Compounds for Chronic Disorders

Abstract

The present disclosure provides compounds and compositions useful for the treatment of chronic disorders, including cancer and viral diseases.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 005,730, filed April 6, 2020, and Indian Application No. 2020 / 41001163, filed January 10, 2020, each of which is incorporated herein by reference in its entirety. [Background technology]

[0002] A chronic condition is a human health condition or disease whose effects are persistent or otherwise long-lasting, or that develops over time. The term chronic is often applied when the course of a disease lasts longer than three months. Common chronic diseases include arthritis, asthma, cancer, chronic obstructive pulmonary disease, diabetes, and some viral diseases, such as hepatitis C and acquired immune deficiency syndrome.

[0003] Cancer, also called malignant tumors, is the abnormal growth of cells. Cancer develops when the body's normal control mechanisms stop working. Old cells do not die, but instead grow uncontrollably, forming new, abnormal cells. These extra cells can form a mass of tissue called a tumor. Some cancers, such as leukemia, do not form tumors.

[0004] There are over 100 types of cancer, including breast cancer, skin cancer, lung cancer, colon cancer, prostate cancer, and lymphoma. Symptoms vary depending on the type.

[0005] Treatment options depend on the type of cancer and its stage. Treatment aims to kill many cancer cells while limiting damage to nearby healthy cells.

[0006] There are three main treatments: Surgery: Direct removal of the tumor Chemotherapy: Using chemicals to kill cancer cells Radiation therapy: Using X-rays to kill cancer cells

[0007] Major unresolved problems associated with metastatic cancer are recurrence after achieving an objective response to chemotherapy, drug-induced side effects of first-line chemotherapy, and delayed response to second-line treatment. Unfortunately, very few options are available for third-line treatment. Therefore, there is an increasing need to identify new chemopreventive agents that may be effective in preventing and / or managing chronic conditions such as cancer.

[0008] Natural products such as flavonoids may be useful for preventing or treating chronic disorders.However, due to low solubility and bioavailability, natural products are not an effective alternative to current therapeutic drugs.Therefore, there is a need in the art to develop new drugs that provide increased bioavailability, solubility, and tissue distribution ability for targeted delivery.Such drugs may be active against various chronic conditions, and in some embodiments, may exhibit anti-cancer or anti-viral activity. [Brief explanation of the drawings]

[0009] The foregoing and following information, as well as other features of the present disclosure, will become more fully apparent from the following description and appended claims, taken in conjunction with the accompanying drawings, in which: The present disclosure will be described with additional specificity and detail using the accompanying drawings, with the understanding that these drawings illustrate only some embodiments according to the present disclosure and therefore should not be considered limiting of its scope.

[0010] [Figure 1] The spectra of Compound I are shown below: a. Mass spectrum b. IR spectrum c. 1H NMR spectrum d. 13C NMR spectrum [Figure 2] The spectra of compound II are shown below: a) Mass spectrum b) IR spectrum c) 1H NMR spectrum d) 13C NMR spectrum [Figure 3]The spectra of compound III are shown below: a. Mass spectrum b. IR spectrum c. 1H NMR spectrum d. 13C NMR spectrum [Figure 4] The spectra of compound IV are shown below: a. Mass spectrum b. IR spectrum c. 1H NMR spectrum d. 13C NMR spectrum [Figure 5] The spectra of compound V are shown below: a. Mass spectrum b. IR spectrum c. 1H NMR spectrum d. 13C NMR spectrum [Figure 6] The spectra of compound VI are shown below: a. Mass spectrum b. IR spectrum c. 1H NMR spectrum d. 13C NMR spectrum [Figure 7] The spectra of compound VII are shown below: a. Mass spectrum b. IR spectrum c. 1H NMR spectrum d. 13C NMR spectrum [Figure 8] The spectra of compound VIII are shown below: a) Mass spectrum b) IR spectrum c) 1H NMR spectrum d) 13C NMR spectrum [Figure 9] The spectra of compound IX are shown below: a. Mass spectrum b. IR spectrum c. 1H NMR spectrum d. 13C NMR spectrum [Figure 10A] Figure 1 shows the anticancer activity of compound I on different cell lines. A: Effect of the molecule on different cancer cell lines, B: Effect of the molecule on normal cell lines, C: Comparison with other standard drugs: Abbreviations MCF-7 (human breast cancer cells), MDAMB 231 (triple-negative breast cancer cell line), PANC-1 (human pancreatic cancer cell line), HT-29 (human colon cancer cell line), T-ALL (T-cell acute lymphoblastic leukemia), HDF (human dermal fibroblasts), AC-16 (human cardiomyocytes), HBMSC (human bone marrow mesenchymal stem cells), MCF-12 A (human normal breast cells), CRL2989 (human normal pancreatic cells), NCM 60 (normal colon epithelial cell line) [Figure 10B] Figure 1 shows the apoptosis induction and mitochondrial membrane potential of Compound I compared to the control. [Figure 11] 1 shows a series of graphs used to elucidate the mechanism of action of compounds of the present disclosure (eg, Compound I) that inhibit histone deacetylase (HDAC) activity. [Figure 12] A series of graphs showing that Compound I induced neural cell type formation. a. Human stem cell-molecular neural differentiation b. Molecular tumor gene expression analysis [Figure 13] 1 shows the inhibition of cancer stem cell markers by Compound I. [Figure 14] 1 shows cancer cell kinetics and treatment of conventional drugs compared to compounds of the present disclosure. [Figure 15] 1 illustrates the breakthrough achieved by the compounds of the present disclosure. [Figure 16] Cancer stem cells and receptors are shown. [Figure 17] Demonstrate aberrant signaling pathways in cancer stem cells and target cancer stem cells. [Figure 18] 1 shows the genes targeted by compounds of the present disclosure for various types of cancer. [Figures 19A-19B] Figure 19 shows the cytotoxicity of anti-cancer drugs assessed by measuring IC50 against a panel of normal cell lines treated without Compound 1 (Figure 19A) and in combination with Compound I (Figure 19B). [Figures 20A-20C] 1 shows an in vivo study in a stage IV metathesis tumor model comparing Compound I of the present disclosure with conventional agents. [Figures 21A-21B] Figures 21A-21D provide a PANC-1 xenograft mouse model evaluating the efficacy of Compound I compared to gemcitabine. [Figures 21C-21D] Figures 21A-21D provide a PANC-1 xenograft mouse model evaluating the efficacy of Compound I compared to gemcitabine. [Figure 22] 1 illustrates steps in the coronavirus replication pathway targeted by compounds of the present disclosure. [Figure 23] Shows how ACE-2 inhibitor binding disrupts virus-receptor interaction. [Figure 24A] The molecular binding site of Nsp15 is shown. [Figure 24B] 1 shows a model illustrating the binding of small molecules to Nsp15. [Figure 24C] 1 shows a model depicting binding site residues proposed to interact with compounds of the present disclosure. [Figures 25A-25H] Figure 25A shows normal Vero cells and Vero cells infected with SARS-CoV-2 at an MOI of 0.1 when treated with different doses of the indicated antiviral agents for 48 hours. Viral yields in the cell supernatants were then quantified by qRT-PCR. Figure 25B shows graphs depicting the mean % inhibition of viral yield and cytotoxicity for drugs (e.g., Compound I), respectively. Experiments were performed in triplicate. Figure 25C shows immunofluorescence microscopy of viral infection upon treatment with Compound I. At 48 hours postinfection, infected cells were fixed and then probed with rabbit serum against the nucleoprotein (NP) of SARS-associated CoV as the primary antibody and Alexa 488-labeled goat anti-rabbit IgG as the secondary antibody, respectively. Nuclei were stained with Hoechst dye. Bar, 20 μm. Figure 25D shows Western blot analysis of nucleoprotein (NP) expression in cells infected with SARS-CoV-2 at an MOI of 0.1 at 24 hours postinfection (pi). Figure 25E shows a graph depicting nuclear protein (NP) expression normalized to GAPDH. Viral yields in infected cell supernatants were quantified by qRT-PCR. Experiments were performed in triplicate. Figures 25F-H show graphs demonstrating that a reduction in viral RNA was observed in both supernatants and cell pellets from samples treated with 1 μM Compound I. [Figures 26A-26B] Figure 26A shows a cell viability assay of calu-3 cells treated with different concentrations of Compound I. Figure 26B shows a percent plaque reduction assay in calu-3 cells treated with different concentrations of Compound I. [Figures 27A-27B]Figure 27A shows H&E staining analysis of liver and kidney samples from a tissue distribution study in nude mice administered a single dose of 10 mg / kg body weight of Compound I. Figure 27B shows the results of a tissue distribution study from 0.5 hours to 96 hours in the heart, lung, muscle, spleen, tibia, and femur of nude mice administered a single dose of 10 mg / kg body weight of Compound I. [Figures 28A-28E] Figures 28A-28E are graphs showing the effects of oral administration of various doses of Compound I on organ weights (Figures 28A-28B), liver weight (Figure 28C), and body weights (Figures 28D-28E) in male and female Wistar rats. [Figures 28F-28K] Figures 28F-28I are graphs showing the effects on hematological parameters (urea, creatinine, etc.) when various doses of Compound I were orally administered to male and female Wistar rats. Figures 28J-28K are graphs showing the effects on electrolytes when various doses of Compound I were orally administered to male and female Wistar rats. [Fig. 28L-28Q] Figures 28L-28O are graphs showing the effect of oral administration of various doses of Compound I on liver function in male and female Wistar rats. Figures 28P-28Q are graphs showing the effect of oral administration of various doses of Compound I on kidney function in male and female mice. [Figures 29A-29B] Figures 29A-29B show histopathological studies from analysis of organ samples of liver, kidney, skeletal muscle, heart, and spleen from both male (Figure 29A) and female (Figure 29B) rats. Tissue samples were collected on the last day of the treatment period. Summary of the Invention

[0011] The present disclosure relates to compounds having anti-cancer and anti-viral activity. The compounds can be used to treat subjects with chronic disorders. The compounds have the structure of Formula 1A: [ka] or any derivative thereof, a pharmaceutically acceptable salt thereof, or a combination thereof; During the ceremony, R1 is H, OH, or alkoxy; R2 is alkoxy or OH; R3 is alkoxy or OH; X is C1-C 15 Alkyl, C2-C 15 Alkenyl, C2-C 15 alkynyl, or aralkyl chains, each of which is independently substituted with at least one alkoxy, OH, ═NH, or oxo group; Y is H or alkyl; X is in the ortho position relative to R2 or in the para position relative to R1. DETAILED DESCRIPTION OF THE INVENTION

[0012] definition "Alkyl" or "alkyl group" refers to a fully saturated straight or branched hydrocarbon chain having from 1 to 15 carbon atoms and attached to the rest of the molecule by a single bond. Unless otherwise specifically stated herein, an alkyl group can be optionally substituted.

[0013] "Alkenyl" or "alkenyl group" refers to a straight or branched hydrocarbon chain having 2 to 15 carbon atoms and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.

[0014] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain radical having 2 to 12 carbon atoms and having one or more carbon-carbon double bonds. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, the alkenylene chain can be optionally substituted.

[0015] "Alkoxy" means a group of the formula -OR a where R a is an alkyl, alkenyl, or alkynyl as defined above having 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.

[0016] An "aralkyl" or "arylalkyl" is a group of the formula -R b -R c where R b is an alkylene or alkenylene group as defined above, and R c is one or more aryl as defined above, e.g., benzyl, diphenylmethyl, etc. Unless stated otherwise specifically in the specification, an aralkyl group may be optionally substituted.

