X 12 -G 10 -or-X 13 -G 11 -X 1 3a - is O-O, O-N, S-S, S-N(SO 2 -N bond), or -C(O)- does not contain S bonds or three (or more) consecutive heteroatoms, where O-SO 2 - O, O-SO 2 -N and N-SO 2 -Except for N. R 100 and R 100a are each independently the lone pair (if applicable), hydrogen, C OR 2c ,-SO 2 R 5c , C may be replaced 1-6 Alkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 3- 6 Cycloalkyl group, optionally substituted phenyl group, optionally substituted 5- or 6-membered hetero It may be an aryl group or an optionally substituted 4- to 7-membered heterocyclic group, R 101 ,R 101a ,R 102 and R 102a are each independently hydrogen, -OH, Halogen; C which may be substituted 1-6 Alkyl group, optionally substituted C 2-6 alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 3-6 cycloalkyl group, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-6 cycloalcoki cy group, optionally substituted amino group, optionally substituted phenyl group, optionally substituted 5-terminal is a 6-membered heteroaryl group, or an optionally substituted 4-7 membered heterocyclic group, or R 1 01 and R 102 , or R 101a and R 102a together with the atoms to which they bond, Forms an optionally substituted 3- to 7-membered cycloalkyl group or heterocyclyl ring.

[0131] In some embodiments, L in Formula II 10 may be empty, and Cy 10 is Cy 11 directly connected to. In some embodiments, L in Formula II 10 is empty, -O-, - C(O)-, -S-, -NR 100 -, -S(O)-, -SO 2 -or-CR 101 R 1 02 - may be. In some embodiments, L in Formula II 10 is-X 1 -G 1 -or is-X 2 -G 2 -X 2a - may be where, X 1 ,X 2 and X 2a is independently , -O-, -C(O)-, -S-, -NR 100a -, -S(O)-, -SO 2 -or- CR 101a R 102a -, and G 1 and G2 are independently -C(O)-, - NR 100a -, -S(O)-, -SO 2 -or-CR 101a R 102a -is.

[0132] In some embodiments, L in Formula II 10 is-X 12 -G 10 - may be. go In some embodiments, X 12 may be replaced with C 2-4 alkenylene group, preferably JPEG2023157021000033.jpg1241, and G 10 is-X 1 -G 1 -or-X 2 -G 2 -X 2a - and where, X 1 ,X 2 and X 2a are independently -O-, -C(O)-, -S-, -NR 100a -, -S(O)-, -SO 2 -or-CR 101a R 102a -, and G 1 and G 2 are independently -C(O)-, -NR 100a -, -S(O)-, -SO 2 -or-CR 1 01a R 102a -is. In some preferred embodiments, L in Formula II 10 teeth JPEG2023157021000034.jpg1241JPEG2023157021000035.jpg2251 or It may be JPEG2023157021000036.jpg1829.

[0133] In some embodiments, compounds of Formula II may have the following core structure: JPEG2023157021000037.jpg158126In formula, L 11 -W 10 may be directly connected to any one ring, preferably two benzene connected to one of the rings, or connected to only one benzene ring, where each ring has one or by multiple suitable substituents described in this application, for example, each substituent is F ;Cl;-OH;-NH 2 ;-SO 2 N.H. 2 ;-SO 2 NH(C 1-4 alkyl);-S O 2 NH(C 1-4 alkanoyl);-COOH; JPEG2023157021000038.jpg1818;-C(O)(O-C 1-10 alkyl), -C(O)(O-C 2-10 alkenyl), -OC(O)NH 2 ;-OC(O)NH(C 1-4 alkyl)-;-O-(CO)-(C 1-4 alkyl);C 1-4 Alkyl group, C 1-4 Alkoxy group, -OH, -NH 2 , and C optionally substituted with 1-3 substituents independently selected from 1-4 Alkyl group ;C 1-4 Alkyl group, C 1-4 Alkoxy group, -OH, -NH 2 , and independent from fluorine C optionally substituted with 1-3 substituents selected from 2-6 Alkenyl group;C 1-4 Al kill group, C 1-4 Alkoxy group, -OH, -NH 2 , and 1 independently selected from fluorine -C optionally substituted with 3 substituents 2-6 Alkynyl group;C 1-4 Alkyl groups and C optionally substituted with 1-3 substituents independently selected from fluorine 3-6 cycloalkyl Base;C 1-4 Substituted with 1-3 substituents independently selected from alkyl groups and fluorine may be C 3-6 Cycloalkoxy group; or C 1-4 Alkyl group, C 1-4 alkoxy group , -OH, -NH 2 , and 1 to 3 substituents independently selected from fluorine. good C 1-4 Alkoxy group; optionally substituted C 3-6 Cycloalkyl group; even if substituted a 4- to 10-membered heterocyclic group that may be substituted; a 5- to 10-membered heteroaryl group that may be substituted; or a substituted may be C 6-10 May be independently selected from aryl groups. For example, some implementations In the state, L 11 -W 10 is NH 2 or NH(C 1-4 alkanoyl) and two ben linked to one of the benzene rings, or linked to only one benzene ring, the other ring being a methane ring. may be substituted with one or two substituents selected from a methoxy group and a methoxy group. In some specific embodiments, the compound of Formula II has a formula according to Formula II-6 or II-7. do. JPEG2023157021000039.jpg36151, During the ceremony, L 11 ,W 10 ,R 20 and m are defined in this application, see e.g. formula II-3, p is 0, 1, 2, 3 or 4, R 22 each time it appears, independently, halogen, -L 11’ -W 10’ , may be replaced C 1-6 Alkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2 -6 Alkynyl group, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted C 3-6 Cycloalkoxy group, optionally substituted group phenyl group; optionally substituted 5- or 6-membered heteroaryl group; or optionally substituted 4-7 is a membered heterocyclic group, or two adjacent R 22 together with the atoms to which they bond, forming an optionally substituted cycloalkyl group, heterocyclic group, aryl group or heteroaromatic ring, Here, L 11’ and W 10’ are defined in this application, see e.g. formula II-2, and -L 11’ -W 10’ is chosen independently each time it appears. L in formula II (e.g., any subformula, e.g., formulas II-1 to II-7) 11 is usually empty Yes, immediately, if applicable, W 10 The base is Cy 11 connected directly to. In some embodiments is L in formula II 11 is C 1-4 alkylene group, C 2-4 alkenylene group, C 2-4 Al kynylene group or C 1-4 It may also be a heteroalkylene group. For example, W 10 The base is methylene Cy via the phosphor group or ethenyl group 11 may be connected to. Multiple types of W 10 The group is applicable to compounds of formula II (eg, formulas II-1 to II-7). good In a preferred embodiment, W 10 Each time a group appears, it is independently -OH, -NH 2 ,-SO 2 N.H. 2 ,-SO 2 NH(C 1-4 alkyl);-SO 2 NH(C 1-4 alkanoyl) ,-COOH, JPEG2023157021000040.jpg1818, -C(O)(O-C 1-10 alkyl), -C(O)(O-C 2-10 alkenyl), -OC(O)NH 2 , -OC(O)NH(C 1-4 alkyl)-, -O-(CO)-(C 1-4 alkyl), -O-(C 1-4 alkyl), where each C 1-4 Alkyl group is independently C 1-4 Alkyl group, C 1-4 Alkoxy group, -OH, -NH 2 , and f It may be substituted with 1-3 substituents independently selected from fluorine. some implementation In the form, W in formula II 10 The groups are -OH, -OMe, -NH 2 ,-SO 2 N.H. 2 ,-SO 2 NH (acetyl), -COOH, JPEG2023157021000041.jpg1818 or -O-C(O)-CH 3 It is. As stated in this application, L 11’ -W 10’ In some embodiments, Cy 10 or C y 11 For example, Ar 10 Or Ar 11 may be selected as a substituent for use in Where to apply , L in formula II (including any of the above sub-formulas of the present application, e.g. formulas II-1 to I-7) 1 1’ each time it appears, e.g. Ar 10 Or Ar 11 (if applicable), independent may be empty, i.e., W 10’ The base is Cy 10 Or Cy 11 can be directly connected to Ku, or C 1-4 alkylene group, C 2-4 alkenylene group, C 2-4 alkynylene group or C 1-4 It is a heteroalkylene group. For example, W 10’ The group is, for example, Ar 10 Or Ar 1 1 (if applicable), Cy via the methylene or ethenyl group 10 Or Cy 1 1 may be connected to. Where applicable, formula II (any subformula of the above in this application, e.g. formula W in (including II-1~II-7) 10’ each time it appears, -OH, -NH 2 ,-SO 2 N.H. 2 ,-SO 2 NH(C 1-4 alkyl), -SO 2 NH(C 1-4 Al Kanoyl), -COOH, JPEG2023157021000042.jpg1818, -C(O)(O-C 1-10 alkyl), -C(O)(O-C 2-10 alkenyl), -OC(O)NH 2 , -OC(O)NH(C 1-4 alkyl)-, -O-(CO)-(C 1-4 alkyl), -O-(C 1-4 alkyl), where each C 1-4 a The lkyl group is independently C 1-4 Alkyl group, C 1-4 Alkoxy group, -OH, -NH 2 , and 1-3 substituents independently selected from fluorine. how many In such embodiments, when applicable, W in formula II 10’ Each instance of -OH, - OMe, -NH 2 ,-SO 2 N.H. 2 ,-SO 2 NH (acetyl), -COOH or -O- C(O)-CH 3 It may be. The plurality of groups can be any applicable formula II (e.g., if applicable, formulas II-1 to II-7) middle R 20 ,R 21 and R 22 Applicable to In some embodiments, R 20 ,R 21 and R 22 each time it appears, independently, F;Cl;-OH;-NH 2 ;-SO 2 N.H. 2 ;-SO 2 NH(C 1-4 alkyl);-SO 2 NH(C 1-4 Arca Noil);-COOH; JPEG2023157021000043.jpg1818;-C(O)(O-C 1-10 alkyl), -C(O)(O-C 2-10 alkenyl), -OC(O)NH 2 ;-OC(O)NH(C 1-4 alkyl)-;-O-(CO)-(C 1-4 alkyl);C 1-4 Alkyl group, C 1-4 Alkoxy group, -OH, -NH 2 , and C optionally substituted with 1-3 substituents independently selected from 1-4 Alkyl group ;C 1-4 Alkyl group, C 1-4 Alkoxy group, -OH, -NH 2 , and independent from fluorine C optionally substituted with 1-3 substituents selected from 2-6 Alkenyl group;C 1-4 Al kill group, C 1-4 Alkoxy group, -OH, -NH 2 , and 1 independently selected from fluorine -C optionally substituted with 3 substituents 2-6 Alkynyl group;C 1-4 Alkyl groups and C optionally substituted with 1-3 substituents independently selected from fluorine 3-6 cycloalkyl Base;C 1-4 Substituted with 1-3 substituents independently selected from alkyl groups and fluorine may be C 3-6 Cycloalkoxy group; or C 1-4 Alkyl group, C 1-4 alkoxy group , -OH, -NH 2 , and 1 to 3 substituents independently selected from fluorine. good C 1-4 It may also be an alkoxy group. In some embodiments, R 20 ,R 21 Reach BiR 22 each time it appears, independently, F;Cl;-OH;-NH 2 , -SO 2 N.H. 2 ,-SO 2 NH(C 1-4 alkyl), -SO 2 NH(C 1-4 arcano il), -COOH; JPEG2023157021000044.jpg1818;-C(O)(O-C 1-10 alkyl), -C(O)(O-C 2-10 alkenyl), -OC(O)NH 2 ;-OC(O)NH(C 1-4 alkyl)-;-O-(CO)-(C 1-4 alkyl);-O-(C 1-6 alkyl);-O-(C 2-6 alkenyl);C 1 -4 Alkyl group, C 1-6 Alkoxy group, -OH, -NH 2 , and independently selected from fluorine. C optionally substituted with 1-3 substituents as specified 1-6 Alkyl group; or C 1-4 alkyl group, C 1-6 Alkoxy group, -OH, -NH 2 , and 1-3 independently selected from fluorine C optionally substituted with substituents 2-6 It may also be an alkenyl group. some implementations In the state, R 20 ,R 21 and R 22 each time it appears, independently -OH ,C 1-4 Alkyl group, C 2-6 Alkenyl group or -O-(C 1-4 alkyl) Good too. In some embodiments, R 20 ,R 21 and R 22 Each of them appears Each time, -OH, -OMe or It may be JPEG2023157021000045.jpg1622. In some embodiments, R 20 one or more instances of R 2 1 one or more instances of and / or R22 One or more instances of L as described in the present application, which is selected based on 11’ -W 10’ It may be. Usually m and p, if applicable, are 0, 1, 2 or 3, preferably 1 or 2. Typically n is 0, 1 or 2, preferably 0 or 1, if applicable.

[0134] In some embodiments, the compound of Formula II is any of Formulas II-8 to II-10 It may have a formula according to one. JPEG2023157021000046.jpg3569, JPEG2023157021000047.jpg3766 or JPEG2023157021000048.jpg3368, During the ceremony, R 20 ,R 22 , m and p are defined in this application. In some embodiments, m is 1 or is 2 and p is 1, 2 or 3. In some embodiments, R 20 and R 22 brain Each time it appears, each one is independently F;Cl;-OH;-NH 2 ,-SO 2 N.H. 2 ,-SO 2 NH(C 1-4 alkyl), -SO 2 NH(C 1-4 alkanoyl), -C OOH; JPEG2023157021000049.jpg1818;-C(O)(O-C 1-10 alkyl), -C(O)(O-C 2-10 alkenyl), -OC(O)NH 2 ;-OC(O)NH(C 1-4 alkyl)-;-O-(CO)-(C 1-4 alkyl);-O-(C 1-6 alkyl);-O-(C 2-6 alkenyl);C 1 -4 Alkyl group, C 1-6 Alkoxy group, -OH, -NH 2 , and independently selected from fluorine. C optionally substituted with 1-3 substituents as specified 1-6 Alkyl group; or C 1-4 alkyl group, C 1-6 Alkoxy group, -OH, -NH 2 , and 1-3 independently selected from fluorine C optionally substituted with substituents 2-6 It is an alkenyl group.

[0135] In some embodiments, any applicable structural unit in Formula II JPEG2023157021000050.jpg2132 may be selected from the following. JPEG2023157021000051.jpg87104In some specific embodiments, the compound of Formula II is JPEG2023157021000052.jpg3167, JPEG2023157021000053.jpg4267, JPEG2023157021000054.jpg3561 or JPEG2023157021000055.jpg3561, Alternatively, it may be a pharmaceutically acceptable salt or ester.

[0136] In some embodiments, the compound of the present application has Formula III or a pharmaceutically acceptable It may also be characterized by salts or esters. JPEG2023157021000056.jpg1942, During the ceremony, Ar 20 is an optionally substituted aromatic ring (e.g. C 6-10 aromatic ring) or may be substituted. a heteroaromatic ring (e.g., a 5-10 membered heteroaromatic ring), L 20 is empty, may be replaced with C 1-6 Alkylene group, optionally substituted C 1-6 Hetae loalkylene group, optionally substituted C 2-6 Alkenylene group, optionally substituted C 2-6 Alkynylene group, optionally substituted C 3-6 Cycloalkylene group, optionally substituted ali -lene group, optionally substituted heteroarylene group, or optionally substituted 4- to 7-membered heterocycle It is a krylene group, W 20 is -OR 1 ;-COR 2 ;-COOR 1a ;-OCOOR 1a ;-NR 3 R 4 ; -CONR 3a R 4a ;-OCONR 3b R 4b ;-SO 2 NR 3c R 4c ;-OSO 2 NR 3d R 4d ;-SR 5 ;-SO 2 R 5a ;-OCOR 2a ;-OSO 2 R 5a ; or JPEG2023157021000057.jpg1818, here, R 1 and R 1a each independently represents hydrogen, an optionally substituted alkyl group, a substituted optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted heteroaryl group It is a good heterocyclic group, R 3 and R 4 are independently hydrogen, -COR 2b ,-SO 2 R 5b , replaced with Moyoi C 1-6 Alkyl group, optionally substituted C 2-6 alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted phenyl group, optionally substituted 5- or 6-membered heteroaryl group, or optionally substituted 4- is a 7-membered heterocyclic group, or R 3 and R 4 are substituted along with the atoms to which they bond. form a 4-7 membered heterocyclic group which may be R 2 ,R 2a ,R 2b ,R 5 ,R 5a and R 5b are each independently hydrogen, -OH, -NR 3e R 4e , C may be replaced 1-6 Alkyl group, optionally substituted C 2-6 a alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 1-6 Arco xy group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted C 3-6 cyclo Alkoxy group, optionally substituted phenyl group; optionally substituted 5- or 6-membered heteroaryl a 4- to 7-membered heterocyclic group that may be substituted, and R 3a ,R 3b ,R 3c ,R 3d ,R 3e ,R 4a ,R 4b ,R 4c ,R 4d and R 4e are each independently hydrogen, optionally substituted C 1-6 Alkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 1 -6 Alkoxy group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted C 3 -6 Cycloalkoxy group, optionally substituted phenyl group; optionally substituted 5- or 6-membered group a teroaryl group; or an optionally substituted 4-7 membered heterocyclic group, or R 3a and R 4a ,R 3b and R 4b ,R 3c and R 4c ,R3d and R 4d or R 3e and R 4e teeth , together with the atoms to which they are bonded, form an optionally substituted 4- to 7-membered heterocyclic group.

[0137] In some embodiments, Ar in Formula III 20 is an optionally substituted benzene ring or a substituted is a 5- or 6-membered heteroaromatic ring which may be For example, in some embodiments, formula II Ar in I 20 is an optionally substituted benzene ring, an optionally substituted thiophene ring, a substituted an optionally substituted furan ring, an optionally substituted pyridine ring, or an optionally substituted pyrimidine ring. There may be. In some embodiments, Ar in Formula III 20 may be replaced with two It may be a ring aryl group or a bicyclic heteroaromatic ring, each of which may be optionally substituted. stomach. In such embodiments, L 20 -W 20 may be connected to any one of the two rings .

[0138] In some embodiments, Ar in Formula III 20 is an optionally substituted benzene ring, also, where two adjacent substituents, together with the carbons to which they connect, are substituted may form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaromatic ring. For example, in some embodiments, Ar in Formula III 20 is a benzo-fused bicyclic aryl group or may be a heteroaromatic ring. For example, in some embodiments, Ar in Formula III 2 0 may have the following structure. JPEG2023157021000058.jpg64147, During the ceremony, -L 20 -W 20 may be connected to any one of the two rings, where either or one or two rings may be substituted.

[0139] In some embodiments, the compound of formula III is of formula III-1, III-2 or III-3 It may have. JPEG2023157021000059.jpg68112In formula, L 20 and W 20 is defined in this application, m is 0, 1, 2 or 3, n is 0, 1, 2 or 3, R 30 and R 31 each time it appears, independently, halogen, -L 20’ -W 20’ , C may be replaced 1-6 Alkyl group, optionally substituted C 2-6 Arkeni group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 1-6 alkoxy group , C may be replaced 3-6 Cycloalkyl group, optionally substituted C 3-6 cycloalco oxy group, optionally substituted phenyl group; optionally substituted 5- or 6-membered heteroaryl group; or an optionally substituted 4-7 membered heterocyclic group, where -L 20’ -W 20’ appears Each time, L 20’ is independently empty and replaced each time it appears. may be C 1-6 Alkylene group, optionally substituted C 1-6 heteroalkylene group, substituted C 2-6 Alkenylene group, optionally substituted C 2-6 Alkynylene group, substituted C 3-6 Cycloalkylene group, optionally substituted arylene group, even if substituted a good heteroarylene group or an optionally substituted 4-7 membered heterocyclylene group, and ,W 20’ Each time it appears, -OR 1 ;-COR 2 ;-COOR 1a ;-O COOR 1a ;-NR 3 R 4 ;-CONR 3a R 4a ;-OCONR 3b R 4b ;-SO 2 NR 3c R 4c ;-OSO 2 NR 3d R 4d ;-SR 5 ;-SO 2 R 5a ;-OCOR 2a ;-OSO 2 R 5a or JPEG2023157021000060.jpg1818, where its R 1 ,R 1a ,R 2 ,R 2a ,R 2b ,R 3 ,R 4 ,R 3a ,R 3 b ,R 3c ,R 3d ,R 3e ,R 4a ,R 4b ,R 4c ,R 4d ,R 4e ,R 5 ,R 5a and R 5b are defined in this application, see e.g. formula III, Ring B is a 4- to 7-membered cycloalkyl ring, a 4- to 7-membered heterocycle, a benzene ring, a 5- or 6-membered heteroaromatic ring rings, each of which consists of 1-3 independently chosen R 31 replaced by Good too, X if valence allows 20 and X 21 are independently empty, -O-, -C(O )-, -S-, -NR 100a -, -S(O)-, -SO 2 -or-CR 101a R 10 2a - and Here, R 100a is the lone pair of electrons (if applicable), hydrogen, COR 2c ,-SO 2 R 5 c , C may be replaced 1-6 Alkyl group, optionally substituted C 2-6 alkenyl group, C may be replaced 2-6 Alkynyl group, optionally substituted C 3-6 Cycloalkyl group, an optionally substituted phenyl group, an optionally substituted 5- or 6-membered heteroaryl group, or a substituted is a 4- to 7-membered heterocyclic group which may be 100a and R 30 or R 31 one side is , together with the atoms to which they are attached, optionally substituted heterocycles or heteroaromatic rings, e.g. an optionally substituted 5- or 6-membered heteroaryl group or an optionally substituted 4- to 7-membered heterocyclic group accomplished, R 101a and R 102a are independently hydrogen, -OH, halogen, if present. C that may be replaced 1-6 Alkyl group, optionally substituted C 2-6 alkenyl group, C may be replaced 2-6 Alkynyl group, optionally substituted C 3-6 Cycloalkyl group, C may be replaced 1-6 Alkoxy group, optionally substituted C 3-6 cycloalkoxy group, An optionally substituted amino group, an optionally substituted phenyl group, an optionally substituted 5- or 6-membered is a heteroaryl group, or an optionally substituted 4-7 membered heterocyclic group, or R 101a and R 102a together with the atoms to which they are bonded, are optionally substituted 3- to 7-membered cycloa forming a alkyl group or a heterocyclyl ring, or R 101a and R 102a One side is R 30 or R 31 Along with the group, an optionally substituted cycloalkyl group or heterocyclyl ring form, R 2c and R5c are each independently hydrogen, optionally substituted C 1-6 alkyl group, C that may be replaced 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, substituted C may be 1-6 Alkoxy group, optionally substituted C 3-6 Cycloalkyl group, substituted C may be 3-6 Cycloalkoxy group, optionally substituted phenyl group; even if substituted a 5- or 6-membered heteroaryl group; or an optionally substituted 4-7 membered heterocyclic group; or two adjacent R 30 or two adjacent R 31 , or R 30 or R 31 Reach BiX 20 or X 21 together with the atoms to which they are bonded, the optionally substituted cycloalkyl a heterocyclic group, an aryl group, or a heteroaromatic ring. X 20 or X 21 If forms a double bond with one of the ring carbons, then this is R 101a and R 1 02a CR in which all exist 101a R 102a This means that the valence of carbon is 4. It is to exceed. In such a case, R 101a and R 102a one of them does not exist , and X 20 or X 21 is the CR defined in this application 101a or CR 102a It is. X 20 or X 21 If forms a double bond with one of the ring carbons, then this is NR 100a And Also, here R 100a is usually a lone pair of electrons. In addition, the structural unit -L 20’ -W 20’ and-L 20 -W 20 Each instance of and may be the same or different.

[0140] In some embodiments, the compound of Formula III may have any of the following structures: JPEG2023157021000061.jpg197170In formula, R 30 , m, R 31 ,n,R 100a ,L 20 and W 20 is defined in this application, and for example For example, with reference to formula III and subformulas of the present application, such as formulas III-1 to III-3, where the tricyclic structure For structures, the piperidine ring or morpholine ring may be substituted. L in formula III (e.g., any subformula, e.g., formulas III-1 to III-3) 20 is usually , is empty, i.e., W 20 The group is Ar 20 connected directly to. In some embodiments, the expression L in III 20 is C 1-4 alkylene group, C 2-4 alkenylene group, C 2-4 Alkini Ren group or C 1-4 It may also be a heteroalkylene group. For example, W 20 The group is methylene group or Ar via ethenyl group 20 may be connected to. Multiple types of W 20 The group is of formula III (e.g., any subformula, e.g., formulas III-1 to III-3) It can be applied to the following compounds. In a preferred embodiment, W in formula III 20 is -OH, -CO Oh, JPEG2023157021000062.jpg1818, -C(O)(O-C 1-10 alkyl), -C(O)(O-C 2-10 alkenyl), -OC(O)NH 2 , -NH 2 ,-SO 2 N.H. 2 ,-SO 2 NH(C 1-4 alkyl); -SO 2 NH(C 1-4 alkanoyl), -OC(O)NH(C 1-4 alkyl)-,- O-(CO)-(C 1-4 alkyl), -O-(C 1-4 alkyl) may also be used. Here, each C 1-4 Alkyl groups are independently C 1-4 Alkyl group, C 1-4 alkoxy group , -OH, -NH 2 , and 1-3 substituents independently selected from fluorine. You may be In some embodiments, Formula III (e.g., any subformula, e.g., Formula III -1~III-3) Medium W 20 The group is -OH, -NH 2 ,-SO 2 N.H. 2 ,-SO 2 N.H. (acetyl), JPEG2023157021000063.jpg1818, -C(O)-(O-C 8 alkyl), -COOH or -O-C(O)-CH 3 It is. As stated in this application, L 20’ -W 20’ In some embodiments, Ar 20 used for may be selected as a substituent. Where applicable, Formula III (any of the above variants of this application) L in the formula (including formulas III-1 to III-3) 20’ each time it appears, independently May be empty, i.e. if applied, W 20’ The group is Ar 20 , or C 1-4 Alkire group, C 2-4 alkenylene group, C 2-4 Alkynylene group or C 1-4 heteroalkylene It may be directly connected to the base. For example, if you apply W 20’ The group is a methylene group or an ethyl group. Ar via nyl group 20 may be connected to. Where applicable, Formula III (as defined above in this application) W in any subformula (including formulas III-1 to III-3) 20’ every time it appears , independently, -OH, -COOH, JPEG2023157021000064.jpg1818, -C(O)(O-C 1-10 alkyl), -C(O)(O-C 2-10 alkenyl), -OC(O)NH 2 , -NH 2 ,-SO 2 N.H. 2 ,-SO 2 NH(C 1-4 alkyl); -SO 2 NH(C 1-4 alkanoyl), -OC(O)NH(C 1-4 alkyl)-,- O-(CO)-(C 1-4 alkyl), -O-(C 1-4 alkyl) may also be used. Here, each C 1-4 Alkyl groups are independently C 1-4 Alkyl group, C 1-4 alkoxy group , -OH, -NH 2 , and 1-3 substituents independently selected from fluorine. You may be In some embodiments, when applicable, W in Formula III 20’ each instance of -OH, -NH 2 ,-SO 2 N.H. 2 ,-SO 2 NH (acetyl), JPEG2023157021000065.jpg1818, -COOH, -C(O)(O-C 8 alkyl) or -O-C(O)-CH 3 Even though good. The plurality of groups may include any applicable formula III (e.g., any subformula, e.g., formulas III-1 to I II-3) Middle R 30 and R 31 Applicable to In some embodiments, R 30 and R 31 each time it appears, independently, F;Cl;-OH;-COOH;- OC(O)NH 2 ;-OC(O)NH(C 1-4 alkyl)-;-O-(CO)-(C 1 -4 alkyl);C1-4 Alkyl group, C 1-4 Alkoxy group, -OH, -NH 2 ,as well as C optionally substituted with 1-3 substituents independently selected from fluorine 1-4 Alkyl group; C 1-4 Alkyl group, C 1-4 Alkoxy group, -OH, -NH 2 , and independent of fluorine C optionally substituted with 1-3 substituents selected from 2-6 Alkenyl group;C 1-4 Archi group, C 1-4 Alkoxy group, -OH, -NH 2 , and 1- independently selected from fluorine. C optionally substituted with 3 substituents 2-6 Alkynyl group;C 1-4 Alkyl groups and fluorocarbons C optionally substituted with 1-3 substituents independently selected from 3-6 cycloalkyl group ;C 1-4 Substituted with 1-3 substituents independently selected from alkyl groups and fluorine Moyoi C 3-6 Cycloalkoxy group; or C 1-4 Alkyl group, C 1-4 alkoxy group, -OH, -NH 2 , and 1-3 substituents independently selected from fluorine. C 1-4 It may also be an alkoxy group. In some embodiments, R 30 and R 31 of Each of them, each time it appears, is independently -OH, C 2-6 Alkenyl group, -O-( C 1-4 alkyl), -COOH or -C(O)(O-C 1-10 alkyl) good. In some embodiments, R 30 and R 31 Each time they appear, -OH or -OMe may be used. In some embodiments, R 30 one or more of instance and / or R 31 One or more instances of independently selected L as described in 20’ -W 20’ It may be. Usually m is 0, 1, 2 or 3, preferably 2 or 3. Usually n is 1, 2 or 3. Ru.