[0017] "Oxo" refers to the following group double bonded to an oxygen atom:

[0018] The term "substituted," as used herein, means any of the above groups in which at least one hydrogen atom is replaced by a bond to a non-hydrogen atom, including, but not limited to, a halogen atom, e.g., F, Cl, Br, and I; an oxygen atom in a group, e.g., hydroxyl, alkoxy, and ester groups; a sulfur atom in a group, e.g., thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; a nitrogen atom in a group, e.g., amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide, and enamine; a silicon atom in a group, e.g., trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups; and other heteroatoms in various other groups. "Substituted" refers to any of the above groups in which one or more hydrogen atoms are replaced by a higher bond (e.g., a double or triple bond) to a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups, and nitrogen in groups such as imine, oxime, hydrazone, and nitrile. For example, "substituted" refers to any of the above groups in which one or more hydrogen atoms are replaced by a higher bond (e.g., a double or triple bond) to a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups, and nitrogen in groups such as imine, oxime, hydrazone, and nitrile. g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h , -OC(=O)NR g R h , -OR g , -SR g , -SOR g , -SO2R g , -OSO2R g , -SO2OR g , =NSO2R g , and -SO2NR g R h "Substituted" includes any of the above groups replaced with -C(=O)R.g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , -CH2SO2NR g R h In the foregoing, R g and R h are the same or different and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituted" further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl group. In addition, each of the foregoing substituents may be optionally substituted with one or more of the above substituents.

[0019] As used herein, [ka] The symbol (which may hereinafter be referred to as a point of attachment bond) refers to a bond that is a point of attachment between two chemical entities, one of which is shown as being attached to the point of attachment bond and the other of which is not shown as being attached to the point of attachment bond. For example, [ka] indicates that the chemical entity "XY" is attached to another chemical entity via a point-of-attachment bond. Furthermore, specific points of attachment to unillustrated chemical entities can be identified by inference. For example, the compound CH3-R 3 (In the formula, R 3 is H or [ka] ) is R 3 is "XY", the bond at the attachment point is R 3 is assumed to be the same bond shown as being attached to CH3.

[0020] "Pharmaceutically acceptable salts" includes, where appropriate, pharmaceutically acceptable base addition salts and acid addition salts, such as metal salts, e.g., alkali and alkaline earth metal salts, ammonium salts, organic amine addition salts, and amino acid addition salts, and sulfonates. Acid addition salts include inorganic acid addition salts, e.g., hydrochlorides, sulfates, and phosphates, and organic acid addition salts, e.g., alkyl sulfonates, aryl sulfonates, acetates, maleates, fumarates, tartrates, citrates, and lactates. Other examples of acid addition salts include acetate, benzenesulfonate (besylate), benzoate, camphorsulfonate, citrate, ethenesulfonate, fumarate, gluconate, glutamate, hydrobromide, hydrochloride, isethionate, lactate, maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, p-toluenesulfonate, and the like. Examples of metal salts include alkali metal salts, such as lithium, sodium, and potassium salts, alkaline earth metal salts, such as magnesium and calcium salts, aluminum salts, and zinc salts. Examples of ammonium salts include ammonium salts and tetramethylammonium salts. Examples of organic amine addition salts include salts with morpholine and piperidine. Examples of amino acid addition salts include salts with glycine, phenylalanine, glutamic acid, and lysine. Sulfonates include mesylates, tosylates, and benzenesulfonates. When the compound has an acidic side chain, suitable pharmaceutically acceptable base addition salts include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.

[0021] The term "therapeutically effective" as applied to a dose or amount refers to the amount of a compound or pharmaceutical preparation sufficient to result in a desired clinical benefit following administration to a patient in need of the compound or pharmaceutical preparation.

[0022] In the following detailed description, reference is made to the accompanying drawings, which form a part of this specification. In these drawings, like symbols typically refer to like components unless the context dictates otherwise. The illustrative embodiments set forth in the detailed description, drawings, and claims are not intended to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein. The aspects of the present disclosure, generally as described herein and illustrated in the figures, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are expressly contemplated herein.

[0023] Generally, the present invention discloses novel therapeutic compounds for treating chronic disorders, including cancer.

[0024] In some embodiments, the present invention provides a compound having the structure of Formula 1A: [ka] During the ceremony, R1 is H, OH, or alkoxy; R2 is alkoxy or OH; R3 is alkoxy or OH; X is C1-C 15 Alkyl, C2-C 15 alkenyl, or aralkyl chains, each of which is independently substituted with at least one alkoxy, OH, ═NH, or oxo group; Y is H or alkyl; Disclosed is a compound, or any derivative thereof, a pharmaceutically acceptable salt thereof, or a combination thereof, wherein X is in the ortho position relative to R2 or the para position relative to R1.

[0025] In some embodiments of the compound of Formula 1A, R1 is H, R2 is -OH, R3 is C1-C3 alkoxyl; X is a C4-C8 alkenyl substituted with two oxo groups; Y is C1-C3 alkyl.

[0026] In some embodiments, the compound of Formula 1A has the structure of Formula 1: [ka] or any derivative thereof, a pharmaceutically acceptable salt thereof, or a combination thereof; During the ceremony, R1 is H, alkoxy, or OH; R2 is alkoxy or OH; R3 is alkoxy or OH; X is C1-C 15 Alkyl, C2-C 15 alkenyl, or aralkyl chains, each of which is independently substituted with at least one alkoxy, OH, ═NH, or oxo group.

[0027] In some embodiments of Formula 1, X is (i) C-C substituted with four substituents independently selected from the group consisting of oxo, -OH, and C-C alkoxy; 10 is alkenyl, or (ii) C8-C substituted with oxo and C1-C3 alkoxy 12 is alkenyl, or (iii) C4-C8 alkenyl substituted with two oxo groups; (iv) C2-C6 alkenyl substituted with oxo and C1-C3 alkoxy; (v) = C1-C6 alkyl substituted with NH; (vi) C2-C3 alkenyl substituted with -OH; (vii) C8-C substituted with oxo and two C1-C3 alkoxy groups 12 alkenyl, or (viii) Aralkyl including C6-C8 alkyl and C6 aryl, wherein the alkyl is substituted with oxo and the aryl is substituted with two alkoxy groups.

[0028] In some embodiments of Formula 1, R1 is H, R2 is C1-C3 alkoxy; R3 is C1-C3 alkoxy; X is a C6-C substituted with oxo, -OH, and two C1-C3 alkoxy groups 10 It is alkenyl.

[0029] In some embodiments of Formula 1, R1 is H, R2 is C1-C3 alkoxy; R3 is C1-C3 alkoxy; X is C8-C substituted with oxo and C1-C3 alkoxy 12 It is alkenyl.

[0030] In some embodiments of Formula 1, R1 is OH, R2 is C1-C3 alkoxy; R3 is C1-C3 alkoxy; X is a C4-C8 alkenyl substituted with two oxo groups.

[0031] In some embodiments of Formula 1, R1 is C1-C3 alkoxy; R2 is OH, R3 is C1-C3 alkoxy; X is a C4-C8 alkenyl substituted with two oxo groups.

[0032] In some embodiments of Formula 1, R1 is H, R2 is OH, R3 is OH, X is C1-C6 alkyl substituted with =NH.

[0033] In some embodiments of Formula 1, R1 is OH, R2 is C1-C3 alkoxy; R3 is C1-C3 alkoxy; X is a C2-C3 alkenyl substituted with OH.

[0034] In some embodiments of Formula 1, R1 is H, R2 is C1-C3 alkoxy; R3 is C1-C3 alkoxy; X is a C8-C substituted with oxo and two C1-C3 alkoxy groups 12 It is alkenyl.

[0035] In some embodiments of Formula 1, R1 is OH, R2 is C1-C3 alkoxy; R3 is C1-C3 alkoxy; X is an aralkyl comprising a C6-C8 alkyl and a C6 aryl, wherein the alkyl is substituted with oxo and the aryl is substituted with two C1-C3 alkoxy groups.

[0036] In some embodiments, the compound of formula 1A has the structure of formula 2: [ka] or any derivative thereof, a pharmaceutically acceptable salt thereof, or a combination thereof; During the ceremony, R1 is H or OH, R2 is alkoxy or OH; R3 is alkoxy or OH; R4 is C1-C 15 Alkyl, C2-C 15alkenyl, aralkyl, each of which is substituted with at least one alkoxy, —OH, or oxo.

[0037] In some embodiments of Formula 2, R4 is [ka] is.

[0038] In some embodiments of Formula 2, R1 is H, R2 is OCH3, R3 is OCH3, R4, [ka] is.

[0039] In some embodiments of Formula 2, R1 is H, R2 is OCH3, R3 is OCH3, R4, [ka] is.

[0040] In some embodiments of Formula 2, R1 is OH, R2 is OCH3, R3 is OCH3, R4, [ka] is.

[0041] In some embodiments of Formula 2, R1 is OH, R2 is OCH3, R3 is OCH3, R4, [ka] is.

[0042] In some embodiments of Formula 2, R1 is H, R2 is OCH3, R3 is OCH3, R4, [ka] is. In some embodiments, Formula 1A has the structure of Formula 3: [ka] or any derivative thereof, a pharmaceutically acceptable salt thereof, or a combination thereof; During the ceremony, R1 is H, alkoxy, or OH; R2 is alkoxy or OH; R3 is alkoxy or OH; R5 is C1-C 12 Alkyl or C2-C 12 alkenyl, which is substituted with one or two substituents independently selected from the group consisting of =NH or oxo.

[0043] In some embodiments of Formula 3, R1 is H, R2 is OH, R3 is OH, R5 is =NH.

[0044] In some embodiments, R5 is in the ortho position relative to R2.

[0045] In some embodiments of Formula 3, R1 is -OC2H5, R2 is OH, R3 is -OCH3, R5, [ka] is.

[0046] In some embodiments of Formula 3, R5 is in the para position relative to R1.

[0047] In some embodiments, the compound of formula 1A has the structure of formula 4: [ka] or any derivative thereof, a pharmaceutically acceptable salt thereof, or a combination thereof; During the ceremony, R1 is OH, R2 is C1-C3 alkoxy; R3 is C1-C3 alkoxy; R6 is C(CH2)OH.

[0048] In some embodiments of Formula 4, R1 is OH, R2 is OCH3, R3 is OCH3, R6 is C(CH2)OH.

[0049] In some embodiments, the present invention provides pharmaceutical compositions comprising one of the compounds described above and a pharmaceutically acceptable carrier.

[0050] In some embodiments of the present disclosure, the pharmaceutically acceptable carrier is selected from the group consisting of acacia, animal oil, benzyl alcohol, benzyl benzoate, calcium stearate, carbomer, cetostearyl alcohol, cetyl alcohol, cholesterol, cyclodextrin, dextrose, diethanolamine, emulsifying wax, ethylene glycol palmitostearate, glycerin, glyceryl monostearate, glycerol stearate, glyceryl monooleate, glyceryl monostearate, water, histidine, hydrochloric acid, hydroxypropyl cellulose, hydroxypropyl-β-cyclodextrin (HPBCD), hypromellose (hydroxypropyl methylcellulose (HPMC)), lanolin, lanolin alcohol, lecithin, medium chain triglycerides, metallic soaps, methylcellulose, mineral oil, monobasic sodium phosphate, monoethanolamine, oleic acid, polyethylene glycol (PEG 3350, PEG 4000, PEG 5000), PEG 6000, PEG 7000, PEG 8000, PEG 9000, PEG 1000, PEG 11000, PEG 1200, PEG 1300, PEG 1400, PEG 1500, PEG 1600, PEG 1700, PEG 1800, PEG 1900, PEG 2000, PEG 2100, PEG 2200, PEG 2300, PEG 2400, PEG 2500, PEG 2600, PEG 2700, PEG 2800, PEG 2900, PEG 3000, PEG 3100, PEG 3200, PEG 3350, PEG 4000, PEG 4100, PEG 4200, PEG 430 6000), polyoxyethylene-polyoxypropylene copolymer (poloxamer), polyoxyethylene alkyl ether, polyoxyethylene castor oil, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, polysorbate, polyoxyethylene (20) sorbitan monolaurate (Tween® 20, Polysorbate 20), polyoxyethylene (20) sorbitan monooleate (Tween® 80, Polysorbate 80), povidone, propylene glycol alginate, saline, sodium chloride, sodium citrate, sodium citrate dihydrate, sodium hydroxide, sodium lauryl sulfate, sodium phosphate monobasic, sodium phosphate dibasic, sorbitan esters, stearic acid, stearyl alcohol, sunflower oil, tragacanth, triethanolamine, vegetable oil, water, xanthan gum, or combinations thereof.

[0051] Any of the chemical structures of Formulae 1A-4 can be prepared according to the exemplary synthetic routes disclosed herein.

[0052] In one embodiment, exemplary compounds I of formula 1A can be prepared according to Scheme I provided below.

[0053] [ka] Chemical synthesis: In a dry three-neck flask, acetylacetone (5 mmol, 0.51 ml) and boron oxide (3.5 mmol, 0.244 g) were dissolved in absolute ethyl acetate and stirred at 40 °C for 30 min. The corresponding aldehyde (10 mmol) and tributyl borate (10 mmol, 2.4 ml) were then added and stirred for another 30 min. n-Butylamine (7.5 mmol) was dissolved in dry ethyl acetate and then added over 15 min. The mixture was heated to 40 °C for 24 h. 5 ml of HCl (10%) was then added and heated to 60 °C for another 1 h. The aqueous phase was extracted several times with ethyl acetate, the organic layer was dried over Na2SO4, and the solvent was evaporated. The insoluble precipitate (part of the product) was filtered off and recrystallized with the residue from various solvents. Purification was carried out by column chromatography (toluene / ethyl acetate (8:2) eluent) and crystallization from ethanol (80%).

[0054] The synthesized compounds of formulas 1A-4 were then subjected to molecular characterization to confirm the structures of these compounds.

[0055] Characterization: The purity of the synthesized products was verified by melting point, thin layer chromatography, HPLC, IR, mass spectrometry, and NMR analysis. From Figures 1-9, the structures of the synthesized compounds of Formulas 1A-4 are elucidated as Compounds I-IX shown in Table 1 below.

[0056] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0057] In some embodiments, compounds of Formulas 1A-4 and compounds I-IX can include cis isomers, trans isomers, or both cis and trans isomers. In some embodiments, compounds of Formulas 1A-4 and compounds I-IX can be mixtures of cis and trans isomers. In some embodiments, compounds of Formulas 1A-4 and compounds I-IX can be cis isomers (i.e., Z-isomers). In some embodiments, compounds of Formulas 1A-4 and compounds I-IX can be trans isomers (i.e., E-isomers).

[0058] In some embodiments, compounds of Formulas 1A-4 and compounds I-IX can include either the R or S stereoisomer and can be mixtures of stereoisomers (e.g., mixtures of diastereomers). In some embodiments, compounds of Formulas 1A-4 can be racemic mixtures or enantiopure.

[0059] In some embodiments, compounds of Formulas 1A-4 and compounds I-IX are enantiopure (e.g., contain either the R enantiomer or the S enantiomer), diastereomerically pure, or contain a mixture of stereoisomers (e.g., a racemic mixture or a mixture of diastereomers). In some embodiments, compounds of Formulas 1A-4 are racemic mixtures. In some embodiments, compounds of Formulas 1A-4 are enantiopure. In some embodiments, compounds of Formulas 1A-4 are diastereomerically pure.

[0060] In some embodiments, an enantiopure compound is a compound having an enantiomeric excess (ee) of greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, or greater than about 99%.

[0061] In some embodiments, a diastereomerically pure compound is a compound having a diastereomeric excess (de) of greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, or greater than about 99%.

[0062] The compounds of the present invention can be used to perform or provide any of the biological functions described herein.

[0063] Pharmaceutical Composition The present disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds disclosed herein. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of one or more compounds of Formula 1A, 2, 3, and / or 4, or pharmaceutically acceptable salts thereof. In other embodiments, the pharmaceutical composition comprises a therapeutically effective amount of one or more compounds selected from Table 1, or pharmaceutically acceptable salts thereof.

[0064] In various embodiments, the amount of a compound of Formulas 1A-4 (including the compounds of Table 1) or a pharmaceutically acceptable salt thereof can be administered in an amount of from about 0.001 mg / kg to about 100 mg / kg body weight (e.g., from about 0.01 mg / kg to about 10 mg / kg or from about 0.1 mg / kg to about 5 mg / kg).

[0065] The concentration of the disclosed compounds in a pharmaceutically acceptable mixture will vary depending on several factors, including the dosage of the compound administered, the pharmacokinetic properties of the compound used, and the route of administration.The drug can be administered in a single dose or multiple doses.The dosing regimen utilizing the compounds of the present invention is selected according to various factors, including the type, species, age, weight, sex, and condition of the patient, the severity of the condition being treated, the route of administration, the patient's renal and hepatic function, and the specific compound or its salt used.Treatment can be administered once a day or more frequently, depending on several factors, including the patient's overall health and the formulation and route of administration of the selected compound.

[0066] The compounds or pharmaceutical compositions of the disclosure may be prepared and / or administered in single or multiple unit dosage forms.

[0067] In some embodiments, compounds of the present disclosure (compounds of Formulas 1-4 and Table 1) are administered to patients with a chronic condition. In the context of some embodiments of the present invention, the term "chronic disorder" refers to acute lymphoblastic, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related lymphoma, anal cancer, appendix cancer, basal cell carcinoma, bladder cancer, brain cancer, brainstem glioma, breast cancer, bronchial adenoma / carcinoid, Burkitt's lymphoma, carcinoid tumor, cerebellar or cerebral astrocytoma, cervical cancer, bile duct cancer, chondrosarcoma, chronic lymphocytic or chronic lymphocytic leukemia, chronic myelogenous or chronic myelocytic leukemia, chronic myeloproliferative disorder, colon cancer, , cutaneous T-cell lymphoma, desmoplastic small round cell tumor, endometrial uterine cancer, ependymoma, esophageal cancer, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gestational trophoblastic tumor, brainstem glioma, hairy cell leukemia, head and neck cancer, cardiac cancer, hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, hypothalamic and visual pathway glioma, intraocular melanoma, islet cell carcinoma, Kaposi's sarcoma, laryngeal cancer, leukemia, lip and oral cavity Cavity cancer, liposarcoma, lymphoma, male breast cancer, malignant mesothelioma, medulloblastoma, melanoma, Merkel cell skin cancer, mesothelioma, metastatic squamous cell neck cancer, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic / myeloproliferative disorders, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-melanoma skin cancer, non-small cell lung cancer, oligodendroglioma, oral cancercancer), oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma, ovarian cancer, ovarian germ cell tumor, epithelial ovarian cancer (surface epithelial-stromal tumor), ovarian low malignant potential tumor, pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germinomas, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary adenoma, plasma cell neoplasia, pleuropulmonary blastoma, primary carcinoma, primary central nervous system lymphoma, primary liver cancer, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis and ureter cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Sézary syndrome group, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, supratentorial primitive neuroectodermal tumor, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, urethral cancer, uterine sarcoma, vaginal cancer, visual pathway and hypothalamic glioma, vulvar cancer, Waldenström's macroglobulinemia, Wilms' tumor, Parkinson's disease and parkinsonian disorders, Huntington's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Shy-Drager syndrome, progressive supranuclear palsy, Lewy body disease, spinal cord ischemia, spinal cord injury "Clinical Uses" refers to, but is not limited to, cerebral infarction, cerebral infarction, spinal cord injuries, ischemic stroke, cerebral infarction, spinal cord injury, and cancer-related brain and spinal cord injuries, multi-infarct dementia, senile dementia, other cognitive impairment, depression, onychomycosis (fungal infection of the nails), gingivitis, and periodontal disease (gum disease), obesity, and diabetes. The compounds disclosed herein are also excellent drug candidates for severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19), as well as different cancers with KRAS oncogene mutations.

[0068] In some embodiments, the chronic condition is cancer. In some embodiments, the cancer is colon cancer, prostate cancer, breast cancer, or leukemia. In some embodiments, the cancer is stage 4 breast cancer. In some embodiments, the colon cancer, prostate cancer, breast cancer, or leukemia is stage 4. In some embodiments, the chronic condition is a KRAS oncogene mutation in various cancers.

[0069] In some embodiments, the chronic condition is a viral infection such as SARS or COVID-19.

[0070] In certain embodiments, the methods, compounds, and compositions described herein are administered in combination with one or more of other antibody molecules, chemotherapy, other anti-cancer therapies (e.g., targeted anti-cancer therapies, gene therapy, viral therapy, RNA therapy, bone marrow transplant, nanotherapy, or oncolytic drugs), cytotoxic drugs, immune-based therapies (e.g., cytokine or cell-based immunotherapy), surgery (e.g., lumpectomy or mastectomy) or radiation treatment, or a combination of any of the foregoing.

[0071] Alternatively, or in combination with the aforementioned combinations, the methods and compositions described herein can be administered in combination with one or more vaccines, e.g., therapeutic cancer vaccines, or other forms of cellular immunotherapy.

[0072] In another embodiment, the methods, compounds, and compositions described herein are used in combination with one, two, or all of oxaliplatin, leucovorin, or 5-FU (e.g., FOLFOX combination therapy). Alternatively, or in combination, the combination further includes a VEGF inhibitor (e.g., a VEGF inhibitor disclosed herein).

[0073] Non-limiting examples of additional therapeutic agents that can be combined with the methods disclosed herein include taxol, imatinib, doxorubicin, paclitaxel, fluorouracil (5-FU), and vinblastine.

[0074] In some embodiments, the methods and compositions described herein can be administered in combination with one or more antiviral agents.

[0075] Non-limiting examples of additional therapeutic agents (e.g., antiviral agents) that can be combined with the methods disclosed herein include remdesivir, lopinavir / ritonavir, favipiravir, chloroquine, hydroxychlorquine, azithromycin, or combinations thereof.