[0141] In some embodiments, the present disclosure provides a compound JPEG2023157021000066.jpg3178, or a pharmaceutically acceptable salt or ester.

[0142] In some embodiments, the present disclosure provides a compound JPEG2023157021000067.jpg3164, or a pharmaceutically acceptable salt or ester, where q is 1, 2, 3, 4 or 5, and Glu is a glucose residue. In some specific embodiments, the book The disclosure is JPEG2023157021000068.jpg6573 further provides a pharmaceutically acceptable salt or ester.

[0143] In some embodiments, the compounds of the present application may be alkaloids that have antimicrobial activity. . As shown in this application, some indole alkaloids such as vinca alkaloids, tabasso Nin, vindoline, vinblastine, vincristine etc., for example Bacillus megaterium This shows that it can effectively kill microorganisms such as bacteria. In some embodiments, the present application The compound is characterized by formula IV-1 or IV-2 and is tabasonine or vindoline and derivatives . JPEG2023157021000069.jpg51123, During the ceremony, R 40 is hydrogen;-COR 2 ;-COOR 1a ;-SO 2 R 5a ;Al may be substituted Kyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted aryl group, optionally substituted heteroaryl is a group or an optionally substituted heterocyclic group, R 41 is -OR 1 ;-OCOOR 1a ;-OCONR 3b R 4b ;-OCOR 2a ;or -OSO 2 R 5a , n is 0 or 1, R 42 ,R 43 and R 44 are each independently hydrogen, -OR 1 ,OCOR 2a ; or -OSO 2 R 5a and L 30 is empty or a methylene group, W 30 is -OR 1 ;-COR 2 ;-COOR 1a ;-OCOOR 1a ;-NR 3 R 4 ; -CONR 3a R 4a ;-OCONR 3b R 4b ;-OSO 2 NR 3d R 4d ;-OCO R 2a ;or-OSO 2 R 5a and here, R 1 and R 1a each independently represents hydrogen, an optionally substituted alkyl group, a substituted optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted heteroaryl group It is a good heterocyclic group, R 3 and R 4 are independently hydrogen, -COR 2b ,-SO 2 R 5b , replaced with Moyoi C 1-6 Alkyl group, optionally substituted C 2-6 alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted phenyl group, optionally substituted 5- or 6-membered heteroaryl group, or optionally substituted 4- is a 7-membered heterocyclic group, or R 3 and R 4 are substituted along with the atoms to which they bond. form a 4-7 membered heterocyclic group which may be R 2 ,R 2a ,R 2b ,R 5 ,R 5a and R 5b are each independently hydrogen, -OH, -NR 3e R 4e , C may be replaced 1-6 Alkyl group, optionally substituted C 2-6 a alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 1-6 Arco xy group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted C 3-6 cyclo Alkoxy group, optionally substituted phenyl group; optionally substituted 5- or 6-membered heteroaryl a 4- to 7-membered heterocyclic group that may be substituted, and R 3a ,R 3b ,R 3c ,R 3d ,R 3e ,R 4a ,R 4b ,R 4c ,R 4d and R 4e are each independently hydrogen, optionally substituted C 1-6 Alkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 1 -6 Alkoxy group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted C 3 -6Cycloalkoxy group, optionally substituted phenyl group; optionally substituted 5- or 6-membered group a teroaryl group; or an optionally substituted 4-7 membered heterocyclic group, or R 3a and R 4a ,R 3b and R 4b ,R 3c and R 4c ,R 3d and R 4d or R 3e and R 4e teeth , together with the atoms to which they are bonded, form an optionally substituted 4- to 7-membered heterocyclic group.

[0144] In some embodiments, the compound of formula IV-1 or IV-2 is a compound of formula IV-3 through IV-6. It may have a formula according to one. JPEG2023157021000070.jpg81163JPEG2023157021000071.jpg77109 or JPEG2023157021000072.jpg7483In formula, R 45 is hydrogen or a methyl group.

[0145] In some embodiments, R of any one of formulas IV-1 to IV-6 40 is hydrogen ,C 1-4 Alkyl group or C 1-4 It may also be an alkanoyl group. L in formulas IV-1 to IV-6 30 is usually empty. However, in some embodiments is L in formulas IV-1 to IV-6 30 is CH 2 It may be. W in formulas IV-1 to IV-6 30 generally refers to the carboxylic acid that can be used in the compositions and methods of the present application. These are acid derivatives, amine derivatives, or alcohol derivatives. Naturally occurring indole al Caloid tabasonine is CO 2 Me group W 30 including as L 30 is empty. C.O. 2 Me The groups can be converted to the corresponding acids, amides, etc. via conventional conversions, or rearranged e.g. It can be reduced or converted to an amine via a Curtius rearrangement. some implementations In the state, W in formulas IV-1 to IV-6 30 is -OH, -NH 2 ,-OSO 2 N.H. 2 ,- COOH, -C(O)(O-C 1-10 alkyl), -C(O)(O-C 2-10 Arche ), -OC(O)NH 2 , -OC(O)NH(C 1-4 alkyl)-, -O-(CO )-(C 1-4 alkyl), -O-(C 1-4 alkyl), where each C 1-4 Alkyl groups are independently C 1-4 Alkyl group, C 1-4 Alkoxy group, -OH, -NH 2 , and 1-3 substituents independently selected from fluorine. . In some embodiments, W in formulas IV-1 to IV-6 30 -OH, -NH 2 ,-O S.O. 2 N.H. 2 , -C(O)-(O-C 8 alkyl), -COOH or -OC(O)NH 2 It may be. In some specific embodiments, the compound may have the following structure. JPEG2023157021000073.jpg3895.

[0146] In some embodiments, the compounds of the present application are glycosides that have antimicrobial activity or pharmaceutically It may also be an acceptable salt or ester. Some glycoside examples, as shown in this application For example, ginsenosides and gallic acid glycosides, such as Bacillus megaterium Shows that microorganisms can be effectively killed. Other useful glycosides have been shown to have antibacterial activity in this field. containing any one of these glycosides known to have, e.g. The corresponding aglycones are phenolic compounds, flavonoids, coumarins, benzoic acids or sulphates. Contains glycosides characterized as terols. Glycosides are usually glucosides. However, other glycosides may be used. In some embodiments, the glycoside is an amphiphile. The antimicrobial activity of the glycosides can be enhanced by disrupting biofilms. can be given gender. In some embodiments, the glycoside is characterized as a saponin For example, it can function as a “surfactant” and contribute to the killing of bacteria. It may contain glycosides derived from multiple types of plants.

[0147] In some embodiments, the glycosides of the present application may be characterized by Formula V. JPEG2023157021000074.jpg4472In formula, Each R 50 are independently hydrogen, -L 50 -D is an oxygen protecting group or sugar residue; L 50 is empty or -C(O)-, D is an optionally substituted aryl group (for example, C 6-10 aryl group), optionally substituted heteroaryl group (e.g. 5-14 membered heteroaryl group), aryl group, heteroaryl group Substituted ring containing two or more rings independently selected from cycloalkyl group, cycloalkyl group and heterocyclic group fused rings (e.g. 8-14 membered, e.g. benzo-fused cycloalkyl groups / heterocycles) group, pyrido-fused cycloalkyl group / heterocyclic group) or a steroid residue having the formula V-A. the law of nature, JPEG2023157021000075.jpg4267Where, if the valence allows, JPEG2023157021000076.jpg826 is a steroid skeleton or any R 51 may be linked to formula V-A via a group, Here R 51 each occurrence independently represents an optionally substituted alkyl group, an optionally substituted alkyl group, an optionally substituted alkyl group, an optionally substituted alkyl group, Good alkenyl group, optionally substituted alkynyl group, -O optionally substituted with oxygen protecting group H, oxo, halogen, optionally substituted cycloalkyl group, optionally substituted alkoxy cy group, optionally substituted cycloalkoxy group, optionally substituted amino group, optionally substituted a phenyl group, an optionally substituted heteroaryl group, or an optionally substituted heterocyclic group; or two R 51 Groups, together with the atom to which they are attached, represent an optionally substituted cyclic group. forming a loalkyl group, heterocyclic group, aryl group or heteroaromatic ring, m is an integer from 1-8, and Here, -L 50 -D is chosen independently each time it appears.

[0148] In some embodiments, each R 50 is hydrogen.

[0149] In some embodiments, from 1 to 4 R 50 are independently chosen -L 50 -D You can. Two or more -L 50 When the -D unit is linked to a pyranose unit in formula V, this They are preferably the same. In some embodiments, one or more (e.g., one or more) is 2) R 50 is a sugar residue linked to the rest of formula V via a glycosidic bond. You can. In some embodiments, the sugar residue is a glucose residue or a rhamnose residue. . L in formula V 50 may be empty or a carbonyl group, i.e. -C(O)-, which is the linking group is a phenolic -OH derived from benzoic acid or a heteroaryl counterpart or a COOH group It depends on whether it is. Multiple types of residues can be used as D, typically phenolic compounds, coumarins, and flavonoids. or sterol-derived residues, and in some embodiments, antimicrobial without glycoside units. may have activity.

[0150] In some embodiments, D may be selected from the following optionally substituted rings: JPEG2023157021000077.jpg80123In formula, R 100a is a lone pair of electrons (if applicable), hydrogen, nitrogen protecting group, optionally substituted C 1 -6 Alkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 a Rukynyl group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted phenyl group , an optionally substituted 5- or 6-membered heteroaryl group, or an optionally substituted 4-7-membered heterocyclic group or R 100a is a heterocycle or heterocycle which may be substituted with a phenyl group or a pyridine ring. Forms an aromatic ring, here, JPEG2023157021000078.jpg826 may be concatenated to D via any available position, and Each ring system of D may be substituted with 1-5 (e.g. 1, 2 or 3) substituents, Each substituent is independently -OH;-COOH;-C(O)(O-C 1-10 alkyl); -C(O)(O-C 2-10 alkenyl);-OC(O)NH 2 ;-OC(O)NH(C 1-4 alkyl)-;-O-(CO)-(C 1-4 alkyl);-NH 2 ;-SO 2 N.H. 2 ;-SO 2 NH(C 1-4 alkyl);-SO 2 NH(C 1-4 alkanoyl); halo Gen; C which may be substituted 1-6 Alkyl group; optionally substituted C 2-6 alkenyl group; C that may be replaced 2-6 Alkynyl group; optionally substituted C 3-6 cycloalkyl group; C that may be replaced 1-6 Alkoxy group; optionally substituted C 3-6 cycloalkoxy group ;Optionally substituted amino group;Optionally substituted phenyl group;Optionally substituted 5 or 6 membered heteroaryl group; or an optionally substituted 4- to 7-membered heterocyclic group.

[0151] In some embodiments, each ring system of D as described above is substituted with 1-5 substituents. each substituent may be independently F;Cl;-OH;-COOH;-C(O )(O-C 1-10 alkyl);-C(O)(O-C 2-10 alkenyl);-OC(O )NH 2 ;-OC(O)NH(C 1-4 alkyl)-;-O-(CO)-(C 1-4 Al kill);-NH 2 ;-SO 2 N.H. 2 ;-SO 2 NH(C 1-4 alkyl);-SO 2 N.H. (C 1-4 alkanoyl);C 1-4 1-3 substituents independently selected from alkyl groups C may be replaced with 1-4 Alkyl group;C 1-4 Alkoxy group, -OH, -NH 2 , and and fluorine;C 1-4 Alkyl group, C 1-4 Alkoxy group, -OH, -NH 2 , and fluorine C optionally substituted with 1-3 substituents independently selected from 2-6 Alkenyl group;C 1 -4 Alkyl group, C 1-4 Alkoxy group, -OH, -NH 2 , and independently selected from fluorine. C optionally substituted with 1-3 substituents as specified 2-6 Alkynyl group;C 1-4 Alkyl group , and C optionally substituted with 1-3 substituents independently selected from fluorine 3-6 cyclo Alkyl group;C 1-4 1-3 substituents independently selected from alkyl groups and fluorine C that may be replaced 3-6 Cycloalkoxy group; or C 1-4 Alkyl group, C 1-4 Al Koxy group, -OH, -NH 2 Substituted with 1-3 substituents independently selected from , and fluorine C may be 1-4 selected from alkoxy groups.