[0076] Numbered embodiments: 1. A compound of formula 1A, [ka] During the ceremony, R1 is H, OH, or alkoxy; R2 is alkoxy or OH; R3 is alkoxy or OH; X is C1-C 15 Alkyl, C2-C 15 Alkenyl, C2-C 15 alkynyl, or aralkyl chains, each of which is independently substituted with at least one alkoxy, OH, ═NH, or oxo group; Y is H or alkyl; A compound, or a pharmaceutically acceptable salt thereof, wherein X is in the ortho position relative to R2 or the para position relative to R1. 2. The compound of embodiment 1, wherein R2 is C1-C3 alkoxy. 3. The compound of embodiment 1 or 2, wherein R3 is C1-C3 alkoxy. 4. X is C1-C 15 Alkyl or C2-C 15 The compound of embodiments 1-3, wherein the alkenyl is substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of an alkoxy, OH, ═NH, or oxo group. 5. The compound of embodiments 1-4, wherein R1 is H or OH. 6. The compound of embodiments 1-5, wherein Y is H. 7. R1 is H, R2 is -OH, R3 is C1-C3 alkoxyl; X is a C4-C8 alkenyl substituted with two oxo groups; The compound of embodiments 1-5, wherein Y is C1-C3 alkyl. 8. Having the structure of formula 1: [ka] During the ceremony, R1 is H, alkoxy, or OH; R2 is alkoxy or OH; R3 is alkoxy or OH; X is C1-C 15 Alkyl, C2-C 15 Alkenyl, C2-C 15 alkynyl, or aralkyl chains, each of which is independently substituted with at least one alkoxy, OH, ═NH, or oxo group; or a pharmaceutically acceptable salt thereof. 9. R1 is H or OH, R2 is C1-C3 alkoxy or OH; R3 is C1-C3 alkoxy or OH; X is C1-C 12 Alkyl, C2-C 12 The compound of embodiment 8, wherein the compound is alkenyl, or aralkyl, each of which is independently substituted with 1, 2, 3, or 4 substituents selected from the group consisting of alkoxy, OH, ═NH, and oxo groups. 10.X is (i) C-C substituted with four substituents independently selected from the group consisting of oxo, -OH, and C-C alkoxy; 10 is alkenyl, (ii) C8-C substituted with oxo and C1-C3 alkoxy 12 is alkenyl, (iii) C4-C8 alkenyl substituted with two oxo groups; (iv) C2-C6 alkenyl substituted with oxo and C1-C3 alkoxy; (v) = C1-C6 alkyl substituted with NH; (vi) C2-C3 alkenyl substituted with -OH; (vii) C8-C substituted with oxo and two C1-C3 alkoxy groups 12 alkenyl, and (viii) The compound of embodiment 8 or 9, which is an aralkyl comprising a C6-C8 alkyl and a C6 aryl, wherein the alkyl is substituted with oxo and the aryl is substituted with two alkoxy groups. 11. The compound according to embodiments 8-10, wherein R2 is alkoxy. 12. The compound according to embodiment 11, wherein R2 is C1-C3 alkoxy. 13. The compound according to embodiment 12, wherein R2 is -OCH3. 14. The compound according to embodiments 8-13, wherein R3 is alkoxy. 15. The compound according to embodiment 14, wherein R3 is C1-C3 alkoxy. 16. The compound according to embodiment 15, wherein R3 is -OCH3. 17. R1 is H, R2 is C1-C3 alkoxy; R3 is C1-C3 alkoxy; X is a C6-C substituted with oxo, -OH, and two C1-C3 alkoxy groups 10 The compound of embodiment 8 or 9, wherein the compound is alkenyl. 18. R1 is H, R2 is C1-C3 alkoxy; R3 is C1-C3 alkoxy; X is C8-C substituted with oxo and C1-C3 alkoxy 12 The compound of embodiment 8 or 9, wherein the compound is alkenyl. 19. R1 is OH, R2 is C1-C3 alkoxy; R3 is C1-C3 alkoxy; The compound of embodiment 8 or 9, wherein X is a C4-C8 alkenyl substituted with two oxo groups. 20. R1 is C1-C3 alkoxy; R2 is OH, R3 is C1-C3 alkoxy; The compound of embodiment 8 or 9, wherein X is a C4-C8 alkenyl substituted with two oxo groups. twenty one. R1 is H, R2 is OH, R3 is OH, The compound of embodiment 8 or 9, wherein X is C1-C6 alkyl substituted with =NH. twenty two. R1 is OH, R2 is C1-C3 alkoxy; R3 is C1-C3 alkoxy; The compound of embodiment 8 or 9, wherein X is C2-C3 alkenyl substituted with OH. twenty three. R1 is H, R2 is C1-C3 alkoxy; R3 is C1-C3 alkoxy; X is a C8-C substituted with oxo and two C1-C3 alkoxy groups 12 The compound of embodiment 8 or 9, wherein the compound is alkenyl. twenty four. R1 is OH, R2 is C1-C3 alkoxy; R3 is C1-C3 alkoxy; The compound of embodiment 8 or 9, wherein X is an aralkyl comprising a C6-C8 alkyl and a C6 aryl, wherein the alkyl is substituted with oxo and the aryl is substituted with two alkoxy groups. 25. Having the structure of formula 2: [ka] During the ceremony, R1 is H or OH, R2 is alkoxy or OH; R3 is alkoxy or OH; R4 is C1-C 15 Alkyl, C2-C 15 Alkenyl, C2-C 15 alkynyl, or aralkyl, each of which is substituted with at least one alkoxy, —OH, or oxo, or a pharmaceutically acceptable salt thereof. 26.R4 is, [ka] 26. The compound of embodiment 25, selected from the group consisting of: 27. The compound according to embodiment 25 or 26, wherein R2 is alkoxy. 28. The compound according to embodiment 27, wherein R2 is C1-C3 alkoxy. 29. The compound according to embodiment 28, wherein R2 is -OCH3. 30. The compound according to embodiments 25-29, wherein R3 is alkoxy. 31. The compound according to embodiment 30, wherein R3 is C1-C3 alkoxy. 32. The compound according to embodiment 31, wherein R3 is -OCH3. 33. R1 is H, R2 is alkoxy; R3 is alkoxy; R4, [ka] 27. The compound of embodiment 25 or 26, wherein 34. R1 is H, R2 is alkoxy; R3 is alkoxy; R4, [ka] 27. The compound of embodiment 25 or 26, wherein 35. R1 is OH, R2 is alkoxy; R3 is alkoxy; R4, [ka] 27. The compound of embodiment 25 or 26, wherein 36. R1 is OH, R2 is alkoxy; R3 is alkoxy; R4, [ka] 27. The compound of embodiment 25 or 26, wherein 37. R1 is H, R2 is alkoxy; R3 is alkoxy; R4, [ka] 27. The compound of embodiment 25 or 26, wherein 38. Having the structure of formula 3, [ka] During the ceremony, R1 is H, alkoxy, or OH; R2 is alkoxy or OH; R3 is alkoxy or OH; R5 is C1-C 12 Alkyl or C2-C 12 alkenyl, which is substituted with one or two substituents independently selected from the group consisting of =NH and oxo, or a pharmaceutically acceptable salt thereof. 39. The compound according to embodiment 38, wherein R5 is =NH. 40. The compound according to embodiment 38 or 39, wherein R5 is in the ortho position relative to R2. 41. A compound according to any one of embodiments 38-40, wherein R2 is OH. 42. A compound according to any one of embodiments 38-41, wherein R3 is OH. 43. A compound according to any one of embodiments 38-42, wherein R1 is H. 44. The compound according to embodiment 38, wherein R5 is: [ka] 45. A compound according to embodiment 38 or 44, wherein R3 is alkoxy. 46. ​​The compound according to any one of embodiments 38, 44, or 45, wherein R3 is C1-C3 alkoxy. 47. A compound according to any one of embodiments 38 or 44-46, wherein R3 is -OCH3. 48. The compound according to any one of embodiments 38 or 44-47, wherein R1 is alkoxy. 49. The compound according to any one of embodiments 38 or 44-48, wherein R1 is C1-C3 alkoxy. 50. A compound according to any one of embodiments 38 or 44-49, wherein R1 is -OC2H5. 51. The compound according to any one of embodiments 38 or 44-50, wherein R2 is -OH. 52. A compound according to any one of embodiments 44-51, wherein R5 is in the para position relative to R1. 53. Having the structure of formula 4, [ka] During the ceremony, R1 is OH, R2 is C1-C3 alkoxy; R3 is C1-C3 alkoxy; The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R6 is C(CH2)OH. 54. R1 is OH, R2 is OCH3, R3 is OCH3, The compound of embodiment 53, wherein R6 is C(CH2)OH. 55. A pharmaceutical composition comprising a compound according to any one of embodiments 1-54 and a pharmaceutically acceptable carrier. 56. A method for treating a chronic disorder in a patient in need thereof, comprising administering a compound according to any one of embodiments 1 to 54 or a pharmaceutical composition according to embodiment 55. 57. Chronic disorders include acute lymphoblastic, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related lymphoma, anal cancer, appendix cancer, basal cell carcinoma, bladder cancer, brain cancer, brainstem glioma, breast cancer, bronchial adenoma / carcinoid, Burkitt lymphoma, carcinoid tumor, cerebellar or cerebral astrocytoma, cervical cancer, bile duct cancer, chondrosarcoma, chronic lymphocytic or chronic lymphocytic leukemia, chronic myelogenous or chronic myelocytic leukemia, chronic myeloproliferative disorder, colon cancer, cutaneous T-cell lymphoma, Desmoplastic small round cell tumor, endometrial uterine cancer, ependymoma, esophageal cancer, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gestational trophoblastic tumor, brainstem glioma, hairy cell leukemia, head and neck cancer, cardiac cancer, hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, hypothalamic and visual pathway glioma, intraocular melanoma, islet cell carcinoma, Kaposi's sarcoma, laryngeal cancer, leukemia, lip and oral cavity Cavity cancer, liposarcoma, lymphoma, male breast cancer, malignant mesothelioma, medulloblastoma, melanoma, Merkel cell skin cancer, mesothelioma, metastatic squamous cell neck cancer, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic / myeloproliferative disorders, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-melanoma skin cancer, non-small cell lung cancer, oligodendroglioma, oral cancercancer), oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma, ovarian cancer, ovarian germ cell tumor, epithelial ovarian cancer (surface epithelial-stromal tumor), ovarian low malignant potential tumor, pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germinomas, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary adenoma, plasma cell neoplasia, pleuropulmonary blastoma, primary carcinoma, primary central nervous system lymphoma, primary liver cancer, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis and ureter cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Sézary syndrome group, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, supratentorial primitive neuroectodermal tumor, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, urethral cancer, uterine sarcoma, vaginal cancer, visual pathway and hypothalamic glioma, vulvar cancer, Waldenström's macroglobulinemia, Wilms' tumor, Parkinson's disease and parkinsonian disorders, Huntington's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Shy-Drager syndrome, progressive supranuclear palsy, Lewy body disease, spinal cord ischemia, spinal cord injury 57. The method of claim 56, wherein the primary cause of the disease is selected from the group consisting of cerebral infarction, cerebral infarction, spinal cord injuries, ischemic stroke, cerebral infarction, spinal cord injury, and cancer-related brain and spinal cord injuries, multi-infarct dementia, senile dementia, other cognitive impairment, depression, onychomycosis (fungal infection of the nails), gingivitis, and periodontal disease (gum disease), obesity, diabetes, SARS, COVID-19, or KRAS oncogene-mutated cancer. 58. The method of embodiment 56 or 57, wherein the chronic disorder is cancer. 59. The method of embodiment 58, wherein the cancer is colon cancer, prostate cancer, breast cancer, or leukemia. 60. The method of embodiment 58 or 59, wherein the cancer has a KRAS oncogene mutation. 61. The method of embodiment 56 or 57, wherein the chronic disorder is SARS or COVID-19. [Example]

[0077] Example 1. Anticancer activity study (Figure 10) The synthesized compounds of formulas 1-4 were evaluated for cell proliferation, apoptosis, cell cycle arrest, reactive oxygen species, and calcium generation, measured using the MTT assay and flow cytometry, respectively. The expression of apoptosis- and proliferation-related proteins was determined by Western blotting. The effects of the molecules on apoptosis-related mRNA expression in cancer cells were detected by RT-PCR. The molecule induces apoptosis and cell cycle arrest in pancreatic cancer cell lines (PANC) When pancreatic adenocarcinoma cells (PANC) were treated with Compound I at various doses (1-100 μg / mL) for 24 and 48 hours, cell viability was significantly reduced in a time- and dose-dependent manner. Exposure of PANC cells to 10 μg / mL resulted in an approximately 65.5 ± 0.88% reduction in viable cells compared to standard 5-fluorouracil (10 μM), which showed a 30.21 ± 0.21% reduction in viable cells at 3 hours. After 24 hours of exposure, the IC 50 The IC values ​​were found to be 5.74 ± 0.02 μg / ml and 5.21 ± 0.19 μM 5-FU. Most importantly, the molecule showed an increase of 85.29% ± 0.98 in protection against normal pancreatic cells, with an IC 50 The toxicity of 5-FU was 40.32 ± 0.98% at 6 hours, while the toxicity of 5-FU was 109.24 μg / ml. Changes in cell morphology were detected by the presence of cell membrane blebbing, chromatin condensation, and apoptotic body formation (Figure 10A).

[0078] In vitro studies indicate that the disclosed compounds may target proteins involved in the G2 / M checkpoint (Figures 10A and 10B), as this checkpoint has been shown to induce arrest at this checkpoint in breast cancer, pancreatic cancer, and other cancers, preventing cells from passing through this checkpoint and entering mitosis.

[0079] Cell proliferation inhibition was demonstrated by inducing apoptosis in a caspase-dependent manner via the intrinsic pathway (caspase-3 and -9), resulting in subsequent loss of mitochondrial potential (ΔΨm) (Figure 10B), increased ROS generation, and DNA damage, resulting in cell cycle arrest in the G0 / G1 phase in a dose- and time-dependent manner.

[0080] The novel molecule is thought to induce cell cycle arrest and senescence changes, possibly by targeting STAT-3, β-catenin / Wnt signaling, MAPK, and / or JAK-1 / 2 / 3 Aurora kinase A, thereby inducing mitotic arrest, changes in the expression of cell cycle-related proteins, and microtubule disruption.

[0081] Example 2. Molecules inhibit histone deacetylase (HDAC) activity Next, we investigated class I HDAC expression during pancreatic tumorigenesis. Briefly, different concentrations of compound I were added and incubated for 24 hours. Western blotting analysis confirmed that the protein expression of class I HDACs was reduced in a dose-dependent manner compared to the control (p<0.05). Compound I significantly inhibited class I HDACs HDAC1, HDAC2, HDAC3, and HDAC8. Collectively, these data indicate that inhibition of class I HDACs by this molecule is sufficient to induce cell death in PANC cell lines. These results suggest that this molecule is a potent HDAC inhibitor. Inhibition of class I HDACs is associated with histone H3 acetylation and upregulation of p21 mRNA and protein expression, which are associated with antiproliferative activity. HDAC6 has also been reported to function as an α-tubulin deacetylase that regulates tubulin stability. Because α-tubulin and histone H3 are mutual downstream targets of HDACs, we further investigated the relationship between protein expression and molecular function. The effect of Compound I on histone H3 acetylation in PANC cells was investigated using Western blot analysis. Compound I induced stronger histone H3 hyperacetylation compared to controls, consistent with its potent inhibitory effect on class I HDAC1, whereas acetyl-α-tubulin was not detected.

[0082] Mechanism of action (Figure 11) Without being bound to any particular theory, the compounds disclosed herein may exhibit one or more of the following mechanisms of action. Induced cell cycle arrest and senescence changes, possibly by targeting STAT-3 β-catenin / Wnt signaling, MAPK, JAK-1 / 2 / 3 Aurora kinase A, induced mitotic arrest and altered expression of cell cycle-related proteins, and disrupted microtubules. It caused loss of mitochondrial membrane potential, cytochrome c release, upregulation of Bax, downregulation of Bcl-2, and cleavage of caspase-3, thereby indicating activation of mitochondria-mediated apoptosis. A multi-targeted kinase inhibitor that inhibits the proliferation of various human cancer cells and cancer stem cells in vitro and in vivo via multiple pathways. ·Histone deacetylase (HDAC) inhibitors and histone methyltransferase (HMT) inhibitors. It downregulates HDAC2 and HDAC3 levels at both the mRNA and protein levels, and also has the potential to downregulate KLF4 levels, which plays an important role in stem cell formation. Each downregulates hTERT levels compared to the standard drug, suberoylanilide hydroxamic acid (SAHA).

[0083] To elucidate the mechanisms underlying the antiproliferative effects, we investigated cell cycle distribution and apoptosis in PANC cells. Early apoptosis was observed as early as 6 h by plasma membrane-bound annexin V-fluorescein isothiocyanate. Compounds I–IX activated the intrinsic pathway of apoptosis by inducing caspase-3 and caspase-9. Mitochondrial involvement of the intrinsic pathway was observed, with significant increases in mitochondrial permeability and cytochrome c release, while mitochondrial membrane potential decreased. Apoptosis was confirmed at the protein level, including Bax, Bcl-2, and survivin, and cell cycle interruption was used as final validation of apoptosis. Propidium iodide / annexin V double staining revealed a preapoptotic cell population in PANC-treated cells at 3 h. Furthermore, we demonstrated by fluorescence-activated cell sorting (FACS) analysis that the induction of cell cycle arrest by molecules involved p21, a key checkpoint control protein. WAF1 / KIP1 , p27 KIP1 , p53, and cyclin A regulation, and observed that HDAC inhibition was shown to result in G0 / G1 arrest, downregulation of cyclin D3, cyclin E1, CDK2, CDK4, and CDK6 expression, and upregulation of p21, p27, and p53 expression in PANC cell lines.

[0084] Example 3. Molecules in human umbilical cord stem cell neurogenesis and neural development - Molecules induced neural cell type formation (Figure 12) At the start of induction, HUMSC cultures phenotypically exhibited large, thin, flattened cell bodies with large nuclei. Molecule-treated MSCs exhibited morphological changes between 48 and 72 hours. At this time point, the MSC population exhibited spherical, refractive cell bodies with dendritic-like processes and long, thin, axon-like projections from the cell body, typical of neurons. After 72 hours of treatment, a higher proportion of neuron-like cells were observed, with shrunken cell bodies and more elongated projections. MSCs maintained this morphology for the duration of induction.

[0085] Example 4. KRAS Degradation Briefly, the present disclosure provides compounds capable of modulating G12C mutant KRAS proteins. In some cases, the compounds act as electrophiles capable of forming covalent bonds with cysteine ​​residues at the K-Ras4BG12C / G12D / G12V-GTP / GDP, K-Ras4BG13D-GTP / GDP, and K-Ras4BQ61H-GTP / GDP mutant proteins. Methods for using such compounds for the treatment of various diseases or conditions, such as cancer, are also provided. Further mechanistic studies have shown that the compound AB-REV-001 can block the formation of a complex between guanosine triphosphate (GTP) and KRAS in vitro. In addition, AB-REV-001 inhibited the KRAS downstream signaling pathways RAF / MEK / ERK and RAF / PI3K / AKT.

[0086] Example 5. Cancer stem cell inhibition Cancer stem cells (CSCs) exhibit unique self-renewal, proliferation, and differentiation capabilities and are therefore thought to play important roles in various aspects of cancer. CSCs have a profound impact on tumor progression, drug resistance, recurrence, and metastasis in various types of malignant tumors. Conventional cancer chemotherapy often fails because most anticancer drugs are ineffective against drug-resistant CSCs. These surviving CSCs lead to recurrence and metastasis. Most studies have reported that conventional therapeutic agents have limited access to CSCs due to their hypoxic microenvironment and their remote location from the vasculature, which delays the effectiveness of anti-CSC drugs (Figure 14). However, the disclosed compounds can overcome this limitation and penetrate deeper to destroy CSCs. Thus, in embodiments, the present invention provides a method for inhibiting cancer stem cell survival and / or self-renewal, comprising administering to cancer stem cells an effective amount of a compound disclosed herein, e.g., Compound I (Figure 13).

[0087] Figure 17 illustrates abnormal signaling pathways in CSCs and strategies for targeting them. Signaling pathways in CSCs that play important roles in self-renewal, drug resistance, tumor recurrence, and distant metastasis have been elucidated. The signaling pathways Notch, Wnt, and Hedgehog signaling, as well as downstream effectors including the transcription factors β-catenin (β-cat), signal transducer and activator of transcription 3 (STAT3), and Nanog, play important roles in CSC characteristics. After interacting with xCT, CD44 variants (CD44v) possess enhanced glutathione synthesis and defense against reactive oxygen species (ROS). This abnormal state allows CSCs to acquire a unique phenotype. The optimal method for eradicating CSCs is to identify the molecules responsible for the specific properties of CSCs, but not normal cells. Targeted CSC phenotypes include Delta-like ligand (DLL), Frizzled (FZD), Janus kinase (JAK), lipoprotein receptor-related protein (LRP), Patched (Ptch), Sonic hedgehog (Shh), and Smoothened (Smo).

[0088] It has been demonstrated that compounds of the present disclosure selectively target cancer stem cells in the tumor microenvironment and destroy CSCs by regulating genes for self-renewal and differentiation. Compounds of the present disclosure inhibited the expression of genes in the following cancers (Figure 18): Breast cancer: CD44+CD24- / low lineage-, ALDH-1 high Liver cancer: CD133+, CD49f+, CD90+ Colon cancer: CD133+, CD44+, CD166+, EpCAM+, CD24+ Pancreatic cancer: CD133+, CD44+, EpCAM+, CD24+ Leukemia:CD34+CD38- Lung cancer: CD133+, ABCG2 高 Leukemia: CD34+, CD38-, HLA-, DR-, CD71-, CD90-, CD117-, CD123+ Reductions in stem cell surface marker expression are seen within 1 hour and for up to 15 hours. No cancer stem cell markers are observed after 24 hours of treatment compared to other standard drugs.

[0089] Example 6: In vitro cancer studies with Compound I Chemotherapy is a drug therapy that uses powerful chemicals to kill rapidly growing cells in the body. However, this therapy exhibits harmful side effects that can range from simple gastritis and hair loss to severe bone marrow suppression, cardiac toxicity, and more. The effects of Compound I of the present invention in combination with chemotherapy drugs were investigated in terms of cytotoxicity. As detailed below, when cells were treated with Compound I of the present invention before treatment with the chemotherapy drugs, the cytotoxicity of chemotherapy drugs such as docetaxel, paclitaxel, pazobanib, endoxon, etoposide, adriamycin, dacromycin, avastin, gemcitabine, cisplatin, and oxaliplatin was significantly reduced.

[0090] The cytotoxicity of anticancer drugs was investigated using a panel of human normal cell lines alone and in combination with Compound I of the present invention. The cytotoxic effect was determined by MTT assay. The following cell lines were used: human epidermal keratinocytes (HaCaT), human dermal fibroblasts (HDF), human bone marrow mesenchymal stem cells (HBMSC), human normal liver cells (THLE2), human cardiac cells (AC-16), human intestinal epithelial cells (HIEC-6), human neural cells (SHSY-5Y), human vascular endothelial cells (HuVEC), human lung epithelial cells (Calu-3), and human lung fibroblasts (MRC 5).

[0091] The data showed a significant decrease in normal cells and morphological changes after treatment with different concentrations (1-500 μM) of anticancer drugs compared to the control (p>0.05). The IC50 values ​​of doxorubicin, gemcitinib, 5-FU, cisplatin, lenolidamide, irinotecan, chloroquine, hydroxychloroquine, vincristine, and vinblastine were found to be averages of 12.90 μM to 40.50 μM, respectively (Figure 19A). Significant levels of apoptosis were observed in all treated normal cell lines compared to the negative control, demonstrating their distinct characteristic features.

[0092] Next, the cells were treated with anticancer drugs in combination with Compound I of the present invention. After combination therapy, increased cell viability was observed, and no signs of cell rounding, granulation, or cell shrinkage were observed, indicating that treatment of normal cells with Compound I reduces the toxic effects induced by anticancer drugs. The IC50 was found to be increased compared to treatment with the anticancer drug alone. The average treatment across all cell lines showed an IC50 of over 100 μM, indicating the cytoprotective effect of Compound I (Figure 19B). No significant apoptotic effect was observed in this combination study, indicating that Compound I reduces the cytotoxicity caused by chemotherapeutic drugs. No significant cytotoxic effect was observed in normal cell lines, even at the highest concentration.

[0093] Example 7: In vivo cancer studies with Compound I Metastasis Research In vivo studies have demonstrated that CIDR1 can suppress tumor growth in xenograft nude mouse models with an improved therapeutic window compared to standard drug therapy. Remarkably, no tumor relapse or recurrence was observed during a 6-month follow-up study.

[0094] Compounds of the present disclosure demonstrated in vivo efficacy in triple-negative breast cancer, pancreatic cancer, liver cancer, and colon cancer models, with a TGI (tumor growth inhibition) of 90% without any mortality or growth inhibition compared to other standard drugs (Figure 20).

[0095] In addition, compounds of the present disclosure significantly disrupted surrounding ECM tissue, resulting in increased quiescence, apoptosis, improved chemotherapy sensitivity, reduced invasion, metastatic spread, and a six-fold reduction in tumor volume and cancer progression in vivo compared to gemcitabine and 5-fluorouracil treatment.