[0152] In some embodiments, D may be selected from: JPEG2023157021000079.jpg210125, During the ceremony, Each phenolic OH group is linked to a sugar (e.g. glucose) via a glycosidic bond. Good too.

[0153] In some embodiments, D is derived from a sterol. For example, some embodiments So, D is JPEG2023157021000080.jpg4257, During the ceremony, R 52 is an optionally substituted alkyl group or an optionally substituted alkenyl group, Here, each remaining -OH group in D is also linked to a sugar via a glycosidic bond. good. Preferably, R 52 teeth It may be JPEG2023157021000081.jpg1235. In any of the embodiments described above, the glycoside may have formula V-1 or V-2. JPEG2023157021000082.jpg82104 or JPEG2023157021000083.jpg80127 In some embodiments, the glycoside may be a compound selected from: JPEG2023157021000084.jpg5360 and JPEG2023157021000085.jpg6655.

[0154] In some embodiments, the compounds of the present application include benzoic acid, benzyl alcohol, coumarins , catechols, polyphenols, chalconoids (including licochalcones), etc. Rubenes such as resveratrol, isoresveratrol, etc., phenolic acids such as p- Hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, protocatechuic acid, gallic acid, vani Phosphoric acid, syringic acid, cinnamic acid, coumaric acids, caffeic acids, ferulic acids, chlorogenic acids , sinapic acids, etc., flavonoids such as catechin, naringenin, quercetin, rutin , chrysin, etc., tannins such as ellagic acid, and pharmaceutically acceptable salts or esters and It may be any one or more compounds selected from the glycosides.

[0155] In some embodiments, the compounds of the present application are Compounds 1-8 or a pharmaceutically acceptable salt or salt. It may be any one or more of the following. JPEG2023157021000086.jpg40361, JPEG2023157021000087.jpg43392, JPEG2023157021000088.jpg33363, JPEG2023157021000089.jpg30544, JPEG2023157021000090.jpg28505, JPEG2023157021000091.jpg27616, JPEG2023157021000092.jpg55637, and JPEG2023157021000093.jpg62528

[0156] The compounds of the present application may typically be isolated from natural sources or, alternatively, may be isolated from conventional chemical sources. Prepared synthetically. For example, each of compounds 1 to 8 is available as a commercial product. It has also been identified as a component in plants. Unless there are indications to the contrary, the foregoing assignment of the present application In certain embodiments, the compounds may be derived from synthetic sources. no instructions to the contrary As far as any of the foregoing embodiments of this application, the compound is in isolated or substantially pure form. may exist. Note that the term "separation form" refers to its origin (e.g., synthetic reaction mixture or refers to a compound isolated and / or concentrated from natural sources). Typically, such isolated The compound may also be substantially pure, e.g., 80%, 85%, 90%, 9% pure by weight. 5% or more. It should also be understood that separation or conversion into a substantially pure form A composition, e.g., a pharmaceutical composition, containing a compound is one in which the compound is separated before being mixed with the other ingredients of the composition. isolated or purified, ie, in isolated or substantially pure form.

[0157] Synthetic chemical conversions and protecting group methods (protection and deprotection) that can be used to synthesize the applicable compounds are described in this book. known in the art and, for example, R. Larock, Comprehensive Organic Transformat ions, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organ ic Synthesis, 3rd version, John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994) and L. Paquette, Encyclopedia of Reagents for Organic Synthesis, John Wiley an d Sons (1995) and later versions thereof.

[0158] pharmaceutical composition In certain embodiments, the composition comprises one or more compounds of the present disclosure and any pharmaceutically acceptable excipients. The present invention relates to a pharmaceutical composition comprising: In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure and a drug. and a chemically acceptable excipient. Pharmaceutically acceptable excipients are those known in the art. Ru. Non-limiting suitable excipients include, for example, capsule materials or additives, such as absorption enhancers, acids, etc. Antioxidant, binder, buffering agent, carrier agent, coating agent, coloring agent, diluent, disintegrant , emulsifiers, extenders, fillers, seasonings, humectants, lubricants, fragrances, preservatives, propellants, release agents, Contains disinfectants, sweeteners, solubilizers, wetting agents and mixtures thereof. Also, Remington's The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro(Lippincott, Will iams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference). discloses a plurality of excipients for preparing pharmaceutical compositions and known techniques for their preparation. has been done.

[0159] Pharmaceutical compositions may include any one or more compounds of the present disclosure. For example, some In embodiments, the pharmaceutical composition has formula I, II, III, IV-1, IV-2, V, any of these or any of compounds 1 to 8, or a pharmaceutically acceptable salt or Contains ester. Unless indicated to the contrary, in any of the foregoing embodiments of this application, the pharmaceutical composition may contain a compound selected from Compounds 1 to 8 or a pharmaceutically acceptable salt or ester. good. Unless indicated to the contrary, in any of the foregoing embodiments of this application, the pharmaceutical composition comprises Compound 1 Free or substantially free of compounds selected from ~8 or pharmaceutically acceptable salts or esters may be excluded from the list.

[0160] Pharmaceutical compositions may include varying amounts of a compound of the present disclosure, which may include multiple factors, such as Depends on the expected use and efficacy of the compound. In some embodiments, the pharmaceutical composition treats comprising an effective amount of a compound of the present disclosure and a pharmaceutically acceptable excipient. In some embodiments , a therapeutically effective amount of a compound of the disclosure may be used to treat AMD (e.g., wet AMD, dry AMD) as described herein. This may be an amount that effectively treats AMD (formula AMD), which is the amount that will effectively treat the AMD. grade and severity, composition of the compound involved, time of administration, route of administration, duration of treatment, compound efficacy. , its clearance and whether another drug is co-administered. some fruit In embodiments, a therapeutically effective amount of a compound of the present disclosure includes, for example, a subject's eye (e.g., intraocular space). , effectively eliminate microorganisms such as Bacillus megaterium in the blood and / or gastrointestinal tract e.g. intestines The amount may be such that it kills the plant or inhibits its growth. In some embodiments, the book A therapeutically effective amount of a disclosed compound can be administered, for example, to a subject's eye (e.g., intraocular space), blood, and / or An amount that effectively kills or inhibits the growth of microorganisms in the gastrointestinal tract, such as the intestines. The microorganism may be, for example, Staphylococcus epidermidis, Pseudomonas S. aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas sp putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus Megatherium, Lactobacillus reuteri, Gardnerella basalis, Enterococca S. faecalis, Cytophaga hutchinsonii, Bacillus licheniformis or Ki One or more species selected from Santomonas oryzae. In some embodiments, the present disclosure A therapeutically effective amount of the compound effectively treats soft drusen symptoms, such as soft drusenoids. It may be an amount that reduces lesions.

[0161] In embodiments, the pharmaceutical compositions of the present application are capable of treating AMD and / or of the present invention. used to kill or inhibit the growth of microorganisms such as Bacillus megaterium. It can be done. The microorganisms of the present application are not particularly limited, and are usually found in, for example, the intraocular space of the subject's eyes. more preferably microorganisms associated with AMD, e.g. Concerning microorganisms that shrink. Unless specified otherwise, any of the foregoing embodiments of this application: The microorganism may include Bacillus megaterium. In some embodiments, the microorganism is , Staphylococcus epidermidis, Pseudomonas aeruginosa, yellow grape Cocci, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomo Solanum maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus ·Reuteri, Gardnerella basalis, Enterococcus faecalis, Cytopha Selected from Bacillus licheniformis or Xanthomonas oryzae It may contain one or more types.

[0162] The active ingredients, pharmaceutically acceptable excipients and / or any other ingredients in said pharmaceutical compositions of the present application. The relative amount of will vary depending on the route of administration of the composition.

[0163] The pharmaceutical compositions of the present application may be prepared to be delivered via any known delivery route. Frequently, the delivery route includes oral, injectable or infusible, topical, intraocular, inhalation, etc. Not restricted.

[0164] In some embodiments, pharmaceutical compositions may be prepared for oral administration. Oral formulations individual units, e.g. capsules, pills, cachets, each containing a predetermined amount of active compound; , lozenges or tablets, powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; or water. It may also be present as a medium oil or water-in-oil emulsion. Excipients for preparing compositions for oral administration are known in the art. Non-limiting suitable excipients include, for example, agar, alginic acid, water. Aluminum oxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol Le, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn star Chi, corn oil, cottonseed oil, crospovidone, diglyceride, ethanol, ethylcellulose , ethyl laurate, ethyl oleate, fatty acid ester, gelatin, germ oil, glucose Glycerol, groundnut oil, hydroxypropyl methane cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, stearin Magnesium acid, malt, mannitol, monoglycerides, olive oil, peanut oil (pea nut oil), potassium phosphate, potato starch, povidone, propylene glycol , Ringer's liquid, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate Thorium salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid , stearyl fumarate, sucrose, surfactant, talc, tragacanth, tetrahydrofurfur Contains lyal alcohol, triglycerides, water, and mixtures thereof.

[0165] In some embodiments, the pharmaceutical composition is administered by injection or infusion, such as intravenous injection or infusion, subcutaneous or prepared for intramuscular injection, or intraocular, eg, intravitreal injection. Injectable / infusible preparations , for example an aqueous solution, suspension, depot, implant or emulsion. Injectable / infusible preparations Excipients for preparing are known in the art. Non-limiting suitable excipients include, for example 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, Flower oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's liquid, safflower oil, rice oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water, and mixtures thereof. nothing. In some embodiments, the pharmaceutical composition is prepared for intraocular administration, e.g., intravitreal injection. Ru.

[0166] In some embodiments, pharmaceutical compositions are prepared for topical use. For topical and topical preparations The excipients are those known in the art.

[0167] The compounds of the present disclosure can be used as a single therapy or in combination with each other; It can also be used in combination therapy. For example, in some embodiments, the The pharmaceutical composition may further include another antibiotic and / or anti-VEGF agent. some In embodiments, such antibiotic and / or anti-VEGF agent are included in a single dosage form. Good too. In some embodiments, the product is commercially available (e.g., FDA approved). Any antibiotics and anti-VEGF agents (such as You may. In some embodiments, the antibiotic is a beta-lactam antibiotic, an amino lycoside antibiotics, tetracycline antibiotics, chloramphenicol antibiotics, Macrolide antibiotics, glycopeptide antibiotics, quinolone antibiotics, nitroimi Dazole antibiotics, rifamycin antibiotics, echinocandin antibiotics, polyenes antibiotics, pyrimidine antibiotics, allylamine antibiotics, or azole antibiotics Or it may be a combination of these. For example, in some embodiments, the antibiotic is , β-lactam antibiotics, such as penicillins (e.g. penicillin V), amoxicillin ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin flucloxacillin, mezlocillin, nafcillin, oxacillin, penicillin G, Examples of peracillin, pivampicillin, pivmecillinum, ticarcillin, and cephalosporins Cephastril, cefadroxil, cephalexin, cephaloglycin, cephaloni um, cephaloridine, cephalothin, cephapirin, cefatridine, cefazaflur , cefazedone, cefazolin, cephalazine, cefuroxazine, ceftesol, cepha Chlor, cefamandole, cefmetazole, cefonicid, cefotetan, cefoxi Chin, cefprozil, cefuroxime, cefzonam, cefcapen, cefdaroxime, cefdi nil, cefditoren, cefetamet, cefixime, cefmenoxime, cefodizime, Cefotaxime, cefpimizole, cefpodoxime, cefteram, ceftibuten, cefti Ofur, ceftaroline, ceftizoxime, ceftriaxone, cefoperazone, ceftazi Gym, cefclizine, cefepime, cefluplenum, cefoselis, cefozopran, Fupirom, Cefquinome, Ceftobiprole, Ceftaroline, Cefaclomedine, Cephalo Ram, Cefaparol, Cefcaner, Cefedrol, Cefenpidone, Cefetrizole , cefibitril, cefmatilene, cefmepidium (cefm) epidium), cefovecin, cefoxazole, cefrotil, cefsumide, cefra Thyme, ceftioxide, thienamycins, monobactams, β-lactamase inhibitors , methoxypenicillins; aminoglycoside antibiotics, such as streptomycin, tammycin, kanamycin (e.g. kanamycin A), tobramycin, amikacin , neomycin (e.g., neomycin B, neomycin C, neomycin E), riboma Icin, micronomycin, azithromycin, dibekacin, sisomicin, netilmycin Syn, paromomycin, bramycin, etc.; tetracycline antibiotics, e.g. Iclin, oxytetracycline, chlortetracycline, doxycycline, etc. ;chloramphenicol antibiotics, e.g. chloramphenicol, thiamphenicol Macrolide antibiotics, such as erythromycin, leucomycin, odorless erythro Mycin, acetylspiramycin, medimycin, josamycin, azithromycin clarithromycin, dirithromycin, roxithromycin, telithromycin, etc. ;Glycopeptide antibiotics, such as vancomycin, norvancomycin, teicopra; quinolone antibiotics, such as norfloxacin, ofloxacin, ciprofloxacin, etc. Sacin, Pefloxacin, Gatifloxacin, Enoxacin, Lomefloxacin, Nalizi oxic acid, levofloxacin, moxifloxacin, besifloxacin; nitroimidazo antibiotics such as metronidazole, tinidazole, ornidazole; synthetic antibiotics, such as rifampicin; echinocandin antibiotics; polyene antibiotics quality; pyrimidine antibiotics; allylamine antibiotics; azole antibiotics; other antibiotics Quality: fosfomycin, capreomycin, cycloserine, lincomycin, clindama Icin, mitomycin, actinomycin D, bleomycin, doxorubicin, iso Niazide, pyrazinamide, cyclosporine, polymyxin B combination e.g. polymyxin Polymyxin B / Trimethoprim, Polymyxin B / Bacitracin, Polymyxin B / Neomycin / gramicidin, etc. may be included.