[0096] When a single dose of the disclosed compounds was combined with standard drug regimens, additional anti-cancer efficacy was demonstrated, showing significant inhibition of tumor recurrence in vivo.

[0097] Pancreatic cancer xenograft model (PANC-1) Study Design: A PANC-1 xenograft mouse model was performed according to the experimental design depicted in Figure 21 A. Tumor volume was monitored over 30 days after administration of PBS alone (vehicle control), 25 mg / kg gemcitabine, and 10 mg / kg Compound I.

[0098] Results: As shown in Figure 21B, tumor volume steadily increases from day 5 to day 30 in mice (n=12) treated with 25 mg / kg gemcitabine. In contrast, mice treated with 10 mg / kg Compound I showed a decrease in tumor volume over the same period. This result is confirmed by imaging studies, which showed no detectable tumors in mice treated with Compound I (Figure 21C).

[0099] The reduction in tumor volume translated into improved survival in mice treated with Compound I (FIG. 21D).

[0100] Comparison with standard drugs Compared to the current standards of care (Table 1 below): Revlimid, Avastin, Herceptin, 5-fluorouracil, and gemcitabine, compounds of the present disclosure were 50-fold more potent in reducing the number of tumor-like nodules, 100-fold more potent in reducing the CSC population, and prevented tumor relapse.

[0101] No significant vital organ toxicity and deaths were observed compared with standard drugs such as Revlimid (100% mortality), Avastin (60% mortality), Herceptin (60% mortality), 5-fluorouracil (70% mortality), and gemcitabine (50% mortality) for treating stage IV cancer.

[0102] Furthermore, compounds of the present disclosure, when administered in combination with standard drugs, reduced mortality, enhanced tumor cell sensitization, and increased therapeutic efficacy. [Table 1-6]

[0103] Downregulation of migration genes and signaling pathways Compared to standard drugs that exhibit limited access to CSCs due to the hypoxic environment, the compounds disclosed herein can prevent metastasis to the lungs and lymph nodes by inhibiting lymphangiogenesis and angiogenesis (VRGFR) in pre-metastatic organs.

[0104] Without being bound by any particular theory, the multi-tyrosine kinase inhibitor can induce apoptosis and suppress the invasiveness of cancer cells by inhibiting activated NF-κB, Akt, ERK2, Tyk2, and PKC. Without being bound by any particular theory, the compound attenuated migration and invasion by inhibiting the PI3K / Akt / mTOR signaling pathway. Without being bound by any particular theory, the compound effectively suppresses cancer cell metastasis, angiogenesis, and invasion via ERK1 / 2-dependent, Akt / NF-κB / mTOR-dependent, and p38 MAPK-dependent NF-κB signaling pathways.

[0105] Regulation of epithelial-mesenchymal transition (EMT) All nine compounds disclosed herein inhibited tumor growth in xenograft mouse models and modulated the expression of mesenchymal and epithelial markers. They suppressed the expression of mesenchymal genes such as fibronectin, vimentin, N-cadherin, TWIST, and SNAIL, and increased the expression of epithelial genes such as Occluding and E-cadherin by specifically targeting the canonical WNT / β-catenin / hedgehog, TGFβ / BMP-SMAD pathways.

[0106] immunomodulation The compounds of the present disclosure increase the number and activity of cytotoxic T cells and promote the activation of macrophages, NK cells, and DCs, which promote APCs to CD4+ and CD8+ by capturing, internalizing, processing, and presenting tumor antigens via MHC class I and class II molecules.

[0107] In vivo tumors treated with these molecules express CD31 + endothelial cells, α-SMA + Cancer-associated fibroblasts and F4 / 80 + They further exhibited reduced ECM deposition and impaired infiltration of macrophages, suggesting that the treatment created a suppressive tumor microenvironment, which in turn suppressed tumor growth, invasion, and metastasis.

[0108] Example 8: Targeting lung cancer stem cells Compound I has significant effects on specific lung cancer stem cell targets, inducing apoptosis and inhibiting metastasis without harming normal cells, which aids in cancer therapy. Compound I is an orally bioavailable multi-tyrosine kinase inhibitor with 120 target proteins that induces apoptosis and suppresses the invasiveness of lung cancer stem cells without causing toxicity to normal cells. Throughout the study, no signs of discomfort were observed in the animals after administration, and no cardiovascular or respiratory disorders were observed.

[0109] Example 9: Compounds of the present disclosure as ACE-2 inhibitors and Nsp15 inhibitors Objective: To determine whether compounds of the present disclosure, e.g., Compound I, may be inhibitors of ACE-2 and Nsp15, proteins involved in the entry and replication of viruses such as SARS-CoV-2 in human cells.

[0110] Background: To infect a human host, a virus must be able to enter individual human cells. The virus uses the host cell machinery to generate copies of itself, which then shed and spread to new cells. Research has demonstrated that SARS-CoV-2 attaches to target cells through an interaction between its spike protein (S) and the host cell protein angiotensin-converting enzyme-2 (ACE-2), a transmembrane enzyme found on the surface of cells. This interaction on the host cell surface is of considerable interest because it initiates the infection process (Figure 22). Therefore, drugs that modulate the biological activity of ACE-2 have been proposed as potential candidates for the treatment of this viral infection.

[0111] Another protein identified from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that may be involved in viral progression is Nsp15 (Figure 22). Nsp15 is 89 percent identical to a protein from the early development of SARS-CoV. Analysis of SARS-CoV revealed that inhibition of Nsp15 can slow viral replication. This newly mapped protein is conserved among coronaviruses and is essential for the coronavirus life cycle and pathogenesis. Initially, Nsp15 was thought to be directly involved in viral replication, but it has recently been proposed to aid viral replication by interfering with the host immune response.

[0112] Results: To evaluate the potential of the disclosed compounds to target ACE-2 and Nsp15, studies were conducted using in silico approaches and molecular docking. These analyses found that Compound I had high binding affinity with all viral proteins tested (Figures 22-24). Specifically, Figure 21 shows the affinity of Compound I for the ACE-2 binding site, resulting in disruption of the interaction between the virus and the receptor. Compound I was also found to have affinity for the Nsp15 binding site, as shown in Figures 24A-24C.

[0113] Summary: This disclosure provides small molecule inhibitors that target S-ACE-2-mediated SARS-CoV-2 entry into human cells. In addition, the disclosed compounds also target Nsp15, which can slow viral replication. Therefore, the compounds of formulas 1-4 have the potential for development as effective drugs against COVID-19.

[0114] Example 10: In vitro antiviral activity of Compound I in Vero cells Study Design: Standard assays were performed to measure the effects of compound I on SARS-CoV-2 cytotoxicity, viral yield, and infectivity (Figure 25). First, the cytotoxicity of compound I was tested in Vero cells. Subsequently, Vero cells were infected with SARS-CoV-2 at a multiplicity of infection (MOI) of 0.1 PFU / cell (Figure 25A) in the presence of various concentrations of compound I. DMSO was used as a vehicle. Efficacy was assessed by quantifying viral copy numbers in cell supernatants by quantitative real-time RT-PCR (qRT-PCR) and confirmed by visualization of viral nucleoprotein (NP) expression by immunofluorescence analysis at 48 hours postinfection (pi) (Figure 25C). Additionally, cells were exposed to test compounds after infection to further assess their potential as prophylactic and therapeutic agents against coronaviruses. The protective effect of compound I in a lung epithelial (Calu-3) cell line was also evaluated.

[0115] Antiviral activity and cytotoxicity: To test the antiviral activity of compound I, Vero cells were infected with a SARS-CoV-2 isolate at an MOI of 0.1 for 2 hours (Figure 25B), followed by the addition of different concentrations of compound I (0.001, 0.01, 1, 3, and 5 μM, respectively). Evaluation of the data obtained from the dose-response curves revealed that compound I exhibited potent antiviral activity with an IC50 of 1 μM (Figure 25B, blue line representing the mean percent viral inhibition) and a CC50 of over 15 μM (Figure 25B, red line representing the drug's cytotoxicity).

[0116] To further determine the efficacy of Compound I, cells infected with SARS-CoV-2 were treated with serial dilutions of Compound I, and 2 hours after infection, both the supernatant and cell pellet were collected for real-time RT-PCR (Figures 25F-H).

[0117] At 24 hours, there was a 100% reduction in viral RNA present in the supernatants of samples treated with Compound I (representing released virions) compared to the vehicle DMSO. Similarly, a 99% reduction in cell-associated viral RNA (representing unreleased and unpackaged virions) was observed with Compound I treatment. At 36 hours, this effect increased to a reduction in viral RNA in Compound I treatments that was statistically significant compared to control samples, indicating that Compound I treatment resulted in an effective loss of virtually all viral material by the 36 hour time point.

[0118] A reduction in viral RNA was observed in both the supernatants and cell pellets from samples treated with 1 μM Compound I at 48 hours, equivalent to a 99% reduction in viral RNA in these samples compared to control samples. Again, no toxicity was observed at any of the concentrations of Compound I tested.

[0119] Immunofluorescence microscopy of virus-infected cells was performed upon treatment with compound I. Specifically, Vero cells were infected with SARS-CoV-2 at an MOI of 0.1 and treated with 1 μM and 1 μM compound I. At 48 h postinfection, infected cells were fixed and then probed with rabbit serum against SARS-associated CoV NP as the primary antibody and Alexa 488-labeled goat anti-rabbit IgG as the secondary antibody, respectively. Nuclei were stained with Hoechst dye. Bar, 20 μm. The staining results show that the viral load, as measured by nuclear protein expression, was substantially reduced in Vero cells treated with both doses of compound I (Figure 25C). These results were confirmed by Western blot analysis of infected cells 24 h postinfection (Figure 25D) and quantified by normalization to GAPDH (Figure 25E).

[0120] Example 11: In vitro activity of Compound I in lung epithelial cells The antiviral activity of compound I was evaluated against SARS-CoV-2 in Calu-3 cultures. A dose-dependent decrease in replication approach was observed between 0.1 and 5 μM compared to untreated controls, with an average IC50 value of 0.01 μM (SARS-CoV-2). To determine whether compound I could inhibit replication, we first evaluated its antiviral activity and cytotoxicity in Calu-3 cells, a continuous human lung epithelial cell line. Compound I inhibited SARS-CoV-2 replication in the cells with an average half-maximal effective concentration (IC50) value of 1.5 μM (Figure 25B). Importantly, we did not observe any cytotoxicity at concentrations up to 100 μM. Therefore, we demonstrated that the 50% cytotoxic concentration (i.e., CC50) of compound I was greater than 100 μM in Calu-3 cells. Taken together, these results suggest that substantial inhibition of SARS-CoV-2 replication is achieved in lung epithelial cells at low micromolar concentrations.

[0121] Example 12: Effect of Compound I on viral infection stages We hypothesized that compound I inhibits SARS-CoV-2 during early replication by inhibiting viral RNA synthesis. To test this hypothesis and determine at which stage of the viral replication cycle compound I inhibited SARS-CoV-2, Vero cells were infected at a multiplicity of infection (MOI) of 0.1 PFU / cell, resulting in a single-cycle infection, and treated with 1 μM compound I at 2-h intervals from 2 h before infection to 10 h after infection. Maximum inhibition was observed when compound I was added 2 h before infection to 2 h after infection. Less inhibition was detected when compound I was added 6–8 h after infection, and no inhibition was observed when compound I was added 10 h after infection. These results indicate that compound I inhibits SARS-CoV-2 during the early stages of infection. Because viral RNA is synthesized early in infection and compound I is involved in inhibiting viral RNA synthesis, we next determined cellular levels of viral RNA by real-time quantitative PCR (qPCR) after treatment with compound I. Treatment with increasing concentrations of Compound I resulted in a decrease in viral RNA levels, which correlated with a decrease in titer. These results suggest that Compound I inhibits SARS-CoV-2 early in infection by interfering with viral RNA replication.

[0122] We investigated whether Compound I could also inhibit SARS-CoV-2 replication in human lung epithelial cells (calu-3 cell line), a model of normal epithelial cell SARS-CoV-2 infection. Results showed that Compound I could inhibit SARS-CoV-2 replication at the same concentration as in VERO cells (IC50 of 10 μM Compound I-treated cells = <102 TCID50 / ml), demonstrating that Compound I's antiviral activity is cell type independent (Figure 26A). As with other coronaviruses, expression of the SARS-CoV genome is mediated by translation of a "nested" set of genomic and subgenomic messenger RNAs produced by a unique mechanism involving discontinuous transcription during RNA synthesis. To determine whether Compound I acts by blocking viral RNA synthesis, as in the case of SARS-CoV-2, Calu-3 cells were infected with SARS-CoV-2 and treated with different concentrations (1.5 μM and 10 μM) of Compound I immediately after the viral adsorption period. Total RNA was extracted 24 hours postinfection and analyzed by RT-PCR. As shown in Figure 26B, compound I treatment caused a dose-dependent reduction in intracellular SARS-CoV-2 RNA levels, reaching greater than 95% inhibition of control at concentrations of compound I that did not affect RNA synthesis in uninfected cells. Viral genomic RNA was quantified in clarified supernatants by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Similar to the effect on infectious titers, a dose-dependent reduction was observed in viral genomic RNA, with a similarly calculated IC50 of 5 μM. Collectively, these data indicate that compound I is a potent antiviral against two genetically distinct emerging CoVs.

[0123] Example 13: Immune Responses of Compounds of the Present Disclosure Compound I has the ability to activate CD4+ helper T cells and CD8+ cytotoxic T cells and generate immune responses in the body to protect against viral infection. Specifically, Compound I increases the number and activity of cytotoxic T cells and promotes the activation of macrophages, NK cells, and DCs, which promote APCs to CD4+ and CD8+ by capturing, internalizing, processing, and presenting antigens via MHC class I and class II molecules.

[0124] Example 14: Proposed mechanism of action in the lung In a xenograft stage 4 metastatic breast cancer animal model, compound I reduced the production of cytokines (tumor necrosis factor alpha [TNF-α] and interleukin-6 [IL-6]) and chemokines (CXCL10, CCL2, CCL3, and CCL5) observed in the lung, which correlated with the migration of natural killer cells and macrophages. Data collected by QPCR gene expression studies showed that by day 7, histopathological evidence showed normal lung pathology without any pneumonitis. Cytokines (TNF-α, IL-6, gamma interferon [IFN-γ], IL-2, and IL-5), chemokines (CXCL9, CXCL10, CCL2, CCL3, and CCL5), and receptors (CXCR3, CCR2, and CCR5) were detected in the lung and were associated with T lymphocyte influx. No signs of clinical disease or histopathological evidence of disease characterized by bronchiolitis, interstitial pneumonia, diffuse alveolar damage, and fibrotic scarring were observed.

[0125] Example 15: Potentiating hydroxychloroquine by reducing side effects in the treatment of COVID-19 Coronavirus disease (COVID-19) is an infectious disease caused by the virus SARS-CoV-2. This disease causes respiratory illness with symptoms such as cough, fever, and, in more severe cases, difficulty breathing. Currently, one drug that may be effective in treating COVID-19 is hydroxychloroquine. However, this drug causes serious side effects, including cardiovascular disease, eye damage, and mild or severe bronchospasm, and also affects mental health. The effect of Compound I of the present invention in reducing the side effects associated with hydroxychloroquine was studied according to methods known in the art. It was found that Compound I of the present invention helps enhance hydroxychloroquine by reducing side effects in the treatment of COVID-19 (Figures 20 and 21).

[0126] Example 16: Pharmacokinetics (PK), Tissue Distribution, and Toxicity The pharmacokinetics and toxicity of Compound I were studied in vivo in a nude mouse model.

[0127] PK research: Analysis of the data indicates that the mean plasma concentrations of Compound I were significantly higher compared to the control group throughout the 6-hour sampling period. After intravenous administration, Compound I was widely distributed to several tissues, including the hippocampus, heart, lung, stomach, liver, mammary gland, kidney, spleen, femur, and tibia (Figures 27A-B). There was a 29-fold increase in the maximum plasma concentration (Cmax) and a 28-fold increase in the area under the curve (AUC) in the treated group compared to the control group (p>0.05).

[0128] Significantly, Compound I was widely distributed in several organs, especially those with high porosity, consistent with its pharmacodynamic activity in these organs. In addition, the distribution volume of Compound I after intravenous administration was found to be significantly higher than that of the control, indicating good tissue distribution. The tissue distribution in this study showed that Compound I administered intravenously at 10 mg / kg reached appropriate pharmacodynamic activity levels in the hippocampus, femur, tibia, and mammary gland, which is relevant to the prevention and treatment of neurodegenerative diseases and other chronic diseases (Figure 27B). No toxicity was observed.

[0129] Tissue-to-plasma ratios of Compound I were obtained in animals at 1, 2, 4, and 24 hours post-dose. At 60 minutes, the highest levels of Compound I were found in the lungs, brain, stomach, liver, mammary gland, and small intestine, all of which are highly perfused organs, followed by the spleen and heart. Up to 72 hours, Compound I was detected in most organs, but not in the femur or kidney. The ratios in most organs continued to increase up to 4 hours. Interestingly, the tissue-to-plasma ratios of Compound I in the hippocampus and brain significantly and continuously increased from 1, 2, and 24 hours post-dose. No signs of discomfort or cardiovascular or respiratory disorders were observed in the animals throughout the study. There was no change in body weight monitored over the 7 days following drug administration.

[0130] PK Results: Pharmacokinetic studies with the compounds disclosed herein revealed prolonged systemic blood circulation with no observed nephrotoxicity, cardiac toxicity, or hepatotoxicity compared to other standard drugs that exhibit severe cardiac, hepatotoxicity, gastrointestinal, and respiratory toxicity.

[0131] Summary: The novel molecules disclosed herein exhibited enhanced pharmacokinetics, biodistribution, and tolerability compared to standard drug administration. In vivo biodistribution studies revealed that the accumulation of the novel molecules in tumors of animal models was significantly higher (P<0.01) than in other organs analyzed.

[0132] Acute Oral Toxicity Studies: Experimental Design: Acute toxicity assays were performed according to the Organization for Economic Cooperation and Development (OECD) Guideline 423 (OECD, 2001a). A total of 60 mice weighing 27-37 g were randomly divided into six experimental groups with 10 mice each (five males and five females per group). After overnight fasting, Compound I was administered to each treatment group via oral gavage at a single dose of 200, 500, 1000, or 2000 mg / kg, respectively. The control group was treated with an equal volume of distilled water. After administration, all animals were individually observed for mortality and general behavioral changes during the first 30 minutes after administration, and then at 2, 4, 6, 10, and 24 hours. Symptoms of toxicity, such as hypoactivity, piloerection, respiratory distress, tremors, and convulsions, were evaluated after various doses. LD50 values ​​were determined according to the method described in OECD Guideline 423 (OECD, 2001a). Animals were observed at least once daily for the remainder of the experiment over a 14-day post-dose period. Body weights were measured at the start of treatment and on days 4, 7, 11, and 14 after dosing. On day 14, mice were sacrificed under anesthesia, and vital organs (heart, kidneys, lungs, spleen, and liver) were removed for macroscopic examination.

[0133] Subchronic Toxicity Studies: Experimental Design: Subchronic toxicity studies were conducted in accordance with OECD Test Guideline 408 for the Testing of Chemicals (OECD, 2008). A total of 48 male and female Wistar rats weighing 170-240 g were randomly divided into four groups (n = 6 males and 6 females per group). Rats in the treatment groups were orally administered Compound I at doses of 200, 500, 1000, and 2000 mg / kg / day. Compound I was administered by oral gavage at 10 mL / kg body weight daily for 28 days. Rats in the control group were orally administered an equal volume of distilled water (vehicle). Body weights of all groups were measured weekly throughout the experimental period. Animals were visually observed for mortality, changes in behavioral patterns, changes in physical appearance, and symptoms of illness. At the end of the treatment period, all rats were fasted overnight (12–16 h) and then anesthetized with urethane via intraperitoneal injection (1 mL / 100 g body weight). Blood samples were collected for measurement of hematological parameters (EDTA-2K coated tubes) and biochemical parameters (dry tubes). After euthanasia, the rats were sacrificed, and organs were removed for necropsy, organ weight measurement, and histopathological examination.

[0134] Urinalysis: During the last week of the treatment period, urinalysis was performed on all rat groups. Fresh urine was collected overnight from all animals to determine specific gravity, pH, leukocytes, nitrite, protein, glucose, ketones, blood, urobilinogen, and bilirubin levels. Urine samples were analyzed using an automated urine analyzer and test strips.

[0135] Hematology and serum biochemistry: For hematological investigations, all animals were fasted overnight but allowed free access to water. Then, rats were anesthetized, and blood samples were collected from the abdominal aorta. Whole blood was collected in EDTA tubes (containing the potassium salt of ethylenediaminetetraacetic acid) and immediately processed for hematological analysis. The measured parameters were red blood cell count (RBC), hematocrit (HCT), hemoglobin (HGB), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH), white blood cell count (WBC), neutrophils (NEU), eosinophils (EOS), basophils (BASO), lymphocytes (LYM), and monocytes (MONO). Hematological analysis was performed using an automated hematology analyzer. For the measurement of biochemical parameters, the dried tubes containing the collected blood were centrifuged at 3,000 rpm for 15 minutes at 5°C to obtain serum. Serum samples were analyzed using an automated biochemistry analyzer. Clinical biochemistry parameters included total serum protein (TP), albumin (ALB), total bilirubin (T-BIL), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), uric acid (URIC), urea (UREA), creatinine (CREA), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglycerides (TG), and glucose (GLU). Calcium (Ca2+), sodium (Na+), potassium (K+), and chloride (Cl2) were also analyzed. ― Serum electrolytes such as ) were also determined.

[0136] Necropsy and organ weight: All rat groups were subjected to a gross necropsy, which included an examination of the thoracic organs, external surfaces, and all internal organs. Vital organs were carefully examined macroscopically for any abnormalities. Various organs, including the heart, liver, kidneys, stomach, lungs, spleen, adrenal glands, thymus, testes, uterus, and ovaries, were then surgically removed, cleaned with ice-cold saline solution, placed on absorbent paper, and then weighed (absolute organ weight in grams). The relative organ weight (ROW) of each animal was then calculated as follows: ROW = [absolute organ weight (g) ÷ rat body weight (g) on ​​the day of sacrifice)] × 100.

[0137] Histopathology: Major organs (lungs, heart, liver, kidneys) and reproductive organs (testes and ovaries) were removed for histopathological examination. After weighing, organs were rapidly fixed in 10% buffered formalin (pH 7.4). After fixation, tissue specimens were dehydrated in a graded series of ethanol (70–100%), washed with toluene, and finally embedded in paraffin. Five-micrometer thin sections were then prepared using a microtome (Leica) and stained with hematoxylin and eosin (H&E) before microscopic examination. Microscopic features of organs in the treated groups were compared with those in the control group, and photomicrographs were recorded.

[0138] Statistical analysis: All data are expressed as mean ± standard deviation (SD). Statistical significance between control and treatment groups was determined by one-way analysis of variance (ANOVA), followed by Dunnett's post-hoc test. Graph Pad Prism version 6.0 for Windows was used for statistical analysis. Data analysis from male and female groups was performed separately, and differences were considered statistically significant at p<0.05.