[0168] In some embodiments, the antibiotic is amikacin, amoxicillin, ampicillin, Luvalsan, Azithromycin, Azlocillin, Aztreonam, Bacitracin, Capre Omycin, carbenicillin, cefaclor, cefadroxil, cephalexin, cef Farotin, cefamandole, cefazolin, cefdinir, cefditoren, cefixime , cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime, Chloro Ramphenicol, Cilastatin, Clarithromycin, Clavulanic acid, Clindamycin clofazimine, cloxacillin, colistin, cycloserine, dalfopristi dapsone, daptomycin, dicloxacillin, dirithromycin, doripenem, doripenem, Xycycline, erythromycin, ethambutol, ethionamide, flucloxacili Fosfomycin, furazolidone, fusidic acid, gentamicin, imipenem, isoni Azide, kanamycin, lincomycin, linezolid, loracarbef, mafenide, melo Penem, methoxypenicillin, metronidazole, mezlocillin, minocycline, mupi Rosin, Nafcillin, Neomycin, Netilmicin, Nitrofurantoin, Oxaciri Oxytetracycline, Paromomycin, Penicillin G, Penicillin V, Piperacy Phosphorus, platensimycin, polymyxin B, pyrazinamide, quinupristin, rapamycin Syn, rifabutin, rifampicin, rifamycin (Ri fampin), rifapentine, rifaximin, roxithromycin, sulfazia silver, spectinomycin, streptomycin, sulbactam, sulfacetamide, Sulfadiazine, Sulfamethizole, Sulfamethoxazole, Sulfanilamide , sulfasalazine, sulfisoxazole, tazobactam, teicoplanin, telaban Telavancin, telithromycin, temocillin, tetracycline, thi Amphenicol, ticarcillin, tigecycline, tinidazole, tobramycin, Rimethoprim, Troleandomycin, Vancomycin, Enoxacin, Lomefloxa Syn, nalidixic acid, ciprofloxacin, levofloxacin, gatifloxacin, moki Cifloxacin, ofloxacin, norfloxacin, cefotetan, cefonicide, Farazine, Cephapirin, Cephalothin, Cefmetazole, Cefotaxime, Moxara ctam, cefepime, ceftaroline fosamil, ceftobiprole, dalbavancin, Meclocycline, methacycline, ertapenem, fidaxomicin, geldanamycin Syn, Herbimycin, Posizolid, Rade zolid), Torezolid, oritavancin (Oritava ncin), spiramycin, sulfadimethoxine, sulfonamide chrysoidine (Su lfonamidochrysoidine), gemifloxacin, nadifloxacin, Trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin, te Ixobactin, Malacidins and It may be selected from a combination of these. Antibiotics can be in any form, e.g. a pharmaceutically acceptable salt form or a corresponding pharmaceutically acceptable salt mixture form; You may. Antibiotics can be prepared and administered by their known routes of administration, and especially There are no restrictions.

[0169] Anti-VEGF drugs are typically biopharmaceuticals that target VEGF, such as ranibizumab, Including Bercept, Bevacizumab, Conbercept, etc.

[0170] Method of treatment Compounds of the present disclosure can be used to treat infections with microorganisms of the present application, such as Bacillus megaterium (e.g., ocular infections). therapeutic activity to treat and / or prevent diseases or disorders associated with Useful as a sex substance. As shown in the Examples section, representative compounds of the present disclosure are In the Toro test, strong effects that kill or inhibit the representative microorganism Bacillus megaterium are used. Indicates purpose. Additionally, the Examples demonstrate that Bacillus cells are tested in vivo, e.g. in the rhesus monkey model of the present application. By killing or inhibiting S. megaterium, antibiotics such as vancomycin We show that drusenoid lesions induced by Tylus megaterium can be reduced.

[0171] Accordingly, in embodiments, the present disclosure provides for the use of a compound of the present disclosure or a pharmaceutical composition of the present application. to treat infections with microorganisms such as Bacillus megaterium, and to treat such infections. The present invention further provides a method for treating or preventing a disease or disorder associated with infection (e.g. AMD). .

[0172] Unless otherwise specified, in any of the foregoing embodiments of this application, the infection may include, for example, the intraocular space. may include eye infections. Any of the foregoing embodiments of this application, unless otherwise specified. In some cases, the microorganism may include Bacillus megaterium. In some embodiments, Microorganisms Staphylococcus epidermidis, Pseudomonas aeruginosa, yellow Color Staphylococcus, Staphylococcus haemolyticus, Pseudomonas putida, Stenoto Lophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lacto Bacillus reuteri, Gardnerella basalis, Enterococcus faecalis, Sa Itophaga hutchinsonii, Bacillus licheniformis or Xanthomonas oryzae It may contain one or more types selected from.

[0173] In embodiments, the compounds of the present disclosure can be used to control microorganisms of the present application, such as Bacillus megaterium. It can be used to kill or inhibit its growth. In some embodiments, the present invention The indicated compound is effective in treating AMD, such as drusen symptoms (hard drusen, soft drusen, mixed drusen). Dry or wet age-related macular degeneration (including drusen and / or degraded drusen), e.g. For example, for treating or preventing dry or wet age-related macular degeneration with soft drusen symptoms. can be used. Compounds of the present disclosure may be used alone, e.g., as described in this application. , may be used in combination with each other and with another antibiotic and / or anti-VEGF drug. It may also be used together.

[0174] In some embodiments, the present disclosure kills the present microorganisms, such as Bacillus megaterium. The present invention provides a method for inhibiting the growth of a plant. In some embodiments, the method comprises: contacting a microorganism with an effective amount of a compound of the present disclosure or the pharmaceutical composition of the present application. stomach In some embodiments, contacting may be in vitro, ex vivo, or in vivo.

[0175] In some embodiments, the present disclosure provides a method for administering the present microbial metaphor in a subject in need thereof. A method of killing or inhibiting the growth of Bacillus megaterium is further provided. . In some embodiments, the method comprises a compound of the present disclosure (e.g., Formula I, II, III, I V-1, IV-2, V, any subformula of these compounds, or any of compounds 1 to 8 or a pharmaceutically acceptable salt or ester) to the subject. Opposition Unless otherwise indicated, in any of the foregoing embodiments of the present application, the method may include compounds selected from compounds 1-8. administering to the subject a compound or a pharmaceutically acceptable salt or ester. Good too. Unless indicated to the contrary, in any of the foregoing embodiments of this application, the method comprises The pharmaceutical composition may further include the step of administering a compound to the subject. Free or substantially free of compounds or pharmaceutically acceptable salts or esters selected from do not have. In some embodiments, the compound or pharmaceutical composition is administered to a subject, e.g. e.g. intraocular space), blood and / or gastrointestinal tract e.g. intestines. or in an amount that inhibits its growth. In some embodiments, the subject has AMD are suffering from. In some embodiments, the subject does not have AMD. some In embodiments of , the subject is at risk of developing AMD. In some embodiments, the The examiner's eye is infected with the microorganism of the present application, such as Bacillus megaterium. some implementation In some embodiments, the method involves the subject being infected with microorganisms, such as Bacillus megateri, in the intraocular space. The method further includes the step of identifying or having identified the substance. In some embodiments, e.g. , the subject is further administered an antibiotic and / or an anti-VEGF agent, as described herein. In such embodiments, the antibiotic and / or anti-VEGF agent is a compound of the present disclosure or the present application. may be administered to a subject simultaneously or sequentially in any order.

[0176] In some embodiments, the present disclosure provides a method for treating or treating AMD in a subject in need thereof. Provide a way to prevent it. In some embodiments, the method includes a compound of the present disclosure (e.g. Compounds of formula I, II, III, IV-1, IV-2, V), any subformula thereof , or any of Compounds 1 to 8, or a pharmaceutically acceptable salt or ester. in a therapeutically effective amount. Unless indicated to the contrary, any of the foregoing implementations of this application In embodiments, the method comprises a compound selected from compounds 1-8, or a pharmaceutically acceptable salt or The method may include administering the ester to the subject. Unless there are instructions to the contrary, before the application In any embodiment described above, the method further comprises administering the pharmaceutical composition to the subject. The pharmaceutical composition may contain a compound selected from compounds 1 to 8 or a pharmaceutically acceptable compound. Free or substantially free of salts or esters. In some embodiments, the method comprises: , for example, the administration of antibiotics and / or anti-VEGF drugs to a subject, as described in this application. Including more tep. In some embodiments, AMD causes drusen symptoms (hard drusen symptoms). Drusen, soft drusen, mixed drusen and / or degraded drusen) or wet age-related macular degeneration, e.g. dry or wet age-related macular degeneration with soft drusen symptoms. It may be a disease. In some embodiments, the method includes the subject applying the present invention to, e.g., the intraocular space. identified as infecting microorganisms such as Bacillus megaterium, or Including more. In some embodiments, the subject has a microbial metaphor of the present application in the intraocular space, for example. infected with Bacillus megaterium. In some embodiments, the method comprises for example in the subject's eyes (e.g. intraocular space), blood and / or gastrointestinal tract e.g. intestines. An amount that effectively kills or inhibits the growth of microorganisms such as Bacillus megaterium and administering the compound or pharmaceutical composition to the subject.

[0177] Administration in this application is not limited to any particular route of administration. For example, in some embodiments Administration is oral, nasal, topical, intraocular, intravitreal, transdermal, pulmonary, inhalation, buccal, sublingual, and intraperitoneal. It may be intravenous, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal and parenteral. Several In embodiments, administration may be oral, topical, intravitreal, intramuscular, subcutaneous, or intravenous. In some embodiments, administration is oral. In some embodiments, the administration is intravitreal. It is within.

[0178] Dosing protocols, such as amount and frequency, depend on multiple factors, such as what is being treated and the disease being treated. Disease or disorder and its severity, composition of compound contained, administration time, administration route, duration of treatment may vary depending on compound potency, its clearance, and whether another drug is coadministered. Ru.

[0179] extract In one aspect, the present disclosure further provides extracts of several traditional Chinese medicines (TCMs) with antibacterial activity. provide. The term Chinese medicine, for example, appears in the corresponding chapter of the Pharmacopoeia of the People's Republic of China (current edition). As stated, it should be interpreted broadly to include both medicinal and non-herbal herbal medicines. Examples section As explained in detail in , multiple species of TCM are used in the representative microorganism of this application, Bacillus megaterium. It was found that it has activity against bacteria. Some of these TCM-derived isolated components are Bacillus Although the extract itself has been identified as having activity against S. megaterium, the It is useful for treating biological infections and related diseases or disorders such as AMD.

[0180] Accordingly, in some embodiments, the present disclosure provides for AM in a subject in need thereof. Provided are methods for treating or preventing D. za uralensis), juniper (e.g. Cynanchum otoph yllum), Forsythia (e.g. Forsythia suspense), Kikoku (e.g., Citrus aurantium L.), Citrus aurantium (e.g., Rehman nia glutinosa Libosch), Citrus re ticulata Blanco), and Panax notogi (e.g. Panax notogi a step of administering to the subject one or more TCM-derived extracts selected from including. In some embodiments, AMD causes drusen symptoms (hard drusen, soft drusen). dry or wet aging (including leusen, mixed drusen and / or degraded drusen) Macular degeneration, even dry or wet age-related macular degeneration with soft drusen symptoms good. In some embodiments, the method includes a method in which the subject receives a microbial analog of the present application, e.g., in the intraocular space. Bacillus megaterium. nothing. In some embodiments, the subject has a microorganism of the present invention, e.g., Bacillus, e.g., in the intraocular space. Infected with Megatherium.

[0181] In some embodiments, the present disclosure kills the subject microorganisms in a subject in need thereof. or a method of killing or inhibiting the growth of the microorganisms of the present application, such as Bacillus megaterium. provides a method of treating a Glycyrrhiza (e.g., Glycyrrhiza uralensis), Juniper (e.g. Cynanchum otophyl lum), Forsythia (e.g. Forsythia suspense), Kikoku (e.g. For example, Citrus aurantium L.), Citrus aurantium (for example, Rehmanni a glutinosa Libosch), Citrus reti (e.g. Citrus reti culata Blanco), and Panax notogins (e.g. Panax notogins eng), the step of administering to the subject one or more TCM-derived extracts selected from . In some embodiments, the subject has AMD. In some embodiments, Subject does not have AMD. In some embodiments, the subject develops AMD There is a risk. In some embodiments, the eye of the subject is infected with a microorganism of the present invention, such as Bacillus melanum. infected with Gatherium. In some embodiments, the method includes a method in which the subject, e.g. During the period, microorganisms such as Bacillus megaterium are identified as infecting or Including more. In some embodiments, for example, as described herein, Biological agents and / or anti-VEGF agents are further administered.

[0182] In some embodiments, the extract may be of a single TCM. For example, how many In some embodiments, the method comprises providing the subject with licorice (e.g., Glycyrrhiza ralensis). In some embodiments, the person The method requires that the subject be exposed to juniper (e.g., Cynanchum otophyllum). administering the extract. In some embodiments, the method provides instruction to the subject. administering an extract of Forsythia suspense (e.g. Forsythia suspense). include. In some embodiments, the method provides the subject with Citrus a urantium L.). In some embodiments , the method involves injecting Rehmannia glutinosa (e.g. Rehmannia glutinosa Li) into the subject. bosch), chimpi (e.g. Citrus reticulata Blanco) administering an extract of. In some embodiments, the method includes providing a sample to the subject. including the step of administering an extract of Panax notoginseng (e.g. Panax notoginseng). nothing.

[0183] In some embodiments, the extract may be a combination extract of two or more TCMs. stomach. For example, in some embodiments, the method includes licorice (e.g., Glycyrrhiza iza uralensis), juniper (e.g. Cynanchum otop hyllum), Forsythia (e.g. Forsythia suspense), Kiko Citrus aurantium L. (e.g. Citrus aurantium L.), Rehma nnia glutinosa Libosch), Citrus r. eticulata Blanco), and Panax notog (e.g. Panax notog A step in which two or more TCM-derived extracts selected from Including. In some embodiments, the method includes (a) licorice (e.g., Glycyr rhiza uralensis), Juniper (e.g. Cynanchum ot ophyllum), forsythia (e.g. Forsythia suspense), Citrus aurantium (e.g. Citrus aurantium L.), Reh mannia glutinosa Libosch), chimpi (e.g. Citrus reticulata Blanco), and panax (e.g. Panax not (b) one TCM derived from one or more other TCMs; administering the extract to the subject. In some embodiments, the method includes (a) Each independently, daylily, juniper, forsythia, kikoku, zigo, chimpi, and 1-7 types selected from TCM and other combinations (not all TCM), and optionally (b) administering to the subject one or more other TCM-derived extracts. Including.

[0184] The extracts herein are generally prepared according to common practice in TCM. For example, the example chapter refer. If more than one TCM is used, each TCM (or any of the TCMs) Extract subgroups) and then combine these extracts or combine the two An extract may be prepared in a manner that simultaneously extracts the above TCMs. Usually the extract is water It is a sex extract. In some embodiments, non-aqueous extracts are also useful. In addition, some T In CM, parts of multiple species of plants are useful, such as leaves, stems, roots, fruits, seeds, etc. of the main application In embodiments, when applied, the extract is not restricted to any particular part of the TCM plant. .

[0185] The extract of the present application may be present or administered in liquid, semi-solid or solid form or any other form. good. For example, the extract may be administered as an aqueous solution, suspension or emulsion. instead, The extract may be manufactured into capsules, tablets, powders, etc. and administered accordingly, usually orally. Administered by mouth. Administration of the extract may follow typical practice for TCM and is not limited to the route of administration. The dosing protocol, e.g. amount and frequency, depends on multiple factors, e.g. the subject being treated, the disease or disorder to be treated and its severity, the composition of the extract contained, and the administration. time, route of administration, duration of treatment, potency of the extract, its clearance and simultaneous use of another drug. The dosage may be adjusted depending on whether or not to administer the drug. In some embodiments, the extract is for example in the subject's eyes (e.g. intraocular space), blood and / or gastrointestinal tract e.g. intestines. An amount that effectively kills or inhibits the growth of microorganisms such as Bacillus megaterium administered in

[0186] Antibiotics As discussed in this application, the present invention relies, in part, on the fact that the intraocular environment is not sterile; This study is based on the surprising discovery that the ocular microbiota may be the cause of AMD. did Accordingly, any antibiotic, such as those known in the art, may be used in the treatment of infections with the microorganisms of the present application. and can be used for the treatment or prevention of AMD. Therefore, some embodiments In this case, the present disclosure can be applied to the microorganisms of the present application, such as Bacillus megana, in a subject in need thereof. Methods of killing or inhibiting the growth of the microorganisms of the present application (e.g., by visual inspection) methods of treating infections (e.g. in the intraocular space) and / or diseases associated with microorganisms or infections or Further provided are methods of treating or preventing a disorder such as AMD, the method comprising administering an antibiotic to a subject. the step of administering the method in an effective amount to the patient. In some embodiments, commercially available Any antibiotic can be used, e.g. antibiotics approved by the US FDA Ru. In some embodiments, the antibiotic is characterized as a broad-spectrum antibiotic. It's okay. In some embodiments, the antibiotic is an antibiotic against Gram-positive bacteria, and Good too. In some embodiments, the subject has AMD. Some embodiments Then, the subject does not have AMD. In some embodiments, the subject develops AMD. There is a risk of illness. In some embodiments, the subject has an eye infection, e.g. One is infected by Bacillus megaterium for example. In some embodiments, AMD is associated with drusen symptoms (hard drusen, soft drusen, mixed drusen and / or dry or wet age-related macular degeneration (including degraded drusen), such as soft drusen It may be dry or wet age-related macular degeneration with symptoms. In some embodiments, the person The method is such that the subject is infected with the microorganism of the present application, e.g. Bacillus megaterium, e.g. in the intraocular space. The method further includes the step of identifying or identifying that a person is present. In some embodiments, the subject For example, the intraocular space is infected with a microorganism such as Bacillus megaterium. how many In such embodiments, the subject has been administered an anti-VEGF drug, e.g., as described herein. Ru.

[0187] The compounds of the present disclosure (see e.g. Compounds section) typically have antibacterial activity and are therefore May be used as a substance. However, the antibiotics described in this chapter do not apply to the compounds of this disclosure (e.g. For example, as defined in this application). In some embodiments, antibiotics The substances are also compounds of the present disclosure. In some embodiments, the antibiotic is a compound of the present disclosure. do not have. In some embodiments, an antibiotic and a compound of the present disclosure are used together in combination therapy, which subjects who require it simultaneously (e.g., as a single dosage form) or in any order. May be administered sequentially.

[0188] In some embodiments, the antibiotic is a beta-lactam antibiotic, an aminoglycoside antibiotic substances, tetracycline antibiotics, chloramphenicol antibiotics, macrolides Antibiotics, glycopeptide antibiotics, quinolone antibiotics, nitroimidazole antibiotics substances, rifamycin antibiotics, echinocandin antibiotics, polyene antibiotics, Limidine antibiotics, allylamine antibiotics, or azole antibiotics, or combinations thereof. It may be a combination.

[0189] In some embodiments, the antibiotic is a beta-lactam antibiotic, such as penicillins ( For example, penicillin V), amoxicillin, ampicillin, bacampicillin, carbenicillin cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafsiri Oxacillin, Penicillin G, Piperacillin, Pivampicillin, Pivmecillinum, Thi Calcilin, cephalosporins such as cephastril, cefadroxil, cephalex Syn, cephaloglycine, cephalonium, cephaloridine, cephalothin, cefapiri cefatridine, cefazafurur, cefazedone, cefazolin, cephalazine, Floxazine, Ceftesol, Cefaclor, Cefamandole, Cefmetazole, Cef fonicid, cefotetan, cefoxitin, cefprozil, cefuroxime, cefzonam, Cefcapene, Cefdaroxime, Cefdinir, Cefditoren, Cefetamet, Cefixi cefmenoxime, cefodizime, cefotaxime, cefpimizole, cefpodoxime , cefteram, ceftibuten, ceftiofur, ceftaroline, ceftizoxime, ceftri Axone, cefoperazone, ceftazidime, cefclizine, cefepime, cefluprenam , cefoselis, cefozopran, cefpirome, cefquinome, ceftobiprole, cefta Lorin, cefaclomedine, cephalolam, cefaparol, cefcanel, cefedrol , cefenpidone, ceftrizole, cefibitril, cefmatilene (cefmati) len), cefmepidium, cefovecin, cefoxazole le, cefrotil, cefsumide, cefratime, ceftioxide, thienamycins, mono Bactams, β-lactamase inhibitors, methoxypenicillins; aminoglycoside antibiotics Substances such as streptomycin, gentamicin, kanamycin (e.g. A), tobramycin, amikacin, neomycin (e.g. neomycin B, neomycin icin C, neomycin E), ribomycin, micronomycin, azithromycin, di Bekacin, sisomicin, netilmicin, paromomycin, bramycin, etc.; Tetrasa Icrine antibiotics, such as tetracycline, oxytetracycline, chlortetra cyclin, and doxycycline, etc.; chloramphenicol antibiotics, e.g. Mufenicol, thiamphenicol, etc.; macrolide antibiotics, e.g. erythromycin Syn, leucomycin, odorless erythromycin, acetylspiramycin, medimycin N, josamycin, azithromycin, clarithromycin, dirithromycin, loki Cithromycin, telithromycin, etc.; glycopeptide antibiotics, e.g. vancomycin quinolone antibiotics, such as norfloxa, norvancomycin, teicoplanin, etc. Syn, ofloxacin, ciprofloxacin, pefloxacin, gatifloxacin, eno Xacin, lomefloxacin, nalidixic acid, levofloxacin, moxifloxacin, besifloxacin; nitroimidazole antibiotics, e.g. metronidazole, tinidazo Rifamycin antibiotics, such as rifampicin; ginsin antibiotics; polyene antibiotics; pyrimidine antibiotics; allylamine antibiotics quality; azole antibiotics; other antibiotics: fosfomycin, capreomycin, cyclo Serine, lincomycin, clindamycin, mitomycin, actinomycin D, blu Reomycin, doxorubicin, isoniazid, pyrazinamide, cyclosporine, polymium Xin B combinations such as polymyxin B / trimethoprim, polymyxin B / bacitra may contain one or more of the following: polymyxin B / neomycin / gramicidin, etc. .

[0190] In some embodiments, the antibiotic is amikacin, amoxicillin, ampicillin, Luvalsan, Azithromycin, Azlocillin, Aztreonam, Bacitracin, Capre Omycin, carbenicillin, cefaclor, cefadroxil, cephalexin, cef Farotin, cefamandole, cefazolin, cefdinir, cefditoren, cefixime , cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime, Chloro Ramphenicol, Cilastatin, Clarithromycin, Clavulanic acid, Clindamycin clofazimine, cloxacillin, colistin, cycloserine, dalfopristi dapsone, daptomycin, dicloxacillin, dirithromycin, doripenem, doripenem, Xycycline, erythromycin, ethambutol, ethionamide, flucloxacili Fosfomycin, furazolidone, fusidic acid, gentamicin, imipenem, isoni Azide, kanamycin, lincomycin, linezolid, loracarbef, mafenide, melo Penem, methoxypenicillin, metronidazole, mezlocillin, minocycline, mupi Rosin, Nafcillin, Neomycin, Netilmicin, Nitrofurantoin, Oxaciri Oxytetracycline, Paromomycin, Penicillin G, Penicillin V, Piperacy Phosphorus, platensimycin, polymyxin B, pyrazinamide, quinupristin, rapamycin Syn, rifabutin, rifampicin, rifamycin (Ri fampin), rifapentine, rifaximin, roxithromycin, sulfazia silver, spectinomycin, streptomycin, sulbactam, sulfacetamide, Sulfadiazine, Sulfamethizole, Sulfamethoxazole, Sulfanilamide , sulfasalazine, sulfisoxazole, tazobactam, teicoplanin, telaban Telavancin, telithromycin, temocillin, tetracycline, thi Amphenicol, ticarcillin, tigecycline, tinidazole, tobramycin, Rimethoprim, Troleandomycin, Vancomycin, Enoxacin, Lomefloxa Syn, nalidixic acid, ciprofloxacin, levofloxacin, gatifloxacin, moki Cifloxacin, ofloxacin, norfloxacin, cefotetan, cefonicide, Farazine, Cephapirin, Cephalothin, Cefmetazole, Cefotaxime, Moxara ctam, cefepime, ceftaroline fosamil, ceftobiprole, dalbavancin, Meclocycline, methacycline, ertapenem, fidaxomicin, geldanamycin Syn, Herbimycin, Posizolid, Rade zolid), Torezolid, oritavancin (Oritava ncin), spiramycin, sulfadimethoxine, sulfonamide chrysoidine (Su lfonamidochrysoidine), gemifloxacin, nadifloxacin, Trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin, te Ixobactin, Malacidins and It may be selected from a combination of these.

[0191] In some embodiments, the antibiotic is administered to the subject, e.g., the subject's eye (e.g., intraocular space), The microorganisms of the present application, such as Bacillus megaterium, in the blood and / or gastrointestinal tract, e.g. It is administered in an amount that will result in the ultimate death or inhibit its growth.

[0192] Antibiotics may be present in any form, for example in the form of their corresponding pharmaceutically acceptable salts or It may also be in the form of a mixture of the corresponding pharmaceutically acceptable salts. Antibiotics are It can be prepared and administered by any given route, and there are no particular limitations. In some embodiments Administration may be oral, topical, intravitreal, intramuscular, subcutaneous or intravenous. Several In embodiments, administration is oral. In some embodiments, administration is intravitreal.

[0193] Dosing protocols, such as amount and frequency, depend on multiple factors, such as the person being treated and the person being treated. Disease or disorder and its severity, composition of antibiotics contained, administration time, administration route, duration of treatment depending on time, antibiotic potency, its clearance and whether another drug is administered simultaneously. Change.

[0194] Exemplary Alternative Embodiment In some aspects, the present disclosure provides a method for creating a model and a model created by the method. Regarding. In another aspect, the present application provides methods for screening pharmaceuticals, and Disclose the medicines that are prescribed. In some embodiments, the present disclosure provides modeling and pharmaceutical Concerning the use of microorganisms in screening.

[0195] In one aspect, the present application discloses a method of creating a model, the method comprising sensing a model carrier with a microorganism. Including the step of dyeing. Microorganisms include bacteria, archaea, protists, fungi, viruses, or or consisting of a combination of these. Preferably, the microorganism comprises a bacterium; Bacteria include the genus Clostridium and the genus Acinetobacter. etobacter), Streptococcus, to Mann Mia (Mannheimia), Fibrobacter (Fibrobacter), Plasma Prevotella, Campylobacter r), Actinomyces, Hymenobacter obacter), Escherichia, Ti ssierella), Klebsiella, Porphyromonas (Porphyromonas), Azospira (Azospira), Achimarina (A quimarina), Achromobacter spp. Acidithiobacillus, Burkholderia holdereria), Marinobacter spp., Treponema spp. (Treponema), Actinosporangium ), Vibrio, Ruminococcus, Methanobrevibacter, Shigella gella), Frankia (Frankia), Aneroplasma (Anaeropl) asma), and one or more species selected from the genus Coprococcus. There may be.