[0139] Toxicity results: Systemic signs and behavioral analysis Clinical signs and symptoms are important observations to monitor the toxic effects of drugs on organs (Jothy et al., 2011). In our present study, no treatment-related deaths were observed in both male and female animals in acute and subacute toxicity studies at specific oral doses of Compound I. During the 14-day (acute) and 28-day (subacute) observation periods, the animals did not show any adverse changes in physical behavior, food consumption, or water consumption. No gross or macroscopic abnormalities were observed in any animals in both groups (acute and subacute toxicity). Therefore, the median lethal dose (LD50) of the drug can be considered to be above 2,000 mg / kg. Substances with an LD50 of less than 2,000 mg are considered relatively safe according to the Globally Harmonized System of Classification (GHS) (Miyagawa, 2010). Therefore, compound I can be classified as category 5 according to the GHS.

[0140] Effects of Compound I on body and organ weights (Figures 28A-28E) Exposure to potentially toxic drugs causes a significant reduction in weight gain in rats (Teo et al., 2002). Changes in body weight and relative organ weights are indicators of toxicity and health assessment in laboratory animals (Piao et al., 2013). The body weights of control and treated rats are shown in Figures 28D-28E. In this study, all rats in each dose group showed sustained weight gain throughout the experimental period, indicating that Compound I did not cause any adverse effects on body weight in both the acute and subacute toxicity groups. Furthermore, no significant differences in weight gain rates were compared between the treatment and control groups.

[0141] Relative organ weight (ROW) Relative organ weights (ROW) of liver, brain, kidney, heart, and spleen from both studies are shown. When evaluated against the control group, the differences between the ROW of the control group and the ROW of the treated group were statistically significant. No significant changes were observed in any organs, therefore it can be demonstrated that administration of Compound I did not cause any adverse effects on vital organs.

[0142] Effects of Compound I on food and water intake The figure shows the effect of Compound I on food and water intake in subacute treatment. · Compound I administered once daily at the test dose for 28 days did not result in significant changes (P>0.05) in food and water intake compared with the control group.

[0143] Effects of Compound I on hematological parameters (Figures 28F-I). Hematological parameters play an important role in establishing drug-induced toxicity (Petterino and Argentino-Storino, 2006). Changes in hematological parameters have excellent predictive value for human safety assessment when data are translated from laboratory animal studies (Olson et al., 2000). The evaluation of hematological parameters is very important in determining the health status of an individual. The reference values ​​for RBC, WBC, PCV, MCH, and MCHC are 7-10x10^6 / μl, 6-18x10^3 / μl, 35%-64%, 14.3-19.5pg, and 26.2-40g / dl, respectively. In this study, the mean values ​​of hematological parameters such as WBC, RBC, PCV, and hemoglobin in both groups (acute and subacute toxicity studies) did not change significantly compared to the control group (Loha et al., 2019). The results suggest that Compound I may not have any toxic substances that could cause conditions such as anemia or other abnormalities. Increased shedding of WBCs is a prominent biomarker of stress and also helps protect the body against several inflammatory conditions such as bacterial infections, leukemia, and bleeding. The results from this study revealed that Compound I did not produce any significant changes in the levels of WBC counts or their subtypes, including neutrophils, lymphocytes, monocytes, and eosinophils, at any dose compared to controls, suggesting that Compound I is non-toxic.

[0144] Effects of Compound I on biochemical parameters (Figures 28L-28Q) Biochemical evaluation is crucial for assessing the safety of drugs on liver and kidney function. Data on biochemical parameters for the control and treatment groups are shown in Figures 28L-28Q. In this study, no significant changes were observed in any of the measured biochemical parameters in the acute and subacute study groups. In this study, the hepatotoxic potential of Compound I was evaluated by measuring the enzymatic activity of aminotransferases (ALAT and ASAT) (see Figures 28L-28M). Abnormally elevated aminotransferase activity (ALAT and ASAT) can often indicate hepatotoxicity [Fortson et al., 1985]. The results showed that the biochemical parameters of the groups treated with doses up to the maximum dose (2000 mg / kg body weight) were not directly affected compared to the control (p>0.05). These findings were consistent with those of acute toxicity, in which mice treated with similar doses did not show any clinical symptoms or behavioral changes. However, there was no effect on the activity of aminotransferases in the treated group compared to the control group (p>0.05). The slight changes in plasma levels of AST, ALT, and ALP activities at doses of 200, 500, 1000, and 2000 mg / kg in both male and female animals clearly indicate that Compound I did not cause liver damage.

[0145] Renal function tests (Figures 28J to 28K) Renal function was also assessed for possible drug-induced toxic effects by measuring urea and creatinine concentrations, as significant changes in either of these parameters could indicate induced nephrotoxicity [Mukinda et al., 2010, Gnanamani, A et al., 2008]. · Creatinine, electrolytes, urea, and uric acid retention in the body are indicators of kidney damage. Changes in the levels of several electrolytes, such as Na+, K+, Cl-, and Mg2+, can also be signs of kidney damage. Our findings revealed that there were no significant differences in creatinine, electrolytes, urea, or uric acid levels at all doses compared to the control group in both male and female rats, and Compound I did not affect serum electrolytes (Na+, Ca2+, Mg2+, and Cl-) (Figures 28J-28K). Furthermore, there were no significant differences in total protein, albumin, conjugated bilirubin, and bilirubin levels compared to the control group. This further supports the safety of Compound I at these doses, as there were no changes in renal function.

[0146] Histopathological study (Figures 29A-29B) Histopathological analysis of liver, kidney, pancreas, heart, lung, stomach, and reproductive organ samples from both male and female rats was performed on the last day of the treatment period, and the results for some of these tissues are tabulated in Figures 29A-B.

[0147] liver: Multiple sections of male livers showed normal hepatocytes in the Compound I-treated group, along with normal portal triads, sinusoidal spaces, and central venous system. Liver sections from female rats from the treatment group showed a nearly normal cellular structure with normal hepatocytes. Normal appearance of the portal triad, including the hepatic portal vein, interlobular bile ducts, and hepatic artery branches, was also observed. Liver sections from both male and female rats from the control group showed normal liver architecture.

[0148] kidney: Multiple sections taken from kidney biopsies of treated male and female rats showed glomeruli, tubules, intestines, and blood vesicles of nearly normal size and shape. There was no strong evidence of acute tubular necrosis or glomerular changes in the Compound I-treated groups. Kidney biopsy sections from control rats showed normal findings in both males and females.

[0149] Pancreas (not shown): Sections of the pancreas from both male and female rats showed normal structure in the control group, while in the Compound I-treated group, few abnormalities were observed in the structure of both the pancreatic acini and islets.

[0150] heart: Heart sections taken from both male and female rats appeared normal in both control and Compound I-treated rats, but no significant changes were observed in male rats.

[0151] Lungs (not shown): In both male and female rats, multiple sections of the lungs showed normal cellular structures, alveoli, and lymphatic vessels in the control-treated group. No lymphocytic infiltration was observed in the Compound I-treated group in both male and female rats.

[0152] Stomach (not shown) Gastric sections from both male and female rats showed normal findings in the control-treated group. In the Compound I-treated group, female rats showed normal cellular architecture with normal mucosa, submucosa, muscularis externa, and serosa, while male rats showed normal cellular architecture without polyp formation or hyperplastic changes.

[0153] Genitalia (not shown) Sections of the reproductive organs, ie, testes in males and ovaries in females, showed normal pathology in both control and Compound I treated groups.

[0154] Example 17: Prediction of recovery in COVID-19 patients after administration of Compound I Dosage: 250 mg of Compound I orally twice daily for 7 days Day 1: Compound I, an orally bioavailable drug, is absorbed in the intestine and distributed systemically. It targets SARS-CoV-2 viral entry, inhibiting replication and proteolytic processing, and shutting down viral protein production within host cells.

[0155] Day 2: Compound I acts as an immunomodulator, stimulating the body's own immune system by increasing the production of anti-inflammatory cytokines and interferons and inhibiting lysosomal activity in host cells that target viral infections. Elevated levels of circulating IL-6 are reduced, which is associated with regulating lung elasticity and protecting against more severe bronchoalveolar inflammation.

[0156] Day 3: The induced immune response further inhibited viral replication, promoted viral clearance from the respiratory tract, induced tissue repair, and elicited a sustained adaptive immune response against the virus, which reduced disease progression. After treatment, peripheral lymphocytes increased, C-reactive protein decreased, and hyperactivated cytokine-secreting immune cells (CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells) decreased within 3–5 days, thereby reducing the cytokine storm induced by SARS-CoV-2.

[0157] Days 4-6: In summary, treatment with Compound I inhibits SARS-CoV-2 virus particles from invading the respiratory mucosa and infecting other cells, then triggers a series of immune responses and the production of a cytokine storm in the body, which may be associated with the critical condition of COVID-19 patients. Patients' lung function and symptoms improved within 4-5 days after administration of Compound I, which can alleviate lung damage caused by the excessive immune response to SARS-CoV-2.

[0158] overview Compound I demonstrated significant inhibitory effects against many key proteins from similar coronaviruses, such as SARS-CoV (Figure 22). This compound inhibits viral enzymes, including the protease ACE-2 receptor and the viral replication protein Nsp15, thereby significantly reducing viral infection and replication within host cells. In vivo studies in mice further demonstrated no toxicity to the animals' normal cells and healthy normal functions, and no disease recurrence, even 9 months after administration. Without being bound by theory, it is believed that the molecules of the present invention have the ability to activate CD4+ helper T cells and CD8+ cytotoxic T cells and generate an immune response in the body to protect against viral infection.

[0159] Furthermore, dose-dependent inactivation of SARS-CoV-2 was observed upon direct exposure to compound I, with a 50% reduction (IC50) achieved at 1 μM. Collectively, the data support the further development of compound I for the treatment of CoV and suggest a novel mechanism of compound I's interaction with the CoV replication complex, which may shed light on important aspects of replication. As described above, pharmacokinetic studies investigated the concentration of compound I at different time intervals after either oral administration or intravenous injection. In tissue distribution, compound I was found to be primarily concentrated in the heart, lungs, liver, and other organs. In the gastrointestinal tract, a significant amount of compound I accumulated in the stomach, suggesting that compound I may be absorbed via gastric tissue and distributed systemically. Additionally, less than 2% of compound I was excreted in either urine or feces, indicating that approximately 98% of compound I was absorbed or distributed to vital organs. Collectively, our current findings provide a more complete understanding of the biological effects of compound I in vivo.

[0160] From the foregoing, it will be understood that various embodiments of the present disclosure have been described herein for illustrative purposes, and that various modifications may be made without departing from the scope and spirit of the present disclosure. Accordingly, the various embodiments disclosed herein are not intended to be limiting, with the true scope and spirit being indicated by the following claims. In certain embodiments, for example, the following are provided: (Item 1) 1. A compound exhibiting novel anti-cancer and anti-viral activity for treating a subject with a chronic disorder, comprising a structure according to Formula 1A:

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Claims

1. A compound of formula 2, or a pharmaceutically acceptable salt thereof: 【Chemistry 32】 During the ceremony, R １ is OH, R ２ is C 1 -C 3 alkoxy; R ３ is C 1 -C 3 alkoxy; R ４ but, 【Chemistry 44】 or a pharmaceutically acceptable salt thereof.

2. R １ is OH, R ２ But OCH ３ and R ３ But OCH ３ and R ４ but, 【Chemistry 45】 2. The compound of claim 1, wherein:

3. The compound 【Chemistry 46】 2. The compound of claim 1, wherein:

4. 10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

5. A composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 4, for treating cancer in a patient in need thereof.

6. The composition of claim 5 , wherein the cancer is pancreatic cancer, liver cancer, colon cancer, lung cancer, prostate cancer, breast cancer, or leukemia.

7. The composition of claim 5 , wherein the cancer has a KRAS oncogene mutation.

8. The compound 【Chemistry 47】 The composition of claim 5 , wherein

9. A composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 4, for treating a viral infection in a patient in need of such treatment.

10. 10. The composition of claim 9, wherein the viral infection is SARS or COVID-19.

11. The compound of claim 1 【Chemistry 48】 10. The composition of claim 9, wherein

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