[0196] In some preferred embodiments, the bacterium is Clostridium tetani. anus), Clostridium perfringens, Botu Clostridium botulinum, Acinetobacter calco Acinetobacter acetate, Acinetobacter rufu Acinetobacter rufi, Acinetobacter baumannii etobacter baumannii), Acinetobacter haemolyticus (Aci netobacter hemolyticus), Acinetobacter junii (Ac inetobacter junii), Acinetobacter johnsoni (Acinet obacter johnsonii), Streptococcus pyogenes (Streptococcus pyogenes) pyogenes), Streptococcus hemolyticus , Porphyromonas asacharo lytica), Porphyromonas gingivalis (Porphyromonas gi) ngivalis), Porphyromonas gingivalis gingivalis), Campylobacter jejuni (Campylobacter jejuni) jejuni), Campylobacter coli , Campylobacter seabirds, Campylobacter Uppsala, Npilo Campylobacter concisely, campylobacter Bacter fetus (Campylobacter fitus), Actinomyces Actinomyces israelii, Actinomyces nes Actinomyces naeslundii, Actinomyces naeslundii Actinomyces odontolyticus, Escherichia coli ( Escherichia coli), Escherichia blattae (Escherichia coli) ia blattae), Escherichia fe rgusonii), Escherichia herma nnii), Escherichia vulneris , Tissierella apical, Klebsiella Klebsiella pneumoniae, Klebsiella odora Klebsiella odorata, Azospirillum brasilense spirillum brasilence), Achromobacter (Achromobacter) cter), Thiobacillus denitrificans (Thiobacillus deni trificans), Thiobacillus ferrooxidans ferrooxidans), Thiobacillus thiooxidans (Thiobacil lus thiooxidans), Thiobacillus neapolitanus (Thiobaci) llus neapolitanus), Burkholderia ), Mycobacterium marinum, Treponema pallidum, Treponema pallidum Treponema hyodysenteriae, Vibrio meschni Vibrio metschnikovi, Ruminococcus albus minococcus albus), Ruminococcus flabefaciens (Rumi) nococcus flavefaciens), Methanoblewibacter luminante Methanobrevibacter ruminantium, Shiga dysentery Shigella dysenteriae, Shigella flexneri ella flexneri), Shigella bogdii ), Shigella sonnei, Frankia eae), Streptomyces albus, Pyudomonas mendocina, Cytococcus sedentarius, Alicycliphilus denis trificans, Achromobacter xyloxidans, Sphingobium chaponica Mycobacterium abscessus, Arthrobacter aurescens, Prevotella dentalis, Sinorhizobium meliloti, Acidovorax ebreus, Staphi Rococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus Phyllococcus haemolyticus, Pseudomonas putida, Stenotrophomonas mal Tofilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri , Gardnerella basalis, Enterococcus faecalis, Cytophaga hatchi N. sonii, Bacillus licheniformis, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter calcoaceticus, Comamonas testosteroni, Myco Bacterium kansasii, Bacillus thuringiensis, Citrobacter coseri, De Adobacter fermentans, Serratia marcescens, Sphingomonas cormorant Itch, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstoni A picketii, Lactobacillus crispatus, Burkholderia multiborans, La Tobacillus delbricii, Meiothermus sylvanus (D), Escherichia coli, Micro Coccus luteus, Bacillus subtilis, Corynebacterium aurinum cosum, Finegordia ·It may be one or more types selected from Magna.

[0197] In some preferred embodiments, the bacteria are Pseudomonas mendocina, Cytococcus Sedentarius, Alicycliphilus denitrificans, Achromobacter xii Roxidans, Sphingobium chaponicum, Mycobacterium abscessus, A Ruthrobacter aurescens, Prevotella dentalis, Sinorhizobium melilote Acidovorax ebreus, Staphylococcus epidermidis, Pseudo Monas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudo Monas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus S. megatherium, Lactobacillus reuteri, Gardnerella basalis, Enterococcus Cass faecalis, Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter calcoase Chicas, Comamonas testosteronii, Mycobacterium kansasii, Bacillus chu - Citrobacter koseri, Diadobacter fermentans, Sera Chia marcescens, Sphingomonas wich, Klebsiella pneumoniae, Si Peudomonas fluorescens, Ralstonia pickettii, Lactobacillus chris Patas, Burkholderia multiborane, Lactobacillus delbricii, Meiosa - Mas sylvanus (D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacillus Even if it is one or more species selected from Therium aurimucosum and Finegordia magna good.

[0198] In some preferred embodiments, the bacteria are Pseudomonas putida, Bacillus megate. One or more species selected from Propionibacterium acnes and Propionibacterium acnes. preferred practice In morphology, the bacterium is Bacillus megaterium.

[0199] In some preferred embodiments, the present disclosure provides a method for creating a model for cataract (Cat). Regarding the method, the method is applicable to Pseudomonas mendocina, Cytococcus sedentarius, A. Lycicliphilus denitrificans, Achromobacter xyloxidans, Sufi Ngobium chaponicum, Mycobacterium abscessus, Arthrobacter au Resens, Prevotella dentalis, Sinorhizobium meliloti or Acidovorac The step of infecting a model carrier with one or more microorganisms selected from S. ebreus include.

[0200] In some preferred embodiments, the present disclosure provides a model for age-related macular degeneration (AMD). Regarding the method for producing Staphylococcus epidermidis, Pseudomonas · Staphylococcus aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas ·Putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus medica Gatherium, Lactobacillus reuteri, Gardnerella basalis, Enterococcus · Faecalis, Cytophaga hutchinsonii, Bacillus licheniformis or Kisa A step in which a model carrier is infected with one or more microorganisms selected from Tomonas oryzae. Including.

[0201] In some preferred embodiments, the present disclosure provides a method for creating a model for glaucoma (GLA). Regarding the method, the method is applicable to Acinetobacter baumannii, Acinetobacter calcoacetica. Comamonas testosteronii, Mycobacterium kansasii, Bacillus thuli genensis, Citrobacter koseri, Diadobacter fermentans or Serraci A step to infect a model carrier with one or more microorganisms selected from A. marcescens. Including.

[0202] In some preferred embodiments, the present disclosure provides a model for Behcet's disease (BD). Regarding the production method, the method is based on Sphingomonas witchi, Klebsiella pneumoniae. , Pseudomonas fluorescens, Ralstonia pickettii, Lactobacillus Lyspatus, Burkholderia multiborane, Lactobacillus delbricii or Infect model carriers with one or more microorganisms selected from Iothermus sylvanus (D) including the step of

[0203] In some preferred embodiments, the present disclosure provides treatment for Vogt-Koyanagi-Harada syndrome (VKH). Regarding the method of creating a model related to Escherichia coli, Micrococcus luteus, 1 selected from the fungi, Corynebacterium aurinum cosum or Finegordia magna Infecting a model carrier with more than one species of microorganism.

[0204] Model carriers include humans, non-human mammals, organs, tissues, tissue sections, tissue extracts, body fluids, It may include one or more of body fluid cultures, cells, viruses, enzymes, and media. non-human suckling Animals may include any mammal for laboratory, pet, or economic use. Exemplary non-human Mammals include mice, rats, rabbits, cats, dogs, pigs, mother cows, bulls, sheep, goats, horses, Includes monkeys or non-human primates. Exemplary organs include heart, liver, lungs, stomach, kidneys, eyes, ears, Including nose and tongue. Tissues, tissue sections and tissue extracts may be derived from any part of the subject or test animal. tissue, tissue sections or tissue extracts. In some embodiments, the organization Including the zona, ciliary body, ciliary body / muscle, vitreous body, retina, choroid, optic nerve, lens, or iris. In some embodiments, tissue extracts include DNA, RNA or proteins. some In embodiments, the body fluids include lymph fluid, cerebrospinal fluid, aqueous humor (AH), vitreous humor (VH), blood , including sweat or urine fluid. In some embodiments, the body fluid culture includes AH and VH cultures. .

[0205] In another aspect, this application discloses the use of microorganisms in the creation of models, and specifically The model carrier is created by infecting a model carrier with the microorganism. Microorganisms and models Defined ranges of carriers are as described herein.

[0206] In a further aspect, the present application provides a model carrier prepared by infecting a model carrier with a microorganism. Disclose the model that will be used. Defined range of microorganisms and model carriers as described in this application It is.

[0207] In a further aspect, the present application discloses a method of screening a pharmaceutical product, the method comprising: It includes a step (1) of applying the model and a step (2) of analyzing the results. preferably The method involves the step of creating a model by infecting a model carrier with microorganisms. step (1), applying the drug to the model (2), and analyzing the results ( 3) Including. Drugs that kill or inhibit microorganisms in models have therapeutic or preventive effects. Then it can be identified.

[0208] Microorganisms include bacteria, archaea, protists, fungi, viruses or combinations thereof; Or consists of these. Preferably, the microorganism comprises a bacterium, the bacterium being Clostridium spp. , Acinetobacter spp., Streptococcus spp., Manhemia spp., Fibrobacter spp. Levotella spp., Campylobacter spp., Actinomyces spp., Hymenobacter spp., Escherichia A spp., Tischierella spp., Klebsiella spp., Porphyromonas spp., Azopyra spp., Akimarina spp. Genus, Achromobacter, Acidothiobacillus, Burkholderia, Marinobacter Genus, Treponema, Actisporangium, Vibrio, Ruminococcus, Methano Brewibuster sp., Shigella sp., Frankia sp., Anelloplasma sp., and Coprococcus It may be one or more species selected from the genus.

[0209] In some preferred embodiments, the bacterium is Clostridium tetani. anus), Clostridium perfringens, Clostridium botulinum (Clostr. idium botulinum), Acinetobacter calcoaceticus (Acine tobacter acetate), Acinetoba luffy (Acinetoba cter rufi), Acinetobacter baumannii (Acinetobacter b auannii), Acinetobacter haemolyticus hemolyticus), Acinetobacter junii junii), Acinetobacter joh nsonii), Streptococcus pyogenes, Streptococcus hemolyticus, Porphyromonas a Porphyromonas asacharolytica, Porphyromonas asacharolytica Porphyromonas gingivalis, Porphyromonas gingivalis Porphyromonas gingivalis , Campylobacter jejuni Campylobacter coli, Campylobacter coli Campylobacter seabirds, Campylobacter seabirds Campylobacter Uppsala, Campylobacter conciseri ( Campylobacter concisely), Campylobacter fetus (C ampylobacter fitus), Actinomyces israelii (Acti nomyces israelii), Actinomyces israelii (Actin omyces naeslundii), Actinomyces odontoliticus (Ac tinomyces odontolyticus), Escherichia coli (Escherichia coli), Escherichia blattae , Escherichia fergusonii, Escherichia hermannii (Escherichia hermannii) Escherichia vulneris, Tisierella apia Tissierella apical, Klebsiella pneumoniae siella pneumoniae), Klebsiella odorata (Klebsiella a odorata), Azospirillum brasilense (Azospirillum b) rasilence), Achromobacter, Thiobacyl Thiobacillus denitrificans, Thiobacillus ferrooxidans ns), Thiobacillus thiooxidans dans), Thiobacillus neapol itanus), Burkholderia, Mycobacterium ·Mycobacterium marinum, Treponema pallidum (Tr eponema pallidum), Treponema hyodysenteriae (Trepon ema hyodysenteriae), Vibrio meshnikovi (Vibrio metschnikovi), Ruminococcus albus (Ruminococcus albus), Ruminococcus flabefaciens (Ruminococcus fl avefaciens), Methanobrewibacter ruminantium (Methano brevibacter ruminantium), Shigella dysenteriae), Shigella flexne ri), Shigella bogdii, Shigella sonnei (Sh igella sonnei), Frankiaceae, streptomy Seth albus (Streptomyces albus), Pseudomonas mendosi Na, Cytococcus sedentarius, Alicycliphilus denitrificans, Acro Mobacter xyloxidans, Sphingobium chaponicum, Mycobacterium ·Abcessus, Arthrobacter aurescens, Prevotella dentalis, Sinorizo Bium meliloti, Acidovorax ebreus, Staphylococcus epidermi Dis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolii Chicas, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megatherium, Lactobacillus reuteri, Gardnerella vagina Squirrel, Enterococcus faecalis, Cytophaga hutchinsoni, Bacillus li Keniformis, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter Ter. calcoaceticus, Comamonas testosteronii, Mycobacterium kansasii , Bacillus thuringiensis, Citrobacter coseri, Diadobacter fur Mentans, Serratia marcescens, Sphingomonas wich, Klebsiella Pneumoniae, Pseudomonas fluorescens, Ralstonia pickettii, Lacto Bacillus crispatus, Burkholderia multiborane, Lactobacillus delbri E. coli, Meiothermus sylvanus (D), Escherichia coli, Micrococcus luteus, 1 selected from grass fungi, Corynebacterium aurinumcosum, Finegordia magna It may be more than one species.

[0210] In some preferred embodiments, the bacteria are Pseudomonas mendocina, Cytococcus Sedentarius, Alicycliphilus denitrificans, Achromobacter xii Roxidans, Sphingobium chaponicum, Mycobacterium abscessus, A Ruthrobacter aurescens, Prevotella dentalis, Sinorhizobium melilote Acidovorax ebreus, Staphylococcus epidermidis, Pseudo Monas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudo Monas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus S. megatherium, Lactobacillus reuteri, Gardnerella basalis, Enterococcus Cass faecalis, Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter calcoase Chicas, Comamonas testosteronii, Mycobacterium kansasii, Bacillus chu - Citrobacter koseri, Diadobacter fermentans, Sera Chia marcescens, Sphingomonas wich, Klebsiella pneumoniae, Si Peudomonas fluorescens, Ralstonia pickettii, Lactobacillus chris Patas, Burkholderia multiborane, Lactobacillus delbricii, Meiosa - Mas sylvanus (D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacillus Even if it is one or more species selected from Therium aurimucosum and Finegordia magna good.

[0211] In some preferred embodiments, the bacteria are Pseudomonas putida, Bacillus megate. One or more species selected from Propionibacterium acnes and Propionibacterium acnes may be used.

[0212] In a preferred embodiment, the bacterium is Bacillus megaterium.

[0213] Model carriers include humans, non-human mammals, organs, tissues, tissue sections, tissue extracts, body fluids, It may be one or more of body fluid cultures, cells, viruses, enzymes, and media. non-human suckling Animals include any mammal for laboratory, pet, or economic use. Exemplary non-human mammals is a mouse, rat, rabbit, cat, dog, pig, mother cow, bull, sheep, goat, horse, monkey or Includes non-human primates. Exemplary organs include the heart, liver, lungs, stomach, kidneys, eyes, ears, nose, and tongue. include. Tissues, tissue sections and tissue extracts refer to tissues, tissue sections and tissue extracts derived from any part of the subject or test animal. Contains tissue sections or tissue extracts. In some embodiments, the tissue is the subject's suspensory ligament, ciliary body. , including the ciliary body / muscle, vitreous body, retina, choroid, optic nerve, crystalline lens, or iris. Several In embodiments, the tissue extract includes DNA, RNA or proteins. Some embodiments In this case, body fluids include lymph fluid, cerebrospinal fluid, aqueous humor (AH), vitreous humor (VH), blood, sweat, or Contains urine fluid. In some embodiments, body fluid cultures include AH and VH cultures.

[0214] Pharmaceuticals include small molecule drugs, chemical drugs, large molecule drugs, biological drugs, or natural drugs (herbal medicines). medicine or Chinese herbal medicine extract).

[0215] Preferably, the medicament is used to treat age-related macular degeneration (AMD), Behcet's disease (BD), Vogt ·Koyanagi-Harada syndrome (VKH), uveitis, retinal disease, keratoconjunctivitis sicca, sympathetic ophthalmitis, Including eyelids, cataracts (Cat), conjunctivitis, meibomian gland cysts, glaucoma (GLA), and floaters. It has therapeutic effects on intraocular diseases or disorders.

[0216] Chemical drugs include β-lactam antibiotics: penicillins, cephalosporins, and β-lactam antibiotics. Tamase inhibitors and methoxypenicillin; aminoglycoside antibiotics: streptomycin Syn, gentamicin, kanamycin, tobramycin, amikacin, neomycin, ri bomycin and novobiocin; tetracycline antibiotics: tetracycline, oxy Tetracycline and chlortetracycline; chloramphenicol antibiotics: Loramphenicol and thiamphenicol; Macrolide antibiotics: Erythromycin leucomycin, odorless erythromycin, acetylspiramycin, medimycin , josamycin and azithromycin; glycopeptide antibiotics: vancomycin, norvancomycin and teicoplanin; quinolone antibiotics: norfloxacin, off Loxacin, ciprofloxacin, pefloxacin and gatifloxacin; nitroimida Zole antibiotics: metronidazole, tinidazole and ornidazole; rifamycin Antibiotics: rifampicin; echinocandin antibiotics, polyene antibiotics, pirimi Zin antibiotics, allylamine antibiotics, azole antibiotics, and other antibiotics: sfomycin, cycloserine, lincomycin, clindamycin, mitomycin, actinomycin D, bleomycin, doxorubicin, isoniazid, pyrazinamide, Cyclosporin or combinations thereof may also be included.

[0217] The biological drug may be an antimicrobial peptide, which is an insect antimicrobial peptide. Microbial peptides: Lepidoptera antibacterial peptides, Diptera antibacterial peptides, Coleoptera antibacterial peptides , Hymenoptera antimicrobial peptides and silkworm antimicrobial peptides; mammalian antimicrobial peptides: pig antimicrobial properties Peptide, sheep antibacterial peptide, bovine antibacterial peptide and human antibacterial peptide; amphibian antibacterial Peptides: Xenopus; Antibacterial peptides from fish, molluscs or crustaceans: Xenopus Cormorant antibacterial peptide, mussel antibacterial peptide and shrimp antibacterial peptide; bacterial antibacterial peptide :bacitracin, gramicidin, polymyxin and nisin; plant antibacterial peptides, or It may also include combinations of these.

[0218] Natural medicines include Astragalus and Polygonatum. , Angelica, Sanqi, Rhizom a Imperatae), Rhubarb Charcoal, Silkum Fritillary Fritillary (Curcuma aromatica), Fritillary Fritillary (Fritillary) Coix Seed, Pinellia, Calci ned ancient ink), Salvia Miltiorrhiz a), Arnebia euchroma, Radix Isatidis), Houttuynia, Honey suckle), Rhizoma Coptis, Scutel laria), Hokoei (Dandelion), Bashiken (Purslane), Samurai Hawthorn, Isatidis Folium, Forengi Leopard (Fructus Forsythiae), Inchin (Herba Artemi) siae Capillaris), Andrographis Pan iculata Nees), Psycho (Radix Bupleuri), Rhubarb (R hubarb), Euphorbia humifusa, emonae), Garlic, Cortex Phellod Endri), Eucommia, Cortex Fraxini ), Fructus Cnidii, Galla Chin ensis), staghorn butterfly (viola yedoensis makino), uba Fructus Mume, Daylily (Radix Glycyrrhizae) , Pericarpium Granati, Schisan dra chinensis), spina gleditsiae, mosquito Terminalia Chebula, Sophora flaves cens), Cortex Pseudolaricis, Inyoukaku ( Epimedium), Artemisia apiacea Hance , extracts of these or combinations thereof.

[0219] The medicinal products of the present disclosure may be oral, injectable or topical; includes mucosal agents, preferably eye drops.

[0220] The pharmaceutical products of the present disclosure include solutions, tablets, pills, capsules, injections, powders, powders for injection, patches, It may be in the form of a coded preparation or a preparation for mucosal administration, preferably eye drops, eye ointment or eye spray. Pharmaceutical preparations, etc.

[0221] In some preferred embodiments, the present disclosure provides a method for treating or preventing cataracts (Cat). Regarding the drug screening method, the steps of the method are as follows. (1) Pseudomonas mendocina, Cytococcus sedentarius, Alicycliphyll S. denitrificans, Achromobacter xyloxidans, Sphingobium s. japonicum, Mycobacterium abscessus, Arthrobacter aurescens, Pre Botella dentalis, Sinorhizobium meliloti or Acidovorax ebreus Create a model by infecting a model carrier with one or more of the microorganisms . (2) Applying pharmaceuticals to the model. (3) Analyze the results. Drugs that can kill or inhibit microorganisms in the model may be identified as having therapeutic or prophylactic effects against.

[0222] In some preferred embodiments, the present disclosure provides a method for treating or preventing age-related macular degeneration (AMD). Regarding the method for screening drugs for the purpose of . (1) Staphylococcus epidermidis, Pseudomonas aeruginosa, yellow blight Staphylococcus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotroph Homonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactowasp Luz reuteri, Gardnerella basalis, Enterococcus faecalis, site Faga hutchinsonii, Bacillus licheniformis or Xanthomonas oryzae A model is created by infecting a model carrier with one or more microorganisms. (2) Applying pharmaceuticals to the model. (3) Analyze the results. Drugs that can kill or inhibit microorganisms in models are used in patients with AMD. may be identified as having therapeutic or prophylactic effects against.

[0223] In some preferred embodiments, the present disclosure provides a method for treating or preventing glaucoma (GLA). Regarding the drug screening method, the steps of the method are as follows. (1) Acinetobacter baumannii, Acinetobacter calcoaceticus, Comamonas Testosterone, Mycobacterium kansasii, Bacillus thuringiensis, Trobacter coseri, Diadobacter fermentans or Serratia marsese create a model by infecting a model carrier with one or more microorganisms in the do. (2) Applying pharmaceuticals to the model. (3) Analyze the results. Drugs that can kill or inhibit microorganisms in the model are for GLA patients. may be identified as having therapeutic or prophylactic effects against.

[0224] In some preferred embodiments, the present disclosure provides a method for treating or preventing Behcet's disease (BD). Regarding the method for screening pharmaceuticals for the purpose of drug administration, the steps of the method are as follows. (1) Sphingomonas witch, Klebsiella pneumoniae, Pseudomonas f. luorescens, Ralstonia pickettii, Lactobacillus crispatus, Burkho Rudelia multiborane, Lactobacillus delbricii or Meiothermus silva model by infecting model carriers with one or more microorganisms of Create. (2) Applying pharmaceuticals to the model. (3) Analyze the results. Drugs that can kill or inhibit microorganisms in models may be harmful to BD patients. may be identified as having a therapeutic or prophylactic effect against.

[0225] In some preferred embodiments, the present disclosure provides treatment for Vogt-Koyanagi-Harada syndrome (VKH). Regarding the method for screening drugs for treatment or prevention, the steps of the method include the following: That's right. (1) Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium aurimco Infect a model carrier with one or more microorganisms of S. sam or Finegordia magna. Create a model by (2) Applying pharmaceuticals to the model. (3) Analyze the results. Drugs that can kill or inhibit microorganisms in the model are for patients with VKH. may be identified as having therapeutic or prophylactic effects against.

[0226] In a further aspect, the present application discloses the use of screening microorganisms in pharmaceuticals, Physically, the drug screening steps are as follows. Modeling with microorganisms A model is created by infecting a carrier and a drug is applied to the model. of pharmaceuticals Screening for therapeutic or preventive effects. Defined microorganisms, model carriers and pharmaceuticals The range is as described above.

[0227] In a further aspect, the present application provides a model for infecting a model carrier with a microorganism. steps to create, apply the drug to the model, and screen positive results for the drug. Discloses a pharmaceutical product identified by the steps of: Microorganisms, model carriers The defined range of is as described above.

[0228] A positive result means that the identified drug can kill or inhibit the microorganism in the model. Taste. Exemplary Embodiments 1-25

[0229] Embodiment 1. Intraocular disease or disorder model comprising infecting a model carrier with a microorganism. How to create a file.

[0230] Embodiment 2. In the method according to Embodiment 1, the microorganism is a bacterium, an archaea, a protist, Contains fungi, viruses or combinations thereof.

[0231] Embodiment 3. In the method described in Embodiment 1, the model carrier is a human or non-human mammal. mammals, organs, tissues, tissue sections, tissue extracts, body fluids, body fluid cultures, cells, viruses, enzymes , one or more of the following media.

[0232] Embodiment 4. In the method according to Embodiment 2, the microorganism is Clostridium sp. Sinetobacter, Streptococcus, Manhemia, Fibrobacter, Plevo Thera, Campylobacter, Actinomyces, Hymenobacter, Escherichia , Tischierella spp., Klebsiella spp., Porphyromonas spp., Azopyra spp., Achimarina spp. Achromobacter spp., Acidothiobacillus spp., Burkholderia spp., Marinobacter spp. Treponema, Actisporangium, Vibrio, Ruminococcus, Metanobre Wibuster, Shigella, Frankia, Anelloplasma, and Coprococcus? Contains one or more types of bacteria selected from

[0233] Embodiment 5. In the method of Embodiment 4, the bacteria are Clostridium tetani, Clostridium perfringens, Clostridium botulinum, Acinetobacter calcoaceticus, Acinetobacter rufi, Acinetobacter Acinetobacter baumannii, Acinetobacter haemolyticus, Acinetobacter juni -, Acinetobacter johnsoni, Streptococcus pyogenes, Streptococcus hemolyticus, Porphyromonas asaka loritica, Porphyromonas gingivalis, Porphyromonas gingivalis, campi Lobacter jejuni, Campylobacter coli, Campylobacter seabird, mosquito Npylobacter uppsala, Npylobacter consiseri, Campylobacter fetus , Actinomyces israelii, Actinomyces neslandii, Actinomyces Ses odontoliticus, Escherichia coli, Escherichia blattae, Escherichia fel Gusoni, Escherichia Hermanni, Escherichia Brunellis, Tisierella Appia Le, Klebsiella pneumoniae, Klebsiella odorata, Azospirillum brazile Achromobacter, Thiobacillus denitrificans, Thiobacillus ferro xydans, Thiobacillus thiooxidans, Thiobacillus neapolitanus, Burke Holderia, Mycobacterium marinum, Treponema pallidum, Treponema hyogeni Centelliae, Vibrio meshnikovi, Ruminococcus albus, Ruminococcus flabefaciens, Methanobrewibacter ruminantium, Shiga Shigella, Shigella ·Shigella flexneri, Shigella boidii, Shigella sonnei, Frankia, Streptomyces ·Albus, Pseudomonas mendocina, Cytococcus sedentarius, Alicycli philus denitrificans, Achromobacter xyloxidans, Sphingobium Mycobacterium chaponicum, Mycobacterium abscessus, Arthrobacter aurescens , Prevotella dentalis, Sinorhizobium meliloti, Acidovorax ebre Staphylococcus epidermidis, Pseudomonas aeruginosa, yellow Staphylococcus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotroph Homonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactowasp Luz reuteri, Gardnerella basalis, Enterococcus faecalis, sit...

Claims

1. A pharmaceutical composition for treating or preventing age-related macular degeneration (AMD) in a subject, comprising ciprofloxacin, or a pharma- ceutical acceptable salt thereof; The pharmaceutical composition further comprises a compound selected from the following compounds 4 to 8, or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】

2. 2. The pharmaceutical composition of claim 1, wherein the subject has been identified as having an infection in the intraocular space with a microorganism selected from Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, and Xanthomonas oryzae.

3. The pharmaceutical composition of claim 2 , wherein the microorganism comprises Bacillus megaterium.

4. The pharmaceutical composition of claim 2 or 3, wherein the pharmaceutical composition is administered to the subject in an amount that effectively kills or inhibits the growth of the microorganism in the intraocular space, blood and / or digestive tract of the subject.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is administered orally.

6. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is administered topically, intravitreally, intramuscularly, subcutaneously or intravenously.

7. 2. The pharmaceutical composition of claim 1, wherein the compound is derived from one or more traditional Chinese medicines (TCMs) selected from Glycyrrhiza Root, Radix Paeoniae Radix, Forsythia Fruit, Radix Anthurium Root, Radix Rehmannia Root, Radix Qianpi, and Radix Sansichi.

Images